Substrate keto-compounds

If A -20-keto steroids are used as substrates, only low yields of A -17a-hydroxy-20-keto compounds are obtained. If a methyl group is also present on the double bond at C-16, the final product is a 16-methylene-17a-hydroxy-20-keto steroid. " ... 

Most of the substrates or products which are interesting for organic chemistry are scarcely soluble in aqueous solutions. Unfortunately, enzymes are often deactivated when used in organic solvents. Successful conversions of the hydro-phobic keto compounds thus can demonstrate general reaction principles for enzyme-catalyzed transformations of hydrophobic substrates. Various concepts concerning the application of enzymes for the transformation of hydrophobic compounds have been developed, but none of them have been applied so far in technical scale. 

Conversion of known substrates of AR to their 3-methylene derivatives resulted in competitive inhibitors, the most effective of which were the 17-keto analogues 3-methylene- (32), 19-hydroxy-3-methylene- (33) and 3-methylene-19-oxo- (34) androst-4-en-17-ones, with apparent values of 4.7, 13 and 24 nM, respectively [167]. A parallel series of 17-hydroxy analogues exhibited lower potency, supporting the general observation that the 17-keto compounds demonstrate higher affinity for the enzyme. 

Use of the enzyme dTDP-glucose-4,6-dehydratase on the substrate dTDP-glucose has generated the corresponding 6-deoxy-4-keto product - but it partly isomerized to the 3-keto compound during workup. 3-Azido-3-deoxy- and 3-deoxy-dTDP-glucose were also substrates affording the 3-modified 6-deoxy-4-keto products. ... 

With certain carbonyl compounds, however, such as 3-keto steroids, the isotopic composition is poor due to the rapid exchange of the activated a-hydrogens in the substrate prior to reduction. The corresponding alcohols, in their thermodynamically more stable configuration, are usually found as... 

With respect to the carbonyl substrate, a variety of additional functional groups is tolerated, e.g. ester, ether, halogen. With compounds that contain an ester as well as a keto or aldehyde function, the latter usually reacts preferentially. Due to its mild reaction conditions the Wittig reaction is an important method for the synthesis of sensitive alkenes, as for example highly unsaturated compounds like the carotinoid 17 shown above. 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

C-chiral hydroxy phosphorus derivatives, which have been described so far in the literature, are secondary alcohols. Thus, the syntheses of non-racemic compounds of this type comprise two main approaches (cf. C-chiral hydroxyalkyl sulfones. Section 2.2) asymmetric reduction of the corresponding keto derivatives and resolution of racemic hydroxyalkanephosphorus substrates. 

Many of the compounds that undergo ready base-catalysed keto i enol prototropic changes, e.g. / -keto esters, l,3-(/ -) diketones, aliphatic nitro compounds, etc., form relatively stable carbanions, e.g. (25), that can often be isolated. Thus it is possible to obtain carbanions from the keto forms of the /J-keto ester (23a) and nitromethane (24a) and, under suitable conditions, to protonate them so as to obtain the pure enol forms (23b) and (24i>), respectively. It thus seems extremely probable that their interconversion follows the intermolecular pathway (a). The more acidic the substrate, i.e. the more stable the carbanion to which it gives rise, the greater the chance that prototropic interconversion will involve the carbanion as an intermediate. 

Interest in the uses of HMPT has also been maintained, but a warning has been issued (by the E. I. du Pont de Nemours Company and the U.S. National Institute for Occupational Safety and Health) about its potential acute toxicity. HMPT has been used in the synthesis of 2,4-bis(dimethylamino)qui nolines,9 8 as a solvent for reactions between carbonyl compounds and sulphur," for the conversion of iV-benzylcarbox-amides into 3-phenylpropionitriles,100 in reactions between metals or organometallic compounds with a variety of organic substrates,101 and as a solvent for alkylation reactions of /J-keto-esters and related compounds in which the alkylation reaction is accompanied by de(alkoxycarbonylation) (Scheme 7).102... 

Table 9.1 shows some examples of the different substrates that can be reduced to various single diastereomers of the same compound, as the keto alcohols and hydroxy esters, by choosing the use of different enzymes. The chemoenzymatic syntheses of the aggregation pheromones (+)-Sitophilure and Sitophilate by the use of the above isolated, NADPH-dependent KREDs were successfully accomplished by our group" with high chemical and optical purities (98 % de, >99 % ee). 

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