Optically Active -Lactones

Lactam, ring formation, 288 Lactones, optically active, 31 Lanthanide complexes epoxy ring opening, 234 hetero-Diels-Alder reactions, 217 nitno-aldol reaction, 228 Laudanosine, 36 Leucine hydrocarboxylation, 168 Lewis acid complexes, 212 Ligands ... 

Asymmetric Polymerization. The chiral organoaluminum catalyst is utilized for asymmetric polymerization of racemic a-methyl and p-methyl p-lactones. Optically active polymers pos-... 

Asymmetric carbonylation of alkenyl halides a-methylene lactones Optically active a-mcthylene lactones can be prepared by carbonylalion of alkenyl halides such as I catalyzed by PdCI2-(R)-BINAP (5 mol %) in the presence of thallium acetate. 

Many examples of stereospecific allylation consistent with the above mechanism have been reported. As one example, the regioselective and highly diastereoselective allylation of the lactone 17 with the optically active allylic phosphate 16 proceeded with no appreciable racemization of the allylic part to give the lactones l8 and 19, and the reaction has been used for the synthesis of a polypropionate chain[26]. 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

Ketene can also be added to trihalosubstituted aldehydes or ketones (12) to form 4-trihalomethyloxetanones. If this addition is performed in the presence of optically active bases such as quinine [130-95-0] chiral lactones are obtained (41,42). 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Lipase-catalyzed intermolecular condensation of diacids with diols results in a mixture of macrocycUc lactones and liuear oligomers. Interestingly, the reaction temperature has a strong effect on the product distribution. The condensation of a,(D-diacids with a,(D-dialcohols catalyzed by Candida glindracea or Pseudomonas sp. Upases leads to macrocycUc lactones at temperatures between 55 and 75°C (91), but at lower temperatures (<45°C) the formation of oligomeric esters predorninates. Optically active trimers and pentamers can be produced at room temperature by PPL or Chromobacterium viscosum Upase-catalyzed condensation of bis (2,2,2-trichloroethyl) (+)-3-meth5ladipate and 1,6-hexanediol (92). 

Methods for the synthesis of optically active (3-lactones (2-oxetanones) 99T6403. 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

The addition of the dianion of /j-sulfmylcarboxylic acids to carbonyl compounds leads to the formation of the corresponding hydroxy derivatives which undergo spontaneous eyclization to give y-lactones. It was found that when optically active ( + )-(/ )-3-(4-methylphenylsulfinyl)pro-panoic acid is used for the reaction, the corresponding diastereomeric /i-sulfinyl-y-lactones are formed in a ratio which is dependent on the substituents of the carbonyl component. However, the diastereoselectivity was always moderate. 

The diastereomeric lactones could be separated by chromatography and converted into optically active lactones by desulfurization with sodium amalgam or by pyrolysis to the corresponding butenolides. 

In y-alkoxyfuranones the acetal functionality is ideally suited for the introduction of a chiral auxiliary simultaneously high 71-face selectivity may be obtained due to the relatively rigid structure that is present. With ( + )- or (—(-menthol as auxiliaries it is possible to obtain both (5S)- or (5/ )-y-menthyloxy-2(5//)-furanones in an enantiomerically pure form293. When the auxiliary acts as a bulky substituent, as in the case with the 1-menthyloxy group, the addition of enolates occurs trans to the y-alkoxy substituent. The chiral auxiliary is readily removed by hydrolysis and various optically active lactones, protected amino acids and hydroxy acids are accessible in this way294-29s-400. 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

Thus, the lithiated SAMP hydrazones of various methyl ketones on addition to 2-(aryl-methylene)- , 3-propanedionates and propanedinitriles provide, after the removal of the auxiliary, (R)-2-( l-aryl-3-oxobutyl)-1,3-propanedioates and -propanedinitriles with high enantiomeric excess (> 95%) in 50 82% yield (sec Table 6) 195,197. Using similar methods optically active (5-lactones (90% to > 96% ee) are obtained198. 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

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. 

We prefer to disconnect the right hand half of the molecule in this way because optically active lactones (59) can be made from glutamic acid (60), another available 1,4-difunctionalised compound (p T 96 ). 

The enantioselectivity was greatly improved by the copolymerization with 7- or 13-membered non-substituted lactone using lipase CA catalyst (Scheme 8) the ee value reached ca. 70% in the copolymerization of (3-BL with DDL. ft is to be noted that in the case of lipase CA catalyst, the (5 )-isomer was preferentially reacted to give the (5 )-enriched optically active copolymer. The lipase CA-catalyzed copolymerization of 8-caprolactone (6-membered) with DDL enan-tioselectively proceeded, yielding the (/ )-enriched optically active polyester with ee of 76%. 

Reaction of optically active a-sulphinyl acetate 298a with prochiral carbonyl compounds proceeds with a high asymmetric induction - , the degree of which depends on the nature of substituents at the carbonyl group (equation 252 Table 22) . The jS-hydroxy sulphoxides 422 formed may be transformed to optically active p-hydroxycarboxylic esters 423 (equation 253) and optically active long-chain lactones 424 99 (equation 254). Corey and coworkers have used this method to introduce a chiral centre at C-3 in their synthesis of maytansin °°, and Papageorgiou and Benezra for the synthesis of chiral a-hydroxyalkyl acrylates 425 ° (equation 255). 

Cycloaddition of the nitrone 161 to the lactone 160 in boiling benzene for 6 h gave a 53 37 10 mixture of the three optically active adducts 162-164 in 66% combined yield (Scheme 9.50). Formation of the diastereoisomers 162-164 can be rationalized in terms of a highly preferred anti approach of the nitrone to the hydroxymethyl group in the transition state. The isomer ratio in the adducts was found to be dependent upon the solvent used in the reaction. Optimization of the reaction or the dia-stereoselectivity by Lewis acid catalysis failed. However, attempts to accelerate the cycloadditions by microwave irradiation, using 1,4-dioxane as the solvent, were successful and the reaction time decreased from hours to less than 10 min with only a... 

Optically Active Lactones from Metal-Catalyzed Baeyer-Villiger-Type Oxidations Using Molecular Oxygen as the Oxidant... 

As shown in Eq. 9.48, optically active alkylidene lactones having an iodoalkyl substituent were prepared from the corresponding optically active epoxy alcohol by means of the Sharpless epoxidation. These represent precursors of optically active functionalized cyclopentanes and cyclohexanes, respectively, as shown in the equation [92]. 

When pyridinium salt 187 was transformed to an indolo[2,3-a]quinolizidine compound in a similar way and the unsaturated lactone 188 was hydrogenated over platina catalyst, a mixture of vallesiachotamine-type compounds (189 di-astereomers) epimeric at C-20 was formed (134). These compounds have also been prepared in optically active form from vallesiachotamine (9), thus producing the first chemical correlation between synthetic and natural vallesiachotamine derivatives (134). 

Asymmetric synthesis of amino acids.1 These lactones can serve as an optically active form of glycine for synthesis of either D- or L-amino acids. Thus (+ )-1 (or (—)-l) on radical bromination is converted into a single monobromide (2), which can be coupled with nucleophilic organometallic reagents, by either an SN1... 

Dioxanone derivatives.1 The optically active 1,3-dioxanone (acetal lactone) 1 is obtained by reaction of (R)-3-hydroxybutyric acid with pivalaldehyde in the presence of an add catalyst. These derivatives can be used to effect enantio-selective reactions at the 2-, 3-, and 4-positions of (R)-3-hydroxybutyric acid. Thus,... 

The change with the concentration cannot be due to the reversible formation and decomposition of a lactone of the ordinary type because we get the effect with ethyl malate as well as with malic add. The change cannot be due to a reversible conversion of laevo-malic acid into dextro-malic add, because then a solution of equivalent amounts of dextro- and laevo-malic acids would become optically active on addition of salts, adds and bases. Hydrochloric add or sodium hydroxide imparts no activity to a solution of d/-malic add. The changes on adding electrolytes to a solution of dextro-malic add are equal and opposite in sign to the changes in laevo-malic acid under the same conditions. 

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