Elsevier

Tetrahedron

Volume 60, Issue 51, 13 December 2004, Pages 11725-11732
Tetrahedron

An environmentally friendly α-hydroxyallylation reaction of the Garner aldehyde: a comparative assessment of alternative Barbier conditions

https://doi.org/10.1016/j.tet.2004.10.007Get rights and content

Abstract

The reaction of 3-bromo-propenyl acetate with the Garner aldehyde promoted by zinc or indium metal is studied in different solvents; besides the stereoselectivity, attention is focused on a comparative environmental assessment of different experiments carried out in NH4Cl, THF or DMF, using green chemistry metrics and a qualitative analysis of environmental risks.

Introduction

The total synthesis of sugars, azasugars and other families of natural products containing densely functionalised appendages such as sugars, sphingosines etc., solicits the development of simple and effective methodologies able to approach structures like 1, which contains a sequence of consecutive functionalised stereocentres. Our retrosynthetic strategy to 1 is depicted in Scheme 1. Thanks to the number of regio- and stereochemically controlled functionalisation reactions of carbon–carbon double bonds, alk-1-en-3,4-diols 2 are recognized as attractive precursors of 1. Thus, we focused our attention on the disconnective approach to 2 based on the formal α-hydroxyallylation of a carbonyl compound 3a (Y1=O) or to an imine derivative (Y1=NR). Of course, if the carbonyl compound or azomethine derivative possess a stereogenic heterosubstituted carbon in the α-position (structure 3b), the stereotetrad 1b becomes accessible.

A number of synthetic equivalents of the formal synthon 4 are available in the literature; they correspond to γ-heterosubstituted allylic organometallic species of general structure 51 (Scheme 2), as shown by the representative list depicted in Table 1. Complexes 5 are divided in two groups, depending on simple diastereoselectivity exhibited in the addition to aldehydes.

Most of γ-heterosubstituted allylic organometallic species 5 are prepared according to a standard lithiation/transmetallation protocol (Scheme 3): a suitable precursor 6 is metallated in anhydrous THF at low temperature with an alkyllithium derivative, then the required metal halide is added to the intermediate allyl lithium 7.

This two-step protocol is affected by high economic and environmental costs associated with the use of an expensive base, the need to adopt strictly controlled conditions (anhydrous solvent, inert atmosphere) and the need to cool to low temperature, an operation which involves energy consumption. All these aspects make it difficult scaling up the overall process.

Chromium derivative 5l, on the other hand, involves a more simple one-pot preparation: acrolein acetal 8 is reacted with Cr(II) and trimethylsilyl iodide (TMSI) in the presence of an aldehyde, so that, as soon as 5l is formed, it is trapped by the carbonyl compound to give 9 (Scheme 4).13a Drawbacks, again in terms of economic and environmental point of views, are represented by the necessity to use 1 equiv of costly and unstable TMSI and an excess (3 equiv) of the eco-toxic salt, chromium(II) chloride.

This reaction recently was greatly improved by adopting a catalytic cycle based on the redox Mn(0)/Cr(II) couple, where Cr is used in catalytic amount (7%) and TMSI is generated in situ from TMSCl and NaI.22

In the last years, with the aim to design less expensive and more environmental benign routes to γ-heterosubstituted allylic organometallic species 5, we proposed to the attention of chemists 3-bromopropenyl acetate 10. The oxidative addition of Zn or In metal to the C–Br bond of 10 (Scheme 5) opens a route to a new class of γ-heterofunctionalised metal complexes 5, namely 3-acetoxy-allylic indium and zinc species 11a and 11b.23

The reaction is carried out at 0 °C in commercial grade (99%) THF, DMF, THF/DMSO mixtures, or even in aqueous solutions of ammonium chloride, and makes use of metals with low eco-toxicity. All these aspects together imply a benefit in terms of economy and ecology with respect to previous processes reported in Scheme 3, Scheme 4.

At last, as refers to the reaction of 11 with carbonyl compounds, two protocols were developed: (i) a Grignard two-step protocol where 11 is prepared in an organic solvent before the carbonyl compound is added, as represented in Scheme 5, (ii) a Barbier one-pot protocol in which 11 is prepared in the presence of the carbonyl compound. Excellent conversions are obtained after 30 min, even though a longer reaction time is seldom adopted to optimize chemical yields of adduct 12.

Here we wish to report a new case study, the hydroxyallylation of Garner aldehyde24 14 using 11a or 11b under Barbier conditions in different solvents. For each condition an assessment on the basis of green chemistry metrics and of a qualitative analysis of environmental risks is presented.

Section snippets

Hydroxyallylation of Garner aldehyde

In a preliminary communication, the reaction of 3-bromopropenyl acetate (10) with the Garner aldehyde 14 promoted by In(0), was reported.25 A Grignard protocol had been adopted, the organoindium species had been preformed in THF, then it had been allowed to react with 14 to give 15a in 66% yield. An overall reaction time of 8 h was required. The usefulness of intermediates 15 as precursors of azasugars or sphingosines is apparent, since they allow, for example, to incorporate the stereodefined

Conclusions

The synthesis of (2S,3S,4R)-2-amino-hex-5-en,1,3,4-triol derivative 16a has been documented via Barbier addition of 3-bromopropenyl acetate 10 to the Garner aldehyde 14, according to an original protocol developed in our lab which exploits either zinc or indium metal. This approach to alk-1-en-3,4-diols, presently, performs as the most convenient α-hydroxyallylation of carbonyl compounds in terms of both economic and environmental criteria, with respect to alternative allylic complexes reported

Materials

Tetrahydrofuran (THF) over molecular sieves (water content less than 0.005%), and N,N-dimethylformamide (DMF) over molecular sieves (water content less than 0.01%), are purchased from Fluka. Zinc dust (<10 micron, >98%) and indium powder (99%) are purchased from Aldrich. Garner aldehyde was prepared following both Dondoni47 and Taylor48 procedures, at a cost about 50% inferior than its commercial price (Aldrich: 1 g, 208.5 €/g). The preparation of 3-bromopropenyl acetate follows the procedure

Acknowledgements

The Ministry of Education (MIUR, Rome) is acknowledged for an FIRB grant to CT and the University of Bologna for financial support.

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