Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

Abstract

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]undecene skeleton from commercially available glycidol as a common starting material. The former include (-)-isolaurallene (1), the enantiomeric form of natural (+)-neolaurallene (2), and (+)-itomanallene A (3c), and the latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α'-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.

Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

“…We were delighted to find that the application of our protocol to TIPS-protected α-alkoxy-substituted amide 92f (R = CH 2 OTIPS) 47 proved successful, and gy; 58 in comparison, the construction of vinyl chloride containing oxocenes via RCM is problematic, as has been alluded to by Steve Weinreb. 59 In addition, we have shown that the requisite RCM substrates can be synthesized in a substrate-controlled fashion via intermolecular amide enolate alkylation that avoids the use of additional chiral auxiliaries through the judicious choice of protecting groups.…”

“…47 Tracing the path from the smallest stars to the largest, we employed chelation-controlled nucleophilic addition, in- Most importantly, in our completely substrate-controlled synthesis, an intermolecular dianion alkylation and INAA sequence provided access to the α,α′-cis-disubstituted oxonene skeleton and α,α′-trans-disubstituted tetrahydrofuran, respectively.…”

“…47 Finally, the first asymmetric total synthesis of (+)-pannosallene (95) was accomplished in a substrate-controlled fashion in 19 steps from TIPS-protected (S)-glycidol, 43b as illustrated in Scheme 37. In addition, our synthesis established the relative stereochemistry between the dioxabicyclic skeleton and the bromoallene unit in 95.…”

“…Our concise synthesis of this C 15 acetogenin containing the rare α,α′-cis-disubstituted tetrahydrofuran moiety features highly stereoselective intermolecular and intramolecular amide enolate alkylations as key steps to establish both sets of relative α,α′-oxymethine configurations in the product. 47 Scheme 38 summarizes our work on the construction of medium-ring oxacyclic skeletons and highlights and compares the RCM and IAEA approaches using the cases of the α,α′-cis-and α,α′-trans-disubstituted oxocenes. It is known that these oxocenes can be constructed by RCM, which is one of the most efficient methods available for the purpose.…”

Cadmium iodide-mediated allenylation of terminal alkynes with ketones

“…A llene moieties have been found in many natural products and pharmaceuticals [1][2][3][4] . Due to the unique reactivities, allenes have also been demonstrated as useful and important starting materials in organic synthesis .…”