Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones: Via dynamic kinetic resolution

Article abstract of DOI:10.1039/c8sc00434j

A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones via dynamic kinetic resolut

Full text of DOI:10.1039/c8sc00434j

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Zatolochnaya, S. Rodríguez, Y. Zhang, K. S. Lao, S. Tcyrulnikov, G. Li, X. Wang, B. Qu, S. Biswas, H. P. R.
Mangunuru, D. Rivalti, J. D. Sieber, J. Desrosiers, J. C. Leung, N. Grinberg, H. Lee, N. Haddad, N. K. Yee, J.
Song, M. C. Kozlowski and C. H. Senanayake, Chem. Sci., 2018, DOI: 10.1039/C8SC00434J.
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Copper-Catalyzed Asymmetric Hydrogenation of 2-Substituted
Ketones via Dynamic Kinetic Resolution
Olga V. Zatolochnaya,a Sonia Rodríguez,*a Yongda Zhang,*a Kendricks S. Lao,a Sergei Tcyrulnikov,b
Guisheng Li,a Xiao-Jun Wang,a Bo Qu,a Soumik Biswas,a Hari P. R. Mangunuru,a Daniel Rivalti,a
Joshua D. Sieber,a Jean-Nicolas Desrosiers,a Joyce C. Leung,a Nelu Grinberg,a Heewon Lee,a Nizar
Haddad,a Nathan K. Yee,a Jinhua J. Song,a Marisa C. Kozlowski,*b Chris H. Senanayakea
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new class of tunable heterophosphole dimeric ligands (O-BABIPhos and N-BABIPhos) have been designed and
synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones
and related heteroaryl ketones via dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers
with up to >99:1 dr and 98:2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT
calculations
revealed
a
novel
heteroligated
dimeric
copper
hydride
transition
state.
Transition metals such as Pd, Pt, Rh, Ru and Ir have been
widely utilized for a large variety of catalytic transformations.[
1]
However, the longꢀterm sustainability of such processes has
C2 vs C4 connectivity
become an increasing concern due to the high cost, limited
abundance and observed toxicity of noble metals.[2] To
overcome these issues, in recent years, there has been a major
endeavor in the field to explore new synthetic methods utilizing
nonꢀprecious metal catalysis.[3] To this end, we have recently
reported several novel methodologies employing Fe, Ni, Co and
Cuꢀcentered catalysts.[4] For example, our laboratories have
developed the first Cuꢀcatalyzed asymmetric propargylation
reaction of aldehydes[4a] whereas the key to obtaining high
enantioselectivities was the use of our bidentate MeOꢀBIBOP
ligand to control the stereochemical course of the reaction.
X
P
P
X
R
X
H
X
P
X
P
2
t-Bu
t-Bu
P
t-Bu
4
H
our previous
work
ref. 4, 5
this work
R
t-Bu
t-Bu
R
R
X = O, NR
BIBOP family
O-BABIPhos and
N-BABIPhos families
Scheme 1. Dimeric Benzoheterophosphole Ligands.
the ligand to afford the desired reactivities and
stereoselectivities (Scheme 1). Encouraged by our success with
the BIBOPꢀCu system, we aspired to design new bidentate
benzooxaphosphole ligands to promote other nonꢀprecious
metal catalyzed fundamental reactions such as asymmetric
hydrogenation of ketones. Herein we report the discovery of a
new class of heterophosphole dimeric ligands (BABIPhos) and
their application in the first copperꢀcatalyzed asymmetric
hydrogenation of 2ꢀsubstitutedꢀ1ꢀtetralones and related
heteroaryl ketones via dynamic kinetic resolution.
MeOꢀBIBOP
belongs
to
a
family
of
Pꢀchiral
benzooxaphosphole (BOP) ligands which have demonstrated
superior abilities to catalyze
a
range of asymmetric
transformations.[5] The modular design of the ligand core
allows for high tunability of steric and electronic properties of
The Cuꢀcatalyzed asymmetric reduction of ketones has been
described in the literature using both silanes and hydrogen.[6]
The silaneꢀbased methods often require cryogenic temperatures
and generate stoichiometric amounts of silane byproducts
rendering them unattractive for scaleup.[7] On the other hand,
greener alternatives based on catalytic hydrogenation are more
challenging and significantly less developed. Shimizu and coꢀ
workers reported the first asymmetric Cuꢀcatalyzed ketone
hydrogenation using BDPP as ligand obtaining good
selectivities with orthoꢀsubstituted aryl and heteroaryl
ketones.[8] Beller’s group described a more general system
using monodentate binaphthophosphepine ligands that provided
selectivities up to 77% ee.[9] More recently, Hatcher and coꢀ
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workers reported the use of modified BoPhoz ligands for
ketone hydrogenation to afford optically enriched alcohol
products with 75:25 to 98:2 er.[10] As part of our longꢀstanding
interest in nonꢀprecious metal catalysis and engineering
innovative catalytic systems, we sought to develop more
efficient methods for Cuꢀcatalyzed asymmetric ketone
hydrogenation.
Table 1. Cu-Catalyzed Asymmetric Hydrogenation of 2-Phenyl-1-tetralone[a]
O
R
(d)
(b) or (c)
P
O
t-Bu
Bu-t
O
P
R
O
2c: R = Me (89%)
[Cu(S,S)-3a)Cl]2
2d
i
: R = -Pr (71%)
: R = 2-MeO-Py (88%)
2e
3a
3b
3c
3d
3e
: 87%
: 60%
: 90%
: 90%
: 85%
: 57%
X
X
P
P
X
R
t-Bu
t-Bu
R
X
P
O
(a)
(b) or (c)
t-Bu
t-Bu
P
t-Bu
O
O
P
OTf
X
3f
1a
1b
2a
: 84%
(X = O)
(X = NPiv)
3g: 57%
3h
2b
: 78%
: 67%
R'
N
P
Bu-t
O
t-Bu
(b) or (c)
(e)
O
P
[a] Conversions were determined by comparison of relative HPLC integration of
alcohol to ketone at 220 nm, diastereo- and enantiomeric ratios (dr and er) were
determined by chiral HPLC. [b]t-AmOH as solvent.
N
R'
2f
: R' = H (72%)
(f) or (g)
2g: R' = Ph (95%)
2h
[Cu(R,R)-3b)Cl]2
: R' = C(O)NHPh (75%)
To further improve the reactivity and selectivity of the reaction,
we decided to synthesize the alternative BOP dimer via the C4ꢀ
coupling which might provide new ligands with different
properties (Scheme 1).[12] Our quest for this type of biaryl
ligands began by exploring the reductive homocoupling of the
corresponding benzooxaphosphole oxide triflate 1a (Scheme 2).
After extensive investigation of the Pdꢀ[13] and Niꢀ
catalyzed[14] protocols for dimerizing aryl halides and
triflates,[15] it was found that under Pdꢀcatalysis in the
presence of BIꢀDIME, aryl triflate 1a was converted to the
corresponding biaryl 2a in 84% yield. Additionally, the
oxaphosphole ring of 2a was alkylated to form C2, C2’ꢀ
Scheme 2. Synthesis of O-BABIPhos and N-BABIPhos. Conditions: (a) 2a (1 equiv),
Pd2(dba)3 (2.5 mol %), BI-DIME (5 mol %, 2a) or DTBPF (5 mol %, 2b), Et4NI (2
equiv), Zn dust (3 equiv), DMAc, 140 C; (b) (Me2HSi)2O (3 equiv), Ti(Oi-Pr)4 (2.3
equiv), THF, 65 C; (c) Et3SiH (3 equiv), Et3N (3 equiv), toluene, 110 C; (d) LDA
(2.5 equiv); then RX (2.5 equiv; 2c MeI, 2d i-PrI, 2e 2-methoxy-6-
(phenylsulfonyl)pyridine), THF, -78 C to r.t.; (e) NaOH, MeOH/H2O, 50 C; (f) 2g:
°
°
°
:
:
:
°
°
PhBr, Pd2(dba)3 (5 mol %), RuPhos (20 mol %), NaOt-Bu (2.4 equiv), THF, reflux;
(g) 2h: PhNHCO (10 equiv), i-Pr2NEt (3.6 equiv), THF, reflux. BI-DIME = 3-(tert-
butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d] [1,3]oxaphosphole, DTBPF =
1,1’-Bis(di-tert-butylphosphino)ferrocene, LDA
RuPhos = 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl.
= lithium diisopropylamide,
2ꢀArylꢀ1ꢀtetralone derivatives were chosen as initial substrates
for the study because the resulting chiral alcohols were required
for one of our ongoing programs. Furthermore the relatively
low pKa of the ketoꢀbenzylic position offers an opportunity for
dynamic kinetic resolution (DKR), creating two adjacent
stereocenters in one single operation. It should be noted that no
examples of Cuꢀcatalyzed asymmetric reduction of ketones via
DKR have been previously reported.[11]
substituted oxide analogs 2c
subsequently reduced to the corresponding phosphines
3a,c-e ꢀBABIPhos) giving access to a new class of bidentate
ꢀe. The phosphine oxides were
(
O
ligands. This route was demonstrated on several hundred grams
scale.
The asymmetric hydrogenation of racemic 2ꢀphenylꢀ1ꢀtetralone
4a was first evaluated using protocols reported by Shimizu,
Beller and Hatcher (Table 1). Low conversions were observed
under Shimizu’s BDPP and Beller’s CatASium KPh conditions.
Hatcher’s modified BoPhoz ligand provided 70% conversion
after 24 h at 400 psi with moderate stereoselectivity of 88:12 dr
and 83:17 er for the major diastereoisomer. Evaluation of chiral
With these ligands in hand, the ketone hydrogenation was
carried out, and we were pleased to find that the reaction with
O
ꢀBABIPhos ligand 3a provided high reactivities and
selectivities up to 91:9 er of single diastereoisomer 5a (Table
1). However, modification of the R group in ꢀBABIPhos did
O
not further improve the enantioselectivity. To obtain more
selective ligands, a new class of dimeric azaphosphole ligands,
BIBOP ligand provided full conversion exclusively to the cis
ꢀ
N
ꢀBABIPhos were designed and prepared to further modulate
diastereomer with 77:23 er, while the reaction with MeOꢀ
BIBOP gave less gratifying results. Phenyl and cyclohexyl
BIBOP analogs exhibited no reactivity in this reaction. Despite
the observed modest stereoselectivities in the initial screening,
these results clearly showed that the anticipated DKR has
occurred under the reaction conditions.
the electronic properties of the ligand by introducing various
functionalities on the nitrogen atom (Scheme 2). Dimerization
of the nitrogenꢀcontaining triflate 1b proved to be much more
challenging and
a wideꢀscope ligand screen led to the
identification of DTBPF as the best ligand that gave good yield
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of biaryl product 2b. Further modification at nitrogen gave
quick access to ꢀBABIPhos analogs 3f
We were delighted to find that the Cuꢀcatalyzed hydrogenation
of 2ꢀphenylꢀ1ꢀtetralone in ꢀAmOH using ꢀBABIPhos 3b as
Table 3. Scope of Cu-Catalyzed Asymmetric Hydrogenation via DKR[a]
N
ꢀh.
t
N
the ligand proceeded in complete diastereoselectivity and 97:3
er (Table 2, entry 1). Reactions with other azaphospholes
bearing different
results (entries 2ꢀ4).
for this transformation. Lower reactivity was observed when
performing the reactions in ꢀBuOH as solvent while iꢀPrOH
N
ꢀsubstitutions gave overall less satisfactory
t
ꢀAmOH proved to be the solvent of choice
Me
OMe
F
OH
OH
OH
OH
t
provided good reactivity but only 92:8 er (entries 5ꢀ6).[16] The
nature of ancillary phosphine played a key role in the reactivity
of our new catalytic system. Thus, no reaction was observed in
the absence of ancillary phosphine or using electronꢀdeficient
triarylphosphines (entries 7ꢀ8). The source of this phenomenon
was further elucidated via DFT calculations (vide infra).
5a: 92%
>99:1 dr
97:3 er
5b: 95%
>99:1 dr
97:3 er
5c: 89%
>99:1 dr
97:3 er
5d: 89%
>99:1 dr
97:3 er
OMe
OH
OH
OH
OMe OH
Me
5e: 91%
>99:1 dr
96:4 er
5f: 94%
>99:1 dr
97:3 er
5g: 85%
>99:1 dr
97:3 er
5h: 50%
>99:1 dr
98:2 er
CF3
Table 2. Optimization of Reaction Conditions[a]
OH
OH
OH
OH
N
O
S
N
N
5i: 78%
>99:1 dr
97:3 er
5j: 83%
>99:1 dr
97:3 er
5k: 91%
>99:1 dr
96:4 er
5l: 90%
>99:1 dr
96:4 er
F
OH
OH
OH
Entry
1
Ligand
3b
PAr3
% 5a[b]
100
50
dr[c]
er[c]
97:3
96:4
86:14
94:6
96:8
92:8
-
Me
OH
Ph
P(3,5-xylyl)3
P(3,5-xylyl)3
P(3,5-xylyl)3
P(3,5-xylyl)3
P(3,5-xylyl)3
P(3,5-xylyl)3
-
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
-
Me
5m: 85%
88:12 dr
94:6 er
5n: 94%
90:10 dr
95:5 er
5o:b 78%
>99:1 dr
76:24 er
5p: 76%
>99:1 dr
84:16 er
2
3f
3
3g
100
50
[a] Isolated yields; diastereomeric and enantiomeric ratios (dr and er) were
determined by chiral HPLC. [b] i-PrOH as solvent.
4
3h
5[d]
6[e]
7
3b
66
3b
100
0
The scope of the reaction was next examined (Table 3). A
variety of racemic 2ꢀarylꢀ1ꢀtetralones were smoothly reduced
3b
under
our
standard
conditions
with
excellent
8
3b
P(3,5-CF3-Ph)3
1
-
-
enantioselectivities (96:4 to 98:2 er, products 5a
ꢀ
h
). Reactions
with heterocycleꢀcontaining substrates were equally effective.
[a] Conditions: H2 (450 psi), CuCl2 (5 mol %), N-BABIPhos (5 mol %), PAr3 (5 mol
%), KOt-Bu (25 mol %), t-AmOH, 20 °C. [b] Determined by comparison of relative Pyridine, furan, thiophene and pyrazoleꢀfused cyclohexanones
HPLC integration of alcohol to ketone at 220 nm. [c] Determined by chiral HPLC.
underwent the Cuꢀcatalyzed hydrogenation in high
stereoselecivities (96:4 to 97:3 er, products 5iꢀl). Furthermore,
[d] t-BuOH as solvent. [e] i-PrOH as solvent.
the hydrogenative DKR of 2ꢀalkylꢀ1ꢀtetralones 4m and 4n
proved to be highly enantioselective with good
diastereoselectivities. Substituted indanone substrate 4o was
reduced under the reaction conditions, albeit with a more
modest er (76:24). Finally, hydrogenation of a 1ꢀcyclohexylꢀ2ꢀ
tetralone (4p) was also successful furnishing the desired
product in synthetically useful enantioselectivity (84:16).
The resulting optically enriched tetralols are valuable building
blocks for synthesis of bioactive molecules. For example,
compound 5q (>99:1 dr, 97:3 er from asymmetric
hydrogenation of 4q, Scheme 3) can be readily deoxygenated to
Both the Cuꢀ
were obtained in quantitative yields by treatment of CuCl with
stoichiometric amount of respective ligand in
dichloromethane at reflux temperature for 2 h. The molecular
structures of the complexes were unambiguously characterized
by single crystal Xꢀray crystallography[17] revealing a chlorideꢀ
OꢀBABIPhos and CuꢀNꢀBABIPhos complexes
a
bridged dicopper complex such as [Cu(
µꢀCl)
(κ2ꢀNꢀ
BABIPhos)]2 with a distorted tetrahedral geometry at both
copper(I) centers, as observed for similar Cu complexes in the
literature (Scheme 2).[18]
2ꢀaryltetralin
6 (97:3 er) which is a key precursor to
pharmaceutically important compounds for treatment of
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arrhythmias
by inhibiting
the
Na+/Ca2+
exchange
mechanism.[19]The only known asymmetric route to such 2ꢀ
aryltetralins required the use of Pdꢀcatalyzed arylation of 1ꢀ
tetralone employing an equimolar amount of highly toxic
tributyltin methoxide.[20]
Scheme 5. Energy of the Model Dimers Relative to the Corresponding Hexameric
Scheme 3. Synthesis of 7-Methoxy-2-Phenyl Tetralin. Conditions: (a) H2 (700 psi),
CuCl2 (5 mol %), 3b (5 mol %), P(3,5-xylyl)3 (5 mol %), KOt-Bu (0.25 equiv), t-
AmOH, 20 °C, 24 h; (b) Et3SiH (8 equiv), TFA (4 equiv), CH2Cl2, 0 °C.
CuH Aggregates. Ligands are Truncated (see SI for details).[31]
DFT analysis of some model higher aggregates demonstrated
that this is not the case, and the heteroligated aggregates
average the stabilities of the homoligated systems (Scheme 5).
This finding led us to propose the involvement of transition
states incorporating two Cu atoms, where different ligands can
be coordinated to each Cu, to explain the mixed ligand effect.
To the best of our knowledge, such transition states
incorporating dimer Cu species had not been previously
calculated for this type of reaction.
To understand the observed mixed ligand effect and to facilitate
further development of the efficient catalysts, we initiated DFT
study of the mechanism of this transformation. The reaction is
believed to proceed via in situ formation of copper hydrides,
where multiple species could be acting as the hydride source
(Scheme 4).[21]
In analyzing hydride transfer transition states for the reduction
of substituted tetralone, transition states incorporating two
copper centers were lower than those incorporating one copper
center for both monodentate and bidentate ligands (Scheme 6).
Scheme 4. Generic Catalytic Cycle for the Cu-Catalyzed Ketone Reduction.
Copper hydrides are known to exist in oligomeric form, with
the exact nature of the oligomer strongly depending on the
identity of the ligand and the reaction conditions.[22] Thus, for
the LCuH species, where L is a phosphine, there is evidence for
existence of the corresponding dimers,[23] trimers,[24]
pentamers,[25] hexamers[26] and octamers.[27] For biaryl
bidentate ligands, analogous to our ligand of interest, only a
SEGPHOSꢀbased system[28] has been examined;[29] NMR and
MS experiments did not provide any conclusive results about
the exact nature of this LCuH species, but suggested the
presence of oligomers. Kinetic studies also pointed to the
oligomeric character of the copper hydride. Previously
published computational studies support the relative instability
of the monomer.[30] Given the wellꢀknown propensity of the
LCuH species to form less reactive oligomers, the greater
reactivity observed here when two different ligands are
employed [bidentate L and monondentate P(3,5ꢀxylyl)3] may
arise from the formation of different aggregates. Specifically,
we theorize that the homoaggregates [L alone or P(3,5ꢀxylyl)3
alone] are less reactive than mixed aggregates incorporating the
two different ligands.
Scheme 6. Relative Energetics of Monomeric (red) and Dimeric (blue) Hydride
Transfer Pathways for Bidentate (left) and Monodentate (right) Ligands31
Following discovery of this lower energy reaction pathway, we
analyzed the relative energetics of the most stable homoꢀ and
heteroꢀligated dimeric transition states (Scheme 7).
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We thank Scott Pennino and Keith McKellop of Boehringer
Ingelheim Pharmaceuticals for HRMS analysis. M.C.K. thanks
the NIH (GM087605 M.C.K.) and Boehringer Ingelheim
Pharmaceuticals for financial support. Computational support
was provided by XSEDE (TGꢀCHE120052).
Notes and references
Scheme 7. Relative Energetics of the Homoligated (leftmost and center) and
Mixed Dimeric Hydride Transfer Transition States.
These results indicate that the heteroligated dimeric
transition state is lower in energy than the monoligated dimeric
transition states, providing more than 1000ꢀfold acceleration of
the hydride transfer. Interestingly, the stabilization of the
heteroligated dimeric transition state is not a purely entropic
phenomenon. That is, P TS and LP TS differ in energy, even
though both have the same molecularity. We hypothesize that
the mixed ligand environment better supports the charge
distribution required for the effective hydride transfer (Scheme
8). Specifically, one Cu center engages in Lewis acid activation
of the carbonyl, for which an electronꢀdeficient L2 would be
superior. And, the second copper center delivers nucleophilic
hydride, which is assisted by an electronꢀrich L1.
[1]
Selected reviews on metal catalysis: a) C. A. Busacca, D. R.
Fandrick, J. J. Song, C. H. Senanayake, Adv. Synth. Catal.
2011, 353, 1825−1864; b) V. Farina, J. T. Reeves, C. H.
Senanayake, J. J. Song, Chem. Rev. 2006 106, 2734−2793; c)
Transition metals for Organic Synthesis (2004) Beller, M. and
Bolm, C. (eds), WileyꢀVCH.
[2] a) F. Roschangar, J. Colberg, P. J. Dunn, F. Gallou, J. D.
Hayler, S. G. Koenig, M. E. Kopach, D. K. Leahy, I.
Mergelsberg, J. L. Tucker, R. A. Sheldon, C. H. Senanayake,
Green Chem. 2017, 19, 281−285; b) P. T. Anastas, J. C.
Warner, Green Chemistry: Theory and Practice, Oxford
University Press, 1998; c) M. Poliakoff, P. Licence, Nature
2007, 450, 810–812; d) C.ꢀJ. Li, B. M. Trost, Natl. Acad. Sci.
U. S. A. 2008, 105, 13197–13202; e) P. T. Anastas, B. Han, W.
Leitner, M. Poliakoff, Green Chem. 2016, 18, 12–13; f) M.
Poliakoff, J. M. Fitzpatrick, T. R. Farren, P. T. Anastas,
Science 2002, 297, 807–810; g) R. Noyori, Nat. Chem. 2009,
1, 5–6.
Scheme 8. Favorable Electronics for the Dimeric Hydride Transfer Transition
State
In summary, a new class of heterophosphole dimeric ligands
(OꢀBABIPhos and NꢀBABIPhos) have been designed and
[3] J. R. Dunetz, D. R. Fandrick, H.ꢀJ. Federsel, Org. Process Res.
Dev. 2015, 19, 1325−1326.
synthesized. These ligands are highly modular and tunable and
have enabled the first example of Cuꢀcatalyzed hydrogenation
of 2ꢀsubstitutedꢀ1ꢀtetralones and related heteroaryl ketones via
dynamic kinetic resolution, simultaneously establishing two
contiguous stereogenic centers with up to >99:1 dr and 98:2 er.
The ligandꢀCu complexes were isolated and characterized by
single crystal Xꢀray, and DFT calculations revealed a novel
heteroligated dimeric copper hydride transition state.
Application of this new series of oxaꢀ and azaphosphole
bisphosphine ligands to other important catalytic reactions is
currently under investigation and will be disclosed in due
course
[4] a) D. R. Fandrick, K. R. Fandrick, J. T. Reeves, Z. Tan, W.
Tang, A. G. Capacci, S. Rodriguez, J. J. Song, H. Lee, N. K.
Yee, C. H. Senanayake, J. Am. Chem. Soc. 2010, 132,
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Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
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[15] See supporting information for optimization of homocoupling
reaction conditions.
[16] See supporting information for detailed optimization of the
reaction conditions.
[17] CCDC 1816601 – [OꢀBABIPhosꢀCuCl]2 and CCDC 1816602
–
[NꢀBABIPhosꢀCuCl]2
contains the supplementary
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