Chiral butyrolactones

Biooxidation of cyclobutanones is a particularly useful transformation, as the corresponding chiral butyrolactones represent highly valuable building blocks for a large variety of natural products as well as bioactive compounds [165]. 

Chiral butyrolactones of type 27 and 28 have substantial value in asymmetric synthesis because they contain readily differentiable difunctional group relationships e.g. 1,5-di-carboxylic acid, 1,4-hydroxy carboxylic acid, 1,6-hydroxy-carboxylic acid, 1,6-diol etc.) that would be difficult to assemble by existing asymmetric condensation and pericyclic processes. Applications of these chiral derivatives of glutaric acid to syntheses of indole, indoline and quinolinone alkaloids are illustrated in Schemes 16-18. 

Other methods of preparation and diastereoselective alkylation of chiral butyrolactones (44) are summarized in the recent review of asymmetric synthesis of lignans (16). 

This is the smallest group of lignan tetrahydrofurans with fewer than ten members. All of reasonably well defined constitution are 3,4-trarw-disubstituted. Of these, most attention has been directed towards burseran, a constituent of Bursera microphylla with tumour-inhibiting properties (82). Optically pure (-)-/ra/w-burseran (82) and (-f-)-cw-burseran (83) were stereoselectively synthesized from chiral butyrolactones and gas chromatographic comparison indicated that the natural... 

Chiral butyrolactone derivatives (32) and (33) react with aldehydes to give the condensation products (34)-(36) as single stereoisomers in high yield (equation 13) both simple stereoselection (TMS and OH syn, see Section 2.4.2.1) and diastereofacial selection are 100%. Another example where a substituent on a cyclic silyl enol ether causes 100% diastereofacial selection is shown in equation (14). ... 

Treatment of allyl sulfide 111 with dichloroketene, generated in situ by reductive elimination of chlorine from trichloroacetyl chloride, results in an intramolecular ketene Claisen rearrangement giving 779 with high, 2-syn selectivity (94% de). Reductive dechlorination and subsequent lactonization affords chiral butyrolactone 780, with an optical purity that exceeds 95%. 

Several noteworthy routes to chiral butyrolactones have been reported this year. Chiral (i )-a-substituted butyrolactones (58) can be obtained from the oxazoline (56) with enrichments of 60—86% by condensation with ethylene oxide followed by O-silylation and alkylation (LDA-RX) to give (57), and finally hydrolysis. By reversing the condensation and alkylation steps, (5)-butyrolactones (58) can be obtained. Valerolactones can be similarly prepared but with slightly lower enrichments. 

The potential for use of chiral natural materials such as cellulose for separation of enantiomers has long been recognized, but development of efficient materials occurred relatively recently. Several acylated derivatives of cellulose are effective chiral stationary phases. Benzoate esters and aryl carbamates are particularly useful. These materials are commercially available on a silica support and imder the trademark Chiralcel. Figure 2.4 shows the resolution of y-phenyl-y-butyrolactone with the use of acetylated cellulose as the adsorbent material. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

Lithiated chiral oxazolines have been shown to react with various electrophiles, generating a new asymmetric center with considerable bias. This process has led to the synthesis of optically active a-alkylalkanoic acids,47 n-hydroxy(methoxy)alkanoic acids,48 / -hydroxy(methoxy)alkanoic acids,49 n-substituted y-butyrolactones,50 and 2-substituted-l,4-butanediols (Fig. 2-4).50... 

Bicyclo-y-butyrolactones.1 The reaction of ketenes with chiral vinyl sulfoxides to obtain optically pure -y-arylsulfanylbutyrolactones (12,177) can be extended to a synthesis of bicyclic butyrolactones. Thus the arylsulfanyl group of 1 undergoes... 

An obvious way to target chiral compounds is to start with a compound in which the chiral center is already present. Here natural products and derivatives offer a rich pool of generally inexpensive starting materials. Examples include L-hydroxy and amino adds. Sometimes, just one out of many chiral centers is predestined to remain, as in the synthesis of vitamin C from D-glucose, or in the preparation of (S)-3-hydroxy-y-butyrolactone from ladose. 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

The cyclopropane aldehyde 156 was identified as a versatile chiral building block for the enantioselective synthesis of 4,5 disubstituted y-butyrolactones of type 158 or 159. Both enantiomers of 156 can be easily obtained in a highly diastereo- and enantioselective manner from fixran-2-carboxylic ester 154 using an asymmetric copper-catalyzed cyclopropanation as the key step followed by an ozonolysis of the remaining double bond (Scheme 25) [63]. Addition of... 

In the past few years, new approaches for the enantioselective synthesis of / -benzyl-y-butyrolactones appeared in the literature. Some of these approaches involve the asymmetric hydrogenation of 2-benzyl-2-butenediols (j [34]), the radical mediated rearrangement of chiral cyclopropanes (r [35]), the transition metal catalyzed asymmetric Bayer-Villiger oxidation of cyclobutanones n [36]), or the enzymatic resolution of racemic succinates (g [37]). 

Two classes of a-hydroxylated lignans have been enantioselectively prepared a) wikstromol (3) [10, 38] and related natural products [39] and b) gomisin A (1) and congeners [40, 41]. In both cases, chiral, non-racemic ita-conic acid derivatives have been synthesized as key compounds for the preparation of -benzyl-y-butyrolactones (either by resolution (g [32]) or by asymmetric hydrogenation (h [25])). 

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