1.3.4- Trisubstituted-lactones

Trisubstituted lactones, e.g., 1, have also been discussed500 and diagnostic 1H and 13C chemical shifts and H. H coupling constants were collected501 to assign diastereomeric lactones of type 2. 

The optically pure (-)-(3/ ,4S )-cA-4-methyl-3-ethenylbutyrolactone 31 ([ ]u —53.0, CHC13) is available from D-glucose23. Its allylation with allyl bromide under the usual conditions (LDA, THF, —78 °C) gave the trisubstituted lactone 32 ([ ]D —27.8, CHC13) in a highly diastereoselec-tive reaction. 

There are some mechanistic implications in the results of the a-alkylation of the trisubstituted lactone 4027. This reaction was Carried out with LDA in tetrahydrofuran at — 78 °C in the presence of HMPA with reactive electrophiles such as iodomethane, allyl bromide and benzyl bromide. In all cases the observed diastereoselectivity was >95% and the yields between 75-92%. 

Moreover, selective iodolactonization to furnish 3,4,5-trisubstituted lactones, when a methyl substituent at C-2 and an oxygenated function at C-3 are present in the unsaturated amide substrate, has been studied. Thus,. > 7-3-hydroxy-iV,./V-2-trimethyl-4-pentenamide (, > -25, R = H), has been lactonized with a selectivity of 98 % to give the 3,4- ra s-4,5-rt.y-4-hydroxy-5-iodomethyl-3-methyl-y-lactone 26A (R = H), due to the 1,3-trans directing ability of the 3-methyl substituent and the 1,2-cis directing ability of the 4-hydroxy group. 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

Triethylammonium formate is another reducing agent for q, /3-unsaturated carbonyl compounds. Pd on carbon is better catalyst than Pd-phosphine complex, and citral (49) is reduced to citronellal (50) smoothly[55]. However, the trisubstituted butenolide 60 is reduced to the saturated lactone with potassium formate using Pd(OAc)2. Triethylammonium formate is not effective. Enones are also reduced with potassium formate[56]. Sodium hypophosphite (61) is used for the reduction of double bonds catalyzed by Pd on charcoal[57]. 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Only c/s-disubstituted and trisubstituted alkenes yield l,4-dioxan-2-ones by way of a cycloaddition reaction when oxidised by dimethyl a-peroxy lactone. An open 1,6-dipolar intermediate is postulated, involving steieoelectronic control <96JA4778>. 

Upon fonnation of intermediate LI, conjugate addition to a chalcone and subsequent proton transfer is proposed to lead to enolate LIII (Scheme 37). An intramolecular aldol addition provides activated carboxylate LIV in which alkoxide acylation regenerates the catalyst and delivers p-lactone LVI which, upon decarboxylation, gives rise to a trisubstituted cyclopentene. 

Strong nucleophiles applied under basic conditions attack epoxides 364a at C(2) with inversion of the configuration, leading to fraw5,rran5-2,3,4-trisubstituted y-lactols 375, which are easily oxidized to the corresponding y-lactones 376 (equation 100) . 

Barbaud C, Fay F, Abdillah F, Randriamahefa S, Guerin P (2004) Synthesis of new homopolyester and copolyesters by anionic ring-opening polymerization of a, a , P-trisubstituted P-lactones. Macromol Chem Phys 205 199-207... 

De Winter J, Coulembier O, Gerbaux P, Dubois P (2010) High molecular weight poly(a, a , P-trisubstituted P-lactones) as generated by metal-free phosphazene catalysts. Macromolecules 43 10291-10296... 

Monobactams have been investigated as p-lactamase inhibitors <98CHE1308, 98CHE1319>. The ketene-imine route to P-lactams was used to obtain 1,3,4-trisubstituted derivatives with high trans selectivity. The enolate from 4-hydroxy-y-lactone reacted with the imine (Ar CH NAr ) to give 59, vdiich cyclized in the presence of lithium chloride at low temperature to yield 60. The compounds were assayed for cholesterol absorption inhibition and 61 (R = = OH, R = F) was found to be a potent inhibitor of 3-hydroxy-3-... 

The utility of the creation of a y-lactone enolate through 1,4-addition of a carbanion and its interception by an electrophile has also been demonstrated in other classes of natural products, e.g., in the enantioselective synthesis of 10-oxa-l 1-methyl PGE2 analogues22. This synthesis starts with 1,4-addition of the sulfone-stabilized anion from 27 to ( + )-(S )-4-methyl-2-buteno-lide which has been prepared in three steps from (—)-(S)-l,2-epoxypropane. The intermediate enolate 28 is reacted with the acetylenic iodide to give the trisubstituted diastereomeric mixture of lactones 29, which is eventually converted into the pure compound 30, both reactions occurring with high diastereoselectivity. 

Condensation of propiolic esters with alkenes.2 Methyl propiolate or tetrolate, when activated by complcxation with the C5H5Fe(CO)2 cation (Fp+), condense with alkenes to form cyclobutenes, 1,3-dienes, and lactones. The type of products formed depend on the structure of the alkene. 1,2-Disubstituted alkenes yield cyclobutenes and 1,3-dienes mainly, whereas 1,1-disubstiluted or trisubstituted alkenes form mainly lactones. 

The aldol (23) on treatment with benzenesulphonyl chloride yields the oxetanone ((3-lactone) (24) which is an intermediate in the synthesis of the butenolides (25) (95SC479). Aliphatic terminal alkynes or arylalkynes react with nitrones in the presence of a copper based catalyst system to give 1,3,4-trisubstituted [3-lactones (95JOC4999). 

A concise and efficient synthesis of racemic five steps from precursor diethyl oxalopropionate <02TL9513>. In the first step, racemic diethyl oxalopropionate was alkylated under basic conditions. The lactonization is the last step of the synthesis and was achieved according to the Mitsunobu protocol. 

Reaction of ketones and a,a-dimethoxyketones in the presence of TiCl4-Bu3N led to the formation of a,p-unsaturated lactones, which were converted to 2,3,4-trisubstituted furans. One of the examples is the preparation of menthofuran, the natural mint perfume <02CC2542>. 

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