Synthetic studies of cyclic peptides stephanotic acid methyl ester, celogentin C, and moroidin

Article abstract of DOI:10.1016/j.tet.2014.05.082

An account of the total synthesis of stephanotic acid methyl ester and celogentin C is presented. The present synthesis features a tandem asymmetric Michael addition/bromination sequence for the synthesis of leucine-tryptophan moiety, and an oxidative coupling reaction to form the tryptophan-imidazole linkage. Moreover, the total synthesis of moroidin had also been studied, and three different synthetic strategies for the construction of the right-hand ring of moroidin were studied.

Full text of DOI:10.1016/j.tet.2014.05.082

Tetrahedron xxx (2014) 1e10
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Tetrahedron
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Synthetic studies of cyclic peptides stephanotic acid methyl ester,
celogentin C, and moroidin
,b,
Lei Li a, Weimin Hu a, Yanxing Jia a
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An account of the total synthesis of stephanotic acid methyl ester and celogentin C is presented. The
present synthesis features a tandem asymmetric Michael addition/bromination sequence for the syn-
thesis of leucine-tryptophan moiety, and an oxidative coupling reaction to form the tryptophan-
imidazole linkage. Moreover, the total synthesis of moroidin had also been studied, and three differ-
ent synthetic strategies for the construction of the right-hand ring of moroidin were studied.
Ó 2014 Published by Elsevier Ltd.
Received 10 April 2014
Received in revised form 14 May 2014
Accepted 21 May 2014
Available online xxx
Keywords:
Total synthesis
Cyclic peptides
Natural product
Tandem reaction
1. Introduction
more potent than the known anti-cancer agent vinblastine
(IC50¼3.6
m
M) in a laboratory experiment. In comparison, moroidin
M) have similar antimitotic
Bicyclic peptides celogentins AeH and J, as well as moroidin
(Fig. 1) were isolated by Kobayashi and co-workers from the seeds
of Celosia argentea,1 which is employed as a traditional herbal
medicine for the treatment of liver and eye diseases in China and
Japan.2 Moroidin had been previously isolated by Williams and co-
workers in 1986 from the leaves of the Australian rainforest bush
Laportea moroides, and the structure of moroidin was further con-
firmed by a single crystal X-ray diffraction analysis.3 Stephanotic
acid (Fig. 1), corresponding to the left-hand part of this bicyclic
peptide family, was isolated by Yoshikawa and co-workers in 2000
from Stephanotis floribunda.4 The unique structure of these bicyclic
peptides contains two unusual cross-links, one joining the trypto-
and celogentins EeJ (IC50¼2.0e4.0
m
activity with vinblastine. Celogentins A, B, and D, the right-hand
rings of which are tripeptides that lack proline residue, are signif-
icantly less active (IC50¼20e30
mM). However, stephanotic acid did
not show any antimitotic activity.4
The impressive biological properties coupled with their un-
precedented molecular architectures made the celogentins and
related compounds enticing targets for chemical synthesis.5e11 The
groups of Hutton,5 Wandless,6 and Campagne7 have reported
synthetic studies in this area, respectively. Moody has reported the
sole total synthesis of stephanotic acid methyl ester, in which, the
key Leu-Trp moiety was constructed through a non-selective hy-
drogenation of dehydroamino acid precursors.8a Castle and co-
workers accomplished the first total synthesis of celogentin C via
an elegant NCS-mediated oxidative coupling for the Trp-His linkage
and a novel Knoevenagel condensation/radical conjugate addition
reaction for the synthesis of Leu-Trp moiety, albeit as a mixture of
all four diastereomers.9 Chen’s group reported the asymmetric total
synthesis of celogentin C by Pd-catalyzed stereoselective CeH ac-
tivation.10 Our group also accomplished the total synthesis of ste-
phan C-6 with the b-carbon of leucine, and the other connecting
the tryptophan C-2 with the imidazole N-1 of histidine. Although
N-linked His residues has been found in other macrocyclic pep-
tides, the Leu-Trp linkage is extremely rare and poses a prominent
synthetic challenge.
The bicyclic peptides of this family inhibit the tubulin poly-
merization, and the antimitotic activity was strongly dependent on
the structure of the right-hand ring.1 Celogentin C (IC50¼0.8
mM),
the only member containing proline fragment, showed four times
phanotic acid methyl ester and celogentin C via a tandem
asymmetric Michael addition/bromination reaction as the key
step.11 Herein, we present a full account of our explorations in the
synthesis of stephanotic acid methyl ester, celogentin C and
moroidin.
* Corresponding author. Tel.: þ86 10 8280 5166; fax: þ86 10 8280 2724; e-mail
address: yxjia@bjmu.edu.cn (Y. Jia).
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.05.082
Please cite this article in press as: Li, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.082

2
L. Li et al. / Tetrahedron xxx (2014) 1e10
R2
O
H
O
N
N
NH2
NH
O
H
H
H
O
O
N
NH2
NH
N
H
N
H
N
H
O
N
H
O
N
H
O
N
HN
O
H
NH
O
HN
HN
H
N
O
O
N
CO2R
O
N
N
H
H
O
N
N
N
H
NH
CO2R1
N
H
O
N
H
celogentin A (1): R = H
celogentin B (2): R = His
moroidin (5): R1 = R2 = H
celogentin D (3): R = His-Lys
celogentin E (6): R1 = Asp, R2 = H
celogentin F (7): R1 = Arg, R2 = H
celogentin G (8): R1 = H, R2 = Me
celogentin H (9): R1 = Asp, R2 = Me
celogentin J (10): R1 = Arg, R2 = Me
H2N
HN
O
NH
H
H
O
O
N
H
N
H
N
H
O
N
CO2H
N
H
O
HN
O
HN
O
HN
O
O
O
H
O
N
H
N
N
NH
N
N
O
N
H
H
N
O
N
H
CO2H
H
celogentin C (4)
stephanotic acid (11)
Fig. 1. Structures of moroidin, celogentins AeH, J, and stephanotic acid.
2. Results and discussions
elegant sequence reported by Castle. The formation of the left-hand
ring would be considered as the total synthesis of stephanotic acid
methyl ester 12, which could be achieved by macrolactamization at
the Val-Trp site. For the stereoselective synthesis of the key Leu-Trp
moiety 13, we envisioned using a tandem asymmetric Michael
addition/bromination followed by azidation strategy, which em-
ploys Evans’ oxazolidinone auxiliary to control the configuration.12
Accordingly, unsaturated carbonyl compounds 14 or 1513 could be
used as Michael reaction acceptor, respectively, corresponding to
2.1. Total synthesis of stephanotic acid methyl ester and ce-
logentin C
At the beginning of 2008, no total synthesis of the family of
celogentins had been reported, and the efficient and stereoselective
synthesis of the Leu-Trp moiety in the ‘left hand’ of the celogentin
had also not been well resolved in previous reports. Our original
plan was to achieve the stereo-controlled total synthesis of celo-
gentin C.
Our synthetic plan of celogentin C is outlined in Scheme 1. A left-
to-right sequence was adopted. The Trp-His CeN coupling and the
final construction of the right-hand ring of 4 would follow the
the isopropyl Grignard reagent and
agent as the Michael reaction donor. In turn, the unsaturated car-
bonyl compounds 14 and -tryptophan C6-Grignard reagent could
be prepared from the known 6-iodo-
-tryptophan derivative 16.14
Although the known 6-iodo- -tryptophan derivative 16 has
L-tryptophan C6-Grignard re-
L
L
L
been prepared from the known Pd-catalyzed annulation method
developed by Zhu and Jia,14 considering the cost of the Pd(OAc)2, it
was not suitable for the large-scale preparation of compound 16.
Therefore, we began to pursue another synthetic approach towards
macrocyclization
H2N
NH
O
NH
H
H
O
N
N
compound 16 starting from the cheap and commercial available
L-
N
H
O
peptide
HN
tryptophan 17 as outlined in Scheme 2. Nitration of -tryptophan 17
L
O
HN
O
coupling
O
with fuming nitric acid in acetic acid following the literature pro-
H
N
O
cess gave the yellow crystal product 18,15 which was treated with
N
H
N
NH
N
O
N
H
CO2H
path a
asymmetric
Michael addition
celogentin C (4)
path b
oxidative
coupling
CO2H
NH2
CO2H
NH2
CO2Me
NHBoc
1. MeOH
TMSCl
HNO3
HOAc
2. Boc2O
Et3N
ref 15
O
N
N
H
18
N
O2N
O2N
H
O
(Boc)2N
CO2Me
H
81%
H
O
CO2Me
N
N
H
O
L
-tryptophan (17)
19
N
O
HN
O
+
O
Ph
CO2Me
NBoc2
CO2Me
NBoc2
H
N
Zn, HOAc
CH2Cl2
Boc2O, DMAP
MeCN
N
N
H
I
O
Boc
N
H
100%
95%
12
15
16
N
N
O2N
H2N
Boc
21
Boc
path b
22
(Boc)2N
CO2Me
(Boc)2N
CO2Me
CO2Me
NBoc2
CO2Me
NHBoc
CO2Me
NBoc2
NaNO2, HCl,
then KI, I2
NO2
O
HO
N3
O
O
path a
72%
N
N
N
N
N
N
I
Boc
Boc
Boc
H
Boc
Ph
O
16
20
23
13
14
Scheme 1. Retrosynthetic analysis of celogentin C (4).
Scheme 2. Synthesis of 6-iodo-L-tryptophan derivative 16.
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L. Li et al. / Tetrahedron xxx (2014) 1e10
3
Table 1
Me3SiCl in dry MeOH followed by the addition of Et3N and Boc2O to
provide the desired mono-Boc product 19 in 81% yield (two steps)
along with trace amounts of 4-nitro- -tryptophan 20. Compound
Optimization of the conjugate addition/bromination cascade sequence
CO2Me
N(Boc)2
CO2Me
N(Boc)2
L
20 is an important intermediate in the total synthesis of natural
product clavicipitic acid.14h Protection of 19 with Boc2O followed by
reduction of nitro group in 21 with Zn dust and HOAc in CH2Cl2
gave the 6-amino derivative 22. Diazotization of aniline followed by
iodination provided the desired product 16 in 72% yield along with
10% reduced compound 23.16 It was noteworthy that the addition of
1 equiv of I2 was crucial for decreasing the yield of the reduced
compound 23.
i-PrMgCl
THF, -30 °C
N
N
I
ClMg
Boc
Boc
16
O
O
CuBr•Me2S
-30 °C
N
O
Ph
CO2Me
N(Boc)2
CO2Me
N(Boc)2
With 6-iodo- -tryptophan derivative 16 in hand, the stage was
L
Ph
O
O
Mg
O
set for the construction of the key Leu-Trp moiety by using the
tandem conjugate addition/bromination sequence. We first in-
vestigated the synthetic route of path a (Scheme 3). Heck reaction
NBS
65%
O
N
O
N
Ph
O
N
N
Br
Boc
Boc
of 16 with
a,b-unsaturated carbonyl compound 24 under the
Pd(OAc)2/Ag2CO3/toluene condition provided 14 in 80% yield.14f,h
Unfortunately, attempts to Michael addition reaction or the tan-
dem Michael addition/azidation reaction using 14 as Michael re-
action acceptor under a variety of reported reaction conditions did
not lead to the desired product.
25
Entry
CuBr$Me2S (equiv)
Solvent
25a
1
2
1.0
1.0
0.1
0.05
0.2
THF/Me2S (1:1)
4%
6%
30%
d
THF
THF
THF
THF
3
4b
5
65%
a
Isolated yield.
Reaction is messy, desired product was not detected.
CO2Me
N(Boc)2
b
O
O
Pd(OAc)2, Ag2CO3
+
N
toluene, 80 °C
80%
might be problem since the amine di-Boc, indole-N-Boc, and
methyl ester are base-sensitive. Surprisingly, chemoselective hy-
drolysis of 26 was effected exclusively by using LiOH in the pres-
ence of hydrogen peroxide to give the azido acid 13 in 95% yield.
Coupling 13 with dipeptide Ile-Val-OtBu (27) provided cyclization
precursor 28 in 82% yield.
Simultaneous deprotection of the N-Boc group and the tert-
butyl ester of 28 with trifluoroacetic acid followed by macro-
lactamization under high-dilution conditions using HATU as cou-
pling agent gave the macrocycle 29 in 48% overall yield as a single
product. It should be mentioned that in Moody’s total synthesis of
stephanotic acid methyl ester, they conducted the macrocyclization
via Leu-Val amide bond formation and found some epimerization
had occurred during the formation of 29. We were pleased to dis-
cover that macrolactamization at the Val-Trp site was devoid of
epimerization.
N
Boc
16
Ph
I
O
24
CO2Me
N(Boc)2
CuBr•Me2S
i-PrMgCl, THF
O
O
messy
or CuBr•Me2S, i-PrMgCl
THF, then Trisyl azide
N
N
Boc
Ph
O
14
Scheme 3. Failed Michael addition or tandem Michael addition/azidation reaction.
We then turned our attention to path b by using carbonyl
compounds 15 as Michael reaction acceptor.12 Accordingly, the
L-
tryptophan C6-Grignard reagent must be used as the Michael re-
action donor. It was originally thought that the preparation of the
L-
tryptophan C6-Grignard reagent could be quite challenging due to
its structural complex and bearing many base-sensitive functional
groups. To our surprise, the L-tryptophan C6-Grignard reagent was
Attempt to reduce the azide group of 29 under Staudinger
condition failed to give the desired corresponding amine. Grate-
fully, reduction of 29 with HCO2NH4 in the presence of 10% Pd/C
successfully provided the desired amine. Finally, coupling the
amine with pyroglutamic acid using HATU gave stephanotic acid
methyl ester 12 in 70% yield, whose physical properties (NMR, MS,
and optical rotation) were essentially identical to those reported for
the natural material.4 Thus, the stereoselective total synthesis of
(ꢀ)-stephanotic acid methyl ester was accomplished in longest
linear 14 steps (4.6% overall yield). This result also confirmed the
tandem Michael addition/bromination reaction yielded the right
stereochemistry of compound 25.
readily prepared by iodo/magnesium exchange following the lit-
erature’s procedure.17 During optimizing the tandem Michael ad-
dition/bromination reaction conditions, we found that the amount
of CuBr$Me2S was crucial for the 1,4-conjugation addition, al-
though the reason is still not clear (Table 1). When the tandem
reaction was performed in the presence of 1.0 equiv of CuBr$Me2S,
only a small amount of the expected product 25 was obtained
(Table 1, entries 1 and 2). When 0.1 equiv of CuBr$Me2S was used,
the desired product 25 was obtained in 30% yield (Table 1, entry 3).
Further optimized the amount of CuBr$Me2S for the tandem re-
action revealed that 0.2 equiv of Cu(I) catalyst gave the best yield of
65% (Table 1, entries 4 and 5). It is noteworthy that the selectivity in
both stereoselective 1,4-addition and stereoselective bromination
were excellent, compound 25 was obtained as a single detectable
diastereomers, and none of other diastereomers were observed in
the crude product.
After completion of the synthesis of stephanotic acid methyl
ester, we turned our attention to the total synthesis of celogentin C
from the key intermediate 13. Coupling of acid 13 with the di-
peptide Leu-Val-OtBu (30),18 following the same procedure as de-
scribed for stephanotic acid methyl ester gave compound 31 in 57%
yield. Treatment of 31 with LiOH in THF/H2O (3:1) followed acidi-
fication using HCl gave the free acid. Coupling the free acid with
Pro-OBn using EDCI and HOBt provided the key intermediate 32,
which was readily converted to (ꢀ)-celogentin C in a four-step
sequence according to the protocol reported by Castle. Thus, our
total synthesis of (ꢀ)-celogentin C was achieved in only 20 steps
With the key intermediate 25 in hand, the synthesis of ste-
phanotic acid methyl ester and celogentin C was illustrated in
Scheme 4. SN2 displacement of the bromo group with NaN3 in DMF
provided
that selective removal of the chiral auxiliary under base condition
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a-azido product 26 in 82% yield. We originally thought
and 1.6% overall yield from the L-tryptophan.

4
L. Li et al. / Tetrahedron xxx (2014) 1e10
CO2Me
N(Boc)2
CO2Me
CO2Me
N(Boc)2
O
O
O
O
LiOH, H2O2
Ile-Val-OtBu (27)
N(Boc)2
HATU, DIPEA, THF
THF/H2O (3:1)
NaN3, DMF
82%
N
O
N
O
HO
N3
O
82%
95%
Ph
Ph
N
N
N
Br
N3
Boc
Boc
Boc
25
26
13
O
O
O
H
N
H
CO2Me
CO2Me
1. TFA, CH2Cl2
2. HATU, HOBt
DIPEA, DMF
Ot-Bu
N
N
H
O
N
1. 10% Pd/C, HCO2NH4
MeOH
N
H
O
N(Boc)2
CO2Me
H
O
O
HN
N3
O
HN
N3
O
HN
O
H2N
O
HN
2. (S)-pyroGlu-OH
48% (2 steps)
H
N
HATU, DIPEA, DMF
70% (2 steps)
N
O
H
N
N
N
t-BuO
O
Boc
H
H
27
28
29
stephanotic acid methyl ester (12)
O
O
N
CO2Me
N(Boc)2
H
H
N
O
O
N
CO2Me
N
N
1. LiOH,
THF/H2O (3:1)
H
O
O
H
O
HO
N3
O
OBn
HN
HN
O
O
O
2. Pro-OBn, EDCl
HOBt, THF
72% (2 steps)
H
57%
(6 steps from 13)
H
N
N
N
Boc
N
H
N
H
O
O
N
N
H
H
13
31
32
H2N
HN
NH
O
N
1. Pro-OBn, NCS, CH2Cl2
1,4-dimethylpiperazine
then 33
NH
H
H
O
CbzHN
HN
N
N
NHPbf
N
H
O
N
H
HN
2. 10% Pd/C, HCO2NH4
MeOH/H2O (5:1)
O
HN
O
O
O
O
O
H
H
O
N
CO2t-Bu
NH2
Ot-Bu
N
3. HBTU, HOBt, DMF
4. TFA/H2O (9:1)
N
NH
N
O
H
30
N
N
H
CO2H
33
HN
celogentin C (4)
Scheme 4. Total synthesis of stephanotic acid methyl ester (12) and celogentin C (4).
2.2. Synthetic studies of moroidin
intermediate 36 in 78% yield. Simultaneous deprotection of the Cbz
and the benzyl ester by hydrogenation provided the cyclization
precursor. Disappointingly, macrolactamization using HATU as
coupling agent failed to give the desired product (Scheme 6). Other
coupling agents (HBTU, EDCI) were screened, but no desired
product was formed.
Despite the total synthesis of celogentin C has been achieved by
three groups, the total synthesis of other members of this family
has not been described yet. Having accomplished the total syn-
thesis of celogentin C and with a large amount of ‘left-hand’ com-
pound 31 in hand, we turned our attention to the synthesis of
moroidin (5). As outlined in Scheme 5, the left-to-right sequence
was also adopted in our synthetic plan. We envisioned that the Trp-
His linkage could be accomplished by NCS-mediated oxidative
coupling, and the formation of the right-hand macrocycle could be
achieved by macrolactamization at three different sites.
Since the final construction of the right-hand ring of celogentin
C was successful by macrolactamization at the Pro-Arg site, we
envisioned that the macrolactamization could be achieved at sim-
ilar Arg-Gly site (path b) (Scheme 7). NCS-mediated oxidative
coupling of 31 with dipeptide 38 gave the desired product 39 in 60%
yield. Hydrolysis of the methyl ester of 39 followed by coupling
with 40 using HBTU as coupling agent provided 41 in 45% yield.
Saponification of the methyl ester and deprotection of the Cbz by
hydrogenation the Cbz provided the cyclization precursor. Once
again, macrolactamization failed to give the desired product. We
were too distressed and confused to understand these results.
We then had to turn our attention to the macrolactamization at
the Trp-His site (path c) (Scheme 8). The key intermediate 45 could
be prepared from 31 following the similar procedure as described
for 41. The macrolactamization was performed after deprotection of
the methyl ester and the Cbz of 45. However, the desired macro-
cycle product was still not detected.
macrocyclization
H
path a
O
O
N
NH2
NH
H
H
N
N
H
O
N
H
NH
path b
HN
O
O
O
N
macrocyclization
path c
NH
CO2H
oxidative coupling
O
H
N
N
H
N
O
N
H
moroidin (5)
Scheme 5. Retrosynthetic analysis of moroidin (5).
The reason why it is difficult for the macrolactamization of
moroidin is still not clear, but these results could serve as a refer-
ence for further synthesis of moroidin.
We first investigated the macrocyclization at Trp-Arg site (path
a) (Scheme 3). Saponification of the methyl ester of 31 (LiOH, THF/
H2O) followed by acidic treatment (HCl) afforded the free acid,
which then coupled with BnOH using EDCI and DMAP provided 34
in 79% yield. Treatment of 34 with 1,4-dimethylpiperazine and NCS
in CH2Cl2 followed addition of tripeptide 35 gave the key
3. Conclusion
We have achieved the stereoselective total synthesis of ste-
phanotic acid methyl ester and celogentin C in longest linear 14
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L. Li et al. / Tetrahedron xxx (2014) 1e10
5
HN
NH
NHPbf
O
H
N
CO2Bn
O
N
H
O
1,4-dimethylpiperazine,
H
CbzHN
CO2Bn
N
1. LiOH, THF/H2O (3:1)
NCS, CH2Cl2, then 35
HN
O
O
N
H
O
31
O
HN
HN
O
2. BnOH, EDCl, DMAP,
THF/DMF(10:1)
78%
H
N
O
N
H
O
H
O
79% (2 steps)
N
N
N
H
H
N
NH
N
O
N
H
34
CO2t-Bu
36
NH
H
O
O
N
NHPbf
NH
H
CbzHN
H
NHPbf
N
H
N
1. MeOH/H2O (5:1)
N
H
O
N
H
10% Pd/C, HCO2NH4
NH
O
HN
O
HN
O
O
O
O
2. HATU, DIPEA,
DMF
H
N
N
H
N
NH
CO2t-Bu
NH
N
O
N
HN
N
H
CO2t-Bu
35
37
Scheme 6. Synthetic studies of moroidin through path a.
H
N
NHPbf
NH
O
O
H
O
H
N
N
CO2Me
CbzHN
N
1,4-dimethylpiperazine,
NCS, CH2Cl2, then 38
N
H
CO2Me
CbzHN
N
H
O
H
O
1. LiOH, THF/H2O (3:1)
HN
O
HN
O
31
O
2. 40, HBTU, HOBt,
DIPEA, THF/DMF(10:1)
45% (2 steps)
O
O
60%
O
H
N
O
N
H
N
N
H
N
N
NH
CO2t-Bu
N
H
N
NH
N
O
N
H
H
CO2t-Bu
39
41
H
NHPbf
NH
N
O
O
HN
H
N
H
NHCbz
1. LiOH, THF/H2O (3:1)
2. Pd/C, H2, MeOH
NH
HN
N
HN
H2N
H
O
O
O
O
N
NHPbf
3. HATU, HOBt
DIPEA, DMF
CO2t-Bu
H
HN
O
N
CO2Me
HN
N
O
40
38
H
N
NH
CO2t-Bu
N
N
N
O
H
H
37
Scheme 7. Synthetic studies of moroidin through path b.
H
O
O
O
N
NHPbf
NH
H
H
H
1. LiOH, THF/H2O (3:1)
2. 44, EDCI, HOBt,
N
CO2Me
N
N
N
H
O
N
H
1,4-dimethylpiperazine
NCS, CH2Cl2, then 42
H
O
NH
DIPEA, THF/DMF(10:1)
HN
O
HN
O
31
CO2Me
O
O
O
82% (2 steps)
69%
H
N
H
N
N
H
NHCbz
CO2t-Bu
N
N
N
H
NHCbz
CO2t-Bu
N
O
N
O
N
N
H
H
43
45
H
O
O
N
NHPbf
NH
H
H
NH
NHPbf
N
1. LiOH, THF/H2O (3:1)
2. Pd/C, H2, MeOH
N
H
O
N
H2N
HN
H
CO2t-Bu
NHCbz
N
NH
N
HN
O
H
O
O
3. HATU, HOBt
DIPEA, DMF
O
HN
H
N
O
N
42
N
H
NH
CO2t-Bu
N
O
44
MeO2C
N
H
37
Scheme 8. Synthetic studies of moroidin through path c.
steps (4.6% overall yield) and 20 steps (1.6% overall yield) from the
commercially available -tryptophan, respectively. The leucine-
tryptophan moiety was constructed via a tandem asymmetric Mi-
chael addition/bromination followed by azidation strategy. The key
Trp-His side-chain linkage was formed by an oxidative coupling
reaction. The total synthesis of moroidin had also been studied.
Three different synthetic strategies were performed for the con-
struction of the right-hand ring of moroidin. Although the total
L
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6
L. Li et al. / Tetrahedron xxx (2014) 1e10
synthesis of moroidin has not been accomplished, these results will
be served as a reference for further synthesis of moroidin.
NaHCO3, extracted with EtOAc, and the combined organic phases
were washed with saturated aqueous NaHSO3, H2O and brine, dried
over Na2SO4. The solvent was evaporated under reduced pressure
and the residue was purified by flash column chromatography
(silica gel, 10e15% EtOAc in petroleum ether, then CH2Cl2 again) to
provide the desired product 16 (7.08 g, 72%) and deiodo product
4. Experimental section
4.1. General information
(0.80 g 10%); 1H NMR (300 MHz, CDCl3)
d 8.50 (s, 1H), 7.48 (d,
All reagents were obtained from commercial suppliers unless
otherwise stated. Tetrahydrofuran (THF) was distilled from potas-
sium sodium alloys; dichloromethane and acetonitrile were dis-
tilled from calcium hydride. N,N-Dimethylformamide (DMF) was
distilled from magnesium sulfate under vacuum. Methanol was
distilled from magnesium methoxide. Flasks were flame-dried
under vacuum and cooled under a stream of nitrogen or argon.
Flash chromatography was performed using silica gel
(200e300 mesh) with solvents distilled prior to use. Visualization
was achieved under a UV lamp (254 nm and 365 nm), and by de-
veloping the plates with phosphomolybdic acid or triketohy-
drindene hydrate in ethanol. 1H NMR were recorded at 300 MHz or
400 MHz NMR spectrometer, 13C NMR at 75 MHz or 100 MHz NMR
spectrometer unless otherwise stated. The following abbreviations
are used for the multiplicities: s: singlet, d: doublet, t: triplet, m:
multiplet, br s: broad singlet for proton spectra. Coupling constants
(J) are reported in Hertz (Hz). Infrared spectra were recorded with
a thin layer of the product on a KBr disk.
J¼7.8 Hz, 1H), 7.27 (s, 1H), 7.23 (d, J¼7.8 Hz, 1H), 5.12 (dd, J¼9.9,
5.1 Hz, 1H), 3.72 (s, 3H), 3.44 (dd, J¼15.0, 5.1 Hz, 1H), 3.29 (dd,
J¼15.0, 9.9 Hz, 1H), 1.60 (s, 9H), 1.30 (s, 18H); 13C NMR (75 MHz,
CDCl3)
d 170.6, 151.7 (2C), 149.0, 136.3, 131.3, 129.8, 124.4, 124.1,
120.4, 116.3, 88.7, 83.9, 83.0 (2C), 58.0, 52.3, 28.0 (3C), 27.6 (6C),
25.3.
4.2.3. (S)-3-Acryloyl-4-phenyloxazolidin-2-one (24). To the solution
of acrylic acid (1.65 g, 22.9 mmol) and Et3N (2.5 equiv) in THF
(volume corresponded to 0.2 M of the oxazolidinone) was added
trimethylacetyl chloride (2.54 g, 21.1 mmol) at ꢀ20 ꢂC. A white solid
was formed instantaneously. The mixture was stirred at ꢀ20 ꢂC for
2.0 h. Lithium chloride (0.82 g, 19.4 mmol) was added, followed by
the oxazolidinone (2.87 g, 17.6 mmol). The mixture was allowed to
warm to room temperature slowly and stirred for 4.0 h. The re-
action was quenched by addition of saturated NH4Cl and the so-
lution was extracted with EtOAc. The organic layer was washed
subsequently with saturated NaHCO3, brine and water, dried over
anhydrous Na2SO4 and filtered. EtOAc was removed in vacuo, and
the residue was purified by flash column chromatography (silica
gel, 12% EtOAc in petroleum ether) provided the desired product 24
4.2. Experimental procedure and physical data
4.2.1. 6-Nitro-
nitration of 6-nitro-
L
-tryptophan derivative 21. To a stirred suspension of
-tryptophan 1815 (6.39 g, 25.7 mmol) in dry
(2.73 g, 71%); 1H NMR (400 MHz, CDCl3)
d
7.52 (dd, J¼11.2, 16.8 Hz,
L
1H), 7.32e7.41 (m, 5H), 6.48 (d, J¼16.8 Hz, 1H); 5.88 (d, J¼10.4 Hz,
1H), 5.50 (dd, J¼3.6, 8.4 Hz, 1H), 4.72 (t, J¼8.8 Hz, 1H), 4.31 (dd,
MeOH (90 mL) was added slowly Me3SiCl (25.0 mL,196 mmol) in an
ice-cold bath. After the addition was completed, the ice-cold bath
was removed and the reaction was stirred at room temperature for
18.0 h. Then, Et3N (50 mL, 361 mmol) and (Boc)2O (8.9 g,
40.8 mmol) were sequentially added. The reaction mixture was
stirred until TLC showed complete protection. The solvent was re-
moved under reduced pressure and the residue was extracted be-
tween water and EtOAc (3ꢁ60 mL). The combined organic layers
were dried over Na2SO4, and then evaporated in vacuo.
J¼3.6, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 164.3, 153.5, 138.8,
132.0, 129.1, 128.7, 127.2, 125.9, 70.0, 57.7.
4.2.4. Unsaturated carbonyl compounds 14. To a solution of com-
pound 16 (323 mg, 0.50 mmol) and (S)-3-acryloyl-4-
phenyloxazolidin-2-one 24 (132 mg, 0.60 mmol) in dry toluene
(2.0 mL) was added Pd(OAc)2 (5.7 mg, 0.025 mmol) and Ag2CO3
(83 mg, 0.3 mmol). The resulting reaction mixture was stirred at
80 ꢂC for 1 day. The solvent was evaporated under reduced pressure
and the residue was purified by flash column chromatography
(silica gel, 20%e25% EtOAc in petroleum ether) to provide the de-
To a solution of above crude product in dry CH3CN (90 mL) was
added DMAP (650 mg, 5.3 mmol) and (Boc)2O (12.4 g, 56.9 mmol)
at room temperature. The mixture was stirred for 1 h, after which
time TLC showed that some starting material still remained. More
(Boc)2O (4.4 g, 20.2 mmol) was added and the mixture was addi-
tionally stirred overnight. The solvent was evaporated, and the
crude purified by silica gel column chromatography to afford 21
sired product 14 (296 mg, 80%) as amorphous solid; ½a D25
ꢀ52.0 (c
ꢃ
0.32, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.34 (s, 1H), 7.97 (d,
J¼15.6 Hz, 1H), 7.90 (d, J¼15.6 Hz, 1H), 7.48e7.54 (m, 3H), 7.33e7.41
(m, 5H), 5.57 (dd, J¼3.84, 8.68 Hz, 1H), 5.18 (q, J¼4.96, 1H), 4.73 (t,
J¼8.76), 4.31 (dd, J¼3.84, 8.84 Hz, 1H), 3.76 (s, 1H), 3.51 (dd, J¼4.88,
14.96 Hz, 1H), 3.35 (dd, J¼10.04, 14.92 Hz, 1H), 1.67 (s, 9H), 1.33 (s,
(8.59 g, 77%); 1H NMR (300 MHz, CDCl3)
d 9.06 (s, 1H), 8.14 (dd,
J¼8.7, 2.1 Hz, 1H), 7.68 (s, 1H), 7.64 (d, J¼8.7 Hz, 1H), 5.19 (dd, J¼9.9,
5.3 Hz, 1H), 3.77 (s, 3H), 3.55 (dd, J¼15.0, 5.3 Hz, 1H), 3.39 (dd,
J¼15.0, 9.9 Hz, 1H), 1.69 (s, 9H), 1.39 (s, 18H); 13C NMR (75 MHz,
18H); 13C NMR (100 MHz, CDCl3)
d 170.6, 164.9, 153.8, 151.8, 149.3,
147.9, 139.2, 135.5, 132.9, 130.9, 129.1, 128.6, 126.6, 126.0, 123.0,
119.3, 116.7, 116.1, 115.5, 84.2, 83.0, 69.9, 58.1, 57.9, 52.3, 28.2, 27.7,
25.5; HRMS (ESI) m/z calcd for C39H47N3O11Na (MþNa)þ 756.3108;
found 756.3112.
CDCl3)
d 170.4, 151.9 (2C), 148.6, 144.9, 135.3, 134.1, 129.3, 119.0,
117.7,116.6,111.5, 84.9, 83.1 (2C), 57.8, 52.3, 27.8 (3C), 27.5 (6C), 25.2.
4.2.2. 6-Iodo- -tryptophan derivative 16. To a solution of nitro-
L
tryptophan 20 (8.59 g, 15.3 mmol) and Zn dust (50.0 g) in CH2Cl2
(180 mL) was slowly added HOAc (14.0 mL) at 0 ꢂC. The solution was
stirred at room temperature for 20 min and then the solution was
filtered. The filtrate was washed with saturated aqueous NaHCO3,
H2O and brine, dried over Na2SO4. The solvent was evaporated
under reduced pressure and the residue was dissolved in THF
(112 mL), H2O (79 mL), and 5% HCl (43 mL). NaNO2 was slowly
added to the solution at 0 ꢂC. After being stirred at 0 ꢂC for 5 min,
the mixture was added to the solution of KI (15.8 g 95.2 mmol) and
I2 (4.06 g 16.0 mmol) in H2O (150 mL), then the resulting reaction
mixture was continued to stir at room temperature for 1.0 h. The
reaction mixture was basified to pH 7e8 with saturated aqueous
4.2.5. (R,E)-3-(4-Methylpent-2-enoyl)-4-phenyloxazolidin-2-one
(15). To the solution of (2E)-isohexenoic acid (2.67 g, 23.4 mmol)
and Et3N (2.5 equiv) in THF (volume corresponded to 0.2 M of the
oxazolidinone) was added trimethylacetyl chloride (2.62 g,
21.7 mmol) at ꢀ20 ꢂC. A white solid was formed instantaneously.
The mixture was stirred at ꢀ20 ꢂC for 2.0 h. Lithium chloride
(0.92 g, 21.6 mmol) was added, followed by the oxazolidinone
(2.92 g, 17.9 mmol). The mixture was allowed to warm to room
temperature slowly and stirred for 4.0 h. The reaction was
quenched by addition of saturated NH4Cl and the solution was
extracted with EtOAc. The organic layer was washed subsequently
with saturated NaHCO3, brine and water, dried over anhydrous
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L. Li et al. / Tetrahedron xxx (2014) 1e10
7
Na2SO4 and filtered. EtOAc was removed in vacuo, and the residue
was purified by flash column chromatography (silica gel, 12% EtOAc
in petroleum ether) provided the desired product 15 (4.33 g, 93%);
was stirred at 0 ꢂC for 15 min, and then 30% H2O2 (0.45 mL, 8 equiv)
was added dropwise followed by dropwise addition of lithium
hydroxide monohydrate (81 mg, 1.93 mmol) in water (1.0 mL). The
resulting mixture was stirred at 0 ꢂC for 6 h. The reaction was
quenched with saturated Na2SO3 and stirred at room temperature
for 30 min. The mixture was acidified with 6 N HCI to pH¼2 and
extracted with EtOAc (3ꢁ20 mL). The combined organic phase was
washed with water (30 mL), brine (30 mL), dried over Na2SO4, and
concentrated in vacuo to give crude product, which was used di-
rectly in the next step.
1H NMR (300 MHz, CDCl3)
d
7.40e7.30 (m, 5H), 7.22 (dd, J¼15.6,
1.2 Hz, 1H), 7.05 (dd, J¼15.6, 6.6 Hz, 1H), 5.48 (dd, J¼8.7, 3.9 Hz, 1H),
4.68 (t, J¼9.0 Hz, 1H), 4.26 (dd, J¼9.0, 3.9 Hz, 1H), 2.52 (m, 1H), 1.07
(d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 165.0, 158.2, 153.8,
139.2, 129.1 (2C), 128.6, 126.0 (2C), 117.6, 69.8, 57.6, 31.3, 21.1, 21.0.
4.2.6. Compound 25. To a solution of iodo-tryptophan 16 (1.29 g,
2.0 mmol) in dry THF (4.0 mL) was added i-PrMgCl (2.0 M, 1.0 mL,
2.0 mmol) dropwise at ꢀ30 ꢂC and the reaction mixture was stirred
at the same temperature for 30 min. CuBr$Me2S (83 mg, 0.4 mmol)
was added to the reaction at ꢀ30 ꢂC and the mixture was warmed
to ꢀ20 ꢂC over 20 min. The unsaturated amide 15 (519 mg,
2.0 mmol) in dry THF (2.0 mL) was added slowly at ꢀ15 to ꢀ10 ꢂC.
After being stirred at the same temperature for 4.0 h, the reaction
mixture was cooled to ꢀ78 ꢂC, and NBS (357 mg, 2.0 mmol) in dry
THF (5.0 mL) was added. After an additional 2.0 h, the mixture was
slowly warmed to 0 ꢂC and then was stirred at 0 ꢂC for 2.0 h the
reaction mixture was quenched with saturated NaHSO3 and
extracted with EtOAc (3ꢁ30 mL). The combined organic phase was
washed with water (30 mL), brine (30 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, 12%e17% EtOAc in petroleum ether) to
A solution of above acid and Ile-Val-OtBu (27) in dry THF
(3.0 mL) at 0 ꢂC was treated with HATU (263 mg, 0.69 mmol) and
DIPEA (0.30 mL, 223 mg, 1.73 mmol). The resulting mixture was
stirred at room temperature for 1 d. The reaction mixture was di-
luted with EtOAc. The organic phase was washed with 1% HCl
(20 mL), saturated NaHCO3 (20 mL), water (20 mL), brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (silica gel, 12%e17% EtOAc in
petroleum ether) to afford the desired product 28 (367 mg) in
a total yield of 78% for two steps; ½a D22
ꢀ35.0 (c 1.00, MeOH); IR
ꢃ
(neat): 3401, 2975, 2108, 1736, 1699, 1655, 1516, 1443, 1370, 1257,
1155, 1088, 851, 768 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.99 (s, 1H),
7.42 (d, J¼8.0 Hz, 1H), 7.36 (s, 1H), 7.06 (d, J¼8.0 Hz, 1H), 6.71 (d,
J¼8.1 Hz, 1H), 6.14 (d, J¼8.4 Hz, 1H), 5.18 (dd, J¼10.2, 5.0 Hz, 1H),
4.34 (d, J¼5.4 Hz, 1H), 4.28 (dd, J¼8.7, 4.8 Hz, 1H), 4.08 (t, J¼7.8 Hz,
1H), 3.75 (s, 3H), 3.48 (dd, J¼15.0, 5.0 Hz, 1H), 3.29 (dd, J¼15.0,
10.2 Hz,1H), 3.02 (dd, J¼8.4, 5.4 Hz,1H), 2.52 (m,1H), 2.08e2.01 (m,
2H), 1.64 (s, 9H), 1.43 (s, 9H), 1.31 (s, 18H), 1.31e1.15 (m, 1H), 1.04 (d,
J¼6.3 Hz, 3H), 0.85e0.66 (m, 16H); 13C NMR (75 MHz, CDCl3)
afford the desired product 25 (1.11 g, 65%); ½a D30
ꢀ64.5 (c 1.00,
ꢃ
MeOH); IR (neat): 2979, 1784, 1735, 1481, 1442, 1370, 1326, 1257,
1139, 1087, 851, 765, 699 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.91 (s,
1H), 7.46 (d, J¼8.2 Hz, 1H), 7.40 (s, 1H), 7.37e7.32 (m, 5H), 7.05 (d,
J¼8.2 Hz, 1H), 6.36 (d, J¼10.4 Hz, 1H), 5.46 (dd, J¼8.8, 4.4 Hz, 1H),
5.21 (dd, J¼10.0, 4.6 Hz, 1H), 4.82 (t, J¼8.8 Hz, 1H), 4.30 (dd, J¼8.8,
4.4 Hz, 1H), 3.76 (s, 3H), 3.50 (dd, J¼15.2, 4.6 Hz, 1H), 3.45 (dd,
J¼10.4, 5.2 Hz, 1H), 3.34 (dd, J¼15.2, 10.0 Hz, 1H), 2.09 (m, 1H), 1.65
(s, 9H), 1.32 (s, 18H), 0.90 (d, J¼6.8 Hz, 3H), 0.80 (d, J¼6.8 Hz, 3H);
d
170.8, 170.5, 170.2, 168.2, 151.6, 149.4, 135.5, 129.6, 124.4, 123.9,
118.6, 116.2, 115.5, 83.4, 82.9, 82.0, 67.0, 58.0, 57.7, 57.6, 55.0, 52.3,
36.9, 31.2, 28.8, 28.1, 27.9, 27.7, 25.5, 24.9, 21.4, 20.4, 18.7, 17.6, 14.9,
11.1; HRMS (ESI) m/z calcd for C48H75N7NaO12 (MþNa)þ 964.5366;
found 964.6365.
13C NMR (100 MHz, CDCl3)
d 170.7, 167.9, 152.9, 151.6, 149.6, 137.7,
135.1, 134.1, 129.7, 129.1, 128.8, 125.8, 124.5, 118.1, 116.3, 83.5, 82.9,
70.0, 58.1, 53.8, 52.2, 30.8, 28.1, 27.7, 25.6, 21.9, 17.9; HRMS (ESI) m/z
calcd for C42H58BrN4O11 (MþNH4)þ 873.3280; found 873.3279.
4.2.9. Macrocycle compound 29. Trifluoroacetic acid (5.0 mL) was
added slowly to a solution of compound 28 (283 mg, 0.30 mmol) in
CH2Cl2 (5.0 mL) at 0 ꢂC. After 2.0 h the reaction mixture was con-
centrated ensuring all excess trifluoroacetic had been removed. The
residue was dissolved in anhydrous DMF (150 mL), cooled to 0 ꢂC,
DIPEA (0.75 mL, 4.31 mmol) and HATU (1.14 g, 3.0 mmol) were
added sequentially. The reaction mixture was allowed to warm to
room temperature, was stirred for 9 days, and then was concen-
trated. The residue was dissolved in EtOAc (50 mL) and was washed
with 1% HCl (20 mL), saturated NaHCO3 (2ꢁ30 mL), and brine
(30 mL). The organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography
(silica gel, 60%e90% EtOAc in petroleum ether) to give the product
4.2.7. Compound 26. To a solution of compound 25 (5.74 g,
6.7 mmol) in DMF (21 mL) was added NaN3 (1.14 g, 17.5 mmol) in
one portion at room temperature. After being stirred for one day,
DMF was removed under vacuum. The residue was diluted with
EtOAc (50 mL) and water (50 mL), and the aqueous phase was
extracted with EtOAc (2ꢁ50 mL). The combined organic extracts
were washed with water (2ꢁ50 mL), brine (2ꢁ50 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, 10%e12% EtOAc in petro-
leum ether) to afford the desired product 26 (4.52 g, 82%); ½a D34
ꢃ
29 (82 mg, 48%); ½a D27
ꢃ
ꢀ18.5 (c 1.00, MeOH); IR (neat): 3328, 2965,
ꢀ29.9 (c 1.00, MeOH); IR (neat): 2978, 2104, 1785, 1736, 1698, 1482,
2101, 1745, 1661, 1513, 1460, 1384, 1211 cmꢀ1 1H NMR (400 MHz,
;
1443, 1370, 1329, 1267, 1255, 1158, 1141, 1089, 851, 762, 701 cmꢀ1
1H NMR (400 MHz, CDCl3)
7.77 (s, 1H), 7.47 (s, 1H), 7.31 (d,
;
CD3OD)
d
7.48 (d, J¼8.4 Hz, 1H), 7.01 (s, 1H), 6.98 (s, 1H), 6.87 (d,
d
J¼8.4 Hz, 1H), 5.48 (m, 1H), 4.03 (d, J¼8.4 Hz, 1H), 3.92 (d, J¼11.6 Hz,
1H), 3.83 (d, J¼6.0 Hz, 1H), 3.78 (s, 3H), 3.48 (dd, J¼14.8, 5.6 Hz, 1H),
3.20e3.11 (m, 2H), 2.32 (m, 1H), 2.02 (m, 1H), 1.64 (m, 1H), 1.45 (m,
1H), 1.11 (m, 1H), 1.03 (d, J¼6.4 Hz, 3H), 0.96 (d, J¼6.4 Hz, 3H),
J¼8.0 Hz, 1H), 6.97 (t, J¼7.6 Hz, 1H), 6.93 (d, J¼8.0 Hz, 1H), 6.69 (t,
J¼7.6 Hz, 2H), 6.35 (d, J¼7.6 Hz, 2H), 5.78 (d, J¼11.6 Hz, 1H), 5.26
(dd, J¼8.8, 4.4 Hz,1H), 5.23 (dd, J¼10.0, 5.0 Hz,1H), 4.57 (t, J¼8.8 Hz,
1H), 4.02 (dd, J¼8.8, 4.4 Hz, 1H), 3.78 (s, 3H), 3.55 (dd, J¼14.8,
5.0 Hz, 1H), 3.38 (dd, J¼14.8, 10.0 Hz, 1H), 3.22 (dd, J¼11.6, 4.0 Hz,
1H), 2.34 (m, 1H), 1.66 (s, 9H), 1.35 (s, 18H), 0.94 (d, J¼6.8 Hz, 3H),
0.92e0.89 (m, 12H); 13C NMR (100 MHz, CD3OD)
d 173.7, 172.2,
171.7, 171.1, 138.4, 131.2, 127.1, 125.6, 120.2, 118.7, 115.8, 110.0, 66.6,
60.0, 59.4, 53.4, 52.8, 51.9, 38.9, 32.4, 30.1, 28.7, 26.0, 22.0, 19.0, 18.9,
15.9, 11.0; HRMS (ESI) m/z calcd for C29H42N7O5 (MþH)þ 568.3242;
found 568.3247.
0.80 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.7, 169.4,
152.8,151.7, 149.3, 137.0, 134.9, 132.1, 129.7, 128.2, 127.7, 125.0, 124.6,
124.5, 118.3, 116.1, 115.9, 83.8, 82.9, 69.5, 58.9, 57.7, 57.3, 52.4, 52.2,
28.5, 28.0, 27.7, 25.4, 21.0, 17.1; HRMS (ESI) m/z calcd for
4.2.10. Stephanotic acid methyl ester (12). A solution of compound
29 (80 mg, 0.14 mmol) in MeOH (3.0 mL) was degassed for 20 min,
then HCO2NH4 (115 mg) and 10% Pd/C (190 mg) was added se-
quentially. The reaction mixture was stirred under argon at room
temperature for 10 h and filtered through filter paper. The filter pad
C
42H54N6NaO11 (MþNa)þ 841.3743; found 841.3738.
4.2.8. Compound 28. To a solution of azido compound 26 (409 mg,
0.50 mmol) in THF (6.0 mL) was added water (2.0 mL). The solution
Please cite this article in press as: Li, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.082

8
L. Li et al. / Tetrahedron xxx (2014) 1e10
was washed with MeOH, and the filtrate was concentrated. The
residue was dissolved in EtOAc (30 mL) and was washed with
saturated NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The
organic layer was dried over Na2SO4 and concentrated in vacuo to
give crude product, which was used directly in the next step.
A solution of above crude product in dry DMF (2.0 mL) at 0 ꢂC
was treated with (S)-pyroglutamic acid (32 mg, 0.25 mmol), DIPEA
(0.1 mL, 0.58 mmol), and HATU (107 mg, 0.28 mmol). The reaction
mixture was allowed to warm to room temperature overnight and
the solvent was removed under vacuum. The residue was dissolved
in EtOAc (30 mL) and was washed with HCl (1 M; 10 mL), saturated
NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, 3%e4% MeOH in CH2Cl2) to give
J¼9.2 Hz, 1H), 7.86 (s, 1H), 7.39e7.38 (m, 5H), 7.35e7.34 (m, 2H),
6.98 (s, 1H), 6.93 (d, J¼8.4 Hz, 1H), 6.87 (s, 1H), 6.73 (d, J¼8.0 Hz,
1H), 5.31 (m, 1H), 5.18 (d, J¼12.4 Hz, 1H), 5.12 (d, J¼12.4 Hz, 1H),
4.85 (t, J¼10.2 Hz, 1H), 4.41 (dd, J¼8.4, 5.6 Hz, 1H), 4.11 (dd, J¼8.4,
2.8 Hz, 1H), 4.02 (m, 1H), 3.90e3.82 (m, 2H), 3.76 (m, 1H), 3.23 (dd,
J¼15.2, 4.6 Hz, 1H), 3.04 (dd, J¼15.2, 7.6 Hz, 1H), 2.98 (dd, J¼11.6,
3.2 Hz, 1H), 2.28e2.20 (m, 2H), 2.13e2.06 (m, 4H), 2.03e1.95 (m,
2H), 1.85 (m, 1H), 1.69 (m, 1H), 1.39e1.34 (m, 2H), 1.24 (m, 1H), 0.85
(d, J¼6.8 Hz, 6H), 0.80e0.75 (m, 9H), 0.69 (d, J¼6.4 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6)
d 177.5, 172.2, 171.9, 171.8, 170.0, 169.5,
169.2,135.9,129.5,128.5,128.1,128.0,126.0,124.2,118.7,117.9,114.3,
108.0, 66.0, 58.7, 57.6, 55.2, 55.0, 52.0, 51.7, 50.0, 46.7, 42.8, 30.3,
29.0, 28.6, 26.8, 26.2, 25.6, 24.9, 23.8, 23.2, 21.8, 20.9, 18.8, 17.7, 17.3;
HRMS (ESI) m/z calcd for C45H60N7O8 (MþH)þ 826.4498; found
826.4496.
stephanotic acid methyl ester 12 (64 mg, 70%); ½a D22
ꢀ112.4 (c 0.50,
ꢃ
MeOH); 1H NMR (400 MHz, DMSO-d6)
d 10.69 (s, 1H), 8.52 (d,
J¼9.2 Hz, 1H), 8.30 (d, J¼10.0 Hz, 1H), 7.87 (s, 1H), 7.43 (d, J¼8.4 Hz,
1H), 7.36 (d, J¼8.4 Hz, 1H), 6.99e6.97 (m, 3H), 6.88 (s, 1H), 5.23 (m,
1H), 4.86 (t, J¼10.4 Hz, 1H), 4.11 (dd, J¼8.8, 3.6 Hz, 1H), 3.88 (dd,
J¼7.6, 6.0 Hz, 1H), 3.76 (dd, J¼10.4, 8.4 Hz, 1H), 3.65 (s, 3H), 3.27 (m,
1H), 3.13 (dd, J¼15.2, 8.8 Hz, 1H), 2.99 (dd, J¼11.6, 3.6 Hz, 1H), 2.24
(m, 1H), 2.13 (m, 1H), 2.08 (m, 2H), 2.01 (m, 1H), 1.71 (m, 1H), 1.62
(m, 1H), 1.22 (m, 2H), 0.92 (d, J¼6.8 Hz, 3H), 0.89 (d, J¼6.8 Hz, 3H),
4.2.13. Celogentin C. Celogentin C was prepared from compound 32
according to the literature procedure;9 1H NMR (400 MHz, DMSO-
d6)
d
11.83 (s, 1H), 9.33 (s, 1H), 8.81 (d, J¼8.8 Hz, 1H), 8.54 (d,
J¼8.8 Hz, 1H), 8.34 (d, J¼9.6 Hz, 1H), 8.14 (d, J¼8.8 Hz, 1H), 7.88 (s,
1H), 7.76 (s, 1H), 7.62 (br s, 1H), 7.56 (d, J¼8.4 Hz, 1H), 7.01 (d,
J¼8.4 Hz, 1H), 6.95 (d, J¼10.4 Hz, 1H), 6.94 (s, 1H), 6.81 (d, J¼6.4 Hz,
1H), 5.62 (dd, J¼15.8, 9.0 Hz, 1H), 4.90 (t, J¼10.6 Hz, 1H), 4.83 (t,
J¼10.4 Hz, 1H), 4.20 (dd, J¼15.8, 9.0 Hz, 1H), 4.15e4.09 (m, 2H),
3.99e3.94 (m, 2H), 3.82e3.74 (m, 1H), 3.56 (t, J¼7.6 Hz, 1H), 3.42 (d,
J¼16.0 Hz, 1H), 3.32 (dd, J¼15.4, 5.8 Hz, 1H), 3.12e3.06 (m, 3H), 2.93
(dd, J¼15.2, 12.8 Hz, 1H), 2.59 (dd, J¼15.2, 11.6 Hz, 1H), 2.27e2.20
(m, 2H), 2.16e2.12 (m, 1H), 2.12e2.06 (m, 2H), 2.03e1.96 (m, 2H),
1.87e1.74 (m, 3H), 1.72e1.65 (m, 1H), 1.63e1.58 (m, 1H), 1.48e1.37
(m, 4H), 1.23e1.15 (m, 1H), 0.83 (d, J¼6.4 Hz, 3H), 0.77 (d, J¼6.0 Hz,
1H), 0.73e0.70 (m, 9H), 0.67 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz,
0.85 (d, J¼6.8 Hz, 3H), 0.77 (d, J¼8.6 Hz, 3H), 0.68e0.63 (m, 6H); 13
C
NMR (100 MHz, DMSO-d6)
d 177.5, 172.2, 171.8, 170.7, 170.0, 169.7,
136.1, 129.8, 125.5, 123.5, 119.0, 117.8, 114.4, 108.4, 58.0, 57.7, 55.2,
55.1, 52.0, 51.9, 51.1, 37.2, 30.5, 29.0, 27.1, 26.8, 25.6, 24.1, 21.8, 18.7,
17.9, 17.3, 15.4, 10.4; HRMS (ESI) m/z calcd for C34H49N6O7 (MþH)þ
653.3657; found 653.3664.
4.2.11. Compound 31. Compound 31 was prepared from azido acid
13 according to the same procedure as that described for stepha-
DMSO-d6) d 177.4, 172.1, 171.3, 171.2, 170.9, 169.3, 169.1, 156.8, 136.5,
notic acid methyl ester 12; ½a D34
ꢃ
ꢀ200.5 (c 1.00, MeOH); IR (neat):
132.8, 131.5, 131.1, 128.6, 124.9, 119.5, 114.0, 100.9, 61.6, 57.2, 55.1,
54.7, 52.1, 51.3, 49.9, 47.2, 46.9, 41.5, 40.5, 31.1, 29.7, 29.0, 26.6, 25.5,
25.0, 23.9, 23.0, 21.7, 20.9, 18.6, 18.2, 17.0; HRMS (ESI) m/z calcd for
3310, 2960, 1741, 1649, 1521, 1456, 1368, 1264, 1214 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6)
d
10.69 (s, 1H), 8.53 (d, J¼8.8 Hz, 1H), 8.39 (d,
J¼10.0 Hz, 1H), 7.86 (s, 1H), 7.37 (d, J¼8.4 Hz, 1H), 7.31 (d, J¼8.4 Hz,
1H), 6.98 (s, 1H), 6.97 (d, J¼8.0 Hz, 1H), 6.90 (s, 1H), 6.80 (d,
J¼8.0 Hz, 1H), 5.22 (m, 1H), 4.86 (t, J¼10.4 Hz, 1H), 4.11 (dd, J¼8.4,
2.8 Hz, 1H), 4.03 (t, J¼9.2 Hz, 1H), 3.88 (t, J¼7.0 Hz, 1H), 3.65 (s, 3H),
3.28 (m, 1H), 3.15 (dd, J¼15.2, 8.4 Hz, 1H), 2.99 (dd, J¼11.8, 3.0 Hz,
1H), 2.24 (m, 1H), 2.12e2.04 (m, 4H), 1.70 (m, 1H), 1.40e1.35 (m,
2H), 1.23 (m, 1H), 0.91 (d, J¼6.8 Hz, 3H), 0.87 (d, J¼6.4 Hz, 3H), 0.85
(d, J¼6.0 Hz, 3H), 0.79e0.75 (m, 6H), 0.69 (d, J¼6.4 Hz, 3H); 13C
C
45H60N7O8 (MþH)þ 1027.5472; found 1027.5455.
4.2.14. Compound 34. To a solution of compound 31 (40 mg,
0.06 mmol) in THF/H2O (3:1, 2.0 mL) was added lithium hydroxide
monohydrate (9 mg, 0.20 mmol) at 0 ꢂC. The resulting mixture was
stirred at 0 ꢂC for 2 h. The reaction mixture was acidified with 6 N
HCI to pH¼2 and was diluted with EtOAc (30 mL). The mixture was
dried over Na2SO4, and concentrated in vacuo to give crude prod-
uct, which was used directly in the next step.
NMR (100 MHz, DMSO-d6)
d 177.4, 172.3, 172.1, 171.7, 169.9, 169.8,
136.0, 129.9, 125.6, 123.4, 119.0, 117.7, 114.5, 108.4, 58.2, 55.14, 55.05,
52.0, 51.9, 51.7, 51.3, 42.9, 30.5, 29.0, 27.0, 26.8, 25.5, 23.7, 23.1, 21.8,
20.9, 18.6, 17.6, 17.3; HRMS (ESI) m/z calcd for C34H49N6O7 (MþH)þ
653.3657; found 653.3651.
A solution of above crude product and benzyl alcohol (108 mg, 1.
mmol) in anhydrous THF/DMF (3:1, 3.0 mL) was treated with DMAP
(12 mg, 0.10 mmol) and EDCI (17 mg, 0.09 mmol) at 0 ꢂC. The
resulting mixture was allowed to warm to room temperature and
stirred for 1 day. The reaction was treated with saturated NaHCO3
(5 mL) and extracted with EtOAc. The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. Preparative TLC (silica
4.2.12. Compound 32. To a solution of compound 31 (33 mg,
0.05 mmol) in THF/H2O (3:1, 2.0 mL) was added lithium hydroxide
monohydrate (21 mg, 0.50 mmol) at 0 ꢂC. The resulting mixture was
stirred at 0 ꢂC for 3 h. The reaction mixture was acidified with 6 N
HCI to pH¼2 and was diluted with EtOAc (30 mL). The mixture was
dried over Na2SO4, and concentrated in vacuo to give crude prod-
uct, which was used directly in the next step.
A solution of above crude product and L-proline benzyl ester
(20 mg, 0.10 mmol) in anhydrous THF (3.0 mL) was treated with
HOBt (13 mg, 0.10 mmol), EDCI (21 mg, 0.11 mmol), and DIPEA
gel, 1:10 MeOH/CH2Cl2 elution) afforded 34 (35 mg, 79%). ½a D25
ꢃ
ꢀ121.4 (c 1.00, MeOH); 1H NMR (400 MHz, DMSO-d6)
d 10.66 (s,
1H), 8.54 (d, J¼9.2 Hz, 1H), 8.39 (d, J¼9.6 Hz, 1H), 7.87 (s, 1H), 7.39
(m, 7H), 6.98 (d, J¼8.0 Hz, 1H), 6.91 (s, 1H), 6.82 (m, 2H), 5.29 (m,
1H), 5.21 (d, J¼12.4 Hz, 1H), 5.12 (d, J¼12.4 Hz, 1H), 4.87 (t,
J¼10.4 Hz, 1H), 4.12 (dd, J¼8.8, 2.0 Hz, 1H), 4.04 (m, 1H), 3.89 (t,
J¼6.8 Hz, 1H), 3.30 (m, 1H), 3.16 (dd, J¼14.4, 8.8 Hz, 1H), 3.01 (dd,
J¼11.6, 2.4 Hz, 1H), 2.24 (m, 1H), 2.14e2.01 (m, 4H), 1.71 (m, 1H),
1.41e1.36 (m, 2H),1.23 (m,1H), 0.90e0.84 (m, 9H), 0.79 (d, J¼7.6 Hz,
3H), 0.78 (d, J¼6.4 Hz, 3H), 0.70 (d, J¼6.0 Hz, 3H); 13C NMR
(25 mL, 0.14 mmol). The resulting mixture was allowed to warm to
room temperature and stirred for 2 days. The reaction was treated
with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (6ꢁ5 mL).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. Preparative TLC (silica gel, 1:10 MeOH/CH2Cl2 elution)
(100 MHz, DMSO-d6)
d 177.4, 172.2, 172.0, 171.0, 169.9, 169.8, 136.0,
135.8,129.8,128.4,128.1,128.0,125.5,123.4,118.9,117.7,114.4,108.2,
79.1, 66.0, 58.1, 55.1, 55.0, 52.0, 51.9, 51.7, 51.2, 42.8, 30.4, 28.9, 27.0,
26.8, 25.5, 23.7, 23.1, 21.8, 20.9, 18.6, 17.6, 17.3; HRMS (ESI) m/z calcd
for C40H53N6O7 (MþH)þ 729.3976; found 729.3961.
afforded 32 (30 mg, 72%). ½a D34
ꢃ
ꢀ128.0 (c 1.00, MeOH); 1H NMR
(400 MHz, DMSO-d6)
d
10.63 (s, 1H), 8.51 (d, J¼9.2 Hz, 1H), 8.33 (d,
Please cite this article in press as: Li, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.082

L. Li et al. / Tetrahedron xxx (2014) 1e10
9
4.2.15. Compound 36. A solution of 34 (23 mg, 0.031 mmol) in
anhydrous CH2Cl2 (4.0 mL) was treated with N,N0-dimethylpiper-
azine (30 mL), followed by NCS (4.1 mg, 0.031 mmol). The resulting
J¼8.4 Hz, 1H), 7.50 (t, J¼4.5 Hz, 1H), 7.36e7.26 (m, 7H), 7.10 (d,
J¼8.0 Hz,1H), 6.94 (d, J¼8.0 Hz,1H), 6.85 (s,1H), 6.73 (br s,1H), 6.44
(br s, 1H), 5.54 (m, 1H), 4.99 (s, 2H), 4.82 (t, J¼10.0 Hz, 1H), 4.44 (m,
1H), 4.23 (m, 1H), 4.10 (dd, J¼8.4, 2.8 Hz, 1H), 3.95 (m, 1H),
3.70e3.62 (m, 3H), 3.59 (s, 3H), 3.14 (m, 1H), 3.05e2.98 (m, 3H),
2.95 (s, 2H), 2.93e2.82 (m, 3H), 2.48 (s, 3H), 2.42 (s, 3H), 2.24 (m,
1H), 2.15e2.07 (m, 3H), 2.00 (s, 3H), 1.78 (m, 1H), 1.72e1.68 (m, 2H),
1.59 (m, 1H), 1.46e1.33 (m, 4H), 1.40 (s, 6H), 1.37 (s, 9H), 0.84e0.68
solution was stirred at room temperature for 6 h, then treated with
Cbz-Arg(Pbf)-Gly-His-OtBu (35, 105 mg, 0.13 mmol), stirred at room
temperature for 24 h, and concentrated in vacuo. Preparative TLC
(silica gel, 1:10 MeOH/CH2Cl2 elution) afforded 36 (36 mg, 78%).
½
a 2D5
ꢃ
ꢀ60.7 (c 1.00, MeOH); 1H NMR (400 MHz, DMSO-d6)
d 11.46
(br s, 1H), 8.54 (d, J¼8.8 Hz, 1H), 8.34 (d, J¼9.2 Hz, 1H), 8.27e8.26
(m, 2H), 8.14 (d, J¼7.8 Hz,1H), 7.92 (s,1H), 7.88 (s,1H), 7.49e7.47 (m,
2H), 7.36e7.26 (m,12H), 7.12 (d, J¼7.2 Hz,1H), 6.96 (d, J¼8.0 Hz,1H),
6.86 (s, 1H), 6.66 (br s, 1H), 6.38 (br s, 1H), 5.56 (m, 1H), 5.14 (d,
J¼12.4 Hz, 1H), 5.05e4.94 (m, 3H), 4.83 (t, J¼10.0 Hz, 1H), 4.47 (m,
1H), 4.10 (dd, J¼8.4, 2.8 Hz, 1H), 4.03e4.00 (m, 2H), 3.74e3.70 (m,
3H), 3.35 (m, 1H), 3.11e2.90 (m, 10H), 2.47 (s, 3H), 2.41 (s, 3H), 2.25
(m, 1H), 2.12e2.08 (m, 3H), 1.98 (s, 3H), 1.83 (m, 1H), 1.69e1.63 (m,
2H), 1.44e1.35 (m, 2H), 1.38 (s, 6H), 1.35 (s, 9H), 1.25e1.15 (m, 4H),
0.82 (d, J¼6.4 Hz, 3H), 0.78e0.72 (m, 12H), 0.68 (d, J¼6.0 Hz, 3H);
(m, 18H); 13C NMR (100 MHz, DMSO-d6)
d 177.4, 172.2, 172.0, 171.9,
170.5,169.5, 169.3, 169.1, 157.4, 156.4, 156.0, 137.6, 137.4, 137.2, 137.0,
134.2, 132.8, 131.4, 130.7, 128.8, 127.7, 127.6, 124.8, 124.3, 119.5,
119.4, 118.0, 116.2, 113.9, 101.3, 86.3, 80.6, 65.4, 59.7, 57.3, 55.1, 54.8,
52.8, 52.1, 51.8, 51.79, 51.3, 43.3, 42.4, 41.8, 31.3, 29.9, 29.0, 28.3,
27.6, 27.5, 26.5, 26.4, 25.5, 23.9, 23.1, 21.8, 20.9, 18.9, 18.6, 18.3, 17.6,
17.1, 12.2; HRMS (ESI) m/z calcd for C73H101N14O16S (MþH)þ
1641.7241; found 1641.7235.
4.2.18. Compound 43. Compound 43 was prepared from compound
31 and Cbz-His-OtBu (42) according to the same procedure as that
13C NMR (100 MHz, DMSO-d6)
d 177.4, 172.2, 171.5, 171.4, 170.5,
169.9, 169.4, 168.6, 157.4, 156.0, 137.4, 137.2, 136.8, 135.6, 134.2,
132.8, 131.4, 130.9, 128.9, 128.3, 128.27, 128.0, 127.9, 127.7, 127.6,
124.8, 124.3, 119.0, 117.9, 116.2, 114.0, 100.7, 86.2, 80.6, 66.3, 65.5,
62.8, 58.2, 57.5, 55.1, 54.8, 54.4, 52.8, 52.0, 51.4, 45.8, 42.4, 42.0, 41.7,
31.2, 30.1, 28.9, 28.2, 27.6, 26.6, 25.5, 23.9, 23.0, 21.7, 20.9, 18.9, 18.4,
described for Compound 36; ½a D25
ꢃ
ꢀ89.2 (c 0.50, MeOH); 1H NMR
(400 MHz, DMSO-d6)
d
11.51 (br s, 1H), 8.56 (d, J¼9.2 Hz, 1H), 8.36
(d, J¼10.0 Hz, 1H), 8.12 (d, J¼8.4 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H),
7.62 (d, J¼8.0 Hz, 1H), 7.46 (d, J¼8.4 Hz, 1H), 7.34e7.28 (m, 6H), 7.09
(d, J¼7.6 Hz, 1H), 6.99 (d, J¼8.4 Hz, 1H), 6.86 (s, 1H), 5.43 (m, 1H),
5.07e4.98 (m, 2H), 4.84 (t, J¼10.0 Hz, 1H), 4.27 (m, 1H), 4.10 (dd,
J¼8.4, 2.8 Hz, 1H), 3.99 (m, 1H), 3.77 (t, J¼8.0 Hz, 1H), 3.56 (s, 3H),
3.32 (m, 1H), 3.05e2.86 (m, 4H), 2.23 (m, 1H), 2.11e2.09 (m, 3H),
1.91 (m, 1H), 1.69 (m, 1H), 1.41 (m, 1H), 1.38 (s, 9H), 1.20 (m, 1H),
0.85e0.74 (m, 15H), 0.69 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz,
18.2, 17.5, 17.1, 12.2; HRMS (ESI) m/z calcd for C79H104N15O16
S
(MþH)þ 1537.7548; found 1537.7517.
4.2.16. Compound 39. Compound 39 was prepared from com-
pound 31 and Cbz-Gly-His-OtBu (38) according to the same pro-
cedure as that described for compound 36; ½a D25
ꢃ
ꢀ78.2 (c 1.00,
DMSO-d6) d 177.4, 172.2, 172.0, 171.6, 171.0, 170.0, 169.4, 155.9, 137.6,
MeOH); 1H NMR (400 MHz, DMSO-d6)
d
11.49 (br s, 1H), 8.56 (d,
137.5, 136.9,132.7, 130.8,128.8,128.3,127.8, 127.2, 124.9, 119.7,118.8,
117.9, 114.0, 100.4, 80.6, 65.4, 57.6, 55.1, 54.8, 54.6, 52.0, 51.9, 51.4,
49.1, 42.1, 31.1, 29.7, 29.0, 27.6, 27.4, 26.6, 25.5, 25.3, 23.9, 23.1, 21.7,
20.9, 18.3, 17.1; HRMS (ESI) m/z calcd for C52H70N9O11 (MþH)þ
996.5195; found 996.5236.
J¼9.2 Hz, 1H), 8.36 (d, J¼9.6 Hz, 1H), 8.25 (d, J¼7.6 Hz, 1H), 8.13 (d,
J¼8.8 Hz, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.51 (t, J¼4.5 Hz, 1H), 7.46 (d,
J¼8.4 Hz, 1H), 7.34e7.29 (m, 6H), 7.11 (d, J¼8.0 Hz, 1H), 6.98 (d,
J¼8.4 Hz, 1H), 6.87 (s, 1H), 5.45 (m, 1H), 5.00 (s, 2H), 4.84 (t,
J¼10.0 Hz, 1H), 4.46 (m, 1H), 4.11 (dd, J¼8.8, 3.6 Hz, 1H), 3.99 (m,
1H), 3.77 (t, J¼8.0 Hz, 1H), 3.65 (d, J¼4.5 Hz, 2H), 3.58 (s, 3H), 3.31
(m, 1H), 3.05e2.90 (m, 4H), 2.25 (m, 1H), 2.15e2.07 (m, 3H), 1.89
(m, 1H), 1.70 (m, 1H), 1.41 (m, 1H), 1.38 (s, 9H), 1.20 (m, 1H),
0.86e0.77 (m, 12H), 0.74 (d, J¼6.4 Hz, 3H), 0.69 (d, J¼6.4 Hz, 3H);
4.2.19. Compound 45. Compound 45 was prepared from com-
pound 43 and Arg(Pbf)-Gly-OMe (44) according to the same pro-
cedure as that described for compound 41. ½a D25
ꢀ66.4 (c 0.25,
ꢃ
MeOH); 1H NMR (400 MHz, DMSO-d6)
d 11.40 (br s, 1H), 8.52 (d,
13C NMR (100 MHz, DMSO-d6)
d
177.4, 172.2, 172.0, 171.6, 170.5,
J¼8.8 Hz, 1H), 8.45 (t, J¼6.0 Hz, 1H), 8.35e8.31 (m, 3H), 7.94 (s, 1H),
7.91 (d, J¼7.9 Hz, 1H), 7.86 (s, 1H), 7.61e7.57 (m, 2H), 7.33e7.25 (m,
6H), 7.11 (d, J¼8.0 Hz, 1H), 6.93 (d, J¼8.0 Hz, 1H), 6.84 (s, 1H), 6.64
(br s, 1H), 6.42 (br s, 1H), 5.56 (m, 1H), 5.06e4.98 (m, 2H),4.82 (t,
J¼10.4 Hz, 1H), 4.34 (m, 1H), 4.26 (m, 1H), 4.10 (dd, J¼8.4, 3.2 Hz,
1H), 3.96 (m, 1H), 3.92e3.80 (m, 2H), 3.68 (t, J¼8.0 Hz, 1H), 3.62 (s,
3H), 3.14e2.84 (m, 9H), 2.48 (s, 3H), 2.43 (s, 3H), 2.23 (m, 1H),
2.15e2.07 (m, 3H), 2.00 (s, 3H), 1.76 (m, 1H), 1.72e1.62 (m, 2H), 1.52
(m,1H),1.46e1.31 (m, 3H),1.40 (s, 6H),1.36 (s, 9H),1.17 (m,1H), 0.83
(d, J¼6.8 Hz, 3H), 0.79 (d, J¼6.4 Hz, 3H), 0.75e0.69 (m, 12H); 13C
169.4, 169.1, 156.5, 137.5, 137.0, 132.8, 130.9, 128.9, 128.3, 127.7,
127.6, 124.9, 119.7, 118.9, 118.0, 114.0, 100.6, 80.6, 65.4, 57.6, 55.1,
54.8, 52.7, 52.0, 51.9, 51.4, 49.0, 48.6, 45.7, 43.3, 42.1, 31.2, 30.0,
29.0, 27.6, 26.6, 25.5, 25.3, 23.9, 23.1, 21.7, 20.9, 18.3, 17.1; HRMS
(ESI) m/z calcd for C54H73N10O12 (MþH)þ 1053.5409; found
1053.5464.
4.2.17. Compound 41. To a solution of compound 39 (31 mg,
0.03 mmol) in THF/H2O (3:1, 2.0 mL) was added lithium hydroxide
monohydrate (13 mg, 0.30 mmol) at 0 ꢂC. The resulting mixture was
stirred at 0 ꢂC for 3 h. The reaction mixture was acidified with 6 N
HCI to pH¼2 and was diluted with EtOAc (30 mL). The mixture was
dried over Na2SO4, and concentrated in vacuo to give crude prod-
uct, which was used directly in the next step.
A solution of above crude product and L-Arg(Pbf)-OMe (20 mg,
0.045 mmol) in anhydrous THF/DMF (10:1, 2.0 mL) was treated
with HOBt (27 mg, 0.20 mmol), HBTU (76 mg, 0.2 mmol), and
NMR (100 MHz, DMSO-d6)
d 177.3, 172.1, 171.5, 171.3, 171.1, 170.9,
170.0, 169.7, 169.2, 157.4, 156.0, 155.8, 137.5, 137.2, 136.9, 134.2,
132.8, 131.4, 130.6,128.7, 128.2, 127.7, 124.8, 124.2,119.5, 119.4,118.0,
116.2, 113.8, 101.2, 86.2, 80.5, 79.1, 65.4, 57.2, 55.1,54.8,54.5, 52.0,
51.8, 51.6, 51.3, 49.3, 42.4, 41.8, 40.4, 31.3, 30.0, 29.6, 28.9, 28.2, 27.6,
26.5, 26.0, 25.5, 25.0, 23.9, 23.0, 21.7, 20.9, 18.8, 18.5, 18.2, 17.5, 17.1,
12.2; HRMS (ESI) m/z calcd for C73H101N14O16S (MþH)þ 1641.7241;
found 1641.7257.
DIPEA (40 mL, 0.22 mmol). The resulting mixture was allowed to
warm to room temperature and stirred for 2 days. The reaction was
treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2
(6ꢁ5 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. Preparative TLC (silica gel, 1:10 MeOH/
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (Nos. 21290180, 20972007), the National Basic
Research Program of China (973 Program, No. 2010CB833200), and
the State Key Laboratory of Drug Research.
CH2Cl2 elution) afforded 41 (19 mg, 45%). ½a D25
ꢀ42.5 (c 0.20,
ꢃ
MeOH); 1H NMR (400 MHz, DMSO-d6)
d 11.41 (br s, 1H), 8.55 (d,
J¼8.8 Hz, 1H), 8.35e8.23 (m, 4H), 7.92 (s, 1H), 7.88 (s, 1H), 7.58 (d,
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10
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