Chiral electron-rich PNP ligand with a phospholane motif: Structural features and application in asymmetric hydrogenation

Article abstract of DOI:10.1021/acs.orglett.0c03159

Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand, the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging diaryl ketones: up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining step.

Full text of DOI:10.1021/acs.orglett.0c03159

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Letter
Chiral Electron-Rich PNP Ligand with a Phospholane Motif:
Structural Features and Application in Asymmetric Hydrogenation
Heng Wang,∥ Yao Zhang,∥ Tilong Yang, Xiaochong Guo, Quan Gong, Jialin Wen,* and Xumu Zhang*
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ABSTRACT: Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand,
the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-
sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the
phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also
discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging
diaryl ketones: up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the
substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining
step.
developed5 from enantiopure starting materials. With more
he observation of a stable chiral phosphorus center at
Troom temperature by Mislow and Horner in the mid- electron-donating property and a more rigid backbone,
revolutionarily high efficiency and enantioselectivity was
achieved in Rh-catalyzed AH of dehydro-amino acids. The
key structural motif in this family was 1-tert-butyl-phospholane,
a chiral rigid five-member ring. As a continuous interest in
developing chiral phosphorus ligands, we have been expecting
the application of this phospholane structural motif in chiral
tridentate ligand. On the basis of our experience in the C2-
symmetric tridentate ligand ambox,6 rigid oxazoline rings in
ambox could increase the conformational restriction of chiral
substituents against substrates. The integration of ZhangPhos
synthon with tridentate PNP ligand design is practical. (Figure
1)
1960s had been the foundation for the development of chiral
phosphine ligands.1 Over the past 60 years, many successful P-
stereogenic bisphosphines such as DIPAMP, BisP*, TangPhos,
DuanPhos, and QuinoxP* have been developed.2 Compared to
bisphosphine ligands with backbone chirality, P-chirogenic
ligands have a stereocenter closer to the transition metals and
therefore might deliver more efficient enantioinduction in
catalysis. Usually a rigid backbone and bulky substituents were
believed to be the key features for achieving high
enantioselectivity for P-stereogenic ligands because this kind
of ligand could offer a relatively stable chiral pocket and
therefore avoid deformation in the enantiodetermining
transition states.
In 2002, Tang and Zhang developed an electron-rich chiral
bisphosphine TangPhos with a phospholane motif,3 which has
been applied in Rh-catalyzed asymmetric hydrogenation (AH)
and many other transition-metal catalyzed asymmetric
reactions. The only drawback was the synthetic approach:
only one enantiomer could be obtained due to the use of
(−)-sparteine in the lithiation step. In 2005, a de novo
synthesized bisphosphine ligand DuanPhos4 was developed,
and both enantiomers could be obtained by resolution. In
2010, the 3rd-generation ligand, ZhangPhos, was successfully
Despite that PNP ligands were applied to a series of metal
complex catalysts for homogeneous hydrogenation,7 the
development of chiral PNP-type ligands was relatively slow.
Many chemists such as Zhang, Abdur-Rashid, Kuriyama,
Received: September 19, 2020
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© XXXX American Chemical Society
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With availability of both enantiomers, pentavalent-phospho-
rus-containing cyclic compound 3 (ZhangPhos monomeric
fragment) has been a valuable synthon for ligand synthesis.
Previous synthesis of 3 involved the use of volatile and
hazardous tBuPH2. We therefore improved the synthetic route
with Knochel’s method.9 The new synthetic route starts from
commercially available (R,R)-diol 1. Treatment with mesyl
chloride and triethylamine at 0 °C and then with sodium
iodide afforded diiodide 2 in 79% yield. This (R,R)-diiodide
was converted to bis-zinc reagent by reaction with zinc
t
powder. The in situ formed organozinc reacted with BuPCl2
overnight at 0 °C, followed by addition of sulfur powder, which
fulfilled the synthesis of ZhangPhos fragment 3 in 22% yield.
Although the formation of bis-zinc reagent gives a high yield,
the following cyclization step is problematic.
Figure 1. Novel PN(H)P ligand for ketone reduction.
s
Deprotonation of 3 with BuLi-TMEDA at −78 °C and the
Morris, Imamoto, Kirchner, Mezzetti, and Beller have put
tremendous efforts into chiral PNP-type ligand development.8
The first chiral PNP-type ligand was reported at 1995 by
Bianchini and Graziani;8a their iridium complex can achieve
over 99% conversion and 54% ee for transfer hydrogenation of
α,β-unsaturated ketones. Despite the high reactivity of Ir, Ru,
Fe, and Mn catalysts with PNP-type ligands, the enantiomeric
induction has long been a problem. In 2017, Morris reported a
chiral PNP with a chiral side arm;8j its iron complex can
achieve over 95% ee and 99% conversion for acetophenone.
However, the reaction scope was somewhat limited. Actually,
to our best knowledge, high enantioselectivity and broad
substrate scope could hardly be achieved at the same time for
most of the transition metal PNP catalysts.
According to our expertise, although the philosophy of
ligands design for tridentate ligands are different from that for
bisphosphine ligands, a rigid skeleton has always been favored
in order for conformational restriction. In addition, the C2-
symmetry will enable the reaction at both top and bottom
sides, and an equal chance for reaction increases the reactivity.
In comparison, only one reaction site is normally favored for
tridentate catalysts with C1-symmetry. While bulky and
electron-donating substituents will be essential in the design
for PNP tridentate ligands because a bulky group can provide a
higher energy difference for enantioselectivity, an electron-
donating group provides a higher reactivity for the hydride
transfer step. Herein we report a novel chiral PNP with both a
highly rigid side arm and electron-rich property. This novel
ligand has been successfully applied in iridium-catalyzed AH of
biaryl ketone with high enantioselectivities (Figure 2).
following addition of DMF yielded chiral aldehyde 4 in 58%
yield. Reductive amination10 was then carried out by mixing 4
with NH4Cl, Ti(OiPr)4, and NaBH4 stepwise in ethanol. Chiral
aminophosphine sulfide (5) was obtained in 78.6% yield. The
reduction of phosphine sulfide was crucial. Traditionally, air-
sensitive P-stereogenic ligands were obtained by deboration
from aminophosphine-borane8g,h,m,n in the last step. However,
in this case we needed to find a reagent which could reduce
aminophosphine sulfide efficiently with both reactive N−H
and eight stereocenters intact, and also, the reaction should be
relatively clean for easier separation of the highly air-sensitive
product. Fortunately, we found that P(NMe2)3 could do this
reaction at 130 °C in 60 h or at 140 °C in 36 h;11 full
conversion was observed by 31P NMR, and 92% isolation yield
was achieved. (Scheme 1)
Scheme 1. Synthesis of Heng-PNP
In order to determine the structural feature of this new
ligand, we prepared its iron complex according to the
literature.12 A white precipitate was observed (Figure 3,
compound 6) after mixing Heng-PNP with FeBr2·THF2. When
bubbling CO into the reaction system, a dark purple clear
solution was formed, which was tentatively assigned to Heng-
PNP/Fe(CO)Br2 (see Supporting Information). Complex 6
has a distorted square pyramidal geometry. The angles of
P(1)−Fe(1)−N(1) and P(2)−Fe(1)−N(1) were 80.1° and
76.9°, different from 78.08° and 77.82° in [i‑PrPN(H)P-
FeBr2].13 The bite angle P(1)−Fe(1)−P(2) in 6 was 155.47°,
larger than 151.363° in [i‑PrPN(H)P-FeBr2]. These differences
Figure 2. Representative catalysts for ketone hydrogenation.
B
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Figure 3. Crystal structure of Heng-PNP/FeBr2 6 (CCDC No.
2006388). Displacement ellipsoids are drawn at the 30% probability
level; hydrogen atoms omitted for clarity. Selected bond lengths (Å):
Fe(1)−P(1) = 2.529, Fe(1)−P(2) = 2.526, Fe(1)−N(1) = 2.256,
Fe(1)−Br(1) = 2.464, Fe(1)−Br(2) = 2.482. Selected angles (deg):
P(1)−Fe(1)−P(2) = 155.4(7), P(1)−Fe(1)−N(1) = 76.9(6), P(2)−
Fe(1)−N(1) = 80.1(5), Br(1)−Fe(1)−Br(2) = 115.5(9), Br(1)−
Fe(1)−P(1) = 93.6(6), Br(2)−Fe(1)−P(1) = 96.6(7), Br(1)−
Fe(1)−P(2) = 100.1(4), Br(2)−Fe(1)−P(2) = 95.5(1), N(1)−
Fe(1)−Br(1) = 103.4(0), N(1)−Fe(1)−Br(2) = 140.8(8).
Figure 4. Optimized structure of IrIII(Heng-PNP)H3 with DFT
calculations.
were probably attributed to the rigid side arm. The chiral
pocket of the NH side was visually narrower compared to the
other side.
We then analyzed the structural features of Heng-PNP in
octahedral d6 metals since such kinds of organometallic
complexes have been widely utilized in asymmetric catalysis.
scope. Efforts on direct AH of benzophenones still deserve
to be made. We therefore chose this kind of challenging ketone
as our target. With 1 mol % Ir/Heng-PNP catalyst and 10 mol
14
t
The structure of IrIII(Heng-PNP)H3 was optimized by DFT
% BuOLi, a range of unsymmetrical benzophenones were
calculation. In the optimized structure of IrIII(Heng-PNP)H3,
the chiral pocket of the NH side is visually larger than the
other side (Figure 4, front view). The bulky tert-butyl group
reaches out due to the conformational restriction by the
phospholane ring (side view). From the top view we could
conclude that bulkiness is located at the northeast and
southwest quadrant (marked with purple in quadrant analysis).
When the substrate falls into the chiral pocket from the top,
the carbonyl moiety is anchored to the nitrogen atom due to
the NH effect.15 The larger group should be located at the
empty southeast quadrant and the smaller group at the
crowded southwest quadrant. We rationalized that enantiodis-
crimination was therefore achieved in ketone reduction.
AH of ketone has been developed as a powerful tool for the
production of enantiopure chiral alcohols. In 1998, Noyori16
reported a Ru/bisphosphine-diamine catalyst which could
achieve AH of simple ketones under mild conditions, and over
80% ee and 2.4 million TON were observed. Chiral PNN-type
ligands such as SpiroPAP, f-amphox developed by Zhou17 and
Zhang18 have been a great success; up to 99.9% ee and over-a-
million TONs were achieved with their iridium catalysts. Also,
a lutidine-based PNN-Mn catalyst19 was developed very
recently; up to 98% ee and 9800 TON were achieved by
Ding and Han. Actually, to our best knowledge, high
enantioselectivity and broad substrate scope could hardly be
achieved at the same time for most of transition metal PNP
catalysts. Although unsymmetrical benzophenones were
successfully reduced by a few catalytic systems,20 direct
hydrogenation of this kind of substrate has still suffers
problems such as efficient enantioinduction and narrow
hydrogenated in hexane (for detailed reaction optimization,
see Supporting Information). Excellent enantioselectivities
were obtained (Scheme 2). With the catalyst, mono-ortho-
substituted benzophenones were hydrogenated with high
enantioselectivities.
AH of those substrates with di-ortho position has been
challenging because of the small steric differences from both
rings, and especially hard for the substrates with similar
electron property on both phenyl rings. To our best
knowledge, Wills’ transfer hydrogenation catalyst20g success-
fully solved this problem very recently. Under the reaction
conditions, desired enantioselectivities were achieved for
several di-ortho-substituted ketones. Compared to f-am-
phox,18,21 Heng-PNP showed superiority in the AH of such
category of substrates (see Supporting Information). The
TON reached 500 for the model substrate under the optimized
conditions.
To illuminate the enantioinduction model, DFT calculation
was conducted. We proposed the catalytically active species
according to the literature.16 Enantioselectivity could be
explained via the interaction between a special chiral pocket
provided by ligand L and the substrate. The geometry of
benzophenone is not coplanar: aryl groups twist with a
dihedral angle. For example, the phenyl ring of 2-
bromobenzophenone conjugates better with the carbonyl
(the dihedral angle is 13°), while the Br-substituted benzene
ring twists at 64° (Figure 5). The DFT calculated ee value was
95% for AH of 9a, which was in agreement with the
experimental observation. The optimized structures enlight-
ened us that the chiral pocket of Heng-PNP/IrIII(H)3 could
C
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Scheme 2. Asymmetric Hydrogenation of Substituted
b
Benzophenone with Ir/Heng-PNP
Figure 5. Distortion, interaction, and activation energies for TS(R)
and TS(S). Blue: distortion energy of 2-bromobenzophenone, red:
distortion energy of [IrH3], black: interaction energy, black (shaded):
activation energy, in kcal/mol.
forward to the application of this ligand in transition-metal-
catalyzed asymmetric reactions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
a
b
Reactions were carried out for 48 h. Reaction conditions: ketone
(0.05 mmol, 1 equiv), tBuOLi (10 mol %), precatalyst 1 (1 mol %) in
hexane under 50 atm H2 at room temperature for 24 h. Isolated yields.
ee values were determined by HPLC on a chiral stationary phase.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03159.
Detailed experimental procedures and characterization
data (PDF)
distinguish two aryl groups by breaking the conjugation
between phenyl ring and carbonyl in the unfavorable transition
state TS(S). We carried out distortion/interaction analysis
using Houk’s model.22 We found that the distortion energy of
2-bromobenzophenone in TS(S) is higher than that in TS(R).
The loss of the conjugation of the substrate in TS(S) makes
the distortion energy of 2-bromobenzophenone and the energy
of TS(S) higher than TS(R).
Accession Codes
CCDC 2006388 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
In summary, an electron-rich PNP ligand Heng-PNP was
developed. The structural property of this novel chiral ligand
was analyzed with its iron(II) complex. The spatial feature was
analyzed by crystal structure and DFT calculation. This
tridentate ligand has been applied in Ir-catalyzed asymmetric
hydrogenation of a range of benzophenones and desired
enantioselectivities were obtained. Impressively, o,o′-disubsti-
tuted biaryl ketones could also be hydrogenated with high ee
values. The chiral pocket of Heng-PNP indicated a new
enantioinduction model for biaryl ketones. We are looking
AUTHOR INFORMATION
Corresponding Authors
■
Jialin Wen − Shenzhen Grubbs Institute and Department of
Chemistry and Academy for Advanced Interdisciplinary Studies,
Southern University of Science and Technology, Shenzhen
518055, China; orcid.org/0000-0003-3328-3265;
Email: wenjl@sustech.edu.cn
Xumu Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
D
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pubs.acs.org/OrgLett
Letter
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0608; Email: zhangxm@sustech.edu.cn
Authors
Heng Wang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; Department of Chemistry, Temple
University, Philadelphia, Pennsylvania 19122, United States
Yao Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Tilong Yang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0002-9126-
8840
Xiaochong Guo − Shenzhen Grubbs Institute and Department
of Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
Quan Gong − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China
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diphosphine Ligands (R)- and (S)-(α-Methylbenzyl)bis(2-
(diphenylphosphino)ethyl)amine and Their Use in the Enantiose-
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(d) Abdur-Rashid, K. Transfer Hydrogenation Process and Catalysts.
U.S. Patent 20050107638, 2005. (e) Yasunori, I.; Wataru, K.; Takaji,
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Tridentate Ligand and Manufacturing Method and Usage Therefor.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03159
Author Contributions
∥H.W. and Y.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Drs. Kexuan Huang and Renchang Tan (alumni of
the Zhang Group in Rutgers) for the altruistic sharing of their
valuable experience in ligand synthesis. This project was
financially supported by the National Natural Science
Foundation of China (21801118), Guangdong Provincial
Key Laboratory of Catalysis (No. 2020B121201002), Science,
Technology and Innovation Commission of Shenzhen
(KQTD20150717103157174).
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