SYNTHESIS OF PETROSIN-C AND PETROSIN-D

Petrosins C and D (5 and 6), diastereomers of the known natural produc ts petrosin (1), petrosin A (2), and petrosin B (3), have been prepare d. 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 th e six-carbon chains linking the two pyridine rings. This approach perm itted the two pyridine subunits (37 and 39) to be joined by alkylation of a lithiated alpha-methylpyridine with an allylic chloride (e.g., 3 7 + 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 se cond (e.g., 54 --> 55 + 56). The bisannulation was completed by hydrob oration and conversion of the primary alcohols into methanesulfonate d erivatives, which cyclized to afford bis-pyridinium derivatives. Reduc tion of these intermediate salts with sodium borohydride provided crys talline 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 an d 6 were completed by enolate methylation. As expected, compounds 5 an d 6 do not form imine derivatives when treated with primary amines, pr esumably because of A(1,3) strain.