Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists

Article abstract of DOI:10.1021/acsmedchemlett.9b00010

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

Full text of DOI:10.1021/acsmedchemlett.9b00010

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Letter
Structure-Based Discovery of Phenyl (3-Phenylpyrrolidin-3-
yl)sulfones as Selective, Orally Active ROR#t Inverse Agonists
James J.-W. Duan, Zhonghui Lu, Bin jiang, Sylwia Stachura, Carolyn A. Weigelt, John S. Sack, Javed
Khan, Max Ruzanov, Michael A. Galella, Dauh-Rurng Wu, Melissa Yarde, Ding Ren Shen, David
J. Shuster, Virna Borowski, Jenny H. Xie, Lisa Zhang, Sridhar Vanteru, Arun Kumar Gupta, Arvind
Mathur, Qihong Zhao, William Foster, Luisa M. Salter-Cid, Percy H Carter, and T. G. Murali Dhar
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00010 • Publication Date (Web): 26 Feb 2019
Downloaded from http://pubs.acs.org on February 27, 2019
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ACS Medicinal Chemistry Letters
Letter
of RORγt suggested that the acyl substituents off the 84
pyrrolidine nitrogen (−COR in 4) could provide a suitable 85
vector toward the C2 acetamide site. An added benefit of the 86
cyclopentane-to-pyrrolidine switch was that the pyrrolidine 87
ring would allow rapid structure−activity relationship (SAR) 88
study through simple acylation reactions.
89
The free NH pyrrolidine 5 (R-enantiomer, Table 1) was 2.5- 90 t1
fold less potent against RORγt than the cyclopentane 3. Small 91
Table 1. Initial Pyrrolidinylsulfone Analogues
d
d
RORγt EC50
PXR EC50
b
LXRα EC50
b
LXRβ EC50
b
a
c
#
nM
nM (% max)
nM (% max)
nM (% max)
5
6
7
8
595 237
434 (110)
480 (100)
ND
2920 (58)
>7500
408 (62)
>7500
>7500
>7500
>7500
>7500
>3750
>7500
>7500
>7500
>7500
1900 (39)
>7500
>7500
>7500
>7500
>7500
>7500
>7500
>7500
2650 1280
b
1040
1260
b
ND
Figure 1. Previously reported sulfonamide 1 and newly designed
benzylsulfone 2, (1-phenylcyclopentyl)sulfone 3, and (3-phenyl-
pyrrolidin-3-yl)sulfone 4.
9
378 224
224 78
88 35
794 (99)
7810 (81)
>2470 (89)
4930 (86)
>50000 (11)
520 (110)
>5140 (72)
10
11
12
13
14
15
55 25
52 bound to RORγt, was that the sulfonyl group adopted a
53 pseudoaxial orientation with respect to the THQ core, and the
54 para-fluorophenyl group was stacked against the phenyl ring of
55 the THQ in a face-to-face fashion, resulting in an overall near
56 U-shaped conformation (3-D picture in Figure 1). While
57 searching for alternative scaffolds, we noticed that phenyl
58 benzylsulfones have been reported to prefer a conformation
59 reminiscent of the binding mode of 1.10,11 Therefore, we set
60 out to explore a series of phenyl benzylsulfones as alternatives
61 to the THQ sulfonamide core.12,13
4340 847
4500 1750
b
4200
a
RORγt reporter assay using a Jurkat cell line; values from two or
more experiments performed in duplicate unless otherwise noted; %
max typically close to 100%. Value from a single experiment
performed in duplicate. % max relative to rifampicin. LXR assays
(agonist mode) were performed using a CV-1 cell line; % max relative
to T0901317. ND = not determined.
b
c
d
62 To quickly assess the impact on activity, the parent phenyl
63 benzylsulfone 2 (Figure 1) was selected as the initial target. In
64 a RORγt inverse agonist assay (a Gal-4 reporter assay using the
65 Jurkat cell line),9 compound 2 exhibited an EC50 of 2980 nM.
66 We envisioned that α,α-disubstitution at the benzyl position
67 would enhance the population of the U-shaped conformation,
68 through the Thorpe−Ingold effect, and in turn improve
69 potency. After exploring different substituents in silico, phenyl
70 (1-phenylcyclopentyl)sulfone 3 (predicted the lowest energy
71 conformation shown in Figure 1) was selected as the target to
72 synthesize. To our delight, this benzylic methylene-to-cyclo-
73 pentane transformation increased RORγt potency by more
74 than 10-fold (232 nM for 3 vs 2980 nM for 2). Unfortunately,
75 compound 3 displayed significant cross reactivity against PXR
76 and liver X receptor α and β (LXRα and LXRβ). We had
77 reported earlier that in the THQ series, the C2 acetamide
78 group of 1 played an important role in significantly right
79 shifting PXR, LXRα, and LXRβ potency,9 so it was logical to
80 explore the acetamide binding site in order to improve
81 selectivity of the sulfone series (3). With this in mind, phenyl
82 (3-phenylpyrrolidin-3-yl)sulfone 4 was designed. Molecular
83 modeling studies of 4 with the ligand-binding domain (LBD)
amide, carbamate, and urea analogues 6−8 (all racemic 92
mixtures) resulted in slightly weaker activity than 5, while 93
the larger cyclopentylcarboxamide 9 (racemic mixture) 94
restored potency to the level of 3. Noteworthy here is that 95
pyrrolidines 5−9 displayed weaker activities against PXR, 96
LXRα, and LXRβ compared to 3.
97
Examination of the RORγt cocrystal structure with an 98
analogue of 1 (compound 33 in ref 9) revealed that the tert- 99
alcohol of the C2 acetamide group is surrounded by polar side 100
chains comprising Arg364, Arg367, and Tyr281 as well as the 101
carbonyl group of Cys285. To engage these amino acids, a 102
biased SAR effort to incorporate polar amide groups was 103
carried out (analogues 10−13, R enantiomer, Table 1). 104
Compared to the cyclopentane 3, compounds 10−12 showed 105
comparable or better potency against RORγt. Importantly, 106
10−12 completely dialed out LXRα and LXRβ activities (>7.5 107
μM). Their PXR EC50 values were also significantly right- 108
shifted (greater than 100-fold) compared to 3, although Ymax 109
values were still high. Carboxylic acid 13 was less active. 110
Analogues incorporating the S-pyrrolidine enantiomer were 111
also evaluated. Compounds 14 and 15, the corresponding S- 112
B
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113 enantiomers of 5 and 12 respectively, were considerably
114 weaker against RORγt.
115 In order to validate the hypothesis regarding the binding
116 conformation of phenyl (3-phenylpyrrolidin-3-yl)sulfones and
117 the proposed engagement of key amino acid residues in the
118 polar pocket, an X-ray structure of 12 with the RORγt LBD
119 was obtained (Figure 2). As predicted from modeling, the
f2
Figure 3. X-ray crystal structure of compound 3 and the LBD of PXR
(PDB ID 6NX1). Compound 3 binds to PXR in alternate
conformations with 70%/30% occupancy, as depicted by thicker
sticks (orange) and skinnier sticks (magenta), respectively. The
carbons of the protein are colored in green. Sulfurs are colored in
yellow, N in blue, O in red, and F in cyan. Hydrogen bonds of 3 with
PXR are indicated by dashed lines.
chain of His407 and the trifluoromethyl groups fill a small 149
hydrophobic pocket. In both binding modes, the cyclopentane 150
ring projects into an enclosed hydrophobic pocket formed by 151
the side chains of Leu209, Val211, Trp299, Leu308, Met323, 152
and Leu324. This structure could explain the reduced PXR 153
potency of 10−12. The substituted pyrrolidines in 10−12 154
would be too polar and sterically encumbered to fit in the small 155
hydrophobic pocket. As a result, analogues 10−12 exhibited 156
Figure 2. X-ray crystal structure of compound 12 and the LBD of
RORγt (PDB ID 6NXH). The carbons of the protein are colored in
pink and those of 12 in green. Sulfurs are colored in yellow, N in blue,
O in red and F in cyan. A hydrogen bond of 12 with Arg367 of
RORγt is indicated by a dashed line.
120 benzyl phenyl sulfone backbone of 12 adopted a near U-
121 shaped conformation and interacts with RORγt in a fashion
122 reminiscent of the bicyclic sulfonamide series (1). Specifically,
123 the p-fluorophenyl group occupies a hydrophobic pocket
124 formed by the side chains of Met365, Val376, Phe378, Phe388,
125 Ile400, and Phe401 (not shown for clarity except Phe388 and
126 Met365) and forms a face-to-face π stacking interaction with
127 the side chain of Phe388. The two CF3 substituents of the
128 hexafluoroisopropanol group also occupy a hydrophobic
129 pocket, formed by the side chains of residues Trp317,
130 Met358, Leu391, Ile397, Ile400, and His479 (some not
131 shown in Figure 2 for clarity). Although the hydroxy group is
132 in the vicinity of His479 on helix 11, it does not appear to have
133 the desired orientation to form a hydrogen bond. The
134 implications of this will become apparent in subsequent SAR
135 studies (vide infra). In the center of the RORγt pocket, the
136 pyrrolidine ring makes hydrophobic contacts with the side
137 chains of Leu324, Met365, and Val361. The pyrrolidine moiety
138 also provides a vector for the 4-acylpiperazinylcarbonyl
139 substituent to bind in the polar acetamide binding pocket.
140 Consistent with our hypothesis, the 4-acyl group forms a
141 hydrogen bond with the side chain of Arg367.
improved selectivity against PXR compared to 3.
157
Using the cyclopentyl sulfone 3 as a starting point, SAR 158
around the hexafluoroisopropyl alcohol moiety was inves- 159
tigated (Table 2). Incorporating a methyl group in place of one 160 t2
of the CF3 resulted in 6-fold loss of RORγt potency (16, 161
racemic mixture). The corresponding ethyl analogue 17 162
(racemic mixture) partially restored activity. Attempts to 163
Table 2. Hexafluoroisopropyl Alcohol SAR
a
b
c
#
R1
R2
RORγt EC50 nM
PXR EC50 nM (% max)
3
CF3
Me
Et
CF3
CF3
CF3
CF3
CF3
OH
OH
OH
NH2
OMe
Me
F
232 28
10 (110)
239 (110)
48 (110)
275 (120)
920 (110)
752 (140)
1010 (130)
229 (110)
d
d
16
17
18
19
20
21
22
1400 390
b
643
888 573
1130 65
b
3650
494
b
142 A crystal structure of 3 in the PXR LBD was also solved.
143 Interestingly, 3 binds to PXR in two binding modes that differ
144 in the orientation of the p-fluorophenylsulfonyl group and the
145 benzene linker between the cyclopentane and the hexafluor-
146 oisopropyl alcohol (Figure 3). The hexafluoroisopropyl alcohol
147 group is positioned in the same fashion in both binding modes:
148 with the hydroxy group forming a hydrogen bond to the side
Cl
271 337
a
RORγt reporter assay using a Jurkat cell line; values from two or
more experiments performed in duplicate unless otherwise noted; %
b
f3
max typically close to 100%. Value from a single experiment
c
d
performed in duplicate. % max relative to rifampicin. Tested as
racemic mixture.
C
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ACS Medicinal Chemistry Letters
Letter
a
Table 3. In Vitro Profile of Perfluoroisopropyl Analogues
a
b
All compounds showed EC50 values greater than 7500 nM in LXRα and LXRβ assays. RORγt reporter assay using a Jurkat cell line; values from
c
two or more experiments performed in duplicate unless otherwise noted; % max typically close to 100%. Value from a single experiment performed
in duplicate. % max relative to rifampicin. Metabolic stability in mouse liver microsome; percentage remaining after 10 min of incubation. ND =
not determined.
d
e
replace the hydroxyl group with an amino, methoxy, methyl,
fluoro, or chloro group all led to weaker RORγt inverse
agonists (18−22). Among them, 21 and 22 were found to
have potency closest to 3. The perfluoroisopropyl analogue 21
was especially interesting because it had dramatically right-
shifted PXR activity compared to 3 (100-fold), while being
only 2-fold less potent at RORγt. The right shift in PXR EC50
for analogue 21 can potentially be explained by the X-ray
cocrystal structures of compounds 12 and 3 (Figures 2 and 3,
respectively). Assuming that 3 binds like 12 in RORγt, the
hydroxy group would not be involved in hydrogen bonding
and, therefore, can be replaced with a fluoro group (21)
without significant loss of activity. In PXR, the hydroxy group
of 3 serves as a hydrogen bond donor. The fluoro replacement
cannot maintain this hydrogen bond. As a result, 21 displayed
similar RORγt potency to the corresponding alcohols 10 and
12 (Table 1), while 24 was 2-fold weaker than 11. Surprisingly,
the cyclohexanecarboxylic acid 26 was quite active with an
EC50 of 119 nM, 35-fold more potent than the corresponding
alcohol 13. The trans-cyclohexane stereochemistry in 26 is
important as the cis isomer 27 was significantly less potent for
RORγt. Replacing the cyclohexane with a piperidine moiety
also resulted in a less potent compound (28).
To gain insight into the potency disconnect, 13 and 26 were
tested in a RORγt binding assay. While the binding IC50 of 26
(55 nM) correlated reasonably well with its Jurkat activity, 13
displayed considerably more potent binding (146 nM) than its
Jurkat IC50. We hypothesized that cell membrane permeability
was probably responsible for the poor functional activity of 13
in the Jurkat assay. Consistent with this hypothesis, compound
13 showed low permeability in Caco-2 assay (permeation
coefficient less than 15 nm/s). In contrast, analogue 26
showed significantly improved permeability (120 nm/s).
The effect of substituents on the phenylsulfone moiety was
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
179 a dramatic loss of PXR potency.
In order to further improve RORγt potency and selectivity
of compound 21 for PXR, SAR of the perfluoroisopropyl
moiety in combination with the pyrrolidinylsulfone scaffold
180
181
182
t3
183 was carried out (Table 3). Compounds 23 and 25 showed
also studied (29−36, Table 3). Replacing the para-fluoro 203
D
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ACS Medicinal Chemistry Letters
Letter
a
204 group (R2) in 26 with a methyl, ethyl, or chloro group (30−
205 32) maintained or slightly improved RORγt activity vs 26,
206 whereas the hydrogen and methoxy analogues (29 and 33) led
207 to reduced activity. Additional analogues of 26 with meta-
208 substituents (R3) were also synthesized. Methyl and ethyl
209 analogues (34 and 35) improved activity by approximately 2-
210 fold vs 26. A larger cyclopropyl analogue 36 was slightly less
211 active.
Table 4. Pharmacokinetic Profile of 26 in balb/c Mice
dose
2 mg/kg (iv)
10 mg/kg (po)
Cmax (μM)
Tmax (h)
6.6
2
AUC (μM·h)
t1/2 (h)
Cl (mL/min/kg)
Vss (L/kg)
F (%)
7.4
7.2
7.2
3.4
36.6
212 The SAR outlined in Table 3 clearly shows that the
213 perfluoroisopropyl moiety consistently improved selectivity
214 against PXR for the pyrrolidinylsulfone series. All compounds
215 in Table 3 showed PXR Ymax under 40%, with most of them
216 having EC50 values greater than the assay limit. These
217 compounds also exhibited excellent selectivity against LXRα
218 and LXRβ, typically with EC50 values greater than 7.5 μM.
219 To identify a tool compound for in vivo studies, majority of
220 the compounds in Table 3 were first tested in a 10 min mouse
221 liver microsome (MLM) assay to get a rough estimation of
222 microsomal stability. Compounds 24 and 25 were found to
223 have moderate stability (69% and 68% remaining after 10 min
224 incubation). In general, compounds with carboxylic acid
225 moieties showed improved stability in the MLM assay (for
226 example, 26, 30, and 34). Compounds 26, 30, and 34 were
227 also tested for protein binding, and 26 was found to have the
228 highest free fraction (3.7% and 10.5% unbound in human and
229 mouse proteins, respectively). Based on its overall profile in
230 terms of RORγt potency, selectivity, metabolic stability, and
231 protein binding, analogue 26 was selected for further
232 evaluation.
233 Compound 26 was inactive against RORα and RORβ in
234 either inverse agonist or agonist mode (>40 μM). In addition
235 to its selectivity against PXR, LXRα, and LXRβ (vide supra),
236 26 displayed IC50 values greater than 150 μM against the
237 broader family of nuclear receptors including androgen
238 receptor, estrogen receptor α, glucocorticoid receptor, and
239 progesterone receptor. Compound 26 was also tested in a
240 panel of 38 additional assays ranging from GPCRs, trans-
241 porters, enzymes, and ion channels and was found to be
242 inactive within the concentration limit of the assays (typically
243 30 μM).
99
a
Dose vehicle: iv− 2.5% N-methyl-2-pyrrolidone, 67.5% polyethylene
glycol 300, 4.5% pluronic F-68, 25.5% water; po− 5% N-methyl-2-
pyrrolidone, 76% polyethylene glycol 300, 19% D-α-tocopheryl
polyethylene glycol succinate (TPGS).
Figure 4. Inhibition of IL-17F production in an IL-2/IL-23 induced
mouse PD model after oral administration of 26.
IL-22, GM-CSF, KC (mouse IL-8), and IL-6 was also observed 267
(data not shown). Collectively, these data demonstrated that 268
26 effectively blocked RORγt-dependent cytokine production 269
in mice.
270
Compound 26 was also tested in an IL23-induced mouse 271
model of acanthosis (see Supporting Information for 272
description of this model).14 As illustrated in Figure 5, 26 273 f5
244 In the Caco-2 assay, 26 demonstrated good permeability (Pc
245 of 120 nm/s) with a modest efflux ratio of 2.6. It showed no
246 significant in vitro inhibition against a panel of cytochrome
247 P450 isozymes (IC50 > 20 μM for 1A2, 1B2, 2C9, 2C19, 2D6,
248 and 3A4), except 2C8 (IC50 of 0.68 μM). In a more accurate
249 t1/2 MLM assay, 26 displayed a stability half-life of greater than
250 120 min, which translated into low clearance (7.2 mL/min/kg)
251 and a long half-life (7.2 h) after intravenous administration of 2
252 mg/kg in mice (Table 4). An oral dose of 10 mg/kg of 26 led
253 to an excellent overall profile with Cmax of 6.6 μM, AUC (area
254 under the curve) of 36.6 μM·h, and an oral bioavailability of
255 99%.
Figure 5. Efficacy of 26 in an IL-23-induced mouse acanthosis model.
t4
significantly reduced ear swelling at both 10 and 50 mg/kg 274
when dosed orally, bid. At the 50 mg/kg bid dose, 26 achieved 275
efficacy nearly equivalent to an anti-IL-23 antibody, which was 276
256 Having identified compound 26 as a highly selective RORγt
257 inverse agonist with an excellent mouse PK profile, we tested
258 the compound in an IL-2/IL-23-stimulated mouse pharmaco-
259 dynamic (PD) model (Figure 4).9 In the study, naive mice
260 were challenged three times with IL-2 and IL-23 (at 0, 7, and
261 23 h) after IL-2 alone priming (−24 h), and 26 was dosed
262 orally 30 min prior to each IL-2/IL-23 challenge. Serum was
263 analyzed 7 h after the last IL-2/IL-23 administration. As shown
264 in Figure 4, at oral bid doses of 5, 15, and 50 mg/kg, 26
265 achieved 47%, 77%, and 98% inhibition of IL-17F production,
266 respectively. In addition, dose-dependent inhibition of IL-17A,
used as the positive control in this model.
277
Detailed protocols for the synthesis of compounds listed in 278
Tables 1−3 are provided in Supporting Information. Schemes 279 s1
1 and 2 highlight representative syntheses of cyclopentylsul- 280 s1s2
fones and pyrrolidinylsulfone 26. The methyl group of 281
commercially available 37 was subjected to radical bromination 282
conditions, and the product mixture (mostly monobromide) 283
was reacted with sodium 4-fluorobenzenesulfinate to provide 284
compound 2 (Scheme 1).15 After protection of the alcohol as a 285
benzyl ether, the resulting intermediate 38 was treated with 286
sodium hydride and (Z)-1,4-dichlorobut-2-ene to give the 287
f4
E
DOI: 10.1021/acsmedchemlett.9b00010
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ACS Medicinal Chemistry Letters
Letter
a
deprotected to give 5. After Boc protection of the pyrrolidine, 303
the resulting alcohol was treated with DAST followed by HCl 304
to yield 40. Finally, BOP-mediated coupling with trans-1,4- 305
cyclohexanedicarboxylic acid monomethyl ester followed by 306
saponification completed the synthesis of 26. The structure of 307
26 was determined by single crystal X-ray analysis (CCDC 308
Scheme 1. Synthesis of Cyclopentylsulfone Analogues
1896035).
309
In summary, a novel series of RORγt inverse agonists was 310
discovered using rational drug design. Cyclopentylsulfone 3 311
exhibited promising RORγt potency, but lacked selectivity 312
against PXR, LXRα, and LXRβ. Subsequent discovery of the 313
pyrrolidinylsulfone in combination with the perfluoroisopropyl 314
group led to discovery of selective RORγt inverse agonists. 315
Lead compound 26 displayed high selectivity in vitro and an 316
excellent pharmacokinetic profile in mouse. When tested in 317
vivo, 26 exhibited dose-dependent activity in an IL2/IL23 318
mouse PD model and achieved biologic-like efficacy in an 319
IL23-induced acanthosis mouse model of psoriasis.
320
a
Reagents and conditions: (a) NBS, AIBN, CCl4, at reflux; (b)
sodium 4-fluorobenzenesulfinate, DMF, 82% two steps; (c) BnBr,
K2CO3, DMF, 87%; (d) (Z)-1,4-dichlorobut-2-ene, NaH, DMF, 70%;
(e) H2, Pd(OH)2/C, MeOH, EtOAc, 39%; (f) Tf2O, KOMe, toluene,
42%; (g) NaN3, TfOH, 40 °C, 61%; (h) H2, Pd/C, MeOH, CH2Cl2,
99%; (i) MeI, K2CO3, DMF, 78%); (j) DAST, CH2Cl2, 85 °C, 54%;
(k) SOCl2, pyridine, at reflux, 46%.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the 323
ACS Publications website at DOI: 10.1021/acsmedchem- 324
321
322
■
S
lett.9b00010.
325
Description of acanthosis model and synthesis and 326
a
Scheme 2. Synthesis of Pyrrolidinylsulfone 26
characterization of new compounds (PDF)
327
328
AUTHOR INFORMATION
■
Corresponding Author
*E-mail james.duan@bms.com. Phone: 609-252-4199.
329
330
ORCID
331
332
333
334
James J.-W. Duan: 0000-0003-2730-9924
Percy H. Carter: 0000-0002-5880-1164
T. G. Murali Dhar: 0000-0003-0738-1021
Notes
335
336
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank Dr. Robert Borzilleri for critical review 338
of the manuscript.
337
■
a
Reagents and conditions: (a) Me2NCH2NMe2, Ac2O, DMF, 60 °C,
339
55%; (b) N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)-
methanamine, TfOH, CH2Cl2, 96%; (c) chiral separation, 43%; (d)
H2, Pd(OH)2/C, HCl, MeOH, 98%; (e) (Boc)2O, i-Pr2NEt, CH2Cl2,
96%; (f) DAST, ClCH2CH2Cl, 50 °C, 77%; (g) HCl, 1,4-dioxane,
99%; (h) trans-1,4-cyclohexanedicarboxylic acid monomethyl ester,
BOP, i-Pr2NEt, DMF, 98%; (i) LiOH, THF, H2O, 78%.
REFERENCES
340
■
(1) Cook, D. N.; Kang, H. S.; Jetten, A. M. Retinoic acid-related 341
orphan receptors (RORs): regulatory functions in immunity, 342
development, circadian rhythm, and metabolism. Nucl. Receptor Res. 343
2015, 101185.
344
(2) Ivanov, I. I.; McKenzie, B. S.; Zhou, L.; Tadokoro, C. E.; et al. 345
The orphan nuclear receptor RORγt directs the differentiation 346
program of proinflammatory IL-17+ T helper cells. Cell 2006, 126, 347
288 cyclopentene product. Reduction of the olefin and cleavage of
289 the benzyl ether in one pot provided 3, which served as an
290 intermediate for additional analogues. For example, 3 was
291 converted to amine 18 via a three-step sequence: triflate
292 formation, azide displacement, and reduction to amine.16
293 Compound 3 was also used to synthesize methyl ether 19,
294 fluoride 21, and chloride 22.17
295 The synthesis of pyrrolidinylsulfone 26 is depicted in
296 Scheme 2. Compound 38 was treated with N,N,N′,N′-
297 tetramethylmethylenediamine and acetic anhydride to give a
298 vinyl sulfone,18 which underwent acid-catalyzed [3 + 2]
299 cycloaddition with N-benzyl-1-methoxy-N-((trimethylsilyl)-
300 methyl)methanamine to provide pyrrolidine 39.19 After
301 resolution of enantiomers using supercritical fluid chromatog-
302 raphy (SFC), the desired R enantiomer was globally
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