Highly enantioselective synthesis of chiral cyclic allylic amines via RH-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ol501421g

Highly regioselective and enantioselective asymmetric hydrogenation of cyclic dienamides catalyzed by an Rh-DuanPhos complex has been developed, which provides a readily accessible method for the synthesis of chiral cyclic allylic amines in excellent enantioselectivities (up to 99% ee). The products are valuable chiral building blocks and could be easily transformed to multisubstituted cyclohexane derivatives.

Full text of DOI:10.1021/ol501421g

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Synthesis of Chiral Cyclic Allylic Amines via
Rh-Catalyzed Asymmetric Hydrogenation
Ming Zhou, Tang-Lin Liu, Min Cao, Zejian Xue, Hui Lv,* and Xumu Zhang*
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
S
* Supporting Information
ABSTRACT: Highly regioselective and enantioselective
asymmetric hydrogenation of cyclic dienamides catalyzed by
an Rh-DuanPhos complex has been developed, which provides
a readily accessible method for the synthesis of chiral cyclic
allylic amines in excellent enantioselectivities (up to 99% ee).
The products are valuable chiral building blocks and could be
easily transformed to multisubstituted cyclohexane derivatives.
hiral allylic amine moieties exist in many biologically
important natural products (Figure 1);1 therefore,
acetamide by using the diphosphine ligand DIOP.8 Since
then, catalytic asymmetric hydrogenation of enamides has been
one of the most powerful approaches to synthesize secondary
chiral amines and impressive progress has been made.9
In the context of our ongoing research in the field of
asymmetric hydrogenation, we are always interested in
asymmetric hydrogenation of new substrates such as function-
alized enamides. Along this line, we recently reported the
synthesis of chiral aliphatic amines through asymmetric
hydrogenation of dienamides with excellent efficiency and
enantioselectivity.10 We envisioned that the approach might be
also suitable for hydrogenation of cyclic dienamides to afford
enantiomerically pure cyclic allylic amines. Herein, we report
the first regio- and enantioselective hydrogenation of cyclic
dienamides in the presence of a chiral rhodium/diphosphine
catalyst, giving chiral cyclic allylic amines in high yields and
excellent enantioselectivities.
C
Figure 1. Selected natural products containing chiral allylic amine
scaffolds.
Various cyclic dienamides can be easily prepared from readily
accessible corresponding α,β-unsaturated ketones under mild
conditions, according to the recently published procedure
(Scheme 1).11 The feasibility of using Rh/diphosphine catalysts
generated in situ in AHs of cyclic dienamides was first
investigated by screening a wide range of diphosphine ligands
considerable effort has been devoted to the synthesis of chiral
allylic amines.2 The most applied approach to chiral allylic
amines is palladium- or iridium-catalyzed enantioselective allylic
amination.3 In addition, several other representative methods,
including catalytic asymmetric rearrangement of prochiral
allylic imidates,4 gold-catalyzed intermolecular hydroamination
of allenes,5 and asymmetric addition of potassium alkenyl-
trifluoroborates to N-tosyl imines,6 have been well documented.
However, most of these methods have a limited substrate scope
and issues related to activities and selectivities. More
importantly, catalytic asymmetric synthesis of chiral cyclic
allylic amines is still rare,3d,7 and enantioselective synthesis of
allylic amines remains a significant challenge.
Scheme 1. Design and Synthesis of Chiral Allylic Amines
Of particular interest for the synthesis of chiral fine chemicals
is asymmetric hydrogenation (AH) for the virtue of high
efficiency, atom economy, and cost effectiveness of the
methodology. In 1972, Kagan reported their pioneering work
on the Rh-catalyzed AH of (E)-N-(1-phenylprop-1-enyl)-
Received: May 18, 2014
© XXXX American Chemical Society
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Letter
with N-(5-phenylcyclohexa-1,5-dienyl)acetamide (3a) as a
model substrate (Figure 2). As illustrated in Table 1, except
8). Subsequently, electron-donating P-chiral diphosphine
ligands developed in our group were screened. It was found
that the Rh-DuanPhos catalyst can give excellent enantiose-
lectivity in the hydrogenation of cyclic dienamides (Table 1,
entry 12). With a shorter reaction time (2 h), 3a could be
completely transformed to 4a with excellent enantioselectivity
and regioselectivity (Table 1, entry 13).
Encouraged by these promising results, the solvent effect was
then investigated. As shown in Table 2, i-PrOH was revealed to
be the best solvent of choice.
Table 2. Solvent Screening for Rh-Catalyzed Asymmetric
a
Hydrogenation of Cyclic Dienamide (3a)
b
b
c
entry
solvent
MeOH
conversion (%)
4a/5a
ee (%)
1
2
3
4
5
>99
>99
>99
>99
>99
>98:2
>98:2
>98:2
>98:2
>98:2
97
97
98
96
96
EtOH
i-PrOH
ethyl acetate
CH2Cl2
Figure 2. Structures of the phosphine ligands for hydrogenation of
cyclic dienamide 3a.
a
Unless otherwise mentioned, all reactions were carried out with a
catalyst/substrate ratio of 1:100, in 1 mL of solvent at room
Table 1. Ligand Screening for Rh-Catalyzed Asymmetric
Hydrogenation of Cyclic Dienamide (3a)
b
1
a
temperature under hydrogen (1 atm) for 2 h. Determined by H
c
NMR spectroscopy. Determined by HPLC analysis using a chiral
stationary phase.
Under the optimized reaction conditions, a variety of cyclic
dienamides were hydrogenated to afford the corresponding
chiral cyclic allylic amines, and the results are presented in
Table 3. Gratifyingly, it appears that the position and the
electronic property of the substituents on the phenyl rings have
little effect on the enantioselectivities (Table 3, entries 1−13).
Substrates containing 2-thiophenyl or 2-naphthyl moieties were
well applicable (Table 3, entries 14, 15). On the other hand,
trienamide 3r was also investigated to yield the single
hydrogenated product with excellent regioselectivity and
enantioselectivity (Table 3, entry 18). Remarkably, the AH of
cyclic dienamide 3q containing an alkyne moiety did not lead
to the corresponding N-(3-(phenylethynyl)cyclohex-2-enyl)-
acetamide, but offered (Z)-N-(3-styrylcyclohex-2-enyl)-
acetamide 4q with comparably high yield, and a slightly lower
ee value was observed (Table 3, entry 17).
b
b
c
entry
ligand
(R)-Binap
conversion (%)
4a/5a
ee (%)
1
>99
>99
>99
>99
51
95:5
96:4
50
69
50
76
46
2
2
(R)-MeO-Biphep
(S)-C3-TunePhos
(S)-SegPhos
3
89:11
94:6
4
5
(R,R)-QuinoxP
JosiPhos
95:5
6
>99
>99
>99
>99
>99
>99
>99
>99
94:6
7
WalPhos
62:38
60:40
51:49
>98:2
92:8
60
95
94
35
80
97
97
8
(S,S)-Me-DuPhos
(S,S)-Et-DuPhos
(S)-Binapine
9
10
11
12
TangPhos
(Sc,Rp)-DuanPhos
(Sc,Rp)-DuanPhos
67:33
>98:2
d
13
To further illustrate the potential utility of this method, the
hydrogenation of N-(5-phenylcyclohexa-1,5-dienyl)acetamide
(3a) was carried out on gram scale, and the desired product was
furnished with 98% yield and 98% ee (Scheme 2a). The
remaining CC bond in product 4 makes it a versatile building
block in synthetic chemistry. In the presence of Crabtree’s
catalyst, the product 4a could be further hydrogenated in
CH2Cl2 at room temperature under hydrogen (50 atm),
affording enantiomerically pure N-(3-phenylcyclohexyl)-
acetamide 5a with a high yield and d.r. value (Scheme 2b).
Meanwhile, epoxidation of 4a was also performed with m-
CPBA in CH2Cl2, giving the desired product 6 in excellent
diastereoselectivity and without loss of enantiomeric purity
(98% ee, >98:2 d.r.). The ring-opening reaction of epoxide 6
was conducted by using NaN3 as a nucleophile in hot water,
affording product 7 with three contiguous stereogenic centers
in excellent enantio- and diastereoselectivities (Scheme 2c).
a
Unless otherwise mentioned, all reactions were carried out with a
[Rh(cod)2]BF4/ligand/substrate ratio of 1:1.1:100, in 1 mL of MeOH
at room temperature under hydrogen (1 atm) for 20 h. Determined
by H NMR spectroscopy. Determined by HPLC analysis using a
chiral stationary phase. Completed in 2 h.
b
c
1
d
for the low activity of (R,R)-QuinoxP, all of the tested ligands
showed high activity and gave 4a as a major product, although
the enantioselectivity varied to some extent depending on the
ligand. Some chiral biaryl bisphosphorus ligands such as Binap,
(R)-MeO-Biphep, (S)-SegPhos, and (S)-C3-TunePhos afforded
promising chemoselectivity and moderate enantioselectivity
(Table 1, entries 1−4). When chiral ferrocenyl ligands were
employed, bad to moderate enantioselectivities were obtained
(Table 1, entries 6−7). When (S,S)-Me-DuPhos was employed,
the enantioselectivity was increased to 95% ee (Table 1, entry
B
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Table 3. Rh-Catalyzed Asymmetric Hydrogenation of
Various Cyclic Dienamides (3)
ASSOCIATED CONTENT
■
a
S
* Supporting Information
Detailed experimental procedures and complete character-
izations of the substrates and hydrogenation products (NMR
spectra, HPLC chromatograms of racemic and enantioenriched
compounds, and HRMS). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: huilv@whu.edu.cn.
*E-mail: xumu@whu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support by a grant from Wuhan
University (203273463), “111” Project of the Ministry of
Education of China, and the National Natural Science
Foundation of China (Grant No. 21372179).
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In conclusion, we have developed a highly regioselective and
enantioselective asymmetric hydrogenation of cyclic diena-
mides to afford cyclic allylic amines with excellent enantiose-
lectivities (up to 99% ee) using a commercially available Rh-
DuanPhos catalyst. With the mild conditions, broad substrate
scope, and readily accessible versatile transformation of cyclic
allylic amines, we anticipate it will find broad applications in
organic synthesis. Efforts to expand this strategy to other
interesting substrates are underway in our laboratory.
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