Pictet-Spengler condensation

The Pictet-Spengler condensation of indole bases and carbonyl compounds to form 3-carbolines involves a slightly different mechanism than the isoquinoline... 

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. ... 

A formal Pictet-Spengler condensation to give 2,3-dihydro-lH-2-benzazepine-3-carboxylic acid 36 was achieved in quantitative yield via a sigmatropic rearrangement of ci5-2,3-methanophenylalanine 35 in the presence of paraformaldehyde and hydrochloric acid at room temperature. It is interesting to note that homophenylalanine 38 did not cyclize to give 37, even under vigorous reaction conditions. 

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. 

One of the most common methods for introducing asymmetry into a Pictet-Spengler condensation reaction is to append a non-racemic auxiliary onto the indole amine or... 

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. 

The reduced pyrido[4,3-g][l,4]benzothiazepine 133 has been detected by HPLC as a novel metabolite in some human urine samples. It arises from Pictet-Spengler condensation of 5-S-cysteinyldopa with formaldehyde. This chemistry also underpins a facile synthesis of the 2,3,4,5-tetrahydro[l,4]benzothiazepine 134 via reaction of formaldehyde with a cysteinylcatechol . 

Oxogambirtannine (344) has been synthesized by Irie et al. (187) via photo-induced rearrangement of spirotetrahydro-P-carboline 346, obtained by Pictet-Spengler condensation of tryptamine and indandione (345). 

Intermediate diketopiperazine derivatives have been employed in the diastereoselective synthesis of benzyltetra-hydroisoquinoline by 1,4-chirality transfer. iV-Cbz-Proline was coupled with 2-(3,4-dimethoxyphenyl)ethylamine and the resulting amide 109, after deprotection, was reacted with phenylpyruvic acid (Cbz = carbobenzyloxy group). Compound 110 underwent acid-catalyzed Pictet-Spengler condensation to yield final tetracyclic... 

Cook and col 1aborators (24) have shown that the Pictet-Spengler condensation of iminium salts of structure 56 (R=alkyl or aryl group) gave only the trans isomer 57 and in high yield. This result can be explained if the stereochemistry of the transition state corresponds to 58 59 where the principle... 

In two steps, Wang and Ganesan convert 4 first into the a,/l-unsaturated imine 6 and then, by an acyliminium Pictet-Spengler condensation, into the /i-carboline 8 (Scheme 1) [5]. The trans diastereomer was formed as a side product, and had to be separated. Treatment of 8 with NBS in aqueous acetic acid by a procedure described in 1969 by van Tamelen [6] results in the formation of the oxindoline 9 through a spiro ring-contraction. The intermediate bromonium ion is generated on the less hindered a-face, in the position opposite to the... 

In Stark contrast, a biomimetic approach [76] that was reported shortly after Weinreb s classical synthesis gave access to 70 in three steps (Scheme 9.8) from the commercially available 4,5-dibromo-2-formylpyrrole 80 and 2-aminohistidine 81. Protection of the pyrrole 80 followed by Lewis acid-catalyzed Pictet-Spengler condensation with 81 gave tetrahydroageladine A 83. Treatment of 83 with chloranil in refluxing chloroform effected aromatization of the imidazopyridine ring system... 

All terpenoid indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 2b). Tryptophan decarboxylase, a pyridoxal-dependent enzyme, converts tryptophan to tryptamine (62, 63). The enzyme strictosidine synthase catalyzes a stereoselective Pictet-Spengler condensation between tryptamine and secologanin to yield strictosidine. Strictosidine synthase (64) has been cloned from the plants C. roseus (65), Rauwolfla serpentine (66), and, recently, Ophiorrhiza pumila (67). A crystal structure of strictosidine synthase from R. serpentina has been reported (68, 69), and the substrate specificity of the enzyme can be modulated (70). 

The most prominent intramolecular reaction of iminium ions with aromatic C-nucleophiles is the long-known Pictet-Spengler condensation of 2-phenylethylamines (8) with reactive carbonyl compounds (9)—by far the most important route to natural and synthetic tetrahydroisoquinolines (10 Scheme 8). 

Furthermore, nonaqueous, especially nonprotic, solvents allow Pictet-Spengler condensation reactions to occur with acid>labile aldehydes e.g. when bearing additional acetal functions) and may significantly influence the stereoselectivity (see below). 

Isotope-labeling experiments and the secondary formation of regioisomers show that the Pictet-Spengler condensation may be reversible under more vigorous conditions. ... 

In a very elegant tandem-type combination of such a modified Pictet-Spengler condensation and an initial Pummerer reaction (e.g. Section 4.2.2.4), the polycyclic framework (75) of the erythrina alkaloid (76 Scheme 37) is formed diastereoselectively, in a single step, from (72) in 72% yield the required acyliminium ion (74) is created by an intramolecular alkylation of the intermediate enamide (73)7 ... 

Pictet-Spengler Condensation with Cyclohexan-1,2 dione... 

A third synthesis of XX, by Sugasawa and Yoshikawa (13), begins with a normal Pictet-Spengler condensation using cyclohexane-1,2-... 

N-Acyliminium ion-mediated Pictet-Spengler reaction has also been applied to the synthesis of tetrahydroisoquinolines [404]. Thus, supported 4-formylbenzoic acid (569) was reacted with 2-(3,4-dimethoxyphenyl)ethylamine (570), affording the corresponding resin-bound imine (571). The latter underwent N-acyliminium ion-mediated Pictet-Spengler condensation in the presence of a number of acid chlorides, sulfonyl chlorides, and a chloroformate under basic conditions to give (572) better yields and purities were obtained using acid chlorides and the chloroformate (Scheme 119). 

An attempt to prepare cephalotaxine and 11-hydroxycephalotaxine from chiral precursors by means of a ring expansion of isoquinoline derivatives prepared by the Pictet-Spengler condensation was made by Hudlicky in 1981 (70,71) as shown in Scheme 37. Acid 210 was prepared by condensation of biogenic amines 208 (X = H or OH) with the pyruvate 209. Borane reduction to the corresponding alcohols 211, followed by acid-catalyzed solvolysis, led to the tricyclic enamines 212 and 213 (77). This approach was modeled on the biogenetic condensation of amines with pyruvates to generate 1,1-disubstituted tetrahydroisoquinolines, ubiquitous in alkaloid biogenesis (70). 

The previous syntheses of cephaeline (2) and isocephaeline (21) in both their racemic and chiral forms included Pictet-Spengler condensation of ( )- and (-)-protoemetines [( )-6 and (-)-6] with 3-hydroxy-4-methoxyphenethylamine as the final step (i). Thus, the syntheses of ( )-6 and (-)-6 mentioned in Section III,A constitute formal racemic and chiral s3mtheses of 2 and 21. 

The synthesis, claimed to be stereospeoific, was achieved by the method earlier achieved for the synthesis of a base like octobirine without one of the methylenedioxy groups (184). The intermediate diketone (159 R = H) resulting from the Pictet-Spengler condensation of the appropriate arylethylamine and the ninhydrin was N-methylated with formaldehyde and formic acid to 159 (R = Me) (mp 118-122°). Reduction of the latter with sodium borohydride in methanol gave the corresponding dihydroxy compound (mp 185-187°) which was identical in spectral properties with the natural base (185). 

The discovery approach to LY414197 involves a traditional Pictet-Spengler condensation of... 

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