Organocatalytic reactions, enantioselection phosphoric acids

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]. 

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. 

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. 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

The enantioselective organocatalytic functionaUzation of carbonyl compounds at the 7 position represents a highly challenging and persistent problem for asymmetric synthesis [33]. Recently, Melchiorre and coworkers [34] reported a chiral Bronsted acid-assisted dienamine catalysis for the direct asymmetric y-alkylation of a-substituted linear a,(l-unsaturated aldehydes (Scheme 43.22). In this reaction, the chiral phosphoric acid 106 can induce the formation of a chiral contact ion-pair from alcohol 103 [35], which may synergistically engage in a matched combination with the chiral covalent dienamine intermediate derived from chiral primary... 

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