Homo-Freidinger Lactams: Stereoselective Synthesis of 4-Aminopiperidin-2-one Derivatives from Aspartic Acid Klaus Weber and Peter Gmeiner* Institut ftirPharmazie und Lebensmittelchemie der Universitiit Erlangen-Ntirnberg, SchuhstraBe 19, D-91052 Erlangen, Germany Fax: +49(9131)852585; E-mail: gmeiner@pharmazie.uni-erlangen.de R ec eived 20 Apri/1998-06-23 Abstract: Starting from aspartic acid a stereoselective synthesis of enantiomerically pure 4-aminopiperidin-2-ones which can serve as conformationally restrained B-amino acid equivalents in peptidomimetics is described. The synthesis is based on the regioselective functionalization of the l,4-bis-electrophile 2b and a diastereoselective introduction of various side chain equivalents into the lactam a-position of 4b,c. Conformationally locked peptide surrogates have been utilized extensively in the design and development of enzyme inhibitors or neuroreceptor ligands. l -4 This strategy afforded valuable information regarding the elucidation of the biologically active conformation of peptides and led to drug candidates with remarkable affinity, selectivity and metabolic stability.5 Among the numerous developments in this field, incorporating the a-amino carboxamide moiety of a peptide backbone into a Freidinger lactam (I) has proven very successful. 6 - 10 On the other hand, B-amino acid derived substructures and the investigation of B-peptides led to interesting peptidomimetics. l1 - 13 As far as we know, a combination of these two strategies was not reported yet. As part of our efforts on the synthesis of enantiopure B-amino acid derivatives, 14.15here we report the first stereoselective synthesis of 4- aminopiperidin-2-ones as lactam-bridged analogs with a B-amino carboxamide substructure (Homo-Freidinger lactams, II). Applying this approach, our initial results on lactam-constrained mimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH 2 16 are presented. The synthesis of aN-protected 4-aminopiperidine in enantiomerically pure form was planned starting from natural aspartic acid (1). Taking advantage of our recently described methodology we were able to functionalize regioselectively the dibenzyl protected aminobutanediol 2a. 17 - 20 Thus, activation of 2a by MesCl gave the bis-electrophile 2b which could be transformed into the azido nitrile 3a by subsequent substitution with LiCN and NaN 3 . Due to an activating anchimeric participation of the dibenzylamino group the leaving group in position 1 is exclusively displaced by the nucleophile which is added first. The formation of regioisomers was not observed. Chemoselective reduction of the azide functionality in the presence of the nitrile group was accomplished under Staudinger conditions 21giving the amino nitrile 3b in 81 % yield. Alternatively, a more direct preparation of 3b is possible when liquid NH 3 is used as the "second nucleophile" instead of NaN 3 . 22 Lactamization of the amino nitrile 3b was induced by HClIMeOH. The reaction sequence is highly practical and efficient providing the amino lactam 4a in 58 % overall yield, based on (S)-aspartic acid (I), as well as the (R)-configured enantiomer of 4a (ent-4a) when commercially available (R)-aspartic acid (ent-I) is used as the starting material. , ¢ °OH OH H 2 N ° 28: X = H 2b : X=Mes 1 . UCN (1.2 eq) THF / DMF, RT. 3h 2b 2 . NaN 3 , DMF, RT, 17h • 85% 1 . UCN (1 . 2 eq) THF IDMF. RT, 3h 2 . NH 3 /MeOH ·30·C • RT. 4d 82% PPh 3 , H 2 0 , THF RT,3d 81% sat. HCI (in MeOH •H , o, 99 : 1) 3b SO·C,12h 70% (from 28) (,t(Z ~ ~ Bn 2N ° 48: Z = H ---------, DMAP, Boc 2 0, NEt 3 CH 2 CI 2 , RT , 18h 71% 4b: Z = Boo 1) NaH (2eq) , THF , O·C 30 min., RT, 30 min 2) BnBr (2 . 5eq), RT, 15h Since 4a should serve as a versatile building block, introduction of substituents representing B-amino acid side chains was envisioned. This should be done by N-protection, deprotonation of the lactam a-position and subsequent reaction with representing electrophiles. We evaluated Boc and, alternatively, benzyl as protecting groups for the lactam function. Thus, deprotonation of the lactam 4 followed byadditionof Boc20 or BnBr afforded 4b 23and 4c, respectively. For the introduction of the Boc group reaction of 4a with Boc20 in the presence of DMAP 24 turned out to be the more convenient and higher yielding alternative. C- alkylation in position 3 was accomplished by deprotonation of 4b with LDA and subsequent trapping with Mel at -78°C. The reaction proceeded with high diastereoselectivity. Only the tran s isomer Sa could be detected by NMR spectroscopy of the crude reaction product. 25 After purification by flash chromatography the methylation product Sa, which represents a conformatively restricted equivalent for B 2 -homoalanine,26 was isolated in 75% yield. Analogously, deprotonation and methylation of the N-benzyl protected lactam 4c resulted in exclusive formation of tran s configured isomer Sb. Since the methylation of 4b proceeded in higher yield and enabled the performance of a selective cleavage of either N-substituents we chose the orthogonally protected lactam 4b for further alkylation reactions. Thus, the lactam bridged 6 2 _ homophenylalanine derivative Sc could be obtained from 4b in diastereomerically pure form when benzyl bromide was usedasan