摘要:

HO2C CO2H NH2 R HO2C NH2 R CO2H N O CO2Me Boc 2 3 1 N O CO2Me Boc R N O CO2Me Boc HO2C NH2 R CO2H HO2C NH2 R CO2H N O CO2Me Boc R + 3 4 5a 5b 5c 6a 6b 6c 7a 7b 7c 8a 8b 8c a = Me; b = Bu; c = Ph i i i i i i i v i v 5a 6a = 5 1; 5b 6b = 1 1 5c 6c = 1 20 The synthesis of a-amino-g-substituted adipic acids stereoelectronic effects during the 1,4-addition of organocuprates to methyl N-tert-butoxy-6-oxo-1,2,3,6-tetrahydropyridine-2-carboxylate Mireille Muller Angèle Schoenfelder Bruno Didier André Mann* and Camille-Georges Wermuth Laboratoire de Pharmacochimie de la Communication Cellulaire ERS 655 Faculté de Pharmacie 74 route du Rhin BP 24 F-67401 Illkirch Cedex France. E-mail andre.mann@pharma.u-strasbg.fr Received (in Liverpool UK) 26th November 1998 Accepted 4th March 1999 The a,b-unsaturated lactam 3 was submitted to 1,4-addition of organocuprate reagents R2CuLiI2 (R = Me Bu or Ph) to provide the 4-substituted compounds 5a–c 6a–c as a mixture of diastereomers; these intermediates were then transformed into the corresponding a-amino-g-substituted adipic acids 7a–c 8a–c.The synthesis of modified and unnatural amino acids is a source of constant inspiration in organic chemistry.1–3 In recent years glutamic acid a major neurotransmitter in the mammalian brain has received considerable attention from chemists involved in neurosciences.4,5 During earlier studies on modified glutamates we and others have found that the g-substituted analogues of structure 1 are invaluable tools for the pharmacological exploration of excitatory amino acid receptors.6,7 Interestingly it was found that the biological activity of such derivatives was largely confined to the 2S,4S diastereomers.For structure–activity studies devoted to this class of amino acids we decided to synthesize compounds of type 2 in which the distal carboxylate is moved an additional methylene unit away from the a-amino acid group compared with 1 generating g- substituted a-amino adipic acids (Adi). As earlier observations have already demonstrated that Adi itself possesses good affinity for the glutamate receptors,8 the introduction of different substituents on the Adi backbone may contribute to a better knowledge of steric demands at the receptor level.9 Our goal was to employ an enantiospecific and diastereoselective synthesis which would provide analogues 2 in which the C-2 and C-4 substituents have the correct configuration for high biological activity.Since we have previously prepared modified glutamic acids using a conjugate addition of organocopper reagents,10 we therefore proposed to submit compound 3 to a similar sequence in the expectation that the presence of the C-2 carboxylate would provide facial selectivity.11,12 We report herein our observations on the diastereoselectivity obtained in the 1,4-addition of organocuprate reagents to the a,b-unsaturated lactam 3. The starting compound 3 was obtained from (S)-lysine in enantiomerically pure form via piperidone 4 following literature reports.13215 The unsaturation was introduced by a sequence involving selenation and oxidative elimination as decribed for the preparation of the corresponding benzyl ester (Scheme 1).15 Since lactam 3 is potentially prone to nucleophilic attack we were pleased to find that the reaction of this substrate in Et2O with different organocuprates gave the expected adducts as mixtures of cis/trans diastereomers (5a–c and 6a–c) in acceptable yields and in moderate to good stereoselectivity.† Examination of the 1H NMR (200 MHz) spectra of the crude mixtures revealed that each diastereomer has a well resolved signal (dd) between d 4.5–4.8 for the hydrogen attached at C-2.Surprisingly in analyzing these signals for the 5a/6a 5b/6b and 5c/6c mixtures we observed that the intensity for the upfield signal (trans diastereomer) increases at the expense of the corresponding downfield one (cis diastereomer). These results indicate a change in the cis trans ratio related to the structure of the transfered substituent.After purification the pattern of the H-5ax proton was identified in each diastereomer as a doublet of doublets (B part of an ABX spin sytem) in which largest J value (around 17 Hz) corresponds to the geminal coupling H-5ax/H5eq. The smaller J value (around 11 Hz) arises from to the coupling between H- 5ax and H-4 and these were of comparable value in all the compounds (5a–c and 6a–c) consistent with an axial disposition of the proton at C-4. As a consequence the Me Bu or Ph substituents attached at C-4 have an equatorial disposition in each diastereomer. For the protons attached at C-2 in 5a and 6a two sets of coupling constants were measured J = 10 and 6 Hz and J = 4 and 2 Hz repectively. From these data it was clear that in the analogues 5a–c the carboxylate adopts an equatorial disposition (large J values = axial orientation of the proton at C-2) whilst in contrast for derivatives 6a–c the carboxylate has Scheme 1 Reagents and conditions i LiHMDS (1.1 equiv.) PhSeCl (1.2 equiv.) THF 278 °C 2 h (78%); ii MCPBA (2 equiv.) CH2Cl2 25 °C 12 h (72%); iii for 5a/6a MeLi (2 equiv.) CuI (1 equiv.) Et2O 278 °C 2 h 5a (68%) and 6a (9%); for 5b/6b BuLi (2 equiv.) CuI (1 equiv.) 278 °C 2 h 5b (35%) and 6b (33%); for 5c/6c PhLi (2 equiv.) CuI (1 equiv.) Et2O 278 °C 2 h 6c (48%); HCl in AcOH reflux 3 h (from 45 to 80%). Chem. Commun. 1999 683–684 683 N CO2Me H O H H Boc N CO2Me H LiO H H H Boc N CO2Me H H Boc R H H LiO R H H H N H2 H4 R N H4 H2 CO2Me R O Boc O Boc CO2Me H3 H3 H3 H5 H5 H5 H5 H3 parallel attack anti- parallel attack TS chair-like TS boat-like 5a–c ( cis) 6a–c ( trans) 10 Hz < J H-2 H-3ax <10.5 Hz 8 Hz < J H-5ax H-4 < 11 Hz 4 Hz < J H-2 H-3ax < 5.6 Hz 7 Hz < J H-5ax H-4 < 12 Hz b a b a an axial orientation (small J values = equatorial orientation of the proton at C-2).These data are consistent with a chair conformation for all of the isolated compounds in which the products 5a–c have the substituents in a 1,3-cis arrangement and 6a–c in a 1,3-trans arrangement. In order to explain these findings we performed calculations on lactam 3 (MOPAC out of SYBYL 6.3) which demonstrated that the conformer having the carboxylate at C-2 in an axial disposition is by far more stable (5 kcal mol21) than the corresponding equatorial conformer‡ (Scheme 1). This result is the obvious consequence of a strong A1,3 strain between the carboxylate at C-2 and the Boc group on the nitrogen atom.16 Based on these calculations and several literature reports on the stereoelectronic effects during conjugated addition in related a,b-unsaturated cyclohexanones or 2,3-dihydro-4-pyridones,17,18 a strong axial bias was expected to operate during the addition of nucleophilic reagents to lactam 3.Therefore one should observe the preferential formation of the cis adducts (5a–c) at the expense of the corresponding trans epimers (6a–c). Indeed for the smallest substituent (R = Me) an appreciable diastereoselectivity in favor of the cis adduct was observed (5a 6a = 5 1). However when the steric demand of the organocuprate was increased (R = Bu) the facial selectivity was lost (5b 6b = 1 1) or for still bulkier groups (R = Ph) the facial steroselectivity was reversed and the trans diastereomer was the only one detected (5c 6c = 1 30).Allinger has discussed a closely related example involving the 1,4-addition of Grignard reagents to 5-methylcyclohex- 2-enone,19 in which the importance of the conformation of the conjugated enolate (chair or boat) produced by parallel or anti-parallel attack was considered. As the carboxylate function in 3 is assumed to be axial the major pathway for the reaction with Me2CuLi2I was via an anti-parallel attack to give the transient enolate of 5a. This intermediate possesses a low energy chair-like conformation (TS chair) in spite of the 1,3-diaxial interaction between the carboxylate and the incoming methyl group.When the nucleophile is larger such as in Bu2CuLi2I (5b/6b) or Ph2CuLi2I (5c/6c) the reaction pathway via parallel attack takes place preferentially due to a competing strong 1,3-diaxial interaction between the carboxylate and the bulky incoming nucleophile. This gives a transient boat-like (TS boat) enolate which collapses to the trans chair conformer. The final transformation of 5a–c and 6a–c into the desired substituted adipic acids was realized under hydrolytic conditions and the amino acids 7a,b and 8a–c were obtained as crystalline hydrochlorides.§ In conclusion the diastereoselectivity observed for the conjugate addition of organocuprates to cyclic enamide 3 could be controlled by an appropriate choice of the transferable nucleophilic reagent. The significant A1,3 strain inherent to the ring system and the size of the nucleophile are probably the key factors responsible for the diastereoselectivity observed in this conjugate addition reaction.Our findings demonstrate that a,b- unsaturated species 3 is an excellent substrate for the preparation of enantiomerically pure (2S,4S)- or (2S,4R)-2-amino- 4-substituted adipic acids. We thank Dr Jacques Royer (Gif sur Yvette France) and Professor Maurizio Taddei (Sassari Italy) for valuable discussions. Notes and references † Selected data for 5a mp 60 °C; Rf 0.30 (hexanes–Et2O = 5 5); [a]D 266.2 (c 5 CHCl3); dH(200 MHz 30 °C) 4.51 (dd J 10.2 and 6.2 1 H) 3.74 (s 3 H) 2.62 (dt J 17 and 2.4 1 H) 2.30 (m 1 H) 2.10 (dd J 17 and 10 1 H) 2.15 (m 1 H) 1.53 (m 1 H),1.48 (s 9 H) 1.02 (d J 6 3 H); dC(50 MHz) 172.1 170.1 151.9 83.6 58.6 52.3 42.7 34.1 28.3 27.7 26.3 20.7.(Calc. for C13H21NO5 C 57.54; H 7.80; N 5.16. Found C 57.3; H 7.9; N 5.2%). For 6a oil; Rf 0.35 (hexanes–Et2O = 6 5); [a]D +20.1 (c 2 CHCl3 30 °C); dH(200 MHz) 4.71 (dd J 4 and 1.8 1 H) 3.80 (s 3 H) 2.66 (ddd J 16.3 3.2 and 1.4 1 H) 2.21 (dd J 9.1 4 and 1.4 1 H) 2.09 (dd J 16.3 and 9.6 1 H) 1.96 (m 1 H) 1.73 (m 1 H) 1.51 (s 9 H) 1.01 (d J 4.2 3 H); dC(50 MHz) 172.2 169.9 152.2 83.6 58.3 52.6 42.8 33.5 29.7 27.9 25.1 21.1. (Calc. for C13H21NO5 C 57.54; H 7.80; N 5.16. Found C 57.6; H 7.6; N 5.1%). ‡ In compound 3 the recorded coupling constant (dd J 4.5) is consistant with an axial orientation of the carboxylate. § Preparation of 7a Lactam 5a (96 mg 0.35 mmol) was heated at reflux for 2 h in a mixture of concentrated HCl (2 ml) and AcOH (4 ml).The mixture was concentrated in vacuo and triturated with Et2O to provide a solid which was filtered to yield 7a (60 mg 81%) as a hygroscopic solid; mp 178 °C; [a]D 279 (c 1 MeOH); m/z (FAB) 176 (M + H+). For 8a mp 196 °C; [a]D +26 (c = 1.8 MeOH); m/z (FAB) 176 (M + H+). 1 F. J. Sardina and H. Rapoport Chem. Rev. 1996 96 1825. 2 R. O. Duthaler Tetrahedron 1994 50 1539. 3 J. Jurczak and A. Golebiowski Chem. Rev. 1989 89 149. 4 M. G. Moloney Nat. Prod. Rep. 1998 205. 5 T. Knöpfel R. Kuhn and A. Allgeier J. Med. Chem. 1995 38 1417. 6 C. G. Wermuth A. Mann A. Schoenfelder R. A. Wright B. G. Johnson J. P. Burnett N.G. Mayne and D. D. Schoepp J. Med. Chem. 1996 39 814. 7 Z.-Q. Gu X.-F.Lin and D. P. Hesson Bioorg. Med. Chem. Lett. 1995 5 1973. 8 R. H. Evans A. A.Francis and J. C. Watkins Brain Res. 1978 148 536. 9 J. Ezquerra C. Pedregal A. Escribano M. C. Carreno and J. L. G. Ruano Tetrahedron Lett. 1995 36 3247. 10 I. Jako P. Uiber A. Mann C. G. Wermuth T. Boulanger B. Norberg G. Evrard and F. Durant J. Org. Chem. 1991 56 5729. 11 N. Krause and A. Gerold Angew. Chem. Int. Ed. Engl. 1997 36 186. 12 P. Perlmutter in Conjugate Addition Reactions in Organic Synthesis Pergamon Oxford 1992 pp. 137–197 and references cited therein. 13 S. A. Hermitage and M. G. Moloney Tetrahedron Asymmetry 1994 5 1463. 14 C. E. Davies T. D. Heightman S. A. Hermitage and M. G. Moloney Synth. Commun. 1996 26 687. 15 P. J. Murray and I. D. Starkey Tetrahedron Lett. 1996 37 1875. 16 R. W. Hoffmann Chem. Rev. 1989 89 1841. 17 P. Deslongchamp in Stereoelectronic Effects in Organic Chemistry Pergamon Oxford 1983 p. 209. 18 J. D. Brown M. A. Foley and D. L. Comins J. Am. Chem. Soc. 1988 110 7445. 19 N. L. Allinger and C. K. Riew Tetrahedron Lett. 1966 7 1269. Communication 8/09274F Scheme 2 Possible transition states and recorded values for coupling constants. 684 Chem. Commun. 1999 683–684

ISSN:1359-7345    

DOI:10.1039/a809274e

出版商:RSC    

年代:1999

数据来源: RSC