Intramolecular crossed-benzoin reaction

As an obvious extension of the benzoin reaction, the cross-coupling of aldehydes or of aldehydes and ketones was first achieved with the thiamine-dependent enzyme benzoylformate decarboxylase. This linked a variety of mostly aromatic aldehydes to acetaldehyde to form the corresponding a-hydroxy ketones, both chemo- and stereoselectively [31]. Synthetic thiazolium salts, developed by Stetter and co-workers and similar to thiamine itself [32], have been successfully used by Suzuki et al. for a diastereoselective intramolecular crossed aldehyde-ketone benzoin reaction during the course of an elegant natural product synthesis [33], Stereocontrol was exerted by pre-existing stereocenters in the specific substrates, the catalysts being achiral. 

In contrast to the previously described intermolecular condensation reaction, intramolecular crossed benzoin reactions have been developed much less for a long time (Cookson and Lane 1976). 

Attempted intermolecular cross-benzoin reactions typically generate a thermodynamically controlled mixture of products [50], although several groups including Enders [51], Suzuki [52] and You [53] have utilised catalysts 116-118 for the intramolecular crossed benzoin of keto-aldehydes (Scheme 12.22). 

Scheme 12.22 Asymmetric intramolecular cross-benzoin reactions...

The benzoin reaction typically consists of the homocoupling of two aldehydes, which results in the formation of inherently dimeric compounds, therefore limiting the synthetic utility. The aoss-benzoin reaction has the potential to produce four products, two homocoupled adducts and two cross-benzoin products. Several strategies have been employed to develop a selective cross-benzoin reaction, including the use of donor-acceptor aldehydes, acyl silanes, acyl imines, as well as intramolecular reactions. 

Suzuki and co-workers reported the intramolecular cross-benzoin reaction utilizing thiazolium pre-catalyst 35 to obtain products such as 37 and 38 (Eq. 3) [49],... 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

The substrates of the enantioselective intramolecular crossed benzoin condensation were varied to widen the scope of the reaction. Promising results were... 

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

Scheme 28. Intramolecular crossed benzoin reaction by Suzuki et al.

Scheme 34. Further scope of the intramolecular crossed benzoin reaction...

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

Hachisu Y, Bode JW, Suzuki K (2003) Catalytic intramolecular crossed aldehyde-ketone benzoin reactions a novel synthesis of functionalized prean-thraquinones. J Am Chem Soc 125 8432-8433 Hachisu Y, Bode JW, Suzuki K (2004) Thiazolium ylide-catalyzed intramolecular aldehyde-ketone benzoin-forming reactions substrate scope. Adv Synth Catal 346 1097-1100... 

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester <06SL2431>. Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation <06H(68)483>. 

Hachisu, Y., Bode, J. W., Suzuki, K. Catalytic Intramolecular Crossed Aldehyde-Ketone Benzoin Reactions A Novel Synthesis of Functionalized Preanthraquinones. J. Am. Chem. Soc. 2003,125, 8432-8433. 

Scheme 7.4 Asymmetric intramolecular cross-benzoin reaction of symmetrical diketones reported by Ema.

Scheme 7.5 Enantioselective intramolecular iV-tethered cross-benzoin reaction reported by You.

In 2005, Enders et al. reported the first enantioselective intramolecular crossed-benzoin reaction catalysed by novel chiral bicyclic D1 or tetracyclic El triazolium carbenes. A number of benzoin products 4 with a quaternary carbon stereocentre were obtained in high yields with good to high enan-tioselectivities (Scheme 20.4). ... 

The intramolecular aldehyde-ketone benzoin reaction catalysed by pre-NHC FI was reported by Suzuki et al. It was found that the size of the substituent at the ketone moiety could influence the enantiomeric excess (Scheme 20.5). Recently, Sakai and Ema reported the intramolecular crossed benzoin reactions of cyclic diketones (Scheme 20.6). " In the presence of 30 mol% of... 

Intramolecular Cross-Benzoin Reaction. In 2003, Suzuki and coworkers [21] reported the intramolecular cross-benzoin reaction utilizing thiazolium precatalyst 8 to gain the corresponding products 7 in good yields (Scheme 7.6). 

Suzuki and co-workers [23] extended the scope of the intramolecular aldehyde-ketone benzoin reaction for the synthesis of natural products with a-keto tertiary alcohols in up to 99% ee. It was found that the size of the substituent at the ketone moiety could influence the enantiomeric excess. For example, 39% ee resulted for the methyl ketone, while 90% ee resulted for the ethyl ketone (Scheme 7.8). To extend the scope of the reaction, they modified the Rovis triazolium salts by introducing electron-withdrawing substituent(s). Under the catalyst of triazolium salt 12, the a-keto tertiary alcohol 14 resulted in 92% yield and 95% ee, which was then transformed into (+)-sappanone B (Scheme 7.9) [24]. An asymmetric desym-metrization strategy was utilized by Saka and Ema for the intramolecular crossed... 

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. ... 

NHC catalysis has been efficiently employed in an intramolecular crossed-benzoin reaction of symmetrical reactants. This desymmetrization strategy can be applied to (g) asymmetric synthesis with chiral NHCs. As an example, bis(acyloin) (91) containing three contiguous quaternary bridgehead chiral centres was synthesized and structurally characterized by X-ray crystallography. 

The enantioselective intramolecular cross-coupUng of aldehydes and ketones to access cyclic a-hydroxy ketones has also been demonstrated. Issues of chemoselectivity are largely avoided in these cases, and the benzoin reaction can be achieved in a highly efficient and enantioselective manner (up to 93% yield and 99% ee) [28]. The usefulness of the intramolecular cross-benzoin reaction was elegantly illustrated in two separate cydizations for the synthesis of seragakinone A, an antifungal and antibacterial natural product [29]. 

In 2006, Enders reported an intramolecular cross benzoin reaction of bifunctional substrates 53 containing aldehyde and ketone groups to give various six-membered cyclic acyloins 54 in moderate to good yields. Up to 98% ee has been obtained upon catalysis by the tetracyclic triazolium salt 52 (Scheme 36.15) [21aj. Suzuki also developed a similar intramolecular asymmetric cross benzoin reaction [2lb]. 

Scheme 36.15 Asymmetric intramolecular cross benzoin reaction.

---