Synthesis of (7S,15S)- and (7R,15S)-dolatrienoic acid.
The stereospecific synthesis of (7S,15S)- and (7R,15S)-dolatrienoic acids (2) was achieved using an approach consisting of 16 linear steps. The C-11--C-16 unit was prepared in seven steps from ethyl (S)-lactate and coupled using a trans-selective Wittig--Schlosser reaction to the C-7--C-10 fragment. Chirality at the C-7 position was introduced using an Evan's-type chiral auxiliary in a cobalt-mediated Reformatsky reaction to give the (3S,11S)-aldehyde 24. Subsequent Wittig reaction with a phosphonium salt derived in three steps from tiglic acid gave (7S,15S)-dolatrienoic acid, one of the four possible diastereoisomers of the nonpeptide portion of the strong cancer cell growth inhibitory cyclodepsipeptide dolastatin 14 (1). A second diastereoisomer, (7R,15S)-dolatrienoic acid, was synthesized employing chiral oxazolidinone 21 by an analogous synthetic route.
Duffield
J J
JJ
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-2404, USA.
Pettit
G R
GR
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D015394:Molecular Structure; D008974:Mollusca / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D013057:Spectrum Analysis; D013237:Stereoisomerism
D000475:Alkenes; D010456:Peptides, Cyclic; C430150:dolatrienoic acid