Practical syntheses of β-amino alcohols via asymmetric catalytic hydrogenation

Full text of DOI:10.1021/jo981590a

8100
J . Org. Chem. 1998, 63, 8100-8101
Sch em e 1
P r a ctica l Syn th eses of â-Am in o Alcoh ols via
Asym m etr ic Ca ta lytic Hyd r ogen a tion
Guoxin Zhu,† Albert L. Casalnuovo,‡ and Xumu Zhang*,†
Department of Chemistry, The Pennsylvania State University,
University Park, Pennsylvania 16802, and DuPont Agricultural
Products, Stine-Haskell Research Center, P.O. Box 30,
Building 300, Newark, Delaware 19714
Received August 7, 1998
Enantiomerically pure â-amino alcohols have been exten-
sively used as building blocks for the syntheses of pharma-
ceuticals1 and insecticidal agents,2 as chiral ligands in
asymmetric catalysis,3 or as auxiliaries4 and resolving
agents5 in asymmetric synthesis. Furthermore, they can be
converted to chiral oxazoline ligands, which show tremen-
dous utility in various asymmetric catalytic processes.6 The
broad application of amino alcohol derivatives has generated
considerable interest in developing efficient synthetic routes
to these compounds.7 Such amino alcohols generally are
obtained by reduction of the corresponding R-amino acids
or esters.8 However, not all of the precursor R-amino acids
are readily available, and sometimes low yields are observed
in this reduction. To overcome these deficiencies, several
alternative asymmetric synthetic methods have been devel-
oped.9 In principle, asymmetric catalytic hydrogenation of
protected â-hydroxy enamides is a practical way to generate
Sch em e 2
such amino alcohols. Although high enantioselectivities and
reactivities have been reported for the asymmetric hydro-
genation of dehydroamino acids,10 there have been no reports
describing the synthesis of â-amino alcohols via asymmetric
catalytic hydrogenation of enamides as illustrated in Scheme
1. Herein, we describe the first highly enantioselective,
practical synthesis of â-amino alcohols using BICP-Rh and
Me-DuPhos-Rh complexes as the catalysts [BICP, 2,2′-bis-
(diphenylphosphino)-1,1′-dicyclopentane; DuPhos, 1,2-bis-
(2,5-dialkylphospholane)benzene]. The key elements of this
method involve: (a) facile synthesis of R-hydroxy ketones, (b)
new enamide formation procedure from oximes using Fe/
Ac2O in DMF as reagents, and (c) high enantioselectivity in
the hydrogenation step.
† The Pennsylvania State University.
‡ DuPont Agricultural Products.
(1) (a) Roemer, D.; Buescher, H. H.; Hill, R. C.; Pless, J .; Bauer, W.;
Cardinaux, F.; Closse, A.; Hauser, D.; Huguenin, R. Nature 1977, 268, 547.
(b) TenBrink, R. E. J . Org. Chem. 1987, 52, 418. (c) Fincham, C. I.;
Higginbottom, M.; Hill, D. R.; Horwell, D. C.; O’Toole, J . C.; Ratcliffe, G.
S.; Rees, D. C.; Roberts, E. J . Med. Chem. 1992, 35, 1472. (d) Auvin-Guette,
C.; Rebuffat, S.; Prigent, Y.; Bodo, B. J . Am. Chem. Soc. 1992, 114, 2170.
(2) Wu, S.; Takeya, R.; Eto, M.; Tomizawa, C. J . J . Pestic. Sci. 1987, 12,
221.
(3) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Butsugan, Y.;
Araki, S.; Watanabe, M. Ferrocenes; VCH: Weinheim, 1995; pp 143-169.
(c) Takehara, J .; Hashiguchi, S.; Fujii, A.; Inoue, S.-I.; Ikariya, T.; Noyori,
R. Chem. Commun. 1996, 233. (d) Peper, V.; Martens, J . Chem. Ber. 1996,
129, 691.
(4) (a) Evans, D. A. in Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, p 1. (b) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: Orlando, 1984;
Vol. 3, p 111. (c) Blaser, H.-U. Chem. Rev. 1992, 92, 935 and references
cited therein. (d) Ghosh, A. K.; Onishi, M. J . Org. Chem. 1996, 61, 2527. (e)
Meyers, A. I.; Brengel, G. P. J . Chem. Soc., Chem. Commun. 1997, 1 and
references therein.
(5) (a) Sawayama, T.; Tsukamoto, M.; Sasagawa, T.; Naruto, S.; Matsu-
moto, J .; Uno, H. Chem. Pharm. Bull. 1989, 37, 1382. (b) Kawai, M.; Omori,
Y.; Yamamura, H.; Butsugan, Y. Tetrahedron: Asymmetry. 1992, 3, 1019.
(6) For a few related reviews, see: (a) Pfaltz, A. Acc. Chem. Res. 1993,
26, 339. (b) Ager, D.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30,
3. (c) Puts, R. D.; Chao, J .; Spagh, D. Y. Synthesis 1997, 431. (d) Ghosh, A.
K.; Mathivanan, P.; Cappiello, J . Tetrahedron: Asymmetry. 1998, 9, 1 and
references therein.
The basic strategy for the synthesis of chiral â-amino
alcohols involves asymmetric hydrogenation of R-arylen-
amides with a MOM-protected â-hydroxy group.11 Rh-
catalyzed asymmetric hydrogenation must tolerate the E
and Z isomers of these enamides since preparation and
isolation of the isomerically pure E and Z isomers are
difficult. Another practical issue in this approach is the
formation of the â-hydroxy-substituted enamide substrates.
We have prepared these MOM-protected â-hydroxy-substi-
tuted enamides in gram quantities from readily available
2-haloacetophenone derivatives 3 as outlined in Scheme 2.11
The first step involves synthesis of 2-hydroxyacetophenone
derivatives 4 through nucleophilic attack on corresponding
2-haloacetophenone by sodium formate. An in situ hydroly-
sis reaction then follows. Nucleophiles other than formate
such as acetate or hydroxide are not desirable for the
synthesis of 2-hydroxyacetophenone derivatives. Protection
of the hydroxy group with methoxymethyl chloride (MOMCl)
went smoothly, giving MOM-protected keto alcohol 5 in good
yield. The key step in the synthesis of enamide 1 is the
conversion of the corresponding oxime 6 of the MOM-
protected keto alcohol by Fe/Ac2O in DMF. The reported
(7) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835 and
references therein.
(8) (a) Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl. 1989, 28,
218. (b) Pridgen, L. N.; Prol, J ., J r.; Alexander, B.; Gillyard, L. J . Org. Chem.
1989, 54, 3231. (c) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77. (d)
Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517. (e) McKennon,
M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568. (f) Dickman, D. A.; Meyers,
A. I.; Smith, G. A.; Gawley, L. Organic Syntheses; Wiley: New York, 1990;
Collect, Vol. VII, p 530. (g) Nicolas, E.; Rusell, K. C.; Hruby, V. J . J . Org.
Chem. 1993, 58, 766.
(9) (a) Ager, D. J .; East, M. B. Tetrahedron 1993, 49, 5683. (b) Harris,
C. E.; Fisher, G. B.; Beardsley, D.; Lee, L. Goralski, C. T.; Nicholson, L.
W.; Singaram, B. J . Org. Chem. 1994, 59, 7746 and references therein. (c)
Tillyer, R. D.; Boudreau, C.; Tschaen, D.; Dolling, U.-H.; Reider, P. J .
Tetrahedron Lett. 1995, 36, 4337. (d) Fisher, G. B.; Goralski, C. T.;
Nicholson, L. W.; Hasha, D. L.; Zakett, D.; Singaram, B. J . Org. Chem. 1995,
60, 2026. (e) Chang, H. T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37,
3219. (f) Reddy, K. L.; Sharpless, K. B. J . Am. Chem. Soc. 1998, 120, 1207
and references therein.
(10) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York,
1993. (b) Sheldon, R. A. Chirotechnology; Marcel Dekker: New York, 1993.
(c) Noyori, R. Asymmetric Catalysis In Organic Synthesis; J ohn Wiley &
Sons: New York, 1994.
(11) The initial demonstration of this strategy was carried out by A.
Casalnuovo, K. M. Sun, R. Shapiro, T. Pahutski, M. Angiolelli, and J .
Feaster using Me-DuPhos-Rh and Me-BPE-Rh catalyst systems. DuPont
Agrichicultural Products, private communication.
10.1021/jo981590a CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

Communications
J . Org. Chem., Vol. 63, No. 23, 1998 8101
Ta ble 1. Liga n d Effect on Rh -Ca ta lyzed Asym m etr ic
Hyd r ogen a tion of a n En a m id e15
Ta ble 2. Asym m etr ic Ca ta lytic Syn th esis of â-Am in o
Alcoh ol Der iva tives via Rh -Ca ta lyzed Hyd r ogen a tion 15
entry
Ar (1)
C6H5 (1a )
p-CH3-C6H4 (1b)
p-MeO-C6H4 (1c)
p-C6H5-C6H4 (1d )
p-Cl-C6H4 (1e)
p-F-C6H4 (1f)
2,4-F2C6H3 (1g)
2-naphthyl (1h )
C6H5 (1a )
p-CH3-C6H4 (1b)
p-MeO-C6H4 (1c)
p-C6H5-C6H4 (1d )
p-Cl-C6H4 (1e)
p-F-C6H4 (1f)
ligand
% ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-BICP
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
(R,R)-Me-DuPhos
94
94
90
99
97
97
98
95
97
96
95
97
98
98
95
98
entry
ligand
% ee
1
2
3
4
(+)-DIOP
88
15
94
97
(R)-BINAP
(R,R)-BICP
(R,R)-Me-DuPhos
method by Kagan12a,b for the synthesis of enamides from
nitriles and Grignard reagents not only generates many
impurities but also cannot be used for making the hetereo-
atom-substituted enamide 1. Conversion of oximes to en-
amides using Barton’s procedure (Ac2O/Py) require high
temperature.12e In a related study, Zard applied Fe/Ac2O
for reduction of vinyl nitrites and formation of acetyl
enamides.12f Recently, Casalnuovo12c and Burk12d indepen-
dently discovered synthetic protocols for conversion of oximes
to enamides with Fe/Ac2O. The presence of DMF in Casal-
nuovo’s procedure is crucial for lowering the reaction tem-
perature, and the reduction reaction of oxime 6 proceeded
cleanly in the presence of Fe/Ac2O to give hetereoatom-
substituted enamide 1.
Hydrogenation of 1 catalyzed by Rh complexes with
different chiral bisphosphines produces â-amino alcohol
derivatives (Table 1). The reaction was typically carried out
at room temperature in toluene with 1 mol % Rh under an
initial H2 pressure of 10 atm for 24-36 h. Our experimental
results show that cationic Rh complexes bearing a variety
of chiral bisphosphines are active catalysts in this transfor-
mation, but the enantioselectivities are ligand dependent.
For examples, by using R-phenylenamide 1a (Ar ) C6H5)
as a model substrate, the hydrogenation catalyzed by
rhodium complexes with three different chiral bisphosphines
bearing diphenylphosphino groups all went in quantitative
yield but with quite different enantioselectivities: 88% ee
with DIOP (entry 1, Table 1), 15% ee with BINAP (entry 2,
Table 1), and 94% ee with BICP (entry 3, Table 1). The
(R,R)-BICP ligand, (2R,2′R)-bis(diphenylphosphino)-(1R,1′R)-
dicyclopentane ((R,R)-BICP, Scheme 1) is a conformationally
rigid chiral 1,4-bisphosphine that was recently reported by
our group as an efficient ligand for the rhodium-catalyzed
asymmetric hydrogenation of dehydroamino acids.13 The
high enantioselectivities in the asymmetric hydrogenation
of these isomeric Z and E mixtures of the MOM-protected
â-hydroxy-substituted enamides 1 demonstrates a broader
utility for our new ligand system. Prior to our study, the
only asymmetric catalysts reported to efficiently hydrogenate
mixtures of (E)- and (Z)-R-arylenamides are the Me-DuPhos-
Rh and Me-BPE-Rh catalysts developed by Burk et al.14
Indeed, high enantioselectivity (97% ee, entry 4) has been
obtained in the hydrogenation of R-arylenamide 1a using a
Me-DuPhos-Rh complex as a catalyst.
2,4-F2C6H3 (1g)
2-naphthyl (1h )
Under the standard set of conditions,15 we have performed
asymmetric hydrogenations of various R-arylenamides 1
with a MOM-protected â-hydroxy group (Table 2) catalyzed
by Rh-BICP and Rh-Me-DuPhos complexes. A variety of
N-acetyl- and O-MOM-protected arylglycinols were obtained
in quantitative yield with high enantiomeric excesses (Table
2). Overall, the BICP-Rh catalyst gives comparable results
with the Me-DuPhos-Rh catalyst. However, the Me-DuPhos-
Rh catalyst displays slightly broader substrate generality
than the BICP-Rh catalyst. For example, while 90% ee was
obtained with the BICP-Rh catalyst for the p-methoxylphen-
yl enamide 1c (entry 3), 95% ee was obtained in the Me-
DuPhos-Rh system under identical conditions (entry 11).
Enamides with either electron-withdrawing groups on the
aryl ring or sterically demanding groups display enhanced
enantioselectivity with the BICP-Rh catalytic system (en-
tries 4-7 vs entries 1-3). The trend is less compelling with
the Me-DuPhos-Rh catalyst. To test if the MOM group is
necessary for high enantioselectivity in this reaction, we
replaced the MOM protective group in enamide 1a with a
methyl group (1i). Under the same reaction conditions, the
enamide (1i) with a â-methoxyl group was hydrogenated in
high yield with 98% ee using the BICP-Rh catalyst. This
result suggests that a variety of substrates with substituents
on the â-position may be hydrogenated with high enantio-
selectivities using the BICP-Rh catalyst. The hydrogenation
products 2 can be easily converted to R-arylglycinols by
deprotection of O-MOM and N-acetyl groups under acidic
conditions. For example, hydrogenation product 2a was
hydrolyzed to (S)-phenylglycinol in 81% yield in acidic MeOH
solution, thus permitting the absolute configuration of
hydrogenation product 2a to be assigned as S. The N-
protected R-arylglycinols can be oxidized to obtain useful
R-arylglycines according to a recent study by Sharpless et
al.9e
In conclusion, we have reported efficient syntheses of
enantiomerically enriched â-amino alcohols using a practical
asymmetric hydrogenation method. Cationic BICP-Rh and
Me-DuPhos-Rh complexes are excellent catalysts for this
transformation.
(12) (a) Kagan, H. B.; Langlois, N.; Dang, T. P. J . Organomet. Chem.
1975, 90, 353. (b) Sinou, D.; Kagan, H. B. J . Organomet. Chem. 1976, 114,
325. (c) Reduction of oximes in the presence of acetic anhydride in DMF by
iron powder provided an excellent way to synthesize enamides from ketones;
the procedure developed by Casalnuovo is provided in the Supporting
Information. (d) Conversion of oximes to enamides with iron powder in acetic
anhydride was also reported by Burk (Burk, M. J . Proc. ChiraTech’ 97
Symp.). A communication was published recently: Burk, M. J .; Casey, G.;
J ohnson, N. B. J . Org. Chem. 1998, 63, 6084. (e) Boar, R. B.; McGhie, J . F.;
Robonson, M.; Barton, D. H. R.; Horwell, D. C.; Stick, R. V. J . Chem. Soc.,
Perkin Trans. 1 1975, 1237. For a related procedure using iron powder and
acetic anhydride, see: (f) Laso, N. M.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron Lett. 1996, 37, 1605.
Ack n ow led gm en t. This work was supported by a
Camille and Henry Dreyfus New Faculty Award and
Teaching-Scholar Award, an ONR Young Investigator
Award, a DuPont Young Faculty Award, Catalytica Phar-
maceuticals, and DuPont Agricultural Products.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data and
experimental details (41 pages).
(13) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997, 119,
1799.
J O981590A
(14) Burk, M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996, 118,
5142.
(15) See Supporting Information.