Enantioselective synthesis of β2-amino acids via Rh-catalyzed asymmetric hydrogenation with BoPhoz-type ligands: Important influence of an N-H proton in the ligand on the enantioselectivity

Article abstract of DOI:10.1021/jo702510m

(Chemical Equation Presented) A series of BoPhoz-type ligands were successfully applied in the rhodium-catalyzed asymmetric hydrogenation of a number of β-substituted or unsubstituted α-(phthalimidomethyl) acrylates, affording good to excellent enantiosel

Full text of DOI:10.1021/jo702510m

substitution,4 Rh-catalyzed C-H activation,5 Cu-catalyzed
conjugate addition,6 rhodium-catalyzed conjugate addition and
enolate protonations,7 and enantioselective H-atom transfer
reactions.8 Because of its inherent efficiency and atom economy,
asymmetric hydrogenation of prochiral dehydro-precursors of
â2-amino acid derivatives represents one of the most efficient
and simplest methods. However, to our knowledge, only a few
examples of the hydrogenation of â2-dehydroamino acid precur-
sors may be found in the literature, and in most cases, the results
are less than satisfactory.9 Jackson et al.9a reported that
enantioselective hydrogenation of some R,â-unsaturated nitriles
bearing a phthalimidomethyl substituent at the R-carbon using
Rh-DuPHOS catalysts afforded â2-amino acid precursors with
moderate ee values of up to 48%, while hydrogenation of the
corresponding R,â-unsaturated carboxylic acid methyl esters
using a Ru-BINAP catalyst gave higher ee values of up to 84%.
Robinson et al.9b described the enantioselective hydrogenation
of a series of (E)-R-substituted â-amidoacrylates using Rh-
catalysts with chiral bidentate phosphine ligands (BPE and
DuPHOS), which gave â2-amino acid derivatives with enanti-
oselectivities of up to 67%. Very recently, Minnaard and Feringa
et al.9c reported the synthesis of â2-amino acids via asymmetric
rhodium-catalyzed hydrogenation of â-substituted R-acetylami-
nomethylacrylic acids employing a mixed ligand system consist-
ing of chiral monodentate phosphoramidites and achiral phos-
phines, in which up to 91% ee was obtained. Qiu et al. have
developed highly enantioselective catalytic hydrogenation of
R-aminomethylacrylates containing a free basic NH group using
the Rh/Et-DuPHOS complex as a catalyst, in which 99% ee
and high isolated yields (>98%) were obtained even in low
catalyst loadings.9d In our recent study,10 we have found that
the D-mannitol derived monodentate phosphite ligand, Man-
niPhos, was highly effective for the rhodium-catalyzed asym-
metric hydrogenation of â-unsubstituted R-(phthalimidomethyl)-
acrylates. However, the results for the â-substituted substrates
are unsatisfactory. Incomplete conversions and moderate enan-
tioselectivities were obtained in most cases even under high H2
pressure (85 atm) and high catalyst loadings (4 mol %) for 36
h. Therefore, the search of the new catalytic system, which could
induce excellent enantioselectivity under lower catalyst loadings
and milder reaction conditions in this Rh-catalyzed transforma-
tion, was undertaken. Very recently, we have developed a highly
enantioselective synthesis of γ-amino acid derivatives via the
Enantioselective Synthesis of â2-Amino Acids via
Rh-Catalyzed Asymmetric Hydrogenation with
BoPhoz-Type Ligands: Important Influence of an
N-H Proton in the Ligand on the
Enantioselectivity
Jun Deng,†,‡ Xiang-Ping Hu,*,† Jia-Di Huang,†,‡
Sai-Bo Yu,†,‡ Dao-Yong Wang,†,‡ Zheng-Chao Duan,†,‡ and
Zhuo Zheng*,†
Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, Dalian 116023, China, and Graduate School of
Chinese Academy of Sciences, Beijing 100039, China
zhengz@dicp.ac.cn; xiangping@dicp.ac.cn
ReceiVed NoVember 21, 2007
A series of BoPhoz-type ligands were successfully applied
in the rhodium-catalyzed asymmetric hydrogenation of a
number of â-substituted or unsubstituted R-(phthalimidom-
ethyl)acrylates, affording good to excellent enantioselectivi-
ties. The results suggested that the presence of an N-H
proton in the BoPhoz backbone could significantly improve
the enantioselectivity, and ligand (Sc,Rp)-1d, bearing two CF3-
groups in the 3,5-position of the phenyl ring of aminophos-
phino moiety, showed the highest enantioselectivity.
Chiral â-amino acids and derivatives are important building
blocks in the synthesis of natural products, â-peptides, and
pharmaceuticals.1 Therefore, an enantioselective method for the
synthesis of these compounds is highly desirable. Although
several enantioselective catalytic methods have been developed
recently for the synthesis of â-substituted â-amino acids (â3-
amino acids),2 there are significantly fewer reports on enanti-
oselective methods for the synthesis of R-substituted â-amino
acids (â2-amino acids).1a,3 The present methods for the catalytic
synthesis of chiral â2-amino acids included Pd-catalyzed allylic
(4) (a) Bower, J. F.; Williams, J. M. J. Synlett, 1996, 685-686. (b) Bower,
J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J. Chem. Soc., Perkin
Trans. 1 1997, 1411-1420.
(5) Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002,
41, 2197-2199.
(6) (a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2003, 125, 3700-3701. (b) Eilitz, U.; Lessmann, F.; Seidelmann, O.;
Wendisch, V. Tetrahedron: Asymmetry 2003, 14, 189-191. (c) Eilitz, U.;
Lessmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003,
14, 3095-3097. (d) Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79-80.
(7) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571-2573.
(8) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235-1238.
(9) (a) Saylik, D.; Campi, E. M.; Donohue, A. C.; Jackson, W. R.;
Robinson, A. J. Tetrahedron: Asymmetry 2001, 12, 657-667. (b) Elaridi,
J.; Thaqi, A.; Prosser, A.; Jackson, W. R.; Robinson, A. J. Tetrahedron:
Asymmetry 2005, 16, 1309-1319. (c) Hoen, R.; Tiemersma-Wegman, T.;
Procuranti, B.; Lefort, L.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L.
Org. Biomol. Chem. 2007, 5, 267-275. (d) Qiu, L.; Prashad, M.; Hu, B.;
Prasad, K.; Repic, O.; Blacklock, T. J.; Kwong, F. Y.; Kok, S. H. L.; Lee,
H. W.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16787-
16792.
† Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
‡ Graduate School of Chinese Academy of Science.
(1) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Abele, S.; Seebach, D. Eur. J. Org.
Chem. 2000, 1-15. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
ReV. 2001, 101, 3219-3232. (d) Nussbaum, F. V.; Spiteller, P. In Highlights
in Bioorganic Chemistry; Schmuck, C., Wennemers, H., Eds.; Wiley-
VCH: Weinheim, Germany 2003; p 63.
(2) Drexler, H.-J.; You, J.; Zhang, S.; Fisher, C.; Baumann, W.;
Spannenberg, A.; Heller, D. Org. Process Res. DeV. 2003, 7, 355-361.
(3) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
(10) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006,
8, 3359-3362.
10.1021/jo702510m CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/30/2008
J. Org. Chem. 2008, 73, 2015-2017
2015

TABLE 1. Ligand and Solvent Screening for Rh-Catalyzed
Asymmetric Hydrogenation of Methyl
(E)-â-Phenyl-r-(phthalimidomethyl)acrylate 2aa
entrya
ligand
solvent
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
ManniPhos
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
d
1a
1b
1c
1d
1e
1d
1d
1d
100
100
100
100
56
71
48
92
d
39
22
54
FIGURE 1. Representative structures of BoPhoz-type ligands.
Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-R,â-
unsaturated carboxylic acid esters with a highly modular
Bophoz-type ligand.11 Because of the structural similarity of
the hydrogenation substrates, we then surmised that these
Bophoz-type ligands may also be effective for the Rh-catalyzed
hydrogenation of R-(phthalimidomethyl)acrylates. As a result,
herein we report an efficient Rh-catalyzed asymmetric hydro-
genation of various â-substituted or unsubstituted R-(phthal-
imidomethyl)acrylates with a finely tuned BoPhoz-type phos-
phine-aminophosphine ligand, in which chiral â2-amino acid
esters could be synthesized in good to excellent enantioselec-
tivities.
In our initial ligand screening experimental, we observed that
the Rh/Me-BoPhoz complex displayed high catalytic activity
in the hydrogenation of methyl (E)-â-phenyl-R-(phthalimidom-
ethyl)acrylate even under 1 mol % of the catalyst loadings and
10 atm of H2 pressure. Although the enantioselectivity was
moderate (56% ee) (entry 2), this result is far superior to that
obtained with ManniPhos reported by us recently.10 Under the
same hydrogenation condition, Rh/ManniPhos showed no
catalytic activity for the hydrogenation of this substrate class
(entry 1). The synthetic methodology of BoPhoz-type ligands
has proved to be highly modular,12 which provides an op-
portunity to find an efficient BoPhoz-type ligand for this
challenging hydrogenation by optimizing its steric environment
through fine structural modifications. As a result, a systematic
investigation of a number of BoPhoz-type ligands with varying
electronic and steric properties was carried out, and some
representative structures are shown in Figure 1.
As shown in Table 1, the structure of the BoPhoz-type ligand
has significant influence in the enantioselectivity, and very
interestingly, the ligands with an N-H proton on the amino
moiety tended to give higher enantioselectivity than those with
a methyl group on the amino moiety. Thus, (Sc,Rp)-BoPhoz 1a
with an N-methyl group gave the hydrogenation product in 56%
ee (entry 2). In contrast, a remarkable increase in the enanti-
oselectivity to 71% ee was observed by the use of (Sc,Rp)-
BoPhoz 1b with an N-H proton in the backbone (entry 3). The
important role of an N-H proton on the amino unit of the
BoPhoz-type ligand can be more clearly appreciated by the
comparison of the enantioselective induction of ligand 1c and
100
15
62
toluene
i-PrOH
a All reactions were performed with 0.25 mmol of substrate at room
temperature under a H2 pressure of 10 atm in 2 mL of solvent for 24 h.
Substrate/Rh(COD)2BF4/ligand ) 1/0.01/0.011. b Conversions were deter-
mined by 1H NMR, HPLC, or GC. c The ee values were determined by
HPLC on a chiral column. d Not determined because of low conversion.
1d, in which ligand 1d with an N-H proton exhibited 92% ee
while ligand 1c with an N-methyl group only showed 48% ee.
The improved enantioselectivity is probably due to the potential
second interaction between the N-H proton in the ligand and
substrate as reported by Hayashi and Noyori et al.;13 however,
the real reason is still unclear. Subsequent optimization in an
effort to attain higher enantioselectivity by the introduction of
a stereogenic P center into the phosphino moiety proved
unfruitful.12g,14 Thus, ligand 1e with a stereogenic phosphino
moiety displayed unexpectedly low conversion (entry 6). A
solvent screening experiment revealed that the catalytic activity
and enantioselectivity are highly depended on the nature of
solvent. Thus, the reaction performed in THF proceeded to
completion; however, the enantioselectivity was low (entry 7).
When the reaction was carried out in toluene or i-PrOH, low
conversion and enantioselectivity was observed (entries 8 and
9).
Having established a highly enantioselective hydrogenation
of methyl (E)-â-phenyl-R-(phthalimidomethyl)acrylate 2a, we
decided to investigate the scope of this challenging reaction on
various â-substituted and unsubstituted R-(phthalimidomethyl)-
acrylates, using (Sc,Rp)-1d as ligand and CH2Cl2 as the standard
solvent. The reaction was performed under a H2 pressure of 10
atm at room temperature for 24 h, and the results are sum-
marized in Table 2. Initially, a variety of â-aryl substrates were
tested, and the results indicated that the substitution pattern and
electronic properties had little effect in the enantioselectivity
(entries 1-6). As shown in Table 2, all of the substrates were
hydrogenated in over 90% ee, suggesting the efficiency of the
present catalytic system for Rh-catalyzed asymmetric hydro-
genation of â-aryl-R-(phthalimidomethyl)acrylates. Among
them, â-p-CF3-substituted substrate 2d was hydrogenated in the
highest enantioselectivity (94% ee) (entry 4). These hydrogena-
tion products can be easily upgraded via recrystallization to a
(11) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.; Yu,
S.-B.; Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825-4828.
(12) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Org. Lett. 2002, 4, 2421-2424. (b) Boaz, N. W.; Large, S. E.; Ponasik, J.
A., Jr.; Moore, M. K.; Barnette, T.; Nottingham, W. D. Org. Process Res.
DeV. 2005, 9, 472-478. (c) Boaz, N. W.; Ponasik, J. A., Jr.; Large, S. E.
Tetrahedron: Asymmetry 2005, 16, 2063-2066. (d) Li, X.; Jia, X.; Xu, L.;
Kok, S. H. L.; Yip, C. W.; Chan, A. S. C. AdV. Synth. Catal. 2005, 347,
1904-1908. (e) Boaz, N. W.; Ponasik, J. A., Jr.; Large, S. E. Tetrahedron
Lett. 2006, 47, 4033-4035. (f) Boaz, N. W.; Mackenzie, E. B.; Debenham,
S. D.; Large, S. E.; Ponasik, J. A., Jr. J. Org. Chem. 2005, 70, 1872-1880.
(g) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. J. Am. Chem. Soc.
2006, 128, 3922-3923.
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Lett. 1986, 27, 191-194. (b) Hayashi, T. Pure Appl. Chem. 1988, 60, 7-12.
(c) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087-
1089. (d) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419-422.
(14) (a) Chen, W.; Roberts, S. M.; Whittall, J.; Steiner, A. Chem.
Commun. 2006, 2916-2918. (b) Chen, W.; McCormack, P. J.; Mohammed,
K.; Mbafor, W.; Roberts, S. M.; Whittall, J. Angew. Chem., Int. Ed. 2007,
46, 4141-4144.
2016 J. Org. Chem., Vol. 73, No. 5, 2008

TABLE 2. Scope of Rh-Catalyzed Asymmetric Hydrogenation of
The coupling of the bromide with potassium phthalimide gave
methyl (E)-R-phthalimidomethyl-â-phenylacrylate 2a in good
yields.16 2a was then hydrogenated with this new catalytic
system in nearly quantitative yields and 92% ee. Complete
hydrolysis of 3a by the with aqueous HCl generated the target
chiral â2-amino acid 4.17
r-(Phthalimidomethyl)acrylate 2 with Ligand 1da
In summary, we have found that BoPhoz-type ligands were
effective for the rhodium-catalyzed asymmetric hydrogenation
of a variety of â-substituted and unsubstituted R-(phthalimi-
domethyl)acrylates under the mild hydrogenation condition (10
atm of H2, room temperature), in which up to 94% ee for
â-substituted substrates and over 99% ee for â-unsubstituted
substrates were achieved. The results indicated that an N-H
proton on the amino unit of the BoPhoz-type ligand is crucial
to achieving high stereocontrol in this transformation, and
(Sc,Rp)-1d with an N-H proton and two CF3-groups in the 3,5-
position of the phenyl ring was demonstrated to be the best
ligand.
ee (%)
entrya
substrate
R′
R′′
yield (%)b
(confign)c
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
99
98
99
95
97
97
95
93
97
99
92 (S)
90 (-)
91 (-)
94 (-)
93 (-)
92 (-)
92 (+)
>99 (S)
>99 (S)
>99 (S)d
p-FC6H4
p-ClC6H4
p-CF3C6H4
m-MeOC6H4
o-MeOC6H4
i-Pr
H
H
H
10
2i
Et
a All reactions were performed with 1.0 mmol of substrate at room
temperature under a H2 pressure of 10 atm in 4 mL of solvent for 24 h
unless otherwise specified. Substrate/Rh(COD)2BF4/ligand ) 1/0.01/0.011.
Full conversions were obtained in all reactions. b Isolated yield. c The ee
values were determined by HPLC on a chiral column. Absolute configuration
assigned by known elution order from chiral HPLC according to the
literature. d Substrate/Rh(COD)2BF4 ) 1000.
Experimental Section
R-(Phthalimidomethyl)acrylates 2a-i were prepared according
to the known methods.10
General Hydrogenation Procedure. To a solution of [Rh-
(COD)2]BF4 (4.0 mg, 0.01 mmol) in 2 mL of CH2Cl2, which was
placed in a nitrogen-filled glovebox, was added the BoPhoz-type
ligand 1d (9.6 mg, 0.011 mmol). The mixture was stirred at room
temperature for 30 min, and then a solution of a substrate (1.0
mmol) in 2 mL of CH2Cl2 was added. The reaction mixture was
transferred to a Parr stainless autoclave. The autoclave was purged
three times with hydrogen, and maintained a hydrogen pressure of
10 atm. The hydrogenation was performed at room temperature
for 24 h. After the hydrogen was carefully released, the solvent
was removed. The residue was filtered through a short SiO2 column
to remove the catalyst. The filtrate was concentrated under reduced
pressure, and the enantiomeric excess was determined by HPLC
on a chiral column.
SCHEME 1. Highly Enantioselective Synthesis of
(S)-(-)-r-Benzyl-â-alanine
Methyl 2-(Phthalimidomethyl)-3-phenylpropanoate (3a). White
1
solid. Mp 89-90 °C. H NMR (400 MHz, CDCl3) δ 2.83-2.88
(m, 1H), 3.05-3.11 (m, 1H), 3.26-3.29 (m, 1H), 3.59 (s, 3H),
3.84-3.89 (m, 1H), 3.98-4.03 (m, 1H), 7.12-7.26 (m, 5H), 7.69-
7.71 (m, 2H), 7.80-7.82 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
35.9, 39.6, 45.8, 52.0, 123.3, 126.5, 128.5, 128.7, 131.9, 134.1,
138.1, 168.0, 173.3. 92% ee was determined by chiral HPLC
(chiralcel OJ-H, i-PrOH/n-hexane ) 10/90, UV 254 nm, 40 °C,
0.8 mL/min), retention times (min) 20.1 (major, S) and 26.0 (minor,
R).
Synthesis of (S)-(-)-R-Benzyl-â-aminopropionic Acid (4). A
mixture of methyl 2-(phthalimidomethyl)-3-phenyl-propanoate (3a)
(1 mmol, 324 mg) and 6 M HCl (15 mL) was heated under reflux
for 24 h. The solution was cooled and washed with ethyl acetate
(3 × 10 mL). The aqueous layer was collected and evaporated to
dryness, which gave 179 mg (89% yield) of amino acid hydro-
chloride as the white solid. Mp 159-161 °C; 1H NMR (400 MHz,
D2O) δ 2.93-2.98 (m, 1H), 3.02-3.12 (m, 3H), 3.18-3.24 (m,
1H), 7.27-7.39 (m, 5H).
very high level (generally over 98% ee) due to their high
crystallinity conferred by the phthalimido group. The high
efficiency of the present catalytic system was also demonstrated
in the hydrogenation of methyl (E)-â-i-Pr-R-(phthalimidom-
ethyl)acrylates 2g, in which full conversion and good enanti-
oselectivity (92% ee) were achieved (entry 7). For the hydro-
genation of this substrate, ManniPhos only gave an ee value of
<50% and incomplete conversion even under 4 mol % catalyst
loadings and 85 atm of H2 pressure.10 In the hydrogenation of
â-unsubstituted substrates 2h and 2i, excellent enantioselectivity
(>99% ee) was obtained even under low catalyst loadings (0.1
mol %) (entries 8-10).
The application of this methodology as a key step in the
efficient synthesis of chiral â2-amino acids is outlined in Scheme
1. Initially, Baylis-Hillman adducts 7 derived from methyl
acrylate were transformed into the corresponding (Z)-allyl
bromide 8 in high yields by treatment with HBr and H2SO4.15
Acknowledgment. We are grateful to the generous financial
support from the National Natural Science Foundation of China
(20472083).
Supporting Information Available: 1H and 13C NMR spectra
and analysis of ee values of the hydrogenation products. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702510M
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J. Org. Chem, Vol. 73, No. 5, 2008 2017