Total synthesis of PDIM A

Article abstract of DOI:10.1246/cl.160152

Total synthesis of phthiocerol dimycocerosate A (PDIM A), a virulent factor of Mycobacterium tuberculosis, has been achieved. Phthiocerol, a component of PDIM A, has been synthesized by subsequent epoxide-opening alkylation reactions with arabinose-derived diepoxide. This route is concise and efficient in supplying PDIM A for biological studies.

Full text of DOI:10.1246/cl.160152

CL-160152
Received: February 15, 2016 | Accepted: February 25, 2016 | Web Released: March 3, 2016
Total Synthesis of PDIM A
Tatsuya Nakamura, Hanae Nakagome, Shoichiro Sano, Tomoko Sadayuki, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555
(E-mail: seijiro@waseda.jp)
Total synthesis of phthiocerol dimycocerosate A (PDIM A),
Our synthetic plan of phthiocerol (2) is shown in Scheme 1.
To establish a highly convergent synthesis, phthiocerol (2) was
divided into three segments, namely, acetylene 4, diepoxide 5,6
and Grignard reagent 6. C2-Symmetrical diepoxide 5 would be
subsequently alkylated with the carbanion derived from 4 and
Grignard reagent 6 to provide an asymmetric chain.7
a virulent factor of Mycobacterium tuberculosis, has been
achieved. Phthiocerol, a component of PDIM A, has been
synthesized by subsequent epoxide-opening alkylation reactions
with arabinose-derived diepoxide. This route is concise and
efficient in supplying PDIM A for biological studies.
The synthesis of acetylene segment 4 is shown in Scheme 2.
The vinylogous Mukaiyama aldol reaction using vinylketene
silyl N,O-acetal 7 with propanal proceeded to give anti-adduct 8
in a stereoselective manner.8 O-Methylation with Meerwein’s
reagent provided methyl ether 9 in good yield. Ozonolysis was
followed by reduction to afford the corresponding primary
alcohol, and the subsequent sulfonylation gave triflate 10 in
good yield. Substitution with lithium acetylide, followed by de-
C-silylation, provided acetylene segment 4.
Keywords: Phthiocerol dimycocerosate A (PDIM A)
Tuberculosis Total synthesis
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Tuberculosis is a widespread problem, and leather infection
disease is caused by Mycobacterium tuberculosis. It is estimated
that 9.6 million people had fallen ill with tuberculosis in 2014.1
In 1999, phthiocerol dimycocerosate A (PDIM A, Figure 1) was
found to be a virulent factor of Mycobacterium tuberculosis.2
PDIM A is required for further investigation of the infection
system of Mycobacterium tuberculosis, but only one precedent
of total synthesis has been reported by Minnaard group.3 During
the course of synthesizing polyketide compounds in our
laboratory,4 we started the synthesis of PDIM A. PDIM A
consists of phthiocerol (2) and mycocerosic acid (3). Recently,
we have achieved the concise synthesis of mycocerosic acid (3).5
Herein, we report the synthesis of phthiocerol (2) as well as the
total synthesis of PDIM A (1).
Me
Me
Me
20
OMe
OH OH
phthiocerol (2)
Me
BrMg
Me
Me
20
O
O
OMe
4
5
6
Scheme 1. Synthetic plan of phthiocerol (2).
Me
Me
Me
Me
Me3OBF4
proton sponge®
Me
CHO
TiCl4
20
OMe
O
O
Me Me
O
Me
O
N
O
XN
Me
Me
Me
Me
Me
Me
TBSO
CH2Cl2
−78 °C, 15 h
97%, dr > 20:1
CH2Cl2
rt, 13 h
92%
O
OH
O
Me
Me
Me
7
8
1) O3
MeOH, CH2Cl2 (1:1)
−78 °C
then NaBH4, 1 h
91%
Me Me
Me
18
Me
18
Me
N
O
OTf
Me
Me
2) Tf2O, pyridine
CH2Cl2
−78 °C, 45 min
94%
OMe
O
O
OMe
10
PDIM A
(1)
9
Me
Me
Me
20
TMS
n-BuLi
OMe
OH OH
phthiocerol (2)
Me
R
Me
Et2O
OMe
11: R = TMS
−78 °C to rt
Me Me Me Me
CO2H
mycocerosic acid (3)
TBAF
CH2Cl2
rt, 3 h
12 h
Me
19
4
: R = H
88% in 2 steps
Figure 1. PDIM A and its components.
Scheme 2. Synthesis of acetylene 4.
550 | Chem. Lett. 2016, 45, 550–551 | doi:10.1246/cl.160152
© 2016 The Chemical Society of Japan

anhydride, MNBA)10 afforded PDIM A (1) in good yield
(Scheme 4). Spectral data of synthetic 1 were consistent with
those of reported data.2a-2c,3b
In conclusion, we accomplished the total synthesis of
PDIM A (1), a virulent factor of Mycobacterium tuberculosis.
Phthiocerol (2) was synthesized by subsequent alkylation of
C2-diepoxide 5. This route is concise and efficient in supplying
PDIM A (1) for biological studies. Biological studies on PDIM
A (1) are now in progress.11
LiHMDS
TPsO
OTPs
O
O
THF
0 °C to rt
30 min
OH OH
12
5
Me
Me
Me
4
OMe
O
Me
OH
n-BuLi, BF3•OEt2
THF
OMe
13
−78 °C, 14 h
61%
Authors are grateful for financial support to The NOVARTIS
Foundation (Japan) for the Promotion of Science, The Kurata
Memorial Hitachi Science and Technology Foundation, and The
Naito Foundation.
MgBr
Me
20
6
Me
Me
20
Me
OH OH
14
cat. CuI
THF, rt, 30 min
65%
OMe
Supporting Information is available on http://dx.doi.org/
10.1246/cl.160152.
Me
H2
Pd/C
References and Notes
Me
Me
1
World Health Organization, Global Tuberculosis Report 2015, 2015,
p. 1.
20
OMe
OH OH
phthiocerol
EtOH
rt, 1.5 h
95%
(2)
2
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Scheme 3. Total synthesis of phthiocerol (2).
Me Me Me Me
CO2H
Me
19
mycocerosic acid (3)
MNBA
Et3N, DMAP
Me
3
4
Me
Me
20
CH2Cl2
rt, 3 days
81%
OMe
OH OH
phthiocerol (2)
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2437.
Me
Me
Me
20
OMe
O
O
O
O
Me
Me
Me
Me
Me
5
6
T. Nakamura, K. Kubota, T. Ieki, S. Hosokawa, Org. Lett. 2016, 18,
132.
Me
Me
Me
a) S. V. Attwood, A. G. M. Barrett, J. Chem. Soc., Perkin Trans. 1
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18
18
Me
Me
7
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PDIM A (1)
Scheme 4. Total synthesis of PDIM A (1).
8
9
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C2-Diepoxide 5 was prepared by the Linclau method
(Scheme 3).6d Treatment of diol 126a with lithium hexamethyl-
disilazide (LiHMDS) produced diepoxide 5, which was reacted
with the acetylide anion of 4 in the presence of boron trifluoride
diethyl etherate (BF3¢OEt2)9 to afford monoalkylated 13 in one
pot. Epoxide 13 was exposed to Grignard reagent 6 to afford
anti-diol 14. Hydrogenation of the resulting acetylene 14
provided phthiocerol (2) in excellent yield.
10 a) I. Shiina, R. Ibuka, M. Kubota, Chem. Lett. 2002, 286. b) I.
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11 Although the first acylation of diol
2 proceeded non-regio-
Finally, condensation of phthiocerol (2) and mycocerosic
acid (3) by using the Shiina reagent (2-methyl-6-nitrobenzoic
selectively, O-protection of 13 would make possible the selective
acylation to provide analogs.
Chem. Lett. 2016, 45, 550–551 | doi:10.1246/cl.160152
© 2016 The Chemical Society of Japan | 551