A Concise, Enantioselective Approach for the Synthesis of Yohimbine Alkaloids

Abstract

We report a concise, enantioselective synthesis of the yohimbine alkaloids (−)-rauwolscine and (−)-alloyohimbane. The key transformation involves a highly enantio-and diastereoselective NHC-catalyzed dimerization and an amidation/N-acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations. This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future biomedical investigations.

Advances in N‐Heterocyclic Carbene Catalysis for Natural Product Synthesis

“…[46] Recently, Scheidt and coworkers reported its asymmetric synthesis, in which they generated three of the five stereocenters and four of the five rings using a sequence of highly enantio-and diastereoselective NHC-catalyzed dimerization and amidation/N-acyliminium ion cyclization (Scheme 17). [47] The enol lactone 72 was afforded in 83 % yield with excellent enantio-and diastereoselectivity (98 % ee, >95:5 dr) from the unsaturated aldehyde 70 in the presence of chiral NHC catalyst 71. Subsequently, the four-ring system in 73 was assembled via amidation/N-acyliminium ion cyclization and selective reduction of the lactam.…”

“…The yohimbine alkaloid rauwolscine ( 74 ), featuring a pentacyclic skeleton, was isolated from Rauwolfia and its structure determined by Witkop in 1943 . Recently, Scheidt and co‐workers reported its asymmetric synthesis, in which they generated three of the five stereocenters and four of the five rings using a sequence of highly enantio‐ and diastereoselective NHC‐catalyzed dimerization and amidation/N‐acyliminium ion cyclization (Scheme ) . The enol lactone 72 was afforded in 83 % yield with excellent enantio‐ and diastereoselectivity (98 % ee, >95:5 dr) from the unsaturated aldehyde 70 in the presence of chiral NHC catalyst 71 .…”

Naturally-Occurring Alkaloids of Plant Origin as Potential Antimicrobials against Antibiotic-Resistant Infections

“…This family of pentacyclic indole alkaloids, which originated from l-tryptophan and secoiridoid monoterpene secologanin, can be subdivided into four different subfamilies, which differ in the stereochemical arrangement around the d-ring. The most representative members are yohimbine, rauwolscine, pseudoyohimbine and reserpine, respectively normal, allo, pseudo or epiallo [83]. Reserpine is an indole alkaloid (Table 3), naturally occurring in Rauwolfia serpentine, which is known to be a competitive inhibitor of both primary and secondary active transporter systems [84][85][86][87][88][89][90][91][92].…”

Recent Advances in Total Synthesis of Alkaloids from α,β‐Unsaturated Aldehydes

“…[33] Significant successes have also been achieved in the total synthesis of indole-containing alkaloids from α,β-unsaturated aldehydes. [34][35][36][37][38][39][40][41][42][43][44][45][46] It should be emphasized that MacMillan's group pioneered catalytic asymmetric indole dearomatization strategies and applied it in the total synthesis of a number of alkaloids 42-48 with high efficiency and selectivity ( Figure 3). [34a-c] Their original sequence based on intermolecular [4 + 2]cycloaddition (Scheme 7).…”

“…Very recently, total synthesis of yohimbine alkaloids, namely (À )-alloyohimbane 91 and (À )-rauwolscine 92, was accomplished via NHC-dimerization of available ethyl 4-oxobuteonate 100 on first stage (Scheme 14). [46] Their method showed the successful use of 1 mol % NHC precatalyst 101 in the construction of a cyclized enol lactone 102 with excellent enantio-and diastereoselectivity (even in multigram scale). Subsequent reaction with tryptamine 103 to give tetracyclic lactam 104.…”