Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn-β-Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone

Article abstract of DOI:10.1021/jacs.9b02220

The first total synthesis of caprazamycin A (1), a representative liponucleoside antibiotic, is described. Diastereoselective aldol reactions of aldehydes 12 and 25-27, derived from uridine, with diethyl isocyanomalonate 13 and phenylcarbamate 21 were investigated using thiourea catalysts 14 or bases to synthesize syn-β-hydroxyamino acid derivatives. The 1,4-diazepanone core of 1 was constructed using a Mitsunobu reaction, and the fatty acid side chain was introduced using a stepwise sequence based on model studies. Notably, global deprotection was realized using palladium black and formic acid without hydrogenating the olefin in the uridine unit.

Full text of DOI:10.1021/jacs.9b02220

Subscriber access provided by UNIV OF LOUISIANA
Article
Total Synthesis of Caprazamycin A: Practical and
Scalable Synthesis of syn-#-Hydroxyamino Acids and
Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone
Hugh Nakamura, Chihiro Tsukano, Takuma Yoshida, Motohiro Yasui, Shinsuke
Yokouchi, Yusuke Kobayashi, Masayuki Igarashi, and Yoshiji Takemoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02220 • Publication Date (Web): 08 May 2019
Downloaded from http://pubs.acs.org on May 8, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
Journal of the American Chemical Society
1
2
3
4
5
6
7
Total Synthesis of Caprazamycin A: Practical and Scalable
Synthesis of syn--Hydroxyamino Acids and Introduction of a
Fatty Acid Side Chain to 1,4-Diazepanone
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hugh Nakamura,† Chihiro Tsukano,*,† Takuma Yoshida,† Motohiro Yasui,† Shinsuke Yokouchi,†
Yusuke Kobayashi,† Masayuki Igarashi,‡ and Yoshiji Takemoto*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
Supporting Information Placeholder
HO
R
NH2
ABSTRACT: The first total synthesis of caprazamycin A
HO
NMe
1
A ( ) Me
O
O
R
H
(1), a representative liponucleoside antibiotic, is described.
Diastereoselective aldol reactions of aldehydes 12 and 25–27,
derived from uridine, with diethyl isocyanomalonate 13 and
phenylcarbamate 21 were investigated using thiourea
catalysts 14 or bases to synthesize syn--hydroxyamino acid
derivatives. The 1,4-diazepanone core of 1 was constructed
using a Mitsunobu reaction, and the fatty acid side chain was
introduced using a stepwise sequence based on model studies.
Notably, global deprotection was realized under using
palladium black and formic acid without hydrogenating the
olefin in the uridine unit.
Me
N
O
O
B
Me
O
O
O
O
O
Me
O
N
Me
O
Me
O
C
MeO
HO2C
OMe
N
H
Me
O
Me
OMe
Caprazamycins
HO
OH
NH2
Me
Me
Me
D
E
Me
HO
HO
NMe
HO
HO
NMe
NH2
F
O
O
Me
H
H
N
O
N
O
O
N
O
Me
HO
G
O
O
Me
O
O
N
HN
HO2C
N
N
H
H
O
O
Me
Me
O
HO
OH
HO
OH
2
3
Caprazol ( )
CPZEN-45 ( )
Figure 1. Caprazamycins, caprazol, and CPZEN-45.
Introduction
HO
R
HO3SO
O
Liponucleoside antibiotics are a class of natural products
with structures comprising uridine attached to amino acids,
namely 5’-C-glycyluridine, an aminoribose, and a fatty acid
NH2
Me
A
O
R
H
Me
N
O
O
HO
O
O
O
NMe
B
C
Me
Me
O
N
O
Me
O
side
chain.
Examples
include
caprazamycins,(1)
A-90289,(4)
and
HO2C
Liposidomycins
N
H
O
Me
liposidomycins,(2)
muraymycins,(3)
HO
OH
(Total synthesis: no report)
sphaerimicins(5) (Figures 1 and 2). Several liponucleoside
antibiotics inhibit bacterial translocase MraY, which is a
peptide glycan enzyme.(6) In the biosynthetic pathway, MraY
is located upstream of the enzyme targeted by -lactam
antibiotics and glycopeptide antibiotics (such as vancomycin).
Therefore, novel antibiotics targeting MraY are expected to
have a broad antimicrobial activity spectrum, including
against multi-drug resistant bacteria such as methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant S. aureus (VRSA).
OH
R
HN
N
O
A4
B5
NH2
O
HO
NH2
Me
O
Me
HO
O
R
Me
Me
O
H
N
O
H
N
H
H
H
O
O
O
HO
HO2C
N
N
N
C2
D2
N
O
N
H
O
O
H
HO2C
Me
Me
NH
H
Muraymycins
HO
OH
O
N
NH
H
HO
NH2
HO
O
Me
O
H
N
O
Me
O
O
O
O
O
Caprazamycins were isolated from Streptomyces sp.
MK730-62F2 by Igarashi and coworkers in 2003 (Figure
1).(1) Structurally, these molecules possess a 1,4-diazepanone,
which is a seven membered ring containing two nitrogen
atoms, retaining the common motif of several liponucleoside
antibiotics. The biosynthesis of caprazamycins was proposed
through in vivo and in silico analysis of the biosynthetic gene
cluster.(7) Recently, an enzyme catalyst that promotes an
aldol-type condensation with glycine and uridine-5’-
aldehyde to construct 5’-C-glycyluridine was identified.(8)
Caprazamycins show
NMe
O
N
O
OMe
Me
O
MeO
HO2C
A-90289 A
(Total synthesis: no report)
N
H
O
Me
OMe
HO
OSO3H
Me Me Me Me Me
Me
OH
O
Me
OH
H
OH
O
N
O
N
O
O
HN
Sphaerimicin A
O
N
O
O
(Total synthesis: no report)
unknown stereochemistry
H
HO
HO3SO
OH
OH
Figure 2. Structures of representative liponucleoside antibiotics.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 18
1
2
3
4
5
6
7
8
9
HO
HO
NH2
Me
O
O
H
N
O
O
O
O
O
Me
O
O
NMe
O
N
O
Me
O
HO2C
MeO
OMe
N
H
O
Me
OMe
HO
OH
1
Caprazamycin A ( )
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph2
P
RuBr2
P
O
O
Ph2
nC12H25
nC12H25
Me
O
O
OBn
OH OBn
O
OH
Me
MeO
18
O
O
O
OH
Me
16
[Asymmetric
reduction]
Me
OMe
HO
O
Me
O
OBn
MeO
OMe
OMe
BnOH
OMe
4
O
Me
17
O
15
O
O
O
[Desymmetrization]
19
Et
Et
Et
Et
OTBS
NHMe
O
O
NHCbz
BOM
CbzO
CbzO
PPh3
TBSO
BnO2C
NHCbz
BOM
NHCbz
O
tBuO2C
O
O
N
N
O
OH
CO2tBu
O
pNs
N
O
O
BOM
N
O
O
pNsHN
O
Troc
N
TBSO
BnO2C
O
O
N
HN
O
Bulky reagent
7a
HO
BnO2C
O
O
N
O
N
HO
O
N
N
H
O
F
H
[Intramolecular
Mitsunobu reaction]
O
N
Me
[Introduction of
-hydroxy amino acid]
H
O
CbzO
Me
O
O
O
O

OCbz
8
Me Me
6a
Me Me
Protected caprazol
5
O
CF3
N3
[ -Selective
Glycosylation]

S
N
O
O
N
N
CF3
BOM
N
O
H
H
BOM
O
O
N
Et Et
9
NMe2
BOM
O
O
14a
N
Thermodynamic
control
O
O
O
N
H
O
N
HN
EtO2C
EtO2C
O
(S, S)-Thiourea catalyst
O
H
OH
H
N
pNsHN
O
H
N
O
MeO2C
O
O
[Practical synthesis
of -hydroxy amino acid]
O
O
O

EtO
OEt
13
O
O
Me Me
NCO
Me Me
Me Me
syn--hydroxy amino acid (
12
[Organocatalyzed aldol reaction]
11a
10
)
Scheme 1. Retrosynthetic analysis of caprazamycin A (1)
When we began investigating the synthesis of liponucleoside
antibiotics, the total synthesis of caprazamycins and
liposidomycins had yet to be reported, although various
synthetic studies towards liponucleoside antibiotics had been
published.(10–14) In 2008, Ichikawa, Matsuda, and coworkers
achieved the first total synthesis of caprazol (2), which is a core
structure in caprazamycins.(6e) In their synthesis, a Sharpless
aminohydroxylation and reductive amination were key
reactions for constructing the syn--hydroxyamino acid moiety
and 1,4-diazepanone core, respectively. After this landmark
report, Shibasaki, Watanabe, and coworkers reported a total
synthesis of caprazol (2) in 2013 based on a Cu-catalyzed
diastereoselective aldol reaction used to construct the syn--
hydroxyamino acid moiety.(13c) However, the introduction of a
caprazamycin-type fatty acid side chain has not been reported.
These preceding studies indicated that the synthesis of
liponucleoside antibiotics presented the following challenges:
antibacterial activity against Mycobacterium tuberculosis,
including the multi-drug resistant strain (MDR-TB), by
inhibiting MraY as mentioned above.(1) Through caprazamycin
derivatization, Takahashi and coworkers developed CPZEN-45,
which exhibits more potent antibacterial activity, particularly
against extensively drug-resistant tuberculosis (XDR-TB).(9)
As MDR-TB and XDR-TB are resistant to at least four of the
core anti-TB drugs, including isoniazid and rifampicin, they
present
a potential public health problem. Therefore,
caprazamycins and CPZEN-45 are receiving attention as seed
compounds for future effective antibiotic drugs. Owing to its
important biological activity and complex structure, we
expected a total synthesis of caprazamycins to provide not only
a synthetic sample and route for synthetic analogs, but also an
opportunity to develop new synthetic strategies.
Synthetic plan
ACS Paragon Plus Environment

Page 3 of 18
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
O
O
C
triphosgene (0.63 eq.)
activated charcoal
(i) Construction of the syn--hydroxyamino acid moiety, (ii)
formation of the 1,4-diazepanone core, and (iii) introduction of
EtO
OEt
O
N
1,4-dioxane (1.4 M)
80 to 100 °C, 59%
the fatty acid side chain. To achieve a total synthesis of
caprazamycin A (1), fatty acid side chain 4 would need to be
introduced to caprazol core 5 at the late stage because these
substructures were expected to be unstable under acidic and
basic conditions due to the presence of -acyloxyester and
acyloxy acetal moieties (Scheme 1). Benzyl (Bn),
benzyloxymethyl (BOM), and benzyloxycarbonyl (Cbz)
groups were selected as protecting groups for the caprazol core
5 that could be removed under mild conditions. The 1,4-
diazepanone motif in 5 would be constructed through a
Mitsunobu reaction(15) of alcohol 6a, itself accessed from syn-
-hydroxyamino acid derivative 10 thorough -selective
glycosylation with glycosyl fluoride 9(12e) and coupling with
secondary amine 7a. To construct the syn--hydroxyamino acid
moiety, we developed an asymmetric synthesis of trisubstituted
oxazolidinones through the thiourea-catalyzed aldol reaction of
2-isocyanatomalonate diester 13.(16,17) Extending this method,
syn--hydroxyamino acid derivative 10, which is a protected
5’-C-glycyluridine, would be synthesized from aldehyde 12
through a diastereoselective aldol reaction with 13 using
thiourea catalysts 14, followed by ring opening of the resultant
oxazolidinone 11a and decarboxylation. In this aldol reaction,
the thiourea catalyst must precisely recognize a nucleophilic
site (aldehyde) to achieve high stereoselectivity, which is
challenging owing to the presence of several functionalities,
including ether, imide, and N,O-acetal groups. The fatty acid
side chain would be synthesized by coupling rhamnose
derivative 15, β-hydroxyester 16, and carboxylic acid 17 (vide
infra). In this report, we describe in full detail the first total
synthesis of caprazamycin A, which was achieved by
overcoming the three challenges described above.(18)
O
O
13
O
2 g prepared
EtO
OEt
HCl
NH2
•
O
O
(1.5 eq.)
Cl
PhO
20
NaHCO3 (2.2 eq.)
EtO
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HN
21
OPh
H2O / Et2O = 1:2 (0.2 M)
rt, 97%
[one step], [practical],
[scalable], [bench stable]
O
30 g prepared
Scheme 2. Preparation of isocyanate 13 and phenylcarbamate 21.
Initially, the diastereoselectivity of the aldol reaction of
aldehyde 12, prepared from a known protected uridine by IBX
oxidation,(20) with diethyl isocyanomalonate 13 or
phenylcarbamate 21 was examined in the absence of thiourea
catalyst 14a (Table 1). While the aldol reaction with isocyanate
13 using 1,8-diazabicyclo(5.4.0)-7-undecene (DBU) as base
(10 mol%) afforded oxazolidinones 11a and 11b in 42% yield,
no selectivity was observed (entry 1). Using Et3N or K2CO3 as
base did not improve the selectivity (entries 2 and 3). Under
these conditions, a small amount of byproduct 22 was obtained
through the reaction of products 11a and 11b with diethyl
isocyanomalonate
13.
Therefore,
less-reactive
phenylcarbamate 21 was employed as a nucleophile. Treatment
of aldehyde 12 with phenylcarbamate 21 (1.0 equiv.) and DBU
(1.0 equiv.) in THF at room temperature gave a 1:2.2 mixture
of desired oxazolidinone 11a and undesired isomer 11b in 59%
yield through phenylcarbamate addition and PhOH elimination
(entry 4).
To control the selectivity through chelation, several additives
were tested.(11v,21,22) Adding ZnCl2 did not affect the selectivity
(entry 5). The aldol reaction with LiBr (1.0 equiv.) resulted in
a 56% yield with a 1:1.5 dr (entry 6). In this reaction, a small
amount of 23 was obtained from elimination of the uracil
moiety. To reverse this diastereoselectivity, we applied the
same conditions using (S,S)-thiourea catalyst 14a, which was
developed for the asymmetric aldol reaction of aldehydes.(16)
The reaction of 12 with diethyl isocyanomalonate 13 in the
presence of 14a (10 mol%) proceeded smoothly, affording
desired oxazolidinone 11a as the major product (64%, 3.1:1 dr,
entry 7). It was significant that the selectivity of this aldol
reaction could be reversed using an organocatalyst. Both the
yield and diastereoselectivity were improved (77%, 6.5:1 dr)
using (S,S)-thiourea catalyst 14b (10 mol%) bearing a bulky
tertiary amine moiety (entry 8). The amount of catalyst 14b
could be reduced to 7 mol%, although this slightly decreased
the diastereoselectivity. Interestingly, the formation of
byproduct 22 was suppressed by reducing the amount of
catalyst 14b. When the amount of catalyst was reduced to 5
mol%, the reaction proceeded slowly to give oxazolidines 11a
and 11b in 68% yield, but with 4.2:1 dr, and a small amount of
starting
Results and discussion
1. Diastereoselective synthesis of syn--hydroxyamino acid
moiety
To investigate the diastereoselective aldol reaction, diethyl
isocyanomalonate 13 was prepared from diethylaminomalonate
hydrochloride 20 using triphosgene following a literature
procedure (Scheme 2).(19) As diethyl isocyanomalonate 13
readily polymerizes in the presence of trace amounts of water,
it was used immediately after preparation. When water was
removed by Kugelrohr distillation, the distilled diethyl
isocyanomalonate 13 could be stored for several weeks. Phenyl
carbamate 21, which is much more stable than 13, was also
prepared in 97% yield by treating 20 with phenyl chloroformate
and sodium bicarbonate under Schotten–Baumann conditions.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 18
1
2
3
4
Table 1. Diastereoselective aldol reaction of aldehyde 12 with thiourea catalysts 14.
5
6
7
8
CF3
O
O
BOM
BOM
BOM
S
Simple
base
O
O
O
O
O
O
N
N
N
or
CF3
O
N
N
HN
EtO2C
EtO2C
O
HN
EtO2C
EtO2C
O
H
O
H
O
H
O
N
N
N
H
H
O
O
O
R2N
9
H
14a
R = Me: (S, S)-
R = nC5H11: (S, S)-
14b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
Me Me
Me Me
11a
Me Me
EtO
OEt
11b
12
(desired)
(undesired)
R'
13 21
or
(1.0 equiv.)
[Organocatalyzed aldol reaction]
11a 11b
entry nucleophile (R')
cat. 14a or 14b or base
solvent
results (
:
)
byproduct
O
BOM
EtO2C
EtO2C
O
O
O
N
22
22
22
1
2
3
13 (R' =NCO)
13 (R' =NCO)
PhMe
PhMe
PhMe
42% (dr = 1:1)
50% (dr = 1:1.8)
60% (dr = 1.3:1)
: 27%
: 10%
: 13%
DBU (10 mol%)
Et3N (10 mol%)
K2CO3 (10 mol%)
O
N
H
N
H
N
O
13
(R' =NCO)
EtO2C
CO2Et
4
5
6
21 (R' = NHCO2Ph)
21 (R' = NHCO2Ph)
21 (R' = NHCO2Ph)
THF
THF
THF
59% (dr = 1: 2.2)
31% (dr = 1:2.1)
56% (dr = 1:1.5)


DBU (100 mol%)
O
O
DBU (100 mol%), ZnCl2
DBU (100 mol%), LiBr
Me Me
23
: 3.8%
22
byproduct
22
7
8
13 (R' =NCO)
13 (R' =NCO)
13 (R' =NCO)
13 (R' =NCO)
14a
14b
14b
14b
PhMe
PhMe
PhMe
PhMe
64% (dr = 3.1:1)
77% (dr = 6.5:1)
81% (dr = 5.0:1)
68% (dr = 4.2:1)
: 7%
: 9%
: 0%
(S,S)-
(S,S)-
(S,S)-
(S,S)-
(10 mol%)
(10 mol%)
(7 mol%)
(5 mol%)
BOM
O
O
N
22
22
9
HN
byproduct
10
a)
23
22:
11
13 (R' =NCO)
14b
PhMe
80% (dr > 1:20)
9.5%
(R,R)-
(10 mol%)
12
a) 15% of starting material
was recovered.
material 12 was recovered (entry 10). Interestingly, the aldol
reaction using (R,R)-thiourea catalyst 14b (10 mol%) gave
undesired isomer 11b in 80% yield in
diastereoselective manner (>1:20 dr) (entry 11). These results
indicated that the aldol reaction of aldehyde 12 with (R,R)-
thiourea catalyst 14b was a matched pair that afforded
undesired isomer 11b.
To explain this diastereoselectivity, a computational model
study of this thiourea-catalyzed aldol reaction using
benzaldehyde was conducted based on a DFT calculation
through hydrogen bonding. The protonated tertiary amine
moiety of thiourea catalyst 14 interacts with the carbonyl group
of aldehyde 12 through hydrogen bonding to afford transition
state D rather than transition state E. Subsequent cyclization of
the resultant alcohol with isocyanate gave desired
oxazolidinone 11a as the main product.
a
highly
We also investigated the aldol reaction of the related
aldehydes 25–27,(24–26) in which two hydroxyl groups were
protected as benzyloxymethyl (BOM), triisopropylsilyl (TIPS),
and t-butyldimethylsilyl (TBS) ethers instead of isopropylidene
acetal (Table 2). When aldehyde 25 was treated with
isocyanomalonate 13 and (S,S)-thiourea 14a in toluene at 0 °C
to room temperature, the reaction proceeded to give desired
product 28a in 55% yield with >9:1 dr (entry 1). In contrast,
when (R,R)-thiourea catalyst 14b was used in an attempt to
reverse the diastereoselectivity, diastereomer 28b was obtained
as a minor product (2:1 dr, entry 2). As such diastereoselectivity
was not obtained using aldehyde 12 bearing an isopropylidene
acetal, it was assumed that this selectivity was derived from the
bulkiness of the hydroxy protecting groups and/or the
conformation of aldehyde 25.(27) Therefore, the reaction was
also performed without chiral thiourea catalyst. When
potassium carbonate was used as a basic catalyst, the reaction
proceeded with high diastereoselectivity (entry 3).
(Scheme
3a,
B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)
level).(23) The calculation suggested that transition state A was
more favorable than transition state B, in which there was steric
repulsion between the phenyl and isocyanate groups. Transition
state C, which is another possible transition state towards
undesired isomer 24b, was not more favorable than B, because
C would be destabilized by steric repulsion between the tertiary
amine and uracil moieties. Consequently, isocyanomalonate 13
would approach from the Si face of benzaldehyde to give S-
isomer 24a. Indeed, this reaction gave S-isomer 24a in 87%
yield with 88% ee.(16) Considering these results, the
stereoselectivity of the reaction of aldehyde 12 with 13 using
thiourea catalyst 14 was rationalized using the following
reaction mechanism (Scheme 3b). Initially, thiourea catalyst 14
recognizes the two carbonyl groups of isocyanomalonate 13
ACS Paragon Plus Environment

Page 5 of 18
Journal of the American Chemical Society
1
2
3
4
CF3
5
(a)
6
7
8
9
S
Me
O
O
F3C
N
H
N
H
N+
H
Me
HN
EtO2C
EtO2C
O
(S)
H
O
O
O
Ph
10
benzaldehyde
CF3
H
EtO
OEt
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24a
88% ee
S-isomer
N
S
C
from Si face
O
A
transition state
F3C
N
N
H
H
(favored, G‡ = 0 kcal/mol)
NMe2
CF3
CF3
cat. (10 mol%)
14a
S
O
O
S
Me
Me
N
O
EtO
OEt
F3C
N
H
N
H
F3C
N
H
N+
NCO
N
H
HN
EtO2C
EtO2C
O
(R)
Me
H
H
13
Me
O
O
O
O
O
H
Ph
[Enantioselective
aldol reaction]
O
H
EtO
OEt
steric
EtO
OEt
24b
R-isomer
N
N
C
C
from Re face
repulsion
O
O
C
transition state
B
transition state
steric repulsion
(unfavored, G‡ = +4.42 kcal/mol)
(unfavored, G‡ = +1.95 kcal/mol)
(b)
CF3
S
O
O
BOM
BOM
BOM
N
N
CF3
O
O
O
O
O
O
N
N
N
H
H
NR2
cat. (10 mol%)
O
O
O
HN
EtO2C
EtO2C
HN
H
H
O
H
O
N
14a 14b
or
N
N
O
O
O
EtO2C
EtO2C
(R = Me or nC5H11
)
H
O
O
O
O
O
O
EtO
OEt
13
11a
desired (major)
11b
Me Me
undesired (minor)
Me Me
Me Me
NCO
12
[Diastereoselective aldol reaction]
14a (R = Me)
64% (dr = 3.1:1)
14b (R = nC5H11) 77% (dr = 6.5:1)
F3C
CF3
S
R
S
N
H
N
H
CF3
R
R
N+
N
H
N
H
CF3
H
R
N+
BOM
N
O
O
O
H
H
OEt
H
O
O
O
O
O
N
EtO
O
O
OEt
N
Me
Me
EtO
H
C
O
H
O
O
N
Si-face
attack
Re-face
attack
O
N
C
O
O
O
BOMN
Me Me
O
D
E
(a) transition state
(favored)
(b) transition state
(unfavored)
Scheme 3. (a) Computational study of thiourea-catalyzed aldol reaction using benzaldehyde and catalyst 14a, based on B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)
(in a vacuum) using Gaussian 09; (b) rationalization of diastereoselectivity of thiourea-catalyzed aldol reaction of aldehyde 12
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 18
1
2
3
4
Table 2. Diastereoselective aldol reaction of aldehydes 25–27 with diethyl isocyanomalonate 13 and phenylcarbonate 21.
5
6
CF3
7
8
9
S
Simple
or
CF3
base
O
O
BOM
BOM
BOM
N
H
N
H
O
O
O
O
N
N
O
O
N
R2N
O
O
HN
EtO2C
EtO2C
HN
EtO2C
EtO2C
O
14a
14b
(S,S)-
(R = Me)
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
H
N
O
O
O
(R = nC5H11
)
H
O
O
RO
OR
RO
OR
R'O
OR'
13
21
(R = NCO) or
(R = NHCO2Ph)
28a
29a
30a
28b
29b
30b
(R = BOM)
(R = TIPS)
(R = TBS)
(R = BOM)
(R = TIPS)
(R = TBS)
EtO
OEt
25
26
27
(R' = BOM)
(R' = TIPS)
(R' = TBS)
[practical]
[scalable]
[inexpensive]
(1.0 equiv.)
R''
PhMe, temperature
(desired)
17.9 g prepared in one batch
(undesired)
[Diastereoselective aldol reaction]
nucleophile (R'')
a b
results ( : )
entry
aldehyde (R')
cat. 14a or 14b or base
temperature
25
25
25
13
13
13
(R'' = NCO)
(R'' = NCO)
(R'' = NCO)
14a
14b
28
28
28
1
2
3
(R' = BOM)
(R' = BOM)
(R' = BOM)
(S,S)-
(60 mol%)
(60 mol%)
0 °C to rt
0 °C to rt
0 °C to rt
: 55% (dr = 9:1)
: 46% (dr = 2:1)
: 68% (dr = 9:1)
(R,R)-
K2CO3 (60 mol%)
26
26
26
13
13
13
(R'' = NCO)
(R'' = NCO)
(R'' = NCO)
29
29
29
4
5
6
(R' = TIPS)
(R' = TIPS)
(R' = TIPS)
K2CO3 (10 mol%)
Et3N (10 mol%)
DIPEA (10 mol%)
0 °C
0 °C
0 °C
: 60% (dr = 4.6:1)
: 53% (dr = 7:1)
: 71% (dr = 13:1)
26
27
21
21
(R' = TIPS)
(R' = TBS)
(R'' = NHCO2Ph)
(R'' = NHCO2Ph)
K2CO3 (100 mol%)
K2CO3 (100 mol%)
29
7
8
0 °C to rt
0 °C
: 62% (dr = 13:1)
30
: 84% (dr > 20:1)
(17.9 g scale)
O
O
BOM
Me
H
O
O
N
O
C
O
BOM
O
N
OH
N
N
Me
O
O
O
O
EtO2C
EtO2C
N
(S)
H
O
N
O
Me
BOM
C
O
O
N
H
TBSO
OTBS
Si
O
O
tBu
31a
(desired)
H
N
O
Me
O
H
Si
Me
Me
F
transition state
tBu
from Si face
G‡ = 0 kcal/mol
TBSO
OTBS
O
30a
(favored)
27
O
O
MeO
OMe
O
C
N
BOM
NCO
13
O
O
BOM
N
N
Me
OH
H
O
O
N
O
N
O
EtO2C
EtO2C
O
(R)
H
O
Me
O
C
H
O
N
Si
TBSO
OTBS
O
tBu
O
O
Me
31b
(undesired)
Me
Me Si
Me
tBu
G
transition state
from Re face
30b
G‡ = +2.10 kcal/mol
(unfavored)
Scheme 4. Computational study of diastereoselective aldol reaction of aldehyde 27 with isocyanate 13, based on B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) (in a
vacuum) using Gaussian 09.
ACS Paragon Plus Environment

Page 7 of 18
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
The reaction of aldehyde 26, bearing TIPS groups, with
After introducing a p-nitrobenzenesulfonyl (pNs) group, the
oxazolidinone ring was opened by treatment with NaOMe to
afford syn--hydroxyamino acid derivatives 10, 38, and 39 in
good yields. Protected compounds 10, 38 and 39 are useful
intermediates for the synthesis of liponucleoside antibiotics.
Indeed, we achieved the total synthesis of CPZEN-45 (3) from
intermediate 39 in 2016.(14a)
isocyanomalonate 13 gave desired oxazolidinone 29a as the
major product with 4.6:1 dr. The selectivity was improved by
using a tertiary amine, with diisopropylethylamine (DIPEA)
proving particularly effective (entries 5 and 6). Furthermore,
we attempted reacting 26 with phenylcarbamate 21, which was
easier to handle than isocyanomalonate 13. Although 1 equiv.
of potassium carbonate was required, this reaction proceeded
smoothly to give desired oxazolidinone 29a in 62% yield with
13:1 dr (entry 7). These conditions using 21 could be applied to
a large-scale synthesis from aldehyde 27 bearing a TBS group
(17-g scale), which could be readily prepared from uridine. The
desired oxazolidinone 30a was obtained in 84% yield with
excellent selectivity (entry 8). To explain this
diastereoselectivity, we estimated an activation energy for the
reaction of aldehyde 27 with isocyanate 13 using DFT
calculation at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)
level (Scheme 4). (23) The results indicated that the activation
energy for transition state F, which affords desired adduct 31a,
was 2.10 kcal/mol lower than that of transition state G, which
affords undesired adduct 31b. In transition state G, there is
steric repulsion between an ester group in 13 and a silyl group
in 27, which would make transition state F preferable.
Resulting adducts 31a and 31b would immediately cyclize to
give oxazolidinones 30a and 30b, respectively. Therefore,
desired oxazolidinone 30a would be the major product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2. Introduction of a fatty acid side chain using model 1,4-
diazepanone
Although Shibasaki, Watanabe, and coworkers had reported
a synthesis of the fatty acid side chain of caprazamycin B,(13d)
the introduction of fatty acid side chain 4 onto a diazepanone
ring had not been reported before we began this synthetic study.
Presumably, this was due to the fatty acid side chain containing
an unstable -acyloxycarboxylic acid structure, meaning that -
elimination and acyl group rearrangement might occur under
basic conditions (Figure 3).
NH2
[ -Elimination]

HO
HO
Me
O
O
H
N
O
O
O
O
O
Me
O
O
NMe
O
N
O
Me
O
HO2C
MeO
OMe
N
Obtained aldol adducts 11a, 28a, and 30a were converted
into syn--hydroxyamino acid derivatives 10, 38, and 39
(Scheme 5). Selective monohydrolysis of 11a, 28a, and 30a
followed by decarboxylation gave thermodynamically stable
trans-oxazolidinones 32–34, respectively. Transesterification
of 32–34 using a tetranuclear zinc cluster(28) to afford methyl
esters 35–37 was essential for concise oxazolidinone ring-
opening.
H
O
Me
OMe
[Epimerization]
[Retro-aldol reaction]
HO
OH
1
Caprazamycin A ( )
Figure 3. Predictable side-reactions when introducing the fatty-acid side chain
of caprazamycin A (1)
Furthermore, several side reactions on the diazepanone ring,
such as epimerization, -elimination, and retro-aldol reactions,
were expected. Therefore, we initially planned to establish a
synthetic route toward model substrate 40 by introducing fatty
acid side chain 4 onto diazepanone 41 (Scheme 6).
O
BOM
N
O
BOM
O
O
O
O
N
O
1. KOH or
LiOH
aq. THF
HN
EtO2C
O
HN
EtO2C
EtO2C
N
N
O
O
MeOH, 50 °C
H
H
Simple diazepanone 41 would be synthesized by coupling
anti--hydroxy amino acid derivative 7b with carboxylic acid
43, derived from serine,(29) followed by an intramolecular
Mitsunobu reaction. To prevent undesired side reactions of the
-hydroxy amino acid moiety under Mitsunobu conditions,
determining appropriate reaction conditions and protecting
groups was important. Fatty acid side chain 4 would be
synthesized by coupling known rhamnose derivative 15(30) with
carboxylic acid 17, followed by condensation with -hydroxy
ester 16 (Scheme 1). Intermediates 16 and 17 would be
prepared by the Noyori asymmetric reduction of keto ester 18
and the desymmetrization of 3-methyl glutaric anhydride 19,
respectively.(31,32)
Zn4(OCOCF3)6O
2. DBU
THF
70 °C
RO
OR
RO
OR
[Single diastereomer]
11a 28a 30a
,
,
32
33
34
(R = CMe2): 86% (2 stpes)
(R = BOM): 64% (2 stpes)
(R = TBS): 71% (2 stpes)
BOM
N
O
BOM
O
O
O
O
N
1. pNsCl
OH
pNsHN
O
N
HN
MeO2C
NaH, DMF
O
N
O
MeO2C
H
2. NaOMe
MeOH
H
RO
OR
RO
OR
10
38
39
(R = CMe2): 65% (2 steps)
(R = BOM): 77% (2 steps)
(R = TBS): 57% (2 steps)
35
36
37
(R = CMe2): quant.
(R = BOM): 91%
(R = TBS): quant.
[syn- -hydroxy- -amino acid derivatives]


Scheme 5. Synthesis of syn--hydroxyamino acid derivatives 10, 38, and 39.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 18
1
2
3
4
5
6
7
8
9
side chain, compounds 41a and 41b were prepared by
introducing methyl and 2,2,2-trichloroethoxycarbonyl (Troc)
groups, respectively. In the synthesis of 41a, an ,-
unsaturated ester 50 was obtained as byproduct owing to the
basic workup after treatment with aqueous hydrogen fluoride
(HF). Consequently, the isolated yield of 41a was low.
Me
O
O
O
O
Me
O
NMe
O
OBn
O
Me
O
EtO2C
MeO
OMe
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
BH3·SMe2
NaBH4
OH
OH
OMe
40
OH
CO2Et
CO2Et
HO
CO2Et
EtO2C
EtO2C
[Introduction of the
unstable side chain]
THF
(ref. 32b)
4 steps
(ref. 32a)
OH
N3
N3
44
(known)
45
(known)
L-(+)-diethyltartarate
Me
O
HO
NR
OBn
1. TBSCl, Imid.
2. H2, Pd/C
3. pNsCl, DIPEA
24% (4 steps)
1. TBSOTf
2,6-lut., 81%
(for R = Et)
2. MeI, K2CO3
3. PhSH, K2CO3
82% (2 steps)
O
O
O
O
Me
MeO
OH
EtO2C
N
pNsHN
O
Me
OH
O
Me
O
41
OMe
OMe
43
BnO
4
OTBS
CO2R
OH
[Mitsunobu
reaction]
pyridine, DCM
TBSO
TBSO
CO2Et
Me
NHMe
or (for R = Bn)
NHpNs
Cl
NMe2
57%
OTBS
NHMe
OH
pNs
pNs
2. Zn4(OCOCF3)6O (cat.)
PhMe/BnOH, heat, 64%
3. MeI, K2CO3
7b
7a
(R = Et)
(R = Bn)
Me
46
HN
HO
OBn
TBSO
EtO2C
TBSO
EtO2C
HN
OBn
4. PhSH, K2CO3 60% (2 steps)
N
O
43
[Amidation]
O
Me
42
(R' = TBS, PMB)
7b
PPh3
DEAD
PhMe
pNs
OBn
OR
Hb
pNs
OBn
PhSH
K2CO3
TBSO
EtO2C
N
TBSO
EtO2C
HN
TBSO
EtO2C
NH
O
OBn
84%
Scheme 6. Planned synthetic route for model diazepanone 41 bearing a fatty
acid side chain.
N
a Me
DMF
90%
N
O
N
H
O
Me
[Mitsunobu
reaction]
Me
(JHa,Hb = 3.3 Hz)
49
CSA
MeOH
68%
48
47
42
(R = TBS)
The synthesis started with known diol 45, prepared from L-
(+)-diethyltartrate in a five-step transformation (Scheme 7).(33)
Selective silylation of the primary alcohol followed by azide
reduction gave an amine that was then protected as the
corresponding pNs-amide. Resultant alcohol 46 was converted
to anti--hydroxyamino acid derivative 7b through silylation of
the secondary alcohol, introduction of a methyl group, and
removal of the pNs group. Compound 7b was coupled with
carboxylic acid 43, derived from L-serine,(14c,29) using Ghosez’s
reagent(34) to afford compound 47 in 57% yield. After selective
removal of the TBS group by treatment with 10-
camphorsulfonic acid (CSA) in MeOH–CH2Cl2 (2:3), the
Mitsunobu reaction(15) of obtained alcohol 42 using diethyl
azodicarboxylate (DEAD) and PPh3 proceeded smoothly to
give 1,4-diazepanone 48 in 92% yield.
Previous studies reported that both the hydroxy group and
ester on the 1,4-diazepanone ring were oriented in pseudo-axial
positions.(11u,v,y) In contrast, our DFT calculation suggested that
the siloxy group and ester on 1,4-diazepanone 48 were oriented
in pseudo-equatorial and pseudo-axial positions, respectively
(Figure 4, conformation X). Conformation X was more stable
than conformation Y, in which both substituents were oriented
in pseudo-axial positions, presumably owing to the presence of
a bulky substituent (pNs group) on the nitrogen atom. The
coupling constant of 3.3 Hz observed between Ha and Hb did
not contradict predicted conformation X. Compound 48 was
converted to secondary amine 49 in 90% yield by treatment
with PhSH and K2CO3. As a model study for introducing the
(R = H)
(for R = Me)
1. (CH2O)n
NaBH(OAc)3
AcOH, 93%
2. 48% aq. HF
CH3CN, rt, 66%
HO
NR
OBn
NMe
O
OBn
EtO2C
EtO2C
N
N
Me
O
Me
or (for R = Troc)
1. TrocCl, pyridine
2. 48% aq. HF
50
41a
41b
(R = Me)
(R = Troc)
14% (undesired)
99% (2 steps)
Scheme 7. Synthesis of 1,4-diazepane 41 using a Mitsunobu reaction.
pNs
Hb
TBSO
EtO2C
N
OBn
N
O
H
a Me
48
(JHa,Hb = 3.3 Hz)
X
Y
G = 2.55 kcal/mol
G = 0 kcal/mol
Figure 4. Possible conformations X and Y of compound 48, calculated using
Gaussian ‘09 at the B3LYP/6-31G(d) level of theory (DFT).
ACS Paragon Plus Environment

Page 9 of 18
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Next, the synthesis of a fatty acid side chain 4 started with
dimethoxybenzyl (DMB)-protected -hydroxy carboxylic acid
55a was attempted.(37) However, reactions using EDCI, DCC,
or PyBOP did not afford desired coupling product 56, with
aldehyde 57 observed as a byproduct produced by a retro-aldol
reaction. In contrast, the reaction of Troc-protected 1,4-
diazepanone 41b with DMB-protected -hydroxy carboxylic
acid 55a using EDCI proceeded smoothly, giving desired
coupling product 58a in excellent yield. For subsequent
transformations, including protecting group removal,
triethylsilyl (TES)-protected -hydroxy carboxylic acid 55b
was employed in this condensation reaction, affording desired
ester 58b in 62% yield. These results indicated that compound
41b was more reactive than 41a in this transformation, despite
having the same conformation. Our DFT calculations suggested
that the enhanced reactivity of 41b might be due to the presence
of a hydrogen bond between the hydroxy and Troc groups
(Figure 5).
the desymmetrization of 3-methyl glutaric acid anhydride 19
using a cinchona alkaloid catalyst developed by Song and
coworkers (Scheme 8).(32) The resulting carboxylic acid 17
(92% ee) was coupled with L-rhamnose derivative 15(30)
through acid chloride formation to give ester 51. After
separating a small amount of the undesired diastereomers, a
benzyl group was removed by hydrogenolysis in the presence
of Pd/C to afford carboxylic acid 52. -Hydroxybenzyl ester 16
was synthesized by Noyori asymmetric reduction(31) of known
-ketoester 18,(35) which was prepared from myristoyl chloride
53. Ester 16 was condensed with carboxylic acid 52 under
Yamaguchi conditions.(13d) Protected fatty acid side chain 54
was successfully converted into the fatty acid fragment of
caprazamycin A (4), which had the same stereochemistry as the
natural product, in the presence of Pd/C under a hydrogen
atmosphere.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ester 58b was treated with zinc and AcOH to reductively
remove the Troc group (Scheme 9). The resultant secondary
amine was subjected to reductive amination followed by
removal of the TES group to furnish N-methylated compound
59 in 66% yield. The glutaric monoester unit 52 was then
successfully introduced to secondary alcohol 59 under
Yamaguchi conditions. This stepwise method for introducing
the fatty acid side chain was robust owing to no decomposition
of the unstable structure and no epimerization. Therefore, this
route would be applicable to introducing the fatty acid side
chains of not only caprazamycins, but related liponucleoside
antibiotics such as liposidomycins and sphaerimicins.
Me
NMe2
Me
Me
Cl
BnOH
OMe
HO
OBn
Me
O
O
O
O
O
then nBuLi
Me
86%, 92% ee
O
OH
19
N
17
CF3
N
NH
S
MeO
OMe
(10 mol%)
OMe
15
O
CF3
O
48%
( = 4:1)
[Desymmetrization]
Me
O
O
OR
51
52
(R = Bn)
(R = H)
H2, Pd/C
92%
O
O
Me
O
MeO
nC12H25
OMe
Cl
OMe
53
3. Total synthesis of caprazol (2) and caprazamycin A (1)
With an established route for introducing the fatty acid side
chain in hand, we next focused on constructing a 1,4-diazepanone
core bearing amino-ribose and uridine moieties and introducing
the side chain to achieve a total synthesis of caprazamycin A.
Glycosylation of syn--hydroxyamino acid derivatives 10 with
compound 9 proceeded in a β-selective manner under the
conditions reported by Matsuda and Ichikawa (Scheme 10).(12)
Reduction of the azide in coupling product 60, followed by
protection of the resulting amine with a Cbz group and methyl
ester hydrolysis afforded carboxylic acid 8. Carboxylic acid 8
was coupled with anti--hydroxyl acid derivative 7a, in which
the secondary alcohol was protected as a TBS ether, using
Ghosez’s reagent(34) via acid chloride formation. Selective TBS
group removal from the primary alcohol of 61a gave
cyclization precursor 6a. To investigate the Mitsunobu
cyclization, compound 6b was also synthesized from
carboxylic acid 8 and anti--hydroxyl acid derivative 7b using
a similar sequence. No -elimination or epimerization were
observed in these transformations.
LDA, THF
BnOAc
H2
OH
(S)-BINAP-RuBr2
(1.6 mol%)
O
O
O
nC12H25
OBn
nC12H25
16
OBn
48%, 94%ee
(2 steps)
2,4,6-trichlorobenzoyl
chloride, DMAP
18
61%
Me
O
Pd black
EtOH-HCO2H
96%
54
(R' = Bn)
Me
O
O
O
OR'
4
(R' = H)
O
Me
O
MeO
OMe
[Fatty acid]
OMe
Scheme 8. Synthesis of fatty acid side chain 4.
With fatty acid side chain 4 and model 1,4-diazepanones 41a
and 41b in hand, our attention turned to introducing the fatty
acid side chain onto the 1,4-diazepanone core. Initially, the
direct coupling of 4 onto model 1,4-diazepanone 41a was
investigated (Scheme 9). When using EDCI, DCC, or PyBOP,
the reaction gave a complex mixture.(36) To avoid undesired -
elimination of the -alkoxyester unit, condensation with 2,4-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 18
1
2
3
4
5
Model study (1)
Me
O
6
7
8
9
Me
O
O
HO
NMe
O
OBn
O
O
O
O
O
O
O
OH
Me
Me
NMe
O
OBn
OBn
EtO2C
N
decomp.
O
Me
O
O
Me
O
Me
MeO
MeO
OMe
N
OMe
OMe
EtO2C
Me
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EDCI
DCC
PyBOP
4
41a
40
Me
Me
O
HO
NMe
DMBO
O
OBn
NMe
O
O
NMe
OBn
DMBO
OH
EtO2C
N
decomp.
N
EtO2C
EtO
(DMB = 2,4-dimethoxybenzyl)
O
Me
Me
N
57
O
Me
55a
41a
O
56
[Retro-aldol product]
Model study (2)
Troc
O
Me
O
Troc
HO
N
Me
O
OBn
EDCI, DMAP
RO
O
N
OBn
58a
R = DMB (
R = TES (
)
RO
OH
EtO2C
N
58b
)
R = DMB, quant.
R = TES, 62%
55a
R = DMB (
)
Me
N
EtO2C
55b
R = TES (
)
O
Me
41b
[Troc group promoted
esterification]
1. Zn, AcOH
2. (CH2O)n, AcOH
NaBH(OAc)3
(R = TES)
O
O
OH
Me
Me
O
3. HF·Py, THF
O
Me
52
O
MeO
OMe
OMe
Me
O
O
O
O
O
Me
NMe
OBn
HO
O
O
Me
40
O
NMe
O
OBn
MeO
OMe
N
EtO2C
2,4,6-trichlorobenzoyl
chloride, DMAP, Et3N
O
Me
OMe
N
EtO2C
59
[Western part of caprazamicins]
Me
66% ( 4 steps)
Scheme 9. Introduction of fatty acid onto diazepanone 41.
reduction of DEAD or DIAD. These results indicated that the
intermolecular SN2 reaction of intermediate 64 was preferred
over the desired intramolecular SN2 reaction. To suppress this
side reaction, we employed sterically bulkier substrate 6a
bearing a TBS group adjacent to the primary alcohol. As
expected, the reaction with DIAD afforded cyclized product 62
in 70% yield. Furthermore, using di-tert-butyl azodicarboxylate
(DBAD), which is bulkier than DIAD, improved the yield to
75%. By increasing the bulkiness of both the substrate and
reagent, the undesired intermolecular SN2 reaction was
suppressed to afford the 1,4-diazepanone product.
Before introducing the fatty acid side chain, cyclized product
62 was converted into protected caprazol 5 to facilitate the final
global deprotection (Scheme 10). After removing the pNs
group, a Troc group was introduced to afford compound 65 in
58% yield over two steps. Two acetal groups were carefully
hydrolysed under acidic conditions and the obtained tetraol was
converted to a Cbz carbonate, followed by treatment under
acidic conditions to remove the TBS group. To confirm the
stereochemistry of protected caprazol 5, it was converted to
caprazol (2). Troc group removal followed by reductive
amination gave a tertiary amine, followed by treatment with Pd
black in the presence of formic acid to give caprazol (2), which
had spectra data identical to those reported previously.(12d,e,13c)
HO
NR
O
OBn
EtO2C
N
Me
Hydrogen bond
(OH and Troc)
41a
41b
(R = Me)
(R = Troc)
41a
41b
(R = Troc)
(R = Me)
Figure 5. Conformations of compounds 41a and 41b calculated by Gaussian
‘09 at the B3LYP/6-31G(d) level of theory (DFT).
Next, we focused on construction the 1,4-diazepanone
skeleton using
a
Mitsunobu reaction. Initially, the
intramolecular Mitsunobu reaction of compound 6b, bearing a
secondary alcohol protected as a p-methoxybenzyl (PMB)
ether, was attempted. Although the cyclization of simple model
compound 42 proceeded smoothly (Scheme 7), the reaction of
6b did not give desired cyclization product, even when diethyl
azodicarboxylate (DEAD) or diisopropyl azodicarboxylate
(DIAD) were employed in the presence of PPh3. Mass
spectrometry analysis indicated that byproduct 63 was
generated in this reaction through an intermolecular SN2
reaction with hydrazine-1,2-dicarboxylate produced by the
ACS Paragon Plus Environment

Page 11 of 18
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
H
O
Et
Et
Et
Et
O
O
O
F
N3
NHCbz
BOM
RO
N3
BOM
OTBS
NHMe
O
O
O
O
N
O
O
BOM
1. PPh3
then CbzCl
2. Ba(OH)2
OH
NsHN
p
O
BnO2C
N
O
O
N
O
O
N
NsHN
O
O
p
NsHN
p
O
aq. NaHCO3, DCM
9
Et Et
MeO2C
O
N
O
N
H
O
MeO2C
HO2C
9
Me
H
H
O
7a
7b
BF3·Et2O, 71%
(R = TBS)
(R = PMB)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
O
O
O
O
[ -Selective Glycosylation]

Me
[gram scale]
Me Me
10
[gram scale]
NMe2 [gram scale]
60
Me Me
8
Me Me
Et
Et
Et
Et
Et
Et
O
O
O
NHCbz
NHCbz
CSA
MeOH/DCM
68%
NHCbz
BOM
O
O
O
O
O
O
OH
OH
OTBS
BOM
BOM
pNs
pNs
pNs
N
O
N
O
N
O
PMB
vs.
TBS
O
O
O
PMBO
BnO2C
TBSO
BnO2C
RO
BnO2C
O
O
O
(R = TBS)
HN
HN
HN
O
O
O
N
N
N
or
N
N
N
H
H
H
O
O
O
Me
Me
Me
3HF·Et3N
77%
(R = PMB)
1.45 g
prepared
[Intramolecular
O
O
O
O
O
O
Mitsunobu reaction]
Me Me
Me Me
Me Me
6b
6a
[gram scale]
61a
61b
(R = TBS): 46% (3 steps)
(R = PMB): 25% (3 steps)
N
CO2R
N
CO2iPr
(DIAD)
RO2C
N
iPrO2C
tBuO2C
N
N
PPh3
PhMe, 0 °C
PPh3
PhMe, 0 °C
70%
or
N
DEAD (R = Et)
or DIAD (R = iPr)
CO2tBu
(DBAD)
75%
Et
Et
Et
O
O
Et
RO2C
Substrate and
Reagent
Et
Et
NH
N
NHCbz
BOM
NHCbz
O
1. K2CO3
PhSH
73%
O
O
O
O
controlled
RO2C
NHCbz
O
BOM
N
O
pNs
N
Ph3P
Troc
N
N
O
O
O
O
O
O
TBSO
O
TBSO
O
O
BOM
pNs
N
N
O
O
O
N
O
N
PMBO
BnO2C
O
2. TrocCl
DMAP
79%
BnO2C
BnO2C
N
N
O
H
N
H
O
Me
O
Me
N
O
O
H
O
Me
62
O
O
Sterically less
hindered
Me Me
Me Me
65
(desired)
CbzO
CbzO
Me Me
64
NHCbz
1. pTsOH, MeOH, 50 °C, 41%
O
BOM
2. CbzCl, DMAP
[No desired product]
 Ph3P=O
Troc
N
O
O
HO
O
N
O
N
3. pTsOH, MeOH, 60 °C
BnO2C
Et
71% (2 steps)
N
H
O
O
Me
Et
CbzO OCbz
NHCbz
BOM
O
RO2CHN
PMBO
HO
O
5
Protected caprazol ( )
NCO2R
NH2
pNs
N
O
O
O
HO
O
O
HN
1. Zn, AcOH
2. (CH2O)n, NaBH(OAc)3
quant. (2 steps)
H
O
N
O
N
O
HO
O
NMe
BnO2C
N
H
O
Me
(R = Et or iPr)
63
O
N
O
HO2C
N
H
O
Me
3. Pd black, EtOH/HCO2H
= 10:1, 46%
Me Me
(undesired)
OH
HO
2
Caprazol ( )
Scheme 10. Investigation of Mitsunobu reaction and synthesis of caprazol (2).
To complete the first total synthesis of caprazamycin A (1),
we carefully applied model studies to couple protected caprazol
5 with fatty acid side chain 55b (Scheme 11). Condensation of
5 with 55b using EDCI successfully proceeded to afford the
desired acylated product without undesired side reactions, such
as -elimination, epimerization, and retro-aldol reaction on the
1,4-diazepanone. After removing the Troc group in the
presence of zinc and acetic acid, the resultant carbamic acid
intermediate was treated with acetic acid to give compound 66
via decarboxylation. Reductive amination of secondary amine
66 was followed by TES group removal to afford corresponding
alcohol 67. Yamaguchi conditions(13d) were applied to introduce
the fatty acid side chain 52 containing rhamnose. Although the
reaction
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 18
1
2
3
4
5
6
7
8
9
CbzHN
O
NHCbz
CbzO
CbzO
CbzO
1. EDCI, DMAP
nC12H25
TESO
O
CbzO
1. (CH2O)n, NaBH(OAc)3
AcOH
O
O
nC12H25
BOM
BOM
Troc
N
OH
55b
O
N
N
O
O
O
TESO
O
HO
O
NH
O
O
O
N
2. HF·Py
N
2. Zn, AcOH, 50 °C
3. AcOH, ClCH2CH2Cl
BnO2C
BnO2C
N
N
43% (5 steps)
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Me
O
Me
OCbz
CbzO
CbzO
OCbz
[Troc group promoted
esterification]
66
5
Protected caprazol ( )
NHCbz
CbzO
NHCbz
Me
O
O
OH
CbzO
CbzO
O
Me
52
O
CbzO
O
Me
O
MeO
OMe
O
O
BOM
nC12H25
BOM
N
OMe
N
O
O
Me
O
O
O
O
O
O
NMe
O
OH
O
O
NMe
O
N
Cl
O
O
Me
O
O
N
MeO
BnO2C
OMe
N
BnO2C
H
N
O
Me
H
Cl
Cl
DMAP, Et3N
64%
OMe
O
Me
CbzO
OCbz
CbzO
OCbz
Protected caprazamycin A
Cl
68
(
)
67
Easily reduced
[Yamaguchi esterification]
NHCbz
Pd source, H2
several solvent
All failed
CbzO
CbzO
NMe
H2N
HO
HO
NMe
O
BOM
O
N
O
O
Me
O
O
Pd black
H
N
O
O
O
N
HCO H
EtOH/
= 20:1
O
O
O
Me
O
2
O
BnO2C
N
H
O
N
O
Me
O
Me
O
98%
MeO
HO2C
OMe
N
CbzO
OCbz
(undesired)
H
O
Me
OMe
[Global deprotection
in the presence of the olefin]
69
HO
OH
1
Caprazamycin A ( )
Scheme 11. The first total synthesis of caprazamycin A (1).
afforded protected caprazamycin A (68), byproduct 69 was
readily formed through -elimination under these conditions.
Therefore, the amounts of Et3N and 4-dimethylaminopyridine
(DMAP) were reduced, and the reaction time was shortened. As
a result, protected caprazamycin A (68) was obtained in 64%
yield.
(20:1:1), the carboxylic acid -proton in 1 was shifted
downfield compared with that measured in
HO
ND3
O
H
Me
HO
NMe
O
H
N
O
O
Me
O
O
O
O
O
Finally, conditions for the global deprotection of five Cbz,
one BOM, and one Bn groups in the protected caprazamycin A
(68) while avoiding reduction of the uracil olefin were
investigated. Using 10% Pd/C under a hydrogen atmosphere
removed the protecting groups, but also resulted in olefin
hydrogenation. Although various palladium (Pd) catalysts,
including 5% Pd/C, Pd/C(en), and Pd(OH)2/C, in the presence
of various hydrogen sources (H2, cyclohexadiene, and formic
acid) were examined, none were able to suppress olefin
reduction. In contrast, treatment with EtOH/formic acid (20:1,
v/v) in the presence of Pd black resulted in a near-quantitative
clean deprotection without olefin reduction. After careful
neutralization, the spectral data, including NMR (DMSO-
d6/D2O, 20:1) and HRMS data, of the synthetic sample were
identical to those of the natural product.(1) Therefore, the first
total synthesis of caprazamycin A (1) was successfully
accomplished. The NMR spectra of caprazamycin A (1) were
concentration- and pKa-dependent (Scheme 12). When NMR
spectra of 1 were measured using DMSO-d6/D2O/DCO2D
O
N
O
Me
O
MeO
O2C
OMe
OMe
N
H
O
Me
HO
OH
ca. 3.8 ppm
DMSO-d /D O = 20:1
Caprazamycin A in
6
2
DCO2D
2DCO2
ND3
HO
HO
D
O
O
Me
O
H
N
O
O
Me
O
O
O
O
NMe
O
N
O
Me
O
MeO
DO2C
OMe
OMe
N
H
O
H
Me
HO
OH
ca. 4.6 ppm
DMSO-d /D O/DCO D = 20:1:1
Caprazamycin A in
6
2
2
Scheme 12. 1H NMR spectrum of caprazamycin A (1).
ACS Paragon Plus Environment

Page 13 of 18
Journal of the American Chemical Society
nucleoside Antibiotics, from Streptomyces sp. J. Antibiot.
2005, 58, 327.
(2) a) Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K.; Izaki,
K.; Nelson, C. C.; McCloskey, J. A. Liposidomycins: Novel
DMSO-d6/D2O (20:1). This indicated that caprazamycin A
was in zwitterion form in DMSO-d6/D2O, but had a
protonated carboxylic acid in the presence of formic acid.
1
2
3
4
5
6
7
8
9
Nucleoside
Antibiotics
Which
Inhibit
Bacterial
Peptidoglycan Synthesis. J. Antibiot. 1985, 38, 1617; b)
Kimura, K.; Ikeda, Y.; Kagami, S.; Yoshihama, M.; Suzuki,
K.; Osada, H.; Isono, K. Selective Inhibition of the Bacterial
Peptidoglycan Biosynthesis by the New Types of
Liposidomycins. J. Antibiot. 1998, 51, 1099; c) Ubukata, M.;
Kimura, K.; Isono, K.; Nelson, C. C.; Gregson, J. M.;
McCloskey, J. A. Structure elucidation of liposidomycins, a
class of complex lipid nucleoside antibiotics. J. Org. Chem.
1992, 57, 6392; d) Kimura, K.; Ikeda, Y.; Kagami, S.;
Yoshihama, M.; Ubukata, M.; Esumi, Y.; Osada, H.; Isono,
K. New Types of Liposidomycins that Inhibit Bacterial
Peptidoglycan Synthesis and are Produced by Streptomyces.
J. Antibiot. 1998, 51, 647; e) Kimura, K.; Kagami, S.; Ikeda,
Y.; Takahashi, H.; Yoshihama, M.; Kusakabe, H.; Osada, H.;
Isono, K. New Types of Liposidomycins that Inhibit
Bacterial Peptidoglycan Synthesis and are Produced by
Streptomyces. J. Antibiot. 1998, 51, 640.
Conclusions
We have developed a diastereoselective aldol reaction of
diethyl isocyanomalonate 13 and phenylcarbamate 21 for the
synthesis of -hydroxy amino acid derivatives. Thiourea
catalyst 14 effectively obtained the desired 5’S-isomer 11a
in the aldol reaction of aldehyde 12 bearing an
isopropylidene acetal moiety. The resultant aldol products
were readily converted into syn--hydroxy amino acid
derivatives 10, 38, and 39 bearing several protecting groups.
The 1,4-diazepanone core structure of caprazamycin A was
obtained using a Mitsunobu reaction. A synthetic route for
introducing a fatty acid side chain was established using a
stepwise sequence. Finally, we achieved the first total
synthesis of caprazamycin A by identifying conditions for
global deprotection without hydrogenation of the olefin in
the uridine unit. These results and the established synthetic
route will guide the synthesis of related liponucleoside
antibiotics bearing fatty acid side chains, including
liposidomycins and spaerimicin A, and investigations into
the synthesis of a related natural product are currently
underway in our laboratory.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.;
Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.;
Williamson, R. T. Structures of the Muraymycins, Novel
Peptidoglycan Biosynthesis Inhibitors. J. Am. Chem. Soc.
2002, 124, 10260.
(4) Fujita, Y.; Kizuka, M.; Funabashi, M.; Ogawa, Y.; Ishikawa,
T.; Nonaka, K.; Takatsu, T. A-90289 A and B, new inhibitors
of bacterial translocase I, produced by Streptomyces sp.
SANK 60405. J. Antibiot. 2011, 64, 495.
(5) Funabashi, M.; Baba, S.; Takatsu, T.; Kizuka, M.; Ohata, Y.;
Tanaka, M.; Nonaka, K.; Ducho, A. P. C.; Chen, W.-C. L.;
Van Lanen, S. G. Structure-based gene targeting discovery of
sphaerimicin, a bacterial translocase I inhibitor. Angew.
Chem. Int. Ed. 2013, 52, 11607.
(6) a) Kimura, K.; Bugg, T. D. H. Recent advances in
antimicrobial nucleoside antibiotics targeting cell wall
biosynthesis. Nat. Prod. Rep. 2003, 20, 252; b) Dini, C.;
Collette, P.; Drochon, N.; Guillot, J. C.; Lemoine, G.;
Mauvais, P.; Aszodi, J. Synthesis of the nucleoside moiety of
liposidomycins: elucidation of the pharmacophore of this
family of MraY inhibitors. Bioorg. Med. Chem. Lett. 2000,
10, 1839.
(7) Kaysser, L.; Lutsch, L.; Siebenberg, S.; Wemakor, E.;
Kammerer, B.; Gust, B. Identification and Manipulation of
the Caprazamycin Gene Cluster Lead to New Simplified
Liponucleoside Antibiotics and Give Insights into the
Biosynthetic Pathway. J. Biol. Chem. 2009, 284, 14987.
(8) Barnard-Britson, S.; Chi, X.; Nonaka, K.; Spork, A. P.;
Tibrewal, N.; Goswami, A.; Pahari, P.; Ducho, C.; Rohr, J.;
Van Lanen, S. G. Amalgamation of Nucleosides and Amino
Acids in Antibiotic Biosynthesis: Discovery of an L-
Threonine:Uridine-5‘-Aldehyde Transaldolase. J. Am. Chem.
Soc. 2012, 134, 18514.
(9) a) Ishizaki, Y.; Hayashi, C.; Inoue, K.; Igarashi, M.;
Takahashi, Y.; Pujari, V.; Crick, D. C.; Brennan, P. J.;
Nomoto, A. Inhibition of the First Step in Synthesis of the
Mycobacterial Cell Wall Core, Catalyzed by the GlcNAc-1-
phosphate Transferase WecA, by the Novel Caprazamycin
Derivative CPZEN-45. J. Biol. Chem. 2013, 288, 30309; b)
Takahashi, Y.; Igarashi, M.; Miyake, T.; Soutome, H.;
Ishikawa, K.; Komatsuki, Y.; Koyama, Y.; Nakagawa, N.;
Hattori, S.; Inoue, K.; Doi, N.; Akamatsu, Y. Novel
semisynthetic antibiotics from caprazamycins A-G:
caprazene derivatives and their antibacterial activity. J.
Antibiot. 2013, 66, 171.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
analytical data (1H and 13C NMR, MS) for all new
compounds as well as summaries of unsuccessful
approaches. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
E-mail: tsukano@pharm.kyoto-u.ac.jp (C. T.).
E-mail: takemoto@pharm.kyoto-u.ac.jp (Y. T.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a Grant-in-Aid for Scientific
Research (S) (JSPS KAKENHI no. JP16H06384, Y.T.), a
Grant-in-Aid for JSPS fellows (H.N.) and JSPS KAKENHI
(Grant No. JP17H05051, C.T.), and JSPS KAKENHI (Grant
No. JP18H04407, C.T.) in the Middle Molecular Strategy.
REFERENCES
(1) a) Igarashi, M.; Nakagawa, N.; Doi, S.; Hattori, N.;
Naganawa, H.; Hamada, M. Caprazamycin B, a Novel Anti-
tuberculosis Antibiotic, from Streptomyces sp. J. Antibiot.
2003, 56, 580; b) Takeuchi, T.; Igarashi, M.; Naganawa, H.
Caprazamycins D, G, D1, G1, Antibiotics, and their
preparation method. JP P2003-12687A, 2003; c) Igarashi,
M.; Takahashi, Y.; Shitara, T.; Nakamura, H.; Naganawa, H.;
Miyake, T.; Akamatsu, Y. Caprazamycins, Novel Lipo-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 18
(10) For review, see: Watanabe, T. Synthesis of Caprazamycins
Diastereoselective syntheses of α-amino-β-hydroxyesters
and Related Natural Products. Heterocycles, 2017, 95, 662.
(11) a) Wlegmann, D.; Spork, A. P.; Niro, G.; Ducho, C. Where
Are They Now? -Ribosylation of an Acid-Labile Glycosyl
Acceptor as a Potential Key Step for the Synthesis of
Nucleoside Antibiotics. Synlett, 2018, 29, 440; b) Nakajima,
N.; Seida, T.; Furuno, A.; Asahi, T.; Kishimoto, T.; Hamada,
M. Synthetic Studies of Liposidomycin Degradation Product:
Model Studies of Diazepanone Ring Construction.
Heterocycles, 2017, 95, 1074; c) Mitachi, K.; Aleiwei, B. A.;
Schneider, C. M.; Siricilla, S.; Kurosu, M. Stereocontrolled
Total Synthesis of Muraymycin D1 Having a Dual Mode of
Action against Mycobacterium tuberculosis. J. Am. Chem.
Soc. 2016, 138, 12975; d) Fer, M. J.; Bouhss, A.; Patrão, M.;
Corre, L. L.; Pietrancosta, N.; Amoroso, A.; Joris, B.;
Mengin-Lecreulx, D.; Calvet-Vitale, S.; Gravier-Pelletier, C.
5’-Methylene-triazole-substituted-aminoribosyl uridines as
MraY inhibitors: synthesis, biological evaluation and
molecular modeling. Org. Biomol. Chem. 2015, 13, 7193; e)
Ichikawa, S.; Yamaguchi, M.; Hsuan, L. S.; Kato, Y.;
Matsuda, A. Carbacaprazamycins: Chemically Stable
Analogues of the Caprazamycin Nucleoside Antibiotics. ACS
Infect. Dis. 2015, 1, 151; f) Spork, A. P.; Büschleb, M.; Ries,
O.; Wiegmann, D.; Boettcher, S.; Mihalyi, A.; Bugg, T. D.
H.; Ducho, C. Lead Structures for New Antibacterials:
precursors of the ribosyl-diazepanone core of the
liposidomycins. Tetrahedron Lett. 2003, 31, 2781; s) Knapp,
S.; Morriello, G. J.; Doss, G. A. Synthesis of the
Liposidomycin Diazepanone Nucleoside. Org. Lett. 2002, 4,
603; t) Gravier-Pelletier, C.; Milla, M.; Merrer, Y. L.;
Depezay, J. C. Liposidomycins − Synthetic Studies Towards
the Ribosyldiazepanone Moiety. Eur. J. Org. Chem. 2001, 16,
3089; u) Knapp, S.; Morriello, G. J.; Nandan, S. R.; Emge, T.
J.; Doss, G. A.; Mosley, R. T.; Chen, L. Assignment of the
Liposidomycin Diazepanone Stereochemistry. J. Org. Chem.
2001, 66, 5822; v) Kim, K. S.; Ahn, Y. H. Synthesis of the
diazepanone-nucleoside portion of liposidomycins by aldol
reaction of the enolate of diazepanone with a nucleoside 5’-
aldehyde. Tetrahedron: Asymmetry 1998, 9, 3601; w) Merrer,
Y. L.; Gravier-Pelletier, C.; Gerrouache, M.; Depezay, J. C.
Access to enantiopure ribosyl-diazepanone core of
liposidomycins. Tetrahedron Lett. 1998, 39, 385; x) Kim, K.
S.; Cho, I. H.; Ahn, Y. H.; Park, J. I. Synthesis of the 1,4-
diazepan-2-one moiety of liposidomycins. J. Chem. Soc.
Perkin Trans. 1 1995, (26), 1783; y) Knapp, S.; Nandan, S.;
Resnick, L. Synthesis of the liposidomycin diazepanone.
Tetrahedron Lett. 1992, 33, 5485.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) a) Ichikawa, S. Function-Oriented Synthesis: How to Design
Simplified Analogues of Antibacterial Nucleoside Natural
Products? Chem. Rec. 2016, 16, 1106; b) Ichikawa, S. Fine
Synthetic Nucleoside Chemistry Based on Nucleoside
Natural Products Synthesis. Chem. Pharm. Bull. 2008, 56,
1059. c) Hirano, S.; Ichikawa, S.; Matsuda, A. Synthesis of
Caprazamycin Analogues and Their Structure−Activity
Relationship for Antibacterial Activity. J. Org. Chem. 2008,
73, 569; d) Hirano, S.; Ichikawa, S.; Matsuda, A.
Development of a Highly β-Selective Ribosylation Reaction
without Using Neighboring Group Participation:ꢀ Total
StereocontrolledSynthesis of
a Bioactive Muraymycin
Analogue. Chem. Eur. J. 2014, 20, 15292; g) Fer, M. J.; Doan,
P.; Prangé, T.; Calvet-Vitale, S.; Gravier-Pelletier, C. A
Diastereoselective Synthesis of 5’-Substituted-Uridine
Derivatives. J. Org. Chem. 2014, 79, 7758; h) Miyaoka, H.;
Wada, J.; Kawashima, E. Synthesis of the Diazepanone-
Nucleoside Core Structure of Liposidomycins and
Caprazamycins Based on 7-Exo Cyclization of Epoxyamine.
Heterocycles 2014, 88, 719; i) Sarabia, F.; Vivar-García, C.;
García-Ruiz, C.; Martín-Ortiz, L.; Romero-Carrasco, A.
Exploring the Chemistry of Epoxy Amides for the Synthesis
of the 2’’-epi-Diazepanone Core of Liposidomycins and
Caprazamycins. J. Org. Chem. 2012, 77, 1328; j) Ii, K.;
Ichikawa, S.; Al-Dabbagh, B.; Bouhss, A.; Matsuda, A.
Function-Oriented Synthesis of Simplified Caprazamycins:
Discovery of Oxazolidine-Containing Uridine Derivatives as
Antibacterial Agents against Drug-Resistant Bacteria. J. Med.
Chem. 2010, 53, 3793; k) Spork, A. P.; Koppermann, S.;
Dittrich, B.; Herbst-Irmer, R.; Ducho, C. Efficient synthesis
of the core structure of muraymycin and caprazamycin
nucleoside antibiotics based on a stereochemically revised
sulfur ylide reaction. Tetrahedron: Asymmetry 2010, 21, 763;
l) Monasson, O.; Ginisty, M.; Mravljak, J.; Bertho, G.;
Gravier-Pelletier, C.; Merrer, Y. L. Synthetic studies towards
diazepanone scaffolds. Tetrahedron: Asymmetry 2009, 20,
2320; m) Xu, X.; Trunkfield, H. A. E.; Bugg, T. D. H.; Qing,
F. L. Synthesis of gem-difluorinated nucleoside analogues of
the liposidomycins and evaluation as MraY inhibitors. Org.
Biomol. Chem. 2008, 6, 157; n) Monasson, O.; Ginisty, M.;
Bertho, G.; Gravier-Pelletier, C.; Merrer, Y. L. Efficient
synthesis of polyfunctionalised enantiopure diazepanone
scaffolds. Tetrahedron Lett. 2007, 48, 8149; o) Fukunishi, S.;
Ubukata, M.; Nakajima, N. Synthetic Studies of
Liposidomycin Degradation Product: Model Studies of
Uracil Group Introduction. Heterocycles 2007, 73, 627; p)
Sarabia, F.; Martin-Ortiz, L.; Lopez-Herrera, F. J. A
Convergent Synthetic Approach to the Nucleoside-Type
Liposidomycin Antibiotics. Org. Lett. 2003, 5, 3927; q)
Yamashita, A.; Norton, E. B.; Williamson, R. T.; Ho, D. M.;
Sinishtaj, S.; Mansour, T. S. Use of Bis-(chiral α-
methylbenzyl)glycine Esters for Synthesis of Enantiopure β-
Hydroxyamino Esters. Org. Lett. 2003, 5, 3305; r) Drouillat,
B.; Poupardin, O.; Bourdreux, Y.; Greck, C.
Synthesis of (+)-Caprazol,
a
Core Structure of
Caprazamycins. J. Org. Chem. 2007, 72, 9936; e) Hirano, S.;
Ichikawa, S.; Matsuda, A. Total Synthesis of Caprazol, a
Core Structure of the Caprazamycin Antituberculosis
Antibiotics. Angew. Chem. Int. Ed. 2005, 44, 1854.
(13) a) Takeuchi, T.; Abe, H.; Watanabe, T.; Shibasaki, M.
Catalytic asymmetric synthesis of CPZEN-45. Tetrahedron
Lett. 2016, 57, 2901; b) Abe, H.; Gopinath, P.; Ravi, G.;
Wang, L.; Watanabe, T.; Shibasaki, M. Synthesis of
caprazamycin B. Tetrahedron Lett. 2015, 56, 3782; c)
Gopinath, P.; Wang, L.; Abe, H.; Ravi, G.; Masuda, T.;
Watanabe, T.; Shibasaki, M. Catalytic Asymmetric Total
Synthesis of (+)-Caprazol. Org. Lett. 2014, 16, 3364; d)
Gopinath, P.; Watanabe, T.; Shibasaki, M. Studies on
Catalytic Enantioselective Total Synthesis of Caprazamycin
B: Construction of the Western Zone. J. Org. Chem. 2012, 77,
9260; e) Gopinath, P.; Watanabe, T.; Shibasaki, M. Catalytic
Enantioselective Desymmetrization of meso-Glutaric
Anhydrides Using a Stable Ni2-Schiff Base Catalyst. Org.
Lett. 2012, 14, 1358.
(14) a) Nakamura, H.; Yoshida, T.; Tsukano, C.; Takemoto, Y.
Synthesis of CPZEN-45: Construction of the 1,4-Diazepin-2-
one Core by the Cu-Catalyzed Intramolecular Amidation of
a Vinyl Iodide. Org. Lett. 2016, 18, 2300; b) Nakamura, H.;
Tsukano, C.; Yasui, M.; Takemoto, Y. Total Synthesis of (−)-
CaprazamycinꢁA. Angew. Chem. Int. Ed. 2015, 54, 3136; c)
Tsukano, C.; Yokouchi, S.; Girard, A. L.; Kuribayashi, T.;
Sakamoto, S.; Enomoto, T.; Takemoto, Y. Platinum
catalyzed 7-endo cyclization of internal alkynyl amides and
its application to synthesis of the caprazamycin core. Org.
Biomol. Chem. 2012, 10, 6074; d) Girard, A. L.; Enomoto,
T.; Yokouchi, S.; Tsukano, C.; Takemoto, Y. Control of 6-
Exo and 7-Endo Cyclizations of Alkynylamides using
ACS Paragon Plus Environment

Page 15 of 18
1
Journal of the American Chemical Society
Platinum and Bismuth Catalysts. Chem. Asian J. 2011, 6,
1321.
(27) For the nucleophilic addition of phosphite to aldehyde 27,
Wiemer and coworkers proposed a chelated transition state,
in which an attractive electrostatic interaction between
silicon and the carbonyl oxygen was postulated; see: Chen,
X.; Wiemer, A. J.; Hohl, R. J.; Wiemer, D. F. Stereoselective
Synthesis of the 5‘-Hydroxy-5‘-phosphonate Derivatives of
Cytidine and Cytosine Arabinoside. J. Org. Chem. 2002, 67,
9331.
(15) Kan, T.; Fukuyama, T. Ns strategies: a highly versatile
synthetic method for amines. Chem. Commun. 2004, (0), 353.
(16) Sakamoto, S.; Kazumi, N.; Kobayashi, Y.; Tsukano, C.;
Takemoto, Y. Asymmetric Synthesis of Trisubstituted
Oxazolidinones by the Thiourea-Catalyzed Aldol Reaction of
2-Isocyanatomalonate Diester. Org. Lett. 2014, 16, 4758.
(17) For recent reviews of thiourea-based catalysts, see: a)
Connon, S. J. Organocatalysis Mediated by (Thio)urea
Derivatives. Chem. Eur. J. 2006, 12, 5418; b) Doyle, A. G.;
Jacobsen, E. N. Small-Molecule H-Bond Donors in
Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713; c)
Connon, S. J. Asymmetric catalysis with bifunctional
cinchona alkaloid-based urea and thiourea organocatalysts.
Chem. Commun. 2008, (0), 2499; d) Zhang, Z.; Schreiner, P.
R. (Thio)urea organocatalysis—What can be learnt from
anion recognition? Chem. Soc. Rev. 2009, 38, 1187; e)
Takemoto, Y. Development of Chiral Thiourea Catalysts and
Its Application to Asymmetric Catalytic Reactions. Chem.
Pharm. Bull. 2010, 58, 593. (f) Auvil, T. J.; Schafer, A. G.;
Mattson, A. E. Design Strategies for Enhanced Hydrogen‐
Bond Donor Catalysts. Eur. J. Org. Chem. 2014, 2014, 2633.
(18) Part of this work has been published in preliminary
communications, see refs. 14a and 14b.
2
3
4
5
6
7
8
9
(28) Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.;
Mashima, K. Enzyme-Like Chemoselective Acylation of
Alcohols in the Presence of Amines Catalyzed by a
Tetranuclear Zinc Cluster. J. Am. Chem. Soc. 2008, 130, 2944.
(29) Roberts, T. C.; Smith, P. A.; Cirz, R. T.; Romesberg, F. E.
Structural and Initial Biological Analysis of Synthetic
Arylomycin A2. J. Am. Chem. Soc. 2007, 129, 15830.
(30) a) Arias-Pérez, M. S.; López, M. S.; Santos, M. J. Imidazole-
promoted 1,4-migration of the tert-butyldiphenylsilyl group:
influence on the selectivity control of the silylation reactions
of carbohydrate OH groups. J. Chem. Soc., Perkin Trans. II,
2002, (0), 1549; b) Evans, D. A.; Black, W. C. Total synthesis
of (+)-A83543A [(+)-lepicidin A].; J. Am. Chem. Soc. 1993,
115, 4497.
(31) a) Noyori, R.; Takaya, H. BINAP: an efficient chiral element
for asymmetric catalysis. Acc. Chem. Res. 1990, 23, 345; b)
Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier,
J. P.; Ben Hassine, B.; Genêt, J. P. Enantioselective
Hydrogenation of -Keto Esters using Chiral Diphosphine‐
Ruthenium Complexes: Optimization for Academic and
Industrial Purposes and Synthetic Applications. Adv. Synth.
Catal. 2003, 345, 261.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) a) Cesa, M. C.; Rinz, J. E.; Kopp, T. T. Aryl oxime
derivatives of hydantoins. U.S. patent, 1987, US 4705864 A;
b) Cesa, M. C.; Rinz, J. E.; Klopman, G.; Kopp, T. T. N,N'-
disubstituted ureas. U.S. patent, 1988, US 4740611 A.
(20) Wang, R.; Steensma, D. H.; Takaoka, Y.; Yun, J. W.;
Kajimoto, T.; Wong, C.-H. A search for pyrophosphate
mimics for the development of substrates and inhibitors of
glycosyltransferases. Bioorg. Med. Chem. 1997, 5, 661.
(21) a) Danishefsky, S. J.; DeNinno, M. P.; Phillips, G. B.; Zelle,
R. E.; Lartey, P. A. On the communication of chirality from
furanose and pyranose rings to monosaccharide side chains:
anomalous results in the glucose series. Tetrahedron 1986,
42, 2809; b) Danishefsky, S. J.; DeNinno, S. L.; Chen, S.-H.;
Boisvert, L.; Barbachyn, M. Fully synthetic stereoselective
routes to the differentially protected subunits of the
tunicamycins. J. Am. Chem. Soc. 1989, 111, 5810; c) Chen,
X.; Wiemer, D. F. -Phosphono Lactone Analogues of
Cytidine and Cytosine Arabinoside Diphosphates:ꢀSynthesis
via Ring Closing Metathesis. J. Org. Chem. 2003, 68, 6597.
(22) Ichikawa and coworkers recently reported controlling
diastereoselectivity in the Mukaiyama aldol reaction of
compound 12 using Lewis acids, see Yamamoto, K.;
Yakushiji, F.; Matsumura, T.; Ichikawa, S. Total Synthesis of
Tunicamycin V. Org. Lett. 2018, 20, 256.
(32) a) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.;
Chin, J.; Song, C. E. A highly reactive and enantioselective
bifunctional
organocatalyst
for
the
methanolytic
desymmetrization of cyclic anhydrides: prevention of
catalyst aggregation. Angew. Chem. Int. Ed. 2008, 47, 7872;
b) Honjo, T.; Tsumura, T.; Sano, S.; Nagao, Y.; Yamaguchi,
K.; Sei, Y. A Chiral Bifunctional Sulfonamide as an
Organocatalyst: Alcoholysis of σ-Symmetric Cyclic
Dicarboxylic Anhydrides. Synlett, 2009, 20, 3279.
(33) a) Mori, K.; Iwasawa, H. Stereoselective synthesis of
optically active forms of δ-multistriatin, the attractant for
european populations of the smaller european elm bark beet.
Tetrahedron, 1980, 36, 87; b) Saito, S.; Bunya, N.; Inaba, M.;
Moriwake, T.; Torii, S. A facile cleavage of oxirane with
hydrazoic acid in dmf A new route to chiral β-hydroxy-α-
amino acids. Tetrahedron Lett. 1985, 26, 5309.
(34) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. Synthesis of acyl halides under very mild
conditions. J. Chem. Soc., Chem. Commun. 1979, (0), 1180.
(35) Taber, D. F.; Deker, P. B.; Fales, H. M.; Jones, T. H.; Lloyd,
H. A. Enantioselective construction of heterocycles.
Synthesis of (R,R)-solenopsin B. J. Org. Chem. 1988, 53,
2968.
(23) The transition states were also calculated with several
different functionals, including dispersion correction. See the
Supporting Information for the details of computational
studies.
(24) Compound 25 was prepared by IBX oxidation of a known
BOM-protected uridine, see: Silva, D. J.; Sofia, M. J. Novel
carbohydrate scaffolds. Assembly of a uridine–mannose
scaffold based on tunicamycin. Tetrahedron Lett. 2000, 41,
855.
(36) Since our total synthesis of caprazamycin A, Shibasaki,
Watanabe, and coworkers succeeded in directly introducing
the fatty acid side chain using 2-methyl-6-nitrobenzoic
anhydride (MNBA) for the total synthesis of caprazamycin B,
see: ref. 13b.
(25) Compound 26 was prepared from uridine in five steps: (i)
TBS protection of the 5’-hydroxy group; (ii) BOM protection
of the nitrogen atom; (iii) TIPS protection of the 2’,3’-
hydroxy groups; (iv) selective removal of the TBS group; and
(v) Dess–Martin oxidation. Also see the supporting
information.
(26) Spork, A. P.; Wiegmann, D.; Granitzka, M.; Stalke, D.;
Ducho, C. Stereoselective Synthesis of Uridine-Derived
Nucleosyl Amino Acids. J. Org. Chem. 2011, 76, 10083.
(37) There are a few reports of the introduction of a simple acyl
group into the 1,4-diazepanone ring, see: a) Hirano, S.;
Ichikawa, S.; Matsuda, A. Structure–activity relationship of
truncated analogs of caprazamycins as potential anti-
tuberculosis agents. Bioorg. Med. Chem. 2008, 16, 5123; b)
Mravljak, J.; Monasson, O.; Al-Dabbagh, B.; Crouvoiseire,
M.; Bouhss, A.; Gravier-Pelletier, C.; Merrer, Y. L. Synthesis
and biological evaluation of a diazepanone-based library of
liposidomycins analogs as MraY inhibitors. Eur. J. Med.
Chem. 2011, 46, 1582; c) also see refs. 11i and 12c.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 17 of 18
Journal of the American Chemical Society
1
2
3
4
Table of Contents (TOC)
5
6
7
8
9
NH2
O
[cyclic peptide ring]
[unstable fatty acid]
HO
HO
NMe
Me
O
O
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
O
O
O
Me
O
O
O
N
O
Me
O
MeO
OMe
OMe
HO2C
N
H
O
Me
[ -hydroxy- -aminoacid]


HO
OH
Caprazamycin A
[The full details]
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18
ACS Paragon Plus Environment