A concise route to the proposed structure of lydiamycin B, an antimycobacterial depsipeptide

Article abstract of DOI:10.1021/ol9024474

[Chemical Equation Presented] The total synthesis of four possible isomers with the proposed structure of antimycobacterial depsipeptide lydiamycin B Is achieved. None of them shows identical NMR data with those reported for natural lydiamycin B, indicati

Full text of DOI:10.1021/ol9024474

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5694-5697
A Concise Route to the Proposed
Structure of Lydiamycin B, an
Antimycobacterial Depsipeptide
Wenhua Li, Jiangang Gan, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
Received October 23, 2009
ABSTRACT
The total synthesis of four possible isomers with the proposed structure of antimycobacterial depsipeptide lydiamycin B is achieved. None
of them shows identical NMR data with those reported for natural lydiamycin B, indicating that further structural revisions are required.
Lydiamycins A-D (1-4, Figure 1) are four cyclic dep-
sipeptides that were isolated from the fermentation broth of
Streptomyces lydicus (strain HKI0343) by Sattler et al.1 The
initial biological evaluation of these compounds revealed that
the lydiamycins A-C could selectively inhibit Mycobacte-
rium smegmatis SG 987, M. Aurum SB66, and M. Vaccae
IMET 10670 in a panel of Gram-positive and Gram-negative
bacteria, yeasts, and fungi. Further studies on the antibiotic
activity of lydiamycin A indicated that this compound is
active against the standard and one multiresistant strain of
M. tuberculosis. This result suggests that lydiamycin A might
have an action mode different from that of available
therapeutics like isoniazid, rifampicine, etambutol, and
streptomycin.1 Thus, total synthesis and subsequent SAR
studies toward lydiamycins could be helpful for the discovery
of novel antituberculosis drugs.2
Structurally, lydiamycins represent a novel class of small
cyclodepsipeptides. Each of them contains two unusual
amino acid residues, namely, Piz (piperazic acid building
Figure 1. Proposed structures of lydiamycins A-D and the
retrosynthetic analysis of lydiamycin B.
block) that is embodied in the cyclodepsipeptide part and
(1) Huang, X.; Roemer, E.; Sattler, I.; Moellmann, U.; Christner, A.;
Grabley, S. Angew. Chem., Int. Ed. 2006, 45, 3067.
(2) For a review on anti-tuberculosis drugs, see: Janin, Y. L. Bioorg.
Med. Chem. 2007, 15, 2479.
dehydropiperazic acid that is connected with the 2-pentyl-
succinic acid (PSA) moieties and the cyclodepsipeptide part.
10.1021/ol9024474  2009 American Chemical Society
Published on Web 11/17/2009

The stereochemistries of the dehydropiperazic acid unit and
the PSA moieties have not been assigned via NMR experi-
ments. The interesting biological activity and remaining
structural questions prompted us to initiate a synthetic
program toward these cyclodepsipeptides.3 Herein, we wish
to disclose our syntheses of four possible isomers with the
proposed structure of lydiamycin B.
As depicted in Scheme 2, our synthesis of the dehydro-
piperazic acid6 fragment started from the known diol 11.6f
Scheme 2. Synthesis of the Acids 6
As illustrated in Figure 1, retrosynthetic analysis of
lydiamycin B 2 led us to disconnect the peptide bond
between L-Ser and the dehydropiperazic acid unit to provide
macrocycle 5 and acid 6. For the synthesis of 5, we planned
to carry out the macrocyclization at the D-Leu-L-Ser site.
To establish the stereochemistry at C(19) and C(25), it was
necessary to develop a diastereoselective approach for the
assembly of the four possible isomers of 6.
The required 2-n-pentyl succinic acid fragment 10 was
prepared by applying an Evans’ diastereoselective alkylation4
as shown in Scheme 1, analogously to works in the Sankyo
Scheme 1. Synthesis of the Acid 10
Selective protection of 11 as its TBDPS ether with
TBDPSCl and imidazole afforded alcohol 12. Sulfonyla-
tion of the hydroxyl group in 12 with triflic anhydride,
followed by exposure of the resulting triflate to tert-butyl
carbazate, provided hydrazide 13 in 84% yield.7 Conden-
sation of 13 with the acyl chloride generated from the
acid 10 in the presence of 2,4,6-collidine gave the
N-acylation product 14. After removal of the TBDPS
group in 14 with TBAF and AcOH to provide alcohol
15, oxidation with IBX in DMSO solution6j was carried
out. A mixture of aldehyde and cyclic hemiaminal was
formed. Upon treatment of this mixture with TFA,
deprotection and subsequent hydrazone formation occurred
to deliver (19R,25R)-6. Following a similar procedure, the
other three diastereomers were prepared.
The assembly of the cyclodepsipeptide part and its
connection with the acids 6 is outlined in Scheme 3. Alcohol
17, obtained from lactone 16 via a known procedure,8-10
was converted into hydrazide 18 through its triflate in 88%
yield. Condensation of 18 with an acyl chloride formed
during the reaction of Cbz-L-Ala with 1-chloro-N,N-2-
trimethyl-1-propen-1-amine11 produced an amide, which was
treated with TBAF and AcOH to provide dipeptide 19 in
95% yield over two steps. After conversion of alcohol 19
group as part of their studies on the matlystatins.5 The lithium
enolate derived from N-acyl oxazolidinone 7 was reacted with
tert-butyl bromoacetate to provide ester 8 in 90% yield.
Removal of the chiral auxiliary using lithium allyloxide afforded
allyl ester 9, which was treated with TFA to form acid 10.
(3) For our recent studies on the synthesis of cyclodepsipeptides, see:
(a) Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem., Int. Ed. 2005, 44, 135.
(b) Xie, W.; Zou, B.; Pei, D.; Ma, D. Org. Lett. 2005, 7, 2775. (c) Zou, B.;
Long, K.; Ma, D. Org. Lett. 2005, 7, 4237. (d) Yu, S.; Pan, X.; Ma, D.
Chem.sEur. J. 2006, 12, 6572. (e) Ma, D.; Zou, B.; Cai, G.; Hu, X.; Liu,
J. O. Chem.sEur. J. 2006, 12, 7615. (f) Xie, W.; Ding, D.; Zi, W.; Li, G.;
Ma, D. Angew. Chem., Int. Ed. 2008, 47, 2844. (g) Tan, L.; Ma, D. Angew.
Chem., Int. Ed. 2008, 47, 3614, and ref 10.
(4) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(5) (a) Tamaki, K.; Ogita, T.; Tanzawa, K.; Sugimura, Y. Tetrahedron
Lett. 1993, 34, 683. (b) Tamaki, K.; Kurihara, S.; Oikawa, T.; Tanzawa,
K.; Sugimura, Y. J. Antibiot. 1994, 47, 1481.
(6) For previous studies on the asymmetric construction of the dehy-
dropiperazic acid derivatives, see: (a) Nakamura, Y.; Shin, C.-G. Chem.
Lett. 1991, 1953. (b) Schmidt, U.; Riedl, B. J. Chem. Soc., Chem. Commun.
1992, 1186. (c) Aspinall, I. H.; Cowley, P. M.; Mitchell, G.; Stoodley, R. J.
J. Chem. Soc., Chem. Commun. 1993, 1179. (d) Schmidt, U.; Riedl, B.
Synthesis 1993, 809. (e) Nakamura, Y.; Ito, A.; Shin, C.-G. Bull. Chem.
Soc. Jpn. 1994, 2151. (f) Schmidt, U.; Braun, C.; Sutoris, H. Synthesis 1996,
223. (g) Ciufolini, M. A.; Xi, N. Chem. Soc. ReV. 1998, 27, 437. (h) Aspinall,
I. H.; Cowley, P. M.; Mitchell, G.; Raynor, C. M.; Stoodley, R. J. J. Chem.
Soc., Perkin Trans. 1 1999, 2591. (i) Ciufolini, M. A.; Valognes, D.; Xi,
N. Angew. Chem., Int. Ed. 2000, 39, 2493. (j) Hannachi, J.-C.; Vidal, J.;
Mulatier, J.-C.; Collet, A. J. Org. Chem. 2004, 69, 2367.
(7) Hoffmann, R. V.; Kim, H.-O. Tetrahedron Lett. 1990, 31, 2953.
Org. Lett., Vol. 11, No. 24, 2009
5695

exclusive diketopiperazine formation in the Cbz-deprotection
step.
Scheme 3. Completion of the Synthesis
Hydrogenolysis of 20 followed by connection of the
liberated amine with Fmoc-D-Leu provided tripeptide 21 in
90% yield. When removing the 1-aminopiperidine group with
N-bromosuccinimide and pyridine in aqueous THF,13 partial
oxidation at the piperazic ring took place, and the resulting
mixture was condensed with Z-Ser-OAllyl to furnish a
mixture of esters 22 and 23 in a ratio of about 1:3. Since the
hydrazone 22 could be transformed into 23 quantitatively
via reduction with NaBH3CN,15 we were able to obtain 23
in 66% overall yield starting from 21. Next, the allyl and
the Fmoc protecting groups were cleaved with palladium
chemistry and diethylamine treatment, respectively. The
liberated amino acid was subjected to macrolactamization
in the presence of HATU/HOAt/i-Pr2NEt16 in a diluted DMF
solution to afford cyclization product 5 in 87% overall yield.
Finally, deprotection of 5 via a Pd(OH)2-catalyzed hy-
drogenolysis and subsequent coupling with each isomer
of 6 produced the corresponding amides. These amides
were sequentially treated with TAS-F and Pd(Ph3P)4/NMA
to deliver four possible isomers of 2. Unfortunately, none
of them showed NMR data identical to those reported for
natural lydiamycin B. It was observed that the major
difference came from the proton signals of the C-8
position. All four isomers of 2 have a chemical shift of
1.27 ppm for these protons, whereas the reported one is
1.45 ppm. This observation implied that the stereochem-
istry of its surrounding amino acid residues might be
misassigned.
In conclusion, we have developed a facile route to
assemble all possible isomers of the proposed structure
of lydiamycin B. However, the total synthesis showed that
the original assignment of the structure was incorrect.
Further investigations on elaborating more analogues to
(11) Schmidt, U.; Kroner, M.; Beutler, U. Synthesis 1988, 475.
(12) Lesimple, P.; Bigg, D. C. H. Synthesis 1991, 306.
(13) Huang, S.-B.; Nelson, J. S.; Weller, D. D. J. Org. Chem. 1991, 56,
6007.
(14) For recent piperazic acid-containing natural products total syntheses
that have used acyl hydrazide protection of the Piz 3-carboxyl to overcome
problems with diketopiperazine formation, see: (a) Hale, K. J.; Cai, J. Chem.
Commun. 1997, 2319. (b) Hale, K. J.; Cai, J.; Williams, G. Synlett 1998,
149. (c) Hale, K. J.; Lazarides, L. Org. Lett. 2002, 4, 1903. (d) Hale, K. J.;
Manaviazar, S.; George, J. H.; Walters, M. A.; Dalby, S. M. Org. Lett.
2009, 11, 733. (e) Hale, K. J.; Manaviazar, S.; Lazarides, L.; George, J.;
Walters, M. A.; Cai, J.; Delisser, V. M.; Bhatia, G. S.; Peak, S. A.; Dalby,
S. M.; Lefranc, A.; Chen, Y.-N. P.; Wood, A. W.; Crowe, P.; Erwin, P.;
El-Tanani, M. Org. Lett. 2009, 11, 737.
into its triflate and deprotection with TFA, intramolecular
N-alkylation occurred spontaneously to give a piperazide.10
This intermediate was condensed with 1-aminopiperidine
(15) Kopka, I. E. Tetrahedron Lett. 1990, 31, 4711.
(16) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
12
(17) For previous studies on the synthesis of γ-hydroxyl piperazic acid
derivatives and the corresponding natural products from other groups, see:
(a) Hassall, C. H.; Ramachandran, K. L. Heterocycles 1977, 7, 119. (b)
Hale, K. J.; Jogiya, N.; Manaviazar, S. Tetrahedron Lett. 1998, 39, 7163.
(c) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998,
37, 2993. (d) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 2995. (e) Depew, K. M.; Kamenecka, T. M.; Danishefsky,
S. J. Tetrahedron Lett. 2000, 41, 289. (f) Hale, K. J.; Hummersone, M. G.;
Cai, J.; Manaviazar, S.; Bhatia, G. S.; Lennon, J. A.; Frigerio, M.; Delisser,
V. M.; Chumnongsaksarp, A.; Jogiya, N.; Lemaitre, A. Pure Appl. Chem.
2000, 72, 1659. (g) Kamenecka, T. M.; Danishefsky, S. J. Chem.sEur. J.
2001, 7, 41. (h) Ushiyama, R.; Yonezawa, Y.; Shin, C.-G. Chem. Lett. 2001,
30, 1172. (i) Makino, K.; Jiang, H.; Suzuki, T.; Hamada, Y. Tetrahedron:
Asymmetry 2006, 17, 1644. (j) Kennedy, J. P.; Brogan, J. T.; Lindsley,
C. W. Tetrahedron Lett. 2008, 49, 4116.
under the assistance of AlCl3 and then silylated with
TBSOTf and 2,6-lutidine to afford protected dipeptide 20
with 51% overall yield from 19. Noteworthy is that using
1-aminopiperidine to protect the carboxylic acid moiety
is essential in this case13,14 because our initial attempts to
protect this position with different ester groups led to
(8) Hanessian, S.; Murray, P.; Sahoo, S. P. Tetrahedron Lett. 1985, 26,
5631.
(9) Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974, 30, 3547.
(10) Li, W.; Gan, J.; Ma, D. Angew. Chem., Int. Ed. 2009, 48, 8891.
5696
Org. Lett., Vol. 11, No. 24, 2009

establish the real structure of this γ-hydroxy piperazic
acid17 containing natural products as well as exploring
their SAR are in progress and will be reported in due
course.
dation of China (grant 20621062 & 20632050) for their
financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. The authors are grateful to the
Ministry of Science and Technology of China (Grant
2010CB833200) and the National Natural Science Foun-
OL9024474
Org. Lett., Vol. 11, No. 24, 2009
5697