Efficient asymmetric synthesis of unnatural β-amino acids

Article abstract of DOI:10.1055/s-2001-16745

The simple and highly enantioselective methanolysis of cyclic meso-anhydrides mediated by cinchona alkaloids leads to a broad variety of dicarboxylic acid mono-methyl esters with up to 99% ee. From these products, unnatural N-protected β-amino esters can be obtained by means of Curtius degradation of the corresponding acyl azides. Subsequent cleavage of the protecting groups leads to the free β-amino acids in excellent yields. By enantiomer differentiating opening of racemic anhydrides, synthetically highly useful regioisomeric amino acid esters become readily available.

Full text of DOI:10.1055/s-2001-16745

SPECIAL TOPIC
1719
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
Efficient
Asymm
a
etric Synth
r
esis of
U
s
nnatural
t
-
Amino
e
A
cids n Bolm,* Ingo Schiffers, Christian L. Dinter, Laurent Defrère, Arne Gerlach, Gerhard Raabe
Institut für Organische Chemie der, RWTH Aachen, Professor-Pirlet-Strasse 1, 52056 Aachen, Germany
Fax +49(241)8888391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
Received 18 April 2001
amino acid precursors. One of those methods makes use
of the simple and highly enantioselective methanolysis of
cyclic meso-anhydrides employing inexpensive and quan-
titatively recoverable cinchona alkaloids as directing ad-
Abstract: The simple and highly enantioselective methanolysis of
cyclic meso-anhydrides mediated by cinchona alkaloids leads to a
broad variety of dicarboxylic acid mono-methyl esters with up to
99% ee. From these products, unnatural N-protected -amino esters
can be obtained by means of Curtius degradation of the correspond- ditives.14–17 As an extension of our work in this field,14 we
ing acyl azides. Subsequent cleavage of the protecting groups leads
now demonstrate that the resulting optically active dicar-
to the free -amino acids in excellent yields. By enantiomer differ-
boxylic acid monoesters are valuable intermediates for the
entiating opening of racemic anhydrides, synthetically highly useful
synthesis of a wide range of unnatural mono- and bicyclic
regioisomeric amino acid esters become readily available.
-amino acids.
Key words: asymmetric ring opening, chiral methyl esters, Curtius
As shown in Scheme 1, the overall reaction sequence in-
volves the asymmetric desymmetrization18 of the meso-
anhydrides19 followed by a subsequent Curtius degrada-
tion of a suitable acyl azide.20 This reaction is highly flex-
ible and permits the introduction of various N-protecting
groups, which later in a given synthesis can selectively be
removed. All synthetic steps are easy to perform giving
highly enantiomerically enriched -amino acid deriva-
tives in good yields.
degradation -amino acids, enantiomer differentiating reaction
Although much less abundant than their -analogues,
-amino acids are ubiquitous in nature. They are produced
in humans, animals, plants, micro- and marine organisms
and have been found either in free form or as part of pep-
tidic products, which often show antibiotic, antifungal,
cytotoxic, and other pharmacological properties.1–3
-Amino acids are also key structural elements of impor-
tant medical compounds such as the promising anticancer
agent Taxol, where the -amino acid side chain is essen-
tial for its biological activity.4 Other important -amino
acid derivatives are the -lactams, which have been found
in antibiotics,5 human leukocyte elastase inhibitors,6 and
cholesterol uptake inhibitors.7 Further interest results
from the pioneering work by Seebach8 and Gellman,9 who
have investigated oligomeric structures of -amino acids.
They found that such -peptides could fold into defined
secondary structures, which are analogous to the ones ob-
served in regular proteins. Furthermore, the reduced nor-
mal metabolism of those “foldermers”10 suggests that
peptides with -amino acid components might also be, in
vivo, metabolically more stable than their regular -amino
acid analogues.11
R
H
H
quinine
quinidine
O
O
O
+ MeOH
R
R
H
H
H
H
CO2H
MeO2C
CO2Me
HO2C
dicarboxylic mono-
dicarboxylic mono-
methylester A
methylester ent-A
Curtius
degradation
R
R
H
H
H
H
Several methods for the synthesis of -amino acids are
well-established,2,12 but only recently the preparation of
optically pure compounds has emerged as an important
and challenging synthetic endeavour. Among the best pro-
tocols for the synthesis of highly enantiomerically en-
riched -amino acids are the ones which make use of the
pool of chiral building blocks such as the Arndt–Eistert
homologation of -amino acids.13 Attractive alternatives
rely on enantioselective reactions and involve the trans-
formation of prochiral starting materials into suitable -
NH-PG
MeO2C
CO2Me
PG-HN
N-protected β-amino
acid ester B
N-protected β-amino
acid ester ent-B
Scheme 1
For the synthesis of N-Cbz protected -amino acid methyl
esters, the corresponding dicarboxylic monoesters were
activated by treatment with ethyl chloroformate and tri-
ethylamine. Addition of an aqueous solution of sodium
azide afforded crude acyl azides, which were dissolved in
benzene and subjected to thermal rearrangement. After re-
moval of the solvent, addition of benzyl alcohol to a me-
thylene chloride solution of the resulting isocyanates in
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1719,1730,ftx,en;C03301ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1720
C. Bolm et al.
SPECIAL TOPIC
the presence of triethylamine gave the desired products. tionary phases. Samples of racemic compounds were used
Thus, by this reaction sequence dicarboxylic monoesters as references. In this context it is important to note that the
1 were converted into the corresponding N-Cbz protected Curtius degradations using diphenylphosphoryl azide22
-amino acid methylesters 2–8 without purification of any led to products containing impurities, which disturbed the
of the intermediates (Table 1).21
HPLC analyses and which could not be removed even by
repeated column chromatography. As Table 1 reveals,
neither epimerization nor racemization occurred during
the reaction sequence for almost all substrates with the
single exception of the transformation shown in entry 7. In
this case, the thermal rearrangement of colorless 1g gave
a deep red crude product which indicated the formation of
diphenylfulvene. As a consequence, a reduced yield of the
corresponding protected amino acid ester 8 was observed,
and its enantiomeric excess deviated significantly from
that of starting material 1g. Probably, a retro Diels–Alder
reaction had taken place leading to the formation of frag-
ments, which upon recombination afforded intermediates
with decreased enantiomeric excess. Recrystallization of
the -amino acid esters 4–6 allowed an increase in the
enantiomeric excesses >99.7% (HPLC analysis). The ab-
solute configurations of the products were confirmed by
comparison of their optical rotations with those of known
compounds. In addition, the findings were verified by the
x-ray crystal structure analysis of 4 (Figure 1).23
Table 1 Preparation of the -Amino Acid Methyl Estersa
H
H
Curtius
degradation
COOMe
COOMe
R
R
(see text)
COOH
NHCbz
H
H
1a–g
2–8
Entry
1
Mono-methyl
Esterb
-Amino Acid Ester
Yield ee
(%)
(%)c
H
1a (95% ee)
69
97
COOMe
NHCbz
H
2
2
3
4
5
6
7
1b (93% ee)
75
73
76
73
66
28
92
H
COOMe
NHCbz
H
H
3
4
1c (95% ee)
1d (97% ee)
1e (96% ee)
1f (99% ee)
1g (95% ee)
95d
96d
96d
99
COOMe
NHCbz
H
H
COOMe
NHCbz
H
5
H
COOMe
NHCbz
H
H
6
7
COOMe
NHCbz
H
H
27
COOMe
Ph
Ph
NHCbz
H
8
a For the conditions see experimental part.
b The ee-values given in parentheses refer to the ones of the mono-me-
thyl esters obtained by the asymmetric methanolysis of the corre-
sponding anhydrides mediated by quinidine. For details see ref. 14.
c Determined by HPLC using chiral stationary phases.
Figure 1 Molecular structure of -amino acid ester 4 as determined
by x-ray crystal structure analysis
d Recrystallization furnished products with > 99.7% ee.
The rearrangement occurred without epimerization as
confirmed by comparison of the diastereomeric ratios of
the starting materials with those of the products (NMR
analysis). The enantiomeric excesses of all compounds
were determined by HPLC using columns with chiral sta-
In the solid state structure of 4, the distance of the amino
hydrogen atom to the carbonyl atom of the carbamate
group on the neighbouring molecule is significantly short-
er than the total of the van der Waals radii of these ele-
ments [2.36(4) Å versus 2.70–2.95 Å).24 Two of the
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
1721
phenyl carbon atoms are at a distance which is situated in
the area of their contact. This is perhaps due to hydropho-
bic interactions of the aromatic rings although this as-
sumption could not be rigorously proven.
H
H
Me
Me
COOMe
NHCbz
Me
Me
COOH
NHCbz
1 N NaOH
98%
H
H
5
13
It is also worthy to note that by the alkaloid-mediated
asymmetric anhydride opening both enantiomers of cis
configurated dicarboxylic monoesters can be selectively
obtained and that conversion into their diastereomeric
trans-isomers has been achieved without racemization.25
Thus, as a consequence of the stereospecificity of the fol-
lowing Curtius degradation both cis and trans configurat-
ed -amino acid derivatives can be prepared from a single
starting material. To illustrate this approach, we synthe-
sized both cis configurated -amino acid ester 7 and its
trans-diastereomer 10 from monoester 1f. Accordingly,
-amino acid ester 10 was obtained via trans-dicarboxylic
monoester 9 with 99% ee in 70% yield.26
H
Me
COOH
H2, Pd/C
99%
Me
NH2
H
14
Scheme 2
reacted smoothly with anisyl-, 2-nitrobenzyl- and phenyl-
ethyl alcohol to give MOZ-, (2-NO2)-Z- and hZ-protected
endo- and exo-16a–c, respectively.32 As a consequence of
the introduction of these various groups, the amino func-
tionalities of the -amino acid esters can selectively be
deprotected by hydrogenation (for Cbz), acid catalyzed
hydrolysis (MOZ),33 photolytic cleavage [(2-NO2)-Z],34
and catalytic hydrogen transfer in the presence of ammo-
nium formate (hZ).35 This extends the scope of potential
chemical manipulations and broadens the applicability of
the multi-functionalized building blocks. The attempted
direct conversion of endo- and exo-15 into endo- and exo-
16d, respectively, by treatment of the isocyanates with
tert-butanol remained unsuccessful.36,37 However, the de-
sired compounds were accessible by a two-step protocol
involving first, the acidic hydrolysis of the isocyanates to
the corresponding amines, and second, the reaction of the
crude amino methylesters with Boc-anhydride giving en-
do- and exo-16d in good yields.38
H
H
COOR
COOMe
X
X
H
H
9: X = COOH
10: X = NHCbz
ent-1a: R = Me,X = COOH
11: R = Me,X = NCO
12•HCl:R = H, X = NH3–Cl+
Figure 2
The possibilities to obtain the free amino acids from the
corresponding dicarboxylic mono-methyl esters or Cbz-
protected amino acid methyl ester were demonstrated by
the transformations of ent-1a into the hydrochloride salt
of 12 and 5 into 14, respectively. Both -amino acids are
known to have interesting biological properties. For ex-
ample, 12 is a potent fungicide called cispentacin. It has
been isolated from the fermentation broths of Streptomy-
ces setonii and Bacillus cereus and was first enantioselec-
tively synthesized by Davies in 1993.27 Compared to other
asymmetric syntheses of this compound,28 the reaction se-
quence described here involving the enantioselective an-
hydride opening followed by the Curtius degradation
offers an attractive alternative. Thus, cispentacin hydro-
chloride (12HCl) was isolated in 91% yield as its hemihy-
drate complex by a simple one-pot reaction involving an
acidic hydrolysis of the intermediate isocyanate 11 to the
corresponding amine followed by acidic ester hydroly-
sis.29
In all cases the stereochemical result of the meso-anhy-
dride opening by methanolysis was uniform: the quini-
dine-mediated reaction always generated the ester
function at the carbonyl group indicated in Scheme 1,
which for the anhydrides with unsubstituted all-carbon
backbones, is the pro-S-carbonyl group. Without excep-
tion, quinine exhibited pro-R-selectivity. The fact that this
rule was strictly valid for a wide range of substrates direct-
ed us to examine the asymmetric openings of racemic an-
hydrides. The cycloaddition product 17 prepared from
isoprene and maleic anhydride served as the first test sub-
strate. As demonstrated by Seebach in his TADDOL-ate
chemistry, the openings of 17 can lead to two regioiso-
meric dicarboxylic acid monoesters 18 and 19, both being
highly enantio-enriched.39 Such enantiomer differentiat-
ing reactions40 are rare41 and the most prominent exam-
ples are asymmetric Baeyer–Villiger reactions of racemic
ketones catalyzed by enzymes42 or metal complexes.43 To
our delight, the alkaloid-mediated methanolysis of 17
gave the two monoesters 18 and 19 with very high enanti-
oselectivities (96% and 97% ee). However, in accordance
with the previous report,39 the product mixture remained
inseparable, which unfortunately prevented the unambig-
uous determination of the absolute configurations of the
products.
The hydrochloride salt of 14 inhibits the growth of Candi-
da albicans in vivo.30,31 Its synthesis began with the sa-
ponification of the ester moiety of 5 followed by removal
of the Cbz-group of the resulting acid 13 by hydrogena-
tion giving -amino acid 14 in excellent yield (Scheme 2).
NMR analysis of 13 confirmed that no epimerization had
occurred during the basic ester hydrolysis.
Next, we examined the introduction of other N-protecting
groups using isocyanates endo-15 and exo-15 as interme-
diates. Both isomers were readily available from the cor-
responding dicarboxylic acid monoesters 1f and 1e and
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

1722
C. Bolm et al.
SPECIAL TOPIC
Table 2 Selected Data of Amino Acid Methyl Esters endo- and exo-16a–d
H
H
CO2Me
X
CO2Me
X
H
H
endo-15: X = NCO
exo-15: X = NCO
endo-16a: X = NH-MOZ
endo-16b: X = NH-(2-NO2)-Z
endo-16c: X = NH-hZ
endo-16d: X = NH-Boc
exo-16a: X = NH-MOZ
exo-16b: X = NH-(2-NO2)-Z
exo-16c: X = NH-hZ
exo-16d: X = NH-Boc
r.t.
Amino-
Ester
Yield 1H NMR (400 MHz, CDCl3), , J (Hz) //
(%)
IR (KBr/film)
(cm–1)
[ ]D
13C NMR (100 MHz, CDCl3),
(c, CHCl3)
endo-16a
endo-16b
62
1.37 (d, J = 9.0, 1H), 1.49 (d, J = 9.0, 1H), 3.09 (s, 2H), 3.20 (dd, J = 3.0,
9.3, 1H), 3.52 (s, 3H), 3.79 (s, 3H), 4.61 (dt, J = 3.6, 9.1, 1H), 5.00 (AB-
system, J = 12.1, 2H), 5.23 (d, J = 9.3, 1H), 6.13–6.16 (m, 1H), 6.36–6.38
(m, 1H), 6.87 (d, J = 8.8, 2H), 7.29 (d, J = 8.8, 2H) // 46.9, 47.6, 47.8, 48.5,
51.8, 54.4, 55.6, 66.7, 114.1, 128.9, 130.2, 133.4, 138.4, 156.2, 159.7, 173.3
2952, 1724, 1515
+1.8
(1.24)
(1.29)
67
60
1.39 (d, J = 9.1, 1H), 1.51 (dt, J = 1.9, 9.1, 1H), 3.14 (s, 2H), 3.22 (dd, J = 2977, 1730, 1527
3.0, 9.1, 1H), 3.62 (s, 3H), 4.58 (dt, J = 3.6, 9.3, 1H), 5.49 (AB-system, J =
15.1, 2H), 5.59 (d, J = 9.3, 1H), 6.20–6.23 (m, 1H), 6.37–6.39 (m, 1H),
7.44–7.48 (m, 1H), 7.57–7.81 (m, 2H), 8.08 (dd, J = 1.4, 8.2, 1H) // 47.2,
47.6, 47.8, 47.9, 51.9, 54.4, 63.4, 125.1, 128.6, 128.8, 133.5, 133.6, 133.9,
138.1, 147.4, 155.5, 173.4
1.9
endo-16c
1.29 (d, J = 9.1, 1H), 1.42 (d, J = 9.1, 1H), 2.82 (t, J = 7.1, 2H), 3.02 (s, 2H), 2977, 1724, 1510
3.13 (dd, J = 3.0, 9.3, 1H), 3.49 (s, 3H), 4.16 (t, J = 7.1, 2H), 4.51 (dt, J =
3.6, 9.3, 1H), 5.15 (d, J = 9.9, 1H), 6.07–6.10 (m, 1H), 6.29–6.31 (m, 1H),
7.12–7.23 (m, 5H) // 35.9, 46.9, 47.6, 47.8, 48.4, 51.8, 54.3, 65.6, 126.6,
128.6, 129.1, 133.5, 138.2, 156.2, 173.4
+6.5
(0.92)
endo-16d
exo-16a
65
64
1.30 (d, J = 9.1, 1H), 1.35 (s, 9H), 1.42 (d, J = 9.1, 1H), 2.99 (s, 1H), 3.02 2972, 1731, 1513
(s, 1H), 3.15 (d, J = 9.1, 1H), 3.55 (s, 3H), 4.52 (br s, 1H), 4.79 (d, J = 8.3,
1H), 6.08–6.11 (m, 1H), 6.35–6.38 (m, 1H) // 28.7, 46.6, 47.4, 47.9, 49.2,
51.8, 54.0, 79.4, 133.1, 138.7, 155.5, 173.2
+29.0
+43.5
(0.78)
(1.81)
1.57 (dt, J = 1.7, 9.3, 1H), 1.94 (d, J = 9.3, 1H), 2.64 (d, J = 8.2, 1H), 2.73 2979, 1729, 1515
(s, 1H), 2.94 (s, 1H), 3.58 (s, 3H), 3.80 (s, 3H), 4.00 (t, J = 8.8, 1H), 5.02
(AB-system, J = 11.8, 2H), 5.43 (d, J = 9.6, 1H), 6.17–6.20 (m, 2H), 6.88
(d, J = 8.5, 2H), 7.30 (d, J = 8.5, 2H) // 44.7, 46.1, 46.7, 48.7, 52.1, 53.5,
55.6, 66.8, 114.1, 128.9, 130.3, 137.4, 138.6, 155.0, 159.7, 174.7
exo-16b
65
1.61 (dt, J = 1.7, 9.3, 1H), 1.98 (d, J = 9.6, 1H), 2.67 (dd, J = 1.4, 8.3, 1H), 2995, 1731, 1524
2.77 (s, 1H), 2.98 (s, 1H), 3.68 (s, 3H), 3.99 (t, J = 8.2, 1H), 5.51 (AB-sys-
tem, J = 15.4, 2H), 5.73 (d, J = 9.6, 1H), 6.19–6.24 (m, 2H), 7.46–7.50 (m,
1H), 7.59–7.67 (m, 2H), 8.10 (dd, J = 1.1, 8.2, 1H) // 44.6, 46.4, 48.9, 52.3,
53.5, 63.6, 125.2, 128.7, 128.9, 133.4, 133.9, 137.3, 138.6, 147.5, 155.3,
174.9
+58.1
(1.49)
exo-16c
exo-16d
61
68
1.57 (d, J = 9.6, 1H), 1.95 (d, J = 9.3, 1H), 2.64 (d, J = 8.2, 1H), 2.71 (s, 1H), 2975, 1729, 1533
2.90–2.95 (m, 3H), 3.62 (s, 3H), 3.98 (t, J = 8.8, 1H), 4.26 (t, J = 7.1, 2H),
5.39 (d, J = 8.8, 1H), 6.17–6.20 (m, 2H), 7.20–7.30 (m, 5H) // 35.9, 44.7,
46.2, 46.6, 48.8, 52.1, 53.3, 65.7, 126.7, 128.7, 129.1, 137.4, 138.6, 156.0,
174.8
+67.6
+64.1
(1.73)
(1.55)
1.43 (s, 9H), 1.59 (dt, J = 1.7, 9.6, 1H), 1.95 (d, J = 9.3, 1H), 2.65 (d, J = 8.0, 2983, 1722, 1516
1H), 2.71 (s, 1H), 3.68 (s, 3H), 3.96 (br t, J = 9.0, 1H), 5.10 (d, J = 8.4, 1H),
6.17–6.22 (m, 2H) // 28.3, 44.4, 45.5, 46.6, 48.2, 51.7, 52.7, 79.3, 137.1,
138.2, 154.8, 174.4
Finally, an insight into the stereochemical details of the mitted to the Curtius degradation. The resulting Cbz-pro-
asymmetric methanolysis of racemic anhydrides was tected amino acid esters 23 and 24 were then separated by
gained by using rac-20 as substrate (Scheme 3). In this column chromatography, which allowed an independent
case, the two isomeric dicarboxylic acid monoesters 21 structural analysis of both isomeric -amino acid deriva-
and 22 were obtained, which were both subsequently sub- tives.
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
1723
In rac-20 the methyl group of the cyclohexane ring is in a
trans position to the anhydride moiety, and we therefore
wondered about reactions of compounds with a cis-meth-
yl substituent. Taking rac-25 as test substrate (Scheme 4),
the two isomeric -amino acid esters 26 and 27 both hav-
ing very high enantiomeric excesses (99 and 91% ee, re-
spectively) were obtained.
O
H
H
H
Me
Me
Me
CO2R
CO2R'
CO2R'
CO2R
O
H
O
H
H
rac-17
18
19
R = H, R' = Me or R = Me, R' = H
Figure 3
Me
Me
Me
1. quinidine, MeOH
2. ClCOOEt, Et3N
3. NaN3 aq.
O
H
H
H
COOMe
NHCbz
NHCbz
The stereochemistry of the enantioselective methanolysis
of rac-20 was deduced from the structure and absolute
configuration of 23, which were determined by compari-
son of the spectral data and sense of optical rotation, re-
spectively, with the ones published by Back.44 The ee-
values of 23 and its regioisomer 24 confirmed the pro-
nounced site-selectivity of the quinidine-mediated open-
ing. Whereas the reaction of 20 gave 21 almost
exclusively, the methanolysis starting from ent-20 was
less selective and afforded 22 as the major product togeth-
er with ent-21 as by-product. Consequently, the overall ee
of 21 was reduced, which was reflected in the different ee-
values of 23 and 24 (84 versus 93% ee, respectively).
Gratifyingly, recrystallizations of the amino acid esters
led to a significant enantiomer enrichment to give 23 and
24 with 98.9% and 99.8% ee, respectively.
+
O
4. benzene, 80 °C
5. BnOH, Et3N
COOMe
H
H
H
O
rac-25
26
65% a
99% ee
27
67% a
91% ee
a) based on the amount of the corresponding
enantiomer of the anhydride in the racemic starting
material
Scheme 4
Besides the separation of 26 and 27 by column chroma-
tography, the former product could be isolated in enan-
tiopure form by crystallization from the regioisomeric
mixture. A single crystal x-ray analysis of -amino acid
ester 2645 ensured the structural assignment of this prod-
uct and verified the site-selectivity of the quinidine-medi-
ated anhydride opening for this substrate. As a
consequence, product 27 must have the structure and ab-
solute configuration indicated in Scheme 4.
In this sequence, 23 is of particular interest since it is a key
intermediate in the total synthesis of the pharmacological-
ly important dendrobatid alkaloid (–)-Pumiliotoxin C.44 It
has previously been synthesized by Back from a reaction
sequence involving an enzymatic hydrolysis of an appro-
priate racemic dimethyl ester. However, due to the fact
that in this key step the wrong enantiomer was formed, a
number of subsequent derivatisation and recyclization
steps were required, which finally gave 23 in only 28%
yield (based on the amount of the desired regioisomer in
the mixture of starting materials). In contrast, the synthe-
sis of 23 outlined in Scheme 3 leads to the amino acid es-
ter in 71% yield in only two steps.
In summary, we have described the transformation of
highly enantiomerically enriched dicarboxylic acid mono-
methyl esters, which are readily obtained from a quini-
dine-mediated methanolyis of meso-anhydrides, into opti-
cally active -amino acids. Through a reaction sequence
involving a Curtius degradation as a key step, a wide
range of fully protected -amino acid derivatives became
available. Their complete deprotection allows the synthe-
Me
Me
Me
H
O
H
H
COOMe
COOH
COOMe
73%a
84% ee
quinidine
O
98.9% eeb
NHCbz
1. ClCOOEt, Et3N
2. NaN3 aq.
3. benzene, 80 °C
4. BnOH, Et3N
H
H
H
O
O
20
+
23
21
+
MeOH
99%
chromatographic separation
H
major
quinidine
minor
H
H
H
H
53%a
COOH
COOMe
COOH
COOMe
NHCbz
+
O
93% ee
99.8% eeb
COOMe
H
H
H
O
Me
Me
Me
Me
24
ent-20
ent-21
22
(minor)
(major)
a) based on the amount of the corresponding
enantiomer of the dicarboxylic acid monoester
in the starting material
b) after recrystallization
Scheme 3
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

1724
C. Bolm et al.
SPECIAL TOPIC
Table 3 Selected Data of Amino Acid Esters 23, 24, 26, and 27a
1H NMR (400 MHz, CDCl3), , J (Hz) //
IR (KBr/film)
(cm–1)
[ ]D
r.t.
Amino- Yield
Ester
(%)b
13C NMR (100 MHz, CDCl3),
(c, CHCl3)
23
72
0.92 (d, J = 6.4, 3H), 1.02–1.06 (m, 1H), 1.33–1.71 (m, 4H), 1.86–1.98 (m,
2H), 2.27 (dd, J = 3.7, 10.1, 1H), 3.36 (s, 3H), 4.10–4.20 (m, 1H), 5.07 (br s,
2H), 5.28 (br s, 1H), 7.32–7.35 (m, 5H) // 19.9, 20.2, 29.1, 31.2, 32.3, 47.8,
51.7, 52.5, 66.6, 128.0, 128.5, 136.6, 155.8, 173.8
2950, 1731, 1513
29.6
(1.01)
24
52
0.94 (d, J = 6.7, 3H), 1.00–1.28 (m, 2H), 1.51–1.61 (m, 2H), 1.71–1.80 (m,
1H), 1.85–1.94 (m, 1H), 2.12–2.20 (m, 1H), 2.89–2.93 (m, 1H), 3.41–3.49 (m,
1H), 3.67 (s, 3H), 5.08 (AB-system, J = 12.4, 2H), 5.62 (br d, J = 9.1, 1H),
7.32–7.36 (m, 5H) // 18.9, 22.1, 28.5, 33.7, 34.0, 44.9, 51.6, 56.0, 66.6, 128.0,
128.5, 136.8, 156.2, 174.6
2952, 1723, 1505
+61.5
(1.12)
26
27
65
67
1.06 (d, J = 7.4, 3H), 2.29–2.33 (m, 2H), 2.70 (br s, 1H), 3.10 (br t, J = 5.1, 1H), 2956, 1733, 1523
3.64 (s, 3H), 4.01–4.08 (m, 1H), 5.02 (br s, 1H), 5.10 (s, 2H), 5.41 (dd, J = 1.7,
9.9, 1H), 5.63–5.68 (m, 1H), 7.30–7.37 (m, 5H) // 18.2, 29.0, 32.8, 47.8, 48.3,
51.1, 66.3, 124.4, 127.9, 128.0, 128.3, 129.7, 136.2, 155.4, 172.1
+148.8 (1.71)
0.99 (d, J = 7.4, 3H), 2.19–2.27 (m, 1H), 2.34–2.43 (m, 1H), 2.54–2.62 (m,
1H), 2.76 (ddd, J = 2.2, 6.3, 11.3, 1H), 3.66 (s, 3H), 4.39–4.43 (m, 1H), 4.82
(br d, J = 10.4, 1H), 5.06 (AB-system, J = 12.4, 2H), 5.32–5.36 (m, 1H), 5.64–
5.69 (m, 1H), 7.33–7.36 (m, 5H) // 17.0, 23.0, 35.0, 43.5, 51.0, 51.4, 52.3, 67.0,
125.3, 128.2, 128.3, 130.3, 136.8, 156.6, 173.6
2961, 1734, 1507
15.8
(1.78)
a For conditions see GP-3 in the experimental section.
b Based on the amount of the corresponding enantiomer of the anhydride in the racemic starting material.
ring opening of cyclic meso-anhydrides and the analytical data of
the corresponding monoesters, see reference 14b.
sis of the corresponding free -amino acids. Furthermore,
we have reported on the enantiomer differentiating open-
ing of racemic anhydrides leading to regioisomeric prod-
ucts which can serve as important building blocks for the
synthesis of natural products.
Preparation of N-Protected Amino Acid Esters using Benzylic
Alcohols; General Procedure (GP-1)
Ethyl chloroformate (1.91 mL, 20 mmol) was added to a mixture of
the appropriate monoester (10 mmol) and Et3N (4.18 mL, 30 mmol)
in anhyd THF (16 mL) at –20 °C. The reaction mixture was stirred
at this temperature for 1 h. A solution of NaN3 (1.95 g, 30 mmol) in
H2O (12 mL) was added at –10 °C. The temperature was gradually
increased to r.t. and stirring was continued for 2 h. The mixture was
diluted with H2O and the product was extracted with EtOAc. The
organic phase was washed with aq. NaHCO3, dried (MgSO4), fil-
tered and concentrated providing the corresponding acyl azide. The
crude acyl azide was dissolved in anhyd benzene (12 mL) and heat-
ed under reflux for 2 h. After removal of benzene, benzylic alcohol
(11 mmol) and Et3N (2.79 mL, 20 mmol) were added to a solution
of the isocyanate in anhyd CH2Cl2 (12 mL) and the reaction mixture
was heated under reflux for 4.5 h. Evaporation of the solvent deliv-
ered an oily residue which was purified by column chromatography
providing the corresponding N-protected amino acid methyl ester.
Unless otherwise specified, all reagents were purchased from com-
mercial suppliers and used without further purification. Toluene and
THF were distilled from sodium benzophenone ketyl radical,
CH2Cl2 from CaH2 under Ar. Petroleum ether, Et2O and EtOAc
were distilled before being use for chromatography. All other sol-
vents were reagent grade and used as received. Unless otherwise
noted, all reactions were carried out under Ar using standard
Schlenk and vacuum line techniques. HPLC-analysis was per-
formed using the Chiracel columns OD, OD-H, and OC or the
Chiralpak columns AD and AS (Daicel), 4.6 250 mm, = 254 nm.
1H and 13C NMR spectra were obtained on a Varian VXR 300,
Gemini 300 or Inova 400 spectrometer and were recorded relative
to TMS as internal standard. Mass spectra were measured on a
Finnigan SSQ 7000 instrument or on a Hewlett Packard GCMS ap-
paratus-system (Column HP-5 MS, 30 m 0.25 mm 0.25 m;
Mass Selective Detector 5973). Mps were measured in open glass
capillaries with a Büchi apparatus and are uncorrected. Optical ro-
tation values were determined on a Perkin–Elmer P241 instrument
at r.t. (approx. 20 °C) using solvents of Merck UVASOL-quality. IR
spectra were recorded on a Perkin–Elmer 1760 FT apparatus. All
microanalyses were obtained with a Heraeus CHN-O-RAPID ele-
mental analyzer at the Institut für Organische Chemie der RWTH
Aachen. Preparative column chromatography: Merck silica gel 60,
particle size 0.040–0.063 mm (230–400 mesh, flash). Analytical
TLC: Silica gel 60 F254 plates, Merck, Darmstadt. Anhydride 20 was
prepared according to literature procedures,46 compound 25 by Di-
els–Alder reaction of maleic anhydride and the corresponding di-
ene. For general experimental procedures of the alkaloid-mediated
(1S,2R)-2-Benzyloxycarbonylamino-cyclopentane-1-carboxylic
Acid Methyl Ester (2)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1a with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (petroleum ether–EtOAc, 1:1)
delivering 2 in 69% yield as a colorless oil.
[ ]D +56.5 (c 2.01, CHCl3).
ee = 97% [HPLC-analysis: Chiralpak AD at r.t., n-heptane–2-PrOH
(90:10), 0.8 mL/min, 254 nm, t1 = 12.6 min, t2 = 14.8 min (major)].
IR (film): 3349, 2952, 1729, 1527, 1455, 1437, 1371 cm–1.
1H NMR (400 MHz, CDCl3): = 1.56–1.73 (m, 2H), 1.76–1.85 (m,
1H), 1.91–2.02 (m, 3H), 3.00 (q, J = 7.4 Hz, 1H), 3.60 (s, 3H), 4.24–
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
1725
4.31 (m, 1H), 5.08 (AB-system, J = 12.6 Hz, 2H), 5.31 (d, J = 8.0
rified by flash chromatography (petroleum ether–EtOAc, 1:1)
Hz, 1H), 7.28–7.35 (m, 5H).
13C NMR (100 MHz, CDCl3): = 22.5, 28.2, 32.4, 47.0, 52.0, 54.5,
66.9, 128.2, 128.3, 128.7, 136.8, 156.0, 174.9.
MS (EI, 70 eV): m/z (%) = 277 (M+, 11), 246 (2), 186 (4), 142 (13),
108 (39), 91 (100).
delivering 5 in 76% yield as a white solid.
Mp 48.5 °C (rac), 55 °C (en).
[ ]D +8.5 (c 1.92, CHCl3).
ee = 96% (99.8% ee after recrystallization from petroleum ether–
EtOAc) [HPLC-analysis: Chiralpak AD at r.t., n-heptane–2-PrOH
(98:2), 0.4 mL/min, 254 nm, t1 = 42.8 min, t2 = 49.0 min (major)].
IR (KBr): 3349, 2912, 1735, 1692, 1531, 1435, 1320, 1254 cm–1.
Anal. Calcd for C15H19NO4 (277.31): C, 64.97; H, 6.91; N, 5.05.
Found: C, 64.82; H, 6.95; N, 5.39.
1H NMR (400 MHz, CDCl3): = 1.58 (s, 3H), 1.62 (s, 3H), 2.07 (dd,
J = 5.8, 17.0 Hz, 1H), 2.18–2.36 (m, 2H), 2.41 (dd, J = 7.4, 17.6
Hz, 1H), 2.77 (dt, J = 3.0, 6.6 Hz, 1H), 3.67 (s, 3H), 4.22–4.28 (m,
1H), 5.07 (AB-system, J = 12.4 Hz, 2H), 5.35 (d, J = 9.3 Hz, 1H),
7.31–7.36 (m, 5H).
13C NMR (100 MHz, CDCl3): = 18.7, 18.9, 31.0, 36.8, 42.5, 47.2,
51.8, 66.6, 123.1, 123.5, 127.9, 128.0, 128.3, 136.3, 155.6, 173.6.
(1S,2R)-2-Benzyloxycarbonylamino-cyclohexane-1-carboxylic
Acid methyl Ester (3)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1b with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (pentane–EtOAc, 1:1) delivering 3
in 75% yield as a colorless oil.
[ ]D +26.2 (c 1.67, CHCl3), [ ]D +27.2 (c 2.30, EtOH) {Lit.47 for
ent-3: [ ]D 29.0 (c 1.00, EtOH)}.
MS (EI, 70 eV): m/z (%) = 286 (4), 167 (10), 166 (100), 165 (25),
121 (15), 107 (68).
ee = 92% [HPLC-analysis: Chiracel OD-H at r.t., n-heptane–2-
PrOH (99:1), 0.7 mL/min, 254 nm, t1 = 18.5 min (major), t2 = 21.3
min].
Anal. Calcd for C18H23NO4 (317.38): C, 68.12; H, 7.30; N, 4.41.
Found: C, 68.28; H, 7.30; N, 4.37.
IR (film): 2939, 2860, 1724, 1506, 1454, 1436, 1358, 1340 cm–1.
(2S,3R)-3-exo-Benzyloxycarbonylamino-bicyclo[2.2.1]hept-5-
ene-2-exo-carboxylic Acid Methyl Ester (6)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1e with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (CH2Cl2–pentane–Et2O, 2:1:1)
delivering 6 in 73% yield as a white solid.
1H NMR (300 MHz, CDCl3): = 1.30–2.04 (m, 8H), 2.80–2.83 (m,
1H), 3.66 (s, 3H), 3.85–3.95 (m, 1H), 5.08 (br s, 2H), 5.58 (d, J =
1.0 Hz, 1H), 7.32–7.35 (m, 5H).
13C NMR (75 MHz, CDCl3): = 22.6, 23.9, 27.0, 29.8, 44.8, 49.8,
51.7, 66.7, 128.1, 128.6, 136.7, 155.8, 174.3.
MS (EI, 70 eV): m/z (%) = 291 (M+, 5), 259 (9), 184 (5), 156 (22),
140 (11), 108 (44), 91 (100).
Mp 81 °C (rac), 57 °C (en).
[ ]D +63.4 (c 1.27, CHCl3).
Anal. Calcd for C16H21NO4 (291.38): C, 65.96; H, 7.26; N, 4.81.
Found: C, 65.76; H, 7.39; N, 5.15.
ee = 96% (recrystallization from petroleum ether–EtOAc gave a
single enantiomer of 6 as analyzed by HPLC) [HPLC-analysis:
Chiralpak AD at r.t., n-heptane–2-PrOH (94:6), 0.7 mL/min, 254
nm, t1 = 21.9 min, t2 = 27.7 min (major)].
(1S,6R)-6-Benzyloxycarbonylamino-cyclohex-3-ene-1-
carboxylic Acid Methyl Ester (4)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1c with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (petroleum ether–EtOAc, 1:1)
delivering 4 in 73% yield as a white solid.
Mp 51 °C (rac), 50 °C (en) (Lit.:48 mp 50–51 °C).
[ ]D +22.4 (c 1.34, CHCl3) {Lit.:48 [ ]D +21.3 (c 1.00, CHCl3)}
IR (KBr): 3310,1735, 1692, 1537, 1342, 1283 cm–1.
1H NMR (400 MHz, CDCl3): = 1.58 (dt, J = 1.7, 9.6 Hz, 1H), 1.95
(d, J = 9.3 Hz, 1H), 2.65 (d, J = 8.2 Hz, 1H), 2.74 (s, 1H), 2.95 (s,
1H), 3.58 (s, 3H), 4.01 (t, J = 9.1 Hz, 1H), 5.08 (AB-system, J =
12.4 Hz, 2H), 5.48 (d, J = 9.3 Hz, 1H), 6.17–6.22 (m, 2H), 7.30–
7.36 (m, 5H).
13C NMR (100 MHz, CDCl3): = 44.3, 45.7, 46.3, 48.4, 51.7, 53.1,
66.6, 127.9, 128.0, 128.3, 136.3, 137.0, 138.2, 155.5, 174.4.
ee = 95% (recrystallization from petroleum ether–EtOAc gave a
single enantiomer of 4 as analyzed by HPLC) [HPLC-analysis:
Chiracel OC at r.t., n-heptane–2-PrOH (93:7), 0.7 mL/min, 254 nm,
t1 = 23.6 min (major), t2 = 27.6 min].
MS (EI, 70 eV): m/z (%) = 237 (5), 236 (37), 192 (4), 175 (14), 159
(4), 106 (3), 91 (100).
Anal. Calcd for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.77; H, 6.02; N, 4.93.
IR: see reference.48b.
1H NMR (300 MHz, CDCl3): = 2.16–2.25 (m, 1H), 2.31–2.42 (m,
2H), 2.49–2.56 (m, 1H), 2.81–2.85 (m, 1H), 3.68 (s, 3H), 4.20–4.26
(m, 1H), 5.09 (AB-system, J = 12.4 Hz, 2H), 5.42 (br d, J = 8.5 Hz,
1H), 5.59–5.69 (m, 2H), 7.29–7.37 (m, 5H).
13C NMR (75 MHz, CDCl3): = 25.6, 30.7, 42.1, 46.9, 52.0, 66.8,
124.8, 125.0, 128.2, 128.6, 136.6, 155.9, 173.9.
(2S,3R)-3-endo-Benzyloxycarbonylamino-bicyclo[2.2.1]hept-5-
ene-2-endo-carboxylic Acid Methyl Ester (7)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1f with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (CH2Cl2–pentane–Et2O, 2:1:1)
delivering 7 in 66% yield as a colorless oil.
MS (EI, 70 eV): m/z (%) = 289 (M+, 5), 245 (2), 138 (11), 108 (8),
91 (100).
[ ]D +2.1 (c 1.39, CHCl3).
Anal. Calcd for C16H19NO4 (289.32): C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.15; H, 6.74; N, 5.03.
ee = 99% [HPLC-analysis: Chiracel OD at r.t., n-heptane–2-PrOH
(85:15), 0.7 mL/min, 254 nm, t1 = 8.8 min, t2 = 12.5 min (major)].
IR (film): = 3403, 2976, 1728, 1509, 1455, 1436, 1337, 1221 cm–1.
(1S,6R)-6-Benzyloxycarbonylamino-3,4-dimethylcyclohex-3-
ene-1-carboxylic Acid Methyl Ester (5)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1d with benzyl alcohol. The crude reaction product was pu-
1H NMR (300 MHz, CDCl3): = 1.37 (d, J = 9.1 Hz, 1H), 1.49 (dt,
J = 1.7, 9.1 Hz, 1H), 3.10 (s, 2H), 3.21 (dd, J = 3.0, 9.4 Hz, 1H),
3.52 (s, 3H), 4.61 (dt, J = 3.4, 9.4 Hz, 1H), 5.07 (AB-system, J =
12.4 Hz, 2H), 5.28 (d, J = 9.1 Hz, 1H), 6.14–6.17 (m, 1H), 6.37–
6.39 (m, 1H), 7.30–7.34 (m, 5H).
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

1726
C. Bolm et al.
SPECIAL TOPIC
13C NMR (75 MHz, CDCl3): = 46.6, 47.3, 47.5, 48.2, 51.5, 54.1,
66.6, 128.1, 128.2, 128.5, 133.2, 136.7, 138.2, 156.0, 173.2.
stirred at r.t. for 1 h. Then the temperature was gradually raised to
100 °C and stirring was continued for 16 h. The mixture was ex-
tracted with Et2O and the aqueous phase was concentrated to pro-
vide the crude product. Repeated treatment with acetone and
evaporation of the solvent delivered the title compound in 91%
yield as a white solid which was recrystallized from EtOH–pentane.
MS (EI, 70 eV): m/z (%) = 236 (19), 192 (4), 176 (5), 175 (13), 142
(3), 106 (3), 91 (100).
Anal. Calcd for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.65; H, 6.26, N, 4.59.
Mp 208 °C (rac), 153 °C (en).
(2S,3R)-7-Benzhydrylidene-3-endo-benzyloxycarbonylamino-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid Methyl Ester
(8)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1g with benzyl alcohol. The crude reaction product was pu-
rified by flash chromatography (petroleum ether–EtOAc, 1:1)
delivering 8 in 28% yield as a white solid.
[ ]D -5.5 (c 1.09, H2O) {Lit.:28d [ ]D -4.5 (c 1, H2O)}.
IR (KBr): 3362, 3229, 2940, 1715, 1652, 1615, 1588, 1499, 1409,
1210 cm–1.
1H NMR (400 MHz, D2O): = 1.52–1.82 (m, 4H), 1.91–2.03 (m,
2H), 2.97 (q, J = 6.3 Hz, 1H), 3.68 (br q, J = 6.3 Hz, 1H).
13C NMR (100 MHz, D2O): = 21.48, 27.45, 29.95, 45.64, 52.91,
176.41.
Mp 111.5 °C (rac), 102 °C (en).
[ ]D 1.5 (c 1.37, CHCl3).
MS (EI, 70 eV): m/z (%) = 129 (12), 111 (2), 100 (9), 82 (9), 69 (12),
56 (100).
ee = 27% [HPLC-analysis: Chiralpak AD at r.t., n-heptane–2-PrOH
(95:5), 0.7 mL/min, 254 nm, t1 = 16.3 min (major), t2 = 20.3 min].
Anal. Calcd for C6H11NO2·HCl·0.5H2O (174.62): C, 41.27; H, 7.50;
N, 8.02. Found: C, 41.28; H, 7.57; N, 8.02.
IR (KBr): 3365, 3324, 1710, 1686, 1526, 1456, 1440, 1357, 1335,
1245 cm–1.
(1S,6R)-6-Benzyloxycarbonylamino-3,4-dimethylcyclohex-3-
ene-1-carboxylic Acid (13)
1H NMR (400 MHz, CDCl3): = 3.45 (dd, J = 3.3, 9.3 Hz, 1H), 3.53
(s, 3H), 3.64 (s, 1H), 3.67 (s, 1H), 4.82 (dt, J = 3.6, 9.3 Hz, 1H), 5.07
(AB-system, J = 12.3 Hz, 2H), 5.39 (d, J = 9.3 Hz, 1H), 6.38 (dd, J
= 3.3, 5.8 Hz, 1H), 6.60 (dd, J = 3.3, 5.5 Hz, 1H), 7.05–7.09 (m,
4H), 7.27–7.34 (m, 11H).
13C NMR (100 MHz): = 48.7, 48.9, 49.5, 52.0, 53.7, 67.0, 124.4,
127.2, 127.3, 128.3, 128.4, 128.7, 129.7, 133.7, 136.7, 138.4, 140.6,
140.7, 149.1, 156.1, 172.4.
A solution of amino acid ester 5 (1.12 g, 3.53 mmol) in MeOH (17
mL) was treated with NaOH (1 N, 9.4 mL) and stirred at r.t. for 4 h.
After acidification with 1 N HCl, the mixture was extracted with
CH2Cl2. The combined organic layers were dried (MgSO4), filtered,
and concentrated providing 1.05 g (3.46 mmol, 98%) of 13 as a
white solid.
Mp 141 °C (rac), 148.5 °C (en).
[ ]D 5.2 (c 1.12, CHCl3).
MS (EI, 70 eV): m/z (%) = 230 (100), 228 (12), 215 (18), 202 (5),
165 (3), 152 (5), 91 (25).
IR (KBr): 3424, 3145, 3065, 1721, 1675, 1521, 1453, 1363, 1306,
1252, 1217 cm–1.
Anal. Calcd for C30H27NO4 (465.54): C, 77.40; H, 5.85; N, 3.01.
Found: C, 77.36; H, 5.87; N, 2.99.
1H NMR (400 MHz, CDCl3): = 1.58 (s, 3H), 1.61 (s, 3H), 2.11 (dd,
J = 6.9, 16.8 Hz, 1H), 2.27 (d, J = 16.8 Hz, 2H), 2.41 (dd, J = 5.8,
17.3 Hz, 1H), 2.80–2.86 (m, 1H), 4.19–4.24 (m, 1H), 5.08 (AB-sys-
tem, J = 12.4 Hz, 2H), 5.51 (d, J = 9.6 Hz, 1H), 7.28–7.34 (m, 5H),
10.18 (br s, 1H).
13C NMR (100 MHz, CDCl3): = 18.7, 18.9, 31.7, 36.4, 42.5, 47.2,
66.7, 123.4, 123.5, 127.9, 128.0, 128.3, 136.2, 155.8, 178.6.
(2R,3R)-3-endo-Benzyloxycarbonylamino-bicyclo[2.2.1]hept-5-
ene-2-exo-carboxylic Acid Methyl Ester (10)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 9 with benzyl alcohol. The crude reaction product was puri-
fied by flash chromatography (pentane–EtOAc, 1:1) delivering 10
in 70% yield as a white solid.
Mp 75 °C (rac), 86 °C (en) [Lit.:26 81–82 °C (en)].
[ ]D -141.4 (c 2.05, CHCl3) {Lit.26 for ent-10: [ ]D + 138.3 (c 2.01,
MS (EI, 70 eV): m/z (%) = 303 (M+, 1), 242 (3), 152 (61), 151 (25),
133 (7), 122 (5), 108 (10), 107 (63), 91 (100).
Anal. Calcd for C17H21NO4 (303.35): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.34; H, 6.82; N, 4.53.
CHCl3)}.
ee = 99% [HPLC-analysis: Chiralcel OD at r.t., n-heptane–2-PrOH
(94:6), 0.6 mL/min, 254 nm, t1 = 21.9 min (major), t2 = 26.8 min].
(1S,6R)-6-Amino-3,4-dimethylcyclohex-3-ene-1-carboxylic
Acid (14)
IR: see reference 26.
A solution of 13 (535 mg, 1.76 mmol) in a mixture of dry MeOH–
CH2Cl2 (3:1, 16 mL) was hydrogenated for 2 h over 10% palladium
on charcoal (90 mg) at r.t. and at 1 atm. The catalyst was removed
by filtration through Celite and washed with dry CH2Cl2. Evapora-
tion of the solvents yielded 296 mg (1.75 mmol, 99%) of 14 as a
white solid.
1H NMR (400 MHz, CDCl3): = 1.49 (d, J = 8.8 Hz, 1H), 1.83 (d,
J = 9.3 Hz, 1H), 1.92 (t, J = 2.5 Hz, 1H), 3.00 (s, 1H), 3.05 (s, 1H),
3.72 (s, 3H), 4.58 (br s, 2H), 5.07 (br s, 2H), 6.15 (dd, J = 3.0, 5.5
Hz, 1H), 6.40 (dd, J = 3.0, 5.5 Hz, 1H), 7.30–7.35 (m, 5H).
13C NMR (100 MHz): = 46.1, 46.2, 47.4, 52.0, 52.6, 55.7, 66.7,
128.0, 128.3, 133.9, 136.1, 139.4, 155.5, 174.2.
Mp (dec.) 237–240 °C (rac), 213–219 °C (en).
[ ]D +30.9 (c 1.02, CHCl3).
MS (EI, 70 eV): m/z (%) = 236 (21), 192 (3), 175 (14), 159 (4), 91
(100), 66 (22).
IR (KBr): 3414, 3104, 2930, 2908, 2880, 1654, 1647, 1618, 1562,
1480, 1357, 1234 cm–1.
1H NMR (400 MHz, D2O): = 1.63 (s, 3H), 1.65 (s, 3H), 2.10–2.22
(m, 2H), 2.30–2.46 (m, 2H), 2.70 (ddd, J = 2.8, 6.6, 12.2 Hz, 1H),
3.71–3.74 (m, 1H).
Anal. Calcd for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.64; H, 6.51; N, 4.66.
(1R,2S)-2-Amino-cyclopentane-1-carboxylic Acid
Hydrochloride Hemihydrate (12HCl0 5H2O)
With modification of GP-1, the isocyanate solution was added drop-
wise to 8 N aq. HCl (24 mL) at 0 °C and the resulting mixture was
13C NMR (100 MHz, D2O): = 18.2, 18.3, 30.8, 33.7, 42.0, 47.9,
121.3, 125.3, 181.2.
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
1727
MS (EI, 70 eV): m/z (%) = 170 (M++H, 7), 169 (M+, 59), 152 (42),
(2S,3R)-3-exo-(2-Nitro-benzyloxycarbonylamino)-
110 (16), 107 (88), 93 (35), 91 (29), 87 (100).
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylic Acid Methyl Ester
(exo-16b)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1e with 2-nitrobenzyl alcohol. The crude reaction product
was purified by flash chromatography (CH2Cl2–pentane–Et2O,
2:1:1) delivering exo-16b in 65% yield as a white solid.
Anal. Calcd for C9H15NO2 (169.22): C, 63.88; H, 8.93; N, 8.28.
Found: C, 63.52; H, 8.63; N, 8.15.
For analytical data of the corresponding hydrochloric salt see the lit-
erature.31
Mp oil (rac), 79–80 °C (en).
(2S,3R)-3-endo-(4-Methoxy-benzyloxycarbonylamino)-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid Methyl Ester
(endo-16a)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1f with p-anisyl alcohol. The crude reaction product was pu-
rified by flash chromatography (CH2Cl2–pentane–Et2O, 2:1:1)
delivering endo-16a in 62% yield as a colorless oil.
For NMR, IR data and optical rotation see Table 2.
MS (EI, 70 eV): m/z (%) = 281 (33), 249 (1), 136 (100), 128 (3), 120
(2).
Anal. Calcd for C17H18N2O6 (346.33): C, 58.96; H, 5.24; N, 8.09.
Found: C, 58.92; H, 5.27; N, 8.06.
For NMR, IR data and optical rotation see Table 2.
(2S,3R)-3-exo-Phenylethoxycarbonylamino-bicyclo[2.2.1]hept-
5-ene-2-exo-carboxylic Acid Methyl Ester (exo-16c)
MS (EI, 70 eV): m/z (%) = 265 (14), 206 (2), 174 (6), 142 (7), 121
(100), 114 (3).
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1e with phenylethyl alcohol. The crude reaction product
was purified by flash chromatography (pentane–Et2O, 1:1) deliver-
ing exo-16c in 61% yield as a white solid.
Anal. Calcd for C18H21NO5 (331.36): C, 65.24; H, 6.39; N, 4.23.
Found: C, 65.02; H, 6.59; N, 4.61.
(2S,3R)-3-endo-(2-Nitro-benzyloxycarbonylamino)-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid Methyl Ester
(endo-16b)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1f with 2-nitrobenzyl alcohol. The crude reaction product
was purified by flash chromatography (CH2Cl2–pentane–Et2O,
2:1:1) delivering endo-16b in 67% yield as a pale yellow oil.
Mp oil (rac), 74 °C (en).
For NMR, IR data and optical rotation see Table 2.
MS (EI, 70 eV): m/z (%) = 251 (8), 250 (52), 218 (2), 128 (1), 105
(100), 104 (76).
Anal. Calcd for C18H21NO4 (315.36): C, 68.55; H, 6.71; N, 4.44.
Found: C, 68.33; H, 6.90; N, 4.44.
For NMR, IR data and optical rotation see Table 2.
N-Boc Protected Amino Acid Esters; General Procedure (GP-2)
With modification of GP-1, the isocyanate solution was added drop-
wise to 8 N aq. HCl (12 mL) at 0 °C. The resulting mixture was
stirred at r.t. for 1 h, carefully neutralized with Na2CO3, and extract-
ed with CH2Cl2. The combined organic layers were dried (MgSO4),
filtered, and concentrated providing the corresponding free amino
acid ester as a viscous oil. The crude product was dissolved in dry
CH2Cl2 (10 mL) and treated with Et3N (1.4 mL, 10 mmol) and
(Boc)2O (2.18 g, 10 mmol). The mixture was stirred at r.t. for 12 h.
Evaporation of the solvent yielded an oily residue, which was puri-
fied by column chromatography to give the corresponding Boc-pro-
tected amino methyl ester.
MS (EI, 70 eV): m/z (%) = 281 (35), 249 (2), 136 (100), 128 (4), 96
(4).
Anal. Calcd for C17H18N2O6 (346.33): C, 58.96; H, 5.24; N, 8.09.
Found: C, 59.22; H, 5.44; N, 8.10.
(2S,3R)-3-endo-Phenylethoxycarbonylamino-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid Methyl Ester
(endo-16c)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1f with phenylethyl alcohol. The crude reaction product was
purified by flash chromatography (pentane–Et2O, 1:1) delivering
endo-16c in 60% yield as a colorless oil.
(2S,3R)-3-endo-(tert-Butyloxycarbonylamino)-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic Acid Methyl Ester
(endo-16d)
Synthesized from dicarboxylic acid monoester 1f according to GP-
2. The crude reaction product was purified by flash chromatography
(pentane–EtOAc, 3:1) delivering endo-16d in 65% yield as a white
solid.
For NMR, IR data and optical rotation see Table 2.
MS (EI, 70 eV): m/z (%) = 284 (2), 250 (100), 218 (3), 105 (42), 104
(21), 91 (5).
Anal. Calcd for C18H21NO4 (315.36): C, 68.55; H, 6.71; N, 4.44.
Found: C, 68.54; H, 6.50; N, 4.84.
Mp 55 °C (rac), 65 °C (en) [Lit.: 36 mp 54–55 °C (rac)].
(2S,3R)-3-exo-(4-Methoxy-benzyloxycarbonylamino)-
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylic Acid Methyl Ester
(exo-16a)
Synthesized according to GP-1 by reaction of dicarboxylic acid mo-
noester 1e with p-anisyl alcohol. The crude reaction product was
purified by flash chromatography (CH2Cl2–pentane–Et2O, 2:1:1)
delivering exo-16a in 64% yield as a colorless oil.
For optical rotation and NMR, IR data see Table 2, for MS data see
reference 36.
Anal. Calcd for C14H21NO4 (267.31): C, 62.90; H, 7.92; N, 5.24.
Found: C, 62.68; H, 8.31; N, 5.18.
(2S,3R)-3-exo-(tert-Butyloxycarbonylamino)-
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylic Acid Methyl Ester
(exo-16d)
For NMR, IR data and optical rotation see Table 2.
MS (EI, 70 eV): m/z (%) = 265 (21), 221 (4), 121 (100), 91 (2).
Synthesized from dicarboxylic acid monoester 1e according to GP-
2. The crude reaction product was purified by flash chromatography
(pentane–EtOAc, 3:1) delivering exo-16d in 68% yield as a white
solid.
Anal. Calcd for C18H21NO5 (331.36): C, 65.24; H, 6.39; N, 4.23.
Found: C, 64.93; H, 6.44; N, 4.57.
Mp 115–117 °C (rac), 69 °C (en) [Lit.: 36 mp 110–112 °C (rac)].
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

1728
C. Bolm et al.
SPECIAL TOPIC
For optical rotation and NMR, IR data see Table 2, for MS data see
reference 36.
[ ]D +148.8 (c 1.71, CHCl3).
ee = 99% (after recrystallization from petroleum ether–Et2O only a
single enantiomer of 26 was detected by HPLC) [HPLC-analysis:
Chiracel OD-H at r.t., n-heptane–2-PrOH (95:5), 0.7 mL/min, 254
nm, t1 = 13.4 min (major), t2 = 18.8 min].
Anal. Calcd for C14H21NO4 (267.31): C, 62.90; H, 7.92; N, 5.24.
Found: C, 62.74; H, 7.94; N, 5.17.
Enantiomer Differentiating Opening of Cyclic Racemic
Anhydrides; General Procedure (GP-3)
For NMR and IR data see Table 3.
MS (EI, 70 eV): m/z (%) = 272 (1), 231 (6), 176 (5), 170 (23), 169
(44), 152 (33), 125 (54), 105 (17), 91 (100).
MeOH (1.22 mL, 30 mmol) was added dropwise to a stirred suspen-
sion of the anhydride (10 mmol) and quinidine (3.57 g, 11 mmol) in
a mixture of toluene and CCl4 (1:1, 50 mL) at –55 °C under Ar. The
reaction mixture was stirred at this temperature for 60 h. During this
period, the material gradually dissolved. Subsequently, the resulting
clear solution was concentrated in vacuo to dryness and the result-
ing residue was then dissolved in EtOAc. The solution was washed
with 2 N HCl and after phase separation, followed by extraction of
the aqueous phases with EtOAc. The organic layer was dried
(MgSO4), filtered and concentrated providing a mixture of the re-
gioisomeric dicarboxylic acid monoesters. Following GP-1 and us-
ing benzyl alcohol, these esters were converted to a mixture of the
corresponding Cbz-protected amino acid esters, which were sepa-
rated by column chromatography.
Anal. Calcd for C17H21NO4 (303.35): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.02; H, 7.11; N, 4.69.
(1S,5R,6R)-6-Benzyloxycarbonylamino-5-methylcyclohex-3-
ene-1-carboxylic Acid Methyl Ester (27)
As described above, chromatography delivered 27 in 67% yield
(based on the amount of the corresponding enantiomer of the anhy-
dride in the racemic starting material) as a colorless oil.
[ ]D 15.8 (c 1.78, CHCl3).
ee = 91% [HPLC-analysis: Chiracel OD at r.t., n-heptane–2-PrOH
(98:2), 0.5 mL/min, 254 nm, t1 = 22.8 min, t2 = 28.4 min (major)].
For NMR and IR data see Table 3.
MS (EI, 70 eV): m/z (%) = 303 (M+, 8), 272 (3), 236 (5), 175 (9),
174 (12), 152 (29), 108 (10), 91 (100).
(1S,2R,6R)-2-Benzyloxycarbonylamino-6-methylcyclohexane-
1-carboxylic Acid Methyl Ester (23)
Synthesized from racemic anhydride 20 according to GP-3. The
crude regioisomeric amino esters 23 and 24 were separated by flash
chromatography (petroleum ether–EtOAc, 95:5) delivering 23 in
72% yield (based on the amount of the corresponding enantiomer of
the anhydride in the racemic starting material) as a white solid.
Anal. Calcd for C17H21NO4 (303.35): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.55; H, 6.97; N, 4.63.
Acknowledgement
Mp oil (rac), 51.5 °C (en).
[ ]D 29.6 (c 1.01, CHCl3) {Lit.:44b [ ]D 26.9 (c 1.02, CHCl3)}.
We thank the Deutsche Forschungsgemeinschaft (DFG) within the
Collaborative Research Center (SFB) 380 “Asymmetrische Synthe-
se mit chemischen und biologischen Methoden” and the Fonds der
Chemischen Industrie for financial support of this work. L. D. ack-
nowledges the Alexander von Humboldt Foundation for a postdoc-
toral fellowship. We also thank Alexandra Büchel, Nicole
Brendgen and Markus Reichelt for experimental contributions.
ee = 84% (98.9% ee after recrystallization from petroleum ether–
Et2O) [HPLC-analysis: Chiralpak AS at r.t., n-heptane–2-PrOH
(97:3), 0.6 mL/min, 254 nm, t1 = 15.0 min (major), t2 = 24.6 min].
For NMR, IR data see Table 3, for MS data see reference 44b.
(1S,2R,3S)-2-Benzyloxycarbonylamino-3-methylcyclohexane-
1-carboxylic Acid Methyl Ester (24)
As described above, chromatography delivered 24 in 52% yield
(based on the amount of the corresponding enantiomer of the anhy-
dride in the racemic starting material) as a white solid.
References
(1) Review: Drey, C. N. C. In Chemistry and Biochemistry of
Amino Acids, Peptides and Proteins, Vol. 4; Weinstein, B.,
Ed.; Marcel Dekker: New York, 1977, 242.
Mp oil (rac), 53 °C (en).
(2) Review: Cole, D. C. Tetrahedron 1994, 50, 9517.
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Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L.
J. Am. Chem. Soc. 1995, 117, 1225.
[ ]D +61.5 (c 1.12, CHCl3).
ee = 93% (99.8% ee after recrystallization from petroleum ether–
Et2O) [HPLC-analysis: Chiracel OD-H at r.t., n-heptane–2-PrOH
(99:1), 0.7 mL/min, 254 nm, t1 = 13.7 min (major), t2 = 16.7 min].
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For NMR and IR data see Table 3.
MS (EI, 70 eV): m/z (%) = 305 (M+, 5), 273 (7), 204 (13), 170 (19),
160 (26), 108 (25), 91 (100).
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Anal. Calcd for C17H23NO4 (305.37): C, 66.86; H, 7.59; N, 4.59.
Found: C, 66.95; H, 7.33; N, 4.88.
(1S,2S,6R)-6-Benzyloxycarbonylamino-2-methylcyclohex-3-
ene-1-carboxylic Acid Methyl Ester (26)
(6) Review: Georg, G. I. Bioorg. Med. Chem. Lett. 1993, 3,
2135.
Synthesized from racemic anhydride 25 according to GP-3. The
crude regioisomeric amino esters 26 and 27 were separated by flash
chromatography (CH2Cl2–EtOAc–pentane, 10:1.4:1) delivering 26
in 65% yield (based on the amount of the corresponding enantiomer
of the anhydride in the racemic starting material) as a white solid.
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Mp 98.5 °C (rac), 118 °C (en).
Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Efficient Asymmetric Synthesis of Unnatural -Amino Acids
1729
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= 289.33, colorless crystal 0.3 0.3 0.3 mm, a = 5.3448(3),
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b = 15.878(2), c = 17.199(3) Å, V = 1459.6(8) Å3,
=
calcd
1.317 gcm–1, = 7.39 cm–1, Z = 4, orthorhombic, space
group P212121 (No. 19), = 1.54179 Å, T = 180 K, /2
scans, 3666 reflections collected, 3013 independent and
2371 observed reflections [I
2 (I)], 266 refined
parameters, R1 = 0.057, wR2 = 0.052, residual electron
density –0.35/0.39 eÅ–3, hydrogens located and refined
isotropically.
(24) (a) Bondi, A. J. Phys. Chem. 1964, 68, 441. (b) Allinger, N.
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(26) In the syntheses of S-1452 metabolites, ent-10 is a key
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K.; Ohtani, M. Chem. Pharm. Bull. 1991, 39, 2842.
(27) (a) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993,
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Tetrahedron: Asymmetry 1996, 7, 1789. (f) Theil, F.;
Ballschuh, S. Tetrahedron: Asymmetry 1996, 7, 3565.
(g) Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A.
G.; Wisdom, R. J. Chem. Soc., Perkin Trans. 1 1991, 2276.
(29) Attempts to hydrolyse the ester moiety of ent-2 under basic
conditions led to epimerization.
(30) Harmat, N. J. S.; Di Bugno, C.; Criscuoli, M.; Giorgi, R.;
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(19) Alternatively, the enantiomerically enriched dicarboxylic
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hydrolysis of meso-diesters. For a recent review, see:
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(32) MOZ = 4-MeO-C6H4CH2CO2-; (2-NO2)-Z = 2-NO2-
C6H4CH2CO2-; hZ = C6H5CH2CH2CO2-.
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calcd
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= 1.281 gcm–1, = 7.45 cm–1, Z = 4, orthorhombic, space
group P212121 (No. 19), = 1.54179 Å, T = 150 K, /2
scans, 3884 reflections collected, 3236 independent and
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2924 observed reflections [I
2 (I)], 199 refined
parameters, R1 = 0.064, wR2 = 0.085, residual electron
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at 1.5 times U of the relevant Leavy atoms prion to final
refinement of the heavy atoms not refined.
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Synthesis 2001, No. 11, 1719–1730 ISSN 0039-7881 © Thieme Stuttgart · New York