Novel and Stereocontrolled Synthesis of Enantiopure and Polyalkyl Substituted Piperidines

Abstract

A flexible and stereodivergent synthesis of enantiopure piperidines with up to four alkyl-substituted chiral centers is reported which proceeds by way of a double nucleophilic addition of primary amines to the 7-oxo-2-enimides 1. These in turn are accessible via the silyloxy-Cope rearrangement of chiral syn-aldol products.Nitrogen-containing heterocycles are abundant in nature and exhibit diverse and important biological properties. 1 One of the parent systems, the piperidine ring, is contained in numerous physiologically active compounds, e.g. coniine, lupetidine, and sedamine. 2 Accordingly, novel strategies for the stereoselective synthesis of enantiopure piperidines continue to receive considerable attention in the field of synthetic organic chemistry. In the past, additions of organometallic reagents to N-acyl pyridinium salts, 3 hetero Diels-Alder reactions with imines 4 , Lewis acid-or electrophile-induced cyclizations of imines or iminium ions 5 and reactions of bicyclic cyano piperidines and lactams 6 have been employed for this purpose to mention the most prominent routes.Recently, we have established that 1,5-hexadienes with a syn-aldol substitution pattern undergo rapid thermal Cope rearrangements with excellent levels of stereocontrol (Scheme 1). 7 The rearrangement products 1 are highly functionalized and have been shown to be useful precursors for the synthesis of enantiopure tetrahydropyrans 8 and polyols. 9 In addition, a total synthesis of the monoterpenol (+)-lasiol has been achieved using this methodology. 10 Scheme 1In our continuing efforts to devise further synthetic applications we made the striking observation that primary amines, e. g. benzyl amine, undergo a double nucleophilic addition to the 7-oxo-2-enimides 1 yielding initially the sensitive tetrahydropyridines which were subsequently hydrogenated to furnish the stable 2,3,4-trisubstituted piperidines 2 (Scheme 2). 11 As a mechanistic rationale we propose that the amine initially attacks the aldehyde 1 to form the imine whose enamine tautomer rapidly adds to the α,β-unsaturated imide to form the nitrogen heterocycle through the half chair-like transition state 3.The stereoselectivity of the cyclization (20:1) is remarkable, the major isomer being the piperidine with the C-2 alkyl group in the axial position. Control experiments with the oxoenimide bearing the achiral oxazolidinone reveal that the stereogenic centers in the chain rather than the chiral auxiliary determine the stereochemistry at the newly formed chiral center. Stereoelectronic reasons may be put forth to explain this stereoselectivity with a more efficient overlap of the nitrogen lone pair and the π*-orbital of the conjugated double bond in the pre-axial orientation. Related intramolecular Michael additions of ester enolates to enoates in a synthesis of cyclohexanes exhibit the same stereochemical preference, albeit less pronounced. 12On the contrary, when 7-oxo-2-enoates 4 readily obtained from the imides 1 by esterification with MgClOMe were treated with benzyl amine...

Cyclization of Zincated α‐N‐Homoallylamino Nitriles: A New Entry to Enantiopure 2,3‐Methanopyrrolidines

“…We reasoned that if, in a similar way, a stereoselective carbozincation took place starting from zincated α‐ N‐ homoallylamino nitriles, such as 2 a , it would provide bifunctional 2‐cyano‐3‐(zinciomethyl)pyrrolidines bearing both an electrophilic α‐amino nitrile moiety and a nucleophilic alkylzinc moiety. As for previously disclosed analogous cyclizations of ω‐stannyl appendages on N ‐acyloxyiminium ions,12 we then anticipated an intramolecular displacement of the cyano group through the well‐known Bruylants reaction between α‐amino nitriles and organometallic nucleophiles, which has been reported, in particular, with organozinc reagents 13–16. If successful, our approach would thus offer a new entry to enantiopure 2,3‐methanopyrrolidines (Scheme ), which are interesting compounds12, 17 that are still challenging to prepare in spite of recent elegant approaches based on the intramolecular Kulinkovich–de Meijere reaction 18…”

“…As for previously disclosed analogous cyclizations of w-stannyl appendages on N-acyloxyiminium ions, [12] we then anticipated an intramolecular displacement of the cyano group through the well-known Bruylants reaction between a-amino nitriles and organometallic nucleophiles, which has been reported, in particular, with organozinc reagents. [13][14][15][16] If successful, our approach would thus offer a new entry to enantiopure 2,3-methanopyrrolidines (Scheme 1), which are interesting compounds [12,17] that are still challenging to prepare in spite of recent elegant approaches based on the intramolecular Kulinkovich-de Meijere reaction. [18]…”

The Bruylants and related reactions

“…Allyl and propargyl zinc halides are quite good nucleophiles and appear as fair substitutes in the Bruylants reaction. [73][74][75] Bernardi et al performed the Bruylants reaction under Barbier and Reformatsky conditions and thus generated the organometallic species in situ. 76 In this work, -aminonitriles were prepared by the Suginome's procedure, from aldehydes and bis(dialkylamino)cyanoboranes.…”

Conjugate Addition of Amines to Sugar Derived Olefinic Esters: Synthesis of Glycosylated Amino Esters as Dna Topoisomerase-Ii Inhibitors

“…[2,3] In our ongoing study of glycoconjugates derived from glycosylated b-amino acids, a novel lead molecule has been developed for inhibition of filarial DNA topoisomerase-II, a target in filarial chemotherapy. [3,4] The common methods for stereoselective synthesis of b-amino acids involve either nucleophilic addition [5] of chiral amines to a,bunsaturated carbonyl or nitrile compounds followed by further chemical manipulation, or nucleophilic addition of amines to chiral olefinic ester derived from chiral molecules. [6] Much information exists for the first approach while only limited information is available for the second one.…”