An Alkylidene Carbene C–H Activation Approach toward the Enantioselective Syntheses of Spirolactams: Application to the Synthesis of (−)-Adalinine

Abstract

A method based on in situ alkylidene carbene generation-C-H insertion reaction of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones is developed for the enantioselective synthesis of 1-azaspiro[4,4]non-6-ene-2-ones and 6-azaspiro[4,5]dec-1-ene-7-ones. The required 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones are prepared from the Wacker oxidation of internal alkenes typified by 5-(but-2-enyl)pyrrolidin-2-ones and 6-(but-2-enyl)piperidin-2-ones, respectively. Excellent regioselectivity (≥92:8) is realized for the Wacker oxidation, and high yields (78-89%) of the desired lactam ketones are obtained. The results from further investigations into the Wacker oxidation suggested that the high regioselectivity of the oxidation in these lactam alkenes might be due to the participation of the lactam nitrogen via intramolecular coordination to Pd(II) during the reaction. Studies on alkylidene carbene generation-C-H insertion reaction of the lactam ketones revealed that the reaction efficiency is sensitive to the reaction temperature and the amount of lithio(trimethylsilyl)diazomethane employed, which led to the development of optimal reaction conditions for effecting alkylidene carbene generation-C-H insertion. Using the optimal reaction conditions, good to high yields (53-76%) of both γ- and δ-lactam spirocycles were obtained. The synthetic utility of the spirolactams was demonstrated by the synthesis of (-)-adalinine.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…The alkylidene carbene generation-CÀ H insertion reaction of enantiopure lactam ketones and its application to the total synthesis of coccinellid alkaloid (À )adalinine have been reported. [82] The protocol involves the generation of alkylidene carbenes 255 by treatment of δ-lactam ketones 253 with lithiotrimethylsilyldiazomethane (LTDM), obtained in situ by reaction of trimethylsilyldiazomethane (TMSDM) 252 and n-BuLi in THF at À 78°C (Scheme 66). Under the optimized reaction conditions, spiro-δ-lactams 254 were obtained in moderate yields (55-72%).…”

Synthesis of Spiro-lactams and Polysubstituted Pyrroles via Ceric Ammonium Nitrate-Mediated Oxidative Cyclization of N-Furan-2-ylmethyl-β-Enaminones

“…Because polysubstituted pyrroles and spiro-lactams have been reported to have potent bioactivities , and various synthetic applications, − we proceeded to synthesize a series of these valuable heterocyclic compounds via reactions of N -furfuryl-β-enaminones with 3 or 6 equiv of CAN, respectively, in THF, as described below . To our knowledge, the conventional methods for synthesis of spiro-lactam usually starts from an amide and need multiple steps to prepare the precursor for cyclization. − This access to spiro-lactams via oxidation of pyrrole ring to form the amide group accompanying with cyclization is of high efficience and novelty and has never been reported.…”

Natural Product Synthesis by Intramolecular Alkylidene Carbene C−H Insertion

“…Annadi and Wee [44] used (Scheme 32) TMSCHN 2 to convert the ternary stereogenic center of the enantiomerically‐pure lactam 6.10 into the quaternary center of the spirofused cyclopentene 6.11 . Via ozonolysis, this was carried on to the ladybug alkaloid adalinine 6.12 .…”