Pictet asymmetric

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

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>. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

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... 

Figure 6.17 Pyrrole thiourea derivatives evaluated for catalytic activity and selectivity in the asymmetric acetyl-Pictet-Spengler reaction.

Scheme 6.52 Products of the asymmetric Pictet-Spengler-type cyclization of p-indolyl ethyl hydroxylactams catalyzed by 53.

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

An asymmetric carbon-transfer reaction was also performed by using 2-(/>-tolyl)sulfmylmethyltetrahydro-l,3-oxa-zine 143 as the chiral aldehyde equivalent in the Pictet-Spengler ring closure with tryptamine, but only moderate diastereoselectivity ( 40% de) was observed in favor of the (l/ )-tetrahydro-/3-carboline 165, and the enantiopure main product could be isolated only in low yield (Scbeme 26) <2001H(55)1937, 2004T9171>. 

Chirality can be induced at the C-l position by the cyclization of o-vinylphenethylamine in the presence of a chiral selenium reagent (Equation 68) <1998S162>. Removal of the selenide gives the 2-methyltetrahydroisoquinoline. The use of the Pictet-Spengler reaction in the asymmetric synthesis of tetrahydroisoquinolines remains active. Therefore the intramolecular reaction of /3-iminosulfoxide 33 yields the chiral product 34 (Equation 69) <1998EJ0435>. 

The Pictet-Spengler reaction, the cyclization of an electron-rich aryl or heteroaryl group onto an imine electrophile, is the established method for the synthesis of tetrahydroisoquinoline and tetrahydro-/ -carboline ring systems. Catalytic asymmetric approaches to these synthetically important structures are mostly restricted to asymmetric hydrogenations of cyclic imines [77, 78]. In a noteworthy... 

Do optically active 1-methyl-TIQs, as sketched in Fig. 32 for the synthesis of (7 )-salsolinol, originate from a Pictet-Spengler reaction of dopamine with acetaldehyde derive from ethanol, or are they the result of a Pictet-Spengler reaction of biogenic amines with pyruvic acid, as sketched in Fig. 33 Based on the accumulated data it seems reasonable to propose that optically active TIQs are formed by the pyruvic acid pathway, and that the pyruvic acids may be derived from an impaired glucose metabolism or an impaired amino acid metabolism. Whether the intermediate TIQ-1-carboxylic acids 91a,b are enzymatically decarboxylated to afford 64a,b in a different enantiomeric ratio, or whether optically active TIQs are formed by oxidative decarboxylation of TIQ 91 to DIQ 120, followed by an asymmetric reduction, remains open to question. 

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

In view of the multifold important biological activities of isoquinoline and P-carboline alkaloids, increasing efforts have been made to perform Pictet-Spengler reactions stereoselectively. The most obvious chiral auxiliary to induce asymmetric control is the stereogenic center of the corresponding aromatic amino acids, such as DOPA or tryptophan. 

The second procedure worth presenting involves the Michael addition of tryptophan ester (22) to pro-pynoate ester (33 R = H) to give (34 R = H), and subsequent acid-induced cyclization via the iminium salt (35 R = H Scheme 19), to afford tetrahydro-P-carboline (36 R = H), which could not be prepared by the simple Pictet-Spengler reaction with malonic hemialdehyde. Again, asymmetric induction can be achieved through the amino acid derived ester function. Extension of this procedure to... 

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. 

To reach our target molecule, the routes involving the cycUzation step looked particularly attractive. The Bischler-Napieralski or related Friedel-Crafts route offers the potential for an asymmetric synthesis through enantio- or diastereoselective reduction of the imine penultimate intermediate, whereas the Pictet-Spengler approach is the shortest possible pathway. 

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