Enantioselective Pictet Spengler reaction

Scheme 3.23 Enantioselective Pictet Spengler reaction of tryptamine derivatives with aldehydes.

Recent efforts pertaining to direct attachment of chiral sidechain to a heteroarene show that enantioselective Pictet-Spengler reaction is achievable in the presence of a multifunctional thiourea An interesting observation is that annulation of pyrroles by this method (with 17) can give different isomers from CC bond formation at an a- or 3-carbon ... 

SCHEME 32.18 Enantioselective Pictet-Spengler reactions catalyzed by norcoclaurine synthase. 

Yamada, H., Kawate, T., Matsumizu, M., Nishida, A., Yamaguchi, K., Nakagawa, M. 1998. Chiral Lewis acid-mediated enantioselective Pictet-Spengler reaction of V(,-hydroxytryptamine with aldehydes. 

Eric N. Jacobsen of Harvard University has devised a family of catalysts for the enantioselective Pictet-Spengler reaction of tryptamine 21. He has now (Organic Lett. 2008, 10, 745) used this approach to prepare the triene 22 in 94% ee. The Diels-Alder cyclization of 22 proceeded with high diastereocontrol to give 23, the immediate precursor of (-)-yohimbine 24. 

List et al. reported enantioselective Pictet-Spengler reaction [176]. On treatment of an aldehyde with geminally disubstituted tryptamine in the presence of (41e) (20mol%) and Na2S04, in situ generated aldimine underwent Pictet-Spengler reaction to furnish tetrahydro P-carbolines in excellent enantioselectivity (Scheme 2.101). It is noted that the presence of geminal substituents on the tryptamine is essential for the reaction to proceed. 

SCHEME 2.78 Regio- and enantioselective Pictet-Spengler reaction of pyrrolo-hydroxylactams. 

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>. 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

Scheme 6.50 Typical tetrahydro-P-carbolines prepared with the 52-catalyzed enantioselective acetyl-Pictet-Spengler reaction.

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004,126, 10558) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2. 

Tatsui G (1928) Synthesis of carboline derivatives. J Pharm Soc Jpn 48 453 159 Taylor MS, Jacobsen EN (2004) Highly enantioselective catalytic acyl-pictet-spengler reactions. J Am Chem Soc 126 10558-10559 Terada M, Uraguchi D, Sorimachi K, Shimizu H (2005) Process for production of optically active amines by stereoselective nucleophilic addition reaction of imines with C nucleophiles using chiral phosphoric acid derivative. PCT Int Appl WO 2005070875 2005-08-04... 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

Taylor, M. S., Jacobsen, E. N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558-10559. Kowalski, P., Mokrosz, J. L. Structure and spectral properties of P-carbolines. Part 9. New arguments against direct rearrangement of the spiroindolenine intermediate into P-carboline system in the Pictet-Spengler cyclization. An MNDO approach. Bull. Soc. Chim. Belg. 1997, 106, 147-149. 

For a thiourea-catalyzed enantioselective acyl-Pictet-Spengler reaction, see Taylor, M.S. and Jacobsen, E.N. (2004) J. Am. Chem. Soc., 126, 10558-10559. 

Strictly catalytic enantioselective Pictet-Spengler cyclizations of tryptamine imi-nes have been rather elusive to date. The most successful results were achieved with A-acyliminium intermediates and thiourea catalysts. The reactions proceed through... 

An enantioselective version of the Pictet-Spengler reaction has been achieved using nitrones formed from Af -hydroxytryptamines by using chiral chloroboranes... 

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... 

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