Synthesis of linear tripeptides for right-hand segments of complestatin

Article abstract of DOI:10.1248/cpb.53.1277

This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is described. Two of them are the precurso

Full text of DOI:10.1248/cpb.53.1277

October 2005
Chem. Pharm. Bull. 53(10) 1277—1290 (2005)
1277
Synthesis of Linear Tripeptides for Right-Hand Segments of Complestatin
Yaeko YAMADA,*,a Ai AKIBA,a Shiho ARIMA,a Chiharu OKADA,a Kiminari YOSHIDA,a Fumihiro ITOU,a
a
Toshitsugu KAI,a Toshiko SATOU,a Kazuyoshi TAKEDA,b and Yoshihiro HARIGAYA
a School of Pharmaceutical Sciences, Kitasato University; Shirokane, Minato-ku, Tokyo 108–8641, Japan: and b Center for
Advanced Technology, Ebara Research Co., Ltd.; 4–2–1 Honfujisawa, Fujisawa 251–8502, Japan.
Received May 26, 2005; accepted July 21, 2005; published online July 28, 2005
This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4
receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is de-
scribed. Two of them are the precursor tripeptides for macrolactamization to the right-hand segment of com-
plestatin at the last step and the other two are the precursor tripeptides for ring-closing reaction using Suzuki
and Stille coupling, respectively, to the right-hand segment of complestatin at the last step. These compounds
and the synthetic procedure will serve for both the synthesis of the right-hand segment and total synthesis of
complestatin in the near future. In addition, consideration of the smooth acidic isomerization of complestatin to
chloropeptin was carried out by density functional theory (DFT) calculation.
Key words complestatin; precursor; right-hand segment; tripeptide
Complestatin (1) was initially isolated from Streptomyces solute stereostructure with 2 except the above D, F-ring junc-
sp. WK-3419 in 19801,2) as an inhibitor of an alternative tion. More recently, three new related compounds with com-
pathway of complement. Later, its planar structure was eluci- plestatin (isocomplestatin, complestatin A and B were dis-
1
dated by Seto et al. by H-NMR in 1989,3) and the absolute covered which have potent inhibitory activity against HIV-in-
structure of the amino acid constructing the A, C, E ring was tegrase.7) Because of their unique structure having a biaryl
also determined to be each L-form by hydrolysis of the ether and a biphenyl moiety together and various interesting
amide bond. In 1994, 1 was isolated by Matsuzaki et al. from biological activities, 1, 2 and their related compounds are an
Streptomyces sp. WK-3490 together with chloropeptin 2 both attractive target for total synthesis (Fig. 1).
as inhibitors of gp120-CD4 receptor (IC values of 3.3 and
Consequently, we have been interested in the total synthe-
2.0 mM for 1 and 2, respectively).4) The absolute stereostruc- sis of 1 and 2 and already achieved the left-hand segment8) of
ture of chloropeptin 2 was determined in 19965) by combina- 1 and 2. In 2003, Hoveyda et al. published an elegant total
tion of acid hydrolysis, molecular dynamics and NMR spec- synthesis of 2.9) However, total synthesis of 1 has not yet
troscopy. According to the published paper concerning the been completed to date. Recently, we have been investigating
planar and absolute stereostructure of complestatin 1 and the synthesis of the right-hand segment of 1 and we are espe-
chloropeptin 23,5) they are bismacrocyclic hepta peptides and cially interested in a cyclic reaction for the right-hand seg-
they differ only at the position of the phenyl-indole ring junc- ment of 1. In this paper, we report the synthesis of four linear
tion D, F (Fig. 1).
compounds 4, 5, 6a, 6b as precursors for cyclic reaction to
In compound 1, the D ring connects at the position of C-6 the right-hand segment (3) of 1 (Figs. 1, 2).
in the F ring having a 17-membered ring as a right-hand seg-
ment, whereas in 2, at the position of C-7 having a 16-mem-
bered ring. As complestatin isomerizes easily to 2 under
acidic composition,6) it is obvious that 1 has the same ab-
Segment 3 is a 17-membered macrocyclic lactam where
Fig. 2. Structures of Linear Tripeptides 4, 5, 6a, 6b for 3 and Cyclization
Points
Fig. 1. Isomerization of Complestatin (1) to Chloropeptin (2)6)
∗ To whom correspondence should be addressed. e-mail: yamadaky@violet.plala.or.jp
© 2005 Pharmaceutical Society of Japan

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Vol. 53, No. 10
Chart 1
the G ring is replaced by a Cbz group, having two amide and
one biaryl bond and consists of three (R)-amino acids, (R)-
3ꢀ5ꢀ-dichloro-4ꢀ-hydroxy-phenylglycine (E-ring), (R)-trypto-
phan (F-ring), (R)-4-hydroxy-phenylglycine (D-ring).
Three different routes (Routes 1, 2, 3) are considered
where ring closure is carried out at the last step for construct-
ing 3 as shown in Fig. 2. Routes 1 and 2 utilize a macrolac-
tamization between ring D and E (Route 1) and ring E and F
(Route 2), respectively, at the last step, while another more
fascinating route utilizes intramolecular Pd-catalyzed ring
closure by Suzuki or Stille coupling between ring D and F at
the last step (Route 3). For the precursor to cyclization, com-
Chart 2. Determination of Optical Purity
pounds 4 and 5 are considered for Route 1 and 2, respec- in 62% yield. The alkaline hydrolysis of 10 (71%), followed
tively, and 6a, 6b are considered for Route 3. When cycliza- by oxidation under oxygen gas using salcomine14) gave 6-
tion is carried out using Suzuki coupling,10) 6a is utilized. iodoindole 12 in 98% yield. As the total yield of 12 (46%
When using Stille coupling,11) 6b is utilized (Fig. 2).
from 7) is fairly high and each step is performed with ease,
In this paper, successful synthesis of four important pre- our route for 12 is very convenient and available.
cursors (4, 5, 6a, 6b) to the right-hand segment of the 17-
membered ring system of complestatin (3) is described.
Addition of L-serine to 12 in AcOH–Ac2O12,15) gave
racemic N-acetyl-tryptophan (RS)-13 in 89% yield. Enzy-
matic optical resolution of (RS)-13 by D-aminoacylase in
phosphate buffer (pH 7.4) afforded the desired (R)-14 in 48%
Results and Discussion
Synthesis of the Linear Precursor 4 by Route 1 1. Syn- yield and non-reacted (S)-13 was recovered in 39% yield.
thesis of (R)-N-Cbz-6-Iodo-tryptophan: First, the synthesis of The Na salt of (S)-13 was heated with Ac2O to reproduce
4 by the most conventional and short route (Route 1) was ex- racemic mixture (RS)-13, which was converted to R-14 by
amined. The synthetic strategy for 4 is depicted in Fig. 3. enzymatic optical resolution in 36% yield. Thus (R)-14 was
This route is characterized by initially making a peptide bond totally obtained in 62% yield from (RS)-13 (Chart 1). As our
between the E and F rings, then connecting the D-ring to the route for preparation of the (R)-6-iodo-tryptophan is very
dipeptide by Stille coupling.
convenient and the yield of each step is fairly high, it is avail-
The success of this route depends upon effective biaryl able for the synthesis of 1, kistamycin16,17) which needs (R)-
cross-coupling between dipeptide 24 (E–F ring) and 20 (D- 6-halogeno-tryptophan. Conversion of (R)-14 to N-carbamate
ring) by Stille coupling as well as stereoselective preparation by carbobenzyloxy (Cbz) chloride afforded (R)-15 quantita-
of the (R)-tryptophan moiety. The iodide at Cꢀ-3 in 20 can be tively (Chart 1).
regarded as a left-hand segment and also it is a functional
group needed for coupling with the left-hand segment to 2). (R)-15 was condensed with (R)-(ꢁ)-phenylethylamine
form 1. using EDCI, hydroxybenzotriazole (HOBT) to afford amide
Optical purity of (R)-15 was determined as follows (Chart
The desired (R)-6-iodo-tryptophan derivative (R)-15 has (R)-16 and none of its diastereomer ((S)-16) was obtained.
not been synthesized yet. In this paper, a new efficient route Compound (S)-16 was obtained as follows. Enzymatic opti-
for synthesis of (R)-15 was designed by enzymatic optical cal resolution of (RS)-13 using L-aminoacylase in a similar
resolution using D-aminoacylase which was already devel- way to D-aminoacylase provided (S)-14, which was converted
oped by us.12) The iodide at C-6 in the indole ring is to con- to Cbz derivative (S)-15, then this was transformed into
nect with the D-ring. Compound (R)-15 was synthesized phenylethylamide (S)-16 similarly. These results proved en-
from commercially available 6-nitroindole (7) (Chart 1). Pro- zymatic resolution proceeded enantiomerically to give opti-
tection of 7 with an acetyl group by acetic anhydride gave ac- cally pure amino acid (R)-14.
etate 8 (96%), which was converted to an amino group by
2. Synthesis of the D and E-Ring Moiety (20, 22): Com-
catalytic reduction using Pd–C (quant.), then the amino mercially available compound 17 was treated with iodine
group was transformed into diazonium salts by NaNO2, fol- monochloride in AcOH18) to provide diiodide 18 in 87%
lowed by Griess reaction using KI13) to afford the iodide 10 yield. Protection of 18 with BOC-ON in the presence of NEt3

October 2005
1279
(quant.), followed by methylation with two equivalents of dioxane, NMP, the yield was the best in DMF. When the re-
i
TMSCHN2 affording the methyl ester 19 in 96% yield. Stille action was performed in the absence of Pr2NEt, the reaction
i
coupling of 19 with (Bu3Sn)2 gave 20 (28%) using (o- rate was retarded to 24 h. The role of Pr2NEt is to raise the
i
tolyl3P)2PdCl2 in the presence of Pr2NEt which was used to electron-donating property in Pd, without stopping the palla-
stabilize the resulting Bu3Sn group and to prompt the trans- dium cycle.8) When the ligand was altered to tBu3P22,23) in the
i
metalation. Addition of Pr2NEt shortened the reaction time presence of CsF, collidine, the same yield (35%) was ob-
from 6 h to 2 h. The low yield of this reaction is caused by in- tained, but the reaction rate was retarded to 18 h. In the case
t
stability of the Bu3Sn group in acidic condition for purifica- of Bu3P, when using the dioxane, NMP as a solvent, the
tion by silica gel and the by-products produced by intermo- yield was also very low. It is reported that Ph3As accelerates
lecular carbon–carbon bond formation.
the rate of transmetalation more than PPh3 (Ph3As : Ph3Pꢂ
Dichlorination of 17 using surfuryl chloride in 1 M HCl in 100 : 1).21)
AcOH19) gave 21 (77%), which was protected by isobutylene
tBu and Boc groups were deprotected at the same time by
gas in H2SO4-dioxane under pressured condition to provide treatment with TFA to give TFA salt 4 quantitatively. The
tert-butyl ester 22 in 60% yield (Chart 3).
yield of each step is fairly good except in the Stille couplings
3. Synthesis of the Precursor Tripeptide 4: Condensation (Chart 3).
i
of 22 and (R)-15 using FDPP in the presence of Pr2NEt
Synthesis of the Linear Precursor 5 by Route 2 Route
provided dipeptide 23 (64%), which was converted to 2 is characterized with initially carrying out Stille coupling
methyl ether 24 by TMSCHN2, quantitatively. Components between the F and D ring moieties and then the E ring moi-
24 and 20 were connected via Stille coupling20) using ety is connected by peptide linkage (Fig. 3). One important
Pd2(dba)3·CHCl3 as a catalyst, Ph3As as a ligand, CuI as an key reaction in this route is to carry out Stille coupling effi-
i
additive21) and Pr2NEt as a base in DMF to provide tripep- ciently and another is how to obtain racemization-prone elec-
tide 25 in 35% yield. Optimization of the reaction conditions tron-deficient dichlorinated amino acid. For the Stille cou-
of this reaction was carried out. Among the solvents DMF, pling, the same optimal reaction conditions as developed in
Chart 3
Fig. 3. Synthetic Strategy of 4, 5 for 3 by Route 1, 2

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Vol. 53, No. 10
Chart 4
Route 1 can be applied. The desired chlorinated amino acid sation of 31 and racemic 28 using EDCI, HOBT, N-methyl-
((R)-28) could not be obtained in optically pure form, regret- morpholine (NMM) afforded a diastereomeric mixture of
fully, according to our process, which is a subject for future 32a and 32b in 34%, 29% yield, respectively, which results
study.
in using racemic mixture 28. The Boc and tert-butyl groups
The amino acids 28 and (R)-29 were synthesized as fol- of the desired 32a were removed at the same time by TFA to
lows (Chart 4). Protection of 21 using Boc-ON (26: quant.), afford the precursor 5 in 93% yield. The development of a
followed by methylation with TMSCHN2 to give 27 (86%), new procedure for optically pure compound (R)-28 is neces-
which was converted to acid 2824,25) by alkaline hydrolysis sary. If such is developed, this route is superior to that using
using LiOH in 94% yield. The optical purity was determined 26 because of its labile phenol group (Chart 4).
as follows. Compound 28 was condensed with (R)-(ꢁ)-
Detailed examination of reaction conditions should be
phenylethylamine to give (R) and (S)-(R)-(ꢁ)-phenylethyl- needed for macrolactamization of 4 and 5 to gain right-hand
amide of 28 (R : Sꢂ5 : 4) as a diastereomeric mixture. From segment 3.
the values of the optical rotation in each compound ([a]2D0 21:
Synthesis of Linear Precursor 6a by Route 3-1 and
ꢃ126.73°; 26: ꢃ121.91°; 27: ꢃ130.06°; 28: ꢃ15.82°), it Route 3-2 Initially, synthesis of 6a was carried out accord-
seems racemization occurred at the step of alkaline hydroly- ing to the strategy in Route 3-1 as shown in Fig. 4. This route
sis resulting from the enolization labile 28.
is characterized by using dipeptide 2 already obtained by
Tryptophan derivative (R)-15 was converted to tert-butyl Route 1. Conversion of 24 to boronic ester 33a, followed by
ester (R)-29 by treatment with excess tert-butylbromide,26) peptide formation with the D-ring moiety 35 should give 6a.
K2CO3 in the presence of benzyltriethylammonium chloride The key reaction of this route is an effective Suzuki–Miyaura
(BTEAC) in dimethylacetoamide (DMAC) in 82% yield.
coupling29) of 24 for 33a. A cyclic reaction of 6a in the last
The precursor 5 was synthesized by two processes, which step would give 3 by Suzuki coupling.11,28)
are differentiated by using chiral hydroxyphenylglycine 26
The reason for using Suzuki coupling is the stability of the
and racemic hydroxyphenylglycine methyl ether 28 (Chart boronic ester against purification with silica gel. Recently, a
4). Stille coupling between 20 and (R)-29 was fairly success- successful synthesis of a model system of the 17-membered
fully performed under the same conditions in Route 1 using right-hand segment of 1 and 2 was reported30) by using
i
Pd2(dba)3·CHCl3, CuI, Ph3As, Pr2NEt in DMF to provide Suzuki coupling, which encouraged us in our work.
biaryl compound 30 in 41% yield. Selective removal of the
A precursor 6a was synthesized as follows (Chart 5).
Boc group by p-TsOH gave the salt 31 (97%), which was Suzuki–Miyaura reaction of dipeptide 24 using bis(pinaco-
condensed with chiral 26 using HATU27) and collidine to late)diboron in the presence of PdCl2(dppf), KOAc in DMSO
provide a chiral phenolic tripeptide (25%), HATU was used at 80 °C yielded a diasteromeric mixture of 33a and 33b
because of its higher reactivity than that of EDCI. The reason (total yield: 64%, 33a : 33bꢂ1.5 : 1). It seems the alkaline
for low producibility of this compound is considered to be condition at high temperature caused racemization at the
the side reaction resulted in an unprotected phenol group. chlorinated phenylglycine moiety. Quantitative separation of
Conversion of the phenol to methyl ether by TMSCHN2 gave each compound in this step was fairly difficult, so isolation of
32a in 34% yield.
diastereomers was carried out at the last step. The tert-butyl
Next, another procedure for 32a was carried out. Conden- group of the diastereomeric mixture (33) was removed by

October 2005
1281
Fig. 4. Synthetic Strategy of 6a, 6b for 3 by Route 3
Chart 5
TFA-CH2Cl2 at 0 °C to room temperature to provide acid 34 (36, 85%), then removal of the Boc group using TFA gave
quantitatively. The Boc group of 19 was removed by p-TsOH TFA salt 37 (quant.), which was neutralized with NMM, fol-
to give the salt 35, quantitatively. After neutralization of the lowed by condensation with 26 using EDCI, HOBT gave
salt 35 by NMM, the resulted amine was condensed with dipeptide 38 (77%), which was converted to dimethyl ether
acid 34 using EDCI to give a diasteromeric isomer (R,R,R)- 39 (82%) by TMSCHN2. Removal of the Boc group by treat-
6a (29%) and (R,R,S)-6a (20%). Partial elimination of the ment with TFA afforded the salt 40, which was neutralized
boronic ester group in the course of the removal of the t- with NaHCO3 to provide an amine 41 quantitatively from 39.
butyl ester in TFA occurred and this caused the low pro-
Transformation of (R)-29 by Suzuki–Miyaura coupling
ducibility of 6a (Chart 5).
using bis(pinacolate)diboron, Pd(dppf)Cl2 at 75 °C in diox-
As described above, racemization in the step of the ane for 2 h afforded 42 in 37% yield and the starting material
boronic esterification of 24 is a drawback of this process. was recovered (32%). Further extension of the reaction time
Then another route for 6a (Route 3-2) was considered as and increased amount of the catalyst resulted in only an in-
shown in Fig. 4. This route is characterized by initially build- crease of the side product caused by intermolecular coupling
ing up the dipeptide 41, then peptide formation with the F- reaction. The removal of the t-butyl ester group by TFA at
ring to give tripeptide 6a. The key reaction of this route is ef- 0 °C gave the acid 43 (quant.). Condensation of 41 with 43
fective boronic esterification of tryptophan (R)-15 by by HATU in the presence of collidine afforded tripeptide 6a
Suzuki–Miyaura coupling. The merit of this route is that the as a single product in 32% yield. This result proved racem-
tryptophan moiety is presumed not to be a racemization- ization did not occur in the course of boronic esterification of
prone compound.
(R)-29 as we expected. The lower yield is mainly attributed
The dipeptide 41 was efficiently synthesized as follows to partial removal of the boronic ester group by TFA in the
(Chart 6). Esterification of 18 by 1 equivalent TMSCHN2 course of the removal of the t-butyl group of 42. Further op-

1282
Vol. 53, No. 10
Chart 6
timization of this reaction conditions will be required (Chart
6).
Synthesis of the Linear Precursor 6b by Route 3-3
The strategy of Route 3-3 is shown in Fig. 4. This route is
characterized by the coupling between the dipeptide 41 and F
ring moiety 46 by peptide bond formation to give tripeptide
6b. Hoveyda et al.9) succeeded in the total synthesis of cou-
pling at the ring-closing reaction in the last step though they
used a trimethylstanann group. Stille coupling can be per-
formed under neutral reaction conditions, which should pre-
vent racemization of dichlorohydroxyphenylglycine. Further-
more, Fu et al. discovered31) Pd/P(tBu)3, which is a mild,
highly reactive and general catalyst for Stille coupling. This
catalyst would be effective for macrocyclic carbon–carbon
coupling, which is assumed not to be easy in a sterically hin-
dered compound. Tripeptide 6b would be expected to cyclize
in a similar manner.9,31) The key reaction in this route for 6b
is effective synthesis of tributyl stannyl derivative 46.
Chart 7
Synthesis of 46 is performed as follows (Chart 7). Meth-
ylation of (R)-15 by TMSCHN2 afforded methyl ester 44
(75%), which was converted to 45 by Suzuki–Miyaura cou-
pling using (Bu3Sn)2 in the presence of (o-tolyl3P)PdCl2, di-
isopropylethylamine affording 45 (45%), followed by alka-
line hydrolysis according to the procedure as described9) in
the literature to provide sodium salt 46 in 99% yield, though
partial removal of the Bu3Sn group (25%) occurred at the
1
same time, which was confirmed by H-NMR. The salt 46
Fig. 5. Stability of the Right-Hand Segment of Complestatin 1 (3) and
Chloropeptin 2 (47) Optimized by DFT Calculation
was used as a mixture because purification was impossible.
Condensation of 46 with dipeptide 41 by treatment with
HATU and collidine gave tripeptide 6b in 54% yield. Opti-
Matsuzaki et al. found32) in his thesis that 1 and 2 were
mization of the reaction conditions in the hydrolysis proce- converted to 2 and 1, respectively, in the solution of MeOH-
dure of 45 will increase the total yield in this route (Chart 7). TFA by monitoring HPLC and that the rate of the conversion
Examination to find the best condition to achieve cyclic re- from 1 to 2 was much faster than that of 2 to 1, from which
action using 6a and 6b should be needed.
they assumed 2 is more stabilized than 1. We consider from
Consideration on Acidic Transformation from Com- the above result that interconversion should occur between 1
plestatin (1) to Chloropeptin (2) by DFT (Density Func- and 2, and thermodynamic equilibrium proceeds to produce
tional Theory) Calculation Jayasuriya et al.6) reported 2 ultimately.
that 1 can be completely transformed into 2 by TFA at 50 °C
To substantiate the above result, we compared the stability
and reported its reaction mechanism. Also, a model com- of the right-hand segment of 1 and 2 by DFT calculation.
pound of the right-hand segment of 1 easily transforms into Two molecules 3 and 47 were chosen as the right-hand seg-
that of 2 by TFA according to the literature.30)
ment of 1 and 2. As shown in Fig. 5, the reference of the ab-

October 2005
1283
Fig. 6. Conformation of the Right-Hand Segment of 1 (3) and 2 (47)
Experimental
General Procedure Melting points were taken on a Yanagimoto hot-
stage and are uncorrected. Optical rotations were measured on a JASCO
model DPI-1000 digital polarimeter. NMR were recorded on a Varian MER-
CURY plus 300, UNITY-400 spectrometers. All the NMR spectra were
taken using CDCl3 as a solvent unless otherwise described. The signals were
assigned by H–1H COSY, DEPT, HMQC, HMBC experiments. Mass spec-
1
Fig. 7. Roussi’s Data for 16- and 17-Membered Macrolactams33)
tra were obtained on a JEOL JMS-DX300 mass spectrometer (low-resolu-
tion mass spectrometry) and JEOL JMS-AX505 HA mass spectrometer
(high-resolution mass spectrometry). Rf values and preparative TLC were
done on Silica gel 60 PF254 (Merck). Flash column chromatography was
done using Silica gel 60 (art.1.09385, Merck). 2M Solution in n-hexane
(Aldrich) was used for TMSCHN2.
solute value (DE) between the 16-membered 47 and the
17-membered 3 in each most stable conformation is
ꢃ6.3 kcal/mol, that is, 47 is more stable than 3.
Each most stabilized stereostructure is shown in Fig. 6.
The indole ring in 17-membered ring 3 is bent to make a
strain in the whole ring whereas, in 16-membered ring 47,
the indole ring is not bent as seen in the figures. The stain of
the indole ring should result in instability of 3 and also easy
transformation from 1 to 2.
We have been interested in knowing which compounds (1,
2) cyclize more easily at the step of the cyclization for the
right-hand segment. Roussi reported33) the result of the cyclic
reaction of 49, 50 under same reaction condition using
Ni(Ph3P)2Cl2 to afford simplified 17- and 16-membered ring
system 51, 52, respectively, in each 17%, 1% yield (Fig. 7).
This showed cyclization for the 16-membered ring is ex-
tremely difficult compared with that for the 17-membered
ring. Both this result and our study for stability calculation
Theoretical Calculations DFT calculation was performed using Spar-
tan ‘04 (for Windows).34) The structures were drawn at the entry-level of
input and minimized. Equilibrium geometry was obtained at B3LYP level of
DFT for each molecule at the ground state form with a 6–31G* basis
set.35—37)
N-Acetyl-6-nitroindoline (8) To a solution of 7 (5.0 g, 30.5 mmol) in
Ac2O (25 ml) was added pyridine (1.25 ml). After the solution was stirred
for 1.4 h at room temperature, precipitated crystals were filtered off to afford
8 (6.0 g, 96%) as yellow crystals. Rf: 0.11 (hexane/AcOEtꢂ1 : 1). mp: 152—
156 °C. 1H-NMR (300 MHz) dH: 2.24 (3H, s, COCH3), 3.27 (2H, t,
Jꢂ8.5 Hz, 3-H2), 4.16 (2H, t, Jꢂ8.5 Hz, 2-H2), 7.23 (1H, d, Jꢂ8.0 Hz, 4-H),
7.82 (1H, dd, Jꢂ2.0, 8.0 Hz, 5-H), 8.88 (1H, d, Jꢂ2.0 Hz, 7-H). 13C-NMR
(75 MHz) dC: 24.11 (q, COCH3), 27.98 (t, 3-C), 49.17 (t, 2-C), 111.42 (d, 7-
C), 118.92 (d, 5-C), 124.32 (d, 4-C), 138.43 (s, 3a-C), 143.59 (s, 7a-C),
147.62 (s, 6-C), 168.96 (s, COCH3). HR-FAB-MS m/z: 207.0771 [MꢁH]ꢁ,
Calcd for C10H11N2O3: 207.0722 [MꢁH].
N-Acetyl-6-aminoindoline (9) To a solution of 8 (5.5 g, 26.7 mmol) in
MeOH (400 ml) was added 10% Pd–C (550 mg) and the mixture was vigor-
indicate that the ease of cyclic reaction to macrolactam is in- ously stirred for 1 h under H2 gas. After the the solution was stirred for 1.4 h
at room temperarure, Pd–C was filtered cautiously and the filtrate was con-
dependent of the stability of the resulting macrolactam.
A closed investigation to find reaction condition for cy-
clization of 4, 5, 6a, and 6b to 3 is necessary in future.
centrated in vacuo to give 9 (4.68 g, quant.) as light pink crystals. Rf: 0.23
(hexane/AcOEtꢂ1 : 2). mp: 187—191 °C. 1H-NMR (300 MHz) dH: 2.20
(3H, s, COCH3), 3.07 (2H, t, Jꢂ8.0 Hz, 3-H2), 3.65 (2H, br s, NH2), 4.02
(2H, t, Jꢂ8.0 Hz, 2-H2), 6.35 (1H, dd, Jꢂ2.0, 8.0 Hz, 5-H), 6.93 (1H, d,
Jꢂ8.0 Hz, 4-H), 7.67 (1H, d, Jꢂ2.0 Hz, 7-H). 13C-NMR (75 MHz) dC: 24.08
Conclusion
(q, COCH3), 28.09 (t, 3-C), 50.61 (d, 2-C), 106.81 (d, 7-C), 113.17 (d, 5-C),
In conclusion, a facile route for the synthesis of the four
124.12 (s, 3a-C), 125.89 (d, 4-C), 144.48 (s, 7a-C), 145.66 (s, 6-C), 171.15
important precursors, tripeptides 4, 5, 6a and 6b, for cycliza-
tion to the right-hand segment (3) of complestatin was
achieved. The precursors 4 and 5 should be utilized for
macrolactamization to 3 at the last step and precursors 6a
and 6b should be utilized for ring-closing reaction to 3 each
using Suzuki and Stille coupling reactions at the last step, re-
spectively. Also, a facile route for the (R)-6-iodo-tryptophan
which is a key compound for the synthesis of the above pre-
cursors was developed. These compounds and the synthetic
procedure described in this paper will serve for the synthesis
of the right-hand segment of complestatin in the near future.
In addition, the stability of 1 and 2 optimized was calcu-
lated by molecular dynamics calculation method.
(s, COCH3). HR-FAB-MS m/z: 176.0959 [M]ꢁ, Calcd for C10H12N2O:
176.0950 [M].
N-Acetyl-6-iodoindoline (10) To a solution of 9 (2.35 g, 13.4 mmol) in
aqueous solution of 80% AcOH (165 ml) were added NaNO2 (1.01 g, 1.1 eq)
in H2O (4.7 ml) and KI (2.44 g, 1.1 eq) in H2O (4.7 ml) at 0 °C under argon.
After the mixture was stirred for 24 h at 0 °C, sodium hydrogen sulfate
(0.1 g) was added, and AcOH was concentrated as an azeotropic mixture
with toluene in vacuo. Resulted residue was diluted with AcOEt (150 ml),
washed with H2O (30 mlꢄ3), dried over Na2SO4, concentrated in vacuo. Pu-
rification of the resulting black oil (4.14 g) by flash column chromatography
(benzene/acetoneꢂ20 : 1) afforded 10 (2.36 g, 62%) as light yellow crystals.
1
Rf: 0.27 (hexane/AcOEtꢂ1 : 2). mp: 102—118 °C. H-NMR (300 MHz) dH:
2.20 (3H, s, COCH3), 3.12 (2H, t, Jꢂ8.5 Hz, 3-H2), 4.01 (2H, t, Jꢂ8.5 Hz,
2-H2), 6.87 (1H, d, Jꢂ8.0 Hz, 4-H), 7.30 (1H, dd, Jꢂ2.0, 8.0 Hz, 5-H), 8.55
(1H, d, Jꢂ2.0 Hz, 7-H). 13C-NMR (75 MHz, CDCl3) dC: 24.20 (q, COCH3),

1284
Vol. 53, No. 10
27.72 (t, 3-C), 48.95 (t, 2-C), 92.06 (s, 6-C), 125.39 (d, 7-C), 125.92 (d, 5- residue was added Ac2O (0.055 ml). After the mixture was stirred for 1.5 h
C), 130.80 (s, 3a-C), 132.38 (d, 4-C), 143.90 (s, 7a-C), 168.68 (s, COCH3). at 90—110 °C, this was basified with 10% ammonia (0.2 ml), diluted with
HR-FAB-MS m/z: 286.9810 [M]ꢁ, Calcd for C10H10NOI: 286.9807 [M].
6-Iodoindoline (11) To a solution of 10 (2.30 g, 8.01 mmol) in MeOH
(115 ml) was added an aqueous solution of 20% NaOH. After the mixture
was stirred for 4.5 h at 75 °C, MeOH was concentrated and the mixture was
H2O (1 ml), extracted with AcOEt (10 mlꢄ3). The H2O layer was acidified
with concentrated HCl, extracted with AcOEt (10 mlꢄ3). The AcOEt layer
was dried over Na2SO4, concentrated in vacuo to afford (RS)-13 (40 mg,
80%) as an oil. [a]2D3 ꢃ1.10° (cꢂ4.2, MeOH). H-NMR data was identified
1
extracted with AcOEt (350 mlꢄ3). The organic layer was dried over with that of (S)-13. To a solution of (RS)-13 (40 mg, 0.108 mmol), D-amino-
Na2SO4, concentrated in vacuo. Purification of the resulting light yellow oil acylase (19.2 mg) in phosphate buffer (0.6 ml) was added CoCl2·6H2O
(1.93 g) by flash column chromatography (hexane/AcOEtꢂ10 : 1) gave 11 (1 mg). After the solution was shaken for 48 h at 37 °C, the reaction mixture
(1.39 g, 71%) as light yellow crystals. Rf: 0.60 (hexane/AcOEtꢂ2 : 1). mp: was filtered through a celite pad. A solution of 10% HCl was dropped to this
83—90 °C. 1H-NMR (300 MHz) dH: 2.98 (2H, dt, Jꢂ1.0, 8.5 Hz, 3-H2), filtrate until pHꢂ5, then extracted with AcOEt (20 mlꢄ3). The water layer
3.26 (1H, br, 1-H), 3.56 (2H, t, Jꢂ8.5 Hz, 2-H2), 6.83 (1H, d, Jꢂ7.5 Hz, 4-
was purified by column chromatography (SEPABEADS sp207, MeOH) gave
1
H), 6.94 (1H, d, Jꢂ2.0 Hz, 7-H), 7.00 (1H, dd, Jꢂ2.0, 7.5 Hz, 5-H). 13C- the desired (R)-14 (13 mg, 36%) as light brown crystals. H-NMR data was
NMR (75 MHz) dC: 29.39 (t, 3-C), 47.46 (t, 2-C), 91.84 (s, 6-C), HR-FAB-
MS m/z: 244.9713 [M]ꢁ, Calcd for C8H8NI: 244.9702 [M].
6-Iodoindole (12) To a solution of 11 (3.2 g, 13.1 mmol) in MeOH was
added salcomine (412 mg, 0.1 eq). After the mixture was stirred for 3.5 h in
identified with that of (R)-14 already obtained.
(R)-N-Carbobenzyloxy-6ꢀ-iodo-tryptophan [(R)-15] To a solution of
(R)-14 (200 mg, 0.604 mmol) in 10% aqueous Na2CO3 (4.0 ml) was added
Cbz-Cl (103 mg, 0.604 mmol) in ether (0.8 ml). After the mixture was stirred
a stream of oxygen at room temperature, it was concentrated in vacuo. Pu- for 3 h at 0 °C, the resulting mixture was acidified with an aqueous solution
rification of the resulting black oil (3.55 g) by flash column chromatography of 10% HCl (pHꢂ3). Precipitated crystals were filtered and washed with
(hexane/AcOEtꢂ8 : 1) afforded 12 (3.12 g, 98%) as light violet crystals. Rf: H2O (5 mlꢄ3) to afford (R)-15 (280 mg, quant.) as white brown crystals. Rf:
0.66 (benzene/acetoneꢂ50 : 1). mp: 70 —71 °C. 1H-NMR (300 MHz) dH: 0.78 (BuOH/AcOH/H2Oꢂ4 : 1 : 5). mp: 125—127 °C. [a]2D3 ꢁ15.48° (cꢂ
6.54 (1H, m, 3-H), 7.10 (1H, dd, Jꢂ2.0, 3.0 Hz, 2-H), 7.43 (total 2H, br s, 4-
0.60, MeOH). 1H-NMR (300 MHz, acetone-d6) dH: 3.21 (1H, dd, Jꢂ7.5,
H, 5-H), 7.70 (1H, d, Jꢂ1.0 Hz, 7-H), 8.01 (1H, br s, 1-H). 13C-NMR 15.0 Hz, 3-Ha), 3.38 (1H, dd, Jꢂ3.5, 15.0 Hz, 3-Hb), 4.55 (1H, br, 2-H),
(75 MHz) dC: 85.66 (s, 6-C), 102.67 (d, 3-C), 119.87 (d, 7-C), 122.20 (d, 4- 4.95, 5.07 (each 1H, d, Jꢂ12.5 Hz, benzyl CH2), 7.21 (1H, s, 2ꢀ-H), 7.25
C), 124.51 (d, 2-C), 126.99 (s, 3a-C), 128.41 (d, 5-C), 136.87 (s, 7a-C). HR- (1H, hidden, NHCO), 7.28 (1H, d, Jꢂ8.0 Hz, 5ꢀ-H), 7.30 (5H, m, benzyl-
FAB-MS m/z: 242.9545 [M]ꢁ, Calcd for C8H6NI: 242.9545 [M].
arom H), 7.45 (1H, d, Jꢂ8.0 Hz, 4ꢀ-H), 7.77 (1H, s, 7ꢀ-H). 13C-NMR
(75 MHz, acetone-d6) dC : 28.09 (t, 3-C), 55.73 (d, 2-C), 66.53 (t, benzyl
CH2), 85.30 (s, 6ꢀ-C), 111.48 (s, 3ꢀ-C), 120.91 (d, 7ꢀ-C), 121.20 (d, 4ꢀ-C),
125.00 (d, 2ꢀ-C), 128.01 (s, 3aꢀ-C), 128.01, 128.35, 128.95 (each d, benzyl-
arom C), 128.35 (d, 5ꢀ-C), 137.93 (s, benzyl-arom C), 138.51 (s, 7aꢀ-C),
(R,S)-N-Acetyl-6ꢀ-iodo-tryptophan (RS)-13 To a mixture of 12 (3.2 g,
12.3 mmol) in AcOH (30 ml) and Ac2O (5.2 ml) was added L-serine (2.6 g,
24.6 mmol). After the solution was stirred for 2 h at 75 °C under argon, it
was diluted with ether (200 ml), and adjusted with 30% aqueous NaOH to
pH 10. The partitioned water layer was ice-cooled and the organic layer was 156.54 (s, NHCO), 173.98 (s, 1-C). HR-FAB-MS m/z: 487.0123 [MꢁNa]ꢁ,
diluted with additional ether (100 ml), extracted with 1 N aqueous NaOH.
Then, the combined water layer was ice-cooled and Na2S2O4 (1.5 mg) was
Calcd for C19H17O4N2INa: 487.0131 [MꢁNa].
(S)-6ꢀ-Iodo-tryptophan [(S)-14] To a solution of (RS)-13 (200 mg,
added to this solution, which was acidified (pHꢂ3) by 5% HCl and kept 0.604 mmol), L-aminocylase (54.0 mg) in phosphate buffer (25 ml) was
standing overnight in a refrigerator. After the precipitated crystals were fil-
tered, the filtrate was concentrated to 1/3, the resulting crystals were filtered,
repeating this procedure further twice. Collecting the crystals gave (RS)-13
added CoCl2·6H2O (5.0 mg). After the solution was shakened for 18 h at
37 °C, the reaction mixture was filtered through a celite pad. A solution of
10% HCl was dropped to this filtrate until pHꢂ5, then extracted with AcOEt
(4.6 g, 89%) as light yellow crystals. The organic layer described above was (15 mlꢄ3). The organic layer was dried over Na2SO4, concentrated in vacuo
dried over Na2SO4, concentrated in vacuo, purified by preparative TLC to provide (R)-13 (73.2 mg, 37%). The water layer was purified by column
(CHCl3/MeOHꢂ20 : 1) to give the starting material 12 (60.2 mg). Rf: 0.17 chromatography (SEPABEADS sp207, MeOH) to give the desired (S)-14
1
(CHCl3/MeOHꢂ20 : 1). mp: 190—195 °C. H-NMR (300 MHz, acetone-d6) (61.1 mg, 37.8%) as light brown crystals. (S)-14: [a]2D4 ꢃ13.88° (cꢂ0.48,
dH: 1.90 (3H, s, COCH3), 3.16 (1H, dd, Jꢂ7.5, 15.0 Hz, 3-Ha), 3.34 (1H, dd,
Jꢂ5.0, 15.0 Hz, 3-Hb), 4.76 (1H, dt, Jꢂ5.0, 7.5 Hz, 2-H), 7.05 (1H, s, 2ꢀ-H),
7.29 (1H, br, NHCO), 7.33 (1H, dd, Jꢂ2.0, 8.0 Hz, 5ꢀ-H), 7.45 (1H, d,
Jꢂ8.0 Hz, 4ꢀ-H), 7.79 (1H, d, Jꢂ2.0 Hz, 7ꢀ-H), 10.27 (1H, br s, 1ꢀ-H). 13C-
NMR (75 MHz, acetone-d6) dC: 22.17 (q, COCH3), 28.00 (t, 3-C), 53.84 (d,
MeOH), HR-FAB-MS m/z: 330.9968 [MꢁH]ꢁ, Calcd for C11H12N2O2I:
330.9935 [MꢁH]. Rf value, H-NMR data were identical with that of (R)-
14.
(S)-N-Carbobenzyloxy-6ꢀ-iodo-tryptophan [(S)-15] To a solution of
(S)-14 (50.0 mg, 0.151 mmol) in 10% aqueous Na2CO3 (1.0 ml) was added
1
2-C), 85.39 (s, 6ꢀ-C), 111.52 (s, 3ꢀ-C), 121.08 (d, 7ꢀ-C), 121.35 (d, 4ꢀ-C), Cbz-Cl (25.8 mg, 0.151 mmol) in ether (0.2 ml). After the mixture was
125.19 (d, 2ꢀ-C), 126.32 (s, 3aꢀ-C), 128.17 (d, 5ꢀ-C), 138.36 (s, 7aꢀ-C), stirred for 2.5 h at 0 °C, the resulting mixture was acidified with an aqueous
170.35 (s, COCH3), 173.38 (s, 1-C). HR-FAB-MS m/z: 373.0033 [MꢁH]ꢁ, solution of 10% HCl (pHꢂ3). The precipitated crystals were filtered and
Calcd for C13H14N2O3I: 373.0049 [MꢁH].
washed with H2O (2 mlꢄ3) to afford (S)-15 (65.6 mg, 89%) as white brown
(R)-6ꢀ-Iodo-tryptophan [(R)-14] To a solution of (RS)-13 (700 mg,
1.89 mmol), D-aminocylase (187 mg) in phosphate buffer (74 ml) was added
CoCl2·6H2O (15.5 mg). After the solution was shakened for 47 h at 37 °C,
the reaction mixture was filtered through a celite pad. A solution of 10%
HCl was dropped to this filtrate until pHꢂ5, then extracted with AcOEt
(80 mlꢄ3). The organic layer was dried over Na2SO4, concentrated in vacuo
crystals. [a]2D4 ꢃ18.22° (cꢂ0.70, MeOH). HR-FAB-MS m/z: 487.0123
1
[MꢁNa]ꢁ, Calcd for C19H17O4N2INa: 487.0133 [MꢁNa]. Rf value and H-
NMR data were identified by comparison with that of (R)-15.
(R)-N-Carbobenzyloxy-6ꢀ-iodo-tryptophan (R)-(ꢁ)-Phenylethylamide
[(R)-16] To a solution of (R)-15 (24.4 mg, 0.053 mmol) in CH2Cl2/THFꢂ
1 : 1 (1.3 ml) were added (R)-(ꢁ)-phenylethylamine (6.4 mg, 0.053 mmol),
to provide (S)-13 (270 mg, 39%). The water layer was purified by column EDCI (10.0 mg, 0.053 mmol), HOBT (7.1 mg, 0.053 mmol) under argon.
chromatography (SEPABEADS sp207, MeOH) to give the desired (R)-14
(299.9 mg, 48%) as light brown crystals. (R)-14: Rf: 0.28 (BuOH/AcOH/
H2Oꢂ4 : 1 : 5). mp: 198—205 °C. [a]2D3 ꢁ11.97° (cꢂ0.64, MeOH). 1H-
NMR (300 MHz, DMSO-d6) dH: 3.00 (1H, dd, Jꢂ8.0, 14.0 Hz, 3-Ha), 3.26
(1H, br d, Jꢂ14.0 Hz, 3-Hb), 3.50 (1H, m, 2-H), 7.20 (1H, br d, Jꢂ8.5 Hz,
After the reaction mixture was stirred for 2 h at room temperature, the solu-
tion was concentrated in vacuo. After the residue was diluted with AcOEt
(50 ml), washed with 10% aqueous solution of NaHCO3 (5 mlꢄ3), 10%
aqueous citric acid (5 mlꢄ3), saturated NaCl (5 mlꢄ3), dried over Na2SO4,
concentrated in vacuo, the resulting yellow brown oil (44.5 mg) was purified
5ꢀ-H), 7.21 (1H, br s, 2ꢀ-H), 7.40 (1H, d, Jꢂ8.5 Hz, 4ꢀ-H), 7.71 (1H, br s, 7ꢀ- by preparative TLC (CHCl3/MeOHꢂ20 : 1) to afford white brown crystals
H), 11.28 (1H, br, 1ꢀ-H). 13C-NMR (75 MHz, DMSO-d6) dC: 26.84 (t, 3-C),
54.57 (d, 2-C), 84.37 (s, 6ꢀ-C), 109.67 (s, 3ꢀ-C), 119.71 (d, 7ꢀ-C), 120.56 (d,
(R)-16 (29.8 mg, 65.3%) as white brown crystals. Rf: 0.34 (hexane/AcOEtꢂ
1 : 1). mp: 151—159 °C. [a]2D4 ꢁ1.43° (cꢂ0.39, CHCl3). 1H-NMR (300
4ꢀ-C), 124.93 (s, 3aꢀ-C), 126.35 (d, 2ꢀ-C), 126.59 (d, 5ꢀ-C), 137.71 (s, 7aꢀ- MHz) dH: 1.31 (3H, d, Jꢂ7.0 Hz, CHCH3), 3.04 (1H, dd, Jꢂ8.0, 15.0 Hz, 3-
C). HR-FAB-MS m/z: 330.9968 [MꢁH]ꢁ, Calcd for C11H12N2O2I: 330.9944 Ha), 3.24 (1H, dd, Jꢂ5.0, 15.0 Hz, 3-Hb), 4.40 (1H, dt, Jꢂ5.0, 8.0 Hz, 2-H),
[MꢁH].
4.97 (1H, q, Jꢂ7.0 Hz, CHCH3), 5.10 (2H, s, benzyl CH2), 5.49 (1H, br d,
(S)-13: [a]2D3 ꢁ19.49° (cꢂ0.49, MeOH). HR-FAB-MS m/z: 373.0055 Jꢂ7.5 Hz, 2-NHCO), 5.68 (1H, d, Jꢂ7.0 Hz, 1-CONH), 6.65 (1H, d,
[MꢁH]ꢁ, Calcd for C13H14O3N2I: 373.0049 [MꢁH]. Rf value and H-NMR
data were quite identical with that of (RS)-13 already described.
Jꢂ2.0 Hz, 2ꢀ-H), 6.96 (2H, m, phenylethyl-arom 2H), 7.23, 7.37 (each 1H,
hidden, 4ꢀ-H, 5ꢀ-H), 7.24 (3H, m, phenylethyl-arom 3H), 7.33 (5H, m, ben-
1
Racemization of (S)-N-Acetyl-7-iodo-tryptophan ((S)-13) and Optical zyl-arom H), 7.65 (1H, s, 7ꢀ-H), 7.77 (1H, br s, 1ꢀ-H). HR-FAB-MS m/z:
Resolution Using D-Aminoacylase Compound (S)-13 was dissolved in
10% aqueous NaOH (0.055 ml) and concentrated in vacuo. To the resulting
568.1084 [MꢁH]ꢁ, Calcd for C27H27IN3O3: 568.1097 [MꢁH].
(S)-N-Carbobenzyloxy-6ꢀ-iodo-tryptophan (R)-(ꢁ)-Phenylethylamide

October 2005
1285
[(S)-16] To a solution of (S)-15 (24.4 mg, 0.053 mmol) in CH2Cl2/THFꢂ 3.73 (3H, s, COOCH3), 3.76 (3H, s, OCH3), 5.25 (1H, d, Jꢂ7.5 Hz, 2-H),
1 : 1 (1.3 ml) was added (R)-(ꢁ)-phenylethylamine (6.4 mg, 0.053 mmol), 5.51 (1H, d, Jꢂ7.5 Hz, NHCO), 7.30 (1H, d, Jꢂ2.0 Hz, 6ꢀ-H), 7.71 (1H, d,
EDCI (10.0 mg, 0.053 mmol), HOBT (7.1 mg, 0.053 mmol) under argon.
After the mixture was stirred for 2 h at room temperature, the solution was
Jꢂ2.0 Hz, 2ꢀ-H). 13C-NMR (75 MHz) dC: 10.41 (tꢄ3, C(CH2)2CH2CH3ꢄ3),
13.64 (qꢄ3, (CH2)3CH3ꢄ3), 27.29 (tꢄ3, CH2CH2CH2CH3ꢄ3), 28.30 (qꢄ3,
concentrated in vacuo. After the residue was diluted with AcOEt (50 ml), C(CH3)3ꢄ3), 29.00 (tꢄ3, CH2(CH2)2CH3ꢄ3), 52.75 (q, COOCH3), 56.34
washed by 10% aqueous solution of NaHCO3 (5 mlꢄ3), 10% aqueous citric
acid (5 mlꢄ3), saturated NaCl (5 mlꢄ3), dried over Na2SO4, concentrated in
(d, 2-C), 61.80 (q, OCH3), 80.31 (s, C(CH3)3), 90.97 (s, 3ꢀ-C), 134.31 (s, 1ꢀ-
C), 136.12 (d, 6ꢀ-C), 137.22 (s, 5ꢀ-C), 138.64 (d, 2ꢀ-C), 154.79 (s, NHCO),
vacuo, the resulting yellow brown oil (42.3 mg) was purified by preparative 164.54 (s, 4ꢀ-C), 171.32 (s, 1-C). HR-FAB-MS m/z: 734.1354 [MꢁNa]ꢁ,
TLC (CHCl3/MeOHꢂ20 : 1) to afford white brown crystals (S)-16 (25.3 mg,
55%) as white brown crystals. Rf: 0.38 (hexane/AcOEtꢂ1 : 1). mp: 135—
Calcd for C27H46O5NNaSn120I: 734.1340 [MꢁNa].
(R)-3ꢀ,5ꢀ-Dichloro-4ꢀ-hydroxy-phenylglycine (21) To a solution of 17
(5.0 g, 29.9 mmol) in 1.0 M HCl in AcOH (100 ml) was dropped SO2Cl2
(6.95 ml, 68.8 mmol) in AcOH (10 ml) during 30 min. After the mixture was
1
140 °C. [a]2D2 ꢃ1.72° (cꢂ0.30, CHCl3). H-NMR (300 MHz) dH: 1.19 (3H,
d, Jꢂ7.0 Hz, CHCH3), 3.10 (1H, dd, Jꢂ7.5, 15.0 Hz, 3-Ha), 3.24 (1H, dd,
Jꢂ5.0, 15.0 Hz, 3-Hb), 4.46 (1H, dt, Jꢂ5.0, 8.0 Hz, 2-H), 4.86 (1H, q, stirred for 30 min at 70 °C and for 2 h at room temperature, it was diluted
Jꢂ7.5 Hz, CHCH3), 5.50 (2H, br, benzyl CH2), 5.40 (1H, br d, Jꢂ8.0 Hz, 2-
NHCO), 5.62 (1H, d, Jꢂ8.0 Hz, 1-CONH), 6.88 (1H, br, 2ꢀ-H), 7.00 (2H, m,
with ether (150 ml) and allowed to stand for 15 min. After the resulting pre-
cipitates were filtered, it was dissolved in 1 N HCl (100 ml) and filtered. The
phenylethyl-arom 2H), 7.22 (3H, m, phenylethyl-arom 3H), 7.23 (each 1H, filtrate was adjusted to pH 5 by 28% aqueous ammoniac solution, then the
hidden, 4ꢀ-H or 5ꢀ-H), 7.33 (5H, m, benzyl-arom-H), 7.56 (1H, d, Jꢂ7.5 Hz, precipitated crystals were filtered, washed with H2O (10 mlꢄ2), acetone
4ꢀ-H or 5ꢀ-H), 7.63 (1H, s, 7ꢀ-H), 8.07 (1H, br s, 1ꢀ-H). HR-FAB-MS m/z: (20 mlꢄ2) to give 21 (5.401 g, 77%) as white crystals. Rf: 0.40 (BuOH/
568.1099 [MꢁH]ꢁ, Calcd for C27H27IN3O3: 568.1097 [MꢁH]. AcOH/H2Oꢂ4 : 1 : 5). mp: 222—225 °C. [a]2D0 ꢃ126.73° (cꢂ1.01, 1 N-HCl).
(R)-4ꢀ-Hydroxy-3ꢀ,5ꢀ-diiodo-phenylglycine (18) To a solution of 17 1H-NMR (300 MHz, CD3OD) dH: 4.47 (1H, s, 2-H), 7.43 (2H, s, 2ꢀ, 6ꢀ-H).
(10.5 g, 63.0 mmol) in AcOH (90 ml) was dropped ICl (22.5 g, 138.6 mmol)
in AcOH (3.4 ml) during 10 min under argon. After the solution was stirred
for 72 h at room temperature, the reaction mixture was poured into ice water
(1000 ml). The precipitated crystals were filtered, washed with EtOH (100
mlꢄ3) to provide 18 (22.6 g, 87%) as light brown crystals. Rf: 0.6 (BuOH/
AcOH/H2Oꢂ4 : 1 : 5). mp: 193—195 °C. [a]2D5 ꢃ83.96° (cꢂ0.50, 1 N-HCl).
13C-NMR (75 MHz, CD3OD) dH: 58.62 (d, 2-C), 123.49 (sꢄ2, 3ꢀ, 5ꢀ-C),
129.36 (dꢄ2, 2ꢀ, 6ꢀ-C), 132.70 (s, 1ꢀ-C), 151.23 (s, 4ꢀ-C), 171.95 (s, 1-C).
HR-FAB-MS m/z: 235.9928 [MꢁH]ꢁ, Calcd for C8H8O3NCl352: 253.9981
[MꢁH].
(R)-3ꢀ,5ꢀ-Dichloro-4ꢀ-hydroxy-phenylglycine tert-Butyl Ester (22)
A
solution of 21 (1.0 g, 4.24 mmol) in 1,4-dioxane (11 ml) and conc.H2SO4
1H-NMR (300 MHz, DMSO-d6) dH: 4.16 (1H, s, 2-H), 7.74 (2H, s, 2ꢀ, 6ꢀ- (1.0 ml) were added into pressure-resistant glass tube vessel (max: 1 MPa).
H), 8.43 (4H, br s, COOH, NH2, OH). HR-FAB-MS m/z: 419.8565 [Mꢁ Isobutene gas (4.90 g, 86.07 mmol) was then introduced to this solution dur-
H]ꢁ, Calcd for C8H8O5NI2: 419.8594 [MꢁH].
ing 1 h under cooling the vessel in dry ice–acetone (at ꢃ78 °C). After the
(R)-N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-diiodo-4ꢀ-methoxy-phenylglycine tube was sealed tightly, the reaction temperature was raised to room temper-
Methyl Ester (19) To a solution of 18 (945 mg, 2.26 mmol) in H2O ature and allowed to stand for 72 h. Then saturated NaHCO3 was added to
(4.0 ml) were added NEt3 (1.9 ml, 3.39 mmol), Boc-ON (574 mg, 2.51 mmol)
in 1,4-dioxane (4.0 ml). After the solution was stirred for 2 h, the resulting
the reaction mixture until basic and the resulting mixture was extracted with
AcOEt (80 mlꢄ3). The organic layer was dried over Na2SO4, concentrated in
mixture was diluted with AcOEt (80 ml), extracted by H2O (30 mlꢄ3). The vacuo affording 22 (0.744 g, 60%) as white crystals. Rf: 0.23 (hexane/
water layer was washed with AcOEt (30 mlꢄ3), acidified by 10% aqueous
AcOEtꢂ1 : 1). mp: 120—122 °C. [a]2D3 ꢃ109.260° (cꢂ0.2, CHCl3). 1H-
citric acid and extracted by AcOEt (80 mlꢄ3). The organic layer was NMR (300 MHz) dH: 1.40 (9H, s, tBu), 3.27 (3H, br s, NH2, OH), 4.33 (1H,
washed with saturated NaCl (30 ml), dried over Na2SO4, concentrated in
vacuo to afford Boc derivative (1.17 g, quant.) as a light brown crystals. The
s, 2-H), 7.21 (2H, s, 2ꢀ, 6ꢀ-H). 13C-NMR (75 MHz) dC : 27.86 (qꢄ3,
C(CH3)3), 57.67 (d, 2-C), 82.38 (s, C(CH3)3), 122.25 (s, 3ꢀ, 5ꢀ-C), 126.65 (d,
product was pure enough and used in the next step without purification. Rf: 2ꢀ, 6ꢀ-C), 133.20 (s, 1ꢀ-C), 147.79 (s, 4ꢀ-C), 172.16 (s, 1-C). HR-FAB-MS
0.85 (BuOH/AcOH/H2Oꢂ4 : 1 : 5). mp: 72—75 °C. [a]2D4 ꢃ88.56° (cꢂ0.51,
m/z: 292.0518 [MꢁH]ꢁ, Calcd for C12H16NO3Cl352: 292.0507 [MꢁH].
(R,R)-6ꢀ-Iodo-N-carbobenzyloxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-hy-
1
CHCl3). H-NMR (400 MHz) dH: 1.28 (9H, s, Boc), 4.97 (1H, d, Jꢂ5.0 Hz,
2-H), 5.82 (1H, br s, OH), 7.75 (2H, s, 2ꢀ, 6ꢀ-H), 8.05 (1H, d, Jꢂ5.0 Hz, droxy-phenylglycine tert-Butyl Ester (23) To a solution of 22 (44.0 mg,
NHCO). 13C-NMR (100 MHz) dC: 28.27 (q, C(CH3)3), 56.82 (d, 2-C), 81.93 0.151 mmol) and (R)-15 (70.0 mg, 0.151 mmol) in THF (4.4 ml) were added
i
(s, 3ꢀ, 5ꢀ-C), 82.55 (s, C(CH3)3), 133.89 (s, 1ꢀ-C), 137.91 (d, 2ꢀ, 6ꢀ-C), FDPP (87.0 mg, 0.227 mmol) and Pr2NEt (58.4 mg, 0.453 mmol). After the
153.41 (s, 4ꢀ-C), 156.87 (s, NHCO). HR-FAB-MS m/z: 541.8939. [Mꢁ mixture was stirred for 24 h at room temperature under argon, the solution
Na]ꢁ, Calcd for C13H15O5NNaI2: 541.8937 [MꢁNa].
To a solution of above Boc derivative (1.035 g, 1.99 mmol) in a mixed sol-
was concentrated in vacuo. Purification of the resulting yellow oil
(308.8 mg) by preparative TLC (CHCl3/MeOHꢂ10 : 1) gave 23 (70.5 mg,
vent of MeOH (3.0 ml) and benzene (4.0 ml) was dropped TMSCHN2 64%) as white crystals. Rf: 0.77 (CHCl3/MeOHꢂ5 : 1). mp: 100—102 °C.
1
t
(3.0 ml, 4.38 mmol) in benzene (4.0 ml) during 30 min. After the mixture
was stirred for 2 h and concentrated in vacuo, the resulting yellow oil 3.11 (1H, dd, Jꢂ7.5, 14.3 Hz, Trp 3-Ha), 3.33 (1H, dd, Jꢂ4.0, 14.3 Hz, Trp
[a]2D0 ꢃ30.30° (cꢂ0.2, CHCl3). H-NMR (400 MHz) dH: 1.34 (9H, s, Bu),
(1.32 g) was purified by flash column chromatography (hexane/AcOEtꢂ
7 : 1) affording 19 (1.05 g, 96%) as white crystals. Rf: 0.89 (CHCl3/MeOHꢂ
7 : 1). mp: 85—86 °C. [a]2D4 ꢃ89.60° (cꢂ0.50, CHCl3). 1H-NMR (300 MHz)
3-Hb), 4.56 (1H, dt, Jꢂ4.0, 7.5 Hz, Trp 2-H), 5.09 (1H, d, Jꢂ7.0 Hz, CHPG
2-H), 5.04, 5.10 (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.43 (1H, d,
Jꢂ7.5 Hz, Trp NHCO), 6.23 (1H, br, OH), 6.85 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-
dH: 1.44 (9H, s, Boc), 3.75 (3H, s, COOCH3), 3.84 (3H, s, OCH3), 5.19 (1H, H), 6.91 (1H, br d, Jꢂ7.0 Hz, CHPG NHCO), 7.08 (2H, s, CHPG 2ꢀ, 6ꢀ-H),
d, Jꢂ7.0 Hz, 2-H), 5.63 (1H, d, Jꢂ6.0 Hz, NHCO), 7.74 (2H, s, 2ꢀ-H, 6ꢀ-H).
13C-NMR (75 MHz) dC: 28.27 (qꢄ3, C(CH3)3), 53.11 (q, COOCH3), 55.64
(d, 2-C), 60.66 (q, OCH3), 80.66 (s, C(CH3)3), 90.79 (s, 3ꢀ, 5ꢀ-C), 136.68 (s,
1ꢀ-C), 138.33 (d, 2ꢀ, 6ꢀ-C), 154.57 (s, NHCO), 138.94 (s, 4ꢀ-C), 170.57 (s,
1-C). HR-FAB-MS m/z: 569.9250 [MꢁNa]ꢁ, Calcd for C15H19O5NNaI2:
569.9250 [MꢁNa].
7.28—7.38 (5H, m, benzyl-arom H), 7.33 (2H, hidden, Trp 4ꢀ-H, 5ꢀ-H),
7.68 (1H, d, Jꢂ2.0 Hz, Trp 7ꢀ-H), 8.21 (1H, br, Trp 1ꢀ-H). HR-FAB-
MS m/z: 760.0459 [MꢁNa]ꢁ, Calcd for C31H30O6N3Cl352INa: 760.0454
[MꢁNa].
(R,R)-6ꢀ-Iodo-N-carbobenzyloxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-me-
thoxy-phenylglycine tert-Butyl Ester (24) To a solution of 23 (156 mg,
(R)-N-tert-Butoxycarbonyl-3ꢀ-iodo-4ꢀ-methoxy-5ꢀ-tributylstannyl- 0.345 mmol) in MeOH (1.6 ml) and benzene (4.7 ml) was added TMSCHN2
phenylglycine Methyl Ester (20) To a solution of 19 (914 mg, 1.67 mmol) (0.208 ml, 0.42 mmol). After the mixture was stirred for 2 h at room temper-
in CH3CN (7.4 ml) were added (Bu3Sn)2 (1.17 g, 2.0 mmol), (o- ature under argon, this was concentrated in vacuo. The resulted yellow oil
i
tolyl3P)2PdCl2 (124 mg, 0.167 mmol), Pr2NEt (215 mg, 5.02 mmol) under
argon. After the mixture was stirred for 2 h at 85 °C, it was concentrated in
vacuo and the residue was dissolved in AcOEt (200 ml), which was washed
(210.3 mg) was purified by preparative TLC (hexane/AcOEtꢂ1 : 1) to give
24 (159 mg, quant.) as white crystals. Rf: 0.70 (hexane/AcOEtꢂ3 : 1). mp:
1
90—93 °C. [a]2D0 ꢃ32.24° (cꢂ0.2, CHCl3). H-NMR (400 MHz) dH: 1.35
t
with H2O (30 mlꢄ2), sat. NaCl aq. (30 mlꢄ1), dried over Na2SO4, and con- (9H, s, Bu), 3.13 (1H, dd, Jꢂ7.5, 14.5 Hz, Trp 3-Ha), 3.30 (1H, dd, Jꢂ5.0,
centrated in vacuo. After purification of the resulting yellow oil (1.32 g) by 14.5 Hz, Trp 3-Hb), 3.87 (3H, s, OCH3), 4.56 (1H, dt, Jꢂ5.0, 7.5 Hz, Trp 2-
flash column chromatography (hexane/AcOEtꢂ20), the resulting oil was
further purified by preparative TLC (benzene/hexaneꢂ2 : 1ꢄ3) to give 20 CHPG 2-H), 5.46 (1H, d, Jꢂ7.5 Hz, Trp NHCO), 6.86 (1H, br, Trp 2ꢀ-H),
(294 mg, 28%) as a light yellow oil. Rf: 0.60 (hexane/AcOEtꢂ3 : 1). 6.92 (1H, d, Jꢂ6.5 Hz, CHPG NHCO), 7.14 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.33
[a]2D1 ꢃ17.21° (cꢂ0.40, CHCl3). 1H-NMR (300 MHz) dH: 0.90 (9H, m, (1H, hidden, Trp 4ꢀ, 5ꢀ-H), 7.28—7.38 (5H, benzyl-arom H), 7.68 (1H, t,
(CH2)3CH3ꢄ3), 1.08 (6H, m, (CH2)2CH2CH3ꢄ3), 1.32 (6H, m, CH2CH2-
Jꢂ1.0 Hz, Trp 7ꢀ-H), 8.23 (1H, brs, Trp 1ꢀ-H). 13C-NMR (100 MHz) dC:
CH2CH3ꢄ3), 1.44 (9H, s, Boc), 1.48—1.68 (6H, m, CH2(CH2)2CH3ꢄ3), 27.79 (qꢄ3, C(CH3)3), 28.04 (t, Trp 3-C), 55.58 (d, Trp 2-C), 60.73 (q,
H), 5.09, 5.14 (each 1H, d, Jꢂ13.0 Hz, benzyl CH2), 5.14 (1H, d, Jꢂ6.5 Hz,

1286
Vol. 53, No. 10
OCH3), 67.21 (t, benzyl CH2), 83.66 (s, C(CH3)3), 86.27 (s, Trp 6ꢀ-C),
110.20 (s, Trp 3ꢀ-C), 120.09 (d, Trp 5ꢀ-C), 120.23 (d, Trp 7ꢀ-C), 123.64 (d,
Jꢂ6.0 Hz, 2-H), 5.70 (1H, br s, OH), 7.36 (2H, s, 2ꢀ, 6ꢀ-H), 8.07 (1H, d,
Jꢂ6.0 Hz, NHCO). HR-FAB-MS m/z: 358.0238 [MꢁNa]ꢁ, Calcd for
Trp 2ꢀ-C), 126.64 (s, Trp 3aꢀ-C), 127.25 (d, CHPG 2ꢀ, 6ꢀ-C), 127.97, 128.43 C13H15O5NCl352Na: 358.0225 [MꢁNa].
(each d, benzyl-arom 2, 6 and 3, 5-C), 127.97, 128.48 (each d, Trp 4ꢀ-C,
(R)-N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxy-phenylglycine
benzyl 4ꢀ-C), 129.35 (s, CHPG 3ꢀ, 5ꢀ-C), 134.15 (s, CHPG 1ꢀ-C), 135.86 (s, Methyl Ester (27) To a solution of 26 (54.5 mg, 0.163 mmol) in a mixture
benzyl-arom 1-C), 137.26 (s, Trp 7aꢀ-C), 151.89 (s, CHPG 4ꢀ-C), 155.81 (s, of MeOH (0.2 ml) and benzene (6.0 ml) was added TMSCHN2 (0.21 ml,
Trp NHCO), 167.89 (s, CHPG 1-C), 170.39 (s, Trp 1-C). HR-FAB-MS m/z: 0.424 mmol) dropwise. After the mixture was stirred for 15 min, this was
774.0579 [MꢁNa]ꢁ, Calcd for C32H32O6N3Cl352NaI: 774.0611 [MꢁNa]ꢁ.
(R,R,R)-2-(3-{6-[5-(N-tert-Butoxycarbonyl-2-methoxycarbonyl-
concentrated in vacuo. The resulting yellow oil (68.8 mg) was purified by
preparative TLC (hexane/AcOEtꢂ1 : 1) to provide 27 (50.2 mg, 86%) as
methlyamino)-3-iodo-2-methoxy-phenyl]indol-3-yl}-2-carbobenzyloxy- white crystals. Rf: 0.52 (hexane/AcOEtꢂ2 : 1). mp: 106—108 °C. [a]2D5
aminopropionylamino)-2-(3,5-dichloro-4-methoxy-phenyl) Acetic Acid ꢃ130.06° (cꢂ0.55, CHCl3). 1H-NMR (300 MHz) dH: 1.41 (9H, s, Boc),
tert-Butyl Ester (25) To a solution of 24 (30.0 mg, 0.037 mmol) and
20 (28.4 mg, 0.037 mmol) in DMF (1.5 ml) were added Pd2(dba)3·CHCl3
3.73 (3H, s, COOCH3), 3.86 (3H, s, OCH3), 5.22 (1H, br d, Jꢂ7.0 Hz, 2-H),
5.66 (1H, d, Jꢂ7.0 Hz, NHCO), 7.30 (2H, s, 2ꢀ, 6ꢀ-H). 13C-NMR (75 MHz)
(4.0 mg, 0.007 mmol), CuI (1.6 mg, 0.015 mmol), Ph3As (5.0 mg, 0.030 dC: 28.32 (q, C(CH3)3), 53.15 (q, COOCH3), 56.37 (d, 2-C), 60.69 (OCH3),
mmol), iPr2NEt (14.3 mg, 0.111 mmol). After the mixture was stirred for 2 h
80.61 (s, C(CH3)3), 127.27 (dꢄ2, 2ꢀ, 6ꢀ-C), 129.62 (sꢄ2, 3ꢀ, 5ꢀ-C), 134.45
at room temperature under argon, this was diluted with ether (80 ml), (s, 1ꢀ-C), 152.14 (s, 4ꢀ-C), 154.43 (s, NHCO), 170.30 (s, 1-C). HR-FAB-MS
washed with saturated NH4Cl (10 mlꢄ3), 10% aqueous KF (10 mlꢄ3), con-
centrated in vacuo. The resulting brown oil (108 mg) was purified by prepar-
m/z: 386.0540 [MꢁNa]ꢁ, Calcd for C15H19O5NCl352Na: 386.0538 [MꢁNa].
N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-Dichloro-4ꢀ-methoxyphenylglycine (28)
ative TLC (silica gel, CHCl3/MeOHꢂ50 : 1), after that, repurified by hexane/ To a solution of 27 (20.0 mg, 0.057 mmol) in MeOH (0.5 ml) and THF
AcOEtꢂ1 : 1 affording 25 (14.6 mg, 35%) as yellow crystals and recovered (0.5 ml) were added LiOH·H2O (4.6 mg, 0.115 mmol) in H2O (0.4 ml). After
24 (9.6 mg) and 20 (3.7 mg). 25: Rf: 0.44 (CHCl3/MeOHꢂ50 : 1). mp: 40—
the mixture was stirred for 40 min at 0 °C, 10% citric acid was added to this
1
43 °C. [a]2D4 ꢃ22.02° (cꢂ0.49, CHCl3). H-NMR (400 MHz) dH: 1.37 (9H, solution until pHꢂ4 and extracted with CHCl3 (5 mlꢄ3) dried over Na2SO4,
t
s, Bu), 1.45 (9H, s, Boc), 3.21 (1H, dd, Jꢂ7.5, 14.5 Hz, Trp 3-Ha), 3.36,
concentrated in vacuo to afford 28 (18.0 mg, 94%). Rf: 0.20 (CHCl3/
3.88 (each 3H, s, OCH3ꢄ2), 3.40 (1H, dd, Jꢂ5.0, 14.5 Hz, Trp 3-Hb), 3.75 MeOHꢂ10 : 1). mp: 130—135 °C. [a]2D0 ꢃ15.82 (cꢂ0.52, CHCl3). 1H-NMR
(3H, s, COOCH3), 4.64 (1H, dt, Jꢂ5.0, 7.5 Hz, Trp 2-H), 5.15 (2H, s, benzyl
CH2), 5.22 (1H, d, Jꢂ6.5 Hz, CHPG 2-H), 5.29 (1H, br d, Jꢂ7.5 Hz, IHPG
2-H), 5.39 (1H, br d, Jꢂ7.5 Hz, Trp NHCO), 5.61 (1H, br d, Jꢂ7.5 Hz,
IHPG NHCO), 6.97 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.00 (1H, br d, Jꢂ6.5 Hz,
(300 MHz) dH: 1.27 (9H, s, Boc), 3.90 (3H, s, OCH3), 5.03 (1H, d, Jꢂ
5.5 Hz, 2-H), 7.37 (2H, s, 2ꢀ, 6ꢀ-H), 8.19 (1H, d, Jꢂ5.5 Hz, NHCO), 12.01
(1H, br, OH). 13C-NMR (75 MHz) dC: 28.31 (q, C(CH3)3), 57.69 (d, 2-C),
60.79 (OCH3), 82.60 (s, C(CH3)3), 127.53 (dꢄ2, 2ꢀ, 6ꢀ-C), 129.29 (sꢄ2, 3ꢀ,
CHPG NHCO), 7.18 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.29 (1H, d, Jꢂ8.5 Hz, Trp 5ꢀ- 5ꢀ-C), 135.56 (s, 1ꢀ-C), 151.86 (s, 4ꢀ-C), 156.76 (s, NHCO), 172.18 (s, 1-C).
H), 7.35 (5H, m, benzyl-arom H), 7.36 (1H, d, Jꢂ2.0 Hz, IHPG 2ꢀ-H), 7.65 HR-FAB-MS m/z: 349.0461 [M]ꢁ, Calcd for C14H17O5NCl352: 349.0484
(1H, br d, Jꢂ8.5 Hz, Trp 4ꢀ-H), 7.58 (1H, br, Trp 7ꢀ-H), 7.74 (1H, d, [M].
Jꢂ2.0 Hz, IHPG 6ꢀ-H), 8.16 (1H, br, Trp 1ꢀ-H). 13C-NMR (100 MHz) dC:
(R)-N-Carbobenzyloxy-6ꢀ-iodo-tryptophan tert-Butyl Ester [(R)-29]
t
27.83 (t, Trp 3-C), 27.76 (qꢄ3, Bu C(CH3)3), 28.30 (qꢄ3, Boc C(CH3)3), To a solution of (R)-15 (135.0 mg, 0.269 mmol) in DMAC (3.3 ml) was
52.92, 60.27, 60.37 (each q, OCH3ꢄ3), 55.50 (d, Trp 2-C), 55.91 (d, CHPG added K2CO3 (1.27 g, 8.61 mmol), (CH3)3CBr (2.16 ml, 17.22 mmol), ben-
2-C), 56.46 (d, IHPG 2-C), 67.28 (t, benzyl CH2), 80.44 (s, Boc C(CH3)3), zyltriethylammonium chloride (66.0 mg, 0.269 mmol). After the mixture was
t
83.67 (s, Bu C(CH3)3), 93.67 (s, IHPG 5ꢀ-C), 110.01 (s Trp 3ꢀ-C), 111.87 stirred for 2.5 h at 55 °C under argon, it was poured into ice-water (30 ml)
(d, Trp 7ꢀ-C), 118.45 (d, Trp 5ꢀ-C), 121.22 (d, Trp 4ꢀ-C), 124.37 (d, Trp 2ꢀ- and extracted with AcOEt (10 mlꢄ3). The organic layer was washed with
C), 127.04 (s, 3aꢀ-C), 127.45 (d, CHPG 2ꢀ, 6ꢀ-C), 128.13, 128.29, 128.58 H2O (5 mlꢄ3), dried over Na2SO4, concentrated in vacuo. The resulting
(each d, benzyl-arom C), 129.48 (s, CHPG 3ꢀ, 5ꢀ-C), 130.63 (d, IHPG 2ꢀ-C), brown oil (205 mg) was purified by flash column chromatography (hexane/
131.71 (s, IHPG 3ꢀ-C), 133.20 (CHPG 1ꢀ-C), 134.43 (s, IHPG 1ꢀ-C), 134.62 AcOEtꢂ4 : 1) giving (R)-29 (125 mg, 82%) as light brown amorphous. Rf:
(s, IHPG 1ꢀ-C), 136.05 (s, benzyl-arom 1-C), 136.19 (s, Trp 7aꢀ-C), 136.19 0.53 (hexane/AcOEtꢂ3 : 2). [a]2D3 ꢃ17.97° (cꢂ0.60, CHCl3). 1H-NMR
(d, IHPG 6ꢀ-C), 136.36 (s, Trp 6ꢀ-C), 152.10 (s, CHPG 4ꢀ-C), 154.74 (s,
IHPG NHCO), 156.10 (s, Trp NHCO), 157.04 (IHPG 4ꢀ-C), 168.22 (s,
(300 MHz) dH: 1.38 (9H, s, tBu), 3.18, 3.27 (each 1H, dd, Jꢂ6.0, 14.0 Hz, 3-
H2), 4.59 (1H, dt, Jꢂ4.5, 6.0 Hz, 2-H), 5.05, 5.13 (each 1H, d, Jꢂ12.0 Hz,
CHPG 1-C), 170.63 (s, Trp 1-C), 171.17 (s, IHPG 1-C). HR-FAB-MS m/z: benzyl CH2), 5.34 (1H, d, Jꢂ6.0 Hz, NHCO), 6.88 (1H, s, 2ꢀ-H), 7.32 (1H,
1044.1951 [MꢁH]ꢁ, Calcd for C47H51O11N4Cl352I: 1044.1976 [MꢁH].
hidden, 4ꢀ-H), 7.33 (5H, m, benzyl-arom H), 7.34 (1H, hidden, 5ꢀ-H), 7.66
(R,R,R)-2-[3-(3-{N-[2-(3,5-Dichloro-4-methoxyphenyl)acetylcarboxy]- (1H, s, 7ꢀ-H), 8.25 (1H, s, 1ꢀ-H). 13C-NMR (75 MHz) dC: 27.97 (qꢄ3,
2-carbobenzyl-oxyaminopropionylamino}indol-6-yl)-5-iodo-4- C(CH3)3), 27.97 (t, 3-C), 54.99 (d, 2-C), 66.83 (t, benzyl CH2), 82.11 (s,
methoxyphenyl]-2-methoxycarbonyl-methylammonium Trifluoroacetate C(CH3)3), 85.90 (s, 6ꢀ-C), 110.43 (s, 3ꢀ-C), 120.00 (d, 7ꢀ-C), 120.43 (d, 4ꢀ-
(4) To a solution of 25 (10.0 mg, 0.0096 mol) in CHCl3 (0.4 ml) was added
C), 123.05 (d, 2ꢀ-C), 127.03 (s, 3aꢀ-C), 127.97, 128.13, 128.37 (each d, ben-
zyl-arom C), 128.02 (d, 5ꢀ-C), 136.14 (s, benzyl-arom C), 137.16 (s, 7aꢀ-C),
TFA (0.4 ml). After the mixture was stirred for 6 h at room temperature, the
reaction mixture was concentrated in vacuo to remove TFA by azeotropic 155.55 (s, NHCO), 170.68 (s, 1-C). HR-FAB-MS m/z: 520.0870 [M]ꢁ,
distillation with benzene to afford 4 (9.3 mg, 97.0%). Rf: 0.12 (CHCl3/ Calcd for C23H25O4N2I: 520.0859 [M].
MeOHꢂ10 : 1). mp: 130—135 °C. [a]2D4 ꢃ19.94° (cꢂ0.14, MeOH). 1H-
NMR (300 MHz, CD3OD) dH: 3.12 (1H, dd, Jꢂ8.0, 16.0 Hz, Trp 3-Ha),
(R,R)-3-{6-[3-(N-tert-Butoxycarbonyl-2-methoxycarbonylmethyl-
amino)-5-iodo-6-methoxyphenyl]indol-3-yl}-2-carbobenzyloxy-amino-
3.22 (3H, s, CHPG OCH3), 3.32 (1H, dd, Jꢂ6.0, 16.0 Hz, Trp 3-Hb), 3.83 propionic Acid tert-Butyl Ester (30) To a solution of 20 (82.0 mg,
(3H, s, IHPG COOCH3), 3.86 (3H, s, CHPG OCH3), 4.56 (1H, dd, Jꢂ6.0, 0.115 mmol) and (R)-29 (60.0 mg, 0.115 mmol) in DMF (2.0 ml) were added
8.0 Hz, Trp 2-H), 4.95 (2H, br, benzyl CH2), 5.12, 5.25 (each 1H, br, IHPG Pd2(dba)3·CHCl3 (24.5 mg, 0.023 mmol), CuI (9.6 mg, 0.046 mmol), Ph3As
i
2-H, CHPG 2-H), 7.14 (3H, hidden, Trp 2ꢀ-H, 4ꢀ-H, 7ꢀ-H), 7.29 (5H, s, ben-
(35.0 mg, 0.092 mmol), Pr2NEt (74.4 mg, 0.345 mmol). After the mixture
zyl-arom H), 7.44 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.55 (1H, d, Jꢂ2.5Hz, IHPG 2ꢀ- was stirred for 1.5 h at room temperature under argon, this was diluted with
H), 7.71 (1H, dd, Jꢂ2.5, 5.0 Hz, Trp 5ꢀ-H), 7.99 (1H, d, Jꢂ2.5 Hz, IHPG 6ꢀ- AcOEt (110 ml), washed with saturated NH4Cl (10 mlꢄ3), 10% aqueous KF
H). HR-FAB-MS m/z: 911.0724 [MꢁNa]ꢁ, Calcd for C38H55O9N4Cl352NaI: solution (10 mlꢄ3), dried for Na2SO4, concentrated in vacuo. Purification of
911.0706 [MꢁNa].
the resulting brown oil (262 mg) by preparative TLC (hexane/AcOEtꢂ3 : 2)
(R)-N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-dichloro-4ꢀ-hydroxy-phenylglycine affording 30 (38.0 mg, 41%) as light yellow crystals and (R)-29 (8.0 mg)
(26) To a solution of 21 (85.0 mg, 0.291 mmol) in H2O (1.0 ml) were
added NEt3 (0.08 ml, 0.437 mmol), Boc-ON (99.0 mg, 0.323 mmol) in 1,4-
dioxane (1.0 ml). After the mixture was stirred for 1 h at room temperature,
the solution was concentrated in vacuo. The residue was dissolved in AcOEt
were recovered. 30: Rf: 0.35 (hexane/AcOEtꢂ3 : 2). mp: 40—44 °C. [a]2D1
ꢃ19.27° (cꢂ0.33, CHCl3). H-NMR (400 MHz) dH: 1.37 (9H, s, Bu), 1.44
(9H, s, Boc), 3.29, 3.31 (each 1H, hidden, Trp 3-H2), 3.32 (3H, s, OCH3),
3.73 (3H, s, COOCH3), 4.64 (1H, dd, Jꢂ5.0, 7.5 Hz, Trp 2-H), 5.06, 5.13
1
t
(30 ml), extracted with H2O (5 mlꢄ3). The water layer was washed with (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.29 (1H, d, Jꢂ7.5 Hz, IHPG 2-H),
AcOEt (5 mlꢄ3), acidified by 10% aqueous citric acid, then extracted with 5.38 (1H, d, Jꢂ7.5 Hz, Trp NHCO), 5.63 (1H, br d, Jꢂ7.5 Hz, IHPG
AcOEt (5 mlꢄ3). The organic layer was washed with saturated NaCl NHCO), 7.05 (1H, d, Jꢂ2.5 Hz, Trp 2ꢀ-H), 7.27 (1H, d, Jꢂ7.5 Hz, Trp 5ꢀ-
(3 mlꢄ1), dried over Na2SO4, concentrated in vacuo to provide 26 (104 mg, H), 7.34 (5H, m, benzyl-arom H), 7.35 (1H, d, Jꢂ2.5 Hz, IHPG 2ꢀ-H), 7.54
quant.) as a yellow oil which was pure enough to use in the next procedure. (1H, s, Trp 7ꢀ-H), 7.61 (1H, d, Jꢂ7.5 Hz, Trp 4ꢀ-H), 7.73 (1H, d, Jꢂ2.5 Hz,
Rf: 0.75 (BuOH/AcOH/H2Oꢂ4 : 1 : 5). mp: 60—62 °C. [a]2D2 ꢃ121.91°
IHPG 6ꢀ-H), 8.23 (1H, s, Trp 1ꢀ-H). 13C-NMR (100 MHz) dC: 27.91 (qꢄ3,
1
(cꢂ0.50, CHCl3). H-NMR (300 MHz) dH: 1.28 (9H, s, Boc), 5.01 (1H, d, tBu C(CH3)3), 27.97 (t, Trp 3-C), 28.29 (qꢄ3, Boc C(CH3)3), 52.89 (q,

October 2005
1287
1
t
COOCH3), 54.95 (d, Trp 2-C), 56.45 (d, IHPG 2-C), 60.13 (q, OCH3), 66.82
(t, benzyl CH2), 80.41 (s, Bu C(CH3)3), 82.10 (s, Boc C(CH3)3), 93.62 (s,
mp: 103—110 °C. H-NMR (400 MHz) dH: 1.38 (9H, m, Bu), 1.40 (9H, s,
Boc), 3.29 (3H, s, IHPG OCH3), 3.30 (2H, hidden, Trp 3-H2), 3.72 (3H, s,
COOCH3), 3.92 (3H, s, CHPG OCH3), 4.64 (1H, dt, Jꢂ5.0, 7.5 Hz, Trp 2-
H), 5.09, 5.13 (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.20 (1H, br d,
Jꢂ7.0 Hz, IHPG 2-H), 5.35 (1H, br d, Jꢂ7.5 Hz, Trp NHCO), 5.47 (1H,
br d, Jꢂ7.0 Hz, CHPG 2-H), 5.80 (1H, br, IHPG NHCO), 6.99 (1H, d,
Jꢂ7.0 Hz, CHPG NHCO), 7.02 (1H, d, Jꢂ2.0 Hz, IHPG 2ꢀ-H), 7.07 (1H, d,
Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.08 (1H, hidden, Trp 7ꢀ-H), 7.25 (1H, dd, Jꢂ2.0,
7.5 Hz, Trp 4ꢀ-H), 7.33 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.34 (5H, m, benzyl-arom
H), 7.57 (1H, hidden, Trp 5ꢀ-H), 7.58 (1H, d, Jꢂ2.0 Hz, IHPG 6ꢀ-H), 8.49
t
IHPG 5ꢀ-C), 110.15 (s, Trp 3ꢀ-C), 111.57 (d, Trp 7ꢀ-C), 118.87 (d, Trp 4ꢀ-
C), 120.76 (d, Trp 5ꢀ-C), 123.72 (d, Trp 2ꢀ-C), 127.50 (s, Trp 3aꢀ-C),
128.12, 128.49 (each d, benzyl-arom C), 130.63 (d, IHPG 2ꢀ-C), 131.37 (s,
IHPG 3ꢀ-C), 134.56 (s, IHPG 1ꢀ-C), 136.04 (s, benzyl-arom 1-C), 136.04 (d,
IHPG 6ꢀ-C), 136.09 (s, Trp 6ꢀ-C), 136.52 (s, Trp 7aꢀ-C), 154.48 (s, IHPG
NHCO), 155.75 (s, Trp NHCO), 156.99 (s, IHPG 4ꢀ-C), 170.96 (s, Trp 1-C),
171.17 (s, IHPG 1-C). HR-FAB-MS m/z: 813.2074 [M]ꢁ, Calcd for
C38H44O9N3I: 813.2122 [M].
(R,R)-2-{3-[3-(tert-Butoxycarbonyl-2-carbobenzyloxyaminoethyl)indol-
6-yl]-4-iodo-5-methoxyphenyl}-2-methoxycarbonylmethyl-ammonium p-
Toluenesulfonate (31) To a solution of 30 (32.7 mg, 0.040 mmol) in EtOH
(1.0 ml) was added p-TsOH (9.2 mg, 0.052 mmol). After the solution was
stirred for 30 min at room temperature, EtOH was concentrated in vacuo.
EtOH (1.0 ml) was again added and the solution was stirred for 30 min. This
procedure was repeated further three times to provide 31 (35.4 mg, 97%) as
yellow brown crystals. Rf: 0.51 (CHCl3/MeOHꢂ10 : 1). mp: 135—142 °C.
[a]2D1 ꢃ4.40° (cꢂ0.18, MeOH). 1H-NMR (300 MHz, CD3OD) dH: 1.34 (9H,
s, tBu), 2.20 (3H, s, p-TsOH CH3), 3.14, 3.24 (each 1H, dd, Jꢂ8.0, 17.0 Hz,
Trp 3-H2), 3.32, 3.83 (each 3H, s, OCH3ꢄ2), 4.44 (1H, dd, Jꢂ5.0, 8.0 Hz,
Trp 2-H), 5.07 (2H, m, benzyl CH2), 5.33 (1H, br, IHPG 2-H), 7.17 (1H,
br s, Trp 2ꢀ-H), 7.21, 7.69 (2H, d, Jꢂ8.0 Hz, p-TsOH 3, 5-H), 7.30 (5H, m,
benzyl-arom H), 7.37 (1H, br d, Jꢂ8.5 Hz, Trp 5ꢀ-H), 7.51 (1H, d, Jꢂ2.5 Hz,
IHPG 2ꢀ-H), 7.57 (1H, d, Jꢂ1.5 Hz, Trp 7ꢀ-H), 7.65 (1H, d, Jꢂ8.5 Hz, Trp
4ꢀ-H), 7.69 (2H, d, Jꢂ8.0 Hz, p-TsOH 2, 6-H), 7.86 (1H, d, Jꢂ2.5 Hz, IHPG
6ꢀ-H). HR-FAB-MS m/z: 736.1523 [MꢁNa]ꢁ, Calcd for C33H36N3O7INa:
736.1496 [MꢁNa].
(R,R,R)-3-[6-(5-{1-[2-(3,5-Dichloro-4-methoxyphenyl)-2-tert-butoxy-
carbonylamino-acethylamino]-1-methoxycarbonylmethyl}-3-iodo-2-
methoxyphenyl)indol-3-yl]-2-carbobenzyloxyaminopropionic Acid tert-
Butyl Ester (32a) To a solution of 31 (10.0 mg, 0.011 mmol) and 26
(4.9 mg, 0.012 mmol) in a mixed solvent of CH2Cl2 and THF (1 : 1, 2.0 ml)
were added HATU (7.0 mg, 0.018 mmol) and collidine (0.49 ml,
0.037 mmol). After the mixture was stirred for 1.5 h at 0 °C under argon, this
was concentrated in vacuo. The residue was dissolved in AcOEt (50 ml),
then the organic solution was washed with saturated NaHCO3 (10 mlꢄ3),
10% aqueous citric acid (10 mlꢄ3), saturated NaCl (10 mlꢄ3). The organic
layer was dried over Na2SO4, concentrated in vacuo. The resulting brown oil
(22.2 mg) was purified by preparative TLC (hexane/AcOEtꢂ1 : 1) to give a
phenol (3.2 mg, 25%) as white brown crystals. Rf: 0.46 (hexane/AcOEtꢂ
1 : 1). [a]2D1 ꢃ18.62° (cꢂ0.40, CHCl3). 1H-NMR (300 MHz) dH: 1.40 (9H, s,
tBu), 1.68 (9H, s, Boc), 3.26 (2H, m, Trp 3-H2), 3.34 (3H, s, IHPG OCH3),
3.73 (3H, s, IHPG COOCH3), 4.66 (1H, dt, Jꢂ5.0, 8.0 Hz, Trp 2-H), 5.09,
5.14 (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.10 (1H, hidden, IHPG 2-H),
5.38 (1H, d, Jꢂ8.0 Hz, Trp NHCO), 5.45 (1H, d, Jꢂ8.0 Hz, CHPG 2-H),
5.50 (1H, d, Jꢂ8.0 Hz, IHPG NHCO), 5.75 (1H, br, OH), 6.90 (1H, br d,
Jꢂ8.0 Hz, CHPG NHCO), 7.06 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.26 (1H, dd,
Jꢂ2.0, 8.0 Hz, Trp 5ꢀ-H), 7.28 (1H, d, Jꢂ2.0 Hz, IHPG 2ꢀ-H), 7.32 (2H, s,
CHPG 2ꢀ, 6ꢀ-H), 7.34 (5H, m, benzyl-arom H), 7.51 (1H, d, Jꢂ2.0 Hz, Trp
7ꢀ-H), 7.62 (1H, d, Jꢂ8.0 Hz, Trp 4ꢀ-H), 7.69 (1H, d, Jꢂ2.0 Hz, IHPG 6ꢀ-
H), 8.16 (1H, br s, Trp 1ꢀ-H). HR-FAB-MS m/z: 1053.1738 [MꢁNa]ꢁ,
Calcd for C46H49Cl352IN4O11: 1053.1717 [MꢁNa].
(1H, br s, Trp 1ꢀ-H). 13C-NMR (100 MHz) dC: 27.93 (qꢄ3, Bu C(CH3)3),
27.93 (t, Trp 3-C), 28.26 (qꢄ3, Boc C(CH3)3), 53.32 (q, COOCH3), 54.94
(d, Trp 2-C), 55.38 (d, CHPG 2-C), 57.22 (IHPG 2-C), 60.10 (q, IHPG
OCH3), 60.94 (q, CHPG OCH3), 66.84 (t, benzyl CH2), 80.74 (s, Boc
t
t
C(CH3)3), 82.10 (s, Bu C(CH3)3), 93.67 (s, IHPG 5ꢀ-C), 110.24 (s, Trp 3ꢀ-
C), 111.21 (d, Trp 7ꢀ-C), 118.77 (d, Trp 5ꢀ-C), 120.68 (d, Trp 4ꢀ-C), 123.80
(d, Trp 2ꢀ-C), 127.41 (s, Trp 3aꢀ-C), 127.77, 128.13, 128.50 (each d, benzyl-
arom C), 129.61 (dꢄ2, CHPG 2ꢀ, 6ꢀ-C), 129.73 (d, IHPG 2ꢀ-C), 130.09
(sꢄ2, CHPG 3ꢀ, 5ꢀ-C), 131.18 (s, IHPG 3ꢀ-C), 133.02 (s, CHPG 1ꢀ-C),
135.78 (s, Trp 7aꢀ-C), 136.06 (s, Trp 6ꢀ-C), 136.30 (s, IHPG 1ꢀ-C), 136.37
(s, benzyl-arom 1-C), 136.69 (d, IHPG 6ꢀ-C), 152.07 (s, CHPG 4ꢀ-C),
155.78 (s, Trp NHCO), 157.24 (s, IHPG 4ꢀ-C), 168.15 (s, CHPG NHCO),
168.15 (s, CHPG 1-C), 170.28 (s, IHPG 1-C), 170.78 (s, Trp 1-C). HR-FAB-
MS m/z: 1044.2003 [M]ꢁ, Calcd for C47H51O11N4ICl352: 1044.1976 [M].
32b Rf: 0.43 (hexane/AcOEtꢂ1 : 1). [a]2D1 ꢃ31.04° (cꢂ0.92, CHCl3).
mp: 44—49 °C. 1H-NMR (300 MHz) dH: 1.37 (9H, m, Bu), 1.41 (9H, s,
t
Boc), 3.30 (2H, m, Trp 3-H2), 3.34 (3H, s, IHPG OCH3), 3.73 (3H, s, IHPG
COOCH3), 3.90 (3H, s, CHPG OCH3), 4.64 (1H, dt, Jꢂ5.0, 7.5 Hz, Trp 2-
H), 5.10, 5.13 (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.12 (1H, hidden,
IHPG 2-H), 5.35 (1H, br d, Jꢂ7.5 Hz, Trp NHCO), 5.44 (1H, br d, Jꢂ6.5 Hz,
CHPG 2-H), 5.66 (1H, br, IHPG NHCO), 6.91 (1H, d, Jꢂ6.5 Hz, CHPG
NHCO), 7.07 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.30 (1H, dd, Jꢂ2.0, 7.5 Hz, Trp
5ꢀ-H), 7.32 (1H, d, Jꢂ2.0 Hz, IHPG 2ꢀ-H), 7.32 (2H, s, CHPG 2ꢀ, 6ꢀ-H),
7.34 (5H, m, benzyl-arom H), 7.50 (1H, s, Trp 7ꢀ-H), 7.62 (1H, d, Jꢂ7.5 Hz,
Trp 4ꢀ-H), 7.69 (1H, d, Jꢂ2.0 Hz, IHPG 6ꢀ-H), 8.16 (1H, br s, Trp 1ꢀ-H).
13C-NMR (75 MHz) dC: 27.93 (qꢄ3, tBu C(CH3)3), 27.93 (t, Trp 3-C), 28.22
(qꢄ3, Boc C(CH3)3), 53.21 (q, COOCH3), 54.94 (d, Trp 2-C), 55.67 (d,
CHPG 2-C), 57.32 (IHPG 2-C), 60.13 (q, IHPG OCH3), 60.73 (q, CHPG
OCH3), 66.83 (t, benzyl CH2), 80.79 (s, Boc C(CH3)3), 82.12 (s, tBu
C(CH3)3), 93.82 (s, IHPG 5ꢀ-C), 110.44 (s, Trp 3ꢀ-C), 111.54 (d, Trp 7ꢀ-C),
118.90 (d, Trp 4ꢀ-C), 120.72 (d, Trp 5ꢀ-C), 123.79 (d, Trp 2ꢀ-C), 127.50 (s,
Trp 3aꢀ-C), 127.79, 128.14, 128.50 (each d, benzyl-arom C), 129.94 (s, ben-
zyl-arom 1-C), 130.66 (dꢄ2, CHPG 2ꢀ, 6ꢀ-C), 130.66 (d, IHPG 2ꢀ-C),
131.17 (s, Trp 6ꢀ-C), 133.47 (s, CHPG 1ꢀ-C), 135.16 (s, IHPG 1ꢀ-C), 136.08
(s, Trp 7aꢀ-C), 136.21 (sꢄ2, CHPG 3ꢀ, 5ꢀ-C), 136.21 (d, IHPG 6ꢀ-C),
136.70 (s, IHPG 3ꢀ-C), 152.42 (s, CHPG 4ꢀ-C), 155.76 (s, Trp NHCO),
157.28 (s, IHPG 4ꢀ-C), 168.51 (s, CHPG 1-C), 170.22 (s, IHPG 1-C),
170.24 (s, CHPG NHCO), 170.99 (s, Trp 1-C). HR-FAB-MS m/z:
1044.2003 [M]ꢁ, Calcd for C47H51O11N4ICl2: 1044.1976 [M].
(R,R,R)-2-(2-{3-[3-(2-Carbobenzyloxy-aminopropionylcarboxy)indol-
6-yl]-5-iodo-4-methoxyphenyl}-2-methoxycarbonylmethylamino)-2-(3,5-
dichloro-4-methoxyphenyl)methylammonium Trifluoroacetate (5) To a
solution of 32a (13.0 mg, 0.014 mmol) in CH2Cl2 (0.5 ml) was added TFA
(0.5 ml) and the mixture was stirred for 1.5 h at room temperature. Then
TFA was removed in vacuo by azeotropic distillation with benzene to afford
5 (10.5 mg, 93%) as white yellow crystals. Rf: 0.20 (CHCl3/MeOHꢂ10 : 1).
mp: 92—97 °C. [a]2D4 ꢃ9.20° (cꢂ0.40, MeOH). 1H-NMR (300 MHz,
CD3OD) dH: 3.21 (1H, dd, Jꢂ8.0, 17.0 Hz, Trp 3-Ha), 3.28 (3H, s, IHPG
OCH3), 3.37 (1H, dd, Jꢂ5.0, 17.0 Hz, Trp 3-Hb), 3.76 (6H, s, CHPG OCH3,
COOCH3), 4.53 (1H, dd, Jꢂ4.5, 8.0 Hz, Trp 2-H), 5.02, 5.07 (each 1H, d,
Jꢂ12.0 Hz, benzyl CH2), 5.07 (1H, br s, CHPG 2-H), 5.59 (1H, s, IHPG 2-
H), 7.01 (1H, dd, Jꢂ2.0, 8.5 Hz, Trp 5ꢀ-H), 7.15 (1H, br, Trp 2ꢀ-H), 7.21
(1H, d, Jꢂ2.5 Hz, IHPG 2ꢀ-H), 7.29 (5H, m, benzyl-arom H), 7.43 (2H, s,
CHPG 2ꢀ, 6ꢀ-H), 7.49 (1H, br s, Trp 7ꢀ-H), 7.55 (H, d, Jꢂ2.5 Hz, IHPG 6ꢀ-
H), 7.59 (1H, d, Jꢂ8.5 Hz, Trp 4ꢀ-H). 13C-NMR (75 MHz, CD3OD) dH:
53.46, 61.39 (each q, CHPG OCH3, COOCH3), 56.08 (d, Trp 2-C), 56.31
(IHPG 2-C), 56.96 (d, CHPG 2-C), 60.46 (q, IHPG OCH3), 67.49 (t, benzyl
CH2), 93.85 (s, IHPG 5ꢀ-C), 111.21 (s, Trp 3ꢀ-C), 112.66 (d, Trp 7ꢀ-C),
111.26 (d, Trp 4ꢀ-C), 120.78 (d, Trp 5ꢀ-C), 125.69 (d, Trp 2ꢀ-C), 128.57 (s,
Trp 3aꢀ-C), 128.78, 129.16, 129.28 (each d, benzyl-arom C), 130.03 (dꢄ2,
CHPG 2ꢀ, 6ꢀ-C), 131.16 (sꢄ2, CHPG 3ꢀ, 5ꢀ-C), 131.47 (s, CHPG 1ꢀ-C),
131.86 (s, IHPG 3ꢀ-C), 132.33 (d, IHPG 2ꢀ-C), 134.59 (s, IHPG 1ꢀ-C),
137.31 (d, IHPG 6ꢀ-C), 137.79 (s, benzyl-arom 1-C), 138.05 (s, Trp
7aꢀ-C), 138.17 (s, Trp 6ꢀ-C), 154.81 (s, CHPG 4ꢀ-C), 158.20 (s, Trp
To a solution of above phenol (2.5 mg, 2.7 mmol) in MeOH (0.1 ml) and
benzene (1.0 ml) was added TMSCHN2 (1.9 ml, 3.24 mmol). After the mix-
ture was stirred for 1.5 h at room temperature under argon, this was concen-
trated in vacuo. Purification of the resulting yellow brown oil (10.3 mg) by
preparative TLC (hexane/AcOEtꢂ1 : 1) afforded 32a (0.8 mg, 34%) as white
brown crystals. Rf: 0.35 (hexane/AcOEtꢂ1 : 1).
(R,R,R) and (S,R,R)-3-[6-(5-{1-[2-(3,5-Dichloro-4-methoxyphenyl)-2-
tert-butoxycarbonylamino-acetylamino]-1-methoxycarbonylmethyl}-3-
iodo-2-methoxyphenyl)indol-3-yl]-2-carbobenzyloxyaminopropionic
Acid tert-Butyl Ester (32a, 32b) To a solution of 31 (35.5 mg, 0.039
mmol) and 28 (16.0 mg, 0.039 mmol) in a mixed solution of CH2Cl2 and
THF (1 : 1, 3.0 ml) were added EDCI (16.0 mg, 0.078 mmol), HOBT
(11.3 mg, 0.078 mmol), NMM (17.1 mg, 0.117 mmol). After the mixture was
stirred for 2.5 h at 0 °C under argon, the resulting solution was concentrated
in vacuo. The residue was dissolved in AcOEt (30 ml) and the solution was
washed with saturated NaHCO3 (5 mlꢄ3), 10% aqueous citric acid
(5 mlꢄ3), saturated NaCl (5 mlꢄ3), dried over Na2SO4, concentrated in
vacuo. Purification of the yellow-brown oil (95.1 mg) by preparative TLC
(hexane/AcOEtꢂ1 : 1) provided 32a (13.9 mg, 34%) and 32b (11.7 mg,
29%) both as white brown crystals.
32a Rf: 0.34 (hexane/AcOEtꢂ1 : 1). [a]2D4 ꢃ13.48° (cꢂ1.18, CHCl3).

1288
Vol. 53, No. 10
temperature, EtOH was removed in vacuo. The residue was again dissolved
in EtOH (1.0 ml) and the solution was stirred for 30 min. Concentration of
the solvent gave 35 (83.8 mg, quant.) as a light yellow oil. Rf: 0.16
(hexane/AcOEtꢂ2 : 1). mp: 212—214 °C. [a]2D4 ꢃ60.90° (cꢂ0.24, CHCl3).
1H-NMR (300 MHz) dH : 2.47 (3H, s, p-TsOH CH3), 3.58, 3.79 (each 3H, s,
OCH3ꢄ2), 5.18 (1H, s, 2-H), 7.16, 7.60 (2H, d, Jꢂ7.5 Hz, p-TsOH 3, 5-H),
7.60 (2H, d, Jꢂ7.5 Hz, p-TsOH 2, 6-H), 7.82 (2H, s, 2ꢀ, 6ꢀ-H), 8.66 (3H,
br s, NH3ꢁ). HR-FAB-MS m/z: 447.8914 [M]ꢁ, Calcd for C10H12O3NI2:
447.8907 [M].
NHCO), 158.39 (s, IHPG 4ꢀ-C), 167.28 (s, CHPG 1-C), 171.26 (s, IHPG
1-C), 175.32 (s, Trp 1-C). HR-FAB-MS m/z: 911.1684 [MꢁNa]ꢁ, Calcd for
C38H35O9N4Cl352NaI: 911.1724 [MꢁNa].
(R,R) and (R,S)-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-
carbobenzyloxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxyphenylglycine tert-
Butyl Ester (33a, 33b) To a solution of 24 (20 mg, 0.027 mmol) in DMSO
(0.8 ml) were added PdCl2(dppf) (2.0 mg, 0.0027 mmol), bis(pinacolate)di-
boron (8.23 mg, 0.032 mmol), KOAc (7.94 mg, 0.081 mmol). After the mix-
ture was stirred for 2.5 h at 80 °C under argon, the solution was diluted with
benzene (50 ml), washed with saturated NaCl (2 mlꢄ3). The organic layer
was dried over Na2SO4, concentrated in vacuo. Purification of the brown oil
by preparative TLC (CHCl3/MeOHꢂ30 : 1) afforded a mixture of 33a
and 33b (13 mg, 64%) both as light brown crystals. Purification of the di-
astereomeric mixture by preparative TLC gave 33a and 33b as a single prod-
uct.
(R,R,R) and (R,S,R)-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-
N-carbobenzyloxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxy-phenylglycyl-
3ꢀ,5ꢀ-diiodo-4ꢀ-methoxyphenylglycine Methyl Ester ((R,R,R)-6a, (R,S,R)-
6a) To a solution of 35 (9.29 mg, 0.015 mmol) in THF (0.3 ml) was added
NMM (1.82 mg, 0.018 mmol) and the solution was stirred for 5 min at room
temperature. Then 34 (10.4 mg, 0.015 mmol) in CH2Cl2 (0.3 ml), EDCI
(5.8 mg, 0.03 mmol) in CH2Cl2 (0.3 ml), HOBT (2.3 mg, 0.015 mmol) were
added to this solution, which was stirred for 2 h under argon at 0 °C. The re-
action mixture was concentrated in vacuo and the residue was dissolved in
AcOEt (100 ml), which was washed with saturated NaHCO3 (5 mlꢄ2), 10%
aqueous citric acid (5 mlꢄ2), saturated NaCl (5 mlꢄ2), dried over Na2SO4,
concentrated in vacuo. Purification of the resulting yellow brown oil
(40.0 mg) by preparative TLC (hexane/AcOEtꢂ1 : 1) afforded (R,R,R)-6a
(3.4 mg, 29%) and (R,S,R)-6a (4.7 mg, 20%) as yellow brown crystals.
(R,R,R)-6a Rf: 0.17 (hexane/AcOEtꢂ2 : 1). mp: 109—115 °C. [a]2D2
33a Rf: 0.58 (CHCl3 : MeOHꢂ50 : 1). mp: 82—88 °C. [a]2D7 ꢁ11.52°
1
t
(cꢂ0.17, CHCl3). H-NMR (300 MHz) dH: 1.34 (9H, s, Bu), 1.38 (12H, s,
boronic ester CH3ꢄ4), 3.18 (1H, dd, Jꢂ7.5, 15.0 Hz, Trp 3-Ha), 3.39 (1H,
dd, Jꢂ5.0, 15.0 Hz, Trp 3-Hb), 3.89 (3H, s, OCH3), 4.58 (1H, dt, Jꢂ8.0,
5.0 Hz, Trp 2-H), 5.10, 5.13 (each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.12 (1H,
hidden, CHPG 2-H), 5.36 (1H, br d, Jꢂ8.0 Hz, Trp NHCO), 6.84 (1H, br d,
Jꢂ7.0 Hz, CHPG NHCO), 7.00 (1H, d, Jꢂ2.5 Hz, Trp 2ꢀ-H), 7.13 (2H, s,
CHPG 2ꢀ, 6ꢀ-H), 7.34 (5H, m, benzyl-arom H), 7.55 (1H, d, Jꢂ7.5 Hz, Trp
5ꢀ-H), 7.60 (1H, d, Jꢂ7.5 Hz, Trp 4ꢀ-H), 7.86 (1H, s, Trp 7ꢀ-H), 8.13 (1H, s,
Trp 1ꢀ-H). 13C-NMR (100 MHz, DMSO-d6) dC: 24.75 (qꢄ4, boronic ester
C(CH3)2ꢄ2), 27.48 (qꢄ3, tBu C(CH3)3), 27.48 (t, Trp 3-C), 55.09 (d, Trp 2-
C), 55.49 (d, CHPG 2-C), 60.60 (q, OCH3), 65.15 (t, benzyl CH2), 81.75 (s,
tBu C(CH3)3), 83.04 (sꢄ2, boronic ester C(CH3)2ꢄ2), 110.03 (s, Trp 3ꢀ-C),
117.78 (d, Trp 5ꢀ-C), 118.18 (d, Trp 7ꢀ-C), 119.96 (s, Trp 6ꢀ-C), 123.63 (d,
Trp 2ꢀ-C), 125.71 (s, CHPG 3ꢀ, 5ꢀ-C), 127.21, 127.46, 128.02, 128.30 (each
d, benzyl-arom C), 128.30 (d, CHPG 2ꢀ, 6ꢀ-C), 129.45 (s, Trp 3aꢀ-C), 134.73
(s, CHPG 1ꢀ-C), 135.58 (s, Trp 7aꢀ-C), 136.74 (s, benzyl-arom 1-C), 150.90
(s, CHPG 4ꢀ-C), 151.57 (s, Trp NHCO), 168.32 (s, Trp 1ꢀ-C), 171.60
(s, CHPG 1-C). HR-FAB-MS m/z: 774.2499 [MꢁNa]ꢁ, Calcd for
C38H44O8N3Cl352B11Na: 774.2496 [MꢁNa].
1
ꢃ49.57° (cꢂ0.13, CHCl3). H-NMR (400 MHz) dH: 1.37 (12H, s, boronic
ester C(CH3)2ꢄ2), 3.17 (1H, dd, Jꢂ7.0, 15.0 Hz, Trp 3-Ha), 3.41 (1H, dd,
Jꢂ5.5, 15.0 Hz, Trp 3-Hb), 3.69 (3H, s, COOCH3), 3.81 (3H, s, IHPG
OCH3), 3.87 (3H, s, CHPG OCH3), 4.63 (1H, br, Trp 2-H), 5.09 (2H, m,
benzyl CH2), 5.33 (1H, d, Jꢂ7.0 Hz, IHPG 2-H), 5.44 (1H, br d, Jꢂ7.0 Hz,
Trp NHCO), 5.47 (1H, d, Jꢂ6.5 Hz, CHPG 2-H), 6.87 (1H, br, CHPG
NHCO), 6.89 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.10 (2H, s, CHPG 2ꢀ,6ꢀ-H),
7.30 (5H, m, benzyl-arom H), 7.44 (1H, br, IHPG NHCO), 7.55 (1H, d,
Jꢂ8.0Hz, Trp 5ꢀ-H), 7.63 (1H, d, Jꢂ8.0 Hz, Trp 4ꢀ-H), 7.76 (2H, s, IHPG
2ꢀ, 6ꢀ-H), 7.87 (1H, s, Trp 7ꢀ-H), 8.09 (1H, s, Trp 1-H). 13C-NMR
(100 MHz) dC: 24.91 (qꢄ4, boronic ester C(CH3)2ꢄ2), 27.97 (t, Trp 3-C),
53.34 (q, COOCH3), 54.83 (d, IHPG 2-C), 55.61 (d, Trp 2-C), 56.00 (CHPG
2-C), 60.67 (q, IHPG OCH3), 60.72 (q, CHPG OCH3), 67.35 (t, benzyl
CH2), 83.61 (sꢄ2, boronic ester C(CH3)2ꢄ2), 91.00 (sꢄ2, IHPG 3ꢀ, 5ꢀ-C),
109.90 (s, Trp 3ꢀ-C), 117.86 (d, Trp 4ꢀ-C), 118.54 (d, Trp 7ꢀ-C), 119.99 (s,
benzyl 1ꢀ-C), 122.55 (s, Trp 6ꢀ-C), 124.84 (d, Trp 2ꢀ-C), 125.91 (d, Trp 5ꢀ-
C), 127.75, 128.17, 128.25 (each d, benzyl-arom C), 128.55 (dꢄ2, CHPG
2ꢀ, 6ꢀ-C), 129.53 (s, Trp 3aꢀ-C), 129.80 (sꢄ2, CHPG 3ꢀ, 5ꢀ-C), 133.88 (s,
CHPG 1ꢀ-C), 135.54 (s, benzyl-arom 1ꢀ-C), 135.96 (s, Trp 7aꢀ-C), 138.60
(s, IHPG 1ꢀ-C), 138.60 (dꢄ2, IHPG 2ꢀ, 6ꢀ-C), 152.49 (s, CHPG 4ꢀ-C),
156.14 (s, Trp NHCO), 159.33 (s, IHPG 4ꢀ-C), 167.85 (s, CHPG 1-C),
169.65 (s, IHPG 1-C), 171.26 (s, Trp 1-C). HR-FAB-MS m/z: 1147.0604
[MꢁNa]ꢁ, Calcd for C44H45O10N4Cl352B11NaI2: 1147.0601 [MꢁNa].
33b Rf: 0.56 (CHCl3/MeOHꢂ50 : 1). mp: 78—84 °C. [a]2D1 ꢁ23.14°
1
t
(cꢂ0.21, CHCl3). H-NMR (300 MHz) dH: 1.34 (9H, s, Bu), 1.38 (12H, s,
boronic ester C(CH3)2ꢄ2), 3.16 (1H, dd, Jꢂ7.0, 15.0 Hz, Trp 3-Ha), 3.37
(1H, m, Trp 3-Hb), 3.90 (3H, s, OCH3), 4.59 (1H, br, Trp 2-H), 5.10, 5.12
(each 1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.19 (1H, d, Jꢂ7.0 Hz, CHPG 2-H),
5.37 (1H, br d, Jꢂ7.0 Hz, Trp NHCO), 6.66 (1H, br d, Jꢂ7.0 Hz, CHPG
NHCO), 6.93 (1H, d, Jꢂ2.5 Hz, Trp 2ꢀ-H), 7.05 (2H, s, CHPG 2ꢀ, 6ꢀ-H),
7.34 (5H, m, benzyl-arom H), 7.55 (1H, dd, Jꢂ2.5, 7.5 Hz, Trp 5ꢀ-H), 7.65
(1H, br d, Jꢂ7.5 Hz, Trp 4ꢀ-H), 7.86 (1H, s, Trp 7ꢀ-H), 8.09 (1H, s, Trp 1ꢀ-
H). 13C-NMR (100 MHz, DMSO-d6) dC: 24.75 (qꢄ4, boronic ester
C(CH3)2ꢄ2), 27.48 (qꢄ3, tBu C(CH3)3), 27.48 (t, Trp 3-C), 55.25 (d, Trp 2-
C), 55.60 (d, CHPG 2-C), 60.57 (q, OCH3), 65.15 (t, benzyl CH2), 81.69 (s,
tBu C(CH3)3), 83.04 (sꢄ2, boronic ester C(CH3)2ꢄ2), 109.91 (s, Trp 3ꢀ-C),
117.75 (d, Trp 5ꢀ-C), 118.18 (d, Trp 7ꢀ-C), 119.96 (s, Trp 6ꢀ-C), 123.63 (d,
Trp 2ꢀ-C), 125.71 (s, CHPG 3ꢀ, 5ꢀ-C), 127.27, 127.93, 128.15, 128.89 (each
d, benzyl-arom C), 128.30 (d, CHPG 2ꢀ, 6ꢀ-C), 129.45 (s, Trp 3aꢀ-C), 134.68
(s, CHPG 1ꢀ-C), 135.53 (s, Trp 7aꢀ-C), 136.81 (s, benzyl-arom 1-C), 150.90
(s, CHPG 4ꢀ-C), 155.51 (s, Trp NHCO), 168.27 (s, Trp 1ꢀ-C), 171.64 (s,
CHPG 1-C). HR-FAB-MS m/z: 774.2468 [MꢁNa]ꢁ, Calcd for
C38H44O8N3Cl2B11Na: 774.2496 [MꢁNa].
(R,S,R)-6a Rf: 0.12 (hexane/AcOEtꢂ2 : 1). mp: 111—118 °C. [a]2D3
1
ꢃ34.72° (cꢂ0.15, CHCl3). H-NMR (400 MHz) dH: 1.37 (12H, s, boronic
ester C(CH3)2ꢄ2), 3.20, 3.29 (each 1H, dd, Jꢂ5.0, 14.0 Hz, Trp 3-H2), 3.61
(3H, s, IHPG COOCH3), 3.77 (3H, s, IHPG OCH3), 3.88 (3H, s, CHPG
OCH3), 4.62 (1H, dt, Jꢂ5.0, 8.0 Hz, Trp 2-H), 5.05 (2H, m, benzyl CH2),
5.37 (1H, d, Jꢂ6.5 Hz, IHPG 2-H), 5.95 (1H, br d, Jꢂ8.0 Hz, Trp NHCO),
5.72 (1H, d, Jꢂ7.0 Hz, CHPG 2-H), 6.86 (1H, br d, Jꢂ7.0 Hz, CHPG
NHCO), 6.95 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 6.96 (1H, m, Trp 2ꢀ-H), 7.32 (5H, m,
benzyl-arom H), 7.50 (2H, brs, IHPG 2ꢀ, 6ꢀ-H), 7.56 (1H, d, Jꢂ8.0 Hz, Trp
5ꢀ-H), 7.66 (1H, d, Jꢂ8.0 Hz, Trp 4ꢀ-H), 7.85 (1H, s, Trp 7ꢀ-H), 7.89 (1H,
br d, Jꢂ6.5 Hz, IHPG NHCO), 8.13 (1H, s, Trp 1-H). 13C-NMR (100 MHz)
dC: 24.90 (qꢄ4, boronic ester C(CH3)2ꢄ2), 28.82 (t, Trp 3-C), 53.41 (q,
COOCH3), 54.25 (d, IHPG 2-C), 55.28 (CHPG 2-C), 55.96 (d, Trp 2-C),
60.58 (q, IHPG OCH3), 60.80 (q, CHPG OCH3), 67.22 (t, benzyl CH2),
83.56 (sꢄ2, boronic ester C(CH3)2ꢄ2), 90.79 (sꢄ2, IHPG 3ꢀ, 5ꢀ-C), 110.02
(s, Trp 3ꢀ-C), 117.81 (d, Trp 4ꢀ-C), 118.59 (d, Trp 7ꢀ-C), 120.00 (s, benzyl
1ꢀ-C), 122.20 (s, Trp 6ꢀ-C), 124.58 (d, Trp 2ꢀ-C), 125.82 (d, Trp 5ꢀ-C),
128.22, 128.25, 128.49 (each d, benzyl-arom C), 129.38 (s, Trp 3aꢀ-C),
129.64 (sꢄ2, CHPG 3ꢀ, 5ꢀ-C), 134.11 (s, CHPG 1ꢀ-C), 135.10 (s, benzyl-
arom 1ꢀ-C), 135.85 (s, Trp 7aꢀ-C), 137.99 (s, IHPG 1ꢀ-C), 137.99
(dꢄ2, IHPG 2ꢀ, 6ꢀ-C), 152.33 (s, CHPG 4ꢀ-C), 156.13 (s, Trp NHCO),
159.07 (s, IHPG 4ꢀ-C), 167.94 (s, CHPG 1-C), 170.03 (s, IHPG 1-C),
171.67 (s, Trp 1-C). HR-FAB-MS m/z: 1147.0597 [MꢁNa]ꢁ, Calcd for
C44H45O10N4Cl352B11NaI2: 1147.0601 [MꢁNa].
(R,RS)-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-carboben-
zyloxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxyphenylglycine (34) To a so-
lution of 33 (11.5 mg, 0.015 mmol) in CH2Cl2 (0.2 ml) was added TFA
(0.2 ml) at 0 °C and the solution was stirred for 1 h, then 2 h at room temper-
ature. TFA was removed in vacuo by azeotropic distillation with benzene to
provide 34 (10.4 mg, quant.) as white-brown crystals. Rf: 0.40 (benzene/
acetoneꢂ5 : 1). mp: 100—110 °C. 1H-NMR (300 MHz) dH: 1.37 (12H, s,
boronic ester CH3ꢄ4), 3.15 (1H, m, 3-Ha), 3.32 (1H, dd, Jꢂ5.0, 14.0 Hz, 3-
Hb), 3.83 (3H, s, OCH3), 4.60 (1H, br, Trp 2-H), 5.08 (2H, br, benzyl CH2),
5.19 (1H, d, Jꢂ6.5 Hz, CHPG 2-H), 5.64 (1H, br, Trp NHCO), 6.89, 6.95
(total 1H, br, CHPG NHCO), 7.00, 7.03 (total 1H, brs, Trp 2-H), 7.11 (2H,
s, CHPG 2ꢀ, 6ꢀ-H), 7.31 (5H, m, benzyl-arom H), 7.52 (1H, d, Jꢂ7.5 Hz,
Trp 5ꢀ-H), 7.58 (1H, d, Jꢂ7.5 Hz, Trp 4ꢀ-H), 7.81, 7.86 (total 1H, s, Trp 7ꢀ-
H), 8.23, 8.42 (total 1H, br s, Trp 1ꢀ-H). HR-FAB-MS m/z: 695.1932 [M]ꢁ,
Calcd for C34H36O8N3Cl2B11: 695.1973 [M].
(R)-2-(3,5-Diiodo-4-methoxyphenyl)-2-methoxy-carbonylmethylam-
(R)-N-tert-Butoxycarbonyl-4ꢀ-hydroxy-3ꢀ,5ꢀ-diiodo-phenylglycine
Methyl Ester (36) To a solution of 18 (2.50 g, 4.82 mmol) in MeOH
(7.5 ml) and benzene (32.5 ml), was added TMSCHN2 (2.9 ml, 5.78 mmol)
monium p-Toluene-sulfonate (35) To
0.125 mmol) in ether (1.0 ml) was added p-TsOH (24.0 mg, 0.138 mmol) in
EtOH (1.5 ml) with stirring. After the mixture was stirred for 30 min at room
a solution of 19 (72.5 mg,

October 2005
1289
FAB-MS m/z: 678.8788 [MꢁH]ꢁ, Calcd for C19H18O5N2Cl352I2: 678.8761
[MꢁH].
(R)-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-carboben-
in benzene (5.0 ml) in portions under argon. After the mixture was stirred
for 1 h at room temperature, the solution was concentrated in vacuo. The
residue (2.52 mg) was purified by flash column chromatography (hexane/
AcOEtꢂ5 : 1) to provide 36 (2.17 g, 85%) as a light yellow crystals. Rf: 0.76
(CHCl3/MeOHꢂ7 : 1). mp: 62—65 °C (CHCl3). [a]2D5 ꢃ98.21° (cꢂ1.01,
CHCl3). IR (KBr) nmax cmꢃ1: 1660 (NHCOO), 1730 (COOMe), 3260
(NHCOO), 3440 (OH). 1H-NMR (400 MHz) dH: 1.43 (9H, s, Boc), 3.73
(3H, s, CH3), 5.16 (1H, d, Jꢂ6.0 Hz, 2-H), 5.61 (1H, d, Jꢂ6.0 Hz, NHCO),
5.84 (1H, s, OH), 7.66 (2H, s, 2ꢀ, 6ꢀ-H). 13C-NMR (100 MHz) dC: 28.25 (q,
C(CH3)3), 53.02 (d, 2-C), 80.57 (s, 3ꢀ, 5ꢀ-C), 82.44 (s, C(CH3)3), 133.02 (s,
1ꢀ-C), 137.83 (d, 2ꢀ, 6ꢀ-C), 153.73 (s, 4ꢀ-C), 154.55 (s, NHCO), 170.79 (s,
1-C). HR-FAB-MS m/z: 555.9114 [MꢁNa]ꢁ, Calcd for C14H17O5NI2Na:
555.9094 [MꢁNa].
(R,R)-N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-dichloro-4ꢀ-hydroxy-phenylglycyl-
4ꢀ-hydroxy-3ꢀ,5ꢀ-diiodo-phenylglycine Methyl Ester (38) A solution of
36 (301 mg, 0.564 mmol) in TFA (0.6 ml) was stirred for 30 min at 0 °C and
concentrated in vacuo to give 37 as light orange crystals, which were dis-
solved in THF (0.7 ml), then neutralized by NMM (66.0 ml, 0.655 mmol) at
ꢃ5 °C. To the resulting solution were added 26 (358 mg, 0.564 mmol) in
CH2Cl2 (0.7 ml), HOBt (88.5 mg, 0.655 mmol). After the mixture was stirred
for 5 h at ꢃ5 °C, it was concentrated in vacuo. The residue was dissolved in
AcOEt (50 ml), washed with 10% citric acid (10 mlꢄ2), saturated NaHCO3
(10 mlꢄ2), saturated NaCl (10 mlꢄ2), dried over Na2SO4, concentrated in
vacuo. The resulting purple crystals (405.0 mg) were purified by flash col-
umn chromatography (hexane/AcOEtꢂ2 : 1) to give 38 (343.8 mg, 77%) as a
light yellow amorphous. Rf: 0.56 (CHCl3/MeOHꢂ5 : 1). mp: 135—137 °C
(AcOEt). [a]2D4 ꢃ84.79° (cꢂ0.50, CHCl3). IR (KBr) nmax cmꢃ1: 1650
(NHCO), 1700 (COOMe), 3300 (OH). 1H-NMR (400 MHz) dH: 1.41
(9H, s, Boc), 3.72 (3H, s, CH3), 5.12 (1H, br, CHPG 2-H), 5.34 (1H, d,
Jꢂ6.5 Hz, IHPG 2-H), 5.68 (1H, d, Jꢂ6.5 Hz, CHPG NHCO), 7.12 (1H,
br d, Jꢂ6.5 Hz, IHPG NHCO), 7.27 (2H, s, CHPG 2ꢀ, 6ꢀ-H), 7.62 (2H, s,
IHPG 2ꢀ, 6ꢀ-H). HR-FAB-MS m/z: 772.8794 [MꢁNa]ꢁ, Calcd for
C22H22O7N2Cl352Br79I2Na: 772.8791 [MꢁNa].
zyloxy-tryptophan tert-Butyl Ester (42) To
a solution of (R)-29
(18.3 mg, 0.035 mmol) in DMSO (0.8 ml), were added Pd(dppf)Cl2 (2 mg,
0.0028 mmol), diboron (10.7 mg, 0.042 mmol), KOAc (10.3 mg,
0.105 mmol) under argon. After the mixture was stirred for 3.0 h at 77 °C,
the reaction mixture was extracted with AcOEt (50 ml). The organic layer
was washed with saturated NaCl (2 mlꢄ5), dried over Na2SO4, concentrated
in vacuo. The resulting residue (83.5 mg) was purified by preparative TLC
(benzene/acetoneꢂ10 : 1) to give 42 (6.7 mg, 36.6%) as a yellow oil and
starting material (R)-29 (5.9 mg, 32%) was recovered. [a]2D3 ꢃ18.8°
1
t
(cꢂ0.12, CHCl3). H-NMR (300 MHz) dH: 1.35 (9H, s, Bu), 1.37 (12H, s,
(CH3)2ꢄ2), 3.24, 3.30 (each 1H, dd, Jꢂ5.5, 16.5 Hz, 3-H2), 4.61 (1H, dt,
Jꢂ5.5, 8.0 Hz, 2-H), 5.04 (2H, s, benzyl CH2), 5.28 (1H, br d, Jꢂ8.0 Hz,
NHCO), 7.06 (1H, d, Jꢂ2.3 Hz, 2ꢀ-H), 7.33 (5H, m, benzyl-arom H), 7.34
(1H, hidden, 5ꢀ-H), 7.53 (1H, dd, Jꢂ1.0, 8.0 Hz, 4ꢀ-H), 7.58 (1H, d,
Jꢂ8.0 Hz, 5ꢀ-H), 7.84 (1H, s, 7ꢀ-H), 8.10 (1H, br s, 1ꢀ-H). HR-FAB-MS m/z:
543.26590 [MꢁNa]ꢁ, Calcd for C29H37O6N2BNa: 543.2642 [MꢁNa].
(R)-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-carbobenzyl-
oxy-tryptophan (43) To a solution of 42 (12.4 mg, 0.238 mmol) in CH2Cl2
(0.3 ml), was added TFA (0.3 ml) at 0 °C. After the solution was stirred for
3.5 h at 0 °C, it was concentrated with benzene azeotrope to give 43
(11.4 mg, quant.) as a yellow oil. Rf: 0.38 (benzene/acetoneꢂ10 : 1). [a]2D3
1
t
ꢃ18.8° (cꢂ0.12, CHCl3). H-NMR (300 MHz). dH: 1.35 (9H, s, Bu), 1.37
(12H, s, (CH3)2ꢄ2), 3.24, 3.30 (each 1H, dd, Jꢂ5.5, 16.5 Hz, 3-H2), 4.61
(1H, dt, Jꢂ5.5, 8.0 Hz, 2-H), 5.04 (2H, s, benzyl CH2), 5.28 (1H, br d,
Jꢂ8.0 Hz, NHCO), 7.06 (1H, d, Jꢂ2.3 Hz, 2ꢀ-H), 7.33 (5H, m, benzyl-arom
H), 7.34 (1H, hidden, 5ꢀ-H), 7.53 (1H, dd, Jꢂ1.0, 8.0 Hz, 4ꢀ-H), 7.58 (1H, d,
Jꢂ8.0 Hz, 5ꢀ-H), 7.84 (1H, s, 7ꢀ-H), 8.10 (1H, br s, 1ꢀ-H). HR-FAB-MS m/z:
543.26590 [MꢁNa]ꢁ, Calcd for C29H37O6N2BNa: 543.2642 [MꢁNa].
R,R,R-6-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-N-carbobenzyl-
oxy-tryptophyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxy-phenylglycyl-3ꢀ,5ꢀ-diiodo-
(R,R)-N-tert-Butoxycarbonyl-3ꢀ,5ꢀ-dichloro-4ꢀ-methoxy-phenylglycyl-
3ꢀ,5ꢀ-diiodo-4ꢀ-methoxy-phenylglycine Methyl Ester (39) To a solution
of 38 (115.8 mg, 0.154 mmol) in benzene/MeOHꢂ5 : 1 (0.6 ml) was added
TMSCHN2 (193 ml, 0.386 mmol) in portions under argon. After the mixture
was stirred for 3 min at room temperature, the solution was concentrated in
vacuo. The residue (116 mg) was purified by preparative TLC (hexane/
AcOEtꢂ3 : 1) to provide 39 (99.0 mg, 82%) as light yellow crystals. Rf: 0.83
(CHCl3/MeOHꢂ50 : 1). mp: 129—131 °C (CHCl3). [a]2D4 ꢃ73.18° (cꢂ0.55,
4ꢀ-methoxy-phenylglycine Methyl Ester (6a) To
a solution of 43
(11.4 mg, 0.025 mmol) in THF/CH2Cl2ꢂ3 : 1 (1 ml), were added 41 (16.7
mg, 0.025 mmol), HATU (9.3 mg, 0.025 mmol), g-collidine (14.9 mg, 0.125
mmol in THF/CH2Cl2ꢂ3 : 1; 0.2 ml) under argon at 0 °C. After the solution
was stirred for 1 h at 0 °C, and for 1.5 h at room temperature, the reaction
mixture was extracted by AcOEt (50 ml). The organic layer was washed with
sat.NaHCO3 (5 mlꢄ2), dried over Na2SO4, concentrated in vacuo. The
residue (45.7 mg) was purified by preparative TLC (hexane/AcOEtꢂ1 : 1) to
give 6a (8.9 mg. 32%). Rf: 0.71 (CHCl3/MeOHꢂ10 : 1). mp: 109—115 °C.
[a]2D2 ꢃ49.57° (cꢂ0.13, CHCl3). 1H-NMR (400 MHz) dH: 1.37 (12H, s,
boronic ester C(CH3)2ꢄ2), 3.17 (1H, dd, Jꢂ7.0, 15.0 Hz, Trp 3-Ha), 3.41
(1H, dd, Jꢂ5.5, 15.0 Hz, Trp 3-Hb), 3.69 (3H, s, COOCH3), 3.81 (3H, s,
IHPG OCH3), 3.87 (3H, s, CHPG OCH3), 4.63 (1H, br, Trp 2-H), 5.09 (2H,
m, benzyl CH2), 5.33 (1H, d, Jꢂ7.0 Hz, IHPG 2-H), 5.44 (1H, br d,
Jꢂ7.0 Hz, Trp NHCO), 5.47 (1H, d, Jꢂ6.5 Hz, CHPG 2-H), 6.87 (1H, br,
CHPG NHCO), 6.89 (1H, d, Jꢂ2.0 Hz, Trp 2ꢀ-H), 7.10 (2H, s, CHPG 2ꢀ, 6ꢀ-
H), 7.30 (5H, m, benzyl-arom H), 7.44 (1H, br, IHPG NHCO), 7.55 (1H, d,
Jꢂ8.0 Hz, Trp 5ꢀ-H), 7.63 (1H, d, Jꢂ8.0 Hz, Trp 4ꢀ-H), 7.76 (2H, s, IHPG
2ꢀ, 6ꢀ-H), 7.87 (1H, s, Trp 7ꢀ-H), 8.09 (1H, s, Trp 1-H). HR-FAB-MS m/z:
1147.0604 [MꢁNa]ꢁ, Calcd for C44H45O10N4Cl352B11NaI2: 1147.0601
[MꢁNa].
(R)-N-Cbz-6-Iodo-tryptophan Methyl Ester (44) To a solution of (R)-
15 (10 mg, 0.022 mmol) in MeOH (0.22 ml) and benzene (0.72 ml), added
TMSCHN2 (0.018 ml, 0.036 mmol) in portions under argon. After the mix-
ture was stirred for 15 min at room temperature, the solution was concen-
trated in vacuo. Resulted residue was purified by preparative TLC
(hexane/AcOEtꢂ1 : 1) to provide 44 (7.7 mg, 75%) as light yellow crystals.
Rf: 0.68 (CHCl3/MeOHꢂ5 : 1). [a]2D3 ꢃ36.5° (cꢂ0.54, CHCl3). 1H-NMR
(400 MHz) dH: 3.26, 3.28 (each 1H, dd, Jꢂ5.0, 17 Hz, 3-H2), 3.60 (3H, s,
OMe), 4.70 (1H, dt, Jꢂ8.0, 5.0 Hz, 2-H), 5.07, 5.12 (each 1H, d, Jꢂ12.0 Hz,
benzyl CH2), 5.29 (1H, d, Jꢂ8.0 Hz, NHCOO), 6.80 (1H, d, Jꢂ2.0 , 2ꢀ-H),
7.25 (1H, d, Jꢂ8.5 Hz, 4ꢀ-H), 7.34 (1H, dd, Jꢂ1.5, 8.5 Hz, 5ꢀ-H), 7.70 (1H,
d, Jꢂ1.5 Hz, 7ꢀ-H), 8.05 (1H, br s, 1ꢀ-NH), 7.34 (5H, m, arom-H). HR-FAB-
MS m/z: 478.0395 [M]ꢁ, Calcd for C20H19O4N2I: 478.0390 [M].
1
CHCl3). H-NMR (400 MHz) dH: 1.42 (9H, s, Boc), 3.73 (3H, s, COOMe),
3.83 (3H, s, IHPG OMe), 3.88 (3H, s, CHPG OMe), 5.14 (1H, br, CHPG 2-
H), 5.36 (1H, d, Jꢂ6.5 Hz, IHPG 2-H), 5.67 (1H, d, Jꢂ6.5 Hz, CHPG
NHCO), 7.12 (1H, br d, Jꢂ6.5 Hz, IHPG NHCO), 7.32 (2H, s, CHPG 2ꢀ, 6ꢀ-
H), 7.72 (2H, s, IHPG 2ꢀ, 6ꢀ-H). 13C-NMR (100 MHz) dC: 28.29 (q,
C(CH3)3), 53.42 (q, COOCH3), 54.77 (d, IHPG 2-C), 57.34 (d, CHPG 2-C),
60.66 (q, IHPG OCH3), 60.73 (q, CHPG OCH3), 80.92 (s, C(CH3)3), 90.96
(s, IHPG 3ꢀ, 5ꢀ-C), 127.76 (d, CHPG 2ꢀ, 6ꢀ-C), 129.97 (s, CHPG 3ꢀ, 5ꢀ-C),
134.83 (s, CHPG 1ꢀ-C), 135.51 (s, IHPG 1ꢀ-C), 138.45 (d, IHPG 2ꢀ, 6ꢀ-C),
152.53 (s, CHPG 4ꢀ-C), 154.91 (s, CHPG NHCO), 159.27 (s, IHPG 4ꢀ-C),
168.60 (s, CHPG 1-C), 169.79 (s, IHPG 1-C). HR-FAB-MS m/z: 800.9098
[MꢁNa]ꢁ, Calcd for C24H26O7N2Cl352Br79I2Na: 800.9104 [MꢁNa].
(R,R)-3ꢀ,5ꢀ-Dichloro-4ꢀ-methoxy-phenylglycyl-3ꢀ,5ꢀ-diiodo-4ꢀ-
methoxy-phenylglycine Methyl Ester TFA Salt (40) To a solution of 39
(147 mg, 0.189 mmol) in CH2Cl2 (0.5 ml), was added TFA (0.5 ml) at 0 °C.
After the mixture was stirred for 2.75 h, the solution was concentrated with
benzene azeotrope to give 40 (152 mg, quant.) as light brown crystals. Rf:
0.67 (hexane/AcOEtꢂ1 : 1). mp: 163—166 °C. [a]2D3 ꢃ72.16° (cꢂ0.2,
1
CHCl3). H-NMR (400 MHz) dH: 2.80 (2H, br, NH2), 3.72 (3H, s, OMe),
3.79 (3H, s, OMe), 3.93 (3H, s, OMe), 5.27 (1H, br, CHPG 2-H), 5.33 (1H,
d, Jꢂ6.0 Hz, IHPG 2-H), 7.53 (2H, br s, CHPG 2ꢀ, 6ꢀ-H), 7.65 (1H, br d,
Jꢂ6.0 Hz, IHPG NHCO), 7.72 (2H, br s, IHPG 2ꢀ, 6ꢀ-H). HR-FAB-MS m/z:
700.8571 [MꢁNa]ꢁ, Calcd for C19H18O5N2Cl352I2Na: 700.8580 [MꢁNa].
(R,R)-3ꢀ,5ꢀ-Dichloro-4ꢀ-methoxy-phenylglycyl-3ꢀ,5ꢀ-diiodo-4ꢀ-
methoxy-phenylglycine Methyl Ester (41) After the salt 40 was neutral-
ized by sat.NaHCO3 (3 ml), the mixture was extracted with AcOEt
(30 mlꢄ3). The organic layer was washed with saturated NaCl (2 mlꢄ2),
dried over Na2SO4, concentrated in vacuo to provide 41 (124 mg, quant.) as
white crystals. Rf: 0.60 (CHCl3/MeOHꢂ10 : 1). mp: 187—189 °C. [a]2D3
(R)-N-Cbz-6-Tributylstannyl-tryptophan Methyl Ester (45) To a so-
lution of 44 (16 mg, 0.033 mmol) in CH3CN (0.5 ml) were added (Bu3Sn)2
(38.7 mg, 0.066 mmol) in CH3CN (0.5 ml), (o-tolyl3P)2PdCl2 (2.6 mg,
1
i
ꢃ71.7° (cꢂ0.2, CHCl3). H-NMR (400 MHz). dH: 1.86 (2H, br, NH2), 3.74
0.0033 mmol), Pr2NEt (17.4 ml, 0.10 mmol) under argon. After the solution
(3H, s, OMe), 3.80 (3H, s, OMe), 3.89 (3H, s, OMe), 4.95 (1H, br, CHPG 2-
H), 5.37 (1H, d, Jꢂ6.0 Hz, IHPG 2-H), 7.48 (2H, br s, CHPG 2ꢀ, 6ꢀ-H), 7.72
(2H, br s, IHPG 2ꢀ, 6ꢀ-H), 8.14 (1H, br d, Jꢂ7.0 Hz, IHPG NHCO). HR-
was stirred for 0.5 h at 75 °C, the mixture was diluted with AcOEt (50 ml),
the organic layer was washed with H2O (3 mlꢄ2), saturated NaCl (3 mlꢄ2),
dried over Na2SO4, concentrated in vacuo. The residue (45 mg) was purified

1290
Vol. 53, No. 10
by flash column chromatography (hexane/AcOEtꢂ4 : 1→3 : 1 (contained 1%
NEt3)) to provide 45 (9.6 mg, 45%) as a yellow oil. Rf: 0.87 (hexane/
AcOEtꢂ1 : 1). [a]2D3 ꢃ26.3° (cꢂ0.60, CHCl3). 1H-NMR (400 MHz) dH: 0.88
(9H, t, CH3ꢄ3), 1.07, 1.34 (6H, m, CH2ꢄ3), 1.55 (6H, m, CH2ꢄ3), 3.29,
3.31 (each 1H, dd, Jꢂ5.5, 15 Hz, 3-H2), 3.69 (3H, s, OMe), 4.71 (1H, dt,
Jꢂ8.5, 5.5 Hz, 2-H), 5.08, 5.12 (each 1H, d, Jꢂ12.5 Hz, benzyl CH2), 5.31
(1H, br d, Jꢂ8.5 Hz NHCOO), 6.93 (1H, d, Jꢂ2.0 Hz, 2ꢀ-H), 7.15 (1H, d,
Jꢂ7.5 Hz, 4ꢀ-H), 7.33 (5H, m, arom-H), 7.44 (1H, d, Jꢂ1.5 Hz, 7ꢀ-H), 7.49
(1H, dd, Jꢂ1.5, 8.5 Hz, 5ꢀ-H), 7.97 (1H, br, 1ꢀ-NH). HR-FAB-MS m/z:
665.2405 [MꢁNa]ꢁ, Calcd for C32H46O4N2NaSn: 665.2377 [MꢁNa].
(R)-N-Cbz-6-Tributylstannyl-tryptophan Carboxylic Acid Sodium
Salt (46) To a solution of 45 (7.5 mg, 0.012 mmol) in MeOH (0.95 ml) was
added 1 N NaOH (0.19 ml). After the solution was stirred for 3 h at 0 °C,
MeOH was evaporated. The mixture was extracted with AcOEt (5 mlꢄ3)
and the organic layer was washed with H2O (1 mlꢄ3), saturated NaCl (1 ml),
dried over Na2SO4, concentrated in vacuo to give 46 (7.5 mg, 99%) as a light
yellow oil. Rf: 0.12 (CHCl3/MeOHꢂ10 : 1). [a]2D3 ꢃ7.20° (cꢂ0.1, MeOH).
1H-NMR (400 MHz, CD3OD) dH: 0.90 (9H, t, CH3ꢄ3), 1.10, 1.34 (each 6H,
m, CH2ꢄ3), 1.57 (6H, m, CH2ꢄ3), 3.14 (1H, dt, Jꢂ7.0, 14.5 Hz, 3-Ha),
3.53 (1H, dt, Jꢂ4.0, 14.5 Hz, 3-Hb), 4.40 (1H, dd, Jꢂ4.0, 7.0 Hz, 2-H),
5.07, 5.12 (each 1H, d, Jꢂ12 Hz, benzyl CH2), 7.02 (1H, s, 2ꢀ-H), 7.24—
7.32 (1H, hidden, 4ꢀ-H), 7.42 (1H, s, 6ꢀ-H), 7.57 (1H, d, Jꢂ8.0 Hz, 5ꢀ-H),
7.97 (1H, br, 1ꢀ-H). HR-FAB-MS m/z: 673.1967 [MꢁNa]ꢁ, Calcd for
C31H43O4N2Na2Sn: 673.2040 [MꢁNa].
(R,R,R)-N-Carbobenzyloxy-6-tributylstannyl-tryptophyl-3ꢀ,5ꢀ-
dichloro-4ꢀ-methoxy-phenylglycyl-3ꢀ,5ꢀ-diiodo-4ꢀ-methoxy-phenyl-
glycine Methyl Ester (6b) To a solution of 46 (7.5 mg, 0.012 mmol) in
THF/CH2Cl2 (3 : 1) (1 ml), were added 41 (7.86 mg, 0.012 mmol), HATU
(4.4 mg, 0.012 mol), collidine (7.0 mg, 0.058 mmol) in THF/CH2Cl2 (3 : 1)
(0.2 ml) at 0 °C under argon and stirred for 2 h. The reaction mixture was di-
luted with AcOEt (50 ml), washed with saturated NaHCO3 (3 mlꢄ2), dried
over Na2SO4, concentrated in vacuo. Purification of the residue (18.5 mg)
by flash column chromatography (silica gel, CHCl3/MeOHꢂ100 : 1 (con-
tained 1% NEt3)) afforded 6b (8.1 mg, 54%) as yellow brown crystals. Rf:
0.76 (CHCl3/MeOHꢂ10 : 1). [a]2D3 ꢁ5.54° (cꢂ0.36, CHCl3). 1H-NMR
(400 MHz, CD3OD) dH: 0.87 (9H, t, CH3ꢄ3), 1.06 (6H, m, CH2ꢄ3), 1.34
(6H, m, CH2ꢄ3), 1.56 (6H, m, CH2ꢄ3), 3.20 (1H, dd, Jꢂ7.0, 12.0 Hz, Tryp
3-Ha), 3.29 (1H, dd, Jꢂ5.0, 12.0 Hz, Trp 3-Hb), 3.73 (3H, s, OMe), 3.77
(3H, s, OMe), 3.88 (3H, s, OMe), 4.71 (1H, m, Trp 2-H), 5.12, 5.21 (each
1H, d, Jꢂ12.0 Hz, benzyl CH2), 5.37 (1H, d, Jꢂ8.5 Hz, 2-H), 5.58 (1H, d,
Jꢂ7.0 Hz, CHPG 2-H), 5.68 (1H, br, IHPG NHCO), 6.74 (1H, br s, CHPG
NHCO), 6.84 (1H, d, Jꢂ2.0 Hz, 2ꢀ-H), 7.12 (2H, s, CHP 2ꢀ, 6ꢀ-H), 7.14 (1H,
d, Jꢂ9.0 Hz, 4ꢀ-H), 7.25, 7.29 (total 5H, m, benzyl arom-H), 7.54 (1H, br d,
Jꢂ9.0 Hz, 5ꢀ-H), 7.67, 7.71, 7.76 (total 2H, each s, IHPG 2ꢀ, 6ꢀ-H), 8.20
(1H, br s, 1ꢀ-H). HR-FAB-MS m/z: 1311.0793 [MꢁNa]ꢁ, Calcd for
C50H60O8N4NaSnI2: 1311.0797 [MꢁNa].
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