Preparation of pure stereoisomers of new or known substituted pyrrolidine or piperidine derivatives, used e.g. as components of chiral catalysts, alkaloids or drugs

摘要

Stereochemically controlled preparation of highly substituted aza-cyclic compounds (I) involves reaction of metallized 2-alkenylsulfoximide compounds with N-protected alpha - or beta -aminoaldehydes, cyclization of the product and cleavage of the sulfonimidoyl-alkyl bond. Some products and intermediates are new compounds. Stereochemically controlled preparation of pyrrolidine or piperidine derivatives of formula (I) or their acid addition salts or protected derivatives comprises: (a) reacting a 2-alkenylsulfoximine of formula (II) successively with a base suitable for deprotonation, an organometallic reagent of formula XM2(OR12)3 (VII) and a stereoisomer of an amino-aldehyde of formula (VIII), to give a stereoisomer of a sulfoxime of formula (IX); (b) cleaving R13 to give an azacyclic substituted sulfoximine compound of formula (Xa), blocking the ring N with a base-stable protective group if R901 = H and cleaving a silyl protective group R11 if still present; (c) preparing (I; Y = O; R8 = R801; R9 = R902) (IA) by either: (c1) reductively cleaving the sulfonylimidoyl-alkyl bond of (Xa) (or a compound obtained by cleaving the silyl protective group R11) to give (I; Y = O; R8 = R801; R9 = R902; R1 = R101; R2 = H)) (IB); or (c2) after electrophilic activation of the sulfonimidoyl unit, cleaving the sulfonylimidoyl-alkyl bond of (Xa; R101 other than H) by base-induced elimination to give (I; Y = O; R8 = R801; R9 = R902; CHR1R2 = -CH=CHR102) (IC); and optionally (d) further converting (IA) by one or more of: Reaction (one or more times, each with inversion of configuration) with a reagent suitable for regenerating OH or forming NH2 in the 3-position; deprotection; alkylation or protection of the ring N; salification; and desalification. n = 0 or 1; R1 = H, 1-6C alkyl or Ph'-A-; Ph' = phenyl (optionally substituted by one or more of A' and OA'); A = lower alkyl; A' = A or lower haloalkyl R2, R3, R6, R7 = H; R4 = H, A or Ph'-A-; or R1 + R2 = =CH2 (optionally substituted by 1-5C alkyl, itself optionally substituted by Ph'); or R3+R4 = CH2CH2; or 3-6C alkylene (optionally containing 1-3 double bonds and optionally over-bridged by 1-2C alkylene (optionally substituted by 1 or 2 A)); R5 = H, A, OH, OA, Ph'-A- or Ph'-A-O-; R8 = H, CN, COOH (optionally esterified), CONH2 (optionally mono- or di-N-substituted), R'8 or 1-12C alkyl (optionally containing one or more of unsaturated bonds and/or substituents selected from halo, OH, OA, COOH (optionally esterified), CN, SH, SA, NH2, NHA, CONH2 (optionally mono- or di-N-substituted) and R'8); R'8 = 3-10C mono- or bicyclic ring system (optionally containing one or more of unsaturated bonds, ring O, N and/or S atoms and/or substituents selected from A', OA, OH, halo and Q); Q = lower alkylenedioxy bonded to two adjacent C; or R5 + R8 = group completing a 5-10C mono- or bicyclic ring system (optionally containing 1-3 unsaturated bonds, one or more ring O, N and/or S atoms and/or one or more substituents selected from A', OA', OH, halo and Q); or R6 + R7 = bond; and R5 + R8 = fused benzene ring (optionally: fused with a further 2-4C group to form an 8-10C bicyclic ring system containing 3-5 double bonds; containing one or more ring O, S and/or N atoms; and/or substituted by one or more of A' OA', OH, halo and Q); R9 = H, A, Ph'-A-O- or amino protecting group; or R8 + R9 = 3-4C alkylene; Y = O or NH; R101 = as R1 but excluding optionally substituted CH2; Ar = Ph (optionally substituted by one or more A); R10 = A, Ph (optionally monosubstituted by A or protected OH) or Ph-A- (optionally monosubstitituted by A in the ring); R1101 = silyl protecting group; X = halo; M2 = tetravalent transition met al; R12 = A, Ph or Ph-A-; R801 = as R8 but with reactive groups blocked by base-stable protecting groups; R901 = H; or R801 + R901 = 3-4C alkylene; R13 = amino protecting group; R11 = H or silyl protecting group; R902 = base-stable protecting group; or R902 + R801 = 3-4C alkylene; R102 = 1-5C alkyl or Ph'-(1-5C) alkylene. Independent claims are included for : (i) (IA) (including derivatives obtained by cleaving a protective group R801 or R901) as new compounds, provided that the 5-(CHR1R2) and 3-OH group are in the trans-configuration and the 4-(R4) group and 3-OH group are in the cis-configuration; (ii) (IB) as new compounds; (iii) intermediates (Xa) (including derivatives obtained by cleaving protective groups) as new compounds, provided that the 5-substituent and 3-OH group are in the trans-configuration and the 4-(R4) group and 3-OH group are in the cis-configuration; (iv) the use of samarium (II) iodide for the reductive desulfurization of (Xa); and (v) the use of the following in the stereochemically controlled preparation of aza-cyclic compounds: (R(S))-4(S)-isopropyl-2-p-toluoyl-4,5-dihydro-(1,2 lambda 6,3) oxathiazole-2-oxide or the corresponding (S(S))-4(S)-, (R(S))-4(R)- or (S(S))-4(R)- compound; or (S(S),N(1S))-N-(1-((tert. butyldimethylsilyl)oxy)methyl)-2-methylpropyl)-S-methyl-S-(4-methylphe nyl)-sulfoximide (sic) or the corresponding (S(S),N(1R))-compound.