Kai-Jiong Xiao

Direct Transformation of Secondary Amides into Secondary Amines: Triflic Anhydride Activated Reductive Alkylation

National Basic Research Program (973 Program) of China [2010CB833200]; NSF of China [21072160, 20832005]; Fundamental Research Funds for the Central Universities of China [201112G001]; Ministry of Education of China

Versatile One-Pot Reductive Alkylation of Lactams/Amides via Amide Activation: Application to the Concise Syntheses of Bioactive Alkaloids (+/-)-Bgugaine, (+/-)-Coniine, (+)-Preussin, and (-)-Cassine

NSF of China [20832005]; National Basic Research Program (973 Program) of China [2010CB833200]

General One-Pot Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides: Rapid Construction of 1-Azaspirocycles and Formal Total Synthesis of (+/-)-Cephalotaxine

Amides are a class of highly stable and readily available compounds. The amide functional group constitutes a class of powerful directing/activating and protecting group for C-C bond formation. Tertiary tert-alkylamine, including 1-azaspirocycle is a key structural feature found in many bioactive natural products and pharmaceuticals. The transformation of amides into tert-alkylamines generally requires several steps. In this paper, we report the full details of the first general method for the direct transformation of tertiary lactams/amides into tert-alkylamines. The method is based on in situ activation of amide with triflic anhydride/2,6-di-tert-butyl-4-methylpyridine (DTBMP), followed by successive addition of two organometallic reagents of the same or different kinds to form two C-C bonds. Both alkyl and functionalized organometallic reagents and enolates can be used as the nucleophiles. The method displayed excellent 1,2- and good 1,3-asymmetric induction. Construction of 1-azaspirocycles from lactams required only two steps or even one-step by direct spiroannelation of lactams. The power of the method was demonstrated by a concise formal total synthesis of racemic cephalotaxine.

A General Method for the One-Pot Reductive Functionalization of Secondary Amides

A one-pot reaction for the transformation of common secondary amides into amines with C-C bond formation is described. This method consists of in situ amide activation with Tf2O-partial reduction-addition of C-nucleophiles. The method is general in scope, which allows employing both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With the use of soft nucleophiles, the reaction proceeded with high chemoselectivity at a secondary amide in the presence of ester, cyano, nitro, and tertiary amide groups.

A Direct and General Method for the Reductive Alkylation of Tertiary Lactams/Amides: Application to the Step Economical Synthesis of Alkaloid (−)-Morusimic Acid D

Full details of the direct and general method for the reductive alkylation of tertiary lactams and amides to give tertiary sec-alkylamines are presented. This one-pot method consists of in situ activation of a lactam or an amide with Tf2O/DTBMP, addition of a Grignard reagent, and reduction of the resulting iminium intermediates. Alkyl, benzyl, and aryl Grignard reagents and several reductants or reducing conditions (LiAlH4, NaBH4, Hantzsch ester, Bu3SnH, Pd(OH)2/C, H2) could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH4), 11:1 (Et3SiH), and 20:1 (catalytic hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application in the concise stereoselective synthesis of piperidine alkaloid (-)-morusimic acid.

General Direct Transformation of Secondary Amides to Ketones via Amide Activation

National Basic Research Program (973 Program) of China [2010CB833200]; National Natural Science Foundation of China [21072160, 20832005]; Scholarship Award for Excellent Doctoral Student, Ministry of Education of China

The First Enantioselective Total Synthesis of (+)-Preussin B and an Improved Synthesis of (+)-Preussin By Step-economical Methods

The first enantioselective total synthesis of (+)-preussin B and an improved synthesis of the antifungal alkaloid (+)-preussin are described. Our approach relied on the four step-economical synthetic methods developed in our laboratory: (1) the cis-diastereoselective reductive dehydroxylation of hemiaminals; (2) the direct amide/lactam reductive alkylation; (3) the one-pot N,O-bisdebenzylation-N-methylation; and (4) the one-step synthesis of malimide from malic acid. Both total syntheses are quite concise, which have been achieved in six steps, and gave overall yields of 25.7% and 27.6%, respectively.