Total synthesis of (-)-caprazamycin a

Article abstract of DOI:10.1002/anie.201411954

Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features a) the scalable preparation of the syn-β-hydroxy amino acid with a thioureacatalyzed diastereoselectiv

Full text of DOI:10.1002/anie.201411954

Angewandte
Chemie
DOI: 10.1002/anie.201411954
Natural Product Synthesis
Hot Paper
Total Synthesis of (À)-Caprazamycin A**
Hugh Nakamura, Chihiro Tsukano, Motohiro Yasui, Shinsuke Yokouchi, Masayuki Igarashi,
and Yoshiji Takemoto*
Abstract: Caprazamycin A has significant antibacterial activ-
ity against Mycobacterium tuberculosis (TB). The first total
synthesis is herein reported and features a) the scalable
preparation of the syn-b-hydroxy amino acid with a thiourea-
catalyzed diastereoselective aldol reaction, b) construction of
a diazepanone with an unstable fatty-acid side chain, and
c) global deprotection with hydrogenation. This report pro-
vides a route for the synthesis of related liponucleoside
antibiotics with fatty-acid side chains.
essential for bacterial cell growth and is biosynthetically
located upstream of an enzyme targeted by b-lactam and
glycopeptide antibiotics (e.g. vancomycin). New antimicro-
bial agents targeting MraY are expected to be active against
vancomycin- and methicillin-resistant Staphylococcus aureus
(VRSA and MRSA).[3] Recently, CPZEN-45, which exhibits
more potent activity against TB, including extensively multi-
drug-resistant TB (XDR-TB), has been developed based on
caprazamycins.[2b,4]
The complex structure and significant biological activities
of caprazamycins have drawn much attention from synthetic
chemists.[5,6] Matsuda, Ichikawa, and co-workers accom-
plished the first total synthesis of palmitoyl caprazol and
caprazol (2), which do not possess a fatty-acid side chain.[7]
Shibasaki, Watanabe, and co-workers recently reported the
synthesis of 2 and the fatty-acid side chain.[8] However, a total
synthesis of the caprazamycins has not yet been reported
because of the difficulty in introducing an unstable fatty-acid
side chain. This difficulty has also hampered the total
synthesis of related liponucleoside antibiotics, such as lip-
osidomycin C (3).[9] Therefore, we initiated a caprazamycin A
(1) synthetic project, which would also be applicable to
related natural products.
C
aprazamycin A (1) was isolated from Streptomyces sp.
MK730-62F2 and is a liponucleoside characterized by a seven-
membered diazepanone core with an amino ribose, a uridine,
and a fatty-acid side chain (Figure 1).[1] Several analogues
It is challenging to introduce a side chain containing
unstable structures. To access caprazamycin A (1), it was
envisioned that the unstable side chains 4 and 5 could be
introduced to the protected caprazol 6 as the final step
(Scheme 1). This would be followed by global deprotection
without adversely affecting any functional groups. Benzyl
Figure 1. Caprazamycin A (1), caprazol (2), and liposidomycin C (3).
isolated by Igarashi et al. in 2003 share these features.
Caprazamycins have antibacterial activity against Mycobac-
terium tuberculosis (TB), including multidrug-resistant TB
(MDR-TB). Biological studies showed that it is an inhibitor of
the peptidoglycan biosynthetic enzyme MraY.[2] MraY is
[*] H. Nakamura, Dr. C. Tsukano, M. Yasui, S. Yokouchi,
Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: takemoto@pharm.kyoto-u.ac.jp
Dr. M. Igarashi
Institute of Microbial Chemistry (BIKAKEN)
Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
(B) (JSPS KAKENHI no. 23390004, Y.T.), a Grant-in-Aid for JSPS
fellows (H.N.) and Meiji Seika Pharma Award in Synthetic Organic
Chemistry (Japan) (C.T.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411954.
Scheme 1. Retrosynthesis of caprazamycin A (1). Cbz=benzyloxycar-
bonyl, BOM=benzyloxymethyl, TES=triethylsilyl.
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Table 1: Optimization of diastereoselective aldol reaction.
(Bn), carboxybenzyl (Cbz), and benzyloxymethyl (BOM)
protecting groups were selected and are readily removed by
palladium-catalyzed hydrogenation. The protected 6 was
prepared using a) the Mitsunobu reaction to construct the
seven-membered diazepanone, and b) a diastereoselective
aldol reaction of the isocyanate 8 and aldehyde 9 with the
thiourea catalyst 10 to obtain the syn-b-hydroxy amino acid
derivative 7.[10]
The fatty-acid side chains 4 and 5 were first prepared. The
b-siloxy carboxylic acid 4 was synthesized from the acid
chloride 11 by a modified Noyori asymmetric reduction[11] of
the b-ketoester 12[12] (Scheme 2). Enantioselective desym-
Entry
Catalyst
Yield [%][a]
Yield [%]
(19)
1
2
3
4
5
Et3N (10 mol%)
50 (d.r.=1:1.8)
64 (d.r.=3.1:1)
77 (d.r.=6.5:1)
80 (d.r.=5.0:1)
80 (d.r.>1:20)
10
7
9
0
10
(S,S)-10a (10 mol%)
(S,S)-10b (10 mol%)
(S,S)-10b (7 mol%)
(R,R)-10b (10 mol%)
[a] Diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy.
selectivity was improved to 6.5:1 by changing to the thiourea
catalyst (S,S)-10b (10 mol%; entry 3). Formation of byprod-
uct 19 was suppressed by reducing the amount of catalyst
(7 mol%; entry 4). Use of the thiourea catalyst (R,R)-10b
(10 mol%) gave the undesired diastereomer 18b in 80%
yield with high selectivity (> 20:1; entry 5). This protocol was
also applied to the large-scale synthesis of 18a.
Scheme 2. Synthesis of the fatty-acid side chains 5 and 6. Reagents
and conditions: a) BnOAc, LDA, THF, À788C; b) H2, (S)-BINAP-RuBr2
(4.0 mol%), MeOH, 508C, 48%, 94% ee for two steps; c) TESOTf, 2,6-
lutidine, CH2Cl2, 08C, 94%; d) H2, 10% Pd/C, EtOAc, 258C, 92%;
e) BnOH, catalyst 14 (10 mol%), CPME, 86%, 92% ee; f) Ghosez
reagent, CH2Cl2, 08C; then nBuLi, THF, 48%; g) H2, 10% Pd/C,
EtOAc, 258C, 92%. BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl, CPME=cyclopentyl methyl ether, Ghosez reagent=1-
chloro-N,N,2-trimethylpropenylamine, LDA=lithium diisopropylamide,
Tf =trifluoromethanesulfonyl, THF=tetrahydrofuran.
The aldol adduct 18a was converted into syn-b-hydroxy
amino acid derivative 7 in good yield by regioselective
decarboxylation and transesterification of the resultant ther-
modynamically stable trans-oxazolidinone in the presence of
the zinc cluster Zn4(OCOCF3)6O (Scheme 3).[16] The minor
isomer was removed during these transformations. Following
the procedure of Matsuda, Ichikawa, and co-workers,[7] the
fluoride 21 underwent b-selective glycosylation, reduction of
the azido group, Cbz protection, and hydrolysis under basic
conditions to give 22. The carboxylic acid 22 was treated with
the Ghosez reagent[17] and coupled with the anti-b-hydroxy
amino acid derivative 23.[18] The TBS group was selectively
removed and construction of the diazepanone core was
extensively investigated. The Mitsunobu reaction of 25 using
PPh3 and di-tert-butyl azodicarboxylate (DBAD) proceeded
to give the seven-membered ring without epimerization or
other side reactions. Finally, protecting group manipulation of
26 gave the protected caprazol 6 and the structure was
confirmed through conversion into caprazol (2).[1,7a,8a]
With the side-chain fragments 4 and 5 and protected
caprazol 6 in hand, we focused on the introduction of the
fatty-acid side chain. This side chain readily decomposes
through b-elimination of the b-acyloxy carbonyl under basic
conditions and cleavage of the O-acylglycoside under acidic
conditions. In fact, attempts to introduce the fatty-acid side
chain 27[19] to model diazepanone 28 using EDCI caused b-
elimination to give unsaturated carboxylic acid 30 instead of
the desired 29 (Scheme 4). DCC and PyBOP were also
metrization of 3-methyl glutaric anhydride (13) using the
cinchona alkaloid catalyst 14 and the procedure reported by
Song and co-workers[13] gave the carboxylic acid 15 with high
enantioselectivity (92% ee). Condensation of 15 with the l-
rhamnose derivative 16,[14] followed by removal of the benzyl
group from ester 17 by hydrogenolysis, gave 5.
Construction of the syn-b-hydroxy amino acid moiety with
an S configuration at C5’ was then investigated. Several
strategies have been employed for this in the past,[5d,e,6g,i–k,7a,8a]
two of which were used for the total synthesis of caprazol.
One is a Sharpless asymmetric aminohydroxylation of the
a,b-unsaturated ester[7a] and the other is the diastereoselec-
tive isocyanoacetate aldol reaction.[8a] We anticipated that the
stereochemistry at C5’ could be controlled with a novel
diastereoselective aldol reaction using the isocyanate 8 in the
presence of an organocatalyst.[10]
Initially, 9[15] was treated with 8 and Et3N (10 mol%) in
toluene to give a mixture of the aldol adducts 18a and 18b in
50% yield with poor diastereoselectivity (1:1.8; Table 1,
entry 1). In contrast, treatment with the (S,S)-thiourea
catalyst 10a (10 mol%) in toluene gave the desired aldol
adduct 18a as the major product in 64% yield (3.1:1), along
with a small amount of byproduct (19; entry 2). The
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Scheme 3. Total synthesis of caprazamycin A (1). Reagents and conditions: a) aq. KOH, THF, 0 to 258C; b) DBU, THF, 708C, 86% (2 steps);
c) Zn4(OCOCF3)6O (3.2 mol%), MeOH, 508C, quant.; d) NaH, pNsCl, DMF, 0 to 258C; e) NaOMe, MeOH, 65% (2 steps); f) 21, BF3·Et2O, 4ꢀ
M.S., CH2Cl2, À308C, 71%; g) PPh3, THF/PhH 1:1; then CbzCl, aq NaHCO3, 0 to 258C; h) Ba(OH)2·8H2O, THF/H2O 4:1, 0 to 258C; i) Ghosez
reagent, CH2Cl2, 08C then 23, aq. NaHCO3, 08C, 46% (3 steps); j) CSA, MeOH/CH2Cl2 1:1, 08C, 68% (17% for recovered 24, b.r.s.m. 82%);
k) PPh3, DBAD, toluene, 08C, 75%; l) K2CO3, PhSH, MeCN, 0 to 258C, 73%; m) TrocCl, DMAP, pyridine, CH2Cl2, 0 to 258C, 79%; n) TsOH·H2O,
MeOH, 608C, 41% and diol having penthylidene acetal (21%); o) CbzCl, DMAP, CH2Cl2, 0 to 258C; p) pTsOH·H2O, MeOH, 25 to 608C, 71% (2
steps); q) 4, EDCI, DMAP, CH2Cl2, 0 to 258C; r) Zn, AcOH/THF, 258C; s) AcOH, ClCH2CH2Cl, 258C; t) (CH2O)n, NaBH(OAc)3, AcOH/
ClCH2CH2Cl, 258C; u) HF·py, THF, 08C to 258C, 43% (5 steps); v) 5, 2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, 0 to 258C, 64%; w) Pd black,
EtOH/HCO2H 20:1, 258C, 98%; x) Zn, AcOH/THF, 25 to 508C; y) (CH2O)n, NaBH(OAc)3, AcOH/CH2Cl2, 258C, quant. (2 steps); z) Pd black,
EtOH/HCO2H 10:1, 258C, 46%. CSA=10-camphor sulfonic acid, DBAD=di-tert-butyl azodicarboxylate, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DMAP=N,N-dimethyl-4-aminopyridine, DMF=N,N-dimethylformamide, EDCI=1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide, M.S.=molecu-
lar sieves, pNs=p-nitrobenzenesulfonyl, TrocCl=2,2,2-trichloroethyl chloroformate, pTs =p-toluenesulfonyl.
of the TES group, 5 was introduced to the resultant alcohol 31
using Yamaguchi conditions to give protected caprazamy-
cin A (32).[8b] Finally, global deprotection with hydrogenation
in the presence of palladium black was successful without
side-chain decomposition. This step completed the first total
synthesis of caprazamycin A (1). The 1H and 13C NMR
spectra, as well as IR and HRMS data for the synthetic
1 matched those of the natural product.[20]
In summary, we have accomplished the first total synthesis
of caprazamycin A in 23 steps (longest linear sequence from
Scheme 4. Initial attempts to introduce fatty acid side chain (27).
aldehyde 9). The key points are a) scalable synthesis of the
syn-b-hydroxy amino acid moiety with a thiourea-catalyzed
diastereoselective aldol reaction, 2) maintaining the struc-
tural integrity of the diazepanone core during introduction of
the fatty-acid side chain, and 3) global deprotection with
hydrogenation. This is the first report detailing the introduc-
tion of the unstable fatty-acid side chain. This strategy should
allow the synthesis of related liponucleoside antibiotics.
ineffective. The b-hydroxy ester of diazepanone may also
decompose through b-elimination and a retro-aldol reaction.
Thus, 4 and 5 were introduced in a stepwise manner.
The final stage of this synthesis began with coupling 4 with
the protected caprazol 6 without epimerization (Scheme 3).
The Troc group was removed under mild reaction conditions
without touching the unstable b-acyloxy moiety. This depro-
tection was followed by reductive amination. After removal
Received: December 12, 2014
Published online: && &&, &&&&
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Keywords: aldol reaction · antibiotics · natural products ·
organocatalysis · total synthesis
.
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[20] The NMR spectrum of caprazamycin A was dependent on
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using [D6]DMSO/D2O/DCO2D (20:1:1) for comparison. Also
see the Supporting Information.
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Natural Product Synthesis
H. Nakamura, C. Tsukano, M. Yasui,
S. Yokouchi, M. Igarashi,
Y. Takemoto*
&&& — &&&
Total Synthesis of (À)-Caprazamycin A
Abra‘capraza’: Caprazamycin A has sig-
nificant antibacterial activity against
Mycobacterium tuberculosis (TB). The first
total synthesis is herein reported and
features the scalable preparation of the
syn-b-hydroxy amino acid with a thiourea-
catalyzed diastereoselective aldol reac-
tion, construction of a diazepanone with
an unstable fatty-acid side chain, and
global deprotection with hydrogenation.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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