Pictet—Spengler production

Starting from L-tryptophan, immobilized on hydroxyethyl polystyrene through its carboxylic group, the intermediate a,[3-unsaturated imine (554) was formed by reaction with 3-methylcrotonaldehyde in pure trimethyl orthoformate (TMOF). The imine was then allowed to react with Fmoc chloride in the presence of pyridine to afford the required tetrahydro-[3-carboline (555) through an N-acylimin-ium ion mediated Pictet-Spengler-type cyclization. Further manipulation of the Pictet-Spengler product afforded the desired demethoxy-FTC as the minor cis isomer, along with its C-3 trans epimer (556) (diastereoisomeric ratio 1 3) (Scheme 115). 

The racemic laudanosine (7g) syntheses were referred to earlier in The Alkaloids (Vol. XII, p. 348). From the racemic mixture it is difficult to obtain (S)-(+)-laudanosine which is widely distributed in nature. The synthesis of its unnatural (R )-form (in poor yields) has been reported (asymmetric reduction of 3,4-dihydropapaverine with lithium butyl-(hydro)dipinan-3a-y borate) (363). Recently, a description of the biogenetic synthesis of these two forms from methyl-L-(+)-3,4-dihy-droxyphenylalaninate hydrochloride by condensation with sodium 3-(3,4-dimethoxyphenyl)glycinate at pH 4 and 35° was given. Thus, a dia-stereoisomeric mixture of the Pictet-Spengler products 11a and lib (ratio... 

Scheme 11 Oxidative ring contraction of Pictet-Spengler product 136 [119]...

Azafluroanthenes were prepared via three steps Pictet-Spengler production of the tetrahydroisoquinoline, followed by microwave-induced direct arylation, and finally deprotection/oxidation (Scheme 81) (13EJO1107).The arylation step is robust enough to tolerate a wide range of substituents—both electron-donating and electron-withdrawing.This approach provides a rapid, mild route to natural products, rufescine and tricHdine. 

Scheme 3.63 depicts a proposed mechanism where amine 164 and aldehyde react to generate the expected Pictet-Spengler product 202 via the iminium species 205. Evidence for the intermediate formation of 202 was observed through LC/MS monitoring, and the reaction with the protonated isonitrile 203 affords the final exocyclic amidine moiety 204. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Ebumamonine was assembled utilizing a Pictet-Spengler cyclization of hydroxy-lactam 52 in the presence of trifluoroacetic acid at low temperature to give a mixture of diastereomers 53 in 95% yield. These compounds were readily separated by chromatography and the a-epimer was further elaborated to give the natural product. 

The acid-catalyzed conversion of the l,2,3,4-tetrahydro-j8-carboline derivative 337 (R = CHg) into the strychnine-type ring system 338 has been attributed to an equilibrium involving the protonated Schiff s base 339 of tryptamine (i.e., the intermediate in the Pictet-Spengler type synthesis of tetrahydro-j8-carbolines, cf. Section III, A, 1, a), and the a- (337) and the j8-condensation products (340). 

For that reason an intramolecular benzannulation was developed, which incorporates all components for the intramolecular alkoxycarbonylation into the naphthoquinone 105 [65]. Based on that strategy a short and convergent pathway for the synthesis of racemic deoxyfrenolicin 108 was accomplished. Xu et al. replaced the allylacetylene 100 in the reaction sequence for nanaomycin A by alkynoate 106. The benzannulation product 107 was an appropriate precursor for a subsequent tandem oxa-Pictet-Spengler cyclisation/DDQ-induced coupling reaction [66]. Following this strategy the total synthesis of enan-tiomerically pure deoxyfrenolicin could be accomplished (Scheme 48). 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

Treatment of the protected aldehyde 342 with a TFA/water/chloroform mixture results in the formation of a 10-membered intermediate iminium cation intramolecular attack of this electrophile at C-2 of the indole (an intramolecular Pictet-Spengler reaction) gives the isolated tetracyclic product 343 in good yield (Equation 124) <1995T4841>. 

Grieco and coworkers have independently described the same type of Pictet-Spengler cyclization reactions involving tryptophan methyl ester and aldehydes, but using methanol as solvent and hydrochloric acid as a catalyst (microwave irradiation, 50 °C, 20-50 min) [416], Moderate to good product yields were obtained. 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

Acetaldehyde is typically formed after ingestion of alcohol (see Section 3.4.7). Since the urine product is racemic, it would appear that a chemical Pictet-Spengler synthesis is being observed here rather than an enzymic one. 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

Another example of Ugi/Pictet-Spengler two-step procedure was employed by El Kaim et al. to prepare polycyclic 1,4-diketopiperazines 228 [69]. The four-component Ugi reaction of homoveratryl isocyanide 229 and a-ketocarboxylic acids 230 allows the formation of Ugi products, which were treated with trifluor-oactic acid to afford tricychc 2,5-diketopiperazines 228 in a Pictet-Spengler-type cyclization (Scheme 42). 

A number of azocino [3,4-1 ] indoles derivatives 58, analogs of jS-carbolines, have been synthesized by the Pictet-Spengler reaction using 3-piperidylindole 57 as the starting material (98TL1441, 01X2039). The products were isolated in various yields as mixtures of distereoisomers. The ratio of stereoisomers depended on the aldehyde used (Scheme 18). 

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

Scheme 6.52 Products of the asymmetric Pictet-Spengler-type cyclization of p-indolyl ethyl hydroxylactams catalyzed by 53.

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

Impressive examples of CIAT processes are shown in Schemes 2.10 and 2.11. In an early synthesis of tadalafil, a Pictet-Spengler reaction was used to prepare the c -6-carboline intermediate 35 in 42% yield (TFA, CH2CI2, 4°C/5 days chromatography) or 58% yield (AcOH, H2O, 50°C/4 days crystalhzation) (Daugan, 1999 Orme et al., 2005). A much improved route utilizing CIAT is shown in Scheme 2.10 (Orme et al., 2005). A dynamic equilibrium was set up between 35 and 36 and the undesired dia-stereomer 36 stayed dissolved in the reaction medium while the product 35 crystallized out, driving the process to completion and raising the yield to 92%. 

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