Biology- and diversity-oriented domino reactions for synthesis of AMPA receptor antagonist IKM-159 and analogues

Article abstract of DOI:10.1055/s-0033-1338543

By natural product inspired diversity-oriented synthesis, we had developed a new class of selective antagonist, IKM-159, for the AMPA receptor. Here, we report syntheses of IKM-159 and skeletally diverse five analogues in racemic forms, two of which are heterotricycles and the other three compounds are truncated analogues, to study the structure-activity relationships. The key reactions are two domino reactions including Ugi/Diels-Alder reaction and domino metathesis reaction. An exceptionally high level of regiocontrol in the cross metathesis reaction is also reported. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338543

3106▌
PAPER
paper
Biology- and Diversity-Oriented Domino Reactions for Synthesis of AMPA
Receptor Antagonist IKM-159 and Analogues
BIOS-DOS for Ligand Discovery
Masato Oikawa,* Yuuki Kasori, Lisa Katayama, Etsuko Murakami, Yuya Oikawa, Yuichi Ishikawa
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Fax +81(45)7872403; E-mail: moikawa@yokohama-cu.ac.jp
Received: 02.08.2013; Accepted after revision: 19.08.2013
As for the combination of MCR and domino reactions,
Abstract: By natural product inspired diversity-oriented synthesis,
domino Michael/Wittig/Michael/Michael reaction be-
we had developed a new class of selective antagonist, IKM-159, for
tween three components has been reported by Hong et al.
the AMPA receptor. Here, we report syntheses of IKM-159 and
skeletally diverse five analogues in racemic forms, two of which are
to provide skeletally diverse, optically active carbocy-
heterotricycles and the other three compounds are truncated ana- cles.13 A multicatalytic system has been also employed
for the synthesis of spiroquinolines.14 The Hong group
logues, to study the structure–activity relationships. The key reac-
tions are two domino reactions including Ugi/Diels–Alder reaction
has further achieved a domino oxa-Michael/Michael/
and domino metathesis reaction. An exceptionally high level of re-
Michael/aldol reaction of three components for antipro-
giocontrol in the cross metathesis reaction is also reported.
liferative natural product (+)-conicol as an application to
BIOS.15
Key words: domino reaction, heterocycles, medicinal chemistry,
metathesis, multicomponent reaction
Ugi four-component coupling reaction, which is one of
the most popular MCRs, provides α-(acylamino)amides.16
Compound collections with appendage diversity have
Diversity-oriented synthesis (DOS) plays a key role in
been, indeed, constructed by Ugi reaction. Furthermore,
discovery of novel small molecules that can be used to
in combination with other reactions (so-called post-Ugi
dissect biology.1 In 2000, DOS was defined as ‘(a pro-
reaction), the compounds can be more varied skeletally.17
cess) that leads to structurally complex and diverse small
In 1999, a milestone in this class is represented by the
molecules’ by Schreiber.2 In 2004, his group introduced
work of Paulvannan.18 He reported a domino Ugi/Diels–
δ-elements to pre-encode skeletal information, so that the
Alder (UDA) reaction employing 2-furfural and fumaric
compound collection can be skeletally diverse.3 They fur-
acid derivatives for aldehyde and carboxylic acid compo-
ther suggested the build/couple/pair strategy for drug dis-
nents, respectively, that yielded 7-oxanorbornene stereo-
covery in 2008.4 On the other hand, in 2006, biology-
selectively in good yield (Scheme 1). Subsequently, the
oriented synthesis (BIOS) was proposed by Waldmann et
Schreiber group extended the reaction to DOS in 2000
al. for the construction of compound collections designed
on the basis of structural motifs of natural products, since
(Scheme 1).19
such collections are expected to be enriched in biochemi-
Paulvannan (1999)
cal and biological activity.5
H2N
Among several DOS approaches, we have been interested
in multicomponent coupling reactions (MCRs)6 in combi-
O
NC
MeOH
89%
HN
H
nation with one-pot, sequential reactions, so-called domi-
no reactions.7 First reported by Robinson in 1917,8 many
MCRs have been developed to date and used to construct
compound collections with appendage diversity.
CO2H
O
N
O
CHO
O
CO2Et
H
H
CO2Et
A domino reaction has been defined as the reaction se-
quence that allows the formation of ‘several bonds in one
sequence without isolating the intermediates, changing
the reaction conditions, or adding reagents’, by Tietze in
1996.9 Recent examples have included a silver-catalyzed
five-step domino reaction from N-arylformimidates.10 For
BIOS, a twelve-step domino reaction was reported by the
Waldmann group in 2012 to develop modulators of cen-
trosome integrity.11 The synthesis of α-(hydroxymeth-
yl)glutamic acid by a domino Michael/Dieckmann
process also belongs to recent examples for BIOS.12
Schreiber et al (2000)
H2N
NC
O
O
OTIPS
H
HO2C
N
N
OTIPS
O
CHO
1) Ugi reaction
O
H
HN
O
H
2) N-allylation
3) metathesis
O
H
Br
N
Br
41%
Scheme 1 Domino UDA reactions for DOS
SYNTHESIS 2013, 45, 3106–3117
Advanced online publication: 12.09.2013
DOI: 10.1055/s-0033-1338543; Art ID: SS-2013-F0532-OP
© Georg Thieme Verlag Stuttgart · New York
Inspired by these precedents, we explored the applicabili-
ty of these processes to the development of ligands for
neuronal receptors,20 since a rough structural analysis car-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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BIOS-DOS for Ligand Discovery
3107
ried out at an earlier stage had pointed out structural sim- Fortunately, the syntheses were completed in 2008, as
ilarities between Schreiber’s product (Scheme 1) and summarized in Scheme 2,23 by featuring two domino re-
naturally derived excitatory amino acids such as dysi- actions; (1) domino UDA reaction (toward 9), and (2)
herbaines 1 and 2 (Figure 1)21 and kainic acid (3).22 Our domino
ring-opening/cross/ring-closing
metathesis
study can be thus recognized as a hybrid between BIOS (ROM/CM/RCM) reaction using vinyl acetate (11 → 13).
and DOS, and we designed 12 artificial glutamate ana- Exceptionally high levels of chemo-, regio-, and stereose-
logues 4A–4L. The formidable challenges in that synthet- lectivities in a series of the transformations shown in
ic study were; (1) domino metathesis reaction that should Scheme 2 successfully allowed us to prepare 12 structur-
be performed in the presence of poorly reactive vinyl ally diverse glutamates 4A–4L in 9.5–16.0% yields over
acetate as the cross-metathesis (CM) substrate, and (2) de- 12–14 steps.
oxygenation of the A-ring lactam.
The neuroactivity of the analogues was then evaluated,
and current- and voltage-clump electrophysiological anal-
H
H
H
CO2H
CO2H
ysis indicated that some analogues markedly reduced ex-
citatory neurotransmission in the highly active, cultured
hippocampal neurons. For example, dihydroxylated ana-
logue 4C (X = O) markedly reduced both action potential
firing frequency by 39.2 ± 11.6% (n = 3). Mice behavioral
assay by intracranial injection (0.02 mg/mouse) revealed
that 4C induces hypoactivity.23b The diverse neuroactivity
of the compound collection has been shown by evaluation
of other analogues (Scheme 2) in vitro and in vivo.23
N
O
HO2C
NH2
O
HO2C
OH
R
dysiherbaine (1, R = NHMe)
neodysiherbaine A (2, R = OH)
kainic acid (3)
(2008)
(this work)
oxo
H
CO2H
Glu
N
H
CO2H
N
A
O
A
H
H
CO2H
O
B
H
CO2H
Encouraged by the preliminary assay data, we then ex-
plored the possibility of shortening the synthetic route by
modification of the final target structure. After several ex-
periments, we discovered that oxo analogue 14 (Figure 2)
retains the pharmacological activity on neuronal receptors
and the efficacy is even greater than 4I, which belongs to
the unsaturated glutamate class (Scheme 2, X = NH). Fur-
thermore, oxo analogue 14 was shown to antagonize (S)-
2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic
acid (AMPA) type subsets with some selectivity for
GluA2 and GluA4; for example, inhibition-response
curves generated by electrophysiological experiments
have indicated the IC50 value for GluA1/GluA2 to be 26 ±
2 μM (currents evoked by 10 mM glutamate).24 We refer
to the second generation oxo analogue 14 as IKM-159.
More recently, a neuroactive enantiomer of IKM-159 was
identified, and the molecular interactions with ligand-
binding domain (LBD) of GluA2 were clarified by crys-
tallographic analysis.25
O
H
X
C
Y
structural
diversity
Y
oxo analogues
twelve glutamate analogues (4A-4L)
X = -NH-, -NH-CH2-, -O-, -O-CH2-
Y = dihydroxylated, saturated, and unsaturated
Figure 1 Natural product inspired hybrid design of artificial gluta-
mate analogues 4A–4L and oxo analogues
NH2
O
(Z)-6
MeO
Bn
PMB
O
N
H
I
COOH
N
MeOH
5
H
50 °C
68%
O
7
O
H
CHO
H
I
CN
8
9
N
N
Mes
Cl
Mes
Ru
O
Cl
HN Bn
O
O
PMB
H
X
12
Bn
PMB
O
H
N
N
H
We were also interested in identifying the functional
groups required for the neuroactivity of IKM-159 (14).
Herein, we report the syntheses of IKM-159 (14) and skel-
etally diverse, five oxo analogues 15–19 in racemic forms,
used to clarify the structure–activity relationships (SARs)
of the novel antagonist of AMPA receptors (Figures 1 and
2). By modifying the route shown in Scheme 2, the syn-
thesis has been successfully performed in reasonable
yields with high chemo-, regio-, and stereoselectivities
over short steps (9–12 steps).
(0.5–10 mol%)
N
10
bases
O
H
OAc
H
H
O
H
O
OAc
X
X
(5 equiv)
49–100%
H
11
13
84–100%
benzene
H
N
H
H
CO2H
CO2H
CO2H
N
N
H
H
H
H
H
H
CO2H
CO2H
CO2H
9–11
steps
O
O
O
H
H
H
X
X
X
OH
Syntheses of tricyclic butyrolactams 14–16, whose struc-
tures are analogous to two natural products, neodysiherba-
ine (2) and kainic acid (3), were performed via
compounds 20 (Scheme 3) and 26 (Scheme 5),23a,c which
were previously reported as intermediates in the synthesis
of artificial glutamate analogues 4A–4L.
OH
dihydroxylated
four glutamates
4A–4D
saturated
four glutamates
unsaturated
four glutamates
4I–4L
4E–4H
Scheme 2 Our previous synthesis of 12 artificial glutamate ana-
logues
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117

3108
M. Oikawa et al.
PAPER
H
H
from metathesis product 13 (X = NNs, Scheme 2).23a,c
Treatment of N-PMB amide 20 with ceric ammonium ni-
trate, followed by deprotection of the 2-nitrobenzenesul-
fonyl (Ns) group (PhSH, Cs2CO3)26 provided unstable
amine 22, which was again protected by the Boc group
(Boc2O) for the sake of chromatographic purification, to
elaborate 23 in 72% yield. Acidic hydrolysis of the Boc
group and two methyl esters furnished piperidine-contain-
ing dicarboxylic acid 14 (IKM-159)24 in good yield (89%)
as the first heterotricyclic analogue bearing a butyrolac-
tam at the A-ring. The synthesis is capable of providing
subgram quantities of IKM-159 (14),24 a new class of an-
tagonist for AMPA receptor, in 22.3% total yield from
(Z)-iodoacrylic acid [(Z)-6] over 11 steps.23a,c
H
H
CO2H
CO2H
CO2H
CO2H
N
N
O
A
O
A
H
H
H
H
O
B
O
B
H
H
HN
HN
C
C
OH
14 (IKM-159)
15
OH
H
H
H
H
CO2H
N
CO2H
N
O
O
A
A
H
H
H
CO2H
CO2H
O
OH
B
O
H
C
16
17
H
H
HO
H
N
A
CO2H
CO2H
CO2H
N
A
The synthetic intermediate 23 was also transformed into
the other dihydroxylated analogue 15. Catalytic osmium
tetroxide mediated dihydroxylation of the C-ring moiety
using 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO) as
a co-oxidant stereoselectively provided diol 24 in 70%
yield. It should be noted that the use of N-methylmorpho-
line N-oxide as the co-oxidant was less efficient for the di-
hydroxylation of 23 (54%). To the best of our knowledge,
this is the first demonstration of the use of TEMPO in the
osmium tetroxide mediated dihydroxylation of olefins.27
Acid treatment (6 M hydrochloric acid, 90 °C) of 24 for
the hydrolysis of all protecting groups successfully pro-
vided analogue 15 in quantitative yield.
O
O
H
H
CO2H
B
O
O
H
B
H
18
19
Figure 2 Second generation oxo analogues IKM-159 (14) and the
skeletally diverse analogues 15–19 (this study)
R
CO2Me
N
O
CAN
MeCN
H2O
20 (R = PMB)
21 (R = H)
H
H
CO2Me
O
H
NsN
78%
The stereochemistry of the C-ring dihydroxy moiety was
independently determined after conversion to acetonide
25 (2,2-dimethoxypropane, CSA) as shown in Scheme 4.
The NOESY spectra of 25 indicated several important
NOEs between protons on each of the α-face and the β-
face, to show that the dihydroxylation had taken place on
the α-face of 23.
1) PhSH
Cs2CO3
MeCN
2) Boc2O
CH2Cl2
72%
H
N
A
H
CO2H
CO2Me
N
O
O
H
H
H
H
HCl (6 M)
CO2H
CO2Me
B
O
O
H
H
HN
R
N
65 °C
89%
C
14 (IKM-159)
22 (R = H)
23 (R = Boc)
piperidine-containing
heterotricyclic diacid
OsO4
TEMPO
t-BuOH
H2O
70%
H
H
H
CO2Me
CO2H
N
N
O
O
A
H
H
H
H
CO2Me
CO2H
HCl (6 M)
O
O
B
H
H
Boc
N
HN
90 °C
100%
C
OH
OH
24
OH
15
dihydroxylated
OH
heterotricyclic diacid
Scheme 4 NOESY analysis of acetonide 25 for stereochemical as-
signment of the C-ring moiety. In the model structure, AB-ring and
the Boc group on the C-ring are omitted for clarity.
Scheme 3 Synthesis of piperidine-containing heterotricyclic ana-
logues 14 (IKM–159) and 15
Synthesis of oxepane-containing heterotricycle 16 is
shown in Scheme 5. Fully protected heterotricycle 26 was
prepared in 16.1% yield over seven steps from 2-furfu-
ral,23a,c and the PMB group was removed by ceric ammo-
nium nitrate to give known lactam 27 in 71% yield.
Thus, by way of a common, advanced intermediate 23,
piperidine-containing heterotricyclic analogues 14 (IKM-
159) and 15 were synthesized from 20, which was derived
Synthesis 2013, 45, 3106–3117
© Georg Thieme Verlag Stuttgart · New York

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BIOS-DOS for Ligand Discovery
3109
Diester 27 was subsequently hydrolyzed with hydrochlo- acid, 65 °C) to furnish desired monocyclic A-ring ana-
ric acid (6 M) at 65 °C, giving rise to dicarboxylic acid 16 logue 17 in 75% yield.
in 47% yield.
As shown in Scheme 7, synthesis of bicyclic AB-ring an-
alogue 18 started with 7-oxanorbornene 9,23 which was
first transformed into bicyclic vinyl acetate 38 by domino
R
H
CO2H
CO2Me
N
metathesis (ROM/CM) in good yield with amazingly ex-
clusive regioselectivity.23a,b After formation of N-Boc im-
ide 39, methanolysis followed by Pinnick oxidation31 and
methylation gave dimethyl ester 41 in 28% yield (from
39). The chemically labile iodo group was then removed
(Ph3SnH, AIBN)32 to give 42, which, in turn, was deprot-
ected stepwise to furnish 18 in 43% yield for two steps.
While we started the synthesis with 7-oxanorbornene 9,
the epimer 28, readily synthesized and purified as shown
in Scheme 6, may be also used for the synthesis of bicyclic
analogue 18.
N
O
A
O
HCl (6 M)
H
H
CO2H
H
H
CO2Me
B
O
O
65 °C
47%
H
O
H
O
C
16
oxepane-containing
heterotricyclic diacid
CAN
MeCN
H2O
26 (R = PMB)
27 (R = H)
71%
Scheme 5 Synthesis of oxepane-containing heterotricyclic analogue
16
The A-ring analogue 17 was synthesized by modification
of the route for analogues 14–16, taking advantage of ex-
ceptionally regioselective domino metathesis as the key
step. As illustrated in Scheme 6, the synthesis started with
domino UDA reaction between amine 5, (E)-3-iodoacryl-
ic acid [(E)-6],28 isocyanide 7, and aldehyde 8. The reac-
tion proceeded quite smoothly at 50 °C to give 7-
oxanorbornene 28 in 70% yield. We have previously re-
ported the four-component coupling reaction using (Z)-3-
iodoacrylic acid proceeded in comparable yield
(68%).23a,b The domino reaction reported here utilizes the
E-isomer and is more convenient because the product 28
is obtained as crystals, that can be readily purified. The 7-
oxanorbornene 28 was then transformed into heterobicy-
cle 30 in excellent yield (99%) by highly regioselective
domino ROM/CM reaction using Hoveyda–Grubbs 2nd
generation catalyst 12.29 It should be noted here that the
CM reaction involves a poorly reactive Fischer-type car-
bene 29 (see the bottom of Scheme 6) that readily con-
structs the glutamate moiety in 30 regioselectively even in
the absence of an alkenyl group for RCM. The mecha-
nism, that involves steric interactions between 7-oxanor-
bornenes and the Fischer-type carbene 29, has been
reported by us23b and is also operative here in the reaction
of 28. In addition, it was found that stereochemistry of the
iodo group influences the reaction yield (see also 9 → 38
in Scheme 7) but not the regioselectivity. Related obser-
vations were also reported by the Rainier group.30 After
formation of N-Boc imide 31, alkaline methanolysis
(K2CO3, MeOH, –20 °C) provided ester aldehyde 32 in
moderate yield (42% for 2 steps). Pinnick oxidation31 of
aldehyde 32 followed by methylation by diazomethane
furnished diester 34 in 73% yield. The N-PMB group was
then removed using ceric ammonium nitrate to give 35 in
57% yield, which was further reacted with zinc metal in
ethanol and water at reflux to induce cleavage of the -
iodo ether moiety, giving rise to diene 36 as a mixture of
E/Z isomers (0.3:0.7) in acceptable yield (75%). Hydroge-
nation (H2, Pd black) of diene 36 proceeded smoothly to
provide 37, which was then hydrolyzed (6 M hydrochloric
I
O
(E)–6
COOH
MeO
Bn
PMB
O
N
NH2
N
H
MeOH
5
H
50 °C
70%
O
7
O
I
CHO
H
H
28
CN
8
O
O
Bn
NH
Bn
Boc2O
DMAP
Et3N
PMB
PMB
O
N
metathesis
catalyst 12
Boc
N
N
I
OAc
OAc
O
O
O
H
H
CH2Cl2
90%
vinyl acetate
benzene
60 °C
I
30
31
E/Z = 0.8:0.2
99%
PMB
O
PMB
O
CO2Me
CO2Me
CO2H
NaClO2
N
N
I
2–methylbut-2-ene
K2CO3
CHO
O
O
H
H
MeOH
–20 °C
NaH2PO4
t-BuOH, H2O
I
32
33
47%
99%
PMB
O
CO2Me
CO2Me
HN
N
I
CH2N2
CAN
CO2Me
CO2Me
O
O
O
H
I
H
THF, Et2O
74%
MeCN, H2O
–5 °C
34
35
57%
H
H
N
N
CO2Me
CO2Me
O
H2
Pd black
O
Zn
OH
OH
CO2Me
CO2Me
MeOH
80%
EtOH, H2O
reflux
36
37
75%
E/Z = 0.3:0.7
H
N
A
CO2H
CO2H
O
N
N
HCl (6 M)
Mes
Cl
Mes
Ru
O
Cl
65 °C
75%
OH
O
17
the Fischer-type carbene
intermediate 29
monocyclic diacid
Scheme 6 Synthesis of monocyclic A-ring analogue 17
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117

3110
M. Oikawa et al.
PAPER
O
Bn
epane tricycle 16 was 5.4% for nine steps. Furthermore,
our strategy was also capable of synthesizing three trun-
cated analogues, namely, monocyclic analogue 17 (5.5%
over 10 steps), and heterobicycles 18 (5.1% over 9 steps)
and 19 (13.7% over 9 steps).
O
PMB
Bn
NH
PMB
O
metathesis
N
N
I
N
H
catalyst 12
H
OAc
O
H
O
vinyl acetate
benzene
O
H
E/Z = 0.93:0.07
H
I
9
38
87%
Skeletally diverse analogues of IKM-159 generated here
will be useful to acquire deeper insight into the mode of
interaction with the AMPA receptor in the central nervous
system. Detailed evaluation with the new analogues 15–
19 is now underway, however, preliminary in vivo assays
on mice have indicated that all truncated analogues 17–19
have significantly lost the activity of IKM-159 (14).33
O
Bn
Boc2O
DMAP
Et3N
PMB
O
CO2Me
PMB
O
N
N
I
Boc
OAc
N
I
K2CO3
CHO
O
O
H
H
CH2Cl2
90%
MeOH
–10 °C
40
39
From the pharmacological study, it had been suggested
that the mode of interaction of IKM-159 with AMPA re-
ceptor may be different from that for the parent agonists,
neodysiherbaine (2) and kainic acid (3). This was con-
firmed from our recent X-ray crystallographic study of the
complex with GluA2 LBD, and in addition, all heteroat-
1)
2)
PMB
N
NaClO2, NaH2PO4
2-methylbut-2-ene
CO2Me
Ph3SnH
AIBN
t-BuOH, THF, H2O
CO2Me
O
H
O
CH2N2, THF, Et2O
toluene
reflux
I
41
28% (from 39)
80%
OH
PMB
CO2Me
CO2Me
CO2Me
CO2Me
NH2
O
HO
I
COOH
(Z)–6
HN
H
Bn
N
N
H
CAN
MeOH
N
44
O
O
H
O
O
O
H
50 °C
77%
MeCN, H2O
0 °C
O
7
O
H
CHO
H
42
43
I
CN
56%
8
45
CO2H
OTBDMS
N
OTBDMS
O
Bn
HN
O
TBDMSCl
imidazole
metathesis
catalyst 12
A
Bn
NH
HCl (6 M)
CO2H
O
N
H
O
N
OAc
B
H
H
O
60 °C
77%
O
H
O
CH2Cl2
92%
vinyl acetate
benzene
DCE, 45 °C
O
18
H
H
I
I
46
47
bicyclic diacid
E/Z = 0.84:016
74%
Scheme 7 Synthesis of bicyclic AB-ring analogue 18
OTBDMS
N
OTBDMS
O
Boc2O
DMAP
Et3N
Bn
CO2Me
N
Boc
N
K2CO3
OAc
The same strategy was also applied to N-hydroxyethyl
AB-ring analogue 19 (Scheme 8). Here, 2-aminoethanol
(44) was employed in the domino UDA reaction, to give
45 in good yield. After protection (45 → 46), metathesis
provided heterobicycle 47 predominantly in acceptable
yield (74%). A sequence including N-Boc imide forma-
tion, methanolysis, Pinnick oxidation,31 and methylation
furnished dimethyl ester 50, which was then deiodinated
by radical reaction32 followed by global deprotection (6 M
HCl) to provide 19 in moderate yield (26% from 47).
Again, the synthesis of 19 may be also performed via the
epimer of 45, which should be obtained using (E)-6 and
may be readily isolated after simple recrystallization.
CHO
O
O
H
O
H
O
CH2Cl2
90%
MeOH
–10 °C
I
I
48
49
OTBDMS
N
1)
2)
NaClO2, NaH2PO4
2-methylbut-2-ene
t-BuOH, THF, H2O
CO2Me
CO2Me
Ph3SnH
AIBN
O
H
O
CH2N2, THF, Et2O
toluene
reflux
68% (from 48)
50
I
76%
OH
OTBDMS
N
In this paper, we report a hybrid BIOS-DOS study of
AMPA receptor antagonist IKM-159 (14) and analogues
15–19 to clarify the SARs by taking advantage of two
domino reactions; Ugi/Diels–Alder reaction and domino
metathesis reaction; an exceptionally high level of regio-
control was realized in the latter domino reaction. Total
yields for IKM-159 (14) and dihydroxylated analogue 15
were 22.3% (11 steps) and 17.6% (12 steps), respectively,
from (Z)-iodoacrylic acid [(Z)-6], whereas that for ox-
CO2H
CO2Me
CO2Me
N
A
HCl (6 M)
CO2H
O
O
H
O
O
B
60 °C
56%
H
19
51
N-(hydroxyethyl)diacid
Scheme 8 Synthesis of N-hydroxyethyl AB-ring analogue 19
Synthesis 2013, 45, 3106–3117
© Georg Thieme Verlag Stuttgart · New York

PAPER
BIOS-DOS for Ligand Discovery
3111
13C NMR (125 MHz, CDCl3): δ = 173.6, 169.3, 169.2, 154.1, 126.7,
125.1, 87.7, 81.1, 74.1, 66.0, 56.3, 52.7, 51.9, 51.3, 41.1, 39.1, 28.2
(3 C).
HRMS (ESI+): m/z [M + H]+ calcd for C19H27N2O8: 411.1762;
found: 411.1761.
oms of IKM-159 except for the B-ring ether oxygen were
shown to form interactions with the LBD.25 The crystallo-
graphic data may explain the observed loss of in vivo bio-
activity of the truncated analogues 17–19. Further studies
are in progress to establish the molecular basis for the in-
teraction and to elucidate the antagonism of IKM-159.
Piperidine-Containing Heterotricyclic Diacid 14 (IKM-159)
A suspension of diester 23 (8.7 mg, 0.023 mmol) in 6 M HCl (0.5
mL) was heated at 65 °C for 10 h. The mixture was then cooled to
r.t. and concentrated under reduced pressure. The residue was puri-
fied by column chromatography (reversed-phase silica gel, 500 mg,
H2O). The active fractions were lyophilized to afford 14 (5.7 mg,
89%) as a white solid.
There are few commercially available antagonists for
AMPA receptor with subunit selectivity. IKM-159 is a
new class of subunit-selective antagonist that can be read-
ily prepared in subgram quantities in 11 steps, and is thus
of use for medicinal research. Indeed, we have already
synthesized more than 700 mg of IKM-159 in total. Fur-
ther structural refinement by our DOS strategy reported
herein will lead us to the development of another antago-
nist with improved efficacy and selectivity.
IR (KBr): 3415, 1725, 1685, 1220 cm–1.
1H NMR (500 MHz, D2O): δ = 6.12 (dd, J = 10.5, 4.5 Hz, 1 H), 6.08
(br d, J = 10.5 Hz, 1 H), 4.53 (m, 1 H), 4.28 (m, 1 H), 4.01 (d,
J = 4.5 Hz, 1 H), 3.84 (dd, J = 17.5, 4.5 Hz, 1 H), 3.72 (d, J = 17.5
Hz, 1 H), 3.59 (s, 1 H), 3.07 (d, J = 18.0 Hz, 1 H), 2.93 (br d,
J = 18.0 Hz, 1 H).
All reactions sensitive to air or moisture were carried out in oven-
dried glassware under argon atmosphere unless otherwise noted.
Solvents were freshly distilled: hexane, toluene, benzene, and THF
were distilled from Na/benzophenone; MeOH was distilled from
Mg. All other reagents were used as supplied unless otherwise stat-
ed. TLC was performed using pre-coated glass plates (Merck 60
13C NMR (125 MHz, CDCl3): δ = 173.9, 173.8, 172.7, 126.7, 121.6,
86.0, 70.5, 66.4, 58.6, 54.9, 42.3, 37.7.
HRMS (ESI+): m/z [M + H]+ calcd for C12H15N2O6: 283.0925;
found: 283.0930.
Diol 24
F254, 1.05715.0009, 0.25-mm thickness). Column chromatography
To a stirred solution of olefin 23 (47.0 mg, 0.12 mmol) in t-BuOH
(1.76 mL) at r.t. were added a solution of TEMPO (13 mg, 0.075
mmol) in H2O (1.76 mL) and 0.04 M OsO4 in t-BuOH (0.31 mL,
0.0124 mol). After 13 h, sat. aq Na2S2O4 (17 mL) was added, and
the mixture was extracted with CHCl3 (3 × 45 mL). The combined
extracts were washed with brine (17 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, 0.8 g, acetone–CHCl3, 4:6) to give
24 (36.2 mg, 70%) as a yellow oil.
was performed using either silica gel (Fuji Silysia Chemical Ltd.
BW-300 or Merck 1.09385.1009), or reversed-phase silica gel (Fuji
Silysia Chemical Ltd. Chromatorex-ODS DM1020T). IR spectra
were recorded on a FT-IR spectrophotometer (Perkin Elmer, Spec-
1
trumOne). H and 13C NMR spectra were recorded on a 400 MHz
(Bruker AVANCE400) or 500 MHz spectrometer (Varian
UNITY500); from TMS with reference to internal residual solvent
[1H NMR, CHCl3/CDCl3 (7.24), H2O/D2O (4.70); 13C NMR, CDCl3
(77.0)]. ESI-TOF mass spectra were measured on a Water LCT Pre-
mier XE spectrometer.
IR (KBr): 3679, 3617, 3421, 3018, 1731, 1709, 1522, 1209 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.95 (br s, 1 H), 4.44 (s, 1 H), 4.42
(m, 1 H), 4.16 (dd, J = 4.0, 4.0 Hz, 1 H), 4.10–3.85 (m, 3 H), 3.72
(s, 3 H), 3.62 (s, 3 H), 3.59 (m, 1 H), 3.37 (m, 1 H), 2.88 (d, J = 16.0
Hz, 1 H), 2.76 (d, J = 16.0 Hz, 1 H), 2.10 (br s, 2 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 173.6, 169.8 (2 C), 156.1, 86.8,
81.5, 80.8, 68.3, 65.3, 65.2, 56.8, 54.1, 52.8, 52.0, 43.6, 39.6, 28.2
(3 C).
N-Boc Piperidine 23
To a stirred solution of 21 (33.8 mg, 0.0683 mmol)23a,c in MeCN
(1.5 mL) at 0 °C were added PhSH (0.014 mL, 0.137 mmol) and
Cs2CO3 (33.4 mg, 0.103 mmol). After stirring at r.t. for 1 h, the mix-
ture was diluted with sat. aq NaHCO3 (5 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined extracts were dried (Na2SO4)
and concentrated under reduced pressure to a final volume of ca. 3
mL. Piperidine 22 thus obtained was unstable and was used without
purification. However, a part of the material of 22 was purified for
the collection of 1H NMR data.
HRMS (ESI+): m/z [M + H]+ calcd for C19H29O10N2: 445.1822;
found: 445.1818.
1H NMR (500 MHz, CDCl3): δ = 6.09–6.06 (m, 2 H), 5.90 (m, 1 H),
4.36 (s, 1 H), 4.14 (br s, 1 H), 3.73 (s, 3 H), 3.63 (s, 3 H), 3.60 (d,
J = 4.0 Hz, 1 H), 3.36 (dd, J = 17.5, 5.0 Hz, 1 H), 3.29 (dd, J = 17.5,
2.0 Hz, 1 H), 3.22 (d, J = 16.5 Hz, 1 H), 3.07 (s, 1 H), 2.98 (d,
J = 16.5 Hz, 1 H).
Dihydroxylated Heterotricyclic Diacid 15
A suspension of N-Boc-amino diester 24 (8.30 mg, 0.019 mmol) in
6 M HCl (0.443 mL) was heated at 90 °C for 22 h. The mixture was
then cooled to r.t. and concentrated under reduced pressure. The res-
idue was purified by column chromatography (reversed-phase silica
gel, 0.75 g, H2O) to give 15 (6.00 mg, 100%) as a light green oil.
Boc2O (0.200 mL, 0.871 mmol) was added to the crude piperidine
22 in CH2Cl2 (ca. 3 mL) thus prepared above, and the mixture was
stirred at r.t. for 1 h. The mixture was then diluted with CH2Cl2 (5
mL), washed with sat. aq NH4Cl (10 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, 2 g, hexane–EtOAc, 8:2) to give
23 (18.9 mg, 72% for 2 steps) as a colorless solid.
IR (neat): 3233, 2925, 1713 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.29 (s, 1 H), 4.22 (m, 1 H), 4.21
(d, J = 3.2 Hz, 1 H), 4.02 (d, J = 3.2 Hz, 1 H), 3.98 (m, 1 H), 3.53
(s, 1 H), 3.20 (m, 1 H), 3.17 (dd, J = 12.0, 4.8 Hz, 1 H), 3.15 (d,
J = 18.0 Hz, 1 H), 2.91 (d, J = 18.0 Hz, 1 H).
13C NMR (100 MHz, D2O): δ = 175.1, 173.3 (2 C), 85.7, 78.2, 65.2,
64.8, 62.5, 56.1, 54.1, 40.9, 37.3.
IR (film): 2976, 1746, 1702, 1395, 1367, 1171, 681 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.86 (d, J = 10.0 Hz, 1 H), 5.81 (s,
1 H), 5.69 (dd, J = 10.0, 2.0 Hz, 1 H), 5.18 (br s, 1 H), 4.69 (d,
J = 6.0 Hz, 1 H), 4.41 (s, 1 H), 4.21 (d, J = 19.0 Hz, 1 H), 3.77 (s, 3
H), 3.65 (d, J = 19.0 Hz, 1 H), 3.59 (s, 3 H), 3.17 (d, J = 8.0 Hz, 1
H), 3.00 (d, J = 15.5 Hz, 1 H), 2.75 (d, J = 15.5 Hz, 1 H), 1.46 (s, 9
H).
HRMS (ESI+): m/z [M + H]+ calcd for C12H17O8N2: 317.0979;
found: 317.0981.
Acetonide 25
To a stirred solution of diol 24 (2.99 mg, 0.00673 mmol) in CH2Cl2
(0.157 mL) at 0 °C were added 2,2-dimethoxypropane (0.00245
mL, 0.020 mmol) and CSA (0.314 mg, 0.00135 mmol). The mixture
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117

3112
M. Oikawa et al.
PAPER
was vigorously stirred at r.t. for 6 h. The mixture was then quenched
by the addition of Et3N (0.157 mL) and concentrated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, 0.7 g, hexane–EtOAc, 5:5) to give 25 (1.60 mg, 49%) as a
colorless oil.
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 12 g, hexane–EtOAc, 45:55) to give 30 (E/Z
0.8:0.2, 450 mg, 99%) as a white foam.
IR (neat): 3683, 3621, 3019, 1709, 1522, 1424, 1223, 1046, 929,
791 cm–1.
IR (neat): 3019, 2979, 1734, 1684, 1215 cm–1.
1H NMR (400 MHz, CDCl3): δ (E/Z = 0.8:0.2) = 7.45 (d, J = 12.4
Hz, 0.8 H), 7.28–7.16 (m, 5 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.76 (d,
J = 7.2 Hz, 0.2 H), 6.75 (d, J = 8.4 Hz, 2 H), 6.65 (br s, 0.8 H), 6.26
(br s, 0.2 H), 5.65 (ddd, J = 16.8, 10.8, 6.0 Hz, 1 H), 5.40 (d,
J = 12.4 Hz, 0.8 H), 5.20 (dd, J = 16.8, 10.8 Hz, 2 H), 4.96 (d,
J = 7.2 Hz, 0.2 H), 4.88 (d, J = 14.8 Hz, 0.8 H), 4.70 (d, J = 4.0 Hz,
0.2 H), 4.65 (d, J = 3.6 Hz, 0.8 H), 4.44 (dd, J = 14.8, 6.0 Hz, 0.8
H), 4.24 (m, 1 H), 4.08 (s, 0.2 H), 3.90 (s, 0.2 H), 3.81 (s, 0.8 H),
3.71 (s, 0.6 H), 3.70 (s, 2.4 H), 3.60 (d, J = 14.8 Hz, 0.8 H), 3.50 (s,
0.8 H), 2.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ (major isomer) = 171.0, 167.5,
167.3, 159.1, 139.5, 138.1, 137.3, 129.6 (2 C), 128.5 (2 C), 127.8 (2
C), 127.5, 126.7, 118.6, 114.1 (2 C), 113.2, 84.7, 83.0, 71.6, 62.2,
55.1, 45.1, 43.6, 28.0, 20.6.
1H NMR (400 MHz, CDCl3): δ = 5.96 (br s, 1 H), 4.55 (br s, 1 H),
4.42 (d, J = 8.0 Hz, 1 H), 4.30 (m, 1 H), 4.30 (d, J = 8.0 Hz, 1 H),
4.29 (s, 1 H), 4.05 (br s, 1 H), 3.73 (s, 3 H), 3.63 (s, 3 H), 3.18 (s, 1
H), 3.07 (d, J = 16.4 Hz, 1 H), 3.02 (m, 1 H), 2.83 (d, J = 16.4 Hz,
1 H), 1.50 (s, 9 H), 1.29 (s, 3 H), 1.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.9, 169.9, 169.7, 109.0 (2 C),
86.3, 75.7, 70.6, 69.5, 64.8, 59.2, 56.4, 52.8, 52.1 (2 C), 39.8, 28.4
(3 C), 26.4, 24.1 (2 C).
HRMS (ESI+): m/z [M + H]+ calcd for C22H33N2O10: 485.2130;
found: 485.2128.
Oxepane-Containing Heterotricyclic Diacid 16
A suspension of diester 2723a,c (7.45 mg, 0.023 mmol) in 6 M HCl
(0.5 mL) was heated at 65 °C for 10 h. The mixture was then cooled
to r.t. and concentrated under reduced pressure. The residue was pu-
rified by column chromatography (reversed-phase silica gel, 500
mg, H2O). The active fractions were lyophilized to afford 16 (3.2
mg, 47%) as a colorless oil.
HRMS (ESI+): m/z [M + H]+ calcd for C28H29O6N2I: 617.1149;
found: 617.1147.
N-Boc Imide 31
To a stirred solution of N-Bn amide 30 (537 mg, 0.850 mmol) in
CH2Cl2 (10.1 mL) at 0 °C were added Boc2O (0.980 mL, 4.25
mmol), DMAP (51.9 mg, 0.425 mmol), and Et3N (0.590 mL, 4.25
mmol). After stirring at r.t. for 2 h, the mixture was diluted with
EtOAc (29 mL) and poured into sat. aq NH4Cl (29 mL). The aque-
ous layer was separated and extracted with EtOAc (3 × 29 mL). The
combined extracts were washed with brine (29 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 30 g, hexane–
EtOAc, 4:6) to give 31 (560 mg, 90%) as a yellow oil. A cyclic en-
amide byproduct (structure not shown, 50.9 mg, 10%) was also ob-
tained as a yellow oil.
IR (KBr): 3440, 1725, 1685 cm–1.
1H NMR (500 MHz, D2O): δ = 5.87 (ddd, J = 12.0, 6.0, 5.0 Hz, 1
H), 5.56 (dd, J = 11.5, 5.0 Hz, 1 H), 4.52 (br s, 1 H), 4.38 (s, 1 H),
4.32 (d, J = 3.0 Hz, 1 H), 3.90 (ddd, J = 11.5, 6.0, 6.0 Hz, 1 H), 3.63
(ddd, J = 11.5, 8.0, 4.5 Hz, 1 H), 3.25 (s, 1 H), 3.11 (d, J = 17.0 Hz,
1 H), 2.84 (d, J = 17.0 Hz, 1 H), 2.38–2.74 (m, 2 H).
13C NMR (125 MHz, D2O): δ = 176.2, 173.4, 173.2, 132.4, 124.3,
85.5, 82.2, 82.0, 69.3, 65.6, 58.9, 39.9, 29.9.
HRMS (ESI–): m/z [M – H]– calcd for C13H14NO7: 296.0770; found:
296.0774.
IR (neat): 3684, 3619, 3019, 1710, 1520, 1423, 1221, 1045, 929,
784 cm–1.
7-Oxanorbornene 28 (Domino UDA Reaction)
To a stirred solution of 2-furfural (8, 0.742 mL, 7.58 mmol) in
MeOH (13 mL) at r.t. were added 4-methoxybenzylamine (5, 0.660
mL, 5.05 mmol), (E)-3-iodoacrylic acid28 [(E)-6, 1.00 g, 5.05
mmol], and benzyl isocyanide (7, 0.923 mL, 7.58 mmol). After stir-
ring at 50 °C for 36 h, the mixture was concentrated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, 50 g, hexane–EtOAc, 5:5) to give 28, which was further pu-
rified by recrystallization (CHCl3–hexane) to give 28 (1.80 g, 70%)
as white crystals; mp 187–188 °C.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 12.4 Hz, 1 H), 7.28–
7.19 (m, 5 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H),
5.71 (ddd, J = 16.8, 10.4, 6.0 Hz, 1 H), 5.42 (s, 1 H), 5.29–5.23 (m,
3 H), 4.82 (d, J = 14.8 Hz, 1 H), 4.77–4.63 (m, 2 H), 4.66 (d,
J = 14.8 Hz, 1 H), 3.83 (m, 1 H), 3.78 (d, J = 14.8 Hz, 1 H), 3.75 (s,
3 H), 3.56 (s, 1 H), 2.07 (s, 3 H), 1.30 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 171.9, 171.5, 167.2, 159.3, 151.7,
139.9, 138.5, 137.1, 130.2 (2 C), 128.3 (2 C), 128.1 (2 C), 127.5,
126.7, 118.6, 114.1 (2 C), 112.8, 85.3, 85.1, 83.4, 70.2, 62.6, 55.2,
47.8, 45.6, 28.5, 27.6 (3 C), 20.7.
IR (neat): 3684, 3619, 3019, 1710, 1520, 1423, 1221, 1045, 929,
784 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C33H38O8N2I: 717.1673;
found: 717.1686.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.21 (m, 5 H), 7.02 (d,
J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 6.69 (br s, 1 H), 6.46 (dd,
J = 6.0, 1.6 Hz, 1 H), 6.32 (d, J = 6.0 Hz, 1 H), 5.04 (dd, J = 4.4, 1.6
Hz, 1 H), 4.82 (d, J = 14.8 Hz, 1 H), 4.41 (ddd, J = 14.8, 14.8, 5.6
Hz, 1 H), 4.04 (s, 1 H), 3.99 (d, J = 3.2 Hz, 1 H), 3.96 (d, J = 14.8
Hz, 1 H), 3.74 (s, 3 H), 2.76 (d, J = 3.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 166.4, 159.3, 137.6, 137.3,
132.6, 132.6, 129.5 (2 C), 128.9 (2 C), 128.0 (2 C), 127.9, 126.6,
114.3 (2 C), 91.4, 62.7, 55.9, 55.2, 45.6, 44.0, 12.7.
Ester Aldehyde 32
To a stirred solution of N-Boc imide 31 (1.48 g, 2.02 mmol) in
MeOH (24.9 mL) at –20 °C was added K2CO3 (140 mg, 1.01
mmol). After 6 h, the mixture was poured into sat. aq NH4Cl (166
mL), and the mixture was extracted with EtOAc (4 × 116 mL). The
combined extracts were washed with brine (166 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 25 g, hexane–
EtOAc, 5:5) to give ester aldehyde 32 (474 mg, 47%) as a white
foam.
HRMS (ESI+): m/z [M + H]+ calcd for C24H24O4N2I: 531.0781;
found: 531.0787.
Heterobicycle 30 (Domino Metathesis Reaction)
IR (neat): 3683, 3620, 3389, 3018, 1622, 1520, 1423, 1215, 1047,
928 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.75 (s, 1 H), 7.09 (d, J = 8.4 Hz,
2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.66 (ddd, J = 16.8, 10.4, 5.6 Hz, 1
H), 5.29 (d, J = 10.4 Hz, 1 H), 5.21 (d, J = 16.8 Hz, 1 H), 4.88 (d,
J = 14.8 Hz, 1 H), 4.78 (d, J = 4.0 Hz, 1 H), 4.27 (s, 1 H), 3.92 (d,
To a stirred solution of 7-oxanorbornene 28 (390 mg, 0.740 mmol)
in benzene (7.0 mL) at r.t. were added vinyl acetate (0.319 mL, 3.68
mmol) and Hoveyda–Grubbs 2nd generation catalyst 1229 (9.10 mg,
0.0147 mmol) after conducting freeze–thaw degasification (2 ×).
After stirring at 60 °C for 4 h, the mixture was concentrated under
Synthesis 2013, 45, 3106–3117
© Georg Thieme Verlag Stuttgart · New York

PAPER
BIOS-DOS for Ligand Discovery
3113
J = 14.8 Hz, 1 H), 3.77 (s, 3 H), 3.77 (s, 1 H), 3.69 (m, 1 H), 3.59
(s, 3 H), 3.53 (d, J = 17.6 Hz, 1 H), 2.74 (dd, J = 17.6, 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 169.4, 159.5, 137.6, 130.0
(2 C), 126.5, 119.1, 114.3 (2 C), 84.1, 83.3, 69.4, 61.8, 55.3, 52.6,
50.4, 45.6, 29.3, 28.2.
HRMS (ESI+): m/z [M + H]+ calcd for C20H23O6NI: 500.0570;
found: 500.0573.
1H NMR (400 MHz, CDCl3): δ = 6.79 (br s, 1 H), 5.70 (ddd,
J = 16.8, 11.2, 6.0 Hz, 1 H), 5.33 (s, 1 H), 5.30 (d, J = 6.8 Hz, 1 H),
4.66 (d, J = 4.0 Hz, 1 H), 4.39 (s, 1 H), 3.79 (m, 1 H), 3.70 (s, 3 H),
3.70 (m, 1 H), 3.65 (s, 3 H), 3.53 (d, J = 17.6 Hz, 1 H), 3.18 (d,
J = 17.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.9, 170.3, 169.7, 137.6, 119.2,
86.8, 82.3, 65.8, 60.8, 52.8, 51.9, 41.5, 29.4.
HRMS (ESI+): m/z [M + H]+ calcd for C13H17O6NI: 410.0101;
found: 410.0090.
Carboxylic Acid 33
To a stirred solution of aldehyde 32 (442 mg, 0.887 mmol) in t-
BuOH (28.2 mL) and H2O (7.05 mL) at 0 °C were added 2-methyl-
but-2-ene (0.470 mL, 4.43 mmol), NaH2PO4·2 H2O (152 mg, 0.975
mmol), and NaClO2 (241 mg, 2.66 mmol). After stirring at r.t. for 7
h, the mixture was diluted with CHCl3 (38 mL) and 1 M HCl (10
drops) was added. The organic layer was separated, and the aqueous
layer was extracted with CHCl3 (3 × 66 mL). The combined extracts
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 1.0 g,
hexane–EtOAc, 5:5) to give 33 (452 mg, 99%) as a yellow oil.
Diene 36
To a stirred solution of iodide 35 (6.30 mg, 0.0154 mmol) in EtOH
(0.900 mL) and H2O (0.100 mL) at r.t. was added zinc metal (5.25
mg, 0.0802 mmol) [granulated, washed successively with 1 M HCl
(1 mL), H2O (20 mL), and EtOH (5 mL)]. After stirring at reflux for
2.5 h, insoluble materials were removed by filtration and the filtrate
was concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 0.6 g, hexane–EtOAc, 7:3)
to give 36 (E/Z 0.3:0.7, 3.28 mg, 75%) as a yellow oil.
IR (neat): 3683, 3620, 3389, 3018, 1622, 1520, 1423, 1215, 1047,
928 cm–1.
IR (neat): 3683, 3620, 3019, 1705, 1522, 1421, 1215, 1045, 928,
748 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 8.4 Hz, 2 H), 6.82 (d,
J = 8.4 Hz, 2 H), 5.66 (ddd, J = 16.8, 10.4, 5.6 Hz, 1 H), 5.28 (d,
J = 10.4 Hz, 1 H), 5.20 (d, J = 16.8 Hz, 1 H), 4.81 (d, J = 14.8 Hz,
1 H), 4.80 (d, J = 4.0 Hz, 1 H), 4.32 (s, 1 H), 4.00 (d, J = 14.8 Hz, 1
H), 3.77 (s, 3 H), 3.71 (s, 1 H), 3.69 (m, 1 H), 3.59 (s, 3 H), 3.56 (d,
J = 17.2 Hz, 1 H), 3.01 (d, J = 17.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 170.9, 169.6, 159.4, 137.9,
130.0 (2 C), 126.7, 119.2, 114.2 (2 C), 84.5, 83.4, 69.0, 61.5, 55.3,
52.7, 45.6, 41.2, 29.3.
1H NMR (400 MHz, CDCl3): δ (E/Z 0.3:0.7) = 6.52 (m, 1 H), 6.45
(d, J = 10.8 Hz, 1 H), 6.36 (ddd, J = 15.2, 10.4, 2.4 Hz, 0.3 H), 6.20
(dd, J = 15.2, 10.4 Hz, 0.3 H), 5.71 (dd, J = 16.8, 9.2 Hz, 0.3 H),
5.54 (dd, J = 10.0, 8.8 Hz, 0.7 H), 5.34 (d, J = 16.4 Hz, 0.7 H), 5.22
(d, J = 10.0 Hz, 0.7 H), 5.12 (m, 0.6 H), 4.29 (d, J = 2.0 Hz, 0.7 H),
4.28 (d, J = 1.6 Hz, 0.3 H), 3.75 (s, 2.1 H), 3.74 (s, 0.9 H), 3.73 (s,
0.9 H), 3.73 (s, 2.1 H), 3.45 (d, J = 10.0 Hz, 0.7 H), 2.97 (d, J = 9.2
Hz, 0.3 H), 2.71 (d, J = 17.2 Hz, 0.3 H), 2.69 (d, J = 17.2 Hz, 0.7
H), 2.47 (d, J = 17.2 Hz, 0.7 H), 2.45 (d, J = 17.2 Hz, 0.3 H).
13C NMR (100 MHz, CDCl3): δ (major isomer) = 175.8, 172.6,
170.5, 136.0, 131.1, 121.1, 120.5, 78.8, 65.4, 52.7, 52.3, 48.4, 38.7.
HRMS (ESI+): m/z [M + H]+ calcd for C13H18O6N: 284.1134;
found: 284.1132.
HRMS (ESI+): m/z [M + H]+ calcd for C20H23O7NI: 516.0519;
found: 516.0522.
Diester 34
To a stirred solution of carboxylic acid 33 (228 mg, 0.444 mmol) in
THF (1.0 mL) at r.t. was added a solution of CH2N2 in Et2O (1.5
mL). The mixture was concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 7.5 g,
hexane–EtOAc, 4:6) to give 34 (173 mg, 74%) as a yellow oil.
Lactam with Butyl Side Chain 37
To a stirred solution of diene 36 (3.35 mg, 0.0118 mmol) in MeOH
(0.400 mL) at r.t. was added Pd black (0.3 mg). The mixture was
stirred vigorously under a H2 atmosphere for 1.5 h. The catalyst was
removed by filtration, and the filtrate was concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy (silica gel, 0.5 g, hexane–EtOAc, 2:8) to give 37 (2.71 mg,
80%) as a colorless oil.
IR (neat): 3019, 1710, 1522, 1423, 1220, 1046, 929, 784 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 8.4 Hz, 2 H), 6.81 (d,
J = 8.4 Hz, 2 H), 5.68 (ddd, J = 16.8, 10.4, 6.0 Hz, 1 H), 5.25 (d,
J = 10.4 Hz, 1 H), 5.18 (d, J = 16.8 Hz, 1 H), 4.81 (d, J = 14.8 Hz,
1 H), 4.79 (d, J = 4.0 Hz, 1 H), 4.32 (s, 1 H), 4.00 (d, J = 14.8 Hz, 1
H), 3.76 (s, 3 H), 3.74 (s, 1 H), 3.64 (s, 3 H), 3.62 (m, 1 H), 3.59 (s,
3 H), 3.47 (d, J = 17.2 Hz, 1 H), 3.01 (d, J = 17.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 169.7, 169.6, 159.3, 138.0,
129.9 (2 C), 126.7, 118.8, 114.1 (2 C), 84.6, 83.0, 69.1, 61.4, 55.2,
52.5, 51.8, 45.5, 41.3, 29.6.
IR (neat): 3679, 3617, 3020, 1705, 1520, 1423, 1216, 1045, 928,
669 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.19 (br s, 1 H), 4.23 (s, 1 H), 3.76
(s, 3 H), 3.73 (s, 3 H), 2.82 (d, J = 17.2 Hz, 1 H), 2.43 (d, J = 17.2
Hz, 1 H), 2.16 (t, J = 6.4 Hz, 1 H), 1.72–1.54 (m, 3 H), 1.40–1.23
(m, 3 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.6, 173.0, 170.6, 78.3, 64.8,
52.6, 52.3, 49.0, 39.2, 30.4, 23.9, 23.0, 13.9.
HRMS (ESI+): m/z [M + H]+ calcd for C13H22O6N: 288.1447;
found: 288.1447.
HRMS (ESI+): m/z [M + H]+ calcd for C21H25O7NI: 530.0676;
found: 530.0677.
Lactam 35
To a stirred solution of N-PMB amide 34 (58.5 mg, 0.111 mmol) in
MeCN (2.27 mL) and H2O (0.5 mL) at –5 °C was added a solution
of CAN (303 mg, 0.553 mmol) in H2O (1.67 mL) portionwise. After
6 h, the mixture was diluted with EtOAc (6 mL) and poured into sat.
aq Na2S2O3 (6.3 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (5 × 8 mL). The combined
extracts were washed with sat. aq NaHCO3 (6.3 mL) and brine (6.3
mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 1.2 g,
hexane–EtOAc, 4:6) to give 35 (25.7 mg, 57%) as a colorless oil.
A-Ring Monocyclic Diacid 17
A suspension of diester 37 (4.49 mg, 0.00780 mmol) in 6 M HCl
(0.300 mL) was heated at 65 °C for 6 h. The mixture was cooled to
r.t. and concentrated under reduced pressure. The residue was puri-
fied by column chromatography (reversed-phase silica gel, ODS,
100–200 mesh, H2O–MeOH, 8:2) to give 17 (3.80 mg, 75%) as a
white solid.
IR (neat): 3377, 2960, 2873, 1713, 1411, 1227, 1085, 947, 900, 856,
633 cm–1.
IR (neat): 3684, 3620, 3019, 1708, 1519, 1424, 1221, 1046, 929,
750 cm–1.
1H NMR (400 MHz, D2O): δ = 4.21 (d, J = 4.0 Hz, 1 H), 2.84 (dd,
J = 16.4, 3.6 Hz, 1 H), 2.65 (d, J = 16.4 Hz, 1 H), 2.39 (m, 1 H),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117

3114
M. Oikawa et al.
PAPER
1.53–1.29 (m, 4 H), 1.27–1.20 (tq, J = 14.4, 7.2 Hz, 2 H), 0.79 (t,
J = 7.2 Hz, 3 H).
ca gel, 10 g, hexane–EtOAc, 4:6) to give 41 (144 mg, 28% from 39)
as a white oil.
13C NMR (100 MHz, D2O): δ = 180.8, 174.5, 174.1, 78.3, 65.9,
IR (neat): 3684, 3617, 3028, 1739, 1702, 1215, 758 cm–1.
49.0, 39.9, 29.7, 23.0, 22.1, 13.0.
HRMS (ESI+): m/z [M + H]+ calcd for C11H18O6N: 260.1134;
found: 260.1134.
1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 8.8 Hz, 2 H), 7.03 (d,
J = 8.8 Hz, 2 H), 5.66 (ddd, J = 16.4, 10.0, 5.6 Hz, 1 H), 5.33 (d,
J = 16.4 Hz, 1 H), 5.27 (d, J = 10.0 Hz, 1 H), 4.92 (d, J = 14.8 Hz,
1 H), 4.15–4.08 (m, 2 H), 3.96 (s, 1 H), 3.86 (d, J = 14.8 Hz, 1 H),
3.74 (s, 3 H), 3.61 (s, 3 H), 3.61 (s, 3 H), 3.31 (m, 1 H), 2.79 (d,
J = 15.2 Hz, 1 H), 2.55 (d, J = 15.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.5, 169.4, 169.2, 159.2, 132.6
(2 C), 129.8 (2 C), 126.7, 120.4, 114.0, 86.9, 84.2, 68.5, 55.1, 52.5,
52.3, 51.9, 45.2, 39.4, 22.3.
N-Boc Imide 39
To a stirred solution of N-Bn amide 38 (356 mg, 0.58 mmol)23a,b in
CH2Cl2 (5.94 mL) at 0 °C were added Boc2O (0.666 mL, 2.90
mmol), Et3N (0.402 mL, 2.90 mmol), and DMAP (35.4 mg, 0.290
mmol). After 1 h, the mixture was diluted with EtOAc (18 mL),
washed with sat. aq NH4Cl (6 mL) and brine (18 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 10 g, hexane–
EtOAc, 4:6) to give 39 (373 mg, 90%) as a white oil.
HRMS (ESI+): m/z [M + H]+ calcd for C21H25O7NI: 530.0676;
found: 530.0667.
Deiodinated Product 42
IR (neat): 3023, 1736, 1695, 1215, 750 cm–1.
To a degassed solution of iodide 41 (56.0 mg, 0.110 mmol) in tolu-
ene (1.3 mL) at r.t. were added AIBN (1.80 mg, 0.011 mmol) and
Ph3SnH (0.046 mL, 0.18 mmol), and the mixture was degassed un-
der reduced pressure. The mixture was stirred at reflux (110 °C) for
1.5 h before concentration under reduced pressure. The residue was
purified by column chromatography (silica gel, 0.75 g, hexane–
EtOAc, 8:2) to give 42 (35.0 mg, 80%) as a white oil.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 12.0 Hz, 1 H), 7.31–
7.18 (m, 5 H), 6.96 (d, J = 8.4 Hz, 2 H), 6.77 (d, J = 8.4 Hz, 2 H),
5.74 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.38 (d, J = 17.2 Hz, 2 H),
5.21 (d, J = 10.4 Hz, 1 H), 5.20 (d, J = 12.0 Hz, 1 H), 4.81 (d,
J = 14.8 Hz, 1 H), 4.79 (s, 1 H), 4.67 (d, J = 14.8 Hz, 1 H), 4.35 (dd,
J = 10.4, 6.8 Hz, 1 H), 3.93–3.79 (m, 2 H), 3.76 (s, 3 H), 3.06 (d,
J = 6.8 Hz, 1 H), 2.07 (s, 3 H), 1.28 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 169.9, 167.2, 159.1, 151.7,
139.2, 137.0, 133.2, 130.2, 130.1, 128.2 (2 C), 128.0, 127.6, 127.5,
126.9, 120.8, 114.0, 113.9, 112.4, 87.3, 85.0, 84.9, 68.1, 55.1, 53.4,
47.7, 45.5, 27.6 (3 C), 20.5, 20.0.
IR (neat): 3686, 3617, 3019, 1708, 1215, 762 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 8.8 Hz, 2 H), 6.82 (d,
J = 8.8 Hz, 2 H), 5.70 (ddd, J = 16.8, 10.4, 6.8 Hz, 1 H), 5.20 (d,
J = 16.8 Hz, 1 H), 5.09 (d, J = 10.4 Hz, 1 H), 4.82 (d, J = 14.4 Hz,
1 H), 4.22 (m, 1 H), 4.18 (s, 1 H), 3.97 (d, J = 14.4 Hz, 1 H), 3.77
(s, 3 H), 3.64 (s, 3 H), 3.60 (s, 3 H), 3.28 (d, J = 7.6 Hz, 1 H), 2.81
(d, J = 15.2 Hz, 1 H), 2.56 (m, 1 H), 2.51 (d, J = 15.2 Hz, 1 H), 1.95
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 170.1, 169.7, 159.3, 137.0
(2 C), 129.8 (2 C), 127.1, 116.7, 114.1, 84.6, 80.8, 69.3, 55.2, 52.5,
51.9, 51.5, 45.4, 40.1, 35.5.
HRMS (ESI+): m/z [M + H]+ calcd for C33H38O8N2I: 717.1667;
found: 717.1670.
Ester Aldehyde 40
To a stirred solution of imide 39 (492 mg, 0.690 mmol) in MeOH
(9.9 mL) at –10 °C was added K2CO3 (71.9 mg, 0.52 mmol). After
6 h, the mixture was poured into sat. aq NH4Cl (62 mL), and the
mixture was extracted with EtOAc (120 mL). The combined ex-
tracts were washed with brine (62 mL), dried (Na2SO4), and concen-
trated under reduced pressure to give crude 36 (505 mg) as an
unstable colorless oil that was used for the next reaction without pu-
rification. For collection of selected data, 2.4 mg of the crude prod-
uct was purified by column chromatography (silica gel, 0.6 g,
hexane–EtOAc, 4:6) to give ester aldehyde 40 (1.6 mg) as a color-
less oil.
HRMS (ESI+): m/z [M + H]+ calcd for C21H26O7N: 404.1709;
found: 404.1705.
Deprotected Amide 43
To stirred solution of N-PMB amide 42 (18.0 mg, 0.045 mmol) in
MeCN (1.01 mL) and H2O (1.02 mL) at –5 °C was added a solution
of CAN (123 mg, 0.225 mmol) in H2O (0.67 mL). After 1 h, the
mixture was warmed to 0 °C, and stirring was continued for 2 h.
Then the mixture was poured into sat. aq Na2S2O3 (2.5 mL) and ex-
tracted with EtOAc (4 × 21 mL). The combined extracts were
washed with sat. aq NaHCO3 (2.5 mL) and brine (2.5 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 1.0 g, hexane–
EtOAc, 1:3) to give deprotected amide 43 (7.1 mg, 56%) as a white
oil.
IR (neat): 3023, 1733, 1215, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.71 (s, 1 H), 7.11 (d, J = 8.4 Hz,
2 H), 6.84 (d, J = 8.4 Hz, 2 H), 5.72 (m, 1 H), 5.45–5.29 (m, 2 H),
4.98 (d, J = 14.8 Hz, 1 H), 4.18 (m, 1 H), 4.08 (m, 1 H), 4.06 (s, 1
H), 3.90 (d, J = 14.8 Hz, 1 H), 3.78 (s, 3 H), 3.64 (s, 3 H), 3.10 (d,
J = 8.0 Hz, 1 H), 2.79 (d, J = 16.8 Hz, 1 H), 2.61 (d, J = 16.8 Hz, 1
H).
IR (neat): 3685, 3619, 3019, 1744, 1714, 1216, 769 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C20H23O6NI: 500.0570;
found: 500.0577.
1H NMR (400 MHz, CDCl3): δ = 6.11 (br s, 1 H), 5.74 (ddd,
J = 16.8, 10.4, 6.8 Hz, 1 H), 5.26 (d, J = 16.8 Hz, 1 H), 5.14 (d,
J = 10.4 Hz, 1 H), 4.39 (dd, J = 11.2, 6.8 Hz, 1 H), 4.36 (s, 1 H),
3.74 (s, 3 H), 3.66 (s, 3 H), 3.21 (d, J = 8.4 Hz, 1 H), 2.91 (d,
J = 15.6 Hz, 1 H), 2.66 (d, J = 15.6 Hz, 1 H), 2.45 (dd, J = 12.0, 5.6
Hz, 1 H), 1.97 (ddd, J = 12.0, 11.2, 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 176.9, 170.5, 169.9, 136.6, 117.3,
87.1, 80.7, 65.5, 52.7, 51.9, 50.2, 40.1, 35.4.
HRMS (ESI+): m/z [M + H]+ calcd for C13H18O6N: 284.1134;
found: 284.1129.
Diester 41
To a stirred solution of crude aldehyde 40 (505 mg) thus obtained
above in t-BuOH (36.8 mL), H2O (9.2 mL), and THF (1.0 mL) at r.t.
were added 2-methylbut-2-ene (0.537 mL, 5.05 mmol), NaH2PO4
(173.0 mg, 1.11 mmol), and NaClO2 (548 mg, 6.06 mmol). After 12
h, the mixture was cooled to 0 °C and 1 M HCl (3 mL) was added.
The mixture was extracted with CHCl3 (3 × 104 mL), and the com-
bined extracts were dried (Na2SO4) and concentrated under reduced
pressure.
AB-Ring Bicyclic Diacid 18
The residue was dissolved in THF (1.0 mL) and Et2O (2.6 mL). The
solution was cooled to 0 °C and a solution of CH2N2 in Et2O (6.0
mL) was added. The mixture was concentrated under reduced pres-
sure, and the residue was purified by column chromatography (sili-
A suspension of diester 43 (6.00 mg, 0.021 mmol) in 6 M HCl
(0.491 mL) was heated at 60 °C for 4.5 h. The mixture was then
cooled to r.t. and concentrated under reduced pressure. The residue
Synthesis 2013, 45, 3106–3117
© Georg Thieme Verlag Stuttgart · New York

PAPER
BIOS-DOS for Ligand Discovery
3115
was purified by column chromatography (reversed-phase silica gel,
0.75 g, H2O) to give 18 (4.12 mg, 77%) as a white oil.
tography (silica gel, 2 g, hexane–EtOAc, 1:1) to give 47 (E/Z
0.84:0.16, 49.0 mg, 74%) as a white foam.
IR (KBr): 3445, 1725, 1689 cm–1.
IR (neat): 3080, 1761, 1682, 1427, 1231, 937, 836, 677 cm–1.
1H NMR (400 MHz, D2O): δ = 5.72 (ddd, J = 17.2, 10.4, 7.2 Hz, 1
H), 5.22 (d, J = 17.2 Hz, 1 H), 5.11 (d, J = 10.4 Hz, 1 H), 4.34 (m,
1 H), 4.31 (s, 1 H), 3.21 (d, J = 8.4 Hz, 1 H), 2.83 (d, J = 16.0 Hz, 1
H), 2.73 (d, J = 16.0 Hz, 1 H), 2.27 (dd, J = 8.4, 5.2 Hz, 1 H), 1.95
(m, 1 H).
13C NMR (100 MHz, D2O): δ = 179.5, 173.8, 173.5, 136.1, 118.1,
86.9, 80.9, 66.6, 50.8, 40.0, 34.2.
1H NMR (400 MHz, CDCl3): δ (E/Z 0.84:0.16) = 7.48 (d, J = 12.0
Hz, 0.84 H), 7.33–7.23 (m, 5 H), 6.82 (d, J = 7.2 Hz, 0.16 H), 6.01
(br s, 1 H), 5.72 (m, 1 H), 5.45 (d, J = 12.0 Hz, 0.84 H), 5.44–5.28
(m, 2 H), 4.94 (d, J = 7.2 Hz, 0.16 H), 4.54 (dd, J = 10.4, 6.0 Hz, 1
H), 4.38–4.29 (m, 2 H), 4.13 (s, 1 H), 3.95 (m, 1 H), 3.90 (dd,
J = 7.2, 3.6 Hz, 1 H), 3.76–3.68 (m, 2 H), 3.00 (d, J = 7.2 Hz, 1 H),
2.87 (m, 1 H), 2.12 (s, 2.52 H), 2.06 (s, 0.48 H), 0.84 (s, 9 H), 0.02
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ (major isomer) = 170.0, 167.8,
167.6, 139.2, 137.2, 133.0, 128.8 (2 C), 128.0 (2 C), 127.9, 121.2,
112.9, 87.1, 84.9, 77.2, 72.6, 62.2, 53.3, 44.5, 43.9, 26.0 (3 C), 20.7,
20.4, 18.3, –5.4 (2 C).
HRMS (ESI–): m/z [M – H]– calcd for C11H12O6N: 254.0665; found:
254.0664.
7-Oxanorbornene 45 (Domino UDA Reaction)
To a stirred solution of 2-aminoethanol (44, 0.049 mL, 0.82 mmol)
in MeOH (2.3 mL) at r.t. were added 2-furfural (8, 0.120 mL, 1.23
mmol), (Z)-3-iodoacrylic acid [(Z)-6, 162 mg, 0.82 mmol],28 and
benzyl isocyanide (7, 0.923 mL, 7.58 mmol). After stirring at 50 °C
for 24 h, the mixture was concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 15 g,
hexane–EtOAc, 7:3) to give 45 (279 mg, 77%) as a brown foam.
HRMS (ESI+): m/z [M + H]+ calcd for C28H40O6N2ISi: 655.1695;
found: 655.1697.
N-Boc Imide 48
To a stirred solution of N-Bn amide 47 (333 mg, 0.53 mmol) in
CH2Cl2 (7.97 mL) at 0 °C were added Boc2O (0.626 mL, 2.65
mmol), Et3N (0.374 mL, 2.65 mmol), and DMAP (32.7 mg, 0.265
mmol). After stirring at r.t. for 1 h, the mixture was diluted with
EtOAc (20 mL) and poured into sat. aq NH4Cl (20 mL). The aque-
ous layer was separated and extracted with EtOAc (3 × 20 mL). The
combined extracts were washed with brine (40 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 20 g, hexane–
EtOAc, 7:3) to give 48 (560 mg, 90%) as a yellow oil.
IR (neat): 3011, 1816, 1686, 1479, 1243, 1243, 1152 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 7.02 (m, 1 H),
6.40 (d, J = 8.0 Hz, 1 H), 6.33 (dd, J = 8.0, 1.6 Hz, 1 H), 5.25 (d,
J = 1.6 Hz, 1 H), 4.50 (d, J = 6.0 Hz, 2 H), 4.38 (s, 1 H), 3.85 (m, 1
H), 3.83 (d, J = 8.0 Hz, 1 H), 3.70 (m, 1 H), 3.50–3.47 (m, 2 H), 2.56
(d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 167.7, 137.3, 135.3, 135.0,
128.9 (2 C), 128.0 (2 C), 128.0, 92.5, 88.9, 64.1, 60.9, 48.5, 45.7,
44.0, 18.2.
IR (neat): 3019, 1739, 1701, 1421, 1216, 744 cm–1.
1H NMR (400 MHz, CDCl3): δ (E/Z 0.9:0.1) = 7.42 (d, J = 12.0 Hz,
0.9 H), 7.29–7.25 (m, 5 H), 6.83 (d, J = 7.2 Hz, 0.1 H), 5.78 (s, 1 H),
5.71 (ddd, J = 17.2, 10.4, 7.2 Hz, 1 H), 5.41 (d, J = 17.2 Hz, 1 H),
5.33 (d, J = 10.4 Hz, 1 H), 5.15 (d, J = 12.0 Hz, 0.9 H), 5.00 (d,
J = 7.2 Hz, 0.1 H), 4.95 (d, J = 14.8 Hz, 1 H), 4.78 (d, J = 14.8 Hz,
1 H), 4.35 (dd, J = 10.8, 7.2 Hz, 1 H), 3.87 (dd, J = 10.8, 6.8 Hz, 1
H), 3.85 (m, 1 H), 3.75–3.62 (m, 2 H), 2.91 (d, J = 6.8 Hz, 1 H), 2.81
(m, 1 H), 2.07 (s, 3 H), 1.40 (s, 9 H), 0.85 (s, 9 H), 0.02 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ (major isomer) = 172.5, 170.3,
167.3, 152.0, 139.2, 137.2, 133.4, 128.4 (2 C), 128.1 (2 C), 127.5,
121.0, 112.9, 87.2, 85.3, 84.7, 77.2, 61.2, 53.0, 48.1, 44.9, 27.9 (3
C), 26.0 (3 C), 20.6, 18.3, –5.3, –5.4.
HRMS (ESI+): m/z [M + H]+ calcd for C18H20O4N2I: 455.0462;
found: 455.0465.
TBDMS Ether 46
To a stirred solution of alcohol 45 (268.0 mg, 0.60 mmol) in CH2Cl2
(13.0 mL) at r.t. were added imidazole (81.7 mg, 1.20 mmol) and
TBDMSCl (99.5 mg, 0.66 mmol). After 13 h, imidazole (20.4 mg,
0.30 mmol) and TBDMSCl (27.3 mg, 0.18 mmol) were supple-
mented. After stirring at r.t. for 3 h, H2O (10 mL) was added and the
mixture was extracted with CHCl3 (3 × 10 mL). The combined ex-
tracts were dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica
gel, 7 g, hexane–EtOAc, 4:6) to give 46 (294.8 mg, 92%) as a col-
orless oil.
HRMS (ESI+): m/z [M + H]+ calcd for C33H48O8N2ISi: 755.2219;
found: 755.2221.
IR (neat): 3300, 2929, 1685, 1559, 1455, 1405, 1215, 641 cm–1.
Ester Aldehyde 49
1H NMR (400 MHz, CDCl3): δ = 7.32–7.25 (m, 5 H), 6.82 (m, 1 H),
6.43 (d, J = 6.0 Hz, 1 H), 6.32 (dd, J = 6.0, 1.6 Hz, 1 H), 5.23 (d,
J = 1.6 Hz, 1 H), 4.52 (dd, J = 14.4, 6.0 Hz, 1 H), 4.49 (s, 1 H), 4.46
(dd, J = 14.4, 6.0 Hz, 1 H), 3.83 (d, J = 8.0 Hz, 1 H), 3.79–3.72 (m,
3 H), 3.17 (m, 1 H), 2.51 (d, J = 8.0 Hz, 1 H), 0.84 (s, 9 H), 0.02 (s,
6 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 167.4, 137.3, 135.5, 135.2,
128.9 (2 C), 128.0, 127.9 (2 C), 92.3, 88.8, 63.9, 62.5, 48.5, 44.9,
43.8, 26.0 (3 C), 18.4, 18.3, –5.3, –5.4.
To a stirred solution of N-Boc imide 48 (369 mg, 0.511 mmol) in
MeOH (7.2 mL) at –20 °C was added K2CO3 (35.2 mg, 0.255
mmol). After 1 h, the mixture was allowed to warm to –10 °C, and
stirring was continued for 3 h. The mixture was then poured into sat.
aq NH4Cl (10 mL), and it was extracted with EtOAc (3 × 10 mL).
The combined extracts were washed with brine (30 mL), dried
(Na2SO4), and concentrated under reduced pressure to give crude 49
(371 mg) as a colorless oil that was used for the next reaction with-
out purification.
HRMS (ESI+): m/z [M + H]+ calcd for C24H34O4N2ISi: 569.1327;
found: 569.1327.
Diester 50
To a stirred solution of crude aldehyde 49 (371 mg), thus obtained
above, in t-BuOH (20.0 mL) and H2O (5.0 mL) at 0 °C were added
2-methylbut-2-ene (0.271 mL, 2.55 mmol), NaH2PO4 (87.5 mg,
0.561 mmol), and NaClO2 (138 mg, 1.53 mmol). After stirring at r.t.
for 2 h, the mixture was cooled to 0 °C and 0.5 M HCl (20 mL) was
added. The mixture was extracted with CHCl3 (3 × 20 mL), and the
combined extracts were dried (Na2SO4) and concentrated under re-
duced pressure.
Heterobicycle 47 (Domino Metathesis Reaction)
To a stirred solution of oxanorbornene 46 (57.2 mg, 0.11 mmol) in
benzene (1.1 mL) and 1,2-dichloroethane (1.4 mL) at r.t. were added
portionwise vinyl acetate (0.0449 mL, 0.53 mmol) and Hoveyda–
Grubbs 2nd generation catalyst 12 (4.08 mg, 0.0171 mmol) under
an argon atmosphere after conducting freeze–thaw degasification (2
×). After stirring at 45 °C for 9 h, the mixture was concentrated un-
der reduced pressure. The residue was purified by column chroma-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117

3116
M. Oikawa et al.
PAPER
The residue was dissolved in THF (3.5 mL) and Et2O (10.5 mL).
The solution was cooled to 0 °C and a solution of CH2N2 in Et2O
(6.0 mL) was added. The mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography
(silica gel, 10 g, hexane–EtOAc, 3:7) to give diester 50 (192 mg,
68% from 48) as a white oil.
The authors are also indebted to Prof. S. Nishiyama (Keio Univer-
sity, Japan) for HRMS facility.
This work was partly supported by the grant for 2010-2012 Strate-
gic Research Promotion (Nos. T2202, T2309, T2401) of Yokohama
City University, Japan. Financial support (a Grant-in-Aid for Scien-
tific Research (21603004)) from the Ministry of Education, Sci-
ence, Sports, Culture and Technology, Japan, is also gratefully
acknowledged.
IR (neat): 3016, 1741, 1700, 1218, 930, 680 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.70 (ddd, J = 17.2, 10.0, 6.4 Hz,
1 H), 5.39 (d, J = 17.2 Hz, 1 H), 5.31 (d, J = 10.0 Hz, 1 H), 4.53 (s,
1 H), 4.31 (dd, J = 14.0, 6.4 Hz, 1 H), 4.15 (dd, J = 10.0, 8.4 Hz, 1
H), 3.98 (m, 1 H), 3.75 (s, 3 H), 3.72–3.67 (m, 2 H), 3.65 (s, 3 H),
3.30 (d, J = 8.4 Hz, 1 H), 2.86 (d, J = 15.6 Hz, 1 H), 2.82 (m, 1 H),
2.56 (d, J = 15.6 Hz, 1 H), 0.84 (s, 9 H), 0.02 (s, 6 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (100 MHz, CDCl3): δ (major isomer) = 170.1, 169.9,
169.4, 132.7, 120.7, 86.8, 84.6, 77.3, 71.3, 62.0, 52.6, 52.1, 44.4,
39.5, 26.0 (3 C), 23.0, 18.2, –5.4, –5.5.
HRMS (ESI+): m/z [M + H]+ calcd for C21H35O7NISi: 568.1222;
found: 568.1219.
References
(1) (a) Mitchison, T. J. Chem. Biol. 1994, 1, 3. (b) Schreiber, S.
L. Bioorg. Med. Chem. 1998, 6, 1127.
(2) Schreiber, S. L. Science 2000, 287, 1964.
(3) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004,
43, 46.
(4) Nielsen, T. E.; Schreiber, S. L. Angew. Chem. Int. Ed. 2008,
47, 48.
(5) Nören-Müller, A.; Reis-Corrêa, I.; Prinz, H.; Rosenbaum,
C.; Saxena, K.; Schwalbe, H. J.; Vestweber, D.; Cagna, G.;
Schunk, S.; Schwarz, O.; Schiewe, H.; Waldmann, H. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 10606.
(6) For recent reviews, see: (a) de Graaff, C.; Ruijter, E.; Orru,
R. V. A. Chem. Soc. Rev. 2012, 41, 3969. (b) Shiri, M.
Chem. Rev. 2012, 112, 3508. (c) van Berkel, S. S.; Bögels,
B. G. M.; Wijdeven, M. A.; Westermann, B.; Rutjes, F. P. J.
T. Eur. J. Org. Chem. 2012, 3543.
(7) For recent reviews, see: (a) Nicolaou, K. C.; Chen, J. S.
Chem. Soc. Rev. 2009, 38, 2993. (b) Núñez, M. G.; García,
P.; Moro, R. F.; Díez, D. Tetrahedron 2010, 66, 2089.
(c) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012,
51, 314. (d) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem.
Res. 2012, 45, 1278.
Deiodinated Product 51
To a degassed solution of iodide 50 (38.8 mg, 0.070 mmol) in tolu-
ene (1.3 mL) at r.t. were added AIBN (1.15 mg, 0.0070 mmol) and
Ph3SnH (0.0285 mL, 0.112 mmol), and the mixture was degassed
under reduced pressure. The mixture was stirred at reflux (110 °C)
for 1 h before concentration under reduced pressure. The residue
was purified by column chromatography (silica gel, 1 g, hexane–
EtOAc, 7:3) to give 51 (22.7 mg, 76%) as a colorless oil.
IR (neat): 3019, 1741, 1686, 1424, 1218, 908, 669 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.71 (ddd, J = 16.8, 10.4, 6.4 Hz,
1 H), 5.21 (d, J = 16.8 Hz, 1 H), 5.10 (d, J = 10.4 Hz, 1 H), 4.62 (s,
1 H), 4.29 (m, 1 H), 3.89 (m, 1 H), 3.74 (s, 3 H), 3.71–3.67 (m, 2 H),
3.66 (s, 3 H), 3.26 (d, J = 8.0 Hz, 1 H), 2.90 (m, 1 H), 2.86 (d,
J = 14.8 Hz, 1 H), 2.51 (d, J = 14.8 Hz, 1 H), 2.48 (dd, J = 8.0, 4.8
Hz, 1 H), 1.96 (dd, J = 8.0, 4.8 Hz, 1 H), 0.85 (s, 9 H), 0.02 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ (major isomer) = 174.5, 170.4,
169.8, 136.9, 120.2, 84.7, 80.6, 71.3, 61.3, 52.5, 51.9, 51.0, 44.4,
40.2, 35.9, 25.8 (3 C), 18.2, –5.5 (2 C).
(8) Robinson, R. J. Chem. Soc., Trans. 1917, 111, 762.
(9) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(10) Oh, C. H.; Karmakar, S.; Park, H.; Ahn, Y.; Kim, J. W.
J. Am. Chem. Soc. 2010, 132, 1792.
HRMS (ESI+): m/z [M + H]+ calcd for C21H36O7NSi: 442.2256;
found: 442.2253.
(11) Dückert, H.; Pries, V.; Khedkar, V.; Menninger, S.; Bruss,
H.; Bird, A. W.; Maliga, Z.; Brockmeyer, A.; Janning, P.;
Hyman, A.; Grimme, S.; Schürmann, M.; Preut, H.; Hübel,
K.; Ziegler, S.; Kumar, K.; Waldmann, H. Nat. Chem. Biol.
2012, 8, 179.
(12) Aydillo, C.; Jiménez-Osés, G.; Avenoza, A.; Busto, J. H.;
Peregrina, J. M.; Zurbano, M. a. M. J. Org. Chem. 2011, 76,
6990.
(13) Hong, B.-C.; Nimje, R. Y.; Lin, C.-W.; Liao, J.-H. Org. Lett.
2011, 13, 1278.
(14) Barluenga, J.; Mendoza, A.; Rodríguez, F.; Fañanás, F. J.
Angew. Chem. Int. Ed. 2008, 120, 7152.
(15) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett.
2010, 12, 776.
(16) (a) Ugi, I. Angew. Chem. 1959, 71, 386. (b) Ugi, I.;
Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(17) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007,
73, 125.
(18) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851.
(19) Lee, D. S.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2,
709.
(20) (a) Oikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett.
2005, 46, 5863. (b) Oikawa, M.; Ikoma, M.; Sasaki, M.
Tetrahedron Lett. 2005, 46, 415. (c) Ikoma, M.; Oikawa, M.;
Sasaki, M. Tetrahedron 2008, 64, 2740. (d) Ikoma, M.;
Oikawa, M.; Sasaki, M. Eur. J. Org. Chem. 2009, 72.
N-(Hydroxyethyl) Diacid 19
A suspension of siloxy diester 51 (5.80 mg, 0.014 mmol) in 6 M
HCl (0.300 mL) was heated at 60 °C for 4 h. The mixture was then
cooled to r.t. and concentrated under reduced pressure. The residue
was purified by column chromatography (reversed-phase silica gel,
0.75 g, H2O) to give 19 (2.12 mg, 56%) as a white oil.
IR (KBr): 3455, 1725, 1650 cm–1.
1H NMR (400 MHz, D2O): δ = 5.71 (ddd, J = 17.2, 10.4, 6.8 Hz, 1
H), 5.20 (d, J = 17.2 Hz, 1 H), 5.10 (d, J = 10.4 Hz, 1 H), 4.50 (s, 1
H), 4.29 (m, 1 H), 3.69 (s, 1 H), 3.70–3.57 (m, 2 H), 3.26 (d, J = 7.6
Hz, 1 H), 3.04 (m, 1 H), 2.80 (d, J = 16.0 Hz, 1 H), 2.71 (d, J = 16.0
Hz, 1 H), 2.33 (dd, J = 7.6, 5.6 Hz, 1 H), 1.98 (ddd, J = 7.6, 6.4, 5.6
Hz, 1 H).
13C NMR (100 MHz, D2O): δ = 177.6, 173.7, 173.3, 136.7, 117.4,
85.0, 81.6, 71.8, 58.7, 52.0, 44.6, 40.3, 34.7.
HRMS (ESI–): m/z [M – H]– calcd for C13H16O7N: 298.0932; found:
298.0930.
Acknowledgment
We thank Prof. Jette S. Kastrup (University of Copenhagen, Den-
mark), Prof. Geoffrey T. Swanson (Northwestern University Fein-
berg School of Medicine, USA), and Prof. Ryuichi Sakai (Hokkaido
University, Japan) for invaluable discussions throughout the work.
Synthesis 2013, 45, 3106–3117
© Georg Thieme Verlag Stuttgart · New York

PAPER
BIOS-DOS for Ligand Discovery
3117
(21) (a) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K.
J. Am. Chem. Soc. 1997, 119, 4112. (b) Sakai, R.; Koike, T.;
Sasaki, M.; Shimamoto, K.; Oiwa, C.; Yano, A.; Suzuki, K.;
Tachibana, K.; Kamiya, H. Org. Lett. 2001, 3, 1479.
(22) Parsons, A. F. Tetrahedron 1996, 52, 4149.
(23) (a) Ikoma, M.; Oikawa, M.; Gill, M. B.; Swanson, G. T.;
Sakai, R.; Shimamoto, K.; Sasaki, M. Eur. J. Org. Chem.
2008, 5215. (b) Oikawa, M.; Ikoma, M.; Sasaki, M.; Gill, M.
B.; Swanson, G. T.; Shimamoto, K.; Sakai, R. Eur. J. Org.
Chem. 2009, 5531. (c) Oikawa, M.; Ikoma, M.; Sasaki, M.;
Gill, M. B.; Swanson, G. T.; Shimamoto, K.; Sakai, R.
Bioorg. Med. Chem. 2010, 18, 3795.
(26) (a) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Kan, T.; Fukuyama, T. Chem. Commun.
2004, 353.
(27) Francais, A.; Bedel, O.; Haudrechy, A. Tetrahedron 2008,
64, 2495.
(28) Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000,
65, 1558.
(29) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(30) (a) Weeresakare, G. M.; Liu, Z.; Rainier, J. D. Org. Lett.
2004, 6, 1625. (b) Liu, Z.; Rainier, J. D. Org. Lett. 2005, 7,
131.
(24) Gill, M. B.; Frausto, S.; Ikoma, M.; Sasaki, M.; Oikawa, M.;
Sakai, R.; Swanson, G. T. Br. J. Pharmacol. 2010, 160,
1417.
(25) Juknaitė, L.; Sugamata, Y.; Tokiwa, K.; Ishikawa, Y.;
Takamizawa, S.; Eng, A.; Sakai, R.; Pickering, D. S.;
Frydenvang, K.; Swanson, G. T.; Kastrup, J. S.; Oikawa, M.
J. Med. Chem. 2013, 56, 2283.
(31) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45,
1175. (b) Bal, B. S.; Childers, W. E. Jr; Pinnick, H. W.
Tetrahedron 1981, 37, 2091. (c) Dalcanale, E.; Montanari,
F. J. Org. Chem. 1986, 51, 567.
(32) Brown, H. C.; Liu, K.-T. J. Am. Chem. Soc. 1970, 92, 3502.
(33) Sakai, R., personal communication.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3106–3117