Total Syntheses of (−)-α-Kainic Acid and (+)-α-Allokainic Acid via Stereoselective C−H Insertion and Efficient 3,4-Stereocontrol

Abstract

Reported herein is a novel approach to the total syntheses of (-)-alpha-kainic acid and (+)-alpha-allokainic acid, where the stereochemistries on C(2), C(3), and C(4) of the pyrrolidine core were introduced efficiently and selectively. A regio- and stereoselective C-H insertion reaction was utilized to prepare the gamma-lactam as an intermediate. A Michael-type cyclization of phenylsulfone with a conjugated acetylenic ketone was developed to prepare the tricyclic ketone as a key intermediate for (-)-alpha-kainic acid. Subsequently, a stereoselective dephenylsulfonylation was carried out successfully to secure the cis relationship at C(3) and C(4) centers. An unprecedented acetylation on the phenylsulfone, followed by a stereoselective dephenylsulfonylation, secured the trans relationship at C(3) and C(4) centers in (+)-alpha-allokainic acid.

Origin of the Base‐Dependent Facial Selectivity in Annulation Reactions of Nazarov‐Type Reagents with Unsaturated Indolo[2,3‐a]quinolizidine Lactams

“…To illustrate the synthetic potential of the methodology and the versatility of pentacyclic Nazarov‐derived adducts in the synthesis of yohimbine‐type targets, we examined the conversion of the enantiopure epiallo derivative 7a into 17a‐carbaakuammigine ( 15 ). Reductive removal of the activating phenylsulfonyl group of 7a using Na/Hg at –78 °C was completely stereoselective, with retention of configuration, leading to the D/E cis ‐fused pentacycle 11 in excellent yield (Scheme ). After chemoselective deprotection of the hydroxy group, the removal of the C‐6 hydroxymethyl substituent of 12 was accomplished in 62 % overall yield by oxidation to a carboxylic acid, followed by tin‐mediated radical decarbonylation of the corresponding acyl selenide .…”

Stereocontrolled Annulations of Indolo[2,3‐a]quinolizidine‐Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine‐Type Derivatives

“…Taking into account that the success of double Michael addition reactions with Nazarov reagents depends upon the presence of an additional electron‐withdrawing group in the starting Michael acceptor,24 to test new annulations with silylated reagent 4 , we selected enantiopure lactam 3 e ,15 which has an activating and easily removable phenylsulfonyl group α to the lactam carbonyl 25. 26 Although the reaction of 4 with unsaturated N‐Boc lactam 3 e took place with only moderate facial selectivity under the usual Cs 2 CO 3 basic conditions ( 5 e / 6 e ratio, 1:2; Table 1, entry 7),27 the expected 3‐H/15‐H cis isomer 6 e was stereoselectively formed when DBU20 was used as the base (Table 1, entry 8).…”

Gold‐Catalyzed Hydrofunctionalizations and Spiroketalizations of Alkynes as Key Steps in Total Synthesis

“…After cleavage of the nosyl group the desired natural compound could be obtained (Scheme 12b). [54] A similar strategy was utilized in the formal total synthesis of the isoquinoline alkaloid Nitidine, [55] which shows strong antitumor activity through inhibition of DNA Topoisomerase I. [56] The Gouault group reported an efficient synthesis of quinolizidine and piperidine alkaloids by a 6-endo-dig cyclization of enantiomerically pure ynones 36 and 37.…”