Stereoselective Synthesis of the C1–C16 Fragment of the Purported Structure of Formosalide B

Abstract

The first stereoselective synthesis of the C1−C16 fragment possessing stereo-enriched fully substituted tetrahydropyran (THP) along with tetrahydrofuran (THF) rings of the proposed structure of formosalide B is described in 12 longest linear steps with 22% overall yield, starting from two cheap and commercially available 1,5-pentanediol and L-glutamic acid, following a convergent approach. The key steps involve in this synthesis are Horner−Wadsworth−Emmons reaction, Sharpless asymmetric dihydroxylation, and acid-mediated ketalization to assemble the substituted THP ring, one-pot Sharpless dihydroxylation−S N 2-type cyclization, and Wittig homologation to construct the THF derivative.

The Formosalides: Structure Determination by Total Synthesis

“…Thorough NMR studies allowed only the relative configuration within each of the three color‐coded stereoclusters to be determined but could not establish their mutual relationships nor their absolute configuration; [9] eight possible combinations (four diastereomers and their respective enantiomers) have hence to be considered. Because of the flexibility of the macrocycle and the lack of crystallographic data, synthesis is arguably the most definitive way to the answer [12] . A priori, such a project must be capable of producing any conceivable isomer [13] .…”

“…Because of the flexibility of the macrocycle and the lack of crystallographic data, synthesis is arguably the most definitive way to the answer. [12] Ap riori, such ap roject must be capable of producing any conceivable isomer. [13] We reasoned that the blueprint sketched in Scheme 1qualifies for such an "integral approach": [14] specifically,t he late-stage attachment of the polyene side chain seemed advisable for the sake of convergence and for stability reasons alike.C onvergence is also imperative for the assembly of the eight diastereomeric macrocyclic cores that are potentially needed.…”

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review

“…Lu and his co-researchers reported the total synthesis of formosalide A in recent times. However, in 2020, Gajula et al [ 126 ] reported the total synthesis of C1-C16 fragment of formosalide B. The synthesis began with the reduction of lactone 305 by using DIBAL-H in the presence of dichloromethane followed by Wittig olefination and treatment with mesylate chloride in the presence of trimethylamine, dimethylaminopyridine and dichloromethane, which gave mesylate ester 306 in 95% yield.…”

The Tetrahydrofuran Motif in Polyketide Marine Drugs

“…The required trans-disubstituted tetrahydrofuran ring 68 was prepared by stereoselective cobalt-catalyzed oxidative cyclization of bishomoallylic alcohol 69, with excellent yield and selectivity (Scheme 12). Mohapatra and co-workers have also reported a stereoselective synthesis of the C1-C16 fragment of formosalide B [52]. A one-pot Sharpless asymmetric dihydroxylation of α,β-unsaturated ester 74, followed by intramolecular S N 2 displacement, produced the desired trans-tetrahydrofuran 75 with a high 88% yield and total stereoselectivity (Scheme 14).…”