Lithium alkynolates

Acetylenic precursors employed in the syntheses of sugars may be divided into three groups (a) aldehydes (usually in the form of acetals), (b) alkyl alkynyl ethers, and (c) alkynols or alkynediols. Some of them are commercially available (for example, 2-butyne-l,4-diol), and others are prepared by Grignard-type reactions between 1-alkynylmag-nesium halides or lithium alkynes and suitable aldehydes, ketones, or epoxides. In this way, the synthesis of substrates having the desired number of carbon atoms, as well as the necessary functional groups, can be achieved. The next step consists in partial saturation of the triple bond to afford the desired cis- or trans-alkene. ct.s-Alkene systems... 

Reduction of la-alkynols to (E)-alkenols." This reaction is often one step in the synthesis of insect pheromones. Sodium in liquid ammonia is generally preferred for this reduction (5, 590). An alternative, general method is reduction with a large excess of lithium aluminum hydride in diglyme-THF. 

The owti-Markownikoff products that predominate with thiols and terminal alkynols in the presence of oxygen or trace amounts of lithium may result from the incursion of radical or radical-ion mechanisms (equations 29 and 30). In fact. 

Elimination. a,a-Dibromoketones undergo dehydrobromination and rearrangement to afford lithium alkynolates on consecutive exposure to LHMDS and BuLi. Such species are intercepted by acid chlorides. 

The synthesis of fragment B will be done according to Scheme 3. The known hexacarbonyldicobalt complexed alkyne (12) will be prepared according to the work done by Krafft and co workers. First, 3-butyn-l-ol (13) will be converted to its rerr-butyldimethylsilyl (TBS) ether by treating a mixture of (13) with TBS-Cl in triethylamine and DMAP. Treatment of the protected alkynol with 5ec-butyl lithium in THF followed by low temperature quench with ethyl chloroformate yields the alkynoate (14). The alkynoate is then complexed with dicobaltoctacarbonyl in petroleum ether to yield (12) in excellent yield. 

A recent approach to lithium alkynolates involves cleavage of some ynol ethers and esters with methyllithium Desilylation of silyl ynol ethers with methyllithium at room temperature in THF solution leads to the selective formation of the corresponding alkynolates (equation 9) k Similarly, alkynyl tosylates can be selectively cleaved with methyllithium at low temperatures (equation 10). ... 

Both types of reactivity of ynolate anion have been reported in the literature. The O-attack is typical for the reactions of lithium ynolates with trialkylchlorosilanes b24,25 dialkyIchlorophosphates. Lithium ynolates, generated as shown in equations 5-10, react with sterically hindered trialkylchlorosilanes in THF affording silyl ynol ethers as primary products (equation 12). However, in some cases the silyl ynol ethers are unstable at room temperature and isomerization to the more stable ketenes, or decomposition, occurs The ketene rearrangement usually occurs in reactions of lithium alkynolates with methyl substituted silyl chlorides a typical example of such a rearrangement is represented by reaction 13 ". ... 

The analogous reaction of lithium alkynolates with trialkylgermanium and trialkyltin chlorides results in the exclusive formation of the corresponding ketenes. However, a mechanism implying the intermediate formation of the ynol derivatives and their subsequent rearrangement to ketenes cannot be ruled out. 

Reactions of lithium alkynolates with dialkylchlorophosphates afford alkynyl phosphate esters as the major products (equation 14). However, reactions with acyl chlorides under similar conditions results in both O-acylation (product 20) and C-acylation (product 21) (equation 15). ... 

Carbon electrophiles such as ketones and aldehydes react with ynolates, forming exclusively products of C-attack. Addition of phenylethynolate (15) to cyclohexanone affords spirolactone 23, the formation of which can be explained by the cyclization of the originally formed ketene 22 (equation 16) . Similarly, the reaction of lithium alkynolates with benzaldehyde can be rationalized by the intermediate formation of ketene 24 (equation 17), however, the final product in this case is the unsaturated acid 25 but not a lactone... 

Reaction of lithium alkynolates with alcohols is especially useful for organic synthesis as a method of ester homologation . In this case ethyl esters of carboxylic acids 27 are used for the generation of lithium alkynolates in a multistep one-pot procedure (equation 19). Subsequent ethanolysis of lithium alkynolate in the presence of HCl gives homologated esters 28 in good yield. 

To date the most simple and general procedure for the preparation of silyl ynol ethers is the reaction of lithium alkynolates, generated in situ from ethyl esters, with silyl chlorides, according to equation 25 k However, this method (equation 25) does not work for the preparation of siloxyalkynes in which R is a lower alkyl group or hydrogen. Danheiser... 

More recently we have reported the preparation of alkynyl esters by the reaction of lithium alkynolates with the corresponding acid chlorides (equations 14 and 15, Section II.B.2). This method works well for the synthesis of alkynyl phosphates, however, it has only limited applicability in the preparation of alkynyl carboxylates. ... 

One of the most practical ways to achieve chiral propargyl alcohol is to add acetylene anion to a carbonyl group in an enantiofacial manner. This art was well demonstrated by Mukayama et al. in 1979 using (2S,2 S)-2-hydroxymethyl-l-[(l-methylpyrrolidine-2-yl)methyl]pyrrohdine as a chiral ligand. The addition of lithium trimethylsilyl acetylide to benzaldehyde afforded the corresponding alkynol in over 92% optical yield. It is noted that the enantioselectivity of the present reaction depended predominantly on the trialkylsilyl group of the acetylene. Scheme 21.7 confirms these observations. 

Spiroketals.- The discovery that this class of compounds includes insect pheromones has stimulated extensive synthetic effort. A variety of 1,6-dioxaspiro[4.4]nonanesand 1, 6-dioxaspiro[4.5]dec-anes have been prepared by reaction of lithium salts of protected alkynols with equimolar amounts of lactones followed by hydrogena tion and acid-catalysed deprotection and cyclisation (Scheme 16). 

Cyclo-octanone was obtained from cyclo-octanol using 2,2,6,6-tetramethylpiperi-dine and two equivalents of per-acid," and has been converted into diperoxide (332 20% isolated) using H2O2 in the presence of anhydrous methanesulphonic acid. Amine-free monolithium acetylide adds to cyclo-octanone to give a good yield of alkynol. Cyclo-octanone reacts with the lithium salt of the 2-(methylthio) oxazole (333) to give thio-epoxide (334) which was desulphurized to methylenecyclo-octane using triphenylphosphine. ... 

Two further syntheses of (+)-epiquinamide (2104), another of the (—)-enantiomer e t-2104 and one of the racemic alkaloid also pre-date the clarification of the natural product s absolute configuration. The route by Tong and Barker used (S)-(—)-pipecohnic acid (192) as chiral precursor (Scheme 267).After Boc protection of the amine and conversion of the carboxylic acid into the aldehyde 2121, diastereoselective addition of the lithium anion of TBS-protected propargyl alcohol gave mainly the (R)-alkynol (—)-2122 (69%) as well as the separable (S)-product, which was isolated as the cyclic carbamate (—)-2123 (5%). Attempts to invert the configuration of 2122 by treating its mesylate with sodium azide also... 

The transition metal-free addition of sodium phosphides to protected alkynols proceeds under mild conditions to selectively form the 1,1-addition products (Scheme 4.286) [73]. The alcohol was deprotonated prior to the addition of the anionic phosphorus reagent to ensure the selective addition to the alkyne. The lithium alkoxide was hydrolyzed after the P—C bond-forming reaction was obtained. The conditions were extremely mild, and moderate yields of the addition product were obtained. 

Most alkynones are reduced to the corresponding / -alkynols with high (62— 82%) enantiomeric excess using a complex formed from lithium aluminium hydride and the amino-alcohol (10). The asymmetric reduction of ketones by borohydride in the presence of quaternary ammonium derivatives of (25,35)-l,4-diaminobutane-2,3-diol has been described. When lithium aluminium... 

A one-carbcMi ring enlargement approach for the synthesis of 8-lactones has been developed by Satoh and Kurihara [123] (Scheme 76). Reaction of the lithium carbanion of chloromethyl phenyl sulfoxide with lactone 336 afforded a diastereo-meric mixture of the hemiacetal 337. Treatment of this adduct with three equivalents of KH in THF generated potassium enolate 338, which on addition of four equivalents of t-BuLi underwent an alkylidene carbenoid rearrangement to give alkynolate 339. Protonation of 339 by the addition of sulfuric acid facilitated the formation of m-hydroxy ketene 340, which underwent an intramolecular cyclization to afford 8-lactone 341. 

The reaction of monodeprotonated [ C2]acetylene with carbonyl compounds has been exploited as a means of extension of the carbon chain of various terpenes and steroids by two [ " C]carbon atoms. In the simplest case, reaction of potassium [ C2]acetylide with steroid ketone 1 and subsequent acid catalyzed cleavage of the enol ether protecting group gave 17a-[ C2]ethynyltestosterone (2). The sequential addition of deprotonated [ C2]acetylene to carbonyl compounds opens access to symmetrical or unsymmetrical [2,3- C2]alkyn-l,4-diols is exemplified in the synthesis of all-tran -/3-[15,15 - C2]-carotene ([ C2]provitamin A). Thus, treatment of lithium [ C2]acetylide with terpene aldehyde 2 followed by double deprotonation of the resultant alkynol 4 and reaction with a second equivalent of 3 provided alkyne-l,4-diol 5 the requisite key intermediate. Subsequent acid-catalyzed dehydration of 5 followed by Lindlar s catalyst-mediated partial hydrogenation and photoisomerization afforded the final product". ... 

Stereoselective reduction of P- or (o-alkynols to corresponding ( )-alkenols has been achieved by Rossi and Carpita 646) with lithium aluminum hydride. Fyles et al. 647,648) have reported further applications of polymer supports in the synthesis of sex attractants. 

Rossi, R., and A. Carpita Insect pheromones Stereoselective reduction of p- orco-alkynols to corresponding ( )-alkenols by lithium tetrahydroaluminate. Synthesis 1977, 561—562. 

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