Lactone enolates. alkylation

Alkylations of P-substituted 6-lactone enolates occur anti to the substituent with high dia-stereoselectivity unless bulky groups are present at the a-position. " Then, conformational effects may lead to a reversal of the diastereofacial differentiation. Other 8-lactone enolates are alkylated with poor diastereoselectivity unless they are cu-disubstituted at the 7- and 6-positions. Still and Galynker have shown that remote substituents may exert a considerable amount of asymmetric induction in mediumring lactone enolate alkylations. The remote substituent can determine which of the lower energy conformations of the enolate are available for alkylation. ... 

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. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 12.5.2), so the correct stereochemistry is established for the C—O bond. The final stereocenter for which configuration must be established is the methyl group at C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not very stereoselective. However, since this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate was formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C(6). 

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. 

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. 

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. 

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. 

Table 5. 2-Alkylalkanoic Acids and a-Alkyl Lactones by Alkylation of Enolates from l-Acyl-2-pyrrolidinemethanols and Their Ethers, Followed by Hydrolysis...

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. 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

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.

Stereoselectivity is often controllable, but it seems to be inconsistent from one type of enolate to another. For example, most heterocyclic five-membered ring enolates seem to prefer syn addition495,518,519 while lactones often give a m -alkylation371,495,520. Asymmetric induction has been used successfully in complex enolate alkylation. The use of the novel, chiral PTC, A-(/ -(trifluoromethyl)benzyl)cinchonium bromide (PTBCBr) has also been used for stereocontrolled alkylation (equation 67) giving an enantiomeric excess of 92%521. 

It has also been found that in medium-sized (8- to 12-membered) lactones containing a single chiral center at a remote position, highly stereoselective formation of a new chiral center adjacent to the carbonyl group occur (equation 79). This effect falls off as the distance between the enolate and the controlling asymmetric center increases561. Such stereocontrol is caused by the conformational properties of the particular lactone being alkylated. 

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bondforming reactions in chemistry. Alkylation of lithium enolates Works with both acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general mechanism is shown below, alkylation of an ester enolate alkylation of a ketone enolate... 

The end result is that the larger of the two groups is on the inside There are other ways to do this too. If we alkylate the enolate of a bicyclic lactone, the alkyl group (black) goes on the outside as expected. But wha t will happen if we repeat the alkylation with a different alkyl group The new enolate will be flat and the stereochemistry at the enolate carbon will be lost. When the new alkyl halide comes in, it will approach from the outside (green) and push the alkyl group already there into the inside. 

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

A-Phthaloyl-protected (S)-phenylalanine has been used as a ligand for rhodium in the formation of metallocarbenes from diazo compounds for C-H insertion reactions (Section D.1.2.2.3.2.). Ar-Sulfonyl-protected (S)-alanine and (S)-valine are efficient ligands for chiral Lewis acids used in the Diels-Alder reaction (Section D.1.6.1.1.1.3.). A -Sulfonyl-pro-tected (S)-phenylalanine methyl ester has been used for the enantioselective protonation of lactone enolates (Section D.2.I.). The terf-butyl ester of (S)-valine readily forms imines with carbonyl compounds which are used for the highly efficient alkylations of their azaenolates (Sections D.1.1.1.4.1D.1.5.2.4.). All these derivatives can be obtained by the standard methods described in Houben-Weyl3. 

Furanes. Grieco et al. have developed a general synthesis of 2,4- and 2,3,4-substituted furanes from substituted y-lactones, as illustrated for the conversion of (1), y-decalactone, into 2-hexyl-4-benzylfurane (5). The lactone enolate of (1) is alkylated to give (2). Selenenylation of the enolate of (2) with phenylselenenyl chloride leads to (3). Selenoxide fragmentation of (3) results almost... 

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