Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere

Article abstract of DOI:10.1002/cmdc.201700333

The synthesis of a new trifluoromethyl oxetane was developed using a Corey–Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere.

Full text of DOI:10.1002/cmdc.201700333

Accepted Article
Title: Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-
Butyl Isostere
Authors: Paramita Mukherjee, Martin Pettersson, Jason K. Dutra,
Longfei Xie, and Christopher W. am Ende
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: ChemMedChem 10.1002/cmdc.201700333
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10.1002/cmdc.201700333
ChemMedChem
Trifluoromethyl Oxetanes: Synthesis and Evaluation as a
tert-Butyl Isostere
Dr. Paramita Mukherjee,*[a] Dr. Martin Pettersson,[b] Jason K. Dutra,[a] Longfei Xie[a] and
Dr. Christopher W. am Ende.*[a]
[a] Pfizer Worldwide Research & Development, Eastern Point Road, Groton,
Connecticut 06340, United States
[b] Pfizer Worldwide Research & Development, 1 Portland Street, Cambridge,
Massachusetts 02139, United States
Corresponding Authors:
Dr. Paramita Mukherjee
Pfizer Inc.
MS8220-3220
Eastern Point Road
Groton, CT 06340
Paramita.Mukherjee@pfizer.com
Dr. Christopher W. am Ende
Pfizer Inc.
MS8220-3262
Eastern Point Road
Groton, CT 06340
Christopher.amEnde@pfizer.com
Key Words: epoxidation, gamma secretase modulators, oxetane, ring expansion, tert-
butyl isostere.
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ChemMedChem
Abstract
The synthesis of a new trifluoromethyl oxetane was developed utilizing a Corey-
Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The
reaction was shown to proceed under mild conditions and displays a broad substrate
scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the
context of the γ-secretase modulator (GSM) program. We demonstrate that the
trifluoromethyl oxetane-containing GSM has reduced lipophilicity, improved lipophilic
efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM
analog, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-
butyl isostere.
Body
Oxetanes are an increasingly prevalent structural motif in drug discovery and
have been used as surrogates for carbonyl groups, geminal-dimethyl and tert-butyl
groups.[1] Furthermore, oxetanes have also been used to increase the polarity of drug
molecules and to improve metabolic stability. Several new synthetic approaches have
recently been developed to facilitate access to a number of useful oxetanes.[2] Herein,
we describe a general synthesis of the trifluoromethyl oxetane substituent and evaluate
the trifluoromethyl oxetane as an isostere for the tert-butyl group in the context of the γ-
secretase modulator (GSM) program (Figure 1).
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10.1002/cmdc.201700333
ChemMedChem
A. Design strategy
O
CF3
nM
O
O
O
N
N
N
N
N
F
N
F
N
N
1
2
O
O
=
=
nM
58
A 42 IC
β
252
A 42 IC
β
50
50
=
=
cLogP 2.8
cLogP 3.5
work:
This
CF3
CF3
O
O
O
O
N
O
N
N
N
N
F
N
F
N
N
4
3
O
O
=
cLogP 1.9
=
=
nM
30
A 42 IC
β
50
cLogP 3.2
B.
Corey-Chaykovsky epoxidation/ring-expansion
O
S
O
S
O
O
=
=
R1
R2
alkyl
alkyl
O
aryl,
aryl,
H,
R1
R2
R1
R2
R1
R2
work:
This
•
•
•
substituent in the literature
O
S
Unexplored
via mild
O
reaction
Synthesis
Isostere for t-Bu
with reduced
Corey-Chaykovsky
and
O
2,2-dimethyltrifluoroethyl
lipophilicity
R1
R1
CF3
CF3
Figure 1. A) Design of the trifluoromethyl oxetane GSM 4. B) Synthesis strategy to
access the novel trifluoromethyl oxetanes via a Corey-Chaykovsky epoxidation/ring
expansion.
γ-Secretase modulators have gained considerable interest as a potential
therapeutic approach for the treatment of Alzheimer’s disease.[3] We have previously
reported on the design of a novel series of GSMs that incorporate a pyridopyrazine-1,6-
dione heterocyclic core.[4] This chemotype provided a significantly improved alignment
of potency, physicochemical properties and absorption, distribution, metabolism and
excretion (ADME) profile. One of the initial leads (1) exhibited moderate in vitro Aβ42
lowering activity (Aβ42[4] IC50 = 252 nM), and a favorable physicochemical profile
(cLogP[5] = 2.8 and CNS MPO[6] = 5.35, Figure 1A). Furthermore, compound 1 had
excellent passive permeability (RRCK[7] Papp,A→B = 17.7×10-6 cm/s) and low potential for
P-glycoprotein (P-gp) mediated efflux (MDR[8] Er = 1.5), as well as good microsomal
stability (HLM[9] CLint,app = 8.8 mL/min/kg). However, further gain in potency was
required to achieve an acceptable human dose projection. Introduction of heteroaryl
rings in place of the 2-CF3 substituent on GSM 1 resulted in excellent potency, but at
the expense of reduced permeability and poor brain penetration.[10] We therefore turned
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10.1002/cmdc.201700333
ChemMedChem
our attention to alkyl substituents to increase sp3 character.[11] Towards this end,
compound 2 was synthesized, which had improved potency (Aβ42 IC50 of 58 nM);[12]
however, the metabolically labile tert-butyl group resulted in poor microsomal stability
(HLM CLint,app = 70.1 mL/min/kg) along with increased lipophilicity (cLogP = 3.5). The
2,2-dimethyltrifluoroethyl group has previously been described as a tert-butyl isostere
with improved metabolic stability.[13] Analogue 3 did indeed have greater microsomal
stability (HLM CLint,app = 24.3 mL/min/kg), as well as improved Aβ42 lowering activity
(IC50 = 30 nM) relative to GSM 2; however, lipophilicity remained high (cLogP = 3.2).[10]
Alternatively, the trifluoromethyl oxetane moiety was envisioned as a more polar
replacement for the tert-butyl and 2,2-dimethyltrifluoroethyl substituents (Figure 1A).
Therefore, we set out to develop an efficient synthesis of trifluoromethyl oxetane GSM 4
and assess the impact of the trifluoromethyl oxetane group on potency, physiochemical
properties and ADME in a pairwise analysis with GSMs 1-3.
General synthetic routes to oxetanes include the intramolecular Williamson ether
synthesis or a Paterno-Büchi [2+2] cycloaddition between a substituted olefin and a
carbonyl group.[2] Alternatively, 2,2-disubstituted oxetanes can be prepared via a
Corey-Chaykovsky epoxidation[14] of an aldehyde or ketone followed by a ring-
expansion (Figure 1B).[15] However, to the best of our knowledge, unsubstituted 2-aryl
and 2-alkyl-2-trifluoromethyl oxetanes have not been previously described in the
literature.[16] We envisioned that a Corey-Chaykovsky epoxidation/ring-expansion of a
trifluoromethyl ketone would provide direct access to the desired trifluoromethyl oxetane
moiety (Figure 1B).[17]
The synthesis of oxetanes from ketones via the intermediacy of epoxides has
previously been reported to require elevated temperatures and prolonged reaction
times.[15] However, with an electron deficient trifluoromethyl ketone, the reaction was
found to proceed under fairly mild conditions. For example, treatment of 1-(5-chloro-2-
methoxyphenyl)-2,2,2-trifluoroethanone with two equivalents of trimethylsulfoxonium
iodide and potassium tert-butoxide at room temperature resulted in rapid formation of
the corresponding epoxide, albeit with an incomplete conversion to the oxetane 5 after
72 hours (see Supporting Information). Further examination of the reaction conditions
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10.1002/cmdc.201700333
ChemMedChem
revealed that 2.2 equivalents of the dimethylsulfoxonium methylide was sufficient to
achieve complete conversion to oxetane 5 (by GCMS) after 15 hours at room
temperature. Upon further optimization, the use of three equivalents of
dimethylsulfoxonium methylide was deemed to be a more general protocol. These
conditions were therefore used to explore the scope of the reaction (Table 1).
Table 1. Synthesis of trifluoromethyl oxetanes
Me3SO+I-
•
•
•
room
Mild,
Aryl,
conditions
temperature
O
CF3
CF3
KOt-Bu
and
heteroaryl
alkyl trifluoromethyl ketones
O
DMSO, RT
15 h
R
R
and
Acidic, basic
reactive
tolerated
groups
potentially
CF3
CF3
CF3
O
O
O
O
MeO
O
CF3
N
F
Cl
HN
O
a
H
CO2
5
6
8
(78%)
(78%)
(76%)
7
(66%)
CF3
H
O
N
H
N
O
O
S
CF3
EtO2C
O2
N
CF3
CF3
N
O2
B(pin)
(46%)
9
10
11
(86%)
(61%)
OMe
(71%)
12
O
O
O
CF3
CF3
CF3
O
Ph
b
13
14
15
(76%)
(75%)
(61%)
Me SO+I-/KOt-Bu
mmol,
Reaction conditions: Trifluoromethyl ketone
1
equiv)
(0.25
equiv),
(3
3
in DMSO
mL) at RT for 15 h. a
isolated.
5
Me SO+I-/KOt-Bu. bUnder reaction condition,
equiv
(1.25
was
3
15
epoxide
We first examined trifluoromethyl ketone substrates bearing an ortho-protected
phenol because of the structural similarity to the trifluoromethyl oxetane in GSM 4.
Towards this end, subjecting the ortho-methyl and allyl ether substrates to the optimized
reaction conditions, generated the corresponding oxetanes 5 and 6 in good yield (Table
1).[18] To further assess the scope and limitations of the reaction, we explored
trifluoromethyl ketone substrates incorporating acidic, basic and sensitive functional
groups. We observed that a free carboxylic acid was tolerated, as demonstrated by the
synthesis of oxetane 7 in 66% yield. Crystallization of carboxylic acid 7 from ethyl
acetate/heptane yielded single crystals suited for X-ray analysis (Figure 2). This
confirmed the structure of the trifluoromethyl oxetane group and showcases the
orientation of the oxetane in relation to the aryl ring. Likewise, a basic amine did not
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10.1002/cmdc.201700333
ChemMedChem
hinder the reaction, as exemplified by the isolation of piperazine 8 in 78% yield. The
reaction was also compatible with heterocyclic trifluoromethyl ketone substrates, as well
as with ester, nitro and boronate functional groups (oxetanes 9-12). Expanding the
scope beyond aryl trifluroromethyl ketones, we found that both benzyl and alkyl
trifluoromethyl ketones could be converted to the respective oxetanes in moderate to
good yield (13 and 14). A limitation to the epoxidation/ring-expansion was observed
when attempting to use a more sterically encumbered aryl trifluoromethyl ketone
substrate. Intermediate epoxide 15 was isolated as opposed to the desired oxetane
even after prolonged reaction times and heating (50 → 100 °C over 24 h).
Figure 2. Crystal structure of trifluoromethyl oxetane 7.
We next sought to apply the epoxidation/ring-expansion reaction to synthesize
GSM 4. Given the broad functional group tolerance, we pursued a route in which the
oxetane was installed in the last step in the sequence (Scheme 1). Alkylation of the
chloroethyl pyridone 16[4] with 5-fluoro-2-hydroxybenzaldehyde proceeded in 21% yield
to give aldehyde 17, with chloride elimination as the major side product. Installation of
the requisite trifluoromethyl ketone was accomplished by a Ruppert–Prakash
trifluoromethylation[19] followed by oxidation with Dess-Martin periodinane.[20] However,
subjecting trifluoromethyl ketone 19 to the optimized reaction protocol described above
(see Table 1) resulted in isolation of the desired oxetane product 4 in only 24% yield.
Analysis of the reaction mixture indicated hydrolysis of the trifluoromethyl ketone to a
carboxylic acid. This problem was solved through a minor modification to the reaction
procedure: by preforming the methylide and then slowly adding it to a solution of ketone
19, the desired trifluoromethyl oxetane GSM 4 was isolated in 59% yield. The ability to
carry out the Corey-Chaykovsky epoxidation/ring-expansion reaction to form the
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10.1002/cmdc.201700333
ChemMedChem
trifluoromethyl oxetane on the fully elaborated GSM template further highlights the
broad substrate scope of this transformation.
CHO
HO
HO
CF3
O
O
CHO
O
F
.
K2CO3 DMSO
,
TMSCF3 K CO
,
Cl
O
O
.
DMF, R2T
3
N
N
N
100 °C
N
N
N
N
N
F
N
O
F
21%
88%
N
N
N
O
O
O
16
17
18
O
CF3
CF3
O
O
Me3SO+I-
O
equiv)
DMP, CH2Cl2
(4
O
→
N
N
N
RT
KOt-Bu
0 °C
equiv)
(4
N
N
N
F
F
DMSO, RT, 15 h
59%
72%
N
N
O
O
19
4
Scheme 1. Synthesis of trifluoromethyl oxetane GSM 4.
We were pleased to observe that the trifluoromethyl oxetane GSM 4 retained
favorable in vitro Aβ-lowering activity as the racemate (IC50 = 74 nM, Table 2). As
predicted, GSM 4 is less lipophilic (ELogD[21] = 3.6) as compared to both the tert-butyl
analog 2 (ELogD = 4.6) and 2,2-dimethyltrifluoroethyl GSM 3 (ELogD = 4.3). As a
result, the lipophilic efficiency (LipE)[22] of the trifluoromethyl oxetane 4 was increased
(LipE = 3.5) relative to analogs 2 and 3 (LipE = 2.6 and 3.2, respectively) despite a
slight reduction in the overall potency. Along with the reduced lipophilicity, the
metabolic stability of oxetane 4 was improved compared to the tert-butyl compound 2
(HLM CLint,app 39.2 vs 74.1 mL/min/kg), although slightly less stable than the
corresponding 2,2-dimethyltrifluoroethyl 3 (HLM CLint,app 25.7 mL/min/kg). The
trifluoromethyl oxetane GSM 4 also maintained good passive permeability and MDR
efflux ratio (RRCK Papp,A→B = 16.3 × 10−6 cm/s; MDR ER = 1.6). Furthermore,
trifluoromethyl oxetane 4 was shown to be stable in aqueous acid, neutral and basic
solutions (pH 1.2, 7.4, and 10, respectively) over 24 hours at 37 °C (see Supporting
Information for details).
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Table 2. Comparison of γ-secretase modulators 1-4.
RRCK
Papp,A→B
[cm/s]f
Aβ42 IC50
HLM CLint,app
Compound
cLogP/ELogDb
LipEc
MDR ERe
[nM]a
[ml/min/kg]d
1
2
3
4
252
58
2.8/3.6
3.5/4.6
3.2/4.3
1.9/3.6
3.0
2.6
3.2
3.5
<8.8
70.0
24.3
37.1
1.5
2.0
1.8
1.6
17.7 × 10−6
12.6 × 10−6
9.3 × 10−6
16.3 × 10−6
30
74
aAβ42 IC50 values were obtained using CHO APPwt cells. Aβ42 IC50 values are the geometric mean of at least three
experiments.[4] bExperimental LogD.[21] cLipophilic efficiency.[22] dHuman liver microsome-derived scaled intrinsic
clearance.[9] eMDR efflux ratio using a MDR1/MDCK assay utilizing MDCK cells transfected with the gene that
encodes human P-glycoprotein.[8] fRRCK cell apparent permeability in the apical to basolateral (A→B) direction.[7]
In summary, we have developed a mild, one-pot synthesis of trifluoromethyl
oxetanes from trifluoromethyl ketones utilizing Corey-Chaykovsky epoxidation/ring
expansion chemistry. The reaction sequence tolerates a variety of functional groups
and can be applied to both aryl and alkyl trifluoromethyl ketones. Additionally, the
trifluoromethyl oxetane moiety was evaluated in the context of the γ-secretase
modulator program as a novel isostere for tert-butyl and 2,2-dimethyltrifluoroethyl
substituents. We observed that the trifluoromethyl oxetane GSM 4 maintained similar
potency while reducing lipophilicity as compared to the tert-butyl and 2,2-
dimethyltrifluoroethyl GSMs (compounds 2 and 3). This, in turn, resulted in an overall
improvement in LipE and metabolic stability of trifluoromethyl oxetane 4 relative to tert-
butyl analog 2, demonstrating the utility of the trifluoromethyl oxetane as a tert-butyl
isostere. We hope this report will encourage others to explore the value of this oxetane.
Experimental Section
General Procedure for the Synthesis of Trifluoromethyl Oxetanes. To a 2-dram vial
containing potassium tert-butoxide (170 mg, 0.75 mmol) in DMSO (1 mL) was added
trimethylsulfoxonium iodide (84 mg, 0.75 mmol) and the reaction was stirred at room
temperature for 10 minutes. A solution of the trifluoromethyl ketone (0.25 mmol) in
DMSO (0.25 mL) was added dropwise to the reaction, and the resulting solution was
stirred at room temperature overnight (15 hours). The crude reaction was partitioned
between diethyl ether and brine. The organic layer was separated, washed once more
with brine, dried over anhydrous sodium sulfate, and concentrated under reduced
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10.1002/cmdc.201700333
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pressure. The crude product was purified by silica gel flash chromatography
(heptane/ethyl acetate) to afford the corresponding trifluoromethyl oxetane.
Acknowledgements
We thank Eric Benvenuti for generating in vitro Aβ42 potency data, Ivan Samardjiev and
Brian Samas for x-ray crytallography analysis, the Pfizer ADME technology group for
generating ADME data, Justin Bellenger for purification support, Chao Li for pH stability
studies and Chris Helal, Patrick Mullins and John Humphrey for insightful discussions.
References:
[1]
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Wuitschik, E. M. Carreira, B. Wagner, H. Fischer, I. Parrilla, F. Schuler, M.
Rogers-Evans, K. Müller, J. Med. Chem. 2010, 53, 3227-3246; c) J. A. Burkhard,
G. Wuitschik, M. Rogers-Evans, K. Müller, E. M. Carreira, Angew. Chem. Int. Ed.
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[3]
[4]
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57, 1046-1062.
[5]
[6]
[7]
Values for cLogP were calculated using the BIOBYTE (www.biobyte.com)
program cLogP, version 4.3
T. T. Wager, X. Hou, P. R. Verhoest, A. Villalobos, ACS Chem. Neurosci. 2010,
1, 435-449.
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J. L. LaPerle, M. C. Michel, G. G. Kay, Br. J. Clin. Pharmacol. 2011, 72, 235-246.
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ChemMedChem
[8]
[9]
B. Feng, J. B. Mills, R. E. Davidson, R. J. Mireles, J. S. Janiszewski, M. D.
Troutman, S. M. de Morais, Drug. Metab. Dispos. 2008, 36, 268-275.
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P. Austin, Drug. Metab. Dispos. 2005, 33, 1304−1311.
[10] M. Pettersson, D. S. Johnson, J. M. Humphrey, T. W. Butler, C. W. am Ende, B.
A. Fish, M. E. Green, G. W. Kauffman, P. B. Mullins, C. J. O’Donnell, A. F.
Stepan, C. M. Stiff, C. Subramanyam, T. P. Tran, B. C. Vetelino, E. Yang, L. Xie,
K. R. Bales, L. R. Pustilnik, S. J. Steyn, K. M. Wood, P. R. Verhoest, ACS Med.
Chem. Lett. 2015, 6, 596-601.
[11] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756.
[12] Compound 2 was synthesized to facilitate pairwise analysis. The des-fluoro
analogue was previously reported.10
[13] a) H. Tanaka, Y. Shishido, Bioorg. Med. Chem. Lett. 2007, 17, 6079-6085; For
additional examples and analyses of tert-butyl isosteres, see: b) D. Barnes-
Seeman, M. Jain, L. Bell, S. Ferreira, S. Cohen, X.-H. Chen, J. Amin, B.
Snodgrass, P. Hatsis, ACS Med. Chem. Lett. 2013, 4, 514-516; c) M. V.
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ChemMedChem 2015, 10, 461-469.
[14] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353-1364.
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Tanaka, K. Nakamura, H. Ohta, Fukuoka Univ. Sci. Reports 1990, 20, 83-87.
[16] A similar 2,2-bis(trifluoromethyl)oxetane has been previously described: E. W.
Cook, B. F. Landrum, J. Heterocycl. Chem. 1965, 2, 327-328.
[17] Synthesis of trifluoromethyl epoxides using the Corey- Chaykovsky reaction has
been described: C. Molinaro, A.-A. Guilbault, B. Kosjek, Org. Lett. 2010, 12,
3772-3775.
[18] Compound 6 and the original synthesis of GSM 4 was initially described in: C.
W. am Ende, B. A. Fish, M. E. Green, D. S. Johnson, P. B. Mullins, C. J.
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ChemMedChem
O'Donnell, M. Y. Pettersson, C. M. Stiff, C. Subramanyam, T. P. Tran, T.
Navaratnam, (Pfizer Inc., New York City, NY, USA), PCT In. Appl. WO
2012131539 A1, 2012.
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G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am. Chem. Soc. 1989, 111,
393-395.
[20] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155-4156.
[21] Lombardo, F. Shalaeva, M.Y. Tupper, K.A. Gao, F. J. Med. Chem. 2001, 44,
2490-2497.
[22] LipE = −log(IC50) − ELogD where IC50 is in molar units and ELogD was
experimentally determined.[21] For additional detail, see: T. Ryckmans, M. P.
Edwards, V. A. Horne, A. M. Correia, D. R. Owen, L. R. Thompson, I. Tran, M. F.
Tutt, T. Young, Bioorg. Med. Chem. Lett. 2009, 19, 4406−4409.
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ChemMedChem
Entry for the Table of Contents
Evaluation:
Synthesis:
O
S
CF3
O
O
O
O
↓
Lipophilicity
LipE
O
O
O
R
CF3
R
CF3
↑
N
N
=
N
N
N
R
alkyl
aryl,
F
N
F
N
N
Metabolic
stability
↑
•
•
•
in Med Chem
O
O
Unexplored
Developed
γ
Synthesis
Isostere for tBu Group
-Secretase Modulator
An epoxidation/ring-expansion approach was utilized to synthesize the trifluoromethyl
oxetane moiety. Analysis of the trifluoromethyl oxetane as a tert-butyl isostere in the
gamma secretase modulator program revealed the oxetane to be a LipE winner with
improved properties.
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