Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

doi:10.1016/j.tetasy.2013.08.011

Tetrahedron: Asymmetry

Volume 24, Issue 19, 15 October 2013, Pages 1149-1188

https://doi.org/10.1016/j.tetasy.2013.08.011 Get rights and content

Abstract

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.

Graphical abstract

Introduction

Oxazolidin-2-ones, were disclosed in 1981 by Evans et al.¹ to have numerous applications and since then a great number of structural modifications of these auxiliaries have been reported.2, 3, 4, 5, 6, 7, 8, 9, 10 A chiral auxiliary is an optically active chemical compound that is added temporarily to an organic reaction and it can convey chirality with an expected stereochemistry in newly formed stereocenters.

The 2-oxo-1,3-oxazolidine ring is a cyclic carbamate framework which is fairly rare in natural products but extremely popular and useful in the asymmetric synthesis of organic compounds. Evans reported on the use of enantiomerically pure 4-substituted oxazolidin-2-ones as chiral auxiliaries in asymmetric synthesis. Oxazolidinones also have various applications as protective groups in the 1,2-aminoalcohol system. Linzolid has recently introduced an oxazolidin-2-one as an antibacterial drug, in the pharmaceutical market.¹¹ Some oxazolidinones (generally called Evans auxiliaries) such as Evans oxazolidinone, mono substituted oxazolidinones 1 and 2, the more highly substituted oxazolidinones 3 and 4, and Super Quats 5 are extremely popular and useful in asymmetric synthesis (Fig. 1).2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

Evans oxazolidinones are among the most important and broadly used chiral auxiliaries for stoichiometric asymmetric methods in total synthesis.

Although Evans chiral oxazolidinones have been extensively employed in many highly diastereoselective reactions such as alkylations, aldol reactions, cycloadditions, Michael additions, aminations, azidations, brominations, hydroxylations, Diels Alder, and conjugate additions,13, 14, 15, 16, 17 their most common applications are in asymmetric aldol reactions.

N-Acyl oxazolidinones can be prepared from the reaction of these auxiliaries with acyl chloride in the presence of n-butyl lithium.1, 18, 19 N-Acylimides20, 21 have been produced with the lithiated oxazolidinones and mixed anhydrides.

Useful reviews on the applications of oxazolidin-2-ones as the chiral auxiliaries have been published.22, 23, 24, 25, 26 We have also recently published a review concerning asymmetric aldol reactions.²⁷ Armed with this experience, in recent years and its importance, we decided to make them classified, up to date, and to show the applications of these chiral auxiliaries in aldol reactions for the total synthesis of various biologically active natural products. It is worthwhile noting that in this short review along with the introduction of the natural products, only the key steps involving the attachment and removal of the chiral auxiliaries have been described and illustrated.

Section snippets

Generation of boron enolates

Chiral oxazolidinone auxiliaries offer an entrance for the synthesis and creation of chiral enolates that are used in highly stereoregulated aldol reactions. It has been a challenging and stimulating task, because the control of both the diastereoselection and enantioselection should be the main concern. The Z-enolates of chiral N-acyl imides undergo an aldol reaction with aldehydes in a highly stereoselective process, providing α-substituted-β-hydroxy imides in high yields. Various aldehydes

Generation of titanium enolates

Titanium enolates have been shown to be highly selective under chelation–controlled aldol reactions. The first reports of asymmetric aldol reactions in the presence of boron and titanium afforded the Evans syn-aldol product 365 with excellent diastereoselectivity. It was reported that chelate-controlled methods usually result in the formation of ‘non-Evans’ product 367. The use of titanium enolates (also Li, Zn or Sn) gives rise to ‘non-Evans syn’ products (Scheme 64).¹⁷⁵

Applications in total synthesis

An Evans aldol reaction

Generation of magnesium enolates

The magnesium-catalyzed aldol reaction was found to display an extraordinarily high asymmetric induction when acyl oxazolidinones were used as chiral auxiliaries. The synthesis of ‘non-Evans anti’ products has been reported by Evans et al. employing MgCl₂-catalyzed aldol reaction (Scheme 70).¹⁸⁶

In addition, the reaction produces anti-aldol products, which were previously problematic to access from aldol reactions of this group of substrates. The reaction is restricted to non-enolizable

Removal of the oxazolidinone auxiliary

After the stereospecific reaction with an oxazolidinone, the chiral auxiliary should be separated from the product and preferably recycled. Two types of cleavage of oxazolidinones have been observed: exocyclic and endocyclic cleavages.⁶ The exocyclic cleavage is usually more desirable but endocyclic cleavage occurs even when the oxazolidinone derived carboximides 406 bear a bulky R¹ group (Scheme 73).

Numerous reagents such as central strategic steps in the total synthesis of a wide variety KOH,

Conclusions and future prospects

In this review, we have presented some highlights of the asymmetric aldol reaction using chiral oxazolidinones for the total synthesis of natural products and complex molecular targets. In these reactions, auxiliary controlled processes are essential tools to generate the desired stereocenters. The availability of the starting materials, ease of cleavage and submission to a wide variety of steroselective reactions indicate that the oxazolidinone auxiliary is an ideal intermediary for asymmetric

Acknowledgments

The authors are thankful to Alzahra Research Council for support.

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Tetrahedron: Asymmetry Report Number 144Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Abstract

Graphical abstract

Introduction

Section snippets

Generation of boron enolates

Generation of titanium enolates

Applications in total synthesis

Generation of magnesium enolates

Removal of the oxazolidinone auxiliary

Conclusions and future prospects

Acknowledgments

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Tetrahedron: Asymmetry Report Number 144
Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis