This manuscript has been reproduced from the microfilm master. UMI films the

text directly from the original or copy submitted. Thus, some thesis and

dissertation copies are in typewriter face, while others may be from any type of

computer printer.

The quality of this reproduction is dependent upon the quality of the copy

submitted. Broken or indistinct print, colored or poor quality illustrations and

photographs, print bleedthrough, substandard margins, and improper alignment

can adversely affect reproduction.

In the unlikely event that the author did not send UMI a complete manuscript and

there are missing pages, these will be noted. Also, if unauthorized copyright

material had to be removed, a note will indicate the deletion.

Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning

the original, beginning at the upper left-hand comer and continuing from left to

right in equal sections with small overlaps. Each original is also photographed in

one exposure and is included in reduced form at the back of the book.

Photographs included in the original manuscript have been reproduced

xerographically in this copy. Higher quality 6" x 9" black and white photographic

prints are available for any photographs or illustrations appearing in this copy for

an additional charge. Contact UMI directly to order.

Bell & Howell Information and Learning 3OO'North Zeeb Road, Ann Arbor, MI 48106-1346 USA

800-521-0600

The Synthesis of the C24C32 Subunit of (+)-Ionomycin

Lisa Cameron

A thesis submitted in conformity with the requirements for the Degree of Master of Science, Graduate Department of Chemistry,

University of Toronto

8 Copyright by Lisa Cameron 1998

National Library Bibliotheque nationale du Canada

Acquisitions and Acquisitions et Bibliographic Services services bibliographiques

395 Wellington Street 395. rue Wellington Ottawa ON K I A O N 4 Ottawa ON K1 A ON4 Canada Canada

The author has granted a non- exclusive licence allowing the National Library of Canada to reproduce, loan, distribute or sell copies of this thesis in microform, paper or electronic formats.

The author retains ownership of the copyright in this thesis. Neither the thesis nor substantial extracts &om it may be printed or otherwise reproduced without the author's permission.

L'auteur a accorde m e licence non exclusive pennettant a la Bibliotheque nationale du Canada de reproduire, preter, distribuer ou vendre des copies de cette these sous la forme de microfichelfih, de reproduction sur papier ou sur format electronique.

L'auteur conserve la propriete du droit d'auteur qui protege cette th&se. Ni la these ni des extraits substantiels de celleci ne doivent etre imprimes ou autrement reproduits sans son autorisation.

Abstract

The Synthesis of the C24-C32 Subunit of (+) -1onomycin Master of Science, 1996, Lisa Cameron

Graduate Department of Chemistry, University of Toronto

Described herein is the Lautens/Colucci total synthesis of ( + )

ionomycin, with specific attention being paid to the synthesis of

the C24-C32 tetrahydrofuranyl subunit. To date, two previous total

syntheses of ( + ) ionomycin, to be discussed, have been published by

the groups of Evans and Hanessian. Also described is the general

chemistry of the formation of tetrahydrofuran rings.

This tetrahydrofuranyl subunit, ring B of ionomycin, is derived

from a geranyl acetate backbone. Sharpless asymmetric epoxidation

and a diastereoselective epoxidation-cyclization sequence are the

key manipulations applied to install the desired stereocentres.

Each of the other three acyclic fragments of ionomycin arise from

exploitation of the versatile chemistry of [ 3 .2.1] oxabicycles,

Chemistry developed in this laboratory which provides

enantiospecific nucleophilic ring opening effects further skeletal

elaboration,

Acknowledgments

I would like to gratefully acknowledge my advisor, Professor Mark

Lautens. His support and encouragement were invaluable throughout

my time spent in the Lautens group. I have learnt a great deal

because of Dr. Lautens, and for that I would like to express my

sincere gratitude.

It is also important for me to thank the members of the Lautens

group, each of whom were eager to lend help and share knowledge.

Their support and friendship is appreciated more than I can say.

Special thanks to Dr. Giliane Bouchard, Jianqing Chen, Greg Hughes,

Dr. Tornislav Rovis, dr. Nick Smith, and lastly, Dr. John Colucci,

who provided the basis for this work.

Finally I would like to thank my family and friends, who always

lead me back on track, wherever it may be.

Abstract Acknowledgments Table of Contents

iii iv

CHAPTER 1 INTRODUCTION TO THE CLASS OF POLYETKER ANTIBIOTICS AND (+ ) IONOMYCIN

1 Introduction 1.1 Introduction to Polyether Antibiotics 1.2 Introduction to the Polyether Antibiotic (+)

Ionomycin 1.3 References and Notes

CHAPTER 2 INTRODUCTION TO THE CHEMISTRY OF ( + ) IONOMYCIN 2 The Chemistry of Ionomycin 2.1 Introduction 2.2 Syntheses of the C1-C9/10 Fragment 2.2.1 Evans Synthesis of the C1-C10 Fragment 2.2.2 Hanessian Synthesis of the C1-C10 Fragment 2.2.3 Lautens/Colucci Synthesis of the C1-C9 Fragment 2.3 Syntheses of the C10/11-C16 Fragment 2.3.1 Evans Synthesis of the Cll-C16 Fragment 2 . 3 . 2 Hanessian Synthesis of the Cll-C16 Fragment 2.3.3 Lautens/Colucci Synthesis of the C10-C16 Fragment 2.4 Syntheses of the C17-C22/23 Fragment 2.4.1 Evans Synthesis of the C17-C22 Fragment 2.4.2 Hanessian Synthesis of the C17-C22 Fragment 2.4.3 Lautens/Colucci Synthesis of the C17-C23 Fragment 2 - 5 References and Notes

CHAPTER 3 THE CHEMISTRY OF THE TETMYDRO-L SUBUNIT 3 The Chemistry of the Tetrahydrofuranyl Subunit 3.1 Synthetic Developments Towards Tetrahydrofuran

Synthesis 3.1.1 Diastereoselective Epoxidation of a Bis

homoallylic Alcohol Followed by Acid Catalyzed Ring Closure

3-1.2 Oxidative Cyclization of 1,s-Dienes 3.1.3 Oxabicyclo [3.2,1] Octenones 3.1.4 Halocyclization 3.1.5 Polyepoxide Cyclization 3-1.6 Miscellaneous Routes to Tetrahydrofurans 3.2 Synthetic Developments Towards the Tetrahydrofuran

Moiety of (+ ) Ionomycin 3.2.1 Wuts 3 . 2 . 2 Spino and Weiler 3.2.3 Evans 3.2-4 Hanessian 3.3 References and Notes

CHAPTER 4 OUR SYNTHESIS OF THE C24-C32 FRAGMENT OF (+) IONOMYCIN

4 Our Synthesis of C24-C32 4.1 Synthetic Strategy and Discussion of Route 4.2 Experimental 4 . 3 References and Notes

CHAPTER 1

INTRODUCTION TO THE CLASS OF

POLmTHER ANTIBIOTICS

AND

(+) -1ONOMYCIN

Introduction

1.1 Introduction to Polyether Antibiotics

Monocarboxylic acid ionophores, also referred to as polyether

antibiotics are a large group of natural products which act to

chelate cations. These ionophores are comparable to crown ethers

in their cation binding ability, but differ significantly in

specificity. Crown ethers complex cations according to relative

dimension of cation and macrocyclic cavity, while polyether

antibiotics are able to chelate cations of varying sizesi. This

class of compounds, derived from various strains of streptomyces

organisms', has stirred much interest in scientific circles, The

interest stems from their unique ability to translocate inorganic

cations through hydrophobic lipid bilayers, which results in a wide

variety of biological functions. Some of these include

antimicrobial agents3, growth promoters in ruminants4, and the

initiation of cardiovascular responses in mammals5.

Although the first polyether antibiotic was isolated in 1950" it

was not until 1967 that a structural elucidation of a member of

this class was achieved7. The makeup of polyether antibiotics

typically consists of a carboxylate group along with several

additional oxygen ligandsa . Substituted tetrahydrofuran and

tetrahydropyran rings, as well as spiroketal functions' are

prevalent in the architecture of these molecules.

The 70 polyether antibiotics that have been isolated to date

present a formidable challenge to synthetic chemists. The

differing stereochemical arrangement of functional groups has

resulted in an unceasing flow of investigation and development of

elegant methodology. Scheme I depicts a small selection from the

class of polyether antibiotics.

Scheme I

Lasalocid A

Monensin

% 5

lRUllIlll

MeHN

Calcirnycin

1.2 In t roduc t ion to the Polyether A n t i b i o t i c (+) -1onomycin

( + I -Ionornycin, (Scheme 2 , was f i r s t i s o l a t e d from t h e fe rmenta t ion

broths of Streptomyces c o n g o b l a t ~ s ~ ~ i n 1978. Ionomycin i s d i s t i n c t

f rom the o t h e r members of t h e p o l y e t h e r antibiotic f a m i l y i n

s e v e r a l impor tan t ways. F i r s t l y , i t i s doubly charged, and

t h e r e f o r e h i g h l y s e l e c t i v e f o r divalent i o n s . T h i s p r o p e r t y i s i n

d i r e c t c o n t r a s t t o the monobasic c h e l a t i n g e f f e c t s o f other

p o l ye ther a n t i b i o t i c s and allows ionomycin t o c h e l a t e d i v a l e n t ions

a s a d i b a s i c a c id i n an oc tahedra l coo rd ina t i on system, as a 1:1

charge-neutral complex." Calcimycin is the only other ionophore

to similarly distinguish between monovalent and divalant cations,

differentiating between calcium and magnesium as its 2:1

ligand/metal complex.12 A second anomaly is present in the P- dicarbonyl functionality at C,-C,,, a rarity in natural products.

This moiety accounts for two of the six charged ligation points,13

and the intense W absorption band at 280 nm that is exhibited by

ionomycin.14 Lastly, while the backbone of ionomycin consists of

one long acyclic chain, and two furanoid rings, other ionophores of

simillar size are of a more polycyclic nature?

Scheme 2

The structure of ( + ) -ionornycin was elucidatsd in 1979 by Gougoutas

et al. l"trructura1 determination was achieved by X-ray

cyrstallography as well 'H and 13C NMR spectroscopic studies. The

dianion salt of ionomycin exhibits an octahedral coordination to

the central cation, typically, ca2+.

1 .Shultz, W - J - ; Etter, M. C.; Pocius, A, V.; Pocius, S. S. J. Am. Chem. SOC. 1980, 102, 7981

2. Westley, J, W. Polyether Antibiotics; Ed. ; Marcel Dekker: New York, 1982; Vol, 1-2

3.M. D. Ruff, Polyether Antibiotics; Naturally Occuring Acid Ionophores (Edited by J. W, Westley) , Vol. I, Ch. 6, Marcel Dekker, New York (1982)

4,M. D o Ruff, Polyether Antibiotics; Naturally Occuring Acid Ionophores (Edited by J. W. Westley) , Vol. I, Ch. 6. Marcel Dekker, New York (1982)

5.H. G . Hanley and J. D. Slack, Ref, 4, Ch. 8; P. W. Reed and G. M. Bokock, R e f . 4, Ch. 9; M. W. Osborne, J. Wenger, M. Zanko, F. Kovzelove and M. R. Cohen, Ref. 4, Ch 10

6-Berger, J. ; Rachlin, A. I.; Scott, W. E.; Sterback, L. H. ; Goldberg, M. W. J. Am. Chem. Soc. 1952, 7 3 , 5295

7 .Monensin: Agatrap, A. ; Chamberlin, J, W. ; Pinkerton, M. ; Steinrauf, L, J. Am. Chem. Soc, 1967, 89, 5737

8 .Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; T a k a c s , J. M, ; Zahler, R J. Am. Chem. Soc. 1990, 112, 5290

9.Boivin, T. L . B. Tetrahedron, 1987, 15, 3309

lO,Liu, C.M.; Herrnann, T, E. J. B i o l . Chem. 1978, 2 5 3 , 5892

Il.Westley, J. W. Adv. Appl . Microbial. 1977, 2 2 , 1 7 7

12.Chaney, M. 0 . ; Demarco, P. V.; Jones, N. D.; Occolowitz, J. I,. J. Am. Chem. Soc. 1974, 96, 1932

13 .Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290

14 ,Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; Takacs, J. M. ; Zahler, R J. Am. Chem. Soc. 1990, 112, 5290

1 5 . W ~ t . s ~ P. G , M.; DfCosta, R.; Butler, W. J. Org. Chem, 1984, 49, 2582

16-Toeplitz, B. K- ; Cohen, A. I. ; Funke, P. T. ; Parker, W. L.; Gougoutas, J. Z . J. Am. Chem. Soc. 1979, 101, 3344

CHAPTER 2

INTRODUCTION TO THE CHEMISTRY OF

(+) IONOMYCIN

2 T h e Chemistry of Ionomycin

2.1 Introduction

(+) -1onomycin is constructed of a 32 carbon skeleton. Of these

carbon centers, 14 exhibit asymmetry. Both a cis and a trans

2,2,5-substituted tetrahydro furanyl ring system are present , as

wel l as a trans disubstituted olefin, and three hydroxyl groups.

A P-diketone and a carboxylic acid group complete the list of

functionality. Also noteworthy are the alternating methyl groups

from C1 to C16 and the propionate derived sequence that forms C17

to C 2 2 ,

Scheme l

TrO 0'

OTMS

TrO /' 17 F G

Constructing the ionornycin backbone with correct relative, and

absolute stereochemistry, is a formidable challenge. A convergent

synthetic approach readily simplifies this challenge. This

strategy entails the construction of smaller, simpler pieces of the

whole, which can then be joined with stereospecificity. Although

the controlled combining of fragments is not always as

straightforward as is hoped, and the final stages of any synthesis

is a poor time to experience problems, covergency is still an

excellent strategy.

Scheme Il

Another advantage of a convergent synthesis the ability to create

functionality upon appending of subunits. Although risky, this

approach is often desirable. In this way, the requisite functional

groups do not necessarily need to exist within the individual

f ragrnents . The retrosyntheses of all groups involved, i. e. Evans,

Hanessian, (Scheme I) , and Lautens/Colucci, (Scheme 11) illustrate this.

Both of the previously published total syntheses of ionomycin

employed similar strategies. Evans and Hanessian applied identical

disconnections in the construction of the ionomycin backbone; C1-

C10, Cll-C16, C17-C22, and C23-C32. In addition, the mode of

coupling of the individually constructed fragments, and the order

of coupling were identical. Different approaches to the individual

subunits make each of the previous synthetic efforts distinct.

2.2 Syntheses of the cI-c~/C~O Fragment

The C9-Cll P-dicarbonyl region of ( + ) ionomycin is an obvious point

of disconnection. Evans and Hanessian chose to make the C1-C9

fragment which could be coupled via aldol condensation of the C10

enolate to the C11 aldehyde. Colucci on the other hand, opted to

construct the C1-C10 fragment, after which the C10 enolate could be

coupled to the C 9 aldehyde.

Once the choice of disconnections was made, the focus was turned to

the stereochemically controlled installation of the syn-1,3-anti-

3,5 methyl triad on the carbon backbone.

2.2.1 Evans Synthesis of the C1-CIO Fragment

A u~lique synthetic approach was used to introduce each of the three

stereocentres of this fragment, C4, C6, and C8. First, Evans used

a chiral aldol reaction developed within their laboratory.' The

boron enolate of the norephedrine-based chiral carboximide', 2, was

added to acetaldehyde, as seen in Scheme 111. This reaction

proceeded highly selectively, with a diastereorneric excess

exceeding 985, and in good yield (93%) to give the P- hydroxycarbonyl, 3. Transesterification with lithium benzyloxide3

affected the removal of the chiral auxiliary. This ester was then

reduced to the diol before Swern oxidation to the aldehyde.

Reduction to the primary allylic alcohol was followed by

condensation with (carbethoxyethylidene) triphenylphosphorane, to

give an a$-unsaturated ester. A second,reduction led to a primary

allylic alcohol which was then iodinated to give compound 4 .

Scheme Ill

Next, the C4 center was established using the same propionate

chiral auxiliary in an asmymetric alkylation approach, also

developed in the Evans laboratory.' The allylic alcohol was first

converted to i tr s corresponding allylic iodide, via Landauer-Rydon

methodology' using methyltriphenoxyphosphonium iodide in DMF. The

alkylated product, 5, was obtained in 73% yield, with a

diastereomeric excess of 96%. A final two carbon extension was

performed using the same sequence outlined directly above to give

the full C1-C10 backbone. Installation of the correct

stereochemistry at C6 remained before completion of the fragment 6.

In order to install the correct stereocentre at C6, the C 9 carbonyl

was carried through the sequence as the corresponding secondary

alcohol. This hydroxyl group could then be exploited in a directed

hydrogenation reaction6 to give the requisite 1,3-syn-dimethyl

relationship. Cationic rhodium catalyst, [m (NBD) (DIPHOS) -41 BF,',

5 mol%, afforded the hydrogenated product in 96% yield, with a

diastereomeric ratio of 94 : 6, favouring the desired stereochemical

orientation at C 6 - This selectivity is assumed to arise from 1,3

strain conformational effectse at the allylic position.

The C1-C10 fragment was obtained in 17 steps starting from (IS, 2 R ) - norephedrine .

2.2.2 Hanessian Synthesis of the C1-C10 Fragment

Hanessian employed two butenolide templates, each derived from L-

glutamic acid, to stereoselectively construct the C1-C10 skeleton,

Scheme IV. (Pheny1thio)methane provided the one remaining carbon

necessary to complete the 10 carbon fragment.

The L-glutamic acid derivative, lactone 7 , has a methyl group which

corresponds to one of the syn-oriented methyl groups in the desired

fragment. A second methyl group was necessary at the ring oxygen

bearing carbon. This was seen to arise from direct nucleophilic

displacement.

Scheme N

L-Glutamic Acid RO

OR --kp

OTBDMS OTBDMS OTBDMS OR -

Epoxide 8 was obtained from the lactone in four steps. Epoxide

opening with (phenylthiomethyl) lithium assisted by DABCO' followed

by protection provided the tosylate, 9. Direct nucleophilic

displacement of the tosylate, with complete inversion of

stereochemistry, was affected by a sulfur assisted1* reaction with

lithium dimethylcuprate." The presence of the sulfide proved to

be pivotal. If a sulfoxide group or an alkyl group were present in

lieu of the sulfide, competitive elimination resulted. Next,

elimination of the thioether group was performed, resulting in a

C9-C10 olefin which underwent Wacker oxidation, unselective

reduction and protection to give silyl ether 10.

In preparation for a Peterson olefination with a second L-glutamic

acid derivative, 11, the primary hydroxyl group was next oxidized

to the aldehyde. The mixture of olefins was hydrogenated to

produce the corresponding saturated lactone, 12, as a mixture of C 9

epimers. The bis (phenylthio) ether was formed via the diol derived

from the lactone, 13. Desulfurization using Raney-nickel gave the

doubly deoxygenated product, which was then oxidized to give

ionomycin f ragnent 1 4 .

The Hanessian synthesis of the C1-C10 fragment of ( + ) ionomycin

required 26 steps from the starting L-glutamic acid.

2.2.3 Colucci/Lautens Synthesis of the C1-C9 Fragment

It was noted early on that the Cl-C9 fragment of ionomycin

contained the 1,3-syn-3,5-anti methyl triad orientation that was

obtained after methylithium induced nucleophilic ring opening of

(3.2.11 oxabicyclic alkenes followed by ozonolysis . "

Scheme V

2 Steps, 65% yield *

- - - - - - 1 Step followed by . d ~ e - 6 ~ e - - -

3 - - - - chromatographic

17 15 seperation, 45% yield 16 - T'ps(&+ - - -

-- - 4 Steps, 39% yield 3 Steps, 84Oh yield = 3 Steps, 77% yield - - - - - - - - - -

Monocycle 15 was obtained from nucleophilic attack (methyl lithium)

at the C7 position of a well known oxabicycle", Scheme V.

Resolution of the resulting diol proceeded by esterification with

a chiral acid. The mandelate ester used served two additional

purposes; to act as a protecting group, and as a hold to

differentiate the two ends of the acyclic fragment after ozonolysis

with reductive workup.

Ozonolytic cleavage resulted in a mixture of hydroxy lactols, 17.

The primary hydroxyl was selectively protected as the s i l y l ether

before removal of the mandelate ester, which was achieved by

treatment with DIBAL-H. At this point, a two carbon extension is

required to complete the 9 C backbone, and to this end,

triphenylcarbo-t-butoxymethylenephosphorane was used, to yield the

monoprotected trio1 18.

The dideoxy product was obtained via application of Barton

conditions. Formation of the thiocarbonate led anly to

deoxygenation at C 7 , and not CS: Barton had previously determined

that simultaneous deoxygenation would not occurT4 and so a

sequential approach was undertaken. To accomplish the task at

hand, namely the second deoxygenation, Rasmus senr s protocol15 was

applied to produce a CS thiocarbonylinidazolide which was then

reduced. It remained for the functionality at both terminals to be

adjusted. This was accomplished in three additional steps.

Treatment with TBAF resulted in deprotection of the silyl ether.

Transesterification was effected by refluxing conc. H2S04 in

methanol. Finally oxidation gave the aldehyde 19 in a total of 17

steps starting from furan, with an overall yield of 2.56.

2.3 Syntheses of the ClO/Cll-C16 Fragment

Evans and Hanessian both constructed the Cll-C16 fragment of

ionomycin, while the Colucci/Lautens synthesis involved the

construction of a CI0-C16 fragment. As with Evans and Hanessian,

Colucci intended to couple the C16 and C17 termini via

Lythqoe'"eaction. Ail three syntheses also sought to use

coupling to join the C1-CIO fragment to CII, or the C1-C9

to C 1 0 as the case may be: A regioselective enolizationi7

a Julia-

the same

f ragmeni

followed

by an aldol condensation to give the desired bond formation, Three

stereocencers ex is^ in each of the two described fragments, C11,

C X , a c C14-

2.3.1 Evans Synthesis of the Cll-C16 Fragment

12 t h e i r ccnstruction of the C11-Cl6 fragment of ionomycin, the

E v m s grccp again used two chiral propionate enolates, Scheme VI.

C r n r a m y l brcmicie was added to t h e Lithium enolate of 20 with

9 8 . 3 : 1 . 7 c i a s t e r e o s e ~ e c t i v i c y . The chiral auxiliary was removed by

redzcion with lithium aluminum h y a r i d e .

Scheme VI

Mesylation of the resulting primary alcohol followed by treatment

with sodium iodide afforded ally1 iodide 22. Due to its greater

nucleophilicity, the prolinol amide enolate was applied to the next

alkylation applied, resulting in a diastereomeric ratio of 97: 3.

The corresponding carboxylic acid was obtained after internally

assisted hydrolysis and treatment with sodium hydroxide. Less than

1% epimerization was observed upon reduction to the Cl1 alcohol

with lithium aluminum hydride, to give 24 . This alcohol was

protected before manipulation of the C16 position. Ozonolysis

followed by reductive workup, provides a handle for further

functionalization; formation of either the phosphonium salt or the

s u l f o n e , 25, to participate in trans olefination through Schlosser-

WittigL8 or 3ulia19 reactions.

2.3.2 Hanessian Synthesis of the C11-C16 Fragment

Hanessian- began his work on ionomycin early on, as did Evans, with

a paper published in 1986" detailing the construction of two

fragments of ionomycin; C2-C10, and Cll-C22, from butenolide

templates. These early routes were not considered synthetically

viable. In 1990, Hanessian published a synthetic route to the C11-

C16 fragmentz2, and it is this approach, illustrated by Scheme VII,

that was later used in their total synthesis.

A series of four steps from L-glutamic acid afforded the chiral

compound 26. Conjugate addition resulted from treatment of 26 with

trithiomethyl lithium to give a diastereomeric ratio of 99:l in

favour of the desired isomer. Installation of a hydroxyl group

alpha to the carbonyl was achieved by trapping of the enolate with

an oxodiperoxornolybdenum (IV) -pyridine-HMPA ~ornplex*~. Raney Nickel

reduction effected the removal of the three C12 thiomethyl groups.

Scheme VII

OTBDPS

k2r0 OTBDPS OTBDPS f

o+ V (M~s)~c''' b" -k2+

OH ,**. OH

28

4-0 29

,,S'K~- 27 30 0

The second butenolide template was formed in s i t u . The epoxide

formed from 28 underwent nucleophilic attack by the sulfone anion

30 to give the hydroxy acid butenolide precursor 31. Lactone

formation was accomplished by treatment with EDCI and DMAP. The

sulfide was oxidized to the sulfoxide which then underwent

elimination to give the butenolide. Treatment with lithiodimethyl

cupr~te effected the second conjugate addition which gave compound

32 with the newly installed stereocentre at C14- A further 8 steps

afforded alcohol 33.

The C16 functional handle remained to be introduced. Sulfonation

of 33 was accomplished by mesylation and subsequent displacement

with lithium thiophenoxide. Oxidation with mCPBA yielded the

targeted compound 34 in a total of 25 steps, starting from L-

glutamic acid. This methylation-hydroxylation sequence is the same

methodology used in the Hanessian synthesis of the C17-C22 fragment

of ionomycin .

2.3-3 ~olucci/Lautens Synthesis of the C10-C16 Fragment

A complete racemic synthesis of the C10-C16 fragment was achieved

by Colucci in 10 steps starting from furan, with an overall yield

of 10%. The more important enantiopure approach, Scheme VIII, was

less direct.

Scheme Vlll

a) 5 moI0h (S)-BINAP. 10 molOk Ni(COD)2, PhMe, 65%. 1-1 equiv. DIBAL-H added via syringe pump over 20 hours; ( b)

KHMDS, PMBCI. cat. "BuNhl , THF, rt; (c)cat. 0s04, NMO, THF, water; (d) Na104, t-butanol, water, NaHCQ ; (e)

(PPH&RhCI. PhH. rt; (f) (Et0)2POCl+S02Ph, DBU, UCI, CYCN. OOC to R; (g) EtOH. Raney Nik, rt; (h) TBAF, THF, rt;

(h) TCDI, THF, refluy (i) (TMS)3SiH, PhMe, cat. AIBN. 1000 C

The enantioselective desymmetrization developed by ~ o v i s ~ ~ was

applied to known oxabicycle 35, prepared in 3 steps from furan.

Selective protection of the ring opened product as the para-

methoxybenzyl ether gave cycloheptenol 36. The choice of PMB as the

protecting group is accredited to i t ' s ability to be selectively

cleaved at a later stage.

Lemiuex oxidation2( was applied to the diprotected cyclic olefin 36,

in lieu of ozonolysis which resulted in partial oxidation of the

PMB group. Diol formation followed by oxidative cleavage to give

the dialdehyde 37, proceeded smoothly with an overall yield of 90%.

An observation made by ~suji~' in 1965 was then applied to the

dialdehyde as a selective means of decarbonylation. He observed

that the pressence of branching alpha to an aldehyde, caused a

decrease in the rate of decarbonylation using stoichiometric

Wilkinsonr s catalyst. With this information in hand, the desired

monaldehyde 38 was obtained in 78% yield over two steps. A

stabilized Wittig reaction under Roush conditiond6 provided the

unsaturated sulfone 39, which was directly reduced to the saturated

sulf one 40, under Raney-nickel catalysis, leaving the PMB ether

intact. Deprotection of the silyl ehter preceded deoxygenation

under Rasmussen' s condition^'^ which afforded the target molecule 41. This piece was accomplished in 13 steps, in an impressive

overall yield of 18.3%.

2 - 4 Syntheses of the ~ 1 7 - ~ 2 2 / ~ 2 4 Fragment of Ionomycin

The C17-C22/C23 fragment consists of four adjacent stereocentres

(C18, C19, C 2 0 , and C Z l ) , with alternating orientation in space.

This propionate derived molecule, having anti anti anti

substitution pattern, lends itself to many synthetic approaches.

Three are outlined below.

2-4.1 Evans Synthesis of the C l 7 - C 2 2 Fragment

Developments in the Evans laboratory showed that addition of the

boryl enolate of crotylimides to aldehydes results in a syn, a-

vinyl adduct. This observation was applied to install the C19 and

C20 stereocentres of ionomycin with high diastereoselectivity via

an aldol condensation, Scheme IX. Reaction of crotylimide 42 with

(S)-0-benzyl-2-methyl-3-hydroxypropionaldehyde, to give 43 in 588

overall yield, based on the alcohol precursor to the aldehyde. The

removal of the chiral auxiliary poses a problem. The competing

electrophilicity of the endocyclic carbonyl moiety necessitates the

activation of the exocyclic carbonyl. This is accomplished by

reformation of the boron aldolate ." Reaction with tri-n-

butylborane and glacial acetic acid followed by reduction gives

the monoprotected trio1 44 with the newly corrected stereochemistry

at C 2 0 . Tosylation and reduction with lithium triethylborohydride"

effected the deoxygenation of the methyl substituent at C20, to

give olefin 45.

Application of Upjohn condition^^^ resulted in a C21 diastereorneric mixture of C21, C22 diols. The primary hydroxyl of both

diastereomers were selectively protected as the silyl ether, so

that the desired 3,s-acetonide could be formed selectively.

Deprotection and oxidation to the aldehyde was carried out before

equilibration of the trans acetonide 49 to the thermodynamically

more stable counterpart 48. Deprotection of the silyl ether, the

thirteenth and final step of this sequence, afforded syn acetonide

50, in a 98:2 equilibration mixture.

Scheme lX

2 . 4 - 2 Hanessian Synthesis of the C17-C22 Fragment

The Hanessian synthesis of C17-C22 involved the same strategy seen

in their synthesis of the Cll-C16 fragment, the selective

methylation of two chiral butenolide templates." Here,

installation of a hydroxyl functionality alpha to the carbonyl

follows methylation in each case, (Scheme X) . Opening of the ring, selective protection of the primary hydroxyl function, and

epoxidation, installed the correct stereochemistry at C19. The

method of acetate extension and replication of the butenolide

template, to afford 55 is described in previous reports.32

Scheme X

Again, conjugate addition of a methyl nucleophile was used to

introduce t h e second methyl group. The syn product was formed

exclusively. Oxidation under the previously applied conditions

resulted in an epirneric mixture of alcohols at the C21 position.

The unwanted diastereomer was favoured in a ratio of 1.7:l. Both

diastereomers of 56 were carried through to the target aldehyde in

a 5 step sequence; reduction of the lactone, formation of the

primary pivalate ester, acetalization, cleavage of the pivalate

esters 57 and 58, and finally Swern oxidatiod3 to afford aldehydes

59 and 60. The undesired enantiomer 59 was easily epimerized to

t h e thermodynamically favoured acetal 60. It is of interest to

note the application of the same equilibration strategy by the

Evans group3' in their synthesis of this fragment.

The synthesis of the C17-C22 fragment was finally accomplished in

25 s t e p s starting f r o m L-glutamic acid.

2 . 4 . 3 Colucci/Lautens Synthesis of the C17-C23 Fragment

The work of ~spiotis" provides us with a route to the known

enarrtiopure dihydroxylated cycloheptenol 61, Oxidative cleavage of

this monoprotected ring system affords the backbone of the C17-C23

fragment- The immediate challenges are inversion of the C21

centre, and differentiation of the dialdehyde that arises from

oxidative cleavage,

Scheme XI

OTlPS OTlPS

Y Y o

OTlPS ?TIPS

OTlPS H"vLL f ,o&o 18 g z0 e i 1 - - TIPSO 0-0 TIPSO OPMB

H ~ P M B

HO 65 66 67

(a) DMSO, (COC1)2, NEt3, CkCr;?, -78%; (b) PhMe,DIBAL-H, -76'~; (c) THF, KHMDS, PMBCI; (d) Q, MeOHICl-&h, -78'~ then

NaBb, rt: (e) CH2Ch, DDQ, Mol. Sieves, rt; (f)TrCI, NEb, DMAP, CYCh, then C k C h , DIBAL-H, - 7 f f ' ~ to PC, then DMSO,

(COCih, NEt3, CH2Ch, -78OC

In response to failed attempts at a Mitsonobu reaction, a simple

oxidation-stereospecific reduction sequence (DIBAL-H) effects the

inversion, leading to a diastereorneric ratio >3O: 1 in favour of the

syn alcohol. Para-methoxybenzyl protection is the final stage

before reductive ozonolysis was carried out. Further reduction

gives the tetrol 65,

Specific manipulation of the C17 aldehyde made use of the

observation of ~ i k a w a ~ ~ et al. Specifically, that anhydrous

oxidation of the benzylic position of para-methoxybenzyl ethers

will result in cyclization onto the cation if an appropriately

positioned hydroxyl group exists. Treatment of 65 with DDQ in

dichloromethane afforded the cyclization product, acetal 66, in 88%

yield. This elegant differentiation was followed by hydroxyl

protection at C17, and reduction of the acetal under Takano's

protocol using DIBAL-H.~' Swern oxidation gave fragment 67 in 12

steps from furan, with an overall yield of 19.6%.

1-Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,

Z.Evans, D. A,; Bartroli, J.;Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127

3.Evans1 D. A.; Ennis, M. D,; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737

4.Evans, D. A,; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737

5-Landauer, S. R.; Rydon, H. N, J. Chem. Soc, 1953, 2224

6.Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203

7.Brownf J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203

8.Hoffmannf R. W. Chem. Rev. 1989, 89, 1841

9.Marshal1, 3 . 11.; Andrew,R. C . J. Org. Chem. 1985, 50, 1602

10 .Alexakis, A. ; Mangeney, P. ; Ghribi, A. ; Marek, S . ; Sedrani, R.; Guir, C . ; Normant, J. Pure Appl. Chem. 1989, 45, 425

11. (a) Lipshutz, B. H. Synthesis, 1987, 3 2 5 (b) Lipshutz, B. H.; Koxlowski, M. A. Tetrahedron, 1984, 40, 5005

12.Coluccif J. Ph. D. Dissertation, University of Toronto, 1987

Prepared in two steps from the cycloaddition of furan and DBK to yield the oxabicyclic ketone followed stereoselective reduction with L-Selectride to give the , ~ ~ ~ ~ O l l l e , u

Cnem. Soc. 1972, 94, 7159 axial alcohol; Brown, H C.; Krishnamurthy, S.; J. Am.

14,Barton, D. H, R.; McCombie, S. J. Chem. Soc.; Perkin Trans. 1 1975, 1574.

15-Rasrnussen, J. R.; Slinger, C . J-; Kordish, R , J.; Newman- Evans, D. D- J. Org. Chem, 1981, 46, 4843

6 a , M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833

17,Mukaiyama, T.; Iwasawa, N,; Stevens, R. W.; Haga, T. Tetrahedron 1984, 40, 1381

18,Schlosser, M,; Christrnann, K, F- Angew. Chem., Int . Ed. Engl. 1966, 5 , 126

19 . Julia, M. ; Paris, J. -M. Tetrahedron Lett. 1973, 14, 4833

2O,Hanessian, S.; Murray, P. J. Can. J. Chern. 1986, 64, 2231

21.Hanessian, S.; Cooke, N. G.; Dehoof, B.; Sakito, Y. J. Am. Chem. SOC. 1990, 112, 5276

22.HanessianI S.; Sahoo, S. P.; Murray, P. J. Tetrahedron Lett. 1985, 26, 2631

23.LautensI M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 0000

24.VanRheenenf V , ; Kelly, R. C , ; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973

25.Tsujif J. ; Ohno, K. Tetrahedron Lett. 1965, 3969

26.Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamunie, S. ; Roush, W. R. ; Sakai, T. Tetrahedron Lett. 1984, 25, 2183

27.Rasmussenf J. R.; slinger, C. J.; Kordish, R. J.; Newrnan- Evans, D. D. J. Org. Chem. 1981, 46, 4843

28.Bartroli, J. Ph.D. Thesis, California Institute of Technology, 1984.

29.Krishnamurthy, S.; Brouwn, H. C. J. Org. Chem 1976, 41, 3064

30.VanRheene11, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973

31.~tork, G.; Rychnovsky, S. P u r e A p p l . Chem. 1987, 59, 345,

32.Hanessian, S.; Hodges, P. J.; Murray, P. J.; Sahoo, S. P. J. Cnem. Soc., Chem. Commun. 1986, 734

33 .Mancuso, A. J.; Huang, S.-L. ; Swern, D. J. Org. Chem. 1978, 43, 2480

3 4 .Dow, R. L. Ph.D. Dissertation, Harvard University, 1985

35 .Aspiotis, R. Masters Degree, University of Toronto, 1997

36. Oikawa, Y. ; Yoshioka, T. ; Yonernitsu, 0 . Tetrahedron Lett. 1982, 23, 885

37.Takan0, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593

CHAPTER 3

CHEMISTRY OF THE TE TRAHYDROFURANYL SUBUNI T

3 The Chemistry of the Tetrahydrofuranyl Subunit

3.1 Synthetic Developments Towards Tetrahydrofuran Synthesis

As stated by Boivin, the construction of a polyether antibiotic is,

to a large extent, an exercise in the preparation of substituted

oxygen heterocycles Total synthetic efforts towards various

polyether antibiotics, over the past forty or so years, has

necessitated the development of new synthetic strategies towards

the tetrahydrofuranyl ring system, As a result, a variety of

regio, chemo, and stereoselective routes to many substituted

tetrahydrofuran moieties', including the cis-2,2,5-trisubstituted

tetrahydrofuranyl subunit of interest, have been put forth,

It should be noted however, that in most cases, the focus has been

on the formation of disubstituted ring systems, and a large gulf

remains between development and our practice, since the B ring of

ionomycin is a 2,2,5-trisubstituted system.

3.1.1 Diastereoselective Epoxidation of a Bis Homoallylic

Alcohol Followed by Acid Catalyzed Ring Closure

Probably the most widely used approach to tetrahydrofuran synthesis

is the epoxidation of a bis homoallylic alcohol followed by acid

catalyzed ring closure. A look at representative developments in

this area follows,

The construction of ether rings through intramolecular attack of

hydroxyl groups on epoxides, has often been applied in the total

syntheses of polycyclic ethers3, such as monensin4, lasalocid A',

and ~varicin.~ Consequently, the development of methodology using

different parameters, such as olef in geometry, solvent, and

epoxidation catalyst, to control the nature of diastereoselectivity

has remained an important synthetic endeavour.

An important advance in epoxidation-cyclization methodology was

reported by Kishi in 1978.7 a,&-unsaturated alcohols were treated

with t-BuOOH in the presence of VO (acac), according to Sharpless'

protocol. The trans 2,5-disubstituted ring product predominated in

a greater than 20:l ratio upon addition of acetic acid. Kishi

invoked two transition state conformations to account for the

observed selectivity, Scheme I. This Kishi transition state model,

has been widely and successfully applied to both predict and

explain the stereoselectivity of epoxidation-cyclization

sequences ?Determination of the favoured product is based on

minimized steric congestion. Factors such as Alr"train, as well

as the bulk, orientation and number of substituents must all be

considered.

Scheme I

This newly developed methodology was applied by Kishi et al. in the

first total synthesis of lasalocid A', Scheme 11. An asymmetric

epoxidation cyclization successfully formed the first trans ring.

The second epoxidation proceeded, as expected, to give the trans

epoxy-alcohol which, upon ring closure, would afford the trans-

tetrahydrofuran. However, in this case it is the cis-ring closing

that is required. Although inversion of the epoxide is possible,

it is a tedious process, and another more direct route was

developed.

Scheme ll

In 1988 Nicolaou et al. sought to better define the stereospecific

construction of oxirane systems, lo again using the Sharpless

asymmetric epoxidation to give chiral materials and intramolecular

epoxide opening via a primary hydroxyl nucleophile. A versatile

synthetic route to monosubstituted 0-heterocycles was developed.

The regioselectivity of cyclizations, whether 6-endo or 5-exo", was

found to be dependant on the electronic nature of the substituent.

As expectedi2, it was found that a p-orbital adjacent to the epoxide

unit activates the carbon-oxygen bond to nucleophilic attack,

resulting in a 6-endo cyclization. The 5-exo cyclization

predominates in the absence of a p-orbital.

After a systematic look at epoxidation-cyclization reactions, it

was concluded that by varying the geometry of the allylic

substrate, the stereochemistry of the epoxide and the nature of the

substituent, any of the mono-substituted oxacycles, shown in Scheme

111, could, to a greater or lesser degree, be formed.

Scheme Ill

Although these studies established well-defined and predictable

routes to mono-substitued THF and THP systems of predesigned

stereochemistry, a reliable route to higher substituted

tetrahydrofuran ring systems remained elusive.

In 1990, the first total synthesis of Teurilene, a polyether

containing 3 tetrahydrofuran moieties, was published by Hashimoto

et al., Scheme IV.I3 In this synthesis, two simultaneous

vanadium (V) catalyzed oxidation-cyclization reactions were

elegantly employed to form two tetrahydrofuran rings with differing

stereoselectivities. Two developments were key to the

stereocontrol of this approach. Firstly, Kishi' s findings that

vanadium(V)-catalyzed epoxidation-cyclization of 4-substituted 4-

en-1-01 systems result in an anti epoxy alcohol which cyclyzes

under standard acid catalysis to afford the trans 2,2,5-

tetrahydrofuranyl ring. And secondly, a developement in their own

total synthesis of thyrsiferol14, that under identical conditions,

5-substituted 4-en-1-01 systems form syn epoxy alcohols which

cyclize to form a c i s fused ring.

Scheme IV

I

34Or6,7 steps 17

.)

. *OMOM

19 25 O h , 70 steps

VO(aca~ )~ , TBHP,

AcOH, benzene

50°C, 7 h - 25%, 1 step

MOM

* 31 %, 4 steps

HO'

The desired cyclization precursor 19 was obtained after

approximately 20 steps. Although arduous, the high yields make the

sequence viable. Simultaneous epoxidation afforded 25% of the bis

epoxide. In addition, 308 of the material underwent

monoepoxidation at the 4-substituted en01 to give the trans

tetrahydrofuran. Tetrahydrofuran 20 could then easily be

transformed into 21, resulting in an overall product yield of 56%

over 2 steps. The third oxacycle was prepared via monomesylation

of 20 at the 4-position, followed by treatment with potassium

carbonate in methanol, to give teuriline, 21. Overall, this

synthesis is an impressive display of stereocontrol manipulation.

3-1.2 Oxidative Cyclization of 1,5-Dienes

In 1965, Klein and Rojahn reported that upon treatment with

potassium penanganate, 1,s-dienes are oxidized to substituted

tetrahydrofurans in lieu of the expected tetrol. This reaction

which spawns 4 new stereocentres, Scheme V, is limited to the

formation of cis oxacycles, as well as by the number of available

diene precursors.

Scheme V

The search for workable routes to polyether antibiotics in the late

1 9 7 0 ' s caused a renewed interest in this methodology. Klein and

Rojahn explored a very limited number of substrates, only those

structurally similar to geraniol and nerol , Walba et . a1 . expanded the applicataions by looking at the extent of stereospecificity in

unsymmetrically substituted olefinic carbons. " In all cases

complete stereospecificity was maintained leading both Walba and

Baldwin, who was doing parallel research", to posit mechanisms to

explain the phenomena.

3.1.3 Oxabicyclo[3,2,I]octenones

The variety of synthetic pathways to [3,2,1] oxabicycles is

extensive .I6 The most common method is probably the stereospecif ic

addition of oxoallyl cations to furans through an endo, boat-like

transition state, with the oxoallyl cation adopting the W

conf~rrnation.~~ Due to the ease and versatility of large scale

production of the starting cycloadduct, the use of these oxabicyles

is particularly attractive. The formation of 2,5-substituted

tetrahydrofurans is just one of the many synthetically valuable

applications of [3,2,1] oxabicyclic ketones, developed in this lab

and others.

Scheme VI

EtOH NaOMe MeOH,rt

OH COQMe

One approach involves treatment of the oxabicyle to Bayer-Villager

conditions. The resulting lactone can then be hydrolyzed to give

a 2,s-substituted tetrahydrofuran. In 1975, White and co-workers

synthesized ( k ) -nonactic acid, a macrocyclic antibiotic with

biological activity as a potassium ionophore by this route (Scheme

VI) .'' Also notable is the work by Noyori et dl., in preparing the

first 2,s-disubstituted ribo-C-nucleosides, published in 1 9 8 0 .2'

Previous work in this area had applied manipulation of readily

available carbohydrates, but Noyori sought stereocontrolled

precursors from bicyclic ketonesOz2 Oxidation of the double bond

of the oxabicyle to give the diol affords a ribose skeleton upon a-

cleavage. In 1982, Hoffman et al, used this same rnethodclogy in

their synthesis of lilac alcohol.23

Molander arrived at the 2,2,5-tetrahydrofuranyl unit with the

relative stereochemistry of ionomycin by applying a Bayer-Villiger

oxidation to a [3 , 2, l] oxabicycle, followed by stereocentre

manipulation and transesterification." Treatment with m-CPBA and

NaHCO, afforded the lactone in 67% yield (89% based on recovered

starting material), which, after functional group manipulation, was

reduced to yield a tetrol tetrahydrofuran, 35 (Scheme VII) . A

notable advantage of this route is the ability to incorporate

substituents directly onto the THF ring, using a substituted

dicarbonyl precursor.

Scheme VII

+ OTMS

An alternative to a-cleavage of the carbonyl, is the Beckmann

rearrangement of the cycloadduct, seen in (Scheme VIII'~). This

method again provides a 2,5-substituted tetrahydrofuranyl moiety.

With the advent of controlled cleavage of [3,2,1] oxabicyles,

another route to natural products presents itself.26

Scheme VllI

0 N-OH 0 8 NI+H.HCI, 80%) - 6 (60%) - a AH'*cwNb

MeSQH, P205 aq. HCI NaOAc, EtOH

3.1.4 Halocyclization

Bartlett et al. Found that y,b-unsaturated alcohols, and ether

derivatives c y c l i z e at O°C with iodine in a~etonitrile.~~ The

stereoselectivity of this reaction is dependant upon the nature of

the oxygen; a free hydroxy cyclizes to form a trans-2,5-

tetrahydrofuan, while the corresponding 0-alkylated product

produces a cis substituted ring. The difference in

stereoselectivity can be accounted for by the steric bulk of the

oxygen protecting group, non-bonding interactions must be minimized

in each case. To date, this approach has not been applied i n a

synthesis of ( + ) -ionomycin-

3.1.5 Polyepoxide Cyclization

Another approach to polyether antibiotics is one developed by

Westley and Cane in their examination of the biosynthesis of

ionoph~res.'~ They proposed that in vivo synthesis occurs via

simultaneous epoxidation of the ene moieties followed by epoxide

opening. With this approach, it is the construction of a backbone

containing necessary stereocentres, that presents the largest

challenge. Idealy, stereoselectivity can arise from chirality

residing in the chair, instead of hydroxyl group directed

epoxidation. This approach was explored in the synthesis of

monensin B, Scheme IX .29 By X-ray analysis, the two trisubstituted

epoxides have the stereochemistry required for monensin B, while

the third epoxide is epimeric. Although the desired fragment was

not reached, it is evident that with fine tuning this synthetic

strategy could prove to be very powerful, having many potential

applications.

Scheme IX

Tris tetrahydrofuran segment of Monensin 6

3.1.6 Miscellaneous Routes to Tetrahydrofurans

While the above described routes to tetrahydrofurans give an idea

of the synthetic developements to this point, it is by no means a

complete list. Further examples are mentioned here.

In her report

spir~ketals~~,

on synthetic routes to 5/6 membered oxacycles, and

Boivin described examples of each of the following;

ring contraction of tetrahydropyrans, ester enolate Claisen

rearrangement, mercuricyclization and cyclization of 1,4-diols.

One more example involves the substitution at the 2 and 5 positions

of a furan followed by catalytic hydrogenation which proceeds to

give a single cis stereois~mer.~'

3.2 Synthetic Developments Towards the Tetrahydrofuran Moiety of

(+) Ionomycin

3.2-1 Wuts

I n t h e i r s y n t h e s i s of t h e t e t r ahydro fu rany l subunit of ( + )

ionomycin pub l i shed i n 1 9 8 4 ~ ~ , Wuts e t al. i n i t i a l l y planned t o

app ly t h e Sharp less Asymmetric s pox id at ion" t o a geraniol a c e t a t e

backbone. I t w a s thought t h a t a l l necessa ry c h i r a l i t y could be

in t roduced and t h a t the d e s i r e d r e l a t i v e s t e r e o c h e m i s t r y could be

e a s i l y manipulated via a s e r i e s of c o n t r o l l e d epoxide opening

r e a c t i o n s .

Scheme X

(a) Se*. t-BuOOh, salicylic acid; (b)TBSCi, DMF, imidazole; (c) MeOH, K2C03; (d)mBuli, TsCI, THF; (e)UEt3BH; (9 n-BU,NF; (g)Ti(O-CPrh. (+)diethyl-(L)-tartrate, t-BuOOH; (h) PhNCO, EbN, CHzCh; (i)HC104,H20, CH3CN; @ mC PBA; (k) VO(acach, t-BuOOH, AcOH

The t r ans format ion , (Scheme X ) , began with a l l y l i c ox ida t i on , which

s e rved two purposes, f i r s t l y t o p rov ide t h e s u b s t r a t e necessa ry f o r

t h e SAE, and secondly t o s e rve as an at tachment p o i n t f r o m which t o

b u i l d t h e ionomycin ske le ton . The c o r r e c t oxidation s t a t e a t C 3 2

was achieved e a r l y on i n a one p o t reaction by removal of the

a c e t y l groupt and reduction of the resulting hydroxyl group.

Removal of the remaining protecting group and Sharpless Asymmetric

Epoxidation afforded the desired chiral epoxide. As planned, the

centers at C 2 5 , C 2 6 and C27 were achieved by a c i d catalyzed opening

of the epoxide, Epoxidation w i t h m-CPBA and ring closure proceeded

with little stereoselectivity.

Scheme XI

OCONHPh AcO- HO-'

(a) Ti(O-CPr)4. (-)diethybD-tartrate, t-BuOOH; (b)PhNCO, Et3N, C k C b , PCb; (e) K2C03, MeOH. Dowex w; (f) TsCI,

pyridine, O'C; (g) Nal, 2-butanone; (h)B ySnH, AIBN, EtOH; (i) t-BuPbSiCI, DMF, imidazole; (j) LiAIH4; (k) K2C03, MeOH;

(I)C&=CHCY-MgCI, THF, room temperature

As predicted following Kishi's transition state models, the use of

VO (acac) resulted in a 20: 1 ratio, favouring the wrong isomer.

At this stage the problem of selectivity might be overlooked, but

the inability to separate the two isomers formed forced a new

approach, Scheme XI.

The C32 hydroxyl group was then realized to be potentially

invaluable in directing the chirality of the epoxide- An ideal

scenario involves the selective opening of a bisepoxide at the

right-nand epoxide before an internal hydroxyl group affects an

opening of the left-hand epoxide to afford the desired furanO3' In

actuality, the required selectivity could not be achieved and a

much less elegant procedure, involving the formation and opening of

one epoxide, and then the other, was initiated. The final

sequence, features the following steps; asymmetric epoxidation,

formation of the phenyl urethane , conversion to the cyclic

carbonate via perchloric acid, protection, base-catalyzed

hydrolysis of the acetate, deprotection followed by a second

asymmetric epoxidation, and finally a Lewis acid catalyzed

cyclization. With the successful completion of the tetrahydro furan

successfully formed, the target molecule was then easily prepared.

While the desired ring closure was achieved in 6 steps, this

alternative route features many redundant functional group

manipulations before the left quarter of ionomycin was obtained.

In total, 14 transformations, with an overall yield of 6% were

required,

3.2.2 Spino 6 Weiler

Spino and Weiler took a different approach to the tetrahydrofuran

subunit of ionomycin, taking advantage of earlier advances made in

the oxidative cyclizations of 1,5-dienes by Klein and Ro j ahn. 3s

Namely, that 1,5-dienes such as geranyl acetate, and neryl acetate,

could be induced t~ undergo cyclization to give a cis-

tetrahydrof uran product. 36 Further advances by Walba et a1. 37 showed

that the stereochemistry of the resulting disubstitued oxacycle was

dependant on the geometry of the diene starting material (Scheme

XII) .

Scheme XI1

The required diene was prepared stereospecifically in 8 steps as

seen in Scheme XIII, applying methodology recently developed in the

Weiler group.38 The selective formation of the E-enolate followed

by formation of the E-en01 phosphate by trapping with

diethylchlorophosphate gives the Z-alkene upon treatment with a

magnesium cuprate. A second dianion alkylation and enol-phosphate

cuprate coupling affords the 1,5-diene 64. Oxidative ring

formation proceeds to give >95% of one isomer, assumed to be the

c i s product based on Walba's work, in 53% isolated yield.

Reduction of the ester group and tosylation, followed by a hydridic

displacement of the tosyl group affected the deoxygenation. At

this stage, a resolution was performed, (attempts to separate the

isomers at an earlier stage had met with little success). Compound

66 was condensed with mandelic acid and the diastereomers were

separated by flash chromatography. The resolving group was then

hydrolyzed. Protection followed by conversion t o the phosphonium

salt completed the synthesis of the tetrahydrofuran fragment.

Scheme Xlll

OMOM

OMOM

COOMe h.ii _ k 67 Ph

OH OH +

OMOM

OTBDMS TBDMS

(a) NaH, n-BuLi. THF, O'C to rt, then MOMO-CH2CH2Br; (b) TEA, DMAP, HMPA, CIPO(OEt)2, -20'~ to rt; (c) MeMgClm MeLi, Cul, THF, -45'~; (d) OIBAL, OOC; (e)PPh3, CBr4, CH2CI;I, - 78 '~ to rt; (f) -CH2COCH-COOMe, THF, OOC to rt; (g) KMN04, acetondH 20, C02, -25'~; (h) LAH, THF, O'C; (i) TsCI, pyn'dine, O'C; (j) LAH, THF, heat; (k) (S)-(+)-O-acetyi mandelic acid, DCC,

DMAP, CH2CI2, O°C, chromatographic seperation

The overall transformation was accomplished in a series of 19

steps, many of which had unreported yields. The lengthiness of the

route coupled with the undesireable formation of a racemic product

that was kinetically resolved at a very late stage, prove to be

significant limitations to this synthetic effort of Spino and

Weiler ,

3-2-3 Evans

In 1990, Evans published his asymmetric total synthesis of

i~nomycin.~' The C 2 2 - C 2 3 bond was planned to be a point of

disconnection, fixing the C 2 3 stereocentre upon subunit assemblage,

With this skeletal breakdown, the tetrahydrofuranyl subunit of

interest extended from C23 to C32. The addition of the boryl

enolate of 12 and the aldehyde illustrated in Scheme XIV, provided

the 10 carbon framework, utilising Evans chiral auxilaries to

direct the stereochemistry at C 2 7 ,

To form the oxacycle, Evans applied the Sharpless VO(acac)?

epoxiaation, resulting, as expected by Kishi, and later Wuts, in

a 4:l selectivity for the wrong diastereomer. Although attempts

were made to invert the stereochernistry, their lack of success

forced an unselective epoxidation with m-CPBA. This course of

action was deemed acceptable due to the high chemical yield and

ease of separation of the two diasteromers. Epoxidation and acid

catalyzed cyclization with the hydroxyl group at C 2 7 acting as an

internal nucleophile was accomplished before attention was directed

to the chirality at C 2 6 .

Scheme XIV

1.,1",1

R BnO 0 OAc

(a) BuzBOTf, Et3N, CH2CI2, - 7 8 ' ~ ~ 68%; (b) MCPBA, EtOAc, 45% based on desired isomer; (c) PhMgBr, THF; 79%; (d)

Cp2TiCI(CH2)AlMe2, Pyridine, THFKoluene, -45 OC to -20°c; 94%; (e) PPTS,CH 2CI2;1 00%; (f) 0 3 , CH2CbMeOH. - 7 8 ' ~ ,

Me2S; 55% over 2 steps (g)MeMgBr, GH2C121Et20, -78'~; (h) TBSOTf, Et3N, C h C b , O'C; 94% (i) H2, PdIC, EtOAc; ( j)

MeS02CI E~JN, CH2Ch, O'C; Nal, NaHC03, Me2CO; 99% (k) PPhs, TolueneJMeCN, 75 OC, 78%

Lactonization which, in addition to removing the chiral auxiliary,

provides an intermediate, that will readily lead to the desired

decarboxylated product. Tebbe methylenation, acid catalyzed

isomerization to the more thermodynamically stable internal enol,

and ozonolysis followed by reductive workup, gives a C26 carbonyl

group which can then undergo diastereoselective nucleophilic

addition. Simple functional group manipulations gave the final

group which can then undergo diastereoselective nucleophilic

addition, Simple functional group manipulations gave the final

C23-C32 subunit as a phosphonium salt which could easily be

transformed into the corresponding ylide to be used in the

appending of subunits, An overall yield of 9% over I1 steps was

achieved.

3 .2 .4 Hanessian

Hanessian' s total synthesis of + ion~mycin~~, seen in Scheme XV,

was received for publication less than one month after Evans' total

synthesis, (although initial work was published by R. Dow in a 1985

Ph.D. thesis). Both syntheses featured a simillar approach to the

tetrahydrofuranyl ring system. The epoxidation-cyclization motif

was once again applied, again with hopes of stereocontrol.

Hanessian chose to use an optically active epoxide, and like Wuts,

geraniol, to form the skeleton of the C23-C32 chain. The terminal

2-methylpropenyl group would be cleaved at a later time to give

Scheme XV

TBMSO d ______)

OTBMS

OTBMS

(a) (D)-Diisopropyl tartrate, Ti(0iPr) 4. TBHP, CH2Cb, 4 A sieves, -20 OC, 30 h, then Me2% -20°c, 62%; (b) 1. EtMgBr, THF, then add Li anion of 86, THF-HMPA, -78 OC to -25%. 18 h, 71 %; (c) 1.03, then excess NaBH 4, MeOH, -78% to -25'C, 3h,

87%; 2 Ac20, Et3N, catalyst DMAP, CH2C12, O°C, 0.5 h, 62% overall; 3. Na, liquing NH 3, -33'~~ 69%; (d) 1. TBHP,

VO(acac)*, 3 A sieves, hexanes 24 h, 94%; (e) 1 . LiAIH 4, ether, -25 OC, 20 min, 86%; 2. PP h 3, imidazole, 1 2, CH2Cb, 91 %

Next, the use of the sulfone anion of geraniol in the pressence of

one equivalent of ethyl magnesium bromide41 was explored. The

coupling proceeded to give a mixture of two seperable

diastereomers, in 41 and 30% yields, Since the sulfone

functionality was removed by reduction with sodium in liquid

ammonia after protection and ozonolysis, both diastereorners were

carried through.

With the backbone constructed, the next challenge was

stereocontrolled ring closure to form the cis trisubstituted

tetrahydro furan. The VO (acac) catalyzed epoxidation-cyclization

sequence persued by Wuts and Evans was again explored, this time

with an impressive degree of success. Whereas Wuts, Evans and

Kishi, attempted this cyclization with a secondary hydroxyl group

as the internal nucleophile, the substrate that Hanessian presented

involved attack at the epoxide by a tertiary hydroxyl group,

Under optimized conditions it was found that the less polar the

solvent, the greater the stereoselectivity, culminating in a ratio

of 9: I cis:trans, when hexanes were used. Yields were

consistently between 70 and 808, with preference for cis decreasing

to 4-5:l with other solvents such as dichloromethane, toluene or

benzene. Three simple functional group manipulations give the

requisite cis-disubstituted tetrahydrofuran subunit in a total of

10 steps with an overall yield of 7 8 ,

For the sake of comparison, the original transition state models

proposed by K i ~ h i ~ ~ applied to the tetrahydrofuran precursors are

illustrated below, (Schemes XVI-XVIII), The observed selectivity

in each of the three scenarios is made apparent.

Scheme XXI: Wuts Transition States

Favoured

OH 46

Disfavoured

t-BuO' OH OR 45

Scheme XVII: Evans Transition States

Scheme XVIII: Hanessian Transition States

Favoured

Ha Fi 89

LBoivin, T, L. B. Tetrahedron, 1987, 43, 3309

2. (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Srnith- Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933 (b)Fukayama, T.; Akasaka, K.; Karanewsky, D.S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259

3 .Hashimotof M I ; Kan, T . ; Nozaki, K. ; Yanagiya, M. ; Shirahama, H.; Matsumoto, T. J. Org. Chem. 1990, 56, 2299

4 . S W.C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105

5-Nakata, T. ; Schmid, G.; Vranesic, B.; Okigawa, MI; Smith- Palmer, T.; Kishi, Y. J. A m . Chem. Soc. 1978, 100, 2933

6.Hoye, T.R.; Suhadonic, J . C . Tetrahedron Lett. 1986, 26,2885

7. Fukuyama, T . ; Vranesi, B; Negri, D. P. ;Kishi, Y. Tetrahedron Lett. 1978, 2741

8 .An illustrative sample (a) Wuts, P. G. M.; DrCosta, R.; Butler, W. 2. Org. Chem. 1984, 49, 2582; (b) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290; (c) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. A m . Chem. Soc. 1990, 112, 5276

9.Nakataf T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith- Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933

lO.Nicolau, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K.; J. Am. Chem. Soc. 1989, 111, 5330, 5335

ll.Baldwin, J. E. J. Chem. Soc. . Chem, Commun, 1976, 734

12.Storkf G.; Cama, L.D.; Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268

13.Hashimot0, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. O r g . Chem. 1991, 56, 2299

14. (a) Hashimoto, M. ; Kan, T. ; Yanagiya, M. ; Shirahama, H. ; Matsumoto, T. Tetrahedron Lett. 1987, 28, 5665. (b) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1988, 29, 1143. (c)Kan, T.; Hashimoto, M.; Yanagiya, M. ; Shirahama, H. Tetrahedron Lett. 1988, 29, 5471. (d) Hashimoto, M. ; Kan, T. ;Nozaki, K. ; Yanagiya, M. ; Shirahama, H. ; Matsumoto, T. J. Org. Chem. 1990, 55, 5088.

lS.Molander, G. A.; Swallow, S. J. Org. Chem. 1994, 59, 7148

16.Walba, D. M.; Wand, M. D.; Wilkes, M. C . J. Am. Chem. Soc. 3979, 101, 4396

17 .Baldwin, J. E,; Crossley, M. J.; Lehtoner,, E.-M. M. Chem. Corn. 1979, 918

18. (a) Hosomi, A.; Tominagaa, Y. [4+3] Cycloadditions. Comprehensive Organic Synthesis; Trost, B. M. ; Fleming, I. (Ed) Pergamon: Oxford, U.K. , 1991, Vol. 5, 593 (b) Mann, J. Tetrahedron, 42, 1986, 4611

19.Arc0, M. J.; Trammell, M. H.; White, J. Do J. Org. Chem. 1976, 42, 2073

20 .Arco, M. J. ; Trarnmell, M. H. ; White, J. Do J. Org. Chem. 1975, 41, 2075

21.Sat0, T; Watanabe, M.; Noyori, R. Chem. Lett. 1980, 679

22.Noyori, R.; Sato, R.; Hayakawa, Y, J. Am. Chem. Soc. 1978, 100, 2561

2 3 . Rabe, S Diplomarbeit, Universitat Hannover, 1982

24.Molandert GI A.; Swallow, S. J. Org. Chem. 1994, 59, 7148

25.Cowlingr A. P I ; Mann, J.; Usrnani, A. A, Perkin Trans. 1981, I2116

26.Mann, J. Tetrahedron, 42, 1986, 4611

27.Rychnovsky, S. D., Bartlett, P. A. J. Am- Chem. Soc. 1981, 103, 3963

31.Cane, D, E.; Liang, T. C.; Hasler, H. J. Am. Chem. Soc. 1982, 104, 7274

29.Sti11, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105

3O.Boivin, T, L. B. Tetrahedron, 1987, 43, 3309

31.Arc0, M. J.; Trammell, M. H. White, J. D, J. Org. Chem. 1976, 41, 2075

32.Wuts, P. G. M. ; DfCosta, R.; Butler, W. J. Org. Chem. 1984, 49, 2582

33.Umbreitf M, A , ; Sharpless, K. B, J. Am. Chem. Soc. 1977, 99, 5526

34.Boivinf T, L, B. Tetrahedron, 1987, 43, 3309

35.Spin0, C.; Weiler, L. TetrahedronLett. 1987, 28, 731

36.Kleinf E. ; Rojahn, W, Tetrahedron, 1965, 21, 2353

37.Walba, D. M.; Wand, M. D.; Wilkes, M. C. J. Am. Chem. Soc. 1979, 101, 4396

3 8 - (a) Sum, F. W.; Weiler, L. Tetrahedron, 1981, 31 Supp I, 303; (b)Alderdice, M. ; Spino, C . ; Weiler, L. T e t r a h e d r o n - 1 9 8 4 , 2 5 , 1 6 4 3

39 .Evans, D. A. ; Dow, R. L.; Shih, T. L. ; Takacs, J. M.; Zahler, R . J. Am. Chem. Soc. 1990, 112, 5290

40.Hanessianf S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem. Soc. 1990, 112, 5276

41.Kocienskif P. J.; Lytgoe, B e ; Ruston, S . J. C h e m . Soc. Perkin Trans, 1 1978, 829

42. Fukayama, T. ; Vranesic, B. ; Negri, D. P , ; Kishi, Y. Tetrahedron Lett. 1978, 26, 2741

CHAPTER 4

OUR SYNTHESIS

OF THE C24-C32 FRAGMENT OF

(+) IONOMYCIN

4 Introduct ion

4.1 Synthetic Strategy and Discussion of the Route

The following synthetic route to the C24-C32 subunit of (+ )

ionomycin was developed by John Coluccil in the Lautens group. In

designing this sequence, Colucci considered several important

factors, such as installation of appropriate stereocenters at C31

and C 2 6 , functionality at C24 suitable to allow easy appendage to

the neighbouring subunit, length of route and of course achieving

a ring closure with the required absolute stereochemistry.

Previous synthetic efforts towards the tetrahydrofuranyl subunit of

ionomycin have provided invaluable information, which was

incorporated into the development of the strategy described below.

Scheme l

viii

The retrosynthesis, shown in Scheme I, illustrates the key

transformation en route to ionomycin. The skeleton of this subunit

is derived from geranyl acetate, which, although one carbon short

of the desired 9 carbon chain, has inherently correct positioning

of the two methyl groups, as well as olefin moieties which can be

functionalized. The architecture of geraniol has proven to be an

excellent point of departure in many previous syntheses of

polyether antibiotics, including ionomycin, as mentioned earlier.2

First, selenium catalyzed allylic oxidation3 of the geranyl acetate

starting material, using a text-butyldihydroperoxide co-oxidant , was performed in order to functionalize the carbon destined to be

C25. It was anticipated that the addition of a methyl-phenyl-

sulfone anion to this centre would provide not only the missing

carbon atom, but an appropriate linkage precursor. The ease of

formation of the sulfone anion makes it ideal for nucleophilic

attack to the planned aldehyde at C23 via a Julia-Lythgoe reaction"

to give an E-olefin, which could then be used in the construction

of the A ring. Of equal importance is the assumed ease with which

the sulphone moiety could be removed following attachment.'

Eventually, cleavage was effected by oxidation of the coupled C17-

C23 and C24-C32 fragments, followed by reduction with SrnI,.

Another foreseen advantage of this approach was the ability to

exploit the penchant of sulfone anion to attack carbonyls. A

greater number of anion equivalents could cleave the acetate, via

nucleophilic attack, leaving a free hydroxyl group to act as a

handle for the planned Sharpless asymmetric epoxidation to follow.

In order to attach the methyl-phenyl-sulfone, the existing hydroxyl

group was first converted to the bromide iii - At this point simple

nucleophilic displacement by the sulfone anion, formed by the

addition of butyllithium to phenyl methyl sulfone in THF at OCC,

afforded iv in 655 yield, along with the dimer as an undesired side

product. The common problem of dialkylation of sulfone-stabilized

carbanions, was investigated by by Pine et a1. . The assumed mode

of action is deprotonation of the mono-alkylated product, Scheme

11. The resultant anion then acts as the new nucleophile to

displace the bromide on the second C24-C32 chain.

Scheme ll

The division between mono and polyalkylated product is believed to

be under thermodynamic control. Although the monosubstituted

sulfone is alkylated much more readily than the unsubstituted

precursor, the monoalkylated anion is thermodynamically less stable

than the phenyl-methyl-sulfone anion.

The possibility that aggregation about the lithium cation could

come into play was also considered by the Pine group. If this were

the case, aggregation would increase as the bulk of the substrate

decreased, reducing the likelyhood of alkylation. Obviously, the

unalkylated iii is less sterically congested than the corresponding

monoalkylated product, iv. Since it is known that the degree of

ion association decreases with potassium in relation to lithium7,

a change in counterion should result in an increase in

monosubstituted product. Pine found this to be true as the base

was switched from butyl-lithium to potassium hydride.

Unfortunately, in our case, such a change in base did not result in

any degree of improvement in the ratio of mono to dialkylated

product. Other variables that were examined without success

include; temperature, rate of addition, the number of equivalents

phenyl sulfone relative

Colucci on the other hand,

the original experimental

The Sharpless asymmetric

to base, and the order of addition.

did not report dialkylation products in

work.

epoxidation, which has proven to be of

pivotal import in the previous syntheses of both ionomycin and

tetrahydrofuran rings, was next applied, Colucci found that with

substrate iv, the catalytic version of the Sharpless asymmetric

epoxidation6 resulted in a decrease in both the yield and

stereoselectivity of the reaction. This compromise could not be

made and allylic alcohol iv was subjected to stoichiometric amounts

of (+)-diisopropyltartrate, titanium isopropoxide and tert-

butylhydroperoxide - Under these conditions, the enantiomeric

excess was found to be >97% by Mosher's ester analysis.' Our

results were in full agreement with this analysis.

It is important to note that a proper workup was found to be

critical to the yields of this reaction. As proposed by Sharpless,

a solution of ferrous sulfate and tartaric acid was used to break

down the titanium isopropoxide. The resulting titanium salts could

then be removed by separation of the aqueous layer. If a trace of

Lewis acidic titanium remained, the epoxide v was found to

decompose at an alarming rate, especially upon concentration.

Next, the epoxide had to be manipulated into the necessary

precursor for the cyclization-epoxidation reaction. Tosylation of

the epoxy-alcohol proceeded without event. This relatively

unstable molecule vi, was then directly subjected to acid catalyzed

opening of the epoxide to form a monotosylated triol. Here,

stereospecific bimolecufar nucleophilic attack occured at the

tertiary centre, resulting in an inversion of stereochemistry.

This backside attack was required to achieve the correct relative

and absolute orientation of stereocentres. Selective protection of

the secondary hydroxyl of viii as the tert-butyldimethylsilyl ether

was the final step in preparation for the ring formation.

The approach decided upon followed Hanessian's beautifully laid

path. We similarly pursued a substrate directed epoxidation,

followed by acid catalyzed cyclization of a 5-substittuted-4-en-l-

01. In this case however, a problem of solvent was encountered.

The use of hexanes as described by Hanessian was not a possibility

due to insolubility. A solution of 3:l heptanes to dichloronethane

was finally found to be suitable, resulting in the best

selectivity, while maintaining solubility. Catalytic amounts of

VO (acac) and 4 equivalents of the co-oxidant, tert-

butylhydroperoxide, were added to the substrate solution twice, at

a 12 h interval. After this period, a catalytic amount of

pyridinium para-toluenesulfonate was added to aid the ring closure.

A final ratio of 7.8: 1 cis/trans was obtained, rivaling Hanessian's

own %I. The two isomers, ix along with itf s counterpart, were

carried through the synthesis together, the separation to be

performed at a later stage.

The deoxygenation at C32 of ix next presented itself. Direct

nucleophilic hydride displacernentlhas impossible due to the

incompatibility of the sulfone group, which suffered various

degrees of reduction as well as displacement. Conversion to the

iodide followed by a radical based reduction lead to the desired

reduced product. The displacement of the tosylate was carried out

in 2-butanone, facilitated by the presence of 18-c-6, to give x.

The diastereomeric tetrahydrofuran mixture was then deiodinated

under standard radical conditions, refluxing toluene, tributyltin

hydride and AIBN as the radical initiator. It was at this point

that separation of the two diastereomers could be accomplished.

The quality of tributyltin hydride was found to be of the utmost

importance. Any degree of contamination could result in

decomposition of the valuable starting material, lowering the yield

from 91% which was possible under optimum conditions.

The final step in the sequence of the C24-C32 chain was the

protection of the hydroxyl group in xi as the labile trimethylsilyl

ether, using the corresponding triflate at -78°C. The fragment xii

could then be coupled as prescribed to the other subunits.

4 - 2 EXPERIMENTAL,

All glassware was flame dried under nitrogen gas and cooled before

use. Solvents and solutions were transferred with syringes and

needles or canulae under standard inert atmosphere techniques.

THF and toluene were distilled from sodium/benzophenone ketyl.

Dichloromethane was distilled from calcium hydride before use.

Both 'H NMR, and 13c NMR spectra were recorded at a 400 MHz Varian

XL400 spectrometer with CDC1, as reference standard (6=7 - 2 4 ppm f o r

'H NMR, and 6=77.O ppm for 13c NMR). Spectral features are

tabulated in the following order: chemical shift (6, pprn); number

of protons; multiplicity (s-singlet, d-doublet, t-triplet, q-

quartet, qn-quintet, sp-septet, rn-complex multiplet, br-broad);

coupling constants (J, Hz) . " C NMR were recorded at 50 or 100 MHz.

Gas chromatography was performed on a Hewlett Packard 5890 gas

chromatograph using an HP-20 carbowax column, and chiral column P-

TA and y-TA. Analytical TLC was performed using EM Separations

precoated silica gel 0.2 mrn layer W 254 fluorescent sheets.

Column chromatography was performed as "Flash Chromatography" as

reported by still1' using (200-400 mesh) Merck grade silica gel.

Phenyl-methyl-sulfone was prepared in a procedure described by

Trost, by oxidation of phenyl methyl sulfide.'*

Since the 'H NMR and 13c NMR data obtained was in full agreement with previous experimental data, no further characterization was

performed. For IR, [a], and HRMS data, see Ph D thesis of John

Colucci, University of Toronto, 1997.

[2Er6E]-Acetic acid 8-hydroxy-3,7-dimethyl-octa-2,6-dienylester

To E sc lu t io -? of salicylic acid (3.52 g, 25.5 m o l ) , selenium

dioxide (565 ng, 5 mmol), and tert-butyl hydroperoxide (127 mL 705

s o l u t i o r , in w a t e r , 917 m o l ) in 90 mL dichloromethane, w a s added

g e r a n y l acetate (50 g, 2 5 5 m o l ) at 10cC, as prescribed by

Sharpless'?. The resulting solution was stirred at rcom temperature

for 4E h. A c this point dimethyl sulfoxide ( 5 0 mL, 917 rnrnol), and

200 rnL of water were added to the reaction. The aqueous pnase was

seperated, extracted with ether (3 x 200 mL) , dried over anhydrous MgSO;, filtered and concentrated in vzcuo. Purification by flash

chromztography ( 1 0 - 4 0 % e thedhexanes ) on silica gel gave known

compound iil' as a yellow oil ( 2 8 - 2 g, 5 2 % )

[2E, 6E j -Acetic acid 8-broma-3,7-dimethyl-octa-2 , 6-dienylester

Br iii

N-brcmosuccinirnide ( 2 1 . 5 g, 121 mmol) w a s added t o a solution of

alcohol ii and triphenylphosphine" ( 3 2 . 6 g, 1 2 4 . 4 m o l ) in 2 2 5 mL

of dichloroneihane s r i r r i n g in a cryobath at -20°C. The s o l i r t i o n

w a s stirred at -2QCC for 2 . 5 h . I n vzcuo c o n c e n t r a t i o n t o

eliminate solvent and flash chromatography of r e s u l t i n g orange

r e s i ~ u e (5-1 04 e t h e r / h e x a n e s on silica gel) gave the known zllyl

brcmide iii'" (23.76 q, 7 6 . 5 % I as a yellow o i l .

I Br iii

THF

To a solution of me thy l p h e n y l s u l f o n e ( 4 3 . 8 g, 280 m o l ) i n 560 r n l

THE' ai O X , w a s added n - b u t y l l i t h i u m ( 1 1 2 . 3 r n l , 280 m r n c l ) via

c a n n u l a . The r e s u l t i n g y e l l o w p r e c i p i t a t e was s t i r r e d f o r 30 min

a t 0°C a n d 1 h a t room temperature. The r e a c t i o n m i x t u r e w a s

c o o l e d t o -20°C and a l l y 1 bromide iii ( 1 6 . 5 g , 6 0 . 1 mmol ) , i n 120

m l o f TEF was added s l o w l y via c a n n u l a , over a p e r i o d o f 30

m i n u t e s . T h e solution w a s s t i r r e d for 2 h as t h e c o o l i n g b a t h

gradually w a r m e d t o room t e m p e r a t u r e . S a t u r a t e d NH,C1 s o l u t i o n ,

( 2 0 0 r n l o f ) , w a s added t o the y e l l o w s o l u t i o n . A f t e r v i g o r o u s

shaking, t h e aqueous l a y e r was s e p a r a t e d , and e x t r a c t e d w i t h e t h y l

a c e t a t e ( 3 x 250 ml) and CH,C12 (1 x 200 ml). The combined o r g a n i c

e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s MgSO: and c o n c e n t r a t e d i n vacuo .

Flash ch roma tog raphy on s i l i c a ge l (30-805 ether/hexanes) g a v e t h e

sulfone i v as a p a l e y e l l o w o i l ( 1 2 . 0 3 g, 65%) .

'H NMR (400 MHz, CDC1,)G 7.90-7 .50 (5H, rn) , 5.34 ( l H r t r J = ~ . O H Z )

5 . 0 9 ( l H f t J = 6 . 6 H z ) , 1 ( l H , m), 3 .13 (2H, m ) , 2 . 3 2 (2H, m),

2 .10-1 .90 (4Hr m), 1.61 (3H, s ) , 1.5s (3H, s ) , 1 . 4 1 ( l H , m ) ; " C NMR

( 1 0 0 MHz, CDC13)6 139 .0 , 138 .8 , 1 3 3 . 6 , 1 3 0 . 9 , 129 .2 , 1 2 8 . 0 , 126 .4 ,

1 2 3 . 6 , 59 .2 , 5 5 . 0 , 3 9 - 0 , 32 .2 , 26.1, 1 6 . 2 , 15 .9 .

To a solution of (+ j -diisopropyltartrate (5.9 mL, 27.6 rnmol,

distilled m d kept under vacuum) and crushed molecular sieves (1 g )

in 2 2 5 r n l dicnlorometnane at -20°C (cryobath) , was added titanicin isoprcpoxide (7.8 m l , 25.8 mmol, freshly distilled), according to

Sharpless protocol. The resulting solution was stirred for 20 min

followed by s l o w addition of sx lphone iv ( 7 - 9 g, 25.8 rnmol) in 55

mL dicnlorrnechane and crushed molecular sieves (0.79 g ) vi a

cannula. This solutior! was again s t i r r e d for 20 min before

addition of tert-butyl hydroperoxide that had been pre-dried over

3 A molecular sieves for 30 min. After stirring overnight (14 h) , at -2OCC, the reaction was warmed to 0°C. A solution of tartaric

acid (58.6 g , 3 9 0 rnmol) and ferrous sulfate (170 g, 611 mmol) in

1.25 L of distilled H,O was prepared and cooled to O°C. The

reaccion mixcure was slowly poured into the stirring aqueous

solution. After stirring for 10 min, the aqueous layer was

separated and e x t r a c t e d with e the r ( 2 x 75 mL). The combined

organic extracts were once again cooled to O°C, and 130 mL of a

precooled solution (0°C) of 30% NaOH in saturated brine was added.

The biphasic solution was stirred vigorously for 1 h at O°C before

separation and extraction of aqueous phase with ether (3 x 100 mlT;)

and dicnloromethane (1 x 100 mL) .I7 Purification by flash

chromatography on silica gel (30-50% etheyl acetate /hexanes) gave

epoxy alcohol v (5.73 g, 69% yield) . Analysis by gas

chromatography revealed an enantiomeric excess of approximately

95%. This is in agreement with earlier experimental result^.'^

[a] = +7.2O (~=2.0, CHC1,) ; 'H NMR (400 MHz, CDC~,) 6 7.88-7.45 ( 5 H r

m), 5-11 (lH, dt, J=0.7, 7.0 Hz), 3 - 7 7 (IH, dd, J= 4-8, 12.1 Hz),

3.67 (lH, dd, J=6.6, 12.1 Hz), 3.15 (2H, m), 2-92 (lH, dd, J=4.8,

6.6 Hz), 2.37 (ZH, m) , 2.03 (2H, rn), 1.72 (IH, m) , 1.61 (lH, ddd,

J=6.6, 8-1, 13-6 Hz), 1.55 (3H, s), 1.46 (lH, ddd, J=7.3, 9.2, 13.9

HZ) , 12.6 ( 3 H f s ) ; 13C NMR (100 MHz, CDC13)6 139.0, 138.8, 133.6,

130-9, 129.2, 128-0, 126.4, 123.6, 59.2, 55.0, 39.0, 32.2, 26.1,

16.2, 15.9.

[ZR, 3R, 3 (3E) -Toluene-4-sulfonic acid 3- (6-benzenesulfonyl-4-methyl-

hex-3-enyl)-3-rnethyl-oxiran-2-ylmethyl ester

The epoxy a l c o h o l v ( 5 . 3 g , 16.24 nmcl) was d i s s o l v e d i n 30 mL of

dichlormethane and stirred at -10°C. To this solution was added

p y r i d i n e ( 2 . 2 mL, 2 7 . 1 mrnol) and f r e s h l y r e c r y s t a l l i z e d pa ra -

toluenesulfor.yl c h l o r i d e (5.2 g, 27 rnmol) . This s o l u t i o n was

stirred for 48 h b e f o r e a second addition of p y r i d i n e ( 0 . 2 2 mL) and

p a r a - t o l u e n e s u l f o n y l chloride ( 0 . 5 2 g ) . A f t e r 1 h , 1 0 0 ml o f water

w a s added and the aqueous l a y e r was s e p e r a t e d and e x t r a c t e d w i t h

dichloromethane ( 3 x 2 0 0 mL) . The organic extracts were dried over

anhydrous Na ,SO, , filtered, and concentrated i n vzcuo. Flash

chroma~oqraphy on silica gel ( 10-40:; ethyl acetate/hexanes gave

t o s y l a t e vi ( 7 . 3 g, 9 3 % ) as a p a l e ye l low oil.

E m . (400 MHz, C D C I , ) G 7.88-7.30 (5H, rn), 4.09 (lH, dd, J'11.1,

5.5 Hz), 4.05 (lH, dd, J=11.1, 5.9 Hz), 3.13 (2H, m), 2 . 9 4 (lH, dd,

J=5.9, 5.5 Hz), 2 . 4 4 (3H, s), 2.36 (3H,s), 1.98 (2H, q, J=7.7 Hz),

1.60-1.38 (4H, m), 1 . 3 (3H, s ) , 1.17 (3H, s ) ; 13c NMR ( 1 0 0 MHz,

c D c ~ : ) ~ 1 4 5 . 0 , 138.9, 133.6, 132.5, 131.6, 129.8, 129.1, 127.9,

127.8, 125.5, 68.4, 60.7, 58.6, 54 .8 , 37.4, 32.1, 23.3, 21.6, 16.6,

15.9.

[2R, 3S, 6E ] -Toluene-4 -SUM onicacid-9-benzenesulfonyl-2,3-dihydroxy-

3,7-dimethyl-non-6-enyl ester

vii

To a rocm temperature solution of t o s y l a t e vi 6 8 g, 3 4 - 5 m o l l

in 1 7 0 m i of a 3 : 1 THF/I-:,O s o l u t i o n was added p r r c h l o r i c acid (0.67

mL, 7 0 % aqueous s o l u t i o n ) . The r e z c t i o n m i x t u r e w a s then heated a t

reflux ( 7 O C C ) for 3 h . The s o l u t i o n w a s cooled t o room temperature

b e f o r e addition of saturated aqueous NH,Cl s o l u t i o n ( 2 0 0 mL) . The

aqueous l a y e r w a s separated and extracted w i t h e t h y l acetate ( 3 x

100 m L ) . The combined organic e x t r a c t s were dried o v e r anhydrous

Na-S04 , filtered, and c o n c e n t r a t e d i n vacuo before purification by

flash chromatograpny on s i l i c a g e l ( 2 0 - 5 0 % ethyl a c e t a t e / h e x a n e s ! . Diol v i i w a s ob ta ined ( 1 2 . 2 g, 72 %)as a pale, milky, o i l .

[ZR, 3S, 6E ] -Toluene-4-sulfonicacid-9-benzenesulfonyl-2- ( (1, l-

dimethylethyl)dimethylsiloxy)-3-hydroxy-3,7-dimethyl-non-6-enyl

ester

viii

T o a s o l u t i o n of d ie1 vii ( 1 2 . 2 g , 2 4 . 6 m o 1 ) i n 4 3 mL of

d i c h l o r o r n e t h a n e a t -2OSC, w a s added 2 , 6 - l u t i d i n e ( 6 . 6 mL, 5 9 m o l ) . T h e s o l u t i o n was s t i r r e d f o r 1 0 min a t -20°C be fo re s l o w a d d i t i o n

cf c21i-bucLyldirnetnylsily1 trifluoromethanesulfonate ( 6 . 6 mL, 2 9

m r n c l ) . The s o l u t i o r , was s t i r r e d a t -20°C f o r 1 h, a f t e r wh ich i t

w a s warned t o 0°C. 1 2 0 rnL o f s a t u r a t e d NH.,Cl s o l u t i o n w a s added.

The aqueous p h a s e w a s s e p a r a t e d and e x t r a c t e d w i t h d i c h l o r o m e t h a n e

( 3 x 1 5 0 mL). The combined o r g a n i c e x t r a c t s w e r e w a s h e d w i t h 1 2 0

mi, o f 0 . 5 M K C 1 s o l u t i o n , a n d 1 2 0 mL of s a t u r a t e d b r i n e s o l u t i o n .

T h e a q u e o u s washes w e r e t h e n e x t r a c t e d w i t h d i c h l o r o m e t h a n e ( 3 x 50

m L i , and t h e combined o r g a n i c extracts were d r i ed o v e r a n h y d r o u s

Na,SO,, f i l t e r e d a n d c o n c e n t r a t e d in v a c u o . P u r i f i c a t i o n b y f l a s h

c h r o m a t o g r a p h y o n s i l i c a gel (20-705 ethyl a c e t a t e / h e x a n e s ) g a v e

t h e s i l y l e t h e r v i i i ( 1 0 . 9 g, 7 3 % ) as a pa l e y e l l o w o i l .

'H NMR ( 4 0 0 MHz, ~ ~ ~ 1 , ) 6 7 . 8 8 - 7 . 3 (9H, m) , 5 . 0 7 ( l H , t , J = 7 . 3 H z ) , 4 - 2 1

(lH, dd, J=10 .3 , 3 . 3 H z ) , 3 . 8 2 ( I H , dd , J=10.3, 3 . 3 H z ) , 3 / 6 6 (lH,

dd, J = 1 0 . 3 , 3 . 3 H z ) , 3 . 6 6 (lH, dd, J=7.3, 2.9 H z ) , 3 . 1 5 (ZH, m),

2 . 4 5 (3H, s ) , 2 . 3 6 (3H, s ) , 1 . 9 8 (3E, m ) , 1 . 5 4 (3H, s ) , 1 . 2 4 ( l H ,

m.), 1 . 0 8 (3E, s ) , 0 . 8 5 (9B, s ) , 0 . 0 8 (3H, s ) , 0 . 0 6 (3H, sl ; I3c NMR

( 1 0 0 MHz, C D C 1 3 ) 6 1 4 4 . 9 , 1 3 9 . 0 , 1 3 3 . 6 , 1 3 1 . 1 , 129.8 , 129.2 , 128 .0 ,

1 2 7 . 9 , 1 2 6 . 6 , 1 2 6 . 5 , 7 6 . 8 , 7 3 . 5 , 7 1 1 5 4 . 9 , 3 7 . 0 , 3 2 . 2 , 25.9,

2 3 . 1 , 2 1 . 8 , 21 .7 , 1 8 . 1 , 1 5 . 9 , - 4 . 0 , - 4 . 9 .

[2R,2 (2S,SR,5 (IS) ) j Benzenesulfonic acid 2-[5-(3-benzenesulfonyl-1-

hydroxy-l-methyl-propyl)-2-methyl-tetrahydro-furan-2-yl]-2-(1-

( ( 1 , l - d i m e t h y l e t h y l ) dirnethylsiloxy) -ethyl ester

viii

Vanady-l z c e t y l a c e t o n a t e ( 3 1 3 no, 1 . 2 mmol) and :A m o l e c u l a r s i e v e s

w e r e a d d e d t o a s o l u t i c n o f s i l y l e t h e r v i i i ( 4 - 8 g , 7 . 9 mmol) i~

4 8 m i of 3 : 1 heptanes /CHZCl2. The g r e e n s c l u t i o n i s s t i r r e d for 3 0

m i r ! a f z e r which t e r t - b u t y l h y d r o p e r o x i d e ( 2 . 8 6 mL of a 5 . 5 M

s o l u t i o n i n ciecane, 15 .71 mmol) , which had b e e n p r e d r i e d o v e r

m o l e c u l a r s ieves f o r 30 m i n , i s added d r o p w i s e . T h e d a r k p u r p l e

s o l u t i o n i s s t i r r e d for 1 2 h . At t h i s t i m e , the s o l u t i o n is a

b r i c k red, and a s e c o n d a d d i t i o n o f vanadyl a c e t y l a c e t o n a t e and

t e r t - b u t y l h y d r o p e r o x i d e (313 mg, and 2 - 0 6 mL r e s p e c t i v e l y ) i s made

t o r egenera te t h e p u r p l e c o l o u r - A f t e r anocher 1 2 h, p y r i d i n i u m

p a r a - t o l i l e n s u l f o n a t e ( 2 0 0 rng, 0 . 8 mmol) i s added. After 4 h of

stirring, the r e a c t i o n mixture i s p u r i f i e d d i r e c t l y b y f l a s h

c h r o m a t o g r a p h y on s i l i c a g e l (20-503 e t h e d h e x a n e s ) . F n

i n s e p a r a b l e m i x t u r e o f cis ix, a n d trans p r o d u c t s ( 3 . 5 g, 718) are

o b t a i n e d as a p a l e y e l l o w o i l i n a r a t i o o f cis t o t r a n s , 7 . 7 : l .

'H NMR ( 4 0 0 MHz, C D C ~ , ) ~ 7 .88-7 .30 (9H, m ) , 4 . S O (lH, dd, 5=10.6 ,

1.8 H z ) , 3 .78 (2H, m), 3.67 ( l H , dd, J=7.3 , 1 3 H z ) , 3 . 3 6 ( l H , ddd,

J=16.8, 1 2 . 5 , 4 . 4 H z ) , 3 . 1 8 ( l H , d t , 5=12.5, 8 . 1 H z ) , 2 . 4 5 (3H, s ) ,

2.20-1.50 (7H, s ) , 1 .16 (3H, s ) , 1 . 0 8 (3H, s ) , 0 . 8 5 (9H, s ) , 0.07

( 6 , s ) ; " C NMR (100 MHz, CDCI,)6 144 .8 , 1 3 9 . 1 , 1 3 3 . 6 , 132 .8 ,

1 2 9 . 8 , 129 .2 , 1 2 7 . 9 , 1 2 7 . 7 , 85.3, 8 4 . 0 , 7 5 . 9 , 7 2 . 9 , 71 .2 , 51 .5 ,

36-3, 2 9 . 8 , 25.8, 24.9, 24 .0 , 21.7, 20.7 , 1 8 - 0 , -3-9, -5.1.

69

[2S,2(2Rt5S,5(1R)) I I-iodo-(4-Benzenesulfonyl-2-15-(1-((1,I-

dimethylethyl) dimethylsiloxy) -ethyl) -5-methyl -tetrahydro-furan-2 - yl] -butan-2-01

OH OTBS

Nal, 2-butanone, 18-c-6 - reflux, 16 h

OH OTBS X

The mixture of ~etrahyarof u r a n y l ether ix and its diastereomer,

( 3 . 5 g, 5.6 mnol) w s s disolved in 12 mL cf 2-butanone before the

sdaicion of sodium iodide (8.4 g, 5 5 . 8 mmol) and 18-c-6 (1- 5 g, 5 - 6 m o l l . The slurry was heated t o a gentle reflux and stirred for I6

h, after which t h e s o l u t i o n was cooled t o room temperature, and 100

mL of saturated brine solution was added. The aqueous phase was

s e p e r a t e d and extracted w i t h ether (3 x 100 ml), dried over

a n h y d r o u s Na,SO,, and c o n c e n t r a t e d i n vacuo. Purification by f l a s h

chromaZography ( 2 0 - 5 0 5 ethyl acetate/hexanes) gave an inseparable

m i x t u r e o f c i s x , and c r a n s iodides ( 2 . 6 ~ 3 80%) as a pale y e l l o w

o i l .

[2s,2(2Rl5Sf5(1R)) 1 (4-Benzenesulfonyl-2- [ S - (1- ( (1,l-

dimethylethyl) dimethylsiloxy) -ethyl) -5-methyl-tetrahydro-furan-Z-

yl 1 -butan-2 -01

Bu3SnH, AlEN , toluene

OH OTBS OH OTBS

r

refl w. 6 h

The mixture of iodides were dissolved in 9.2 mL of toluene. First

tributyltin nydride ( 2 . 5 mL, 9 rnmol) , and then AIBN ( 1 8 - 5 mg, 0.14

mmol} were added, and the mixture was heated to reflux for 6 fi.

Direct purification by flash chromatography on silica gel (5%-30%

e~her/toluene) prov ided the desired cis isomer xi, (1.2 g, 59%) as

a colourless oil.

'H W R (400 MEz, c D c I J ~ 7.90-7.50 (SH, m ) , 3.78 (lH, t, J=7-3 Hz),

3.58 (IH, q, J=6.2 Hz), 3.32 (lH, ddd, J=4.4, 12.5, 16.8 Hz), 3.16

(lH, dc, J=4.8, 12.8 H z ) , 2.21 (1H, s ) , 2.00-1.50 (6, m) 1.09 ( 3 H ,

s ) , 1.07 (3H, s), 1.05 (3H, d, J=6.2 Hz), 0.85 (9H, s), 0.05 (3E,

S) , 0.03 (3H, s ) ; " C NMR (100 MHz, C D C ~ , ) ~ 139.1, 133.6, 129.2,

127.9, 85-0, 84.2, 73.0, 72.1, 51.6, 34.3, 29.6, 25.9, 25.5, 23-8,

20.5, 18-53, 18.0, -4.0, -4.5.

71

[ 2 S , 2 (2R) , SR, 5 (1s) ] -5- [3-Benzenesulfonyl-I- (trimethylsilyloxy) -I- methyl-propyl ] -2- (1 - ( (I, 1-dimethylethyl) dimethylsiIoxy) -ethyl) -2- methyl-tetrahydrofuran

OH OTBS

NEt3, TMSOTf

S02Ph qJ+ a+ OTMS OTBS

xii

First trietnylamine ( 0 . 9 7 mL, 41 mmol) and then trimethylsilyl

trif Iuorornechanesulfonate ( 0 . 6 5 mL, 3 . 3 6 rnrnol) w e r e added to a

solution of alcohol xi in 1 8 mL of dichloromethane at -78OC. After

3h of scirring at - 7 8 " C , 1 mL of methanol was added to the reaction

mixture. The solution was then warmed to room temperature and 100

rnL of saturated brine solution was added. The aqueous phase was

seperaiea, extracted with dichloromethane (3 x 200 mL), dried over

a n h y d r o ~ s N a , S O , , fil terea, and concentrated in vacuo, Purification

by flash chromatcgraphy on silica gel (20-40% ethyl acetate/hexanes

w i t h 5 % triethyl mine) gave fragment xii as a colourless oil (1.3

g, 9 3 % ) .

'H NMR ( 4 0 0 MHz, CDCl,)6 7 .90 -7 .50 ( S H , m ) , 3 . 6 5 (lH, t, J=7 - 0 H z ) ,

3 . 4 3 (lH, q, J=6.2 Hz) 3 . 2 0 (2H, m), 1 . 9 5 - 1 . 5 0 (6H, m ) , 1 . 0 6 (3H,

s ) , 1 - 0 0 (3H, s ) , 0 . 9 9 (3H, d, J=6.2 H z ) , 0 . 8 4 (9H, s ) , 0 . 0 2 (3H,

s ) , - 0 . 0 1 (9H, s ) ; I3c NMR (100 MHz, CDc13)6 1 3 9 . 1 , 1 3 3 . 4 , 1 2 9 . 1 ,

1 2 8 . 0 , 8 5 . 7 , 82 .8 , 7 5 . 7 , 73 .4 , 5 2 - 0 , 3 5 . 9 , 32 .7 , 2 6 . 3 , 2 5 . 8 , 23 .0 ,

1 8 . 9 , 18.4, 1 7 . 9 , 2.4, -3 .9 , - 4 . 8 .

1-Colucci, J. Ph. D. Dissertation, University of Toronto, 1997

2. (a) Hashimoto, M. ; Harigaya, H. ; Yanagiya, M. ; Shiragama, H I J. Org. Chem. 1991, 56, 2299 (b) Wuts, P. G. M.; D'Costa, R. Butler, W. J. Org. Chem. 1984, 49, 2582 (c) Hanessian, S.; DeHoff, B.; Sakito, Y. J. A m . . Chem. Soc. 1990, 112, 5276

3.Umbreit, M. A*; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526

44a) Julia, M.; Paris, J-M. Tetrahedron Lett. 1973, 14, 4833 (b) Kocienski, P. J. ; Lythgoe, B.; Waterhouse, I. J. Chem. Soc., Perkin Trans. I 1978, 829

5.(a) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135 (b) Smith, 111, A. B. ; Hale, K. J.; McCauley, Jr., J. P. Tetrahedron Lett. 1989, 30, 1037

6.Pine, S. H.; Shen, G.; Bautista, J.; Sutton, Jr., C . ; Yamada, W-; Apodaca, L. J. 0rg. Chern. 1990, 55, 2234

TArnett, E. M.; Maroldo, S. G . ; Schriver, G. W.; Schilling, S. L.; Troughton, E. B. J. Am. Chem. Soc. 1985, 107, 2091

8.Ga0, Y. ; Hanson, R. M. ; Klunder, J. M. ; KO, S . Y . ; Masamuni, H-; Sharpless, K. B. 3. Am. Chem. Soc. 1987, 109, 5765

9-Colucci, J. Ph. D. Dissertation, University of Toronto, 1997

lO.Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1980, 45, 849

l S t , W. C.; Kahn, M.; Miltra, A. J. Org. Chem. 1978, 43, 2923

12.Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 3455

13.Umbreit, M.A.; Sharpless, K.B. %Am. Chem. Soc. 1977, 99, 5526

14.Umbreit, M.A.; Sharpless, K.B. % A m . Chem. Soc. 1977, 99, 5526

15.0ehlschlagerf A. C.; Wong, J. W.; Verigin, V. G.; Pierce, H- D. Jr. J. Org. Chem, 1983, 48, 5009

16.0ehlschlager, A. C * ; Wong, J. W.; Verigin, V. G , ; Pierce, H. D. Jr. J. Org. C h m , 1983, 48, 5009

17.Ga0, Y.; Hanson, R.M.; Klunder, J.M.; KO, S.Y,; Masamune, H.; Sharpless, K. B, J, Am. Chem. Soc. 1987, 109, 5765

18.Coluccif J. Ph. D. Dissertation, University of Toronto, 1997