Studies of transannular (4+3) cycloadditions and application to the synthesis of (+)-cortistatin A

Abstract

The first transannular (4+3) cycloadditions based on the activation of epoxy enolsilanes have been realized. Six macrocyclic epoxy ketones were converted to enolsilanes, then treated with a catalytic amount of TESOTf at low temperatures, in some cases as a one pot reaction, to afford cycloadducts 3.44, 3.51, 3.55, 3.56, 3.57, 3.58, and 3.79, with 5-7-6, 5-7-5, 6-7-5, 5-7-6, 6-7-7 fused ring systems. Cycloadduct 3.53 was not formed under similar conditions. In addition, treatment of epoxy ketone 3.40 with base at 0 °C provided cycloadduct 3.44 directly in good yield and as a single diastereomer. These conditions for inducing (4+3) cycloaddition of epoxy ketones were discovered for the first time, and represent a more atom and step-economical protocol for inducing reaction. Cycloaddition of enantiomerically enriched (+)-3.40 provided (+)-3.44 with conservation of ee. Under similar conditions, O-tethered epoxy ketone 3.65 also afforded cycloadduct 3.73 diastereoselectively. Since cycloadduct 3.44 has the correct relative stereochemistry of cortistatin A, an anti-angiogenic and anti-leukemic marine natural product, a new asymmetric synthesis employing this transannular (4+3) cycloaddition as the key strategy towards cortistatin A was pursued. Our attempt started from commercially available diketone 4.17, which was alkylated to afford 4.16. Asymmetric desymmetrization of diketone 4.16 using Noyori’s reduction provided an enantiomerically enriched alcohol 4.15. This alcohol was converted to enol triflate 4.24, which underwent Suzuki-Miyaura coupling to install the furan moiety to furnish diol 4.14 after deprotection. A hydroxyl-directed hydrogenation of the double bond using Crabtree’s catalyst afforded diol 4.26, which was converted to ketal 4.13 in overall 12 steps. Ketal 4.13 was alkylated with optically enriched epoxide 4.49, which was synthesized via a Sharpless epoxidation to furnish alcohol 4.50. Protection and deprotection steps led to alcohol 4.52, which was converted to enone 4.48 in 3 steps. Enone 4.48 was cyclized via ring-closing metathesis to afford macrocyclic enone 4.53. After epoxidation, epoxide 4.47 was subjected to the (4+3) cycloaddition conditions. However, under both basic and Lewis acidic conditions, the cycloaddition failed to provide the expected cycloadduct 4.54, which may be due to the stereochemistry at C3 being opposite to that found in cortistatin A.