Elsevier

Tetrahedron

Volume 67, Issues 27–28, 8 July 2011, Pages 5107-5124
Tetrahedron

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

https://doi.org/10.1016/j.tet.2011.05.019Get rights and content

Abstract

While developing new variations of the Prins cyclisation reaction, the effect of the choice of Lewis acid on the outcome of the reaction and the product(s) has been investigated, yielding hitherto unseen dihydropyran products in the Prins cyclisation reaction of homoallylic alcohols, and two new modifications of the reaction: the triflate-trapped Prins adduct and the Mukaiyama–Aldol–silyl-Prins reaction. Two of these methods are employed in two complementary total syntheses of the important perfumery compound, (±)-Civet.

Introduction

The classical Prins cyclisation reaction, where a homoallylic alcohol reacts with a carbonyl component under Bronsted or Lewis acid-promoted conditions, has become one of the major methods for di- and tetrahydropyran synthesis of the 21st century and there are several excellent reviews on this process.1 More recently, the Prins reaction has also been adapted for the preparation of nitrogen containing heterocycles, the appropriately named aza-Prins reaction.2, 3, 4, 5, 6, 7, 8, 9

However, with many variations and modifications of the Prins reaction now appearing in the literature, what makes a particular Lewis acid a good choice for a reaction? And are there still any surprises to be uncovered in the influence of a Lewis acid on the outcome of the Prins cyclisation? We have been developing variants of the Prins reaction for a number of years, and yet still have no definitive answer to why certain Lewis acids are better than others at promoting different versions of these reactions. Herein we report on the effects of Lewis acids on the outcomes of three new incarnations of the Prins reaction, to give unexpected pyran-containing products.

Section snippets

Lewis acids in the Prins reaction

The generally accepted mechanism for the Prins reaction is illustrated in Scheme 1. After acid-promoted activation of the aldehyde, there is oxocarbenium ion formation followed by 6-endo cyclisation to a secondary tetrahydropyranyl carbocation, which may then be trapped by a nucleophile, most commonly from the original acid.

Many Lewis acids have been used in the Prins reaction, most commonly giving a halogen at the 4-position of the tetrahydropyran: in our own work and from others Cl from InCl3

Conclusions

So is there any way to predict the optimum Lewis acid for the Prins reaction? Sadly no. Through extensive Lewis acid screening, we have been able to report the development of new avenues of exploration for the Prins reaction, including obtaining hitherto unseen dihydropyran products and the inclusion of the silyl-Prins reaction in a domino process. Finally, two of the methods developed have successfully been applied in natural product total synthesis.

General

Petroleum ether or petrol refers to the fraction boiling between 40 °C and 60 °C. Dichloromethane was distilled over calcium hydride. Diethyl ether, THF and toluene were distilled over sodium and benzophenone, which was used as an indicator. All other solvents were obtained anhydrous and used directly in the reaction vessel. All reactions were carried out under an atmosphere of nitrogen unless otherwise stated using vacuum/nitrogen manifold. All glassware, syringes and needles were pre-dried in

Acknowledgements

We wish to thank the following: EPSRC (DTA studentships to F.C. and M.P.); Pfizer (CASE award to M.P.); AstraZeneca (CASE award to F.C.); Queen Mary University of London (studentships to D.G. and J.W.); the University of Exeter (studentship to S.G.); Mr. Greg Coumbarides for fluorine NMR spectra and other NMR experiments. The EPSRC National Mass Spectrometry Service (Swansea, UK) is gratefully acknowledged for running all high resolution mass spectra. The EPSRC National Crystallography Service

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