Tryptophane Derivatives

Reserpine, rescinnamine, and deserpidine have been employed since the early 1950s for the treatment of essential hypertension and as tranquilizers. Ajmalicine is used especially in Europe, in conjunction with other agents to treat hypertension and other cardiovascular disorders. 

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Interestingly, G jrey et al.", employing a similar tryptophan-derived catalyst (3.4), observed a 99% enantiomeric excess (ee) in the Diels-Alder reaction of 2-bromoacrolein with cyclopentadiene... 

The appearance of the 2-(indol-3yl)ethylamine (tryptamine) unit in both tryptophan-derived natural products and in synthetic materials having potential pharmacological activity has generated a great deal of interest in the synthesis of such compounds. Several procedures which involve either direct 3-alkylation or tandem 3-functionalization/modification have been developed. Similarly, methodology applicable to preparation of tryptophan analogues has been widely explored. 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

The preferred formation of 261 over 260 is in accord with the well-known positional order 3 > 2 for reactivity of unsubstituted indole. Aiming at total synthesis of leptosin alkaloids, an application of this methodology to the 1-hydroxy-L-tryptophan derivatives seems to be promising. 

The structure of the complex of (S)-tryptophan-derived oxazaborolidine 4 and methacrolein has been investigated in detail by use of H, B and NMR [6b. The proximity of the coordinated aldehyde and indole subunit in the complex is suggested by the appearance of a bright orange color at 210 K, caused by formation of a charge-transfer complex between the 7t-donor indole ring and the acceptor aldehyde. The intermediate is thought to be as shown in Fig. 1.2, in which the s-cis conformer is the reactive one. 

Among the many chiral Lewis acid catalysts described so far, not many practical catalysts meet these criteria. For a,/ -unsaturated aldehydes, Corey s tryptophan-derived borane catalyst 4, and Yamamoto s CBA and BLA catalysts 3, 7, and 8 are excellent. Narasaka s chiral titanium catalyst 31 and Evans s chiral copper catalyst 24 are outstanding chiral Lewis acid catalysts of the reaction of 3-alkenoyl-l,2-oxazolidin-2-one as dienophile. These chiral Lewis acid catalysts have wide scope and generality compared with the others, as shown in their application to natural product syntheses. They are, however, still not perfect catalysts. We need to continue the endeavor to seek better catalysts which are more reactive, more selective, and have wider applicability. 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

Tryptophan derived catalyst 17 also allows the additions of a-unsubstituted enol ethers to aldehydes to be directed in an enantioselective manner38. 

The chromatogram is freed from mobile phase in a stream of warm air, immersed i j the reagent solution for 1 to 2 s or homogeneously sprayed with it until the layer begion to be transparent, then after drying in a stream of warm air it is heated to 105-120 O for 5-30 min and occasionally (tryptophan derivatives) [16] for 40 min. In exceptional cases evaluation is made without heating (trenbolone [12]). <... 

In the same area, a (5)-tryptophan-derived oxazaborolidine including a p-tolylsulfonylamide function has been used by Corey et al. to catalyse the enantioselective Diels-Alder reaction between 2-bromoacrolein and cyclo-pentadiene to form the corresponding chiral product with an unprecedented high (> 99% ee) enantioselectivity (Scheme 5.27)." This highly efficient methodology was extended to various 2-substituted acroleins and dienes such as isoprene and furan. In addition, it was applied to develop a highly efficient total synthesis of the potent antiulcer substance, cassiol, as depicted in Scheme 5.21... 

Scheme 5.27 L-Tryptophan-derived i-tolylsulfonylamide ligands for B-catalysed Diels-Alder reactions and synthesis of cassiol.

Kilar, F. and Fanali, S., Separation of tryptophan-derivative enantiomers with iron-free human serum transferrin by capillary zone electrophoresis, Electrophoresis, 16, 1510, 1995. 

The construction of novel tetracyclic ring systems 1-142, which can be considered as hybrids of the I e Ira h y dropy r ro I o 12,3 - fo] i ndo le and tetrahydroimidazol[l,2-o]in-dole ring system, has been described by Herranz and coworkers [40]. The exposure of tryptophan-derived a-amino nitrile 1-140 to acidic conditions triggers a stereoselective tautomerization to give 1-142 in quantitative yield (Scheme 1.35). 

A very attractive anionic/anionic/pericyclic/anionic fourfold domino sequence was developed by Kuehne s group, as illustrated in Scheme 2.147 [336]. Herein, on treatment of the enantiopure tryptophane-derived diester 2-644 with a, 3-unsatu-rated aldehydes 2-645 at 70 °C in benzene with benzoic acid and freshly activated... 

Hydrolysis of allyl ester 201b was performed with diethylamine in the presence of Pd(PPh3)4. The carboxylic acid 201c thus obtained could be amidated with a tryptophan derivative using l-(3-dimethylaminopropyl)-3-ethylcarbodiimide as... 

Carbolines (see also Section 12.17.3.3) can be prepared by a Pictet-Spengler reaction between tryptophan derivatives and aldehydes. This general reaction gives compounds such as 405, which provide the starting point for the synthesis of a range of fused pyrazinocarbolines, as shown in Scheme 94. 

L-tryptophan is compulsory, the biosynthetic machinery displays wide latitude in its ability to condense a second auxiliary amino acid—L-alanine in the case of (+)-ll,ll -dideoxyverticillin A (1)—to afford a tryptophan-derived diketopiperazine intermediate 13. Mirroring Woodward and Robinson s biogenetic hypothesis for the calycanthaceous alkaloids, single-electron oxidation of the electron-rich tryptophan residue would likely initiate an oxidative dimerization of the diketopiperazine precursor with concomitant cyclization to yield the octacyclic intermediate 17. Subsequent A-methylation of the amides would then yield an unembellished skeletal core of the dimeric epipolythiodiketopiperazine alkaloids. The first step en route... 

Racemic fluorinated tryptophan derivatives 31 were obtained from 3-methylene indole 29 and fluorinated imines 30 using the imino-ene reaction (Equation (18)).28 The highest yields were obtained for the more electrophilic imines (R2 = SC>2Ph, Ts, SC Me). Moreover, these reactions took place at ambient temperature. 

Fig. 24.8 Heteroalanines, tryptophan derivatives and glycosylated a-amino acid derivatives.

Very high enantioselectivities were obtained in the reaction between cyclopentadiene and a-bromoacrolcin using (S )-tryptophan derived oxazaborolidine catalyst (S)-369b. The Diels-Alder adduct (2R)-366 was obtained with at least 99% enantiomeric excess233. 

The list of tryptophan-derived molecules could be extended almost without end tryptophan is the parent molecule of the indole alkaloids, a large group of plant compounds. 

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