Towards the Sarpagine‐Ajmaline‐Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N‐Demethyl Alstolactone Diastereomer

Abstract

the strategy involving the use of functionalized tetrahydro‐6H‐cycloocta[b]indol‐6‐one is reported as a key intermediate for synthesis of members of the sarpagine‐ajmaline‐macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans’ syn‐selective aldolization; 2) Liebeskind–Srogl cross‐coupling using the phenylthiol ester of 3‐chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3‐disubstituted indoles; and 3) ring‐closing metathesis (RCM) for the formation of the eight‐membered ring. An N‐allylation followed by intramolecular 1,4‐addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)‐demethyl‐3,5‐diepi‐alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.

Structure units oriented approach towards collective synthesis of sarpagine-ajmaline-koumine type alkaloids

“…Treatment of 27 with TFA in the presence of PhSH yielded natural polyneuridine (2) in 90% yield 91,92 . Corey-Kim oxidation of 2 provided the biosynthetic precursor polyneuridine aldehyde (3) 3,4,21 . Upon exposure to acidic conditions (Ac 2 O and TfOH, modification of Cook's conditions 35 ), an inseparable mixture of C17 stereoisomers (30a and 30b, 63% yields in two steps, dr = 1.1:1 based on 1 H-NMR) was obtained.…”

“…1. Because of their characteristic indole-fused azabicyclo[3.3.1]-nonane structures and prominent biological activities, sarpagine-ajmaline-koumine related alkaloids have attracted attention from the organic synthetic community for decades [17][18][19][20][21][22][23][24][25] . Synthetic efforts have resulted in a number of elegant strategies and culminated with the synthesis of a series of sarpagine˗ajmaline-koumine type alkaloids.…”

“…The last category is Kwon's intramolecular Friedel-Crafts acylation approach 54 . Numerous sarpagine˗ajmaline-koumine type alkaloids have been synthesized based on above-mentioned strategies, however, quebrachidine, vincamedine, and its analogues are not yet conquered to our knowledge by total synthesis [17][18][19][20][21][22][23][24][25] . The natural alkaloid quebrachidine ( 5) and its N-methyl congener vincamajine (6) and vincamedine (7) are among the most highly functionalized and synthetically challenging ajmaline type alkaloids.…”

“…In this work, we report a structure-unit-oriented strategy towards the synthesis of 14 natural monoterpenoid indole alkaloids. Although numerous synthetic methods have been developed for sarpagine-ajmaline alkaloids as well as structurally related analogues, flexible and unified synthetic routes that lead to collective synthesis of these types of alkaloids, especially towards both 19-E and 19-Z isomers, are rarely documented [17][18][19][20][21][22][23][24][25] .…”

Total Synthesis of Sarpagine Alkaloid (−)-Normacusine B

“…Structurally, as exemplified by (+)-normacusine B (Figure , 1 ), (+)-vellosimine ( 2 ), (+)- N a -methyl-16-epipericyclivine ( 3 ), and (−)-trinervine ( 4 ), sarpagine alkaloids harbor a characteristic indole-fused cage-like skeleton containing the fully integrated azabicyclco­[3.3.1]­nonane and azabicyclo­[2.2.2]­octane moieties . The intriguing architectures of this family have attracted continuous interests from the synthetic community, resulting in the development of many impressive synthetic strategies, − especially in the enantiospecific construction of the indole fused azabicyclo­[3.3.1]­nonane scaffolds with the correct configurations at stereocenters C3 and C5. ,,,,,,− …”