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Diastereo- and Enantioselective Synthesis of a-(b-Aminoalkyl)-Substituted g-Lactams by Michael Addition to Nitroalkenes Dieter Enders,* Pascal Teschner, Gerhard Raabe Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany Fax +49(241)8888-127; E-mail: [email protected] Received 3 February 2000

Abstract: a-(b-Aminoalkyl)-substituted g-lactams 5a-e were synthesized in three steps in good overall yields (37 - 61%) and diastereo- and enantiomeric excesses (de ≥96%, ee = 82 - ≥96%). In the key step metalated N-dialkylamino lactam (S)-1 underwent 1,4-addition to nitroalkenes 2 to afford the Michael adducts 3, which were converted to the protected amines 4. After subsequent reductive cleavage of the N-N-bond with lithium in liquid ammonia the title compounds 5 were obtained. The relative and absolute configuration of the major diastereomer was determined by X-ray structure analysis on (R, R, S’)-3b. Key words: asymmetric synthesis, lactams, Michael addition, nitroalkenes, reduction

a-Substituted g- and d-lactams1 represent interesting biologically active compounds and natural products.2 In addition, they are useful building blocks for alkaloid synthesis3 and since lactams are cyclic amides, they can be converted to their corresponding amino acids by ring opening. The class of g-lactams is of special interest, because their derivatives, the g-aminobutanoic acids (GABA), are of great importance in the regulation of neurological disorders.4

matography the major diastereomer of 3a was obtained in diastereomerically pure form and 1,4-adduct 3c with a diastereomeric excess of 85%. The major diastereomer of compound 3b was isolated with de ≥ 96% after recrystallization from diethyl ether/pentane. In the 1,4-additions to aromatic nitroalkenes 2d-f it was found, that by changing the reaction temperature from -100∞C to -40∞C and the reaction time from 14 h to 1 - 1.5 h the diastereoselectivities and yields were slightly increased. All the crude products of the aromatic Michael adducts consisted of three diastereomers with diastereomeric ratios between 16:34:50 (3e) and 5:18:77 (3d), corresponding to diastereoselectivities of 50 - 77%. The major diastereomers were isolated by HPLC.

Michael addition reactions are very useful in the formation of carbon-carbon bonds5 and a great variety of asymmetric Michael additions has been developed in recent years.6 Nitroalkenes are excellent Michael acceptors, as the nitro group can be converted into a broad range of functionalities7 and various methods for asymmetric Michael additions to nitroalkenes are available.8 We have already reported a protocol for the asymmetric aalkylation9 and Michael addition to (E)-enoates of N-dialkylamino lactams.10 Now we present an extension of our previous methodology for the synthesis of a-substituted glactams by diastereoselective Michael addition of lactam 1, bearing (S)-2-(1-ethyl-1-methoxypropyl)pyrrolidine as auxiliary on the lactam nitrogen, to nitroalkenes. The conjugate addition of lactam 1, prepared according to the literature procedure,11 to aliphatic nitroalkenes 2a-c was performed after lithiation for 3-4 h with 1.2 equiv LDA in THF at -78∞C and addition of the nitroalkenes at -100∞C. After warming to room temperature and work-up the crude adducts 3a-c were obtained in moderate to good diastereoselectivities (80 - 90%). For compound 3a two diastereomers (de = 81%) were observed, the other aliphatic examples showed diastereomeric ratios of 7:7:86 for 3b and 8:12:80 for 3c respectively. After column chro-

Reagents and Conditions: a) 1. LDA, THF, -78∞C. 2. (E)RCH=CH2NO2, 2a-g (see Table 1), -40∞C or -100∞C. b) 1. NaBH4, Pd/C, THF, MeOH. 2. Boc2O, NEt3. c) Li, NH3, -33∞C. Scheme

The relative and absolute configuration of the newly formed stereogenic centres of the major diastereomer of 3b was determined by X-ray-structure analysis to be (R,R,S’) (Figure).12 The sense of asymmetric induction alpha to the carbonyl group for the major diastereomers is

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Table 1 Synthesis of Nitro Lactams 3 by Diastereoselective Michael Addition of (S)-1 to Nitroalkenes 2.

were obtained in moderate to good yields (61-76%). Epimerisation during the conversion to 4 was not observed, since the de-values of the products were found to be the same as of the starting material. Table 2 Synthesis of Protected Amino Lactams 4 by Reduction of the Nitro Compounds 3 and Subsequent Protection of the Amino Function

a

Yield before separation of diastereomers; in brackets yield of major diastereomer. b Determined by 1H NMR and 13C NMR spectroscopy. c After column chromatography. d After recrystallization. e After HPLC.

in agreement with that observed previously in the a-alkylation of N-dialkylamino lactams.9 The relative configuration (anti) is in accordance with our findings for the formation of Michael adducts of enoates and lithiated Ndialkylamino lactams.10 The stereochemistry of the major diastereomer of the other Michael adducts 3 is based on the assumption of a uniform mechanism operating in the addition to nitroalkenes.

a

Determined by 1H NMR and 13C NMR spectroscopy.

The auxiliary was removed from compounds 4a-e by NN-bond-cleavage using lithium in ammonia. The title asubstituted lactams 5 were obtained with good yields and excellent diastereomeric excesses (de ≥96%) and good to excellent enantiomeric excesses (ee = 82 - ≥96%). However, this method showed limitations in the application of substituted aromatic compounds, owing to Birch-reduction (4f) or lithium-alkoxy-exchange (4g) leading to complex product mixtures. The diastereomeric excesses of the a-substituted lactams 5 were determined by 1H and 13C NMR spectroscopy. The enantiomeric excesses of 5a, b, c, e were determined by gas chromatography with a chiral stationary phase. The ee-value of 5d was deduced from the de-value of the corresponding (R)-Mosher-amide, which was synthesized from 5d by removal of the protective group with TFA and subsequent amide formation with (S)-a-methoxy-a-(trifluoromethyl)-phenyl-acetyl chloride.15 Table 3 Synthesis of the Title Compounds 5 by Reductive Cleavage of the N-N-Bond of the N-Dialkylamino Lactams 4

Figure

Crystal Structure of Michael Adduct (R,R,S’)-3b.12

In order to remove the auxiliary we envisaged a reductive cleavage of the N-N bond using lithium in liquid ammonia,13 since this method has been successfully employed in the reactions of similar a-substituted lactams.9,10 The nitro compounds 3 were reduced14 to the corresponding amines with NaBH4 in a mixture of MeOH and THF in the presence of a catalytic amount of Pd on charcoal in order to avoid decomposition by elimination of nitrous acid. The crude amines were immediately protected as tert-butylcarbamates (Boc). The N-protected amines 4

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a

Determined by 1H NMR and 13C NMR spectroscopy. b Determined by GC on a chiral stationary phase (Chirasil-L-Val 25 m). c Based on the de-value of the corresponding Mosher-Amide (1H NMR).

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Diastereo- and Enantioselective Synthesis of a-(b-Aminoalkyl)-Substituted g-Lactams

In conclusion, we have developed an efficient method for the asymmetric Michael addition of metalated N-dialkylamino lactams to nitroalkenes. After reduction of the nitro group, amine protection and reductive removal of the auxiliary the title a-substituted lactams, which represent bifunctional “double” GABA-precursors, were obtained with high diastereomeric and enantiomeric excesses. General procedure for the Michael addition of lithiated Ndialkylamino lactam (S)-1 to nitroalkenes: To a solution of N-dialkylamino lactam 1 (1.5 mmol) in THF (7 mL) at -78∞C was slowly added a solution of lithium diisopropylamide (1.8 mmol) in THF (15 mL) using a double-ended needle. The mixture was stirred for 3-4 h at -78∞C. In the case of the aliphatic substituted nitroalkenes the reaction mixture was cooled to -100∞C and Michael acceptors 2 (1.8 mmol, neat) were added dropwise. The mixture was stirred overnight at -78∞C and then warmed to -30∞C. For the addition to aromatic nitroalkenes the solution was allowed to warm to -40∞C and the Michael acceptors, dissolved in 1-2 mL THF, were added. The reaction mixture was stirred for 1 - 1.5 h at this temperature. The reactions were quenched by addition of sat. aq. NH4Cl (15 mL). The aqueous phase was extracted three times with 50 mL CH2Cl2. The combined organic phases were washed with 25 mL of H2O and dried over MgSO4. After removal of the solvent, the residue was purified by flash chromatography (SiO2; diethyl ether/pentane, 1:2) to afford the Michael adducts 3. General procedure for the conversion of the nitro lactams 3 to protected N-dialkylamino lactams 4: The Michael adducts 3a-f (1.0 mmol) were dissolved in a 1:1-mixture of MeOH and THF (20 mL/mmol) and cooled to 0∞C. Then 50 mg/mmol Pd on charcoal and 4 mmol NaBH4 were added. The flask was immediately closed tightly and the mixture was stirred at rt overnight. To remove the Pd-charcoal the reaction mixture was filtered through Celite washing three times with 5 mL of MeOH. Then Boc2O (2 mmol) and NEt3 (2 mmol) were added and after stirring for two hours the solvent was removed in vacuo. The crude product was dissolved in CH2Cl2 (20mL/mmol) and washed twice with H2O (20 mL) and then brine (20 mL). After drying over MgSO4 the solvent was removed and the residue purified by flash chromatography (SiO2; diethyl ether/pentane, 1:2 containing 1% of Et3N). General procedure for the N-N bond cleavage (preparation of the title compounds 5): Pieces of lithium wire (5 equiv) were added to liquid NH3, which was placed in a three necked flask with dry-ice condenser. To the dark-blue solution the a-substituted N-dialkylamino lactams 4 in dry THF (10 mL/mmol) were added at -78∞C. Then the cooling bath was removed and the solution was kept under reflux (-33∞C) until the blue colour disappeared (after 5-15 min). The reaction was quenched with solid NH4Cl (12 equiv) and the NH3 was evaporated at rt. The solid residue was dissolved in a 1:1mixture of CH2Cl2 and pH 7-buffer (20 mL/mmol) and the

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aqueous phase was extracted with CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, concentrated in vacuo, and the crude products were purified by chromatography (SiO2; diethyl ether or diethyl ether/ MeOH, 10:1).16,17

Acknowledgement This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 380) and the Fonds der Chemischen Industrie. We like to thank Degussa-Hüls AG, BASF AG, the former Hoechst AG and Bayer AG for the donation of chemicals.

References and Notes (1) General reviews on lactams: a) Backes, J. In Houben-Weyl, 4th ed., Vol. E16, part 2; Klamann, D., Ed.; Thieme: Stuttgart, 1991, p 31. b) Schnell, H.; Nentwig, J.; Wieland, T. In Houben-Weyl, 4th ed., Vol. 11, part 2; Müller, E., Ed.; Thieme: Stuttgart, 1958, p 511. c) Boyd, G. V. In The Chemistry of Acid Derivatives, The Chemistry of Functional Groups, Patai, S., Ed.; Wiley: Chichester, 1979, p 516; 1992; p 588. d) Ghosez, L.; Marchand-Brynaert, J. In Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon: Oxford, 1991, p 90. e) Davies, D. E.; Storr, R. C. In Comprehensive Heterocyclic Chemistry, Vol. 7, Katritzky, A. R.; Rees, C. W.; Lwowski, W., Eds.; Pergamon: Oxford, 1984, p 247. (2) a) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Webber, S. E.; Marakovits, J. T.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Ford, C. E.; Burke, B. J.; Rejto, P. A.; Hendrickson, T. F.; Tuntland, T.; Brown, E. L.; Meador, III, J. W.; Ferre, R. A.; Harr, J. E. V.; Kosa, M. B.; Worland, S. T. J. Med. Chem. 1999, 42, 1213. b) Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S. Chem. Commun. 1999, 133. c) Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.; Chang, C. T.-C.; Cook, J. J.; Gould, R. J.; Ihle, N. C.; Hartman, G. D.; Lynch, J. J.; Lynch, R. J.; Manno, P. D.; Schaffer, L. W.; Smith, R. L. J. Med. Chem. 1995, 38. 3332. (3) a) Lakshmaiah, G.; Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999, 64, 1699. b) Alves, J. C. F.; Simas, A. B. C.; Costa, P. R. R. Tetrahedron: Asymmetry 1999, 10, 297. (4) a) Roberts, E.; Chase, T. N.; Tower, D. B. GABA in Nervous System Functions; Raven: New York, 1976. b) KrogsgaardLarsen, P. In Comprehensive Medicinal Chemistry, Vol. 3; Sammes, P. G.; Taylor, J. B., Eds.; Pergamon: Oxford, 1990, p 493. c) McAlonan, H.; Stevenson, P. J. Tetrahedron: Asymmetry 1995, 6, 239. (5) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series Vol. 9; Baldwin, J. E.; Magnus, P. D., Eds.; Pergamon: Oxford, 1992. (6) For general reviews about asymmetric Michael additions see: a) Yamamoto, Y.; Pyne, S.G.; Schinzer, D.; Feringa, B. L.; Jansen, J. F. G. A. In Houben-Weyl, 4th ed., Vol. E21b, Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1995; chapter 1.5.2. b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. c) Leonard, J.; Diez-Barra, E.; Merino, S. Eur. J. Org. Chem. 1998, 2051. (7) a) Patai, S., The Chemistry of Amino, Nitroso and Nitro Compounds, and their Derivatives, Supplement F, Wiley: New York, 1982. b) Olah, G. A., Narang, S. C. In Organic Nitro Chemistry Series, Feuer, H., Ed.; Verlag Chemie: Weinheim, 1990. c) Feuer, H.; Nielsen, A. T. Nitro Compounds, Verlag Chemie: Weinheim, 1990.

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(8) a) Enders, D.; Otten, T. Synlett 1999, 747 and references cited therein. b) Thominiaux, C.; Roussé, S.; Desmaële, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015. (9) Enders, D.; Gröbner, R.; Raabe, G.; Runsink, J. Synthesis 1996, 941. (10) Enders, D.; Teschner, P.; Raabe, G. Heterocycles 2000, 52, 733. (11) Enders, D.; Brauer-Scheib, S.; Fey, P. Synthesis 1985, 393. (12) Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CDDC-140025. Copies of the data can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, [fax: int. code+44(1223)336-033, e-mail: [email protected]]. (13) For references see: Enders, D.; Lochtman, R.; Meiers, M.; Müller, S. F.; Lazny, R. Synlett 1998, 1182. (14) a) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 1998, 1771. b) Petrini, M.; Ballini, R.; Rosini, G. Synthesis 1987, 713. (15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (16) Selected analytical and spectroscopic data of compounds 3, 4, 5: (S,R,S)-3b: 1H NMR (400 MHz, CDCl3): d = 0.84, 0.89 (2 t, J = 7.7 Hz, 6H, 2CH2CH3), 0.98 (t, J = 7.4 Hz, 3H, CH2CH3), 1.45-2.12 (m, 12H, 3CH2CH3, NCH2CH2, CH2CH2CH2N), 2.50 (m, 1H, CHCHCO), 2.62 (dt, J = 3.7, 9.1 Hz, 1H, CHCHCO), 3.13 (m, 2H, NCH2), 3.23 (s, 3H, COCH3), 3.45 (m, 2H, CH2CNCO), 3.70 (br. s, 1H, NCH), 4.37 (dd, J = 7.2, 12.6 Hz, 1H, CHHNO2), 4.77 (dd, J = 6.3, 12.9 Hz, 1H, CHHNO2); 13C NMR (100 MHz, CDCl3): d = 7.97, 8.84, 11.61, 20.42, 21.20, 24.00, 24.28, 26.13, 26.27, 39.84, 41.25, 49.88, 52.38, 65.09, 80.04, 76.85, 172.32; MS (CI, isobutane): m/z = 357 (M++2), 356 (M++1), 326, 325, 324, 322, 311, 254; IR (CHCl3): n = 2970, 2935, 2880, 2830, 1675, 1550, 1460, 1440, 1415, 1385, 1355, 1300, 1275, 1245,

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1180, 1165, 1140, 1095, 1170, 1095, 1070, 1045, 925, 910, 740, 720 cm-1; Anal. calcd. for C18H33N3O4: C 60.82, H 9.36, N 11.82. Found: C 60.74, H 9.34, N 11.66. (S,R,S)-4b: 1H NMR (300 MHz, CDCl3): d = 0.86, 0.87, 0.94 (3t, J = 7.4 Hz, 9H, 3CH2CH3), 1.42 (s, 9 H, C(CH3)3), 1.302.00 (m, 12H, 3CH2CH3, NCH2CH2CH2, CONCH2CH2), 2.52 (dt, J = 3.3, 9.3 Hz, 1H, CHCHCO), 3.00-3.20 (m, 5H, NCH2CH2CH2, CH2NHCOO-t-Bu, CHCHCO), 3.28 (s, 3H, OCH3), 3.42 (m, 2H, CONCH2), 3.58 (br. s, 1H, NCH), 5.20 (s, 1H, NHCOO-t-Bu); 13C NMR (75 MHz, CDCl3): d = 8.08, 8.64, 11.94, 19.52, 22.44, 23.80, 26.02, 26.25, 28.46, 39.97, 42.58, 41.77, 50.22, 52.27, 64.91, 78.89, 79.89, 156.33, 174.29; MS (CI, isobutane): m/z = 427 (M++2), 426 (M++1), 394, 324, 257, 201, 201, 140, 101, 87, 70; IR (CHCl3): n = 3350, 2970, 2935, 2880, 1695, 1510, 1455, 1390, 1365, 1275, 1250, 1170, 1120, 920, 875, 665 cm-1; Anal. calcd. for C23H43N3O4: C 64.91, H 10.18, N 9.87. Found: C 64.70, H 10.01, N 10.40. (R,S)-5b: 1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3H, CH2CH3), 1.43 (s, 9H, C(CH3)3), 1.32, 1.45 (2m, 2H, CH2CH3), 1.96 (m, 2H, CONCH2CHH, CHCHCO), 2.13 (m, 1 H, CONCH2CHH), 2.58 (dt, J = 3.9, 7.9 Hz, 1H, CHCHCON), 3.13 (m, 1H, CHHNHCOO-t-Bu), 3.32 (m, 1H, CHHNHCOO-t-Bu), 3.33 (m, 2H, CONCH2), 5.34 (m, 1H, NHCOO-t-Bu), 6.91 (s, 1H, CONH); 13C NMR (100 MHz, CDCl3): d = 11.92, 22.64, 22.77, 28.43, 39.87, 42.66, 41.62, 40.62, 78.85, 156.26, 180.49; MS (CI, isobutane): m/z = 257 (M++1), 202, 201, 157; IR (CHCl3): n = 3315, 2965, 2930, 2875, 1695, 1520, 1460, 1390, 1365, 1275, 1255, 1175, 1070, 1040, 1010 cm-1; Anal. calcd. for C13H24N2O3: C 60.91, H 9.44, N 10.93. Found: C 60.54, H 9.70, N 11.36. (17) All new compounds showed suitable spectroscopic data (IR, NMR, MS) and correct elemental analyses.

Article Identifier: 1437-2096,E;2000,0,05,0637,0640,ftx,en;G03000ST.pdf

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