Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues

Article abstract of DOI:10.1002/anie.201801659

The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl₃-catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid-labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction.

Full text of DOI:10.1002/anie.201801659

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Total Synthesis and Biological Evaluation of Siladenoserinol A
and its Analogues
Authors: Masahito Yoshida, Koya Saito, Hikaru Kato, Sachiko
Tsukamoto, and Takayuki Doi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801659
Angew. Chem. 10.1002/ange.201801659
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10.1002/anie.201801659
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis and Biological Evaluation of Siladenoserinol A
and its Analogues
Masahito Yoshida,[a] Koya Saito, [a] Hikaru Kato, [b] Sachiko Tsukamoto, [b] and Takayuki Doi*[a]
Abstract: The total synthesis of a novel p53–Hdm2 interaction
inhibitor siladenoserinol A has been achieved. The AuCl3-catalyzed
hydroalkoxylation of an alkynoate derivative smoothly and
regioselectively proceeded to afford a bicycloketal in excellent yield.
A glycerophosphocholine moiety was successfully introduced by the
Horner-Wadsworth-Emmons reaction using an originally developed
phosphonoacetate derivative. Finally, removal of the acid labile
protecting groups, followed by regioselective sulfamate formation of
the serinol moiety afforded the desired siladenoserinol A, and its
benzoyl analogue was also successfully synthesized. The biological
evaluation showed that the sulfamate is essential for the biological
activity, and modification of the acyl group on the bicycloketal can
improve the inhibitory activity against the p53–Hdm2 interaction.
could help developing a library of analogues to elucidate the
mode of action. Herein, we report the first total synthesis and
biological evaluation of a novel p53–Hdm2 interaction inhibitor
called siladenoserinol A and its analogues.
O
O
O
O–
O
Cl
Cl
O
NH
O
P
N+Me3
N
AcO
N
O
O
O
11
O
OAc
O
OH
NHSO3H
N
O
Siladenoserinol A (1)
Nutlin-3a (2)
Figure 1. Structures of 1 and 2.
Siladenoserinol A (1) was isolated from the extract of a tunicate
of the family didemnidae collected in Indonesia in 2013, and 1
possesses a 6,8-dioxabicyclo[3.2.1]octane skeleton with two
long carbon chains containing unique sulfamated serinol and
glycerophosphocholine moieties (Figure 1).1 A variety of natural
products containing the 6,8-dioxabicyclo[3.2.1]octane skeleton
have shown to exhibit unique biological activities including
pheromonization, cytotoxicity against cancer cells, and inhibition
of HIV integrase.2 Interestingly, siladenoserinol A (1) exhibits
potent inhibitory activity against the p53–Hdm2 (human murine
double minute 2) interaction (IC50 = 2.0 M).1 The tumor
suppressor p53 is essential for the induction of the apoptosis of
cancer cells. The upregulation of Hdm2 in the cancer cells is
well known to downregulate p53 by a direct interaction that
subsequently induces ubiquitination of the p53 and triggers
proteasomal degradation. Therefore, the p53–Hdm2 interaction
has been a target for drug discovery in cancer therapeutics.3
Several small molecule inhibitors for the above interaction have
been extensively developed; for instance, the cis-imidazoline
derivative nutlin-3a (2) strongly inhibits the p53–Mdm2
interaction (IC50 = 0.09 M) by binding to the p53 binding
pockets on the Mdm2.4 Most of the inhibitors related to nutlin-3a
(2) act as a mimic of three key hydrophobic residues of p53
(Phe19, Trp23, and Leu26). However, the shape and size of
siladenoserinol A (1) is different from the small molecule
inhibitors, suggesting an alternative binding mechanism for p53-
Hdm2 interaction. The total synthesis of siladenoserinol A (1)
The retrosynthesis of 1 is illustrated in Scheme 1. The
desired 1 could be obtained from 3 by regioselective formation
of the sulfamate in a serinol moiety. A glycerophosphocholine
moiety in 3 can be introduced by esterification; however,
coupling with the corresponding ,-unsaturated acid is known
to be sluggish owing to low reactivity of the acid moiety, and
facile isomerization of the resulting ,-unsaturated ester is also
observed.5 Thus, we chose the Horner–Wadsworth–Emmons
(HWE) reaction of
4 with 5 to directly introduce the
glycerophosphocholine concomitantly via the formation of an
,-unsaturated ester. A side chain containing a serinol moiety
in 4 can be introduced onto 6 by Julia-Kocienski olefination with
7, and it can be utilized to prepare analogues possessing the
side chain with an arbitrary length. The key intermediate
bicycloketal 6 would be regioselectively prepared by double
hydroxylation of the alkynoate 8.6
Horner-Wadsworth
-Emmons Reaction
O
O
O–
O
O
P
N+Me3
AcO
O
O
O–
O
O
O
P
N+Me3
O
O
O
AcO
11
O
OAc
O
O
O
11
O
OH
OAc
NHSO3
H
Regioselective
Sulfamate Formation
BocN
3
Siladenoserinol A (1)
Double
Hydroalkoxylation
OEt
O
OEt
OBn
P
O
O
O–
O
N+Me3
OBn
O
P
BnO
OH
OH
O
O
AcO
O
O
OAc
BnO
5
O
O
O
11
O
O
11
O
OMe
Bicycloketal 6
O
O
BocN
SO2 BocN
N
4
Alkynoate 8
N
Julia-Kocienski
Olefination
N
Ph
7
N
Scheme 1. Retrosynthesis of siladenoserinol A (1).
[a]
Dr. M. Yoshida, Dr. K. Saito, and Prof. Dr. T. Doi
Graduate School of Pharmaceutical Sciences
Tohoku University
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail:
Dr. H. Kato, and Prof. Dr. S. Tsukamoto
Graduate School of Pharmaceutical Sciences
Kumamoto University
Toward
the
preparation
of
the
6,8-
dioxabicyclo[3.2.1]octane skeleton,7 we initially investigated
Pd(II)-, Au(I)-, and Au(III)-catalyzed double hydroalkoxylation8 in
a model study using the alkynoate 9,9 and the results are
summarized in Table 1. Notably, the reaction in the presence of
5 mol% of AuCl3 was smoothly complete within 5 min at ambient
[b]
5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801659
Angewandte Chemie International Edition
COMMUNICATION
1) (COCl)2, DMSO
NEt3, CH2Cl2
–78 °C, 1 h
temperature to provide the desired bicycloketal 10 in 79% yield
(entry 4).
O
1) BH3•SMe2, B(OMe)3
THF, rt, 12 h
HO
HO
Ph
O
Ph
O
14, BuLi
OH
OH
2) PhCH(OMe)2
p-TsOH, CH2Cl2
rt, 36 h
O
2) Ohira-Bestmann
K2CO3, MeOH
rt, 2 h
THF, DMPU
–50 °C to 0 °C, 6 h
88%
O
O
13
D-Malic acid (11)
12
OBn
2 steps 90%
2 steps 88%
14:
Br
5
Table 1. Investigation of the reaction conditions for the double
hydroalkoxylation of 9.
OBn
1) Red-Al®, Et2
rt, 3 h
O
OBn
OBn
6
conc. HCl
DIBAL-H
6
6
Ph
O
HO
Ph
O
MeOH, rt, 2 h
77%
toluene, 0 °C, 3 h
2) PhCH(OMe)2
p-TsOH, CH2Cl2
rt, 24 h
OH
93%
O
HO
O
Conditions
O
O
O
OH
O
15
16
17
2 steps 97%
rt, 30 °C
OMe
OMe
Alkynoate 9
1) K2OsO2(OH)4•2H2
O
NH2
Bicycloketal 10
(DHQD)2PHAL, MsNH2
OBn
OBn
OBn
K2CO3, K3[Fe(CN)6
tBuOH-H2O, rt, 12 h
]
TsCl
Li
6
NEt3, DMAP
NH2
O
O
O
BnO
BnO
Entry
Catalyst [mol%]
PdCl2(MeCN)2 [5]
AuClPPh3/AgOTf [5]
AuClPPh3 [5]
AuCl3 [5]
Solvent
MeCN
MeCN
MeCN
MeCN
THF
Time
12 h
Yield of 10 [%][a]
O
BnO
BnO
2) 2,2-DMP, p-TsOH
CH2Cl2, rt ,12 h
2 steps 99%
CH2Cl2, rt ,12 h
99%
DMSO, rt, 1 h
95%
OH
OH
19
OTs
20
18
1
2
3
4
5
6
7
8
9
10
52
69
0
OBn
OBn
OBn
ClCO2Me
BuLi
O
O
OH
OH
O
O
9 h
90% aq AcOH
THF
–78 °C, 1 h
92%
BnO
reflux, 1 h
91%
BnO
O
O
10 h
OMe
OMe
21
22
Alkynoate 8
5 min
10 min
15 min
20 min
45 min
18 h
79
56
72
75
77
0[b]
0[b]
Scheme 2. Preparation of the cyclization precursor alkynoate 8.
AuCl3 [5]
AuCl3 [5]
CH2Cl2
Toluene
MeCN
MeCN
MeCN
As the precursor alkynoate 8 was successfully prepared,
synthesis of the bicycloketal 23 was performed by AuCl3-
catalyzed double hydroalkoxylation (Scheme 2). To our delight,
the reaction of alkynoate 8 in our optimized conditions afforded
bicycloketal 23 in 83% yield as the sole product. The structure of
23 was confirmed by the nOe between Ha and Hb. Methyl ester
23 was reduced by DIBAL-H at –78 °C to give aldehyde 6 in
99% yield. Julia–Kocienski olefination of the aldehyde 6 with
sulfone 79, followed by hydrogenation of the resulting alkene
concomitantly with removal of the benzyl groups afforded the
diol 24 in 90% yield. After selective oxidation of the primary
alcohol in 24 by TEMPO-PhI(OAc)2,12 acetylation of the
secondary alcohol on the bicycloketal furnished the aldehyde 4
to be ready for the HWE reaction with the phosphonoacetate 5
(Scheme 3).
AuCl3 [5]
AuCl3 [1]
AgOTf [5]
AlCl3 [5]
12 h
[a] Isolated yield. [b] Substrate 9 was quantitatively recovered.
With the optimal conditions for the bicycloketal formation in
hand, the cyclization precursor alkynoate 8 was synthesized and
details are shown in Scheme 2. D-Malic acid (11) was reduced
using BH3•SMe2/B(OMe)3, and the resulting 1,3-diol was
protected to afford benzylidene acetal 12. After oxidation of the
primary alcohol in 12, alkynylation of the resulting aldehyde was
performed using Ohira-Bestmann reagent10 to provide alkyne 13
in 88% yield. Alkylation of the terminal alkyne with the bromide
14 afforded 15, which was treated with HCl/MeOH to yield the
diol 16. Selective reduction of the endo-alkyne using Red-Al®,
followed by protection of diol afforded 17. Regioselective
cleavage of the acetal moiety in 17 was carried out using DIBAL-
H to provide the alcohol 18 in 93% yield. Sharpless asymmetric
hydroxylation11 of the alkene moiety in 18 stereoselectively
proceeded, and the resulting 1,2-diol was protected using 2,2-
dimethoxypropane under acidic conditions to afford 19. After
modification of the primary alcohol in 19 to the tosylate 20,
alkynylation of 20 using lithium acetylide-ethylendiamine
complex furnished the terminal alkyne 21 in 95% yield. Acylation
of the terminal alkyne in 21 proceeded smoothly to afford the
methyl ester 22, and removal of the acetal moiety in 22 afforded
the alkynoate 8 in 91% yield.
O
H
OBn
BnO
AuCl3
OBn
OBn
6
OH
OH
BnO
(5 mol%)
O
O
O
O
Hb
BnO
O
MeCN, 30 °C
5 min, 83%
Ha
MeO
OMe
NOE
OMe
O
23
Alkynoate 8
OH
1) 7, LHMDS, THF
–78 °C, 1 h
HO
OBn
BnO
DIBAL-H
O
O
11
O
O
O
BocN
CH2Cl2
–78 °C, 5 min
99%
O
2) H2, Pd(OH)2/C, THF
rt, 30 h, 90%
O
24
6
11
O
1) TEMPO, PhI(OAc)2
AcO
O
O
O
CH2Cl2, rt, 12 h, 90%
O
11
BocN
SO2
Ph
N
N
O
O
BocN
2) Ac2O, NEt3, DMAP
CH2Cl2, rt, 2 h, 78%
N
N
7
4
Scheme 2. Preparation of the aldehyde 4 via the Au(III)-catalyzed double
hydroalkoxylation of 8.
Because of an unprecedented method for the introduction
of a glycerophosphocholine moiety to the aldehyde 4, the
reaction conditions for the HWE reaction with the
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10.1002/anie.201801659
Angewandte Chemie International Edition
COMMUNICATION
O
O
O–
O
O
phosphonoacetate 59 were initially investigated using
benzaldehyde in a model study and the results are summarized
in Table 2. When the reaction using sodium hydride in THF was
attempted, the complex mixture was obtained because a base-
sensitive phosphonocholine moiety would be lost owing to the
strongly basic conditions (entry 1). Regarding the HWE reaction,
the Masamune-Roush condition13 is known to be effective for the
AcO
5
O
O
P
N+Me3
AcO
DBU, LiBr
O
O
11
O
O
O
O
11
O
BocN
OAc
THF
rt, 1 h, 64%
O
BocN
4
3
O
P
O–
O
O
N+Me3
AcO
O
SO3•Py, Et3N
3 M HCl
O
O
O
11
O
OAc
THF–H2O (1:1)
1,4-dioxane
rt, 2 h, 83%
OH
rt, 4 h, 58%
NH2•HCl
base-sensitive substrate to prepare
a corresponding ,-
26
unsaturated ester. As expected, the reaction using reported
conditions (DBU, LiCl) was performed at ambient temperature to
O
O
O–
O
OEt
O
P
N+Me3
OEt
AcO
O
P
O
O
O–
O
O
O
N+Me3
O
11
O
P
OAc
afford the desired 25 in 52% yield without forming
a
O
OH
NHSO3H
O
OAc
corresponding Z-isomer (entry 2). Notably, the use of LiBr as an
additive was more effective in promoting the reaction,14 and the
reaction in THF smoothly proceeded to afford the ,-
unsaturated ester 25 in 67% yield (entry 4).
5
Siladenoserinol A (1)
[a]25D +16.2 (c 1.30, MeOH)
lit. [a]21D +14 (c 32, MeOH)
Scheme 3. Total synthesis of siladenoserinol A (1).
Table 2. Investigation of the reaction conditions for HWE reaction of
benzaldehyde using 5.
After the total synthesis of 1, the synthesis and biological
evaluation of siladenoserinol analogues were then
OEt
investigated.17 The results of biological evaluations for the
natural product 1 and its analogues are shown in Table 3.18 The
inhibitory activity of synthetic 1 was identical to that of the
natural product as a positive control (IC50 = 17 M, entry 1),
whereas the desulfamated analogue 26 did not exhibit potent
inhibition of p53-Hdm2 (entry 2). Notably, the benzoyl analogue
27 exhibited a fivefold potent inhibitory activity (IC50 = 3 M,
entry 3) compared with the natural product 1. The above
observation indicates that the sulfamate moiety is crucial for
inhibiting the p53-Hdm2 interaction, and modification of the acyl
group on the 6,8-dioxabicyclo[3.2.1]octane skeleton would be a
promising derivatization to enhance the inhibition of the p53-
Hdm2 interaction.
O
OEt
O
O
O–
O
P
Conditions
PhCHO
O–
O
Ph
O
P
N+Me3
O
O
O
P
N+Me3
O
OAc
O
OAc
5
25
Entry
Base
[equiv]
Additive
[equiv]
Solvent
Time
[h]
Yield of 25 [%][a]
1
2
3
4
5
NaH [2]
DBU [2]
DBU [2]
DBU [5]
DIEA [5]
-
MeCN
MeCN
MeCN
THF
2
trace
52
LiCl [2]
LiBr [2]
LiBr [2]
LiBr [2]
5
2
61
2
67
THF
24
49
Table 3. Inhibitory activity for p53–Hdm2 interaction of 1 and its analogues.
[a] Isolated yield.
O
O
O
O
O
P
NMe3
R1O
O
O
O
11
O
OAc
OH
NHR2
Having
an
efficient
method
to
introduce
a
glycerophosphocholine moiety by the HWE reaction, we applied
this method for the total synthesis of 1. The introduction of a
glycerophosphocholine moiety to aldehyde 4 was smoothly
achieved by treatment with the phosphonoacetate 5 under the
optimized conditions (Table 2, entry 4), and the resulting 3 was
afforded in 64% yield without losing a base sensitive choline
moiety.15 Finally, removal of the acid-labile protecting groups in
Entry
1
Compound
Siladenoserinol A (1)
R1
Ac
R2
IC50 [M]
SO3H
Synthetic: 17
(Natural: 17)
2
3
Desulfamate analogue 26
Benzoate analogue 27
Ac
Bz
H
-
SO3H
3
3
quantitatively afforded 26, and regioselective sulfamate
formation of the serinol moiety using the sulfur trioxide-pyridine
complex (SO3•Py)16 furnished siladenoserinol A (1), spectral
data of which–including specific rotation–were in good
agreement with those of the natural product (Scheme 3).1
In conclusion, we have achieved the total synthesis of
siladenoserinol A (1) and its analogues for the first time. The key
intermediate bicycloketal 23 was successfully prepared by the
AuCl3-catalyzed regioselective double hydroalkoxylation of an
alkynoate
derivative
8
in
83%
yield.
As
the
dioxabicyclo[3.2.1]octane skeleton is often found in the structure
of biologically active natural products, thus the AuCl3-catalyzed
reaction we developed could be broadly applicable in the
preparation
of
a
variety
of
privileged
6,8-
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10.1002/anie.201801659
Angewandte Chemie International Edition
COMMUNICATION
[5]
[6]
a) S. Liu, D. F. O'Brien, Macromolecules 1999, 32, 5519–5524; b) M. S.
Christensen, P. J. Pedersen, T. L. Andresen, R. Madsen, M. H.
Clausen, Eur. J. Org. Chem. 2010, 719–724.
dioxabicyclo[3.2.1]octane skeletons. The two aliphatic side
chains
were
smoothly
installed
onto
the
6,8-
dioxabicyclo[3.2.1]octane skeleton. The phosphonoacetate
derivative 5 originally prepared smoothly reacted with the
aldehyde 4 under the optimized conditions (DBU, LiBr, THF) to
Hydroalkoxylation of ,-unsaturated ketone or ester derivatives in an
intramolecular Michael fashion is also a powerful method to prepare a
heterocyclic system often found in the biologically active natural
products: a) K. Nakatani, A. Okamoto, M. Yamanuki, I, Saito, J. Org.
Chem. 1994, 59, 4360–4361; b) M. Yoshida, Y. Fujino, K. Saito, T. Doi,
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2013, 52, 4470–4473; e) B. M. Trost, C. E. Stivala, K. L. Hull, A. Huang,
D. R. Fandrick, J. Am. Chem. Soc. 2014, 136, 88–91; f) M. Yoshida, K.
Saito, Y. Fujino, T. Doi Tetrahedron 2014, 70, 3452–3458; g) L. Yang,
Z. Lin, S.–H. Huang, R. Hong. Angew. Chem. Int. Ed. 2016, 55, 6280–
6284.
introduce
the
side
chain
possessing
the
glycerophosphonocholine moiety. Finally, removal of the acid
labile protecting groups, which was followed by regioselective
sulfamate formation furnished the desired 1. Its benzoyl
analogue 27 was also successfully synthesized, and it exhibited
a fivefold potent p53–Hdm2 inhibitory activity compared with the
natural product. Notably, the potent activity was not observed for
its desulfamated analogue, indicating that a sulfamate on the
serinol moiety should be crucial for the desired p53-Hdm2
inhibition. Further investigation based on the analogue synthesis
would assist in the elucidation for the mode of action and in the
discovery of novel drug candidates targeted at the p53–Hdm2
interaction.
[7]
[8]
Recent review for the synthesis of 6,8-dioxabicyclo[3.2.1]octane
skeleton, and the references are therein, W. Zhang, R. Tong, J. Org.
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Gold catalysts are often utilized for hydroalkoxylation of alkynoate
derivatives leading to tetrahydropyran-fused heterocycles: a) B. Liu, J.
K. De Brabander, Org. Lett. 2006, 8, 4907–4910; b) A. Aponick, C.–Y.
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C. Tzschucke, J. Crecente-Campo, S. McGrath, S. V. Ley, Eur. J. Org.
Chem. 2009, 11, 1698–1706. d) I. Volchkov, K. Sharma, E. J. Cho, D.-
S. Lee, Chem. Asian J. 2011, 6, 1961–1966; e) M. C. Blanco Jaimes, C.
R. N. Böhling, J. M. Serrano-Becerra, A. S. K. Hashmi, Angew. Chem.
Int. Ed. 2013, 52, 7963–7966; f) S. R. K. Minkler, N. A. Isley, D. J.
Lippincott, N. Krause, B. H. Lipshutz, Org. Lett. 2014, 16, 724–726; g)
K. Belger, N. Krause, Eur. J. Org. Chem. 2015, 220–225.
Acknowledgements
This work was supported by JSPS KAKENHI, Grant no.
JP15H05837 (Grant-in-Aid for Scientific Research on Innovative
Areas: Middle Molecular Strategy).
[9]
Details of the synthesis are described in the supporting information.
Keywords: bicycloketal • glycerophosphocholine • serinol lipid •
PPIs • total synthesis
[10] a) S. Ohira, Synth. Commun. 1989, 19, 561–564; b) S. Müller, B.
Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521–522.
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J. Am. Chem. Soc. 1993, 115, 8463–8464.
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[15] Esterification of the ,-unsaturated acid derived from the aldehyde 4
(Allyl diethylphosphonoacetate, NaH, THF; cat. Pd(PPh3)4, PhSiH3,
CH2Cl2, 71% in 2 steps) with a glycerophosphocholine did not proceed
Example for the biologically active natural products containing 6,8-
dioxabicyclo[3.2.1]octane skeleton: a) R. M. Silverstein, R. G. Brownlee,
T. E. Bellas, D. L. Wood, L. E. Browne, Science 1968, 159, 889–891; b)
G. W. Kinzer, A. F. Fentiman, T. F. Page, R. L. Foltz, J. P. Vite, G. B.
Pitman, Nature 1969, 221, 477–478; c) N. Takada, K. Suenaga, K.
Yamada, S.-Z. Zheng, H.-S. Chen, D. Uemura, Chem. Lett. 1999,
1025–1026; d) S. S. Mitchel, D. Rhodes, F. D. Bushman, D. J. Faulkner,
Org. Lett. 2000, 2, 1605–1607; e) S. Yin, C.-Q. Fan, L. Dong, J.-M. Yue,
Tetrahedron 2006, 62, 2569–2575.
using
the
following
conventional
conditions
(DIC/DMAP,
PyBroP/DIEA/DMAP, triphosgene/2,6-collidine/DMAP).
[16] D. T. Warner, L. L. Coleman, J. Org. Chem. 1958, 23, 1133–1135.
[17] Synthesis of the benzoyl analogue 27 was successfully achieved in the
similar manner to the total synthesis of 1 (supporting information).
[18] Evaluation of the inhibitory activity for p53-Hdm2 interaction was
performed as previously reported; H. Kato, T. Nehira, K. Matsuo, T.
Kawabata, Y. Kobashigawa, H. Morioka, F. Losung, R. E. P.
Mangindaan, N. J. de Voogd, H. Yokosawa, S. Tsukamoto,
Tetrahedron 2015, 71, 6956–6960.
[3]
[4]
a) P. Chène, Nat. Rev. Cancer 2003, 3, 102–109; b) S. Wang, Y. Zhao,
D. Bernard, A. Aguilar, S. Kumar, Top. Med. Chem. 2012, 8, 57–80.
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Liu, Science 2004, 303, 844–848.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801659
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
OEt
OEt
M. Yoshida, K. Saito, H. Kato, S.
Tsukamoto, T. Doi*
O
Horner-Wadsworth
-Emmons Reaction
AuCl3-Catalyzed
Double Hydroalkoxylation
P
O
O
O
O
O
P
NMe3
O
O
O
O
O
P
NMe3
O
AcO
OBn
OAc
BnO
O
O
O
11
O
O
O
OAc
Page No. – Page No.
11
OH
O
O
O
NHSO3H
Regioselective
BocN
SO2
Ph
Julia-Kocienski
Olefination
N
A Total Synthesis and Biological
Evaluation of Siladenoserinol A And
Its Analogues
Sulfamate Formation
N
N
N
Siladenoserinol A (1)
The total synthesis of a novel p53–Hdm2 interaction inhibitor siladenoserinol A has
been achieved. catalytic amount of AuCl3 efficiently promoted double
A
hydroalkoxylation leading to the bicycloketal in high yield. Unique side-chains were
successfully introduced by Julia-Kocienski reaction and the HWE reaction using
originally developed phosphonoacetate. Finally, regioselective sulfamate formation
of the serinol moiety furnished siladenoserinol A and its analogues.
This article is protected by copyright. All rights reserved.