A Practical Approach for Enantio- and Diastereocontrol in the Synthesis of 2,3-Disubstituted Succinic Acid Esters: Synthesis of the pan-Notch Inhibitor BMS-906024

Article abstract of DOI:10.1055/s-0035-1561636

An oxidative intermolecular enolate heterocoupling reaction was employed for the synthesis of anti-2,3-disubstituted succinic acid mono- and differentially protected diesters. Tactical approaches to access all the diastereomers are discussed. The method w

Full text of DOI:10.1055/s-0035-1561636

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
C. A. Quesnelle et al.
Letter
Synlett
A Practical Approach for Enantio- and Diastereocontrol in the Syn-
thesis of 2,3-Disubstituted Succinic Acid Esters: Synthesis of the
pan-Notch Inhibitor BMS-906024
Claude A. Quesnelle*a
Patrice Gilla
Soong-Hoon Kima
Libing Chena
Yufen Zhaoa
CF3
CF3
CF3
O
O
Me
N
O
O
O
O
N
NH2
(R)
(S)
OtBu
+
N
HO
OtBu
H
N
(S)
O
O
O
Brian E. Finka
CF3
CF3
CF3
Mark Saulniera
David Frennessona
Michael P. DeMartinob
Phil S. Baranb
BMS-906024
Ashvinikumar V. Gavaib
a Bristol-Myers Squibb Research and Development, P. O. Box
4000, Princeton, NJ 08543, USA
Claude.Quesnelle@BMS.com
b Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received: 22.12.2015
Accepted after revision: 13.04.2016
Published online: 18.05.2016
Although several methods are known to give disubsti-
tuted succinic acids, few exhibited the desired broad scope
and diastereoselectivity. For example, Deccico4 showed that
either syn or anti selectivity may be obtained depending on
the choice of chiral oxazolidinone 3 and chiral secondary
triflate 4 (Scheme 1). However, low yields of the desired
anti-succinate precluded the application of this method for
our needs. McClure5a and others5b showed that anti-selec-
tive products can be obtained through decarboxylation of 5,
but the generality of this method has not been established.
Martin6 showed that an Ireland–Claisen route (6 to 2) can
provide anti-selective products, but this method is limited
to functionalities that can be derived from an allyl group.
Crimmin7 showed that only syn-selective products could be
obtained upon alkylation of ester 7. Recently, Baran8a re-
ported an efficient method for generation of 2,3-disubsti-
tuted succinic acids via a copper-mediated oxidative eno-
DOI: 10.1055/s-0035-1561636; Art ID: st-2015-r0992-l
Abstract An oxidative intermolecular enolate heterocoupling reaction
was employed for the synthesis of anti-2,3-disubstituted succinic acid
mono- and differentially protected diesters. Tactical approaches to ac-
cess all the diastereomers are discussed. The method was applied to the
synthesis of a potent anticancer agent, BMS-906024.
Key words oxidative enolate coupling, chiral succinic acid, pan-Notch
Inhibitor BMS-906024
2,3-Disubstituted succinic acids and derivatives are
found in many drugs and drug candidates and as a sub-
structure of natural products.1,2 In recent work aimed at the
discovery of novel anticancer agents, BMS-654 (Figure 1)
was identified as a potent pan-Notch inhibitor.3 Develop-
ment of further structure–activity relationships (SAR) re-
quired rapid access to either mono-protected or orthogo-
nally di-protected succinic acid esters with anti-configura-
tion in the succinamide portion of the molecule as shown
in BMS-654.
R2 CO2R
O
O
R'
O
R'
O
O
R
O
R2 = allyl
R1
O
R1
O
O
R2
6
5
decarboxylation
Ireland–Claisen
R'
O
R
O
R1
O
2
Me
O
O
O
O
O
O
N
N
R2-X
NH2
2
R2
O
N
N
H
O
3
O
TfO
CO2R
(S)
(S)
R1
N
O
R1
OR
CO2R
HO
R2
Ph
R1
O
7
8
9
3
4
alkylation
oxidative enolate coupling
alkylation
1
Scheme 1 Strategies to synthesize 2,3-disubstituted succinic acids
Figure 1 BMS-654 (Notch1/2/3/4 IC50 = 2/1/3/2 nM)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
C. A. Quesnelle et al.
Letter
Synlett
late coupling (e.g., 8 + 9 to 2). It is the aim of this Letter to
expand the scope of the oxidative enolate coupling reaction
and the strategy for separation of the resulting diastereo-
mers for rapid access to enantio- and diastereomerically
pure 2,3-disubstituted succinic acid mono- and differen-
tially diprotected esters. The method was optimized for the
synthesis of BMS-906024, a highly potent pan-Notch inhib-
itor currently undergoing phase 1 clinical evaluation.3
Scheme 2 depicts the oxidative intermolecular enolate
heterocoupling route employed for the synthesis of 2,3-
disubstituted succinic acid esters. The efficiency of the cop-
per(II) 2-ethylhexanoate mediated heterocoupling process
was optimized by employing a modest excess (1.75 equiv)
of the ester coupling partner 9 and by carrying out enolate
formations in separate reaction vessels. A detailed proce-
dure for a representative enolate coupling reaction (Table 1,
entry 2) is provided.9 As illustrated in Table 1, a variety of
lipophilic moieties were tolerated in this reaction. Lower
yields for the coupling reaction with trifluorobutyl amide
(Table 1, entry 8) may be attributed to the reduced reactivi-
ty of the corresponding enolate. As noted before,8 there was
complete stereocontrol at the oxazolidinone α-carbon and
modest diastereoselectivities were observed in favor of the
desired anti diastereomer at the carbon atom situated β to
the oxazolidinone moiety. Chemoselective removal of the
chiral auxiliary with lithium peroxide10 provided the corre-
sponding succinic acid monoester 11 in excellent yield
while retaining the diastereomeric ratio as determined by
1H NMR spectroscopy.
R2
Ot-Bu
O
O
R2
*
O
O
9
O
(R)
a
O
N
Ot-Bu
O
N
R1
R1
O
(S)
8
10
Li+
O
Al
R2
O
O
O
b
c
Ot-Bu
Ot-Bu
HO
O
*
R2
R1
11
R1
O
12
O
R2
O
R2
d
(R)
(S)
R1
14
Ot-Bu
BnO
HO
*
R1
O
O
O
13
e
f
R2
O
R2
Ot-Bu
OH
HO
BnO
R1
R1
O
O
16
15
Scheme 2 Oxidative enolate coupling route to 2,3-disubstituted suc-
cinic acid esters. * Indicates a mixture of isomers at this center. Reagents
and conditions: (a) (1) 8, LDA, toluene, THF, –78 °C to 0 °C to –78 °C; (2)
9, LDA, toluene, THF, –78°C; (3) Cu(2-ethylhexanoate)2, –78 °C to 40 °C;
(b) LiOH, H2O, H2O2, 0 °C; (c) LDA, THF, Et2AlCl, hexane, –78 °C to 0 °C;
(d) BnBr, K2CO3, DMF; (e) H2, 10% Pd/C, EtOAc; (f) TFA, CH2Cl2, r.t.
Epimerization11 at the β-carbon (bearing the R2 group)
was carried out by subsequent treatment with LDA and di-
ethylaluminum chloride followed by kinetic quench with
methanol to afford 13 as a mixture enriched, in many in-
stances significantly, in the desired anti diastereomer. A
representative example of the exact procedure followed for
the epimerization is given.12 Several factors may influence
the outcome of this transformation. One potentially key
factor driving the selectivity is the kinetic quench of a pos-
tulated seven-membered aluminum enolate 12. Molecular
modelling suggests that the R1 group and one of the ethyl
groups on the aluminum assume a pseudo-axial conforma-
tion, thereby partially blocking one face of the enolate
during the transfer of the proton, resulting in the addition
of the proton from the more open face. Additionally, com-
paring models of aluminum enolates for Table 1, entries 2
and 12, it also appears that the extra bulk of the R2 group in
entry 12 (Table 1) may cause a rotation of the t-Bu group
such that one of the methyl groups of the t-Bu may now en-
croach upon the open face. This may explain the observed
reduction in diastereoselectivity (Table 1, entries 11 and
12). The selectivity may also be dependent on the efficiency
of formation and equilibration of the aluminum enolate. For
sterically encumbered enolates (e.g. Table 1, entries 11 and
12), additional amounts of LDA (3.4 equiv) and Et2AlCl (3.5
equiv) provided a marginal improvement in diastereoselec-
tivity while the use of the standard procedure (ref. 12) re-
sulted in no enrichment.
At this stage, the mixture of the two diastereomers
could be carried forward and subsequent products separat-
ed by chiral chromatography. Alternatively, 13 was convert-
ed into the corresponding benzyl ester under standard con-
ditions and the desired anti diester 14 was separated by sil-
ica gel column chromatography.13 Selective ester
deprotection conditions provided enantio- and diastereo-
merically pure anti-monoesters 15 and 16 in excellent
yields.
Following the initial lead BMS-654 (1, Figure 1), avail-
ability of these 2,3-disubstituted succinic acid monoesters
greatly aided in rapid generation of SAR for pan-Notch in-
hibitors culminating in the identification of 18 (BMS-
906024) as the clinical candidate.3 Table 2 highlights the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
C. A. Quesnelle et al.
Letter
Synlett
Table 1 Synthesis of 2,3-Dialkyl Succinic Acid Esters
Entry
R1
R2
Yield (%),a drb
10
11
47
12
99
13
81
67
48
(1.5:1.0)
1
2
n-Pr
CF3(CH2)2
CF3(CH2)2
(7.6:1.0)
66
(1.6:1.0)
96
(9.0:1.0)
CF3(CH2)2
CF3(CH2)2
91
80
31
(1.5:1.0)
87
(2.5:1.0)
3
4
53
56
63
(1.2:1.0)
99
(14.0:1.0)
CF3(CH2)2
96
97
F
47
(1.4:1.0)
99
(12.3:1.0)
F
5
CF3(CH2)2
65
50
(1.3:1.0)
>99
(9.9:1.0)
c
6
7
8
9
Me2CHCH2
Me3CCH2
CF3CH2
CF3(CH2)2
CF3(CH2)2
CF3(CH2)2
CF3CH2
88
17
76
64
–
60
(1.2:1.0)
d
–
28
(1.0:1.0)
97
(4.6:1.0)
c
–
49
(1.2:1.0)
83
(1.4:1.0)
c
CF3(CH2)2
–
F
F
51
91
(9.0:1.0)
c
10
CF3(CH2)2
>99
–
(nd)e
31
(2.1:1.0)
97f
(3.3:1.0)
11
12
13
CF3(CH2)2
CF3(CH2)2
CF3(CH2)3
55
49
37
53
O
54
(1.3:1.0)
95f
(2.2:1.0)
c
–
27
(1.5:1.0)
d
c
–
–
a Isolated yield.
b Diastereomeric ratios determined by 1H NMR integration.
c Benzyl esters not prepared.
d Epimerization not performed.
e Not determined.
f LDA (3.4 equiv) and Et2AlCl (3.5 equiv) were used.
importance of S,R,S absolute configuration in this series for
achieving high level of pan-Notch potency. As illustrated in
Scheme 3, (3S)-amino-1,4-benzodiazepin-2-one 1714 was
coupled with 15 in the presence of TBTU and triethylamine
to give the corresponding amide. Ester hydrolysis with tri-
fluoroacetic acid was followed by amide formation with
ammonium chloride under standard conditions to produce
18 in good yield. The absolute configuration of 18 was con-
firmed by X-ray diffraction studies.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
C. A. Quesnelle et al.
Letter
Synlett
Table 2 Effect of 2,3-Succinamide Configuration on Notch 1/3 Inhibi-
tory Potency
References and Notes
(1) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem.
Rev. 1999, 99, 2735.
Compd
Configuration
Notch IC50 (nM)
Notch 3
(2) (a) Chukwujekwu, J. C.; de Kock, C. A.; Smith, P. J.; van Heerden,
F. R.; van Staden, J. Planta Med. 2012, 78, 1857. (b) Ishihara, J.;
Tokuda, O.; Shiraishi, K.; Nishino, Y.; Takahashi, K.; Hatakeyama,
S. Heterocycles 2010, 80, 1067. (c) Huang, Y.-L.; Chen, C.-C.; Hsu,
F.-L.; Chen, C.-F. J. Nat. Prod. 1998, 61, 1194. (d) Brown, K.;
Devlin, J. A.; Robins, D. J. Phytochemistry 1984, 23, 457.
(3) Gavai, A. V.; Quesnelle, C.; Norris, D.; Han, W.-C.; Gill, P.; Shan,
W.; Balog, A.; Chen, K.; Tebben, A.; Rampulla, R.; Wu, D.-R.;
Zhang, Y.; Mathur, A.; White, R.; Rose, A.; Wang, H.; Yang, Z.;
Ranasinghe, A.; D’Arienzo, C.; Guarino, V.; Xiao, L.; Su, C.;
Everlof, G.; Arora, V.; Shen, D. R.; Cvijic, M. E.; Menard, K.; Wen,
M.-L.; Meredith, J.; Trainor, G.; Lombardo, L. J.; Olson, R.; Baran,
P. S.; Hunt, J. T.; Vite, G. D.; Fischer, B. S.; Westhouse, R. A.; Lee,
F. Y. ACS Med. Chem. Lett. 2015, 6, 523.
Notch 1
18
19
20
21
22
23
24
25
S,R,S
S,R,R
S,S,S
S,S,R
R,R,S
R,R,R
R,S,S
R,S,R
2
3
1893
>5000
57
1679
>5000
73
646
537
>5000
271
>5000
400
>5000
>5000
(4) Decicco, C. P.; Nelson, D. J.; Corbett, R. L.; Dreabit, J. C. J. Org.
Chem. 1995, 60, 4782.
Me
CF3
O
N
(5) (a) McClure, K. F.; Axt, M. Z. Bioorg. Med. Chem. Lett. 1998, 8,
143. (b) Fujisawa, T.; Igeta, K.; Odake, S.; Morita, Y.; Yasuda, J.;
Morikawa, T. Bioorg. Med. Chem. 2002, 10, 2569.
(6) Pratt, L. M.; Bowles, S. A.; Courtney, S. F.; Hidden, C.; Lewis, C.
N.; Martin, F. M.; Todd, R. S. Synlett 1998, 531.
O
NH3
S
N
a, b, c
Ot-Bu
R
HO
S
O
CF3
(7) Beckett, R. P.; Crimmin, M. J.; Davis, M. H.; Spavold, Z. Synlett
1993, 137.
(8) (a) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 11546. See also: (b) Csákÿ, A. G.; Plumet, J. Chem. Soc.
Rev. 2001, 30, 313. (c) Guo, F.; Clift, M. D.; Thomson, R. J. Eur. J.
Org. Chem. 2012, 4881.
15
17
CF3
Me
O
O
N
R
NH2
N
S
S
H
N
O
(9) Five separate vessels, all appropriately dried, were set up as fol-
lows:
CF3
1) a flask fitted with a stir bar to be used to prepare LDA, purged
with N2;
18
2) a flask containing bis(2-ethylhexanoyloxy)copper, placed
under vacuum for several hours to remove oxygen, then purged
with N2;
3) a flask of appropriate size (this will be the main reaction
flask, the larger the better for efficient heat transfer later in the
procedure was found to be ideal) equipped with a stir bar was
charged with LiCl, placed under vacuum then dried with a heat
gun until all traces of water were removed, then purged with
N2;
4) a flask charged with the amide starting material, purged with
N2;
5) a flask equipped with a stir bar was charged with the ester
starting material, purged with N2.
Scheme 3 Synthesis of BMS-906024. Reagents and conditions: (a) TBTU,
Et3N, DMF (89%); (b) TFA, CH2Cl2 (75%); (c) NH4Cl, EDC, HOBt, Et3N,
DMF (79%).
In conclusion, the oxidative intermolecular enolate het-
erocoupling reaction and subsequent epimerization proto-
col afforded a rapid and efficient entry to enantio- and dia-
stereomerically pure anti-2,3-disubstituted succinic acid
esters in acceptable yields. Differential protection of these
succinic acid esters provided access to each individual dia-
stereomer. This synthetic methodology led to rapid SAR
generation and the identification of BMS-906024 as a po-
tent pan-Notch inhibitor currently undergoing phase 1 clin-
ical evaluation for the treatment of cancer.
Procedure
A 0.5 M solution of LDA was prepared by the addition of a solu-
tion of 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold
(–78 °C) solution of diisopropylamine (5.3 mL, 37.2 mmol) in
THF (59 mL) under N2. The solution was stirred at 0 °C for 15
min.
A solution of (S)-4-isopropyl-3-(5,5,5-trifluoropenta-
Acknowledgment
noyl)oxazolidin-2-one (2.45 g, 9.2 mmol) in toluene (15.3 mL)
was added with stirring to dry LiCl (1.96 g, 46.2 mmol). The
mixture was cooled to –78 °C, and the freshly prepared 0.5 M
solution of LDA (21.0 mL, 10.5 mmol) was added. The reaction
mixture was stirred at –78 °C for 10 min, at 0 °C for 10 min, and
cooled to –78 °C. Meanwhile, the freshly prepared 0.5 M solu-
tion of LDA (37.0 mL, 18.5 mmol) was added to a cold (–78 °C)
solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1
mmol) in toluene (15.3 mL). After 25 min of stirring at –78 °C,
We thank the Department of Discovery Synthesis for resynthesis and
purification support. We also acknowledge Janet Caceres Cortes, the
Departments of Lead Discovery Profiling and Discovery Analytical
Sciences for DMPK assays and compound characterization efforts.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
C. A. Quesnelle et al.
Letter
Synlett
this reaction mixture was transferred via cannula into the cold
(–78 °C) LiCl/enolate solution. After an additional 5 min of stir-
ring at –78 °C, solid powdered bis(2-ethylhexanoyloxy)copper
(9.02 g, 25.8 mmol) was rapidly added to the reaction vessel
through a funnel, and the flask was rapidly recapped with a
septum. The vessel was immediately removed from the cold
bath and immersed into a warm (40 °C) water bath with rapid
swirling. The reaction mixture changed from the initial tur-
quoise to a dark green then to a brown color. After 20 min of
stirring, the reaction mixture was poured into 5% aq NH4OH
(360 mL) and extracted with EtOAc (2 × 150 mL). The combined
organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (Teledyne ISCO CombiFlash
Rf, 0–60% EtOAc in hexanes, RediSep silica gel, 120 g). Concen-
tration of appropriate fractions provided the product tert-butyl
(2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-
carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as a
stirred at –78°C for 5 min, then at 0 °C for 15 min, and trans-
ferred via cannula dropwise (over 25 min) to a cold (–78 °C)
solution of a 1.7:1 ratio for 3-(tert-butoxycarbonyl)-6,6,6-trifluoro-
2-(3,3,3-trifluoropropyl)hexanoic acid (1.99 g, 5.4 mmol) in
THF (18 mL). The mixture was stirred at –78 °C for 15 min, then
at 24 °C for 15 min, and again at –78°C for 15 min. A 1 M solu-
tion of diethylaluminum chloride in hexanes (11.4 mL, 11.4
mmol) was added dropwise via syringe, and stirring was con-
tinued at –78 °C for 10 min, at 24 °C for 15 min, and again at –78 °C
for 15 min. MeOH (25 mL) was rapidly added, and the flask was
swirled vigorously while warming to room temperature. The
reaction mixture was concentrated to ca. 25% of the original
volume. EtOAc (100 mL), aq 1 M HCl (50 mL), and ice (75 g) were
added. The aqueous layer was extracted with EtOAc (2 × 100
mL). The combined organics were washed with a solution of a
mixture of KF (2.85 g) in water (75 mL) and aq 1 M HCl (13 mL),
then subsequently washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure to provide
the product (2R,3S)-3-(tert-butoxycarbonyl)-6,6,6-trifluoro-2-
(3,3,3-trifluoropropyl)hexanoic acid (2.13 g, >99%) as a pale
yellow oil. Relative integration of the t-Bu peaks in 1H NMR
established a 9:1 ratio for the anti/syn diastereomers, respec-
tively.
1
pale yellow oil. H NMR indicated that the product was a 1.6:1
mixture of diastereomers, as determined by integration of the
multiplets at 2.74 and 2.84 ppm. 1H NMR (400 MHz, CDCl3): δ =
4.43–4.54 (2 H, m), 4.23–4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54,
6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H,
ddd, J = 10.29, 6.27, 4.02 Hz), 2.37–2.48 (2 H, m), 2.20–2.37 (3 H,
m), 1.92–2.20 (8 H, m), 1.64–1.91 (5 H, m), 1.47 (18 H, s), 0.88–
0.98 (12 H, m).
anti-Isomer: 1H NMR (400 MHz, CDCl3): δ = 2.64–2.76 (2 H, m),
2.04–2.35 (4 H, m), 1.88–2.00 (2 H, m), 1.71–1.83 (2 H, m), 1.48
(9 H, s).
(10) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(11) Xue, C.-B.; Decicco, C. P.; Cherney, R. J.; Arner, E.; Degrado, W.
F.; Duan, J.; He, X.; Jacobson, I.; Magolda, R. L.; Nelson, D. WO
9851665, 1998.
(12) To a cold (–78 °C), stirred solution of DIPA (1.7 mL, 11.9 mmol)
in THF (19 mL) under nitrogen was added a 2.5 M solution of n-
BuLi in hexanes (4.8 mL, 12.0 mmol). The reaction mixture was
(13) The residue was purified by flash chromatography using a Tele-
dyne ISCO CombiFlash Rf system with an external ELS detector,
and a gradient from 60–100% toluene and hexane.
(14) Rittle, K. E.; Evans, B. E.; Bock, M. G.; DiPardo, R. M.; Whitter, W.
L.; Homnick, C. F.; Veber, D. F.; Freidinger, R. M. Tetrahedron Lett.
1987, 28, 521.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E