Amides, conjugate addition

Michael additions to conjugated carbonyls can be catalyzed by gold species. Among them, arene additions are the most studied area but other nucleophiles can attack the gold-coordinated enones as well. In fact, the intermolecular aza-Michael additions of carbamates to enones was reported in 2002 with both Au(I) and Au(III) salts, and in 2007 an intramolecular aUcoxide and amide conjugate addition has been developed and applied to the synthesis of (+)-andrachcinidine (equation 132). In the latter case, the enones are formed as intermediates in a previous gold-catalyzed step that is the hydration of an alkyne and methanol loss. Then the cyclization takes place to give piperidines. 

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. 

One of the reactions used in determining the sequence ot nucleotides in a strand of DNA is reaction with hydrazine. Propose a mechanism for the following reaction, which occurs by an initial conjugate addition followed by internal amide formation. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

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%). 

Alternatively, to avoid difficult separation of diastereomers 18a and epi-18a, the Fmoc-y9 -amino acid of unlike configuration 26 can be obtained as a single dia-stereoisomer in a three-step reaction sequence via conjugate addition of the Li-amide derived from (S)-N-benzyl-l-phenylethylamine (Davies methodology [113]) to tert-butyl tiglate [105] (Scheme 2.3). 

Conjugate addition can also be carried out by fluoride-mediated disilylation. A variety of a, (3-unsaturated esters and amides have been found to undergo this reaction.136... 

Silyl esters of trivalent phosphorus acids have been used successfully in conjugate addition reactions using acrylates,393 395 nitriles,394 amides,396 397 ketones and aldehydes,398-404 and nitro compounds.387... 

A wide range of substrates have been reported to proceed successfully to conjugate addition products with the monobasic forms of phosphorous acids, including esters,371415416 amides,417-419 nitriles,415 420 acid chlorides,421 enamides,375 and nitro compounds.422-424... 

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). 

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