Todd:Catalytic, Asymmetric Pictet-Spengler Reaction
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
Katina J. Selvaraj, 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
Alice E. Williamson, School of Chemistry, The University of Sydney, NSW 2006, Australia
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The Pictet-Spengler (PS) reaction is just over a century old.Pictet, Spengler 1911 The reaction is a cyclization between an amine that carries an aromatic ring, and an aldehyde, usually catalyzed by acid (Scheme 1911 Pictet Spengler 2). The original reaction employed formaldehyde and phenethylamine, to give the tetrahydroisoquinoline scaffold. Several years after the original report tryptamine was found to perform well in the reaction permitting access to a range of tetrahydrocarbolines.[Tatsui 1928] A wide range of variations on these original themes have been investigated,Stöckigt 2011, Whaley, Govindachari[Youn 2006][Larghi 2011] such as cases where the amine component is acylated or alkylated, those where ketones are employed rather than aldehydes so as to generate quaternary centres adjacent to the aromatic ring, and reactions employing alcohols rather than amines - the so-called oxo-PS reaction.
The reaction is important for two reasons. Firstly, Nature uses this chemistry. Enzymes ("pictet spenglerases") carry out the PS cyclization to produce important intermediates which feed into many biological pathways that result in bioactive small molecules, such as strychnine, morphine, vinblastine and reserpine.
All monoterpene indole alkaloids are thought to be made via this route, the key intermediate of which is strictosidine, formed from a PS reaction between tryptamine and secologanin.
Secondly, and probably consequently, the general structures one can access through the PS reaction - alkaloids with a stereocentre adjacent to an aromatic ring - are often highly bioactive, and are of interest for the development of new medicines. This has led to a great deal of interest in controlling the stereochemical outcome of PS reactions. Most of this work has involved understanding diastereoselective PS reactions, employing either an existing stereocentre that remains in the final product (often derived from an amino acid) or a stereocentre in a chiral auxiliary that is eventually removed, directs the ring closure.Cook 1995(Need: What was the first diastereoselective example? Cook 1992 Cook[Larghi 2005, review, no DOI][Youn 2006] This approach has been used in several notable total syntheses, among them (-)-suaveoline (Cook, 1992) and (-)-phalarine (Danishefsky, 2010). (Need: combine the two structures below with the general scheme for this part)
Several important pharmaceuticals may be synthesized with the PS reaction, for example the widely-used anthelmintic praziquantel, tadalafil (Cialis(TM)) used for erectile disfunction, the painkiller Etodolac and the promising new antimalarial compound NITD609 (Scheme Intro - Relevant Drugs). The biological activity of these compounds typically arises from one enantiomer: for example the (S) enantiomer of Etodolac (10.1021/jm00366a025) and the (R)- enantiomer of praziquantel (10.1371/journal.pntd.0000357); ent-NITD609 is inactive (10.1126/science.1193225). The potency of this class of compounds leads to great market value: $1.7 Bn for tadalafil alone in 2010.(Need: full reference inserting at end)(Eli Lilly Annual Report 2010, available at http://investor.lilly.com/annuals.cfm) Efficient enantioselective methods for the PS reaction would be very desirable, and progress to date in this field is the subject of this review. It is now certainly possible to carry out some PS reactions to give products with high enantiomeric excess. However, the scope of these processes is limited (as we shall see) reducing their impact on the preparation of bioactive compounds industrially. The PS reaction has been used in the racemic industrial synthesis of X, for example, but the enantiopure material is obtained through a resolution.(Need: example here - someone please check http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107522/)
Enantioselective approaches, where the stereocontrol of the cyclization is not governed by a stereocentre already in the cyclization precursor, have received much less attention than the diastereoselective, racemic or achiral version of the PS reaction. It was shown in 1996 that the PS reaction could be effected with superstoichiometric Lewis acid - in this case the cyclization of the (Z)-nitrone derived from Nb-hydroxytryptamine using diisopinocampheylchloroborane (Ipc2BCl) to give the corresponding tetrahydro-β-carboline products (Scheme Nakagawa 1998).(10.1016/0957-4166(96)00134-6 and 10.1021/jo980810h and 10.3987/REV-98-SR1) The racemic cyclization could be effected with Bronsted acid and a number of achiral Lewis acids, but it was found that Ipc2BCl gave high yields and ee with reduced temperatures. Lowering the quantity of Ipc2BCl to 0.5 eq. caused a significant reduction of yield, while attempts to alter the Lewis acidity by substitution of the chloride (with e.g. fluoride or triflate) did not improve yield or ee. The proposed reaction mechanism involved the formation of an iminium ion with coordination of the nitrone oxygen to the Ipc2BCl boron centre, and preliminary modeling confirmed a difference in transition state energies for approach of the indole from the re- and si-faces of the iminium ion. It was found that iminium ions derived from electron-deficient aldehydes gave poor enantioselectivity, but that these cyclizations were effective (with 74% ee in the case of the nitrone derived from 4-nitrobenzaldehyde) when a different reagent was added, a boronate incorporating two BINOL ligands (X) that had been previously described by Yamamoto for aldol-type reactions of imines.(10.1021/ja00102a019) The mechanism of action of such a boronate was suggested to involve replacement of one of the coordinating BINOL oxygen atoms with that on the nitrone, and it is not clear why such a mechanism could not operate catalytically. Nevertheless this was the first report of a reagent-controlled enantioselective PS reaction; earlier work by Nakagawa employing a similar approach had led to cyclization, but to give enantioenriched spiroindoline products.Paper Chiral Bronsted acids were ultimately successfully applied to the catalytic, enantioselective PS reaction through the use of a phosphoric acid, rather than a boronate, as described below.
A chiral Lewis acidic silane reagent (X, Scheme Leighton 2009) was shown to be effective in promoting highly enantioselective PS reactions.(Leighton 2009 10.1002/anie.200806110) The substrates (e.g., X) contained α-ketoamide ketimines: NMR studies suggested that following O-silylation, the proton from the NH group transfers to the reagent's nitrogen atom and activates the complex (X) to cyclization. Electron-withdrawing groups on the N-aryl ring improved the reaction rate. The quaternary stereocentre could be generated even with sterically demanding aryl groups appended to the imine, such as 1-naphthyl (product ee 87%). A one-pot procedure was also developed in which the initial amine and α-ketoamide were allowed to react, followed by the addition of the silane (X). The process was shown to be effective on a 5 mmol scale with 1.3 equivalents of silane, which was quantitatively recovered following work-up of the reaction. It was subsequently shown that the same (now commercially-available[Leighton 2010]) reagent could be used with similar effectiveness in the synthesis of the more ususual PS reaction products X and X, derived from the less common indole amines (1H-indol-4-yl)methanamine and 2-(1H-indol-1-yl)ethanamine.[Leighton 2012 10.1021/ol300922b] The latter heterocyclic framework had just been synthesized using the enzyme strictosidine synthase (see section X).
It is important to note that several papers have been published which contain brief sections devoted to topics covered in this review (Botta 2012, Jacobsen 2013, Cozzi 2015, Wang 2016). Although these articles do not focus specifically on asymmetric, catalytic Pictet-Spengler reactions, they demonstrate the broad range of applications of related chemistry.
It is perhaps surprising that there are still no examples of Lewis acid-catalyzed asymmetric PS reactions. In a recent study (10.1016/j.tetlet.2011.08.071) a small number of chiral Lewis acidic complexes were shown to effect conversion in a PS reaction between tryptamine and isatins, but there was negligible enantioinduction; high product ee was ultimately achieved with Bronsted acid catalysis, to which we now turn.
Brønsted Acid Organocatalysis
(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, which 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 arylated BINOLs 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 (What's "high" for this reaction? Akiyama reports 81-96% ee, and given that the group reports several "100% yields" I'm inclined towards suspicion -MAT). Limitations to the methodology were that an ortho hydroxy group was required on the N-aryl ring of the aldimine (Why? Mechanistic raionale? - MAT), and that aldimines derived from aliphatic aldehydes did not participate effectively. Typical catalyst loading was 10 mol%. The structure of the catalyst itself may be thought of as a chiral proton, i.e., a proton surrounded by a chiral environment, particularly given the aromatic rings of the BINOL and the 3-substituents are non-coplanar. However, the proposed mechanism operates 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)
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), utilizing acetylacetonate nucleophiles in place of silyl enolates. Terada, like Akiyama, notes the important influence of the 3,3'-position of the naphthyl rings on the enantioselectivity of the reaction. A followup paper later that same year incorporates furan nucleophiles (10.1021/ja046185h).
Since these early examples, several reactions have been reported 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 Brønsted 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.
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.
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.
This methodology has been employed in the syntheses of three natural products. The PS reaction used in the synthesis of (-)-arboricine (10.1021/ol900888e) (Scheme Hiemstra 2009) involved an aldehyde containing a dioxolane-protected ketone group. Aminal formation, observed when the ketone was used unprotected, was prevented. It is notable that this protecting group withstands the PS cyclisation, and that the yield and ee of the cyclization were both dramatically improved by its use. 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)
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.
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.
Bernardi and Bencivenni presented the first asymmetric synthesis of medicinally-relevant spiroindolones from tryptamines and isatins (Scheme Spiroindolones 2011) (10.1002/adsc.201100050). A number of (S)-BINOL derived phosphoric acids were screened, but all gave poor enantioselectivity except the (S)-TRIP catalyst originally used by List (A). The reaction performed best in DMF. The addition of molecular sieves gave no improvement, and it was found that the reaction can tolerate moisture. The conditions were applicable to tryptamines with electron-withdrawing or electron-donating substitutents at the 5-position, and to a variety of substituted isatins, although the presence of a bulky benzyl substituent at nitrogen reduced enantioselectivity. At the same time, Franz screened a greater variety of catalysts in reactions between 5-methoxy tryptamine and isatins (10.1016/j.tetlet.2011.08.071). Lewis acidic complexes proved ineffective, and although a thiourea catalyst gave some enantioselectivity, it was determined that (S)- and (R)-BINOL derived phosphoric acids were most effective, giving very high enantioselectivities and yields in some cases. Notably, phosphonic acid gave near quantitative yield but no enantioselectivity. The 3,3'-substituents on the BINOL ring system strongly influenced the enantioselectivity; interestingly, even when the substituents were changed such that the axial chirality was reversed (for example, from 9-anthracenyl to 2,4,6-tri-i-Pr-phenyl), the same spiroindolone enantiomer resulted, that is, the sense of enantioselection was inverted. The (S)-TRIP catalyst used by Bernardi and Bencivenni was investigated again (Scheme Spiroindolones (B)). Various substituted isatins were well tolerated, but tryptamines with substituents at positions other than the 5-position were not. This method was extended to N-propargylated isatins, and the resulting N-propargylated spiroindolones were converted to biologically interesting triazoles via copper-catalysed azide-alkyne cycloaddition reactions (10.1021/co300003c).
Chiral phosphoric acids have also been used in catalytic asymmetric PS-type reactions to give 7-membered indolo[3,4-cd]-benzapines x. Tian and co-workers reported the phosphoric acid catalysed reaction of 4-(2-aminoaryl)insoles x with para-methoxybenezene (PMB) protected aryl imines. X (Scheme X). The researchers screened a number of imine and aldehyde nucleophiles and found that: 1) PMB to be the optimum imine protecting group, 2) the reaction proceeded with higher ee at greater concentration and 3) PMB protected imines reacted with higher enantioselectivity than their corresponding aldehyde (90 compared to 83% ee).
Control reactions with N–Methyl indole x gave the corresponding product in just 3% ee. This result suggested that the indole NH may play an important role in the transition state determining enantioselectivity. Taken together with the postulated importance of the H2NPMP leaving group, Tian proposed a transition complex where the cyclisation precursor x, catalyst x and trans-imination byproduct x are organised through hydrogen bonding, resulting in highly enantioselective cyclisation.
A noteworthy experiment showed the reluctance of 4-(2-aminophenyl)-7-azaindole x to react with PMP protected imine x under analogous reaction conditions. Intriguingly, the corresponding aldehyde x did react and gave the desired product x in good yield and high ee (77 and 90% respectively). This result again highlights the importance of hydrogen-bonding in the transition state and could also suggest that changing the nucleophile from imine to aldehyde results in a different mechanistic pathway.
SPINOL-derived phosphoric acids have also found widespread use as catalysts for asymmetric Pictet-Spengler reactions and related reactions. These catalysts are structurally similar to BINOL-derived phosphoric acids, however, they are more rigid. In some reactions, SPINOL-derived catalysts have shown greater activity and enantioselectivity than BINOL-derived catalysts. The first example of their use in enantioselective Pictet-Spengler reactions employed N-protected tryptamines to give N-protected tetrahydro-β-carbolines, which could be further utilised in the synthesis of bioactive compounds (Scheme 2013-2015 SPINOLs (A)) (10.1002/chem.201103207). Using the reaction between N-α-naphthylmethyl tryptamine and p-bromobenzaldehyde as a model, a variety of BINOL- and SPINOL-derived catalysts was screened; the catalyst shown gave the best results. The reaction proceeded well in both polar and non-polar solvents. A range of aliphatic and aromatic aldehydes was tolerated, but it seems that an aromatic N-protecting group was required on the tryptamine. Replacing the indole hydrogen with a methyl group decreased the enantioselectivity significantly. To demonstrate the utility of the reaction, it was employed in an asymmetric total synthesis of (-)-harmicine. Similar SPINOL-phosphoric acids have since been used to catalyse an iso-Pictet-Spengler reaction between C-2-linked o-aminobenzylindoles and trifluoromethyl ketones to give benzazepinoindoles (Scheme 2013-2015 SPINOLs (B)) (10.1039/c4cc02295e), and a Pictet-Spengler-type reaction between 2-(1H-pyrrol-1-yl)anilines and α-ketoamides to give pyrrolobenzo-1,4-diazines (Scheme 2013-2015 SPINOLs (C)) (10.1002/chem/201500823). These examples indicate the broad substrate scope of this approach, and scale-up experiments were successful in both cases. Interestingly, when an N-H (capable of hydrogen bonding) was replaced by N-Bn or N-Me (incapable of hydrogen bonding), the reaction did not proceed at all. The catalyst shown in (B) has also been utilised in reactions between N-allyltryptamines and 1,n-allenalaldehydes to give tetrahydro-β-carbolines bearing 1-substituted allenes (10.1021/500448j) and 1,3-substituted allenes (10.1002/chem.201500273).
Hiemstra used the enantiomer of (S)-TRIP, (R)-TRIP, as a catalyst in the synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines from N-substituted phenylethylamines (Scheme Hiemstra 2014) (10.1021/jo501099h). The phenylethylamine starting material was essentially a dopamine derivative: the 3-hydroxy substituent activates the para-position for ring closure, while the 4-methoxy substituent protects the catechol moiety against air oxidation. The primary amine itself, and N-methyl and N-benzyl phenylethylamines gave inadequate ortho/para regioselectivity and poor enantioselectivity, but N-(o-nitrophenylsulfenyl) phenylethylamines gave very high regioselectivity (less than 5% ortho product) and improved enantioselectivity. It was suggested that this moderately electron-withdrawing substituent prevented catalysis by weakly acidic phenolic OH, and thus increased catalysis by the BINOL-derived phosphoric acid. The enantioselectivity was further increased by adding (S)-BINOL as cocatalyst, and by flowing argon over the solution at 90 °C to azeotropically remove water (other drying agents had a detrimental effect on yield and enantioselectivity). Benzaldehydes with an electron-withdrawing substituent at the para-position performed well. However, p-methoxy benzaldehyde and benzaldehyde itself gave poor enantioselectivities, as did benzaldehydes with substituents at the meta- or ortho-positions. Aliphatic aldehydes performed better, with further improvement upon addition of acetic acid as cocatalyst. The enantiomeric purity of some products was improved by recrystallisation, but yields were reduced significantly due to crystallisation of a racemate. This methodology was used to synthesise a number of natural products and potential drugs.
This approach was extended to the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines (10.1021/acs.joc.5b00509). In addition to the methoxy substituent previously employed, a methoxymethyl (MOM) substituent was also employed to protect the catechol. This group is readily removed by acid, and its use allowed the preparation of isoquinolines with varying substituents at the 6- and 7-positions (Scheme Hiemstra 2015). The reaction was applicable to a variety of reactive substituted phenylacetaldehydes, but it had to be performed at room temperature to prevent decomposition. As a result, azeotropic removal of water was not possible, so magnesium sulfate was used as a drying agent instead.
Seidel demonstrated a novel internally conjugate-base-stabilised Brønsted acid catalysis strategy which addresses one of the major challenges in Pictet-Spengler methodology -- the low reactivity of the imine or iminium ion intermediates -- to enable reactions of unmodified tryptamine (Scheme Seidel 2014) (10.1021/ol403773a). The catalyst has both a carboxylic acid group and an anion-recognition site; Seidel proposed that the carboxylic acid group protonates the initially formed imine, giving an iminium ion, while the anion-recognition site stabilises the resulting carboxylate ion via hydrogen bonding. It is thought that the cationic iminium ion and the anionic deprotonated catalyst form an ion pair (inset) in which the iminium ion is more reactive because it is not stabilised by hydrogen bonding. Using the reaction of tryptamine and p-chlorobenzaldehyde as a model reaction, catalysts with various anion-recognition sites were evaluated. A catalyst with a thiourea group gave the greatest enantioselectivity (94% ee), however, yields remained low (38%), even after extending the reaction time from 48 h to 96 h. This was likely due to product inhibition: the product is more basic than the starting materials. Achiral Brønsted acids (unable to promote the racemic reaction) were added to protonate the product and therefore reduce product inhibition. Malonic acid gave the best result, increasing the yield (>95%) without reducing the enantioselectivity significantly, but this additive was ineffective with other aldehydes. Alternatively, the products were Boc-protected in situ, which successfully reduced product inhibition. To prevent the formation of N-Boc tryptamine, tryptamine and p-chlorobenzaldehyde were allowed to form the imine before (Boc)2O was added. This strategy was applicable to benzaldehyde itself, and benzaldehydes with electron-withdrawing subsitutents at the para-position, but not to benzaldehydes with electron-donating substituents or with substituents at other positions. Aliphatic aldehydes also performed poorly.
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. A number of studies on the reactivity of iminium ions have revealed that their substitution pattern accounts for their 'cationic character'. N-acyliminium ions represent some of the most reactive electrophilic systems. The electron-withdrawing group reduces the amount of electron density on the nitrogen and therefore its ability to stabilise the cation. Electrophilic addition to acyliminiums is generally fast and irreversible whereas additions to less reactive N-alkyliminiums can be reversible. Ref
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.
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.
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.
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. The absolute configuration of the molecule was established through the highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction at the start of the synthesis.
In the same year Jacobsen extended the scope of possible aromatic nucleophiles for the thiourea-catalysed ‘’N’’-acyl-Pictet-Spengler reaction to include pyrroles (Jacobsen_2008). Pyrrolohydroxylactams were shown to undergo Pictet-Spengler cyclisation in good yields using reaction conditions very similar to those employed for corresponding β-indolyl ethyl hydroxylactam condensations. Jacobsen used the same thiourea catalyst employed in the above synthesis of (+)-Harmicine (same as in Scheme: (Jacobsen 2007)). Total Synthesis of (+)-Harmicine), albeit at a loading double that required for the indole nucleophiles. For the majority of pyrrole substrates examined, very high enantioselevtivity was achieved. Further to this, Jacobsen was able to illuminate the regioselectivity of the catalyst by exploiting the fact that pyrroles possess two nucleophilic sites at C2 (or C5) and C3 (or C4). Regiocontrol was induced using the bulky protecting group, triisoproylsilyl (TIPS) attached to the pyrrole nitrogen so as to favour C4-selective cyclisations. High yields were achieved with excellent enantioselectivity reported in most cases.
In 2009, Jacobsen published complementary research into the intermolecular addition of indoles to N-acyliminium ions. A chiral thiourea Schiff base was used to catalyse the highly enantioselective reaction of both electron-rich and electron-deficient indole nucleophiles using a catalyst loading of 5 mol % and 10 mol % respectively Jacobsen 2009 (2).
(KAB adding stuff) In the same year, 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. Benzoic acid was required for the reaction to proceed with aryl aldehydes. Aliphatic aldehydes did not require benzoic acid - increased ee. Less nucleophilic tryptamines, such as the 5-methoxy were unreactive under neutral conditions. Unclear why.
The proposed catalytic cycle describes imine protonation 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.
In 2011, Jacobsen, Lee, and Klausen published further work on a thiourea/benzoic acid cocatalyzed "iso-Pictet-Spengler" reactions, so named due to the alternate connectivity of the 2-substituted isotryptamine starting material. This altered substrate permits synthesis of optically pure tetrahydro-γ-carbolines. Jacobsen reports a straightforward procedure for upgrading the produced tetrahydro-γ-carbolines' enantiopurity through Boc protection of the free amine, followed by crystallization or trituration. This simple preparative step elevates the ee to >99% in nearly all published examples. The group's optimized conditions are applied to a single aromatic ketone, generating a quaternary center with high ee (98% post-trituration), albeit with reduced yield (53%, 2 steps). Jacobsen cautions that one limitation of the method is the need for a slight excess of the thiourea catalyst relative to BzOH, to avoid a deleterious racemic background reaction.
In 2010, for use in a non-Pictet-Spengler reaction, Jacobsen highlighted the correlation between an increase in the stabilising cation-π interaction abilities of a thiourea catalyst and an increase in reaction enantioselectivity. Incrementally larger arene substituents were attached to a thiourea catalyst for use in the bicyclisation of hydroxylactam Jacobsen 2010. Yield and ee increased correspondingly. However, the use of nucleophiles with aromatic systems larger than 4-pyrenyl had a negative effect on either enantioselectivity or reactivity. Whether a similar trend would be observed when applying such catalysts to the Pictet-Spengler reaction is yet to be determined.
Alternative Nucleophiles in the Catalytic Asymmetric Pictet Spengler Reaction
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" Paper - 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.
Strictosidine Synthase Mechanism: O'Connor 2008 compares acid-base effects of non-enzymatic aqueous solution vs. enzyme-catalysed reactions (using kinetic isotope effects). The rate-determining step appears to be the same for both systems. O'Connor also discusses the pH dependence of enzymatic catalysis, but not for binding of substrate, and proposes an enzyme mechanism involving key residue Glu309; deprotonation of tryptamine increases its nucleophilicity for aldehyde attack (emphasis on proximity of the Glu residue to the substrate). Lack of significant conformational change on binding of the substrate.
O'Connor 2010 TL - 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 key Glu309, a carboxylate residue in the active site.
With regard to the mechanisms of SPINOL-derived phosphoric acid catalysed reactions:
- Lin and Wang (10.1002/chem.201103207) propose that "the [indole] N-H bond of the tryptamine enhances the enantioselectivity...the bifunctional nature of the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic iminimum intermediate, generated in situ through hydrogen-bonding interactions in the Pictet-Spengler reaction".
- Lin (10.1039/c4cc02295e) again suggests that "the bifunctional nature of the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic group of the ketoimine intermediate through hydrogen bonding".
- Lin (10.1002/chem.201500823) presents computational studies suggesting "an unexpected attractive non-classical arene C-H···N hydrogen bond". Again, "the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic group of the substrate through a two-point catalyst-substrate hydrogen bonding interaction". Also, "triple hydrogen bonds hold the transition structure rigidly and allow the catalyst's 9-phenanthryl groups to influence the enantioselectivity...the directing effect of the triple hydrogen-bonding interaction is crucial in the catalyst activating the reaction and inducing chirality".
Mechanism explanations? Mechanistic Insights into a BINOL-Derived Phosphoric Acid-Catalysed Asymmetric Pictet-Spengler Reaction, L. M. Overvoorde, M. N. Grayson, Y. Luo, J. M. Goodman, J. Org. Chem 2015, 80, 2634-2640. [htt://dx.doi.org/10.1021/jo5028134 Paper]
ILT - Mar 29 2016 - Interactions between Thiourea and Imines. Prelude to Catalysis, V. de P.N. Nziko and Steve Scheiner, J. Org. Chem. 2015, 80, 10334−1034. Paper - ab initio calculations for thiourea-imine interaction
(Aim of this section should be to describe preparative uses of these enzymes, and whether they are able to do reactions we can't with small molecules. Mechanistic insights (crucial here) should go in the mechanism section, to provide a comparison with what's known of small molecule systems.)
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 tetrahydroisoquinoline or tetrahydro-β-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 (NCS), 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 utilizing a multi-enzyme cascade. First, the group transferred the genes encoding tryptamine halogenase RebH (from soil bacteria) into C. roseus hairy root culture. They then developed a modified STR enzyme, STRvm, capable of recognizing and turning over halogenated Trp precursors. The group used MS and 2D NMR methods to confirm detection of downstream halogenated alkaloids. (O'Connor, Nature 2010, 461)
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.
The substrate tolerance of strictosidine synthase was further extended by Stockigt and a multi-institutional team in a JACS 2012 paper. 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.
An alternative approach to the plant-derived chemoenzymatic synthesis of indole alkaloids has been discovered in the use of a transgenic yeast culture of Saccharomyces cerevisiae (Verpoorte, 2001). The cDNAs of STR and strictosidine glucosidase (SGD) from Catharanthus roseus were introduced into a buffered solution of the yeast culture and left to grow for two days. Secologanin and tryptamine were then added and after a two-day incubation period, strictosidine formed in concentrations up to 2 gL 1 in the medium. Moreover, Verpoorte et al. demonstrated the effective use of Symphoricarpus albus berry extract as a more affordable, alternative source of secologanin compared to the commercially available substrate. No effect on alkaloid yield was observed when the extract was used in place of pure secologanin.
In 2016 Kroutil et al. reported the two-step, catalyst-directed diastereoselective synthesis of novel C3-methylated strictosidine derivatives using ω–transaminase and STR enzymes. The first stereogenic centre was created during the amination of five different prochiral indolylketones employing L- and D-alanine catalysed by (S)- and (R)-selective transaminase, respectively. The (S)- and (R)-α-methyltryptamine enantiometrically pure products were subsequently condensed with secologanin in a Pictet-Spengler reaction using STRs sourced from five different plants. Of the five enzymatic catalysts employed, the STR procured from Ophiorriza pumila (OpSTR) resulted in the highest yields of the C3-methyl-substituted strictosidine derivatives (up to 97 %) with diastereomeric excesses of >98 % reported. The STR derived from Rauvolfia serpentina (RsSTR) and a mutant V208A (RvSTR) variant were also capable of catalyzing this reaction however they proved to be three times less active than OpSTR. Synthesis was conducted both simultaneously, using a one-pot cascade approach, and in a stepwise manner. For all active STRs, performing the reaction in a stepwise fashion resulted in higher yields. Kroutil hypothesised that this may be the result of transaminase catalysing the amination of secologanin when using the one-pot approach.
A complementary study was undertaken to establish whether the stereoselectivity of the Pictet-Spengler reaction is dependent upon the presence of the STR. An experiment was designed which compared the stereochemical outcome of the Pictet-Spengler reaction with the presence of OpSTR being the only variable. When OpSTR was used the Pictet-Spengler reaction product with an (R)-configuration at C1 formed preferentially over the other diastereomer. When the reaction proceeded in the absence of the enzyme, the (S)-diastereomer formed preferentially; thus demonstrating that the stereochemistry of the reaction is indeed catalyst-directed.
We now turn to the preparative applications of another well-documented Pictet-Spenglerase, norcoclaurine synthase (NCS). In 2010, Macone et al. published what they claimed to be the first example of a green Pictet-Spengler reaction. With the aim of producing a scalable, clean and efficient synthetic route to (S)-norcoclaurine, a one-pot chemoenzymatic approach was developed using recombinant NCS from Thalictrum flavum in aqueous conditions. Using a bacterial E. coli expression system optimised in previous work (Ilari 2008, 2009), His-tagged NCS was employed to catalyse the Pictet-Spengler condensation of dopamine with 4- hydroxyphenylacethaldehyde (4-HPAA). This afforded (S)-norcoclaurine in high yield (>80 %) and 93 % ee. The main factor limiting attempts to scale up such a synthesis is the instability of the substrates in aqueous conditions at pH 7. Dopamine readily oxidises in aqueous solutions exposed to air and 4-HPAA polymerises in both acidic and basic conditions. In order to address the problem associated with dopamine, the authors trialled a variety of modifications to the reaction conditions including de-aeration, different solvent mixtures and the addition of reductants. The addition of sodium ascorbate to the reaction mixture was found to be the most effective approach and in the presence of this reductant, dopamine concentrations increased ten-fold. Synthesis of 4-HPAA in situ in the presence of hypochlorite reduces the likelihood of polymerisation. However, the authors agreed that this unwanted side reaction still limits the potential of this chemoenzymatic synthesis.
The use of enzymes to catalyse the Pictet-Spengler reaction has increased the versatility of the Pictet-Spengler reaction and allowed for access to a greater variety of asymmetric tetrahydroisoquinoline and tetrahydro-β-carboline motifs. However the in the presence of Pictet-Spenglerases only a relatively small number of substrates show high activity. In order to address this issue and expand the substrate library, Hailes et al. developed a novel fluorescence-based high throughput assay designed to determine the tolerance of Coptis japonica norcoclaurine synthase (CjNCS2) for a range of non-natural substrates. The assay was used to investigate the activity of nearly forty aldehyde and amine analogues in CjNCS2. The assay was comprised of fluorescamine in spirolacetone which produces highly fluorescent pyrrolidinones in the presence of primary amines, such as dopamine, and non-fluorescent furanones in the presence of secondary amines, such as norcoclaurine. In this way it was possible to quantitatively track the depletion of the primary amine substrate during the Pictet-Spengler condensation, and thus determine the substrate’s activity in the enzymatic catalyst. Hailes et al. conducted assays of numerous aryl and aliphatic acetaldehyde and aldehyde analogues with varying substitution patterns, and electron-withdrawing and donating groups. These studies revealed that para-substituted arylacetaldehydes were very active in CjNCS2 with conversion rates >80 % for both electron-withdrawing and donating substituted analogues. In contrast, meta-substituted analogues were tolerated to a smaller extent with conversion rates near 50 %. The enzyme shows little or no tolerance for the benzaldehydes studied and 2-napthaldehyde. In addition, it was demonstrated that CjNCS2 does not tolerate sterically hindered substrate analogues, such as cinnamaldehyde. Similarly, the group investigated the activity of CjNCS2 against an array of aromatic amine substrates. In their reaction with 4-HPAA, amine analogues possessing a meta-phenol group were shown to be particularly well tolerated by the enzyme with conversion rates ranging from 33-81 %. However, the introduction of a hydroxyl moiety to the ethylamine functional group significantly reduced the enzyme’s tolerance of the substrate. In the absence of this meta-phenol, substrates proved non-active. Similarly, electron-donating amines and halides in the meta-position were not tolerated by the enzyme.
Miscellaneous Related Systems, or Known Catalysts not yet used for the 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.
Non-BINOL derived Bronsted acids (other relevant, perhaps tartrate-derived, biologically relevant?)
Internal Lewis-acid assisted urea catalysis (see: Mattson, OL 2011 and 2012)
Enzyme mutagenesis to accept varied heterocyclic precursors (thiophenes, furans, pyrroles), extension of Stockigt 2012 work
"Interrupted" Pictet-Spengler reactions, perhaps to start cascade synthesis
Merge Denmark and Leighton work, see if "base-assisted silicon catalysis" might turn over the PS
Lewis acids for Friedel-Crafts-type reactions: http://www.sciencedirect.com/science/article/pii/S0040402009009302
PS of non-activated phenethylamine with aldehydes to give THIQs: One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler reaction using zeolite catalysts, Adrienn Hegedus and Zoltan Hell, TetLett 2004 45, 8553–8555. DOI: 10.1016/j.tetlet.2004.09.097 Paper
PS of non-activated phenethylamine to give THIQ (clay): Pictet-Spengler condensation reactions catalyzed by a recyclable H+-montmorillonite as a heterogeneous Brønsted acid, DOI: 10.1007/s11426-010-0073-4
Achiral LA-catalysed PS to give THIQs: Catalytic Pictet-Spengler reactions using Yb(OTf)3, Manabe, K., D. Nobutou, et al. Bioorganic & Medicinal Chemistry 2005 13(17): 5154-5158. DOI: 10.1016/j.bmc.2005.05.018 Paper
- Development of the Pictet-Spengler Reaction Catalyzed by AuCl3/AgOTf, S. W. Youn, The Journal of Organic Chemistry 2006 71(6), 2521-2523. DOI: 10.1021/jo0524775 Paper
- Calcium-Promoted Pictet-Spengler Reactions of Ketones and Aldehydes, M. J. V. Eynden, K. Kunchithapatham, J. P. Stambuli, Journal of Organic Chemistry 2010, 75, 8542. DOI: 10.1021/jo1019283 Paper
Conclusions, and what's needed in this field
We will write this section last. Conclusions to address advantages and disadvantages of known systems, wrt temp, recoverability, ee, substrate scope.
Currently no examples of catalytic, asymmetric oxa-PS reaction? Review of oxo-PS is Larghi 2011, and has no cat. enantioselective examples
There might be, but if so, they're covered under different names...like Prins cyclizations, Friedel-Crafts, or anomeric (sugar) arylation. It might require a lot of digging! - MAT
An (S)-BINOL-phosphoric acid was employed to catalyse an asymmetric oxa-Pictet-Spengler reaction as part of an iridium(III)-catalysed isomerisation/Brønsted acid catalysed Prins-type cyclisation sequence. It was suggested that the acid protonates the enol ether substrate to generate an oxocarbenium ion intermediate, which then forms an ion pair with the chiral conjugate base and undergoes an oxa-Pictet-Spengler reaction. Pyran-fused indoles were obtained in up to 75% yield with 60% ee. (A Tandem Isomerization/Prins strategy: Iridium(III)/Bronsted Acid Cooperative Catalysis, V. M. Lombardo, C. D. Thomas and K. A. Scheidt, Angew. Chem. Int. Ed. 2013, 52, 12910-12914. Paper)
Design of "mini-proteins" (think Marcey Waters, Manfred Reetz, or Scott Miller) to accomplish PS reaction in non-biological environment
Substrate limitations: all known examples are based on tryptamine. No examples with original PS system of an activated benzene ring. No examples with other Ar rings such as furans, thiophenes? One with pyrroles (Jacobsen). One iso-PS reaction (Jacobsen). Recent example of cat asymm on ISQ ring system - first reported: Monitoring On-Chip Pictet-Spengler Reactions by Integrated Analytical Separation and Label-Free Time-Resolved Fluorescence, Ohla Stefan; Beyreiss Reinhild; Fritzsche Stefanie; et al. Source: CHEMISTRY-A EUROPEAN JOURNAL 2012, Volume: 18, 1240-1246 DOI: paper
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)
- Ueber die Bildung von Isochinolin-derivaten durch Einwirkung von Methylal auf Phenyl-aethylamin, Phenyl-alanin und Tyronsin, A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036. Paper
- Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92 (may be 453-459). Need to find this paper!
- The Pictet-Spengler Condensation: A New Direction for an Old Reaction, E. D. Cox and J. M. Cook, Chem. Rev. 1995, 95, 1797- 1842 Paper
- Asymmetric Synthesis of Isoquinoline Alkaloids, M. Chrzanowska and M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341-3370 Paper
- The Pictet-Spengler Reaction in Nature and in Organic Chemistry, J. Stöckigt, A. P. Antonchick, F. Wu and H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 8538-8564 Paper
- The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds, W. M. Whaley and T. R. Govindachari, Organic Reactions 1951, 6, 151-190 Paper
- Enantiospecific Total Synthesis of the Ajmaline Related Alkaloids (-)-Suaveoline, (-)-Raumacline, and (-)-Nb-Methylraumacline, X. Fu and J.M. Cook, J. Am. Chem. Soc. 1992, 114, 6910-6912 Paper
- Resolution of etodolac and anti-inflammatory and prostaglandin synthetase inhibiting properties of the enantiomers, C. A. Demerson, L. G. Humber, N. A. Abraham, G. Schilling, R. R. Martel and C. Pace-Asciak, J. Med. Chem 1983, 26, 1778-1780. Paper
- The Pictet-Spengler Reaction: Efficient Carbon-carbon Bond Forming Reaction in Heterocyclic Synthesis, S. W. Youn, Org. Prep. Proc. Int. 2006, 38, 505-591 [Paper]
- Taste, A New Incentive to Switch to (R)-Praziquantel in Schistosomiasis Treatment, T. Meyer, H. Sekljic, S. Fuchs, H. Bothe, D. Schollmeyer, C. Miculka, PLoS Negl Trop Dis 2009, 3, e357 Paper
- Spiroindolones, a Potent Compound Class for the Treatment of Malaria, M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E. González-Páez, S. B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175-1180 Paper
- The Total Synthesis of Enantiopure Phalarine via a Stereospecific Pictet-Spengler Reaction: Traceless Transfer of Chirality from L-tryptophane, J.J. Trzupek, D. Lee, B.M. Crowley, V.M. Marathias, S.J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 8506-8512 Paper
- Synthesis of Oxacycles Employing the Oxa-Pictet-Spengler Reaction: Recent Developments and New Prospects, E. L. Larghi and T. S. Kaufman, Eur. J. Org. Chem. 2011, 5195-5231 Paper
Diastereoselective Intro Section:
- 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
- The Intermolecular Pictet-Spengler Condensation with Chiral Carbonyl Derivatives in the Stereoselective Syntheses of Optically-active Isoquinoline and Indole Alkaloids, E. L. Larghi, M. Amongero, A. B. J. Bracca and T. S. Kaufman, ARKIVOC 2005 (xii) 98-153. [Link here: http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2005/12/]
Lewis Acid Intro Section:
- A New Evidence for the Presence of a Spiroindolenium Species in the Pictet-Spengler Reaction, T. Kawate, M. Nakagawa, K. Ogata, and T. Hino, Heterocycles, 1992, 33, 801-811. [Need DOI]
- A New Chiral BLA Promoter for Asymmetric Aza Diels-Alder and Aldol-Type Reactions of Imines, K. Ishihara, M. Miyata, K. Hattori, T. Tada and H. Yamamoto, J. Am. Chem. Soc. 1994, 116, 10520–10524. Paper
- Enantioselective Asymmetric Pictet-Spengler Reaction Catalyzed by Diisopinocampheylchloroborane, T. Kawate, H. Yamada, T. Soe and M. Nakagawa, Tetrahedron: Asymmetry 1996, 7, 1249-1252 Paper
- 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
- Pictet-Spengler Reactions of N-b-Hydroxytryptamines and Their Application to the Synthesis of Eudistomins, T. Hino and M. Nakagawa, Heterocycles 1998, 49, 499-531 Paper
- Highly Enantioselective Pictet–Spengler Reactions with α-Ketoamide- Derived Ketimines: Access to an Unusual Class of Quaternary α-Amino Amides, F. R. Bou-Hamdan and J. L. Leighton, Angew. Chem. Int. Ed. 2009, 48, 2403-2406 Paper
- Powerful and Versatile Silicon Lewis Acids for Asymmetric Chemical Synthesis, J. L. Leighton, Aldrichimica Acta 2010, 43, 3-12 [Paper available at http://www.sigmaaldrich.com/chemistry/chemical-synthesis/learning-center/aldrichimica-acta.html]
- Direct and Highly Enantioselective Iso-Pictet Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures, Heike Schönherr and James L. Leighton, Org. Lett. 2012, 14, 2610-2613 Paper
- 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. 
- 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
- An Easy Entry to Optically Active Spiroindolinones: Chiral Brønsted Acid-Catalysed Pictet-Spengler Reactions of Isatins, S. Duce, F. Pesciaioli, L. Gramigna, L. Bernardi, A. Mazzanti, A. Ricci, G. Bartoli and G. Bencivenni, Adv. Synth. Catal. 2011, 353, 860-864. 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
- Catalytic Stereoselective Synthesis of Diverse Oxindoles and Spirooxindoles from Isatins, J. P. MacDonald, J. J. Badillo, G. E. Arevalo, A. Silva-García and A. K. Franz, ACS Comb. Sci. 2012, 14, 285-293. Paper
- Catalytic Asymmetric Pictet–Spengler- Type Reaction for the Synthesis of Optically Active Indolo[3,4-cd]benzazepines, D-J. Cheng, H-B Wu, S-K. Tian, Org. Lett. 2011, 13, 5636-5639. Paper
- Highly Enantioselective Pictet-Spengler Reaction Catalyzed by SPINOL-Phosphoric Acids, D. Huang, F. Xu, X. Lin and Y. Wang, Chem. Eur. J. 2012, 18, 3148-3152. Paper
- Enantioselective synthesis of benzazepinoindoles bearing trifluoromethylated quaternary stereocenters catalyzed by chiral spirocyclic phosphoric acids, X. Li, D. Chen, H. Gu and X. Lin, Chem. Commun. 2014, 50, 7538-7541. Paper
- Triply Hydrogen-Bond-Directed Enantioselective Assembly of Pyrrolobenzo-1,4-diazine Skeletons with Quaternary Stereocenters, X. Shen, Y. Wang, T. Wu, Z. Mao and X. Lin, Chem. Eur. J. 2015, 21, 9039-9043. Paper
- Pd(0)-Catalyzed Tandem Deprotection/Cyclization of Tetrahydro-β-carbolines on Allenes: Application to the Synthesis of Indolo[2,3-ɑ]quinolizidines, Valerian Gobé and Xavier Guinchard, Org. Lett. 2014, 16, 1924-1927. Paper
- Stereoselective Synthesis of Chiral Polycyclic Indolic Architectures through Pd0-Catalysed Tandem Deprotection/Cyclization of Tetrahydro-β-carbolines on Allenes, Valérian Gobé and Xavier Guinchard, Chem. Eur. J. 2015, 21, 8511-8520. Paper
- Organocatalytic Enantioselective Pictet-Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines, E. Mons, M. J. Wanner, S. Ingemann, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2014, 79, 7380-7390. Paper
- Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids, A. Ruiz-Olalla, M. A. Würdemann, M. J. Wanner, S. Ingemann, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2015, 80, 5125-5132. Paper
- Conjugate-Base-Stabilized Bronsted Acids: Catalytic Enantioselective Pictet-Spengler Reactions with Unmodified Tryptamine, N. Mittal, D. X. Sun and D. Seidel, Org. Lett. 2014, 16, 1012-1015. Paper
- 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, 13404-13405. Paper
- Catalytic Asymmetric Total Synthesis of (+)-Yohimbine, D. J. Mergott, S. J. Zuend and E. N. Jacobsen, Org. Lett. 2008, 10, 745-748. Paper
- Regio- and Enantioselective Catalytic Cyclization of Pyrroles onto N-Acyliminium Ions, I. T. Raheem, P. S. Thiara, and E. N. Jacobsen, Org. Lett. 2008, 10, 1577-1580. Paper
- Enantioselective, Thiourea-Catalyzed Intermolecular Addition of Indoles to Cyclic N-Acyl Iminium Ions, E.A. Peterson and E.N. Jacobsen, Angew. Chem. Int. Ed. 2009, 48, 6328–633. 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
- Enantioselective Thiourea-Catalyzed Cationic Polycyclizations, R.R. Knowles, S. Lin, and E.N. Jacobsen, J. Am. Chem. Soc. 2010, 132, 5030–5032. Paper
- Thiourea-Catalyzed Enantioselective Iso-Pictet-Spengler Reactions, Y. Lee, R. S. Klausen and E. N. Jacobsen, Org. Lett. 2011, 13, 5564-5567. Paper
- Biotransformation of tryptamine and secologanin into plant terpenoid indole alkaloids by transgenic yeast, A. Geerlings, F. Redondo, A. Contin, J. Memelink, R. van der Heijden and R. Verpoorte, Appl. Microbiol. Biotechnol. 2001, 56, 420-424. Paper
- Strictosidine Synthase: Mechanism of a Pictet-Spengler Catalyzing Enzyme, J.J. Maresh, L-A. Giddings, A. Friedrich, E.A. Loris, S. Panjikar, B.L. Trout, J. Stockigt, B. Peters, S.E. O'Connor. J. Am. Chem. Soc. 2008, 130, 710-723. Paper
- Cloning, expression, crystallization and preliminary X-ray data analysis of norcoclaurine synthase from Thalictrum flavum, A. Pasquo, A. Bonamore, S. Franceschini, A. Macone, A. Boffi and A. Ilari, Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. 2008, 64, 281–283. Paper
- Structural Basis of Enzymatic (S)-Norcoclaurine Biosynthesis, A. Ilari, S. Franceschini, A. Bonamore, F. Arenghi, B. Botta, A. Macone, A. Pasquo, L. Bellucci and A. Boffi, J. Biol. Chem. 2009, 284, 897–904. Paper
- Integrating carbon-halogen bond formation into medicinal plant metabolism, W. Runguphan, X. Qu, S.E. O'Connor. Nature 2010, 468, 461-467. Paper
- Biocatalytic Asymmetric Formation of Tetrahydro-B-carbolines, P. Bernhardt, A.S. Usera, and S.E. O'Connor, Tetrahedron Lett. 2010, 51, 4400-4402. Paper
- An enzymatic, stereoselective synthesis of (S)-norcoclaurine, A. Bonamore, I. Rovardi, F. Gasparrini, P. Baiocco, M. Barba, C. Molinaro, B. Botta, A. Boffia, and A. Macone, Green Chem. 2010, 12, 1623–1627. Paper
- 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. Zou, and J. Stöckigt, J. Am. Chem. Soc. 2012, 134, 1498-1500. Paper
- The Catalytic Potential of Coptis japonica NCS2 Revealed – Development and Utilisation of a Fluorescamine-Based Assay, T. Pesnot, M. C. Gershater, J. M. Ward and H. C. Hailes, Adv. Synth. Catal. 2012, 354, 2997–3008. Paper
- Stereoselective Cascade to C3-Methylated Strictosidine Derivatives Employing Transaminases and Strictosidine Synthases, E.-M. Fischereder, D. Pressnitz and W. Kroutil, ACS Catal. 2016, 6, 23−30. Paper
Papers we're not including, and why (arranged by date)
Insert details of papers here if they are not being used, and explain why.
- Enantioselective synthesis of isoquinoline alkaloids, Z. Czarnocki, D. B. Maclean and W. A. Szarek, Can. J. Chem. 1986, 64, 2205-2210. Paper - Not asymmetric catalysis. Use of (R)-glyceraldehyde starting starting material followed by separation of diastereomers.
- 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.
- Pictet-Spengler Reaction of Biogenic Amines with (2R)-N-Glycoxyloylbornane-10.2-sultam. Enantioselective Synthesis of (S)-(+)-N-Methylcalycotamine, Z. Czarnocki, J. B. Mieczkowski, J. Kiegiel, Z. Arazny, Tet. Asymm. 1995, 6, 2899–2902. - Enantioselective but not catalytic. 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.
- Synthesis of Optically Pure Pyrroloquinolones via Pictet–Spengler and Winterfeldt Reactions, W. Jiang, Z. Sui and X. Chen, Tetrahedron Lett. 2002, 43, 8941-8945. Paper diastereo
- 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
- Stereoselectivity of Superacid-Catalyzed Pictet-Spengler Cyclisation Reactions, S. Nakamura, M. Tanaka, T. Taniguchi, M. Uchiyama, T. Ohwada, Org. lett. 2003, 12, 2087–2090. - about diastereoselective stereoselectivity not asymmetric reactions
- An efficient synthetic approach to optically active b-carboline derivatives via Pictet–Spengler reaction promoted by trimethylchlorosilane, R. Tsuji, M. Nakagawa and A. Nishida, Tetrahedron: Asymmetry 2003, 14, 177- 180. Paper diastereo
- Metal-free organocatalysis through explicit hydrogen bonding interactions, P. R, Schreiner, Chem. Soc. ReV. 2003, 32, 289. (DOI:10.1039/b107298) Paper - Does not address Pictet-Spengler
- Regiospecific, Enantiospecific Total Synthesis of the 12-Alkoxy-Substituted Indole Alkaloids, H. Zhou, X. Liao, J. M. Cook, Org. Lett. 2004, 6, 249–252. - chiral auxillary approach
- The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids, E. L. Larghi, M. Amongero, A. B. J. Bracca, T. S. Kaufman ARKIVOC 2005, xii, 98-153. - chiral auxillary approach
- Asymmetric Synthesis of Isoquinoline Alkaloids,M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341–3370. - chiral auxillary approach
- Organocatalytic Asymmetric Aza-Friedel-Crafts Alkylation of Furan, D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc. 2004, 126, 11804-11805. Paper - chiral auxillary approach
- 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.
- Simple indole alkaloids and those with a nonrearranged monoterpenoid unit, T. Kawasaki, K. Higuchi, Nat. Prod. Rep., 2005, 22, 761–793. Paper - not catalytic asymmetric
- 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.
- Application of modified Pictet–Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines, S. Duggineni, D. Sawant, B. Saha, B. Kundu, Tetrahedron 2006, 62, 3228–3241. - extension to picket-spengler but not catalytic asymmetric.
- Cascade Reactions in Total Synthesis, K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134–7186. Paper - features pictet-spengler but not catalytic asymmetric.
- Synthesis of (±)-Strychnofoline via a Highly Convergent Selective Annulation Reaction, A. Lerchner, E. M. Carreira Chem. Eur. J. 2006, 12, 8208–8219.  - not catalytic or pictet-spengler
- 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.
- N-terminal labeling of proteins by the Pictet–Spengler reaction, T. Sasaki, K. Kodama, H. Suzuki, S. Fukuzawa and K. Tachibana, Bioorg. Med. Chem. Lett. 2008, 18, 4550–4553 Paper - Not asymmetric
- (Thio)urea organocatalysis—What can be learnt from anion recognition?, Z. Zhang, P. Schreiner, Chem. Soc. Rev. 2009, 38, 1187 – 1198 (DOI: 10.1039/B801793J) Paper - will be including more up to date paper in mechanism section Paper
- The Asymmetric Pictet-Spengler Reaction, M. Lorenz, M. L. van Linn and J. M. Cook, Curr. Org. Synth. 2010, 7, 189-223 Paper - this is a recent review, but persistently difficult to get hold of, so I suggest we do not include a link it. Waldmann's is I think more available and covers relevant material.
- K. Pulka, Curr. Opin. Drug Discov. Devel. 2010, 13, 669–684 - referenced from Franz 2011 but not easily available (MHT Feb 2) - ignore?
- Diastereoselective Synthesis of Indoloquinolizidines by a Pictet-Spengler?lactimiation Cascade, H. Fang, X. Wu, L. Nie, X. Dai, J. Chen, W. Cao, G. Zhao, Org. Lett, 2010, 23, 5366–5369 - diastereoselective
- Synthesis of beta-Carbolines from Aldehydes and Ketones via the alpha-Siloxy alpha,beta-Unsaturated Esters, S. He, Z. Lai, D. X. Yang et al. Tetrahedron Lett, 2010, 51, 4361-4364 paper - syntheses are rac.
- Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization Strategy for the Enantioselective Synthesis of Deoxy Analogues of (+)-Nanomycin A Methyl Ester, (+)-Eleutherin, (+)-Allo-Eleutherin, and (+)-Thysanone, R. T. Sawant, S. G. Jadhav and S. B. Waghmode, Eur. J. Org. Chem. 2010, 4442-4449 Paper - diastereoselective
- Electrochemical Deallylation of alpha-Allyl Cyclic Amines and Synthesis of Optically Active Quaternary Cyclic Amino Acids, P. G. Kirira, M. Kuriyama and O. Onomura, Chem. Eur. J. 2010, 16, 3970-3982 paper - electrochemical generation of iminium ions - not relevant.
- Organocatalytic Strategies for the Asymmetric Functionalization of Indoles, G. Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010, 39, 4449-4465 paper - not relevant - focus is indoles.
- Catalytic Asymmetric Synthesis of Both Enantiomers of 4-Substituted 1,4-Dihydropyridines with the Use of Bifunctional Thiourea-Ammonium Salts Bearing Different Counterions, K. Yoshida, T. Inokuma, K. Takasu and Y. Takemoto, Molecules 2010, 15, 8305-8326. Paper - not Pictet-Spengler.
- Pictet-Spengler condensation reactions catalyzed by a recyclable H+-montmorillonite as a heterogeneous Brønsted acid, Y.F. Wang, Z.B. Song, C.X. Chen, J.S. Peng, Sci. China: Chem. 2010, 53, 562-568 Paper - Not asymmetric
- Enantioselective Synthesis of Unsymmetrical Triarylmethanes by Chiral Brønsted Acids, F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He, and S.-L. You, Eur. J. Org. Chem. 2010, 47-50 (DOI: 10.1002/ejoc.200901164) Paper - Not Pictet-Spengler
- Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet–Spengler-type cyclization sequence, A. Znabet, J. Zonneveld, E. Janssen, F.J.J. De Kanter, M. Helliwell, N.J. Turner, E. Ruijter and R.V.A. Orru, Chem. Commun. 2010, 46, 7706–7708. 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.
- Highly Enantioselective Mannich Reactions with alpha-Aryl Silyl Ketene Acetals and Imines, G. T. Notte, J. M. B. Vu and J. L. Leighton, Org. Lett. 2011, 13, 816-818 paper - adaptation of Leighton's methodology to Mannich reactions.
- Catalytic Asymmetric Synthesis of 1,1-Disubstituted Tetrahydro-beta-carbolines by Phase-transfer Catalyzed Alkylations, S. Shirakawa, K. Liu, H. Ito et al. Chem. Commun. 2011, 47, 1515-1517 paper - not PS, not relevant
- Chiral Phosphoric Acid-catalysed Friedel-Crafts Alkylation Reaction of Indoles with Racemic Spiro Indolin-3-ones, Q. Yin and S.-L. You. Chem. Sci. 2011, 2, 1344-1348 paper - non-PS, not relevant - chiral phos acid + indole + imine.
- General and Efficient Organocatalytic Synthesis of Indoloquinolizidines, Pyridoquinazolines and Quinazolinones through a One-Pot Domino Michael Addition-Cyclization-Pictet-Spengler or 1,2-Amine Addition Reaction, M. Rueping, C. M. R. Volla, M. Bolte and G. Raabe, Adv. Synth. Catal. 2011, 353, 2853-2859. Paper - diastereoselective.
- A Straightforward Synthesis of N-Monosubstituted Alpha-keto Amides via Aerobic Benzylic Oxidation of Amides, J. Shao, X. Huang, S. Wang et al. Tetrahedron 2012, 68, 573-579 paper - not relevant - just synthesis of ketoamides.
- Lipase-Catalyzed Kinetic Resolution of 2-Phenylethanol Derivatives and Chiral Oxa-Pictet–Spengler Reaction as the Key Steps in the Synthesis of Enantiomerically Pure Tricyclic Amines, C. Ketterer and B. Wünsch, Eur. J. Org. Chem. 2012, 2428.  - diastereoselective
- α‑Oxo-γ-Butyrolactam, N‑Containing Pronucleophile in Organocatalytic One-Pot Assembly of Butyrolactam-Fused Indoloquinolizidines, H.-L. Zhu, J.-B. Ling, and P.-F. Xu, J. Org. Chem. 2012, 77, 7737−7743 Paper - Diastereoselective
- Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies, R.A. Al-Horani, U.R. Desai, Tetrahedron 2012, 68, 2027-2040 Paper - Not asymmetric
- Chiral 2-aminobenzimidazole bifunctional organocatalysts: effect of di-CF3 and TFA on catalytic mechanisms, M. Lee, L. Zhang, Y. Park, H. Park, Tetrahedron 2012, 68, 1452-1459 Paper - Not Pictet-Spengler
- Gold-Catalyzed Domino Cycloisomerization/Pictet−Spengler Reaction of 2‐(4-Aminobut-1-yn-1-yl)anilines with Aldehydes: Synthesis of Tetrahydropyrido[4,3‐b]indole Scaffolds, B. V. Subba Reddy, M. Swain, S.M. Reddy, J.S. Yadav, and B. Sridhar J. Org. Chem. 2012, 77, 11355−11361 Paper - Not asymmetric
- Primary and secondary amine-(thio)ureas and squaramides and their applications in asymmetric organocatalysis, M. Tsakos, C. G. Kokotos, Tetrahedron 2013, 69, 10199-10222. Paper - no discussion specifically about PS.
- Mild and efficient cyanuric chloride catalyzed Pictet–Spengler reaction, A. Sharma, M. Singh, N.N. Rai and D. Sawant, Beilstein J. Org. Chem. 2013, 9, 1235–1242 Paper - Not asymmetric
- A Pictet-Spengler ligation for protein chemical modification, P. Agarwala, J. van der Weijdena, E.M. Slettena, D. Rabukab, and C.R. Bertozzi, PNAS 2013, 110, 46-51 Paper - Not asymmetric
- Hydrazino-Pictet-Spengler Ligation as a Biocompatible Method for the Generation of Stable Protein Conjugates, P. Agarwal, R. Kudirka, A.E. Albers, R.M. Barfield, G.W. de Hart, P.M. Drake, L.C. Jones, and D. Rabuka, Bioconjugate Chem. 2013, 24, 846−851. Paper - Not asymmetric
- Synthesis of biologically active pyridoimidazole/imidazobenzothiazole annulated polyheterocycles using cyanuric chloride in water, A. K. Pandey, R. Sharma, A. Singh, S. Shukla, K. Srivastava, S. K. Puri, B. Kumar and M. S. Chauhan, RSC Adv. 2014, 4, 26757-26770. Paper - not enantioselective.
- An acid-free Pictet–Spengler reaction using deep eutectic solvents (DES), S. Handy, M. Wright, Tetrahedron Lett. 2014, 55, 3440–3442 Paper - Not asymmetric
- Organocatalytic Asymmetric Mannich Cyclization of Hydroxylactams with Acetals: Total Syntheses of (—)-Epilupinine, (—)-Tashiromine, and (—)-Trachelanthamidine, D. Koley, Y. Krishna, K. Srinivas, A.A. Khan, and R. Kant, Angew. Chem. Int. Ed. 2014, 53, 13196-13200. Paper - Not Pictet-Spengler
- Synthesis of 1-(1-aryl-1H-1,2,3-triazol-4-yl)-β-carboline derivatives, N.T. Pohodylo, V.S. Matiichuk, M.D. Obushak, Russ. J. Org. Chem. 2014, 50, 275-279. Paper - Not Pictet-Spengler or asymmetric.
- Synthesis of fused-tricyclic indole derivatives through an acid-promoted skeletal rearrangement, T. Yokosaka, T. Kanehira, H. Nakayama, T. Nemoto and Y. Hamada, Tetrahedron 2014, 70, 2151-2160 Paper - Not asymmetric
- Synthesis of (S)- and (R)-Harmicine from Proline: An Approach Toward Tetrahydro-β-carbolines, C.S. Lood and A.M.P. Koskinen, Eur. J. Org. Chem. 2014, 2357–2364 Paper - Not Pictet-Spengler, diastereoselective
- Total Synthesis of (±)-Lycorine from the Endo-Cycloadduct of 3,5-Dibromo-2-pyrone and (E)‐β-Borylstyrene, H-S Shin, Y-G Jung, H-K Cho, Y-G Park, and C-G Cho, Org. Lett. 2014, 16, 5718−5720 Paper - Stereochemistry predetermined
- Bioglycerol-derived carbon−SO3H as a recyclable catalyst for the synthesis of tetrahydro-β-carbolines, G. Niranjan Reddy, B. Maheshwar Rao, M. Vijay, B.L.A. Prabhavathi Devi, R.B.N. Prasad and B.V. Subba Reddy, Can. J. Chem. 2015, 93, 341–347. Paper - not asymmetric
- Diastereodivergent Pictet–Spengler Cyclization of Bicyclic N-Acyliminium Ions: Controlling a Quaternary Stereocenter, B. de Carné-Carnavalet, J.-P. Krieger,B. Folléas, J.-L. Brayer, J.-P. Demoute, C. Meyer and J. Cossy, Eur. J. Org. Chem. 2015, 6, 1273–1282. Paper - diastereoselective
- Synthesis of tetrahydro-β-carbolines, β-carbolines, and natural products, (±)-harmicine, eudistomin U and canthine by reductive Pictet Spengler cyclization, D.S. Pakhare, R.S. Kusurkar, Tetrahedron Letters 2015, 56, 6012–6015. Paper - Not asymmetric
- Synthesis of Novel Tetrazole Containing Quinoline and 2,3,4,9-Tetrahydro-1H-β-Carboline Derivatives, M. Ghandi, S. Rahimi, and N. Zarezadeh, J. Heterocyclic Chem. 2015. Paper - Not asymmetric
- Synthesis of Quinoline-Fused 1‐Benzazepines through a Mannich-Type Reaction of a C,N-Bisnucleophile Generated from 2‐Aminobenzaldehyde and 2‐Methylindole, L. Min, B. Pan, and Y. Gu, Org. Lett. 2016, 18, 364−367. Paper - Not enantioselective