Design of phosphorus ligands with deep chiral pockets: Practical Synthesis of chiral β-arylamines by asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.201300646

WingPhos, a C₂-symmetric bisphosphorus ligand with a deep and well-defined chiral pocket was developed. It has shown high efficiency in the rhodium-catalyzed asymmetric hydrogenation of (E)-β-aryl-N-acetyl enamides, cyclic β-aryl enamides, and heterocyclic β-aryl enamides. A series of chiral β-arylisopropylamines, 2-aminotetralines, and 3-aminochromans can be synthesized with excellent ee values (nbd=3,5-norbornadiene; TON=turnover number). Copyright

Full text of DOI:10.1002/anie.201300646

Angewandte
Chemie
DOI: 10.1002/anie.201300646
Homogeneous Catalysis
Design of Phosphorus Ligands with Deep Chiral Pockets: Practical
Synthesis of Chiral b-Arylamines by Asymmetric Hydrogenation**
Guodu Liu, Xiangqian Liu, Zhihua Cai, Guangjun Jiao, Guangqing Xu, and Wenjun Tang*
Despite the signficant advances in asymmetric hydrogenation,
the development of novel and efficient chiral phosphorus
ligands to solve new synthetic challenges continues to an
important goal.[1] C2-Symmetric chiral bisphosphorus ligands
such BINAP,[2] DuPhos,[3] and TangPhos[4] are among the most
versatile and important ligands for asymmetric hydrogena-
tion, yet they are not universal. To expand their synthetic
utilities, one common strategy is to develop structurally
similar ligands, such as Tol-BINAP, Xyl-BINAP, Et-DuPhos,
or iPr-DuPhos by increasing the size of the substituents on the
phosphorus centers (Figure 1a). Such modifications lead to
strategy: 1) The R groups that protrude directly forward to
the substrate coordination site can lead to a dramatic
conformational variation of the chiral pocket; 2) the R
groups are in close proximity to the metal center and the
substrate, thereby providing a well-defined and deep chiral
pocket. We herein report the development of WingPhos (L5)
by using this strategy.
Chiral b-arylamines exist in numerous biologically inter-
esting natural products and therapeutic agents. For examples,
such moieties commonly exist in a series of naphthylisoquino-
line alkaloids such as michellamine B and korupensamine A
(Scheme 1).[5] They also serve as pivotal structural units for
Figure 1. Design of novel chiral bisphosphorus ligand L5 (WingPhos)
with a deep chiral pocket (9-An=9-anthracenyl).
the design of ligands with deeper chiral pockets mainly owing
to the increased bulk of the Rꢀ groups, which protrude slightly
forward to the substrate coordination. In this study we adopt
a new strategy to design a ligand with a deep chiral pocket by
installing R groups that protrude directly forward to the
substrate coordination site. There are two advantages of this
Scheme 1. Selected natural products and therapeutic agents containing
chiral b-arylamines.
many active pharmaceutical ingredients such as 3,4-methyl-
enedioxyamphetamine (MDA),[6a] tamsulosin,[6b] selegiline,[6c]
arformoterol,[6d] rotigotine,[6e] and silodosin.[6f] Development
of efficient asymmetric synthetic methods of chiral b-aryl-
amines has thus become a subject of significant interest.[7]
However, the asymmetric hydrogenation of b-aryl enamides
to prepare chiral b-arylamines remains underdeveloped.
Zhang, Lei, and co-workers reported high enantioselectivities
on the asymmetric hydrogenation of (Z)-b-aryl enamides by
using a Rh–TangPhos catalyst.[8] Nevertheless, low ee values
were observed with thermodynamically more stable sub-
[*] Dr. G. Liu, X. Liu, Z. Cai, G. Jiao, G. Xu, Prof. Dr. W. Tang
State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
[**] We are grateful to NSFC-21272254, the “Thousand Plan” Youth
program, State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, and Boehringer
Ingelheim.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300646.
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Table 1: Asymmetric hydrogenation of (E)-N-[1-(3,4-dimethoxyphenyl)-
strates, (E)-b-aryl enamides. Zhou and co-workers reported
high ee values with (Z)- or (E)-b-aryl enamides when using
a chiral monophosphane or phosphite ligand, albeit with
limited turnover numbers (substrate/catalyst (s/c) ratio ꢀ
100).[9] For hydrogenation of cyclic[10] or heterocyclic[11] b-
aryl enamides, few efficient chiral rhodium catalysts are
available. We herein report an efficient method for the
synthesis of acyclic, cyclic, or heterocyclic chiral b-arylamines
by hydrogenation of readily accessible (E)-b-aryl enamides.
Excellent reactivity (turnover number (TON) up to 10000)
and enantioselectivities (up to > 99% ee) have been achieved
by employing the Rh–L5 catalyst.
Although both (Z)- and (E)-b-aryl enamides have been
studied for asymmetric hydrogenation, efficient asymmetric
hydrogenation of (E)-b-aryl enamides is more desirable from
a practical point of view, because they are more thermody-
namically stable and can be selectively synthesized. Among
various synthetic methods of b-aryl enamides,[12] we chose to
employ reductive acylation of nitroalkenes[13] to prepare (E)-
b-aryl enamides for synthetic easiness and cost effectiveness.
Thus, Henry reaction between aryl aldehydes and nitro-
alkanes provided (E)-nitroalkenes in high yields. Reductive
acylation of nitroalkenes according to a reported procedure
led to the formation of 3 as E/Z isomeric mixture.[15] By
optimizing the reaction conditions, (E)-b-aryl enamides were
formed preferentially and could be isolated in moderate to
good yields without column chromatography (Scheme 2).
This rapid and economical method holds promise for practical
synthesis of (E)-b-aryl enamides.
prop-1-en-2-yl]acetamide.[a]
Entry
Ligand
s/c
200
200
200
200
200
200
200
10000
ee [%][b]
1
2
3
4
5
6
(R)-BINAP
(R,S)-Josiphos
3
13
27
11
35
74
97
97
L1
L2
L3
L4
L5
L5
7
8[c]
[a] The hydrogenations were carried out in dichloromethane (2 mL) for
12 h with 3a (0.1 mmol), [Rh(nbd)2]BF4 (0.5 mmol; nbd=3,5-norborna-
diene), and ligand (0.6 mmmol) unless otherwise specified; all reactions
proceeded completely; the absolute configuration was determined as R
by comparing the optical rotation with reported data. [b] Determined by
HPLC on a Chiralcel AD-H column. [c] 3a (1 mmol), [Rh(nbd)(L5)]BF4
(0.1 mmol), dichloromethane (2 mL), 808C, H2 (750 psi), 20 h.
substrate/catalyst ratio (s/c = 10000) was employed (Table 1,
entry 8), thus demonstrating the high reactivity and efficiency
of ligand L5 for this transformation.
With Rh–L5 as the catalytic system, different substituted
(E)-b-aryl-N-acetyl enamides were hydrogenated to provide
an array of chiral b-arylamines in good to excellent enantio-
selectivities. High ee values were achieved regardless of the
electronic property or the substitution pattern on the benzene
ring (Table 2). An excellent ee value (> 99% ee) was also
achieved with a substrate containing a 4-methoxy substituent
Table 2: Asymmetric hydrogenation of (E)-b-aryl-N-acetyl enamides.[a]
Entry
R’
R’’ (3)
ee [%][b] (4)
Scheme 2. Syntheses of (E)-b-aryl-N-acetyl enamides from aldehydes
and nitroalkanes. R’=substituents on the aromatic ring; R”=Me or
Et.
1
2
3
4
5
6
7
8
Ph
Me (3b)
Me (3c)
Me (3d)
Me (3e)
Me (3 f)
Me (3g)
Me (3h)
Me (3i)
Me (3j)
Me (3k)
Me (3l)
Me (3m)
Me (3n)
Et (3o)
97 (4b)
99 (4c)
98 (4d)
>99 (4e)
96 (4 f)
99 (4g)
98 (4h)
98 (4i)
98 (4j)
99 (4k)
97 (4l)
96 (4m)
93 (4n)
98 (4o)
98 (4p)
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
3,5-(BnO)2C6H3
2-ClC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
1-naphthyl
2-naphthyl
3-thiophenyl
Ph
The asymmetric hydrogenation of (E)-N-[1-(3,5-dimeth-
oxyphenyl)prop-1-en-2-yl]acetamide (3a) was investigated
with various chiral rhodium catalysts. The hydrogenations
were conducted at room temperature at a hydrogen pressure
of 300 psi for 12 h. It was found that well-known chiral ligands
such as BINAP, Josiphos, and Tangphos[8] did not provide
superb enantioselectivities (Table 1, entries 1–2). Ligand
BIBOP (L1), which was highly effective for hydrogenation
of a-aryl-N-acetyl enamides in our previous study,[14] proved
to be inefficient (Table 1, entry 3). A low ee was also observed
when MeO-BIBOP (L2) was applied (Table 1, entry 4).
Gratifyingly, the enantioselectivity increased dramatically
when ligands L3–5 containing various aryl groups as R groups
were employed (Table 1, entries 5–7). When L5 with anthra-
cenyl groups was applied, the enantioselectivity reached
97%. An excellent ee value was also achieved when a high
9
10
11
12
13
14
15
4-MeOC6H4
Et (3p)
[a] The hydrogenations were carried out in dichloromethane (0.5 mL) at
508C, under 750 psi of H2 for 12 h with substrate (0.1 mmol) and
[Rh(nbd)(L5)]BF4 (0.5 mmmol); the absolute configuration was assigned
as R by comparing the optical rotation with reported data[8,9] or by
analogy; the yields were >99%. [b] Determined by chiral HPLC, see
Supporting Information for details.
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as the R’ group, thereby providing an important chiral
intermediate 4e for the synthesis of b-adrenoceptor agonist
drug arformoterol[8d] and a1 receptor antagonist tamsulosin
(Table 2, entry 4).[8b] Halogen substituents at various positions
of the aromatic rings were tolerable (Table 2, entries 7–10).
Substrates containing 1-naphthyl or 2-naphthyl moieties were
well applicable (Table 2, entries 11,12). A 3-thiophenyl sub-
strate also provided a good ee value (Table 2, entry 13).
Excellent enantioselectivities were also achieved on sub-
strates with a-ethyl substituents (Table 2, entries 14–15).
Asymmetric hydrogenation of cyclic b-aryl-N-acetyl
enamides constitutes an attractive method for the syntheses
of chiral cyclic b-arylamines. Although a few ruthenium
catalysts have been reported to be effective in the synthesis of
cyclic b-aryl-N-acyl enamides,[10] the enantioselectivities were
often dependent on the structure of the acyl group.[11a] In
contrast, very limited success has been achieved with chiral
rhodium catalysts.[10c] We were pleased that the Rh–L5
catalyst was equally effective for asymmetric hydrogenation
of various substituted cyclic b-aryl-N-acetyl enamides,
thereby leading to the formation of a series of chiral 2-
aminotetralines and 3-aminochromanes in excellent enantio-
selectivities (Table 3). At a 1 mmol scale, hydrogenation of N-
(5-methoxy-3,4-dihydronaphthalen-2-yl)acetamide yielded
a key chiral intermediate for the dopamine agonist roti-
gotine[6e] in 96% ee with up to 2000 TON (Table 3, entry 3).
Heterocyclic substrates were equally effective (Table 3,
entries 5–7), and the corresponding chiral 3-aminochromanes
(up to 98% ee) are important intermediates for various
therapeutic agents.[11]
To understand the high enantioselectivity observed with
the Rh–L5 catalyst, a rhodium complex [Rh(nbd)(L5)]BF4
was prepared, and a C2-symmmetric structure with a deep
chiral pocket was revealed by X-ray crystallography.[15] The
two anthracenyl groups of L5 protrude directly forward to the
norbornadiene component and could have a steric effect on
substrate coordination (Figure 2a). The rhodium metal center
is well sandwiched between the two anthracenyl groups, with
a parallel distance of approximately 8 ꢁ. The distance
between the rhodium center and the ipso carbon atom of
the anthracenyl group is approximately 4.4 ꢁ, shorter than
a phenyl substituent (ca. 5.2 ꢁ). Thus, the orientation of an
aromatic substrate could be well-defined when coordinating
to the catalyst.
Table 3: Asymmetric hydrogenation of cyclic b-aryl-N-acetyl enamides
5.[a]
Entry Substrate
1
s/c Product
200
ee [%][b]
96
Figure 2. a) The X-ray structure of [Rh(nbd)(L5)]BF4 (H atoms and BF4
anion are omitted for clarity; selected parameters: ] P-Rh-P=85.58;
bond length of Rh–P: 2.325 ꢀ, Rh–ipsoC of anthracenyl: 4.478,
4.411 ꢀ); b) A stereochemical model for asymmetric hydrogenation of
(E)-b-phenyl-N-acetyl enamides with the Rh–L5 catalyst.
2
200
2000
96
96
3[c]
4
5
200
200
96
94
Owing to the structural similarity between (E)-b-aryl-N-
acetyl enamides and (E)-b-(acylamino)acrylates, a reaction
mechanism via monohydrides with the b-carbon atom bound
to rhodium is proposed.[16] Hence, substrate coordination of
a Rh–L5 dihydride complex[17] provides two possible coordi-
nation modes I and II (Figure 2b). Strong steric interaction is
foreseen between the aromatic substituent of the substrate
and an anthracenyl group of the ligand in mode I. Less steric
interaction is expected in mode II, which could undergo
insertion and reductive elimination to yield the chiral hydro-
genation product with correct stereochemistry.
To further demonstrate the synthetic utility of this
methodology, the chiral hydrogenation product 4a was
converted to a tetrahydroisoquinoline compound 8 in 90%
overall yield through two simple transformations (Scheme 3).
The chiral amine 8 is a key chiral building block for the
6
7
200
200
98
97
[a] The hydrogenations were carried out in dichloromethane (0.5 mL) for
12 h with substrate (0.1 mmol) and [Rh(nbd)(L5)]BF4 (0.5 mmmol);
complete conversion; the absolute configuration was assigned by
comparing the optical rotation with reported data[10,11] or by analogy; the
yields were >99%; [b] Determined by HPLC using a chiral stationary
phase, see details in the Supporting Information; [c] 5b (1 mmol),
[Rh(nbd)(L5)]BF4 (0.5 mmol), dichloromethane (2 mL), 808C, H2
(750 psi), 20 h.
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Scheme 3. Synthesis of useful intermediates 8 and 10 by using this
hydrogenation methodology.
syntheses of michellamine B and korupensamine A.[5a]
A
highly functionalized enamide 9 was also successfully hydro-
genated in the presence of [Rh(nbd)(L5)]BF4 (0.1 mol%) to
provide chiral amide 10 in 96% ee and 95% yield. Compound
10 is a key chiral intermediate for the a1 adrenoceptor
antagonist silodosin.[6f]
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Y. Chen, R. P. Volante, Org. Lett. 2003, 5, 4749.
In summary, we have successfully developed a novel C2-
symmetric bisphosphorus ligand WingPhos with a deep and
well-defined chiral pocket that has shown high efficiency in
the rhodium-catalyzed asymmetric hydrogenation of (E)-b-
aryl-N-acetyl enamides, cyclic b-aryl enamides, and hetero-
cyclic b-aryl enamides. A series of chiral b-arylisopropyl-
amines, 2-aminotetralines, and 3-aminochromanes can be
synthesized with excellent ee values at high s/c ratios (up to
10000 TON). The methodology has been successfully applied
to the syntheses of several key chiral intermediates of natural
products and therapeutic agents. Since (E)-b-aryl-N-acetyl
enamides can be easily synthesized from readily available
materials, this method holds promise for practical syntheses of
various chiral b-arylamine compounds. A study towards this
end is actively under investigation.
[13] N. M. Laso, B. Quiclet-Sire, S. Z. Zard, Tetrahedron Lett. 1996,
37, 1605.
Received: January 24, 2013
Published online: && &&, &&&&
[14] a) W. Tang, B. Qu, A. G. Capacci, S. Rodriguez, X. Wei, N.
Haddad, B. Narayanan, S. Ma, N. Grinberg, N. K. Yee, S.
Krishnamurthy, C. H. Senanayake, Org. Lett. 2010, 12, 176;
b) 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, 7600.
[15] CCDC 921480 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[16] Gridnev and Imamoto first proposed this mechanism in hydro-
genation of (E)-b-(acylamino)acrylates with BisP* as the ligand,
see: a) M. Yasutake, I. D. Gridnev, N. Higashi, T. Imamoto, Org.
Lett. 2001, 3, 1701; b) I. D. Gridnev, M. Yasutake, N. Higashi, T.
Imamoto, J. Am. Chem. Soc. 2001, 123, 5268.
Keywords: aryl enamides · asymmetric catalysis ·
homogeneous catalysis · hydrogenation · phosphorus ligands
.
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Communications
Homogeneous Catalysis
G. Liu, X. Liu, Z. Cai, G. Jiao, G. Xu,
W. Tang*
&&&& — &&&&
Design of Phosphorus Ligands with Deep
Chiral Pockets: Practical Synthesis of
Chiral b-Arylamines by Asymmetric
Hydrogenation
WingPhos, a C2-symmetric bisphospho-
rus ligand with a deep and well-defined
chiral pocket was developed. It has
shown high efficiency in the rhodium-
catalyzed asymmetric hydrogenation of
(E)-b-aryl-N-acetyl enamides, cyclic b-aryl
enamides, and heterocyclic b-aryl en-
amides. A series of chiral b-arylisopro-
pylamines, 2-aminotetralines, and 3-ami-
nochromans can be synthesized with
excellent ee values (nbd=3,5-norborna-
diene; TON=turnover number).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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www.angewandte.org
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