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Master's Theses Theses and Dissertations

1992

The Synthesis of Chiral Building Blocks Using Beta-Hydroxy Sulfoxide Dianions

Carla M. Edwards Loyola University Chicago

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 1992 Carla M. Edwards The Synthesis of Chiral Building Blocks Using Beta­ Hydroxy Sulfoxide Dianions

by Carla M. Edwards

A Thesis Submitted to the Faculty of the Graduate School of Loyola University of Chicago in Partial Fulfillment of the Requirements for the Degree of Master of Science May 1992 Copyright by Carla Marie Edwards, 1992 All rights reserved

11 TABLE OF CONTENTS

PAGE

COPYRIGHT PAGE...... n

ACKNOWLEDGEMENTS...... XVll

VITA...... XVlll

LIST OF TABLES...... XIX

LIST OF FIGURES...... xx

LIST OF SCHEMES...... XXI

ABBREVIATIONS...... XXlll

CHAPfER I. INTRODUCTION...... 1 II. STATEMENT OF PURPOSE...... 5

III. RES ULTS...... 6

IV. DISCUSSION...... 16

PART 1. The synthesis of 1,2-O-isopropylidene-2-(R)­ glyceraldehyde (3) and 1,2-O-isopropylidene-2-(S)-

glyceraldehyde (6)...... 16 A. The synthesis of 1,2.5,6-bis-O-isopropylidene-

D-mannitol (2)...... 16 B. The synthesis of 1,2-O-isopropylidene-2-(R)-

glyceraldehyde (3)...... 17 C. The synthesis of 1.2-isopropylidene-L-ascorbic

acid (5)...... 19

111 D. The attempted synthesis of 2.3-O­

isopropylidene-2-(S)-glyceraldehyde (6) from (5)...... 20 E. The synthesis of 1,2-isopropylidene-L-gulonic-y-

lactone (8)...... 22 F. The attempted synthesis of 1,2-O­

isopropy lidene-2-(S)-glyceraldehyde (6) from

(8)...... 23 PART 2. The synthesis of 1,2-O-isopropylidene-2-(R.S)-

3-(R,S)-hydroxy-4-phenylsulfenyl butane (9), (10), 1.2- O-i sopropy 1idene-2-(R)-3-(R,S )-hy droxy-4-pheny 1s ul fi ny 1 butane (11) and phenyl sulfonyl butane (12)...... 24 A. The synthesis of 1.2-O-isopropylidene-2-(R)-3- (R,S)-trihydroxy-4-phenylsulfenyl butane

(9)...... 24 B. The attempted synthesis of 1.2-O­ isopropy lidene-2-( S )-3-(R, S )-trihydroxy-4-

phenylsulfenyl butane (10)...... 26 C. The synthesis of 1.2-O-isopropylidene-2- (R)-3-(R.S)-trihydroxy-4-phenylsulfinyl butane

(11)...... 27 D. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S)-trihydroxy-4-phenylsulfonyl butane

(12)...... 28

lV PART 3. The generation and reaction of C-0- sulfur-stabilized dianions...... 29 A. The synthesis of 1,2-0-isopropylidene-2-(R)- 3-(R,S )-trihydroxy-4-pheny 1sul f ony 1-6-heptene

(13)...... 30 B. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-deutero-4-pheny lsulfiny 1 butane

(14)...... 30 C. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-pheny ls ulfiny 1-6-heptene

(15)...... 31 D. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-pheny lsul finyl pentane

(16)...... 32 E. The synthesis of 1.2-0-isopropylidene-2-(R)-3- (R,S )-5-(R,S )-tetrahydroxy-4-phenyls ulfinyl

hexane (17)...... 32 F. The· synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-5-(R,S )-tetrahydroxy-4-pheny lsulfiny I-

octane (18)...... 33

V G. The synthesis of 1,2-0-isopropylidene-2-(R)-3-

(R, S )-5-(R,S )-tetrahydroxy-4-phenyl sul finyl-6-

phenyl hexane (19)...... 34 H. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-5-tetrahy droxy-4-phenyl sul fi nyl-5-

methyl hexane (20)...... 34 I. The attempted synthesis of 1,2-0- i s opropy Ii dene-2-(R)-3-(R,S )-5-tetrahydroxy-4-

phenylsulfinyl-5-ethylheptane (21)...... 35 PART 4. The generation of the dianion of 1,2-0- isopropylidene-3-(R)-2-(R,S)-trihydroxy-1-methyl phenylsulfenyl butane (9) and investigational chemistry of derivatives of (26)...... 35 A. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-deu tero-4-pheny ls ul f eny 1

butane (22)...... 35 B. The synthesis of 1,2-0-isopropylidene-2-(R)- 3-(R,S)-trimethylsiloxy-4-phenylsulfenyl butane

(23)...... 38 C. The synthesis of 1,2-0-isopropylidene-2-(R)- 3-(R. S )-tri me thy Is il ox y-4-methy 1-4-

phenylsulfenyl butane (24)...... 39

VI D. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-acetoxy-4-pheny lsulfeny l butane

(25)...... 40 E. The synthesis of 1.2-O-isopropylidene-2-(R)-3-

oxo-4-phenylsulfenyl butanone (26)...... 41 F. The synthesis of 1.2-O-isopropylidene-2-(R)-3- oxo-4-methyl-4-pheny lsul feny I butanone

(27)...... 42 G. The synthesis of 1,2-O-isopropylidene-2-(R)-3- oxo-4-phenylsulfenyl-5-(R,S)-hydroxy hexanone

(28)...... 43 H. The synthesis of 1.2-O-isopropylidene-2-oxo-3- phenylsulfeny 1-5-(R,S )-hydroxy-5-pheny 1

pen tan one (29)...... 44 I. The synthesis of 1.2-O-isopropylidene-2-(R)-3- oxo-4-phen y ls ulfeny 1-5-hy droxy-5-m ethy 1

hexanone (30)...... 45 PART 5. The condensation reactions of prochiral Michael acceptors with methyl phenylsulfinyl anion and the dianion of (32)...... 46 A. The synthesis of 3-(R,S)-hydroxy-4-

phenylsulfinyl-1-butene (31)...... 46 B. The synthesis of 2-methyl-3-(R,S)-hydroxy-4-

phenylsulfinyl-l-butene (32)...... 48

Vll C. The synthesis of 1-phenyl-trans-2-methyl- (R,S)-3-hydroxy-4-phenylsulfinyl-1-butene

(33)...... 49 D. The synthesis of 2-methyl-3-(R,S)-hydroxy-4-

phenylsulfinyl-1,6-hexadiene (34)...... 50 PART 6. The assignment of the 3-hydroxyl s tereochemistry in 1,2-O-isopropylidene-2-(R)-3-(R,S )­ trihydroxy-4-phenylsulfonyl butane (12) and 1.2-O- i sopropy lidene-2-(R)-3-(R. S )-trihydroxy-4- phenylsulfenyl butane (9) ...... 51 A. The separation of 1,2-O-isopropylidene-2-(R)-3- (S)-trihydroxy-4-phenyl sulfonyl butane (35) from 1,2-O-i sopropy Ii dene-2-(R )-3-(R)-tri hy droxy-4-

phenyl sulfonyl butane (36) using preparative HPLC...... 52 B. The separation of 1.2-O-isopropylidene-2-(R)-3- (R)-trihydroxy-4-phenylsulfenyl butane (37) from 1,2-O-i sopropy lid en e-2-( R )-3-( S )-trih ydrox y-4-

phenylsulfenyl butane (38) using preparative HPLC...... 54

Vlll 10. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-trihydroxy-4-pheny Is ulfiny 1-6-heptene

(15)...... 75 11. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S)-trihydroxy-4-phenylsulfinyl pentane

(16)...... 75 12 The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-5-(R, S )-tetrahy droxy-4-phenyl s ul finy I hexane (17)...... 77 13. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-5-(R,S )-tetrahy droxy-4-ph enyls ul finy I octane (18)...... 77 14. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-5-(R,S )-tetrahydroxy-4-phenyl s ulfiny I

6-phenyl hexane (19)...... 78 15. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-5-tetrah ydroxy-4-pheny Is ul fin yl-5- methyl hexane (20)...... 79 16. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S )-trimethy lsiloxy-4-pheny ls ul fen y I butane (23)...... 79 17. The synthesis of 1,2-O-isopropylidene-2-(R)- 3-(R,S)-acetoxy-4-phenylsulfenyl butane

(25)...... 80

XI 1. The synthesis of 1,2,5,6-bis-O-isopropylidene-

D-mannitol (2)...... 62 2. The synthesis of 1.2-0-isopropylidene-2-(R)- glyceraldehyde (3)...... 63 3. The synthesis of 1.2-isopropylidene-L-ascorbic acid (5)...... 64 4. The synthesis of 1,2-isopropylidene-L-gulonic-y- lactone (8)...... 65 5. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S)-trihydroxy-4-phenylsulfenyl butane

(9)...... 66 6. The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-pheny lsulfiny 1 butane

(11)...... 68 7. The synthesis of 1.2-0-isopropylidene-2-(R)- 3-(R,S)-trihydroxy-4-phenylsulfonyl butane

(12)...... 69 8. The synthesis of 1,2-0-isopropylidene-2-(R)- 3-(R,S )-trihydroxy-4-phenyls ulfonyl-6-heptene

(13)...... 72 9. ' The synthesis of 1,2-0-isopropylidene-2-(R)-3- (R,S )-trihydroxy-4-deutero-4-pheny Is ulfinyl butane

(14)...... 74

X C. The synthesis of 1.2-O-isopropylidene-2-(R)-3- (S)-trihydroxy butane (39) and 1.2-O- isopropy I idene-2-(R)-3-(R)-trihydroxy butane

(40)...... 54 PART 7. Isopropylidene migration studies of 1,2-O­ isopropy lidene-2-(R)-3-(R,S )-trihydrox y-4-

pheny lsulfinyl butane (11) and attempted sugar formation using deprotected and derivitised 1.2-O-isopropylidene- 2-(R )-3-( R, S )-5-(R.S )-tetrah y droxy-4-

phenylsulfinyl-octane (18)...... 55 A. The attempted synthesis of 2.3-O- i sopropy lidene-2-(R)-3-(R,S )-4-pheny lsul finy 1

butan-1-ol (41)...... 55 B. The attempted synthesis of 1.2-O- i sopropy Ii dene-2-(R)-3-(R ,S )-5-(R,S )-diacetox y-4-

phenylsulfinyl-octane (42)...... 57 C. The attempted synthesis of 2-(R)-3-(R.S)- 5-(R,S )-tetrahy droxy-4-ph eny ls ul finy 1-octan e

(43)...... 58 D. The attempted synthesis of l-oxo-2-(R)- 3-(R,S )-5-(R.S )-trihydroxy-4-phenyl sul finy I

octanal ( 44)...... 58 V. EXPERIMENTAL SECTION...... 60 PART A. The synthesis of compounds...... 62

IX 18. The synthesis of 1.2-O-isopropylidene-2-(R)- 3-oxo-4-phenylsulfenyl butanone

(26)...... 81 I 9. The synthesis of 1.2-O-isopropylidene-2-(R)- 3-oxo-4-phenylsulfenyl-5-(R.S )-hydroxy hexanone

(28)...... 83 20. The synthesis of 1.2-O-isopropylidene-2-oxo- 3-pheny ls ulfeny 1-5-pheny 1-4-pentenone

(29a)...... 84 21. The synthesis of 1.2-O-isopropylidene-2-(R)- 3-acetoxy-4-pheny lsul feny 1-3-hexenone

(30a)...... 86 22. The synthesis of 3-(R.S)-hydroxy-4-

pheny lsulfiny I- I -butene (31)...... 8 8 23. The synthesis of 2-methyl-3-(R.S)-hydroxy-4- phenylsulfinyl-1-butene (32)...... 89 24. The synthesis of 1-phenyl-trans-2-methyl- (R,S )-3-hydroxy-4-pheny lsulfiny I-I -butene

(33)...... 90 25. The synthesis of 2-methyl-3-(R,S)-hydroxy-4- phenylsulfinyl-l ,6 hexadiene (34 )...... 92 26. The separation of 1,2-O-isopropylidene-2-(R)- 3-(S)-trihydroxy-4-phenyl sulfonyl butane (35) from 1.2-O-isopropylidene-2-(R)-3-(R)-trihydroxy-

XII 4-phenyl sulfonyl butane (36) from using preparative HPLC...... 93 27. The separation of 1,2-0-isopropylidene-2-(R)- 3-(R)-trihydroxy-4-phenylsulfenyl butane (37) from 1,2-0-isopropylidene-2-(R)-3-(S)-trihydroxy- 4-phenylsulfenyl butane (38) using preparative HPLC...... 94 28. The synthesis of 1,2-0-isopropylidene-2-(R)- 3-(S)-trihydroxy butane (39) and 1,2-0- isopropylidene-2-(R)-3-(R)-trihydroxy butane

(40)...... 96

VI. SPECTRAL APPENDICES...... 98 1. 1,2.5 ,6-bis-0-isopropylidene-D-mannitol

(2)...... 99 2. 1,2-0-isopropylidene-2-(R)-glyceraldehyde

(3)...... 104 3. 1,2-isopropy lidene L-ascorbic acid

(5)...... 109 4. 1,2-isopropylidene-o-Gulonic-y-lactone

(8)...... 114 5. 1,2-0-isopropy lidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfenyl butane (9)...... 119 6. 1,2-0-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfinyl butane (11)...... 125

Xll l 7. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfonyl butane (12)...... 131 8. 1,2-O-isopropy Ii dene-2-(R)-3-(R,S )-trihydroxy-4- phenylsulfonyl-6-heptene (13)...... 137 9. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- deutero-4-phenylsulfinyl butane (14)...... 140 10. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfinyl-6-heptene (15)...... 143 11. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfinyl pentane (16)...... 148 12. 1 ,2-O-isopropylidene-2-(R)-3-(R,S )-5-(R,S )- tetrahydroxy-4-phenylsulfinylhexane (17)...... 152 13. 1,2-O-isopropylidene-2-(R)-3-(R,S)-5-(R,S )- tetrahydroxy-4-phenylsulfinyl octane (18)...... 155 14. 1,2-O-isopropylidene-2-(R)-3-(R,S)-5-(R,S )- tetrahydroxy-4-pheny lsulfinyl-6-phenyl hexane

(19)...... 160 15. 1,2-O-isopropy lidene-2-(R)-3-(R,S )-5-tetrahydroxy­ hydroxy-4-phenylsulfiny 1-5-methyl hexane

(20)...... 165 16. 1,2-O-isopropylidene-2-(R)-3-(R,S)- trimethylsiloxy-4-pheny lsulfeny I butane

(23)...... 169 17. 1,2-O-isopropylidene-2-(R)-3-(R,S)-acetoxy-4- phenylsulfenyl butane (25)...... 173

XIV 18. 1.2-O-isopropylidene-2-(R)-3-oxo-4-phenylsulfenyl butanone (26)...... 178 19. 1.2-O-isopropylidene-2-(R)-3-oxo-4-phenylsulfenyl-

5-(R.S)-hydroxy hexanone (28)...... 183 20. 1.2-O-isopropylidene-2-oxo-3-phenylsulfenyl-5- phenyl-4-pentenone (29a)...... 188 21. 1,2-O-isopropylidene-2-(R)-3-acetoxy-4- phenylsulfenyl-3-hexenone (30a)...... 193 22. 3-(R,S)-hydroxy-4-phenylsulfinyl-l-butene

(31)...... 197 24. 2-methyl-3-(R,S)-hydroxy-4-phenylsulfinyl-1- butene (32)...... 202 25. l -phenyl-trans-2-methyl-(R,S)-3-hydroxy-4- phenylsulfinyl- l-butene (33)...... 207 26. 2-methyl-3-(R,S)-hydroxy-4-phenylsulfinyl-1,6- hexadiene (34)...... 213 27. 1,2-O-isopropylidene-2-(R)-3-(S)-trihydroxy-4- phenyl sulfonyl butane (35) from 1,2-O-isopropylidene- 2-(R)-3-(R)-trihydroxy-4-phenyl sulfonyl butane (36) from using preparative HPLC...... 217 28. 1,2-O-isopropylidene-2-(R)-3-(R)-trihydroxy-4- phenylsulfenyl butane (37) from 1,2-O-isopropylidene-2- (R)-3-(S)-trihydroxy-4-phenylsulfenyl butane (38) using preparative HPLC...... 222

xv 29. 1,2-0-isopropy lidene-2-(R)-3-(S)-trihydroxy butane (39) and 1,2-0-isopropylidene-2-(R)-3-(R)-trihydroxy

butane ( 40)...... 226

VII. SUMMARY...... 232

VIII. BIBLIOGRAPHY...... 234

XVI ACKNOWLEDGEMENTS

The author wishes to thank her Research Director, Dr. Charles M. Thompson for his advice and patience throughout the course of this work and Dr. Kenneth Olsen and Dr. Duarte Mota De Freitas for their helpful suggestions. The author would also like to thank Abbott Laboratories for their financial assistance. Of the many friends and colleagues that offered support and advice, special thanks goes to the Abbott Laboratory spectroscopic and analytical staff and to Mr. Michael Tufano, Mr. David Bacino, and Mr. Douglas Steinman for their helpful suggestions. Finally, the author wishes to thank her husband, Bradley P. Nelson, for his patience, love and moral support throughout the work on this thesis. This thesis is dedicated to the authors' husband, Bradley P. Nelson, son, Andrew Edwards Nelson, and grandmother Luta Julianna Keri Parkansky whose bravery and determination were a constant inspiration.

XVll VITA

Carla M. Edwards was born in Green Bay, Wisconsin on August 5, 1960 to Roger Edwards and Helen Parkansky Edwards. After graduating from St. Joseph Academy in 1978, Carla attended UW-Milwaukee and UW-Oshkosh where she received a Bachelor of Science degree in Zoology. Carla then attended UW-Madison where she earned a Bachelor of Science m Biochemistry in 1985. In June of 1985, Carla joined Abbott Laboratories where she is currently employed as an Associate Scientist in Pharmaceutical Discovery. In January of 1988, Carla enrolled as a part-time student in the graduate school of Loyola University of Chicago Department of Chemistry. She expects to receive a Master of Science degree in May 1992. In September 1985, Carla married Bradley P. Nelson, J.D. On June 7, 1991. Carla and Brad welcomed Andrew Edwards Nelson to the world. The Nelsons make their home in Evanston with their son Andrew, German shorthaired pointer, Sam and domestic shorthaired feline, Chester.

XVlll LIST OF TABLES PAGE

Table 1. Oxidative cleavage reactions to obtain chiral glyceraldehydes (3) and (6)...... 7

Table 2. Formation of sulfur stabilized dianion substrates...... 8

Table 3. -- Dianion reactions with (11)...... 10

Table 4. Reactions of compound (9) and (26) ...... 11

Table 5. Reactions of Michael acceptors with methyl phenyl sulfoxide ...... 13

Table 6. Separation of the diastereomers of (9), (12) and (37), (38)...... 13

Table 7. Attempted formation of an unnatural sugar from (18)...... 15

XIX LIST OF FIGURES PAGE

Figure 1...... I

Figure 2...... 2 Figure 3...... 3 Figure 4...... 17

Figure 5...... 30 Figure 6...... 38 Figure 7...... 43 Figure 8...... 45 Figure 9...... 49 Figure 10...... 57

xx LIST OF SCHEMES PAGE

Scheme 1...... 18 Scheme 2...... 20 Scheme 3...... 23

Scheme 4...... 26 Scheme 5...... 27 Scheme 6...... 28 Scheme 7...... 29 Scheme 8...... 31 Scheme 9...... 31

Scheme 10...... 36

Scheme 11...... 38

Scheme 12...... 40 Scheme 13...... 40

Scheme 14...... 42

Scheme 15...... 44

Scheme 16...... 48 Scheme 17...... 49 Scheme 18...... 50

Scheme 19...... 51 Scheme 20...... 53

Scheme 21...... 53 Scheme 22...... 55

XXI Scheme 23 ...... ···················· ...... 56 Scheme 24...... 58 Scheme 25...... 59 Scheme 26...... 23 3

XXll ABBREVIATIONS

THF: Tetrahydrofuran DMPU; 1,3-Dimethyl-3,4.5 ,6-tetrahydro-2( I H)-pyrimidinone RT: Room temperature: 25 °c DABCO: l ,4-Diazabicyclo[2.2.2]octane DMSO: Methyl sulfoxide DMS: Dimethyl sulfide NCS: N-Chlorosuccinimide N2; Nitrogen gas mCPBA; Metachloroperbenzoic acid DMF: N.N-Dimethyl formamide

0 ex ;lsopropylidene

xxm CHAPTER I

INTRODUCTION

The generation of amons from activated carbons has been used extensively by synthetic organic chemists as a means of carbon-carbon bond formation and as a way of introducing unique functional groups into molecules through electrophilic condensation reactions. I Depending on the source of activation, the conditions needed for abstraction of a proton from the activated carbon could range from mildly basic to strongly basic with the possible use of co-solvents such a DABCO (l ,4-Diazabicyclo[2.2.2]octane) (Figure 1) or DMPU ( 1,3-Dimethyl-3 ,4,5 ,6-tetrahydro-2( 1 H)-pyrimidinone) (Figure

2) to help stabilize the incipient anion.2.3

Figure 1

N

DABCO 2

Although these reactions generally resulted in minimal side product formation and moderate to good yields, the method was limited to simple molecules that possessed little diverse functionality. From a synthetic standpoint, it was desirable to develop methods that would incorporate the favorable attributes of anion chemistry but be able to extend this to polyfunctional, biologically important precursors.

Figure 2

DMPU

Fortuitously, in 1958, Harris et aI.4 published a paper detailing the isolation of a terminally alkylated compound from the dipotassium salt of benzylacetone. Since that publication, the use of dianions as means of carbon-carbon bond formation and regioselective condensation in polyfunctional molecules has become increasingly popular.5,6,7 In particular, the use of O,C prochiral sulfur dianions (F)gure 3) in condensation reactions has been widely cited in the literature as a tool for carbon-carbon bond formation, 3 stereoselective generation of chiral centers and as a source of building blocks for natural product synthesis. 8,9 .10

Figure 3

Of all the O.C sulfur dianions cited m the literature. the resonance-stabilized. sulfone dianion is one of the most widely investigated. Beta-hydroxy sulfone dianions have been successfully reacted with alkyl halides. aldehydes and ketones. 8,9 .10 The stereochemistry of the prochiral chiral centers was established by the degree of chelation of the metal cation with the oxyanion and oxygen sulfonyl group. The stereochemistry of the product also was found to be dependent on the choice of solvent and electrophile. The use of THF as a solvent coupled with a bulky electrophile favored the formation of erythro isomers in the major product. I OJ 1 Beta-hydroxy sulfone dianions have been successfully utilized to produce natural product building blocks such as 2(5H)-furanones and optically active lactones (1 ). 8.12 Beta-hydroxy sulfoxide dianions also have been generated and reacted with D20. alkyl halides and aldehydes.9J3 The stereochemical outcomes of 4

these prochiral additions varied with the reaction time as well as the degree of chelation of metal cation with the sulfinyl group and oxyanion_ 13 Finally, a beta-hydroxy sulfide dianion has been postulated as the reactive intermediate in the conversion of 2-hydroxy-1,3-bis-(phenylthio)-propane to the corresponding cyclopropanol (2).14 The dearth of literature precedent in this area suggests the degree of difficulty associated with the generation of a non-resonance stabilized carbanion beta to an oxyanion. CHAPTER II

STATEMENT OF PURPOSE

The work presented in this thesis represents the first attempt at combining a chiral building block structure within an O,C sulfur stabilized dianion framework to make a pro-sugar building block. In particular. we investigated the selective coupling of a chiral beta-hydroxy sulfoxide dianion with carbonyl electrophiles in order to generate novel, chain extended building blocks that possess four chiral centers. Synthetic schemes illustrating these reactions are found in Chapter IV. Tables summarizing the results of all experiments are found in Chapter III.

5 CHAPTER III

RESULTS

The synthesis of 1,2-0-isopropy lidene-2-(R)­ glyceraldehyde (3) was initiated using D-mannitol as the starting material, protecting this with two isopropylidene groups followed by oxidative cleavage of the protected, chiral, R-glyceraldehyde. The epimer S-glyceraldehyde was prepared using L-ascorbic acid as the starting material. L-Ascorbic acid was then protected similarily and was oxidatively cleaved to form the 1,2-0-isopropylidene-2-(S)-glyceraldehyde (6) derivative (Table 1). Thioanisole and methyl phenyl sulfoxide were successfully condensed with 1,2-0-isopropylidene-2-(R)­ glyceraldehyde (3) to form 1,2-0-isopropylidene-2-(R)-3-

(R,S)-trihydroxy-4-phenylsulfenyl butane (9) and 1,2-0- i sopropy lidene-2-(R)-3-(R,S )-trihydroxy-4-pheny ls ul finy 1 butane (11). We were unable to form 1,2-0-isopropylidene-2-

(S)-3-(R.S )-trihydroxy-4-phenylsulfeny 1 butane (10) using 1,2-

0-isopropylidene-2-(S )-glyceraldehyde (6) as the electrophile.

Both (9) and (11) were oxidized to give the sulfone derivative. 1,2-0-isopropy lidene-2-(R)-3-(R,S )-trihydroxy-4- phenylsulfonyl butane (12) (Table 2). 6 7

Table 1. Oxidative cleavage reactions to obtain chiral glyceraldehydes (3) and ( 6).

0 0 r-lH r-lH 0 0 0 0 /, 1/ (3) (6) Scheme substrate product %yielda, b

I (1) (2) 95a 1 (2) (3) 30-4oa 2 (4) (5) 98a 2 (5) (6) 2-3a,b 3 (7) (8) 50a 3 (8) (6) 3_5a,b a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material 8

Table 2. Formation of sulfur stabilized dianions

x=O; (9) x=l; (11) x=2; (12) Scheme substrate product %yielda

5 (3) (9) 6 (3) (11) 7 (3) (12)

a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material 9

The dianion of 1.2-0-isopropylidene-2-(R)-3-(R,S)­

trihydroxy-4-phenylsulfonyl butane (12) was successfully formed and trapped using methyl iodide and deuterated acetone. Likewise, the dianion of 1,2-0-isopropylidene-2-(R)-3-(R,S)­

trihydroxy-4-phenylsulfinyl butane (11) was formed and trapped with allyl bromide, methyl iodide and deuterated acetone. The dianion of (11) was successfully condensed with acetaldehyde, butyraldehyde and benzaldehyde. The results from the condensation reactions resulting from the use of acetone and 3-pentanone as the electrophiles were not as sucessful as the reactions using aldehydes as the electrophiles (Table 3). The dianion of 1,2-0-isopropylidene-2-(R)-3-(R,S)­ trihydroxy-4-phenylsulfenyl butane (9) was not formed and no trapped derivatives were observed. The silyl ether and acetate of (9) were formed in an effort to separate the diastereomers as well as to explore resonance versus inductive effects m blocked beta-hydroxy sulfide derivatives. Silica gel chromatographic separations of these ester derivatives were not successful. Preparative hplc was performed on the parent compounds (9) and (12) in order to separate the diastereomers and determine the absolute configurations at the 2-hydroxy position. The diastereomers of (9) and (12) were separated and an attempt was made to deprotect the compounds to give the chiral isopropylidene glycerols. The deprotection reaction 1 0

Table 3. Diani on reactions with (11)

HO (0) x

sl--0 ~ ;; , A..,.. yo R '\

x=l; (11) (14); R=D (18); R=CH(OH)CH2CH2CH3 x=2: (12) (15); R=allyl (19); R=CH(OH)Ph (16); R=methyl (20); R=CH(OH)(CH3)2 (17): R=CH(OH)CH3 (21); R=CH(OH)(Et)2

Scheme substrate product %yielda, b

8 (12) (13) 15a 9 (11) ( 14) 50 9 (11) (15) 15a 9 (11) (16) 15a 9 (11) (17) 10a 9 (11) (18) 13a 9 (11) (19) 7a 9 (11) (20) 3a 1 0 (11) (21) b a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material I 1

Table 4. Reactions of compound (9) and (26)

HO 0 ~s--Q ,rvs--O 0 0 X xo ' (9) ' (2 6)

Scheme substrate product %yielda, b, d

I 0 (9) (22) d I I (9) (23) 26a I 2 (9) (24) 70a 1 3 (9) (25) b 1 4 (9) (26) 30a I 5 (26) (27) 10a I 6 (26) (28) 20a 1 7 (26) (29) 15a I 8 (26) (30) 2a a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material 1 2 went much better with the sulfide derivative than with the sulfone. An optical rotation was performed on the separated. chiral glycerols and was comparable with the literature values. The diastereofacial selectivity was found to be in favor of the syn diastereomer in a ratio of 6:4 (Table 4). The secondary hydroxyl of 1.2-0-isopropylidene-2-

(R)-3-(R,S)-trihydroxy-phenylsulfenyl butane (9) was oxidized using a standard procedure to give 1,2-0-isopropylidene-2-(R)-

3-oxo-4-phenylsulfenyl butanone (26). The anion of (26) was formed and was trapped using methyl iodide. Acetaldehyde was successfully condensed with the anion of (26) to form 1.2-0- i sopropy 1idene-2-(R)-3-oxo-4-pheny 1s ulfeny 1-5-(R,S )-hydroxy butanone (28). The anion of (26) was also condensed with benzaldehyde to give directly the dehydration product rather than the alcohol (29). We also attempted to add acetone and 3- pentanone to this anion. However, the desired products were not isolated. With acetone as the electrophile, dehydration products were again directly observed. When the acetone condensation reaction was quenched using acetic anhydride, the 2-acetate ester of the enol ether was formed. Unprotected prochiral Michael electrophiles acrolein. methacrolein and a-methyl-trans-cinnamaldehyde were reacted with the anion of (11) to form the desired unsaturated beta-hydroxy sulfoxide derivatives (31), (32), and (33) (Table 5). The condensation reaction was found to occur 1 3

Tahle 5. Reactions of Michael acceptors with meth)'I phenyl sulfoxide

(31); R'=H, R=H (32); R'=H, R=CH3 (33); R'=Ph, R=CH3

Scheme substrate product %yielda

1 6 acrolein (31) 45a 1 7 methacrolein (32) 10a 1 8 a-methyl- (33) 8oa trans- c1nnam- aldehyde 1 9 (31) (34) 10a

Table 6. Separation of the diastereomers of (9),(12) and (37),(38)

Scheme substrate product %yielda

20 ( 12) (35), (36) 2 1 (9) (37), (38) 22 (37), (38) (39), ( 40) a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material 1 4 in a L2 fashion rather than in a 1.4 fashion. The dianion of the methacrolein derivative was formed and trapped with allyl bromide. This experiment showed that dianion chemistry could be extended to non-traditional prochiral building block substrates. These Michael adducts could be stereoselectively functionalized at the olefin to form chiral, polyhydroxylated building blocks The results of the HPLC separations of the diastereomers of (9) and (12) are tabulated in Table 6. Finally, pilot experiments were performed on the parent (11) and condensation adduct (18) to try to establish limits on the degree of required protection prior to oxidation/cyclization steps to form unnatural sugars. An acetonide migration reaction was performed on (11) and was found to give mixed products. The adduct (18) was treated with acetic anhydride and was found to be highly selective although resistant to acetylation conditions. The adduct (18) was also deprotected usmg Amberlyst 18 and a Corey-Kim oxidation was attemped on this material in the hope of isolating a cyclization product. The results from this experiment were inconclusive (Table 7). 1 5

Table 7. Attempted formation of an unnatural sugar from (18)

HO 0

11--0s ~ #

( 18) Scheme substrate product %yielda, b, c, d

23 (11) ( 41) 40a 24 (18) ( 42) b,d 25 ( 42) ( 43) b,d 26 ( 43) ( 44) C a yields after purification, b poor yields, c side reactions major products, d recovered unreacted starting material CHAPTER IV

DISCUSSION

PART 1. Synthesis of 1.2-O-isopropylidene-2-(R)- glyceraldehyde (3) and 1,2-O-isopropylidene-2-(S )­ glyceraldehyde (6) (Schemes 1, 2, 3)

A. Synthesis of 1.2,5,6-bis-O-isopropylidene-D-mannitol

(2). The synthesis of 1.2,5,6-bis-O-isopropylidene-D­ mannitol (2) was attempted using two literature procedures.15.16 D-mannitol was dissolved in anhydrous acetone and ZnC12 was added to the slurry with stirring at RT for 24 hours.15 The reaction mixture was analyzed by tlc and found to be 85% complete giving two new product spots. When compared with authentic sample (available from Aldrich). the major product co-spotted with authentic sample. However, 25- 30% of crude product was found to be the triisopropylidene D­ mannitol compound (Fi~ure 4). The Baer paper, 15 also noted the production of the triisopropylidene derivative. An alternative method was then sought that would give (2) without this side product. The best method for the exclusive production of (2) was found to be that cited by Kierstead and 16 1 7 co-work ers. 16 Here D-mannitol was dissolved in DMSO in the presence of 2.2-dimethoxypropane with a catalytic amount of· tosic acid under N2 at RT for 24 hours.

Figure 4

~ 0 0 ~ rl h 0 0 /'\

Tlc analysis of the crude reaction mixture showed near complete reaction to the desired compound (2). The reaction mixture was easily worked up using successive ethyl acetate washes. The organic phase was evaporated to a white solid that was recrystallized with hot hexane to give 95% yield of white, needle-like crystals. Because of the mild reaction conditions and high yields of crystalline material, this procedure was considered the method of choice for subsequent preparations of (2). B. Synthesis of 2,3-0-isopropylidene-2-(R)-

glyceraldehyde (3). The oxidation of (2) to (3) was first carried out usmg a modified procedure described by Kierstead and co- 1 8 workers.16 The bis-isopropylidene derivative (2) was disso1ved in anhydrous toluene and reacted with Pb(OAc)4 at RT. After 20 minutes, the reaction was shown to be complete via tic. The white slurry was filtered and the filtrate was neutralized with anhydrous K2CO3 and refiltered. However, after evaporation in vacuo, it was found that the product co­ evaporated with the toluene into the receiving trap.

Scheme 1 X 0 HO OH 0

r-<"'H ~ ~ 0 0 HO OH 0 0 A /~ (1) (2) (3)

In order to avoid this problem, anhydrous methylene chloride was used as a lower boiling reaction solvent.17 The use of methylene chloride was found to give minimal co-evaporation and distillation of the resulting solution gave 35-40% yield of the desired aldehyde (3). Although this method gave the desired aldehyde in fair yields, the toxicity of Pb(OAc)4 coupled with the carcinogenic properties of alkyl halides made 1 9 this method very undesirable as a preparative method of obtaining (3). An alternative method was reported by Kuszmann 18 where NaIO4 was used as the oxidizing agent resulting in an aqueous solution of (3). For our purposes. however. it was necessary to maintain anhydrous conditions to ensure successful reactions. Even though this method was mild and relatively free from toxicants. the aqueous aldehyde solution would not be useful to us from a synthetic standpoint. Recently. Schmid and colleguesl 9 reported a new preparative method for the synthesis of both (2) and (3).

C. Synthesis of 1.2-isopropylidene L-ascorbic acid (5). Since the series of reactions described in this thesis required the production of chiral building blocks of glyceraldehyde, it was of interest to prepare the optical antipode of (3). This goal was initiated using L-ascorbic acid as the chiral building block starting material. Using a procedure described by Jackson and Jones,20 L-ascorbic acid was dissolved in acetone and acetyl chloride was gradually added to the slurry. After stirring this slurry at RT for 24 hours. the reaction was found to be complete. Simple suction filtration furnished the product (5) as white crystalline needles. The procedure was free from side reactions and was readily amenable to scale-up synthesis giving 98 % yield. 20

Scheme 2

OH 0 / -oH )< 0 0 0 ,IH 0 ... 0 ...... 01/ 0 HO OH HO OH (4) (5) (6)

D. The synthesis of 2-3-0-isopropylidene-2-(S)-

glyceraldehyde (6) from (5). The synthesis of 1.2-0-isopropylidene-2-(S)­

glyceraldehyde (6) followed a literature procedure described by

Jung and Shaw.21 The small scale synthesis of (6) involved

first reducing the double bond of (5) followed by oxidative cleavage of this protected lactone with Pb(OAc)4 m ethyl acetate. The first step was pH dependent and had to be followed for four hours. The slurry was then stirred overnight and azeotroped to a white powder with absolute ethanol. The spectral data obtained for this intermediate suggested a great deal of salt formation. The oxidative cleavage was performed using the powder in ethyl acetate and Pb(OAc)4 as the oxidizing 2 1

agent. The reaction was found to be complete via tic analysis within 2 hours. After neutralization and several suction filtrations and rinses, the filtrate was evaporated, in vacuo, to a clear, oily solution. The oil was fractionally distilled at room pressure giving a major fraction at 139-143 °c. The oil was stored at -25 °c under N2. The analytical data obtained on this oil suggested the desired aldehyde had formed, however, the yields were poor ( I 0-15 %) . Scale up experiments were attempted usmg 40 g of substrate (5). The results were even more discouraging than that found at the 4 g scale. Besides the hazards of this experiment (120 g Pb(OAc)4), the product yield was estimated to be around 5 % yield via tic. It was suggested in several publications22 that the desired aldehyde (6) was not only unstable in organic solvents and subject to racemization but that the procedure as proposed by Jung and Shaw21 was not amenable to scale up because of the tendency of the aldehyde to undergo overreaction in the reduction step. An alternate procedure also was attempted using LiAlH4 as the reducing agent and NaIO4 as the oxidant.23 The procedure called for dissolving substrate in THF over N2 and cooling this mixture to O 0 c. The LiAlH4/fHF solution was added to substrate and the mixture was stirred at O 0 c for I hour followed by heating to reflux temperature for 0.5 hour. After IO minutes of heating, the solution turned to an 22 preparative scale. Alternate literature methods usmg other prochiral starting materials would perhaps help solve some of the problems associated with working on a preparative scale.24, 25, 26 Aldehyde instability could perhaps be reconciled by trapping the aldehyde in situ 27 with the subsequent use of the derivitized aldehyde as a prochiral substrate. E. Synthesis of 1,2-isopropylidene-L-gulonic-y-lactone

(8). One of the possible factors cited for the poorer than expected yields of (6) from the Jung and Shaw procedure could be overreaction in the reduction of the double bond of 1,2- isopropy lidene L-ascorbic acid (5).22 Since this was a possible source of the synthetic problems we had been having in the synthesis of (6), we decided it was of interest to find a procedure that used both a reduced and protected derivative of L-ascorbic acid as the substrate. A procedure that involved the protection of the reduced form of L-ascorbic acid (7) was found in the literature and the synthesis was attempted.22 The protection of the substrate was conducted with 2-methoxy propene, tosic acid and DMF at 10-25 °c. After 24 hours, the reaction was judged complete via tic and was worked up. The remaining DMF was removed either by repeated ethyl acetate washes or concentratin~ the solution under reduced pressure at RT. The 23 resulting yellow-orange solid was repeatedly washed with a hexane/ethanol mixture and was suction filtered. The resulting residue resembled off-white, plate-like crystals. The

procedure gave 50% yield of >98 % pure (8).

Scheme 3

OH 0 /

0 OH )< 0 0 r--<' H 0 ,.. 0 ~ 0 0 1/ (7) (8) (6)

F. The synthesis of 1.2-O-isopropylidene-2-(S)-

glyceraldehyde (6) from (8).

The substrate (8) was suspended m water and cooled to 5 °c. The oxidant, NaIO4, was added portion-wise to the substrate solution while the pH was kept at 5.5 with 2N NaOH. The reaction was judged complete via tic in 3.5-4 hours. Although the literature synthesis proposed to isolate the aldehyde in aqueous solution, we needed to isolate the aldehyde in as near as anhydrous conditions as we could in the synthesis for subsequent anion additions. The work-up procedure was modified so that the aqueous aldehyde solution was rinsed 3 times with 10 mL portions of ethyl acetate. The ethyl acetate 24 solution was fractionally distilled at room pressure to give an aldehyde enriched ethyl acetate solution. The solution of (6) was stored at -25 °c under N2. The product yields using this modified method were comparable to the Jung and Shaw procedure. Overall for the two steps. the yields of (6) from the Hubschwelen22 procedure ranged from 3-5 % yield. The only apparent advantage of this method over the Jung and Shaw method was the use of relatively non-hazardous NaI04 as the oxidant.

PART 2. Synthesis of 1,2-0-isopropylidene-2-(R,S)-3-

(R,S)-trihydroxy-4-phenylsulfenyl butane (9) (10) 1,2-0- i s opropy 1i dene-2-( R)-3-(R,S )-trihy droxy-4- phenylsulfinyl butane (11) and phenyl sulfonyl butane (12) (Schemes 4, 5, 6, 7).

A. The synthesis of 1,2-0-isopropylidene-2-(R)-3-(R,S )-

trihydroxy-4-phenylsulfenyl butane (9). The reaction of the anion of thioanisole with (3) was first attempted according to a modified procedure by Corey and Seebach.28 Nmr analysis of the crude oil suggested a diastereomeric mixture of desired (9) had formed in the reaction as well as other products from side reactions and unreacted thioanisole. Because the crude oil was a complex mixture of products and starting material, it was difficult to 25 determine if any diastereofacial selectively had occurred in the reaction. The crude oil was chromatographed on a silica gel gravity column, to give an odorless, clear oil. The analytical data of the purified oil suggested the desired compound had formed in a 60/40 mixture of diastereomers. After repeated attempts at separating these isomers by conventional means, the mixture was ultimately separated by the use of preparative hplc. Apart from the nox10us odor of this reaction and difficulty in separating the diastereomers, this procedure was found to be satisfactory on a preparative scale giving 30-40% yield of (9). In our hands, the use of cosolvent28 (DMPU), was not found to greatly enhance the yields of desired product. The unresponsiveness of the reaction to the addition of DMPU could have been due to the nature of the anion generated as well as subsequent stabilization of the anion by chelation with the spectator metai.29 The impure and unstable nature of the aldehyde electrophile30, 31 could have also contributed to the apparent ineffectiveness of co-solvent as well as add to the side product formation in the reaction. 26 Scheme 4

0 OH ,<'H ~s-(J yo • yo

' (3) ' (9)

B. The attempted synthesis of 1,2-O-isopropylidene-2- (S)-3-(R,S)-trihydroxy-4-phenyl sulfenyl butane (10).

The initial conditions used for the synthesis of (10) were identical to those used for the production of (9). The worked up sample was chromatographed and the product isolated as an oil, was analyzed. The product was found to be a thioanisole adduct but a more precise analysis suggested that elimination had occurred. The procedure was once again tried generating the thioanisole anion at -10 °c but by adding the aldehyde at -78 °c and quenching at 1 minute, 5 minute and 10 minute time intervals. The yellow color was found not to be as pronounced in these runs as they were in the first experiment. However. the aldehyde was not entirely consumed in any of these reactions. Two products were formed in these reactions: one identical to the elimination product isolated in the first experiment and the other was isolated in a small amount and was not identified. The problem with this reaction could have originated from several sources. The unstable nature of the 27 aldehyde coupled to the resulting stereochemistry of the adduct might have led to decomposition or elimination products as the major components of the reaction.

Scheme 5

0 OH ~s-{J r-<'H • xo 01/0 '\ ' (6) (10)

C. The synthesis of 1,2-0-isopropylidene-2-(R)-3-(R,S)- trihydroxy-4-phenylsulfinyl butane (11). The synthesis of this compound was conducted in a similar fashion as in the phenyl sulfide (9) case. The procedure leading to the formation of (11) was found to be readily extended to preparative scale. The only disadvantage of the procedure was that the methyl phenyl sulfoxide was sold as a very hard, white crystalline, moisture and heat sensitive solid that came in a small brown, glass bottle. Placing the sample at RT for 5-10 minutes under N2, prior to weighing out, expedites the procurement of the compound from the bottle. The nmr data obtained for the pure sulfoxide (11) was very complex due to the introduction of another chiral center at the sulfoxide moiety. As a result, it is not known whether or not 28 diastereofacial selectivity occurred in this reaction. The separation of the various sulfoxide isomers via silica gel chromatography was attempted and was only partially successful.

Scheme 6

0 OH O r-?H ~s (,,) yo • '\ yo '\ (3) (11)

D. The synthesis of 1.2-0-isopropylidene-2-(R)-3-(R.S)- trihydroxy-4-phenyl sulfonyl butane (12). The synthesis of 1.2-0-isopropylidene-2-(R)-3- (R.S)-hydroxy-phenyl sulfonyl butane (12) was of interest because the phenyl sulfonyl moiety was used as a resonance stabilized chromophore in many literature examples of dianion32. 33 and anion generation.34. 35 It was of interest to see whether or not our adduct would perform in accordance with literature precedent and serve as a model for sulfinyl dianion additions.

The substrate for the reaction was either (9) or (11). differing in the number of equivalents of oxidizing agent. (mCPBA) that was used. In the former case. 2-3 equivalents of 29 mCPBA were necessary to complete the oxidation of the sulfide to the sulfone while m the latter case, 1.5-2.5 equivalents of mCPBA were needed to complete the oxidation of the sulfoxide to the sulfone. The reactions were carried out at RT with dry methylene chloride as the solvent. In both cases, it was found that the isopropylidene protecting group was cleaved if the system was not buffered. As a result. 1.5 equivalents of K2CO3 was added to the reaction mixture to prevent protecting group cleavage. The addition of K2CO3 probably slowed the reaction down and contributed to the use of excess mCPBA. The end result was the clean formation desired sulfone in 40% yield after chromatography for both reactions.

Scheme 7

OH 0 yo~~--0

x=0 (9) ' (12) x=l (11)

PART 3. The attempted generation and reaction of C-O sulfur stabilized dianion. (Scheme 8, 9). 30 A. The synthesis of 1,2-O-isopropylidene-2-(R)-3-(R.S)- trihydroxy-4-phenylsulfonyl-6-heptene (13 ). As a first approximation to the character of this novel. pro-sugar building block series, the trapping of the sulfone stabilized dianion (Figure 5) was attempted using allyl bromide as the alkylating agent.36, 37, 38

Figure 5

The use of co-solvent (DMPU) was found to be necessary for the solubilization of the incipient dianion. Nmr analysis of the oil suggested the formation of the desired allyl adduct (13). B. The synthesis of 1,2-O-isopropylidene-2-(R)-3-(R,S)- trihydroxy-4-deutero-4-phenylsulfinyl butane (14). The beta-hydroxy sulfoxyl stabilized dianion was formed using a literature procedure designed for use on another beta-hydroxy sulfonyl compound.39, 40 The reaction was quenched with deuterated methanol and the crude oil was analyzed for deuterium incorporation via comparison of the proton spectrum of the product and the substrate (11). The proton spectrum of the quenched reaction showed a 3 I disappearance of certain peaks suggesting dianion formation and trapping with deuterium had occurred. There was about a '50% recovery of mass after work-up. This fair recovery could be a indicator as to the nature and reactivity of this particular dianion to these conditions.

Scheme 8 OH ;-0 ~f-0 0 0 0 ... / \

( 12) ( 13)

Scheme 9

OH 0 OH 0 ~~-0 ,... A~-0 0 0 R yo X ' ' ( 11) (14); R=D (18); R=CH(OH)(CH2)2CH3 (15); R=allyl (19); R=CH(OH)Ph (16): R=methyl (20): R=CH(OH)(CH3)2 (17): R=CH(OH)CH3 (21 ): R=CH(OH)(Et)2

C. The synthesis of 1.2-0-isopropylidene-2-(R)-3-(R.S)-

trihydroxy-4-phenyls ulfiny 1-6-heptene ( 15). 32 Alkylation with ally I bromide of (11) was conducted usmg a modified literature procedure 10, 11, 12

followed for the sulfonyl butane (13). The yield of product

(15) was found to be around 30%. The low yield of the reaction could be due to moisture in the system, impurities in the allyl bromide or the sulfoxide causing side reactions. The congested nature of the' dianion transition state could also result in a lower than expected yield for the reaction, leading to a lower incorporation of the allyl bromide electrophile with respect to deuterium. D. The synthesis of 1,2-O-isopropylidene-2-(R)-3-(R.S)-

trihydroxy-4-phenylsulfinyl pentane (16).

The alkylation of (11) was performed usmg the conditions cited for the synthesis of the allyl derivative (15). In this case the alkylating agent was methyl iodide. There was a 70% recovery of crude product after work-up. The crude oil was chromatographed on a silica gel gravity column, resulting in two sets of fractions with an overall yield of 50% of desired product (16). Nmr analysis of the oil suggested the formation of the desired methyl adduct. E. The synthesis of 1,2-O-isopropylidene-2-(R)-3-(R,S)-

5-(R,S)-tetrahydroxy-4-phenylsulfinyl-hexane (17). Since the experiments to trap an incipient dianion were moderately successful, an attempt was then made to add a series of carbonyl electrophiles to the transiently generated 33 dianion. The first carbonyl electrophile that was condensed with (11) was the sterically unincumbered and reactive acetaldehyde. As with the formation of (14), (15), (16), a modified literature procedure was used in an attempt to form

(17). Acetaldehyde is a relatively reactive carbonyl electrophile, because of its small size. Although reactive, acetaldehyde may not add to the dianion as readily as deuterated acetone or alkyl halides. This may account for the lower yields of this reaction in comparison to the former two anion additions. Additionally, the acetaldehyde used for the synthesis was not distilled prior to use. This also may account for the low yields of desired (17) through the introduction of impurities and moisture. F. The attempted synthesis of 1.2-0-isopropylidene-2- (R)-3-(R,S )-5-(R,S )-tetrahydroxy-4-pheny 1s ul finy 1

octane (18). The next aldehyde that was added to the sulfoxide dianion was butyraldehyde. Butyraldehyde was chosen as an electrophile because of its long carbon chain. Although butyraldehyde was distilled and presumed to be anhydrous, impurities and/or moisture in the butyraldehyde or the starting sulfoxide could have played a role in a low yield for this experiment. 34 G. The attempted synthesis of 1,2-0-isopropylidene-2- (R )-3-(R, S )-5-(R,S )-tetrahy droxy-4-pheny ls ulfin y 1-

5-phenyl hexane (19). Benzaldehyde was chosen as the next carbonyl electrophile because of its availability, and its conjugated system. Mechanistically, it is also of interest to observe whether elimination or addition will predominate in this reaction. The isolated product was found to be the desired addition product (19).

H. The attempted synthesis of 1,2-0-isopropylidene-2- (R)-3-(R,S )-hy droxy-4-pheny lsul finy 1-5-hy droxy-5-

methyl-hexane (20). The next series of experiments used ketones as the electrophile in the reaction. Although carbonyl electrophiles m the form of symmetric ketones would not result in the generation of a new chiral center, it was of interest to see whether or not ketones of this type were active enough to add to the generated dianion and at what level desired product formation would occur. Acetone was chosen as the first ketone carbonyl electrophile because of its small size, and availability. The reaction gave a mixture of the desired acetone adduct and other UV ( +) side-products. 35 I. The attempted synthesis of 1.2-0-isopropylidene-2- (R)-3-(R,S )-hydroxy-4-pheny ls ulfiny 1-5-hydroxy-5- ethyl-heptane (21). The next ketone used as an electrophile in the dianion reaction was 3-pentanone. 3-Pentanone was chosen as an electrophile because of its long, aliphatic chain. In general, the two ketones used as electrophile candidates for addition to the sulfoxide dianion, gave many side products, similar crude product yields and poor desired product formation. Perhaps the additional R group present in ketones as opposed to aldehydes increases steric congestion and creates a softer carbonyl carbon making it more incompatible with the dianion resulting in less desired product formation. PART 4 The attempted generation of the dianion of 1.2- 0-isopropy 1idene-2-(R)-3-(R,S )-trihydroxy-4- phenylsulfenyl butane (9) and investigational chemistry of derivatives of (26) (Schemes 10, 11, 12, 13, 14, 1 5)

A. The attempted synthesis of 1,2-0-isopropylidene-2-

(R )-3-( R,S )-trihy droxy-4-deu tero-4-phen y 1s ul feny 1 butane (22). Since there 1s little or no precedent for the generation of dianions from beta-hydroxy methyl phenyl 36 sulfides. an attempt was made to generate a dianion with our substrate (9), and trap this dianion with deuterated methanol. ·

Scheme IO

OH OH ~s (,) ~s(J) • 0 0 D 0 0 X X'\ '\ (9) (22)

The generation of the dianion was attemped as noted m part 3. Deuterated methanol (2 eq) was added to individual reactions at varying time intervals; 30 minutes, 1 hour, 1.5 hour, 2 hours. 3 hours. and 5 hours. In nearly each case, (3 hour and 5 hour quenches were exceptions), the addition of deuterated methanol turned each solution from pale yellow to near colorless. In each case, however. no deuterium incorporation was evident via nmr analysis of the alpha methylene proton resonances. This result suggests that no dianion of (9) formed in the reaction. In fact at the 3 hour and 5 hour time points, there was evidence via nmr, that the solvent or the oxy-anion of substrate had started to react with n-BuLi to form side products. Perhaps this would explain the presence of color in these reaction after deuterated acetone was added to the reaction as compared with the other reactions. Several reaction temperatures were also 37 tried while varymg the times of deuterated acetone additions; 30 minutes/0 °c, 1 hour/0 °c. 30 minutes/-40 °c, 1 hour/-40 · oc. All of the reactions resulted in no deuterium incorporation and each showed evidence of degradation reactions. Anhydrous diethyl ether was also tried as a solvent for these reaction using the same criteria and time points as already cited for the runs using THF. Similarly, no deuterium incorporation was observed for these reactions. Solvent degradation products were observed to form at the 2 hour time points for this series of reactions. Alternate bases were tried to see if the dianion of (9) could be generated using these as opposed to n-BuLi as the base. Reactions using NaH, LDA, sec-BuLi, and t-BuLi all resulted in no deuterium incorporation in the product. Finally, a combination of literature procedures from other classes of compounds were used in an attempt to generate the dianion of

(9). The conclusion reached as a result of these experiments was that no dianion was generated from (9) possibly because of destabilizing inductive effects and lack of a resonance stabilized sulfur moiety alpha to the second generated anion leading to low acidity of this proton (Figure 6). 38

Figure 6

o- 0 - b-}_ fl,s-0 ~s-0 .,,. - r{ oo'5H o, o yo ~ '\ *

B. The synthesis of 1,2-0-isopropylidene-2-(R)-3-(R,S)-

trimethylsiloxy-4-phenylsulfenyl butane (23). Since the desired dianion of (9) was not generated by conventional or by following extensions of literature procedure, it was of interest to observe whether an anion could be generated alpha to the sulfur moiety when the hydroxide group at position 2 was blocked with a protecting group.

Scheme 11

(9) (23)

The TMS (trimethylsilyl) group was chosen as a potential protecting group because of its relative ease of removal (using fluoride ion), and its stability in the presence of 39

mild to strong bases. Since the 2-hydroxy position was diastereomeric, it was also of interest to see whether or not derivitization at this position with TMS would result in a favorable separation of the isomers via tic and ultimately via chromatography. Several attempts were made to separate the isomers via tic, however, all were unsuccessful.

C. The synthesis of L2-O-isopropylidene-2-(R)-3-(R.S)­ trimethylsiloxy-4-methyl-4-phenylsulfenyl butane (24). The attempted generation of an anion alpha to the

sulfide group of (23) was conducted using anhydrous THF as the solvent 2.2 equivalents of DMPU as co-solvent. and 1.8 equivalents of base (NaH, LDA. sec-BuLL n-BuLi and t-BuLi) m successive experiments. After 3 hours at -78 OC/N2, 2 equivalents of methyl iodide was added to the solutions and stirred at -78 °C1N2 for 15 minutes. In each case. mini work- up and tic showed little or no reaction. This resulted in 80-

90 % recovery of unreacted starting material (23) after work­ up. These experiments demonstrated that even with the inductive factor eliminated by blocking the 2-hydroxy position, the inherent low acidity of the alpha sulfide proton was still a formidable barrier to the generation of an anion of (23). Alternatively. the sterically congested protecting group did not permit approach of the RLi reagent. 40

Scheme 12

( 23) (24)

D. The synthesis of 1.2-0-isopropylidene-2-(R)-3-(R.S)- acetoxy-4-phenylsulfenyl butane (25). As cited in part 4 example B. the attempt at separating the silyl sulfide derivative epimers (23) by tlc analysis and column chromatography failed. An attempt was then made to form the acetate ester at the 3-hydroxyl in order to separate the epimers.

Scheme 13

•

(9) (2 5)

The acetylation of (9) was conducted in accordance with a conventional procedure49 using dry pyridine as the solvent with 1.5 equivalents of acetic anhydride as the acetylating 4 I

agent. Chromatography enriched the mixtures to not greater

than 70%. E. The synthesis of 1,2-O-isopropylidene-2-(R)-3-oxo-4-

phenylsulfenyl butanone (26). Since the elimination of the inductive factor did not appear to raise the acidity of the alpha sulfide proton substantially, it was of interest to see if one activated the beta position, whether or not anion generation in the alpha position would be observed. The oxidation of the 2-hydroxy to the ketone would serve as a activator to the alpha position via resonance stabilization of the incipient anion. The oxidation of the 2 hydroxyl group was accomplished using the Corey-Kim modification of Swern oxidation conditions (Scheme 14).40,41 It was observed that if the reaction temperature deviated much higher than -10 °c, unidentified, more non-polar, elimination products were formed in the reaction as well as the desired ketone (26). Chromatography was immediately performed on the crude yellow, smelly oil product resulting in 30% yield of desired beta-keto sulfide (26). This oil was stored at -25 °c under nitrogen when it was observed that the product decomposed after sitting under nitrogen at room temperature for several days. Because of its instability at room temperature, data procurement was a problem for this compound especially for micro analysis. 42

Scheme 14

OH ~s-{J XO •

' (9) ( 2 6)

F. The synthesis of 1.2-0-isopropylidene-2-(R)-3-oxo-4- methyl-4-phenylsulfenyl butanone (27). The attempted generation of the anion of (26) was performed using the same procedure as cited for part 4, example C. This result seemed peculiar because in other similar substrates, NaH seemed to able a strong enough base to abstract a proton from a carbon alpha to a ketone.43 An example of this reaction can be illustrated by the aldol condensation reaction. With the reaction of NaH and compound (26). we were able to trap the oxy-acetate of the enol ether using acetic anhydride (Figure 7). This result suggested that the anion of (26) was indeed generated. However. some other factors must have been operating in the system to prevent reaction with an electrophile. 43

FiJ!ure 7

OAc ~s--Q yo '\

G. The synthesis of 1.2-O-isopropylidene-2-(R)-3-oxo-4-

phenylsulfonyl-5-(R,S)-hydroxy hexanone (28). Carbonyl additions also were attempted on the beta-keto sulfide (26) derivative with the intent of gaining a better understanding as to the character of the anion m solution with the ultimate hope of determining what conditions would be suitable for the generation of a dianion from (11). The first attempted carbonyl electrophile addition was acetaldehyde. Hplc analysis of the purified mixture showed the isomers to be present in a 60/40 ratio suggesting some diastereofacial selectivity occurred in this reaction. The presence of unreacted starting material in this product could suggest that the system was not anhydrous or the titer of the t-BuLi was lower than anticipated. There was no observed trapping of the enol form of the beta-keto sulfide using acetaldehyde. Another experiment was attempted using 1.3 equivalents of acetic anhydride, as a quencher, in hopes of trapping the enol as the acetate. No acetylated ene sulfide was isolated from this experiment. 44

H. The synthesis of 1,2-O-isopropylidene-2-(R)-3-oxo-4- phenylsulfony 1-5-(R,S )-hydroxy-5-pheny 1 pen tan one (29). The next electrophile that was added to (26) was benzaldehyde. The reaction was quenched in two fashions, one­ half with l0%NH4Cl/ether followed by washes with 5% NaHCO3 and brine and the other half with 1.3 equivalents of acetic anhydride.

Scheme 15

0 ~s-Q_> 0 0 X'\ (26) (27) ;R=methyl (28);R=CH(OH)CH3 (29);R=CH(OH)Ph (30);R=CH(OH)(CH3)2

From the aqueous quench the resulting oil was purified to afford eliminated benzaldehyde adduct (29a) (Figure 8) as product in a product yield of 15 %. This result suggested that extended conjugation was a stabilizing factor for the benzaldehyde adduct. 45

Figure 8 0 s-0 - xo..... ~ ' (29a)

Trapped acetoxy enol of beta-keto sulfide (26) (Figure 7) was observed in the acetic anhydride quenched experiment. I. The attempted synthesis of 1,2-O-isopropylidene-2- (R)-3-oxo-4-pheny lsulfony 1-5-hydroxy-5-methy 1

hexanone (30). Acetone was chosen as the ketone carbony 1 candidate because of its small size. The reaction was quenched in two ways, one-half with 10% NH4Cl/ether followed by washes with 5% NaHCO3 and brine and the other half with 1.3 equivalents of acetic anhydride. After evaporation to a near colorless oil. the crude product yield was found to contain 50% of starting material. From both quenches the resulting oils were purified giving eliminated acetone adduct from the 10% NH4Cl/ether quench and trapped enol beta-keto sulfide from the acetic anhydride quench. These findings suggest that a substantial amount of the enol form of the beta-keto sulfide 1s present in solution and is available for condensation with the 46 electrophile. acetone. However a large amount of unreacted starting material was recovered with little or no desired (30) · found in the reaction. This also suggests that resonance stabilization and extended conjugation are powerful driving forces in reaction dealing with the formation of anions alpha to a beta-keto sulfide. In terms of addressing the dianion formation problem of (9), these reactions show that the inductive effect plays a role in destabilizing the generation of a second anion alpha to an oxy-anion and methyl phenyl sulfide. Most importantly, these reactions show that resonance stabilization of the second generated anion is a powerful and necessary requirement for dianion formation in the series of compounds where (9) is the parent.

Part 5 The condensation reactions of prochiral Michael acceptors with methyl phenylsulfinyl anion and attempted generation of a dianion from 2-methyl-3-(R,S)-hydroxy- 4-phenylsulfinyl-l-butene (32) (Schemes 16, 17, 18, 19)

A. The synthesis of 3-ene-3-(R,S)-hydroxy-4-

phenylsulfinyl-1-butene (31). The stereoselective generation of chiral centers has been used extensively in literature44.45 as a strategy for designing a chiral molecule without having to rely on using 47

expensive chiral building blocks and dealing with unstable reactive intermediates such as 1,2-0-isopropylidene-2-(R)­

glyceraldehyde (3). Besides the former two problems associated with starting from a chiral building block framework. we found that protecting groups can sometimes be Jost during synthetic manipulations exposing the chiral centers to attack by bases and other reactants. The other problem we encountered was the toxicity issue. We had to use large amounts of lead tetracetate to generate required amounts of 1,2-0-isopropylidene-2-(R)-glyceraldehyde (3) due to the instability of (3) and the poor yields from the synthesis. As a result of these problems, it was of interest to investigate if other prochiraJ· derivatives of the beta-hydroxy sulfoxide (11), could be formed without having to deal with the isopropylidene protecting group and conventional prochiral building blocks. The first attempt at the construction of prochiral methyl phenyl sulfoxide was performed using a traditional Michael acceptor, acrolein. with the hope that 1,2 addition would occur predominantly over 1,4 addition (Figure 9). 48

Figure 9

0 0 ~ -o 0 d \_Jl~"'H ...,s"-0 ~ # • ~2C ~~-o

0 -o II - H ..,.s-Q/J -• ;--J---H ~c o-~ 0

As Scheme 16 illustrates, the reaction occurred in a 1,2 fashion to give (31) in 45 % yield.

Scheme 16

0 OH 0 ~H • ~~-o ( 31)

B. The synthesis of 2-methyl-3-(R,S)-hydroxy-4- phenylsulfinyl-l-butene (32). Since the first reaction with acrolein was successful in giving the desired 1,2 adduct. it was of interest 49 to extend this synthesis to other Michael acceptors to create adducts with varying degrees of substitution at the vinyl bond.· Methacrolein was tried as the next Michael electrophile because of its substitution pattern. The reaction is illustrated in Figure 17.

Scheme 17

0 OH 0 =<'H • ~~--o (32)

C. The synthesis of 1-phenyl-trans-2-methyl-(R,S)-3- hydroxy-4-phenylsulfinyl-1-butene (33 ). The next Michael acceptor adduct that was prepared was l-benzyl-trans-2-methyl-(R,S)-3-hydroxy-4- phenylsulfinyl-l-butene (33) using a-methyl-trans­ cinnamaldehyde (Scheme 18). In general. all three of the preparations of prochiral Michael adducts gave purer compounds, higher yields of products with shorter reaction times than their chiral building block brothers (11) and (12). 50

Scheme 18

0 0 H + /s"--0 ~ /J ~--o

(33)

The compounds were stable at room temperature in vacuo for several weeks without observing evidence of decomposition or oxidation. D. The synthesis of 2-methyl-3-(R,S)-hydroxy-4- phenylsulfinyl-1,6-hexadiene (34). Finally, since we wished to extend the use of these adducts to di anion chemistry. the preparation of the dianion of (32) was attempted using the same procedure used for the trapping of the dianion of (11) with allyl bromide. The low yield of the reaction could be due to moisture in the system, impurities in the allyl bromide or the sulfoxide causing side reactions. However, this experiment does demonstrate that dianion chemistry can be successfully extended to this achiral system. One can then propose to stereoselectively hydroxylate the double bond44A5,46 in order to form the structure necessary to make unnatural sugars (Scheme 19). 5 1

Scheme 19

OH 0

• ~--o

(32) ( 34)

Part 6. The assignment of stereochemistry about the hydroxyl group in 1.2-0-isopropylidene-2-(R)-3-(R.S)­ trihydroxy-4-phenylsulfonyl butane (12) and 1.2-0- i sopropy lidene-2-(R )-3-(R .S )-trihy droxy-4- phenylsulfenyl butane (9) (Schemes 20, 21, 22)

The preparation of intermediates (9) and ( 12) generated a chiral center at position 2 while a similar preparation of (11) gave 2 chiral centers at position 1. 2 and at the sulfoxide. Of these three compounds. (9) or (12) seemed better candidates for the assignment of stereochemistry at position 2 because the absence of the additional chiral center of the sulfoxide simplifies the proton spectrum and enhances the possibility of the separation of the epimers usmg conventional means. In order to resolve the epimers. several strategies were attempted:

(1) the formation of derivatives at position 2 and the separation of diastereomers using chromatography, 52

(2) preparative hplc of the parent molecules (9) and (12).

The preparative hplc was used to follow the cleavage of the sulfur moieties to form the protected aliphatic alcohols (39) and (40). The optical rotations of the alcohols were then compared with with those cited in the literature47 values. Out of the intermediates (9) and (12), the sulfide (9) cleaved the most cleanly to liberate the protected alcohol.

A. The separation of 1,2-O-isopropylidene-2-(R)-3-(S)-

trihydroxy-4-phenyl sulfonyl butane (35) from 1,2-O- i sopropy lidene-2-(R)-3-(R )-trihy droxy-4-phen y 1 s ul fony 1 butane (36) using preparative HPLC. The yields of purified compound from a supposedly pure mixture were suprizingly low. This result could have been due to non-organic salts being present m the sample or compound ( desired compound or salts) being retained on the column. Upon standing at room temperature, both samples solidified to give white crystalline solids. The nmr spectra showed the samples to be 97% pure. Stereochemistry was determined by oxidizing (37) using the conditions cited in the experimental section, example 7. The proton spectra obtained from this sample was identical to that of (35). One of the sulfonyl epimers, (35), was found to have an optical rotation of [a]25D -5.040 (c=l .3, MeOH). An optical rotation was not run on 53 ep1m. er (]6), due to the small quantity of material obtained after work-up.

Scheme 20

~!.,, (,1) O 0 X (35) ~!-V.,.. 0 0 X ' ' (12) QH ~-v ~ s ~ I. ~a.... xo (36) '

Scheme 21

~s .,.. ~1) 0 0 (37) ~s-Q.... X O 0 X ' ' (9) OH _J==\

~s~.,,. O 0 X (38) ' 54

B. The separation of 1.2-O-isopropylidene-2-(R)-3-(R)- trihydroxy-4-phenylsulfenyl butane (37) from 1.2-O- i sopropy 1iden e-2-(R)-3-( S )-tri hy droxy-4-phen y 1s u 1f eny 1 butane (38) using preparative HPLC. Optical rotations were performed usrng methanol as the solvent. Epimer (37) was found to have an optical rotation of [a]25o-46.80 (c=l.19.MeOH) (Scheme 21).

C. The synthesis of 1.2-O-isopropylidene-2-(R)-3-(S)- trihydroxy butane (39) and 1.2-O-isopropylidene-2-(R)- 3-(R)-trihydroxy butane ( 40). The respective sulfide epimers (37) and (38) were cleaved to the protected aliphatic compounds (39) and ( 40) (Scheme 22). Optical rotations were performed on both samples and compared with the literature values. For the derivative from (37). the rotation was [a]25D =33.9° (c=0.73, C6H6). [a]25o=33.80 (c=l.6, C6H6) (lit)47; the derivative from (38) was found to be [a]25D =2.90 (c=l.14, C6H6), [a]25D =5.9°

(c=l .4.C6H6) (lit)_47 The rotation for (39) probably does not match up perfectly because of trace amounts of Raney nickel residue of other benzyl impurities in the system that were difficult to remove due to the water soluble nature of the cleavage products of (37) and (38). Although the rotations of the cleavage products of (37) and (38) do not precisely match up with the literature values, the order of magnitude of the 55

values suggest the following structure assignments; (37) gives

(39) and (38) gives (40).

Scheme 22

OH 0 H __r-=--\ ~s-----U-1. Raney nickel ~ o,/o • xo / "\ (37) "\ (39)

QH ~ H ____;-==\ Raney nicke 1 ~s~ • o,/o /, (38) " ( 40)

PART 7. Isopropylidene migration studies of 1.2-0- i sopropy Ii dene-2-(R)-3-(R,S )-tri hydrox y-4- phenylsulfinyl butane (11) and attempted sugar formation usingdeprotected and derivitised 1,2-0-isopropylidene-2- (R)-3-(R,S )-5-(R,S) tetrahy droxy-4-pheny ls ul finy I- octane (18) (Schemes 23, 24, 25) A. The attempted formation of 2,3-0-isopropylidene-2- (R)-3-(R,S)-4-phenylsulfinyl butan-1-ol (41) Since we were successful in preparing the necessary building blocks required for the synthesis of unnatural sugars, it was of interest to see whether or not protection or deprotection steps would be necessary prior to 56

the final oxidation/cyclization steps. One strategy utilized was that of acetonide migration.SO, 51,52 As a pilot attempt, · (11) was used as the substrate for the reaction (Scheme 23). There were several literature procedures to chose from but the most reasonable for our purposes was that described by Williams52 where the substrate was dissolved in methanol in the presence of a catalytic amount of sulfuric acid. After subjecting (11) to these conditions, hplc analysis of the resulting product mixture clearly showed new peaks had formed at the expense of substrate peaks.

Scheme 23

I f'o • ~~--0 HO

( 11) ( 41)

The nmr spectra of the crude product clearly showed shifts m the isopropylidene methyl peaks. However, the reaction appeared to be incomplete leading to the conclusion that the 1,2 isopropylidene must be the more thermodynamically stable product53 or the barrier to migration was too high. 57

B. The attempted synthesis of 1.2-0-isopropylidene-2- (R )-3-(R,S )-5-(R.S )-di acetoxy-4-pheny Is ul fi ny I- octane (42). An acetylation reaction of the buytraldehyde

sulfoxide adduct (18) was conducted usrng dry pyridine as the solvent and using 2.1 equivalents of acetic anhydride as the acetylating agent. After purification and analysis by nmr and ms, it was revealed that only 1 hydroxyl was converted to the acetate (Figure 11, Scheme 24). The results of the experiment show that some acetylation proceeded selectively but to derivitise both hydroxyls would require more forceful conditions. Figure 10

X= Acetate or H 58

Scheme 24 OH 0s-{J OAc 0s--0 OH • OAc

( 18) (42)

C. The attempted synthesis of 1-hydroxy-2-(R)-hydroxy- 3-(R.S )-5-(R.S)-tetrahydroxy-4-pheny ls ulfiny I-octane ( 43). The deprotection of (18) was conducted usmg a common literature procedure48 for the deacetonidation of alcohols (Scheme 25). Nmr analysis revealed that the desired ( 43) liberated pro-sugar adduct had formed in the reaction. D. The attempted synthesis of 1-oxo-2-(R)-hydroxy-3- (R.S )-5-(R.S )-trihy droxy-4-pheny ls ulfiny 1-octan al ( 44). The substrate used for this reaction possessed 4 hydroxyls~ 2 primary and 2 secondary. The oxidation of ( 43) was performed on a small scale (15mg) in the hopes that some determination could be made as to oxidation selectively and propensity to form cyclization products. 59

Scheme 25 OH 0s--0 OH 0s--0 OH ----t•• OH

(18) (43)

The oxidation was carried out using the Corey-Kim modifiation of Swem oxidation conditions.40 After work-up. the analysis of the 10 mg of isolated product oil proved to be inconclusive. Further experimentation to produce larger and purer quanities of intermediate (3). in particular. could lead to success in producing the desired chiral. pro-sugar analogs. CHAPfERV

EXPERIMENT AL

Unless otherwise noted. materials were obtained from commercial suppliers and used without further purification. Melting points were taken in a Thomas-Hoover capillary apparatus and were uncorrected. Elemental analyses were obtained for some of the new compounds reported. Elemental analyses were performed by the Abbott analytical department. Ir, nmr. and mass spectra were recorded by the Abbott structural chemistry department. E Merck silica gel (70-230 mesh) obtained from VWR Scientific was used for column chromatography. Preparative chromatography was performed on selected examples usmg a 20x20 60F-254 Merck preparative plate in accordance with the following standard procedure: the sample was loaded onto the plate using 0.5-1.0 mL methylene chloride and the dried plate was immersed in 100 mL of a mobile phase, the plate was run to 1 cm from the origin. thoroughly dried and the UV ( +) bands were carefully extracted using a single edged razor blade. The silica was crushed with a motor and pestle and immersed in a 50/50 mixture of methanol/ethyl acetate for 1 h. gravity filtered and

60 6 l

concentrated. Preparative HPLCs were run usmg YMS semi­ preparative (C 18: 20x250 mm) columns. Nmr spectra were determined on a General Electric GN-300 spectrometer operating at 300.1 MHz. Chemical shifts were expressed in ppm downfield from internal tetramethylsilane. Significant 1H Nmr data were tabulated m the order: multiplicity (s. singlet; d. doublet: t. triplet: q. quartet:. m. multiplet: b. broad. ex. exchangeable with D2O). number of protons. designation and coupling constants where applicable. Most of the 1H Nmr data were run on diastereomeric mixtures of compounds. As a result. the 1H Nmr data collected was fairly complex and the integration of protons was estimated based upon these mixtures. Some selected compounds were analyzed on a General Electric GN-500 spectrometer operating at 500.1 MHz. 13c nmr spectra were all proton-decoupled and carbons were assigned using DEPT experiments. The IR spectra were recorded on a Perkin-Elmer Model 71 0A infrared spectrometer. The carbon tetrachloride used as a solvent in the IR analysis contained less than 0.03 % H2O while the chloroform used contained 0.5-1 % ethanol. The IR spectra run in 0.15 % carbon tetrachloride were also run with 3mm cells. Mass spectra were obtained with a Hewlett­ Packard 5985A mass spectrometer or a Kratos Ms-50 with El source (70eV). 62

All solvents and reagents were purified when necessary according to standard literature methods. Air- or water-sensitive reactions were conducted under nitrogen atmosphere utilizing standard techniques. All substrates were dried for 48 h in vacuo over P2O5. As with any chemical experimentation, the utmost care should be taken when working with known sensitizers, mutagens and teratogens such as lead tetracetate, aceloin, acetaldehyde, chlorinated hydrocarbons and toluene. Working in a ventilated hood while wearing gloves and a lab coat is highly recommended.

PART A. The synthesis of compounds 1. 1.2,5,6-bis-O-isopropylidene-D-mannitol (2). D-mannitol 5.46 g; (30 mM Aldrich) was added to an oven dried, round bottom flask containing 9 mL of rapidly stirring DMSO. p-Toluene sulfonic acid (0.03 g; 0.157 mM) was added to the white slurry and the mixture was stirred at RT under nitrogen. 2,2-Dimethoxypropane 9.2 mL; (2.49 equiv) was added to the slurry via syringe. After 45 min the slurry turned to a clear solution and stirring was continued at RT for 18 h. The reaction was judged complete via tic analysis and the clear solution was poured into a separatory funnel containing 200 mL ethyl acetate and 150 mL of 5% NaHCO3. A white precipitate formed in the aqueous phase. The aqueous phase was washed 63 with 3x 100 mL portions of ethyl acetate and the orgamc washes were combined, extracted with brine and dried with anhydrous Na2SO4. The organic phase was gravity filtered and the solvent was evaporated in vacuo to give a dense, white solid. The residue was crystallized with the minimum amount of boiling hexane and cooled at RT to give 5.1 g of fluffy white crystals. Procedure yields 95 % after crystallization. Rf=0.31 (toluene:methanoL 10:2 mL). m.p. 119° C; [a]25D +1.60 (c=l, MeOH) litl6 [a]25D + 1.90 (c= 2, MeOH). lH-NMR (CD3OD): b 4.25-

4.15 (m ,4H), 3.95 (m, 2H), 3.65 (m, 2H), 1.35 (s, 6H), 1.33 (s, 6H). 13C-NMR (CD3OD): b 109, 76, 71, 67(CH2O), 26, 25. IR

(KBr): 3450-3300, 3000-2950, 1390-1380( d), 1260. 1220, 1185 cm-1. Mass spectrum (DCI/NH3): m/e 280 (m+l7), 263 (m+ 1). Anal. Calcd for C12H22O6(262.30): 54.95 %C. 8.45 %H; Found: 55.16 %C, 8.59 %H.

2. 2,3-O-isopropylidene-2-(R)-glyceraldehyde (3). To an oven dried, 500 mL round bottom flask was added dried 4 angstrom molecular sieves followed by 100 mL of dry methylene chloride. Lead tetraacetate (3.8 g; 8.5 mM; 1.12 equiv.) was added to the solvent and the yellow-orange mixture was stirred at RT under nitrogen. The substrate (2 g; 7.6 mM) was dissolved in 100 mL methylene chloride and added portionwise to the lead tetracetate mixture. After 15 min, the reaction progress was checked with KI paper. A negative 64 response was interpreted as complete reaction. The yellow­ orange slurry was filtered in vacuo through celite giving a clear. light-yellow solution. The filtrate was stirred rapidly with a magnetic stirrer while 50 g of K2CO3 was added portionwise to the solution. The mixture was stirred for 0.5 h at RT. The yellow solution turned deep, rusty brown in color and a brown precipitate formed in the solution. Note: this phenomenon only occurred roughly 50% of the time, otherwise. the solution remained colorless. The slurry was suction filtered through celite and concentrated down to a yellow oil that contained some methylene chloride residue. The residue was fractionally distilled between 139 °c and 143 °c to give a colorless liquid. The aldehyde was stored at -25 °c for several weeks without observed significant decomposition or racemization. 35-40% yield, Rf=0.34 (toluene:methanol. 10:2 mL). ltt-NMR (CDCl3): b 9.8 (s, lH), 4.2 (m, lH), 4.07 (m, 2-H),

1.3 (s, 3H), 1.2 (s, 3H), 13C-NMR (CDCl3): b 210, 115, 83, 77, 69. 29. 25. IR (0.15%. CCl4, 3mm cell): 3500-3450. 2950- 2800. 1735 cm-I. Mass spectrum (DCI/NH3): m/e 148 (m+l7), 131 (m+ 1). Anal. Calcd for C6Hl0O3 (130): %C 55.37. %H 7.74;

Found %C 55.38. %H 7.67.

3. 1.2-isopropylidene L-ascorbic acid (5). L-ascorbic acid (10 g; 56.7 mM) and 40 mL anhydrous acetone were combined in an oven dried 100 mL 65 flask. This slurry was stirred at RT for 5-10 mm. Acetyl chloride (1 mL; 14 mM) was added to the slurry and the mixture was stirred at RT. At 15 min. the reaction slurry began to form a clear solution. In 1 h, the clear solution began to reform a flocculant, white slurry. After 18 h. the reaction was analyzed by tic and was shown to be complete. The slurry was suction filtered and the residue crystals were dried in vacuo. 98 % yield Rf=0.1 (toluene:methanol. 10:2 mL). m.p. 214-218 (dec.)0 C; Iit21 217-2220 C ; [a]25D -47.700 (c=l.35. MeOH). 1H-NMR

(CD3OD): b 4.65-3.9(m, 6H), 1.35 (m, 6H). 13C-NMR (CD3OD): b 173. 154. 120, 111. 76, 75, 67(CH2O), 27. 26. IR (KBr): 3300, 3000, 1720, 1630, 1330, 1170 cm- 1. Mass spectrum (DCI/NH3): m/e 234 (m+17). 217 (m+l). Anal. Calcd C9H12O6

(216.19): %C 50.00. %H 5.59: Found %C 49.98, %H 5.57.

4. 1.2-isopropylidene-L-gulonic-y-lactone (8). L-gulonic-y-lactone (0.221 g; 1.24 mM) was dissolved in DMF and stirred at RT. p-Toluene sulfonic acid (1.8 mg) was added to the substrate solution. under nitrogen. and the reaction mixture was cooled to 10 °c with an ice/water bath. 2-Methoxypropane (154 mL: 1.61 mM) was added dropwise to the substrate solution and this mixture was stirred at 10 °c for 15 min. The cooling bath was removed and the mixture was stirred at RT for 24 h. After 24 h, tlc analysis showed complete reaction to a more non-polar product. The reaction 66 was quenched with 0.28 g anhydrous Na2CO3 and the slurry was stirred for 2 h, suction filtered and evaporated to a yellow oil. The oil was transferred to a round bottom flask and placed under reduced pressure for 24 h to give a pale, orange solid that was suspended in 3 mL acetonitrile and concentrated to a solid. The solid was crystallized using 0.5 mL hot toluene. The white-orange plates were washed repeatedly with hexane:ethanol (9: 1) and dried to give 98.6 mg of the desired compound. 50% yield Rf=0.14 (toluene:methanol, 10:2 mL). m.p. 167-170 oc, 167-168 oc (lit)22 [a]25D +38.30 (c=0.7, MeOH)

[a]25D +39.00 (c=l, MeOH).(lit)22. ltt-NMR (CDCI3): b 4.5-3.6(m,

4H), 4.2 (m, lH), 3.85 (m, IH), 1.35 (s, 3H), 1.3 (s, 3H). 13c-NMR (CDCI3): b 177, 111, 83, 76, 71, 70, 65 (CH2O), 26, 25. IR (KBr): 3518, 3459, 1770, 1760 cm-I. Mass spectrum. (DCI/NH3): 236 (m+l7), m/e 219 (m+l). Anal. Cale for C9H14O6(218.20): %C

49.54. %H 6.47: Found %C 49.50, %H 6.52.

5. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfenyl butane (9). Thioanisole (3.8 mL: 32.4 mM: 1.2 equiv.) was added to a 500 mL round bottom flask containing 38.5 mL anhydrous THF and dried 4 angstrom molecular sieves under N2. The thioanisole solution was cooled to -10 °c with an acetone/ice bath and (11.3 mL: 32.4 mM: 1.2 equiv.) of n-BuLi (2.5 M in hexane) was added portionwise. The resulting light yellow 67 anion solution was stirred at -10 °c for 30 mm pnor to the addition of aldehyde (3). After 0.5 h, aldehyde (3) (3.5 g: 26.9 mM) was added to the anion solution whereupon the color of the solution changed from a light yellow color to colorless and finally to a brighter yellow color over the course of 10 mm. The cooling bath was removed and the reaction mixture was stirred at RT for 15 min. Mini-work-up and tic indicated that the reaction was near 85 % complete resulting in 3-4 more non­ polar, UV(+) products. The yellow solution was poured into a separatory funnel containing 150 mL of 10% NH4Cl. The aqueous mixture was washed with 2x50 mL portions of ether. The ether layers were combined and washed with 100 mL of 5 % NaHCO3 followed by 100 mL brine. The ether layer was dried over anhydrous Na2SO4, gravity filtered and concentrated in vacuo to give 4 g of a smelly, yellow oil. The crude oil was purified via chromatography on a silica gel gravity column (solvent system composed of CHCl3:ethyl acetate, 40: 1 mL) affording 1.87 g of clear, odorless oil of (9). Procedure afforded a 28 % yield of an epimeric mixture of the desired products after chromatography. Rf=0.48 (toluene:methanol, 10:2 mL). ltt-NMR (CDCl3): o 7.4- 7.18 (m, l0H, aromatic), 4.25 (m, lH), 4.05 (m, lH), 3.8-4.1 (m. 3H), 3.85 (m, lH). 3.65 (m, 2H), 3.35 (m, lH), 3.09 (m, 2H), 2.9 (m, IH). 2.55 (m, IH) 2.53 (m, lH) 1.35-1.45 (s, 12H). 13C-NMR (CDCl3): o 129-126, 109, 77, 70, 66(CH2O), 37(CH2S), 26, 25. 68

IR (0.15%. CCl4. 3mm cell): 3560. 3080-3060(s). 3000-2880 cm-1. Mass spectrum (DCI/NH3): m/e 272 (m+ 17), 255 (m+ l ). · 197. 162. Anal. Calcd for C13H18O3S (254.346): 61.39 %C. 7.13 %H; Found 61.11 %C. 6.94 %H

6. 1,2-O-isopropy lidene-2-(R)-3-(R,S )-trihydroxy-4-

phenylsulfinyl butane (11). Methyl phenyl sulfoxide (3.23 g; 23 mM; 1.2 equiv.) was added to a 500 mL round bottom flask containing 31.5 mL anhydrous THF and dried 4 angstrom molecular sieves under N2. The sulfoxide solution was cooled to -10 °c with an acetone/ice bath and 9.23 mL (23 mM; 1.2 equiv.) of 2.5 M n­ BuLi (in hexane) was added portionwise to the sulfoxide solution. The resulting light yellow anion solution was stirred at -10 °c for 15 min. Aldehyde (3) (2.5 g; 19.2 mM) was added to the anion solution whereupon the color of the solution changed from a light yellow color to colorless and finally to a brighter yellow color over the course of 10 min. The cooling bath was removed and the reaction mixture was stirred at RT for 10 min. Mini-work-up and tic indicated that the reaction was near 95% complete resulting in 3-4 more non-polar. UV(+) products. The yellow solution was poured into a separatory funnel containing 150 mL of 10% NH4CI. The quenched reaction mixture was washed with 2x50 mL portions of ether. The ether layers were combined. washed with 100 mL of 5% NaHCO3, and 69

100 mL brine. The ether layer was dried over anhydrous Na2SO4, gravity filtered and concentrated down in vacuo to give 3.5 g of a smelly, off-white oil. The crude oil was purified via chromatography on a silica gel gravity column (toluene:ethyl acetate, 16: 1 mL). After I Liter of IO mL fractions, the solvent system was changed to ethyl acetate. The procedure afforded 12 % yield of an epimeric mixture of desired product (11 ). Rf=0.27 (ethyl acetate). I H-NMR (CDCl3): b 7.7-7.5 (m, 5H, aromatic), 4.4-3.9 (m. 4H), 3.1-3.25 (m, IH), 2.85-3.0 (m, IH), 1.45 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H), I.I (s. 3H). 13C-NMR (CDCl3): b 132-124, 109, 77, 70, 66(CH2O), 60(CH2SO). 26, 25. IR (Film): 3450-3300, 3000-2900, 1420(s), 1380-1390, 1260, 1210, 1060. 850(s), 750(s), 690(s) cm-I. Mass spectrum (DCI/NH3): m/e 288 (m+l7), 271 (m+l), 255, 197, 158. Anal. Cale for C13H18O4S (270.346): %C 57.76, %H 6.71: Found %C 57.42, %H 6.59.

7. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4- phenylsulfonyl butane (12). Thioether (9) was dried for 48 h in vacuo over P2O5.

Compound (9) (2.2 g; 8.66 mM; 1.0 equiv.) was added to a 500 mL round bottom flask containing 105 mL anhydrous methylene chloride. dried 4 angstrom molecular sieves and crushed K2CO3 (1.43 g; 10.3 mM; 1.2 equiv.). Next, m-CPBA (3.29 g; 17.3 mM; 2 equiv.) was added to the solution. The cloudy. white reaction 70 mixture was stirred at RT under N2 for 20 mm and was analyzed by tic and the reaction was found to be 85 % complete giving 2-3 more polar, UV(+) products. The white solution was poured into a separatory funnel containing 200 mL of 5 % NaHCO3. The solution was carefully swirled and vented. The quenched reaction mixture was backwashed with 2x50 mL portions of methylene chloride. The methylene chloride layers were combined and washed with 200 mL brine. dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1.75 g of a white solid. The crude solid was purified via chromatography on a silica gel gravity column (CHCl3:ethyl acetate, 9: 1 mL). The procedure afforded 39% yield of an epimeric mixture of desired product (12). Characterization (See 7b). 7b. 1,2-O-i sopropy lidene-2-(R)-3-(R,S )-tri hy droxy-4- phenylsulfonyl butane (12).

Sulfoxide (11) was dried for 48 h in vacuo over P2O5_ Compound (11) (3.97 g: 1.47 mM: 1.0 equiv.) was added to a 100 mL round bottom flask containing 16 mL anhydrous methylene chloride dried 4 angstrom molecular sieves and crushed K2CO3 (0.121 g; 0.88 mM; 0.6 equiv.). Next, m-CPBA 0.253 g; (1.47 mM; 1 equiv.) was added to the solution. The cloudy, white reaction mixture was stirred at RT under N2 for 20 min and was analyzed by tlc and the reaction was found to be 25% complete. An additional 0.1 g of m-CPBA was added to 7 1 the reaction mixture in an effort to advance the reaction to completion. The reaction was checked via tic at 15 min after · the last addition of m-CPBA and was found to be around 90% complete to give 2-3 more polar, UV(+) products. The white solution was poured into a separatory funnel containing I 00 mL of 5 % NaHCO3. The quenched reaction mixture was washed with 2x25 mL portions of methylene chloride. The methylene chloride layers were combined and were then washed with 100 mL brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 0.34 g of a white solid. The crude solid was purified via chromatography on a silica gel gravity column (CHCl3:ethyl acetate, 9: 1 mL). The procedure afforded

44 % yield of an epimeric mixture of desired product (12). Rt=0.44 (CHCl3:ethyl acetate, 9:1 mL). ltt-NMR (CDCl3): 5 7.95- 7.55 (m, l0H, aromatic), 4.1-3.9 (m, 4H), 3.49-3.6 (m, 2H), 3.2 (m, 2H), 1.27 (s, 3H), 1.1 (s, 3H). 13C-NMR (CDCl3): 5 139-129, 109, 76, 67, 66(CH2O), 59(CH2SO2), 26, 25. IR (Film): 3300- 3450, 2900-3000, l 420(s), 1380-l 390(s), 1260, 1210, 1060, 850(s), 750(s), 690(s) cm-I. Mass spectrum (DCI/NH3): m/e 304 (m+l7), 287(m+l). 218. Anal. Calcd for C13H18O5S

(286.345): %C 54.53, %H 6.34; Found %C 54.14, %H 6.28. General Procedure for Beta-Hydroxy Sulfone Dianion Generation For Alkyl Halides. Sulfone (12) (59.7 mg; 0.21 mM, 1.0 equiv.) was added to a 10 mL round bottom flask containing 1.3 mL 72

anhydrous THF and dried 4 angstrom molecular sieves under N2. The sulfone solution was cooled to -78 °c with an acetone/dry ice bath. n-BuLi (2.5 M in hexane) (0.183 mL: 0.46 mM: 2.2 equiv.) was added portionwise to the sulfone solution. DMPU (55 microliters; 0.46 mM: 2.2 equiv.) was added dropwise to the basic solution. The resulting light yellow-green dianion solution was stirred at -78 °c for 30 min prior to the addition of electrophile. After 30 min. the electrophile (1.5 equiv.) was added to the dianion solution whereupon the color of the solution changed from a light yellow-green color to colorless and finally to a brighter yellow color over the course of 30 min. The cooling bath was removed and the reaction mixture was stirred at RT for 1.5 h. The yellow solution was poured into a separatory funnel containing 10 mL of 10% NH4Cl. The quenched reaction mixture was washed with 2x10 mL portions of ether. The ether layers were combined and washed with 10 mL of 5% NaHCO3 followed by 10 mL brine. The ether layer was dried over anhydrous N a2SO4, filtered and concentrated in vacuo to give a crude oil. The crude oil was purified via preparative or column chromatography.

8. 1,2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4-

phenylsulfonyl-5-heptene (13). Reaction with ally] bromide. 73

40 mg of crude (13) was purified usmg a preparative chromatography with the procedure affording 8.2 mg of an epimeric mixture of desired product (13). 15% yield. Rf=0.49 (ethyl acetate). ltt-NMR (CDCl3): b 7.9-7.5 (m. 5H, aromatic). 5.85-5.65 (m. 2H), 5.2-5.0 (m, 4H), 4.61-4.55 (m, lH). 3.9 (m, IH), 3.7 (m. lH), 3.3 (m, lH), 3.15 (m, lH), 2.95 (m, IH), 2.7-2.6 (m, 2H), 1.45-1.35 (s, 6H). IR (Film): 3600-3500. 3000-2950. 1640-1660(s), 1445(s). 1380-1370(s), 1170. 1060, 850(s), 750(s), 690(s) cm-1. Mass spectrum (DCI/NH3): m/e 344 (m+ 17), 326 (m+ 1 ). Anal. Calcd for C t6H22O5S

(326.410): %C 58.88, %H 6.79; Found %C 59.20, %H 6.81.

General Method for Beta-Hydroxy Methyl Phenylsulfinyl Dianion Generation For Alkyl Halides and Deuterated Electrophiles. Sulfoxide (11) (0.215 g; 0.797 mM;l .0 equiv.) was added to an oven dried, 10 mL round bottom flask containing 2.5 mL anhydrous THF and dried 4 angstrom molecular sieves under N2. The sulfoxide solution was cooled to -78 °c with an acetone/dry ice bath. n-BuLi (2.5 M in hexane) (0.7 mL; 1.75 mM: 2.2 equiv.) was added portionwise to the sulfone solution followed by DMPU (2.5 mL; 1.75 mM; 2.2 equiv.). The resulting light yellow-green dianion solution was stirred at -78 °c for 30 min prior to the addition of electrophile. After 30 mm, the electrophile(l.19 mM; 1.5 equiv.) was added to the dianion 74 solution whereupon the color of the solution changed from a light yellow-green color to colorless and finally to a brighter yellow color over the course of 30 min. The cooling bath was removed and the reaction mixture was stirred at RT for 2 h. Mini-work-up and tlc indicated that the reaction was near 95 % complete resulting in at least 2-3 more non-polar, UV ( +) products. The yellow solution was poured into a separatory funnel containing 50 mL of 10% NH4Cl. The quenched reaction mixture was washed with 2x20 mL portions of ether. The ether layers were combined and were then washed with 50 mL of 5 % NaHCO3 followed by 50 mL brine. The ether layer was dried over anhydrous Na2SO4, and concentrated in vacuo . The crude oil was chromatographed via silica gel chromatography (toluene:ethyl acetate 10:6 mL~ ethyl acetate) or preparative chromatography. 9. 1,2-O-isopropy lidene-2-(R)-3-(R,S )-trihydroxy-4-

deutero-4-phenylsulfinyl butane (14). Reaction with deuterated methanol. Rr-0.45 (ethyl acetate). lH-NMR (CDCI3): o 7.7-7.5 (m, 5H, aromatic), 4.25-4.2 (m, lH), 4.1 (m, lH), 4.05-3.9 (m, 4H), 3.3-3.15 (m, lH), 3.0-2.85(m, 2H), 1.41 (s, 3H), 1.32 (s 3H), 1.25 (s, 3H), 1.05 (s, 3H). IR (CDCI3): 3450-3300, 3000-2900, 1420( s), 1380-1390, 1260, 1210, 1060, 850(s), 750(s), 690(s) cm-1. Mass spectrum (DCI/NH3): m/e 288 (m+17), 272 (m+l), 255, 197, 162. 75

l 0. 1,2-O-isopropy 1idene-2-(R)-3-(R,S )-trihydroxy-4-

phenylsulfinyl-5-heptene (15). Reaction with allyl bromide.

The procedure afforded 13 % of (15) (mixture of isomers) after silica gel chromatography (toluene:ethyl acetate I 00:6 mL ethyl acetate). Rf=0.40 ( ethyl acetate). 1H-NMR (CDCl3): 6 7.7-7.5 (m, SH, aromatic), 5.85-5.65 (m, IH), 5.55- 5.45 (m, lH), 5.25-4.95 (m, 3H), 4.65 (m. IH), 4.25-3.9 (m. 4H), 3.15-3.05 (m, lH), 2.95-2.89 (m, lH), 2.8-2.6 (m, 2H) ,2.45-2.35 (m, lH). 2.1-2.0 (m. lH), 1.72 (s. 3H), 1.45 (s. 3H). 1.35 (s. 3H), 1.15 (s, 3H). 13C-NMR (CDCl3): 6 134. 131-125, 119(CH2O), 109. 77, 76. 70, 67(CH2O), 60(CH2SO), 27, 25. Mass spectrum (DCI/NH3): m/e 328 (m+17). 311 (m+l), 202, 184. Anal. Calcd for C16H22O4S (310.411): %C 61.91, %H 7.14; Found %C 61.50,

%H 6.91.

11. 1.2-O-isopropylidene-2-(R)-3-(R,S)-trihydroxy-4-

methyl-4-phenylsulfinyl pentane (16). Reaction with methyl iodide. The procedure afforded 13% of (16) (mixture of isomers) after silica gel chromatography(toluene:ethyl acetate, 100:6; ethyl acetate). Rf=0.31 (toluene:MeOH, 10:2 mL). lH­ NMR (CDCl3): 6 7.7-7.5 (m, 5H. aromatic). 4.25-4.2 (m, lH), 4.15-4.1 (m .lH). 4.05-3.9 (m. 4H), 3.3-3.15 (m. lH). 3.0-2.85 (m. 2H), 1.41 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H), 1.05 (s. 3H). 76

13C-NMR (CDCl3): 6 132-124, 110, 77, 75, 70, 66.5(CH2O), 27, 25. 7 . Mass spectrum (DCI/NH3): m/e 299 (m+ 17), 285 (m+ 1), 265. 147. 131. Anal. Calcd for C14H20O4S (284.373): %C

59.13. %H 7.09: Found %C 59.25, %H 6.91.

General Method for Beta-Hydroxy Methyl Phenylsulfinyl Dianion Generation

Sulfoxide (11) (0.215 g: 0.797 mM: 1.0 equiv.) was added to an oven dried, 10 mL round bottom flask containing 2.5 mL anhydrous THF and dried 4 angstrom molecular sieves under N2. The sulfoxide solution was cooled to -78 oc with an acetone/dry ice bath. n-BuLi (2.5 M in hexane) (0.7 mL;l.75 mM: 2.2 equiv.) was added portion wise to the sulfone solution followed by DMPU (2.5 mL: 1.75 mM; 2.2 equiv.). The resulting light yellow-green dianion solution was stirred at -78 °c for 30 min prior to the addition of electrophile. After 30 min, the electrophile (1.19 mM: 1.5 equiv.) was added to the dianion solution whereupon the color of the solution changed from a light yellow-green color to colorless and finally to a brighter yellow color over the course of 1.5 hr. The cooling bath was removed and the reaction mixture was stirred at RT for 5-10 mm. Reaction progress was monitored via mini-work-up and tlc. The yellow solution was poured into a separatory funnel containing 50 mL of 10% NH4CI. The quenched reaction mixture was washed with 2x20 mL portions of ether. The ether layers 77

were combined and washed with 50 mL of 5% NaHCO3 followed by 50 mL brine. The ether layer was dried over anhydrous Na2SO4, and concentrated in vacuo to give an oil. The crude oil was purified using column or preparative chromatography (toluene:ethyl acetate, 100:6 mL;ethyl acetate). 12. 1,2-O-isopropylidene-2-(R)-3-(R,S)-5-(R,S )-

tetrahydroxy-4-phenylsulfinyl hexane (17). Reaction with acetaldehyde. The procedure afforded 10% yield of (17) (mixture of isomers) after silica gel chromatography (toluene:ethyl acetate, 100:6 mL; ethyl acetate). Rf=0.44 (ethyl acetate). lH­

NMR (CDCl3): b 7.7-7.5 (m, 5H, aromatic), 4.4-4.35 (m, l-2H), 4.3 (m, lH), 4.1-3.95 (m, 4-5H), 3.15 (m,IH), 2.95-2.85 (m. IH), 1.6 (m, I H), l.4-l.3(s, 6H), 1.15 (s, 2H), 0.9 (s, lH). IR (CDCJ3): 3450, 3000-2950, 1420(s), 1385-1390(s), 1250, 1220, 1150, I 070, 850(s), 690(s) cm-I. Mass spectrum (DCI/NH3): m/e 315 (m+l), 255. Anal. Calcd for C15H22O5S (314.399): %C 57.31,

%H 7.05; Found %C 57.53, %H 6.91.

13. 1.2-O-isopropylidene-2-(R)-3-(R,S)-5-(R,S )- tetrahydroxy-4-phenylsulfinyl-octane (18). Reaction with butyraldehyde.

The procedure afforded 13% of (18) (mixture of isomers) after silica gel chromatography(toluene/ethyJ acetate, 10/0.6mL; ethyl acetate). Rf=0.4 (ethyl acetate). 78 [a]25o -47.70° (c=l.35, MeOH). 13c-NMR (CDCl3): 5 141, 131- 129. 124, 110, 75, 71, 69(CH2O), 37(CH2SO), 26, 25, 19(CH2), 14. ltt-NMR (CDCI3): 5 7.7-7.5 (m. SH, aromatic), 4.45 (m, lH), 4,25 (m, lH), 4.15-4.0 (m, 4H), 3.8 (m, lH), 3.0 (m, lH), 1.8 (m, lH), 1.65(m, lH), 1.4 (s, 3H), 1.35 (s, 3H), 1.05-0.9 (m ,4H), 0.3 (m, 1H). IR (Film): 3500-3250, 3000-2950, 1540(s), 1370- 1390(s), 1250, 1210, 1065(s), 1010-1025(s), 850(s), 750(s) cm-1. Mass spectrum (DCI/NH3): m/e 360 (m+l7), 343 (m+l), 216, 199, 162. Anal. Calcd for C17H26O5S (342.453): %C 59.63, %H 7.65; Found %C 59.83, %H 7.86

14. 1,2-O-isopropylidene-2-(R)-3-(R,S )-5-(R,S )-

tetrahydroxy4-pheny lsulfinyl-5-phenyl hexane (19). Reaction with benzaldehyde.

The procedure afforded 5% yield of (19) (mixture of isomers) after silica gel chromatography(toluene/ethyl acetate, 100:6 mL; ethyl acetate). Rr=0.38 ( ethyl acetate). ltt-NMR (CDCl3): 5 7.75-7.2 (m, l0H, aromatic), 5.4 (m, lH), 4.4

(m, lH), 4.15-3.9 (m, 4H), 3.45 (m, IH), 3.15 (m, lH), 2.35 (m, lH), 1.55 (s. 6H), 1.1 (s, 3H), 0.9 (s, 3H) IR (0.15%, CC14, 3mm cell): 3600-3300, 3100-2950, 1450(s), 1380(s), 1245, 1220, 1150, 1065, 850(s), 740(s) cm- I. Mass spectrum (DCI/NH3): m/e 377 (m+l), 271, 250, 162, 138. Anal. Calcd for C20H25O4S (377.479): %C 63.64, %H 6.68; Found %C 63.50, %H 6.91. 79

15. The synthesis of 1,2-O-isopropylidene-2-(R)-3- (R. S )-5-(R,S )-tetrah ydroxy-4-ph eny Is u 1fi ny 1-5- methyl hexane (20). Reaction with acetone.

The procedure afforded 2 % yield of (20) (mixture of isomers) after silica gel chromatography(toluene/ethyl acetate, 10/0.6mL:ethyl acetate). Rf=0.38 ( ethyl acetate). 1H- NMR (CDCl3): b 7.7-7.5 (m, SH, aromatic), 4.0 (m, 4H), 3.25 (m. 2H). 2.95-2.85 (m, 2H), 1.7 (s, 3H). 1.6 (s, 2-3H), 1.4 (s, 3H). 1.3 (s, 3H). 1.05. 13c-NMR (CDCl3. 500 MHz): b 132-124. 109, 73. 71, 62, 58(CH2SO), 56, 30, 25. 22, 14. Mass spectrum (DCI/NH3): m/e 346 (m+ 17). 329 (m+ 1), 288, 271.

16. 1,2-O-isopropylidene-2-(R)-3-(R,S)-

trimethyl siloxy-4-pheny lsulfenyl butane (23).

Sulfide (9) (1.1 g: 4.3 mM; 1.0 equiv.) was added to an oven dried. 250 mL round bottom flask containing 100 mL anhydrous DMF (distilled over CaH2). Imidazole (0.198 g: 2.85 mM: 0.66 equiv.) was added to the sulfide solution and the mixture was stirred at RT. Trimethylsilylchloride (1.0 mL: 12.9 mM: 3 equiv.) was added to the sulfide solution via syringe over a period of 5 min. The resulting solution was stirred at RT for 18 hrs. The reaction mixture was analyzed by tlc and found to be about 85 % complete affording a more non-polar, UV ( +) product. The clear solution was poured into a separatory funnel containing 200 mL ethyl acetate. 5% NaHCO3 was added to this 80

solution and the mixture was vigorously shaken. A white precipitate formed in the aqueous phase. The aqueous phase was backwashed with 3x 100 mL portions of ethyl acetate and the organic washes were combined and dried with 150 mL brine and anhydrous Na2SO4. The organic phase was filtered and the solvent was evaporated in vacuo to give a colorless oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 42% yield of (23) (mixture of isomers) after silica gel chromatography (petroleum ether:ethyl acetate, 9:1 mL). Rr=0.77

(toluene:methanol, 10:2 mL). ltt-NMR (CDCI3): b 7.4-7.2 (m, SH), 4.15-4.1 (m, lH), 4.05-4.0, (m, lH). 3.85-3.8 (m, 2H). 3.3-3.2 (m 1H). 3.0-2.9 (m. lH). 1 .4. (s, 3 H), 1.3. (s. 3 H) 0.l-0.3(s, 9H). 13C-NMR (CDCl3): b 136-126, 109, 78, 72. 66(CH2O). 38, 36 (CH2S), 26; 25, 0.3-0.5. Mass spectrum (DCI/NH3): m/e 344 (m+ 17). 327 (m+ 1). Anal. Calcd for C16H26O3SSi (326.529):

%C 58.85. %H 8.03; Found %C 59.00. %H 7.77.

17. 1,2-O-isopropylidene-2-(R)-3-(R,S)-acetoxy-4-

phenylsulfenyl butane (25).

Sulfide (9) (0.15 g; 0.59 mM. 1.0 equiv.) was added to an oven dried. 50 mL round bottom flask containing 17 mL anhydrous pyridine. Acetic anhydride (0.12 mL: 1.24 mM; 2.1 equiv.) was added to the sulfide solution via a synnge over a period of 5 mm. The resulting solution was stirred at RT for 8 1

18 hrs. After 18 hrs, the reaction mixture was analyzed by tlc (toluene:methanol 10:2 mL) and was found to be 85% complete

to a more non-polar, UV ( +) product. The clear solution was poured into a separatory funnel containing 100 mL saturated copper sulfate solution. The aqueous phase was backwashed with 2x50 mL portions of methylene chloride and the organic washes were combined and dried with 50 mL brine and anhydrous Na2SO4. The organic phase was filtered and the

solvent was evaporated in vacuo to give a colorless oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 66% yield of epimeric mixture of (25) after silica gel chromatography (petroleum ether:ethyl acetate, (9: 1 mL). Rf=0.72 (toluene:methanol, 10:2 mL). lH-NMR (CDCl3): c 7.4-7.2 (m, 5H), 5.05 (m, 2H), 4.15-4.1 (m, lH), 4.05-4.0, (m, lH), 3.85-3.8 (m, 2H), 3.3-3.2 (m, lH), 3.0-2.9 (m, lH), 2.05 (s, 3H), 1.98 (s, 2H), 1.4, (s, 3H), 1.3, (s, 3H) 1.3 (s, 3H). 13C-NMR (CDCl3): c 170, 136-126, 109, 78, 72, 66(CH2O), 36.5(CH2S), 26, 25, 20. IR (Film): 3100-2950, 1740, 1450-1445(s), 1380-1375, 1245, 1210, 1150, 1065, 850(s), 740(s) cm-I. Mass spectrum (DCI/NH3): m/e 314 (m+ 17), 297 (m+ 1). Anal. Calcd for C15H20O4S (296.384): %C 60.79, %H

6.80: Found %C 60.78, %H 6.91.

18. 1,2-O-isopropylidene-2-(R)-3-oxo-4-methyl- phenylsulfenyl butanone (26). 82

Sulfide (9) (7 .22 g: 28.4 mM: 1 equiv.) was dissolved in 24 mL of dry toluene and set aside. NCS (10.2 g: 76.2 mM; 2.68 equiv) was dissolved in 80 mL sieve dried toluene and

cooled to -10 °c with an acetone/ice bath. DMS (7 .69 mL; 110 mM; 3.9 equiv) was added to the stirring slurry. The mixture was stirred for 20 min at -10 °c. After 20 min, the substrate solution was added to the slurry and this was stirred for 15 min at -10 °c. The reaction was analyzed by tic via mini work­ up and the reaction was shown to be 85 % complete resulting in 3-4 new UV(+) products. The reaction was quenched by adding (Et)3N (4.75 mL, 34.lmM, 1.2 equiv) to slurry. After stirring for 3-5 min at -10 °c, the reaction mixture was poured into a separatory funnel containing toluene and was washed once with 150 mL 5% NaHCO3_ The aqueous phase was washed with 2x50 mL portions of toluene and the organic phases were combined and dried over anhydrous Na2SO4. The toluene layer was filtered and evaporated to a smelly, brown-yellow oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 30% yield of (26) after silica gel chromatography (hexane:ethyl acetate, 100:7.5 mL). Rf=0.17 (toluene:methanol, 10:2 mL) lH-NMR (CDCI3): b 7.4-7.2 (m, SH). 4.65 (m JH). 4.2-3.85 (m, 4H), 1.49, (s, 3H), I .4, (s, 3H). 13c-NMR (CDCI3): b 204, 130-127, 111, 79. 72, 66(CH2O), 40(CH2S), 26, 24.5. IR (15%, CCI4, 3mm cell) 3700, 3500, 83

3080-3060(s), 3000-2900, 1720 cm-I. Mass spectrum (DCIINH3): m/e 270 (m+ 17), 254 (m+ 1).

19. 1,2-O-isopropy lidene-2-(R)-3-oxo-4-phenyl s ulfeny 1- 5-(R,S)-hydroxy hexanone (28). Sulfide (26) (0.750 g; 2.97 mM; 1.0 equiv.) was added to an oven dried, I 00 mL round bottom flask containing 15 mL anhydrous THF. The sulfide solution was cooled to -78 oc with an acetone/dry ice bath. t-BuLi (1.3 M in pentane) (2.0 mL; 3.87 mM; 1.3 equiv.) was added portion-wise. After each t­ BuLi addition, the substrate solution turned bright yellow and disappeared after a few seconds. After all the t-BuLi was added to the solution, the color remained bright yellow for most of the duration of the reaction. The reaction mixture was stirred at -78 °c under nitrogen for 1 hr. Acetaldehyde (0.22 mL; 3.86 mM; 1.3 equiv.) was added to the basic solution over a 2-3 minute period. The color of the reaction mixture changed from a yellow color to a light yellow color. The cooling bath was removed and the reaction mixture was stirred at RT for 5- 10 min. Mini-work-up and tic indicated that the reaction was near 75% complete resulting in 2-3 more non-polar, UV(+) products. The light yellow solution was poured into a separatory funnel containing 150 mL of 10% NH4Cl. The quenched reaction mixture was backwashed with 2x50 mL portions of ether. The ether layers were combined and were 84

then washed with 150 mL of 5% NaHCO3 followed by 100 mL brine. The ether layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give 800 mg of a off-white oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 30% yield of (28) after silica gel chromatography (hexane:ethyl acetate .100:75 mL). Rf=0.7 (toluene:methanol. 10:2 mL) epimeric mixture of (28) and unreacted starting material. lH-NMR (CDCl3): 5 7.5-

7.2 (m, I0H), 5.05 (m. IH), 4.65 (m, lH), 4.2 (m. 2H), 4.1 (m ,lH), 3.95-3 .85 (m, 2H), 2.1 (m. 2H), 1.55 (s, 3H), 1.45 (s, 3H), l .4, (s, 3H), 1.38. (s, 3H), 1.35 (s. 3H). 13C-NMR (CDCI3): 5 204. 196, 149. 130-126. 111. 79, 78. 72, 66(CH2O), 40(CH2S). 26. 25, 17. IR (Film) 3700, 3500, 3080-3060(s), 3000-2900, 1715 cm~ 1. Mass spectrum (DCI/NH3): 296 (m+ 1), 279, 270.

20. 1,2-O-isopropylidene-2-oxo-3-phenylsulfenyl-5- phenyl-4-pentenone (29a). Sulfide (26) (0.3 g; 1.19 mM; 1.0 equiv.) was added to an oven dried, 100 mL round bottom flask containing 12 mL anhydrous THF. The sulfide solution was cooled to -78 °c with an acetone/dry ice bath. t-BuLi (1.7 M in pentane) (0.98 mL: 1.55 mM: 1.3 equiv.) was added portion-wise to the sulfide solution. After each t-BuLi addition. the substrate solution turned bright yellow and disappeared after a few seconds. After all the t-BuLi was added to the solution, the color 85 remained bright yellow for most of the duration of the reaction. The reaction mixture was stirred at -78 °c under nitrogen for 30 min. Benzaldehyde (0.29 mL: 2.86 mM: 2.4 equiv.) was added to the basic solution over a 2-3 minute period. The color of the reaction mixture changed from a yellow color to a bright ye11ow color. The cooling bath was removed and the reaction mixture was stirred at RT for 5-10 min. Mini-work-up and tlc indicated that the reaction was near 95 % complete resulting in 2-3 more non-polar, UV(+) products. One half of the reaction was worked up in the usual fashion. Acetic anhydride (0.18 mL; 1.9 mM: 1.6 equiv.) was added via syringe to the other half of the reaction mixture and this was stirred at RT under nitrogen for 15 min before quenching in the usual fashion. Mini work-up a tlc of the acetic anhydride quenched reaction suggested that the product make-up was identical to the product make-up obtained from the other half of the reaction indicating no hydroxyls remained. The bright yellow solution was poured into a separatory funnel containing 150 mL of 10% NH4Cl. The quenched reaction mixture was backwashed with 2x50 mL portions of ether. The ether layers were combined and were then washed with 150 mL of 5% NaHCO3 followed by 100 mL brine. The ether layer was dried over anhydrous Na2SO4. filtered and evaporated in vacuo to give 400 mg of a smelly. orange-yellow oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure 86

affords 26% yield of eliminated. desired product (29a) and unreacted benzaldehyde after silica gel chromatography (hexane:ethyl acetate, 20: l mL). Rf=0.62 (toluene:methanoL 10:2 mL) ltt-NMR (CDCl3): o 7.5-7.1 (m, l0H), 5.25 (m, lH), 5.1 (m. lH), 4.65 (m, lH), 4.25-4. l (m, 2H), 4.0-3.9 (m, lH), 2.2 (m, 3H), 1.45 (s, 3H), 1.4, (s, 3H). l3c-NMR (CDCl3): b 167. 145, 130-127, 115, 110, 74, 57(CH2O), 40, 21, 18, 15. IR (Film) 3450-3350. 3000-2950, 1760, 1380-13 75 (s ), 1200-1190, 1150, 1050, 850, 695 cm-I. Mass spectrum (DCI/NH3): m/e 358 (m+l7), 341 (m+l), 312. 254.

21. 1,2-O-isopropylidene-2-(R)-3-(R,S)-acetoxy-4-

phenylsulfenyl-3-hexenone (30a). Sulfide (26) (0.3 g: 1.19 mM: 1.0 equiv.) was added to an oven dried, 100 mL round bottom flask containing 12 mL anhydrous THF. The sulfide solution was cooled to -78 °c with an acetone/dry ice bath and t-BuLi (1.7 M in pentane) (0.98 mL: 1.55 mM: 1.3 equiv.) was added portion-wise to the sulfide solution. After each t-BuLi addition, the substrate solution turned bright yellow and disappeared after a few seconds. After all the t-BuLi was added to the solution. the color remained bright yellow for most of the duration of the reaction. The reaction mixture was stirred at -78 oc under nitrogen for 30 min. Acetone (0.21 mL: 2.86 mM: 2.4 equiv.) was added to the basic solution over a 2-3 minute period. The color of the 87

reaction mixture changed from a yellow color to a dull yellow color. The cooling bath was removed and the reaction mixture was stirred at RT for 5-10 min. Mini-work-up and tic (toluene:methanol 10:2 mL or hexane:ethyl acetate 10:2 mL) indicated that the reaction was near 95 % complete resulting m 2-3 more non-polar, UV(+) products. One half of the reaction was worked up in the usual fashion. Acetic anhydride (0.18 mL; 1.9 mM; 1.6 equiv.) was added via syringe to the other half of the reaction mixture and this was stirred at RT under nitrogen

for 15 min before quenching in the usual fashion. Mini work-up and tic of the acetic anhydride quenched reaction suggested that the product make-up was different than the product make­ up obtained from the other half of the reaction. The bright yellow solution was poured into a separatory funnel containing 150 mL of 10% NH4Cl and the reaction mixture was backwashed with 2x50 mL portions of ether. The ether layers were combined and were then washed with 150 mL of 5% NaHCO3 followed by 100 mL brine. The ether layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give 200 mg of a smelly. orange-yellow oil. The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 26% yield of an epimeric mixture of elimination and the isolation of 50 mg of acetylated enol ether of the starting material (30a) after silica gel chromatography (hexane:ethyl acetate. 20: 1 mL). Rf=0.72 (toluene:methanol, 88

10:2 mL). lH-NMR (CDCl3): b 7.4-7.25 (m, 5H). 6.3 (m. IH), 4.65 (m. IH). 4.1 (m, IH). 4.0-3.9 (m. IH). 2.2 (m. 3H). 1.45 (s. 3H).

1.4. (s. 3H). 13C-NMR (CDC13): b 167. 145. 130-127. 115. 1 IO. 76. 67(CH2O), 26, 25. 19. IR (Film) 3000-2950, 1760, 1380- 1375(s). 1200-1 I 90. 1150. 1050, 850, 695 cm- 1. Mass spectrum (DCI/NH3): m/e 311 ( m + 1), 292. 253.

22. 3-(R.S)-hydroxy-4-phenylsulfiny I-I -butene (31). Methyl phenyl sulfoxide (3.77 g: 27 mM: 1.2 equiv.) was added to an oven dried. I 00 mL round bottom flask containing 19 mL anhydrous THF. The methyl phenyl sulfoxide solution was cooled to -10 °c with an acetone/ice bath. n-BuLi (2.5 M in hexane) (10.7 mL: 27 mM: 1.2 equiv.) was added portion-wise to the sulfoxide solution. The resulting light yellow anion solution was stirred at -10 °c for 20 min prior to the addition of 97% acrolein. After 20 min, acrolein (1.5 mL: 22.4 mM; 1 equiv.) was added to the anion solution whereupon the color of the solution changed from a light yellow color to colorless and finally to a brighter yellow color over the course of 15 min. The cooling bath was removed and the reaction mixture was stirred at RT for 1-2 min. Mini-work-up and tic indicated that the reaction was near 95 % complete resulting in

3-4 more non-polar, UV ( +) products. The yellow solution was poured into a separatory funnel containing l 00 mL of 10% NH4Cl. The quenched reaction mixture was backwashed with 2x50 mL portions of ether. The ether layers were combined and 89 were then washed with 100 mL of 5% NaHCO3 followed by 100 mL brine. The ether layer was dried over anhydrous Na2SO4. filtered and evaporated in vacuo to give 3.5 g of a smelly. off­ white oil. The procedure afforded 45 % yield of an epimeric mixture of (30) after silica gel chromatography (hexane:ethyl acetate, 20: 1 mL). Rf=0.4 (ethyl acetate). 1H-NMR (CDCl3): 5 7.7-7.5 (m, 5H), 6.0-5.8 (m. lH). 5.4-5.2 (m, 2H), 4.85-4.7.(m. IH), 3.9-3.7 (m, lH), 3.1-2.75 (m, 2H). 1.7 (s, IH). 13c-NMR (CDCl3): 5 143. 137-130. 124, l 16(CH2). 110. 69, 66. 63(CH2SO). IR (Film) 3400-3330. 3000-2950. 1420. I 030- 1020(s). 1000, 920. 770, 690 cm-I. Mass spectrum (DCI/NH3): m/e 214 (m+l7). 197 (m+l).

23. 2-methy 1-3-(R,S)-hydroxy-4-phenyl sulfinyl-1-

butene (32). Methyl phenyl sulfoxide (3.04 g; 21.7 mM; 1.2 equiv.) was added to an oven dried. 100 mL round bottom flask containing 19 mL anhydrous THF. The methyl phenyl sulfoxide solution was cooled to -10 °c with an acetone/ice bath. n- BuLi (2.5 M in hexane) (8.7 mL; 21.7 mM: 1.2 equiv.) was added portion-wise to the sulfoxide solution. The resulting light yellow anion solution was stirred at -10 °c for 20 min prior to the addition of methacrolein. After 20 min, methacrolein ( 1.5 mL 18.1 mM: I equiv.) was added to the anion solution whereupon the color of the solution changed from a light yellow 90 color to colorless and finally to a brighter yellow color over the course of 15 min. The cooling bath was removed and the· reaction mixture was stirred at RT for 1-2 min. Mini-work-up and tlc indicated that the reaction was near 95% complete resulting in 3-4 more non-polar. UV(+) products. The reaction was worked up as cited in example 23. The ether layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give white solid. The white solid was purified via chromatography on a silica gel gravity column. The procedure afforded 70% yield of an epimeric mixture of (32) after silica gel chromatography (hexane:ethyl acetate, 100:6 mL). R[=0.36 (ethyl acetate). H-NMR (CDCl3): b 7.65-7.5 (m, 5H), 5.1 (s, lH), 4.9 (s. IH), 4.6 (m, lH), 3.7 (m, lH). 3.15-3.05 (m, IH), 2.85- 2.75 (s. IH). l.7(s. 3H). 13c-NMR (CDCI3): b 145, 143, 129- 124, 112(CH2), 69, 63(CH2SO). 18. IR (KBr) 3400-3250(b), 3100-2900, 1660-1620, 1440(s), 1080(s), 1060(s), 1020- 101 0(s), 900(s), 750(s), 690(s) cm-I. Mass spectrum (DCI/NH3): m/e 228 (m+l7), 211 (m+l), 195, 177. Anal. Calcd for C11H14O2S(210.293): %C 62.83, %H 6.71; Found %C 62.74, %H 6.72.

24. 1-phenyl-trans-2-methyl-(R,S)-3-hydroxy-4- phenylsulfinyl-1-butene (33). Methyl phenyl sulfoxide (1.8 g; 12.7 mM; 1.2 equiv.) was added to an oven dried, 100 mL round bottom flask 9 1 containing 19 mL anhydrous THF. The methyl phenyl sulfoxide solution was cooled to -10 °c with an acetone/ice bath. n-BuLi (2.5 M in hexane) (5.1 mL: 12.7 mM; 1.2 equiv.) was added portion-wise to the sulfoxide solution The resulting light yellow anion solution was stirred at -10 °c for IO min prior to the addition of a-methyl-trans-cinnamaldehyde. After 10 min, (l.5 mL: 10.7 mM; 1 equiv.) of a-methyl-trans-cinnamaldehyde was added to the anion solution whereupon the reaction color progressed as usual. The reaction monitoring and workup proceeded as previously cited in example (31). The procedure afforded an off-white oil that was purified via chromatography on a silica gel gravity column. The procedure afforded 80% yield of epimeric mixture of (33) after silica gel chromatography (toluene:ethyl acetate, 25: 1 mL:ethyl acetate). Rr-0.49 (ethyl acetate). ltt-NMR (CDCl3): b 7.7-7.1 (m, lOH), 6.65 (m, lH), 6.6 (m, lH), 5.1 (s lH), 4.85 (m, lH). 4.72 (m, IH), 3.95-3.85 (s, 1H), 3.25-3.15 (m, 3H), 2.95 (m, lH), 2.85 (m, lH), 2.35 (s. 3H), 1.87 (s. 3H), 1.8 (s, 3H). 13C-NMR (CDCI3): b 144. 137, 131,-124, 74, 71, 62(CH2SO), 14, 13. IR (Film) 3250- 3300(b), 3100-2810, 1600-1590, 1440(s). 1080(s), 1020- 1030(s), 760(s), 700(s) cm-1. Mass spectrum (DCI/NH3): m/e 304 (m+ 17). 287(m+ 1), 269, Anal. Calcd for C11H1402S(): Cale. %C 71.30, %H 6.39: Found %C 71.66. %H 6.49. 92

25. 2-Methyl-3-(R,S )-hydroxy-4-phenylsulfinyl-1.6- hexadiene (34). Sulfoxide (32) (50 mg: 0.48 mM: 1.0 equiv.) was added to an oven dried, 10 mL round bottom flask containing 0.65 mL anhydrous THF. The sulfoxide solution was cooled to - 78 oc with an acetone/dry ice bath. n-BuLi (2.5 M in hexane) (0.2 mL; 1.05 mM; 2.2 equiv.) of was added portion-wise to the sulfoxide solution. DMPU (63 µliters; 1.05 mM; 2.2 equiv.) was added dropwise to the basic solution. The resulting light yellow-orange dianion solution was stirred at -78 °c for 30 min prior to the addition of allyl bromide. After 30 min, 33 µliters (0.71 mM; 1.5 equiv.) of allyl bromide was added to the dianion solution whereupon the color of the solution changed from a light yellow-orange color to colorless over the course of 30 min. The reaction was monitored and quenched as previously cited in example (31 ). The crude oil was purified via chromatography on a silica gel gravity column. The procedure afforded 9% yield of epimeric mixture of (34) after silica gel chromatography (toluene:ethyl acetate, 100:6 mL; ethyl acetate). Rf=0.49 ( ethyl acetate). 1H-NMR (CDCl3, 500 MHz): 6 7.6-7.5 (m, 5H), 6.0-5.9 (m, lH), 5.55-5.4 (m, lH). 5.15 (s. 1H). 5.05 (s. lH), 4.9 (m, 2H). 4.4 (m. lH), 2.85 (m. lH), 2.3 (m, lH), 2.1 (m, lH), 1.8 (s. 3H). 13c-NMR (CDCl3): 6 143. 140. 134. 131-124. 118-117, 114, 112(CH2), 75, 71, 64-63(CH2SO), 93

27, 19, 17. Mass spectrum (DCI/NH3): m/e 268 (m+l7). 251

(m+l).

26. The separation of 1,2-O-isopropylidene-3-(R)-3-(S)-

hydroxy-4-phenylsulfonyl butane (35) from 1.2-O- i sopropy lidene-2-(R )-3-(R)-hy droxy-4-pheny ls ul f on y I butane (36) using preparative HPLC. The substrate was dissolved in 3 mL of methanol and 450 microliter injections were made onto the column. A total of 0.5 gram of a 60/40 mixture of sulfone (12) was injected on to a semi-preparative hplc column using water, 65 % methanol, 30 g/L NaOAc*3H2O, 1.5 mL/L glacial acetic acid and 20 mL/L ethylene glycol as the mobile phase. The flow rate was 11 mL/minute with the sensitivity set at 16. Two sharp peaks were separated out on the column with a retention time of (1) 12 min and the other with a retention time of (2) of 14 min. The respective samples were poured into separatory funnels containing 100 mL 5% NaHCO3. The aqueous layers were back washed with 2x50 mL portions of methylene chloride, were dried with I 00 mL portions of brine and suspended over anhydrous Na2SO4. After basic aqueous work­ up, the eluents were evaporated to (1) I 00 mg colorless oil and (2) 300 mg colorless oil. Upon standing at RT, both samples solidified to give white crystalline solids. The nmr spectra showed the samples to be 97% pure. [a]25D -5.040 (c=l .3, 94

MeOH). (35). Rf=0.4 ( chloroform:ethyl acetate. 9: 1 mL). 1H­ NMR (CDCI3): 5 7.95-7.55 (m JOH aromatic). 4.1-3.9 (m. 4H). 3.6-3.49 (m, 2H). 3.2 (m. 1H). 1.27 (s, 3HL 1.1 (s. 3H). 13c-NMR (CDCI3): 5 139-129, 109, 76. 67. 66(CH2O), 59(CH2SO2), 26. 25. Mass spectrum (DCI/NH3): m/e 304 (m+l7). 287 (m+l).

218.

(36). 1H-NMR (CDCl3): 5 7 .95-7.55 (m, 1OH aromatic), 4.1-3.9 (m, 4H). 3.6-3.49 (m, 2H), 3.2 (m, lH), 1.27 (s. 3H), 1.1 (s. 3H). 13C-NMR (CDCl3): 5 139-129. 109 76, 67, 66(CH2O), 59(CH2SO2), 26.3, 25. Mass spectrum (DCI/NH3): m/e 304 (m+17), 287 (m+l). 218. Anal. Calcd for C13H18O5S (286.345):

%C 54.53. %H 6.34; Found %C 54.04, %H 6.28.

27. The separation of 1,2-O-isopropylidene-2-(R)-3-(R)- hydroxy-4-phenylsulfenyl butane (37) from 1,2-O- i sopropy lidene-2-(R )-3-( S )-hydroxy-4-pheny 1s ul f eny I butane (38) using preparative HPLC. The substrate was dissolved in 3 mL of methanol and 450 microliter injections were made on to the column. A total of I gram of a 70/30 mixture of sulfide (9) was injected on to a semi-preparative hplc column using water, 60% methanol. and 30 g/L NH4OAc as the mobile phase. The flow rate was 11 mL/minute with the sensitivity set at 16. Two sharp peaks were separated out on the column with a retention 95 time of 21 mm and 26 mm. The respective samples were poured into separatory funnels containing 100 mL 5% NaHCO3. The aqueous layers were back washed with 2x50 mL portions of methylene chloride, were dried with I 00 mL portions of brine and suspended over anhydrous Na2SO4. After basic aqueous work-up, the eluents were evaporated to 568 mg colorless oil (faster eluting component) and 200 mg colorless oil (slower eluting component). Upon standing at RT, both samples solidified to give white crystalline solids. The nmr spectra showed the samples to be 95% pure. (37). Rr=0.5 ( chloroform:ethyl acetate, 9: I mL). [cx]25o-46.80 (c= 1.19,MeOH). lH-NMR (CDCl3): b 7.18-7.4 (m 5H aromatic), 4.25 (m, IH), 4.05 (m, IH), 3.85 (m,IH), 3.65 (m, 2H), 3.09 (d, 2H), 2.53 (d, IH) 1.45-1.35 (s, 6H). Mass spectrum (DCI/NH3): m/e 272 (m+ 17), 255 (m+l), 197, 162.

(38). 1H-NMR (CDCI3): b 74-7.18 (m, 5H aromatic), 4.1-3.8 (m, 3H), 3.65 (m, 2H), 3.35 (m, lH), 2.9 (m, lH), 2.55 (d, lH) 1.45- 1.35 (s, 12H). 13C-NMR (CDCI3): b 129-126, 109, 77, 70, 66(CH2O), 37(CH2S), 26, 25. IR (CDCl3): 3600-3250(b), 3100- 2900, 1660-1620, 1480, l 440(s), 1280, 1220, 1080(s), 1060( s), 900(s), 750(s), 690(s) cm-1. Mass spectrum (DCI/NH3): m/e 272 (m+l7), 255 (m+l), 197, 162. Anal Calcd for C13H18O3S (254.346): 61.39%C, 7.13%H; Found 61.11%C, 6.94%H. 96

28. 1,2-O-isopropylidene-2-(R)-3-(S)-hydroxy butane (39) and 1,2-O-isopropy]idene-2-(R)-3-(R)-hydroxy

butane (40). Substrate (37) or (38) respectively, (0.112 g; 0.44 mM) were dissolved in 10 mL methanol and stirred at RT. Plugs of activated #28 wet Raney nickel (3 mL) were added to the substrate solution rinsing the nickel into the reaction vessel with water. The grey slurry was stirred at RT and the reaction progress was monitored via tlc analysis. At 30 min, the reaction mixture was analyzed by tlc and was shown to be 98 % complete to a more polar, UV (-) product. The slurry was poured into 200 mL methanol and was carefully gravity filtered making sure that all of the nickel residue remained moistened with methanol wash. The filtrate was refiltered over a micropore filtration apparatus and this filtrate was evaporated in vacuo to a clear colorless oil which solidified upon standing at RT (39). Rf=0.4 (toluene:MeOH, 10:2 mL). [a]25o=33.80 (c=l.6, C6H6) (lit)47, [a]25D =33.9° (c=0.73, C6H6) . ltt-NMR (CDCl3): o 4.1-3.82 (m, 4H), 2.09 (m, lH), 1.42-1.36 (s, 6H), 1.16(d, 3H, J =6.5 Hz). 13C-NMR (CDCl3): o 129-126, 109, 77, 70. 66(CH2O), 37(CH2S), 26, 25. Mass spectrum (DCI/NH3): m/e

164 ( m + 17). 14 7 ( m + I ) . 97

(40). [a]25D =5.9° (c=l.4.C6H6) (lit)47. [a]25D =2.90 (c=l.14. c6H6)- lH-NMR (CDCl3): 6 4.01 (dd, IH. J 1'1=7.5 Hz. J 1'2=6.5 Hz). 3.93 (m. 2H). 3.67 (dd. 1HJ 1'1 =7.5 Hz. J l '2=6.5 Hz). 3.72-

3.61 (m. 3H), 2.73 (s. IH). 1.45-1.35 (s. 6H). 1.14 (d. 3H. J =6.5 Hz). 13C-NMR (CDCl3): see example (39). Mass spectrum (DCI/NH3): m/e 164 (m+ 17). 147( m+ 1). Anal. Calcd for C7H14O3 (146.20): 57.51 %C. 9.65%H~ Found %C 57.62. %H 9.85. CHAPTER VI

SPECTRAL APPENDICES

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0 ,/-H 0 0 )<

(3)

-,--~-,--r--r---,----r- -T--,---,..--.~--r--,· ••-y--,----r-·r-·-,---. 200. ViO. 100. ',O 0 rt•M - IT!l:-·'r7::· ·1,;'.'?·1,1ir,;:r,E11l'11'.%1r:r111,w!l1'~111,,!':': :] l!liil:'1!: ;'.;, (;i :fill T1!,Ji1!1ITI!~ ·: ·: :_'.:r,~· ; Jf;ITI ij::.- J;·' ··.i-._1 •11: ii1'1 ;'','I: i'1 i• :,,,1 ilr i .,!',:I':' l'il .,j, ;,,, i ii• .:.· , .,·,i:;, :: i!j . 1.:. :i; i ' 'I 1', ., I ''j• ·;•, 1' 1',1 I I ,,; ., ' i ,!,1 ' I I· !: ' ,I '.:,,,·.. ,. ·, ' : I I I 'i I I:,: 1,; ·: ,·1, I '11:1 ''P :1, '1· ;i! ,I:,,, .; ,. ,, I ;, I. , I,: . ,·1•.l 1·:::1 ·:,qi.I' :.. ,1, : ;· ::,, !:'_ 1' ,'!1 11:i •:1 I,,. . " ,. :·, I : :1 ' I . . I ' ,, I ,111 ,,,,I"' '1 I I, I ,,, '., I '' . ''. 1·· I . ': ' I': ,., ·'1 ,., I ' '. I'! . ! i I' I .. _! :' ',i' ',,,· "': ·, ,'• !·' ,, 1 I ·:1 ' ' ,· !1 . I ., ' I, I . l I • '1· I . I i' I 'I : : !· I I' ' I I I ,·,"' ; r-,7:·!"I Lf~\ ~,•,~-,.,.,.,r.-,111 ,11, ,: , ,,,_ . ' " .. ': .:· 1·.1 ' 1-.-'· I - i I I''.' ; . ' ,I.,·· 1-· :,:: •,I; 11!· I.. ,.- I I I 0 I ' _·1 -1· 1 · ·1 :;, l:!ln: :I ·.j:" I, ! ,, , ..,. , ...,·, ', •.I· / -j- "I . ,, . -:,: ,,:,1, ;.-:, ,, , : : I:: .. ,· 1-· I I\ 'i ,, I . I . I I ' :! . 'I I T ! I I!, ' i, : .,,. : 1P· : I H : . I ·,-: . ! I I 'I . ,·: : : ~! : Ii I; • ! : I. : '., t ·; I j i ;, · td· I ' . . ' " ,. I : ' ' ,;. I, I ' I I ,! ... I. i ~.I"" '"l .: ' 0 0 ! I I I.. . . . , :: .. ,:;, ;_~ . ~:: ;I: ~,1,,j,; il·j',, :!~ .;· .', (: . ·, ,,_.... ,,r--- i J I ti ! · .. ;~. :. ': · ;I'·,1: ,,,, 1 ,,, ;1,, 1 ·: : ii· i,,i ::' , j· -•~ ,.[~ :~ X ', -~'ti-::!.;;;~: ,:;t ;,i 1r:·,: 111· ''1· 1i:11 :ii,, '1i1·: \ ,: ·.~ •:_,,.. _1- ., .:.,.. ti I ,i:, '111 i I I ; ~ u• I ' ,I!:-: ! :i: ':ii 1:: :'1! 11 ,,· 11.; I 11:i ':,:~:I·,;_-· ::;-.- ; I " I : !' ' :! I I ~ !: ' ! ' I I i !I I' · I ' I' : I ,, . i I I I !; .i : ' 1· ... (3) ! : 'I '' ' '. 111 I' I 'I ,,1, ,I 1,.1 il1· 1' I :: . I' ' '·1 l:11 ;.,, ,,, ,,, I 'I' I ''I' l"I l'I ': ' I i •~1 ,.,, 1 11 1 I ! ! ,,- ), ::!1 !!1 '1! 1111 lJ1i II 'I I! I !'1: I~, !il1 !:'; 1 ., I 1 I ! I •· I -,:,1,,1 ,, ,1 :I ~1111~1:11:,,';:'1111 I I I ,., I ,,,, ''I I I I '1 • I I !_ Jj - ' .' .i: !I I II 1'1!! ~·1 II~! ',1•' '. ' --r i :_ ' --; i, 1! jl I 'I 1 , ii 11, ,,i: 1i' i' ; .

;1.1 1 .. I. J_,_2 lli il " lll lU i~.!!.L ; 'J. -~'~1~Jl1 fil 'illlHI I 11111 .11,1111 111111 l,•1111 IIIIHI ~111111, ,'t.lnl ,''lllft ,', Ult , IUNI It 1111 It

...... 0 -..l I I

- 11 I

(3) I '5

Mil

..L...fl ...... _.,.,J,, •,\~1 •.,•I • • "' m, •I 1~'.'{Jli!:'T""',...,.rrt...,.r-N.....,,...... ,,...... ;4fi2'T'5.....,~....,..,..,.,.....,...... ,,....,...... ;~;;i"!qi;....,,...... ~_, 100 I 'SQ 200 2"50 ~00 4t.llJ 4'50 soo

0 00 MMrl198037.NOT 38731-18 IN COJOO 122 8/25/91 0(300

0 / _oX 0 0

HO OH

(5)

- Nt-m 198047. NOT 38731-18 IN tOJOD $22 8/25/91 QE300 IIINlfl \fe••l•l'II J 11 0 /

0 X 0 0

HO OH

(5) I I

,----,~r-,-·-r--i-.-.·•-,- I I 200. 150. PPM 100. ~0. 0.

-0 80 48 NOi NMR1938731-1 8 [N COJOO 122 8/25/91 orJoo ox an1~v,.,~, .. ,.,1 ti 0 0 0

(5)

-r-··-·,--·,·--1-·~· ,. ,.. ··,-·' __ _.-r···,-·-,. -·-·,--. •·11111 I ;, "(~ 1',0. l'l'M

...... -...... : I. - I,'·•1 ·1 : ··II

I·1:l -,I' ·'·

0 / i . ai

_o X ,._a, 0 Ill ., 0 Ill - I j I I : ·\ ,.

HO OH I I I I (5) I I : h: I i I : I . I I I I I I I ; :111 •I ·. i ,: .: .1: I 1,li ;lU•/ ' . I•: ,!!'i I I .: I, ·j. !. ' . ' I I 0 ~+-00-0--.----+----+-~-+---1.--~t-~+-~--+"'-""_,3 00 3 00 2 00 2~00 2 no I 00. 1 on 1 nn , ;;,,--, - N 0 / ... • • •• •• ox0 .. ... IIP ltl •• ., ,, HI ,,, ,,. 0 ,,--"'! • .... ••• "' "' . -.~" .. ... ••• ,.. ••• ... ,:,_ .. ,.. HO OH .. :• ••• ...... , 114 14ft ...... ,,, ... ~ ___ ••• •ti l:"ft -""---- (5) --

...... NMR138781. NOT 3/112-89T IN CDJOD $3 _, 4/3/90 02300 HMt v•• , •• ,., J •• )<0/ 0

0 HO

{8) LL_J_ 1 • • • • 1 • • , , r--,-r-·------·----- 1 , , • , 1 , • , , 1 , , , , 1 , , , , r--r-r--.-..,.,-.-, , • 1 , , , • T 10. 0 9. 0 8. 0 7 . 0 6. 0 ~p~ 4. 0 3. 0 2. 0 1 . 0 0. 0

-...... NMR145942.NOT 37112-89 IN C0300 $7 i/dl:h) )E3ou .. ~ v...... J ,. )<0/ 0

0 HO

(8)

,---.--·T--•-,-· ·-,·--·,-·-, -- .. ,.... ·-·,·---, .... ··1·---- ... I 200. l'iO. !iO. 0.

..... NMR145943.NOT 37112-84 IN COJOO $7 G/8/90 aE:.wu Alll""'41 Y••·.t, "' .I It )<0 / 0

0 HO I "

(8)

---,--·r•-,--- ,- ··t ---y---~-·--1·• ··- 1 ··-,----,.••-•·r-..,.- r-r·•- ,--·-··,---·-, I ?00. l~iO. 100 JIJ 0 1lpt,1·

...... ITflii'Jffj'J;f' ''Tf1T~~~ rm l"'I nirrm ITT1l r.nlrn [ijilFI ;~·1 'I w1nrITilrrifmn TTTT jfj' 11:'jllll II 1m1 nn 'I If' I ii 11 ,:r: !:f :f \l!i_! ,~! lfll 1l_li 1111ij1 !!!111111Ji111·1 , ~!l ! I 1111 lr!! ! ~i1J:ti IW !11i ,U :~1l 1t11I.111!1 ~-n:1 ;!(:.;!.\ i! !i 1 1 1 1 . ' ' ,:,i. :.,: ::I! : 1·· :11 l:11: •1 :111 ill . 11! I I. ,·'I!!:! :. ,,,, ;111111· '.11 :!:: 111! '11 I!,:,•,! 11:11 1·i 11 : ; ;· I . I ,. ,.,, Jfi I' i1· I ,. ·1d1 ''11 I I I 11 '·1 'I '11 ·,,'ti' ,,, •·I 'I .• '·. 1·11 'I. H 1' I hi 'i,. I' . . , '.. ·,:! ;i:: ·1': :,,· !.,: ,,L \. lfi1 'ijl. 11. i; : :, liJ. i., !' i '1' 1 ·~· :: r !:'.i .!iii' i ·I, ;,1'1 di!':-: ! : J. --~ ·-·· ...... r l .,;.i IT r·'T t;I, '1' .. ~ ·-" ,..,f I -- .J, ..• f "'tr i, .. ,.,~ .'.: .,· ' .I ·•: ·-l'•,. ,:,' .,ll!j .. '·ji' . jll ·1·1 ,'.. ,,., 11•· 11i1 I !It .,.,, . ;. 1·:1 i•I' I•· I q ' '.' .,,i ,., ~ 11:, ,: .• 'I · . I : ,, .•: :··• 111,' I !1 'I ,I 11'. : I j·,, :. ·I ··' I. ,. I.;,: I I!, : ', ' I I ·. ' ..c. •.••..•. •. . ' I ,. '·1 ·' ·1 .• , l'I' .. , ..... ,, .. ,,,. "t 11, I ...•• I : ' ; ! -1 190 IKoA: 31. tz-:e9 "~ 1,s1 '..'.: :·•,: !I p :: : : : ,:•' i;: . · :, ; : · : •', :,,, ;,•, ' ;ij-~ 1 1 !l::i .·;, '"' t1. ·; ,j' J\fj,;,i! i'.·,: :IT· ,:;:c.; ;/ililJ i,~Iii~! i "1·nni!Ml;:;i '.~, :~; .'.,;; li~ :; :rT;' (ri:rri 1W}:Ll ·,;f1 J"' . I: i,· :' :y 1'1:~P.- r;;, ,,...,fh,,. ' ,rm, I I! ' : ,·~· ,·, . Ii Iri I I! ,,· r.' I. I 1 1 I,,, I .I ; I I . • i I '• ii ,; .. , ••I• I 11 ii I I ii I 1, I, . I'·' I ' ! , I I· ' '. JI I ; 1'. • , ::1 • ,~ I ., ; k: I,!;··~ ~l 1on :•:',· :n i,I~ [!'11 Ii . ti ;i'1· ; r1 fl 11;1 I ti •1i ;· :iir v· .... - I \ 0 ·:·• . ' ' . , /... ~,; Jji :i11 ·. !i. :!,i I II~,,, ii L !ii . i . r ll . : i1: . i --1; I :J , :.. :., 11 ;,· ,h .:•I,,! I I I '! ·, .. I• • , I! !I, 1 ·U I::• - · ! I: , 0 ... r,s .. -- - !t :11 I I ·1 w,·,11 i f j ' IJ j j, r1 ; ·ml :·;- .. . i ' i~ :: ~ m, HO "' ... : ' t.t: ::1·11 w I I •1' ,· 'I : 1,· l '! :, : : :., : ,' I u 11 •• 'I I:,11'~~11· I. ' I ' . , ,, .... " .. i ' :,! !ii .1.:: i! I II I ' ' I Ii l ii ! l~I . 1. ; ; I .. ~~ .. ,; ';;.'~7'lmt ' I : i II I I TT (j:P :- ... '! (8) t \. ii Jl; ~ iillij; I~, ' i ! I ! !!1, 11 ~~I 1~; ~: ! 1 ~,. J.:11 :q1· I I,,, I ', ' 1· I '1~' ii,, 111,11 , !'!i .i:·. >I !, 11 '1r :11 11 1 '"" """ "" """" ...... I '· , : , .i ; · :; , .:,., ,, ·.· !, • , l , JI, ·'·I, tr' .;1; . ·:.·•1::: - ·-· ·;:: 7T-" ·1 I ,, . d,• :~r it;;·: •. ··+ ··1 .. , !•, ,, II I .1, I :1 ' ' ' ' .•. i '•j!;: ,; J; I I I•'· i i';I '• ' I : J. ·· . tfii :111,@n · ·:111 illi Iii' ill; ,;i; t L_i •1 ou 31,00 3. oo z oo 2~00 2 oo I oo ! 1 oo 1~00 1 no 11nn , no .nn ~n,,

- llll) 2 ' Ill 21, 60

0 / •O

20 203 101 12! 1•2 161 11• 253 21, I ..... 180 129 1•0 180 290 220 lU ·'lee 0 let 2•0 uo ox0 ee 0 HO ,o

48

lt (8} 2'2 JU ,se •1, 4H • ?llO ?20 J•ll 340 ?to •(.10 •29 HO •O •~o

..... -00 NMR 170889. NOT 38731-102 IN COCL3 S14 1/14/91 OZ300 AlltNt "•••••"'' J II ,--Jv·-0 0 -0 ;< (9)

...... NMR171235.NDT 38731-102 IN CDCL3/0?.0 116 1/16/91 0[300 ,Jv·-0 0 0 1/ (9)

N 0 NMRl54614.NOT 37112-40 IN COCL3 $21 8/21/90 0[3(10

OH -0 ---­ ,--!vs ~ u

0 0 X (9)

I I I I I l 200. 150. 100. 50. 0 PPM

...... N NMfl154Gl~.NDT 31112·-40 TN COCL3 $21 8/21/90 Q[300

(9)

-,--.-...-...-...-,---r--r~---.---.---.---..---..- .,. I I I I I I ' 200. 1!JO. !,O. 0.

N N ' I ' --,-,.-,---1 · .. 1 - il1 d I 1 ; 11• I 1 ·1111-' ,ti1·1 ,. 11 • ·' I',. ' ·1 ' ' I >r1•1!· I I, 1 1 I' ,I,, ' I• ' . I I l I i I ' :: . I. I I ' '[i' I ' 7-25-89 CCL~ 3~907·1 78 CHE!-12~ II "'0 I ' I I I ,, . I I ,' I ·, 0 r ,Jv·-0 "' :1 .., u fo . i 01/0 (9) 1-- IO ... I . i !, i i. I ' I 0r, : I I I ! I ! I I

I I

- I 7 ,Jv·-0 0 0 )< (9) 2 !5

"'t'•'t

~L ...... ,...... ,...... ii ii ii I ~~ =o ~w ~o

...... NMR157692 38731-16 i~DT 9/19/90 CDC 3 $18 02300 ,UIHNII Ve, tied I 10

( 11)

-N Vt NMR157994.MDT 38731-16 IN CDC 3/020 $20 9/20/90 OE300 ,,. ... Y•••••"'' J 11

( 11 )

;='.=. .=. .=. :;::, :;::, :;::, :;::, ;::, :;::, :;::, :;::., ...:, :;::, r;:, ~,:;::, :;:::, :;::, ,=, :;::, ::;:, :::;:::, ::;:, ::;:, ::;:, ::;:, :::;:, ::;:, ::.,., l~tl,1 ...-' -. T , .. r .~-,:::::-,~-,=.,::;:.~,::,., ~. :..:;:,::;:, :::;:, ::;:, ~. :-1,:, 10.0 9.0 8.0 7.0 6.0 ~p~ 4.0 3.0 2.0 1.0 0.0

...... NMn158009.NDT 38131-104 JN CDCL3 120 ~/20/90 or :i 11 (l '"•N, "'"••1•1111 ,, II

( 11 )

. I • , I • • I • 1 ?.00. 150. 1 •ju. •) PPM NMl'l158010.N01 38/31-104 IN COCL3 i20 9/20/90 OE.100 .... .,. y,.,. '""' ' ,.

.l ! II .. I I

( 11)

,--,- ,·- I .. , I I I 1 ?.00. 150 100 ~b 0. l'r>M

...... N 00 ! .. ,·:ri -- . 1- ,_ ,,, . i'•:' 1 . •I .r;: r·,r' T'" 1 :1 ,' ,· ' '! . I I . ; I • I ·I I I,, .I ;,- i ,::j i • . : ~ : . . I . I ·: I. :1. 9·22·90 flLH ;8731·16 CHE-~16; a, ' I OI

IO a,

"',.. 'i"' «o :: IO I: "'er,-.z ~,. . i ( 11) N .. "'•

;;;

u,,m~·-,11--J... lu_o __ 3"T~-oo--'l.-.ii_u_o_2-,,l-o-o--26r-o-o--,u+-io-o--, .... ~,-,11-,•.,..,1_111-.-. -, .....:,-,,-, -,~u,-11-, --u-Ut-,-t.i•LJ· ·,i,11,

,..... 268 •E•9'5 IH-

89 271 .-2 ,lv;-00 ,o 48 0 0 197 -I X I 2~'5 28-

( 11) 1~8 I •01 541 I. . I i l 8 I I I T I :: 198 280 388 •88 see

...... w 0 NMR 1803n. NOT 38731-146 [N CDCL3 S22 3/22/91 OE300 A#'f141Ye•-.lu1fl It

0 ~~-0 0 -0 )<

( 12)

I' I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ' 'I ' ' ' ' I 10. 0 9. 0 8. 0 7 . Cl 6. Cl ~f'J~ 4. 0 3. Cl 2. Cl 1 . Cl O. Cl

-.... NMR180512.IIIDT 38731-146 IN CDCLJ/020 S22

3/25/91 I/ OF. 30 0 .,,,.... v., ...... J ••

0 I /~-0 ~ '-/0 0 0 1/ v ( 12) -

~

I I I I ~JL_. ___ I I I I I I I I I I I ~I I I I ' ' ' I I ' ' ' I ' I ' I ' ' I ' ' ' I ' ' ' ' I ' ' ---~I ' ' ' I 10. 0 9. Cl 8. 0 7. Cl 6. Cl ~p ~ 4. 0 3. Cl 2. Cl 1. 0 0. 0 - NM112~',r:2s NOT 417!.I 7-1(' 1 IN CDCL3 fr,, 317/82 QF:3'Jr.

0 ~~-0 0 -0 1/

( 12)

...--~---.,---~~--r--.--~-.--,---,---,-'----r--.--~-.--.---.---,,--~-7 2 r,r, 1sr, . 111 ,, . () PPM

..... NMfli:'c'<,1,;11, NOT 417!,7-lGl IN cn\.,L3 ,,, ,l /7 /;;,' ()[.jt,f, ._,.,Nt 'I•• I• ,.1 .f If

0 I/i-0 r-:...... ,, 0 . .. ., ''.. 0 0 X ( 12)

,. ... ,' ' .. r .,. - ' - •r••. ·1• •-·, . I ,- - I I ..,. ·1•· ;,,1,r, 1'., ~ J 1111 1 ~; 'J . f' I'M I ·.-r. ... 1 ., r I I I i 'i I I I ' ' I • n ~-13·9( FILM ~~731·10? lHE l1~ ll 0 "'

~~-0 ,..·\I O I' 0 -0 ; ·· 1/ i I

( 12) N ,., i

,u

.., '1tH1H

...... 304 • E+86 100

80

0

60 ,-:ZA-0.,.. 0 0 0 3 /, 40 li4 2 I 1~2 286 7 I ( 12) 20 147 ml 191

0 I 188 2a11 309 499 :see 600

...... NMR 177 19 7 . ND T I • 38731-1448 INC CL3 $1 3/1/91 OE300 AIIINMI V1•1IR111f I II

( 13) 1 1 1 1 11 TI, '•~:r·..· ;,.i_·r.. :.:._: ·,:·r~1; ·!~:l;!.·:~ [::: ';: ;:, !nl: ".Ii ,,,;: ',µ,!l '1'11 111111111 'Ill! !lli, :111 (, ::.': ::.:: , r:::1,· 11 I, ' ' '. I '·'' .. I I ' I I ·1 ! 'II I!' l ' ., ''' . 1 ·n· ·: . ·: ''.'" ;; ;'.]i Ii '1 ;:j ' : .. j '., .. 1~I l li :i:1 , ·1 I,' , I ::1; p'• , . 1 .!)· -: r·. . :ii :i:: I ::;i :! :jl! 'i!I ,iii ill 'i u· I I i11i di, j;i1 ii:! !jl: ,!!: 1:, : .. :ii· ; :· -.• ':: 'i:_. i:; ;·rt"[ ·r I ;•,hl >1 1,1111: I 111' 11 1 I 1,11r ill"' n\! :1~111·',I !,111 i['ii ::· 1 ,· · ,~ · '/, ~' F.,\~ 3 ~?: :;~~ !~:, rtu 1d; I 1 ·, , .I I :::: :!; 1· :i: :·;·,, :,ii :.i: !!1 ; .:.; . ..; b ...... IT,, __ -,~ ,- .,, -1.l ~ti• l I: . . ... i-J. -· •• , f I I' I:1 ' . 'i· ' --~ : ., n; . krt.. ;I I''·'·! 11, ! ,,~ i I, I1 I :'1 ~T :i:i \: ;ii',!:'.'! ii' I 1 · 1•. , : .. \·f· n , :i: ·:: ::; 11:: 1·H1 di:, 1 , l . ,·1, , ! : 11: ;;;, , ; •. :· 1;., :: . 0 1 I~·· :,i.,.. O• ... -- - ... -,. . --!·... i-- -;· .. ,.. -..• ! :,;,., :I I1 •,::, 1•1 ~',II .,' :111, I·~.I , :••,,,. ' - ... } "'. 111•: • 1·.,! 1. :: .,,, I v·: I ,.: . .·. ·'. ".; ,I j•. I ; ',.:, ·. IL~ I ., ; ; • I .... Ii ! ' ; ; I I ~ :-0 I. l:r. ' .. i ... .,., . .· .. C:. -· :L:.l:11• ·:; . ; :I. .: j . ~ 0 I ..i,I . ; ,' ·. \!/. ,. . i .1 I, .... !,. i"! I • '.; , I 1.1 j 0 I .. :.:!ll ' i I -1, I •. ·l·;'. L ',. ,,: ,N I I I i I 1: t-- '. I . f I . .': I • : ; I ! : '. j ~ li :i' I I • I I 1/ i~ ! I · 1 i: I 1:> i! . '' I ': ':; :· I ! I I i •. I ' .I ; ~ I ' ' ; Ii i '' : I i I :II) I I: ,; . I.'• ·, ,!i; I i I ( 13) d, 0 ' I· ; I· ;_ .. · · i;·:I -: ,. : . , I• , - , • • , . • ;I·,.: ·, . . . . , 1·· ·, ii ·1 I I 'I ··11 · ,;: .:·, :''1' ij ·,: 1'1 ::: : ; . !111 ! I j: . :I' ... · ,." ',1•1':!t I 1' :It !•.1 I I 1 , · ,J; : . :- . , - ;., :r .;,: ri 11 i::; iW ,r, :i:1 11,i ., •.•~! 1 1 1 :t ::: : :1·;· . I . ';H ;;:I :i11,'ll 11l1; /11r I dii iil1 iill ,:;: . :•:· lj -I \1;;;;1 :'1.., I a, •a,·'1:. If,- --'---l•-'-L...i..:.µ....:..&...i..l.4-''1J.L.J-'-4'-'.LllU~ Iii, 1hi,!l \UIKI Jl,UO 3t00 ,!1100 2~UO 2· 00 I 00 ILOU ,~uu I lllll llK.111 llllll '·''" ,,

w 00 3•4 •E•06 100

0 eo

69 0«~-0

1/ ~o ( 13) ~ .. I 2'5i I 2 e I:~ ~•H I

191 3~6 I

• 180 2811 386 •90 ~ee 600 NMR170727.NDT 38131-105 IN CD

( 14)

r 10. 0

- I I : I ; I : . , , 'I ' .. I ' ; . ; I. ' .. ,,j, ,... 1,:.1··•.•1·" 1 ·· I I ' '!II ""I·':. . I '. 'I I I • I. ; .. :, .: ... ,, ,:· •''I"''!' ':ii • I ' . ,· I ,.'1 ·· 1 : 1· I : i I ·, . : ' I' . : .Ii,!· . i: i I : • ' • I '' Ii' . I,;,1 1 1 ' , . : ' · ; . I , 11 · I 1 ~0-2•1-

·\ I ,.:.-1 1·-+-- ·,1· ;_! .1. : 1T. I . \ .r ' .J I I ; .•.,. ,,'· ~ ' I i:iv.~• i I I ' ; l;I ! . . ' .! ir •· I ' , ..•·'

I Ii i ( 14) 1 1 I i'I !~ !1I •,:·I I !I I

I I • I . ' I ' I i ' I i I ···, -~--• ,, 1 I ·l'·•'J ,1 · 1111111 .11,nn 3~110rio----;··~·•:'1· z IOO _;_J[__:""t}...i•2'100 I I . ' -•I' ;:I,•, ' •'i' I. z 00 I no I :uL I in; ,tm'. ''''"i--1 --.1.~ tl)() 162 • E+85 108

t-3

80 0 197 272 I ,;Z/-0 68 2 145 0 O o I 163 ~ 181 48 X 1!01.... 255

( 14) 1:9 289 28

221 t11,_ ,, I Jul.i II I I e I "l r l : 188 289 388 401 588 689 789 NMR 1594Ei'f. NOT 38731-28-7 IN CL 3 S3 10/4/90 02300 ...... v•• , ...... I ,.

I

( 1 5)

, , , , , , ' , , , , , , , , , , , , , . ' , , , 'o' o ,d.'o' I '9'_0' I '8'.o'' /o'' 's'.o' ~~~ 4.0 3.0 2.0 1.0 .

...... NM~l59!180.NDr 38/31-27-7 IN :OCL3/020 $8 I0/8/!'.I() OF: 3 OO _.,,.... Y•• ,t ,11f l II

( 15)

I I ' I I I ' ' I I I I I ' 10.0 9.0 8.0 NMR160932.NDT CDCL3 116 3 8 7 3 1-2 8-7 IN I011119o OE 300 , ••,,.... 1/f•tllllflf J '

( 15)

-.-.2Ao•~o-. I I

- NMR160933.ND1 38731-28· f IN CDCL3 $16 10/17/90 Of 3 00 A•"tMllt V•• .1 ... ,,,, , II

OH 0-0. ; ;-II /

.I

( 15)

1 ·-· I I I I I ' I I I I I l 150. rrt.1 100. 50. 0

...... 311 • E+06 109

88 0 OH ;-Q 3 ,o

2 •O 32$

( 15) 20 2'J2 I 329 351

0 109 280 399 489 588 600

..... NMR207353. NOT I 38731-196B INC CL3 $8 11/8/91 02300 AINMlfl we,•l•d I. II

( 16)

r•-1 I ··r' ,.,.,I,-,-·,,-,-,~-,,-, I, . .,., •.,-,--r-r-,-r,· 1-r-·1-,-,-,_,.-,.-, ...... T"'T"l~'-1· 10.0 9.o e.o 1.0 u.o ,1~~ 4.o 3.0 2.0 1.0 o.o

- R207801.NOT NM IN 38731-1968 ~DCL3 $12 11/12/91 QEJOO ...... "••..f•"' •.••

( 16)

150.

..... NMR207802.NOT 38731-1968 IN COCL3 $12 11/12/91 QF:H,l! ' ..,..,,, .... , ., .. ,-

( 16)

r----r---,· --·,- .-.,-·-· .. -,--.--• .... -•-....-,--·, ...... -I -·1- .. -1-•-·r--,-••1·--,---~ :-inn. 1r,n. 1011. ,·,o. 0 l'l'M

,..... Vl 0 li6 •C•tl5 I ,:,,:i -~ 0 ,[/-0 ::o CH3 O 0 "!(t I~.~ 1/, I

.:i'I ( 16) 2S~ -;:

::(,- H•I '~,; ~69 "~1~.,m e, j I •~~ .n 211 l _I;-__ o J,!1~,A. l, .Jl, .h.~~ d~,...J,.1.....,.._J . ¥ . . . . ,_....-...... - ...... ,,_~,"T~-,--~~~------0 I ii•) ~l)j 300 .,1;,1 MO

...... NMR184499.NDT 38731-1728 IN CL3 $25 4/25/91 QZ300

( 17)

~ I I I I I r-r,.....-r.....-r• r'""""'"'""r-r-rr•,··1·•1··r- ,·,-r .-,-,.,-,-,-I I I I ,-,.., .. ,. 10. 0 9. 0 8. 0 7. 0 fi. 0 ,~,,~~ 4. 0 :1. 0 ;>. O 1 . o O. O i '

...111

u ' "'Zo ~"'.. ( 17) I I N I I 0 10 !

I I I

...... ______~•E•96 - 315 315 180

0 OH ;-Q IJ8 271 I 3 OH 60

162 191) 288 •9 I I 2 332 ( 17) 296 I •91 20 I

418 'i~~ I 9 189 289 399 489 588 609

- NMR171414.NDT 38731-86C IN CD L3 $17 1/17/91 Ci[JOO A"""" v~r,1,,,., ,1 11

( 18) /

r1-.-,-...,.-,-r--rr-r..--,-,------..... -,--.--...... -rr-r I I f I I I --r-,--,-r,-r--rr-.--r-r-r,..., I f I I .-....-,- 10. 0 9.0 8.0 1.0 (i,0 p~~ -1.0 3.0 2.0 1.0 0.0

- NMR175453 NOT 3 8 7 3 1--1301\ IN CDCL3 115 2/ 17 /91 lEJOO All,_.. v.,,,,.,., J 1t

'

( 18) :,

l ,J ...... I ., ". i hJ <• JI cl 'I I \\ r I. n' .. , ,.,, ,•, ... --•~-~-,'.-,, "" T"''" I., J J I. 200. 150. 1{J IJ. ')·' pj>r,,t so.

- NMR175454.\JJT 38131-13(,A IN C~CL3 $15 2/17/91 1E 300 I~ V•• 11•""' I fl

( 18)

--,,--,----,---.---,...---.---.---,-..-----,---,----,--,-~---.--.-'-..-----T-" ., . ·-~ -,- - ..,..- . 7 2 C, (, . 1 SC,. 0;'~ 10C.. !:,<,. C,

...... ,. 11·19-90 rllH 3~731·~~0 lHf.-222 ;:,- ,,.,,~-·- ·-.. .. ---..-~ ./ ,_; '" ,, ,.

L, u.., ( \ \ 0 7:. OH

600 - ---,-..------216 •E•05 108

S(I 0 OH ;-0 1?9 €(1 1 OH

162 343 4(.'I I

( 18) ICII I ;?I)

~~I) I

•88 688 800 •

..... NMR184504.NDT 38731-1768 INC CL3 S25 4/25/91 OZ300

( 19) ---

°'0 NMR205797.NDT 38731-1768 IN C~CL3 $26 I 0/Q8/9 1 OE300 AfllfMllt Ve•s.l•1"'t J 10

( 19)

..... - NMR205798.NOT 38731-1768 IN r.OCL3 S~6 10/28/91 l)[ J ,rn - .. v., ...... J ,.

OH

0 0 OH X ( 19)

r-·-···, I f ' I I • I I • I I 1 I I 1····-r-·--~- I ?UII. l!iO. 100. 'iO. rJ. l'l'M I' 1· --11:•: I" 1 I,I ::! '' I"'• I! ,.:•11 ••"I I I ! 1. :: ·: 1 I , , ;·1 ·; '.,. 1:'i! :!1; l'1lr 111 11 l ::rr ;i:' iii: (ii. I I I I t ~ % :i '< : ' I . I : i; i! _ . I:;. i I '1 ·,; ;',·I.: ,t:11 :,:,ii i ,!I ,:lj! I;. i I I ' I ' ::,, II' ,:,· I· 11 'II 1:,, ' I --1::: I: :1 .. I I I I '' ' ,,I l'J :!'. ::, I I ,.,,I.' I' , i'., ! I ,t, ! . . ! I !: · ~ Ir,: ~: ;: Ii I ! I I'.! :I·: i;p . ir !:! . -- ! .. I ;i; 1 : I I ' ' I ; 'ii'·:: ii '!I I I I I ·, ,, :,, '1'11 '"'' 1·1, ·, ' ,. I I . . I • J ~- ··:, : •' I • ; I :·, . •' : I ,,,. I I,· "'I"''' .1 ,MIU•,,.,, r, ~ -:pt: .,I•' I~•:· 11 1Jj •' ! . '" ' I ! ! ; I '1 JI 1 ·1 · i,:'.:1!';::,;1;'/· I I : : I ' ~ - I I • : : . ' • I ! : ti I . : ' ,; I , i -·l . I .. : .,I I iVI I LI i ·, I iI i 'J I I t"·- I I ! ; I· 'I::, I !II ' ' ' r ',1 I i I I I I I I , ·' I ~ -I ' ' I 7- i ·I ~·U . i , ·.. .r . ~. I : .,1' , i I i I ' j : f I ' I ; ~ : I . I .. I ' iI I I • • . ' ~ I;,:;, .•. _: ii:•.·. I 'i; ·•1:: ; ·1· ' '1 · . I ! I ,_, ' : ii,' .:·• I • ,,,I I I • : I ' I . ' I ~ ' I I I ' I ( 19) ,.. I ·11 ! i.. .· i::I ,:l··i ,!:;;);i:: :i::: :I!:, .. ;.. ,... :ii! I . •• r lo' . . .!! 1! .• q:; !·I,'.: L , ,: . I "' i! .. : ,: ·1 'l::,,,1t·· __ , .,,,',I. ··t··• .... " :,·,·. 1· '' , ·, • 1, , .. , • ,,, ,;n ti'I Ii \11; ,! !!q : ·1 · ·1 , I ' I .. ', . ,: ·r ;i ·: ·11 , ·:·., 11,···'·'. :,' !. , I , '. , :,n j -1 I :: · : ':,j: :j!j j, 1' 1[.I ,: • I- '~Hi:• I I ,,, -l---'--1---'-'-+--'---f-=--~:-'--::+:-~-t-~-'- ~· ,.,,.· -,--'...,__+-.::'."'.J....a.• '-t-_._-+---'-'---4~'--'--+----'-­ .,.1111 •d ~ I ,111nn l~on zooo I mo 11mo 1~00 12nu 1c11111 unc, u;,_, ' "' " ' 162 377 •E•0G •~e I I

0 80 138 OH I 250 ~-o I 60 OH 233 I 129.,

40 ISO 271 I 288 ( 19) I

20 357 I 394 I 304 • I It I I I I I • : 389 489 509 6011 708

...... tJMR184509. NOT 3873I-I7-ln {N Cl CL:] t?'i 4/25/9 I OZ3Cl0 ...... "'••!I ...... J ,.

(20) - ,,,,,,,,.,,-~.--r~ 10.0 9.0 8.0 7.0 6.0 ~p~

...... NMH16~!:::,!J.NDT ~37~1-~7 IN CD~~~ !2G 1/4/H, ._;r--.,~ (.,!J A.1NMI Vt•''""' .I 11

(20)

--.--,- r-·• -•, ·· 1··-· .., .. • 'I"'" .., ·- -· 1 ~ .. ·• .... I • · 1• r· ··r ... t· • .. I · ·t ·· t ·, - , 1 ~. l l . 1!, 1., • I' I'M 1!J l, . :., 1., • I,

- ':,'1 ·· "r·; ii I .:!i !::: lj i~ri, ! r,, 11 r~ll 11!~ ri,r f[:: I l' 1;: !!li !!i! ii I T,· 1 I ~ I r,.

...... 329

270

401

(20)

~00 coo

...... °'00 NMR115799.NDT 34907-218'IN CDCL3 S31 9/1/89 02300 MfM "•• •I•"' J II

OSl(CH 3JJ ,-A/·-0 0 -0 /

(23)

- NMR121337.NOT 34717-258A JN CDCL3 $?1 10/?.5/89 0[300 ..... ,..,. v..,,,.,,., .J 10

(23)

I, i., I ,I J • ,, ,., I I ., ' I "\

,--....---,----,---,-...... ,...--,.--,,_.-.--....----,:--,--,- 1· --·,-·-·1-···r'"'"'f '1 ··-r I I ' 7 200. 150. 100. 50. PPM 0

...... -.I 0 N~lr! I;:> lT!P, ND I l. f U ?SP,!\ TN CDCI :l t? I 1()-';"i/}~'l (JI l(ll1

A•orrt 'Ir• ,.,,., ~ 11 ,;:::l~-o 01/0

(23)

-, --,-,--,-,--,--.- ' ' 1J(1, I I .---,----.-T;., (I I) I '.ill Pl'M ',(_I (I

--.J 2~9 •E•O~ IOO 3H

to ,J::)-0 ,-2 60- 0 0 X 40 (23) .... ,

20-

,-271 3?7 2?7 e I l ll ~ 189 298 380 4GD soe

...... NMR205709.NDT 38731-192 IN CDrLJ $25 10/26/91 02300 ,fv·-0 0 0 X (25)

,. n 4 ,, NMR?06316. NOT 38731-192 IN COCL3 $30 10/:3()/91 QF.1 () () ,,h t-Pl Y•• • ff I I'." ' ,-fv·-0 oxo

(25) I ..

•· .. 1-,-,- -- I I .... I .. I - .. I -·· I I I I I I · I I I ·1··- I ;, ()(). l!iO. 10 (). so. 0. l'l'M

...... NMR?o1:n 11. NO f 38731-192 IN rorL·: ! ,. 10/31/91 Of 3 00

(25)

I ., ·,·- ,-, -· ,·-,-•-,----, -•, I . I ,--·,--,·--, 1I; (J . ;, I J 11 . rrM 10/J. ~iU. 0

,..... 1 '! ·!··· ::1i.:1:,1,· 11'1,'iilllj1', ·11,1llll1l 1iil11J·i. : : ' ." !. I ~ I '. ' ' I ' • ' • ' ' I I

I i I I ' : .fi: ,·: j: • • · t : • · . . ,• ' I '• .. ; ti. I. ,., '., I : I ; ! :I' :' ;· ':;!; u: ·1i1 1!. !;: ,.:: i ,:j. 1. ;· I i I . I I ' . I : ' ' I ' ,. ; ;:· 1:1: I ; :I.'I' . .: '·I:,,,,·'' 1;1, I ' • I • '. I I . L,,11, I.,, ·I 1.1, l. I'. I I :: II ·I· n1"1111 ~117:1~~1,:·' ..~:~.,:':~ :i \,•1: ,,:.~••: :1 ,: ,• I •(·•·· .. ·•:,\..,...-r_ ''l/~·--·~ 'i ! '1 :•;' ·,, lT,;: : i l:, ! ir, '1/\ 'I\/;

,· . . • I I •I!· . I I · '' . ~--0 .. . : I. i I !:, : I ,, , 1 1· ::I . oxo I .: ----··,. I . ! I I'·: i I I I I j I I : I ; ' : I I ;,:, (25) I I I I • : I I i:. I ' I I j I

I j .j • : i,:, I ; : ! '. i I I!:,' ' I : ! 1 I . ,i!I . ,d,,i!, ( I I I ,, I • I . .-!..JI L: ..... I... Llil ·:,J1:i ,,111:i:, !II; LJ( L,d.; ,, .Iii· . I . I ' I ••· 11 ,,,. I ,1 .•111 ,I, let I , • 11 Ml , 1tlll I ;.•lflNI I ,1lttl 11,fHt I '1! 111 I It• I 1 • ,, ,, ,

,...... 2,9 •E•0'5 t(l•)

314 ,-Jv·-0 SC' I 0 .;u. •~·; 0 X 1,2 4(• ,n (25)

~o 14~ 2~4 240 ~< I I n1 8 I ~ J I 0 lr~ ICJO J200 309 •00 ~eo 1;60

...... J .....J I w.m 1:U'l f I. NO I ~,11:.,-R.; TN cnru in ?. I?? /Ill' OlJC'('I '"'•" V,-• I ,., .J 10 ,}v·-0 0 0 X (26)

IO. 0 9. 0 R. 0 7. 0 fi. 0 ~~~ 4. 0 :l. 0 2. 0 1 . 0 0. 0 70 NDT NMR1222 CDCL3 SI 3490"f-282A IN 11/2/89 0[300 ,, ,111...._ ...... ,., J ,)v·-0 - ' ' ' .

(26)

~ -·-.,0 ?.00, 150.

- NM~ 122271. NOT 34907-282A IN CDCL3 SI 11/2189 OE300 All,_,. I/er 1hfll J ti

(26)

,---,--,-·-,•-1-· .,.--1··-·,-·-,·-··r-· •--r---.--.--...-· -,--- I 200. 150. 100. ~O. 0. PPM

-00 0 ! I . ' . ,.1, • • I ·p :•! .. I :, I ·11··· II' I " ! ; I''''.: I I .· i~: ! I I I I I i I I I. I I 11 ·!I ·0'1 ltl ~ 3'1'l01 ·C:5lfl tMt I JI I I I I

:·-·v·;!' ~ I I '':. l,J : .' ulo ,--!v·-0 ,_.,,_ I'

0 0 111 ' ! C,.f .. I. .. . I I ;< N I I Cl I ·:.i;:. j., I "' i ·;,:: I ,1!;:'. I I.. . .. : I 1·. I (26) , ., I I' .i I iI ! : ::, I 1. I Cl +---~--.--~---.---.-----'----+----'---.------v, •000 ~ 00 ll,'JO J~OO 3 00 JOoo znoo. Z60U z•,oo Z 00 Z 00 I 00 I 00 l'iN , 5 WAVr.NUMQC~

..... 00..... ------2::::7:::0------•E+06 100·

80· ,!v·-0 r-1 60 0 0 X 40 195 I (26)

253 20 1€-2

101 145 -1~6 e i I 100 200 300 480 500 600

-00 N N,\,U I;-· :i / Jt,. NOT ;l4t (17-2!•4 IN L.01 L3 f 14 11/ 1'.:i/8 11 •!l:h,11 '"""'" y.,. I "'' • hf

0 s-Q

OH

(28)

-L- ... ..•. J ~-- L. -.... I' ' I I ' I t I ' I ' I .I .I I I r-·-1I ' I I I I I I • I lv. t, !1. c, i:I I, 1. 1. c 11 ~·r~ ;1 NMR 12390 I. NOT 4~90/-254 IN CDCL3 $15 11/16189 0[300 ~ .... Vt•·,l ,1"11 4 1t

0 s-Q

OH

(28)

..... NMf{ 121<10?. NOi , ,()0/-?~4 IN CDCL3 $ 15 11/16/8!) ()[300 .\lll~"fl >If'• . t,1nf J 10

0 s-Q

. I OH

(28)

-,-...-,-,•-~--,.~r---r--r~,---1 ·•, I ' I ' ' . ·7 ?00 1~0 rrM 100. '.JO 0

-00 Vl 0

OH

(28)

...... 2;0 296 •E+85 100

2~! 0 s-Q ~!)

OH €0

195 40 162 I (28) I 253 I 20 IOI 171

75 l ..I, 238

0 ••; "! . . I. I, ft l~~J..J lr I 100 200 300 400 500 6~0

00- -.....J NMfll'1R•,17.NOT en, l f"l ~fl12-1/HA TN 11:11:i,

(29a)

00 00 NMn1s1R5 7 .NnT 37117-1R4A IN cncL3 f10 7/30/DO OE300

0 s-Q ~

(29a)

..---.--~-...----.- - r-r-1 -, ---. ---.--,.--,- .... ~ r-· I -,-r- ~- -.-- 7 200. 150. 10). PPM 50. 0

..... MMl1151 R 5 /l. Mf") T :P 117-1R.;.A IN Cf1C 1.3 r,10 1/31)1!)1) ')[ 31) I)

,. .. ..,._ V•••I•""' J 'I)

0 s-Q ~ 0 0 ~~~1'141~Mlt.J,Jutii1JJJi11 1/ ~~~•-I • (29a)

I I I I I rrM 11) () .5 I) I)

......

'°0 I,

0 s-Q ,. I I '• '{\ ,(I . ,,\ ' I (29a)

' j I I I

1,111 1

,...... -----:~------254 -•E+05 100

341 80 '

0 311 I s-Q 237 270 60 7 I ~ 0 0 358 40 144 X I 1?!5 (29a) I 20 IOI I

.... .It.. 0 t--'----...... - -6'001-···- .. -.-.. ···-r··· ··-·-, IJ LL200 •89 800

...... N.\1"n 141~78 NIHlN :.:tlL!-11~,\ l,·1 \,·L '., t~· / 4/JI.• /:·1- ()ZJl" ll 4IM41 Ve,il•t1f 1, 11 ,):,·-0 0 -0 X (30a) NMR143325.NDT 37112-118A IN CDCL3 $15 5/16/90 QE300 ,)v·-0OAc 0 -0 )<

(30a)

,---,-.--1 1 200. 150. PPM 100. SO. 0

...... NMf1143:l?(j NDI" :1/11?-1181\ TN CDCl.3 Sl:i 5/16/90 or: 3 oo A,,iN!-fl ;/~• 1lnnf J 10

(30a)

.----.---..---r--r----r----,· -- ., .. · -, · · f I ·1 I ... I I I I ' I I ' I 2 l l ,~o. 100. PPM ~ 0. 0 253 •E•Bf. 188

8ll 3 68

29? . 2 OAc 4 237 I 28 127 165 1B3 195 217 I 279 327 353 367 405 I 1. I r I I I r I ~·-0 8 188 208 388 408 0 0 580 •E•B!- X 100 B8

3 (30a) 68

48 2

2

0 508 '88 788 888 C:,00 NMR156665.NDT 37112-29-8 IN JDCL3 $11 9/11/90 02300 AftNMft V•,1lo"I I 10

(31)

r1 I I I 1·1··1•·1 I,., J"f 1·,-r,,-•·1-,-,-,~--,-,-,-,-1-,-r,-1 1•111--r-,-,,-,,-·r-r7-r·1 10. 0 9. 0 8. 0 7. 0 6. 0 ~p~ 4. 0 3. 0 2. 0 1. 0 NMR158014.NOT 3 7 112-29-8 IN CDCL3 $20 9/21/90 OE300 Mt:t,fit V•, ~ lod J 10

(31)

I I I I I 200. 150. 100. 50. 0. PPM

-\0 00 NMR158015.NDT 37 112-29-8 IN CDCL 31 $20 9/21/90 0[300

I I

(31)

I I I I I 200. 150. 100. 50. 0 PPM - r l ·,,. - ,, I, i. I I i;, I I. 1.:' ,,: i: I I I 11,:J. ! '. 1 · .. , j I I' i l l I I i ., I' ~ : I I . I I ! I i \: 1. ! ! i ! . i i i ! I ! i . 'j ~,... 9-22-90 FILM 37112-29-B CHE-21~ ! 01

": 0 01

I/'

"'a, u l\ u U' .ti ;:I .... i: z . "'"'~ 01 (31) !!' "' " "' w'" u• UI 111 "' '".,, t---,,.-,t-Jfl--J-,~-II-Cl--,!,-Ul-l0:---.!-.'1,-n-0--2--;....0-(Ill •--l.;..IJO- •--t-...-,11-11--1-r't-111-l--1 ,.-,,-,n--,~,-,,,-,.-~,.-, 11-, ---'-r;;;--···~,

N 0 0 214 •E +07• 100- 197 I I

80-

OH 0 ~~-o 60

40 (31)

393 20 I .!JS I

163,.; e I I I I 7 ~ 100 200 _...... , de 2~0 .. 300 ....,. ... , 350 ,'. -~- · 400

N 0...... NMR158029. NOT \ 38731-12 IN CDCL3 $20 9/21/90 QZ300 MNMI Ver1l•fltf I 10

(32)

1 •••• 1 .... , ...... -, •• , , 1 • , , • 1 •• , , 1 , , , , 1 •• , , 1 , , , , 1 , , , , 1 , , , , r . 10. 0 9. 0 8. 0 7. 0 6. 0 ~p ~ 4. 0 3. 0 2. 0 1 . 0 , 0. 0

N 0 N NMR158826 I 38731 . NOT -12 IN 9/28/90 . CDCL3 $27 QE300 A."Ht41 Y•• :i I c,nl J 10

(32) L 200 150. 100. I PPM 50 0

N 0 w NMR158827.NOT 38731-12 IN CDCL3 $27 9/28/90 QE300 AANJ41 Ye•:110"1 J 10

/ •I

.I I' (32)

I I I I I 200. 150. PPM 100. 50. 0. !. . ·1 ·· r·.. I . I · i · ' 11r: I:-:I 'i : : I I I' ·1 I \i ; i I ; i I ! ID I 10-1-90 KBR 3~73,' 1-IZ, I CHE-218: i '

' ! . j I I o .., ~II' ...a: ,... r 111. G:z ,.' Ir·~,_ I I N I I I I I (32) "' I I I ! I I I I i i I I ,,, . I .I I ! i a I I I . I I I I i I I I "'""' 1111 :11,nn ,vnn lOOO ~•inn 2 no Inn lfillll 1'11111 lr'llll I~.~-~-,---,1.1111 •1 "

N 0 VI 2,11 228 • E+e6

(32)

309 400

N 0 0-, NMR157234. NOT 37112-10A IN CP< :_3 $14 9/ 14/90- QZ300 AAM411 Vu I l•d J II ---- ~

(33) I ,/ i I

I " - J ...... ~ ,l \j I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 10.0 9.o a.o ?.o s.o ~r,J ~.o 3·_,1 2·.o 1. 0 0. 0

N 0 -..J NMR157993.NDT 38731-lOA IN J .3/020 $20 9/20/90 QF.:300

(33)

N 0 00 N MR158009. NOT I 38731-104 IN CDCL3 s 0 9/20/90 QE300 AI\Nt,11 v~" loi,I 3 10

(33)

I, I I ~

r--,.---,- ·-· I I , --·-r--- ··,------r-- .. ·,--- ·r··~ I I 7 200. 150. 50. 0.

N 0 \0 NMR158010.NDT 38731-104 IN CDCL3 t20 9/20/90 QE300 AIINt-11 V•rtlo"f ,J 10

(33) I I I I

. I I 200. 1~0. Jr.:'o .

..... 0 . ·I· --T- -.- --~,II. i I :I ;iii: •. :!j. .. .- · :1:- · · . I . ~ .,··.: ··- • i'1 ! :. • I '..,J • I ..i' I I I 9-22-90 F'ILH 3e1:11-1b11 tHEJ21s

.,"'

;::

kJ ~m~ lC ~ C[ ... .. IC,­,_ . ! (33) N ; "' "' .. i f N"' i

'· I ' I i ....,too=--:1:-r:o:::o--:::3To~o=---:2±0-=o--=2~:l".o::-::o:---::2±00=---:-:,! t::o:::o:---:,too=---:-,,~i-::o:::o--:-1x:n~n=--""'.1:r.:n-..::n--x:n::-::o:---Y-.:-n,,=--:-~,

-N 269 199-

--1

89-

69

49 2e: (33) 394 I .0-

188 168 178 253 I I i I i I I I I I • 188 2811 398 •99 S09 608

N NMl"l16-t17;1 NOr 3t',7 3 I ··Hi [N CO C J .a•ri 11/ I0/C,(, ... or1ou

·• J '" / ------.----~~

(34)

.....N NMR164661.NDT 38131-46 [N C ~I 3/D2O $14 11/14/90 0[300

(34)

1. 0 0. (l

-N NMn 111 U1'1Ci NOi 3 d 13 I - 4 6 TN CDCL 3 '2 0 12112190 I CNSOO

I

(34)

~ ·1·-•· I I I I I I ' ' ' I ' I ' ' 1 200 1~0 1() () :>O 0

...... N 2:51 •£+06

s0 3 0 OH ;-0 60

2

40

20 (34) 107 231 I 124 142 268 I I 0 100 200 300 •00 500

-N NMR175124.N T 38731-128 I D L3 t13 2/14/91 QE300

0

,--(_r 'V' /~-o 0 0 -0 X (35)

I I I I I I I I I I I I I I I I I I I I I I I I I I I ..,.....,.--rr-1-,..., ...... -r ...... I ., ,.. ,.,. I ., I , .., . ,. I 10. 0 9. 0 8. 0 7. 0 fi. ,, PPM 4. ,, 2. 0 2. 0 1. 0 0 11

N I , •• ,.,. 'I,, 1·•· 11 ,, I I I I ·1:, ':' ·: I' ,t :,i ,:: I . i I ' 'I ·I ', ' 'I :': l I I ! '1 ''1· ;.ii Ii I: ri-i ·: . i . 1 1 !I 2-16-91 FIU1 38731-127 CHE~233' I ''I·., ' J I· I! 0 "' I I ' ;I i!' '':, I. 0 0 m

1 /~-0 ... ~"'-./0 "' 0 0

/ ' ' (35) I j I 0 I I ' "' ! i : I i . I-.. : .

0 +---.----,----;r--+--'--~_.._·-r,i ,-,,-----½--+---,--~---,.--,--- ~ oo 3 oo 3 oo 2 oo 2~00 2 oo .. ~ ..~? ...... 1 __ 00 1~00 1 oo I oo 00 no

N -00 304 100

so 0

~=-o0 ~o 0 -0

X 4~ (35) ·o 2 286

e 200 480 600 809 NMR106u42 NrT 34907-718 It CDCL3 S3U 5/31/89 v-- OZ3CJCJ ... --~ '••,l•n• I If

0 V ~ ~-0 ~ .,.. 0 0 0 _I 1/ _,,I (36) 1-

i---

~ " fa \..\. JI\ I, I I I I I I I I I I I I I I I I I I I I I I I I ' I I ' I I I I I I I I I I I I I I I I I ' I ' I - 10. 0 9 (I 8 c, 7. c, G. CJ ~p~ 4. (1 3 (1 2. (1 1.' (J (J ' (J

N N 0 ... •• ~ '"l '!' ,n l•I 111 1r,1 In• ••· -,,1•,,~:'.::;,'IJJJ •"'7!;,_.':.,' ,, I ...... ," ..... , ... ;···~-.:::~·I ."" ''" 0 0 r--:"...... , r:-·'''· .. ,~ ~~,, . lt,n X .. (36)

...... NMR184010 NOT 38731-182A IN COCL3 S22 4/22/91 OE3v0 An•II \1•1•.1••Af I 11

:-OH s -0~ A ~ 0 0 )<

(37)

N N N 197 •E•96 189

1~2 272 I :-~ s -0~ II 89 2'5 I ~ 3 0 0 X 68 (37) •O

14~ 164 28 r 179 198 I 27• e 188 21!8 389 •09 508 NM~184012.NOT 38731-1828 IN CDCL3 S22 4/22dil I 0[300

(38) 255 • E+ll7 189 117 I ,-1 88- 272

,-Jv·-0 '9 0 0 162 )< •e I

(38) 28· 145 I .!J8 191 IU 274 I I J I. .TI I . r I I I I ' 189 2811 398 499 508

N N VI NMR184710.l'IDT 3873 1-183 IM CDCL3 $26 4/2619 I 02300 "'"NM't V•• I,,., J 11

OH ~ 0 0 A

(39)

_.___ --~-·r·r------·-····--·--··· '·- -· .L.. _____ I.[ I I I I' ''' I I I 'I ' ' I I ' ' 'I ' I I I I I I I I I I I I I I I 10,0 !l.O i ! I 8 0 7. 0 6. 0 ~[)~ -'. fJ 'J 'I 2. fl 1 . " 0 () •·I,, ! 11 1 • , j 1::. · , •;. I ~!; ::: : Jr ;I' . ' ! i OH ''

~ i 0 0 i g ' 1/ ,_Ill I i I I i (39) I I l I I I I l I ' I I ' ':i

1

1 : . ; : I : :1· j , __ I ..i: J· ,,,,;-;"''' -:.~....~,11:.1~l1iiiin~7Jli,· ~111111 ..i,Jli-1/~-: ;,•l1111 zuuo 'f' ·l! ~- .I11,flll 1111111LL,L_ Ill II I 7~---:'

N N -.l •E•9J 11.10

88 OH

~ 60 0 0 1/ 162 •8 98 86 I 181 12~ (39) I I e• ! II 1,~ 29 07 2

9 108 i,e ' 288 2~9 399

N N 00 NMR184510.NDT 38731-181 IN CDCL3 S25 4/25/91 OZ300 ' ,ut,..... "•···' ·"' J ,.

OH ,---(' 0 -0 1/ ( 40)

I I I I I I I I I I I ' I I I I ' I I 'II' I I I I I I I I I I ' I I I I I ' I I ' I I I I I ' ' I I 10.0 9.0 8.0 7.0 6.0 ~p~ 4.0 3.0 2.0 1.0 0.0

N N I.O OH U'I 0

0 0

I I i 1/ "' I . I ~o :: UJ i . i . _, ( 40) .. ·'

N 0 "'

tt;N 2

N w 0 16:> •:•D• 11!1! ------i.r------

80 - ,(' ,. 0 0 I 126 A I

(40)

285 22• 232 I ,r

281 258 308

N w CHAPTER VII

SUMMARY

The objective of this project was to prepare pro­ sugar building blocks in a stereoselective synthesis using beta­ hydroxy sulfoxide dianions. This goal was realized with the successful preparation of 1.2-0-isopropylidene-2-(R)-3-(R,S )-

5-(R,S)-tetrahydroxy-4-phenylsulfinyl hexane (17), 1.2-0- i sopropy 1i dene-2-(R)-3-(R, S )-5-(R,S )-tetrah y drox y-4- pheny Is u] finyl-octane (18), 1,2-0-i sopropy lidene-2-(R)-3- (R,S )-5-(R,S )-tetrahydroxy-4-pheny 1s ulfiny 1-6-pheny 1 hexane

(19), and 1,2-0-isopropylidene-2-(R)-3-(R,S)-5-tetrahydroxy-

4-phenylsulfinyl-5-methyl hexane (20). Additionally, we were able to extend dianion chemistry to other structurally related compounds. However, we were unable to prepare the dianion of the beta-hydroxy sulfide (9). We also explored the chemistry of the beta-keto phenyl sulfide derivative (26) in order to investigate the reactivity of the alpha protons under strongly basic conditions. The stereochemistry at the 2-hydroxy position was assigned for the preparation of 1,2-0- i sopropy lidene-2-(R )-3-(R,S )-trihydroxy-4-pheny ls ulfeny 1 butane (9). Finally, we were unable to form an unnatural sugar using an unprotected building block (18) in the synthesis. 232 233

(Scheme 26) We attempted this synthesis only once usmg a small amount (15 mg) of 75% pure substrate. We are confident that given an adequate supply of pure substrate. further experimentation will give the desired unnatural sugar products.

Scheme 26

HQ OH

0 H (l) HO OH X t o_: o HO -:

, / (2) )( i i ( 44) 0 HO ,--0 (3) OH XO i ( 43)

HO 0 HO ~s'V XO • OH (11) (18) CHAPTER VIII

BIBLIOGRAPHY

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/'j ',, ' The / ' · submitted by __~_··_ 1·1_-,_·_,_·1 ______has been read and approved by the following committee:

Dr. Charles M. Thompson, Director Associate Professor, Chemistry Loyola University of Chicago

Dr. Duarte Mota De Freitas Associate Professor, Chemistry Loyola University of Chicago

Dr. Ken Olsen Associate Professor, Chemistry Loyola University of Chicago

The final copies have been examined by the director of the ,,:;lt and the signiture which appears below verifies the fact that any necessary changes have been incorporated and that the /~(. J,j is now given final approval by the Committee with reference to content and form. I I · The //u d iJ is, therefore 1 accepted in partial fulfillment of the requirements for .. ,., / (. thde egreeo f ·//1{J:1(•J , 1 , _;(i'.,nll

Date Director's Signature,