Asymmetric Pictet—Spengler Reaction

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

In 2007, Hiemstra et al. established a catalytic asymmetric Pictet-Spengler reaction that proceeds via (V-sulfenyliminium ions (Scheme 15) [27], Treatment of iV-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f (5 mol%, R = 3,5-(CF3)2-CgH3) afforded tetrahydro-P-carbohnes. After completion of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot... 

Yu, P., Wang, T., Li, J., Cook, J. M. Enantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine and Talcarpine as Well as the Improved Total Synthesis of Alstonerine and Anhydromacrosalhine-methine via the Asymmetric Pictet-Spengler Reaction. J. Org. Chem. 2000, 65, 3173-3191. 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

In 1988, Zhang et al. ° achieved the synthesis of the optically active tetracyclic ketone 160, in a stereospecific fashion by employing the asymmetric Pictet—Spengler reaction. Many improvements have been made to prepare both the Na-H and the Na-Me tetracyclic ketones (158 and 160, respectively). The Pictet—Spengler reaction is now carried out in one pot to provide only the desired iraws-diastereomer with high diaster-eoselectivity and enantioselectivity. As illustrated in Scheme 2, after Nb-benzylation of d-(+)-tryptophan methyl ester (156) with benzaldehyde and sodium borohydride in methanol, trifluoroacetic acid (TFA) was added to the reaction vessel at 0 °C to neutralize the reaction mixture. After removal of the solvent, CH2CI2, TFA, and methyl 4,4-dimethoxybutyrate... 

Scheme 6.21 Asymmetric Pictet-Spengler reactions reported by Jacobsen and by List.

In 2012, You and co-workers developed a cascade ring-closing metathesis/ isomerization/asymmetric Pictet-Spengler reaction, employing ruthenium complex (Hoveyda-Grubbs II catalyst) and chiral phosphoric acid as the... 

Stronger Brpnsted acids have also been applied to this reaction. List and coworkers used the phosphoric acid 125 to fairly good effect in the asymmetric Pictet-Spengler reaction of indole 124 and a range of aldehydes (Scheme 1.30) [40]. However, the limitation of this approach was the requirement for a diester functionality to control the electronic properties of the primary amine. 

Scheme 5.40 Br0nsted-add catalyzed asymmetric Pictet-Spengler reaction...

More recently, Jacobsen s group [67] developed a similar approach under dual catalysis combining a chiral thiourea and a weak Brpnsted acid for the enantioselective synthesis of A-unsubstituted carboline derivatives. Alternatively, Hiemstra and co-workers [68] considered the use of A-sulfenyliminium ions as intermediates in the asymmetric Pictet-Spengler reaction in the presence of chiral phosphoric acids. Due to the easy acid-mediated removal of the sulfenyl group, this methodology is also powerful for accessing A-unsubstituted products. 

In 2008, a similar asymmetric Pictet-Spengler reaction was applied to the total synthesis of (+)-yohimbine (209) (11 steps, 14% overall yield), an important member of the monoterpenoid indole alkaloids as shown in Scheme 17.35 [82]. The synthesis involved two key steps, which are the acyl-Pictet-Spengler reaction of tryptamine derivative 199 with aldehyde 203 (97% ee) and a stereoselective intramolecular Diels-Alder reaction of 206 with the simultaneous generation of four new stereogenic centers [83]. 

NCS catalyzes isoquinoline formation via an asymmetric Pictet-Spengler reaction (ii). The reaction entails an acid-catalyzed electrophilic addition of an iminium ion. The mechanism is a two-step process in which the iminium ion is generated first from the condensation reaction between the aldehyde carbonyl (such as 4-HPAA) and dopamine. Two types of NCS (CjNCSl and CjPRlOA) have been isolated from Coptis japonica cells and characterized [21]. CjPRlOA has been sufficiently expressed in an active form in E. coli. Conversely, CjNCSl forms a larger complex in plant cells. Therefore, the recombinant enzyme expressed in E. coli cells has considerably lower activity than that of the native enzyme. 

Review on asymmetric Pictet-Spengler reaction Lorenz, M., van Linn, M.L., and Cook, J.M. (2010) Curr. Org. Synth., 7,... 

Seayad J, Seayad AM, List B (2006) Catalytic asymmetric Pictet-Spengler reaction. J Am Chem Soc 128 1086-1087... 

SCHEME 2.6 Phosphoric acid-catalyzed asymmetric Pictet-Spengler reactions. 

Kinetic isotope measurements for the cyclocondensation step of the Knorr pyrrole synthesis suggest that two protic solvent molecules participate in a rate-determining ketone protonation before cyclization and dehydration. Chiral SPDqOL-phosphoric acids (39) promote asymmetric Pictet-Spengler reactions (Scheme 27). i... 

Tian et al. have presented catalytic asymmetric Pictet-Spengler reactions of 4-(2-aminoaryl)indoles (263) with imines (264) in the presence of a commercially available chiral phosphoric acid (261) to give indolo[3,4-cd][l]benzazepines (265) in good to excellent yields and ee (Scheme 68). Enantioselective direct amination of enamides (266) with azodicarboxy-late (267) catalysed by chiral, non-racemic calcium bisphosphate complex (270), afforded optically active products (268-269) (Scheme 69). ... 

Wang et al. have developed an efficient SPINOL-phosphoric acid (160) catalysed asymmetric Pictet-Spengler reaction of a-naphthylmethyl ttyptamines (158) with a wide range of aliphatic and aromatic aldehydes, affording a series of highly enantioenriched tetrahydro-) -carboline derivatives (159) (Scheme 57)7 ... 

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