Lithium amide conjugate addition

Since their isolation over 40 years ago, there have been several syntheses of the homahum alkaloids (—)-homaline (1), (—)-hopromine (2), (—)-hoprominol (3), and (—)-hopromalinol (4). In by far the most high yielding strategy, we have employed our lithium amide conjugate addition... 

Abraham, E., Brock, E.A., Candela-Lena, J.I., Davies. S.G., Georgiou, M., Nicholson, R.L., Perkins, J.H., Roberts, P.M., Russell, A.J., Sanchez-Femandez, E.M., Scott, P.M., Smith, A.D., and Thomson, J. E. (2008) Asymmetric synthesis of N,0,0,0-tetra-acetyl o-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylUne via lithium amide conjugate addition. Org. Biomol. Chem., 6,1665—1673. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

In 1994, lithium amide 23 was used in the conjugate addition of 2-cyclohexenone to afford optically active adduct with up to 97% ee (Scheme 13).28-29 A dimeric structure was proposed as the intermediate, where the phenyl group in 23 blocked the bottom face and the cyclohexenone substrate approached from the upper face. 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

Methylbenzoic acid 513 can be laterally lithiated with two equivalents of lithium amide base (LDA" or L1TMP °) or alkyllithium provided the temperature is kept low to avoid addition to the carbonyl group (Scheme 201). It is usually preferable to carry out the lithiation using aUcyllithiums", since with lithium amides the subsequent reaction of 514 with electrophiles is disrupted by the presence of the amine by-product (diisopropylamine, for example) . The dilithio species 514 is stable in THF even at room temperature, and (as with the amide 483) since LDA will also dilithiate 515 stabilization presumably comes principally from conjugation with the carboxylate. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

We have already established that RCHO and RCOC1 are poor at conjugate addition while ketones and esters are better. An extreme example is the amide 61 that does conjugate addition even with the lithium enolate 60 of cyclohexanone.8... 

The reactivity of 2-alkyloxazoles in base-catalyzed additions and condensations is due to the intermediacy of delocalized anions analogous to (142). 2-Methyl-4,5-diphenyloxazole forms the adduct (278) by the action of benzophenone in liquid ammonia containing lithium amide (equation 89), and 2-methylbenzoxazole condenses with diethyl oxalate in the presence of potassium ethoxide to yield the keto ester (279). Anions with more extended conjugation are involved in the condensation of 2-(propen-l-yl)benzoxazole with diethyl oxalate (equation 90) and in the formation of the stilbene derivative (280) from 5-phenyl-2-p-tolyloxazole and benzylideneaniline (78AHC(23)l7l). 

The ability of lithium amides to add on enoates to provide lithium enolates has been known for some while161. This reaction has found many useful synthetic applications, one of the most spectacular being the tandem, stereocontrolled, conjugate additions (Scheme 38)162. 

SCHEME 39. Diastereoselective conjugate addition of Davies chiral lithium amide followed by diastereocontrolled oxidation of the intermediate enolate169... 

Alkyl (/f)-3-[Af-Alkyl-(/ )-l-phenylethylamino butanoates (21) by the Conjugate Addition of Secondary Lithium Amides to Alkyl ( )-2-Butenoates General Procedure24 ... 

In the total synthesis of (—)-secodaphniphylline, an asymmetric [l,4]-conjugate addition was used to establish relative and absolute stereocontrol.The lithium enolate of a trans-2,5-dimethylpyrrolidine-derived amide adds in a Michael fashion to a cyclic a,p-unsaturated ester, with subsequent enolate trapping, to afford the desired product in 64% yield and 92 8 diastereose-lection (eq 6). 

A useful technique to accomplish overall vicinal dialkylation of enones is to trap the enolate initially formed in the conjugate addition with TMS-Cl, and then regenerate the enolate under suitable conditions for its alkylation. Lithium 1-enolates of 3,5-dialkylcyclohexanones generated from the reaction of the corresponding TMS enol ethers with lithium amide in liquid ammonia-THF can be alkylated efficiently in liquid ammonia-THF, even with an unreactive alkylating agent such as n-butyl iodide (Scheme 10). ... 

Patterson and Fried found that the clean lithium enolate (14), generated by conjugate addition of the lithium divinylcuprate (15) to cyclopentenone with subsequent trapping of the initial enolate with TMS-Cl and cleavage of the TMS enol ether with lithium amide in liquid ammonia-THF, could be alkylated in a reasonable yield with the (Z)-allylic iodide (16) to give the 11-deoxyprostaglandin derivative (17 ... 

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