8-Lactone chiral

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). 

Chiral Lactones and Polyesters. Similar to intermolecular reactions described previously. Upases also catalyze intramolecular acylations of hydroxy acids the reactionsults in the formation of lactones. 

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Efficient methods for the production of tetrahydro-5-oxo-3-furanalkanoates use chiral lactones based on 2(5//)-furanones as Michael acceptors110-114 (see Section 1.5.2.4.1.2.5.). For... 

The enzyme-mediated Baeyer-Villiger oxidation to chiral lactone intermediates has received considerable attention in recent years as it offers several advantages in chemo-, regio-, and stereoselectivity compared to other catalytic strategies... 

Both chiral lactones and ketones have been utilized in asymmetric synthesis of bioactive compounds like lipoic acid [175[ and natural products like various insect pheromones [176[. 

Chiral lactones were also obtained by cyclocarbonylation of chiral acetylenic alcohols with Pd and thiourea (H2NCSNH2) (Scheme 32). No loss in chirality was observed, but large amounts of Pd and thiourea were used (10 mol %) since the catalyst deactivates by forming metal particles. The catalytic precursor (Pdl2 > PdCl2) and the ratio of thiourea to Pd were very important, thiourea being necessary for this reaction. The active species was supposed to be [Pd(thiourea)3l]I, which forms in situ from [Pd(thiourea)4]l2 and [Pd(thiourea)2]l2. It had to be a partially dissociated species since [Pd(thiourea)4](Bp4)2 was inactive [121]. 

Chiral lactones were also formed by cyclocarbonylation [ 122] with chiral catalysts, such as Pd-poly-L-leucine catalytic system. For example, but-2-en-l-ol led to the corresponding cychc chiral lactone in the presence of Pd catalysts with chiral ligands (Scheme 33). About 10 mol% of Pd(II) chloride... 

The enantioselective hydrogenation of a,fj- or / ,y-unsaturated acid derivatives and ester substrates including itaconic acids, acrylic acid derivatives, buteno-lides, and dehydrojasmonates, is a practical and efficient methodology for accessing, amongst others, chiral acids, chiral a-hydroxy acids, chiral lactones and chiral amides. These are of particular importance across the pharmaceutical and the flavors and fragrances industries. 

Synthesis of Optically Pure Chiral Lactones by Cyclopentadecanone Monooxygenase-catalyzed Baeyer-Villiger Oxidations... 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

Addition of 2,6-dimethoxypyrimidine-4-cerium chloride 371 to the chiral lactone 370 occurred without racemization of the chiral center, and the product 372 was subsequently used in a successful total synthesis of (—)-7-epicylindro-spermopsin <2002JA4950, 2005JOC1963>. The cerium reagent was prepared situ from 4-bromo-2,6-dimeth-oxypyrimidine by sequential addition of butyllithium and cerium trichloride. Addition of the same dimethoxypyrimidine-4-cerium derivative to a chiral lactam has also been reported <1999J(P1)1193>. 

Enantioselective reduction of prostereogenic anhydrides la-g with 4 equivalents of chiral reducing reagent, obtained from lithium aluminum hydride, enantiomerically pure (M)-, 1 -bi-2-naph-thol and ethanol, provides easier access to chiral lactones as exemplified by 3a-g.10 la. Absolute configurations of lactones 3 are based on chemical correlation and the ee value for 3b is determined by HPLC on the chiral column Chiralcel OB-H (Daicel Chemical Industries, Ltd.)101b. 

Horse liver alcohol dehydrogenase (HLADH (E.C. 1.1.1.1), commercially available) is a well-documented enzyme capable of catalyzing the enantioselective oxidation of acyclic and cyclic meso-configurated dimethanol derivatives to chiral lactols and further to the corresponding chiral lactones with high enantioselectivity and in high yield (Table 11) 162 ,69. Incases where the two enantiomeric lactols are formed, a kinetic enantiomer separation can occur in the second oxidation step166. 

Asymmetric hydroalkoxycarbonylation of a-methylstyrene is also examined, leading to 3-phenyl-butanoic acid, the //< r///< /-product. The highest ee is at best 60% for this substrate.When an allylic alcohol is treated with a chiral Pd complex under GO, cyclohydrocarbonylation takes place to give the corresponding 7-butyrolactone in an asymmetric manner (Equation (6)). Similarly, chiral -lactones and other lactams can also be synthesized. 

The chiral lactone alcohol derivative (178)181) can be readily prepared from natural (S)-glutamic acid, the cheapest chiral a-amino acid. Lactone (178) was alkylated to yield optically active 3-substituted lactone alcohol derivatives, (179) and (180), which were intermediates in the stereoselective synthesis of various natural products 182). 

The chiral lactone (178) has been used for the synthesis of a variety of natural products, such as sugars, lignans, terpenes, alkaloids, and P-lactams as a chiral building block 182c,184). The use of (178) as a powerful inductor of asymmetry was mainly established by Takano et al. 181, 84> one can expect more highly interesting reports from this group. 

Compared with aldehydes, ketones and esters are less reactive electrophiles in the addition of dialkylzincs. This makes it possible to perform a unique reaction that cannot be done with alkyllithium or Grignard reagents, which are too reactive nucleophiles. For example, Watanabe and Soai reported enantio- and chemoselective addition of dialkylzincs to ketoaldehydes and formylesters using chiral catalysts, affording enantiomerically enriched hydroxyketones 30 (equation 12)43 and hydroxyesters 31 in 91-96% , respectively (equation 13). The latter are readily transformed into chiral lactones 3244. 

It is also possible to prepare chiral lactones through these metallated oxazolines. Lactone chirality is, of course, dependent on the order of introduction of the electrophilic groups, as displayed in Scheme 92. 

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