Regioselective Synthesis of Acyclic -Enediynes via an Acid-Catalyzed Rearrangement of 1,2-Dialkynylallyl Alcohols. Syntheses, Computational Calculations, and Mechanism.

A novel synthesis of acyclic -enediynes has been established by an acid-catalyzed rearrangement of 1,2-diyn-2-propen-1-ols possessing a C-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 and the C-methyl-substituted failed to give enediynes, whereas the C-aryl-substituted and underwent the allylic rearrangement to provide predominantly -enediynes and at room temperature or below. Under similar acidic conditions, enediyne alcohol produced and with the same regio- and cis/trans diastereoselectivity observed for . Allyl alcohol , an isomer of , also provided enediynes and after a prolonged reaction (90 h) at room temperature in the presence of CSA and EtOH. These results suggested that the same allylic cations were obtained from allyl alcohols and or and 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 (-)- and (-)- furnished racemic products. In general, the -MeOPh-substituted allyl alcohol gave a better regioselectivity than the Ph-substituted . In the reactions with alcohols, the regioisomeric ratios were 100:0 (:) for and ca. 96:4 (:) for ; the ratios decreased to ca. 90:10 (:) for and ca. 70:30 (:) for when thiols were used. The cis/trans diastereoselectivity is higher for allyl alcohol (100% for at 20 °C) compared to that for (: = 80:20-94:6 at 0 °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 C carbon to form the thermodynamically much more stable enediynes. Under the best reaction conditions (1 equiv of CSA and 2 equiv of EtOH in CHCl, 20 °C), a number of acyclic -enediynes can be synthesized in three steps from the commercially available α-bromocinnamaldehyde ().