Alkyl-substituted enals

An alternate approach, pioneered by Kunz and MacMillan, proceeds by reaction of sulfur ylides with a,(3-unsaturated iminium ions, formed by reaction of a,p-enals with enantiomerically pure amines. In this approach the sulfur ylide (9.87) reacts with a range of (3-aryl- and P-alkyl-substituted enals, including (9.88), in the presence of the dihydroindole (9.89) to give the cyclopropane with ees ranging from 89 to 96%. More recently, it has been shown that replacement of the carboxylate functional group in (9.89) with an isosteric tetrazolic acid gives an improved catalyst that effects cyclopropanation with 99% ees in all cases studied. 

Bis(phenylsulfonyl)methane has also been employed as an acidic carbon pronucleophile related to malonates and 1,3-diketones with success in the Michael reaction with ot,p-unsaturated aldehydes using 31c as catalyst (Scheme 3.6). The reaction showed a remarkable substrate scope when alkyl-substituted enals were employed but failed when cinnamaldehyde was tested as Michael acceptor. Alternatively, a more acidic cyclic gem-bissulfone has been used as Michael donor, keeping the high yields and enantioselectivities observed for the reaction and also allowing to expand the scope of the reaction to several aromatic enals.In all cases, the chemistry of the sulfonyl group was employed to generate a methyl group after metal-mediated desulfuration or, alternatively. 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

An interesting synthesis of highly enantioenriched acyclonucleosides has been described employing as key step the addition of 9//-purines to alkyl substituted enals catalyzed by 7 (Scheme 11.19 (c)). Acyclonucleosides, which are potential antiviral drags, were obtained in 82-89% yield and up to 99% ee. 

Synthesis of y-Lactams. The Lewis acidic properties of Mg(OrBu)2 and Lewis basic properties of carbenes have been exploited in a cooperative catalytic cycle leading to the elegant synthesis of y-lactams. The reaction is a formal [3+2] cycloaddition, and the Mg alkoxide base is presumed to be involved in chelation to the hydrazone species 7. Thus, in the presence of 5 mol % Mg(OrBu)2,5 mol % L, and 15 mol % TBD as the base, 9 is obtained in 78% yield with 7 1 dr and 97% ee (eq 3). The reaction tolerates a wide variety of aryl-substituted hydrazones and a. -unsaturated aldehydes, while alkyl-substituted enals furnish moderate yields. 

Dienamine is a recent extension of the enamine concept to extended donors by using the principle of vinylogy. By extension of the enamine to conjugated dienamine starting from alkyl substituted enals or enones, it allows for the functionalization of a,p-unsaturated carbonyls in a- or 7-position using various electrophiles (Scheme 11.26). This potential of amine catalysts to promote extended functionalization is highly interesting, but because of its relative infancy, few synthetic applications of such activation have been reported to date. 

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

The Michael-type addition of thiols to a,p-unsaturated aldehydes has been reported to proceed very efficiently using O-TMS protected diarylprolinol 31c as catalyst (Scheme 3.32). The low configurational stability of the adducts at r.t. led the authors to modify the reaction conditions, which finally involved carrying out the reaction at -24 °C and reducing the adducts in situ, furnishing the corresponding y-thio alcohols in excellent yields and enantioselectivities. Both alkyl- and aryl-substituted enals could be used as suitable Michael... 

Vicario reported that cyclopropanation also works well in water.Using typical Cl catalyst, the reaction worked well with p-aryl substituted enals, however, it failed with alkyl enals. Therefore, they used a 4-hydro3gr>roliii derived catalyst with a long aliphatic chain C2b (Figure 8.3). Later, this laboratory introduced a dialkylamino group in the 4 position of the... 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

One of the first synthetic applications of organoboranes in radical chemistry is the conjugate addition to enones (Scheme 23, Eq. 23a) and enals reported by Brown [58-61]. Addition to -substituted enones and enals are not spontaneous and initiation with the oxygen [62], diacetyl peroxide [63], or under irradiation [63] is necessary (Eq. 23b). A serious drawback of this strategy is that only one of the three alkyl groups is efficiently transferred, so the method is restricted to trialkylboranes derived from the hydroboration of easily available and cheap alkenes. To overcome this limitation B-alkylboracyclanes have been used but this approach was not successful for the generation of tertiary alkyl radicals [64,65]. 

Fp-substituted enones and enals undergo cyclocarbonylations on treatment with metal hydrides or metal alkyls to provide y-lactones (Scheme 1.15) [45], Similarly, electron-rich primary amines afford dihydropyrrolones with iron-substituted (Z)-enals in the presence of titanium tetrachloride and triethylamine [46],... 

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