Total synthesis of the proposed structure for itralamide b

Article abstract of DOI:10.1055/s-0033-1340872

A stereocontrolled total synthesis of the cyclodepsipeptide, itralamide B, has been achieved. Both R- and S-stereoisomers of the side chain were attached to the macrocyclic ring, however, the synthesized structure appears to be different from that of the

Full text of DOI:10.1055/s-0033-1340872

1014▌
LETTER
letter
Total Synthesis of the Proposed Structure for Itralamide B
Total Synthesis of Itralamide B
Xiaoji Wang,*a Chanshan Lv,a,b Junyang Liu,b,c Linjun Tang,a Junmin Feng,a Shoubin Tang,b Zhuo Wang,c
Yuqing Liu,c Yi Meng,b Tao Ye,*c Zhengshuang Xu*a,b
a
School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, 330013, P. R. of China
E-mail: professorwxj@163.com
b
Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen, Xili, Nanshan District,
Shenzhen, 518055, P. R. of China
E-mail: xuzs@pkusz.edu.cn
c
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax +85222641912; E-mail: tao.ye@polyu.edu.hk
Received: 28.12.2013; Accepted after revision: 05.02.2014
lute stereochemistry assignment based on NMR tech-
niques and computation-assisted conformational
analyses.2 Total synthesis plays a critical role in marine
natural product structure elucidation, and this approach
has led to the overwhelming majority of natural product
structural revisions. In addition, total synthesis provides
materials for biological testing towards pharmaceutical
development. We have undertaken the total synthesis of
natural marine cyclodepsipeptides,3 and have successfully
revised the structure of several natural products.4
Abstract: A stereocontrolled total synthesis of the cyclodepsipep-
tide, itralamide B, has been achieved. Both R- and S-stereoisomers
of the side chain were attached to the macrocyclic ring, however,
the synthesized structure appears to be different from that of the ma-
rine natural product.
Key words: natural products, total synthesis, macrolactonization,
configuration determination, stereoselectivity
Naturally occurring cyclodepsipeptides often exhibit
unique biological properties and are thus attractive candi-
dates for drug development.1 The bioactivities of natural
cyclodepsipeptides range from insecticidal, antiviral and
antibacterial to cytotoxic and antiproliferative. The con-
formation of the cyclodepsipeptides is largely determined
by the skeleton of the macrocycle and the side-chain moi-
eties, some of which may contain different conformers at
ambient temperature in solution. This conformational
flexibility can complicate structural elucidation and abso-
Itralamides A and B (1; Scheme 1) were isolated from the
lipophilic extract of Lyngbya majuscula collected from
the eastern Caribbean.5 The structures of these molecules
were determined mainly on the basis of NMR, MS spec-
tral data, and chemical manipulation involving the use of
Marfey’s method.6 Itralamides A and B featured high con-
tent of N-methylation of their amino acid fragments, with
four of the six amino acids being modified. The N-methyl-
threonine was identified as an unusual occurrence in nat-
Ph
O
H
N
N
O
H
N
R1
O
N
macrolactonization
A
N
O
N
O
HO
O
O
O
O
O
*
+
O
O
N
R1
O
O
N
O
Cl
Cl
HN
HN
O
DMBA
NH
N
(R)-3 or (S)-3
R2
1a
*
B
Cl
amide formation
Cl
(R)-3 or (S)-3
Ph
itralamide A R1 = Me, R2 = i-Pr
itralamide B (1) R1 = i-Pr, R2 = Me
O
+
2
H
N
N
Ph
O
N
O
CO2t-Bu
H
HO
N
HO
O
N
O
O
N
O
Cbz
N
O
CO2t-Bu
+
O
N
HN
O
N
Cbz
N
AllylO
NHCbz
5
amide formation
2
4
Scheme 1 Retrosynthetic analysis of itralamide B (1)
SYNLETT 2014, 25, 1014–1018
Advanced online publication: 14.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340872; Art ID: ST-2013-W1173-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Itralamide B
1015
ural product structures; it has been found in only a few according to the same reaction sequence by the use of (S)-
bioactive natural cyclopeptides, including coibamide A7 6 as starting material.
and papuamides A–D.8 Itralamides were found to contain
O
O
O
OH
O
an interesting branched chlorinated moiety, 4,4-dichloro-
3-methylbutanoic acid (DMBA), linked through an amide
bond to N-methylthreonine. This chlorinated unit could
potentially be derived from valine presumably involves
the novel chlorination of unreactive carbon. The presence
of this chlorinated moiety also suggested that itralamides
may originate from cyanobacteria.9 Itralamide B (1) was
found to be cytotoxic toward human embryonic kidney
(HEK293) with an IC50 value of around 6 μM. Previously,
we reported the total synthesis of dichlorinated cyclodep-
sipeptides lyngbyabellin A10 and sintokamide C.11 Here
we report on our efforts in the total synthesis of
itralamide B with the aim of assigning the absolute stereo-
chemistry of the methyl group of DMBA.
The retrosynthetic analysis is illustrated in Scheme 1.12
Because the absolute stereochemistry of the side chain
was not established, we planned a convergent synthetic
approach involving the attachment of two possible diaste-
reomers of the side chain [(R)-3 and (S)-3] to the cy-
clodepsipeptide core 1a in the late stage (Scheme 1,
route A). Accordingly, 1a can be constructed from acyclic
precursor 2 through a macrolactonization reaction. Hexa-
peptide 2 was envisaged to be synthesized from tetrapep-
tide 4 and dipeptide 5. However, although this strategy is
appealing, macrocyclic intermediate 1a might undergo
O,N-acyl migration.13 In this respect, we followed an un-
ambiguous approach that included the installation of the
two possible stereoisomers of side chain prior to the for-
mation of the macrocycle (Scheme 1, route B).
O
Ph
iv, v
i–iii
O
Ph
N
N
O
O
41%
77%
O
Ph
O
Ph
Bn
(R)-6
Bn
8
7
90%
O
vi
Cl
Cl
H
OH
O
vii
viii
O
Ph
Ph
Cl
Cl
O
78%
74%
O
O
Ph
O
Ph
(S)-3
10
9
O
Cl
OH
N
O
Cl
O
Bn
(S)-6
(R)-3
Scheme 2 Synthesis of DMBA fragments (R)-3 and (S)-3. Reagents
and conditions: (i) NaHMDS, THF, –78 °C, BrCH2CO2 Bu (dr >
96:4); (ii) TFA, CH2Cl2; (iii) Ph2C=NNH2, DIB, I2; (iv) Na2CO3,
H2O2, THF–H2O; (v) BH3·Me2S, THF; (vi) TCCA, TEMPO,
NaHCO3, CH2Cl2; (vii) P(OPh)3, Cl2, Et3N, CH2Cl2; (viii) TFA,
CH2Cl2.
t
With the requisite subunit 3 in hand, we next turned our
attention to the construction of peptide fragments 4 and 5.
The synthesis began with the preparation of different
N-methylated amino acids, including L-Ala, D-Phe, and
L-Thr, by employing a facile, two-pot reductive amination
approach.19 Coupling of D-N-Boc-Val-OH (11) with N-
Me-Ala-OMe (12) in the presence of HATU20 and HOAt
produced the dipeptide in 72% yield. Hydrolysis of the
methyl ester, followed by peptide bond formation with N-
Me-Phe-OMe (13) by using HATU and HOAt as coupling
reagents, furnished tripeptide 14 in 69% yield over two
steps. The N-terminal Boc group of tripeptide 14 was ex-
changed for a Cbz group through a two-step manipulation,
which included trifluoroacetic acid promoted cleavage of
Boc group and reprotection of the resulting free amine as
its Cbz carbamate through the action of CbzOSu and so-
dium bicarbonate. Removal of the methyl ester produced
the corresponding carboxylic acid, which was then cou-
pled with amino ester 15 by the action of PyAOP21 to fur-
nish tetrapeptide 4 in 81% yield (Scheme 3).
The synthesis of 4,4-dichloro-3-methylbutanoic acid (3)
commenced with an Evans alkylation reaction14,4d
(Scheme 2). Treatment of (R)-4-benzyl-3-propionyloxa-
zolidin-2-one (6) with NaHMDS at –78 °C, followed by
addition of tert-butyl bromoacetate, produced the corre-
sponding alkylation adduct, which was transformed into
benzhydryl ester 7 through a two-step sequence including
cleavage of the tert-butyl ester group through the action of
trifluoroacetic acid followed by treatment of the resultant
acid with benzophenone hydrazine, in the presence of (di-
acetoxyiodo)benzene and iodine.15,4g Subsequent hydro-
lysis of the chiral auxiliary of 7, with sodium carbonate
and hydrogen peroxide, afforded the corresponding acid,
which was then reduced to alcohol 8 by borane dimethyl-
sulfide in 77% yield over the two steps.16 Oxidation of al-
cohol 8 with TCCA and 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO), buffered with sodium bicarbonate in di-
chloromethane,17 gave aldehyde 9 in 90% yield, which
was subjected to chlorination with triphenyl phosphite
and chlorine in the presence of triethylamine in dichloro-
methane to afford the dichlorinated product 10 in 78%
yield.18,11 Acidic cleavage of benzhydryl ester 10 afforded
the corresponding carboxylic acid (S)-3 in 74% yield,
which was ready to be incorporated into the macrocyclic
core of itralamide B. The enantiomer (R)-3 was prepared
Ph
O
Ph
O
OMe
H
N
N
HO
N
N
O
O
NHBoc
11
N
O
iv–vii
i–iii
O
O
Ot-Bu
O
81%
OMe
50%
NHBoc
14
NHCbz
4
Ph
O
H2N
O
OMe
HN
NH
Ot-Bu
O
12
13
15
Scheme 3 Preparation of tetrapeptide 4. Reagents and conditions:
(i) 12, HATU, HOAt, DIPEA, CH2Cl2; (ii) LiOH, THF–H2O; (iii) 13,
HATU, HOAt, DIPEA, CH2Cl2; (iv) TFA, CH2Cl2; (v) CbzOSu,
NaHCO3, MeCN; (vi) LiOH, THF–H2O; (vii) 15, PyAOP, HOAt,
DIPEA, CH2Cl2.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1014–1018

1016
X. Wang et al.
LETTER
Ph
O
Ph
O
The preparation of dipeptide 5 is illustrated in Scheme 4.
Initially, condensation of N-Me-N-Cbz-Thr-OH (16) with
the tert-butyl N-methyl alanine ester by the action of
BOPCl22 and DIPEA produced the corresponding dipep-
tide, however, selective removal of the tert-butyl ester un-
der acidic conditions proved difficult because various
reaction conditions led to extensive dehydration of the
threonine residue. To circumvent this problem, allyl ester
was selected as the appropriate protecting group for this
substrate; under similar condensation conditions, dipep-
tide 5 was obtained in 51% yield. The allyl ester could be
easily removed to afford 17 in 98% yield by the action of
Pd2(dba)3 and Ph3P in the presence of a secondary amine
in THF.
O
O
H
H
N
N
N
N
N
CO2t-Bu
N
i, ii
O
Ot-Bu
O
HO
O
60%
O
O
HN
NHCbz
4
N
N
Cbz
2
iii, iv
Ph
60%
Ph
O
N
H
O
N
H
N
N
N
O
v, vi
O
N
O
CO2t-Bu
O
O
21%
O
HO
O
O
N
O
O
N
HN
HN
N
Cl
N
Cl
O Cl
AllylO
O
N
HO
O
N
O
OH
O
OH
O
OH
O Cl
(S)-itralamide B (1)
18
i
HO
ii
Ph
HO
N
51%
98%
O
H
N
N
N
N
Cbz
O
O
N
Cbz
Cbz
HO
16
5
17
N
Cbz
17
N
O
O
Scheme 4 Preparation of dipeptide 5. Reagents and conditions:
(i) N-Me-Ala-OAllyl, BOPCl, DIPEA, CH2Cl2; (ii) Pd2(dba)3, Ph3P,
Et2NH, THF, 0 °C.
O
O
O
O
N
HN
N
Cl
HO
Cl
HO
Cl
O Cl
O Cl
(S)-3
O Cl
(R)-3
Hydrogenolysis of the Cbz group of 4 and condensation of
the crude free amine with acid 17 through the action of
HATU/HOAt, afforded 2 in 60% yield. Cleavage of the
N-Cbz protecting group of 2 was facilitated by the use of
Pd/C catalyst in methanol, and the resulting amine was
then condensed with (S)-4,4-dichloro-3-methylbutanoic
acid [(S)-3], employing HATU and HOAt as the coupling
reagents, to give 18 in 60% yield. After removal of the
tert-butyl ester of 18 by the action of BF3·OEt2 in dichlo-
romethane,23 the resulting hydroxy acid was subjected to
macrolactonization by carboxylic acid activation under
(R)-itralamide B (1)
Scheme 5 Completion of the total synthesis of itralamide B (1). Re-
agents and conditions: (i) H2, Pd/C, MeOH; (ii) 17, HATU, HOAt,
DIPEA, CH2Cl2; (iii) Pd/C, H2, MeOH; (iv) (S)-3, HATU, HOAt,
DIPEA, CH2Cl2; (v) BF3·OEt2, CH2Cl2; (vi) MNBA, DMAP, tolu-
ene–THF.
Acknowledgment
Shiina’s conditions,24 to afford the (S)-DMBA-containing We acknowledge financial support from the NSFC (21062006,
stereoisomer, (S)-itralamide B (1), in 21% yield.25 The
(R)-itralamide B (1) was also prepared from (R)-4,4-di-
chloro-3-methylbutanoic acid [(R)-3] by the same route
used for the synthesis of the S-stereoisomer (Scheme 5).
To our disappointment, the 1H and 13C NMR spectra of both
synthetic stereoisomers [(S)-itralamide B and (R)-itral-
21072007, 21272011), the Hong Kong Research Grants Council
(Projects: PolyU 5040/10P; PolyU 5037/11P, PolyU 5020/12P;
PolyU5030/13P), the Fong Shu Fook Tong Foundation, the Joyce
M. Kuok Foundation, and The Shenzhen Bureau of Science, Tech-
nology and Information (JC200903160367A, JC201005260220A,
JC201005260102A, ZYC201105170351A). X.J.W. would also like
to thank the Jiangxi Province Departments of Education
(KJLD12036) and Science & Technology ([2013]138).
amide B] were different from those of natural itralamide B.
Significant discrepancies in the 13C NMR spectra were
most apparent for the two isopropyl groups of valine, the
two N-methyl groups of alanine, and the ester carbonyl and
methyl group of threonine.26 It would appear that the error
in the original assignment of the stereochemistry of
itralamide B lies somewhere in the macrocycle.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) Lemmens-Gruber, R.; Kamyar, M. R.; Dornetshuber, R.
Curr. Med. Chem. 2009, 16, 1122.
(2) Suyama, T. L.; Gerwick, W. H.; McPhail, K. L. Bioorg.
Med. Chem. 2011, 19, 6675.
(3) (a) Liu, H.; Liu, Y.; Wang, Z.; Xing, X.; Maguire, A. R.;
Luesch, H.; Zhang, H.; Xu, Z.; Ye, T. Chem. Eur. J. 2013,
19, 6774. (b) Long, B.; Tang, S.; Chen, L.; Qu, S.; Chen, B.;
Liu, J. Y.; Maguire, A. R.; Wang, Z.; Liu, Y.; Zhang, H.; Xu,
Z. S.; Ye, T. Chem. Commun. 2013, 49, 2977. (c) Boyaud,
F.; Mahiout, Z.; Lenoir, C.; Tang, S.; Wdzieczak-Bakala, J.;
Witczak, A.; Bonnard, I.; Banaigs, B.; Ye, T.; Inguimbert, N.
In summary, we have developed a stereocontrolled route
for the total synthesis of the proposed structure for
itralamide B. Efforts toward the total synthesis of addi-
tional diastereoisomers are underway in our laboratory. A
more detailed account of this work and further studies to-
ward the establishment of the stereochemistry of
itralamide B and biological evaluation of diastereoiso-
mers will be disclosed in due course.
Synlett 2014, 25, 1014–1018
© Georg Thieme Verlag Stuttgart · New York

LETTER
Org. Lett. 2013, 15, 3898. (d) Wang, L.; Xu, Z.; Ye, T. Org.
Total Synthesis of Itralamide B
1017
Lanza, T. J.; Pessolano, A. A.; Caldwell, C. G. Tetrahedron
Lett. 1990, 31, 1237. (m) Mauger, A. B.; Stuart, O. A. Int. J.
Pept. Protein Res. 1987, 30, 481.
Lett. 2011, 13, 2506. (e) Liu, H.; Liu, Y. Q.; Xu, Z. S.; Ye,
T. Chem. Commun. 2010, 46, 7486. (f) Liang, S.; Xu, Z. S.;
Ye, T. Chem. Commun. 2010, 46, 153. (g) Li, S.; Liang, S.;
Tan, W. F.; Xu, Z. S.; Ye, T. Tetrahedron 2009, 65, 2695.
(h) Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z. S.; Ye, T.
Synlett 2008, 2379. (i) Pang, H. W.; Xu, Z. S.; Ye, T. Lett.
Org. Chem. 2005, 2, 703. (j) Chen, H. L.; Xu, Z. S.; Ye, T.
Tetrahedron 2005, 61, 11132. (k) Chen, Z. Y.; Deng, J. G.;
Ye, T. ARKIVOC 2003, (vii), 268.
(14) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.;
Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411.
(15) Lapatsanis, L.; Milias, G.; Paraskewas, S. Synthesis 1985,
513.
(16) Rodríguez-Escrich, C.; Urpí, F.; Vilarrasa, J. Org. Lett.
2008, 10, 5191.
(17) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001,
3, 3041.
(18) (a) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F.
J. Org. Chem. 2007, 72, 2216. (b) Gao, S.; Wang, Q.; Chen,
C. J. Am. Chem. Soc. 2009, 131, 1410.
(19) White, K. N.; Konopelski, J. P. Org. Lett. 2005, 7, 4111.
(20) (a) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(b) Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.;
Zhang, C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.;
Mügge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.;
Bienert, M. Angew. Chem. Int. Ed. 2002, 41, 441.
(21) Albericio, F.; Cases, M.; Alsina, J.; Triolo, S. A.; Carpino,
L. A.; Kates, S. A. Tetrahedron Lett. 1997, 38, 4853.
(22) (a) Tung, R. D.; Rich, D. H. J. Am. Chem. Soc. 1985, 107,
4343. (b) Tung, R. D.; Rich, D. H. J. Org. Chem. 1986, 17,
3351.
(4) (a) Dai, L.; Chen, B.; Lei, H.; Wang, Z.; Liu, Y.; Xu, Z.; Ye,
T. Chem. Commun. 2012, 48, 8697. (b) Liu, J.; Ma, X.; Liu,
Y.; Wang, Z.; Kwong, S.; Ren, Q.; Tang, S.; Meng, Y.; Xu,
Z.; Ye, T. Synlett 2012, 783. (c) Gao, X. G.; Liu, Y. Q.;
Kwong, S. Q.; Xu, Z. X.; Ye, T. Org. Lett. 2010, 12, 3018.
(d) Chen, B.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z. S.; Ye, T.
Chem. Commun. 2010, 46, 574. (e) Li, S.; Liang, S.; Xu, Z.
S.; Ye, T. Synlett 2008, 569. (f) Peng, Y. G.; Pang, H. W.;
Ye, T. Org. Lett. 2004, 6, 3781. (g) Xu, Z. S.; Peng, Y. G.;
Ye, T. Org. Lett. 2003, 5, 2821.
(5) Jiménez, J. I.; Vansach, T.; Yoshida, W. Y.; Sakamoto, B.;
Pörzgen, P.; Horgen, F. D. J. Nat. Prod. 2009, 72, 1573.
(6) Bhushan, R.; Brückner, H. Amino Acids 2004, 27, 231.
(7) Medina, R. A.; Goeger, D. E.; Hills, P.; Mooberry, S. L.;
Huang, N.; Romero, L. I.; Ortega-Barria, E.; Gerwick, W.
H.; McPhail, K. L. J. Am. Chem. Soc. 2008, 130, 6324.
(8) Ford, P. W.; Gustafson, K. R.; McKee, T. C.; Shigematsu,
N.; Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; Dilip de
Silva, E.; Lassota, P.; Allen, T. M.; Van Soest, R.; Andersen,
R. J.; Boyd, M. R. J. Am. Chem. Soc. 1999, 121, 5899.
(9) Ridley, C. P.; Bergquist, P. R.; Harper, M. K.; Faulkner, D.
J.; Hooper, J. N.; Haygood, M. G. Chem. Biol. 2005, 12, 397.
(10) Lyngbyabellin A was isolated from marine cyanobacterium
Lyngbya majuscule, see: (a) Luesch, H.; Yoshida, W. Y.;
Moore, R. E.; Paul, V. J.; Mooberry, S. L. J. Nat. Prod. 2000,
63, 611. Its structure and absolute stereochemistry were
confirmed by total syntheses, see: (b) Pang, H. W.; Xu, Z. S.;
Chen, Z. Y.; Ye, T. Lett. Org. Chem. 2005, 2, 699.
(23) Evans, E. F.; Lewis, N. J.; Kapfer, I.; Macdonald, G.; Taylor,
R. J. K. Synth. Commun. 1997, 27, 1819.
(24) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822.
(25) Synthesis of Itralamide B (1): Compound 18 (23.0 mg,
0.03 mmol, 1.0 equiv) was dissolved in CH2Cl2 (1.0 mL) at
0 °C, and BF3·OEt2 (34 μL, 0.3 mmol, 10.0 equiv) was
added dropwise to the solution at 0 °C. The reaction solution
was allowed to warm to r.t. and stirred for 0.5–1.0 h
(reaction monitored by TLC). The reaction was quenched by
the addition of saturated NH4Cl (2 mL) and diluted with
CH2Cl2 (60 mL). The organic phase was washed with
saturated NH4Cl (3 × 20 mL) and brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo to afford the
crude hydroxy acid. A solution of this hydroxy acid in
THF–PhMe (10 mL, 1:1) was slowly added to a solution of
DMAP (33 mg, 0.3 mmol, 10.0 equiv) and MNBA (47 mg,
0.14 mmol, 5.0 equiv) in PhMe (10 mL) at 0 °C. The
reaction mixture was warmed to r.t., then stirred and heated
to 60 °C for 2 d. The reaction mixture was diluted with
EtOAc (100 mL) and washed successively with saturated
NH4Cl (3 × 20 mL) and brine (2 × 20 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by flash chromatography (EtOAc) to afford (S)-
itralamide B (1; 5.0 mg, 21%).
(c) Yokokawa, F.; Sameshima, H.; Shioiri, T. Tetrahedron
Lett. 2001, 42, 4171.
(11) Jin, Y.; Liu, Y. Q.; Wang, Z.; Kwong, S.; Xu, Z. S.; Ye, T.
Org. Lett. 2010, 12, 1100.
(12) All the attempts to close the macrocycle by
macrolactamization met with failure. The detailed studies
will be reported in due course.
(13) (a) Taniguchi, A.; Sohma, Y.; Kimura, M.; Okada, T.; Ikeda,
K.; Hayashi, Y.; Kimura, T.; Hirota, S.; Matsuzaki, K.; Kiso,
Y. J. Am. Chem. Soc. 2006, 128, 696. (b) Coin, I.; Dölling,
R.; Krause, E.; Bienert, M.; Beyermann, M.; Sferdean, C. D.;
Carpino, L. A. J. Org. Chem. 2006, 71, 6171. (c) Yoshiya,
T.; Sohma, Y.; Kimura, T.; Hayashi, Y.; Kiso, Y.
(S)-Itralamide B (1): [α]D25 –44.63 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.45–7.12 (m, 5 H), 6.90 (d,
J = 9.6 Hz, 1 H), 6.47 (d, J = 8.0 Hz, 1 H), 5.99 (d,
J = 2.9 Hz, 1 H), 5.75–5.65 (m, 2 H), 5.53–5.43 (m, 1 H),
5.08 (q, J = 6.8 Hz, 1 H), 4.98 (dd, J = 7.9, 4.2 Hz, 1 H),
4.71 (dd, J = 9.4, 4.1 Hz, 1 H), 4.62 (q, J = 7.6 Hz, 1 H),
3.66 (dd, J = 15.5, 4.9 Hz, 1 H), 3.33 (d, J = 23.6 Hz, 3 H),
3.19 (d, J = 7.1 Hz, 3 H), 3.17–3.07 (m, 3 H), 3.07–2.94 (m,
3 H), 2.87 (dd, J = 15.6, 12.1 Hz, 1 H), 2.80 (d, J = 4.0 Hz,
1 H), 2.76–2.65 (m, 1 H), 2.46 (dd, J = 16.5, 7.5 Hz, 1 H),
2.28–2.21 (m, 1 H), 2.06–1.99 (m, 1 H), 1.29 (d, J = 2.0 Hz,
3 H), 1.26 (d, J = 2.8 Hz, 3 H), 1.20 (dd, J = 6.6, 3.5 Hz,
3 H), 1.08–1.01 (m, 6 H), 0.92 (dd, J = 9.4, 7.2 Hz, 6 H),
0.80 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ =
174.89, 172.84, 172.53, 170.65, 170.17, 169.90, 169.47,
137.35, 128.54, 128.34, 126.48, 78.18, 69.62, 56.92, 56.75,
54.69, 54.68, 53.98, 51.43, 40.65, 35.75, 33.92, 33.77,
Tetrahedron Lett. 2006, 47, 7905. (d) Sohma, Y.; Taniguchi,
A.; Skwarczynski, M.; Yoshiya, T.; Fukao, F.; Kimura, T.;
Hayashi, Y.; Kiso, Y. Tetrahedron Lett. 2006, 47, 3013.
(e) Sohma, Y.; Hayashi, Y.; Kimura, M.; Chiyomori, Y.;
Taniguchi, A.; Sasaki, M.; Kimura, T.; Kiso, Y. J. Pept. Sci.
2005, 11, 441. (f) Sohma, Y.; Sasaki, M.; Hayashi, Y.;
Kimura, T.; Kiso, Y. Chem. Commun. 2004, 124. (g) Mouls,
L.; Subra, G.; Enjalbal, C.; Martinez, J.; Aubagnac, J.-L.
Tetrahedron Lett. 2004, 45, 1173. (h) Horikawa, M.;
Shigeri, Y.; Yumoto, N.; Yoshikawa, S.; Nakajima, T.;
Ohfune, Y. Bioorg. Med. Chem. Lett. 1998, 8, 2027. (i) Seo,
H.; Lim, D. J. Org. Chem. 2009, 74, 906. (j) Lécaillon, J.;
Gilles, P.; Subra, G.; Martinez, J.; Amblard, M. Tetrahedron
Lett. 2008, 49, 4674. (k) Stawikowski, M.; Cudic, P.
Tetrahedron Lett. 2006, 47, 8587. (l) Durette, P. L.; Baker,
F.; Barker, P. L.; Boger, J.; Bandy, S. S.; Hammond, M. L.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1014–1018

1018
X. Wang et al.
LETTER
2.78 (m, 1 H), 2.78–2.67 (m, 1 H), 2.43 (dd, J = 16.7,
32.15, 31.83, 31.12, 31.00, 30.54, 19.90, 19.63, 17.82,
17.10, 15.61, 15.35, 14.10, 13.82. HRMS (ESI): m/z
6.0 Hz, 1 H), 2.25 (dd, J = 11.9, 5.9 Hz, 1 H), 2.04 (d,
J = 9.5 Hz, 1 H), 1.38 (dd, J = 18.4, 7.2 Hz, 3 H), 1.30 (d,
J = 6.7 Hz, 3 H), 1.20 (d, J = 6.6 Hz, 3 H), 1.06 (d,
+
[M+Na]+ calcd for C38H58Cl2N6NaO8 : 819.3585; found:
819.3587.
(R)-Itralamide B (1): [α]D25 –42.33 (c 0.2, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.24–7.16 (m, 5 H), 6.89 (d,
J = 9.1 Hz, 1 H), 6.48 (d, J = 7.8 Hz, 1 H), 6.04 (d,
J = 2.9 Hz, 1 H), 5.78–5.63 (m, 1 H), 5.49 (dd, J = 6.6,
3.2 Hz, 1 H), 5.45–5.35 (m, 1 H), 5.12–5.02 (m, 1 H), 4.98
(dd, J = 7.8, 4.2 Hz, 1 H), 4.71 (dd, J = 9.3, 4.0 Hz, 1 H),
4.67–4.55 (m, 1 H), 3.66 (dd, J = 15.3, 5.1 Hz, 1 H), 3.28 (d,
J = 63.9 Hz, 3 H), 3.18 (s, 3 H), 3.13 (d, J = 23.1 Hz, 3 H),
3.01 (d, J = 11.3 Hz, 3 H), 2.93 (d, J = 15.7 Hz, 1 H), 2.90–
J = 6.8 Hz, 6 H), 0.92 (dd, J = 11.7, 7.0 Hz, 6 H), 0.80 (d,
J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 174.88,
172.83, 172.56, 170.68, 170.17, 169.85, 169.51, 137.37,
128.55, 128.34, 126.48, 78.02, 69.64, 56.88, 56.75, 54.75,
54.22, 53.99, 51.47, 40.45, 35.98, 33.97, 33.78, 32.18,
31.85, 31.12, 31.02, 30.55, 19.89, 19.63, 17.82, 17.09,
17.07, 15.60, 15.05, 13.83 ppm. HRMS (ESI): m/z [M+Na]+
+
for C38H58Cl2N6NaO8 : 819.3585; found: 819.3589.
(26) See the Supporting Information for detailed analyses.
Synlett 2014, 25, 1014–1018
© Georg Thieme Verlag Stuttgart · New York

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