Elsevier

Tetrahedron

Volume 62, Issue 28, 12 July 2006, Pages 6681-6694
Tetrahedron

The direct preparation of functionalised cyclopropanes from allylic alcohols or α-hydroxyketones using tandem oxidation processes

https://doi.org/10.1016/j.tet.2005.12.078Get rights and content

Abstract

New manganese dioxide-mediated tandem oxidation processes (TOPs) have been developed, which facilitate the direct conversion of allylic alcohols and α-hydroxyketones into polysubstituted functionalised cyclopropanes. In the simplest version, the oxidation of an allylic alcohol is carried out in the presence of a stabilised sulfurane, and the intermediate α,β-unsaturated carbonyl compound undergoes in situ cyclopropanation. By using a combination of stabilised phosphorane and sulfurane, the direct conversion of allylic alcohols or α-hydroxyketones into functionalised cyclopropanes is achieved, with in situ cyclopropanation being followed by Wittig olefination, or vice versa. The application of these methods to a formal synthesis of the lignan (±)-picropodophyllone, and to novel analogues of the insecticide allethrin II, is described.

Introduction

We have recently developed a range of manganese dioxide-mediated tandem oxidation processes (TOPs) in which primary alcohols are oxidised and the intermediate aldehydes are trapped in situ to give alkenes, imines, oximes, amines, nitriles, esters, amides and heterocyclic systems via one-pot procedures.1 These TOP sequences offer a number of advantages to the organic chemist: they are operationally straightforward, the MnO2 and its by-products being removed by a simple filtration; they result in a reduced number of operations, giving significant time–cost benefits; and they allow the use of ‘difficult’ carbonyl intermediates (i.e., those that are volatile, toxic or noxious) as they are prepared and elaborated in situ. The initial studies referred to above concentrated on 1,2-additions to the intermediate carbonyl compounds, as illustrated in Scheme 1 for the oxidation–Wittig reaction of allylic alcohols 1 in which the intermediate conjugated aldehydes 2 are trapped by a stabilised phosphorane 3 giving the product dienes 4. However, since the seminal research of Corey and Chaykovsky and others,2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g) it is well known that sulfuranes undergo 1,4-addition to α,β-unsaturated carbonyl compounds to produce the corresponding cyclopropanes. Cyclopropanes are widespread in natural products and biologically active analogues, and are valuable synthetic intermediates.3, 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), 3(m), 3(n), 3(o), 3(p), 3(q), 3(r), 3(s) We therefore decided to investigate whether a manganese dioxide-mediated TOP sequence could be carried out using stabilised sulfuranes 5 to produce a one-pot procedure for converting allylic alcohols into polysubstituted cyclopropanes 6 (Scheme 1). Herein, we describe detailed results concerning TOP sequences involving oxidation–cyclopropanation and their applications in target molecule synthesis.4, 4(a), 4(b)

Section snippets

Tandem oxidation–cyclopropanation reactions

In order to determine the viability of an oxidation–cyclopropanation sequence, we first examined the reaction of 2-methyl-2-propen-1-ol 1a with activated MnO2 in the presence of (carbethoxymethylene)dimethylsulfurane 5a, prepared from the commercially available sulfonium salt,2d and powdered 4 Å molecular sieves in benzene at reflux (Scheme 2). We were delighted to observe the formation of the desired cyclopropanecarboxaldehyde 6a in 37% yield, indicating that sulfurane 5a is compatible with

Tandem oxidation–cyclopropanation–Wittig reactions

We were intrigued by the possibility that the cyclopropanecarboxaldehyde products 6 could be exploited in further in situ transformations. We decided to first examine the tandem oxidation–cyclopropanation–Wittig sequence, as we have already established the compatibility of phosphoranes with MnO2.1 We hoped to tune the reaction conditions so that both sulfuranes and phosphoranes could be used in situ, in the presence of MnO2, to allow first oxidation, followed by sulfurane-mediated

Tandem oxidation–Wittig–cyclopropanation reactions

We have previously described the manganese dioxide tandem oxidation–olefination of α-hydroxyketones 12 leading, by way of intermediate α-keto aldehydes 13, to γ-ketocrotonates 14 in synthetically useful yields (Scheme 5).7

In the current study, we envisaged a complementary oxidation–olefination–cyclopropanation sequence, in which the alcohol is treated with MnO2, phosphorane and sulfurane but, of course, in this case, olefination has to occur first, followed by in situ cyclopropanation of the

Applications in target molecule synthesis

In order to validate the TOP–cyclopropanation methodology, we decided to examine applications in target molecule synthesis. In the first example (Scheme 8), we prepared cyclopropane 17, which was utilised by Murphy and Wattanasin as a late-stage intermediate in their synthesis of (±)-picropodophyllone8 which, along with related lignan lactones, is of interest as a cancer chemotherapeutic agent. Allylic alcohol 16 was treated with MnO2 and sulfurane 5a in DCE at reflux. We were delighted to find

General details

NMR spectra were recorded on Jeol EX-270 and ECX-400 spectrometers. Diastereomer ratios were obtained by 1H NMR integration. Chemical shifts (δ) are given in parts per million (ppm), using the residual solvent as reference (CDCl3 unless otherwise stated), and coupling constants are given in Hertz (Hz). IR spectra were recorded on ThermoNicolet IR100 or ATI Mattson Genesis FTIR spectrometers, as thin films between NaCl plates. Mass spectra were recorded on a Fisons analytical autospec instrument

Acknowledgements

We are grateful to the EPSRC for support (ROPA Fellowship, S.A.R. and studentship, R.J.P.), to the École Normale Supérieure de Lyon and Université Claude Bernard Lyon 1 for ERASMUS exchange support (M.O.).

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