Thiourea Brpnsted acid catalysts

In 2009, Klausen and Jacobsen disclosed another activation pathway, in which the thiourea catalyst enhances the acidity of a relatively weak Brpnsted acid catalyst, and applied this to an enantioselective version of the Pictet-Spengler cyclization [149]. This increase on the acidity of the Br0nsted acid allows the protonation of the imine substrate and to the formation of an iminium ion with a chiral counterion, which is stereoselectively attacked by a nucleophile (Scheme 2.28). 

More recently, new developments of chiral hydrogen bond donor catalysts [72,73], especially the urea/thiourea type catalysts, have led to the realization of the combined use of achiral Brpnsted acid catalysts and chiral thiourea catalysts. Representative examples are summarized herein. 

The cooperative effect of Brpnsted acid catalysts and thiourea catalysts has been noticed by the Shi group (Fig. 18) [74]. In their 2007 paper on chiral thiourea-phosphine catalyzed asymmetric aza-Morita-Baylis-Hillman reaction, Shi and co-workers described that when they used a freshly prepared 77-benzylidene-4-methylbenzenesulfonamide substrate, much lower yield and enantioselectivity of the aza-Morita-Baylis-Hillman product was obtained compared with their initial result when using a long-stored substrate. They subsequently found that the long-stored substrate contained a small amount of 4-methylbenzenesulfonamide and... 

It must be noted that chiral thiourea catalysts have been used earlier to catalyze the asymmetric Mannich reaction. Jacobsen and Wenzel reported the enantioselective synthesis of A-Boc-protected p-amino acids from silyl ketene acetals and A-Boc-protected imines using the thiourea catalyst 123 (Scheme 11.24). Here, the chiral thiourea-derived Brpnsted acid catalyst (the application of chiral Brpnsted acids in the... 

Br0nsted acids such as thioureas 2 represent hydrogen-bonding catalysts. Phosphoric acids 3, AT-triflyl phosphoramides 4, and dicarboxyUc acids 5 are examples of stronger specific Brpnsted acids (Fig. 1). 

Chiral Brpnsted acids are divided into two categories. The first are neutral Brpnsted acids such as thiourea [35b] and TADDOL derivatives, also known as hydrogen-bonding catalysts, and the second are sponger Brpnsted acids such as BINOL derivatives or phosphoric acids. 

Thus, the reaction would start by the condensation between the aldehyde and the thiourea to give an imine I (Scheme 9.11, A), which would be promoted by Brpnsted acid. The catalyst could be involved in the activation of such imine (B) for the subsequent attack of the p-ketoester (C), through formation of a chiral iminium species II, to undergo an enantioselective Mannich reaction, as suggested by DFT calculations. The ensuing cyclization reaction (D) and dehydration (E) afiford the desired chiral Biginelli products and released the chiral phosphoric acid catalyst restarting the catalytic cycle. 

Miao, Chen, and coworkers have reported an efficient enantioselective Biginelli reaction catalyzed by a chiral bifunctional primary amine-thiourea derivative 43 with a carbohydrate in the catalyst skeleton and using an external Brpnsted acid in a cooperative way, with t-BuNH TFA as additive (Scheme 9.15) [54]. This protocol renders a wide range of optically active DHPMs 44 in high yields and with good to excellent enantioselectivities (up to 99% ee). 

The majority of the organocatalysts that are commonly employed are chiral Lewis or Brpnsted bases, and the catalytic potential of base functionalities has been referred to in previous chapters to some extent already. As discussed before, the use of chiral primary or secondary amines for enamine or iminium activation belongs to the most important applications of asymmetric organocatalysts nowadays. In addition, also the interplay between an acidic (thio)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such bifunctional thiourea-containing acid-base catalysts, chiral catalysts containing a (Lewis or... 

Chen et al. [26] reported the use of a bifunctional thiourea catalyst 61 during the organocatalyzed thia-Michael addition of thiophenol to unsaturated imide 58c (Scheme 3.29). Michael adduct 60c was obtained in 60% ee and 97% yield by conducting the reaction in dichloromethane at -78°C. The authors speculated that while the tertiary amine of the bifunctional catalyst 61 would act as a proton shuttle according to a Brpnsted acid/base catalysis, the presence of the thiourea moiety might possibly cooperate in the stabilization of the more stable Z-enolate intermediate via hydrogen bond formation as illustrated in Scheme 3.31. 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

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