ORGANIC LETTERS
Facile and Enantiospecific Syntheses of (6S ,7 ,7R )-6-Chloro-7-benzyloxy-, )-6-Chloro-7-benzyloxy-, (7 S )-Halo-, )-Halo-, and (7S )-Hydroxy-cocaine )-Hydroxy-cocaine and Natural ()-Cocaine from D-()-Ribose
2011 Vol. 13, No. 11 2916–2919
Tony K. M. Shing* and King H. So Department of Chemistry and Center of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
[email protected] Received April 13, 2011
ABSTRACT
First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D -()-ribose via a trans -acetonide -acetonide controlled endo -selective -selective intramolecular nitrone-alkene nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.
Notorious tropane alkaloid ( )-cocaine (1)1 is a powerful stimulant of the central nervous system, and its neuronal reinforcing properties are attributable to its inhibit inhibition ion 2 of dopamine reuptake. Cocaine abuse has been a pivotal medica med icall pr probl oblem em in th thee wor world,and ld,and 1.6mill 1.6millioncurr ioncurrentuser entuserss 3 by age 12 are estimated in the U.S. Furthermore, cocaine abuse has indirectly enhanced the spread of human immunodeficiency munodefic iency virus infection and drug-re drug-resistant sistant tube4 rculcosis. To dat date, e, an effe effectiv ctivee medic medicatio ation n to trea treatt pat patient ientss addic ad dicte ted d to coc cocai aine ne is st still ill elu elusi sive ve an and d re resea searc rch h ef effo fort rt on the synthes syn thesis is of coca cocaine ine anal analogue oguess for bioe bioeval valuati uation on must continue cont inue.. Trem Tremendo endous us stu studies dies have been made on C2 and C3 cocaine analogues, but C6 and C7 analogues are (1) Simoni, Simoni, D.; Ron Rondan danin,R.; in,R.; Rob Robert erti, i, M. In Targe Targets ts in Heter Heterocyc ocyclic lic Systems; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of Chemistry: Roma, 1999; Vol. 3 , pp 147 183. (2) (a) Ritz, M. C.; Lamb, R. J.; Goldberg, S. R.; Kuhar, M. J. Science 1987 1987,, 237 , 1219–1223. (b) Kuhar, M. J.; Ritz, M. C.; Boja, J. W. Trends Neurosci. 1991, 14,, 299–302. (c) Koob, G. F.; Bloom, F. E. 1991, 14 Science 1988 242,, 715–723. 1988,, 242 (3) Substance Substance Abuse and Mental Health Services Administration. Administration. (2010). Results from the 2009 National Survey on Drug Use and Health: Vol. I. Page 1. Summary of National Findings (Office of Applied Studies, NSDUH Series H-38A, HHS Public Publication ation No. SMA 10 4586Findings), Rockville, MD. http://oas.samhsa.gov/NSDUH/2k9NSDUH/2k9ResultsP.pdf. (4) Herman, B. H.; Elkashef, A.; Vocci, F. Drug Discovery Today: Therapeutic Strategies 2005 2,, 87–92. 2005,, 2
10.1021/ol2009686 r 2011 American Chemical Society Published on Web 05/05/2011
relatively underexplo underexplored. red.5,6 This is because C2 and C3 analog ana logues ues wer weree re readi adily ly der derive ived d fr from om ()-co )-cocain cainee (1) whereas access to C6 and C7 analogues must rely on total synthesis.. Existing C6 and C7 analogues were synthesized synthesis as racemates by modifying the classical Willst€ atter synthatter 5a,b esiss of co esi cocai caine ne.. Resoluti Reso lution on is requ required ired to pro produce duce enantiopure analogues which hampers the development of a pharmacotherapy. Recently, Davis et al. described the asymmetric synthesis of cocaine C1-alkyl analogues using essentially an asymmetric variant of the Tufariello (5) For some reports of synth synthesis esis of cocai cocaine ne analo analogues, gues, see: (a) racemic 6 β- and 7 β-methoxylated cocaine: Simoni, D.; Stoelwinder, J.; Koziko Koz ikowsk wski, i, A. P.;Johns P.;Johnson,K. on,K. M.;Bergm M.;Bergmann ann,, J. S.;Ball, R. G. J. Med Med.. Chem. 1993, 36,, 3975–39 3975–3977. 77. (b) (b) rac racemi emicc 6 β- and 7 β-hydroxylated 1993, 36 cocaine: cocai ne: Kozikowski, Kozikowski, A. P.; Simoni, D.; Manf Manfredin redini, i, S.; Roberti, M.; Stoelwinder, J. Tetrahedron Lett. 1996 1996,, 37 , 5333–5336. (c) enantiopure C1-alkyl cocaine analogues: Davis, F. A.; Theddu, N.; Edupuganti, R. Org. Lett. 2010 12,, 4118–4121. 2010,, 12 (6) For some reports of synthesis of C2 and C3 tropane analogues, see: (a) Carroll, F. I.; Blough, B. E.; Mascarella, S. W.; Navarro, H. A.; Eaton, J. B.; Lukas, R. J.; Damaj, M. I. J. Med. Chem. 2010 2010,, 53 53,, 8345– 8353. 835 3. (b)Steho (b)Stehouwe uwer, r, J. S.; Jarkas Jarkas,, N.; Zen Zeng, g, F.; Voll, Voll, R. J.; Wil Willia liams, ms, L.; Camp, V. M.; Malveaux, E. J.; Votaw, J. R.; Howell, L.; Owens, M. J.; Goodman, M. M. J. Med. Chem. 2008 51,, 7788–7799. (c) Zhang, S.; 2008,, 51 Izenwasser, S.; Wade, D.; Xu, L.; Trudell, M. L. Bioorg. Med. Chem. 14,, 7943–7952. (d) Bois, F.; Baldwin, R. M.; Kula, N. S.; Baldes2006,, 14 2006 sarini, R. J.; Innis, R. B.; Tamagnan, G. Bioorg. Med. Chem. Lett. 2004 2004,, 14,, 2117–2120. 14 2117–2120. (e) Zhao, L.; Johnson, K. M.; Zhang Zhang,, M.; Flippe FlippennAnderson, J.; Kozikowski, A. P. J. Med. Chem. 2000 43,, 3283–3294. 2000,, 43
synthesis synthes is of coca cocaine. ine.5c Ena Enanti ntiospe ospecifi cificc synt synthes heses es of C6 and C7 coc cocain ainee an analo alogu gues es hav havee no nott bee been n ad addre dress ssed ed in the literature, and herein, we report facile and efficient syntheses of (6S (6S ,7R ,7R)-6-chloro-7-benzyloxy-, (7S (7S )-hydroxy-, )-hydroxy-, (7 ( 7S ))chloro-, (7S (7S )-methanesulfonyl )-methanesulfonyloxy-, oxy-, and (7 (7S S )-iodo-cocaine )-iodo-cocaine analogues from inexpensive D-()-ribose (2) via a trans trans-acetonide controlled controlled endo-selective endo-selective intramolecular nitronealkene cycloaddition (INAC) reaction7 as the key step. The cocaine framework in these analogues was corroborated by conversion into natural ( )-cocain )-cocainee (1).8 Our retrosynthesis is based on the construction of a seven-membered seven-memb ered bridged carbocycle 3 via a key endoendo7 selective INAC reaction of nitrone 4, which is readily prepared from D -()-ribose (2) (Scheme 1). Our previous work7 has ind indicat icated ed that hept-6-enos hept-6-enoses es cont containi aining ng a 3, 4-trans 4trans-acetonide -acetonide direct the INAC reactions to give endo cycloadducts cycloaddu cts (cyclohepta (cycloheptanes) nes) exclusive exclusively. ly. The stereoch stereochememistry of the ring junction is also controlled by the trans trans-acetonide whereby the newly formed CN bond is anti is anti to to the C3 alkoxy group. Hence, nitrone 4 is expected to give the bri bridged dged cycl cyclohep oheptane tane 3 and the meth methoxyc oxycarb arbonyl onyl group must be in the β -face as shown, a consequence of the stereospecificity stereospecificity of the pericyclic reaction (E (E -alkene -alkene to β-methoxycarbony group). The C1, C2, and C3 stereocenters in the cocaine analogues would therefore be established in one synthetic operation, i.e. the INAC reaction.
its E -geometry. its E -geometry. Regioselective acid hydroly hydrolysis sis of the terminal acetonide in 6 followed by glycol cleavage oxidation oxidation12 gave aldehyde 7, which condensated with MeNHOH to generate nitrone 4. INAC reaction produced a mixture of inseparable insepara ble seven-mem seven-membered bered endo endo-cycloadduct -cycloadduct 3 and sixmemberedexo membered exo-cycloadduct -cycloadduct 8 in a rat ratio io of 20: 20:1, 1, re resp spect ectiv ively ely 1 ( H NMR spectral analysis). It is noteworthy that an R, -unsatur aturated ated este esterr as the dipo dipolaro larophil philee did did not indu induce ce the β-uns formatio form ation n of an endo-cyc endo-cycload loadduct duct anti anticipa cipated ted from an electronic effect,13 thereby confirming the steric control of the endo-mode endo-mode of cycloaddition is attributable to the trans-ace trans -acetoni tonide de grou group. p. Thi Thiss mixt mixture ure of inse insepara parable ble cycloadducts 3 and 8 was then subjected to TFA hydrolysis to yield a mixture of diols 9 and 10, respective respectively, ly, separable on column chromatography. The structures of 9 and 10 were confirmed by X-ray crystallography. crystallography.14
Scheme 2. Syntheses of Cocaine Analogues 13, 14, 15, and ()Cocaine (1)
Scheme 1. Retrosynthesis of Cocaine Analogues
The syntheses of cocaine analogues and ( )-cocaine (1) are shown in Scheme 2. D-()-Ribose (2) was transformed into alke alkene ne 5 in thre threee step stepss invo involvin lving g aqu aqueous eous indium 9 allylation, acet acetonat onation, ion, and benzy benzylati lation on as repo reported rted previously.10 Cross metathesis of 5 with methyl acrylate catalyzed by a second generation Grubbs catalyst11 afforded R, β -unsaturated urated ester 6 in an excellent yield. The β-unsat large coupling constant (J (J = = 15.7 Hz) of the two alkene signals observed in the 1 H NMR spectrum of 6 6 confirmed (7) (a)Shing (a)Shing,, T. K.M.; Won Wong,W. g,W. F.;Ikeno F.;Ikeno,, T.;Yamad T.;Yamada,T. a,T. Chem.; Eur. J. 2009 Eur. 15,, 269 2693–2 3–2707 707.. (b)Shing (b)Shing,, T. K. M.;Wong,A. W. F.;Ikeno F.;Ikeno,, 2009,, 15 T.; Yamada, T. J. T. J. Org. Chem. 2006 71,, 3253–3263. 2006,, 71 (8) For previous asymmetric syntheses of cocaine, see: (a) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998 63,, 4069–4078. (b) Lee, 1998,, 63 J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000 2000,, 65 65,, 4773–4775. (c) Mans, D. M.; Pearson, W. H. Org. Lett. 2004 6,, 3305–3308. (d) Davis, F. A.; 2004,, 6 Theddu, N.; Edupuganti, R. Org. Lett. 2010 2010,, 12 12,, 4118–4121. (e) Cheng, G.; Wang, X.; Zhu, R.; Shao, C.; Xu, J.; Hu, Y. J. Org. Chem. 2011 76,, 2011,, 76 2694–2700. (9) Prenner, R. H.; Schmid, B. W. Liebigs Ann. Chem. 1994 1994,, 73–78. (10) Shing, Shing, T. K. M.; Wong, Wong, W. F.; Ikeno, Ikeno, T.; Yamada Yamada,, T. Org. Lett. 9,, 207–209. 2007,, 9 2007 (11) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000 122,, 3783–3784. 2000,, 122
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With the diol 9 in hand, it was regioselec regioselectively tively esterified with Tf 2O and the monotriflate ester formed was then treat tre ated ed wit with h bas basic ic Me MeOH OH to giv givee epo epoxid xidee 11. Rane Raney-Ni y-Nickel ckel (12) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997 62,, 2622–2624. 1997,, 62 (13) Our studies showed that the INAC of nitrone 22 , bearing an R , cis-acetonide, -acetonide, gave exo gave exo-cycloadduct -cycloadduct 23 exclu β-unsaturated ester and a cis sively. The regio- and stereochemistry was confirmed by X-ray crystallographic analysis of its benzoate 24 (CCDC 681970). 2917
mediated hydrogenolysis of 11 11 yielded azetidine-diol 12. The NO bond of 11 11 was first cleaved to give the corresponding amine, which opened the epoxy ring at C6 to afford bicyclo[4.1.1] diol 12.15 The formation of a bicyclo[4.1. [4. 1.1] 1] sk skele eleto ton n in inst stead ead of th thee tr tropa opane ne st stru ructu cture re (by at atta tackcking C5) mi might ght be ra ratio tional nalize ized d by Ba Baldw ldwin in’s ’s ru rule, le,16 in whi which ch thee 4th 4-Exo Exo--Tet cycliz cyclizatio ation n (lea (leading ding to a bicy bicyclo[ clo[4.1. 4.1.1] 1] skeleton) is more favored than the 5-Endo 5-Endo--Tet Tet cyclization (leading to a tropane skeleton). skeleton). This azetidine-diol azetidine-diol 12 was then transformed into (6S (6S ,7R ,7R)-6-chlor )-6-chloro-7-benzy o-7-benzyloxy loxy cocaine cai ne (13) by a one one-p -pot ot rea react ction ion of ben benzoy zoylat lation ion and mesylation in excellent overall yield. The C3-OH of 12 was first benzoylated, benzoylated, and the remaining free C5-OH in 16 was th then en mes mesyla ylated ted (Sc (Schem hemee 3). As th thee aza aza-b -bri ridge dge is isanti anti to to the C5-O C5-OMs Ms grou group, p, neig neighbo hborin ring-gr g-group oup part particip icipatio ation n would assist the mesylate ion in 17 to dissociate easily, giving givi ng ammo ammoniu nium m ion 18.17 Then the nucl nucleoph eophilic ilic chlo chloride ride ion attacke attacked d th thee C6R position position of 18 to fu furni rnish sh (6 (6S S ))chloride 13. The release of ring strain from the bicyclo[4.1.1] skeleton to the tropane ring is probably the driving force for the attack at C6 instead of C5.
Scheme 3. Proposed Mechanism from 12 to 13
Thus, (6 Thus, (6S S ,7R ,7R)-6-chlo )-6-chloro-7-ben ro-7-benzyloxy zyloxy cocaine was obtained for the first time in 12 steps with 26% overall yield from 13 in the presence of D-()-ribose (2). Hydrogenolysis of 13 Raney-Nickel provided the first synthesis of another cocaine analogue, (7S (7S )-hydroxy )-hydroxy cocaine (14) (13 steps, 19% from 2). Th This is alc alcoho oholl 14 is th thee 77-ep epim imer er of th thee kn know own n (7 (7R R)5b,18 1 hydroxy cocaine. The H NMR spectrum of (7R (7R)hydroxy cocaine (obtained from Prof. K. D. Janda) was found to be very similar to that of 14 14, except for their H7 splitting pattern (dd in (7R (7 R)-hydroxy-cocaine and ddd in our 14), which is in good agreement with the observations on its structurally related compounds in the literature. 5a The third ()-cocaine analogue, (7S (7S )-chloro-cocaine )-chloro-cocaine (15) (14 st steps eps,, 17% fr from om 2), was synt synthesi hesized zed by reac reacting ting 14 with MsClat70 C in a sea sealedtube ledtube.. Th Thee mes mesyla ylate te 19 form formed ed was displaced readily readily by a chloride ion at an elevated temperature tu re to gi give ve 15 (Sc (Schem hemee 4). Th Thee pre presen sence ce of a chl chlor orine ine at atom om in 15 was agai again n conf confirm irmed ed by mass spec spectro trometr metry. y. Fro From m the 1 H NMR sp spect ectru rum m of 15, th thee S -stereo -stereochem chemistr istry y of Cl7 was assign ass igned ed by com compar paring ing its cou coupli pling ng con consta stant nt (J 1,7 6.4 4 Hz Hz)) 1,7 = 6. 5a,b with that in stru structur cturally ally rela related ted compou compounds. nds. The retention of configuration upon the displacement reaction of (7S (7 S )-mesylate )-mesylate 19 by a chloride ion might be rationalized by th thee pro propo posed sed mec mechan hanis ism m sh shown own in Sch Scheme eme 4. The neighbor neig hboringing-grou group p part particip icipatio ation n of the azaaza-bri bridge dge enco encoururaged the dissociation of the mesylate in 19 to form ammonium ion 20 and the chloride ion then attacked from the C7R-face of 20 (7 S )-chloro-cocaine )-chloro-cocaine (15). 20, furnishing (7S
Scheme 4. Proposed Mechanism from 14 to 15
The presence of a chlorine atom in 13 was confirmed by mass spectrometry. The tropane skeleton in 13 was assigned sign ed by 1H1H con connec necti tivit vities ies fr from om th thee 2D COS COSY Y NM NMR R spect sp ectru rum m an and d th thee st stro rong ng NO NOE E cor corre relat lation ion bet betwee ween n H6 and H7 supported the S the S -stereochemistr -stereochemistry y of the chloride at C6.
(14) Please refer to Supporting Information for X-ray structures of 9 (CCDC 737152) and 10 (CCDC 752110) . (15) The The struc structure ture of azetid azetidine-d ine-diol iol 12 was confirmed confirmed by X-ray crystallographic analysis of its tribenzoate derivative (CCDC 798275). Its preparation is described in the Supporting Information. (16) Baldwin, J. E. J. E. J. Chem. Soc., Chem. Commun. 1976 1976,, 734–736. (17) The existence of such ammonium ion 18 was supported by the racemization of acetate product upon acetylation of L-2R-tropanol as reported by Archer et al.; see: Archer, S.; Lewis, T. R.; Bell, M. R.; Schulenberg, J. W. J. Am. Chem. Soc. 1961 83,, 2386–2387. 1961,, 83 2918
The cocaine framework in these analogues was corroborated by the transformation of chloride 15 into natural ()-cocaine (1) via Raney-Nickel mediated hydrogenolysis.. Th sis Thee phy physic sical al an and d sp spect ectra rall dat data a of sy synt nthet hetic ic ()-cocaine (1) wer weree in ful fulll acc accor ordan dance ce wit with h th those ose report reported ed in th thee 8a literature. Thus natural ()-cocaine (1) was also synthesized in 15 steps from D-()-ribose (2) with 13% overall yield. The overall yield of this synthetic scheme was found to be higher than the recently reported (þ)-cocaine synthesis (9% overall yield from methyl 4-nitrobutanoate) by Davis et al.5c,19 The lower cost of our starting material (18) The (7R (7R)-hydroxy cocaine had been used to synthesize haptens for immunopharmacotherapy in cocaine abuse; see: Ino, A.; Dickerson, T. J.; Janda, K. D. Bioorg. Med. Chem. Lett. 2007 2007,, 17 , 4280–4283. (19)) (a)Simon (19 (a)Simoneau eau,, B.; Bra Brassa ssard,P. rd,P. Tetrahedron 1988 44,, 1015 1015–1022 –1022.. 1988,, 44 (b) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001 3,, 759–762. 2001,, 3
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ensures ensur es th that at our av avenu enuee is mor moree eco econo nomic mical al an and d our synthetic route has great potential for synthesis of other ()-cocaine analogues analogues..
Scheme 5. Synthesis of ()-Cocaine Analogues 19 and 21
For example, when alcohol 14 was mesylated at room temperature, temperat ure, (7 (7S S )-methanesulfony )-methanesulfonyloxy loxy cocaine ( 19) in in-stead stea d of chlo chloride ride 15 was iso isolat lated ed (Sc (Schem hemee 5). Th This is me mesyl sylat atee 19 readily undergoes displacement reactions with nucleophiles. When 19 reacted with the iodide anion, (7S (7S )-iodo)-iodococaine coca ine (21) was fo form rmed. ed. Th Thee re reten tentio tion n of con confi figur gurati ation on of thee iod th iodid idee in 21 was also rati rational onalized ized by neig neighbo hboring ring-group participation as described previously. This iodide
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believed eved to be reactive reactive towa toward rd radi radical cal reactio reactions ns hence 21 is beli forming even more ()-cocaine analogues analogues.. To conclude, we have provided a facile, practical, and high hig h yi yield eldin ing g acc accessto essto fiv fivee ()-co )-cocain cainee anal analogue ogues, s, (6 (6S S ,7R ,7R)6-chloro-7-benzylo 6-chloro -7-benzyloxy-, xy-, (7 (7S S )-hydroxy-, )-hydroxy-, (7S (7S )-chloro-, )-chloro-, (7S (7S ))methanes meth anesulfo ulfonylo nyloxy-, xy-, and (7 (7S S )-iodo)-iodo-coca cocaine, ine, in 1215 steps with 1426% overall yields from inexpensive D-ribose. Halo-ana Halo-analogues logues 13, 15, and 21 are also valuable valuable synthetic intermediates which can be elaborated via ionic or radical reactions into a wide variety of cocaine analogues. Research in this direction is in progress. supported Acknowledgment. This work was financially supported by a CUHK direct grant and Center of Novel Functional Molecules. We thank Professor K. D. Janda (The Scripps Research Rese arch Inst Institu itute) te) for kin kindly dly pro providi viding ng the 1H NMR spectrum of (7R (7R)-hydro )-hydroxy xy cocaine for comparis comparison. on. Supporting Information Available. Experimental procedures cedu res and pro produc ductt char charact acteri erizati zation. on. Thi Thiss mat materi erial al is available free of charge via the Internet at http://pubs. acs.org.
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