Dienolates Michael additions

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

Michael addition of tin(II) dienolates.1 The tin(II) dienolates of (3,y-enones undergo y-selective addition to acyclic ot,(3-enones to give frans-l,7-enediones. If the reaction is carried out at high dilution, the intermediate tin(II) enolate can undergo an intramolecular aldol cyclization to give a cyclohexenol. 

A double ir-face selective aptotic Michael addition of the lithium dienolate, derived from the chiral senecioate (119), to cyclopentenone served for the total synthesis of (-)-kushimone (120 Scheme 45).137-138 The selectivity of the key reaction was rationalized by the assumption of a transition state as shown in (121a). A related approach involves the Michael addition of enolates, derived from chiral propionates, to methyl ( )-crotonate (Scheme 46).139 The formation of the threo isomer (122) as the major product indicates a transition state structure as shown in (121b). This method was utilized in the synthesis of the marine natural product 7,20-diisocyanoadociane (123 Scheme 47).140... 

Sequential double Michael addition of cyclic dienolates, generated from (107) or (108), to fulvene (109) has been developed as a method for rapid access to the tricyclo[5.3.0. 2,5]alkane system (Scheme 24).90... 

In an asymmetric approach to the bicyclo[2.2.2]octane ring system, a double Michael addition has been employed using phenylmenthyl acrylate as the initial Michael acceptor. The condensation of the dienolate, generated with Lithium Diisopropylamide, reacts with the acrylate to afford the bicyclo[2.2.2]octane derivative (eq 6). The de for the reaction is only 50% however, it is highly endo selective (>95%). ... 

Not surprisingly the dienolate dianion from a carboxylic acid can also be generated by a cyclization reaction of the sort described in Scheme 2.31. Intramolecular Michael addition of the phenolate 4.5 (half-life 60 s at 39 °C) [70] gives the dianion... 

Ester enolates. Oppolzer showed in 1983 that the Z(Gj-dienolate shown in Scheme 5.30a adds to cyclopentenone with 63% diastereoselectivity [160]. Additionally, the enolate adduct can be allylated selectively, thereby affording (after purification) a single stereoisomer having three contiguous stereocenters in 48% yield. The transition structure illustrated is not analogous to any of those illustrated in Scheme 5.29 because cyclopentenone is an s-trans-Z-enone, whereas the enones in Scheme 5.29 are s-cis-E. In 1985, Corey reported the asymmetric Michael addition of the EfOj-enolate of phenylmenthone propionate to -methyl crotonate as shown in Scheme 5.30b [161]. The product mixture was 90% syn, and the syn adducts were produced in a 95 5 ratio, for an overall selectivity of 86% for the illustrated isomer. The transition structure proposed by the authors to account for the observed selectivity is similar to that shown in Scheme 5.29c, but with the enone illustrated in an s-trans conformation. Intramolecular variations of these reactions were reported by Stork in 1986, as illustrated in Scheme 5.30c and 5.29d [162]. Two features of... 

The Michael addition of the dienolate anion (90), readily generated from 1-trimethylsilyloxybuta-1,3-diene, to suitable acceptors provides an attractive alternative to the Diels-Alder reaction (Scheme 22). ... 

In efforts towards a synthesis of eremolactone, the dienolate (158) has been found to react with the cyano-ester (159) to give (160) (probable stereochemistry shown) most likely via a double Michael addition rather than a Diels-Alder reaction. Highly substituted cyclohexanes have been prepared by cycloadditions between cyclohexa-1,3-dienes and nitroso-compounds followed by N—O and olefinic bond cleavage (Scheme 12). ... 

Hong and coworkers [62] reported a sequential double-Michael addition of lithium dienolates 255 to pentafulvene 47 (Scheme 7.56). The reaction provides an efficient route to the tricyclo[5.3.0.w ]alkane ring systems 256. In addition, the reaction is attractive as two bonds and three stereocenters are formed in one step with high stereoselectivity. 

Aside from Coreys phenylmenthyl propanoate 424, several chiral enolates have been utilized for Michael additions with substantial degrees of diastereoselectiv-ity. Yamaguchi s group developed a series of chiral amide enolates 436 and studied the conjugate addition to crotonates [210]. Another remarkable early contribution came from Oppolzer and coworkers who used dienolate 437 for diastereoselec-tive consecutive additions to cyclopentenone and allylation [211]. The auxiliaries 436 and 437 served for total syntheses of terpenoid natural products. Diastereos-elective Michael additions were also achieved by means of imidazolidinone-based lithium enolate 438 [212] - another showcase of the efficiency of imidazolidinone 118 [54] (Scheme 4.94). 

The use of silyl dienolates in additions to iminium ions is known as the vinylogous Mannich reaction and constitutes an important expansion of this classic. Inter- and intramolecular versions of this transformation have been studied in great detail by Martin in the context of numerous total syntheses [110, 117]. As an example, silyl dienolate 128 intercepted iminium ion 127 to yield adduct 129 in 69% yield (Scheme 11.20) [118]. Subsequently, this adduct could be efficiently converted into 131 by addition to methyl vinyl ketone and intramolecular Michael reaction. Further elaborations of this key intermediate afforded the indole alkaloid (-)-ajmalicine (132). 

Scheme 1.20. Double Michael-type addition of dienolate 220 to Cgo, affording after workup the thermodynamically more stable Irans-disubstiluted ketone ( )-219. Due to steric congestion, the corresponding civ-adduct is not available through Diels-Alder reaction with the silyl enol ether corresponding to 220. Reduction of the racemic ketone ( )-219 with DIBAL-H diastereoselec-tively affords alcohol ( )-223.

Enders and coworkers [300] used the lithiated carbanion of the chiral ami-nonitrile 1.70 as a Michael donor. Additions of this species to a,P-unsaturated esters are performed at -100°C. After removal of the chiral residue with aqueous CuS04, 3-branched-4-ketoesters are obtained with a high enantiomeric excess (Figure 7.66). 2-Cyclohexenone can also be used as an acceptor with equally good results [1453], Dienolate 7.100 has also been proposed as a chiral Michael donor [1454], but its reactions with a,p-unsaturated aldehydes give low chemical yields. 

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