Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction

Article abstract of DOI:10.1021/jo001679s

A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.

Full text of DOI:10.1021/jo001679s

J . Org. Chem. 2001, 66, 4525-4542
4525
Efficien t Asym m etr ic Syn th esis of Biologica lly Im p or ta n t
Tr yp top h a n An a logu es via a P a lla d iu m -Med ia ted
Heter oa n n u la tion Rea ction
Chunrong Ma,† Xiaoxiang Liu,† Xiaoyan Li,† J udith Flippen-Anderson,‡ Shu Yu,‡ and
J ames M. Cook*,†
Department of Chemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53201,
and Laboratory for the Structure of Matter, Code 6030, Naval Research Laboratory, 4555 Overlook Ave,
SW, Washington, DC 20375
capncook@csd.uwm.edu
Received November 29, 2000
A novel and concise synthesis of optically active tryptophan derivatives was developed via a
palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne.
The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the
Scho¨llkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Scho¨llkopf
chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from
D-valine while the D-isomers required for natural product total synthesis would originate from the
inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction
were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39.
More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on
a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids
when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total
synthesis of tryprostatin A (9a ) was accomplished in 43% overall yield employing this palladium-
mediated process.
Sch em e 1
In tr od u ction
Indoleamine 2,3-dioxygenase (IDO) is a monomeric
42kd heme-containing enzyme that uses superoxide to
cleave the indole 2,3-double bond.1 One of the func-
tions of IDO in cells is the oxidation of L-tryptophan to
kynurenine, a principle metabolic pathway for L-tryp-
tophan (Scheme 1).
Many intermediates in the kynurenine pathway, such
as quinolinic acid and kynurenic acid, are known to be
active in the CNS. Quinolinic acid has been shown to be
present in the mammalian brain, to be an agonist for the
excitatory amino acid receptors of the N-methyL-D-
aspartate (NMDA) receptor-ion channel complex, and to
cause excitotoxic brain lesions when present in high
concentrations.2-4 Moreover, the elevation of IDO activ-
ity, which results in the elevation of quinolinic acid
concentrations as a consequence, is observed in HIV- and
AIDS-associated dementia and wasting.5,6 Other acute/
chronic immunological and inflammatory diseases, which
include parasitic, bacterial, viral, and fungal infections,
have been associated with an increase in IDO activity.7-9
Other inflammatory diseases that are deleteriously af-
fected by increased levels of IDO include meningitis,
septicemia, and arthritis, etc.8-13 Moreover, acute inflam-
matory events involving the induction of IDO are also
associated with spinal cord injury and with brain is-
chemia. A host of both acute and chronic immunological
and inflammatory disorders have been directly attributed
to the increased activity of IDO principally initiated by
the upregulation of the inflammatory cytokine interferon-
γ. When interferon-γ levels are upregulated, IDO levels
5
are upregulated!14 More recently, Mellor et al. have
shown that the IDO enzyme is involved in the survival
of the concepti during pregnancy. Consequently, inhibi-
tors of the IDO enzyme have important clinical implica-
tions. This has stimulated the search for inhibitors of this
enzyme system that are required to study and to control
the symptoms of diseases affected by this upregulation.
† University of WisconsinsMilwaukee.
‡ Naval Research Laboratory.
(1) Botting, N. Chem. Soc. Rev. 1995, 24, 401.
(2) Perkins, M. N.; Stone, T. W. Brain Res. 1983, 259, 172.
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(4) Whetsell, W. O.; Shwarcz., R. Neurosci. Lett. 1989, 97, 271.
(5) Munn, D.; Zhou, M.; Attwood, J .; Bondarev, I.; Conway, S.;
Marshall, B.; Brown, C.; Mellor, A. Science 1998, 218, 1191.
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M.; Malone, D. S. Adv. Exp. Med. Biol. 1991, 294, 425.
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Shahmanesh, M. Clin. Chem. 1998, 44, 858.
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(10) Gupta, S. L.; Carlin, J . M.; Pyati, P.; Dai, W.; Pfefferkorn, E.
R.; Murphy, M. J . Infect. Immun. 1994, 62, 2277.
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Byrne, G. I. Infect., Immun. 1994, 62, 3705.
(12) J acoby, D. B.; Choi., A. M. Free. Rad. Biol. Med. 1994, 16, 821.
(13) Dai, W.; Pan, H.; Kwok, O.; Dubney, J . P. J . Interferon Res.
1994, 14, 313.
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Reibnegger, F.; Wachter, A. Adv. Exp. Med. Biol. 1991, 294, 505.
(8) Malone, D. G.; Dolan, P. W.; Brown, R. R.; Kalayoglu, M. V.;
Byrne, G. I.; Ozaki, Y. Rheumatol. 1994, 21, 1011.
10.1021/jo001679s CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/06/2001

4526 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
F igu r e 1. Alkaloids related to 6-methoxytryptophan.
The first competitive IDO inhibitor, 2,5-dihydro-L-
phenylalanine (Ki ) 230 µM), was reported by Watanabe
and co-workers in 1978.15 Since then, Cady and Sono
have also reported examples of competitive inhibitors of
IDO.16 Further research by Peterson et al.17 and Southan
et al.18 has focused on the development of additional
tryptophan analogues and related compounds to deter-
mine the SAR for interaction at the IDO active site.
Although several compounds have exhibited inhibitory
activity against IDO, none of these compounds inhibit
IDO below micromolar levels. Therefore, highly potent
inhibitors of human IDO (with low nanomolar affinity)
are still required. On the basis of previous studies,17,19
Na-methyl-L-tryptophan was prepared and remains the
most potent tryptophan-based competitive inhibitor re-
ported to date.17,19 This is important, for Mellor et al.,
using (()-Na-methyltryptophan, elegantly implicated the
IDO enzyme in the arrest of T-cells important in survival
of concepti during pregnancy (the “pregnancy paradox”).5
For these reasons, synthesis of optically active L-tryp-
tophan derivatives are necessary in the search for more
potent inhibitors of IDO. Due to the lack of efficient
methods to synthesize optically active ring-A substituted
tryptophans, a facile asymmetric synthesis of tryptophan
derivatives was of interest. Moreover, a facile entry into
ring-A methoxylated tryptophan alkyl esters would pro-
vide building blocks for the total synthesis of many ring-A
alkoxylated indole alkaloids that possess antimalarial,
antiamoebic, and antihypertensive activity.20-22
For example, a number of Alstonia alkaloids represent
ring-A oxygenated natural products found in the macro-
line/sarpagine series including alstophylline 323,24 and Nb-
demethylalstophylline oxindole 5 (see Figure 1).25 These
bases could presumably be synthesized from 6-methoxy-
D-tryptophan via the trans transfer of chirality in the
asymmetric Pictet-Spengler reaction.26,27 In addition to
the macroline/sarpagine monomeric indole alkaloids,
several bisindole alkaloids contain a 6-methoxytryp-
tophan fragment: macralstonine 6,28,29 alkaloid H 8,30-32
and the newly isolated O-methylmacralstonine 7 (Figure
1).33,34 O-Methylmacralstonine 7 is the 19-O-methyl
(20) Keawpradub, N.; Houghton, P. J .; Eno-Amooquaye, E.; Burke,
P. J . Planta Med. 1997, 63, 97.
(21) Keawpradub, N.; Kirby, G. C.; Steele, J . C. P.; Houghton, P. J .
Planta Med. 1999, 65, 690.
(22) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J . D.; Said, I. M.;
Kirby, G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(23) Garnick, R. L.; LeQuesne, P. W. J . Am. Chem. Soc. 1978, 100,
4213.
(24) Bi, Y.; Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline
Related Alkaloids. In Studies in Natural Products Chemistry, Bioactive
Natural Products, Part A; Basha, F. Z., Rahman, A., Eds.; Elsevier
Science: Amsterdam, 1993; Vol. 13, p 383.
(25) Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline Related
Sarpagine Alkaloids In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9,
p 23.
(26) Zhang, L. H.; Cook, J . M. J . Am. Chem. Soc. 1990, 112, 4088.
(27) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J . M. J . Am. Chem.
Soc. 1994, 116, 9027.
(28) Cook, J . M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
(29) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J . M.
J . Chem. Soc., Chem. Commun. 1972, 1346.
(30) Lazar, H. A. Ph.D. Thesis, University of Michigan, 1972.
(31) Burke, D. E.; Cook, G. A.; Cook, J . M.; Haller, K. G.; Lazar, H.
A.; LeQuesne, P. W. Phytochemistry 1973, 12, 1467.
(32) Garnick, R. L., Ph.D. Thesis, Northeastern University, 1977.
(15) Watanabe, Y.; Fujiwara, M.; Hayaishi, O.; Takeuchi, T.; Umeza-
wa, H. Biochem. Biophys. Res. Commun. 1978, 85, 273.
(16) Cady, S. G.; Sono, M. Arch. Biochem. Biophys. 1991, 292, 326.
(17) Peterson, A. C.; Migawa, M. T.; Martin, M. J .; Hamaker, L. K.;
Czerwinski, K. M.; Zhang, W.; Arend, R. A.; Fisette, P. L.; Ozaki, Y.;
Will, J . A.; Brown, R. R.; Cook, J . M. Med. Chem. Res. 1994, 3, 531.
(18) Southan, M.; Truscott, R.; J amie, J .; Pelosi, L.; Walker, M.;
Maeda, H.; Iwamoto, Y.; Tone, S. Med. Chem. Res. 1996, 5, 343.
(19) Peterson, A. C.; Laloggia, A. J .; Hamaker, L. K.; Arend, R. A.;
Fisette, P. L.; Ozaki, Y.; Will, J . A.; Brown, R. R.; Cook, J . M. Med.
Chem. Res. 1993, 3, 473.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4527
Sch em e 2
derivative of macralstonine 6; however, this minor struc-
tural change has resulted in significantly enhanced
antiplasmodial potency. Macralstonine 6 exhibited weak
activity against the multidrug-resistant K1 strain of
Plasmodium falciparum cultured in human erythrocytes
with an IC50 value of 8.92 µM, while O-methylmacral-
stonine 7 was 10 times more active than 6 (IC50 ) 0.85
µM).21 The enhanced activity of 7 might result from
increased lipophilicity, which would facilitate transport
across cell membranes of the red blood cells or the
parasites.21 This is in agreement with the previously
reported activity of 19-O-acetylmacralstonine.22 In addi-
tion, there are at least 20 other sarpagine/macroline/
ajmaline alkaloids that contain ring-A alkoxy groups.35
For the total synthesis of the above indole alkaloids,
optically pure 6-methoxytryptophan would serve as an
important building block. Any route developed to provide
optically active 6-methoxytryptophan for alkaloid syn-
thesis must be capable of scale-up and be relatively easy
to perform. This serves as one objective of the present
research. In addition to the macroline/sarpagine alka-
loids, tryprostatins A (9a ) and B (9b) (Figure 1), which
are closely related to tryptophan, have been isolated as
secondary metabolites from the fermentation broth of a
marine fungal strain of Aspergillus fumigatus BM939.39-41
It was found that tryprostatins A (9a ) and B (9b) com-
pletely inhibited cell cycle progression of tsFT210 cells
in the G2/M phase at a final concentration of 50 µg/mL
(9a ) and 12.5 µg/mL (9b), respectively.39-41 Tryprostatins
A (9a ) and B (9b) contain a 2-isoprenyltryptophan moiety
and a proline residue, the latter of which is located in
the diketopiperazine unit. These indole alkaloids differ
from the representatives of the fumitremorgin series,
for ring C has not been formed between positions de-
signated C(18) and N(10).42 The biological activity and
unique 2-isoprenyltryptophan units of 9a and 9b prompted
interest in such molecules. The first enantiospecific total
synthesis of tryprostatin A was reported by Gan et al.43,44
Described herein is a concise, enantiospecific route to the
tryptophan moiety of these natural products that is
improved over the previous route.45
tion P r ocess. A few of the current methods to synthesize
optically active tryptophan derivatives include synthesis
and subsequent resolution of the racemic compound,46
transformation of a readily available optically active
amino acid into tryptophan derivatives,47-49 or synthesis
of the indole precursor followed by reaction with the
Scho¨llkopf chiral auxiliary.44,50 However, these methods
suffer either from length of steps or poor versatility in
terms of the substitution pattern in ring A. It was decided
to develop a convergent route to tryptophan derivatives
that enjoys both efficiency and versatility (Scheme 2) and
is capable of scale-up to the multihundred gram level.
Initially, a convergent synthetic route to substituted
tryptophans was attempted via the J app-Klingemann/
Fischer indole strategy previously developed by Abra-
movitch and Shapiro.51 The Scho¨llkopf chiral auxiliary
was chosen in regard to asymmetry since this can be
prepared in either enantiomeric form and on large scale.52
The details of this approach are illustrated in Scheme 3
and in the Supporting Information. Model reactions were
executed in an attempt to synthesize 5-methoxytryp-
tophan. As shown in Scheme 4, the Scho¨llkopf chiral
auxiliary 19 was deprotonated with 2 equiv of n-butyl-
lithium at -78 °C followed by nucleophilic attack on
2-bromoethanol. The oxygen anion that resulted was
trapped with p-toluenesulfonyl chloride, after which the
reaction was warmed to facilitate the bromide replace-
ment of the tosylate to provide 20; the bromide ion had
been generated in the previous step. This one-pot process
provided the alkyl bromide 20 in 80% yield. The key
R-alkylated ethyl acetoacetate intermediate 16 was pre-
pared in 85% yield by alkylation of ethyl acetoacetate
Resu lts a n d Discu ssion
a . Asym m etr ic Syn th esis of Rin g-A Su bstitu ted
Tr yp top h a n s via a P a lla d iu m -Ca ta lyzed An n u la -
(33) Yamazaki, M.; Suzuki, K.; Fujimoto, H.; Akiyama, T.; Sankawa,
U.; Iitaka, Y. Chem. Pharm. Bull. 1980, 28, 861.
(34) Isidro, N.; Manalo, G. D. J . Phillipine Pharm. Assoc. 1967, 53,
8.
(35) Lounasmaa, M.; Hanhine., P.; Westersund, M. The Sarpagine
Group of Indole Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, 1999; Vol. 52.
(36) Cook, J . M. Ph.D. Thesis,. University of Michigan, 1971.
(37) Burke, D. E.; Cook, J . M.; LeQuesne, P. W. J . Am. Chem. Soc.
1973, 95, 546.
(38) Kishi, T.; Hesse, M.; Vetter, W.; Gemenden, C. W.; Taylor, W.
I.; Schmid, H. Helv. Chim. Acta 1966, 49, 946.
(39) Cui, C.; Kakeya, H.; Okada, G.; Onose, R.; Ubukata, M.;
Takahashi, I.; Isono, K.; Osada, H. J . Antibiot. 1995, 48, 1382.
(40) Cui, C.; Kakeya, H.; Osada, H. J . Antibiot. 1996, 49, 534.
(41) Cui, C.; Kakeya, H.; Okada, G.; Onose, R.; Osada, H. J . Antibiot.
1996, 49, 527.
(42) Steyn, P. S.; Vleggaar, R. Tremorgenic Mycotoxins In Progress
in the Chemistry of Organic Natural Products; Herz, W., Grisebach,
H., Kirby, G. W., Zachmiester, L., Eds.; Springer-Verlag, Vienna: 1985;
Vol. 48, p 1.
(43) Gan, T.; Cook, J . M. Tetrahedron Lett. 1997, 38, 1301.
(44) Gan, T.; Liu, R.; Yu, P.; Zhao, S.; Cook, J . M. J . Org. Chem.
1997, 62, 9298.
(46) Gerig, T. G.; Klinkenborg, J . C. J . Am. Chem. Soc. 1980, 102,
4267.
(47) Masumi, F.; Takeuchi, H.; Kondo, S.; Suzuki, K.; Yamada, S.
Chem. Pharm. Bull. 1982, 30, 3831.
(48) Hino, T.; Taniguchi, M.; Gonsho, A.; Nakagawa, M. Heterocycles
1979, 12, 1027.
(49) Irie, K.; Ishida, A.; Nakamura, T. Chem. Pharm. Bull. 1984,
32, 2126.
(50) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 7411.
(51) Abramovitch, R. A.; Shapiro., D. S. J . Chem. Soc. 1956, 4589.
(52) Hamaker, L. K. Ph.D. Thesis, University of WisconsinsMil-
waukee, 1995.
(45) Zhao, S.; Gan, T.; Yu, P.; Cook, J . M. Tetrahedron Lett. 1998,
39, 7009.

4528 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
Sch em e 3
Sch em e 5
Sch em e 4
prepared the 5-HT1D receptor agonist MK-0462 on a very
large scale employing this annulation strategy.60 Conse-
quently, this approach was chosen as the desired con-
vergent route to synthesize optically active tryptophans
(Scheme 2).
The synthetic strategy for the preparation of optically
active ring-A substituted tryptophans 12 was envisaged
to rely on the heteroannulation of o-iodoaniline deriva-
tives 13 with the internal alkyne 14. The alkyne 14 would
be made available by diastereoselective alkylation of the
Scho¨llkopf chiral auxiliary 19. The Scho¨llkopf chiral
auxiliary was chosen here for the preparation of L-
tryptophans would be available from D-valine, while the
D-isomers would originate from the inexpensive L-valine
(Scheme 3).52 The silyl group was introduced into the
internal alkyne 14 to control the regioselectivity of the
annulation process because of its size.53 This versatile
moiety could be readily removed or transformed into
another functional group when necessary.
As indicated, the approach to the synthesis of chiral
tryptophans began with the diastereoselective prepara-
tion of propargyl-substituted Scho¨llkopf chiral auxiliary
14 (Scheme 5). The popular Scho¨llkopf chiral auxiliary,
bis-lactim ether 19, derived from D-valine and glycine,
was readily available on a large scale (see the Supporting
Information for experimental details).44,52 Metalation of
the bis-lactim ether 19 with n-butyllithium in THF at
low temperature was followed by alkylation with a
variety of electrophiles and usually proceeded with a high
degree of trans diastereoselectivity.61-63 Initial attempts
to prepare 14 rested on reaction of the Scho¨llkopf chiral
auxiliary 19 with 3-bromo-1-(trimethylsilyl)-1-propyne
(entry 1, Table 1). Unfortunately, the alkylation process
furnished 16 with low diastereoselectivity (14a /14b ) 2.5:
1). Presumably, the selectivity was low because the
with bromide 20 (see Scheme 4). However, numerous
attempts to synthesize 5-methoxyindole derivative 21 by
the Fischer-indole cyclization of a J app-Klingmann azo-
ester intermediate failed. No indole product was obtained
either by acid-mediated cyclization or thermal-effected
cyclization. However, both intermediates, acetylester 16
and bromide 20, could serve as templates for the syn-
thesis of other unnatural R-amino acids.
In 1991, Larock et al.53 reported an excellent method
for the preparation of indoles that involved the pal-
ladium-catalyzed heteroannulation of internal alkynes
with o-iodoanilines. Applications of this method have
been extended in Larock’s group54-57 to the syntheses of
indenones,58 benzofurans,59 etc. Importantly, Chen et al.
(58) Larock, R. C.; Doty, M. J .; Cacchi, S. J . Org. Chem. 1993, 58,
4579.
(59) Larock, R. C.; Yum, E. K.; Doty, M. J . J . Org. Chem. 1995, 60,
3270.
(60) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Reamer, R. A.;
Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1994, 35, 6981.
(61) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798.
(62) Scho¨llkopf, U. In Topics in Current Chemistry; Boschke, F. L.,
Ed.; Springer: Berlin, 1983; Vol. 109, p 65.
(63) Scho¨llkopf, U. Tetrahedron 1983, 39, 2085.
(53) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(54) Larock, R. C.; Roesch, K. R. Org. Lett. 1999, 1, 1551.
(55) Larock, R. C.; Roesch, K. R. Org. Lett. 1999, 1, 553.
(56) Larock, R. C.; Gagnier, S. V. J . Org. Chem. 2000, 65, 1525.
(57) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4529
Ta ble 1. Dia ster eoselective Syn th esis of In ter n a l Alk yn e
14
Sch em e 6
T
isolated 14a (trans)/
entry X (leaving groups) solvent (°C) yield (%) 14b(cis)a
1
2
3
4
5
6
7
8
-Br
THF
THF -100
THF
DME
THF
-78
80
78
75
74
72
72
70
80
2.5:1
1.6:1
11:1
5:1
-Br
-OTs
-OTs
-OSO2CH3
-OSO2(p-CH3OPh) THF
-OPO(OEt)2
-OPO(OPh)2
-78
-58
-78
-78
-78
-78
5:1
12:1
12:1
46:1
THF
THF
a
The ratios were determined by the integration of the 1H NMR
spectrum of the crude reaction mixture.
Ta ble 2. Resu lts fr om th e P a lla d iu m -Ca ta lyzed
Heter oa n n u la tion P r ocess
rodlike propargyl system of the electrophile was not bulky
enough to provide high diastereoselectivity at the site of
reaction. Bis-lactim ethers derived from unnatural amino
acids, have been reported to provide exceptionally high
asymmetric induction,64,65 but the relative cost and
limited availability excluded them from this approach.
It was decided to study the alkylation conditions and
modify the leaving group on 22 (Scheme 5) to provide
substituted Scho¨llkopf chiral auxiliary 14 with high
diastereoselectivity. The electrophiles represented by 22
(Table 1) were prepared either in situ by deprotonation
of 3-trimethylsilyl-2-propyn-ol followed by trapping with
various sulfonyl chlorides or chlorophosphates or by
treatment of 3-trimethylsilyl-2-propynol with the corre-
sponding sulfonyl chloride or chlorophosphate at 0 °C in
the presence of KOH in diethyl ether.66 As illustrated in
Table 1, when the process was carried out at very low
temperature, the selectivity was not improved (entry 2).
Variation of the solvent (entry 4, Table 1) did not improve
the diastereoselectivity. However, the leaving group does
play an important role in formation of the desired trans
diastereomer in preference to its cis counterpart. When
the leaving group was bulkier and less prone to undergo
SN2 substitution, the diastereoselectivity increased (en-
tries 6-8, Table 1). Alkylation of the Scho¨llkopf chiral
auxiliary 19 with diphenyl (trimethylsilyl)propargyl phos-
phate provided the best trans diastereoselectivity (entry
8, Table 1, trans/cis ) 46:1, >96% de). Only a trace of
the undesired cis isomer was observed and was removed
easily by chromatography. Presumably, the lesser reac-
tivity of the phosphate and the bulkier size are the main
factors for such an outcome. Further experiments are
underway to obtain a fuller understanding of the effect
of the leaving group (see section c). The substituted
o-iodoanilines 13a -g were prepared via direct iodination
of the corresponding substituted anilines.67,68 With the
internal alkyne 14a and substituted o-iodoanilines 13a-h
in hand, the palladium-catalyzed heteroannulation reac-
tion was carried out (Scheme 6). The results of this
process are summarized in Table 2. Lithium chloride was
found to be a crucial component of this coupling process
in agreement with the findings of Larock53 and Yum.69
Addition of PPh3 retarded the reaction rate and resulted
Pd(OAc)2
(%)
product
regioisomer yield (%)
entry
X1
X2
alkyne
1
2
3
4
5
6
7
8
9
H
H
14a
14a
14a
14a
14a
25b
25
25
25
25
25
5
5
5
5
5
5
10
5
5
8
NDa
ND
ND
15 (24d )
22 (24e)
4 (27e)
14 (27e)
ND
81 (23a )
70 (23b)
63 (23c)
50 (23d )
65 (23e)
83 (26e)
72 (26e)
62 (26f)
80 (26g)
67 (26g)
65 (26h )
77 (26i)
CH3 CH3
CH3
F
NO2
NO2
NO2
F
Cl
Cl
OMe
H
H
H
H
H
H
H
Cl
Cl
H
ND
10
11c
12d
10 (27g)
<5
<5
5
5
OMe
25
a
The 2,3-regioisomer was not detected or isolated. The ratio
was determined by integration of the 1H NMR spectrum of the
b
crude reaction mixture. The synthesis of this material will be
discussed in section d. c This is based on unpublished data (Xuebin
d
Liao and J ames M. Cook). This case will be discussed in more
detail in section d.
Sch em e 7
in the isolation of recovered starting material and
diminished yields. Use of an excess of alkyne 14a in this
sequence was beneficial to the process. For the substrate
listed in entry 2, the biaryl byproduct was isolated if only
one equivalent of alkyne 14a was employed. For electron-
deficient iodoanilines (entries 4 and 5, Table 2), the
heteroannulations were appreciably faster but with
reduced regioselectivity. For these cases, the desired
products 23d and 23e were obtained in 50% and 65%
yield, respectively, along with the desilyated regioisomers
24d and 24e, isolated in 15% and 22% yield, respectively.
For 4,5-dichloro-2-iodoaniline, 10% of the regioisomer 27g
was generated even though the bulkier triethylsilyl group
25 was employed (entry 10, Table 2; Scheme 7). In
contrast to its trimethylsilyl counterpart, the triethylsilyl
group in regioisomer 27g was retained, presumably
because the TES group is more stable than the TMS
(64) Scho¨llkopf, U.; Neubauer, H.-J . Synthesis 1982, 861.
(65) Richter, L. S.; Gadek, T. R. Tetrahedron: Asymmetry 1996, 7,
427.
(66) Svatos, A.; Attygalle, A. B.; Meinwald, J . Tetrahedron Lett.
1994, 35, 9497.
(67) Sy, W.-W. Synth. Commun. 1992, 22, 3215.
(68) Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J .
Chem. Soc., Perkin Trans. 1 1993, 1941.
(69) Park, S. S.; Choi, J .-K.; Yum, E. K. Tetrahedron Lett. 1998, 39,
327.

4530 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
Sch em e 8
Sch em e 9
moiety. However, when 5% of the Pd(OAc)2 catalyst was
employed in place of 10%, no 2,3-regioisomer 27g could
be detected by integration of the 1H NMR spectrum (entry
9, Table 2) of the crude product. In this manner, 26g was
prepared in regiospecific fashion, as desired. For electron-
rich systems (entries 11 and 12, Table 2), the annulation
process took place in 65% yield to provide the 5-meth-
oxyindole derivative 26h 70 and in 77% yield to furnish
the 6-methoxyindole derivative 26i. For both cases, less
than 5% of the 2,3-regioisomer was detected by integra-
1
tion of the H NMR spectrum of the crude material.
The catalytic cycle for the heteroannulation process is
believed to follow that reported originally by Larock.71,72
The regiochemical outcome is controlled by the insertion
process.70.71 It appears the controlling factor in the
insertion process is the steric interactions present in the
developing carbon-carbon bond or the orientation of the
alkyne immediately prior to syn insertion of the alkyne
into the arylpalladium bond. Alkyne insertion occurs so
as to generate the least steric strain in the vicinity of
the shorter, developing carbon-carbon bond rather than
the longer carbon-palladium bond.71 The arylpalladium
bond and the alkyne must be parallel in order for the
syn addition to occur; consequently, the alkyne may adopt
an orientation in which the more sterically demanding
silyl group (TES) is situated away from the sterically
encumbered aryl group (see ref 70 for details). However,
since the regioselectivity decreased significantly for the
annulation with electron-deficient iodoanilines (Table 2),
electronic factors must also play a role in the regiochem-
istry of the catalytic process. For the aryl iodides sub-
stituted with electron-withdrawing groups, the heteroan-
nulations took place at a much faster rate, with a
concomitant decrease in regioselectivity as mentioned.
To complete the synthesis of tryptophans, the pyrazine
group in indoles 23a -e and 26e-h must be hydrolyzed
and the silyl group required removal. When the indoles
23a -23c were stirred with aqueous hydrochloric acid in
THF (Scheme 8), the pyrazine moiety was hydrolyzed to
the resulting amino acid ethyl ester with concomitant
removal of the silyl group to provide the tryptophan ethyl
esters 28a -c directly. As shown in Scheme 8, electron-
donating groups (X1 or X2) promoted the required
protonation at C(2) or stabilized the â-silylcation or both
to facilitate cleavage of the silyl moiety. The subsequent
saponification furnished L-tryptophan derivatives 29a -c
in good yields. However, for indoles substituted with
electron-withdrawing groups in ring A, the acid-mediated
desilylation was troublesome, as expected (Scheme 9a).
For the fluorine-substituted tryptophan 23d , aqueous 6
N HCl instead of 2 N HCl was required to cleave the
trimethylsilyl group. For the nitro-substituted tryptophan
23e, desilylation failed under acidic conditions; however,
when 23e was treated with aqueous 2 N KOH in ethanol
at 78 °C for 6 h, smooth removal of the silyl group
occurred (Scheme 9b). Acid-mediated hydrolysis of the
desilylated intermediate 32, followed by saponification
of the ester moiety, provided the desired 5-nitro-L-
tryptophan 34 in good yield. For the dichloro-substituted
indole 26g, the triethylsilyl group was removed by
treatment with tetrabutylammonium fluoride (Scheme
(70) Liao, X.; Cook, J . M. Unpublished data. See also: Ma, C. Ph.D.
Thesis, University of WisconsinsMilwaukee, 2000.
(71) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998,
63, 7652-7662.
(72) Amatore, C.; J utand, A.; Suarez, A. J . Am. Chem. Soc. 1993,
115, 9531.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4531
Sch em e 10
F igu r e 2. Structures of three important tryptophan ana-
logues.
9c). Hydrolysis and saponification under similar condi-
tions to 32 provided 5,6-dichloro-D-tryptophan 37. The
optical rotation of the optically active tryptophans ob-
tained in this process were in good agreement with the
literature values,49,73 where available.
b . Asym m et r ic Syn t h esis of Im p or t a n t Tr yp -
top h a n An a logu es. In the continued effort to search for
potent inhibitors of IDO, it was of interest to evaluate
the IDO activity of the three structurally distinct and
optically active tryptophan analogues: L-isotryptophan
38, L-benzo[f]tryptophan 39, and L-homotryptophan 40
(Figure 2). Multistep syntheses of the racemic form of
these three tryptophan analogues have been reported
previously;74-76 however, none of them have been pre-
pared enantioselectively. Described below is an efficient
preparation of these three tryptophan analogues in
optically active form (D or L) via the Scho¨llkopf chiral
auxiliary.
Sch em e 11
Racemic isotryptophan was first synthesized by Korn-
feld and was reported to exhibit some bacteriostatic
activity.74 The stereoselective synthesis of isotryptophan
38 developed here is depicted in Scheme 10. Palladium-
catalyzed Heck coupling of o-iodoaniline with alkyne 4177
provided the aminoarylalkyne 42 in high yield. Intramo-
lecular cyclization of 42 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 43. One possible pathway for the epimerization is
shown in Scheme 11b. Organocopper compounds are
considerably less basic than Grignard or organolithium
reagents, but basicity increases when the temperature
is raised. As indicated in Scheme 11, the indolylcopper
intermediate could abstract a proton from the chiral
center in the pyrazine group under the high reaction
temperatures (80-90 °C). The reprotonation of the
stabilized anion that results could occur from either face
and effect epimerization of the cyclic pyrazine. How-
ever, additional experiments are required to determine
if this is reasonable. This problem, however, was allevi-
ated by addition of ethylene glycol to the medium as a
proton source to suppress epimerization. In this fashion,
indole 43 was obtained in 80% yield accompanied by only
6% of the epimerized (*) material, which was removed
by flash chromatography. The desired L-isotryptophan 38
was obtained in 72% yield by acidic hydrolysis of 43,
followed by subsequent saponification(see the Experi-
mental Section for details).
The linear benzo[f]tryptophan was suggested as a
potential fluorescent amino acid probe because of its red-
shift from the natural amino acid.75 In 1997, McLaughlin
(73) Fluka catalog 1999/2000, 648.
(74) Kornfeld, E. C. J . Org. Chem. 1951, 16, 806.
(75) Yokum, T. S.; Tungaturthi, P. K.; McLaughlin, M. L. Tetrahe-
dron Lett. 1997, 38, 5111.
(76) Snyder, H. R.; Pilgrim, F. J . J . Am. Chem. Soc. 1948, 70, 1962.
(77) Ma, C.; Yu., S.; He, X.; Liu, X.; Cook, J . M. Tetrahedron Lett.
2000, 41, 2781.

4532 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
Sch em e 12
Sch em e 13
moindole 5080 was employed as the starting bromide.
Lithium halogen exchange of 50 with tert-butyllithium
was followed by nucleophilic attack on the oxirane, the
anion of which was trapped with p-toluenesulfonyl
chloride to generate the tosylate 51 in one reaction vessel.
Alkylation of the anion of the Scho¨llkopf chiral auxiliary
with 51 furnished the intermediate 52 in high yield and
diastereospecific fashion. Hydrolysis of 52 and subse-
quent desilylation followed by saponification provided
L-homotryptophan 40 in high yield.
first reported the synthesis of Nb-Boc-benzo[f]tryptophan
in racemic form.75 As described above, an efficient pal-
ladium-catalyzed heteroannulation sequence was devel-
oped for the synthesis of ring-A substituted optically
active tryptophans. This approach was extended to
L-benzo[f]tryptophan 39 (Scheme 12). The required 3-iodo-
2-aminonaphthalene 46 was synthesized as previously
reported (see the Supporting Information for details).77,78
Heteroannulation of 46 and the internal alkyne 25
generated the key benzo-fused indole 47, accompanied
by 15% of the 2,3-substituted regioisomer, which was
easily removed by flash chromatography. Desilylation of
47 was achieved with TBAF in THF to provide interme-
diate 48; treatment of 48 with 1 N aqueous HCl/THF had
failed to effect the desilylation. L-Benzo[f]tryptophan 39
was obtained in 75% yield by acidic hydrolysis of 48,
followed by saponification. As expected, analysis by
spectroscopy indicated the UV absorption of L-benzo[f]-
tryptophan 39 was red-shifted ∼60 nm from the absorp-
tion of natural L-tryptophan. This analogue may provide
an efficient probe to study biological processes (as well
as peptides) that involve tryptophan (IDO, TDO, etc.).
c. Dia ster eoselective Alk yla tion of th e Sch o1llk op f
Ch ir a l Au xilia r y.81 In the early 1980s, Scho¨llkopf
developed an excellent chiral auxiliary 19 to prepare a
large variety of amino acids.61 It can be readily prepared
from L-valine and glycine on a large scale.44,52 Numerous
applications of this Scho¨llkopf chiral auxiliary in the
synthesis of optically active unnatural amino acids have
been reported, including the synthesis of the antitumor
agent OF 4949-III/IV,82 R-deuterated R-amino acids,83 and
tryptophan analogues.50,84 In a few cases, however, alky-
lation of the Scho¨llkopf chiral auxiliary suffered from poor
diastereoselectivity.61,85 Attempts to overcome this draw-
back have been carried out by modification of the chiral
auxiliary through replacement of the isopropyl group in
19 with bulkier groups such as tert-butyl to increase the
diastereoselectivity.64,65 Although the alkylation selectiv-
ity was increased, the relative cost and availability of
those modified bis-lactim ethers have limited their
utilization.64,65 Because of the popularity of the Scho¨llkopf
chiral auxiliary 19, the focus here has shifted from the
chiral auxiliary itself to the electrophiles employed for
alkylation (Scheme 14). More specifically, a variety of
leaving groups have been employed to provide a simple
and practical solution to the problem mentioned above.
Studies of the effect of the leaving group on alkylation
diastereoselectivity were carried out by employing the
Homotryptophan was prepared previously by Snyder
as a racemate.76 The strategy for the asymmetric syn-
thesis of L-homotryptophan 40 was to effect a two-carbon
homologation of an indole moiety to be followed by
alkylation of the Scho¨llkopf chiral auxiliary, as depicted
in Scheme 13. Initially, N-sulfonyl-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.79 However,
in our hands, this carbanion at [C(3)] was readily
converted into the thermodynamically more stable car-
banion at position-2 (at -78 °C) due to the stabilizing
effect of the N-sulfonyl group adjacent to the negative
charge. Consequently, the N-TBDMS-substituted 3-bro-
(80) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J . J . Org.
Chem. 1994, 59, 10.
(81) Ma, C.; He, X.; Liu, X.; Yu, S.; Zhao, S.; Cook, J . M. Tetrahedron
lett. 1999, 40, 2917.
(82) Boger, D. L.; Yohannes, D. J . Org. Chem. 1990, 55, 6000.
(83) Rose, J . E.; Leeson, P. D.; Gani, D. J . Chem. Soc., Perkin Trans.
1 1992, 1563.
(84) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 9133.
(85) Gan, T. Ph.D. Thesis, University of WisconsinsMilwaukee,
1997.
(78) Kelly, R. T.; Kim, M. H. J . Am. Chem. Soc. 1994, 116, 7072.
(79) Saulnier, M. G.; Gribble, G. W. J . Org. Chem. 1982, 47, 757.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4533
Sch em e 14
and 5, Table 3), tosylate provided the best results when
the alkylation yield was balanced against stereoselectiv-
ity.
Although alkylation with the diphenyl phosphates
provided very high diastereoselectivity, the lower yields
in some cases compromised its utility. During the alky-
lation process, the electrophilic phosphorus could compete
for the anion of the Scho¨llkopf chiral auxiliary with the
electrophilic carbon atom, thus diminishing the yield of
the desired carbon alkylation. In support of this hypoth-
esis, decreased yields on carbon alkylation with diphenyl
phosphate were found to be coupled with the production
of phenol, a byproduct of alkylation at phosphorus.70 An
attempt to improve the yield of the alkylation was
executed by modification of the character of the anion of
the Scho¨llkopf chiral auxiliary 19. When the lithium salt
of 19 was transmetalated to provide a higher order (HO)
organocuprate,86,87 the alkylated products 55c and 56c
were isolated in 81% yield in contrast to the 40% yield
obtained with the lithium salt of 19 (entry 4, Table 3).
However, the diastereoselectivity decreased from 97% de
to 68% de. The alkylation mechanism may have changed
when the lithium salt of 19 was converted into the higher
order organocuprate resulting in lower de. Much work
remains to be done on this system to understand this
decrease.
Ta ble 3. Effect of th e Lea vin g Gr ou p on th e Alk yla tion
Selectivity of th e Sch o1llk op f Ch ir a l Au xilia r y 19
Examination of the yields and diastereoselectivities in
Table 3 provides a rational basis for the selection of the
alkylating agent in the Scho¨llkopf approach to amino
acids. In most cases, diphenyl phosphate and tosylate
were found to be far superior to bromide, although the
allylic system in entry 4 proves to be an exception.
Further work is underway to understand the high % de
achieved with the diphenyl phosphates.
a
The % de was determined by integration of the 1H NMR
spectrum of the crude reaction mixture.
d . Efficien t Syn th esis of 6-Meth oxytr yp top h a n a s
Well a s a n Im p r oved Tota l Syn th esis of Tr yp r osta -
tin A. The enantiospecific synthesis of a number of
Alstonia macroline/sarpagine alkaloids has been reported
that employed the trans 1,3-transfer of asymmetry dur-
ing the Pictet-Spengler reaction;88-90 use of D-(+)-tryp-
tophan provided the natural series via this approach.26,27
Studies of the synthesis of ring-A oxygenated indole
alkaloids (see Figure 1) has prompted the need for a
preparative synthesis of 6-alkoxy-D-(+)-tryptophans via
a route that would also provide the L-(-) enantiomers, if
desired. D-(+)-Tryptophans via this chemistry (trans
transfer of asymmetry) would provide the natural alka-
loids in the Alstonia series, while the L-(-)-isomers would
furnish the unnatural antipodes for biological screen-
ing.24,25,88-90 Although both the Moody azide and re-
giospecific bromination methods can be employed to
synthesize 6-methoxytryptophan,44,91 it was felt the pal-
ladium-catalyzed heteroannulation process could provide
6-methoxytryptophan in a shorter and more efficient
manner. More importantly, Chen et al. demonstrated this
type of palladium-catalyzed reaction could be easily
scaled up.60
bromide, tosylate, and diphenyl phosphate to effect
alkylation of the Scho¨llkopf chiral auxiliary 19 at ali-
phatic, benzylic, propargylic, and allylic electrophilic
centers.81
The diphenyl phosphates and tosylates were prepared
either in situ by deprotonation of the corresponding
alcohol with n-butyllithium followed by trapping of the
resulting oxygen anion with a sulfonyl chloride or chlo-
rophosphate or by treatment of the corresponding alcohol
with benzene sulfonyl chloride or chlorophosphate at 0
°C in the presence of KOH in diethyl ether.66,70 Alkyla-
tions of the Scho¨llkopf chiral auxiliary 19 were carried
out in THF at -78 °C for 6 h. The diastereoselectivity
1
was determined by integration of the H NMR spectrum
of the crude material. The results are depicted in Table
3.
As shown in Table 3, alkylation with the diphenyl
phosphates furnished high diastereoselectivity (>95%) in
all cases. The tosylate provided better diastereoselectivity
than the bromide with the exception of one case (entry
4, Table 3). Bromide has been the leaving group most
commonly employed;61-63 unfortunately, it provided the
poorest diastereoselectivity in most cases. In terms of
both alkylation yield and selectivity, however, both
tosylate and diphenyl phosphate exhibited specific ad-
vantages. At the propargylic position (entries 1 and 2,
Table 3), diphenyl phosphate was the best group to effect
efficient and selective alkylation. At the allylic position
(entry 4, Table 3), the bromide was the leaving group of
choice in agreement with the previous reports of Scho¨llko-
pf.61 At the aliphatic and benzylic positions (entries 3
(86) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(87) Beugelmans, R.; Bigot, A.; Bois-Choussy, M.; Zhu, J . J . Org.
Chem. 1996, 61, 771.
(88) Bi, Y.; Cook, J . M. Tetrahedron Lett. 1993, 34, 4501.
(89) Czerwinski, K. M.; Deng, L.; Cook, J . M. Tetrahedron Lett. 1992,
33, 4721.
(90) Zhang, L. H. Ph.D. Thesis, University of WisconsinsMilwaukee,
1990.
(91) Allen, M. S.; Hamaker, L. K.; LaLoggia, A. J .; Cook, J . M. Synth.
Commun. 1992, 22, 2077.

4534 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
Sch em e 1568
Sch em e 17
Sch em e 16
Sch em e 18
The synthesis began with a large-scale preparation of
the 5-methoxy-2-iodoaniline 59. Since the direct iodona-
tion of m-anisidine lacked regioselectivity, attention
turned to the classic Sandmeyer reaction.68As shown in
Scheme 15, commercially available 2-nitro-3-methoxya-
niline 57 ($63/500 g, Aldrich) was diazotized under
standard conditions, followed by treatment of the diazo-
nium ion that resulted with KI to give the iodo derivative
58 in 90% yield. Reduction of the nitro group was effected
with hydrazine in the presence of a catalytic amount of
FeCl3 and active carbon in refluxing methanol to furnish
the desired ortho iodoaniline 59 in 93% yield (100 g scale).
With o-iodoaniline 59 in hand, the diastereoselective
preparation of the internal alkyne 25 (Scheme 16) was
addressed. The THP-protected propargyl alcohol 60 was
treated with n-BuLi, followed by quenching with TESCl
to give the TES derivative in 95% yield. Hydrolysis of
the THP group was effected with a catalytic amount of
PPTS(pyridine p-toluenesulfonic acid) in methanol to
afford the TES-protected propargyl alcohol 61 in 95%
yield. Activation of the hydroxyl group by the diphenyl
chlorophosphate moiety was realized in greater than 90%
yield. The diphenyl phosphate that resulted was then
stirred with the anion of the Scho¨llkopf chiral auxiliary
19 (derived from L-valine) at -78 °C to provide the alkyne
25 in 90% yield and greater than 96% de.
With both the TES-substituted alkyne 25 and the
iodoaniline 59 readily available, the annulation was
carried out in the presence of only 1% Pd(OAc)2 to afford
the desired indole 62 in 77% yield (Scheme 17) on a 300
g scale. No racemization of the chiral center was observed
under these conditions. When this process was run on a
>10 g scale, only a trace amount of the 2,3-regioisomer
was isolated (less than 5%). Under similar conditions, the
annulation of TMS-substituted alkyne 14a with the
iodoaniline 59 provided the corresponding indole in only
61% yield. This again illustrated that the TES-substi-
tuted alkyne 25 was preferred over the TMS-substituted
counterpart for palladium-catalyzed annulations.60 Treat-
ment of the indole derivative 26i with aqueous 2 N HCl
in EtOH effected both hydrolysis of the Scho¨llkopf chiral
auxiliary and removal of the indole-2-silyl group to
provide optically active 6-methoxy-D-tryptophan ethyl
ester 62. Consequently, 6-methoxy-D-tryptophan ethyl
ester 62 can be synthesized in optically active fashion
and the route is amenable to scale-up to the multihun-
dred gram level.
In addition, 6-methoxy-Na-methyl-D-tryptophan 64 can
be readily prepared from 26i for the Scho¨llkopf chiral
auxiliary is an excellent protecting group for the amino
acid functionality of tryptophans. As shown in Scheme
18, treatment of indole 26i with sodium hydride followed
by addition of methyl iodide, resulted in the methylation
of the indole Na-H to provide 63 in 95% yield. The Na-
methyl indole 63 can be crystallized from hexanes to
furnish white crystals. The absolute stereochemistry of
63 was determined by single-crystal X-ray analysis (see
Figure S1 in the Supporting Information). The data
obtained were accurate enough to provide the absolute
configuration at C11 as R and at C14 as S. This X-ray
structural analysis confirmed the stereochemical and
regiochemical assignment of the entire series of tryp-
tophans obtained from the palladium-catalyzed annula-
tion. The desired 6-methoxy-Na-methyl-D-tryptophan 64
was obtained in 93% yield by facile desilylation and
hydrolysis of 63. Currently, studies on the total synthesis
of alstophylline 3 with this ester 64 are underway.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4535
Sch em e 19
tuted internal alkyne 25 was found to provide better
yields and regioselectivity60 than the trimethylsilyl
(TMS)-substituted agent 14a . For electron-rich indoles
that resulted from the annulation, both desilylation and
hydrolysis of the pyrazine group took place simulta-
neously under acidic conditions. Subsequent saponifica-
tion provided the desired optically active tryptophans.
However, for electron-deficient indoles, desilylation would
not take place under mildly acidic conditions. Alterna-
tively, desilylation was achieved with TBAF or potassium
hydroxide followed by subsequent hydrolysis and saponi-
fication to furnish the tryptophans. In addition, the
efficient diastereoselective synthesis of three tryptophan
analogues (L-isotryptophan 38, L-benzo[f]tryptophan 39
and L-homotryptophan 40) with potential activity toward
IDO have been completed. These syntheses make avail-
able any of these tryptophans as D or L isomers in
optically active form for the study of biological processes
(IDO, TDO, etc.). The Scho¨llkopf/palladium-catalyzed
heteroannulation protocol is short, practical, and versa-
tile in operation because of the variety of iodoanilines
and the availability of the Scho¨llkopf chiral auxiliary in
both enantiomeric forms. Studies of the effect of the
leaving group on the alkylation diastereoselectivity were
carried out by employing the bromide, tosylate, and
diphenyl phosphate to effect alkylations of the Scho¨llkopf
chiral auxiliary 19 at aliphatic, benzylic, propargylic, and
allylic electrophilic centers. Alkylation with the diphenyl
phosphates furnished exceptionally high diastereoselec-
tivity (>95%) in all cases. The tosylate provided better
diastereoselectivity than the bromide with the exception
of one case. Examination of the yields and diastereose-
lectivities in Table 3 provides a rational basis for the
selection of alkylating agent in the Scho¨llkopf approach
to amino acids. In most cases, diphenyl phosphate and
tosylate were found to be far superior to bromide, al-
though a few exceptions existed. With both the TES-
substituted alkyne 25 and the iodoaniline 59 readily
available, the Pd0-mediated annulation was then carried
out in the presence of only 1% Pd(OAc)2 to afford the
desired 6-methoxylindole 26i in 77% yield. Treatment of
the indole derivative 26i with aqueous 2 N HCl in EtOH
effected both the hydrolysis of the Scho¨llkopf chiral
auxiliary and the removal of the indole-2-silyl group to
provide optically active 6-methoxy-D-tryptophan ethyl
ester 62 for natural product total synthesis. Conse-
quently, 6-methoxy-D-tryptophan ethyl ester 62 was
synthesized in optically active fashion and the route was
amenable to scale-up to the multihundred gram level.
The 2-silylindole 26i was also reacted with NBS and 2
equiv of di-tert-butyl dicarbonate in a one-pot fashion to
afford the key intermediate 26i, which resulted in an
improved synthesis of tryprostatin A (9a ).
The first enantiospecific total synthesis of tryprostatin
A was reported by Gan et al.,43,44 with the bromide 65 as
a synthetic intermediate. With the chemistry developed
above, it was felt this intermediate could be synthesized
from the readily available indole derivative 26i. As
depicted in Scheme 19, the 2-silylindole 26i, which was
synthesized in 77% yield via a palladium-catalyzed
annulation, was treated with NBS in acetonitrile for 30
min, until analysis by TLC indicated complete reaction.
Subsequent addition of 1 equiv of di-tert-butyl dicarbon-
ate to the same reaction vessel, however, furnished the
desired BOC-protected 2-bromoindole 65 in only 40%
yield while about half of the Na-H intermediate remained
unreacted. Analysis of the reaction course suggested that
the reaction byproduct (N-silylsuccinimide) might con-
sume 1 equiv of di-tert-butyl dicarbonate, thus resulting
in the insufficient supply of di-tert-butyl dicarbonate for
the desired transformation. Indeed, N-BOC-succinimide
was isolated from the reaction mixture. Consequently, 2
equiv of di-tert-butyl dicarbonate was needed to com-
pletely convert 26i into 65. As indicated in Scheme 19,
Na-BOC-2-bromoindole 65 was prepared in 87% yield in
a one-pot fashion via treatment of 26i with NBS and 2
equiv of di-tert-butyl dicarbonate. The spectral data of
bromide 65 are identical to those reported by Gan.44
Conversion of 65 into tryprostatin A (9a ) can be executed
following the route of Gan et al.44 and Zhao. 45 Therefore,
an improved total synthesis of tryprostatin A (9a ) has
been accomplished via a palladium-catalyzed heteroan-
nulation process. The new synthesis is shorter (seven
steps from commercial material 59), easier to perform,
and more efficient (43% overall yield from 59 when
coupled with the improved procedure for removal of the
BOC group in the final step45).
Con clu sion
Internal alkyne 14a was prepared in greater than 96%
de via alkylation of the Scho¨llkopf chiral auxiliary 19
employing diphenyl phosphate as a leaving group. The
palladium-catalyzed heteroannulation reaction of inter-
nal alkyne 14a or 25 and substituted o-iodoanilines 13
was carried out to provide 2-silylindoles. Lithium chloride
was found to be a crucial component of this Pd0-mediated
coupling process. Addition of the PPh3 ligand retarded
the reaction rate and resulted in the isolation of recovered
starting material and diminished yields. For electron-
deficient iodoanilines, the heteroannulations were ap-
preciably faster but with reduced regioselectivity. More
importantly, annulation with triethylsilyl (TES)-substi-
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover melting
point apparatus or an Electrothermal model IA8100 digital
melting point apparatus and are reported uncorrected. The
1H NMR spectra were recorded on a Bruker 250-MHz or 300-
MHz multiple-probe instrument. Infrared spectra were re-
corded on a Nicolet Dx FTIR DX V5.07 spectrometer or a
Perkin-Elmer 1600 Series FT-IR spectrometer. Low-resolution
mass spectral data (EI/CI) were obtained on a Hewlett-Packard
5985 B gas chromatograph-mass spectrometer. High-resolu-
tion mass spectral data were taken on a VG autospectrometer
(double focusing high-resolution GC/mass spectrometer, UK).
Optical rotations were measured on a J ASCO DIP-370 pola-

4536 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
rimeter. Microanalyses were performed on a Perkin-Elmer
240C carbon, hydrogen, and nitrogen analyzer.
Analytical TLC plates employed were E. Merck Brinkman
UV active silica gel (Kieselgel 60 F254) on plastic, while silica
gel 60b for flash chromatography was purchased from E. M.
Laboratories.
Indoles were visualized with Dragendorf’s reagent or a
saturated solution of ceric ammonium sulfate in 50% sulfuric
acid. Ketones or aldehydes were visualized with an aqueous
solution of 2,4-dinitrophenylhydrazine in 30% sulfuric acid.
Methanol (MeOH) and ethanol (EtOH) were dried by distil-
lation over magnesium metal and iodine. Tetrahydrofuran
(THF), benzene, toluene, dioxane, and diethyl ether were dried
by distillation from sodium benzophenone ketyl. Methylene
chloride was dried over MgSO4 and then distilled over P2O5.
Triethylamine was dried over CaH2 and then distilled over
KOH.
2-iodoaniline (200 mg, 0.91 mmol), (2R,5S)-3,6-diethoxy-2-iso-
propyl-5-[3-(trimethylsilyl)prop-2-ynyl]-2,5-dihydropyrazine 14a
(322 mg, 1 mmol), palladium(II) acetate (8 mg, 0.036 mmol),
lithium chloride (39 mg, 0.91 mmol), sodium carbonate (193
mg, 1.8 mmol), and DMF (12 mL). The reaction mixture was
degassed and then heated at 100 °C under argon until the
starting iodoaniline was no longer detected on analysis by TLC
(30 h). The DMF was removed under reduced pressure, and
the residue was taken up in CH2Cl2 (50 mL). The suspension
that resulted was allowed to pass through a Celite pad to
remove insoluble solids. The solution was concentrated in a
vacuum, and the product was purified by flash chromatogra-
phy (silica gel, hexane/EtOAc 98:2) to afford 23a as an oil (301
1
mg) in 81% yield. 23a : IR (NaCl) 3415, 2952, 1687 cm-1; H
NMR (300 MHz, CDCl3) δ 0.41 (s, 9H), 0.67 (d, 3H, J ) 6.8
Hz), 1.03 (d, 3H, J ) 6.8 Hz), 1.19 (t, 3H, J ) 7.1 Hz), 1.30 (t,
3H, J ) 7.1 Hz), 2.27 (m,1H), 2.88 (dd, 1H, J ) 9.6, 14.2 Hz),
3.54 (dd, 1H, J ) 3.6, 14.2 Hz), 3.87 (t, 1H), 4.14 (m, 5H), 7.05
(t, 1H, J ) 7.9 Hz), 7.13 (t, 1H, J ) 8.0 Hz), 7.32 (d, 1H, J )
8.1 Hz), 7.72 (d, 1H, J ) 7.9 Hz), 7.93 (s, br, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 0, 14.6, 14.8, 14.9, 17.1, 19.7, 32.4, 59.1,
61.0, 61.2, 111.1, 119.1, 121.0, 122.6, 123.4, 130.1, 134.4, 138.7,
163.3, 164.2; MS (EI) m/e (rel intensity) 413 (M+, 4), 202 (100),
186 (18), 169 (36), 160 (11); exact mass calcd for C23H35N3O2-
Si 413.2499, found 413.2473. This material was employed
directly in a later step.
Diph en yl 3-(Tr im eth ylsilyl)pr op-2-yn yl P h osph ate 22c.
To a solution of 3-(trimethylsilyl)prop-2-yn-1-ol (1.4 g, 11.7
mmol) and diphenyl chlorophosphate (3.52 g, 13.1 mmol) in
diethyl ether (30 mL) at -50 °C was added powdered potas-
sium hydroxide (4.18 g, 74 mmol). The mixture that resulted
was allowed to warm to 0 °C over 20 min and stirred at 0 °C
for 12 h. The reaction mixture was poured into ice-water (100
mL), and the ether layer was separated. The aqeous layer was
extracted with ether (2 × 50 mL). The combined ether layer
was washed with water until the water washing was no longer
alkaline to pH paper. The ether solution was dried (MgSO4),
and the solvent was removed under reduced pressure. The
colorless residue was chromatographed on silica gel (hexane/
EtOAc 8:1) to provide pure 22c (3.6 g) in 92% yield. 22c: IR
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[5,6-d im eth yl-2-(tr i-
m eth ylsilyl)-3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 23b.
The 4,5-dimethyl-2-iodoaniline, (2R,5S)-3,6-diethoxy-2-isopro-
pyl-5-[3-(trimethylsilyl)prop-2-ynyl]-2,5-dihydropyrazine14a ,
palladium(II) acetate, lithium chloride, and sodium carbonate
in DMF were heated under conditions analogous to those
employed for the preparation of 23a above to provide 23b as
(NaCl) 3067, 2956, 2178, 1588 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 0.15 (s, 9H), 4.85 (d, 2H, J ) 10.8 Hz), 7.28 (m, 10H);
MS (EI) m/e (rel intensity) 360 (M+, 49), 307 (16), 251 (16),
213 (43), 131 (100). This material was used in a later step
without further characterization.
1
a oil in 70% yield. 23b: IR (NaCl) 3355, 2964, 1687 cm-1; H
NMR (300 MHz, CDCl3) δ 0.39 (s, 9H), 0.68 (d, 3H, J ) 6.8
Hz), 1.03 (d, 3H, J ) 6.9 Hz), 1.22 (t, 3H, J ) 7.1 Hz), 1.32 (t,
3H, J ) 7.1 Hz), 2.25 (m,1H), 2.33 (s, 3H), 2.36 (s, 3H), 2.95
(dd, 1H), 3.5 (dd, 1H), 3.86 (t, 1H), 4.13 (m, 5H), 7.1 (s, 1H),
7.49 (s, 1H), 7.72 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 0,
14.8, 14.9, 17.1, 19.6, 20.5, 20.9, 32.0, 32.5, 59.3, 60.9, 61.2,
107.8, 111.3, 121.0, 123.3, 127.6, 128.5, 131.6, 133.3, 137.7,
163.2, 164.2; MS (EI) m/e (rel intensity) 441 (M+, 2.2), 230
(100), 214 (11), 169 (28); exact mass calcd for C25H39N3O2Si
441.2812, found 441.2823. This material was employed in a
later step.
3-(Tr im eth ylsilyl)p r op -2-yn yl Tosyla te 22d . p-Toluene-
sulfonyl chloride, 3-(trimethylsilyl)prop-2-yn-1-ol, and pow-
dered potassium hydroxide were reacted under conditions
analogous to those employed for the preparation of 22c above
to provide 22d as a colorless oil in 90% yield. 22d : 1H NMR
(300 MHz, CDCl3) δ 0.07 (s, 9H), 3.87 (s, 3H), 4.69 (s, 2H),
6.99 (d, 2H, J ) 9 Hz), 7.88 (d, 2H, J ) 8.9 Hz). This material
was used in a later step without further characterization.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[3-(tr im eth ylsilyl)-
p r op -2-yn yl]-2,5-d ih yd r op yr a zin e 14a . To a solution of
(2R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine 19 (0.827 g,
3.9 mmol) in dry THF (25 mL) under nitrogen was syringed
n-BuLi (2.5 M, 1.72 mL, 4.3 mmol) dropwise at -78 °C. This
solution was stirred at -78 °C for 30 min. To this solution
was added slowly a solution of diphenyl 3-(trimethylsilyl)prop-
2-ynyl phosphate 22c (1.4 g, 39 mmol) in dry THF (20 mL)
that was cooled to -78 °C. After the reaction mixture was
allowed to stir for 6 h at -78 °C, it was allowed to slowly warm
to room temperature. The solution was then quenched with
the addition of water (2 mL). The THF was removed under
reduced pressure, and the residue was partitioned between
water (20 mL) and diethyl ether (60 mL). The organic layer
was separated, and the aqueous layer was extracted with ether
(3 × 30 mL). The combined organic layers were washed with
brine and dried (MgSO4). After removal of solvent under
reduced pressure, the residue was purified by chromatography
(silica gel, hexane/EtOAc 98:2) to afford 14a as a oil (1.0 g) in
(2R,5S)-3,6-Diet h oxy-2-isop r op yl-5-[5-m et h yl-2-(t r im -
eth ylsilyl)-3-in dolyl]m eth yl-2,5-dih ydr op yr a zin e 23c. The
4-methyl-2-iodoaniline, (2R,5S)-3,6-diethoxy-2-isopropyl-5-[3-
(trimethylsilyl)prop-2-ynyl]-2,5-dihydropyrazine14a, palladium-
(II) acetate, lithium chloride, and sodium carbonate in DMF
were heated under conditions analogous to those employed for
the preparation of 23a above to provide 23c as a oil in 70%
yield. 23c: IR (NaCl) 3427, 2964, 1687 cm-1 1H NMR (300
;
MHz, CDCl3) δ 0.39 (s, 9H), 0.67 (d, 3H, J ) 6.8 Hz), 1.02 (d,
3H, J ) 6.9 Hz), 1.20 (t, 3H, J ) 7.1 Hz), 1.31 (t, 3H, J ) 7.1
Hz), 2.30 (m,1H), 2.42 (s, 3H), 2.85 (dd, 1H, J ) 9.6, 14.2 Hz),
3.51 (dd, 1H, J ) 3.4, 14.1 Hz), 3.87 (t, 1H), 4.0-4.22 (m, 5H),
6.96 (dd, 1H, J ) 1.3, 8.3 Hz), 7.20 (d, 1H, J ) 8.3 Hz), 7.51
(s, 1H), 7.83 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 0.1,
14.9, 15.0, 17.2, 19.7, 21.9, 32.1, 32.4, 59.3, 61.0, 61.2, 110.7,
120.7, 123.0, 124.3, 128.2, 134.5, 137.1, 163.3, 164.2; MS (CI,
CH4) m/e (rel intensity) 428 (M + 1+, 100); exact mass calcd
for C24H37N3O2Si 427.2655, found 427.2562. This material was
employed in a later step.
80% yield. 14a : IR (NaCl) 2950, 2167, 1688 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 0.01 (s, 9H), 0.61 (d, 3H, J ) 6.8 Hz),
0.95 (d, 3H, J ) 6.9 Hz), 1.19 (m, 6H), 2.2 (m, 1H), 2.63 (m,
2H), 3.87 (t, 1H, J ) 3.3 Hz), 4.05 (m, 5H); 13C NMR (75.5
MHz, CDCl3) δ 0.4, 14.4, 14.8, 16.7, 19.2, 26.6, 31.6, 54.6, 60.7,
60.8, 61.0, 86.6, 103.6, 161.2, 164.3; MS (EI) m/e (rel intensity)
322 (M+, 12), 294 (8), 279 (13), 211 (76), 169 (100), 141 (8);
exact mass calcd for C17H30N2O2Si 322.2077, found 322.2078.
This material was used directly in a later step.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[5-flu or o-2-(tr im e-
th ylsilyl)-3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 23d . The
4-fluoro-2-iodoaniline, (2R,5S)-3,6-diethoxy-2-isopropyl-5-[3-
(trimethylsilyl)prop-2-ynyl]-2,5-dihydropyrazine 14a , palla-
dium(II) acetate, lithium chloride, and sodium carbonate in
DMF were heated under conditions analogous to those em-
ployed for the preparation of 23a above to provide 23d as a
oil in 50% yield as well as 15% of the 2,3-regioisomer 24d .
1
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[2-(tr im eth ylsilyl)-
3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 23a . In a 100 mL
round-bottom flask equipped with a stirring bar were placed
23d : IR (NaCl) 3462, 3391, 2952, 1687 cm-1; H NMR (300
MHz, CDCl3) δ 0.41 (s, 9H), 0.67 (d, 3H, J ) 6.8 Hz), 1.02 (d,
3H, J ) 6.8 Hz), 1.22 (t, 3H, J ) 7.1 Hz), 1.31 (t, 3H, J ) 7.1

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4537
1
Hz), 2.28 (m,1H), 2.82 (dd, 1H), 3.52 (dd, 1H, J ) 3.3, 14.3
Hz), 3.87 (t, 1H, J ) 3.3 Hz), 4.10 (m, 5H), 6.89 (m, 1H), 7.23
(m, 1H), 7.4 (dd, 1H, J ) 2.5, 10.1 Hz), 7.92 (s, br, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 0, 14, 15, 17.3, 19.8, 32.3, 32.5, 59.3,
61.2, 61.4, 105.7, 106.1, 111.0, 111.3, 111.5, 111.7, 123.7, 130.6,
130.8, 135.3, 136.9, 156.5, 159.6, 163.6, 164.0; MS (EI) m/e (rel
intensity) 431 (M+, 3), 221 (18), 220 (100), 169 (59); exact mass
calcd for C23H34FN3O2Si 431.2404, found 431.2394. This mate-
rial was employed directly in a later step. 24d : IR (NaCl) 3368,
(NaCl) 2942, 2355, 1684 cm-1; H NMR (300 MHz, CDCl3) δ
0.82-0.94 (m, 18H), 1.04 (d, 3H, J ) 6.9 Hz), 1.19-1.24 (m,
6H), 2.15 (m, 1H), 2.71 (dd, 1H), 3.41 (dd, 1H, J ) 2.8, 14.3
Hz), 3.86-4.13 (m, 6H), 7.35 (s, 1H), 7.75 (s, 1H), 7.83 (s, br,
1H).
5,6-Dim eth yl-L-tr yp top h a n Eth yl Ester 28b. To a solu-
tion of optically pure (2R,5S)-3,6-diethoxy-2-isopropyl-5-[5,6-
dimethyl-2-(trimethylsilyl)-3-indolyl]methyl-2,5-dihydropyra-
zine 23b (208 mg, 0.5 mmol) in THF (8 mL) at 0 °C was slowly
added an aqueous solution of 2 N HCl (7 mL). The mixture
was allowed to warm to room temperature and stirred for 2
h. Ice (5 g) was added to the solution, and the pH of the
reaction mixture was adjusted to 8 with aqueous NH4OH
(concentrated) at 0 °C. The mixture was then extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(Na2SO4), and the solvent was removed under reduced pres-
sure. The residue that resulted was purified by flash chroma-
tography (silica gel, EtOAc) to afford 28b (117 mg) in 86%
yield. 28b: [R]27D ) 1.92 (c ) 1.8, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.24 (t, H, J ) 7.1 Hz), 1.83 (s, br, 2H), 2.33 (s, 6H),
2.99 (dd, 1H, J ) 7.8 Hz and J ) 14.3 Hz), 2.24 (dd, 1H, J )
4.6 Hz and J ) 14.3 Hz), 3.79 (m, 1H), 4.14 (q, 2H, J ) 7.1
1
2966, 1689 cm-1; H NMR (300 MHz, CDCl3) δ 0.73 (d, 3H, J
) 6.9 Hz), 1.0 (d, 3H, J ) 6.9 Hz), 1.36 (m, 6H), 2.26 (m, 1H),
2.99 (dd, 1H), 3.41 (dd, 1H, J ) 3.2, J ) 14.8 Hz), 3.88 (t, 1H,
J ) 3.5 Hz), 4.15-4.24 (m, 5H), 6.22 (s, 1H), 6.8 (m, 1H), 7.16
(m, 2H), 9.26 (s, br, 1H); MS (CI, CH4) m/e (rel intensity) 360
(M+ + 1, 100), 340 (17), 211 (11).
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[5-n itr o-2-(tr im eth -
ylsilyl)-3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 23e a n d
th e Regioisom er 24e. The 4-nitro-2-iodoaniline 13e, (2R,5S)-
3,6-diethoxy-2-isopropyl-5-[3-(trimethylsilyl)prop-2-ynyl]-2,5-
dihydropyrazine 14a , palladium(II) acetate, lithium chloride,
and sodium carbonate in DMF were reacted under conditions
analogous to those employed for the preparation of 23a above
to provide 23e as a oil in 65% yield as well as 22% of the 2,3-
regiosiomer 24e. 23e: IR (NaCl) 3379, 2952, 1687, 1515, 1461
Hz), 6.94 (s, 1H), 7.12 (s, 1H), 7.34 (s, 1H), 7.92 (s, br, 1H); 13
C
NMR (75.5 MHz, CDCl3) δ 12.4, 18.3, 18.6, 29.0, 53.0, 59.1,
108.0, 109.8, 117.0, 120.4, 124, 126.5, 129.5, 133.0, 176.1. This
material was used in a later step without further characteriza-
tion.
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.46 (s, 9H), 0.68 (d, 3H,
J ) 6.8 Hz), 1.01 (d, 3H, J ) 6.9 Hz), 1.20 (t, 3H, J ) 7.1 Hz),
1.34 (t, 3H, J ) 7.1 Hz), 2.28 (m,1H), 2.89 (m, 1H), 3.62 (dd,
1H, J ) 2.9, 14.3 Hz), 3.92 (m, 1H), 4.16 (m, 5H), 7.35 (d, 1H,
J ) 9 Hz), 8.07 (dd, 1H, J ) 2.2, 9 Hz), 8.27 (s, br, 1H), 8.8 (d,
1H, J ) 2.2 Hz); MS (EI) m/e (rel intensity) 458 (M+, 2), 247
(87), 212 (72), 169 (100); exact mass calcd for C23H34N4O4Si
458.2349, found 458.2355. 24e: IR (NaCl) 3329, 1731, 1660,
L-Tr yp top h a n eth yl ester 28a was prepared in 90% yield
following the procedure for preparation of 28b. 28a : 1H NMR
(300 MHz, CDCl3) δ 1.24 (t, 3H, J ) 7.1 Hz), 1.82 (s, br, 2H),
3.05 (dd, 1H, J ) 7.7 Hz and J ) 14.4 Hz), 3.29 (dd, 1H, J )
4.8, 14.4 Hz), 3.81 (m, 1H), 4.17 (q, 2H, J ) 7.1 Hz), 7.07 (d,
1H, J ) 2.1 Hz), 7.10-7.20 (m, 2H), 7.35 (d, 1H, J ) 8.0 Hz),
7.62 (d, 1H, J ) 7.8 Hz), 8.22 (s, br, 1H). This material was
used in a later step without further characterization.
5-Meth yl-L-tr yp top h a n eth yl ester 28c was prepared in
91% yield following the procedure for preparation of 28b.
1
1521 cm-1; H NMR (300 MHz, CDCl3) δ 0.75 (d, 3H, J ) 6.9
Hz), 1.02 (d, 3H, J ) 6.9 Hz), 1.36 (m, 6H), 2.28 (m, 1H), 2.99
(dd, 1H), 3.50 (dd, 1H), 3.94 (t, 1H, J ) 3.3 Hz), 4.16-4.26 (m,
5H), 6.45 (s, 1H), 7.28 (d, 1H, J ) 9.1 Hz), 8.04 (dd, 1H, J )
9.0 Hz and J ) 2.0 Hz), 8.50 (d, 1H, J ) 2.0 Hz), 9.88 (s, br,
1H); MS (CI, CH4) m/e (rel intensity) 387 (M+ + 1, 100).
(2S,5R)-3,6-Dieth oxy-2-isop r op yl-5-[5-n itr o-2-(tr ieth yl-
silyl)-3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 26e. The 4-ni-
tro-2-iodoaniline 13e, TES-substituted alkyne 25, 5 mol %
palladium(II) acetate, lithium chloride, and sodium carbonate
in DMF were heated under conditions analogous to those
employed for the preparation of 23a above to provide 26e as
an oil in 83% yield. 26e: IR (NaCl) 3391, 2951, 1683, 1513,
28c: [R]27 ) 1.06° (c ) 2.5, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.26 (t, 3H, J ) 7.1 Hz), 1.75 (s, br, 2H), 2.45 (s, 3H),
3.01 (dd, 1H, J ) 7.8, 14.4 Hz), 3.25 (dd, 1H, J ) 4.7, 14.4
Hz), 3.8 (dd, 1H, J ) 4.7, 7.6 Hz), 4.17 (q, 2H, J ) 7.0 Hz),
7.01 (m, 2H), 7.25 (d, 1H, J ) 3.8 Hz), 7.39 (s, 1H), 8.23 (s, br,
1H). This material was used in a later step without further
characterization.
5-F lu or o-L-tr yp top h a n Eth yl Ester 30. To a solution of
optically pure (2R,5S)-3,6-diethoxy-2-isopropyl-5-[5-fluoro-2-
(trimethylsilyl)-3-indolyl]methyl-2,5-dihydropyrazine 23d (216
mg, 0.5 mmol) in THF (8 mL) at 0 °C was slowly added an
aqueous solution of 6 N HCl (7 mL). The mixture was allowed
to warm to room temperature and stirred for 4 h. Ice (10 g)
was added to the solution, and the pH of the reaction mixture
was adjusted to 8 with aqueous NH4OH (concentrated) at 0
°C. The mixture was then extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried (Na2SO4), and the
solvent was removed under reduced pressure. The residue
which resulted was purified by flash chromatography (silica
1
1463 cm-1; H NMR (300 MHz, CDCl3) δ 0.61 (d, 3H, J ) 6.8
Hz), 0.93 (m, 18H), 1.13 (t, 3H, J ) 6.8 Hz), 1.24 (t, 3H, J )
6.3 Hz), 2.18 (m, 1H), 2.81 (dd, 1H), 3.51 (dd, 1H), 3.90 (m,
3H), 4.10 (m, 3H), 7.26 (d, 1H, J ) 9.0 Hz), 7.99 (dd, 1H, J )
7.0, 2.0 Hz), 8.23 (s, br, 1H), 8.78 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 3.3, 7.3, 14.2, 16.7, 19.0, 31.7, 31.9, 58.7, 60.8, 110.3,
117.5, 118.7, 126.8, 129.2, 136.1, 141.0, 141.1, 162.9, 163.4;
MS (EI) m/e (rel intensity) 500 (M+, 8), 289 (88), 212 (100),
169 (37); exact mass calcd for C26H30N4O4Si 500.2819, found
500.2837. This material was directly employed in a later step.
(2S,5R)-3,6-Dieth oxy-2-isop r op yl-5-[5,6-d ich lor o-2-(tr i-
eth ylsilyl)-3-in dolyl]m eth yl-2,5-d ih ydr op yr a zin e 26g a n d
th e Regioisom er 27g. The 4,5-dichloro-2-iodoaniline 13g,
TES-substituted alkyne 25, 5 mol % palladium(II) acetate,
lithium chloride, and sodium carbonate in DMF were heated
under conditions analogous to those employed for the prepara-
tion of 23a above to provide 26g as an oil in 80% yield. 26g:
IR (NaCl) 3454, 2956, 1685 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.61 (d, 3H, J ) 6.8 Hz), 0.92 (m, 18H), 1.19 (t, 3H, J ) 7.1
Hz), 1.25 (t, 3H, J ) 7.1 Hz), 2.2 (m,1H), 2.69 (dd, 1H), 3.44
(dd, 1H, J ) 2.9, 14.3 Hz), 3.83-4.15 (m, 6H), 7.34 (s, 1H),
7.82 (s, 1H), 7.92 (s, 1H). 13C NMR (75.5 MHz, CDCl3) δ 3.4,
7.2, 14.2, 14.3, 16.7, 19.0, 31.7, 31.8, 58.8, 60.7, 60.8, 60.9,
111.6, 122.1, 122.5, 123.7, 125.5, 129.5, 134.5, 137.0, 163.1;
MS (EI) m/e (rel intensity) 523 (M+, 7), 312 (67), 212 (100),
169 (32); exact mass calcd for C26H39Cl2N3O2Si 525.2159, found
525.2144; calcld 523.2189, found 523.2165. This material was
employed directly in a later step. When 10mol % of palladium-
(II) acetate was employed, the yield for 26g dropped to 67%
while 10% of the 2,3-regioisomer 27g was isolated. 27g: IR
gel, EtOAc) to afford 30 (102 mg) in 82% yield. 30: [R]27
)
D
1
11.0° (c ) 1.7, CHCl3); H NMR (300 MHz, CDCl3) δ 1.25 (t,
3H, J ) 7.1 Hz), 1.64 (s, br, 2H), 3.02 (dd, 1H, J ) 7.5, 14.5
Hz), 3.22 (dd, 1H, J ) 5, 14.5 Hz), 3.78 (m, 1H), 4.15 (m, 2H),
6.93 (m, 1H), 7.1 (d, 1H, J ) 2.4 Hz), 7.24 (m, 2H), 8.6 (s, br,
1H); 13C NMR (75.5 MHz, CDCl3) δ 14.6, 31.0, 55.3, 61.4, 104,
104.3, 110.8, 111.1, 111.9, 112.1, 112.3, 125.1, 128, 133.1, 158,
159.8, 175.0. This material was used in a later step without
further characterization.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-(5-n itr o-3-in d olyl)-
m eth yl-2,5-d ih yd r op yr a zin e 32. To pyrazine 23e (105 mg,
0.23 mmol) in 95% ethanol (10 mL) was added powdered KOH
(300 mg, 5.4 mmol). The reaction mixture that resulted was
heated to reflux for 8 h. Analysis by TLC (silica gel) indicated
the absence of starting material; consequently, the solvent was
removed under reduced pressure. The residue was taken up
in CH2Cl2 and washed with water (2 × 15 mL). The organic
layer was dried (Na2SO4), and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-

4538 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
tography (silica gel, EtOAc/hexanes 95:5) to afford 32 (76 mg)
(c ) 0.67, 0.5 N aqueous NaOH), IR (KBr) 3389, 1667, 1583,
1467 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 9H), 2.85
(dd, 1H, J ) 9.5, 15.1 Hz), 3.27 (dd, 1H, J ) 3.5, 15.0 Hz),
3.38 (dd, 1H, J ) 3.7, 9.3 Hz), 7.05 (s, 1H), 7.11 (s, 1H), 7.29
(s, 1H), 10.59 (s, br, 1H); MS (CI, CH4) m/e (rel intensity) 233
(M+ + 1, 100), 216 (100), 187 (20), 158 (19). Anal. Calcd. for
C13H16N2O2‚1/7H2O: C, 66.48; H, 6.99; N, 11.93. Found: C,
66.72; H, 6.92; N, 11.70.
L-Tr yp top h a n 29a was prepared in 88% yield from L-
tryptophan ethyl ester 28a following the procedure employed
for preparation of 29b. The optical rotation and spectral data
for 29a were identical to those obtained for an authentic
sample from Aldrich Chemical Co. When the product 29a was
heated under the conditions of saponification employed in the
previous experiments for 20 h, no racemization of 29a was
observed.
1
in 86% yield. 32: IR (NaCl) 3368, 2961, 2347, 1692 cm-1; H
NMR (300 MHz, CDCl3) δ 0.56 (d, 3H, J ) 6.8 Hz), 0.83 (d,
3H, J ) 6.9 Hz), 1.14 (t, 3H, J ) 7.1 Hz), 1.29 (t, 3H, J ) 7.1
Hz), 2.08 (m,1H), 3.22-3.29 (m, 3H), 3.93 (m, 1H), 4.11 (m,
3H), 4.27 (m, 1H), 7.01 (s, 1H), 7.23 (d, 1H, J ) 9.0 Hz), 7.98
(dd, 1H, J ) 2.2, 9.0 Hz), 8.47 (s, br, 1H), 8.80 (d, 1H, J ) 2.2
Hz); 13C NMR (75.5 MHz, CDCl3) δ 14.2, 14.3, 16.4, 18.9, 20.9,
29.2, 31.5, 56.3, 60.4, 60.6, 110.7, 114.6, 117.2, 117.3, 125.9,
127.8, 138.7, 141.4, 162.1, 163.6; MS (EI) m/e (rel intensity)
386 (M+, 12), 289 (9), 212 (41), 169 (100), 141 (13); exact mass
calcd for C20H26N4O4 386.1954, found 386.1944. This material
was employed directly in the next step.
5-Nit r o-L-t r yp t op h a n E t h yl E st er 33. To a solution of
(2R,5S)-3,6-diethoxy-2-isopropyl-5-(5-nitro-3-indolyl)methyl-
2,5-dihydropyrazine 32 (93 mg, 0.24 mmol) in THF (4 mL) at
0 °C was slowly added an aqueous solution of 2 N HCl (3 mL).
The mixture was warmed to room temperature and stirred for
2 h. Ice (5 g) was added to the solution, and the pH of the
reaction mixture was adjusted to 8 with an aqqueous solu-
tion of NH4OH (concentrated) at 0 °C. The mixture was then
extracted with CH2Cl2 (3 × 40 mL). The combined organic
layers were dried (Na2SO4), and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (silica gel, EtOAc) to afford 33(54 mg) in 91%
yield. 33: [R]27D ) 18.8° (c ) 1.14, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.29 (t, 3H, J ) 7.1 Hz), 1.68 (s, br, 2H), 3.18 (m,
1H), 3.26 (m, 1H), 3.84 (m, 1H), 4.19 (m, 2H), 7.23 (s, 1H),
7.34 (d, 1H, J ) 9.0 Hz), 8.07 (dd, 1H, J ) 2.2, 9.0 Hz), 8.58
(d, 1H, J ) 2.2 Hz), 8.8 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 14.6, 30.5, 55.0, 61.7, 111.6, 113.0, 116.6, 118.2, 126.5, 127.5,
140.0, 142.5, 176.0. This material was used in a later step
without further characterization.
5-Meth yl-L-tr yp top h a n 29c was prepared in 87% yield
from 5-methyl-L-tryptophan ethyl ester 28c following the
procedure employed for preparation of 29b . 29c: mp 272-
273 °C dec; [R]27 ) 10.82° (c ) 0.61, 1 N aqueous HCl) [lit.49
D
mp 275-277 °C, [R]20 ) 11.2° (c ) 1.0, 1 M aqueous HCl)];
D
IR (KBr) 3400, 1661, 1590, 1406 cm-1
;
1H NMR (300 MHz,
DMSO-d6) δ 2.38 (s, 3H), 2.89 (dd, 1H, J ) 9.3, 15.1 Hz), 3.29
(dd, 1H, J ) 3.6, 15.1 Hz), 3.42 (dd, 1H, J ) 3.6, 9.4 Hz), 6.89
(d, 1H, J ) 8.3 Hz), 7.14 (s, 1H), 7.23 (d, 1H, J ) 8.2 Hz), 7.33
(s, 1H), 10.75 (s, br, 1H); MS (EI) m/e (rel intensity) 218 (M+,
3), 144 (100), 115 (14). Anal. Calcd for C12H14N2O2: C, 66.04;
H, 6.47; N, 12.84. Found: C, 66.45; H, 6.17; N, 12.55.
5-Nitr o-L-tr yp top h a n 34 was prepared in 84% yield from
5-nitro-L-tryptophan ethyl ester 33 following the procedure
employed for preparation of 29b. 34: mp 264-266 °C dec;
[R]27 ) 49.9° (c ) 0.9, 1 N aqueous HCl) [lit.49 mp 266-268
D
°C, [R]20 ) 49.1° (c ) 1.0, 1 N aqueous HCl)]; IR (KBr) 3411,
D
1
5-F lu or o-L-tr yp top h a n 31. Into a 25 mL round-bottom
flask were added 5-fluoro-L-tryptophan ethyl ester 30 (85 mg,
0.33 mmol), aqueous 1 N NaOH (1.0 mL, 1 mmol), and ethanol
(1.5 mL). The solution was heated to 50 °C for 2 h. Analysis
by TLC (silica gel) indicated that all the starting material had
disappeared (material now had Rf ) 0). Most of the EtOH was
removed under reduced pressure. A piece of ice was dropped
into the flask and the mixture was brought to pH ) 6-7 with
an aqueous solution of 2 N HCl at 0 °C. The water in the
solution that resulted was removed under reduced pressure
until a white precipitate appeared. The total volume of solution
was reduced to 0.5 mL. Cold water (1 mL) was then added,
and the precipitate that formed was collected by vacuum
filtration, washed with cold water (3 × 1 mL), and dried to
provide 5-fluoro-L-tryptophan 31 (54 mg) in 70% yield. 31:
[R]27 ) 5.6° (c ) 0.98, 0.1 M aqueous HCl) [lit.73 [R]27 ) 5.5°
1600, 1580 cm-1; H NMR (300 MHz, DMSO-d6) δ 3.12 (dd,
1H, J ) 7.5, 15.0 Hz), 3.29 (dd, 1H, J ) 4.2, 15.1 Hz), 3.44
(dd, 1H, J ) 4.5, 7.4 Hz), 7.44 (s, 1H), 7.51 (d, 1H, J ) 9.0
Hz), 7.97 (dd, 1H, J ) 2.2, 9.0 Hz), 8.63 (d, 1H, J ) 2.2 Hz),
11.07 (s, br, 1H); MS (EI) m/e (rel intensity) 175 (64), 159 (24),
129 (100). MS (CI, CH4) m/e (rel intensity) 250 (M+ + 1, 19),
234 (22), 206 (54), 189 (100), 159 (33). Anal. Calcd. for
C
11H11N3O4‚2/5H2O: C, 51.52; H, 4.64; N, 16.39. Found: C,
51.78; H, 4.38; N, 16.09.
(2S,5R)-3,6-Diet h oxy-2-isop r op yl-5-(5,6-d ich lor o-3-in -
d olyl)m eth yl-2,5-d ih yd r op yr a zin e 35. The silyl compound
26g (0.732 g, 1.4 mmol) was dissolved in 1 M tetrabutylam-
monium fluoride (TBAF) in THF (4 mL). The solution was
stirred at room temperature for 30 min until analysis by TLC
(silica gel) indicated the absence of starting material. Water
(20 mL) was added, and the mixture was extracted with ether
(3 × 40 mL). The combined ether layer was dried (MgSO4),
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (silica gel,
EtOAc/hexanes 4:96) to afford 35 (0.469 g) in 82% yield: IR
D
D
(c ) 1, in 0.1 M HCl]; mp 275-276 °C dec; IR (KBr) 3455,
1
1660, 1591, 1487 cm-1; H NMR (300 MHz, D2O) δ 3.14 (dd,
1H, J ) 7.7, 15.3 Hz), 3.28 (dd, 1H, J ) 4.9, 15.3 Hz), 3.89
(dd, 1H, J ) 4.9, 7.7 Hz), 6.92 (dt, 1H, J ) 2.4, 9.2 Hz), 7.21
(s, 1H), 7.27 (dd, 1H, J ) 2.5, 10.1 Hz), 7.33 (dd, 1H, J ) 4.6,
8.9 Hz); 13C NMR (75.5 MHz, D2O) δ 26.8, 55.3, 103.3, 103.5,
108, 110.4, 110.8, 112.9, 113.1, 127, 127.2, 127.3, 131.2, 156.3,
159.4, 175.0; MS (EI) m/e (rel intensity) 222 (M+, 3), 148 (100),
101 (19). Anal. Calcd for C11H11FN2O2‚1/8H2O: C, 58.86; H,
5.05; N, 12.48. Found: C, 59.11; H, 4.96; N, 12.21.
(NaCl) 3443, 3176, 2969, 1691 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.55 (d, 3H, J ) 6.8 Hz), 0.83 (d, 3H, J ) 6.9 Hz),
1.18 (t, 3H, J ) 7.1 Hz), 1.28 (t, 3H, J ) 7.1 Hz), 2.08 (m, 1H),
3.11-3.24 (m, 3H), 3.91 (m, 1H), 4.03-4.09 (m, 3H), 4.22 (m,
1H), 6.85 (d, 1H, J ) 2.3 Hz), 7.30 (s, 1H), 7.66 (s, 1H), 7.98
(s, br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 14.2, 14.3, 16.4, 18.9,
20.9, 29.3, 31.4, 56.5, 60.3, 60.4, 111.8, 112.1, 120.8, 123.0,
124.6, 125.2, 128.2, 134.4, 162.1, 163.5; MS (EI) m/e (rel
intensity) 413 (M+, 1.2), 411 (M+, 7.5), 409 (M+, 12), 212 (55),
198 (28), 169 (100); exact mass calcd for C20H25 Cl2N3O2
409.1324, found 409.1282.
5,6-Dim eth yl-L-tr yp top h a n 29b. Into a 25 mL round-
bottom flask were added 5,6-dimethyl-L-tryptophan ethyl ester
28b (79 mg, 0.30 mmol), 1 N aqueous NaOH (1.0 mL, 1 mmol),
and EtOH (1.5 mL). The solution that resulted was heated to
50 °C for 2 h. Analysis by TLC (silica gel) indicated that all
the starting material had disappeared and the new material
was on the baseline (Rf ) 0). Most of the EtOH was removed
under reduced pressure. A piece of ice was dropped into the
flask, and the mixture was brought to pH ) 6-7 with an
aqueous solution of 2 N HCl at 0 °C. The water in the
suspension that resulted was removed under reduced pressure
until the volume of the mixture was reduced to about 0.5 mL.
Cold water (1 mL) was added, and the precipitate that formed
was collected by vacuum filtration, washed with cold water (3
× 1 mL), and dried to provide 5,6-dimethyl-L-tryptophan 29b
(60 mg) in 85% yield. 29b: mp 277-279 °C dec; [R]27D ) -6.57°
5,6-Dich lor o-D-tr yp top h a n eth yl ester 36 was prepared
in 90% yield from 35 following the procedure for preparation
of 30. 36: [R]27D ) -29.09° (c ) 1.1, C2H5OH); IR (NaCl) 3352,
1
3154, 1725, 1446 cm-1; H NMR (300 MHz, CDCl3) δ 1.20 (t,
3H, J ) 7.1 Hz), 1.55 (s, br, 2H), 2.95 (dd, 1H, J ) 7.2, 14.5
Hz), 3.10 (dd, 1H, J ) 5.0, 14.5 Hz), 3.71 (dd, 1H, J ) 5.0, 7.2
Hz), 4.09 (m, 1H), 6.95 (d, 1H, J ) 2.0 Hz), 7.29 (s, 1H), 7.61
(s, 1H), 8.53 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3) δ 14.1,
30.2, 54.6, 61.1, 110.8, 112.6, 119.7, 123.5, 124.9, 125.8, 127.2,
134.9, 175.1. This material was used in the next step without
further characterization.

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4539
procedure employed for the preparation of 29b. 38: [R]27
5,6-Dich lor o-D-tr yp top h a n 37 was prepared in 86% yield
from 5,6-dichloro-D-tryptophan ethyl ester 36 following the
procedure employed for preparation of 29b. 37: mp 274-276
°C dec; IR (KBr) 3424, 1662 cm-1; 1H NMR (300 MHz, D2O) δ
3.28 (dd, 1H, J ) 8.1, 14.8 Hz), 3.43 (dd, 1H, J ) 5.5, 14.8
Hz), 4.03 (dd, 1H, J ) 5.3, 7.6 Hz), 7.35 (s, 1H), 7.69 (s, 1H),
7.88 (s, 1H); MS (EI) m/e (rel intensity) 202 (13), 200 (79), 198
(100), 164 (17), 128(33); MS (CI, CH4) m/e (rel intensity) 275
(M+ + 1, 51), 273 (M+ + 1, 100), 258 (76), 239 (29), 222 (40),
200 (27). Anal. Calcd for C11H10Cl2N2O2: C, 48.37; H, 3.69; N
10.26. Found: C, 48.47; H, 3.85; N, 9.99.
)
D
-17.9° (c ) 1.26, in 0.2 N NaOH); mp 222-224 °C dec (lit.74
mp 220-222 °C dec); IR (KBr) 3394, 1597, 1499 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 3.03 (dd, 1H, J ) 8.0, 15.3 Hz), 3.33
(dd, 1H, J ) 5.0, 15.3 Hz), 3.59 (dd, 1H, J ) 8.0, 5.0 Hz), 6.25
(s, 1H), 6.98 (m, 2H), 7.31 (d, 1H, J ) 8.0 Hz), 7.42 (d, 1H, J
) 7.7 Hz), 11.4 (s, br, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ
30.3, 54.0, 100.5, 111.3, 118.9, 119.6, 120.6, 128.6, 136.2, 136.6,
170.1; MS (EI) m/e (rel intensity) 204 (M+, 9), 131 (21), 130
(100); exact mass calcd for
C11H12N2O2 204.0899, found
204.0894. Anal. Calcd for C11H12N2O2‚1/2H2O: C, 61.96; H, 6.15;
N, 13.14. Found: C, 62.21; H, 5.98; N, 12.95.
(2R,5S)-3,6-Dieth oxy-2-isop r opyl-5-[3-(2-a m in op h en yl)-
p r op -2-yn yl]-2,5-d ih yd r op yr a zin e 42. The (2R,5S)-3,6-di-
ethoxy-2-isopropyl-5-(prop-2-ynyl)-2,5-dihydropyrazine 41(377
mg, 1.5 mmol) and 2-iodoaniline (300 mg, 1.4 mmol) were dis-
solved in dry triethylamine (20 mL) in a 100 mL round-bottom
flask. The solution was degassed with argon for 10 min after
which (PPh3)2PdCl2 (19.2 mg, 0.027 mmol) and CuI (5.2 mg,
0.027 mmol) were added under Ar. The reaction mixture was
degassed with argon for another 10 min. The yellow solution
that resulted was stirred at room temperature for 18 h and a
precipitate gradually appeared. Analysis by TLC (silica gel)
indicated the absence of starting material. The reaction
mixture was concentrated under vacuum to dryness, and the
residue was taken up in ether. The solid was removed by
vacuum filtration, and the ether was removed under reduced
pressure. The residue was purified by flash chromatography
(silica gel, EtOAc/hexanes 5:95) to afford 42 (443 mg) in 95%
(2R,5S)-3,6-Dieth oxy-2-isopr opyl-5-[1H-2-(tr ieth ylsilyl)-
ben zo[f]in d ol-3-yl]m eth yl-2,5-d ih yd r op yr a zin e 47. In a
100 mL round-bottom flask equipped with a stirring bar were
placed 2-amino-3-iodonaphthalene 46 77(194 mg, 0.72 mmol),
(2R,5S)-3,6-diethoxy-2-isopropyl-5-[3-(triethylsilyl)-prop-2-ynyl]-
2,5-dihydropyrazine 25 (289 mg, 0.79 mmol), palladium(II)
acetate (7 mg, 0.031 mmol), lithium chloride (30 mg, 0.72
mmol), sodium carbonate (152 mg, 1.4 mmol), and dry DMF
(10 mL). The reaction mixture was degassed at room temper-
ature and then heated to 100 °C under argon until the starting
material was no longer detected on analysis by TLC (30 h).
The DMF was then removed under reduced pressure and the
residue was taken up in CH2Cl2 (50 mL). The suspension which
resulted was allowed to pass through a pad of Celite to remove
insoluble solids. The filtrate was concentrated under reduced
pressure and the pyrazine was purified by flash chromatog-
raphy (silica gel, hexanes/EtOAc, 98:2) to afford 47 as an oil
(236 mg) in 65% yield. 47: IR (NaCl) 2956, 1686 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.68 (d, 3H, J ) 6.8 Hz), 1.02 (m, 18H),
1.16 (t, 3H, J ) 7.1 Hz), 1.30 (t, 3H, J ) 7.1 Hz), 2.28 (m,1H),
2.99 (dd, 1H, J ) 9.6, 14.1 Hz), 3.60 (dd, 1H, J ) 4.7, 14.2
Hz), 3.93 (m, 2H), 4.2 (m, 4H), 7.29 (m, 2H), 7.73 (s, 1H), 7.85
(m, 3H), 8.26 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 3.7, 7.5,
14.39, 14.44, 16.7, 19.2, 31.7, 32.2, 58.8, 60.6, 60.9, 80.2, 105.2,
118.1, 122.1, 123.1, 123.6, 127.2, 128.1, 128.3, 130.5, 131.6,
136.7, 139.0, 163.0, 163.8; MS (EI) m/e (rel intensity) 505 (M+,
19), 362 (13), 337 (24), 310 (23), 294 (100), 212 (29), 169 (38);
exact mass calcd for C30H43N3O2Si 505.3124, found 505.3146.
This material was employed in a later step without further
characterization.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[1H-ben zo[f]in d ol-
3-yl]m eth yl-2,5-d ih yd r op yr a zin e 48. The (2R,5S)-3,6-di-
ethoxy-2-isopropyl-5-[1H-2-(triethylsilyl)benzo[f]indol-3-yl]m-
ethyl-2,5-dihydropyrazine 47(150 mg, 0.3 mmol) was dissolved
with 1 M tetrabutylammonium fluoride (TBAF) in THF (4 mL).
The solution was stirred at room temperature for 2 h until
analysis by TLC (silica gel) indicated the absence of starting
material. Water (20 mL) was added to the solution, and the
mixture was extracted with ether (3 × 40 mL). The combined
ether layer was dried (MgSO4), and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (silica gel, EtOAc/hexanes 3:97) to afford 48
(99 mg) in 85% yield. 48: IR (NaCl) 2956, 1686 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.63 (d, 3H, J ) 6.8 Hz), 0.90 (d, 3H, J )
6.9 Hz), 1.22 (t, 3H, J ) 7.1 Hz), 1.38 (t, 3H, J ) 7.1 Hz), 2.17
(m, 1H), 3.3 (m, 1H), 3.91 (m, 1H), 4.02 (m, 1H), 4.16 (m, 4H),
4.41 (m, 1H), 7.14 (s, 1H), 7.36 (m, 2H), 7.74 (s, 1H), 7.90 (m,
3H), 8.14 (s, 1H); MS (CI, CH4) m/e (rel intensity) 392(M+ +1,
100); exact mass calcd for C24H29N3O2 391.2260, found 391.2236.
This material was employed in the next step.
yield. 42: IR (NaCl) 2964, 1688, 1488 cm-1 1H NMR (250
;
MHz, CDCl3) δ 0.71 (d, 3H, J ) 6.8 Hz), 1.04 (d, 3H, J ) 6.8
Hz), 1.28 (m, 6H), 2.28 (m, 1H), 2.96 (m, 2H), 4.01 (m, 1H),
4.16 (m, 7H), 6.62 (m, 2H), 7.06 (m, 1H), 7.17 (dd, 1H, J ) 1,
8.8 Hz); MS (CI, CH4) m/e (rel intensity) 342 (M+ + 1, 100),
211 (3). This material was used in the next step without
further characterization.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-(2-in d olyl)m eth yl-
2,5-d ih yd r op yr a zin e 43. Into a 25 mL round-bottom flask
equipped with a stirring bar were added (2R,5S)-3,6-diethoxy-
2-isopropyl-5-[3-(2-aminophenyl)-prop-2-ynyl]-2,5-dihydropy-
razine 42 (100 mg, 0.29 mmol), CuI (56 mg, 0.29 mmol),
ethylene glycol (1.5 g), and anhydrous DMF (8 mL). The
mixture was degassed and subsequently heated to 95 °C for
20 h until analysis by TLC (silica gel) indicated the absence
of starting material. The DMF was removed under reduced
pressure, and the residue was dissolved in CH2Cl2 (100 mL).
The organic solution was washed with water (5 × 30 mL),
brine, and dried (Na2SO4). The CH2Cl2 was removed under
reduced pressure. The residue was purified by flash chroma-
tography (silica gel, EtOAc/hexanes 2:98) to afford 43 (80 mg)
as a white solid in 80% yield. 43: [R]27 ) - 21.6° (c ) 0.98,
D
EtOAc); IR (NaCl) 3385, 1686 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.76 (d, 3H, J ) 6.8 Hz), 1.03 (d, 3H, J ) 6.8 Hz), 1.34 (m,
6H), 2.24 (m, 1H), 3.10 (m,1H), 3.50 (m, 1H), 3.89 (t, 1H, J )
3.6 Hz), 4.26 (m, 5H), 6.28 (s, 1H), 7.12 (m, 2H), 7.29 (m, 1H),
7.55 (d, 1H, J ) 7.6 Hz), 9.27 (s, br, 1H); MS (CI, CH4) m/e
(rel intensity) 342 (M+ +1, 100), 211 (3); exact mass calcd for
C
20H27N3O2 341.2103, found 341.2097. This material was
employed in the next step without further characterization.
(2S)-2-Am in o-3-(1H-in d ol-2-yl)-p r op ion ic a cid eth yl es-
ter 45 was prepared in 90% yield from (2R,5S)-3,6-diethoxy-
2-isopropyl-5-(2-indolyl)methyl-2,5-dihydropyrazine 43 follow-
ing the procedure employed for the preparation of 28b. 45:
1H NMR (300 MHz, CDCl3) δ 1.32 (t, 3H, J ) 7.1 Hz), 1.88 (s,
br, 2H), 3.03 (dd, 1H, J ) 8.3, 14.9 Hz), 3.24 (dd, 1H, J ) 4.0,
14.9 Hz), 3.76 (dd, 1H, J ) 4.0 Hz and J ) 8.3 Hz), 4.27 (q,
2H, J ) 7.1 Hz), 6.33 (s, 1H), 7.15 (m, 2H), 7.35 (d, 1H, J )
8.1 Hz), 7.59 (d, 1H, J ) 7.7 Hz), 9.48 (s, 1H); 13C NMR (75.5
MHz, CDCl3) δ 14.1, 32.6, 54.5, 61.3, 100.9, 110.7, 119.5, 119.8,
121.2, 128.2, 135.7, 136.0, 174.8; MS (EI) m/e (rel intensity)
232 (M+, 18), 130 (100); exact mass calcd for C13H16N2O2
232.1212, found 232.1212. This material was employed directly
in the next step.
(2S)-2-Am in o-3-(1H-ben zo[f]in d ol-3-yl)-p r op ion ic a cid
eth yl ester 49 was prepared in 85% yield from (2R,5S)-3,6-
diethoxy-2-isopropyl-5-[1H-benzo[f]indol-3-yl]methyl-2,5-dihy-
dropyrazine 48 under conditions analogous to those employed
for preparation of 28b. 49: 1H NMR (300 MHz, CDCl3) δ 1.25
(dt, 3H, J ) 2.3, 7.2 Hz), 1.65 (s, br, 2H), 3.17 (dd, 1H, J )
7.5, 14.4 Hz), 3.39 (dd, 1H, J ) 4.9, 14.4 Hz), 3.91 (m, 1H),
4.16 (m, 2H), 7.27 (s, 1H), 7.35 (m, 2H), 7.77 (s, 1H), 7.87 (d,
1H, J ) 7.4 Hz), 7.9 (dd, 1H, J ) 2.0, 7.5 Hz), 8.01 (s, br, 1H),
8.1 (s, 1H). This material was used directly in the next step
without further characterization.
(2S)-2-Am in o-3-(1H-in d ol-2-yl)-p r op ion ic a cid (L-isot-
r yp top h a n ) 38 was prepared in 85% yield from (2S)-2-amino-
3-(1H-indol-2-yl)-propionic acid ethyl ester 45 following the
(2S)-2-Am in o-3-(1H-ben zo[f]in d ol-3-yl)p r op ion ic a cid
(L-ben zo[f]tr yp top h a n ) 39 was prepared in 83% yield from

4540 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
(2S)-2-amino-3-(1H-benzo[f]indol-3-yl)-propionic acid ethyl es-
ter 49 under conditions analogous to those employed for
preparation of 29b. 39: [R]27D ) 90.57° (c ) 0.53, 1 N aqueous
HCl); mp 283-285 °C dec; IR (KBr) 3400, 1706, 1661, 1594
that resulted was allowed warm to room temperature and
stirred for 5 h. The reaction was quenched with H2O, and the
mixture that resulted was partitioned between water and
ether. The organic layer was dried (MgSO4), and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography (silica gel, ether/hexanes 1:6) to
afford 52 (1.7 g) in 92% yield. 52: 1H NMR (300 MHz, CDCl3)
δ 0.55 (s, 6H), 0.76 (d, 3H, J ) 6.8 Hz), 0.89 (s, 9H), 1.03 (d,
3H, J ) 6.9 Hz), 1.27 (m, 6H), 2.15 (m, 2H), 2.24 (m, 1H), 2.66
(m, 2H), 3.95 (t, 1H, J ) 3.4 Hz), 4.16 (m, 5H), 6.9 (s, 1H), 7.1
(m, 2H), 7.44 (dd, 1H, J ) 1.5, 7.1 Hz), 7.57 (m, 1H); 13C NMR
(75.5 MHz, CDCl3) δ -4.0, 14.36, 14.38, 16.6, 19.1, 19.5, 20.3,
26.3, 31.9, 34.4, 55.2, 60.5, 60.8, 106.8, 113.8, 118.1, 118.9,
119.1, 121.2, 127.7, 131.1, 141.5, 163.1, 163.4. This material
was used in the next step without further characterization.
(2S)-2-Am in o-4-(1-ter t-bu tyld im eth ylsilylin d ol-3-yl)bu -
tyr ic Acid Eth yl Ester 53. To a solution of optically pure
(2R,5S)-3,6-diethoxy-2-isopropyl-5-[2-(1-tert-butyldimethylsi-
lyl-indol-3-yl)ethyl]-2,5-dihydropyrazine 52 (1.20 g, 2.64 mmol)
in THF (6 mL) at 0 °C was slowly added an aqueous solution
of 2 N HCl (3 mL). The mixture that resulted was allowed to
warm to room temperature and then stirred for 1 h. Ice (10 g)
was added to the solution, and the pH of the reaction mixture
was adjusted to 8 with aqueous NH4OH (concentrated) at 0
°C. The mixture was then extracted with ether (3 × 100 mL).
The combined organic layers were dried (MgSO4), and the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (silica gel, hexanes/ether 5:1)
to afford 53 (940 mg) in 99% yield. 53: 1H NMR (300 MHz,
CDCl3) δ 0.69 (s, 6H), 1.00 (s, 9H), 1.38 (dt, 3H, J ) 3.1, 7.1
Hz), 1.74 (s, br, 2H), 2.09 (m, 1H), 2.25 (m, 1H), 2.98 (t, 2H, J
) 8 Hz), 3.62 (m, 1H), 4.27 (q, 2H, J ) 7.1 Hz), 7.09 (s, 1H),
1
cm-1; H NMR (300 MHz, DMSO-d6) δ 3.12 (dd, 1H, J ) 8.9,
15.2 Hz), 3.44 (dd, 1H, J ) 3.7, 15.2 Hz), 3.60 (dd, 1H, J )
3.8, 8.7 Hz), 7.28 (m, 2H), 7.48 (s, 1H), 7.83 (s, 1H), 7.91 (m,
2H), 8.11 (s, 1H), 10.97 (s, br, 1H); 13C NMR (75.5 MHz,
DMSO-d6) δ 27.6, 54.8, 106.5, 108.9, 115.7, 122.3, 123.4, 127.5,
127.9, 128.3, 129, 129.9, 137.6, 170.2; MS (EI) m/e (rel
intensity) 254 (M+, 23), 180 (100), 60 (14); exact mass calcd
for C15H14N2O2 254.1055, found 254.1051. Anal. Calcd for
C
15H14N2O2‚H2O: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.38;
H, 5.78; N, 9.99.
3-Br om o-1-(ter t-bu tyldim eth ylsilyl)in dole 50.80 An oven-
dried, 500 mL three-neck, round-bottom flask equipped with
a magnetic stirring bar, 100 mL pressure-equalizing addition
funnel, and an argon inlet and outlet tube was charged with
indole (8.0 g, 0.068 mol) and THF (200 mL). The solution was
stirred and cooled to -78 °C with a dry ice/EtOAc bath. A
solution of butyllithium in hexanes (47 mL of a 1.6 M solution,
0.075 mol) was added dropwise via a cannula. The mixture
was warmed to -10 °C, stirred for 15 min, and then cooled to
-50 °C. A solution of tert-butyldimethylsilyl chloride (11.6 g,
0.077 mol) in THF (60 mL) was added dropwise to this
mixture. The temperature was allowed to warm to 0 °C, and
after 3 h the reaction mixture was cooled again to -78 °C.
Freshly crystallized NBS (12.18 g, 0.068 mol) was added via
a solid addition funnel, and the mixture that resulted was
stirred in the dark at -78 °C for 2 h and then allowed to warm
to room temperature. Hexanes (100 mL) and pyridine (1 mL)
were added, and the suspension that resulted was filtered
through a pad of Celite. The filtrate was evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (silica gel, hexanes) to provide 50 (17.8 g) as
a colorless solid in 84% yield. 50: 1H NMR (300 MHz, CDCl3)
δ 0.60 (s, 6H), 0.93 (s, 9H), 7.17 (s, 1H), 7.20 (m, 2H), 7.48 (m,
1H), 7.54 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ -3.6, 19.8,
26.6, 94.1, 114.5, 119.6, 121, 122.9, 130.1, 130.3, 140.7. The
spectral data for 50 were identical to that reported in the
literature.80
7.24 (m, 2H), 7.59 (dd, 1H, J ) 1.5, 7.1 Hz), 7.69 (m, 1H); 13
C
NMR (75.5 MHz, CDCl3) δ 13.0, 16.0, 18.3, 20.2, 25.1, 34.0,
53.0, 59.5, 112.7, 116.1, 117.5, 118.1, 120.2, 126.8, 129.6, 140.3,
174.9. This material was used directly in the next step without
further characterization.
(2S)-2-Am in o-4-(1H-in d ol-3-yl)bu tyr ic Acid (L-Hom ot-
r yp top h a n ) 40. An oven-dried, 25 mL, round-bottom flask
equipped with a magnetic stir bar, rubber septum, and a
nitrogen inlet and outlet tube was charged with (2S)-2-amino-
4-(1-tert-butyldimethylsilylindol-3-yl)butyric acid ethyl ester
53 (0.8 g, 2.2 mmol) and THF (10 mL). The mixture was
stirred, and then a 1 M solution of tetrabutylammonium
fluoride (TBAF) in THF (2.2 mL, 2.2 mmol) was added. After
the solution was stirred for 10 min at room temperature, it
was poured into a saturated aqueous solution of sodium
carbonate (30 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with water (10 mL)
and dried (Na2SO4), and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography (silica gel, hexanes/ether 2:1) to afford an oil (518
mg): 1H NMR (300 MHz, CDCl3) δ 1.17 (t, 3H, J ) 7.3 Hz),
1.88 (m, 1H), 2.08 (m, 1H), 2.79 (t, 2H, J ) 7.8 Hz), 3.47 (m,
1H), 4.07 (m, 2H), 6.87 (s, 1H), 7.02 (m, 1H), 7.08 (m, 1H),
7,24 (d, 1H, J ) 7.9 Hz), 7.52 (d, 1H, J ) 7.7 Hz), 8.55 (s, br,
1H). To this oil was added ethanol (7.5 mL), water (5 mL),
and aqueous 2 N NaOH (0.4 mL). The mixture that resulted
was heated at 60 °C for 4 h until analysis by TLC (silica gel)
indicated complete absence of starting material. Ethanol was
removed under reduced pressure, and the mixture was then
brought to pH 7 (pH paper) to give a white solid 40 (397 mg)
2-(1-ter t-Bu tyld im eth ylsilylin d ol-3-yl)eth yl Tosyla te
51. To a solution of 3-bromo-1-(tert-butyldimethylsilyl)indole
50 (2.5 g, 8 mmol) in THF (40 mL) was added t-BuLi (1.7M,
10.0 mL, 2.2 equiv) slowly at -78 °C. The above solution was
stirred for 10 min. Ethylene oxide (0.90 mL, 18 mmol) was
collected in a graduated cylinder at -78 °C that had been
covered with a septum, after which time cold THF (2 mL) was
syringed into the cylinder. The solution that resulted was
added dropwise to the indolyl anion solution through a cannula
at -78 °C. The reaction mixture that resulted was allowed to
warm to room temperature over a period of 2 h and stirred
for another 2 h. Then p-toluenesulfonyl chloride (1.50 g, 8
mmol) was added to the above pale yellow solution, and this
mixture was stirred at room temperature for 10 h. The reaction
solution was then quenched with H2O and the mixture which
resulted was partitioned between H2O and EtOAc. The organic
layer was dried (MgSO4) and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography (silica gel, ether/hexanes 1:4) to afford 51 (1.70 g) in
84% yield. 51: 1H NMR (300 MHz, CDCl3) δ 0.71 (s, 6H), 1.03
(s, 9H), 2.50 (s, 3H), 3.24 (t, 2H, J ) 7.2 Hz), 4.4 (t, 2H, J )
7.2 Hz), 7.1 (s, 1H), 7.24 (m, 2H), 7.34 (d, 2H, J ) 8.2 Hz),
7.52 (d, 1H, J ) 7.3 Hz), 7.58 (d, 1H, J ) 8.2 Hz), 7.81 (d, 2H,
J ) 8.3 Hz). This material was used in a later step without
further characterization.
in 83% yield. 40: [R]27 ) 37.5° (c ) 0.24, in CH3COOH); mp
D
268-270 °C dec; IR (KBr) 3397, 1660 cm-1; 1H NMR (300 MHz,
DMSO-d6) δ 1.96 (m, 1H), 2.09 (m, 1H), 2.77 (t, 2H, J ) 8.0
Hz), 3.21 (m, 1H), 6.96 (m, 1H), 7.05 (m, 1H), 7.11 (s, 1H),
7.33 (d,1H, J ) 8 Hz), 7.54 (d, 1H, J ) 7.8 Hz), 10.8 (s, br,
1H); 13C NMR (75.5 MHz, DMSO-d6) δ 21.1, 31.9, 54.0, 111.3,
113.8, 118.0, 118.4, 120.8, 122.1, 127.1, 136.3, 169.8; MS (CI,
CH4) m/e (rel intensity) 219 (M+ + 1, 100), 175 (12), 130 (20);
exact mass calcd for C12H14N2O2 218.1054, found 218.1055.
Anal. Calcd for C12H14N2O2‚1/5H2O: C, 64.97; H, 6.54; N 12.63.
Found: C, 64.51; H, 6.42; N, 12.21.
(2R,5S)-3,6-Dieth oxy-2-isop r op yl-5-[2-(1-ter t-bu tyld im -
eth ylsilylin d ol-3-yl)eth yl]-2,5-d ih yd r op yr a zin e 52. To a
solution of (2R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine
19 (0.89 g, 4.2 mmol) in dry THF (30 mL) under nitrogen was
added n-BuLi (2.5 M, 1.7 mL, 4.3 mmol) dropwise at -78 °C
via a syringe. This solution was stirred at -78 °C for 30 min.
To this solution was added slowly a solution of tosylate 47 (1.52
g, 3.54 mmol) in THF (10 mL) at -78 °C. The reaction mixture
3-(Tr ieth ylsilyl)p r op -2-yn -1-ol 61. To a solution of 2-prop-
2-ynyloxytetrahydropyran 60 (103 g, 0.74 mol) in anhydrous

Synthesis of Biologically Important Tryptophan Analogues
J . Org. Chem., Vol. 66, No. 13, 2001 4541
THF (800 mL) at -78 °C was slowly added n-BuLi (2.5 M,
293 mL). The solution that resulted was stirred at -78 °C for
1 h, after which time chlorotriethylsilane (100 g, 0.67 mol) was
added quickly. The reaction solution that resulted was allowed
to warm to room temperature and stirred for 1 h. The reaction
mixture was quenched with H2O (10 mL), and the THF was
removed under reduced pressure. The residue was partitioned
between water (500 mL) and ethyl ether (250 mL). The organic
layer was separated, and the aqueous layer was extracted with
ether (2 × 150 mL). The combined ether layers were dried (Na2-
SO4). After the ether was removed under reduced pressure,
the residue was dissolved in CH3OH. To this solution was
added PPTS (pyridinium p-toluenesulfonic acid, 17 g, 0.068
mol), and the solution that resulted was stirred for 24 h at
room temperature. The CH3OH was removed under reduced
pressure, and the residue was dissolved in ether (200 mL).
The ethereal solution was then washed with a saturated
aqueous solution of sodium bicarbonate and dried (Na2SO4).
After the ether was removed under reduced pressure, the
residue was subjected to vacuum distillation at 80 °C (0.3
mmHg) to provide the title compound 61 (102 g, 90%). 61: 1H
NMR (300 MHz, CDCl3) δ 0.61 (q, 6H, J ) 7.9 Hz), 0.99 (t,
9H, J ) 7.7 Hz), 1.60 (t, 1H, J ) 6.1 Hz), 4.29 (d, 2H, J ) 6.1
Hz). The spectral data for 61 were identical to that reported
in the literature.93
(2S,5R)-3,6-Diet h oxy-2-isop r op yl-5-[3-(t r iet h ylsilyl)-
p r op -2-yn yl]-2,5-d ih yd r op yr a zin e 25. The triethylsilyl pro-
pargyl alcohol 61(100 g) was dissolved in anhydrous ethyl
ether (1 L), and then diphenyl chlorophosphate (1 equiv, 157.9
g) was added. The solution that resulted was cooled in a dry
ice bath to below -10 °C, and solid 85% KOH (1.5 equiv, 50 g)
was added. The mixture was then stirred vigorously with an
overhead stir overnight (the temperature was kept below 5
°C). The suspension that resulted was filtered to remove
inorganic solids, and the filtrate was concentrated under
reduced pressure. The residue was flash evaporated several
times with dry THF on a rotovapor under vacuum until
examination of the NMR spectrum indicated the absence of
the peak due to water: 1H NMR (300 MHz, CDCl3) for the
residue δ 0.48 (q, 6H, J ) 7.9 Hz), 0.86 (t, 9H, J ) 7.8 Hz),
4.76 (d, 2H, J ) 10.6 Hz), 7.15 (m, 10H). In a separate flask,
1 equiv (124.7 g) of the Scho¨llkopf chiral auxiliary 19 was
dissolved in dry THF (1 L), to which n-BuLi (1.1 equiv, 2.5 N,
235 mL) was added. The solution that resulted was stirred at
-78 °C for 1 h, after which time the previous residue (dissolved
in 500 mL of dry THF, which had been cooled to -78 °C) was
added dropwise to the anion of the Scho¨llkopf chiral auxiliary.
After addition was complete, the solution was allowed to stir
for 2 h at -78 °C and then allowed to warm to room temp-
erature The reaction mixture was quenched by slow addition
of H2O. The solvent was removed under vacuum, and the
residue was partitioned between water (200 mL) and ethyl
ether (500 mL). After separation of the ether layer, the water
layer was extracted with ethyl ether (3 × 500 mL). The
combined ether layers were dried (Na2SO4). After the ether
was removed under reduced pressure, the residue was purified
by flash chromatography (silica gel, EtOAc/hexanes 2:98) to
provide 25 (192 g) in 90% yield. 25: [R]27D ) -36.09° (c ) 0.92,
CHCl3); IR (NaCl) 2945, 2175, 1686 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.51 (q, 6H, J ) 7.4 Hz), 0.70 (d, 3H, J ) 6.8 Hz),
0.94 (t, 9H, J ) 7.7 Hz), 1.02 (d, 3H, J ) 6.9 Hz), 1.27 (t, 3H,
J ) 7.08 Hz), 1.28 (t, 3H, J ) 7.1 Hz), 2.30 (m,1H), 2.69 (dd,
1H, J ) 16.6, 4.3 Hz), 2.84 (dd, 1H, J ) 16.5, 4.4 Hz), 3.97 (t,
1H, J ) 3.3 Hz), 4.06-4.20 (m, 5H); 13C NMR (75.5 MHz,
CDCl3) δ 4.5, 7.3, 14.3, 16.7, 19.1, 26.5, 31.7, 54.6, 60.6, 60.7,
61, 83.5, 104.5, 161.2, 164.2; MS (EI) m/e (rel intensity) 364
(M+, 17), 307 (27), 211 (60), 169 (100), 141 (14); exact mass
calcd for C20H36N2O2Si 364.2546, found 364.2588. Anal. Calcd
for C20H36N2O2Si‚1/5H2O: C, 65.24; H, 9.96; N, 7.61. Found:
C, 65.01; H, 9.82; N, 7.57.
(5R,2S)-3,6-Diet h oxy-2-isop r op yl-5-[6-m et h oxy-2-(t r i-
eth ylsilyl)-3-in d olyl]m eth yl-2,5-d ih yd r op yr a zin e 26i. To
a three-neck flask (3 L) equipped with an overhead stir were
charged 2-iodo-5-methoxyaniline 59 (150 g) and the Scho¨llkopf
derivative 25 (265 g), as well as lithium chloride (2.55 g),
sodium carbonate (159 g), palladium(II) acetate (1.75 g), and
dry DMF (2L). The mixture was then degassed with a vacuum
pump at room temperature. The suspension that resulted was
heated for 36 h at 100 °C under an atmosphere of Ar.
Examination of the mixture by TLC (silica gel) indicated the
iodoaniline 59 had been consumed, and then the reaction
mixture was cooled to room temperature and the DMF was
removed under vacuum (aspirator). Methylene chloride (2L)
was added to the residue, and the suspension that resulted
was filtered to remove unwanted salts. After removal of the
CH2Cl2, the crude product was purified by flash chromatog-
raphy (silica gel, 2% EtOAc/hexanes) to give 77% of the desired
6-methoxy substituted indole 26i. 26i: [R]27 ) - 21.39° (c )
D
1.58, in CHCl3); IR (NaCl) 3388, 2944, 1683 cm-1
;
1H NMR
(300 MHz, CDCl3) δ 0.67 (d, 3H, J ) 6.8 Hz), 0.85-1.05 (m,
18H), 1.20 (t, 3H, J ) 7.1 Hz), 1.30 (t, 3H, J ) 7.1 Hz), 2.25
(m,1H), 2.80 (dd, 1H, J ) 13.5, 10.6 Hz), 3.46 (dd, 1H, J )
14.1, 3.1 Hz), 3.84 (s, 3H), 3.88 (t, 1H, J ) 3.9), 4.01-4.21 (m,
5H), 6.70 (dd, 1H, J ) 8.7, 2.2 Hz), 6.82 (d, 1H, J ) 2.1 Hz),
7.60 (d, 1H, J ) 8.7 Hz), 7.77 (s, br, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 4.1, 7.9, 14.7, 14.8, 17.1, 19.5, 32.1, 32.5, 56.0, 59.3,
60.9, 61.0, 61.1, 93.9, 109.3, 121.8, 124.4, 124.7, 130.5, 139.5,
157.0, 163.1, 164.2; MS (CI, CH4) m/e (rel intensity) 486 (M+
+ 1, 100), 456 (13), 372 (51), 274 (27); exact mass calcd for
C
27H43N3O3Si 485.3074, found 485.3055. This material was
employed directly in the next step.
6-Meth oxy-D-tr yp top h a n Eth yl Ester 62. To a solution
of optically pure (2S,5R)-3,6-diethoxy-2-isopropyl-5-[6-meth-
oxy-2-(triethylsilyl)-3-indolyl]methyl-2,5-dihydropyrazine 26i
(15 g, 31 mmol) in THF (200 mL) at -78 °C was slowly added
the solution of aqueous HCl in ethanol (50 mL, concentrated
aqueous HCl/ethanol, 1:5). The mixture was allowed to warm
to 0 °C and stirred for 30 min. An aqueous solution of 2 N
HCl (150 mL) was added to this solution, and the mixture was
stirred at room temperature for another 2 h. Ice (100 g) was
added to the solution, and the pH of the reaction mixture was
adjusted to 8 (pH paper) with aqueous NH4OH (concentrated)
at 0 °C. The mixture was then extracted with EtOAc (3 × 250
mL). The combined organic layers were dried (Na2SO4), and
the solvent was removed under reduced pressure. The residue
which resulted was purified by flash chromatography (silica
gel, gradient elution: EtOAc/hexanes 3:7, to remove L-valine
ethyl ester, then EtOAc) to afford 62 (6.98 g) in 86% yield. 62:
[R]27 ) - 5.07° (c ) 0.71, in CHCl3); IR (NaCl) 3365, 1730,
D
1625 cm-1; H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H, J ) 7.1
1
Hz), 1.60 (s, br, 2H), 3.0 (dd, 1H, J ) 7.7, 14.3 Hz), 3.22 (dd,
1H, J ) 14.4, 4.8 Hz), 3.78 (m, 1H), 3.81 (s, 3H), 4.15 (q, 2H,
J ) 7.2 Hz), 6.80 (m, 2H), 6.90 (d, 1H, J ) 2.0 Hz), 7.45 (d,
1H, J ) 8.5 Hz), 8.15 (s, br, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 14.0, 30.7, 54.5, 54.9, 60.8, 94.7, 109.2, 111.0, 119.1, 121.8,
121.9, 136.5, 156.1, 175.2; MS (CI) m/e 263 (M+ + 1, 100). Anal.
Calcd for C14H18N2O3: C, 64.12; H, 6.87; N, 10.69. Found: C,
63.96; H, 6.98; N, 10.54.
(5R,2S)-3,6-Dieth oxy-2-isop r op yl-5-[6-m eth oxy-1-m eth -
yl-2-(t r ie t h ylsilyl)-3-in d olyl]m e t h yl-2,5-d ih yd r op yr a -
zin e 63. To a mixture of 26i (100 g, 0.21 mol), methyl iodide
(44 g, 0.31 mol), and anhydrous DMF (1000 mL) at 0 °C was
added sodium hydride (60% in mineral oil, 12.4 g) in several
portions. After this mixture was stirred for 2 h, analysis by
TLC (silica gel) indicated the absence of starting material. The
reaction solution was quenched with water (8 mL), and the
mixture that resulted was subsequently poured into hexanes
(5000 mL) to precipitate out sodium hydroxide that was
removed by filtration. The solvent was then removed under
reduced pressure, and the residue was crystallized from
hexanes at 0 °C to afford 63 as white needlelike crystals in
several crops. The product in the mother liquor was purified
by flash chromatography (silica gel, EtOAc/hexanes, 3:97). The
combined material 63 (94 g) was obtained in 90% yield. 63:
[R]27D ) -17.53° (c ) 0.81, in CHCl3); mp 91-92 °C; IR (NaCl)
(92) Meerwein, H. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, p 1080.
(93) Ostwald, R.; Chavant, P.; Stadtmueller, H.; Knochel, P. J . Org.
Chem. 1994, 59, 4143.

4542 J . Org. Chem., Vol. 66, No. 13, 2001
Ma et al.
1
2945, 1688, 1613 cm-1; H NMR (300 MHz, CDCl3) δ 0.63 (d,
matography (silica gel, EtOAc) to afford 64 as a light yellow
oil. 64: [R]27 ) - 7.21° (c ) 2.01, CHCl3) [lit.52 [R]27 ) -
3H, J ) 6.8 Hz), 0.95 (m, 15H), 0.98 (d, 3H, J ) 6.9 Hz), 1.14
(t, 3H, J ) 7.1 Hz), 1.23 (t, 3H, J ) 7.1 Hz), 2.23 (m, 1H), 2.80
(dd, 1H, J ) 14, 4.5 Hz), 3.45 (dd, 1H, J ) 14, 3.5 Hz), 3.73 (s,
3H), 3.84 (s, 3H), 3.85 (m, 1H), 3.90-4.15 (m, 5H), 6.65 (m,
2H), 7.50 (d, 1H, J ) 9.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ
4.8, 7.6, 14.3, 14.4, 16.7, 19.1, 31.6, 31.9, 33.1, 55.7, 59.2, 60.4,
60.5, 60.7, 91.9, 108.2, 121.2, 124.2, 124.6, 132.3, 140.6, 156.7,
162.7, 163.9; MS (CI, CH4) m/e (rel intensity) 500 (M+ + 1,
100), 470 (16), 386 (14), 288 (21). Anal. Calcd for C28H45N3O3-
Si: C, 67.29; H, 9.08; N, 8.41. Found: C, 67.49; H, 9.16; N, 8.34.
X-r a y exp er im en ta l d a ta for 63: C28H45N3O3Si, (0.43 ×
0.26 × 0.18 mm), monoclinic, space group P21, a ) 7.710(1) Å,
b ) 19.596(1) Å, c ) 19.730(1) Å, â ) 90.31(1)°, V )2980.8(3)
Å3, Z ) 4, Fcalc ) 1.11 mg mm-3, µ ) 0.93 mm-1, F(000) ) 1088,
4269 unique data, R1 ) 0.038 for 4014 observed data. Further
data are available in the Supporting Information.
Data were collected on a Bruker P4 automated serial
diffractometer with a graphite monochromator in the incident
beam. Face corrected. The structure, with two molecules per
asymmetric unit, was solved by routine application of direct
methods and refined by full-matrix least-squares on F2 values
using programs in the SHELXTLPLUS package.94 The abso-
lute configuration was clearly indicated by the experimental
data (Flack parameter ) 0.005 (30)). Other parameters refined
included the coordinates and anisotropic thermal parameters
for all non-hydrogen atoms. Hydrogen atoms were included
using a riding model. Additional experimental details, ORTEP
illustration (Figure S1), and structural analysis are available
as Supporting Information, and coordinates are also available
from the Cambridge Crystallographic Database.95
6-Meth oxy-Na -m eth yl-D-tr yp top h a n Eth yl Ester 64. To
a solution of optically pure (5R,2S)-3,6-diethoxy-2-isopropyl-
5-[6-methoxy-1-methyl-2-(triethylsilyl)-3-indolyl]methyl-2,5-di-
hydropyrazine 63 (50 g, 0.1 mol) in THF (1000 mL) at 0 °C
was slowly added a cold aqueous solution of 2 N HCl (875 mL).
The mixture was allowed to warm to room temperature and
stirred for 2 h. Ice (800 g) was added to the solution, and the
pH of the reaction mixture was adjusted to 8 (pH paper) with
aqueous NH4OH (concentrated) at 0 °C. The mixture was then
extracted with CH2Cl2 (4 × 1000 mL). The combined organic
layers were dried (Na2SO4), and the solvent was removed
under reduced pressure. After all of the solvent appeared to
be removed, the residue was subjected to Kugelrohr distillation
at 80 °C (0.3 mmHg) to remove L-valine ethyl ester while pure
1-methyl-6-methoxy-D-tryptophan ethyl ester 64 (25.7 g, 93%)
remained. An analytical sample was obtained by flash chro-
D
D
7.09° (c ) 2.06, in CHCl3)]; IR (NaCl) 3374, 3311, 2980, 2938,
1736, 1623, 1560, 1490 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.30 (t, 3H, J ) 7.1 Hz), 1.62 (s, br, 2H), 2.99 (dd, 1H, J ) 7.7,
14.4 Hz), 3.24 (dd, 1H, J ) 14.3, 4.7 Hz), 3.65 (s, 3H), 3.79 (dt,
1H, J ) 7.4, 2.6 Hz), 3.89 (s, 3H), 4.18 (q, 2H, J ) 7.1 Hz),
6.75-6.83 (m, 3H), 7.48 (d, 1H, J ) 8.6 Hz); 13C NMR (62.9
MHz, CDCl3) δ 14.1, 30.6, 32.5, 55.2, 55.8, 60.6, 93.1, 108.9,
109.8, 119.6, 122.6, 126.5, 137.8, 156.6, 175.0; MS (EI) m/e (rel
intensity) 276 (M+, 4), 174 (100), 159 (11). Anal. Calcd for
C15H20N2O3: C, 65.18; H, 7.30; N 10.14. Found: C, 64.96; H,
7.36; N, 10.24. The spectral data for 67 were identical to that
reported by Hamaker.52
(5S,2R)-3,6-Dieth oxy-2-isop r op yl-5-[1-ter t-bu tyloxyca r -
bon yl-2-br om o-6-m eth oxy-3-in d olyl]m eth yl-2,5-d ih yd r o-
p yr a zin e 65. To a solution of (5S,2R)-3,6-diethoxy-2-isopropyl-
5 -[6-m e t h oxy-2 -(t r ie t h yls ilyl)-3-in d olyl]m e t h yl-2 ,5 -
dihydropyrazine 26i (500 mg, 1.03 mmol) in acetonitrile (40
mL) at 0 °C was syringed a solution of NBS (183 mg, 1.03
mmol) that had been dissolved in acetonitrile (10 mL). The
reaction mixture was stirred at 0 °C for 30 min, at which time
analysis by TLC (silica gel) indicated the absence of starting
material. To this solution were then added 4-(dimethylamino)-
pyridine (DMAP, 7 mg, 0.057 mmol) and di-tert-butyl dicar-
bonate (450 mg, 2.06 mmol) at room temperature. After the
reaction solution was stirred for another 1 h, analysis by TLC
(silica gel) indicated the disappearance of the intermediate.
The solvent was removed under reduced pressure and the
residue was partitioned between CH2Cl2 (100 mL) and H2O
(100 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 80 mL). The combined
organic layers were dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography (silica gel, EtOAc/hexanes 4:96) to afford
65 (492 mg) as an oil in 87% yield. The spectral data for 65
were identical to that reported by Gan et al. in the literature.44
This material was converted into tryprostatin A employing the
procedure of Gan43 and Zhao.45
Ack n ow led gm en t. We wish to acknowledge the
Office of Naval Research, NIDA, and NIMH for support
of this work. Our thanks go to Shuo Zhao and Xuebin
Liao for help on technical matters.
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedure for the synthesis of compounds 13b-g, 17-19 (large
scale), 41, 46 and 58, 59 (large scale). The ORTEP illustration
and data for X-ray structure 63. This material is available free
of charge via the Internet at http://pubs.acs.org.
(94) Sheldrick, G. 1995. SHELXTL-PLUS Version 5.03, Bruker
Analytical X-ray Systems, Madison, WI.
(95) Cambridge Crystallographic Database, 12 Union Road, Cam-
bridge CB2 1EZ, U.K.
J O001679S