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Regiospecific carbon-carbon bond formation via ring opening of vinyl oxiranes with an organoaluminum reagent

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Regiospecific carbon-carbon bond formation via ring opening of vinyl oxiranes with an organoaluminum reagent
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Cuevas, Mapi M., 1952-
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v, 80 leaves : ill. ; 28 cm.

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Argon ( jstor )
Chlorides ( jstor )
Epoxy compounds ( jstor )
Esters ( jstor )
Ethers ( jstor )
Flasks ( jstor )
Hydroxy acids ( jstor )
Mass spectra ( jstor )
Reagents ( jstor )
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Chemistry thesis Ph.D
Diethyl-carbo-tert-butoxy methylalane ( lcsh )
Dissertations, Academic -- Chemistry -- UF
Epoxy compounds ( lcsh )
Organoaluminum compounds ( lcsh )
Prostaglandins -- Synthesis ( lcsh )
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bibliography ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1988.
Bibliography:
Includes bibliographical references.
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Typescript.
General Note:
Vita.
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by Mapi M. Cuevas.

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REGIOSPECIFIC CARBON-CARBON BOND FORMATION VIA RING
OPENING OF VINYL OXIRANES WITH AN ORGANOALUMINUM
REAGENT
BY
MAPI M. CUEVAS
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988
10 OF F LIBRARIES


ACKNOWLEDGEMENTS
The author wishes to express her gratitude to
Professor Merle Battiste for his guidance and advice.
Special thanks go to Merle's Perles for helping to
mantain her sanity or lack thereof. Separate thanks go
to Jim Rocca for all the help he has given with
spectroscopic problems, and to Dr. Awartani for his
chemical advice. My deepest gratitude goes to the
Graduate School for the three year fellowship. Finally,
thanks go to Luis, for helping me through the "Ph.D.
blues".


TABLE OF CONTENTS
PAGE
ACKNOWLEDGEMENTS ii
ABBREVIATIONS iv
ABSTRACT v
CHAPTER I INTRODUCTION 1
CHAPTER II THE NATURE OF THE REAGENT 13
CHAPTER III SCOPE OF THE OXIRANE OPENING.... 25
CHAPTER IV SYNTHETIC APPLICATIONS 39
CHAPTER V EXPERIMENTAL 51
General 51
Reagents and Solvents 52
Apparatus and Technique 52
APPENDIX LIST OF REAGENTS PURCHASED
FROM SPECIFIC CHEMICAL SUPPLY
HOUSES 76
BIBLIOGRAPHY 77
BIOGRAPHICAL SKETCH 80
i i i


ABBREVIATIONS
DEAD
DIBAL
DME
DMSO
Et
eq
LDA
MCPBA
Me
MTM
mm
m
M
Py
THF
TMS
B.P.
PDC
tert-butyl
diethylazodicarboxylate
diisobutyl aluminum hydride
dimethoxy ethane
dimethyl sulfoxide
ethyl
equivalent
lithium diisopropyl amine
meta-chloroperbenzoic acid
methyl
methy1thiome thyl
millimole
mole
Molar
pyridine
tetrahydrofuran
trimethylsilyl
boiling point
pyridinium dichromate
IV


Abstract of Dissertation Presented to the Graduate
School of the University of Florida in Partial
Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
REGIOSPECIFIC CARBON-CARBON BOND FORMATION VIA RING
OPENING OF VINYL OXIRANES WITH AN ORGANOALUMINUM
REAGENT
BY
Mapi M. Cuevas
December 1988
Chairman: Merle A. Battiste
Major Department: Chemistry
The reaction of diethyl-carbo-tert-butoxy
methylalane with both cyclic and acyclic vinyl epoxides
was studied as a potential route to unsaturated enones
and carbocyclic compounds. Two formal syntheses, one of
cis-jasmone and the other of a prostaglandin
intermediate, exemplify the new methodology of this
acetate anion equivalent in its reaction with cyclic
vinyl epoxides. An interesting one-step conversion of
trans hydroxy acids to cis lactones involving the use
of DEAD reagent and triphenylphosphine is also shown.
v


CHAPTER I
INTRODUCTION
The past 20 years have brought about tremendous
advancements in the area of organometallic chemistry.
The chemistry of organoaluminum, particularly alkenyl
and alkynyl alans, has proven to be singularly useful
in the synthesis of natural products.'* Organoaluminum
compounds exhibit chemical properties that are somewhat
different from organolithium, organomagnesium and even
their boron congeners. In 1955, referring to aluminum
alkyls, Ziegler commented that even though the analogy
to the grignard reagent is tempting, these aluminum
2
alkyls behave "peculiarly". Only one Al-C bond reacts
in a grignard fashion. Once this Al-C bond is added to
a substrate such as a carbonyl compound, the aluminum
bond in the product formed is attached to oxygen.
Immediately, the reactivity of the other Al-C bonds
decreases greatly and no further addition occurs. These
differences in reactivity and selectivity of
organoaluminum compounds are instrumental to their
synthetic utility.
1


2
Epoxides may be considered pseudocarbonyls in
their reactions with organometals. Their synthetic
potential is greater, since many times they are far
more accessible as starting materials than carbonyls.
The organometallic reagent may act as a nucleophile or
as a Lewis Acid in its reactions with epoxides. Three
competing mechanistic pathways are possible as can be
seen in Figure 1.1.
Figure 1.1
This scheme illustrates the reactions of
organometals with alkyl epoxides. In general,
dimethylmagnesium, methyllithium and cuprates give


3
Table 1.1 Alkylation of Epoxides by Trialkyl Alans
Epoxide R^AI Conditions Products Yield (%)
E'3AI
CUH30; 80
Epoxide: Alone
1 = 2
98
M*3AI C6HU;35
86
/ Et,AI
Et20;35
49


4
predominantly nucleophilic ring opening at the least
hindered site to furnish 21, while methylgrignards give
predominantly halohydrins. In the case of
trialkylaluminum reagents ring opening at the
substituted carbon often predominates. Some products
from rearrangement are also observed, though not
exclusively. The ratio of each seems to vary with
3
solvent and reaction conditions (Table 1.1).
The opening of alicyclic epoxides by
organoaluminum reagents and further elaboration of the
intermediates formed could provide a useful route to
important natural products. For example, an expedient
route to lactones or alpha-substituted ketones can be
achieved through nucleophilic addition of an acetate
anion equivalent to oxiranes (Figure 1.2).
Figure 1.2


5
The classic method of epoxide openings with
malonic ester enolates is not often practical since it
involves harsh conditions (refluxing ethanol) and is
. . 4
sensitive to stenc effects. Most recently,
organometallies have been used to modulate the
reactivity and selectivity of enolate type anions.
Application of aluminum enolates to ring opening of
allylic epoxides in this laboratory evolved from
consideration of alkynyl alane research and
methodology. Fried has developed useful synthetic
methods in prostaglandin synthesis which allowed the
opening of alicyclic epoxides with alkynyl aluminum
reagents. These alans, prepared from addition of
diethylaluminum chloride to lithium acetylides in
toluene, gave satisfactory yields of the
trans-2-alkynyl cycloalkanols (Table 1.2).^
In 1976, the first acetate anion equivalent using
an organoaluminum reagent was reported by Danishefsky.^
Ultimately interested in the preparation of
trans-lactones from epoxides, Danishefsky reacted
cyclohexene oxide with 2.5 equivalents of
diethylcarbo-tert-butoxymethyl alane _13_ at -30 to -40 C
to give the hydroxy ester 12_ in 34% yield (Fig. 1.3).
Only the trans product was observed. This reagent was
prepared by the addition of Et2AlCl solution to lithio
tert-butylacetate, JJ^, (Rathke's salt).^
Reaction of


6
Table 1.2 Reactions of Epoxides with Alkynyl Alans
Epoxide
Alone
Temp.(C) T i me (h rs) V ¡ e I d (%)
B
25 '8 77
85 72 30
25 18 9 8
90 7 2 3 8
OCH 0
2 5 2 0 7 8
85 7 2 59
OCH 0


7
Rathke's salt alone with cyclohexene oxide in toluene
had afforded only 8% of \2_. Subsequently the yield of
this alane reaction was improved to 68% by allowing the
reaction temperature to rise to ambient temperature and
prolonging the reaction at this temperature for 6 hrs.
Attempts to utilize this alanyl methodology with a
ring-A steroidal epoxide, however, failed and
Danishefsky abandoned this approach.
10
+ Et2AICH2COO'Bu
13
1 2
6 8%
Figure 1.3
Spurred by Danishefsky's initial success with the
Rathke alane, Dr. Melean Visnick decided to utilize it
O
in his synthesis of ()-anastrephin (Figure 1.4). Only
one regio-and stereoisomer was isolated from the alane
reaction.


8
Figure 1.4
When the reaction medium was toluene, the yield
was 24%, but a solvent change to THF increased the
yield to 87%. Previously, standard literature
procedures had been carried out in hydrocarbon solvents
or toluene. A literature search did not fully reveal
why toluene had been the solvent of choice. Most
reaction temperatures were 25C or higher and the
stability of alans in such polar solvents as THF or
DME seemed to have been questioned at these
temperatures. In 1975 Crosby and Stephenson reported
that the products formed in the reaction of 3,4-epoxy
cyclopentene with diethylhex-l-ynylaluminum was solvent
9
dependent (Figure 1.5). They proposed the following
rationalization. In the absence of polar solvents the
oxophilicity of the aluminum causes a rearrangement of
epoxide _]_4 to the enone 1_8^ which then reacts with the
alkynyl alane to give the cyclopentenol 19.


9
ldllJ 1 ^
y
dL l. i 11 w L w x i. ^ ^ ^ o1 ^ ^ w ^ ^ ^
R
y
X
> +
Et9 AICH-COO'Bu >
Epoxide
Solvent Temp(C) Time(hrs) Yield(%)
och3
25
1 2
24
DME
-55
0.5
9 2
0CH3
25
2
25
THF
55
1
87
DME 55 1 85
THF 30
2
No R x n


10
Visnick's studies of the solvent effect in the reaction
of diethylcarbo- tert-butoxymethyl alane 1_3 with
epoxides are summarized in Table 1.3.^. In all cases
the nucleophilic attack occurred at the allylic carbon
and no rearrangements were reported.
Since the aluminum reagent is better solvated and
less aggregated in polar solvents such as THF it should
be more reactive and less sensitive to steric and
entropic effects than in such solvents as toluene or
hexane.
14
R = C = CBu
]_9_
84 %
Figure 1.5
The main interest of this research work is (a) to
explore the scope of diethylcarbo-tert-butoxymethyl
alane 13 in its reactions with -unsaturated


11
epoxides, (b) to investigate the generality of the
regiospecific opening at the allylic position, and (c)
to illustrate its applications to the synthesis of
natural products.
As can be seen from Figure 1.6, cyclic unsaturated
epoxides could be converted into cis- or trans-lactones
or substituted cycloalkenones in essentially two steps.
The applicability of the oxirane opening by alane L3
will be exemplified in the formal synthesis of
cis-jasmone as well as a known prostaglandin
intermediate.


12
Figure 1.6


CHAPTER II
THE NATURE OF THE REAGENT
The initial goal of this research was to
investigate the generality of the alane reaction with
various cyclic unsaturated epoxides. Visnick had
ascertained that a minimum of 2.3 equivalents seemed to
be necessary in order for the reaction to proceed with
g
good yields. The working assumption was that one
equivalent of the aluminum species was required to
coordinate with the epoxide oxygen while possibly
another delivered the acetate anion. This simplistic
assumption invoked the existence of a monomeric
reagent.
Figure 2.1
13


14
Based on the regioselectivity shown, the first
mechanism for the reaction was presumed to be as shown
in Figure 2.1. As shown, one equivalent of the alane
complexes with the epoxide weakening the carbon-oxygen
bond and rendering the allylic site partially positive.
A second equivalent of the reagent probably delivers
the acetate anion equivalent.
This type of mechanism suggests that the reaction
could be run with only one equivalent of Rathke's salt
and an excess of diethylaluminum chloride. Recent
stoichiometric studies done by a member of Dr.
Battiste's research group seem to support the need for
an excess amount of the Rathke alane. The yields of the
reaction were poor to nonexistent when one equivalent
of Rathke's salt and a slight excess of Et^AlCl were
used.^ The formation of chlorohydrin seems to
predominate in cases where Et2AlCl is in excess.
Several attempts have been made to try and
elucidate the structure of the Rathke alane. NMR
studies have proven inconclusive and seem to suggest
the possibility of several species in solution. The NMR
samples were prepared as in the general procedure (see
experimental) except that after the solvents were
removed under vacuum, THF-dg was added. NMR samples of
the dimethylcarbo-tert-butoxymethylalane, 2_5, were also
prepared in hopes that conversion from methyl to ethyl


15
groups would permit a clearer view of the metalated
alkyl region of the spectrum. Both the proton and
carbon NMR showed more peaks than would be expected for
. 12
a simple monomeric species.
Me2AlCHJCOO,Bu
2_5
Figure 2.2
Rathke prepared 1ithio-t-butyl acetate by treating
t-butyl acetate with LDA. In his characterization of
this salt in benzene, Rathke reports two partially
resolved doublets at 3.14 and 3.44 ppm and an infrared
band at 1620 cm ^. No band was observed between 1675
-112
and 2000 cm This leads to the conclusion that
Rathke's salt is a true enolate with the structure as
shown in Figure 2.3.
Figure 2.3
One of the questions this research wished to
address was whether the aluminum metal was on carbon as


16
in structure 26. or on oxygen as in 2J_. In three
separate NMR experiments, there was no evidence of
vinyl protons for the alans made from either Me^AlCl
or Et2AlCl.
O
II ,
R Al CH2 Co'Bu
RjAl O C
2 7
R = Me or Et
Figure 2.4
The literature offers conflicting structures for
aluminum enolates, no doubt enhanced by the scarcity of
aluminum enolates known as compared to those of other
metals. Japanese workers have published a number of
papers in which they use several aluminum enolates in
13
aldol type reactions (Figure 2.5). They draw the
enolate formed as shown in 2J3 without giving direct
literature precedents for it. In 1974, Jeffrey, Meister
and Mole reported the isolation and characterization of
the aluminum enolates formed by reaction of mesityl
oxide with Me^Al in the presence of nickel acetyl
acetonate using ether or cyclopentane as a solvent.^


17
Figure 2.5
The Z- and E-enolates shown in Figure 2.6 were
unusually stable. Cryometric studies showed that the
structure of the Z-enolate was dimeric while the
structure of the E-enolate was composed of dimers and
trimers. Spectral studies proved that a definite
vinyloxy structure existed- as shown in 2J7. The dimers
were held together by Al-O-Al bridges rather than by
Al-O-C-C-Al bridges. The lack of vinyl protons,
however, in our spectra still worried us.
o
Ni(acac)
Me.CrzCHC 4- AIMe. 1 >.
^Me Ei20 or CsH)2
/
C:=C
Figure 2.6
'Bu
\
Me
/
\
OAI
31


18
/OZnBr
BrZn-CH.COO Bu CH,=C .
2 ^OBu
32 3 3
Figure 2.7
The Reformatsky reagent is analogous to the alane
enolate and the identity of its structure has also been
the object of discussion. The unsettling question of
whether the zinc intermediate possesses either
structure 3_2 or 3_3 seems to have been finally answered
in two papers.
In 1982, Orzinni, Pelizonni and Ricca conducted
spectroscopic studies of the Reformatsky reagent
prepared from t-butyl bromo-acetate.^ No significant
change was seen for the C-l carbon, either in the
proton or carbon NMR, (see Table 2.1) as would have
3
been expected if a change in hybridization from an sp
2
to an sp carbon had occurred to give structure 33.
They concluded that there was no evidence to support an
oxygen metallated species.


19
Table 2.1 Spectroscopic Data for Reformatsky
Intermediate
ch3coo'bu
1 2 t
BrZnCH2COOBu
(ppm)
h(S)
Sol ven t
C1
C2
ch3
DM SO
22.2
169.5
1.84 (s. 3H )
Py
M
*
1.93 (s. 3H)
HMPT
23.1
170.2
THF
21-3
168 8
1.85 (s. 3H)
-ch2-
DMSO
20.8
177.4
1.04
Py
20-4
179.5
2.00
HMPT
22.1
179.0
THF
22.7
186.2
1.88
Py = pyridine


20
In 1983, Dutch researchers published X-ray data
that gave the first molecular stucture for the
Reformatsky reagent 3_5.^ X-ray diffraction analysis in
THF showed a dimer in which each zinc was surrounded by
two oxygen, one bromine and one carbon atom as in
Figure 2.8.
THF
j.
\ .. O., O Bu
Zn" "C^
*' l
HCH HCH
I
Zn
'BuO
/ \
THF
36
Figure 2.8
The dimer, an eight-membered, non-planar ring
showed normal single bond distances for the Zn-C and
Zn-0 bonds. The researchers conclude that it is
incorrect to describe the reagent as either C- or O-
metallated. They proposed two possible mechanisms for
the reaction of the Reformatsky reagent with
electrophiles, such as a ketone (Figure 2.9).
Mechanism 3_8 is a six centered one which, according to
studies, shows less steric hindrance and is favored by
the investigators.


21
R
R
OBu1
1 CH:
OBu
ZnBr
BulO C / -
I.'-" I
O Zn
/
THF
THF
37
38
Figure 2.9
In as much as the Rathke alane 1_3, behaves as a
Reformatsky reagent, we propose a similar structure to
that in 3_6. The data we have collected, though
inconclusive, does suggest- a non-monomeric species
which has no vinyloxy protons. With these in mind, we
would like to propose the following structure for
reagent ^3 (Figure 2.10).


22
E'7 + \
/ o
O'Bu
\
V+ Al
nCHt
39
Figure 2.10
In fact, Fried has proposed a similar intermediate
for the reaction of alkynylalanes with epoxides (Figure
2.11) .17
Based on the requirement for at least two
equivalents of alane, we can also speculate on a
mechanism for its reaction with epoxides (Figure 2.12).
Evidence to support both the structure and mechanism
will be discussed further in the following chapters.


23
Figure 2.11


24
Fiqure 2.12


CHAPTER III
SCOPE OF OXIRANE OPENING
In general, reactions of vinyl epoxides with
organocopper, organolithium and organomagnesiura
reagents follow a predominantly 3^2 process. Some of
1 8
these results are summarized in Table 3.1. When the
metal is lithium or magnesium, a variety of
nucleophilic attacks are seen, depending on reaction
conditions. Cuprates and alanates give exclusively S^2'
products.
In 1987, Naruta and Maruyama reported that highly
regioselective 1,2 addition products to vinyl epoxides
19
had not been developed. They published results
describing succesful additions of allylstannanes to
vinyl epoxides using BF^OET^.
As can be seen by their mechanism (Figure 3.1),
the BF^ complexes with the epoxide and induces ring
opening before attack of the stannane reagent. In fact,
when a substituent was placed at the olefinic terminus
that could stabilize a positive charge, such as a
phenyl group, the 1,4 adduct is formed in good yield.
25


26
Table 3.1 Reactions of Metaloalkyl Reagents with Vinyl
Epoxides
Epoxide
R M
% Products
d
a
b
c
R'= H
CH3L (LiBr)*
7
38
55
0
CH3MgBr
1
36
44
19
(CH^Cuti
0
6
94
0
R'= Me

Me Al Me3
0
0
100
0


27
The reaction occurs at the site with the more
stabilized cationic character.
Figure 3.1
In our estimation, the addition of acetate alans
to vinyl epoxides would then be a new complimentary
approach to those already "available. The first step in
our research involved studying the reaction of the
acetate alane with a variety of cyclic vinyl epoxides
as shown in Table 3.2. Epoxides 4_9, 51-53 and 5_5 were
prepared from the enones. Alkaline epoxidation was
followed by a Wittig or Peterson olefination reaction
as shown in Table 3.3. Epoxides 5_0 and 5_4 were prepared
by peracid epoxidation of the corresponding diene
(Figure 3.2).
In all cases except one the reaction with the
alane gave the corresponding trans-hydroxy ester in
good to moderate yields. Compound 4_9 was difficult to


28
work with due to its volatility and the low yields
shown may be attributed to this. Yields for compound
were, as might be expected, poor due to the
neutralization of 1 equivalent of alane by the hydroxyl
proton and formation of t-butyl acetate in the reaction
medium which subsequently reacts with another
equivalent of the alane. This was avoided by protecting
the alcohol functionality.
Figure 3.2
Methylene cyclohepteny 1 oxide, 5_5, to our
surprise, failed to react cleanly. Its reaction with
the alane was sluggish. If reaction times were extended
over three hours, the substrate decomposed into a
myriad of products. A catalytic amount of BF^- 0Et2 was
added in order to induce ring opening, without success.
The best yield of the hydroxy ester achieved with the
Rathke Alane was 10%. These results seem to indicate
that some stringent electronic requirements exist in


29
Table 3.2 Reactions of Vinyl Epoxides with Rathke
E po xid e
Alane
P roduct
Reactions in THF oi 60 to 40C
e = coo'bu
Yield (%)
61
50
36
94
80
92
10


30
Table 3.3 Synthesis of Vinyl Epoxides
l h202/OH
100 0"3 PMe/BuLi 49 H
1
TMS
100 liCHCOOEt 86 COOEt
2
94 #3PMe/Buli 56 H
3
100 67 H


31
the transition state. We know that the reaction does
not occur through a free carbonium ion intermediate
since only the trans-adduct is seen in all cases.
Instead, partial weakening of the C-0 bond occurs
before the nucleophile attacks. Nucleophilic addition
occurs at the position most capable of stabilizing the
incipient positive character on the epoxide after
complexation. Coplanarity of the p orbitals of the
double bond with the incipient cationic site as shown
in Figure 3.3 is necessary.
Figure 3.3
The 3-methylene-l 2-oxidocycloheptane 5_5 being
conformationally more flexible than the cyclopentyl or
cyclohexyl substrates, does not seem to favor the
appropriate configuration. At approximately the same
time that these experiments were carried out, a paper
by Mas, Malacria and Gore appeared involving the
reaction of lithium trialkynylborates with acyclic
20
vinyl epoxides. They stressed the fact that
regioselective reagents that induce ring opening at


32
either site of or £> to the vinyl group in acyclic vinyl
epoxides are few (Figure 3.4). The alkynyl borates they
reacted with vinyl epoxides gave opening only,
making these reagents a complementary approach to the
more abundant S' processes available for vinyl
epoxides.
R3
r\7 + -csc-br|
1 2 t A
R = Bu; R =Et;R i R =H
R1=0;R2rEt;R3, R4=H
Figre 3.4
With this in mind, the alane opening of the cyclic
epoxides seemed encouraging and it would be interesting
to find out if the acyclic cases, which were more
flexible, less conformationally biased than the cyclic
vinyl epoxides molecules discussed previously would be
as clean. The synthesis of various acyclic vinyl
epoxides was undertaken. The reaction of the epoxides
with the alane was performed in the usual way, with 3
equivalents of the alane in THF. Reaction times varied
slightly. The results are summarized in Table 3.4. As
can be seen, in general, the alane gave predominantly
46%
36%


33
Table 3.4 Reactions of Acyclic Vinyl Epoxides with
Rathke Alane
Epoxide
Products
Y i e I d ( % \
' Isolated yield
E = COOfBu


34
1,2 addition at the site to the double bond, though
this was not exclusive as in the cyclic cases. It was
to be expected that the lack of rigidity of these
molecules would lower the regioselectivity of addition.
No conjugate addition, however, was observed. To our
surprise 7_4 did not react at all. It was even recovered
unchanged after three hours of reaction.
The possible explanation for this lack of
reactivity is the following. A steric interaction
between the alkyl group and the vinyl hydrogen as shown
in Figure 3.5 would disfavor alignment of the p
orbitals of the double bond with the C-0 bond of the
epoxide. This would not allow for partial C-0 bond
breaking. The alane does not appear to be a
sufficiently strong Lewis acid to open the epoxide by
complexation alone. Two other oxiranes similar to 74,
with substituents cis to the vinyl were synthesized in
order to corroborate this assumption.
Figure 3.5


35
2,2-Cyclohexyl-l-vinyl epoxide, 7_5' was prepared
using dimethyl allyl sulfonium ylide as shown in Figure
3.6. 1 l-Dimethyl-2-vinyl epoxide, 7_6, was synthesized
from the reaction of 2-methyl-2,4-pentadiene with MCPBA
(Figure 3.6). When combined with Rathke alane, both of
these substrates failed to react, even at extended
reaction times or when the reaction mixture was allowed
to come to ambient temperatures. It was possible to
confirm this sterically induced misalignment through
NMR studies.
Figure 3.6
The best substrate to use seemed to be
1,1-dimethyl- 2-vinyl epoxide, since the chemical shift
of the two methyl groups should provide information as
to the preferred orientation of the vinyl group. It
would be expected that in order to avoid bumping
between the methyl and the vinyl hydrogen as shown in


36
Figure 3.5, the preferred conformation would place the
p orbitals of the double bond almost orthogonal to the
C-0 bond. This in turn would shield the vicinal methyl
group.
As can be seen in Figure 3.7, the two methyl
groups in the epoxide are distinctly separate when
compared to a small quantity of the starting diene. The
methyl assignments are based on analogy to the chemical
shifts of methyls in similar compounds as well as NOE
studies done on the dimethyl vinyl epoxide.
The methyl group syn to the vinyl group shows a
shielding of 0.08 ppm when compared to the anti methyl
indicating a preferred conformation such as that shown
in Figure 3.5. The vinyl hydrogen is staggered between
the two methyl groups while the p orbitals of the
double bond are aligned with the methyl group and
almost orthogonal to the conformation required for
reaction with the alane. Sauleau and coworkers report a
similar effect in the reaction of sodium phenoxide with
21
substituted oxiranes (Figure 3.8). Depending on the
R', r" ,and R'" substituents the amounts of conjugate
versus direct addition of phenoxide to the oxirane
vary. In the case where R' R" = CH^ and R, R'" = H,
direct addition at carbon 1 accounted for 33% of the
products. Twenty two percent was conjugate addition,
but of this only the E isomer was seen. When the system


o
b
Figure 3.7
PPM


38
is loaded with R' R" and R'" = CH^ only direct addition
was observed due to the unfavorable steric interactions
that would be required for conjugate addition.
r = r,=h;r'=r'=ch3
R = H;R'=R=R' = CH3
R R
I I
-0--O C c C=CH,
III
r oh r
OH
-0--O-CH2 c = c--r
I, I.. I,
R R R
OH B
/ OH
(/ \ CHo CCCR
i- i- t
c
Relative ?6 Yields
_A_ B. C_
33 22 II
100
Figure 3.8
General and mild methods providing regioselective
1,2 addition products with vinyl oxiranes are scarce.
The Rathke alane provides such a route in exclusion of
the 1,4 addition so frequently seen with other
organometal1ic reagents. Ring opening of cyclic
epoxides is regiospecific and the trans-hydroxy esters
produced are important intermediates in natural product
synthesis. In acyclic cases, the regioseleetivity of
the aluminum enolate is far superior to that observed
v/ith other organometall ic compounds.


CHAPTER IV
SYNTHETIC APPLICATIONS
Following the study of the vinyloxiranes with the
acetate alane, its synthetic applicability needed to be
explored. As was shown in Chapter I, the hydroxy esters
offer a potential route to lactones as well as 2,3-
disubstituted enones. Many of the important natural
products shown in Figure 4.1 could be conveniently
prepared from the synthetic sequence shown in Figure
1.6.
Figure 4.1
39


40
The jasmone family, as exemplified in cis-jasmone
and dihydrojasmone, are important compounds in
perfumery. The prostaglandins, in their immense variety
have proven to be of great interest in pharmaceuticals
for their vasodepressant and muscle relaxant
properties.
The 2,3-disubstituted alkanone or alkenone pattern
seen in all of these compounds may be achieved by
conversion of the hydroxy esters produced from the
Rathke alane reaction with the appropriate epoxide. In
this research a formal synthesis of cis-jasmone and a
prostaglandin PG analog previously synthesized by Corey
were undertaken to illustrate the synthetic
applicability of the alane reactions. Corey's
intermediate has been subseguently converted to
1l-deoxy-PGE^ and 1l-deoxy-PGF^.^^
Conversion of the hydroxy esters prepared from the
alane and vinyl epoxides to enones involves oxidation
and subseguent isomerization of the double bond.
Various oxidative processes were tried, the most
convenient one being a variation of Czernecki's PDC
23
oxidation. The PDC oxidations were carried out in dry
methylene chloride with molecular sieves and a
catalytic amount of dry acetic acid. The sieves were
ground and activated by heating in the reaction vessel
under vacuum for several minutes. After cooling, the


41
other materials were added. For the oxidation procedure
to work well the reaction should be done under an inert
atmosphere and all the reagents freshly distilled or
dried. Table 4.1 shows the results of the PDC
oxidations.
Table 4.1 PDC Oxidations of Hydroxy Esters
E = C02*Bu
Exocyclic double bonds isomerized to give the
conjugated enone under the reaction conditions. In the
case were the double bond was inside the ring, the
isomerization did not occur but could be readily
achieved by reaction with p-toluene sulfonic acid. In


42
the case of 7_9> the ester could be hydrolyzed to the
carboxylic acid in K^CO^ in methanol. This constitutes
a formal synthesis of cis-jasmone. The subsequent steps
in Figure 4.2 were reported in the literature by
d i 24
Birch.
Figure 4.2
The use of 3-methylene cyclopentene oxide 4_9 in
the synthesis of another prostanoid intermediate was
halted due to the difficulty in isolating this
compound. The yields after Wittig reaction on
2,3-oxidocyclopentanone were not encouraging. Its
subsequent reaction with the alane also suffered due to
the extreme volatility of the compound. It was almost
impossible to isolate completely from solvent. Even
when it was stored in the refrigerator in a paraffin
wrapped vial it evaporated in a few days. In order to
avoid this difficulty in handling, a separate synthesis
of Corey's prostaglandin intermediate 8J5 was undertaken
as can be seen in the retrosynthetic scheme in Figure


43
4.3. The cis-lactone structure could be constructed
from the trans-hydroxy ester by isomerizing the
hydroxyl carbon and lactonizing. This could be
accomplished in a single step by a novel reaction
utilizing DEAD reagent and triphenylphosphine. The
hydroxy ester in turn could be derived from the
reaction of Rathke alane and the vinyl epoxide, 52_. The
protected allylic alcohol in 5_2 evolves from Peterson
olefination of 2,3-oxido-cyclopentanone.
Figure 4.3


44
Peterson olefination of 2,3-oxido-cyclopentanone
gave an 88% mixture of the Z- and E-epoxy esters in a
ratio of 7:4 DIBAL reduction of the esters afforded
the Z- and E-allylic alcohols Subsequent reaction
with an excess of Rathke alane gave the trans-hydroxy
ester _58 in poor yield. As mentioned previously the
presence of a hydroxyl group neutralizes 1 equivalent
of the alane which allows the formation of t-butyl
acetate and ensuing side reactions. When the Z- and
E-epoxy alcohols were protected as the MTM ethers, 52,
the yield was then improved to 94%.
The Z- and E-trans-hydroxy esters 59_ were hydrolyzed
under mild conditions to the trans-hydroxy acids
(Figure 4.4). Lactonization and epimerization of the
hydroxyl carbon could be accomplished by utilizing
triphenylphosphine and the DEAD reagent. This method
had not been described in the literature previously
even though the use of the DEAD reagent in conversion
2 5
of alcohols to esters was well known.
The accepted mechanism of conversion of an alcohol
to an ester is shown in Figure 4.5.


45
DIBAL
3NoH ; MTMCI
64 %
/^OMTM
^COO'Bu
59 OH
KOH >
95%
DEAD; 03P
53%
Figure 4.4


46
N
H +
£n_n_E 4- ROP03
-* R'COOR + 0,p +- EN NE
J H H
Figure 4.5
A similar process could be used to form the
cis-lactone After formation of the triphenyl
phosphine adduct 89_, shown in figure 4.6. The
carboxylate anion acts as an intramolecular nucleophile
with backside displacement of triphenylphosphine oxide.
Figure 4.6
Since previous examples of this reaction were not
known, the reaction was attempted with the
cyclohexenehydroxy acid, 9_0, previously prepared by
reaction of the 1,3-cyclo-hexadiene epoxide with the
Rathke alane and hydrolysis to the hydroxy acid. The


47
trans-hydroxy acid was then treated with triphenyl
phosphine and DEAD reagent in THF to furnish 78% of the
cis-lactone, 91.
Encouraged with this reaction the lactonization
process was attempted with the--prostaglandin
intermediate 8_7_. The reaction was clean and afforded
the lactone in 90% yield. The Z- and E-lactones were
separable by flash chromatography at this point.
Separation of isomers, however, was not essential to
the success of the synthesis as can be seen in the
subsequent steps.
Confirmation of the cis orientation for the Z- and
E-MTM-lactones was determined by spectral studies. The
respective proton spectra may be compared in Figure
4.8. The most pronounced difference between isomers is
shown in the D and Dj_ protons which exhibit a complex
multiplet for the E-isomer due to coupling with H and L
protons. The Z-isomer shows only a coupling to the
vinylogous proton. The vinyl proton, in turn, shows a


48
E-lactone
Z- lac tone
Fiqure 4.8


49
broad triplet for the Z-isomer while proton A for the E
isomer exhibits more fine structure due to coupling to
_D, D_|_ as well as _F and G. NOE studies done by Mr. Jim
Rocca confirm the structures shown. The Z-MTM-lactone
showed a 4.1% NOE between proton E_ and [), D_|_, as well
as a 5.4% NOE between _E and B. No NOE was observed
between protons _E and A. This is consistent with the
Z-cis lactone. The E isomer on the other hand showed a
4.8% NOE between EC and Ei as well as a 4.2% NOE between
protons _E and A.
Following lactonization, the MTM protecting group
was removed using AgNO^. PDC oxidation to the aldehyde,
utilizing the PDC oxidation with molecular sieves
described previously, afforded the Z- and
E-aldehydes 9_3 (Figure 4.9).
It was conceived that the trans orientation of the
side group in Corey's lactone 8_5, could best be
achieved by preparing the oc (3 -unsaturated vinyl
ether, 94_, which upon acid hydrolysis should give the,
unsaturated aldehyde, trans to the lactone ring as the
thermodynamically preferred product. Further
elaboration of the side chain should provide access to
the 11-deoxy-prostaglandins of the PG series.


50
Figure 4.9


CHAPTER V
EXPERIMENTAL
General
Melting points were recorded using a Thomas-Hoover
capillary melting point apparatus. Analyses were
performed by Atlantic Microlab, Inc. of Atlanta,
Georgia.
Spectra
Infra-red spectra were recorded on a Perkin-Elmer
283B Spectrophotometer. Routine mass spectra were
obtained on an Associated Electronics Industries model
MS-30 mass spectrometer at 70 eV. High resolution mass
determinations were handled on the same instrument
further eguipped with a Nova Systems 4 computer. Proton
and/or Carbon NMR were recorded on a Varian Model
EM-360, a JEOL Model FX-100, Varian XL-200, or 300.
Chemical shifts were recorded relative to
tetramethylsilane, unless otherwise noted, at 0.00 S .
Carbon chemical shifts were relative to the
deuterochloroform resonance at 77.00 ppm, unless
otherwise noted.
51


52
Reagents and Solvents
Many of the reagents used in this work were
obtained from several chemical supply houses. The alkyl
lithium solutions were titrated using 2,5-dimethoxy-
2 6
benzylalcohol. Some of the liquid reagents were
purified by distillation. Solvents such as
tetrahydrofuran (THF) and diethyl ether were distilled
from sodium-benzophenone prior to use in an apparatus
27
described by Brown. Dimethylsulfoxide (DMSO),
diisopropyl amine and methylene chloride were distilled
from calcium hydride and stored over activated sieves
or used immediately.
Apparatus and Technique
All air sensitive reactions were run in glassware
that had been flame-dried under vacuum. The glassware
was filled with an inert atmosphere of nitrogen or
argon by successive evacuation and backflushing through
28
a Firestone valve. Liquid reagents were added to the
reaction vessel through standard syringe techniques.
Flash chromatography or distillation was used for the
29
isolation of pure materials.
General procedure for epoxidation of cycloalkenones
The enone (1.0 eq.) was added to a mixture of 30%
(3.0 eq.) and methylene chloride at 15 C.
Dropwise addition of 6 N NaOH (0.5 eq.) followed


53
maintaining the reaction temperature between 15 20
C. The mixture was then allowed to come to ambient
temperature. Upon completion the reaction was quenched
with water and extracted with methylene chloride.
Extracts were washed with brine and dried over Na2SO^.
After removal of solvent, Kugelrohr distillation of
crude afforded desired keto epoxides in 90 100%
yields.
2.3-oxidocyclohexane-l-one ; B.P. 66-70 C, 10 mm Hg;
IR (neat) 1760 (s), 865 (s), 795 (s) cm 3; 3 H NMR (60
MHZ, CDC13) 3.65 (bd, 1H), 3.20 (dd, 1H), 2.80 1.50
(m, 6H) ; 13C NMR (CDC13) 205.5, 55.5, 54.8, 36.0,
22.5, 16.7. mass spectrum (70 eV) m/e 112 (32), 83
(18), 55 (100), 28 (24); 94% yield.
2.3-oxidocyclopentane-l-one ; IR (neat) 1745 (s), 1174
(s) ,
840
( s )
, 730
(s) cm-1; 1H NMR
( 60
MHZ, CDC13)
3.93
(d,
1H)
, 3.30
(d, 1H), 2.41 1
.90
(m, 4 H); 13C
NMR
(CDC1
3 }
209.2 ,
57.2, 54.0, 29.7,
22
.4 ppm; High
resolution mass spectrum calculated mass of 98.03678,
found 98.03711; 100% yield.
2,3-oxidocycloheptane-l-one : IR (neat) 1700 (s), 930
(m), 835 (s); 3H NMR (60 MHZ, CDC13) 3.43 (d, 2H),
2.92-1.38 (m, 8H); 13C NMR (CDC13) 205, 59, 55, 40, 27,
24, 23 ppm; mass spectrum (70 eV) m/e 126 (11), 97


54
(27); 83 (19); 70 (58); 55 (85); 41 (100); 39 (43); 27
(49); 28 (24). B.P. 45C at 15 mm Hg. Yield:
quantitative. In the case of cycloheptenone, methanol
was used as solvent.
General preparation of methylene epoxides
A three necked flask with 1.0 to 1.3 equivalents
of methyltriphenylphosphonium bromide and stirrer was
dried overnight in a vacuum oven at 40 -50 C. The
flask was then fitted with vacuum and thermometer
adapters as well as septa. The flask was flushed with
argon by means of a firestone valve and charged with
dry THF. After cooling to -78C, 1.0-1.3 equivalents of
n-buty11ithium were added slowly. The colored solution
was stirred for 1 hr at -78C. 1.0 equivalent of the
keto epoxide dissolved in a small amount of THF was
added to the ylide. The reaction mixture was allowed to
come to room temperature slowly and quenched with
saturated NH^CL solution, extracted with ether or
pentane, washed with brine and dried over Na2SO^.
Purification of crude was achieved by Kugelrohr
distillation.
3-methylene-1,2-oxidocyclohexane: IR (neat) 3000-2900
(s), 900 (m), 730 (m); XH NMR (60 MHZ, CDC13) 5.37 (s,
1H), 5.26 (s, 1H), 3.43 (bs, 2H), 2.4-1.2 (m, 6H); 13C


55
NMP (CDC13) 143, 116, 55, 54, 29, 24, 20 ppm; 56%
yield.
3-methylene-1,2-oxidocyclopentane: B.P. 48 C at 10 mm
Hg;1H NMP (60 MHZ, CDC13) 5.16 (bs,lH), 4.85 (bs, 1H)
3.68- 3.40 (m, 2H), 2.23- 1.5 (m, 4H); 49% yield. This
compound was extraordinarily volatile and was not fully
separated from solvent before reaction with the alane.
3-methylene-1,2-oxidocycloheptane: B.P. 30C at 10 mm
Hg; 1H NMR (60 MHZ, CDC13) 5.00 (s, 1H), 4.92 (s,lH),
3.37 (d,1H), 3.10 (t, 1H), 2.4-1.2 (m, 8H); 13C NMR
(CDC13) 147, 115, 60, 57, 34, 29, 28, 24; 67% yield.
General preparation of methylene hydroxy esters
A 250 ml three necked flask was fitted with a
magnetic stirring bar, thermometer and septum inlet. It
was flame dried, flushed with argon and charged with 3
equivalents diisopropyl amine and hexane. This was then
cooled to -78C and 3 equivalents n-buty11ithium, 2.5 M
in hexane were added. The solution was stirred from 15
minutes to an hour after which 3 equivalents of t-butyl
acetate were added dropwise, keeping the temperature
between -75 to -70C. After stirring for 30 minutes,
the solution was allowed to come up to 0C at which
time the volatiles were removed in vacuo. This was
followed by addition of THF and subsequent cooling to


56
-78C. The solution was then charged with 3 equivalents
of diethylaluminum chloride, 1.8 M in toluene. After a
few minutes, 1 equivalent of the methylene epoxide was
added in 5 ml THF. It was allowed to react at
approximately -50C until reaction was complete.
Quenching was best achieved by cannula transfer of
solution to an erlenmeyer flask containing ice and 1.2
M HC1. The mixture was vigorously stirred by means of a
mechanical stirrer. This was followed by extraction
with ether. The extracts were dried over MgSO^ and
evaporated to give the crude product. Flash
chromatography on silica gel eluting with ethyl
acetate/hexane (or pentane) afforded the desired
hydroxy esters.
3-methylene-2-(methylenecarbo-t-butoxy)-l-cyclo-
pentanol: 1H NMR (60 MHz, CDC13 ) 4.93 4.92 (q, 2H),
3.70 (s, 1H), 2.70 1.70 (m, 8H), 1.40 (s, 9 H) ppm;
13C NMR (CDC13 ) 173.4, 151.9, 106.6, 81.1, 78.1,
48.0, 38.5, 32.3, 29.4, 28.0 ppm; mass spectrum (70 eV)
m/e 139 (28.6), 138 (84.7), 110 (14.7), 93 (63.3), 57
( 100 ) 41 (33.7 ) .
Reaction of 3,4-epoxy-cyclopent-1-enewith Rathke
a lane.


57
Procedure as described in general procedure.
Isolated yield 50%, after flash chromatography with 40%
ethyl acetate/ pentane.
2-(methylenecarbo-t-butoxy)-3-cyclopentene-l-ol (57):
IR (CC14) 3400, 1710, 1150 cm"1; 1HNMR (NT-300, CDC13)
5.68 (m, 1H), 5.51 (m, 1H), 4.18 (m, 1H), 3.06 (bs,
1H), 2.87 (m, 1H), 2.78-2.15 (m, 4H), 1.45 (s, 9H);
13CNMR (CDC13) 173.1, 131.4, 129.0, 80.9, 78.3, 50.7,
40.8, 39.3, 28.0 ppm; Mass spectrum (70 eV) m/e 142
(7%), 124 (50%), 107 (16%), 96 (19%), 83 (23%), 79
(23%), 57 (100%), 41 (41%).
3 1
Reaction of 3,4-epoxy-cyclohex-l-ene with Rathke
Alane
As in general procedure for alane. Isolated yield
after flash chromatography 84%. IR (neat) 3430, 1725,
1140 cm-1; 1HNMR (NT-300,CDC1 ) 5.65 (m, 1H), 5.43 (d,
1H), 3.55 (m, 1H), 3.19 (bs, 1H), 2.58 (d, 1H), 2.53
(bs, 1H), 2.23 (sextet, 1H), 2.12 (m, 2H), 1.92 (m,
1H), 1.70-1.57 (m, 1H), 1.45 (s, 9H) ppm; 13CNMR
(CDC13) 172.9, 128.0, 127.3, 80.7, 71.6, 41.1, 39.9,
30.4, 28.0, 24.2 ppm; Mass spectrum (70 eV) m/e 138
(16%), 112 (5%), 79 (13%), 74 (13%), 59 (27%), 57(31%),
45 (18%), 31 (45%), 28 (100%).
Peterson Olefination of 2,3-epoxy eyelopentanone


58
To 1.50 ml diisopropyl amine (10.7 mmol) in THF,
under argon, 6.40 ml of n-butyl lithium, 1.6 M in
hexane (10.7 mmol) were added slowly at -15C. The
solution was cooled to -78C, followed by addition of
ethyltrimethylsilylacetate, 1.90 ml (10.4 mmol). The
reaction was stirred for 30 min. at -78C. 1.00 g of
2,3-epoxy cyclopentanone in THF was added (10.2 mmol).
Allowed to react for 2 hrs. at -78C, then allowed to
come to room temperature. The orange solution was
quenched with 25 ml of saturated ammonium chloride and
extracted with ether. Volatile-s were stripped under
vacuo. Kugelrohr distillation afforded 1.37 g of the
Z- and E-isomers 86Z and 86E (80% yield) in a ratio of
7:4 (Z : E),b.p. 72C at 0.5mm Hg. IR (neat) 2960 (m),
1715 (s), 1653 (m), 1222 (s), 1135 (s) cm-1; 1H NMR
(100 MHZ, CDC13) Z-isomer 5.95 (bs, 1H), 4.82 (d, 1H),
4.24 (q, 2H), 3.82 (m, 1H), 2.56-1.83 (m, 4H), 1.30 (t,
3H); E-isomer 5.96 (bs, 1H), 4.21 (q, 2H), 3.69 (d,
1H), 3.02 (bs,1H), 2.56-1.83 (m, 4H), 1.29 (t, 3H); 13C
NMR (CDC13) Z-isomer 165.7, 159.9, 117.9, 59.9, 59.6,
54.2, 27.5, 25.4, 14.1; E-isomer 165.7, 160.4, 116.3,
60.1, 59.8, 54.2, 26.5, 24.9, 14.1; mass spectrum (70
eV) m/e 168 (0.81), 140 (23), 123 (35), 112 (100), 97
(26), 67 (45), 55 (40), 41 (50), 39 (77), 29 (46), 27
(54) .


59
Preparation of epoxy allylic alcohols (51Z and 51E)
A three-necked flask fitted with vacuum adapter,
stirring bar and thermometer was flame dried under
vacuum. After cooling to room temperature the flask was
charged with 5.05 g (30.1 mm) of the ester epoxides 86E
and 86Z and 100 ml of dry THF. The solution was cooled
to -78C. 60.2 ml of a 1.0 M DIBAL solution was added
slowly. The reaction mixture was stirred at -78C for 1
hour then at -50C for 2 hours after which it was
guenched with 25 ml of methanol. The gelatinous product
was filtered through Celite using hot methanol.
Evaporation of solvent under vacuum afforded 3.79 g of
E and Z epoxy allylic alcohols 51Z and 51E,
(quantitative yield). 3H NMR ( 300 MHZ, CDCl^) Z-isomer
5.76 (m, 1H), 4.32 (d, 2H), 4.20 (m, 1H), 3.92 (d, 1H),
3.76 (dd, 1H), 2.40- 1.60 (m, 4H); E-isomer 5.9 (m,lH),
4.15 (dxAB, 2H), 4.10 (m, 1H), 3.64 (dd, 1H), 3.73 (dd,
1H), 2.40-1.60 (m, 4H); 13C NMR (CDC13) Z-isomer
142.0, 126.2, 59.9, 58.7, 54.3, 26.5, 22.1; E-isomer
141.7, 125.5, 59.8, 58.5, 54.3, 25.9, 22.1; High
resolution mass spectrum calculated for C^H.qC^
126.0680, found: 126.0683.
Protection of the epoxy allylic alcohols as the MTM
ethers (52Z and 52E)


60
NaH (2.56 g, 60% oil dispersion) were added to a
flame dried flask under argon and washed with hexane,
3x10 ml. The flask was then charged with 100 ml of THF
and cooled to approximately 0C before adding 3.50 g of
the epoxy allylic alcohols (27.8 mm) in 5 ml THF; 2.38
ml of methylthiomethyl chloride were added at
approximately 5C and allowed to react for 6 hrs. The
mixture was quenched at room temperature with 25 ml
saturated NaHCO^, extracted with ether and washed with
brine and more saturated sodium bicarbonate. The
organic extracts were dried over Na2SO^. The solvent
was evaporated under vacuum and the crude product
purified by passing through a sintered glass funnel
filled with silica gel using gradient elution
increasing from 10% ethyl acetate/pentane to 50%. 4.17
g (81% yield) of MTM-ethers 52Z and 52E were recovered.
:H NMR (300 MHZ, CDC13) Z-isomer 5.68 (t, 1H), 4.67 (s,
2H ) ,
4.24 (dd,
1H)
, 4.14 (dd,
1H)
, 3.8 (d,
1H), 3.68
(m,
1H), 2.36-
1.50
(m, 4 H),
2.10
(s, 3H);
E-isomer
5.86
(t, 1H),
4.64
(s, 2H) 4
.12
(dd, 1H),
4.07 (dd,
1H) ,
3.72 (m,
1H) ,
3.63 (d, 1H),
2.36-1.50
(m, 4 H),
2.15
(s, 3H);
13c
NMR (CDC13)
Z-isomer 144
.1, 122.4,
73.9
, 63.8, 59
.5,
54.1, 26.5,
25.
9 13.6;
E-isomer
143.4, 121.8, 73.9, 63.9, 59.2, 58.4, 25.5, 22.1, 13.6;
Mass spectrum (70 eV) m/e 186 (0.06%), 138 (15%), 125,


61
109 (54%), 108 (26%), 81 (100%), 79 (70%), 67 (20%), 61
(100%), 53 (41%) 41 (51%) .
Preparation of Z- and E-hydroxy esters (59)
Procedure as in general preparation of hydroxy
esters. To 0.79 g of LDA prepared in hexane, 0.80 g of
t-butylacetate was added. After formation of Rathke's
salt, 3.67 ml Of 1.8M solution of Et^AlCl in toluene
were charged into the flask followed by 0.412 g of
oxirane 5_2. The final product was a pale yellow oil,
0.6237 g of the hydroxy ester 5_9 (94% yield) after
flash chromatography using 10% acetone/C^C^ NMR
(300 MHZ, CDC13) Z-isomer 5.52 (t, 1H), 4.63 (m, 2H),
4.07 (m, 2H), 2.89
(m,
1H) 2
.69-1.98
(m,
6H) ,
2.21
(s ,
3H ) 1
.70-1.63 (m,
2H ) ,
1.47
(s, 9H)
t
E-isomer
5.35
(m,
1H) 4
.62 (m, 2H),
3.97
-3.86
(m, 2H)
t
2.80 (m,
2H ) ,
2.69-1
.98 (m, 6H),
2.15
(s, 3 H), 1.64
(m,
2H ) ,
1.43
(s ,
9H); 13C NMR (CDC1
3) z-
isomer
172.6,
148 .
8, 118
.7,
81.3,
78.8, 74.6,
64.7 ,
46.0,
39.6,
32
5,
30.9,
28.0
f
14.0;
E-isomer 173
.4, 147.5,
117.8,
81
.3,
77.9,
74.2
r
64.5,
48.2, 38.8,
32.4,
28.0,
26.0 ,
14
.0
ppm.
Reaction of Rathke
Alane with
3,4-epoxy-3
-methyl-
1-butene33
A dry three necked flask fitted with vacuum and
thermometer adapters as well as a stirring bar was
charged with 5.02 ml of diisopropyl amine (0.036m)


62
under argon. The flask was cooled to -78 C after the
addition of 20 ml of hexane. To this solution 14.4 ml
of a 2.5 M solution of n-butyllithium in hexane (0.036
m) were added and the reaction mixture allowed to stir
for 20 min. at -78C; 4.8 ml of t-butyl acetate were
added dropwise and again allowed to stir for
approximately 20 min after which the solution was
brought to 0C and the solvents removed under vacuum.
After Rathke's salt was allow to dry at room
temperature under vacuum, 35 ml of THF were added and
the solution cooled to -78C. After cooling 20.0 ml of
a 1.8 M solution of Et^AlCl in toluene (0.036 m) were
added followed after 5 min with 1.0 g of
3,4-epoxy-l-butene (0.0119 m). After 2 hours at -60C,
the reaction was guenched by transferring the solution
via cannula to an erlenmeyer flask containing ice and
30 ml 1.2 M HC1. The mixture was stirred vigorously
with a magnetic stirring bar to avoid formation of
gels. Extracted with ether (3 x 30 ml), washed the
organic extracts with brine and dried over NaoS0^.
After filtration and removal of solvents, flash
chromatography using 20% ethyl acetate/hexane furnished
two regioisomers in the ratio of 7:1. Yield 63%. The
major isomer was 3-(hydroxymethyl)-3-methy1-t-buty1-
4-pentenoate (69) and the minor isomer was 4-hydroxy-
4-methy1-t-butyl-5-hexenoate(70 ) .


63
3-(hydroxymethyl)-3-methyl-t-butyl-4-pentenoate (69):
IR (neat) both isomers 3440 (s), 1720 (s), 1170 (s)
cm-1; 1HNMR (200MHz, CDC13) 5.85 (dd, 1H), 5.15-5.03
(m,2H), 3.48 (d,2H), 2.33 (d,3H), 1.46 (s,9H), 1.11
(s,3H); 13CNMR (CDC13) 171.7, 143.0, 113.6, 80.8, 69.5,
43.1, 41.5, 28.0, 21.2 ppm; Mass spectrum (70eV) m/e
145 (7%), 127 (27%), 114 (69%), 96 (14%), 85 (25%), 71
(43%), 57 (100%), 43 (25%), 41 (31%).
4-hydroxy-4-methy1-t-buty1-5-hexenoate(70);
1HNMR (200 MHz, CDC13) 5.79 (dd, 1H), 5.18 (dd, 1H, J=
1.2 Hz and 17 Hz), 5.01 (dd, 1H, J= 1.2 Hz and 11 Hz),
2.24 (m, 2H), 1.75 (m, 3H), 1.38 (s, 9H), 1.22 (s, 3H);
13CNMR (CDC13) 173.8, 144.3, 112.3, 80.4, 72.5, 36.5,
30.4, 28.3, 28.0 ppm; Mass spectrum (70 eV) m/e 182
(.07%), 144 (10%), 126 (71%), 111 (26%), 85 (35%),
71(26%), 57 (100%), 41 (30%).
Reaction of Rathke alane with butadiene monoxide
A flame dried three necked flask fitted with
magnetic stirring bar, vacuum and thermometer adapter
under argon was charged with 1.80 ml diisopropyl amine
(12.8 mm) and 15 ml of hexane. The solution was cooled
to -78C and then 8.60 ml of 1.5 M solution of
n-butyllithium in hexane were added and stirred for 30
min 1.72 ml of t-butyl acetate (12.8 mm) were added
dropwise at -78C. The reaction mixture was stirred for


64
another 30 min before allowing the solution to come to
0C and the solvents evaporated under vacuum. After the
white Rathke salt was dry, 20 ml of THF were charged
into the flask and cooled to -78C At this
temperature 7.20 ml of a 1.8 M solution of Et2AlCl
(12.96 mm)in toluene were carefully added followed by
0.326 g of epoxide (0.428 mm). The solution was allowed
to react at -50C for 1 hr. It was quenched with 15 ml
of 3% HC1 and extracted with ether. The organic
extracts were washed with brine and dried over MgSO^.
Two regioisomers were formed in a ratio of 3:1. They
were purified by flash chromatography using 30% ethyl
acetate/hexane.
Yield: 22% The major one being 3-(methylenehydroxy)-
t-butyl-4-pentenoate (66) and the minor product was
4-hydroxy-t-butyl-5-hexeneoate (67).
3-(hydroxymethyl)-t-butyl-4-pentenoate (66):
IR (neat) both isomers 3415 (bs); 1723 (s); 1150 (s)
cm1; 1HNMR (300 MHZ, CDC13) 5.78-5.66 (m, 1H), 5.16
(t, 2 H), 3.57 (d,2H), 2.72 (m, 1H), 2.46-2.24 (dAB
pattern, 3H), 1.45 (s, 9H); 13CNMR (CDC1 ) 171.9,
137.8, 116.9, 80.7, 65.2, 42.8, 37.4, 28.0 ppm; Mass
spectrum (70eV) m/e 113(12%), 100(30%), 71(22%),
57(100%), 54(16%), 43(16%), 41(38%), 29(25%).
4-hydroxy-t-buty1-5-hexeneoate ( 67):


65
IR (neat) both isomers 3415 (bs); 1723 (s); 1150 (s)
cm"1; 1HNMR (60 MHZ, CDC13) 5.9 (M,1H), 5.3 (M, 2H),
4.25 (bs,1H), 2.6-1.0 (m. 5H), 1.5 (s,9H) ppm; 13CNMR
(CDC13) 173.3, 140.5, 114.8, 80.4, 72.1, 31.8, 31.5,
28.0 ppm; Mass spectrum (70 eV) m/e 130 (3%), 112(37%),
71 (30%), 57(100%), 41(34%), 28(10%).
Reaction of styrene oxide with Rathke alane
Procedure as in general procedure for alane
reaction. Yield 64%. Two products isolated by flash
chromatography using 15% ethyl acetate/pentane.The
ratio of regioisomers was 4:1. The major product was
4-hydroxy-3-pheny1-t-butyl-butanoate (76a) and the
minor 4-hydroxy-4-phenyl-t-butyl-butanoate (76b).
4-hydroxy-3-phenyl-t-butyl-butanoate (72): White solid,
melting point 44-48C. IR (neat) both isomers 3010 (s),
1712 (s), 1368 (s), 1212 (s) cm"1; 1HNMR (XL-200,CDC13)
7.28 (m, 5H), 3.78 (d, 2H), 3.30 (m, 1H), 2.65 (dAB,
2H), 2.63 (bs,1H), 1.35 (s, 9H); 13CNMR (CDC13) 171.9,
141.1, 128.5, 127.8, 126.9, 80.6, 66.9, 44.7, 38.6,
27.9; Analysis: calculated 71.16% C, 8.53% H Found
71.10% C, 8.57% H.
4-hydroxy-4-phenyl-t-butyl-butanoate (73 ) :
IR (neat) both isomers 3010 (s), 1712 (s), 1368 (s),
1212 (s) cm-1; 3HNMR (300 MHz,CDC13) 7.34 (m, 5H), 4.73


66
(t, 1H), 2.58 (bs, 1H), 2.33 (t, 2H), 2.02 (q, 2H),
1.44 (s, 9H) ppm; 13CNMR (CDC13) 173.3, 144.2, 128.4,
127.5, 125.7, 80.5, 73.6, 34.0, 31.9, 28.1 ppm; Mass
spectrum (70 eV) m/e 180 (15%), 162 (21%), 161 (40%),
117 (40%), 107 (67%), 105 (39%), 91 (28%), 79 (34%), 77
(38%), 57 (100%), 41 (66%), 28 (50%).
Preparation of 3,7-dimethyl-2,3-oxo-6-octen-l-al
o
Molecular sieves (2.76 g, 4A) were ground and
activated by flame drying under vaccum in the reaction
vessel. After cooling to room temperature and flushing
with argon, 24.37 g of PDC (0.065 m) were added under
an argon atmosphere; 30 ml of CH^C^ were charged into
the flask, cooled with an ice bath, and 5.23 g of
3,7-dimethyl-2,3-oxo-6-octen-l-ol33 (0.0231 m) were
added in 20 ml of The mixture was allowed to
react overnight. The crude mixture was filtered through
Celite followed by filtering through a plug of SIO^
with 10% MgSO^ using CH^Cl^. Kugelrohr distillation of
the crude afforded 1.23 g of pure aldehyde (32% yield).
IR (CC14) 3020-2840 (s), 1710 (s) cm"1; 1H NMR (300
MHz,CcD ) 9.20 (s, 1H), 4.97 (bs, 1H), 2.90 (s,lH),
b b
2.25-1.0 (m, 4 H), 1.61 (s, 3H), 2.4 (s, 3H), 1.45 (s,
3H); 13C NMR (C Dg ) 198.6, 132.2, 123.3, 63.4, 38.4,
25.7, 23.7, 17.6, 17.0 ppm.
Wittiq reaction of 3,7-dimethy1-2,3-oxo-6-octen-1-a 1


67
A 150 three necked flask was dried in a vacuum
oven overnight with 3.10 g of methyltriphenylphospho-
nium bromide (8.70 mm) at 56C. The flask was then
fitted with vacuum and thermometer adapters as well as
a stirrer. It was evacuated and flushed with argon
several times. 50 ml of dry THF were charged into the
flask and the mixture chilled to -50C. At this
temperature, 3.56 ml of n-butyl1ithium 2.5 M in hexane
were added (8.70 mm). The ylide color was bright yellow
after approximately 30 min, 1.49 g of the aldehyde were
added and the solution allowed' to come to room
temperature. After 3 hrs, it was quenched with 50 ml of
water, extracted with ether and dried over MgSO^ after
washing with brine. The solvents were evaporated under
vacuum at which point a large amount of
triphenylphosphine oxide crystallized. The liquid
remaining was decanted and the salts washed with
pentane. The organic liquids were combined, and the
solvents evaporated. Kugelrohr distillation afforded
0.823 g of the vinyl epoxide 7_4 (74% yield). IR (CCl^)
3059 (s), 1634 (s), 1971 (s) cm"1; 1H (300 MHz, CgD
5.56-5.49 (m, 1H), 5.18 (d, 1H); 4.98 (m, 2H), 3.09 (d,
1H), 2.07-1.99 (dd, 2H), 1.55-1.24 (m, 2H), 1.52 (s,
3H), 1.38 (s, 3H) 1.02 (s, 3H); 13C NMR 134.6, 131.6,
124.3, 119.0, 63.1, 69.1, 33.8, 25.7, 24.1, 17.6, 16.7;


68
High resolution mass spectrum calculated for C,.Hlo0,
II 1 O
166.1362, found: 166.1357.
Reaction of Rathke alane with vinyl epoxide 74
Compound 7_4 was reacted with 3 equivalents of
alane as described in the general procedure for alane
reactions After three hours and allowing reaction
temperatures to rise from -60 to -10C. No product
arising from reaction with the epoxide was seen. In
order to corroborate lack of reactivity 3 more
equivalents of the alane reagent were quickly in a
separate reaction vessel and cannula transferred to the
first. It was allowed to react overnight at room
temperature. After the usual workup, the vinyl oxirane
was recovered unchanged.
Preparation of 1,l-cyclohexyl-2-vinyl-oxirane (75)
A three necked flask fitted with vacuum adapter,
stirring bar and thermometer was flame dried under
vacuum and 19.6 g (0.11 moles) of allyldimethyl
sulfonium bromide over an atmosphere of argon. The
sulfonium salt was prepared by stirring a mixture of
dimethylsulfide and allylbromide overnight. THF, 100
ml, was charged into the flask and cooled to 0C; 44 ml
of 2.5 M n-butyl lithium (0.11 moles) were added and
stirred for 30 min. The color of the ylide was deep
red. When 1.8 g (0.018 moles) of cyclohexanone were


69
injected into the flask, the color turned from red to
faint yellow after addition. The reaction mixture was
allowed to come to room temperature and react for 2
hrs. It was quenched with 75 ml of ice water; extracted
with ether and dried over Na^SO^. Yield was 57% by G.C.
Short path distillation, 25 mm Hg at 65-70C, afforded
the oxirane contaminated with cyclohexanone. Washing
with 10% NaHSO^ and passing through a small plug of
SO2 using 20% ether/pentane gave the pure oxirane. IR
(neat) 3100- 2860 (s), 1640 (m), 1447 (s) cm-1; *H NMR
(300 MHz, CDCL3) 5.82-5.71 (m, 1H), 5.47 (dd, 1H, J=
17, 2Hz), 5.31 (dd, 1H, J= 11, 2 Hz), 3.18 (d, 1H, J= 5
Hz), 1.77- 1.68 (m, 2H) 1.60-1.45 (m,8H); 13C NMR
(CDC13) 133.2, 119.8, 64.7, 64.3, 35.4, 29.3, 25.5,
25.0, 24.7 ppm.
Synthesis of 1,l-dimethyl-2-vinyl-oxirane (76)
To a flame dried flask fitted with vacuum adapter
and septa, 5.16 g of Na3C03 ( 48.7 mm) were added.
MCPBA (7.89 g, 45.7 mm) were added under an atmosphere
of argon as well as 14 ml of ether (dry). The flask was
cooled to 0C and 1.4 ml (12 mm) of 2-methyl-2,4-
dimethyl-pentadiene were charged into the flask. The
mixture was allowed to react for 45 min. The reaction
mixture was filtered to remove solids and most of the
ether distilled through a vigreaux column. Vacuum


70
transfer of the remaining residue afforded 9 mg (0.092
mm) of epoxide 94% pure which would be used directly in
reaction with the Rathke alane.
1H NMR (300 MHz, CDCL3) 5.64 (m, 1H), 5.38 (dd, 1H, J=
17, 2 Hz), 5.27 (dd, 1H, J= 11 Hz,2 Hz), 3.14 (d, 1H,
J= 5 Hz), 1.28 (s, 3H) 1.20 (s, 3H); 13C NMR (CDC13)
125.9, 120.0, 64.4, 60.2, 30.9, 24.6 ppm.
Reaction of 1,l-dimethyl-2-vinyl-oxirane with Rathke
Alane
A 0.3 mm solution of the Rathke alane was prepared
in 8 ml of THF following the general procedure for the
alane formation. An ether solution of the oxirane 16_
along with a standard were added at -60 C. The
reaction was monitored for 50 minutes no observable
product arising from reaction with the epoxide 7_6 was
seen. In order to test the formation of the alane 0.01
ml of methylene cyclohexane oxide was added to react
with the alane. Conversion of 5_3 to the hydroxy ester
60 was evidenced by G.C. monitoring within 20 min.
Oxidation of hydroxy ester (60) to enone (80)
Hydroxy ester 6_0 (0.632 g) was oxidized using
o
1.789 g of ground 3A molecular sieves, 3.764 g of PDC
and a catalytic amount of dry acetic acid in methylene
chloride. The procedure has been previously described
on page 66. After 3 hrs, the slurry was filtered


71
through a sintered glass funnel filled with a mixture
of SiC>2 and 10% MgSO^, eluting with ether. This gave
0.516 g of enone 80_ (82% yield). 1HNMR ( 300 MHz, CDC13)
3.28 (s, 2H), 2.40 (m, 4H), 1.98 (m, 2H), 1.94 (s, 3H),
1.43 (s, 9H); 13C 199.8, 170.6, 157.9, 129.8, 80.4,
37.1, 32.7, 31.8, 27.9, 22.0, 21.5.
PDC oxidation of methylene hydroxy ester (56)
Compound 5_6 (58.8 mg) was oxidized with 0.506 g
PDC, 0.722 g molecular sieves, a catalytic amount of
acetic acid and 10 ml of methylene chloride as
previously described. It was allowed to react
overnight. Filtration through SiO^ and 10% MgSO^ gave
the crude enone 7_9 which was purified by using 30%
ethyl acetate/pentane (63% yield). 3HNMR(60 MHz, CDCl^)
3.16 (s, 2H), 2.80-2.20 (m, 4H), 2.09 (s, 3H), 1.47 (S,
9H); 13CNMR (CDC13) 208.0, 172.8, 169.5, 149.8, 80.9,
34.1, 31.8, 29.6, 28.0, 17.5 ppm.
Oxidation of cyclopentene hydroxy ester (57)
The alcohol, 0.149 g (0.753 mm), was oxidized with
o
the following: 0.73 g of ground molecular sieves, 3A,
1.500 g of PDC and a catalytic amount of acetic acid in
methylene chloride. After reacting for 1 hr the slurry
was filtered through SiC^ and 10% MgSO^, to give 0.106
g of 2-(methylenecarbo-t-butoxy)-3-cyclopenten-l-one
(77) (84% yield). 1HNMR (100 MHz, CDC13) 6.11 (m, 2H),


72
3.24-3.10 (m, 1H), 2.93 (s, 2H), 2,61-2.30 (m, 2H),
1.43 (s, 9H); 13CNMR (CDC13) 217.0, 170.5, 132.2,
128.4, 80.9, 48.5, 42.4, 36.0, 28.0 ppm.
Oxidation of cyclohexene hydroxy ester (61),
o
Finely ground molecular sieves (0.786 g, 3A) were
activated by heating vigorously for 5 min. in a 25 ml
flask under vacuum After allowing to come to room
temperature 1.18 g of PDC (3.14 mm) were added along
with a stirring bar and and 12 ml of freshly distilled
methylene chloride. The mixture was placed under argon,
and cooled with ice water. At this time the hydroxy
ester, 0.224 g (1.06 mm), was charged into the flask
via syringe followed by a catalytic amount of dry
acetic acid. The slurry turned dark brown upon addition
of the alcohol. After 1 hour, the mixture was filtered
through 10% MgSO^/SiO^ and the solids washed with
ether. The yield of 2-(me thylenecarbo-t-butoxy)-3-
cyclohexen-1-one (78) was 97% (0.2163 g). IR (neat)
1720 1148 cm"1; 1HNMR (100 MHz, CDC13) 6.0-5.5 (m,
2H) 3.4 (bs, 1H), 2.8-2.2 (m, 6H), 1.4 (s, 9H); 13CNMR
(CDC13) 209.7, 171.2, 128.4, 127.5, 80.7, 45.1, 38.1,
36.3, 28.1, 26.4 ppm.
Hydrolysis of t-butyl ester (61) to the acid (90)
To a 100 ml flask were added the following, 2.0 g
of hydroxy ester 6J_ (0.013 m), 40 ml of methanol and


73
1.79 g of K^CO^. The mixture was stirred for 2 days
after which it was acidified with 6M HC1 to a pH of 2,
extracted with ether (4x35 ml) and dried over MgSO^.
Evaporation of solvent gave 1.4821 g of 9_0 in 73%
yield. IR (neat) 3680-2800 (s), 1710 (s), 910 (m) cm ^
1HNMR (200 MHz, CDC13) 6.25 (bs, 1H), 5.64 (m, 1H),
5.42 (d, 1H), 3.60 (m, 1H), 2.66-1.10 (m, 7H); 13CNMR
(CDC13) 177.7, 127.7, 127.5, 71.8, 40.6, 38.4, 30.2,
24.2 ppm; Mass spectrum (70 eV) m/e 138 (3), 110 (2),
84 (12), 74 (47), 59 (80), 45 (51), 31 (100), 28 (69).
Lactonization of cyclohexene hydroxy acid (90)
A 25 ml three necked flask was fitted with
thermometer, stirring bar, and vacuum adapter. It was
flame dried under vacuum and flushed with argon.
Triphenyl phosphine (0.5128 g) were added under a
positive pressure of argon followed by 20 ml of dry
THF. The hydroxy acid (0.210g) dissolved in THF was
charged into the flask and the reaction mixture cooled
to 10C. At this point, 0.29 ml of DEAD reagent was
added and a catalytic amount of acetic acid. After
reaction was complete, the solvent was evaporated in
vacuo and the crude cis lactone was purified by flash
chromatography using 40% ethyl acetate/pentane to give
0.140 g of lactone 9_1 in 78% yield. IR (neat) 3011,
1762, 1273 cm-1; 1HNMR (CDC13, XL-200) 5.90 (m, 1H),


74
5.48 (d, 1H), 4.76 (m, 1H), 3.02 (m, 1H), 2,76 (AB
quartet, 1H), 2.30 (dd, 1H), 2.20- 1.10 (m, 4H); 13CNMR
(CDC13) 176.8, 128.7, 125.6, 78.1, 35.8, 34.4, 24.6,
19.1 ppm; High resolution mass spectrum calculated:
138.0680, found: 138.0685.
Preparation of MTM-hvdroxy acid (87)
To a 50 ml one neck flask were added the
following: 1.03 g of hydroxy ester 8J7 (3.41 mm), 15 ml
of absolute ethanol, 1 ml of water, and 0.660 g of KOH
(11.8 mm). The mixture was stirred and heated at 43-47
C under argon for 13 hrs. The ethanol mixture was
concentrated in the rotovap. The slurry was acidified
with 1.2 M HC1 to a pH of 2, extracted with ether (4 X
20 ml) and dried over MgS04. This afforded 0.6842 g of
a brown, very viscous oil (82% yield) which was
lactonized without further purification. IR (neat)
3700-2800 (s), 1715 (s), 1430 (w), 1245 (w), 1050 (s)
-1
cm
Preparation of cis-MTM-lactone (88)
A 25 ml three necked flask was fitted with
thermometer, stirring bar and vacuum adapter. It was
flame dried and flushed with argon. Triphenylphosphine,
0.197 g (0.730 mm), was added under an argon
atmosphere; 15 ml of dry THF were charged into the
flask followed by 110 mg of the hydroxy acid 87


75
(0.447mm) in THF. The mixture was cooled to 10C.
Dropwise addition of the DEAD reagent, 0.11 ml (0.699
mm), followed and allowed to react for 1 hr. The
solvent was evaporated and flash chromatography using
35% ethyl acetate/pentane gave the E and Z MTM lactones
(90% yield by G.C.). IR (CC14) 3300-2810 (m),1775 (s),
1165 (m) cm-1; XH NMR (300 MHZ, CDCL3) Z-isomer 5.58
(t,
1H)
r
5.09
(t,
1H)
t
4.63
(AB
quartet,
2H ) 4
.04
(d,
2H) ,
3.
51
(m,
1H)
, 3.
02
-2.92
(dd
, 1H
/
J=
18
, 10
Hz ) ,
2.65
-2.
48
(m,
1H)
, 2.
43
-2.40
(dd
, 1H
f
J=
18
, 2.
5 Hz ) ,
2.44
-2.
35
(m,
1H)
, 2.
22
-2.18
(in,
1H)
r
2.16
(s,
3 H )
r
1.85
-1.
72
(m,
1H)
; E-
isomer
5.57
- 5.
50
(m
r
1H) ,
5.
01
(t,
1H)
r
4.63
( s ,
2H )
t
4.17-
4.01
(m,
2H) ,
3
.34
(m,
1H) ,
2.98
-2.
89
(dd
, 1H
, J=
18
,9 Hz ) 2
.63-
2.
55
(m
, 1H) ,
2.54
-2 .
47
(dd
, 1H
, J=
18
, 1.6
Hz )
, 2.
43
(m
/
1H) ,
2.
31-
2.22
(m
r
1H) ,
2.15 (s
f
3H ) ,
1.94
-1.81
(m,
1H) ;
13c
NMR
(CDC13)
z
-isomer
176.
7,
148 .
3, 121.1
/
85.
4,
74 .
6,
65.0 ,
44.3
, 37.
3, 31.4,
26 .
6,
14.0
; E-
isomer
176.
6, 148.
5,
119.
6,
85
.7,
74.6
, 64
.3
. 40.
25,
36.3
f
31 .
5,
30.
8,
14.0;
High resolution mass spectrum calculated: 228.0820:
found 228.0853


APPENDIX
LIST OF REAGENTS PURCHASED FROM SPECIFIC CHEMICAL
SUPPLY HOUSES
2-cyclopentenone- Aldrich
DIBAl- Aldrich
n-buty11ithium- Aldrich
diethyl aluminum chloride- Aldrich
PDC- Aldrich
MCPBA- Aldrich
triphenylphosphine- Aldrich
MTM chloride- Aldrich
EthyltrimethyIsilylacetate- Aldrich
t-butyl acetate- Aldrich
sodium hydride- Alfa
Aldrich Chemical Co.
P.O. Box 355,
Milwaukee, Wisconsin 53201
Alfa Products- Thiokol/Ventron Division
P.O. Box 299
152 Andover Street
Danvers, Massachusetts 01923
76


BIBLIOGRAPHY
1. G. Zweifel and J.A. Miller, "Synthesis Using
Alkyne-Derived Alkenyl- and Alkynylaluminum
Compounds", Organic Reactions, Vol. 32, John Wiley
and Sons, New York, 1984, Chapter 2.
2. K. Ziegler, Experentia Suppl. II, 278, (1955).
3. (a) A. J. Lundeen and A.C. Oehlschlager, J.
Organometal. Chem., 25, 337 (1970). (b) J. L. Namy,
E. Henry-Basch and P. Freon, C.R. Acad. Sc. Ser. C,
269, 1222, (1969). (c) J. L. Namy, E. Henry-Basch
and P. Freon, Bull, Soc. Chim. 6^, 2249 ( 1970 ).
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3899 (1973). J. Fried M. Mehra, C. Lin and W.
Kao, Ann. N.Y. Acad. Sci., 180 38 (1971).
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8. M. Visnick, Ph. D. dissertation, University of
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10. M.Visnick, Ph. D. dissertation, University of
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11. C. Campbell and M. Battiste unpublished results.
12. Spectroscopic studies done by Jim Rocca, Curt
Campbell and Mapi Cuevas.
77


78
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BIOGRAPHICAL SKETCH
Mapi Cuevas was born on March 18, 1952, in Rio
Piedras, Puerto Rico. She received a B.S. in chemistry,
magna cum laude, from the University of Puerto Rico in
May 1973 after three years of undergraduate studies.
From August 1973 to June 1975 she taught science and
mathematics at Baldwin High School, Guaynabo, Puerto
Rico and was named Science Chairperson from 1974-1975.
In the summer of 1975, after moving to Gainesville, she
worked for three years at Golden Hills Academy. A
career move to North Fort Myers to teach at the local
high school followed. Ms. Cuevas was science instructor
at North Fort Myers High school until 1983 when she was
admitted to graduate studies at the University of
Florida. From 1983 to 1986 she was awarded a GPOP
Fellowship by the Graduate School. From 1987 to 1988
Mapi co-authored a physical science textbook for
Harcourt Brace Jovanovich and was curriculum
coordinator of the undergraduate organic laboratory at
UF for the 1986-87 school year. Most recently she is an
adjunct instructor of chemistry at Santa Fe Community
College.
80


I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
Merle A. Battiste, Chairman
Professor of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
William R. Do1bier, Jr/ j
ProfeSSOr rhomi cfrvV >
of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
William M.Jones\3
Professor of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.


I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
Professor of Biochemistry and
Molecular Biology
This dissertation was submitted to the Graduate Faculty
of the Department of Chemistry in the College of
Liberal Arts and Sciences and to the Graduate School,
and was accepted as partial fulfillment of the
requirements for the degree of Doctor of Philosophy.
December 1988
Dean, Graduate School


....




UNIVERSITY OF FLORIDA
3 1262 08556 7732


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FILES



REGIOSPECIFIC CARBON-CARBON BOND FORMATION VIA RING
OPENING OF VINYL OXIRANES WITH AN ORGANOALUMINUM
REAGENT
BY
MAPI M. CUEVAS
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988
10 OF F LIBRARIES

ACKNOWLEDGEMENTS
The author wishes to express her gratitude to
Professor Merle Battiste for his guidance and advice.
Special thanks go to Merle's Perles for helping to
mantain her sanity or lack thereof. Separate thanks go
to Jim Rocca for all the help he has given with
spectroscopic problems, and to Dr. Awartani for his
chemical advice. My deepest gratitude goes to the
Graduate School for the three year fellowship. Finally,
thanks go to Luis, for helping me through the "Ph.D.
blues".

TABLE OF CONTENTS
PAGE
ACKNOWLEDGEMENTS ii
ABBREVIATIONS iv
ABSTRACT v
CHAPTER I INTRODUCTION 1
CHAPTER II THE NATURE OF THE REAGENT 13
CHAPTER III SCOPE OF THE OXIRANE OPENING.... 25
CHAPTER IV SYNTHETIC APPLICATIONS 39
CHAPTER V EXPERIMENTAL 51
General 51
Reagents and Solvents 52
Apparatus and Technique 52
APPENDIX LIST OF REAGENTS PURCHASED
FROM SPECIFIC CHEMICAL SUPPLY
HOUSES 76
BIBLIOGRAPHY 77
BIOGRAPHICAL SKETCH 80
i i i

ABBREVIATIONS
DEAD
DIBAL
DME
DMSO
Et
eq
LDA
MCPBA
Me
MTM
mm
m
M
Py
THF
TMS
B.P.
PDC
tert-butyl
diethylazodicarboxylate
diisobutyl aluminum hydride
dimethoxy ethane
dimethyl sulfoxide
ethyl
equivalent
lithium diisopropyl amine
meta-chloroperbenzoic acid
methyl
methy1thiome thyl
millimole
mole
Molar
pyridine
tetrahydrofuran
trimethylsilyl
boiling point
pyridinium dichromate
IV

Abstract of Dissertation Presented to the Graduate
School of the University of Florida in Partial
Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
REGIOSPECIFIC CARBON-CARBON BOND FORMATION VIA RING
OPENING OF VINYL OXIRANES WITH AN ORGANOALUMINUM
REAGENT
BY
Mapi M. Cuevas
December 1988
Chairman: Merle A. Battiste
Major Department: Chemistry
The reaction of diethyl-carbo-tert-butoxy
methylalane with both cyclic and acyclic vinyl epoxides
was studied as a potential route to unsaturated enones
and carbocyclic compounds. Two formal syntheses, one of
cis-jasmone and the other of a prostaglandin
intermediate, exemplify the new methodology of this
acetate anion equivalent in its reaction with cyclic
vinyl epoxides. An interesting one-step conversion of
trans hydroxy acids to cis lactones involving the use
of DEAD reagent and triphenylphosphine is also shown.
v

CHAPTER I
INTRODUCTION
The past 20 years have brought about tremendous
advancements in the area of organometallic chemistry.
The chemistry of organoaluminum, particularly alkenyl
and alkynyl alanés, has proven to be singularly useful
in the synthesis of natural products.'*’ Organoaluminum
compounds exhibit chemical properties that are somewhat
different from organolithium, organomagnesium and even
their boron congeners. In 1955, referring to aluminum
alkyls, Ziegler commented that even though the analogy
to the grignard reagent is tempting, these aluminum
2
alkyls behave "peculiarly". Only one Al-C bond reacts
in a grignard fashion. Once this Al-C bond is added to
a substrate such as a carbonyl compound, the aluminum
bond in the product formed is attached to oxygen.
Immediately, the reactivity of the other Al-C bonds
decreases greatly and no further addition occurs. These
differences in reactivity and selectivity of
organoaluminum compounds are instrumental to their
synthetic utility.
1

2
Epoxides may be considered pseudocarbonyls in
their reactions with organometals. Their synthetic
potential is greater, since many times they are far
more accessible as starting materials than carbonyls.
The organometallic reagent may act as a nucleophile or
as a Lewis Acid in its reactions with epoxides. Three
competing mechanistic pathways are possible as can be
seen in Figure 1.1.
Figure 1.1
This scheme illustrates the reactions of
organometals with alkyl epoxides. In general,
dimethylmagnesium, methyllithium and cuprates give

3
Table 1.1 Alkylation of Epoxides by Trialkyl Alanés
Epoxide R^AI Conditions Products Yield (%)
E'3AI
CUH30; 80
Epoxide: Alone
1 = 2
98
8"\¡7 M*3AI C6HU--35°
86
Et,AI
Et20;35°
49
1 7

4
predominantly nucleophilic ring opening at the least
hindered site to furnish 21, while methylgrignards give
predominantly halohydrins. In the case of
trialkylaluminum reagents ring opening at the
substituted carbon often predominates. Some products
from rearrangement are also observed, though not
exclusively. The ratio of each seems to vary with
3
solvent and reaction conditions (Table 1.1).
The opening of alicyclic epoxides by
organoaluminum reagents and further elaboration of the
intermediates formed could provide a useful route to
important natural products. For example, an expedient
route to lactones or alpha-substituted ketones can be
achieved through nucleophilic addition of an acetate
anion equivalent to oxiranes (Figure 1.2).
Figure 1.2

5
The classic method of epoxide openings with
malonic ester enolates is not often practical since it
involves harsh conditions (refluxing ethanol) and is
. . . 4
sensitive to stenc effects. Most recently,
organometallies have been used to modulate the
reactivity and selectivity of enolate type anions.
Application of aluminum enolates to ring opening of
allylic epoxides in this laboratory evolved from
consideration of alkynyl alane research and
methodology. Fried has developed useful synthetic
methods in prostaglandin synthesis which allowed the
opening of alicyclic epoxides with alkynyl aluminum
reagents. These alanés, prepared from addition of
diethylaluminum chloride to lithium acetylides in
toluene, gave satisfactory yields of the
trans-2-alkynyl cycloalkanols (Table 1.2).^
In 1976, the first acetate anion equivalent using
an organoaluminum reagent was reported by Danishefsky.^
Ultimately interested in the preparation of
trans-lactones from epoxides, Danishefsky reacted
cyclohexene oxide with 2.5 equivalents of
diethylcarbo-tert-butoxymethyl alane 1_3 at -30 to -40 °C
to give the hydroxy ester ]_2 in 34% yield (Fig. 1.3).
Only the trans product was observed. This reagent was
prepared by the addition of Et2AlCl solution to lithio
tert-butylacetate, JJ^, (Rathke's salt).^
Reaction of

6
Table 1.2 Reactions of Epoxides with Alkynyl Alanés
Epoxide
Alone
Temp.(C) T i me (h rs) V ¡ e I d (%)
B
25° '8 77
85° 72 30
25° 18 9 8
90° 7 2 3 8
OCH 0
2 5° 2 0 7 8
85° 7 2 59
OCH 0

7
Rathke's salt alone with cyclohexene oxide in toluene
had afforded only 8% of 12^. Subsequently the yield of
this alane reaction was improved to 68% by allowing the
reaction temperature to rise to ambient temperature and
prolonging the reaction at this temperature for 6 hrs.
Attempts to utilize this alanyl methodology with a
ring-A steroidal epoxide, however, failed and
Danishefsky abandoned this approach.
10
+ Et2AICH2COO'Bu
13
1 2
6 8%
Figure 1.3
Spurred by Danishefsky's initial success with the
Rathke alane, Dr. Melean Visnick decided to utilize it
O
in his synthesis of (t)-anastrephin (Figure 1.4). Only
one regio-and stereoisomer was isolated from the alane
reaction.

8
Figure 1.4
When the reaction medium was toluene, the yield
was 24%, but a solvent change to THF increased the
yield to 87%. Previously, standard literature
procedures had been carried out in hydrocarbon solvents
or toluene. A literature search did not fully reveal
why toluene had been the solvent of choice. Most
reaction temperatures were 25°C or higher and the
stability of alanés in such polar solvents as THF or
DME seemed to have been questioned at these
temperatures. In 1975 Crosby and Stephenson reported
that the products formed in the reaction of 3,4-epoxy
cyclopentene with diethylhex-l-ynylaluminum was solvent
9
dependent (Figure 1.5). They proposed the following
rationalization. In the absence of polar solvents the
oxophilicity of the aluminum causes a rearrangement of
epoxide _]_4 to the enone 1_8^ which then reacts with the
alkynyl alane to give the cyclopentenol 19.

9
IdülU 1•^
y
dL l. i 11 w l wx i. ^ o1 ‘ ^ ^ ^
R
y
X
>° +
Et9 AICH-COO'Bu >
Epoxide
Solvent Temp(C) Time(hrs) Yield(%)
och3
25°
1 2
24
DME
-55°
0.5
9 2
0CH3
25°
2
25
THF
55°
1
87
DME 55° 1 85
THF 30°
2
No R x n

10
Visnick's studies of the solvent effect in the reaction
of diethylcarbo- tert-butoxymethyl alane 1_3 with
epoxides are summarized in Table 1.3.^. In all cases
the nucleophilic attack occurred at the allylic carbon
and no rearrangements were reported.
Since the aluminum reagent is better solvated and
less aggregated in polar solvents such as THF it should
be more reactive and less sensitive to steric and
entropic effects than in such solvents as toluene or
hexane.
14
R = C = CBu
]_9_
84 %
Figure 1.5
The main interest of this research work is (a) to
explore the scope of diethylcarbo-tert-butoxymethyl
alane 13 in its reactions with -unsaturated

11
epoxides, (b) to investigate the generality of the
regiospecific opening at the allylic position, and (c)
to illustrate its applications to the synthesis of
natural products.
As can be seen from Figure 1.6, cyclic unsaturated
epoxides could be converted into cis- or trans-lactones
or substituted cycloalkenones in essentially two steps.
The applicability of the oxirane opening by alane L3
will be exemplified in the formal synthesis of
cis-jasmone as well as a known prostaglandin
intermediate.

12
Figure 1.6

CHAPTER II
THE NATURE OF THE REAGENT
The initial goal of this research was to
investigate the generality of the alane reaction with
various cyclic unsaturated epoxides. Visnick had
ascertained that a minimum of 2.3 equivalents seemed to
be necessary in order for the reaction to proceed with
g
good yields. The working assumption was that one
equivalent of the aluminum species was required to
coordinate with the epoxide oxygen while possibly
another delivered the acetate anion. This simplistic
assumption invoked the existence of a monomeric
reagent.
Figure 2.1
13

14
Based on the regioselectivity shown, the first
mechanism for the reaction was presumed to be as shown
in Figure 2.1. As shown, one equivalent of the alane
complexes with the epoxide weakening the carbon-oxygen
bond and rendering the allylic site partially positive.
A second equivalent of the reagent probably delivers
the acetate anion equivalent.
This type of mechanism suggests that the reaction
could be run with only one equivalent of Rathke's salt
and an excess of diethylaluminum chloride. Recent
stoichiometric studies done by a member of Dr.
Battiste's research group seem to support the need for
an excess amount of the Rathke alane. The yields of the
reaction were poor to nonexistent when one equivalent
of Rathke's salt and a slight excess of Et^AlCl were
used.^ The formation of chlorohydrin seems to
predominate in cases where Et2AlCl is in excess.
Several attempts have been made to try and
elucidate the structure of the Rathke alane. NMR
studies have proven inconclusive and seem to suggest
the possibility of several species in solution. The NMR
samples were prepared as in the general procedure (see
experimental) except that after the solvents were
removed under vacuum, THF-dg was added. NMR samples of
the dimethylcarbo-tert-butoxymethylalane, 2_5, were also
prepared in hopes that conversion from methyl to ethyl

15
groups would permit a clearer view of the metalated
alkyl region of the spectrum. Both the proton and
carbon NMR showed more peaks than would be expected for
. , 12
a simple monomeric species.
Me2AlCHJCOO,Bu
2_5
Figure 2.2
Rathke prepared 1ithio-t-butyl acetate by treating
t-butyl acetate with LDA. In his characterization of
this salt in benzene, Rathke reports two partially
resolved doublets at 3.14 and 3.44 ppm and an infrared
band at 1620 cm ^. No band was observed between 1675
-112
and 2000 cm . This leads to the conclusion that
Rathke's salt is a true enolate with the structure as
shown in Figure 2.3.
Figure 2.3
One of the questions this research wished to
address was whether the aluminum metal was on carbon as

16
in structure 26_ or on oxygen as in 27.
separate NMR experiments, there was no
vinyl protons for the alanés made from
or Et2AlCl.
In three
evidence of
either Me^lCl
O
II ,
R2Al CH2 C—O Bu
26
R = Me or Et
RjAl O-
2 7
c
"Np'Bu
Figure 2.4
The literature offers conflicting structures for
aluminum enolates, no doubt enhanced by the scarcity of
aluminum enolates known as compared to those of other
metals. Japanese workers have published a number of
papers in which they use several aluminum enolates in
13
aldol type reactions (Figure 2.5). They draw the
enolate formed as shown in 2J3 without giving direct
literature precedents for it. In 1974, Jeffrey, Meister
and Mole reported the isolation and characterization of
the aluminum enolates formed by reaction of mesityl
oxide with Me^Al in the presence of nickel acetyl
acetonate using ether or cyclopentane as a solvent.^

17
Figure 2.5
The Z- and E-enolates shown in Figure 2.6 were
unusually stable. Cryometric studies showed that the
structure of the Z-enolate was dimeric while the
structure of the E-enolate was composed of dimers and
trimers. Spectral studies proved that a definite
vinyloxy structure existed- as shown in 2J7. The dimers
were held together by Al-O-Al bridges rather than by
Al-O-C-C-Al bridges. The lack of vinyl protons,
however, in our spectra still worried us.
o
Ni(acac)
Me,C“CH—C 4- AIMe. 1 >.
^Me Ei20 or CSH)2
/
c-=c
Figure 2.6
'Bu
\
Me
/
\
OAI —
31

18
/OZnBr
BrZn-CH.COO Bu CH,=C .
2 NOBu
32 3 3
Figure 2.7
The Reformatsky reagent is analogous to the alane
enolate and the identity of its structure has also been
the object of discussion. The unsettling question of
whether the zinc intermediate possesses either
structure 3_2 or 3_3 seems to have been finally answered
in two papers.
In 1982, Orzinni, Pelizonni and Ricca conducted
spectroscopic studies of the Reformatsky reagent
prepared from t-butyl bromo-acetate.^ No significant
change was seen for the C-l carbon, either in the
proton or carbon NMR, (see Table 2.1) as would have
3
been expected if a change in hybridization from an sp
2
to an sp carbon had occurred to give structure 33.
They concluded that there was no evidence to support an
oxygen metallated species.

19
Table 2.1 Spectroscopic Data for Reformatsky
Intermediate
ch3coo'bu
1 2 t
BrZnCH2COOBu
(ppm)
’h(S)
Sol ven t
C1
c2
• ch3
DM SO
22.2
169.3
1.84 (s. 3H )
Py
M
1.93 (s. 3H)
HMPT
23.1
170.2
THF
213
168 8
1.83 (s. 3H)
-ch2-
DMSO
20.8
177.4
1.04
Py
20-4
179.5
2.00
HMPT
22.1
179.0
THF
22.7
186.2
1.88
Py = pyridine

20
In 1983, Dutch researchers published X-ray data
that gave the first molecular stucture for the
Reformatsky reagent 3_5.^ X-ray diffraction analysis in
THF showed a dimer in which each zinc was surrounded by
two oxygen, one bromine and one carbon atom as in
Figure 2.8.
THF
j.
\ .. O., O Bu
Zn" "C^
*' l
HCH HCH
I „
Zn
'BuO
/ \
THF
36
Figure 2.8
The dimer, an eight-membered, non-planar ring
showed normal single bond distances for the Zn-C and
Zn-0 bonds. The researchers conclude that it is
incorrect to describe the reagent as either C- or O-
metallated. They proposed two possible mechanisms for
the reaction of the Reformatsky reagent with
electrophiles, such as a ketone (Figure 2.9).
Mechanism 3_8 is a six centered one which, according to
studies, shows less steric hindrance and is favored by
the investigators.

21
R
R
OBu1
1 °CH:
OBu
Zn—Br
BulO C / -
o'—Zn.—
/
THF
THF
37
38
Figure 2.9
In as much as the Rathke alane ^3, behaves as a
Reformatsky reagent, we propose a similar structure to
that in 3_6. The data we have collected, though
inconclusive, does suggest- a non-monomeric species
which has no vinyloxy protons. With these in mind, we
would like to propose the following structure for
reagent ^3 (Figure 2.10).

22
e'>-;^CH2^c/
e'7 + \
/ o
O'Bu
\
y+ m
-c\ /'\E,
nCHt
39
Figure 2.10
In fact, Fried has proposed a similar intermediate
for the reaction of alkynylalanes with epoxides (Figure
2.11) .17
Based on the requirement for at least two
equivalents of alane, we can also speculate on a
mechanism for its reaction with epoxides (Figure 2.12).
Evidence to support both the structure and mechanism
will be discussed further in the following chapters.

23
Figure 2.11

24
Fiqure 2.12

CHAPTER III
SCOPE OF OXIRANE OPENING
In general, reactions of vinyl epoxides with
organocopper, organolithium and organomagnesiura
reagents follow a predominantly 3^2 ' process. Some of
1 8
these results are summarized in Table 3.1. When the
metal is lithium or magnesium, a variety of
nucleophilic attacks are seen, depending on reaction
conditions. Cuprates and alanates give exclusively S^2'
products.
In 1987, Naruta and Maruyama reported that highly
regioselective 1,2 addition products to vinyl epoxides
19
had not been developed. They published results
describing succesful additions of allylstannanes to
vinyl epoxides using BF^,0ET2.
As can be seen by their mechanism (Figure 3.1),
the BF^ complexes with the epoxide and induces ring
opening before attack of the stannane reagent. In fact,
when a substituent was placed at the olefinic terminus
that could stabilize a positive charge, such as a
phenyl group, the 1,4 adduct is formed in good yield.
25

26
Table 3.1 Reactions of Metaloalkyl Reagents with Vinyl
Epoxides
Epoxide
R M
% Products
d.
a
b
c
R'= H
CH3LÍ (LiBr)*
7
38
55
0
CH3MgBr
1
36
44
19
(CH^CuLi
0
6
94
0
R'= Me
• •
Me Al Me3
0
0
100
0

27
The reaction occurs at the site with the more
stabilized cationic character.
Figure 3.1
In our estimation, the addition of acetate alanés
to vinyl epoxides would then be a new complimentary
approach to those already "available. The first step in
our research involved studying the reaction of the
acetate alane with a variety of cyclic vinyl epoxides
as shown in Table 3.2. Epoxides _49_, 51-53 , and 5_5 were
prepared from the enones. Alkaline epoxidation was
followed by a Wittig or Peterson olefination reaction
as shown in Table 3.3. Epoxides 5_0 and 5_4 were prepared
by peracid epoxidation of the corresponding diene
(Figure 3.2).
In all cases except one the reaction with the
alane gave the corresponding trans-hydroxy ester in
good to moderate yields. Compound 4_9 was difficult to

28
work with due to its volatility and the low yields
shown may be attributed to this. Yields for compound
were, as might be expected, poor due to the
neutralization of 1 equivalent of alane by the hydroxyl
proton and formation of t-butyl acetate in the reaction
medium which subsequently reacts with another
equivalent of the alane. This was avoided by protecting
the alcohol functionality.
Figure 3.2
Methylene cyclohepteny 1 oxide, 5_5, to our
surprise, failed to react cleanly. Its reaction with
the alane was sluggish. If reaction times were extended
over three hours, the substrate decomposed into a
myriad of products. A catalytic amount of BF^- 0Et2 was
added in order to induce ring opening, without success.
The best yield of the hydroxy ester achieved with the
Rathke Alane was 10%. These results seem to indicate
that some stringent electronic requirements exist in

29
Table 3.2 Reactions of Vinyl Epoxides with Rathke
E po xid e
Alane
P roduct
Reactions in THF oi —60 to — 40°C
e = coo'bu
Yield (%)
61
50
36
94
80
92
10

30
Table 3.3 Synthesis of Vinyl Epoxides
l h202/OH
100 0"3 PMe/BuLi 49 H
1
TMS
100 LiCHCOOEt 86 COOEt
2
94 #3PMe/Buli 56 H
3
100 " ' 67 H

31
the transition state. We know that the reaction does
not occur through a free carbonium ion intermediate
since only the trans-adduct is seen in all cases.
Instead, partial weakening of the C-0 bond occurs
before the nucleophile attacks. Nucleophilic addition
occurs at the position most capable of stabilizing the
incipient positive character on the epoxide after
complexation. Coplanarity of the p orbitals of the
double bond with the incipient cationic site as shown
in Figure 3.3 is necessary.
Figure 3.3
The 3-methylene-l , 2-oxidocycloheptane , 5_5 , being
conformationally more flexible than the cyclopentyl or
cyclohexyl substrates, does not seem to favor the
appropriate configuration. At approximately the same
time that these experiments were carried out, a paper
by Mas, Malacria and Gore appeared involving the
reaction of lithium trialkynylborates with acyclic
20
vinyl epoxides. They stressed the fact that
regioselective reagents that induce ring opening at

32
either site of or £> to the vinyl group in acyclic vinyl
epoxides are few (Figure 3.4). The alkynyl borates they
reacted with vinyl epoxides gave opening only,
making these reagents a complementary approach to the
more abundant S' processes available for vinyl
epoxides.
R3
rí\7 + r’-c=c-br2
1 2 t A
R = Bu; R = Et; R i R =H
R1=0;R2rEt;R3, R4=H
Figúre 3.4
With this in mind, the alane opening of the cyclic
epoxides seemed encouraging and it would be interesting
to find out if the acyclic cases, which were more
flexible, less conformationally biased than the cyclic
vinyl epoxides molecules discussed previously would be
as clean. The synthesis of various acyclic vinyl
epoxides was undertaken. The reaction of the epoxides
with the alane was performed in the usual way, with 3
equivalents of the alane in THF. Reaction times varied
slightly. The results are summarized in Table 3.4. As
can be seen, in general, the alane gave predominantly
46%
36%

33
Table 3.4 Reactions of Acyclic Vinyl Epoxides with
Rathke Alane
Epoxide
Products
Y i e I d ( % \
' Isolated yield
E = COOfBu

34
1,2 addition at the site to the double bond, though
this was not exclusive as in the cyclic cases. It was
to be expected that the lack of rigidity of these
molecules would lower the regioselectivity of addition.
No conjugate addition, however, was observed. To our
surprise 7_4 did not react at all. It was even recovered
unchanged after three hours of reaction.
The possible explanation for this lack of
reactivity is the following. A steric interaction
between the alkyl group and the vinyl hydrogen as shown
in Figure 3.5 would disfavor alignment of the p
orbitals of the double bond with the C-0 bond of the
epoxide. This would not allow for partial C-0 bond
breaking. The alane does not appear to be a
sufficiently strong Lewis acid to open the epoxide by
complexation alone. Two other oxiranes similar to 74,
with substituents cis to the vinyl were synthesized in
order to corroborate this assumption.
Figure 3.5

35
2,2-Cyclohexyl-l-vinyl epoxide, 7_5' was prepared
using dimethyl allyl sulfonium ylide as shown in Figure
3.6. 1 , l-Dimethyl-2-vinyl epoxide, 7j5, was synthesized
from the reaction of 2-methyl-2,4-pentadiene with MCPBA
(Figure 3.6). When combined with Rathke alane, both of
these substrates failed to react, even at extended
reaction times or when the reaction mixture was allowed
to come to ambient temperatures. It was possible to
confirm this sterically induced misalignment through
NMR studies.
Figure 3.6
The best substrate to use seemed to be
1,1-dimethyl- 2-vinyl epoxide, since the chemical shift
of the two methyl groups should provide information as
to the preferred orientation of the vinyl group. It
would be expected that in order to avoid bumping
between the methyl and the vinyl hydrogen as shown in

36
Figure 3.5, the preferred conformation would place the
p orbitals of the double bond almost orthogonal to the
C-0 bond. This in turn would shield the vicinal methyl
group.
As can be seen in Figure 3.7, the two methyl
groups in the epoxide are distinctly separate when
compared to a small quantity of the starting diene. The
methyl assignments are based on analogy to the chemical
shifts of methyls in similar compounds as well as NOE
studies done on the dimethyl vinyl epoxide.
The methyl group syn to the vinyl group shows a
shielding of 0.08 ppm when compared to the anti methyl
indicating a preferred conformation such as that shown
in Figure 3.5. The vinyl hydrogen is staggered between
the two methyl groups while the p orbitals of the
double bond are aligned with the methyl group and
almost orthogonal to the conformation required for
reaction with the alane. Sauleau and coworkers report a
similar effect in the reaction of sodium phenoxide with
21
substituted oxiranes (Figure 3.8). Depending on the
R', r" ,and R'" substituents the amounts of conjugate
versus direct addition of phenoxide to the oxirane
vary. In the case where R' , R" = CH^ and R, R'" = H,
direct addition at carbon 1 accounted for 33% of the
products. Twenty two percent was conjugate addition,
but of this only the E isomer was seen. When the system

Figure 3.7
OJ

38
is loaded with R' , R" and R'" = CH^ only direct addition
was observed due to the unfavorable steric interactions
that would be required for conjugate addition.
r = r,’’=h;r'=r"=ch3
r=hír'=r”=r'‘=ch3
R R”
I I
JQ'—O—C—C — C— CH3
r' oh r”'
A
OH
-S’—0—CHp — C = C —R
1, I.. I,
R R R’
OH B
/ — OH
(/ \ CHp —C—C—C—R
i- it k
C
Reldlive ?6 Yields
_A_ B. C_
33 22 II
100 — —
Figure 3.8
General and mild methods providing regioselective
1,2 addition products with vinyl oxiranes are scarce.
The Rathke alane provides such a route in exclusion of
the 1,4 addition so frequently seen with other
organometal1ic reagents. Ring opening of cyclic
epoxides is regiospecific and the trans-hydroxy esters
produced are important intermediates in natural product
synthesis. In acyclic cases, the regioseleetivity of
the aluminum enolate is far superior to that observed
v/ith other organometall ic compounds.

CHAPTER IV
SYNTHETIC APPLICATIONS
Following the study of the vinyloxiranes with the
acetate alane, its synthetic applicability needed to be
explored. As was shown in Chapter I, the hydroxy esters
offer a potential route to lactones as well as 2,3-
disubstituted enones. Many of the important natural
products shown in Figure 4.1 could be conveniently
prepared from the synthetic sequence shown in Figure
1.6.
Figure 4.1
39

40
The jasmone family, as exemplified in cis-jasmone
and dihydrojasmone, are important compounds in
perfumery. The prostaglandins, in their immense variety
have proven to be of great interest in pharmaceuticals
for their vasodepressant and muscle relaxant
properties.
The 2,3-disubstituted alkanone or alkenone pattern
seen in all of these compounds may be achieved by
conversion of the hydroxy esters produced from the
Rathke alane reaction with the appropriate epoxide. In
this research a formal synthesis of cis-jasmone and a
prostaglandin PG analog previously synthesized by Corey
were undertaken to illustrate the synthetic
applicability of the alane reactions. Corey's
intermediate has been subseguently converted to
1l-deoxy-PGE^ and 1l-deoxy-PGF^.^^
Conversion of the hydroxy esters prepared from the
alane and vinyl epoxides to enones involves oxidation
and subseguent isomerization of the double bond.
Various oxidative processes were tried, the most
convenient one being a variation of Czernecki's PDC
23
oxidation. The PDC oxidations were carried out in dry
methylene chloride with molecular sieves and a
catalytic amount of dry acetic acid. The sieves were
ground and activated by heating in the reaction vessel
under vacuum for several minutes. After cooling, the

41
other materials were added. For the oxidation procedure
to work well the reaction should be done under an inert
atmosphere and all the reagents freshly distilled or
dried. Table 4.1 shows the results of the PDC
oxidations.
Table 4.1 PDC Oxidations of Hydroxy Esters
E = C02*Bu
Exocyclic double bonds isomerized to give the
conjugated enone under the reaction conditions. In the
case were the double bond was inside the ring, the
isomerization did not occur but could be readily
achieved by reaction with p-toluene sulfonic acid. In

42
the case of 7_9' the ester could be hydrolyzed to the
carboxylic acid in K^CO^ in methanol. This constitutes
a formal synthesis of cis-jasmone. The subsequent steps
in Figure 4.2 were reported in the literature by
d â–  i 24
Birch.
Figure 4.2
The use of 3-methylene cyclopentene oxide 4_9 in
the synthesis of another prostanoid intermediate was
halted due to the difficulty in isolating this
compound. The yields after Wittig reaction on
2,3-oxidocyclopentanone were not encouraging. Its
subsequent reaction with the alane also suffered due to
the extreme volatility of the compound. It was almost
impossible to isolate completely from solvent. Even
when it was stored in the refrigerator in a paraffin
wrapped vial it evaporated in a few days. In order to
avoid this difficulty in handling, a separate synthesis
of Corey's prostaglandin intermediate 8J5 was undertaken
as can be seen in the retrosynthetic scheme in Figure

43
4.3. The cis-lactone structure could be constructed
from the trans-hydroxy ester by isomerizing the
hydroxyl carbon and lactonizing. This could be
accomplished in a single step by a novel reaction
utilizing DEAD reagent and triphenylphosphine. The
hydroxy ester in turn could be derived from the
reaction of Rathke alane and the vinyl epoxide, 52_. The
protected allylic alcohol in 5_2 evolves from Peterson
olefination of 2,3-oxido-cyclopentanone.
Figure 4.3

44
Peterson olefination of 2,3-oxido-cyclopentanone
gave an 88% mixture of the Z- and E-epoxy esters in a
ratio of 7:4 . DIBAL reduction of the esters afforded
the Z- and E-allylic alcohols Subsequent reaction
with an excess of Rathke alane gave the trans-hydroxy
ester _58 in poor yield. As mentioned previously the
presence of a hydroxyl group neutralizes 1 equivalent
of the alane which allows the formation of t-butyl
acetate and ensuing side reactions. When the Z- and
E-epoxy alcohols were protected as the MTM ethers, 52,
the yield was then improved to 94%.
The Z- and E-trans-hydroxy esters 59_ were hydrolyzed
under mild conditions to the trans-hydroxy acids
(Figure 4.4). Lactonization and epimerization of the
hydroxyl carbon could be accomplished by utilizing
triphenylphosphine and the DEAD reagent. This method
had not been described in the literature previously
even though the use of the DEAD reagent in conversion
2 5
of alcohols to esters was well known.
The accepted mechanism of conversion of an alcohol
to an ester is shown in Figure 4.5.

45
DIBAL
3NoH ; MTMCI
64 %
/^OMTM
^COO'Bu
59 OH
KOH >
95%
DEAD; 03P
53%
Figure 4.4

46
«N
H +
£—m_n-E 4- ROP03
-*■ R'COOR + 0,p +- EN—NE
J H H
Figure 4.5
A similar process could be used to form the
cis-lactone After formation of the triphenyl
phosphine adduct 89_, shown in figure 4.6. The
carboxylate anion acts as an intramolecular nucleophile
with backside displacement of triphenylphosphine oxide.
Figure 4.6
Since previous examples of this reaction were not
known, the reaction was attempted with the
cyclohexenehydroxy acid, 9_0, previously prepared by
reaction of the 1,3-cyclo-hexadiene epoxide with the
Rathke alane and hydrolysis to the hydroxy acid. The

47
trans-hydroxy acid was then treated with triphenyl
phosphine and DEAD reagent in THF to furnish 78% of the
cis-lactone, 91.
Encouraged with this reaction the lactonization
process was attempted with the--prostaglandin
intermediate 8_7. The reaction was clean and afforded
the lactone in 90% yield. The Z- and E-lactones were
separable by flash chromatography at this point.
Separation of isomers, however, was not essential to
the success of the synthesis as can be seen in the
subsequent steps.
Confirmation of the cis orientation for the Z- and
E-MTM-lactones was determined by spectral studies. The
respective proton spectra may be compared in Figure
4.8. The most pronounced difference between isomers is
shown in the D and Dj_ protons which exhibit a complex
multiplet for the E-isomer due to coupling with H and L
protons. The Z-isomer shows only a coupling to the
vinylogous proton. The vinyl proton, in turn, shows a

48
E-lactone
Z-lac tone
Fiqure 4.8

49
broad triplet for the Z-isomer while proton A for the E
isomer exhibits more fine structure due to coupling to
_D, D_|_ as well as _F and G. NOE studies done by Mr. Jim
Rocca confirm the structures shown. The Z-MTM-lactone
showed a 4.1% NOE between proton E_ and [), D_|_, as well
as a 5.4% NOE between E and B. No NOE was observed
between protons _E and A. This is consistent with the
Z-cis lactone. The E isomer on the other hand showed a
4.8% NOE between EC and Ei as well as a 4.2% NOE between
protons _E and A.
Following lactonization, the MTM protecting group
was removed using AgNO^. PDC oxidation to the aldehyde,
utilizing the PDC oxidation with molecular sieves
described previously, afforded the Z- and
E-aldehydes 9_3 (Figure 4.9).
It was conceived that the trans orientation of the
side group in Corey's lactone 8_5, could best be
achieved by preparing the oc , (3 -unsaturated vinyl
ether, 9_4_, which upon acid hydrolysis should give the,
unsaturated aldehyde, trans to the lactone ring as the
thermodynamically preferred product. Further
elaboration of the side chain should provide access to
the 11-deoxy-prostaglandins of the PG series.

50
Figure 4.9

CHAPTER V
EXPERIMENTAL
General
Melting points were recorded using a Thomas-Hoover
capillary melting point apparatus. Analyses were
performed by Atlantic Microlab, Inc. of Atlanta,
Georgia.
Spectra
Infra-red spectra were recorded on a Perkin-Elmer
283B Spectrophotometer. Routine mass spectra were
obtained on an Associated Electronics Industries model
MS-30 mass spectrometer at 70 eV. High resolution mass
determinations were handled on the same instrument
further eguipped with a Nova Systems 4 computer. Proton
and/or Carbon NMR were recorded on a Varian Model
EM-360, a JEOL Model FX-100, Varian XL-200, or 300.
Chemical shifts were recorded relative to
tetramethylsilane, unless otherwise noted, at 0.00 & .
Carbon chemical shifts were relative to the
deuterochloroform resonance at 77.00 ppm, unless
otherwise noted.
51

52
Reagents and Solvents
Many of the reagents used in this work were
obtained from several chemical supply houses. The alkyl
lithium solutions were titrated using 2,5-dimethoxy-
2 6
benzylalcohol. Some of the liquid reagents were
purified by distillation. Solvents such as
tetrahydrofuran (THF) and diethyl ether were distilled
from sodium-benzophenone prior to use in an apparatus
27
described by Brown. Dimethylsulfoxide (DMSO),
diisopropyl amine and methylene chloride were distilled
from calcium hydride and stored over activated sieves
or used immediately.
Apparatus and Technique
All air sensitive reactions were run in glassware
that had been flame-dried under vacuum. The glassware
was filled with an inert atmosphere of nitrogen or
argon by successive evacuation and backflushing through
28
a Firestone valve. Liquid reagents were added to the
reaction vessel through standard syringe techniques.
Flash chromatography or distillation was used for the
29
isolation of pure materials.
General procedure for epoxidation of cycloalkenones
The enone (1.0 eq.) was added to a mixture of 30%
(3.0 eq.) and methylene chloride at 15 °C.
Dropwise addition of 6 N NaOH (0.5 eq.) followed

53
maintaining the reaction temperature between 15 - 20°
C. The mixture was then allowed to come to ambient
temperature. Upon completion the reaction was quenched
with water and extracted with methylene chloride.
Extracts were washed with brine and dried over Na2SO^.
After removal of solvent, Kugelrohr distillation of
crude afforded desired keto epoxides in 90 - 100%
yields.
2.3-oxidocyclohexane-l-one ; B.P. 66-70 °C, 10 mm Hg;
IR (neat) 1760 (s), 865 (s), 795 (s) cm 3; 3 H NMR (60
MHZ, CDC13) 3.65 (bd, 1H), 3.20 (dd, 1H), 2.80 - 1.50
(m, 6H) ; 13C NMR (CDC13) 205.5, 55.5, 54.8, 36.0,
22.5, 16.7. mass spectrum (70 eV) m/e 112 (32), 83
(18), 55 (100), 28 (24); 94% yield.
2.3-oxidocyclopentane-l-one ; IR (neat) 1745 (s), 1174
(s) ,
840
( s )
, 730
(s) cm-1; 1H NMR
( 60
MHZ, CDC13)
3.93
(d,
1H)
, 3.30
(d, 1H), 2.41 - 1
.90
(m, 4 H); 13C
NMR
(CDC1
3 }
209.2 ,
57.2, 54.0, 29.7,
22
.4 ppm; High
resolution mass spectrum calculated mass of 98.03678,
found 98.03711; 100% yield.
2,3-oxidocycloheptane-1-one : IR (neat) 1700 (s), 930
(m), 835 (s); NMR (60 MHZ, CDC13) 3.43 (d, 2H),
2.92-1.38 (m, 8H); 13C NMR (CDC13) 205, 59, 55, 40, 27,
24, 23 ppm; mass spectrum (70 eV) m/e 126 (11), 97

54
(27); 83 (19); 70 (58); 55 (85); 41 (100); 39 (43); 27
(49); 28 (24). B.P. 45°C at 15 mm Hg. Yield:
quantitative. In the case of cycloheptenone, methanol
was used as solvent.
General preparation of methylene epoxides
A three necked flask with 1.0 to 1.3 equivalents
of methyltriphenylphosphonium bromide and stirrer was
dried overnight in a vacuum oven at 40 -50 °C. The
flask was then fitted with vacuum and thermometer
adapters as well as septa. The flask was flushed with
argon by means of a firestone valve and charged with
dry THF. After cooling to -78°C, 1.0-1.3 equivalents of
n-buty11ithium were added slowly. The colored solution
was stirred for 1 hr at -78°C. 1.0 equivalent of the
keto epoxide dissolved in a small amount of THF was
added to the ylide. The reaction mixture was allowed to
come to room temperature slowly and quenched with
saturated NH^CL solution, extracted with ether or
pentane, washed with brine and dried over Na2SO^.
Purification of crude was achieved by Kugelrohr
distillation.
3-methylene-1,2-oxidocyclohexane: IR (neat) 3000-2900
(s), 900 (m), 730 (m); XH NMR (60 MHZ, CDC13) 5.37 (s,
1H), 5.26 (s, 1H), 3.43 (bs, 2H), 2.4-1.2 (m, 6H); 13C

55
NMP (CDC13) 143, 116, 55, 54, 29, 24, 20 ppm; 56%
yield.
3-methylene-1,2-oxidocyclopentane: B.P. 48 °C at 10 mm
Hg;1H NMP (60 MHZ, CDC13) 5.16 (bs,lH), 4.85 (bs, 1H)
3.68- 3.40 (m, 2H), 2.23- 1.5 (m, 4H); 49% yield. This
compound was extraordinarily volatile and was not fully
separated from solvent before reaction with the alane.
3-methylene-1,2-oxidocycloheptane: B.P. 30°C at 10 mm
Hg; 1H NMR (60 MHZ, CDC13) 5.00 (s, 1H), 4.92 (s,lH),
3.37 (d,1H), 3.10 (t, 1H), 2.4-1.2 (m, 8H); 13C NMR
(CDC13) 147, 115, 60, 57, 34, 29, 28, 24; 67% yield.
General preparation of methylene hydroxy esters
A 250 ml three necked flask was fitted with a
magnetic stirring bar, thermometer and septum inlet. It
was flame dried, flushed with argon and charged with 3
equivalents diisopropyl amine and hexane. This was then
cooled to -78°C and 3 equivalents n-butyl1ithium, 2.5 M
in hexane were added. The solution was stirred from 15
minutes to an hour after which 3 equivalents of t-butyl
acetate were added dropwise, keeping the temperature
between -75 to -70°C. After stirring for 30 minutes,
the solution was allowed to come up to 0°C at which
time the volatiles were removed in vacuo. This was
followed by addition of THF and subsequent cooling to

56
-78°C. The solution was then charged with 3 equivalents
of diethylaluminum chloride, 1.8 M in toluene. After a
few minutes, 1 equivalent of the methylene epoxide was
added in 5 ml THF. It was allowed to react at
approximately -50°C until reaction was complete.
Quenching was best achieved by cannula transfer of
solution to an erlenmeyer flask containing ice and 1.2
M HC1. The mixture was vigorously stirred by means of a
mechanical stirrer. This was followed by extraction
with ether. The extracts were dried over MgSO^ and
evaporated to give the crude product. Flash
chromatography on silica gel eluting with ethyl
acetate/hexane (or pentane) afforded the desired
hydroxy esters.
3-methylene-2-(methylenecarbo-t-butoxy)-l-cyclo-
pentanol: 1H NMR (60 MHz, CDC13 ) 4.93 - 4.92 (q, 2H),
3.70 (s, 1H), 2.70 - 1.70 (m, 8H), 1.40 (s, 9 H) ppm;
13C NMR (CDC13 ) 173.4, 151.9, 106.6, 81.1, 78.1,
48.0, 38.5, 32.3, 29.4, 28.0 ppm; mass spectrum (70 eV)
m/e 139 (28.6), 138 (84.7), 110 (14.7), 93 (63.3), 57
( 100 ) , 41 (33.7 ) .
Reaction of 3,4-epoxy-cyclopent-1-enewith Rathke
a lane.

57
Procedure as described in general procedure.
Isolated yield 50%, after flash chromatography with 40%
ethyl acetate/ pentane.
2-(methylenecarbo-t-butoxy)-3-cyclopentene-l-ol (57):
IR (CC14) 3400, 1710, 1150 cm"1; 1HNMR (NT-300, CDC13)
5.68 (m, 1H), 5.51 (m, 1H), 4.18 (m, 1H), 3.06 (bs,
1H), 2.87 (m, 1H), 2.78-2.15 (m, 4H), 1.45 (s, 9H);
13CNMR (CDC13) 173.1, 131.4, 129.0, 80.9, 78.3, 50.7,
40.8, 39.3, 28.0 ppm; Mass spectrum (70 eV) m/e 142
(7%), 124 (50%), 107 (16%), 96 (19%), 83 (23%), 79
(23%), 57 (100%), 41 (41%).
3 1
Reaction of 3,4-epoxy-cyclohex-l-ene with Rathke
Alane
As in general procedure for alane. Isolated yield
after flash chromatography 84%. IR (neat) 3430, 1725,
1140 cm-1; 1HNMR (NT-300,CDC13) 5.65 (m, 1H), 5.43 (d,
1H), 3.55 (m, 1H), 3.19 (bs, 1H), 2.58 (d, 1H), 2.53
(bs, 1H), 2.23 (sextet, 1H), 2.12 (m, 2H), 1.92 (m,
1H), 1.70-1.57 (m, 1H), 1.45 (s, 9H) ppm; 13CNMR
(CDC13) 172.9, 128.0, 127.3, 80.7, 71.6, 41.1, 39.9,
30.4, 28.0, 24.2 ppm; Mass spectrum (70 eV) m/e 138
(16%), 112 (5%), 79 (13%), 74 (13%), 59 (27%), 57(31%),
45 (18%), 31 (45%), 28 (100%).
Peterson Olefination of 2,3-epoxy eyelopentanone

58
To 1.50 ml diisopropyl amine (10.7 mmol) in THF,
under argon, 6.40 ml of n-butyl lithium, 1.6 M in
hexane (10.7 mmol) were added slowly at -15°C. The
solution was cooled to -78°C, followed by addition of
ethyltrimethylsilylacetate, 1.90 ml (10.4 mmol). The
reaction was stirred for 30 min. at -78°C. 1.00 g of
2,3-epoxy cyclopentanone in THF was added (10.2 mmol).
Allowed to react for 2 hrs. at -78°C, then allowed to
come to room temperature. The orange solution was
quenched with 25 ml of saturated ammonium chloride and
extracted with ether. Volatile-s were stripped under
vacuo. Kugelrohr distillation afforded 1.37 g of the
Z- and E-isomers 86Z and 86E (80% yield) in a ratio of
7:4 (Z : E),b.p. 72°C at 0.5mm Hg. IR (neat) 2960 (m),
1715 (s), 1653 (m), 1222 (s), 1135 (s) cm-1; 1H NMR
(100 MHZ, CDC13) Z-isomer 5.95 (bs, 1H), 4.82 (d, 1H),
4.24 (q, 2H), 3.82 (m, 1H), 2.56-1.83 (m, 4H), 1.30 (t,
3H); E-isomer 5.96 (bs, 1H), 4.21 (q, 2H), 3.69 (d,
1H), 3.02 (bs,1H), 2.56-1.83 (m, 4H), 1.29 (t, 3H); 13C
NMR (CDC13) Z-isomer 165.7, 159.9, 117.9, 59.9, 59.6,
54.2, 27.5, 25.4, 14.1; E-isomer 165.7, 160.4, 116.3,
60.1, 59.8, 54.2, 26.5, 24.9, 14.1; mass spectrum (70
eV) m/e 168 (0.81), 140 (23), 123 (35), 112 (100), 97
(26), 67 (45), 55 (40), 41 (50), 39 (77), 29 (46), 27
(54) .

59
Preparation of epoxy allylic alcohols (51Z and 51E)
A three-necked flask fitted with vacuum adapter,
stirring bar and thermometer was flame dried under
vacuum. After cooling to room temperature the flask was
charged with 5.05 g (30.1 mm) of the ester epoxides 86E
and 86Z and 100 ml of dry THF. The solution was cooled
to -78°C. 60.2 ml of a 1.0 M DIBAL solution was added
slowly. The reaction mixture was stirred at -78°C for 1
hour then at -50°C for 2 hours after which it was
guenched with 25 ml of methanol. The gelatinous product
was filtered through Celite using hot methanol.
Evaporation of solvent under vacuum afforded 3.79 g of
E and Z epoxy allylic alcohols 51Z and 51E,
(quantitative yield). 3H NMR ( 300 MHZ, CDCl^) Z-isomer
5.76 (m, 1H), 4.32 (d, 2H), 4.20 (m, 1H), 3.92 (d, 1H),
3.76 (dd, 1H), 2.40- 1.60 (m, 4H); E-isomer 5.9 (m,lH),
4.15 (dxAB, 2H), 4.10 (m, 1H), 3.64 (dd, 1H), 3.73 (dd,
1H), 2.40-1.60 (m, 4H); 13C NMR (CDC13) Z-isomer
142.0, 126.2, 59.9, 58.7, 54.3, 26.5, 22.1; E-isomer
141.7, 125.5, 59.8, 58.5, 54.3, 25.9, 22.1; High
resolution mass spectrum calculated for C^H^O^
126.0680, found: 126.0683.
Protection of the epoxy allylic alcohols as the MTM
ethers (52Z and 52E)

60
NaH (2.56 g, 60% oil dispersion) were added to a
flame dried flask under argon and washed with hexane,
3x10 ml. The flask was then charged with 100 ml of THF
and cooled to approximately 0°C before adding 3.50 g of
the epoxy allylic alcohols (27.8 mm) in 5 ml THF; 2.38
ml of methylthiomethyl chloride were added at
approximately 5°C and allowed to react for 6 hrs. The
mixture was quenched at room temperature with 25 ml
saturated NaHCO^, extracted with ether and washed with
brine and more saturated sodium bicarbonate. The
organic extracts were dried over Na2SO^. The solvent
was evaporated under vacuum and the crude product
purified by passing through a sintered glass funnel
filled with silica gel using gradient elution
increasing from 10% ethyl acetate/pentane to 50%. 4.17
g (81% yield) of MTM-ethers 52Z and 52E were recovered.
:H NMR (300 MHZ, CDC13) Z-isomer 5.68 (t, 1H), 4.67 (s,
2H ) ,
4.24 (dd,
1H)
, 4.14 (dd,
1H)
, 3.8 (d,
1H), 3.68
(m,
1H), 2.36-
1.50
(m, 4 H),
2.10
(s, 3H);
E-isomer
5.86
(t, 1H),
4.64
(s, 2H) , 4
.12
(dd, 1H),
4.07 (dd,
1H) ,
3.72 (m,
1H) ,
3.63 (d, 1H),
2.36-1.50
(m, 4 H),
2.15
(s, 3H);
13c
NMR (CDC13)
Z-isomer 144
.1, 122.4,
73.9
, 63.8, 59
.5,
54.1, 26.5,
25.
9 , 13.6;
E-isomer
143.4, 121.8, 73.9, 63.9, 59.2, 58.4, 25.5, 22.1, 13.6;
Mass spectrum (70 eV) m/e 186 (0.06%), 138 (15%), 125,

61
109 (54%), 108 (26%), 81 (100%), 79 (70%), 67 (20%), 61
(100%), 53 (41%) , 41 (51%) .
Preparation of Z- and E-hydroxy esters (59)
Procedure as in general preparation of hydroxy
esters. To 0.79 g of LDA prepared in hexane, 0.80 g of
t-butylacetate was added. After formation of Rathke's
salt, 3.67 ml Of 1.8M solution of Et^AlCl in toluene
were charged into the flask followed by 0.412 g of
oxirane 5_2. The final product was a pale yellow oil,
0.6237 g of the hydroxy ester 5_9 (94% yield) after
flash chromatography using 10% acetone/C^C^ • NMR
(300 MHZ, CDC13) Z-isomer 5.52 (t, 1H), 4.63 (m, 2H),
4.07 (m, 2H), 2.89
(m,
1H) , 2
.69-1.98
(m,
6H) ,
2.21
(s ,
3H ) , 1
.70-1.63 (m,
2H ) ,
1.47
(s, 9H)
t
E-isomer
5.35
(m,
1H) , 4
.62 (m, 2H),
3.97
-3.86
(m, 2H)
t
2.80 (m,
2H ) ,
2.69-1
.98 (m, 6H),
2.15
(s, 3 H), 1.64
(m,
2H ) ,
1.43
(s ,
9H); 13C NMR (CDC1
3) z-
isomer
172.6,
148 .
8, 118
.7,
81.3,
78.8, 74.6,
64.7 ,
46.0,
39.6,
32
• 5,
30.9,
28.0
f
14.0;
E-isomer 173
.4, 147.5,
117.8,
81
• 3,
77.9,
74.2
t
64.5,
48.2, 38.8,
32.4,
28.0,
26.0 ,
14
.0
ppm.
Reaction of Rathke
Alane with
3,4-epoxy-3
-methyl-
1-butene33
A dry three necked flask fitted with vacuum and
thermometer adapters as well as a stirring bar was
charged with 5.02 ml of diisopropyl amine (0.036m)

62
under argon. The flask was cooled to -78 °C after the
addition of 20 ml of hexane. To this solution 14.4 ml
of a 2.5 M solution of n-butyllithium in hexane (0.036
m) were added and the reaction mixture allowed to stir
for 20 min. at -78°C; 4.8 ml of t-butyl acetate were
added dropwise and again allowed to stir for
approximately 20 min after which the solution was
brought to 0°C and the solvents removed under vacuum.
After Rathke's salt was allow to dry at room
temperature under vacuum, 35 ml of THF were added and
the solution cooled to -78°C. After cooling 20.0 ml of
a 1.8 M solution of Et^AlCl in toluene (0.036 m) were
added followed after 5 min with 1.0 g of
3,4-epoxy-l-butene (0.0119 m). After 2 hours at -60°C,
the reaction was guenched by transferring the solution
via cannula to an erlenmeyer flask containing ice and
30 ml 1.2 M HC1. The mixture was stirred vigorously
with a magnetic stirring bar to avoid formation of
gels. Extracted with ether (3 x 30 ml), washed the
organic extracts with brine and dried over NaoS0^.
After filtration and removal of solvents, flash
chromatography using 20% ethyl acetate/hexane furnished
two regioisomers in the ratio of 7:1. Yield 63%. The
major isomer was 3-(hydroxymethyl)-3-methy1-t-buty1-
4-pentenoate (69) and the minor isomer was 4-hydroxy-
4-methy1-t-butyl-5-hexenoate(70 ) .

63
3-(hydroxymethyl)-3-methyl-t-butyl-4-pentenoate (69):
IR (neat) both isomers 3440 (s), 1720 (s), 1170 (s)
cm-1; 1HNMR (200MHz, CDC13) 5.85 (dd, 1H), 5.15-5.03
(m,2H), 3.48 (d,2H), 2.33 (d,3H), 1.46 (s,9H), 1.11
(s,3H); 13CNMR (CDC13) 171.7, 143.0, 113.6, 80.8, 69.5,
43.1, 41.5, 28.0, 21.2 ppm; Mass spectrum (70eV) m/e
145 (7%), 127 (27%), 114 (69%), 96 (14%), 85 (25%), 71
(43%), 57 (100%), 43 (25%), 41 (31%).
4-hydroxy-4-methy1-t-buty1-5-hexenoate(70);
1HNMR (200 MHz, CDC13) 5.79 (dd, 1H), 5.18 (dd, 1H, J=
1.2 Hz and 17 Hz), 5.01 (dd, 1H, J= 1.2 Hz and 11 Hz),
2.24 (m, 2H), 1.75 (m, 3H), 1.38 (s, 9H), 1.22 (s, 3H);
13CNMR (CDC13) 173.8, 144.3, 112.3, 80.4, 72.5, 36.5,
30.4, 28.3, 28.0 ppm; Mass spectrum (70 eV) m/e 182
(.07%), 144 (10%), 126 (71%), 111 (26%), 85 (35%),
71(26%), 57 (100%), 41 (30%).
Reaction of Rathke alane with butadiene monoxide
A flame dried three necked flask fitted with
magnetic stirring bar, vacuum and thermometer adapter
under argon was charged with 1.80 ml diisopropyl amine
(12.8 mm) and 15 ml of hexane. The solution was cooled
to -78°C and then 8.60 ml of 1.5 M solution of
n-butyllithium in hexane were added and stirred for 30
min 1.72 ml of t-butyl acetate (12.8 mm) were added
dropwise at -78°C. The reaction mixture was stirred for

64
another 30 min before allowing the solution to come to
0°C and the solvents evaporated under vacuum. After the
white Rathke salt was dry, 20 ml of THF were charged
into the flask and cooled to -78°C . At this
temperature 7.20 ml of a 1.8 M solution of Et2AlCl
(12.96 mm)in toluene were carefully added followed by
0.326 g of epoxide (0.428 mm). The solution was allowed
to react at -50°C for 1 hr. It was quenched with 15 ml
of 3% HC1 and extracted with ether. The organic
extracts were washed with brine and dried over MgSO^.
Two regioisomers were formed in a ratio of 3:1. They
were purified by flash chromatography using 30% ethyl
acetate/hexane.
Yield: 22% The major one being 3-(methylenehydroxy)-
t-butyl-4-pentenoate (66) and the minor product was
4-hydroxy-t-butyl-5-hexeneoate (67).
3-(hydroxymethyl)-t-butyl-4-pentenoate (66):
IR (neat) both isomers 3415 (bs); 1723 (s); 1150 (s)
cm”1; 1HNMR (300 MHZ, CDC13) 5.78-5.66 (m, 1H), 5.16
(t, 2 H), 3.57 (d,2H), 2.72 (m, 1H), 2.46-2.24 (dAB
pattern, 3H), 1.45 (s, 9H); 13CNMR (CDC1 ) 171.9,
137.8, 116.9, 80.7, 65.2, 42.8, 37.4, 28.0 ppm; Mass
spectrum (70eV) m/e 113(12%), 100(30%), 71(22%),
57(100%), 54(16%), 43(16%), 41(38%), 29(25%).
4-hydroxy-t-butyl-5-hexeneoate (67):

65
IR (neat) both isomers 3415 (bs); 1723 (s); 1150 (s)
cm"1; 1HNMR (60 MHZ, CDC13) 5.9 (M,1H), 5.3 (M, 2H),
4.25 (bs,1H), 2.6-1.0 (m. 5H), 1.5 (s,9H) ppm; 13CNMR
(CDC13) 173.3, 140.5, 114.8, 80.4, 72.1, 31.8, 31.5,
28.0 ppm; Mass spectrum (70 eV) m/e 130 (3%), 112(37%),
71 (30%), 57(100%), 41(34%), 28(10%).
Reaction of styrene oxide with Rathke alane
Procedure as in general procedure for alane
reaction. Yield 64%. Two products isolated by flash
chromatography using 15% ethyl acetate/pentane.The
ratio of regioisomers was 4:1. The major product was
4-hydroxy-3-pheny1-t-butyl-butanoate (76a) and the
minor 4-hydroxy-4-phenyl-t-butyl-butanoate (76b).
4-hydroxy-3-phenyl-t-butyl-butanoate (72): White solid,
melting point 44-48°C. IR (neat) both isomers 3010 (s),
1712 (s), 1368 (s), 1212 (s) cm"1; 1HNMR (XL-200,CDC13)
7.28 (m, 5H), 3.78 (d, 2H), 3.30 (m, 1H), 2.65 (dAB,
2H), 2.63 (bs,1H), 1.35 (s, 9H); 13CNMR (CDC13) 171.9,
141.1, 128.5, 127.8, 126.9, 80.6, 66.9, 44.7, 38.6,
27.9; Analysis: calculated 71.16% C, 8.53% H Found
71.10% C, 8.57% H.
4-hydroxy-4-phenyl-t-butyl-butanoate (73 ) :
IR (neat) both isomers 3010 (s), 1712 (s), 1368 (s),
1212 (s) cm-1; 3HNMR (300 MHz,CDC13) 7.34 (m, 5H), 4.73

66
(t, 1H), 2.58 (bs, 1H), 2.33 (t, 2H), 2.02 (q, 2H),
1.44 (s, 9H) ppm; 13CNMR (CDC13) 173.3, 144.2, 128.4,
127.5, 125.7, 80.5, 73.6, 34.0, 31.9, 28.1 ppm; Mass
spectrum (70 eV) m/e 180 (15%), 162 (21%), 161 (40%),
117 (40%), 107 (67%), 105 (39%), 91 (28%), 79 (34%), 77
(38%), 57 (100%), 41 (66%), 28 (50%).
Preparation of 3,7-dimethyl-2,3-oxo-6-octen-l-al
o
Molecular sieves (2.76 g, 4A) were ground and
activated by flame drying under vaccum in the reaction
vessel. After cooling to room temperature and flushing
with argon, 24.37 g of PDC (0.065 m) were added under
an argon atmosphere; 30 ml of CH^C^ were charged into
the flask, cooled with an ice bath, and 5.23 g of
3,7-dimethyl-2,3-oxo-6-octen-l-ol33 (0.0231 m) were
added in 20 ml of The mixture was allowed to
react overnight. The crude mixture was filtered through
Celite followed by filtering through a plug of SIO^
with 10% MgSO^ using CH^Cl^. Kugelrohr distillation of
the crude afforded 1.23 g of pure aldehyde (32% yield).
IR (CC14) 3020-2840 (s), 1710 (s) cm"1; 1H NMR (300
MHz,CcD ) 9.20 (s, 1H), 4.97 (bs, 1H), 2.90 (s,lH),
b b
2.25-1.0 (m, 4 H), 1.61 (s, 3H), 2.4 (s, 3H), 1.45 (s,
3H); 13C NMR (C Dg ) 198.6, 132.2, 123.3, 63.4, 38.4,
25.7, 23.7, 17.6, 17.0 ppm.
Wittiq reaction of 3,7-dimethy1-2,3-oxo-6-octen-1-a 1

67
A 150 three necked flask was dried in a vacuum
oven overnight with 3.10 g of methyltriphenylphospho-
nium bromide (8.70 mm) at 56°C. The flask was then
fitted with vacuum and thermometer adapters as well as
a stirrer. It was evacuated and flushed with argon
several times. 50 ml of dry THF were charged into the
flask and the mixture chilled to -50°C. At this
temperature, 3.56 ml of n-butyl1ithium 2.5 M in hexane
were added (8.70 mm). The ylide color was bright yellow
after approximately 30 min, 1.49 g of the aldehyde were
added and the solution allowed' to come to room
temperature. After 3 hrs, it was quenched with 50 ml of
water, extracted with ether and dried over MgSO^ after
washing with brine. The solvents were evaporated under
vacuum at which point a large amount of
triphenylphosphine oxide crystallized. The liquid
remaining was decanted and the salts washed with
pentane. The organic liquids were combined, and the
solvents evaporated. Kugelrohr distillation afforded
0.823 g of the vinyl epoxide 7_4 (74% yield). IR (CCl^)
3059 (s), 1634 (s), 1971 (s) cm"1; 1H ( 300 MHz, C
5.56-5.49 (m, 1H), 5.18 (d, 1H); 4.98 (m, 2H), 3.09 (d,
1H), 2.07-1.99 (dd, 2H), 1.55-1.24 (m, 2H), 1.52 (s,
3H), 1.38 (s, 3H) 1.02 (s, 3H); 13C NMR 134.6, 131.6,
124.3, 119.0, 63.1, 69.1, 33.8, 25.7, 24.1, 17.6, 16.7;

68
High resolution mass spectrum calculated for C.,H,o0,
II 1 O
166.1362, found: 166.1357.
Reaction of Rathke alane with vinyl epoxide 74
Compound 7_4 was reacted with 3 equivalents of
alane as described in the general procedure for alane
reactions After three hours and allowing reaction
temperatures to rise from -60 to -10°C. No product
arising from reaction with the epoxide was seen. In
order to corroborate lack of reactivity 3 more
equivalents of the alane reagent were quickly in a
separate reaction vessel and cannula transferred to the
first. It was allowed to react overnight at room
temperature. After the usual workup, the vinyl oxirane
was recovered unchanged.
Preparation of 1,l-cyclohexyl-2-vinyl-oxirane (75)
A three necked flask fitted with vacuum adapter,
stirring bar and thermometer was flame dried under
vacuum and 19.6 g (0.11 moles) of allyldimethyl
sulfonium bromide over an atmosphere of argon. The
sulfonium salt was prepared by stirring a mixture of
dimethylsulfide and allylbromide overnight. THF, 100
ml, was charged into the flask and cooled to 0°C; 44 ml
of 2.5 M n-butyl lithium (0.11 moles) were added and
stirred for 30 min. The color of the ylide was deep
red. When 1.8 g (0.018 moles) of cyclohexanone were

69
injected into the flask, the color turned from red to
faint yellow after addition. The reaction mixture was
allowed to come to room temperature and react for 2
hrs. It was quenched with 75 ml of ice water; extracted
with ether and dried over Na^SO^. Yield was 57% by G.C.
Short path distillation, 25 mm Hg at 65-70°C, afforded
the oxirane contaminated with cyclohexanone. Washing
with 10% NaHSO^ and passing through a small plug of
SÍO2 using 20% ether/pentane gave the pure oxirane. IR
(neat) 3100- 2860 (s), 1640 (m), 1447 (s) cm-1; *H NMR
(300 MHz, CDCL3) 5.82-5.71 (m, 1H), 5.47 (dd, 1H, J=
17, 2Hz), 5.31 (dd, 1H, J= 11, 2 Hz), 3.18 (d, 1H, J= 5
Hz), 1.77- 1.68 (m, 2H) 1.60-1.45 (m,8H); 13C NMR
(CDC13) 133.2, 119.8, 64.7, 64.3, 35.4, 29.3, 25.5,
25.0, 24.7 ppm.
Synthesis of 1,l-dimethvl-2-vinyl-oxirane (76)
To a flame dried flask fitted with vacuum adapter
and septa, 5.16 g of Na3C03 ( 48.7 mm) were added.
MCPBA (7.89 g, 45.7 mm) were added under an atmosphere
of argon as well as 14 ml of ether (dry). The flask was
cooled to 0°C and 1.4 ml (12 mm) of 2-methyl-2,4-
dimethyl-pentadiene were charged into the flask. The
mixture was allowed to react for 45 min. The reaction
mixture was filtered to remove solids and most of the
ether distilled through a vigreaux column. Vacuum

70
transfer of the remaining residue afforded 9 mg (0.092
mm) of epoxide 94% pure which would be used directly in
reaction with the Rathke alane.
1H NMR (300 MHz, CDCL3) 5.64 (m, 1H), 5.38 (dd, 1H, J=
17, 2 Hz), 5.27 (dd, 1H, J= 11 Hz,2 Hz), 3.14 (d, 1H,
J= 5 Hz), 1.28 (s, 3H) , 1.20 (s, 3H); 13C NMR (CDC13)
125.9, 120.0, 64.4, 60.2, 30.9, 24.6 ppm.
Reaction of 1,l-dimethyl-2-vinyl-oxirane with Rathke
Alane
A 0.3 mm solution of the Rathke alane was prepared
in 8 ml of THF following the general procedure for the
alane formation. An ether solution of the oxirane 16_
along with a standard were added at -60 °C. The
reaction was monitored for 50 minutes no observable
product arising from reaction with the epoxide 7_6 was
seen. In order to test the formation of the alane 0.01
ml of methylene cyclohexane oxide was added to react
with the alane. Conversion of 5_3 to the hydroxy ester
60 was evidenced by G.C. monitoring within 20 min.
Oxidation of hydroxy ester (60) to enone (80)
Hydroxy ester 6_0 (0.632 g) was oxidized using
o
1.789 g of ground 3A molecular sieves, 3.764 g of PDC
and a catalytic amount of dry acetic acid in methylene
chloride. The procedure has been previously described
on page 66. After 3 hrs, the slurry was filtered

71
through a sintered glass funnel filled with a mixture
of SiC>2 and 10% MgSO^, eluting with ether. This gave
0.516 g of enone 80_ (82% yield). 1HNMR ( 300 MHz, CDC13)
3.28 (s, 2H), 2.40 (m, 4H), 1.98 (m, 2H), 1.94 (s, 3H),
1.43 (s, 9H); 13C 199.8, 170.6, 157.9, 129.8, 80.4,
37.1, 32.7, 31.8, 27.9, 22.0, 21.5.
PDC oxidation of methylene hydroxy ester (56)
Compound 5_6 (58.8 mg) was oxidized with 0.506 g
PDC, 0.722 g molecular sieves, a catalytic amount of
acetic acid and 10 ml of methylene chloride as
previously described. It was allowed to react
overnight. Filtration through SiO^ and 10% MgSO^ gave
the crude enone 7_9 which was purified by using 30%
ethyl acetate/pentane (63% yield). 3HNMR(60 MHz, CDCl^)
3.16 (s, 2H), 2.80-2.20 (m, 4H), 2.09 (s, 3H), 1.47 (S,
9H); 13CNMR (CDC13) 208.0, 172.8, 169.5, 149.8, 80.9,
34.1, 31.8, 29.6, 28.0, 17.5 ppm.
Oxidation of cyclopentene hydroxy ester (57)
The alcohol, 0.149 g (0.753 mm), was oxidized with
o
the following: 0.73 g of ground molecular sieves, 3A,
1.500 g of PDC and a catalytic amount of acetic acid in
methylene chloride. After reacting for 1 hr the slurry
was filtered through SiC^ and 10% MgSO^, to give 0.106
g of 2-(methylenecarbo-t-butoxy)-3-cyclopenten-l-one
(77) (84% yield). 1HNMR (100 MHz, CDC13> 6.11 (m, 2H),

72
3.24-3.10 (m, 1H), 2.93 (s, 2H), 2,61-2.30 (m, 2H),
1.43 (s, 9H); 13CNMR (CDC13) 217.0, 170.5, 132.2,
128.4, 80.9, 48.5, 42.4, 36.0, 28.0 ppm.
Oxidation of cyclohexene hydroxy ester (61),
o
Finely ground molecular sieves (0.786 g, 3A) were
activated by heating vigorously for 5 min. in a 25 ml
flask under vacuum . After allowing to come to room
temperature 1.18 g of PDC (3.14 mm) were added along
with a stirring bar and and 12 ml of freshly distilled
methylene chloride. The mixture was placed under argon,
and cooled with ice water. At this time the hydroxy
ester, 0.224 g (1.06 mm), was charged into the flask
via syringe followed by a catalytic amount of dry
acetic acid. The slurry turned dark brown upon addition
of the alcohol. After 1 hour, the mixture was filtered
through 10% MgSO^/SiO^ and the solids washed with
ether. The yield of 2-(me thylenecarbo-t-butoxy)-3-
cyclohexen-1-one (78) was 97% (0.2163 g). IR (neat)
1720 , 1148 cm"1; 3 HNMR (100 MHz, CDC13) 6.0-5.5 (m,
2H) , 3.4 (bs, 1H), 2.8-2.2 (m, 6H), 1.4 (s, 9H); 13CNMR
(CDC13) 209.7, 171.2, 128.4, 127.5, 80.7, 45.1, 38.1,
36.3, 28.1, 26.4 ppm.
Hydrolysis of t-butyl ester (61) to the acid (90)
To a 100 ml flask were added the following, 2.0 g
of hydroxy ester 6J_ (0.013 m), 40 ml of methanol and

73
1.79 g of K^CO^. The mixture was stirred for 2 days
after which it was acidified with 6M HC1 to a pH of 2,
extracted with ether (4x35 ml) and dried over MgSO^.
Evaporation of solvent gave 1.4821 g of 9_0 in 73%
yield. IR (neat) 3680-2800 (s), 1710 (s), 910 (m) cm 3
1HNMR (200 MHz, CDC13) 6.25 (bs, 1H), 5.64 (m, 1H),
5.42 (d, 1H), 3.60 (m, 1H), 2.66-1.10 (m, 7H); 13CNMR
(CDC13) 177.7, 127.7, 127.5, 71.8, 40.6, 38.4, 30.2,
24.2 ppm; Mass spectrum (70 eV) m/e 138 (3), 110 (2),
84 (12), 74 (47), 59 (80), 45 (51), 31 (100), 28 (69).
Lactonization of cyclohexene hydroxy acid (90)
A 25 ml three necked flask was fitted with
thermometer, stirring bar, and vacuum adapter. It was
flame dried under vacuum and flushed with argon.
Triphenyl phosphine (0.5128 g) were added under a
positive pressure of argon followed by 20 ml of dry
THF. The hydroxy acid (0.210g) dissolved in THF was
charged into the flask and the reaction mixture cooled
to 10°C. At this point, 0.29 ml of DEAD reagent was
added and a catalytic amount of acetic acid. After
reaction was complete, the solvent was evaporated in
vacuo and the crude cis lactone was purified by flash
chromatography using 40% ethyl acetate/pentane to give
0.140 g of lactone 9_1 in 78% yield. IR (neat) 3011,
1762, 1273 cm-1; 1HNMR (CDC13, XL-200) 5.90 (m, 1H),

74
5.48 (d, 1H), 4.76 (m, 1H), 3.02 (m, 1H), 2,76 (AB
quartet, 1H), 2.30 (dd, 1H), 2.20- 1.10 (m, 4H); 13CNMR
(CDC13) 176.8, 128.7, 125.6, 78.1, 35.8, 34.4, 24.6,
19.1 ppm; High resolution mass spectrum calculated:
138.0680, found: 138.0685.
Preparation of MTM-hydroxy acid (87)
To a 50 ml one neck flask were added the
following: 1.03 g of hydroxy ester 8_7 (3.41 mm), 15 ml
of absolute ethanol, 1 ml of water, and 0.660 g of KOH
(11.8 mm). The mixture was stirred and heated at 43-47
C under argon for 13 hrs. The ethanol mixture was
concentrated in the rotovap. The slurry was acidified
with 1.2 M HC1 to a pH of 2, extracted with ether (4 X
20 ml) and dried over MgS04. This afforded 0.6842 g of
a brown, very viscous oil (82% yield) which was
lactonized without further purification. IR (neat)
3700-2800 (s), 1715 (s), 1430 (w), 1245 (w), 1050 (s)
-1
cm
Preparation of cis-MTM-lactone (88)
A 25 ml three necked flask was fitted with
thermometer, stirring bar and vacuum adapter. It was
flame dried and flushed with argon. Triphenylphosphine,
0.197 g (0.730 mm), was added under an argon
atmosphere; 15 ml of dry THF were charged into the
flask followed by 110 mg of the hydroxy acid 87

75
(0.447mm) in THF. The mixture was cooled to 10°C.
Dropwise addition of the DEAD reagent, 0.11 ml (0.699
mm), followed and allowed to react for 1 hr. The
solvent was evaporated and flash chromatography using
35% ethyl acetate/pentane gave the E and Z MTM lactones
(90% yield by G.C.). IR (CC14) 3300-2810 (m),1775 (s),
1165 (m) cm-1; XH NMR (300 MHZ, CDCL3) Z-isomer 5.58
(t,
1H)
t
5.09
(t,
1H)
t
4.63
(AB
quartet,
2H ) , 4
.04
(d,
2H) ,
3.
51
(m,
1H)
, 3.
02
-2.92
(dd
, 1H
/
J=
18
, 10
Hz ) ,
2.65
-2.
48
(m,
1H)
, 2.
43
-2.40
(dd
, 1H
f
J=
18
, 2.
5 Hz ) ,
2.44
-2.
35
(m,
1H)
, 2.
22
-2.18
(in,
1H)
r
2.16
(s,
3 H )
r
1.85
-1.
72
(m,
1H)
? E-
isomer
5.57
- 5.
50
(m
r
1H) ,
5.
01
(t,
1H)
r
4.63
( s ,
2H )
t
4.17-
4.01
(m,
2H) ,
3
.34
(m,
1H) ,
2.98
-2.
89
(dd
, 1H
, J =
18
,9 Hz ) , 2
.63-
2.
55
(m
, 1H) ,
2.54
-2.
47
(dd
, 1H
, jj
18
, 1.6
Hz )
, 2.
43
(m
/
1H) ,
2.
31-
2.22
(m
r
1H) ,
2.15 (s
1
3H ) ,
1.94
-1.81
(m,
1H) ;
13c
NMR
(CDC13)
z
-isomer
176.
7,
148 .
3, 121.1
/
85.
4,
74 .
6,
65.0 ,
44.3
, 37.
3, 31.4,
26 .
6,
14.0
; E-
isomer
176.
6, 148.
5,
119.
6,
85
.7,
74.6
, 64
.3
. 40.
25,
36.3
t
31 .
5,
30.
8,
14.0;
High resolution mass spectrum calculated: 228.0820:
found 228.0853

APPENDIX
LIST OF REAGENTS PURCHASED FROM SPECIFIC CHEMICAL
SUPPLY HOUSES
2-cyclopentenone- Aldrich
DIBAl- Aldrich
n-buty11ithium- Aldrich
diethyl aluminum chloride- Aldrich
PDC- Aldrich
MCPBA- Aldrich
triphenylphosphine- Aldrich
MTM chloride- Aldrich
EthyltrimethyIsilylacetate- Aldrich
t-butyl acetate- Aldrich
sodium hydride- Alfa
Aldrich Chemical Co.
P.O. Box 355,
Milwaukee, Wisconsin 53201
Alfa Products- Thiokol/Ventron Division
P.O. Box 299
152 Andover Street
Danvers, Massachusetts 01923
76

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Campbell and Mapi Cuevas.
77

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33
K.B. Sharpless And T. Katsuki, J â–  Am. Chem. Soc.,
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BIOGRAPHICAL SKETCH
Mapi Cuevas was born on March 18, 1952, in Rio
Piedras, Puerto Rico. She received a B.S. in chemistry,
magna cum laude, from the University of Puerto Rico in
May 1973 after three years of undergraduate studies.
From August 1973 to June 1975 she taught science and
mathematics at Baldwin High School, Guaynabo, Puerto
Rico and was named Science Chairperson from 1974-1975.
In the summer of 1975, after moving to Gainesville, she
worked for three years at Golden Hills Academy. A
career move to North Fort Myers to teach at the local
high school followed. Ms. Cuevas was science instructor
at North Fort Myers High school until 1983 when she was
admitted to graduate studies at the University of
Florida. From 1983 to 1986 she was awarded a GPOP
Fellowship by the Graduate School. From 1987 to 1988
Mapi co-authored a physical science textbook for
Harcourt Brace Jovanovich and was curriculum
coordinator of the undergraduate organic laboratory at
UF for the 1986-87 school year. Most recently she is an
adjunct instructor of chemistry at Santa Fe Community
College.
80

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
Merle A. Battiste, Chairman
Professor of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
William R. Do1bier, Jr/ j
Professor rh^mi <= t-r-\A ^
of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
William M.Jones\3
Professor of Chemistry
I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
John (S. Dorsey
AsNsooiate Professor of C

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of Doctor
of Philosophy.
Professor of Biochemistry and
Molecular Biology
This dissertation was submitted to the Graduate Faculty
of the Department of Chemistry in the College of
Liberal Arts and Sciences and to the Graduate School,
and was accepted as partial fulfillment of the
requirements for the degree of Doctor of Philosophy.
December 1988
Dean, Graduate School

UNIVERSITY OF FLORIDA
3 1262 08556 7732


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