Chiral lactone product

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... 

Atroposelective cleavage of configurationally unstable lactone cycle in biaryl derivatives as effective route to chiral natural products and useful reagents 99S525. 

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... 

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[. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

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>. 

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. 

The reactions described here do not cause any racemization of the readily epimerizable aldehyde starting material. No 5/ -isomers were detected by chiral HPLC of the final lactone product. In addition, these conditions are suitable for large-scale reactions. DeCamp et al.[19] mentioned that they converted 600 g of a-amino aldehyde derivatives into the desired lactone. 

Asymmetric reduction of prochiral carbonyl compounds for the production of chiral alcohols D-pantoyl lactone production by... 

ASYMMETRIC REDUCTION OF PROCHIRAL CARBONYL COMPOUNDS FOR THE PRODUCTION OF CHIRAL ALCOHOLS D-PANTOYL LACTONE PRODUCTION BY ASYMMETRIC REDUCTION... 

Bringmann, G. Menche, D. Stereoselective Total Synthesis of Axially Chiral Natural Products via Biaryl Lactones, Acc. Chem. Res. 2001,34,615-624. 

Chelation with copper(ll) Lewis acids has been used to change the reactivity of bis ketenes toward alcohols. The alcoholysis of 52 in the presence of copper acetylaceto-nate derivatives afforded the cyclic lactones 54 (Sch. 14) [35]. The addition of alcohols to 52 without the Lewis acid led to the formation of ketene esters 53 which would not undergo cyclization upon treatment with the copper(ll) complexes. It is suggested that chelation of the bis-ketene in a jr-fashion accounts for the lactone products. Although chiral Lewis acids were used, the products were obtained as racemates probably because of very facile epimerization. 

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%. 

Chiral lactones were synthesized by stereoselective reduction reactions with a carbohydrate auxiliary [178]. The benzyl protected 3,6-anhydro-a-D-glucopyranoside 279 was acylated with acid halide 280, and the product 281 was reduced with Zn(BH4)2 (Scheme 10.91). The alcohol 282 was obtained with a high diastereomeric excess (96 4). Cleavage from the auxiliary by... 

Bringmann G, Menche D (2001) Stereoselective total synthesis of axially chiral natural products via biaryl lactones. Acc Chem Res 34 615-624... 

One interesting aspect of asymmetric catalysis is that sequential reactions with a chiral catalyst can often lead to an enhancement in the enantioselectivity over a single transformation with the same catalyst in a process called kinetic amplification. Doyle was able to exploit this phenomenon in the synthesis of novel tricyclic products from the bis-diazoacetate of irans-1,4-cyclohexanediol (56, Scheme 12) [71]. Although formation of C2-symmetric product 58 was expected, resulting from the typically preferred five-membered insertion event, it was found that 57 could be produced preferentially with appropriate choice of catalyst, and with very high ee (95-99%). Bis- )-lactone 59 was never the major product, but could be formed as up to 34% of the product mixture. Notably, similar catalyst-controlled mixtures of [1- and y-lactone products were also obtained with diazoacetates derived from cholesterol derivatives [72],... 

When a quaternary carbon atom is produced in the acylation process, racemization is not possible and the stereochemical outcome can be affected by the presence of an adjacent stereocenter. Treatment of the chiral lactone (168) with LDA and acetyl cyanide gave the diastereomeric products (169) and (170) in the ratio 60 1 (equation 44). ... 

Stereoselective total synthesis of axially chiral natural products via biaryl lactones 01ACR615. 

Better success has been achieved in asymmetric induction by utilizing chiral auxiliaries on the acceptors [57]. Among the diverse auxiliaries tested, A-methylephe-drine proved to provide the highest ee s of the desired lactone products (Eq. 49). 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

Cyclic ketene silyl acetal 536 has been used in a synthesis of the chiral -lactone 541 (Scheme 76). The chelation-controlled aldol reaction of 536 with 464 gives 5y -adduct 537 as the sole product [173]. 

Another route to chiral lactones 130-a and 130-b was employed by Schultz and Pettus in the synthesis of (—)-ebumamonine and (—)-aspidospermidine [340], In the case of (—)-ebumamonine the cyclization was carried out on the aldehyde 130-A, and yielded the product with 18 1 selectivity for the desired a-stereoisomer. For (—)-aspidospermidine, the cyclization of 130-C was done in refluxing acetic acid, yielding a 1 1 mixture of stereoisomers. The product was taken on to ( )-aspido-spermine by an acid-catalyzed rearrangement (40% H2SO4, 100-110°C). The reason for the considerable difference in stereoselectivity of the two Pictet-Spengler cyclizations is not clear. 

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