Tryptophan derivatives synthesis

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. 

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... 

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.

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. 

Bohn Rhoden CR, Westermann B, Wessjohann LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) 13 ... 

Rhoden CRB, Westermann B, Wessjoharm LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) (13) 2077-2082 Szardenings AK, Burkoth TS, Lu HH, Tien DW, Campbell DA (1997) A simple procedure for the solid phase synthesis of diketopiperazine and diketomorpholine derivatives. Tetrahedron 53(19) 6573-6593... 

The chiral oxazaborolidines introduced in Section 2.1.3.5 as enantioselective aldol addition catalysts have also been found to be useful in Diels-Alder reactions. The tryptophan-derived catalyst A, for example, can achieve 99% enantioselectivity in the Diels-Alder reaction between 5-benzyloxymethyl-l,3-cyclopentadiene and 2-bromopro-penal. The adduct is an important intermediate in the synthesis of prostaglandins.64... 

A new approach to the synthesis of racemic tryptophan derivatives employs as the essential starting material the enamine (14), prepared by the reaction of o-nitrotoluene with dimethylformamide dimethyl acetal. One of the two new... 

The ethyl aluminum dichloride-catalyzed Michael alkylations of some indoles with N-(diphcnylmethylcnc)-a,()-didehydroamino acid esters allowed successful short synthesis of the tryptophan derivative and the 1,1-diphenyl-p-carboline derivatives, as well as compounds 253 and 252 (Scheme 55) [ 178]. 

Indoles may as well serve as dienophilic compounds for hetero Diels-Alder reactions with nitrosoalkenes. However, the resulting adducts are not stable and undergo further conversion to oximes which represent useful intermediates for the straightforward synthesis of tryptophane derivatives [376,377]. 

The intramolecular Heck reaction and similar transition metal-catalyzed cyclizations are commonly used in organic synthesis as illustrated by the preparation of 3-cyanoindole 63 (Scheme 38) <2004BMC2867>. Similar Heck cyclizations have also been employed in the syntheses of tryptophan derivatives <1996T14975>. Solid phase protocols based... 

Whilst carbamate derivatives of indoles and pyrroles are easily prepared, they have limited synthetic utility because they are easily attacked by nucleophiles. For example, A -Aloc525 and A -Cbz526 derivatives of tryptophan are known, but they are destroyed by piperidine. Boc derivatives of indoles, pyrroles and imidazoles are sufficiently hindered to be synthetically useful For example, N-Boc indole is stable towards piperidine and it can be metallated in the 2-position with ferf-butyllithium.527 Nevertheless, they are still more easily cleaved by nucleophiles than Boc-derivatives of secondary amines as illustrated by the fact that Boc-derivatives of pyrrole are cleaved with sodium methoxide, ammonia or hydrazine in methanol527 In tryptophan derivatives, the Ar>w-Boc group is less susceptible to aridolysis than an Na-Boc group with trifluoroacetic acid. However, the M"-Boc group can be cleaved selectively by thermolysis as illustrated by a step in a synthesis of Asperazine [Scheme 8,271 ].52 ... 

Joshi et al. have reported a diastereospecific synthesis of pentacyclic /3-lactams by 6-exo-trig/7-endo-dig tandem radical cyclization [33]. On the occasion of the total synthesis of new sargine-type alkaloids, Takayama et al. have disclosed a formation of pentacyclic derivatives from a tryptophan derivative [34]. 

The treatment of /Vb-methoxycarbonyl-L-tryptophan methyl ester (9) with trifluoroacetic anhydride in trifluoroacetic acid gave directly the A -trifl uoroacetyl cyclic tautomer with excellent diastereoselectivity [90% yield, endo/exo 97 3 ( ll NMR)]60. Furthermore, pure A a-sulfonyl-entfo-derivatives (X-ray) were prepared from lo206,61 and were employed to prepare homochiral a-, / -, and a, -substituted tryptophan derivatives and pyrrolo[2,3-b]indole alkaloids206 59 62. Similarly, the /Va-acetyl-enc/o-pyrrolo-indole 10 was used for the synthesis of 5-substituted L-tryptophan derivatives63,64. 

Amines via condensations. Tryptophan derivatives are obtained by reaction of indoles with A-substituted aziridinecarboxylic esters at 0° or room temperature. Stoichiometric amount of Sc(OTf)3 is required. By SclOTfjj catalysis the Strecker-type synthesis from aldehydes, amines, and BujSnCN can be carried out either in organic solvents or in water. Pictet-Spengler reaction is directly accomplished using acetals. ... 

The degree of asymmetric induction in the photocycloaddition reaction can be quite high with substrates containing a stereogenic center. Winkler, Scott and Williard have reported that irradiation of 1-tryptophan-derived vinylogous amide 107 led to the isolation of ketoimine 108 in 91% yield as a single diastereomer . Closure to the tetracyclic portion of the aspidosperma ring system 109 was achieved in two steps by formation of the silyl enol ether with LDA and r-butyl dimethylsilyl triflate followed by treatment with tetrabutylammonium fluoride (TBFA). Conversion of 109 to 110 with >97% optical purity was then achieved. As 110 is an intermediate in Biichi s synthesis of vindorosine, the sequence outlined in Scheme 26 represents a formal total synthesis of vindorosine. 

The ability to accommodate altered levels of intermediates depends on the type of compounds involved. In A. thaliana, tryptophan-derived oximes are key intermediates in the formation of the phytohormone indole acetic acid as well as in the synthesis of glucosinolates. CYP83A1 and CYP83B1 are the enzymes responsible for converting oximes into glucosinolates. Overexpression... 

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