Total synthesis of rhizoxin D, a potent antimitotic agent from the fungus Rhizopus chinensis.
Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the beta carbon of the (Z)-alpha,beta-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired beta-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from delta-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.
White
James D
JD
Department of Chemistry, Oregon State University, Corvallis 97331-4003, USA. james.white@orst.edu
Blakemore
Paul R
PR
Green
Neal J
NJ
Hauser
E Bryan
EB
Holoboski
Mark A
MA
Keown
Linda E
LE
Nylund Kolz
Christine S
CS
Phillips
Barton W
BW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D012233:Rhizopus / Q000737:chemistry*
D000970:Antineoplastic Agents; D007783:Lactones; C479980:rhizoxin D