Lactones enolate intermediate

A highly Z-selective olefination of a-oxy and a-amino ketones via ynolate anions has been reported (Scheme 9).43 The stereocontrol mechanism has been explained by (g) orbital interactions between the s orbital of the breaking C-O bond or n orbital of the enolate and the s orbital of the C-O or C-N bonds of the substituent in the ring opening of the /I-lactone enolate intermediates, and/or the chelation to lithium. 

Tetrasubstituted alkenes (214) were obtained with high Z selectivity (>99 1) by reaction of ynolates (211) with a-oxy- and a-amino-ketones (212 X = OR, NR2) (g) at room temperature. According to experimental and theoretical studies, the high Z selectivity is induced by orbital interactions in the ring opening of the /3-lactone enolate intermediate (213), rather than by the initially presumed chelation of the lithium atom.260... 

Ynolate anions react with acylsilanes at low temperature to give P-lactones 48 in good yields. When the reaction is conducted at room temperature the isolated product is a (1-silyl-a,p-unsaturated ester via a P-lactone enolate intermediate <02JACS6840>. 

Removal of the unsaturated side-chain appendage from C-8 in 22 provides diol lactone 23 and allylic bromide 24 as potential precursors. In the synthetic direction, a diastereoselective alkylation of a hydroxyl-protected lactone enolate derived from 23 with allylic bromide 24 could accomplish the assembly of 22, an intermediate that possesses all of the carbon atoms of PGF2o- It was anticipated that preexisting asymmetry in the lactone enolate would induce the... 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

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. 

The reaction of 3-ketoacids with allyl carboxylates is also believed to proceed via a palladium enolate intermediate.126 Less than complete stereospecificity is also observed in these reactions (equation 163). Interestingly, the bicyclic lactone substrate employed to ascertain the stereointegrity of this reaction, in addition to being incapable of any syn-anti isomerization, cannot epimerize the starting material by car-boxylate attack at the metal. The observed stereochemical leakage could be due to epimerization of the intermediate allyl complex (equation 164) or reductive elimination of an allylpalladium enolate (retention) (equation 165). 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

Lactones are normally stable compounds, which have found ample application as synthetic intermediates, and, quite recently, have been detected as the central structural unit in physiologically active natural products like obaflorin (123) and lipstatin (124). Characteristic applications of 3-lactones in synthesis are the stereospecific CO2 elimination to form di- and tri-substituted alkenes (e.g. from 125 equation 40) or Grignard addition to the carbonyl group e.g. equation 41). Particularly useful is the formation of 3-lactone enolates (126), which react with a variety of electrophiles (EX) wiA high stereocontrol (equation 42). Organocuprates may be used in chain elongations to form 3-branched carboxylic acids (equation 43). ... 

Under acidic conditions, this is followed by decarboxylation, giving an enol intermediate, which then tautomerises to the ketone product. Addition of the hydroxyl group of trifluoroperacetic acid to the ketone gives a tetrahedral intermediate. Donation of the electrons in the H-0 bond, 1,2-migration of one of the alkyl groups and loss of the carboxylate anion then gives the product lactone. 

The mannose-derived lactone 40, produced by ozonolysis of the corresponding alkene, undergoes a modified Fujimoto-Belleau reaction yielding the vinyl phosphonate cyclohexenone 41.1 The epimeric lactone 43 however, yields the anticipated cyclcohexenone 42 (Scheme 12). Formation of 41 is rationalized by invoking hydroxide elimination from an enolate intermediate rather than the anticipated elimination of (MeO)2P(0)OH. 

Danishefsky and coworkers has approached Terreulactone A, with their efforts outtined in Scheme 12.58 [107]. The enol intermediate 242 was readily obtained from the Wieland-Miescher ketone 241 by chemo- and stereoselective reduction, protection of die resultant alcohol, dimethy-lation, followed by a two-step oxidation sequence. Then the enol intermediate 242 was subjected to a stereoselective ring contraction condition to afford 243. Lactonization of 243 followed by appropriate functional group management provided the A, B, C rings of terreulactone A 245, which they hoped to convert to 240 and expected to couple 240 with a suitable E,F progenitor 239 by the [3+3] cycloaddition strategy. Their completion of the total synthesis of terreulactone A 238 is under way. 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

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). 

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