Lactones acids

Review Problem 12 Suggest a synthesis of the lactone acid TM 167. 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

When monocrotaline is hydrogenolysed the acid scission product is monocrotalic acid, CgHigOj, m.p. 181-2°, [a]p ° — 5-33° (HgO), which provides a methyl ester, m.p. 79-80°, [ ]d°° — 16-2° (EtOH), containing one active H atom and a p-bromophenacyl ester, m.p. 162-3°. It is a lactonic acid, which on boiling with sodium hydroxide solution loses carbon dioxide and produces a/3-dimethyllaevulic acid (monocrotic acid, II). 

CHsjOH. CHlCgHg). CH(COOH). CH. COOH COOH. CHlCgHg). CH(CHaOH). CH. COOH COOH. CH(C2Hg). CH(COOH). CH. CH OH AomoPilopic acid is very stable, and is probably therefore the y-lactonic acid of one of these three hydroxy-acids. Further, pilopic acid seems to be produced from its higher homologue by loss of carbon dioxide and oxidation of the contiguous carbon atom. Of the four y-lactonic acids derivable from these three hydroxy-acids only two (I and II) answer these conditions,... 

Lithium aluminum hydride (LiAlH4) is the most powerful of the hydride reagents. It reduces acid chlorides, esters, lactones, acids, anhydrides, aldehydes, ketones and epoxides to alcohols amides, nitriles, imines and oximes to amines primary and secondary alkyl halides and toluenesulfonates to... 

Lacton-bindung, /, lactonic linkage, -saure, /. lactonic acid, lactone acid (a compoimd which is both an acid and a lactone) lactonic acid, D-galactonic acid. 

C2 aH1gO]1 Lactone, acid Asthma drug (57) W486... 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Sodium borohydride is a much milder reducing agent than lithium aluminium hydride and like the latter is used for the reduction of carbonyl compounds like aldehydes and ketones. However, under normal conditions it does not readily reduce epoxides, esters, lactones, acids, nitriles or nitro groups. 

As a model study for this methodology, Evans and Bartroli carried out the synthesis of (+)-Prelog-Djerassi Lactonic acid 47 [14b] [27], which is a degradation product of either methymycin or narbomycin [28] and has some of the important structural features present in macrolide antibiotics. 

Note that aldol condensations I, II and III concern the creation of a relative configuration 2,3-syn, which can be easily achieved starting from the (Z)-enolates 74a-74c. Scheme 9.27 summarises the synthesis of 93 and 95, which are equivalent to fragments B and A, respectively. Compound 88 is the abovementioned Prelog-Djerassi lactonic acid 42 which is obtained in optically pure from (>98% ee). On the other hand, for the stereochemical control of the aldol condensation IV a different methodology is necessary whih involves the coupling of two structurally predefined reactants and which will not be discussed here (Scheme 9.28). An important feature of this reaction is that the coordination of Li" " with the oxygen atom at the P-position of the aldehyde 95 is mainly responsible for the observed stereoselection [22e]. 

The reaction is generally applicable to a variety of substrate types, as illustrated in Table I.10 Compatible functionality includes hydroxyl, ester, lactone, acid, ketone, and electron-poor olefins such as those conjugated to a-ketones. Some selectivity between isolated double bonds is also found. The reaction generally gives nearly quantitative yields with simple olefins... 

Like enamines, dihalocarbenes add smoothly to enol ethers and in many cases it is possible to isolate the dihalocyclopropyl intermediates which are valuable synthons for chloroenones (cf. Section 4.7.3.7.1). The earliest example of the addition of a dihalocarbene to an enol ether was provided by Parham,6,79 who studied the addition of dichlorocaibene to dihydropyran (equation 22). An example which illustrates the synthetic potential of the process is the conversion of the cyclohexanone enol ether (6) to the dichlorocy-clopropane (7 equation 23).80 The latter served as a useful intermediate in a stereospecific synthesis of Prelog-Djerassi lactonic acid. 

Cyclic hydroboration (10, 397). Two laboratories1,2 have reported stereoselective syntheses of the Prelog-Djerassi lactonic acid (4), both of which involve cyclic hydroboration of a slightly different 1,5-diene. One of these syntheses is outlined in... 

Scheme 19 Telomerization of butadiene with carbon dioxide can give lactones, acids and esters...

Intramolecular condensation of co-hydroxycarboxylic acids is a standard method to prepare lactones. Acid catalysts or more elaborate mediators are usually required as well as continuous removal of water. Transition-metal-catalyzed cyclocarbonylation of unsaturated alcohols is a fascinating alternative, which proceeds under neutral conditions [26]. Intramolecular hydroesterification of... 

The group-selective aldolization/desymmetrization of w -dialdehyde with a boron enolate of TV-propionylsultam yielded lactols with simultaneous generation of four stereogenic centers. Oxidation followed by saponification of the sultam moiety provided the Prelog-Djerassi lactonic acid in 61-71% overall yields (Equation (183)).689... 

A 250-mL, round-bottomed flask is equipped with a magnetic stirring bar and charged with 100 g of the foregoing crude lactone acid (Note 9). The flask 1s fitted with a Clalsen distillation apparatus and connected to a vacuum pump (Notes 10 and 11). The flask is gradually heated with an oil bath (160°C) until gas evolution ceases (Note 12). At this point the oil bath 1s removed and the black, viscous oil is distilled with the use of a flame (Note 13). The product, 58 g (7016), is collected as a colorless oil at 146-154°C (0.03 mm). The distillate crystallizes in the receiver, mp 66-68°C (Notes 14 and 15). 

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