Total synthesis of (+)-4,5-deoxyneodolabelline.
The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxyneodolabelline (1) has been accomplished. The highly efficient approach is characterized by the convergent assembly of dihydropyrans 2ab and cyclopentylsilanes 3ab. Allylic silane 3a was prepared from 2-methyl-2-cyclopentenone via a copper-catalyzed 1,4-addition followed by diastereoselective alkylation of the resulting enolate. A chemical resolution of racemic cyclopentanone 8 was effected by (S)-CBS-catalyzed borohydride reduction. Direct hydroxymethylation of the enantioenriched ketone 8 to form allylic alcohol 14 was achieved by a Stille palladium-catalyzed cross-coupling from the cyclopentenyl triflate 13. Treatment of the corresponding allylic phosphate 15 with trimethylsilylcopper reagent provided for displacement with allylic transposition yielding the exocyclic allylsilane 3a with excellent diastereoselectivity. Dihydropyrans 2a and 2b were prepared from optically pure acyclic acetals via ring-closing metathesis. Coupling of 3a and 2a or 2b via the carbon-Ferrier protocol gave trans-2,6-disubstituted dihydropyrans 30 and 35 with complete stereoselectivity. Vanadium-based pinacol coupling reactions were explored for closure of the medium-sized carbocycle to yield syn-diol 33. X-ray diffraction studies of the monobenzoate 34 have provided unambiguous stereochemical assignments. Substantial ring strain accounted for the lack of alkene products typical of reductive elimination using TiCl(3) and zinc-copper couple (McMurry) conditions leading to 37. Finally, the natural product 1 was obtained via Swern oxidation of the diol 37.
Williams
David R
DR
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, USA. williamd@indiana.edu
Heidebrecht
Richard W
RW
D000478:Alkylation; D000818:Animals; D003517:Cyclopentanes / Q000737:chemistry; D004224:Diterpenes / Q000138:chemical synthesis*; D008974:Mollusca / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry; D012821:Silanes / Q000737:chemistry
C472957:4,5-deoxyneodolabelline; D003517:Cyclopentanes; D004224:Diterpenes; D011714:Pyrans; D012821:Silanes; C115566:dolabellane