Diastereoselective one-pot Wittig olefination–Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

Abstract

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.

Synthesis of Luffarin L and 16-epi-Luffarin L Using a Temporary Silicon-Tethered Ring-Closing Metathesis Reaction

“…Wittig 30,31 reaction of 2-deoxy-D-ribose (Scheme 3) gave triol 11 in excellent yield, the intermediate for the synthesis of lactones 5 and 6 (Schemes 3 and 4). The 1,2-protection of 11 was carried out with 2,2-dimethoxypropane 32 and p-toluenesulfonic acid in order to obtain 12 that by a Mitsunobutype inversion 33−35 Ring-Closing Metathesis Silicon-Assisted and Synthesis of Luffarin L (1) and 16-epi-Luffarin L (2). Once lactones 5 and 6 were obtained, the synthesis of luffarin L and 16-epi-luffarin L was continued using the following methodology.…”

“…Wittig , reaction of 2-deoxy- d -ribose (Scheme ) gave triol 11 in excellent yield, the intermediate for the synthesis of lactones 5 and 6 (Schemes and ). The 1,2-protection of 11 was carried out with 2,2-dimethoxypropane and p -toluenesulfonic acid in order to obtain 12 that by a Mitsunobu-type inversion − led to intermediate 7 . This compound was deprotected with PPTS to give triol 13 that by treatment with benzaldehyde dimethyl acetal in the presence of camphorsulfonic acid gave 14 .…”

Applications of Mitsunobu Reaction in total synthesis of natural products

“…They applied Horner‐Wadsworth‐Emmons (HWE) and Ramberg Backlund reactions in their strategy. However, several other protocols were reported for the synthesis of natural and its synthetic analogues from varitriol. However the total synthesis of 77 completed with reaction between sulfone 81 and 82 in the presence of lithium hexamethyl disilazane in THF as solvent .…”

Copper-Catalyzed Direct Allenylation of Inactive Cyclic Ethers

“…Cyclic ethers are one of the most important structural motifs widely found in natural products and synthetic pharmaceuticals, such as anticancer drug (Tegafur), antifungal drug (Ketoconazol), and antiviral drug (Didanosine, Ribavirin, and Zalcitabine) (Figure ). Consequently, it is of great significance to develop versatile methods to synthesize structural various cyclic ether derivatives.…”