Six-membered lactone

COi is another molecule which reacts with conjugated dienes[10,95,96], COt undergoes cyclization with butadiene to give the five- and six-membered lactones 101. 102. and 103, accompanied by the carboxylic esters 104 and 105[97.98], Alkylphosphines such as tricyclohcxyl- and triisopropylphosphine are recommended as ligands. MeCN is a good solvent[99],... 

Aldonic acids exist m equilibrium with their five or six membered lactones They can be isolated as carboxylate salts of their open chain forms on treatment with base... 

Electrophilic cyclizations of unsaturated amides to form five- and six-member lactones 98T13681. 

JA742). However, the heterocyclization of 4-phenylethynylpyrazole-3- and 4-phenylethynylpyrazole-5-carboxylic acid in alcohol or acetonitrile solutions in the presence of AgNOs caused, once again, the closure of the six-membered lactones. 

Since the -elimination mechanism requires formation of a six-membered cyclic transition state, this reaction is not possible for five- or six-membered lactones, but may be applied to higher homologs. 

Less important methods are the self condensation of w-hydroxy acid and the ring opening of lactones and cyclic esters. In self condensation of w-hydroxy acids, cyclization might compete seriously with linear polymerization, especially when the hydroxyl group is in a position to give five or six membered lactones. 

The mechanism is Ei (see p. 1322). Lactones can be pyrolyzed to give unsaturated acids, provided that the six-membered transition state required for Ei reactions is available (it is not available for five- and six-membered lactones, but it is for larger rings ). Amides give a similar reaction but require higher temperatures. 

Another family of enzymes that exhibit the same properties are mammalian paraoxonases, whose original activity is hydrolysis of five- and six-membered lactones [104]. 

This next example involves the well-known plant kawa. A psychoactive beverage made from the roots of this plant is used widely in the islands of the southwestern Pacific Ocean either for ritualistic or routine consumption. Kava is the common name for Piper methysticum Forst. f. from which several compounds responsible for the pharmacological activity have been isolated and identified. Representative structures of the family of styrylpyrones, commonly called kavalactones, are given in Fig. 6.6. The compounds are based upon a carbon skeleton consisting of a styryl function (C C ) attached to a six-membered lactone ring. The fundamental compound, kawain, is shown as structure [547]. Structural variants include... 

Five-membered unsubstituted lactone, y-butyrolactone (y-BL), is not polymerized by conventional chemical catalysts. However, oligomer formation from y-BL was observed by using PPL or Pseudomonas sp. lipase as catalyst. Enzymatic polymerization of six-membered lactones, 8-VL and l,4-dioxan-2-one, was reported. 8-VL was polymerized by various lipases of different origins. The molecular weight of the enzymatically obtained polymer was relatively low (less than 2000). 

In analogy with the oxybromination reaction of allenyl alcohols, allenyl acids 12 afforded five- and six-membered lactones 13 on treatment with lithium bromide in the presence of palladium acetate (Scheme 17.8) [7, 8],... 

Scheme 13 Formation of a six-membered lactone in the cyclocarbonylation of geraniol...

Geraniol is an interesting substrate that presents a hindered terminal C = C bond and an allylic function. The carbonylation reaction gives, beside the acid, the six-membered lactone and not the butyrolactone that means that initially an isomerization step occurred as depicted in Scheme 13. The most adapted ligand to obtain good selectivity in this lactone is dppb [98]. In the case of perillyl alcohol such an isomerization does not occur and the C5-lactone is produced (Scheme 14) [99]. 

Lemer and Benkovic examined the possibility of performing an intramolecular cyclisation reaction [30]. They chose the formation of a six-membered lactone ring from a hydroxy ester (12) and observed that only one single enantiomer of the 5-lactone (14) in 94% ee was formed from the corresponding 5-hydroxy ester. Moreover, the stereospecific ring closure reaction was accelerated by the antibody -elicited from the transition-state analog 15- by about a factor of 170. 

Unsaturated lactone 74 (Scheme 7.21) can be viewed as an oxygen heterocyclic analogue of 2-cyclohexenone, and it has recently been reported that catalytic 1,4-additions of Et2Zn to 74 can indeed be accomplished with high enantioselectivity. For adduct 76, Reetz achieved a remarkable 98% ee when employing ferrocene-based diphosphonate ligand 23 [48]. Using diphosphite 24, Chan et al. achieved an ee of 92% for the six-membered lactone 74 and a 56% ee for the five-membered lactone 25 [49c]. 

The cyclization method of Ochiai et al (85CPB989), used for reduced furans 94, affords a mixture of six-membered lactone 243 and the rearranged y-keto acid 244 when acid 242 is the substrate. 

In 1998, Ito et al. isolated clausamine-A (217), -B (218), and -C (219), each in their racemic form from the branches of C. anisata (173). The clausamines have a 1-oxygenated carbazole framework with an annulated six-membered lactone in the 3,4-position. They represented the first examples of naturally occurring carbazole alkaloids with a lactone moiety (173). Later in the same year, Wu et al. reported four further carbazolelactone alkaloids, clausevatine-D (220), -E (221), -E (222), and -G (223), from the root bark of C. excavata (Rutaceae) (174). This plan is a wild shrub... 

Despite these favorable results, the Pd-catalyzed lactonization with alkyl-substituted alkynes generally gives unattractive mixtures of five- and six-membered lactones. In marked contrast, the Pd-catalyzed reaction of alkynylzincs with (Z)-/J-iodoacrylic acid gives only the expected enynoic acids135, which can then be selectively lactonized to give either five- or six-membered lactones136 (Scheme 41). 

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (1). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine I. The inelhod can also be used for preparation of macrocyclic lactones under high-dilution... 

Hydroxy acids, compounds that contain both a hydroxyl and a carboxylic acid function, have the capacity to form cyclic esters called lactones. This intramolecular esterification takes place spontaneously when the ring that is formed is five- or six-membered. Lactones that contain a five-membered cyclic ester are referred to as 7-lactones their six-membered analogs are known as 8-lactones. 

Withanolides. Withanolides are Cis-steroidal lactones that are isolated from the Solanaceae plant family. Withanolides are characterized by an ergostane-type skeleton, the Cl 7-side chain of which is transformed into a six-member lactone ring. The withanolides and the related crgostancs arc tile only known natural steroids obtained Ifum the same family dial have representatives with both a- and -orientations of the Cl7 side chain. 

Five- or six-membered lactones also are formed by internal esterification when either y- or 8-hydroxy acids are heated. Under similar conditions, /3-hydroxy acids are dehydrated to a,/3-unsaturated acids, whereas a-hydroxy acids undergo bimolecular esterification to substances with six-membered dilactone rings called lactides ... 

Lactone formation can happen even resulting in the generation of seven-membered lactones, which are usually less favoured than five or six-membered lactones. 

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... 

Homologation of lactones.2 An efficient method for homologation of five- and six-membered lactones is formulated in equation (I). 

Although cyclization using an amine is more common, there are examples with oxygen nucleophiles. An alcohol was employed37 to give both five- and six-membered lactones (Fig. 12). In a similar vein are the... 

Scheme 24. Six-membered lactones or lactals prepared using 6-exo-trig radical cyclization...

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