One and two-electron cyclizations of pi-bonds

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Title:
One and two-electron cyclizations of pi-bonds
Physical Description:
vi, 87 leaves : ill. ; 29 cm.
Language:
English
Creator:
Xie, Yongping, 1956-
Publication Date:

Subjects

Subjects / Keywords:
Ring formation (Chemistry)   ( lcsh )
Intermolecular forces   ( lcsh )
Chemistry thesis, Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre:
bibliography   ( marcgt )
non-fiction   ( marcgt )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1995.
Bibliography:
Includes bibliographical references (leaves 81-86).
Statement of Responsibility:
by Yongping Xie.
General Note:
Typescript.
General Note:
Vita.

Record Information

Source Institution:
University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 002046396
oclc - 33424646
notis - AKN4331
System ID:
AA00002058:00001

Full Text












AND


TWO-ELECTRON


CYCLIZATIONS


OF PI-BONDS


YONGPING


A DI
OF THE


SSERTATION PRESENTED TO THE GRADUATE SCHOOL
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY


UNIVERSITY


OF FLORIDA


1995






























This


dissertation


is dedicated


my parents
















ACKNOWLEDGMENTS


would


like


especially


thank


advisor


Eric


Enholm


advice,


encouragement,


patience


unwavering


support


throughout


this


research


writing


following


dissertation


feel


fortunate


have


worked


with


such


profess


ional.


thank


Department


of Chemistry


University


Florida,


memb


ers


committee


helped


with


completion


of this


research.


Finally,


thank


wife


and


daughter


their


help


understanding.

















TABLE


ACKNOWLED GEMENT S


ABSTRACT


OF CONTENTS


S ii


. S S S .* . 0 *S . *. S S . v


CHAPTERS


INTRODUCTION. . . .. .. . .. ... . 1


A SYNTHETIC

HALICHONDRIN


APPROACH

B USING


TO THE


C44-C54


A MOFFAT-TYPE


PORTION


CYCLIZATION


. .. 20


ynthetic
ynthesis
ynthesis


Plan
of th
of th


of the
e C49-
e C44-


to C54
sununit
sununit


Precursc


* S S S
* ft S S


* a a a
* S S S


,r . 21
. .. .. ... 22
. .. ... 27


FREE


RADICAL


CYCLIZATIONS


OF ALDEHYDES


AND


c4J-


UNSATURATED


KETONES


PROMOTED


BY O-STANNYL


KETYLS


. 32


CYCLIZATIONS


FRAGMENTATION


REACTIONS


ALDEHYDES


PROMOTED


BY O-STANNYL


KETYLS


General ......... .....
Experimental Procedures


and Results . .. .. . 5


LIST


OF REFERENCES


BIOGRAPHICAL


SKETCH


S. . .. .. . ... .. .. 81

* . . . . . . . .. . 87


EXPERIMENTAL .. ........ ...
















Abstract


of Dissertation Presented to the Graduate School


of the


University of Florida


in Partial Fulfillment


of the


Requirements

ONE AND TW


for the Degi

)- ELECTRON


:ee


of Doctor of Philosophy


CYCLIZATIONS OF PI-BONDS

By


Yongping X:

May, 1995


Chairman:


Major Departme


Eric Enholm
nt: Chemistry


This


dissertation


investigated


intramolecular


ring


formation


between


alkenes,


carbonyls,


other


X-bonds


one-


two-electron process.


first


area


study


included


synthetic


approach


towards


portion


antitumor


natural


compound halichondrin


B by


enantiospecific


route.


After


step


synthesis,


an a,P-unsaturated ester was


obtained which


was


studied


substrate


Moffat-type


Wittig-Michael


cyclization


reaction.


Furthermore,


a great


deal


important


synthetic methodology


on heterocycles


discussed.


second area


study


investigated


reactivity


intramolecular


vclizations


promoted


AV


a tin


ketvl


Under


I


I









allylic


0-stannyl


ketyl.


Upon


subsequent


hydrogen


atom


abstraction,


a tin


enolate


was


afforded


which


participated in


intramolecular


directed


aldol


reaction.


Although


substrates


with


two


carbonyls


can


lead


several


possible


aldol


products,


only


single


product


was


obtained.


three


new


stereocenters


resulted


annulated


bicyclic


alcohols


in a highly


stereoselective manner,


as determined by


single


crystal


x-ray


analysis.


reaction


represented


very


mild


usually


alternative


requires


strong


metal


hindered


enolate

bases


formation


such


which


LDA


strongly


reductive


dissolving


metal


conditions


achieve


success.


third


area


study


investigated


possibility


intramolecular


radical


elimination


reactions.


Allylic


phenyl

examined

showed t


sulfone


under


hat


sulfide)


the

tin


radical

ketyl ab


and


reaction


*stracts


aldehyde p

conditions.

hydrogen fa


carterr

The


sister


were


studies


than


adds


to double bond to promote an


elimination reaction.















CHAPTER


INTRODUCTION


Man y


biologically


interesting


molecules,


such


polyether


antibiotics


and


lactones,


have


and


6-membered


heterocyclic


activity

interest


rings.

these

their


structural


compounds


synthesis,


have


complexity

stimulated


especially,


and biological

considerable


formation


their


ring


system.


Among


many


cyclization methods,


ring-


formation by functionalization


of a double bond is


one


of the


most


used


reported


reactions


and


unsaturated


aci


organic


developed

ds into i


the


synthesis.

conversion


.odolactones,


Since


Bougault


P,Y-


related


8,y-

and


interesting


methods


have


been


exploited,


showing


utility


this


new


synthetic


tool.


basic


procedure,


now


referred


halolactoniza-


tion,


was


to dissolve


unsaturated


acid


aqueous


sodium


bicarbonate,


next


treat


with


solution


iodine


aqueous


potassium iodide;


iodolactone


would separate


from


reaction medium.


conversion


of 6,r-pentenoic


acid


into the Y-iodolactone


is a


simple example


(Scheme


1-1) .









which


carboxylate


then


undergoes


anion


give


intramolecular


halolactone


displacement


product.


CH2=CHCH2CH2CO2H


KI, 12


NaHCO3


Scheme 1-1


Dowle


and


Davies


reviewed


uses


halolactonization


application


synthetic


tool


organic


chemistry


(Scheme


UNSATURATED ACID


Process 2







OTHER PRODUCTS


Process 1


HALOLACTONE


DEHALOGENATED


UNSATURATED


LACTONE


LACTONE


Scheme 1-2


Processes


are


of parti


cular


value


syntheses.


In Kishi's


first


total


synthesis


of halichondrins,


vitamin


and


vitamin


unsaturated


acids


were


subjected


odolactonizations,


followed


reductive


removal


odine


with


tri-n-butyltin


hydride


This


gave


y-lactones


r U









render


unsaturated


lactones


form


intermediates


natural


products.


Recently,


variety


investigations


factors


affecting


stereochemistry


ring


formation


been


carried


out.


The


kinetic


NaHC03


O/CH


thermodynamic


I2/MeCN)


conditions


used


reaction


can


determine


high


stereoselectivity


towards


cis-


trans-


iodolactones.


substituent s


starting


compound


configuration


double


bond


can


also


strongly


influence


stereochemistry.


Tetrahydrofurans


tetrahydropyrans


can


formed


from


starting


materials


containing


unsaturated


hydroxy


groups


in a haloetherification


reaction


Scheme


1-3) .


reagents


87%


.OBn


OBn


Hg(II)
77%


HgCl


Scheme 1-3


I2/NaHCO3,


Hg(OAc)


, PhSeC1,


III)


have


induced


HOH


^ .OH









in acetonitrile


under


reflux


had


undergone


spontaneous,


Michael-type,


ring


closure


to give


furanose


C-glycoside


HOH2C
OH

0 O


HOH2


Ph3P=CHX


8a. X=CN
8b. X=CO2Me


.CH=CHX


(":B


HOH2C


HOH2C


base


H=CHX


HOH2I


12a, X=CO2Me
b. X=CN


Scheme 1-4


major


compound


however,


compound


was


treated


with


methanolic


sodium


methoxide


methanol


and


benzene,


isomer


predominated.


This


observation


suggested


that


isomer


was


kinetic


product


and


e-ca


talyzed


equilibration of


gradual


conversion


more


OCH2X
(1 O









Salomon6f


synthesized


halichondrins;


Keck,


Kanchensky


and


Enholml3


synthesized


pseudomonic


acid


(Scheme


1-5)


using


the Moffat-type


reaction.


(Ph)3PCH=CHCOCH3


TBSO #^..


TBS 4.


CH2=CHCOCH3
OH


TS c/l '
dlS


14 15


O(CH2)gCO2H


H"It.


Pseudomonic Acid C


Scheme 1-5


synthesis


of heterocycles


containing nitrogen


also


possible


proper


starting


substrates


are


used.


direct


intramolecular


cyclization


amines


and


double


bonds


rarely


been


employed


owing


difficulties


connected


with


this


kind


reaction.


synthesis


bicyclic


ring









cyclized


products


with


various


electrophiles,


such


Br2,


HgC12


and PhSBr14


(Scheme


1-6) .


85%


Scheme 1-6


Furthermore,


oxygen-


nitrogen-centered


anions


attack


upon


allylic


system


bearing


leaving


group,


intramolecular


process


may


occur


form


heterocyclic


compounds.

pathways w


There


yhich


are


are


three


relevant


types


these


anionic

studies,


p-elimination


summarized


Scheme


1-7.


15,16


intramolecular version,


heteroatom


tethered


allylic


function


several


sitesl6


Scheme


1-7)


While


most


common


transformation


exo-trig


depicted


19 -*20,


worth


noting


that


examples of 23-+24,


with


leaving group part


the tether,


have


been


Common


successful


leaving


without


groups


here


additional

include


structural


wide


features.


variety


epoxides,


mesylates,


tosylates and halides,


to mention a


few.


The

reactions


bond-formation


can


and


bond-breaking


regarded


tandem


sequence


addition


SN'

and


elimination.


present


evidence,


not


clear









C'u


oz J


C'


M
-Xe


-xo


Scheme 1-7


dependent


release


leaving


group


the


same


transition s

intermolecular


tate


anionic


There

SN' e


are


hundreds


eliminations,


examples


unfortunately,


less


known


about


intramolecular


version.


Only


total


about


examples


are


known


and


more


than


half


these


reactions


exist


fairly


recent


literature


since


1980.


Although


the hardness


and sometimes


variable


nucleophilic


properties


of alkoxide


ions


can


prove


to be a disadvantageous


synthetic


utility,


these


factors


can


overcome


the


leaving


group


suitable.


For


instance,


regioselective


monotosylation


diol


leads


directly


to a-agarofuran.


anti-relationship


between


leaving


group


and


alkoxide


facilitates


reaction.


Carbinol


follows


an SN'










CH3


TsCI


CH3


CH3


CH3


--IIH
,CH3

CH3


CH3


CH3

'CH3


NHCO2t-Bu


TsOH


CH2C12


CO2t-Bu


Scheme 1-8


Another


very


important


methodology


obtain


polyfunctionalized


tetrahydrofurans


and


tetrahydropyrans


epoxidation


olefin,


followed


ring


sure


with


catalytic


subsequent


amount


Sharpless


camphorsulfonic


asymmetric


acid


epoxidation


CSA)


applied,


ring


closure


can


create


two


chiral


centers.


shown


Scheme


1-9,


tartrate


ester


can


produce


two


enantiomers


from


same


compound,


followed


type


ring


CH3


/CH3

CH3


w .










Cywin


recently


synthesized


hemibrevetoxin


and


antibiotic zincophorin.


a


CH2OH


CH20H


CH2OH


CH20H


C CH2IOH


(a) Sparpless epoxidation (b) CSA, CH2C1l

Scheme 1-9


Chapter


this


dissertation


investigated


synthetic


approach


towards


portions


Halichondrin


enantiospecific


route


that


shorter


and


more


accessible


The


than


proposed


only


highly


currently


convergent


available


synthesis


synthesis.


utilized


6e, 6f


two


subunitss"


constructed


10-13


steps


that


arise


from


carbohydrates


and


asymmetric


epoxidation


technology.


Key


steps


route


that


lead


great


simplification


include


application


Moffat-type


Wittig-Michael


clization


reaction


using


unsaturated


ester


substrate,


A~~~~ fl t- .


i A .


ft


II










precursor,


the


formation


stablized


ylide


acyl


imidazolide.


Chapter


this


dissertation


will


show


aldol


cyclizations


initiated


free


radicals.


free-radical


reaction


chemical


process


which


molecules


having


unpaired


will


electrons


focus


are


ring


involved.


formation


Part


this


between


dissertation


special


type


free


radical


and


double


bonds


This


general


type


reaction


become


important


organic


synthesis.


Most


radical


cyc


lizations


involve


double


triple


bonds


various


substituents


simple


alkyl


substituted


carbon


centered


radical


may


considered


essentially


nucleophilic


character


because


inductive


effect


the


alkyl


groups;


contrast,


the


trifluoromethyl


radical


electrophilic.


V
9
I
I
9
I
I


EWG


LUMO


SOMO


9
9
9
9
9
9
9
9
9
9
9


Figure 1-1

Orbital interaction between nucleophilic radical and electron-poor
alkene









These


results


can


described


simplified


frontier


molecular


orbital


theory.


23,24


singly


occupied


molecular


orbital


SOMO)


radical


orbital


selects


LUMO)


either


Figure


the


lowest


or the


unoccupied


highest


occupied


molecular


molecular


orbital


(HOMO


(Figure


1-2)


of the


alkene


system.


R.

SOMO


EDG


HOMO


Figure 1-2


Orbital interaction between electrophilic radical and electron-rich
alkene


Electrophilic


radicals


have


SOMO


energies


which


are


that


interaction


with


the


HOMO


electron


rich


alkene


dominant,


whereas


the


effect


electron


withdrawing


substituent


olefin


reduce


LUMO


energy


such


extent


that


this


reaction


becomes


favored


nucleophilic


radicals.


Unlike


cationic


intramolecular


cyclizations


which


provide


six-membered


rings,


five-membered


rings


are


dominant










investigations


prefer


radical


strain-free


ring


chair-like


formation.


transition


The cyclizations

state, selecting


substituents


in pseudoequatorial


positions on the


ring.


Although


the


there


combination


are many methods


tributyltir


to provide

hydride


free


(TB


radicals,

TH) and


azobisisobutylnitrile


(AIBN)


the


most


popular


and


classical


method


radical


reactions.


The


thermal


decomposition


AIBN


produces


cyanoisopropyl


radicals


which


are


usually


reactive


enough


abstract


substrate' s


hydrogens,


are


capable


abstracting


hydrogen


atom


from


weak


Sn-H


bond


tributyltin


hydride


(TBTH)


give


designed


tributyltin


radical


(Scheme


1-10)


N2t


nBu3Sn- H


+ nBu3Sn*


Scheme 1-10


TBTH


commercially


available


can


readily


prepared


For


more


than


twenty


years


utilization


- n m -


ILJI J -..'a .C- a 4- -.- a -


>____/


~Hh~


rrL ~i M Ln


I


A


1 1 LJ*i1r v


k- ~


~Uh


k









relegated


to the


area


of polymer


chemistry.30


New


information


many


kinds


radicals,


their


properties


and


use


organic


synthesis


simply


erupted


publications.


More


and


more


complex


molecules


have


been


synthesized


radical


are


reactions


from


advantages


worldwide


free


radicals


research


over


groups.


ions


There


organic


synthesis


harsh


Neutral


react ions


mild


cations


reaction


anions.


conditions


Solvation


contrast


effects


are


much


less


important


neutral


free


radical


reactions.


Radical


reactions


not


necessarily


need


protecting


groups.


Additionally,


regio-


stereo-


and


chemoselectivities


some


free


radical reactions


are high and predictable.


There


atom


are


group


broad


abstraction


classes


(Scheme


free


1-11)


radical


and


reactions:


addition


multiple


bonds


nBu3Sn*

39


BusSn-X

42


X=Halogen,


-SeR',


-NO2


Scheme 1-11


Deoxygenation


suitable


reactions


sulphonate


by traditional


ester with


ionic displacement


lithium aluminium hydride


are


often


sluggish


or unsuccessful


with


carbohydrates.


Barton


and


McCombie's


research


sulfur-related


deoxygenation


-SR',









shown


Scheme


1-12,


reaction


believed


proceed


reversible


addition


organostannyl


radical


thiocarbonyl


group


followed


fragmentation


intermediate


carbon


centered


radical


give


a carbonyl


group


with


concomitant


liberation


derived


alkyl


radicals


nBu3Sn*


.SnBu3


X


nBu3Sn*

39


.SnBu3



X


X=SMe, Ph, OPh, OC6F5, SPh


Scheme 1-12


hydroxy


compounds


include


primary,


secondary,


tertiary


diols.


will


use


this


methodology


total


synthesis


halicondrin


radical


intermediate


produced


this


method


can


also


undergo


further


intramolecular


cyclization


through


a chair-like


transition


state


(Scheme


1-13).


Cor


lact


one


important


drug


precursor,


was


prepared


alkyl


radical


which


was


formed


l









steroselectivities


(Scheme


1-13)


The


main


criticism


regarding


free


radical


radical


chemistry


been


planar


that


entity


carbon


and


centered


hence


high


stereoselection


impossible


carbon-carbon


bond


forming


reactions.


Motherwell


(page


rebuffs


this


argument


saying


that


"the


planarity


enolate


anions,


iminium


ions


even


free


carbocations


not


hindered


the


effective


operation


stereoelectronic


control


elements


leading


stereospecific reactions.


nBu3SnH
ATIRN/PhMe
A
Ph


Ph*1"


OMe


Ph" 0***"


"'*OH


Scheme 1-13


Both


linear


and


angular


triquinane


natural


product


skeletons


have


been


constructed


tandem


radical


cyclizations


step.


29e, f


example


f tandem


Ph "


".,,,o


.









alkyne.


This


demonstrates


evidence


that


sometimes


free


radical


cyclization


reactions


can


give


an easy


solution


complex


natural


product


synthesis.


second


intramolecular


part


this


cyclizations


dissertation


free


radicals


will


focus


generated


from


ketone


carbonyls.


When


TBTH


reacts


with


-,,il


several


carbonyl


"" Ill


Scheme 1-14


functions


in polar


solvents


under


Lewis


acid


catalysis


TBTH


donates


hydride


carbonyl


carbon


center


give


alkoxide.


Conversely,


free


radical


pathway


can


also


occur


with


nonpolar

tributylt:


solvents,

in radical


AIBN,

adds


and


heat


oxygen


cheme

atom


carbon-oxygen


double


bond


to form


O-stannyl


ketyl


Bu3Sn-H/AIBN
PhH, 80C


SnBu3


BuSn-H~


SnBu3


Bu3Sn*


Scheme 1-15


This


carbon-centered


radical


can


engage


variety









radical


can


now


repeat


process.


The


free


alcohol


obtained when


the tin alkoxide


ketyl


can


is quenched with


regarded


water.


pseudo-protected


radical


anion,


where


O-Sn


bond


certain


degree


ionic


character


electronegativity


differences


(Scheme


1-16)


between


oxygen


and


tin.


apparent


challenge


synthetic


chemist s


investigate both


radical


and anionic


elements of


reactivity which are presented by this


species.


nBu3


+- SnBu3


8- "u
O-SnBu3


Scheme 1-16


Prior


Enholm's


studies,


very


papers


coupling

reported.


ketones


39,40,41


From


aldehyde)


nonreagent


and

based


olefins

methods,


were

both


photochemical


electrochemical


approach


can


produce


ketyl


radical


anion.


35,36


early


1986,


Beckwith


and


Roberts


gave


first


example


(Scheme


1-17)


aldehyde


coupled


system.


olefin


reaction


with


TBTH


undoubtedly


assemble


involves


ring


bicyclic


closure of


ketyl


reaction


Although


was


yield


slow


was


require


excellent, t

i additional


:hey

TBT]


found

H and


that

AIBN


completion.


They


thought


that


formation









activated


alkene


would


solve


problems


They


used


a more


electrophilic


double


bond


uridine


ring


system


cyclization


an aldehyde


O-stannyl


ketyl.


N
N


CO2Me


TBTH/AIBN0
PhH, 800C


90%


.Me
S~


Scheme 1-17


1989,


aldehydes


Enholm


readily


Prasad


cyclized


demonstrated


onto


that


tethered


ketones


olefinic


appendages


shown


in Scheme


1-18,


cyclized


products


were


produced


5-exo-trig


cyclization


activated


olefin.


yield


cyclization


was


obtained


when


unactivated


olefin


system


was


used.


Enholm


Burroff


also


obtained


both


TBTH/AIBN


PhHK


800C


73%


62


Scheme 1-18


spiro


fused


bicyclic


ring


systems


tandem


cyclizations


with


this


methodology


Additionally,


they


examined


behavior


of a,p-unsaturated


ketones


and


their


cyclizations


addition


monocyclic


activated


bicyclic


olefins.


cyclopentanes


Highly


were


functionalized


obtained.


* -S *5 1


.,.",,O


jh


i -I i


*


1 I


r- .


f1









was


discovered


which


now


believe


first


examples


of a free


radical aldol-like


reaction promoted by TBTH.


Chapter


this


dissertation


discusses


the


intramolecular


coupling


aldehydes


(a,J-unsaturated


ketones


with


tributyltin hydride


and our


interesting


results.


Since


both


aldehydes


and


ketones


can


form


O-stannyl


ketyls,


more


than


one


product


can


obtained by


different


pathways.


Deuterium-labeling


single


crystal


x-ray


studies


provided


possible cyclization mechanisms.















CHAPTER


A SYNTHETIC


APPROACH


TO THE


C44-C54


PORTION


OF HALICHONDRIN


USING


A MOFFAT-TYPE


CYCLIZATION


Halichondrin


(Scheme


antitumor


polyether


macrolide


isolated


from


Halichondria


Okadai,


black


sponge


found


Pacific


coast


Japan,


early


1986


Yoshimasa


Hirata


and


Daisuke


Uemura


6a,b


They


obtained


only


very


minute


from


a huge


sample


sponges.


Scientists


from


Japan


National


Cancer


Institute


confirmed


that


Halichondrin


currently,


medicinally


important


antimitotic


agent


which


shows


great


promise


with


remarkable


preliminary


cytotoxicity


studies


CH3


CH3


H H


45 H


H -
H3 C


HO,,..
1.51


HO,,..


'CH3









structure


molecule,


determined


X-ray


analysis,


asymmetric


long


centers,


unbroken


an array


chain


carbon


of cyclic


ether


atoms,


rings,


which


two


are


cis-fused


two


are


tetrahydropyrans,


ketal


linkages,


dioxaspiro [4


which


4]nonane


are


system.


The


spiro,


absolute


involving


stereoc


1,6-


hemi


structure


crystal


halichondrin


x-r


been


bioactive


correlated


relative,


single


the


bromophenacyl


ester


of norhalichondrin


Several


synthetic


constructions


portions


halichondrin


Kim


and


Salomon6f


have


appeared


and


recent,


lengthy,


total


synthesis


been


completed


Aicher


Spring


1992


.We


have


started


synthetic


than


approach


other


which


synthetic


highly


route.


convergent


this


and


shorter


dissertation


will


only


concerned


with


left


side


C44-


precursor.


Synthetic


Plan


Precursor


features


route


are


shown


Scheme


2-2,


are


numerically


listed


below:


target


can


antithetically


disconnected


acylic


redu


fragment


later


assuming


proper


alcohol


ketone


which


stereochemistry


can


well-


44 tQ -54.













RO.


R .


CH3
mCH3


CH3


C44-C5 4 SEGMENT


RQ RQ
S
C


reduce C50 to alcohol later
by C51 1,2-chelation control


44
CO2CH3


II
O CH3


C02CH3


PPh3


68 0
C49-C54 SUBUNIT


II
O CH3


= 4-methoxybenzyl
- SiPh2tBu


C44-C48 SUBUNIT


Scheme 2-2


spiroketal


thermodynamic


and


can


be equilibrated


with


acid


water.


stereochemistry


of C48-C49


is equatorial


can


be epimerized


a Moffatt-type


equilibrati


on.


Disconnection


of the


C48-C49


double


bond


reveals


simple


chiral


nonracemic


subunits,


(C49


-C54)


which


can


generated


carbohydrate


template


and


(C44-C48


which


can


be prepared


asymmetric


epoxidation


technology


* --


I -


RO,,.


RO,

RO/









selected


well-known


D-ribonolactone


(70)


the


starting


material


g/$4


.00,


90%,


Aldrich)


which


requisite


A highly


absolute


stereochemistry


selective


protection


our


of primary


route


(Scheme


alcohol


with


tert-butyldimethylsilyl


chloride


and


subsequent


esterification


remaining


hydroxyls


afforded


compound


After


deoxygenation


and


hydrogenation


double


bond


protected


3-deoxyribonolactone


was


obtained.


Attempted


epimerization


with


variety


bases


failed to provide


TBDPS


53' OH


HO"


TBDPS


TBDPS


AcC" '&OAc


OAc


TBDPS


TBDPS


OAc 75


'OAc


Key: (a) t-Bu(Ph)2SiC1, Pyridine, 70%; (b) Ac2O, Pyridine, O0C, 93%; (c) DBU,
THF, 87%; (d) H2, Pd/C (10%), ethanol, 94.3%; (e) DBU

Scheme 2-3


Pho *nsr~ior I*


- 3 C C -i *4-


molt -


S;: "1 nor


1.2 -. s-i-


"OH


HO,"


r-- I --III


FTlh P T'<= f Fr rf


1 I I I










oxidation


carboxylic


acid


was


needed


later


.The


selective


acid-catalyzed


cleavage


,5-isopropylidine


ketal


followed


silylation


primary


alcohol


produced


compound


42,4


key


intermediate


with


three


was


chiral


produced


radical


centers


corresponding


C50,


C53,


deoxygenation


reactions


methods


and


1,44


different

similar


TBDPS


TBDPS


PhOSC



TBDPSO


MeS


1110


TBDPS


TBDPS


-,II OH


"OH


OH
83


Key: (a) HOAc (70%), 80%; (b) t-Bu(Ph)2SiCl, Pyridine, 92%; (c) PhOCSC1, MeLi,
THF, 83.3%; (d) NaH, CS2, MeLi, THF, 72.2%; (e) TBTH, AIBN, PhH, 80C,

74%; (f) TBTH, Toluene, reflux, 75.3%; (g) HOAc or HC1


Scheme 2-4


a


4- aC aI-a


l-~ aJ- 1..


U I


,i v' 0 n ama


*- an -n a a nat-l


C


i I


1









Because


simultaneous


cleavage


silyl


protecting


group


under


acidic


conditions,


removal


acetonide


always


gave


low yield


diol


This


unusual


because


tert-butyldiphenylsilyl


ethers


have


a greater


stability to acids


than other


silyl


ethers.


Benzyl


ethers


are


very


stable


bases,


acids


and


oxidative


reagents.


To avoid protecting


group


cleavage


change


rewarding


yields


more


because


(Scheme


stable


formation


Primary


O-benzyl


diol


alcohol


moiety


provided


was


85 proved


satisfactory


obtained


reduction


86 and immediate


protection as


acetonide.


isomers


resulting


from


dioxolane


group


migration


were


observed.


Silylation


with


the


highly


active


TBSTf


was


followed


catalytic


hydrogenation


provide


alcohol


Jones


oxidation


of the


primary


alcohol


to carboxylic acid


was


difficult,


both


acetonide


silyl


ether


groups


were


partially


cleaved


reaction


conditions.


two-step


oxidation


(first


aldehyde,


then


carboxylic


acid)


also


provided a


low yield of product.


best


result


was


observed


using


RuO4


(produced


reaction


ruthenium


(III)


chloride


sodium metaperiodate)


three


solvent


system.


method,


yield


carboxylic


acid


was


obtained.


Reaction


with


1,1-carbonyldiimidazole


formed


imidazolide


intermediate


This


intermediate


can









TBDPS


I,1111


".,111


"llll


""OH


y 0


V -O
TBS 0 OBn


TBSOH
TBSC -^ OH


T -Q

N
91


Key: (a) TBAF, THF, 83


__ "


TBS


=N


(b) BnCI, DMF, NaH, 89%


^.-O
so% PPh3
49


(c) HCl-Dioxane (1:1),


(d) NaBH4, ethanol, 85%


(f) TBSTf, 2,6-lutidine, CH2C12, 100%


(e) Me2C(OMe)2, acetone, p-TsOH, 75.6%;


(g) H2, Pd/C (10%), ethanol, 97


RuO4, CC1, MeCN,


H20, 81


(i) 1,1-carbonyldiimidazone, THF (j) THF


CH2=PPh3,


52%









Svnthes is


of the


subunit


(69)


In order


to convert


2-propyn-ol


to key


intermediate


(Scheme


2-6),


hydroxy


group


was


silylated,


followed

oxide,


addition


which


gave


carbon


very


low


chain


yield.


with ethylene

Although many


different


reach


tion


conditions


were


tried,


was


always


low


Protection


hydroxy


group


and


selective


deprotect ion


obtained


alcohol


Some


ether


was


cleaved


presence


of DMF


and


NaH.


THF


was


used


instead


of DMF,


no reaction


occurred.


Hq


TBS


TBS


OMPM


94 95


HK


OMPM


Key: (a) t-BuMe2SiCl, DMF, Imidazole, 81%; (b) (1) nBuLi,


THF, (2) BF3.O(Et)2


then ethylene oxide, 32%; (c) MPMC1, NaH, DMF, 30%; (d) TBAF, THF, 59%

Scheme 2-6


very


carried


out


good


alternative


improve


two-step


yield


synthesis


(Scheme


was


Compound


V


w v


44-.48.


TBS(l


__


*


_
















--OMPM


--OMPM

98



MPM= CH2 JOMe


Ho


Key: (a) MPMC1, NaH, DMF, 87.5%


(b) nBuLi, (CH20)n, THF, 73%


Scheme 2-7


With


alcohol


hand,


epoxide


was


readily


obtained


from


trans


alkene


treatment


with


lithium


aluminum


hydride


Sharpless


epoxidation


(Scheme


2-8)


In both


reactions,


hydroxyl


group


may


control


stereochemistry


these


conversions.


The


regio-


and


stereoselective


addition


methyl


group


epoxide


formed


diol


101,


followed


protection


the


hydroxyl


groups,


gave


good


yield.


Although


some


dibenzyl


ethers


were


formed


both


hydroxyl


groups


diol


105,


starting


using


material


Raney


can


nickel


reco


vered


which


catalytic


very


hydrogenation


selective


benzyl


ether


protecting


groups


p-methoxybenzyl


(MPM)


group


compound


was


selectively


removed


with


-dichloro-5, 6-


cyano-1,4


-benzoquinone


(DDQ


furnish


product


Oxidation


with


Jones


reagent


and


methylation


with


diazomethane,


followed


hydrogenation


afforded


---OH









S--OMPM


OMPM


HO"


OMPM


OMPM


OMPM


CH3


CH3


OMPM


CH3
103


TBS


OTBS
Bn OH

CH3
104


CH3


'CO2CH3

105


rrBS


CO2CH3


CH3


OTBS


I
[ CH3


Key: (a) LAH, ether, 85%


106

CO2CH3


(b) D-(-)-DET(0.13eq), Ti(OiPr)4(0.leq), tBuOOH


(2.0eq), CH2C12, sieves,


-200C,87


(c) Me3A1, Hex-CH2C12, 100%


(d) BnC1


NaH,DMF


47%


(e) TBSC1, DMF


, imidazole, 90%


(f) 1.


DDQ, CH2C12-H20,


_ __










With


C44-C48


and


C49-C54


subunits


and


place,


coupling


reaction


was


carried


out


refluxing


benzene


provide


alkene


(Scheme


2-9)


This


reaction


only


been


attempted


one


time


yield.


NMR


indicated sole


trans alkene


geometry


in 67.


TBS


PPh3


U
* I

CH3


44
CO2CH3


C49-C54 SUBUNIT


C44-C48 SUBUNIT


PhH


TBS


or 'O
*
* a
* U


reflux
50%


II -"
O CH3


44
CO2H


Scheme 2-9


Because


a model


there


reaction


was


was


only


cyclization


carried out


test


precursor


feasibility


Moffatt-type


cyclization


(Scheme


1-4)


this


system.


Catalyti


hydrolysis


3,4-dihydro-2H-pyran


was


followed


reaction


with a methyl


ketone


ylide


to produce


acyclic


compound


108.


Ester


was


prepared


Jones


oxidation


a o+-or F 4 n A f a i :


14 n 7 nvmo+ hI no


T.m rt nn a


nh c!P rt7<=t/


1 1( ~ a<


1 1 1


1


nr~ -









Iodolactonization


and


reductive


removal


the


iodine


(Process


of Scheme


1-2)


may provide


lactone


because


Kishi' s


synthesis


obtained a


similar


intermediate


using


this


strategy.


'OTHP

108


25%


CO2CH3


34%


Key: (a) 1) H20, HC1, 2) Ph3P=CHCOCH3, CH2C12; (b) 1) Jones
reagent, 2) CH2N2, ether, (c) LiOH

Scheme 2-10


Now


have


prepared


both


C44-C48


and


C49-C54


subunits


and


completed


the


coupling


reaction


prepare


key


intermediate


Although model


Moffat-type


cyclizations


were


successful,


synthesis


many


features


other


useful


reactions


adaptations


are


interesting.


of Sharpless


asymmetric


epoxidation,


free


radical


deoxygenation


carbohydrate


ring


and


formation


stablized


ylide


acyl


imidazolide.















CHAPTER


FREE


RADICAL


CYCLIZATIONS


OF ALDEHYDES


(X,B-UNSATURATED


KETONES


PROMOTED


BY O-STANNYL


KETYLS


An activated


olefin,


is referred


to by


free


radical


chemists,


alkene


possesses


some


type


electron


withdrawing


substituent


such


ester,


nitrile,


aroma


tic


ring,


which


functions


facilitate


addition


reach


tions


the


C system


Figure


3-1)


only


can


aldehyde


readily


cyclize


activated


olefin


stannyl


ketyl


intermediate


(Scheme


1-15) ,


ketone


can


undergo


a similar


reaction,


shown


in Scheme


0


3-1.


39,57


CO2CH3


TBTH


,AIBN


PhH, 800C


CO2CH3


+


69%


Scheme 3-1


reaction


probably


mediated


homolytic


chain


mechanism


and


proceeds


addition


tributyltin


radical to tl


ketone


carbonyl


o produce


O-stannyl









been


reported.


subsequent


5-hexenyl-1-oxy


cyclization,


addition


activated


olefin,


produces


carbon-


centered


free


radical


intermediate


116.


transfer


hydrogen atom from tributyltin hydride then renders


CH302C


+BuSn-
Bu3Sn-- .


nBu3SnH
ATIBN
80 C, PhH


CO2CH3
+nBu3SnH


Bu3Sn
I


I02CH3
5-exo-trig


Bu3Sn-Q
ai


CO2CH3


-nBu3Sn*


116

H20 or


- CO2CH3



112


Scheme 3-2


tributyltin


noteworthy


contains


radical


that


useful


which


prior


tin


repeats


H20


alkoxide


the


workup,


process.


intermediate


functionality


and


capability to afford other useful addends.29a


been


documented


that


activated


alkene


could


also


reduced


though


related


process.


8-59


When


tributyltin


hydride


reacts


with


unsaturated


ester


nitrile


functional


group,


olefin


hydrostannylated









were


not


observed


products


any


the


examples


attempted.


reasoned


that


tributyltin


radical


was


undergoing

concurrently


rapid

with


and


reversible


slower


addition


reversible


the


alkene


addition


carbonyl


form


the


O-stannyl


ketyl,


however,


once


the


cyclization


occurs,


not


readily


reversible,


similar


many

not


free

the f


radical


favored


reactions.


stereochemistry


Although


syn-products


reactions,


they


were

still


formed in


substantial


amount s


(Schemes


1-18,


3-1)


which helps


support


the


idea


that


the


cyclization


readily


reversible.


If a nonactivated


olefin,


citronellal


(118),


was


treated


under


the


same


conditions


reactions


above,


simple


acylic citronellol


(119)


was


produced in


yield.


TBTH, AIBN


CHO


PhH, 800C


OH

95%


Scheme 3-3


clear


from


this


example


that


stannyl


ketyl


radical


immediately


cyclize


and


was


subsequently


reduced


another


molecule


TBTH


because


rate


cyclization


slow with

hydrogen


nonactivated olefins

atom abstraction from


and

TBTH


competes

SThis r


with


resultt


rate


showed


that









this


kind


reaction.


With


ketyls,


alkoxylate


imparts


making


some


negative


radical


even


character


more


onto


nucleophilic


radical,


than


thus


simple


carbon-centered radical by


increasing the


energy


SOMO.


An electron


withdrawing


substituent


olefin


reduces


LUMO


energy


such


extent


that


better


orbital


overlap


with


higher


energy


SOMO' s


ketyl


(Figure


Enholm and Kinter examined the behavior


of a,p-unsaturated


ketones


and


their


intramolecular


additions


activated


olefins


Resonance


contributors,


supported


Huckel


calculations,


indicate


radical anion


of an a,zp-unsaturated


Scheme 3-4


ketone


(Scheme


3-4)


radical


density


located


P-carbon


122,


while


remaining


portion


divided


equally


between


carbonyl


carbon


and


the


carbonyl


oxygen


120.


In each


case,


free


radical


electron-


rich


p-carbon


(instead


the


actual


tin


ketyl


radical)


cyclized onto an


electron-deficient


olefin.


Precursors


used


form


O-stannyl


ketyls


generally


have









(nBu3Sn*)


which


never


been


studied


before.


Compound


bears


choice


two


potentially


reactive


carbonyls.


Previous


studies


steric


arguments


might


favor


attack


the aldehyde


leading to O-stannyl ketyl addition to the


nBu3Sn*


)Hn
CHO


Bu3Sn
6+


CHO


Bu3Sn
8+


1),
CHO


Bu3Sn
8+


aldol


Q n
CHO
127


Scheme 3-5


B-olefin


site


direct


reduction


alcohol.


Alternatively,


nBu3Sn*


attack


cyclohexenone


moiety


affords


resonance


stabilized


allylic


O-stannyl


ketyl


4-125.


hydrogen


P-position


atom


of 125,


transfer


a tin


enolate


occurs


regioselectively


126 would be


prepared by


novel


approach.


resulting


enolate


can


now


undergo


intramolecular


aldol


with


tethered


aldehyde


prepare


the bicvl


structure


(Scheme


3-5).


also


possible


.


. .


-%


I I


--









interesting


combination


free


radical


and


enolate


chemistry


required


this


reaction


exemplifies


new


rapidly-emerging


class


of sequential


one-


two-electron


reactions.


This


chapter


describes


preliminary


result


s for


this


new


cyclization


protocol


where


annulation


result


directed tin

These studies


aldol

also


based


2-electron


introduce


mild


mode


reactivity.


alternative


current


enolate


chemistry


which


avoids


NaH,


LDA,


LHMDS,


other


strongly


reductive


conditions


such


dissolving


metal


media


(Scheme


3-6)


To test


this


hypothesis,


cyclohexenones


NaOCH3


R3SiO" H3C


'"CH2CH=O


80%


R3SiO" H3C


H3C
3


1) LDA, THF,


CH3


-70C


2) CH3CH2CH=O
85%


H3C

H3C


OH
6HCH2CH3


CH3


Scheme 3-6


similar


were


constructed


bearing


suitably


tethered


aldehydes


electrophiles


their


enolate


cyclizations


were


then


examined.


best


our


knowledge,


neutral


free


radical


approaches


to aldol


chemistry


using


nBu3SnH


have


___









readily


prepared


from


Grignard


reagent


derived


from


chlorobutanol


reaction


with


3-ethoxy-2-cyclohexanone


(129),


followed


standard


Swern


oxidation.


63,64


enolate


cyclization


was


promoted by treatment


with


COMgBr


51%


129 13OEt


CHO


81%


76.4%


mp 120.8-121.7
(a) 1. THF-PhH; 2. Swern oxidation; (b) nBuSnH, AIBN, PhH, 80C
(c) C1COC6H4Br, THF-Pyridine
Scheme 3-7


tributyltin


hydride


under


free


radical


conditions


which


afforded


the


cis-decalone


alcohol


eld.


Interestingly,


three


new


stereocenters


resulted


from


the


cyclization,


one bearing the


alcohol


and


two arising


from the


cis-decalin


ring


fusion.


Only


single


product


zould









single


crystal


x-ray


crystallography


needed


obtained.


Compound


had


converted


into


p-bromobenzoate


ester


(133


prior


stereochemical


confirmation


x-ray


studies.


This


gave


only


better


quality


crystals,


incorporated


heavy


atom


(Br)


into


the


structure.


O.R.T.E.P.


plot


shown


Figure


Spiro-


cyclization


p-carbon-centered


radical


with


tethered


aldehyde


may


have


been


particularly


blocked


formation


of a hindered quaternary


center,


thus,


second


example where


this


was


not


possible


was examined next.


Aldehyde


(Scheme


3-8)


bears


different


pattern


substitution


cyclohexenone


and


was


constructed


adapting


general


protocol


Becker


al..


was


prepared


from


Robinson


annulated


product


which


was


protected


with


concomitant


olefin


migration


afford


66,67


Introduction


4-carbon


alcohol


appendage


ozonolysis,


reduction,


and


deprotection


gave


ketone


Aldehyde


138,


O-stannyl


enolate


precursor,


was


prepared


Swern


oxidation.


were


pleased


this


case


find


hydride-mediated


cyclization


gave


seven-membered


annulated

in 62%


ring,

yield.


constructing


with


bicylic


the


alcohol


example


a crystal


above,


other


diastereomers


were


present


NMR,


however,


some


unreacted


remained


(ca.


17%)


this


case.


Single


crystal






40











cv)









r
0








en
en
N
c~) p.'-
02 O,4
C..) U
I-
C
C)
'a-
o
>1
-o
1~~
>11
0


r
CN
I-
C-,

N








41














S



0

r
0









C-)
f%~.
c~) 0~i
rn
-4
4-
N
o
I-
C.)
~
cntE

I-
I
Co
C)

In

C)

C-)


0









clo[4


.3.1]nonane


skeleton.


An O.R.T. E. P.


plot


shown


in Figure


3-2.


98%


72%


HH


HO"


(


K


81.2%


81%


H3C'


^/^s ^CHO


62%


CH3


mp 66.7-68.50C
139


Key: (a) (HOCH2)2 pTsOH, PhH, Heat; (b) 1.


03; 2. NaBH4; (c) THF-


H20, (HO2C)2, heat; (d) Swern ox.; (e) TBTH, AIBN, PhH, 800C

Scheme 3-8


Two


chemical


studies,


shown


in Schemes


3-10,


were


conducted


which


support


aldol


clization


allylic


O-stannyl


ketyl


mechanism


(Scheme


Compound


was


reacted


with


tributyltin


deuteride


and


formed


only


deuterated


compound


after


stopping


the


reaction


ca.


L


I


I









juncture


annulation


reaction;


however,


does


rule


out


O-stannyl


ketyl


formation


aldehyde.


CHO


nBuSnD
AIBN


PhH
80C


Scheme 3-9


Thus,


alternative


explanation


cyclization


that


ketyl


forms


aldehyde


carbonyl


site


and


lization


occurs


attack


a-position


enone.


This


possibility


cannot


ruled


out,


seems


unlikely,


because


intramolecul


O-stannyl

ar attack


ketyl


nuc


eophilic


electrophilic


P-pos


radical


ition


alkene


should


be favored.


39,41


this


occurred


in the


case


CH3(CH)8CHO


nBuSnH (1.2 eq.)
AIBN


PhH, 800C


141 (1.0 equiv.)


142 (1.0 equiv.)


(5%)


CH3(CH)gCH20H


(83%, recovered)


- a a -a -









138,


six-


rather


than


observed


seven-membe red


ring


would have prevailed.


A study to distinguish between


ketyls


aldehyde


2-cyclohexenone


compared


and


decanal


(142)


simple


competition


experiment,


shown


Scheme


3-10.


predicted,


was


formed


more


rapidly


than


144,


which


suggests


a preference


for the


resonance


stabilized allylic 0-


stannyl


ketyl


2-cyclohexenone over the O-stannyl


ketyl


aldehyde.


small


amount


decyl


alcohol


(144)


formed


dilution


reaction


mixture


from


slight


excess


(1.2


equiv.


hydride


used.


basis


these


observations,


propose


that


free


radicals


are


involved


cyclization


step,


rather


proceeds via the tin


enolate


(Scheme 3-5)


summarize


these


findings,


new


free


radical


method


construction


carbon-carbon


bonds


from


allylic


stannyl


carbonyl


ketyls


addition


cycloalkanols,


been


developed.


promoted


where


three


nBu3SnH


new


directed


led


stereocenters


aldol-type


annulated


resulted


highly


stereoselective


manner.


These


studies


provide


neutral method


prepare


enolates


which may


have


future


applications to


intermolecular aldol-type


reactions.
















CHAPTER


CYCLIZATION AND SN'


FRAGMENTATION REACTIONS PROMOTED


BY O-


STANNYL KETYLS


Chapter


intramolecular


Schemes


anionic


and


elimination


demonstrate


reaction.


the


similar


process


can


anionic


exi


found


reactions,


which


the radical

fewer studies


sometimes


domain.


23,26


Compared


radical


called


process


B-scission


"fragmentation"


Interesting


and


work


can


this


occur


area


after


been


cyclization


produced


laboratories


Curran,


Keck,


Danishefsky


and others.


specific


example


from


Ueno's


group


shown


in Scheme


Functions


which


are


ejected


here


include,


R3Sn*


PhS*


nBuSnH


AIBN


PhIH, 800C


145


-PhS*


r -









Although


ketyls


have


been


used


perform


variety


synthetic


tasks,


surprisingly,


they


have


never


been


examined


intramolecular


cyclizations


followed


elimination


bimolecular


reactions.


examples


single


with


SmlI2.


study


describes


series


two


closely


related


were


sodium


reactions,


used


ketyls


bicyclic


to construct


(Scheme


ketones


several


4-2),


with


natural


with


general


products


patchouli


structure


using


alcohol


skeleton


No other


studies


in this area


exist.


THF


148 149


..MM


Scheme 4-2


proposed


plan


tin


ketyl


cyclization


presented


Scheme


4-3.


Tributyltin


radical


addition


aldehyde


carbonyl


starting


material


generates


stannyl


ketyl


152.


This


ketyl


radical


subsequently


cyclized


with


olefin


6-exo-trig


processes.


radical


elimination


leaving


groups


(*SPh


and


*SO2Ph)


should


give


alkoxide


153,


which


could


then


quenched by


water


to yield the


final


cyclized


compound


154.


took


used 14


advantage


starting


previous


compound


work


which


(see


was


Chapter


first


and


reduced


II _









group


benzenesulfinate


anion


gave


very


yield


(<10%)


of 156.


was


later


discovered


that


methanesulfonate


nBu3SnH,_
AIBN
80 "C, PhHi


f


S- (c
cSnBu3
8+


yclization)


SPh, SO2Ph


NSnBu3
8+


H20 or


Scheme 4-3


OTBS


99%


OTBS


55%


OTBS


59%


CHO


77%


Key: (a) NaBH4, CH3OH (b) NEt3, CH3SO2C1, CH2C12 (c) nBuLi,


loCT I'TS. /(A\ i AU TTI.tH. / -1\ 0' r


(4f TD'ITT A TNM PD-"









generated


anion


situ


was


Deprotection


easily


and


Swern


displaced


oxidation


phenylsulfide


furnished


intermediate


157,


which


was


then


subjected


radical


reaction


conditions.


Unfortunately,


starting


aldehyde


was


just


reduced


to primary


alchhol


(Scheme


4-4)


thought


that


there


were


two


possible


reasons


s failure:


spiro


-cyclization


p-carbon


was


too


hindered;


phenyl


sulfide


was


very


good


leaving


group;


thus,


second


example


was


examined


next


(Scheme


4-5)


Aldehyde


bears


a different


pattern


of substitution


ring


which


an allylic


sulfone


group


does


not


lead


a,b,c
69%


OTBS


OTBS
65%


S02Ph


SO2Ph


77%


OTBS


02Ph


163
Key: (a) NaBH4, CH3OH (b) NEt3, CH3SO2C1, CH2C12 (c) nBuLi,
PhSH, THF; (d) m-CPBA, pyridine; (e) TBAF, THF; (f) Swern ox.;
fal TRTT- ATRNiT PhiH









formation


of a hindered


quaternary


center


between


p-carbon


tethered


aldehyde.


Compound


was


obtained


synthesis


analogous


Scheme


except


oxidation


sulfide

aldehyde


160

162


produced


still


sulfone


produced


161.


primary


Radical

alcohol 1


reaction


L63.


Both


examples


show


that


with


these


functionalities


a tin


ketyl


abstracts


hydrogen


atom


faster


than


adds


double


bond.


conc


lude


from


ese


studies


that


this


general


approach


to SN'


cyclizations


will


successful


thus,


this


work


was


halted


this


point.


Futher


studies


may


involve


use


trialkyltin


functions


which


are


SN' -


eliminated


use


of acyclic


precursors.

















CHAPTER


EXPERIMENTAL SECTION


General


NMR


spectra


were


recorded


QE-300,


VXR-300


instrument.


internal


Residual


reference


chloroform


spectra


ppm)


measured


was


CDC13.


used


spectra


were


recorded


Perkin


Elmer


1600


infrared


spectrophotometer.


Melting


points


were


acquired


Thomas


Hoover


capillary


melting


point


apparatus


and


were


uncorrected.


All


reactions


were


conducted


oven-dried


1200C)


glassware


under


atmospheres


argon.


Air-


and


moisture-sensitive


compounds


were


introduced


via


syringe


Combustion


analyses


were


performed


Chemistry


Department,


University


of Florida,


Atlantic Microlabs,


Inc.


(Norcross,


GA) .Mass


spectra


and


exact


mass


measurements


were


performed


Finnigan


MAT95Q,


Finnigan


4515,


Finnigan


ITD


mass


spectrometers.


GC experiments


were


performed


Varian


3500


capillary


chromatograph


using


fused


silica


capillary


column


(DB5-30W;


film thickness


.25 l4).


All


reagents


solvents


were


analytical


grade and


were


,,a c1


T0+- r hhvr n fiir


ryol A 7cor


ITFW. -


t oniene.n


benzene


#"' I !









using


phosphomolybdic


acid


ethanol


followed


heating


indicator.


Flash


chromatography


was


performed


using


(230-


mesh)


silica


standard


flash


chromatographic


techniques.


Experimental


Procedures


and Results


Compounds


71->74


These


identical


that


prepared


Barret


and


coworkers.


1 2-I sopropvlidene-5-O-Diphenvl-t-butvlsilvl-l-xvlofura-


nose (78)


42,43


diisopropylidenexylofuranose


(76)


(57.22


0.249


mol)


was


dissolved


acetic


acid


150


ml),


and


mixture


was


tired


room


temperature,


finally


evaporated.


residue


was


evaporated


with


toluene


added brine


.The


aqueous


phase


was


extracted


with


ethyl


acetate


and


combined


extracts


were


dried


and


evaporated


under


reduced


pressure


yield


1,2-O-Isopropylidene-D-xylofurano


(77)


80%)


The


proton


and


spectra


were


identical


with


that


authenic


sample42;


NMR


(CDCl3)


(1H,


1.48


(1H,


(2H,


(1H,


4.42


(1H,


(1H,


. F


5.59


13C NMR


(CDCl3,


MHz)


.95,


9g,


* -









Diol


(15g,


mmol),


imidazole


12.3g,


mmol),


tert-butyldimethylsilyl


chloride


.84g,


mmol)


were


stirred


DMF


room


temperature


reaction


mixture


was


partitioned


between


diethyl


ether


water


and


aqueous


phase


extracted


with


diethyl


ether


x 100


.The


organic


phase


was


washed


with


water,


dried


over


MgSO4,


concentrated


vacuo


to afford,


after


recr


ystallization


from


hexane,


alcohol


91%)


white


crystalline


solid,


. 69-71OC.


Rf=0


(35%


THF-


hexanes


MHz


NMR


(CDC1


(9H,


.09-4,17


(1H,


(1H,


and


(10H,


NMR


CDC13,


78.41,


85.31,


MHz)


18.97,


.86,


26.08,


.37,


26.60,


.79,


.69,


.81,


62.61,


.93,


76.59,


.39,


(KBr,


film)


3470


930,


2855,


1428,


1388,


1219,


1116


1011


821,


708;


Anal.


Calcd


C24H3205Si


, 67.26;


Found:


, 67.35;


.56.


1,2-Isopropylidene-3-O-phenyl-chlorothionoformate-5-0-


Diphenyl-t-butylsilyl-b-xylofuranose (79).


To a stirred


solution


.23g


mmol)


of alcohol


THF


was


added


.393


ether


methylithium


an ice


bath


stirred


vigorously.


After


phenyl


chlorothionoformat e


mmol)


was


added


s),









yellow,


thick


oil


(0.246g,


Rf=0.61


THF-


hexanes)300


1H NMR


(CDCl3)


(9H,


1.33


(3H,


1.55


3.97


(2H,


J=23


4.58


(1H,


4.78


(1H,


dd),


(1H,


dd),


(1H,


J=12


Hz),


7.00-7.


7.20


and


7.67-7.73


13H,


NMR


(CDCl3,


MHz)


19.14,


26.24,


26.62,


60.23,


78.72,


82.81,


85.04,


.89,


.29,


.66,


.60,


.73,


.76,


129.53,


.78,


.92,


.96,


134.71,


135.44,


153.21,


193.95;


IR 3518


(br),


3070,


1590


(m),


1427,


1277,


894;


Anal


. Calcd


C32H3606SiS:


65.93;


.43.


Found


66.01;


.57.


1.2-Isopropylidene-3-O-(S-methyldithiocarbonate)-5-0-


-b-xvlofuranose


(80) .


A round-bottomed flask


was


charged with


(93.3 mmol)


alcohol


imidazole,


mL of


THF.


Over


5-min


period,


(140


mmol)


sodium


hydride


dispersion


was


added.


After


reaction


mixture


was


stirred


20 min,


21.32


(280 mmol)


of carbon


disulfide


was


added.


Stirred


was


iodomethane


continued


was


added


single


min,


22.5g


portion.


(159


After


mmol)


15 min,


solution


was


filtered


and


filtrate


concentrated


rotary


evaporator


followed by


addition


diethyl


ether


(350


organic


extract


was


washed


with


saturated


sodium


bicarbonate


solution


and


water


xl00mL),


: C,


Diphenvl-t-butvlsilvl










96.5%)


Rf=0.37


(35%


THF-hexanes)300


MHz


NMR


(CDC13)


(9H,


1.08


(3H,


1.31


(3H,


, 1.54


(1H,


2.49


(2H,


7.32-7.48


(1H,


5.90


.62-7.


(10H,


(1H,


NMR


(CDC


MHz)


19.03,


19.07,


.65,


60.18,


79.09,


82.71,


83.88,


.86,


112.22,


.67,


.75,


127.83,


.71,


.93,


.46,


.60.


1.2-Isopropylidene-3-Deoxy-5-0-D iphenyl-t-butylsilyl-b-


xylofuranose


(81)


31,44b


0.85


mmol)


was


dissolved


distilled PhCH3


49 mg


mmol)


of AIBN


0. 61 mL


(2.0


mmol)


of n-Bu3SnH


were


added.


solution


was


degassed


with


argon


15 min and then


heated at


750C


3 h.


Solvent


was


evaporated and


resi


was


chromatographed


on silica


with


ethyl


acetate


-hexane


(80:20


to give


a crystalline


solid


(0.46 g,


74.1%)


. 62


.5-64


Rf=0


THF-hexanes


m.p.


.5-64


MHz


NMR


CDC1


1.06


(9H,


1.32


(3H,


1.52


(1H,


1.88


(1H,


(1H,


3.79


(2H,


(1H,


(1H,


7.33-


and


7.64-7


(12H,


m) ; 13


NMR


CDC13,


MHz)


.69,


, 64.68,


78.52,


80.68,


105.71,


111.10,


.81,


129.59,


129.65,


.51,


135.64;


KBr,


film)


3471,


3057


854,


1976


(w),


1922,


1589,


1386,


1222


(s) ,


974,


, *









A round-bottomed flask


mmol)


was


toluene


charged


and


with


37.14


47.2


(127


(91.2


mmol)


tributyltin


hydride.


The


reaction


mixture


was


heated


reflux


until


analysis


indicated


disappearance


starting


materials


(6-8


During


this


time


colur


reaction


solution


was


changed


from


Hlow to colorless.


Work-


and


purification


above


method


give


75.3%),


proton


and


spectra


were


identical


with


that


of authentic


sample


obtained


from


Preparation


diol


To a stirred


solution


were


added


water


and HOAc


room temperature.


After


reaction mixture

concentrated under


was


neutralized


reduced


pressure.


with

The


NaHC03,

residue


and

was


extracted


with


CH2C12,


extract


was


washed


with brine,


dried,


and


evaporated


leave


oil.


residue


was


chromatographed


silica


with


diethyl


ether-hexane


(85:15)


give


which


was


mixture


two


aromeric


isomers


.164


40%);


Rf=0


THF-hexanes);


MHz


NMR


(CDCl3)


.82-2


(2H,


(1H,


br),


3.02


(1H,


, br),


3.48-3


(2H,


4.21-4.54


(1H,


and


.62-7.73


(10H,


13c


NMR


(CDCl3,


MHz)


19.04,


19.10,


26.69,


31.93,


33.81,






56


1.2-Isopropylidene-3-Deoxy-5-hydroxy-3-xylofuranose (B4).


Compound


mmol)


THF


was


added


solution


tetra-n-butylammonium


fluoride


THF


and


resultant


mixture


was


stirred


room


temperature


mixture


was


concentrated


vacuo


and


purified


flash


chromatography


diethyl


ether/


exane


to afford


a white


crystle


.9%)


Rf=0


THF-hexanes


NMR


(CDC1


(2H,


(1H,


(1H,


(1H,


(1H,


(1H,


NMR


(CDCl3,


26.2


78.5


80.0,


(KBr,


film)


3481


(b),


2966


1454,


1381


(m),


1266,


1165,


1019


852,


656;


Anal.


Calcd


C8H1406,


calculated


: 55.16%,


.10;


found


: 55


.33%,


.17%.


I 2-Isopropylidene-3-Deoxy-5-benzyl-b-xylofuranose (85).


Sodium


hydride


suspension


mineral


oil)


was


washed


with


hexane,


dried,


suspended


DMF


Alcohol


34.4


mmol)


DMF


was


added


dropwise


00C.


benzyl


After


chloride


evolution


(4.77


hydrogen


mmol


had


was


ceased,


added


benzyl


and


mixture


was


allowed


reach


room


temperature


overnight.


Water


was


added


and


mixture


was


extracted


with


hexane,


wash


with


water,


dried


over


MgSO4,


concentrated









1.78


4.39


(1H,


(1H,


2.04


4.57


(1H,


(2H,


3.58


4.71


(2H,


(1H,


3.88


5.82


(1H,


(1H,


(5H,


NMR


(CDC13,


MHz)


6.07,


.63,


35.10,


70.60,


73.29,


77.00,


.51,


.92,


.48,


.22,


.95;


2986


(m),


2934


(m),


1454,


1372


1214


(m),


1164,


1094


(s),


1024


(s),


851,


(m),


698;


mass


spectrum


(EI)


(11),


(20.3),


(100),


(21.1),


(41) ;


exact


mass


C14H2004


calcd


64.1364,


found


.1361.


Preparation


of diol


stirred


(15 mL,


dioxane


room temperature.


solution


After


15 h,


were


added


reaction


mixture


was


neutralized


with


NaHCO3,


and


concentrated


under


reduced


pressure.


residue


was


extracted


with


CH2C12,


extract


was


washed


with


brine,


dried,


and


evaporated


leave


an oil.


res


idue


was


chromatographed


silica


with


diethyl

aromeric


ether to

isomers


give


5.52


a oil


.5%)


which


was


Rf=0.11


a mixture


(35%


THF-hexan


two

es);


NMR


C13,


MHz


.82,


34.07,


.13,


.14,


72.38,


73.10,


75.37,


76.39,


77.79,


96.86,


102.57,


.49,


127.51,


.64,


.70,


128.30,


.23,


137.77;


3384


2930


(s),


1720


(w) ,


1453,


1361,


1044


(br.),


(m) ,


698.


br.),









solution


diol


(5.29


mmol)


absolute


ethanol


(20 mL)


was


added to a


solution


sodium borohydride


absolute


ethanol


o0c.


After


stirring


acetone


acetic


acid


was


until


added


with


was


vigorous


evolved.


stirring,


After


followed by


removal


solvent

ethyl


vacuo,


acetate


and


residue


saturated


was


dissolved


aqueous


ammonium


mixture


chloride.


Saturated


sodium


disulfate


was


added


until


aqueous


layer


was


about


then


extracted


with


ethyl


acetate


mL) ,


combined


organic


layers


were


dried.


Removal


solvent


in vacuo provided the triol as an oil.


solution


triol,


2,2-dimethoxypropane


(3.0


30.8


mmol),


TsOH


in Me2CO


was


stirred


room


temperature


After


addition


CH2C12


mL),


solution


was


washed


successively


with


aqueous


NaHC03


and


water,


dried.


solvent


was


evaporated


under


reduced


pressure


chromatographed


silica


column


give


(3.38


54.0%);


MHz


NMR


CDC13


(3H,


1.39


(3H,


1.74


(2H,


(1H,


3.44


(2H,


3.55


(1H,


4.05


(1H,


(1H,


(2H,


.22-


13C NMR


CDC13,


35.


.51,


68.7


69.25,


73.11,


73.85,


74.2


76.57,


108.81,


127.49,


128.17,


137.80.









was


added


tert-butyldimethylsilyl


trifluoromethanesulfonate


(1.51


6.57


mmol)


over


00C.


reaction


mixture


was


stirred


h at


room


temperature


was


diluted


with


CH2C12,


washed


with


NaHCO3,


dried


with


Na2SO4.


Flash


chromatography


through


silica


afforded


(1.77


, 100%)


oil;


NMR


(CDCl3)


0.06


(6H,


(9H,


1.18-1.36


(1H,


1.40


(3H,


1.46


(3H,


1.51


(1H,


(1H,


(1H,


3.51


(3H,


.22-7.34


(5H,


NMR


(CDC13,


MHz)


19.62,


.79,


29.15,


9.77,


65.75,


67.87,


69.31,


73.24,


98.63,


127.45,


127.54,


128.17,


.93.


Preparation of primary


alcohol


Compound


(1.2


3.15


mmol)


was


hydrogenated


absolute


ethanol


presence


Pd-C


ordinary pressure and


temperature


overnight.


After


removal


catalyst


filtration,


evaporation


solvent


left


oily


alcohol


97.5%),


NMR


CDCl3)


0.06


(6H,


(9H,


.19-1


(2H,


1,40


1.46


(3H,


2.62


(1H,


.41-3


(4H,


(2H,


13C NMR


CDC13,


MHz)


18.22,


19.75,


.79,


29.15,


29.77,


66.94,


66.77,


69.29,


69.54,


98.55.


2 4-Dihydroxyacetonide-5-t-butyldimethyls iloxYPel tanoic I I I acid









of water


cooled


to 00C.


Ruthenium


(III)


chloride


trihydrate


0.11


mmol)


was


added,


followed


sodium


metaperiodate


12.3


mmol)


over


min.


reaction


mixture


was


allowed


stir


h at


room


temperature,


quenched


with


30 mL of


dichloromethane.


The aqueous


layer was


separated and


extracted with


dichloromethane


30 mL).


organic


extracts


were


dried


filtered


through


Celite


545.


dark


solution


was


concentrated


and


then


purified


silica


chromatography


(pure


ethyl


acetate)


to provide


as an oil


0.75


81.0%);


H NMR


(CDCL3)


0.89


(9H,


1.22-1.55


(2H,

q),


.69(11H,


m) 1,48

3.95-4.26


(6H,

(2H,


(1H,

(1H,


(1H,


NMR


(CDCl3,


MHz)


18.22,


19.41,


29.53,


30.13,


66.29,


68.04,


69.50,


99.45,


174.58.


Preparation


vlide


solution


acid


(28;


469


mmol)


intetrahydrofuran


was


added


1, 1-carbonyldiimidazole


(287


1.77


mmol)


After


min,


when


evolution


carbon


dioxide


had


ceased,


the


mixture


was


added


Wittig


reagent


.734


geneaated


4.42


from


mmol)


methyltriphenylphosphonium


M butyllithium


bromide


(1.85


mmol)


mixture


benzene


was


stirred


room


temperature.


solution


After


ammonium


reaction


chloride









ether,


give


pure


(466


white


foma;


MHz

(2H,


NMR


1,48


(CDCl3)


(6H,


0.06

. 2.:


(6H,


(1H,


s),

t),


0.88

3.53


(9H,

(1H,


s),

m) ,


1.21-1.43


.68 (1H,


3.95-


7.40


-7.75


(15H,


NMR


CDC13,


MHz


67.17,


18.33,


70.45,


19.77,


73.37,


25.88,


73.53,


30.06,


98.57,


32.32,


.63,


.56,


.80,


49.01,


131.89,


131.93,


133.09,


191.57.


l- tert-butyldimethylsiloxy-2-propyne (93)


A solution


(0.1 mol)


of propargyl alcohol


92),


18.1


(0.12


t-BuMe2SiCl,


imidazole


DMF


was


stirred


room


temperature.


mixture


was


then


diluted


with


hexane


washed


35 mL)


with


water,


dried,


evaporated.


Distillation


residue


gave


13.8


81.2


of 93:


mm) ;


1H NMR


(CDCl3)


(6H,


0.89


(9H,


2.36


(1H,


4.22


J= 2


Hz);


C NMR


(CDCl3,


8 18


.09,


25.64,


51.2


.75,82


.23,


.42.


1- tert-butvldimethvlsiloxv-2-Dentvn-5-ol


(94)


solution


n-butyllithium


hexane


mmol)


was


added


solution


mmol)


-780C,


and


the


mixture


was


stirred


min.


Borontrifluoride


etherate


(0.7


was


added


solution









adding


aqueous


ammonium


chloride.


The


organic


layer


was


extracted


with


diethyl


ether,


dried,


evaporated.


Column


chromatography


residue,


using


60:40


hexane-diethyl


ether,


gave


pure


(0.4


32%)


liquid;


1H NMR


(CDCl


(6H,


0.89


(2H,


2.98


(1H,


(2H,


(2H,


NMR


(CDC13,


MHz)


18.23,


25.76,


51.85,


60.80,


80.19,


81.97;


Anal.


Calcd


C11H220


calculated


61.62%,


10.34;


found


61.74%,


10.27%.


l-tert-butyldimethylsiloxy-5- (tert-butyldimethylsil) oxy-2-


pentyn


951


NaH


dispersion


3.26


mmol)


was


added


stirred


solution


alcohol


mmol)


dimethylformamide


(DMF)


(15 mL)


room temperature.


After


min,


4-methoxybenzyl


chloride


(MPMC1)


(511


3.26 mmol)


was


added


and


the


mixture


was


stirred


The


reaction


mixture


was


poured


into


aqueous


NH4C1


and


extracted


with


diethyl


ether.


combined


extract


was


washed


with


brine,


dried


(MgS04),


and


evaporated


leave


oil,


which


was


chromatographed


silica


column


with


n-hexane/ether


eluant


give


compound


(530


50.7


1H NMR


(CDCl3)


0.06


(3H,


0.84


(9H,


, m) ,


3.63


(2H,


(2H,


.4-


:15)


r






63




5- (4-methoxybenzyl) -2-pentyn-1-ol (96).


Method


Compound


(180


was


desilylated


described


the


preparation


alcohol


afford


compound


58.7%);


Rf=0.28


(35%


THF-


hexanes),


MHz


NMR


(CDC13


(2H,


3.02


(1H,


(2H,


3.77(3H,


(2H,


4.45


(2H,


(2H,


13C NMR


CDCl3,


MHz)


19.87,


50.69,


55.02,


67.70,


72.32,


79.54,


82.44,


113.60,


129.21,


129.71,


159.03;


3416


(br.) ,


2864


(m),


2225


(w) ,


1612,


1513,


1362,


1248


, 1094,


1031(m),


mass


spectrum


(EI)


(18.2),


.9),


10),


(100),


(7.8),


(28.3),


(22.5) ,


(15.7);


exact


mass


(EI)


C13H1603


calcd


220.1099,


obsd 220.1127.


Method


B49:


A solution


(16.77


88.15


mmol)


and


(300


was


treated


dropwise


-780C


with


BuLi


35.3


solution


hexane,


mmol),


and


the


reaction


mixture


was


allowed


warm


room


temperature


overnight.


Paraformaldehyde


(3.44


mmol,


dried


vacuo


was


added


followed


THF


(150


mL).


resulting


mixture


was


heated


reflux


and


after


cooling


room


temperature,


was


poured


into


brine


organ


layer


was


washed


with


saturated


aqueous


NH4C1


mL) ,


dried,


and


evaporated


Purification


flash






64




1-O- (4-methoxybenzyl) -3-butyn (9B1):


NaH


disper


sion


mmol)


was


added


stirred


solution


3-butyn-l-ol


(97)


mmol)


dimethylformamide


DMF)


0OC.


After


min,


methoxybenzyl


chloride


(MPMC1)


mmol)


was


added


mixture


was


stirred


.The


work-up


and


purification


procedure


was


same


described


preparation


afford


compound


87.5%);


Rf=0


THF-hexanes)300


MHz


NMR


CDC13


Rf=0


THF-


hexanes


NMR


(CDC13)


2.45


.74(3H,


(2H,


(2H,


NMR


(CDC13,


MHz)


54.90,


67.95,


69.20,


81.13,


.53,


.05,


.85,


.99;


IR 3291


862,


1612


1513


1361


(w),


1248


1098,


1034


822;


Anal.


Calcd


C12H1402


75.76;


.42.


Found:


75.68;


.47.


5 -(4-methoxybenzyl)-2-trans-pentene-1-ol (99).


solution


lithium


aluminum


hydride


mmol)


diethyl


ether


(200


was


added


solution


ohol


(17.0


77.2


mmol)


diethyl


ether


.The


reaction


mixture


was


allowed


room


temperature


stirred


and


then


was


cooled.


Water


was


added









Celite


506.


organic


layer


was


washed


with


water,


dried,


and


evaporated.


The


residue


was


subjected


column


chromatography,


using


hexane-diethyl


ether,


give


pure


compound


85.6%)


a oil;


1H NMR


(CDCl3)


2.33


(2H,


(2H,


(2H,


6.86


(2H,


NMR


CDCl3,


MHz)


.46,


55.09,


63.22,


69.15,


72.36,


113.60,


129.17,


130.19,


130.92,


159.00;


3404


(br.),


2933


2858,


1612,


1513


(s),


1463,


1301,


1248


, 1095,


1034,


971,


mass


spectrum


(EI)


(12.4),


(100) ,


.7);


exact


mass


C13H1803


calcd,


222.1255,


obsd


222.1244.


(2s-trans) -5- (4-methoxybenzyl) -ethyloxranemethanol (100) .


Titanum


(IV)


isopropoxide


(1.62


5.68


mmol)


was


added


suspension


4-A


powdered


molecular


sieve


CH2C12


mL) ,


and


diethyl


D-tartrate


mmol)


After


anhyhydrous


tert-


butylhydroperoxide


(37.8


mmol)


was


added.


After


another


min,


alcohol


was


added


slowly


syringe.


reaction mixture


was


stirred


h at


and


then


flask


was


sealed and placed in


freezer


(-22


24 h.


showed


starting


material,


was


quenched


with


water


and


allowed


warm


room


temperature.









aqueous


layer


was


extracted


with


EtOAc


mL).


combined


organic


were


dried,


concentrated,


and


chromatographed,


using


hexane-ethyl


acetate


4:6,


give


desired compound 100


an oil


11.40 g,


84.7%);


300 MHz


NMR


(CDCl3)


8 1.8


(2H,


(1H,


3.01


(1H,


3.32


(1H,


3.76


(2H,


13C NMR


CDC13,


4.41


(2H,


300 MHz)


6.85


31.46,


(2H,


.41,


54.80,


54.82,


58.30,


61.53,


66.19,


72.26,


113.40,


128.90,


129.87,


158.80;


3432


(br.),


2933,


862,


1612,


1513


1363,


1248


(s),


1098


1033,


820;


mass spectrum


(EI)


11.2


52.3),


(12.3) ,


(100),


(13.4),


exact mass


for C13H1804


calcd,


238.1205,


obsd


238.1170.



Preparation of diol 101.


A solution of epoxy alcohol 100


(16.0 g,


67.1 mmol)


hexane


was


added


dropwise


solution


trimethylaluminium


(0.2 M,


100 mL,


201 mmol)


in hexane at


After


stirring


min,


the


reaction


mixture


was


diluted


with


CH2C12


and


water


After


stirring another


40 min at


room temperature the mixture was


filtered and the remaining solid was washed with ether


The


combined


organic


solution


was


dried


and


concentrated.


Purification


residue


silica


(s),


mL) ,









(1H,


4.42


(2H,


6.86


7.24


(2H,


13C NMR


(CDCl3,


300 MHz)


8 15.97,


.45,


54.97,


55. 00,


64.43,


67.76,


72.50,


75.80,


113.58,


129.17,


129.84,


159.00;


IR 3395


(br.


, 2932,


2872,


1612,


1513,


1463,


1364,


1302,


1248,


1086


(s),


1035,


821,756,


733.


Preparation of secondary alcohol 102.


1,2-Diol 101


(5.24 g,


20.6 mmol)


was mono-benzylated


described


for


preparation


compound


afford


primary alcohol


(0.8 g,


11.6%);


and the


secondary alcohol 102


an oil


(3.85 g,


55.9%);


300 MHz 1H NMR


(CDCl3)


8 0.89


1.81


(2H,


2.91


3.39-3.65


(5H,


3.78


4.42


(2H,


, 4.54


(2H,


6.85


(2H,


13C NMR


(CDC13,


300 MHz)


6 15.90,


32.27,


33.47,


55.18,


55.16,


67.88,


72.53,


73.28


, 74.21,


113.69,


.63,


128.34,


129.20,


130.33,


138.06,


159.07


Preparation of compound 103.


The


secondary


alcohol


102


(3.8


11.4


mmol)


was


silylated


described for the preparation of compound 93 by


silica gel


column chromatography to afford compound 103


(5.0


, 100 %)


an oil;


300 MHz


1H NMR


(CDCl3)


8 0.03


(6H,


0.88


(12H, m),


1.41


(1H, m),


1.81


(2H,


.35-3.54


(3H,


6.83


(2H,


5H, m ;


3H, m),









73.11,


75.25,


113.56,


127.29,


127.41,


128.13,


129.03,


.61,


138.33,


158.94.


Preparation


of orimarv


alcohol


104.


stirred


solution


MPM


ether


103


mmol)


CH2C12


and


water


(0.3


was


added


dichloro-5,6-dicyano-1,4-benzoquinone


(DDQ)


(632


mmol)


mixture


was


stirred


room


temperature


minm,


then


diluted


with


CH2C1


mL),


washed


with


saturated


aqueous


NaHCO3,


dried


(Na2


SO4),


evaporated


leave


crude


oil.


solution


crude


ethanol


was


added


with


solid


sodium borohydride


(110


mmol)


mixture


was


allowed


warm


room


temperature.


The m

under


mixture


was


reduced


neutralized


pressure,


and


with


diluted


diluted


with


AcOH, concentrated

water. Extraction


with


ether


and


usual


workup


delivered


crude


alcohol


104,


which


was


purified by


flash


chromatography


hexane-


ether)


afford


pure


compound


(0.65


89.3%);


MHz


NMR


(CDCl3)


(6H,


0.88


(9H,


0.95


(3H,


(2H,


(2H,


1.92


4.49


(2H,


(1H,


3.49


(5H,


(3H,


13C NMR


.61-


(CDCl3,


MHz)


18.11,


19.90,


35.03,


35.35,


61.65,


74.49,


75.01,


77.00,


129.27,


129.36,


130.03,


139.93.









The


alcohol


104


(5.28


16.2


mmol)


was


oxidized


described


for the


preparation


of compound 90 to afford a acid


crude


oil;


13c


NMR


(CDC13,


MHz)


.15,


.89,


29.72,


.34,


.42,


36.13,


.61,


73.34,


74.59,


.66,


was


128.33,


carried


.15,


with


179.85.


diazomethane


Esterification


(generated


acid


from


diazald


and


potassium


hydroxide


ethanol/ether


poured


ioto


reaction


flask)


ether


Nitrogen


was


bubbled


through


yellow


reaction mixture


until


solution


became


clear.


Evaporation


silica


chromatography


ether/hexane)


afforded


ester


an oil


81.2


1H NMR


CDCl3)


(6H,


0.87


(9H,


, 0.96


(3H,


2.11


(1H,


2.24


(1H,


(1H,


, m),


3.65


(3H,


(5H,


NMR


CDC13,


16.85,


18.10,


.84,


33.57,


35.98,


51.30,


51.34,


27.65,


73.25,


74.53,


127.49,


127.55,


128.26,


138.19,


.93.


Preparation


of primary


alcohol


106.


ester


(100


0.281


mmol)


was


hydrogenated


described


the


preparation


compound


afford


alcohol


an oil


61.0%);


1H NMR


(CDC1


(6H,


(9H,


(1H,


(1H,


dd),


.41-3


(3H,


(3H,


NMR


13c









Preparation


aldehvde


mixture


alcohol


(320


1.16


mmol)


and


Dess-Martin


periodinane


(i.42


mmol)


was


stirred


dichloromethane


cloudy


mixture


was


quenched


with


saturated


aqueous


sodium


thiosulfate


mL),


diluted


with


ethyl


acetate


mL) ,


and


stirred


until


organic


layer


became


clear.


organic


solution


was


dried,


concentrated,


and


purified


flash


chromatography


(2:8


ether/hexane)


furni


aldehyde


NMR


(CDC13


0.08


(6H,


(9H,


(3H,


(1H,


(3H,


3.87


(1H,


13c


NMR


(CDC13,


MHz)


16.32,


17.98,


25.54,


.99,


35.51,


51.28,


51.32,


80.44,


172.71,


.24.


Preparation


of compound


Aldehyde


(180


0.32


mmol


Wittig


compound


(110


0.40


mmol)


were


treated


with


toluene


under


reflux


Evaporation


and


silica


chromatography


ether/hexane


afforded acid


an oil


MHz


NMR


(CDCl3)


(12H,


0.88


(9H,


(9H,


0.98


(3H,


1.30


(2H,


1.44


(3H,


1.47


(3H,


(1H,


(2H,


2.42


(1H,


(1H,


(3H,


(1H,


(1H,


(1H,









.49,


66.66,


69.59,


.95,


74.89,


99.90,


124 .02,


148.61,


.36,


197.84.


Preparation


of a.B-unsaturated ketone


108.


solution


3,4-dihydro-2H-pyran


(12.7


mmol)in


70 mL of


water was


added HC1


(4.6 mmol,


.6 mL of


one


mol


solution)


quenched

extracted


with


time s


After a

saturated


with


bout


two


NaNH4


ethyl


hours,


and


acetate


the

The


the mixture

aqueous layer

organic phase


was

was

was


dried


over


MgSO4


and


concentrated


vacuo


give


crude


aldehyde,


which


mmol)


was placed into a


250 mL RBF


along with

reagent (43


magnetic


135 mmol)


stirrer.


was


The


dissolved in


methyl


CH2C12


ketone


Wittig


(100 mL)


placed


into


large


addition


funnel.


CH2C12


was


added


the


aldehyde


reaction


flask


and


ylide


solution

reaction


was

was


slowly

allowed


added


the


proceed


reaction


overnight


and


mixture.


was


extracted


with


H20


. the


organic


layer


was


dried


with


Na2SO4


and


concentrated


vacuo.


Column


chromatography


residue


produced


1,98


colorless


mmol,


MHz


NMR


(CDCl3


.48-1.88


(12H,


(5H,


3.33-3.


3.71-3.


4.57


(1H,


6.08


(1H,


(1H,


13C


NMR


(CDCl3,


MHz)


19.70,


.95,


.53,


26.86,


29.31,


30.79,


32.30,


62.35,


67.11,









The


protected


alcohol


108


(0.2


0.88


mmol)


was


oxidized


and


esterificated


described


give,


after


flash


chromatography,


ester


(0.118


, 0.693


mmol)


colorless


oil;


MHz


NMR


(CDCl3)


(2H,


(2H,


(3H,


(2H,


(1H,


(1H,


26.75,


6.79


31.54,


(1H,


33.12,


13c


51.51,


NMR


131.74,


(CDCl3,


146.67,


MHz)


173.38,


.16,


199.7.


3-butanal-2-cvclohexnenone


(131).


63,64


oxalyl


chloride


(0.84


mmol


methylene


chloride


was


added


DMSO


1.034


mmol)


over


5-min


period


with


concomitant


-780C,


and after


10 mi


-780C,


the


alcohol


(1.0


mmol)


methylene


chloride


was


added


over


min,


resulting


cloudy


solution


which


was


stirred


min.


this


was


added


(30.1


mmol)


triethylamine,


and


mixture


was


stirred


30 min


-780C.


cooling bath


was


removed


and


water


was


added.


Extraction


with


methylene


chloride


mL),


drying


over


anhydrous


MgS04,


and


flash


chromatography


afforded


aldehyde


(0.988


83.3


an oil,


which


was


identical


that


prepared by


Godlesky


co-workers.


(+,-)-octahvdro-8-hvdroxv-l-(2H)-nanhthalenone


(132).









(0.10


TBTH


(1.12


3.85


mmol) ,


solution


was


carefully


degassed by


bubbling


with


argon


reaction


was


heated


800C


(bath


temperature)


manner


that


level


bath


was


lower


than


level


solution.


UV active


After


staring


thin


aldehyde


layer


chromatography


remaining


indicated


reaction


was


complete.


solvents


were


removed


under


reduced


pressure


and


crude


was


subjected


flash


chromatography


silica


isolate


thick


(0.294


22%)


using


hex/ether-30:70


solvent


Rf=0


THF-hexanes);


1H),


1H NMR


2.32


(CDCl3)


2H),


1.86-2


4.19


1H),


2H),


2H),


3H),


1.44


NMR


CDC13,


MHz


.47,


66.79,


58.88,


39.74,


37.23,


28.82,


27.76,


24.33,


20.03;


(neat


NaCl


plate


3407


(brod.


2932


(s),


2864,


1705


1447,


1128,


1050,


971,


cm 1;


HRMS


calcd:


C10H1602,


168.1150,


found


.1125;


Anal.


Calcd:


71.39%,


9.59;


found:


71.31%,


9.91%.


We used hexane,


ethyl


alcohol,


2-propanol


as solvents


obtain


crystals


from


alcohol


131,


unfortunately,


them failed.



(+,-)-octahydro-8-oxo-papabrobenzeneester-1-(2H)-


naehthalenone


(133).


2H),










evaporation,


followed


full


pump,


give


the


desired


compound


colorless


needles.


4-Bromobenzoyl


chloride


.78g,


3.57


mmol)


was


dissolved


10 mL of


pyridine


(1:1)


and


solution


alcohol


1.19


mmol)


pyridine


was


added


flask


dropwise


.The


mixture


was


stirred


was


then


poured


into


10 mL of


water


and


extracted


with


methylene


chloride


The


extract


was


washed


with


sodium


bicarbonate


solution,


dried


MgSO4)


. Evaporation


silica


gel)


solvent


obtained


and


ester


flash


(0.32


chromatography


76.4%,


using


hex/ether-65:


solvent


Rf=0


THF-hexanes);


1H NMR


(CDC13)


7.87


2H),7.56


2H),


1H) ,


2.84


, 1H) ,


2H),


1H),


.1-1


131.12,


10H) ;


130.55,


13C NMR


128.87,


CDC13,


127.45,


69.97,


MHz)


8210


54.09,


.32,


40.46,


.40,


36.47,


.66,


27.58,


27.38,


22.91,


.16.


Recrystallization


from


mL of ethanol


room temperature


(one


week)


obtained


desired


ester


as colorless crystal,


m.p.


120.8-121.7


4a-methyl-4. 4a. 5.6.7. 8-hexahydronaphthelen-2-one (134)


prepared by the method of Heathcock and


coworkers.


Alkene


dialcohol


and


alcohol


137.


Were


identical


that


prepared


Becker


and


CO-


135;









Prepared


Swern


oxidationxx


137;


Rf=0.37


THF-


hexanes);


NMR


(CDC13


9.78


1H) ,


6.70


1H),


1H) ,


2.38-2


4H),


1.98


1H),


1.79


, 1.67


2H),


1.65


3H);


NMR


(CDCl3,


MHz)


.24,


199.


159.07,


.93,


44.50,


40.65,


36.01,


34.52


, 34.47,


25.09,


17.13;


(neat


NaCI


plate


3340,


955,


1723,


1681,


1391,


1120,


HRMS


Anal.


calcd:


Calcd:


C10H1702


73.30%,


(M+1


, 8.95;


.1228,


found:


found


72.90%,


181.1262;


9.05%.


(+, -) -endo-5-hydroxy-1-methylbicyclo 4


.3.11decan-7-one


(139)


Rf=0


THF-hexanes)


:300


MHz


1H NMR


(CDCl3)


3.61


2H),


1H),


2H),


1H),


NMR


(CDCl3,


MHz)


.11,


75.24,


50.49,


38.20,


37.61,


.15,


37.02,


35.81,


31.91,


31.17,


19.55;


(KBr


film)


3410


(brod.


2932


(m),


2860,


1701


1448


(w) ,


1313,


1227,


1057


cm-1;


Exact


mass


C11H1802,


calc.


.1306,


found:


182.1320;


Anal.


Calcd:


72.49%,


9.95;


found


72.35%,


10.06%.


used


2-propanol


hexane


(1:1)


solvent


recrystallize


alcohol


room temperature


obtained


desired


coulorless


crystal


four


days,


m.p.


68.50C.


: C,


cm- 1










tertiary


13c


NMR


resonance


PPM


and


loss


resonance


NMR


.86-2


PPM


which


now


integrated


instead


of 2H.


3- (4'-t-butyldimethylsiloxybutane)-2-cyclohexenone (141).


Prepared


standard


methods


from


known


alcohol


Rf=0


THF-hexanes);


NMR


CDC13)


, 2H),


4H),


, 9H),


.21-2


6H),
;13C


.049


NMR


(CDCl3,


MHz)


.80,


.35,


.62,


37.71,


37.27,


.18,


29.51,


.86,


.16,


.63,


18.23


(neat


oil


NaCI


plates


, 2858,


1672


, 1462,


1255,


1102,


836,


Anal.


C16H


002Si,


68.0


10.71;


found:


68.01%,


.92%.


Decvl


Aldehvde


(142)


commercially


available


from


Aldrich


Chemical


and


used


3- (4'-t-but


yldimethylsiloxybutane)


-2-cye


lohexanone


(143)


Rf=0


THF-hexanes


NMR


(CDCl3)


.18-2


.4H)


.5-2


7H),


1.18-1


4H),


9H),


.045


6H); 13C


NMR


(CDC13,


MHz)


.42,


62.91,


41.45,


39.02,


.34,


.76,


31.20,


, 2H)


C,


, H,


cm-1;









C16H3202Si,


Calcd:


67.54%,


11.34;


found:


67.43%,


11.52


Alcohol


(144) .


compared


with


commercially


available


sample


from


Aldrich Chemical


3-hydroxy-1-(4'-t-butyldimethylsiloxybutane)cyclohexene


keton


141


mmol)


was


reduced


described


preparation


compound


104


afford


alcohol


as an oil


99.3%


MHz


IH NMR


CDC13)


(6H,


0.86


1.34-1.56


(6H,


.68-1


(6H,


2.42


(1H,


4.13


(1H,


5.44


(1H,


NMR


(CDC13,


MHz


18.27,


19.15,


.60,


.91,


28.34,


31.89,


37.23


123.98;


Anal.


C16H3


67.57%,


11.31;


found:


67.58%,


11.57%.



3-Phenylthio-1-(4'-butyldimethylsiloxybutane)cvclohexene


(156)


solution


alcohol


155


mmol)


and


triethylamine


(1.65


16.3mmol)


methylene


chloride


was


added


methanesulfonyl


chloride


(1.37


Decyl









butyllithium


(5.01


solution


hexane,


mmol


thiophenol


mmol)


mL of


THF.


lithium


solution


thiophenoxide


at -15


solution


was


react ion


added


was


then


the


allowed


first


warm


room


temperature.


After


stirring


overnight,


reaction


mixture


was


partitioned


between


mL of ether


mL of


saturated


ammonium


chloride.


organic


layer


was


separated


dried,


and


solvent


was


removed


vacuo.


flash


chromatography


afforded


product


54.5


oil;


MHz


NMR


(CDC13


.35-1


.68-1


(6H,


3.35


(2H,


3.54


(2H,


(1H,


(1H,


7.12


-7.44


(5H,


NMR


CDCl


, 23


28.2,


37.8,


63.2,


l-Butanal-3-


(phenylthio) cyclohexene


(1571.


protected


alcohol


was


deprotected


and


oxidized


scr


ibed


and


give


aldehyde


157


color


ess


Alcohol


: 300


NMR


(CDC13


.39-2


12H,


(1H,


(2H,


NMR


(CDCl3,


MHz


19.67,


.68,


.69,


.28,


.51,


44.55,


62.56,


.94,


.45,


.16,


.14,


141.76









19.65,


19.88,


28.05,


28.71,


36.95,


43.16,


44.46,


121.99,


126.55,


128.79,


131.33,


135.98,


.64,


202.29.


3-Phenvlthio-6-methyl-6-(4'-t-


butyldimethylsiloxybutane)cyclohexene (160)


The


keton


159


was


reduced


described


the


preparation


compound


to afford


an alcohol


an oil


NMR


(CDCl3)


0.02


(6H,


0.86


(3H,


.2-1.99


(10H,


(2H,


4.08


(1H,


NMR


(CDC13,


MHz)


20.15,


0.37,


.92,


, 33.53,


.57,


42.04,


66.45,


.56,


128.


139.11,


139.94;


Anal.


for C17H340


2Si,


Calcd:


68.39%,


11.48;


found:


68.14%,


11.65%


Sulfide


160 was


obtained from above


alcohol


as described


for the


preparation


compound 149;


1H NMR


(CDCl3)


(6H,


0.87


(3H,


1.17-1.97


(10H,


5.52


NMR


(CDCl3,


MHz


820.


.55,


25.98,


26.02,


26.89,


32.50,


33.64,


42.3


, 63.11,


.78,


125.40,


126.53,


126.62,


.36,


.52,


Preparation


139.89.


sulfone


161.


solution


(0.95


mmol)


and


Pyridine


was


treated


-400C


with


m-CPBA


50-60%,


6.08


, 2









chromatography


provided


sulfone


60.6%);


NMR


(CDC13)


(6H,


(9H,


0.90


(3H,


0.98-1.55


(8H,


1.91


(2H,


3.51


(2H,


(3H,


m); 1


NMR


(CDCl3,


MHz)


42.06,


19.98,


62.91,


.05,


116.


.93,


.78,


.44,


129.27


33.40,


.44,


.31,


.65;


Anal .


3H3803


Calcd:


65.35%,


.06%;


found:


65.24%,


Preparation


of aldehyde


162.


Deprotect ion


compound


161


described


produced


alcohol,


followed


oxidation


described


aldehyde


as a colorless


oil.


Alcohol


same


compound 163):


1H NMR


(CDCl3)


0.91


(3H,


1.1-2.2


(11H,


3.59


(2H,


3.71


1H,


(2H,


(3H,


m); 1


NMR


(CDCl


MHz)


19.45,


19.67,


.06,


.92,


33.33,


40.75,


41.19,


62.63,


116.59,


.81,


128.84,


, 133.57,


.98.


Aldehyde


300


NMR


(CDCl3)


0.72-2


11H,


(2H,


7.48-7


(2H,


NMR


CDCl3,


MHz


19.65,


19.88,


28.05,


.71,


36.95


43.16,


44.46,


121.99,


126.55,


128.79,


131.33,


135.98,


.64,


202.14.
















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BIOGRAPHICAL


SKETCH


Yongping


was


born


Lanzhou,


China,


1956.


After


graduating


spent


from


almost


Lanzhou


three


years


Secondary


High


farmer


School


Yuzhong


1973,


County,


Ganshou


Province,


and


spent


years


electrician


Lanz


Company


In


1978


enrolled


Lanzhou


University


1982.


August


received


1982,


B.S.


became


organic

research


chemistry

associate


July

Bee


Rese


arch


Institute


Chinese


Academy


Agriculture,


Beijing.


1984


the


Institute


send


him


Italy


visiting


scholar


. He


visited


almost


major


Italian


citi


program


USA


M.S.


ten


graduate


degr


months.


program


organic


June,


1989,


chemistry.


chemistry


arrived


After


Wright


obtaining


State


University

Chemistry


August


at University


1991,


of Florida


entered

. His P


the


h.D.


Department

in chemistry


expected


Purdue


May,


University


1995.


West


Upon


completion,


Lafayette,


Indiana,


will

where


move

he


will


work


the


Department


Medicinal


Chemistry


and


Pharmacognosy


as a postdoctoral


fellow.







I certify that
opinion it conforms
presentation and is
a dissertation for


I have read this study and that in my
to acceptable standards of scholarly
fully adequate, in scope and quality,
the degree of Doctor of Philosophy.


J. Eri
Associ
Chemi


I certify that
opinion it conforms
presentation and is
a dissertation for


holm, Chairman
Professor of


I have read this study and that in my
to acceptable standards of scholarly
fully adequate, in scope and quality,
the degree of Doctor of Philosophy.


Kirk S.
Associat
Chemist


change
Professor of


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,
a dissertation for the degree of D.ctor of Philosophy.


n R.'Reynold
hociate Profe
chemistry


sor of


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,
a dissertation for the degree of Doctor of Philosophy.


David E. Richardson
Professor of Chemistrv








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.


'% L.


Nicholas Bodor
Graduate Research Professor
of Medical Chemistry


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.


May,


1995


Dean,


Graduate School




















LD
1780
199




UNIVERSITY OF FLORIDA
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