Patent DE-10051136-A1 (DE)
Title: New alpha-hydroxy-ketone derivatives, useful as intermediates for biologically active polyketides, terpenoids, epothilones and their derivatives
Inventor: WESSJOHANN LUDGER A
IPC: C07D417/06
Filed: 2000-10-16
Abstract: alpha -Hydroxy-ketone (acyloin) compounds (I), in non-racemic, optically active or racemic form at the  alpha -hydroxy-position, and their hydroxy-protected derivatives are new. Also new are several classes of new intermediates for and conversion products of (I). alpha -Hydroxy-ketone (acyloin) compounds of formula (I), in non-racemic, optically active or racemic form at the  alpha -hydroxy-position, and their hydroxy-protected derivatives are new: R1  = H, alkyl, aryl, aralkyl (e.g. arylmethyl or arylethyl), vinyl, alkynyl (preferably propynyl), allyl (preferably 3,3-dialkylallyl; sic), cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these;  R2  = alkyl, aryl, alkaryl (e.g. arylmethyl or arylethyl), vinyl, alkynyl (preferably propynyl), allyl (preferably alkylallyl, 3,3-dialkylallyl, E- or Z-3-haloallyl or 3,3-dihaloallyl; sic), cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these; and n = 0-3. Independent claims are included for:  (1) new intermediates for and conversion products of (I), having formulae R1-C(Z)-CH(R2)-C(O)-R3 (V), Aux-N asterisk -C(O)-CHR'2-O-P' (VI), (VII), (X), (Xa), (XI), (XIa), (XII), (XIII), (XVa) and (XVb); (2) the preparation of the new compounds; and (3) the preparation of epothilone compounds of formula (XVI), by ring-closing lactonization, Reformatsky-type reactions and/or macro-aldolization of (XVa) or (XVb). Aux-N asterisk  = N-O-alkyl (preferably N-OMe) or an Evans auxiliary of the oxazolidinone or imidazolidinone type; H, Me, Et or propyl (especially Me);  R'2  = allyl derivative group of formula (a);  B<1> - B<3>  = single bond, triple bond, double bond (in E-, Z- or E/Z-mixture form), epoxide or cyclopropane ring (in E-, Z- or E/Z-mixture form), in particular B<1> being a Z-double bond or epoxide and B<1> and B<3> being single bonds;  R4  = H, halo, alkyl, aryl, aralkyl (e.g. arylmethyl or arylethyl), vinyl, cycloalkyl (preferably 3-7 membered), CHnFn-3, oxacycloalkyl (preferably 3-7 membered) or a combination of these, especially H, Me, Et or Cl;  n = 0-3; E  = Me, CH2OH, CH2OP', CHO, COOR, COOP', CH2X, CON(R)2, CON(P')2, CON(OMe)Me or CN, especially CH2OH, CH2OP' or CHO;  P'  = protecting group;  P''  = H or P';  X  = H, OH, halo or other leaving group;  R, R', R''  = as R4 but not halo; preferably R = H, Me or Et, R' = H and R'' = Me;  Nu  = R, OP', OR, N(P')2, dialkylamino, SP', alkylthio, SeP', alkylselenyl, CN, N3 or aryl, especially H or alkyl; Y  = S, NH, NP', NR or O;  R3  = alkyl, aryl, aralkyl (e.g. arylmethyl or arylmethyl), alkoxyalkyl or fluoroalkyl (preferably Me, Et or propyl);  Z'  = O, =N-Nu, =CH-heteroaryl, =CH-aryl or P(R3)3 (all in E-, Z- or E/Z-mixture form), especially (E)-(2-methylthiazol-4-yl)-CH= or (E)-(2-methyloxazol-4-yl)-CH=;  X' = as X but not H;  Y'  = OH, OR, OP', NH2, N(R)2, N(P')2, SR or SH; Y''  = OH, OR, OP', NH2, N(R)2, N(P')2, SR, SH, Cl, Br or C(R')2-G; Z''  = O, OH, OP', NH, NH2, NR, N(R)2, NP', N(P')2, SR, SP' or R;  G = E, CN, COR, dialkyl phosphonate, SO2R, SO2OR, CF3, CCl3 or NO2;  in (VII), (X), (Xa), (XI), (XII), (XIII), (XVa), (XVb) and (XVI) aryl moieties are phenyl, naphthyl, benzyl or their derivatives; and heteroaryl moieties are 5- or 6-membered heteroaryl containing one or more O, S or N atoms, optionally substituted by 1-4 of alkyl, alkoxy and halo: