Highly enantioselective asymmetric hydrogenation of β-acetamido dehydroamino acid derivatives using a three-hindered quadrant rhodium catalyst

Article abstract of DOI:10.1021/ol048386w

(Chemical Equation Presented) A previously reported three-hindered quadrant chiral ligand and its corresponding rhodium complex provide high enantioselectivity for the asymmetric hydrogenation of β-acetamido dehydroamino acid substrates. Both (E)- and (Z)-substrates are hydrogenated with high enantioselectivity in all of the reported examples. Asymmetric hydrogenation of a cyclic β-acetamido dehydroamino acid substrate in 85% ee is also reported.

Full text of DOI:10.1021/ol048386w

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3645-3647
Highly Enantioselective Asymmetric
Hydrogenation of -Acetamido
â
Dehydroamino Acid Derivatives Using a
Three-Hindered Quadrant Rhodium
Catalyst
He-Ping Wu and Garrett Hoge*
Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105
garrett.hoge@pfizer.com
Received August 13, 2004
ABSTRACT
A previously reported three-hindered quadrant chiral ligand and its corresponding rhodium complex provide high enantioselectivity for the
asymmetric hydrogenation of -acetamido dehydroamino acid substrates. Both (E)- and (Z)-substrates are hydrogenated with high
â
enantioselectivity in all of the reported examples. Asymmetric hydrogenation of a cyclic
is also reported.
â-acetamido dehydroamino acid substrate in 85% ee
The continuing importance of chiral â-amino acids to medici-
nal chemistry is highlighted by the number of recent reports
and reviews that detail convenient chiral methodologies to
access them.1 Although asymmetric hydrogenation of â-ac-
etamido dehydroamino acids with chiral homogeneous cata-
lysts is a methodology that offers promise for the synthesis
of â-amino acids, a stumbling block for this approach has
been poor selectivity during the hydrogenation of mix-
tures of the configurational isomers of the substrates. While
(E)-substrates can be hydrogenated in high enantiomeric
excess using a variety of known catalysts, only a few cata-
lysts can hydrogenate (Z)-substrates with synthetically practi-
cal selectivity.2 To exacerbate this issue, the synthesis of an
exclusively (E)-isomer substrate has not been realized via
current methodologies. In fact, the (Z)-isomer is often the
major product produced via these synthetic protocols.2
Therefore, there is a need for efficient catalysts that can
hydrogenate both (E)- and (Z)-â-acetamido dehydroamino
acids in high enantiomeric excess.
We recently reported the synthesis of both enantiomers
of ligand 1 featuring an HPLC chiral separation crux (Figure
1).3 Resolved rhodium complexes of the ligand, 2, were
demonstrated to provide very high enantioselectivity for a
(2) (a) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907-
6910. (b) Holz, J.; Monsees, A.; Jiao, H.; You, J.; Komarov, I. V.; Fischer,
C.; Drauz, K.; Bo¨rner, A. J. Org. Chem. 2003, 68, 1701-1707. (c) Tang,
W.; Wang, W.; Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509-
3511. (d) Lee, S.-g.; Zhang, Y. J. Org. Lett. 2002, 4, 2429-2431. (e) Pen˜a,
D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002,
124, 14552-14553. (f) Tang, W.; Zhang, X. Org. Lett. 2002, 23, 4159-
4161. (g) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett.
2001, 11, 1701-1704.
(1) (a) Ikemoto, N.; Tellers, D. M.; Dreher, S. D.; Liu, J.; Huang, A.;
Rivera, N. R.; Njolito, E.; Hsiao, Y.; McWilliams, J. C.; Williams, J. M.;
Armstrong, J. D., III; Sun, Y.; Mathre, D. J.; Grabowski, E. J. J.; Tillyer,
R. D. J. Am. Chem. Soc. 2004, 126, 3048-3049. (b) Ma, J.-A. Angew.
Chem., Int. Ed. 2003, 42, 4290-4299. (c) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991-8035. (d) Gademann, K.; Hintermann, T.; Schreiber, J. V.
Curr. Med. Chem. 1999, 6, 905. (e) EnantioselectiVe Synthesis of â-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1996.
10.1021/ol048386w CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/03/2004

the hydrogenation of (E)-3 in entries 1-4. Each produced
99% ee with complete conversion in fast reaction times
(complete in less than 15 min). Entries 5-8 depict results
for the identical solvent screen on substrate (Z)-3. All entries
afforded 96% ee or greater with reaction times similar to
those observed for (E)-3. For reactions performed in THF
we observed subtle pressure effects. The initial screen at 20
psi (entry 6) provided 96% ee with complete conversion to
product. However, when the initial applied pressure over the
reaction solution was increased to 50 psi, the enantiomeric
excess of the reaction decreased to 94% (entry 9). Performing
the reaction at 6 psi produced the highest enantiomeric excess
(99%) for THF (entry 10). Entry 11 depicts asymmetric
hydrogenation of a 1:1 mixture of (E)- and (Z)-3 in THF
solvent and 20 psi H2. These conditions produced 98% ee
product.
Figure 1. Structure of ligand (R)-1 and catalyst (S)-2.
variety of classic substrates, R-acetamido dehydroamino
acids, during catalyzed asymmetric hydrogenation. We also
reported the practical synthetic utility of the rhodium complex
in the asymmetric hydrogenation of a substrate precursor to
the pharmaceutical candidate, pregabalin.4 Associations were
drawn between the observed high enantioselectivity and the
structure of ligand 1 that features three bulky tert-butyl
groups located in the vicinity of the rhodium catalysis center.
To further highlight the utility of the design of ligand 1 and
its corresponding rhodium catalysts, we report the highly
enantioselective hydrogenation of both (E)- and (Z)-â-
acetamido dehydroamino acids.
A broader screen of â-acetamido dehydroamino acid
derivatives was then undertaken to examine the efficacy of
this catalyst system for this substrate class (Table 2). Entries
Table 2. Asymmetric Hydrogenation of â-Acetamido
Dehydroamino Acid Derivatives, 5a-e, Using (S)-2 as a
Catalysta
Table 1 depicts an initial screen for the application of
catalyst (S)-2 to the asymmetric hydrogenation of (E)- and
Table 1. Asymmetric Hydrogenation of (E)- and
(Z)-Methyl-3-acetamido-2-butenoate Using (S)-2 as a Catalysta
olefin
entry substrate configuration
solvent
psi H2 ee (%)b
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5c
5d
5e
5e
5e
5e
5e
5e
(E)
(Z)
(E)
(Z)
(E)
(Z)
(E)
(Z)
(Z)
(Z)
(Z)
(Z)
THF
THF
THF
THF
THF
THF
THF
THF
MeOH
EtOAc
EtOAc
EtOAc
20
20
20
20
20
20
20
20
20
20
50
6
99 (R)
96 (R)
98 (R)
98 (R)
99 (S)
96 (S)
99 (S)
78 (S)
69 (S)
84 (S)
66 (S)
92 (S)
entry
substrate
(E)-3
(E)-3
(E)-3
(E)-3
(Z)-3
(Z)-3
(Z)-3
(Z)-3
(Z)-3
(Z)-3
(E)-3/(Z)-3 (1:1)
solvent
psi H2
ee (%)b
1
2
3
4
5
6
7
8
9
MeOH
THF
EtOAc
CH2Cl2
MeOH
THF
EtOAc
CH2Cl2
THF
20
20
20
20
20
20
20
20
50
6
99 (R)
99 (R)
99 (R)
99 (R)
96 (R)
96 (R)
98 (R)
97 (R)
94 (R)
99 (R)
98 (R)
10
11
12
10
11
THF
THF
20
a Reactions were performed on 1 mmol of substrate at room temperature
with a substrate concentration of 0.2 M. Each was complete within 15 min.
b Enantiomeric excesses were determined via chiral GC as described in
Supporting Information.
a Reactions were performed on 1 mmol of substrate at room temperature
with a substrate concentration of 0.2 M. Each was complete within 15 min.
b Enantiomeric excesses were determined via chiral GC as described in
Supporting Information.
1-4 depict the results of hydrogenation of both (E)- and
(Z)-5a (R ) propyl) and 5b (R ) isobutyl). High enantio-
meric excesses of 6a and 6b (>96%) were obtained for each
case. Identical conditions for the case of (E)-5c (R ) tert-
butyl, entry 5) provided 6c in 99% ee. The (Z) isomer of 5c
was not observed during the synthesis of the substrate;
therefore, this isomer was not tested. Entry 6 depicts the
(Z)-methyl-3-acetamido-2-butenoate, 3. Four solvents (MeOH,
THF, EtOAc, and CH2Cl2) were examined at 20 psi H2 for
(3) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.;
Bao, J. J. Am. Chem. Soc. 2004, 126, 5966-5967.
(4) (a) Lauria-Horner, B. A.; Pohl, R. B. Expert Opin. InVestig. Drugs
2003, 12, 663. (b) Selak, I. Curr. Opin. InVestig. Drugs 2001, 2, 828.
3646
Org. Lett., Vol. 6, No. 20, 2004

result for substrate (Z)-5d (R ) phenyl). Only two catalysts
have been reported to provide high enantiomeric excess for
phenyl and substituted phenyl â-acetamido dehydroamino
acid derivatives.2c-d Catalyst (S)-2 provided product 6d in
96% ee.
Scheme 1. Asymmetric Hydrogenation of Cyclic â-Acetamido
Dehydroamino Acid 7 Using (S)-2 as a Catalyst
Entry 7 depicts the result of the hydrogenation of substrate
5e. The (E)-isomer was hydrogenated in 99% ee at 20 psi
H2 in THF. However, the hydrogenation of (Z)-5e provided
6e in only 78% ee under the same conditions (entry 8). We
found a solvent influence on the degree of enantioselectivity
for this substrate. When the reaction was run in MeOH (entry
9), the enantiomeric excess of 6e was 69% under essentially
the same reaction conditions as those described for entry 8.
However, when the reaction was performed in EtOAc, the
enantiomeric excess of 6e increased to 84% ee (entry 10).
C2-symmetrical ligands during asymmetric hydrogenation.
Provided the few catalysts that have been reported to provide
high enantioselectivity for the hydrogenation of (Z)-isomers
of â-acetamido dehydroamino acids, this report continues
to challenge the need for C2-symmetry in asymmetric hy-
drogenation ligand design. Broader applications of this
catalyst to a variety of substrate types will unveil the true
potential of the ligand.
The design of ligand 1 may also have impact in other areas
of asymmetric catalysis. Bisphosphine transition metal cata-
lysts have been shown to provide high enantiomeric excess
for a variety of catalytic transformations other than asym-
metric hydrogenation.6 It remains to be seen if ligand 1 can
successfully be applied to these transformations as well.
Similar to results reported in Table 1, we found more
dramatic pressure effects for the hydrogenation of (Z)-5e.
Using EtOAc as a solvent, increasing the hydrogen pressure
over the reaction to 50 psi produced 66% ee (entry 11).
However, in entry 12 the pressure of the reaction was reduced
to 6 psi. These conditions provided 6e in 92% ee.
Finally, a recently published Communication describes
highly enantioselective hydrogenation of cyclic â-acetamido
amino acid substrates using bisphosphine ruthenium com-
plexes.5 However, it was mentioned that the electron-rich
Rh-(S,S,R,R)-Tangphos complex provided no reactivity for
the transformation under 50 psi H2. Scheme 1 depicts the
asymmetric hydrogenation of cyclic â-acetamido dehy-
droamino acid 7 using (S)-2 as a catalyst. The result of 85%
ee shows potential for the application of rhodium catalysts
to this substrate class.
Acknowledgment. Pfizer, Inc., is acknowledged for con-
tinuing support of this research.
Supporting Information Available: Materials and meth-
ods, synthetic procedures for the synthesis of substrates 3
and 5, and methods for the evaluation of enantiomeric
excesses of 4, 6, and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048386W
In conclusion, more evidence has been presented in
this Communication that the three-hindered quadrant motif
of rhodium catalysts derived from ligand 1 can provide
enantioselectivities equal to the current state-of-the-art with
(5) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570-
9571.
(6) Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372.
Org. Lett., Vol. 6, No. 20, 2004
3647