Electron-donating and rigid p-stereogenic bisphospholane ligands for highly enantioselective rhodium-catalyzed asymmetric hydrogenations

Article abstract of DOI:10.1002/anie.201002990

More electron donating, more rigid: A new highly electron-donating P-stereogenic bisphospholane ligand (ZhangPhos) was synthesized in a practical and highly enantioselective manner from a commercially available chiral source. Better or comparable enantioselectivities and reactivities than TangPhos were achieved in rhodium-catalyzed hydrogenation of various functionalized olefins (see scheme; nbd=3,5-norbornadiene). Copyright

Full text of DOI:10.1002/anie.201002990

Angewandte
Chemie
DOI: 10.1002/anie.201002990
Ligand Design
Electron-Donating and Rigid P-Stereogenic Bisphospholane Ligands
for Highly Enantioselective Rhodium-Catalyzed Asymmetric
Hydrogenations**
Xiaowei Zhang, Kexuan Huang, Guohua Hou, Bonan Cao, and Xumu Zhang*
Development of chiral phosphorus ligands has drawn inten-
sive interest owing to their significant role in transition-metal-
catalyzed asymmetric reactions.[1] Catalytic asymmetric
hydrogenation has been widely used as a practical and
efficient method in the synthesis of chiral molecules.[2]
Although excellent enantioselectivities have been obtained
by using benchmark ligands such as dipamp (1,2-ethanediyl-
bis[(2-methoxyphenyl)phenylphosphane]),[3] binap (2,2’-bis-
have high enantioselectivity, reactivity, and with broad
substrate scope for asymmetric hydrogenation. Herein, we
report a new highly electron-donating and conformationally
rigid P-stereogenic bisphospholane ligand 3 (named Zhang-
Phos; Figure 1) where both enantiomers can be synthesized
conveniently. High enantioselectivities and reactivities have
been achieved at room and elevated temperature in rhodium-
catalyzed hydrogenation of various functionalized alkene
derivatives.
(diphenylphosphanyl)-1,1’-binaphthyl),[4]
DuPhos
(1,2-
bis(phospholano)benzene derivatives),[5] and more recently
TangPhos[6] 1 and DuanPhos[7] 2 (Figure 1), it is still highly
desirable to develop ligands that can be prepared easily and
Since the discovery of the landmark ligand dipamp, more
attention has been paid to P-stereogenic phosphorus ligands
because the chiral environment induced by the ligands is close
to the transition metal centers. For example, BisP* (1,2-
bis(alkylmethylphosphino)ethane),[8] miniphos (1,2-bis(alkyl-
methylphosphino)methane),[9] and trichickenfootphos (tert-
butylmethylphosphino-di-tert-butylphosphinomethane)[10]
provide excellent enantioselectivities in asymmetric hydro-
genation, especially for the challenging tetra-substituted
olefins. However, the development of P-stereogenic ligands
is still limited owing to difficulty with synthesizing them. Our
research group has ever reported a P-stereogenic ligand 1,
TangPhos, which is one of the most efficient ligands for
asymmetric hydrogenation.[6] More recently, many other
groups found that TangPhos exhibited the highest enantiose-
lectivities for diverse transition-metal-catalyzed asymmetric
reactions such as arylcyanation and alkylation of imidazoles
at high temperatures.[11] However, only one enantiomer of
TangPhos (1S,1S’,2R,2R’-1) is readily available owing to the
requisition of chiral induction from (À)-sparteine. Later on,
we introduced another P-stereogenic phosphorus ligand 2,
DuanPhos, with both enantiomers being available.[7] But the
synthesis of DuanPhos requires resolution in the final step
and its electron-donating ability is not as strong as that of
TangPhos. The wide applications of TangPhos[11] and Duan-
Phos[12] encourage us to develop a more synthetically practical
and conformationally rigid P-stereogenic bisphospholane
scaffold 3, ZhangPhos. The two five-membered phospholane
rings in the backbone of 3 are believed to restrict the
conformational flexibility and lead to high enantioslectivity. It
is envisioned that the electron-rich bis(trialkylphosphane)
structure contributes to the high reactivity. In addition to the
excellent enantioselective induction, the two chiral cyclohex-
ane rings on the backbone are expected to further benefit the
electron-donating ability and conformational rigidity of 3.
Ligand 3 was synthesized in a straightforward manner in
five steps from a commercially available chiral source,
(1S,2S)-1,2-cyclohexanedicarboxylic acid (4), which was re-
duced to chiral diol 5 quantitatively (Scheme 1; see the
Figure 1. Structure of the three P-stereogenic phosphorus ligands.
[*] X. Zhang, K. Huang, Dr. G. Hou, B. Cao, Prof. Dr. X. Zhang
Department of Chemistry and Chemical Biology and
Department of Pharmaceutical Chemistry
Rutgers, The State University of New Jersey
Piscataway, New Jersey 08854 (USA)
Fax: (+1)732-445-6312
E-mail: xumu@rci.rutgers.edu
X. Zhang
Department of Chemistry, The Pennsylvania State University,
University Park, Pennsylvania 16802 (USA)
[**] This work was supported by the National Institutes of Health
(GM58832). The Bruker 400 MHz NMR spectrometer used in these
studies was purchased with grant no. 1S10RR023698-01A1 from the
National Center for Research Resources (NCRR), a component of
the NIH. We thank Dr. T. Emge for solving the crystal structure.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002990.
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Table 1: Rhodium-catalyzed asymmetric hydrogenation of a-(acylami-
no)acrylic acids and esters.[a]
Entry
10
R1
R2
ee [%][b]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
H
nPr
iPr
Ph
Me
Me
H
H
Me
H
Me
Me
Me
Me
Me
Me
H
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
Ph
p-FC6H4
p-FC6H4
p-MeOC6H4
p-CF3C6H4
m-BrC6H4
o-ClC6H4
2-thienyl
2-naphthyl
Ph
Scheme 1. Synthesis of ligand 3. Reagents and conditions: a) LiAlH4,
9
98%; b) 1. SOCl2, NEt3; 2. RuCl3·XH2O, NaIO4, 88% (over 2 steps);
c) tBuPH2, nBuLi, S, 81%; d) sBuLi, [Fe(acac)3], 50%, e) Si2Cl6, ben-
zene, 90%. acac=acetylacetone.
10
11
12
13
14[c]
Me
Supporting Information for experimental details and analyt-
ical data). Cyclic sulfate 6 was obtained in 88% yield and was
synthesized according to a known procedure.[13] Reaction of 6
with lithiated tert-butylphosphane, and subsequent in situ
protection with sulfur powder afforded enantiomerically pure
phosphane sulfide 7 (> 99% ee was determined by HPLC on
a chiral statioanry phase).[14] A homocoupling mediated by
[Fe(acac)3] in the presence of sec-butyllithium provided the
C2-symmetric bisphosphane sulfide 8 in 50% yield, along with
recovered starting material 7 (25%). The absolute configu-
ration of 8 was determined by X-ray crystallographic analy-
sis.[15] Desulfuration of 8 with hexachlorodisilane[6a] afforded
ligand 3, (1S,1’S,2R,2’R,3aS,3’aS,7aS,7’aS)-ZhangPhos, as a
white crystalline solid in 90% yield.
Ligand 3 was then used in the rhodium-catalyzed hydro-
genation of various prochiral alkene derivatives. The cationic
Rh complex, [Rh(ZhangPhos)(nbd)]BF4 (9; nbd = 3,5-nor-
bornadiene), was prepared and used directly as the catalyst
precursor. a-(Acylamino)acrylic acids and esters were hydro-
genated under very mild conditions (in methanol at room
temperature under 20 psi of H2 for 12 h).[16] Full conversions
and extremely high enantioselectivities (> 99% ee exclu-
sively) were obtained in the hydrogenation of both a-
(acylamino)acrylic acids and their ester derivatives
(Table 1). The catalyst can tolerate a wide array of substituted
phenyl rings and thio ring (Table 1, entries 5–12), as well as
the N-benzoyl derivative (Table 1, entry 14). To further
evaluate the catalytic efficiency of the Rh–ZhangPhos
system in asymmetric hydrogenation, methyl 2-acetamido-3-
(4-fluorophenyl)acrylate (10g) was hydrogenated using
0.002 mol% of complex 9 under the same reaction conditions.
In this way, (S)-11g was obtained with > 99% ee in quanti-
tative yield within 4 hours, thus indicating a high turnover
number (TON = 50000) and a high turnover frequency
(TOF = 12500 hÀ1) for the Rh–ZhangPhos catalyst.
[a] The reactions were carried out at room temperature under 20 psi of
H2 in MeOH for 12 hours with 9 (1 mol%) as the catalyst precursor.
Conversions were 100%. [b] The ee values were determined by GC or
HPLC on a chiral stationary phase using a Chiralsil-VAL III FSOT or a
Chiralcel OJ column, respectively. The ee values of the acids were
determined for the corresponding methyl ester by treatment with
TMSCHN2. The absolute configurations of the products were determined
as S by comparison of the retention times of two enantiomers with
reported data.[6a] [c] The protecting group on N was changed form Ac to
Bz for this reaction. Bz=benzoyl, TMS=trimethylsilyl.
entries 1–8). Rh–ZhangPhos also showed tolerance to the E/
Z mixture of trisubstituted enamides and gave excellent
enantioselectivity (Table 2, entries 10 and 11). High turnover
(10000) was also obtained in the hydrogenation of N-(1-(4-
bromophenyl)vinyl)acetamide (12g) with > 99% ee in quan-
Table 2: Rhodium-catalyzed asymmetric hydrogenation of a-arylenami-
de.[a]
Entry
12
R1
R2
ee [%][b]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Ph
H
H
H
H
H
H
H
H
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
m-MeC6H4
m-MeOC6H4
m-BrC6H4
p-MeC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
2-naphthyl
Ph
9
10
11
H
Me
Me
j
k
p-CF3C6H4
[a] See footnotes of Table 1. For the E/Z ratio of 12j–k, see reference [17].
[b] The ee values were determined by GC or HPLC on a chiral stationary
phase using a Chiral Selective 1000 or a Chiralcel OD-H column,
respectively. The absolute configurations of the products were deter-
mined as S by comparison of their retention times of two enantiomers
with reported data.[6a]
A variety of a-arylenamides 12 were also hydrogenated
with the Rh–ZhangPhos catalyst to afford enantiomerically
pure amides (Table 2). Ee values of more than 99% were
achieved exclusively in the hydrogenation of enamides 12,
regardless of the substituents on the phenyl ring (Table 2,
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titative yield. These results are among the best reported to
date.
expected to reduce the flexibility of ligand 3 and sustain high
enantioselectivity at high temperature. Indeed, some prelimi-
nary results of hydrogenations requiring higher temperature
showed that ZhangPhos has better tolerance to high temper-
ature than TangPhos. As shown in Table 4, the hydrogenation
of N-aryl b-enamino esters 17[6d] (Table 4, entries 1–3) and a-
aryl imino esters 18[6e] (Table 4, entries 4 and 5), where a
temperature of 508C was needed, Rh–ZhangPhos delivered
higher enantioselectivities than Rh–TangPhos. It is expected
that ZhangPhos will have promising applications in asym-
metric catalytic processes, which require elevated temper-
ature.[11a,b]
The two chiral cyclohexane rings fused on the phospho-
lane rings are expected to make ZhangPhos more conforma-
tionally rigid and electron-donating than TangPhos. It has
been demonstrated that high rigidity and a well-defined
structure are beneficial to achieving high enantioselectivity.[2]
As shown in Table 3, Rh–ZhangPhos gave higher or com-
parable enantioselectivities compared to Rh–TangPhos in the
hydrogenation of another three types of prochiral olefins:
enol acetates 14 (Table 3, entries 1–5), b-(acetylamino)acry-
lates 15 (Table 3, entries 6–10), and itaconic acid derivatives
16 (Table 3, entries 11 and 12). For the hydrogenation of
aromatic enol acetates, which serves as an alternative to direct
hydrogenation of ketones, increase of enantioselectivity was
observed by using Rh–ZhangPhos as the catalyst, especially
for 14b (from 92% to 98% ee; Table 3, entry 2). b-(Acetyl-
amino)acrylates remain challenging substrates for asymmet-
ric hydrogenation, which can form nonnatural chiral b-amino
acids. With Rh–ZhangPhos, the hydrogenation of both E and
Z isomers of b-(acetylamino)acrylates derivatives 15 gave
high enantioselectivities (from 92% to more than 99% ee). In
particularly, for ortho-substituted substrate 15e, a significant
increase in enantioselectivity (from 74% to 92% ee) was
obtained with the Rh–ZhangPhos complex (Table 3,
entry 10).
Table 4: Rhodium-catalyzed asymmetric hydrogenation of N-aryl b-
enamino esters and a-aryl imino esters.[a]
Entry
Substrate
ee [%][b]
ZhangPhos
TangPhos
1
2
3
17a Ar=Ph,R=Me
17b Ar=Ph,R=Et
17c Ar=p-FC6H4, R=Et
93(+)
96(+)
98(+)
91(À)[c]
95(À)[c]
96(À)[c]
95(S)[d]
95(À)[d]
In asymmetric catalysis, the enantioselectivity generally
decreases at high temperature as a result of the ligand
flexibility. The conformationally rigid cyclohexane rings were
4
5
18a Ar=Ph
18b Ar=o-MeOC6H4
97(R)
97(+)
[a] For 17, the reactions were carried out at 508C in TFE under 6 atm of
H2 for 18 hours with 9 (1 mol%). For 18, the reactions were carried out at
508C in CH2Cl2 under 50 atm of H2 for 24 hours with 9 (1 mol%).
Conversions were 100%. [b] The ee values were determined by GC or
HPLC on a chiral stationary phase (see references [6d,e]). [c] Data from
reference[6d]. [d] Data from reference [6e]. PMP=para-methoxyphenyl,
TFE=trifluoroethanol.
Table 3: Rhodium-catalyzed asymmetric hydrogenation of enol acetates,
b-(acetylamino)acrylates and itaconic acid derivatives.[a]
Entry
Substrate
ee [%][b]
ZhangPhos
TangPhos
In conclusion, we have designed and developed a new
highly electron-donating, P-stereogenic bisphospholane
ligand 3 (ZhangPhos), which can be synthesized practically
and highly enantioselectively from a commercially available
chiral reagent. Ligand 3 exhibited extremely high enantiose-
lectivities (up to 99% ee) and reactivities (up to 50000 TON)
for rhodium-catalyzed hydrogenation of a wide range of
functionalized olefin derivatives. Compared to TangPhos and
DuanPhos, better or comparable enantioselectivities were
achieved with ZhangPhos, which suggests that the chiral
cyclohexane rings on its backbone make the ligand more
conformational rigid. Especially, better enantioselectivities
obtained at high temperature makes ZhangPhos a promising
ligand for high temperature asymmetric catalysis. Further
studies to optimize the synthesis of ZhangPhos and explore its
application in diverse asymmetric catalytic reactions will be
reported in due course.
1
2
3
4
5
14a Ar=Ph
97(S)
98(S)
97(S)
>99(S)
99(S)
96(R)[c]
92(R)[c]
97(R)[c]
99(R)[c]
97(R)[c]
14b Ar=p-FC6H4
14c Ar=p-ClC6H4
14d Ar=p-NO2C6H4
14e Ar=2-naphthyl
6
7
8
9
15a R=Me (E)
15b R=Me (Z)
15c R=Et (E)
15d R=Ph (Z)
15e R=o-MeC6H4 (Z)
>99(S)
97(S)
>99(S)
95(R)
>99(R)[d]
97(R)[d]
>99(R)[d]
94(S)[d]
10
92(R)
74(S)[d]
11
12
16a R=Me
16b R=H
>99(R)
>99(R)
99(S)[c]
99(S)[c]
[a] See footnotes of Table 1. Solvent was ethyl acetate for 14, THF for 15,
and 16. [b] The ee values were determined by GC or HPLC on a chiral
stationary phase (see references [6b,c]). The absolute configurations of
the products were determined by comparison of the retention times of
two enantiomers with reported data. [c] Data from reference [6c].
[d] Data from reference [6b].
Received: May 18, 2010
Published online: July 26, 2010
Keywords: asymmetric synthesis · hydrogenation ·
.
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ligand design · P-stereogenic ligands · rhodium
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form P-stereogenic phosphorus ligands was also applied in the
Esphos
(1,1ꢀ-(1,2-phenylene)bis[hexahydro-2-phenyl-1H-
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