Benzoin stereoselectivity

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

In contrast to the oxidation of prochiral esters and amides, which induces only moderate ee, sodium enolates of ketones give high stereoselectivity with (+)-147 or (—)-147 as the oxidant (Scheme 4-56 and Table 4-21). The highest stereoselectivity has been observed in the oxidation of the sodium enolate of deoxybenzoin 150, in which benzoin 149 can be obtained in over 95% optical purity. 

A novel and more general method to enable biocatalyzed conversion and synthesis of hydrophobic compounds involves the use of gel-stabilized aqueous-organic two-phase systems [8], Features, advantages, disadvantages, and perspectives of this method in asymmetric synthesis will be discussed in this chapter, illustrated for the stereoselective benzoin condensation and the reduction of ketones catalyzed by thiamine pyrophosphate (TPP)-dependent lyases and NAD(P)H-dependent alcohol dehydrogenases, respectively. 

Native BAL is a versatile catalyst in the stereoselective carboligation of aryl aldehydes (Scheme 3.2.1), yielding R-configured benzoins with 99% ee [21]. 

The thiazolium and, particularly, triazolium catalysts discussed above have been developed to the extent that they perform remarkably well in the asymmetric benzoin condensation of aromatic aldehydes. Triazolium catalysts are also very effective in the (non-stereoselective) condensation of aliphatic aldehydes [250]. It seems, however, that no catalyst is yet available that enables condensation of aliphatic aldehydes with synthetically useful enantioselectivity. The best ee yet obtained are in the range 20-25%, e.g. in the dimerization of the straight-chain C2-C7 aldehydes [251]. 

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. 

Disubstituted 1,3-oxathianes 316, prepared from benzaldehyde and the corresponding 3-mercaptoalkanol, have been stereoselectively deprotonated at the equatorial position to yield, after reaction with electrophiles, 2,2-disubstituted products. t.S j-Benzoin was obtained in 75% ee in the case of using compound 316 (R = OTBS), after reaction with benzaldehyde and final deprotection of the major product 317 with NCS and silver nitrate (Scheme 83)490. 

Reduction of tosylhydrazones Tosylhydrazones of benzoin derivatives (1) are reduced by NaBHsCN in the presence of TsOH stereoselectively to eryffcro-dia-stereomers (2) in excellent yield. 

Upon treating certain (but not all) aromatic aldehydes or glyoxals (a-keto aldehydes) with cyanide ion (CN ), benzoins (a-hydroxy-ketones or acyloins) are produced in a reaction called the benzoin condensation. The reverse process is called the retro-benzoin condensation, and it is frequently used for the preparation of ketones. The condensation involves the addition of one molecule of aldehyde to the C=0 group of another. One of the aldehydes serves as the donor and the other serves as the acceptor. Some aldehydes can only be donors (e.g. p-dimethylaminobenzaldehyde) or acceptors, so they are not able to self-condense, while other aldehydes (benzaldehyde) can perform both functions and are capable of self-condensation. Certain thiazolium salts can also catalyze the reaction in the presence of a mild base. This version of the benzoin condensation is more synthetically useful than the original procedure because it works with enolizable and non-enolizable aldehydes and asymmetric catalysts may be used. Aliphatic aldehydes can also be used and mixtures of aliphatic and aromatic aldehydes give mixed benzoins. Recently, it was also shown that thiazolium-ion based organic ionic liquids (Oils) promote the benzoin condensation in the presence of small amounts of triethylamine. The stereoselective synthesis of benzoins has been achieved using chiral thiazolium salts as catalysts. 

The catalytic hydrogenation of optically active benzoin oxime resulted in the stereoselective formation of optically active erythro diphenylethanolconine in... 

Under mechanochemical conditions, bifunctional benzil 71 is specifically reduced by NaBU, when used in a 4 1 stoichiometric ratio to quantitatively give racemic benzoin 72 (Scheme 6.26). Such result has never been described in solution reactions of these reagents. Furthermore, both carbonyl groups of 71 were quantitatively reduced to dihydrobenzoin (17/18), if a 2 1 ratio of 71 and NaBU, was applied under the otherwise identical conditions of Table 6.17. This stoichiometric synthesis provides meso-13 and rac-74 in 80% and 20% yields, respectively. This stereoselectivity compares with the reported 100 0 ratio in methanol (2h at 25°C) and the 85 15 ratio of 73/74 in ethanol (overnight). 

In an acetonitrile suspension, the intermediate a-cyanoalkoxide can be trapped by acyl chlorides to give cyanohydrin esters. In a preparation of synthetic pyrethroids, the comparison between the sonicated reaction and its PTC equivalent gave an advantage to the latter in terms of reaction time and yield. i A modest change in stereoselectivity is observed in some cases. The same reaction in the presence of ammonium chloride leads to a-amino nitriles, the first step of the Strecker amino acid synthesis.4 72 xhe procedure is more efficient in the presence of alumina. The formation of by-products, cyanohydrins or benzoins, is avoided. From an experimental viewpoint, the work-up is considerably easier than with conventional procedures, and consists mostly of a simple filtration. With ketones, and in the presence of ammonium carbonate, a hydantoin is formed (Eq. 21)7 ... 

Consult with your instructor before performing this experiment, in which you will determine the stereoselectivity of the reduction of benzoin with sodium borohydride. Follow either the Miniscale or Microscale Procedure described for reducing 9-fluorenone to reduce benzoin with sodium borohydride. but use ethanol rather than methanol as the solvent. After slowly adding 3 M HCI to decompose the excess borohydride. add enough water to adjust the solvent composition to 50% v v) ethanol and water. You may recrystallize the crude product from 50% (v v) ethanol and water. Obtain the melting point and the IR. H. and NMR spectra of the purified product for characterization. Compare these data with those for racemic and meso-hydrobenzoin to determine the identity of the product and the stereochemistry of the reduction. If authentic samples of racemic and meso-hydrobenzoin are available, determine mixed melting points to support your assignment. 

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

Benzaldehyde lyase (BAL) from Pseudomonas fluorescens (Table 10.4, entries 6-15) is one of the most efficient catalysts for the homo- and cross-carboligation reaction of aromatic and aliphatic aldehydes, because of its broad substrate range and its high (P)-stereoselectivity [14,57,58,65]. The ability of BAL to catalyze the cleavage of benzoins can also be instrumental in the resolution of racemic mixtures of these compounds [65]. 

Hischer T, Gocke D, Fernandez M, Hoyos P, Alcantara AR, Sinisterra JV, Hartmeier W, Ansorge-Schumacher MB. Stereoselective synthesis of novel benzoins catalysed by benzaldehyde lyase in a gel-stabilised two-phase system. Tetrahedron 2005 61 7378 7383. 

---