Efficient asymmetric synthesis of important tryptophan analogs for biological research via the Schollkopf chiral auxiliary

Article abstract of DOI:10.1016/S0040-4039(00)00263-X

An efficient method has been developed via the Schollkopf chiral auxiliary for the asymmetric synthesis of the important tryptophan analogs: L-isotryptophan, L-benzo[f]tryptophan and L-homotryptophan. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00263-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2781–2785
Efficient asymmetric synthesis of important tryptophan analogs
for biological research via the Schöllkopf chiral auxiliary
Chunrong Ma, Shu Yu, Xiaohui He, Xiaoxiang Liu and James M. Cook ∗
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Received 22 December 1999; accepted 8 February 2000
Abstract
An efficient method has been developed via the Schöllkopf chiral auxiliary for the asymmetric synthesis of
the important tryptophan analogs: L-isotryptophan, L-benzo[f]tryptophan and L-homotryptophan. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: tryptophan analogs; Schöllkopf chiral auxiliary; isotryptophan; benzo[f]tryptophan; homotryptophan.
Indoleamine 2,3-dioxygenase (IDO) is an interferon-γ-induced protein that is the first enzyme in the
pathway involved in degradation of tryptophan in macrophages and other cells. Many inflammatory
diseases and neurodegenerative diseases have been linked to aberrant L-tryptophan metabolism effected
by the elevation of IDO activity.1 One class of competitive IDO inhibitors are tryptophan analogs. For
example, the compounds with structures generated by replacement of the N–H function of the indole
ring of tryptophan with O or S exhibited moderate inhibitory activity towards rabbit intestine IDO.2 It
was further demonstrated that the L-isomer of Na-methyl tryptophan was the most competitive inhibitor
of IDO reported to date and bound in preference to the D-isomer.2,3 In the continued effort to search for
potent inhibitors of IDO, it was of interest to evaluate IDO activity of the three structurally distinct and
optically active tryptophan analogs: L-isotryptophan 1, L-benzo[f]tryptophan 2 and L-homotryptophan
3. Multistep syntheses of the racemic form of these three tryptophan analogs have been previously
reported.4 However, none of them have been prepared enantioselectively. In this communication, we
wish to report an efficient preparation of these three tryptophan analogs in optically active form (D or L)
via the Schöllkopf chiral auxiliary.
∗
Corresponding author. Tel: 414-229-5856; fax: 414-229-5530; e-mail: capncook@csd.uwm.edu (J. M. Cook)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00263-X
tetl 16543

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Scheme 1.
Racemic isotryptophan was first synthesized by Kornfeld and was reported to exhibit some bacterios-
tatic activity.4a The stereoselective synthesis of isotryptophan 1 developed here is depicted in Scheme 1.
Schöllkopf et al. reported the preparation of alkyne 5 in 60% de by alkylation of the Schöllkopf chiral
auxiliary 8 with propargyl bromide.5 Previous studies in our laboratory have indicated that alkylation of
8 would take place with high diastereoselectivity when diphenylphosphate was employed as the leaving
group.6 However, a considerable amount of allene was obtained when propargyl diphenylphosphate was
stirred with the anion of 8. Importantly, alkyne 5 could be obtained by alkylation of 8 with triethylsilyl-
substituted propargyl diphenylphosphate 10 to furnish 9 in high yield and diastereoselectivity,6 followed
by desilylation to generate 5 (Scheme 2). Palladium-catalyzed coupling of ortho-iodoaniline 4 with
alkyne 5 provided the aminoaryl alkyne 6 in high yield. Intramolecular cyclization of 6 was successfully
promoted by CuI while PdCl2 and NaAuCl4 both failed to effect the cyclization. Initially, the CuI
promoted reaction was carried out in pure DMF. Unfortunately, these conditions resulted in significant
epimerization of the chiral center («) in 7. One possible pathway for the epimerization is shown in Fig.
1; however, additional experiments are required to determine if this is reasonable. This problem was
alleviated by addition of ethylene glycol to the medium as a proton source to suppress epimerization.
In this fashion, indole 7 was obtained in 80% yield accompanied by only 6% of the epimerized («)
compound which was removed by flash chromatography. The desired L-isotryptophan 1 was obtained in
72% yield by acidic hydrolysis of 7, followed by subsequent saponification.
Scheme 2.

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Fig. 1.
The linear benzo[f]tryptophan was suggested as a potential fluorescent amino acid probe because of
its red-shift from the natural amino acid.4b In 1997, McLaughlin et al. first reported the synthesis of
Nb-Boc-benzo[f]tryptophan in racemic form.4b In the course of the search for active ligands at IDO,
an efficient synthesis of ring-A-substituted optically active tryptophans was developed.7 This approach
was extended to L-benzo[f]tryptophan 2, as shown in Scheme 3. The 3-iodo-2-aminonaphthalene 11 was
prepared via halogen exchange with 3-bromo-2-nitronaphthalene 14,8 which was followed by reduction
of the nitro group (Scheme 4). Heteroannulation of 11 and the internal alkyne 9 generated the key
benzofused indole 12 accompanied by 15% of the 2,3-substituted regioisomer which was easily removed
by flash chromatography. Desilylation of 12 was achieved with TBAF in THF to provide intermediate
13. Treatment of 12 with 1N aqueous HCl failed to effect the desilylation. L-Benzo[f]tryptophan 2 was
obtained in 75% yield by acidic hydrolysis of 13, followed by saponification. As expected, spectroscopy
indicated the UV absorption of L-benzo[f]tryptophan 2 was red-shifted ∼60 nm from the absorption of
natural L-tryptophan. This analog 2 may provide an efficient probe to study biological processes (as well
as peptides) which involve tryptophan (IDO, TDO, etc).
Scheme 3.
Scheme 4.
Homotryptophan was prepared earlier by Snyder and Pilgrim as a racemate.4c To date, no enan-
tioselective synthesis has been reported to our knowledge. The strategy for the asymmetric synthesis
of L-homotryptophan 3 was to effect a two-carbon homologation of an indole moiety to be follo-
wed by alkylation of the Schöllkopf chiral auxiliary, as depicted in Scheme 5. Initially, N-sulfonyl-

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3-bromoindole was chosen as the starting material to effect the lithium halogen exchange (t-BuLi) to
generate a carbanion at position 3 as previously reported by Gribble and Saulnier.9 However, in our
hands, this carbanion at C(3) was readily converted into the thermodynamically more stable carbanion
at position 2 at −78°C due to the stabilizing effect of the N-sulfonyl group adjacent to the carbanion.
Consequently, the N-TBDMS-substituted 3-bromoindole 1610 was used as the starting indole. Lithium
halogen exchange of 16 with t-butyllithium was followed by nucleophilic attack on the oxirane, the anion
of which was trapped with p-toluenesulfonyl chloride to generate the tosylate 17 in one pot. Alkylation
of the anion of the Schöllkopf chiral auxiliary 8 with 17 furnished the intermediate 18 in high yield
and stereoselective fashion. Hydrolysis of 18 and subsequent desilylation, followed by saponification
provided L-homotryptophan 3 in high yield.
Scheme 5.
In summary, the efficient stereoselective synthesis of three tryptophan analogs with potential activity at
IDO have been completed. These syntheses make available any of these tryptophans as D- or L-isomers
in optically active form for the study of biological processes (IDO, TDO, etc).
Acknowledgements
The authors wish to thank the NIMH (MH46851) for generous financial support.
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