Lactones six-membered

Coumarin (7.88) is a well-known 6-lactone (six-membered ring) of natural origin found in various preparations such as some tobaccos, alcoholic beverages, and cosmetics. Besides reactions of oxidation, reduction, and conjugation, coumarin is also subject to lactone hydration in vivo and in the presence of microsomes [170-174], The resulting metabolites include ortho-coumaric acid (7.89) formed directly from coumarin, 3-(2-hydroxyphenyl)-propionic acid (7.91) formed following reduction of coumarin to dihydrocou-... 

The carbonyl absorption of saturated 5-lactones (six-membered ring) occurs in the same region as straight-chain, unconjugated esters. Unsaturation a to the C=0... 

Lactones with unstrained six-membered rings are similar to noncyclic esters. As the ring becomes smaller the C—C—O angle decreases and the frequency of the carbonyl stretching vibration increases. Saturated 5-lactones (six-membered ring) have a carbonyl band at 1750-1735 cm"L Saturated... 

No 0-allylation is observed in formation of the six-membered ring compound 79 by intramolecular allylation of the /3-keto ester 78(15,57]. Intramolecular allylation is useful for lactone fonnation. On the other hand, exclusive formation of the eight-membered ring lactone 81 from 80 may be in part derived from the preference for the nucleophile to attack the less substituted terminus of the allyl system[58]. 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

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],... 

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 Lac tones that contain a five membered cyclic ester are referred to as 7 lactones, their six membered analogs are known as 8 lactones... 

Lactones whose rings are three or four membered (a lactones and p lactones) are very reactive making their isolation difficult Special methods are normally required for the laboratory synthesis of small ring lactones as well as those that contain rings larger than SIX membered... 

Section 19 15 An intramolecular esterification can occur when a molecule contains both a hydroxyl and a carboxyl group Cyclic esters are called lactones and are most stable when the nng is five or six membered... 

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... 

Results of fluorination of lactones with sulfur tetrafluoride depend on the ring size. y-Butyrolactone undergoes ring cleavage to give y-fluorobutyryl fluoride, which IS further fluormated to 1,1,1,4-tetrafluorobutane. The six-membered 1,4-di-... 

Reactions that are expected to produce hydroxy acids often yield the derived lactones instead if a five- or six-membered ring can be formed. 

Reactions of vinylogous amides with methanesulfonyl chloride also led to the formation of six-membered rings. Here the initial attack on oxygen produces a zwitterionic intermediate which can collapse to an enol sulfonic acid lactone (383,469). 

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. 

In the case of y,6-unsaturated acids, five-membered rings (y-lactones) are predominantly formed (as shown above note that Markovnikov s rale is followed), but six-membered and even four-membered lactones have also been made by this procedure. There is a gem- dimethyl effect that favors formation of 7-11 membered ring lactones by this procedure. ... 

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. 

Since five-membered rings are formed faster than four or six-membered rings, an otherwise electronically Symmetrical double bond (35) or (36) will be captured intramolecularly to give a y-lactone (37) in acid. 

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... 

Various cyclic esters have been subjected to hpase-catalyzed ring-opening polymerization. Lipase catalyzed the ring-opening polymerization of 4- to 17-membered non-substituted lactones.In 1993, it was first demonstrated that medium-size lactones, 8-valerolactone (8-VL, six-membered) and e-caprolactone (e-CL, seven-membered), were polymerized by lipases derived from Candida cylindracea, Burkholderia cepacia (lipase BC), Pseudomonas fluorescens (lipase PF), and porcine pancreas (PPL). °... 

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). 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

Bromomethyl-3,4-dibromo-3,4-dihydrocoumarin 1 (Fig. 11.4) and its chloro-methylated analogue 2b rapidly and progressively inactivate a-chymotrypsin and also the activities of a series of trypsin-like proteases. A benzyl substituent characteristic of good substrates of a-chymotrypsin was introduced at the 3-position to make inhibition more selective. This substituted dihydrocoumarin 3 irreversibly inhibited a-chymotrypsin and other proteases. These functionalized six-membered aromatic lactones, and their five- and seven-membered counterparts, 3//-benzofuran-2-ones 2a26 and 4,5-dihydro-3//-benzo[b]oxepin-2-ones 2c,27 were the first efficient suicide inhibitors of serine proteases. Their postulated mechanism of action is shown in Scheme 11.2. 

Mechanistically, a-methylenecyclopentenone (2-391) reacts with ester enolate 2-392 in a Michael addition to give the enolate 2-393, which is then trapped with an aldehyde 2-394 generating the alcoholate 2-396. This eventually cyclizes through lactonization to afford 2-397 in good yield. The products 2-397 are obtained as single diastereomer thus, it can be assumed that the aldol reaction proceeds via the six-membered chair-like transition state 2-395. 

Lipase catalyzed the ring-opening polymerization of medium-size lactones, d-valerolactone (<5-VL, six-membered) and -caprolactone (c-CL, seven-mem-bered). Lipases CC, PF and PPL showed high catalytic activity for the polymerization of <5-VL [74,75]. The molecular weight of the polymer obtained in bulk at 60 °C was relatively low (less than 2000). 

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