Uhm Phd 9615565 R.Pdf

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PART I: THE STEREOSELECTIVE SYNTHESIS OF CANNABINOIDS

PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL A AND ITS ANALOGS

A DISSERTAnON SUBlVtITIED TO THE GRADUATE DIVISION OF THE UNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR TIlE DEGREE OF

DOCTOR OF PHILOSOPHY IN CHElVtISTRY DECEMBER 1995

By Xianglong Zou

Dissertation Committee: Marcus A. Tius, Chairman Charles F. Hayes Craig M. Jensen Edgar F. Kiefer Robert S. H. Liu UMI Number: 9615565

This microform edition is protected against unauthorized copying under Title 17, United States Code.

UMI 300 North Zeeb Road Ann Arbor, MI 48103 iii ACKNOWLEDGEMENTS

I would like to thank my advisor, Professor Marcus A. Tius, not only for guidance but also for his patience and encouragement during the completion or. this work. I also wish to thank the other members of my dissertation committee for their assistan~e and encouragement.

I thank members of the Tius group, past and present, for being helpful and understanding. Many thanks to Dr. David Drake for proofreading this dissertation and Dr. Walter Niemczura, Mike Burger and Wesley Yoshida for their valuable help in obtaining NMR and mass spectral data.

I would like to thank my wife Ling Cui and my daughter Susan fer their love and support.

Finally, I would like to thank Professor Marcus A. Tius for his support in the form of research assistantship and the Department of Chemistry of the University of Hawaii for support in the form of a teaching assistantship. IV ABSTRACT

Part I: The stereoselective total synthesis of each of the two diastereomeric C6-hydroxyhexahydrocannabinols is described. The extension of isopropenyl to hydroxymethyl was accomplished by the use of an ene reaction with formaldehyde in the presence of methylalurninum bis(2,6-diphenylphenoxide). Stereochemistry of the two final products was controlled by an intramolecular mercuration. Biological testing showed that the analogs exhibit different degrees of binding to the CB 1 cannabinoid receptor.

Part II: The total synthesis of a dienone precursor of sarcophytol A is described. The conversion of dienone to sarcophytol A has been reported. Hence, this is the formal total synthesis of sarcophytol A. Interesting features of this synthesis include an alkynylation of an allylic halide, macrocyclization, and C-alkylation of a 1,3-diketone with isopropyl iodide. Selective reduction of diketone to dienone was accomplished with DIBAL. It is noteworthy that conversion of sulfoxide directly to the corresponding enone did not succeed through a Pummerer rearrangement. Attempted conversion of sulfone to dienone in the target molecule was not successful and eliminated product was obtained. A synthesis of canventol is also described. Biological testing has shown that canventol is a more potent antitumor promotor than sarcophytol A even though canventol is structurally simpler. v

TABLE OF CONTENTS

ACKNOWLEDGEMENTS .iii ABSTRACT .i v LIST OF ABBREVIATIONS viii

PART I STEREOSELECTIVE SYNTHESIS OF CANNABINOIDS

INTRODUCTION 1

1. Background 1 2. The Structural and Stereochemical Requirements for Biological Activity 3 3. Previous Synthetic Approaches towards Cannabinoids 7

RESULTS AND DISCUSSION 1 4

1. Retrosynthesis of 1213-Hydroxymethyl-9-nor-913- Hydroxyhexahydrocannabinol. 14 2. Stereospecific Ring Opening of Cuprate Adduct.. l 5 3. Formation of Tetraol l 8 4. Stereoselective Synthesis of 12p-Hydroxymethyl-9- nor-913-Hydroxyhexahydrocannabinol.. 19 5. Stereoselective Synthesis of 14a-Hydroxymethyl-9- nor-9p-Hydroxyhexahydrocannabinol.. 2 1 6. Biological Activities of the Synthetic Compounds 2 4

CONCLUSION 2 6 EXPERIMENTAL 2 7 REFERENCES : 5 2 vi

PART II TOTAL SYNTHESIS OF SARCOPHYTOL A AND ITS ANALOGS

A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS .5 6

INTRODUCTION 5 6

1. Background 5 6 2. Synthesis of Canventol and Its Analogs 5 6 3. Biological Activity 60

EXPERIMENTAL 6 1 REFERENCES 7 3

B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A 7 4

INTRODUCTION 74

1. Background 74 2. Previous Approaches to Macrocyclization 75 a. Stabilized Anion Additions 75 b. Alkynyl Anion Addition 76 3. Previous Synthetic Approaches to Sarcophytol A 77 a. Takayanagi et. al. 77 b. Takahashi et. al. 79 c. Kodama et. al. 8 0 d. Li et. al. 8 0

RESULTS AND DISCUSSION 8 2

1. Retrosynthesis of Sarcophytol A 8 2 2. Synthesis of Alkynyl Acetate 8 3 3. Formation of Cyclic Alkynyl Alcohol.. 8 5 4. Synthesis of Alkylated Sulfoxide 8 8 vii

'5. Pummerer Rearrangement of Alkylated Sulfoxide. Attempted Synthesis of Enone 9 0 a. Model Study 90 b. Attempted Conversion of Sulfoxide to Enone 92 c. Attempted Synthesis of Ester 93 6. Reevalu,ation of Retrosynthesis 96 7. Synthesis of Alkylated Diketone 96 8. Selective Reduction of 1,3-Diketone. Synthesis of Dienone 99

CONCLUSION 10 1 EXPERIMENTAL 102 REF'ERENCE:S 124 VUl

LIST OF ABBREVIATIONS

Ac acetyl Ar aromatic br broad C Celsius c concentration cat. catalytic CBD Cannabidiol a:JN Correlated Spectroscopy CSCM Chemical Shift Correlation Map 6 8 Delta-8-

6 9- Delta-9- d doublet DBA Dibenzyl acetone DBU l,8-diazabicyclo[5.4.0]JJnctec-7-ene dd doublet of doublets ddd doublet of doublet of doublets DIBAL diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N ,N-dimethylformamide DMSO dimethyl sulfoxide dt doublet of triplets FE ethoxyethyl ix

Et ethyl Et20 diethyl ether eV electron volt EVE ethyl vinyl ether g gram h hour Hz Hertz HHC Hydroxyhexahydrocannabinol HMBC Heteronuclear Multiple Bond Correlation HMPA Hexamethylphosphoramide HMQC Heteronuclear Multiple Quantum Correlation HPLC High Pressure Liquid Chromatography HRMS high resolution mass spectrum IR infrared J coupling constant KHMDS potassium bis(trimethylsilyl)amide LAH lithium aluminum hydride LDA lithium diisopropylamide m multiplet M Molar mg milligram MHz megahertz x min minutes mL milliliter mmol millimole n-Bu normal butyl NMR nuclear magnetic resonance nOe nuclear Overhauser effect Oxaziridine 2 -(p-toluenesulfony1)-3 -aryloxaziridine Ph phenyl PPTS pyridium para-toluenesulfonate p-TSA para-toluenesulfonic acid pyr. pyridine q quartet Rf retention factor s singlet SAR Structure Activity Relationship sat'd saturated t triplet tert-B u tertiary butyl TBDM tertiary-butyldimethyIs ilyl TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride me tetrahydrocannabinol Xl

THF tetrahydrofuran TMS trimethylsilyl Ts toluenesulfonyl PART I: THE STEREOSELECTIVE SYNTHESIS OF CANNABINOIDS 1

INTRODUCTION

1. Background

Cannabis sativa L. was one of the first plants to be used for fiber, food, medicine and in social and religious rituals.! Its medical properties have been recognized for thousands of years in different societies. In Assyria, cannabis, known as azallu, was used for pain alleviation and its seed was prescribed for treatment of depression, "evil eye", and kidney stones.2 The medical applications of cannabis were also well recognized by Chinese in their traditional folk medicine formulations, some of which are still followed today. Cannabis was used for alleviation of pain, clearing blood and treatment of hyperthermia.3 Externally, cannabis was used as a poultice, or as a constituent of various ointments for swellings and bruises. The plant ex.tracts were used in Europe for a long time for treatment of chronic headaches and certain psychosomatic

disorders.4 ,5 Although cannabis has its origins in folk medicine. considerable interest for its use in standard medical practice was generated in the early 19th century when the British scientist O'Shaugnessy applied various cannabis preparations to animal and human clinical experiments.6 The most important observation made by O'Shaugnessy was that cannabis was a potent antinauseant agent.

Since then various medical potentials were observed.7•8 Despite these observations of potential medicinal uses, little progress was made 2

toward practical medical use. The main reason was that no pure constituents of cannabis had been isolated and the variety of crude plant preparations made it difficult to obtain reproducible clinical results. The situation was dramatically changed after a series of compounds with cannabimimetic activity were synthesized by

Adams and Todd9. 10 and subjected to biological tests)l The most widely tested compound was parahexyl, ~6a.lOa-THC 1.

1 Parahexyl

In 1964, the isolation and elucidation of the major psychotropically active constituent, ~9-tetrahydrocannabinol, (- )_~9_ THe 2, by Mechoulam12 indicated that the modern era of cannabis chemistry had arrived for synthesis, pharmacology, metabolism and clinical investigation. For convenience, the following dibenzopyran numbering system will be used throughout this dissertation. 3

2. T~e Structural and Stereochemical Requirements for Biological Activity

Previous studies have shown that alteration of the basic cannabinoid structure dramatically altered the biological activity.I3 Although the structure activity relationships (SAR) for cannabinoids are relatively well established, some observations still need to be clarified. Generally, a classical cannabinoid contains three major parts: (a) a phenol (A ring) with C-3 side chain, (b) a six-membered ring (B ring) with oxygen substitution, (c) a six-membered C ring. In the early 1940's, the SAR of several synthetic cannabinoids were investigated by Loewe.14 Since the identification of the structure of (-)-69-THC in the 1960's, a large amount of biological data has been recorded for both natural and synthetic cannabinoids. Much of this data comes from whole animal bioassays, and the methods for assessment of activities include the overt behavior test in rhesus monkeys or baboons,14 dog ataxia test,15 spontaneous activity test 10 rats and mice,16 drug discrimination test.!7 Limited data is available from humafls, for a small number of cannabinoids. Some tentative rules for SARs formulated by Mechoulam18 in the early 1970's are still consistent with what has been observed for newly synthesized cannabinoids. Most of the active cannabinoids, including (- )_~9_ THC, have a benzopyran structure and cannabinoids in which the pyran ring has been cleaved, e.g. cannabidiol (CBD, 3), show complete loss of activity. Although a pyran ring is a requirement for activity. the 4

benzopyran itself does not confer activity. Substitution of oxygen with nitrogen retains the activity, as illustrated by levonantradol 4. Surprisingly, some cannabinoids which do not contain the

~ "' /'N (CH2bCsHs OH H 3 Cannabidiol (CBD) 4 Levonantradol benzopyran structure, referred to as non-classical cannabinoids, are more potent than (-)-~9-THC. For example, CP-47,497 Sand CP 55,940 6 are ten times more potent than (-)-~9-THC itself. This indicates that the benzopyran ring may not be an absolute requirement for activity,19

OH (NAH) OH

( CH20H (SAH) 5 CP-47,947 6 CP·55,940

Furthermore, SAR studies have also shown that the hydroxyl at C-l has to be free or esterified. Etherification of the phenol led to either complete loss or reduction in activity, whereas the phenolic ester 5

retains the activity.20 The replacement of hydroxyl by amino or other ·heteroatoms eliminates the activity. It is also known that the side chain at C-3 is of considerable importance for cannabinoid activity. In general, elongation and branching of the side chain increase the activity. Johnson and Melvin21 reported that compounds 7 and 8 are analgesically more active than (- )-9-nor-9~- hydroxyhexahydrocannabinol (HHC. 9) and (-)-.19-THC. The most

OH OH

7 A = CH(CH3)(CH2)4CSHS 9 HHC 8 A = CH (CH3)CH(CH3)(CH2)4CH3

active side chains identified thus far are l,l-dimethylheptyl and 1,2 dimethylheptyl. It is interesting to note that substitution of an all carbon chain by one containing oxygen at different positions does not considerably influence the activity.22 ...... , "1' ••• In contrast to the well established structural requirements for activity, stereochemical aspects of the SAR need more investigation due to the difficulties in purification of cannabinoids in large

amounts and enantiomeric contamination of cannabinoids used In early in vivo testing.23 Considerable efforts have been made to establish stereochemical SARs. It was found that the stereochemistry at C-6a, C-IOa should be trans (6aR, IOaR) and that an equatorial 6

substituent at C-9 was more active than an axial one. Molecular shape:"plays an important part in determining the pharmacology of cannabinoids. Recently, Makriyannis24 suggested that cannabinoids with all three rings coplanar are inactive, or have very low activity, and analogs in which the C-ring deviates from planarity are pharmacologically' active. Enormous differences in activity between enantiomeric pairs have been observed. Mechoulam25 reported that (-)-1l-0H-~8_THC-DMH (HU210) was about 87 times more active than (- )-~ 9-THC. Its (+)-enantiomer was inactive in the pigeon drug discrimination test. Similar results were demonstrated by Johnson and Melvin26 on other enantiomeric pairs. For example, levonantradol 4 was active in a series of tests for analgetic and other natural cannabimimetic responses (spontaneous activity, hypothermia and catalepsy), however, its enantiomer was inactive in these tests.

CH20H 10 HU 210 11 CP-55,244

It should be emphasized that the stereospecificity for classical or synthetic cannabinoids is consistent with the results for non-classical cannabinoids. Generally, a conformation in which the southern 7

aliphatic hydroxyl (SAH) is syn to the northern aliphatic hydroxyl (NAH), is required for activity. The non-classical analog, CP-47,497 5, includes the minimal structural requirements for activity and is approximately 10-fold more potent than naturally occurring (_)_.6,9- THC with respect to analgesic activity. Conversely, CP-55,244 11

which contains a: conformationally more defined syn SAH group is 50-fold more potent than its simpler congener and shows a high degree of enantioselectivity.27

3. Previous Synthetic Approaches towards Cannabinoids

Since the isolation and elucidation of the structure of (_)_.6,9 -THC in 1964, several hundred papers related to the synthesis of cannabinoids and their analogs have appeared.28 The main reason for early synthetic afforts was to understand whether the parent cannabinoids themselves were biologically active or whether the activity was derived from one or more biologically active metabolites. Recently, the interest in these compounds was driven by the commercial need for metabolites of (_)_.6,9-THC as analytical standards in the calibration of assays for the accurate detection of cannabinoids in urine. Further, much effort has been devoted to the design of analogs that may serve as probes in order to increase the understanding of the mechanism responsible for cannabinoid pharmacology in man and also as potential therapeutic agents.29 Several syntheses directed toward .6,9_, .6,8-THC and their analogs have been reported.30 Generally, chiral cyclic monoterpenoids and olivetol 8

were the key starting materials In these syntheses. A facile and practi~al method to (-)-L\9-THe was developed by Mechoulam and co-

workers in 1972 (scheme 1).31 Therein, (-)-verbenol 12, which itself

SCHEME 1

OH a .. ~ + 0OH HO 12 13 14

Reagents: (a) p-toluenesulfonic acid. CHZC1Z; (b) BF3·EtZO, room temperature; (c) ZnClz. HCl (g); (d) potassium tert-amylate. was prepared from p-pinene, was condensed with olivetol 13 in methylene chloride in the presence of p-toluenesulfonic acid to produce condensation adduct 14 which was obtained in 60% yield 9

after chromatography. The treatment of adduct 14 with boron trifluoride etherate in methylene chloride at room temperature for 10 min gave ~8-THC 15 in 80% yield. It should be pointed out that in the p-toluenesulfonic acid catalyzed condensation, 4-(2 olivetyl)pinene 14 was the only product isolated. No abnormal isomers were obtained. In 14 the C-6a and C-I0a hydrogens are trans, presumably due to steric factors. The conversion of 15 to 16 was accomplished in quantitative yield by adding gaseous hydrochloric acid at low temperature with catalytic zinc chloride. Treatment of 16 with potassium tert-amylate led to (_)_~9-THC 2 in 90% yield. The overall yield of (_)_~9-THC (2) from (-)-verbenol 12 was ca. 43%. The advantages of the synthesis were the ready availability of starting materials and the reasonable yields. The major urinary metabolite of ~9_THC, Il-nor-~9-THC-9- carboxylic acid 22, has received much attention as an internal reference in a number of immunological screening tests which have been developed to ascertain whether an individual has used marijuana. In the synthesis of (- )_~9_THC metabolites, the principle was to indentify an available terpene which would provide the carbon atoms for the C-ring and also establish the absolute sense of asymmetry of the final product, for example, (-)-1l-nor-~9-THC-9- carboxylic acid 22. Although a number of synthetic approaches to 22 have been reported,32.33 the shortcomings of these syntheses were either that they were long, produced racemic product or were low yielding. A novel, efficient synthesis was reported in our laboratory (scheme 2),34 Therein, the starting material, monoacetate 18, was 10

SCHEME 2

CHO OCOCH3 HO OH 4 steps 6 .. OI + ~ ~ 17 18

a b .. ~O I ~o I 1 9 20 OH COOH

c d, e .. ~O I 22

Reagents: (a) BF3·Et20; (b) TBSCI. CH2CI2; (c) LAH. THF; (d) Swern oxidation; (e) Sodium chlorite, 2-methylbut-2-ene, CH2 C12. prepared from R -(+)-perillaldehyde34 17 in 4 steps. The conversion of 18 to 19 was accomplished by exposure of a dichloromethane solution of olivetol 13 and 18 to freshly distilled boron trifluoride etherate at ooC for 2 h. The yield of 19 was ca. 30% and it was 11

subsequently converted to final product 22 by protection as sHyl ether ~O, reduction to 21, oxidation and deprotection in good yield. Recently, a convenient synthesis of ~8_THC metabolites was

reported in our labaratory (scheme 3),35 wherein (+)-apoverbenone

SCHEME 3

o 0 OEE

+ 8 ~ 23 24

OS02CF3 OEE b • c

EEO HO 26 27

OS02CF3 COOCH3 ~ OH OH d .. I ~O 28 29 Reagents: (a) Mixed higher-order cuprate; (b) KN(TMS)2 or LOA, then PhN(S02CF3)2; (c) PPTS, methanol; (d) BF3"Et20. CH2Cl2; (e) PdCI2(PPh3)2, K2C03. CO, THF. methanol.

23, which was prepared from (-)-J3-pinene, was used as a starting 12

material. Olivetol 13 was converted to its bis(ethoxyethyl)ether 24 in 77% yield by treatment in diethyl ether with a small excess of ethyl vinyl ether in the presence of p-toluenesulfonic acid. The lithiated olivetol derivative was transferred to 1 equivalent of lithium 2-thiophenecyanocuprate in THF. The mixed, higher order cuprate was treat.ed with a THF solution of apoverbenone and boron trifluoride etherate (1/1) at -780C for 2 h and cuprate adduct 25 was obtained in 66% yield. Consecutive treatment of adduct 25 with potassium hexamethyldisilylamide followed by bis«(trifluoromethyl)sulfonyl)oxy)aniline in THF at OOC led to enol triflate 26. Exposure enol triflate 26 to pyridinium tosylate in methanol gave the dihydroxy compound 27 in 65% yield from 26. A solution of 27 in anhydrous dichloromethane was treated at 25°C with an excess of boron trifluoride etherate for 8 h and cyclic vinyl triflate was obtained in 87% yield. Transposition of the double bond during cyclization leads specifically to the ~8-series. The stereochemistry of the ring junction was determined by the trans cuprate addition to the geminal dimethyl bearing bridge. Treatment of a solution of 28 in methanolic THF with 10% mol PdCI2(PPh3h, potassium carbonate and a static atmosphere of CO at 250C led to methyl ester 29 in 72% yield. Although all these syntheses are for classical cannabinoids, some of these synthetic methods could be applied to non-classical cannabinoids. For example, the cuprate addition which forms the trans ring junction and the cleavage of the ring. Since non-classical cannabinoid CP-55,940 was more active as an analgesic than morphine, its increase in potency was attributed in 13 part to the introduction of the new hydroxypropyl binding component in the southern portion of the molecule. Significantly, both the arylcyclohexyl bond and the hydroxypropyl groups are not conformationally restricted. 14

RESULTS AND DISCUSSION

The aim of this work was to synthesize non-classical cannabinoids which combine the structural elements of CP-55,940 6 and HHC 9 and to study the relationships between stereochemistry and their activity.

1. Retrosynthesis of 1213- H yd roxy m ethyl- 9- nor -9 ~ hydroxyhexahydrocannabinol

In order to synthesize compound 30, intermediate 32 was envisioned as a potential precursor to the product 30, because it is possible to convert 32 to 30 by an ene reaction followed by stereoselective cyclization (scheme 4).

SCHEME 4

OH OH

:> :> I HO~OH ~ HO 31 0 0

RO 33 15

Compound 31 would be prepared through an ene reaction on the intermediate 32. The compound 32 could be obtained from a two step procedure involving the ring opening of compound 33.

2. Stereospecific Ring Opening of Cuprate Adduct

The starting· material for the synthesis, (+)-apoverbenone 23, was prepared from cheap and readily available (-)-13-pinene 34 according to Huffman's method36 via ozonolysis of (-)-~-pinene 34 to nopinone 35, followed by lead tetraacetate oxidation and acetic acid hydrolysis (scheme 5). Olivetol 13 was converted to its bis-2-

SCHEME 5

0 0 a .. b, C 8 ~ • G/1' 34 35 23

Reagents: (a) 03; (b) isopropenyl acetate; then Pb(OAc)4; (c) aq. HOAc, room temperature.

OH OEE a .. HO EEO

13 24 Reagents: (a) p-toluenesulfonic acid, ethyl vinyl ether, CH2 CIZ 00 C. 16

ethoxyethyl ether 24 in 75% yield by treatment with a small excess of EVE in the presence of a catalytic amount of PPTS. The cuprate addition was carried out according to a published procedure37 (scheme 6): Bis-2-ethoxyethyl ether 24 can be

Reagents: (a) Mixed high-order cuprate. BF3·EtZO. THF, -78°C; (b). PPTS, methanol; (c) TBSCI. DMAP; (d) TMSI. CCI4. OOC; (e) DBU. benzene. deprotonated selectively using n-butyllithium in THF at 25°C. The lithiated bis-2-ethoxyethyl ether of olivetol was converted to the 17

mixed higher-order cuprate by transferring to a solution of lithium 2-thiophenecyanocuprate in THF at -78°C which was prepared according to the procedure published by Lipshutz.3 8 The mixed higher-order cuprate solution was then treated with a THF solution of (+)-apoverbenone 23 and boron trifluoride etherate (I/l) at -780C. The progress of the reaction can be monitored by tIc. After 30 min. the reaction was quenched with a solution of saturated NH4CI/NH40H (9/1) and the product was purified by silica gel column chromatography. The yield of cuprate adduct 2S was 70-80%. Treatment of 25 with PPTS in methanol at 250C led to 36 in quantitative yield. Exposure of resorcinol 36 to tert-butyldimethylsilyl chloride and imidazole in DMF at 230C produced bis-tert-butyldimethylsilyl ether 37 in 85% yield. Cleavage of the cyclobutane ring in adduct 37 under the influence of trimethylsilyl iodide (generated in situ from allyltrimethylsilane and iodine) at OOC gave rise to tertiary iodide 38 which was immediately converted to 39 by treatment with DBU in benzene at 23°C. It should be emphasized that the regiospecific elimination which forms the

388 3ab 18

isopropenyl substituent of 39 is due to a stereoelectronic effect39 caused by the aryl substituent at C-5: The steric bulk of the aryl group prevents iodine and H-6a from adopting a trans-anti conformation which would lead to the undesired elimination product.

3. Formation of Tetraol

The next task was to append a hydroxymethyl group to the

isopropenyl methyl of 39. An obvious approach was to make use of an acid catalyzed ene reaction with formaldehyde (scheme 7).

SCHEME 7

o o

a b ~ ~ ~ :I OTBS HO~OTBS 39 40 OH OH

c -I ~ HO~OTBS 41

Reagents: (a) Trioxane. Me3A1, 2.6-diphenylphenol; (b) NaBH4. THF/isopropanol; (c) n-Bu4N+F-, THF. aoc. 19

Dimethylaluminum chloride was initially used as the Lewis acid, but the yield of 40 was too low (ca. 20%) and the reaction did not proceed to completion. A very efficient reagent, methylaluminum bis(2,6-diphenylphenoxide)formaldehyde, which was prepared from trimethylaluminum, 2,6-diphenylphenol and trioxane In dichloromethane at DoC, has been reported by Yamamoto,39a Exposure of 39 to Yamamoto's reagent in dichloromethane at room temperature for 1 h followed by quenching with sodium bicarbonate led to 40 in 55% yield. Treatment of 40 with sodium borohydride in THF/isopropanol (9/1) at 230C led to equatorial alcohol 41 in 88% yield. Removal of both TBS protecting groups was accomplished to produce tetraol 42 in 90-96% yield by simply exposing diol 41 to tetra-n-butylammonium fluoride in THF at room temperature. Compound 42 was envisioned as a potential precursor in the synthesis of both the target molecules 30 and 43.

4. Stereoselective Synthesis of 12~·Hydroxymethyl·9·nor· 9~·Hydroxyhexahydrocannabinol

Several methods for the non-stereoselective cyclization of tetraol 42 can be imagined. However, control of the stereochemistry at C-6 posed a difficult challenge, since cyclization of 42a leads to 43 whereas, 42b leads to 30. Also, there was no reason a priori to expect any conformational preference between 42a and 42b. In fact, 20 H ..

HO OH 428 42b treatment of tetraol 42 with p-toluenesulfonic acid in refluxing toluene led to 1:1 diastereoisomeric mixture of 30 and 43. The protonation of the isopropenyl group presumably led to a tertiary planar carbocation which was attacked by the phenolic hydroxyl

OH OH

30 with a complete lack of stereochemical bias. This result with proton as the electrophile was disheartening, but it suggested that the

OH OH

a .. -I ~ . ~ A' HO OH 42 30

Reagents: (a) Hg(OAc)2. NaOH; NaBH4. room temperature, 21

problem might be overcome by altering the mechanism, through the use of an alternative electrophile. Treatment of tetraol 42 with mercuric acetate39b in THF at OOC for 30 min, followed by reductive demercuration with sodium borohydride in aqueous sodium hydroxide led to a 86: 14 (hplc: 25cm, 10 ~ Econosil column; 80/20 ethyl acetate/heximes) mixture of compounds 30 and 43 in 75% yield. The determination of stereochemistry in compound 30 was based on nOe analysis: irradiation of the pseudoaxial methyl group (0 = 1.10 ppm) led to enhancement of the C-I0a benzylic methine signal (0 = 2.52 ppm). The assignment of stereochemistry is also supported by the IH-NMR data of various THe derivatives in which the 6a methyl is always at higher field (1.10 ppm) than that of the 6~ methyl.39 This approach provided the stereoselective route to compound 30.

5. Stereoselective Synthesis of 14a.-Hydroxymethyl-9.nor 9~-Hydroxyhexahydrocannabinol

In order to prepare compound 43, the Swern oxidation of 40 presumably gave the ~,.y·unsaturated aldehyde 44 which underwent spontaneous isomerization to a single conjugated aldehyde 45 (scheme 8). The E-geometry of the double bond of aldehyde 45 was determined by examination in 1H-NMR spectrum at 300 MHz: no coupling between the vinylic methyl and vinylic hydrogen was observed. Reduction of both carbonyl groups in 4S with sodium borohydride in a mixed solvent (THF/isopropanol) led to 46 in 80% yield. Cleavage of the phenolic protecting groups with tetra -n- 22

SCHEME 8

o o ..

44 o OH

b .. ..

OH OH

d e .. I )HO HO 47

Reagents: (a) Swern oxidation; (b) room temperature 30 h: (c) NaBH4. methanol; (d) n-Bu4N+F-, THF; (e) Hg(OAc)2, NaOH: NaBH4. butylammonium fluoride led to tetraol 47. Mercuration demercuration of 47 with sodium borohydride led to a 15:85 mixture of 30 and 43 in 80% yield. The stereochemistry was 23

assigned by nOe analysis: irradiation of the C-14 methylene group m isomer 43 led to enhancement of the C-IOa benzylic methine signal (0 = 2.52 ppm).

The results from the above syntheses demonstrated that each of the two diastereomers was available selectively, however the origin of the stereoselectivity was not easily rationalized. Some of the results in this area are contradictory. For example, Sinay40 has shown that intramolecular oxymercuration of 48 produces 49, in which the -CH2HgCI group is axial. The stereochemistry in this case was attributed to coordination by the adjacent benzyloxy group to

~\_O~~ Bn BnO~~ BnO 0 BnOBnO BnO~OBn 48 49 HgCI the incoming mercurio species. On the other hand, Ganem41 reported only equatorial product 51 from the intramolecular aminomercuration of 50, even though an adjacent benzyloxy group was present to direct the axial stereochemistry. In Kozikowski's42 synthesis of dactylomelynes, the high degree of stereoselectivity

~ NHBn ~~~~r BnO~~ .. Bno~~n BnO BnO OBn BnO 50 51 24 during the cyclization of 48 was attributed to the equatorial preference of the bulky alkylmercurial group in a chair-like transition state. It is perhaps significant that in the solid state of the

H~ rrH·~OH.; MeO'" m .. HHH! O! ! OH 52 product, rotation about the CI-C3 bond in 53 places the chloromercury group syn to the C7 hydroxyl, suggesting that in this case, the stereoselectivity may in fact be traced to a directing effect by hydroxyl. In the case of both 42 and 47, oxymercuration took place so as to place the alkylmercurial group axial in the developing dihydrobenzopyran ring. In the absence of any heteroatomic directing effect, the stereochemical preference may be due to the anomeric effect of the positively charge mercurio species43 in the transition state. The mercury is clearly exercising a profound effect on the stereochemistry, as shown by the observation that fluorodesilylation of compound 45, followed by reduction with sodium borohydride, produced a I: I mixture of 30 and 43.

6. Biological Activities of the Synthetic Compounds

Compounds 30 and 43 as well as their uncyclized precursor 42, were tested for their affinities for the cannabinoid CB 1 receptor 25

using rat brain membranes and [3H]-CP-55,940 as the radioligand.44 Of tht:se, compound 30, in which the hydroxyethyl group has a /3 equatorial relative configuration, was shown to possess considerable affinity for the CB 1 receptor (ICSO = 100 nM), while compounds 43 and 42 exhibited much weaker affinities (ICSO =3.2 IJ.M; 0.10 IJ.M, respectively). The above biochemical data demonstrates the strict stereochemical requirements for a favorable ligand/receptor interaction imposed by the cannabinoid receptor on the hydroxypropyl pharmacophore. 26

CONCLUSION

In conclusion, the design and stereoselective synthesis of two cannabinoids from 39 in high yield have been described. Several features are noteworthy: (1) compound 39 is a versatile precursor for the synthesis of other cannabinoids. (2) Stereoselective cyclization was achieved by intramolecular oxymercuration. Biological testing has shown that compound 30 had very good activity whereas compound 43 showed much weaker binding to the CB 1 receptor than 30. These results showed that the stereochemistry of the hydroxyethyl sidechain effects activity significantly. 27

EXPERIMENTAL

General: IH-NMR and 13C NMR spectra were recorded at 300 MHz IH (75.5 MHz 13C) or 500 Hz IH (125.8 MHz BC) in either deuteriochloroform (CDCI3) with chloroform (7.26 ppm, 77.00 ppm 13C) or deuteriobenzene (C6D6) with benzene (7.15 ppm IH, 128.00 ppm 13C) as an internal reference. Chemical shifts are given in 0; multiplicities are indicated as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet); coupling constants (1) are reported in hertz (Hz). Infrared spectra were recorded on a Perkin Elmer IR 1430 spectrometer. Electron impact mass spectra were recorded on a VG-70 SE mass spectrometer. Thin-layer chromatography (tic) was performed on EM Reagents precoated silica gel 60 F-254 analytical plates (0.25 mm). Flash column chromatography was performed on Brinkmann silica gel (0.040-0.063 mm). Tetrahydrofuran (THF), diethyl ether, 1,2 dimethoxyethane (DME) were distilled from sodium-benzophenone ketyl, N,N-dimethylformamide (DMF), triethylamine (Et3N), and boron trifluoride-etherate (BF3·Et20) from calcium hydride, carbon tetrachloride (CCI4), dichloromethane (CH2CI2) from phosphorus pentoxide. Other reagents were obtained commercially and used as received unless otherwise specified. All moisture sensitive reactions were performed under a static nitrogen or argon atmosphere in flame-dried glassware. The purity 28 and homogeneity of the products on which the high resolution mass spectr~l data are reported were determined on the basis of 300 MHz IH-NMR (>94%) and multiple elution tic analysis, respectively. 29

OH OEE

EEO 13· 24

Procedure:

To a solution of olivetol 13 (lg, 5.55 mmol) in dichloromethane (20 ml) at 230C was added ethyl vinyl ether (1.35 ml, 13.88 mmol), followed by a catalytic amount (ca. 50 mg) of PPTS in dichloromethane. The reaction mixture was stirred at 230C and the progress of the reaction was monitored by tIc. After 7 h, the reaction mixture was diluted with ether, washed with sat'd aqueous NaHC03, followed by brine, and was dried (NaZS04). Solvent evaporation in vacuo gave the crude bis-2-ethoxyethyl olivetol which was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in hexanes. The yield of the reaction was 70-85%. 30

OEE

EEO 24

Bis-2-ethoxyethyl olivetol 24:

IH-NMR (CDC13, 300 MHz, ppm): a 6.49-6.47 (br s, 2H), 5.35 (q, J = 5.1 Hz, 2H), 3.81-3.73 (m, 2H), 3.59-3.49 (m, 2H), 2.52 (t, J = 7.5 Hz, 2H), 1.61-1.56 (m, 2H), 1.49 (d, J = 5.4 Hz, 6H), 1.33-1.27 (m, 4H), 1.21 (t, J = 6.9, 6H), 0.89 (t, J =6.3 Hz, 3H).

13C-NMR (CDC13, 75 MHz, ppm): a 157.8, 145.3, nO.8, 103.8, 99.5, 61.5, 36.1, 31.4. 30.9, 22.5, 20.3, 15.2, 13.9.

IR (neat, em- l ): 2990, 2920, 2850, 1590, 1450, 1380, 1150, lll0, 1080, 1050. 31

0 0 OEE .. ~ + EEO 23 24 25

Procedure:

To a solution of 311 mg (0.956 mmol) of bis-2-ethoxyethyl olivetol 24 in THF (IS ml) at OOC was added n-butyllithium solution in hexane (0.85 ml, 1.150 mmol) during 20 min. The mixture was stirred at OOC for 10 min and then at 250C for 2.5 h. In a separate flask 3.85 ml (0.956 mmol) of a solution of lithium 2 thienylcyanocuprate in THF was cooled to -78°C. The lithiated olivetol ether was transferred by cannula to the cuprate solution over a 20 min period. Following addition, the reaction mixture was placed in an ice bath for 10 min, cooled to -78°C, and stirred for 1.5 h. To the pale yellow cuprate solution was added a mixture of 200 mg (1.470 mmol mmol) of (+)-apoverbenone (23) and 0.20 ml (1.470 mmol) of BF3.Et20 in 1.5 ml of THF at -78°C. The mixture was stirred at -780C until tic (5% ethyl actate in hexane) showed the disappearance of the starting material (lh). The reaction was diluted with ether (30 ml), washed with concentrated NH40H/saturated 32

NH4CI (1/9) solution, extracted with ether, and dried (MgS04). Evapo~ation of the solvent in vacuo and purification of the crude product by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane produced 225 mg (70% yield) as a mixture of diastereomers due to the asymmetric center on each of the two ethoxyethyl protecting group.

4 -[4 - n - pentyl-2,6-bis (2 -ethoxyethyl)phenyl] - 6,6 -d im ethyl 2-nopinone 25:

!H-NMR (CDCI3, 300 MHz, ppm): d 6.59 (s, IH), 6.55 (s, IH), 5.46-5.39 (m, 2H), 4.16-4.09 (m, IH), 3.74-3.64 (m, 2H), 3.38-3.29 (m, IH), 2.56-2.45 (m, 6H), 2.22 (br s, IH), 1.61-1.56 (m, 4H), 1.48 (d, J = 5.1 Hz, 6H), 1.35 (s, 3H), 1.33-1.31 (m, 2H), 1.22-1.16 (m, 6H), 0.98 (s, 3H), 0.89 (t, J = 6.7 Hz, 3H).

IR (neat, cm-!): 2975, 2925, 2860, 1710, 1605, 1570, 1430, 1380, 1070, 1050. 33

a,. a

25 36

Procedure:

To a solution of compound 2S (150 mg, 0.33 mmol) in 25 ml of methanol was added ca. 25 mg of PPTS. The reaction mixture was stirred at 25°C until tic indicated that both ethoxyethyl groups had been removed (ca. 5 h). The reaction mixture was diluted with ether, washed with brine and was dried over MgS04. Evaporation of the solvent followed by flash chromatography eluting with 15% ethyl acetate in hexane produced 80 mg (78% yield) of resorcinol 36 as single isomer. 34

Resorcinol 36 :

IH-NMR (CDCI3, 300 MHz, ppm): 0 6.17 (s, 2H), 5.13 (s, 2H, exchangeable with D20), 3.95 (t, J =8.1 Hz, IH), 3.47 (dd, J = 18.9, 7.8 Hz, IH), 2.68-2.39 (m, 5H), 2.30 (t, J = 5.4 Hz, IH), 1.36 (s, 3H), 1.31 1.26 (m, 4H), 0.99 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H).

I3C-NMR (CDC13, 75 MHz, ppm): 0 217.2, 155.3, 142.6, 113.7, 108.6, 57.9, 46.8, 42.3, 37.9, 35.2, 31.5, 30.6, 29.5, 26.2, 24.4, 22.5, 22.1, 14.0.

IR (CC4, em-I): 3350, 2950, 2850, 1680, 1620, 1590, 1430, 1265, 1020.

Mass spectrum (70 eV, m/e): 316 (M+), 310, 273, 247, 233, 219, 206, 193, 150, 83, 69, 57. 35

o o

•

36 37

Procedure:

To a solution of resorcinol 36 (158 mg. 0.50 mmol) and tert butydimethylsilyl chloride (453 mg. 3.00 mmol) in 10 ml N.N dimethylformamide (DMF) at 230C was added imidazole (410 mg. 6.00 mmol). The mixture was stirred at 230C for 16 hand 50 ml ether was added. The organic phase was washed with water. dried (MgS04) and evaporated. The crude product was purified by flash column chromatography on silica gel (5% ethyl acetate in hexane) to give 231 mg (85% yield) of 37. 36

Ketone 37:

IH-NMR (CDCI3, 300 MHz, ppm): a 6.27(s, 2H), 3.98 (m, IH), 3.75 (d, J = 6.9 Hz, IH), 3.68 (d, J = 6.9 Hz, IH), 2.56-2.36 (m, 6H), 2.21 (m, IH), 1.56-1.30 (m, 2H), 1.55 (s, 3H), 1.32 (s, 3H), 0.98 (s, 6H), 0.86 (s, 18H), 0.02 (s, 12H).

IR (neat, em-I): 2960, 2860,1710,1600,1560,1460,1420,1150, 1050.

Mass spectrum (70 eV, role): 544 (M+), 487, 377, 215, 168, 73.

Calculated mass for C32Hs603Si2: 544.3767, found: 544.3748. 37

o o ..

T880 37 39

Procdure:

A solution of iodine (343 mg, 1.35 mmol) and allyltrimethylsilane (156 mg, 1.37 mmol) in 5 ml CCl4 was stirred at DoC for 2 h. Ketone 37 (480 mg, 0.88 mmol) in 3 ml CCl4 was added. The reaction mixture was stirred at DoC for 30 min, then quenched by adding aqueous sat'd Na2S203. The mixture was extracted with ether. The organic solution was dried (MgS04) and evaporated. The crude product 38 was dissolved in 5 ml benzene at 23°C and excess DBU (ca. 4 mmol) was added. The solution was stirred for 2 h at 230C and diluted with 20 ml ether. The organic solution was washed with water, dried (MgS04) and evaporated. The residue was purified by flash chromatography (10% ethyl acetate in hexane) on silica gel to give 250 mg (52% over yield) of 39. 38

Ketone 39:

IH-NMR (CDCI3, 300 MHz, ppm): () 6.22 (s, IH), 6.20 (s, IH), 4.66 (d, J = 0.3 Hz, IH), 3.47 (td, J = 12.0, 3.0 Hz, IH), 3.17 (dd, J = 14.1, 13.5 Hz, IH), 2.48 (m, 3H), 2.33-1.67 (m, 6H), 1.56 (s, 3H), 1.32 (m, 4H), 1.06 (s, 9H), 0.98 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz), 0.35 (s, 3H), 0.32 (s, 3H), 0.23 (s, 3H), 0.16 (s, 3H).

IR (neat, em-I): 3010, 2960, 1720, 1610, 1560, 1470.

Mass spectrum (70 eV, role): 544 (M+), 487, 379, 258, 194, 110, 73.

Calculated mass for C32HS603Si2: 544.3767, found: 544.3794. 39

o o

~ I ~ HO~OTBS 40

Procedure:

To a solution of 2,6-diphenylphenol (134 mg, 0.55 mmol) in 2 ml CH2Clz was added 0.17 ml of a 1.6 M solution of trimethylaluminum in toluene (0.27 mmol) at 230C. The solution turned light brown and was stirred for 1 h at 230C, cooled to DoC, and trioxane (11 mg, 0.12 mmol) in 1 ml CHZClz was added. The mixture was stirred for 1 h at DoC. Ketone 39 in 2 ml CH2CIZ was added and the solution was stirred for additional 2 h. Sat'd aqueous NaHC03 was used quench the reaction. The reaction mixture was extracted with CHzClz and the organic phase was dried (MgS04) and evaporated. The residue was purified by flash column chromatography on silica gel (20% ethyl acetate in hexane) to give 58 mg (50-55% yield) of 40.

-- ~--~. -~ ..._.. 40

Compound 40:

IH-NMR (CDCI3, 300 MHz, ppm): a 6.24 (s, IH), 6.20 (s, IH), 4.97 (s, IH), 4.68 (s, IH), 3.75 (m, IH), 3.58 (q, J = 12.3, 12.0 Hz, 2H), 3.36 (m, 2H), 2.48-2.05 (m, 6H), 1.71-1.50 (m, 3H), 1.55 (s, 3H), 1.30-1.25 (m, 3H), 1.05 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.32 (s, 3H), 0.24 (s, 3H), 0.16 (s, 3H).

IR (neat, em-I): 3450, 2980,1710,1570,1420,1100.

Mass spectrum (70 eV, m/e): 574 (M+), 487, 379, 73, 69.

Calculated mass for C33HSS04Si2: 574.3957, found: 574.3915. 41

a OH .. -I ~ HO~OTBS

40 41

Procedure:

To a solution of ketone 40 (80 mg, 0.14 mmol) in 10 ml of a mixture of THF and isopropanol (9:1) at 230C was added sodium borohydride (8 mg, 0.21 mmol) portionwise, and the mixture was stirred for 30 min. The reaction was quenched with water and the mixture was extracted with ether. The organic layer was dried (MgS04) and evaporated. The crude product was purified by flash column chromatography (20% ethyl in hexane) on silica gel to give 70 mg (85-88% yield) of alcohol 41. 42

Diol 41:

IH-NMR (CDCh, 300 Hz, ppm): d 6.22 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H), 4.61 (s, IH), 3.69 (m, IH), 3.54 (tt, 5.7, 5.7 Hz, 2H), 3.35 (m, IH), 2.89 (m, IH), 2.41 (dd, 7.8, 7.5 Hz, 2H), 2.09 (m, 3H), 1.86 (m, 1H), 1.55 (s, 3H), 1.57-1.24 (m, 7H), 1.06 (s, 9H), 1.02 (s, 9H), 0.88 (dd, J = 6.0, 5.7 Hz, 3H), 0.33 (s, 3H), 0.32 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).

IR (neat, em-I): 3340, 2970, 2880, 1600, 1420, 1050. 43

OH OH

Procedure:

To a solution of 41 (40 mg, 0.07 mmol) in 6 ml THF at 23°C was added tetra-n-butylammonium fluoride hydrate (73 mg, 0.28 mmol) portionwise. The mixture was stirred for 1 hand 30 ml ether was added. The organic phase was washed with water, dried (MgS04) and evaporated. The residue was purified by flash column

chromatography (80% ethyl acetate In hexane) on silica gel to give 23 mg (90-96% yield) of tetraol 42.

------44

TetraoI 42:

lH-NMR (CD3COCD3, 300 MHz, ppm): 0 8.00 (br, IH, exchangeable with D20), 6.16 (s, IH), 6.14 (s, IH), 5.61 (s, IH, exchangeable with D20), 4.84 (d, J = 1.5 Hz, IH), 4.47 (s, IH), 3.64 (m, IH), 3.54-3.31 (m, 3H), 3.03 (m, IH), 2.33 (dd, J = 8.1, 6.9 Hz, 2H), 2.15 (m, 2H), 1.79 (m, 2H), 1.55-1.19 (m, 10H), 0.86 (dd, J = 6.9, 6.6 Hz, 3H).

l3C-NMR (CD3COCD3, 75 MHz, ppm): 0 157.6, 156.0, 151.1, 141.7, 115.8, 109.8, 108.5, 107.6, 71.1, 61.6, 46.4, 40.4, 38.6, 37.1, 36.7, 36.0, 32.9, 32.2, 31.5, 23.1, 14.2.

IR (neat, cm- l ): 3350, 2960, 2880, 1620, 1590, 1420, 1040.

Mass spectrum (70 eV, role) 572 (M+): 516, 515, 445, 405, 377, 100, 95, 73. Calculated mass for C33HS604Sh: 572.3717, found: 572.3741. 45

o o

~I# HO OTBS 40

Procedure:

Dimethylsulfoxide (0.52 mmol) was added to the solution of oxalyl chloride (0.35 mmol) in 2 ml CH2Cl2 at -780C. After 8 min, 48 mg of 40 (0.08 mmol) in 1 ml CH2C12 was added slowly. The mixture was stirred for 15 min, then triethylamine (0.22 mmol) was added at -780C. The mixture was warmed to 230C and stirring was continued for 12 h. The reaction was quenched with water. The organic layer was washed with brine, dried (MgS04) and evaporated. The crude product was purified by flash column chromatography 20% ethyl acetate in hexane) on silica gel to give 41 mg in 85% yield of ketoaldehyde 45. 46

Ketonealdehyde 45:

IH-NMR (CDC13, 300 MHz, ppm): B9.82 (d, J =7.9 Hz, IH), 6.22 (s, IH), 6.18 (s, IH), 5.86 (d, J = 7.9 Hz, IH), 3.76 (m, IH), 3.56 (m, IH), 3.20 (dd, J = 13.5, 11.2 Hz, IH), 2.41 (m, 3H), 2.05 (m, IH), 1.99 (s, 3H), 1.80-1.57 (m, 5H), 1.25 (m, 4H), 1.06 (s, 9H), 0.99 (s, 9H), 0.88 (t, J = 6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).

IR (neat, em-I): 2980,2880,1720,1680,1605,1570,1100.

Mass spectrum (70 eV, role) 572 (M+): 515, 445, 405, 377, 100, 95, 73.

Calculated mass for C33HS604Si2: 572.3717, found: 572.3741. 47

I )'HO HO 47

Tetraol 47:

The same procedure was followed as in the conversion of (41) to (42). Ketoaldehyde 4S (25 mg) was converted to diol 4S (18 mg, 72% yield). Desilylation produced 10 mg of tetraol 47 in 92% yield.

IH-NMR (CD3COCD3, 300 MHz, ppm): 07.60 (br d, exchangeable with DzO, 1H), 6.15 (s, 1H), 6.12 (s, 1H), 5.34 (dd, J = 6.6, 6.0 Hz, 1H), 3.88 (m, 1H), 3.76 (m, 1H), 3.64 (m, 1H), 3.33 (td, J = 11.7, 3.3 Hz, 1H), 2.33 (dd, J = 7.8, 7.5 Hz, 2H), 2.17-1.96 (m, 3H), 1.84 (m, 1H), 1.65-1.23 (m, 9H), 1.48 (s, 3H), 0.86 (dd, J = 7.2, 6.6 Hz 3H).

IR (neat, cm- 1): 3400, 3010, 2980, 1600, 1420, 1100.

Mass spectrum (70 eV, m/e) (no M+): 330 (M+-HzO), 312, 217, 194, 193, 150, 79. 48

OH OH

42 30

Procedure:

Mercuric acetate (28 mg, 0.06 mmol) was added to a solution of tetraol 42 (20 mg, 0.06 mmol) in 3 ml THF in one portion at 23 0C. The mixture was stirred for 18 h. Excess sodium borohydride (0.12 mmol) in 0.5 ml 2.5 M aqueous NaOH (0.5 ml) was added, and the mixture was stirred for additional 10 h. Sat'd aqueous Na2C03 (0.5 ml) was added and the mixture was stirred for another 4 h. The reaction mixture was decanted from metallic mercury and was partitioned between water and ether. The organic phase was dried (MgS04) and evaporated. The residue was purified by flash chromatography on silica gel to give 15 mg (75% yield) of a 86:14 mixture of products 30 and 43. The pure product was purified by hplc (80% ethyl acetate in hexane). 49

1213- Hydroxymethyl-9-nor-9 ~ -hydroxyahydrocannabinol 30:

IH-NMR (CDC13, 500 MHz, ppm): 0 6.21 (d, J = 1.5 Hz, IH), 6.11 (br, IH, exchangeable with DzO), 6.10 (d, J = 1.5 Hz, IH), 3.97-3.81 (m, 3H), 3.55-3.52 (m, IH), 2.86 (br, 1H, exchangeable with D20), 2.52 (td, J = 11.1, 2.1 Hz, IH), 2.41 (dd, J = 8.5, 7.0 Hz, 2H), 2.16 (m, IH), 1.95 (t, 5.8 Hz, 2H), 1.84 (m, IH), 1.66-1.53 (m, 4H), 1.40-1.26 (m, 5H), 1.14 1.01 (m, IH), 1.10 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

13C-NMR (CDC13, 125 MHz, ppm): 0 155.1, 153.9, 142.9, 109.6, 109.0, 108.2, 79.9, 70.9, 58.9, 46.3, 41.1, 38.6, 35.5, 35.4, 33.2, 31.6, 30.6, 25.7, 22.5, 17.8, 14.0.

IR (neat, em-I): 3400, 2980, 1600, 1480, 1350, 1050.

Mass spectrum (70 eV, m/e) 348 (M+): 257, 193, 167, 150, 149.

Calculated mass for C2IH3204: 348.2300, found: 348.2308. 50

~I ) HO HO 47 43

Procedure:

Compound 43 (8 mg) was prepared in 80% yield from 10 mg of 47 by the same procedure for 30. The ratio of 43:30 was 85:15. 51

14cx- Hyd roxymethyl-9-nor-9~-Hydroxyhexahydrocannabinol 43:

IH-NMR (CDCI3, 500 MHz, ppm): 0 6.20 (d, J = 0.9 Hz, IH), 6.09 (d, 0.9 Hz, IH), 5.97 (br, IH, exchangeable with DzO), 3.87 (m, 2H), 3.73 (m, IH), 3.48 (m, IH), 2.53 (td, J = 11.4, 2.0 Hz, IH), 2.44 (m, 2H), 2.18 (m, IH), 1.97-1.83 (m, 4H), 1.58-1.33 (m, 8H), 1.42 (s, 3H), 1.05 (q, J = 7.2, 6.9 Hz, IH), 0.87 (dd, J = 7.2, 6.9 Hz, 3R).

13C-NMR (CDCI3, 125 MHz, ppm): 0 155.1, 154.2, 143.2, 109.2 (2C), 108.3, 78.5, 70.8, 59.1, 49.7, 38.8, 35.7, 35.4, 32.8, 32.7, 31.5, 30.6, 25.7, 24.7, 22.5, 14.0.

IR (neat, cm- 1): 3400, 2980, 1610, 1450, 1350, 1100.

Mass spectrum (70 eV, m/e) 348 (M+): 285, 257, 231, 217, 193, 149.

Calculated mass for CZIH3204: 348.2300, found: 348.2295. 52

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1. Schultes, R. E.; Hofmann, A. The Botany and Chemistry of Halucinogens, 2nd ed., Charles C Thomas, Springfield, 111., 1980. 2. Campbell Thompson, R. A Dictionary of Assyrian Botany, the British Academy, London, 1949. 3. (a) Touw, M. J. Psychoactive Drugs, 1981, 13, 23. (b) Li, C. P. Chinese Herbal Medicine, Pub!. No. 75-732, U. S. Department of Health, Education and Welfare, Washington, D. C., 1974. 4. Mechoulam, R. The Pharmacohistory of Cannabis sativa. In: Cannabinoids as Therapeutic Agents, Mechoulam, R. ed., CRC Press, Boca Raton, FL, 1986, pp. 1-19. 5. Kabelik, J.; Krejci, S,; Santavy, F. Bull Narc. 1960, 12, 5. 6. O'Shaugnessy, W. B.; Trans. Med. Phys. Soc. Bombay 1839, 8, 421. 7. O'Shaugnessy, W. B. Pharmacol. J. Trans. 1843,2, 594. 8. O'Shaugnessy, W. B. Cannabis. In: The Bengal Dispensatory and Pharmacopoeia, Bishop's College Press, Calcutta, 1841, 579. 9. Adams, R. Harvey Lect. 1941·1942,37, 168. 10. Todd, A. R. Experientia 1946, 2, 55. 11. Loewe, S. Arch. Exp. Pathol. Pharmacol. 1950,211, 175. 12. Gaoni, Y.; Mechoulam, R. J. Am. Chern. Soc. 1964,86, 1646. 13. Mechoulam, R.; Edery, H. Structure-activity relationships in the 53

cannabinoid series, in Marijuana: Chemistry, Pharmacology, Metabolism and Clinical Effects, Mechoulam, R., Ed., Academic Press, New york, 1073. 14. Dewey, W. L.; Martin, B. R.; May, E. L. Cannabinoid stereoisomers: Pharmacological effects, in Handbook of Stereoisomers: Drugs in Psychopharmacology, Smith, D. F. ed., CRC press, boca Raton, FL. 1984, 317. 15. Razdan, R. K. Pharmacol. Rev. 1986,38, 75. 16. Little, P. J.; Compton, D. R.; Martin, B. R. J. Pharmacol. Exp. Ther. 1988, 247, 1046. 17. Jarbe, T. U. C.; Hituene, A. J.; Mechoulam, R., Srebnik, M.; Breuer, A. Eur. J. Pharmacol. 1988, 156, 361. 18. Mechoulam, R.; Devane, W. A.; Glaser, R. Cannabinoid geometry and biological activity in Marijuana/Cannabinoids Neurobiology and Neurophysiology, Murphy & Bartke, Ed., CRC Press, Boca Raton, FL, 1992, 1. 19. (a) Houry, S.; Mechoulam, R.; Fowler, P. J.; Macko, E.; Loev, B. J. Med. Chem. 1974,17, 287. (b) Houry, S.; Mechoulam, R.; Loev, B. J. Med. Chern. 1975, 18, 951. 20. Banerjee, S. P.; Mechoulam, R.; Snyder, S. H. J. Pharmacol. Exp. Ther. 1975,194, 75. 21. Johnson, M. R.; Althuis, T. H.; Bindra, J. S.; Harbert, C. A.; Melvin, L. S.; Milne, G. M. NIDA Res. Monogr. Ser., 1981,34, 68. 22. Johnson, M. R.; Melvin, L. S.; Althius, T. H.; Bindra, J. S.; Harbert, C. A.; Milne, G. M.; Weissman, A., J. Clin. Pharmacol. 1981,271s, 54

21. 23. Matsumoto, K.; Stark, P.; Meister, R. G. J. Med. Chem. 1977,20, 17. 24. Makriyannis, A.; Rapaka, R. S. Life Science 1990,47, 2173. 25. Mechoulam, R.; Feigenbaum, J. J.; Lander, N.; Segal, M.; Jarbe, T. U. C.; Hiltuene, A. J.; Consore, P. Experientia 1988,44, 762. 26. Johnson, M. R.; Milne, G. M. J. Clin. Pharmacol. 1981,21, 367. 27. Charalambous, A.; Marciniak, G.; Lin, S. Y.; Friend, F. L.; Compton, D. R.; Martin, B. R.; Wang, C. L. J.; Makriyannis, A. Neurosci. Biobehav. Rev. 1991, 40, 471. 28. Kannangara, G. C. K. Ph. D. Dissertation, University of Hawaii, 1994. 29. Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc. 1974, 96, 5860. 30. Tius, M. A.; Kannangara, G. S. K. Tetrahedron 1992,48, 9173. 31. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1972, 94, 6159. 32. Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem. Soc. 1967, 89, 5934. 33. Pitt, C. G.; Fowler, M. S.; Sathe, S.; Srivastava, S. C.; Williams, D. L. J. Am. Chem. Soc. 1975,97, 3798. 34. (a) Tius, M. A.; Gu, X. Q..; Kerr, M. A. J. Chem. Soc., Chem. Commun. 1989, 62. (b) Tius, M. A.; Kerr, M. A. Synth. Commun. 1988, 1905. (c) Tius, M. A.; Gu, X. Q. J. Chem. Soc., Chem. Commun. 1989, 1171. 35. Tius, M. A.; Kannangara, G. S. K. J. Org. Chem. 1990,51, 5463. 55

36. Huffman, J. W.; Joyner, H. H.; Lee, M. D.; Jordan, R. D.; pennington, W. T. J. Org. Chern. 1991,56, 2081. 37. Tius, M. A.; Kannangara, G. S. K.; Kerr, M. A.; Grace, K. J. S. Tetrahedron, 1993,49, 3291. 38. Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.; McCarthy, K. E. J. Organornet. Chem. 1985,285, 437. 39. (a) Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J. Am. Chem. Soc. 1990,112,7422. (b) Brown, H. C.; Geoghegan, P. J. Jr. J. Org. Chern. 1975,35, 1844. 40. (a) Uliss, D. B.; Razdan. R. K.; Dalzell, H. C. J. Am. Chern. Soc. 1974,96, 7372. (b) Archer, R. A.; Boyd, D. B.; Demarco, P. V.; Tyminski, I. J.; Allinger, N. L. J. Am. Chem. Soc. 1970,92, 5200. 41. (a) Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc., Chern. Commun. 1981, 375. (b) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985,26, 4981. 42. Kozikowski, A. P.; Lee, J. J. Org. Chern. 1990,55, 863. 43. Tius, M. A.; Busch-Petersen, J. Tetrahedron Lett. 1994,35, 5181. 44. Tius, M. A.; Makriyannis, A.; Zou, X. L.; Abadji, V. Tetrahedron, 1994,50, 2671.

------.-._- -- PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL A AND ITS ANALOGS 56

A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS

INTRODUCTION 1. Background

The aim of this project was to synthesize some structurally simplified analogs of the natural product sarcophytol A 55 and to subject them to biological testing for cancer preventative activity. The analogs 56-59, which are structurally related to sarcophytol A, were designed by Professor Tius and their biological activity was evaluated in Professor Hirota Fujiki's laboratory.l

55 sarcophytol A 56 canventol OH R

2. Synthesis of Canventol and Its Analogs

The synthesis of analog 56, which has been named canventol by Dr. Fujiki, was accomplished by following the synthetic route outlined 57

below (scheme 1). The conversion of compound 60 to enone 62 was carried out by following the published procedure:2 Birch reduction

SCHEME 1

OCH3

&COOH a cey; b .,~ COOLi I~ .. III if 60 61 62

c d e ... 65 III ™CY ... OMe 63 64

.. g f ..

57 65 56

Reagents; (a) Li/NH3, THF. -78°C; (b) isopropyl iodide; aqueous HCI. 600C; (c) FeCI3/CH3MgBr. TMSCI. Et3N. HMPA; (d) 2,2-dimethoxypropane. TiCI4, OOC; (e) HCI04; (t) NaBH4. CeCI3. methanol; (g) MeLi. Et20. OOC. of anisic acid 60, followed by alkylation with isopropyl iodide led to carboxylic acid 61. Hydrolysis of 61 in aqueous Hel produced enone 62 in 45% overall yield. Formation of the thermodynamic enolate of 62 and trapping with 58

chlorotrimethylsilane led to enol ether 63 which was exposed to 2,2 dimethoxypropane and titanium tetrachloride at OOC to give enone

64 in 49% overall yield.4,5 Elimination of methanol from enone 64 in the presence of perchloric acid produced dienone 65 in 51 % yield. The reduction of dienone 65 with sodium borohydride and cerous chloride gave crystalline (d, l)-canventol (56) in 96% yield. Treatment of dienone 65 with methyllithium led to analog 57 in quantitative yield. The overall yield in this synthesis of canventol was 24% from enone 62. Its shortcomings are the use of HMPA and the low yield for the elimination of methanol from enone 64. These problems were largely overcome during a novel, efficient synthesis of analogs S8 and 59 (scheme 2). Nopinone 35, which was

SCHEME 2

o 0 0 0 0 O~ a b .. Gt°~/i'. • GJ I 35 66 67 0 0 0 OH R R c O~ d e .. R •

58 R = CH 68 69 3 59 R = C2 Hs

Reagents: (a) Diallyl carbonate, NaH, DME; (b) TMSI, CCI4; (c) RX, acetone, K2C03; (d) Pd(OAc)2, THF, 800C; (e) NaBH4, methanol. 59

prepared from (-)-f3-pinene,6 was converted to ketoester 66 in 80% yield by treatment of 35 with diallyl carbonate in DME. Ring cleavage of 66 was achieved by treatment with TMSI in CCl4 at OOC led to tertiary iodide 67 in 60-70% yield.7 Alkylation of 67 with iodomethane or iodoethane followed by elimination produced ketone 68 in 50-60% yield respectively. Treatment of 68 with catalytic palladium acetate led to dienone 69 in 80% yield.8 Reduction of dienone 69 gave products 58 and 59 in 90% yield.9 The advantages of this synthesis were the cheap, available starting material and its applicability for larger scale. This method was applied to the synthesis of canventol. It was shown that alkylation of 66 with isopropyl iodide led to a (3:2) mixture of O-alkylated 70 and C-alkylated 71 products. Starting material 66 was recovered by hydrolysis of 70 under acidic condition.

0 0 Jo ~o~ a GY'0~ ~o~ ~ ... ~ + ~ I I I 0

66 70 71 Reagents: (a) acetone, K2C03, isopropyl iodide.

Recently, a novel synthetic method to canventol was developed by our laboratory10 and it provides the possibility of production on kilogram scale. Further investigation of this synthesis will be undertaken by our group. 60

3. Biological Activity

The testing which was performed in Professor Fujiki's laboratory in Japan showed that canventol inhibited tumor promotion induced by okadaic acid on mouse skin initiated with 7,12 dimethylbenz(a)anthracene in the two stage carcinogenesis experiment. Canventol inhibited tumor promotion more strongly than sarcophytol A, even though canventol has a simpler structure than sarcophytol A.II

---.------... 61

EXPERIMENTAL

&COOHOCH3 _

60 62

Procedure:

A three-neck flask was charged with 15.2 g (100 mmol) of 0 methoxybenzoic acid and 100 ml of THF. The solution was stirred and ammonia (400 ml) was distilled in to give a thick white suspension. The reaction mixture was maintained at reflux under a nitrogen atmosphere and lithium wire (washed sequentially with hexane, ethyl ether) was added in 2 cm pieces until a blue solution was maintained. The reaction vessel was cooled in a dry ice-acetone bath and 1,2-dibromoethane (2 ml) added, followed by 2-iodopropane 12 ml (120 mmol). The reaction mixture was warmed to room temperature under nitrogen and the resultant yellow slurry diluted with 100 ml water, then acidified with 100 ml concentrated aqueous HCl. Hydroquinone (200 mg) was added and the solution refluxed for 30 min. The solution was cooled to room temperature and extracted with CH2C12. The solvent was removed and the residue purified by chromatography to give 3.84 g of enone 62 in 50% yield.

------62

62 Enone 62:

IH-NMR (CDCI3, 300 MHz, ppm): 6.21 (dd, J =7.2, 6.9 Hz, IH), 2.87 2.78 (sept, IH), 2.40-2.29 (m, 4H), 1.96-1.87 (m, 2H), 0.97-0.96 (d, 6.9 Hz, 6H).

IR (neat, em-I): 3050, 2960, 1660, 1440, 1380, 1100. 63 if 62 63

Procedure:

To a solution of anhydrous ferric chloride (257 mg, 2.2 mmol) in 15 ml of anhydrous ether at OOC under an atmosphere of N2 was slowly added an ethereal solution of methylmagnesium bromide (2.2 ml, 6.6 mmol). The resulting slurry was stirred for 1 h at 25°C, then enone 62 (276 mg, 2.0 mmol) dissolved in 5 ml ethyl ether was slowly added over a period of 10 min. After 30 min, Me3SiCI (0.84 ml, 6.6 mmol), Et3N (0.95 ml, 6.8 mmol), HMPA (0.38 ml, 2.2 mmol) were added in that order. The solution was stirred overnight, diluted with 10 ml ethyl ether and poured into cold saturated NaHC03 solution. The aqueous layer was extracted with 15 ml ether. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting colorless oil was filtered through a plug of silica gel (5% EtOAc/Hexanes) to remove HMPA and Et3N. The eluant was concentrated to give a colorless oil 63 which was used in the subsequent reaction without further purification. 64 6"-----..... OMe 63 64

Procedure:

Under nitrogen, 2,2-dimethoxypropane (0.12 ml, 1.0 mmol) was added slowly to a solution of TiC4 (1.0 mmol) in 10 ml anhydrous

CHzCl2 at -780 C. After 5 min, compound 63 (210 mg, 1.0 mmol) dissolved in 5 ml CHzCl2 was added. The deep red solution was stirred for 30 min at -780C and then 5 ml water added and the mixture was warmed to room temperature. The aqueous layer was extracted with 10 ml CH2CIZ. The organic layer was dried over anhydrous MgS04, filtered and concentrated. The residue was purified by silica gel chromatography to give 126 mg of the desired product 64 in 60% yield.

Methoxyketone 64:

IH-NMR (CDCI3, 300 MHz, ppm): 6.75 (s, IH), 3.25 (s, 3H), 2.63-2.50 (m, 2H), 2.38-2.26 (m, IH), 2.03-1.96 (m, IH), 1.71-1.56 (m, IH), 1.17 (s, 3H), 1.10 (s, 3H), 1.02 (d, J = 3.0 Hz, 3H), 0.99 (d, J = 2.7 Hz, 3H).

IR (neat, cm- 1): 3050, 2960, 1680, 1450, 1380, 1050. 65

OMe 64 65

Procedure:

To a solution of compound 64 (294 mg, 1.4 mmol) in 12 ml CF3CH20H, excess perchloric acid was added slowly at 250C. The solution was heated to 400C for 30 h and then 10 ml water added. The mixture was extracted with 10 ml ether and the organic layer dried over anhydrous MgS04, filtered and concentrated. The oily residue was purified by silica gel chromatography to give 120 mg of the desired product 65 in 50% yield.

Dienone 65:

IH-NMR (CDC13, 300 MHz, ppm): 7.25 (s, IH), 2.97 (sept, IH), 2.66 (t, J = 6.9 Hz, 2H), 2.46 (dd, J = 7.5 Hz, J = 6.6 Hz, 2H), 1.93 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H).

IR (neat, cm- 1): 3050, 2940, 1670, 1450, 1380, 1050. 66

65 56

Procedure:

To a stirring solution of compound 65 (100 mg, 0.56 mmol mg) in 5 ml CH30H at 25°C, CeC13 (138 mg, 0.56 mmol) was added. After 5 min, NaBH4 (22 mg, 0.56 mmol) was added, the solution was stirred for 2 min and water added. The mixture was extracted with 10 ml ethyl ether. The organic layer was dried over anhydrous MgS04, filtered and concentrated. The residue was purified by chromatography to give 98 mg crystalline desired product 56 in 95% yield.

Canventol 56:

IH-NMR (CDCI3, 300 MHz, ppm): 6.32 (s, IH), 4.24 (dd, J = 6.9, 6.6 Hz, IH), 2.52 (sept, IH), 2.37 (m, 2H), 1.81-1.76 (m, 8H), 1.11 (t, J = 7.2 Hz,6H).

13CNMR (CDCI3, 75 MHz, ppm): 127.5, 126.8, 120.9, 66.0, 32.4, 31.79, 22.59, 21.64, 21.32, 20.86, 19.68.

IR (neat, em-I): 3500, 3030, 2980, 1620, 1450, 1380, 1100, 1050. 67

65 57

Procedure:

To a solution of dienone 65 (45 mg, 0.25 mmol) in 10 ml ethyl ether was added CH3Li (0.3 mmol) at OOC. The mixture was stirred for 5 min at OOC and 10 ml water was added. The organic layer was dried over anhydrous MgS04 and solvent removed. The residue was purified by flash chromatography to give 40 mg of the desired product 57 in 89% yield.

Alcohol 57:

IH-NMR (CDC13, 300 MHz, ppm): 6.37 (s, 1H), 2.80-2.67 (m, 1H), 2.35 2.26 (m, 1H), 2.15-2.04 (m, 1H), 1.71 (s, 3H), 1.66-1.62 (m, 2H), 1.60 (s, 3H), 1.21-1.19 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H).

IR (neat, em-I): 3350, 2980, 1480, 1350. 1100, 1050. 68

o 0 o 0 O~ .. O~ )t'-.. ----i.._ ~I I 66 67

Procedure:

To a solution of allyltrimethylsilane (684 mg, 6.0 mmol) in 5 ml CCl4 at OOC was added iodine (762 mg, 6.0 mmol). The mixture was stirred for 1 h at ooC. The starting material 66 (1.11 g, 5.0 mmol) in 5 ml CCl4 was added and the solution was stirred for 30 min at OOC. The solution was washed with sat'd aqueous NazSz03 solution. The solvent was removed and the residue purified by flash chromatography to give 950 mg of the desired product 67 in 55% yield (the compound was not isolated). 69

o 0 o 0 O~ O~ R

68 R = CH3 67 69 R = C2Hs

Procedure:

A mixture of compound 67 (0.68 mmol), 2 ml acetone, potassium carbonate (280 mg, 2.03 mmol) and 0.5 ml alkyl iodide was refluxed in a sealed tube for 10 h. The solution was cooled to room temperature and filtered. The acetone was removed under reduced pressure. The residue was purified by flash chromatography to give 120 mg of compounds 68 or 69 in 75-80% yield.

Compound 69:

IH-NMR (CDCI3, 300 MHz, ppm): 5.92-5.72 (m, 1H), 5.31 (d, J = 17.1 Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.65-4.51 (m, 2H), 3.23 (d, J = 14.4 Hz, 1H), 2.73-2.30 (m, 4H), 2.21 (d, J = 14.4 Hz, 1H), 1.74 (s, 3H), 1.70 (s, 3H), 1.33 (s, 3H).

IR (neat, em-I): 3040, 2980, 1730, 1710, 1640, 1460, 1380, 1140. 70

o 0 o o~ A

68 R=CH3 69 Ro=C2Hs

Procedure:

A mixture of compound 68 or 69 (0.48 mmol), Pd(OAch (0.1 mmol), diphenylphosphinoethane (dppe) (0.05 mmol), in 5 ml acetonitrile was refluxed for 1h. The solution was cooled to room temperature, filtered, and 20 ml water was added. The mixture was extracted with ethyl ether and the organic layer was dried over anhydrous MgS04. The crude product was purified by flash chromatography to give 45 mg of the desired product dienone in 57 60% yield.

Dienone 72:

IH-NMR (CDCI3, 300 MHz, ppm): 7.26 (s, 1H), 2.70 (d, J = 6.9 Hz, 1H), 2.65 (d, J =7.2 Hz, 1H), 2.49-2.44 (m, 2H), 2.32-2.24 (dd, J = 15.0, 14.7 Hz, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H).

IR (neat, cm-l ): 3030, 2980, 1680, 1640, 1450, 1380, 1100. 71

o OH R R

II'

58 R = CH3 59 R = C2Hs

Procedure:

To a stirring solution of dienone (0.27 mmol), CeCl3 (0.27 mmol) in 5 ml CH30H at room temperature was added NaB14 (0.27 mmol). After 5 min, 20 ml water was added and the mixture was extracted with ethyl ether. The organic layer was dried over anhydrous MgS04 and the solvent was removed. The crude product was purified by chromatography to give 10 mg desired products 58 or 59 in 88-90% yield.

Compound 58:

IH-NMR (CDCI3, 300 MHz, ppm): 6.29 (s, IH), 4.10 (d, J = 2.1 Hz, IH), 2.32 (t, J = 6.3 Hz, 2H), 1.89 (s, 3H), 1.85-1.70 (m, 2H), 1.78 (s, 3H), 1.74 (s, 3H).

IR (neat, cm- l ): 3350, 2980, 1640, 1450, 1380, 1200, 1050. 72

Compound 59:

IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, IH), 4.18 (m, IH), 2.35 (t, J = 5.1 Hz, 2H), 2.28-2.21 (dd, J = 14.7, 15.0 Hz, 2H), 1.83-1.78 (m, 2H), 1.80 (s, 3H), 1.75 (s, 3H), 1.10 (dd, J = 7.5, 7.2 Hz, 3H).

13C-NMR (CDCh, 75 MHz, ppm): 140.3, 127.0, 126.8, 122.1, 67.2, 31.8, 27.4, 21.7, 20.7, 19.6, 12.7.

IR (neat, em-I): 3350, 2980, 1640, 1450, 1380, 1100, 1050. 73

REFERENCES

1. Professor H. Fujiki, Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104, Japan. 2. (a) Taber, D. ,F. J. Org. Chern. 1976,41, 2649. 3. (a) Zank, G. A.; Rauchfuss, T. B.; Wilson, S. R. J. Am. Chem. Soc. 1984, 106, 7620. 4. Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15. 5. (a) Coxon, J. M.; Hydes, G. J.; Steel, P. J. Tetrahedron, 1985,42, 5213. (b) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1981,103, 5454. 6. Grimshaw, J.; Grimshaw, J. T.; Juneja, H. R. J. Chem. Soc. Perkin Trans. 1 1972, 50. 7. (a) Kato, M.; Kamat, Y. P.; Tooyama, Y., Yoshikoshi, A. J. Org. Chem. 1989,54, 1536. (b) Jung, M. E.; Blumenkopf, T. A. Tetrahedron Lett. 1978,29, 3657. 8. (a) Wilhelm, F. Newer Methods of Preparative Organic chemistry Vol 2, 1963, Academic Press, New York. (b) Fatiadi, A. J. Synthesis 1987, 85. 9. Minami, I.; Nisar, M.; Yuhara, M.; Shimizu, I.; Tsuji, J. Synthesis 1987, 992. 10. Tius, M. A.; Zhuo, J. C. Unpublished Result.

11. Komori, A.; Suganuma, Okabe, S.; ZOll, X. L.; Tius, M. A.; Fujiki, H. Cancer Res. 1993,53, 3462. 74 B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A

INTRODUCTION

1. Background

Cembranes are fourteen membered, diterpenoid natural products which were isolated from terrestrial and marine sources in the 1970's.1 The structures range from the simple hydrocarbon cembrane 73, found in pine 0leoresins,2 to those containing highly oxygenated stereocenters such as sinularin 74.3 The biological activities in the cembrane series have been found to be diverse: from cytotoxins4-6 to termite allomones.7-9 For example, sarcophytol ASS, which was isolated from Sarcophyton glaucum,lO inhibits tumor promotion by teleocidin in the two-stage carcinogenesis model in

73 cembrane 74 sinularin

55 sarcophytol A 75

mouse skin. II Due to the biological activities and interesting structu.ral features, cembranes have become attractive targets for total synthesis.12 The major obstacles for synthesis are macrocyclization, the introduction of functionality and asymmetric centers on the fourteen membered ring.

2. Previous Approaches to Macrocyclization

The development of an efficient method of macrocyclization is the key step for a successful cembrane synthesis. Unlike small nngs (e.g. 5, 6), the number of degrees of freedom is much larger in the open-chain precursor for larger ring (e.g. 14). Therefore, the entropy barrier can become a problem, and bimolecular reaction can predominate over the intramolecular cyclization. The bimolecular processes, which lead to dimeric or oligomeric products, can be suppressed at high dilution. There are several general methods of macrocyclization that have been successfully used for cembrane synthesis which will be discussed next. a. Stabilized Anion Additions

Sulfur and cyanohydrin stabilized anions have been used for direct cyclization. For example, a sulfone stabilized carbanion was reported by Marshall I3 in the synthesis of dl-7(8)-deoxyasperdiol in which a sulfone iodide 7S was cyclized to 76 in 53% yield by treatment with KN(TMSh in THF in the presence of 18-crown-6. An 76

ethoxyethyl-protected cyanohydrin-derived anion 77 also under~ent cyclization to 78 in 83% yield in the synthesis of mukulol by Takahashi.14

a ...

I S02Ph 75 R = CH2Ph 76 NC 0 OEE b

77 78

Reagents: (a) KN(TMS)2. THF. 18-crown-6; (b) NaN(TMS)2. THF, Hel. b. Alkynyl Anion Addition

The most recent method of cyclization is that of direct addition of an alkynyl anion to aldehydes (e.g. 79) or allylic halides (e.g. 81). This method was previously developed for the formation of ten membered rings15 and was first used for cembrane synthesis in our laboratory.16 The yields of the reaction were 30-60%. There are several other methods for cyclization e.g. intramolecular Horner Emmons reaction,17 and radical cyclization18 all of which have been used in the synthesis of cembranes. 77

-H a CHO -----1-._

'---====--H b Br

Reagents: (a) LiN(TMS)2, THF. 50°C; (b) LiN(TMS)2, LiI, THF.

3. Previous Synthetic Approaches to Sarcophytol A

The geometrical structure and absolute configuration of sarcophytol A were confirmed to be 2Z, 4£, 8£, 12£ and IS, respectively.19 So far, several methods have been developed to the synthesis of sarcophytol A. a. Takayanagi et. al.

The first total synthesis of sarcophytol A was accomplished by Takayanagi et. al. in 1990 (scheme 1).20 Therein trans, trans-farnesal was converted to nitrile 83 by a Wittig reaction. Sharpless oxidation of compound 83 led to allylic alcohol 84 in 52% yield (based on the 78 consumed starting material 83, which was converted to the chloride 8S by treatment with PPh3 and CC4. Treatment of 8S with DIBAL at Doe followed by hydrolysis of the intermediate imine led to dienal 86. The unstable conjugated dienal 86 was converted to the

SCHEME 1 , a b eN .. .. X 83 84 X = OH 85 X = CI

d , c .. CHO .. CI CI 86 87

e .. 55

Reagents: (a) SeOz, t-BuOOH, CH2CIZ, OOC; then CCI4, PPh3; (b) DIBAL, THF, OOC; (c) TMSCN; (d) LiN(TMS)Z, THF, 550C; n-Bu4NF, THF, OOC; (e) (S)-Z-(2,6 xylidinomethyl)pyrrolidine, LAH, EtZ 0, -78°C. cyanohydrin trimethysilyl ether 87. The macrocyclization of 87 was immediately carried out by adding a solution of LiN(TMSh in the presence of 18-crown-6, followed by n-Bu4NF to give dienone 88 in 79 60% yield. Treatment of 88 with the asymmetric reducing reagent prepar~d by mixing LAH in ether with (S)-2-(2,6-xylidinomethyl) pyrrolidine at -78°C led to optically active 55 of 93% ee in 88% yield.

b. Takahashi et. al. Another new synthesis of sarcophytol A was developed by Takahashi et. al. (scheme 2).21 Therein compound 89 was prepared

SCHEME 2

89 90

Reagents: (a) LiN(TMS)2, THF, 50°C; (b) LiCu(CH3)2. THF, DoC. from trans, trans-farnesol in seven steps. Macrocyclization of 89 with NaN(TMSh in THF, followed by deprotection, led to enone 90 in 45% yield. Methyl cuprate addition to the conjugated exocyclic double bond of 90 was followed by spontaneous 13-elimination of alkoxide from the cuprate adduct to produce dienone 88 in 50% yield. 80 c. Kodama et. al. Recently, a novel synthesis to sarcophytol A was achieved by a [2,3] Wittig rearrangement (scheme 3).22 Alcohol 92 was prepared from geranial 91 in seven steps. Cyclization of 92 led to cyclic ether 93 in 9% yield. Rearrangement of 93 with n-BuLi at -78°C produced sarcophytol A 55· in 90% yield. Obviously, the defect of this synthesis was the poor yield (9%) of cyclization of 92.

SCHEME 3

7 steps...

91 92

a b ... ----1..._ 55

Reagents: (a) CC13CN, NaH; p-toluenesulfonic acid; (b) n-BuLi, THF. d. Li et. al.

Macrocyclization by titanium-induced coupling of a dicarbonyl compound was also achieved in the synthesis of sarcophytol A23. Compound 94 was prepared from acetone in eight steps and macrocyclization was carried out by treatment of 94 with TiCI3-AICI3 81 (1/3) and Cu-Zn alloy at 55°C in THF. Sarcophytol A SS was obtained in 63% yield (scheme 4).

SCHEME 4

o a A 8 steps .. ---I"~ 55

Reagents: (a) TiCI3-AICI3 (1/3), Cu-Zn alloy, THF, 550 C.

The development of a novel and efficient method of the synthesis of sarcophytol A will be disussed in the following chapter. 82

RESULTS AND DISCUSSION

1. Retrosynthesis of Sarcophytol A

Sarcophytol A SS was envisioned as being prepared from cyclic alkynyl alcohol 96 (scheme 5). Our strategy and key steps are: (1) the preparation of precursor acyclic alkynyl aldehyde 97 for macrocyclization. (2) the introduction of isopropyl (C-2) and sulfoxide (C-l) groups on the 14-membered ring (3) the conversion of sulfoxide 9S to enone 88. The advantages of starting the synthesis with trans, trans-farnesol are that it contains three trisubstituted alkenes which fit the pattern for sarcophytol A.

SCHEME S

88 95

OH CHO ===> , H

96 97 83 2. Synthesis of Alkynyl Acetate

Starting material trans, trans-farnesol 98 was converted to farnesyl acetate 99 in the presence of acetic anhydride and pyridine in quantitative yield. Sharpless oxidation24 of 99 led to allylic alcohol

SCHEME 6

a OAe b

98 R= H 100 99 R = Ae c .. OAe

H 101 102

Reagents: (a) (CH3CO)20, pyridine, CH2CI2; then Se02, t-BuOOH, DOC; (b) MsCI, LiBr, THF; (c) Acetylene, K2C03, NaI, CuI, acetone.

100 in 25% yield (scheme 6). There are several features of the Sharpless oxidation which are noteworthy: (l) the regiochemical preference of the oxidation made it possible to oxidize the E-terminal

CH3 (2) the methylene (-CHZ-) which IS next to the acetyl group was not oxidized (3) the low yield (25%) of the reaction and the tedious column chromatography in the initial step made the reaction very difficult to perform on large scale. Treatment of allylic alcohol 100 with MsCI, NEt3 and lithium bromide at DOC led to allylic bromide 84 101 in 85% yield.25 Because of the instability of this allylic bromide, 101 was purified by short flash chromatography and used for subsequent acetylene displacement immediately. To complete the conversion from 101 to 102, acetylene gas was bubbled into a mixture of CuI, K2C03, NaI and acetone at room temperature for 2 h and then 101 was added dropwise.26 The mixture was stirred for 2 days and 102 was isolated in 60% yield. Several other conditions were also examined. Replacement of acetone by DMF led to 102 in very poor yield (20-30%), even though the reaction time was short (5 h). Direct displacement of bromide 101 with sodium acetylide or lithium acetylide in THF at OOC did not succeed, the reaction did not take place and only starting material 101 was isolated. It has to be pointed out that acetylene displacement of 101 led to some dimeric and SN2' byproducts (103 and 104 30% yield). The probable mechanism of dimerization might be as follows:

SN2' ~ V~~rI 102 SN2 100 103 S~ y~

104 85 Byproducts 103 and 104 were inseparable from desired product 102. Optimization of the reaction conditions did not give rise to a yield better than 60%. The reaction was repeated at high dilution (e.g. 0.005, 0.003, 0.001 M), but this led to no improvement of the yield.

3. Formation of Cyclic Alkynyl Alcohol

Hydrolysis of 102 with KzC03 in methanol produced 105 in 85% yield. Swern oxidationZ7 of 105 led to aldehyde 97. The overall yield

SCHEME 7

-::::-- CHO H a 102 ,

105 97

Reagents: (a) KZC03, methanol, Z30C; (b) DMSO, (COCI)Z, Et3N, CHZCIZ, -78°C.

from 102 to 97 was 60% (scheme 7). Although several methods for macrocyclization have been applied to cembrane synthesis, only a few cases of macrocyclization by direct addition of an alkynyl anion to an aldehyde exist. The method was first used in the synthesis of sinularin 74 in our laboratory, but the yield was very poor (30%).16 86 As mentioned above, several factors also affect the macrocyclization, e.g. te"mperature, base and concentration. What we did first was the use of different bases at the same temperature and highly dilute concentration. When NaN(TMS)z was used at room temperature in THF, the reaction proceeded well. Product 96 was obtained in 50 60% yield. Use of LiN(TMS)z resulted in incomplete reaction (10% yield). When the stronger base KN(TMS)z was used, the cyclic allenic

OH a ..

106

Reagents: (a) NaN(TMS)2, THF, room temperature; (b) KN(TMS)2, THF, room temperature. alcohol 106 was obtained in 60% yield. A possible mechanism to account for the formation of allene 106 was by attack of cyclic alcohol 96 by KN(TMS)z, so that the allene was formed after cyclization. But when KN(TMSh was added to the solution of 96 in 87

00 ...

106

THF at room temperature, no allene 106 was isolated. Another possibility was that the allene 106 was formed from 107 before

SCHEME 8

~ CHO

97 ... ---...... -106

107

cyclization (scheme 8), although no evidence has been obtained to confirm this assumption. Further work needs to be done on this reaction. Allenic alcohol 106 was characterized by IH-NMR, IR and mass spectrometry: IR showed a strong allene absorption band at 1960 em-I. Also, the appearance of the allenic protons (5.6-5.8 ppm) on allene 106 in the IH-NMR spectrum and the exact mass matched the proposed structure. 88

4. Synthesis of Alkylated Sulfoxide

To prepare the allenic sulfoxide 111, the following conditions were examined in a model reaction in order to develop optimal conditions for the real system (scheme 9).28 Compound 108 was prepared from I-hexyn-3-01. The solution of compound 108 was added dropwise to the mixture of CuI and isopropyllithium

SCHEME 9

OH a .. H>=C~ b ... ~H SOPh H 1-Hexyn-3-ol 108 109

Reagents: (a) PhSCI, Et3N, Et20, -78°C; (b) isopropyllithium. lithium-2 thienylcyanocuprate. THF, -780C or CuI. isopropylmagnesium chloride, THF. aoc.

or isopropylmagnesium bromide in THF at -780C. The mixture was stirred for 2 h, the reaction was worked up with saturated NH4CI and adduct 109 was obtained in 50% yield. Mixed higher-order cuprate with lithium-2-thienylcyanocuprate led to the same adduct in 58% yield. For the real system, allenic sulfoxide 111 was prepared by [2,3] sigmatropic rearrangement of sulfenate ester 110 derived from alkynol 96. Treatment of 96 with PhSCI at -78°C in diethyl ether led to 111 in 80% yield (scheme 10).28 The reaction was quenched at 89 -78°C and compound 111 was purified by flash chromatography. The el.ectrophilicity of the sp carbon (C-2) of the allene III allowed the use of a cuprate to introduce the isopropyl appendage at C-2. For the real system, the cuprate addition to the allene 111 did not work with CuI and isopropyllithium or isopropylmagnesium bromide and the reaction was· messy. Thus, an alternative mixed higher-order reagent was examined. Isopropyllithium was prepared from

SCHEME 10

OH a

96 110

SOPh 111 95

Reagents: (a) PhSCI. Et3N. Et20, -780C; (b) isopropyllithium. lithium-2 thienylcyanocuprate. THF. -78°C. isopropyl chloride and lithium sand according to the published procedure: isopropyl chloride and lithium sand were refluxed in pentane for 10 h. 29 The solution was transferred to another flask to get it away from the excess lithium sand and was titrated under 90 nitrogen. The mixed higher-order cuprate reagent was prepared by addition of isopropyllithium to a solution of lithium-2 thienylcyanocuprate30 in THF at -780C. The mixture was stirred for 10 min and then the solution of 111 in THF was added. The mixture was stirred for 2 h and the reaction was worked up with saturated NH4Cl. The crude mixture was purified by flash chromatography. Alkylated sulfoxide 95 was isolated in 60% yield as a diastereomeric mixture. Sulfoxide 95 was characterized by JR, IH-NMR and HRMS. The chemical shift of the methine proton at C-I was 3.5 ppm in the 1H-NMR spectrum.

5. Pummerer Rearrangement of Alkylated Sulfoxide. Attempted Synthesis of Enone

a. Model Study The Pummerer rearrangement, the conversion of a sulfoxide to the carbonyl group of aldehyde, is well known,31 but very few reactions have been carried out for conversion to a ketone. The reason is not clear. It might be due to elimination during rearrangement or during hydrolysis. Before we worked on the real system, several conditions were examined in the following model system (scheme 11). Sulfoxide 113 was prepared from perillaldehyde 112 in 5 steps. Treatment of 113 with trifluoroacetic anhydride at -78°C followed by hydrolysis with aqueous NaHC03 did not give ketone 115 and the reaction was messy. Oxidation of compound 114 with m-CPBA led to sulfoxide 116 followed by hydrolysis in aqueous NaHC03 and no ketone 115 was isolated. An 9 1 SCHEME 11

OCOCF3 CHO SPh 5 steps.. ~

112

117 115 116

Reagents: (a) TFAA. CH2CI2. -780C; (b) aqueous NaHC03, room temperature; (c) H202. THF. room temperature; (d) n-BuLi, then TMSOOTMS. THF. -78°C; (e) m CPBA. CH2CI2. (lOC. alternative method which oxidizes the carbon next to the sulfoxide group was also considered. Treatment of 113 with different bases (e.g. LDA, n-BuLi, KN(TMSh, Na(TMSh, sec-BuLi etc.) in THF at -780C, followed by oxidants (e.g. TMSOOTMS. oxaziridine, H20Z, Oz etc.) did not produce the desired ketone 115. Since the conversion of sulfone to the corresponding ketone by oxidation was previously reported,32 sulfoxide 113 was oxidized to sulfone 117 with H20Z in 40% yield in THF at room temperature. Treatment of 117 with n-BuLi in THF at 92

-78°C followed by TMSOOTMS or oxaziridine led to ketone in 40% and 20% yield respectively. Replacement of n-BuLi with other different bases (e.g. LDA, KN(TMS)2) did not improve the yield.

b. Attempted Conversion of Sulfoxide to Enone

Since there were significant structural differences between the real and model systems, direct conversion of sulfoxide 95 to the corresponding ketone 88 was attempted~ even though the model reaction did not work well. Treatment of sulfoxide 95 with trifluoroacetic anhydride at -780C followed by hydrolysis with aqueous NaHC03 led to several compounds and the reaction was messy (scheme 12). The crude compounds were characterized by

SCHEME 12

c ..

119

Reagents: (a) TFAA, ·78oC; aq. NaHC03; (b) 30% H202, THF, 23°C; (c) n-BuLi, (TMSO)2, THF, -780C. 93 IR. IR did not show any evidence of carbonyl group absorption. The difficu~ty of this Pummerer rearrangement made us consider an alternative approach. Compound 9S was oxidized to sulfone 118 with HZ02 in 40% yield. Attempted optimization of the reaction conditions did not increase the yield. The conversion of 118 to ketone 88 with n-BuLi/ TMSOOTMS did not succeed. Only compound 119 was isolated due to elimination. ~-Elimination probably took place under the influence of the strong base (n-BuLi) and compound

119 was formed. Compound 119 was characterized by IR and 1H NMR. There was no sulfoxide absorption in IR. Disappearance of the methine proton at C-I (3.8 ppm) and the appearance of vinylic protons (5.6-5.8 ppm) matched the structure of compound 119. Other conditions were also attempted: When NaN(TMS)z and TMSOOTMS were used, only starting material 118 was isolated. The formation of the anion of compound 118 from deprotection by Na(TMS)z was confirmed by trapping with D20. Different oxidants (e.g. 02, oxizaridine) were also tried with NaN(TMS)z; none of these conditions gave the desired dienone 88. These results made necessary a change in strategy, therefore, substituents other than sulfoxide and sulfone were considered. c. Attempted Synthesis of Ester

The conversion of alkynyl carbonate to allenic ester has been reported by Tsuji in good yield.33 The model study was carried out in the following system (scheme 13). Compound 120 was prepared 94

from l-hexyn-3-01. Allenic ester 121 was obtained In 80% yield

SCHEME 13

OCOOCH3 ~ ~C=

Reagents: (a) Pd2(DBA)3. PPh3. CO. CH30H. 40oC; (b) isopropyllithium. lithium 2-thienylcyanocuprate. THF. -780C.

by treatment of 120 with a catalytic amount of Pd2(DBAh and CO in methanol. Cuprate addition to 121 with the mixed higher-order reagent led to ester 122 in 55% yield. It was hoped that the same chemistry could be applied to our system. Therefore, cyclic alcohol 96 was converted to carbonate 123 by treatment with methyl chloroformate and DMAP at room temperature (scheme 14). Compound 123 was treated with the conditions which were developed for the model reaction, but the reaction only gave the isomerized ester 125 in 20% yield rather than allenic ester 124.43 Compound 125 was characterized by IH-NMR, IR and HRMS. A possible mechanism for the formation of 125 from 124 was by a [1,5] sigmatropic rearrangement. The ease with which 124 rearranged to 125 suggests that the conjugated triene 125 is thermodynamically more stable than allene 124. These results made 95 it very difficult to continue our synthesis using the current route, althou~h enone 88 might be prepared from intermediate 125 by

SCHEME 14

OCOOCH3 a b 96

c d ._------

125 126

e f ._----- ...... _------.....

127 88

Reagents: (a) CH30COCI, DMAP. El20, DoC; (b) Pd2(DBA)3. PPh3. CO. CH30H. 4QoC; (c) cuprale; (d) hydrolysis; (e) oxidation; (0 isomerization. cuprate addition, hydrolysis, oxidation and isomerization. Therefore, on the basis of all of these results, we decided on a more reliable alternative route. 96 6. Reevaluation of Retrosynthesis

We considered that the difficulties encountered in the above synthetic routes might be avoided by the following the pathway which is summarized in scheme 15. The key steps are: (1) selective reduction of 128 followed by dehydration to enone 88 (2) C alkylation of diketone 129 with isopropyl iodide (3) conversion of cyclic alkynyl alcohol 96 to diketone 129. The reactivity difference between the conjugated carbonyl and nonconjugated carbonyl groups is well-documented.3 4

SCHEME 15

128 129

7. Synthesis of Alkylated Diketone

Oxidation of the cyclic alkynyl alcohol 96 with manganese dioxide in CH2Cl2 at room temperature led to alkynyl ketone 130 in 60% yield (scheme 16). Compound 130 was characterized by IR, IH NMR, 13C-NMR, and HRMS. Conjugate addition of methanol to 130, 97

SCHEME 16

OH o a b ...

96 130

129

mediated by K2C03, followed by hydrolysis with concentrated CF3COOH in acetone, produced diketone 129 in 50-60% overall yield from 130.35 It should be pointed out that the yield for the conjugate addition of methanol depends on the reaction temperature. The reaction produced the desired product at ooC. But at higher temperature (e.g. room temperature) the reaction resulted in several uncharacterized compounds. To perform the alkylation step, several conditions in a model system were examined. Generally, alkylation of a 1,3-diketone with a secondary halide produces both 0- and C alkylated products.36 For the model system, 5,5-dimethyl-l,3- 98

o o-l Jio--a· ~o 132 133 ~ + 133

134

Reagents: (a) NaN(TMS)2. THF. 2-iodopropane; (b) DMSO. K2C03. 2-iodopropane. 40°C.

cyclohexanedione 132 was chosen as the starting material. When strong base (e.g. LOA, NaH, KN(TMS)2, Na(TMS)z, LiN(TMSh) was used, reaction led to either O-alkylated product 133 or some uncharacterized compounds regardless of solvent. Based on these results, a weak base (e.g. K2C03) and a more polar solvent (e.g. DMF, DMSO) were considered. It was found that only DMSO was the solvent which gave minor C-alkylation 134 and major O-alkylated products 133. The ratio of C-alkylated to O-alkylated product was 2:8. Other solvents (acetone, THF, DMF) led only to O-alkylated products. Thus, OMSO was our first choice for the real reaction. 99

a ..

128

Reagent: (a) K2C03, DMSO, 2-iodopropane, 40°C.

Treatment of diketone 129 with isopropyl iodide in DMSO at 400C only produced C-alkylated diketone 128 in 50% yield without any O-alkylated product, and this material was used for the subsequent selective reduction step. The problem of the alkylation was that we were unable to reproduce this reaction and got 50% yield only three times. Attempted optimization of the conditions of the reaction with other solvents was not successful.

8. Selective Reduction of 1,3·Diketone. Synthesis of Dienone A reactivity difference between the two carbonyl groups (C-l & C-4) of compound 128 was predicted. It has been reported that a conjugated ketone could be selectively reduced by sodium borohydride and cerium(lIl) chloride in the presence of a saturated ketone in good yield.34 Treatment of diketone 128 with sodium borohydride and cerium (III) chloride produced diol 135 in 65% 100

a ..

128 88

135

Reagents: (a) DIBAL, OOC, CHZC1Z; (b) NaBH4, CeC13, CH30H.

yield. Other reducing reagents (e.g. L-selectride, LAH) were also tried. None of these reagents gave the desired product. Addition of DIBAL to a solution of 117 at DOC in CHzClz produced dienone 88 in

20% yield. Enone 88 was characterized by IR, 1H-NMR and mass spectrometry. The spectral data were identical to the published data for 88.z0 Reduction of dienone 88 to 55 has been accomplished in previous syntheses,ZO,21 hence our methodology represents an effective synthetic pathway to sarcophytol A. 101

CONCLUSION

The total synthesis of dienone 88 has been accomplished in ten steps from farnesol. The conversion of 88 to sarcophytol A has been reported during previous syntheses. Hence, this work provides a formal total synthesis of sarcophytol A. There are several reactions which are noteworthy:

1. Acetylene displacement of 101 produced 102 10 60% yield. The polarity of the solvent affects the yield of the reaction and so far acetone has proved to be the best solvent for the reaction. 2. The macrocyclization of 97 to 96 took place in 50-60% yield. When KN(TMSh was used, allenic product 106 was isolated in 60% yield. The mechanism for formation of allene 104 is not clear at this time. 3. Alkylation of 1,3-diketone 129 with a secondary halide in DMSO only gave C-alkylated product 128 in 50% yield, without any observed O-alkylated product. 4. Selective reduction of 128 to dienone 88 was achieved by DIBAL in moderate yield. 102

EXPERIMENTAL

OAe .. OAe OH

99 100

Procedure:

To stirred a mixture of 1 mi CHZCIZ, SeOz (5 mg, 0.05 mmol) and salicylic acid (32 mg, 0.23 mmol) was added TBHP (0.82 mI, 8.2 mmol) at OOC. Farnesyl acetate 99 (600 mg, 2.14 mmol) in 2 ml CHzClz was added dropwise. After 4 h, the mixture was washed with NaOH followed by brine. The crude product was purified by column chromatography in 20% EtOAc/hexanes to give 174 mg of the desired product 100 in 27% yield. 103

OAe

100

Allylic alcohol 100:

IH-NMR (CDC13, 300 MHz, ppm): 5.34 (m, 2H), 5.10 (dd, J =6.0, 5.4 Hz, IH), 4.57 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.10-2.00 (m, 8H), 2.05 (s, 3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H).

IR (neat, em-I): 3030, 2980,1740,1620,1450,1380,1100,1050.

Mass spectrum (70 eV, m/e): 280 (M+), 262, 237, 220, 189, 135, 121, 93, 81, 68.

Calculated mass for CI7H2803: 280.2039, found: 280.2050. 104

OAe .. OAe Br

100· 101

Procedure:

To alcohol 100 (28 mg, 0.10 mmol) in 5 ml THF was added NEt3 (0.04 ml, 0.29 mmo!) and the mixture was brought to OOC. MsCI (0.02 ml, 0.21 mmol) and LiBr (67 mg, 0.77 mmol) were added. The solution was warmed to room temperature. Sat'd NaHC03 solution was added and the mixture was extracted with Et20. The solvent was dried and removed in vacuo. The crude product was purified by chromatography to give 31 mg bromide 101 in 90% yield. 105

OAe

101 Bromide 101:

IH-NMR (CDCI3, 300 MHz, ppm): 5.6-5.5 (dd, J = 7.2, 6.9 Hz, IH), 5.34 5.32 (dd, J = 7.2, 6.9 Hz, IH), 5.10-5.08 (dd, J = 6.6, 5.4 Hz, IH), 4.60 4.58 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.20-2.00 (m, 8H), 2.05 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H), 1.60 (s, 3H).

IR (neat, cm- 1): 2950, 1740, 1620, 1450, 1380, 1100, 1050.

Mass spectrum (70 eV, m/e): 263, 203, 187, 159, 135, 119, 107, 93, 79. 106

OAc ...

H 101 105

Procedure:

Acetylene was passed through a mixture of 5 ml acetone, KzC03 (28 mg, 0.20 mmol), CuI (21 mg, 0.22 mmol) and NaI (30 mg, 0.20 mmol) at room temprature. Allylic bromide 101 (34 mg, 0.1 mmol) was added to the mixture and stirred at room temperature for 48 h. The mixture was filtered and the solvent removed. The residue was

added to a mixture of K2 CO 3 and methanol, stirred for 1 h at room temperature, then water was added and the mixture was extracted with EtzO. The solvent was dried and removed. The crude product was purified by chromatography to give 12 mg of lOS in 50% overall yield. 107

H 105

Alcohol lOS:

IH-NMR (CDC13, 300 MHz, ppm): 5.44-5.37 (m, 2H), 5.17 (dd, J = 6.9, 6.6 Hz, IH), 4.15 (d, J = 6.6 Hz, 2H), 2.87 (s, 2H), 2.10-2.00 (m, 9H), 1.68 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H).

IR (neat, cm- 1): 3350, 3300, 2980, 2100, 1630, 1450, 1380, 1100.

Mass spectrum (70 eV, m/e): 246 (M+), 231, 213, 199, 189, 171, 159, 119, 91, 77. 108

105 97

Procedure:

To oxalyl chloride (0.69 ml, 0.79 mmol) in 1.0 ml CH2C12 at -78°C was added DMSO (0.065 ml, 0.92 mmol). The solution was stirred for 5-8 min and alcohol 105 (60 mg, 0.26 mmol) in 2.0 ml CH2CIZ was added over a period of 5 min. After 15 min, Et3N (0.18 ml, 1.32 mmol) was added and the solution was allowed to warm to room temperature. The solution was extracted with CH2Ch. The crude product was purified by chromatography to give 50 mg of aldehyde 97 in 80% yield. 109

Aldehyde 97:

IH-NMR (CDCI3, 300 MHz, ppm): 10.00 (d, J = 8.1 Hz, IH), 5.90 (m, 1H), 5.40 (m, IH), 5.10 (m, IH), 2.80 (s, 2H), 2.40-2.00 (m, 9H), 1.68 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).

IR (neat, cm- l ): 3300, 2980, 2960, 2100, 1670, 1630, 1450, 1380.

Mass spectrum (70 eV, m/e): 244, 229, 215, 211, 205, 201, 197, 145, 119, 91, 77.

Calculated mass for C17H240: 244.1850, found: 244.1838. 110

CHO a OH H ..

97 96

Procedure:

To a solution of aldehyde 97 (30 mg, 0.12 mmol) in 20 ml THF was added 0.37 ml, 1.0 N, NaN(TMSh in a :;iugie porLion at room temperature. After 5 min, IN Hel was added and the solution was extracted with Et20. The combined ethereal extracts were washed with brine dried and solvent was removed in vacuo. The crude product was purified by chromatography to give 18 mg of alkynyl alcohol 96 in 50-60% yield. 111

Alkynyl alcohol 96:

IH-NMR (CDCI3, 300 MHz, ppm): 5.61 (m, 1H), 5.40 (d, J = 8.4 Hz, 1H), 5.10-5.00 (m, 2H), 2.83 (s, 2H), 2.40-2.00 (m, 8H), 1.65 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H).

I3C-NMR (CDCI3, 125 MHz, ppm): 136.8, 133.9, 128.8, 126.7, 125.7, 123.3, 85.1, 82.5, 59.3, 38.7, 38.4, 27.4, 24.6, 23.4, 17.5, 15.8, 15.0.

IR (neat, em-I): 3350, 3010, 2960, 2210, 1620, 1480, 1350, 1200.

Mass spectrum (70 eV, m/e): 244, 226, 211, 205, 197, 183, 169, 157.

Calculated mass for C17H240: 244.1827, found: 244.1849. 112

SOPh

111 96

Procedure:

To a solution of alkynyl alcohol 96 (20 mg, 0.08 mmol) and (0.04 ml, 5.6 mmol) Et3N in 3 ml EtzO at -780C was added very slowly PhSCI (25 mg, 0.16 mmol) in 2 ml EtzO. The solution was stirred for 5 min at -78°C. Water was added and the reaction mixture was warmed to room temperature. The solution was extracted with EtzO and the organic layer was dried over MgS04. The solvent was removed and the residue was purified by chromatography to give 23 mg of desired product sulfoxide 111 in 80% yield. 113

SOPh

111

Sulfoxide 111: lH-NMR (CDCI3, 300MHz, ppm): 7.50-7.27 (m, 5H), 6.40-6.35 (m, IH), 5.57-5.53 (d, J = 10.8 Hz, IH), 5.16-5.11 (ro, IH), 4.98-4.94 (m, IH), 2.90-2.84 (d, J = 16.8 Hz, IH), 2.50-2.45 (d, J = 16.8 Hz, IH), 2.19-2.11 (ro, 8H), 1.74 (d, J = 0.9 Hz, 3H), 1.52 (s, 3H), 1.48 (s, 3H).

IR (neat, cm- l ): 3030, 1940, 1640, 1560, 1440, 1380, 1080, 1050.

Mass spectrum (70 eV, role): 352 (M+), 336, 275, 267, 243, 236, 226, 185, 143, 109.

Calculated mass for C23H2SS0: 352.1869, found: 352.1841. 114

SOPh

111' 95

Procedure:

To 2.8 ml of a 0.1 M solution of Cu(CN)(Th)Li in THF was added 0.78 ml of a 0.36 M solution of isopropyllithium in pentane dropwise at -780C. The mixture was stirred for 5 min and sulfoxide 111 (20 mg. 0.057 mmol) in 2 ml THF was added. The mixture was further stirred for 1 h and the sat'd NH4CI was added. The mixture was extracted with Et20. The solvent was dried and removed in vacuo. The crude product was purified by chromatography to give 12 mg of alkylated sulfoxide 9S in 57% yield. 115

Alkylated sulfoxide 95:

IH-NMR (CDC13, 300 MHz, ppm): 7.66-7.42 (m, 5H), 6.32 (d, J = 11.7 Hz, 1H), 5.64 (d, J = 11.7 Hz, IH), 4.97-4.87 (m, 2H), 4.21 (dd. J = 10.8, 3.0 Hz, IH). 2.50-2.45 (m, 2H), 2.18-1.83 (m, 9H), 1.67 (s, 3H), 1.54 (s, 3H), 1.35 (s, 3H), 1.12 (d, J =6.6 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H).

IR (neat. cm- 1): 3030, 2980, 1600, 1580, 1450, 1380, 1280, 1050.

Mass spectrum (70 eV, m/e): 270, 255, 227, 187, 159, 120, 105, 84. 116

OH o

96 130

Procedure:

To a solution of alkynyl alcohol 96 (12 mg, 0.05 mmol) in 5 ml CH2Cl2 at OOC was added 90 mg (3x30 mg, 1.03 mmol) manganese dioxide in 15 min. The mixture was stirred until tic showed no starting material remaining. The mixture was filtered and the CH2Cl2 was removed in vacuo. The crude product was purified by chromatography to give 7 mg of desired product ketone 130 in 50 60% yield. 1 17

130

Ketone 130:

IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, lH), 5.72 (dd, J = 5.7, 5.1 Hz, IH), 5.11 (d, J = 0.9 Hz, lH), 2.97 (s, 2H), 2.31 (s, 4H), 2.23-2.18 (m, 4H), 2.06 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).

13C-NMR (CDC13, 125 MHz, ppm): 177.9, 155.7, 134.8, 128.3, 127.3, 126.1, 124.0,93.1, 87.6, 38.4, 38.3, 27.5, 24.3, 23.6, 19.7, 17.7, 14.8.

IR (neat, em-I): 3030, 2970, 2250, 1660, 1620, 1450, 1380, 1200.

Mass spectrum (70 eV, m/e): 242 (M+), 227, 199, 173, 159, 145, 115, 91, 77.

Calculated mass for C17H2Z0: 242.1646, found: 242.1658. 118

130 129

Procedure:

A mixture of (10 mg, 0.04 mmol) ketone 130 and 1 mg K2C03 in 2 ml methanol was stirred at OOC for 30 min and then warmed to room temperature for 1 h. The mixture was filtered and the methanol was removed in vacuo. The residue was dissolved in 5 ml acetone and 2 drops of CF3COOH was added. The solution was stirred for 3 h and water was added. The mixture was extracted with Et20 and dried over anhydrous MgS04. The solvent was removed and the crude product was purified by chromatography to give 6 mg of desired product diketone 129 in 60% overall yield. 119

129

Diketone 129:

lH-NMR (CDCI3, 300 MHz, ppm): 5.97 (s, IH), 5.06 (t, J =6.3 Hz, 1H), 4.91 (t, J = 6.0 Hz, IH), 3.50 (s, 2H), 3.20 (s, 2H), 2.28-2.14 (m, 8H), 2.11 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H).

IR (neat, cm- l): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.

Mass spectrum (70 eV, m/e): 260 (M+), 192, 163, 134, 121, 107, 95, 82.

Calculated mass for Cl7H2402: 260.1772, found: 260.1783. 120

129 128

Procedure:

A mixture of (10 mg, 0.04 mmol) diketone 129 and 30 mg K2C03 in 2 ml DMSO was heated to 400C in a sealed tube. The color of the solution changed to yellow in 10 min and (0.05 ml, 5.00 mmol) isopropyl iodide was added. The mixture was stirred for 1 hand cooled down to room temperature. Water was added, the solution was extracted with Et20 and the organic layer was dried over anhydrous MgS04. The solvent was removed and the residue was purified by chromatography to give 6 mg of desired product 128 in 50% yield.

------_.- ~.-.-_.. _- 121

128

Alkylated diketone 128:

IH-NMR (CDCI3, 300 MHz, ppm): 5.96 (s, IH), 4.98 (dd, J = 6.9, 6.3 Hz, IH), 4.86 (dd, J = 6.4, 5.4 Hz, IH), 3.40 (d, J = 10.2 Hz, IH), 2.96 (s, 2H), 2.51-2.23 (m, 9H), 2.11 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H), 0.89 0.84 (dd, J = 6.6, 6.0 Hz, 6H).

I3C-NMR (CDCI3, 125 MHz, ppm): 205.4, 194.9, 160.7, 134.6, 129.0, 128.6, 123.9, 123.7, 76.3, 52.0, 40.5, 38.8, 28.1, 24.8, 24.3, 21.2, 20.4, 19.3, 17.3, 15.4.

IR (neat, em-I): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.

Mass spectrum (70 eV, m/e): 302 (M+), 259, 234, 203, 163, 150, 135, 121, 95, 82.

Calculated mass for C20H3002: 302.2232, found 302.2238. 122

128 88

Procedure:

To a solution of alkylated diketone 128 (15 mg 0.05 mmol) in 2 ml CHzC1z was added highly dilute DIBAL solution (0.5 eq, 0.025 mmol, 0.3 rol) in CHzClz at aoc. The mixture wqS stirred for 10 min and IN HCI was added. The solution was extracted with CHzClz and dried over anhydrous MgS04. The solvent was removed and the residue was purified by chromatography to give 4 mg of desired dienone 88 in 30% yield. 123

Dienone 88:

IH-NMR (CDCI3, 300 MHz, ppm): 6.23-6.20 (dd, ] = 12.0, 1.5 Hz, IH), 5.90-5.88 (d, ] = 11.5 Hz, IH), 5.02-4.99 (td, ] = 5.5, 1.0 Hz, IH), 4.96 4.93 (t, 6.5 Hz, IH), 3.15 (s, 2H), 2.70-2.65 (sept, IH), 2.20-2.07 (m, 8H), 1.75 (d, ] = 1.0 Hz, 3H), 1.72 (s, 3H), 1.47 (s, 3H), 1.08 (d, ] = 7.0 Hz,6H).

IR (neat, em-I): 3030, 3010, 2980, 1680, 1620, 1380, 1250.

Mass spectrum (70 eV, m/e): 286 (M+), 271, 243, 203, 175, 150, 135, 121, 107, 91, 81.

Calculated mass for C20H300: 286.2334, found: 286.2316. 124

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