Total synthesis of (+/-)-communesin F.

Since the isolation of potent cytotoxic communesins A and B from a marine fungal strain of Penicillium sp. in 1993,1 eight members (A-H) of this structurally intriguing indole alkaloid family were consecutively disclosed over the past 5 years2 (Figure 1). Although the polycyclic framework and multiple stereocenters of communesins have attracted intensive synthetic efforts toward skeletal construction in recent years,3 the successful synthesis of members of this indole alkaloid family still remains unresolved.4 In this communication, we describe the first total synthesis of (()communesin F. In view of construction of the multi-ring system (Figure 1), we envisioned that formation of the F ring could be accomplished by displacement of the imidate ether group with the second amine group on the G ring (5 to 6) at a later stage of the synthesis. An acid-catalyzed cyclization of 4, after introducing an allylic alcohol side chain at C12a of 3 by a Heck reaction, could readily generate the azepine ring. Stereoselective R-allylation of the ester functional group of 2 would lead nicely to set up the C8 quaternary carbon and would guarantee the subsequent formation of the C, E, F, and G rings with the correct stereochemical centers. The pentacyclic substructure 2 with a C7 quaternary carbon could be efficiently assembled from diazo 1 using a methodology of intramolecular cyclopropanation, ring opening, and ring closing reactions, the methodology of which was developed in our group.5 As demonstrated in Scheme 1, the preparation of 3 commenced with indole 76 and acid 8.5 Condensation of 7 and 8, followed by two steps of functional transformation from ketone to diazo, furnished 1. Treatment of 1 with CuOTf led to the formation of a stable cyclopropane intermediate 9 in an 88% yield as a mixture of two diastereomeric isomers in a 1.6:1 ratio. Reduction of the azide group in 9 with PBu3 in aqueous THF resulted in a two-step cascade reaction of cyclopropane ring collapse and ring closure with an in situ generated aniline, to give the kinetic product 2 in an 83% yield as a single diastereoisomer. For stereoselective generation of the C8 quaternary center by R-allylation for further construction of the E ring, the nitrogen in 2 had to be protected first with a methoxycarbonyl group. The N5-protection was easily completed to afford carbamate 10 in excellent yield when 2 was treated with methyl chloroformate and DMAP in CHCl3. Interestingly, quantitative conversion of 10 to its epimer 11 was realized by treatment of 10 with DMAP in CH2Cl2 at room temperature. We originally thought that epimeric carbamates 10 and 11 might provide diastereomeric allylation products, but both isomers yielded the same compound 3 as the sole product with an 84% yield when 10 and 11 were treated with NaH and allyl bromide in dry DMF at 0 °C for 1 h, then at 65 °C for 3 h, respectively. Successful isolation of the ketene acetal intermediate 12 confirmed that R-allylation of this type of six-membered lactone proceeded through a stereoselective 3,3-rearrangement.7 In such a rearrangement, one face of the dihydropyran ring was completely shielded by the bromophenyl group to provide 3 with a secured cis relationship between the C7 ethylene group and the C8 allylic side chain, verified by a NOEDs experiment of 3. Completion of the total synthesis of communesin F from 3 is depicted in Scheme 2. Oxidative cleavage of the double bond in 3 gave aldehyde 13 in a 95% yield. Conversion of the aldehyde functionality of 13 into an amine, followed by heating the resulting amino product with MeONa in MeOH at reflux, furnished the E ring and left the hydroxyl group of the C7 side chain unprotected (14). Dess-Martin oxidation, conversion of the resulting aldehyde Figure 1. Retrosynthetic analysis of communesin F.