Enantioselective organocatalytic phosphoric acids

Soon afterward, MacMillan s group properly explored this organocatalytic reductive amination, observing that the ortho-triphenylsilyl phosphoric acid 17n in the presence of 5-A MS facilitates the desired coupling of acetophenone and 4-OMe-aniline in high conversion and with excellent levels of enantiocontrol at 40 C (87% yield, 94% ee) [55]. Authors report also the reduction of the pyruvic acid-derived cyclic imino ester with excellent enantioselectivity. However, implementation of the corresponding ethyl-substituted imine resulted in a dramatic decrease in... 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

Later on, the Rueping group reported an organocatalytic enantioselective reduction of pyridine 180 (Scheme 17.30) [74], according to the procedure described by Bohlmann and Rahtz [75]. The key step in the synthesis of decahydroquinolines from the pumiliotoxin family involved Hantzsch dUiydropyridine 172 as the hydride source and involved BINOL-phosphoric acid 181 as a chiral Br0nsted acid catalyst... 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

Similarly, using BINOL phosphoric acid catalyst 191, Hiemstra and co-workers developed an organocatalytic Pictet-Spengler (PS) reaction of tryptamine derivative 189 and 4 -oxo-pentanal 190 as a key step to achieve the key intermediate 192 (86% yield, 89% ee), which was then converted to (—)-arboricine (193) [78] by a sequence of reactions including diasteroselective Pd(0)-catalyzed iodoalkene-enolate cycUza-tion (33% overall yield, 6 steps) (Scheme 17.32) [79]. Importantly, only 1 mol% loading of catalyst 191 on a 10 mmol Pictet-Spengler (PS) reaction scale gave the compound 192 in 92% yield, but with relative low enantioselectivity (78% ee). 

Gong and co-workers [80] developed an organocatalytic enantioselective nucleophilic substitution reaction of 3-hydroxyoxindoles with enecarbamates catalyzed by chiral phosphoric acid, which provided a new approach for the preparation of 3,3 -disubstituted oxindoles with a quaternary all-carbon stereogenic center. They demonstrated the efficiency of this methodology in the enantioselective construction of (-h)-folicanthine (198) (Scheme 17.33). Under the optimized reaction conditions, the enantioselective substimtion reaction of 194 with enecarbamate 195 using catalyst 196 afforded 197 in 82% yield and 90% ee. Compound 197 was then transformed into (+)-folicanthine (198) by a 12-step sequence in 3.7% overall yield. 

A highly enantioselective organocatalytic Friedel-Crafts aminoalkylation of indoles with in situ generated imines was reported by Zhang s group using a multicomponent approach. Chiral phosphoric acid 121 as an efficient catalyst... 

Gong and coworkers reported the first enantioselective organocatalytic Biginelli reaction (Scheme 9.8) [44]. Thus, chiral phosphoric acid 29 efficiently activated the process between an aldehyde 10, a thiourea 24 or urea 11,... 

It worth to mention that despite the importance of the Kabachnik-Fields reaction, stereoselective versions for the synthesis of enantioenriched a-aminophosphonates are scarce [212, 213], and only few enantioselective examples have been published to date (for reviews on enantioselective catalytic direct hydrophosphonylations of imines, see Refs. [162a-c]). Organocatalytic examples use well-known chiral binol-derived phosphoric acid organocatalysts (Fig. 12.6,80 and 81) [214], and regarding metal catalysis, chiral scandium(III)-A,A -dioxide and... 

An organocatalytic, enantioselective version of this reaction was reported in 2013 by Lin s group, which was based on the use of a chiral SPINOL-phosphoric acid derivative 35 as catalyst (Figure 3.3) [28]. This process proceeds in moderate to good yields (39-65%) and in very good diastereo (dr up to 20 1) and enantioselectivities (ee up to 99%). 

The first asymmetric organocatalytic synthesis of helicenes (182) has been reported by List et al. A novel SPINOL-derived phosphoric acid (183), bearing 7i-extended pirenyl substituents, catalysed asymmetric synthesis of helicenes (182) through an enantioselective Fischer indole reaction (Scheme 48). °... 

Quite recently. Rueping et al reported Nazarov cyclization reaction catalyzed by a phosphoramide (Scheme 2.107) [185]. Although phosphoric acid (41k) is effective for the Nazarov reaction, use of an N-triflyl phosphoramide (50b) improved the enantioselectivity. This is the first example of the enantioselective organocatalytic electrocyclization reaction. 

List has developed the concept of asymmetric counter-ion directed catalysis and applied it in organocatalytic transformations. One of the first pioneering studies in the synergic use of organocatalyst and transition metal was the combination of a Pd(0) catalyst with a chiral phosphoric acid in a highly enantioselective Tsuji-Trost type a-allylation of branched aldehydes (Scheme 26.12) [81]. 

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