Sulfinyl Homo- and Hetero-Dienes from Sulfenic Acids: An Approach Towards Six-membered Nitrogen Heterocycles in Enantiomerically Pure Form

Abstract

Two different synthetic pathways are presented that provide access to enantiopure sulfinyl hydrazones; in both addition of sulfenic acid/unsaturation represents the crucial step of the procedure. The obtained results are discussed in terms of regioselectivity in the formation of a-and/or b-sulfinyl a,b-unsaturated products when sulfenic acids are reacted with substrates showing carbonyl conjugated triple bonds, and/or their derivatives. Despite its structural limitations, (R S ,E,E)-2-[(1S)-isoborneol-10-sulfinyl]-2-butenal dimethylhydrazone (6) behaves as 1-azabuta-1,3-diene in hetero Diels-Alder reaction with N-methylmaleimide, giving a unique cycloadduct with complete endo and facial selectivities.Cyclic structures represent a relevant portion of the skeleton of several natural substances. Six-membered rings are building blocks in carbohydrates, alkaloids, terpenes, steroids, and a tremendous number of other biomolecules. Their widespread presence in nature represents the main reason for the interest generated by reactions such as the Diels-Alder (DA) cycloaddition which supplies a straightforward and stereocontrolled access to six-membered cyclic molecules.The development of an efficient and original methodology to generate a diene skeleton, bearing an enantiopure sulfinyl group, 1 directed our research towards DA reactions of such substrates with commonly used dienophiles, with the aim of testing the efficiency -as chiral auxiliary -of the sulfoxide substituent directly linked to a diene carbon, and possibly obtaining functionalized six-membered rings in enatiomerically pure form. The high degree of stereochemical control observed in the cycloadditions of diene 1 with methyl acrylate in the presence of LiClO 4 (Scheme 1) 2 prompted us to involve several different sulfinyl dienes in catalyzed and uncatalyzed homo-DA reactions. 3 We were also interested in investigating the reactivity of our sulfinyl dienes in hetero-DA (HDA) cycloadditions, which give an easy access to very useful heterocyclic molecules. Pyranoid 4 and thiopyranoid 5 derivatives 2-5 were synthesized following the approaches shown in Scheme 1. The most common heterodienophiles such as glyoxylates for pyranoid and thioketones for thiopyranoid systems cycloadded to suitable sulfinyl dienes with a satisfying stereochemical control and/or easy separation of the diastereomeric cycloadducts by chromatography. On the other hand, the facile access to high yields of enantiomerically pure b-sulfinyl a,b-unsaturated carbonyl compounds suggested their use as heterodienes in inverse electron-demanding DA reactions, giving an alternative access to enantiopure pyranoid systems (see, for instance, the synthesis of 3 in Scheme 1). 6 Scheme 1In this paper we discuss the effectiveness of the synthetic pathways a and b (Scheme 2) towards enantiopure sulfinyl a,b-unsaturated dimethylhydrazones, obtained by addition of suitable sulfenic acids to alkynyl hydrazones (pathway a) or alternatively by addition of sulfenic acids to alkynyl carbonyl compounds and subseque...

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

“…229 Despite constraints of unfavorable diene configuration, (R S ,E,E)-2-[(1S)-isoborneol-10-sulfinyl]-2-butenal N,N-dimethylhydrazone (292; Scheme 55) acted as 1-azabuta-1,3-diene in a reaction with N-methylmaleimide, giving a cycloadduct (293) in 20% yield and with total endoselectivity and facial selectivity. 230 Enantiopure, sulfinyl R, -unsaturated hydrazones were prepared by addition of isoborneolsulfenic acidsthe chiral auxiliarysto the corresponding alkynyl hydrazones, or by reaction of the chiral sulfenic acid with an alkynyl aldehyde or ketone, and subsequent hydrazone formation with H 2 NNMe 2 .…”