Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid-3 (TRPV3) Antagonist

Article abstract of DOI:10.1021/acs.joc.6b02443

An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee.

Full text of DOI:10.1021/acs.joc.6b02443

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Note
Stereoselective Synthesis of a Dipyridyl Transient
Receptor Potential Vanilloid-3 (TRPV3) Antagonist
Eric A. Voight, Jerome F Daanen, Robert G Schmidt, Arthur Gomtsyan, Michael J. Dart, and Philip R. Kym
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02443 • Publication Date (Web): 04 Nov 2016
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Scheme 1. Original synthesis of TRPV3 antagonist 1
Stereoselective Synthesis of a Dipyridyl Transient
Receptor Potential Vanilloid-3 (TRPV3)
Antagonist
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Eric A. Voight,* Jerome F. Daanen, Robert G. Schmidt, Arthur
Gomtsyan, Michael J. Dart, Philip R. Kym
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Centralized Lead Optimization – Discovery Chemistry &
Technology, AbbVie, Inc., 1 N Waukegan Rd, North Chicago,
Illinois, 60064
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eric.a.voight@abbvie.com
RECEIVED DATE (will be automatically inserted after
manuscript is accepted).
An efficient asymmetric synthesis of dipyridyl TRPV3
antagonist 1 is reported. The 4ꢀstep route involves two CꢀC
bond forming steps, a highly diastereoselective alkene
hydration, and asymmetric ketone hydrosilylation in 97%
ee.
The original route to TRPV3 antagonist 1 was sufficient to
provide gram quantities of material. However, several route
improvements would be needed to access larger quantities of
material. Oxidative cleavage of the starting material olefin 2
caused a need for ketone protection/deprotection steps and a
nonꢀselective lateꢀstage reintroduction of the carbon atom that
was cleaved. Furthermore, sodium borohydride reduction
gave racemic 6, requiring enantiomer separation via chiral
The identification of effective and safe small molecule
analgesic agents is still a largely unmet medical need.1
Transient receptor potential vanilloidꢀ3 (TRPV3) is one of the
members of the TRP family of nonꢀselective cation channels
implicated in the perception of pain.2 Pyridinols such as 1
(Figure 1) are potent TRPV3 antagonists and demonstrate
analgesic efficacy in preclinical models of neuropathic pain.3
Following extensive lead optimization efforts, an efficient
synthesis of pyridinol 1 was required to allow advanced
preclinical characterization of the compound as a potential
drug candidate.
HPLC.
Despite efforts to find stereoselective ketone
reduction and methyl addition conditions to increase the
efficiency of the original route, little progress was made.
Clearly, an alternative route was required.
Scheme 2. Retrosynthetic analysis
Figure 1. Structure of dipyridyl TRPV3 antagonist 1
The original synthesis of 1 began with commercially
available methylenecyclobutane 2 (Scheme 1).3 Oxidative
cleavage of the olefin and ketone protection provided
cyanoketal 3, which was deprotonated with KHMDS and
added to fluoropyridine 4 to furnish pyridylnitrile 5. Addition
of 2ꢀpyridyllithium to
borohydride gave racemic secondary alcohol 6.
5
and reduction with sodium
Ketal
deprotection facilitated chiral HPLC separation of enantiomers
to provide enantiopure alcohol 7. Finally, methyllithium
addition generated a mixture of diols 1 and 8, which could be
separated by silica gel chromatography to give TRPV3
antagonist 1 in 8 steps and 3% overall yield from 2.
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Towards a new route to TRPV3 antagonist 1, we envisioned
With dipyridyl ketone 11 in hand, routes A and B (Scheme
a retrosynthesis involving lateꢀstage diastereoselective olefin
functionalization of alkene 9, which would arise from an
asymmetric ketone reduction of bispyridylketone 11 (Route A,
Scheme 2). Alternatively, the order of steps could be
switched, with asymmetric reduction of ketone 10 preceded by
olefin functionalization (Route B, Scheme 2). Each route
would utilize 11 as a key intermediate, which could arise via
two CꢀC bond forming steps: SnAr addition of the anion of
nitrile 2 to fluoropyridine 4 and 2ꢀpyridyl anion addition to
pyridylnitrile 12 to furnish key intermediate 11. A further
advantage of these routes was the use of readily available
starting materials 2 and 4, which were the same starting
materials utilized in the original route. Finally, ketones 10 and
11 provided new opportunities for identification of
asymmetric reduction conditions that could lead to efficient
pathways to diol 1.
2) were investigated simultaneously. Route A required
enantioselective reduction of 11 (Scheme 4). Unfortunately,
as with asymmetric reduction attempts in the original route, all
initial transfer hydrogenation,5 CBS reduction,6 or DIPꢀCl
reduction7 attempts failed. As an alternative reduction
approach, copperꢀcatalyzed asymmetric hydrosilylation was
considered.7 This recently developed method, pioneered by
Lipshutz,7a,b was successfully applied to cyclohexyl 2ꢀ
pyridylketone by Wu and coworkers,7f albeit with moderate
enantioselectivity (63% ee) and extended reaction times (48 h)
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at ꢀ50 oC.
When these conditions were applied to
pyridylketone 11, using (S)ꢀBINAP as ligand, complete
o
hydrosilylation was observed in only 10 min at 0 C, giving
pyridinol ent-9 in 66% yield (50% ee).8 With this encouraging
preliminary result, alkene functionalization was investigated.
Initial attempts at directed epoxidation, dihydroxylation, and
halohydrin formation failed.
Much to our delight, a
Scheme 3. Preparation of key intermediate 11
Markovnikov hydration of the methylenecyclobutane of ent-9
could be achieved with 50% aq sulfuric acid,9 giving an
improved 2:1 dr (by LCMS) in favor of the desired diol ent-1
compared to the original MeLi addition approach (Scheme 1).
Further optimization of Route A was not pursued since
preliminary Route
B results appeared more promising
(Scheme 5).10
Table 1. Markovnikov hydration of 11
The preparation of key intermediate 11 began with the
union of nitrile 2 with fluoropyridine 4 (Scheme 3). Addition
of a NaHMDS solution to a solution of nitrile 2 and
fluoropyridine 4 was key to efficient nitrile anion SnAr, which
was complete after only 5 min.4 The reaction was more rapid
and generated less byproducts than the comparable reaction
between ketal 3 and fluoropyridine 4 in the original route
(Scheme 1), providing pyridylnitrile 12 in sufficient purity for
the next reaction without the need for purification. From
crude nitrile 12, a solution of 2ꢀpyridyllithium was prepared
by addition of nꢀbutyllithium to 2ꢀbromopyridine. Nitrile 12
was added to the 2ꢀpyridyllithium solution, providing key
intermediate 11 in 74% overall yield from nitrile 2 after acidic
hydrolysis.
temp
dr
(10:13)
Yield of
10 (%)
entry
acid (% aq)
time
(oC)
1
2
3
4
H2SO4 (50)
H2SO4 (50)
H3PO4 (85)
HBF4 (48)
100
23
40
5 min
15 hr
22 hr
2.5 hr
2:1
2:1
50:1
56
61
71
90
50
9:1
An alternative route was also considered, involving olefin
functionalization of key intermediate 11 followed by
asymmetric hydrosilylation (Route B, Scheme 2). The Route
A Markovnikov hydration conditions gave similar selectivity
with a shorter reaction time (Table 1, entry 1). Optimization
of the hydration of alkene 11 began with investigation of
lower temperature in an attempt to improve selectivity (entry
2). Unfortunately, reaction at ambient temperature only
resulted in a longer reaction time (15 h) with no selectivity
Scheme 4. Route A to dipyridyl TRPV3 antagonist 1
improvement.
decomposition, other concentrated acid solutions also led to
olefin hydration as shown in Table 1. Concentrated
While weak or dilute acids led to
phosphoric acid (entry 3) gave remarkably high selectivity
(50:1). However, tertiary phosphate was a major byproduct
that could not be avoided or converted to desired product.
While the phosphate could be washed away with aqueous
NaHCO3, the yield was limited to 71%. Tetrafluoroboric acid
proved to be optimal (entry 4), giving a 9:1 dr after 2.5 hr at
o
50 C with no other byproducts. Desired tertiary alcohol 10
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could be isolated in 90% yield after chromatography. The
In conclusion, an efficient route to dipyridyl TRPV3
antagonist 1 was identified, improving the synthesis from 8
steps, 3% overall to 4 steps, 60% overall yield. The route
mechanistic rationale for the selectivity observed in this
hydration has not been investigated, but intramolecular
delivery of water to a tertiary carbocation via a hydrated
ketone may be involved in the selective formation of 10
(Figure 2).11
involved two CꢀC bond forming steps,
diastereoselective Markovnikov hydration
a
surprisingly
of
a
methylenecyclobutane, and a highly enantioselective ketone
asymmetric hydrosilylation. This route was used to rapidly
produce 125 g of TRPV3 antagonist 1,13 enabling advanced
preclinical studies.
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O
N
CF3
N
N
major
CF3
H
HO
HO
product
N
H
Scheme 5. Route B to dipyridyl TRPV3 antagonist 1
HO
Me
10
Figure 2. Possible mechanism for selective formation of 10
After securing efficient access to cyclobutanol 10,
optimization of the asymmetric hydrosilylation was pursued
(Table 2). The preliminary conditions employed for route A
using (S)ꢀBINAP as ligand gave the product pyridinol entꢀ1 in
moderate yield and poor enantioselectivity (Table 2, entry 1).8
Switching to THF with (R)ꢀBINAP improved the selectivity
slightly (entry 2). Moving to more electron rich and/or
sterically hindered BINAP derivatives, PꢀPhos and Segphos
ligands were considered.7 Indeed, (R)ꢀxylꢀPꢀPhos gave desired
diol with a higher ee of 82% when the reaction was carried out
Experimental Section
o
at ꢀ70 C (entry 4). Switching to (R)ꢀDTBMꢀSegphos, we
were surprised to find that the opposite enantiomer was
produced, although with an excellent degree of
enantioinduction (93% ee, entry 5).12 Finally, using (S)ꢀ
General Procedures. All solvents and reagents were
purchased at the highest commercial quality and used without
further purification. 1H NMR and 13C NMR spectra were
recorded at the specified temperature using 300 or 400 MHz
spectrometers. The data are reported as follows: chemical shift
in ppm from internal tetramethylsilane standard on the δ scale,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q
= quartet, qn = quintet, m = multiplet), coupling constants
(Hz), and integration. All IR spectra were collected using a
FTꢀMIR spectrometer with a Germanium (Ge) single bounce
internal reflecting element.
o
DTBMꢀSegphos at ꢀ30 C, with a 1:1 Cu/ligand ratio and a
low temperature AcOH quench, desired product 1 was
produced in 90% isolated yield with 97% ee.
The
spectroscopic data for TRPV3 antagonist 1 generated via the
new route were indistinguishable from material prepared via
the original route.
Table 2. Asymmetric hydrosilylation of 10
Pyridylnitrile
12.
A
solution
of
3ꢀ
methylenecyclobutanecarbonitrile 2 (2.00 g, 21.5 mmol), 2ꢀ
fluoroꢀ4ꢀ(trifluoromethyl)pyridine 4 (3.55 g, 21.5 mmol), and
toluene (20 mL) was cooled to < 5 oC and sodium
bis(trimethylsilyl)amide (1 M in toluene, 23.6 mL, 23.6 mmol)
o
was added dropwise at < 5 C. After 5 min, 3.6 M aq NH4Cl
solution (20 mL) was added, the layers were separated, and
the organic layer was washed with water (2 x 10 mL) and
brine (10 mL). The organic layer was dried (Na2SO4),
concentrated,
and
crude
3ꢀmethyleneꢀ1ꢀ(4ꢀ
(trifluoromethyl)pyridinꢀ2ꢀyl)cyclobutanecarbonitrile 12 (5.12
g, 21.5 mmol, >99%) was used without further purification.
temp
(oC)
yield
(%)
entry
ligand
solvent
ee (%)
1
2
3
4
5
ent-14
14
15
15
entꢀ16
0
0
0
ꢀ70
0
PhCH3
THF
THF
THF
THF
31 (ent-1)
49
52
52
89
62
Dipyridylketone 11. A solution of 2ꢀbromopyridine (3.13 ml,
50
67
82
o
32.2 mmol) in THF (10 mL) was cooled to < ꢀ70 C and n-
o
BuLi (12.9 ml, 32.2 mmol) was added dropwise at < ꢀ70 C.
93 (ent-1)
After
5 min, 3ꢀmethyleneꢀ1ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀ
6a
16
ꢀ30
PhCH3
97
90
yl)cyclobutanecarbonitrile 12 (5.12 g, 21.5 mmol) was added
as a solution in THF (5 + 2 + 2 mL THF rinse) dropwise at < ꢀ
a4 mol% Cu(OAc) was used instead of 10 mol%
2
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65 C. After 5 min, 2 N HCl (51 mL) was added and the
solution was heated to 50 oC for 15 min. The biphasic
solution was cooled to ambient temperature, diluted with
MTBE (50 mL), and the layers were separated. The organic
layer was washed with brine (20 mL), dried (Na2SO4), and
0.019 ml, 0.15 mmol) was added and the solution was stirred
for 10 min at 50 °C. The mixture was cooled to ꢀ35 °C and
((1s,3s)ꢀ3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀ
yl)cyclobutyl)(pyridinꢀ2ꢀyl)methanone 10 (250 mg, 0.743
mmol) in toluene (2 mL) was added over 15 min, keeping the
internal temperature < ꢀ30 °C. Phenylsilane (1 equiv, 0.0925
mL, 1.49 mmol) was then added at < ꢀ30 °C. After 40min,
acetic acid (0.085 ml, 1.5 mmol) was added and the mixture
was warmed to ambient temperature. The layers were
separated, and the organic layer was washed with 2 N HCl (2
x 10 mL), water (10 mL), and saturated aq NaHCO3 (10 mL).
The combined aq layers were back extracted with MTBE (3 x
10 mL), then the combined organic extracts were dried
(Na2SO4) and concentrated. The residue was purified by
column chromatography (0ꢀ50% EtOAc/heptanes gradient
elution) to give (1R,3s)ꢀ3ꢀ((S)ꢀhydroxy(pyridinꢀ2ꢀyl)methyl)ꢀ1ꢀ
methylꢀ3ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl)cyclobutanol 1 (227
mg, 0.671 mmol, 90 %). On larger scale (>10 g), TRPV3
antagonist 1 was isolated in >99% ee and >99% HPLC purity
via initial HCl salt isolation (1 equiv 12 N HCl, 5:1
EtOAc/IPA) in 91% yield, followed by freeꢀbase (aq
NaHCO3) isolation (83% yield) and 5% iꢀPrOH/heptanes
crystallization (x 2) in 76% yield. MP 119ꢀ121 oC; 1H NMR
(400 MHz, DMSOꢀd6) δ 8.57 (d, J = 5.1 Hz, 1H), 8.28 – 8.23
(m, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (dd, J = 5.1, 1.6
Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.08 (ddd, J = 7.5, 4.8, 1.2
Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 5.77 (d, J = 3.3 Hz, 1H),
4.95 (brs, J = 2.7 Hz, 2H), 2.91 (d, J = 12.1 Hz, 1H), 2.84 (d,
J = 12.1 Hz, 1H), 2.59 (dd, J = 12.0, 3.7 Hz, 1H), 2.50 (dd, J
= 12.0, 3.7 Hz, 1H) 0.83 (s, 3H). 13C NMR (101 MHz,
DMSO) δ 166.0, 161.8, 149.5, 147.8, 136.1, 136.0, 123.5,
122.4, 121.3, 118.9, 116.4, 80.2, 67.1, 46.0, 45.7, 45.2, 29.2.
HRMS (ESI+) m/e calcd for [M + H]+ C17H17N2O2F3
338.1242, found 338.1243. [α]D = ꢀ42.5 (c 1.0, MeOH).
Chiral SFC analysis revealed 97.0% ee.
10
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concentrated.
chromatography (0ꢀ20% EtOAc/heptanes, gradient elution)
giving (3ꢀmethyleneꢀ1ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀ
yl)cyclobutyl)(pyridinꢀ2ꢀyl)methanone 11 (5.08 g, 16.0 mmol,
74 % over 2 steps) as a light yellow oil that solidified on
standing. On larger scale (>10 g), ketone 11 was isolated in
The residue was purified by column
o
57% yield using iꢀPrOH crystallization. MP = 112ꢀ114 C;
1H NMR (400 MHz, Chloroformꢀd) δ 8.56 (d, J = 5.1 Hz, 1H),
8.37 (dt, J = 4.9, 1.2 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.82
(s, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.30 – 7.25 (m, 2H),
4.96 (p, J = 2.4 Hz, 2H), 3.74 – 3.65 (m, 2H), 3.39 – 3.31 (m,
2H). 13C NMR (101 MHz, DMSO) δ 198.4, 165.5, 151.3,
150.5, 148.8, 142.9, 138.0, 137.9, 127.5, 123.8, 123.4, 117.3,
115.5, 108.5, 54.3, 41.5. HRMS (ESI+) m/e calcd for [M +
H]+ C17H13N2OF3 318.0980, found 318.0991.
Dipyridyl alcohol 10. A solution of (3ꢀmethyleneꢀ1ꢀ(4ꢀ
(trifluoromethyl)pyridinꢀ2ꢀyl)cyclobutyl)(pyridinꢀ2ꢀ
yl)methanone 11 (510 mg, 1.60 mmol) and aq tetrafluoroboric
o
acid (48%, 2.5 mL) was heated to 50 C. After 2.5 hr, the
yellow solution was poured into saturated aq NaHCO3 (20
mL) and extracted with EtOAc (100 mL). The organic layer
was washed with brine (20 mL), dried (Na2SO4), and
concentrated to a yellow oil. The residue was purified via
column chromatography (0ꢀ40% ethyl acetate/heptanes
gradient elution) to give ((1s,3s)ꢀ3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀ(4ꢀ
(trifluoromethyl)pyridinꢀ2ꢀyl)cyclobutyl)(pyridinꢀ2ꢀ
yl)methanone 10 (486 mg, 1.45 mmol, 90 %) as the major
diastereomer. On larger scale (>10 g), tertiary alcohol 10 was
isolated using heptanes trituration in 75% yield (upgrading dr
from 9:1 to 24:1) and the minor diastereomer was completely
rejected during isolation of 1. MP = 85ꢀ87 C; 1H NMR (400
o
Corresponding Author
MHz, DMSOꢀd6) δ 8.65 (d, J = 5.1 Hz, 1H), 8.41 (ddd, J =
4.7, 1.8, 0.9 Hz, 1H), 7.96 (dt, J = 7.9, 1.2 Hz, 1H), 7.93 –
7.88 (m, 2H), 7.50 – 7.47 (m, 1H), 7.44 (ddd, J = 7.5, 4.7, 1.4
Hz, 1H), 4.99 (s, 1H), 2.95 – 2.89 (m, 2H), 2.84 – 2.77 (m,
2H), 1.17 (s, 3H). 13C NMR (101 MHz, DMSO) δ 198.4,
164.7, 151.4, 150.7, 148.7, 138.0, 137.3, 127.5, 124.0, 123.4,
117.3, 117.0, 67.7, 50.7, 46.7, 29.3. HRMS (ESI+) m/e calcd
for [M + H]+ C17H15N2O2F3 336.1086, found 336.1087.
* E-mail: eric.a.voight@abbvie.com
Acknowledgment. We thank the AbbVie Structural Chemistry
group for compound characterization support and Erin Jordan for
chiral analytical SFC data.
Disclosures. All authors are employees of AbbVie. The design,
study conduct, and financial support for this research were provided
by AbbVie. AbbVie participated in the interpretation of data, review,
and approval of the publication.
TRPV3 antagonist 1. A mixture of copper(II) acetate
monohydrate (5.94 mg, 0.030 mmol), (S)ꢀ(+)ꢀ5,5'ꢀbis[du(3,5ꢀ
diꢀtꢀbutylꢀ4ꢀmethoxyphenyl)phosphino]ꢀ4,4'ꢀbiꢀ1,3ꢀ
benzodioxole [(S)ꢀ(+)ꢀDTBMꢀSegphos 35.1 mg, 0.030 mmol]
and toluene (2 ml) was stirred at ambient temperature for 10
min, then heated to 50 °C for 15 min. Phenylsilane (0.2 equiv,
Supporting Information Available. NMR spectra of all new
compounds and chiral SFC data for compound 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
References and Notes
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(1) Woolf, C. J. Overcoming obstacles to developing new analgesics. Nat.
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5
6
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(2) For recent reviews on TRP channels as pain targets, see: a) Julius, D.
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Chung, M.ꢀK. Open Pain J. 2013, 6, 119.
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McGaraughty, S. P.; Gauvin, D. M.; Joshi, S. K.; Banfor, P. N.; Segreti, J. A.;
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(8) Moderate isolated yields reported for asymmetric hydrosilylation in
Scheme 4 and Table 2 were a consequence of employing unoptimized
workup/isolation techniques which led to complex mixtures.
Low
temperature AcOH quench proved critical for efficient product isolation. See
the experimental section preparation of final product 1 for details.
(9) a) Markownikoff, W. I. Annalen der Chemie Pharmazie 1870, 153, 228.
b) Riesz, P.; Taft, R. W., Jr.; Boyd, R. H. J. Am. Chem. Soc. 1957, 79, 3724.
(10) When optimized Table 2 asymmetric hydrosilylation conditions were
applied to pyridylketone 11, decomposition was observed, perhaps due to
competing olefin hydrosilylation.
(11) For an experimental study on the formation of pyridinium ketone
hydrates in aqueous solution, see: Huang, S.; Miller, A. K.; Wu, W.
Tetrahedron Lett. 2009, 50, 6584.
(12) The effect of temperature on reversal of the sense of enantioꢀinduction in
hydrosilylation of pyridyl ketones was studied by Wu and coworkers,7e,f
although in their studies, 2ꢀpyridylketones did not display this behavior.
Detailed investigations of temperature effects were not carried out in our
studies, although these subtle effects on selectivity may explain the reversal
we observed with different BINAP derivatives.
(13) Yields and experimental details described herein are for small scale
optimization experiments using silica gel chromatography for isolation.
Larger scale (>10 g) isolation procedures are included in the experimental
section. These isolation procedures were unoptimized, favoring purity over
recovery. Therefore, chromatography procedures and yields were used for the
purpose of this study since they more accurately reflect reaction efficiency.
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