Chelates hydroxy ketones

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

Reduction of (3-hydroxy ketones through chelated TSs favors. yy -l,3-diols. Boron chelates have been exploited to achieve this stereoselectivity.129 One procedure involves in situ generation of diethylmethoxyboron, which then forms a chelate with the (3-hydroxyketone. Reduction with NaBH4 leads to the vyn-diol.130... 

The use of trifluorosilanes permits reactions through hexacoordinate silicon, which presents an opportunity for chelation control. For example, a-hydroxy ketones give syn diols.110... 

The high enantioselectivity shown in the above reactions can be attributed to two important factors. First, coordination of the Lewis acid with the a-hydroxy ketone moiety of dienophile 17 or 19 leads to the formation of a rigid five-membered chelate 21. This chelate causes the differentiation of the two dia-stereotopic faces of the enone system. Second, arising from the established absolute configuration of 17 and 19, within 21, the Diels-Alder reaction proceeds with the enone fragment at its cisoid position (yyu-planar). 

Reduction of a-methyl-fi-hydroxy ketones,2 The r-butyldimethylsilyl ethers of these ketones, in which chelation is difficult, are reduced by lithium aluminum hydride with a high degree of 1,2-anri-selectivity. This reaction can therefore afford either aM ,a/iri-l,3-diols or anti,syn- 1,3-diols with high selectivity. 

Hydroxy ketones also give primarily syn 1,3-diols when chelates prepared with BC13 are reduced with quaternary ammonium salts of BH4 or BH3CN-.88... 

The syntheses of 1,3-amino alcohols from /1-hydroxy ketones were examined with O-benzyloximes possessing a CF3 group based on the following hypothesis. In these reduction systems, the intramolecular reduction might be expected to proceed through cyclic transition states to form syn 1,3-amino alcohol as indicated by the formation of the aluminum fluoride chelate (seven-membered chelate) in Fig. 5 [30]. 

Mikami has also reported a related ene-like process involving glyoxylates and ketone-derived enolsilanes 42 (Eq. 8B2.11) [17]. The enol ether adducts 43 yield the corresponding P-hydroxy ketone upon treatment with mild acid. On the basis of an analysis of the stereo- and regiochemical outcome of the addition reaction Mikami has invoked a monodentate complex between aldehyde and metal, in contrast to the typical transition-state structures involving glyoxylates that are suggested to involve metal/aldehyde chelates. 

The cycloaddition of a nitrile oxide with a chiral allylic ether affords an isoxazoline with selectivity for the pre/-isomer. This selectivity increases with the size of the alkyl substituent and is insensitive to the size of the allyl oxygen substituent. However, allyl alcohols tend to form the / ar/ isomcr preferentially, although the selectivity is often low.427"434 The product of dipolar cycloadditions based on nitrile oxides, the isoxazoline moiety, can be converted into a large variety of functional groups under relatively mild conditions.3 Among other products, the addition can be used to prepare P-hydroxy ketones (Scheme 26.17).435 The isoxazoline moiety can be used to control the relative stereochemistry through chelation control.436,437... 

Lil reagent system. It is widely believed that the high. -selectivity originates from a chelate formed between the p-hydroxy ketone and the lithium cation. This locks the ketone into a rigid conformation that is preferentially reduced from the least-hindered direction. For compound... 

In addition to accelerating the rate of carbonyl reduction, chelation can be used to control the diastereoselectivity of reductions and carbon-carbon bondforming reactions through highly organised transition states. Keck showed that appropriately subsituted p-hydroxy ketones are stereoselectively reduced by... 

Even though the model shown above is consistent with the stereochemical outcome, Flowers has shown that changing the reaction conditions or the substituents in the (3-hydroxy ketone substrates can have an impact on the stereochemical outcome of the chelation-controlled reaction.23,24 A more detailed discussion of the mechanism of this reduction can be found in Chapter 4, Section 4.3. 

Conagenin (39) is a promising anticancer natural product isolated in 1991 from the culture broths of Streptomyces roseosporus20 (Scheme 4.1n). The chelation-controlled Zn(B 114)2 reduction of the p-hydroxy ketone 40 produced the 1,3-syn-diol 41 in 30 1 diastereoselectivity. Protection of the hydroxyl groups gave the bis-acetate 42, which was then subjected to oxidative cleavage to afford the acid 43. 

A boat form can also be invoked 83). It should be noted that the direction of attack is opposite to that proposed for chelation controlled reduction of p-hydroxy ketones 104W. 

Stereoselective reduction of a y-hydroxy ketone. Reaction of the y-liydroxy ketone 1 with LiAIHj. ZnBHi. or NaBHj yields about equal amounts of the two possible diols. However, reduction 4 ith Li(C,H,),BH (2 cquiv.) yields only one product (2) in yield. The high stereoi-icicctivity is attributed to formation of a chelated boron intermediate that favors attack by the hydride from the (3-facc. The diol (2) is converted by TsCI into ancistrofuran (3), a ddfensive secretion of certain termites. 

Stereoselective reduction of -hydroxy ketones." Boron chelates of p-hydroxy ketones are reduced by sodium borohydride stcrcoseicctivciy to, vvn-l,3-diols (equation I). Even higher, sy -selectivity obtains on similar reduction of. wn-a-substituted-p-hydroxy... 

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

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