Enantioselective synthesis of anti-β-amido-α-hydroxy esters via asymmetric transfer hydrogenation coupled with dynamic kinetic resolution

Article abstract of DOI:10.1016/j.tetlet.2013.07.100

The asymmetric transfer hydrogenation of β-amido-α-keto esters providing the corresponding anti-β-amido-α-hydroxy esters via dynamic kinetic resolution is reported. The use of a commercially available, or simply prepared, chiral ruthenium catalyst results in good yields as well as high diastereoselectivities and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2013.07.100

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of anti-b-amido- -hydroxy esters via
a
asymmetric transfer hydrogenation coupled with dynamic kinetic
resolution
Marvin Villacrez a, Peter Somfai a,b,
⇑
a Centre for Analysis and Synthesis, Lund University, PO Box 124, 221 00 Lund, Sweden
b Institute of Technology, University of Tartu, Nooruse 1, 504 41 Tartu, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric transfer hydrogenation of b-amido-a-keto esters providing the corresponding anti-b-
amido-a-hydroxy esters via dynamic kinetic resolution is reported. The use of a commercially available,
or simply prepared, chiral ruthenium catalyst results in good yields as well as high diastereoselectivities
and enantioselectivities.
Received 18 June 2013
Revised 6 July 2013
Accepted 19 July 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dynamic kinetic resolution
Asymmetric transfer hydrogenation
Ruthenium
Enantioselective
1,2-Amino alcohols
The b-amino-a-hydroxy ester functionality, and the related vic-
inal amino alcohol moiety, are found in a variety of biologically
active natural products.1 The importance of 1,2-amino alcohols is
also well recognized in asymmetric synthesis, where the need for
chiral auxiliaries and ligands is continuously increasing.2 Not sur-
prisingly, the asymmetric synthesis of these structures has
received considerable attention.3
It has been shown that asymmetric transfer hydrogenation (ATH)
coupled with dynamic kinetic resolution (DKR)4 can be applied to
the formation of
we have previously shown that ATH/DKR of
esters 1 offers an efficient entry to anti- -amido-b-hydroxy esters
(Scheme 1).6 This strategy relies on the stereochemical lability of
the -stereocenter in 1, allowing for two stereocenters to be
introduced in the asymmetric reduction. The b-amido- -hydroxy
ester 4 could, in theory, be obtained from 3 using a similar ATH/
DKR approach, thus accessing the regioisomeric amino alcohol
derivatives. The realization of such a strategy would depend on
the rate of racemization of the b-stereocenter in substrate 3, which
must be faster than the rate of transfer hydrogenation. Although this
kinetic scenario is indeed operating in the ATH/DKR of ester 1, it is
not obvious that it should also hold true for regioisomer 3, in which
the rate of racemization would be expected to be lower than
that in 1.
a
-substituted-b-hydroxy esters.5 In addition,
a
-amido-b-keto
Scheme 1.
a
In an elegant study, Johnson and co-workers demonstrated that
-keto esters can be reduced using ATH/DKR to
the corresponding b-alkyl-substituted
yield, distereoselectivity, and enantioselectivity, thus lending
considerable support for the proposed conversion of ketone 3 into
amido alcohol 4.7 More recently, the Johnson group reported the
asymmetric synthesis of compound 4 from 3 using an asymmetric
transfer hydrogenation coupled with kinetic resolution,8 which
prompted us to report our findings in this area. Herein, we report
a
b-alkyl-substituted
a
a
a
-hydroxy esters in high
our results on the enantioselective synthesis of anti-b-amido-a-
hydroxy esters via ATH/DKR.
We began our investigation of the ATH/DKR of b-amido-a-keto-
esters by subjecting substrate 5a9 and [RuCl2(cymene)]2 to a series
of 1,2-diphenylethane-1,2-diamine (DPEN) and 2-amino-1,2-
diphenylethanol (DPAE) derived chiral ligands in DMF using HCO2-
⇑
Corresponding author. Tel.: +46 70 6936377; fax: +46 46 2228209.
E-mail address: peter.somfai@chem.lu.se (P. Somfai).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.100
Please cite this article in press as: Villacrez, M.; Somfai, P. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.07.100

2
M. Villacrez, P. Somfai / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Asymmetric transfer hydrogenation of 5aa
Entry
Ligand
Solvent
Yieldb (%)
Time (h)
drb
erc
1
2
3
4
5
7
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
Et3N:HCO2H (2:5)
H2O:CH2Cl2
95
95
73
97
88
90
94
93
95
1
1
5
1
0.5
1
1
1
1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
3:1
94:6
95:5
8d
9
78:22
81:19
83:17
90:10
94:6
10
11
8d
8d
8d
8d
6
7
8
92:8
9e
n.d.f
a
Reactions performed by heating [Ru(cymene)Cl2]2 (0.05 equiv) and the ligand (0.15 equiv) in 2-propanol (c 0.1 M) at 80 °C for 1 h. After cooling to rt the solvent was
removed and the catalyst was added to a solution of 5a (1 equiv, c 0.1 M) and HCO2H/Et3N (5:2, 5 equiv).
b
Yield and dr determined by 1H NMR spectroscopy of the crude reaction mixture.
Determined by chiral HPLC analysis of the crude reaction mixture.
Commercially available RuCl[(R,R)-FsDPEN](p-cymene) was used.
Reaction was performed using emulsion conditions, see Ref. 6b.
c
d
e
f
Not determined.
decreased upon prolonged reaction time, going from dr >20:1
(anti:syn) when the reaction was terminated after 1 h to 3:1 (anti:-
syn) when it was allowed to stand overnight. It is believed that this
is the result of epimerization of the a-stereocenter under the reac-
Table 2
Substrate scope of the ATH/DKR reactiona
tion conditions and that the dr obtained after prolonged reaction
times represents the equilibrium value under the present condi-
tions. Furthermore, 6a was not stable during purification by flash
chromatography on silica gel resulting in a 40–50% isolated yield,
compared to 95% yield as determined by 1H NMR spectroscopy of
the crude reaction mixture using an internal standard.
With the optimized conditions in hand the scope of the reaction
was examined and the performance of several aromatic substrates
5a–g was investigated (Table 2).12 Both electron-rich (entries 2 and
3) and electron-poor (entry 4) aromatics performed well, affording
the corresponding anti-amino alcohols as the only detectable dia-
stereomer in good yields and high er. Somewhat surprisingly, the
m-bromo derivative 5f was reduced with only modest er, while
the corresponding o-bromo compound 5e yielded amino alcohol
6e in high er. It was also noted that the heteroaromatic substrate
5g was tolerated under the reaction conditions, affording 6g in
good yield and selectivity.
Entry
5, R=
Yieldb (%)
Time (h)
erc
1
2
3
4
5
6
7
a, Ph
95
96
96
89
78
68
92
1
1
1
2
2
2
1
95:5
98:2
94:6
99:1
94:6
62:38
94:6
b, p-MeOC6H4
c, p-MeC6H4
d, p-FC6H4
e,o-BrC6H4
f, m-BrC6H4
g, 3-Thienyl
a
To a solution of the substrate (1 equiv) in DMF (c 0.1 M) was added RuCl[(R,R)-
FsDPEN](p-cymene) (5 mol %) and HCOOH/Et3N (5:2, 5 equiv), and the resultant
mixture was stirred at rt for the indicated time.
Yield and dr (>20:1 in each case) determined by 1H NMR spectroscopy of the
b
crude reaction mixture.
In conclusion, a rapid and straightforward diastereo- and enan-
c
Determined by chiral HPLC analysis of the crude reaction mixture.
tioselective synthesis of anti-b-amido-a-hydroxy esters via ATH/
DKR of the corresponding b-amido- -keto esters has been devel-
a
H:Et3N as the reducing agent (Table 1, entries 1–5). In all cases the
corresponding b-amido-a-hydroxy ester 6a was obtained in good
oped. The present protocol makes use of a commercially available
ligand–catalyst complex, thus making it easy and operationally
straightforward to perform.
yield and excellent diastereoselectivity, favouring the anti diaste-
reomer.10 The optimal conditions used the pentafluorinated DPEN
derivative 8 as ligand, affording 6a in 95:5 er (Table 1, entry 2).11
Next, the influence of changing the solvent on the reaction out-
come was investigated, but solvents other than DMF resulted in
inferior results (entries 2 and 6–9). Several aspects of this reaction
are noteworthy. Compared to the ATH/DKR of the regioisomeric
Acknowledgment
The authors would like to thank Lund University and the Esto-
nian Ministry of Education (project no. SF0180073s08) for funding.
a
-amido-b-keto esters, which normally take 1–7 days to reach
References and notes
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8 (entry 2). This difference in reactivity is perhaps due to the in-
creased electrophilicity of the
to that of the regioisomeric b-carbonyl derivative, resulting in a
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a-carbonyl carbon in 5a compared
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M. Villacrez, P. Somfai / Tetrahedron Letters xxx (2013) xxx–xxx
3
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ꢀ
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0.1 mmol) in DMF (1 mL) was transferred to a vial containing RuCl[(R,R)-
Stereoselective Synthesis of anti-b-Hydroxy-
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of -Amino Acids; American Chemical Society, 2009; Vol. 1009, pp 227–238.
a
-Amino Acids Using anti-
FsDPEN](p-cymene) (3.5 mg, 4.9
lmol) After stirring for 10 min, HCO2H/Et3N
(40 L, 0.5 mmol) was added. Upon completion of the reaction, the mixture
l
a
was diluted with Et2O (5 mL) and H2O (5 mL), the phases were separated and
the aqueous layer was extracted with Et2O (3 ꢂ 5 mL). The organic phase was
dried (Na2SO4) and concentrated. 1H NMR analysis of the crude reaction
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mixture indicated
a 95% yield (2-methoxynaphthalene as the internal
standard). The residue was purified by flash chromatography (15%
EtOAc:heptane) to give 6a as a white solid (20 mg, 65%). 1H NMR (400 MHz,
CDCl3):
d 7.34–7.23 (m, 5H), 5.62–5.60 (d, J = 8.5 Hz, 1H), 5.12–5.10 (d,
8. Goodman, C. G.; Do, D. T.; Johnson, J. S. Org. Lett. 2013, 15, 2446–2449.
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Jiang, N.; Chen, S.; Peng, C.; Zhang, X.; Zou, Y.; Zhang, S.; Wang, J. Tetrahedron
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J = 8.5 Hz, 1H), 4.58 (br s, 1H), 4.19–4.07 (m, 2H), 2.90–2.89 (d, J = 6.7 Hz, 1H),
1.43 (s, 9H), 1.26–1.23 (t, J = 7.15 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 172.0,
153.5, 130.1, 128.1, 129.7, 76.9, 73.1, 62.3, 55.5, 28.3, 14.1.
Please cite this article in press as: Villacrez, M.; Somfai, P. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.07.100