Conjugate addition followed by alkylation

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

Samuel Danishefsky of Columbia University has also described (J. Am. Chem. Soc. 2005, 127, 8298) a total synthesis of 1, starting from the pyroglutamate derivative 10. Conjugate addition followed by alkylation established the lactam framework. Intramolecular cyclization of 12 gave 13, establishing the aminated quaternary center. The oxygenated quaternary center was then constructed by phenylselenyl-mediatcd cyclization of 14. The end game of this synthesis used the already-established cyclohexenyl zinc addition, which worked as well with 16 as it had with 7. 

The copper-mediated 1,4-addition reactions are thought to proceed through complex electron-transfer mechanisms. The first isolable intermediate is an enolate ion, which can be trapped by alkylating species, as shown in Section 18-4. Conjugate addition followed by alkylation constitutes a useful sequence for a,jS-dialkylation of unsaturated aldehydes and ketones. 

Using the achiral lithium amide derived from Af-trimethylsilylbenzylamine, an enantioselective conjugate addition followed by alkylation has been realized by Tomioka and coworkers by using the chiral additive 1,2-diphenyl-1,2-dimethoxyethane [149]. Various enantioselective conjugate additions of nitrogen, oxygen, and sulfur nucleophiles under in situ protonation of the intermediate enolate, without trapping with other electrophiles have been described [144]. 

This unique pattern is represented in a rather special 2 1 condensation of alkyl isocyanoacetates with aldehydes (equation 129). Mechanistically, an initial conjugate addition followed by an anionic cyclization is likely. Yields of around 60% are obtained (74JOC1980). 

Scheme 3.35. Tetrahydrofurar synthesis by means of MOM a-alkoxy alkyl cuprate conjugate additions followed by Lewis acid-promoted cyclization (MOM = methoxymethyl) [129].

Tandem reactions, in which a second enolate reaction follows on from the first, can allow us to make cyclopropanes (see Chapter 25, p. 586), by conjugate addition followed by C-alkylation, or epoxides, by aldol addition followed by O-alkylation. This epoxide was used in the synthesis of the drug Darusentan. 

Conjugate addition to (35 ,7a/ )-3,7a-dihydro-3-phenyl-l//,5f/-pyrrolof1,2-r ]oxazol-5-onc (8) yields the saturated -substituted bicyclic lactams 9 with complete diastereoselectivity13. Treatment of the latter with 2.2 equivalents of lithium diisopropylamide in tetrahydrofuran at — 78 °C, followed by alkylation with a haloalkane, furnishes the a,/i-dialkylatcd products 10 with excellent selectivity (d.r. >98.5 1.5, determined by H and 13CNMR)13. In this case the major diastereomer has the cw-relationship between the newly introduced substituent (R2) in the pyrrolidine ring and the fused oxazolidinc ring rcsiduc13. 

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

Similarly, conjugate addition of trimethyisilyllithium to hydrazones of a,/(-unsaturated cyclic ketones, followed by alkylation, gives exclusively fra/w-adducts (>98% de) which on hydrolysis produce the corresponding trans-2-alkyl-3-silyl ketones34. 

Complexes of the type (RsQ)2MX2 (R alkyl or aryl Q=P, As, Sb M=Ni, Pd, Pt and X=halogen or pseudohalogen) have been found to catalyze hydrogenation of all but one double bond (68-70) in polyolefins. In the palladium and platinum complexes, catalytic behavior is enhanced by the addition of a compound of the type M Xa or M X4 (M = Si, Ge, Sn, or Pb). The hydrogenation process occurs with very rapid isomerization to the conjugated isomer followed by a rapid reduction to the monoene product. The mechanism shown in Fig. 29 has been proposed for this system. 

Conjugate additions of thioacetals (159) to a,3-unsaturated esters (158) followed by alkylation using iodomethane leads... 

Conjugate addition of organocuprates to a,/S-unsaturated carbonyl compounds, followed by alkylation of the resulting enolates, leads to regiospecific ot, -dialkylation (Boeckman, 1973). This method can be applied to the synthesis of valerane (CCLIX) (Posner et al., 1974,1975a). The enolate intermediates are acylated as well. The method leads to a new synthesis of 7-oxoprosta-glandins (Tanaka et al, 1975). 

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