Secondary alcohols substrates

More recently, a series of sol-gel hydrophobized nanostructured silica matrices doped with the organocatalyst TEMPO (SiliaCat TEMPO) entered the market as suitable oxidation catalysts for the rapid and selective production of carbonyls and carboxylic acids. In the former case, SiliaCat TEMPO selectively mediates the oxidation of delicate primary and secondary alcohol substrates into valued carbonyl derivatives (Scheme 5.2), retaining its potent activity throughout several reaction cycles (Table 5.2).33 Using this catalyst, for example, enables the synthesis of extremely valuable a-hydroxy acids with relevant selectivity enhancement by coupling of SiliaCat TEMPO with rapid Ru04-mediated olefin dihydroxylation (Scheme 5.3).34... 

Scheme 6.16 Product range of the 9-catalyzed tetrahydropyranylation of primary and secondary alcohol substrates.

The AdHs have been further subdivided into primary (PAdH) and secondary (SAdH) enzymes, based on their preference for primary or secondary alcohols. Substrate specificity and site-directed mutagenesis studies with the SAdH from Thermoanaerobacter ethanolicus have shown this enzyme to have a very broad profile, such that certain alkynyl ketones and ketoesters serve as substrates.33-35... 

Kinetic Resolution by Transesterification. Asymmetric transformation involving acylation of chiral alcohols is by far the most common example of kinetic resolution by lipase-catalyzed transesterification, most commonly with irreversible vinyl esters. This field is now becoming the most widely applied technique involving lipases. Recent reports of the numerous secondary alcohol substrates include various monocyclic (eq 6) andacyclic compounds, cyanohydrins, sulfones, and glycals, to name a few. 

A two-step extraction procedure, typically 9-10.5 MPa CO2 at 60 °C, dropping to 8 MPa in the collector, over 90 h to extract the alcohol followed by 20 MPa and 45 °C also worked well for other secondary alcohol substrates so that yields of each of the unreacted alcohol and the recovered ester can be > 90% with ee values > 90%. The ee is generally lower for the ester than for the recovered alcohol, the exception being PhCH2CH2CH(OH)CH3, where only 72.5% of the ester was recovered ee 88.2%). The recovered alcohol (92.4%) had an ee of only 65% [69]. 

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

The thermolysis of xanthates derived from primary alcohols yields one olefin only. With xanthates from secondary alcohols (acyclic or alicyclic) regioisomeric products as well as fi/Z-isomers may be obtained see below. While acyclic substrates may give rise to a mixture of olefins, the formation of products from alicyclic substrates often is determined by the stereochemical requirements the /3-hydrogen and the xanthate moiety must be syn to each other in order to eliminate via a cyclic transition state. 

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

The wide substrate tolerance of lipases is demonstrated by the resolution of organometallic substrates [129-131]. The presence of tin, selenium, or tellurium in the structure of secondary alcohols does not inhibit the lipase activity and enantiopure organometallic alcohols were obtained by acylation in organic media (Figure 6.48). 

Compounds containing susceptible C—H bonds can be oxidized to alcohols. " Nearly always, the C—H bond involved is tertiary, so the product is a tertiary alcohol. This is partly because tertiary C—H bonds are more susceptible to free-radical attack than primary and secondary bonds and partly because the reagents involved would oxidize primary and secondary alcohols further. In the best method, the reagent is ozone and the substrate is absorbed on silica gel. Yields as high as 99% have been... 

As with the reduction of aldehydes and ketones (16-23), the addition of organometallic compounds to these substrates can be carried out enantioselectively and diastereoselectively. Chiral secondary alcohols have been obtained with high ee values by addition to aromatic aldehydes of Grignard and organolithium compounds in the presence of optically active amino alcohols as ligands. ... 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Oxidation of cyclobutanol by a Cr(VI)-V(IV) couple appears to involve attack of Cr(IV) upon the substrate to yield a free radical, (Section 2.5). This implies the following possible variation in the Westheimer scheme for a secondary alcohol ... 

All the oxidants convert primary and secondary alcohols to aldehydes and ketones respectively, albeit with a great range of velocities. Co(III) attacks even tertiary alcohols readily but the other oxidants generally require the presence of a hydrogen atom on the hydroxylated carbon atom. Spectroscopic evidence indicates the formation of complexes between oxidant and substrate in some instances and this is supported by the frequence occurrence of Michaelis-Menten kinetics. Carbon-carbon bond fission occurs in certain cases. 

The oxidations of formic acid by Co(III) and V(V) are straightforward, being first-order with respect to both oxidant and substrate and acid-inverse and slightly acid-catalysed respectively. The primary kinetic isotope effects are l.Sj (25°C)forCo(IU)and4.1 (61.5 C°)for V(V). The low value for Co(lII) is analogous to those for Co(IIl) oxidations of secondary alcohols, formaldehyde and m-nitrobenzaldehyde vide supra). A djo/ h20 for the Co(III) oxidation is about 1.0, which is curiously high for an acid-inverse reaction . The mechanisms clearly parallel those for oxidation of alcohols (p. 376) where Rj and R2 become doubly bonded oxygen. 

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. 

The results of the series of reactions shown in eq. 2 are listed in Table 1 together with our early reported data on the hydrogenation of 2-octanone (Z) [4]. The hydrogenation on all substrates proceeded smoothly and gave the corresponding chiral secondary alcohol. In the case of 3, 4, S, and 6, some amounts of lactone were produced as by-product. From this study, quite interesting stereochemical behavior... 

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

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