Patent DE-19921580-A1 (DE)
Title: Preparation of pure stereoisomers of new or known substituted pyrrolidine or piperidine derivatives, used e.g. as components of chiral catalysts, alkaloids or drugs
Inventor: REGGELIN MICHAEL
IPC: C07D209/52
Filed: 1999-05-10
Abstract: 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.