Y-Lac tones

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

As mentioned earlier in the discussion of cyclizations leading to (3-lactones, the (3-lactones formed from halolactonization of 1,4-dihydrobenzoic acids readily rearrange to produce bridged ring y-lac-tones.19 In some cases, the substitution pattern favors formation of the y-lactone even under conditions of kinetic control (equation 23).20 Synthesis of a variety of y-lactones by iodolactonization of dihydroben-zoic acid derivatives has been reported recently by Hart (equation 24).91 Attempted iodolactonization of the acid in the case where R = H resulted primarily in an oxidative decarboxylation however, iodolactonization was effected using the amide derivative. 

The Mannich adducts are readily transformed to optically active a-amino-y-lac-tones via a one-pot diastereoselective reduction and lactonization sequence and the tosyl group exchanged for a Boc group via a two-step procedure. The cop-per(II) ion is crucial for the success of this reaction [21]. It has the properties necessary both to generate the enol species in situ and, in combination with the C2-symmetric ligand, coordinate it as well as the imine in a bidentate fashion. The reaction proceeds via a cyclohexane-like transition state with the R substituent of the enol in the less sterically crowded equatorial position, which is required to obtain the observed diastereoselectivity (Fig. 5). 

The enantioselective intramolecular C-H insertion of alkyl diazoacetates has been used to prepare a variety of pharmaceutical and natural products [1], One example is the synthesis of (-)-enterolactone (8) shown in Scheme4 [2], The Rh2(4S-MPPIM)4-catalyzed reaction of 6 favors C-H insertion to form the y-lac-tone 7 in 93 % ee, which was the readily converted to 8. Competing C-H insertion at the highly activated benzylic C-H bond to form a /3-lactone was not observed, which illustrates the strong preference for five-membered ring formation over six-membered. 

Several variations of this reaction are possible. The halo acid is boiled with a solution of sodium in absolute alcohol as in the formation of y-bu-tyrolactone (67%), or the dry sodium salt of a halo acid is heated under vacuum as in the preparation of 8-valerolactone (30%). The corresponding esters are sometimes refluxed with alcoholic potassium hydroxide or decomposed thermally at 15 180° whereby a molecule of an alkyl halide is eliminated. The latter process is valuable in making a-alkyl-y-lac-tones of higher-molecular-weight acids since the y-bromo esters are available by the free-radical addition of a-bromo esters to 1-olefins. 

Reaction of the a-carbanion of an alkyl aryl sulfoxide (RCH2SOAr) with aldehydes may give four dia-stereomers. In general, the reaction is highly diastereoselective with respect to the a-sulEnyl carbon, but poorly diastereofacially selective with respect to attack on the carbonyl component. In fact, the a-carb-anion (31) of benzyl t-butyl sulfoxide adds to an aldehyde to produce only two diastereomers (32a) and (32b). As shown in Scheme 10, the selectivity increases when the counterion is A transition state structure (33) is proposed to account for the anti stereoselection. Addition of the dianion of (/ )-3-(p-to-lylsulfinyOptopionic acid (34) to aldehydes affords two main diasteieoisomeric 3 (p-tolylsulfinyl)-y-lac-tones (35 R = Ph and Bu. ca. 60 40). These isomers (35) were separated by chromatography, and their... 

Cpierenone, U5P. Eplcrenone. 9,lla-epoxy-l7a-hy-droxy-3-oxopregn-4-enc-7a.2l-dicarboxylic acid, y-lac-tone. methyl ester (Inspra). is a new aldosterone antagonist that was approved by the FDA in 2002 for the treatment of hypertension. 

However, in the Aleksinac shale bitumen geolipid constituents were identified which had not been found earlier in ancient sediments a homologous C -C. series of aliphatic y-lactones, a homologous series of four members of 6-lactones, two cyclic y-lac-tones (dihydro- and tetrahydroactinidiolide), as well as a homologous series of methyl esters of fatty acids (C -C -) ... 

The method has been apphed to the reductive cross-coupling of ethyl -arylacrylates with aldehydes in the presence ofTMSCl [160]. Addition of Mg metal to a solution of ethyl -arylacrylate, aldehyde, and TMSCI in DMF provided the corresponding y-lac-tones as a cis/trans stereoisomeric mixture in good to excellent yields (Scheme 3.142). 

Metal catalyzed enantioselective C-H insertions of carbenes have so far not been studies in great detail. Copper catalysts are of no use for this type of reaction, rhodium(Il) catalysts, however, allow intramolecular C-H insertions, for example, in the alkyl group of diazoacetates with longer chains. The formation of five-membered rings such as y-lac-tones is favored. [Rh2(55-mepy)4] affords... 

The optically active homoaldol products 306 are easily converted into y-lac-tones 307 by four different pathways, which require an oxidation step (see Sect. 4.4). Applications in target synthesis include the natural products (-i-)-quer-... 

Rhodium-catalysed carbenoid insertion has been used to make fused y-lac-tones, as in the conversion of diazoesters of type 93 into products 94 (R = H, COMe, C02Me), in which the indicated exo-isomer strongly predominated. When the readily-accessible uridine derivative 95 is treated as indicated in Scheme 5, the lactone 96 is obtained, and this can be used to make nucleosides 97 containing other bases, either purines or pyrimidines. ... 

At this juncture, with the entire carbocyclic core of aspidophytine established, an advanced staging area had been reached from which the total synthesis could hopefully be completed after a few finishing touches. Specifically, what remained was the fusion of the y-lac-tone and the excision of the unwanted carbon atom with the introduction of a double bond inside the adjacent cyclohexane ring. 

In analogy to allyl halogenides, iodobenzene and other aromatic iodo derivatives can be reacted with Ni(CO)4 and acetylene at reaction temperatures above 100 °C with formation of y-ketoacids or their esters [418, 442], which may be considered as hydrolysis products of p,y-unsaturated y-lac-tones or as hydrogenation products of a,p-unsaturated y-ketoacids or -esters. a,p-Unsaturated y-ketoacids or -esters will be hydrogenated under the reaction conditions, but do not take up carbon monoxide because of the presence of electrophilic substituents. Besides allyl halogenides, allyl alcohols, -ethers and -esters may also be reacted to give unsaturated acids or esters. 

Masuda M, Nishimura K 1981 Absolute configurations of quercus lactones, (3R,4i )- and (3S,45)-3-methyl-4-octanolide, from oak wood and chiroptical properties of mono-cyclic y-lac-tones. Chem Lett 1333-1336... 

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