Regioselective synthesis of acyclic cis-enediynes via an acid-catalyzed rearrangement of 1,2-dialkynylallyl alcohols.: Syntheses, computational calculations, and mechanism

A novel synthesis of acyclic cis-enediynes 2 has been established by an acid-catalyzed rearrangement of 1,2-diyn-2-propen-1-ols 1 possessing a C-3-aryl group in the presence of water, alcohols, or thiols. Reactivity of allyl alcohols and regio- and cis/trans diastereoselectivity of the allylic migration were examined. In the presence of(+/-)-10-camphorsulfonic acid (CSA), the parent allyl alcohol 5 and the C-3-methyl-substituted 9 failed to give enediynes, whereas the C-3-aryl-substituted 12 and 29 underwent the allylic rearrangement to provide predominantly cis-enediynes 16 and 31 at room temperature or below. Under similar acidic conditions, enediyne alcohol 13 produced 16b and 16d with the same regio and cis/trans diastereoselectivity observed for 12. Allyl alcohol 30, an isomer of 29, also provided enediynes 31c and 32c after a prolonged reaction (90 h) at room temperature in the presence of CSA and EI;OH. These results suggested that the same allylic cations were obtained from allyl alcohols 12 and 13 or 29 and 30 even though the ease of ionization differed for each substrate. Involvement of allylic cations in the product-forming step was confirmed by the finding that chiral allyl alcohols (-)-12 and (-)-18c furnished racemic products. In general, the p-MeOPh-substituted allyl alcohol 29 gave a better regioselectivity than the Ph-substituted 12. In the reactions with alcohols, the regioisomeric ratios were 100:0 (31:33) for 29 and ca. 96:4 (16:17) for 12; the ratios decreased to ca. 90:10 (31:33) for 29 and ca. 10:30 (16:17) for 12 when thiols were used. The cis/trans diastereoselectivity is higher for allyl alcohol 12 (100% for 16 at 20 degrees C) compared to that for 29 (31:32 = 80:20-94:6 at 0 degrees C). Computational calculations at the RHF/3-21G level, carried out on the model compounds and allylic cations, indicated that nucleophilic trapping takes place preferentially at the Cg carbon to form the thermodynamically much more stable enediynes. Under the best reaction conditions (1 equiv of CSA and 2 equiv of EtOH in CH2Cl2, 20 degrees C), a number of acyclic cis-enediynes can be synthesized in three steps from the commercially available alpha-bromocinnamaldehyde (10).