The first asymmetric synthesis of (-)-morusimic acid D, a 2,3-trans-2,6-cis-2-methyl-6-substituted piperidin-3-ol containing alkaloid is reported. The key steps are the reductive alkylation of N,O-diprotected 3-hydroxyglutarimide, a stepwise reductive alkylation, and an asymmetric aldol-type reaction using a modified Evans chiral auxiliary

Huang, Pei-Qiang

Liu, Liang-Xian

Xu, Wei-Xuan

Yu, De-Sheng

黄培强

Synlett

Xiamen University Institutional Repository

LETTER 1189First Asymmetric Synthesis of Piperidine Alkaloid (–)-Morusimic Acid DAsymmetric Synthesis of (–)-Morusimic Acid DD Sheng Yu,a Wei-Xuan Xu,a Liang-Xian Liu,a Pei-Qiang Huang*a,ba Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of ChinaFax +86(592)2186400; E-mail: pqhuang@xmu.edu.cnb The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of ChinaReceived 4 January 2008SYNLETT 2008, No. 8, pp 1189–1192xx.xx.2008Advanced online publication: 16.04.2008DOI: 10.1055/s-2008-1072737; Art ID: W00408ST© Georg Thieme Verlag Stuttgart · New YorkAbstract: The first asymmetric synthesis of (–)-morusimic acid D,a 2,3-trans-2,6-cis-2-methyl-6-substituted piperidin-3-ol contain-ing alkaloid is reported. The key steps are the reductive alkylationof N,O-diprotected 3-hydroxyglutarimide, a stepwise reductivealkylation, and an asymmetric aldol-type reaction using a modifiedEvans chiral auxiliary.Key words: asymmetric synthesis, N-acyliminium ions, imides, al-dol reaction, piperidines, alkaloids, morusimic acid DSubstituted, hydroxylated piperidines constitute a class ofnatural products exhibiting important bioactivities.1 As akey structural feature shared by many piperidine alka-loids, 2-methyl-6-substituted piperidin-3-ols with differ-ent stereochemical patterns have been the targets ofnumerous synthetic efforts, which have culminated in anumber of methods for the synthesis of these molecules.2–8 Because most of this class of piperidine alkaloids pos-sess a 2,3-cis stereochemistry with either a 2,6-cis-stere-ochemical pattern (A, Figure 1), or a 2,6-transstereochemistry pattern (B), much attention has been de-voted to the construction of cis-2-methylpiperidin-3-olskeleton.3 Only a few methods are available for the syn-thesis of trans-2-methylpiperidin-3-ols,4 although severalmethods have been developed for the syntheses of struc-turally related piperidine alkaloids prosophylline5 and mi-cropine,6 quinolizidine alkaloids clavepictines7 andpictamine,7a as well as decahydroquinoline alkaloid lepa-din D.8 In 2002, two 2,3-trans-2,6-cis-2-methyl-6-substi-tuted piperidin-3-ol containing alkaloids, morusimic acidsC (1) and D (2) were isolated from white ripened fruit ofM. alba grown in Turkey.9In continuation of our studies on the development of pro-tected 3-hydroxyglutarimide-based synthetic methodolo-gy,10–12 we now report an application of this methodologyto the first asymmetric synthesis of morusimic acid D (2),an alkaloid having a 2,3,6-trans,trans stereochemistry.As displayed retrosynthetically in Scheme 1, both the C2methyl group and the 2,3-trans stereochemistry were en-visioned to be introduced by the reductive alkylationmethod10,11 starting from the protected 3-hydroxyglutar-imide 6.12 The C6 side chain with 2,6-cis stereochemistrywas considered to be accessible by another diastereoselec-tive reductive alkylation method.13The synthesis commenced with (R)-3-benzyloxy-1-(4-methoxybenzyl)glutarimide [(R)-6],12 which was pre-pared from D-glutamic acid following essentially the pro-cedure described for its enantiomer (Scheme 2).12For the reductive methylation, although our previousstudy showed that the addition of methyl magnesium io-dide (3 molar equiv) to (S)-3-hydroxyglutarimide deriva-tive (S)-6 in THF at –78 °C yielded a diastereomericmixture of N,O-acetal 10 and its C6 adduct in 86:14 C2/C6 regioselectivity, it was found that almost only the C2addition product was obtained when undertaking the reac-Figure 1 Some alkaloids containing a 2-methyl-6-substituted pipe-ridin-3-ol moietyNOHMeH(CH2)9NHR(CH2)nOHazimic acid, n = 5, R = COOHcarpamic acid, n = 7, R = COOHspectaline, n = 12, R = COMespectalinine, n = 12, R = CH(OH)Meleptophyllin, n =10, R = CH(OH)CH2OHMeANHMeC(O)(CH2)10OCORMespectamine A, R = Phspectamine B, R = Meiso-6-cassine, R = Hmorusimic acid C, X = Glu (1)morusimic acid D, X = H (2)BHOO OXScheme 1 Retrosynthetic analysis of (–)-morusimic acid DNOBnMeOBocmorusimicacid D(2)4(5R,6S)-5 (R)-6BocHNMeOBnOOH9BocHNMeOBnO OHOHO39NOBnOPMBODownloaded by: Xiamen University. Copyrighted material.1190 D.-S. Yu et al. LETTERSynlett 2008, No. 8, 1189–1192 © Thieme Stuttgart · New Yorktion in CH2Cl2 and at –20 °C. The subsequent reductivedehydroxylation under ionic hydrogenolytic conditions14(Et3SiH/BF3·OEt2, CH2Cl2, –78 °C to r.t.) furnished pre-dominantly trans-11 (trans/cis = 92:8). Cleavage of theN-(4-methoxybenzyl) group by treating (5R,6S)-11 withceric ammonium nitrate (CAN) in MeCN–H2O (3:1)15 atroom temperature gave lactam (5R,6S)-12 in 58% yield(Scheme 2).Next, we turned our attention to the introduction of thechiral C6 side chain. To this end, another diastereoselec-tive reductive alkylation method13 was adopted. Thus, lac-tam 12 was first converted [(Boc)2O, Et3N, DMAP,CH2Cl2, 24 h] to imide (5R,6S)-5, an activated form13b ofthe former (Scheme 2). Reaction of Grignard reagent 1316with imide (5R,6S)-5 in CH2Cl2 at –78 °C proceededsmoothly to give the ring-opening product 14 in 68%yield. To introduce the ethoxycarbonylmethyl group, theTBS group in compound 14 was cleaved under acidic con-ditions (BF3·OEt2, CH2Cl2, 0 °C) to give 15 in 92%yield.17 The resulting alcohol 15 was oxidized with Dess–Martin periodinane (DMP)18 to give aldehyde 4 in quanti-tative yield (Scheme 3).For the asymmetric carboxymethylation, an enzymaticmethod,19 Evans asymmetric aldol-type reaction,20 andBrown’s asymmetric allylation reaction21 were all plausi-ble. We sought to use Evans’ aldol chemistry in view ofits excellent enantio- and diastereoselectivities, as well asits compatibility with different substituents that may beuseful for the synthesis of analogues of (–)-morusimicacid D. To take advantages of the progress in Evans aldolchemistry,22,23 oxazolidine-2-thione derivative 17 was se-lected for the asymmetric aldol reaction, where the chloroatom will serve as a stereodirecting group for the asym-metric aldol-type reaction.20 The starting oxazolidine-2-thione 16 was prepared in 91% yield by the method re-ported by Wu.24 Successive treatment of oxazolidine-2-thione 16 with n-butyllithium and chloroacetyl chloridegave 17 in 85% yield. Asymmetric aldol reaction of 4 with17 under Crimmins’ conditions [TiCl4, (i-Pr)2EtN, N-methylpyrrolidin-2-one (NMP), CH2Cl2, 0 °C]23 provided18 as the only isolable diastereomer in 70% yield(Scheme 4).Scheme 4The subsequent steps required for the synthesis of moru-simic acid D (2) included N-Boc deprotection, one-pot re-ductive cyclization–debenzylation, dechlorination, andcleavage of the chiral auxiliary. Attempts to cleave theprotecting group Boc by TFA, followed by Pd(OH)2 orPd/C-catalyzed hydrogenolysis to obtain 19 was unsuc-cessful, and other attempts under the conditions shown inScheme 5 also failed.After extensive trials, it was found that after the cleavageof the chiral auxiliary under Evans’ conditions25 (LiOH,H2O2, THF–H2O, 1 h) selective dechlorination could beachieved by subjecting 20 (colorless oil, yield 92%) toAbushanab’s hydrogenation conditions26 [H2 (l atm), 10%Pd/C, Et3N, MeOH, 24 h, r.t.], which furnished thedechloro product 3 in 85% yield along with 10% of the re-covered starting material (Scheme 6).Scheme 2NO OOBnPMBMeMgI–20 °C to –15 °CNOOBnPMBOHMeEt3SiH, BF3·OEt2–78 °C to r.t.NOOBnPMBMeCANMeCN–H2O(3:1), r.t.NOOBnMe(Boc)2O, DMAP Et3N, CH2Cl2, 24 hNOOBnMeBoc92%85%58%95%OHCONPMBOKOt-Bu, THF92%75% overall–78 °C to –62 °CNO OOHPMBAg2O, BnBrEt2O, r.t., 7 d98%(R)-9ref. 123 stepsHH(R)-610(5R,6S)-11(5R,6S)-12 (5R,6S)-5(R)-GluCH2Cl2(R)-8Scheme 3BrMgOTBSCH2Cl2, –78 °C68%HNMeOBnOCH2Cl2, 0 °C92%DMPCH2Cl2, r.t.quant.OTBSHNMeOBnOOHHNMeOBnOO14154H9999135BocBocBoc BF3·OEt2TiCl4, (i-Pr)2NEtNMP, CH2Cl2BocHNMeOBnO OHNClOOSBn70%BocHNMeOBnOO4H1899OHNSBnn-BuLi, ClCH2COClTHF, –78 °C, 15 min85%ONSBnClO171617Downloaded by: Xiamen University. Copyrighted material.LETTER Asymmetric Synthesis of (–)-Morusimic Acid D 1191Synlett 2008, No. 8, 1189–1192 © Thieme Stuttgart · New YorkFinally, treatment of 3 with trifluoroacetic acid in dichlo-romethane at 0 °C for one hour, followed by subjectingthe resulting crude product to catalytic hydrogenolysis(10% Pd/C, H2, MeOH, r.t., 24 h) led, in one pot, to theformation of morusimic acid D (2) in 75% yield as a whitepowder {[a]D20 –14.0 (c 0.25, MeOH), lit.9 [a]D20 –14.6 (c0.25, MeOH)}. The 1H NMR and 13C NMR spectral dataof the synthetic material are identical with those reportedfor the natural morusimic acid D (2).9Alternatively, morusimic acid D methyl ester (22)27 couldbe obtained in one pot by treatment of 3 with trifluoroace-tic acid, followed by catalytic hydrogenolysis in methanolusing Pearlman’s catalyst [Pd(OH)2/C (20 mol%), H2, 1atm] for three hours, and then stirring with concentratedhydrochloric acid for 24 hours (Scheme 7).In summary, by modifying the reaction conditions, theC2/C6 regioselectivity of the addition of methyl magne-sium iodide to N,O-diprotected 3-benzyloxyglutarimide 6was improved from 86:14 to at least 95:5. On the basis ofthis reaction, the first asymmetric synthesis of (–)-moru-simic acid D is achieved in 11 steps with an overall yieldof 13% from (R)-6, with all the three stereocenters estab-lished in excellent diastereoselectivities.AcknowledgmentThe authors are grateful to the NSFC (20572088), Qiu Shi Science& Technologies Foundation, and the program for Innovative Rese-arch Team in Science & Technology (University) in Fujian Pro-vince for financial support. We thank Professor Y. F. Zhao for theuse of her Bruker Dalton Esquire 3000 plus LC-MS apparatus.References and Notes(1) For reviews on the piperidine alkaloids, see: (a) Strunz, G. M.; Findlay, J. A. Pyridine and Piperidine Alkaloids, In The Alkaloids, Vol. 26; Brossi, A., Ed.; Academic Press: New York, 1985, 89. (b) Numata, A.; Ibuka, T. In The Alkaloids, Vol. 31; Brossi, A., Ed.; Academic Press: New York, 1987. (c) Schneider, M. 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(i) Dransfield, P. J.; Gore, P. M.; Prokeš, I.; Shipman, M.; Scheme 5NOHMeHNO OH9LiOH, H2O2;TFAPd(OH)2/C, H20 °C, 2 h;EtOH, 1 dHNMeOBnO OHNClOOSBn18192TFA;Pd(OH)2/C, H2; or Pd/C, H2;9OSBnBocScheme 6LiOH, H2O2THF–H2O (4:1), 1 h92%HNMeOBnO OHClOHOHNMeOBnO OHOHOPd/C, H2Et3N, MeOH24 h85%1820993BocBocScheme 785% (from 3)NOBnMeHHOO OH921TFACH2Cl20 °C, 1 h10% Pd/C, H2MeOH, r.t., 24 h75% (from 3)20% Pd(OH)2/CH2, 3 hMeOH–concd HCl24 hCF3CO223NOHMeHHOO OH922NOHMeHMeOO OH9orDownloaded by: Xiamen University. Copyrighted material.1192 D.-S. Yu et al. LETTERSynlett 2008, No. 8, 1189–1192 © Thieme Stuttgart · New YorkSlawin, A. M. Z. Org. Biomol. Chem. 2003, 1, 2723. (j) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004, 45, 421. (k) Jourdant, A.; Zhu, J. P. Heterocycles 2004, 64, 249. (l) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767. (m) Kim, I. S.; Ryu, C. B.; Li, Q. R.; Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2007, 48, 6258. (n) Fuhshuku, K.-i.; Mori, K. 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Chem. 1990, 55, 4109.(22) For recent reviews on the asymmetric aldol reaction, see: (a) Arya, P.; Qin, H. P. Tetrahedron 2000, 56, 917. (b) Csákÿ, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313.(23) (a) Crimmins, M. T.; She, J. Synlett 2004, 1371. See also: (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883.(24) Wu, Y. K.; Yang, Y. Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990.(25) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141.(26) Saibaba, R.; Sarma, M. S.; Abushanab, E. Synth. Commun. 1989, 19, 3077.(27) All new compounds gave satisfactory analytical and spectral data. Selected physical and spectral data for morusimic acid D methyl ester (22): pale yellow powder; mp 132–135 °C; [a]D20 –11.3 (c 0.4, CHCl3). IR (film): 3387, 2929, 2854, 1731, 1438, 1380, 1305, 1165, 1061 cm–1. 1H NMR (400 MHz, CD3OD): d = 1.40 (s, 3 H), 1.22–1.68 (m, 20 H), 2.09 (m, 2 H), 2.30–2.50 (m, 2 H), 2.92 (m, 1 H), 3.08 (m, 1 H), 3.42 (s, 1 H), 3.64 (s, 3 H), 3.95 (m, 1 H). 13C NMR (100 MHz, CD3OD): d = 16.00, 26.52, 26.56, 28.33, 30.43, 30.48, 30.52, 30.56, 30.59, 32.92, 34.26, 38.05, 43.25, 52.15, 58.49, 59.24, 69.23, 70.70, 173.92. ESI-HRMS: m/z calcd for C19H38NO4 [M + H]+: 344.2795; found: 344.2798.Downloaded by: Xiamen University. Copyrighted material.

First asymmetric synthesis of piperidine alkaloid (-)-morusimic acid D

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First asymmetric synthesis of piperidine alkaloid (-)-morusimic acid D

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