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

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.     

New glyco-oxazolidin-2-ones as chiral auxiliaries in boron-mediated asymmetric aldol reactions

Two new chiral glyco-oxazolidin-2-one auxiliaries based on d-glucose are described. Some N-acyl derivatives were synthesized and used in dialkylboron-mediated asymmetric aldol reactions. All reactions delivered as the major diastereomer those predicted by the Zimmerman–Traxler model and were separated by column chromatography and mostly isolated in moderate to good yields.     

Chiral boron enolate aldol additions to chiral aldehydes

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.     

Highly selective acetate aldol additions using mesityl-substituted chiral auxiliaries

[reaction: see text] Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted N-acetyloxazolidinethione and N-acetylthiazolidinethione auxiliaries are reported. These additions proceed in high yields and diastereoselectivities (93:7 to 98:2) for aliphatic, aromatic, and ,-unsaturated aldehydes. Double diastereoselective acetate aldol additions are also reported and are found to proceed in high yields and diastereoselectivities (90:10 to 97:3).     

Enantioselective synthesis of alpha-terpineol and nephthenol by intramolecular acyloxazolidinone enolate alkylations

Enolate anions generated from norterpenyl bromides bearing oxazolidinone chiral auxiliaries at the chain termini underwent efficient, stereo-biased cyclizations to form 6- and 14-membered rings in novel synthetic routes to alpha-terpineol and nephthenol enantiomers.     

Optically pure polyfluoroalkanesulfinamides: synthesis and application as promising and monitorable chiral auxiliaries

Efficient synthesis of enantiopure polyfluoroalkanesulfinamides (PFSAs) has been achieved. Their application as novel chiral auxiliaries with an electron-withdrawing and (19)F NMR monitorable polyfluoroalkyl group was initially demonstrated in an asymmetric Strecker reaction under mild conditions.     

Imidazolidin-2-ones as practical, efficient chiral auxiliaries in Diels-Alder reactions

The readily prepared (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and its 4-cyclohexyl analogue proved to be very powerful face-selective auxiliaries in catalysed Diels-Alder cycloadditions of their ,β-unsaturated N-acyl dienophile derivatives.     

Titanium enolates of thiazolidinethione chiral auxiliaries: versatile tools for asymmetric aldol additions

[formula: see text] Asymmetric aldol additions using chlorotitanium enolates of thiazolidinethione propionates proceed with high diastereoselectivity for the "Evans" or "non-Evans" syn product depending on the nature and amount of the base used. With (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.     

Enantiopure beta-hydroxysulfoxide derivatives as novel chiral auxiliaries in asymmetric biaryl Suzuki reactions

[reaction: see text] Highly diastereoselective biaryl Suzuki coupling reactions of (1R)-1-(2-iodo or bromophenyl)-2-(R)-(4-tolylsulfinyl)-1-ethanol derivatives with various aryl- or naphthylboronic acids (or esters) were performed with high yields (up to 99%) and an excellent control of the axial chirality (up to 98% de).     

Asymmetric synthesis with diphenylphosphine oxides: Bicyclic aminals and oxazolidines as chiral auxiliaries

Syntheses of six novel phosphine oxide chiral auxiliaries are described. The auxiliaries are composed of the diphenylphosphinoyl (Ph₂PO) group and either proline-derived bicyclic aminals or norephedrine-derived oxazolidines. One auxiliary is used in the synthesis of an optically active β-hydroxy phosphine oxide.     

Modified guanidines as chiral auxiliaries

Investigations on modified guanidines, prepared by newly developed methods, as potential chiral auxiliaries led to reasonable asymmetric induction not only in catalytic but also in stoichiometric asymmetric syntheses. These guanidine-mediated reactions may contribute to the development of green chemistry because of their possible application as re-cyclable (economically favored) and easily functionalizable (widely applicable) auxiliaries.     

Enantiopure bicyclic piperidinones: stereoselectivity in lactam enolate alkylations

The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6-oxopipecolic acid, have been investigated. Alkylation can proceed with predominantly exo-diastereoselectivity, but the efficiency of this process depends on the substitution at the hemiaminal ether system. These products can be readily deprotected to give substituted hydroxymethyl lactams in good yield.     

Acetate aldol reactions of chiral oxocarbenium ions

Chiral oxocarbenium ions have been exploited to carry out highly diastereoselective and enantioselective acetate aldol addition reactions. The chiral auxiliary has been optimized to give the product with good diastereoselectivity.     

Application of acyclic chiral auxiliaries on alkylation reactions

The application in alkylation reactions of an acyclic chiral auxiliary is described. The synthesis is straightforward from a chiral primary amine and a double acylation. A characteristic of this auxiliary is its modular design formed by an achiral part (acyl) and a chiral component (primary amine) so it can be tuned for different reactions without difficulty. The alkylation proceeds with excellent diastereoselectivity because the conformational flexibility of the enolate is restricted by the formation of a chelate and the allylic 1,3-strain.     

Asymmetric synthesis of 3-butylphthalide using isomannide and isosorbide as chiral auxiliaries

A new approach for asymmetric syntheses of (S) and (R)-3-n-butylphthalide (NBP) is presented.The diastereoselective addition of dibutylzinic to aromatic aldehyde 10 or 11 generated from isomannide-or isosorbide-derived chiral auxiliary afforded S-NBP or R-NBP in high optical yields.     

Diastereoselective titanium enolate aldol reaction for the total synthesis of epothilones

[formula: see text] The development of a highly diastereoselective addition of the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient entry to the total synthesis of the epothilone family. The new aldol process is robust and tolerates a wide range of functional groups.     

Zirconium enolate as a new erythro-selective aldol condensation reagent

Zirconium enolates, prepard from lithium enolates and bis(cyclopentadienyl)zirconium dichloride, undergo a facile aldol condensation with aldehydes to give predominantly the erythro product regardless of the geometry of the starting enolates.