Enantiospecific synthesis of optically active 6-methoxytryptophan derivatives and total synthesis of tryprostatin A1

Article abstract of DOI:10.1021/jo971640w

A concise preparation of optically active L or D-6-methoxytryptophan ethyl ester 21 was developed via the Fischer indole/Schollkopf from 6- methoxy-3-methylindole 16 (four steps, 58% overall yield). This method was extended to the enantiospecific total sy

Full text of DOI:10.1021/jo971640w

9
298
J . Org. Chem. 1997, 62, 9298-9304
En a n tiosp ecific Syn th esis of Op tica lly Active
-Meth oxytr yp top h a n Der iva tives a n d Tota l Syn th esis of
Tr yp r osta tin A1
6
Tong Gan, Ruiyan Liu, Peng Yu, Shuo Zhao, and J ames M. Cook*
Department of Chemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53201
Received September 3, 1997X
A concise preparation of optically active L or D-6-methoxytryptophan ethyl ester 21 was developed
via the Fischer indole/Sch o¨ llkopf protocol from 6-methoxy-3-methylindole 16 (four steps, 58% overall
yield). This method was extended to the enantiospecific total synthesis of tryprostatin A (11) via
a regiospecific bromination process as a key step. In addition, 6-methoxy-2-bromotryptophan ethyl
ester (32), a potential intermediate for indole alkaloid synthesis, was prepared via this strategy.
In tr od u ction
Indole alkaloids have long held a prominent position
in natural product chemistry because of their structural
relationship to the essential amino acid tryptophan and
the corresponding metabolites of tryptophan, such as the
2
-4
neurotransmitter serotonin.
One group of indole
alkaloids studied intensely in recent years has been
isolated from Alstonia species.5 As shown in Figure 1,
a number of these Alstonia alkaloids are ring-A oxygen-
ated indole bases in the macroline/sarpagine series such
,6
7
,8
as alstophylline (1),
(
b
N -desmethylalstophylline oxindole
9
10
a
2), and 11-methoxy-N -methyldihydropericyclivine (not
shown). These bases could presumably be synthesized
from 6-methoxy-D-tryptophan via the trans transfer of
chirality in the asymmetric Pictet-Spengler reaction.5,6
In addition to the macroline/sarpagine monomeric
alkaloids, 18 Alstonia bisindole alkaloids have also been
reported.5 At least three of these bisindole bases contain
F igu r e 1.
,6
stonine (4) effects a progressively increasing drop in blood
pressure when administered to dogs;
acetate derivative of macralstonine has been reported to
exhibit antimalarial and antiamoebic activity. A few
of these bisindole alkaloids have been synthesized bio-
1
1-14
18,19
a 6-methoxytryptophan unit: macralstonine (4),
an-
moreover the
gusticraline,15 and alkaloid H.
16,17
The alkaloid macral-
2
0
X
Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) This study was reported in preliminary form. See: Gan, T.;
mimetically from condensation of the two monomeric
Cook, J . M. Tetrahedron Lett. 1997, 38, 1301.
2) Pelletier, S. W. Chemistry of the Alkaloids; Van Nostrand
Reinhold Book Corporation: New York, 1970.
3) Raffauf, R. F. A Handbook of Alkaloids and Alkaloid-Containing
Plants; Wiley-Interscience: New York, 1970.
4) Glasby, J . S. Encyclopedia of the Alkaloids; Plenum Press: New
York, 1975.
13,21,22
units by LeQuesne et al.
as well as in this labora-
(
23,24
tory.
alstophylline provided macralstonine (4) while alkaloid
H could be formed by coupling of macroline and N
The biomimetic coupling of macroline and
1
3
(
b
-
(
2
2
desmethylalstophylline (3) in a similar process.
(
5) Bi, Y.; Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline
Alstonia alkaloids represent only a small group of bases
which could potentially be prepared from 6-methoxytryp-
tophan derivatives. To illustrate the importance of a
multigram synthetic route to optically active 6-methoxy-
tryptophans, a number of other biologically active ring-A
oxygenated alkaloids are presented in Figure 2. Most
notable among these are the important Catharanthus
antitumor alkaloids vinblastine (5) and vincristine (6).
The pharmacology, structure-activity relationships, and
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.
(6) 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.
(7) Ratnayake, C. K.; Arambewela, L. S. R.; DeSilva, K. T. D.;
Rahman, A.; Alvi, K. A. Phytochemistry 1987, 26, 868.
(
8) Stoll, A.; Hofmann, A. Helv. Chim. Acta 1953, 36, 1143.
(9) Rahman, A.; Silva, W. S. J .; Alvi, K. A.; DeSilva, K. T. D.
Phytochemistry 1987, 26, 865.
10) Arambewela, L. S. R.; Ranatunge, T. Phytochemistry 1991, 30,
740.
(
1
(18) Talapatra, S. K.; Adityachaudhury, N. Science and Culture
1958, 24, 243.
(19) Isidro, N.; Manalo, G. D. J . Phillipine Pharm. Assoc. 1967, 53,
8.
(
(
(
11) Cook, J . M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
12) Sharp, T. M. J . Chem. Soc. 1934, 1227.
13) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J . M.
J . Chem. Soc., Chem. Commun. 1972, 1346.
14) Kishi, T.; Hesse, M.; Vetter, W.; Gemenden, C. W.; Taylor, W.
I.; Schmid, H. Helv. Chim. Acta 1966, 49, 946.
15) Ghedira, K.; Zeches-Hanrot, M.; Richard, B.; Massiot, G.; Le
Men-Olivier, L.; Sevenet, T.; Goh, S. H. Phytochemistry 1988, 27, 3955.
(20) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J . D.; Said, I. M.;
Kirby, G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(21) Burke, D. E.; Cook, J . M.; LeQuesne, P. W. J . Am. Chem. Soc.
1973, 95, 546.
(22) Garnick, R. L. Ph.D. Thesis, Northeastern University, 1977.
(23) Bi, Y.; Cook, J . M.; LeQuesne, P. W. Tetrahedron Lett. 1994,
35, 3877.
(
(
(16) Lazar, H. A. Ph.D. Thesis, University of Michigan, 1972.
17) Burke, D. E.; Cook, G. A.; Cook, J . M.; Haller, K. G.; Lazar, H.
(
A.; LeQuesne, P. W. Phytochemistry 1973, 12, 1467.
(24) Gan, T.; Cook, J . M. Tetrahedron Lett. 1996, 37, 5037.
S0022-3263(97)01640-X CCC: $14.00 © 1997 American Chemical Society

Synthesis of 6-Methoxytryptophan Derivatives
J . Org. Chem., Vol. 62, No. 26, 1997 9299
F igu r e 2.
therapeutic uses of these clinically important bisindoles
2
5
have been reviewed extensively. Certainly, 6-methoxy-
tryptophan might serve as an important intermediate for
the construction of 11-methoxytabersonine (7), the 19R-
hydroxy derivative 8, and 11-methoxyvincadifforimine
(9). The active series of mycotoxins, the fumitremorgins,
including the convulsant agent fumitremorgin B (10)
have been isolated from a variety of Aspergillus and
Penicillium species.26 These alkaloids effect severe trem-
F igu r e 3.
indole protocol and a Sch o¨ llkopf chiral auxiliary.3
method appeared to be a more practical route for the
synthesis of 6-methoxytryptophan and its derivatives on
large scale. 6-Methoxytryptophan derivatives are not
only important for the synthesis of indole alkaloids but
orgenic responses in mice on either intraperitoneal or oral
administration.2
7,28
It is known that at least one of these
3-35
This
agents owes its activity to interaction in the GABA
system.29 As mentioned, for the total syntheses of the
above indole alkaloids, optically active 6-methoxytryp-
tophan could serve as an important building block.
In 1992, a method for the synthesis of 1-(benzenesulfo-
nyl)-6-methoxy-D-(-)-tryptophan ethyl ester was re-
ported30 which employed the Moody azide pyrolysis
also as potential inhibitors for the enzyme indoleamine
36
2
,3-dioxygenase.
More recently, tryprostatins A (11) and B (12) have
followed by formylation under Vilsmeier-Haack condi-
been isolated as secondary metabolites of a marine fungal
strain BM939 and shown to completely inhibit cell cycle
progression of tsFT210 cells in the G2/M phase at a final
tions as key steps.3
0,31
This approach required the
synthesis of the intermediate azides on large scale as well
as pyrolysis in refluxing xylene. Because this strategy
required the potential storage of gram quantities of
hazardous azidocinnimate intermediates, a new route to
concentration of 50 µg/mL of 11 and 12.5 µg/mL of 12,
respectively.3
7-39
Tryprostatins A (11) and B (12) contain
a 2-isoprenyltryptophan moiety and a proline residue,
which comprise the diketopiperazine unit (Figure 3).
These indole alkaloids differ from representatives of the
fumitremorgin series for ring-C has not been formed
between the positions designated C(18) and N(10).
Although bases in the fumitremorgin series have been
studied extensively,26 only a few natural products struc-
turally related to 11 and 12 have been reported, to date.
The biological activity and unique 2-isoprenyltryptophan
units of 11 and 12 prompted interest in such molecules.
6
-methoxytryptophan was envisaged. Recently, a re-
giospecific bromination of 3-methylindole was developed
in our laboratory32 and this method was employed in the
synthesis of optically active 5-methoxy-L-(-)- or D-(+)-
tryptophan by utilizing the J app-Klingmann/Fischer
26
2
6
(
25) Brossi, A.; Suffness, M. The Alkaloids; Academic Press: New
York, 1990; Vol. 37.
26) Steyn, P. S.; Vleggaar, R. Tremorgenic Mycotoxins In Progress
(
in the Chemistry of Organic Natural Products; Herz, W., Grisebach,
H., Kirby, G. W., Eds.; L. Zechmiester: 1985; Vol. 48, p 1.
(
27) Yamazaki, M.; Suzuki, K.; Fujimoto, H.; Akiyama, T.; Sankawa,
U.; Iitaka, Y. Chem. Pharm. Bull. 1980, 28, 861.
28) Yamazaki, M.; Fujimoto, H.; Kawasaki, T. Chem. Pharm. Bull.
980, 28, 245.
29) Norris, P. J .; Smith, C. C. T.; DeBelleroche, J .; Bradford, H. F.;
Mantle, P. G.; Thomas, A. J .; Penny, R. H. C. J . Neurochem. 1980, 34,
3.
(33) Zhang, P.; Cook, J . M. Synth. Commun. 1995, 25, 3883.
(34) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 7411.
(35) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 9133.
(36) 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.
(37) Cui, C.; Kakeya, H.; Okada, G.; Onose, R.; Ubukata, M.;
Takahashi, I.; Isono, K.; Osada, H. J . Antibiot. 1995, 48, 1382.
(38) Cui, C.; Kakeya, H.; Osada, H. J . Antibiot. 1996, 49, 534.
(39) Cui, C.; Kakeya, H.; Okada, G.; Onose, R.; Osada, H. J . Antibiot.
1996, 49, 527.
(
1
(
3
(
30) Allen, M. S.; Hamaker, L. K.; LaLoggia, A. J .; Cook, J . M. Synth.
Commun. 1992, 22, 2077.
31) Hamaker, L. K. Ph.D. Thesis, University of Wisconsins
Milwaukee, 1995.
32) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 3103.
(
(

9
300 J . Org. Chem., Vol. 62, No. 26, 1997
Gan et al.
Sch em e 1
recovered by Kugelrohr distillation and reused. In this
manner, 6-methoxy-L-tryptophan ethyl ester (21) was
synthesized enantiospecifically in four steps from 6-meth-
oxy-3-methylindole (16) in 58% overall yield. Use of the
Sch o¨ llkopf chiral auxiliary derived from L-valine provided
the D-enantiomer of 21.
For the total synthesis of tryprostatin A (11), 2-iso-
prenyltryptophan derivatives were required. Since the
regiospecific bromination of 3-methylindoles were achieved
at the indole 2-position via an electrophilic process or at
3
2
the 3-methyl position under free radical conditions, this
method appeared to be useful for the preparation of a
2
-isoprenyltryptophan. The 2-bromo group could serve
as synthetic equivalent for the isoprenyl group, and the
-bromomethyl function could be coupled with the anion
3
of the Sch o¨ llkopf chiral auxiliary 19 to obtain the desired
tryptophan moiety. Consequently, the total synthesis of
1
1 began with regiospecific bromination of 17 at the
indole C(2) position to yield 2-bromoindole 22 in 95%
yield under electrophilic conditions (Scheme 3). Further-
more, when 2-bromoindole 22 was reacted with NBS
under free radical conditions (AIBN, ∆), dibromide 23
was obtained as illustrated in 93% yield. When dibro-
mide 23 was coupled with the anion of the Sch o¨ llkopf
chiral auxiliary 19 at -78 °C, a mixture of diastereomers
24a and 24b in a ratio of 4:1 was obtained in 91% yield.
The structures of 24a and 24b were established by proton
and carbon NMR spectroscopy and by comparison to
indoles in the 5-methoxy series.41 Since the enantiose-
lectivity of formation of 24a :24b was disappointing,
another approach for the preparation of 11 was envis-
aged.
Resu lts a n d Discu ssion
We report here the enantiospecific synthesis of 6-meth-
oxy-L- and D-tryptophan derivatives and its application
to the synthesis of tryprostatin A (11) via a regiospecific
bromination sequence as a key step. The synthesis began
with the Fischer indole cyclization via a J app-Kling-
mann azo-ester intermediate (Scheme 1). This sequence
was originally reported by Abramovitch and Shapiro and
reviewed.40 When m-anisidine (13) was treated with
sodium nitrite and concentrated aqueous HCl, followed
by the addition of the anion of ethyl R-ethylacetoacetate,
the J app-Klingmann azo-ester intermediate was formed.
When this intermediate was heated in a solution of 3 N
ethanolic HCl, a mixture of ethyl 6-methoxy-3-methyl-
indole-2-carboxylate (14a ) and its 4-methoxy isomer 14b
was obtained in a ratio of 10:1. The desired 6-methoxy-
indole isomer 14a was isolated from the mixture by
simple crystallization. Although this sequence was
exothermic, this method was far safer to execute on large
scale than the Moody azide pyrolysis. Hydrolysis of the
ester 14a under alkaline conditions yielded the corre-
sponding carboxylic acid 15 which was converted into
indole 16 via the subsequent copper/quinoline-mediated
decarboxylation sequence. This procedure provided the
It was decided to return to the 6-methoxy-3-(bromo-
methyl)indole 18 as the starting template since 18 had
earlier been shown to react with the anion of Sch o¨ llkopf
chiral auxiliary 19 to provide only the desired trans
diastereomer 20 (Scheme 2). Regiospecific bromination
of 20 at the indole C(2) position to furnish 24a was
accomplished in 85% yield when 20 was stirred with NBS
in CH Cl at room temperature (Scheme 4). Initially, it
2
2
was feared that competitive bromination would take
place both at the indole C(2) position and the C(3)
methylene group, but fortunately the latter process did
not occur under these conditions. It was believed the
6
-methoxy group increased the electron density at the
indole C(2) position; therefore, electrophilic substitution
took place smoothly. In contrast, in the 5-methoxypyra-
zine series treatment of the indole with NBS in CH Cl
6
-methoxy-3-methylindole (16) in excellent yield.
To employ the Sch o¨ llkopf chiral auxiliary in the indole
2
2
led to multibromination.42 This indicated, as expected,
that the 6-methoxy group played a major role in the
regiospecific bromination at C(2). The regiospecific bro-
mination at the indole C(2) position of 20 provided a route
to the 6-methoxy-2-bromo trans pyrazine 24a in enan-
tiospecific fashion. When bromide 24a was treated with
n-butyllithium at -78 °C, followed by addition of isopre-
nyl bromide (4-bromo-2-methylbutene) 25, 2-isopre-
nylpyrazine 26 was isolated in 86% yield. Since the
Sch o¨ llkopf chiral auxiliary can tolerate strongly alkaline
system, protection/deactivation of the indole N(H) moiety
was required. When 6-methoxyindole 16 was stirred
with di-tert-butyl dicarbonate in the presence of DMAP,
N-BOC protected indole 17 was realized in 99% yield
(
Scheme 1). The protected 3-methylindole 17 was then
treated with NBS in the presence of AIBN to provide the
-(bromomethyl)indole 18, as illustrated in Scheme 2.
3
When bromide 18 was coupled with the anion of the
Sch o¨ llkopf chiral auxiliary (19) (derived from D-va-
line),3
0,31,33,41
only the desired trans diastereomer 20 was
obtained. The pyrazine 20 was hydrolyzed with a 2 N
aqueous HCl solution/THF to remove the D-valine ethyl
ester, and then the BOC protecting group was removed
on stirring with a 4 N aqueous HCl solution/MeOH in a
one-pot reaction. D-Valine ethyl ester can readily be
33
conditions, again it served as a protecting group for the
amino acid functionality to prevent any racemization.
The pyrazine group from 26 was removed under acidic
conditions (aqueous HCl, THF) in 94% yield to provide
D-valine ethyl ester and the 2-isoprenyltryptophan 27
(Scheme 4).
(
(
40) Abramovitch, R. A.; Shapiro, D. S. J . Chem. Soc. 1956, 4589.
41) Liu, R. Ph.D. Thesis, University of WisconsinsMilwaukee,
1
996.
(42) Zhao, S.; Cook, J . M. Unpublished results.

Synthesis of 6-Methoxytryptophan Derivatives
J . Org. Chem., Vol. 62, No. 26, 1997 9301
Sch em e 2
Sch em e 3
Sch em e 4
Sch em e 5
Sch em e 6
As illustrated in Scheme 5, when the 6-methoxy-2-
isoprenyltryptophan 27 was stirred with N-(trichloro-
ethoxycarbonyl)(Troc)-L-prolyl chloride (28)43 in the pres-
pyrazine group (Scheme 6). These bromo derivatives (31
and 32) may be important intermediates for the prepara-
tion of unusual tryptophan derivatives with various
substituents at the indole 2-position via palladium-
catalyzed coupling reactions. These types of unusual
tryptophan derivatives may also be potential inhibitors
2 2
ence of triethylamine in CH Cl at 0 °C, the desired
dipeptide 29 was obtained. The Troc protecting group
was then removed under reductive conditions when 29
was heated with Zn (dust) in refluxing MeOH.43 Finally,
formation of the diketopiperazine unit and removal of
BOC protecting group from the indole N(H) function were
achieved when dipeptide 30 was heated at 160 °C (neat)
to furnish tryprostatin A (11) in 50% overall yield [from
36
for the enzyme indoleamine 2,3-dioxygenase.
In summary, a concise preparation of optically active
L- or D-6-methoxytryptophan ethyl ester 21 was devel-
oped via the Fischer indole/Sch o¨ llkopf chiral auxiliary
from 6-methoxy-3-methylindole (16). This method was
extended to the first enantiospecific total synthesis of
tryprostatin A (11) via a regiospecific bromination process
as a key step. In addition, 6-methoxy-2-bromotryptophan
ethyl ester (32) was prepared. This approach should also
provide a route for the synthesis of other unusual
tryptophans or indoles which carry substituents at the
indole 2-position. Further work in this areas is in
progress and will be reported in due course.
2
9 (Scheme 5)].
In addition to tryprostatin A (11) and the 6-methoxy-
-isoprenyltryptophan ethyl ester (27), the 6-methoxy-
-bromotryptophan ethyl ester (32) was also prepared by
2
2
removal of the BOC function with potassium tert-butoxide
and water,44 followed by acid-mediated hydrolysis of the
(
(
43) Boyd, S. A.; Thompson, W. J . J . Org. Chem. 1987, 52, 1790.
44) Gassman, P. G.; Schenk, W. N. J . Org. Chem. 1977, 42, 918.

9
302 J . Org. Chem., Vol. 62, No. 26, 1997
Gan et al.
Exp er im en ta l Section
and copper powder (2.5 g) under nitrogen for 2.5 h. The copper
powder was removed by filtration, after which the filtrate was
brought to pH 2-3 with an aqueous solution of 6 N HCl, and
the solution which resulted was extracted with diethyl ether
(4 × 100 mL). The combined organic layers were washed with
Melting points are reported uncorrected. The 1H NMR
spectra were recorded at 250 MHz or 500 MHz.
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.
Alkaloids were visualized with Dragendorf’s reagent or a
saturated solution of ceric ammonium sulfate in 50% sulfuric
acid or with an aqueous solution of (2,4-dinitrophenyl)hydra-
zine in 30% sulfuric acid. Methanol (MeOH) and ethanol
brine and dried (MgSO
4
). The solvent was removed under
reduced pressure to afford 16 as a brown solid (43.7 g,
4
8
93.6%): mp 129-131 °C (lit. mp 127 °C); IR (KBr) 2915, 1625,
-
1 1
3
1455 cm ; H NMR (250 MHz, CDCl ) δ 2.45 (s, 3 H), 3.79 (s,
3 H), 6.78 (dd, 1 H, J ) 1.8 and 8.6 Hz), 6.83 (m, 2 H), 7.43 (d,
1 H, J ) 8.5 Hz), 7.72 (s, br, 1 H); MS (EI) m/e (relative
intensity) 161 (84), 146 (100), 118 (42).
(
EtOH) were dried by distillation over magnesium metal and
1-(ter t-Bu t yloxyca r b on yl)-6-m et h oxy-3-m et h ylin d ole
(17). To a solution of 6-methoxy-3-methylindole 16 (5.0 g, 31
mmol) in distilled acetonitrile (150 mL) were added di-tert-
butyl dicarbonate (7.44 g, 34.1 mmol) and DMAP (0.195 g, 1.6
mmol). The reaction mixture was stirred at rt for 12 h. The
solvent was removed under reduced pressure. The residue was
iodine. Tetrahydrofuran (THF), benzene, toluene, dioxane,
and diethyl ether were dried by distillation from sodium-
benzophenone ketyl. Methylene chloride was dried over
MgSO
over CaH
4
and then distilled over P
2 5
O . Triethylamine was dried
2
and then distilled over KOH. All chemicals were
purchased from Aldrich Chemical Co. unless otherwise indi-
cated.
Eth yl 6-Meth oxy-3-m eth ylin d ole-2-ca r boxyla te (14a ).
To a mixture of m-anisidine 13 (12.3 g, 0.1 mol), concd
aqueous HCl (25 mL), and water (40 mL) was added a solution
dissolved in CH
solution of 1 N HCl (2 × 50 mL). The aqueous layer was
extracted with CH Cl
(3 × 30 mL). The combined organic
layers were dried (K CO ). After removal of solvent under
2 2
Cl (100 mL) and washed with an aqueous
2
2
2
3
reduced pressure, the residue was solidified to afford 17 (8.12
g, 99%) as a yellow solid: mp 45-46 °C; IR (KBr) 2950, 1720,
of NaNO
2
(7.6 g, 0.11 mol in 10 mL of water) in a dropwise
-
1
1
manner at -5 °C. After addition, the mixture was stirred at
1620, 1455 cm ; H NMR (250 MHz, CDCl ) δ 1.65 (s, 9 H),
3
0
°C for 15 min and brought to pH 3-4 by addition of sodium
2.22 (s, 3 H), 3.87 (s, 3 H), 6.87 (dd, 1 H, J ) 2.2 and 8.6 Hz),
7.22 (s, 1 H), 7.54 (d, 1 H, J ) 8.6 Hz), 7.72 (br, s, 1 H); MS
acetate (8.3 g, 0.1 mol). In a separate flask, a solution of ethyl
+
R-ethylacetoacetate (15.8 g, 0.1 mol) in ethanol (80 mL) at 0
(EI) m/e (relative intensity) 261 (M , 42), 205 (100), 161 (52),
1
°
C was treated with an aqueous solution of KOH (0.1 mol in
146 (45), 117 (21). Anal. Calcd for C15
H
19NO
3
‚ /
5
H
2
O: C,
1
0 mL of H
2
O), followed by addition of ice (200 g). The
68.01; H, 7.38; N 5.28. Found: C, 68.06; H, 7.27; N, 5.17.
1-(ter t-Bu t yloxyca r b on yl)-3-(b r om om et h yl)-6-m et h -
oxyin d ole (18). A solution of 1-(tert-butyloxycarbonyl)-6-
diazonium salt prepared above was immediately added to the
alkaline solution of ethyl R-ethylacetoacetate. The mixture
was then adjusted to pH 5-6 and stirred at 0 °C for 4 h. After
the mixture was kept a further 12 h at 4 °C, it was extracted
with ethyl acetate (4 × 200 mL). The combined extracts were
4
methoxy-3-methylindole 17 (4.0 g, 15.3 mmol) in CCl (120 mL)
was heated to reflux after which N-bromosuccinimide (2.87 g,
16.1 mmol) and AIBN (120 mg) were admixed carefully and
added in three portions. The mixture was refluxed for 20 min.
Another portion of AIBN (60 mg) was then added. The
mixture was kept at reflux for 50 min and then allowed to
cool. The succinimide which resulted as a precipitate was
filtered off and washed with hexane (4 × 10 mL). The solvents
were removed under reduced pressure to afford 3-(bromom-
4
washed with brine and dried (MgSO ). Most of the solvent
was removed under reduced pressure, and the liquid residue
which remained was added dropwise to a solution of anhydrous
3
and the addition was carried out at a rate at which the
temperature remained at 70 °C. After addition, the mixture
was held at 78 °C for 2 h. The solvent was removed under
reduced pressure, and the residue which remained was treated
N ethanolic HCl at 70 °C. This is an exothermic process,
1
ethyl)indole 18 as a brown oil (4.79 g, 92%): H NMR (250
MHz, CDCl ) δ 1.65 (s, 9 H), 3.86 (s, 3 H), 4.61 (s, 2 H), 6.90
3
with water (20 mL) and CH
was extracted with CH Cl
organic layers were washed with brine and dried (Na
2
Cl
(3 × 50 mL), and the combined
SO ).
2
(100 mL). The aqueous layer
(dd, 1 H, J ) 2.0 and 8.1 Hz), 7.50 (d, 1 H, J ) 8.2 Hz), 7.52
(s, 1 H), 7.70 (br, s, 1 H). The crude residue of 3-(bromom-
ethyl)indole was flash evaporated under reduced pressure with
dry THF three times and used directly in a later step without
further purification. It is unstable on silica gel.
2
2
2
4
Purification on a short wash column (silica gel, ethyl acetate/
hexane, 1:3) gave a mixture of 14a and 14b (10:1 ratio as
1
determined by H NMR) as a dark brown solid. Recrystalli-
(3S,6R)-3-[[1-(ter t-Bu tyloxyca r bon yl)-6-m eth oxy-3-in -
d olyl]m eth yl]-3,6-d ih yd r o-6-isop r op yl-2,5-d ieth oxyp yr a -
zin e (20). To a solution of (3R)-3,6-dihydro-6-isopropyl-2,5-
zation of this mixture from ethyl acetate furnished pure 14a
as brown crystals. Additional quantities of 14a could be
obtained by chromatography of the mother liquor followed by
crystallization (combined 17.1 g, 73.5%). 14a : mp 122-124
6
diethoxypyrazine (Sch o¨ llkopf chiral auxiliary) (19) derived
from D-valine (3.41 g, 16.1 mmol) in dry THF (60 mL) under
nitrogen at -78 °C was added n-BuLi (2.5 M, 7.08 mL, 17.7
mmol) dropwise. The solution which resulted was stirred at
-78 °C for 30 min and treated slowly with a solution of crude
3-(bromomethyl)indole 18 (4.79 g, about 14.1 mmol) in THF
(30 mL). The mixture was stirred at -78 °C for 20 h and then
allowed to slowly warm to rt. The solution was concentrated
under reduced pressure and diluted with a saturated aqueous
4
6
-1 1
°
C (lit. mp 122 °C); IR (KBr) 3330, 1669, 1467 cm ; H NMR
(
(
(
(
250 MHz, CDCl
3
) δ 1.4 (t, 3 H, J ) 7.1 Hz), 2.6 (s, 3 H), 3.81
s, 3 H), 4.4 (q, 2 H, J ) 7.1 Hz), 6.78 (d, 1 H, J ) 1.8 Hz), 6.8
dd, 1 H, J ) 8.8 and 1.9 Hz), 7.5 (d, 1 H, J ) 8.4 Hz), 8.55
br, 1 H, D O exchangeable); MS (EI) m/e (relative intensity)
2
2
33 (48), 187 (100), 159 (53), 144 (21), 116 (23). This reaction
was run on a 300 g scale with no loss in yield.
-Meth oxy-3-m eth ylin d ole (16). A mixture of 14a (72 g,
.3 mol), EtOH (150 mL), KOH pellets (85%, 60 g, 0.9 mol),
solution of NaHCO
CH Cl
(3 × 20 mL). The combined organic layers were
washed with brine (30 mL) and dried (K CO ). After removal
3
. The aqueous layer was extracted with
6
0
2
2
and water (100 mL) was heated to reflux for 1 h. The volume
was reduced to 100 mL under reduced pressure and acidified
with an aqueous solution of 3 N HCl. The precipitate which
resulted was collected on a filter, washed with distilled water,
and dried in a vacuum oven at 80 °C to afford 6-methoxy-3-
methylindole-2-carboxylic acid (15) as a white solid (61.5 g,
2
3
of solvent under reduced pressure, the residue was purified
by flash chromatography (silica gel, hexane/ethyl acetate, 10/
1
) to afford 20 as an oil (6.04 g, 91%): [R]27
) +24.7 (c ) 0.9,
1 1
D
-
in CHCl
MHz, CDCl
3
); IR (NaCl) 2970, 1730, 1690 cm ; H NMR (250
) δ 0.63 (d, 3 H, J ) 6.8 Hz), 0.92 (d, 3 H, J ) 6.9
3
00%): mp 202-203 °C (lit.47 mp 200-201 °C). This acid 15
Hz), 1.21 (t, 3 H, J ) 7.1 Hz), 1.29 (t, 3 H, J ) 7.1 Hz), 1.62 (s,
9
3
Hz), 6.80 (dd, 1 H, J ) 2.2 and 8.6 Hz), 7.21 (s, 1 H), 7.42 (d,
1
1
H), 2.15 (m, 1 H), 3.13 (d, 2 H, J ) 4.8 Hz), 3.53 (t, 1 H, J )
.4 Hz), 3.84 (s, 3 H), 3.94-4.16 (m, 4 H), 4.25 (q, 1 H, J ) 3.8
(59.5 g, 0.29 mol) was then heated to reflux in a well-stirred
mechanical stirrer) mixture of distilled quinoline (125 mL)
(
H, J ) 8.6 Hz), 7.67 (br, s, 1 H); 13C NMR (62.90 MHz, CDCl
)
3
(45) Depew, K. M.; Danishefsky, S. J .; Rosen, N.; Sepp-Lorenzino,
L. J . Am. Chem. Soc. 1996, 118, 12463.
(
46) Wieland, T.; Grimm, D. Chem. Ber. 1965, 98, 1727.
47) Blaikie, K. G.; Perkin, W. H. J . Chem. Soc. 1924, 125, 296.
(48) Fleming, I.; Woolias, M. J . Chem. Soc., Perkin Trans. 1 1979,
827.
(

Synthesis of 6-Methoxytryptophan Derivatives
J . Org. Chem., Vol. 62, No. 26, 1997 9303
δ 14.4, 16.7, 19.0, 28.2, 29.4, 31.7, 55.6, 56.1, 60.4, 60.5, 60.7,
dissolved in CH
solution of cold NaHCO
extracted with CH Cl
(3 × 60 mL). The combined organic
layers were washed with brine and dried (K CO ). The solvent
2
Cl
2
(100 mL) and treated with a 10% aqueous
8
1
2.9, 99.0, 111.5, 116.7, 120.1, 122.8, 125.3, 136.1, 149.8, 157.7,
3
(30 mL). The aqueous layer was
+
62.3, 163.5; MS (EI) m/e (relative intensity) 471 (M , 47), 261
2
2
(21), 212 (100), 169 (67), 141 (20), 57 (51). Anal. Calcd for
2
3
C
26
H
37
N
3
O
5
: C, 66.22; H, 7.91; N 8.91. Found: C, 66.23; H,
was removed under reduced pressure to afford a mixture of
24a and 24b (80/20). The mixture was separated by flash
chromatography (silica gel, hexane/ethyl acetate, 15/1) to afford
24a (7.99 g, 72%) and 24b (2.12 g, 19%). 24a : an oil; IR (NaCl)
7
.90; N, 8.55.
L-6-Meth oxytr yp top h a n Eth yl Ester (21). To a solution
of pyrazine 20 (100 mg, 0.21 mmol) in THF (2.5 mL) at 0 °C
was added an aqueous solution of 2 N HCl (0.8 mL). The
reaction mixture was allowed to warm to rt and stirred for
-
1 1
2970, 1735, 1690 cm ; H NMR (250 MHz, CDCl ) δ 0.62 (d,
3
3 H, J ) 6.8 Hz), 0.97 (d, 3 H, J ) 6.8 Hz), 1.17 (t, 3 H, J )
7.1 Hz), 1.28 (t, 3 H, J ) 7.1 Hz), 1.67 (s, 9 H), 2.20 (m, 1 H),
2.92 (dd, 1 H, J ) 8.1 and 13.9 Hz), 3.28 (dd, 1 H, J ) 4.6 and
13.9 Hz), 3.68 (t, 1 H, J ) 3.3 Hz), 3.84 (s, 3 H), 3.95-4.25 (m,
5 H), 6.80 (dd, 1 H, J ) 2.2 and 8.6 Hz), 7.38 (d, 1 H, J ) 8.6
1
.5 h. The solution was concentrated under vacuum. MeOH
(0.5 mL) was added after which an aqueous solution of 4 N
HCl (7 mL) was added at 0 °C. The reaction mixture was
allowed to warm to rt and stirred for 4 h. A cold aqueous
solution of 15% NH
tracted with CH Cl
(3 × 25 mL). The combined organic layers
were dried (K CO ) and concentrated under vacuum. The
residue was purified by flash chromatography (silica gel,
EtOAc to EtOAc:MeOH ) 95:5) to provide L-6-methoxytryp-
tophan ethyl ester 21 (40 mg, 70%) as an oil. 21: [R]
Hz), 7.63 (d, 1 H, J ) 2.1 Hz); 13C NMR (62.90 MHz, CDCl
)
4
OH was added. The solution was ex-
3
2
2
δ 14.3, 14.4, 16.6, 19.1, 28.2, 31.0, 31.5, 55.6, 55.8, 60.5, 60.7,
2
3
84.5, 99.6, 107.8, 111.6, 119.7, 120.6, 123.7, 137.3, 149.4, 157.7,
+
162.8, 163.4; MS (EI) m/e (relative intensity) 551 (M , 17), 549
+
(M , 17), 470 (64), 414 (61), 370 (58), 341 (32), 240 (49), 238
2
7
D
) +
36 3 5
(49), 212 (72), 169 (100), 141 (39). Anal. Calcd for C26H N O -
Br: C, 56.73; H, 6.59; N 7.63. Found: C, 56.97; H, 6.47; N,
-
1
5
.1 (c ) 0.92, in CHCl
3
); IR (NaCl) 3365, 2925, 1730, 1625 cm
;
1
H NMR (250 MHz, CDCl ) δ 1.22 (t, 3 H, J ) 7.1 Hz), 1.79 (s,
3
7.48. 24b: an oil; IR (NaCl) 2970, 1730, 1690, 1360, 1310,
-
1 1
br, 2 H), 2.97 (dd, 1 H, J ) 7.8 and 14.4 Hz), 3.21 (dd, 1 H, J
3
1235, 1155, 1035 cm ; H NMR (250 MHz, CDCl ) δ 0.74 (d,
)
2
4.7 and 14.3 Hz), 3.77 (s, 3 H), 3.73-3.80 (m, 1 H), 4.14 (q,
H, J ) 7.2 Hz), 6.73-6.78 (m, 2 H), 6.84 (s, 1 H), 7.44 (d, 1
3 H, J ) 6.8 Hz), 1.01 (d, 3 H, J ) 6.8 Hz), 1.18 (t, 3 H, J )
7.1 Hz), 1.24 (t, 3 H, J ) 7.1 Hz), 1.67 (s, 9 H), 2.05 (m, 1 H),
2.88 (dd, 1 H, J ) 8.6 and 13.9 Hz), 3.27 (dd, 1 H, J ) 4.8 and
13.9 Hz), 3.84 (s, 3 H), 3.82-4.28 (m, 6 H), 6.83 (dd, 1 H, J )
2.3 and 8.6 Hz), 7.38 (d, 1 H, J ) 8.6 Hz), 7.64 (d, 1 H, J ) 2.3
1
3
3
H, J ) 9.3 Hz), 8.67 (s, br, 1 H); C NMR (62.90 MHz, CDCl )
δ 14.0, 30.7, 54.9, 55.5, 60.8, 94.7, 109.2, 110.7, 119.1, 121.8,
21.9, 137.0, 156.4, 175.2; MS (EI) m/e (relative intensity) 262
8), 160 (100), 145 (13), 117 (11); exact mass calcd for
262.1317, found: 262.1346.
-(ter t-Bu tyloxyca r bon yl)-2-br om o-6-m eth oxy-3-m eth -
ylin d ole (22). To a solution of 1-(tert-butyloxycarbonyl)-6-
methoxy-3-methylindole 17 (6.0 g, 23.0 mmol) in CCl (90 mL)
1
(
C
Hz); 13C NMR (62.90 MHz, CDCl
) δ 14.2, 14.4, 17.7, 19.6, 28.2,
3
14
H
1
18
N
2
O
3
31.8, 31.9, 55.7, 55.9, 60.4, 60.6, 61.2, 84.4, 99.8, 107.7, 111.7,
119.5, 120.8, 123.6, 137.6, 137.5, 149.3, 157.7, 162.6, 163.2;
+
+
MS (EI) m/e (relative intensity) 551 (M , 5), 549 (M , 5), 414
(10), 368 (17), 240 (33), 238 (35), 169 (100), 141 (25). Anal.
Calcd for C26H N O Br: C, 56.73; H, 6.59; N 7.63. Found:
36 3 5
C, 57.10; H, 6.85; N, 7.48.
(3S,6R)-3-[[1-(ter t-Bu tyloxyca r bon yl)-2-br om o-6-m eth -
oxy-3-in d olyl]m e t h yl]-3,6-d ih yd r o-6-isop r op yl-2,5-d i-
eth oxyp yr a zin e (24a ). To a solution of the pyrazine 20 (700
4
was added N-bromosuccinimide (4.30 g, 24.1 mmol). The
mixture was heated to reflux for 60 min. The reaction solution
was allowed to cool to rt. The succinimide which resulted was
filtered off and washed with hexane (4 × 15 mL). The filtrates
were combined, and the solvents were removed under reduced
pressure to afford 22 (7.42 g, 95%) as a brownish residue: 1
H
2 2
mg, 1.49 mmol) in dry CH Cl (60 mL) was added NBS (0.292
NMR (250 MHz, CDCl
H), 6.86 (dd, 1 H, J ) 2.3 and 8.7 Hz), 7.30 (d, 1 H, J ) 8.7
Hz), 7.67 (d, 1 H, J ) 2.3 Hz); The crude residue of 2-bromo-
-methylindole 22 was used directly in a later step without
further purification.
-(ter t-Bu tyloxyca r bon yl)-2-br om o-3-(br om om eth yl)-
-m eth oxyin d ole (23). A solution of 22 (7.42 g, 21.8 mmol)
in CCl (90 mL) was heated to reflux after which an admixture
of N-bromosuccinimide (NBS) (4.30 g, 24.1 mmol) and AIBN
200 mg) was carefully added in one portion under Ar. After
3
) δ 1.69 (s, 9 H), 2.22 (s, 3 H), 3.86 (s,
g, 1.64 mmol) at rt. The reaction mixture was stirred at rt
for 30 min after which the solvent was removed under reduced
pressure. The residue was subjected to a short wash column
(silica gel, ethyl acetate:hexane ) 1:10) to provide 24a (700
mg, 86%) as an oil. All spectroscopic data were identical with
that for 24a reported in the previous experiment.
(3S,6R)-3-[[1-(ter t-Bu t yloxyca r b on yl)-2-isop r en yl-6-
m eth oxy-3-in d olyl]m eth yl]-3,6-d ih yd r o-6-isop r op yl-2,5-
d ieth oxyp yr a zin e (26). To a solution of 2-bromopyrazine
24a (1.74 g, 3.09 mmol) in dry THF (25 mL) at -78 °C under
nitrogen was added a solution of n-BuLi (2.5 M, 1.64 mL, 4.10
mmol) dropwise. The resultant mixture was stirred at -78
°C for 30 min and then warmed to 0 °C for 10 min. Then
isoprenyl bromide (4-bromo-2-methylbutene) 25 (1.03 g, 6.91
mmol) was added quickly at 0 °C. The mixture was stirred at
0 °C for 1 h and warmed to rt overnight. The solvent was
removed under reduced pressure. The residue was taken up
3
3
1
6
4
(
completion of the addition, three portions of AIBN (3 × 50 mg)
were added every 7 min. The mixture was heated at reflux
for 60 min and cooled to rt. The succinimide which resulted
was filtered off and washed with hexane (4 × 15 mL). The
filtrates were combined, and the solvents were removed under
reduced pressure to yield 23 (8.50 g, 93%) as a brown oil: 1
H
NMR (250 MHz, CDCl
3
) δ 1.69 (s, 9 H), 3.85 (s, 3 H), 4.61 (s,
2
H), 6.89 (dd, 1 H, J ) 2.2 and 8.5 Hz), 7.44 (d, 1 H, J ) 8.5
in CH
The aqueous layer was extracted with CH
The combined organic layers were dried (K
2
Cl
2
and washed with a 5% aqueous solution of NaHCO
Cl
(3 × 50 mL).
CO ). After
3
.
Hz), 7.66 (d, 1 H, J ) 2.2 Hz); MS (EI) m/e (relative intensity)
2
2
+
4
1
19 (M , 19), 363 (15), 282 (12), 240 (99), 238 (100), 219 (11),
75 (9), 158 (38), 129 (14). The crude oil of 2-bromo-3-
2
3
removal of the solvent under reduced pressure, the residue
was purified by flash chromatography (silica gel, hexane/ethyl
acetate 15/1) to provide 26 (1.44 g, 85%) as an oil: IR (NaCl)
(
bromomethyl)indole 23 was used in the next step without
further purification.
3S,6R)-3-[[1-(ter t-Bu tyloxyca r bon yl)-2-br om o-6-m eth -
-
1 1
(
3
2970, 1730, 1690 cm ; H NMR (250 MHz, CDCl ) δ 0.61 (d,
oxy-3-in d olyl]m e t h yl]-3,6-d ih yd r o-6-isop r op yl-2,5-d i-
eth oxyp yr a zin e (24a ) a n d (3R,6R)-3-[[1-(ter t-Bu tyloxy-
car bon yl)-2-br om o-6-m eth oxy-3-in dolyl]m eth yl]-3,6-dih y-
d r o-6-isop r op yl-2,5-d ieth oxyp yr a zin e (24b). A solution of
3 H, J ) 6.8 Hz), 0.94 (d, 3 H, J ) 6.8 Hz), 1.18 (t, 3 H, J )
7.1 Hz), 1.31 (t, 3 H, J ) 7.1 Hz), 1.61 (s, 3 H), 1.63 (s, 9 H),
1.70 (s, 3 H), 2.19 (m, 1 H), 2.88 (dd, 1 H, J ) 7.4 and 14.2
Hz), 3.23 (dd, 1 H, J ) 3.9 and 14.3 Hz), 3.56 (t, 1 H, J ) 3.4
Hz), 3.69 (d, 2 H, J ) 6.0 Hz), 3.83 (s, 3 H), 3.94-4.22 (m, 5
H), 5.16 (t, 1 H, J ) 5.8 Hz), 6.78 (dd, 1 H, J ) 2.3 and 8.5
Hz), 7.37 (d, 1 H, J ) 8.6 Hz), 7.65 (d, 1 H, J ) 2.3 Hz); MS
3
1
the Sch o¨ llkopf chiral auxiliary 19 (5.11 g, 24.1 mmol) in THF
50 mL) was treated with n-butyllithium (2.5 M in hexane,
0.5 mL, 26.3 mmol) at -78 °C under nitrogen. The solution
(
1
+
which resulted was stirred at -78 °C for 30 min after which
a cold solution of dibromide 23 (8.50 g, 20.2 mmol) in THF (30
mL) under nitrogen was added dropwise. After the mixture
was allowed to stir at -78 °C for 20 h, the reaction solution
was slowly warmed to rt. Most of the solvent was removed
under reduced pressure, and the residue which resulted was
(EI) m/e (relative intensity) 539 (M , 65), 439 (11), 328 (16),
272 (58), 228 (100), 212 (55), 169 (31), 141 (16), 57 (48). Anal.
Calcd for C31
45 3 5
H N O : C, 68.99; H, 8.40; N 7.79. Found: C,
68.69; H, 8.66; N, 7.40.
(S )-1-(t er t -Bu t yloxyc a r b on yl)-2-isop r e n yl-6-m e t h -
oxyt r yp t op h a n E t h yl E st er (27). To a solution of 2-

9
304 J . Org. Chem., Vol. 62, No. 26, 1997
Gan et al.
prenylpyrazine 26 (1.27 g, 2.36 mmol) in THF (30 mL) at 0 °C
was added an aqueous solution of 2 N HCl (10 mL). The
reaction mixture was allowed to warm to rt. and stirred for
13C NMR (62.90 MHz, CDCl
28.3, 45.4, 54.6, 55.7, 59.2, 94.9, 104.4, 109.3, 118.3, 120.0,
3
) δ 17.9, 22.6, 25.1, 25.8, 25.7,
122.3, 135.1, 136.3, 156.3, 165.8, 169.4; MS (EI) m/e (relative
+
1
.5 h. A cold aqueous solution of 15% NH
solution was concentrated under vacuum and diluted with
CH Cl . The aqueous layer was extracted with CH Cl . The
combined organic layers were dried (K CO ) and the solvents
4
OH was added. The
intensity) 381 (M , 4), 228 (100), 212 (14), 198 (9); MS (CI,
CH
4
) m/e (relative intensity) 382 (M + 1, 100), 228 (8); exact
2
2
2
2
mass calcd for C22H N O
27 3 3
381.2052, found 381.2044. The
2
3
spectral data for 11 were identical with that reported by Osada
were removed under vacuum. The residue was purified by
flash chromatography (silica gel, ethyl acetate) to provide
et al.38
(3S,6R)-3-[(6-Meth oxy-2-br om o-3-in d olyl)m eth yl]-3,6-
d ih yd r o-6-isop r op yl-2,5-d ieth oxyp yr a zin e (31). To a so-
lution of potassium tert-butoxide (0.65 g, 5.8 mmol) in dry
1
-BOC-2-isoprenyl-6-methoxytryptophan ethyl ester (27) (0.95
-
1
27
g, 94%) as an oil: IR (NaCl) 2975, 1730, 1615 cm ; [R]
+
D
)
1
15.2 ° (c ) 0.92, in CHCl
3
); H NMR (250 MHz, CDCl
3
) δ
diethyl ether (10 mL) at 0 °C was added water (26 mg, 1.44
1
1
3
3
5
7
.22 (t, 3 H, J ) 7.1 Hz), 1.46-1.55 (m, 2 H), 1.63 (s, 9 H),
.66 (s, 3 H), 1.71 (s, 3 H), 2.82 (dd, 1 H, J ) 8.8 and 14.2 Hz),
.12 (dd, 1 H, J ) 5.0 and 14.2 Hz), 3.68 (d, 2 H, J ) 5.1 Hz),
.70 (m, 1 H), 3.83 (s, 3 H), 4.13 (qd, 2 H, J ) 2.1 and 7.1 Hz),
.16 (t, 1 H, J ) 5.1 Hz), 6.82 (dd, 1 H, J ) 8.5 and 2.3 Hz),
.33 (d, 1 H, J ) 8.5 Hz), 7.69 (d, 1 H, J )2.3 Hz); 13C NMR
mmol).44 The mixture was kept at 0 °C for 5 min and treated
with a solution of the pyrazine 24a (300 mg, 0.55 mmol) in
dry diethyl ether (8 mL). The solution which resulted was
allowed to warm to rt and stirred for 1.5 h. Water (10 mL)
was added to quench the reaction. The aqueous layer was
extracted with diethyl ether (3 × 30 mL). The combined
(62.90 MHz, CDCl
3
) δ 14.0, 18.0, 25.5, 26.0, 28.1, 30.4, 55.6,
organic layers were washed with brine (20 mL) and dried (K -
2
6
1
0.9, 83.5, 100.3, 111.3, 114.0, 118.5, 122.3, 123.7, 131.7, 136.6,
CO ). After removal of solvent under reduced pressure, the
3
37.0, 150.4, 157.4, 175.0; MS (EI) m/e (relative intensity) 430
crude product 31 was obtained (208 mg, 85%) via a wash
column (silica gel, EtOAc/hexane ) 9:1) and used in the next
step without further purification. 31:
+
(M , 3), 272 (36), 228 (100); exact mass calcd for C24
H
34
N
2
O
5
4
30.2468, found 430.2481. This material was employed di-
1
H NMR (300 MHz,
rectly in the next step.
CDCl ) δ 0.60 (d, 3 H, J ) 6.8 Hz), 0.91 (d, 3 H, J ) 6.9 Hz),
3
Th e cou p lin g of 2-isop r en yl-6-m eth oxytr yp top h a n (27)
w ith Tr oc-p r olin yl Ch lor id e To P r ovid e 29. To a solution
of 2-isoprenyl-6-methoxytryptophan 27 (300 mg, 0.69 mmol)
1.19 (t, 3 H, J ) 7.1 Hz), 1.30 (t, 3 H, J ) 7.1 Hz), 2.05-2.20
(m, 1 H), 3.04 (dd, 1 H, J ) 6.5 and 14.1 Hz), 3.22 (dd, 1 H, J
) 4.4 and 14.1 Hz), 3.37 (t, 1 H, J ) 3.3 Hz), 3.79 (s, 3 H),
3.98-4.33 (m, 5 H), 6.60-6.70 (m, 2 H), 7.40 (d, 1 H, J ) 8.7
in dry CH
2 2
Cl (15 mL) and triethylamine (200 mg, 2.00 mmol)
was added a solution of [[(2,2,2-trichloroethyl)oxy]carbonyl]-
Hz), 7.84 (s, br, 1 H); 13C NMR (62.90 MHz, CDCl ) δ 14.4,
3
4
3
L-prolinyl chloride 28 (321 mg, 1.05 mmol) in CH
dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h
and at rt for 2 h. The mixture was diluted with CH Cl and
washed with a 15% aqueous NaHCO solution. The aqueous
2
Cl
2
(40 mL)
16.5, 19.1, 20.6, 30.2, 31.1, 55.6, 56.5, 60.2, 60.5, 60.7, 93.9,
107.0, 109.3, 112.2, 119.9, 122.8, 136.5, 156.3, 162.6, 163.5;
2
2
MS (CI, CH ) m/e (relative intensity) 450 (M + 1, 100), 452
4
3
(M + 1, 98).
layer was extracted with CH
organic layers were dried (K
2
Cl
CO
2
(3 × 50 mL). The combined
L-6-Meth oxy-2-br om otr yp top h a n Eth yl Ester (32). To
a solution of the pyrazine 31 (100 mg, 0.222 mmol) in THF
2
3
). The solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (silica gel, hexane/ethyl acetate 2/1) to provide
(10 mL) was added an aqueous solution of 2 N HCl (10 mL) at
0
°C. The reaction mixture was allowed to warm to rt and
2
1
9 (412 mg, 84%) as an amorphous powder: IR (NaCl) 2980,
728, 1365, 1325, 1165, 1130 cm ; H NMR (250 MHz, CDCl )
3
stirred at rt for 2 h. The solution was concentrated under
reduced pressure and then diluted with water (10 mL). The
aqueous layer was extracted with CH
combined organic layer was dried (K CO
removed under reduced pressure. The residue was separated
-1 1
δ 1.11 (t, 3 H, J ) 7.1 Hz), 1.63 (s, 9 H), 1.64 (s, 3 H), 1.70 (s,
2
Cl
2
(3 × 30 mL). The
3
2
7
1
H), 1.75-2.30 (m, 6 H), 3.08 (d, 2 H, J ) 6.3 Hz), 3.45 (s, br,
H), 3.62 (d, 2 H, J ) 5.3 Hz), 3.82 (s, 3 H), 4.05 (q, 2 H, J )
.1 Hz), 4.25 (t, 1 H, J ) 7.2 Hz), 4.69 (s, br, 2 H), 5.12 (s, br
H), 6.81 (dd, 1 H, J ) 2.3 and 8.6 Hz), 7.31 (d, 1 H, J ) 8.6
2
3
), and the solvent was
by flash chromatography to provide 32 (70 mg, 92%). 32: IR
-1
27
(
NaCl) 3360, 2930, 1730, 1625 cm ; [R]
D
) +11.1 (c ) 0.7,
Hz), 7.65 (d, 1 H, J ) 2.1 Hz); MS (CI, CH
intensity) 704 (M + 1, 5), 604 (32), 528 (63), 428 (100), 228
55), 115 (86). Anal. Calcd for C32 Cl : C, 54.67; H,
.02; N 5.98. Found: C, 54.44; H, 6.16; N, 5.60.
Tr yp r osta tin A (11). A solution of indoloproline 29 (100
4
) m/e (relative
1
in CHCl
3
); H NMR (250 MHz, CDCl
3
) δ 1.20 (t, 3 H, J ) 7.2
Hz), 2.18 (s, br, 2 H), 2.94 (dd, 1 H, J ) 8.2 and 14.3 Hz), 3.17
dd, 1 H, J ) 5.2 and 14.3 Hz), 3.77 (s, 3 H), 3.83 (dd, 1 H, J
5.3 and 8.2 Hz), 4.13 (q, 2 H, J ) 7.1 Hz), 6.68 (d, 1 H, J )
.0 Hz), 6.73 (dd, 1 H, J ) 2.1 and 8.7 Hz), 7.37 (d, 1 H, J )
(
6
H
42
N
3
O
8
3
(
)
2
8
3
1
mg, 0.14 mmol) and activated Zn dust (93 mg, 1.42 mmol) in
dry MeOH (10 mL) was heated at reflux under nitrogen for 2
h. The solvent was removed under reduced pressure. The
13
.7 Hz), 8.55 (s, br, 1 H); C NMR (62.90 MHz, CDCl
1.0, 54.9, 55.7, 61.1, 94.3, 107.0, 109.9, 111.2, 118.9, 122.2,
36.8, 156.7, 175.1; MS (CI, CH ) m/e (relative intensity) 341
3
) δ 14.1,
4
residue was passed through a wash column (silica gel, CHCl
MeOH 95/5) and used directly. The dipeptide 30 was heated
neat) at 160-180 °C for 45 min. The residue was purified by
flash chromatography (silica gel, CHCl /MeOH 95/5) to afford
tryprostatin A 11 (25 mg) as a solid in 50% yield. 11: [R]
3
/
(M + 1, 24), 343 (M + 1, 22).
(
Ack n ow led gm en t. The authors thank the NIMH
3
2
7
(MH46851) for generous financial support and Professor
Hiroyuki Osada for providing authentic tryprostatin A
for comparison purposes. While this work was in
progress we learned Professor Danishefsky’s group had
D
3
8
27
)
- 65.9 (c ) 0.97, in CHCl
3
) {lit. [R]
)}; H NMR (250 MHz, CDCl
s, 3 H), 1.85-2.07 (m, 3 H), 2.27-2.34 (m, 1 H), 2.89 (dd, 1
D
) -69.7 (c ) 0.70,
1
in CHCl
3
3
) δ 1.73 (s, 3 H), 1.76
(
H, J ) 11.4 and 15.0 Hz), 3.41 (d, 2 H, J ) 7.2 Hz), 3.53-3.72
recently finished the total synthesis of tryprostatin B
(
(
m, 3 H), 3.81 (s, 3 H), 4.05 (dd, 1 H, J ) 6.9 and 7.7 Hz), 4.32
dd, 1 H, J ) 2.7 and 11.1 Hz), 5.28 (dd, 1 H, J ) 5.8 and 8.6
45
(
2). We thank Professor Danishefsky for sharing this
information prior to publication.
Hz), 5.61 (s, 1 H), 6.74 (dd, 1 H, J ) 2.2 and 8.6 Hz), 6.81 (d,
1
H, J ) 2.1 Hz), 7.32 (d, 1 H, J ) 8.6 Hz), 7.80 (s, br, 1 H);
J O971640W