Synthesis of petrosins C and D

Petrosins C and D (5 and 6), diastereomers of the known natural products petrosin (1), petrosin A (2), and petrosin B (3), have been prepared. The synthetic route involved initial creation of a 16-membered bis-pyridine intermediate, exemplified by compounds 7, 28, and 52. Several different methods for formation of the macrocycle were evaluated, and the most efficient (Schemes 7-9) involved use of Z double bonds in the six-carbon chains linking the two pyridine rings. This approach permitted the two pyridine subunits (37 and 39) to be joined by alkylation of a lithiated alpha-methylpyridine with an allylic chloride (e.g., 37 + 39 --> 40 and 49 --> 45). Bisannulation of compounds 7 and 28 was complicated by a surprising lack of acidity of the a-pyridyl methylene groups. Eventually, this problem was solved by stepwise introduction of two allyl groups, using the more acidic sulfone for introduction of the first (e.g., 52 --> 53) and direct allylation to introduce the second (e.g., 54 --> 55 + 56). The bisannulation was completed by hydroboration and conversion of the primary alcohols into methanesulfonate derivatives, which cyclized to afford bis-pyridinium derivatives. Reduction of these intermediate salts with sodium borohydride provided crystalline bis-enol ethers (60 and 63) and the relative configuration was established by single-crystal X-ray analysis of 63. After hydrolysis of the enol ethers to the corresponding ketones, the syntheses of 5 and 6 were completed by enolate methylation. As expected, compounds 5 and 6 do not form imine derivatives when treated with primary amines, presumably because of A(1,3) strain.