Pictet-Spengler cyclisation

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). 

A Pictet-Spengler cyclisation realised the synthesis of pyrimido[4,5-Z)]-l,4-benzodiazepine derivatives (andllie analogous 1,4-benzoxazepines and 1,4-benzothiazepines) <05JOC9629>. 

A small library of 4,5-dihydro-l,4-benzoxazepin-3(2/f)-ones was prepared by polymer assisted solution phase synthesis based on saheyhe aldehydes, a-bromoaeetie acid esters and primary amines <05MI643>. As noted previously, pyrimido[4,5-fe][l,4]-benzoxazepines (and diazepines, and thiazepines) can be accessed via a neat variation of the Pictet-Spengler cyclisation. The compounds are of interest as inhibitors of particular receptor tyrosine kinases <05JOC9629>. Liu et al. have also reported a synthesis of 5,6-dihydro-pyrimido[4,5-Z)][l,4]benzoxazepines 173, 174 based on a cyclocondensation of the imines 172 <05TL7523>. The advantage of the approach was the incorporation of poorly reactive pyrimidyl amines 170,171. 

One of the most powerful methods for the construction of tetrahydroisoquinoline systems is the Pictet-Spengler cyclisation. The reaction consists of the condensation of a b-phenylethylamine derivative with a carbonyl compound, generating an imine (Schiffs base), which undergoes cyclisation via an intramolecular electrophilic aromatic substitution yielding the isoquinoline derivative. The Pictet-Spengler reaction is traditionally carried out in a protic solvent with acid catalysts, usually acetic acid or trifluoroacetic acid. 

Apart from the reports mentioned above, there are sustainable monofunctional thioureas that successfully induce chirality. In 2007, Jacobsen and coworkers reported the enantioselective Pictet-Spengler cyclisation of hydroigrlactams. Utilising as little as 0.1 mol% of thiourea 10, indolizinone and quinolizinone products were afforded in high yields and high enan-tioselectivities (Scheme 19.14) via a counterion transition state. ... 

Scheme 19.14 Enantioselective Pictet-Spengler cyclisation of hydrojiylactams employing thiourea 10.

Of the well-known methods to prepare isoquinolines, including the Pictet-Spengler and Bischler-Napieralski cyclisation, the Pomeranz-Fritsch reaction is the only direct generally accepted method for the construction of the fully unsaturated isoquinoline ring system. 

An intramolecular Pictet-Spengler type cyclisation in the intermediates 100, readily prepared in turn from 99, gave the new dihydropyrimido[4,5-fc][l,4]benzodiazepines 101. Yields were generally good to excellent (101, R1 = H, R2 = Pr, 65%) <06T2563>. 

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

Several applications of this methodology have appeared from Mariano s group, however, we will demonstrate the synthetic potential of this discovery by citing here the two most important examples. Synthesis of ( +) Xylopinine (205), a protoberberine alkaloid, has been performed [161] from the photocyclisation of 204 in methanol. Similarly, a erythrane ring system (207) has been constructed [162] from the photoreactions of 206. Some other interesting aspects of this chemistry have been related to a novel Pictet-Spengler [163] type cyclisation and the chemistry of allene cation radicals [164]. 

The isoquinoline ring system is readily accessible by well known methods such as Pictet-Spengler 2 , Pomaranz-Fritz 22 >, Bischler-Napierlaski and their modified procedures. Despite this, however, certain specific methoxy isoquinolines are not readily synthesised by the usual methods as mentioned in the beginning of the chapter. This is because the above methods are acid catalyzed and lead only to certain specific orientation in the cyclisation reaction. Isoquinoline ring system can be synthesised through aromatic lithiation reaction, which obviates the difficulties mentioned above. 

Introduction of a 2-prenyl group as an electrophile can also be achieved via Pictet-Spengler condensation of indoles with suitable C5 aldehydes. The cell cycle inhibitor 6-demethoxyfumitremorgin C (47), isolated from Aspergillus fumigatus, can be synthesised by condensation of L-tryptophan methyl ester (42) and prenal (43) as the initial step [68-70]. It is possible to isolate the intermediate imine, which reacts to a mixture of diastereomeric p-carbolines (44) under acidic conditions. A problem is always the low diastereoselectivity of the cyclisation step, as observed for 44 by the Ganesan and Bailey groups in their very similar three-step syntheses of 47 (Scheme 10). 

The Pictet-Spengler reaction has been utilised in a three-component reaction between iV-(2-aminoethyl)pyrroles, enals and keto esters (Scheme 8.29). This reaction afforded chiral pyrrolopiperazines. Vinylogous reactivity of 2-vinyl pyrrole has been utilised in the formal [2 + 2] cycloaddi-tion, which proceeds via Michael addition followed by cyclisation. ... 

In 2013, Terada and Toda reported a relay catalysis for a ternary reaction sequence composed of double bond isomerisation, protonation of the double bond, and enantioselective Pictet-Spengler-type cyclisation, which was accomplished using a binary catalytic system consisting of a ruthenium hydride complex and a chiral phosphoric acid. As shown in Scheme 7.47, the intramolecular reaction of allylamides led to the corresponding chiral tetrahydroisoquinoline derivatives in moderate to good yields and insufficient enantioselectivities of 18 to 53% ee. 

The Pictet Spengler type cyclisation of isatins (258) and tryptamines (259) catalysed by chiral phosphoric acids (253, 261-262) provided spiro-2-indolones products (260) in excellent yields (up to 99%) and enantio-selectivity (up to 98 2 er) (Scheme 67). " ... 

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