Highly Enantioselective Synthesis of Fluorinated β-Amino Ketones via Asymmetric Organocatalytic Mannich Reactions: A Case Study of Unusual Reversal of Regioselectivity

Abstract

The highly enantioselective direct Mannich protocol employing fluoroacetone, p-anisidine, and aldehydes catalyzed by 4-siloxyproline was developed, allowing efficient access for pharmaceutically important fluorinated β-amino ketones. On the basis of DFT calculations and mechanistic probes, the origin of an unusual reversal of regioselectivity was unraveled.

organocatalysis - Mannich reaction - DFT calculation - fluoroacetone - β-amino ketones

References and Notes

1a List B. J. Am. Chem. Soc.  2000,  122:  9336 

1b List B. Pojarliev P. Biller WT. Martin H. J. Am. Chem. Soc.  2002,  124:  827 

2a Notz W. Sakthivel K. Bui T. Zhong G. Barbas CF. Tetrahedron Lett.  2001,  42:  199 

2b Cordova A. Notz W. Zhong G. Betancort JM. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1842 

2c Cordova A. Watanabe S. Tanaka F. Notz W. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1866 

2d Zhang H. Mifsud M. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  9630 

For recent reviews, see:

3a Verkade JMM. van Hemert LJC. Quaedflieg PJLM. Rutjes FPJT. Chem. Soc. Rev.  2008,  37:  29 

3b Ting A. Schaus SE. Eur. J. Org. Chem.  2007,  5797 

4a Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 

4b Gerebtzoff G. Li-Blatter X. Fischer H. Frentzel A. Seelig A. ChemBioChem  2004,  5:  676 

4c Jeschke P. ChemBioChem  2004,  5:  570 

5a Asymmetric Fluoroorganic Chemistry: Synthesis, Applications and Future Directions   Ramachandran PV. American Chemical Society; Washington DC: 2000. 

5b Biomedical Frontiers of Fluorine Chemistry   Ojima I. McCarthy JR. Welch JT. American Chemical Society; Washington DC: 1996. 

5c Welch JT. Eswarakrishnan S. In Fluorine in Bioorganic Chemistry   John Wiley and Sons; New York: 1990. 

5d Resnati G. Tetrahedron  1993,  49:  9385 

6 Zhong G. Fan J. Barbas CF. Tetrahedron Lett.  2004,  45:  5681 

7a Chen X.-H. Luo S.-W. Tang Z. Cun L.-F. Mi A.-Q. Jiang Y.-Z. Gong L.-Z. Chem. Eur. J.  2007,  13:  689 

7b Xu X.-Y. Wang Y.-Z. Cun L.-F. Gong L.-Z. Tetrahedron Asymmetry  2007,  18:  237 

For extensive substrate scope of ketones, see:

8a Notz W. Watanabe S.-I. Chowdari NS. Zhong G. Betancort JM. Tanaka F. Barbas CF. Adv. Synth. Catal.  2004,  346:  1131 

8b Chowdari NS. Ahmad M. Albertshofer K. Tanaka F. Barbas CF. Org. Lett.  2006,  8:  2839 

9 Two examples of Mannich reaction between fluoroacetone with preformed PMP-imine derived from activated ethyl glyoxalate were reported with low ee (61% for ref. 2b) of 14%, see: Cobb AJA. Shaw DM. Longbottom DA. Gold JB. Ley SV. Org. Biomol. Chem.  2005,  3:  84 

10 Hayashi Y. Yamaguchi J. Hibino K. Sumiya T. Urushima T. Shoji M. Hashizume D. Koshino H. Adv. Synth. Catal.  2004,  346:  1435 

11

DFT calculations were carried out with the Gaussian 09 package (Frisch M. J. et al. Gaussian 03, Revision D.01, Gaussian, Inc.: Wallingford, CT, 2004). The geometries for two enamines and two possible transition states which involved hydrogen bonding, are fully optimized by M06 method using 6-31G+(d,p) basis set. The geometries have been confirmed to be equilibrium geometries or transition states by the harmonic frequencies calculations at the same level of theory. The energy values in the gas phase are further calculated with M06/6-311++G(d,p) method based on the optimal geometries and corrected with the zero-point energy calculated from M06/6-31G+(d,p) method. Solvent effect from DMSO is mimicked by the PCM model and single point energy calculation is done with M06/6-311++G(d,p) with the gas phase geometry.

12

Normally, the Mannich reaction will proceed at the more substituted site, see ref. 8a. Reversal of regioselectivity was observed previously, see ref. 8b.

13 We found the linear product was rather sensitive in the presence of acid, and will slowly undergo dimerization upon prolonged storage, thus all aldehydes used in this study were distilled or recrystallized prior to usage, and the products were stored after reduction to corresponding alcohol. For reduction, see: Hayashi Y. Tsuboi W. Shoji M. Suzuki N. J. Am. Chem. Soc.  2003,  125:  11208 

The addition of H₂O will slightly improve the ee, for similar observations, see:

14a Enders D. Grondal C. Vrettou M. Synthesis  2006,  2155 

For our previous study on the role of H₂O in the transition state, see:

14b Lu M. Zhu D. Lu Y. Hou Y. Tan B. Zhong G. Angew. Chem. Int. Ed.  2008,  47:  10187 

14c Zhu D. Lu M. Chua PJ. Tan B. Wang F. Yang X. Zhong G. Org. Lett.  2008,  10:  4585 

14d Tan B. Zeng X. Lu Y. Chua PJ. Zhong G. Org. Lett.  2009,  11:  1927