Enantioselectivity enantioselective lactone

The first asymmetric synthesis of (—)-Y-jasmolactone, a fruit fiavor constituent, vas achieved via the enantioselective lactonization (desymmetrization) of a prochiral hydroxy diester promoted by porcine pancreas lipase (PPL) (Figure 6.23) [71]. 

Scheme 38 Enantioselective lactone formation via haloalcohol radical conjugate addition...

Enantioselective lactonization.5 Monoprotonation of the disodium salt (1) of 4-hydroxypimelic acid in ethanol results in cyclization to a y-lactone (2) in high yield. If 1 equiv. of (1S)-CSA is used optically active 2 is formed in yields as high... 

There are many aspects of these Rh-mediated cyclizations that are yet to be explored. What factors, for instance, govern the ratio of 25 to 26 (Scheme 1)1 Would an Rh catalyst that was more readily polarizable and so more sensitive to electronic effects give a higher proportion of 25 The enantioselective lactone cyclizations of Doyle [15] are particularly intriguing. Attempts toward enantioselective carbocyclization using a chiral rhodium catalyst have to date [16] not... 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

Chiral lactones can be formed from ketones via the Bacyer-Villiger reaction. Such lactones are potentially useful synthons for a number of natural products (37). Many of the examples of enantioselective lactone formation have been demonstrated using cyclohexanone oxygenase isolated from various Acinetobacter spedes (37,38). Figure 14 shows the enzymatic lactonization of methylcyclohexanone, which gave an 80% yield with an enantiomeric excess greater than 98%. 

Recently, Osa and coworkers [502] have reported highly enantioselective electroca-talytic oxidation of racemic monoalcohols using a TEMPO-modified graphite felt electrode in the presence of (—)-sparteine. Optically almost pure i -isomeric alcohols remained unreacted. Highly enantioselective lactonization of racemic diols was also achieved by using the same TEMPO-modified electrode to give (S)-isometric lactones [503]. 

In 2004, a similar methodology was applied by Harayama s group to the synthesis of another natural product, (-)-steganone, having antileukemic properties. Hence, the key step of the synthesis was the enantioselective lactone-opening reaction, performed with a combination of... 

Upon careful examination of reaction parameters, Tanaka and coworkers successfully developed a highly enantioselective lactone synthesis by reaction with both aldehydes and activated ketones as the coupling partners for the synthesis of spirocyclic benzopyranones. Cationic Rh catalysts were again found to be the most efficient. Importantly, homodimerization of the parent 2-aIkynylbenzaldehydes was not observed under the optimized conditions [92]. 

The use of isolated enzymes in organic solvents has already found its niche in organic synthetic laboratories, both in academia and industry (14, 75). Enzymes have emerged as very useful tools for the synthesis of optically active lactones by enantioselective lactonization of racemic yhydroxy esters, cohydroxy esters, and 5-hydroxy esters into enantioenriched y-butyrolactones, colactones, and 5-lactones, respectively (76,77,78). Isolated enzymes, such as lipases (20) and esterases (27) have also been exploited for preparing optically active four-, five- and six-membered lactones by enantioselective ring-opening... 

The enantioselective lactonization of 5-oxo-5-phenylpentanoic acids 64 was studied using chiral A, -iodanes 66 to yield 5-benzoyldihydrofuran-2(3/7)-ones 65, albeit with low ee values (Scheme 26) [83]. Scope of this asymmetric lactmiizatirHi process was further studied by employing other chiral aryl iodides such as 67 [84]. 

Scheme 1.8 Enantioselective -lactone formation catalyzed by the chiral oxazaborolidine.

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

Soon after the disclosure of the total synthesis of ( )-gingkolide B, (see ref. 8a) Corey reported a concise, enantioselective synthesis of tetracyclic lactone 23, see Corey, E. J. Gavai, A. V. Tetrahedron Lett. 1988, 29, 3201. Thus, in principle, gingkolide B could be synthesized in its naturally occurring enantiomeric form. 

An (E)-selective CM reaction with an acrylate (Scheme 61) was applied by Smith and O Doherty in the enantioselective synthesis of three natural products with cyclooxygenase inhibitory activity (cryptocarya triacetate (312), cryptocaryolone (313), and cryptocaryolone diacetate (314)) [142]. CM reaction of homoallylic alcohol 309 with ethyl acrylate mediated by catalyst C led (E)-selectively to d-hydroxy enoate 310 in near quantitative yield. Subsequent Evans acetal-forming reaction of 310, which required the trans double bond in 310 to prevent lactonization, led to key intermediate 311 that was converted to 312-314. 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

The initial results of an early directed evolution study are all the more significant, because no X-ray data or homology models were available then to serve as a possible guide [89]. In a model study using whole E. coU cells containing the CHMO from Adnetohacter sp. NCIM B9871,4-hydroxy-cydohexanone (3 5) was used as the substrate. The WT leads to the preferential formation of the primary product (i )-36, which spontaneously rearranges to the thermodynamically more stable lactone (R)-37. The enantiomeric excess of this desymmetrization is only 9%, and the sense of enantioselectivity (R) is opposite to the usually observed (S)-preference displayed by simple 4-alkyl-substituted cydohexanone derivatives (see Scheme 2.10) [84—87]. 

As the WT CHMO was known to react (S) selectively with simple four-substituted cyclohexanone derivatives [84—87], it was logical to test mutant 1-K2-F5 as a catalyst in the BV reaction of other ketones. For example, when 4-methoxycyclohexanone (38) was subjected to the BV reaction catalyzed by mutant 1-K2-F5, almost complete enantioselectivity was observed in favor of the (S)-lactone (39) (98.5% ee), in contrast to the WT, which is considerably less selective (78% ee) (see Scheme 2.11) [89]. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

Dimerization of methylketene is catalyzed by an amine, trimethylsilylquinine, to give the P-lactone enantioselectively (Scheme 27) [129]. The catalyst amine attacks the ketene to form an ammonium enolate, an electron donating alkene. The donor is strong enough to react with a ketene across the C=0 bond. That is why the P-lactone is obtained instead of the 1,3-cyclobutandione, the uncatalyzed dimerization product of the monosubstituted ketene. 

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