Catalytic asymmetric total synthesis of (+)-caprazol

Article abstract of DOI:10.1021/ol501397b

Catalytic asymmetric total synthesis of caprazol, a lipo-nucleoside antibiotic, has been accomplished employing two of the stereoselective C-C bond forming reactions as key transformations. The stereochemistries of the β-hydroxy-α-aminoester moiety at the juncture of the uridine part and diazepanone part, and of the β-hydroxy-α-amino acid moiety embedded in the diazepanone system, were constructed using a diastereoselective isocyanoacetate aldol reaction (dr = 88:12) and an enantioselective anti-nitroaldol reaction catalyzed by a Nd/Na-chiral amide ligand (dr = 12:1, 95% ee), respectively.

Full text of DOI:10.1021/ol501397b

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Total Synthesis of (+)-Caprazol
Purushothaman Gopinath, Lu Wang, Hikaru Abe, Gandamala Ravi, Takashi Masuda, Takumi Watanabe,*
and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: Catalytic asymmetric total synthesis of caprazol,
a lipo-nucleoside antibiotic, has been accomplished employing
two of the stereoselective C−C bond forming reactions as key
transformations. The stereochemistries of the β-hydroxy-α-
aminoester moiety at the juncture of the uridine part and
diazepanone part, and of the β-hydroxy-α-amino acid moiety
embedded in the diazepanone system, were constructed using
a diastereoselective isocyanoacetate aldol reaction (dr = 88:12)
and an enantioselective anti-nitroaldol reaction catalyzed by a
Nd/Na-chiral amide ligand (dr = 12:1, 95% ee), respectively.
espite the large number of chemotherapies available,
tuberculosis,4 yet it has never been a molecular target of clinical
Dtuberculosis (TB) remains a serious infectious disease anti-TB drugs.
(+)-Caprazol (1) is a core structure of caprazamycins and a
causing human mortality. Moreover, public health has become
further endangered by the emergence of extensively multidrug-
resistant TB (XDR-TB), for which most of the available clinical
drugs are ineffective. In 2003, lipo-nucleoside antibiotics
caprazamycins were reported as promising anti-TB natural
products.1 Caprazamycins comprise a mixture of seven
constituents possessing aliphatic side chains of varying lengths
and branched patterns. Among them, caprazamycin B (3)
exhibits the most potent anti-TB activity, due mainly to the
inhibition of MraY,2 a key enzyme in the peptidoglycan
biosynthesis pathway of the pathogens (Figure 1). Semisynthetic
structure−activity relationship (SAR) studies starting from
natural caprazamycins were thoroughly executed to identify
CPZEN-45 (2)3 an anti-XDR-TB agent. It is noteworthy that the
mechanisms underlying the intriguing anti-XDR-TB activity is
the inhibition of WecA,2 an enzyme involved in the biosynthesis
of mycolyl arabinogalactan, which is essential for Mycobacterium
minor component of caprazamycin production by fermentation.
Although caprazol itself exhibits only weak anti-TB activity,5
most of its molecular skeleton is shared by CPZEN-45; caprazol
would be a reasonable starting point toward SAR studies of
WecA inhibitors to combat XDR-TB by an unprecedented mode
of action. Therefore, we attempted to establish an efficient
synthetic route to caprazol and caprazamycins that is amenable to
developing a structurally and stereochemically diverse library of
compounds. This synthetic route is expected to accelerate SAR
studies, which in turn will facilitate the discovery of more
promising lead compounds and the identification of a
pharmacophore of WecA inhibitors using chemical biology
approaches.
Although tremendous effort by many research groups has
focused on building the framework of caprazamycin-related
natural products including liposidomycins6 in an asymmetric
manner, only one total synthesis of a natural product of this class,
caprazol, has been completed to date by Matsuda and Ichikawa et
al.7 In these reports, two key stereochemical issues were
addressed by taking advantage of Sharpless’ asymmetric
aminohydroxylation of the α,β-unsaturated ester and the chirality
of D-serine. A subsequent series of comprehensive SAR studies5,8
focused on antibacterial leads, including antimethicillin-resistant
Staphylococcus aureus (MRSA) and antivancomycin-resistant
enterococci (VRE) agents.8c Whereas other attempts relied on a
number of C−H, C−O, and C−N bond formations and/or a
chiral pool as starting material to furnish the requisite
stereochemistry,9 stereoselective C−C bond-forming reactions
were scarcely adopted.9j−l,10,11 Our approach centered on
catalytic enantio- and diastereoselective aldol-type chemistry to
Received: May 15, 2014
Figure 1. Structure of caprazol and related compounds.
© XXXX American Chemical Society
A
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Letter
provide the stereocontrol required for the synthesis of caprazol
and caprazamycin B, which enabled the construction of the
molecular architecture and simultaneous installation of the
correct configuration, making the entire synthetic process more
efficient. Along this line, we previously reported the catalytic
asymmetric synthesis of the side-chain portion (western zone) of
caprazamycin B12 utilizing a direct catalytic enantioselective
thioamide aldol reaction.13 It also included a newly developed
catalytic enantioselective alcoholysis of 3-methylglutaric anhy-
dride.14
Table 1. Optimization of anti-Selective Catalytic
Enantioselective Nitroaldol Reaction
Scheme 1 summarizes our approach to address the key
stereochemical issues associated with β-hydroxy-α-amino acid
a
b
c
entry
5:6
x
temp (°C)
yield (%)
dr
ee (%)
1
2
3
4
5
6
1:5
3
6
9
6
9
9
9
9
9
9
9
−40
−40
−40
−60
−60
−60
−60
−60
−60
−60
−60
52
85
97
<3
52
87
45
68
66
66
75
8:1
85
75
74
nd
96
95
95
94
95
95
95
1:5
2.4:1
1.2:1
nd
Scheme 1. Key Stereoselective Aldol-Type Processes in This
Study
1:5
1:5
1:5
18:1
9:1
1:10
1:10
10:1
5:1
d
7
15:1
12:1
15:1
6:1
8
9
10
2:1
e
11
5:1
12:1
a
b
c
All of the reactions were conducted in concentration of 0.25 M.
NMR yield using 1,1,2,2-tetrachloroethane as an internal standard.
d
Determined by HPLC methods using a chiral stationary phase.
A
e
carbon nanotube-confined catalyst was used. The reaction was
performed for 120 h.
Prolonging the reaction time to 120 h improved the chemical
yield up to 75% with a slight loss of dr (dr = 12:1, 95% ee, entry
11), which was set as the standard protocol in the present study.
To clarify the factors affecting dr upon changing the ratio of the
substrates, a more detailed study is needed and currently
ongoing. It is noteworthy that the nitroaldol process using 5 and
6 as the substrates under conventional conditions (treatment of
base) is troublesome, which gives not only anti- and syn-products
but also double nitroaldol and Michael adducts to result in a
complex mixture.
moieties located inside the diazepanone ring system and between
the diazepanone and uridine units. The former would utilize a
highly anti-selective nitroaldol reaction catalyzed by a heteroge-
neous heterobimetallic Nd/Na-chiral amide ligand complex that
was recently developed in our laboratory.15 Notably, single
proton transfer during the C−C bond assemblage in this reaction
realizes perfect atom economy. The latter should take advantage
of substrate-controlled diastereoselective isocyanoacetate aldol
reaction.
Next, the NO2 group of 4 was reduced to a primary amine by
an In-mediated process, followed by protection as TBS ether 11
(Scheme 2). The NH2 functionality was then tentatively
Scheme 2. Synthesis of the Diazepanone Precursor 14
Table 1 shows the optimization of the anti-selective
asymmetric nitroaldol reaction using cinnamaldehyde (5) and
O-benzylnitroethanol (6)16 as the substrates catalyzed by the
Nd/Na-chiral amide ligand (10) complex to afford adduct 4. All
reactions were conducted at the concentration 0.25 M (based on
5 for entries 1−7 and 6 for entries 8−11). At first, a 5-fold
amount of 6 toward 5 was used, and the reactions were
performed for 72 h at −40 °C with varying catalyst loading
(entries 1 to 3). Although less loading gave a better dr and ee, the
selectivity of each was unsatisfactory. Upon lowering the
temperature to −60 °C, both the dr and ee improved, although
9 mol % of catalyst was required to realize an acceptable reaction
rate (entries 4 and 5). Use of an increased amount of 6 improved
the yield but lowered the dr (entry 6). The carbon nanotube
condition17 was beneficial to anti-selectivity, although the
reaction rate was slowed (entry 7). Switching the ratio of the
substrates afforded similar results (entry 8 vs 6) and was
advantageous toward saving commercially unavailable substrate
6. Although a ratio of 2:1 still afforded a reasonable dr (7:1, entry
10) and an excellent ee, a 5:1 ratio is preferred (entry 9).
protected with Troc to give 12, to which the Me group was
introduced by a conventional procedure to afford a masked
secondary amine 13. Removal of the Troc gave 14 uneventfully.
Next, we examined the diastereoselective isocyanoacetate
aldol reaction, the other key stereoselective transformation. A
similar approach employing ribose-derived aldehyde was
B
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Letter
reported by Le Merrer,11 where trans-oxazoline with an incorrect
configuration was the major product (26:74). Our preliminary
study using PMB-protected uridine-derived aldehyde is shown in
Scheme 3. As presumed based on Le Merrer’s results, the
decomposition. Acid hydrolysis conducted with the crude
material occurred uneventfully to obtain β-hydroxy-α-amino
ester 19. Satisfied with the successful key stereoselective C−C
bond formation, we undertook further transformations toward
caprazol inspired by Matsuda and Ichikawa’s procedure.5,7
The NH2 group was protected as a benzyl carbamate (20),
with which an O-glycosylation procedure7b was applied with
some modification. The acceptor 20 and donor 21 were coupled
under Lewis acidic conditions with BF3·OEt2 (36 h, −30 °C) to
afford the desired β-anomer 22 in 72% yield. Successful
interconversion of the functional groups (N3 to BocNH) gave
23, which was followed by the nucleophilic cleavage of the ester
to give a carboxylic acid 24.
Scheme 3. Preliminary Study of Diastereoselective
Isocyanoacetate Aldol Reaction
This set the stage for the endgame of the synthesis including
the diazepanone formation. The precedents generally required
either reductive amination or lactamization for the cyclization
other than some exceptions such as Takemoto’s Pt-catalyzed 7-
endo cyclization of an internal alkynyl amide.19 In the present
study, we adopted a reductive amination. Coupling of the two
segments (14 and 24) was achieved using the DEPBT method20
to give the amide intermediate 25 (Scheme 5). The benzylidene
moiety of 25, a hidden formyl functionality, was oxidatively
cleaved to afford a cyclization precursor 26.
formation of an undesired diastereomer of trans-oxazoline
predominated when Et3N and 8 (1.2 equiv) were treated with
the isopropylidene-protected aldehyde 15 in CH2Cl2. Changing
the protective group from isopropylidene to TIPS (17)
improved the selectivity, but the dr (ca. 1:1) remained
unsatisfactory. The Cu(I)-catalyzed conditions reported by
Kirchner18 dramatically increased the dr to 88:12. Even with
this method, the isopropylidene congener 15 gave a poor result
(40:60), demonstrating that the correct choice of the protecting
group for the ribose part is crucial.
Scheme 5. Construction of the Diazepanone System and
Completion of the Total Synthesis
Actually, protection of the NH was not needed in the synthetic
pathway: the aldol process of 8 and 9 proceeded more cleanly
with the same selectivity by changing the solvent from CH2Cl2 to
THF (88:12) at the expense of a slightly longer reaction time (2 h
vs 3 h; Scheme 4). At this step, the oxazoline product 7 could not
be purified on silica gel because of its susceptibility to
Scheme 4. Synthesis of Uridine-Derived Carboxylic Acid 24
Hydrogenolysis using Pd-catalysts under a H2 atmosphere
with AcOH as an additive removed the Cbz and Bn groups with
the utmost efficiency with concomitant intramolecular imine
formation to result in 27. An undesired reaction, hydrogenation
of the double bond on uracil, however, also proceeded. Although
Kurosu et al. recently reported that formic acid as an additive
suppresses the intractable side reaction,21 this new protocol did
not work in the present system. Unfortunately, it was difficult to
eliminate the side products associated with this over-reduction at
any of the later steps of the synthesis. Eventually, hydrogenolysis
upon gentle heating without acid was found to work
satisfactorily: removal of the Cbz and Bn groups and
instantaneous cyclization proceeded with 5% Pd−C under
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization of new data, HPLC data, and experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Gopinath, P.; Watanabe, T.; Shibasaki, M. J. Org. Chem. 2012, 77,
9260.
AUTHOR INFORMATION
Corresponding Authors
■
(13) (a) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J.
Am. Chem. Soc. 2009, 131, 18244. (b) Iwata, M.; Yazaki, R.; Chen, I.-H.;
Sureshkumar, D.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2011,
133, 5554. (c) Kawato, Y.; Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki,
M. Tetrahedron 2011, 67, 6539.
(14) Gopinath, P.; Watanabe, T.; Shibasaki, M. Org. Lett. 2012, 14,
1358. (b) Matsunaga, S.; Shibasaki, M. Synthesis 2013, 45, 421.
(15) (a) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett.
2008, 49, 272. (b) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860. (c) Nitabaru, T.;
Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2012, 51, 1644.
(16) Gefflaut, T.; Martin, C.; Delor, S.; Besse, P.; Veschambre, H.;
Bolte, J. J. Org. Chem. 2001, 66, 2296.
*E-mail: twatanabe@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JST, ACT-C, KAKENHI
(No. 23590037), and Takeda Science Foundation. P.G. thanks
the JSPS for the Postdoctoral Fellowship for Foreign Researcher.
We thank Dr. Masayuki Igarashi (BIKAKEN) for providing a
sample and spectral data of 3; Dr. Ryuichi Sawa, Ms. Yumiko
Kubota, Ms. Kiyoko Iijima, and Ms. Yuko Takahashi
(BIKAKEN) for collection of spectral data; and Mr. Kazuki
Hashimoto and Ms. Chiharu Sakashita (BIKAKEN) for technical
support.
(17) Sureshkumar, D.; Hashimoto, K.; Kumagai, N.; Shibasaki, M. J.
Org. Chem. 2013, 78, 11494.
(18) Benito-Garagorri, D.; Bocokic,
2006, 47, 8641.
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V.; Kirchner, K. Tetrahedron Lett.
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Yokouchi, S.; Girard, A.-L.; Kuribayashi, T.; Sakamoto, S.; Enomoto, T.;
Takemoto, Y. Org. Biomol. Chem. 2012, 10, 6074.
(20) Li, H.; Jiang, X.; Ye, Y.; Fan, C.; Romoff, T.; Goodman, M. Org.
Lett. 1999, 1, 91.
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