Asymmetric Transesterification

CAL-B-conjugated MOFs showed no loss of enantioselectivity and activity in transesterification of ( )-l-phenylethanol with vinyl acetate at room temperature. The authors speculated that the enhanced rate acceleration of 3D MOF compared with ID and 2D MOFs could be explained by confined spaces nearby the surface-anchored enzymes for substrates to contact enzymes more efficiently. In addition, the Am groups of IRMOF-3 presumably help to maintain the optimum pH for the enzymatic reaction. 

In the light of the above-mentioned nonexhaustive list of examples, MOFs are used in the fine chemical synthesis either as self-supported catalysts or as catalyst carriers in a ship-in-a-hotth concept by encapsulation or grafting of active species. However, we need to look critically at the possibility to generalize these key examples in order to design ideal and universal hybrid catalysts. The development of future applications of these functionalized solids requires taking into account the synthetic limitations of MOF materials and, motivated by early examples of homochiral MOF catalysts (Section 10.4), it seems necessary to focus efforts toward soft reaction conditions and sophisticated biomimetic applications. 

Strengths and Weaknesses of MOF Catalysts More David Than Goliath 

Like in the legend, zeolites can be compared to Goliath, a powerful giant, solid as a rock, when MOFs are closer to David, weaker but smarter than Goliath. Nevertheless, if David defeats Goliath in the book, issues still remain for MOFs to beat zeolites as catalysts. 

However, if their weakness comes mainly from their hybrid nature, this provides them with the ability to be finely tunable and to easily grow in sophistication. Soft and sophisticated are two appropriate adjectives to define both the MOF catalysts and the applications where they will be most successful. From numerous examples in the following about fine chemical synthesis involving soft reaction conditions, the most striking appHcation is in enantioselective catalysis (Section 10.4) where the products with the highest sophistication and value added can be generated. 

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The lipase-catalyzed asymmetric transesterification was performed using isopropenyl acetate in organic media affording the ( -alcohol in high enantiomeric excess (>99% ee). 

Kato, Y., Fujiwara, I., and Asano, Y. 2000. Synthesis of optically active a-monobenzoyl glycerol by asymmetric transesterification of glycerol. /. Mol. Catal. B Enzym., 9, 193-200. 

Acyloxygen fission (63 64), e.g., propiolactone reacts with MeOH, H+ to give 64 (Nu = OMe). A Pseudomonas sp. lipase-promoted asymmetric transesterification reaction allows kinetic resolution of racemic 2-oxetanones <2000J(PI)71>. 

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

The asymmetric transesterification of cyclic me o-diols, usually with vinyl acetate as an irreversible acyl transfer agent, includes monocyclic cycloalkene diol derivatives, bicyclic diols, such as the ej o-acetonide in eq 12, bicyclic diols of the norbomyl type, andorganometallic l,2-bis(hydroxymethyl)ferrocenepossessing planar chirality. 

Xiong J, Wu J, Xu G, Yang L. 2008. Kinetic study of hpase catalyzed asymmetric transesterification of mandelonitrile in solvent-free system. Chem Eng J 138 258-263. 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Ir-catalyzed allylic substitutions employing allylic alcohols as substrates and diethyl malonate as pronucleophile were first reported by Takeuchi and coworkers [11]. Here, the substitution step was found to be preceded by OH activation via transesterification to a malonic ester derivative. The asymmetric alkylation of cinnamic alcohol was similarly accomplished by Helmchen and colleagues, using a PHOX ligand and the procedure described in Section 9.2.3 [19]. 

The first 10-step total asymmetric synthesis of herbarumin III (42) in 24% overall was reported in 2004 by Gurjar and coworkers who later synthesized the compound using the RCM approach. Thereafter, a chemoenzymatic asymmetric synthesis of 42 which fixed the hydroxyl stereocenters (C7 and C9) by lipase catalyzed irreversible transesterification was described. 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

In 2002, the asymmetric synthesis of 3-substituted 3-hydroxy-p-lactams has been reported to be realized by metal-mediated l,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne and optically pure azetidine-2,3-diones [64]. This latter starting material was prepared via Staudinger reaction followed by sequential transesterification and Swem oxidation (Scheme 15), [65]. 

Recently, Maeda and coworkers utilized the (S, S) -le-catalyzed asymmetric alkylation of phenylglycine-derived Schiffbase 42 (R1 = Ph) for the stereoselective synthesis of a 4-hydroxy-2-phenylproline framework [27]. After hydrolysis and transesterification, the resulting (S)-49 was derivatized to its N-tosylate 50. Subsequent treatment of 50 with Br2 in CH2C12 resulted in the formation of y-lactone 51 with high diastereos-electivity this was then treated with NaH in methanol to give essentially pure (2 S,4R)-4-hydroxy-2-phenylproline derivative 52 in 80% yield from 50 (Scheme 5.25). 

In order to reduce the time needed to perform a complete kinetic resolution Lindner et al53 reported the use of the allylic alcohol 30 in enantiomerically enriched form rather than a racemic mixture in kinetic resolution. Thus, the kinetic resolution of 30 was performed starting from the enantiomerically enriched alcohol (R) or (S)-30 (45%) ee obtained by the ruthenium-catalyzed asymmetric reduction of 32 with the aim to reach 100 % ee in a consecutive approach. Several lipases were screened in resolving the enantiomerically enriched 30 either in the enantioselective transesterification of (<5)-30 (45% ee) using isopropenyl acetate as an acyl donor in toluene in non-aqueous medium or in the enantioselective hydrolysis of the corresponding acetate (R)-31, (45% ee) using a phosphate buffer (pH = 6) in aqueous medium. An E value of 300 was observed and the reaction was terminated after 3 h yielding (<5)-30 > 99% ee and the ester (R)-31 was recovered with 86% ee determined by capillary GC after 50 % conversion. 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

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