Oxazolidinethione and Thiazolidinethione Auxiliaries

chemfiles volume 6 article 10

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 (Scheme 12). 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.2 However, the corresponding oxazolidinones are only able to achieve poor diastereoselectivities in this particular transformation.3

Scheme 12

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 13)! 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

Scheme 13

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 14).

Scheme 14

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 15).6

Scheme 15

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 16). This stereoinducing step proceeded in excellent yield (87%) and gave a diastereomeric ratio of >98:2.7

Scheme 16

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  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.

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