Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.08.093

A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 wit

Full text of DOI:10.1016/j.bmcl.2009.08.093

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6213–6217
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates
as ADAMTS-5 (Aggrecanase-2) inhibitors
a
a
a
a
a
Makoto Shiozaki a, , Hiroto Imai , Katsuya Maeda , Tomoya Miura , Katsutaka Yasue , Akira Suma ,
Masahiro Yokota a, Yosuke Ogoshi a, Julia Haas b, Andrew M. Fryer b, Ellen R. Laird b, Nicole M. Littmann b,
Steven W. Andrews b, John A. Josey b, Takayuki Mimura a, Yuichi Shinozaki a, Hiromi Yoshiuchi a,
*
Takashi Inaba a,
*
a Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki Osaka 569-1125, Japan
b Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2)
inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereo-
chemistry and substituents, we found compound 22 with an Agg-2 IC50 = 7.4 nM, the most potent ADAM-
TS-5 inhibitor reported so far.
Received 22 July 2009
Accepted 31 August 2009
Available online 3 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
SAR
ADAMTS-5 (Aggrecanase-2) inhibitors
2-Phenyl-1-
sulfonylaminocyclopropanecarboxylates
Osteoarthritis (OA) is a degenerative disease that occurs in a
large proportion of the elderly. It is characterized by degradation
of articular cartilage that leads to significant joint pain and inflam-
mation and eventually results in impaired mobility. No effective
treatment to halt the progression is currently available, and the
discovery of disease modifying osteoarthritis drugs (DMORDs)
has been eagerly awaited for a long time.
2 IC50 = 0.073 lM) is shown in Table 1; for this series, appropriate
heterocycles tethered to the sulfonamide nitrogen (e.g., the imid-
azole-4-carboxylate ester in 1) are a significant contributor to po-
tency. The preferred configuration is (1R,2S), as the enantiomer 2
displayed a significant loss of potency. In the course of pursuing
this N-substituted series, we found that non N-substituted 1-sulfo-
nylamino-2-phenylcyclopropane carboxylates are also potent, but
their enantiomeric preference is (1S,2R), in sharp contrast to the
N-substituted series. Compound 4, having the (1S,2R) configura-
Aggrecan, the major proteoglycan in cartilage, endows articular
cartilage with its unique compressive resistance. In osteoarthritic
cartilage, aggrecan is cleaved at the Glu373-Ala374 site1 by
aggrecanases which are members of the ADAMTS (a disintegrin
and metalloprotease with thrombospondin motifs) family of zinc
metalloproteases. Among aggrecanases, much attention has been
recently paid to ADAMTS-5 (Aggrecanase-2), since ADAMTS-5
knock-out mice have been shown to be more resistant to progres-
sion of cartilage degradation in a surgically induced osteoarthritis
model as well as in a short term inflammatory arthritis model.2,3
Thus, this enzyme is currently believed to be a promising pharma-
cologic target to prevent OA.
tion, inhibited ADAMTS-5 with an IC50 of 0.084 lM, whereas its
enantiomer 3 was slightly less active. Since the ligand efficiency5,6
of 4 is much greater than that of 1, which is one of the most potent
compounds in the previous N-substituted series, we decided to
investigate the non-N-substituted series in our ADAMTS-5 inhibi-
tor program. In this paper, we report on our efforts to optimize sul-
fonamide 4, which led to discovery of compound 22, the most
potent ADAMTS-5 inhibitor reported to date.
Figure 1 illustrates our proposed binding modes for compounds
1 and 4. The inverted stereochemical preferences are consistent
with orientation of the sulfonamide nitrogen toward solvent when
substituted (1) or hydrogen-bonded to the backbone carbonyl of
Gly380 when unsubstituted (4). The lower activity of 3 results
from loss of this hydrogen bond. Such alternate sulfonamide orien-
tations have been observed crystallographically for metallopro-
teinase inhibitors of inverted stereochemistry.7
In a preceding paper4 we have disclosed a series of N-substi-
tuted 2-phenyl-1-sulfonylaminocyclopropane carboxylates as
ADAMTS-5 inhibitors. A representative analog (compound 1, Agg-
* Corresponding authors.
E-mail address: makoto.shiozaki@ims.jti.co.jp (M. Shiozaki).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.093

6214
M. Shiozaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6213–6217
Table 1
In terms of its structural features, compound 4 is divided into
two components, an arylsulfonyl headpiece and a cyclopropane
core. We initially varied the arylsulfonyl headpiece to see its effect
on inhibitory activity.
The results are summarized in Table 2. Compound 5, possessing
a thiophene ring instead of the proximal benzene ring of 4, was of
In vitro ADAMTS-5 inhibitory activity of 1-[4-(4-Cl-phenyl)phenyl]sulfonylamino-2-
phenylcyclopropanecarboxylates
O
O
R
Cl
S
N
1
2
HO
O
Table 2
Compd Configuration
R
%Inhibition at Agg-2 IC50
In vitro ADAMTS-5 inhibitory activity of 2-phenyl-1-sulfonylaminocyclopopanecarb-
oxylates with various head groups
0.3
lM
(lM)
O O
H
N
N
O
HCl
HCl
R
S
N
1
2
(1R,2S)
(1S,2R)
0.073
N
N
*
*
OMe
O
HO
O
18%
OMe
Compd
R
ADAMTS-5
%Inhibition at 1.0
H
H
3
4
(1R,2S)
(1S,2R)
0.210
0.084
*
*
l
M
IC50 (lM)
Cl
5
0.060
S
*
6
7
8
9
0.094
Cl
S
*
48
S
*
Cl
Cl
N
0.100
0.080
S
*
*
N
N
Cl
S
Figure 1. Proposed binding modes for compounds 1 and 4. The inhibitors were
docked manually into the X-ray structure of ADAMTS-5 (PDB accession code 3B8Z8).
The inhibitors are depicted in green, the protein surface is violet, and selected
sidechains are shown in white. The zinc ion is portrayed as a blue sphere. Electronic
contacts are shown as dashed yellow lines.
Figure 2. Proposed binding mode for 9. The color scheme is as described for Figure
1. Note that an alternate rotamer of the distal pyrazole is sterically tolerated, but
would suffer from an electronic repulsion from the carbonyl of Ser440. The
resulting orientation places the distal chlorine atom into a small depression within
the S10 pocket.

M. Shiozaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6213–6217
6215
comparable potency to 4 (IC50 = 0.060
l
M). Models comparing 4
bromothiophene in the presence of a copper catalyst.9 A Negishi
coupling was applied to make 16, which was subjected to ClSO3H
to give 17 in a single step.
and 5 suggest that the terminal chlorine atom can reside in a sim-
ilar position in the enzyme pocket, consistent with their similar
activities. From a synthetic point of view, we decided to keep the
thiophene ring constant while varying the distal aromatic ring be-
cause the corresponding sulfonyl chlorides could be prepared un-
After the exploration of the arylsulfonyl headpiece discussed
above, we next focused on the cyclopropane core portion. To inves-
tigate the effects of substituents on the inhibitory activity, a methyl
group was initially introduced at the 2-, cis-3-, or trans-3-position
of the cyclopropane ring in a stereoselective fashion. Results using
the newly-discovered two thienylsulfonyl groups as headpieces are
shown in Table 3. A marked improvement in potency was observed
for the 2- and cis-3-methylated compounds, while introduction of a
methyl group in the trans-3-position virtually showed no effect. It
is interesting to note that methyl group introduction in the 2-posi-
tion is slightly more effective than in the cis-3 position for the 4-
chlorophenyl series (compare 18 and 19), while methylation of
the cis-3-position increased the potency more markedly than 2-
der much milder conditions. There was
a clear positional
preference of the chlorine atom on the distal benzene ring and
ortho-substituted analog 7 had greatly reduced potency; this is ex-
pected to arise from a significantly larger torsion between the two
aryl rings and resulting steric incompatibility with the S10 pocket.
The meta-substituted analog 6 had comparable potency to 5.
Replacement of the distal benzene ring with heteroaromatics was
well tolerated. The pyridine and pyrazole analogs (8 and 9) had
IC50s of 0.10 and 0.080 lM, respectively.
Figure 2 illustrates the proposed binding mode for compound 9.
For the illustrated orientation, the pyrazole nitrogen is not in-
volved in a direct hydrogen bonding interaction; we hypothesize
that an electronic repulsion to the backbone carbonyl of Ser440
(ca. 2.8 Å distance from the pyrazole ring) drives the orientation
as depicted, which in turn allows the chlorine atom to occupy a
small surface depression near the sidechain of Ser440.
Table 3
Effects of substituents on the cyclopropane ring for 2-phenyl-1-sulfonylamin ocyclop-
opanecarboxylates
O
O
O O
O
O
N
O O
R S N
H
H
H
H
R
S
N
R
S N
R
S
2
Compounds 4–9 were prepared as shown in Scheme 1. Com-
mercially available carboxylic acid 10 was treated with SOCl2 in
MeOH to give ester 11, which was further transformed to 4–9 via
coupling reactions with sulfonyl chlorides followed by ester hydro-
lysis. 5-(Chloropheny)thiophenesulfonyl chlorides (13a–c) were
prepared in two steps: sulfonylation with sulfuric acid in the pres-
ence of Ac2O, and successive chlorination with SOCl2. 13d was sim-
ilarly prepared from 12d, which was obtained from 14 and 2-
HO
HO
HO
HO
3
O
O
O
O
unmethylated
2-methylated
cis-3-methylated trans-3-methylated
Compd
R
Cyclopropane
Methylation
ADAMTS-5 IC50
M)
(l
5
18
Unmethylated
2-Methyl
cis-3-Methyl
trans-3-Methyl
0.060
0.010
0.021
0.120
Cl
19
20a
S
O
H
*
HCl
N
H2N
MeO
a
b
O
HO
4-9
N
N
9
21
22
Unmethylated
2-Methyl
cis-3-Methyl
0.080
0.032
0.0074
Cl
O
O
S
*
11
10
a
Racemic compound.
c
R
R
O
S
O
S
S
Cl
13a (R=2-Cl-Phenyl)
13b (R=3-Cl-Phenyl)
13c (R=4-Cl-Phenyl)
13d (R=4-Cl-1-pyrazolyl
12a (R=2-Cl-Phenyl)
12b (R=3-Cl-Phenyl)
12c (R=4-Cl-Phenyl)
12d (R=4-Cl-1-pyrazolyl
N
N
Cl
Cl
d
S
NH
N
14
12d
Cl
Cl
N
N
e
f
BrZn
S
S
O
O
S
S
Cl
15
16
17
Scheme 1. Reagents and conditions: (a) SOCl2, MeOH, rt, 12 h (99%); (b) (i) 4-(4-Cl-
phenyl)phenyl]sulfonyl chloride or 13a–d or 17, Et3N, CHCl3, rt, 6 h, (ii) 4 N NaOH,
MeOH, THF, 100 °C, 4 h (37–86%, two steps); (c) (i) Ac2O, c-H2SO4, AcOEt, 0 °C to rt,
24 h, (ii) DMF, SOCl2, 90 °C, 8 h (47–80%, 2 steps); (d) 2-bromothiophene, Cu2O,
salicyl aldoxime, Cs2CO3, DMF, 120 °C, 15 h (68%); (e) 2,5-dichloropyridine,
Pd(dppf)Cl2ꢀCH2Cl2, THF, 50 °C, 8 h (30%); (f) ClSO3H, rt, 12 h (27%).
Figure 3. Hypothesized binding mode for compound 22. The color scheme is as
described for Figure 1. The rotamer of the phenyl group at C2 is expected to be
twisted slightly by the presence of the cis-3-methyl group, which may enhance
hydrophobic contact to the cleft surface near Met381.

6216
M. Shiozaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6213–6217
Table 4
methyl-substitution for the 4-pyrazole series (compare 21 and 22).
Models for these compounds suggest that for both series the 2-
methyl substituent introduces an additional hydrophobic contact
to Thr378, which resides above the active site cleft, while cis-3-
methylation leads to a slight rotation of the phenyl substituent at
the 2-position. This rotation may enhance contact to Met381, which
forms a hydrophobic patch on the cleft surface (Fig. 3). Compound
22, with an IC50 of 7.4 nM, is the most potent ADAMTS-5 inhibitor
reported to date. Although a definitive explanation for the larger
enhancement of cis-3-methylation on the pyrazole series remains
elusive, we propose that the activity arises from the compact nature
of the S10 biaryl substituent, and a resultant ability to adjust posi-
tion for maximal contact of the phenyl ring.
Investigation of the amino acid portion of [5-(4-Cl-pyrazole-1-yl)thiophene-2-yl]sul-
fonamides
N
Cl
N
O
O
S
S
NHR
Compda
NHR
Agg-2
%Inhibition at 1.0
lM
IC50 (lM)
H
N
*
27
ꢁ0.84
HO
O
Compounds 18–22 were prepared as shown in Scheme 2. Selec-
tive hydrolysis of the less hindered ester of racemic rac-23a–c,10–12
followed by a Curtius rearrangement, gave compounds rac-24a–c,
which were subjected to hydrolysis conditions to give rac-25a–c.
Optically pure 25b–c, obtained by chiral resolution as (+)-quini-
dine salts, and rac-25a were then esterified before Boc deprotec-
tion in the presence of TsOHꢀH2O. Coupling of thus obtained 26b,
26c and rac-26a with 13c, and successive cleavage of the t-Bu ester
under acidic conditions provided 18, 19 and 20, respectively. Com-
pounds 21 and 22 were similarly prepared via coupling of 26b and
26c with 13d, respectively.
H
N
*
28
3.5
HO
O
H
N
*
29
30
0.77
0.36
HO
O
O
H
N
*
HO
The significant improvement in potency achieved by introduc-
tion of a methyl group on the cyclopropane core prompted us to
pursue further investigation of this part of the molecule. A variety
of alkyl-substituted cyclopropane analogs, as well as a cyclobutane
analog, was synthesized in racemic form (Table 4). Diminishing the
contact of the C-2 phenyl group by removal (28) or homologation
(31) resulted in significant loss of activity. Re-introduction of
hydrophobicity with alkylation at C2 led to restoration of some
activity (29 and 30), while enhanced activity by addition of a sec-
ond methyl group (32 and 33) is consistent with the positional
preference of methylation found in the phenyl substituted series
possessing a chloropyrazole headpiece (see 21 and 22). Although
a gain in potency was observed by increasing the size and hydro-
phobicity of the 2-alkyl substituent in 28 from methyl to i-propyl
and cyclohexyl (28–30), the marked inhibitory activity found in
H
N
*
31
32
33
25
HO
O
O
O
H
N
*
19.6
HO
H
N
*
0.80
HO
a
All compounds are racemic.
O
O
O
H
H
EtO
EtO
R2
N
R2
N
R2
O
EtO
O
HO
a
b
R3 R1
R3 R1
O
R3 R1
O
O
rac-23a (R1=Me, R2=R3=H)
rac-23b (R2=Me, R1=R3=H)
rac-23c (R3=Me, R1=R2=H)
rac-24a (R1=Me, R2=R3=H)
rac-24b (R2=Me, R1=R3=H)
rac-24c (R3=Me, R1=R2=H)
rac-25a (R1=Me, R2=R3=H)
rac-25b (R2=Me, R1=R3=H)
rac-25c (R3=Me, R1=R2=H)
O
H
N
R2
c
25b (R2=Me, R1=R3=H)
25c (R3=Me, R1=R2=H)
rac-25b
rac-25c
O
HO
R3 R1
O
H2N
R2
d
rac-25a
25b
25c
e
18-22
O
R3 R1
O
rac-26a (R1=Me, R2=R3=H)
26b (R2=Me, R1=R3=H)
26c (R3=Me, R1=R2=H)
Scheme 2. Reagents and conditions: (a) (i) 4 N NaOH, EtOH, rt, 12 h, (ii) DPPA, t-BuOH, Et3N 110 °C, 12 h (32–88%, 2 steps); (b) 4 N NaOH, EtOH, 100 °C, 12 h (96–99%);
(c) (+)-quinidine, i-PrOH, AcOEt, rt, 12 h (30%, 99% ee for 25b, 36%, 100% ee for 25c); (d) (i) Me2NCH(Ot-Bu)2, toluene, 100 °C, 5 h, (ii) p-TsOHꢀH2O, MeOH, 12 h (74–99%, 2
steps); (e) (i) 13c or 13d, pyridine, CHCl3, 12 h; (ii) TFA, CHCl3, 12 h (24–84%, 2 steps).

M. Shiozaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6213–6217
6217
O
O
O
H
MeO
MeO
N
H2N
HCl
a
b
O
MeO
MeO
O
O
34
35
36
O
O
H
R2
R1
N
R2
R1
H2N
EtO
R2
R1
HCl
EtO
EtO
c
d
O
EtO
R3
R3
R3
O
O
O
38a (R1=Me, R2=R3=H)
38b (R1= -Pr, R2=R3=H)
39a (R1=Me, R2=R3=H)
39b (R1= -Pr, R2=R3=H)
37a (R1=Me, R2=R3=H)
37b (R1= -Pr, R2=R3=H)
i
i
i
38c (R1=
c
-Hex, R2=R3=H)
39c (R1= -Hex, R2=R3=H)
c
37c (R1= -Hex, R2=R3=H)
c
38d (R1=CH2Ph, R2=R3=H)
39d (R1=CH2Ph, R2=R3=H)
37d (R1=CH2Ph, R2=R3=H)
38e (R1=R2=Me, R3=H)
39e (R1=R2=Me, R3=H)
37e (R1=R2=Me, R3=H)
38f (R1=R3=Me, R3=H)
39f (R1=R3=Me, R2=H)
37f (R1=R3=Me, R2=H)
f
O
O
O
O
e
37f
S
36, 39a-f
27-33
40
Scheme 3. All compounds are racemic. Reagents and conditions: (a) (i) 4 N NaOH, MeOH, rt, 12 h; (ii) DPPA, Et3N, t-BuOH, 130 °C, 12 h (95%, two steps); (b) 4 N HCl in 1,4-
dioxane, 12 h (30%); (c) (i) 4 N NaOH, MeOH, rt, 12 h; (ii) DPPA, Et3N, t-BuOH, 130 °C, 12 h (40–87%, 2 steps); (d) 4 N HCl in 1,4-dioxane, 12 h (63–99%); (e) (i) 13d, pyridine,
CHCl3, rt, 12 h; (ii) 8 N NaOH, EtOH, 100 °C, 12 h (23–81%, 2 steps); (f) diethyl malonate, NaH, DMF, 75 °C, 12 h (57%).
the phenyl derivative 9 could not be reproduced in the alkyl series.
Expansion of the cyclopropane core of 9 to cyclobutane (27) re-
sulted in a complete loss of activity. The expanded ring would be
expected to create a steric clash between the phenyl ring and
Met281. Given these observations, the presence and the position
of the phenyl group on the cyclopropane core appear to be crucial
for potent inhibitory activity.
Synthesis of compounds 27–33 is shown in Scheme 3. Following
the same procedure described in Scheme 2, 36 and 39 were synthe-
sized from 34 and 37 through 35 and 38, respectively, via three
steps: selective hydrolysis of the less hindered ester, Curtius rear-
rangement and deprotection of the amino group. 37a–e were pre-
pared according to known procedures,13–20 and 37f was
synthesized by alkylation of diethyl malonate with 40.21 Coupling
reactions of thus obtained 36 and 39 with 13d followed by sapon-
ification of the ester moiety gave 27-33 as racemates.
In summary, we have found a series of non-N-substituted 2-phe-
nyl-1-sulfonylamino-cyclopropane carboxylates possessing (1S,2R)
configuration as novel ADAMTS-5 inhibitors. A dramatic potency
gain was observed by introduction of a methyl group on the 2- or
cis-3 position of the cyclopropane core, and compound 22
(IC50 = 7.4 nM) was found to be the most potent ADAMTS-5 inhibitor
reported to date. 22 also displayed good to excellent selectivity over
MMP-1 and TACE (IC50s were 180 nM and 4000 nM, respectively). In
addition, this compound is orally bioavailable and shows a good
pharmacokinetic profile in rats (BA = 81%, T1/2 = 4.5 h).
References and notes
1. Liu, R. Q.; Trzaskos, J. M. Curr. Med. Chem. Anti-inflamm. Anti-Allergy Agents
2005, 4, 251.
2. Glasson, S. S.; Askew, R.; Sheppard, B.; Carito, B.; Blanchet, T.; Ma, H.-. L.;
Flannery, C. R.; Peluso, D.; Kanki, K.; Yang, Z.; Majumdar, M. K.; Morris, E. A.
Nature 2005, 434, 644.
3. Stanton, H.; Rogerson, F. M.; East, C. J.; Golub, S. B.; Lawlor, K. E.; Meeker, C. T.;
Little, C. B.; Last, K.; Farmer, P. J.; Campbell, I. K.; Fourie, A. M.; Fosang, A. J.
Nature 2005, 434, 648.
4. Shiozaki, M.; Maeda, K.; Miura, T.; Ogoshi, Y.; Haas, J.; Fryer, A. M.; Laird, E. R.;
Littmann, N. M.; Andrews, S. W.; Josey, J. A.; Mimura, T.; Shinozaki, Y.;
Yoshiuchi, H.; Inaba, T. Bioorg. Med. Chem. Lett. 2009, 19, 1575.
5. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
6. Abad-Zapatero, C.; Metz, J. T. Drug Discovery Today 2005, 10, 464.
7. Pavlovsky, A. G.; Williams, M. G.; Ye, Q. Z.; Ortwine, D. F.; Purchase, C. F., 2nd;
White, A. D.; Dhanaraj, V.; Roth, B. D.; Johnson, L. L.; Hupe, D.; Humblet, C.;
Blundell, T. L. Protein Sci. 1999, 8, 1455.
8. Mosyak, L.; Georgiadis, K.; Shane, T.; Svenson, K.; Hebert, T.; Mcdonagh, T.;
Mackie, S.; Olland, S.; Lin, L.; Zhong, X.; Kriz, R.; Reifenberg, E. L.; Collins-Racie,
L. A.; Corcoran, C.; Freeman, B.; Zollner, R.; Marvell, T.; Vera, M.; Sum, P.-. E.;
Lavallie, E. R.; Stahl, M.; Somers, W. Protein Sci. 2008, 17, 16.
9. Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004, 4,
695.
10. Ohishi, J. Synthesis 1980, 9, 690.
11. Georgakopoulou, G.; Kalogiros, C.; Hadjiarapoglou, L. P. Synlett 2001,
1843.
12. Francisco, G.-. B.; Michael, D. B. F.; Susanne, K.; Laxma, K.; Sergei, K.; Maxime, S.
Adv. Synth. Catal. 2008, 350, 813.
13. Lasa, M.; Lopez, P.; Cativiela, C. Tetrahedron: Asymmetry 2005, 16, 4022.
14. Liu, H.; Auchus, R.; Walsh, C. T. J. Am. Chem. Soc. 1984, 106, 5335.
15. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
16. Hercouet, A.; Godbert, N.; Le Corre, M. Tetrahedron: Asymmetry 1998, 9,
2233.
17. Verhe, R.; De Kimpe, N.; De Buyck, L.; Courtheyn, D.; Schamp, N. Synthesis 1978,
7, 530.
18. Krief, A.; Hevesi, L.; Chaboteaux, G.; Mathy, P.; Sevrin, M.; De Vos, M. J. J. Chem.
Soc., Chem. Commun. 1985, 23, 1693.
Acknowledgments
19. Doyle, M. P.; Hu, W. ARKIVOC 2003, 7, 15.
20. Goudreau, S. R.; Marcoux, D.; Charette, A. B. J. Org. Chem. 2009, 74, 470.
21. O’leary, J.; Colli, C.; Wallis, J. D. Synlett 2003, 675.
The authors wish to thank our Analytical Research and Develop-
ment Laboratories for collecting analytical data. Dr. Jun-ichi Haruta
is also acknowledged for his continuous encouragement.