Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.08.090

The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for i

Full text of DOI:10.1016/j.bmcl.2010.08.090

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6273–6276
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors
Stephen P. O’Connor a, , Ying Wang a, Ligaya M. Simpkins a, Robert P. Brigance a, Wei Meng a, Aiying Wang b,
⇑
Mark S. Kirby b, Carolyn A. Weigelt c, Lawrence G. Hamann a
a Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA
b Department of Metabolic Diseases, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA
c Department of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied
pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvert-
ible atropisomers was used as the starting point for investigation. The effects of substituent pattern and
type as well as stereochemical effects on inhibitor potency are discussed.
Received 28 July 2010
Revised 16 August 2010
Accepted 18 August 2010
Available online 22 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Dipeptidyl peptidase 4
DPP4
Atropisomerism
The serine protease dipeptidyl peptidase IV (DPP4) is the pri-
mary enzyme responsible for the in vivo degradation of the incre-
tin hormone glucagon-like peptide 1 (7–36) amide (GLP-1) to the
inactive GLP-1 (9–36) amide.1 The demonstrated ability of GLP-1
to promote glucose stimulated insulin secretion2 and pancreatic
b-cell preservation3 led to considerable interest in the pharmaco-
logical inhibition of DPP4 as a method for the treatment of type
2 diabetes.4 Several DPP4 inhibitors have reached advanced stages
of development5 where they have shown fasting plasma glucose
reductions, lowering of glycosylated hemoglobin (HbA1c), im-
proved glucose tolerance, and have been well tolerated in a wide
clinical population.6 Furthermore, both sitagliptin (JANUVIA™)
and saxagliptin (ONGLYZA™) are now FDA approved for the treat-
ment of type 2 diabetes mellitus, alone or in combination with
other oral antidiabetic agents.
of restricted rotation (atropisomerism)8 in ortho-substituted
analogs of this series.
We had originally conceptualized the synthesis of a series of
analogs of 1 utilizing a late-stage coupling strategy to install various
aryl replacements for the 2,4-dichlorophenyl ring. A disappointing
lack of reactivity of any suitable imidazolopyrimidine coupling
partners (chloride, bromide, triflate) toward conditions to intro-
duce this biaryl bond led us to proceed with a more lengthy yet gen-
erally effective route (Schemes 1–3). A conserved component of all
of the desired inhibitors, the (2-methoxyphenyl)imidazolo portion,
was derived from 2-amino-4-(2-methoxyphenyl)imidazole (3),
which was obtained by the condensation of 2-aminopyrimidine
with 2-bromo-20-methoxyacetophenone (92% yield), followed by
cleavage of intermediate 2 with hydrazine hydrate in ethanol in
93% yield (Scheme 1).
First generation inhibitors from these laboratories, including
saxagliptin, were based on a dipeptidic motif loosely resembling
the DPP4 cleavage products. As part of our ongoing research pro-
gram, we recently disclosed our preliminary findings in establish-
ing alternative chemotypes as novel DPP4 inhibitor scaffolds
wherein we described aminomethyl-substituted bicyclic hetero-
aromatics culminating with the discovery of the potent imidazolo-
pyrimidine 1 (Ki = 15 nM, Table 2).7 Herein we provide further
elaboration of the structure–activity relationships (SAR) around
this lead by modification of the lower aromatic appendage (2,4-
dicholophenyl in 1) and the existence of and biochemical impact
With 3 in hand the synthesis of 4-chlorophenyl analog 9 began
with the Knoevenagel condensation of 4-chlorobenzaldehyde and
t-butyl acetoacetate to give enone 4 in 87% yield (Scheme 1). Com-
bination of 4 with aminoimidazole 3 using NaOMe in MeOH/THF at
70 °C provided the dihydroimidazolopyrimidine 5, which was oxi-
dized to 6 with DDQ (46% over two steps). A three-step process of
t-butyl ester cleavage with TFA, acid chloride formation using oxa-
lyl chloride, and reduction with NaBH4 gave alcohol 7 (29% over
three steps). Conversion of 7 to the chloride 8 proceeded smoothly
with methylsulfonyl chloride/Et3N (90% yield), followed by subse-
quent reaction with 7 M ammonia in MeOH at elevated tempera-
tures in
a sealed tube to provide product 9 (75% yield).
Compounds 18 and 22–24 (Table 2) were also made using this
method.
⇑
Corresponding author. Tel.: +1 609 818 4996.
E-mail address: steve.oconnor@bms.com (S.P. O’Connor).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.090

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S. P. O’Connor et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6273–6276
aminomethyl component of the final products early on in the se-
quence. Combination of 10 with aminoimidazole 3 using Hunig’s
base in IPA at 75 °C gave 11 (34% yield); subsequent dehydration
of the amide with trifluoroacetic anhydride produced 12 (91%
yield); and finally, oxidation with DDQ afforded imidazolopyrimi-
dine nitrile 13 (70% yield). After an extensive survey of reductive
methods for adjusting the oxidation state of the nitrile down to
that of a primary amine (wherein H2 addition to the imidazolopyr-
imidine core and dechlorination were the major by-products),
hydrogenolysis with Raney Ni emerged as the most selective set
of conditions for the conversion of 13 to the desired aminomethyl
analog 1 (58% yield), minimizing the amount (<10%) of dechlori-
nated by-products formed. Additional compounds produced using
this method included 14–17, 19–21, and 25 and 26 (Table 2). All
compounds obtained by either method were of 98% or greater pur-
ity9 and gave appropriate 1H and 13C NMR spectra as well as posi-
tive ion MS data.10
During the optimization of the reduction of 13 to 1 we observed
a significant solvent effect on the reaction profile. While compound
13 was very soluble in methylene chloride (>20 mg/mL), the reduc-
tion with Raney Ni and H2 did not occur, and only starting material
was recovered (Table 1, first entry). When the solvent was changed
to MeOH, in which 13 had much lower solubility (<4 mg/mL), over-
reduction occurred with dechlorinated products 14 (loss of 4-chlo-
rine atoms from 1) and 15 (loss of both the 2- and 4-chlorine atoms
from 1) as the only products observed (Table 1, second entry).
Significantly more favorable results were obtained through the
use of the mixed solvent 1:1 CH2Cl2/CH3OH, which provided the
best conversion of 13 to 1 (92%) with an isolated product yield of
58%.
Scheme 1. Reagents and conditions: (a) EtOH, reflux (92%); (b) EtOH, hydrazine
hydrate, 70 °C (93%); (c) toluene, piperidine (87%); (d) 3, NaOCH3, THF, CH3OH,
70 °C; (e) DDQ, CH2Cl2 (46% over two steps); (f) TFA, CH2Cl2; (g) oxalyl chloride,
DMF, CH2Cl2; (h) NaBH4, THF, DMF, ꢀ78 °C (29% over three steps); (i) CH3SO2Cl,
Et3N, CH2Cl2 (90%); (j) 2 M NH3 in CH3OH, 70 °C (75%).
Compounds 1, 9, and 14–26 were evaluated for their ability to
inhibit DPP4 (Table 2). All compounds were tested in vitro against
purified human DPP4 using the substrate H-Gly-Pro-pNA, measur-
ing production of p-nitroaniline at 405 nm over 15 min.5c In addi-
tion, the inhibition of the homologous yet physiologically
undefined proteases DPP811 and DPP912 were also determined.
While all of the compounds tested showed either minimal or no
inhibition of DPP8/9 (all Ki’s >3982 nM, with many >30,000 nM,
Table 2) the level of DPP4 inhibition displayed a significant depen-
dence on substitution pattern and type. The unsubstituted phenyl
analog 15 had lost 16-fold in potency (Ki = 241 nM) relative to the
initial lead 1 (Ki = 15 nM), while mono-chloro substituted com-
pounds demonstrated the regiochemical preference of ortho>para>-
meta (14 = 26 nM, 9 = 96 nM, 16 = 1530 nM). The 3-fluoro analog 19
(Ki = 550 nM) was slightly more active than the 3-chloro compound
16, while combination of the 3-fluoro group with substitution at C-
4 of the phenyl ring provided only modest potency enhancements
as shown for 20 and 21 (Ki = 495 and 438 nM, respectively) or the
loss of activity as in 22 (Ki >10,000 nM). The 2,6- and 3,4-dichloro-
phenyl compounds 17 (Ki = 113 nM) and 18 (Ki = 612 nM), respec-
tively, were weaker inhibitors than either of the 2- or 4-
monochloro analogs (14 and 9, respectively). This suggests that
the greater level of inhibition observed for 2,4-dichloro compound
1 results from a more favorable space filling interaction in the DPP4
Scheme 2. Reagents and conditions: (a) piperidine, AcOH, IPA, 70 °C (65%); (b) 3, (i-
Pr)2NEt, IPA, 75 °C (34%); (c) TFAA, Et3N, CH2Cl2 (91%); (d) DDQ, CH2Cl2 (70%); (e)
RaNi, H2 (1 atm), 1:1 CH2Cl2/CH3OH (58%).
Table 1
Conditions and results for the reaction in Scheme 3
Solvent/time (concn of 13)
13a
1a
14a
15a
Scheme 3. Raney nickel reduction of cyano compound 13 to 1/14/15.
CH2Cl2/44 h (0.050 M)
100
(100)
—
—
—
—
CH3OH/21 h (0.010 M)
—
83
(50)
8
17
—
A shorter route to this class of products was also devised and
executed (Scheme 2). Acetoacetamide was used in the initial Knoe-
venagel condensation with 2,4-dichlorobenzaldehyde to give en-
one amide 10, installing the requisite nitrogen of the
1:1 CH2Cl2/CH3OH/21 h (0.025 M)
—
92
(58)
a
Percent conversion by LC analysis (isolated yield, %).

S. P. O’Connor et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6273–6276
6275
Table 2
2,4,6-trisubstituted-phenyl
(Ki = 19 nM) was one of the most potent compounds against
DPP4. Comparison of the Ki’s for 2,4-dichloro compound
analogs.
Trichloro
analog
26
DPP4/DPP8/DPP9 inhibition for 1, 9, and 14–26
Compound
DPP4 Kia
(nM)
DPP8 Ki
(nM)
DPP9 Ki
(nM)
1
(Ki = 15 nM) and 26 indicated that the addition of the third chlorine
atom to the lower phenyl ring was tolerated without loss of
potency. However, the 2,6-dichlorophenyl analog 17 (Ki = 113 nM)
was fourfold less active than the 2-chlorophenyl compound 14.
A key feature of some of these molecules, apparent from the 1H
NMR spectra, was the existence of restricted rotation (atropisom-
erism)8 around the biaryl bond linking the lower phenyl ring to
the bicyclic core. Molecules such as 1 and 14 contain unsymmetri-
cally substituted phenyl rings with at least one ortho-group. This
resulted in an AB-quartet in the 1H NMR spectra for the –CH2–
NH2 methylene protons due to their diastereotopicity. The thermal
stability of the individual atropisomers was qualitatively assessed
on other analogs within this and a similar series of compounds.13 It
was demonstrated that the barrier to free rotation was sufficiently
large that <5% of racemization occurred in DMSO at >100 °C over
several days, while no detectable racemization was observed in hu-
man and rat plasma after 3 h at 37 °C. To address the effect of
atropisomerism on target potency, the separation and in vitro anal-
ysis of the individual atropisomers of 1 and 14 was carried out.
A survey of chiral columns and conditions allowed for the sep-
aration of the individual atropisomers of 114 and 14.15 The in vitro
data for these compounds are shown in Table 3. We tentatively as-
signed the absolute configurations for (+)-1, (ꢀ)-1, (+)-14, and (ꢀ)-
14 shown in Table 3 based on a correlation of measured DPP4
inhibitory potency with results of modeling of the individual enan-
tiomers of 1 into the DPP4 active site.16 The two views of (Sa)-117
shown in Figure 1 suggest that the 2-chloro substituent occupies
a hydrophobic pocket in the enzyme, whereas the opposite enan-
tiomer would place the chlorine in a more sterically encumbered
position clashing with the aryl ring of Tyr666.
Cl
1
15
9
7836
>10 Kb
>30 K
Cl
Cl
9
96 28
>30 K
Cl
14
15
26 18
>10 K
>30 K
>10 K
>30 K
241 34
16
17
1530 451
>30 K
>30 K
>30 K
>30 K
Cl
Cl
Cl
Cl
113
7
18
19
20
612 95
550 43
495 145
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
Cl
F
F
The data in Table 3 show a significant potency enhancement
resulting from resolution of the individual atropisomers. The im-
proved activities for (+)-1 (Ki = 9 nM) and (+)-14 (Ki = 11 nM) rela-
tive to corresponding enantiomers represent 27-fold and 74-fold
enhancements in Ki, respectively. While compound (+)-1, the most
potent member of this series represents a highly active compound
with respect to biochemical potency, as reported earlier this class
of molecules displayed liabilities that remained to be eliminated.7
We have described the synthesis and DPP4 inhibitory activity
for a series of replacements for the 2,4-dichlorophenyl ring in com-
pound 1. All compounds were selective against DPP8 and DPP9.
Cl
21
22
23
24
25
26
438 52
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
>30 K
F
CH3
>10 K
F
CF3
>10 K
CF3
Cl
CH3
Table 3
CH3
DPP4/DPP8/DPP9 inhibition for (+)-1, (ꢀ)-1, (+)-14, and (ꢀ)-14
113 13
Compound
DPP4 Kia (nM)
DPP8 Ki (nM)
DPP9 Ki (nM)
CH3
F
Cl
Cl
F
(+)-1
9
1
3982
>10 Kb
27
19
7
4
Cl
Cl
CH3
Cl
Cl
(ꢀ)-1
241 117
>10 K
>10 K
Cl
Cl
Cl
a
(+)-14
(ꢀ)-14
11
9
>10 K
>10 K
>10 K
>10K
All Ki values are the mean SD of at least triplicate determinations.
10 K = 10,000; 30 K = 30,000.
b
814 84
active site. Example 23 (Ki >10,000 nM) has a 3-CF3 group which
further demonstrates the disfavorable impact of sterics in this
region of the pharmacophore. Compounds 24–26 were symmetrical
a
All Ki values are the mean SD of at least triplicate determinations.
10 K = 10,000.
b

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S. P. O’Connor et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6273–6276
Figure 1. Model of (Sa)-1 in DPP4 active site from two perspectives.
(s, 1H), 7.50 (t, J = 6.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H),
4.28 (d, J = 4.9 Hz, 1H), 4.09 (d, J = 4.9 Hz, 1H), 3.90 (s, 3H), 2.95 (s, 3H); 13C
NMR (CD3OD, 125 MHz) d 159.0, 145.6, 141.0, 135.8, 133.9, 133.7, 132.6, 130.9,
130.3, 126.8, 122.7, 119.7, 113.3, 111.1, 56.6, 37.4, 24.5. MS m/z: [M+H]+ 413.0.
11. (a) Abbott, C. A.; Yu, D. M. T.; Woollatt, E.; Sutherland, G. R.; McCaughan, G. W.;
Gorrell, M. D. Eur. J. Biochem. 2000, 267, 6140; (b) Chen, Y.-S.; Chien, C.-H.;
Goparaju, C. M.; Hsu, J. T.-A.; Liang, P.-H.; Chen, X. Protein Expr. Purif. 2004, 35,
142; (c) Jiaang, W.-T.; Chen, Y.-S.; Hsu, T.; Wu, S.-H.; Chien, C.-H.; Chang, C.-N.;
Chang, S.-P.; Lee, S.-J.; Chen, X. Bioorg. Med. Chem. Lett. 2005, 15, 687; (d)
Lankas, G. R.; Leiting, B.; Roy, R. S.; Eiermann, G. J.; Beconi, M. G.; Biftu, T.; Chan,
C.-C.; Edmundson, S.; Feeney, W. P.; He, H.; Ippolito, D. E.; Kim, D.; Lyons, K. A.;
Ok, H. O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.; Qian, X.; Reigle, L.; Woods, A.;
Wu, J. K.; Zaller, D.; Zhang, X.; Zhu, L.; Weber, A. E.; Thronberry, N. A. Diabetes
2005, 54, 2988.
The existence of isolable atropisomers provided enhanced activity
as illustrated for preferred isomer (+)-1. Modification of other re-
gions of these molecules to enhance potency and minimize liabil-
ities has been described in
a recent disclosure from these
laboratories.13
References and notes
1. (a) Hansen, L.; Deacon, C. F.; Orskov, C.; Holst, J. J. Endocrinology 1999, 140,
5356; (b) Kieffer, T. J.; McIntosh, C. H. S.; Pederson, R. A. Endocrinology 1995,
136, 3585.
2. (a) Larsen, P. J.; Holst, J. J. Regul. Pept. 2005, 128, 97; (b) Deacon, C. F. Regul. Pept.
2005, 128, 117; (c) Dupre, J. Regul. Pept. 2005, 128, 149.
12. Ajami, K.; Abbott, C. A.; McCaughan, G. W.; Gorrell, M. D. Biochem. Biophys. Acta
2004, 1679, 18.
3. List, J. F.; Habener, J. F. Am. J. Physiol. Endocrinol. Metab. 2004, 286, E875.
4. (a) Villhauer, E. B.; Coppola, G. M.; Hughes, T. E. Annu. Rep. Med. Chem. 2001, 36,
191; (b) Drucker, D. J. Expert Opin. Investig. Drugs 2003, 12, 87; (c) Weber, A. E. J.
Med. Chem. 2004, 47, 4135; (d) Nielsen, L. I. Drug Discov. Today 2005, 10, 703.
5. Sitagliptin: (a) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He,
H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B. E.; Lyons, K.; Marsilio, F.; McCann,
M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R. S.; Wu, J. K.; Wyvratt,
M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2005, 48,
141; Vildagliptin: (b) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.;
Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russell, M. E.; Hughes, T. E. J. Med.
Chem. 2003, 46, 2774; Saxagliptin: (c) Augeri, D. J.; Robl, J. A.; Betebenner, D. A.;
Magnin, D. R.; Khanna, A.; Robertson, J. G.; Simpkins, L. M.; Taunk, P. C.; Huang,
Q.; Han, S.-P.; Abboa-Offei, B.; Wang, A.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.;
Welzel, G. E.; Biller, B. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. J. Med. Chem.
2005, 48, 5025; Alogliptin: (d) Feng, J.; Zhang, Z.; Wallace, M. W.; Stafford, J. A.;
Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi,
K.; Xu, R.; Webb, D. R.; Gwaltney, S. L., II J. Med. Chem. 2007, 50, 2297.
6. Sitagliptin: (a) Aschner, P.; Katzell, H. L.; Guo, H.; Sunga, S.; Williams-Herman,
D.; Kaufman, K. D.; Goldstein, B. J. Diabetes Obes. Metab. 2010, 12, 252;
Vildagliptin: (b) Foley, J. E.; Sreenan, S. Horm. Metab. Res. 2009, 41, 905;
Saxagliptin: (c) Deacon, C. F.; Holst, J. J. Adv. Ther. 2009, 26, 488; Alogliptin: (d)
Nauck, M. A.; Ellis, G. C.; Fleck, P. R.; Wilson, C. A.; Mekki, Q. Int. J. Clin. Pract.
2009, 63, 46.
13. Meng, W.; Brigance, R. P.; Chao, H. J.; Fura, A.; Harrity, T.; Marcinkeviciene, J.;
O’Connor, S. P.; Tamura, J. K.; Xie, D.; Zhang, Y.; Klei, H. E.; Kish, K.; Weigelt, C.
A.; Turdi, H.; Wang, A.; Zahler, R.; Kirby, M. S.; Hamann, L. G. J. Med. Chem.
2010, 53, 5620.
14. The separation of the enantiomers of racemic 1 was carried out using a
Chiralpak AD-H column (20 ꢁ 250 mm) eluting with EtOH/heptane/Et2NH
20:80:0.1 at 20 mL/min; 254 nm detection. Faster eluting isomer (+)-1:
25:2
tR = 11.2 min; ½
a
ꢂ
(3.51 ꢁ 10ꢀ6, CH3OH) = +125.93°. Slower eluting isomer
589
25:4
589
(ꢀ)-1: tR = 16.1 min; ½
a
ꢂ
(3.39 ꢁ 10ꢀ6, CH3OH) = ꢀ103.24°. The enantiomeric
excesses were determined using
a
Chiralpak AS column (4.6 ꢁ 250 mm)
eluting with IPA/heptane/Et2NH 25:75:0.1 at 1.0 mL/min, 254 nm detection:
(+)-1 (tR = 8.2 min), 100% ee; (ꢀ)-1 (tR = 11.2 min), 100% ee.
15. The separation of the enantiomers of racemic 14 was carried out using a
Chiralpak AD-H column (20 ꢁ 250 mm) eluting with EtOH/heptane/Et2NH
20:80:0.1 at 20 mL/min; 254 nm detection. Faster eluting isomer (+)-14:
25:4
589
tR = 11.5 min; ½
a
ꢂ
(7.33 ꢁ 10ꢀ6, CH3OH) = +117.05°. Slower eluting isomer
25:9
589
(ꢀ)-14: tR = 16.3 min;
½aꢂ
(7.96 ꢁ 10ꢀ6
,
CH3OH) = ꢀ133.17°. The
enantiomeric excesses were determined using
a Chiralpak AD column
(4.6 ꢁ 250 mm) eluting with IPA/heptane/Et2NH 25:75:0.1 at 1.0 mL/min,
254 nm detection: (+)-14 (tR = 10.6 min), 100% ee; (ꢀ)-14 (tR = 13.1 min),
100% ee.
16. The modeling of compound 1 was based on the X-ray structure described in the
following reference: Rasmussen, H. B.; Branner, S.; Wiberg, F. C.; Wagtmann, N.
Nat. Struct. Biol. 2003, 10, 19.
17. The ‘Sa’ stereochemical designation refers to the axis of asymmetry imparted to
the molecule by virtue of the restricted rotation around the biaryl bond; see
also: Oki, M. Top. Stereochem. 1984, 14, 1.
7. Brigance, R. P.; Meng, W.; Fura, A.; Harrity, T.; Wang, A.; Zahler, R.; Kirby, M. S.;
Hamann, L. G. Bioorg. Med. Chem. Lett. 2010, 20, 4395.
8. Atropisomerism. In Tetrahedron Symposia-In-Print; Clayden, J., Ed.; Elsevier:
Amsterdam, 2004; Vol. 60, pp 4335–4558.
9. Compound 17 was obtained in 94% purity.
10. Data for compound 1: 1H NMR (CD3OD, 500 MHz) d 7.97 (d, J = 1.7 Hz), 7.85
(dd, J = 1.1, 7.7 Hz, 1H), 7.78 (dd, J = 1.7, 8.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.70