Todd:Catalytic, Asymmetric Pictet-Spengler Reaction

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The Catalytic, Asymmetric Pictet-Spengler Reaction

Katrina A. Badiola, School of Chemistry, The University of Sydney, NSW 2006, Australia
Murray N. Robertson, School of Chemistry, The University of Sydney, NSW 2006, Australia
Michael A. Tarselli, Biomedisyn Corp., Woodbridge, CT, United States of America
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia

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Introduction

What is the PS reaction
Give first example, with reference
Give one notable academic example
Give one industrial example

Describe biological relevance of the structures thus obtained - natural and synthetic

Hence the asymmetric version of the reaction is of interest.

Refer to recent reviews, such as: Current Organic Synthesis 2010 and the Waldmann Angew 2011 review

First diastereoselective example
Include: Cook 1992 Cook

Enantioselective

Lewis Acids

Nakagawa (10.1021/jo980810h) reported the first example of a reagent-controlled enantioselective Pictet-Spengler reaction in 1998. He used a chiral Lewis acid to promote the enantioselective cyclization of nitrones to give Nb-hydroxytetrahydro-β-carbolines. Treatment of nitrone with (-)-Ipc₂BCl in DCM at -78 °C gave the desired product in 94% yield with 83% ee. Replacing the chlorine atom of the Ipc₂BCl in an attempt to alter the Lewis acidity of the boron did not improve yield or ee. The reaction should proceed via an iminium ion intermediate, in which the boron of Ipc₂BCl is coordinated to the oxygen of the nitrone. The stereochemical outcome can be explained by assuming a transition state involving the nucleophilic attack of indole onto the C=N double bond from the less hindered side.

Scheme: (Nakagawa 1998). Pictet-Spengler Reaction of Nitrones with Diisopinocampheylchloroboranes

A small number of chiral complexes of Lewis Acids were used as part of a screen to identify catalysts for an asymmetric PS reaction between tryptamine and isatins, and while conversion was observed with several complexes there was negligible enantioinduction; high product ee was ultimately achieved with Bronsted acid catalysis (vide infra). Franz 2011

Bronsted Acids

(Note - consider a diagram section at start which includes the structures of all the BINOL-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.

Chiral Brønsted acids have been shown to be effective in the catalytic, asymmetric PS reaction, and this builds on earlier work demonstrating the ability of such compounds to catalyze the reaction between nucleophiles and iminium ions.

Akiyama (10.1002/anie.200353240) reported chiral phosphoric acids prepared from BINOL in the enantioselective Mannich-type coupling of silyl enolates with aldimines (Scheme Akiyama 2004). High yields and enantio- (as well as, in appropriate cases, diastereo-) selectivities were observed with a variety of substituted aldimines and enolates. Limitations to the methodology were that an ortho hydroxy group was required on the N-aryl ring of the aldimine, and that aldimines derived from aliphatic aldehydes did not participate effectively. The catalyst was typically used at a loading of 10 mol%. The structure of the catalyst itself may be thought of as a chiral proton, i.e., a proton surrounded by a chiral structure, particularly given the aromatic rings of the BINOL and the 3-substituents are not coplanar. However, the mechanism was proposed to operate via an ion pair of phosphate and iminium ion. The bond-forming event would naturally disrupt such an ion pair, ensuring catalytic turnover. (ultimately need a scheme of this very general idea (nice example in the Akiyama paper here) but may go in mechanism section)

Scheme (Akiyama 2004). Enantioselective Mannich-type Coupling of Enolates and Aldimines Catalyzed by Chiral Phosphoric Acids

At the same time Terada (10.1021/ja0491533) reported similar catalysts in the enantioselective Mannich reaction for the synthesis of β-aminoketones (Scheme Terada 2004a), again noting the important influence of the 3-position of the naphthyl rings in the enantioselectivity of the reaction. The nucleophile could be changed to furan (10.1021/ja046185h) (maybe include).

Scheme (Terada 2004a). Enantioselective Mannich-type Reaction in the Synthesis of β-Aminoketones

Since these early reports, several further examples have been reported of reactions that can be catalysed by these or related structures (reference reviews of chiral bronsted acid catalysts here).(Terada 2010 Bull Chem Soc Jpn 10.1246/bcsj.20090268)

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-catalyzed 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.

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 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) (Scheme Hiemstra 2009) 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. The partially saturated (and slightly more sterically crowded) (R)-H8-Binol-PA catalyst was also shown to be effective. This catalyst was subsequently used for the key step in the synthesis of (+)-yohimbine (Scheme Hiemstra 2011).(10.1021/jo201657n). The natural product was to be synthesized via a Diels-Alder precursor that could itself be made using an enantioselective PS reaction. However, the aldehyde required for the PS reaction was β,γ-unsaturated and this was likely to result in the unproductive formation of an enamine from the initially-formed iminium ion. This substrate limitation necessitated use of a latent double bond, in this case a phenylselenide; this group survived the successful PS cyclization and could be eliminated to the double bond via oxidation to the selenoxide. A similar synthetic strategy was employed in the synthesis of the related corynanthe alkaloid family. (10.1002/chem.201103150)

Scheme (Hiemstra 2009). Key Enantioselective PS Reaction in the Synthesis of (-)-Arboricine

Scheme (Hiemstra 2011). Enantioselective PS Reaction in the Total Synthesis of (+)-Yohimbine

Dixon included a chiral phosphoric acid as part of a reagent cocktail effecting a cascade sequence involving a Pictet-Spengler-like cyclization (Scheme Dixon 2009).(10.1021/ja9024885) Tryptamines and lactones formed ketoamides with an appended π-nucleophile that underwent enantioselective cyclizations in the presence of chiral phosphoric acids, and it was again shown that aromatic substitution of the BINOL ring system was essential for high ee. The method could be used with more substituted lactones to effect high levels of diastereocontrol: the combination of a disubstituted enol lactone with tryptamine gave isolable intermediates, the structures of which implied that the formation of the reactive iminium ion was fast and reversible, and that final ring closure occurred with one matched catalyst/substrate pair. The mechanism of the enantiodetermining cyclization is presumed to be via a tight ion pairing between iminium ion and catalyst conjugate anion. High yields and stereoselectivities could be obtained for diverse products using this methodology, which was shown to be compatible with a one-pot cascade process that also included a gold(I)-catalyzed step to generate the initial lactone.

Scheme (Dixon 2009). Cascade Cyclizations Involving an Enantioselective PS Reaction

The method was broadened to allow the use of racemic keto acids and esters in place of the enol lactones, again with polycyclic products being produced in high yield and ee (79-98%). (10.1021/ol101651t). If the reaction time was reduced, enamides could again be isolated, one achiral and the other chiral with an ee of only 7%. Either enamide gave the intended product with an ee of 83% when resubjected to the reaction conditions, supporting the fast, reversible formation of iminium ions which are trapped by an enantioselective cyclization event controlled by the chiral acid. Possibly mention the racemic oxo acid.

Scheme: (Dixon 2010). Pictet-Spengler-Type Reaction of Tryptamines with γ-Ketoacids - MHT marks this for deletion, to be replaced by v2 combined scheme below

Dynamic Kinetic Asymmetric Cyclisation Cascade: (Dixon 2010).Enantioselectivity Dependence on Equilibrium and Iminium Cyclisation Rate-Constants - MHT marks this for deletion

Scheme (Dixon 2010). Cascade Cyclization Catalyzed by a Chiral Bronsted Acid with Isolable Achiral or Near-racemic Intermediate Enamides - MHT this is a combined scheme containing both the overall reaction outcome and a mention of some intermediates, though not, as yet, the oxoamide (compound 7 in the paper)

Franz (10.1016/j.tetlet.2011.08.071) screened a number of catalysts in the search for a means of creating medicinally-relevant spirocyclic structures from tryptamine and isatin. Lewis acidic complexes were ineffective, and though thioureas gave some enantioinduction, it was found that Bronsted acid catalysts were the most effective, giving products in sometimes excellent ee in often near-quantitative yields. Interestingly the 3,3'-substituents on the BINOL ring system strongly influenced the enantioinduction, to the extent that changing this substituent (from e.g., anthracenyl to triisopropylphenyl) reversed the sense of enantioinduction (strictly, the (S)-enantiomer of one catalyst gave the same enantiomer of product as did the (R)-enantiomer of the other catalyst.) Unsurprisingly the outcome of the reaction was dependent on the choice of solvent as well as the electronic and steric substitution pattern of both coupling partners. (Citations done, but leads to 10.1002/adsc.201100050 - MHT doing Jan 23 - very similar, which may require a proper merge here)

Scheme: (Franz 2011). Phosphoric Acid-Catalyzed Spirocyclization of Isatins - MHT - need to fix steric clash on phosphate, and orient reagents more like product

Scheme: (Franz 2011). spirocyclization mechanism - MHT marks this for deletion because the mech is kind of obvious from what has been already discussed.

Organocatalysts

(Note - This section may need a short segue of 3-5 sentences to lay out why we'd go this way, as opposed to Lewis acids / Bronsted / enzymes. Why go to organocatalysts? Lower temp, recoverable, higher ee, substrate scope issues? - MAT) MHT reply: well, they were developed independently and concurrently, so there doesn't have to be a logic. However, you're right in that we ought to compare the different systems at the end. Will insert reminder in later section, and if you agree, then delete this text.

In 2004, Jacobsen reported his initial work on asymmetric catalysis of the acyl-Pictet-Spengler reaction using chiral thioureas. Jacobsen realised the inherent challenge of developing an asymmetric Pictet-Spengler catalyst involved low reactivity of the imine substrate. Additionally, previously reported racemic efforts had involved Lewis acid catalysts paired with highly reactive agents at high temperatures. Jacobsen enhanced the reaction by increasing the electrophilicity of the iminium intermediate through formation of the corresponding N-acyliminium ion (MAT - Why? We need to explore this concept a bit...) Early screening experiments showed cyclization occuring at -30 °C in 59% ee. While screening individual reaction parameters, Jacobsen discovered that product chirality exhibited a strong dependence upon the structure of the acylating agent, reaction solvent, and temperature.

Scheme: (Jacobsen 2004). Catalytic Asymmetric Acyl-Pictet-Spengler Reactions

Under optimized conditions (-30 °C, ether, 5 mol% catalyst), Jacobsen's thiourea delivered enriched tetrahydro-B-carbolines in 65-81% yields, and up to 95% ee.

A proposed mechanism for the thiourea-catalysed enantioselective Pictet-Spengler-Type cyclization was published by Jacobsen in 2007. Interestingly, key experimental observations, supported by DFT computational analyses, pointed towards an SN1-type pathway in these cyclizations, with catalysis via a previously unprecedented anion-catalyst hydrogen bonding mechanism.

An extensive screen of acidic additives revealed that either chlorotrimethylsilane or the combination of HCl and 3 Å molecular sieves afforded high levels of conversion and enantioselectivity, but that water had a deleterious effect on catalyst activity. Furthermore, a quite significant inverse correlation between conversion and reaction concentration was observed, with reactions run at lower concentrations affording substantially improved yields.

As a direct demonstration of the applicability of this new methodology, Jacobsen applied the enantioselective hydroxylactam cyclization to the total synthesis of (+)-harmicine with the cyclization proceeding in 97% ee followed by subsequent LiAlH4 reduction affording the natural product in only four steps from tryptamine. (Note - picture reads "Hermicine" - MAT)

Scheme: (Jacobsen 2007). Total Synthesis of (+)-Harmicine

Variable temperature 1H NMR studies of reaction mixtures indicated that formal dehydration and formation of the corresponding chlorolactam is rapid and irreversible. Further observation of enhanced reactivity of alkylated versus reduced derivatives suggests that an SN2-type displacement of chloride is not operative in the cyclization reaction, which points instead to an SN1-type mechanism. Since the enantio-determining step is likely either the addition of the indole to the N-acyliminium ion (b → c or b → d), or alkyl migration of the spiroindoline intermediate (c → d), catalyst interaction with at least one of these species is required. However, there is no viable Lewis basic site for catalyst binding to substrate in c or d.

Scheme: (Jacobsen 2007). Proposed Reaction Mechamism

Therefore, Jacobsen proposed that the thiourea catalyst promotes enantioselective cyclization by inducing dissociation of the chloride counterion and forming a chiral N-acyliminium chloride-thiourea complex. Noticeable halide counterion effects and solvent effects on enantioselectivity lend proof to this theory. Furthermore, it was suggested that catalysis and enantioinduction may result from initial abstraction of a chloride anion from a in an SN1-type rate determining step (a → b) and subsequent cyclization mediated by the resulting anion-bound thiourea. This mode of catalytic generation of cationic intermediates was previously reported in the well-established anion-binding properties of ureas and thioureas. Further, the possibility of high levels of enantioinduction induced through counterion interactions is well precedented in chiral phase-transfer catalysis and has recently been demonstrated in the context of asymmetric counterion-directed catalysis.

In 2007, Jacobsen published a review titled “Small-Molecule H-Bond Donors in Asymmetric Catalysis” identifying chiral hydrogen-bond donors used for enantioselective synthesis. The area regarding to the PS reaction referred to previous work reported by Jacobsen. Concluding, Jacobsen stated his surprise at both phosphoric acids and thiourea derivatives being capable of mediating enantioselective transformations of prochiral iminium and N-acyliminium ion intermediates as they exist in opposite ends of the spectrum of the pKa scale of known H-bond donor catalysts.

In 2008, Jacobsen put his previously discovered enantioselective thiourea-acyl-Pictet-Spengler catalyst to use in the total synthesis of (+)-yohimbine. The synthesis was achieved in 11 steps and 14% overall yield with the absolute configuration of the molecule being established through the highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction at the start of the synthesis.

Scheme: (Jacobsen 2008). Total Synthesis of (+)-Yohimbine

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

What is Known of the Mechanisms of Existing Systems

Terada (10.1021/ja0491533) mentions (wrt Bronsted acids) "1) Tetradentate structure around the phosphorus(V) atom would prevent free rotation at R of the phosphorus center by formation of a ring structure. This characteristic feature cannot be found in other possible Brønsted acids, such as carboxylic and sulfonic acids, etc. 2) Their appropriate acidity16 should catch up the imine through hydrogen bonding without loose ion-pair formation. 3) Their phosphoryl oxygen should function as a Lewis basic site, and thus a phosphoric acid could function as a bifunctional catalyst."

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. Franz noticed strong effect of 3,3'-substituents, with similar sterically-demanding groups reversing enantioinduction.

Limitation: avoiding β,γ-unsaturated aldehydes, which tend to tautomerise from the intermediate iminium ion to the unreactive, conjugated enamine, e.g. in Hiemstra 2011.

Dixon 2010 (10.1021/ol101651t). Both isolated enamide intermediates (epimers?) gave the same ee on treatment with the chiral BINAP (to drive rxn to completion). The proposed mechanism was that both reactions underwent rapid epimerisation through a common prochiral enamide intermediate (steady state?). Also, suggested enantioselectivity arose from facial differentiation imposed by the tight ion pair between the binol phosphoric acid conjugate base and the iminium ion.

Terada Review (10.1246/bcsj.20090268): Phosphoric acids as stronger Bronsted acids than thioureas or than TADDOL (used in the Rawal Nature paper). Considered other possible acids including sulfonic (too strong), carboxylic and sulfuric (free rotation problem), and phosphoric - just right, and chiral info is closer to proton. (When deprotonated, the O minus and P=O sites interconvert, right, but this is unimportant?) Phosphoric acids not expected to form loose ion pairs. Expected to be H-bonding etc that keeps components together. Ring system employed in the BINOL derivatives makes more rigid. Good? Mechanistic proposal in Figure 4. H-bonding network, not ion pair. Developed phosphorodiamidic acid in Synlett 2006, 133. Figure 11 has mechanistic cycle that may be of interest to PZQ. Do all the enecarbamate reactions known to function have N-H's?

Solvents: toluene found to be a good solvent for a number of these reactions, e.g. 10.1021/ja9024885. No clear trend observed in Franz 2011; DCM happens to be the best, but...

Thiourea mechanism: Franz 2011 has Jacobsen ligands as giving good conversion but moderate ee, but the Takemoto ligand giving no conversion.

Clearly the main issue with regards the mechanism is the need for an electron-rich ring for the PS reaction to occur. Franz 2011 looked at this a little, though there are two steps in the mechanism - imine formation and cyclization, so one needs to be careful interpreting results.

Enzymatic Catalysis

Stockigt and Waldmann's 2011 ACIEE review on the Pictet-Spengler reaction eloquently opens with discussion of the two known families of "Pictet-Spenglerases" - enzymes that take as their substrates an electron-rich aromatic, appended to an ethylamine, and an aldehyde - and transform them into asymmetric tetrahydroquinoline or tetrahydro-B-carboline motifs. Strictosidine synthase (STR1), first isolated in 1975 by Scott and Lee, cyclizes natural product precursors belonging to the strychnos and ajmaline alkaloid pathways. Norcoclaurine synthase (NCR), isolated in 1981 by Nagakura from plant cell cultures, which condenses tyrosine-derived aldehydes and dopamine to form a variety of benzoisoquinoline precursors.

A variety of different halogenated and alkylated tryptamine precursors have been incorporated into final alkaloid structures using STR1. (O'Connor, JACS 2008)

In 2010, O'Connor and coworkers reported 3 strictosidine synthase homologs, isolated from R. serpentina (RsSTS), C. roseus (CrSTS), and O. pumila (OpSTS). Previous research by O'Connor and Stockigt had shown that variations to the tryptamine synthon (electron-rich, electron-deficient) were tolerated by the enzymes, but that aldehydes other than secologanin were not turned over. The O. pumila isolate, a lower homolog (~60% sequence identity to RsSTS or CrSTS) was capable of catalyzing the PS reaction between tryptamine and various non-native aldehydes. Tetrahydro-B-carbolines thus formed had >98% ee.

A computational model was generated for the OpSTS active site, which determined that a reversible mixture of diastereomeric intermediate carbolines were formed, but that only the 2(R)3(S) diastereomer was capable of subsequent deprotonation by Glu309, a carboxylate residue in the active site.

The substrate tolerance of strictosidine synthase was further extended by Stockigt and a multi-institutional team in a JACS 2012 paper. Strictosidine synthase (STR1), after substrate-directed mutagenesis, was able to turn over heteroatom-containing tryptamines such as 7-N tryptamine (indazole ethanamine). The resulting secologanin conjugate was detected by HRMS.

Miscellaneous Other Systems/Ones not yet used for PS

This is a very important section where we describe some obvious things that can be tried next in the field. Reviews are not proposals, but making maps gives you a clear sense of what has not yet been explored.

Conclusions, and what's needed in this field

We will write this section last

References

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

Diastereoselective:

• Enantiospecific Formation of Trans 1,3-Disubstituted Tetrahydro-β-carbolines by the Pictet-Spengler Reaction and Conversion of Cis Diastereomers into Their Trans Counterparts by Scission of the C-1/N-2 Bond, E. D. Cox, L. K. Hamaker, J. Li, P. Yu, K. M. Czerwinski, L. Deng, D. W. Bennett and J. M. Cook, J. Org. Chem. 1997, 62, 44-61. Paper

Lewis Acid Section:

• Chiral Lewis Acid-mediated Enantioselective Pictet-Spengler Reaction of N-b-Hydroxytryptamine with Aldehydes, H. Yamada, T. Kawate, M. Matsumizu, A. Nishida, K. Yamaguchi and M. Nakagawa, J. Org. Chem. 1998, 63, 6348-6354. Paper

Brønsted Section:

• Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted Acid, T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566-1568. Paper
• Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation, D. Uraguchi and M. Terada, J. Am. Chem. Soc. 2004, 126, 5356-5357. Paper
• 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
• Organocatalytic Enantioselective Total Synthesis of (-)-Arboricine, M. J. Wanner, R. N. A. Boots, B. Eradus, R. de Gelder, J. H. van Maarseveen and H. Hiemstra, Org. Lett. 2009, 11, 2579-2581. Paper
• Enantioselective Brønsted Acid-Catalyzed N-Acyliminium Cyclization Cascades, M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt and D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 10796-10797. [1]
• Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective Carbon-Carbon Bond Forming Reactions, M. Terada, Bull. Chem. Soc. Jpn. 2010, 83, 101-119. Paper
• Direct Enantioselective Brønsted Acid Catalyzed N-Acyliminium Cyclization Cascades of Tryptamines and Ketoacids, C. A. Holloway, M. E. Muratore, R. I. Storer and D. J. Dixon, Org. Lett., 2010, 12, 4720-4723 Paper
• Total Synthesis of (+)-Yohimbine via an Enantioselective Organocatalytic Pictet-Spengler Reaction, B. Herle, M. J. Wanner, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2011, 76, 8907-8912. Paper
• Enantioselective Syntheses of Corynanthe Alkaloids by Chiral Brønsted Acid and Palladium Catalysis, M. J. Wanner, E. Claveau, J. H. van Maarseveen and H. Hiemstra, Chem. Eur. J. 2011, 17, 13680-13683. Paper
• Enantioselective Pictet-Spengler Reactions of Isatins for the Synthesis of Spiroindolones, J. J. Badillo, A. Silva-Garcia, B. H. Shupe, J. C. Fettinger and A. K. Franz, Tetrahedron Lett. 2011, 52, 5550-5553. Paper

Organocatalysis Section:

• Highly Enantioselective Catalytic Acyl-Pictet-Spengler Reactions, M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558-10559. Paper
• Small-Molecule H-Bond Donors in Asymmetric Catalysis, A. G. Doyle and E. N. Jacobsen, Chem. Rev. 2007, 107, 5713-5743. Link? <-- (MHT, Jan 22) - has this paper been read and relevant mechanistic ideas incorporated?
• Enantioselective Pictet-Spengler-Type Cyclizations of Hydroxylactams: H-Bond Donor Catalysis by Anion Binding, I. T. Raheem, P. S. Thiara, E. A. Peterson and E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404-page?. Paper
• Catalytic Asymmetric Total Synthesis of (+)-Yohimbine, D. J. Mergott, S. J. Zuend and E. N. Jacobsen, Org. Lett. 2008, 10, 745-748. Paper
• Weak Brønsted Acid-thiourea Co-catalysis: Enantioselective, Catalytic Protio-Pictet-Spengler Reactions, R. S. Klausen and E. N. Jacobsen, Org. Lett. 2009, 11, 887-890. Paper
• Thiourea-Catalyzed Enantioselective Iso-Pictet-Spengler Reactions, Y. Lee, R. S. Klausen and E. N. Jacobsen, Org. Lett. 2011, 13, 5564-page?. Paper

Enzyme Section:

• Biocatalytic Asymmetric Formation of Tetrahydro-B-carbolines, P. Bernhardt, A.S. Usera, and S.E. O'Connor, Tetrahedron Lett. 2010, 51, 4400-4402.

• Scaffold Tailoring by a Newly Detected Pictet-Spenglerase Activity of Strictosidine Synthase: From the Common Tryptoline Skeleton to the Rare Piperazino-indole Framework, F. Wu, H. Zhu, L. Sun, C. Rajendran, M. Wang, X. Ren, S. Panjikar, A. Cherkasov, H. Zhou, and J. Stockigt, J. Am. Chem. Soc. 2012, 134, 1498-1500.

Papers we're not including, and why (arranged by date)

Insert details of papers here if they are not being used, and explain why.

• Asymmetric Pictet-Spengler Reactions Employing N,N-Phthaloyl Amino Acids as Chiral Auxiliary Groups, H. Waldmann, G. Schmidt, H. Henke and M. Burkard, Angew. Chem., Int. Ed. Engl. 1995, 34, 2402-2403. Paper - Diastereoselective. Use of stoichiometric chiral auxiliaries.
• Asymmetric Control in Pictet-Spengler Reaction by Means of N-Protected Amino Acids as Chiral Auxiliary Groups, G. Schmidt, H. Waldmann, H. Henke and M. Burkard, Chem. Eur. J. 1996, 2, 1566-1571. Paper - Diastereoselective. Use of stoichiometric chiral auxiliaries.
• Enantiopure Tetrahydro-β-carbolines via Pictet−Spengler Reactions with N-Sulfinyl Tryptamines, C. Gremmen, B. Willemse, M. J. Wanner, G.-J. Koomen, Org. Lett. 2000, 2, 1955-1958. [Paper]- Use of chiral auxiliary.
• Enantiopure tetrahydroisoquinolines via N-sulfinyl Pictet–Spengler reactions, C. Gremmen, M. J. Wanner, G Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885-8888. Paper - Use of chiral auxiliary and excess acid.
• Enantioselective Addition of Amines to Ketenes Catalyzed by a Planar-Chiral Derivative of PPY: Possible Intervention of Chiral Brønsted-Acid Catalysis, B. L. Hodous, G. C. Fu, J. Am. Chem. Soc., 2002, 124, 10006-10007, Paper - Reaction of pyrroles with ketenes catalysed by a PPY planar-chiral 4-(pyrrolidino)pyridine (PPY), which is Fe π-bonded complex. Not Pictet-Spengler.
• A Chiral Acrylate Equivalent for Metal-Free Diels-Alder Reactions: endo-2-Acryloylisoborneol, C. Palomo, M. Oiarbide, J. M. Garcia, A. Gonzalez, A. Lecumberri, A. Linden, J. Am. Chem. Soc. 2002, 124, 10288 Paper - Not relevant. Not chiral acid, use of chiral aux. in Diels-Alder.
• General Approach for the Synthesis of Sarpagine Indole Alkaloids. Enantiospecific Total Synthesis of (+)-Vellosimine, (+)-Normacusine B, (-)-Alkaloid Q3, (-)-Panarine, (+)-Na-Methylvellosimine, and (+)-Na-Methyl-16-epipericyclivine, J. Yu, T. Wang, X. Liu, J. Deschamps, J. Flippen-Anderson, X. Liao and J. M. Cook, J. Org. Chem. 2003, 68, 7565-7581. Paper - diastereoselective
• Organocatalytic Asymmetric Aza-Friedel-Crafts Alkylation of Furan, D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc. 2004, 126, 11804-11805. Paper - Maybe include, but non-PS, simple extension of previous paper.
• Organocatalytic Asymmetric Direct Alkylation of α-Diazoester via C−H Bond Cleavage, D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc. 2005, 127, 9360-9361. Paper - extension to a system too far removed from PS reaction.
• Chiral Brønsted Acid Catalyzed Enantioselective Hydrophosphonylation of Imines:  Asymmetric Synthesis of α-Amino Phosphonates, T. Akiyama, H. Morita, J. Itoh and K. Fuchibe, Org. Lett. 2005, 7, 2583–2585. Paper - simple extension to other nucleophile.
• Stereocontrolled Total Synthesis of (-)-Eudistomin C, T. Yamashita, N. Kawai, H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc. 2005, 127, 15038-15039. Paper - Diastereoselective.
• An Improved Total Synthesis of (+)-Macroline and Alstonerine as Well as the Formal Total Synthesis of (-)-Talcarpine and (-)-Anhydromacrosalhine-methine, X. Liao, H. Zhou, J. Yu and J. M. Cook, J. Org. Chem. 2006, 71, 8884-8890. Paper - presumed diastereoselective, but relevant chemistry is actually in J. Org. Chem. 2000, 65, 3173.
• Total Synthesis of the Opioid Agonistic Indole Alkaloid Mitragynine and the First Total Syntheses of 9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol, J. Ma, W. Yin, H. Zhou and J. M. Cook, Org. Lett. 2007, 9, 3491-3494. Paper - diastereoselective.
• Total Synthesis of (–)-Corynantheidine by Nickel-Catalyzed Carboxylative Cyclization of Enynes, T Mizuno, Y. Oonishi, M. Takimoto, and Y. Sato, Eur. J. Org. Chem. 2011, 2606-2609. Paper - diastereoselective PS as part of longer synthesis.