Asymmetric transfer hydrogenation coupled with dynamic kinetic resolution in water: Synthesis of anti -β-hydroxy-α-amino acid derivatives

Article abstract of DOI:10.1021/ol303115v

The use of asymmetric transfer hydrogenation combined with dynamic kinetic resolution for the synthesis of β-hydroxy-α-(tert-butoxycarbonyl) amino esters in water is described. This procedure provides the desired amino alcohols in good yields, diastereoselectivities, and enantioselectivities. A surfactant is employed to achieve good yields due to the hydrophobic nature of both the catalyst and substrate. The reaction setup is operationally simple, and nondegassed water can be used as the solvent.

Full text of DOI:10.1021/ol303115v

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6334–6337
Asymmetric Transfer Hydrogenation
Coupled with Dynamic Kinetic
Resolution in Water: Synthesis of
anti-β-Hydroxy-r-amino Acid Derivatives
Brinton Seashore-Ludlow,*,† Franc-ois Saint-Dizier,† and Peter Somfai*,‡,§
Organic Chemistry, Department of Chemical Science and Engineering,
KTH Royal Institute of Technology, 100 44 Stockholm, Sweden, Centre for Analysis and
Synthesis, Lund University, Box 124, 221 00 Lund, Sweden, and Institute of Technology,
University of Tartu, Nooruse 1, 504 11 Tartu, Estonia
brinton@kth.se; Peter.Somfai@chem.lu.se
Received November 12, 2012
ABSTRACT
The use of asymmetric transfer hydrogenation combined with dynamic kinetic resolution for the synthesis of β-hydroxy-R-(tert-butoxycarbonyl)-
amino esters in water is described. This procedure provides the desired amino alcohols in good yields, diastereoselectivities, and enantio-
selectivities. A surfactant is employed to achieve good yields due to the hydrophobic nature of both the catalyst and substrate. The reaction setup
is operationally simple, and nondegassed water can be used as the solvent.
The development of methods for the stereoselective con-
struction of β-hydroxy-R-amino acids and their derivatives
is of signifiant interest due to the high frequency of such
architectures in natural products and pharmaceuticals.
For example, this particular molecular arrangement is
found in sphingosine,1 cyclomarin C,2 the papuamides,3
the thiopeptide antibiotic, GE2270A,4 and vancomycin,5
all of which possess important biological properties.
Furthermore, derivatives of these compounds can also be
used as chiral auxiliaries and chiral building blocks.6
An elegant approach to the desired chiral subunits is the
asymmetrictransfer hydrogenation (ATH)7 or asymmetric
hydrogenation (AH)8 of configurationally labile β-keto-
esters bearing an R nitrogen substituent. Such a reaction
sequence proceeds through a dynamic kinetic resolution
(DKR) and sets the configuration of both stereocenters.9
† KTH Royal Institute of Technology.
‡ Lund University.
§ University of Tartu.
(1) (a) Llaveria, J.; Diaz, Y.; Matheu, M. I.; Castillon, S. Org. Lett.
2008, 11, 205–208. (b) Torssell, S.; Somfai, P. Org. Biomol. Chem. 2004,
2, 1643–1646. (c) van den Berg, R. J. B. H. N.; van den Elst, H.;
Korevaar, C. G. N.; Aerts, J. M. F. G.; van der Marel, G. A.; Overkleeft,
H. S. Eur. J. Org. Chem. 2011, 2011, 6685–6689.
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Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721–2724.
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Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; Dilip de Silva, E.;
Lassota, P.; Allen, T. M.; Van Soest, R.; Andersen, R. J.; Boyd, M. R.
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(6) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–
876.
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Genet, J.-P. Chem. Commun. 2004, 1296–1297. (b) Mohar, B.; Valleix,
A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C. Chem.
Commun. 2001, 2572–2573. (c) Xu, Z.; Zhu, S.; Liu, Y.; He, L.; Geng, Z.;
Zhang, Y. Synthesis 2010, 811–817.
(8) (a) Makino, K.; Iwasaki, M.; Hamada, Y. Org. Lett. 2006, 8,
4573–4576. (b) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetra-
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Fujii, T.; Maeda, T.; Hibino, T.; Makino, K. Chem. Commun. 2008,
6206–6208. (d) Hamada, Y.; Makino, K. Stereoselective Synthesis of
anti-β-Hydroxy-R-Amino Acids Using anti-Selective Asymmetric Hy-
drogenation. In Asymmetric Synthesis and Application of R-Amino Acids;
American Chemical Society: 2009; Vol. 1009, pp 227À238.
(9) Pellissier, H. Tetrahedron 2003, 59, 8291–8327.
(4) Nicolaou, K. C.; Dethe, D. H.; Leung, G. Y. C.; Zou, B.; Chen, D.
Y.-K. Chem.;Asian J. 2008, 3, 413–429.
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r
10.1021/ol303115v
Published on Web 12/10/2012
2012 American Chemical Society

Table 1. Optimization of the ATH via DKR Reaction of 1a
entry
methoda
arene/ligand
surfactant (equiv)
XO2CH (equiv)
temp (°C)/time
yieldb
drc
erd
1
2
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/3
p-cymene/4
benzene/5
benzene/5
benzene/5
benzene/5
benzene/5
À
NaO2CH (5 equiv)
NaO2CH (15 equiv)
NaO2CH (15 equiv)
NaO2CH (15 equiv)
LiO2CH (15 equiv)
KO2CH (15 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
NaO2CH (5 equiv)
20 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/3 d
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
30 °C/16 h
20 °C/3 d
<5%
50%
31%
18%
80%
46%
26%
24%
70%
54%
28%
30%
82%
80%
81%
À
À
SDS (0.5 equiv)
SDS (0.1 equiv)
SDS (1 equiv)
16:1
À
77:23
À
3
4
À
À
5
SDS (0.5 equiv)
SDS (0.5 equiv)
SDS (0.5 equiv)
SDS (0.5 equiv)
SDS (0.5 equiv)
SDS (0.5 equiv)
SDS (0.5 equiv)
CTAB (0.5 equiv)
Tween 20 (0.2 equiv)
Tween 20 (0.2 equiv)
Tween 20 (0.2 equiv)
7:1
55:45
70:30
93:7
À
6
16:1
20:1
21:1
9:1
7
8
9
86:14
66:33
96:4
93:7
96:4
97:3
96:4
10
11
12
13
14
15e
9:1
14:1
7:1
12:1
13:1
12:1
20 °C/3 d
a A: [RuCl2(p-cymene)]2 (3 mol %) and (S,S)-TsDPEN (10 mol %) were mixed for 1 h at 30 °C in degassed water. Then the substrate (1 equiv), SDS
(equiv given), and formate salt (equiv given) were added, and the reaction was heated at 30 °C. B: [RuCl2(arene)]2 (3 mol %) and (S,S)-ligand (10 mol %)
were mixed for 1 h at 40 °C in CH2Cl2. The CH2Cl2 was removed, and then the substrate (1 equiv), surfactant (equiv given), NaO2CH (5 equiv), and
degassed water were added; the reaction was heated at 30 or 20 °C. b Isolated yields of products after flash chromatography. c The diastereomeric ratio
was measured by 1H NMR. d The enantiomeric ratio was measured by chiral HPLC. e Deionized water, not degassed water.
We have recently applied this strategy to the construction
of anti-β-hydroxy-R-(tert-butoxycarbonyl)amino esters in
water/CH2Cl2 emulsions with NaO2CH as the reducing
agent.10 Given the broad substrate scope of this reaction in
a two-solvent emulsion, we became interested in exploring
the possibility of omitting the organic solvent and utilizing
only water. Water is the preferred solvent, because it is eco-
nomical, nontoxic, nonflammable, and readily obtainable.11
Such a reaction sequence is, therefore, desirable as it
would provide a greener approach to these valuable com-
pounds. A number of protocols for the ATH of ketones
and imines in water have been developed, and this is a
topic that has received much attention in recent years.12
However, for the related ATH coupled DKR reactions,
methods using water as the solvent are scarce. Furthermore,
although ATH of water insoluble ketones that are liquid
under the reaction conditions is well-known, fewer reports
of ATH in water for solid ketones have been disclosed.
Herein, we report our results toward ATH via DKR in
water of solid ketones.
Inspired by the results of Xiao in which ATH is per-
formed on water and in air, we attempted to reduce ketone
1a using similar conditions (Table 1, entry 1).13 Surpris-
ingly for ketone 1a less than 5% conversion was observed
and the substrate and catalyst formed an aggregate in the
water. Unlike many of the previously reported ketone and
imine substrates explored in ATH in aqueous media, 1a is
not water-soluble and is a solid at the reaction temperature
(mp = 96 °C).14,10 We then opted to explore the use of a
surfactant to overcome the low reactivity of 1 in water.12b,g,15
Gratifyingly, by introducing 0.5 equiv of SDS (Sodium
dodecyl sulfate), we were able to isolate 2a in 50% yield
and 77:23 er (entry 2). Testing various amounts of surfac-
tant revealed that 0.5 equiv of SDS was best (entries 2À4).
€
(10) (a) Seashore-Ludlow, B.; Villo, P.; Hacker, C.; Somfai, P. Org.
Lett. 2010, 12, 5274–5277. (b) Seashore-Ludlow, B.; Villo, P.; Somfai, P.
Chem.;Eur. J. 2012, 7219–7223.
(11) (a) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246. (b)
Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302–6337. (c)
€
Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772.
(13) (a) Wu, X.; Xiao, J. Chem. Commun. 2007, 2449–2466. (b) Wu,
X.; Li, X.; Hems, W.; King, F.; Xiao, J. Org. Biomol. Chem. 2004, 2,
1818–1821. (c) Wu, X.; Liu, J.; Di Tommaso, D.; Iggo, J. A.; Catlow,
C. R. A.; Bacsa, J.; Xiao, J. Chem.;Eur. J. 2008, 14, 7699–7715.
(14) Wang, W.; Li, Z.; Mu, W.; Su, L.; Wang, Q. Catal. Commun.
2010, 11, 480–483.
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Asymmetry 2009, 20, 2033–2037. (b) Yin, L.; Shan, W.; Jia, X.; Li, X.;
Chan, A. S. C. J. Organomet. Chem. 2009, 694, 2092–2095. (c) Rhyoo,
H. Y.; Park, H.-J.; Suh, W. H.; Chung, Y. K. Tetrahedron Lett. 2002, 43,
269–272. (d) Schlatter, A.; Kundu, M. K.; Woggon, W.-D. Angew.
Chem., Int. Ed. 2004, 43, 6731–6734.
(12) (a) Wang, C.; Wu, X.; Xiao, J. Chem.;Asian J 2008, 3, 1750–
1770. (b) Wang, F.; Liu, H.; Cun, L.; Zhu, J.; Deng, J.; Jiang, Y. J. Org.
Chem. 2005, 70, 9424–9429. (c) Wang, C.; Li, C.; Wu, X.; Pettman, A.;
Xiao, J. Angew. Chem., Int. Ed. 2009, 48, 6524–6528. (d) Ariger, M. A.;
Carreira, E. M. Org. Lett. 2012, 14, 4522–4524. (e) Tang, L.; Lin, Z.;
Wang, Q.; Wang, X.; Cun, L.; Yuan, W.; Zhu, J.; Deng, J. Tetrahedron
Lett. 2012, 53, 3828–3830. (f) Liu, J.; Zhou, Y.; Wu, Y.; Li, X.; Chan,
A. S. C. Tetrahedron: Asymmetry 2008, 19, 832–837. (g) Ahlford, K.;
Adolfsson, H. Catal. Commun. 2011, 12, 1118–1121. (h) Ma, Y.; Liu, H.;
Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett. 2003, 5, 2103–2106. (i) Li,
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Org. Lett., Vol. 14, No. 24, 2012
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formed in the previous protocol, or inefficiently enclosed
within the micelle. We then preformed the catalyst in an
organic solvent, which was removed prior to the addition
of the water, substrate, surfactant, and reducing agent.16
Immediately a boost in yield was observed, and signifi-
cantly we could reduce the amount of reducing agent to
5 equiv of NaO2CH, which enhanced the enantioselectivity
(entries 2 and 9). Having finally achieved a reasonable
yield, we then examined several other ligands in hopes of
attaining superior enantioselectivity. FDPEN 4, which
had been previously reported for similar compounds,
gave a low enantioselectivity.17 Surprisingly, switching to
BnDPAE (5) gave a markedly lower yield but an enantios-
electivity within the desired range. This suggests that
relatively small alterations in the ligand backbone can
significantly impact the reactivity of the catalyst in water,
even though the catalysts provide comparable yields in
triethylammonium formate (5:2) azeotrope.10b We then
hypothesized that the low yield in the reaction with
BnDPAE could be due to the charge interactions between
the surfactant and the formate. In previous studies a
positivelycharged surfactant was found toperformbest.12b
However, testing CTAB (hexadecyltrimethylammonium
bromide) again resulted in low yields and enantioselec-
tivities. Interestingly, employing a neutral surfactant,
Tween 20 (Polyoxyethylene (20) sorbitan monolaurate),
resulted in both good yields and enantioselectivities.18
Presumably the use of the neutral surfactant allows for
the formate salt to easily enter the micelles. Running the
reaction at ambient temperature for a longer period of
time gave slightly increased enantio- and diastereoselec-
tivities. Furthermore, using deionized, but not degassed,
water gave equivalent results, further simplifying the
reaction procedure.
Table 2. Substrate Scope of the ATH via DKR Reactiona
With working conditions in hand, we then wanted to
investigate the substrate scope of the ATH via a DKR
reaction in water. In general this method gives high yields,
diastereoselectivities, and enantioselectivities for a broad
range of substrates. Substitution at the para position is well
tolerated (Table2, entries 2À4), aswellaselectron-rich and
-poor substrates (entries 2, 4, 6). The 3-bromo substrate 1e
gave a good yield and diastereoselectivity, but the enan-
tioselectivity was rather poor (entry 5).19 A low enantios-
electivity for the 3-chloro-substituted substrate had been
observed in our previous work, although the 3-bromo-
substituted substrate yielded high enantioselectivities un-
der these conditions.10 2-Substition of the aromatic group
was also well tolerated (entry 6). Both the heteroaromatic
substrate 1g and alkenyl substrate 1h gave good yields,
diastereoselectivities, and enantioselectivities(entries7 and
8). The alkyl substrates 1i and 1j both gave slightly lower
a [RuCl2(benzene)]2 (3 mol %) and (S,S)-BnDPAE (10 mol %) were
mixed for 1 h at 40 °C in CH2Cl2. The CH2Cl2 was removed, and then the
substrate (1 equiv), surfactant (equiv given), NaO2CH (5 equiv), and
water were added; the reaction was run at ambient temperature for 72 h.
b Isolated yield. c Measured by 1H NMR d Measured by chiral HPLC.
e [RuCl2(p-cymene)]2 (3 mol %) and (S,S)-TsDPEN (10 mol %) were used.
f Er determined by Mosher ester method. See Supporting Information.
We then examined the effect of the counterion on the
hydrogen source to see if this would impact the yield and
enantioselectivity. This revealed a dependence on the
counterion for both the reaction yield and enantioselec-
tivity. It was found that LiO2CH gave a higher yield but
distinctly lower enantioselectivity (compare entries 2
and 5). KO2CH gave similar results to NaO2CH; however
a slightly lower enantioselectivity was obtained (com-
pare entries 2 and 6). We then decreased the amount of
NaO2CH as a means to increase the enantioselectivity.
This had the desired effect, but the yield also decreased
significantly (entry 7). Unfortunately, leaving the reac-
tion for 3 days did not improve the yield (entry 8).
(16) The reactions were run under N2 as irreproducible results were
obtained when the reactions were run in air.
(17) Liu, Z.; Shultz, C. S.; Sherwood, C. A.; Krska, S.; Dormer, P. G.;
Desmond, R.; Lee, C.; Sherer, E. C.; Shpungin, J.; Cuff, J.; Xu, F.
Tetrahedron Lett. 2011, 52, 1685–1688.
(18) Due to the large molecular weight of Tween 20, 20 mol % of this
surfactant is equivalent in weight to 50 mol % SDS or CTAB.
(19) We also tried halving the amount of NaO2CH to increase the
enantioselectivity, but the enantioselectivity remained poor.
Disappointed by the low yields and enantioselectivities,
we then investigated an alternative preparation of the cata-
lyst, surmising that the active catalyst was inadequately
6336
Org. Lett., Vol. 14, No. 24, 2012

yields, and the enantioselectivity of the 2j was poor (entries
9 and 10). This could be due to the steric bulk of the tert-
butyl moiety, as increased steric bulk is known to decrease
the enantioselectivity in ATH reactions.12b
Given the success of the above method for a broad range
of substrates, we wondered if preparation of the catalyst in
water with a surfactant would furnish similar results. Since
such a procedure would completely obviate the need for an
organic solvent, we investigated a protocol where the
ruthenium precatalyst, (S,S)-BnDPAE, and Tween 20
were stirred in water, followed by the addition of the
substrate and reducing agent. Gratifyingly, essentially
identical results were obtained for the reduction of
substrate 1a into product 2a (Scheme 1; compare Table 1,
entry 13). To verify the applicability of this method we
reexamined several other substrates 1b, 1g, and 1c. This
provided the corresponding products 2b, 2g, and 2c in
comparable yields, enantioselectivities, and diastereoselec-
tivities as before and confirmed the generality of this
method (compare Table 2).
In conclusion, we have developed an efficient and
practical method for the construction of anti-β-hydroxy-
R-amino acid derivatives in water with a surfactant, re-
moving the need for an organic solvent. This method gives
high yields, diastereoselectivities, and enantioselectivities
for a broad range of substrates, including aryl-, alkenyl-,
and alkyl-subsituted β-ketoesters. Unlike previous reports,
the use of high melting solids is tolerated, and because the
reaction proceeds via a DKR, vicinal stereocenters are
generated. Furthermore, we have uncovered a counterion
effect in the reaction in negatively charged micelles and found
that a neutral surfactant is best for the [RuCl2(benzene)]2 and
(S,S)-BnDPAE catalyst combination. Our studies revealed
that subtle differences in the ligand backbone greatly influ-
ence the activity of the catalyst in water, which should offer
insight into further development of ATH via DKR in water.
Scheme 1. Results for ATH via DKR in Water with Catalyst
Formed in Water with Surfactanta
Acknowledgment. The authors would like to thank
KTH Royal Institute of Technology, Lund University,
and the Estonian Science Foundation (Grant No. 7808)
for funding.
Supporting Information Available. Information regard-
ing the preparation of 1aÀ1j and 2aÀ2j and 1H spectra of
2aÀ2j are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
a [RuCl2(benzene)]2 (3 mol %), (S,S)-BnDPAE (10 mol %), and
Tween 20 (20 mol %) were mixed for 1 h at 40 °C in water. Then the
substrate (1 equiv) and NaO2CH (5 equiv) were added, and the reaction
was run at 30 °C for 24 h. Substrate 1g resulting in product 2g was run at
ambient temperature for 72 h.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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