Highly Enantioselective Synthesis of syn-β-Hydroxy α-Dibenzylamino Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale Preparation of Droxidopa

Article abstract of DOI:10.1021/acs.orglett.7b01982

A highly efficient preparation of enantiomerically pure syn aryl β-hydroxy α-dibenzylamino esters is reported. The outcome was achieved via dynamic kinetic resolution and asymmetric transfer hydrogenation of aryl α-dibenzylamino β-keto esters. The desired products were obtained in high yields (up to 98%) with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (up to >99% ee). Furthermore, this method was applied for the gram-scale preparation of droxidopa.

Full text of DOI:10.1021/acs.orglett.7b01982

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Synthesis of syn-β-Hydroxy α‑Dibenzylamino
Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale
Preparation of Droxidopa
Guodong Sun,†,§ Zihong Zhou,† Zhonghua Luo,† Hailong Wang,† Lei Chen,† Yongbo Xu,† Shun Li,†
Weilin Jian,† Jiebin Zeng,† Benquan Hu,† Xiaodong Han,† Yicao Lin,† and Zhongqing Wang*,†,§
†HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P.R. China
§State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan 523871, P.R. China
S
* Supporting Information
ABSTRACT: A highly efficient preparation of enantiomeri-
cally pure syn aryl β-hydroxy α-dibenzylamino esters is
reported. The outcome was achieved via dynamic kinetic
resolution and asymmetric transfer hydrogenation of aryl α-
dibenzylamino β-keto esters. The desired products were
obtained in high yields (up to 98%) with excellent
diastereoselectivity (>20:1 dr) and enantioselectivity (up to
>99% ee). Furthermore, this method was applied for the gram-scale preparation of droxidopa.
drawbacks such as high pressure and air-sensitive catalysts being
required. DKR asymmetric transfer hydrogenation (DKR-
ATH) with hydrogen donors instead of hydrogen gas is more
attractive because of its low cost and operational simplicity. In
this field, several groups have recently described the reduction
of these related compounds in their N-monoprotected
forms10a−d or hydrochloride salts10e,f through Ru-catalyzed
DKR-ATH. Nevertheless, anti diastereomers are often obtained
as the major products (Scheme 1, previous work). For the
hiral aryl β-hydroxy α-amino acids and derivatives are
Cimportant structural motifs in many pharmaceutical
molecules. For example, aryl β-hydroxy α-amino acids are
found in droxidopa1 and a BMS drug candidate,2 in addition to
chloramphenicol,3 thiamphemicol,4 florenicol,5 and all their
corresponding derivatives (Figure 1). Furthermore, chiral aryl
β-hydroxy α-amino acids are also found in natural products
such as cyclomarins6 and ustiloxins.7
Scheme 1. Previous Reports of the Synthesis of Aryl β-
Hydroxy α-Amino Esters and This Work
Figure 1. Examples of chiral pharmaceuticals derived from aryl β-
hydroxy α-amino acids and derivatives.
Because of the great importance of aryl β-hydroxy α-amino
acids, much effort has been devoted to developing asymmetric
methods to prepare these useful compounds.8 Among these
methods, asymmetric hydrogenation via dynamic kinetic
resolution (DKR) of racemic aryl α-amino β-keto esters is
regarded as a powerful synthetic method. The method for DKR
asymmetric hydrogenation (DKR-AH) of racemic aryl α-amino
β-keto esters with chiral ruthenium catalysts was first reported
by Noyori in 1989.9a It provided the syn-aryl β-hydroxy α-
amino esters with high diastereo- and enantioselectivities and
has thus been developed further since then. However, the AH
of related compounds9 remains problematic due to some
synthesis of the syn diastereomers, successful results are rarely
reported,11 and these generally proceed either with poor
enantioselectivities or diastereoselectivities. Therefore, an
asymmetric synthesis of syn-aryl β-hydroxy α-amino acids
with high diastereo- and enantioselectivities is still challenging
and highly desirable.
Received: July 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01982
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Letter
Previously, Guanti et al.12 reported a practical method to
prepare syn-β-hydroxy α-amino esters by reduction of α-
dibenzylamino β-keto esters with NaBH4, but the method
provided only racemic products, although the diastereoselectiv-
ities were perfect (up to >99:1 dr). In light of this, we envisaged
that an asymmetric method for the reduction of aryl α-
dibenzylamino β-keto esters with Ru-catalyzed DKR-ATH
could be developed to prepare enantiomerically pure syn aryl β-
hydroxy α-dibenzylamino esters (Scheme 1, this work).
oxo-tethered Ru(II) catalyst (R,R)-CAT05 developed by
Ikariya and co-workers.15 Surprisingly, the chiral
Cp*MTfDPEN catalysts (M = Rh or Ir, Table 1, entries 6
and 7) both showed no catalytic activities for this reaction.
Subsequently, the influence of the base on the activity of this
DKR asymmetric transfer hydrogenation was evaluated. The
secondary amine diethylamine proved to be the optimal base
and could significantly shorten the reaction time (full
conversion in 24 h, Table 1, entry 9), while other bases
could not play such a role (Table 1, entries 8, 10, and 11). Most
importantly, it was observed that 91% conversion could be
achieved using only 5 mol % catalyst without decreasing the
stereoselectivity or prolonging the reaction time (Table 1, entry
12). Hence, the optimized reaction conditions use oxo-tethered
Ru(II) catalyst (R,R)-CAT05 as the catalyst in a mixture of
HCOOH and diethylamine (5:2, 3 equiv, as the hydrogen
donor) in DCM at reflux (40 °C) for 24 h.
Our initial investigation was carried out using HCOOH/
Et3N as hydrogen donor, with 5a as the model prochiral
substrate in DCM at reflux. Thus, a series of catalysts (Table 1,
Table 1. Optimization of the Reaction Conditions for the
a
DKR-ATH of 5a
With the optimized conditions in hand, a wide range of
substrates were used in the reaction. The results are
summarized in Scheme 2. Substrates with electron-donating
Scheme 2. DKR-ATH of Aryl α-Dibenzylamino β-Keto
a
Esters 5a−l Catalyzed by (R,R)-CAT05
b
c
d
entry
catalyst
base
Et3N
conv (%) dr (syn/anti) ee (%)
1
2
3
4
5
6
7
8
(R,R)-CAT01
(R,R)-CAT02
(R,R)-CAT03
(R,R)-CAT04
(R,R)-CAT05
(R,R)-CAT06
(R,R)-CAT07
(R,R)-CAT05
(R,R)-CAT05
(R,R)-CAT05
(R,R)-CAT05
(R,R)-CAT05
19
36
ND
ND
83
92
Et3N
Et3N
32
ND
92
Et3N
97
>20:1
>20:1
ND
99
Et3N
97
>99
ND
ND
>99
>99
>99
>99
>99
Et3N
trace
trace
91
Et3N
ND
DIPEA
Et2NH
iPr2NH
tBuNH2
Et2NH
>20:1
>20:1
>20:1
>20:1
>20:1
e
9
>99
99
10
11
99
f
12
91
a
Reaction conditions: 5a (1.67 mmol), HCO2H/base (5:2) (3 equiv),
b
DCM(8.0 mL) at reflux (40 °C) for 40 h. Determined by HPLC.
c
d
Determined by 1H NMR. Determined by chiral HPLC using a
e
f
CHIRALPAK IA column. 24 h. 5.0 mol % of (R,R)-CAT05 was
used. ND= not detected.
a
General conditions: 10 mol % of (R,R)-CAT05, substrates 5a−l
(1.67 mmol), HCOOH (5.01 mmol), and Et2NH (2.00 mmol) were
(R,R)-CAT01 to (R,R)-CAT07) were screened under these
conditions. The Ru(II) catalyst (R,R)-CAT01 afforded the
desired product 6a in low conversion (19%, Table 1, entry 1).
(R,R)-CAT02 and (R,R)-CAT03 both showed a moderate
conversion (>30%, Table 1, entries 2 and 3). Notably, a Ru(II)
catalyst (R,R)-CAT04, containing a trifluoromethanesulfonyl
group on the nitrogen atom, exhibited a higher catalytic activity
and afforded 6a in 97% conversion with >20:1 dr and 99% ee
(Table 1, entry 4). These above results indicated that the
sulfonyl function on the sulfonamide group may affect the
reactivity or stereoselectivity.13 As previously reported,
“tethered” Ru (II) catalysts showed better activity and
stereoselectivities in the ATH reaction due to their better
rigidity.14 Indeed, the best result (97% conversion, >20:1 dr
and >99% ee, Table 1, entry 5) was provided by the unique
stirred at 40 °C in DCM for 24 h. Isolated yields after column
chromatography18 were reported, dr ratios were determined by H
1
NMR of the crude reaction mixture, and only a single diastereomer
was visible for most of the products; ee values were determined by a
b
c
CHIRALPAK IA column. Reaction time 15 h. Reaction time 48 h.
d
5.0 mol % of (R,R)-CAT05 was used.
(5a, 5b, 5d, 5g, 5h, and 5l) or electron-withdrawing (5c, 5f, and
5i) substituents all gave excellent stereoselectivity (>20:1 dr
and >99% ee) and good-to-excellent yields (78−98%) under
the optimized conditions. In particular, the substrate 5f afforded
the desired product 6f in 98% isolated yield, with >20:1 dr and
99.9% ee within 24 h. However, analysis of the electronic effect
displayed that the substrates with electron-withdrawing
substituents (5c and 5i, 15 h) at the para-position converted
B
DOI: 10.1021/acs.orglett.7b01982
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
faster than those with electron-donating substituents (5g and
5h, 48 h). Furthermore, this method was also successfully
applied to heteroaromatic substrates, such as 5j and 5k, which
showed good yields and stereoselectivities too. The lower
enantioselectivity of 5k might be due to the weak CH/π
interaction between the pyridine ring and η6-arene ligand of the
Ru catalyst.16 Only the syn diastereomers17 were obtained in all
the above cases. It was believed that the dibenzyl substituents at
the nitrogen atom may play a key role on the stereoselectivity.
To test this idea, the diallylamino derivative 5e was synthesized
and subjected to the reaction. As expected, 6e was obtained
with lower dr and ee value (13:1 dr, 96% ee).
Experimental details and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangzhongqing@hecpharm.com.
ORCID
Guodong Sun: 0000-0003-3785-7641
Zihong Zhou: 0000-0002-9905-6957
Zhongqing Wang: 0000-0001-5194-4157
In order to demonstrate the practicality of this method, the
further application for the synthesis of Droxidopa was
performed as follows (Scheme 3) . The DKR-ATH reaction
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 3. Gram-Scale Synthesis of Droxidopa
We gratefully acknowledge financial support from the State Key
Laboratory of Anti-Infective Drug Development (Sunshine
Lake Pharma Co., Ltd.), (No. 2015DQ780357). We thank
Zeping Zhan and Guozhu Liu (HEC Pharm Co., Inc.) for
NMR assistance and Lina Zhu and Baolei Luan (HEC pharm
Co., Inc.) for HPLC and optical rotation assistance.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01982.
́ ́
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D
DOI: 10.1021/acs.orglett.7b01982
Org. Lett. XXXX, XXX, XXX−XXX