Asymmetric benzoin reaction

Asymmetric Benzoin Reactions Thiazolium Salt Pre-Catalysts... 

The first asymmetric benzoin reactions were reported by Sheehan and Hannemann nsing chiral thiazolinm salt pre-catalyst 100 of unknown absolute configuration [40], Low yields and enantioselectivities were obtained, and although a wide range of thiazolium salt pre-catalysts have since been studied, of which 101-105 are representative, the enantioselectivities obtained for the condensation of benzaldehyde using thiazolium pre-catalysts are generally poor (Scheme 12.19) [41],... 

Scheme 12.19 Chiral thiazolium pre-catalysts for the asymmetric benzoin reaction...

Table 1 Substrate scope of the asymmetric benzoin reaction [FXl]...

The triazol-5-ylidene 12 was found to be a powerful catalyst for the conversion of formaldehyde to glycolaldehyde in a formoin reaction [25.] The concept of triazolium salt catalysis appeared to show promise, and consequently our research group undertook the synthesis of a variety of chiral triazolium salts for the asymmetric benzoin reaction [26]. However, the ce-values and catalytic activities shifted widely with slight structural changes in the substitution pattern of the triazolium system. The most active catalyst 15 (Fig. 9.4) afforded benzoin (6, Ar = Ph) in its (R -configuration with 75% ee and a satisfactory yield of 66%. 

Enders D, Breuer K, Teles JH (1996b) A novel asymmetric benzoin reaction catalyzed by a chiral triazolium salt. Preliminary communication. Helv Chim Acta 79 1217... 

The development of efficient chiral NHC catalysts has proved to be a challenging task. For instance, following the first attempts at developing an asymmetric benzoin reaction, carried out by Sheehan and co-workers in 1966 using chiral thiazolium salt-derived NHCs [118], in 2002 Enders and Kallfass achieved enantiomeric excesses of 90% by means of a chiral triazolium salt-derived NHC [119]. These catalysts are usually generated in situ by treatment of chiral triazolium salts (see Figure 2.25) by a suitable base. 

FIGURE 2.26. Transition state model for the NHC-catalyzed asymmetric benzoin reaction. 

A review of the asymmetric Stetter and asymmetric benzoin reactions focuses mainly on two classes of highly successful catalysts NHCs and metallophosphites. A new NHC, pyrido[l,2-a]-2-ethyl[l,2,4]triazol-3-ylidene (99), is a powerful catalyst of benzoin condensation in the presence of potassium f-butoxide. A DFT study of the mechanism suggests that the f-butanol solvent is explicitly involved. o-Phthalaldehyde chalcones (100) undergo intramolecular aldehyde-ketone crossed-benzoin condensation to naphthalenone tertiary alcohols (101) in yields up to 94%, in 20 min, using NHC catalysis. ... 

In 1966, Sheehan reported a remarkable asymmetric benzoin reaction catalyzed by chiral thiazolium salts with moderate levels of enantioselectivity [56-59]. In 2002, Enders and coworkers made an important breakthrough when they reported the first highly enantioselective intermolecular benzoin reaction catalyzed by a triazolium salt derived from ferf-leucine [Eq. (1)] [60]. Since then, catalyst development for NHC catalysis has seen exponential growth for new triazolium salts derived from chiral amino acids and amino alcohols. 

A.S. Demir, T. Diinnwald, H. Iding, M. Pohl, M. Muller, Asymmetric benzoin reaction catalyzed by benzoylformate decarboxylase. Tetrahedron Asymmetry 10 (1999) 4769-4774. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Scheme 12.22 Asymmetric intramolecular cross-benzoin reactions...

Suzuki and co-workers recently applied the asymmetric intramolecular benzoin reaction to the synthesis of the homoisoflavonoid (-F)-sappanone B 122 [54]. The authors found that triazolium salt pre-catalyst 120 gave the best results for the... 

It should, however, be pointed out that - where applicable - product composition can be significantly different. For example, whereas thiazolium catalysts afford exclusively dihydroxyacetone with formaldehyde as substrate, the triazolium systems afford glycolic aldehyde (plus glyceraldehyde and C4 and C5 sugars as secondary products) [246], Catalyst-dependent differences in the relative rates of the partial reactions within the catalytic cycle (Scheme 6.105) most probably account for this phenomenon. A subsequent study by Enders et al. on chiral triazolium salts identified the derivative 233 as a first catalyst for the asymmetric benzoin condensation that affords substantial enantiomeric excesses (up to 86%) with satisfactory chemical yields (Table 6.3) [247]. 

In the benzoin condensation, a new stereogenic center is formed, as the product is an a-hydroxy ketone. Consequently, many chemists aspired to develop heterazolium-catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions [9]. For example, Sheehan et al. presented the first asymmetric benzoin condensation in 1966, with the chiral thiazolium salt 7 (Fig. 9.2) as catalyst precursor [10]. 

Scheme 9.6 Asymmetric intramolecular crossed benzoin reaction, according to Enders et al.

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]. 

Lithium phosphites also can catalyze the silyl benzoin reaction of acylsilanes. Its asymmetric version is successfully achieved by a lithium phosphite derived from a homochiral diol.236 Thiazolium salt 32 effectively promotes conjugate acylation of a, 3-unsaturated carbonyls with acylsilanes in the presence of DBU (Equation (61)).237,237a The active catalyst of this sila-Stetter reaction would be a carbene species generated from 32 by deprotonation. 

Applying (S)-102 in the asymmetric benzoin condensation hS i-ben-zoin (6, R = Ph) was produced in very good enantioselectivity (90% ee, 83% yield) (Enders and Kallfass 2002). The condensation of numerous other aromatic aldehydes 6 yielded the corresponding a-hydroxy ketones 85 with excellent enantiomeric excesses up to 99%. As previously observed, electron-rich aldehydes gave higher asymmetric inductions than the electron-deficient ones. Lower reaction temperatures (0°C instead of room temperature) or lower amounts of catalyst caused decreased yields but slightly enhanced enantiomeric excesses (Scheme 27). 

With the enantioselective intramolecular benzoin reaction established as a synthetic tool, and in combination with our efforts in the synthesis of bioactive natural products bearing a quaternary a-hydroxy ketone unit (Davis and Weismiller 1990 Heller and Tamm 1981), such as the 4-chromanone derivative (S)-eucomol (Bohler and Tamm 1967 Crouch et al. 1999), a catalytic asymmetric synthesis of various 3-hydroxy-4-chromanones brought about by the chiral triazolium salts 127, 123b and 102 as pre-catalysts was investigated (Enders et al. 2006d). The sterically different pre-catalysts were chosen in order to adjust the catalyst system to the steric and electronic properties of the substrates 128. A screening of the reaction conditions indicated 10 mol% of the... 

Enders D, Hilttl MRM (2006) Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441 861-863 Enders D, Kallfass U (2002) An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew Chem Int Ed Engl 41 1743-1745... 

Enders D, Muller-Huwen A (2004) Asymmetric synthesis of 2-amino-1,3-diols and D-erythro-sphinganine. Eur J Org Chem 2004 1732 Enders D, Niemeier O (2004) Thiazol-2-ylidene catalysis in intramolecular crossed aldehyde-ketone benzoin reactions. Synlett 2004 2111-2114... 

Enders D, Niemeier O, Balensiefer T (2006c) Asymmetric intramolecular cros-sed-benzoin reactions by N-heterocyclic carbene catalysis. Angew Chem Int Ed Engl 45 1463... 

Enders D, Niemeier O, Raabe G (2006d) Asymmetric synthesis of chromanones via N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reactions. Synlett 2006 2431... 

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