Enantioselectivity lactone formation

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

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%. 

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

You and co-workers have demonstrated enantioselective y-lactone formations nsing glyoxalate 163, achieving up to 78% ee with the NHC derived from chiral triazohum salt 164, although with low levels of diastereoselectivity (Scheme 12.35) [70],... 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and -lactones, respectively (equations 137 and 138) The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of -alkenes in bicyclic y-lactone formation . Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enantioselectivity in intramolecular cyclopropanation (equation 139) ". On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140). ... 

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. 

Instead of malonic esters the lithium dianions of carboxylic acids may also be used, as shown by equation (77). Enantioselective 7-lactone formation has been achieved by Meyers as a ramification of his... 

Ketene [2 + 2] cycloaddition with disubstituted ketones or aldehydes with phosphine catalysis gives P-lactone formation with a preference for the traws-diastereomer (Scheme 4.32). The formation ofphosphonium eno-late intermediates was monitored using NMR, and based on the NMR observation of the intermediates a mechanism was proposed in which the phosphonium enolate 158 reacted with a second molecule of the ketene forming intermediate 159, which then was acylated by the aldehyde followed by loss of 158 and formation of the product p-lactone. The use of the chiral phosphine catalyst BINAPHANE gave enantioselective product formation. 

Ye applied his catalytic system to enantioselective p-lactam and p-lactone formations via Staudinger-like reactions with imines or ketones (Scheme 14.22). Furthermore, the reaction with benzoyldiazenes gave the corresponding oxadiazin-6-ones issue of a [4+2] cycloaddition reaction, instead of the reported [2+2] DMAP derivatives, as nucleophilic catalysts. The postulated formation of an azolium enolate upon reaction of the NHC with the ketene in these reactions was evidenced experimentally by the isolation and full characterization of such zwitterionic adducts in model reactions. ... 

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]. 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

Ester-tethered enyne systems cycloisomerized to give lactone products (Eq. 11) [24]. Eor example, enyne 6 reacted under the Alder-ene conditions of [Rh(COD)Cl]2/BlNAP/ AgSbEg to give the corresponding lactone (Eq. 11). Once again free hydroxyl groups on the allylic terminus were incorporated into the cyclization precursors and subjected to the Alder-ene conditions, which led to the exclusive formation of the tautomerized products in good yields and enantioselectivities (Eq. 12). 

Intramolecular ylide formation with the lactone carbonyl oxygen (53) in 145 provided a carbonyl ylide 146 that was trapped with Al-phenyl maleimide to give cycloadduct 147. Likewise (54), carbonyl yhde 149, derived from ester 148, suffers intramolecular cycloaddition with the tethered alkene to deliver acetal 150 in 87% yield. An enantioselective version of this process has also been described (Scheme 4.33). 

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

Garbe L-A, Tressl R (2004) Metabolism of deuterated t/jreo-dihydroxy fatty acids in Saccha-romyces cerevisiae Enantioselective formation and characterization of hydroxylactones and y-lactones. Helv Chim Acta 87 180... 

Reaction of cinnamyl alcohol (36) catalyzed by Rh-BINAPHOS gives the product as lactol 37 (1 1 mixture of diastereomers at the anomeric carbon) with high enantioselectivity (88% ee) [94] (Scheme 7.7). The enantiopurity of lactol 37 is determined by oxidizing the lactol to the corresponding lactone 38. In the same manner, homoallyl alcohol (39) is converted to the corresponding a-methyl-y-butyrolactone (42) with 73% ee via lactol 40 [94] (Scheme 7.7). However, the regioselectivity of the reaction is not favorable to the formation of 40, forming achiral 6-lactol 41 as the major product. 

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