Stereocontrolled total synthesis of (-)-myriocin

Article abstract of DOI:10.1016/j.tetasy.2008.12.020

The stereocontrolled total synthesis of (-)-myriocin 1 is reported. Optically active epoxide 9 was converted from symmetrical cyclohexadiene 8, utilizing an enzymatic kinetic resolution. The three sequential stereogenic centers of 1 were constructed by a regioselective epoxide-opening reaction and a Hofmann rearrangement. Elongation of the side chain was efficiently accomplished by the Julia-Kocienski reaction.

Full text of DOI:10.1016/j.tetasy.2008.12.020

Tetrahedron: Asymmetry 19 (2008) 2771–2773
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereocontrolled total synthesis of (À)-myriocin
Makoto Inai, Toshihiro Goto, Takumi Furuta , Toshiyuki Wakimoto, Toshiyuki Kan
*
School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereocontrolled total synthesis of (À)-myriocin 1 is reported. Optically active epoxide 9 was con-
verted from symmetrical cyclohexadiene 8, utilizing an enzymatic kinetic resolution. The three sequen-
tial stereogenic centers of 1 were constructed by a regioselective epoxide-opening reaction and a
Hofmann rearrangement. Elongation of the side chain was efficiently accomplished by the Julia–Kocien-
ski reaction.
Received 8 October 2008
Accepted 10 December 2008
Available online 30 January 2009
Published by Elsevier Ltd.
1. Introduction
HO
(+)-Myriocin (also known as thermozymocidine and ISP-1) 1
was initially isolated in 1972 from Myriococcus albomycens and
Mycelia sterilia.1 Fujita et al., who isolated 1 from Isalia sinclairii
in 1994, have reported that it exhibits 10- to 100-fold more potent
immunosuppressive activity than cyclosporine A.2 Recently, Kiuchi
et al. have developed a novel immunosuppression drug utilizing 1
COOH
OH
H2N
HO
O
(-)-myriocin 1
as a lead compound.3 Because the
a-disubstituted-a-amino acid
RO
OR
motif has attracted much attention due to its significance in bio-
logical investigations,4 many total syntheses of (+)-1 have been re-
ported.5 The unique structure and remarkable bioactivity of 1 as
PTO2S
CHO
+
HN
O
O
O
RO
O
well as our recent interest in
a-trisubstituted-a-amine com-
2
3
pounds6 have prompted us to investigate the total synthesis of 1.
Herein, we report a stereocontrolled total synthesis of (À)-myrio-
cin 1.
RO
RO
RO
OR
OH
Scheme 1 illustrates our synthetic plan. The conversion to a
highly polar a-amino acid function could be carried out in a later
HO
stage of the synthesis. Because elongating the side chain should
be suitable for a Julia–Kocienski reaction7 with aldehyde 2, phenyl
tetrazole (PT)-sulfone 3 could serve as a key intermediate. During
the course of our synthetic study on altemicidin,6c we have found
RO
HOOC
MeOOC
COOH
OR
OR
6
5
4
that a Curtius rearrangement8 of an
a
-hydroxy carboxylic acid
Scheme 1. Retrosynthesis of (À)-myriocin 1.
derivative proceeds smoothly to provide the desired -disubsti-
a
tuted oxazolidinone. Thus, we expected that the oxazolidinone ring
of 3 could be constructed from carboxylic acid 4. Because oxidative
cleavage of the double bond of 5 and successive reduction should
readily provide 4, the crucial step in the total synthesis of 1 should
be the stereoselective construction of 5, including the quaternary
carbon.
2. Results and discussion
As shown in Scheme 2, optically active key intermediate 11 was
readily prepared in six-steps from benzoic acid 7. The quaternary
carbon of 11 was constructed via reductive alkylation of 7 under
Birch conditions.9 Upon treatment of 7 with MOMCl in a solution
of Na and liq. NH3, the alkylation reaction proceeded smoothly,
and continuous cleavage of the methyl ether of the MOM group
with AlCl3 and NaI10 provided the desired carboxylic acid 8.
Although several enantiospecific desymmetrizations of cyclohexa-
diene 8 and/or its derivative were investigated, direct oxidation
* Corresponding author. Tel.: +81 0 54 264 5746; fax: +81 0 54 264 5745.
E-mail address: kant@u-shizuoka-ken.ac.jp (T. Kan).
Present address: Institute for Chemical Research, Kyoto University, Uji, Kyoto
611-0011, Japan.
0957-4166/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.12.020

2772
M. Inai et al. / Tetrahedron: Asymmetry 19 (2008) 2771–2773
1) Li, NH3 /THF
;MOMCl, 70%
1) NBS
CH3CN/H2O
HOOC
2) AlCl3, NaI
CH3CN
2) K2CO3
MeOH/H2O
58% (3 steps)
COOH
7
OH
8
PLE-A
(AMANO)
O
HOOC
O
O
+
MeOOC
MeOOC
IPE/pH=7 buffer
OH
OH
9 (racemic)
OR
(>99% ee)
10
9
Boc2O
DMAP
: R = H
CH3CN 32% (2 steps)
11
: R = Boc
Scheme 2. Synthesis of optically active epoxide 11.
was difficult.11 Hence, we selected the following stepwise oxida-
tion. Upon treatment of 8 with NBS, bromolactonization easily
afforded the desired b-lactone. Without purification, treatment of
the b-lactone with K2CO3 and MeOH, basic hydrolysis of the lac-
tone and subsequent epoxide formation proceeded to give racemic
epoxide 9. Conversion to enantiomerically pure epoxide 9 was per-
formed by enzymatic hydrolysis. Upon treatment of racemic 9 with
pig liver esterase PLE-A (AMANO),12 asymmetric hydrolysis of the
methyl ester resulted in optically active 9 (>99% ee). This transfor-
mation has an advantage; it does not require chromatographic
purification. Pure 9 was obtained by a simple extraction. Conver-
sion to desired carbonate 11 was carried out by treatment with
Boc2O and DMAP.
With requisite optically active epoxide 11 in hand, we then fo-
cused our attention on the construction of the three sequential ste-
reogenic centers of key intermediate 18, as shown in Scheme 3. A
cyclic carbonate was formed by treatment of epoxide 11 with 60%
HClO4. A stereospecific ring-opening reaction afforded 12 as a sin-
gle diastereomer. After protecting the secondary alcohol with a
MOM group, basic hydrolysis of cyclic carbonate group of 12 gave
diol 13. After protecting the primary alcohol as a TBDPS derivative
and the secondary alcohol as a MOM ether, incorporation of the
nitrogen atom onto the quaternary carbon was examined. Because
a Hofmann rearrangement13 gave an excellent result for this trans-
formation, the methyl ester of 14 was converted to amide 15 in
three steps, involving basic hydrolysis, incorporation of pentafluor-
ophenol (PfpOH), and treatment with ammonia. The double bond
of 15 was oxidatively cleaved by ozonolysis, and subsequent treat-
ment with NaBH4 afforded the corresponding diol 16. Upon treat-
ment of 16 with PhI(OAc)2, the desired Hofmann rearrangement
proceeded smoothly and the oxazolidinone ring of 17 was formed
by trapping in situ generated isocyanate by the primary alcohol.
Condensation of 17 and 1-phenyl-1H-tetrazolethiol (PTSH) was
achieved via a modified Mitsunobu reaction with di-2-methoxy-
ethyl azodicarboxylate (DMEAD)14 and PPh3. A DMDO-mediated
oxidation of the sulfide gave desired sulfone 18.
1) MOMCl
DIPEA
DMAP
CH2Cl2
HO
O
MOMO
HO
60% HClO4
CH3CN
11
2) NaH
MeOH
COOMe
MeOOC
O
O
OH
12
13
1) 3M LiOH
MeOH/THF
2) PfpOH
EDCI, DMAP
CH2Cl2
1) TBDPSCl
Imidazole
DMF
MOMO
MOMO
48% (4 steps)
2) MOMCl
DIPEA
CH2Cl2
93%
3) liq. NH3
83% (3 steps)
MeOOC
OTBDPS
14
MOMO
MOMO
OTBDPS
OH
O3; NaBH4
HO
MOMO
H2NOC
CH2Cl2/MeOH
Coupling of PT-sulfone 18 and side chain aldehyde 1915 was
achieved by a Julia–Kocienski reaction, as shown in Scheme 4.
Upon treatment of 18 and 19 with KHMDS, the coupling reaction
yielded predominantly (E)-alkene 20.7 After deprotection of the
TBDPS group, transformation of the primary alcohol to carboxylic
acid 21 was performed by a 1-methyl-2-azaadamantane N-oxyl
(1-Me-AZADO)-mediated oxidation, which was developed by
Iwabuchi and co-workers.16 Finally, simultaneous removal of the
MOM and ketal groups of 21 with hydrochloric acid and subse-
quent hydrolysis of the oxazolidinone and lactone rings with
sodium hydroxide furnished (À)-myriocin 1. All spectroscopic data
of which (1H NMR, 13C NMR, IR, and HRMS) fully agreed with those
of natural myriocin.
MOMO
CONH2
OTBDPS
16
15
MOMO
OTBDPS
1) PTSH
DMEAD, PPh3
toluene
HO
PhI(OAc)2
HN
O
toluene
97%
(2 steps)
MOMO
2) DMDO
O
82% (2 steps)
17
PT = Phenyl tetrazole
MOMO
HN
OTBDPS
PTO2S
MOMO
3. Conclusion
O
O
18
In conclusion, we have developed an efficient stereocontrolled
synthesis of (À)-myriocin 1. Our synthetic method may be
Scheme 3. Synthesis of key intermediate 18.

M. Inai et al. / Tetrahedron: Asymmetry 19 (2008) 2771–2773
2773
MOMO
OTBDPS
CHO
KHMDS
O5
O 5
O5
O5
HN
O
18
+
DME
MOMO
19
O
20
1) TBAF
THF
61% (2 steps)
MOMO
COOH
O5
O 5
HN
2) 1-Me-AZADO
PhI(OAc)2, NaClO2
CH3CN/pH=6.4 buf f er
MOMO
O
21
O
1) 6M HCl
MeOH
65%
HO
(2 steps )
COOH
OH
2) 3M NaOH
MeOH
78%
HO H2N
O
(–)-myriocin 1
Scheme 4. Completion of the total synthesis of (À)-myriocin 1.
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