No abstract

Directed ortho dilithiation of bis(diethylcarbamate) or bis-(MOM)-protected (S a )-1,1Ј-bi(2-naphthol) followed by treatment with R 2 S 2 [R = Me, Ph (X-ray structure)] or Me 2 Se 2 cleanly affords the 3,3Ј derivatives; the free naphthols are produced on deprotection. In the case of the bis(MOM) series, but not that of the bis(carbamates), some racemisation occurs. The ligand 2,2Ј-dihydroxy-3,3Ј-dimethylthio-1,1Ј-binaphthalene shows optimal performance in the addition of

No abstract

No 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...

Enantiopure piperidines 4 may be accessed in very good overall yields and high stereoselectivity from the bifunctional products 2 of the silyloxy Cope rearrangement of chiral aldol products 1 by sequential nucleophilic addition of primary amines and subsequent hydrogenation. The reaction is proposed to proceed by initial imine formation followed by an intramolecular aza‐conjugate addition to the α,β‐unsaturated imide. The stereoselectivity is controlled by A(1.2) strain between the imine N‐alkyl group and the conjugate double bond. In an alternate approach, polyalkyl‐substituted piperidines were prepared by the addition of organozinc reagents to cyanopiperidines readily obtained from the Cope products in the presence of a silver salt.