Organocatalysis by Networks of Cooperative Hydrogen Bonds: Enantioselective Direct Mannich Addition to Preformed Arylideneureas

Abstract

The concept of noncovalent organocatalysis by means of networks of cooperative hydrogen bonds (NCHB organocatalysis) has been explored. Arylideneureas were chosen as ideal substrates because of their powerful donor-acceptor properties. We have examined their uncatalyzed, direct Mannich reaction with acetoacetates in comparison with that catalyzed by a number of salan derivatives capable of providing a network of cooperative hydrogen bonds. Catalyst D [(R,R)-N,N'-bis(salicyl)cyclohexane-1,2-diamine] was found to drive the above direct Mannich reaction in an enantioselective manner, thereby allowing the synthesis of several Biginelli dihydropyrimidinones with high enantioselectivity. DFT calculations (B3LYP-D-PCM/6-31+G*//B3LYP/6-31+G*) revealed that the NCHB organocatalyst lowers the energy barrier of the reaction. The NCHB organocatalysts appear to function as biomimetic catalysts.

Towards Enzyme‐like, Sustainable Catalysis: Switchable, Highly Efficient Asymmetric Synthesis of Enantiopure Biginelli Dihydropyrimidinones or Hexahydropyrimidinones

“…and Ooi et al ,. in which unprecedented organocatalytic capacities of some hydrogen bond networks have been reported (Figure ), we demonstrated that the network of cooperative hydrogen bonds present in salan organocatalysts was capable of driving the direct Mannich addition of acetoacetates (NuH) to preformed arylideneureas (E) in an enantioselective, enzyme‐like manner (Scheme ) and eventually, after acid treatment, gives rise to Biginelli DHPMs …”

“…Actually, best results were obtained when 2 equivalents of TMG were employed, thus leading to enantioselectively enriched HHPMs 2 in good overall yield with a ≈9:1 diasteromeric ratio and a quite high enantiomeric excesses (Scheme ). The relative stereochemistry of the major diastereomer was inferred from their ROESY spectra, and its absolute (4 R , 5 R , 6 S ) stereochemistry deduced from that of the corresponding DHPMs 3 that result by treatment of 2 with aqueous acid . The ROESY spectra also revealed that the minor stereoisomer was the (4 S , 5 R , 6 S ) epimer.…”

“…[9] Following the pioneering work of Rawal et al [10] and Ooi et al [11] ,i nw hich unprecedented organocatalytic capacities of some hydrogen bond networks have been reported ( Figure 1), [12] we demonstrated that the network of cooperative hydrogenb onds present in salan organocatalysts was capable of driving the direct Mannich addition of acetoacetates (NuH) to preformeda rylideneureas (E) in an enantioselective, enzyme-like manner (Scheme1)a nd eventually,a fter acid treatment, gives rise to Biginelli DHPMs. [13] After provingt he NCHB (network of cooperative hydrogen bonds) concept, we aimed at moving as tep aheadt owards enzyme-like, sustainablec atalysis, convincedt hat the limitations found in using preformed,t hough unstable, arylideneureas could be removed by using a-ureidosulfones as precursors. [14] The incoming challenge was to avoid the undesirable effects that the incorporationo fapreliminarya cid-base step mighti nduce upon stereoselectivity and chemical yield, as both the organocatalyst and the NuH reactw ith bases.W e, now,w ould like to report ao ne-pot, scalable, highly efficient, [15] and switchable asymmetric synthesiso feither enantiopure HHPMs or DHPMs starting from a-ureidosulfones, based on an NCHB organocatalyst [16,17] that also functions in the presence of suitable organic bases (Scheme 2).…”

“…Accordingly,t he pK a of NuH should be somewhat higher than that of the conjugate acid of the organicb ase (BH + )e mployed to deprotonate the sulfone. [28] For the opposite case, if pK aEnol < pK aBHþ ,t he enantioselective route that involves the ionp air EH + ·Nu À [13] could be overdue by the racemic one, as plenty Nu À would then be available. [29] Also of great concern was the integrity of the organocatalysts network of cooperative hydrogen bonds under these basic conditions.…”

“…The relative stereochemistry of the major diastereomer was inferred from their ROESY spectra, [40] and its absolute (4R,5 R,6 S)s tereochemistry deduced from that of the corresponding DHPMs 3 that result by treatment of 2 with aqueous acid. [13] The ROESY spectra also revealed that the minor stereoisomer was the (4S,5 R,6 S)e pimer.T his is the first time that an one-pot, syntheticr oute towards diastereoand enantioselectively enriched HHPMs 2 is reported in the literature. [41] As fort he case of DHPMs, we have also explored the preparation of HHPMs in up to 2mmol scale.…”