INFORMATION TO USERS

This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer.

The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction.

In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.

Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book.

Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order.

UMI University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600

Order Number 9411971

Synthesis of optically pure 4-aryl-2-hydroxytetronic acids: Stereogenically labile aci-reductones

Hopper, Allen Taylor, Ph.D. The Ohio State University, 1993

UMI 300N.ZeebRd. Ann Arbor, MI 48106

SYNTHESIS OF OPTICALLY PURE 4-ARYL-2-HYDR0XYTETR0NIC ACIDS: STEREOGENICALLY LABILE acf-REDUCTONES

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University

By

Allen T. Hopper, B. S.

*****

The Ohio State University 1993

Dissertation Committee: Approved by Dr. Robert W. Brueggemeier Dr. Albert H. Soloway UAmid^l^^^aaviser Dr. Dennis R. Feller College of Pharmacy Dr. Richard P. Swenson This dissertation is dedicated to my family and friends who enabled me to maintain my perspective on life, who inspired me through their own accomplishments and endeavors, and who provided encouragement, help and most importantly friendship.

n ACKNOWLEDGEMENTS

To the following, I express my gratitude and sincere appreciation for their support of this dissertation thesis

Professor and Dean Donald T Witiak, my advisor, for his patience, guidance, inspiration and never ending support

Mr Jack Fowble and Mr John Miller, for help in analyzing and interpreting NMR spectra and providing me with mass spectral data, but probably more importantly, for their friendship and encouragement

Dr Dennis R Feller and Dr Karl J Romstedt for providing the associated pharmacological studies

The faculty and staff for their help and suggestions

My colleagues and good friends Kim, Mustapha, Kristin, Soheila, Donny, Dave, Padmaja, Brock, Shabana, Knsten and Jake

Financial assistance for training grant support (NCI-2T32CA09498-06) is gratefully acknowledged

m VITA

October 18, 1965 Born - Columbus, Ohio 1987-1988 Teaching Assistant, Department of Chemistry, Bowling Green State University, Bowling Green, Ohio. 1988 B.S. Biology, Bowling Green State University, Bowling Green, Ohio. 1988-1990 Graduate Teaching Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio. 1990-1991 Research Associate, College of Pharmacy, The Ohio State University, Columbus, Ohio.

1991-1993 NIH Carcinogenesis Training Grant Fellow, The Ohio State University, Columbus, Ohio.

PRESENTATIONS Hopper, A.T.; Witiak, D.T., "Approaches to the asymmetric synthesis of 4-aryl-2-hydroxytetronic acids." presented at the 203rd American Chemical Society Meeting, San Francisco, California, April 5, 1992.

Hopper, A.T.; Witiak, D.T., "Approaches to the asymmetric synthesis of 4-aryl-2-hydroxytetronic acids." presented at the 25th annual Graduate Student Meeting in Medicinal Chemistry, Michigan University, Ann Arbor, Michigan, June 28-30, 1992.

TV Hopper, A.T.; Witiak, D.T., "Approaches to the asymmetric synthesis of 4-aryl -2-hydroxytetronic acids: aci-Reductones which stimulate IL-2-induced lymphokine activated killer (LAK) activity." Presented at the International Cancer Conference, Columbus, Ohio, September 9, 1992. Witiak, D.T.; Triozzi, P.L.; Feller, D.R.; Romstedt, K.J.; Tehim, A.K.; Hopper, A.T.; Mantri, P.M., "4-Substituted-2-hydroxytetronic acid aci-reductones improve lymphokine-activated killer cell activity in vitro." Presented at the Eighty-Fourth Annual Meeting of the American Association for Cancer Research, Abstract Number 2363, Orlando, Florida May 19-22, 1993.

CHAPTER Newman, H.A.I.; Hopper, A.T.; Witiak, D.T., In: Medicinal Chemical and Biochemical Aspects of Antilipidemic Drugs, Witiak, D.T.; Newman, H.A.I.; Feller, D.R. (Eds.); Elsevier: Amsterdam, The Netherlands, 1991, Chapter 12.

FIELD OF STUDY Major Field: Pharmacy

v TABLE OF CONTENTS

DEDICATION ii

ACKNOWLEDGEMENTS iii

VITA iv

INTRODUCTION 1

CHAPTER PAGE

I. MEDICINAL CHEMISTRY BACKGROUND 44

II. STATEMENT OF THE PROBLEM 51

III. RESULTS & DISCUSSION 54 A. THE BUTENOLIDE OXIDATION APPROACH 54 B. THE ALDOL CONDENSATION APPROACH 66

IV. EXPERIMENTAL SECTION 89

VI BIBLIOGRAPHY 145

vii INTRODUCTION

Numerous ac7-reductones possess significant biological properties Among these are L-ascorbic acid (1; Vitamin C),1 the antiscorbutic vitamin, and certain 4-aryl-2-hydroxytetromc acids which possess antilipidemic and anti-platelet activities, inhibit cyclooxygenase2 and are synergistic with IL-2-induced lymphokine activated killer (LAK) cell activity Several reviews are available which emphasize reductone chemistry wherein portions are devoted to ac7-reductones Eistert and von Euler3 first reviewed the "Chemie Und Biochemie der Reduktone und Reduktonate" in 1957 Included are individual chapters devoted to the chemistry, physical properties and syntheses of triose reductone, cyclic ac7-reductones including ascorbic acid, and the biochemistry of <3C7-reductones other than ascorbic acid Schank,4 in 1972, published a review covering the literature subsequent to the Eistert and von Euler work Schank's "Reductones" describes in detail, the structure, synthetic chemistry, analytical methods and physical properties of reductones and aci- reductones However, no comprehensive review of the chemical properties and synthetic methodology related to aci-reductones is available after 1972 except for those which only discuss the

1 2 chemistry of ascorbic acid and closely related carbohydrate relatives.56,7 Other reviews of interest discuss DNA cleaving reactions induced by reductones,89 reductone interactions with nucleotides,10 reductones in chemistry and biochemistry,11 and the development of aci-reductones as antilipidemic agents.2

HO OH 1

I. GENERAL CHARACTERISTICS AND PHYSICAL PROPERTIES OF aci-REDUCTONES Reductones are defined as molecules which possess a characteristically high reducing potential; this physical property has subsequently been attributed to the stabilized enediol moiety 2. The tautomeric forms of enediol 2, namely acyloins 3 and 4 are not considered reductones as they do not possess the characteristic redox potential of this class of compounds. Thus, reductones must contain R and R1 substituents such that tautomeric form 2 predominates, aci- Reductones, considered the most important and largest class of reductones, include those compounds which possess both a vinylogous acid functionality as found in structure 5 as well as a reducing potential. Thus, aci-reductones contain the identifying enediol moiety and a conjugated carbonyl group illustrated in structure 6. Oxidation of aci-reductone 6 provides triketo (dehydro) species 7. 3 2(5/-/)-Fura none (8) contains the vinyl ogous acid grouping and is known as tetronic acid. Tetronic acid (8) has a pKa of 3.76, while 2-hydroxytetronic acid (9) has a pKa of 4.37.12 Ascorbic acid (1), which possesses the 2-hydroxytetronic acid functionality, has pKa's of 4.2 (monoanion) and 11.5 (dianion).13 ac/-Reductones also include those molecules which contain hetero atoms capable of tautomerization similar to 2-hydroxytetronic acid (9). One example is 2-aminotetronic acid14 (10).

R R1 R R1 R R1 y^ —-^ >=< ^— y-{ HO 0 **~~ HO OH 0 OH 3 2 4

R' R' R1

HO 5 HO OH o 0

£r £?° fT HO HO OH HO NH, 8 9 10

ac/-Reductones exist as intramolecularly hydrogen bonded species such that all three oxygen atoms are on the same side of the 4 molecule Hydrogen bonding forms two five-membered rings depicted as resonance structures 6a and 6b Alternatively, enolizable /?- diketones exist as six-membered hydrogen bonded species illustrated for ethyl acetoacetate (11) Crystallography, together with lH NMR studies of ac7-reductones, provide evidence consistent with the assigned resonance structure 6a,b 4

H ;»

6b

II. acf-REDUCTONE OXIDATION <3C7-Reductones undergo oxidation to generate dehydro species 7 This process is reversible and has been observed both in vivo and in vitro Aqueous iodine solutions are utilized to oxidize ascorbic acid (1) to dehydroascorbic acid (13) on large scales 15 The 13C NMR spectrum indicates such products exist as hydrated monomers lodometnc titration may be employed for quantitative determinations Additionally, 1,4-benzoquinone16 or air and Pd/C catalyst17 oxidize ascorbic acid to dehydroascorbic acid Stirring ascorbic acid under pressurized 02 with inexpensive Norit "Extra" activated charcoal as catalyst18 yields cleaner products in shorter reaction times Recrystallization of this material from methyl ethyl ketone provides 5 small crystals of dehydroascorbic acid (m.p. 230-232°C). When dehydroascorbic acid is generated using chloranil16 as oxidant a melting point of 240-242°C is obtained. Ruiz et al19 determined that oxidation of ascorbic acid (1) on a mercury electrode in acidic medium occurs by the sequential transfer of two electrons. The resonance stabilized intermediate ascorbate radical 12 is long lived and observable in the ESR spectrum. Such species are produced using a wide variety of oxidizing radicals.13 The one-electron oxidation potential of ascorbate radical at pH 7 is 0.30 V vs the normal hydrogen electrode (NHE). Ascorbate radical exhibits a maximum at 360 nm with a molar absorptivity of 3300 M^cm"1.13 Similarly, reductic acid (19), the carbon analogue of 2-hydroxytetronic acid (9), 2-hydroxytetronic acid. 4-methyl-2-hydroxytetronic acid (20) and 2,3.4- tn'oxopyrrolidine (21) form detectable resonance stabilized radical anions.13

HO OH HO OH 0 0 19 20 21

Ascorbic acid (1) oxidation using hydrogen peroxide20 has been studied at different pHs. At all pHs ascorbic acid reduces H202 to

H20 and OH. The resultant ascorbate radical 12 reacts rapidly with OH to yield dehydroascorbic acid 13 and hydroxide anion. At pH 4 the reaction does not proceed further, and dehydroascorbic acid is isolated in high yield. At pH 7 or greater, the dehydroascorbic acid is further oxidized to L-threonate (17) and oxalate (18) via proposed intermediates 14, 15 and 16. Nucleophilic attack by peroxide affords 14. which undergoes hydration yielding 15 and carbon bond fragmentation with loss of hydroxide anion to generate labile ester 16. Hydrolysis affords L-threonate (17) and oxalate (18).

<3C7'-Reductones also undergo oxidation in dimethylformamide by

21 reaction with superoxide anion radicals (02" ) generated in situ.

Ascorbic acid (1) oxidation by 02" exhibits second order kinetics with k = 2.8 X 104 M'V1.21 The overall stoichiometry of the reaction is:

3 Ascorbic Acid (1) + 2 0, -> 3 Dehydroascorbic acid (13)

+ 2H20 + 20H" 7

Subsequently, and in the presence of excess 02" . dehydroascorbic acid

(13) reacts to yield oxalate (18), threonate (17). and 02. Thus, one molecule of ascorbic acid has the potential to consume 2.5 molecules of 02' without producing reactive intermediate radicals. *H NMR and 13C NMR analyses reveal dehydroascorbic acid (13) exists as a pentacyclic dimer 22 in non-aqueous solvents.22 This dimer equilibrates between symmetrical and asymmetrical 1,4-dioxane flip conformers of 2222 with the asymmetric conformation

1 thermodynamically more stable by 3.0 ± 0.5 kJ mol" . Addition of H20 results in dissociation of the dimer affording two equivalents of bicyclic monomer 23. Hydration of monomer 23 produces hydrated dehydroascorbic acid 24 which decomposes to numerous products.

H 8,0 °^V°^° Degradation

•>- HoH [^CO H Products H0O OH 24

Dehydroascorbic acid 13 undergoes rapid hydrolysis in the presence of hydroxide anion or H20 to form 2.3-diketogulonic acid 8 (25).2123 Following oxidation of the cumarin ac/-reductone 26 with

24 02" triketo compound 27 is isolated. Extended reaction time results in the formation of numerous degradation products. Benzopyranone 27 undergoes hydroxide-anion catalyzed benzylic acid rearrangement25-26 to form the 3-furanone 28. Subsequently, salicylate 29 is generated in a three step sequence involving decarboxylation, oxidative cleavage, and final decarboxylation. 9

Ascorbic acid (1), 4-Methyl-2-hydroxytetronic acid (20). and the acetonide of ascorbic acid 30 undergo reaction with 02~ to yield the corresponding dehydro species 13, 31 and 32, respectively.24 Carbon bond cleavage generates intermediates 16, 33 and 34 which are rapidly hydrolyzed to oxalate (18) and threonate (17). 2- hydroxypropanoic acid (35) and the acetonide derivative 36 of threonate, respectively. 10

2 ] -sr- ° " » "' » HO OH o n OH oH OB[ i R - y 13 R - y

.OH E HO HO-^ >H - » H O^OH ° V° 0 OH .OH 18 16 R = \„tOH 17 R = V„oH

1 33 R - Me 35 R - Me

34 R = \..i o 36 R -

Dehydroascorbic acid (13) also forms erythroreductone (38) under non-oxidative conditions27. Hydrolysis of dehydroascorbic acid yields 2,3-diketogulonic acid (25) and decarboxylation yields a- ketoaldehyde 37. Tautomerization of aldehyde 37 provides aci- reductone 38 stabilized in an intramolecular hydrogen bonded form. 11

HO Y«OH

OH f HO"/ -CO,

C02" HO 25 \ ,• O HO HO» ^ • H'^f^N^^OH OH OH H 38 37

III. SYNTHESES FOR aci-REDUCTONES Syntheses for 2-hydroxytetromc acids other than ascorbic acid (1) were reviewed by Haynes and Plimmer12 in 1960, and by Shank in 1972.4 Methods for the production of ascorbic acid, which have been extensively reviewed,567 may be modified for the synthesis of other 4-substituted-2-hydroxytetronic acids. 2-Hydroxytetromc acids are generally prepared using three different routes: (1) hydroxyl group insertion at the 2 position of the corresponding tetromc acid nucleus: (2) intramolecular Claisen cyclization of substituted glyoxylate esters: and (3) base-promoted cyclization of 2.4- dihydroxy-3-ketobutanoates. Schmidt and Hirsenkorn28 prepared, by 2-hydroxyl group insertion, the "top half" of chlorothncolide (39), an antibiotic which contains a spiro-fused 2-0-tetromc acid moiety. 12 To produce this system cyclohexanone 40 is condensed with the lithio dianion of /?-methoxyacrylate (41) to provide spiro tetronate 42. a-Lithiation (t-BuLi, lithium cyclohexylisopropylamide. -80°C), boron ester formation [B(0Me)3] and oxidative hydrolysis (tBuOOH, Et3N) yields chlorothricolide synthon 43.

H =n .OH

39

Me CL^Li C02Me

^f'oQMe(

42 H

C02Me ..»*' c t-BuLi , LCI A, -8 °* ; , C^"y

Witiak and Tehim29 synthesized the 5- and 6-membered spiro 2- hydroxytetronic acids illustrated for the 5-membered ring system 47. 13 Propargyl alcohol 44 is converted to methyl tetronate 45 upon treatment with sodium methoxide. Attempted hydroxylation at the 2- position by a-lithiation and reaction with dibenzoyl peroxide provides only a 6% yield of the corresponding 2-benzoyloxytetronic acid. However, the 2-hydroxyl group is introduced in good yields by lithiation using LDA. boronate ester formation [B(MeO)3] and oxidative hydrolysis (AcOH, H202). Methyl 2-hydroxytetronate (46) is converted to ac/-reductone 47 by stirring in 48£ HBr at 45°C for 12 h.

OH NaOMe, MeOH 0,Et r»- ••cp° Me 44 ° 45

LDA, -7 B(OMe) ^tft^gpc^^^ o£C AcOH, H202 MeO ~" HO 46 47

Previously, Schank and Blattner30 had synthesized spiro aci- reductone 47 from the corresponding tetronic acid 48. Thus, diazotransfer using tosylazide provides 2-diazofuranedione 49. Conversion to the 2-acetoxy-2-chloro compound 50 is carried out using pivaloyl chloride and acetic acid, and subsequent reduction (Nal.

Na2S205, H20) followed by hydrolysis yields 4,4-disubstituted-2- hydroxytetronic acid 47 via acetyloxy intermediate 51. 14

,P _ JO CICOC(CH ) A/ I Tosylazide, S\Ll 3/ 3 \jy E,3N, DMF ' \-/V^i RCO,H OH 0 48 49 O

o o 50 51 47

Ireland and Thompson31 utilize the Claisen condensation for construction of 2-hydroxytetronic acids. Geminal dimethyl ester 52 is cyclized to tetronic acid derivatives using lithium diisopropylamide as base.32 Methyl tetronate 54 is obtained when the reaction mixture containing lithiated species 53 is treated with methyl fluorosulfonate. Reaction of 2,3-dimethoxyfuranone 54 with the lithium salt of 1-n-propylsulfide in HMPA yields geminal dimethyl tetronic acid 55, whereas reaction of tetronate 54 with BBr3 provides methyl 2-hydroxytetronate 56. Conversion to 2-hydroxytetronic acid

57 is accomplished by acetylation (Ac20, Pyr) of 2-methoxytetronic acid 55 and ether cleavage using BBr3. 15

MeO, 2.2 eq • LDAL'O^X CH3OSQ2F

MeO O OMe 53 52 M HC =^X L,8.n.C.H,,, ^K> Z1-^ HMPA MeO 54 O MeO 55 O V MeO^/S-, BBr CH M 3- ?C'?. MeO O 54

HO VS 1 Ac P r *^r ° • ?°- V r /—^ 2. BBr3, CH2CI2 MeO O HO 'O 55 57

The protection strategies developed for 4,4-dimethyl-2- hydroxytetronic acid (57) are incorporated into Ireland and Thompson's convergent synthesis of chlorothricolide (39). Diels Alder adduct 59 is prepared from acylated maleic anhydride intermediate 58 and butadiene. Claisen cyclization is effected with LDA at -78°C in THF. Quenching with methyl fluorosulfonate at 0°C in HMPA provides methyl tetronate 60. Selective reduction with lithium triethylborohydride at 0°C provides alcohol 61. Hydroxyl protection

(TBDMSCl. Imd, DMF), epoxidation (MCPBA, LiC104. Et20), methyl cuprate epoxide opening, and methylation (Mel, KH) of the resultant alcohol 16 provides spiro tetronate 62. The "top half" synthon 63 is completed by silyl group deprotection (AcOH). oxidation (PCC) to the corresponding aldehyde, and reaction with vinyl magnesium bromide.

OMe °^VV Butadiene, A (wX^J .? DA. THF -78 C; MeOS0 F O ° OMe 2 58 59

1 . TBDMSCI , Imd. 2. MCPBA. LICIO«. Et O ...O a 3. Me2CuLI * W 4. Mel, KH " OMe OMe OMe OMe 60 61 1 . AcOH.H-O.THF., ^ Me\JL 550*C0 C. 2*24 h "e^V^sMeO^xk. T1.„0 2. PCC. CH2CI2 L^v TBDMSCOOU^30 3 -^NlgBr ^Y^^/^0

62 63

Moderately different protecting group strategies are required for completion of the chlorothricolide synthesis.33 Thus, the benzyloxy protected Claisen cyclization precursor 65 is prepared by Diels Alder reaction of maleic anhydride derivative 64 with butadiene, followed by methanolysis (MeOH. reflux) and esterification

(CH2N2). Intramolecular Claisen reaction with benzyloxyacetate 65 using LDA proved not to be successful owing to competing /?- elimination. However, reverse addition of lithium 17 hexamethyldisilazide (LiHMDA) at -78°C and subsequent reaction at -30°C for 5 h provides tetronate 66 after quenching with methyl fluorosulfonate Sodium methoxi de-catalyzed epimenzation provides diastereomer 67 Lithium triethylborohydnde reduction, hydroxyl group protection (TBDMSC1, Imd, DMF) and epoxidation yields intermediate oxirane 68 Preparation of the "top half" synthon 69 is completed by methyl cuprate epoxide opening, alcohol protection L7?-(tnmethylsilyl)ethoxymethyl chloride, diisopropy I ethyl amine] and benzyl group deprotection (10% Pd/C, H2)

1. Bu t ad i ene , A LiHMDA,-78 C 2. MeOH, A —*-30"c, 5h

3. CH2N2 Et20 2 MeOS02F 64 65 OBn

LiEt3BH TBDMSCI, Imd MeO MCPBA, Li CIO. OMe OBn OMe OBn 66 67

SEM'

1 . LiMe2Cu TBDMSCk^ 2 SEMCI, EtN(IPf)2rTBDMS0^,^ OMe OBn 3 H2, 10% Pd/C 68 69

Witiak and Tehim29 also prepared 5- and 6-membered spiro-2- hydroxytetromc acids using strategies developed by Ireland and Thompson 31 This method is superior to use of hydroxyl group insertion methods because fewer steps are necessary and overall yields are 18 higher. For example. Claisen cyclization of easily prepared methoxy or benzyloxy thiocarboxylate intermediates 71 and 72. respectively using LDA or LiHMDA at -78°C occurs in high yields. Methoxytetronic acid 73 undergoes deprotection by acetylation and subsequent reaction with BBr3, whereas benzyloxytetronic acid 74 is convertible to target 2-hydroxytetronic acid 47 by transfer hydrogenation.

/? A. R=Me, ^S/H nBuLi, ^V°\ LDA' -78'C l QWH. c,OCCH2OR \J\C0^^^n 70 OH 71 R = CH3 LiHMDA, -78*C H /\>k^OR A. R=Me " ? Ac p f H \J\yJ — ?°t y ; ^ /vV~° v 0 BBr3, CH2CI2,-78C V-Vo-VC 73 R - CH3 B. R=Bn ^ ^X) 74 R « Bn 10% Pd/C, QJ 47

Witiak and Tehim34 developed the first synthesis for optically pure (5)-(+)-4-phenyl-2-hydroxytetronic acid (77) using the Claisen cyclization under kinetically controlled conditions. The 2-benzyloxymethoxyacetate derivative 75 of the corresponding methyl mandelate undergoes such cyclization at -100°C using the sterically hindered non-nucleophilic base, lithium dicyclohexylamide. Subsequent benzyl group deprotection of tetronic acid 76 generates the desired compound 77 in low overall yields; 12ft for both steps. QA^OBO LIDCyA, -100 C OC0 2CH3 30%

10% Pd/C 0 40%

Stork and Rychnovsky35 developed methods for the stereocontrolled synthesis of erythronolide A (78). Their scheme relies on the construction of intermediate 2-benzyloxytetronic acids of the type 80. Thus, the protected [/-lactone 79 is converted to 2-benzyloxytetronic acid 80 by hydroxy group protection (tn'methylsilyl chloride, Imd), LiHMDS-promoted 1,2-addition of ethyl benzyloxyacetate, and subsequent deprotection and cyclization (MeOH,

K2C03). Further elaboration of tetronic acid 80 is effected by ethylidene acetal protection of the side chain hydroxyl moieties. Methyl displacement of the acidic 3-hydroxyl group is performed by phase transfer halogenation [(PhO)2P(0)Cl. Na2C03, Bu4NBr] and subsequent treatment with ZnMe2 to provide 3-methyl substituted lactone 81. Simultaneous double bond hydrogenation and benzyl group cleavage is effected using Rh/alumna catalyst. Hydroxyl group protection (Me3SiNMe2) followed by treatment of lactone 82 with the lithium anion of ethyl 2-benzyloxyacetate. and subsequent cyclization and deprotection (K2C03, MeOH) provides 2-benzyloxytetronic acid 83 containing 5 stereocenters of the absolute configuration found in erythronolide A (78).

78

O 1 . TMSCI , Imd, DMF 2 . LI HMDS, Et0 CCH OBn t¥ 0H 2 2 o-l'" THF, 50 C HO" " OH K2C03 MeOH 79 80

1 . ace t al , CSA 1 . Rh/AI2Q3, H- 2. (PhO)2P(0)CI 2 . TMSNMe, Na2C03, Bu4NBr 3. ZnMe2, Ni (AcAc)2 81

o^o 2. Li HMDS, Et02CCH2OBn o^N) OH "OTMS THF, -50 C 3. K2CQ3 , MeOH 82

D-Erythroascorbic acid (88)36 is prepared in four steps from D- glucose (84). Thus, oxidation using 02 and KOH of D-glucose (84) 21 affords D-arabinonate (85). Cyclization (H+) yields lactone 86. Vanadium pentoxide-catalyzed oxidation provides keto ester 87, which is cyclized to target ac7-reductone 88 in NaOAc/MeOH by warming to reflux.

CHO

H- -OH C02K OH HOH,C HO -H o KOH HO- -H + 2 • H H- -OH " H- -OH H- -OH H- -OH OH CH2OH CH2OH 86 84 85

C02CH3 HOH ,c^>A^o VnOe NaOAc.MeOH H- -OH H- -OH HO OH

CH2OH 88 87

A recently developed synthesis for L-ascorbic acid (1) involves electrochemical oxidation of protected glucitol 89 to form keto acid 90. Protecting group hydrolysis (0.1N HC1) and lactonization produces vitamin C (1) via deprotected intermediate 91. C02H

<> )H a I ,Ca(OH)2 HCI H- H H- -OH *> CH2OH 89 90

C02H HCI HO -H H- -OH HO -H CH2OH 91

Older methods for the production of 2-aminotetronic acids include reduction of the corresponding 2-nitro- and 2-diazotetronic

12 acids using Na amalgam or H2 and Pd/C catalyst, respectively'. Recently, Hamada et al.14 developed a method for the stereoselective synthesis of 2-amino-4-substituted-tetronic acids containing alkanyl, hydroxyalkanyl and aryl functions. These ac/-reductones are useful synthons for the preparation of 3-amino-2,3,6-trideoxyhexoses 97. Thus, coupling optically pure glyoxylic acid derivatives 92 with isocyanoacetic ester 93 using diphenyl phosphorazidate (DPPA) yields oxazole intermediates 94 without racemization. Warming oxazoles 94 in acid provides 2-aminotetronic acids 95, which are highly susceptible to oxidation, and therefore, are isolated as their corresponding tert-butyloxycarbamate (BOO derivatives 96. Stereospecific catalytic hydrogenation of these reductones provides tetrahydro-4-hydroxy-3-amino-2-furanones 97. Further manipulation provides entry into numerous optically pure compounds containing 3 or more stereocenters.

OR' C02Me / ~< + ( (Ph0) P(0)N Y_/ 2 3 -• CO.C02H NMCr NaH '=\ 92 93 94 ^0 R -pF=° BOC2O ( »-(V°

H0 NH 2 HO NHBOC 95 96 E 50 Rh/Al 2o3 „ -(} H2 HO NHRflC 97

N-Substituted-3,4-dihydroxysuccinimide aci-reductones 102 are prepared in 5 steps from malenimide 98. Thus, reaction with tosyl azide in Et3N and MeOH produces diazo compound 99. N-methylation

(CH3I. NaH). ozonolysis and reductive diazo hydrolysis [(tert-butyl alcohol, Rh(0Ac)2)] yields tert-butyloxysuccinimide 101. Acid catalyzed hydrolysis of the tert-butyl ether produces <3C7'-reductone 102. 24

l,3-Diketo-2-halocyclohexane 103 fails to undergo reaction with acyloxy anions at rt.37 Furthermore, monoketal 104 and diketal 105 are not reactive toward acyloxyanion nucleophilic displacement. Insertion of a 2-hydroxy group is accomplished by reaction of the enamine anion of 106 with diacyl peroxides. Warming 2-acyloxy derivative 107 in a solution of MeOH and H20 provides vinylogous acid 108. 25

RCO,' No Reac t i on & 103

No Reac t i on

No Reac t i on

MaH "^Y^0^*

OH OCOR H2Q, MeOH f^f

108

Schank et al.38 synthesized 2,3-dihydroxycyclohexanone reductones 111 starting with acyloxyenaminones of the type 109 by either of two methods. Thus, KOH-promoted hydrolysis of acyloxyenamine 109 provides enol 110 and this enol undergoes acid catalyzed conversion to target <3C7-reductone 111. Alternatively, acyloxyenamine 109 is convertible to vinylogous acid 108 by treating with acid. Hydrolysis of the acyloxy moiety is effected by warming in H20. 26

,OCOR KOH

NH2 OH " JL ' ^OCOR „ ' 1 JDCOR

108

Witiak et al.39 developed several methods for the preparation of 3.4-dihydroxy-l-benzopyran-2-one <3C7-reductones, compounds with antiaggregatory and antilipidemic properties. Reaction of protected 1,4-dibenzyloxy-2-methylformate 112 with the lithium anion of ethyl 2-benzyloxyacetate yields benzyloxy derivative 113. Cleavage of the benzyl moieties by transfer hydrogenation (10% Pd/C, cyclohexene) and lactonization (HC1. MeOH) yields target 2-pyranone reduc'tone 114.

Q^jOEt Li+-S0Bn

1. 10% Pd o OH 2. 10% HCI, MeOH 114

Alternatively. /?-keto esters of the type 115 are convertible to a-oxygenated intermediates 116 or 117 by reaction of the NaH-produced 27 anion with benzoyl peroxide or dibenzylperoxydicarbonate. Transfer hydrogenation, acid catalyzed lactonization and benzolyoxy cleavage

(pTsOH, EtOH/H20. reflux) results in target ac7'-reductone 118.

C 2Et " JL v ° NaH,(C6H5C02)2 H

Q or (C6HsCH2OC02)2 115 O' 116 R » C6H5 O ^^JX^p 117 R = OCA 2. H+ C$C OH 118

cis- and trans-Hexahydro-3,4-dihydroxy-2-pyranones (122) are available by reaction of the corresponding cyclohexanes 119 with the a-benzylcarbonate derivative of Mel drum's acid 120 to provide intermediate 121. Hydrolysis and cyclization (TsOH. MeOH), followed by transfer hydrogenation produces target 122.

° O 121 O 119 120

1. TsOH, MeOH 2. 10% Pd/C, jf*} H OH 122 IV. aci-REDUCTONES AS CHIRONS L-Ascorbic acid (1) and its relatives D-isoascorbic acid (123), L-isoascorbic acid (124) and D-ascorbic acid (125) are a popular source of novel chirons. Such acZ-reductones are inexpensive, readily available and convertible into chiral building blocks. Few steps are required to generate useful substances because of the high oxidation state of the starting materials. Much acZ-reductone chemistry has been advanced through synthesis of these novel building blocks.

HO OH HO OH HO OH HO OH 1 123 124 125

Recently, vitamin C was used as starting material for the preparation of patulolides A (126) and C (127)404142 and for the synthesis of the methyl ester of A K-Toxin II (128). The optically pure synthesis of these natural products relies on the conversion of L-ascorbic acid to L-methyl threonate (130) which serves as starting material in the synthesis of patulolide A (126) and C (127). "A 29 H3C n 1

Patuohde A 126 Patuolide C 127

CCLH 128

The acetonide 30 of L-ascorbic acid (1) can be oxidatively degraded using K2C03 and aqueous permanganate to provide the potassium salt of L-threonate 129. Acidification followed by treatment with

CH2N2 provides the chiral synthon L-methyl threonate (130) in 75% overall yield. Lithium aluminum hydride (LAH) reduction and epoxidation of chiron 130 under Mitsunobu conditions provides epoxide 131. Oxirane opening using 6-heptenyl cuprate followed by hydroxyl group protection (TBDPSC1, Imd) yields terminal olefin 132. Epoxidation (MCPBA), reductive (LAH) oxirane ring opening and acetylation provides optically pure protected tetraol 133 as a 1:1 mixture of diastereomers. Acetonide hydrolysis, oxidative cleavage

(NaI04) to aldehyde 134. Horner Emmons olefination (triethylphosphoniurn acetate) and saponification produces E-hydroxy acid 135. Lactonization affords macrocycle 136, and separation of 30 the C-ll isomers followed by silyl group removal produces patulolide C (127).

0 (CH3),CO, 0 K C0 , 2 3 +. "{I/O 1. HCl/MeOH CuSO, — / aq. KMnO 4 HO"f ^ 2. CH2JJ2 C02K 129

H / O HO I pph, o;"i " Cu(I)I; TBDPSO - CO,CH 3 '''.J 130 3 131 2. TBDPSC1, Imd 132

1. MCPBA 2. LAH OAc 1. AcOH TBDPSO 3. Ac-O, Pyr 2. NaI04

QAc 1. Q-P(CH2C02Et)3> *H TBDPSO H 2. NaOH TBDPSO 134

CI H3C ,*# 1. Separate C-ll CI 0 Et3N isomers -• 0 • Patulolide C 2. DMAP, Xylene, 4 V^ 'OTBDPS 2. TBAF o 136 127

Cohen and coworkers43 developed enantiospecific syntheses for leukotrienes C4. D4 and E4 wherein asymmetry is incorporated via D- araboascorbic acid (123; D-isoascorbic acid). Oxidative cleavage using alkaline hydrogen peroxide20 and subsequent acetonide formation 31 provides optically pure L-threonolactone (139) in 60-70% overall yield. The proposed mechanism involves ascorbic acid oxidation to its corresponding dehydro species. Nucleophilic attack by the peroxide anion generates intermediate 137. Subsequent attack of the C-6 hydroxyl on the C-3 carbonyl results in carbon bond fragmentation and loss of oxalate to produce dihydroxylactone 138.43 Cohen rationalized the poor conservation of carbons as minimal owing to their already high oxidation state and symmetry.

HO

0O /i0, , 0 - n 137 HO OH o"S> DMP, H+ H .A L H 60-70% 138 o' -o 139

D-Isoascorbic acid (123) is an inexpensive and readily available chiral source previously converted to lactone 139 by Weidenhagen and Wegner.44 These authors treated isoascorbic acid 123 with p-toluenediazonium bisulfate to produce hydrazine 141 likely via intermediate 140. Warming to 100°C in H20 gave 2,3-dihydroxylactone 138 which is protected as its acetonide derivative 139 in only 30% overall yield. 32

>0H HO

HO H202, H Na2C03 HO OH ^-fvo o. ™ 123 140 o"S HN. H ,.\ L H HO NH 2. -7,DMP—^—, 777+H+ H/„\ /..«H 0 (30%) 139 141

L-threonolactol 142 may be prepared on the 100 g scale by DIBAL-H reduction of the corresponding lactone. Wittig reaction using the triphenylphosphine salt of 2-methyl-1.3-dioxane 143, benzoylation of the resultant alcohol, and hydrogenation of the olefin produces optically pure 1,3-dioxane 144. Propanol ester 145 is prepared by ozonolysis of the dioxane ring. Acid catalyzed

(CF3C02H/H20) acetonide hydrolysis and cyclization produces tf-lactone 146. The secondary alcohol is converted to its corresponding chloride with inversion of configuration. Subsequent reaction with sodium methoxide produces optically active epoxide 147, which is readily converted to aldehyde 148 useful as starting material for the multi-step preparation of leukotrienes C4. D4 and E4. 33

0-

H„L_LH •H,A/l,H 2. ciCOC6H5, Pyr O^ 0

S^O S>^°H 3. H2, Pd/C 0 144 139 142 0^° 0v "i0 ,« /°H H°x ,°^f o, CF3C02H / \_/ 1- CH3S02C1 ** 0 2. CH3ONa 146

Leukotrienes C4, D4 and E4

In 1960, Perel and Dayton45 reported an improved method for the synthesis of L-threonolactone (138) using L-ascorbic acid (1) as starting material. The side chain of L-ascorbic acid (1) is protected as its acetonide 30 using the method of Micheel and Hasse46

(anhydrous CuS04, dry acetone, 95ft yield). Treatment of acetonide 30 with potassium carbonate and aqueous potassium permanganate solution47 affords potassium 3,4-0-isopropylidine-L-threonate (129). Deprotection and lactonization is effected in 65ft yield by passing an aqueous solution of the salt through a column of Amberlite IR-120 (H) resin. 0 H 0 K C0 KMn0 :0 (CH3)2CO, ""Y' V^0 2 3. | 78% CuS04, (95%) H\—r H° . 0H HO^OH i 30 0 """\ .o. n H / n Amberlyst resir^ \ f^ H0 C02K OH 129 138

Jung and Shaw48 were first to report the use of (L)-ascorbic acid (1) for the synthesis of (/?)-glycerol acetonide 154, a chiral synthon previously difficult to obtain, and used in the preparation of numerous enantiomerically pure biologically active compounds. In their first attempt, L-Ascorbic acid (1) was protected as its acetonide derivative 30 [acetone, AcCl (cat.)]. Oxidative degradation of the acetonide to the corresponding (S)-glyceraldehyde acetonide (153) using Pb(0Ac)4 or ozone only takes place in poor yields. Dimethylation (CH2N2) of the acetonide (30) generates lactone 149. Ozonolysis provides dimethyl ester 150 in 80-95& yields, but, unfortunately, ester 150 is not useful for the preparation of target glycerol 154. CH N Q(CH3)2CO 0 2 2 0 0 02CC02Me AcCl, * Et 0/MeOH*H*' Me2S7 H 80-85% 50% 80-95% C02CH3 H0 ->« OH H3CO OCH 30 149 150

CH.N-, 91% (CH,)7C0, ••••—•••••• ^-^^ ZnCl2, 34%

In a successful procedure, acetonide 30 is reduced (NaBH4) and converted to its sodium salt 152. Oxidative cleavage C(Pb(0Ac)4] in the same pot generates unstable aldehyde 153. 'This aldehyde is immediately reduced with NaBH4 to provide (/?)-glycerol acetonide 154 in 30-42% overall yield from L-ascorbic acid.

Pb(OAc) •x, NaBH„ X CO2" EtOAc 2. NaOH ^

-^ C^ vs >°-> O LiAlH4 \^OH HaI04 A J NaBH4 '\J CHO CH2OH H0 OH ,_. ,_. 153 154 155

Vekemans et. al.50 reported a new "convenient" method for the synthesis of D-glyceric acid acetonide (158) and its enantiomer from D-isoascorbic acid (123) and L-ascorbic acid (1). respectively. For the D isomer, ascorbate 123 is protected as its dimethylacetonide using the method of Chittenden,51 or as its 2-cyclohexane-l,3- dioxolane using the method of Watanabe et.al.52. R. Voeffray's53 oxalate extrusion method (H202 CaC03) is used to produce the a-hydroxy acid 157. which is converted to target D-glyceric acid 158 in 93-94^ yield through use of RuCl3. DMP, SnCl 0 H,0_, CaCO, '2W2 100%

X 0^0 °- 9 NaOCl, RuCl, (cat. ) pH - 8, 94% HO H02C C02H 158 157

Vekemans also reports use of either vitamin C (1) or isovitamin C (124; L-isoascorbic acid) for the production of chiral butenolides,54,55 as well as the preparation of three enantiomerically pure 4,5.6-trihydroxy-nor-D-leucines56 [Example shown is 4(S) .5(S) ,6-trihydroxy-nor-/Meucine (164)]. Stereospecific

57 reduction of L-ascorbic acid C10X Pd/C, 50 psi H2. 50°C) and acetonide formation produces optically pure erythro lactone 159. Reaction with 1 equivalent of mesyl chloride (MsCl) provides regioisomer 160 in good yield. Addition of a second equivalent of MsCl in pyridine generates elimination product 161. Catalytic hydrogenation of mesolate 161 yields saturated lactone 162 which undergoes SN2 displacement with sodium azide. Reduction (H2, 10£

Pd/C) of azide 163 and warming to reflux in H20 leaves hydroxylated norleucine 164. 38

V HO nw °» S> X^S^ 1 -10* pd/C , HcVS^0 1- 1 V=A 50 psi H2, 50*C VM Pyridin e H H HO OH 2.DMP. SnCI2

W° OMS °& ^VHgg° MsCI , Pyr. , y^Jk 10% Pd/C

H H HOMs 160 W 161

All-

NaN, , DMF r ~~^yPs-ss" - O 1. H-, 10% Pd/C TF \—/ 2. HzO, A 162 N3 OH NH,+ 163

XV

0H icyi 164 Optically pure butenolides 166 are available from 2.3-dihydroxybutanolide 159 using methodology developed by Hanessian.58 Reaction of vicinal diol lactone 159 with dimethoxydimethyl aminomethane and subsequent treatment with iodomethane provides tertiary amine 165. Upon warming in acetonitrile. butenolide 166 is formed. Stirring butenolide 166 in the presence of Et3N provides a mixture of C-4 isomers 166 and 167 in a ratio of 3:5, respectively. Conversion of butenolide 166 to saturated lactone 168 occurs readily using catalytic hydrogenation. 39

H H 2. Mel 1 V 159 H H 165 X 0X K V°HH H* H H H 167 H H 166 168

Most recently Vekemans described the synthesis of novel furanone chirons from vitamin C.59 The L-ascorbic acid reduction product 169 is brominated at C-2 and C-6 by the action of HBr in AcOH. Acetylation produces dibromodiacetyloxylactone 170. Stirring this lactone in acidic methanol produces dihydroxylactone 171 which may be reduced (Pd/C. H2) affording saturated 6-bromolactone 172.

Epoxylactone 173 is prepared by treating bromolactone 172 with Ag20 in

H20 at 0°C. Alternatively, dibromodiacetyloxylactone 170 may be converted to the a..^-unsaturated lactone 174 using an alcohol solution of sodium bisulfite and sodium sulfite. 40

HQ OH Br» JOAc

nfefHOY&ljyg50" 1, HBr-AcOH *o0i_f MeOH, H* IPH 2- Ac*°' Pyr iPer 169 170

B \ *PH

H Br 172 171 17Z 173

Br Br. OAc x jOAc

0 0 A^VV NaHSQ3, Na.SO^ ^^V^

]—[ MeOH:H20 (9:1) /\ H H Br mH 170

Poss and Smyth60 report total syntheses for D-mycinose (178) and L-talonic lactone (182) using D-isoascorbic acid (123) and L- ascorbic acid (1), respectively, as starting materials. For the preparation of either compound, the key step involves conversion of an enediol moiety to the corresponding diol via a 5-hydroxyl group- directed catalytic hydrogenation. Thus, for D-mycinose (178) D- isoascorbic acid (123) is converted to its 6-bromo derivative 175 (HBr. AcOH. 22°C, 992) by the method of Ashery and Kilany.61

Methylation (CH2N2. MeOH. 22°C. 962) of the 2 and 3 hydroxyl groups

followed by reductive cleavage (MeOH. 5% Pd-C. 2eq. Et3N. 25 psi H2, 41 24 hr, 79$) of the bromide62 generates 6-deoxy-2,3-dimethyoxy ascorbic acid (176). 5-Hydroxyl group-directed hydrogenation (1800 psi) of the double bond using Rh(Diphos-4)(NBD)BF4 as catalyst produces a single compound 177 by beta addition of hydrogen. When Pd/C is used as catalyst a single isomer is produced by alpha addition of hydrogen.

.OH :0 1. CH2N2, MeOH HBr, AcOR H \ —/ 22°C, 96% 24h, 99% 2. 5% Pd/C HO OH 125 psi H2, OCH3 OCH3 123 Et3N 176

Rh(Diphos-4)(NBD)BF 4 ^f >0 HO 0.2 eg), CH2C12 V ^° OH H CH H2 (1800 psi) ) ( OCH3 ° 3 OCH OCH3 3 178 177

Similar strategy is employed for the synthesis of L-talonic lactone (182)63 from L-ascorbic acid (1). Acetonide protected derivative 179 does not undergo asymmetric hydrogenation as in the synthesis of D-mycinose (178) owing to the absence of a 5-hydroxyl moiety. 2.3-Dihydroxy protection of acetonide 30 is as its annelated

+ 1.4-benzodioxane derivative 179. Benzyl oxymethylation (H ; ClCH20Bn) affords 5-hydroxy intermediate 180. Hydrogenation using Rh(DIphos-

4)(NBD)BF4 catalyst results in ^-addition of hydrogen to yield lactone 181 in 90$ yield. Deprotection by hydrogenation over Pearlman's catalyst provides L-talonic lactone 182.

1. H+, MeOH, 99%, 2. ClCH,OBn, CH2C12 , iPr2NEt o\ / 180 HO O HO H (1950 psi) 2 H,, Pearlman's Rh(DIphos-4)(NBD)BF4 _2 . • 0.2 eq in CH2C12, 90% cat, 1 atra

Abushanab and co-workers also devised strategies to convert L- ascorbic (1) and D-isoascorbic (123) acids into useful chiral synthons including l,2-0-isopropylidene-1.2(/?),4-butanetriol

(186) 64.65.66.67 [_./\scorbic acid (1) acetonide is oxidatively degradated using the procedure of Micheel and Hasse.46 Methylation and LAH reduction yields starting protected tetraol 183. Additionally, various protection and deprotection strategies allow for the stereoselective synthesis of each of the four possible stereoisomers of 183. Epoxidation of intermediate 183 under Mitsonobu conditions provides oxirane 184 and deoxygenation using triphenylphosphine leaves olefin 185. Hydroboration (9-BBN) of 43 optically pure butene 185 and oxidative hydrolysis (30$ H202) provides optically pure protected butanetriol 186. Recently, Yamagata et al.68 utilized such optically pure chirons for the synthesis of long chain a-hydroxy acids.

PPh. y^ljDH PPha, DEAD, ^L^

184 183 S)H

I 30% H 0 L : 2 2 ^ I 2 2 186 ^X>H 185

In summary, L-ascorbic acid (1) and its relatives D-isoascorbic acid (123), D-ascorbic acid (125) and L-isoascorbic acid (124) are readily convertible into numerous chirons including L-methyl threonate (120), L-threonolactone (138), (/?)-glycerol acetonide (154), and (S)-glyceric acid (158), as well as numerous optically pure functionalized lactones, polyolbutanes and epoxides. These chirons of known absolute configuration have been successfully manipulated to construct leukotrienes. patulolides A and C. long chain a-hydroxy acids, ^-lactam antibiotics.69 D-mycinose (178) and L-talonic lactone (182). CHAPTER I

MEDICINAL CHEMISTRY BACKGROUND

In the early 1980's Witiak et al70. developed a novel concept in drug design wherein carboxylic acid functionalities in drugs were mimicked by the 2-hydroxytetronic acid moiety. An early known analogue, which was initially prepared by Dahn,71,72,73,74 was proposed as a mimic for clofibric acid (187), the active antilipidemic metabolite of clofibrate. Generally, Carboxylic Acid Mimic ac7-Reductone analogues, abbreviated, CAM-R analogues have pka's near 5, similar to that of clofibric acid (pka 4.7),7075 and numerous other carboxylic acid containing drugs, metabolites and antimetabolites. Additionally, 2-hydroxytetronic acid-derived compounds possess a range of biologically relevant redox potentials

(E: = 0.112- 0.157 at pH 7.4), similar the redox potential of L- 39 ascorbic acid (1) (Ex = 0.162 V at pH 7.4). . This drug design concept has been extended to the construction of compounds which mimic carboxylic acid containing metabolites of enzymes possessing redox cycling active sites.

Racemic 4-aryl-2-hydroxytetronic acids were first synthesized by Dahn et al nj2J3J4 Condensation of aromatic carboxaldehydes 188

44 with glyoxal sodium bisulfite and KCN in basic medium produce cyclic enamines 189. Originally, Dahn proposed tetrommides 192 as the products. However, their stability toward acid hydrolysis and conversion to acyclic amide 193 upon standing at room temperature over several weeks, suggests that tautomer 189 is the product.

+ Oxidation using acidic sodium nitrite (NaN02, H ) produces dehydro species 190 and reduction (Ascorbic acid, MeOH) affords tetromc acids 191.

KCN, CHO 10% NaN02, [CH(OH)S03Na]2> H2S04 & 2N Na2C03 188 R 189

Ascorbic Acid, 0$" MeOH, reflux 1 190

4 -8 weeks H *

Free radicals are now known to play significant roles in numerous disease states including cancer,76 atherosclerosis, rheumatoid arthritis, postischemic reoxygenation injury,77 senile

45 dementia and aging . Reactive oxygen species (ROS) are generated by the action of free radicals on dioxygen (02). Free radicals are produced via numerous biological processes including xenobiotic metabolism and lipid peroxidation. One electron reduction of 02 yields superoxide anion radicals (02""). Further, in vivo reduction of 02" by both enzymatic and nonenzymatic processes yield other ROS including H202 which undergoes metal-catalyzed reduction to the highly reactive tissue damaging hydroxyl radical (HO). Self defense mechanisms76 for this process include the enzymes superoxide dismutase, which converts 2 molecules of 02" to H202 and 02; catalase, which converts 2 moles of H202 into 1 mole each of H20 and 02: glutathione peroxidase which consumes one equivalent of H202 in the oxidation of glutathione; and numerous small molecule ROS scavengers79 such as ascorbic acid, a-tocopherol and retinoic acid. 4-Aryl-2-hydroxytetronic acids 191 have antioxidant efficiencies similar to probucol and about twice that of a-tocopherol.79

Certain 2-hydroxytetronic acid acZ-reductones exhibit a synergistic effect in combination with interleukin-(IL)-2 to induce-LAK activity80. LAK activity is being investigated as a means to treat cancers which are not responsive to conventional therapies.81 IL-2-induced-LAK activity is down regulated by

82 80 prostaglandin E2 and ROS. 4-Chlorophenyl-2-hydroxytetronic acid, possibly via its ability to block prostaglandin synthesis and scavenge ROS. improves LAK activity induced by IL-2. In standard 4- hour 51Cr release assays, these compounds improve LAK activity from 47 IL-2-treated human peripheral blood mononuclear cells (PBMC) comparable to the synergism observed with a combination of indomethacin, superoxide dismutase and catalase.80 This improvement is of the same magnitude observed when PBMC are depleted of monocytes. ac7-Reductones of this type inhibit experimentally induced

+2 (Cu /02) oxidation of LDL. Such oxidized LDL particles, ie. LDL0X are thought to be involved in the atherogenic process,83 and therefore, these compounds have potential as antiatherogenic agents75. Additionally, these ac/-reductones have potential as antithrombotic drugs since they block platelet aggregation induced by ADP. The antioxidant drug probucol also inhibits platelet aggregation.2 Biphenyl-2-hydroxytetronic acid 194, a proposed mimic for the classical prostaglandin H synthetase inhibitor biphenyl acetic acid,84 inhibits cyclooxygenase (CO). Arachidonic acid (195) serves as substrate for CO, and certain 2-arylpropanoic and acetic acids such as indomethacin (196) are antimetabolites for the enzyme. Optically pure (/?)- and (S)-arachidonic acid CAM-R analogues 197 were recently synthesized in our laboratory85 and the preparation of indomethacin CAM-R analogue 198 is being investigated86. 48

Reduction of the active site of a redox enzyme by the aci- reductone 199 should ultimately generate dehydro species 200. In aqueous medium such triketo compounds are rapidly hydrated at the site of the most electrophillic central carbonyl function. Possibly, within the enzyme active site, water is relatively less available and dehydro species such as 200 will undergo reaction with enzyme nucleophilic groups (i.e. -NH2. -SH. or -OH). This would result in hemiacetal type covalent linkages at C-2 (i.e. structure 201). 49

"5=r ^ E-^° -^ *-£- H HO OH ^ o 0 o 0H 199 200 201

In the case of reaction with primary amino groups subsequent dehydration would also yield imines. Such a reaction occurs between 2,3-diaminobenzene and dehydroascorbic acid (13), resulting in the formation of several imines including 202 and 203.87

NH- <& NH-

202 X—' 203

Further, reaction of p-fluorophenylhydrazine with dehydroascorbic acid generates hydrazone 204.88 Addition of a second equivalent of the hydrazine to the reaction mixture produces bishydrazone 205. Ultimately, determination of whether similar nucleophilic additions take place between CAM-R drugs and redox enzymes such as CO will be examined. 50

HO _,* OH

HN^NH2 U "® H 0 N-NH 204

%

S-XHN ^NH2 CHAPTER II

STATEMENT OF THE PROBLEM

The objectives of this research are to develop new syntheses for optically pure 4-aryl-2-hydroxytetronic acids. As described in the medicinal chemical background section, these compounds are proposed as important tools in the investigation of enzymatic and radical scavenging mechanisms. It is well known that enantiomers often have significantly different enzymatic activities and in the case of cyclooxygenase enantioselectivity for arylpropanoic acid antimetabolites is well documented.89 Structure activity studies employing optically pure <3C7-reductones is expected to provide insight concerning the mechanism by which such drugs act. For example, a eudismic ratio of greater than 1 may indicate a drug- enzyme interaction to be important, whereas eudismic ratios of 1 may infer a biological mechanism via non-enzymatic or radical scavenging processes.

Published chemistry to obtain optically pure stereogenically labile 2-hydroxytetronic acids is virtually nonexistent (see Introduction: Syntheses for ac7-Reductones). Syntheses for 4,4-disubstituted-tetronic acids generally relies on the use of

51 strong base or on the production of reaction intermediates which are not applicable for the assembly of compounds containing a labile asymmetric center. Ascorbic acid syntheses have not, as yet, proved useful for the preparation of 4-aryl-2-hydroxytetronic acids of known absolute configuration. Additionally, the asymmetric center found in many of the precursors to the final targets are also easily racemized. The chiral center is particularly labile since this carbon contains a proton positioned between a carbonyl group and an aromatic ring. Thus the pKa of this proton is 5 or more pKa units lower than the pKa for alkyl-substituted compounds such as ascorbic acid (1). The lability of the asymmetric center may be likened to that of mandelic acid, which undergoes racemization (1) upon DCC- promoted esterification using catalytic DMAP, (2) in KCN-catalyzed ester hydrolysis and (3) in LiOH-catalyzed ester hydrolysis at pH <12.5.90-91 Witiak and Tehim34 developed the first synthesis for optically pure (S)-(+)-phenyl-a-hydroxytetronic acid (77) using a Claisen cyclization under kinetically controlled conditions. 2-Benzyloxymethoxyacetate 75 undergoes such cyclization at -100°C using the sterically hindered non-nucleophilic base, lithium dicyclohexylamide. Subsequent benzyl group deprotection generates the desired compound in low overall yields. Unfortunately, the increased potential for racemization of compounds containing other electron withdrawing aryl substituents during these low yielding procedures have limited the usefulness of this technology. 53

,„ - 'CH2OCH2C6H5 LiN(Cy)2 *1r -100'C / C02CH3 30% 75 0 o—'^f 0-\ ^CH C H ^ 2 6 5 10% pd/c OH cyclohexene' 40% ^^X' OH ^ 760H 77

Two new approaches for the stereocontrolled synthesis of optically pure 4-aryl-2-hydroxytetronic acids are described: One involves butenolide-oxidation methodology and the second considers the aldol condensation. The aldol condensation approach proved successful and its usefulness is demonstrated through the construction of the pure enantiomers of phenyl- (77 and 206), p-chlorophenyl- (207 and 208) and biphenyl- (209 and 210) 2- hydroxytetronic acids.

/^*~OH CHAPTER III

RESULTS & DISCUSSION

A. THE BUTENOLIDE-OXIDATION APPROACH This approach considers the asymmetric synthesis of 2- hydroxytetronic acids by oxidation of the corresponding optically active hydroxylated ^-lactone intermediates 212-215. These intermediates are available via different methods from aryl lactones 216 or 217. Such an approach requires the construction of optically pure lactones 216 or 217 and the conversion of such lactones to the desired targets 211 under nonracemizing conditions. The general method of Midland is useful to prepare optically active 4-biphenyl-a,/?-unsaturated~butenolide 223. Biphenyl-4- carboxaldehyde 218 is condensed with the lithio salt of ethyl propiolate93 in THF at -90°C to yield the corresponding racemic alcohol 219. Optically pure acetylenic alcohols of this type have been prepared via resolution,94 while optically active products have been synthesized by asymmetric reduction of corresponding 4-keto-2- butynoate esters.92 For synthetic methods development, optically pure (> 98% ee) butenolides are not necessary; therefore, the asymmetric induction method of Brown95 is used for the preparation of optically active (82% ee) propargyl alcohol 219 employed in these studies. Crude racemic alcohol 219 is oxidized to the corresponding ketone using Jones reagent at 15-20°C. Asymmetric reduction using Alpine borane prepared from 92% ee (l/?)-(+)-a-pinene produced95 propargyl alcohol 219 (83% yield and 82% ee). Enantiomeric excess is determined by integration of the methine proton resonance signals at 6 6.75 and 6.73 of the corresponding (+)-a-methoxy-Q!-trifluoromethyl- phenylacetate (MTPA) esters 221 and 222.% CHO 1. LiCCC02Et THF, -90*C 2. Jones Ox. C0 Et 3. Alpine Borane 2

Ph h *CF3 JL/ OMe X v °220 0 f««CF3 OMe Pyr, cci4 CO,Et CO-Et

2 Catalytic reduction (30 psi H ) of alkyne 219 over 5* Pd/BaS04 poisoned with quinoline provides a c/s-conjugated olefin, which is not isolated, but lactonized in EtOAc/hexanes with 3 drops of concentrated HC1. The optically active (/?)-(-)-butenolide 223 precipitates from solution as a light yellow solid in yields of 55- 65£. The double bond easily isomenzes to the /?.K-position with loss of optical activity. Thus, silica gel chromatography, stirring in

THF containing one drop of Et3N. or stirring in dimethylformamide (DMF) results in the isolation of a highly crystalline, bright red compound identified as isomer 224 by lH NMR and mass spectral analysis. The sensitivity of the 2(5W)-furanone 223 to undergo isomenzation and concomitant racemization limits the number of reagents and reaction conditions available for oxidative transformation to acf-reductone precursors 212-215. 57

1. H2, Pd/BaS04, Quinoline, MeOH C02Et 2. H+, EtOAc/Hex 223

1. Si02 2. DMF, rt 3. THF, Et,N (cat)

Dihydroxylation of 2(5//)-furanone 223 following the method of 97 Mukaiyama et al. (KMn04, 18-crown-6 ether, CH2C12. -43°C) generates optically active (-)-C7's-2.3-dihydroxylactone 225. Hydroxyl group addition occurs anti (20:1) to the biphenyl system. Yields above A0% are only obtained when' reactions are carried out on small scale (< 0.5 mmol). On larger scale (1 mmol) yields decline to 20-25&. All 9798 attempts to perform this dihydroxylation using 0s04. " alkaline 100 101 H202. or Ag0C0CH3 and I2 (Prevost reaction) fail.

KMnC" •OH 18-Crown-6 OH CH2C12 -43°C 223 225 Nonetheless, dihydroxylactone 225. synthesized in small quantities, is a possible lower oxidation state precursor to the target <3C7'-reductone. Silver carbonate on celite, reported as a highly selective reagent for the production of acyloins from the corresponding vicinal diols102, proved to be an ineffective oxidant. Warming to reflux a solution of lactone 225 in benzene or toluene containing 10 equivalents of AgC03 on celite for 24-48 h gave no reaction. Similarly, vicinal diol oxidation to a-dicarbonyl compounds under Swern conditions using trifluoroacetic anhydride (TFAA)103 as activator fails to yield product.

1. AgC03/Celite

toluene or CfiH6 reflux 24-48 h • No Reaction 2. TFAA, DMSO, Et3N

Monobenzylation (BnBr, NaH, Bu4NI. THF) produces benzyloxy regioisomers 226 and 227 in a ratio of 2:1, but attempted Swern oxidation using TFAA as activator again yields no reaction. The poor reactivity of this substrate combined with difficulty in production of starting dihydroxylactone 225 has complicated this approach. Others report difficulty in oxidizing 2- and 3-hydroxydihydro-2(3W)- furanones.104 For these reasons no further work has been carried out using this approach. 59

226 R = H; R' = Bn 227 R - Bn; R' = H TFAA, DMSO, • No Reaction Et3N

Formation of a-keto lactones 213 and subsequent /?-hydroxylation may be viewed as a second oxidative route to tetronic acid targets 211. Additionally, a third approach involves reversal of the oxidative steps; /9-hydroxylation and subsequent a-keto formation. One possible advantage of this scheme over the former is the reduced potential for racemization. The chiral carbon of the ^-hydroxy lactone 214 is not adjacent to a carbonyl or a conjugated enone moiety as in lactone 213.

a-Keto intermediate 230 may be prepared from saturated lactone 223 by the method of Wasserman and Ives.105 Pd/C-catalyzed 60 hydrogenation of unsaturated lactone 223 produces lactone 228 in high yield. Treatment with tr/s-dimethylaminomethane (excess) at 60°C for 8 h produces enamine 229. a highly crystalline tan colored compound.

Photooxygenation in CH2C12 using Rose Bengal as sensitizer generates the corresponding a-keto tautomer 230. Attempts to perform 0-

hydroxylation using Mo05 Pyr HMPA (MoOPH) complex on the lithium anion of intermediate 230 fails.106 Insertion of the 3-hydroxyl function also fails when iodosobenzene is employed as oxidant.107

1. LDA, MoOs-Pyr HMPA Product aci-Reductone 2£ • Were Not Isolated or Observed 2. C6H5IO, in Reaction Mixtures BF,Et,0, H,0

Conversion of substrate 230 to target acf-reductones may be acomplished by enol ether formation and subsequent oxidation of the double bond using either dihydroxylation or epoxidation methods. 61 Deprotection of the proposed resultant labile hemiketal is expected to occur during acidic reaction work up. Attempted protection of enol 230 using methyl iodide and NaH or TMSC1 and pyridine is unsuccessful. However, because 230 is acidic (soluble in b% Na2C03 solution) use of diazomethane affords enol ether 231 in high yield.

OCH, CH2N2,

Et2o, o°c

Unfortunately, oxidation with KMn04 (18-crown-6 ether, -43°C), as described for butenolide 223. fails and only starting material is recovered. When reaction temperatures are increased to 0°C. over oxidation takes place. Treatment of enol ether 231 with MCPBA in

MeOH at -10°C and with 1 equivalent of MCPBA in CH2C12 at 22°C produces no reaction. Oxidation with 2 equivalents of MCPBA in CH2C12 at 40°C for 6 h yields starting material and benzoic acid. Oxidation with alkaline H202 results in decomposition as does reaction with t-

BuOOH and Triton B, while use of Pb(0Ac)4 yields no reaction. This lack of reactivity involving attempted oxidation of similar substrates is also substantiated in the literature. For example, flavones are resistant to oxidation by KMn04, Se02 and other 62 oxidants108. /?-0xo enol ethers only undergo sluggish reaction at elevated temperatures when a large excess of the powerful oxidant dimethyldioxirane109 is employed. The use of dimethyldioxirane for the selective oxidation of enol ether lactones to target aci- reductones was not attempted, but may be the reagent of choice for such a synthetic transformation108. Interestingly, all decomposition reactions occur in the presence of basic materials and oxidant or elevated temperatures. Additionally, in basic solutions double bond migration likely occurs; the red color of furanone 224 is observed.

1. KMn04, CH2C12, 18-Crown-6 ether -43°C OCH, „ Attempts 1-3 Produced 3 2. mcpba, MeQH, -10°^ No Reaction, while 3. Pb(OAc) 4-6 Resulted in 4. mcpba, CH2C12, 40°C Decomposition. 5. t-BuOOH, triton B 6. Alkaline H202

Introduction of a /?-hydroxyl group prior to insertion of the a- keto group, may represent a practical approach to the synthesis of <3C/-reductones. 1,4-Addition of the hydroxyl moiety may be performed using chemistry developed by Fleming et al110111. Copper-promoted 1,4-addition of dimethyl(phenyl)silyl lithium produces masked /?- hydroxy lactone 232 in 50% yield. Silyl oxidative cleavage using either bromine or mercuric acetate in peracetic acid provides /?- hydroxylactone 233 in 50ft yield. As predicted from the mechanism of the reaction110 only one isomer, presumably resulting from retention of configuration, is produced.

Several hydroxy1 protecting groups were investigated during attempted conversions of /?-hydroxylactone 233 to target aci- reductones. Reaction with benzoyl chloride yields lactone 234 and treatment with tr/s-dimethyl aminomethane provides a highly crystalline bright yellow compound determined to be the fully conjugated enamine 238 rather than desired product. This structural assignment was confirmed by conversion of butenolide 223 to dienamine 238 upon treatment with tr/s-dimethyl aminomethane. Protection of alcohol 233 as it's trimethyl silyl (TMS) ether 235, tert- butyldimethyl silyl (TBDMS) ether 236 or tetrahydropyranyl (THP) ether 237 followed by treatment with tr/s-dimethylaminomethane also affords dienamine 238.

Photooxidation was performed on dienamine 238 to produce 2,3- furandione 239, ultimately protected as ketal 240. Conversion of ketal 240 to optically active 2-hydroxytetronic acids may be possible through use of monoisopinocampheylborane (ipcBH2) reduction and oxidative hydrolysis.112113 However, reduction of a less sterically hindered substrate. 2(3W)-furanone 224, with ipcBH2 fails, and to date, asymmetric reduction of protected a-keto lactone 240 has not been attempted. 238

H0CH2CH20H, TsOH

C6H6, reflux

/?-Hydroxylactone 233 may be oxidized to the corresponding tetronic acid 241 under Swern conditions using TFAA as activator. However, this reaction proceeds in only 30$ yield.114 This method is not useful for production of optically pure ac7-reductones. as other methods are available for the higher yielding preparation of optically active tetronic acids of the type 241. Further, whereas 4,4-disubstituted-tetronic acids serve as precursors to corresponding 2-hydroxytetronic acids, the methods employed likely will lead to racemization of chiral compounds with enolizable hydrogens at position number 4. .0 o- ' TFAA, DMSO, Et-N, -60°C-^ 0°C 66 B. THE ALDOL CONDENSATION APPROACH Obvious precursors115 to the 2-hydroxytetronic acid functionality are keto ester intermediates 242 or 245 Fundamentally, these intermediates are available from chiral acylanions 243 or 247 and ethyl glyoxalate 244 or aldehyde 246, respectively a-Keto ester precursor 245 is expected to be more stable to racemization owing to placement of the carbonyl moiety For this reason synthetic attempts are biased toward construction of this a-keto ester This convergent approach is fashioned after several of the older ascorbic acid syntheses For example, Helfench and Peters116 condensed the cyanohydnn of tetracetyl-d-threose with ethyl glyoxalate in methanol using sodium methoxide as base Other related examples are found in the introductory section

OR' ' "

H C02R- => L I i R ° ° 243 244 or OR"' jO^r'^XrY H r.C0 2R" 245 ° »« 2«

Condensation of acyl anions 243 or 247 with the appropriate aldehyde 244 or 246, respectively, are required for preparation of the prerequisite acyloins The electropositive aldehyde carbon demands conversion to a compound which accomplishes inversion of the 67 systems electronics such that anions are easily prepared. At the same time the resulting condensation products must be readily convertible to the desired carbonyl system. One older method which produces these properties in situ resides in the benzoin condensation.117 This reaction only generates product when performed with aromatic aldehydes and glyoxalates. In such systems, addition of potassium cyanide produces the corresponding cyanohydrin anion 249 which rearranges to the more favorable carbon anion 250 owing to resonance stabilization. The mechanism of the benzoin condensation reaction illustrates why such benzyl hydrogens are labile and why compounds such as mandeloaldehyde precursors of the type 246 are easily racemized. Condensation of the cyanohydrin anion 250 with aryl aldehyde 248 produces intermediate 251. Cyanide elimination yields benzoin 252.

OH i ,C + H 248 *=* Or- OT 249 250 248

NC 0

+ KCN 68 Dithianes and protected cyanohydrins118 are available as acyl carbanion mimics for nucleophilic acylation119 reactions. Ethyl glyoxalate equivalents include ethyl 1.3-dithiane-2-carboxylate 253. ethyl l,3-dithiolane-2-carboxylate 254. ethynyloxyethyl ether 255120121 and protected cyanohydrins of ethyl glyoxalate 256. In summary, preparation of target ac/-reductones by this approach requires synthesis of optically pure a-hydroxyarylaldehydes and their condensation with an ethyl glyoxalate equivalent, deprotection and cyclization.

OEt QEt OEt S SN 0 o^yS °'^ Y > H-=-oEt 0

Published methods for the preparation of optically active a-hydroxy aldehydes include Bakers' yeast catalyzed reduction of /?-keto-di-p-tolylthiomethane derivatives122; LAH reduction of diastereomeric a-p-arylthio-/?-oxosulfoxides123; and Sharpless resolution124 of protected /?-butene-a-hydroxybenzene and ensuing ozonolysis.125126 These methods were not used to produce aldehydes of the type 246 as they either do not result in optically pure products, are excessively complex, or provide low yields of the unprotected aldehyde. Optically pure aldehydes of the type 246 may be prepared in a straightforward manner by diisobutylalumminum hydride (DIBAL-H) reduction of appropriately substituted optically pure mandelate precursors. Optically pure enantiomers of mandelic acid are commercially available. However, optically pure enantiomers of the p-chloro- 270 and p-phenylmandelic 259 acids are not. Numerous methods exist for the manufacture of optically active and optically pure derivatives of mandelic acid. A wide range of chiral bases are used to resolve mandelic acid precursors including methyl benzyl amine127, brucine128 and ephedrine129. Partial separation of enantiomers is accomplished with optically active solvents130 such as (-)-menthone, (-)-menthyl acetate and (+)-limonene. Anion-exchange chromatography using a chiral stationary phase constructed of l-p-nitrophenyl-2-amino-l,3- propanediol ,131 or chromatography through starch132 successfully separates mandelic acid enantiomers. Reduction of 1-menthyl benzoyl formate with Na-amalgam followed by saponification of the menthyl ester provides 1-mandelic acid133. Asymmetric syntheses of mandelic acid precursors include the Alpine borane reduction of methyl benzoyl formate and oxygenation of Evan's chiral imide enolate134.

Procedures developed for the production of racemic mandelic acid derivatives are well documented in the literature. Ando's135 scheme relies upon the condensation of benzene derivatives with ethyl

ketomalonate in the presence of SnCl4. This affords hydroxy diesters which after saponification and decarboxylation liberate racemic mandelic acid derivatives. The approach formulated by Compere136 70 generates mandelic acid derivatives in one step and in high yield by condensing substituted benzaldehydes with bromoform in the presence of potassium hydroxide and lithium chloride. Furthermore, mandelic acid is obtained in 45$ yield by subjecting a-chloroacetophenone to aqueous alkali137 under normal atmospheric conditions. Racemic biphenyl a-hydroxy acid 259 is prepared by cyanohydrin formation and in situ silation.138 Hydrolysis of protected cyanohydrin 257 using concentrated HCl provides acetamide 258 which is converted to mandelic acid derivative 259 by refluxing in methanolic KOH. Racemic p-chlorophenyl-a-hydroxy acid 270 is produced in a similar manner.

OTMS KCN, Zn(CN)2 TMSC1, CH3CNt cone. HCl reflux, 24 h' 24-48 h

KOH, MeOH reflux, 2 h

Optically active (/?)-p-phenylmandelate 262 is formulated by

Fischer esterification (MeOH, HCl, reflux), oxidation (PCC, CH2C12) 71 and asymmetric reduction of the resulting a-keto ester 261 with Alpine borane95 prepared from 92ft ee (l/?)-(+)-a-pinene. Enantiomeric excess is 82ft based upon :H NMR analysis of the corresponding (+)-MTPA esters.

OCH, MeOH, H+. PCC, CH,C1, reflux

OCH, OCH, Alpine borane

Optically active (/?)-p-chloromandelates 266 may be synthesized using a different procedure. p-Chloroacetophenone undergoes a-

139 bromination (Br2. AcOH), in high yield. Subsequent reaction of a- 140 bromoacetophenone 264 with Se02 in MeOH at reflux for 24 h generates a-keto ester 265 in 35% yield. Asymmetric reduction with Alpine borane prepared from 92ft ee (l/?)-(+)-a-pinene generates (R)-(-)-methyl p-chloromandelate 266. 72

0 OH 0CH S C 3 ^^VY*^\-f^' 3 Alpine borane^ r^ V^Ti^° ^

Cl^"265 ° 01^^266 °

There is considerable literature precedence for the diastereoselective reduction of a-keto menthyl esters141 and for the resolution of mandelates by use of menthyl esters.142143144145 Originally, we proposed that optically pure [(/?)- or (S)'j-p- phenylmandelyl aldehydes, necessary for the synthesis of target aci- reductones for biological investigations, would be available by DIBAL-H reduction of the corresponding (+)-menthyl ester 269. Thus, racemic biphenyl-a-hydroxy acid 259, protected (AcCl or

Ac20. Pyr, CH2C12) as its acetyloxymandelate 267, is esterified with (lS.2/?.5S)-(+)-menthyl using the coupling reagent dicyclohexylcarbonyldiimide (DCC) and a catalytic amount of dimethyl aminopyridine (DMAP). This produces a sticky mixture of

146 diastereomers. Acetate hydrolysis (0.5 N K2C03) and Jones oxidation produces optically pure a-keto menthyl ester 268. Asymmetric reduction using Alpine borane results in a diastereomeric 73

mixture of c.a. 8:2. Recrystallization using EtOH/H20 provides both optically and diastereomerically pure a-hydroxy menthyl ester 269. The diastereomeric excess (de), determined by integration of the benzylic proton resonance signals at 5 5.13 (major) and 5.18 (minor) of the two diastereomers, is > 98ft for the recrystallized compound. Optically and diastereomerically pure (l/?,2S.5/?)-(-)-menthyl ester 273 for the p-chlorophenyl analogue 270 is also available by use of this methodology.

OH OAc AcCl or 1. (+)-menthol DCC, DMAP, Ac20, Pyr, CH2C12 2. K2C03, MeOH 3. Jones Ox.

Alpine Borane Recryst. from EtOH/H-0

OH OAc AcCl 1. (-)-menthol or DCC, DMAP, ACjO, Pyr, CH2 2. K2C03, MeOH „CrV 3. Jones Ox. C1 270 271

OH 1. Alpine Borane^ 2. Recryst. 0V from EtOH/H 0 el c1^^ 272 2 273 74 Conversion to starting optically pure aldehyde 275 is accomplished by hydroxyl group protection (TBDMSC1. Imd. DMF) of alcohol 273 and subsequent DIBAL-H reduction147148 of the (-)-menthyl ester 274. The isolated yield of this optically active aldehyde is only 20£. Because of steric hinderance to reduction, a mixture of starting material, over-reduced product (1° alcohol) and desired aldehyde 275 is obtained. Use of longer reaction times, increased temperatures and excess reagent does not improve reaction yields.

OH \ OTBDMS l^V^ffZ-tZ^^ TBDMSC1, Imd f^vS<0' DMF 16 h rlJL*J ° - KJ 0 Cl"^ 273 97% Cl-^^

DIBAL-H -• C1^^275

Alternatively, hydrolysis (NaOH) of the menthyl ester 273 generates mandelic acid 276. Esterification (CH2N2) and hydroxyl group protection (TBDMSC1, Imd. DMF) produces methyl ester 277 in c.a. 90£ overall yield. Unfortunately, the optical purity of the corresponding (+)-MTPA ester of methyl p-chloromandelate 266 75 indicates approximately 3-5£ of the compound undergoes racemization during ester hydrolysis.

OH 1. CH2N2, Et2o 2. TBDMSCl, Imd. DMF

OTBDMS OCH, DIBAL-H 85%

Hydrolysis of menthyl ester149 273 to mandelic acid 276 is accomplished using a variety of conditions. Saponification reactions may be monitored for racemization by isolating the unsaponified

! menthyl ester 273 at time t1/2 (thin layer chromatography). H NMR analysis is useful for determination of optical purity. Hydrolysis

[0.2 M LiOH in H20:MeOH (1:5); solutions at a pH < 12.5 (LiOH or

NaOH): KCN-catalyzed transesterification in MeOH:H20 (8:2) (reflux)] produces 3-10% racemization at t1/2. Use of other reagents such as bisCtri butyl tin) oxide150 or boron tri bromide151 do not yield product. Another method attempted for conversion of menthyl ester 273 to aldehyde 275 includes reduction of the TBDMS protected hydroxy ester 76 274 to produce primary alcohol 279. However, oxidation to the corresponding aldehyde does not take place and generally results in decomposition of starting material. Aldehydes of the type 275 are unstable and decompose completely within 48 h. These compounds likely rearrange to a-hydroxyacetophenone derivatives when allowed to stand at room temperature.

OTBDMS OH l TBDMSC1, 1 ^ ^ - v / Imd. DMF |/^v^ s ^\Z^- 2. 2 eq. DIBAL-H ll J „0V C1^279 Ci 273 Oxidation Attempts Decomposition Products

Production of the optically pure (/?) isomer of p-chloromandelic acid 270 is accomplished by resolution using chiral methyl benzyl amine and recrystallization of salt 280 from absolute EtOH. The optical purity of hydroxy acid 276 may be monitored by conversion of a small sample to methyl mandelate derivative 266. The *H NMR signal for the benzyl proton of the corresponding (+)-MPTA ester is observed. The optically and diastereomerically pure salt is subsequently converted into enantiomerically pure aldehyde 275 in high yield. 77

1. (R)-(+)-methyl- • • »••••••——^^ benzylamine abs. EtOH 2. Recrystallization

Thus, the free acid 276 is obtained by washing an ether solution of salt 280 with 5% aqueous HC1. The ether layer is separated, cooled to 0°C and titrated with CH2N2 to obtain optically pure methyl mandelate 266. Hydroxyl group protection (TBDMSC1. Imd. DMF) and DIBAL-H reduction gives the desired optically pure starting material 275 in nearly 88$ yield. Optically pure enantiomers of the biphenyl and phenyl aldehydes are also available using similar procedures.

OH

1. 5% HC1 soln OCH, jprV 2. CH N 0°C 2 2> + ,^y °NH3

1. TBDMSC1, Imd. DMF 2. DIBAL-H, -78°C 85% 275 78 The lithium salt of ethyl 1.3-dithiane-2-carboxylate is condensed with optically pure aldehyde 275 at -78°C in THF to yield 30£ of hydroxy dithiane 281 in a diastereomeric ratio of 1.7:8.3.

Oxidative hydrolysis of dithane 281 using HgCl2 buffered with CaC03 in

80£ aqueous CH3CN results in no reaction even when warmed to reflux for 4 h. Reaction with NBS, AgN03 and 2,4,6-collidine as described by Corey and Erickson152 provides a mixture of products none of which correspond to ac/-reductone precursors of the type 245. Reaction of hydroxy dithiane 281 with TBAF in THF at rt provides spiro lactone 282. This intermediate is not conducive to oxidative dithiane hydrolysis owing to the sensitivity of the <3C7'-reductone product under oxidizing conditions.

OTBDMS 1,3-dithiane- C0 Et 2-carboxylate, LDA 2 THF -78°C, 30%

TBAF, THF

The low yield of aldol product is likely a result of poor conversion under reversible conditions of aldehyde 275 to aldol product 281 and not to decomposition or side reactions. The newly formed carbon-carbon bond is likely labile, and retroaldol reaction may occur. Trapping the alkoxide anion formed in the aldol 79 condensation is expected to prevent retroaldol reaction and improve reaction yields. Furthermore, protection of the hydroxyl function provides intermediates with increased stability during the generation of a-keto esters 245. Following the method of Belletire et a/.153 the lithium salt of ethyl l,3-dithiane-2-carboxylate is treated at -78°C with a mixture of aldehyde 275 and pivaloyl chloride (1:1) to furnish a 1.7:8.3 ratio of pivaloyl dithiane diastereomers 283 in 60% overall yield. Dithiane hydrolysis is performed by use of N- chlorosuccinimide (NCS) and AgN03 in aqueous CH3CN at rt. This furnishes 80% of protected /?-hydroxy-a-keto ester intermediate 284. Cyclization is induced with TBAF affording a-pivaloyloxytetronic acid 285.

OTBDMS LDA, 1,3-dithiane- 0Y 2-carboxylate, CI ^ 275

OTBDMS ^ ,CO,Et JL TBAF F NCS, A8NOa (l^f? 6 ' ™ CH3CN:H20 (8:2) Ji^J 0 0 83% C1 ^C=0 284

Interestingly, the pivaloyl group undergoes 0*0 acyl migration during the cyclization. Evidence for the assigned structure 80 includes: (1) broad OH stretching absorbance signals in the infra red; (2) solubility in NaHC03 solution; and (3) reaction with diazomethane in ether at 0°C to produce a mixture of two regioisomers 286 and 287 in the ratio 2:1. This is unlike the 2:3 mixture of regioisomers generated in the reaction of 5,5-dimethyltetronic acid

154 with CH2N2. The methoxy proton resonance signals at 6 4.05 (major), and 3.72 (minor), are assigned to the tetronate and 4- furanone structures, respectively. The pivaloyloxy regioisomer's 287 and 286 exhibit *H NMR signals at 6 4.05 (minor) and 3.89 (major) corresponding to the methoxy group for tetronate 287 and 4-furanone

286, respectively. Steric factors most likely force CH2N2 to react at the lactone carbonyl and therefore produce 4-furanone 286 rather than expected tetronate 287 as the major product.

OCH,

CH2N2, Et2Q 0°C

287

XW NMR analysis of the (/?)-(+) -methyl benzyl amine salt of racemic

2-pivaloyloxytetronic acid in CDC13 clearly demonstrates a 1:1 mixture of diastereomers. The resonance signals corresponding to the enantiomeric furanone protons at 6 5.20 (/?-tetronic acid) and 5.11 (S-tetronic acid) are easily visible. For optically pure salts a single resonance peak is observed. Racemic 2-pivaloyloxytetronic acid is synthesized by treating p-chlorophenyl-a-hydroxytetronic acid with excess pivaloyl chloride and pyridine in CH2C12. The production of the 2-pivaloyloxy intermediate 285 provides additional evidence for the assigned structure of cyclized product 285. This assignment is in agreement with literature precedence; numerous examples exist demonstrating the steric selectivity of pivaloyl chloride146. The acidic hydroxyl group of the 2-hydroxytetronic acid function is adjacent to a phenyl ring rendering the position more sterically hindered when compared to the hydroxyl at the 2-position. Furthermore, bonding of the pivaloyl moiety to the 3-hydroxyl group generates an anhydride equivalent (i.e. vinylogous anhydride) which likely undergoes rapid hydrolysis. General methods for the cleavage of pivaloyl esters146 involve hydroxide anion hydrolysis or hydride reduction. Reductive cleavage is not appropriate since simultaneous destruction of the furanone ring is likely to occur. Alkaline hydrolysis is unsatisfactory since racemization is likely to take place. Attempted hydrolysis with base confirms this prediction and results either in no reaction or decomposition. No reaction takes place upon treatment of tetronic acid 285 with bistributyltinoxide in refluxing benzene. Attempted cleavage with a Pseudomonas species enzyme155 in 1.0 M phosphate buffer at pH 7 also does not produce reaction after 7 days; starting

material is recovered. Stirring in a mixture of Et3N and 15ft aq EtOH (1:1) results in no reaction after 24 h. Successful hydrolysis is effected by warming to reflux a

solution of pivaloate ester 285 in MeOH:H20:concentrated HC1 (8:1:1) for 24 h. Unfortunately, the 2-hydroxytetronic acid thus isolated, as observed by *H NMR analysis of the diastereomeric (/?)-(+)- methyl benzyl amine salt, is partially racemized. The product is approximately 90ft ee. Hydrolysis of the pivaloate group with

AcOH:THF:H20 (3:1:1) at reflux for 12 h results in ac/-reductones of

86ft ee. Warming the pivaloate intermediate 285 to reflux in AcOH:H20 (8:2) produces 2-hydroxytetronic acid 207 with 92ft ee. Warming the

pivaloate ester in AcOH:H20 (9.5:0.5) produces target ac/-reductone 207 of better than 95ft ee. whereas optically pure (>98ft ee by XH NMR analysis'of diastereomeric salts) target 207 is obtained in 60ft yield

by warming the pivaloate intermediate in AcOH:H20 (9.8:0.2) for 24 h at a gentle reflux.

AcOH:H„0 (9.8:0.2) 60%

In summary, a method is now available for the production of optically pure 4-aryl-2-hydroxytetronic acids. The reaction scheme 83 affords target acZ-reductones in 23£ overall yield starting from pure methyl benzyl amine salts of mandelic acid precursors. The difficulty experienced in hydrolysis of the pivaloyl ester prompted studies of different protecting group strategies. Use of either acetyl chloride or benzyloxychloroformate rather than pivaloyl chloride in aldol condensation reactions produces parallel results as described for the production pivaloyl ester 283. The rational behind the use of these protecting groups relies upon available methods for deprotection. Benzyl carbonates are reductively cleaved (catalytic hydrogenation), whereas acetyl esters are hydrolyzed under relatively mild conditions. Both aldol condensation derivatives 288 and 289 are readily converted to their corresponding a-keto esters 290 and 291 using methods similar to those described for the synthesis pivaloyl derivative 284 (i.e. NCS, AgN03. 20 min, high yield). Unexpectedly, attempted cyclization of these derivatives using TBAF resulted in decomposition products. Although, the pivaloyl ester is viewed as a poor protecting group, apparently its steric influences and resistance to saponification force cyclization to form desired tetronic acids. 84

OTBDMS LDA, OTBDMS 1,3-dlthiane- f CO,Et 2-carboxylate, '2* RCOC1 ii i • o-^ w THF 78 c 60% S zr^s^ 275 - ° - ci'^^o-/ "N R 288 R = Me OTBDMS 289 R = BnO C Et NCS, AgHQ3 ^ ^S¥Av_/ °2 TBAF, THF Deco CH3CN:H20 (8:2f JT JJ ^Xj, • n>P°^tion

cl )E=O R 290 R = Me 291 R = BnO

Possibly, decomposition of intermediates 290 and 291 occur by fluoride catalyzed silyl deprotection and intramolecular attack of the free alkoxide on the benzyl carbonate 292 or acetate 293 protecting groups. Subsequent retroaldol reaction of intermediate anions 294 or 295 probably occurs in route to further product degradation. This suggestion remains speculative since intermediate glyoxalates 298 and aldehydes 296 or 297 have not been isolated and characterized. Other protecting groups examined include benzyloxy or methoxy intermediates, which are expected to be resistant to intramolecular 0*0 migration. However, trapping alkoxide intermediates in the aldol condensation reaction using either benzyl bromide or iodomethane fails. 85

OTBDMS jf CQ Bt

£VW0 ' TBAP, THF. Ojrt 5=2;

290 R - Me ^^ R * Me 291 R « BnO 293 R " Bn0 o u C0.E1 *R «0 0O^^ut" ^OEt Further Decomposition CI 294 R - Me ci ^ 298 295 R =• BnO 296 R - Me 297 R « BnO

a-Keto-/?-pivaloyl ester 284, when warmed to reflux in a solution of concentrated HCl:H20:MeOH (1:1:8) for 24 h. produces target 2-hydroxytetronic acid 207 in 84£ ee. The reaction, as monitored by TLC, reveals that all cyclization to 2- pivaloyloxytetronic acid 285 takes place during the first hour and that the remaining 23 h are required for pivaloate ester hydrolysis. 86

OTBDMS

HCl:H,0:MeOH 2 1 0T< (1:1:8) 285 284

207

Hydrogenation of the benzyl carbonate 291 to acyloin 299 [H2 (1.5 atm), 10* Pd/C, 45 min] followed by warming in a solution of concentrated HCl:H20:MeOH (0.5:1.0:8.5) for 1.5 h produces target aci- reductone 207 in reasonable yield, but with only 55* ee. The unexpected increase in rate of racemization is likely a result of acid catalyzed tautomerization to acyloin precursors of the type 242. which are highly susceptible to acid-induced racemization and enolization. Apparently, the pivaloyl ester does not allow intermediate 284 to undergo such tautomerization and enolization resulting in racemization. These results also indicate that the target 2-hydroxytetronic acids are less readily racemized than are the corresponding mandelate precursors. The 2-hydroxyl group donates electrons in the direction of the asymmetric center (C-4) thereby creating increased electron density at C-3. Evidence for this is 87 provided by comparing the pKa values of 2-substituted-tetronic acids. Tetronic acid (8) has a pKa of 3.76, 2-acetyltetronic acid, a compound containing an electron withdrawing group in the 2-position. has a pKa of 1.8, and 2-hydroxytetronic acid (9) has a pKa of 4.3712. Clearly, the 2-hydroxyl group provides increased electron density at C-3 with a concomitant decrease in acidity of the 3-hydroxyl function found in the unsubstituted tetronic acid (8).

OTBDMS CO„Et OTBDMS CO„Et

(0.5:1:8.5) 55% ee

In conclusion, a synthetic scheme has been developed to produce optically pure (>98£ ee) 4-aryl-2-hydroxytetronic acids. The methodology, as described for the synthesis of (/?)-p-chlorophenyl-2- hydroxytetronic acid 207. has been used to prepare its (S)-enantiomer 208. the (/?)- and (5)-phenyl-2-hydroxytetronic acids (206 and 77) and the (/?)- and (5)-(biphenyl)4-yl-2-hydroxytetronic acids (209 and 210). Ultimately, by altering protecting group strategies one may be able to improve overall yields and develop sequences with fewer synthetic steps. However, early investigations employing a variety of different groups for protection of the C-3 hydroxyl moiety have not lead to improvements in the original synthetic methodology. CHAPTER IV

EXPERIMENTAL SECTION

Melting points were determined in open capillaries with a Thomas-Hoover Uni-Melt Apparatus and are uncorrected. Infrared spectra were recorded by a Laser Precision Analytical RFX-FTIR spectrometer (model TSI-400). Nuclear magnetic resonance spectra were obtained with either an IBM-Bruker model NR/250 or NR/270 FT NMR spectrometer. TMS (CDC13, DMS0-c/6, acetone-c/6, CD30D or D20) was used as internal standard. Chemical shifts were reported on the 6 scale with peak multiplicities: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; t, triplet; q, quartet; m, multiplet. THF was distilled from Na/Benzophenone ketyl;

CH2C12 was dried over P205; and DMF was distilled and stored over molecular sieves. Optical rotations were taken on a Perkin-Elmer model 241 polarimeter using a 10 cm, 1 mL cell. Mass spectra were acquired with either a Kratos MS25RFA or a VG 70-250S mass spectrometer. Elemental analyses were performed by Galbraith Laboratories, Inc., Knoxville, TN.

89 90 Racemic Ethyl 4-[(l,l'-Biphenyl)4-yl]-4-hydroxy-2-butynoate (219): A

500 mL 3-necked round bottom flask under N2 atmosphere containing 125 mL of dry THF (freshly distilled from Na/benzophenone) and 12.2 mL

(120 mmol) of ethyl propiolate was cooled to -90°C (C02/ether). nBuLi (165 mmol; 103 mL of 1.6 M) was added dropwise via an addition funnel over a 30-45 min period. The tan solution was stirred for 20 min and 20 g (110 mmol) of 4-biphenylcarboxaldehyde (218) dissolved in 100 mL of THF was added dropwise via an addition funnel. The reaction mixture was stirred for 2 h at -90°C, and 20 mL of glacial AcOH was added with vigorous stirring. The ice bath was removed and the reaction mixture, after warming to rt was diluted with 1000 mL of ether. The ether solution was washed with 1 X 50 mL of H20, 3 X 50 mL of saturated NaHC03 solution, 1 X 50 mL of H20 and 2 X 50 mL of brine, dried (Na2S04) and concentrated. Generally better overall yields were obtained when the crude product was taken directly to the corresponding ketone without further purification. However, the crude product on smaller scale (50 mmol) was purified by chromatography on silica gel (70-230 mesh) using a gradient elution with hexanes:EtOAc (9.5:0.5), (9.0:1.0), (8.5:1.5) and recrystalized from benzene and hexanes to produce 8.5 g (60%) of acetylenic alcohol 219 as white plates: m.p. 60-62°C. IR (KBr pellet) 3400 (broad),

1 2250, 1750, 1250 cm" ; *H NMR (CDC13) 6 7.6-7.3 (m, 9 H), 5.61 (d, J = 5.2 Hz, 1 H), 4.24 (q, J = 7.1 Hz, 2 H), 2.42 (d, J = 5.2 Hz, 1 H),

1.31 (t, J = 7.1 Hz, 3 H); Anal. Calcd for C18H1603 + 1/8 H20: C, 76.51; H, 5.80. Found: C, 76.59; H, 5.82. Ethyl 4-[(l,l'-Biphenyl)4-yl]-4-oxo-2-butynoate (300): To a 1000 mL round bottom flask containing crude ethyl 4-hydroxy-2-butynoate 219, in 500 mL of acetone at 10-15°C was added Jones reagent156 dropwise with vigorous stirring. The reaction was monitored by TLC. After disappearance of starting material, the green chromium salts were removed by filtration through celite and the solution was concentrated. The remaining black mixture was taken up in 1000 mL of ether and washed with 2 X 50 mL of H20, 2 X 50 mL of NaHC03 solution,

1 X 50 mL of H20 and 1 X 50 mL of brine, dried (Na2S04) and concentrated leaving an impure yellow oil. Chromatography on silica gel (70-230 mesh) using hexanes:EtOAc (9:1) produced 23g (75%) of ketone 300 from aldehyde 218: m.p. 75.5-77°C; IR (KBr pellet) 1714,

1 ! 1650. 1604, 1267 cm" . H NMR (CDC13) 6 8.21-8.17 (m, 2 H) 7.76-7.45 (m, 7 H), 4.36 (q, J = 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H). 13C

NMR (CDC13) 6 175.6, 152.3, 147.9, 139.4, 134.6, 130.3, 129.0, 128.7,

127.5, 127.3, 80.5, 79.9, 63.0, 13.9. Anal. Calcd. for C18H1403: C, 77.68; H, 5.07. Found: C, 77.61: H, 5.21.

(/?)•(-)-Ethyl 4-[(l,l,-Biphenyl)4-yl]-4-hydroxy-2-butynoate9592 (219):

A dry 50 mL 2-necked round bottom flask under N2 atmosphere with magentic stir bar containing 2.8 g (10 mmol) of acetylenic ketone 300 was treated with 6.0 mL (20 mmol) of 92 % ee Alpine borane (prepared from (i/?)-(+)-a-pinene). The solid reaction mixture turned to a thick orange oil after 12 h and was determined to be complete after 18 h by HH-NMR analysis of the crude reaction mixture by observing the upfield shift of the ethyl ester protons. The reaction flask was cooled to 0°C and 1 mL of acetaldehyde was added with vigorous stirring. The liberated a-pinene was removed by distillation (80- 90°C, 0.3 mm Hg) leaving a brown viscous oil which was diluted with 25 mL of ether. The mixture was cooled to 0°C and 1.0 mL (17 mmol) of ethanolamine was added dropwise with vigorous stirring. A tan precipitate formed immediatly and after 30 min was filtered (sintered glass funnel packed with celite) and washed with 3 X 10 mL of ether.

The combined filtrate was washed with 2 X 5 mL of brine, dried (MgS04) and concentrated. The oil was purified over silica gel (70-230 mesh) with EtOAc:hexanes (1:9) as elutant to give 2.34 g (83$) of optically active 219. The optical purity was determined to be 82% ee (90 % ee adjusted) by integration of the methine proton resonance signal of the corresponding Mosher esters 221 and 222. All spectral data was identical with (±)-2-butynoate 219.

Mosher Ester Derivatives 221 and 222 of Racemic Ethyl 4-[(l,l'- Biphenyl)4-yl]-4-hydroxy-2-butynoate96 (219): To a 2-dram vial with stir bar and septum under N2 was added 0.4 mL of pyridine, 30 microliters of (+)-MTPA-Cl 220, 0.2 mL of CC14 and 0.028 g of acetyenic alcohol 219 dissolved in 0.4 mL of CC14. The suspension was stirred for 2 h at rt and diluted with 25 mL of ether and 5mL of 10% aqueous HC1. The ether layer was seperated and washed with 2 X 5 mL of 10 % aqueous HC1 and 2 X 5 mL of brine, dried (MgS04) and concentrated. The residue was dried under reduced pressure for 3 hrs 93 providing a crude oil containing diastereomers 221 and 222 with !H NMR

(CDC13) 6 7.63-7.31 (m, 72 H (excess Mosher reagent)), 6.75 (s, 1 H), 6.73 (s, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.25 (q. J = 7.2 Hz, 2 H) 3.60-3.40 (m, 37 H (excess Mosher reagent)), 1.31 (t, J = 7.2 Hz, 6 H), 1.21 (m, 8 H).

The Mosher Ester Derivative 221 of /?-(-)-Ethyl 4-[(l,l'-Biphenyl)4- y"l]-4-hydroxy-2-butynoate (219) was prepared by a procedure identical to the preparation of diastereomeric derivatives 221 and 222 using R- MTPA-C1 220 and/?-(-)-ethyl 4-[d,l'-biphenyl )-4-yl]-4-hydroxy-2- butynoate (219) as starting material. !H NMR signal of the diastereomeric methine protons in CDC13 were observed at 6 6.75 (s, 1.01 H) and 6.73 (s, 0.11 H).

(/?)-(-)-5-[(l,l'-Biphenyl)4-yl]-2(5//)-furanone (223) C.A. [54614-91- 4]157: To a 250 mL hydrogenation flask was added 40 mg of 5%

Pd/BaS04, 15 mL of MeOH and 8-10 drops of quinoline. The mixture was placed on the Paar hydrogenator for 15 min at 30 psi. Optically active acetylenic alcohol 219 (2.21 g; 7.9 mmol) in 25 mL of MeOH was hydrogenated at 32 psi. After 8 mmol of hydrogen was consumed (approximatly 20 min) the catalyst was removed by gravity filtration and the filtrate was concentrated. The yellow oil was diluted with ether, washed with 10 mL of 10% aqueous HCl, 1 mL of cone. HCl, 15 mL of H20 and 15 mL of brine and concentrated leaving a yellow-brown oil. The oil was dissolved in a minimum amount of EtOAc (approx. 1 mL) and warmed on a steam bath. Hexanes were added until the compound began to oil out at reflux. EtOAc was added as needed to prevent the material from oiling out as the solution cooled to rt. Cone. HC1 (3 drops) was added, and the butenolide 223 precipitated as a light yellow solid after 10 min. The compound was filtered, dissolved in

100 mL of ether, washed with 2 X 20 mL of H20, IX 20 mL of brine, dried (Na2S04) and concentrated leaving 1.12 g (60%) of butenolide 223: m.p. 143-149°C dec; ajj2 -219° (c = 0.036, MeOH); IR (KBr

1 X pellet) 1753, 1733 cm" ; H NMR (CD3C0CD3) 6 7.87 (dd, J = 1.7, 5.6 Hz, 1 H), 7.74-7.64 (m, 4 H), 7.50-7.33 (m, 5 H), 6.29 (dd, J = 2.1,

13 5.6 Hz, 1 H), 6.24 (dd, JAB + JAX = 3.8 Hz, 1 H); C NMR (CD3C0CD3) 6 173.4, 157.6, 142.7, 141.1, 135.4, 129.8, 128.5, 128.3, 128.1, 127.8, 121.2, 84.7; MS (EI) M+ 236 (98.4), 207 (-C:0, 16.4), 181 (-HC:CHC:0, 100), 152 (53.6), 118 (11.2), 76 (34.8), 55 (13.9). 5-[(l,l'-Biphenyl)4-yl]-dihydro-3,4-dihydroxy-2(3/y)-furanone97 (225):

To a 2-necked 15 mL flask under N2 atmosphere was added 0.094 g (0.40 mmol) of butenolide 223, 15 mg (0.04 mmol) of 18-crown-6 ether and 2 mL of CH2C12. The mixture was cooled to -42°C (C02/CH3CN) and 80 mg

(0.50 mmol) of powdered KMn04 (0.50 mmol) was added in three portions (40 mg, 20 mg and 20 mg) over 1 h with stirring. After 2 h, 0.5 mL of Na2S03 was added and after five min, the solution was neutralized by addtion of S% aq. H2S04. The clear colorless solution was extracted with 5 X 15 mL of CH2C12, dried (Na2S04) and concentrated. The product was purified over silica gel (70-230 mesh) using a gradient elution begining with hexanes:EtOAc [(8:2) through (1:1)] leaving 80 mg (758) of diol lactone 225. An analytical sample was recrystallized from CH2C12 and hexanes: m.p. 169-172°C IR (KBr 1 l pellet) 3540 (broad), 3360 (broad), 1780, 1160 cm" ; H NMR (CDC13) 6 7.63-7.34 (m, 9 H), 5.64 (s, 1 H). 4.50 (s, 2 H), 3.0 (broad singlet

! exchangable 1.5 H); H NMR (CDC13/D20) 6 7.63-7.34 (m. 9 H), 5.63 (s, 1 H), 4.50 (d, J = 4.9 Hz, 1 H), 4.48 (d, J = 4.9 Hz, 1 H); *H NMR (CD3COCD3) 6 7.73-7.34 (m, 9 H), 5.49 (s, 1 H), 5.04 (broad s, 1 H) 4.89 (broad s, 1 H), 4.49 (m, 1 H), 4.44 (m, 1 H). Anal. Calcd. for

C15H1404 + 1/8 H20: C, 70.51; H, 5.27. Found: C, 70.41; H, 5.14.

5-[(1,1*-Biphenyl)4-yl]-dihydro-4-(dimethyl)phenylsilyl -2(3/0- furanone (232) was synthesized by methodology developed by I. Fleming et al.110 A 0.37 M THF solution of dimethyl (phenyl )silyl lithium (33 mL, 12.0 mmol) was added to a 100 mL 2-necked flask protected from light under N2 atmosphere with stir bar and 1.14 g (6.0 mmol) of copper (I) iodide at -23°C (CC14/C02). The suspension was stirred for 4 h and 1.4 g (6.0 mmol) of (/?)-(-)-butenolide 223 dissolved in a minimum volume of THF was slowly added. Stirring was continued for 50 min and the mixture was poured into 25 g of ice and 5 mL of cone. HCl. The aqueous layer was separated and extracted with 3 X 25 mL of CHCI3, and the combined organic layers were washed with 1 X 15 mL of

H20, IX 15 mL of 10% NaHC03 solution, 1 X 15 mL of H20 and 1 X 15 mL of brine, dried (MgS04) and concentrated leaving an oil. Purification was performed by chromatography on silica gel (70:230 mesh) using EtOAc:hexanes (1:9) yielding 1.5 g (688) of 232. Recrystallization of a small sample from EtOAc/Hexanes produced white needles: m.p.

1 103-104°C IR (KBr pellet) 1790 cm" ; *H NMR (CDC13) 6 7.58-7.27 (m, 14 H), 5.25 (d, J = 10.2 Hz, 1 H). 2.70 (dd. J = 17.4, 9.0 Hz, 1 H), 2.52 (dd, J = 17.4, 12.2 Hz, 1H), 2.11 (ddd, J = 12.2, 9.0, 10.2 Hz,

13 1 H), 0.28 (s, 3 H), 0.24 (s, 3 H); C NMR (CDC13) 5 176.6, 141.9. 140.5, 138.0, 135.2, 133.8, 129.8, 128.8, 128.2, 127.6, 127.3, 127.2

127.1, 84.6, 32.6. 32.3, -4.4. Anal. Calcd. for C24H2402Si + 1/4 H20: C. 76.45; H, 6.55. Found: C, 76.11; H. 6.56.

5-[(l,l'-Biphenyl)4-yl]-dihydro-4-hydroxy-2(3/y)-furanonemi58'159 (233) C.A. [75695-13-5] Procedure A: To a 15 mL round bottom 3- necked flask containing a drying tube, stir bar, septum, and 0.093 g (0.25 mmol) of ^-dimethyl(phenyl)silyl lactone 232 in 2.0 mL of glacial acetic acid was added 36 mg (0.30 mmol) of KBr, 62 mg of sodium acetate (anhydrous), and 310 jA. of 32 % AcOOH (slowly with cooling) followed by the addition of 184 mg of sodium acetate and 0.95 mL of 32 % AcOOH. The reaction mixture was stirred for 2 h and monitored by TLC. After 18 h the mixture was gently warmed (40°C) for 2 h and then allowed to stir at room temp for 24 h. Addition of 25 mL of ether and 2.5 g of sodium thiosulfate resulted in a suspension which was stirred vigorously for 0.5 h, filtered through celite and concentrated. The residue was taken up in 30 mL of ether and washed with NaHC03 solution, H20 and brine, dried (Na2S04) and concetrated. The material was purified by silica gel chromatography

(70-230 mesh) using CHCl3:Me0H (95:05). A total of 28 mg (46%) of desired optically active alcohol 233 ((+)-rotation) was isolated: m.p. 203-223 (dec); IR (KBr pellet) 3426, 3075, 3047. 1784, 1479,

1 ] 1430, 1018, 997, 725, 692 cm' ; H NMR (CD3C0CD3) 6 7.72-7.33 (m, 9 H), 5.39 (d, J = 3.6 Hz, 1 H), 4.53 (ddd. J = 3.6, 4.5, 6.5 Hz, 1 H), 2.91 (dd, J = 17.5, 6.5 Hz, 2 H), 2.52 (dd, J = 17.5, 4.5 Hz, 1 H). Procedure B: Mercuric acetate (2.05 g; 6.45 mmol) was added to a stirred solution of /?-silyl lactone 232 (1.60 g; 4.3 mmol) in 47.8 mL of 15 % AcOOH [24 mL of glacial AcOH and 23.8 mL of 32 % AcOOH]. The mixture was stirred at rt for 3 h and diluted with 400 mL of ether. The solution was washed with sodium thiosulfate solution, H20,

NaHC03 solution (careful!) and brine, dried (MgS04) and concentrated. A total of 1.2 g of material containing 233 was isolated and used in subsequent reactions without further purification.

4-Benzoyloxy-5-[(l,l'-Biphenyl)4-yl]-dihydro-2(3/y)-furanone (234):

To a 10 mL round bottom flask with stir bar under N2 at 0°C was added

0.10 g (0.4 mmol) of ^-hydroxylactone 233, 1 mL of CC14. 0.3 mL of DMF, 0.18 mL (2.2 mmol) of pyridine and 0.07 mL (0.6 mmol) of benzoyl chloride. The reaction mixture was stirred over night at rt and diluted with 15 mL of Et20. The organic layer was separated and washed with 1 X 1 mL of H20 and 1 X 1 mL of brine, dried (Na2S04) and concentrated. Filtration through silica gel (70-230 mesh) using EtOAc:Hexanes (1:9) as elutant furnished 70 mg (50%) of 234: m.p.

l 97-99°C; W NMR (CDC13) 6 8.10-8.06 (m, 2 H), 7.67-7.34 (m, 13 H), 5.78 (s, 1 H), 5.57-5.55 (m, 1 H), 3.04 (dd, J = 18.4, 6.3 Hz, 1 H), 2.77 (dd, J = 18.4, 1.3 Hz, 1 H); MS (EI) M+ 358.1226 (0.13% for

C23H1804). 237 (12.37%). 236 (66.84%), 181 (59.41%), 105 (100%, C^).

5-[(l,l'-Biphenyl)4-yl]-dihydro-4-((l,l- dimethylethyl)dimethylsilyl)oxy-2(3//)-furanone (236): A mixture of 62 mg (0.25 mmol) of /?-hydroxylactone 233, 56 mg (0.37 mmol) of TBDMSCl, 35 mg (0.5 mmol) of imidazole and 3 mL of DMF was stirred at rt for 8 h under N2. The reaction mixture was diluted with 15 mL of ether, washed with 2 X 1 mL of H20 and 2 X 1 mL of brine, dried

(Na2S04) and concentrated: *H NMR (CDC13) 6 7.62-7.34 (m. 9 H), 5.29 (d, J = 4.0 Hz, 1 H), 4.36 (m, 1 H), 2.83 (dd J = 6.4. 17.3 Hz, 1 H). 2.54 (dd, J = 5.2, 17.3 Hz, 1 H), 0.87 (s, 9 H), 0.01 (s, 3 H). 0.00 (s. 3H); MS (EI) M+ 311 (4.03). 283 (9.89), 269 (74.65), 193 (81.61), 181 (96.45). 101 (100; q^Sij).

5-[(l.l'-Biphenyl)4-yl]-dihydro-2(3/y)-furanone (228) C.A. [40885-19- 6]: Butenolide 223 (2.36 g, 10.0 mmol) was dissolved in 50 mL of EtOAc and hydrogenated at 50 psi for 2 h using 50 mg of 10% PdZC as catalyst. The catalyst was removed by gravity filtration and the filtrate was concentrated leaving 2.3 g (95%) of saturated lactone

1 l 228: m.p. 104-105°C; IR (KBr pellet) 1750 cm" ; W NMR (CDC13) 6 7.63-7.54 (m, 4 H), 7.47-7.31 (m. 5 H). 5.54 (dd, J = 8.0, 6.2 Hz. 1 H), 2.73-2.63 (m, 3 H), 2.26-2.11 (m. 1 H); MS (EI) M+ 238 (17.5). 5-[(1.1'-Biphenyl)-4-yl]-dihydro-3-[(dimethyl amino)methylene)-2(3/7)- furanone (229) was prepared by the method of Wasserman and Ives105. To 1.4 g (5.8 mmol) of lactone 228 under argon atmosphere was added 2 mL of DMF and 1.4 mL (9.0 mmol) of tr7's-(dimethylamino)methane. The suspension was stirred for 24 h at 60 to 70°C. All volatile substances were removed under vacuo (0.3 mm Hg, 60°C) and the crude product was recrystallized from EtOAc and Et20 to produce light brown needles (1.1 g; 65*): m.p. 189-19FC, IR (KBr pellet) 1710, 1625, 1490, 1446, 1325, 1298, 1194, 1130, 1060, 1014, 997, 951, 843 cm"1;

! H-NMR (DMS0-d6) 6 7.69-7.64 (m, 4 H), 7.49-7.33 (m, 5 H), 7.10 (s, 1 H), 5.43 (dd, J = 6.19, 8.82 Hz, 1 H), 3.61 (dd, J = 8.38, 14.57 Hz,

1 H). 2.99-2.90 (m, 7 H). Anal. Calcd. for C19H19N02: C, 77.79; H, 6.53; N, 4.78. Found: C, 77.22; H, 6.63; N, 4.81.

5-[(l,l'-Biphenyl)-4-yl]-3-hydroxy-2(5/y)-furanone (230): The procedure of Wasserman and Ives105 was followed. To a 125 mL Pyrex tube (2.7 cm X 27 cm) was added 0.29 g (1.0 mmol) of

(dimethylamino)methylene lactone 229, 100 mL of anhydrous CH2C12 and 20 mg of Rose Bengle (sensitizer). The pyrex tube was inserted into a large cold finger wrapped in foil, in a manner that provided a 2 X 20 cm area for illumination and prevented condensation on the surface of the cold finger (Note, the reaction failed when condensation formed on the surface of the cold finger). The cold finger's condenser was evacuated (vacuum pump) and cooled to c.a. -5°C

(MeOH/ice). A 2-holed rubber stopper with an 02 inlet and outlet was 100 inserted into the pyrex reaction tube. Oxygen was bubbled through a fritted disk positioned at the bottom of the reaction vessel and the reaction was illuminated at a distance of 50 cm with a 650 W halogen lamp (DWY-650) at 70 V (rheostat). The reaction was monitored by TLC

(product Rf slightly less than that of starting material in MeOH:CHCl3 (9:1)). Decolorizing charcoal (c.a. 5 g) was added and the solution was stirred at rt for 10 minutes, filtered through celite, washed with 2 X 15 mL of CH2C12 and concentrated. The product was triturated with CH2C12 and hexanes which left 0.16 g (63%) of 230 as an off white solid: m.p. 138-145°C: IR (KBr pellet) 3400, 3190, 1770, 1650, 1350

1 ! cm" ; H NMR (CD3C0CD3) 6 7.64-7.32 (m. 9 H), 6.35 (d, J = 2.1 Hz, 1 H), 5.95 (d, J = 2.05 Hz, 1 H). MS (EI) 252 (37), 207 (100); HRMS,

Calcd. for C16H1203 252.078644; Found: 252.077713.

5-[(l,l'-Biphenyl)-4-yl]-3-methoxy-2(5tf)-furanone (231): Dimethyl aminomethylene lactone 229 (0.5 g; 1.6 mmol) was photooxidized as described above, stirred with charcoal, filtered through celite and concentrated. The crude enol lactone 230, without purification, was dissolved in 50 mL of ether, cooled to 0°C and titrated with CH2N2 until the solution remained slightly yellow. The reaction mixture was concentrated, filtered through silica gel (70- 230 mesh) using EtOAc:hexanes (30:70) as elutant and recrystallized from MeOH to produce 0.3 g (65%) of 231 as white needles: m.p. 140- 142°C ; IR (KBr pellet) 1759, 1660, 1236, 1134, 761 cm"1; XH NMR

(CD3C0CD3) 6 7.71-7.62 (m, 4 H), 7.49-7.32 (m, 5 H), 6.61 (d, J = 2.12 Hz. 1 H). 6.08 (d, J = 2.07 Hz. 1 H). 3.84. (s, 3 H). Anal. Calcd.

for C17H1403: C. 76.68%; H, 5.30%. Found: C. 76.31; 5.40.

5- [d,r-Biphenyl)-4-yl] -3- [(dimethyl ami no Methylene] -2(3/7) -furanone (238). Under argon atmosphere were combined 0.52 g (2.2 mmol) of 4- biphenyl-2-butenolide 223. 1.4 mL (9.0 mmol) of tns- (dimethyl amino)methane and 1.0 mL of DMF. The mixture was stirred for 8 h at 55°C. All volatile substances were removed under vacuo (0.3 mm Hg, 50°C) and recrystallization from acetone/EtOAc provided 0.6 g (94%) of 238 as yellow crystals: m.p. 222-223.5°C; lH NMR

(CDC13) S 7.68-7.57 (m, 6 H), 7.47-7.30 (m. 4 H), 6.62 (s, 1 H), 3.23

(s. 6 H). Anal. Calcd. for C19H17N02 + 1Z4 H20; C, 77.13; H, 5.96; N. 4.73: Found: C. 76.87; H, 5.82; N. 4.76. (±)-a-Acetyloxy-4-chlorophenylacetic acid14114214314414515°161 m 163 (271): p-Chloromandelic acid (270) (14.2 g; 76 mmol) and 30 mL (420 mmol) of acetyl chloride were combined with stirring under argon. The mixture was warmed (gentle reflux) for 45 mm. Excess acetyl chloride was removed by distillation (8 mm Hg, 100°C) and subsequently dried under reduced pressure. The crude acetyl p-

chloromandelic acid was dissolved in 600 mL of Et20, washed with 2 X

50 mL of H20 and extracted with 3 X 50 mL of sat. NaHC03 solution.

The NaHC03 solution was washed with 1 X 50 mL of Et20, acidified with

10% aqueous HC1 and extracted with 3 X 150 mL of Et20. The organic

layer was washed with 2 X 50 mL of H20 and 2 X 50 mL of brine, dried

(Na2S04) and concentrated leaving 12.8 g (74%) of a-acetyloxy acid 271 102 as a viscous light-yellow oil. A small sample was crystallized from

X ether and hexanes: H NMR (CDC13) 6 7.45-7.35 (m, 4 H), 5.88 (s, 1 H), 2.17 (s. 3 H).

(-)-[(l/?,2S,5/?)-5-Methyl-2(l-methyl)ethyl-l-cyclohexyl] p- Chlorophenyl-a-oxoacetate (272): (±)-a-Acetyloxyacetate 271 (26.5 g; 116 mmol), 26.2 g (127 mmol) of DCC and 19.8 g (127 mmol) of

(l/?,2S,5/?)-(-)-menthol were dissolved in 600 mL of CH2C12 (distilled from P205). Dimethyl aminopyridine (DMAP) (1.5 g; 12 mmol) was added and a white precipitate immediately formed. The mixture was agitated slightly several times to ensure complete mixing of the reagents and subsequently was allowed to stand for 12 h. The suspension was filtered and washed with 3 X 100 mL of CH2C12. The combined filtrate was washed with 3 X 300 mL of H20, 3 X 300 mL of AcOH:H20 (0.5:9.5), 3

X 300 mL of H20, 2 X 200 mL of NaHC03 solution, 1 X 300 mL of H20 and

1 X 300 mL of brine, dried (MgS04) and concentrated. The diastereomeric mixture of (-)-menthyl esters was dissolved in 800 mL of MeOH, and 200 mL of a 0.5 N K2C03 solution was added. THF (500 mL) was added and the solution was stirred for 3 h. The reaction mixture was acidified with 10% HC1 to pH 5, concentrated and diluted with

2000 mL of CHC13. The aqueous phase was separated and the organic layer was washed with 2 X 200 mL of H20 and 1 X 200 mL of brine, dried

(Na2S04) and concentrated.

The crude mixture containing (-)-menthyl a-hydroxyacetate diastereomers was dissolved in 500 mL of acetone. A freshly prepared 103 solution of Jones reagent was slowly added while the reaction temperature was maintained between 15°C and 25°C. Isopropanol (40 mL) was added when TLC analysis indicated starting material was absent. The green chromium salts were filtered and washed with small portions of acetone, and the combined filtrate was concentrated and diluted with 1000 mL of Et20. The organic layer was washed with 2 X 200 mL of

H20, 2 X 100 mL of sat. NaHC03 solution, 1 X 200 mL of H20 and 1 X 200 mL of brine, dried (Na2S04) and concentrated leaving a yellow oil. The a-keto ester 272 was purified by chromatography over silica gel (70-230 mesh) using EtOAc:Hexanes (0.5:9.5) as elutant to produce 28 g (75%) of ketone 272 as a light yellow oil: ajj° -43.0° (c = 1.596, EtOH). IR (NaCl plates), 2958, 2929, 2871, 1726, 1689, 1589, 1201,

1 ! 1174, 1088, 991 cm" ; H NMR (CDC13) 6 1.97'-1.92 (m, 2 H), 7.52-7.47 (m, 2 H), 4.99 (dt, J = 4.45, 10.93 Hz, 1 H), 2.20-2.12 (m. 1 H), 1.99-1.87 (m, 1 H), 1.79-1.47 (m, 4 H), 1.25-1.00 (m, 2 H), 0.97-0.77 (m, 10 H). a-Chlorophenyl-a-oxoacetic Acid (301): Methyl a-keto- p-chlorophenylacetate 265 (20 g; 100 mmol) dissolved in 300 mL of

MeOH:H20 (3:1) was saponified by the slow addition of 6 g (150 mmol) of NaOH dissolved in 60 mL of H20. The solution was acidified with

10% HC1, concentrated and extracted with 3 X 100 mL portions of Et20.

The Et20 solution was washed with 2 X 30 mL of H20 and 1 X 30 mL of brine, dried (Na2S04) and concentrated leaving 18.2 g (98%) of the corresponding a-ketoacetic acid 301: *H NMR (CDC13) 8 8.6 (s. 1 H), 13 8.25-8.15 (m, 2 H), 7.45-7.55 (m, 2 H); C NMR (CDC13) 6 183.4, 161.7, 142.6, 132.5, 130.2, 129.4.

(+)-1(1S,2R,5S)-5-Methyl-2(l-methyl)ethyl-l-cyclohexyl] p- Chlorophenyl-a-oxoacetate (302): a-Ketoacetic acid 301 (18.2 g; 100 mmol). 22.7 g (110 mmol) of DCC and 17.2 g (110 mmol) of (1S.2R.5S)-

12 (+)-menthol were dissolved in 600 mL of CH2C12 (distilled from P205) . 4-Dimethyl aminopyridine (1.2 g; 10 mmol) was added and a white precipitate immediately formed. The mixture was agitated slightly several times to ensure complete mixing of the reagents and was allowed to stand for 12 h. The suspension was filtered and washed with 3 X 100 mL of CH2C12. The combined filtrate was washed with 3 X

300 mL of H20, 3 X 300 mL of AcOH:H20 (0.5:9.5), 3 X 300 mL of H20, 2

X 200 mL of NaHC03 solution, 1 X 300 mL of H20 and 1 X 300 mL of brine, dried (MgS04) and concentrated. The (+)-menthyl a-ketoacetate 302 was purified by chromatography over silica gel (70-230 mesh) using EtOAc:hexanes 0.5:9.5 as elutant: a[j2 +48.8° (c = 1.03, EtOH);

Anal. Calc. for C18H2303C1; C, 66.97: H, 7.18. Found: C, 66.83: H. 7.14.

(/?)-(-)-[(l/?,2S.5/?)-5-Methyl-2(l-methyl)ethyl-l-cyclohexyl] a- Hydroxy-a-p-chlorophenylacetate (273): (-)-a-Keto menthyl ester 272 (28 g; 87 mmol) was dried in a 500 mL round bottom flask and 50 mL (167 mmol) of Alpine borane95 (prepared from (l/?M+)-a-pinene of greater than 92% ee) was added under an argon atmosphere. The reaction mixture was stirred for 24 h and cooled to 0°C. Acetaldehyde (9.0 mL; 160 mmol) was added. Volatile substances were removed by distillation (0.3 mm Hg, 70-80°C) and the resultant oil was diluted with 400 mL of Et20 and cooled to 0°C. Ethanolamine (10 mL; 163 mmol) was added with vigorous stirring. The salts were filtered through celite and washed with 2 X 50 mL of Et20. The combined filtrate was washed with 1 X 50 mL of H20 and 1 X 50 mL of brine, dried (Na2S04) and concentrated. The crude product was dried under reduced pressure (0.3 mm Hg, 75°C) and recrystallized from

EtOH/H20 five times to yield diastereomerically pure (-)-menthyl oi- hydroxyacetate 273: m.p. 105-106°C; ajf -119° (c = 1.83, EtOH); IR (KBr pellet) 3452, 3404, 2956, 2933, 2868, 1732, 1201. 1180, 1092

-1 X cm ; H NMR (CDC13) 6 7.34-7.27 (m, 4 H), 5.06 (s, 1 H), 4.63 (dt, J = 4.44, 10.92 Hz, 1 H), 2.05-1.97 (m, 1 H), 1.67-1.40 (m. 3 H), 1.27- 1.16 (m, 1 H), 1.07-0.93 (m, 2 H), 0.90-0.74 (m, 5 H), 0.60 (d, J =

6.98 Hz, 3 H), 0.39 (d. J = 6.93 Hz, 3 H); Anal. Calcd. for C18H2503C1; C, 66.55; H, 7.76; Found: C, 66.30; H, 7.69.

(/?)-(-)-[d/?,2S,5/?) -5-Methyl-2(1-methyl)ethyl -1 -cyclohexyl] a-((l.l- Dimethylethyl)dimethylsilyl)oxy-p-chlorophenylacetate (274): (-)-Menthyl a-hydroxyacetate 273 (1.62 g; 5.0 mmol), 1.13 g (7.5 mmol) of TBDMSC1 and 0.68 g (10.0 mmol) of Imdidazole were combined under N2 and dissolved in 10 mL of dry DMF. The solution was stirred for 22 h at rt and partitioned between 75 mL of Et20 and 5 mL of H20. The aqueous layer was separated and the organic phase was washed with 2 X 5 mL of H20 and 1 X 10 mL of brine, dried (Na2S04) and concentrated. The compound was dried under reduced pressure (0.3 mm Hg. 65°C) leaving 2.0 g (92%) of silyl ether 274 as a colorless oil. An analytical sample was prepared by filtering a small amount of compound through a pad of silica gel (70-230 mesh) using EtOAc:hexanes (0.5:9.5) as elutant: ajf -77.7° (c = 0.47. EtOH); IR (NaCl plates) 2956. 2929, 2858, 1751, 1727, 1253. 1174, 1134. 1093 cm" l l ; H NMR (CDC13) 6 7.39-7.25 (m, 4 H), 5.11 (s, 1 H), 4.59 (dt. J = 4.40, 10.84 Hz, 1 H), 1.94-1.85 (m. 1 H), 1.65-1.54 (m, 2 H), 1.48- 1.21 (m, 3 H), 1.01-0.73 (m, 15 H), 0.70 (d, J = 6.94 Hz, 3 H), 0.48 (d, J = 6.90 Hz, 3 H). 0.10 (s, 3 H), 0.01 (s. 3 H). Anal. Calcd. for C24H3903ClSi: C, 65.65; H. 8.95. Found: C, 66.02; H, 9.07.

(tf)-(-)-p-Chlorophenyl-«-[((1,1-dimethyl ethyl)dimethylsilyl)oxy]- acetaldehyde (275): A 50 mL 2-necked round bottom flask was equipped with a septum and nitrogen inlet was added 0.87 g (2.0 mmol) of /?-(-)-menthyl acetate 274 dissolved in 10 mL of dry toluene. The solution was cooled to -78°C (C02/acetone) and 2.2 mL (2.2 mmol) of a 1.0 M solution of DIBAL-H in toluene was added slowly (5 min) with stirring. The reaction mixture was stirred for 1 h at -78°C and poured onto 50 g of ice and 75 mL of CHC13. The mixture was stirred vigorously for 30 min and the CHC13 layer was separated. The aqueous phase was washed with 50 mL of CHC13 (emulsion) and the combined CHC13 extracts were washed with brine 1 X 80 mL, dried (Na2S04) and concentrated leaving a mixture of aldehyde 275 and (-)-menthol. Chromatography over silica gel (70-230 mesh) using EtOAc:hexanes (0.5:9.5) as elutant provided 0.08g (18ft) of aldehyde 275 as an oil identical in all respect with 275 prepared from methyl ester 277.

(±)-a-Acetyloxy[(l,l'-biphenyl)4-yl]acetic Acid164165 (267): a-Hydroxybiphenyl acetic acid 259 (1.45 g; 6.4 mmol) dissolved in 15 mL of CH2C12, 0.6 ml_ (6.4 mmol) of acetic anhydride and 0.8 mL (10 mmol) of pyridine was stirred under argon for 45 min. The mixture was diluted with 60 mL of Et20 and extracted with 3 X 10 mL of NaHC03 solution. The combined aqueous extracts were washed with 25 mL of

Et20, acidified with 10% aqueous HC1 and extracted with 2 X 30 mL of

Et20. The pooled organic extracts were washed with 25 mL of 10ft aqueous HC1. 25 mL of H20 and 25 mL of brine, dried (Na2S04) and concentrated. Recrystallization from Et20 and Hexanes produced 1.6 g (94ft) of acetate 267 as white stars: m.p. 120-136°C (lit10 134°C):

X H NMR (CDC13) 6 8.77 (s (broad). 1 H), 7.62-7.32 (m, 9 H), 5.98 (s. 1 H), 2.19 (s. 3 H):

(+)-[(lS.2/?.5S)-5-Methyl-2(l-methyl)ethyl-l-cyclohexyl] a-Oxo[(l.l'- biphenyl)4-yl]acetate (268): (±)~a-Acetyloxybiphenyl acetate 267 (14.1 g; 52 mmol), 11.8 g (57 mmol) of DCC and 8.9 g (57 mmol) of

(IS,2R,5S)-(+)-menthol were dissolved in 300 mL of CH2C12 (distilled 166 from P205) . 4-dimethylaminopyridine (0.7 g; 5.7 mmol) was added and a white precipitate immediatly formed. The reaction mixture was agitated slightly several times at 30 sec intervals to ensure 108 complete mixing of the reagents and subsequently was allowed to stand for 12 h. The suspension was filtered and washed with 3 X 50 mL of

CH2C12. The combined filtrate was washed with 3 X 150 mL of H20, 3 X

150 mL of AcOH:H20 (0.5:9.5), 3 X 150 mL of H20, 2 X 100 mL of NaHC03 solution, 1 X 150 mL of H20 and 1 X 150 mL of brine, dried (MgS04) and concentrated. The diastereomeric mixture (1:1) of menthyl esters was dissolved in 400 mL of MeOH, and 100 mL of a 0.5 N K2C03 solution was added. THF (300 mL) was added and the solution was stirred for 3 h. The reaction mixture was acidified with 10% HC1 (pH 5), concentrated and diluted with 1000 mL of CHC13. The aqueous phase was separated and the organic layer was washed with 2 X 100 mL of H20 and 1 X 100 mL of brine, dried (Na2S04) and concentrated. The crude mixture containing menthyl a-hydroxyacetate diastereomers was dissolved in 250 mL of acetone. A freshly prepared solution of Jones reagent was added slowly and the reaction temperature was maintained between 15 and 25°C. Isopropanol (20 mL) was added after TLC analysis indicated the absence of starting material. The green chromium salts were filtered with suction, washed with small portions of acetone, and the combined filtrate was concentrated and diluted with 1000 mL of Et20. The organic solution was washed with 3 X 100 mL of H20, 2 X 50 mL of sat. NaHC03 solution,

1 X 100 mL of H20 and 1 X 100 mL of brine, dried (Na2S04) and concentrated leaving a yellow oil. Filtration through silica gel (70-230 mesh) using EtOAc:Hexanes (0.5:9.5) as elutant produced 16.3 109 g (85%) of ketone 268 as a light yellow oil: a2,2 +31.6° (c = 2.554, EtOH): IR (NaCl plates) 2960, 2927, 2871, 1734, 1685, 1602, 1452,

1 1317, 1305, 1215, 1186, 1007, 991. 762, 746 cm" ; *H NMR (CDC13) 6 8.09-8.04 (m, 2 H). 7.76-7.61 (m, 4 H), 7.52-7.38 (m, 3 H), 5.03 (dt, J = 4.44, 10.92 Hz, 1 H), 2.24-2.16 (m, 1 H), 2.04-1.92 (m, 1 H), 1.79-1.65 (m, 2 H), 1.64-1.48 (m, 2 H), 1.31-1.06 (m, 3 H), 0.98-0.85

(m, 9 H). Anal. Calcd. for C24H2803; C, 79.09; H, 7.74: Found: C, 78.75; H, 7.79.

(S)-(+)-[(lS.2/?,5S)-5-Methyl-2(l-methyl)ethyl-l-cyclohexyl] c^Hydroxy[(l,l'-biphenyl)4-yl]acetate (269): a-Keto menthyl ester (16 g; 44 mmol) 268 was dried in a 250 mL round bottom flask and 22.5 mL (75 mmol) of Alpine borane95 (prepared from (IS>)-(-)-a-pinene of 98% ee) was added under an argon atmosphere. The reaction mixture was stirred for 24 h, cooled to 0°C and 4.2 mL (75 mmol) of acetaldehyde was added. Volatile substances were removed by distillation (0.3 mm

Hg. 70-80°C) and the resultant oil was diluted with 200 mL of Et20 and cooled to 0°C. Ethanolamine (4.6 mL; 75 mmol) of was added with vigorous stirring. The salts that formed were filtered through

celite and washed with 2 X 50 mL of Et20. The combined filtrate was washed with 1 X 50 mL of H20 and 1 X 50 mL of brine, dried (Na2S04) and concentrated. The crude product was dried under reduced pressure

(0.3 mm Hg, 75°C) and recrystallized from EtOH/H20 to produce 10 g (62%) of 100% de material: m.p. 99.5-102°C; af +112.4° (c = 1.46, EtOH); IR (KBr pellet) 3444, 2956, 2863, 1728, 1489, 1389, 1296, 1 X 1207, 1180, 1093, 1074, 755 cm" : H NMR (CDC13) 6 7.57-7.30 (m, 9 H), 5.13 (s. 1 H), 4.65 (dt, J = 4.41, 10.91 Hz, 1 H), 3.6 (d, 1 H), 2.06-2.01 (m, 1 H), 1.66-1.35 (m. 4 H), 1.30-0.77 (m, 9 H), 0.55 (d, J = 6.98 Hz, 3 H), 0.38 (d. J = 6.92 Hz, 3 H); Anal. Calcd. for

C24H3003 + 1/8 H20 C, 78.17; H, 8.27: Found: C, 78.17; H, 8.41. p-Chlorophenyl-a-hydroxyacetic Acid167164135168 (270): To a 2- necked 500 mL round bottom flask equipped with a condenser, nitrogen inlet and septum was added 35 g (250 mmol) of p-Chlorophenylcarboxaldehyde. 49 g (750 mmol) of KCN, 0.3 g (2.5 mmol) of Zn(CN)2. 135 mL of dry CH3CN and 80 mL (625 mmol) of TMSC1. The suspension was warmed to reflux with stirring and after 18 h an additional 35 mL (300 mmol) of TMSC1 was added. The mixture was maintained at reflux for 18 h, cooled, filtered (scintered glass), washed with 3 X 30 mL of CH3CN, and the combined filtrate was concentrated to a solid (Rotovap). The crude cyanohydrin was ground into a fine powder, diluted with 400 mL of cone. HCl and stirred for 24 h. The yellow suspension was poured on to 1500 g of ice,

filtered, washed with several portions of H20 and dried leaving the crude acetamide, which may be recrystallized from THF and CH2C12: m.p. 120-121°C.

The crude acetamide was dissolved in 600 mL of a 5 M solution of KOH in methanol and warmed to reflux for 2 h, cooled to rt, concentrated, poured into 400 g of ice and acidified with 10 % aqueous HCl. The suspension was extracted with 3 X 500 mL of Et20 and Ill the combined Et20 extracts were washed with 1 X 200 mL of H20 and extracted with 3 X 75 mL of NaHC03 solution. The combined NaHC03 extracts were washed with 2 X 50 mL of Et20, acidified with 10% aqueous HC1 and extracted with 3 X 250 mL of Et20. The combined organic extracts were washed with 1 X 75 mL of H20 and 2 X 75 mL of 136 brine, dried (Na2S04) and concentrated: m.p. 98-106°C, (lit m.p. 119-120°C).

Methyl p-Chlorophenyl-a-hydroxyacetate169 (303): A 250 mL round bottom flask containing 5.6 g (30 mmol) of p-chloromandelic acid 270 and 100 mL of cone HCl:MeOH (1:9) was warmed to reflux for 12 h. The solution was concentrated under reduced pressure, diluted with 250 mL of Et20 and washed with 1 X 30 mL of H20, 2 X 30 mL of NaHC03 solution, 1 X 30 mL of H20 and 1 X 30 mL of brine. The organic layer was dried (Na2S04) and concentrated leaving 5.0 g (83%) of p- 13 chloromandelate 303: (lit m.p. 55°C) 'H-NMR (CDC13) S 7.36-7.28 (m, 4 H), 5.13 (s, 1 H), 3.72 (s, 3 H), 3.67 (br s, 1 H (exchanges with

D20)).

Methyl p-Chlorophenyl-a-oxoacetate (265) C.A. [37542-28-2]: Selenium dioxide140 (35.5 g: 320 mmol) was dissolved in 250 mL of MeOH (warm to reflux with stirring) and 19.6 g (315 mmol) of a-bromo-4- chloroacetophenone139 was added. The reaction mixture was warmed to reflux for 24 h, cooled, filtered and concentrated leaving an orange oil. The oil was diluted with 1500 mL of Et20 and washed with 3 X 200 mL of H20 and 1 X 200 mL of brine, dried (Na2S04) and concentrated.

The crude oil was crystallized from Et20 and hexanes at -20°C. The white needles were filtered while cold and washed with small portions of cold hexanes to yield 22 g (35%) of 265: m.p. 56-57°C, XH-NMR

13 (CDC13) 6 8.0-7.9 (m, 2 H), 7.5-7.4 (m. 2 H), 3.9 (s, 3 H); C-NMR (CDC13) 6 184.4, 163.5, 141.6, 131.4. 131.0, 129.3. 52.7.

(/?)-(-)-p-Chlorophenyl-a-hydroxyacetic acid (276) C.A. [32189-36-9]: a-Ketoacetate 265 (16.0 g; 80 mmol) was dried under reduced pressure for 12 h in a 250 mL flask. The flask was filled with argon and 36 mL (120 mmol) of Alpine borane95 (prepared from (i/?)-(+)-a-pinene of 93% ee) was added. The solid reaction mixture turned to a red suspension after 8 h. The mixture was now stirred and after 16 h was cooled to 0°C. Acetaldehyde (6.7 mL) was added with stirring. All volatile materials were removed by distillation (80°C, 0.3 mm Hg), and the resultant orange oil was taken up in 200 mL of Et20 and cooled to 0°C. Ethanolamine (8 mL; 135 mmol) was added. The reaction mixture was stirred vigorously for 30 min, filtered (scintered glass packed with celite) and washed with 3 X 25 mL of Et20. The combined filtrate was washed with 1 X 50 mL of H20 and 2 X 30 mL of brine, dried (Na2S04) and concentrated leaving an orange oil. The crude hydroxyacetate 266 was dissolved in 325 mL of MeOH, and 75 mL of an aqueous 0.42 M solution of NaOH was added with stirring and at rt over a 2 h period. After an additional 2 h the solution was acidified to pH 6 with 10% aqueous HC1, concentrated under reduced pressure and diluted with 300 mL of H20 and 75 mL of sat. NaHC03 solution. The solution was washed with 2 X 150 mL of

Et20. acidified to pH 1 with 10% aqueous HC1 and extracted with 3 X

150 mL of Et20. The Et20 solution was washed with 1 X 30 mL of H20 and 2 X 30 mL of brine, dried (Na2S04) and concentrated leaving 12.5 g (84%) of optically active acid 270, 72% ee, am -96.12° (MeOH).

(S)-(+)-p-Chlorophenyl-a-hydroxyacetic Acid was synthesized by a nearly identical procedure as described for (/?)-(-)-enantiomer 276. The only difference was that the reduction was performed with Alpine borane prepared from (15)-(-)-a-pinene of 98% ee.

(/?)-(+)-Methyl benzyl amine Salt (280) of (/?)-(-)-p-Chlorophenyl-a- hydroxyacetic acid (276): The 72% ee acid (12.5 g; 67 mmol) was dissolved in 250 mL of absolute EtOH and warmed to reflux on a steam bath. (/?)-(+)-Methyl benzyl amine (8.6 mL; 67 mmol) was added and the flask was removed from the steam bath, seeded with a small crystal of the salt, wrapped in cotton and not disturbed for 48 h. The crystals were filtered, washed with 6 X 25 mL portions of cold absolute EtOH and dried leaving 14.65 g (71%. 83% based on 72% ee) of the diastereomeric salt. The salt was recrystalized twice from EtOH to yield 12.5 g of the diastereomerically and optically pure salt 280 of p-chloromandelic acid: m.p. 194-200°C, off -49.7° (c = 0.316, MeOH), a2* -190° (c = 0.316, MeOH). 114 (S)-(-)-Methyl benzyl amine Salt of (S)-(+)-p-Chlorophenyl-a- hydroxyacetate was prepared as described for the (/?)-(-)-enantiomer

22 276: m.p. 194-200°C; off +48.7° (c = 0.624. MeOH), a Hg365 +185 (c = 0.624, MeOH).

(/?)-(-)-p-Chlorophenyl-a-hydroxyacetic Acid (276): (R)-(-)-Amine salt 280 (4.6 g; 15 mmol) was added to a separatory funnel containing

150 mL of Et20 and 40 mL of 5% aqueous HCl and shaken vigorously until

the salt dissolved. The Et20 layer was separated and washed with 1 X

25 mL of b% aqueous HCl. 2 X 25 mL of H20 and 1 X 25 mL of brine,

dried (Na2S04) and concentrated leaving 2.7 g (97%) of optically pure a-hydroxyacetic acid 270. For analytical data, a small sample was

recrystallized as white needles from CH2C12 and Pet ether: m.p. 117- 119°C (lit170 m.p.l20.5-121°C); off -129° (c = 0.966. EtOH).

(S)-(+)-p-Chlorophenyl-a-hydroxyacetic Acid was prepared as described for (/?)-(-)-enantiomer 276: m.p. 116-119°C; off +132° (c = 1.42, EtOH).

(/?)-(-)-Methyl p-Chlorophenyl-a-hydroxyacetate (266) C.A. [32174- 34-8]: A solution of (/?)-(-)-p-chloromandelic acid (276) (2.6 g; 14 mmol) in 100 mL of Et20 was cooled to 0°C and titrated with CH2N2 until the yellow color of CH2N2 persisted. Evaporation of sovent provided 2.65 g (96%) of methyl ester 266 as a colorless oil: off - 110° (c = 1.102. EtOH). 115 (S)-(+)-Methyl p-Chlorophenyl-a-hydroxyacetate was prepared as described for the (/?)-(-)-enantiomer 266: ojf +103° (c = 1.555, EtOH).

(/?)-(-)-Methyl p-Chiorophenyl-«-[((1,1- dimethyl ethyl)dimethyl si lyDoxy]-acetate (304): a-Hydroxy acetate 266 (2.05 g; 10.0 rnmol). 2.26 g (15.0 mmol) of TBDMSC1, 1.09 g (16.0 mmol) of Imdazole and 10 mL of DMF were combined in a 100 mL round bottom flask and stirred under argon for 18 h. The reaction mixture was diluted with 150 mL of Et20. washed with 3 X 25 mL of H20 and 1 X

25 mL of brine, dried (Na2S04), and concentrated. The compound was dried under reduced pressure (0.3 mm Hg, 60°C) for 1.5 h to yield 3.03 g {91%) of tert-butyldimethylsilyloxyacetate 304 as a colorless

X oil: ajf -60° (c = 0.616, EtOH); H-NMR (CDC13) 6 7.41-7.37 (m, 2 H). 7.32-7.27 (m, 2 H), 5.18 (s, 1 H), 3.66 (s, 3 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.02 (s, 3 H).

(S)-(+)-Methyl p-Chlorophenyl-a-[((1,1- dimethylethyl)dimethylsilyl)oxy]-acetate was prepared as described for the (/?)-(-)-enantiomer 304: ajf +59° (c = 0.652, EtOH).

(R) - (-) -p-Chl orophenyl -a- [((1,1 -dimethyl ethyl) dimethyl si lyDoxy]- acetaldehyde (275): To a 100 mL 2-necked round bottom flask was equipped with a septum and nitrogen inlet was added 3.0 g (9.5 mmol) of (/?)-(-)-methyl acetate 304 dissolved in 55 mL of dry toluene. The solution was cooled to -78°C (C02/acetone) and 12 mL (12 mmol) of a 1.0 M solution of DIBAL-H in toluene was added slowly (5 mm) with stirring. The reaction mixture was stirred for 1 h at -78°C and poured into 100 g of ice and 100 mL of CHC13 The reaction flask was rinsed with 100 mL of CHC13 and the mixture was stirred vigorously for

30 min. After separation of the CHC13 layer, the aqueous phase was washed with 100 mL of CHC13 and the combined CHC13 extracts were washed with brine 1 X 80 mL, dried (Na2S04) and concentrated leaving 2.5 g (93%) of aldehyde 275 as a clear colorless oil of better than 95% purity (!H-NMR). The aldehyde was not further purified owing to it's instability to temperatures above 60°C and to silica gel: ajf

-33.71° (c = 0 330, EtOH); 'H-NMR (CDC13) 6 9.47 (d. J = 2 0 Hz, 1 H), 7.33-7.32 (m. 4 H), 4 95 (d, J = 2.0 Hz, 1 H), 0 92 (s, 9 H), 0.10 (s. 3 H), 0.02 (s, 3 H).

(S)-(+)-p-Chlorophenyl-a-[((l,l-dimethylethyl)dimethylsilyl)oxy]- acetaldehyde was prepared as described for the (/?)-(-)-enantiomer 275: off +46.5° (c = 0.316, EtOH)

(4/?)-(-)-Ethyl 2-Carboxylate-2-[/?-(4-chlorophenyl)-a-((2.2- dimethyl )l-propanoyl )oxy-/?-(( 1,1 -dimethyl ethyl) dimethyl si lyUoxy] - 1,3-dithiane (283). A solution of 0.52 mL (3.3 mmol) of ethyl 1.3- dithiane-2-carboxylate171172153 in 10 mL of THF (freshly distilled from Na/benzophenone) under argon was cooled to -78°C (C02/acetone) and 2.2 mL (3.3 mmol) of 1.5 M LDA (solution in cyclohexanes) was added with stirring. The reaction mixture was removed from the dry ice bath for 10 min, cooled to -78°C and stirred for 1 h. A solution consisting of 0.85 g (3.0 mmol) of (/?)-(-)-acetaldehyde 275, 2 mL of THF and 0.41 mL (3.3 mmol) of pivaloyl chloride was added dropwise. Stirring was continued for 2 h at -78°C and for 1 h at rt. The

reaction mixture was diluted with 100 mL of Et20 and washed with 1 X

20 mL of H20, 2 X 20 mL of b% aqueous HCl, IX 20 mL of H20 and 1 X 20 mL of brine, dried (Na2S04) and concentrated. Chromatography over silica gel (70-230 mesh) using EtOAc:Hexanes (0.5:9.5) provided 1.1 g (62%) of dithiane 283 as a diastereomeric mixture in the ratio of

(8.4:1.6) (integration of the benzyl protons at 6 5.92 (major) and 5.83 (minor)). The major diastereomer crystallized from the oil upon standing 4 to 8 days: m.p. 88-89°C; IR (KBr. pellet) 2978, 2967, 2929, 2858, 1741, 1724, 1225, 1144, 1101, 1022. 858, 838 cm"1; JH-NMR

(major diastereomer) (CDC13) 6 7.32-7.15 (m, 4 H), 5.83 (d, J = 7.3

Hz, 1 H), 5.11 (d. J = 7.3 Hz), 4.18-4.04 (m, 2 H -0CH2CH3), 3.26 (ddd, J = 3.4, 10.5, 14.0 Hz, 1 H), 3.08 (ddd, J = 3.2. 10.8, 14.0 Hz, 1 H), 2.83-2.69 (m, 2 H), 2.07-1.83 (m, 2 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.97 (s, 9 H), 0.73 (s, 9 H), 0.05 (s, 3 H), -0.26 (s. 3

H). Anal, calcd. for C26H4105SiS2Cl; C, 55.64%, H, 7.36%; Found: C, 55.37; H, 7.63.

(45)-(+)-Ethyl 2-Carboxylate-2-[)8-(4-chlorophenyl)-a-((2f2- dimethyl)l-propanoyl)oxy-/?-((l,l-dimethyl ethyl )dimethyl si lyDoxy]- 1,3-dithiane was prepared by a procedure identical to that described 118 for the synthesis of (/?)-(-)-enantiomer 283. The mixture of diastereomers that formed (8.4:1.6) was not separated.

(4/?) -(-) -Ethyl 4-(p-Chlorophenyl) -3- ((2,2-dimethyl )l-propanoyl )oxy) - 4-((l,l-dimethylethyl)dimethylsilyl)oxy-2-oxobutanoate152 (284): To a solution of 3.25 g (24.3 mmol) of N-chlorosuccinimide and 4.7 g (27.8 mmol) of AgN03 in 200 mL of CH3CN:H20 (8:2) was added a solution of 2.9 g (5.17 mmol) of pivaloyl dithiane diastereomers 283 in 10 mL of acetone. The reaction mixture was stirred at rt for 25 min and quenched by the addition of the following at 1 min intervals: 2 mL of saturated Na2S03 solution, 2.0 mL of saturated Na2C03 solution, 2.0 mL of brine and 200 mL of CH2Cl2:Hexanes (1:1). The organic layer was separated, washed with 1 X 30 mL of brine, dried (MgS04) and concentrated. Filtration through silica gel using EtOAc:Hexanes (9.5:0.5) as elutant provided 2.0 g (82%) of a-keto ester 284 as an 8.4:1.6 mixture of diastereomers (integration of *H NMR for the benzylic protons at 6 5.82 (minor) and 5.59 (major) in the form of a colorless oil: IR (NaCl plates) 2960, 2933, 2860, 1738, 1274, 1261,

1 X 1151, 1092 cm" : H-NMR (CDC13) for major diastereomer 6 7.40-7.30 (m, 4 H), 5.59 (d, J = 8.0 Hz, 1 H), 4.96 (d, J = 8.0 Hz, 1 H), 4.29 (q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.06 (s, 9 H), 0.78 (s, 9 H), -0.06 (s, 3 H), -0.26 (s, 3 H); Anal, calcd. for

C23H3506SiCl: C, 58.64: H. 7.49: Found; C, 58.39; H, 7.55. 119 (4S)-(+)-Ethyl 4-(p-Chlorophenyl)-3-((2,2-dimethyl)l-propanoyl)oxy)- 4-((1,1-dimethylethyl)dimethylsilyl)oxy-2-oxobutanoate was prepared by a procedure identical to the one described for the (4/?)-(-)- enantiomer 284.

(/?)-(-) -5-(p-Chlorophenyl)-3-((2,2-dimethyl)-1-propanoyl)oxy-4- hydroxy-2(5tf)-furanone (285): (4/?)-(-)-a-Keto ester 284 (0.38 g; 0.8 mmol) was dissolved in 25 mL of THF and 1.0 mL (1.0 mmol) of a 1.0 M solution of tetrabutylammoniumflouride in THF was added dropwise with stirring. The solution turned green, then yellow, and after 10 min 5 mL of 10% aqueous HCl and 75 mL of Et20 were added. The Et20 layer was separated and washed with 1 X 10 mL of 5$ aqueous HCl solution, 2

X 10 mL of H20 and 1 X 10 mL of brine, dried (Na2S04) and concentrated in vacuo leaving 235 mg (94%) of tetronic acid 285: m.p. 93-95°C; of -70.34° (c = 0.118, EtOH): IR (KBr, pellet) 3700-2600 (broad, vinylogous acid), 1770, 1749, 1660, 1495, 1323, 1302, 1130, 1091,

-1 X 1007 cm ; H NMR (CDC13) 5 7.45-7.30 (m, 4 H), 5.65 (s, 1 H), 1.35

(s, 9 H); Anal, calcd. for C15H1505C1 + 1/4 H20; C, 57.15; H, 4.96: Found; C, 56.88; H, 5.08.

(S)-(+)-5-(p-Chlorophenyl)-3-((2,2-dimethyl)-1-propanoyl)oxy)-4- hydroxy-2(5W)-furanone was prepared by a procedure identical to the

(/?)-(-)-enantiomer 285. Recrystallization from Et20 and Hexanes provided a white powder: m.p. 104-110°C; af +85° (c = 1.312, EtOH). 120 5-(p-Chlorophenyl)-3-((2,2-dimethyl)l-propanoyl )oxy-4-methoxy-2(5//) - furanone (287) and 5-(p-Chlorophenyl)-3-((2,2-dimethyl)l- propanoyl)oxy-l-methoxy-4(5/7)-furanone (286) : A solution of 0.30 g (1 mmol) of 2-pivaloyloxytetronic acid 285 and 20 mL of ether was

cooled to 0°C and CH2N2 was added until the characteristic color of diazomethane persisted. The solution was concentrated and the resultant solid was dried in vacuo leaving a (2:1) mixture of 286 and

! 287: H NMR (CDC13) 6 7.30-7.25 (m. 6 H), 5.53 (s, 1 H (major)), 5.45 (s, 0.5 H), 4.05 (s. 1.5 H). 3.89 (s. 3 H (major)). 1.28 (s. 9 H (major)). 1.25 (s. 4.5 H).

The (/?)-(+)-Methyl benzyl amine Salt 305 of Racemic 5-(p-ChlorophenyD- 3-((2,2-dimethyl)-l-propanoyl)oxy)-4-hydroxy-2(5/y)-furanone (285) was prepared by dissolving 0.23 g (1.0 mmol) of p-chlorophenyl-2-

hydroxytetronic acid in a mixture of 2 mL of pyridine, 2 mL of CH2C12 and 0.14 mL (1.1 mmol) of pivaloyl chloride under argon. The solution was stirred at rt for 12 h followed by the addition of 1 mL of saturated NaHC03. After 1 h the mixture was diluted with 20 mL of

Et20 and extracted with 3 X 3 mL of NaHC03 solution. The aqueous

layer was washed with 1 X 5 mL Et20 and acidified with 10% HCl solution and extracted with 2 X 20 mL of Et20. The organic layer was washed with 1 X 5 mL of 10% HCl solution, 2 X 5 mL of H20 and 1 X 5 mL of brine, dried (MgS04) and concentrated leaving a white waxy solid. Racemic crude tetronic acid 285 (0.015 g, 0.05 mmol) was dissolved in

0.75 mL of CDC13 containing 0.01 mL (0.1 mmol) of (R)- 121 methyl benzyl amine and 1 drop of D20. *H NMR (CDC13) 6 7.36-7.27 (m, 22 H (Note the extra 4 protons are from excess amine)), 5.20 (s, 1 H ((/?,/?)-diastereomeric salt)), 5.11 (s, 1 H ((S./?)-diastereomeric salt)), 3.98 (q, J = 6.9 Hz, 2.5 H (excess amine), 1.40 (d, J = 6.9 Hz, 8 H (excess amine)), 1.28 (s, 18 H).

The (/?)-(+)-Methylbenzyl amine salt of (tf)-(-)-5-(p-Chlorophenyl)-3- ((2,2-dimethyl)-l-propanoyl)oxy-4-hydroxy-2(5//)-furanone (285) was prepared by mixing 0.015 g (0.05 mmol) of tetronic acid 285 in 0.75 mL of CDC13, 0.01 mL (0.1 mmol) of (/?,)-methyl benzyl amine and 1 drop of l D20. H NMR (CDCI3) 6 7.36-7.27 (m, 9 H (2 additional protons were from excess amine)), 5.20 (s, 1 H), 3.98 (q, J = 6.9 Hz, 1.2 H (excess amine), 1.40 (d, J = 6.9 Hz, 4 H (excess amine)), 1.28 (s, 9 H).

The (/?)-(+)-Methyl benzyl amine Salt of (S)-(-)-5-(p-Chlorophenyl)-3- ((2,2-dimethyl)-l-propanoyl)oxy-4-hydroxy-2(5/y)-furanone (285) was prepared by mixing 0.018 g (0.06 mmol) of (5)-(+)-tetronic acid 285 in 0.75 mL of CDC13 and 0.02 mL (0.2 mmol) of (/?;-methyl benzyl amine. :H NMR (CDCI3) 6 7.33-7.19 (m, 19 H (excess amine)), 5.13 (s. 1 H),

4.30 (s, 7 H (RNH3 + excess amine)), 3.99 (q, J = 6.7, 3 H (excess amine)), 1.34 (d, J = 6.7, 9 H (excess amine), 1.24 (s, 9 H).

(/?)-(-)-p-Chlorophenyl-2,3-dihydroxy-2(5W)-furanone (207): Pivaloyl tetronic acid 285 (165 mg, 0.53 mmol) and 10 mL of AcOH:H20 (9.8:0.2) were combined with stirring and warmed to c.a. 100°C for 24 h. The stir bar was removed and rinsed with 2 mL of /PrOH and the yellow solution was concentrated leaving an oil that was crystallized by warming on a steam bath and adding 2 mL of CHC13 and 1 mL of hexanes. The flask was allowed to cool slowly to rt and subsequently at 0°C for 3 h, filtered and washed with small portions of CHC13:hexanes (1:1) to yield 50 mg of optically pure 2-hydroxytetronic acid 207. The mother liqueur was concentrated on a steam bath and diluted with hexanes until the solution became slightly turbid. Upon cooling, an additional 20 mg of product was isolated to yield a total of 70 mg (58%) of tetronic acid 207: m.p. 173-176°C (dec); og -128° (c = l 0.24, EtOH): W NMR (CD3C0CD3) 6 7.48-7.37 (m. 4 H), 5.69 (s, 1 H).

(S)-(+)-p-Chlorophenyl-2,3-dihydroxy-2(5W)-furanone (208) was prepared by a procedure identical to the one described for the R- enantiomer 207: m.p. 165-168°C dec; ajf +105.4° (c = 0.242. EtOH).

The (/?)-(+)-Methylbenzyl amine Salt of Racemic 5-(p-Chlorophenyl)-3,4- dihydroxy-2(5/7)-furanone was prepared by dissolving 12 mg (0.05 mmol) of the racemic 2-hydroxytetronic acid in 0.8 mL of CDC13. The initial suspension was taken into solution by the addition of 0.01 mL (0.1 mmol) of (/?)-(+)-methyl benzyl amine. The lH NMR spectrum was taken immediatly of the sample before crystallization. Separation of the diastereomeric benzylic protons was best observed after addition of

X D20, but addition of D20 also initiates crystallization: H-NMR 123

(CDC13) 6 7.28-7.02 (m. 20 H (excess amine)). 6.23 (br s, 12 H (RNH3 + excess amine)), 4.96 (s, 1 H), 4.91 (s, 1 H), 3.77 (q, J = 6.8 Hz, 2.5 H (excess amine), 1.22 (d, J = 6.8 Hz, 7 H (excess amine)).

The (/?)-(+) -Methyl benzyl amine Salt of (/?)-(-)-5-(p-Chlorophenyl)-3.4- dihydroxy-2(5//)-furanone 207 was greater than 98^ de by lW NMR analysis (/?)-(-)-2-hydroxytetromc acid 207 (12 mg; 0.05 mmol) was dissolved in 0.8 mL of CDC13 containing 0.01 mL (0 1 mmol) of (/?)-(+)- : methyl benzyl amine and 1 drop of D20. H NMR (CDC13) 6 7.28-7.02 (m, 9 H), 4.93 (s, 1 H), 3 92 (br q, J = 6 8 Hz, 1 H). 1 27 (d, J = 6.8 Hz, 3 H)

The (/?)-(+)-Methyl benzyl amine Salt of (S)-(+)-5-(p-Chlorophenyl)-3.4- dihydroxy-2(5tf)-furanone (208) was greater than %% de by lW NMR analysis (S)-(+)-2-hydroxytetromc acid 208 (12 mg; 0.05 mmol) was dissolved in 0.8 mL of CDC13 containing 0.02 mL (0 2 mmol) of (/?)-(+)- l methyl benzyl amine. W NMR (CDC13) 6 7.31-7 07 (m, 26 H (excess amine)), 4.92 (s, 1 H), 4.22 (s, 11 H (RNH3 + excess amine)), 3.97 (q, J = 6.7 Hz, 4 H (excess amine)), 1.34 (d, J = 6.7 Hz, 12 H (excess amine)).

[(l,l'-Biphenyl)4-yl]-a-hydroxyacetamide138173 (258). To a 25 mL- round bottom flask containing a reflux condenser fitted with a nitrogen inlet and 3 0 g (16 5 mmol) of 4-biphenylcarboxadehyde (218) was added 3.21 g (49.4 mmol) of KCN. 0.019 g (0.16 mmol) of Zn(CN)2, 9 124 mL of CH3CN and 3.1 mL (40.3 mmol) of TMSCl. The reaction mixture was warmed to reflux under N2 with stirring for 20 h and an additional 2 mL (26 mmol) of TMSCl was added. The mixture was maintained at reflux for 10 h, cooled to rt and filtered through a scintered glass funnel. The KCN filter cake was washed with 2 X 5 mL portions of

CH3CN and the combined filtrate was concentrated (Rotavap) to a yellow solid. The solid was ground to a powder and diluted with 40 mL of cone HC1 and stirred for 20 h. The pink-orange suspension was poured over ice (lOOg) and filtered leaving 3.6 g (96%) of crude acetamide

258. Recrystallization from THF:CH2C12 left 3.0 g (80%) of acetamide

258 as light yellow flakes: m.p. 225-227°C Hl-NMR (CD30D) 6 7.62- 7.52 (m, 6 H), 7.44-7.31 (m, 3 H), 5.04, (s, 1 H)

[(l,l'-Biphenyl)4-yl]-a-hydroxyacetic acid164 (259): To a solution of 2.7g (11.9 mmol) of a-hydroxyacetamide 258 in 67 mL of MeOH was added 17 g of KOH. and the solution was warmed to reflux for 1 h. The reaction mixture was cooled to rt and concentrated (Rotavap), poured into 20 g of crushed ice and acidified with 10% aqueous HC1. The precipitate (hydroxy acid) thus obtained was filtered, washed with small portions of H20, dried and recrystallized from EtOH-H20 as white crystals: m.p. 200-201 (lit.174 m.p. 201-203°C).

Methyl a-[(l.l'-Biphenyl)4-yl]-a-hydroxyacetate (260): A 250 mL R.B. flask containing a condenser, drying tube, and 7.5 g (32.8 mmol) of a-hydroxyacetic acid (259) dissolved in 150 mL of cone HCl:MeOH (1:9) 125 was warmed to reflux for 2 h. The solution was concentrated under reduced pressure, and the residue was dissolved in 250 mL of Et20. The

Et20 solution washed with 1 X 50 mL of H20, 2 X 50 mL portions of 10 %

NaHC03 solution, 2 X 30 mL of H20 and 2 X 30 mL of brine, dried

(MgS04) and concentrated. The crude methyl acetate was recrystallized from EtOAc and Hexanes leaving 6.5 g (82%) of acetate 260: *H NMR

(CDC13) 6 7.63-7.32 (m, 9 H), 5.22 (d. broad, 1 H), 3.78 (s, 3 H), 3.45 (d, broad, 1 H).

Methyl a-[(l,l'-Biphenyl)4-yl]-a-oxoacetate (261): Method A; To a 100 mL round bottom flask with attached drying tube was added 2.42 g (10.0 mmol) of methyl a-hydroxyacetate 260, 1.84 g (12 mmol) of pyridinium chlorochromate (PCC) and 70 mL of CH2C12. The suspension was stirred at rt for 24 h. An additional 1.0 g (7 mmol) of PCC was added and stirring continued for 20 h. The reaction was quenched by the addition of 15 mL of Et20, filtered and concentrated under reduced pressure. Filtration over silica gel (70-230 mesh) using CHCl3:MeOH (97:03) as elutant produced a yellow oil which crystallized upon standing leaving 1.85 g {11%) of a-keto ester 261. Method B. To a 100 mL R.B. flask with 1.9 g (7.8 mmol) of methyl a-hydroxyacetate 260 dissolved in 50 mL of acetone at 15°C was added Jones reagent157 (chromic acid solution) with stirring at a rate to maintain the reaction temperature under 20°C. The reaction was monitored by TLC and after the disappearance of starting material 5 mL of 7'PrOH was added. The green chromium salts were removed by filtration, washed with 3 X 15 mL portions of acetone and the filtrate was concentrated. The crude mixture was diluted with 100 mL of Et20, and the Et20 solution was washed with 2 X 20 mL of H20 and 2

X 20 mL of brine, dried (MgS04) and concentrated. Recrystallization from EtOAc and Hexanes provided 1.2 g (6A%) of a-keto ester 261: m.p. 61-62°C; Hl-NMR (CDC13) 6 8.13-8.05 (m. 2 H), 7.74-7.62 (m. 4 H), 7.53-7.44 (m, 3 H), 3.98 (s, 3 H). tf-Methyl a-[(1.1'-Biphenyl)4-yl]-a-hydroxyacetate (262): To a 2- necked round bottom flask containing 2.4 g (10.0 mmol) of methyl a-

[(1,1'-biphenyl)4-yl]-a-oxoacetate under N2 was added 6 mL (20 mmol) of Alpine borane95 prepared from 92% ee (I/?)-(+)-a-pinene. The reaction mixture was stirred at rt for 18 h. The resultant off white solid was diluted with 3 mL of THF, cooled to 0°C, and 2 mL (35 mmol) of acetaldehyde was added. All volatile substances were removed by distillation (85°C, 0.3 mm Hg) and the intermediate boronate ester was diluted with 25 mL of Et20, cooled to 0°C and hydrolyzed with 1.3 mL (22 mmol) of ethanolamine. The suspension was stirred for 30 min at 0°C, filtered through a celite packed scintered glass funnel and washed with 2 X 10 mL portions of Et20. The combined filtrate was washed with 1 X 10 mL of H20 and 2 X 10 mL of brine, dried (MgS04) and concentrated. a-Hydroxyacetate 262 was filtered through silica gel (70-230 mesh) using hexanes:EtOAc (90:10) as elutant and recrystallized from EtOAc and Hexanes to provide 1.1 g (46 X) of optically active (/?)-(-)-methyl acetate 262. Resolution of Racemic [(l,r-Biphenyl)4-yl]-a-hydroxyacetic acid (260) with (/?)-(+)-Methyl benzyl amine and (5)-(-)-Methyl benzyl amine. The racemic acid 260 (22.8 g; 100 mmol) was dissolved in 350 mL of absolute EtOH and warmed to reflux on a steam bath. (/?)-(+)- Methyl benzyl amine (12.8 mL; 100 mmol) was added, the flask removed from the steam bath, and the contents seeded with a small crystal of the salt. The flask was wrapped in cotton and not disturbed for 48 h. The crystals were filtered, washed with 6 X 25 mL portions of cold absolute EtOH and dried leaving c.a. 18 g of the crystalline salt. The salt was recrystallized three times using approximately 15 mL of ethanol for each gram of compound to yield 10 g [28% yield, 57% adjusted based on 50 mmol of (/?)-acid 306] of the diastereomerically and optically pure salt 308 of p-phenylmandelic acid 306: m.p. 196- 205°C, ajf -49.7° (c = 0.306, MeOH). The filtrate from the first recrystallization was concentrated and diluted with 500 mL of Et20. The Et20 solution was washed with 3

X 50 mL of 10% aqueous HC1, 2 X 50 mL of H20 and 2 X 50 mL of brine, dried (Na2S04) and concentrated leaving 10 g (45 mmol) of optically active (S)-(+)-hydroxy acid 307. The acid was dissolved in c.a. 250 mL of absolute EtOH, the solution warmed to reflux, and 5.7 mL (45 mmol) of (S)-(-)-methyl benzyl amine was added. The flask was wrapped in cotton and foil and set on a cork ring without disturbance for 48 h. The crystals were filtered and washed with a minimum of cold EtOH. The salt was recrystallized 3 times using approximately 15 mL of EtOH for each 1 g of diastereomeric salt 309 leaving 8 g (23%, 46% adjusted) of 309: m.p. 197-207°C; off +44.2° (c = 0.624, MeOH).

(/?)-(-)-[(l.l'-Biphenyl)4-yl]-a-hydroxyacetic acid (306): (R)-(-)- Amine salt 308 (2.65 g; 7.6 mmol) was added to a separatory funnel containing 150 mL of Et20 and 40 mL of 5% aqueous HC1, and the suspension was shaken vigorously until the salt dissolved. The Et20 layer was separated and washed with 1 X 25 mL of 5% aqueous HC1, 2 X

25 mL of H20 and 1 X 25 mL of brine, dried (Na2S04) and concentrated leaving 1.7 g (98%) of optically pure a-hydroxyacetic acid 306. For analytical data, a small sample was recrystallized as white needles from THF and CH2C12: m.p. 210-212°C; off -135.2° (c = 0.318, EtOH).

(S)-(+)-[(l,l'-Biphenyl)4-yl]-a-hydroxyacetic acid (307) was prepared as described for (/?)-(-)-enantiomer 306 using (S)-(+)-Amine salt 309: m.p. 212-215°C; off +133.7° (c = 0.662, EtOH).

(/?)-(-)-Methyl [(1,1'-Biphenyl)4-yl]-a-hydroxyacetate (262): A solution of 1.7 g (7.5 mmol) of (/?)-(-)-p-phenylmandelic acid 306 in

75 mL of Et20 was cooled to 0°C and titrated with CH2N2 until the yellow color of persisted. Evaporation of solvent provided 1.8 g (99%) of methyl ester 262 as a white crystalline solid: m.p. 103- 106°C; off -121.0° (c = 0.482, EtOH). 129 (S)-(+)-Methyl [(1,l'-Biphenyl)4-yl]-a-hydroxyacetate (310) was prepared as described for the (/?)-(-)-enantiomer 262: m.p. 103-106°C off +120.7° (c = 0.372, EtOH).

The Mosher Ester of Racemic Methyl [(1,1'-Biphenyl)4-yl]-a- hydroxyacetate (260): To a dry 10 mL round bottom flask equipped with a stir bar and 30 mg (0.13 mmol) of (/?)-(+)-a-methoxy-a- (trifluoromethyl) phenyl acetic acid C(/?)-(+)-MTPA] under argon atmosphere was added 0.5 mL of oxalyl chloride containing 0.1 % of DMF. The solution was stirred for 1 h, and the excess oxalyl chloride was removed under reduced pressure (25°C, 0.3 mm Hg, 25 min). (/?)-(-)-MTPA-Cl was placed under argon atmosphere and 12 mg (0.05 mmol) of racemic methyl [(1,1'-biphenyl)4-yl]-a-hydroxyacetate,

(260) 0.2 mL of CH2C12 and 2 drops of pyridine were added. The solution was stirred for 27 h. The reaction mixture was diluted with

30 mL of Et20 and extracted with 1 X 5 mL of H20, 1X5 mL of 10% aqueous HCl, 1 X 5 mL of H20, 1X5 mL of saturated NaHC03 solution, 1

X 5 mL of H20 and 1 X 5 mL of brine, dried (Na2S04) and concentrated.

The crude solid was dried under reduced pressure: ^-NMR (CDC13) 6 7.66-7.35 (m, 28 H), 6.15 (s, 1 H), 6.13 (s, 1 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.70 (d, J = 1.15 Hz, 3 H). 3.56 (d, J = 0.98 Hz. 3 H).

The Mosher Ester of (R)-i-)-Methyl [(1,1*-Biphenyl)4-yl]-a- hydroxyacetate (262) was prepared as described for the Mosher ester X derivative of racemic acetate 260: H-NMR (CDC13) 8 7.66-7.31 (m. 14 H). 6.13 (s. 1 H). 3.78 (s. 3 H), 3.70 (d, J = 1.15 Hz. 3 H).

The Mosher Ester of (S)-(+)-Methyl [(1,1'-Biphenyl)4-yl]-a- hydroxyacetate (310) was prepared as described for the Mosher ester derivative of racemic acetate 260: Hi-NMR (CDC13) 6 7.61-7.35 (m, 14 H). 6.15 (s, 1 H), 3.75 (s, 3 H). 3.56, (d, J = 0.98 Hz, 3 H).

(/?)-(-) -Methyl [(1,1' -Biphenyl )4-yl] -a- ((1,1-dimethyl ethyl) - dimethyl silyDoxyacetate 311: a-Hydroxyacetate 262 (1.8 g; 7.5 mmol), 1.8 g (12.0 mmol) of TBDMSCl, 0.82 g (12.0 mmol) of imidazole and 10 rri of DMF were combined in a 100 ml_ round bottom flask and stirred under argon for 18 h. The reaction mixture was diluted with

150 mL of Et20, washed with 3 X 25 mL of H20 and 1 X 25 mL of brine, dried (Na2S04), and concentrated. The compound was dried under reduced pressure (0.3 mm Hg, 60°C) for 1.5 h to yield 2.6 g (98%) of tert-butyl dimethyl silyloxyacetate 311 as a cloudy white oil: ajf

X -71.9° (c = 0.9.14, EtOH): H-NMR (CDC13) 6 7.59-7.33 (m, 9 H), 5.28 (s. 1 H). 3.70 (s, 3 H), 0.92 (s, 9 H), 0.12 (s, 3 H), 0.05 (s, 3 H).

(S)-(+)-Methyl [(1,1'-Biphenyl)4-y]l-a-((1,1-dimethyl ethyl)- dimethylsilyDoxyacetate (312) was prepared as described for the (/?)- (-)-enantiomer 311 from (S)-(+)-methyl p-phenylmandelate 310: oif +68.8° (c = 0.780, EtOH). 131 (/?)-(-)-[d.l'-Biphenyl )4-yl]-tt-((l. 1- di methyl ethyl) dimethyl si lyDoxy-acetaldehyde (313): A 100 mL 2-

necked round bottom flask was equipped with a septum, N2 inlet and 2.6 g (7.4 mmol) of (/?)-(-)-methyl acetate 311 dissolved in 45 mL of dry

toluene. The solution was cooled to -78°C (C02/acetone), and 9 mL (9 mmol) of a 1.0 M solution of DIBAL-H in toluene was added slowly (5 min) with stirring. The reaction mixture was stirred for 1 h at -

78°C and poured into a mixture of 100 g of ice and 100 mL of CHC13.

The reaction flask was rinsed with 100 mL of CHC13 and the mixture was

stirred vigorously for 30 min. After separation of the CHC13 layer,

the aqueous phase was washed with 100 mL of CHC13 (emulsion!) and the

combined CHC13 extracts were washed with brine 1 X 80 mL, dried

(Na2S04) and concentrated leaving 2.3 g (95%) of aldehyde 313 as a

colorless oil which was not further purified: H-I-NMR (CDC13) 6 9.54 (d, J = 2.1 Hz, 1 H), 7.63-7.35 (m, 9 H), 5.05 (d, J = 2.1 Hz, 1 H), 0.97 (s, 9 H), 0.14 (s, 3 H), 0.07 (s, 3 H).

(S)-(+)-[(1.1'-Biphenyl)4-yl]-a-((1.1- di methyl ethyl) dimethyl si lyDoxy-acetaldehyde (314) was prepared from (5)-(+)-methyl a-silyloxymandelate 312 as described for the (/?)-(-)- enatiomer 313: og +36.6° (c = 1.01, EtOH).

(4/?)-(-)-Ethyl 2-[^((l,l'-Biphenyl)4-yl)-a-((2,2-dimethyl)l- propanoyDoxy-/? -((1,1 -dimethyl ethyl )dimethyl si lyl )oxy]ethane-2- carboxylate-l,3-dithiane153171172 (315): A solution of 0.52 mL (3.3 132 mmol) of ethyl l,3-dithiane-2-carboxylate in 10 mL of THF (freshly distilled from Na/benzophenone) under argon was cooled to -78°C

(C027acetone) and 2.2 mL (3.3 mmol) of 1.5 M LDA (solution in cyclohexanes) was added with stirring. The reaction flask was removed from the dry ice bath for 10 min and subsequently cooled to -78°C and stirred for 1 h. A solution consisting of 0.98 g (3.0 mmol) of (/?)-(-)-acetaldehyde 313, 2 mL of THF and 0.41 mL (3.3 mmol) of pivaloyl chloride was added drop-wise with stirring. Stirring was continued for 2 h at -78°C and for 1 h at rt. The reaction mixture was diluted with 100 mL of Et20 and washed with 1 X 20 mL of H20, 2 X

20 mL of 5% aqueous HC1, IX 20 mL of H20 and 1 X 20 mL of brine, dried (Na2S04) and concentrated. Chromatography over silica gel (70- 230 mesh) using EtOAc:Hex (0.5:9.5) provided 1.1 g (623!) of dithiane 315 as a diastereomeric mixture in the ratio of (8.5:1.5) (integration of the benzyl protons at <5 5.92 (major) and 5.65 (minor)). The diastereomers were separated by chromatography (major was slightly less polar) for analytical purposes; !H-NMR (major diastereomer) (CDC13) 6 7.57-7.30 (m, 9 H), 5.92 (d, J = 7.4 Hz, 1 H),

5.18 (d, J = 7.4 Hz, 1 H), 4.20-4.04 (m, 2 H -0CH2CH3), 3.27 (ddd, J = 3.5, 10.4, 13.9 Hz, 1 H), 3.09 (ddd. J = 3.2, 10.7, 14.0 Hz, 1 H), 2.83-2.72 (m, 2 H), 2.07-1.83 (m. 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 0.95 (s, 9 H), 0.75 (s, 9 H), 0.07 (s, 3 H), -0.22 (s, 3 H). Anal, calcd. for C32H4605SiS2: C, 63.76%, H, 7.69%. Found: C, 63.25; H, 7.64. (45)-(+)-Ethyl 2-[/M(l,r-Biphenyl)4-yl)-a-((2,2-dimethyl)l- propanoyl)oxy-/?-((l,l-dimethyl ethyl)dimethyl si lyl )oxy]ethane-2- carboxylate-l,3-dithiane (316) was prepared by a procedure identical to that described for the synthesis of (/?)-(-)-enantiomer 315. The mixture of diastereomers that formed (8.5:1.5) was not separated.

(4/?)-(-)-Ethyl 4-[(l,l'-Biphenyl)4-yl]-3-((2,2-dimethyl)l- propanoyl)oxy-4-((1,1-dimethyl ethyl)dimethylsilyl)oxy-2- oxobutanoate152 (317): To a solution of 0.54 g (4.0 mmol) of N-

chlorosuccinimide and 0.77 g (4.5 mmol) of AgN03 in 20 mL of CH3CN:H20 (8:2) was added a solution of 0.6 g (1.0 mmol) of pivaloyl dithiane diastereomers 315 in 2 mL of acetone. The reaction mixture was stirred at rt for 25 min and quenched by the addition of the

following at 1 min intervals: 1 mL of saturated Na2S03 solution, 1.0 mL of saturated Na2C03 solution, 1.0 mL of brine and 80 mL of

CH2Cl2:Hexanes (1:1). The organic layer was separated, washed with 2

X 20 mL of H20 and 1 X 30 mL of brine, dried (MgS04) and concentrated. Filtration through silica gel using EtOAc:Hex (9.5:0.5) as elutant provided 0.36 g (70%) of a-keto ester 317 as an 8.5:1.5 mixture of diastereomers (integration of *H NMR for the benzylic protons at 6 (minor) and 5.71 (major) in the form of a colorless oil: lW-WR

(CDC13) for major diastereomer 6 7.63-7.35 (m, 9 H), 5.71 (d, J = 7.9 Hz, 1H), 5.06 (d, J = 7.9 Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.10 (s, 9 H). 0.82 (s, 9 H), -0.01 (s, 3 H), 134

-0.20 (s, 3 H); Anal, calcd. for C29H40O6Si: C, 67.94; H. 7.86: Found: C. 67.67, H, 7.81.

(4S)-(+)-Ethyl 4-[(l,r-Biphenyl)4-yl]-3-((2,2-dimethyl)l- propanoyl)oxy-4-((1,1-dimethyl ethyl)dimethyl silyl)oxy-2-oxobutanoate12 (318) was prepared by a procedure identical to the one described for (4/?)-(-)-enantiomer 317

(/?)-(-)-5-[(l,r-Biphenyl)4-yl]-3-((2,2-dimethyl)-l-propanoyl)oxy-4- hydroxy-2(5//)-furanone (319): (4/?)-(-)-a-Keto ester 317 (0.35 g: 0.7 mmol) was dissolved in 20 mL of THF, and 0 8 mL (0 8 mmol) of a 1 0 M solution of TBAF in THF was added drop-wise with stirring. The reaction solution turned yellow, and after 10 min 5 mL of 10% aqueous

HCl and 75 mL of Et20 were added. The Et20 layer was separated and washed with 1 X 10 mL of 5% aqueous HCl solution, 2 X 10 mL of H20 and

1 X 10 mL of brine, dried (Na2S04) and concentrated in vacuo leaving 235 mg (94%) of tetromc acid 319. A sample was recrystallized as white plates from acetone and hexanes: m.p. 213-220°C dec; off - 82.3° (c = 0.164, EtOH), IR (KBr, pellet) 2983, 2934, 1774, 1752,

1 X 1676, 1130, 1122, 1085 cm , H NMR (CDC13) 6 7.65-7 36 (m. 9 H), 5.74

(s, 1 H), 1.36 (s. 9 H), Anal calcd. for C21H2005 C, 71.58; H, 5.72: Found: C. 70 54, H, 4.75.

(S)-(+)-5-[(1,1'-Biphenyl)4-yl]-3-((2,2-dimethyl)-1-propanoyl)oxy-4- hydroxy-2(5tf)-furanone (320) was prepared by a procedure identical to the one used to prepare (/?)-(-)-enantiomer 319: m.p. 210-215°C dec: ajf +84.8° (c = 0.466, EtOH).

Optical Purity was Determined by *H NMR of the Diastereomeric Salt of (/?)-(-)-5-[(1,1*-Biphenyl)4-yl]-3-((2,2-dimethyl)-1-propanoyl)oxy-4- hydroxy-2(5//)-furanone (319) with (/?)-(+)-Methylbenzyl amine. The sample was prepared by mixing 0.015 g (0.05 mrnol) of tetronic acid

319 in 0.75 mL of CDC13 and 0.01 mL (0.1 mrnol) of X (/?;-methyl benzyl amine: H NMR (CDC13) 6 7.46-7.22 (m. 26 H (excess amine)), 5.27 (s, 1 H), 4.02 (q, J = 6.7 Hz, 3.4 H (excess amine)),

3.39 (br s. 11.6 H (NH3 + excess amine)), 1.35 (d, J = 6.7 Hz, 10 H (excess amine)), 1.24 (s, 9 H).

(/?)-(-)-5-[(l,l'-Biphenyl)4-yl]-2,3-dihydroxy-2(5//)-furanone (209):

Pivaloyl tetronic acid 319 (180 mg, 0.50 mrnol) and 10 mL of AcOH:H20 (9.8:0.2) were combined with stirring and warmed to c.a. 100°C for 24 h. The stir bar was removed and rinsed with 2 mL of iPrOH and the yellow solution was concentrated leaving an oil that was crystallized from a refluxing mixture CHC13 (2 mL) and hexanes (1 mL). The flask was allowed to cool slowly to rt and subsequently at 0°C for 3 h, filtered and washed with small portions of CHCl3:hexanes (1:1) to yield 50 mg of optically pure 2-hydroxytetronic acid. The mother liquor was concentrated on a steam bath and diluted with hexanes until the solution became slightly turbid. Upon cooling, an additional 20 mg of product was isolated to yield a total of 70 mg 136 (52%) of tetronic acid 209: m.p. 207-210°C (dec); (lit racemic ?' );

! of -154° (c = 0.13. EtOH) H NMR (DMS0-d6) 6 7.72-7.65 (m. 4 H). 7.50- 7.34 (m. 5 H). 5.76 (s, 1 H), 3.35 (br s, 2 H).

(S)-(+)-5-[(l,l'-Biphenyl)4-yl]-2.3-dihydroxy-2(5//)-furanone (210) was prepared by a procedure identical to the one described for (R)-(-

2 2 )-enantiomer 209: m.p. 182-187°C dec: a D +145° (c = 0.11, EtOH)

The Salt of Racemic 5-[(l,l'-Biphenyl)4-yl]-3,4-dihydroxy-2(5tf)- furanone with (/?)•(+)-Methyl benzyl amine was prepared by diluting 12 mg (0.05 mmol) of the racemic 2-hydroxytetronic acid in 0.8 ml_ of

CDC13. The suspension was taken into solution by the addition of 0.01 mL (0.1 mmol) of (/?)-(+)-methylbenzylamine. The *H NMR spectrum was taken immediately and prior to crystallization. Addition of D20 J resulted in sample crystallization within 2-4 min: H-NMR (CDC13) 6 7.61-7.18 (m, (excess amine)), 5.08 (s, 1 H), 5.03 (s, 1 H), 3.97 (q,

J = 6.7 Hz, (excess amine)), 3.84 (br s, (NH3 + excess amine)), 1.33 (d, J = 6.7 Hz, (excess amine).

The Salt of (/?)-(-)-5-[(l,l' -Biphenyl)4-yl]-3,4-dihydroxy-2(5//)- furanone (209) with (/?)-(+)-Methyl benzyl amine was determined to be greater than 98% de by lW NMR analysis. The sample was prepared as X described for the preparation of the racemic salt: W NMR (CDC13) 8

7.58-7.25 (m, 22 H (excess amine)), 5.69 (br s. 7 H (NH3 + excess 137 amine)), 4.98 (s, 1 H), 3.96 (q. J = 6.7 Hz, 2 H (excess amine)), 1.34 (d, J = 6.7 Hz, 7 H (excess amine)).

The Salt of (S)-(+)-5-[(l,r -Biphenyl)4-yl]-3,4-dihydroxy-2(5//)- furanone (210) with (/?)-(+)-Methylbenzyl amine was determined to be greater than 98% de by aH NMR analysis. The sample was prepared as

X described for the racemic salt: H NMR (CDC13) 6 7.54-7.19 (m, (excess amine)), 5.05 (s, 1 H), 4.03 (q, J = 6.6 Hz, ). 3.28 (br s,

NH3 + excess amine), 1.35 (d, J = 6.6 Hz,) (/?)-(-)-Methyl a-Hydroxybenzeneacetate (321): A solution of (/?)-(-)- mandelic acid (1.52 g; 10 mmol) in 70 mL of Et20 was cooled to 0°C and titrated with CH2N2 until the yellow color persisted. Evaporation of sovent provided 1.65 g (99%) of methyl ester 321 as a colorless oil which crystallized upon standing: m.p. 54-55°C ajf

(S)-(+)-Methyl a-Hydroxybenzeneacetate (322) was prepared as described for the (/?)-(-)-enantiomer 321. The oil crystallized upon standing: m.p. 54-56°C, og +125° (c = 2.30. EtOH).

(/?)-(-) -Methyl a- [((1,1 -Dimethylethyl)dimethylsilyl )oxy]- benzeneacetate (323): a-Hydroxy acetate 321 (1.65 g; 10.0 mmol), 2.26 g (15.0 mmol) of TBDMSCl, 1.16 g (17.0 mmol) of imidazole and 12 mL of DMF were combined in a 100 mL round bottom flask and stirred under argon for 18 h. The reaction mixture was diluted with 150 mL of Et20, washed with 3 X 25 mL of H20 and 1 X 25 mL of brine, dried (Na2S04) and concentrated. The compound was dried under reduced pressure (0.3 mm Hg. 60°C) for 1.5 h to yield 2.8 g (99%) of tert- butyldimethyl silyloxyacetate 323 as a colorless oil: a2,2 -53.6° (c =

X 1.25, EtOH); H-NMR (CDC13) 6 7.47'-1.27 (m, 5 H), 5.22 (s, 1 H), 3.67 (s, 3 H), 0.90 (s, 9 H), 0.09 (s. 3 H). 0.02 (s. 3 H).

(S)-(+)-Methyl

(/?)-(-)-a-[((1,1-Dimethyl ethyl)dimethylsilyl)oxy]benzeneacetaldehyde (325): To a 100 mL 2-necked round bottom flask equipped with a septum and nitrogen inlet was added 2.8 g (10 mmol) of (/?)-(-)-methyl acetate 323 dissolved in 55 mL of dry toluene. The solution was cooled to -78°C (C02/acetone) and 12 mL (12 mmol) of a 1.0 M solution of DIBAL-H in toluene was added slowly (5 min) with stirring. The reaction mixture was stirred for 1 h at -78°C and poured into 100 g of ice and 100 mL of CHC13. The reaction flask was rinsed with 100 mL of CHC13 and the mixture was stirred vigorously for 30 min. After separation of the CHC13 layer, the aqueous phase was washed with 100 mL of CHCI3 (emulsion) and the combined CHC13 extracts were washed with brine 1 X 80 mL, dried (Na2S04) and concentrated leaving 2.2 g (88%) of aldehyde 325 as a clear colorless oil of greater than 90% purity (Hl-NMR). The aldehyde was not further purified: af -39.5° X (c = 0.612. EtOH); H-NMR (CDC13) 6 9.51 (d. J = 2.2 Hz. 1 H), 7.40- 7.29 (m, 5 H), 5.00 (d. J = 2.2 Hz. 1 H). 0.95 (s, 9 H), 0.12 (s. 3 H) 0.04 (s. 3 H).

(S)-(+)-a-[((1,1-Dimethyl ethyl)dimethylsi lyl)oxy]benzeneacetaldehyde (326) was prepared as described for the (/?)-(-)-enantiomer 325: ajf +39.6° (c = 0.442, EtOH).

(4/?)-(-)-Ethyl 2-Carboxylate-2-[a-((2,2-dimethyl)l-propanoyl)oxy-)ff- ((l,l-dimethylethyl)dimethylsnyl)oxy-j?-phenyl]-l,3-dithiane (327): A solution of 1.58 mL (10.0 mmol) of ethyl 1,3-dithiane-2- carboxylate153171172, in 25 mL of THF (freshly distilled from

Na/benzophenone) under argon was cooled to -78°C (C02/acetone) and 6.7 mL (10.0 mmol) of 1.5 M LDA (solution in cyclohexanes) was added with stirring. The reaction mixture was removed from the dry ice bath for 10 min, cooled to -78°C and stirred for 1 h. A solution consisting of 2.26 g (9.0 mmol) of (/?)-(-)-acetaldehyde 325, 6 mL of THF and 1.25 mL (10 mmol) of pivaloyl chloride was added dropwise with stirring and stirring was continued for 2 h at -78°C and for 1 h at

rt. The reaction mixture was diluted with 200 mL of Et20 and washed with 1 X 20 mL of H20, 2 X 20 mL of b% aqueous HC1, IX 20 mL of H20 and 1 X 20 mL of brine. The organic layer was dried (Na2S04) and concentrated. Chromatography over silica gel (70-230 mesh) using EtOAc:Hexanes (0.5:9.5) and distillation (0.3 mm Hg, 110°C) to remove excess ethyl l,3-dithiane-2-carboxylate provided 3 g (63£) of dithiane ### as an 8.3:1.7 mixture of diastereomers (integration of the benzylic protons at 6 5.92 (major) and 5.67 (minor)). An analytical sample of the pure major diastereomer was isolated by chromatography: IR (NaCl plates) 2960, 2929, 2904, 1729, 1279, 1250, 1215, 1140, 1113. 1093, 1057, 1030, 847, 838 cm"1; !H NMR of the major isomer (CDC13) 6 7.35-7.18 (m, 5 H), 5.92 (d, J = 7.7 Hz, 1 H),

5.11 (d, J = 7.7 Hz, 1 H), 4.22-4.08 (m, 2 H (-0CH2CH3)), 3.33 (ddd, J = 3.5, 10.5, 14.0 Hz, 1 H), 3.09 (ddd, J = 3.2, 10.8, 14.0 Hz, 1 H), 2.86-2.71 (m, 2 H), 2.10-1.86 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H), 0.96 (s, 9 H), 0.73 (s, 9 H), 0.06 (s, 3 H), -0.24 (s, 3 H); Anal, calcd. for C26H4205SiS2; c. 59.29; H, 8.04. Found: C, 59.01; H, 7.28.

(4S)-(+)-Ethyl 2-Carboxylate-2-[c^((2,2-dimethyl)l-propanoyl)oxy-/?- ((1,1 - dimethyl ethyl)dimethyl silyl)oxy-0-phenyl]-l,3-dithiane (328) was prepared by a procedure identical to that described for the synthesis of the (/?)-(-)-enantiomer 327. The mixture of diastereomers that formed (8.3:1.7) was not separated.

(4fl)-(-)-Ethyl 4-Benzene-3-((2,2-dimethyl)l-propanoyl)oxy)-4-((l.l- dimethyl ethyl )dimethyl si lyl)oxy-2-oxobutanoate152 (329): To a solution of 0.54 g (4.0 mmol) of N-chlorosuccinimide and 0.77 g (4.5 mmol) of AgN03 in 20 mL of CH3CN:H20 (8:2) was added a solution of 0.53 g (1.0 mmol) of pivaloyl dithiane diastereomers 327 in 2 mL of acetone. The reaction mixture was stirred at rt for 25 min and quenched by the addition of the following at 1 min intervals: 1 mL of saturated Na2S03 solution; 1.0 mL of saturated Na2C03 solution; 1.0 141 mL of brine and 70 ml_ of CH2Cl2:Hexanes (1:1). The organic layer was separated, washed with 1 X 15 mL of brine, dried (MgS04) and concentrated (note, it is essential that all solvent is removed prior to chromatography or excess succinimide will elute with compound). The crude product was diluted with EtOAc:hexanes (1:9) and filterd through silica gel using EtOAc:Hexanes (9.5:0.5) as elutant to provide 0.30 g (70%) of a-keto ester 329 as an 8.3:1.7 mixture of diastereomers ((!H NMR) integration of the benzylic protons at 6 5.72 (minor) and 5.65 (major)) in the form of a colorless oil: IR (NaCl plates) 2960, 2931, 2860, 1736, 1271, 1259, 1153, 838 cm"1; !H-NMR

(CDC13) for mixture 6 7.41-7.25 (m, 6 H (major and minor)), 5.71 (d, J = 5.4 Hz, 0.2 H (minor)), 5.66 (d, J = 8.0 Hz, 1 H (major)). 5.23 (d, J = 5.4 Hz, 0.2 H (minor)), 4.98 (d, J = 8.0 Hz, 1 H (major)), 4.28 (q. J = 7.2 Hz, 2 H (major)), 4.14 (q. J = 7.2 Hz, 0.4 H (minor)). 1.34 (t, J = 7.2 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 0.6 H (minor)), 1.16 (s, 1.8 H (minor)), 1.05 (s, 9 H (major)), 0.84 (s, 1.8 H (minor)), 0.78 (s, 9 H (major)). 0.02 (s, 0.6 H (minor)), 0.01 (s. 3 H (major)), -0.02 (s, 0.6 H (minor)), -0.04 (s, 3 H (major)); Anal, calcd. for C23H3606Si: C, 63.27; H, 8.31: Found; C, 62.90; H, 7.60.

(4S)-(+)-Ethyl 4-Benzene-3-((2,2-dimethyl)l-propanoyl)oxy)-4-((1,1- dimethylethyl)dimethylsilyl)oxy-2-oxobutanoate (330) was prepared by a procedure identical to the one described for the (4/?)-(-)- enantiomer 329. (/?)-(-)-5-Benzene-3-((2,2-dimethyl)-l-propanoyl)oxy-4-hydroxy-2(5/y)- furanone (331): (4/?)-(-)-a-Keto ester 329 (0.28 g; 0.64 mmol) was dissolved in 20 mL of THF and 0.7 mL (0.7 mmol) of a 1.0 M solution of tetrabutylammonium flouride in THF was added dropwise with stirring. The reaction solution turned yellow, and after 10 min 5 mL of 10% aqueous HC1 and 75 mL of Et20 were added. The Et20 layer was separated and washed with 1 X 10 mL of S% aqueous HC1 solution, 2 X

10 mL of H20 and 1 X 10 mL of brine, dried (Na2S04) and concentrated in vacuo leaving 170 mg (%%) of tetronic acid 331. An analytical sample was recrystallized from CHC13 and hexanes: m.p. 135-138°C; ajf -80.4° (c = 0.734, EtOH); IR (KBr pellet) 3037, 2989, 2976, 2937, 2875, 2717, 1762, 1651, 1481, 1456. 1367, 1340, 1290, 1265, 1128,

1 : 1018, 771 cm" ; H NMR (CDC13) 6 7.42-7.39 (m, 5 H), 5.69. (s. 1 H),

1.35 (s, 9 H): Anal, calcd. for C15H1605; C. 65.21; H, 5.84: Found; C, 64.76; H, 5.62.

(S)-(+)-5-Benzene-3-((2,2-dimethyl)-l-propanoyl)oxy)-4-hydroxy-2(5tf)- furanone (332) was prepared by a procedure identical to the (/?)-(-)- enantiomer 331. m.p. 136-139°C, oif +81.9° (c = 0.804, EtOH).

(/?)-(-)-2,3-Dihydroxy-5-phenyl-2(5tf)-furanone (206): Pivaloyl tetronic acid 331 (0.17 g, 0.62 mmol) and 10 mL of AcOH:H20 (9.8:0.2) were combined with stirring and warmed to c.a. 100°C for 24 h. The stir bar was removed and rinsed with 2 mL of iPrOH and the yellow solution was concentrated leaving an oil that was crystallized by warming on a steam bath and adding 2 nt of CHC13 and 1 mL of hexanes. The flask was allowed to cool slowly to rt and subsequently at 0°C for 3 h. The crystalline solid was filtered and washed with small portions of CHC13:hexanes (1:1) to yield 50 mg of optically pure 2- hydroxytetronic acid. The mother liqueur was concentrated on a steam bath and diluted with hexanes until the solution became slightly turbid. Upon cooling, an additional 15 mg of product was isolated to yield a total of 65 mg (55*) of tetronic acid 206: m.p. 164-170°C (dec): lit racemic 155°C; ajf -140° (c = 0.546, EtOH).

(S)-(+)-2,3-Dihydroxy-5-phenyl-2(5W)-furanone (77) was prepared by a procedure identical to the one described for the preparation of the

29 22 /?-enantiomer 206: m.p. 165-170°C dec. lit . 142-143°C: a Na589 +135° (c = 0.512. EtOH) lit a22 +109.4° (c = 0.80: MeOH).29

The (/?)-(+)-Methylbenzyl amine Salt of (±)-3,4-Dihydroxy-5-phenyl- 2(5//)-furanone was prepared by dissolving 12 mg (0.05 mmol) of the racemic 2-hydroxytetronic acid in 0.8 mL of CDC13. The initial suspension was taken into solution by the addition of 0.01 mL (0.1 mmol) of (/?)-(+) -methyl benzyl amine. The :H NMR spectrum was taken immediatly before crystallization took place. Better separation of the diastereomeric benzylic protons was observed after addition of

J D20, but D20 initiates crystallization: H-NMR (CDC13) 6 7.37-7.19 (m, 24 H (diastereomeric mixture + excess amine)), 4.99 (s. 1 H (diastereomer ###)), 4.96 (s, 1 H (diastereomer ###)), 4.77 (br s. 7 144

H (RNH3 + excess amine)), 3.70 (q, J = 6.7 Hz, 3 H (diasteromeric mixture + excess amine)), 1.18 (d, J = 6.7 Hz, 8 H (diastereomeric mixture + excess amine)).

The (/?)-(+)-Methylbenzyl amine Salt of (/?)-(-) -3.4-Di hydroxy-5-phenyl - 2(5W)-furanone (206) was greater than 98% de by XH NMR analysis. (/?)- (-)-2-Hydroxytetronic acid 206 (12 mg; 0.05 mmol) was dissolved in

0.8 mL of CDC13 containing 0.01 ml_ (0.1 mmol) of (/?)-(+)- ! methyl benzyl amine: H NMR (CDC13) 6 7.32-7.18 (m, 16 H), 6.04 (br s,

6 H(RNH3 + excess amine)), 4.88 (s, 1 H), 3.84 (q, J = 6.7 Hz, 2 H (excess amine)), 1.26 (d, J = 6.7 Hz, 6 H (excess amine)).

The (/?)-(+)-Methyl benzyl amine Salt of (S)-(+)-3,4-Dihydroxy-5-phenyl- 2(5W)-furanone (77) was in greater than 98% de by !H NMR analysis. (5)-(+)-2-Hydroxytetronic acid 77 (12 mg; 0.05 mmol) was dissolved in 0.8 mL of CDCI3 and 0.02 mL (0.2 mmol) of (/?)-(+) -methyl benzyl amine. lH NMR (CDCI3) 6 7.30-7.17 (m, 14 H (excess amine)), 6.40 (br s. 6 H

(NH3 + excess amine)), 4.98 (s, 1 H), 3.72 (q, J = 6.7 Hz, 1.6 H (excess amine)), 1.22 (d, J = 6.7 Hz, 5 H (excess amine)). BIBLIOGRAPHY

King, C. G.; Burns, J. J. "Second Conference on Vitamin C" The New York Academy of Sciences, N.Y. N.Y., 1975. Witiak. D.T.; Feller, D.R.; Newman, H.A.I,; Kim, S.U.; Esbenshade, T.A.; Kamanna, V.S., "Medicinal Chemistry Aspects of Antilipidemic Drugs: Aci-Reductone Antilipidemic and Antiaggregatory Agents" Actual. Chim. Ther., 1988, 15, 41-62.

von Euler, H.; Eistert, B., Chemie und Biochemie der Reduktone und Reduktonate, Ferdinand Enke Verlag, Stuttgart, 1957. Schank, K., "Reductones", Synthesis, 1972, 176-90. Seib, P.A., "Oxidation, monosubstitution and industrial synthesis of ascorbic acid" Int. J. Vitam. Nutr. Res., Suppl., 1985, 27(vitamins), 259-306. Crawford, T.C.; Crawford, S.A., "Synthesis of L-ascorbic acid" Adv. Carbohydr. Chem. Biochem., 1980, 37, 79-155. Crawford, T.C., "Synthesis of L-ascorbic acid." Adv. Chem. Ser.. 1982, 200(Ascorbic Acid: Chem., Metab., Uses), 1-36. Kashimura, N.; Morita, J., "Nucleic acid cleavage activity of some carbohydrate derivatives", Yuki Gosei Kagaku Kyokaishi, 1984, 42(6), 523-35. Murakami, H., "Studies on the intracellular DNA breaking reaction with reductones", Nippon Nogei Kagaku Kaishi, 1983, 57, 55-62. Omura, H., "Reductones", Eiyo To Shokuryo, 1978, 31, 9-26.

Obata, H., "Reductone", Kagaku, 1979, 34, 456-61. Haynes, L.J.: Plimmer, J.R., "Tetronic acids." Quart. Rev., 1960, 292-315.

145 146 13. Neta, P.; Dizdaroglu, M.. "Radiation chemistry of enones." Chem. Enones, 1989, 2, 757-80. 14. Hamada, Y.; Kawai, A.; Matsui, T.; Hara, 0.; Shioin, T., "4- Alkoxycarbonyloxazoles as beta-hydroxy-alpha-amino acid synthons: efficient, stereoselective syntheses of 3-amino- 2,3,6-tndeoxyhexoses and a hydroxy amino acid moiety of AI-77- B", Tetrahedron, 1990, 46, 4823-4846. 15. Berger, S. "Vitamin C-A 13C magnetic resonance study." Tetrahedron, 1977, 33. 1587-1589. 16. Mueller-Molot, W., "Crystalline dimenc dehydroascorbic acid. I. Preparation and recrystallization." Hoppe-Seyler's Z. Physiol. Chem. 1970, 351, 52-55. 17. Dietz, H., "Erne neue darstellung der dimeren dehydro-L- ascorbinsaure und ihre dissoziation in losung." Liebigs Ann. Chem., 1970, 738, 206-208. 18. Ohmon , M.; Higashioka, H.; Takagi, M., "Pure dehydro-L- ascorbic acid prepared by 02-oxidation of L-ascorbic acid with active charcoal as catalyst." Agric. Biol. Chem., 1983, 47, 607-608. 19. Ruiz, J.J.; Aldaz, A.; Dominguez, M., "Mechanism of L-ascorbic acid oxidation and dehydro-L-ascorbic acid reduction on a mercury electrode. I. Acid medium." Can. J. Chem. 1977, 55, 2799-2906. 20. Isbell, H.S.; Frush, H.L., "Oxidation of L-ascorbic acid by hydrogen peroxide: Preparation of L-threonic acid." Carbohydrate Res. 1979. 72, 301-304. 21. Sawyer, D.T.; Chiencato Jr., G. ; Tsuchiya, T., "Oxidation of ascorbic acid and dehydroascorbic acid by superoxide ion in aprotic media." J. Am. Chem. Soc, 1982, 104, 6273-6278. 22. Hvoslef, J.; Pedersen, B., "The structure of dehydroascorbic acid in solution." Acta Chemica Scand. B 1979, 33, 503-511. 23. Wisser, K.; Heimann, W.; Mogel, E., "Em neues redukton aus dem abbau der L-(+)-ascorbinsaure strukturermittlung und synthese." Chem. Mikrobiol. Technol. Lebensm., 1972, 1, 106-109. 24. Frimer, A.A.; Marks, V.; Gilinsky-Sharon, P., "On the reactions of superoxide with keto enols, ac7-reductones and ascorbic acid derivatives." Free Rad. Res. Comms., 1991, 12-13, 93-98. 147 25. Gowal, H.; Dao. L.H.; Dahn, H., "20. Nucleophilic 1,2-shifts of alkoxycarbonyl and carboxylate groups in the benzilie-acid type rearrangement of a,/?-dioxobutyric esters." Helv. Chim. Acta. 1985, 68. 173-180. 26. Gowal, H.; Spiess, A.; Ballenegger, M.; Due, L.; Moll, H.; Schlunke, H-P.; Dahn, H., "225. Nucleophilic 1,2-shifts of carboxamide groups in the benzi1-benzilie acid type rearrangement of 4-aryl-2,3-dioxobutyramides and of quinisatine." Helv. Chim. Acta.. 1985, 68. 2132-2139. 27. Wisser, K.; Heilmann, W.; Mogel, E., "Constitution and synthesis of an acZ-reductone formed on non-oxidative degradation of dehydroascorbic acid." Angew. Chem. Internat. Edit.. 1968, 7, 732. 28. Schmidt, R.R.; Hirsenkorn, R., "Investigations for synthesizing chlorothricolide." Tetrahedron Lett. . 1984, 25, 4357-4360. 29. Witiak, D.T.; Tehim, A.K., "Synthetic approaches to 4-spiro-2- hydroxytetronic acids." J. Org. Chem. 1987, 52, 2324-2327. 30. Schank, K.; Blattner, R., "5-und 6-Ring-reduktone aus 2-diazo- 1,3-dicarbonyl-verbindungen. Eine schonende alternative zur klassichen "virkochungsmethode." Chem. Ber. 1981, 114, 1958- 1962. 31. Ireland, R.E.; Thompson, W.J., "An approach to the total synthesis of chlorothricolide: The synthesis of the top half." J. Org. chem.. 1979, 44, 3041-3052. 32. Brandange, S.; Flodman, L; Norberg, A., "Studies on the intramolecular Claisen condensation; facile synthesis of tetronic acids." J. Org. Chem. 1984, 49, 927-928. 33. Ireland, R.E.; Varney. M.D., "Approach to the total synthesis of chlorothricol ide: Synthesis of (±)-19,20-dihydro-24-O- methylchlorothricolide, methyl ester, ethyl carbonate." J. Org. Chem. 1986, 51, 635-648. 34. Witiak, D.T.; Tehim, A.K., "Efficient synthesis of optically pure stereogenically labile 4-substituted-2-hydroxytetronic acids", J. Org. Chem.. 1990, 55. 1112-1114. 35. Stork, G.; Rychnovsky, S.D., "Iterative butenolide construction of polypropionate chains." J. Am. Chem. Soc. 1987, 109, 1564- 1565. 148 36. Liang, Y.T.S.; Liu, X.S.; Seib, P.A., "Synthesis of D- erythroascorbic acid." J. Carbohydrate Chemistry, 1990, 9, 75- 84. 37. Hesse, G.; Forderreuther, M., "The use of glycol sulfite for the preparation of ethylene ketals." Chem. Ber. 1960, 93, 1249- 1251. 38. Adler, M.; Schank, K.; Schmidt, V., "Introduction of oxygen functions into the a-position of /?-diketones, 2) Defunctionalisations of 2-acyloxy-3-sec-amino-2-cyclohexen-l- ones." Chem. Ber., 1979, 112. 2324-2331. 39. Witiak, D.T.; Kim, S.K.; Tehim, A.K.; Sternitzke, K.D.; McCreery, R.L.; Kim, S.U.; Feller, D.R.; Romstedt, K.J.; Kamanna, V.S.; Newman, H.A.I., "Synthetic <3C7-reductones: 3,4- Dihydroxy-2W-l-benzopyran-2-ones and their cis- and trans- 4a,5,6,7,8,8a-hexahydro diastereomers. Antiaggregatory, antilipidemic, and redox properties compared to those of the 4- substituted 2-hydroxytetronic acids." J. Med. Chem. 1988, 31. 1437-1445. 40. Yang, H.; Kuroda, H.; Miyashita, M.; Irie, H., "Synthesis of the simple macrolides, patulolide A and patulolide C." Chem. Pharm. Bull., 1992, 40, 1616-1618. 41. Irie H.; Kitagawa, T.; Miyashita, M.; Zhang, Y., "Synthesis of methyl esters of AF-toxin Ila and lie, toxins to Japanese white pear produced by Alternaria alternata strawberry pathotype." Chem. Pharm. Bull., 1991, 39, 2545-2549. 42. Irie, H.; Matsumoto, K.; Kitagawa, T.; Zhang, Y., "Synthesis of the methyl ester of AK-toxin II, a host-specific toxin to Japanese white pear, and its congeners: Structure-toxicity relationship of the toxin." Chem. Pharm. Bull., 1990, 38, 1451. 43. Cohen, N.; Banner, B.L.; Lopresti, R.J.; Wong, F.; Rosenburg, M.; Kiu, Y-Y.; Thorn, E.; Liebman, A.A., "Enantiospecific syntheses of leukotrienes C4, D4, and E4 and [14,15- 3 H2]Leukotriene E4 dimethyl ester." J. Am. Chem. Soc, 1983, 105, 3661-3672. 44. Weidenhagen, R.; Wegner, H.; Lung, K.H.; Nordstrom, L., "Action of diazonium salts on ascorbic acid; a general reaction of dienols." Chem Ber. 1939, 72B, 2010-2020. 45. Perel, J.M.; Dayton, P.G., "A Convenient synthesis of crystalline L-threonolactone." J. Org. Chem. 1960, 25, 2044. 149 46. Micheel. F.: Hasse, K., "2-Desoxy-L-ascorbic acid." Ber.. 1936, 69B. 879-881. 47. Reichstein, T.; Grussner, A.; Bosshard, W., "Structure of acetone-L-ascorbic acid." Helv. Chim Acta. 1935, 18. 602-608. 48. Jung, M.E.; Shaw, T.S., "Total synthesis of (R)-glycerol acetomde and the anti epileptic and hypotensive drug (-)-gamma- ami no-beta-hydroxybutync acid (GABOB): Use of vitamin C as a chiral starting material. J. Am. Chem. Soc. 1980, 102. 6304- 6311. 49. Takano, S.; Numata, H.; Ogasawara, K., "An efficient synthesis of (S)-5-hydroxymethyl-2(5W)-furanone." Heterocycles, 1982, 19. 327-328. 50. Emons, C.H.H.; Kuster, B.F.M ; Vekemans, J.A.J.M.; Sheldon, R.A., "A new convenient method for the synthesis of chiral C3- synthons." Tetrahedron Asymmetry. 1991, 2, 359-62. 51. Chittenden, G.J.F., "An improved, simplified synthesis of l,2:5,6-di-0-isopropylidene-D-manmtol." Carbohydr. Res.. 1980, 84. 350-352. 52. Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K., "Facile synthesis of l,2:5,6-di-0-cyclohexylidene-D-manmtol and 2,3-O-cyclohexylidene-D-glyceraldehyde." Agric. Biol. Chem., 1984, 48, 1841-1844. 53. Voeffray, R., "Process for the preparation of pure enantiomers of 2,2,4-tnsubstituted 1,3-dioxolanes from (lso)ascorbate ketals " Eur. Pat. Appl. EP 325967, (CI. C07D317/20), 02 Aug 1989. CH Appl. 88/253, 26 Jan 1988; 11 pp. 54. Vekemans, J.A.J.M.; Franken, G.AM.; Chittenden, G.J.F.; Godefroi, E.F , "An efficient synthesis of (S)-5-hydroxymethyl- 2(5H)-furanone." Tetrahedron Lett. 1987, 28, 2299-2300. 55. Vekemans, J.A.J.M.; Franken, G.A.M.; Dapperens, C.W.M.; Godefroi, E.F.; Chittenden, G J F , "Vitamin C and isovitamin C derived chemistry. 3. Chiral butenolides via efficient 2,3- didehydroxylations of L-gulono-, D-mannono-, and D-nbono-1,4- lactones." J. Org. Chem.. 1988, 53. 627-633. 56. Vekemans, J A.J.M.; de Bruyn, R.G.M.; Cans, R.C.H.M.; Kokx, A.J.P.M.; Komngs, J.J.H.G.; Godefroi, E.F.; Chittenden, G.J.F., "Vitamin C and isovitamin C derived chemistry. 2. Synthesis of some enantiomencally pure 4,5,6-tnhydroxylated norleucines." J. Org. Chem.. 1987, 52. 1093-1099. 150 57. Andrews, G.C.; Crawford, T.C.; Bacon, B.E., "Stereoselective, catalytic reduction of L-ascorbic acid: A convenient synthesis of L-gulono-l,4-lactone." J. Org. Chem. 1981, 46, 2976-2977. 58. Hanessian, S.; Bargiotti, A.; LaRue, M., "A mild and stereospecific conversion of vicinal diols into olefins." Tetrahedron Lett. , 1978, 737-740. 59. Vekemans, J.A.J.M.; Dapperens, C.W.M.; Classen, R.; Koten, A.M.J.; Godefroi, E.F., "Vitamin C and Isovitamin C derived chemistry. 4. Synthesis of some novel furanone chirons", J. Org. Chem., 1990, 55, 5336-5344. 60. Poss, A.J.; Smyth, M.S., "The total synthesis of D-mycinose." Tetrahedron Lett., 1988, 29, 5723-5724. 61. Ashry, E.E.S.H.; Kilany, E.Y., "Bromodeoxy-isoascorbic acid and derivatives thereof.", Carbohydrate Research, 1980, 80, c23-24. 62. Kiss, J.; Berg, K.P.; Dirscherl, A.; Oberhansli, W.E.; Arnold, W., "181. Synthesis and properties of 6-deoxy-6-halogen- derivatives of L-ascorbic acid." Helv. Chim Acta, 1980, 63, 1728-1739. 63. Poss, A.J.: Smyth, M.S., "The total synthesis of L-talonic lactone." Tetrahedron Lett., 1989, 39, 5201-5202. 64. Abushanab. E.; Bessodes, M.; Antonakis, K., "Practical enantiospecific syntheses of (+) erythro-9-(2S-hydroxy-3R- nonyl) Adenine." Tetrahedron Lett, 1984, 25, 3841-3844 65. Mikkilineni, A.B.; Kumar, P.; Abushanab, E., "The chemistry of L-ascorbic and D-isoascorbic acids. 2. R and S GlyceraIdehydes from a common intermediate." J. Org. Chem., 1988, 53, 6005- 6009. 66. Saibaba, R.; Sarma, M.S.P.; Abushanab, E., "The chemistry of L- ascorbic and D-isoascorbic acids. 3: Efficient syntheses of pure R- and S- l,2-0-isopropylidene-l,2,4-butanetriols." Synth. Comm., 1989, 19, 3077-3086. 67. Abushanab, E.: Vemishetti, P.; Leiby, R.W.; Singh, H.K.; Mikkilineni, A.B.: Wu, D.C.-J.; Saibaba, R.; Panzica, R.P., "The chemistry of /.-ascorbic and D-isoascorbic acids. 1. The preparation of chiral butanetriols and -tetrols." J. Org. Chem., 1988, 53. 2598-2602. 68. Yamagata, K.: Yamagiwa, Y.; KamikawaJ., "Synthesis of chiral long-chain a-hydroxy acids from L-ascorbic acid. Useful components for the synthesis of cerebrosides." J. Chem. Soc. Perkin Trans. 1, 1990, 3355-3357. 69. Wei, C.C.; Bernardo, S.D.; Tengi, J.P.; Borgese, J.; Weigele, M., "Synthesis of chiral /^-lactams using L-ascorbic acid." J. Org. Chem.. 1985, 50. 3462-3467. 70. Witiak. D.T.; Kokrady. S.S.; Patel, S.T.; Huzoor-Akbar; Feller, D.R., "Hypocholesterolemic and antiaggregatory properties of 2- hydroxytetronic acid redox analogues and their relationship to clofibric acid." J. Med. Chem. 1982, 25. 90-93. 71. Dahn, H.; Lawendel, J.S.; Hoegger, E.F.; Schenker, E., "Reductone. II. The isolation of 5-aryl-3-hydroxytetronimide from aromatic and heterocyclic-aromatic aldehydes, glyoxal, and potassium cyanide." Helv. Chim. Acta. 1954, 37. 1309-1318. 72. Dahn, H.; Lawendel, J.S., "The elucidation of the structure of 5-aryl-3-hydroxytetronimides." Helv. Chim. Acta, 1954, 37. 1318-1327. 73. Dahn, H.; Lawendel, J.S.; Hoegger, E.F.; Fischer, R.; Schenker, E., "A new preparation of aromatically substituted reductones." Experientia. 1954, 10. 245-246. 74. Dahn, H.; Hauth, H., "Uber decarboxylierung und reduktion von 4-phenyl-2,3-diketo-butyrolacton." Helv. Chim. Acta. 1956, 39. 1366. 75. Witiak, D.T.; Kim, S.K.; Romstedt, K.; Newman, H.A.I.: Feller, D.R., "Comparative antiaggregatory activity in human platelets of a benzopyranone aci-reductone, clofibric acid, and a 2,3- dihydrobenzofuran analogue." J. Med. Chem. 1986, 29. 2170-2174. 76. Sun, Y., "Free radicals, antioxidant enzymes, and carcinogenesis." Free Radical Biology & Medicine. 1990, 8. 583- 599. 77. Halliwell, B., "Oxidants and human disease: Some new concepts." FASEB. 1987, 358-364. 78. Florence, T.M., "Free radicals, antioxidants and cancer prevention." Proc. Nutr. Aust.. 1990, 15. 88-93. 79. Pryor, W.A.; Cornicelli, J.A.; Devall, L.J.; Tait, B.; Trivedi, B.K.; Witiak, D.T.; Wu, M., "A rapid screening test to determine the antioxidant potencies of natural and synthetic antioxidants." J. Org. Chem.. 1993, 58. 3521-3532. 80. Witiak. D.T.; Triozzi, P.L., Feller, D.R.; Romstedt. K.J.; Tehim, A.K.; Hopper, A.T.; Mantri, P.M., "4-Substituted-2- hydroxytetronic acid aci-reductones improve lymphokine- activated killer cell activity in vitro." Presented at the 1993 American Association for Cancer Research meeting, Florida. 81. Rosenberg, S.A., "Adoptive immunotherapy of cancer using lymphokine activated killer cells and recombinant interleukin- 2." In Important Advances in Oncology (eds DeVita, V.T.; Hellman, S.; Rosenberg, S.A.) 1986, pp. 55-91. Lippincott, Philadelphia. 82. Rappaport, R.S.; Dodge, G.R., "Prostaglandin E inhibits the production of human inter!eukin 2." J. Exp. Med.. 1982, 155, 943-948. 83. Quinn, M.T.; Parthasarathy, S.; Fong, L.G.; Steinberg, D., "Oxidatively modified low density lipoproteins: A potential role in recruitment and retention of monocyte/macrophages during atherogenesis." Proc. Natl. Acad. Sci. USA. 1987, 84, 2995-2998. 84. Tolman, D.L.; Birnbaum, J.E.; Chiccarelli, F.S.; Panagides. J.; Sloboda, A.E., "Inhibition of prostaglandin activity and synthesis by fenbufen a new nonsteroidal antiinflammatory agent and one of its metabolites." Adv. Prostalandin Thromboxane Res. 1976, 1. 133-8. 85. Mantri. P.; Witiak, D.T., unpublished results. 86. Braghlioli, D.; Witiak, D.T., unpublished results. 87. Ashry, E.S.H.E.; Rahman, M.A.A.; Kilany, Y.E.; Rashed, N., "Reaction of dehydro-L-ascorbic acid analogures with o- phenylenediamine." Carbohydrate Research, 1986, 153, 146-149. 88. Kilany, Y.E.; Rashed, N.; Mansour, M.: Ashry, E.S.H.E., "Synthesis and rearrangement of mono and bis-(p- fluorophenyDhydrazones of dehydro-L-ascorbic acid." J. Carbohydrate Chemistry. 1988, 7, 187-198. 89. Witiak, D.T.; Inbasekaran, M.N., "Pharmaceuticals, optically active." Encyclopedia of Chemical Technology. 1978, 17, 311-45. 90. Hopper, A.T.; Witiak, D.T., unpublished results 91. Whitesell, J.K.; Reynolds, D., "Resolution of chiral alcohols with mandelic acid." J. Org. Chem., 1983. 48. 3548-3551. 92. Midland, M.M.; Tramontane A., "The synthesis of naturally occurring 4-alkyl- and 4-alkenyl-gamma-lactones using the asymmetric reducing agent /?-3-pinanyl-9- borabicyclo[3.3.1]nonane." Tetrahedron Lett. 1980, 21, 3549- 3552. 93. Midland, M.M.; Tramontane A.; Cable, J.R., "Synthesis of Alkyl 4-hydroxy-2-alkynoates." J. Org. Chem, 1980, 45, 28-29. 94. Mori, K.; Akao, H., "Synthesis of optically active alkynyl alcohols by microbial asymmetric hydrolysis of the corresponding acetates." Tetrahedron Lett. , 1978, 4127-4130. 95. Brown, H.C.;, Pai , G.G., "Selective reductions. 37. Asymmetric reduction of prochiral ketones with B-(3-Pinanyl)-9- borabicyclo[3.3.1]nonane." J. Org. Chem., 1985, 50, 1384-1394. 96. Dale, J.A.; Dull, D.L.; Mosher, H.S., "a-Methoxy-a- trifluoromethylphenyl acetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and amines." J. Org. Chem., 1969, 34, 2543-2549. 97. Mukaiyama, T.; Tabusa, F.; Suzuki, K., "The stereoselective synthesis of 2,3-cis-dihydroxy-i/-butyrolactones by the oxidation of K-butenolides with KMn04-crown ether." Chem. Lett. 1983, 173-174. 98. VanRheenen, V.; Kelly, R.C.; Cha, D.Y., "An improved catalytic 0s04 oxidation of olefins to cis-l,2-glycols using tertiary amine oxides as the oxidant." Tetrahedron Lett., 1976, 1973- 1976. 99. Wai , J.S.M.; Marko, I.; Svendsen, J.S.; Finn, M.G.; Jacobsen, E.N.; Sharpless, K.B., "A mechanistic insight leads to a greatly improved osmium-catalyzed asymmetric dihydroxylation process." J. Am. Chem. Soc. 1989, 111, 1123-1125. 100. Swern, D., "Epoxidation and hydroxylation of ethylenic compounds with organic peracids." Organic Reactions, 1953, 7, 379-421. 101. Wiberg, K.B.; Saegebarth, K.A., "An 0-18 tracer study of the "wet" and "dry" Prevost reactions." J. Am. Chem. Soc, 1957, 79, 6256-6261. 102. Fetizon, M.; Golfier, M.; Louis, J-M., "Highly selective oxidations of diols by silver carbonate." Chemical Comm. 1969, 1102. 154 103. Amon, CM.; Banwell. M.G.; Gravatt, G.L., "Oxidation of vicinal diols to a-dicarbonyl compounds by trifluoroacetic anhydride "activated" dimethyl sulfoxide." J. Org. Chem.. 1987. 52. 4851- 4855. 104. Wrobel, J.E.; Ganem, B., "Total synthesis of (-)-vertinolide. A general approach to chiral tetronic acids and butenolides from allylic alcohols." J. Org. Chem. 1983. 48. 3761-3764. 105. Wasserman, H.H.; Ives, J.L., "Reaction of singlet oxygen with enamino lactones. Conversion of lactones to a-keto lactones." J. Org. Chem.. 1978, 43. 3238-3240. 106. Vedejs, E.; Engler, D.A.; Telschow, J.E., "Transition-metal peroxide reactions. Synthesis of a-hydroxycarbonyl compounds from enolates." J. Org. Chem.. 1978. 43. 188-196. 107. Moriarty, R.M.; Duncan, M.P.; Prakash, 0., "Hypervalent iodine oxidation of silyl enol ethers. A direct route to a-hydroxy ketones." J. Chem. Soc. Perkin Trans. 1. 1987, 1781-1784. 108. Adam, W.; Golsch, D.; Hadjiarapoglou, L., "Epoxidation of flavones by dimethyldioxirane." J. Org. Chem.. 1991. 56. 7292- 7297. 109. Adam, W.; Hadjiarapoglou, L, "Dimethyldioxirane epoxidation of /?-oxo enol ethers." Chem. Ber. 1990. 123. 2077-2079. 110. Ager, D.J.; Fleming, I.; Patel, S.K., "The conjugate addition of a silyl group to enones and its removal with copper(II) bromide: A protecting group for the a,/?-unsaturation of a,/?- unsaturated ketones." J. Chem. Soc. Perkin Trans. I. 1981, 2520-2526. 111. Fleming, I.; Sanderson, E.J., "A one-pot conversion of the phenyl dimethyl silyl group into a hydroxyl group." Tetrahedron Lett.. 1987, 28. 4229-4232. 112. Brown, H.C.; Jadhav, P.K.; Desai, M.C., "Direct chiral synthesis of boronic acids and esters of high optical purity via asymmetric hydroboration displacement." J. Am. Chem. Soc, 1982, 104. 4303-4304. 113. Brown, H.C.; Singaram, B., "Chiral synthesis via organoboranes. 1. A simple procedure to achieve products of essentially 100% optical purity in hydroboration of alkenes with monoisopinocampheylborane. Synthesis of boronic esters and derived products of very high enantiomeric purities." J. Am. Chem. Soc. 1984, 106. 1797-1800. 155 114. Wrobel, J.E.; Ganem, B., "Total synthesis of (-)-vertinolide. A general approach to chiral tetronic acids and butenolides from allylic alcohols." J. Org. Chem. 1983, 48, 3761-3764. 115. Warren, S. "Organic synthesis: The disconnection approach." 1989 John Wiley & Sons, Chichester. 116. Helferich, B.; Peters, 0., "Eine neue Ascorbinsaure-synthese." B. 1937, 70, 465-468. 117. Ide, W.; Buck, J.S., "The synthesis of benzoins." Org. React.. 1948, IV. 269-304. 118. Stork, G.; Maldonado, L, "Anions of protected cyanohydrins as acyl carbanion equivalents and their use in a new synthesis of ketones." J. Am. Chem. Soc. 1971, 93. 5286-5287. 119. Seebach, D., "Methods and possibilities of Nucleophilic acylation." Angew. Chem. internat. Edit.. 1969, 8. 639-649. 120. Muller, P.; Godoy, J., "Ru-Catalyzed oxidation of substituted acetylenes to a-keto esters and a-keto amides with iodosylbenzene." Tetrahedron Lett., 1982, 23. 3661-3664. 121. Bassignane, L; Brandt, A.; Caciagli, V.; Re, L., "Novel applications of the potassium chlorate-osmium tetroxide oxidizing system. Synthesis of a-dicarbonyl derivatives from acetylenic compounds. Synthesis of a 2,3-dihydroxy-l,4-dione from a 2,5-dialkylfuran." J. Org. Chem.. 1978, 43, 4245-4247. 122. Guanti, G. Banfi, L; Narisano, E.; guaragna, A., "Bakers' yeast mediated synthesis of protected a-hydroxyaldehydes." NATO ASI Ser.. 1986, Ser. C, 178 (Enzymes Catal. org. Synth), 343-345. 123. Giuseppe G.; Narisano, E.; Pero, F.; Banfi, L; Scolastico, C, "Asymmetric synthesis of protected a-hydroxyaldehydes via reduction of a-arylthio-jS-oxosulphoxides." J. Chem. Soc, Perkin Trans. I, 1984, 189-193. 124. Gao, Y.; Klunder, J.M.; Hanson. R.M.; Masamune, H.; Ko, S.Y.; Sharpless, K.B., "Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization." J. Am. Chem. Soc. 1987, 109, 5765-5780. 125. Heathcock, C.H.; Young, S.D.; Hagen, J.P.; Pirrung, M.C.; White, C.T.; VanDerveer, D., "Acyclic stereoselection. 9. Stereochemistry of the addition of lithium enolates to a-alkoxy aldehydes." J. Org. Chem. 1980, 45, 3846-3856. 126. Burke, S.D.; Pacofsky, G.J.; Piscopio, A.D., "Synthesis of Ethisolide, isoavenaciolide, and avenaciolide." J. Org. Chem. 1992, 57. 2228-2235. 127. Smith, L., "Separation of mandelic acid into its active components by means of phenyl ethyl amine." J. Prakt. Chem., 1912, 84. 743-744. 128. Hiroshic S.; Ryohei, 0. "A method of resolution of racemic compounds with optically active ion-exchange resins." Kanazawa Daigaku Kogakubu Kiyo 1960. 2, 215-217. 129. Manecke, G.; Guenzel, G., "Application of a nitrated copolymer from methacrylic acid and methacrylic acid m-fluoroanilide to the preparation of enzyme resins, to the resolution of racemic compounds, and to tanning experiments." Makromol. Chem., 1962, 51, 199-216. 130. Dashkevich, L.B., "Resolution of mandelic acid with optical active solvents." Trudy Leningrad. Khim.-Farm. Inst. 1959, 6, 29-32. 131. Rogozhim, S.V.; Davankov, V.A.; S-Zhuchkova, L.Y., "Unsymmetrical anion-exchange sorbents based on optical isomers of l-p-nitrophenyl-2-amino-l,3-propanediol and its derivatives." Izv. Akad. Nauk SSSR, Ser. Khim. 1971, 2, 459- 461. 132. Chara, M.; Fujita, I.; Kwan, T., "The selective adsorption of optical antipodes as revealed by chromatographic techniques." Bull. Chem. Soc. Japan 1962, 35, 2049-2051. 133. Mckenzie, A.; Humphries, H.B.P., "Studies in asymmetric synthesis (VIII). The asymmetric synthesis of 1-mandelic acid." J. Chem. Soc. 1909, 95, 1105-15. 134. Evans, D.A.; Morrissey, M.M.; Dorow, R.L., "Asymmetric oxygenation of chiral imide enolates. A general approach to the synthesis of enantiomerically pure a-hydroxy carboxylic acid synthons." J. Am. Chem. Soc, 1985, 107. 4346-4348. 135. Ando, T., "Reaction between ethyl ketomalonate and aromatic hydrocarbons. I. Condensations in the presence of stannic chloride." J. Chem. Soc Japan. 1935, 56, 745-56. 136. Compere, E.L., "Synthesis of a-hydroxyarylacetic acids from bromoform, arylaldehydes, and potassium hydroxide, with lithium chloride catalyst." J. Org. Chem.. 1968, 33. 2565-2566. 137. Eaborn, C. Interaction of phenacyl chloride and aqueous alkali." J. Chem. Soc. 1957, 1935-1936. 138. Rasmussen, J.K.; Heilmann, S.M., Org. Synth. 1984, 62. 196-201. 139. Langley, W.D.; "p-Bromophenacyl bromide." Organic Reactions Collective Vol. I. 1956 (2nd ed.). pp. 121. 140 Schaefer, J.P.; Corey, E.J., "New synthesis of a-keto esters." J. Org. Chem.. 1959, 1825. 141. "A new convenient method for the synthesis of chiral C3- synthons." Tetrahedron asymmetry, 1991, 2(8) 771-4. 142. Findlay, A.; Hickmans, E.M., "Partial racemization of menthyl /?-mandelate." J. Chem. Soc. 1909, 95. 1386-92. 143. Vavon, G.; Antonim, A. ."Asymmetric synthesis by group exchange. The case of phenylglyoxylic acid and its menthyl ester." Compt. rend. 1950. 230. 1870-2 144. Vavon, G.; Antonim, A.; Delepine, M.M., "Synthese asymetnque par echange functionnel. Cas des acides phenyl- et a- naphtylglyoxyliques opposes aux menthol, neomenthol et isoborneol actifs." Compt. rend. 1951, 232. 1120-2. 145. McKenzie, A.; Humphries, H.B.P., "The asymmetric synthesis of 7-mandelic acid." Proc. Chem. Soc. 1909, 164. 146. Greene. T.W.; Wuts. P.G.M., "Protective groups in organic synthesis." 2nd ed., John Wiley and sons, city, 1991. 147. Kobayashi, Y.; Takemoto, Y; Kamijo, T.; Harada, H.; Ito, Y.; Terashima, S., "A stereoselective synthesis of the (2R.3S)- (2S,3/?)-3-amino-2-hydroxybutync acid derivatives, the key components of a renin inhibitor and bestatin." Tetrahedron. 1992, 48. 1853-1868. 148. Yoon, N.M.; Gyoung. Y.S., "Reaction of dnsobutylaluminum hydride with selected organic compounds containing representative functional groups." J. Org. Chem. 1985, 50. 2443-2450. 149. Gassman, P.G.; Schenk, W.N., "A general procedure for the base- promoted hydrolysis of hindered esters at ambient temperatures." J. Org. Chem.. 1977. 42. 918-920 150. Mata, E.G.; Mascaretti, O.A.. "Mild and effective cleavage of esters with bis(tnbutyltin) oxide: A useful application in the deprotection of POM penicillanate esters." Tetrahedron Lett., 1988, 29. 6893-6896. 151. Felix. A.M., "Cleavage of protection groups with boron tribromide." J. Org. Chem., 1974, 39, 1427-1429. 152. Corey, E.J.; Erickson, B.W., "Oxidative hydrolysis of 1,3- dithiane derivatives to carbonyl compounds using N- halosuccinimide reagents." J. Org. Chem. 1971, 36, 3553-3560. 153. Belletire, J.L.; Walley, D.R.; Fremont, S.L., "Dealkylative decarboxylation. IV. A novel approach to ketene thioacetals," Tetrahedron Lett. 1984, 25(50), 5729-5732. 154. Pattenden, G.; Clemo, N.G., "Naturally occurring 5-methoxy- 3(2H)-furanones. Re-assignment of structures to the Aspertetronine group of natural products." Tetrahedron Lett. 1982, 23. 589-592. 155. Terao, Y.; Akamatsu, M.; Achiwa, K., "Synthesis of chiral 3- substituted K-^ctones and 9-furanosyl adenine from (/?)-2-(2,2- diethoxlyethyl)-l,3-propanediol monoacetate prepared by lipase- catalyzed reaction." Chem. Pharm. Bull. 1991, 39, 823-825.

156. Fieser, L.F.; Fieser, M., "Jones Reagent." Reagents for organic synthesis. 1967, 1, 142. 157. Nickl, J.; Engel, W.; Teufel, H.; Engelhardt, G., "Anti inf1ammatory 4-(4-biphenylyl)-4-hydroxycrotonolactones." Ger. Offen. 2,314,929 (CI. C07d, A 61k), 10 Oct 1974, Appl. P2314929.3, 26 Mar 1973; 12pp. 158. Chiccarelli, F.S., "4-Hydroxy-4-biphenyllybutyric acid." U.S. 4,219,668 (CI. 562-469; C07C69/76), 26 Aug 1980, Appl. 54,741,05 Jul 1979; 5pp. 159. Chiccarelli, F.S., "Lactone metabolites of 3-(4- biphenylylcarbonylpropionic acid." U.S. 4,247,466 (CI. 260- 343.6: C07D307/32), 27 Jan 1981, Appl. 54,748, 05 Jul 1979; 4pp. 160. Kinishi, R.; Nakajima, Y.; Oda, J.; Inouye, Y.,"Asymmetric reduction of a-ketoesters with sodium borohydride by chiral phase transfer catalysts." Agric. Biol. Chem. 1978. 42(4). 869- 72. 161. Kaneko, T.; Turner, D.L.; Newconb, M.; Bergbreiter, D.E., "Polarity reversed prelog reactions." Tetrahedron Lett. 1979, (2) 103-106. 162. Gluchowski, C.; Cooper, L; Bergbreiter, D.E.; Newconb, M., "Preparation of /^-lactams by the condensation of lithium ester enolates with aryl aldimines." J. Org. Chem. 1980, 45, 3413-16 163. Ivanov, P.M., "Stereochemical applications of potential energy calculations. Part VI. Molecular mechanics study of conformations of (-)-menthyl esters of the stereoisomer^c (5)- and (/?)-mandelic acids." J. Mol. Struct. 1986, 140(3-4), 359- 63. 164. Riebsomer, J.L.; Stauffer, D.; Glick, F.; Lambert, F., "Preparation of substituted mandelic acids and their bacteriological effects." J. Am. Chem. Soc, 1942. 64, 2080-1. 165. Anschutz, R.; Bocker, R., "The tetronic acid group. II. Action of acetylmandelyl chloride on sodium malonic ester and sodium cyanoacetic ester." Ann., 1910, 368, 53-75. 166. Hassner, A.; Alexanian, V. "Direct Room temperature esterification of carboxylic acids." Tetrahedron Lett., 1978, 4475-4478. 167. Riebsomer, J.L.; Irvine, J.; Andrews, R., "The preparation of substituted mandelic acids and their bacteriological effects", 1938, 60, 1015-1016. 168. Korver. 0. "Optical rotatory dispersion and circular dichroism of substituted mandelic acis." Tetrahedron, 1970, 5507-5518. 169. Mori, N.; Tanaka, Y.; Tsuzuki, Y., "Intramolecular hydrogen bonds. VII. Methyl mandelates and related compounds." Bull. Chem. Soc. Japan, 1966, 39, 1490-1495. 170. Jenkins, S.S., "The preparation and some properties of the chloromandelic acids, their methyl esters and amides." J. Am. Chem. Soc, 1931, 53. 2341. 171. Seebach, D., "Nucleophile acylierung mit 2-1 ithium-1.3- dithianen bzw. -1,3,5-trithianen," Synth., 1969, 17-36. 172. Flippin, L.A.; Dombroski, M.A., "Aldol Condensations of ethyl l,3-dithiolane-2-carboxylate and ethyl l,3-dithiane-2- carboxylate with chiral aldehydes. Exceptional diastereoface selectivity from two convenent acetate equivalents," Tettrahedron Lett., 1985, 26(25), 2977-2980. 173. Grunewald. G.L.; Brouillette, W.J.; Finney, J.A., "Synthesis of a-hydroxyamides via the cyanosilylation of aromatic ketones." Tetrahedron Lett. 1980, 21, 1219-1220. 160 174. Blicke, F.F.; Grier, N., "Antispasmodics." J. Am. Chem. Soc 1943, 65, 1725-1728.