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.¹  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).²  However, the corresponding oxazolidinones are only able to achieve poor diastereoselectivities in this particular transformation.³

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.⁴

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).

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.⁵  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 imidazole⁴ or organoaluminum compounds (Scheme 4).⁶

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 >98:2.⁷

Product #	Product Name/Description	Structure	Add to Cart
39933	(S)-4-Isopropyl-1,3-thiazolidine-2-thione
05329	(R)-4-Isopropyl-1,3-thiazolidine-2-thione
39911	(S)-4-Phenyl-1,3-thiazolidine-2-thione
05802	(R)-4-Phenyl-1,3-thiazolidine-2-thione
06357	(S)-4-Benzyl-1,3-thiazolidine-2-thione
42787	(R)-4-Benzyl-1,3-thiazolidine-2-thione
04987	(S)-4-Isopropyl-1,3-oxazolidine-2-thione
08914	(R)-4-Isopropyl-1,3-oxazolidine-2-thione
08913	(S)-4-Phenyl-1,3-oxazolidin-2-thione
00762	(R)-4-Phenyl-1,3-oxazolidine-2-thione
08416	(S)-4-Benzyl-1,3-oxazolidine-2-thione
00749	(R)-4-Benzyl-1,3-oxazolidine-2-thione

References:

(1) Velàzquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303.

(2) Hodge, M. B.; Olivo, H. F. Tetrahedron 2004, 69, 9397.

(3) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.

(4) Crimmins, M. T. et al. J. Org. Chem. 2001, 66, 894.

(5) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775.

(6) Paquette, L. A.; Braun, A. Tetrahedron Lett. 1997, 38, 5119.

(7) Crimmins, M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128, 4936.