Total Synthesis of (+)-4,5-Deoxyneodolabelline

Abstract

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.

Organocatalysis in Synthesis: L-Proline as an Enantioselective Catalyst in the Synthesis of Pyrans and Thiopyrans

“…Polyfunctionally substituted pyrans are no doubt an important class of heterocycles due to their great biological and pharmacological importance [1,2,3,4,5,6]. The addition of active methylene reagents to arylidenemalononitrile in the presence of homogeneous basic catalysts has been extensively used in the past for the synthesis of these compounds [7,8,9,10,11,12].…”

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

“…We have already described in our preliminary communication5 how this methodology can be applied to the formal synthesis of (+)‐4,5‐deoxyneodolabelline,18 Crinipellin B,17 and Guanacastepene A 19…”

Carbon-Ferrier rearrangements in ionic liquids using Yb(OTf)3 as catalyst

“…The stereoselectivity of the latter reaction is usually good in favor of the ␣-anomer, except in cases of conformational control [21]. Finally, it has to be noted that this reaction was one of the key steps of several elegant total synthesis of bioactive natural products [22][23][24][25]. As part of our ongoing studies on the potential uses of RTILs [26,27], we have studied this carbon-Ferrier rearrangement in ionic liquids, under lanthanide salt catalysis.…”