4-Alkyl-7-lactones, synthesis

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

The initial rrans-alkylated lactones can be easily epimerized in situ by enolization and protonation from the less hindered face using /-butyl bromide as the proton source (eq 9). Further handling of the so-formed cis isomers allows for the total synthesis of dihydromevinolin (17) and several analogs of import as cholesterol lowering agents. ... 

Starting Material for Asymmetric Syntheses. (3R,4R)-Dipivaloyltartaric anhydride, the direct precursor of (2R,3R)-DPTA, has been used as starting material for the synthesis of (3/ ,4/ )-dipivaloyltartrimide, its N-chloro and N-bromo derivatives (eq 9) , and epimeric (3R,4R)-dipivaloyl-5-alkyl lactones (eq 10), which are valuable intermediates for access to optically active polyhydroxy compounds. ... 

IsHiBASHi, H., H. Nakatani, T.S. So, T. Fujita, M. Ikeda Alkylative Lactonization of y,5-Unsaturated Esters with a-Chlorosulfides. A Concise Synthesis of the Mono-terpene Lactone from Chrysanthemum flosculosum. Heterocycles, 31, 215 (1990). 

Another C—H activation strategy for lactone synthesis involves the ring closure of benzoic acids with dihaloalkanes [111]. Yu and coworkers recently developed a directed C—H functionalization/alkylation approach using Pd catalysts. Direct access to phthalides and 3,4-dihydroisocoumarins was possible using dibromo-methane and 1,2-dichloroethane, respectively (Scheme 2.56). 

Alkylation to form substrates which undergo intramolecular Diels-Alder reaction is controlled by choice of metal (Pd, Mo, W) template . [MoCp(cyclohexadiene) (CO)2 J" " may be used to control functionalisation of the 6-membered ring in particular a novel stereocontrolled lactone synthesis O effects of m- or p-... 

In 2012, the Fukuyama group reported the total synthesis of the entire family of amathaspiramides, including amathaspiramide F and the C3-epimeric amathaspiramides A-E. This was the first report of the synthesis of any amathaspiramide other than amathaspiramide F. Fukuyama s retrosynthetic analysis was based on a common cyclic imide 23, which could be elaborated to the entire family of natural products (Scheme 8). The cychc imide 23 would be assembled through a key Curtius rearrangement of alkylated lactone 24. 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

The telomer 145 of nitroethane was used for the synthesis of recifeiolide (148)[121], The nitro group was converted into a hydroxy group via the ketone and the terminal double bond was converted into iodide to give 146. The ester 147 of phenythioacetic acid was prepared and its intramolecular alkylation afforded the 12-membered lactone, which was converted into recifeiolide (148),... 

The acid 19 has been dimerized, although in low yield, in the course of a perhydro-phenanthrene synthesis [141]. When the oxidation potential of the double bond is sufficiently lowered by alkyl substituents, lactone formation by oxidation of the couble bond rather than of the carboxyl group occurs (Eq. 7) [142] (see also chap. 15). 

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