Dehydration enantioselective

ABSTRACT Zeolite Y modified with chiral sulfoxides has been foimd catal rtically to dehydrate racemic butan-2-ol enantioselectively depending on the chiral modifier used. Zeolite Y modified with R-l,3-dithiane-1-oxide shows a higher selectivity towards conversion of S-butan-2-ol and the zeolite modified with S-2-phenyl-3-dithiane-1-oxide reacts preferentially with R-butan-2-ol. Zeolite Y modified with dithiane oxide demonstrates a significantly higher catalsdic activity when compared to the unmodified zeolite. Computational simulations are described and a model for the catalytic site is discussed. 

Experiments with these catalysts, from an old study by Schwab and Rudolph,3 showed that enantioselectivity occurs at the metal-quartz interface during enantioselective dehydrations of racemic 2-butanol. Klabunovskii and colleagues expanded on this idea and prepared a chiral Ni-quartz catalyst that... 

Toda et al. reported that the topotactic and enantioselective photodimerization of coumarin and thiocoumarin takes place in single crystals without significant molecular rearrangements [49]. Molecular motion needs to be called upon to explain the photochemically activated cycloaddition reaction of 2-benzyl-5-benzylidenecyclopentanone. The dimer molecules, once formed, move smoothly in the reactant crystal to form the product crystal [50]. Harris et al. investigated the reactivity of 10-hydroxy-10,9-boroxophenanthrene in the solid state and the mechanism of the solid-state reaction was characterized by both X-ray diffraction and thermal analysis [51]. It was demonstrated that the solution chemistry of 10-hydroxy-10,9-boroxophenanthrene is different from that in the solid state, where it undergoes dimerization and dehydration to form a monohydride derivative. 

One of the first optically active allenes reported was synthesized by enantioselective dehydration of a racemic allylic alcohol in the presence of (+)-10-camphorsulfonic acid as the chiral catalyst125,126. The initial optical rotation of the tetraarylallene is low, but can be increased to [a],2/1 +351 (cyclohexane) after several recrystallizations. 

It was found that MpSCD is able to restore dehydration-induced structural perturbations to a certain extent. Results were interpreted to show that enantioselectivity and structural intactness in the various solvents investigated were clearly related. Increased enzyme activity, in contrast, is mainly caused by increased structural flexibility of subtilisin in the solvents by M(iCD. Similar results have been reported for subtilisin Carlsberg [124]. 

We have put forward (J. Am. Client. Soc. 2004, /26, 13900) an alternative approach to the enantioselective construction of cyclic quaternary centers. Addition of phenylacetylene to cyclopentanone followed by dehydration and Shi epoxidation gave the epoxide 10. Opening of the epoxide with allylmagnesium chloride proceeded with inversion, to give II. The alcohol 11 can also be carried on to bicyclic products, exemplified by the sulfone 12. 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

Fig. 4 and Table 4 summarize some other reaction types and also some very special cases of enantioselection. Quartz catalysts (Ml) have been used for dehydration (45) and isomerization (44) reactions (again with very low ee) and Cu-tartrate (M6) catalyzes the carbene addition 43 with an acceptable optical yield, giving an intermediate in a steroid synthesis [49]. 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

Activation by a factor of 105 closes most of the gaps between specific activity levels in water and organic solvents. The state of affairs regarding the preparation of highly active enzyme formulations for use in non-aqueous media is summarized by Lee and Dordick (Lee, 2002). Improved mechanistic understanding of enzyme function and activation in dehydrated environments will lead to the development of a broad array of techniques for generating more active, stable, and enantioselective and regioselective tailored enzymes for synthetically relevant transformations. This, in turn, should result in an increase in the opportunities for enzymatic processes to be developed on a commercial scale. 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Disubstituted cyclopentane-1,3-diones and cyclohexane-1,3-diones were used as substrates. After formation of the aldol adducts subsequent intramolecular dehydration furnished products of types 94 and 96. The asymmetric intramolecular aldol reaction proceeds with a broad variety of natural amino acids as organocata-lysts. Among these L-proline was usually found to be the most versatile. For example, conversion of the 2,2-disubstituted cyclopentane-1,3-dione 93 in the presence of L-proline gave the desired product 94 in 86.6% yield and with enantioselectivity of 84% ee [97]. This example and a related reaction with a 2,2-disubstituted cyclohexane-1,3-dione 95 are shown in Scheme 6.42. Chiral induction depends... 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

Optically pure (+)-(i )-3-phenylsulfanyl-l,3-diarylpropan-l-ones are readily available by the enantioselective Michael addition of thiophenols to chalcones. After reduction, acidic dehydration of the racemic alcohol affords a mixture of the racemic cis- and trans- 2,4-disubstituted thiochromans (Scheme 164). A detailed consideration of the stereochemical outcome of the reaction with unsymmetrically substituted diaryl derivatives suggests the involvement of a [1,3] PhS shift via a four-membered sulfonium intermediate and this is backed up by theoretical calculations <2003T3621>. 

Agami C (1988) Mechanism of the proline-catalyzed enantioselective aldol reaction. Recent advances. Bull Soc Chim Fr 3 499-507 Agami C, Meynier F, Puchot C, Guilhem J, Pascard C (1984) New insights into the mechanism of the proline-catalyzed asymmetric Robinson cycliza-tion structure of two intermediates. Asymmetric dehydration. Tetrahedron 40 1031-1038... 

Thiosalicylaldehydes afford chiral thiochromene-3-carbaldehydes 39 on reaction with a,P-unsaturated aldehydes catalysed by a chiral pyrrolidine silyl ether. Initial activation of the enal triggers sequential Michael and aldol reactions and dehydration completes the highly enantioselective synthesis <06JA10354, 06TL8547>. In a similar manner, cyclic enones afford cycloalkanone[ ]thiochromenes <06TL8679>. 

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