Pictet-Spengler reaction

The Pictet-Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde. Usually an acidic catalyst is employed and the reaction mixture heated, []

An analogous reaction with an aryl-β-ethanol is called Oxa-Pictet-Spengler reaction.

Reaction mechanism

It is the electrophilicity of the imine double bond that is the driving force of the cyclization.cite journal | author = Cox and Cook | year = 1995 | journal = Chemical Reviews | volume = 95 | issue = 6 | pages = 1800–1802 | doi = 10.1021/cr00038a004 | title = The Pictet-Spengler condensation: a new direction for an old reaction] The reaction mechanism occurs by initial formation of an iminium ion (4) followed by electrophilic substitution at the 2-position. After deprotonation, the desired product {6) is formed. The reaction shown is an example of a 6-endo-trig reaction, which is favoured by Baldwin's ring closure rules.

Variations

Pictet-Spengler tetrahydroisoquinoline synthesis

Replacing an indole with a 3,4-dimethoxyphenyl group give the reaction named the Pictet-Spengler tetrahydroisoquinoline synthesis. Reaction conditions are generally harsher than the indole variant, and require refluxing conditions with strong acids like hydrochloric acid or trifluoroacetic acid.

N-Acyliminium Pictet-Spengler Reaction

Instead of catalyzing the Pictet-Spengler cyclization with strong acid, one can acylate the iminium ion forming the intermediate N-acyliminium ion. The N-acyliminium ion is a very powerful electrophile and most aromatic ring systems will cyclize under mild conditions with good yields. [cite journal | author = B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi, and C. A. Maryanoff | title = Cyclizations of N-acyliminium ions | journal = Chem. Rev. | volume = 104 | pages = 1431–1628 | year = 2004 | doi = 10.1021/cr0306182]

Tadalafil is synthesized via the N-acyliminium Pictet-Spengler reaction. [cite journal | author = Bonnet, D.; Ganesan, A. | journal = J. Comb. Chem. | year - 2002 | volume = 4 | issue = 6 | pages = 546–548 | title = Solid-Phase Synthesis of Tetrahydro-β-carbolinehydantoins via the N-Acyliminium Pictet-Spengler Reaction and Cyclative Cleavage | doi = 10.1021/cc020026h | year = 2002] This reaction can also be catalyzed by AuCl₃ and AgOTf. [cite journal | author = Youn, S. W. | journal = J. Org. Chem. | year = 2006 | volume = 71 | pages = 2521–2523 | doi = 10.1021/jo0524775|title = Development of the Pictet-Spengler Reaction Catalyzed by AuCl₃/AgOTf ]

Asymmetric Pictet-Spengler reaction

When the Pictet-Spengler reaction is done with an aldehyde other than formaldehyde, a new chiral center is created. Several substrate- or auxiliary-controlled diastereoselective Pictet-Spengler reactions have been developed. [cite journal | author = Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. | journal = Org. Lett. | volume = 2 | year = 2000 | pages = 1955–1958 | doi = 10.1021/ol006034t | title = Enantiopure Tetrahydro-β-carbolines via Pictet-Spengler Reactions with N-Sulfinyl Tryptamines] [a)" The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids" Enrique L. Larghi, Marcela Amongero, Andrea B. J. Bracca, and Teodoro S. Kaufman Arkivoc (RL-1554K) pp 98-153 2005 ( [http://arkat-usa.org/ark/journal/2005/I12_Lederkremer/1554/1554.asp Online Review] ); b) Teodoro S. Kaufman “Synthesis of Optically-Active Isoquinoline and Indole Alkaloids Employing the Pictet-Spengler Condensation with Removable Chiral Auxiliaries Bound to Nitrogen”. in “New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles”; Ed.: J. L. Vicario. ISBN 81-7736-278-X. Research SignPost, Trivandrum, India. 2005. Chapter 4, pp. 99-147.] Additionally, Seayad "et al." have published a chiral Lewis acid that catalyzes asymmetric Pictet-Spengler reactions. [cite journal | author = Seayad, J.; Seayad, A. M.; List, B. | journal = J. Am. Chem. Soc. | year = 2006 | volume = 128 | pages = 1086–1087 | doi = 10.1021/ja057444l | title = Catalytic Asymmetric Pictet-Spengler Reaction]

Tryptophans: Diastereocontrolled reaction The reaction of enantiopure tryptophan or its short-chain alkylesters leads to 1,2,3,4-tetrahydro-"β"-carbolines in which a new chiral center at C-1 adopts either a "cis" or "trans" configuration towards the C-3 carboxyl group. The "cis" conduction is kinetically controlled, i.e. it is performed at lower temperatures. At higher temperatures the reaction becomes reversible and usually favours racemisation. 1,3-"trans" dominated products can be obtained with "N_b"-benzylated tryptophans, which are accessible by reductive amination. The benzyl group can be removed hydrogenolytically afterwards. As a rough rule, ¹³C NMR signals for C1 and C3 are downfield shifted in "cis" products relative to "trans" products (see steric compression effect). [cite journal | doi = 10.1021/ja00543a012 | year = 1980 | author = Ungemach, F. | title = General method for the assignment of stereochemistry of 1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines by carbon-13 spectroscopy |journal = J. Am. Chem. Soc.| volume = 102 | pages = 6976 ]

ee also

* Bischler-Napieralski reaction

References