Optically active aromatic and heteroaromatic α-amino acids by a one-pot catalytic enantioselective addition of aromatic and heteroaromatic C-H bonds to α-imino esters

Article abstract of DOI:10.1021/jo0256787

The development of a practical one-pot catalytic enantioselective procedure for the synthesis of non-natural aromatic and heteroaromatic α-amino acids is reported. Starting from readily available starting materials and application of a chiral BINAP-Cu(I) catalyst, the optically active products are formed with readily removable N-protecting groups. The scope of the reaction is demonstrated by the addition of substituted furans, thiophenes, pyrroles, and aromatic compounds to N-alkoxy-carbonyl-α-imino esters in good yields and with enantioselectivities up to 96% ee for the furans, 93% ee for the thiophenes, and 98% for the aromatic compounds. The protecting groups are readily removed, and various transformations of the aromatic and heteroaromatic a-amino acids are demonstrated. The coordination of the N-alkoxycarbonyl α-imino ester to the chiral BINAP-Cu(I) complex and the enantioselectivity of the catalyst is discussed on the basis of the DFT calculations and X-ray crystallographic data.

Full text of DOI:10.1021/jo0256787

4352
J . Org. Chem. 2002, 67, 4352-4361
Op tica lly Active Ar om a tic a n d Heter oa r om a tic r-Am in o Acid s by a
On e-P ot Ca ta lytic En a n tioselective Ad d ition of Ar om a tic a n d
Heter oa r om a tic C-H Bon d s to r-Im in o Ester s
Steen Saaby, Pau Bayo´n, Pompiliu S. Aburel, and Karl Anker J ørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
kaj@chem.au.dk
Received March 4, 2002
The development of a practical one-pot catalytic enantioselective procedure for the synthesis of
non-natural aromatic and heteroaromatic R-amino acids is reported. Starting from readily available
starting materials and application of a chiral BINAP-Cu(I) catalyst, the optically active products
are formed with readily removable N-protecting groups. The scope of the reaction is demonstrated
by the addition of substituted furans, thiophenes, pyrroles, and aromatic compounds to N-alkoxy-
carbonyl-R-imino esters in good yields and with enantioselectivities up to 96% ee for the furans,
93% ee for the thiophenes, and 98% for the aromatic compounds. The protecting groups are readily
removed, and various transformations of the aromatic and heteroaromatic R-amino acids are
demonstrated. The coordination of the N-alkoxycarbonyl R-imino ester to the chiral BINAP-Cu(I)
complex and the enantioselectivity of the catalyst is discussed on the basis of the DFT calculations
and X-ray crystallographic data.
In tr od u ction
The synthesis of optically active aromatic and het-
eroaromatic R-amino acids is a challenge in organic
chemistry, and only a few research groups have suc-
ceeded in the development of a catalytic asymmetric
approach to heteroaromatic R-amino acids applying
either the asymmetric Strecker reaction7 or the Sharpless
amino-hydroxylation reaction,8 giving the corresponding
furfuryl R-amino cyanides or alcohols, respectively. Meth-
ods based on enzymatic or Lewis-acid-catalyzed kinetic
resolution of racemic starting materials as well as the
use of chiral templates have also been reported.1a,9
The catalytic enantioselective addition of aromatic and
heteroaromatic C-H bonds to R-imino esters, an aza-
Friedel-Crafts reaction,10 is the direct approach to
optically active aromatic and heteroaromatic R-amino
acids. However, despite the great potential, only very few
protocols for the catalytic asymmetric version of this
reaction have been reported.11,12 Recently, we com-
municated the catalytic formation of optically active
aromatic R-amino acids by the addition of electron-rich
Optically active R-amino acids constitute some of the
most important molecules in living cells. A fundamental
challenge in organic chemistry is the development of
catalytic enantioselective C-C bond-forming reactions,
which give access to this class of optically active building
blocks using simple starting materials. A number of
methods for the construction of optically active aromatic
and heteroaromatic R-amino acids have been developed.1
However, despite the relatively simple structure, the
formation of these nonracemic adducts is difficult due to
base-catalyzed epimerization of the acidic R-methine
proton.2
Optically active aromatic R-amino acids are important
molecular fragments in many molecules of biological
importance such as cephalecins,3 nocardicins,4 and gly-
copeptides of the vancomycin family.5 The heteroaromatic
R-amino acids are also an interesting and important class
of amino acids, and in particular, the furyl glycine
derivatives have received increased attention due to the
large number of structural equivalents and synthetic
applications of the heteroaromatic moiety.6
(7) (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J .
Am. Chem. Soc. 1996, 118, 4910. (b) Takamura, M.; Hamashima, Y.;
Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem. 2000, 112, 1716;
Angew. Chem., Int. Ed. Engl. 2000, 39, 1650. (c) Takamura, M.;
Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Chem. Pharm.
Bull. 2000, 48, 1586.
(1) For leading references, see, e.g.: (a) Williams, R. M.; Hendrix,
J . A. Chem. Rev. 1992, 92, 889. (b) Yet, L. Angew. Chem. 2001, 113,
900; Angew. Chem., Int. Ed. Engl. 2001, 40, 875. (c) Reddy, K. L.;
Sharpless, K. B. J . Am. Chem. Soc. 1998, 120, 1207 and references
therein.
(8) Li, G. G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451.
(2) (a) Smith, G. G.; Sivakua, T. J . Org. Chem. 1983, 48, 627. (b)
Bodanszky, M.; Bodanszky, A. Chem. Commun. 1967, 591.
(3) Spencer, J . L.; Flynn, E. H.; Roeske, R. W.; Sriv, F. Y.; Chaivette,
R. R. J . Med. Chem. 1966, 9, 746.
(4) Townsend, C. A.; Brown, A. M. J . Am. Chem. Soc. 1983, 105,
913.
(9) Enzymatic/kinetic resolution and chiral templates: For reviews,
see, e.g.: (a) Zhou, W.; Lu, Z.; Xu, Y.; Liao, L.; Wang, Z. Tetrahedron
1999, 55, 11959. (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(10) For reviews of Friedel-Crafts alkylation reactions, see: (a)
Smith, M. B. Organic Synthesis; McGraw-Hill: New York, 1994; p
1313. (b) Heaney, H. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 733. (c)
Roberts, R. M.; Khalaf, A. A. in Friedel-Crafts Alkylation Chemistry.
A Century of Discovery; Dekker: New York, 1984. (d) Olah, G. A.
Friedel-Crafts Chemistry; Wiley-Interscience: New York, 1973.
(11) Saaby, S.; Fang, X.; Gathergood, N.; J ørgensen, K. A. Angew.
Chem. 2000, 112, 4280; Angew. Chem., Int. Ed. 2000, 39, 4114.
(12) (a) J ohannsen, M. Chem. Commun. 1999, 2233. (b) Yao, S.;
Saaby, S.; Hazell, R. G.; J ørgensen, K. A. Chem. Eur. J . 2000, 6, 2435.
(5) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem. Rev.
1995, 95, 2135.
(6) For leading references, see, e.g.: (a) Maier, M. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995;
p 236. (b) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett 1998, 105. (c) Zhou, W.; Lu, Z.; Xu,
Y.; Liao, L.; Wang, Z. Tetrahedron 1999, 55, 11959. (d) Kappe, C. O.;
Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179.
10.1021/jo0256787 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002

Optically Active Aromatic and Heteroaromatic R-Amino Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4353
Ta ble 1. Effect of N-Ca r boa lk oxyim in op h osp h a n es 1,
Alk yl Glyoxyla tes 2, Solven t, a n d Cou n ter ion on th e
Ca ta lytic En a n tioselective Aza -F r ied el-Cr a fts Rea ction
of N-Alk oxyca r bon yl r-Im in o Ester s 3a -h w ith
2-Meth ylfu r a n 4a
aromatic compounds to R-imino esters using chiral Lewis
acid catalysis.11 Two examples of catalytic enantioselec-
tive aza-Friedel-Crafts reactions using furan as the
substrate are known from the literature; however, poor
results in terms of both yield and enantiomeric excess
were obtained.12 In relation to the addition of aromatic
and heteroaromatic compounds to R-imino esters, it
should be noted that catalytic enantioselective addition
reactions of aromatic and heteroaromatic compounds to
carbonyl compounds and R,â-unsaturated systems have
also recently been achieved.13,14
In this paper, we disclose the development of a simple
one-pot procedure for the synthesis of optically active
aromatic, furfuryl, thiophenyl, and pyrrolyl R-amino acid
derivatives using chiral Lewis acid catalysis (eq 1).
Protected aromatic and heteroaromatic R-amino acids are
obtained directly by this procedure where aromatic and
heteroaromatic C-H bonds are added to R-imino ester
electrophiles activated by a chiral BINAP-Cu(I) catalyst.
aza-
Lewis
acid
entry ylide R1
R2 imine
yielda (%) eeb,c (%)
1
2
3
4
5
6d
7
8
9
1a
t-Bu Et
3a
3b
3c
3d
3e
3c
3f
3g
3h
3e
3e
3h
CuPF6
5a , <20
5b, 61
5c, 31
5d , 37
5e, 56
5c, 25
5f, 21
5g, 30
5h , 35
5e, 29
30 (R)
52 (R)
73 (R)
79 (R)
84 (R)
64 (R)
55 (-)
79 (R)
88 (R)
81 (R)
66 (R)
90 (R)
1b i-Pr Et
1c
1d Bn
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuClO4
Et
Et
Et
1e
1c
1e
1e
1e
1e
1e
1e
Me Et
Et Et
Me Bn
Me i-Pr
Me Me
Me Et
Me Et
Me Me
10
11
CuOTf‚Tol 5e, 31
CuPF6
12e
5h , 39
a
b
Isolated yields based on the aza-ylide (1). Determined by
chiral HPLC or GC (see the Supporting Information for further
details). c The absolute configuration of 5h was derived from a
crystalline N-tosyl derivative 12, which was analyzed by X-ray
analysis (see the Supporting Information for further details). The
configurations of 5a -e were assigned by deprotection and subse-
quent standard protecting group transformations18 and mutual
comparison of the samples obtained. The absolute configuration
d
of 5g was assigned by analogy (HPLC traces). Solvent: toluene.
e Solvent: toluene/CH2Cl2 (19:1).
Resu lts a n d Discu ssion
Recently, we reported the development of a catalytic
enantioselective addition of electron-rich aromatic com-
pounds to N-alkoxycarbonyl R-imino esters,11 The R-imino
ester electrophiles were generated via an aza-Wittig
reaction (eq 2, Scheme 1) and reacted with the aromatic
substrates catalyzed by a BINAP-Cu(I) complex without
any purification (eq 3, Scheme 1).
tive addition of aromatic, as well as heteroaromatic
compounds, to R-imino esters.
Preliminary studies revealed that low temperature
(-78 °C) and the choice of solvent (toluene) was crucial
for the exclusion of byproducts15 and the enantioselec-
tivity of the catalytic reaction. A series of reactions
between 4a and a number of different imines 3a -h were
conducted in the presence of (R)-Tol-BINAP-CuPF6 as
the catalyst11,12,16 (eq 4) in order to optimize the enanti-
oselectivity. The results are presented in Table 1.
Sch em e 1
However, an attempt to extend the scope of the reaction
to include also heteroaromatic compounds was met with
limited success, as the reaction of 2-methylfuran 4a with
a methoxycarbonyl-protected R-imino ester 3e afforded
the corresponding furfuryl R-amino acid in poor yield
(17%) and with low enantiomeric excess (41% ee). Fur-
thermore, several of the electron-rich aromatic com-
pounds reacted with moderate yields and enantioselec-
tivities using the first reaction protocol.11 These observa-
tions prompted us to develop a general reaction protocol,
which was applicable for both the catalytic enantioselec-
The N-alkoxycarbonyl R-imino esters 3a -h were pre-
pared via an aza-Wittig reaction of the N-carboalkoxy-
(15) When performing a reaction in, e.g., CH2Cl2 at room temper-
ature, a substantial amount of an unidentified byproduct was formed.
The molecular weight (HRMS) of the compound indicates a structure
that consists of one aromatic moiety and the addition of two imine
molecules.
(13) (a) Erker, V. G.; van der Zeijden, A. A. H. Angew. Chem. 1990,
102, 543; Angew. Chem., Int. Ed. Engl. 1990, 29, 512. (b) Ishii, A.;
Mikami, K. J . Fluorine Chem. 1999, 97, 51. (c) Gathergood, N.; Zhuang,
W.; J ørgensen, K. A. J . Am. Chem. Soc. 2000, 122, 12517. (c) Ishii, A.;
Soloshonok, V. A.; Mikami, K. J . Org. Chem. 2000, 65, 1597. (d)
Zhuang, W.; Gathergood, N.; Hazell, R. G.; J ørgensen, K. A. J . Org.
Chem. 2001, 66, 1009.
(14) (a) Zhuang, W.; Hansen, T.; J ørgensen, K. A. Chem. Commun.
2001, 347. (b) J ensen, K. B.; Thorhauge, J .; Hazell, R. G.; J ørgensen,
K. A. Angew. Chem. 2001, 113, 164; Angew. Chem., Int. Ed. 2001, 40,
160. (c) Paras, N. A.; MacMillan, D. W. C. J . Am. Chem. Soc. 2001,
123, 4370. (d) Austin, J . F.; MacMillan, D. W. C. J . Am. Chem. Soc.
2002, 124, 1172.
(16) For the use of BINAP-Cu(I) complexes as catalysts, see, e.g.:
(a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J . Am. Chem. Soc.
1998, 120, 4548. (b) Drury, W. J ., III; Ferraris, D.; Cox, C.; Young, B.;
Lectka, T. J . Am. Chem. Soc. 1998, 120, 11006. (c) Yao, S.; Fang, X.;
J ørgensen, K. A. Chem. Commun. 1998, 2547. (d) Yao, S.; J ohannsen,
M.; Hazell, R. G.; J ørgensen, K. A. Angew. Chem. 1998, 110, 3318;
Angew. Chem., Int. Ed. 1998, 37, 3121. (e) Ferraris, D.; Young, B.; Cox,
C.; Drury, W. J ., III; Didding, T.; Lectka, T. J . Org. Chem. 1998, 63,
6090. (f) Fang, X.; J ohannsen, M.; Yao, S.; Gathergood, N.; Hazell, R.
G.; J ørgensen, K. A. J . Org. Chem. 1999, 64, 4844. (g) Ferraris, D.;
Dudding, T.; Young, B.; Drury, W. J ., III; Lectka, T. J . Org. Chem.
1999, 64, 2168. (h) J uhl, K.; Hazell, R. G.; J ørgensen, K. A. J . Chem.
Soc., Perkin Trans. 1 1999, 2293.

4354 J . Org. Chem., Vol. 67, No. 12, 2002
Saaby et al.
Ta ble 2. Yield Op tim iza tion by Va r ia tion of th e
Electr on ics a n d Ster ics of th e Aza -Ylid e 1
iminophosphanes 1 and the corresponding alkyl glyoxy-
lates 2 (eq 2, Scheme 1) and used directly in the catalytic
reaction (eq 3, Scheme 1) without any purification.
Initially, we anticipated that the size of the imine-
protecting group would affect the enantioselectivity of the
reaction, and as shown in entries 1-5 in Table 1, the
enantiomeric excess of the furfuryl R-amino acids 5a -e
increased gradually from 30% to 84% ee by reducing the
steric size of the R1-substituent of the carbamate. The
same trend was observed varying the R2-substituent on
the ester functionality (Table 1, entries 5 and 7-9) as
the enantiomeric excess was further increased to 88%
using an imine having the smallest substituent (methyl)
in both the ester and carbamate moieties. The protected
furfuryl R-amino acids were formed in a regioselective
manner, as the substitution only occurs at the 5-position
of 2-methylfuran. A change of the copper(I) Lewis acid
counterion from PF6 to the stronger coordinating ClO4
and TfO anions caused a reduction in both yield and
enantiomeric excess from 84% to 81% and 66% ee,
respectively (Table 1, entries 5, 10, and 11). The best
reaction conditions in terms of enantioselectivity using
the N-carboalkoxyiminotriphenylphosphanes as the imi-
ne precursors are outlined in entry 12. The use of imine
3h affords the aza-Friedel-Crafts adduct 5h in 39%
isolated yield (two steps) with a high enantioselectivity
of 90% ee.
entry aza-ylide R1 R2 R3 yield of 5h (%) ee of 5h (%)
1b
2c
3d
4e
1e
1f
1g
1h
Ph
Bn
Bn
Ph
Ph
Bn
Ph
Ph
Ph
39
59
46
8
90
89
88
0
n-Bu n-Bu n-Bu
a
(R)-Tol-BINAP-CuPF6 (10 mol %), toluene/CH2Cl2 (19:1), -78
b
°C, 44-48 h. 40 °C, 90 min, toluene, 2.0 equiv of methyl
glyoxylate. c rt, 50 min, toluene, 1.2 equiv of methyl glyoxylate.
rt, 20 min, toluene, 1.1 equiv of methyl glyoxylate. e Nonopti-
d
mized reaction conditions.
in the reaction mixture, the catalyst complex was per-
turbed or decomposed completely as 5h was formed as a
racemate (Table 2, entry 4). It was found that excess
amounts of 2 did not have any effects on the isolated yield
of 5h .
With the optimized reaction conditions in hand, a
series of reactions of different heteroaromatic substrates
4a -k were performed in order to demonstrate the scope
and synthetic applicability of the reaction (eq 6). The
The moderate yield of the optically active furfuryl
R-amino acid 5h (39%) was addressed to a low purity of
the crude R-imino ester solution used in the catalytic
reaction. Full conversion of the aza-ylide 1e was moni-
1
tored by H NMR spectroscopy; however, a substantial
amount of imine decomposition was detected using the
reaction conditions outlined in eq 4. These observations
prompted us to optimize of the reaction conditions in
order to improve the yield of the reaction (eq 5). Substi-
results are presented in Table 3. The protected 5-substi-
tuted furyl glycines 5h -o were formed in generally good
yields and high to excellent enantioselectivities (up to
96% ee) using the alkyl-, benzyl-, aryl-, and methoxy-
substituted furans 4a -f as substrates (Table 3, entries
1-6). 3-Methylfuran 4g also reacted using the present
reaction conditions, affording the furfuryl R-amino acid
5n in a good yield, though with a slightly lower enanti-
oselectivity (Table 3, entry 7). Disubstituted furans such
as 4h could also be used as the substrates, and the
corresponding optically active heteroaromatic R-amino
acid was obtained with good enantioselectivity; however,
the yield was moderate due to a substantial amount of
the double addition product.15 It should be noted that the
catalytic enantioselective reaction using furan as sub-
strate was found to be sluggish, giving a mixture of
isomeric products in low yield. Activated thiophenes 4i,j
also reacted under the optimized reaction conditions
affording the optically active thiophenyl R-amino acid
derivatives 5p ,q in high yields and excellent enantiose-
lectivities up to 94% ee (Table 3, entries 9 and 10). The
(R)-Tol-BINAP-CuPF6 complex also catalyzed the reac-
tion of imine 3h with N-methylpyrrole 4k with selective
substitution in the 2-position. However, a drop in enan-
tioselectivity was observed (59% ee), probably caused by
the ability of the more Lewis-basic nitrogen atom in the
substrate to interact with the copper(I) catalyst. This
explanation was supported by the observation that lower
ee values were measured when an increase of the amount
of 2-methylfuran (4 equiv) was used in the reaction with
the different imines. When more polar solvents such as
Et2O, THF, C6H5CF3, CH2Cl2, dioxane, TBME, or MeNO2
were used for the catalytic asymmetric reaction lower
enantioselectivities were also found.
tution of one of the phenyl groups in the aza-ylide 1 with
the more electron-donating benzyl group improved the
rate and purity of the first reaction step in which the
imine is formed. The overall yield of the furfuryl R-amino
acid was hence increased from 39% to 59%, without
notably affecting the high ee value (Table 2, entry 1 vs
2). The purity of the imine derived from methyl glyoxylate
and aza-ylide 1g was excellent (ca 95%), but surprisingly
the yield of 5h decreased to 46%. We expect this observa-
tion to be a consequence of competitive coordination of
the imine and the phosphine oxide to the Cu(I) catalyst.
However, as long as the phosphine oxide is sufficiently
bulky, the catalytic enantioselectivity of the Lewis acid
complex is maintained (Table 2, entries 1-3). When the
more Lewis basic tributylphosphine oxide was present

Optically Active Aromatic and Heteroaromatic R-Amino Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4355
Ta ble 3. Ca ta lytic Asym m etr ic Aza -F r ied el-Cr a fts Rea ction s of Differ en t Heter oa r om a tic Su bstr a tes 4a -j w ith th e
N-Moc-P r otected r-Im in o Meth yl Ester 3h
entry
R1
R2
substrate (equiv)
X
product
yielda (%)
eeb (%)
1
2
Me
Et
t-Bu
Bn
p-MeO-Ph
MeO
H
Me
MeO
p-Me2N-Ph
H
H
4a (2)
4b (2)
4c (10)
4d (5)
4e (2)
4f (1.2)
4g (2)
4h (2)
4i (1.2)
4j (2)
O
O
O
O
O
O
O
O
S
5h
5i
59
89
H
64
88
3
H
5j
33
96
4
H
5k
5l
40c
82 (45)d
63
95
5
H
74 (99.5)d
6
H
5m
5n
5o
5p
5q
5r
96
72
84
94
93
59
7
Me
Me
H
55
8
24
9
75
10
11
H
H
S
56e
55
4k (1.2)
NMe
a
b
Isolated yields based on the aza-ylide. Determined chiral HPLC or GC (see the Supporting Information for further details). c A
d
byproduct (14) formed in 23% yield was isolated and characterized (see the Supporting Information). Numbers in parentheses refer to
yield and enantiomeric excess after a single recrystallization from Et2O/hexane. e Yield determined by 1H NMR spectroscopy.
Ta ble 4. Resu lts for th e Rea ction of Differ en t Ar om a tic
An efficient and clean synthesis of methoxycarbonyl-
Su bstr a tes w ith Im in es
protected imines via the aza-ylide 1e is limited tonon-
1
polar solvents, whereas no imine can be detected by H
NMR spectroscopy when the reaction is performed in,
e.g., THF, although the conversion of starting material
is complete. However, the imine synthesis using the more
reactive benzyldiphenylphosphine derived aza-ylide 1f is
very efficient, also in polar solvents.
A series of electron-rich aromatic compounds 6a -h
were reacted with different imines under optimized
reaction conditions providing the aromatic R-amino acid
7a -h (eq 7) in high yields and with good to excellent
enantioselectivities (up to 98% ee) (Table 4). Generally,
the results achieved using the present reaction condition
were better in terms of enantioselectivity than the results
previously obtained.11 An example is that the yield and
enantioselectivity increased from 68% to 81% and 72%
ee to 96% ee, respectively, in the case of meta-methoxy-
N,N-dimethylaniline 6b as substrate, using this new
procedure.
Selective Dep r otection a n d F u n ction a l Gr ou p
Tr a n sfor m a tion s. A selective deprotection of the two
amino functionalities and further transformations of the
free aniline derivative is outlined in Scheme 2. By
reaction of the aromatic R-amino acid 7a with iodosoben-
a
Addition of the imino electrophile occurs exclusively in the
zene and TMSN3, and subsequent hydrolysis of the
para position to the nitrogen substituent of the aromatic substrate.
formed bis-azide, the unprotected aniline derivative 8
b
Isolated yields based on the aza-ylide. c Determined chiral HPLC
d
was isolated in a high yield of 83%. The aromatic amino
group was then removed by diazotization and subsequent
copper-catalyzed decomposition of the diazonium salt in
saturated aqueous H3PO2 to give 9. Several synthetic
procedures are available for the transformation of dia-
zonium salts into halogens or hydroxyl groups.18 These
selective transformations provide the access to versatile
optically active building blocks, e.g., nonsubstituted
naphthalene and anthracene derived R-amino acids
(7g,h ) as well as para-substituted phenylglycins. The
or GC (see the Supporting Information for further details). (R)-
Tol-BINAP-CuPF6 (10 mol %), toluene/THF (3:7), -78 °C, 24 h.
e (R)-Tol-BINAP-CuPF6 (10 mol %), CH2Cl2, -78 °C, 24 h. f (R)-
Tol-BINAP-CuPF6 (5 mol %), CH2Cl2, -78 °C, 24 h.
R-methine proton of arylglycines is highly susceptible to
racemization in either basic or acidic aqueous media. This
problem was recognized in several attempts to remove
the methoxycarbonyl protecting group using either strong
basic or acidic solvolysis. However, by treatment of 7a
with TMSI in MeCN provided 11 in 84% yield. All
transformations in Scheme 2 were conducted without
detectable loss of optical purity, apart from the conversion
of 8 into 9 where a minor loss of enantiomeric excess was
observed (90% ee to 88% ee). The racemization-prone
heteroaromatic R-amino acid 5h was also selectively
deprotected in high yield (>71%), although some race-
mization was observed (89% ee to 81% ee).
(17) For selective removal of the N-methoxycarbonyl protecting
group: Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(18) (a) Doyle, M. P, Siegfried, B.; Dellaria, J . F., J r. J . Org. Chem.
1977, 42, 2426. (b) Barbero, M.; Degani, I.; Dughera, S.; Fochi, R. J .
Org. Chem. 1999, 64, 3448. (c) Citterio, A.; Arnoldi, A. Synth. Commun.
1981, 11, 639. (d) Cohen, T.; Dietz, A. G., J r.; Miser, J . R. J . Org. Chem.
1977, 42, 2053.

4356 J . Org. Chem., Vol. 67, No. 12, 2002
Saaby et al.
Sch em e 2a
a
Key: (a) PhIO, TMSN3, CH2Cl2, -40 °C, 3 h; (b) saturated aqueous NaHCO3, THF (1:1), rt, 48 h; (c) NOBF4, CH2Cl2, 0 °C, 35 min;
(d) concd aq H3PO2, Cu2O (cat.), 0 °C, 40 min; (e) TMSI (1.5 equiv), CH3CN, 60 °C, 45 min; (f) MeOH, rt, 20 min.
It appears that the absolute configuration of the
product was dependent on the N-protecting group as the
N-Moc-protected R-imino ester 3h gave the R enantiomer
of the aza-Friedel-Crafts adduct 7a (lower left corner
in Figure 1), while the N-Boc-protected R-imino ester 3a
gave the S enantiomer of the aza-Friedel-Crafts adduct
7i. The chiral induction of the reaction was also depend-
ent on the temperature, and when, e.g., THF was used
as the solvent the enantiomer in excess changed from S
to R at lower temperatures. These observations could
indicate that more than one reactive transition species
exists in solution.
To obtain mechanistic information, the absolute con-
figuration of the aza-Friedel-Crafts products 5h and 7a
was resolved by X-ray analysis of the corresponding tosyl
and camphanic acid derivatives 12 and 13 (see the
Supporting Information). Both compounds could be as-
signed as the R configuration at the newly formed chiral
center. An interesting byproduct (14) was formed in the
catalytic enantioselective addition of 2-benzylfuran to
different solvents and at different temperatures. The enan-
F igu r e 1. Enantiomeric excess of 7i (eq 7) obtained in
R-imino ester 3h (Table 3, entry 4). The formation of 14
can be explained by deprotonation at the benzylic position
in the intermediate σ-complex 15, rather than deproto-
nation at the 2-position, which would restore the aromatic
furan structure. The byproduct 14 was found to have the
same high level of enantiomeric excess as the expected
major product 5k ; thus, 15 is believed to be a common
intermediate on the two different reaction paths. The
relative stereochemistry of 14 was also assigned by X-ray
analysis.
tiomeric excess and absolute stereochemistry of 7a is shown
in the lower left corner.
Mech a n istic Con sid er a tion s. The mode of coordina-
tion of the imines 3a -h to the copper(I) catalyst is an
intriguing problem as the enantioselectivity of the aro-
matic R-amino acids depends on the nitrogen protecting
group. Performing two identical reactions except for the
structure of the imine protecting group (N-Moc vs N-Boc),
the absolute configuration of the product changed from
R to S using the same enantiomer (R) of the chiral Tol-
BINAP-Cu(I) complex as the catalyst (Figure 1). A series
of reactions of the N-Boc-protected R-imino ester 3a with
N,N-dimethylaniline 6a (eq 8) was performed in different
solvents, and the enantiomeric excess was measured as
a function of temperature. The results are presented in
Figure 1.

Optically Active Aromatic and Heteroaromatic R-Amino Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4357
The orientation of the 2-substituted furan approaching
the R-imino ester shown in Figure 2 is in agreement with
the relative stereochemistry of compound 14, which was
resolved by X-ray analysis. The observed enantioselective
induction is also in agreement with results obtained in
a study of aza-Diels-Alder reactions in which the same
catalyst was applied12b as well as X-ray crystallographic
data obtained by Lectka.16e
As evident from the results in Table 1 (vide supra),
the enantioselectivity of the aza-Friedel-Crafts reaction
is very dependent on the choice of imine N-protecting
group. Application of the more bulky carbamates, e.g.,
the N-Boc-protecting group, caused a substantial reduc-
tion in the enantioselectivity compared to the results
obtained using the R-imino esters protected with the
small methyl carbamate (entry 1 vs 5, Table 1). Further-
more, a much lower reaction rate was observed perform-
ing reactions of the R-imino ester 3a . To investigate this
pronounced steric effect, the structure of the R-imino
ester 3a coordinated to the (R)-Tol-BINAP-Cu(I) catalyst
was optimized.19 A five-membered tetrahedral intermedi-
ate with coordination of the R-imino-ester nitrogen atom
and the ester carbonyl oxygen atom to the copper(I)
center was anticipated as discussed above. The optimized
structures of R-imino esters 3h and 3a coordinated to the
(R)-Tol-BINAP-Cu(I) catalysts are shown in Figure 3.
The optimized intermediate of R-imino ester 3h coor-
dinated to the catalyst (16, Figure 3) is shown along the
R-imino ester axis, and it appears that one of the tolyl
groups of the BINAP ligand effective shields the Si-face
of the R-imino ester, leaving the Re-face open for reaction
with the substrate. However, when the bulky N-Boc-
protecting group of R-imino ester 3a is used, the imine
is twisted into the orientation outlined in 17 to the right
in Figure 3 and the intermediate becomes almost sym-
metrical compared to the intermediate in 16, which can
account for the low enantioselectivity and reaction rate
observed.
F igu r e 2. Calculated tetrahedral intermediate of the R-imino
ester 3h coordinated to the (R)-Tol-BINAP-CuPF6 complex.
The approach of a 2-methylfuran to the Re-face of the imino
double bond is shown to account for both the absolute config-
uration of 5h as well as the relative stereochemistry of
byproduct 14 (the carbon atoms of 2-methylfuran and 1h are
light gray).
A number of different coordination modes of imine 3h
to the CuPF6-(R)-Tol-BINAP complex is in principle
possible. However, an intermediate in which the more
Lewis-basic nitrogen atom and the ester carbonyl oxygen
atom are coordinated to the copper(I) center is most
likely. On the basis of the absolute configuration of
compounds 12 and 13 (X-ray analysis), a bidentate
tetrahedral five-membered coordination of imine 3h to
the (R)-Tol-BINAP-Cu(I) complex can be envisaged.
Further support for such an intermediate has been
obtained from DFT calculations19 of the intermediate in
which the R-imino ester 3h is coordinated to the (R)-Tol-
BINAP-Cu(I) catalyst. The optimized structure of this
intermediate is shown in Figure 2. It appears from the
intermediate that one of the tolyl groups of the BINAP
ligand shields the Si-face of the R-imino ester, leaving
the Re-face open for reaction with the aromatic substrate.
Con clu sion
Optically active aromatic and in particular heteroaro-
matic R-amino acids have normally been relatively
complicated to synthesize. In conclusion, we have devel-
F igu r e 3. DFT-optimized structures of R-imino esters 3h and 3a coordinated to (R)-Tol-BINAP-Cu(I).

4358 J . Org. Chem., Vol. 67, No. 12, 2002
Saaby et al.
N,N-Dimethyl-1-aminoanthracene, N,N-dimethylindoline, and
N-methyl-1,2,3,4-tetrahydroquinoline were all prepared from
the corresponding amines (MeI, NaH, THF, reflux, 15 h).
oped a simple one-pot procedure for the synthesis of
versatile directly protected optically active aromatic and
heteroaromatic R-amino acids. This new reaction gives
an easy access to important chiral building blocks, using
simple starting materials and an easy-available catalyst.
The catalytic enantioselective reaction tolerates a number
of diverse substrates and in general the products are
formed in good to high yields and with enantioselectivi-
ties from 59% up to 98% ee. Selective deprotections and
subsequent structural transformations of the aza-Friedel-
Crafts products were conducted without notable loss of
optical purity, demonstrating the practical synthetic
utility of the presented reaction. The absolute stereo-
chemistry of a number of phenyl- and furyl glycine
derivatives was determined by X-ray analysis, and on the
basis of experimental results, DFT calculations, and
crystallographic data, the mechanism and reaction path
have been disclosed.
A Rep r esen ta tive Exp er im en ta l P r oced u r e for th e
Syn th esis of Aza -Ylid s, (1a ). A solution of methyl chloro-
formate (2.92 g, 0.031 mol), trimethylsilyl azide (4.95 g, 0.043
mol) and a few drops of pyridine in dry toluene (31 mL) is
stirred at 80 °C for 30 min under an argon atmosphere. Then
toluene (62 mL) is added and the solution is cooled to 0 °C.
Benzyldiphenylphosphine29 (8.56 g, 0.031 mol) is dissolved in
dry degassed toluene (60 mL) and added dropwise to the
previous cooled solution at 0 °C. At the end of addition, the
mixture is stirred at 0 °C for 5 min and then left to warm to
room temperature (approximately 30-45 min). The solvent is
distilled off and the solid residue is recrystallized from EtOAc:
hexane (4:1). The product 1a is isolated as a white crystalline
1
solid (8.0 g, 74%); mp 152-153 °C; H NMR δ 7.67-7.62 (m,
4H), 7.49-7.45 (m, 2H), 7.39-7.34 (m, 4H), 7.08-7.03 (m, 3H),
6.85-6.82 (m, 2H), 4.04 (d, 3J (H,H) ) 14 Hz, 2H), 3.61 (s, 3H);
13C NMR δ 162.9, 132.66, 132.64, 132.5, 132.4, 130.36, 130.32,
128.9, 128.8, 128.58, 128.55, 127.9, 127.32, 127.28, 126.9,
53.05, 53.02, 35.6, 33.0; 31P NMR (162 MHz, CDCl3) δ 25.9;
HRMS C21H20NO2P [M + Na]+ calcd 372.1129, found 372.1121.
Exp er im en ta l Section
A Gen er a l P r oced u r e for th e Syn th esis of Dir ectly
P r otected r-Am in o Acid s. To a flame dried Schlenk tube
equipped with a magnetic stirring bar is added the aza-ylide
1a (140 mg, 0.40 mmol) and dried under vacuum at room
temperature for 1 h before toluene (0.66 mL) is added by
syringe. After stirring for 10 min, the suspension is added a
0.42 M solution of methyl glyoxylate in toluene (1.14 mL, 0.48
mmol) and stirred for another 15 min at ambient temperature
before the white milky slurry is cooled to -78 °C. (Complete
1
Gen er a l Meth od s. The H NMR, 13C NMR, and 31P NMR
spectra were recorded at 300 or 400, 100, and 162 MHz,
respectively. The chemical shifts are reported in ppm downfield
to TMS (δ 0) for 1H NMR and relative to the central CDCl3
resonance (δ 77.0) for 13C NMR. Solvents were dried according
to standard procedures. Flash chromatography (FC) was
carried out using the FlashMaster II. The enantiomeric excess
(ee) of the products was determined by chiral HPLC (Daicel
Chiralpak AS/AD or Daciel Chiralcel OD/OJ columns) or chiral
GC (Chiraldex B-PM or G-TA columns). All solvents were dried
and distilled prior to use, and all catalytic reactions were
performed under nitrogen or argon atmosphere.
Ma ter ia ls. All glyoxylate esters were prepared by ozonolysis
of the corresponding maleates and distilled prior to use.20 All
N-carboalkoxyiminotripenylphosphanes were prepared follow-
ing literature procedures.21 Benzyldiphenylphosphine and (R)-
(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl 98%, ((R)-Tol-
BINAP), 2-ethylfural, 2-t-Bu-furan, 2,3-dimethylfuran, N,N-
dimethylaniline, N,N-dimethyl-1-naphthylamine, (CuOTf)2‚
Tol, 2-methylfuran, 2-methoxyfuran, 2-methoxythiophene,
3-dimethylaminoanisole, and N-methylpyrrole were purchased
commercially and used as received. 2-Benzylfuran,22 2-(4-
methoxy)phenylfuran,23 2-(4-N,N-dimethylaminophenyl)th-
iophene,24 4-methyl-3,4-dihydro-2H-[1,4]oxazine (7f),25 N-phenyl-
3-pyrroline,26 CuPF6‚4MeCN,27 CuClO4‚4MeCN,27 and iodoso-
benzene28 were prepared according to literature procedures.
1
imine formation should be checked by H NMR spectroscopy,
as full conversion of the aza-ylide is crucial to achieve good
results.) A catalyst solution prepared by drying CuPF6‚4MeCN
(15 mg, 0.040 mmol) and (R)-Tol-BINAP (30 mg, 0.044 mmol)
in a flame dried Schlenk tube under vacuum for 1 h and
subsequently dissolved in a mixture of CH2Cl2 (0.20 mL) and
toluene (2.0 mL) is added by syringe and after stirring for 30
s the aromatic substrate (0.80 mmol) is added in one portion.
After 44 h, the reaction mixture is filtered through a plug of
silica and eluted with Et2O (50 mL). The crude product is
concentrated in vacuo and purified by FC to give the directly
protected R-amino acid.
ter t-Bu t oxyca r b on yla m in o(5-m et h yl-fu r a n -2-yl)a ce-
tic a cid eth yl ester 5a : 1H NMR δ 6.19 (d, 3J (H,H) ) 2.8 Hz,
3
1H), 5.91-5.90 (m, 1H), 5.44 (d, J (H,H) ) 8.0 Hz, 1H), 5.33
(d, 3J (H,H) ) 8.1 Hz, 1H), 4.26-4.16 (m, 2H), 2.25 (s, 3H),
3
1.44 (s, 9H), 1.19 (t, J (H,H) ) 7.3 Hz, 3H); 13C NMR δ 169.4,
154.9, 152.5, 147.1, 109.0, 106.5, 80.2, 61.9, 51.8, 28.2, 14.0,
13.5; [R]rtD ) -20.1 (c ) 1.0 in CHCl3) (31% ee); GC (Chiraldex
G-TA, 70-140 °C (10 °C/min), 140-145 °C (1 °C/min) then
145 °C isotherm) tR ) 38.33 min (major enantiomer), tR ) 38.96
min (minor enantiomer); HRMS C14H21NO5 [M + Na]+ calcd
306.1317, found 306.1311.
(19) Density Functional Theory (DFT) calculations were performed
using the J aguar electronic structure program (J aguar 4.0, Schrod-
inger, Inc., Portland, Oregon, 2000). The BLYP pure density functional
was chosen, as it provides geometries similar to those of the more
accurate B3LYP hybrid functional but with a substantial savings in
computertime. The copper atom was given the LACVP effective core
potential basis, the phosphorous atoms the polarised double-ú 6-31G*
basis, and the remaining atoms the double-ú 6-31G basis. After
convergence of the geometries the stability of the minima was tested
by re-optimization after small displacements had been made in the
coordinates, and it was confirmed that the same structures were
recovered.
(20) J ung, M. E.; Shishido, K.; Davis, L. H. J . Org. Chem. 1982, 47,
891.
(21) (a) Kricheldorf, H. R. Synthesis 1972, 695. (b) Vidal, J .; Guy,
L.; Ste´rin, S.; Collet, A. J . Org. Chem. 1993, 53, 4791 and references
therein.
(22) Wu, H.; Lin, C. J . Org. Chem. 1996, 61, 3820.
(23) Tanis, S. P.; Deaton, M. V.; Dixon, L. A.; Macmills, M. C.;
Raggon, J . F.; Collins, M. A. J . Org. Chem. 1998, 63, 6914.
(24) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020.
(25) Kotha, S.; Kuki, A. Chem. Commun. 1992, 404.
(26) Ding, Z.; Tufariello, J . J . Synth. Commun. 1990, 20, 227.
(27) Kubas, G. J . Inorganic Synthesis, Vol. XIX; Schriver, D. F., Ed.;
Wiley: New York, 1979; p 90.
Isop r op oxyca r b on yla m in o(5-m e t h ylfu r a n -2-yl)a ce -
tic a cid eth yl ester 5b: 1H NMR δ 6.15 (d, 3J (H,H)) 3.0 Hz,
3
1H), 5.85-5.84 (m, 1H), 5.49 (bd, J (H,H) ) 7.9 Hz, 1H), 5.23
(d, 3J (H,H) ) 8.1 Hz, 1H), 4.85 (sep, 3J (H,H) ) 6.3 Hz, 1H),
4.32-4.08 (m, 2H), 2.19 (s, 3H), 1.21-1.15 (m, 9H); 13C NMR
δ 169.2, 155.3, 152.6, 146.9, 109.2, 106.5, 68.9, 62.0, 52.0, 22.1,
14.0, 13.5; [R]rt ) -45.0 (c ) 0.25 in CHCl3) (52% ee); GC
D
(Chiraldex G-TA, 70-140 °C (10 °C/min), 140-145 °C (1 °C/
min) then 145 °C isotherm) tR ) 36.60 min (major enantiomer),
tR ) 37.55 min (minor enantiomer); HRMS C13H19NO5 [M +
Na]+ calcd 292.1161, found 292.1159.
Eth oxyca r bon yla m in o(5-m eth ylfu r a n -2-yl)a cetic a cid
eth yl ester 5c: 1H NMR δ 6.22 (d, 3J (H,H) ) 3.2 Hz, 1H),
5.92-5.91 (m, 1H), 5.58 (bd, 3J (H,H) ) 6.2 Hz, 1H), 5.41 (d,
3J (H,H) ) 8.1 Hz, 1H), 4.30-4.10 (m, 4H), 2.26 (s, 3H), 1.26
3
3
(t, J (H,H) ) 7.4 Hz, 3H), 1.25 (t, J (H,H) ) 7.1 Hz, 3H); 13C
(28) Lucas, H. J .; Kennedy, E. R.; Formo, M. W. Organic Synthesis;
Wiley: New York, 1955; Collect. Vol. III, p 483.
(29) Benzyldiphenylphosphine was handled in a glovebox (air sensi-
tive).

Optically Active Aromatic and Heteroaromatic R-Amino Acids
NMR δ 169.1, 155.6, 152.6, 146.9, 109.2, 106.5, 62.0, 61.3, 52.0,
J . Org. Chem., Vol. 67, No. 12, 2002 4359
(s, 3H), 1.24 (s, 9H); 13C NMR δ 169.7, 164.8, 156.1, 146.3,
14.4, 14.0, 13.5; [R]rt ) -73.6 (c ) 0.25 in CHCl3) (73% ee);
108.8, 102.9, 52.9, 52.5, 52.1, 32.6, 28.9; [R]rt ) -132.0 (c )
D
D
GC (Chiraldex G-TA, 70-140 °C (10 °C/min), 140-145 °C (1
°C/min) then 145 °C isotherm) tR ) 34.27 min (major enanti-
omer), tR ) 35.72 min (minor enantiomer); HRMS C12H17NO5
[M + Na]+ calcd 278.1004, found 278.1000.
1 in CHCl3) (95% ee); GC (Chiraldex B-PM, 70-110 °C (5 °C/
min), 110 °C isotherm (10 min), 110-160 (2 °C/min) then 160
°C isotherm: tR ) 41.00 min (major enantiomer), tR ) 41.32
min (minor enantiomer); HRMS C13H19NO5 [M + Na]+ calcd
292.1161, found 292.1165.
Ben zyloxyca r b on yla m in o(5-m et h ylfu r a n -2-yl)a cet ic
1
a cid eth yl ester 5d : H NMR δ 7.40-7.30 (m, 5H), 6.22 (d,
(5-Ben zylfu r an -2-yl)m eth oxycar bon ylam in oacetic acid
m eth yl ester 5k : 1H NMR δ 7.32-7.19 (m, 5H), 6.25 (d,
3J (H,H) ) 3.2 Hz, 1H), 5.91 (d, 3J (H,H) ) 3.0 Hz, 1H), 5.64
(bd, 3J (H,H) ) 7.5 Hz, 1H), 5.46 (d, 3J (H,H) ) 8.3 Hz, 1H),
3.93 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H); 13C NMR δ 169.5, 156.0,
155.3, 147.3, 137.5, 128.7, 128.5, 126.6, 109.4, 107.3, 52.9, 52.5,
3
3J (H,H) ) 2.6 Hz, 1H), 5.92-5.91 (m, 1H), 5.72 (bd, J (H,H)
) 8.1 Hz, 1H), 5.43 (d, 3J (H,H) ) 8.2 Hz, 1H), 5.12 (s, 2H),
4.29-4.14 (m, 2H), 2.25 (s, 3H), 1.25 (t, 3J (H,H) ) 7.1 Hz, 3H);
13C NMR δ 169.0, 155.4, 152.7, 146.7, 136.1, 128.5, 128.2,
128.1, 109.3, 106.6, 67.1, 62.1, 52.1, 14.0, 13.5; [R]rt ) -84.4
D
(c ) 1.0 in CHCl3) (79% ee); HPLC (Daciel Chiralcel OD,
hexane/2-propanol 97/3, 1 mL/min) tR ) 17.0 min (minor
52.0, 34.4; [R]rt ) -132.0 (c ) 1 in CHCl3) (95% ee); HPLC
D
(Daicel Chiralpak AS, hexane/2-propanol 95/5, 1 mL/min) tR
) 18.3 min (minor enantiomer), tR ) 25.7 min (major enanti-
omer); HRMS C16H17NO5 [M + Na]+ calcd 326.1004, found
326.1005.
enantiomer), tR ) 25.9 min (major enantiomer); HRMS C17H19
-
NO5 [M + Na]+ calcd 340.1161, found 340.1164.
Meth oxycar bon ylam in o(5-m eth ylfu r an -2-yl)acetic acid
eth yl ester 5e: 1H NMR δ 6.20 (d, 3J (H,H) ) 2.8 Hz, 1H),
5.90-5.89 (m, 1H), 5.68 (bd, 3J (H,H) ) 7.2 Hz, 1H), 5.40 (d,
3J (H,H) ) 8.3 Hz, 1H), 4.28-4.15 (m, 2H), 3.67 (s, 3H), 2.23
(s, 3H), 1.24 (t, 3J (H,H) ) 7.0 Hz, 3H); 13C NMR δ 169.1, 156.0,
Meth oxyca r bon yla m in o[5-(4-m eth oxyp h en yl)fu r a n -2-
1
yl]a cetic a cid m eth yl ester 5l: H NMR δ 7.53 (dt, J (H,H)
3
) 8.7 Hz, 2.5 Hz, 2H), 6.88 (d, J (H,H) ) 9.3 Hz, 2H), 6.44 (d,
3J (H,H) ) 3.4 Hz, 1H), 5.40 (d, 3J (H,H) ) 3.0 Hz, 1H), 5.88
(bd, 3J (H,H) ) 7.7 Hz, 1H), 5.55 (d, 3J (H,H) ) 8.1 Hz, 1H),
3.80 (s, 3H), 3.76 (s, 3H), 3.69 (s, 3H); 13C NMR δ 169.4, 159.2,
156.0, 154.3, 147.2, 125.2, 123.2, 114.0, 110.6, 104.1, 55.2, 52.9,
152.6, 146.8, 109.2, 106.5, 62.0, 52.4, 52.1, 14.0, 13.5; [R]rt
)
D
-103.4 (c ) 1.0 in CHCl3) (81% ee); GC (Chiraldex B-PM, 70
°C (isotherm 5 min), 70-150 °C (2 °C/min) then 150 °C
isotherm) tR ) 45.44 min (minor enantiomer), tR ) 45.72 min
(major enantiomer); HRMS C11H15NO5 [M + Na]+ calcd
264.0848, found 264.0849.
52.4, 52.0; [R]rt ) -108 (c ) 1.0 in CHCl3) (74% ee); HPLC
D
(Daicel Chiralpak AS, hexane/2-propanol 95/5, 1 mL/min) tR
) 29.3 min (minor enantiomer), tR ) 39.1 min (major enanti-
omer); HRMS C16H17NO6 [M + Na]+ calcd 342.0954, found
342.0955.
Meth oxycar bon ylam in o(5-m eth ylfu r an -2-yl)acetic acid
ben zyl ester 5f: 1H NMR δ 7.34-7.25 (m, 5H), 6.20 (d,
3
3J (H,H) ) 3.2 Hz, 1H), 5.91-5.90 (m, 1H), 5.64 (bd, J (H,H)
Met h oxyca r b on yla m in o(5-m et h oxyfu r a n -2-yl)a cet ic
3
3
) 8.3 Hz, 1H), 5.49 (d, J (H,H) ) 8.2 Hz, 1H), 5.25-5.17 (m,
a cid m eth yl ester 5m : 1H NMR δ 6.21 (d, J (H,H) ) 3.1 Hz,
2H), 3.69 (s, 3H), 2.23 (s, 3H); 13C NMR δ 169.0, 156.1, 152.7,
146.6, 135.2, 128.5, 128.3, 127.9, 109.5, 106.6, 67.5, 52.5, 52.2,
13.5; [R]rtD ) -45.2 (c ) 0.25 in CHCl3) (55% ee); HPLC (Daicel
Chiralpak AS, hexane/2-propanol 97/3, 1 mL/min) tR ) 17.6
min (minor enantiomer), tR ) 27.8 min (major enantiomer);
HRMS C16H17NO5 [M + Na]+ calcd 326.1004, found 326.1003.
Meth oxycar bon ylam in o(5-m eth ylfu r an -2-yl)acetic acid
isop r op yl ester 5g: 1H NMR δ 6.19 (d, 3J (H,H) ) 3.2 Hz,
1H), 5.69 (bd, 3J (H,H) ) 8.2 Hz, 1H), 5.34 (d, 3J (H,H) ) 8.2
3
Hz, 1H), 5.07 (d, J (H,H) ) 3.44 Hz, 1H), 3.79 (s, 3H), 3.74 (s,
3H), 3.66 (s, 3H); 13C NMR δ 169.3, 161.5, 156.0, 138.3, 110.2,
80.2, 57.7, 52.9, 52.4, 51.9; [R]rtD ) -114 (c ) 1 in CHCl3) (96%
ee); HPLC (Daicel Chiralpak AS, hexane/2-propanol 90/10, 1
mL/min) tR ) 23.9 min (minor enantiomer), tR ) 28.7 min
(major enantiomer); HRMS C10H13NO6 [M + Na]+ calcd
266.0641, found 266.0633.
3
1H), 5.91-5.89 (m, 1H), 5.64 (bd, J (H,H) ) 7.0 Hz, 1H), 5.37
Meth oxycar bon ylam in o(4-m eth ylfu r an -2-yl)acetic acid
(d, 3J (H,H) ) 8.3 Hz, 1H), 5.07 (sep, 3J (H,H) ) 6.3 Hz, 1H),
m eth yl ester 5n : H NMR δ 7.24 (s, 1H), 6.20 (s, 1H) 5.78
1
3
3.69 (s, 3H), 2.24 (s, 3H), 1.26 (d, J (H,H) ) 6.3 Hz, 3H), 1.18
(bd, 3J (H,H) ) 7.4 Hz, 1H), 5.48 (d, 3J (H,H) ) 8.3 Hz, 1H),
3.73 (s, 3H), 3.67 (s, 3H), 2.08 (s, 3H); 13C NMR δ 169.6, 156.1,
143.8, 141.8, 118.4, 113.3, 52.9, 52.4, 49.8, 9.5; [R]rtD ) -124.0
(c ) 1.0 in CHCl3) (72% ee); HPLC (Daicel Chiralpak AD,
hexane/2-propanol 95/5, 1 mL/min) tR ) 12.4 min (major
(d, 3J (H,H) ) 6.2 Hz, 3H); 13C NMR δ 168.6, 156.1, 152.5,
147.0, 109.1, 106.5, 69.8, 52.4, 52.2, 21.6, 21.4, 13.5; [R]rt
)
D
-70.4 (c ) 0.5 in CHCl3) (79% ee); GC (Chiraldex B-PM, 70-
140 °C (10 °C/min), 140-160 °C (2 °C/min) then 160 °C
isotherm) tR ) 16.11 min (minor enantiomer), tR ) 16.35 min
(major enantiomer); HRMS C12H17NO5 [M + Na]+ calcd
278.1004, found 278.1006.
enantiomer); tR ) 14.9 min (minor enantiomer); HRMS C11H15
-
NO5 [M + Na]+ calcd 250.0691, found 250.0690.
(4,5-Dim et h ylfu r a n -2-yl)m et h oxyca r b on yla m in oa ce-
1
Meth oxycar bon ylam in o(5-m eth ylfu r an -2-yl)acetic acid
tic a cid m eth yl ester 5o: H NMR δ 6.11 (s, 1H), 5.68 (bd,
1
3
m eth yl ester 5h : H NMR δ 6.21 (d, J (H,H) ) 3.2 Hz, 1H),
5.91-5.90 (m, 1H), 5.69 (bd, 3J (H,H) ) 6.9 Hz, 1H), 5.42 (d,
3J (H,H) ) 8.2 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.24 (s, 3H);
13C NMR δ 169.6, 156.0, 152.7, 146.6, 109.4, 106.5, 52.9, 52.4,
3J (H,H) ) 7.2 Hz, 1H), 5.37 (d, 3J (H,H) ) 8.2 Hz, 1H), 3.75 (s,
3H), 3.67 (s, 3H), 2.14 (s, 3H), 1.88 (s, 3H); 13C NMR δ 169.6,
156.0, 148.0, 145.3, 114.9, 111.7, 52.9, 52.4, 51.9, 11.2, 9.9;
[R]rtD ) -130.0 (c ) 1 in CHCl3) (84% ee); GC (Chiraldex B-PM,
70-110 °C (5 °C/min), 110-160 °C (2 °C/min) then 160 °C
isotherm) tR ) 40.73 min (minor enantiomer), tR ) 40.92 min
(major enantiomer); HRMS C11H15NO5 [M + Na]+ calcd
264.0848, found 264.0845.
51.9, 13.4; [R]rt ) -123.0 (c ) 1 in CHCl3) (87% ee); HPLC
D
(Daicel Chiralpak AS, hexane/2-propanol 97/3, 1 mL/min) tR
) 19.2 min (minor enantiomer), tR ) 25.2 min (major enanti-
omer); HRMS C10H13NO5 [M + Na]+ calcd 250.0691, found
250.0692.
Meth oxyca r bon yla m in o(5-m eth oxyth iop h en -2-yl)a ce-
1
3
(5-Eth ylfu r a n -2-yl)m eth oxyca r bon yla m in oa cetic a cid
tic a cid m eth yl ester 5p : H NMR δ 6.65 (d, J (H,H) ) 3.7
3 3
1
3
m eth yl ester 5i: H NMR δ 6.22 (d, J (H,H) ) 2.4 Hz, 1H),
5.92-5.91 (m, 1H), 5.68 (bd, 3J (H,H) ) 6.9 Hz, 1H), 5.43 (d,
3J (H,H) ) 8.6 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.58 (q,
3J (H,H) ) 7.5 Hz, 2H), 1.18 (d, 3J (H,H) ) 7.4 Hz, 3H); 13C
NMR δ 169.6, 158.4, 156.0, 146.4, 109.1, 104.9, 52.9, 52.4, 52.0,
Hz, 1H), 5.07 (d, J (H,H) ) 4.3 Hz, 1H), 5.71 (bd, J (H,H) )
3
7.1 Hz, 1H), 5.43 (d, J (H,H) ) 7.7 Hz, 1H), 3.83 (s, 3H), 3.76
(s, 3H), 3.67 (s, 3H); 13C NMR δ 170.5, 166.5, 155.8, 124.1,
124.0, 103.2, 60.1, 53.9, 52.9, 52.4; [R]rt ) -131 (c ) 1 in
D
CHCl3) (94% ee); HPLC (Daicel Chiralpak AS, hexane/2-
propanol 90/10, 1 mL/min) tR ) 21.8 min (minor enantiomer),
tR ) 43.1 min (major enantiomer); HRMS C10H13NO5S [M +
Na]+ calcd 282.0412, found 282.0416.
[5-(4-Dim et h yla m in op h en yl)t h iop h en -2-yl]m et h oxy-
ca r bon yla m in oa cetic a cid m eth yl ester 5q: 1H NMR δ 7.42
(d, 3J (H,H) ) 8.5 Hz, 2H), 6.99-6.96 (m, 2H), 6.70 (d, 3J (H,H)
) 8.8 Hz, 2H), 5.76 (bd, 3J (H,H) ) 7.6 Hz, 1H), 5.61 (d, 3J (H,H)
) 7.8 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 2.98 (s, 6H); 13C NMR
δ 170.6, 155.9, 150.0, 146.0, 135.3, 127.1, 126.7, 122.1, 120.4,
21.2, 11.8; [R]rt ) -131 (c ) 0.5 in CHCl3) (88% ee); HPLC
D
(Daicel Chiralpak AS, hexane/2-propanol 95/5, 1 mL/min) tR
) 12.5 min (minor enantiomer), tR ) 15.2 min (major enanti-
omer); HRMS C11H15NO5 [M + Na]+ calcd 264.0848, found
264.0847.
(5-ter t-Bu t ylfu r a n -2-yl)m et h oxyca r b on yla m in oa ce-
1
3
tic a cid m eth yl ester 5j: H NMR δ 6.21 (d, J (H,H) ) 2.8
3
3
Hz, 1H), 5.91 (d, J (H,H) ) 5.9 Hz, 1H), 5.59 (bd, J (H,H) )
6.5 Hz, 1H), 5.46 (d, J (H,H) ) 7.3 Hz, 1H), 3.77 (s, 3H), 3.71
3

4360 J . Org. Chem., Vol. 67, No. 12, 2002
Saaby et al.
112.3, 53.6, 53.0, 52.5, 40.3; [R]rt ) -144 (c ) 1.0 in CHCl3)
10, 1 mL/min) tR ) 43.8 min (minor enantiomer), tR ) 54.2
min (major enantiomer); HRMS C14H18N2O5 [M + Na]+ calcd
317.1113, found 317.1118.
D
(94% ee); HPLC (Daicel Chiralpak AS, hexane/2-propanol 90/
10, 1 mL/min) tR ) 23.0 min (minor enantiomer), tR ) 29.7
min (major enantiomer); mp 141-144 °C; HRMS C17H20N2O4S
[M + Na]+ calcd 371.1041, found 371.1037.
(4-Dim eth ylam in on aph th alen -1-yl)eth oxycar bon ylam i-
n oa cetic Acid Meth yl Ester 7g. See ref 11.
Meth oxyca r bon yla m in o(1-m eth yl-1H-p yr r ol-2-yl)a ce-
(4-Dim eth yla m in oa n th r a cen -1-yl)eth oxyca r bon yla m i-
n oa cetic Acid Meth yl Ester 7h . See ref 11.
1
3
tic a cid m eth yl ester 5r : H NMR δ 6.60 (t, J (H,H) ) 2.3
Hz, 1H), 6.06-6.02 (m, 2H), 5.50-5.44 (m, 2H), 3.75 (s, 3H),
3.68 (s, 3H), 3.66 (s, 3H); 13C NMR δ 170.8, 156.1, 126.9, 123.6,
(4-Am in op h en yl)m eth oxyca r bon yla m in oa cetic Acid
Meth yl Ester 8. To a flame-dried flask was added iodosoben-
zene (435 mg, 1.98 mmol) and the mixture stirred under
vacuum for 1 h at room temperature before CH2Cl2 (6.6 mL)
was added and the suspension cooled to -40 °C. Compound
7a (132 mg, 0.5 mmol) and azidotrimethylsilane (0.26 mL, 1.98
mmol) were added, and the resulting mixture was stirred
vigorously for 3 h, poured directly into ice-water (50 mL), and
subsequently extracted with CH2Cl2 (3 × 15 mL). The organic
extract was concentrated in vacuo to half the volume, THF
(22.5 mL) and saturated aqueous NaHCO3 (22.5 mL) were
added, and the mixture was stirred for 48 h before being
neutralized by 1 M aqueous HCl. The organic solvents were
removed in vacuo, and the aqueous fraction was extracted with
CH2Cl2 (3 × 15 mL). Drying of the organic extracts over Na2-
SO4 afforded the crude product, which was purified by FC
(EtOAc/pentane 1:1) to give 8 in 78% isolated yield as a light
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.04 (d, 3J (H,H) )
107.6, 107.3, 52.7, 52.4, 50.3, 33.9; [R]rt ) -82 (c ) 1.0 in
D
CHCl3) (59% ee); HPLC (Daicel Chiralpak AS, hexane/2-
propanol 90/10, 1 mL/min) tR ) 16.4 min (minor enantiomer),
tR ) 23.9 min (major enantiomer); HRMS C10H14N2O4 [M +
Na]+ calcd 249.0851, found 249.0817.
( 4 -D i m e t h y l a m i n o p h e n y l ) m e t h o x y c a r b o n y l -
a m in oa cetic a cid m eth yl ester 7a : 1H NMR (400 MHz,
CDCl3) δ 7.18 (d, 3J (H,H) ) 8.6 Hz, 2H), 6.65 (d, 3J (H,H) )
3
3
8.6 Hz, 2H), 5.61 (bd, J (H,H) ) 5.8 Hz, 1H), 5.22 (d, J (H,H)
) 7.0 Hz, 1H), 3.68 (s, 3H), 3.64 (s, 3H), 2.91 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 171.9, 155.9, 150.4, 127.9, 123.6, 112.3,
57.3, 52.5, 52.2, 40.3; [R]rt ) -146.3 (c ) 0.8 in CHCl3) (98%
D
ee); HPLC (Daciel Chiralcel OD, hexane/2-propanol 90/10, 1
mL/min) tR ) 17.2 min (minor enantiomer), tR ) 22.8 min
(major enantiomer); HRMS C13H18N2O4 [M + Na]+ calcd
289.1164, found 289.1168.
[4-(2,5-Dih yd r op yr r ol-1-yl)p h en yl]m et h oxyca r b on y-
la m in oa cet ic a cid m et h yl est er 7b : 1H NMR (400 MHz,
CDCl3) δ 7.19 (d, 3J (H,H) ) 8 Hz, 2H), 6.46 (d, 3J (H,H) ) 8
Hz, 2H), 5.19 (s, 2H), 5.60 (bd, 3J (H,H) ) 6.6 Hz, 1H), 5.21 (d,
3J (H,H) ) 7.0 Hz, 1H), 4.07 (s, 4H), 3.69 (s, 3H), 3.64 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 172.1; 156.0, 147.1, 128.3, 126.2,
3
3
7.8 Hz, 2H), 6.54 (d, J (H,H) ) 7.8 Hz, 2H), 5.65 (bd, J (H,H)
) 6.2 Hz, 1H), 5.14 (d, 3J (H,H) ) 7.0 Hz, 1H), 3.62 (s, 3H),
3.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 156.0, 146.7,
128.2, 125.9, 115.1, 57.3, 52.5, 52.2. [R]rt ) -96.2 (c ) 1 in
D
CHCl3); HRMS C11H14N2O4 [M + Na]+ calcd 261.0851, found
122.9, 111.3, 57.5, 54.3, 52.6, 52.3; [R]rt ) -112.6 (c ) 1.0 in
261.0851.
D
CHCl3) (88% ee); HPLC (Daciel Chiralpak AD, hexane/2-
propanol 95/5, 1 mL/min) tR ) 31.8 min (minor enantiomer),
tR ) 38.8 min (major enantiomer); mp ) 112-114 °C; HRMS
Meth oxyca r bon yla m in op h en yla cetic Acid Meth yl Es-
ter 9. A dry flask under argon atmosphere was charged with
NOBF4 (24 mg, 0.20 mmol) and CH2Cl2 (10 mL). Compound 8
(45 mg, 0.19 mmol) dissolved in CH2Cl2 (4 mL) was added
dropwise at 0 °C and stirred for 35 min. The diazonium salt
was treated with saturated aqueous H3PO2 (0.16 mL) and a
catalytic amount of Cu2O (4 mg). Saturated aqueous NaHCO3
was added until basic pH and the organic layer separated. The
aqueous layer was extracted with CH2Cl2 (3 × 20 mL), the
combined organic phases were dried over MgSO4, and the
solvent was removed in vacuo. Purification by FC (EtOAc/
hexane 1:2) gave the title compound as a crystalline solid in
83% yield: 1H NMR (400 MHz, CDCl3) δ 7.33-7.30 (m, 5H),
5.74 (bd, 3J (H,H) ) 6.6 Hz, 1H), 5.34 (d, 3J (H,H) ) 7.4 Hz,
1H), 3.70 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
C
15H18N2O4[M + Na]+ calcd 313.1164, found 313.1161.
(4-Dim et h yla m in o-2-m et h oxyp h en yl)m et h oxyca r b o-
n yla m in oa cetic a cid m eth yl ester 7c: 1H NMR (400 MHz,
3
3
CDCl3) δ 7.11 (d, J (H,H) ) 8.5 Hz, 1H), 6.23 (dd, J (H,H) )
8.5, 2.3 Hz, 1H), 6.17 (d, 3J (H,H) ) 2.3 Hz, 1H) 5.76 (bd,
3J (H,H) ) 8.5 Hz, 1H), 5.36 (d, 3J (H,H) ) 8.5 Hz, 1H), 3.78 (s,
3H), 3.65 (s, 3H), 3.63 (s, 3H), 2.93 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 172.3, 169.8, 157.7, 156.4, 152.0, 130.6, 113.2, 104.3,
95.6, 55.2, 54.4, 53.1, 52.5, 40.4; [R]rt ) -131.0 (c ) 1 in
D
CHCl3) (96% ee); HPLC (Daciel Chiralcel OD, hexane/2-
propanol 85/15, 1 mL/min) tR ) 14.5 min (minor enantiomer),
tR ) 34.1 min (major enantiomer); mp ) 124-126 °C; HRMS
C14H20N2O5 [M + Na]+ calcd 319.1270, found 319.1266.
171.3, 155.9, 136.5, 126.8, 128.5, 127.1, 57.8, 52.7, 52.3; [R]rt
D
Eth oxyca r bon yla m in o(1-m eth yl-2,3-d ih yd r o-1H-in d ol-
5-yl)a cetic a cid Meth yl Ester 7d . See ref 11.
) -46.8 (c ) 1 in CHCl3) (88% ee); HPLC (Daciel Chiralcel
OD, hexane/2-propanol 90/10, 1 mL/min) tR ) 26.4 min (minor
enantiomer), tR ) 32.1 min (major enantiomer); mp ) 88-
88.5 °C; HRMS C11H13NO4 [M + Na]+ calcd 246.0742, found
246.0741.
Met h oxyca r bon yla m in o(1-m et h yl-1,2,3,4-t et r a h yd r o-
1
qu in olin -6-yl)a cetic a cid m eth yl ester 7e: H NMR (400
MHz, CDCl3) δ 7.00 (d, 3J (H,H) ) 8.6 Hz, 1H), 6.89 (s, 1H),
6.49 (d, 3J (H,H) ) 8.6 Hz, 1H), 5.58 (bd, 3J (H,H) ) 7.0 Hz,
Am in o-(4-(d im eth yla m in o)p h en yl)a cetic a cid m eth yl
ester 11. See ref 11.
3
1H), 5.16 (d, J (H,H) ) 7.0 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H),
3
3
3.19 (t, J (H,H) ) 5.6 Hz, 2H), 2.84 (s, 3H), 2.71 (t, J (H,H) )
6.2 Hz, 2H), 1.95-1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
172.0, 155.9, 146.8, 127.5, 125.9, 123.7, 122.9, 110.7, 57.4, 52.5,
(5-Ben zylid en e-2,5-d ih yd r ofu r a n -2-yl)m eth oxyca r bo-
1
n yla m in oa cetic a cid m eth yl ester 14: H NMR δ 7.51 (d,
3
3J (H,H) ) 7.7 Hz, 2H), 7.29 (t, J (H,H) ) 7.7 Hz, 2H), 7.13 (t,
52.2, 51.0, 38.8, 27.6, 22.0; [R]rt ) -130.1 (c ) 1 in CHCl3)
D
3J (H,H) ) 7.5 Hz, 1H), 6.34 (dd, J (H,H) ) 5.9 Hz, 2.3 Hz, 1H),
6.24 (dd, J (H,H) ) 5.8 Hz, 1.6 Hz, 1H), 5.82 (m, 1H), 5.40 (s,
(92% ee); HPLC (Daciel Chiralcel OD, hexane/2-propanol 85/
15, 1 mL/min) tR ) 11.4 min (minor enantiomer), tR ) 17.2
min (major enantiomer); HRMS C15H20N2O4 [M + Na]+ calcd
315.1321, found 315.1326.
3
1H), 5.29 (bd, J (H,H) ) 8.7 Hz, 1H), 4.75 (dd, J (H,H) ) 9.4
Hz, 2.0 Hz, 1H), 3.89 (s, 3H), 3.65 (s, 3H); 13C NMR δ 169.6,
159.1, 156.7, 135.9, 130.5, 129.6, 128.3, 127.7, 125.5, 99.8, 89.5,
Me t h oxyca r b on yla m in o(4-m e t h yl-3,4-d ih yd r o-2H -
ben zo[1,4]oxa zin -7-yl)a cetic a cid m eth yl ester 7f: 1H
NMR (400 MHz, CDCl3) δ 6.80 (d, 3J (H,H) ) 8.2 Hz, 1H), 6.72
(d, 3J (H,H) ) 2.0 Hz, 1H), 6.58 (d, 3J (H,H) ) 8.2 Hz, 1H), 5.58
(bd, 3J (H,H) ) 7.0 Hz, 1H), 5.17 (d, 3J (H,H) ) 7.0 Hz, 1H),
56.3, 53.0, 52.5; [R]rt ) -524.8 (c ) 0.5 in CHCl3) (99.9% ee);
D
HPLC (Daicel Chiralpak AS, hexane/2-propanol 90/10, 1 mL/
min) tR ) 10.1 min (minor enantiomer), tR ) 12.8 min (major
enantiomer); mp 91-93 °C; HRMS C16H17NO5 [M + Na]+ calcd
326.1004, found 326.1006.
3
4.25 (t, J (H,H) ) 4.3 Hz, 2H) 3.70 (s, 3H), 3.64 (s, 3H), 3.23
(t, 3J (H,H) ) 4.7 Hz, 2H), 2.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.7, 160.0, 144.2, 136.8, 125.7, 120.4, 114.4, 112.4,
64.8, 57.3, 52.6, 52.3, 48.8, 38.8; [R]rtD ) -49.0 (c ) 1 in CHCl3)
(67% ee); HPLC (Daciel Chiralcel OD, hexane/2-propanol 90/
X-r a y Wor k . Crystals of 12, C15H17NO5S, are orthorhombic,
P21212, with unit cell: a ) 5.116(3) Å, b ) 16.909(10) Å, c )
17.746(11) Å, V ) 1535(2) Å3, Z ) 4. Data collected at 120K
on a SMART diffractometer with CCD detector. The structure

Optically Active Aromatic and Heteroaromatic R-Amino Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4361
solved by direct methods30 and refined by least-squares
methods to final R ) 0.083, Rw ) 0.079, GOF ) 1.33 using
1604 reflections with I > 2σ(I), including 547 Bijvoet pairs.
The crystals were tiny needles with poor diffracting power,
but the absolute configuration was determined by least-
squares refinement of the Rogers’ factor,31 which is expected
to be 1 for the correct hand, -1 for the wrong hand; the result
was 1.9(5), which is (although not ideal) enough to decide the
chirality unambiguously.
Crystals of 14, C16H17NO5, are monoclinic, P21, with unit
cell: a ) 5.767(2) Å, b ) 29.913(9) Å, c ) 9.307(3) Å, â )
108.022(4), V ) 1527(1) Å3, Z ) 4. Data were collected at 120K
on a SMART diffractometer with CCD detector. The structure
solved by direct methods and refined by least-squares methods
to final R ) 0.102, Rw ) 0.114, GOF ) 1.89 using 3505
reflections with I >3σ(I). Crystals were thin, intergrown,
twinned needles. The two molecules in the asymmetric unit
are related by a local 2-fold axis, giving rise to pseudo-
orthorhombic twinning. The twin ratio was refined to 1.98 for
the present crystal. The pseudosymmetry gave rise to correla-
tions making anisotropic refinement impossible.
Ack n ow led gm en t. This work was made possible by
a grant from The Danish National Research Foundation.
Thanks are expressed to Dr. Rita G. Hazell for X-ray
analysis and Dr. Mark Roberson for the theoretical
calculations.
Su p p or t in g In for m a t ion Ava ila b le: Deprotection and
assignment of the absolute configuration of 5h . Complete X-ray
data for compounds 12 and 13. This material is available free
of charge via the Internet at http://pubs.acs.org.
(30) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Moliterni, A., G., G.; Burla, M. C.; Polidori, G.; Camalli, M.; Spagna,
R. SIR97, University of Bari, Italy, 1997.
(31) Rogers, D. Acta Crystallogr. 1981 A37, 734.
J O0256787