Total Synthesis and Determination of the Absolute Configuration of (+)‐Intricatetraol

Abstract

Intricatetraol (1), a member of a family of squalene-derived triterpene polyethers named oxasqualenoids, [1] was isolated from the red alga Laurencia intricata by Suzuki et al. in 1993. A crude fraction containing intricatetraol (1) as the major component exhibited cytotoxic activity against P388 "leukemia cells" with an IC 50 value of 12.5 mg mL À1 .[2] The structural analysis was mainly carried out by NMR spectroscopic methods. Although it was found that the molecule has C 2 symmetry, the cis configuration within the tetrahydrofuran ring, the R configuration at C11 (C14), the relative configurations at C6 and C7 (C18 and C19), C10 and C11 (C14 and C15), and at bromine-bonded C3 (C22) remained to be determined.There are many other types of oxasqualenoids; however, it is often difficult to determine their configurations even by highly advanced spectroscopic methods, especially for the acyclic portions that include stereogenic quaternary carbon centers, such as C6-C7 (C18-C19) and C10-C11 (C14-C15) in 1. These difficulties have prompted attempts to determine the configurations of oxasqualenoids by chemical synthesis. [3] Furthermore, the presence of the vicinal bromochloro functionality in 1 makes the problem of stereochemical assignment even more inaccessible. An enantioselective method for the synthesis of the vicinal bromochloro functionality, [4] which also occurs in the marine polyhalogenated monoterpene halomon (2), a promising anticancer agent, [5] has never been developed. Herein we report the total assignment of the configuration of (+)-intricatetraol (1) as 3 through the first asymmetric total synthesis of this natural product. The synthesis features the enantioselective construction of the vicinal bromochloro functionality through a pathway in which the configuration is secured.Suzuki et al. suggested structure 4, which disregards the configuration at C3 (C22), as a possibility on the basis of the hypothetical biogenesis, [2] and recently we [6] and Ujihara [7] independently confirmed this assignment. Our retrosynthetic analysis of the target compound 4 is depicted in Scheme 1. We envisaged that it would be efficient to dimerize by olefin metathesis the functionalized fragment 5, which represents half of the molecule, because of the C 2 symmetry of the natural product. The R or S configuration at the carbon atom attached to bromine in 5 could be introduced through epoxide chemistry. The desired trihydroxytetrahydrofuran 6 might be constructed by the stereospecific and stereoselective oxacycScheme 1. Retrosynthetic analysis of the target compound 4. AD= asymmetric dihydroxylation, AE = asymmetric epoxidation.[*] Prof.

Stereoselective Halogenation in Natural Product Synthesis

“…[58] The vicinal bromochloride moiety was constructed via stereospecific transformations of a stereoisomerically pure epoxide 155 . Epoxide opening with dilithium tetrabromonickelate afforded the secondary bromide 156 with inversion of configuration at the less hindered carbon atom.…”

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

“…The teams of Morimoto and Galano-Oger performed a Payne rearrangement which induced a 5-exo-tet cylization for the synthesis (+)-Intricatetraol, 28 (+)-Omaezakianol 29 and Phytofuran (Scheme 8). 30…”

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…The first of the two cascades is similar to the cascade cyclization used to construct 147, the THF-containing subunit of C 2 -symmetric oxasqualenoid intricatetraol [180]. Diepoxides 143 and 144 rearranged to the functionalized tetrahydrofurans 146 and 147, respectively, under basic conditions.…”