Lithium ynolates esters

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

A naphthalene-catalyzed (<10%) lithiation of a,a-dibromo esters 152 in THF at —78°C was used to generate ester dianions 153, which by warming at 0°C gave lithium ynolates 154. These intermediates were trapped by carbonyl compounds, for instance benzophenone, to give, after final hydrolysis with water, a,/3-unsaturated acids 155 (Scheme 55)" ... 

Lithium ynolates from a-keto dianions derived from esters. 742... 

Lithium ynolates from lithium ester enolates. 746... 

The a-chloro-a-sultinyl ketone 20 was prepared from methyl benzoate and chloromethyl phenyl sulfoxide 19 after in situ a-lithiation. Compound 20 is dimetallated by KH and f-BuLi to give the keto dianion 21, which is converted into a potassium/lithium ynolate 22 (equation 7). The resulting metal ynolates are converted into thioesters, carboxylic acids, amides and esters (Section V). 

The a-bromo esters 39 are treated with LDA to form the bromo ester enoiates 40, which are subjected to lithium-halogen exchange with t-BuLi (3 equiv) at —78 °C. The resulting dilithium ester dianions 41 are thermally cleaved at 0 °C into the ynoiates 42 in good yields (equation 12). This procedure finally regenerates LDA from diisoprpylamine and t-BuLi along with the lithium ynolate (equation 12 ). 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

The reaction of thiol esters with lithium ynolates (equation 67) takes place by a route different than the one shown in equation 65 for alcohol esters. Thiol esters (162) undergo a two-carbon homologation to S-keto thiol esters 165 in good yield. Intermediates 163 undergo a two-step rearrangement to a S-keto thiol ester enolate (165), via elimination of lithium thiolate to yield a ketene (164), followed by the nucleophilic attack of the thiolate on 164. Finally, the homologated S-keto thioester (165 ) is obtained on acidification of the reaction mixture . ... 

Reactions of alkynyl esters with nucleophilic reagents usually involve the attack of the nucleophile on the electrophilic acyl moiety (i.e. C==0, P=0, SO2) but not the triple bond. A typical example of such a process is the formation of lithium ynolates in the reaction of alkynyl tosylates with methyl lithium (see equation 10 in Section II.B.l). Similarly, the base-catalyzed hydrolysis of alkynyl esters most likely proceeds via OH attack on the acyl moiety and the subsequent standard mechanistic steps. 

In the olefination of an ester carbonyl, the elimination of alkoxide, leading to a ketene, causes low yield. If this side reaction becomes the major reaction course, it would be a new reaction other than olefination. The reaction of thiol esters (thiolates are better leaving groups than alkoxides) with lithium ynolates takes place by a route different from that for alcohol esters (Fig. 43). Thiol esters 122 undergo a two-carbon homologation to afford p-keto thiol esters 126 in good yield. 

A similar sequence starting from esters rather than ketones ends up with lithium ynolates 316. These may be trapped as 1-alkynyl trimethylsilyl ethers or hydrolyzed to carboxylic acids that are homologous to the starting material (Scheme 1-246). ... 

Although the Michael addition of metal ynolates to a,/ -unsaturated carbonyl compounds is expected to give six-membered cycloadducts, 1,2-addition to carbonyl groups usually precedes 1,4-addition. The cycloaddition of the lithium-aluminum ate complex of silyl-substimted ynolate 112 with ethyl benzylideneacetoacetate (113), which is doubly activated by the ester and keto functions, gives the y-lactone 114 via a [4 4- 2] type cycloaddition (equation 46). Diethyl benzylidenemalonate (115) affords the uncyclized ketene 116 by reaction with 112 (equation 47). This could be taken as evidence for a stepwise mechanism for equation 46. ... 

Although this method is convenient in the laboratory and we can successfully carry out work on up to a 10-g scale, tert- or sec-butyllithium is somewhat expensive and should be handled carefully, especially on a large scale. With this in mind, we develop a more practical method for the synthesis of ynolates using reductive lithiation (Fig. 7). The dibromo esters 22 are treated with lithium naphthalenide at —78 °C to give the ynolates in good yield. Naphthalene-cataZyzeri reductive lithiation of the dibromo esters 22 is also achieved, providing the ynolates... 

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