Synthesis of Enantiopure 3-Hydroxypiperidines from Sulfinyl Dienyl Amines by Diastereoselective Intramolecular Cyclization and [2,3]-Sigmatropic Rearrangement

Abstract

The highly diastereoselective base-promoted intramolecular cyclization of a variety of enantiopure sulfinyl dienyl amines provides novel sulfinyl tetrahydropyridines that are readily converted to 3-hydroxy tetrahydropyridines via sigmatropic rearrangement. The influence of N- and C- substituents on the process has been studied. Procedures to shorten the sequence such as the tandem cyclization followed by [2,3]-sigmatropic rearrangement, as well as cyclization of the free amine, under Boc- or ArSO- deprotection conditions have been examined. Good to excellent levels of selectivity are generally observed for the reported transformations (dr: 75/25 to >98/2). A novel protocol to access substituted amino dienyl sulfoxides is also reported.

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts

“…De la Pradilla and co-workers have exploited the suprafacial nature of this reaction in their syntheses of pseudoconhydrine ( 212 ) as well as the core-structures of ent -dysiherbaine and deoxymalayamicin A ( 213 ) (Scheme a). , The Chida group reported a racemic application of the Mislow–Braverman–Evans rearrangement in their total synthesis of angelastatin . In contrast to these applications, Manthorpe and co-workers observed an unwanted degradative [2,3]-sigmatropic rearrangement of vinyl bissulfoxide intermediates 216 en route to (9 R ,10 S )-dihydrosterulic acid (Scheme b) .…”

From Allylic Sulfoxides to Allylic Sulfenates: Fifty Years of a Never-Ending [2,3]-Sigmatropic Rearrangement

“…First, enantiopure amino 1-sulfinyl dienes 410 , derived from lithiated sulfinyl dienes and sulfinimines, could cyclize to allylic sulfoxides 411 , which could undergo the [2,3]-rearrangement. Second, the cyclization of amino 2-sulfinyl dienes 412 , similarly to the alcohol analogues, could be a viable alternative . The feasibility of the first approach was established by treating sulfinyl diene 414 with K 2 CO 3 , which led in a single operation to piperidinol trans - ent - 415 in good yield.…”

“…Second, the cyclization of amino 2-sulfinyl dienes 412, similarly to the alcohol analogues, could be a viable alternative. 264 The feasibility of the first approach was established by treating sulfinyl diene 414 with K 2 CO 3 , which led in a single operation to piperidinol trans-ent-415 in good yield. In contrast, the more readily available S diastereomer of 414 was very sluggish and provided mixtures of cis and trans products.…”

Base-Induced Sulfoxide-Sulfenate Rearrangement of 2-Sulfinyl Dienes for the Regio- and Stereoselective Synthesis of Enantioenriched Dienyl Diols

“…2a In this context, during the last years, our group has developed the diastereoselective Michael-type addition to 1and 2-sulfinyl dienes (1 and 2) to generate transient allylic sulfoxides I that evolved through [2,3]-sigmatropic rearrange-ment (Scheme 1b). We have applied this tandem process intramolecularly for the stereoselective synthesis of enantiopure functionalized dihydropyrans 5 and tetrahydropyridinols 6 as well as intermolecularly for the synthesis of acyclic 2-ene-1,4-diols, 7 1,4-aminoalcohols, 8 and 1,4-hydroxysulfides 9 with a high degree of stereocontrol.…”