BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.8b00139

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.

Full text of DOI:10.1021/acs.orglett.8b00139

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for
Asymmetric Hydrogenation
Guisheng Li,* Olga V. Zatolochnaya,* Xiao-Jun Wang, Sonia Rodríguez, Bo Qu,
Jean-Nicolas Desrosiers, Hari P. R. Mangunuru, Soumik Biswas, Daniel Rivalti,
Shuklendu D. Karyakarte, Joshua D. Sieber, Nelu Grinberg, Ling Wu, Heewon Lee, Nizar Haddad,
Daniel R. Fandrick, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake
Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, Ridgefield, Connecticut 06877, United
States
S
* Supporting Information
ABSTRACT: Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-
dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-
catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An
efficient route toward various analogues was also established, giving access to phosphines
with different electronic and steric properties. The newly obtained ligands demonstrated
high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and
trisubstituted enamides. This new class of ligands is complementary to previously
described bidentate benzooxaphosphole ligands BIBOP.
he development of chiral ligands remains a central theme in
homogeneous asymmetric catalysis. Since the discovery of
bidentate biaryl dihydrobenzooxaohosphole (BABIPhos) li-
gands possessing an achiral biaryl backbone and their application
in asymmetric hydrogenation of functionalized di- and
trisubstiluted alkenes.
T
BINAP,1 numerous atropisomeric phosphine ligands based on a
biaryl backbone have been developed and established as key tools
in asymmetric hydrogenation and other catalytic transformations
(Figure 1A).2 Advances in this area are focused on modification
To access this class of ligands, we aimed to developed
transition-metal catalyzed reductive homocoupling of aryl triflate
2 to construct a biaryl backbone.4,5 Notably, bidentate biaryl
ligands are traditionally obtained by introduction of a phosphine
moiety into preformed bis-functionalized biaryl derivatives.2
Thus, under Pd-catalyzed homocoupling conditions using
sterically hindered o-Tol3P ligand 2a can be converted to the
desired biaryl phosphine oxide, albeit in low conversion and with
poor selectivity (Table 1, entry 1). Hydrolysis and reduction of
the triflate group were the major observed side reactions.
Notably, high temperature (140 °C) was required to initiate the
homocoupling. Screening of the ligands revealed that biaryl
monodentate ligands XPhos or BI-DIME6 provided full
conversion and minimized byproduct formations (entries 2
and 4). More sterically hindered ligands, such as t-BuXPhos or
Me-BIDIME, were less effective (entries 3 and 5). In general,
bidentate ligands did not promote homocoupling (entries 6 and
7), with the exception of DTBPF (entry 8), which provided
excellent conversion. However, in this case, purification of the
dimeric phosphine oxide from the reaction mixture was found to
be challenging. The presence of an external halide source proved
to be crucial, as only traces of product were observed without any
additives (entry 9). Tetraethylamonium iodide was identified as
an optimal salt leading to the clean formation of the product
Figure 1. Bidentate biaryl phosphine ligands.
of a chiral biaryl skeleton for fine-tuning of the steric and
electronic properties of the ligand, as well as its dihedral angle.
We have envisioned that shifting chirality from a biaryl axis into
phosphorus atom can offer a complementary mode of stereo-
induction around the metal center while preserving the rigidity of
the transition state due to the biaryl architecture of the ligand.
Given our recent success in development of chiral ligands based
on a benzooxaphosphole core,3 we were naturally interested in
further expanding our library with biaryl bidentate phosphorus
ligands (Figure 1B). Herein, we report a new series of P-chiral
Received: January 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reductive Homocoupling of 2a
Scheme 2. Synthesis of C7,C7′-Substituted BABIPhos
a
Analogues
a
Conditions: (a) TBDPSCl (1.1 equiv), Et3N (1.3 equiv), DMAP (5
mol %), THF, rt, 88%; (b) NBS (1.03 equiv), CH3CN, rt, quant; (c)
TBAF (0.63 equiv), THF, rt; 83%; (d) BnBr (1.05 equiv), K2CO3 (1.2
equiv), DMF, rt, quant; (e) ArB(OH)2 (1.2 equiv), PdCl2(PPh3)2 (2
mol %), Na2CO3 (2.4 equiv), dioxane/water, 80 °C; (f) Pd/C (10 wt
%), H2 (300 psi), MeOH, rt; (g) PhNTf2 (1.1 equiv), Et3N (2.0
equiv), CH2Cl2, rt; (h) Pd2(dba)3 (2.5 mol %), XPhos (7.5 mol %),
KBr (2 equiv), Zn (3 equiv), DMAc, 140 °C; (i) (Me2HSi)2O (3
equiv), Ti(O-i-Pr)4 (2.3 equiv), THF, 65 °C.
a
Conditions: 2a (1 equiv), Pd2dba3 (2.5 mol %), Ligand (7.5 mol %),
b
MX (2 equiv), Zn dust (3 equiv), DMAc, 140 °C, 3h. Relative HPLC
integration of 2a, 3a, and other side products.
the aryl triflates and the desired biaryls 3c−f were isolated in 78−
96% yields. Finally, phosphine oxide reduction completed the
synthesis of bis-benzooxaphospholes 1c−f of different electronic
nature. It is noteworthy that this newly developed strategy for the
synthesis of modified triflates 2 opens avenue for expansion not
only BABIPhos ligands’ library but also related families of
previously disclosed ligands, such as BIBOP, BI-DIME, and
other benzooxaphosphole series.3
(entry 11). Importantly, Zn dust was found to be essential, as
only traces of product were observed if Zn mesh was used.
Using the optimized reaction conditions (Table 1, entry 11),
aryl triflate 2a was converted to the corresponding dimeric
phosphine oxide in 78% yield after crystallization (Scheme 1).
a
Scheme 1. Synthesis of BABIPhos Ligands
Furthermore, various C2,C2′-substituted BABIPhos ana-
logues could be easily accessed by modification of the parent
phosphine oxide 3a via a deprotonation/alkylation strategy
previously employed for the synthesis of various benzooxaphosp-
hole ligands, such as POP, BoQPhos, and JoshPhos.7
Gratifyingly, this procedure was also suitable for the synthesis
of modified bis-benzooxapospholes 1g−i allowing for further
modulation of steric properties around the phosphorus atom of
the ligands (Scheme 3).
a
Conditions: (a) 2a (1 equiv), Pd2(dba)3 (2.5 mol %), BI-DIME (7.5
mol %) or XPhos (7.5 mol %), Et4NI (2 equiv), Zn (3 equiv), DMAc,
140 °C; (b) (Me2HSi)2O (3 equiv), Ti(O-i-Pr)4 (2.3 equiv), THF, 65
°C.
Scheme 3. Synthesis of C2,C2′-Substituted BABIPhos
a
Analogues
Reduction of this product furnished the desired bis-phosphine 1a
(BABIPhos) in high yield. Additionally, analogous bis-
benzooxaphosphole 1b bearing a less hindered phenylphosphine
moiety was obtained following this route.
In order to expand the newly discovered family of phosphines,
an efficient route for the synthesis of aryl triflates 2 possessing
substitution at the C7 positions has been developed next
(Scheme 2). The route commenced with the synthesis of aryl
bromide 5 via bromination of common intermediate 46 after
protection of phenol with bulky TBDPS group in order to avoid
bromination at the C5 position. Further protecting group
manipulations led to the benzyl-protected aryl bromide 6. Its
subsequent derivatization by Suzuki cross-coupling with various
boronic acids delivered a series of benzooxaphosphole oxides 7
bearing an extended aryl backbone. These intermediates were
then converted to the corresponding aryl triflates 2c−f in high
yields. The developed Pd-catalyzed reductive homocoupling was
effective regardless of the electronic nature of C7-substituents of
a
Conditions: (a) LDA (2.5 equiv), RX (2.5 equiv; MeI for 3g, i-PrI for
3h, 2-methoxy-6-(phenylsulfonyl)pyridine for 3i), THF, −78 °C to rt;
(b) (Me2HSi)2O (3 equiv), Ti(O-i-Pr)4 (2.3 equiv), THF, 65 °C.
To gain information on the coordination ability of the newly
obtained bisphosphines, complex [Rh(S,S)-BABIPhos)(NBD)]-
BF4 was synthesized (Figure 2). As predicted, BABIPhos binds to
the Rh center though both phosphorus atoms form a seven-
membered ring chelate. Notably, the distance between Rh and P
atoms as well as the P−Rh−P angle are similar to those described
for analogous [Rh((R)-BINAP)(NBD)]BF4.8 On the other
B
DOI: 10.1021/acs.orglett.8b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indicating the importance of the t-Bu substituent on the
phosphorus atom for stereoinduction. Testing of ligands 1c−f
revealed that reactivity and selectivity of the reduction is
independent of the electronic nature of biaryl backbone, as in
all cases high performance was observed (entries 3−6). The
ligands possessing C2,C2′-substitution were not suitable for this
transformation as loss of reactivity and/or selectivity was noted
in these reactions (entries 7−9). To further verify the robustness
of Rh−BABIPhos catalytic system, other reaction parameters
were quickly examined. The reaction was equally efficient with
different Rh-sources (entries 10 and 11), in several solvents
(entries 12 and 13), and under various hydrogen pressure
(entries 14 and 15). A slight decrease of enantioselectivity was
found only under temperatures higher than 60 °C (entry 16).10
Hydrogenation of various trisubstituted enamides in the
presence of 1 mol % of Rh−BABIPhos catalyst was investigated
next (Table 3). Thus, different 2-amino-3-phenyl acrylates were
Figure 2. X-ray structure of [Rh((S,S)-1a)(NBD)]BF4 complex.
hand, the biaryl dihedral angle is considerably smaller in the case
of the BABIPhos-containing complex, compared to that of
BINAP-based analogue, which creates a more rigid environment
around the metal center and can potentially lead to unique
catalytic properties of the complex.
Encouraged by the structural features of the BABIPhos−Rh
complex, we were intrigued to test its catalytic abilities. For that
purpose, we selected hydrogenation of enamides, as this
transformation became a measure for efficiency of emerging
ligands,9 including the ones developed by our laboratories.3a,7a
Therefore, trisubstituted enamide 8a was subjected to hydro-
genation in the presence of Rh(NBD)2BF4 and newly obtained
ligands (Table 2). Gratifyingly, employment of parent
BABIPhos ligand (1a) led to an excellent reactivity and
selectivity of the reaction delivering the desired α-amino acid
derivative 9a in >99% ee (entry 1). In comparison, reaction in the
presence of analogous ligand (1b) possessing phenyl phosphine
moiety yielded the product as a racemic mixture (entry 2),
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of
a
Trisubstituted Enamides
Table 2. Screen of Reaction Conditions for Rh-Catalyzed
a
Asymmetric Hydrogenation of Enamides
a
Conditions: 8 (1 equiv), Rh(NBD)2BF4 (1 mol %), BABIPhos (1a)
(1 mol %), MeOH, 100 psi of H2, 20 °C.
successfully converted to α-amino acid derivatives in high yields
and >98% ee, regardless of the protecting group on nitrogen
(entries 1−3) or the nature of the ester (entry 4). The
hydrogenation of acid-containing analogue 8e was also efficient,
although a slight decrease of enantioselectivity (98% ee) was
observed. Notably, Rh-catalyzed hydrogenation of this substrate
in the presence of (S)-BINAP gave the product in 84%
enantiopurity.1 Additionally, different substitution of the double
bond is well tolerated, including alkyl (8f), electron-rich (8g),
electron-deficient (8h) aryl, and heteroaryl (8i,j) groups. The
reduction of 3,3-disubstituted acrylate derivatives leading to β-
amino acid analogues gave the desired products 9k and 9l in good
yield and moderate selectivity.
The generality of this system was further confirmed by
hydrogenation of disubstituted enamides 10 (Scheme 4). High
yields and enantioselectivities were achieved under standard
reaction conditions for both phenyl- (10a) and naphthyl-
substituted (10b) substrates.
In order to streamline selection between benzooxaphosphole
based ligands, the catalytic properties of BABIPhos were
compared to those of another dimeric ligand BIBOP, for
a
Conditions: 8a (1 equiv), Rh(NBD)2BF4 (1 mol %), ligand (1 mol
%), solvent (0.1 M).
C
DOI: 10.1021/acs.orglett.8b00139
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
Scheme 4. Rh-Catalyzed Asymmetric Hydrogenation of
Disubstituted Enamides
a
CCDC 1816605 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
a
Conditions: 10 (1 equiv), Rh(NBD)2BF4 (1 mol %), BABIPhos (1a)
(1 mol %), MeOH, 100 psi of H2, 20 °C.
*E-mail: guisheng.li@boehringer-ingelheim.com.
*E-mail: olga.zatolochnaya@boehringer-ingelheim.com.
ORCID
which highly enantioselective hydrogenation of enamides was
previously reported (Table 4).3a It was found that BABIPhos
Olga V. Zatolochnaya: 0000-0003-3680-2913
Xiao-Jun Wang: 0000-0002-9403-3502
Bo Qu: 0000-0001-7347-0108
Table 4. Comparison between BABIPhos and BIBOP in Rh-
Catalyzed Asymmetric Hydrogenation of Enamides
a
Jean-Nicolas Desrosiers: 0000-0003-3859-2390
Hari P. R. Mangunuru: 0000-0002-5038-9654
Joshua D. Sieber: 0000-0001-6607-5097
Daniel R. Fandrick: 0000-0002-4522-0643
Notes
The authors declare no competing financial interest.
entry
substrate
ligand
er
1
2
3
4
5
6
8a
1a
99.7:0.3
96.5:3.5
91:9
ACKNOWLEDGMENTS
We thank Scott Pennino and Keith McKellop of Boehringer
Ingelheim Pharmaceuticals for HRMS analysis.
■
8a
BIBOP
1a
8k
8k
BIBOP
1a
97:3
10a
10a
98:2
REFERENCES
■
BIBOP
96:4
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a
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Chin. J. Chem. 2018, 36, 153. Notably, the authors declare that attempts
for homocoupling of aryl triflate 2a directly were not successful.
(6) Li, G.; Wang, X.-j.; Zhang, Y.; Tan, Z.; DeCroos, P.; Lorenz, J. C.;
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Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2010, 12, 1104. (b) Qu,
(1a) is the ligand of choice for reduction of 2-amino acrylate 8a,
giving access to the corresponding α-amino acid in 99.7:0.3 er
versus 96.5:3.5 er in the case of hydrogenation with BIBOP
under identical reaction conditions (entry 1 and 2). On the other
hand, BIBOP outperformed BABIPhos in reduction of 3-amino
acrylate 8k (entry 3 vs 4). In case of disubstituted enamide 10a,
only slight advantage of BABIPhos over BIBOP was found with
both ligands delivering synthetically useful results (entries 5 and
6).
In conclusion, a novel family of dimeric biaryl ligands based on
a rigid benzooxaphosphole core (BABIPhos) has been disclosed.
Palladium-catalyzed reductive homocoupling of aryl triflates was
adopted for sterically demanded benzooxaphospholes, giving
straightforward access to biaryl bisphosphines oxides and
subsequently to the corresponding bisphosphine ligands. High
catalytic performance of these ligands was showcased in Rh-
catalyzed hydrogenation of alkenes, thus demonstrating high
potential of these ligands for enantioselective catalysis.
Applications of this new set of bisphosphine ligands to other
catalytic reactions are currently under investigation and will be
disclosed in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00139.
Experimental procedures, NMR spectra, HPLC chroma-
tograms (PDF)
D
DOI: 10.1021/acs.orglett.8b00139
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(10) See the SI for more details.
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