Lactone enolate

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. 

Vinyl triflates derived from lactone enolates are also viable coupling partners In Ni(ll)/Cr(ll)-mediated carbon-carbon bond forming reactions... 

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). 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

The synthesis in Scheme 13.49 features use of an enantioselective allylic boronate reagent derived from diisopropyl tartrate to establish the C(4) and C(5) stereochemistry. The ring is closed by an olefin metathesis reaction. The C(2) methyl group was introduced by alkylation of the lactone enolate. The alkylation is not stereoselective, but base-catalyzed epimerization favors the desired stereoisomer by 4 1. 

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 enolate generated by reaction of lactone 88 with lithium diisopropylamide (LDA) is quenched with an excess of methyl iodide to give methyl lactone 89 in excellent yield. As expected, the electrophilic attack is stereoselective for the less sterically hindered convex face of the lactone enolate, giving the product with the desired 7iJ-stereochemistry with greater than 95 5 selectivity (Equation 22) <1997TL3817>. 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

The first report of a successful a-alkylation of a lactone enolate was the high yielding conversion of the bicyclic y-lactone 1 into the stereoselectively methylated derivative 21. 

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. 

A striking example of enolate stability is that of 2, a ft-lactone enolate. Deprotonation of 1 with LDA at — 78 °C yields 2, which is stable at this temperature and can be alkylated to give 3a in excellent yields (see the following table). The diastereoselectivity is >98 249 51. When the enolate 2 is warmed to room temperature the expected -elimination occurs and pure (E)-4 is formed in quantitative yield. 

A straightforward explanation for the unexpected stability of / -lactone enolate 2 has been put forward, a stereoelectronic reason in the rigid system 2 the essential orbitals are held orthogonal to each other as in 2 thus, an elimination reaction has a much higher activation energy than in an open system49. 

Intramolecular alkylations of y-lactone enolates are merely variants of the examples mentioned in the previous sections (Section 1.1.1.3.2.2.1.). A striking feature of these reactions is their efficiency with mild bases such as l,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium er -butoxide instead of the lithium amides. 

C. Reactions of Magnesium Ester Enolates and Magnesium Lactone Enolates with Electrophiles... 

Asymmetric synthesis in aldol-type reaction involving magnesium ester or lactone enolates has also been reported. Enolate of (—)-menthyl or (-l-)-bornyl acetate reacts with substituted benzophenones or a-naphtophenones to yield, upon hydrolysis of the resulting esters, optically active /3-hydroxyacids. Although these results are interpreted in terms of a steric factor. Prelog s rules are not applicable to these reactions (equation 88). 

Synthesis of the 24R isomer was commenced by stereoselective hydroxymethy-lation of the enolate of lactone 30. Introduction of methyl groups at C25 and C26 was achieved by addition of MeLi to give 24R depresosterol (33). Alternatively, trapping of the lactone enolate with acetone followed by LiAlH reduction gave the 245 epimer (34). Spectral comparison indicated that the 24R sterol is identical with the natural product. 

The Claisen rearrangement of lactonic enolates provides a new route to cycloalkenes. Cyclocitral was converted to the lactone (642) through a multistep sequence, the lactone deprotonated with LDA in THF at -78 °C, and the enolate quenched with f-butyldimethyl-chlorosilane (80JA6889, 6891). The crude ketene acetal (643) was heated at 110 °C for 10 h, and the product treated with fluoride ion to afford a single acid. Replacement of the quaternary carboxyl group by hydroxyl was accomplished through use of the carboxy inversion reaction (Scheme 147). The product (645) of this last reaction was identical with an authentic sample of widdrol in all respects excluding its optical rotation. 

The addition of Grignard reagents or organolithiums (alkenyl, alkyl, alkynyl, allyl or aryl) to nitroenamines (281)213 was reported by Severin to afford P-substituted-a-nitroalkenes.214 b Similarly, ketone enolates (sodium or potassium), ester enolates (lithium) and lactone enolates (lithium) react to afford acr-nitroethylidene salts (294) which, on hydrolysis with either silica gel or dilute acid, afford 7-keto-a,(3-unsaturated esters or ketones (295)2l4c-d or acylidene lactones (296).214 Alternatively, the salts (294, X s CH2) can be converted to -y-ketoketones (297) with ascorbic acid and copper catalyst. 

In contrast, a-nitroalkenation adducts (298) are obtained with thermodynamic enolates of a-sub-stituted ketones or esters in addition, Fuji reports that enantioselective addition of a-subsdtuted lactone enolates to chiral nitroenamines is cation dependent with zinc affording maximum enantioselectivity.213... 

Grieco and co-workers (147) have carried out the kinetic protonation at -78° of the lactone enolate 474 and obtained a 3.5 1 ratio of 475 and 476. Axial protonation is again not highly favored. This low selectivity may be due to competing C and 0 protonation. 

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... 

The Mannich reaction of an aldehyde enol (example Formula C in Figure 12.14) or a ketonic enol (example Formula C in Figure 12.15) often proceeds beyond the hydrochloride of a /l-aminocarbonyl compound or the Mannich base. The reason is that the secondary amine or its hydrochloride, which has previously been incorporated as part of the iminium ion, is relatively easy to eliminate from these two types of product. The elimination product is an a,fi-unsaturated aldehyde (example Formula E in Figure 12.14) or an a,/l-unsaturated ketone (example Formula D in Figure 12.15)—that is, an a,/l-unsaturated carbowyl compound. Figure 13.51 will show how the Mannich reaction of a carboxylated lactonic enol provides access to an a-methylene lactone, that is, an a,/l-unsaturated carboxyl compound. 

Fig. 13.41. Alkylation of an enantiomerically pure lactone enolate (B) for the preparation of enantiomerically pure a-a l kyl- - h yd roxyca r boxy li c acids and enantiomerically pure 1,2-diols, respectively. In the lactone Cthe carboxyl group may react with water or with a hydride donor. In any case, the leaving group released is a hemiacetal anion that decomposes to pivalaldehyde and the a-alkyl-a-hyd roxyca rboxylic acid D or the enantiomerically pure 1,2-diol E.

Resonance form B identifies it as a formylated ester- or lactone enolate and resonance form... 

Fig. 13.50. a-Methylenation of an ester (in this special case of a lactone) via aldol condensation of the resulting a-formylated ester enolate (in this special case a lactone enolate) B <- B with paraformaldehyde. Here, the migration of the formyl groups E —> C is considered to proceed intramolecularly, but an inter-molecular process is equally conceivable. 

Fig. 13.51. a-Methylenation of a lactone via Mannich reaction (cf. Figure 12.14 and 12.15) of the a-carboxylated lactone enolate or lactone enol derived thereof. Another approach to a-methylenation of not only lactones, but normal carboxylic acid esters, is presented in Figure 13.50. 

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