Synthesis of (-)-longithorone A: Using organic synthesis to probe a proposed biosynthesis

Abstract

We present a full report of our enantioselective synthesis of (؊)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared atropselectively, providing examples of ene-yne metathesis macrocyclization. The 1,3-disubstituted dienes produced from the macrocyclizations represent a previously unreported substitution pattern for intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were used as removable atropisomer control elements and were installed by using a highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and 27.A n intriguing question in natural product biosynthesis is whether nature uses Diels-Alder reactions. The answer to this question appears to be yes, because there are many examples of spontaneous Diels-Alder reactions in biosyntheses (1) as well as recently documented examples (2-4) of enzymatically influenced Diels-Alder reactions. Longithorone A (1) is a marine natural product that attracted our attention because of its unusual structure, but even more so because of the biosynthetic proposal of Schmitz and co-workers (5, 6) that invoked two Diels-Alder reactions. Schmitz has proposed that 1 arises from the combination of [12]-paracyclophane quinones 2 and 3 by an intermolecular Diels-Alder reaction, affording ring E, and a transannular (7) Diels-Alder reaction, generating rings A, C, and D (Fig. 1).We viewed this interesting proposal as an opportunity to use organic synthesis to make protected versions of 2 and 3 and test, in the laboratory, the feasibility of the proposed Diels-Alder reactions (8). In particular, we were hopeful that our experiments might suggest whether the intermolecular Diels-Alder reaction occurs preferentially between compound 4, which has already undergone a transannular Diels-Alder, and paracyclophane 2 to generate 1 or between paracyclophanes 3 and 2 to generate 5, followed by a transannular Diels-Alder to afford 1.The isolation (5) of longithorones B (9) and C, [12]-paracyclophane quinones that closely resemble the structures of 2 and 3, provided some support for the proposed biosynthesis of longithorone A (Fig. 2).We found it intriguing that longithorones B and C exhibit atropisomerism (10-12) and are single enantiomers. From these observations, we recognized that 2 and 3 must be constructed atropselectively to test whether the absolute and relative stereochemistry of 1 is derived solely from the planar chirality of 2 and 3. Finally, the isolation of longithorone I suggested that the biosynthesis of 1 may first involve an intermolecular Diels-Alder reaction between 2 and 3 followed by a...

Natural Products with Anti‐Bredt and Bridgehead Double Bonds

“…Schmitz and co-workers proposed that the key step in the biogenesis of these compounds was a [4+2] cycloaddition of 148 with 149 giving rise to the bicyclo[13.3.1] system. [93] In the total synthesis of (À)-longithorone A (138) published by Shair and co-workers, [96] this [4+2] cycloaddition was successfully modeled using appropriately protected synthetic equivalents of 148 and 149 to furnish the bicyclic core, giving credence to the proposed biosynthetic pathway (Scheme 9).…”

Quinones as Dienophiles in the Diels–Alder Reaction: History and Applications in Total Synthesis

“…In 2002, Matthew Shair and co-workers at Harvard published a biomimetic total synthesis of the unusual heptacyclic natural product longithorone A. [68] This was unique in that unlike all of the syntheses discussed so far, the quinone Diels-Alder reaction was the final step in the synthetic sequence. Although the natural product itself appears formidable, as it possesses both a number of contiguous stereogenic centers and atropisomerism resulting from hindered rotation around the lone G-ring quinone, an intriguing biosynthetic proposal by Helm and Schmitz, [69] based on two Diels-Alder reactions, appeared to simplify the problem greatly.…”

Dearomatization Strategies in the Synthesis of Complex Natural Products

“…1:1.4; Scheme 22). [59] Further oxidation of both hydroquinone moieties led to the corresponding dearomatized bis(parabenzoquinone) intermediate 171 which spontaneously underwent transannular Diels-Alder cycloaddition to simultaneously forge the last three rings of the natural product (90 % yield). This synthesis was highlighted by two consecutive key transformations first constructing the cyclohexene ring by [4+2] cycloaddition and then assembling the last three rings in a single oxidative dearomatization/Diels-Alder cycloaddition sequence.…”

“…It is noteworthy that the use of a 1,1-disubstituted alkene as the dienophile in the inverse-demand [4+2] cycloaddition allowed the formation of the crucial quaternary stereocenter. Subsequent modifications of the N,O-ketal moiety, redox adjustments, and separation of the enantiomers by HPLC finalized the synthesis of (+)-fendleridine (59).…”