Lactones enolate formation from

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

In 1993, Enholm described the Sml2-mediated aldol reactions of ot-benzoyl lactones derived from carbohydrates with ketones.153 For example, treatment of lactone 136 with Sml2 in the presence of (+ )-dihydrocarvone 137 gave aldol adduct 138 in good yield and in high diastereoisomeric excess (Scheme 5.97). In this example, HMPA is used as an additive to increase the reduction potential of Sml2 and thus to facilitate Sm(III) enolate formation from the ot-benzoyl lactone.153... 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

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). ... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

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. 

Oxetanones (/3-Lactones).—Electronic effects in the thermal decarboxylation of 3- and 4-aryl-2-oxetanones indicate that the reaction is concerted but proceeds through a polar transition state. Thermal decarboxylation of /3-lactones is the key step in a convenient synthesis of benzyl enol ethers from a-benzyloxyacetic acids (Scheme 9) and also in the formation of (E)-l-halogeno-l-cyano-2-aryl-ethenes from halogeno-cyanoketens and aryl aldehydes. 

The treatment of an ester (or lactone) with a base and a silyl halide or trillate gives rise to a particular type of sUyl enol ether normally referred to as a silyl ketene acetal. The extent of O- versus C-silylation depends on the structure of the ester and the reaction conditions. The less-bulky methyl or ethyl (or 5-tert-butyl) esters are normally good substrates for O-silylation using LDA as the base. Acyclic esters can give rise to two geometrical isomers of the silyl ketene acetal. Good control of the ratio of these isomers is often possible by careful choice of the conditions. The f-isomer is favoured with LDA in THF, whereas the Z-isomer is formed exclusively by using THF/HMPA (1.24). Methods to effect stereoselective silyl enol ether formation from acyclic ketones are less well documented. ... 

Formation of the unexpected oxazolidinone in G18 proved to be crucial because models showed that direct C-acylation of the C-9 enolate derived from G17 was sterically disfavored. However, treatment of G18 with sodium meth-oxide did afford lactone G20 in 70% yield. Enolate G19 is postulated as the intermediate, and as in the case of the actinobolin analogue (E8, Scheme 18), regioisomeric enolization at C-7 is of no consequence, since acylation at that site is a less favored reaction. 

Optically active dihydropyranones were synthesized by Smith and co-workers [43] by a highly stereoselective chiral isothiourea-catalyzed intermolecular Michael/lactonization cascade from arylacetic acids and p,7-unsaturated a-ketoesters (Scheme 16.21). This strategy is based on the generation of chiral enolate directly from carboxylic acid activated by the in situ formation of a mixed anhydride and the organocatalyst. 

The enol acetate group has been shown to be stable to the conditions of semicarbazone formation from another ketone group in the molecule [137], and to the action of a Grignard reagent on a concomitant enol lactone group [138]. 

Highly hindered bases such as (20) deprotonate the methyl group of methyl ketones specifically. In the presence of an aldehyde, aldol reaction occurs before enolate equilibration can take place. The same base promotes the addition of ester and lactone enolates to aldehydes and ketones. However, it has been noted that at low temperature (—70 °C), the more accessible lithium diethylamide deproto-nates only the methyl group of methyl ketones. Addition of a second aldehyde or ketone species at this temperature leads to the exclusive formation of jS-ketoIs derived from this enolate. ... 

The acid chloride precursor for the multicomponent reaction was accessed (Scheme 11) through the method that was developed in the theopederin D synthesis. The sequence largely followed the excellent route that was reported by Nakata." Our variation on this route was the incorporation of a catalytic asymmetric (3-lactone formation" " from acetaldehyde and propionyl chloride in the presence of 44 to yield, after opening with the lithium enolate of t-butyl... 

In addition to the range of asymmetric routes toward 13-lactone and (3-lactam scaffolds, Lewis bases have been used to access a variety of other important four-membered heterocyclic classes via formal [2+2] cycloadditions. In this section, the use of tertiary amines or NHCs to generate ammonium or azolium enolates, respectively from ketenes and their subsequent application toward the formation of other synthetically interesting heterocycles, will be discussed. A series of reports concerning the use of sulfenes, the sulfonyl equivalents of ketenes, in Lewis base-catalyzed asymmetric [2+2] cycloadditions will also be detailed. 

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