Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (−)-Quebrachamine, (+)-Aspidospermidine, (−)-Aspidospermine, (−)-Pyrifolidine, and Related Natural Products

Abstract

A uniformly strategic total synthesis of Aspidosperma alkaloids (+)-vincadifformine, (-)-quebrachamine, (+)-aspidospermidine, (-)-aspidospermine, (-)-pyrifolidine, and nine others from efficiently constructed tricyclic ketone 13 is reported. Highlights of these divergent and practical syntheses include (i) stereoselective intermolecular [4 + 2] cycloaddition to establish a C-E ring with one all-carbon quaternary stereocenter (C-5) and two bridged contiguous cis-stereocenters (C-12 and C-19), (ii) a Pd/C-catalyzed hydrogenation/deprotection/amidation cascade process to assemble the D ring, and (iii) Fischer indolization to forge the A-B ring.

The [4 + 2] Cycloaddition of 2‐Pyrone in Total Synthesis

“…For example, vinblastine and vincrisitine were two well‐known drugs which were widely used in clinics for the treatment of various cancers . Combining their intriguing chemical structures and important biological activities, aspidosperma alkaloids attracted extensive attention from the synthetic community …”

“…Recently, Jiang and coworkers reported an efficient strategy to provide the enantiopure key tricyclic intermediate 378 in only eight steps (Scheme ), which could lead to a uniformly strategic total synthesis of fourteen Aspidosperma alkaloids, including (+)‐vincadifformine ( 380 ), (–)‐quebrachamine ( 381 ), (+)‐aspidospermidine ( 383a ), (–)‐aspidospermine ( 385b ), (–)‐pyrifolidine ( 385c ) and so on (Scheme ) [72a]. Jiang's strategy relied on the utilization of [4 + 2] reaction of 3‐ethyl‐5‐bromo‐2‐pyrone 365 with easily accessible chiral pentacyclic enamine 374 , providing hydroindolyl lactone 375 in 54% overall yield with good exo selecitivity ( exo / endo = 7: 1).…”

“…As their continuous research interest in divergent total synthesis of Aspidosperma and Vinca alkaloids, Jiang and his co‐workers reported a modified route to synthesize (–)‐jerantinines A ( 398 ), C ( 397 ), E ( 394 ), (–)‐16‐methoxyterbosonine ( 396 ), (–)‐vindoline ( 399 ) and (–)‐vinblastine ( 400 ) [72b]. As shown in Scheme , the intermediates 389a and 389b with the main structural skeleton with accurate stereochemistry of Aspidosperma alkaloids were prepared from 3‐ethyl‐5‐bromo‐2‐pyrone 365 and enamine 386 .…”

Visible‐Light‐Mediated C(sp3)–H Thiocarbonylation for Thiolactam Preparation with Potassium Sulfide

“…Hydroxymethyl thiolactam cyclothialidine[1c] serves as a DNA gyrase inhibitor (Figure a). Moreover, thiolactam structural unit plays a vital role as an active functional group in organic chemical transformations, which has been applied for the formation of C—C bond and C=C bond as well as the construction of complex compounds such as jerantinine . However, limited methods have been developed for the synthesis of thiolactam due to the special structure with C=S bond (Figure b) .…”

Asymmetric Total Synthesis of Vincadifformine Enabled by a Thiourea‐Phosphonium Salt Catalyzed Mannich‐Type Reaction

“…[4] Since the isolation and structure elucidation of vincadifformine,f our splendid syntheses in asymmetric versions have been achieved. [5] Each has its own feature in assembling the three-contiguous cis-stereocenters in the Er ing. In 2011, Pandey et al demonstrated ac ascade strategy to simultaneously construct C/E rings as well as the C12/C19 stereogenic centers in one pot.…”