New alpha-hydroxy-ketone derivatives, useful as intermediates for biologically active polyketides, terpenoids, epothilones and their derivatives

• Main Authors: HENKE, ERIK, KUIT, WOUTER, WESSJOHANN, LUDGER A, ORRU, ROMANO, SCHEID, GUENTHER, BORNSCHEUER, UWE
• Format: Patent
• Language: English; German
• Published: 23.01.2003
• Edition: 7
• Subjects: ACYCLIC OR CARBOCYCLIC COMPOUNDS; ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAININGELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN,SULFUR, SELENIUM OR TELLURIUM; APPARATUS THEREFOR; CHEMISTRY; CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION ORPROCESSING OF GOODS; GENERAL METHODS OF ORGANIC CHEMISTRY; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; HETEROCYCLIC COMPOUNDS; METALLURGY; ORGANIC CHEMISTRY; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS; TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINSTCLIMATE CHANGE

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 - B = 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 being a Z-double bond or epoxide and B and B 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: Die Erfindung betrifft racemische und insbesondere nicht-racemische Acyloine, deren Derivate, Verfahren zu deren Herstellung sowie deren Verwendung zur Herstellung von Epothilonen und deren Derivaten. Insbesondere betrifft die Erfindung die Herstellung von Acyloinen in nicht-racemischer Form durch Diastereomerentrennung oder -synthese mit Auxiliaren sowie durch enzymatische Recematspaltung. DOLLAR A Eine besonders bevorzugte Verbindung weist die folgende allgemeine Formel auf: DOLLAR F1