Enantioselectivity Stetter reaction

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

The Chi group reported in 2011 the enantioselective Stetter reaction between enals and modified chalcones proceeding through a Michael-type addition of NHC-bound enal acyl anions to the Michael acceptors. The Stetter reaction with p-alkyl enals afforded the Michael addition products with good enantioselectivity and yields (14 examples, up to 93% yield, 94% ee). While P-aryl enals were tested in this reaction, up to moderate yield was achieved. This was because the enolate pathway (giving Diels-Alder products)" dominated, which was difficult to suppress under these reaction conditions (Scheme 7.26). 

Enals (92) react with modified chalcones (e.g. 93) in an enantioselective Stetter reaction, giving highly functionalized products (94) in ees up to 97%, using chiral NHC catalysis. A Michael-type addition of NHC-bound enal acyl anion to the chalcone is proposed. ... 

Scheme 21. Novel chiral thiazolium salts - catalysts for enantioselective Stetter reactions and acyloin condensations...

In 2008, Enders and coworkers reported the first high-yielding enantioselective intermolecular Stetter reactions employing chalcones and aryUdene-malonates as acceptors and N-Bn triazolium salt 71 as precatalyst (Schemes 18.11 and 18.12) [48]. The use of an N-benzyl instead of the usual N-aryl substituent on the triazolium ring was crucial for the activity and selectivity of the catalyst. Rovis et al. subsequently disclosed a highly enantioselective Stetter reaction of alkylidene-... 

Although these recent developments show that various substrates can be used to obtain Stetter products in high yields and enantiomeric ratios, the required combination of aldehyde, acceptor, catalyst, and reaction conditions is both critical and difficult to anticipate. The enantioselective Stetter reaction between aliphatic... 

Since these early groundbreaking studies, the field of conjugate addition reactions has experienced noteworthy advances. The reactions constitute a vital method for the formation of new bonds f to carbonyl groups. Multiple innovative approaches to effect diastereoselective [21, 27-36] and enantio-selective [34—47] conjugate additions of a wide variety of nucleophiles to an equally large spectrum of acceptors have appeared. These form the greater part of the discussion in this chapter (Sections 12.2-12.7), followed by sections on conjugate reductions (12.8) [32, 38] and recent advances in enantioselective Stetter reactions (12.9) [41, 48, 49]. 

The first asymmetric intramolecular Stetter reactions were reported by Enders and co-workers utilising triazolium salt pre-catalyst 125. Treatment of substrate 123 generated 1,4-dicarbonyl compound 124 in good yield and enantioselectivity [56]. These salicylaldehyde-derived substrates 123 have since become the standard test substrates for the development of new catalysts for the asymmetric intramolecular Stetter reaction. Bach and co-workers have achieved moderate enantioselectivities using axially-chiral thiazolium pre-catalyst 126 [41], whilst Miller and co-workers have developed peptidic thiazolium pre-catalyst 127 [57]. In 2005, Rovis and coworkers showed that the NHCs derived from triazolium salts 128-130 were excellent catalysts for the asymmetric intramolecular Stetter reaction of a wide range of substrates, giving typically excellent yields and enantioselectivities [58]. The iV-pentafluorophenyl catalyst 129 currently represents the state of the art in asymmetric Stetter reactions (Scheme 12.24) [59]. 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Rovis and co-workers have recently shown that the NHC derived from triazoUum pre-catalyst 151 catalyses the intermolecular Stetter reaction of glyoxamides 149 with alkylidene malonates 150. Enantioselectivities of np to 91% have been obtained with typically good to excellent yields of the corresponding Stetter prod-nets (Scheme 12.32) [68]. 

Rovis and co-workers have also extended the intermolecular Stetter reaction to inclnde nitroaUcenes as the electrophilic component. Fluorinated triazolinm precatalyst 155 was effective in catalysing the reaction of a variety of heteroaromatic aldehydes 153 with nitroalkenes 154 to generate P-nitroketones in excellent yields and enantioselectivities. The authors propose that stereoelectronically induced conformational effects on the catalyst skeleton are key to the high selectivities observed with flnorinated catalyst 155 (Scheme 12.33) [69],... 

In 2002, Rovis and co-workers developed a series of triazolinm pre-catalysts, 75 and 76, and reported a highly enantioselective intramolecnlar Stetter reaction [66]. These tetracyclic strnctnres bear a fnsed-ring system in order to restrict rotation, taking advantage of the concept first introduced by keeper and Rawal, and further provide the ability to add steric bulk on both sides of the reacting site, blocking three of the fonr quadrants (Scheme 11, contrast Model A vs Model B) [67]. 

The geometry of the Michael acceptor has been shown to play an important role in the intramolecnlar Stetter reaction [70,72], In the case of salicylaldehyde derived substrate 90, which contains a c -l,2-disubstituted aUcene, no reaction occurs under standard reaction conditions. The same is not true with trisubstituted olefin acceptors. Cychzation of p,p-disubstituted substrate E)-9 provides cyclized product in high yield and 91% ee Eq. 7. The corresponding (Z)-isomer gives a similar yield although the enantioselectivity is decreased to 86%. 

Utilizing prochiral a,a-disubstituted Michael acceptors, the Stetter reaction catalyzed by 76a has proven to be both enantio- and diastereoselective, allowing control of the formation of contiguous stereocenters Eq. 8 [73]. It is noteworthy that a substantial increase in diastereoselectivity is observed, from 3 1 to 15 1, when HMDS, the conjugate acid formed upon pre-catalyst deprotonation, is removed from the reaction vessel. Reproducible results and comparable enantioselectivities are observed with free carbenes for example, free carbene 95 provides 94 in 15 1 diastereoselectivity. The reaction scope is quite general and tolerates both aromatic and aliphatic aldehydes (Table 9). 

In 2004 and 2005, respectively, Bach and Miller independently described the use of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular Stetter reaction. Bach and co-workers employed an axially chiral A-arylthiazolium salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77]. Miller and co-workers found that thiazolium salts embedded in a peptide backbone 65 could impart modest enantioselectivity on the intramolecular Stetter reaction [78]. In 2006, Tomioka reported a C -symmetric imidazolinylidene 112 that is also effective in the aliphatic Stetter reaction, providing three examples in moderate enantioselectivities (Scheme 17) [79]. 

While catalysts and reaction protocols are well established for the enantioselective intramolecular Stetter reaction, asymmetric intermolecular Stetter products are much more difficult to obtain using known methodologies. A report by Enders and co-workers described the first asymmetric intermolecular Stetter reaction utilizing n-butanal and chalcone [4], When thiazolium salt 114 is used in this system the reaction proceeds in 39% ee, albeit in 4% yield of 113. The authors comment that both thiazolium and triazolium pre-catalysts perform poorly. The yield was increased to 29% yield with thiazolium pre-catalyst 115 although a loss in enanti-oselectivity was observed (Scheme 18) [80]. 

Chiral and achiral 1,2,4-triazolium salts were synthesized and found to be bench stable precursors of NHCs that efficiently catalyse both Stetter reactions and additions to a-bromoaldehydes in an enantioselective fashion.51... 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

The triazolium salt 2 has also been used as a purely organic catalyst [17]. It is an active catalyst for asymmetric benzoin-type condensation reactions yielding the reaction products with enantiomeric excesses of 20-80%, which at the time marked a major advance with respect to the previously established catalysts (Scheme 5, Eq. 1) [18]. It was also found to catalyze the asymmetric intramolecular Stetter reaction with moderate to good enantioselectivities (41-74% ee) (Scheme 5, Eq. 2) [19]. 

Kerr MS, Rovis T (2004) Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. J Am Chem Soc 126 8876-8877... 

Moore JL, Kerr MS, Rovis T (2006) Enantioselective formation of quaternary stereocenters using the catalytic intramolecular Stetter reaction. Tetrahedron 62 11477-11482... 

With respect to the application of asymmetric carbene catalysis as a tool for enantioselective synthesis, the last decade s major success is based on substantial improvements in catalyst development. Early reports dealt with implementing chirality in thiazolium scaffolds (Sheehan and Hunneman 1966 Sheehan and Hara 1974 Dvorak and Rawal 1998), but their catalytic performance suffered from either low yields or low ee-values. In this regard, the investigation of triazole heterocycles as an alternative core structure (Enders et al. 1995) has played a crucial role to provide heterazolium precatalysts improving both asymmetric benzoin and Stetter reactions. An intramolecular Stetter reaction yielding chromanones upon cyclization of salicylaldehyde-derived substrates is commonly used as a benchmark reaction to compare catalyst efficiency (Scheme 1 Ciganek 1995 Enders et al. 1996 Kerr et al. 2002 Kerr and Rovis 2004). 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

Kerr, M. S., Read de Alaniz, J., Rovis, T. A Highly Enantioselective Catalytic Intramolecular Stetter Reaction. J. Am. Chem. Soc. 2002, 124, 10298-10299. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

Variants of the Michael addition include the allylation of cyclopropenone acetals and the intramolecular Stetter reaction. So far, only moderate enantioselectivity for the latter reaction has been achieved. (Note that the same chiral catalyst is useful for benzoin condensation. )... 

A series of chiral triazolium salts have been reacted with a base to form the corresponding chiral carbenes, which was shown to catalyze the Stetter reaction efficiently and to provide 1,4-dicarbonyl products in high yields and enantioselectivities (eq 33). A survey of common bases identified KHMDS as providing an optimal balance between the yield and selectivity in this reaction. The reaction is sensitive to the nature of the Michael acceptor while electron deficient -alkenes provided the desired product in good yields and enantioselectivities, no reaction was observed in the case of Z-alkenes. ... 

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