Secondary amines aldol reaction, stereoselectivity

Thioamides of secondary amines are deprotonated with isopropyhnagnesium to give (Z)-enolates. Thioamides of primary amines react with two equivalents of /-PrMgBr to afford dianions that have been shown to have the (Z)-configuration. These magnesium species are versatile intermediates in stereoselective aldol reaction (equation 50, Table 5 ... 

The detailed mechanistic explanation pictures the initial weak interaction among the bifunctional thiourea catalyst 158, the malonic ester 157 as nucleophile, and the nitroalkane 140 as electrophile that should promote the first chemo- and stereoselective Michael addition. The resulting adduct A would be poised to participate directly in the second catalytic cycle by acting as donor in a regioselective ititro-Michael reaction with the a,p-unsaturated aldehyde 95, here activated as iminium ion by the secondary amine catalyst (5)-76. The new inteimediate B, with its aldehyde and malonate moiety suitably spatial disposed, would undergo a base-promoted aldol cychzation to efficiently generate the planned cyclohexanol 159 in moderate yield (up to 87%) and marvelous enantioselectivity (up to >99% ee). 

In 2009, Bella et al. reported a formal [4 + 2] cycloaddition of substituted atylacetaldehydes and 2-cyclohexen-l-one which was promoted by a chiral thiazolidine catalyst and chiral quinine via enamine formation and spontaneous intramolecular aldol reaction (Scheme 2.4). The stereoselection depended upon the secondary amine catalyst, whereas the secondary catalyst was involved in the enhancement of the nucleophilicity of the derived enamine, probably through deprotonation of the carboxylic group. There... 

Although the number of successful applications of primary amino acids in stereoselective organocatalysis is far fewer than for the secondary amine, a few interesting examples are worth pointing out. The diversity of primary amino acids in aldol and Mannich reactions has been reviewed recently [48]. Several primary amino acids, such as alanine, valine, tryptophan, and threonine have been used as orga-nocatalysts. For instance, Barbas and coworkers have demonstrated the use of a L-threonine catalyzed protocol towards the synthesis of syn-l,2-diols through direct aldol reaction between a-hydroxyketones and para-nitrobenzaldehyde (Figure 17.13) [49]. 

The most famous secondary amine employed in organocatalysis is prohne. In addition to the examples reported in the introduction regarding the use of proline under aqueous conditions, it is worth further describing other applications of proline under the same conditions. No enantioselectivity was observed in prohne-catalyzed aldol reactions in phosphate buffer [38] and aqueous micelles [39]. When proline was used with camphorsulfonic acid as co[Pg.682]

Barton oxidation was the key to form the 1,2-diketone 341 in surprisingly high yield, in order to close the five-membered ring (Scheme 38). The conditions chosen for the deprotection of the aldehyde, mercuric oxide and boron trifluoride etherate, at room temperature, immediately led to aldol 342. After protection of the newly formed secondary alcohol as a benzoate, the diketone was fragmented quantitatively with excess sodium hypochlorite. Cyclization of the generated diacid 343 to the desired dilactone 344 proved very difficult. After a variety of methods failed, the use of lead tetraacetate (203), precedented by work performed within the stmcmre determination of picrotoxinin (1), was spectacularly successful (204). In 99% yield, the simultaneous formation of both lactones was achieved. EIcb reaction with an excess of tertiary amine removed the benzoate of 344 and the double bond formed was epoxidized with peracid affording p-oxirane 104 stereoselectively. Treatment of... 

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