Total synthesis of (-)-tubingensin B enabled by the strategic use of an aryne cyclization

Abstract

Tubingensin B is an indole diterpenoid that bears a daunting chemical structure featuring a disubstituted carbazole unit, five stereogenic centres-three of which are quaternary-and a decorated [3.2.2]-bridged bicycle. We describe our synthetic design toward a concise and enantiospecific total synthesis of tubingensin B, which hinges on the strategic use of a transient aryne intermediate. Although initial studies led to unexpected reaction outcomes, we ultimately implemented a sequence of carbazolyne cyclization followed by Rh-catalysed fragmentation to install the seven-membered ring and vicinal quaternary stereocentres of the natural product. Coupled with a late-stage radical cyclization to construct the [3.2.2]-bridged bicycle, these efforts have enabled the total synthesis of tubingensin B. The design and evolution of our succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

Figure 1 |. The structures of tubingensins B and A.

a, Tubingensin B (1) possesses an intricate hexacyclic ring system bearing a bicyclo[3.2.2]nonane core and five stereogenic centres, three of which are quaternary. Although its simpler counterpart tubingensin A (2) has been synthesized previously, there is no reported total synthesis of 1. b, Crystal structure oftubingensin B (1).

Figure 2 |. Retrosynthetic analysis of tubingensin B.

The natural product 1 was envisioned to arise through a series of disconnections that would enable the rapid generation of molecular complexity. Key strategies highlight: a radical cyclization to forge the bicyclo[3.2.2]nonane core, a carbazolyne cyclization for the formation of the seven-membered ring containing vicinal quaternary centres, and the union of two fragments via Suzuki–Miyaura coupling. MOM, methoxymethyl.

Figure 3 |. Synthesis of coupling fragment 7 and assembly of tetrasubstituted alkene 13.

a, Vinyl iodide 7 was synthesized on gram scale from known aryl triflate 8 in four steps. b, Hydroboration of known olefin 11 and subsequent palladium-catalysed Suzuki–Miyaura coupling with vinyl iodide 7 gave 13. MOM, methoxymethyl; DMF, dimethylformamide; THF, tetrahydrofuran; MsCl, methanesulfonyl chloride; DMIPS, dimethyl(isopropyl)silyl; 9-BBN, 9-borabicyclo[3.3.1]nonane; dba, dibenzylideneacetone.

Figure 4 |. The key aryne cyclization forges the C20–C11 linkage.

Enol ether 15 was synthesized in three steps from 13 and assessed in the critical carbazolyne cyclization. Although the use of conventional aryne cyclization conditions delivered the undesired cyclobutenol 16, switching to longer reaction times and higher temperatures furnished the desired pentacyclic ketone 17. 18-crown-6, 1,4,7,10,13,16-hexaoxacyclooctadecane; MOM, methoxymethyl; DMIPS, dimethyl(isopropyl)silyl; THF, tetrahydrofuran; m-CPBA, meta-chloroperbenzoic acid; TESCl, triethylsilyl chloride.

Figure 5 |. Radical cyclization and first generation total synthesis of tubingensin B.

Radical cyclization precursor 19 was prepared using several functional group manipulations. In turn, the radical cyclization led to the efficient assembly of the [3.2.2]nonane core and provided bicycle 20. Following further manipulations, 1 was obtained, albeit with its C19 epimer forming predominantly in the final step. MOM, methoxymethyl; THF, tetrahydrofuran; TIPSOTf, triisopropylsilyl trifluoromethanesulfonate; AIBN, azobisisobutyronitrile; TBAF, tetrabutylammonium fluoride; DMP, Dess–Martin Periodinane; BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.

Figure 6 |. Concise total synthesis of tubingensin B.

To overcome arduous functional group manipulations, alkyl selenide 22 was prepared and employed in the key aryne cyclization. To complete the synthesis, several key steps including rhodium-catalysed cyclobutenol ring-opening, radical cyclization, and diastereoselective reduction were executed. This second-generation total synthesis affords (−)-tubingensin B (1) in 9 steps from fragments 11 and 7. MOM, methoxymethyl; DMIPS, dimethyl(isopropyl)silyl; TESCl, triethylsilyl chloride; cod, 1,5-cyclooctadiene; AIBN, azobisisobutyronitrile; DM-SEGPHOS,(R)-(+)-5,5′−Bis[di(3,5-xylyl)phosphino]-4,4′-bi-1,3-benzodioxole,[(4R)-(4,4′-bi-1,3-benzodioxole)-5,5′diyl]bis[bis(3,5-dimethylphenyl)phosphine].