Bioisosteric approach to the discovery of imidazo[1,2-a]pyrazines as potent Aurora kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.10.008

Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.

Full text of DOI:10.1016/j.bmcl.2010.10.008

Bioorganic & Medicinal Chemistry Letters 21 (2011) 592–598
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Bioisosteric approach to the discovery of imidazo[1,2-a]pyrazines as potent
Aurora kinase inhibitors
Zhaoyang Meng a, , Bheemashankar A. Kulkarni a, Angela D. Kerekes b, Amit K. Mandal a, Sara J. Esposite b,
⇑
David B. Belanger a, Panduranga Adulla Reddy a, Andrea D. Basso c, Seema Tevar c, Kimberly Gray c,
Jennifer Jones c, Elizabeth B. Smith d, Ronald J. Doll b, M. Arshad Siddiqui a
a Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States
b Department of Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
c Department of Oncology Discovery Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
d Department of Discovery Technologies, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase
inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several
new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 August 2010
Revised 29 September 2010
Accepted 1 October 2010
Available online 12 October 2010
Keywords:
Aurora kinase inhibitors
Imidazo[1,2-a]pyrazine
Bioisosterism
Mitosis is a key step in the cell cycle governing the distribution
of genetic material to the daughter cells. Errors in this process
cause the formation of cells with abnormal chromosome content
and lead to genetic instability, a common hallmark of cancer.1
The Aurora kinase family comprises three highly homologous ser-
ine/threonine protein kinases, Aurora A, B, and C. Aurora kinases
are critical regulators of cell cycle progression. Aurora A functions
in centrosome regulation and mitotic spindle formation; Aurora B
is required for correct chromosome alignment, segregation, spindle
checkpoint function, and cytokinesis; and although the role of
Aurora C is less known, it is believed to be more closely related
to Aurora B with overlapping functions and similar localization
patterns.1 Aurora A and B are known to be frequently overexpres-
sed in a wide range of different human tumors, including breast,
lung, colon, ovarian, and pancreatic cancers. As enzymes specific
for and essential to cell growth and division, inhibitors of Aurora
kinase have the potential to be useful for the control of tumor cell
growth. Hence, inhibition of Aurora kinases is emerging as an
attractive target for cancer treatment. At present, a number of Aur-
ora kinase inhibitors, including Aurora A-selective, Aurora B-selec-
tive, and Aurora A and B dual kinase inhibitors are being evaluated
in preclinical and clinical assessment for the treatment of cancer.2
Due to the different role and function of Aurora kinase isoforms in
mitosis, currently it is not clear whether compounds with different
selectivity profiles within the Aurora family will represent distinct
clinical opportunities.
Recently, we reported the discovery of imidazol[1,2-a]pyrazines
as Aurora kinase inhibitors.3 Lead compound 1 was identified as
Aurora A/B dual inhibitors (IC50: 64 nM and 613 nM, respectively)
with submicromolar on-target cell based activity, but with no oral
availability (Fig. 1). As we have described earlier,3 the importance
H
N
H
N
N
N
6
3
N
N
N
N
N
N
8
1
NH
NH
S
S
N
N
1
2
Aurora A IC50 < 4 nM
Aurora B IC50 < 13 nM
phos-HH3 IC50 = 250 nM
Rapid Rat PK (p.o.10 mg/kg)
AUC = 0 nM.hr
Aurora A IC50 = 13 nM
Aurora B IC50 = 8.1 nM
phos-HH3 IC50 = 1260 nM
Rapid Rat PK (p.o.10 mg/kg)
AUC = not tested
⇑
Corresponding author.
E-mail address: zhaoyang.meng@merck.com (Z. Meng).
Figure 1. Previously disclosed, potent Aurora kinase inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.008

Z. Meng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 592–598
593
SEM
N
N
SEM
N
N
N
R1
N
N
a
e
N
O
6
+
NH
S
N
O
H2N
S
N
S
4a R1 = CH3
4b R1 = CN
5a R1 = CH3
R
CH3
5b R1 = CN
4c R1 = CO2Me
5c R1 = CO2Me
5d R1 = CO2H
5e R1 = CONR3R4
5f R1 = CH2R3R4
3
b
c
d
Scheme 1. Reagents and conditions: (a) NaH, DMF, rt; (b) NaOH, THF–MeOH–H2O, rt; (c) R3R4NH, HATU, NMM, DMF, rt; (d) LiAlH4, DCM–Et2O, 40 °C; (e) 4 N HCl in dioxane,
60 °C.
unsubstituted pyrazole ring at C-3 and the methyl group at C-6,
we focused our attention on installing substituted sulfur contain-
Table 1
ing heterocycles such as thiophenes and thiazoles. Herein, we wish
to report the synthesis and structure–activity relationships (SAR)
of the new thiophene- and thiazole-based Aurora A and B dual
inhibitors.
Aurora A and B inhibition data for 6a–h
H
N
N
As shown in Scheme 1, a variety of amino thiophene groups
(4a–c) were appended to the C-8 position of the imidazo-[1,2-a]-
pyrazine core through the displacement of the methyl sulfone of
intermediate 35 to afford compound 5. Saponification of the methyl
ester 5c resulted in acid 5d which was then converted to the
amides 5e through HATU-mediated coupling. The corresponding
amine 5f was obtained by reduction of the amide 5e. Removal of
the SEM protecting group under acidic conditions provided final
compounds 6a–h.
N
N
N
NH
S
5'
4'
R1
Compds R1
Aurora Aa IC50
Aurora Ba IC50
(nM)
Phos-HH3a IC50
(nM)
(nM)
The analogs synthesized were evaluated in the assays6 and the
results are shown in Table 1. The C-40 position of the thiophene,
corresponding to the region originally occupied by the methyl
group in isothiazole lead 1, proved sensitive to changes, as most
of the analogs had only moderate or no activity against both Aur-
ora A and B. For example, compound 6a, the direct analog of 1
but lacking the isothiazole nitrogen, is less potent than 1. Changing
the methyl to a CN group (6b) resulted in moderate Aurora A and B
activity with weak cell potency. Analogs with substituents such as,
carboxylic acid (6c), ester (6d), and amide (6e, 6f), were found to be
less active. However, compared to amides (6e, 6f), corresponding
amines (6g, 6h) were much more potent for Aurora A and B enzy-
matic activity including the cellular potency (6h).
CH3
CN
CO2H
6a
6b
6c
6d
30
74
149
42
>10,000
3176
3000
1060
3000
2273
Not tested
Not tested
CO2CH3
O
6e
6f
965
3000
5
3000
3000
613
613
Not tested
Not tested
>1000
N
O
H
N
6g
6h
N
H
N
64
140
a
Unlike the isothiazole, the thiophene has two possible positions
(C-40 and C-50) that could be substituted to optimize for potency
and PK. As shown in Schemes 2–4, we prepared a series of com-
pounds 11a–i with various substitutents at the C-50 position of
the thiophene ring.
Assay conditions listed in Ref. 6.
of the sulfur atom of the isothiazole ring for activity, we sought to
investigate this further with bioisosteric4 heterocycles containing a
sulfur atom. An additional goal was to optimize for the pharmaco-
kinetic (PK) properties. Keeping the preferred combination of the
The amide derivatives 11b–d and the amine analog 11e were
prepared following the sequence presented in Scheme 2. The
SEM
SEM
N
N
N
N
e
11b-d
R3
N
NHBoc a,b
c
NH2
N
N
e
d
R4
11e
S
7
S
8
HO2C
N
N
R3
N
R3
N
O
R4
N
R4
N
NH
S
NH
S
9
O
10
Scheme 2. Reagents and conditions: (a) R3R4NH, EDCI, Et3N, DMF, rt; (b) 20% TFA/DCM, rt; (c) 3, NaH, DMF, rt; (d) LiAlH4, DCM–Et2O, rt; (e) 4 N HCl in dioxane, rt.

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Z. Meng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 592–598
SEM
SEM
N
N
N
N
N
N
e
a
d
N
N
H2N
N
R3
N
3
N
11f-g
+
O
S
R4
NH
NH
S
S
R2
O
12
14
13a R2 = CO2Me
13b R2 = CH2OH
13c R2 = CHO
b
c
Scheme 3. Reagents and conditions: (a) NaH, DMF, rt; (b) DIBAL, THF, ꢀ78 °C; (c) Dess–Martin, DCM, rt; (d) R3R4NH, NaBH(OAc)3, DIEA, DCE, rt; (e) 4 N HCl in dioxane, rt.
SEM
SEM
N
N
N
N
c
b
11i
N
a
c
N
N
11h
3
+
H2N
S
N
N
N
N
O
15
NH
S
NH
S
16
O
17
Scheme 4. Reagents and conditions: (a) NaH, DMF, rt; (b) piperidine, Ti(OiPr)4, rt overnight, then NaBH4, MeOH, rt; (c) 4 N HCl in dioxane, rt.
Table 2
Aurora A and B inhibition data for 11a–i
H
N
N
N
N
N
NH
S
5'
R2
Compds
R2
Aurora Aa IC50 (nM)
Aurora Ba IC50 (nM)
Phos-HH3a IC50 (nM)
1171
O
11a
5
24
S N
O
O
11b
11c
64
64
17
34
858
N
N
N
O
O
>1000
S
11d
64
21
>1000
11e
11f
14
13
324
184
N
64
613
N
N
F
F
11g
11h
11i
16
99
13
23
87
21
>1000
>1000
>1000
F
N
O
a
Assay conditions listed in Ref. 6.

Z. Meng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 592–598
595
Table 3
Aurora A and B inhibition data for 25a–l
H
N
N
N
N
N
NH
S
5'
R2
4'
R1
Compds
R1
R2
Aurora Aa IC50 (nM)
Aurora Ba IC50 (nM)
17
Phos-HH3a IC50 (nM)
858
H
O
11b
64
N
N
N
N
N
N
N
N
N
CH3
O
O
O
O
O
O
O
O
25a
25b
25c
25d
25e
25f
64
40
64
83
64
2
18
278
213
613
33
2354
166
O
OH
>10,000
168
613
14
N
N
N
O
O
165
25g
64
613
981
25h
25i
64
64
613
613
86
88
O
O
O
N
N
CH3
CH3
25j
25k
25l
14
21
31
13
324
43
N
N
N
613
12
58
O
a
Assay conditions listed in Ref. 6.
amides, 9, were obtained from 5-(tert-butoxycarbonylamino)thio-
phene-2-carboxylic acid (7) through a three step reaction sequence:
amide coupling, Boc deprotection, and sulfone displacement. Lith-
ium aluminum hydride reduction of the amide 9b provided the
amine 10. Removal of the SEM group from amides 9 and amine 10
afforded the desired analogs 11b–e.
Cyclic amines, such as the fluoro substituted piperidine analogs
11f and 11g, could also be synthesized via the reductive amination
route as shown in Scheme 3. The key intermediate aldehyde 13c
was prepared by first transforming methyl ester 13a to primary
alcohol 13b which was then oxidized using the Dess–Martin
reagent.
As shown in Table 2, substituents at C-50 position of the thio-
phene ring were better tolerated, for example, sulfonamide (11a),
amide (11b–d), amine (11e–h), and ketone (11i) provided potent
Aurora A/B inhibitors with range of modest cellular activities. Con-
verting the amide (11b) to the corresponding amine (11e) did not
provide a significant enhancement in potency which is different
from the trend observed in the C-40 series. In order to minimize
the metabolic oxidation of the piperidine ring, fluorine was incor-
porated. The introduction of one F group at the 4-position of piper-
idine ring (11f) slightly improved the cell potency. In contrast, two
fluorine substituents at the 4-position of the piperidine ring (11g)
resulted in a loss of cell activity. Benzylic site substitution with a
methyl group to mitigate oxidation (11h) resulted in the loss of
Aurora A and B activity.
The synthetic route to compound 11i–h is shown in Scheme 4.
Compound 11h with a methyl group at the benzylic position was
prepared through a Ti(OiPr)4-mediated reductive amination reac-
tion of ketone 16 followed by acidic deprotection of the SEM group.
With the individual C-40 and C-50 substituents optimized at the
thiophene ring, we directed our next effort toward the preparation

596
Z. Meng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 592–598
N
R1
O
O
O
O
b
O
O
a
21
N
N
R1
+
R1 = Me, iPr, CF3,
CH2OMe, CH2OPMB
O
R1
O
O
OH
OH
S
H2N
18
19
20
R3
N
N
R4
O
O
O
O
c
a
21a NR3R4 = morpholine
21b NR3R4 = piperidine
21c NR3R4 = NEt2
O
Cl
Cl
+
O
S
O
22
20a
H2N
SEM
SEM
SEM
N
N
N
N
N
N
g
f
25a - 25i
R3
R1
N
N
N
e
g
d
N
N
N
R3
N
N
N
25j - 25l
3
+
R4
CO2Et
R4
N
NH
N
NH
22
H2N
S
S
21, 21a-c
S
R1
NH
24
S
EtO2C
O
R1
23
R1
Scheme 5. Reagents and conditions: (a) NH4OAc, HOAc, PhH, refluxing, Dean-Stark trap; (b) S-flakes, then Et2NH, EtOH; (c) R3R4NH (2 equiv), then S-flakes, EtOH; (d) 3, NaH,
DMF; (e) R3R4NH, iPrMgCl, THF, 0 °C to rt; (f) LiAlH4, DCM–Et2O, rt; (g) 4 N HCl in dioxane, rt.
BocHN
BocHN
BocHN
BocHN
O
H2N
S
S
N
a
b,c
f,c
N
O
S
Br
O
N
26
N
28
27
d
H2N
S
N
S
S
e
N
N
N
O
29
30
31
H
N
N
g
3
N
h
33 a-b
N
O
N
S
O
32
Scheme 6. Reagents and conditions: (a) Pd (dppf)Cl2, Mo(CO)6, DIEA, EtOH, refluxing; (b) piperidine, AlMe3, THF, ꢀ78 °C; (c) TMSI, DCM; (d) tributyl(vinyl)stannane, Pd(Ph3)4,
dioxane, refluxing; (e) NaIO4/OsO4, dioxane:H2O (3:1), 2,6-lutidine, rt; (f) piperidine, NaBH(OAc)3, HOAc (cat.), DCM; (g) 2 N HCl in dioxane; (h) 28 or 31, NaH, DMSO.
of thiophene derivatives with substituents at both C-40 and C-50 po-
sition. Scheme 5 outlines the synthesis of C-40 and C-50 di-substi-
tuted thiophene analogs.
As shown in Table 3, C-40 and C-50 di-substituted thiophene ana-
logs were found to show good activity against both Aurora A and B.
A small alkyl group is preferred at C-40 (R1 = H, 11b vs R1 = Me, 25a).
However, presumably due to lack of adequate polarity, as the alkyl
group becomes larger and branched, the enzymatic and cell poten-
cies began to drop (R1 = iPr, 25b). Interestingly, R1 groups at C-40
with non-acidic polar groups (25c, 25e–g) were well tolerated dis-
playing good enzymatic and cell potency. Encouragingly, with more
polar R1 and R2 groups at the corresponding C-40 and C-50 position of
thiophene ring led to further improvement in cellular activity was
seen (25h, 25i, 25k, and 25l), perhaps due to improvement in the
physico-chemical properties of these molecules.
As shown in Scheme 5, amino thiophenes 21 with various
substituent at the C-40 position were synthesized according to
the published procedure.7 A modified route was used to obtain
21a–c which had different amine group at the C-40. Ethyl
4-chloro-3-oxobutanoate 22 was condensed with 2-cyanoacetic
acid 19 through a Knoevenagel reaction to afford 20a as a mixture
of (E)- and (Z)-regioisomers. Treatment of 20a with an excess of
different secondary amines followed by sulfur flakes in EtOH pro-
vided 21a–c. Another key reaction was the direct conversion of
ethyl ester 22 into the corresponding amide 23 via an iPrMgCl
mediated reaction.8
In addition to thiophenes as a replacement for the isothiazole,
the potential utility of aminothiazoles as bioisosteres was ex-

Z. Meng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 592–598
597
Table 4
Several compounds were selected for preliminary pharmacoki-
netic investigation in rat9 and the results are reported in Table 5.
While low exposure was observed for all three amide analogs
(25a, 25c, and 25e), amine derivatives showed better oral PK in
the rat (11e and 11f). Combined with their good enzymatic and cell
potency, the amine containing thiophene compounds such as 11e
and 11f provide a good template for further development of orally
bioavailable Aurora kinase inhibitors.
Aurora A and B inhibition data for 33a and 33b
H
N
N
N
N
N
In summary, replacement of the isothiazole in the lead com-
pound 1 by a bioisoteric moiety, such as thiophene and thiazole,
led to potent Aurora A/B inhibitors that displayed good cell based
activity. SAR development in the thiophene and thiazole series will
provide the basis for development of more potent and orally bio-
available Aurora kinase inhibitors.10,11
NH
S
R2
N
R2
Aurora Aa
IC50 (nM)
Aurora Ba
IC50 (nM)
Phos-HH3
IC50 (nM)
a
Compds
O
33a
33b
178
274
Not tested
377
N
Acknowledgment
64
613
N
We thank Drs. John Piwinski, Neng-Yang Shih, Paul Kirschmeier,
and W. Robert Bishop for support of this work.
a
Assay conditions listed in Ref. 6.
References and notes
Table 5
1. (a) Andrews, P. D. Oncogene 2005, 24, 5005; (b) Pollard, J. R.; Mortimore, M. J.
Med. Chem. 2009, 52, 2629; (c) Carpinelli, P.; Moll, J. Curr. Opin. Drug Discov. Dev.
2009, 12, 533; (d) Carmena, M.; Ruchaud, S.; Earnshaw, W. C. Curr. Opin. Cell
Biol. 2009, 21, 796.
2. (a) Coumar, M. S.; Cheung, C. H.; Chang, J. Y.; Hsieh, H. P. Expert Opin. Ther. Pat.
2009, 19, 321; (b) Lok, W.; Klein, R. Q.; Saif, M. W. Anti-Cancer Drugs 2010, 21,
339; (c) Dar, A. A.; Goff, L. W.; Majid, S.; Berlin, J.; El-Rifai, W. Mol. Cancer Ther.
2010, 9, 268; (d) Shimomura, T.; Hasako, S.; Nakatsuru, Y.; Mita, T.; Ichikawa,
K.; Kodera, T.; Sakai, T.; Nambu, T.; Miyamoto, M.; Takahashi, I.; Miki, S.;
Kawanishi, N.; Ohkubo, M.; Kotani, H.; Iwasawa, Y. Mol. Cancer Ther. 2010, 9,
157; (e) Hardwicke, M. A.; Oleykowski, C. A.; Plant, R.; Wang, J.; Liao, Q.; Moss,
K.; Newlander, K.; Adams, J. L.; Dhanak, D.; Yang, J.; Lai, Z.; Sutton, D.; Patrick,
D. Mol. Cancer Ther. 2009, 8, 1808.
Rat oral PK data of selected compounds
H
N
N
N
N
N
NH
R
3. Belanger, D. B.; Curran, P. J.; Hruza, A.; Voigt, J.; Meng, Z.; Mandal, A. K.;
Siddiqui, M. A.; Basso, A. D.; Gray, K. Bioorg. Med. Chem. Lett. 2010, 20, 5170.
4. (a) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147; (b) Moreira, L. M.;
Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23.
5. Yu, T.; Belanger, D. B.; Kerekes, A. D.; Meng, Z.; Tagat, J. R.; Esposite, S.; Mandal,
A. K.; Xiao, Y.; Kulkarni, B. A.; Zhang, Y.; Curran, P. J.; Doll, R. J.; Siddiqui, M. A.
PCT Int. Appl., 2008, 156614 A2, pp 287, WO.
6. Biochemical assays: Aurora A and Aurora B kinase assays were performed in low
protein binding 384-well plates. Compounds were diluted in 100% DMSO to the
desired concentrations. For the Aurora A assay, each reaction consisted of 8 nM
enzyme (Aurora A, Upstate), 100 nM Tamra-PKAtide (Molecular Devices,
Compds
R
Rat AUC (nM h)a
1184
S
S
S
11e
N
N
N
11f
1175
697
F
5TAMRA-GRTGRRNSICOOH), 25 lM ATP, 1 mM DTT, and kinase buffer
(10 mM Tris, 10 mM MgCl2, 0.01% Tween 20). For the Aurora B assay, each
reaction consisted of 26 nM enzyme (Aurora B, Invitrogen), 100 nM Tamra-
25a
O
PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH), 50 lM ATP, 1 mM
DTT, and kinase buffer (10 mM Tris, 10 mM MgCl2, 0.01% Tween 20). Dose–
response curves were plotted from inhibition data generated in duplicate, from
8 point serial dilutions of inhibitory compounds. Concentration of compound
was plotted against kinase activity, calculated by degree of fluorescent
polarization. To generate IC50 values, the dose–response curves were then
fitted to a standard sigmoidal curve and IC50 values were derived by non-linear
regression analysis. Immunofluorescent assays: HCT-116 cells were plated at
O
S
25c
25e
212
N
O
O
15,000 cells per well in poly-D-lysine coated black micro-clear 384-well tissue
N
culture plates. For the phos-Histone H3 assay, cells were first treated with
0.4 mg/ml nocodazole. Sixteen hours later cells were treated in triplicate with
compound (0.1% final DMSO concentration) for 1 h. Cells were fixed with
PreferÒ fixation solution (Anatech) plus 1000 nM Hoechst 33342 dye and
incubated for 30 min at room temperature. The fixation solution was removed
and cells were washed with PBS. Cells were permeabilized with 0.2% Triton-X
in PBS and incubated for 10 min. Cells were washed with PBS and incubated
with PBS containing 3% FBS for 30 min. Cells were then stained overnight at
4 °C with Phos-Histone H3 (Ser10)-Alexa Flur 488 Conjugate antibody (Cell
Signaling) solution in PBS plus 3% FBS. Cells were washed with PBS and then
immunofluorescence images were captured at 10ꢁ with BD Pathway 855
automated fluorescent microscope (BD Bioscience). Percent positive cells were
quantitated using Hoechst staining for cell number using Attovision software
(BD Bioscience). To generate IC50 values, the dose–response curves were then
fitted to a standard sigmoidal curve and IC50 values were derived by non-linear
regression analysis.
0
S
N
O
a
AUC0–6 h (10 mg/kg, po, in 20% HPBCD).
plored. Key thiazole analogs, 33a and 33b, were prepared accord-
ing to Scheme 6. Better yields were obtained when the amine
and amide groups were pre-installed onto the thiazole moiety be-
fore the sulfone displacement reaction.
As shown in Table 4, the amide compound 33a only demon-
strated moderate activity against both Aurora A and B, perhaps
due to rigid amide group that might misalign favorable interac-
tions. However, more flexible amine 33b displayed excellent activ-
ity for both enzymatic and cell assays.
7. Marques, P. A.; Doss, R. M.; Urbach, A. R.; Dervan, P. B. Helv. Chim. Acta 2002, 85,
4485.
8. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.

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