Versatile synthons for optically pure alpha-amino aldehydes and alpha-amino acids: (+)- and (-)-4,5-dialkoxy-2-oxazolidinones.

Article abstract of DOI:10.1021/ol015535r

Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically pure alpha-amino aldehydes and alpha-amino acids, respectively.

Full text of DOI:10.1021/ol015535r

ORGANIC
LETTERS
2001
Vol. 3, No. 6
897-899
Versatile Synthons for Optically Pure
r-Amino Aldehydes and r-Amino Acids:
(+)- and
(−)-4,5-Dialkoxy-2-oxazolidinones
Toru Morita, Yusuke Nagasawa, Syunsuke Yahiro, Hirofumi Matsunaga, and
Takehisa Kunieda*
Faculty of Pharmaceutical Sciences, Kumamoto UniVersity, 5-1 Oe-honmachi,
Kumamoto 862-0973, Japan
tkuni@gpo.kumamoto-u.ac.jp
Received January 9, 2001
ABSTRACT
Both enantiomers of trans-5-benzyloxy-4-methoxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which are readily accessible
from simple 2-oxazolone heterocycles, represent good candidates for a new class of chiral synthons for use in the preparation of optically
pure r-amino aldehydes and r-amino acids, respectively.
Optically active R-amino aldehydes,1 as well as the corre-
sponding R-amino acids,2 have great potential as chiral
building blocks for the synthesis of polyfunctional unusual
amino acids, amino polyols, and peptide mimics, which
include enzyme inhibitors, aminosugar antibiotics, and sym-
pathomimetic amines. The diverse nature of the functional
groups contained by the above compounds and the impor-
tance of accessing their absolute configuration require the
development of an effective synthesis of R-amino aldehydes
with the diverse side chains in optically pure form. The
N-protected R-amino aldehydes can be generally prepared
via the reduction of amino acids or derivatives thereof1a,3 or
by oxidation of the related 2-amino alcohols.1a-c In most
cases, however, the isolation of R-amino aldehydes in
optically pure form under either the basic or acidic conditions
employed in the synthesis is not a simple task. There have
appeared very few practically useful chiral synthons for a
wide variety of R-amino aldehydes generated under mild,
neutral conditions. This is in contrast to several types of chiral
synthons for R-amino acids, the utility and versatility of
which are well established.2
In this paper we wish to report on some promising chiral
synthons, (+)- and (-)-trans-4-methoxy-5-benzyloxy- (BMOx)
and trans-4,5-dimethoxy-2-oxazolidinones (DMOx), which
function as electrophilic “chiral R-methoxyglycinal” deriva-
tives (Figure 1).
The stereospecific substitution of the 4-methoxy groups
Figure 1. New chiral synthons for R-amino aldehydes and R-amino
acids.
10.1021/ol015535r CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/21/2001

Scheme 1. Synthesis of Chiral Synthons 1a,b and 2a,ba
i
a (a) NBS, ROH, dioxane. (b) iPr2NEt, BnOH. (c) Pr2NEt, MeOH. (d) MacCl 11, NaH, THF. (e) BH3‚THF, 12 (0. equiv), THF. (f) Step
e was repeated. (g) Cs2CO3, MeOH, then recrystallization. (h) LiBH4/MeOH (1:2), THF. (i) MeOH, BF3‚OEt2.
of 1 and 2 for a variety of alkyl groups or aryl groups,
followed by hydrogenolytic and oxidative ring cleavage,
provides direct routes to optically pure R-amino aldehydes
and R-amino acids, respectively.
4,5-dialkoxy derivatives 6. This enantioselective deacetyla-
tion procedure proved to be, in practice, effective for the
kinetic resolution of 4-tert-butoxy-5-methoxy-2-oxazolidi-
nones (6, R ) t-Bu), when the cis-fixed amino alcohols
12a-c (Figure 2) were used as chiral ligands, as seen in
Chiral Synthons, BMOx and DMOx (Scheme 1). The
4,5-dialkoxy-2-oxazolidinones are readily accessible from a
simple 2-oxazolone heterocycle,4 which has been shown to
be sufficiently reactive to serve as a building block for the
2-amino alcohol skeletons found in a variety of bioactive
compounds. The 3-acetyl-2-oxazolone (3) underwent regio-
and stereoselective electrophilic addition with NBS in
alcoholic media to give the trans-5-bromo-4-alkoxy adducts
4 exclusively, which were alcoholyzed with benzyl alcohol
or methanol in the presence of tertiary amines. The optical
resolution of the trans-5-benzyloxy-4-methoxy-2-oxazolidi-
nones (BMOx) (5) thus formed was readily performed with
the aid of 2R-methoxy-1S-apocamphanecarbonyl chloride
(Mac-Cl) (11)5 to give the diastereomeric N-Mac 7 and 8
derivatives, which were readily separable by chromatography
on silica gel. The reductive removal of the chiral auxiliary
from 7 and 8 gave (+)- and (-)-BMOx (1a and b),
respectively, in 77% yield, each of which serves as new class
of chiral synthons for a wide range of R-amino aldehydes.
An alternative procedure involving kinetic resolution
through an amino alcohol-catalyzed enantioselective deacy-
lation with borane6 was explored with the trans-3-acetyl-
Figure 2. Chiral reagents used for optical resolution.
Table 1. The R,R-diphenyl-2-pyrrolidinemethanol and the
derived B-methyl oxazaborolidines were much less effective
as catalysts. The enantioselectivity was most affected by the
size of the 4-alkoxy group. As a result, the bulky tert-butoxy
was found to be the choice of substituents for achieving the
highest selectivity. Using this method, the enantiomeric trans-
Table 1. Enantioselective Borane-Mediated Deacetylation of
3-Acetyl-4,5-dialkoxy-2-oxazolidinones 6 Catalyzed by Amino
Alcohols 12
(1) For reviews, see: (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989,
89, 149. (b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30 1531. (c)
Reetz, M. T. Chem. ReV. 1999, 99, 1121.
(2) For reviews, see: (a) Williams, R. M. Synthesis of Optically ActiVe
R-Amino Acids; Pergamon press: Oxford, 1989. (b) Williams, R. M.
Aldrichimica Acta 1992, 25, 11.
yield (ee)a (%)
BH3‚THF temp time
entry
R
ligand
(equiv)
(°C)
(h)
9
10
1
2
3
4
5
6
7
Me
iPr
12a
12a
12a
12a
12a
12b
12c
2
2
2
2
2
2
2
20
20
20
0
20
20
0
1
2
2
6
3
4
24 (19) 76
17 (51) 83
41 (75) 59
39 (80) 61 (62)
26 (96) 74
(3) For an example, see: Sawamura, M.; Nakayama, Y.; Kato, T.; Ito,
Y. J. Org. Chem. 1995, 60, 1727.
tBu
tBu
tBu
tBu
tBu
(4) For reviews, see: (a) Kunieda, T.; Ishizuka, T. Studies in Natural
Products Chemistry, StereoselectiVe Synthesis (Part H); Atta-ur-Rahman,
Ed.; Elsevier Science Publishers: Amaterdam, 1993. (b) Kunieda, T.;
Ishizuka, T. J. Synth. Org. Chem. Jpn. 1997, 55, 1018.
(5) Ishizuka, T.; Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Pharm.
Bull. 1990, 38, 1717.
40 (75) 60
4.5 35 (76) 63
(6) (a) Hashimoto, N.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1998,
39, 6317. (b) Yokoyama, K.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett.
1999, 40, 6285.
a Determined by HPLC.
898
Org. Lett., Vol. 3, No. 6, 2001

4-tert-butoxy-5-methoxy compounds 9 and 10 were obtained
in 38% (99% ee) and 33% (99% ee), although a repeated
resolving procedure was required in the case of the partially
differentiated former isomer. On successive treatment with
MeOH/BF3‚OEt2, both of the 4-tert-butoxy enantiomers 9
and 10 were converted to (+)- and (-)-DMOx (2a and b),
respectively, in excellent yields.
Table 2. Conversion Yields to 4-Substituted 2-Oxazolidinones
13, R-Amino Aldehydes 15, and R-Amino Acids 16
yield (%)
entry
synthon
R′
13
15
1
2
3
4
5
1b
Bu
iPr
tBu
Ph
Bn
76
76
74
80
90
87
80
97
81
93
Optically Pure R-Amino Aldehydes and R-Amino Acids
(Scheme 2). The chiral trans-4,5-dialkoxy-2-oxazolidinones,
yield (%)
Scheme 2. Conversion to R-Amino Aldehydes 15 and
R-Amino Acids 16a
entry
synthon
R′
13
16
6
7
8
9
10
11
2b
Bu
71
80
71
72
83
78
80
85
98
100
70
iPr
tBu
Ph
Bn
allyl
100
was verified by HPLC analysis or by oxidation to the
authentic R-amino acids, and no detectable racemization was
detected during the ring opening, which proceeded under
strictly neutral conditions.
a (a) R′Li or R′MgX, CuCN, LiCl, BF3‚OEt2, THF (R′ ) allyl:
allylTMS, TiCl4, CH2Cl2). (b) (Boc) 2O, NEt3, DMAP, CH2Cl2. (c)
t
H2, Pd-C, MeOH. (d) KMnO4, KOH, BuOH, H2O then CH2N2
A variety of optically pure (S)-N-Boc-R-amino acids 16
were synthesized by the direct oxidation of N-Boc-4-
substituted 5-methoxy-2-oxazolidinones 14b with either
KMnO4 or PDC under basic conditions. An optical purity
in excess of 99% ee was confirmed by HPLC analysis on
chiral columns. The use of NaBH4 in place of oxidizing
agents such as KMnO4 and PDC resulted in the direct
formation of optically pure N-Boc-2-amino alcohols, which
were also satisfactory precursors for 2-oxazolidinone aux-
iliaries, as previously shown.8
In conclusion, the (+)- and (-)-trans-4-methoxy-5-ben-
zyloxy- (BMOx) and trans-4,5-dimethoxy-2-oxazolidinones
(DMOx), which are readily accessible in stable, crystalline
forms from simple heterocycle 2-oxazolones, represent good
candidates for a new class of chiral synthons for use in the
preparation of a wide variety of optically pure R-amino
aldehydes and R-amino acids, as well as 2-amino alcohols.
or PDC, MeOH, KOH, DMF.
BMOx and DMOx, which can be regarded as chiral
R-methoxyglycinal equivalents, were treated with organo
cuprates in the presence of BF3‚OEt2, resulting in the
regioselective replacement of the 4-methoxy group with prim.
to tert-alkyl and aryl groups with full retention of configu-
ration. It is assumed that this reaction proceeds via the acyl-
iminium ion and the subsequent cuprate attack is effectively
controlled by the vicinal OR groups. Thus, trans-4-
substituted 5-alkoxy derivatives 13 were exclusively formed
with no detectable contamination by cis-isomers. The facile
conversion to the 4-substituted compounds 13 as well as into
R-amino aldehydes and R-amino acids via N-Boc derivatives
14 is summarized in Table 2. It is also noteworthy that N-tert-
butoxycarbonylation greatly facilitates the ring cleavage of
2-oxazolidinones.7
Supporting Information Available: General experimen-
tal procedures and characterizations of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Hydrogenolysis of the N-Boc-4-substituted 5-benzyloxy-
2-oxazolidnones 14a with H2/Pd-C proceeded at room
temperature to give (S)-N-Boc-R-amino aldehydes 15 in
optically pure form. An optical purity in excess of 99% ee
OL015535R
(7) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
(8) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997, 53, 1275.
Org. Lett., Vol. 3, No. 6, 2001
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