A Concise Synthesis of (−)‐Aplyviolene Facilitated by a Strategic Tertiary Radical Conjugate Addition

Abstract

Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products. [1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8-C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8. [3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 ( Figure 1A), [4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B). [5] In this latter effort, the key C8-C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6. [6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.As described in the accompanying communication, [7] our initial attempt to streamline the synthesis by using a tertiary organocuprate derived from cis-perhydroazulene nitrile 9 in the key fragment coupling was prevented by exclusive formation of adduct 11, which is epimeric to aplyviolene at the critical quaternary carbon stereocenter ( Figure 1C). This unexpected stereochemical outcome of the organocuprate conjugate addition reaction provoked consideration of an alternative strategy in which the C8-C14 σ-bond would be formed by the union of the tertiary radical 12 and enone 13 ( Figure 1D, X = leaving group). Reductive silylation of the coupled product 14 would then provide enoxy silane 8, an advanced intermediate in the synthesis of (−)-aplyviolene. Despite the many advances in stereoselective radical chemistry, [ 8 ] bimolecular reactions that transform trialkylsubstituted tertiary radicals to stereogenic quaternary carbons are extremely rare.

A Radical Cascade Enabling Collective Syntheses of Natural Products

“…Recent advances in photocatalytic radical reactions [24][25][26][27][28][29][30][31] have provided great opportunities in the synthesis of natural products. [32][33][34][35] Here, we report a photocatalytic radical cascade with excellent stereo-, regio-, and chemoselectivity to prepare libraries of chiral tetrahydrocarbolinones under mild conditions. This radical cascade can be scaled up and can generate two of the three monoterpenoid indole-alkaloid skeletons, including the corynanthe-type and aspidosperma-type alkaloids, by varying easily accessible substrates.…”

Nickel‐Catalyzed Cross‐Coupling of Redox‐Active Esters with Boronic Acids

“…[3,4] Thefact that all of these activated esters not only prime the carboxyl for nucleophilic attack but also accept an electron from al ow-valent metal in an SET-based thermal process was previously unrecognized. [5,6] Whereas the former process allows for ester and amide formation, the latter enables as imple thermal decarboxylative radical formation with immediate capture by that transition metal (Ni). [3][4][5]7] Herein, ar eaction analogous to the venerable Suzuki coupling for the cross-coupling of activated alkyl carboxylic acids with aryl and vinyl boronic acids is reported exhibiting ab road substrate scope,s calability,f unctional group tolerance,a nd inherent accessibility.…”

Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp3)−H Functionalization under Mild Reaction Conditions

“…Recently,v isible-light catalysis has provided au seful new entry to the initiation of radical reactions under mild reaction conditions with good functional-group compatibility,h owever,a lkoxyl radical generation under photoredox conditions is unknown (Scheme 1b). [11,12] Theu tilization of unactivated C(sp 3 )ÀHb onds to engage in new CÀCb ond formation is desirable,b ut it is difficult to control the regioselectivity and chemoselectivity. [13] The alkoxyl radical easily activates C À Hb onds by as elective intramolecular 1,5-hydrogen atom transfer (1,5-HAT) reaction because of the higher oxygen-hydrogen bond energy.…”