Evans-Type Auxiliaries

Evans-Type Oxazolidinethione And Thiazolidinethione Auxiliaries

The asymmetric aldol reaction mediated by chiral auxiliaries is considered to be one of the most important methods for asymmetric C-C bond formation. Chiral oxazolidinethiones and thiazolidinethiones, structural variants of the well-known Evans oxazolidinones, have proven to be highly selective and efficient chiral auxiliaries. The acetate aldol reaction of titanium enolates of the N-acylated auxiliaries with aldehydes results in excellent diastereoselectivities. Interestingly, the syn aldol product was obtained in high diastereomeric ratio when using 1 equivalent of sparteine, while the anti aldol product was obtained preferentially when 2 equivalents of base were employed (Scheme 1). However, the corresponding oxazolidinones are only able to achieve poor diastereoselectivities in this particular transformation.

Evans oxazolidinones

Scheme 1.Evans oxazolidinones

In a series of experiments, Crimmins has shown in detail that by choosing the appropriate reaction conditions it is possible to selectively synthesize aldol condensation products bearing either “Evans-syn” or “non-Evans-syn” stereochemistry starting with the same chiral auxiliary (Scheme 2). Both N-propionyl oxazolidinethiones and N-propionyl thiazolidinethiones can be used to this effect. The change in facial selectivity in the aldol additions is proposed to be a result of switching between chelated and nonchelated transition states in the mechanistic pathway.

Evans-syn or non-Evans-syn aldol condensation products

Scheme 2.Evans-syn or non-Evans-syn aldol condensation products

Iterative aldol sequences with high diastereoselectivity can also be accomplished. Crimmins demonstrated the utility of this methodology in an iterative aldol sequence giving access to either the syn-syn-syn adduct or syn-anti-syn adduct depending on the reaction conditions (Scheme 3).

syn-anti-syn adduct

Scheme 3.Syn-anti-syn adduct

In contrast to the oxazolidinone analogs, the N-acyl thiazolidinethiones and N-acyl oxazolidinethiones can be directly reduced to their corresponding aldehydes and the chiral auxiliary by reductive cleavage with diisobutylaluminum hydride. Alcoholysis using methanol and imidazole leads to the corresponding esters, while transamination to the Weinreb amides can be accomplished by treatment with N,O-dimethylhydroxylamine hydrochloride in the presence of imidazole or organoaluminum compounds (Scheme 4).

N-acyl thiazolidinethiones and N-acyl oxazolidinethiones reduction

Scheme 4. N-acyl thiazolidinethiones and N-acyl oxazolidinethiones reduction

Recently, the thiazolidinethione auxiliary was successfully applied by Crimmins and DeBaillie in a convergent enantioselective total synthesis of Bistramide A, a member of a new class of bioactive molecules isolated from the marine ascidian Lissoclinum bistratum with neuro- and cytotoxic properties as well as effects on cell cycle regulation. The pyran ring fragment was constructed diastereoselectively in a total of 10 steps starting from the TIPS-protected aldehyde and the chlorotitanium enolate of (4S)-N-propionyl-4-benzylthiazolidine-2-thione (Scheme 5). This stereoinducing step proceeded in excellent yield (87%) and gave a diastereomeric ratio of >98:2.

Pyran ring fragmentation

Scheme 5.Pyran ring fragmentation

Product Information


Velazquez F, Olivo H. 2002. The Application of Chiral Oxazolidinethiones and Thiazolidinethiones in Asymmetric Synthesis. COC. 6(4):303-340.
Hodge MB, Olivo HF. 2004. Stereoselective aldol additions of titanium enolates of N-acetyl-4-isopropyl-thiazolidinethione. Tetrahedron. 60(42):9397-9403.
Evans DA, Bartroli J, Shih TL. 1981. Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates. J. Am. Chem. Soc.. 103(8):2127-2129.
Crimmins MT, King BW, Tabet EA, Chaudhary K. 2001. Asymmetric Aldol Additions:  Use of Titanium Tetrachloride and (?)-Sparteine for the Soft Enolization ofN-Acyl Oxazolidinones, Oxazolidinethiones, and Thiazolidinethiones. J. Org. Chem.. 66(3):894-902.
Crimmins MT, Chaudhary K. 2000. Titanium Enolates of Thiazolidinethione Chiral Auxiliaries:? Versatile Tools for Asymmetric Aldol Additions. Org. Lett.. 2(6):775-777.
Paquette LA, Braun A. 1997. A modular approach to marine macrolide construction. 2. Concise stereocontrolled synthesis of the C17?C28 (CD) spiroacetal component. Tetrahedron Letters. 38(29):5119-5122.
Crimmins MT, DeBaillie AC. 2006. Enantioselective Total Synthesis of Bistramide A. J. Am. Chem. Soc.. 128(15):4936-4937.