Preparation of 7-halo-indoles by thallation of N-formylindoline and their attempted use for synthesis of the right-hand segment of chloropeptin

Article abstract of DOI:10.1248/cpb.54.788

7-Substituted (Cl, Br, I) indoles were synthesized by using thallation of N-formylindoline as a key reaction. Two precursor tripeptides for the right-hand segment of chloropeptin were synthesized by using (R)-7′-iodo and 7′-bromotryptophans derived from each 7-substituted indole (I, Br) obtained by the above procedure.

Full text of DOI:10.1248/cpb.54.788

788
Chem. Pharm. Bull. 54(6) 788—794 (2006)
Vol. 54, No. 6
Preparation of 7-Halo-indoles by Thallation of N-Formylindoline and
Their Attempted Use for Synthesis of the Right-Hand Segment of
Chloropeptin
Yaeko YAMADA,* Shiho ARIMA, Chiharu OKADA, Ai AKIBA, Toshitsugu KAI, and Yoshihiro HARIGAYA
School of Pharmaceutical Sciences, Kitasato University; 5–9–1 Shirokane, Minato-ku, 108–8641 Tokyo, Japan.
Received November 14, 2005; accepted February 28, 2006; published online March 8, 2006
7-Substituted (Cl, Br, I) indoles were synthesized by using thallation of N-formylindoline as a key reaction.
Two precursor tripeptides for the right-hand segment of chloropeptin were synthesized by using (R)-7ꢀ-iodo and
7ꢀ-bromotryptophans derived from each 7-substituted indole (I, Br) obtained by the above procedure.
Key words 7-substituted indole; thallation; formyl group; tripeptide
In 1994, choropeptin (1)1) was isolated by Matsuzaki et al. formylindoline as a key reaction and also their conversion to
from Streptomyces sp. WK-3490 together with complestatin the (R)-7ꢀ-substituted tryptophan using our method already
(2) both as inhibitors of gp120-CD4 receptor (concentration reported6) are described. Next, an effective synthesis of two
causing 50% inhibition (IC50) values of 2.0 and 3.3 mM for precursor tripeptides for 3 is described by using the obtained
1 and 2, respectively). The absolute stereostructure of (R)-7ꢀ-bromo and 7ꢀ-iodotryptophan.
chloropeptin was determined in 19962) by combination of
acid hydrolysis, molecular dynamics and NMR spectroscopy. Results and Discussion
It is a bismacrocyclic heptapeptide having a biaryl ether and
At first, effective synthesis of 7-substituted indoles was
biphenyl moiety. Because of its unique structure together performed. The direct introduction of halogen into a trypto-
with interesting biological activity, 1, 2 and related com- phan at the position of 2ꢀ and 5ꢀ-C was already reported7);
pounds are an attractive target for synthesis. In 2003, Hov- however, selective halogenation directly at the position of 7ꢀ-
eyda et al. first reported an elegant total synthesis of 1.3)
C in tryptophan has not been reported. We planned the pro-
We have been interested in the synthesis of 1 and 2 and al- cedure for (R)-7ꢀ-substituted tryptophan using 7-substituted
ready reported4) a synthesis of the left-hand segment of 1 and indole. Connection of a serine with it should give racemic N-
2 and also synthesis of linear tripeptides which are key inter- acetyl-7ꢀ-substituted tryptophan, which should be followed
mediates for the right-hand segment of 2.5) Now, we are by enzymatic resolution by D-aminoacylase6) to afford (R)-7ꢀ-
working to develop a route for the right-hand segment of 1. substituted tryptophan.
We planned the synthesis of 3 as the right-hand segment of 1.
The synthetic procedure of the 7-substituted indoles is as
Compound 3 is a 16-membered macrocyclic lactam con- follows. 7-Substituted indoles were already synthesized by
sisted of (R)-4ꢀ-hydroxy-3ꢀ,5ꢀ-dichlorophenylglycine (E- Somei et al.8,9) using N-acetyl indoline as a starting material
ring), (R)-tryptophan (F-ring), (R)-4ꢀ-hydroxyphenylglycine and carrying out the thallation of it as a key reaction, fol-
(D-ring), and the D, E-rings and E, F-rings are each con- lowed by substitution reaction with halogen, removal of the
nected by a peptide bond whereas, the D, F rings are con- acetyl group, dehydrogenation to afford halogeno indoles.
nected by a biaryl bond (Fig. 1).
Our procedure for 7-substituted indoles is a modification of
The success of the synthesis of 3 depends upon how to get the Somei method using N-formylindoline.
the (R)-7ꢀ-substituted tryptophan and how to connect the D,
Considerable synthetic utility of thallium trifluoroacetate
F rings by biaryl coupling. In this paper, at first, an effective (TTFA) in organic chemistry has been reported up to date.10)
route for the 7-substituted indoles by using thallation of N- Among them, there is an attractive report, in which Taylor et
al.11) found that high ortho thallation occurred in substituted
aromatic compounds such as benzoic acid, methyl benzoate.
Also, they reported their use of the resulting arylthallium
ditrifluoroacetates with aqueous KI giving selectively ortho
substituted aryl iodide (Fig. 2). Somei et al.8,9) also reported
a regioselective synthetic method for 7-halogenoindoles by
thallation at the 7-C position with TTFA chelating to an N-
acetyl carbonyl group (Fig. 2). However, when the carbonyl
Fig. 1
Fig. 2
∗ To whom correspondence should be addressed. e-mail: yamadaky@violet.plala.or.jp
© 2006 Pharmaceutical Society of Japan

June 2006
789
Chart 1. Synthesis of 7-Chloro, Bromo and Iodoindoles
group of N-acetyl is used for thallation, strong reaction con-
dition is required for removal of the acetyl group, such as a
strong base (40% NaOH).9) The selection of the functional
group is important for effective use of this thallation method
as a key reaction. Various functional groups such as COOH,
COOMe, CH2OH were used for regioselective thallation of
substituted benzenes in the literature.11) However, the formyl
group, which is expected more easily to be removed, has not
been used as a functional group for thallation up to date, so
we examined use of the N-formyl group to perform selective
thallation at 7ꢀ-C in indoline to obtain 7-substituted indolines
(Chart 1).
Chart 2. Synthesis of (R)-N-Cbz-7ꢀ-iodotryptophan
Three halogens (I, Br, Cl) and a hydroxyl group were ex-
amined to obtain 7-substituted indoles by thallation of N-
formylindoline and successive synthesis of 7-iodo, bromo,
chloro indoles was achieved as shown in Chart 1.
7-Bromoindole (8b) was obtained as follows. Indoline (3)
was treated by HCOOH12) and EDCI (1-(3-Dimethylamino-
propyl)-3-ethylcarbodiimide) in pyridine to give N-formyl
derivative 4 in 94% yield. Thallation was performed by
Chart 3. Determination of Optical Purity of (R)-7ꢀ-Iodotryptophan ((R)-
11c)
adding TTFA to the solution of 4 in TFA (trifluoroaceticic functional group for thallation.
acid) to afford thallium complex 5, which was treated with
Next, preparation of the (R)-7ꢀ-halogenotryptophan from
CuBr2 in DMF at 135 °C to give the bromide 6b in 73% yield 7-halogenoindole was carried out. The synthesis of (R)-7ꢀ-
from 4. Alkaline hydrolysis of 6b by 20% NaOH at 80 °C for bromotryptophan ((R)-10b) and its Cbz derivative ((R)-11b)
30 min afforded indoline 7b in 94% yield. Dehydrogenation was already reported by us6) by using enzymatic resolution
of 7b was carried out under a stream of oxygen gas in the by D-aminoacylase and its procedure is shown in Chart 2. In
presence of salcomine9) as a catalyst to give 7-bromoindole this paper, (R)-7ꢀ-iodotryptophan was prepared according to
(8b) in 79% yield (total yield from 3: 54%). 7-Chloroindole our procedure.6) Addition of L-serine to 8c in the presence of
(8a) was obtained from 4 in a similar manner except for Ac2O in AcOH gave racemic N-acetyl tryptophan ((RS)-9c)
using CuCl2 at the step of the substitution reaction in 46% in 84% yield. This was treated with D-aminoacylase in the
total yield from 4. 7-Iodoindole (8c) was also prepared in a presence of CoCl2 as a co-enzyme in phosphate buffer at pH
similar manner as the above procedure. In this case, KI was 7.4 to provide (R)-7ꢀ-iodotryptophan ((R)-10c, 45%) and (S)-
used at the step of the substitution reaction using H2O as a 9c (46%).
solvent and 10% NaOH was used at the step of the removal
The amino group of (R)-10c was protected by treatment
of the formyl group with ease. Thus the formyl group was re- with carbobenzyloxy chloride (Cbz-Cl) and 10% Na2CO3 in
moved more easily than an acetyl group (40% NaOH)9) and it aqueous ether solution to afford (R)-11c in 88% yield (Chart
will be removed with much more mild conditions using a 2).
weak base such as NaHCO3 according to the literature.12)
Optical purity of (R)-10c was determined according to our
Using the formyl group on thallation will serve to enlarge the recent report procedure same as (R)-7ꢀ-bromotryptophan6)
utility of its method in compounds having an alkaline-sensi- and (R)-6ꢀ-iodotryptophan5) (Chart 3). Compound (R)-11c
tive functional group other than indolines.
was condensed with (R)-(ꢁ)-phenylethylamine using DECI
Next, synthesis of 7-hydroxyindole was examined accord- and hydroxy-benzotriazole (HOBT) to afford amide (R)-12c
ing to the procedure in a literature.13) Thallated complex 5 as a single product in 65% yield and none of its diastereomer
obtained from
4 in a similar way was treated by (S)-12c was obtained. Compound (S)-12c was synthesized as
CuSO4·5H2O in DMF–H2O to afford 6d in low yield (25%), follows. Enzymatic optical resolution of (RS)-9c using L-
which resulted in stopping further examination. Thus, three aminoacylase in a similar way to D-aminoacylase afforded
7-halogenoindoles were obtained using a formyl group as a (S)-10c in 45% yield, which was converted to Cbz derivative

790
Vol. 54, No. 6
Chart 4. Synthesis of Tripeptide 16
Chart 5. Synthesis of Tripeptide 22
(S)-11c in 86% yield, then this was transformed into formed according to the procedure15) however, cyclic product
phenylethylamide (S)-12c in 59% yield. These results proved 3 could not be obtained in spite of alternation of the amount
enzymatic resolution proceeded enantiomerically to give op- of the catalyst (0.04—1.8 eqivalent), solvent (DMF, THF,
tically pure amino acid (R)-10c, which is the same case as HMPA), regretively. More reactive condition should be
that of 6ꢀ-iodotryptophan5), 6ꢀ-bromo and 7ꢀ-bromotrypto- needed to achieve carbon–carbon coupling between biaryl
phan.6) Thus a new amino acid (R)-10c was obtained effec- halide of 16, because fairly strong steric interaction between
tively.
the tryptophan moiety and phenylglycine is considered. Next,
Next, synthesis of two precursors (16), (22) for the right- another precursor 22 for 3 was planned as shown in Chart 5.
hand segment of cholopeptin by using the amino acid (R)- The precursor 22 should be utilized for macrocyclic lac-
11b and (R)-11c was examined. The synthesis of 16 from tamization at the last step to provide 3. The precursor 22 was
(R)-11b was performed as shown in Chart 4. The precursor prepared by using (R)-11c. The reason for using 7ꢀ-iodotryp-
16 should be utilized for 3 by biaryl coupling using organic tophan is that aryl iodide is a more strong coupling reagent
metals as a catalyst. Dipeptide 15 was already obtained by us than aryl bromide in Stille coupling. The synthesis of 3ꢀ,5ꢀ-
using compound 13 and 14.5) The synthetic method and de- dichlorophenylglycine tert-butyl ester (17) was already re-
tailed experimental procedure of compounds 13, 14 and 15 ported by us.5) Connection of 17 to (R)-11c by using FDPP in
i
were already described in our preliminary paper.5) The Boc the presence of Pr2NEt provided dipeptide 18 in 56% yield.
group of dipeptide 15 was removed by TFA, followed by The phenol was protected to afford methyl ether 19 by TM-
neutralization with NMM (N-methylmorpholine) to afford a SCHN2 in 94% yield. The synthesis of tributylstanann deriv-
dipeptideamine as an intermediate, which was condensed ative 20, which is a key compound for Stille coupling, was
with (R)-11b by treatment with EDCI and HOBT (hydroxy also already described in our paper.5) Coupling reaction be-
benzotriazole) to give tripeptide 16 in 76% total yield from tween 20 and 19 was carried out at the condition of Stille
5,16,17)
15. Intramolecular carbon–carbon couplings between biaryl coupling using Pd2(dba)3·CHCl3
as a catalyst, CuI, as
i
halide by using an organometalic catalyst of Ni such as an additive, Ph3As as a ligand, Pr2NEt as a base to give
(Ph3P)2NiCl2 were successively achieved for the synthesis of biarylic tripeptide 21 in 39% yield, successively. The Boc
Vancomycin14) and a model compound in Kistamycin.15) In- group of 21 was removed by TFA–CHCl3 solution (1 : 1) to
tramolecular cyclization of a precursor 16 using (Ph3P)2NiCl2 provide a precursor 22 for 3 quantitatively. Detailed examina-
as a catalyst, Zn as an additive and Ph3P as a ligand was per- tion of the reaction condition should be needed for macrolac-

June 2006
791
MeOH (19 ml) was added 20% aqueous solution of NaOH (19 ml) and the
mixture was stirred for 30 min at 75 °C. After the reaction mixture was
cooled to room temperature, it was diluted with water (50 ml), extracted with
CHCl3 (50 mlꢂ2). The organic layer was washed with saturated NaCl
(50 ml), dried over Na2SO4, concentrated in vacuo to afford 7b (465 mg,
tamization, which is a subject for future study.
In conclusion, 7-substituted (Cl, Br, I) indoles were syn-
thesized using thallation of N-formylindoline as a key reac-
tion according to a modified procedure in the literature. In
this paper, the formyl group was newly proved to be a useful 94%) as light brown oil. Rf: 0.72 (hexane/AcOEtꢃ2 : 1). IR (CHCl3) nmax
cmꢄ1: 530 (Ar-Br), 1505, 1610 (arom), 3450 (NH). 1H-NMR (300 MHz) dH:
functional group for thallation. In addition, two precursor
tripeptides for the right-hand segment of chloropeptin were
synthesized by using 7-iodo and 7ꢀ-bromotryptophans de-
rived from each 7ꢀ-substituted indole (I, Br) which were ob-
tained by the above procedure.
3.14 (2H, t, Jꢃ8.5 Hz, 3-H2), 3.61 (2H, t, Jꢃ8.5 Hz, 2-H2), 6.56 (1H, t,
Jꢃ7.5 Hz, 5-H), 7.02 (1H, dt, Jꢃ7.5, 1.0 Hz, 4-H), 7.15 (1H, dd, Jꢃ1.0,
7.5 Hz, 6-H), 7.40 (1H, s, 1-H). 13C-NMR (100 MHz) dC: 150.09 (s, 7a-C),
130.49 (s, 3a-C), 129.78 (d, 6-C), 123.35 (d, 4-C), 119.612 (d, 5-C), 103.21
(s, 7-C), 46,70 (t, 2-C), 30.85 (t, 3-C). HR-EI-MS m/z: 196.9840 [M]ꢁ,
Calcd for C8H8NBr79: 196.9824 [M].
Experimental
7-Bromoindole (8b) To a solution of 7b (1.24 g, 6.30 mmol) in MeOH
General Procedures Melting points were taken on a Yanagimoto hot- (250 ml) was added salcomine (205 mg, 0.630 mmol). After the solution was
stage and are uncorrected. Optical rotations were measured on a JASCO stirred in a stream of oxygen gas for 3 h at room temperature, the reaction
model DPI-1000 digital polarimeter. 1H- and 13C-NMR were recorded on mixture was concentrated in vacuo to provide a black oil (1.12 g), which was
Varian VXR-300, Varian MERCURY plus 300 and UNITY-400 spectrome- purified by flash column chromatography (hexane/AcOEtꢃ20 : 1) to give 8b
ters. All the NMR spectra were taken using CDCl3 as a solvent unless other- (1.69 g, 73%) as light purple crystals Rf: 0.56 (hexane/AcOEtꢃ3 : 1). mp:
wise described. The signals were assigned by 1H–1H COSY, DEPT, HMQC, 45—48 °C (CHCl3) (lit.9): 42—43 °C). IR (KBr) nmax cmꢄ1: 510, 580 (Ar-
1
HMBC experiments. Mass spectra were obtained on JEOL JMS-AX505 H, Br), 1580, 1620 (arom), 3420 (NH). H-NMR (400 MHz) dH: 6.66 (1H, dd,
JEOL JMS-DX300 mass spectrometer (low-resolution mass spectrometry) Jꢃ2.0, 3.0 Hz, 3-H), 7.04 (1H, t, Jꢃ7.5 Hz, 5-H), 7.25 (1H, t, Jꢃ3.0 Hz, 2-
and JEOL JMS-AX505 HA mass spectrometer (high-resolution mass spec-
H), 7.39 (1H, d, Jꢃ7.5 Hz, 4-H), 7.63 (1H, d, Jꢃ7.5 Hz, 6-H), 8.33 (1H, br s,
trometry). Rf values and preparative TLC were done on Silica gel 60 PF254 1-H). 13C-NMR (100 MHz) dC: 103.79 (d, 2-C), 104.61 (s, 7-C), 119.91 (d,
(Merck). Flash column chromatography was done using Silica gel 60 6-C), 120.95 (d, 5-C), 124.28 (d, 4-C), 124.65 (d, 3-C), 128.96 (s, 3a-C),
(art.1.09385, Merck). 2 M Solution in n-hexane (Aldrich) was used for
TMSCHN2.
134.53 (s, 7a-C). HR-EI-MS m/z: 194.9680 [M]ꢁ, Calcd for C8H6NBr79:
194.9684 [M].
The abbreviations used in NMR data are as follows CHPG: 3ꢀ,5ꢀ-dichloro-
7-Chloro-N-formylindoline (6a) To a solution of 4 (502 mg, 3.40
4ꢀ-hydroxy-phenylglycine; IHPG: 3ꢀ,5ꢀ-dichloro-4ꢀ-hydroxyphenylglycine; mmol) in TFA (16.5 ml) was added a solution of TTFA (3.7 g, 6.80
Trp: tryptophan.
mmol) in TFA (8.5 ml) dropwise during 20 min under argon. After the mix-
ture was stirred for 24 h at room temperature, the reaction mixture was con-
centrated in vacuo by azeotropic distillation with a solution of benzene
(20 mlꢂ3) and 1,2-dichloroethane (20 mlꢂ3) to provide 5 as a black tarry
N-Formylindoline (4) To a solution of EDCI (16.1 g, 84.0 mmol) in
CHCl3 (45 ml) was added formic acid (7.73 ml, 168 mmol) dropwise at 0 °C
under argon. After the mixture was stirred for 5 min, a solution of 3 (5.0 g,
42.0 mmol) in pyridine (30 ml) was added dropwise during 30 min, then oil. After the residue was dissolved in DMF (15 ml), CuCl2 (1.83 g,
the temperature was raised to room temperature. After the mixture was 13.6 mmol) was added to the mixture. After the mixture was stirred for 24 h
stirred for 24 h, it was concentrated in vacuo to remove pyridine by azeo- at room temperature, further it was stirred for 30 min at 120—150 °C, 6 h at
tropic distillation with benzene (35 mlꢂ4). The residue was dissolved in 60—70 °C, then stirred for 22 h at room temperature under argon. The reac-
CHCl3 (500 ml) and the solution was washed with saturated NaCl tion mixture was concentrated in vacuo and the residue was dissolved in a
(100 mlꢂ3), dried over Na2SO4, evaporated in vacuo. Resulting red-
purple residue (7.15 g) was purified by flash column chromatography tered off through celite pad. After the filtrate was partitioned in organic and
(hexane/AcOEtꢃ3 : 1→2 : 1) to give 4 (5.81 g, 94%) as red-purple crystals.
water layers, the organic layer was washed with saturated NaCl (20 mlꢂ3),
Rf: 0.33 (hexane/AcOEtꢃ2 : 1). mp: 64—65 °C (CHCl3) (lit.18): 62—63 °C) dried over Na2SO4, concentrated in vacuo. The resulting residue was purified
IR (KBr) nmax cmꢄ1 1500, 1600 (arom), 1660 (NCHO). 1H-NMR by flash column chromatography (hexane/AcOEtꢃ5 : 1) to give 6a (392 mg,
(300 MHz) dH: 3.15, 3.18 (total 2H, t, Jꢃ8.5 Hz, 3-H2), 4.05, 4.11 (total 2H,
63%) as light yellow crystals. Rf: 0.30 (hexane/AcOEtꢃ2 : 1). mp: 116—
mixture of CHCl3/MeOHꢃ95 : 5 (100 ml) and saturated NaCl (10 ml), fil-
:
t, Jꢃ8.5 Hz, 2-H2), 7.01—7.09, 7.15—7.26 (4H, m, arom-H), 8.51, 8.92 118 °C (CHCl3). 1H-NMR (300 MHz) dH: 3.14 (2H, t, Jꢃ8.5 Hz, 3-H2), 4.15
(total 1H, s, CHO). HR-EI-MS m/z: 147.0684 [M]ꢁ, Calcd for C9H9ON:
147.0684 [M].
7-Bromo-N-formylindoline (6b) To a solution of 4 (1.50 g, 10.2 mmol)
(2H, dt, Jꢃ1.0, 8.5 Hz, 2-H2), 6.95 (1H, t, Jꢃ8.0 Hz, 5-H), 7.12 (1H, dq,
Jꢃ8.0, 1.0 Hz, 4-H), 7.18 (1H, dd, Jꢃ1.0, 8.0 Hz, 6-H), 9.63 (1H, s, CHO).
13C-NMR (100 MHz) dC: 27.62 (t, 3-C), 45.54 (t, 2-C), 118.35 (s, 7-C),
in TFA (10 ml) was added a solution of TTFA (13.9 g, 25.5 mmol) in TFA 124.15 (d, 4-C), 124.55 (d, 5-C), 129.65 (d, 6-C), 135.80 (s, 3a-C), 137.75
(25 ml) dropwise during 30 min under argon. After the mixture was stirred (s, 7a-C), 160.53 (s, CHO). HR-FAB-MS m/z: 182.0364 [M]ꢁ, Calcd for
for 6 h at room temperature, further solution of TTFA (1.42 g, 2.60 mmol) in
TFA (5 ml) was added to this mixture and this was stirred for 5 h. The reac-
C9H9ONCl35: 182.0373 [M].
7-Chloroindoline (7a) To a solution of 6a (765 mg, 0.17 mmol) in
tion mixture was concentrated in vacuo by azeotropic distillation with a so- MeOH (30 ml) was added 20% aqueous solution of NaOH (30 ml) and the
lution of benzene (30 mlꢂ3) and 1,2-dichloroethane (30 mlꢂ3) to provide 5
as black tarry oil. The residue was dissolved in DMF (40 ml), then CuBr2
(9.11 g, 40.8 mmol) was added. After the mixture was stirred for 2 h at
solution was stirred for 30 min at 80 °C. After the reaction mixture was
cooled to room temperature, it was diluted with water (200 ml), extracted
with CHCl3 (200 mlꢂ3). The organic layer was washed with saturated
135 °C, the reaction mixture was concentrated in vacuo. The residue was NaCl (100 mlꢂ2), dried over Na2SO4, concentrated in vacuo. Resulting
dissolved in a mixture of CHCl3/MeOHꢃ95 : 5 (500 ml) and saturated NaCl
residue was purified by flash column chromatography (hexane/AcOEtꢃ
(20 ml), then the mixture was filtered off through celite pad. After the filtrate 20 : 1) to afford 7a (465 mg, 94%) as light peach crystals. Rf: 0.59
was partitioned in an organic layer and a water layer, the organic layer was (hexane/AcOEtꢃ2 : 1). mp 41—42 °C (CHCl3 : MeOHꢃ10 : 1). 1H-NMR
washed with saturated NaCl (50 mlꢂ2). The water layer was extracted with (300 MHz) dH: 3.11 (2H, t, Jꢃ8.5 Hz, 3-H2), 3.62 (2H, t, Jꢃ8.5 Hz, 2-H2),
CHCl3 (50 ml). The combined organic layer was dried over Na2SO4, concen-
6.52 (1H, t, Jꢃ7.5 Hz, 5-H), 6.99 (1H, dd, Jꢃ7.5, 1.0 Hz, 4-H), 7.01 (1H,
trated in vacuo to give a brown oil (13.7 g). The oil was purified by flash col- dd, Jꢃ1.0, 7.5 Hz, 6-H), 7.40 (1H, s, 1-H). HR-EI-MS m/z: 153.0341 [M]ꢁ,
umn chromatography (hexane/AcOEtꢃ7 : 1→2 : 1) to give 6b (1.69 g, 73%)
as yellow crystals. Rf: 0.27 (hexane/AcOEtꢃ2 : 1). mp: 53—54 °C (CHCl3).
Calcd for C8H8NCl35: 153.0341 [M].
7-Chloroindole (8a) To a solution of 7a (509 mg, 3.32 mmol) in MeOH
IR (KBr) nmax cmꢄ1: 550 (Ar-Br), 1500, 1600 (arom), 1660 (NCHO). 1H- (32 ml) was added salcomine (107 mg, 0.33 mmol). After the mixture was
NMR (300 MHz) dH: 3.11 (2H, t, Jꢃ8.0 Hz, 3-H2), 4.15 (2H, dt, Jꢃ1.0, stirred in a stream of oxygen gas for 24 h at room temperature, the reaction
8.0 Hz, 2-H2), 6.90 (1H, t, Jꢃ7.9 Hz, 5-H), 7.19 (1H, dq, Jꢃ7.9, 1.2 Hz, 4- mixture was concentrated in vacuo. Resulting residue was purified by flash
H), 7.38 (1H, dd, Jꢃ1.2, 7.9 Hz, 6-H), 9.73 (1H, s, CHO). 13C-NMR column chromatography (hexane/AcOEtꢃ20 : 1) to give 8a (470 mg, 94%)
(100 MHz) dC: 160.421 (d, N-CHO), 139.431 (s, 7a-C), 136.320 (s, 3a-C),
as light purple crystals Rf: 0.63 (hexane/AcOEtꢃ3 : 1). mp: 57—58 °C
132.869 (d, 6-C), 125.048 (d, 5-C), 124.669 (d, 4-C), 105.704 (s, 7-C), (CHCl3) (lit.9): 59.0—59.5 °C (hexane)). IR (KBr) nmax cmꢄ1: 740, 780 (Ar-
45.639 (t, 2-C), 27.911 (t, 3-C). HR-FAB-MS m/z: 224.9789 [M]ꢁ, Calcd for Cl), 1480, 1560 (arom), 3400 (NH). H-NMR (400 MHz) dH: 6.59 (1H, dd,
1
C9H8ONBr79: 224.9776 [M].
Jꢃ2.5, 3.5 Hz, 3-H), 7.04 (1H, t, Jꢃ8.0 Hz, 5-H), 7.18, 7.54 (each 1H, dd,
Jꢃ1.0, 8.0 Hz, 4-H, 6-H), 7.26 (1H, d, Jꢃ3.5 Hz, 2-H), 8.54 (1H, br, 1-H).
7-Bromoindoline (7b) To a solution of 6b (564 mg, 2.50 mmol) in

792
Vol. 54, No. 6
HR-EI-MS m/z: 151.0196 [M]ꢁ, Calcd for C8H6NCl35: 51.0189 [M].
N-Formyl-7-iodoindoline (6c) A mixture of 4 (1.00 g, 6.80 mmol) and
TTFA (7.3 g, 13.6 mmol) in TFA (28 ml) was stirred for 24 h under argon at
room temperature. The reaction mixture was concentrated in vacuo by
azeotropic distillation with benzene (10 mlꢂ5) to provide 5 as tarry oil. The
residue was dissolved in a solution of KI (9.06 g, 54.4 mmol) in H2O
(32.6 ml) and the mixture was stirred for 1 h at room temperature. The reac-
tion mixture was dissolved in a solution of CH2Cl2/MeOHꢃ95 : 5 (600 ml)
and filtered off through celite pad. The filtrate was partitioned in organic and
water layers. After the water layer was extracted with CH2Cl2 (100 mlꢂ4),
combined organic layer was washed with 10% Na2S2O3 (100 mlꢂ2), satu-
rated NaCl (100 ml), dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (hexane/AcOEtꢃ
5 : 1→3 : 1) to give 6c (1.56 g, 62%) as light brown crystals. Rf: 0.36
(hexane/AcOEtꢃ2 : 1). mp: 99 °C. 1H-NMR (400 MHz) dH: 3.08 (2H, t,
Jꢃ8.0 Hz, 3-H2), 4.16 (2H, t, Jꢃ8.0 Hz, 2-H2), 6.77 (1H, t, Jꢃ7.5 Hz, 5-H),
7.22 (1H, dq, Jꢃ7.5, 1.0 Hz, 4-H), 7.64 (1H, dd, Jꢃ1.0, 7.5 Hz, 6-H), 9.74
(1H, s, CHO). 13C-NMR (100 MHz) dC: 28.39 (t, 3-C), 45.75 (t, 2-C), 76.00
(s, 7-C), 125.46 (d, 4-C), 125.86 (d, 5-C), 136.33 (s, 3a-C), 139.45 (d, 6-C),
142.98 (s, 7a-C), 160.42 (d, CHO). HR-FAB-MS m/z: 273.9752 [MꢁH]ꢁ,
Calcd for C9H9ONI: 273.9729 [MꢁH].
7-Iodoinoline (7c) To a solution of 6c (463 mg, 1.7 mmol) in MeOH
(14 ml) was added 10% aqueous NaOH (14 ml) and the mixture was stirred
for 30 min at room temperature. The reaction mixture was cooled to room
temperature, then diluted with H2O (30 ml). The solution was extracted with
CHCl3 (36 mlꢂ2) and the organic layer was washed with NaCl (36.0 ml),
dried over Na2SO4, concentrated in vacuo to afford 7c (376 mg, 91%) as
light yellow oil. Rf: 0.60 (hexane/AcOEtꢃ2 : 1). 1H-NMR (300 MHz) dH:
3.14 (2H, t, Jꢃ8.5 Hz, 3-H2), 4.16 (2H, t, Jꢃ8.0 Hz, 2-H2), 6.56 (1H, t,
Jꢃ7.5 Hz, 5-H), 7.02 (1H, dt, Jꢃ1.0, 7.5 Hz, 4-H), 7.15 (1H, dd, Jꢃ1.0,
7.5 Hz, 6-H), 7.40 (1H, s, 1-H). HR-FAB-MS m/z: 244.9702 [M]ꢁ, Calcd for
C8H8NI: 244.9709 [M].
into organic and water layers. The water layer was ice-cooled and the or-
ganic layer was extracted with 1 N aqueous NaOH (35 mlꢂ2). After the com-
bined alkaline water layer was ice-cooled, Na2S2O4 (50 mg) was added to
this solution, which was neutralized with 5% HCl, and was concentrated in
vacuo until precipitates were separated out, then the mixture was allowed to
stand for overnight in refrigerator. The precipitates were filtered off to afford
(R,S)-9c (1.60 g, 84%) as white crystals. The organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification of the residue by preparative
TLC (CHCl3/MeOHꢃ30 : 1) gave starting material 8c (86 mg).
(R,S)-9c Rf: 0.7 (butanol/AcOH/H2Oꢃ4 : 1 : 5). mp: 215—220 °C. 1H-
NMR (300 MHz, acetone-d6) dH: 1.91 (3H, s, COCH3), 3.18 (1H, dd, Jꢃ7.5,
15.0 Hz, 3-Ha), 3.32 (1H, dd, Jꢃ5.0, 15.0 Hz, 3-Hb), 4.80 (1H, dt, Jꢃ5.0,
7.5 Hz, 2-H), 6.88 (1H, t, Jꢃ7.5 Hz, 5ꢀ-H), 7.27 (1H, br, NHCO), 7.30 (1H,
d, Jꢃ2.5 Hz, 2ꢀ-H), 7.53 (1H, d, Jꢃ7.5 Hz, 6ꢀ-H), 7.66 (1H, d, Jꢃ7.5 Hz, 4ꢀ-
H), 10.02 (1H, br s, 1ꢀ-H). 13C-NMR (75 MHz, acetone-d6) dC: 22.66 (q,
COCH3), 28.28 (t, 3-C), 53.62 (d, 2-C), 76.56 (7ꢀ-C), 112.83 (s, 3ꢀ-C),
119.68 (d, 4ꢀ-C), 121.47 (d, 5ꢀ-C), 121.55 (d, 2ꢀ-C), 125.06 (d, 6ꢀ-C), 129.23
(s, 3aꢀ-C), 131.18 (d, 7aꢀ-C), 170.09 (s, COCH3), 173.35 (s, 1-C). HR-FAB-
MS m/z: 373.0055 [MꢁH]ꢁ, Calcd for C13H14O3N2I: 373.0049 [MꢁH].
(R)-7ꢀ-Iodotryptophan ((R)-10c) To
a solution of (RS)-9c (1.8 g,
4.84 mmol) and D-aminoacylase (578 g) in phosphate buffer (227 ml, pH 7.4)
was added CoCl2·6H2O (3 mg). After the solution was shaken for 24 h at
37 °C, the reaction mixture was adjusted at pH 5 with 1 N HCl, then filtered
off through celite pad. The filtrate was extracted with AcOEt (400 mlꢂ3)
and the organic layer was dried over Na2SO4, concentrated in vacuo to afford
(S)-9c (482 mg, 46%). The water layer was purified by column chromatogra-
phy (SEPABEADS SP207, H2O: 1 l→MeOH: 2 l) to provide (R)-10c
(717 mg, 45%) as white powder.
(R)-10c Rf: 0.41 (butanol/AcOH/H2Oꢃ4 : 1 : 5). mp: 175—179 °C. [a]D20
1
ꢁ9.25° (cꢃ0.50, MeOH). H-NMR (300 MHz, CD3OD) dH: 3.16 (1H, dd,
Jꢃ8.5, 15.5 Hz, 3-Ha), 3.48 (1H, dd, Jꢃ4.5, 15.5 Hz, 3-Hb), 3.85 (1H, dt,
Jꢃ4.5, 9.0 Hz, 2-H), 6.85 (1H, t, Jꢃ7.5 Hz, 5ꢀ-H), 7.29 (1H, s, 2ꢀ-H), 7.51
(1H, d, Jꢃ7.5 Hz, 6ꢀ-H), 7.73 (1H, d, Jꢃ7.5 Hz, 4ꢀ-H). 13C-NMR (75 MHz,
CD3OD) dC: 28.55 (t, 3-C), 56.58 (d, 2-C), 76.83 (s, 7ꢀ-C), 111.19 (s, 3ꢀ-C),
119.72 (d, 4ꢀ-C), 121.84 (d, 5ꢀ-C), 126.12 (d, 6ꢀ-C), 128.99 (s, 3aꢀ-C),
131.90 (d, 6ꢀ-C), 131.90 (s, 7aꢀ-C), 174.28 (s, 1-C). HR-FAB-MS m/z:
352.9774 [MꢁNa]ꢁ, Calcd for C11H11O2N2INa: 353.0049 [MꢁNa].
(R)-N-Carbobenzyloxy-7ꢀ-iodotryptophan ((R)-11c) To a solution of
(R)-10c (225 mg, 0.64 mmol) in 10% aqueous Na2CO3 (4.0 ml) was added
Cbz-Cl (145 mg, 0.85 mmol) in ether (0.2 ml). After the mixture was stirred
for 1.25 h at 0 °C, it was acidified with 10% HCl (pH 3). Resulting precip-
tates were filtered off, washed with water (2 mlꢂ2) and dried to provide (R)-
11c (258.6 mg, 88%) as white crystals. Rf: 0.75 (butanol/AcOH/H2Oꢃ
4 : 1 : 5). mp: 122—124 °C. [a]D27 ꢄ22.13° (cꢃ0.47, acetone). 1H-NMR
(300 MHz, acetone-d6) dH: 3.22 (1H, d, Jꢃ8.5, 15.0 Hz, 3-Ha), 3.38 (1H, dd,
Jꢃ5.0, 15.0 Hz, 3-Hb), 4.63 (1H, s, 2-H), 5.04 (2H, s, benzyl-CH2), 6.83
(1H, t, Jꢃ7.5 Hz, 5ꢀ-H), 7.20—7.46 (8H, m, benzyl-arom-5H, NHCO, 1ꢀ-H,
2ꢀ-H), 7.53 (1H, d, Jꢃ7.5 Hz, 6ꢀ-H), 7.68 (1H, d, Jꢃ7.5 Hz, 4ꢀ-H). HR-
FAB-MS m/z: 464.0211 [M]ꢁ, Calcd for C19H17O4N2I: 464.0233 [M].
(S)-7ꢀ-Iodotryptophan ((S)-10c) To a solution of (RS)-9c (300 mg,
0.806 mmol) in phosphate buffer (38 ml, pH 7.4) were added L-aminoacylase
(96.3 mg), CoCl2·6H2O (9.2 mg). After the solution was shaken for 24 h at
37 °C, the reaction mixture was adjusted at pH 5 with 1 N HCl, then filtered
off through celite pad. The filtrate was extracted with AcOEt (70 mlꢂ3).
The water layer was purified by column chromatography (SEPABEADS
SP207, H2O: 300 ml→MeOH: 600 ml) to provide (S)-10c (120 mg, 45%) as
white powder. Rf: 0.41 (butanol/AcOH/H2Oꢃ4 : 1 : 5). mp: 240—242 °C.
[a]D20 ꢄ7.50° (cꢃ0.13, MeOH). HR-FAB-MS m/z: 330.9946 [MꢁH]ꢁ,
Calcd for C11H12O2N2I: 353.9944 [MꢁH]. 1H-NMR data were identical with
that of (R)-10c.
7-Iodoindole (8c) To a solution of 7c (695 mg, 2.83 mmol) in MeOH
(90.4 ml) was added salcomine (93 mg, 0.28 mmol). After the mixture was
stirred for 4 h under bubbling oxygen gas, this was concentrated in vacuo to
provide black oil (1.25 g). Purification of the oil by flash column chromatog-
raphy (hexane/AcOEtꢃ100 : 1) gave 8c (682 mg, 99%) as light purple crys-
tals. Rf: 0.72 (benzene/acetoneꢃ20 : 1). mp: 55—57 °C (hexane) (lit.9):
55.0—56.0 °C (hexane)) 1H-NMR (400 MHz) dH: 6.70 (1H, dd, Jꢃ2.0,
3.0 Hz, 3-H), 6.89 (1H, t, Jꢃ7.5 Hz, 5-H), 7.27 (1H, t, Jꢃ3.0 Hz, 2-H), 7.55
(1H, d, Jꢃ7.5 Hz, 4-H), 7.61 (1H, d, Jꢃ7.5 Hz, 6-H), 8.24 (1H, s, 1-H). 13C-
NMR (100 MHz) dC: 76.35 (s, 7-C), 104.18 (d, 3-C), 120.85 (d, 6-C), 121.52
(d, 5-C), 123.54 (s, 3a-C), 124.33 (d, 2-C), 127.83 (s, 7a-C), 130.62 (d, 4-C).
HR-FAB-MS m/z: 242.9545 [M]ꢁ, Calcd for C8H6NI: 242.9545 [M].
N-Formyl-7-hydoxyindoline (6d) To
a solution of 4 (502 mg,
3.40 mmol) in TFA (15 ml) was added a solution of TTFA (3.7 g, 6.80 mmol)
in TFA (8.0 ml) dropwise during 20 min under argon. After the mixture was
stirred for 24 h at room temperature, the reaction mixture was concentrated
in vacuo by azeotropic distillation with a solution of benzene (20 mlꢂ3) to
provide 5 as a black tarry oil. The residue was dissolved in a mixture of
DMF–H2O (1 : 1, 15 ml) and CuSO4·5H2O (3.40 g, 13.6 mmol) was added to
the mixture. After the mixture was stirred for 5 h at 120 °C, then stirred for
5 d at room temperature under argon. The reaction mixture was concentrated
in vacuo and the residue was dissolved in a mixture of CHCl3/MeOHꢃ95 : 5
(150 ml) and saturated NaCl (20 ml). The mixture was filtered off through
celite pad. After the filtrate was partitioned in organic and water layers, the
organic layer was washed with saturated NaCl (20 mlꢂ3), dried over
Na2SO4, concentrated in vacuo. Resulting residue was purified by flash col-
umn chromatography (silica gel, benzene/acetoneꢃ50 : 1→30 : 1) to give 6d
(139 mg, 25%) as light yellow crystals. mp: 133—134 °C. 1H-NMR
(300 MHz) dH: 2.86, 2.93 (each 2H, t, Jꢃ9.0 Hz, 3-H2), 3.89, 4.06 (each 2H,
t, Jꢃ9.0 Hz, 2-H2), 6.70, 6.78 (each 1H, dq, Jꢃ7.0, 1.0 Hz, 4-H), 6.94, 7.08
(each 1H, t, Jꢃ7.0 Hz, 5-H), 7.02, 7.03 (each 1H, d, Jꢃ7.0 Hz, 6-H), 10.05,
11.65 (each 1H, s, CHO), 12.47 (total 2H, s, OH). Each paired signal is at-
tributable to stereoisomers resulted in two kinds of aldehyde groups; one of
which makes chelation with the OH group and the other is not chelated and
oppositely directed to the OH group. HR-FAB-MS m/z: 163.0633 [M]ꢁ,
Calcd for C9H9O2N: 163.0633 [M].
(S)-N-Carbobenzyloxy-7ꢀ-iodotryptophan ((S)-11c) To a solution of
(S)-10c (263 mg, 0.795 mmol) in 10% aqueous Na2CO3 (5.0 ml) was added
Cbz-Cl (35.5 mg, 0.795 mmol) in ether (0.3 ml). After the mixture was
stirred for 2 h at 0 °C, it was acidified with 10% HCl. Resulting preciptates
were filtered off, washed with water (2 mlꢂ2) and dried to provide (S)-11c
(318.7 mg, 86%) as white crystals. Rf: 0.75 (butanol/AcOH/H2Oꢃ4 : 1 : 5).
mp: 108—110 °C. [a]D20 ꢁ20.63° (cꢃ0.40, acetone). HR-FAB-MS m/z:
487.0132 [MꢁNa]ꢁ, Calcd for C19H17O4N2INa: 487.0131 [MꢁNa]. Data of
MS, 1H-NMR data were identical with that of (R)-11c.
(R,S)-N-Acetyl-7ꢀ-iodotryptophan ((RS)-9c) To
a solution of 8c
(1.15 g, 5.87 mmol) in AcOH (13.8 ml) and Ac2O (4.6 ml) was added D-ser-
ine (1.23 g, 11.7 mmol). After the solution was stirred for 2.5 h at 75 °C
under argon, the reaction mixture was diluted with ether (115 ml). The solu-
tion was made basic by adding 30% aqueous solution of NaOH dropwise,
then ether (173 ml) was added to this solution. The mixture was partitioned
(R)-N-Carbobenzyloxy-7ꢀ-iodotryptpphan (R)-(ꢁ)-Phenylethylamide
((R)-12c) To a solution of (R)-11c (20 mg, 0.043 mmol) in THF (1 ml)
were added (R)-(ꢁ)-phenylethylamine (5.2 mg, 0.043 mmol), EDCI (8.3 mg,
0.043 mmol), HOBT (5.8 mg, 0.043 mmol). After the mixture was stirred for
2 h at room temperature under argon, the solution was concentrated in

June 2006
793
vacuo. Resuted residue was purified by preparative TLC (CHCl3 :
MeOHꢃ5 : 1) to give (R)-12c (15.7 mg, 65%) as white brown powder. Rf:
0.84 (CHCl3 : MeOHꢃ5 : 1). mp: 193—195 °C. [a]D20 ꢁ10.12° (cꢃ0.17,
CHCl3). 1H-NMR (400 MHz) dH: 1.31 (3H, d, Jꢃ7.5 Hz, CH(CH3),
3.04 (1H, dd, Jꢃ8.3, 14.3 Hz, 3-Ha), 3.24 (1H, dd, Jꢃ5.5, 14.3 Hz,
3-Hb), 4.44 (1H, m, 2-H), 4.97 (quint., Jꢃ7.5 Hz, CH(CH3)), 5.09 (2H, s,
benzyl-CH2), 5.54 (1H, br, 2-NHCO), 5.74 (1H, d, Jꢃ7.5 Hz, 1-NHCO),
6.76 (1H, d, Jꢃ2.0 Hz, 2ꢀ-H), 6.85 (1H, t, Jꢃ7.5 Hz, 5ꢀ-H), 6.93 (2H, m,
phenylethyl-arom H), 7.25 (3H, m, phenylethyl-arom H), 7.33 (5H, m, ben-
zyl-arom H), 7.53 (1H, d, Jꢃ7.5 Hz, 6ꢀ-H), 7.62 (1H, br d, Jꢃ7.5 Hz, 4ꢀ-H),
7.85 (1H, br, 1ꢀ-H). HR-FAB-MS m/z: 568.1093 [MꢁH]ꢁ, Calcd for
C27H27O3N3I: 568.1097 [MꢁH].
(S)-N-Carbobenzyloxy-7ꢀ-iodotryptpphan (R)-(ꢁ)-Phenylethylamide
((S)-12c) To a solution of (S)-11c (20 mg, 0.043 mmol) in THF (1 ml) were
added (R)-(ꢁ)-phenylethylamine (5.2 mg, 0.043 mmol), EDCI (8.3 mg,
0.043 mmol), HOBT (5.8 mg, 0.043 mmol). After the mixture was stirred for
2 h at room temperature under argon, the solution was concentrated in
vacuo. Resuted residue was purified by preparative TLC (CHCl3 :
MeOHꢃ5 : 1) to give (S)-12c (14.3 mg, 59%) as white brown powder. Rf:
0.82 (CHCl3 : MeOHꢃ5 : 1). mp: 185—187 °C. [a]D20 ꢄ4.51° (cꢃ0.25,
CHCl3). 1H-NMR (400 MHz) dH: 1.17 (3H, d, Jꢃ7.5 Hz, CH(CH3),
3.09 (1H, dd, Jꢃ8.0, 14.0 Hz, 3-Ha), 3.30 (1H, dd, Jꢃ5.5, 14.0 Hz,
3-Hb), 4.46 (1H, m, 2-H), 4.91 (quint., Jꢃ7.0 Hz, CH(CH3)), 5.09 (2H, s,
benzyl-CH2), 5.51 (1H, br, 2-NHCO), 5.75 (1H, d, Jꢃ7.5 Hz, 1-NHCO),
6.87 (1H, t, Jꢃ7.5 Hz, 5ꢀ-H), 6.98 (1H, d, Jꢃ2.0 Hz, 2ꢀ-H), 7.01 (2H, m,
phenylethyl-arom H), 7.22 (3H, m, phenylethyl-arom H), 7.33 (5H, m, ben-
zyl-arom H), 7.56 (1H, d, Jꢃ7.5 Hz, 6ꢀ-H), 7.63 (1H, br d, Jꢃ7.5 Hz, 4ꢀ-H),
8.09 (1H, br, 1ꢀ-H). HR-FAB-MS m/z: 568.1095 [MꢁH]ꢁ, Calcd for
C27H27O3N3I: 568.1097 [MꢁH].
3-Hb), 4.58 (1H, br, Trp 2-H), 5.11, 5.15 (total 2H, each d, Jꢃ14.0 Hz, ben-
zyl-CH2), 5.13 (1H, hidden, CHPG 2-H), 5.38 (1H, d, Jꢃ7.5 Hz, Trp
NHCO), 6.07 (1H, br s, OH), 6.83 (1H, t, Jꢃ7.5 Hz, Trp 5ꢀ-H), 6.90 (1H, br,
CHPG NHCO), 7.00 (1H, d, Jꢃ2.0 Hz, Trp 2ꢀ-H), 7.10 (2H, s, CHPG 2ꢀ, 6ꢀ-
H), 7.34 (5H, m, benzyl-arom 5H), 7.54 (1H, d, Jꢃ7.5 Hz, Trp 4ꢀ-H), 7.55
(1H, d, Jꢃ7.5 Hz, Trp 6ꢀ-H), 8.18 (1H, s, Trp 1ꢀ-H). HR-FAB-MS m/z:
760.0459 [MꢁNa]ꢁ, Calcd for C31H30O6N3Cl352NaI: 760.0454 [MꢁNa].
(R,R)-7ꢀ-Iodo-N-carbobenzyloxytryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-
methoxyphenylglycine tert-Butyl Ester (19) To
a solution of 18
(45.0 mg, 0.06 mmol) in a mixture of MeOH (0.45 ml) and benzene
(0.75 ml) was added a solution of TMSCHN2 (40.5ml, 0.08 mmol) in ben-
zene (0.75 ml). After the mixture was stirred for 24 h at room temperature
under argon, the reaction mixture was concentrated in vacuo. Resulting
residue was purified by preparative TLC (hexane/AcOEtꢃ2 : 1) to give 19
(52.0 mg, 94%) as light yellow crystals. Rf: 0.38 (hexane/AcOEtꢃ2 : 1).
t
[a]D24 ꢄ24.0° (cꢃ0.5, CHCl3). 1H-NMR (400 MHz) dH: 1.35 (9H, s, Bu),
3.13 (1H, dd, Jꢃ7.5, 15.0 Hz, Trp 3-Ha), 3.35 (1H, dd, Jꢃ5.0, 15.0 Hz, Trp
3-Hb), 3.88 (3H, s, OMe), 4.59 (1H, br q, Jꢃ6.5 Hz, Trp 2-H), 5.11, 5.15
(each 1H, d, Jꢃ12.5 Hz, benzyl-CH2), 5.16 (1H, d, Jꢃ6.5 Hz, CHPG 2-H),
5.39 (1H, br d, Jꢃ7.0 Hz, Trp NHCO), 6.85 (1H, t, Jꢃ7.5 Hz, Trp 5ꢀ-H),
6.89 (1H, br d, Jꢃ6.5 Hz, CHPG NHCO), 7.01 (1H, d, Jꢃ2.0 Hz, Trp 2ꢀ-H),
7.15 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.34 (5H, m, benzyl-arom-5H), 7.54 (1H, d,
Jꢃ7.5 Hz, Trp 4ꢀ-H), 7.56 (1H, d, Jꢃ10.0 Hz, Trp 6ꢀ-H), 8.18 (1H, s, Trp
1ꢀ-H). 13C-NMR (100 MHz) dC: 27.75 (q, C(CH3)3), 28.28 (t, Trp 3-C),
55.47 (d, Trp 2-C), 55.85 (d, CHPG 2-C), 60.71 (q, CHPG OCH3), 67.22 (t,
benzyl-CH2), 83.67 (s, C(CH3)), 111.62 (s, Trp 3ꢀ-C), 118.72 (d, Trp 4ꢀ-C),
121.57 (d, Trp 5ꢀ-C), 123.62 (d, Trp 2ꢀ-C), 127.39 (d, CHPG 2ꢀ, 6ꢀ-C),
127.39 (s, Trp 3aꢀ-C), 128.10, 128.24, 128.55 (d, benzyl-arom), 129.47 (s,
CHPG 3ꢀ, 5ꢀ-C), 131.04 (d, Trp 6ꢀ-C), 134.31 (s, CHPG 1ꢀ-C), 136.02 (s,
benzyl-arom 1-C), 136.99 (s, Trp 7aꢀ-C), 152.07 (s, CHPG 4ꢀ-C), 155.98 (s,
Trp NHCO), 168.05 (s, CHPG 1-C), 170.47 (s, Trp 1-C). HR-FAB-MS m/z:
774.0624 [MꢁNa]ꢁ, Calcd for C32H32O6N3Cl352NaI: 774.0611 [MꢁNa].
(R,R,R)-2-(3-{6-[5-(N-tert-Butoxycarbonyl-2-methoxycarbonyl-
methlyamino)-3-iodo-2-methoxyphenyl]indol-3-yl}-2-carbobenzy-
(R,R,R)-7ꢀ-Bromo-N-carbobenzyloxytryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-
methoxyphenylglycyl-3ꢀ,5ꢀ-diiodo-4ꢀ-methoxyphenylglycine
Methyl
Ester (16) Dipeptide 15 (101 mg 0.13 mmol) was dissolved in TFA
(0.5 ml) at 0 °C and the mixture was allowed to stand 30 min. The reaction
mixture was concentrated in vacuo to provide TFA salts (108 mg) as light
yellow crystals. To a solution of this salt in DMF (0.2 ml) were added NMM
(21.3 ml, 0.194 mmol), (R)-11b (64.5 mg, 0.16 mol) in DMF (0.5 ml), EDCI
(37.2 mg, 0.19 mmol) in DMF (0.8 ml), HOBt (21.0 mg, 0.16 mmol), and the
mixture was stirred for 7 h at ꢄ5 °C under argon. After the reaction mixture
was concentrated in vacuo, resulting residue was dissolved in AcOEt
(30 ml). The solution was washed with 10% citric acid (5 mlꢂ2), saturated
NaHCO3 (5 mlꢂ2), saturated NaCl (5 mlꢂ2), dried over Na2SO4, concen-
trated in vacuo. The residue was purified by column chromatography (silica
gel, CHCl3 : MeOHꢃ500 : 1) to afford 16 (105 mg, 76%) as white yellow
crystals. Rf: 0.52 (benzene/acetoneꢃ5 : 1). mp: 178—180 °C (CHCl3). [a]D25
ꢄ45.59° (cꢃ0.25, CHCl3). 1H-NMR (400 MHz) dH: 3.11 (1H, dd, Jꢃ7.5,
15.0 Hz, Trp 3-Ha), 3.36 (1H, dd, Jꢃ5.0, 15.0 Hz, Trp 3-Hb), 3.70 (3H, s,
COOMe), 3.83 (3H, s, IHPG OMe), 3.88 (3H, s, CHPG OMe), 4.58 (1H, m,
Trp 2-H), 5.08, 5.13 (each 1H, d, Jꢃ12.0 Hz, CH2-Ph), 5.31 (1H, br d,
Jꢃ7.0 Hz IHPG 2-H), 5.38 (1H, d, Jꢃ6.0 Hz, CHPG 2-H), 5.47 (1H, br d,
Jꢃ7.0 Hz, Trp NHCO), 6.83 (1H, br, IHPG NHCO), 6.93 (1H, br s, Trp 2ꢀ-
H), 6.94 (1H, br t, Jꢃ7.0 Hz, Trp 5ꢀ-H), 7.13 (1H, br, CHPG NHCO), 7.14
(2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.30 (1H, d, Jꢃ7.0 Hz, Trp 6ꢀ-H), 7.32 (5H, m,
CH2-Ph), 7.54 (1H, br d, Jꢃ7.0 Hz, Trp 4ꢀ-H), 7.76 (2H, s, IHPG 2ꢀ, 6ꢀ-H),
8.15 (1H, br s, Trp 1ꢀ-H). 13C-NMR (100 MHz) dC: 28.47 (t, Trp 3-C), 53.39
(q, COOCH3), 54.83 (d, CHPG 2-C), 55.41 (d, Trp 2-C), 55.94 (d, IHPG 2-
C), 60.71 (q, OCH3ꢂ2), 67.33 (t, CH2-Ph), 91.04 (s, IHPG 3ꢀ, 5ꢀ-C), 105.03
(s, Trp 7ꢀ-C), 111.28 (s, Trp 3ꢀ-C), 117.92 (d, Trp 4ꢀ-C), 121.10 (d, Trp 5ꢀ-
C), 123.87 (d, Trp 2ꢀ-C), 124.86 (d, Trp 6ꢀ-C), 127.79 (d, CHPG 2ꢀ, 6ꢀ-C),
128.17, 128.316 (each d, benzyl-arom-C), 128.57 (s, Trp 3aꢀ-C, benzyl-
arom-C), 129.93 (s, CHPG 3ꢀ, 5ꢀ-C), 133.84 (s, CHPG 1ꢀ-C), 134.96 (s, Trp
7aꢀ-C), 135.44 (s, IHPG 1ꢀ-C), 135.44 (d, CH2-Ph), 138.55 (s, IHPG 2ꢀ, 6ꢀ-
C), 152.61 (s, CHPG 4ꢀ-C), 156.04 (s, Trp NHCO), 159.41 (s, IHPG 4ꢀ-C),
167.68 (s, CHPG 1-C), 169.60 (s, IHPG 1-C), 170.85 (s, Trp 1-C). HR-FAB-
MS m/z: 1098.8838 [MꢁNa]ꢁ, Calcd for C38H33O8N4Cl352Br79I2Na:
1098.8846 [MꢁNa].
loxyaminopropionylamino)-2-(3,5-dichloro-4-methoxyphenyl)
Acetic
Acid tert-Butyl Ester (21) To a solution of 20 (65 mg, 0.092 mmol), 19
(138 mg, 0.183 mmol) in DMF (6.5 ml) were added Pd2(dba)3CHCl3 (19 mg,
0.018 mmol), CuI (7 mg, 0.037 mmol), Ph3As (22 mg, 0.073 mmol). After
the mixture was stirred for 2 h at room temperature under argon, the reaction
mixture was diluted with ether (100 ml), then the solution was washed with
saturated NH4Cl (20 mlꢂ2), 10% KF (20 mlꢂ3), dried over Na2SO4, con-
centrated in vacuo. The residue was purified by preparative TLC (CHCl3) to
give 21 (36.7 mg, 39%) as light brown powder. Rf: 0.24 ( CHCl3 ). [a]D24
1
t
ꢄ26.40° (cꢃ0.5, CHCl3). H-NMR (400 MHz) dH: 1.33 (9H, s, Bu), 1.44
(9H, s, Boc), 3.22 (1H, dd, Jꢃ7.5, 15.0 Hz, Trp 3-Ha), 3.27, 3.29 (total 3H,
each s, CHPG OCH3), 3.37 (1H, dd, Jꢃ5.5, 15.0 Hz, Trp 3-Hb), 3.74 (3H, s,
IHPG COOCH3), 3.86 (3H, s, IHPG OCH3), 4.61 (1H, br, Trp 2-H), 5.13,
5.15 (total 2H, each d, Jꢃ12.0 Hz, benzyl-CH2), 5.24 (1H, dd, Jꢃ2.5,
7.5 Hz, CHPG 2-H), 5.31 (1H, d, Jꢃ7.5 Hz, IHPG 2-H), 5.44 (1H, br d,
Jꢃ6.5 Hz, Trp NHCO), 5.67 (1H, br d, Jꢃ7.5 Hz, IHPG NHCO), 6.92 (1H,
d, Jꢃ2.0 Hz, Trp 2ꢀ-H), 7.13, 7.16 (each 1H, s, CHPG 2ꢀ, 6ꢀ-H), 6.97 (1H,
br, CHPG NHCO), 7.23 (1H, t, Jꢃ7.5 Hz, Trp 5ꢀ-H), 7.34 (5H, m, benzyl-
arom-H), 7.45 (1H, d, Jꢃ2.0 Hz, IHPG 6ꢀ-H), 7.49 (1H, d, Jꢃ7.5 Hz, Trp
4ꢀ-H), 7.66 (1H, d, Jꢃ7.5 Hz, Trp 6ꢀ-H), 7.83 (1H, d, Jꢃ2.0 Hz, IHPG 2ꢀ-
H), 8.53 (1H, s, Trp 1ꢀ-H). 13C-NMR (400 MHz) dC: 27.71 (q, CHPG
C(CH3)3), 27.82 (t, Trp 3-C), 28.28 (q, IHPG C(CH3)3), 52.97 (q, IHPG
COOCH3), 55.20, 55.47 (each br s, Trp 2ꢀ-C), 55.73, 55.83 (each d, CHPG
2-C), 56.38 (d, IHPG 2-C), 60.45, 60.52 (each q, CHPG OCH3), 60.68,
60.71 (each q, IHPG OCH3), 67.18 (t, benzyl CH2), 80.48 (s, Boc C(CH3)3),
83.56 (s, tBu C(CH3)3), 93.47 (s, IHPG 5ꢀ-C), 109.91 (s, Trp 3aꢀ-C), 111.33
(s, Trp 3ꢀ-C), 118.99, 119.16 (d, Trp 4ꢀ-C), 120.06, 120.13 (d, Trp 5ꢀ-C),
121.57 (s, Trp 7ꢀ-C), 123.31, 123.41 (d, Trp 6ꢀ-C), 124.02, 123.80 (each d,
Trp 2ꢀ-C), 127.43, 123.46 (each d, CHPG 2ꢀ, 6ꢀ-C), 128.10, 128.23, 128.54
(d, benzyl arom-C), 129.46 (s, benzyl 4ꢀ-C), 131.51, 131.64 (d, IHPG 6ꢀ-H),
132.71 (s, IHPG 3ꢀ-C), 133.78, 133.84 (s, CHPG 1ꢀ-C), 134.27, 134.37 (s,
IHPG 1ꢀ-C), 135.12 (s, benzyl arom 1-C), 136.09 (s, Trp 7aꢀ-C), 136.89 (d,
IHPG 2ꢀ-C), 152.06 (s, CHPG 4ꢀ-C), 154.72 (s, IHPG NHCO), 156.03 (s,
Trp NHCO), 156.29 (s, IHPG 4ꢀ-C), 168.18 (s, CHPG 1-C), 170.68 (s, Trp
NHCO), 170.94 (s, IHPG 1-C). HR-FAB-MS m/z: 1067.1903 [MꢁNa]ꢁ,
Calcd for C47H51O11N4Cl352NaI: 1067.1874 [MꢁNa].
(R,R)-7ꢀ-Iodo-N-carbobenzyloxytryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-hydrox-
yphenylglycine tert-Butyl Ester (18) To a mixture of 17 (200 mg,
0.68 mmol) and (R)-11c (315 mg, 0.68 mmol) in THF (10 ml) were added
FDPP (260 mg, 0.41 mmol), DIEA (183 mg, 0.41 mmol). After the solution
was stirred for 22 h at room temperature under argon, the reaction mixture
was concentrated in vacuo. Resulting residue was purified by preparative
TLC (CHCl3/MeOHꢃ10 : 1) to afford 18 (286 mg, 56%) as white crystals.
(R,R,R)-2-[3-(3-{N-[2-(3,5-Dichloro-4-methoxyphenyl)acetylcarboxy]-
2-carbobenzyl-oxyaminopropionylamino}indol-7-yl)-5-iodo-4-
methoxyphenyl]-2-methoxycarbonylmethylammonium Trifluoroacetate
(22) A solution of 21 (5 mg, 0.0048 mmol) in TFA (0.6 ml) was stirred for
1
t
Rf: 0.77 (CHCl3/MeOHꢃ10 : 1). H-NMR (400 MHz) dH: 1.34 (9H, s, Bu),
3.13 (1H, dd, Jꢃ7.0, 15.0 Hz, Trp 3-Ha), 3.35 (1H, dd, Jꢃ5.0, 15.0 Hz, Trp

794
Vol. 54, No. 6
3.4 h at 0 °C under argon. The reaction mixture was concentrated in vacuo to
remove TFA by azeotropic distillation with benzene to afford 22 contita-
tively. Rf: 0.30 (CHCl3 : MeOHꢃ5 : 1). 1H-NMR (400 MHz, CD3OD) dH:
3.13 (1H, dd, Jꢃ8.0, 14.5 Hz, Trp 3-Ha). 3.31 (1H, dd, Jꢃ6.0, 14.5 Hz, Trp
3-Ha), 3.23 (3H, s, IHPG OMe), 3.83 (3H, COOMe), 3.86 (3H, s, OMe),
4.56 (1H, dd, Jꢃ6.5, 7.7 Hz, Trp 2-H), 5.04 (2H, s, benzyl CH2), 5.23 (1H,
s, IHPG 2-H), 5.34 (1H, br s, CHPG 2-H), 7.14 (1H, d, Jꢃ3.0 Hz, Trp 2ꢀ-H),
7.14 (1H, hidden Trp 5ꢀ-H), 7.29 (5H, benzyl arom-H), 7.44 (2H, br s,
CHPG 2ꢀ, 6ꢀ-H), 7.55 (1H, d, Jꢃ2.5 Hz, IHPG 6ꢀ-H), 7.70 (2H, m, Trp 6ꢀ,
4ꢀ-H), 7.99 (1H, d, Jꢃ2.0 Hz, IHPG 2ꢀ-H). 13C-NMR (100 MHz, CD3OD)
dC: 54.20 (q, COOMe), 56.25 (d, IHPG 2-C), 57.00 (d, CHPG 2-C), 57.18
(d, Trp 2-C), 60.89 (t, Trp 3-C), 60, 89 (q, IHPG OMe), 61.22 (q, CHPG
OMe), 67.71 (t, benzyl CH2), 94.50 (s, IHPG 5ꢀ-C), 111.32 (s, Trp 3ꢀ-C, Trp
3aꢀ-C), 120.25 (d, Trp 5ꢀ-C), 120.25 (d, Trp 6ꢀ, 4ꢀ-C), 122.25 (s, Trp 7ꢀ-C).
123.62 (d, Trp 5ꢀ-C), 125.61 (d, Trp 2ꢀ-C), 128.77, 128.85, 129.27, 129.32,
3) Deng H., Jung J.-K., Liu T., Kunz K. W., Snapper M. L., Hoveyda H.,
J. Am. Chem. Soc., 125, 9032—9034 (2003).
4) Kai T., Kajimoto N., Konda (Yamada) Y., Harigaya Y., Takayanagi H.,
Tetrahedron Lett., 40, 6289—6292 (1999).
5) Yamada Y., Akiba A., Arima S., Okada C., Yoshida K., Itou F., Kai T.,
Satou T., Takeda K., Harigaya Y., Chem. Pharm. Bull., 53, 1277—
1290 (2005).
6) Konda-Yamada Y., Okada C., Yoshida K., Umeda Y., Arima S., Sato
N., Kai T., Takayanagi H., Harigaya Y., Tetrahedron, 58, 7851—7861
(2002).
7) Hasegawa M., Yamada K., Nagahama Y., Somei M., Heterocycles, 51,
2815—2821 (1999).
8) Somei M., Saida Y., Heterocycles, 23, 3113—3114 (1983).
9) Somei M., Saida Y., Funamoto T., Ohta T., Chem. Pharm. Bull., 35,
3146—3154 (1987).
129.39 (each d, benzy-arom-C), 129.46, 129.54 (each d, CHPG 2ꢀ, 6ꢀ-C), 10) Mckillop A., Bromley D., J. Org. Chem., 37, 88—92 (1972).
130.01, 130.41 (each s, CHPG 3ꢀ, 5ꢀ-C), 130.72 (s, IHPG 3ꢀ-C), 133.44 (d, 11) Taylor E. C., Kienzle F. K., Robey R. L., McKillop A., Hunt J. D., J.
IHPG 6ꢀ-C), 135.13 (s, Trp 7aꢀ-C), 135.20 (s, IHPG 1ꢀ-C), 136.60 (s, CHPG
1ꢀ-C), 138.09 (s, benzyl 1ꢀ-C), 139.27 (d, IHPG 2ꢀ-C), 153.33 (CHPG 4ꢀ-C), 12) Waki M., Meienhofer J., J. Org. Chem., 42, 2019—2020 (1977).
158.33 (s, NHCOO), 160.16 (s, IHPG 4ꢀ-C), 169.80 (s, COOMe), 172.31 (s, 13) Somei M., Iwasa E., Yamada F., Heterocycles, 24, 3065—3069 (1986).
Am. Chem. Soc., 93, 4845—4850 (1971).
COOH), 173.95 (s, Trp 1-C). HR-FAB-MS m/z: 889.0934 [MꢁH]ꢁ, Calcd 14) Nicolaou K. C., Chu X.-J., Ramanjulu J. M., Nararajam S., Brase S.,
for C38H56O9N4Cl352I: 889.0904 [MꢁH].
Rubsam F., Boddy C. N. C., Angew. Chem. Int. Ed. Engl., 36, 1539—
1540 (1997).
References
15) Beugelmans R., Roussi G., Zamora E. G., Carbonnelle A. C., Tetrahe-
dron, 55, 5089—5112 (1999).
16) Wipf P., Yokokawa F., Tetrahedron Lett., 39, 2223—2226 (1998).
17) Farina V., Kapadia S., Krishnan B., Wang C., Liebeskind L. S., J. Org.
Chem., 59, 5905—5911 (1994).
1) Matsuzaki K., Ikeda H., Ogino T., Matsumoto A., Woodruff H. B.,
Tanaka H., Omura S., J. Antibiot., 47, 1173—1174 (1994).
2) Gouda H., Matsuzaki K., Tanaka H., Hirono S., Omura S., MaCauley
J. A., Sprengeler P. A., Furst G. T., Smith A. B., J. Am. Chem. Soc.,
118, 13087—13088 (1996).
18) Shaw J. T., Tyson F. T., J. Am. Chem. Chem., 78, 2538—2540 (1956).