A Novel Organocatalytic Tool for the Iminium Activation of α,β-Unsaturated Ketones

Abstract

Asymmetric aminocatalysis has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. Recent studies have established the unique ability of primary amine catalysis to participate in processes between sterically demanding partners, thus overcoming the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. With this in mind, we introduced the primary amine catalyst salt 1, made by combining the easily available 9-amino-9-deoxy-epi-hydroquinine with N-Boc-d-phenylglycine as the chiral counteranion. Salt 1 exhibits high reactivity and selectivity in the enantioselective conjugate additions of a series of different nucleophiles to unsaturated ketones. The rationale behind the development of this general and efficient iminium activator of enones is discussed.

1 Introduction

2 Iminium Catalysis

3 Iminium Activation of Unsaturated Ketones

3.1 Chiral Primary Amines in Iminium Catalysis

3.2 Asymmetric Counteranion-Directed Catalysis

4 A New Catalyst Salt for Iminium Activation of Enones: 9-Amino-9-deoxy-epi-hydroquinine and N-Boc-d-phenylglycine

4.1 Friedel-Crafts Alkylation of Indoles

4.2 Oxa-Michael Addition

4.3 Sulfa-Michael Addition

5 Summary and Outlook

amines - asymmetric catalysis - ketones - organocatalysis - Michael additions

References

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In this report, an initial attempt to perform an asymmetric version of the reaction using the MacMillan second generation imidazolidinone 7 afforded poor selectivity (28% ee). Recently, a low selectivity (up to 29% ee) addition of indole to chalcone promoted by d-camphorsulfonic acid was reported, see:

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See also:

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<A NAME="RA48708ST-43">43</A> Carreira EM. Lee W. Singer RA. J. Am. Chem. Soc.  1995,  117:  3649 

<A NAME="RA48708ST-44A">44a</A> Fraústo da Silva JR. Williams RJP. The Biological Chemistry of the Elements   Oxford University Press; New York: 2001. 

<A NAME="RA48708ST-44B">44b</A> Metzner P. Thuillier A. Sulfur Reagents in Organic Synthesis   Academic Press; New York: 1994. 

<A NAME="RA48708ST-44C">44c</A> Nudelman A. The Chemistry of Optically Active Sulfur Compounds   Gordon & Breach; New York: 1984. 

<A NAME="RA48708ST-44D">44d</A> Chatgilialoglu C. Asmus K.-D. Sulfur-Centered Reactive Intermediates in Chemistry and Biology   Springer; New York: 1991. 

<A NAME="RA48708ST-45">45</A> For a comprehensive review on asymmetric sulfa-Michael additions, see: Enders D. Lüttgen K. Narine AA. Synthesis  2007,  959 

For selected examples, see:

<A NAME="RA48708ST-46A">46a</A> Kanemasa S. Oderaotoshi Y. Wada E. J. Am. Chem. Soc.  1999,  121:  8675 

For an organocatalytic asymmetric strategy, see:

<A NAME="RA48708ST-46B">46b</A> Zu L. Wang J. Li H. Xie H. Jiang W. Wang W. J. Am. Chem. Soc.  2007,  129:  1036 

For organocatalytic asymmetric strategies, see:

<A NAME="RA48708ST-47A">47a</A> Hiemstra H. Wynberg H. J. Am. Chem. Soc.  1981,  103:  417 

<A NAME="RA48708ST-47B">47b</A> McDaid P. Chen Y. Deng L. Angew. Chem. Int. Ed.  2002,  41:  338 

<A NAME="RA48708ST-48A">48a</A> Brandau S. Maerten E. Jørgensen KA. J. Am. Chem. Soc.  2006,  128:  14986 

<A NAME="RA48708ST-48B">48b</A> Wang W. Li H. Wang J. Zu L. J. Am. Chem. Soc.  2006,  128:  10354 

<A NAME="RA48708ST-48C">48c</A>

See also reference 17h.

<A NAME="RA48708ST-49A">49a</A> Skarżewski J. Zielińska-Blajet M. Turowska-Tyrk I. Tetrahedron: Asymmetry  2001,  12:  1923 

<A NAME="RA48708ST-49B">49b</A> Li H. Zu L. Wang J. Wang W. Tetrahedron Lett.  2006,  47:  3145 

<A NAME="RA48708ST-50">50</A>

The results obtained when using 9-amino-9-deoxy-epi-hydroquinine (2) in combination with various acidic counterparts (TFA, PTSA, N-Boc-l-phenylalanine) in the organocatalyzed SMA did not show any appreciable improvement in terms of enantioselectivity, confirming the superior efficiency of the catalyst salt 1. Remarkably, consistent with previous observations, use of the opposite enantiomeric counteranion (N-Boc-l-phenylglycine) afforded the same enantiomeric sulfa-Michael adduct with lower reactivity and selectivity, illustrating a marked case of a matched/mismatched catalyst-ion pair combination.

<A NAME="RA48708ST-51">51</A> Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  Wiley-VCH; New York: 1999.  Chap. 6. p.454 

<A NAME="RA48708ST-52">52</A> In the absence of an acidic counteranion, the non-protonated 9-amino-9-deoxy-epi-hydroquinine is still able to promote the sulfa-Michael addition, albeit with lower reactivity, presumably by activating the nucleophilic component 36 through Brønsted-base catalysis; however, the observed low optical purity (8% ee) together with reversal in the stereochemistry supports an iminium ion activation mode of catalysis when the chiral salt 1 is employed. The iminium ion activation path is also corroborated by the lower reactivity observed when more encumbered α-substituted enones are employed. For similar mechanistic considerations on this type of catalyst salt, see: Wang X. Reisinger CM. List B. J. Am. Chem. Soc.  2008,  130:  6070 

<A NAME="RA48708ST-53">53</A>

Preliminary studies on conjugate additions to (E)-4-phenyl-3-buten-2-one (11) promoted by catalyst salt 1 afforded encouraging results: aza-Michael addition of N-(benzyl-oxycarbonyl)hydroxylamine: 96% ee; phospha-Michael addition of diphenylphosphine: 56% ee.

For reviews on organocatalytic domino reactions, see:

<A NAME="RA48708ST-54A">54a</A> Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 

<A NAME="RA48708ST-54B">54b</A> Guillena G. Ramón DJ. Yus M. Tetrahedron: Asymmetry  2007,  18:  693