Oxidative Allene Amination for the Synthesis of Azetidin‐3‐ones

Abstract

Regioselectivity in the aziridination of silyl-substituted homoallenic sulfamates is readily diverted to the distal double bond of the allene to yield endocyclic bicyclic methyleneaziridines with excellent stereocontrol. Subsequent reaction with electrophilic oxygen sources initiates facile rearrangement to densely functionalized, fused azetidin-3-ones in excellent dr, effectively transferring the axial chirality of the allene to central chirality in the products. The steric nature of the silyl group dictates which of the two rings of the fused azetidin-3-one will undergo further functionalization, providing an additional element of diversity for the preparation of enantioenriched azetidine scaffolds with potential biological activity.

Fluorinated Amine Stereotriads via Allene Amination

“…An alternative approach could employ the Strecker product 10a (see Table 2), with hydrolysis of the nitrile delivering the same product 29 . N-Boc protection/ring-opening/elimination of 7a , similar to that previously reported, 5j furnished 30 . Compound 30 could be further elaborated into the protected β -amino acid 31 through a simple sequence of ozonolysis, Pinnick oxidation, and esterification.…”

“…5 These allenes are easily synthesized from the corresponding propargyl alcohols through a three-step sequence involving a Johnson–Claisen rearrangement using (EtO) 3 CMe, followed by LiAlH 4 reduction and sulfamate formation. 5a,d,f,i Employing an enantioenriched propargyl alcohol in the allene synthesis delivers efficient axial-to-point chirality transfer to furnish enantioenriched stereotriads.…”

“…5 These allenes are easily synthesized from the corresponding propargyl alcohols through a three-step sequence involving a Johnson–Claisen rearrangement using (EtO) 3 CMe, followed by LiAlH 4 reduction and sulfamate formation. 5a,d,f,i Employing an enantioenriched propargyl alcohol in the allene synthesis delivers efficient axial-to-point chirality transfer to furnish enantioenriched stereotriads. 5a,i,j However, our early efforts to incorporate valuable fluorines into the triad products 3 delivered only moderate yields and poor dr , stimulating further efforts to improve upon these initial results.…”

“…5a,d,f,i Employing an enantioenriched propargyl alcohol in the allene synthesis delivers efficient axial-to-point chirality transfer to furnish enantioenriched stereotriads. 5a,i,j However, our early efforts to incorporate valuable fluorines into the triad products 3 delivered only moderate yields and poor dr , stimulating further efforts to improve upon these initial results. In this letter, we report methods to introduce fluorine into allenes in both an electrophilic and nucleophilic manner to provide novel building blocks not easily synthesized using alkene functionalization strategies.…”

“…A variety of nucleophiles are known to successfully open the intermediate bicyclic methyleneaziridine resulting from Rh-catalyzed aziridination of 4 (Scheme 1), including H 2 O, MeOH, PhSH, and PhNH 2 . 5a Unfortunately, treatment of the corresponding enesulfamates with an array of electrophilic fluoride reagents, including Selectfluor, NFSI, 1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, showed variable dr or unproductive reaction in the imine formation. Eventually, we found that the combination of a bulky OTBS group at C1 of the enesulfamate 5 with Selectfluor enabled promising diastereocontrol in the addition of 5 (Table 1, entry 1) to the electrophile, furnishing 6a as the major stereoisomer.…”