Highly enantioselective hydrogenation of o-alkoxy tetrasubstituted enamides catalyzed by a Rh/(R, S)-josiphos catalyst

Article abstract of DOI:10.1021/acs.orglett.5b00401

Rh/(R,S)-JosiPhos complex-catalyzed asymmetric hydrogenation of o-alkoxy tetrasubstituted enamides has been achieved, and it furnished a set of β-amino alcohol analogues in high yields and excellent enantiomeric excesses (>99% conversion, up to 99% ee).This method provides valuable chiral building blocks in chiral pharmaceuticals and useful motifs for catalysts.

Full text of DOI:10.1021/acs.orglett.5b00401

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Hydrogenation of ο‑Alkoxy Tetrasubstituted
Enamides Catalyzed by a Rh/(R,S)‑JosiPhos Catalyst
Jingjing Meng, Min Gao, Hui Lv,* and Xumu Zhang*
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
S
* Supporting Information
ABSTRACT: Rh/(R,S)-JosiPhos complex-catalyzed asymmetric hydrogenation
of o-alkoxy tetrasubstituted enamides has been achieved, and it furnished a set of
β-amino alcohol analogues in high yields and excellent enantiomeric excesses
(>99% conversion, up to 99% ee).This method provides valuable chiral building
blocks in chiral pharmaceuticals and useful motifs for catalysts.
Enantiopure β-amino alcohols are valuable building blocks for
the synthesis of pharmaceuticals.1 The incorporation of bulky
β-amino alcohol motifs allows for the development of chiral
ligands2 and chiral auxiliaries,3 glycine templates,4 as well as
organocatalysts5 in asymmetric catalysis (Figure 1). Therefore,
tetrasubstituted enamides remains a challenge. Although our
group recently achieved Rh/DuanPhos-catalyzed asymmetric
hydrogenation of tetrasubstituted α-acetoxy-β-enamido esters
and afforded syn β-amino alcohol motifs with excellent
enantioselectivities, there are several challenges need to be
solved, such as E substrate limitation and low turnover number
(S/C = 20/1) (Scheme 1).12j Therefore, achieving asymmetric
Scheme 1. Hydrogenation Methods for Making Chiral β-
Amino Alcohol Motifs
Figure 1. Selected applications of β-amino alcohol motif and their
derivatives.
hydrogenation of Z-tetrasubstituted substrates with low catalyst
loading is highly desired (Figure 2). Herein, we disclose a
developing efficient synthetic routes for making chiral amino
alcohols has attracted considerable interest. Over the past two
decades, great efforts have been devoted to the synthesis of β-
amino alcohol derivatives, and many methods have been
developed. Typical approaches included Sharpless asymmetric
aminohydroxylation,6 ring-opening of chiral epoxides7 and
aziridines,8 nucleophilic addition to protected imines,9 aldol
reaction of aldehydes,10 and so on. However, these approaches
suffer from some drawbacks such as limited substrate scope,
low functional group tolerance, and poor atom economy.
Alternatively, asymmetric hydrogenation of o-alkoxy enamides,
one of the most straightforward routes to synthesize β-amino
alcohols, could solve this problem.
In the past decades, great progress had been made in
transition-metal-catalyzed asymmetric hydrogenation of enam-
ides, and it has become a robust and readily accessible route to
making chiral amines.11,12 However, in most cases, these
approaches are only suitable for less steric di- or trisubstituted
enamides, and highly efficient hydrogenation of hindered
Figure 2. Structures of the phosphine ligands for hydrogenation of 5a.
Received: February 7, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b00401
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Organic Letters
Letter
highly enantioselective hydrogenation of (Z)-o-alkoxy tetrasub-
stituted enamides catalyzed by the Rh/JosiPhos complexes for
anti chiral β-amino alcohol synthesis.
Our strategy for the synthesis of β-amino alcohol analogues 6
is described in Scheme 2. First, (Z)-o-alkoxy-tetrasubstituted
as ligand, the reaction gave the best results and provided 6a in
99% yield and 91% ee (entries 11−14).
In order to further optimize the reaction conditions, solvents
and Rh(I) species were evaluated. As shown in Table 2, the
Table 2. Solvent and Rh(I) Species Screening for Rh-
Catalyzed Asymmetric Hydrogenation
a
Scheme 2. Design and Synthesis of β-Amino Alcohol
Analogues 6
b
c
entry
solvent
conversion (%)
ee (%)
1
1,2-dichloroethane
dichloromethane
toluene
0
52
-
52
35
55
-
2
3
35
4
THF
56
5
ethyl acetate
dioxane
trace
>99
>99
>99
>99
>99
>99
enamide 5a13 was efficiently synthesized and chosen as a model
substrate to optimize the reaction conditions. The Rh-
(cod)2BF4/DuanPhos catalytic system, previously found to be
effective in hydrogenation of (E)-tetrasubstituted enamides,
exhibited very poor reactivity and enantioselectivity, but when
electron-rich TangPhos was employed, the reaction worked
very smoothly and afforded the desired product 6a with
excellent yield and 86% ee (Table 1, entries 1−2). (S)-Binapine
6
85
91
86
94
92
93
7
methanol
8
propan-2-ol
trifluoroethanol
Rh(NBD)2BF4
Rh(COD)2SO3CF3
9
10
11
a
Unless otherwise mentioned, all reactions were carried out with a
Rh(COD)2BF4/ligand/5a (0.05 mmol) ratio of 1:1.1:100, at 40 °C, 40
atm hydrogen for 24 h. The conversion of the isolated product based
on consumed starting material. Determined by HPLC analysis using a
chiral stationary phase.
b
c
Table 1. Ligand Screening for Rh-Catalyzed Asymmetric
a
Hydrogenation of 5a
reaction showed dramatic solvent effects. Generally, aprotic
solvents except dioxane had negative effects on this reaction,
but the reaction exhibited excellent activities when protic
solvents were employed, of which trifluoroethanol gave the best
results and furnished the desired products in 99% yield and
94% enantioselectivity (Table 2, entries 1−9). In addition,
Rh(I) species such as Rh(NBD)2BF4 and Rh(COD)2SO3CF3
were also investigated and showed the same activities but
slightly lower ee values (Table 2, entries 10 and 11). Under the
optimized reaction conditions (Table 2, entry 9), a variety of o-
alkoxy-tetrasubstituted enamides were examined (Table 3). To
our delight, all aryl group substituted substrates examined here
can work smoothly and afford the corresponding chiral β-amino
alcohols in quantitative yield with excellent enantiomeric
excesses. It was revealed that the position and the electronic
property of the substituents on the phenyl rings have little
effect on the conversion and enantioselectivities (entries 1−10).
However, the profile of this system has not yet been completely
established for cyclic enamides. The hydrogenation of cyclic
enamides derived from α-indanone and α-tetralone gave
excellent yields but with poor enantioselectivities (entries 11
and 12). The corresponding five-membered cyclic enamide
gave moderate ee (56%). Significantly lower ee was observed
for the enamide made from α-tetralone (3.7%).14 Since there is
a need to develop a catalyst to handle all substrates, we will next
continue to develop a simple but powerful strategy for
addressing this problem.
b
c
d
entry
ligand
conversion (%)
ee (%) (config )
1
(Sc,Rp)-DuanPhos
(Sc,Rp)-TangPhos
(S)-binapine
5
>99
>99
67
5 (1R,2S)
86 (1S,2R)
51 (1S,2R)
61 (1R,2S)
68 (1R,2S)
-
2
3
4
(S,S)-Me-DuPhos
(S,S)-Et-DuPhos
(R,R)-Quinoxp
(R)-MeO-Biphep
(S)-SegPhos
5
78
6
0
7
trace
4
-
8
4 (1R,2S)
-
9
(S)-Binap
trace
trace
>99
>99
>99
>99
10
11
12
13
14
(S)-C3-TunePhos
(R,S)-JosiPhos
(S)-WalPhos
-
91 (1S,2R)
46 (1R,2S)
45 (1R,2S)
7 (1R,2S)
TaniPhos
(S,S)-f-binaphane
a
Unless otherwise mentioned, all reactions were carried out with a
Rh(COD)2BF4/ligand/5a (0.05 mmol) ratio of 1:1.1:100, at 40 °C, 40
atm hydrogen for 24 h. The conversion of the isolated product based
on consumed starting material. Determined by HPLC analysis using a
chiral stationary phase. Assignment through comparison of sign of
optical rotation and chiral HPLC elution order with configurationally
defined sample.
b
c
d
and DuPhos exhibited good activities for this reaction but
furnished 6a only with moderate enantioselectivities (entries
3−5). (R,R)-Quinoxp and some chiral biaryl bisphosphorus
ligands such as (R)-MeO-Biphep, (S)-SegPhos, (S)-Binap, and
(S)-C3-TunePhos are sluggish for this transformtaion (entries
6−10). When ferrocene-type chiral phosphorus ligands were
employed, the reaction worked very well and gave the desired
product with excellent yields. Remarkably, using (R,S)-JosiPhos
To demonstrate the potential utilities of the protocol for
synthesis of β-amino alcohols, the reactions were carried out on
gram scale, and the desired products 6a, 6e, and 6h could be
prepared in high yields and excellent enantioselectivities (94−
97% ee). Moreover, when the catalyst loading was decreased to
0.1 mol %, there was no influence on the yield and
enantioselectivity (Scheme 3).
B
DOI: 10.1021/acs.orglett.5b00401
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Organic Letters
Letter
* E-mail: xumu@whu.edu.cn.
Notes
Table 3. Asymmetric Hydrogenation of Enamides Catalyzed
by a Rh/(R,S)-Josiphos Complex
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for 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 Nos. 21372179, 21432007, and
21402145).
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, characterization data, and copies of
1H, 13C, and 19F NMR spectra as well as HPLC results. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: huilv@whu.edu.cn.
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DOI: 10.1021/acs.orglett.5b00401
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DOI: 10.1021/acs.orglett.5b00401
Org. Lett. XXXX, XXX, XXX−XXX