Todd:Catalytic, Asymmetric Pictet-Spengler Reaction

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The Catalytic, Asymmetric Pictet-Spengler Reaction

Katrina Badiola, School of Chemistry, The University of Sydney, NSW 2006, Australia
Murray N. Robertson, School of Chemistry, The University of Sydney, NSW 2006, Australia
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia

Additional authors - add alphabetically if you contribute something substantial (e.g., the summary of a paper with a scheme). Final arbitration on authorship (as opposed to acknowledgement) lies with Mat Todd

(This article is intended as a stand-alone review. It also acts as background to the open science project to find a catalytic, asymmetric route to praziquantel. The review is open source, meaning anyone can add and edit. When it is deemed to be up to date, comprehensive, error-free and well-written, it will be submitted for publication to a peer-reviewed open access journal, but editing can continue here after that point. This page is currently active - when this changes <= these words will be changed (and you can see when the last edit of this page was made at the bottom). References for this page may be found in full at the Mendeley page). If you want to get in touch to ask questions please do not use email. You can use the talk page (tab above), or directly insert a question on this page (below) with your initials, or discuss via Google+ pages: Mat, (please add other public places where you can be contacted if you contribute as an author).

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Schemes: Use Wiley/Angewandte settings for the .cdx files and add below as 300 dpi .png files.

Introduction

Importance of the structural motifs constructed with the reaction:

• Brown, R. T. In Indoles; Saxton, J. E., Ed.; Wiley- Interscience: New York, 1983; Part 4 (The Monoterpenoid Indole Alkaloids)
• Bentley, K. W. Nat. Prod. Rep. 2004, 21, 395-424 and references therein
• W. Jiang, J. Guan, M. J. Macielag, S. Zhang, Y. Qiu, P. Kraft, S.

Bhattacharjee, T. M. John, D. Haynes-Johnson, S. Lundeen, Z. Sui, J. Med. Chem. 2005, 48, 2126 – 2133

Carbolines:

• Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793
• Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Anderson, J. F.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565–7581
• Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. J. Org. Chem. 2006, 71, 8884–8890
• Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491–3494
• Herraiz, T. J. Chromatogr. A 2000, 881, 483–499
• Herraiz, T.; Galisteo, J.; Chamorro, C. J. Agric. Food Chem. 2003, 51, 2168–2173.

Racemic/Achiral

To Do:

• Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036.
• Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92 (may be 453-459).
• Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797- 1842 (especially their tryptophan ester strategy)
• Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341-3370.
• Nature: Naoi, M.; Maruyama, W.; Nagy, G. M. Neurotoxicology 2004, 25, 193- 204

Diastereoselective

To Do:

• Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J. M. J. Org. Chem. 1997, 62, 44-61 and references therein.
• Czarnocki, Z.; MacLean, D. B.; Szarek, W. A. Can. J. Chem. 1986, 64, 2205-2210.
• Czarnocki, Z.; Suh, D.; MacLean, D. B.; Hultin, P. G.; Szarek, W. A. Can. J. Chem. 1992, 70, 1555-1561.
• Czarnocki, Z.; Mieckzkowsi, J. B.; Kiegiel, J.; Arazn ́y, Z. Tetrahyedron: Asymmetry 1995, 6, 2899-2902.
• Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2402-2403.
• Schmidt, G.; Waldmann, H.; Henke, H.; Burkard, M. Chem. Eur. J. 1996, 2, 1566-1571.
• Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2, 1955-1958.
• Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885-8888.
• Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177- 180.

Enantioselective

Lewis Acids

To Do:

• Non-catalytic borane: Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354
• Hino, T.; Nakagawa, M. Heterocycles 1998, 49, 499-531.
• Leighton Angew 2009

Bronsted Acids

(Note - consider a diagram section at start which includes the structures of all the binap-derived catalysts so we don't have to include in the individual schemes). i.e. we draw them at start and then number them then just include the numbers in the schemes.

List reported the first Bronsted acid-catalyzed enantioselective Pictet-Spengler reaction in 2006 (10.1021/ja057444l). Chiral, substituted phosphoric acids were shown to be effective in the PS cyclization of tryptamines with a number of aliphatic and aromatic aldehydes (Scheme List 2006). The diester functionality was found to be necessary, presumably due to promotion of a clean reaction through the Thorpe-Ingold effect (and an aldol side reaction was observed when the esters were absent). Lower yields were typically observed when the methoxy group was absent from the tryptamine aromatic ring.

Scheme (List 2006). Chiral Phosphoric Acid PS Cyclization of Typtamine Diesters

In 2007, Hiemstra reported the enantioselective synthesis of tetra-β-carbolines via the in situ formation of N-sulfenyliminium ions (10.1002/anie.200701808). Stabilization of the intermediate iminium by the N-tritylsulfenyl group was effective at promoting the acid-catalyzed PS reaction by substituted enantiopure binaphthyl-derived phosphoric acids. Several substitutions were assayed in the 2-position of the catalyst, with no clear trend being observed in the ee of product obtained. The N-S bond in the N-tritylsulfenyl product was found to be susceptible to homolytic cleavage, but this could be suppressed by the addition of a radical scavenger. A one-pot process was developed that allowed precipitation of the product as a salt, and this was applied to the synthesis of a variety of substituted tetra-β-carbolines with high yield and high ee. The reaction was also demonstrated on a multi-gram scale.

Question: Why does the sulfenyl help? Paper says should stabilize intermediate iminium ion and favour cyclization over competitive enamine formation) Paper gives: The use of N-sulfenyl substituents as protecting groups is known in peptide synthesis; see a) L. Zervas, D. Borovas, E. Gazis, J. Am. Chem. Soc. 1963, 85, 3660 – 3666 ; for reviews on sulfenamide chemistry, see b) F. A. Davis, U. K. Nadir, Org. Prep. Proced. Int. 1979, 11, 33–51; c)L. Craine, M. Raban, Chem. Rev. 1989, 89, 689 – 712 ; d) I. V. Koval, Russ. Chem. Rev. 1996, 65, 452 – 473.

Scheme (Hiemstra 2007). Enantioselective PS Cyclization via N-Sulfenyliminium Intermediates

An extension to this methodology was developed that allowed the synthesis of enantioenriched N-benzyl-protected versions of similar products from the relevant protected tryptamines and diverse aldehydes (10.1021/jo8010478). During optimization it was found that removal of water was essential for high enantioinduction presumably because water prevents effective association between catalyst and cyclization precursor. Several control reactions were performed under the optimized conditions that suggested this PS reaction was irreversible. The best-performing catalyst was the triphenylsilyl-substituted binaphthyl system, delivering up to 100% conversion and high ee values (78-85%). The ee obtained was sensitive to the aldehyde employed. Of the aliphatic aldehydes, no product was observed with the enolizable phenylacetaldehyde and low ee (8%) was obtained with 3-phenylpropanal. While electron-deficient aromatic aldehydes generally gave products with high ee as expected, there were exceptions that performed poorly; 3-chlorobenzaldehyde gave near-racemic product, for example.

Scheme (Hiemstra 2008). Enantioselective Phosphoric Acid PS Cyclization of N-Benzyltryptamines

This methodology has been employed in the syntheses of three natural products. The PS reaction employed in the synthesis of (-)-arboricine (10.1021/ol900888e) involved an aldehyde containing a dioxolane-protected ketone group, preventing an aminal formation that was observed when the ketone was used unprotected, but it is notable that this protecting group withstands the PS cyclization, and that the yield and ee of the cyclization were both dramatically improved by the use of the protecting group.

(+)-yohimbine 2011 (10.1021/jo201657n).

In the synthesis of (+)-yohimbine, the highest ee obtained from the PS of the achiral N-monosubstitued tryptamine with achiral aldehydes was in the presence of the H₈-BINOL phosphoric acid catalyst (slightly greater steric hinderance than the BINOL phosphoric acid).

Avoiding β,γ-unsaturated aldehydes, which tend to tautomerise from the intermediate iminium ion to the unreactive, conjugated enamine. (KAB, relevant to the PS?)

(–)-corynantheidine (10.1002/ejoc.20110014).

Scheme (Hiemstra 2009). Key enantioselective PS reaction in the synthesis of (-)-Arboricine

Scheme (Hiemstra 2011). Chiral PS in the Total Synthesis of (+)-Yohimbine (KAB, not sure about ee for this step, but the mix of N-Boc protected diastereomers is obtained with 82% yield in the following protection)

The enantioselective potency of chiral phosphoric acids in catalytic Mannich-type reactions were independently reported by Akiyama (10.1002/anie.200353240) and Terada (10.1021/ja0491533) in 2004. A number of substituted enantiopure BINOL phosphoric acids were screened by the two groups and both found that aromatic β-substitution of the BINOL acids increased the enantioselectivity of the catalysts. Terada outlined the advantageous properties of binapthyl-derived phosphoric acids for use as Bronsted acid catalysts (KAB, to go in the mechanism section?). The synthesis of β-aminoketones from N-Boc protected aldimides in the slight excess of β-diketone(?) using the 4-(β-naph)benzoyl substitued BINOL phoshoric acid catalyst gave excellent ee values of up to 98%.

(Not sure where this should go, or which aspect to focus on, KAB) Terada et al (J. Am. Chem. Soc. 2004, 126, 5356-5357) (10.1021/ja0491533) - Summary of summary (TBC 11/01/12): Evaluation of chiral phosphoric acids (CPA) in direct Mannich-type reactions. Synthesis of beta-aminoketone. Advantageous properties of CPA include tetradentate P(V) preventing rotation by forming ring structure (not formed in carboxylic or sulfonic acids). Acidity. Lewis base site at phosphoric oxygen = bifunctional catalyst. Extension of the aromatic substitution to the para direction improved enantioselectivity (up to 95% ee). Para and ortho-substituted. Determined absolute configuration reacting to phenylglycine (conserved chirality?) - Still working on this, KAB

Terada (b)

Scheme (Terada 2004a). Mannich-type Reaction to give Chiral β-Aminoketones

In 2011, Franz reported a comparison of catalyst systems to determine the factors responsible for efficient catalytic activity and selectivity in this Pictet–Spengler type reaction. The effect of solvent and temperature was examined for the phosphoric acid catalyzed reactions in order to improve the enantioselectivity. DCM performed the best for reaction rate and enantioselectivity

Scheme: (Franz 2011). Phosphoric acid-catalyzed spirocyclization of isatins

Interestingly, Franz showed the same (S)-enantiomer of spiroindolone was obtained for (R) and (S) catalysts despite them having the opposite configurations of axial chirality. He therefore concluded that the substituents on the binaphthyl system direct the stereoinduction for the spirocyclization. This is contrary to several other instances that have been reported previously where the 3,30-substitution on the chiral phosphoric acid catalyst has been shown to reverse the sense of enantioselection. The effect of substitution was also examined for spirocyclization, providing insight into the limitations of this methodology. Yield and enantioslectivity varied as these substitution patterns were change.

Scheme: (Franz 2011). spirocyclization mechanism

To Do:

Early work on addition reactions to aldimines catalyzed by binaphthol-derived chiral phosphoric acids: Akiyama: ((a) Angew. Chem., Int. Ed. 2004, 43, 1566-1568; (b) Org. Lett. 2005, 7, 2583-2585; (c) Akiyama, T. PCT Int. Appl. WO 200409675, 2004; (d) Adv. Synth. Catal. 2005, 347, 1523-1526 Terada: ((a) J. Am. Chem. Soc. 2004, 126, 5356-5357. (b) J. Am. Chem. Soc. 2004, 126, 11804-11805. (c) J. Am. Chem. Soc. 2005, 127, 9360-9361; (d) Terada, M.; Uraguchi, D.; Sorimachi, K.; Shimizu, H. PCT Int. Appl. WO 2005070875, 2005.).

The strengths of these chiral phosphoric acids is governed by:
Akiyama Chem Rev 2007
Terada ChemComm 2008

Reviews: a) S.J. Connon, Angew. Chem. Int. Ed. 2006, 45, 3909–3912
b) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999 – 1010
c) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520–1543
d) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407–3417

Organocatalysts

First report: Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558-10559 N-acetyl difficult to remove? Limited to aliphatic?

In 2009 Jacobsen reported asymmetric Pictet-Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid. A number of optically active tetrahydro-β-carbolines were obtained in high ee.

Scheme: (Jacobsen 2009). Bronsted Acid and H-Bond Donor Co-catalysis mechanism

The catalytic cycle for this was proposed where imine protonation is induced by a thiourea catalyst via H-bonding to the conjugate base of a weak Bronsted acid additive. The highly reactive protioiminium ion then cyclizes and aromatizes to generate the desired product and Bronsted acid cocatalyst. Examples also show that this thiourea catalyst promotes highly enantioselective Pictet-Spengler reactions on electronically and structurally diverse substrates.

Scheme: (Jacobsen 2009). Thiourea and Benzoic Acid Catalyzed Pictet-Spengler Reaction

Jacobsen published further work continuing with his cocatalyzed thiourea/benzoic acid Iso-Pictet-Spengler reactions in 2011. Here he focused on the synthesis of optically pure tetrahydro-γ-carbolines. He reports a straightforward procedure for upgrading the ee of the tetrahydro-γ-carbolines products by Boc protecting the free amine. This simple step elevates the ee to greater than 99% in nearly all the examples shown and by simple crystallization or trituration. Furthermore, the use of ketone substrates was also demonstrated and shown to proceed to similar yields and ee’s

Scheme: (Jacobsen 2011). Iso-Pictet-Spengler Reaction using a ketone and upgrading ee by Boc protecting and trituration

To Do:

Iso-Pictet-Spengler (C3 of indole) Jacobsen 2011- MNR Done

Thiourea plus a proton: Jacobsen 2009 - MNR Done

Franz 2011 - MNR Done, in Bronsted Acids

Cook 1992

Mechanism

Interesting --> Cook et al, "Study of the Cis to Trans Isomerization of 1-Phenyl-2,3-disubstituted Tetrahydro-β-carbolines at C(1). Evidence for the Carbocation-Mediated Mechanism" DOI: 10.1021/jo8028168 - Proposes mechanism for the racemisation via retro Pictet-Spengler of enantioenriched tetrahydro-β-carbolines synthesised from tryptamines and aldehydes.

For binaphthyl-derived phosphoric acids are there any trends in the nature of the substituents vs. ee obtained? In Hiemstra 2007 no clear trend is visible in Table 1.

Miscellaneous Other Systems/Ones not yet used for PS

Enzymatic examples:
Norcoclaurine synthase Tanner 2007
Strictosidine Synthase [10.1021/ja077190z Stoeckigt 2008]

References

Papers included in the review should be listed here when the description of the science is complete. The papers may be found in full at the Mendeley page)

Bronsted Section:

• Catalytic Asymmetric Pictet-Spengler Reaction, J. Seayad, A. M. Seayad and B. List, J. Am. Chem. Soc. 2006, 128, 1086-1087. Paper
• Catalytic Asymmetric Pictet-Spengler Reactions via Sulfenyliminium Ions, M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba, J. H. van Maarseveen and H. Hiemstra, Angew. Chem. Int. Ed. 2007, 46, 7485-7487. Paper
• Enantioselective BINOL-phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-benzyltryptamine, N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de Gelder, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2008, 73, 6405-6408. Paper