Synthetic studies towards the identification of novel capuramycin analogs with mycobactericidal activity

Article abstract of DOI:10.3987/COM-08-S(F)38

Expeditious syntheses of capuramycin, an effective MraY inhibitor in vivo, analogs are described. Synthetic schemes reported here are extremely useful for the generation of capuramycin analogs to identify minimum structure requirement to exhibit antimycobactericidal activity.

Full text of DOI:10.3987/COM-08-S(F)38

HETEROCYCLES, Vol. 77, No. 1, 2009
217
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 217 - 225. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd July, 2007, Accepted, 15th August, 2008, Published online, 18th August, 2008.
DOI: 10.3987/COM-08-S(F)38
SYNTHETIC STUDIES TOWARDS THE IDENTIFICATION OF NOVEL
CAPURAMYCIN ANALOGS WITH MYCOBACTERICIDAL ACTIVITY
Michio Kurosu* and Kai Li
Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th
birthday.
Department of Microbiology, Immunology, and Pathology, College of
Veterinary Medicine and Biomedical Sciences, Colorado State University, 1682
Campus Delivery, Fort Collins, CO 80523-1682, USA.
E-mail: michio.kurosu@colostate.edu
Abstract – Expeditious syntheses of capuramycin, an effective MraY inhibitor in
vivo, analogs are described. Synthetic schemes reported here are extremely useful
for the generation of capuramycin analogs to identify minimum structure
requirement to exhibit antimycobactericidal activity.
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for nearly two million
deaths annually.1 In particular, people who have HIV-AIDS patients are susceptible to TB infection.2
Moreover, the emergence of multidrug-resistant strains of Mtb seriously threatens TB control and
prevention efforts.3 Recent studies have shown that infection with Mtb enhances replication of HIV and
may accelerate the progression of HIV infection to AIDS. In addition, there are significant problems
present with respect to treatment of AIDS and TB co-infected patients; rifampicin (a key drug of DOTS
therapy) shows significant interactions with protease inhibitors and non-nucleoside reverse transcriptase
inhibitors.4 Therefore, it is an urgent need to identify in vivo effective mycobactericidal drug leads which
interfere with unexploited bacterial molecular targets.
Since peptidoglycan (PG) is an essential bacterial cell-wall polymer, the machinery for PG biosynthesis
provides a unique and selective target for antibiotic action.5 By far, the most commonly exploited target in
PG synthesis are the penicillin binding proteins (PBPs), which are inhibited by the β-lactams and
glycopeptides. Unfortunately, these compounds are of limited use in TB infections due to the interplay of
β-lactamase activity and the relative impermeability of the mycolic acid layer in mycobacteria.6 Three
other biosynthetic steps in PG synthesis can be targeted by antibiotics in current clinical use; these

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HETEROCYCLES, Vol. 77, No. 1, 2009
antibiotics include bacitracin, D-cycloserine and fosfomycin.7 Regrettably, all are of limited usefulness in
treating TB.8 Thus, PG biosynthesis appears to be a source of unexploited drug targets in mycobacterial
pathogens. Earlier cytoplasmic steps in peptidoglycan biosynthesis are catalyzed by highly conserved
Mur enzymes. Therefore, inhibitors of any of these enzymes (MurA~F) would likely possess a broad
spectrum of action. However, in spite of significant efforts by pharmaceutical industries, MurA~F
inhibitors have not yet yielded drug leads.9 Similarly, there is no antibiotic or a small molecule directed
against MraY, which transfers UDP-N-acetylmuramyl-L-alanyl-γ-D-glutamyl-meso-diaminopimelyl-
D-alanyl-D-alanine (Park’s nucleotide) to a molecule of prenyl phosphate forming Lipid I, being
developed for drugs for clinical trials. However, MraY inhibitors such as nucleoside antibiotics exhibit
significant antibacterial activity in vitro.10 Although many MraY inhibitors of natural product origin (i.e.
liposidomycins, caprazamycins, and muraymycins)11 are very complex and no extensive medicinal
chemistry efforts with these molecules have been reported,12 the structures of capuramycin (1)13 and
A-500359A (214, Figure 1), isolated from Streptomyces spp., are less complicated and their chemical
synthesis to perform medicinal chemistry seems to be feasible.
OTIPS
OAc
O
O
O
H2N
AcO
AcO
O
R
NH
O
BOM
O
N
O
O
N
HN
N
STol
NH2
HO
ii
O
N
H
H
OH
O
O
O
+
O
H
OH
MeO
OH
HN
MeO
OTBS
capuramycin: R = H (1)
A-500359A: R = Me (2)
R
i
iii
O
O
NH
O
NH
O
H
H
H
O
O
H
O
O
O
N
N
HN
N
H
HN
O
N
H
O
O
O
O
OH
HO
OH
R2O
OR1
R2O
OR1
OH
OH
3a: R1 = H, R2 = Me
3b: R1 = Me, R2 = H
4a: R1 = H, R2 = Me
4b: R1 = Me, R2 = H
O
O
O
NH
O
O
NH
O
H
H
H
O
H
O
O
O
N
N
HN
N
HN
O
N
H
O
H
O
O
HO
OH
OH
R2O
OR1
R2O
OR1
OH
OH
6a: R1 = H, R2 = Me
6b: R1 = Me, R2 = H
5a: R1 = H, R2 = Me
5b: R1 = Me, R2 = H
Figure 1. Structures of capuramycin (1) and A-500359A (2), the synthons (i, ii, and iii) for their
syntheses, and designed capuramycin analogs 3a~6b.

HETEROCYCLES, Vol. 77, No. 1, 2009
219
To date, however, only one total synthesis of capuramycin was reported by Knapp and Nandan.15 Their
synthesis requires 21 linear steps from diisopropylidine-D-glucofuranose and seems to be difficult to
apply to the synthesis of the diversity structures of capuramycin analogs. A Sankyo group in Japan
reported chemical modification of A-500359A (2) and biological evaluation of A-500359A analogs.16 We
have recently established a flexible synthesis of campuramycin using the synthons, i, ii, and iii (Figure 1),
and obtained extensive knowledge of synthetic accessibility of capuramycin analogs.17 However, our
synthetic route for campuramycin relies on 1) oxidative cleavage to generate the carboxyamide, and 2)
oxidation of the 6-position of mannose moiety of the coupling product (i + ii) to form the
manno-pyranuronate. These additional several steps required for the synthesis of intact capuramycin core
structure are not ideal for the generation of a library of capuramycin analogs in a time-efficient manner.
Therefore, we envisioned identifying the indispensable functionalities of capuramycin to exhibit
antimycobactericidal activity. To this end we plan to synthesize the decarboxyamide-capuramycin 3a, and
its congeners 4a, 5a, 6a, and their methyl isomer 3b, 4b, 5b, 6b (Figure 1). Because the saturated analogs
4a, 4b, 6a, and 6b can be synthesized by skipping the elimination step, we, thus, focused in establishing
expeditious preparations of 3a, 3b, 5a, and 5b. Herein, we describe a highly flexible synthesis of
capuramycin analogs 3a, 3b, 5a, and 5b with a minimum number of protecting group manipulations.
O
O
O
O
NH
NH
O
OC(NH)CCl3
R3
P
O
HO
O
N
N
HN
N
H
O
O
O
O
OH
AcO
R4
O
OAc
H
R2O
OR1
R2O
OR1
OH
+
8a: R3 = OAc, R4 = H
8b: R3 = H, R4 = OAC
segment B
7a: R1 = TBS, R2 = Me
7b: R1 = Me, R2 = TBS
3a: R1 = H, R2 = Me
3b: R1 = Me, R2 = H
O
segment A
O
NH
O
O
H
O
N
Cl
P =
Cl
H
HN
Cl
OH
N
H
O
O
HN
NH2
OH
R2O
OR1
O
OH
Cl
10
OMe
9
5a: R1 = H, R2 = Me
5b: R1 = Me, R2 = H
segment C
Figure 2. Revised synthetic route for capuramycin analogs 3a~5b.
The revised synthetic route for 3a, 3b, 5a, and 5b includes 1) pyranulonidations of 7a and 7b (Segment
A) with the pyranuroates donors 8a and 8b (Segment B), 2) the base-catalyzed elimination reactions of
the coupling products (7 + 8) to furnish the α,β-unsaturated esters, 3) amide-forming reaction with
Segment C, and 4) global deprotections in a single step (Figure 2). In order to perform pyranurosylation

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HETEROCYCLES, Vol. 77, No. 1, 2009
and elimination reactions with a minimum number of protecting group manipulations, choice of
protecting groups for each building block (7 and 8) requires careful consideration. In addition, it is very
important to devise a flexible synthetic route for the generation of a wide variety of capuramycin analogs
from the point of medicinal chemistry.
Limited examples of glycosylations with pyranuronoates were found in literatures, and the Schmidt
glycosylation conditions using Lewis acid are the standard for pyranulonidation reactions.18 Having
considered the synthetic and medicinal chemistry aspects described above and limited examples of
pyranulonidations,
we
decided
to
introduce
the
protecting
group,
(2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl alcohol (10) which showed an unusual
stability to Brønstead acids (i.e. 15% TFA, 30% HF, 2N HCl, and HBr/AcOH), Lewis acids (i.e. TiCl4,
ZnCl2, AlCl3, B(C6F5)3, BCl3, BBr3, TMSOTf, and La(OTf)3), and bases (i.e. 40% NH4OH, 10% LiOH,
and DBU).19 Such a protecting group would enable us to accomplish the synthesis of capuramycin
analogs 3a, 3b, 5a, and 5b with a minimum number of deprotection/protection manipulations.
O
O
O
O
BOM
BOM
BOM
BOM
N
N
N
N
HO
N
N
N
N
TBSCl (2.5 equiv)
TBSO
TBSO
TBSO
O
O
KH
O
O
O
O
O
O
Imidazole (4 equiv)
DMF-THF
(4 / 1)
/ DMF
89%
HO
OH
TBSO
HO
-O
OK
OTBS
O
K+
- 10 oC
TBS
11
BOM: benzyloxymethyl
12
R-I, KH
/ DMF
R-I
95%
O
85%
O
BOM
BOM
N
N
N
N
TBSO
TBSO
O
O
O
O
RO
OTBS
TBSO
13b: R = Me
OR
13a: (R = Me) + 13b
(13a : 13b = 3~5 : 1)
O
O
O
BOM
N
BOM
N
NH
N
N
HO
HO
N
TBSO
90% TFA
CH2Cl2
H2 / 10% Pd-C
MeOH
O
O
O
O
O
O
- 5 oC
R2O
OR1
R2O
OR1
R2O
OR1
100%
14a: R1 = TBS, R2 = Me
14b: R1 = Me, R2 = TBS
7a: R1 = TBS, R2 = Me
7b: R1 = Me, R2 = TBS
13a: R1 = TBS, R2 = Me
13b: R1 = Me, R2 = TBS
75~95%
Scheme 1. Syntheses of the functionalized uridine derivatives 7a and 7b.

HETEROCYCLES, Vol. 77, No. 1, 2009
221
The convenient syntheses of the glycosyl acceptors 7a and 7b were illustrated in Scheme 1. The
N(3)-BOM uridine 1120 was subjected to double-silylation reactions with TBSCl and imidazole in DMF
to furnish the 2’,5’-O-di-TBS product 12 in 89% yield. It was realized that the treatment of 12 with KH
underwent the silyl group migration to furnish the potassium 2’-alkoxide which could be alkylated with a
variety of electrophiles (i.e. MeI, EtI, octyl iodide, and allyl bromide); the silyl migration of 12 was
completed within 0.5 h and followed by methylation with MeI provided 13b (R = Me) in 95% yield.21
The structures of 13a and 13b were established through 1H-NMR NOESY experiments. On the contrary,
the treatment of 12 with KH in the presence of MeI (10 equiv) yielded a mixture of 13a and 13b with
3~5:1 (13a / 13b) selectivity. Selective desilylation of the primary TBS group of 13 with cooled 90%
TFA (–5 oC) followed by hydrogenolysis of the BOM group gave rise to the partially protected-uridines
7a and 7b in 75~95 % overall yield.
O
O
O
R1
O
O
R1
O
R1
O
P
P
P
HO
Cl3CCN
1) Ac2O, Py.
NH4OAc
DMF
AcO
AcO
NH
CCl3
O
AcO
AcO
AcO
AcO
HO
HO
DBU (0.05 equiv)
/ CH2Cl2
2) 10, DICI, DMAP
/ CH2Cl2
R2
R2
R2
O
OH
OAc
OH
OH
8a: (!-anomer), R1 = OAc, R2 = H
8b: ("-anomer), R1 = H, R2 = OAc
80~85%
18a: R1 = OAc, R2 = H
18b: R1 = H, R2 = OAc
17a: R1 = OAc, R2 = H
17b: R1 = H, R2 = OAc
91~95%
19
85% overall
O
Cl
P =
Cl
1) RuCl3, NaIO4
CCl4-CH3CN-water
H
Cl
OH
NH
O
N
HO
2) 10, DICI, DMAP
/ CH2Cl2
O
BF3-OEt2, MS4A
/ CH2Cl2
7a: R1 = TBS, R2 = Me
7b: R1 = Me, R2 = TBS
Cl
OMe
R2O
OR1
86% overall
rac-10
OH
OH
1) TrCl, Py.
then Ac2O
60 oC
2) 90% TFA
OH
O
OAc
O
O
HO
HO
AcO
AcO
P
OAc
O
O
O
AcO
O
P
H
H
OH
OAc
AcO
NH
O
NH
15
16
O
O
AcO
AcO
90% overall
N
O
N
O
O
O
OAc
R2O
OR1
R2O
OR1
DICI: N,N'-diisopropylcarbodiimide
HOAt: 1-hydroxy-7-azabenzotriazole
EDCI: N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride
NMM: N-methylmorpholine
19a: R1 = TBS, R2 = Me
19b: R1 = Me, R2 = TBS
49~50% from 8b
20a: R1 = TBS, R2 = Me
20b: R1 = Me, R2 = TBS
25~40% from 8a
DBU / benzene
O
O
65~85%
O
1) 50% TFA / CH2Cl2
O
P
NH
O
NH
O
O
O
EDCl, HOAt
NMM / DMF-THF (1/1)
O
2)
N
N
HN
N
O
O
O
R3
R3
H
O
HN
NH3Cl
R4
R4
R2O
OR1
R2O
O
OR1
OAc
OH
9
21a: ("-anomer) R1 = TBS, R2 = Me, R3 = OAc, R4 = H
21b: ("-anomer) R1 = Me, R2 = TBS, R3 = OAc, R4 = H
22a: (!-anomer) R1 = TBS, R2 = Me, R3 = H, R4 =OAc
22b: (!-anomer) R1 = Me, R2 = TBS, R3 = H, R4 = OAc
3a: ("-anomer) R1 = H, R2 = Me, R3 = OH, R4 = H
3b: ("-anomer)R1 = Me, R2 = H, R3 = OH, R4 = H
5a: (!-anomer) R1 = H, R2 = Me, R3 = H, R4 = OH
5b: (!-anomer) R1 = Me, R2 = H, R3 = H, R4 = OH
3) LiOH (5 equiv)
/ THF-water (10/1)
90~95% overall
Scheme 2. Syntheses of the capuramycin analogs 3a, 3b, 5a and 5b.

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HETEROCYCLES, Vol. 77, No. 1, 2009
D-Gluco-pyranuroate glycosyl donor 8b was synthesized in four steps with greater than 68% overall yield
from glucuronic acid (19). On the other hand, synthesis of D-manno-pyranuroate donor 8a requires
additional
several
steps
to
selectively
oxidize
the
6-OH
group
of
16.15
1,2,3,4-Tetra-O-acetyl-D-mannopyranose (16) was oxidized under typical Sharpless conditions (RuCl3,
NaIO4) and the generated carboxylic acid was esterified with rac-10.22 Selective cleavage of the anomeric
acetate of 17a followed by the reaction of the free anomeric alcohol with Cl3CCN in the presence of
catalytic amount of DBU afforded the β-imidate 8a; the conversion of 8a from D-mannose was greater
than 50% overall yield.
The gluculonidations of alcohols with 8b are known to be low yielding reactions and several variations of
glucuronate imidates have been devised in order to improve reactivity.23 Nonetheless, the
gluculonidations of 7a and 7b with 8b were examined under typical Schmidt conditions. It was observed
o
that TMSOTf (5~10 mol%) catalyzed gluculonidation of 7a with 8b at –20 C furnished the orthoester
exclusively with near quantitative yield. Rearrangement of the orthoester to the desired β-glycoside 19a
were not observed at elevated temperature or under the conditions of an increased amount of TMSOTf
(100~250 mol%). Interestingly, the same reaction was successfully catalyzed by using BF3•OEt2 (300
o
mol%) at –20 C to afford 19a in 50% yield without the formation of the orthoester; however, this
transformation under these conditions required a relatively long reaction time of 10~14 h. Similarly, 7b
could be coupled with 8b to furnish 19b in 49% yield. Although the desired product 20a and 20b could
be synthesized by the reaction of 7a and 7b with 8a via the conditions performed for the syntheses of 19,
D-manno-pyranulonidation resulted in lower isolation yields (25~40% yields) due to the formation of the
orthoesters. In general, the orthoester formation observed using acetyl group-protected glycosyl donors is
able to be diminished by using pivaloyl protecting groups, however, we could not improve D-manno-
pyranulonidations with disarmed donors such as the benzoyl- or pivaloyl-protected
D-manno-pyranuronate imidate.24 Even though isolation yields for 19 and 20 were moderate, these
products could be isolated simply by column chromatography. In addition, 8a, 8b, 7a, and 7b could be
synthesized a multi-gram quantity without difficulty. Thus, further reaction optimization was not
undertaken for this program. E2 elimination reactions of 19 and 20 with a stoichiometric amount of DBU
furnished 21 and 22 in 65~85% yields. (2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl ester
and TBS groups were simultaneously deprotected with 50% TFA to provide the acid-alcohol and
trifluoroacetic acid ester of 10.25 The resulting crude mixture was coupled with (2S)-aminocaprolactam
(9) under a condition of HOAt, EDCI, and NMM to yield the ligation product in quantitative yield. The
acetyl-protected decarboxyamide-capuramycin analogs were hydrolyzed by using LiOH in aq. THF to
provide 3a, 3b, 5a, and 5b in 90~95% yields.26 Thus, we demonstrated a flexible synthesis of
capuramycin analogs in which the 2’,3’-positions in ribose, 4-deoxy-4-hexenuronic acid, and amide

HETEROCYCLES, Vol. 77, No. 1, 2009
223
moieties can be selectively functionalized or be replaced with a wide range of physicochemically
interesting building blocks. It is worthwhile mentioning that
rac-(2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol (10) is one of very few protecting
groups which 1) are stable to Brønstead bases and Lewis acids, 2) can be cleaved by a volatile acid such
as TFA, and 3) are reusable. Introduction of a protecting group possessing such chemical properties in the
synthesis of capuramycin analogs enable us to synthesize desired analogs with a minimum number of
protecting group manipulations. We will 1) functionalize the 2’- and 3’-positions of Segment A (Figure 2)
with a wide range of alkyl groups, 2) introduce the other pyranuronate and furanonate in place of
D-manno-pyranuronate (Segment B), and 3) diversify the structure of molecules with a wide variety of
primary and secondary amines (Segment C). Detailed structure antimycobactericidal activity relationship
of library molecules based on capuramycin will be reported elsewhere.
ACKNOWLEDGEMENTS
We thank the National Institutes of Health and Colorado State University for generous financial support.
Mass spectra were obtained on instruments supported by the NIH Shared Instrumentation Grant
GM49631.
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b) S. Ichikawa, S. Shuto, N. Minazawa, and A. Matsuda, J. Org. Chem., 1997, 62, 1368.
21. Because 13b was isolated exclusively in the conversion of 12 to 13b it was concluded that the
C3-TBS silyl group did not migrate to the C2-position. Thus, no rapid equivilation of the silyl group
was taking place.

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22. We have not observed separation of the diastereomers caused by rac-10 throughout the syntheses of
21 and 22.
23. J. R. Harding, C. D. King, J. A. Perrie, D. Sinnott, and A. V. Stachulski, Org. Biomol. Chem., 2005,
3, 1501.
24. Trace amounts of the desired coupling product were isolated with the pivaloyl- or benzoyl-protected
imidate of D-manno-pyranuronate.
25. The TFA ester of 10 was saponified with NH3 in MeOH (for 12 h) to regenerate 10 in quantitative
yield.
26. Syntheses of 4a, 4b, 6a, and 6b (Figure1) were accomplished by skipping the elimination step (19
→ 22) in Scheme 2. Representative physical data for the molecules listed in Figure 1 were listed
1
below. 3a: [α]20 +14.2 (c 0.1 in MeOH); IR (film) 3378, 1680, 1070 cm-1; H NMR (400 MHz,
D
CDCl3) δ 7.90 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 3.2 Hz, 1H), 5.93 (d, J = 3.2 Hz, 1H), 5.72 (d, J = 8.4
Hz, 1H), 5.19 (d, J = 4.8 Hz, 1H), 4.57 (d, J = 10.2 Hz, 1H), 4.35 (t, J = 4.0 Hz, 1H), 4.20 (t, J = 4.2
Hz, 1H), 4.16-4.07 (m, 3H), 3.80 (dd, J = 4.4, 8.8 Hz, 2H), 3.25 (m, 2H), 2.00 (m, 2H), 1.84 (m, 2H),
13
1.57 (m, 1H), 1.37 (m, 1H); C NMR (100 MHz, CDCl3) δ 176.9, 166.2, 162.7, 152.2, 143.5,
142.5, 109.8, 103.3, 103.0, 88.5, 85.0, 82.0, 71.2, 768.3, 67.8, 67.5, 58.9, 53.4, 42.5, 32.5, 29.9,
29.2; HRMS (ESI) Calcd. for C22H30N4NaO11 (M+Na)+: 549.1809; found: 549.1812. 5a: [α]20
D
+12.0 (c 0.5 in MeOH); IR (film) 3390, 1681, 1463, 1087 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.87
(d, J = 8.1 Hz, 1H), 6.05 (d, J = 3.9 Hz, 1H), 5.99 (d, J = 4.8 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 5.16
(d, J = 4.5 Hz, 1H), 4.56 (d, J = 11.1 Hz, 1H), 4.33 (t, J = 5.1 Hz, 1H), 4.18 (dd, J = 2.1, 11.1 Hz,
1H), 4.12 (t, J = 3.3 Hz, 2H), 4.01 (t, J = 4.8 Hz, 1H), 3.91 (dd, J = 2.7, 11.1 Hz, 1H), 3.79 (t, J = 4.2
13
Hz, 1H), 3.48 (s, 3H), 3.26 (m, 2H), 1.97 (m, 2H), 1.82 (m, 2H), 1.52-1.34 (m, 2H); C NMR (100
MHz, CDCl3) δ 176.8, 166.3, 162.5, 152.4, 143.6, 143.0, 109.7, 103.2, 102.8, 88.4, 84.6, 84.3, 72.0,
70.4, 70.1, 67.5, 58.8, 53.5, 42.6, 32.5, 30.0, 29.2; HRMS (ESI) Calcd. for C22H30N4NaO11 (M+Na)+:
549.1809; found: 549.1815.