Domino Hydroformylation/Enantioselective Cross‐Aldol Addition

Abstract

A domino hydroformylation/enantioselective cross-aldol reaction sequence is reported. Starting from simple alkenes enantiomerically pure aldol addition products, which represent valuable building blocks for polypropionate construction, can be obtained in a one-pot operation.Keywords: aldol reaction; asymmetric synthesis; domino reactions; homogeneous catalysis; hydroformylation; organocatalysis Skeleton expanding operations meeting the conditions of atom economy belong to the most valuable transformations in organic synthesis, provided all levels of selectivity can be controlled. [1] In this context the direct cross-aldol reaction between two enolizable carbonyl components is a highly attractive albeit difficult transformation. Recently, elegant solutions have been developed in order to control chemo-and stereoselectivity [2][3][4] among which organocatalysis [5,6] has proven particularly useful. Remarkably, even direct and enantioselective cross-aldol coupling between two non-equivalent aldehydes could be realized based on enamine catalysis which has been employed for propionate building block synthesis as well as for the de novo construction of carbohydrate derivatives. [7][8][9] A difficult task in these reactions is to avoid the formation of the homodimer aldols. On the one hand this requires aldehyde components which show significant rate differences in enamine formation. On the other hand, the homo-aldol of the aldehyde component, which is supposed to serve as the nucleophilic donor, has to be suppressed. The current solution to this problem is to keep the concentration of the donor aldehyde low by employing slow syringe pump addition. [7] As an attractive alternative one might speculate to generate the aldehyde in a low stationary concentration in the course of a catalytic carbon-carbon bond forming reaction meeting the criteria of atom economy such as the hydroformylation of alkenes.[10] This would result in a synthetically appealing domino hydroformylation/organocatalytic aldol addition which starting from alkene feedstocks would furnish enantioenriched aldolates in a one-pot operation (Scheme 1). [11,12] A crucial factor for success of this approach is the correct adjustment of the hydroformylation rate to the rate of proline-catalyzed aldol addition since accumulation of the donor aldehyde would facilitate undesired homodimerization of that component. This requires selective hydroformylation catalysts which can operate at temperatures as low as 0-5 8C, which is the temperature range in order to achieve optimal diastereo-and enantioselectivity in the course of the organocatalytic aldol step. Thus, rhodium(I) catalysts modified with either triphenylphosphine or the selfassembling pyridone ligands L1 and L2 (Scheme 2) which have proved to furnish particularly reactive and regioselective hydroformylation catalysts at low temScheme 1. Design of a domino hydroformylation/organocatalytic cross-aldol reaction.

Domino‐Hydroformylation/Aldol Condensation Catalysis: Highly Selective Synthesis of α,β‐Unsaturated Aldehydes from Olefins

“…Initial attempts were carried out in the presence of [Rh(acac)(CO) 2 ] (acac = acetylacetone) and Naphos (L6). Unfortunately unlike previous reports, [19][20][21] the conversion was slightly decreased and only a trace amount of condensation product 3 a was formed using the standard catalyst for aldol reactions, l-proline (entry 2). [22] In general, catalytic experiments were performed at 65 8C in the presence of 0.1 mol % of [Rh(acac)(CO) 2 ] and 0.2 mol % of L6 under 10 bar of syngas.…”

“…Scheme 1. [20] Interestingly, recently the first enantioselective intermolecular sequential hydroformylation/cross-aldol process has been reported by Breit et al [21] but this process requires a large excess of olefin or aldehydes and its substrate scope is still limited. In general, aldol products are only observed as unwanted side products in olefin conversions under hydroformylation conditions.…”

An Iron/Amine‐Catalyzed Cascade Process for the Enantioselective Functionalization of Allylic Alcohols

“…[8] Pivotal to this reactivity is the use of highly reactive carbonyl substrates, namely ketones or aldehydes, that entail severe drawbacks, such as tedious substrate preparation, toxicity, or possible decomposition or product racemization. [9] Furthermore, we anticipated that combining the two orthogonal catalytic cycles (iminium activation and borrowing-hydrogen catalysis) would enhance the hydrogen-transfer activity of easily accessible iron complexes. [9] Furthermore, we anticipated that combining the two orthogonal catalytic cycles (iminium activation and borrowing-hydrogen catalysis) would enhance the hydrogen-transfer activity of easily accessible iron complexes.…”

2.07 The Aldol Reaction: Organocatalysis Approach

“…[164][165][166][167] A one-pot Rh complex-catalyzed hydroformylation, following (S)-proline-catalyzed enantioselective cross-aldol reaction sequence, is one example ( Table 5). 168 Simple alkenes 310 are transformed in situ to aliphatic aldehydes 311, giving aldol products 312 in good yields with excellent stereoselectivities in a one-pot operation.…”