The direct catalytic enantioselective synthesis of protected aryl β-hydroxy-α-amino acids

Article abstract of DOI:10.1002/anie.200462125

The combination of three reagents-a tridentate pybox ligand (pybox = pyridine bis(oxazoline)), magnesium perchlorate, and Huenig base (iPr ₂EtN)-allows the catalytic generation of a chiral glycine enolate from 1 that undergoes highly enantiosel

Full text of DOI:10.1002/anie.200462125

Angewandte
Chemie
Enantioselective Synthesis
The Direct Catalytic Enantioselective Synthesis of
Protected Aryl b-Hydroxy-a-Amino Acids**
Michael C. Willis,* Gary A. Cutting,
Vincent J.-D. Piccio, Matthew J. Durbin, and
Matthew P. John
b-Hydroxy-a-amino acid units are present in a significant
number of biologically interesting compounds. Aryl-substi-
tuted variants are an important subclass and are responsible
for a range of biological functions. For example, natural
products such as vancomycin,[1] ristocetin,[1] and biphenomy-
cin A[2] display significant antibiotic activity, the cyclomarins[3]
display anti-inflammatory properties, whereas the exochelins
are involved in cellular iron(iii) transport.[4] Designed mole-
cules have also been implicated in functions such as hypo-
tension.[5] A variety of methods for the enantioselective
synthesis of this important structural unit have been
[*] Dr. M. C. Willis, G. A. Cutting, V. J.-D. Piccio, M. J. Durbin
Department of Chemistry
University of Bath
Bath, BA27AY (UK)
Fax: (+44)1225-386231
E-mail: m.c.willis@bath.ac.uk
Dr. M. P. John
Chemical Development Division
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road
Stevenage, SG12NY (UK)
[**] This work was supported by the EPSRC, the University of Bath, and
GlaxoSmithKline. The EPSRC Mass Spectrometry Service at the
University of Wales, Swansea, is also thanked for their assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462125
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reported.[6,7] One of the most attractive routes, which involves
Table 1: Catalyst evaluation and optimization for the direct addition of
imide 3 to benzaldehyde.[a]
À
the simultaneous formation of a C C bond and the creation
of two stereogenic centers, is the aldol addition of a glycine
equivalent 1 to a suitable aldehyde (Scheme 1).
Entry
Ligand
Base
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
6
7
8
9
10
8
8
8
8
8
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
Et3N
30
65
76
51
53
75
72
86
75
60
55:45
65:35
80:20
65:35[d]
70:30
95:5
12
7
76
44
45
10
60
90
82
80
5
6[e]
7[f]
8[g]
9[g]
10[g]
Scheme 1. The direct catalytic aldol route to aryl b-hydroxy-a-amino
acids. X=OR, NR2; P=protecting group.
95:5
85:15
80:20
85:15
Bu3N
A number of highly selective variants of this process are
established, although in the majority of examples a preformed
enolate or an enolate surrogate, such as an enol silane, is
employed.[8] Direct catalytic enantioselective variants are still
scarce.[9] We recently reported the direct addition of isothio-
cyanate-substituted ester 2 to a range of aryl aldehydes using
an achiral catalyst generated from Mg(ClO4)2, bipyridine, and
triethylamine.[10] Herein we document the extension of this
system into a highly enantioselective variant that employs
commercially available catalyst components.
[a] General conditions: imide (1 equiv), benzaldehyde (1.1 equiv),
Mg(ClO4)2 (10 mol%), ligand (11 mol%), base (20 mol%), CH2Cl2,
À788C. [b] Isolated yields. [c] Measured by 1H NMR spectroscopy. [d] ee
value of major diastereomer, measured by chiral HPLC using a Chiracel
OD column. [e] 1:1 CH2Cl2/THF. [f] Reaction at room temperature.
[g] 4 ꢀ molecular sieves added.
Early attempts at developing an enantioselective reaction
were based on our achiral reaction and involved exchange of
bipyridine for a range of enantiomerically pure bidentate
ligands, which were used in combination with Mg(ClO4)2,
Hꢀnig base, and ester 2. The enantioselectivities obtained
were uniformly low. In the expectation of generating more-
ordered enolates, we refocused on the use of oxazolidinone
Table 2: The enantioselective addition of imide
3
to aromatic
aldehydes.[a]
3
[11] as a glycine equivalent.[12] The addition of 3 to benzalde-
hyde was selected as a test reaction, and a range of ligands,
bases, and solvents were evaluated (Table 1). To aid in the
determination of ee values of the products, the direct adducts
were treated immediately with a solution of magnesium
alkoxide to yield the corresponding ester derivatives.[12a]
Bidentate bis(oxazolines) used in combination with
Mg(ClO4)2 and Hꢀnig base generated poorly selective
catalysts (entries 1 and 2),[13] however, the switch to a pyridine
bis(oxazoline) (pybox) ligand generated a catalyst that
delivered the product with a much improved value of
76% ee (entry 3). Variation of the ligand substituents from
phenyl to tert-butyl and benzyl resulted in decreased selec-
tivities (entries 4 and 5). All of the reactions described so far
had been conducted in methylene chloride; the use of a 1:1
mixture of CH2Cl2 and THF had a dramatic effect and
reduced the enantioselectivity to only 10% (entry 6). Increas-
ing the reaction temperature to ambient temperature also
resulted in reduced selectivity (entry 7). As a precaution
against degradation of the hygroscopic Mg(ClO4)2, molecular
sieves were added to the system, and an increase in selectivity
to 90% ee was observed (entry 8).[14] Finally, variation of the
base employed was also explored and Hꢀnig base was found
to be optimal (entries 9 and 10).
Entry
Ar
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
C6H5
86
69
85
74
88
95
79
84
88
64
78
85:15
85:15
87:13
85:15
88:12
91:9
73:27
82:18
50:50
72:28
93:7
90
86
93
94
92
91
87
86
89[e]
87
95
4-MeO-C6H4
4-EtO-C6H4
4-MeS-C6H4
4-Me-C6H4
4-Et-C6H4
4-Ph-C6H4
3-Me-C6H4
2-Me-C6H4
2-Naphthyl
3-Cl-4-PMBO-C6H4
9
10
11
[a] General conditions: imide (1 equiv), aldehyde (1.1 equiv), Mg(ClO4)2
(10 mol%), 8 (11 mol%), iPr2EtN (20 mol%), CH2Cl2, À788C. [b] Iso-
lated yields of combined diastereomers. [c] Measured by 1H NMR
spectroscopy. [d] ee value of major diastereomer, measured by chiral
HPLC using Chiracel OD column. [e] ee of anti diastereomer; ee=62%
for syn diastereomer.
and aryl substituents were readily accommodated in the para
position of the aldehyde with observed enantioselectivities of
up to 94% ee (entries 1–7). In all cases the syn-aldol adduct
was obtained as the major diastereomer with selectivities of
up to 91:9. Substitution in the meta position was also tolerated
well (entry 8), however the presence of an ortho substituent
With optimized conditions in hand, we next explored the
scope of the process with respect to the aryl aldehyde
component (Table 2).[15] A wide variety of heteroatom, alkyl,
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Angewandte
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resulted in a 50:50 ratio of diastereomers (entry 9). 2-
Naphthaldehyde is also a good substrate with the required
aldol adduct obtained in 87% ee (entry 10). The final entry is
significant as the substitution pattern of the product matches
that of one of the functionalized tyrosine residues (AA-6) of
vancomycin:[16] Reaction with 3-chloro-4-OPMB-benzalde-
hyde (PMB = p-methoxybenzyl) yielded the protected amino
acid in 78% yield as a 93:7 ratio of syn:anti diastereomers
with an impressive 95% ee.
In summary, a simple catalyst system assembled from an
enantiomerically pure tridentate ligand, a Lewis acidic metal,
and an amine base efficiently generates a chiral glycine
enolate derived from oxazolidinone 3. The enolate undergoes
enantioselective addition to a range of aryl aldehydes to
provide protected aryl b-hydroxy-a-amino acids in good
yields with high enantioselectivities. The utility of the method
has been exemplified by the preparation of a constituent
amino acid of the natural product vancomycin. Importantly,
all of the catalyst components are commercially available and
the reactions are simple to perform. Studies to explore the
addition of similar chiral enolates to alternative electrophiles
and to apply these enolization conditions to alternative
nucleophilic components are underway and will be reported
in due course.
[1] Glycopeptide Antiobiotics, (Ed.: R. Nagarajan), Marcel Dekker,
New York, 1994.
[2] M. Ezaki, M. Iwami, M. Yamashita, S. Hashimoto, T. Komori, K.
Umehara, Y. Mine, M. Kohsaka, H. Aoki, H. Imanaka, J.
Antibiot. 1985, 38, 1453.
[3] M. K. Renner, Y.-C. Shen, X.-C. Cheng, P. R. Jensen, W.
Frankmoelle, C. A. Kauffman, W. E. Fenical, E. Lobkovsky, J.
Clardy, J. Am. Chem. Soc. 1999, 121, 11273.
[4] R. Barclay, C. Ratledge, J. Bacteriol. 1983, 153, 1138.
[5] B. Herbert, I. H. Kim, K. L. Kirk, J. Org. Chem. 2001, 66, 4892.
[6] For a discussion of the different approaches used to prepare the
b-hydroxy-tyrosine units found in glycopeptide antibiotics, see:
K. C. Nicolaou, C. N. C. Boddy, S. Brꢃse, N. Winssinger, Angew.
Chem. 1999, 111, 2230; Angew. Chem. Int. Ed. 1999, 38, 2096.
[7] For recent examples, see: a) K. Makino, T. Goto, Y. Hiroki, Y.
Hamada, Angew. Chem. 2004, 116, 900; Angew. Chem. Int. Ed.
2004, 43, 882, for ketone reductions; b) C. Loncaric, W. D. Wulff,
Org. Lett. 2001, 3, 3675, for aziridine opening; c) D. L. Boger,
M. A. Patane, J. Zhou, J. Am. Chem. Soc. 1994, 116, 8544; for
epoxide opening; d) L. Dong, M. J. Miller, J. Org. Chem. 2002,
67, 4759, for dihydroxylation; e) I. H. Kim, K. L. Kirk, Tetrahe-
dron Lett. 2001, 42, 8401, for aminohydroxylation.
[8] Selected examples: a) H. Sugiyama, T. Shioiri, F. Yokokawa,
Tetrahedron Lett. 2002, 43, 3489; b) J. B. MacMillan, T. F.
Molinski, Org. Lett. 2002, 4, 1883; c) S. Caddick, N. J. Parr,
M. C. Pritchard, Tetrahedron 2001, 57, 6615; d) M. Horikawa, J.
Busch-Peterson, E. J. Corey, Tetrahedron Lett. 1999, 40, 3843;
e) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998,
120, 431; f) J. Kobayashi, M. Nakamura, Y. Mori, Y. Yamashita,
S. Kobayashi, J. Am. Chem. Soc. 2004, 126, 9192.
[9] a) Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108,
6405; b) D. A. Evans, J. M. Janey, N. Magomedov, J. S. Tedrow,
Angew. Chem. 2001, 113, 1936; Angew. Chem. Int. Ed. 2001, 40,
1884; c) H. Suga, K. Ikai, T. Ibata, J. Org. Chem. 1999, 64, 7040;
d) N. Yoshikawa, M. Shibasaki, Tetrahedron 2002, 58, 8289; e) T.
Ooi, M. Taniguchi, M. Kameda, K. Maruoka, Angew. Chem.
2002, 114, 4724; Angew. Chem. Int. Ed. 2002, 41, 4542.
[10] M. C. Willis, V. J.-D. Piccio, Synlett 2002, 1625.
[11] Oxazolidinone 3 was prepared from the corresponding azide,
according to the procedure reported for a chiral derivative in
Reference [12a]. See Supporting Information for details.
[12] For examples of the use of a chiral version of 3 in diastereose-
lective aldol additions, see: a) D. A. Evans, A. E. Weber, J. Am.
Chem. Soc. 1986, 108, 6757; b) D. A. Evans, A. E. Weber, J. Am.
Chem. Soc. 1987, 109, 7151; c) M. A. Lago, J. Samanen, J. D.
Elliot, J. Org. Chem. 1992, 57, 3493; d) D. L. Boger, S. L. Colletti,
T. Honda, R. F. Menezes, J. Am. Chem. Soc. 1994, 116, 5607. See
also Reference [5].
Experimental Section
General procedure for direct catalytic enantioselective aldol reaction,
as exemplified by the preparation of (4S,5R)-ethyl 5-phenyl-2-thioxo-
1,3-oxazolidine-4-carboxylate (Table 2, entry 1): Mg(ClO4)2 (15 mg,
0.07 mmol),
2,6-bis((R)-4,5-dihydro-4-phenyl-2-oxazolyl)pyridine
(28 mg, 0.08 mmol), and 3-(2-isothiocyanatoacetyl)-oxazolidin-2-one
(128 mg, 0.69 mmol) were stirred for 1 h in dry methylene chloride
(15 mL) in the presence of activated, powdered 4 ꢁ molecular sieves
(200 mg) under nitrogen at room temperature. The temperature was
then lowered to À788C and after 15 min, benzaldehyde (77 mL,
0.76 mmol) and diisopropylethylamine (24 mL, 0.14 mmol) were
added, and the mixture was stirred for a further 24 h at À788C. The
reaction was quenched with saturated aqueous ammonium chloride
(5 mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 10 mL). The organic portions were
combined, washed with brine (5 mL), dried (MgSO4), and concen-
trated under reduced pressure. The residue was dissolved in dry THF
(15 mL), and the solution was cooled to 08C. A solution of methyl
magnesium bromide (3m in diethyl ether, 0.30 mL, 0.89 mmol) in
ethanol (3.3 mL) at 08C was added through a cannula. After 3 min,
the reaction was quenched by addition of aqueous phosphate buffer
solution (5 mL, pH 7). The mixture was concentrated under reduced
pressure, and the residue was taken up in aqueous HCl (1m, 10 mL)
and CH2Cl2 (10 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 ꢂ 10 mL). The organic
portions were combined, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by flash chromatography
(SiO2, 98:2 CH2Cl2/EtOAc) to provide the title compound as colorless
crystals.
[13] For the use of a Mg–bis(oxazoline) catalyst system in the direct
enantioselective addition of malonate derivatives to nitro-
alkenes, see: J. Ji, D. M. Barnes, J. Zhang, S. A. King, S. J.
Wittenberger, H. E. Morton, J. Am. Chem. Soc. 1999, 121,
10215.
[14] The addition of 20 mol% water to the reaction resulted in a
significant reduction in the enantioselectivity of the process (50–
60% ee depending on the exact reaction).
[15] The absolute configuration of the benzaldehyde adduct (Table 2,
entry 1) was established by X-ray crystallography; the remaining
adducts are assigned by analogy.
[16] N. J. Skelton, D. H. Williams, M. J. Rance, J. C. Ruddock, J.
Chem. Soc. Perkin Trans. 1 1990, 77.
Received: September 27, 2004
Published online: January 28, 2005
Keywords: aldol reaction · amino acids · asymmetric catalysis ·
.
Lewis acids · magnesium
Angew. Chem. Int. Ed. 2005, 44, 1543 –1545
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1545