Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02554

The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMS_NAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. The structure-activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116.

Full text of DOI:10.1021/acs.joc.8b02554

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Article
Asymmetric Total Synthesis and Evaluation of
Antitumor Activity of Ophiorrhisine A and Its Derivatives
Tadayoshi Onozawa, Mariko Kitajima, Noriyuki Kogure, and Hiromitsu Takayama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02554 • Publication Date (Web): 19 Nov 2018
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Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its
Derivatives
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3 Tadayoshi Onozawa, Mariko Kitajima, Noriyuki Kogure, and Hiromitsu Takayama*
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4 Department of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical
5 Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
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Table of Contents/Abstract Graphic
CO2
NH
Ph
OH
CO2Me
NH
Ph
F
CO2Me
NH
Ph
O2N
construciton of
14-membered ring
O
O
O
O
O
O
O
Ph
O
O2N
OH
O
O
Ph
Ph
N
N
H
H
O
H
N
Ph
via IMSNAr
N
Ph
N
HN
Me3N
NR2
H
H
NBn2
(atrop isomer mixture)
NBn2
O
CO2Me
ophiorrhisine A derivatives
R
1
H Me Bn,
, ,
=
N
,N-dimethyl amino acids
, etc.
1
ophiorrhisine A ( )
Structure confirmation of
1
Evaluation of antitumor activity of and its derivatives
7
8
9
ABSTRACT: The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide
isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic
substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring,
resulting in confirmation of its structure and absolute configuration. Structure-activity relationship study
of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer
cell lines A549, HT29, and HCT116.
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INTRODUCTION
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Ophiorrhisine A (1, Figure 1)1 is a new cyclic peptide isolated from Ophiorrhiza nutans (Rubiaceae)
collected in Thailand in the course of our chemical investigation of new and bioactive alkaloids.2 The
structure featuring a 14-membered paracyclophane ring and a novel N,N,N-trimethylated tyrosine residue
in the side chain and its absolute configuration were inferred by spectroscopic analysis and biosynthetic
considerations. The stereochemistry at C-3, the aryl-alkyl ether bond, was different from that of common
known cyclopeptide alkaloids.3a Cyclopeptide alkaloids possessing 13-, 14-, or 15-membered cyclophane
rings are widely found in several plants belonging to genera Rhamnaceae, Pandaceae, and Rubiaceae.3a
Owing to their interesting biological properties, such as sedative, antibacterial, antifungal, antitumor, and
antiplasmodial activities, total synthetic and/or biological studies of this class of natural products have
been pursued.3 Herein, we report the asymmetric total synthesis of 1 to confirm its structure and absolute
configuration, and a structure-activity relationship (SAR) study of 1 and its derivatives, focusing on
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antitumor activity.
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3
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5
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10
CO2
14
1
NH
O
O
O
4
3
7
N
H
22 O
HN
OH
23
Me3N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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Figure 1. Ophiorrhisine A isolated from Ophiorrhiza
nutans (Rubiaceae) collected in Thailand.
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3
4
5
6
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8
9
RESULTS AND DISCUSSION
The retrosynthesis of 1 is shown in Scheme 1. We envisioned that target molecule 1 would be obtained
from compound 2 through the hydrolysis of the methyl ester, the methylation of the N,N-dimethylamine
group, and the deprotection of the phenolic hydroxyl group. 2 would be produced by the condensation of
cyclic compound 3 and tyrosine derivative 4. 3 would be constructed through the intramolecular aromatic
nucleophilic substitution reaction (IMSNAr) of tripeptide 5, which would be obtained by the successive
condensation of (3R)-hydroxyphenylalanine derivative 6 and L-phenylalanine derivatives 7 and 8.
2710
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Scheme 1. Retrosynthesis of Ophiorrhisine A (1)
CO2Me
NH
Ph
OBn
CO2
NH
Ph
OH
1
1
O
O
O
3
O
3
O
O
Ph
Ph
N
N
H
H
HN
Condensation
HN
O
O
Me2N
Me3N
2
1
Intramolecular
SNAr reaction
F
1
CO2Me
NH
O2N
Ph
H
N
1
O
O
3
OH
O
O
3
Ph
Ph
N
Ph
N
H
H
NH2
3
NBn2
O
CO2Me
5
OBn
CO2H
Me2N
4
OH
3
Ph
O2N
CO2Me
CO2H
Ph
1
NH2
BocHN
CO2H
F
NBn2
6
7
8
50
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12
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13
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First, we synthesized (3R)-hydroxyphenylalanine derivative 6 through the inversion of the
stereochemistry of the hydroxyl group in known (3S)-hydroxyphenylalanine derivative 10 (Scheme 2). 10
was prepared from cinnamic tert-butylate (9) according to the Davies method.4 After Boc protection of
the amino group of 10, 115 was mesylated in dichloroethane at 0 °C. After the reaction was completed as
judged by TLC monitoring, the reaction mixture was warmed to 60 °C to induce an intramolecular
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6
cyclization by the SN2 reaction of the carbonyl group of Boc to give oxazolidinone, which was treated
with Boc2O to afford compound 126 in 70% yield over 2 steps. The oxazolidinone ring of 12 was opened
by methanolysis in the presence of Cs2CO3 to generate (3R)-hydroxyphenylalanine derivative 136 in good
yield. Deprotection of the Boc group under acid condition at 0 °C, dibenzylation with BnBr in the
presence of NaHCO3, and removal of the tert-butyl group with TFA afforded carboxylic acid 6 in
excellent yield over 3 steps.
1
2
3
4
5
6
7
8
9
10
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Scheme 2. Synthesis of Carboxylic Acid 6
5 steps
OH
S
OH
Boc2O
CO2t-Bu
CO2t-Bu
CO2t-Bu
Ph
Ph
Ph
DCM, rt
quant.
NH2
10
NHBoc
11
9
O
1) MsCl, Et3N
DCE, 0 °C to 60 °C
OH
R
TFA
Cs2CO3
CO2t-Bu
O
NBoc
CO2t-Bu
Ph
DCM, 0 °C
92%
2) Boc2O, DMAP
DCM, rt,
70% (2 steps)
MeOH, rt
80%
NHBoc
13
Ph
12
BnBr
NaHCO3
OH
OH
OH
TFA, rt
CO2t-Bu
CO2t-Bu
CO2H
Ph
Ph
Ph
then DIPEA
98%
THF/DMSO
(4:1), reflux
93%
NH2
14
NBn2
15
NBn2
6
7
8
9
The synthetic route shown in Scheme 2 provided 6 in good overall yield but required 12 steps to
obtain 6 from 9. Thus, we developed a shorter synthetic route by using the Evans-aldol reaction to
directly construct the desired stereochemistry (Scheme 3). Bromoacetylation of (–)-oxazolidinone 16,7
which was prepared from L-phenylalanine in 4 steps, afforded known compound 17.8 17 was subjected to
amination with dibenzylamine in the presence of DIPEA to give Evans-aldol reaction substrate 18 in good
yield. In reference to the Davies method,8 the Evans-aldol reaction of 18 with 9-BBNOTf, DIPEA, and
benzaldehyde afforded oxazolidinone 19 as a single diastereomer. Hydrolysis of 19 under the optimum
reaction conditions (H2O2, LiOH, THF/H2O) generated 6 in 64% yield.
10
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42
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13
14
15
16
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Scheme 3. Alternative Synthetic Route for Carboxylic Acid 6
O
Br
O
O
O
O
O
Bn2NH
DIPEA
Br
Br
NBn2
n-BuLi
O
NH
Bn
O
N
O
N
THF
THF
40 °C
97%
Me
Me
Me
Me
Me
–78 °C to 0 °C
76%
Bn
17
Bn
18
Me
16
O
O
OH
Ph
LiOH
H2O2 aq.
OH
9-BBNOTf
DIPEA
CO2H
O
N
Ph
then PhCHO
DCM
–78 °C to 0 °C
86%
THF/H2O (4:1)
0 °C to rt
64%
NBn2
Me
Me
NBn2
6
Bn
19
55
17
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18
57
19
Next, we synthesized tripeptide 5 from commercially available 4-fluorobenzaldehyde (20) (Scheme
4). Nitration of 20, reduction of aldehyde, and bromination by the Appel reaction yielded bromide 21,9
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which was subjected to the Finkelstein reaction to give iodide 22.10 Stereoselective alkylation of bromide
21 or iodide 22 with Schöllkopf reagent11 in the presence of copper cyanide12 afforded alkylated
compound 23 as a single diastereomer. Cleavage of the chiral auxiliary in 23 with dilute aqueous HCl in
MeCN gave chiral phenylalanine derivative 8,13 which was then coupled with N-Boc-L-phenylalanine (7)
to afford dipeptide 24. Removal of the Boc group followed by chemoselective condensation with
1
2
3
4
5
6
7
8
9
(3R)-hydroxyphenylalanine
derivative
6
using
10
11
12
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM)14 in MeOH/MeCN
138
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15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
afforded tripeptide 5 in excellent yield.
Scheme 4. Synthesis of Tripeptide 5
(R)-Schöllkopf
reagent
n-BuLi, CuCN
1) HNO3, H2SO4,
–5 °C to rt, 66%
CHO
O2N
F
X
THF, –78 °C
2) NaBH4, MeOH
rt, 98%
F
22
21
82% from
59% from
NaI
acetone
rt, 90%
3) Br2, DPPE, DCM
–20 °C to rt, 96%
20
21
22
R
R
Br
I
:
:
=
=
OMe
7
Boc-Phe-OH (
EDCI, HOBt, DIPEA
)
O2N
F
CO2Me
O2N
F
0.25 N HCl aq.
N
NH2
N
Me
DCM, rt
90%
MeCN, rt
97%
OMe Me
23
8
OH
F
CO2H
Ph
O2N
Ph
NHBoc
NBn2
Ph
H
6
2) , DMT-MM
DIPEA
OH
O
O2N
F
N
1) TFA
H
N
Ph
N
H
O
DCM
0 °C
MeOH/MeCN
(1:1), rt, 93%
(2 steps)
CO2Me
NBn2
O
CO2Me
24
5
32
9
33
34
10
35
11
With tripeptide 5 in hand, the key IMSNAr-based cyclization was performed in reference to the
conditions used by Zhu’s group15 (Scheme 5). Under the optimized reaction conditions (TBAF, powdered
4Å molecular sieves, DMF), the cyclization of 5 proceeded to form the 14-membered paracyclophane in
44% yield as a mixture of inseparable atropisomers, 25a and 25b, in the ratio of 5:1. The strong NOE
correlation between protons H-3 and H-14 in 25a revealed its configuration, as shown in Scheme 5.
Reductive removal of the nitro group in 25a and 25b was performed in a two-step operation [1) Fe,
NH4Cl, H2O/EtOH; 2) t-BuONO, H3PO2, THF] to provide desired 14-membered cyclopeptide core 26 in
89% yield (2 steps). Hydrogenolysis of 26 in the presence of Pd/C proceeded smoothly to provide
primary amine 3, which was condensed with N,N-dimethyl-O-benzyl-L-tyrosine 416 using DMT-MM in
MeOH/DCM to afford cyclophane 2 in 86% yield over 2 steps. After the hydrolysis of 2 with LiOH in
THF/H2O, selective methylation of the dimethylamine in the side chain of 27 with iodomethane in the
presence of both acetic acid and DIPEA gave zwitterionic compound 28 possessing a carboxylic acid
function and a trimethylated amine function. Finally, removal of the O-benzyl group of the tyrosine
residue afforded ophiorrhisine A (1) in 90% yield. All spectral data of synthetic 1, including NMR, mass,
optical rotation, and experimental circular dichroism (ECD) data, were identical to those of natural
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5321
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ophiorrhisine A (1).1 Thus, the structure of 1 including its absolute configuration was confirmed.
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2
3
4
5
6
7
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9
Scheme 5. Total Synthesis of Ophiorrhisine A (1)
OB
F
2)
CO2H
CO2Me
CO2Me
CO2Me
O2N
Ph
H
N
dif.
NOE
14
14
H
O
O2N
O
1) Fe, NH4Cl
H2O/EtOH
(1: 2), 80 °C
Me2N
TBAF
MS4Å
NH
Ph
NH
Ph
NH
Ph
4
O
O
O
O
OH
O
15 O
15O
O
H
DMT-MM, DIPEA
O2N
3
3
Ph
Ph
Ph
N
N
N
DMF
70 °C
44%
Ph
N
MeOH/DCM (1:1)
rt, 86%
2) t-BuONO
H3PO2, THF
0 °C to rt
H
H
H
H
NBn2
NBn2
NR2
NBn2
O
CO2Me
(2 steps)
1) Pd/C, H2
MeOH, rt
26: R = Bn
3: R = H
25a
25b
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
89% (2 steps)
CO2
Ph
CO2Me
CO2
CO2
10
10
10
10
NH
NH
Ph
OBn
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
MeI, AcOH
DIPEA
Pd/C, H2
LiOH•H2O
Ph
OBn
Ph
4
3
7
Ph
Ph
Ph
Ph
N
N
N
N
H
O
H
O
H
O
H
MeCN/MeOH
(5:1), rt, 58%
(2 steps)
THF/H2O (1:1)
rt, 98%
MeOH, rt
90%
HN
OBn
HN
HN
HN
O
OH
23
23
23
23
Me3N
Me2N
Me2HN
Me3N
2
27
28
1
ophiorrhisine A ( )
2
3
4
5
6
7
8
9
We next set our sights on the syntheses of the derivatives of 1 for SAR studies, focusing on antitumor
activity (Schemes 6 and 7). The derivatives were designed by referring to the structures of other natural
cyclopeptide alkaloids having significant bioactivities.3c, 17 The N,N,N-trimethylated tyrosine moiety in 1
was replaced by other residues and the carboxylic acid was capped as methyl ester to reduce polarity and
improve cell wall penetration. First, the amino group in 3 was dimethylated with formaldehyde in the
presence of Pd/C to give 29, and was acylated with Ac2O to afford 30. Next, we synthesized derivatives
possessing N,N-dimethylated amino acid residues. Removal of the benzyl group of 2 afforded tyrosine
derivative 31. Coupling of 3 with N-Cbz-L-phenylalanine followed by reductive amination with
formaldehyde gave phenylalanine derivative 32. The combination of 3 with N,N-dimethyltryptophan•HCl
salt 33 in the presence of DMT-MM and DIPEA afforded tryptophan derivative 34.
10
32
33
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34
35
12
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13
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Scheme 6. Syntheses of Ophiorrhisine A Derivatives 29, 30, and 31
CO2Me
HCHO aq.
Pd/C, H2
NH
Ph
O
O
O
O
MeOH/DCM
(1:1), rt
CO2Me
NH
Ph
Ph
N
59%
H
NMe2
O
O
O
29
Ph
Ph
N
CO2Me
NH
H
NH2
Ac2O
3
O
O
DCM
0 °C to rt
80%
Ph
N
H
NHAc
26
from
30
CO2Me
CO2Me
NH
Ph
OBn
O
O
NH
Ph
OH
O
O
Pd(OH)2/C
H2
O
O
Ph
N
Ph
H
N
MeOH/DCM
(1:1), rt
HN
Me2N
O
H
O
HN
Me2N
62%
2
31
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Scheme 7. Syntheses of Ophiorrhisine A Derivatives 32 and 34
3
4
5
6
7
8
9
1) Cbz-Phe-OH
DMT-MM, DIPEA
MeOH/DCM (1:1)
rt, 89%
CO2Me
NH
Ph
O
O
O
2) HCHO aq.
Pd/C, H2
MeOH, rt, 40%
Ph
N
H
O
HN
Me2N
3
HO2C
Me2N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
32
•HCl
N
CO2Me
NH
H
33
O
DMT-MM, DIPEA
O
O
Ph
MeOH/MeCN (1:1)
rt, 52%
Ph
N
H
O
HN
Me2N
NH
34
1
2
3
4
5
6
7
Synthetic compound 1 and its derivatives 3, 26, 29, 30, 31, 32, and 34 were evaluated for cytotoxicity
toward human cell lines A549, HT29, and HCT116 (Table 1). As presumed, compound 1 showed no
antitumor activity (IC50 > 15 M). However, derivatives 3, 26, 29, 32, and 34, which lack an ionic
character compared to 1, exhibited modest cytotoxicity.
8
9
10
Table 1. Cytotoxicity of Ophiorrhisine A and Derivatives 3, 26, 29, 30, 31, 32, and 34 toward
Human Cell Lines A549, HT29, and HCT116
IC50 (M)
HT29
>15
33
34
11
35
36
37
Sample
Ophiorrhisine A (1)
A549
>15
HCT116
>15
26
3
29
30
31
32
34
>15
>15
10.8
>15
>15
9.0
7.0
>15
7.1
>15
>15
>15
11.6
3.9
>15
>15
12
13
38
39
14
40
3.5
10.0
0.0075
2.9
8.4
0.0075
15
41
42
43
44
>15
0.0093
Colchicine
16
17
45
46
18
47
CONCLUSIONS
19
We have accomplished the first asymmetric total synthesis of ophiorrhisine A (1), which enabled us to
confirm the inferred structure and the absolute configuration of 1. Zhu’s IMSNAr method to construct a
14-membered paracyclophane ring was applied as the key step. Furthermore, we synthesized derivatives of 1 and
investigated the cytotoxicity of 1 and its derivatives toward human cancer cell lines A549, HT29, and
HCT116. Ophiorrhisine A derivatives 3, 26, 29, 32, and 34 showed not significant but modest cytotoxic
activity.
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EXPERIMENTAL SECTION
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General Experimental Procedures. UV: recorded in MeOH on a JASCO V-560 instrument. IR:
1
2
3
4
5
6
7
8
1
13
recorded on a JASCO FT/IR-230 spectrophotometer. H and C{1H} NMR spectra: recorded on JNM
ECZ-400 and JNM ECS-400 at 400 MHz (1H) or 100 MHz (13C), and JNM ECZ-600 and JNM ECA-600
at 600 MHz (1H) or 150 MHz (13C), respectively. J values are given in Hz. ESIMS: JEOL JMS
T100GCV. HRESIMS: JEOL JMS-T100LP AccuTOF LC-plus. ECD: JASCO J-720WI. TLC: precoated
silica gel 60 F254 plates (0.25 mm thick) and precoated RP-18 F254 plates (Merck, Tokyo, Japan),
precoated amino-silica gel plates (Fuji Silysia Chemical. Tokyo, Japan). Column chromatography: silica
gel 60 (70–230 mesh, Merck, Tokyo, Japan), silica gel 60N [40–50 m (for flash chromatography), Kanto
Chemical, Tokyo, Japan], Chromatorex NH (100–200 mesh, Fuji Silysia Chemical, Tokyo, Japan),
Cosmosil 75C18-OPN (Nacalai Tesque, Kyoto, Japan). Medium pressure liquid chromatography (MPLC):
C.I.G. prepacked column CPS-HS-221-05 (silica gel, Kusano Kagakukikai, Japan), Ultra Pack NH-40A
(amino-silica gel, Yamazen, Osaka, Japan), and Ultra Pack ODS-A-40A (ODS, Yamazen, Osaka, Japan).
t-Butyl Ester 9. To a solution of cinnamic acid (2.96 g, 20.0 mmol) in DCM (30 mL, 0.67 M) were
added oxalyl chloride (1.8 mL, 1.05 eq.) and DMF (75 L, 5 mol%) at room temperature under Ar
atmosphere. After the reaction mixture was stirred for 1.5 hours at the same temperature, the solvent was
removed by evaporation. The residue was dissolved in THF (20 mL) and the solution was cooled to 0 °C.
9
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14
15
16
o
17
To the solution was added 1 M KOt-Bu solution in THF (24 mL, 1.2 eq.) at 0 C under Ar atmosphere
18
over 10 minutes. After stirring for 30 minutes, the reaction was quenched by adding water. The aqueous
layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried
over MgSO4, filtered, and evaporated under reduced pressure to afford 9 (3.90 g, 96%) as a pale yellow
oil, without further purification. 1H NMR (400 MHz, CDCl3)  7.59 (1H, d, J = 16.0 Hz), 7.52–7.50 (2H,
19
20
21
13
22
overlapped), 7.38–7.35 (3H, overlapped), 6.37 (1H, d, J = 16.0 Hz), 1.54 (9H, s). C{1H} NMR (100
23
MHz, CDCl3)  166.3, 143.5, 134.7, 129.9, 128.8, 127.9, 120.2, 80.5, 28.2.
24
(3S)--Hydroxyphenylalanine Derivative 10. In reference to the Davies method, 10 was synthesized
from 9 over five steps. Data are consistent with literature values.4 []25D +45.3 (c 0.65, MeOH); literature
value: []20D +44.7 (c 1.0, MeOH).
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(3S)--Hydroxyphenylalanine Derivative 11. To a solution of 10 (1.43 g, 6.0 mmol) in DCM (12 mL,
0.5 M) was added Boc2O (1.37 mL, 1.05 eq.) at room temperature under Ar atmosphere. After stirring for
1.5 hours at the same temperature, the reaction was quenched by adding water. The organic layer was
washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The
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residue was purified by silica gel flash chromatography (AcOEt/hexane = 1:4) to afford 11 as a white
1
32
solid (2.0 g, quant.): []25 +69.8 (c 0.97, CHCl3); H NMR (400 MHz, CDCl3)  7.35–7.27 (5H,
D
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33
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overlapped), 5.32 (1H, d, J = 5.9 Hz), 5.19 (1H, br s), 4.60 (1H, dd, J = 6.6, 3.0 Hz), 4.14 (1H, d, J = 6.9
13
34
Hz), 1.45 (9H, s), 1.38 (9H, s); C{1H} NMR (100 MHz, CDCl3)  168.6, 156.6, 139.5, 128.1, 127.8,
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60
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126.2, 83.7, 80.5, 75.3, 60.2, 28.2, 27.8. Data are consistent with literature values.5
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Oxazolidinone 12. To a solution of 11 (1.23 g, 3.65 mmol) and DIPEA (1.9 mL, 3.0 eq.) in
dichloroethane (18.2 mL, 0.2 M) was added dropwise MsCl (0.84 mL, 3.0 eq.) at 0 °C under Ar
atmosphere. After stirring for 30 minutes at the same temperature, the reaction mixture was warmed to
60 °C and then stirred for 12.5 hours at the same temperature. The reaction was quenched by adding
saturated NaHCO3 aq. The aqueous layer was extracted three times with CHCl3. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The
crude residue was used in the next reaction without further purification. To a solution of the above residue
in DCM (18.2 mL) were added DMAP (222 mg, 50 mol%) and Boc2O (0.81 mL, 1.1 eq.) successively at
room temperature under Ar atmosphere. After stirring for 1.5 hours, the reaction mixture was washed
with saturated citric acid aq. and brine, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane = 1:9) to afford 12
9
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11
12
138
14
15
9
16
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17
11
18
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25
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12
as a white solid (927 mg, 70% over 2 steps): []24D +15.0 (c 0.47, CHCl3); H NMR (400 MHz, CDCl3)
1
13
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 7.47–7.37 (5H, overlapped), 5.33 (1H, d, J = 4.1 Hz), 4.50 (1H, d, J = 5.0 Hz), 1.55 (9H, s), 1.51 (9H,
13
15
s); C{1H} NMR (100 MHz, CDCl3)  167.4, 151.0, 148.3, 137.5, 129.3, 129.1, 124.9, 84.5, 83.8, 76.1,
16
61.4, 27.9, 27.8. Data are consistent with literature values.6
17
(3R)--Hydroxyphenylalanine Derivative 13. To a solution of 12 (141.3 mg, 0.39 mmol) in MeOH (3.9
mL, 0.1 M) was added Cs2CO3 (38 mg, 0.3 eq.) at room temperature under Ar atmosphere. After stirring
for 2 hours at the same temperature, the reaction was quenched by adding 10% citric acid aq. The
aqueous layer was extracted three times with CHCl3. The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by
18
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33
19
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22
amino silica gel flash chromatography (MeOH/AcOEt/hexane = 0.1:1:4) to afford 13 as a white solid
1
23
(105.3 mg, 80%): []24 –9.1 (c 1.4, CHCl3); H NMR (400 MHz, CDCl3, VT 55 °C)  7.39–7.26 (5H,
D
40
41
24
42
overlapped), 5.25 (1H, br s), 5.10 (1H, d, J = 3.7 Hz), 4.42 (1H, br s), 2.87 (1H, br s), 1.42 (9H, s), 1.35
13
25
(9H, s); C{1H} NMR (100 MHz, CDCl3)  169.8, 155.7, 140.0, 128.2, 127.9, 126.3, 82.5, 79.9, 74.5,
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59.9, 28.2, 27.9. Data are consistent with literature values.6
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(3R)--Hydroxyphenylalanine Derivative 14. To a solution of 13 (436.3 mg, 1.29 mmol) in DCM (13
mL, 0.1 M) was added TFA (4.0 mL, 40 eq.) at 0 °C under Ar atmosphere. After stirring for 1 hour at the
same temperature, the reaction was quenched by adding saturated NaHCO3 aq. to pH 8–9. The aqueous
layer was extracted three times with CHCl3. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and evaporated under reduced pressure to afford 14 as a colorless solid without
further purification (281.8 mg, 92%): []22D +19.4 (c 0.66, CHCl3); 1H NMR (400 MHz, CDCl3)  7.37–
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7.26 (5H, overlapped), 4.73 (1H, d, J = 5.5 Hz), 3.52 (1H, d, J = 5.5 Hz), 1.34 (9H, s); C{1H} NMR
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(100 MHz, CDCl3)  172.5, 140.9, 128.2, 127.8, 126.5, 81.7, 74.6, 61.0, 27.8. Data are consistent with
literature values.18
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(3R)--Hydroxyphenylalanine Derivative 15. To a solution of 14 (135.0 mg, 0.57 mmol) in
THF/DMSO (4:1, 3.0 mL, 0.2 M) were added NaHCO3 (191 mg, 4.0 eq.) and benzyl bromide (0.2 mL,
3.0 eq.) at room temperature under Ar atmosphere. After refluxing at 90 °C for 28 hours, the reaction was
quenched by adding water. The aqueous layer was extracted three times with AcOEt. The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane = 1:9) to afford 15
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6
7
8
9
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as a white solid (221.7 mg, 93%): []23 –168.6 (c 0.38, CHCl3); H NMR (400 MHz, CDCl3)  7.39–
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7.29 (10H, overlapped), 7.25-7.15 (5H, overlapped), 4.90 (1H, d, J = 10.1 Hz), 4.17 (2H, d, J = 13.3 Hz),
4.14 (1H, s, OH), 3.51 (2H, d, J = 13.3 Hz), 3.30 (1H, d, J = 10.1 Hz), 1.37 (9H, s); 13C{1H} NMR (100
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MHz, CDCl3)  168.6, 140.3, 138.1, 129.2, 128.6, 128.0, 127.8, 127.5, 81.8, 69.6, 68.0, 54.7, 28.2. Data
are consistent with literature values.19
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Carboxylic Acid 6 from 15. TFA (2.2 mL, 0.1 M) was added to 15 (93.0 mg, 0.22 mmol) at room
temperature under Ar atmosphere. After stirring for 2 hours, TFA was removed by evaporation and H2O
and DIPEA (1 mL) were added to the residue at 0 °C. The aqueous layer was extracted four times with
AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified by silica gel flash chromatography
21
13
22
23
14
24
25
15
26
27
16
28
17
(AcOH/AcOEt/hexane = 0.1:4:6) to afford 6 as a white amorphous powder (78.8 mg, 98%): []26 –176
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D
1
18
(c 0.53, CHCl3); H NMR (400 MHz, CDCl3)  7.38–7.29 (10H, overlapped), 7.24–7.17 (5H,
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overlapped), 5.11 (1H, d, J = 8.7 Hz), 4.07 (2H, d, J = 13.3 Hz), 3.75 (2H, d, J = 13.3 Hz), 3.58 (1H, d, J
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= 8.7 Hz); C{1H} NMR (100 MHz, CDCl3)  172.4, 139.9, 136.1, 129.4, 128.9, 128.3, 128.2, 128.0,
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127.2, 69.3, 67.0, 54.9. Data are consistent with literature values.19
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Oxazolidinone 16. AcCl (0.4 mL) was added dropwise to MeOH (2.0 mL, 0.5 M) at 0 °C under Ar
atmosphere. After stirring for 5 minutes, L-phenylalanine (165.2 mg, 1.0 mmol) was added to the
solution. The reaction mixture was refluxed at 80 °C for 3 hours. After cooling to room temperature, the
reaction was quenched by adding 30% NH3 aq. The aqueous layer was extracted three times with CHCl3.
The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under
reduced pressure. The crude residue was used in the next reaction without further purification. To a
solution of the above residue in THF (2.0 mL) was added Boc2O (218.3 L, 1.0 eq.) at room temperature
under Ar atmosphere. After stirring for 1 hour at the same temperature, the reaction mixture was diluted
with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The crude residue was used in the next reaction without further
purification. To a solution of the above residue in THF (5.0 mL) was added dropwise a 3 M MeMgBr
solution in Et2O (1.3 mL, 4.0 eq.) at 0 °C under Ar atmosphere. After stirring for 15 minutes at the same
temperature, the reaction mixture was allowed to warm to room temperature and stirred for a total of 3
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hours. The reaction was quenched by adding saturated NH4Cl aq. The aqueous layer was extracted three
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times with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The crude residue obtained by purification by silica gel short-column
flash chromatography was used in the next reaction without further purification. To a solution of the
above residue in THF (3.0 mL) was added KOt-Bu (118.3 mg, 1.2 eq.) at room temperature under Ar
atmosphere. After stirring for 45 minutes at the same temperature, the reaction was quenched by adding
10% citric acid aq. to pH 4–5. The aqueous layer was extracted two times with AcOEt. The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane = 3:7 to 1:1
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8
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14
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gradient) to afford 16 as a pale yellow solid (170.8 mg, 83.2% over 4 steps): []22 –102.4 (c 1.0,
D
16
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17
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CHCl3); H NMR (400 MHz, CDCl3) 7.36–7.32 (2H, overlapped), 7.29–7.25 (1H, m), 7.19–7.17 (2H,
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overlapped), 5.28 (1H, br s), 3.69 (1H, ddd, J = 10.8, 3.6, 0.8 Hz), 2.84 (1H, dd, J = 13.2, 3.6 Hz), 2.59
13
12
(1H, br dd, J = 13.2, 10.8 Hz), 1.48 (3H, s), 1.46 (3H, s); C{1H} NMR (100 MHz, CDCl3)  158.0,
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21
13
136.8, 128.9, 128.7, 127.0, 83.1, 62.9, 36.9, 27.4, 21.8. Data are consistent with literature values.7
Bromoacetyl Oxazolidinone 17. To a solution of 16 (170.8 mg, 0.83 mmol) in THF (2.8 mL, 0.1 M)
was added dropwise a 1.55 M n-BuLi solution in hexane (0.59 mL, 1.1 eq.) at –78 °C under Ar
atmosphere and the mixture was stirred for 10 minutes at the same temperature. After the addition of
2-bromoacetyl bromide (86.3 L, 1.2 eq.), the reaction mixture was allowed to warm to room temperature
and stirred for 1.5 hours. The reaction was quenched by adding 10% citric acid aq. The aqueous layer was
extracted once with AcOEt. The organic layer was washed with saturated NaHCO3 aq. and brine, dried
over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
chromatography (AcOEt/hexane = 1:9) to afford 17 as a pale yellow oil (206.7 mg, 76%): []22D –27.8 (c
22
23
14
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25
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16
28
17
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18
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20
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36
37
1
22
0.71, CHCl3); H NMR (400 MHz, CDCl3) 7.35–7.23 (5H, overlapped), 4.58 (1H, d, J = 12.4 Hz), 4.51
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(1H, dd, J = 9.6, 3.7 Hz), 4.44 (1H, d, J = 12.4 Hz), 3.19 (1H, dd, J = 14.4, 3.7 Hz), 2.59 (1H, br dd, J =
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14.4, 9.6 Hz), 1.40 (3H, s), 1.39 (3H, s); C{1H} NMR (100 MHz, CDCl3) 166.6, 152.1, 136.4, 129.0,
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128.7, 126.9, 83.3, 64.0, 34.9, 28.6, 28.3, 21.8. Data are consistent with literature values.8
Evans-aldol Reaction Substrate 18. To a solution of 17 (2.61 g, 8.0 mmol) in THF (26 mL, 0.3 M)
were added DIPEA (1.68 mL, 1.2 eq.) and Bn2NH (1.84 mL, 1.2 eq.) at room temperature under Ar
atmosphere. The reaction mixture was warmed to 40 °C and stirred for 4 hours at the same temperature.
The reaction mixture was diluted with AcOEt and the organic layer was washed with water and brine,
dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel
flash chromatography (AcOEt/hexane = 1:9 to 3:7 gradient) to afford 18 as a colorless oil (3.42 g, 97%):
[]22D –16.2 (c 1.08, CHCl3); 1H NMR (400 MHz, CDCl3) 7.38–7.37 (4H, overlapped), 7.31–7.22 (11H,
overlapped), 4.50 (1H, dd, J = 9.6, 4.1 Hz), 3.94 (1H, d, J = 18.6 Hz), 3.86 (1H, d, J = 18.6 Hz), 3.81 (4H,
d, J = 13.7 Hz), 3.13 (1H, dd, J = 14.4, 4.1 Hz), 2.86 (1H, dd, J = 14.4, 9.6 Hz), 1.35 (3H, s), 1.32 (3H, s);
13C{1H} NMR (100 MHz, CDCl3) 171.7, 152.5, 139.2, 136.8, 129.1, 128.8, 128.7, 128.3, 127.1, 126.8,
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82.8, 63.1, 57.5, 55.4, 35.3, 28.4, 22.2. Data are consistent with literature values.8
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Oxazolidinone 19. To a solution of 18 (468.5 mg, 1.1 mmol) in DCM (11 mL, 0.1 M) was added
freshly prepared 1 M 9-BBNOTf solution in toluene (1.32 mL, 1.2 eq.) at 0 °C under Ar atmosphere.
After stirring for 10 minutes, DIPEA (0.27 mL, 1.4 eq.) was added to the reaction mixture and this was
stirred for 20 minutes at the same temperature. After the addition of fresh benzaldehyde (122 mL, 1.1 eq.)
at –78 °C, the reaction mixture was stirred for 30 minutes and allowed to warm to 0 °C. The reaction was
quenched by adding MeOH/30% H2O2 (1:1) and stirred for 30 minutes at room temperature. The aqueous
layer was extracted three times with CHCl3. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
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138
14
15
9
16
10
17
chromatography (AcOEt/hexane = 1:9) to afford 18 (65.0 mg, 13% recovered) and 19 as a white solid
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11
(516.7 mg, 86%): []22 –36.1 (c 1.06, CHCl3); H NMR (400 MHz, CDCl3) 7.39–7.17 (20H,
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overlapped), 5.25 (1H, d, J = 9.6 Hz), 4.77 (1H, d, J = 9.6 Hz), 4.30 (1H, dd, J = 7.8, 6.6 Hz), 4.03 (2H, d,
J = 14.2 Hz), 3.84 (1H, s), 3.43 (2H, d, J = 14.2 Hz), 2.85 (1H, dd, J = 14.2, 7.8 Hz), 2.80 (1H, dd, J =
13
22
23
13
14
14.2, 6.6 Hz), 1.26 (3H, s), 0.58 (3H, s); C{1H} NMR (100 MHz, CDCl3) 169.9, 151.8, 139.0, 138.7,
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25
15
136.5, 129.4, 129.1, 128.7, 128.4, 128.3, 128.1, 127.3, 127.0, 81.9, 71.9, 66.3, 62.7, 54.6, 36.1, 26.9, 21.7.
Data are consistent with literature values.8
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17
The 1 M 9-BBNOTf solution in toluene was prepared as follows. 9-BBN dimer (671 mg, 2.75 mmol)
was added into a vial equipped with a stirrer bar under Ar atmosphere in a glove box. The vial was sealed
with a septum and then toluene (5 mL, 1.0 M) and TfOH (0.44 mL, 5 mmol) were added using a syringe.
The color of the reaction mixture changed from colorless to red. After the reaction mixture was refluxed
at 120 °C for 1 hour, its color became pale yellow. The reaction mixture was cooled to room temperature
and used in the next reaction without further purification.
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Carboxylic Acid 6 from 19. To a solution of 19 (1.0 g, 1.82 mmol) in THF/H2O (4:1, 18 mL, 0.1 M)
were added 30% H2O2 aq. (0.37 mL, 2.0 eq.) and 0.8 M LiOH aq. (4.5 mL, 2.0 eq.) at 0 °C under Ar
atmosphere. The reaction mixture was stirred for 30 minutes and then allowed to warm to room
temperature. After stirring for 20 hours at the same temperature, the reaction was quenched by adding
saturated Na2SO3 aq. and stirred for 1 hour. After the addition of AcOH to the solution to pH 4–5, the
aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by
silica gel flash chromatography (5% AcOH-AcOEt/CHCl3 = 1:9) to afford 6 as a white amorphous
powder (419.5 mg, 64%). Data are consistent with those of carboxylic acid 6 from 15.
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4-Fluoro-3-nitrobenzyl Bromide (21). To a solution of conc. H2SO4 (24 mL) and conc. HNO3 (3 mL)
was added dropwise 4-fluorobenzaldehyde (20) (5 mL, 47.5 mmol) at –5 °C under open air. After the
addition of 20, the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction
mixture was slowly added to cold water containing ice and the aqueous layer was extracted three times
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with DCM. The combined organic layers were washed with saturated NaHCO3 aq. and brine, dried over
MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
chromatography (Et2O/hexane = 1:3 to 3:7 gradient) to afford 4-fluoro-3-nitrobenzaldehyde as a pale
1
2
3
4
5
6
7
8
1
yellow solid (5.28 g, 66%): H NMR (400 MHz, CDCl3)  10.04 (1H, s), 8.60 (1H, dd, J = 6.8, 1.6 Hz),
8.20 (1H, ddd, J = 8.8, 4.0, 2.4 Hz), 7.50 (1H, dd, J = 10.0, 8.8 Hz). Data are consistent with literature
values.20 To a solution of 4-fluoro-3-nitrobenzaldehyde (5.26 g, 31.1 mmol) in MeOH (78 mL, 0.4 M)
was added NaBH4 (705 mg, 0.6 eq.) in one portion at 0 °C under Ar atmosphere. The reaction mixture
was allowed to warm to room temperature and stirred for 20 minutes at the same temperature. The
reaction mixture was concentrated by evaporation and diluted with water. The aqueous layer was
extracted three times with CHCl3. The combined organic layers were dried over MgSO4, filtered, and
evaporated under reduced pressure. The residue was purified by silica gel short-column flash
chromatography (AcOEt) to afford 4-fluoro-3-nitrobenzyl alcohol as a pale yellow solid (5.19 g, 98%):
1H NMR (400 MHz, CDCl3)  8.07 (1H, dd, J = 6.9, 2.3 Hz), 7.63 (1H, ddd, J = 8.7, 6.4, 2.3 Hz), 7.28
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13
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(1H, dd, J = 10.5, 8.7 Hz), 4.75 (2H, d, J = 5.0 Hz), 2.10 (1H, t, J = 5.5 Hz, OH); C{1H} NMR (100
25
26
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MHz, CDCl3)  154.7 (d, J = 265 Hz), 137.9 (d, J = 3.8 Hz), 137.2 (d, J = 6.7 Hz), 133.6 (d, J = 8.6 Hz),
124.0 (d, J = 2.9 Hz), 118.5 (d, J = 21 Hz), 63.2. Data are consistent with literature values.9 To a solution
of 1,2-bis(diphenylphosphino)ethane (7.24 g, 0.6 eq.) in DCM (61 mL) was added a 6.25 M Br2 solution
in DCM (7.3 mL, 1.5 eq.) using a syringe at –20 °C under Ar atmosphere. After stirring for 15 minutes, a
solution of 4-fluoro-3-nitrobenzyl alcohol (5.19 g, 30.5 mmol) in DCM (60 mL) was added via a cannula
to the reaction mixture at the same temperature. After the reaction mixture was stirred for 2 hours at the
same temperature, it was allowed to warm to room temperature and stirred overnight. The reaction
mixture was diluted with 50% Et2O/hexane (120 mL) and filtered through a pad of Celite® with
Et2O/hexane (2:1, 50 mL × 2), and the filtrate was concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography (AcOEt/hexane = 1:1) to afford 4-fluoro-3-nitrobenzyl
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1
25
bromide (21) as a yellow solid (6.82 g, 96%): H NMR (400 MHz, CDCl3)  8.11 (1H, dd, J = 6.9, 2.3
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Hz), 7.67 (1H, ddd, J = 8.5, 6.9, 2.3 Hz), 7.29 (1H, dd, J = 10.5, 8.7 Hz), 4.49 (2H, s); C{1H} NMR
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(100 MHz, CDCl3)  155.1 (d, J = 267 Hz), 137.1 (d, J = 8.6 Hz), 136.0 (d, J = 8.6 Hz), 135.0 (d, J = 3.8
Hz), 126.5 (d, J = 1.9 Hz), 119.0 (d, J = 22 Hz), 30.3. Data are consistent with literature values.9
4-Fluoro-3-nitrobenzyl Iodine (22). To a solution of 21 (1.52 g, 6.5 mmol) in acetone (13 mL, 0.5 M)
was added NaI (1.17 g, 1.2 eq.) at room temperature. The reaction mixture was stirred for 20 minutes at
the same temperature under Ar atmosphere. The reaction mixture was quenched with cold water and
extracted two times with AcOEt. The combined organic layers were washed two times with brine, dried
over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by
recrystallization from 20%AcOEt/hexane to afford 4-fluoro-3-nitrobenzyl iodine 22 as pale yellow
needles (1.65 g, 90%): m.p.; 80–81 °C; 1H NMR (400 MHz, CDCl3)  8.07 (1H, dd, J = 6.9, 2.3 Hz), 7.64
12
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(1H, ddd, J = 8.5, 6.9, 2.3 Hz), 7.25 (1H, dd, J = 10.5, 8.7 Hz), 4.44 (2H, s); C{1H} NMR (100 MHz,
CDCl3)  154.6 (d, J = 267 Hz), 137.2 (d, J = 6.7 Hz), 136.7 (d, J = 3.8 Hz), 135.7 (d, J = 8.6 Hz), 126.0
(d, J = 2.9 Hz), 119.0 (d, J = 21 Hz), 1.1. Data are consistent with literature values.10
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Alkylated Compound 23. CuCN (423.2 mg, 1.5 eq.) was added into a vial equipped with a stirrer bar
and dried well over 1 hour under reduced pressure. The residue was dissolved in THF (20 mL) and the
solution was cooled to 0 °C with stirring. To a solution of Schöllkopf reagent (870.3 mg, 1.5 eq.) in THF
(7 mL) in another vial was added 1.55 M n-BuLi solution in hexane (3.05 mL, 1.5 eq.) at –78 °C under Ar
atmosphere. After stirring for 10 minutes, this solution was added to the other vial via a cannula. After the
reaction mixture was stirred for 10 minutes at 0 °C, it was cooled to –78 °C. To the reaction mixture was
added a solution of 22 (884.8 mg, 3.15 mmol) in THF (3 mL) via a cannula. The reaction mixture was
rinsed with THF (2 mL) at the same temperature over 5 minutes and stirred for 15 minutes. The reaction
was quenched by adding saturated NH4Cl aq./30% NH4OH aq. (9:1) at –78 °C and allowed to warm to
room temperature. The aqueous layer was extracted three times with AcOEt. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The
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residue was purified by silica gel flash chromatography (AcOEt/hexane = 1:9) to afford alkylated
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16
compound 23 as a pale yellow oil (871.2 mg, 82%): []25 +37.7 (c 0.46, CHCl3); H NMR (400 MHz,
D
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CDCl3)  7.91 (1H, dd, J = 7.6, 2.1 Hz), 7.38 (1H, m), 7.14 (1H, dd, J = 10.7, 8.6 Hz), 4.29 (1H, dd, J =
9.6, 4.1 Hz), 3.73 (3H, s), 3.69 (3H, s), 3.56 (1H, dd, J = 3.4, 3.4 Hz), 3.17 (1H, dd, J = 13.4, 4.5 Hz),
3.13 (1H, dd, J = 13.7, 5.5 Hz), 2.17 (1H, qd, J = 6.9, 3.4 Hz), 0.97 (3H, d, J = 6.9 Hz), 0.64 (3H, d, J =
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6.9 Hz); C{1H} NMR (100 MHz, CDCl3)  164.4, 161.7, 154.3 (d, J = 264 Hz), 136.9 (d, J = 7.7 Hz),
21
136.5 (d, J = 6.7 Hz), 134.8 (d, J = 3.8 Hz), 127.4 (d, J = 2.9 Hz), 117.6 (d, J = 21 Hz), 60.7, 55.8, 52.5,
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+
22
52.4, 38.6, 31.7, 18.9, 16.5; HRMS (ESI) m/z: [M+H]+ calcd for C16H21FN3O4 338.1516, found
23
338.1538; IR (ATR) max 1695, 1538, 1351, 1241, 1015 cm-1.
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Chiral Phenylalanine Derivative 8. To a solution of 23 (101.5 mg, 0.30 mmol) in acetonitrile (1.5 mL,
0.2 M) was added 0.25 N HCl aq. (3.0 mL, 2.5 eq.) at room temperature under Ar atmosphere. After
stirring for 3 hours at the same temperature, the reaction was quenched by adding saturated NaHCO3 aq.
The aqueous layer was extracted four times with CHCl3. The combined organic layers were dried over
Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
chromatography (MeOH/AcOEt/CHCl3 = 3:30:70) to afford chiral phenylalanine derivative 8 as a yellow
oil (70.5 mg, 97%). As compound 8 easily formed a dimer under concentrated condition, it was used
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immediately in the next reaction. Otherwise, it should be stored as an HCl salt. []D +13.0 (c 0.4,
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CHCl3); H NMR (400 MHz, CDCl3)  7.93 (1H, dd, J = 7.1, 2.2 Hz), 7.49 (1H, m), 7.22 (1H, dd, J =
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10.8, 8.5 Hz), 3.73 (3H, s), 3.71 (1H, dd, J = 7.8, 5.0 Hz), 3.10 (1H, dd, J = 13.7, 5.0 Hz), 2.91 (1H, dd, J
= 13.7, 7.8 Hz), 1.55 (2H, br s, NH2); 13C{1H} NMR (100 MHz, CDCl3)  174.9, 154.4 (d, J = 264 Hz),
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137.1 (d, J = 7.7 Hz), 136.5 (d, J = 8.6 Hz), 134.7 (d, J = 4.8 Hz), 126.6 (d, J = 2.9 Hz), 118.3 (d, J = 21
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Hz), 55.4, 52.3, 52.4, 39.6. Data are consistent with literature values.13
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Dipeptide 24. To a solution of 8 (68.3 mg, 0.28 mmol) in DCM (1.4 mL, 0.2 M) were added
N-Boc-L-phenylalanine (89 mg, 1.3 eq.), DIPEA (54 L, 1.1 eq.), HOBt (48 mg, 1.1 eq.), and EDCI (60
mg, 1.1 eq.) successively at room temperature. After stirring for 2 hours under Ar atmosphere, the
reaction was quenched by adding 10% citric acid aq. The aqueous layer was extracted three times with
CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated
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under reduced pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane =
1:1) to afford dipeptide 24 as a pale yellow solid (123.6 mg, 90%): []25 +36.5 (c 1.07, CHCl3); H
1
D
NMR (400 MHz, CDCl3, VT 55 °C)  7.71 (1H, dd, J = 6.9, 2.3 Hz), 7.33–7.12 (7H, overlapped), 6.45
(1H, d, J = 6.9 Hz, NHCOO), 4.90 (1H, d, J = 7.3 Hz, NHCO), 4.77 (1H, dd, J = 13.3, 6.0 Hz), 4.31 (1H,
dd, J = 14.6, 6.9 Hz), 3.69 (3H, s), 3.18 (1H, dd, J = 14.2, 6.0 Hz), 3.08-3.03 (3H, overlapped), 1.40 (9H,
s); 13C{1H} NMR (100 MHz, CDCl3)  171.2, 170.6, 155.4, 154.6 (d, J = 265 Hz), 137.0 (d, J = 6.7 Hz),
136.5 (d, J = 8.6 Hz), 136.2, 133.0 (d, J = 3.8 Hz), 129.2, 128.7, 127.0, 126.6 (d, J = 2.9 Hz), 118.5 (d, J
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22
11
12
13
23
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= 20 Hz), 80.5, 55.9, 52.9, 52.7, 37.8, 36.7, 28.1; HRMS (ESI) m/z: [M+Na]+ calcd for C24H28FN3NaO7
+
24
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512.1809, found 512.1839; IR (ATR) max 3332, 3301, 1740, 1663, 1540, 1521, 1352, 1295, 1250, 1167
cm-1.
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Tripeptide 5. To a solution of 24 (161.9 mg, 0.33 mmol) in DCM (1.7 mL, 0.2 M) was added TFA
(0.76 mL, 30 eq.) at 0 °C under Ar atmosphere. After stirring for 2 hours at the same temperature, the
reaction was quenched by adding saturated NaHCO3 aq. to pH 8–9 and diluted with water. The aqueous
layer was extracted three times with CHCl3. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and evaporated under reduced pressure for 10 minutes to afford a yellow solid
residue. As the residue easily formed a dimer, it was used immediately in the next reaction without further
purification. To a solution of the above residue (129.6 mg, <0.33 mmol) in MeOH/acetonitrile (1:1, 6.6
mL) were added a solution of 6 (131.5 mg, 1.1 eq.) in MeOH/acetonitrile (1:1, 1.4 mL), DIPEA (86.5 L,
1.5 eq.), and DMT-MM (137.0 mg, 1.5 eq.) at room temperature. After stirring for 2 hours at the same
temperature under Ar atmosphere, the reaction was quenched by adding 10% citric acid aq. The aqueous
layer was extracted three times with AcOEt. The combined organic layers were washed with saturated
NaHCO3 aq. and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue
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was purified by silica gel flash chromatography (AcOEt/hexane = 2:3) to afford tripeptide 5 as a pale
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yellow amorphous powder (226.3 mg, 93% over 2 steps): []24 –103.8 (c 0.46, CHCl3); H NMR (400
D
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MHz, CDCl3)  7.38–7.26 (10H, overlapped), 7.22–7.17 (12H, overlapped), 7.11 (1H, dd, J = 10.5, 8.2
Hz), 6.26 (1H, d, J = 7.8 Hz, NHCO), 5.90 (1H, d, J = 7.8 Hz, NHCO), 5.08 (1H, d, J = 9.2 Hz), 4.71
(1H, m), 4.61 (1H, ddd, J = 7.3, 5.5, 5.5 Hz), 4.09 (1H, br s, OH), 3.98 (2H, d, J = 13.7 Hz), 3.75 (3H, s),
3.16 (1H, d, J = 8.7 Hz), 3.11 (1H, dd, J = 14.4, 6.4 Hz), 3.08 (2H, d, J = 13.7 Hz), 3.00 (1H, dd, J = 13.7,
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59
60
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5.5 Hz), 2.91 (1H, dd, J = 14.4, 8.9 Hz), 2.76 (1H, dd, J = 13.7, 6.9 Hz); C{1H} NMR (100 MHz,
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CDCl3)  170.4, 170.1, 169.1, 154.4 (d, J = 265 Hz), 140.7, 138.1, 137.0 (d, J = 8.6 Hz), 136.4 (d, J = 7.7
Hz), 136.1, 133.1 (d, J = 3.8 Hz), 129.1,129.0, 128.8 128.75, 128.3, 127.9, 127.6, 127.4, 126.4 (d, J = 1.9
Hz), 118.4 (d, J = 21 Hz), 70.2, 67.9, 54.4, 53.8, 53.0, 52.7, 37.3, 36.9; HRMS (ESI) m/z: [M+H]+ calcd
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9
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+
for C42H42FN4O7 733.3038, found 733.3073; IR (ATR) max 3393 (br), 1745, 1667, 1539, 1496, 1454,
1354, 1251, 1217, 753, 702 cm-1.
14-Membered Paracyclophanes 25a and 25b. A suspension of 1.0 M TBAF solution in THF (0.95 mL,
1.1 eq.) and powdered 4Å molecular sieves (420 mg, pre-dried under vacuum) in DMF (138 mL) was
stirred over 2 hours at room temperature. To the suspension was added a solution of 5 (629.3 mg, 0.86
mmol) in DMF (34 mL) via a cannula over 25 minutes at the same temperature under Ar atmosphere. The
reaction mixture was warmed to 70 °C and stirred for 27 hours. After cooling to room temperature, the
reaction mixture was filtered through a pad of Celite® with AcOEt and the filtrate was diluted with water
and extracted four times with AcOEt. The combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
chromatography (AcOEt/hexane = 2:3) to afford a mixture of inseparable atropisomers, 25a and 25b, as a
pale yellow solid (268.9 mg, 44%, in the ratio of 5:1): []24D –134.8 (c 0.84, CHCl3, 25a:25b = 5:1); 1H
NMR (600 MHz, CDCl3)  7.67 (1H, d, J = 2.1 Hz, H-13), 7.43–7.41 (3H, overlapped), 7.35–7.31 (5H,
overlapped), 7.20–7.17 (3H, overlapped), 7.13–7.12 (6H, overlapped), 6.91 (1H, d, J = 8.9 Hz, H-14),
6.65–6.64 (4H, overlapped, Bn), 5.72 (1H, d, J = 4.8 Hz, H-3), 5.63 (1H, d, J = 8.9 Hz, NH), 5.50 (1H, d,
J = 11.0 Hz, NH), 5.01 (1H, ddd, J = 11.7, 11.0, 6.9 Hz, H-10), 4.53 (1H, ddd, J = 8.9, 7.6, 7.6 Hz, H-7),
3.75 (3H, s, CO2Me), 3.48 (1H, dd, J = 13.7, 6.8 Hz, H-11a), 3.38 (1H, d, J = 4.8 Hz, H-4), 2.87 (1H, dd,
J = 14.4, 8.2 Hz, H-27), 2.82 (1H, dd, J = 14.4, 7.6 Hz, H-27), 2.60 (1H, dd, J = 13.7, 11.7 Hz, H-11b);
13C{1H} NMR (150 MHz, CDCl3)  170.7 (C-34), 170.1 (C-8), 169.0 (C-4), 153.9 (C-1), 141.9, 136.9,
135.4, 135.3, 130.0, 129.1, 128.9, 128.7, 128.3, 127.9, 127.8, 127.6, 127.3, 127.2, 126.6, 125.8, 120.1,
88.2 (C-3), 65.1 (C-4), 54.7, 52.8, 52.3, , 51.9, 39.9, 37.8; HRMS (ESI) m/z: [M+H]+ calcd for
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35
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+
25
C42H41N4O7 713.2975, found 713.2937; IR (ATR) max 3393, 1745, 1667, 1539, 1496, 1454, 1354, 1251,
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26
1217, 753, 702 cm-1.
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14-Membered Cyclopeptide Core 26. To a solution of a mixture of 25a and 25b (2.4 mg, 3.4 mol) in
H2O/EtOH (1:2, 0.34 mL, 0.01 M) were added Fe powder (2.0 mg, 10 eq.) and NH4Cl (0.55mg, 3 eq.) at
room temperature. After refluxing for 1 hour at 80 °C under Ar atmosphere, the reaction mixture was
cooled to room temperature and diluted with water. The aqueous layer was extracted five times with
AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue (2.3 mg) was filtered through a pad of standard Al2O3
silica and then used in the next reaction immediately without further purification. To a solution of the
above residue (2.1 mg, <3.1 mol) in THF (0.3 mL, 0.01 M) were added 0.63 M H3PO2 solution in THF
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5029
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52
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(0.1 mL, 20 eq.) and 0.2 M tert-BuONO solution in THF (46 L, 3 eq.) at 0 °C under Ar atmosphere.
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After stirring for 5 minutes, the reaction mixture was allowed to warm to room temperature and stirred for
1 hour. The reaction mixture was diluted with AcOEt, washed with water, saturated NaHCO3 aq., and
brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by
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2
3
4
5
6
7
8
silica gel preparative thin-layer chromatography (AcOEt/hexane = 2:3) to afford 26 as a white solid (2.0
1
mg, 89% over 2 steps): []23 –42.2 (c 0.49, CHCl3); H NMR (600 MHz, CDCl3)  7.39–7.36 (3H,
D
9
overlapped), 7.33–7.26 (2H, overlapped), 7.26 (1H, m), 7.19–7.10 (12H, overlapped), 6.86 (1H, dd, J =
8.2, 2.1 Hz), 6.74–6.72 (5H, overlapped), 5.65 (1H, d, J = 8.2 Hz), 5.55 (1H, d, J = 4.1 Hz), 5.04 (1H, d, J
= 11.0 Hz), 4.90 (1H, ddd, J = 11.7, 11.0, 6.2 Hz), 4.36 (1H, ddd, J = 8.2, 7.6, 6.9 Hz), 3.74 (3H, s), 3.42
(1H, d, J = 4.1 Hz), 3.40 (1H, dd, J = 13.1, 6.2 Hz), 2.84 (1H, dd, J = 13.7, 7.6 Hz), 2.80 (1H, dd, J =
13.7, 6.9 Hz), 2.48 (1H, dd, J = 13.1, 11.7 Hz); 13C{1H} NMR (150 MHz, CDCl3)  171.2, 169.9, 169.4,
160.1, 138.6, 135.9, 131.5, 130.8, 130.3, 129.3, 128.6, 128.0, 127.8, 127.2, 127.1, 125.9, 121.5, 118.4,
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24
25
26
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11
+
12
87.7, 64.5, 55.3, 53.3, 53.1, 52.5, 40.4, 38.6; HRMS (ESI) m/z: [M+H]+ calcd for C42H42N3O5 668.3125,
13
found 668.3116; IR (ATR) max 3358, 3314, 3286, 3061, 3028, 1733, 1653, 1511, 1496, 1451, 1365,
1232, 755, 700 cm-1.
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Primary Amine 3. To a solution of 26 (13.2 mg, 0.02 mmol) in MeOH/DCM (1:1, 1.0 mL, 0.02 M) was
added Pd/C (10%, 6.3 mg, 30 mol%) at room temperature. The reaction mixture was stirred for 3.5 h at
room temperature under hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite®
with MeOH. The filtrate was evaporated under reduced pressure to afford 3 as a white solid without
further purification (10.1 mg, quant.): []23D –32.5 (c 1.23, MeOH); 1H NMR (600 MHz, CD3OD)  7.62
(2H, d, J = 7.6 Hz), 7.48 (2H, dd, J = 7.6, 7.6 Hz), 7.40 (1H, dd, J = 7.6 Hz), 7.23–7.12 (6H, m), 6.95
(1H, dd, J = 8.6, 2.1 Hz), 6.82 (1H, dd, J = 8.2, 2.1 Hz), 6.86 (1H, dd, J = 8.6, 2.1 Hz), 5.76 (1H, br s),
4.87 (1H, m), 4.36 (1H, dd, J = 7.9, 7.6 Hz), 3.87 (1H, br s), 3.69 (3H, s) , 3.36 (1H, dd, J = 13.4, 5.8 Hz),
2.85 (1H, dd, J = 13.7, 7.6 Hz), 2.67 (1H, dd, J = 13.7, 7.9 Hz), 2.59 (1H, dd, J = 13.4, 11.7 Hz); 13C{1H}
NMR (150 MHz, CD3OD)  172.6, 171.4, 159.4, 137.7, 134.1, 133.0, 131.6, 130.4, 130.2, 129.8, 129.4,
127.8, 126.8, 122.6, 120.2, 84.5, 59.1, 55.5, 54.2, 52.8, 40.7, 38.3; HRMS (ESI) m/z: [M+H]+ calcd for
27
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31
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34
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21
36
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38
39
40
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42
43
44
45
46
22
23
24
25
+
26
C28H30N3O5 488.2186, found 488.2209; IR (ATR) max 3355, 3210, 3037, 2955, 1734, 1667, 1608, 1558,
27
1508, 1456, 1285, 1223, 1173, 1013, 702 cm-1.
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49
N,N-Dimethyl-O-benzyltyrosine Methyl Ester. AcCl (0.8 mL) was added dropwise to MeOH (4.0 mL,
0.5 M) at 0 °C under Ar atmosphere. After the solution was stirred for 5 minutes, L-tyrosine (362.4 mg,
2.0 mmol) was added to the solution. The reaction mixture was refluxed at 80 °C for 1 hour. After cooling
to room temperature, the reaction was quenched by adding 30% NH3 aq. The aqueous layer was extracted
four times with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered,
and evaporated under reduced pressure. The crude residue was used in the next reaction without further
purification. The above residue was dissolved in MeOH (2.0 mL) and Pd/C (10 mol%) and formalin (2.5
eq., 36%) were added to the solution at room temperature. The reaction mixture was stirred for 1 hour
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under hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® with MeOH. The
filtrate was purified through an amino silica gel pad with MeOH/CHCl3 (1:1) to afford
N,N-dimethyltyrosine methyl ester as a white solid. This was used in the next reaction without further
purification. To a solution of N,N-dimethyltyrosine methyl ester (111.7 mg, 0.5 mmol) in DMF (2.5 mL,
0.2 M) was added NaH (20 mg, 1.0 eq., 60%) at 0 °C. After stirring for 10 minutes at the same
temperature under Ar atmosphere, BnBr (59.4 L, 1.0 eq.) was added dropwise to the solution. The
reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction was
quenched by adding water. The aqueous layer was extracted three times with AcOEt. The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane = 2:3) to afford
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
10
11
N,N-dimethyl-O-benzyltyrosine methyl ester as a colorless oil (150.3 mg, 96%): []25 +25.1 (c 0.92,
D
1
12
CHCl3); H NMR (400 MHz, CDCl3)  7.43–7.30 (5H, overlapped), 7.12–7.09 (2H, overlapped), 6.89–
21
13
6.88 (2H, overlapped), 5.02 (2H, s), 3.60 (3H, s), 3.37 (1H, dd, J = 9.6, 5.5 Hz), 2.99 (1H, dd, J = 13.7,
9.6 Hz), 2.87 (1H, dd, J = 13.7, 5.5 Hz), 2.38 (6H, s); 13C{1H} NMR (100 MHz, CDCl3)  171.9, 157.4,
137.0, 130.3, 130.0, 128.5, 127.9, 127.5, 114.7, 69.9, 69.8, 51.0, 41.9, 34.9; HRMS (ESI) m/z: [M+H]+
22
23
14
24
25
15
26
27
+
16
calcd for C19H24N1O3 314.1756, found 314.1744; IR (ATR) max 2948, 2786, 1731, 1611, 1510, 1455,
28
29
17
1382, 1297, 1240, 1164, 1025, 826, 738, 696, 629 cm-1.
30
18
N,N-Dimethyl-O-benzyltyrosine 4. To a solution of N,N-dimethyl-O-benzyltyrosine methyl ester (40.5
mg, 0.13 mmol) in THF/H2O (2:1, 1.0 mL, 0.13 M) was added LiOH•H2O (8 mg, 1.5 eq.) at room
temperature. After stirring for 9 hours at 50 °C, the reaction was quenched b adding 1 N HCl aq. to pH 1–
2. The aqueous layer was extracted four times with 10% MeOH/CHCl3. The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue
was purified by silica gel flash chromatography (5% AcOH-MeOH/CHCl3 = 1:4) to afford
31
32
19
33
34
20
35
21
36
37
22
38
39
23
40
41
24
N,N-dimethyl-O-benzyltyrosine 4 as a white amorphous powder (30.8 mg, 80%): []26 +41.8 (c 0.79,
D
42
1
43
25
44
MeOH); H NMR (400 MHz, CD3OD)  7.43 (2H, overlapped), 7.35 (2H, overlapped), 7.29 (1H, m),
26
7.24 (2H, overlapped), 6.97 (2H, overlapped), 5.07 (2H, s), 4.27 (1H, dd, J = 8.2, 6.0 Hz), 3.35 (1H, dd, J
= 14.2, 6.0 Hz), 3.19 (1H, dd, J = 14.2, 8.2 Hz), 2.96 (6H, s); 13C{1H} NMR (100 MHz, CD3OD)  170.1,
159.8, 138.6, 131.5, 129.5, 128.9, 128.5, 127.7, 116.4, 71.0, 70.0, 42.4, 33.8. Data are consistent with
literature values.16
45
46
27
47
48
28
49
50
29
51
30
Cyclophane 2. To a solution of 3 (14.9 mg, 0.031 mmol) in MeOH/DCM (1:1, 0.8 mL, 0.04 M) were
added 4 (11.1 mg, 1.2 eq.), DIPEA (22 L, 4 eq.), and DMT-MM (17.2 mg, 2 eq.) at room temperature.
After stirring for 4 hours at the same temperature under Ar atmosphere, the reaction was quenched by
adding 10% citric acid aq. The aqueous layer was extracted three times with CHCl3. The combined
organic layers were washed with saturated NaHCO3 aq. and brine, dried over Na2SO4, filtered, and
52
53
31
54
55
32
56
57
33
58
34
59
60
35
evaporated under reduced pressure. The residue was purified by amino silica gel flash chromatography
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(AcOEt/hexane = 4:1) to afford cyclophane 2 as a white solid (20.3 mg, 86% over 2 steps): []25D +8.0 (c
0.37, CHCl3); 1H NMR (600 MHz, CDCl3)  7.69 (1H, br d, J = 9.0 Hz, NH-21), 7.52 (2H, d, J = 7.8 Hz,
H-18), 7.43–7.40 (4H, overlapped, H-19, Bn), 7.37 (2H, dd, J = 7.8, 7.8 Hz, Bn), 7.32-7.29 (2H,
overlapped), 7.24–7.18 (3H, overlapped), 7.15 (1H, dd, J = 8.4, 2.4 Hz, H-13), 7.06 (2H, d, J = 7.2 Hz,
H-31), 6.97 (1H, dd, J = 8.4, 2.4 Hz, H-14), 6.88 (1H, dd, J = 8.4, 2.4 Hz, H-15), 6.87 (2H, d, J = 8.4 Hz,
H-26), 6.80 (1H, dd, J = 8.4, 2.4 Hz, H-16), 6.79 (2H, d, J = 8.4 Hz, H-27), 6.09 (1H, d, J = 8.2 Hz,
NH-6), 5.63 (1H, s, H-3), 5.02–4.98 (3H, overlapped, H-9, Bn), 4.89–4.85 (2H, overlapped, H-4, 10),
4.19 (1H, br m, H-7), 3.67 (3H, s, CO2Me) , 3.37 (1H, dd, J = 13.8, 6.0 Hz, H-11a), 3.16 (1H, dd, J = 7.2,
7.2 Hz, H-23), 2.81 (1H, dd, J = 13.2, 4.8 Hz, H-29a), 2.72 (1H, dd, J = 13.2, 9.6 Hz, H-29b), 2.71-2.65
(2H, overlapped, H-24), 2.44 (1H, dd, J = 13.8, 11.4 Hz, H-11b), 2.14 (6H, s, H-35); 13C{1H} NMR (150
MHz, CDCl3)  172.9 (C-22), 170.8 (C-34), 169.5 (C-8), 166.6 (C-5), 159.0 (C-1), 157.0 (C-28), 137.9
(C-17), 137.2 (Bn), 135.8 (C-30), 132.1 (C-25), 131.6, 131.2, 130.8, 130.0 (C-26), 129.2 (C-31), 128.6,
128.5, 128.4, 128.0, 127.9, 127.5, 126.9, 125.8 (C-18), 121.5, 119.4, 114.6, 86.2 (C-3), 71.3 (C-23), 70.0
(Bn), 56.4 (C-4), 54.9 (C-7), 52.9 (C-10), 52.5 (Me), 42.5 (C-35), 39.9 (C-29), 38.3 (C-11), 33.1 (C-24);
2
3
2
4
5
3
6
7
4
8
9
5
6
7
8
9
10
11
12
13
14
15
16
10
17
18
11
19
20
12
21
13
22
23
14
24
25
+
15
HRMS (ESI) m/z: [M+H]+ calcd for C46H49N4O7 769.3601, found 769.3581; IR (ATR) max 3308, 3032,
26
27
16
2931, 1739, 1648, 1509, 1226, 1029, 751, 698 cm-1.
28
29
17
30
Carboxylic acid 27. To a solution of 2 (2.5 mg, 3.3 mol) in THF (0.15 mL) was added 0.066 N LiOH
aq. (0.15 mL, 3 eq.) at 0 °C under Ar atmosphere. The reaction mixture was warmed to room temperature
and stirred for 15 hours at the same temperature. The reaction was quenched by adding AcOH to pH 3–4.
The aqueous layer was extracted three times with CHCl3. The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by
silica gel preparative thin-layer chromatography (MeOH/CHCl3 = 1:4) to afford carboxylic acid 27 as a
white solid (2.4 mg, 98%). Otherwise, the residue was used in the next reaction without purification.
[]27D +18.8 (c 0.12, MeOH);.1H NMR (600 MHz, CD3OD)  7.58 (2H, d, J = 7.6 Hz), 7.41 (2H, d, J =
6.9 H), 7.37–7.36 (4H, overlapped), 7.31–7.26 (2H, overlapped), 7.17–7.14 (5H, overlapped), 7.05 (1H,
m), 6.88 (1H, dd, J = 8.2, 2.1 Hz), 6.85 (1H, dd, J = 8.2, 2.1 Hz), 6.81-6.79 (3H, overlapped), 6.72-6.71
(2H, overlapped), 5.75 (1H, s), 5.00 (2H, s), 4.85 (1H, d, J = 2.1 Hz), 4.68 (1H, dd, J = 11.7, 6.2 Hz), 4.20
(1H, dd, J = 9.0, 4.7 Hz), 3.45 (1H, dd, J = 13.1, 6.2 Hz), 3.14 (1H, m), 2.92 (1H, dd, J = 13.7, 4.7 Hz),
2.72 (1H, dd, J = 13.7, 9.0 Hz), 2.68-2.61 (2H, overlapped), 2.53 (1H, dd, J = 12.4, 12.4 Hz), 1.96 (6H,
18
31
32
19
33
34
20
35
21
36
37
22
38
39
23
40
41
24
42
4325
44
26
45
46
27
47
48
28
49
29
50
51
13
30
s); C{1H} NMR (150 MHz, CD3OD)  178.4, 173.3, 171.4, 168.6, 159.6, 158.6, 140.5, 139.0, 138.6,
52
53
31
135.1, 132.5, 132.2, 131.5, 131.1, 130.5, 129.5, 129.3, 128.8, 128.6, 128.5, 127.5, 127.1, 122.6, 120.1,
116.8, 87.0, 71.7, 71.0, 57.7, 57.4, 55.7, 42.5, 40.1, 40.1, 35.6; HRMS (ESI) m/z: [M+H]+ calcd for
54
55
32
56
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33
C45H47N4O7 755.3445, found 755.3449; IR (ATR) max 3310, 3032, 2925, 1652, 1610, 1512, 1454, 1376,
57
58
34
1227, 1177, 1028, 748, 698 cm-1.
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Zwitterionic Compound 28. To a solution of crude 27 (9.2 mg, <9.6 mol) in MeOH/acetonitrile (1:5,
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0.5 mL, 0.02 M) were added AcOH (2.7 L, 5 eq.), DIPEA (6.7 L, 4 eq.), and MeI (6.1 L, 10 eq.) at
room temperature under Ar atmosphere. After stirring for 2 hours at the same temperature, the reaction
mixture was concentrated under reduced pressure. The residue was purified by ODS flash
2
2
3
4
3
4
5
6
7
chromatography (H2O/MeOH = 1:3) to afford zwitterionic compound 28 as a white solid (4.3 mg, 58%),
1
8 5
9
together with carboxylic acid 27 (1.8 mg, 24%). []23 +6.0 (c 0.22, MeOH); H NMR (600 MHz,
D
6
7
8
9
CD3OD)  7.62 (2H, d, J = 7.6 Hz), 7.43 (2H, d, J = 7.6 Hz), 7.39–7.38 (4H, overlapped), 7.32 (1H, t, J =
7.6 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.22–7.21 (4H, overlapped), 7.16 (1H, dd, J = 8.2, 2.1 Hz), 7.11 (1H,
m), 6.85 (1H, dd, J = 8.2, 2.1 Hz), 6.82-6.81 (2H, overlapped), 6.78 (1H, dd, J = 8.2, 2.4 Hz), 6.75 (1H,
dd, J = 8.2, 2.4 Hz), 6.64–6.62 (2H, overlapped), 5.77 (1H, d, J = 2.1 Hz), 5.11 (1H, d, J = 2.1 Hz), 5.00
(1H, d, J = 11.7 Hz), 4.97 (1H, d, J = 11.7 Hz), 4.68 (1H, dd, J = 11.7, 6.0 Hz), 4.15 (1H, dd, J = 9.6, 4.1
Hz), 3.92 (1H, dd, J = 10.7, 3.4 Hz), 3.45 (1H, dd, J = 13.1, 6.0 Hz), 3.11 (1H, dd, J = 13.1, 3.4 Hz), 3.06
(1H, dd, J = 13.1, 10.7 Hz), 2.94 (1H, dd, J = 13.7, 4.1 Hz), 2.71 (9H, s), 2.65 (1H, dd, J = 13.7, 9.6 Hz),
2.52 (1H, dd, J = 13.1, 11.7 Hz); 13C{1H} NMR (150 MHz, CD3OD)  178.3, 171.4, 166.8, 166.6, 159.5,
159.4, 140.5, 139.0, 138.7, 135.1, 132.6, 131.6, 131.5, 130.6, 129.5, 129.4, 128.9, 128.9, 128.5, 127.6,
127.1, 126.7, 122.4, 119.7, 116.5, 86.6, 77.0, 71.0, 57.8, 57.3, 55.6, 52.5, 40.2, 40.1, 32.9; HRMS (ESI)
10
11
12
13
14
15
16
10
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
11
12
13
14
15
+
16
m/z: [M+H]+ calcd for C46H49N4O7 769.3601, found 769.3620; IR (ATR) max 3298, 3064, 3036, 2925,
17
1644, 1609, 1541, 1515, 1455, 1392, 1233, 1178, 1038, 740, 701 cm-1.
18
Ophiorrhisine A (1). To a solution of 28 (3.4 mg, 4.4 mol) in MeOH (0.2 mL, 0.02 M) was added
Pd/C (10%, 1.4 mg, 30 mol%) at room temperature. The reaction mixture was stirred for 1.5 h at room
temperature under hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® with
MeOH. The filtrate was evaporated under reduced pressure. The residue was purified by ODS flash
chromatography (H2O/MeOH = 1:1) to afford ophiorrhisine A (1) as a colorless solid (2.7 mg, 90%):
19
20
21
37
22
38
39
40
41
42
43
44
23
[]24 +5.7 (c 0.13, MeOH); ECD (c 0.15 mM, MeOH, 24 °C, Synthetic)  ( nm) +0.4 (258), +27.4
D
24
(233), +15.6 (226), –0.2 (217), –12.6 (212), 0 (207); [ECD (c 0.17 mM, MeOH, 24 °C, Natural)
1
25
 ( nm) +0.4 (258), +11.2 (234), +7.1 (227), –0.3 (218), –5.0 (213), –2.0 (207)]; H NMR (600 MHz,
4526
46
CD3OD)  7.61 (2H, d, J = 7.6 Hz, H-18), 7.37 (2H, d, J = 7.6 Hz, H-19), 7.29 (1H, t, J = 7.2 Hz, H-20),
7.24 (2H, dd, J = 8.2, 7.6 Hz, H-32), 7.20 (2H, d, J = 8.2 Hz, H-31), 7.15 (1H, dd, J = 8.2, 2.1 Hz, H-13),
7.11 (1H, t, J = 7.6 Hz, H-33), 6.87 (1H, dd, J = 8.2, 2.1 Hz, H-16), 6.78 (1H, dd, J = 8.2, 2.1 Hz, H-15),
6.77 (2H, d, J = 8.2 Hz, H-26), 6.75 (1H, dd, J = 8.2, 2.4 Hz, H-14), 6.58 (2H, d, J = 8.2 Hz, H-27), 5.78
(1H, d, J = 2.1 Hz, H-3), 5.04 (1H, d, J = 2.1 Hz, H-4), 4.67 (1H, dd, J = 11.7, 6.2 Hz, H-10), 4.18 (1H,
dd, J = 9.6, 4.8 Hz, H-7), 3.95 (1H, m, H-23), 3.45 (1H, dd, J = 13.1, 6.2 Hz, H-11a), 3.08 (1H, dd, J =
13.7, 3.4 Hz, H-24a), 3.03 (1H, dd, J = 13.1, 9.6 Hz, H-24b), 2.94 (1H, dd, J = 13.7, 4.8 Hz, H-29a), 2.70
27
47
48
28
49
50
29
51
30
52
53
31
54
55
32
56
57
13
33
(9H, s, H-35), 2.66 (1H, dd, J = 13.7, 9.6 Hz, H-29b), 2.53 (1H, dd, J = 13.1, 11.7 Hz, H-11b); C{1H}
58
34
NMR (150 MHz, CD3OD)  178.4, 171.3, 167.0, 166.7, 159.3, 158.0, 140.5, 138.7, 135.1, 132.6, 131.5,
59
60
35
130.5, 129.4, 128.8, 127.6, 127.1, 125.4, 122.5, 119.7, 117.0, 86.4, 77.1, 57.9, 57.4, 55.5, 52.6, 40.1,
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33.1; HRMS (ESI) m/z: [M+H]+ calcd for C39H43N4O7 679.3132, found 679.3119; IR (ATR) max 3396,
3057, 1660, 1592, 1516, 1452, 1395, 1224 cm-1.
2
2
3
4
3
5
Derivative 29. To a solution of 3 (7.2 mg, 11 mol) and Pd/C (10%, 3.4 mg, 30 mol%) in MeOH/DCM
(1:1, 0.54 mL, 0.02 M) was added formalin (7.5 L, 9 eq.) at room temperature. The reaction mixture was
stirred for 18 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered
through a pad of Celite® with MeOH. The filtrate was evaporated under reduced pressure. The residue
was purified by amino silica gel flash chromatography (AcOEt/hexane = 3:2 to 4:1 gradient) to afford
derivative 29 as a white solid (3.3 mg, 59%): []22D –32.3 (c 0.17, CHCl3); 1H NMR (600 MHz, CDCl3) 
7.51 (2H, d, J = 8.2 Hz), 7.41 (2H, dd, J = 7.9, 7.9 Hz), 7.33 (1H, dd, J = 7.6, 7.6 Hz), 7.25 (2H, dd, J =
7.9, 7.9 Hz), 7.20 (1H, dd, J = 7.6, 7.6 Hz), 7.13-7.11 (3H, overlapped), 7.04 (1H, dd, J = 8.2, 2.1 Hz),
6.84-6.83 (2H, overlapped), 5.76 (1H, d, J = 8.6 Hz, NH), 5.55 (1H, d, J = 3.6 Hz), 5.15 (1H, d, J = 10.3
Hz), 4.92 (1H, ddd, J = 11.3, 11.3, 6.0 Hz), 4.21 (1H, ddd, J = 9.0, 7.8, 7.2 Hz), 3.74 (3H, s), 3.41 (1H,
dd, J = 13.2, 6.0 Hz), 3.36 (1H, d, J = 3.6 Hz), 2.78 (2H, d, J = 7.6 Hz), 2.49 (1H, dd, J = 13.2, 12.0 Hz),
2.45 (6H, s, NMe2); 13C{1H} NMR (150 MHz, CDCl3)  171.2, 170.0, 168.9, 160.0, 139.5, 136.2, 131.4,
130.6, 130.5, 129.3, 128.5, 128.2, 127.3, 126.8, 125.6, 121.6, 118.9, 87.9, 69.8, 54.0, 53.0, 52.5, 42.6,
6
7
4
8
9
5
6
7
8
9
10
11
12
13
14
15
16
10
17
18
11
19
20
12
21
22
13
23
14
24
25
15
26
27
+
16
40.0, 38.4; HRMS (ESI) m/z: [M+H]+ calcd for C30H34N3O5 516.2499, found 516.2501; IR (ATR) max
28
29
17
3318, 3063, 3030, 2952, 2926, 2882, 1739, 1653, 1511, 1447, 1368, 1281, 1236, 1170, 1115, 1023 cm-1.
Derivative 30. To a solution of 26 (11.7 mg, 17.5 mol) in MeOH/DCM (1:1, 0.7 mL, 0.025 M) was
added Pd/C (10%, 5.6 mg, 30 mol%) at room temperature. The reaction mixture was stirred for 3.5 hours
at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a pad of
Celite® with MeOH. The filtrate was evaporated under reduced pressure and the residue was used in the
next reaction without further purification. To a solution of the above residue (8.7 mg) in DCM (0.7 mL,
0.03 M) was added Ac2O (3.3 L, 2 eq.) at 0 °C under Ar atmosphere. After the addition, the reaction
mixture was allowed to warm to room temperature and stirred for 14.5 hours. The reaction mixture was
diluted with CHCl3 and washed with saturated NaHCO3 aq., 10% citric acid aq., and brine. The organic
layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified
30
3118
32
19
33
34
20
35
36
21
37
22
38
39
23
40
41
24
42
43
25
44
26
45
46
27
by silica gel flash chromatography (AcOEt) to afford derivative 30 as a white solid (7.5 mg, 80% over 2
47
48
1
28
steps): []22 –15.6 (c 0.37, CHCl3); H NMR (600 MHz, CDCl3)  7.47 (2H, d, J = 7.6 Hz), 7.40 (2H,
D
49
50
29
dd, J = 7.6, 7.6 Hz), 7.33 (1H, dd, J = 7.6, 7.6 Hz), 7.24-7.22 (3H, overlapped), 7.15 (1H, dd, J = 8.2, 2.1
Hz), 7.07 (2H, overlapped), 6.94 (1H, dd, J = 8.4, 2.4 Hz), 6.88 (1H, dd, J = 8.6, 2.4 Hz), 6.81 (1H, dd, J
= 8.2, 2.1 Hz), 6.42 (1H, d, J = 9.6 Hz, NH), 6.15 (1H, d, J = 8.9 Hz, NH), 5.56 (1H, d, J = 2.1 Hz), 5.06
(1H, d, J = 10.3 Hz), 4.99 (1H, dd, J = 9.6, 2.1 Hz), 4.87 (1H, ddd, J = 11.2, 11.2, 5.7 Hz), 4.25 (1H, ddd,
J = 9.3, 9.3, 5.5 Hz, H-7), 3.69 (3H, s) , 3.37 (1H, dd, J = 13.4, 6.2 Hz), 2.81 (1H, dd, J = 13.4, 5.2 Hz),
51
30
52
53
31
54
55
32
56
57
33
58
13
34
2.77 (1H, dd, J = 13.4, 9.6 Hz), 2.44 (1H, dd, J = 13.4, 12.0 Hz), 1.91 (3H, s, Ac); C{1H} NMR (150
59
60
35
MHz, CDCl3)  170.9, 170.0, 169.5, 166.9, 159.2, 137.7, 135.6, 131.7, 131.0, 130.8, 129.3, 128.5, 128.4,
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128.1, 127.0, 126.0, 121.1, 119.0, 86.8, 56.1, 54.7, 52.9, 52.4, 40.2, 38.3, 22.9; HRMS (ESI) m/z:
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2
3
4
5
6
7
8
+
[M+Na]+ calcd for C30H31N3NaO6 552.2111, found 552.2125; IR (ATR) max 3308, 3063, 3032, 2952,
2927, 1740, 1644, 1509, 1452, 1382, 1280, 1227, 1170, 1032 cm-1.
Derivative 31. To a solution of 2 (6.4 mg, 8 mol) in MeOH/DCM (1:1, 0.2 mL, 0.04 M) was added
Pd(OH)2/C (20%, 2.8 mg, 50 mol%) at room temperature. The reaction mixture was stirred for 1.5 hours
at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a pad of
Celite® with MeOH. The filtrate was evaporated under reduced pressure. The residue was purified by
9
10
11
12
13
14
15
16
silica gel preparative thin-layer chromatography (MeOH/CHCl3 = 1:19) to afford derivative 31 as a white
1
solid (3.5 mg, 62%): []20 +13.8 (c 0.18, CHCl3); H NMR (600 MHz, CD3OD)  7.59 (2H, d, J = 8.4
D
10
17
Hz), 7.39 (2H, dd, J = 8.4, 8.4 Hz), 7.29 (1H, dd, J = 8.4, 8.4 Hz), 7.21 (2H, dd, J = 7.5, 7.5 Hz), 7.15–
7.12 (4H, overlapped), 6.89 (1H, dd, J = 8.1, 2.1 Hz), 6.87 (1H, dd, J = 8.1, 2.1 Hz), 6.83 (1H, dd, J =
8.4, 2.1 Hz), 6.81 (2H, d, J = 8.4 Hz), 6.61 (2H, d, J = 8.4 Hz), 5.76 (1H, s), 4.91 (1H, s), 4.85 (1H, d, J =
6.0 Hz), 4.83 (1H, dd, J = 12.0, 6.6 Hz), 4.17 (1H, dd, J = 8.4, 7.2 Hz), 3.67 (3H, s), 3.36–3.31 (2H,
overlapped), 2.81 (1H, dd, J = 13.2, 8.4 Hz), 2.76 (2H, d, J = 6.6 Hz), 2.67 (1H, dd, J = 13.2, 6.6 Hz),
2.56 (1H, dd, J = 13.2, 12.6 Hz), 2.10 (6H, s, NMe2); 13C{1H} NMR (150 MHz, CD3OD)  172.7, 171.7,
168.3, 160.0, 157.1, 140.3, 137.9, 133.4, 132.8, 131.2, 130.4, 129.4, 129.4, 128.7, 127.6, 127.0, 122.7,
120.3, 116.2, 86.9, 71.4, 58.0, 55.5, 54.2, 52.7, 42.4, 40.7, 38.2, 35.5; HRMS (ESI) m/z: [M+H]+ calcd
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
11
12
13
14
15
16
17
+
18
for C39H43N4O7 679.3132, found 679.3117; IR (ATR) max 3321, 3061, 3029, 2954, 1734, 1653, 1614.
19
1516, 1450, 1376, 1225, 1172, 1039, 825, 759 cm-1.
20
Derivative 32. To a solution of 3 (7.4 mg, 0.015 mmol) in MeOH/DCM (1:1, 0.3 mL, 0.05 M) were
added N-Cbz-L-phenylalanine (6.8 mg, 1.5 eq.), DIPEA (10.5 L, 4 eq.), and DMT-MM (8.3 mg, 2 eq.)
at room temperature. After stirring for 4 hours at the same temperature under Ar atmosphere, the reaction
was quenched by adding 10% citric acid aq. The aqueous layer was extracted three times with AcOEt.
The combined organic layers were washed with saturated NaHCO3 aq. and brine, dried over Na2SO4,
filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash
21
37
22
38
39
40
41
23
24
42
4325
44
26
chromatography (AcOEt/hexane = 1:1 to 7:3 gradient) to afford corresponding tetrapeptide as a white
45
46
27
47
1
solid (10.4 mg, 89%): []21 +2.4 (c 0.32, CHCl3); H NMR (600 MHz, CDCl3)  7.46 (2H, d, J = 7.6
D
48
49
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Hz), 7.35–7.15 (18H, overlapped), 6.91 (2H, br s), 6.82 (2H, overlapped), 6.21 (1H, s), 5.62 (1H, s), 5.18
(1H, d, J = 8.2 Hz), 5.10 (1H, d, J = 12.4 Hz), 5.02 (1H, d, J = 12.4 Hz), 4.99 (1H, d, J = 8.9 Hz), 4.85
(1H, ddd, J = 11.0, 11.0, 6.2 Hz), 4.47 (1H, br s), 3.65 (3H, s), 3.32 (1H, dd, J = 13.2, 5.8 Hz), 3.00 (1H,
dd, J = 14.2, 5.8 Hz), 2.91 (1H, br s), 2.80 (1H, dd, J = 13.1, 5.5 Hz), 2.75 (1H, dd, J = 13.1, 9.6 Hz), 2.43
(1H, dd, J = 12.4, 12.4 Hz); 13C{1H} NMR (150 MHz, CDCl3)  171.2, 171.0, 169.6, 166.5, 159.3, 155.9,
137.6, 136.6, 136.6, 135.8, 132.0, 131.1, 130.9, 129.6, 129.4, 128.6, 128.4, 128.2, 128.2, 128.1, 127.9,
127.0, 126.9, 126.4, 121.5, 119.1, 86.8, 67.0, 57.0, 54.5, 53.0, 52.2, 40.2, 39.0, 38.4; HRMS (ESI) m/z:
5029
51
30
52
53
31
54
55
32
56
57
33
58
34
59
60
+
35
[M+Na]+ calcd for C45H44N4NaO8 791.3057, found 791.3076; IR (ATR) max 3313, 3064, 3031, 2961,
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2924, 2853, 1732, 1706, 1686, 1644, 1509, 1454, 1387, 1348, 1261, 1219, 1169, 1096, 1028, 804, 744,
699 cm-1. To a solution of corresponding tetrapeptide (9.5 mg, 12 mol) and Pd/C (10%, 14.2 mg, 110
mol%) in MeOH (0.6 mL, 0.02 M) was added formalin (13.8 L, 15 eq.) at room temperature. The
reaction mixture was stirred for 8.5 hours at room temperature under hydrogen atmosphere. The reaction
mixture was filtered through a pad of Celite® with MeOH. The filtrate was evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (MeOH/CHCl3 = 1:19) to afford
derivative 32 as a white solid (3.3 mg, 40%): []23D +4.0 (c 0.11, CHCl3); 1H NMR (600 MHz, CD3OD)
 7.60 (2H, d, J = 7.6 Hz), 7.40 (2H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 7.6, 7.6 Hz), 7.24 (2H, dd, J = 7.2,
7.2 Hz), 7.16–7.12 (7H, overlapped), 6.98 (2H, d, J = 6.9 Hz), 6.90-6.86 (2H, overlapped), 6.84 (1H, dd,
J = 8.2, 2.1 Hz), 5.77 (1H, s), 4.85–4.83 (2H, overlapped), 4.18 (1H, dd, J = 7.6, 7.6 Hz), 3.67 (3H, s),
3.35–3.32 (2H, overlapped), 2.83–2.80 (3H, overlapped), 2.66 (1H, dd, J = 13.4, 7.2 Hz), 2.65 (1H, dd, J
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
11
13
12
= 12.7, 12.7 Hz), 2.05 (6H, s); C{1H} NMR (150 MHz, CD3OD)  172.7, 171.7, 168.5, 160.0, 140.3,
13
137.9, 133.4, 132.7, 131.3, 130.4, 130.2, 129.4, 128.7, 127.6, 127.3, 127.0, 122.8, 120.3, 86.9, 71.3, 58.0,
+
14
55.5, 54.2, 52.7, 42.4, 40.7, 38.2, 36.2; HRMS (ESI) m/z: [M+H]+ calcd for C39H43N4O6 663.3183,
15
found 663.3182; IR (ATR) max 3318, 3029, 2950, 2930, 1742, 1643, 1607, 1507, 1454, 1435, 1363,
1282, 1225, 1171, 1033 cm-1.
16
17
N,N-Dimethyltryptophan•HCl salt (33). To a solution of N-Cbz-L-tryptophan (338.4 mg, 1.0 mmol),
BnOH (154 mL, 1.5 eq.), and DMAP (24 mg, 20 mol%) in DCM (2 mL, 0.5 M) was added DCC (206.3
mg, 1.0 eq.) at room temperature. After stirring for 4 hours at the same temperature under Ar atmosphere,
the reaction mixture was passed through a silica gel pad with AcOEt to afford a crude residue. The
residue was used in the next reaction without further purification. To a solution of the above residue in
THF (5 mL, 0.2 M) was added Boc2O (218 L, 1.0 eq.) in the presence of DMAP (24 mg, 20 mol%) at
room temperature. More Boc2O was added until the reaction was completed. The reaction mixture was
quenched by adding 10% citric acid aq. and extracted once with AcOEt. The organic layer was washed
with saturated NaHCO3 aq. and brine, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by silica gel flash chromatography (AcOEt/hexane = 1:4) to afford
18
19
20
21
37
22
38
39
40
41
42
43
23
24
25
44
26
45
46
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55
56
57
58
59
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N-Cbz-L-Trp(Boc)OBn as a colorless oil (477.5 mg, 90%): []22 +18.4 (c 1.31, CHCl3); UV (MeOH)
D
28

max (nm): 294, 285, 264, 259, 229, 203; 1H NMR (600 MHz, CDCl3)  8.11 (1H, br s), 7.46 (1H, d, J =
29
7.6 Hz), 7.34–7.32 (10H, overlapped), 7.19–7.17 (3H, overlapped), 5.38 (1H, d, J = 7.6 Hz), 5.13–5.08
(3H, overlapped), 5.04 (1H, d, J = 11.7 Hz), 4.78 (1H, dd, J = 13.7, 6.2 Hz), 3.26-3.22 (2H, m), 1.64 (9H,
30
13
31
s); C{1H} NMR (150 MHz, CDCl3)  171.4, 155.6, 149.5, 136.2, 135.3, 134.9, 130.4, 128.6, 128.5,
32
128.4, 128.2, 128.1, 124.5, 124.2, 122.6, 118.9, 115.3, 114.7, 83.7, 67.4, 67.0, 54.2, 28.2, 28.0; HRMS
+
33
(ESI) m/z: [M+Na]+ calcd for C31H32N2NaO6 551.2158, found 551.2186; IR (ATR) max 3361, 2978,
34
1732, 1519, 1455, 1372, 1257, 1159, 1088, 1060, 749, 698 cm-1. To a solution of N-Cbz-L-Trp(Boc)OBn
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(8.8 mg, 0.017 mmol) and formalin (5 L, 4 eq.) in AcOEt/MeOH (2:1, 0.2 mL, 0.1 M) was added Pd/C
(1.8 mg, 10 mol%) at room temperature. After stirring for 3 hours under hydrogen atmosphere, the
reaction mixture was filtered through a pad of Celite® with MeOH. The filtrate was used in the next
reaction without further purification. To a solution of the above filtrate was added 4 N HCl aq. (1 mL) at
room temperature. After stirring for 1.5 hours at the same temperature, the reaction mixture was
evaporated with a base trap under reduced pressure. The residue was purified by ODS chromatography
(H2O/MeOH = 3:2) to afford N,N-dimethyltryptophan•HCl salt (33) as a pale brown solid (4.2 mg, 96%
over 2 steps): []23D +57.6 (c 0.21, 0.2 N HCl aq.); UV (MeOH) max (nm): 290, 281, 274, 220; 1H NMR
(600 MHz, D2O)  7.58 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.19 (1H, s), 7.14 (1H, dd, J = 8.2,
6.9 Hz), 7.07 (1H, dd, J = 8.2, 6.9 Hz), 3.82 (1H, dd, J = 7.6, 6.2 Hz), 3.35 (1H, dd, J = 15.5, 6.2 Hz),
3.28 (1H, dd, J = 15.5, 7.6 Hz), 2.83 (3H, s), 2.75 (3H, s); 13C{1H} NMR (150 MHz, D2O)  173.4, 136.7,
127.2, 125.2, 122.7, 120.0, 119.0, 112.6, 108.1, 71.4, 43.3, 41.0, 24.6; HRMS (ESI) m/z: [M+H]+ calcd
2
3
4
5
6
7
8
9
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10
17
18
11
19
20
12
21
22
+
13
for C13H17N2O2 233.1290, found 233.1268; IR (ATR) max 3406, 3260, 3057, 2925, 1625, 1458, 1393,
23
14
1357, 748 cm-1.
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25
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Derivative 34. To a solution of 3 (9.0 mg, 18 mol), 33 (5.1 mg, 1.2 eq.), and DIPEA (12.6 L, 4 eq.)
in MeOH/MeCN (1:1, 0.36 mL, 0.05 M) was added DMT-MM (10.0 mg, 2 eq.) at room temperature.
After stirring for 4 hours, the reaction mixture was quenched by adding 10% citric acid aq. and extracted
three times with AcOEt. The combined organic layers were washed with saturated NaHCO3 aq. and brine,
dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel
preparative thin-layer chromatography (MeOH/CHCl3 = 1:19) to afford derivative 34 as a colorless solid
(6.7 mg, 52%): []21D +33.8 (c 0.30, MeOH); UV (MeOH) max (nm): 290, 282, 273, 219; 1H NMR (600
MHz, CD3OD)  7.56 (2H, d, J = 7.6 Hz), 7.52 (1H, d, J = 8.2 Hz), 7.36 (2H, dd, J = 7.6, 7.6 Hz), 7.32
(1H, d, J = 8.2 Hz), 7.27 (1H, dd, J = 7.2, 7.2 Hz), 7.21–7.19 (2H, overlapped), 7.13-7.11 (4H,
overlapped), 7.07 (1H, dd, J = 7.6, 7.6 Hz), 6.99 (1H, dd, J = 7.6, 7.6 Hz), 6.89–6.86 (2H, overlapped),
6.82 (1H, dd, J = 8.2, 2.1 Hz), 6.79 (1H, s), 5.76 (1H, s, H-3), 4.88 (1H, overlapped with DOH), 4.83 (1H,
dd, J = 11.7, 6.2 Hz), 4.18 (1H, dd, J = 7.6, 7.6 Hz), 3.66 (3H, s), 3.55 (1H, m), 3.33 (1H, m), 3.05 (2H, d,
J = 6.9 Hz), 2.81 (1H, dd, J = 13.1, 8.2 Hz), 2.66 (1H, dd, J = 13.1, 6.9 Hz), 2.56 (1H, dd, J = 12.4, 12.4
26
27
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17
30
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32
19
33
34
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35
36
21
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3822
39
23
40
41
24
42
43
25
44
26
45
46
27
47
48
13
28
Hz), 2.15 (6H, s); C{1H} NMR (150 MHz, CD3OD)  172.7, 171.7, 168.4, 160.0, 140.3, 138.0, 137.9,
49
50
29
133.4, 132.7, 131.3, 130.5, 129.4, 129.3, 128.7, 128.6, 127.6, 127.0, 124.7, 122.7, 122.3, 120.3, 119.7,
119.1, 112.3, 87.0, 70.0, 58.0, 55.5, 54.3, 52.7, 42.4, 40.7, 38.2, 26.0; HRMS (ESI) m/z: [M+H]+ calcd
51
30
52
53
+
31
for C41H44N5O6 702.3292, found 702.3305; IR (ATR) max 3312, 1741, 1706, 1652, 1609, 1508, 1455,
54
55
32
1437, 1362, 1281, 1225, 1171, 1032, 743, 701 cm-1.
56
57
33
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
1H and 13C{1H} NMR spectra for synthetic compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: takayamah@faculty.chiba-u.jp
ORCID
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Hiromitsu Takayama: 0000-0003-3155-2214
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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This work was supported by JSPS KAKENHI Grant Numbers 16H05094 and 17H03993.
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