Work

Multicomponent Reactions: Synthesis of Spirocyclic Tetrahydropyran Derivatives by Prins Cyclization

Year: 2002

Type: article

Abstract: Substituted spirocyclic tetrahydropyranyl mesylates and tosylates have been synthesized in good yields using a Prins-type cyclization of various cyclic ketones, a homoallylic alcohol and either methanesulfonic or p-toluenesulfonic acid under non-aqueous conditions.The mesylates thus produced could then be transformed into the corresponding Boc-protected amines using an efficient two step procedure.Multicomponent reactions that provide functionalized products in a single operation, particularly on a cyclic or heterocyclic framework are of enormous importance in natural product synthesis as well as in medicinal chemistry.1 Recently, we reported the TiCl 4 -promoted synthesis of a variety of substituted tetrahydrofurans and tetrahydropyrans by a novel multicomponent coupling reaction.2 In our continuing interest in probing enzyme active sites with designed ligands, we require a range of spirocyclic tetrahydropyranyl amines.3 For straightforward access to these heterocycles, we became interested in the potential application of the Prins cyclization, which has been the subject of much attention in recent years.4 Typically, aromatic aldehydes or olefinic acetals are reacted with Lewis acids or protic acids such as trifluoromethanesulfonic acid and trifluoroacetic acid to provide Prins cyclization products.5 However, applications of aliphatic and aromatic ketones have received far less attention.In the early 1950's, Hanschke 6 reported the synthesis of 4-halotetrahydropyran derivatives using HCl or HBr and various ketones in 36-50% yield.Recently, Li and co-worker 7 developed the Prins-type cross coupling reaction with allylic alcohols and various ketones in the presence of InCl 3 /SnCl 4 .Thompson et al. 8 have also shown an approach to a spirocyclic ether by TiCl 4 -mediated transacetalization-cationic cyclization.Interestingly, the Prins-type reaction utilizing methanesulfonic acid has seen only limited attention thus † This work is dedicated to Professor A. I. Meyers on the occasion of his 70 th birthday.

Source: Heterocycles

DOI: 10.3987/com-02-s(m)63

Authors: Arun K. Ghosh, Dongwoo Shin, Gary Schiltz

Institution: University of Illinois Chicago

Language: English

Topic: Organic Chemistry Synthesis Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: diamond

Funders: National Institutes of Health, National Institute of General Medical Sciences

Awards: DESIGN AND SYNTHESIS OF NONPEPTIDE PROTEASE INHIBITORS, Design & Synthesis of Nonpeptide Protease Inhibitors