Enantioselective direct Mannich reaction

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

Enantioselective Direct Mannich Reaction Products with One Stereogenic Center... 

Figure 3.2 Assumed mechanism of enantioselective direct Mannich reaction catalyzed by chiral phosphoric acid.

Scheme 3.2 Enantioselective direct Mannich reaction of various imines.

Terada et al. found the direct Mannich reaction between iV-Boc-protected aldi-mines 11 and acetyl acetone (12) to be catalyzed by different phosphoric acids 3 (Scheme 6). Varying the aromatic groups at the 3,3 -positions influenced the yields slightly (88-99%), but the enantioselectivities to a high degree (12-95% ee). 

Later in 2007, Gong utilized If and saturated derivative 2 in a direct Mannich reaction between in situ generated N-aryl imines and cyclic ketones as well aromatic ketones (Scheme 5.3) [10], It was found that electron poor anilines as coupling partners gave the highest enantioselectivities. The authors postulate that acid promoted enolization of the ketone forms the reactive enol which adds to the protonated aldimine. 

Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2 with a-imino ester 79 was achieved with high enantioselectivity by the utilization of N-spiro chiral quaternary ammonium bromide le as catalyst (Table 5.14) [42],... 

The phase-transfer-catalyzed direct Mannich reaction of 28 with a-imino ester 64 was achieved with high enantioselectivity by using 32e as catalyst (Scheme 4.23) [63]. This method enables the catalytic asymmetric synthesis of differentially protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the util-... 

Development of the First Brpnsted Acid Assisted Enantioselective Brpnsted Acid Catalyzed Direct Mannich Reaction... 

Uraguchi D, Sorimachi K, Terada M (2004) Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. J Am Chem Soc 126 11804-11805 Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vachal P, Jacobsen EN (2000) Enantioselective catalytic addition of HCN to ketoimines. Catalytic synthesis of quaternary amino acids. Org Lett 2 867-870... 

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

In this review we will attempt to highlight the most important contributions toward the realization of a catalytic, enantioselective, vinylogous Mannich reaction and show the current state of the art. This chapter is organized in such a way that vinylogous Mannich reactions of preformed silyl dienolates in Mukaiyama type reactions will be discussed first followed by direct vinylogous Mannich reactions of unmodified substrates. 

Terada and co-workers reported the direct Mannich reaction of 1,3-pentanedione with N-Boc-aldimines catalyzed by 21c, leading to (3-amino ketones with excellent enantioselectivities (Equation 10.36) [75]. 

Scheme 2.5 Diastereo- and enantioselective direct Mannich-type reaction of aldi-mines with 1,3-dicarbonyl compounds with the use of chiral lithium(i) binaphtholate.

A highly q -selective and enantioselective direct Mannich-type reaction of aldimines 32 and trichloromethyl ketones 33 was developed by Shibasaki using a chiral Pybox (31)-lanthanum(m) lithium(i) heterobimetallic catalyst (Scheme 2.23). The 2-thiophenesulfonyl moiety of 32 can be readily removed by using magnesium metal. Moreover, a trichloromethyl ketone moiety can be transformed to ester, dithiane, and syn- and anti-trichloromethyl carbinols in high yields. 

Ishihara et al. developed a Mg(ii)-binaphthonate catalysed highly enantioselective direct Mannich-type reaction between aldimines 3 and malonates 4 to form adducts 5 (Scheme 3.1). It was speculated that the cooperative acid-base Mg(ii)-BINOL catalyst activates both the aldimine and malonate, and the divalent Mg(ii) centre would be firmly bound to both BINOL and malonate through ionic and coordinate bonds. Indeed, the Mg(ii)-BINOL catalyst prepared in situ from BINOL and dibutylmagnesium under anhydrous conditions could efficiently promote the reaction in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

Q. Guo, J. C.-G. Zhao, Org. Lett. 2013, 15, 508-511. Highly enantioselective three-component direct Mannich reactions of unfunctionalized ketones catalyzed by bifiinc-tional organocatalysts. 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

Scheme 5.98 Enantioselective and diastereoselective direct Mannich reactions catalyzed by...

In 2007, Ooi and coworkers introduced chiral tetraaminophosphonium salts as a new class of Bronsted acids [166]. Similar to the guanidine/guanidinium case, these tetraaminophosphonium salts act as Bronsted bases in their neutral/ deprotonated (triaminoiminophosphorane) form, while they can also be used as mono-functional Bronsted acids in their protonated, phosphonium form. Phos-phonium salt 67, when neutralized in situ with KO Bu, was shown to be a highly effective catalyst in the enantioselective Henry reaction of nitroalkanes with various aromatic and aliphatic aldehydes (Scheme 10.65). The same strategy was further applied to the catalytic asymmetric Henry reaction of ynals [167] and hydrophosphonylation of ynones (Scheme 10.66) [168]. Brfunctional catalysis using this scaffold were also obtained using the carboxylate salts of tetraaminophosphoniums in the direct Mannich reaction of sulfonyl imines with azlactones (Scheme 10.67) [169]. 

---