A Sakurai−Prins−Ritter Sequence for the Three-Component Diastereoselective Synthesis of 4-Amino Tetrahydropyrans

Abstract

A simple one-pot procedure for the Sakurai-Prins-Ritter sequence allows rapid assembly of 4-acylamino-2,6-substituted tetrahydropyrans in high yields and with excellent diastereoselectivity from readily available 4-acetoxy-1,3-dioxanes, allylsilanes, and nitriles. A variety of nitriles have been shown to participate. Diastereoselectivities are uniformly high and observed stereochemistry of cation trapping proceeds according to Alder's model of the 4-tetrahydropyranyl cation.

On the choice of Lewis acids for the Prins reaction; two total syntheses of (±)-Civet

“…Both TMSOTf 42 and TESOTf 43,44 have been utilised in cyclisation reactions where an external nucleophile (to the Lewis acid), such as acetate (from TMSOAc) or acetonitrile has trapped the carbocation, or the cyclisation has been intramolecular and an internal nucleophile has trapped the carbocation, normally forming a second ring. In(OTf) 3 has been used with NH 4 SCN to trap eSCN at the 4-position 45 and also with benzaldehyde or anisole in an ionic liquid in a Prins-FriedeleCrafts reaction 46 and also bismuth triflate catalysed PrinseRitter reactions.…”

“…Data presented are for the major isomer from the inseparable mixture. R f 0.28 (5% EtOAc in hexane); n max /cm À1 (CHCl 3 ) 3085, 2923, 1495, 1246, 1085 42.7 (CH 2 ), 33.6 (CH 2 ), 31.6 (CH 2 ), 24.6 (CH 2 ), 23.0 (CH 2 ), 21.8 (CH 2 ); m/z (EI þ ) 115 (60% [C 6 H 11 O 2 ]). HRMS could not be obtained.…”

2.03 Prins Reactions and Carbonyl, Imine, and Thiocarbonyl Ene Reactions

“…Addition of TfOH generated the alkoxonium ion which cyclized to the tetrahydropyranyl cation, which was trapped by acetonitrile to give amide 415. 222 The equatorial amide is the major product when R¼ H as expected from preferred equatorial attack. The axial amide is the major product when R¼ Me, because trapping of the cation with acetonitrile is now reversible and the isomer with an equatorial methyl and axial NCCH 3 is more stable.…”

“…The axial amide is the major product when R¼ Me, because trapping of the cation with acetonitrile is now reversible and the isomer with an equatorial methyl and axial NCCH 3 is more stable. 222 An internal nucleophile can also be used to trap the tetrahydropyranyl cation as in the conversion of unsaturated hydroxy acid 416-417 with an aldehyde and TMSOTf. 224 Alkoxonium ions have also been formed by Mukaiyama aldol reactions.…”

6.07 Ritter-Type Reactions

“…Intramolecular trapping of the nitrilium ion intermediate by a proximal protected hydroxy group yields the spiro oxazoline product with strict stereocontrol. 242 …”