Synthesis of the Cortistatin Pentacyclic Core by Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling

Abstract

The pentacyclic core skeleton of the cortistatins has been prepared in a stereoselective fashion by strategic use of an alkoxide-directed metallacycle-mediated annulative cross-coupling. This metal-centered tandem reaction delivers a polyunsaturated hydrindane and establishes the C13 stereodefined quaternary center with high levels of stereocontrol. Subsequent regio- and stereoselective global hydroboration results in the realization of the DE-trans ring fusion and a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit was then accomplished through phenolic oxidation/ trans-acetalization, chemoselective reduction, regioselective cleavage and intramolecular alkylation at C5.

Chasing Polycyclic Natural Products: 5/6/5‐ or 5/6/6‐Carbotricyclic Scaffold Construction via Stereodivergent Diels‐Alder Reaction of Chiral Hydrindanes and Their Boron Complexes

“…Especially organocatalysis proved to be a powerful tool for the enantioselective construction of hydrindanes [33–39] . Furthermore, hydrindanes were employed as precursors of lycopladine A [40] and other anellated polycyclic natural products [41–43] or analogues [44–46] . In addition to the reported methodologies, we have established an alternative approach towards the hydrindane scaffold [47] .…”

“…[33][34][35][36][37][38][39] Furthermore, hydrindanes were employed as precursors of lycopladine A [40] and other anellated polycyclic natural products [41][42][43] or analogues. [44][45][46] In addition to the reported methodologies, we have established an alternative approach towards the hydrindane scaffold. [47] According to our previous report, 4-substituted tetrahydroindanones 3a-c were prepared via a two-step sequence consisting of an organocatalytic asymmetric 1,4-addition on cyclopentene-1-carbaldehyde and subsequent aldol condensation.…”

From Metallacycle-Mediated Annulative Cross-Coupling to Steroidal Tetracycles through Intramolecular C9–C10 Bond Formation

“…Indeed, we have already established an oxidative rearrangement reaction where a C9 methyl substituent can be migrated to C10 in a suprafacial manner (see Figure 1A; 4 → 5). 3 As depicted in Figure 4, the triflate-containing hydrindane substrates 11−14 were first desilylated at C11 by the action of HCl in THF, 9 and subsequent Heck reaction was accomplished by treatment with Pd 2 (dba) 3 , rac-BINAP, and 1,2,2,6,6-pentamethylpiperidine (PMP) and stirring in toluene at 110 °C. 10 In all cases where cyclization ensued, tetracyclic products were formed with exquisite levels of stereoselectivity in favor of the C9/C13 syn-isomers (ds ≥20:1; eqs 8−10 in Figure 4).…”