Chiral lactones synthesis

Methods for lactone synthesis by transition metal catalysis involving C—O formation developed over the past 50 years have demonstrated much promise. Indeed, lactones have inspired the discovery of new organometallic transformations, design of metal catalysts, and detailed understanding of reaction mechanisms. Issues of waste minimization and stereoselectivity have been addressed. Future developments for chiral lactone synthesis will likely focus on establishing efficient transformations with broad scope and application in complex molecule total synthesis, especially in regards to macrolactonization where entropic costs often plague intramolecular reactivity with undesired intermolecular reactions. 

Hogan, M.C. Woodley, J.M. (2000). Modelling of two enzyme reactions in a linked cofactor recycle system for chiral lactones synthesis. Chemical Engineering Science, Vol. 55, No.ll, (June 2000), pp 2001-2008... 

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[. 

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

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>. 

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. 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

Chiral lactones. The aldol type condensation of this reagent with an aldehyde has been used to synthesize two chiral five- and six-membered lactones in > 80% ee. The synthesis of the six-membered lactone (R)-( + )-d-n-hexadecanolactone (5), a pheromone of the Oriental hornet, from the /-butyl ester (1) of the sulfoxide is formulated in equation (I).1... 

As a final example in this series of alkaloids, the enantio-selective synthesis of (+)-tacamonine is illustrated, which is also based on enzymatic generation of a chiral lactone related to the approaches described above. 

KP Lok, TJ Jakovac, JB Jones. Enzymes in organic synthesis. 34. Preparation of enantiomerically pure exo- and endo-bridged bicyclic [2.2.1] chiral lactones via stereospecific horse liver alcohol dehydrogenase catalyzed oxidations of meso di-ols. J Am Chem Soc 107 2521-2526, 1985. 

This novel annelation not only provides a route to chiral lactones, but was applied to a synthesis of a diol (8) from the acetal 7 as a precursor to (- )-lardolure (9). 

Andreana et al. [25] have recently invoked RCM to prepare /J,y-unsaturated <5-lactones (Scheme 3). Exposure of dienes of general type 13 to either 2 or 4 (which could be used at lower loadings) readily furnished lactones 14. For other examples of a,/ -unsaturated <5- and y-lactone synthesis by RCM see Ref. [26]. Variation of the configuration at the chiral carbons and the ligand for the asymmetric dihydroxylation reaction allows access to an array of biologically important dideoxy-sugar derivatives. 

Another efficient method is the electrochemical oxidation of NADH at 0.585 V vs Ag/AgCl by means of ABTS2- (2,2,-azinobis(3-ethylbenzothiazoline-6-sulfonate)) as an electron transfer mediator [96]. Due to the unusual stability of the radical cation ABTS, the pair ABTS2 /ABTS is a useful mediator for application in large-scale synthesis even under basic conditions. Basic conditions are favorable for dehydrogenase catalyzed reactions. This electrochemical system for the oxidation of NADH using ABTS2 as mediator was successfully coupled with HLADH to catalyze the oxidation of a meso-diol (ws >-3,4-dihydroxymethylcyclohex-l-ene) to a chiral lactone ((3aA, 7aS )-3a,4,7,7a-tetrahydro-3//-isobenzofurane- l-one) with a yield of 93.5% and ee >99.5% (Fig. 18). 

Few synthetically useful examples of the oxidation of ethers by oxygen or ozone have been publish-ed.7 96 Q0 In 1978, Ourisson and coworkers reported that ozonization of the natural product cedrane oxide (43) on silica gel at -78 °C led to the formation of the corresponding lactone (44) in 30% yield (equation 32).A small amount of the tertiary alcohol (45) was also produced. Later, in the course of a chiral total synthesis of compactin, Hirama examined the ozonolysis of the alkene (46 equation 33). ° Under carefully controlled conditions, selective ozonolysis of the double bond could be achieved in 88% yield. However, when excess ozone was employed, significant amounts of the benzoate (47) were obtained, even at -78 C. In subsequent studies, benzyl ethers of primary and secondary alcohols,and carbohydrates were oxidized to the corresponding benzoates in excellent yields. Surprisingly, no further synthetic rqrplications of this reaction have been reported. 

Another example of a highly regio- and enantiospccific microbial Baeyer-Villiger reaction is the transformation of racemic bicyclic ketone 17 by Acinetobacter TD 63433. This leads to chiral lactones 18 and 19 which are of particular interest as synthons for prostaglandin synthesis. Interestingly, each enantiomer of the racemic substrate reacts with a different regioselectivity for the oxygen atom insertion, and the enantioselectivity of the reaction is excellent. 

Fig. 5. Biosynthetic pathways for (I) 6-methylsalicylic acid and (II) the triacetic acid lactone. The structures of the intermediates have not been identified. The stereochemical course of the prochiral carbons (C-2 and C-4 in the triketide intermediate, C-3 and C-5 in 6-MSA) was investigated using R)- and (S)- [l- C,2- H]malonic acid extender substrate analogs in a coupled assay with 6-MSAS and succinyl-CoA transferase. The distinguishable hydrogens originating from the chiral malonyl CoA are labeled with H and H. Triacetic acid lactone synthesis is catalyzed by 6-MSAS in the absence NADPH...

An aldol reaction with chiral /3-benzyloxy aldehyde provides a method for the stereodivergent synthesis of both syn and anti diastereomers [97] with high diastereo-selectivity dictated primarily by the chirality of the BINOL-Ti catalyst (1) rather than the /1-benzyloxy aldehyde (Sch. 37) [98]. The aldol products can be used as useful key intermediates for /1-lactone synthesis [99]. 

A preparatively useful synthesis of (R)-lipoic acid involves Baeyer-Villiger monooxygenase-catalyzed biotransformation of 2-(2-acetoxyethyl)cyclohexanone 351 to the key precursor, that is, chiral lactone 352 (Scheme 68) < 1997BMCL253, 1995CC1563>. The enzyme-catalyzed lactone 352 was then converted by a standard reaction procedure into the desired acid on enantioselective esterification of racemic lipoic acid, using C. rugosa lipase. 

The chiral mono-Cp cr-cyclohexadienyl compound shown in Scheme 201 has been synthesized. The reaction with benzaldehydes proceeds with excellent diastereoselectivity. This reactivity has been used for the synthesis of nephrosteranic acid and chiral lactone compounds.23... 

Other syntheses of the tetracyclic intermediates 434 and 436 that merit mention, and thus constitute additional formal syntheses of (-1-)-quebrachamine, have been contributed by Fuji et aL and by Asaoka and Takei. Fuji s approach (279) starts with the chiral lactone 446, which is readily available from 2-ethyl-5-valerolactone. Partial reduction to the aldehyde stage, followed by acetal formation, gave 447, which on condensation and reduction (lithium aluminum hydride) gave a mixture of C-3 epimers 434, the late intermediate in the (+)-quebrachamine synthesis (Scheme 41). 

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