Addition of Organometallic Reagents to Chiral N‐Methoxylactams: Enantioselective Syntheses of Pyrrolidines and Piperidines

Abstract

Enantioselective iridium-catalyzed allylic substitutions were used to prepare N-allyl hydroxamic acid derivatives that were suitable for ring-closing metathesis, giving N-methoxylactams. Reactions of these derivatives with Grignard or organolithium compounds gave hemiaminals, which could be reduced diastereoselectively via acyliminium intermediates to give cis-piperidines or cis-pyrrolidines with substituents in the 2,6- or 2,5-positions, respectively. In addition, compounds with a quaternary carbon center could be synthesized by corresponding reactions with potassium cyanide/AcOH. The procedures were applied in the syntheses of alkaloids (-)-209D and (+)-prosophylline.

Chemoselective Reductive Nucleophilic Addition to Tertiary Amides, Secondary Amides, and N‐Methoxyamides

“…Indirect methods require a preactivation step, which is a transformation of the amide functionality into a more reactive species, for example, an acylamide (DeNinno,3a Suh)3c or thioamide (Murai) 3d. e Direct methods, without the preactivation step, proved possible by using tert ‐formamides (de Meijere,3f Bélanger),3i tert ‐amides (Huang),3g, h, m–o sec ‐amides (Huang),3k and N‐alkoxyamides (Kibayashi,4f Sato and Chida,4a, b Vincent and Kouklovsky,4c, d Helmchen) 4e. However, the chemoselective version of the reaction has remained a formidable challenge because of the use of reactive organometallic reagents such as Grignard reagents and organolithium reagents prohibits functional‐group compatibility with sensitive functional groups 7.…”

Regio‐ and Stereoselective 1,2‐Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers

“…In particular, for 3 m-o, reduction with LiBEt 3 H was optimal, and for 3 l, 3 p, and 3 q, reduction with K(iPrO) 3 BH proved to be the most effective. The relative configurations of the two newly formed stereocenters were rigorously determined by X-ray structural analysis for the ethylation/reduction products 3 m and 3 n and the benzylation/reduction product 3 p. [13] These X-ray structures establish that upon introducing alkyl groups (R) larger than a methyl group, steric interactions, which result from the newly formed and adjacent quaternary stereocenter, control the face selectivity of reduction rather than the more distant R 6 substituent.…”

“…Phenyl-, alkyl-, and silyloxymethyl-substituted alkynyl Grignard reagents all added diastereoselectively and in good yields (6 a-e). [14] Allyl cerium reagents also added in high yields and with excellent diastereoselectivities (6 f,g), [15] including for the preparation of the cis-fused bicyclic piperidine 6 g with tetrasubstituted carbon atoms at the two bridgehead positions. Finally, X-ray structural analysis of 6 d and 6 g [13] establishes that when the alkylation step introduces a stereocenter the face selectivity for nucleophilic attack is controlled by steric interactions at this adjacent quaternary site and is consistent with that previously observed in the alkylation/reduction sequence.…”

“…Alkylation consistently occurs opposite to the R 6 group as rigorously established by X-ray structural analysis of 3 e as well as for multiple other alkylation products (3 g, 3 m, 3 n, 3 p, 6 d, and 6 g). [13] The Lewis-acid-mediated benzylation provided a more modest 5:1 ratio (3 f).…”

Evidence and isolation of tetrahedral intermediates formed upon the addition of lithium carbenoids to Weinreb amides and N-acylpyrroles

“…The corresponding tetrahedral intermediates could be easily isolated and characterized in high to excellent chemical yields. Accordingly, aromatic (3)(4)(5)(6)(7)(8)(9)(10)(11) and heteroaromatic (12-13) Weinreb amides provided the O-TMS protected hemiaminals regardless of the electronic behavior of the substituents across the ring. Notably, the presence of an exchangeable iodine atom on the aromatic ring did not have a detrimental effect (10), thus highlighting an excellent chemoselectivity during the carbenoid generation event starting from ICH 2 Cl.…”