MacMillan’s Imidazolidinones: Powerful Chiral Organocatalysts

Biographical Sketches

Thomas Poisson was born in Normandie in 1982, and received his Master degree in 2005 from the University of Rouen under the supervision of Prof. G. Dupas. In the same year he started his PhD research under the supervision of Dr. V. Levacher. His research interests involve the development of new asymmetric organocatalytic reactions.

Introduction

During the last seven years, many research groups have developed the concept of iminium activation. The advantage of this approach is that the iminium generated in situ by equilibrium between an α,β-unsaturated carbonyl compound (ketone or aldehyde) and a secondary amine salt can replace the traditional use of Lewis acid to lower the LUMO of the electrophile (Figure [1] ). [1]

Figure 1 Lewis acid activation vs iminium activation

A small collection of chiral imidazolidinone salts have been shown to be widely efficient for a broad range of asymmetric transformations such as Friedel-Crafts alkylation, [2] Diels-Alder cycloaddition, [3] hydrogenation of α,β-unsaturated carbonyl compounds [4] and cascade catalysis. [5]

Furthermore, these chiral imidazolidinones can be used for the classical enamine activation of ketone or aldehyde [6] in aldol or addition reactions. [5]

This concept first reported by MacMillan [3] is now an efficient tool in organocatalysis. [7] Indeed, this reagent is a good alternative to toxic, hazardous and expensive metals.

Numerous catalysts are commercially available (Figure [2] ), or can be easily prepared from inexpensive natural amino acids. [3]

Moreover, it has been recently reported that the commercially available chiral amine salts derived from these imidazolidinones can be used for iminium activation in total synthesis, demonstrating that this concept can be applied to the preparation of complex target molecules. [8]

Figure 2 Commercially available chiral imidazolidinone catalysts

Abstract

(A) MacMillan and co-workers [3] have reported the first enantioselective organocatalytic Diels-Alder cycloaddition under mild conditions with excellent enantioselectivities for both stereoisomers (exo and endo). This methodology can also be applied to an intramolecular version. [9]
(B) Isoxazolidines are useful synthons in amino acid synthesis. [10] MacMillan and co-workers [11] were the first to report organocatalysed 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes. This reaction led to the formation of isoxazolidines with high enantio- and diastereoselectivities.
(C) Hechavarria Fonseca and List [12] have reported the asymmetric intramolecular Michael addition of a formyl enone providing a ketoaldehyde with good diastereoselectivity and high enantiomeric purity.
(D) Chiral imidazolidinones have been used in the addition of π-nucleophiles (pyrroles, indoles, anilines and silyloxyfuranes) to α,β-unsaturated aldehydes. [2] [13] The resulting chiral adducts are important building blocks for the preparation of natural products. [14]
(E) Organocatalytic reduction of α,β-unsaturated aldehydes was performed by List and and co-workers. [4] The iminium generated in situ reacted with the Hantzsch ester hydride donor to provide enantiomerically pure hydrogenated aldehydes. The authors noticed that the enantiomeric excess is not related to the geometry of the double bond.
(F) Asymmetric electrophilic fluorination can be performed by reaction of N-fluorobenzenesulfonimide (NFSI) with the enamine intermediate generated during the catalytic cycle. [15a] This highly enantioselective fluorination process provides a concise and versatile route to a variety of α-fluoro alcohols or aldehydes (chlorination reactions are also possible). [15b]
(G) MacMillan and co-workers [5] reported a cascade reaction where the imidazolidinone is first used to promote the formation of an iminium intermediate. Then, the latter reacts with the furan resulting in the formation of an enamine which is finally chlorinated. This cascade reaction was performed with good diastereoselectivity and high enantioselectivity.

References

1 Kagan HB. Riant O. Chem. Rev.  1992,  92:  1007 

2 Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2001,  123:  4370 

3 Ahrendt KA. Borths CJ. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  4243 

4 Yang J W. Hechavarria FonsecaMT. Vignola N. List B. Angew. Chem. Int. Ed.  2005,  44:  108 

5 Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 

6a List B. Chem. Commun.  2006,  819 

6b List B. Acc. Chem. Res.  2004,  37:  548 

6c Marigo M. Jørgensen KA. Chem. Commun.  2006,  2001 

7a Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 

7b Berkessel A. Gröger H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis   Wiley-VCH; Weinheim: 2005. 

8a Kinsman AC. Kerr MA. J. Am. Chem. Soc.  2003,  125:  14120 

8b Robichaud J. Tremblay F. Org. Lett.  2006,  8:  597 

8c King HD. Meng Z. Denhart D. Mattson R. Kimura R. Wu D. Qi G. Macor JE. Org. Lett.  2005,  7:  3437 

9 Wilson RM. Jen WS. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  11616 

10 Fredrickson F. Tetrahedron  1997,  53:  403 

11 Jen WS. Wiener JJM. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  9874 

12 Hechavarria Fonseca M. T. List B. Angew. Chem. Int. Ed.  2004,  43:  3958 

13a Austin JF. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  1172 

13b Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  7894 

13c Brown SP. Goodwin NC. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  1192 

14a Pederson RL. Fellows IM. Ung TA. Ishihara H. Hajela SP. Adv. Synth. Catal.  2002,  344:  728 

14b Kim SG. Kim J. Jung H. Tetrahedron Lett.  2005,  46:  2437 

15a Beeson T. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  8826 

15b Brochu MP. Brown SP. MacMillan DWC. J. Am. Chem. Soc.  2004,  126:  4108