Methanolysis enantioselectivity

A very efficient and practical process for desymmetrization of meso-anhydrides was reported by Bolm et al. in 1999 and in subsequent publications (Scheme 13.3) [9, 10]. In their approach, which is a further development and improvement in the use of alkaloids as catalysts, (—)-quinine (2) or (+)-quinidine (3) in this case, low reaction temperature and solvent optimization proved crucial to achieving optimum enantioselectivity. Under their conditions methanolysis of several meso anhydrides (8a-g, 9a-g, Scheme 13.3) can be achieved in good yields and with excellent enantiomeric excesses in the presence of equimolar amounts of the inexpensive and readily available alkaloids 2 and 3 [9, 10]. 

A catalytic asymmetric in situ reduction of N-H imines has been achieved in a sequence in which trifluoroacetophenones, ArCOCF3, are first converted to silylimines [using LiN(SiMe3)2], and then on to give trifluoromethylated amine salts, Ar-C(CF3)-NH2.HC1, in good to excellent yield and ee.5s The intermediate N-H imines can be isolated via methanolysis of the N-Si bond, while the enantioselective reduction can be carried out using a chiral borane auxiliary. 

In an alternate process, enantioselective enzymatic acylation of racemic a-methyl-l,3-benzodioxole-5-ethanol (55, Fig. 17) was developed using Amano lipase PS-30 (lipase from Pseudomonas cepacia) with vinyl acetate as acylating agent in n-hexane benzene (2 1). This process gave (+)-56 in 54% yield with 80% ee and (-)-57 in 46% yield with 96% ee After separation of alcohol (+)-56 from acetate (-)-57 by methanolysis in the presence of K2CC)3, the acetate was converted to alcohol (-)-56 in 95% yield with 96% ee Mitsunobu inversion of (-)-56 provided (+)-56 in 94% yield with 96% ee The conversion of (.S )-alcohol 56 to (-)-talampanel was carried out in 54% overall yield (Easwar and Argade, 2003). 

Figure 11.2 Effect of (a) concentration and (b) temperature on the enantioselectivity in the methanolysis of 15 catalyzed by 13.

Figure 3.9 summarizes our synthesis of the enantiomers of JH I in 1988.28 If we want to employ the same strategy as used for the synthesis of JH III, the synthesis of JH I demands the execution of the diastereo-and enantioselective reduction of a prochiral 1,3-diketone A. Unfortunately, reduction of A with fermenting baker s yeast was nondiastereoselective, giving both B and C. After extensive screening of yeasts, Pichia terricola KI 0117 donated by Kirin Brewery Co. was found to achieve highly stereoselective reduction to give >99% of B with 99% ee. Since both of the 3,5-dinitrobenzoates D and E were crystalline, these could be purified by recrystallization, and 100% pure E was secured. Conversion of E to F was achieved by methanolysis followed by acetonide formation. The enantiomeric purity of F was proved to be ca. 100% ee by HPLC analysis of bis-MTPA ester G derived from F. 

An additional strategy employed by Sih and co-workers involved sequential enzyme-catalyzed reactions. Pseudomonas lipases were found to tolerate a wide range of substrates although the enantioselectivity was generally only moderate. However, by first performing a methanolysis of the oxazolinone followed by a separate enzyme-catalyzed hydrolysis under kinetic resolution conditions, a highly enantio-merically enriched product could be obtained, as shown in Fig. 9-211491. 

The first enantioselective synthesis of retronecine (22) and its enantiomer (-)-22 has been reported by conversion of D-glucose, via diacetone glucose, to 3-azido-l,2-(9-isopropylidene-5,6-di-(9-mesyl-a-D-glucofuranose (77) " (Scheme 2). " Reductive cy-clization of 77 by hydrogenation followed by protection of the resulting secondary amine afforded the pyrrolidine derivative 78. Compound 78 was treated with lithium chloride to give 79, which underwent reduction followed by methanolysis of the isopropylidene... 

A lipoprotein lipase from Pseudomonas sp. effected not only regioselective acetylation of the orthoester 95 without observing the acylation of the axial hydroxyl groups but also enantioselective butyroylation (>95% ee) of symmetrical 4,6-dibenzoate 203 which was derived from the acetate 202 by benzoylation and acidic methanolysis (Scheme 4-10). 79 Regioselective chemical acylation of the equatorial hydroxyl group in 95 was also reported using benzoyl (64% yield) and p-nitrobenzoyl chlorides (51%).79... 

Kinetic resolutions. Baylis-Hillman adducts are deracemized by exploiting their reactivity toward Pd(0)-catalyzed substitution, using chiral ligand 2. Both the planar chiral DMAP derivative 3 and the axially chiral analogue (4) ° and 5" have been developed as catalysts for enantioselective acylation. Benzylic alcohols undergo enantioselective acylation with the aid of 6. Methanolysis of meio-anhydrides in the presence of a cinchona alkaloids is a good way to desymmetrize such compounds. ... 

The Diels-Alder reaction of 2-azadienes also benefits from the presence of an electron-donating substituent, to enhance the reactivity with electron-deficient dienophiles. Cycloaddition with alkynyl dienophiles and aromatization leads to substituted pyridines (3.54). Silyloxy-substituted 2-azadienes such as 68 are effective dienes and have been used to prepare substituted 2-pyridones and piperidones after methanolysis (3.55). Asymmetric hetero Diels-Alder reactions with the chiral Lewis acid catalyst 66 provide access to the piperidone products with very high enantioselectivity. ... 

Sunitha S, Kanjilal S, Reddy PS (2007) Ionic liquids as reaction medium for Upase-catalyzed methanolysis of sunflower oil. Biotechnol Lett 29 1881-1885 Sunna A, Hunter L, Hutton C et al. (2002) Biochemical characterization of a recombinant ther-moalkalophilic lipase and assessment of its substrate enantioselectivity. Enzyme Microb Technol 31 472 76... 

Fu has demonstrated that a dynamic kinetic resolution using the nonenzy-matic catalyst (12.95) can be achieved. The azlactone (12.114) is very prone to racemisation, whilst the ring-opened product (12.115) is stable under the reaction conditions. Thus the product is formed by methanolysis under dynamic resolution conditions (see Section 3.1), albeit with moderate enantioselectivity so far. 

The imididazolidinone 180 (10-20 mol%, Fig. 4.35) catalyzed the homo-aldol dimerization process of an aldehyde and also the cross-aldol reaction between eno-lizable aldehydes (5, source of nucleophile, 10 equiv.) and aromatic aldehydes (2, electrophile). For both cases, the yields were high (58-90%), the anti-diastereo-selectivity was moderated (60-86% de) and the enantioselectivity was excellent (91-97% ee). To prevent a hemiacetal reaction of the initial aldol product 29 with another equivalent of aldehyde, the reaction was quenched by a methanolysis process to form the corresponding dimethyl acetal [259]. 

Table 4.2 shows that very often the reaetions proeeed in high yields and very high enantioselectivities. Nonetheless, the reader must be warned that the ee values usually refer to recrystallised eompounds and therefore the optieal purity of the crude products could be lower. This detail, however, is rarely discussed in the literature, although an exeeption ean be foimd in entry 33. The methanolysis of aminophosphine boranes 8 with two aromatie groups (entries 12 6) does not seem to be particularly sensitive to sterie hindering sinee it is not prevented by 0,0-disubstituted groups (entries 21 and On the other... 

The synthesis was reported of the enantiomers of phenothiazinyl ethanol derivatives and their acetates via lipase B (CALB)-catalysed acylation of racemic alcohols and/or enantioselective methanolysis of the relevant racemic esters (Scheme 4.7) [11]. Both enantiomers were produced with high ee (>99%) and with high enan-tioselectivity (E = 200). 

The enantioselective Dieckmann-type annulation was carried out as follows. c/5-Cyclohex-4-ene-l,2-bisacetic (5)-IPTT diamide was added to a suspension of 35% KH in mineral oil and DMF under ice-cooling. Mter being stirred at the same temperature for 3 h, the resultant bicyclic (5)-IPTT amide product was subjected to methanolysis with K2CO3 in MeOH gave the methyl ester in 69% overall yield and in 96% ee (eq 5). ... 

This approach is exemplified by the protonation of a chiral MOF and its use in the enantioselective methanolysis of d5-2,3-epoxybutane [100] (Reaction 4) ... 

Early in the 1960s, Pracejus and co-workers reported on the first enantioselective protonation of ketene through an alcoholysis of disusbstituted ketene 58a in the presence of cinchona alkaloid derivative Q (Scheme 31.20). Remarkably, high levels of selectivity were obtained when the methanolysis of methylphenylketene was conducted at 110°C in the presence of 1 mol% of 0-acetyl quinine Q. The enantioselection of the reaction was found to be highly temperature dependent indeed, at —40°C, racemic ester 59a was obtained. The authors explained this... 

These modified cinchona alkaloids (68) have usually been used as ligands in the Sharpless asymmetric dihydroxylation [76, 77]. Deng developed a protocol based on a catalytic amount of the alkaloid derivatives (5-30 mol%) acting at room temperature in ether as solvent. Under these conditions, methanolysis of several monocyclic, bicyclic, and tricyclic succinic or glutaric anhydrides was achieved in good yields and excellent ee (Table 7.2). The catalysts can be recovered by a simple extractive procedure and reused without any loss in yield and enantioselectivities [73-75]. 

Scheme 7.16 Enantioselective methanolysis of meso-anhydride catalyzed by bicyclic tertiary amines 77...

In 2007, Me et al. reported asymmetric methanolysis of cyclic mera-anhydrides with tripodal 2,6-tran -l,2,6-trisubstituted piperidine 83 as chiral amine catalyst (Table 7.5) [86]. A good level of enantioselectivity (up to 81% ee) was achieved in the presence of a catalytic amount of 1-5 mol% catalyst. 

Highly enantioselective aldol reactions of acetylphosphonates (304), in which the acetylphosphonate was directly used as an enolate precursor for the first time, and activated carbonyl compounds (305) have been realised with cinchona alkaloid derived catalysts (307) or (308). Through an in situ methanolysis of the phosphonate group of the original aldol... 

Recently, Crich et al. [191] developed a general enzymatic as3mimetrical synthesis of a-amino acids. This method describes the use of the lipase PS-30 from Pseudomonas cepacia to catalyze the enantioselective methanolysis of a variety of 4-substituted 2-phen-yloxazolin-5-one derivatives 105 in a nonpolar organic solvent to yield optically active N-benzoyl-L-a-amino acid methyl esters 106 in 80-99% e.e. s (Fig. 36). The e.e. was further improved by the protease-catalyzed kinetic resolution to yield enantiomerically pure N-benzoyl-L-a-amino acids 107. 

Figure 36 Enantioselective enzymatic methanolysis of 4-substituted 2-phenyloxazolin-5-one.

Using the post-synthetic modification method, aspartic add (L2 Scheme 10.6) [49] and chiral proline (L5 in Scheme 10.6) [50] were incorporated into MOFs. These chiral MOFs exhibited low-to-moderate enantioselectivity in the asymmetric catalysis, such as the methanolysis of ds-2,3-epoxybutane and asymmetric aldol reactions. 

---