Conjugate umpolung

The reactions discussed above have focused on an a1 to d1 umpolung, as exemplified by the reaction of the resulting d1 nucleophile with aldehydes (benzoin condensation [9]) or with Michael acceptors (Stetter reaction [38]) [3]. In contrast, a,/ -unsaturated aldehydes can react as d3 nucleophiles by utilizing a conjugated umpolung that involves a homoenolate reactivity. 

Scheme 9.19 Postulated catalytic cycle for the conjugated umpolung .

Abstract. N-Heterocyclic carbenes (NHC) have become an important class of organocatalysts and class of ligands for transition-metal catalysis. In organocat-alyzed umpolung reactions, thiazolium salt-derived NHC have been used successfully for decades. Even so, during recent years there has been an increased interest in NHC-catalyzed transformations and many new reactions have been developed. This article focuses on the use of NHC in the conjugate umpolung of ,f>-unsaturated aldehydes. 

We (and in parallel Bode et al.) were pleased to find that the IMes-catalyzed conjugate umpolung of a,(j-unsaluralcd aldehydes has a broad scope (Burstein and Glorius 2004 Burstein et al. 2006 Schrader et al. 2007 Sohn et al. 2004 He and Bode 2005 Sohn and Bode 2005) (For related applications of NHC in organocatalysis, see Chow and Bode 2004 Reynolds et al. 2004 Chan and Scheidt 2005 Reynolds and Ro-vis 2005 Zeitler 2006 Nair et al. 2006a,b He et al. 2006 Fischer et al. 2006 Chiang et al. 2007 Philips et al. 2007 Maki et al. 2007). Under optimized conditions, a 1 1 mixture of cinnamaldehyde and the ben-zaldehyde derivative in THF was treated with IMes (prepared in situ from IMes HCl and an excess of KOtBu) and stirred at ambient temperature for 16 h (Table 1). A variety of differently substituted aromatic... 

Scheme 8. Proposed catalytic cycle of the conjugate umpolung...

As many natural products contain y-butyrolactone fragments (Seitz and Reiser 2005) the scope of this conjugate umpolung reaction was investigated in detail. 

Scheme 10. Conjugate umpolung using different imine substrates (Sohn et al.

Butenediol 13 was envisioned to be an ideally suited building block, allowing the synthesis of substrates for the conjugate umpolung cyclization reaction in only two steps. A highly regioselective epox-... 

Scheme 18). The formation can be explained by the initial conjugate umpolung of the aldehyde and subsequent 1,4-addition to the unsaturated ketone. After proton transfer, an intramolecular aldol-type addition results in the formation of the aforementioned zwitterions. Nucleophilic displacement of the imidazolium moiety by the alkoxide provides the p-laclonc, which exhibits increased strain, since it is annulated to a cyclopentane ring. Consequently, the P-lactone breaks apart and liberates CO2 and the observed cyclopentene products (Scheme 19). 

In conclusion, the conjugate umpolung of a,P-unsaturated aldehydes represents a versatile and powerful method to synthesize different cyclic products such as f)- and y-lactones and cyclopentenes. More valuable applications based on the NHC-catalyzed umpolung are expected to be discovered in due course. 

Burstein C, Glorius F (2004) Qrganocatalyzed conjugate umpolung of a,fS-unsaturated aldehydes for the synthesis of y-butyrolactones. Angew Chem Int Ed 43 6205-6208... 

Burstein C, Tschan S, Xie X, Glorius F (2006) N-Heterocyclic carbene-cata-lyzed conjugate umpolung for the synthesis of y-butyrolactones. Synthesis 2006 2418-2439... 

Schrader W, Handayani PP, Burstein C, Glorius F (2007) Investigating organo-catalytic reactions mass spectrometric studies of a conjugate umpolung reaction. Chem Comm 2007 716-718... 

C. Dresen, M. Richter, M. Pohl, S. Liideke, M. Muller, The enzymatic asymmetric conjugate umpolung reaction, Angew. Chem. Int. 49 (2010) 6600-6603. 

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