Synthesis of Tridentate Chiral Spiro Aminophosphine?Oxazoline Ligands and Application to Asymmetric Hydrogenation of α-Keto Amides

Article abstract of DOI:10.1002/adsc.201900251

A new type of tridentate chiral spiro aminophosphine?oxazoline ligands (SpiroOAP) have been synthesized through four steps. The SpiroOAP ligands are highly efficient for the asymmetric hydrogenation of α-keto amides, providing a variety of synthetically useful α-hydroxy amides with excellent enantioselectivity (up to 98% ee) and turnover numbers (up to 10,000). (Figure presented.).

Full text of DOI:10.1002/adsc.201900251

Title: Synthesis of Tridentate Chiral Spiro Aminophosphine-oxazoline
Ligands and Application to Asymmetric Hydrogenation of α-Keto
Amides
Authors: Qi-Lin Zhou, Feng-Hua Zhang, Chen Wang, and Jian-Hua Xie
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900251
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10.1002/adsc.201900251
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Tridentate Chiral Spiro Aminophosphine-oxazoline
Ligands and Application to Asymmetric Hydrogenation of α-
Keto Amides
Feng-Hua Zhanga, Chen Wanga, Jian-Hua Xiea and Qi-Lin Zhoua,b*
a
State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Tel: 0086-22-23500011
E-mail: qlzhou@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071,
b
China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
synthesized tridentate chiral spiro ligands SpiroPAP
and SpiroSAP, which show excellent enantio-
selectivity and unprecedented activity (up to 4.5
million TON)[6] in the hydrogenation of simple
ketones and β-keto esters. However, when we applied
these two tridentate ligands for the asymmetric
hydrogenation of -keto amides, only up to 82% ee
and 84% ee were obtained, respectively. For
improving the enantioselectivity and activity of the
iridium catalyst, we designed a new type of tridentate
chiral spiro phosphine ligands, SpiroOAP (1), by
introducing an oxazoline moiety into the molecule
(Figure 1). We hope to increase the enantioselectivity
of the catalysts in the asymmetric hydrogenation of
-keto amides by varying the substituent and
configuration on the oxazoline ring of the ligands.
Abstract: A new type of tridentate chiral spiro
aminophosphine-oxazoline ligands (SpiroOAP) have
been synthesized through four steps. The SpiroOAP
ligands are highly efficient for the asymmetric
hydrogenation of α-keto amides, providing a variety
of synthetically useful α-hydroxy amides with
excellent enantioselectivity (up to 98% ee) and
turnover numbers (up to 10,000).
Keywords: Tridentate ligand, Chiral spiro catalyst;
Asymmetric hydrogenation, Iridium, -Keto amides.
Transition metal-catalyzed asymmetric hydroge-
nation of unsaturated compounds is an efficient and
convenient method for the synthesis of chiral
molecules in optical form, which had been applied in
wide field such as pharmaceuticals, pesticides,
flavors, and fragrances. Since Knowles and co-
workers[1] reported that the chiral phosphine can
control the enantioselectivity of rhodium-catalyzed
hydroge-nation of dehydroamino acid derivatives,
many chiral ligands have been developed for the
asymmetric hydrogenation of various unsaturated
compounds such as olefins, ketones, and imines. The
breakthrough in the asymmetric hydrogenation of
simple ketone was made by Noyori and co-workers[2]
in the 1990s with the catalyst BINAP-ruthenium-
diamine complexes. Inspired by this work, many
diphosphine ligands have been developed for the
asymmetric hydrogenation of ketones in the last two
decades[3]. For enhancing the stability of the catalyst,
tridentate phosphine ligands containing nitrogen
moiety, such as PNP[4] and PNN[5] were designed and
applied for the asymmetric hydrogenation of ketones.
During our studies on the iridium-catalyzed
asymmetric hydrogenation of ketones, we have
Figure 1. Tridentate chiral spiro ligands
The tridentate chiral spiro phosphine ligands
SpiroOAP were synthesized from the ligands
SpiroAP[7]. The reductive amination of SpiroAP with
ethyl glyoxalate afforded the ester 2 in 96% yield.
The ester 2 was hydrolyzed to the acid 3 in 89% yield
with LiOH. The condensation of the acid 3 with
enantiomerically pure 2-amino alcohols in the
presence of HOBt (1-hydroxybenzotriazole) and
EDCI-HCl (1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride) gave the amides 4 in 73-97%
1
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10.1002/adsc.201900251
Advanced Synthesis & Catalysis
yield. The cyclization of the amides 4 provided the
target ligands SpiroOAP in 53-82% yield. The
ligands SpiroOAP are stable and can be purified by
silica gel column chromatography (Scheme 1).
Flavour Extract Manufacturers Association) (top part);
Asymmetric hydrogenation of -keto amides catalyzed by
Ir-SpiroOAP (bottom part).
The hydrogenation of N,N-dimethyl-2-oxo-2-
phenylacetamide (5a) was performed in EtOH under
12 atm of H2 to evaluate the new ligands. As shown
in Table 1, all iridium catalysts with ligands 1
displayed high reactivity, the yields are >99%.
However, the enantioselectivity of catalysts varied
with the substituent and configuration on the
oxazoline ring of ligand. When the steric hindrance of
the substituent on the oxazoline ring increased from
methyl (1a) to tert-buty (1d), the enantioselectivity
changed from 88% ee to 97% ee (Table 1, entries 3, 4
and 6–8). The combination of the configurations of
the ligand is critical for the enantioselectivity, with
(Ra,R) being the choice of the configuration of the
ligand (entry 4 vs entry 5). A study of solvent showed
that the MeOH gives even higher enantioselectivity
(98% ee, entry 9). It is delighted to find that the
K2CO3 is also a suitable base for the reaction, giving
excellent yield and enantioselectivity (entry 11). The
weaker basicity and low loading of K2CO3 endowed
this reaction with another advantage, tolerating more
functional groups in the substrates
Scheme 1. Synthesis of ligands SpiroOAP (1).
Optical -hydroxy amides are important motifs for
the synthesis of biologically active compounds[8].
Chiral -hydroxy ketones, which can be obtained
from the optical -hydroxy Weinreb amides through
a nucleophilic addition with Grignard reagents, are a
class of flavors[9] (Figure 2). Transition metal-
catalyzed asymmetric hydrogenation of -keto
amides is a straightforward access to optical -
hydroxy amides. However, in a sharp contrast to -
Table 1. Asymmetric hydrogenation of -keto amide 5a.
Optimization of the reaction conditions.a
keto esters[10], -keto esters[11] and -keto acids[12]
,
the asymmetric hydrogenation of -keto amides has
been less studied. Only a few examples were reported
on the asymmetric hydrogenation of -keto amides
with high enantioselectivity.[13] However, these
methods still suffered from low efficiency or limited
substrate scope. Therefore, efficient chiral ligands
with high enantioselectivity, high activity, and wide
substrate scope are desired for the catalytic
asymmetric hydrogenation of -keto amides.
Yield
ee
Entry
Ligand
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Base
(%)b (%)c
1
2
SpiroPAP
SpiroSAP
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
82
84
88
92
68
93
97
90
98
25
98
3
(R )-1a
a
4
(R ,R)-1b
a
5
(R ,S)-1b
a
6
(R ,R)-1c
a
7
(R ,R)-1d
a
8
(R ,R)-1e
a
9
MeOH tBuOK
iPrOH tBuOK
(R ,R)-1d
a
10d
(R ,R)-1d
a
11
MeOH K2CO3
(R ,R)-1d
a
[a]Reaction conditions: 1.0 mmol scale, 0.17 mol%
[Ir(COD)Cl]2, 0.37 mol% ligand, 2 mol% base, 4.0 mL
Figure 2. Representative biologically active compounds
containing -hydroxy amide moiety and flavors (FEMA =
2
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10.1002/adsc.201900251
Advanced Synthesis & Catalysis
[c]
[d]
solvent, rt,1-2 h. [b] Isolated yield. [c] Determined by HPLC
with chiral OD-H. [d] Reaction time is 22 h.
100% conv., 15 h.
time is 24 h.
Ligand (Ra,S)-1b used.
Reaction
(R1 = Me) underwent the hydrogenation smoothly,
providing the desired product 6q in 99% yield with
91% ee. The secondary -keto amide substrates can
also be hydrogenated to -hydroxy amides in high
yield, however, with lower enantioselectivity (6r
(74% ee) and 6s (79% ee), respectively). As we
expected, the -keto Weinreb amides are suitable
substrates for the asymmetric hydrogenation
catalyzed by Ir-SpiroOAP, affording the desired
products with 78−91% yield and 87−94% ee (6t–6x).
Under the optimized reaction conditions, a variety
of -keto amides were hydrogenated to -hydroxy
amides and the results are summarized in Table 2.
The tertiary -keto amide substrates showed high
yield and high enantioselectivity in the hydrogenation
reaction (Table 2, 6a – 6q). The catalyst (Ra,R)-1d
exhibited high activity, its TON reaches 10,000 (6h).
The functional groups on the benzene ring of
substrates, such as halogen, trifluoromethyl, ether,
and ester were tolerated in the reaction. The
electronic property of the substituents on the benzene
ring of substrates has a little influence on the
enantioselectivity of reaction, with electron-
withdrawing group at ortho- and meta-position giving
slightly lower ee (6c, 6d and 6g). It was delighted to
find that the substrate with an acetyl group
The hydrogenation products, optical -hydroxy
amides, can be readily converted to β-amino alcohols,
-hydroxy ketones and other useful compounds. For
example, the reduction of -hydroxy amide 6h with
LiAiH4 produced β-amino alcohol 7 (72% yield, 99%
ee), which is an intermediate for the synthesis of 1,2-
amino ether ligands[14]. The addition of PhMgBr to 6t
afforded -hydroxy ketone 8 (79% yield, 90% ee),
which is a widely used flavor (Scheme 2).
Table 2 The asymmetric hydrogenation of α-keto amides
catalyzed by Ir-(Ra,R)-1d a
Scheme 2 Transformations of the hydrogenation products
In summary, a new type of chiral tridentate spiro
PNN ligands SpiroOAP have been synthesized
through four steps. The iridium catalysts coordinated
with ligands SpiroOAP showed high activity and
enantioselectivity for the asymmetric hydrogenation
of ‑ keto amides. By using catalysts Ir-SpiroOAP, a
variety of chiral -hydroxy amides have been
synthesized with excellent enantioselectivity (up to
98% ee) and turnover numbers (up to 10,000).
Further investigations on the applications of the new
ligands to other asymmetric reactions are underway
in our group.
Experimental Section
The catalyst precursor [Ir(COD)Cl]2 (1.2 mg), Ligand 1d
(3.1 mg), and anhydrous MeOH (1 mL) were added under
Ar atmosphere to a hydrogenation vessel (20 mL). The
vessel was then placed in an autoclave and purged with
hydrogen by pressurizing to 12 atm. The mixture was
stirred for 10 min to give a clear yellow solution. After
releasing the pressure, -keto amide (1.0 mmol), K2CO3
(2.8 mg) and MeOH (3 mL) were added through the
[a]
Reaction conditions: 1.0 mmol scale, 0.17 mol%
[Ir(COD)Cl]2, 0.37 mol% (Ra,R)-1d, 0.02 mmol K2CO3,
4.0 mL MeOH, rt,1-6 h, isolated yield. TON = 10,000.
[b]
3
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10.1002/adsc.201900251
Advanced Synthesis & Catalysis
injection port. The autoclave was then pressurized to 12
atm of H2 and the reaction mixture was stirred at room
temperature until no obvious hydrogen pressure drop was
observed. After releasing the hydrogen pressure, the
solvent was removed, and the residue was purified with
column chromatography on silica gel. The enantiomeric
excess of product was determined by HPLC on a chiral
stationary phase.
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We thank the National Natural Science Foundation of
China (Nos. 21532003, 21790330 and 21871152) and the
“111” project (B06005) of the Ministry of Education of
China for financial support.
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4
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10.1002/adsc.201900251
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis
of
Tridentate
Chiral
Spiro
and
Aminophosphine-oxazoline
Ligands
Application to Asymmetric Hydrogenation of -
Keto Amides
Adv. Synth. Catal. Year, Volume, Page – Page
Feng-Hua Zhang, Chen Wang, Jian-Hua Xie, Qi-
Lin Zhou*
5
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