Synthetic studies of incednine: synthesis of C1-C13 pentaenoic acid segment

Article abstract of DOI:10.1016/j.tetlet.2009.02.203

Stereoselective synthesis of the C1-C13 pentaenoic acid segment (4) of the novel antibiotic incednine (1) is described.

Full text of DOI:10.1016/j.tetlet.2009.02.203

Tetrahedron Letters 50 (2009) 2270–2273
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies of incednine: synthesis of C1–C13 pentaenoic acid segment
*
Takashi Ohtani, Hiroshi Kanda, Kensuke Misawa, Yoshifumi Urakawa, Kazunobu Toshima
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of the C1–C13 pentaenoic acid segment (4) of the novel antibiotic incednine (1)
Received 26 January 2009
Revised 26 February 2009
Accepted 27 February 2009
Available online 4 March 2009
is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Incednine
Antibiotic
Apoptosis
Pentaene
Horner–Wadsworth–Emmons olefination
In 2008, Imoto and co-workers reported the isolation of a novel
antibiotic, incednine (1), from Streptomyces sp. Although determi-
nation of the configuration at the C-23 stereocenter was supported
by computer modeling studies and the stereochemistry was not to-
tally clear, they also disclosed the structural elucidation of 1.1 This
novel natural product exhibited significant inhibitory activity
against the anti-apoptotic oncoproteins Bcl-2 and Bcl-xL, with a
mode of action distinct from those of other inhibitors which inhibit
the binding capacity of Bcl-xL to pro-apoptotic protein Bax. These
proteins are overexpressed in many cancers, resulting in the
expansion of transformed populations and advancement of the
multidrug-resistant stage.2–4 Therefore, 1 is expected to be a lead-
ing compound in the development of novel anti-tumor drugs, and
it is also expected to be a useful tool for further study of the Bcl-2
and Bcl-xL functions. The identification of its target protein could
provide a new insight into the anti-apoptotic mechanism of Bcl-2
family proteins.
thesis. The aglycon 2 is prepared from the pentaenoic acid segment
4, which is prepared from ethylene glycol (6), and the tetraene seg-
ment 3. The pentaene structure in 4 is constructed by various olef-
ination reactions, and the creation of the C-10 and C-11
stereocenters is achieved by Sharpless asymmetric epoxidation5
of the allylic alcohol 5 (Fig. 1).
The synthesis of pentaenoic acid segment 4, corresponding to
the C1–C13 of 1, is summarized in Schemes 1 and 3. We first syn-
thesized the known epoxide 9, referring to the procedure of Shi-
mizu and Nakata.6 Ethylene glycol (6) was protected as a mono-
PMB ether using PMBCl and KOH at 130 °C in 92% yield.7 The
resulting primary alcohol 7 was then converted into the a,b-unsat-
urated ester 8 by a one-pot Swern oxidation-Wittig reaction,8
using Ph3PC(Me)CO2Et, in 99% yield with E selectivity. After reduc-
tion of 8 to the allylic alcohol 5 in 99% yield using DIBAL-H, 5 was
treated with Ti(O-iPr)4, (À)-DIPT, and TBHP at À78 °C (Sharpless
asymmetric epoxidation) to furnish epoxide 9 in 78% yield with
90% ee. At this stage, we examined the regioselective introduction
of a hydroxyl group function to epoxide 9. After many attempts, we
finally found that applying Honda’s conditions9 using Me4NB-
H(OAc)3 gave the desired diol 10 in high yield (92%). The terminal
hydroxyl group of 10 was protected as a TBS ether in 94% yield, and
the acetyl group was then removed using NaOMe to give diol 11 in
78% yield. It was found under these conditions that migration of
the silyl group produced 11 and 12 in a ratio of 78:21. Fortunately,
however, the undesired silyl ether 12 could easily be converted
into the desired 11 by treatment with NaOMe in MeOH. Protection
of the 1,2-diol in 11 as a cyclic acetal isopropylidene group, using
Me2C(OMe)2 and CSA, followed by deprotection of the TBS group
with TBAF and Swern oxidation of the resulting primary alcohol
produced aldehyde 13 in 88% overall yield. Subsequent Wittig
Structurally, 1 has been shown to contain several unique fea-
tures. It contains
a-methoxy-a,b-unsaturated amide structure
and independent conjugated pentaene and tetraene systems in
the 24-membered macrolactam core. Furthermore, the macrolac-
tam core is coupled with two amino sugars by b-glycosidic bonds.
Because of its important biological activity and novel molecular
architecture, 1 has been deemed as a prime target for total synthe-
sis. Herein we report the stereoselective synthesis of the C1–C13
pentaenoic acid segment 4.
In our strategy for the total synthesis of 1, as shown in Figure 1,
the C-11 glycosidic bond is constructed in the last stage of the syn-
* Corresponding author. Tel./fax: +81 45 566 1576.
E-mail address: toshima@applc.keio.ac.jp (K. Toshima).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.203

T. Ohtani et al. / Tetrahedron Letters 50 (2009) 2270–2273
2271
13
23
1
11
O
HN
O
OH
O
OMe
O
NHMe
O
Incednine(1)
OH
MeHN
13
M = B(OR)2, SnR3
M
11
HO
OH
HN
OH
O
1
H2N
3
2
OMe
+
13
I
OH
1
HO
PMBO
10
CO2H
11
11
TESO
6
OTES
5
OMe
4
Figure 1. Retrosynthetic analysis of incednine (1).
O
OP
OH
d
b
HO
PMBO
R
PMBO
ethylene glycol (6) : P = H
8 : R = CO2Et
5 : R = CH2OH
a
c
9
7
: P = PMB
e
HO
HO
HO
f,g
OTBS
+
OH
OH
PMBO
PMBO
PMBO
OH
OTBS
(21%)
OAc
11 (78%)
12
10
h
i-k
O
O
Ph3P
CO2Me
PMBO
14
CO2Me
PMBO
CHO
O
O
l
15
13
m
3 steps
OMe
PO
OP
O
PMBO
CO2Me
PMBO
CO2Me
O
16
17 : P = H
18
n
: P=TES
Scheme 1. Reagents and conditions: (a) PMBCl, KOH, 130 °C, 3 h (Dean–Stark), then 35 °C, 14 h, 92%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C to rt, 1 h, then Ph3PC(Me)CO2Et,
rt, 30 min, 99%; (c) DIBAL-H, PhMe, À78 °C, 20 min, 99%; (d) Ti(Oi-Pr)4, (À)-DIPT, TBHP/decane, MS4A, CH2Cl2, À20 °C, 65 h, 78% (90% ee); (e) Me4NBH(OAc)3, PhMe, 60 °C,
13 h, 92%; (f) TBSCl, imid., DMF, 0 °C to rt, 3 h, 94%; (g) NaOMe, MeOH, À20 °C, 24 h, 78%; (h) NaOMe, MeOH, 0 °C to rt, 75%; (i) Me2C(OMe)2, CSA, acetone, 0 °C, 2 h, 98%; (j)
TBAF, THF, rt, 5 h, 97%; (k) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C to À20 °C, 1.5 h, 93%; (l) 14, PhMe, 60 °C, 21 h, 97% (E/Z = 79/21); (m) PPTS, MeOH, rt to 40 °C, 4 d, 64%; (n)
TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 20 min, 98%.

2272
T. Ohtani et al. / Tetrahedron Letters 50 (2009) 2270–2273
reaction of 13 with 1410 introduced the diene structure, producing
15 in 97% yield with E/Z = 79/21. Although the E/Z isomers were
inseparable at this stage, we were able to separate them at the fol-
lowing stage. Compound 15 was converted to the tetraene segment
16 in three steps (1: DIBAL-H reduction (93%); 2: One-pot MnO2
oxidation-Wittig reaction using Ph3PC(Me)CHO (74%); and 3:
Horner–Wadsworth–Emmons reaction using (i-PrO)2P(O)CH(O-
Me)CO2Me (49%)). Unfortunately, all attempts to selectively re-
move the PMB group in 16 failed due to instability under acidic
and oxidative conditions. It was also predicted that deprotection
of the isopropylidene group at the C10 and C11 positions in the lat-
ter step would prove to be a difficult problem in the synthesis of 1.
Therefore, at this stage, the cyclic acetal of 15 was removed using
PPTS in MeOH, and the resulting diol 17 was protected with TES
groups using TESOTf and 2,6-lutidine to give 18 in 63% overall
yield.
Fortunately, we found that optical resolution of diol 17 using
the chiral resolving reagent (R)-3a-allyl-3,3a,4,5-tetrahydro-2H-
cyclopenta[b]furan (CPF)11 developed by Nemoto et al. was effec-
tive (Scheme 2). Subjecting 17 to CPF in the presence of catalytic
amounts of PPTS in PhMe led to the corresponding acetals in 99%
yield as a mixture of diastereomers, 19 (94%) and 19’ (5%), which
could easily be separated by flash column chromatography
(CH2Cl2/EtOAc = 10/1 (DRf = 0.089)). Removal of CPF from 19 using
PTSA in MeOH gave (2S,3R)-17 as a single enantiomer in 99% yield.
Enantiomerically pure 18, obtained as described above, was
treated with DIBAL-H to reduce the ester function, and the result-
ing allylic alcohol was oxidized with MnO2 and then treated with
O
HO
HO
HO
CPF
a
PMBO
CO2Me
PMBO
CO2Me
PMBO
PMBO
CO2Me
CO2Me
O
O
OH
+
O
O
17 (90%e.e.)
b
HO
19
19'
(5%)
(94%)
OH
(2S, 3R)-17
single enantiomer
Scheme 2. Reagents and conditions: (a) CPF, PPTS, PhMe, rt, 1.5 h, 99%; (b) p-TsOH, MeOH, rt, 2 h, 99%.
OMe
CO2Me
TESO
PMBO
OTES
21
3 steps
TESO
TESO
OHC
a,b
c,d
18
PMBO
CO2Et
CO2Et
OTES
OTES
20
22
e
13
13
I
I
f,g
h,i
CHO
TESO
4
CO2Et
TESO
OTES
OTES
24
23
Scheme 3. Reagents and conditions: (a) DIBAL-H, PhMe, À78 °C, 30 min, 95%; (b) MnO2, PhMe, 40 °C, 5 h, then Ph3PC(Me)CO2Et, 40 °C, 16 h, 95%; (c) DDQ, CH2Cl2/pH 7.2
phosphate buffer (1/1), 0 °C to rt, 19 h, 72%; d) Dess–Martin periodinane, pyr., CH2Cl2, 0 °C to rt, 17 h, 92%; (e) (Ph3P+CH2I)IÀ, NaHMDS, HMPA, THF, À98 °C, 1 h, 67%; (f) DIBAL-
H, PhMe, À78 °C, 10 min, 98%; (g) MnO2, CH2Cl2, 40 °C, 2 h, 77%; (h) (MeO)2P(O)CH(OMe)CO2Me, KHMDS, 18-crown-6 ether, THF, 0 °C to rt, 1 h, 82%; (i) 1.0 M KOH aq, 1,4-
dioxane, 0 °C to 30 °C, 2 h, 66%.

T. Ohtani et al. / Tetrahedron Letters 50 (2009) 2270–2273
2273
Ph3P=C(Me)CO2Et to furnish the
a
,b-unsaturated ester 20 in 90%
the 21st Century COE Program ‘Keio Life-Conjugated Chemistry’
and the High-Tech Research Center Project for Private Universities:
Matching Fund Subsidy, 2006–2011, from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology of Japan (MEXT).
overall yield. At this stage we again constructed an enol ether
structure 21 in three steps (1:DIBAL-H reduction (78%); 2:MnO2
oxidation (89%):3. Horner–Wadsworth–Emmons reaction using
(MeO)2P(O)CH(OMe)CO2Me) (54%)). Unfortunately, deprotection
of PMB group of 21 was again unsuccessful. Therefore, we next at-
References and notes
tempted to introduce a vinyl iodide structure to the
a,b-unsatu-
rated ester 20 in advance. It was found, fortunately, that removal
of the PMB group in 20 with DDQ proceeded very smoothly, and
Dess–Martin oxidation of the resulting alcohol gave aldehyde 22
in 66% overall yield. Wittig reaction of 22 with (Ph3P+CH2I)IÀ in
the presence of NaHMDS and HMPA in THF at À98 °C led to vinyl
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iodide 23 in 67% yield with Z selectivity. The a,b-unsaturated ester
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in 23 was reduced by DIBAL-H, and the resulting allylic alcohol was
oxidized by MnO2 to furnish aldehyde 24 in 75% overall yield. Fi-
nally, Horner–Wadsworth–Emmons olefination of 24 using
(MeO)2P(O)CH(OMe)CO2Me in the presence of KHMDS and 18-
crown-6 ether12 in THF, followed by hydrolysis using KOH, gave
the C1–C13 pentaenoic acid segment 413 in 54% overall yield.
In conclusion, we achieved a stereoselective synthesis of penta-
enoic acid segment 4, which is a key segment in the synthesis of
incednine (1).
9. Honda, T.; Mizutani, H. Heterocycles 1998, 48, 1753.
10. Buchta, A.; Andree, F. Chem. Ber. 1959, 92, 3111.
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Acknowledgments
We sincerely thank Professor M. Imoto and Dr. Y. Futamura of
Keio University, and Dr. Y. Takahashi of the Microbial Chemistry
Research Center, for providing us with very useful information on
the chemical and physical properties of incednine. We also thank
ZEON Corporation for providing the chiral resolving reagent,
ALBO-V, a CPF reagent. This research was supported in part by
13. Selected 1H NMR (300 MHz, CDCl3) (d, SiMe4; J Hz) data for 4: d 6.77 (1H, s, H3),
6.54 (1H, dd, J = 11.1 and 13.8 Hz, H6), 6.44 (1H, d, J = 13.8 Hz, H5), 6.35 (1H,
dd, J = 10.5 and 11.1 Hz, H7), 6.33 (1H, d, J = 7.8 Hz, H13), 6.26 (1H, dd, J = 10.5
and 14.7 Hz, H8), 6.16 (1H, dd, J = 7.8 and 8.4 Hz, H12), 5.89 (1H, d, J = 14.7 Hz,
H9), 4.12 (1H, d, J = 8.4 Hz, H11), 3.71 (3H, s, C2–OMe), 2.13 (3H, s, C4–Me), 1.36
(3H, s, C10–Me), 0.94 and 0.93 (each 9H, t, J = 8.4 Hz, (CH3CH2)3Si), 0.58 (12H, m,
(CH3CH2)3Si).