ronghui lin et al- enantiospecific synthesis of natural (-)-cocaine and unnatural (+)-cocaine from...

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E n a n t i o s p e c i f i c S y n t h e s i s o f N a t u r a l (-) - C o c a i n e a n d U n n a t u r a l

(+) -Cocai ne f rom D - a n d L-Glut am i c Aci d

Ronghui Lin, Josep Castells, and Henry Rapoport*

Department of Chemistry, University of California, Berkeley, California 94720

Received J anuary 27, 1998

N a t u r a l (-)-cocaine and unnatural (+)-cocaine have been synthesized enantiospecifically from D-a n d L-glut amic acid, respectively. The axial-equatorial substitut ents were intr oduced by a stereo-an d r egiospecific dipolar cycloaddition t o the corr espondin g (1 R ,5S )- an d (1S ,5 R )- N -BOC-nortropeneswith (ethoxycar bonyl)form onitr ile N -oxide. A sequence of subsequen t st ereochem ically contr olledtra nsforma tions converted the fused isoxazoline to th e requisite β-hydroxy ester. Synth esis of thek e y i n t er m e d ia t e N -BOC-nortr openes involved constru ction of th e 8-azabicyclo[3.2.1]octan eframework by Dieckma nn condensat ion of cis-5-substitut ed D- and L-proline esters. For comparison,(1 R ,5S )- N -BOC-nortropene also was derived by degradation from natu ral cocaine. The cis-5-substituted D- and L-proline esters were obtained by sulfide cont raction and subsequent cata lytichydrogenation to induce stereospecifically the C-5 stereochemistry from D- and L-thiopyroglutamate,which in turn were prepared from D- a n d L-glutamic acids, respectively.

I n t r o d u c t i o n

(-)-Cocaine is the flagship compound of a family of tropan e alkaloids isolated from th e leaves of Erythroxylon

coca that have been exhaustively reviewed.1 The pro-found behavioral and neur onal reinforcing pr operties of cocaine are commonly believed to be associated with itsinhibition of dopamine reupt ake,2 and it s abuse is a ma jorsocial and h ealth problem. There is no effective medica-tion for the t reatm ent of cocaine addition. As a result,major efforts are being expended in the search for cocaineantagonists3 and developm ent of a ntibodies and vac-cines.4 F or t h e s e p u r p o se s, a p r od ig iou s n u m b er of cocaine-related tropane analogues have been synthe-sized,3,5 leading t o high affinity a nd selective cocainereceptor l igands and providing inform ation about thestructure/activity relationship of cocaine-related tropanederivatives.

Cocaine contains an 8-azabicyclo[3.2.1]octane frame-work and is one of the eight possible stereoisomers of met hyl 3-(ben zoyloxy)-8-met hyl-8-azab icyclo[3.2.1]octan e-2-carboxylate.2b In a ddition to const ru ction of this azabi-cyclo ring system, the major hurdle to its synthesis hasbeen cont rol of stereochemistry, both of enant iomeric

integrity a nd of th e therm odynam ically unstable a xial

carboxylate function. Most of the n onracemic cocaineanalogues were synthesized by t he derivatization of natural cocaine,3c,e,4d,5a-g,j,k while others were obtained byresolution or separ ation of racemic or diastereomericreaction m ixtures.5d,h,l,n,p,q The original and classicalMann ich-type constr uct for th e t ropane skeleton, devel-oped over half a centu ry ago by Willstatt er, Robinson,an d Sch op f 6 as the f irst biom im etic synthesis, is s ti l lem ployed, for exam ple, in recent syntheses of 6- and7-hydroxylated cocaine7 and unnatural (+)-cocaine, whichemployed a chemical resolution.8 Several methods em-

(1) Lounasmaa, M. Alkaloids 1988, 33 , 1.(2) (a) Koob, G. F.; Bloom, F. E. S cience 1988, 242 , 715. (b) Carr oll,

F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1992 , 35 ,969.

(3) (a) Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.;Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1993, 36 , 2886.

(b) Davies, H. M. L.; Saikali, E.; Hu by, N. J . S.; Gilliatt, V. J .; Matasi,J. J.; Sexton, T.; Childers, S. R. J . M e d . Ch e m. 1994, 37 , 1262. (c)Kelkar, S. V.; Izenwasser, S.; Katz, J . L.; Klein, C. L.; Zhu, N.; Trudell,M. L. J. Med. Chem. 1994, 37 , 3875. (d) Kozikowski, A. P.; Sa iah, M.K. E.; Johnson, K. M.; Bergmann, J . S. J. Med. Chem. 1995, 38 , 3086.(e) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J . L.; Kuzemko, M.A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.; Kuhar, M.J . J . M e d . Ch em. 1995, 38 , 379. (f) Neumeyer, J . L.; Tamagnan, G.;Wang, S.; Gao, Y.; Milius, R. A.; Kula, N. S.; Baldessarini, R. J. J .

Med. Chem. 1996, 39 , 543.(4) (a) Landry, D. W.; Zhao, K.; Yang, G. X.-Q.; Glickman, M.;

Georgiadis, T. M. Science 1993, 259 , 1899. (b) Carrer a, M. R. A.; Ashley,J. A.; Parsons, L. H.; Wirsching, P.; Koob, G. F.; Janda, K. D. Na t u r e1995, 378 , 727. (c) Sakurai, M.; Wirsching, P.; Janda, K. D. Tetrahedron

Lett. 1996, 37 , 5479. (d) Berkman, C. E .; Underiner, G. E.; Cashman,J. R. J. Org. Chem. 1996, 61 , 5686.

(5) (a) Kline, R. H., Jr.; Wright, J.; Fox, K. M.; Eldefrawi, M. E. J . Med. Chem. 1990, 33 , 2024. (b) Kozikowski, A. P.; Xiang, L.; Tan aka ,

J.; Bergmann, J . S.; Johnson, K. M. Med. Chem. R es. 1991, 1, 312. (c)Milius, R. A.; Saha, J. K.; Madras, B. K.; Neumeyer, J. L. J. Med. Chem.1991, 34 , 1728. (d) Carroll, F. I.; Lewin, A. H.; Abraham, P.; Parham,K.; Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1991, 34 , 883. (e) Car roll,F. I.; Gao, Y.; Rahma n, M. A.; Abraha m, P.; Par ham , K.; Lewin, A. H.;Boja, J. W.; Kuhar, M. J . J. Med. Chem. 1991, 34 , 2719. (f) Carroll, F.I.; Gao, Y.; Abraham , P.; Lewin, A. H.; Lew, R.; Pa tel, A.; Boja, J . W.;K u h a r , M . J . J . M e d . Ch e m. 1992, 35 , 1813. (g) Kozikowski, A. P.;Roberti, M.; Xiang, L.; Bergman n, J . S.; Callaha n, P. M.; Cunningha m,K. A.; Johnson, K. M. J . M e d . Ch e m. 1992, 35 , 4764. (h) Wang, S.;Gao, Y.; Laruelle, M.; Baldwin, R. M.; Scanley, B. E.; Innis, R. B.;N e u m e y e r , J . L . J . M ed . C h em . 1993, 36 , 1914. (i) Simoni, D.;Stoelwinder, J .; Kozikowski, A. P.; J ohnson, K. M.; Bergmann, J. S.;Ball, R. G. J. Med. Chem. 1993, 36 , 3975. (j) Carroll, F. I.; Abraham,P.; Kuzemko, M. A.; Gray, J. L.; Lewin, A. H.; Boja, J. W.; Kuhar, M.J . J . C h em . S o c. , C h em . C om m u n . 1993, 4 4. (k ) C a r r ol l, F . I .;Mascarella, S. W.; Kuzemko, M. A.; Gao, Y.; Abraham, P.; Lewin, A.H.; Boja, J. W.; Kuhar , M. J. J. Med. Chem. 1994 , 37 , 2865. (l) Meltzer,P. C.; Liang, A. Y.; Madras, B. K. J . M ed . Ch e m. 1994 , 37 , 2001. (m)

Aronson, B.; Enmon, J . L.; Izenwasser, S.; Katz, J. L.; Kelkar, S. V.;Luo, L.; Nolan, S. P .; Trudell, M. L. J. Med. Chem. 1996, 39 , 1560. (n)Chen, Z.; Izenwasser, S .; Katz, J. L.; Zhu, N .; Klein, C. L.; Trudell, M.L. J . M e d . Ch e m. 1996, 39 , 4744. (o) Chang, A.-C.; Burgess, J. P.;Mascarella, S. W.; Abraham , P.; Kuha r, M. J .; Carroll, F. I. J . M e d .Chem. 1997, 40 , 1247. (p) Thiruvazhi, M.; Abraham, P.; Kuhar, M. J.;Carr oll, F. I. Chem. Commun. 1997 , 555. (q) Kozikowski, A. P.; Simoni,D.; Baraldi, P. G.; Lampr onti, I.; Manfredini, S. Bioorg. Med. Chem.

Lett. 1996, 6 , 441.(6) (a) Willsta t ter , R. Ber. 1896, 29 , 936. (b) Willstat ter , R. Liebigs

Ann. Chem. 1903, 32 6 , 23. (c) Robinson, R. J. Chem. Soc. 1917, 11 1,762. (d) Schopf, C.; Leh ma n, G . Liebigs Ann . 1935, 51 8, 1.

(7) Kozikowski, A. P.; Simoni, D.; Man fredini, S.; Roberti, M.;Stoelwinder, J . Tetrahedron Lett. 1996, 37 , 5333.

(8) Lewin, A. H.; Naser ee, T.; Carroll, F. I. J . Heterocycl. Chem. 1987,24 , 19.

4069 J. Org. Chem. 1998, 63 , 4069-4078

S0022-3263(98)00153-4 CCC: $15.00 © 1998 American Ch emical SocietyPublished on Web 05/15/1998



ploy cycloaddition reactions, including th e reaction of rh odium(II)-sta bilized vinylcar benoids with pyr roles,9 [3+ 4] cycloaddition of iron oxyallyl cations to pyrrole,10

nitrone cycloaddition,11 nit roso cycloaddition,12 and pyr-idinium betaine-based dipolar cycloaddition.13 Asym-metric versions of cycloadditions for the stereospecific

synthesis of cocaine-related tropane ana logues ar e rela-tively few and still suffer from low yield and poorstereoselectivity. Thus, there are lacking sa tisfactoryenantiospecific and generally applicable synthetic meth-ods for the synthesis of cocaine and related tr opaneanalogues.

Recently, we have developed a number of methods forthe enantiospecific synthesis of aza apical azabicyclos 14

related to the tropane fram ework. We have sought t oadapt and extend these routes t o cocaine-related tropanesby methodology that might provide scope and accessibil-ity. Herein we report an enantiospecific route for th esynthesis of optically pure natural (-)-cocaine and un -n a t u r a l (+)-cocaine from simple an d readily a vailable

compounds.

R e s u l t s a n d D i s c u s s i o n

Since cocaine is a cis-2,3-disubstituted tropane, the cis-d is u b st i t u en t s w er e t o b e i n t r od u ce d b y r e gi o- a n dstereospecific fun ctionalization of t he carbon-carbondouble bond of chiral 2-tropenes. Design for synth esisof the 8-azabicyclo[3.2.1]octane skeleton of the tropanealkaloids, such as that of tropene, was related to ourmethods for t he synt heses of ferru ginine, anat oxin, and

other bicyclos, which involved construction of the bicyclicframework by a tr ansa nn ular cyclizat ion of appr opriatelycis-5-substituted D- or L-proline ester.14 For the presentcase, Dieckmann condensation was proposed as the bestrout e for const ru ction of th e functiona lized 8-azabicyclo-[3.2.1]octan e skeleton. The resultin g β-keto ester product

then would be converted to a tropene whose carbon-carbon double bond would be suitable for the cis-carboxy-hydroxylation by dipolar cycloaddition pr ocedures. Aspreviously shown, the cis-5-substituted D- or L-prolineester would be obtain ed from t hiopyrogluta mat e by sulfurcontraction and subsequent catalytic hydrogenation toster eospecifically fix th e geomet ry at C-5. This pr ojectionis shown in Figure 1.

Thiolactam, ( R )-1-benzyl-5-thionoproline tert -butyl es-ter (4), was first prepared a s reported 14e from D-glutamicacid. As shown in Scheme 1, dibenzyl d l-malate (2) waseasily obtained by esterification of d l-malic a cid (1) in95% yield. Triflate 3, prepared in situ from the 2-hydroxyester 2 by treatm ent with Tf 2O and 2,6-di-tert -butyl-4-

m ethylpyridine, reacted with the ( R )-thiolactam 4, fol-lowed by sulfide contraction (PPh 3 / N -methylpiperidine),to give the vinylogous carbamat e 5 as a 5.5/1 mixtur e of i som e r s i n 6 9% y i el d. B y c h a n gi n g t h e b a se t o 2 , 6-lutidine, these procedures were significantly simplified,and the yield of 5 was increased t o 76%.

Treatmen t of olefin 5 under catalytic hydrogenationconditions (H 2, 10% Pd/C) was expected to proceed bydebenzylation, followed by decarboxylation, a nd th enhydrogenat ion of the resultan t pyrroline t o give the cis-5-substituted D-proline esters 6 . But debenzylation wassluggish, and the m ajor product resulted m erely fromolefin h ydrogenation. Treatm ent of olefin 5 w i t h a m -monium formate in the presence of catalytic 10% Pd/C

in MeOH at reflux, however, gave the debenzylated,decarboxylated, an d h ydrogenated product 6 in 87% yield.Esterification of the amino acid 6 with MeOH/HCl atroom temp eratu re afforded a mixtur e of th e mixed methyltert -butyl diester and methyl diester 7; the sam e reactionat reflux gave the dimethyl ester 7 in 95% yield.

N -Benzyl diester 8a w a s o b t a in e d b y t r e a t m e n t of diester 7 with benzyl bromide in t he pr esence of K2CO 3

in 96% yield. Dieckma nn conden sat ion of th is diester 8a

was rea dily accomplished in 90% yield by tr eatm ent with200 mol % of KHMDS at -78 °C for 1 h. The cyclizationproduct, β-keto ester 9a , exists pr edomina nt ly as its enol.Conceivably, Dieckmann condensation of diester 8a couldafford two β-keto esters. Exclusive form ation of 9a

(9) Davies, H. M. L.; Matasi, J . J .; Hodges, L. M.; Huby, N. J . S.;Thornley, C.; Kong, N.; Houser, J. H. J . Or g. Ch e m. 1997, 62 , 1095and references therein.

(10) Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. J . Am. Ch e m.

Soc. 1978, 10 0, 1786.(11) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.;Wong, S . C.; Ali, S. A. J . Am . Ch e m. S o c. 1979, 101 , 2435.

(12) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Org. Chem. 1985, 50 ,1818.

(13) (a) Pham, V. C.; Charlton, J. L. J. Org. Chem. 1995 , 60 , 8051.(b) Lomenzo, S. A.; Enmon, J . L.; Troyer, M. C.; Trudell, M. L. S y n t h .Co mmu n . 1995, 25 , 3681. (c) Ru mbo, A.; Mourino, A.; Cast edo, L.;Masca rena s, J . L. J. Org. Chem. 1996, 61 , 6114. (d) Kozikowski, A. P.;Araldi, G. L.; Ball, R. G. J. Org. Chem. 1997, 62 , 503.

(14) (a) Hern and ez, A. S.; Tha ler, A.; Castells, J .; Rapoport, H . J .Org. Chem. 1996, 61 , 314. (b) H erna nd ez, A.; Rapoport, H . J . Or g.Chem. 1994, 59 , 1058. (c) Hern an dez, A.; Marcos, M.; Rapoport , H. J .Org. Chem. 1995, 60 , 2683. ( d) Sar di na, F.; J . ; Howar d, M. H.;Koskinen, A. M. P.; Rapoport, H. J . Or g. Ch e m. 1989, 54 , 4654. (e)Petersen, J . S.; Fels, G.; Rapoport, H . J . Am . Ch em. S o c. 1984, 106 ,4539 and t he r elat ed r efer ences t her ein. ( f) Koskinen, A. M. P.;Rapoport, H. J . M e d . C h e m . 1985, 28 , 1301. (g) Campbell, J. A.;Rapoport, H. J. Org. Chem. 1996, 61 , 6313.

F i g u r e 1 . Proposed route to natur al (-)-cocaine and unnatural (+)-cocaine from the corresponding glutamic acid.

4070 J. Org. Chem., Vol. 63, No. 12, 1998 Lin et al.



undoubtedly results from t he u se of excess base an d t heinability of the other isomer to form a stabilizing enolateat the bridgehead.

Many attem pts to hydrolyze β-keto ester 9a underconventional alkaline (LiOH/THF/H 2O, LiOH/MeOH/ H 2O) or acidic (HCl/MeOH/H 2O) conditions were unsuc-cessful. Cleavage and simultan eous decarboxylation t oketone 10 by treatm ent of β-keto ester 9a with TMSCl/ NaI or n-BuSH/NaH also failed. Nucleophilic displace-ment of the methyl group and simultaneous decarboxy-

lation to ketone 10 finally was achieved by t reatm entwith NaI in pyridine at reflux in 90% yield.

S in ce i t w a s c le a r t h a t t h e ol efi n fu n ct i on i n t h eprojected tropene would best undergo dipolar cycloaddi-tion with a nitrile oxide after the tert -am ine h ad beenconverted to a nonnucleophilic carbamate (and as wasconfirmed by preliminary experiments, see the followingtext), ketone 10 was converted to N -BOC ketone 11 in90% yield by cata lytic hydrogenolytic d ebenzylation inthe presence of (BOC)2O.

The necessity of carbamate functionality led to con-sideration of introducing t he BOC group initially andavoiding benzylation-debenzylation. Thus, secondaryam ine 7 was protected with a BOC group to give 8b in

93% yield. Treatm ent of diester 8b with 200 mol % of KHMDS at -78 °C for 6 h gave, in 85% yield, β-keto ester9b , also existing predominant ly as its enol. As with th etertiary amine, nucleophilic cleavage and decarboxylationof β-keto ester 9b with NaI in pyridine at reflux gaveketone 11 in 87% yield. Although th ese transformat ionswith BOC protection eliminated two steps in the conver-sion of 7 t o 11 , compared to the t ran sformations with the N -benzyl group, the overall yield is slightly lower. N -BOC ketone 11 then was converted to its tosylhydrazonein 88% yield, from which olefin (1 R ,5S )-(+)-12 wa sobtained by reaction with N aH in 70% yield.

For confirmation th at we were on t he correct pat h, wep r oce ed e d t o ob t a in t h i s k e y i n t er m e di a t e, N -BOC-

nortr opene ((+)-12 ), by degrada tion from nat ur al cocaine.As shown in Scheme 2, ecgonidine hydrochloride (13 ) wasfirst obtained by hydrolysis and dehydration of natural(-)-cocaine hydrochloride in concentrat ed HCl un derreflux.15 Catalytic h ydrogenat ion of ecgonidine hydro-chloride (13 ) afforded dihydroecgonidine hydrochloride(14 ), which was converted t o phenyl selenides (15 ) by thephotochemically induced radical decarboxylation proto-col16 in 72% combined yield. The phen yl selenide (15)was obtained as two separable diastereom ers (3/1).

Oxidation of the phenyl selenides (15) w it h N a I O4 a f-forded corresponding mixtures of phenyl selenoxides ingood yield. The ph enyl selenoxides were found to un -dergo a slow elim ination t o (-)-tropene (16 ) a t r oomtemperat ure on the basis of 1H NMR analysis. A similaroxidation an d elimination of a pyridyl sulfide t o giveracem ic tropene has been reported.17 Pyrolysis andsimultan eous Ku gelrohr distillation of the ph enyl selen-oxides provided (-)-2-tropene (16) i n 5 7% y ie ld , i naddition to recovered phenyl selenide (15 ) and diphenyldiselenide in 39% and 33% yield, respectively.

Cycloaddition of 2-tropene (16) with a nitrile N -oxide,(tetrahydro-2 H -pyran-2-yloxy)acetonitrile oxide, whichhas been developed for the cis-carboxyhydroxylation of

olefins,18 w a s i n ve st i ga t e d . T h e n i t r il e N -oxide wasprepared in situ in the presence of triethylamine,18 bu tnone of the cycloaddition product was observed under alarge variety of conditions, an d su bstan tial qua ntities of 2-tropene (16 ) were recovered. Cycloaddition of 2-tropenewith another nitrile N -oxide, (ethoxycarbonyl)formoni-t r i le ox id e, g en e r a t ed i n s it u a n d u s ed for t h e ci s-cyan ohydroxylation of olefins, 18 also failed to afford any

(15) Leete, E . J . Am . Ch em. S oc . 1982, 104 , 1403.(16) Bart on, D. H. R.; Bridon, D.; Zard, S. Z. Heterocycles 1987, 25 ,

449.(17) Newcomb, M.; Marquardt, D. J.; Kumar, M. D. Tetrahedron

1990, 46 , 2345.(18) Kozikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983, 48 , 366.

S c h e m e 1 . S y n t h e s is o f ( 1 R ,5S )- N -BOC-nortropene

Synthesis of Natural (-)-Cocaine and Unnatural (+)-Cocaine J. Org. Chem., Vol. 63, No. 12, 1998 4071



cycloadduct. The lack of cycloaddition t o tr opene withthese two nitrile N -oxides was a scribed to a combinat ionof factors: low reactivity of olefin a nd poten tial in ter ac-tion of th e nu cleophilic electr on lone pa ir on t he n itrogenof tropene with the nitrile N -oxides or their precursors.

To convert (-)-tropene (16) to its BOC derivative, itwas dem ethylated an d carbam oylated in 45% yield bytreatment with 1-chloroethyl chloroformate (ACE-Cl) ind r y t o lu e n e a t r e fl u x. T h e r e s u lt i n g c a r ba m a t e w a s

metha nolized by refluxing in MeOH an d t hen convertedto its BOC derivative. Alth ough this a pproach pr ovidedaccess to compound (+)-12, the overall yield was low.Alternat ively, the phenyl selenide 15 was demethylatedand converted to a carbam ate by treatm ent with ACE-Cl in refluxing toluene. Methanolysis an d t reatm entwith triethylamine and (BOC)2O gave compound 17 in98% yield. Oxidation of t he phenylselenide 17 withNaIO4 in THF/H 2O and subsequent elim ination of theresulting selenoxides in refluxing THF in the presenceof triethylamine provided (1 R ,5S )-(+)-12 in 91% yield.

The 2-tropene derivative ((1 R ,5S )-(+)-12 ) obtained bydegradation of natu ral cocaine is identical to th e totallysynthet ic product obtained from D-glutam ic acid an d d l-

m a l ic a c id . T h u s , t h e d e gr a d a t ion p r od u ct s er v ed t oconfirm the identity and stereochem istry of t ropeneana logues obtained from D-glutam ic acid and also toestablish t he absolute configurat ion of the fina l products.Moreover, th ough 2-tropinone19 as well a s ecgonidine15

have been reported as cocaine degradation products and,especially ecgonidine, have been widely used as chiralbuilding blocks for the synthesis of cocaine-related tro-pane a nalogues, the enan tiomeric pure 2-tropene (16 ) andi t s d e r iv a t iv e (+)-12 d es cr i be d h e r e h a v e n ot b ee n

reported previously. In particular, tr opene 12 , readilyprepared in 32% overall yield from d l-malic acid andeither D- or L-glutam ic acid, provides an att ractive basisfor t he synt hesis of nu merous an alogues derived from th ereactions of the d ouble bond.

The dipolar cycloaddition of (1 R ,5S )- N -BOC nortropene(12 ) was investigated with ethoxycarbonylformonitrileoxide. An addition product was isolated in good yield,to which structure 18 was assigned as sh own in S cheme3. The optimal procedure for th e cycloaddition requiresa slow addition of excess ethyl chlorooximidoacetat esolution to a m ixture of (+)-12 a n d N a 2CO 3 in binaryTHF/H 2O solvents so as t o minimize the dimerization of the nitrile N -oxide and to m aintain a weakly alkalinemedium , avoiding depr otection of th e BOC group on (+)-12 . The stereo- and regiochem istry of the adduct waspredicated on projections that the exo-face was lesssterically congested and qualitative calculations of thepolarization of the double bond. Of course, definitiveproof would await ultimat e conversion of 18 to cocaine.

Treatm ent of 18 with NaOH in EtOH/H 2O at refluxresulted in epimerization at C-2 while forming a β-hy-

droxy carboxylic acid, N -BOC-pseudonorecgonin e, instea dof the desired N -BOC-norecgonine. Pr esumably, N -BOC-pseudonorecgonine was formed via hydrolysis of the ethylester, decarboxylation, and fragmentation of the isox-azoline ring a nd hydrolysis of the resulting β-hydroxynitrile, accompanied by epimerization of the C-2 axialsubstitu ent, either nitrile, amide, or carboxylate.20 Mildhydrolysis, however, of ethyl ester 18 w i t h N a O H i nEtOH/H 2O, followed by careful acidification, gave thecarboxylic acid 19 in 95% yield. Therma l decarboxylationand fragmentat ion of th e isoxazoline ring of 19 was bestachieved by heating at 105-110 °C to give β-hydroxy(19) (a) Bell, M. R.; Archer, S. J . Am. Ch e m. S o c . 1960, 82 , 4642.

(b) Zhang, C.; Lomenzo, S. A.; Ballay, C. J., II; Trudell, M. L. J. Org.Chem. 1997, 62 , 7888. (c) Zhang, C.; Gyermek, L.; Trudell, M. L.;Tetrahedron Lett. 1997, 38 , 5619. (20) F in dla y, S. P . J . Am . Ch e m. S o c. 1954, 76 , 2855.

S c h e m e 2 . D e g r a da t i on o f (-)-Coc ai ne to (1 R ,5S )-Tr ope ne s




nitrile 20 . What rem ained was to convert the nitrile toacid without epimerization.

Hydrolysis of the β-hydroxy nitrile 20 under acidicconditions (HCl, H 2SO 4, BF 3 /HOAc) to the β-hydroxycarboxylic acid was un successful. Under these acidicconditions, t he BOC group was r eadily cleaved, an d t hegenerated pr otonat ed nitr ogen caused pr otonat ion of thenitrile to become more difficult; also, elimination of the β-hydroxy group became significan t. A mu ch milder and

stepwise route was devised. The β-hydroxy nitr ile washydrolyzed in 94% yield to the corresponding β-hydroxyamide 21 without epimerization at C-2, by treatment of nitrile 20 with aqueous H 2O2 in t he pr esence of Na 2CO 3

in acetone/H 2O.To decrease the hydrophilicity of hydroxy amide 21 , it

first was converted to benzoate 22 (benzoic anhydride,DMAP) in 96% yield. Removal of the BOC group in 90%yield was followed by reductive m ethylation at thebridgehead nitrogen of 23 with aqueous formaldehydea n d N a B H 3CN to give tertiary am ine 24 in 75% yield.Nitrosation of the primary amide proved to be an idealway t o generat e carboxylic acid 25 with th e stereochem-i st r y a t C -2 u n a f fe ct e d . T h is w a s a ccom p li sh e d b ytreatm ent of amide 24 with a Na NO2, glacial HOAc/Ac2O(1/2) solution in 93% yield. Meth yl ester forma tion th enfurnished the target m olecule, natural (-)-cocaine, in95% yield.

Following the sam e protocols, u nnat ural (+)-cocainewas synt hesized from (1S ,5 R )- N -BOC nortr opene (-)-12 ,itself prepared from L-glutamic and d l-malic acid.

The enan tiomeric integrity of synthesized natu ral a ndu n n a t u r a l coca i n e w a s d et e r m in e d b y ch i r a l H P L Ca n a l ys is . Au t h e n t i c n a t u r a l (-)-cocaine was prepar edfrom (-)-cocaine hydrochloride.21 Thus, th e enant iomericp u r i t y o f ou r s yn t h e t ic (-)-cocaine prepared from D-

g lu t a m i c a ci d w a s fou n d t o b e 1 0 0 %, w h il e t h a t of u n n a t u r a l (+)-cocaine synt hesized from L-glutamic acidhad an er of 98/2, which could be improved to 100% by asingle recrystalization.

C o n c l u s i o n

We have developed an enantiospecific synthetic routeto enant iomerically pure nat ural and unn atu ral cocaines.

The com ponent com pounds of t his synthesis are D- orL-glutamic acid, d l-m alic acid, and glycine. The keyintermediate is the chiral tropene 12, form ed via Dieck-mann condensation of cis-5-substituted D- or L-prolineester and the regio- and stereospecific functionalizationof this tr opene. The protocols and st art ing and interm e-diate compounds are quite versatile and should providescope for further extension to chiral cocaine ana logues.

E x p e r i m e n t a l S e c t i o n

G e n e r a l P r o c e d u r e s . Melting points were determined ona Thomas-Hoover UniMelt capillary a ppara tus and are uncor-rected. Column chromat ogra phy was performed using 230-400 mesh silica gel, and TLC analyses were performed on

aluminu m-backed silica gel 60 F 254, 0.2 mm plat es visualizedwith UV light (254 nm), followed by heating with ethanolicphosphomolybdic acid. Fina l organic solutions were dr ied overNa 2SO 4 before filtration and evaporation using a BerkeleyRotavap. 1H a nd 13C N MR s p ect ra w ere record ed w it htetram ethylsilane (δ 0.0 for 1H), and CDCl3 (δ 77.0 for 13C),(CD 3)2SO (δ 39.5 for 13C), an d CD3OD (δ 49.0 for 13C ) a sinternal reference. 1H coupling consta nts, J , are reported inH z; D E PT exp erimen t s w ere carri ed ou t w it h 13C N M Racquisition, and the carbon multiplicities are l isted as (0)quat erna ry, (1) meth ine, (2) meth ylene, (3) meth yl. All chemi-cal shifts are reported in δ p pm . T HF a n d E t2O were dr iedby distillation from Na-benzophenone ketyl under nitrogen;pyridine, 2,6-lutidine, hexanes, C6H 6, E t 3N , D MF, CH 3CN ,CH 2Cl 2, ClCH 2CH 2Cl, and N -methylpiperidine were dried bydistillation from CaH 2 under argon; anhydrous MeOH was

(21) Stenberg, V. I.; Singh, S. P.; Nara in, N. K. J. Org. Chem. 1977,42 , 223.

S c h e m e 3 . S y n t h e s is o f (-)-Coc ai ne fr om (+)- N -BO C-nor tr ope n e , (+)-12




distilled from Mg; acetyl chloride, oxalyl chloride, benzalde-hyde, and benzyl alcohol were distilled prior t o use. Tf 2O wasfreshly distilled from P 2O5 before use. Elemental microana ly-s es w ere d et ermi n ed b y t h e Microan al yt i cal L ab orat o ry,University of California, Berkeley.

D i b e n z y l d l -Malate (2). To a solution of d l-malic a cid(26.80 g, 200 mmol) and benzyl alcohol (41.3 mL, 43.2 g, 400mmol) in dr y C6H 6 (400 mL) in a 1 L r ound-bottom flask wasadded p-toluenesulfonic a cid monohydrate (3.8 g, 20 mmol).To the flask was att ached a Dean-Stark water separator witha reflux condenser. The reaction mixture was h eated at reflux

for 4 h, cooled to room temperature, and then washed withH 2O (1 00 m L ), 5 % a q u eou s K2CO 3 (1 00 mL ), s at u rat edNaHCO3 (100 mL), and sat urat ed NaCl (100 mL). The organiclayer was dried, filtered, and evaporated. Chromatographyof the residue on silica gel, eluting first with 2% MeOH/ CH 2Cl2

and then with 5% MeOH/CH 2Cl 2, gave the product a s a paleyellow oil (59.4 g, 95%): 1H NMR (CDCl3) δ 7.40-7.35 (m,10H), 5.20 (s, 3H), 5.12 (s, 3H), 4.60 (m, 1H ), 3.22 (d, 1H, J )

5.4, exchangeable with D2O), 2.90 (m, 2H); 13C NMR (CDCl3)δ 173.1 (0, 1C), 170.2 (0, 1C ), 135.4 (0, 1C), 135.0 (0, 1C), 128.6,128.5, 128.4, 128.3, and 128.2 (1, 6C), 67.6 (2, 1C), 67.3 (1,1C), 66.7 (2, 1C). Anal. Calcd for C34H 37NO 6: C, 68.8; H, 5.8.Found: C, 69.0; H, 5.8.

(2 R )-( E a n d Z)- N -Benzyl-5-[1′,2 ′-bis(benzyloxycarbon-y l ) e t h y l i d e n e ] p r o l i n e t er t-Butyl Ester ((-)-5). To a solu-tion of dibenzyl d l-malat e (15.51 g, 49.4 mmol) and 2,6-lutidine

(5.80 g, 6.27 mL, 54.1 mmol) in CH 2Cl 2 (150 mL) at -25 °Cu n d er N 2 was added dropwise Tf 2O (12.86 g, 7.67 mL, 45.5mmol) over 15 min, and the reaction mixture was stirred for2.75 h between -10 and -5 °C. To the resulting solution of crude triflate 3 a t -10 °C was added D-thiolactam 414e (11.53g, 39.5 mmol), and the solution was stirred for 24 h at roomtemperatur e. The reaction m ixture was then cooled at 0 °C,PP h 3 (1 9. 45 g , 7 4 .1 mmol ) w as ad d ed , an d t h e res u lt i n gsolution was allowed to warm to room temperature over 1 h.After the solution wa s cooled t o -12 °C, N -methylpiperidine(9.0 mL, 74.2 mmol) was added dropwise over 15 min, and themixture was allowed to warm to -3 °C and stirred for 14 h.The reaction mixture was washed with 0.5 M KH 2P O4 (2 ×400 mL) and satu rated NaH CO3 (400 mL), the aqu eous washeswere extracted separately with CH2Cl 2, an d t h e co mb i n edorganic layers were dr ied (Na2SO 4), filtered, and evapora ted.

T h e g u mmy r es id u e w as t h en t r i t u rat ed w i t h 7 /3 h exan es / EtOAc. The hexanes/EtOAc extracts were dr ied, filtered, andevapora ted t o a gum my solid, which wa s dissolved in CH 2Cl 2.Chromatography, eluting with 1/4 EtOAc/hexanes, gave theproduct (+)-5 as a colorless t hick oil (16.70 g, 76%): [R]21

D

-16.8° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.38-7.12 (m, 15H),5.10 (d, J ) 2.1, 2H), 5.00 (s, 2H ), 4.82 (d, J ) 16.3, 1H), 4.40(d, J ) 16.3, 1H), 3.88 (dd, J ) 8.4, 4.9, 1H), 3.48 (m, 2H),3.35-3.20 (m, 2H), 2.20 (m, 1H), 2.00 (m, 1H), 1.45 (s, 9H);13C NMR (CDCl3) δ 173.2 (0, 1C), 169.0 (0, 1C), 164.9, (0, 1C),137.3 (0, 1C), 136.8 (0, 1C), 136.0 (0, 1C), 128.8, 128.6, 128.4,128.3, 128.2, 128.1, 127.8, 127.4, and 127.1 (each 1, ea ch 1C),88.8 (0, 1C), 81.8 (2, 1C), 66.1 (1, 1C), 65.2 (2, 1C), 53.1 (2,1C), 34.0 (2, 1C), 34.0 (2, 1C), 33.9 (2, 1C), 27.8 (3, 1C), 26.3(2, 1C). Anal. Calcd for C34H 37NO 6: C, 73.5; H, 6.7; N, 2.5.Found: C, 73.1; H, 6.9; N, 2.2.

(2S )-( E a n d Z)- N -Benzyl-5-[1′,2 ′- b i s ( b e n z y l o x y c a r b o n -y l ) e t h y l i d e n e ] p r o l i n e t er t -Butyl Ester ((+)-5, Structu reN o t S h o w n ) . This enantiomer was prepared similarly from2 an d L-thiolactam 4:14e [R]22

D +17.4° (c 1.0, CHCl3); spectra land chromatographic properties identical with (+)-5.

(2 R ,5S )-5-[1′-(2 ′- H y d r o x y c a r b o n y l ) e t h y l ] p r o l i n e t er t -Butyl Ester ((+)-6). To a degassed solution of the ethylidenecompound (-)-5 (20.84 g, 37.5 mmol) and amm onium forma te(35.43 g, 563 mmol) in MeOH (250 mL) was added 10% Pd/C(12 g), and the resulting suspension was heated at reflux for12 h; th e white solid condensing on the wall of the condenserw as remo ved rep eat edl y. T h e react ion mi xt u re w as t h enfiltered, the filter was rinsed with MeOH, and th e filtrat e wasevaporated to give an oil residue. 1H NMR analysis showedtha t th e residue was mainly the desired amino acid containingsmall amounts of ammonium format e and solvent. Chroma-

tography on a short column (20% MeOH/CH 2Cl 2) gave (+)-6(7.93 g, 87%): [R]22

D +1.5° (c 1.0, MeOH); 1H N MR (CDCl3) δ4.12 (dd, 1H), 3.42 (m, 1H), 2.50-1.62 (m, 8H), 1.30 (s, 9H);13C NMR (CDCl3) δ 178.7, 170.3, 83.0, 60.5, 59.4, 34.0, 30.8,29.7, 29.0, 27.9.

(2S ,5 R )-5-[1′-(2 ′- H y d r o x y c a r b o n y l ) e t h y l ] p r o l i n e t er t -B u t y l E s t e r ( (-) - 6 , s t r u c t u r e n o t s h o w n ) : [R]22

D -1.4° (c

1.4, MeOH); spectral and chromatographic properties identicalwith (+)-6.

(2 R ,5S )-5-[1′-(2 ′-Methoxycarbonyl)ethyl]proline Meth-y l E s t e r ( (+)-7). Acetyl chloride (1 mL) was added dropwise

to MeOH (5 mL) at 0 °C, the solution was stirred for 15 min,and then to this solution was added a MeOH solution (5 mL)of crude (+)-6 (199 mg). The resulting mixtur e was heated atreflux for 14 h an d then evapora ted. The residue was dissolvedin CH 2Cl 2 and washed with 10% Na 2CO 3; the organic layerw as d ri ed , fi lt ered, an d evap orat ed ; an d t h e res id u e w aschromatographed, eluting with 10% MeOH/CH 2Cl2 to give thediester (+)-7 as a colorless oil (170 mg, 95%): [R]21

D +20.0° (c

1.0, CHCl3); 1H NMR (CDCl3) δ 3.80 (s, 3H), 3.75 (s, 3H ), 3.15(br, 1H), 2.80 (m, 1H), 2.60-1.85 (m, 8H), 1.40 (m, 1H); 13CNMR (CDCl3) δ 175.2, 173.7, 59.7, 59.1, 52.0, 51.5, 31.7, 31.3,30.7, 29.9. Anal. Calcd for C 10H 17NO 4: C, 55.8; H, 8.1; N,6.5. Found: C, 55.5; H, 8.1; N, 6.4.

(2S ,5 R )-5-[1′-(2 ′-Methoxycarbonyl)ethyl]proline Meth-yl Ester ((-)-7, structure not shown): [R]22

D -19.4° (c 1.25,CHCl3); spectral a nd chroma tographic properties identical with

(+)-7.(2 R ,5S )- N -Benzyl-5-[1 ′-(2 ′-methoxycarbonyl)ethyl]pro-

l i n e M e t h y l E s t e r ( (+)-8a). To an CH 3CN solution (14 mL)of (+)-7 (2.33 g, 10.8 mmol) and benzyl bromide (1.97 g, 1.38mL, 11.5 mmol) under magnetic stirring was added K 2CO 3

(4.93 g, 36.5 mmol). The resulting su spension was st irred atroom temperature for 14 h and filtered, the solid was washedwith CH 2Cl2, and the filtrat e was evaporated. Chromatogra-phy (1/4 EtOAc/hexanes) of the residue gave (+)-8 a s acolorless oil (3.16 g, 96%): [R]21

D +2.8° (c 1.1, CHCl3); 1H NMR(CDCl3) δ 7.30-7.15 (m, 5H), 4.00 (d, J ) 13.8, 1H), 3.66 (m,4H), 3.46 (s, 3H), 3.30 (dd, 1H), 2.80 (m, 1H), 2.42 (m, 1H),2.28 (m, 1H) 2.25-1.50 (m, 6H); 13C NMR (CDCl3) δ 174.8,174.0, 138.0, 129.3, 127.9, 126.9, 66.0, 63.2, 57.3, 51.3, 51.2,30.1, 29.4, 29.0, 28.1. Anal. Calcd for C17H 23NO 4: C, 66.9;H, 7.6; N, 4.6. Found: C, 66.5; H, 7.8; N, 4.5.

(2S ,5 R )- N -Benzyl-5-[1 ′-(2 ′-methoxycarbonyl)ethyl]pro-l i n e M e t h y l E s t e r ( (-) - 8 a , s t r u c t u r e n o t s h o w n ) : [R]22

D

-1.9° (c 1.05, CHCl3); spectral and chromatographic propertiesidentical with (+)-8a .

Methyl (1 R ,5S)-8-Benzyl-8-azabicyclo[3.2.1]-2-octanone-3-carboxylate ((+)-9a). To a solution of diester (+)-8a (3.16g, 10.34 mm ol) in THF (100 mL) a t -78 °C was added a 1 MKHMDS solution in THF (22.6 mL, 22.6 mm ol). The rea ctionmixture was stirred at -78 °C for 1 h and then poured intoan ice-cooled mixtur e of EtOAc (700 mL) an d pH 7.0 phosphat ebuffer (700 mL). The resulting mixture was separated, theaqueous phase was further extracted with EtOAc (4 × 20 0mL), and the combined organic phases were washed withsaturated NaCl (200 mL), dried, fil tered, and evaporated.Chromatography of the residue, using 1/4 EtOAc/hexanes aseluent, gave the bicyclic ketone (+)-9a (2.55 g, 90%). NMR

ana lysis indicated t his compound exists predominant ly in th eenol form: [R]20

D +116° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 8.30(br, 1H, exchangeable with D2O), 7.40-7.12 (m, 5H), 3.80-3.60 (m, 5H), 3.40-3.30 (m, 2H), 2.62 (dd, 1H ), 2.20-1.85 (m,4H), 1.50 (m, 1H); 13C NMR (CDCl3) δ 173.7, 172.7, 139.0,128.7, 128.2, 126.9, 91.8, 59.9, 55.3, 52.7, 51.3, 32.8, 29.4, 27.4.Anal. Calcd for C16H 19NO 3: C, 70.3; H, 7.0; N, 5.1. Found:C, 70.0; H, 7.3; N, 5.0.

Methyl (1S ,5 R)-8-Benzyl-8-azabicyclo[3.2.1]-2-octanone-3-carboxylate ((-)-9a, structure not shown): [R]22

D -108°(c 1.0, CHCl3); spectral and chromatographic properties identi-cal with (+)-9a .

(1 R ,5S )-8-Ben zyl-8-azabicyclo[3.2.1]-2-octan one ((-)-10). To a solution of (+)-9a (1.07 g, 3.91 mm ol) in pyridine(35 m L) was a dded NaI (11.7 g, 78 mmol). The suspensionw as h eat ed at refl u x fo r 8 h an d t h en ev ap o rat ed , an d t h e




residue was par titioned between H 2O (50 mL) and CH 2Cl 2 (50mL). The aqueous phase was extra cted with additional CH2Cl2

(3 × 50 mL), and the combined organic phase was washed withs at u rat ed a q u eou s N a 2S2O3 (50 mL), dried, fil tered, an devapora ted. Chromat ograph y of the residue, eluting with 1/2EtOAc/hexanes, gave the ketone (-)-10 as an oil (758 mg,90%): [R]21

D -9.8° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.38-7.10 (m, 5H), 3.68 (s, 2H), 3.38 (m, 2H), 2.42-2.15 (m, 4H),1.82-1.70 (m, 4H); 13C NMR (CDCl3) δ 210.0, 138.6, 128.5,128.3, 127.1, 69.8, 56.9, 54.4, 33.0, 29.9, 26.8, 26.7.

(1S ,5 R )-8-Ben zyl-8-azabicyclo[3.2.1]-2-octan one ((+)-

1 0, s t ru c t u re n o t s h o w n ): [R]22D +9.6° (c 1.0, CHCl3);spectral and chromatographic properties identical with (+)-10 .

(1 R ,5S )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2 -o c t a n o n e ( (-)-11). To a degassed solution of (-)-10 (1.42g, 6.70 mmol) in MeOH (60 mL) were added (BOC) 2O (4.78 g,21.9 mmol) an d 10% Pd/C (321 mg). The resu lting suspen sionwas stirred under H 2 (balloon) for 5 h, filtered, a nd evaporated.The solid residue, dissolved in a small amount of CH 2Cl2, waschromat ogra phed, elutin g with 1/2 EtOAc/hexan es, to give (-)-11 as a white solid (1.43 g, 96%): mp 92-93 °C; [R]20

D -21.9°(c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.42 (bs, 1H), 4.18 (bs, 1H),2.50-2.15 (m, 4H), 1.90-1.70 (m, 4H), 1.45 (s, 9H); 13C NMR(CDCl3) δ 205.9, 153.5, 80.2, 64.2, 52.5, 32.4, 30.4, 28.2, 27.6.Anal. Calcd for C12H 19NO 3: C, 64.0; H, 8.5; N, 6.2. Found:C, 64.2; H, 8.5; N, 5.9.

(1S ,5 R )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2 - o c t a n o n e ( (+) - 1 1 , s t r u c t u r e n o t s h o w n ) : [R]11

D +21.6°(c 1.0, CHCl3); spectral and chromatographic properties identi-cal with (-)-11 .

(2 R ,5S )- N -( t er t-Butyloxycarbonyl)-5-[1 ′-(2 ′- m e t h o x y -carbonyl)ethyl]proline Methyl Ester ((+)-8b). A solutionof (+)-7 (3.5 g, 16.26 mmol) in MeOH (100 mL), (BOC)2O (8.87g, 40.65 mmol), and Et 3N (0.14 mL, 1 mm ol) was stirred a troom t emperat ure for 14 h a nd t hen evaporated, giving an oilyresidue that was chromatographed, eluting with 1/2 EtOAc/ hexanes, t o give (+)-8b as a colorless oil (4.76 g, 93%): [R]20

D

+21° (c 1.0, CHCl3); 1H NMR (CDCl3, 58 °C) δ 4.3 (bs, 1H),3.9 (bs, 1H), 3.72 (s, 3H ), 3.66 (s, 3H), 2.45-1.50 (m, 8H), 1.43(bs, 9H); 13C NMR (CDCl3, 58 °C) δ 173.5, 173.4, 79.9, 59.9,57.7, 51.6, 51.1, 30.9, 29.7, 28.2, 27.3. Anal. Calcd forC14H 21NO 5: C, 59.4: H, 7.5; N, 4.9. Found: C, 59.8; H, 7.8;

N, 4.9.(2S ,5 R )- N -BOC-5-[1 ′-(2 ′- m e t h o x y c a r b o n y l ) e t h y l ] p r o -

l i n e M e t h y l E s t e r (-) - 8 b , s t r u c t u r e n o t s h o w n ) : [R]21D

-19° (c 1.0, CHCl3); spectral an d chromatograph ic propertiesidentical with (+)-8b .

M e t h y l ( 1 R ,5S )-8-( tert -Butyloxycarbonyl)-8-azabicy-clo[3.2.1]-2-octa non e-3-carbo xylate ((+)-9b). To a solutionof diester (+)-8b (2.20 g, 7.0 m mol) in dry THF (70 m L) at-78 °C was added 1 M KHMDS solution in THF (15.3 m L,15.3 mmol). The reaction mixture was stirr ed at -78 °C for 6h and poured into an ice-cooled mixture of EtOAc (500 mL)and pH 7.0 phosphat e buffer (500 mL), and t he aqueous pha sew as fu rt h er ext ract ed w it h E t O Ac (4 × 2 00 m L ). T h ecombined organic phase was washed with saturated NaCl (200mL), dried, filtered, and evaporated. Chromat ograph y of theresidue using 1/2 EtOAc/hexanes as eluent gave the β-keto

ester (1.69 g, 85%). NMR an alysis indicated th is compoundexists predominantly in i ts enol form: [R]21

D +60° (c 1.0,CHCl3); 1H NMR (CDCl3, 58 °C) δ 8.18 (br, 1H), exchangeablewith D2O), 4.20 (bs, 2H), 3.75 (s, 1H), 2.80 (bs 1H ), 2.20-1.58(m, 5H), 1.45 (bs, 9H); 13C NMR (CHCl3, 58 °C) δ 174.4, 172.8,153.9, 92.2, 80.0, 56.2, 52.6, 51.2, 33.2, 30.3, 29.3, 28.3. Anal.Calcd for C15H 25NO 6: C, 57.1; H, 8.0; N, 4.4. Found: C, 57.4;H, 8.3; N, 4.6.

M e t h y l ( 1S ,5 R )-8-( tert -Butyloxycarbonyl)-8-azabicy-clo[3.2.1]-2-octanon e-3-carbox ylate ((-)-9b, structure nots h o w n ) : [R]22

D -60° (c 1.0, CHCl3); spectral and chromato-graphic properties identical with (+)-9b .

(1 R ,5S )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2 - o c t a n o n e ( (-)-11). To a solution of (+)-9b (1.00 g, 3.53mm ol) in pyridine (35 mL) was added NaI (10.6 g, 70.6 mm ol),and the suspension was heated at reflux for 7.5 h and then

evapora ted to dryness. The residue was part itioned betweenH 2O (50 mL) and CH 2Cl 2 (50 mL), and the aqueous phase wasextracted with additional CH 2Cl 2 (3 × 50 mL). The organicphases were combined and washed with saturated aqueousNa 2S2O3 solution (50 mL), dried, filtered, and evaporated togive an oily residue. Chromatography of this residue using1/2 EtOAc/hexanes gave ketone (-)-11 as a white solid (693mg , 8 7%): mp 9 2-9 3 °C. Sp ect ral an d ch romat o grap h i cproperties were identical to those of (-)-11 prepar ed from (-)-10 .

(1 R ,5S )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2-octene ((+)-12). To a solution of p-toluenesulfonhydrazide(1.42 g, 7.62 mm ol) in MeOH (10 mL) was a dded ket one (-)-11 (1.43 g, 6.35 mm ol). The mixture was stirred at roomt e m pe r a t ur e for 2 h , a n d t h e r e su lt in g w h it e s oli d w a srecrystalized from CH 2Cl 2 to give (1 R ,5S )-8-( tert -butyloxy-carbonyl)-8-azabicyclo[3.2.1]-2-octanone p -tosylhydra-z o n e (2.2 g, 88%): mp 175-180 °C dec; 1H NMR (CDCl3) δ8.9 (s, 1H), 7.85 (m, 2H), 7.8-7.6 (m, 1H), 7.3-7.18 (m, 2H),4.82 (d, 1H, m ajor), 4.50 and 4.30 (each bs, ea ch 1H, m inor),4.02 (bs, 1H, major), 2.22 and 2.20 (each s, each 3H), 2.30-1.40 (m, 8H), 1.25 (s, 9H); 13C NMR (CDCl3) δ 160.7, 155.8,143.9, 143.2, 135.5, 135.3, 129.5, 1229.2, 128.2, 128.1, 80.9,79.7, 55.3, 51.4, 33.8, 29.2, 28.3, 28.2, 28.1, 27.0, 26.2, 21.5,21.4, 18.8. Anal. Calcd for C19H 27N3O4S‚H 2O: C, 55.5; H, 7.1;N, 10.2. Found: C, 55.8; H, 6.8; N, 10.3.

A suspension of the above hydrazone (100 mg, 0.254 mmol)and NaH (36.6 mg, 1.52 mmol) in toluene was st irred a t r oomtemperat ure for 30 min and then heated a t r eflux for 5 h. Afterbeing cooled to room temperature, the mixture was neutralizedw it h s at u rat ed aq u eou s N H 4Cl s ol u t ion , an d t h e aq u eou sp h as e w as fu rt h er ext ract ed w it h CH2Cl 2. T h e comb in edorganic phase was dr ied, fil tered, and evaporated. Chroma-tography of the residue with 1/2 EtOAc/hexanes gave olefin(+)-12 as an oil (37.0 mg, 70%): [R]22

D +3.0° (c 1.0, CHCl3);IR (CHCl3) 1675 cm-1; 1H NMR (CDCl3) δ 6.02 (bs, 1H), 5.55(m, 1H), 4.35 (bs, 1H), 4.25 (bs, 1H), 2.68 (m, 1H), 2.18 (bs,1H), 2.20-1.60 (m, 4H), 1.42 (s, 9H); 13C NMR (CDCl3) δ 154.1,133.1, 123.9, 79.1, 53.6, 35.0, 34.3, 30.2, 28.5, 28.4. Anal. Ca lcdfor C12H 19NO 2: C, 68.9; H, 9.2; N, 6.7. Found: C, 68.7; H,9.3; N, 6.6.

(1S ,5 R )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2-octene ((-)-12, structure not shown): [R]22

D -3.0° (c 1.0,CHCl3); spectral a nd chroma tographic properties identical with(+)-12 .

E c g o n id i n e ( (1 R ,5S )-8-Methyl-8-azabicyclo[3.2.1]-2-o c t e n e - 2 - c a r b o x y l i c A c i d ) H y d r o c h l o r i d e ( 1 3 ) . (-)-Co-caine hydrochloride (20.0 g, 58.86 mmol) was refluxed inconcentra ted H Cl for 24 h.15 The reaction mixture was cooledto room temperature, diluted with H 2O (150 mL), and ex-tracted with Et 2O (4 × 150 mL). The aqueous solution wasevaporated to give a white solid (14.27 g) that was recrystal-lized from E tOH /EtOAc (1/1) to give ecgonidine hydr ochloride(13 , 11.31 g, 86%): mp 240-242 °C dec (lit.15 mp 253-258 °C);[R]22

D -54° (c 0.93, MeOH). Anal. Calcd for C9H 14NO 2Cl: C,53.1; H, 6.9; N, 6.9. Found: C, 53.0; H, 6.9; N, 6.8.

D i h y d r o e c g o n i d i n e H y d r o c h l o r i d e ( 1 4). To a degassedsolution of ecgonidine hydrochloride (13 , 6.20 g, 30.44 mmol)

i n MeO H w as ad d ed 5 % Pd / C (2 . 3 0 g ), an d t h e res u l t an ts u s pen s ion w as h y drog en at ed (6 0 p s i , r t ) for 6 .5 h . T h ereaction m ixtur e was filtered, the filtrat e was evaporated, an dthe solid r esidue was digested with MeOH. Evaporation of the methanol solution and recrystallization from 1/3 EtOH/ EtOAc gave hydroecgonidine hydrochloride (14 , 5.84 g, 93%):mp 260-262 °C dec (lit.22 mp 263 °C); [R]22

D -8.9° (c 1.10,MeOH); 1H NMR analysis of 14 in CD3OD revealed that thiscompound existed as a 5/1 diastereomeric mixture: for m ajordiastereomer, 1H NMR (CD3OD) δ 4.13 (m, 1H), 3.89 (m, 1H ),3.03 (m, 1H), 2.81 (s, 3H), 2.31-2.29 (m, 2H), 2.05-1.96 (m,4H), 1.86-1.82 (m, 2H); 13C NMR (CD3OD) δ 18.7 (2), 23.2(2), 24.9 (2), 29.6 (3), 40.0 (3), 45.1 (1), 65.3 (1), 65.8 (1), 173.4

(22) Keimatsu, S.; Inoue, S. J . Ph a r m. S o c . J p n . 1925, 51 8, 354;Chem. Abstr. 1925, 19 , 2671.




(0); for minor diastereomer, 1H NMR (CD3OD) δ 4.10 (m, 1H),3.82 (m, 1H). Anal. Calcd for C9H 16NO 2Cl: C, 52.6; H, 7.8;N, 6.8. Found: C, 52.9; H, 8.1; N, 6.7.

(1 R ,5S )-8-Methyl-2-(phenylseleno)-8-azabicyclo[3.2.1]-o c t a n e ( 1 5) . To a suspension of carboxylic acid 14 (11.95 g,58.10 mmol) and oxalyl chloride (2.8 mL, 4.01 g, 31.60 mmol)in CH 2ClCH 2Cl (550 mL) in a 2 L round-bottom flask underN 2 was added DMF (1.72 mL) over 0.5 h. The mixture wasstirred at room t emperature for 12 h and then evaporated todryness. Dry CH2ClCH 2Cl (300 m L) was a dded to t he solidres id u e an d evap orat ed ; t h i s p ro ces s w as rep eat ed . T h e

res u lt an t p ale y el low s ol id w as d is s ol ved i n 5 70 mL of CH 2ClCH 2Cl by gentle war ming; the solution was cooled t o 0°C and then covered with aluminum foil, and in the dark, Et 3N(17.9 mL) wa s added, followed by dropwise addition over 50min of N -hydroxy-2-th iopyridone (8.13 g)23 in CH 2ClCH2Cl (460mL). The mixture was allowed to warm t o room tempera tur e,stirred for 1.5 h, then evaporated to dryness at room temper-atur e. To the residue in the dark and under a N2 atmospherew as ad d ed 1 L o f CH 2Cl 2, cooled 0 °C, and then diphenyldiselenide (60.2 g)24 was added. The solution was irra diatedwith two tungsten lamps at 0 °C for 2 h a nd th en allowed tow a r m t o r o om t e m pe r a t ur e ove r 3 0 m i n . T h e r e s u lt in gmixture was concentr ated t o about 500 mL, and H 2O (200 mL)was added. After t he aqueous pha se was basified, with solidNa 2CO 3, i t was extracted with CH 2Cl 2 (4 × 2 00 mL ). T h eorganic layers were combined and extracted with 10% tar tar ic

acid (5 × 200 mL) and t he ta rta ric acid extracts were ba sifiedwith solid Na 2CO 3 and th en extracted with CH 2Cl 2, which wasdried and evaporat ed. The residue was chr omatographed (15%MeOH/Et 2O) to give the product as two diastereomers in 72%total yield, composed of a major diastereomer as a pale yellowoil (8.84 g, 54%) and a minor diastereomer as a light browncrystalline solid (2.88 g, 18%): ma jor dia ster eomer, [R]22

D +84°(c 1.08, CHCl3); 1H N MR (CDCl3) δ 1.50-1.51 (m, 1H), 1.52-1.56 (m, 2H), 1.80-2.10 (m, 5H), 2.26 (s, 3H), 3.13 (m, 2H),3.61 (ddd, J ) 12.6, 4.8, 2.7, 1H), 7.18-7.26 (m, 3H), 7.45-7.53 (m, 2H); 13C NMR (CDCl3) δ 22.9 (2), 24.2 (2), 25.8 (2),32.2 (3), 40.5 (3), 45.7 (1), 60.6(1), 65.8 (1), 126.9 (1), 128.7 (1),129.1 (0), 133.6 (1). Anal. Calcd for C14H 19NSe: C, 59.8; H,6 .8 ; N , 5 .0 . Fou n d : C, 5 9. 8; H , 6 . 8; N , 5 . 2. For mi n ordiastereomer: [R]22

D +58° (c 1.15, CHCl3); 1H NMR (CD3OD)δ 1.35 (d, J ) 12.8, 1H), 1.53 (q, J ) 8.7, 1H), 1.71 (dd, J )

9.3, 5.2, 1H), 1.9-2.1 (m, 5H ), 2.23 (s, 3H), 3.07 (m, 1H), 3.28(m, 1H), 3.42 (m, 1H), 7.21-7.28 (m, 3H) 7.50-7.91 (m, 2H);13C NMR (CD3OD) δ 23.2 (2), 24.6 (2), 26.7 (2), 29.6 (2), 42.3(3),49.6 (1), 62.3 (1), 67.5 (1), 126.4 (1), 128.7 (1), 132.3 (0), 133.0(1 ). An al . Calcd for C14H 19N Se: C, 5 9 .8 ; H , 6 .8 ; N , 5 .0 .Found: C, 59.5; H, 6.9; N, 4.9.

(-)-Tropen e (16). To a solution of the phenyl selenide 15(major diast ereomer, 1.59 g, 5.67 mm ol) in THF (20 mL) cooledto 0 °C was added dropwise a solution of NaIO4 (3.61 g, 16.89mmol) in H 2O (20 mL ). T h e mi xt u re w as s t i rred at roomtemperatu re for 2 h, and the r esulting precipitate was removedby filtration and washed with THF (50 mL) and CH 2Cl 2 (100mL). The filtrate a nd washings were concentra ted to aboutone-fifth volume, poured into saturated NaHCO3 (150 mL), andt h en ex t ract ed w i t h CH 2Cl 2 (5 × 100 mL). The combinedorganic extra ct was dr ied, filtered, and evaporat ed to give the

corresponding selenoxide as a 1/1 mixture of diastereomersby 1H N MR an alysis. The selenoxide (1.68 g, 5.67 mm ol) wasp yrol yzed an d d is t il led from a K u gelroh r ap p arat u s i n apreheated oven at 75 °C/0.08-0.10 Torr. The product wascondensed into a bulb, cooled with dry ice-acetone. Whenpyrolysis was completed (0.5 h) the system was swept withN 2; the distillate was tropene 16 (0.40 g, 57%). The pyrolysisres id u e w as d is s ol ved i n a s mal l amo u n t of CH 2Cl 2 a n dchromatographed (10% MeOH/CH 2Cl 2) to give diphenyl di-selenide (0.29 g, 33%) and recovered phenylselenide 15 (0.63g, 39%). For tr opene (-)-16 : [R]21

D -47° (c 1.05, CH Cl3); 1HNMR (CDCl3) δ 1.54-1.75 (m, 2H), 1.81-1.87 (m, 1H), 1.97-

2.20 (m, 2H), 2.37 (s, 3H), 2.50 (d, J ) 19, 1H), 3.19 (m, 2H),5.52-5.55 (m, 1H ), 5.74-5.77 (m, 1H); 13C NMR δ 29.7 (2),31.8 (2), 33.8 (2), 36.5 (3), 57.7 (1), 58.9 (1), 122.9 (1), 130.7(1).

T r o p e n e h y d r o c h l o r i d e was prepared by adding metha-nolic HCl to an ether solution of tropene (16 ): mp 2 58-260°C dec. Anal. Calcd for C8H 13N‚H Cl‚H 2O: C, 54.1; H, 9.1; N,7.9. Found: C, 54.2; H, 9.1; N, 7.9.

(1 R ,2S ,5S )-8-( tert -Butyloxycarbonyl)-2-(phenylseleno)-8-azabicy clo[3.2.1]octan e (17). To a solution of the phen-ylselenide 15 (major diastereomer, 1.36 g, 4.84 mmol) in

toluene was added dropwise 1-chloroethyl chloroformate (ACE-Cl, 0.70 mL, 6.78 mmol). The resu lting solution was refluxedfor 24 h and then evaporated to give (1 R ,2S ,5S )-8-(1′-chlo-roethox ycarbony l)-2-(phen ylselen o)-8-azabicyclo[3.2.1]-o c t a n e : 1H NMR (CDCl3) δ 7.58 (m, 2H), 7.25 (m, 3H), 6.62(m, major, 1H) and 6.55 (m, minor, 1H), 4.40-4.15 (m, 2H),3.70-3.38 (m, 1H), 2.20-1.45 (m, 17H); 13C NMR (CDCl3) δ150.2, 150.0, 133.4, 133.0, 132.9, 129.1, 127.3, 127.2, 127.0,82.9, 82.6, 57.8, 57.7, 53.7, 53.5, 45.0, 44.5, 31.6, 31.5, 27.4,27.3, 25.4, 25.3, 24.7, 24.6, 24.2, 23.5.

The chloroethoxy intermediat e was dissolved in MeOH (40mL) and refluxed for 2 h, and then the solution was evaporatedto a white foam that was redissolved in MeOH (45 mL). Tothis solution was added Et 3N (0.94 mL, 7.74 mmol) dropwiseover 10 m in; (BOC)2O (1.69 g, 14.49 mmol) was then added,an d s t i rr i n g w as co n t i n u ed at ro o m t emp erat u re fo r 1 5 h .

E v aporat i on l eft a res id u e t h a t w as d i s sol ved i n a s mal lam ount of 10% CH3OH/CH2Cl2 and chromatographed, elutingwith CH 2Cl 2 an d t h en 2 % CH 3OH/CH 2Cl2, to give 17 , majordiastereomer, a s a colorless oil (1.73 g, 98%): [R]22

D -52° (c

1.0, CHCl3); 1H NMR (CDCl3) δ 7.52 (bs, 2H), 7.25 (bs, 3H),4.30-4.10 (m, 2H), 3.65-3.48 (bs, 1H), 2.20-1.15 (m, 17H);13C NMR (CDCl3) δ 153.0, 146.7, 133.4, 129.1, 127.1, 79.3, 57 .7,52.7, 45.0, 31.4, 27.5, 27.4, 24.9, 24.1. Anal. Calcd for C18-H 25NO 2Se: C, 59.0; H, 6.9; N, 3.9. Found: C, 58.9; H, 6.9; N,4.5.

The minor diaster eomer of 17 was obtained as a white solidsimilarly from the minor diastereomer of phenylselenide 15 :mp 104-105 °C; [R]22

D +71° (c 1.0, CHCl3); 1H NMR (CDCl3)δ 7.65 (bs, 2H), 7.22 (bs, 3H), 4.70-4.20 (m, 2H), 3.40 (bs, 1H),2.20-1.30 (m, 17H); 13C NMR (CDCl3) δ 152.7, 133.5, 130.3,128.6, 126.9, 79.1, 57.2, 52.4, 47.0, 29.7, 28.2, 27.4, 26.6, 22.9.

Anal. Calcd for C18H 25NO 2Se: C, 59.0; H, 6.9; N, 3.9. Found:C, 58.9; H, 7.2; N, 3.8.

(1 R ,5S )-8-( tert -Butyloxycarbonyl)-8-azabicyclo[3.2.1]-2-octen e ((+)-12). From 17: To a solution of 17 (1.00 g, 2.73mmol) in THF (35 mL) at 0 °C was a dded dropwise a solutionof NaIO4 in water (35 mL). The reaction mixture was stirredat r oom temperature for 1 h. The THF was evaporated un derreduced pressure at r oom temperatur e, and the remainder waspartitioned between water and CH 2Cl 2 (50 mL). The aqueousphase was further extracted with CH 2Cl 2 (3 × 50 mL), andthe combined organic phase was dried, filtered, an d evapo-rated. Chromatography of the residue, eluting with CH 2Cl 2,gave (+)-12 as a colorless oil (520 mg, 91%); spectral andchromatographic data were identical to those reported a bove.

F r o m (-)16. To a s olut ion of (-)-16 (50 mg, 0.41 mm ol) indry toluene (2.0 mL) was added dropwise 1-chloroethyl chlo-

roformate (0.70 mL, 6.78 mmol). The resu lting solution wasrefl u xed for 1 6 h an d t h en evap orat ed . T h e res id u e w aschromatographed (10% MeOH/CH 2Cl 2) to give an oil that wasdissolved in MeOH (2.0 mL) and refluxed for 16 h . Evapora-tion left a white foam, which was redissolved in MeOH (2.0mL); Et 3N (44 µL, 0.365 mmol) was added dropwise, followedby stirring for 10 m in; and th en (BOC)2O (159 mg, 0.73 mm ol)was added. The reaction mixture was stirred at r oom tem-perature for 14 h a nd then evaporated. Chromatography of the resulting residue (1/2 EtOAc/hexanes) gave (+)-12 a s acolorless oil (26 mg, 32% from 16 ), which was identical to th ecompound obtained from 17 above.

E t h y l ( 3 aS ,3b R ,5a S ,6 aS )-7-( tert -Butyloxycarbonyl)-7-azabicyclo[3.2.1]octano[2,3- d ] i s o o x a z o l e - 3 - c a r b o x y l a t e((-)-18). To a solution of (+)-12 (1.00 g, 4.78 mmol) in THF(20 mL) was added a solution of Na 2CO 3‚H 2O (12.32 g, 99.4

(23) Barton, D. H. R.; Bridon, D.; Ferna ndez-Picot, I.; Zard, S. Z.Tetrahedron 1987, 43 , 2733.

(24) Sharpless, K. B.; Young, M. W. J . Or g. Ch e m. 1975, 40 , 947.




mmol) in H 2O (40 mL). To this stirred mixture was a ddedeth yl chlorooximidoacetat e (14.49 g, 95.56 mmol)18 in THF (40mL ) at 0 . 3 9 mL / h w i t h a s y ri n g e p u mp , an d s t i rr i n g w ascontinued at room t emperature for 16 h. The aqueous layerw as ex t ract ed w i t h E t 2O (5 × 60 mL), and the combinedorganic layer was dried, filtered, and evaporat ed. The residuewas chroma tographed, elut ing with 1/2 EtOAc/hexan es, to give(-)-18 as a colorless oil (1.22 g, 78%): [R]22

D -20° (c 1.0,CHCl3); IR (CHCl3) 1740, 1685 cm-1; 1H N MR (CDCl3) δ 1.39(t , J ) 7.2, 3H), 1.42 (s, 9H), 1.55-1.90 (m, 2H), 1.9-2.2 (bs,4H), 3.4-3.6(m, 1H), 4.0-4.6 (m, 3H), 4.92 (bs, 1H), 5.24 (dd, J ) 8.0, 18.2, 1H); 13C NMR (CDCl3) δ 13.8 (3), 27.3 (2), 28.0(3), 29.1 (2), 30.3 (22), 36.0 (2), 49.6 (1), 50.5 (1), 51.2 (1), 53.3(1), 62.3 (2), 76.7 (1), 77.7 (1), 79.7 (0), 151.6 (0), 152.4 (0),153.0 (0), 160.3 (0). Anal. Calcd for C16H 24NO 25: C, 59.2; H,7.4; N, 8.6. Found: C, 59.3; H, 7.3; N, 8.9.

E n a n t i o m e r (+) -1 8 ( s t ru c t u r e n o t s h o w n ) : [R]25D +12 °

(c 1.0, CHCl3); spectral and chromatographic properties identi-cal with (-)-18 .

(3 aS ,3 b R ,5 aS ,6 aS )-7-( t er t - B u t y l o x y c a r b o n y l ) - 7 - a z a -bicyclo[3.2.1]octano[2,3- d ]isooxazole-3-carboxylic Acid((-)-19). To a solution of (-)-18 (795 mg, 2.45 mmol) in EtOHat 0 °C was added 10% aqueous NaOH (35 mL) dropwise. Thereaction mixture was stirred at 0 °C for 1 h and then at roomtempera tur e for 1.5 h. The resulting clear solution was cooledto 0 °C, diluted with H 2O (45 mL), and acidified to pH 5.0 bydropwise addition of cold 10% HCl an d t hen it was extracted

with 1/3 i-PrOH/CHCl3 (7 × 45 mL). The combined organicphase was dried, filtered, and evaporated to give a hygroscopicwhite foam ((-)-19 , 700 mg, 96%): [R]22

D -17.5° (c 1.0, CHCl3);1H NMR (CDCl3) δ 1.44 (t, J ) 7.2, 3H), 1.50-2.10 (m, 6H),3.40-3.60 (m, 1H), 4.14 and 4.35 (bs, 1H), 4.92 and 5.05 (bs,1H), (5.16 (q, J ) 8.5, 1H); 13C NMR (CDCl3) δ 24.7 (3), 27.4an d 28.5 (2), 49.8 (1), 51.3 and 52.9 (1), 77.2 an d 78.0 (1), 80.7(0), 152.0 (0), 152.7 an d 153.2 (0), 161.8 (0). Anal. Calcd forC14H 20N 2O5‚H 2O: C, 53.5; H, 7.0; N, 8.9. Found: C, 53.7; H,7.0; N, 8.7.

E n a n t i o m e r (+)-19 (structure not sh own ): [R]22D +17.2°

(c 1.0, MeOH); spectral a nd chroma tographic properties identi-cal with (+)-19 .

(1 R ,2 R ,3S ,5S )-8-( tert-Butyloxycarbonyl)-2-cyano-3-hy-droxy-8-azabicyclo[3.2.1]octane ((-)-20). Acid (-)-19 (5.96g, 20.11 mmol) under N 2 was heated in an oil bath at 105-

110 °C for 40 m in. After being cooled to room t empera tur e,the solid residue was chromatographed (10% MeOH/CH 2Cl2)to give (-)-20 as a white solid (4.06 g, 80%): mp 139-140 °C;[R]23

D -9.0° (c 1.0, CHCl3); 1H NMR (CDCl3, 58 °C) δ 1.50 (s,3H), 1.58-1.65 (dd, 2H), 1.79-2.05 (m, 4H), 2.42 (bs, 1H), 3.07(dd, 1H), 4.15 (m, 1H), 4.42 (m, 1H), 4.61 (m, 1H); 13C NMR(CDCl3) δ 27.9, 28.3, 38.2, 41.9, 52.1, 54.0, 63.1, 80.5, 117.4,152.5. Anal. Calcd for C13H 20N 2O3: C, 61.9; H, 8.0; N, 11.1.Found: C, 61.6; H, 8.2; N, 11.2.

E n a n t i o m e r (+) -2 0 ( s t ru c t u r e n o t s h o w n ) : [R]24D +7.2°

(c 1.0, CHCl3); spectral and chromatographic properties identi-cal with (+)-19 .

(1 R ,2 R ,3S ,5S )-8-( tert -Butyloxycarbonyl)-3-hydroxy-8-a z a b i c y c l o [ 3 .2 .1 ] o c t a n e -2 -c a r b o x a m i d e ( (+)-21). To asolution of (-)-20 (3.18 g, 12.60 mmol) in acetone (60 mL) wereadded H 2O (30 mL) and 10% Na 2CO 3 (60 mL). To the resulting

solution at 0 °C was added 30% aqueous H 2O2 dropwise (30mL), and the r eaction m ixture was stirred at room t empera-ture for 24 h a nd then concentra ted to about 100 mL. Theremaining aqueous phase was extracted with 1/3 i-PrOH/ CHCl3 (6 × 300 mL), and the combined organic phase wasdried, filtered, and evapora ted. Recrystallization from THF/ hexanes gave (+)-21 (3.20 g, 94%): mp 153-154 °C; [R]22

D

+18.4° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 1.45 (s, 3H), 1.64-2.02 (m, 6H), 2.79 (dd, 1H), 4.15 (bs, 1H), 4.38 (bs, 1H), 4.65(bs, 1H), 5.63 (bs, 2H), 7.28 (bs, 1H ); 13C NMR (CDCl3) δ 27.7,28.2, 39.0, 49.5, 52.8, 54.1, 64.4, 80.1, 153.4, 175.7. Anal. Ca lcdfor C13H 20N 3O3: C, 57.8; H, 8.3; N, 10.4. Found: C, 58.0; H,8.3; N, 10.6.

E n a n t i o m e r (-)-21 (structure not sh own ): [R]22D -18.0°


(1 R ,2 R ,3S ,5S)-8-( tert-Butyloxycarbonyl)-3-(benzoyloxy)-8-azabicyclo[3.2.1]octane-2-carboxamide ((-)-22). A solu-tion of (+)-21 (1.85 g, 6.83 mmol), benzoic anhydride (3.09 g,13.66 mmol) and DMAP (1.83 g, 15.03 mmol) in CH 2Cl 2 (16mL) was stirred at r oom t emperature for 12 h. The reactionmixture was diluted with Et 2O (300 mL), and the organic layerwas washed with H 2O (2 × 230 mL), 10% aqueous NaHCO3

(80 mL), and then H 2O (230 mL), dried, filtered, and evapo-rated. Chromatography of the crude solid with 5% MeOH/ CH 2Cl 2 gave (-)-22 (2.58 g, 96%): mp 207-208 °C; [R]22

D

-29.8° (c 1.0, CHCl3); 1H NMR (CDCl3, 58 °C) δ 1.43 (s, 3H),

1.73 (dd, 2H), 1.89-2.01 (m, 4H), 2.53 (ddd, 1H), 2.98 (dd, 1H),4.45 (bs, 1H), 5.43 (m, 1H), 5.91 (bs, 1H), 6.40 (bs, 1H), 7.36(t, 2H), 7.51 (t, 1H), 7.97 (d, 1H); 13C NMR (CDCl3) δ 27.3,28.1, 28.2, 33.6, 49.0, 52.1, 54.8, 67.1, 79.6, 128.2, 129.5, 1290.7,132.9, 152.9, 165.8, 171.6. Anal. Calcd for C20H 26N 2O5: C,64.2; H, 7.0; N, 7.5. Found: C, 64.1; H, 7.0; N, 7.3.

E n a n t i o m e r (+)-22 (structure not sho wn ): [R]22D +28.1°


(1 R ,2 R ,3S ,5S )-3-(Benzoyloxy)-8-azabicyclo[3.2.1]octane-2 -c a r b o x a m i d e ( (-)-23). To a solution of (-)-22 (374 mg,1.0 mmol) in CH 2Cl 2 was added TFA (2.7 mL) dropwise, thes o l u t i o n w as s t i rred at ro o m t emp erat u re fo r 1 h , an d t h ereaction mixture was evaporated to give a residue that waspartitioned between CH2Cl 2 a n d s a t u r a t e d N a H C O3. Th eaqueous phase was further extracted with CH 2Cl2 (3 × 20 mL),

an d t h e comb in ed org an ic p h as e w as d ried , f il t ered , an devaporat ed. Chromatography of the r esidue with 10% MeOH/ CH 2Cl 2 gave (-)-23 (247 mg, 90%): mp 163-164 °C; [R]22

D

-43.5° (c 1.0, CHCl3); 1H N MR (CDCl3) δ 1.74-2.12 (m, 6H),2.88 (d, J ) 7.1, 1H), 3.09 (bs, 1H ), 3.68 (d, J ) 2.5, 1H), 3.74(d, J ) 5.0, 1H), 5.36 (m, 1H ), 6.01 (bs, 1H), 7.38 (t, 2H), 7.52(t, 1H), 7.97 (d, 1H); 13C NMR (CDCl3) δ 28.2, 29.2, 34.8, 49.2,53.3, 56.3, 66.7, 128.2, 129.5, 129.9, 132.9, 165.8, 174.0. Anal.Calcd for C15H 18N2O3: C, 65.7; H, 6.6; N, 10.2. Found: C, 65.5;H, 6.8; N, 10.1.

E n a n t i o m e r (+)-23 (structu re not sh own ): [R]22D +36.0°


(1 R ,2 R ,3S ,5S )-3-(Benzoyloxy)-8-methyl-8-azabicyclo-[3.2.1]octane -2-carboxamide ((-)-24). To a solution of (-)-23 (325 mg, 1.19 mmol) in CH 3CN (25 mL) were added 37%

aqueous formaldehyde solution (0.49 mL, 6.13 mmol) andNaBH 3CN (0.123 g, 2.04 mmol), a nd the suspension wasstirred at room tempera ture for 1 h. The reaction mixture wasthen acidified to pH 6 with glacial HOAc, stirred for 0.5 h,basidifed to pH 8-9 with aqueous NH 4OH, and partitionedbetween CH 2Cl2 (200 mL) and sa tur ated a queous NaH CO3 (50mL). The aqueous phase was further extracted with CH2Cl2

(4 × 50 mL), and the organic layers were combined, dried,filtered, an d evaporated to give a yellowish oil. Chromat og-raphy (gradient from 10%-20% MeOH/CH 2Cl 2 with 0.5%E t 3N) gave (-)-24 as a hygroscopic foam (257 mg, 75%): [R]24

D

-19.5° (c ) 1.0, CHCl3); 1H NMR (CDCl3) δ 1.66-1.77 (m, 2H),2.04-2.19 (m, 4H), 2.24 (s, 3H), 2.88 (d, J ) 7.4, 1H), 3.27 (bs,1H), 3.36 (d, J ) 5.9, 1H), 5.32 (m, 1H ), 6.44 (bs, 1H), 7.38 (t,2H), 7.50 (t, 1H ), 8.00 (d, 1H), 9.29 (bs, 1H); 13C NMR (CDCl3)δ 24.6, 25.5, 35.4, 40.1, 51.0, 60.1, 62.8, 65.5, 127.9, 128.0,

129.4, 130.0, 132.6, 165.6, 173.6. Anal. Calcd for C 16H 22N 2-O4‚H 2O: C, 62.73; H, 7.24; N, 9.14. Foun d: C, 62.47; H, 6.98;N, 9.48.

E n a n t i o m e r (+)-24 (structu re not sh own ): [R]22D +19.0°


(1 R ,2 R ,3S ,5S )-3-(Benzoyloxy)-8-methyl-8-azabicyclo-[3.2.1]octan e-2-carboxy lic Acid ((-)-25). To a solution of (-)-24 (96 mg, 0.33 mmol) in a mixture of glacial HOAc andAc2O (1/2, 3.75 mL) at 0 °C was added NaNO 2 (230 mg, 3.33mmol). The suspension was stirred at 0 °C for 16 h an d roomt emp erat u re for 8 h an d t h en ev ap orat ed t o d ry n es s an dtriturated with 20% MeOH/CH 2Cl 2. The resulting solutionwas then concentr ated, and th e residue was chromat ograph edwith 20% MeOH/CH 2Cl2 to give (-)-25 (89 mg, 93%): mp 191-192 °C (lit.21 mp 196-197 °C, lit.25 mp 1 94-195 °C); [R]22

D




-48.3° (c 1.6, H 2O) [lit.25 -45.39° (50% aq EtOH)]; 1H NMR(CDCl3) δ 1.88-2.01 (m, 2H ), 2.15-2.32 (m, 4H ), 2.50 (s, 3H),3.05 (dd, J ) 4.6, 6.6, 1H), 3.49 (bs, 1H), 3.61 (bs, 1H), 5.38(m, 1H), 7.40 (t, 2H), 7.53 (t, 1H), 8.02 (d, 1H); 13C N MR(CDCl3) δ 24.2, 25.4, 34.5, 38.6, 48.7, 60.6, 63.7, 64.4, 128.3,129.5, 129.8, 133.1, 165.7, 172.3.

E n a n t i o m e r (+)-25) (structure not shown): [R]22D +47°

(c 1.0, H 2O); spectral and chromatographic properties identicalwith (+)-24 .

M e t h y l ( 1 R ,2 R ,3S ,5S )-3-(Benzoyloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane -2-carboxy late ((-)-Cocaine). Into a

solution of (-)-25 (80 mg, 0.28 mmol) in CH 2Cl 2 (6 mL) waspassed CH 2N 2 [generated by dropwise addition of 4 N NaOHsolution (10 mL) to a solution of Diazald (920 mg, 4.34 mmol)in EtOH (10 mL)] via a N 2 s t ream. W h en t h e react i on w ascomplete (persisten t yellow color), the mixtur e was evaporated.Chromatography of the residue with 5% MeOH/CH 2Cl 2 gave(-)-cocain e (80 mg, 95%): mp 93-94 °C (lit.21 mp 98 °C); [R]23

D

-16.2° (c 1.2, CHCl3); er 100% (chiral HPLC, Chiralpak ODcolumn, 10% i-PrOH/hexanes, 1 mL/min at 274 nm, t R 5.02min); 1H NMR (CDCl3) δ 1.73 (m, 2H), 1.88 (m, 1H), 2.10-2.19 (m, 2H), 2.24 (s, 3H), 2.44 (m, J ) 2.6, 11.8, 1H), 3.03 (t,

3H), 3.30 (bs, 1H), 3.57 (d, 1H), 3.72 (s, 3H), 5.25 (m, 1H), 7.42(t, J ) 7.5, 2H), 7.54 (t, J ) 7.6, 1H), 8.02 (dd, J ) 1.3, 7.5,1H);13C NMR (CDCl3) δ 25.2, 25.4, 35.5, 41.1, 50.2, 51.4, 61.6, 64.8,66.9, 128.3, 129.7, 130.3, 132.9, 166.2, 170.7. Authenticnatural (-)-cocaine was prepared from a solution of (-)-cocainehydrochloride (280 mg) in H 2O (2.0 mL) at 0 °C, which wasb as ifi ed t o p H 8-9 by dropwise addition of concentra tedaqueous NH 4OH, extraction with Et 2O (5 × 20 mL), drying,filtering, and evaporating to give a white solid (237 mg, 95%):mp 9 3-94 °C (lit.21 mp 98 °C); [R]23

D -17.2° (c 1.0, CHCl3),-28.4° (c 1.0, EtOH); er 100%.

(+)-Cocaine: mp 93-94 °C (lit.8 mp 98 °C); [R]24D +16.5°

(c 1.0, CHCl3) (lit.8 +15.5°); er 98/2 (chiral H PLC, Chir alpak OD column, 10% i-PrOH/hexanes, 1 mL/min at 274 nm, t R 7.92min); spectra l and chromatographic properties identical with(-)-cocaine.

A c k n o w l e d g m e n t . J.C. thanks the CIRIT, Gener-alitat Cata lunya, Spa in, for a Postdoctoral Fellowship.We are grateful to Dr. Rao Rapaka and the NationalInsti tute on Drug Abuse for a generous gift of (-)-cocaine hydr ochloride.

JO980153T(25) Lasslo, A.; Marine, W. M.; Waller, P. D. J. Org. Chem. 1956 ,

21 , 958.


ronghui lin et al- enantiospecific synthesis of natural (-)-cocaine and unnatural (+)-cocaine from...

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