Synthesis and stereostructure of 3-amino-5- and -6-hydroxybicyclo[2.2.1] heptane-2-carboxylic acid diastereomers

Article abstract of DOI:10.1007/s00706-005-0369-9

All-endo-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid and two epimers of 3-amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid were prepared via 1,3-oxazine or γ-lactone intermediates by the stereoselective functionalization of endo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. Their structures were proved by IR and NMR spectroscopy, with the use of HMQC, HMBC, DEPT, and DIFFNOE techniques. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-005-0369-9

Monatshefte f €u r Chemie 136, 2051–2058 (2005)
DOI 10.1007/s00706-005-0369-9
Synthesis and Stereostructure of 3-Amino-
5- and -6-hydroxybicyclo[2.2.1]heptane-2-
carboxylic Acid Diastereomers
1
1
2
1;ꢀ
M a´ rta Palk o´ , Elvira S a´ ndor , P a´ l Soh a´ r , and Ferenc F u¨ l o¨ p
1
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701, POB 121, Hungary
Research Group for Structural Chemistry and Spectroscopy, Hungarian Academy
of Sciences and Institute of General and Inorganic Chemistry, E €o tv €o s L ꢀo r a´ nd
University, H-1518 Budapest, POB 32, Hungary
2
Received February 15, 2005; accepted (revised) March 23, 2005
Published online September 28, 2005 # Springer-Verlag 2005
Summary. All-endo-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid and two epimers of 3-
amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid were prepared via 1,3-oxazine or ꢀ-lactone
intermediates by the stereoselective functionalization of endo-3-aminobicyclo[2.2.1]hept-5-ene-2-car-
boxylic acid derivatives. Their structures were proved by IR and NMR spectroscopy, with the use of
HMQC, HMBC, DEPT, and DIFFNOE techniques.
Keywords. Amino acids; Heterocycles; IR spectroscopy; NMR spectroscopy; Cyclization.
Introduction
During the past decade considerable attention has been directed towards the synthe-
sis of hydroxy-ꢁ-amino acids [1–6]. These compounds constitute an important
class of amino acids, because of their occurrence in many biologically relevant
compounds, including Paclitaxel (Taxol) and Docetaxel (Taxotere), which are
among the most effective chemotherapeutic agents [7, 8]. The alicyclic hydroxy-
ꢁ
-amino acids can be used as building blocks for the preparation of modified
analogues of biologically active peptides [9, 10]. Hydroxylated alicyclic ꢁ-amino
acids and their derivatives can be widely used for the synthesis of various hetero-
cyclic compounds [11–17]. Our present aim was the synthesis and structure anal-
ysis of the title hydroxylated alicyclic ꢁ-amino acids.
Results and Discussion
The key step in the synthesis of all-endo-3-amino-6-hydroxybicyclo[2.2.1]heptane-
2
-carboxylic acid (4) was the stereoselective iodolactonization [15] of N-Boc-
ꢀ Corresponding author. E-mail: fulop@pharm.u-szeged.hu

2
052
M. Palk o´ et al.
Scheme 1
endo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1). The iodolactoniza-
tion was performed under two-phase conditions, furnishing iodolactone 2,
which was reduced with Bu SnH to give lactone 3. The N-Boc lactone was
3
converted to the all-endo isomer of hydroxy-amino acid 4 by acidic hydrolysis
(
Scheme 1).
When N-acetylamino ester 5 was reacted with N-iodosuccinimide [16] (NIS) or
N-bromosuccinimide (NBS) a tricyclic 1,3-iodo- or -bromooxazine derivative (6a
or 6b) was obtained stereoselectively. When dehalogenated with Bu SnH under
an argon atmosphere, 6a or 6b yielded 7. The hydrolysis of oxazine 7 with dilute
3
Scheme 2

3
-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid
2053
hydrochloric acid at room temperature gave N-acetyl-hydroxy amino acid 8. When
8
was boiled in acidic solution, endo ! exo isomerization took place and the
forced conditions resulted in 3,5-di-endo-2-exo-3-amino-5-hydroxybicyclo[2.2.1]
heptane-2-carboxylic acid hydrochloride (9) as the main product. The mother
liquor was treated with a large excess of propylene oxide and, after fractional
crystallisation, compound 10 was isolated as a diastereomerically enriched (8:2)
mixture (Scheme 2). The correct configurations of hydroxylated amino acids 9
a
Table 1. Characteristic IR frequencies and H NMR data for compounds 2–5, 7–9, and 11
1
b
c
d
e
f
g
g
h
Compound Amide-I band ꢂC¼O band CH s(9H) CH t(3H) CH qa(2H) NH broad
3
3
2
r
2
3
4
5
7
8
9
1
1688
1693
–
1788
1775
1763
1730
1733
1732
1714
1732
1.44
1.42
–
–
–
–
–
–
–
4.15
4.81
4.67
6.4
r
1654
1676
1680
–
1.86
1.86
2.35
–
1.20
1.24
–
4.04
4.10
–
–
12.9
–
–
ꢁ12.6
ꢁ7.9
1
–
–
1.21
4.10
Compound
Norbornane=ene moiety
i
k
0
l
0
m
n
o
r
p
H–1
H–2
H–3
H–4
H–5
H–6
CH (7)
2
r
2
3
4
5
7
8
9
3.24
3.24
3.40
3.10
2.08
2.80
2.78
2.95
3.13
3.02
3.25
4.15
4.11
3.82
4.72
4.03
4.24
3.76
3.77
2.90
2.56
2.63
3.10
2.35
ꢁ4.9
5.17
4.81
5.01
6.27
1.94, 2.34
1.58, 1.73
1.70, 1.77
1.35, 1.45
1.41, 1.48
1.53, 1.64
1.26, 1.33
1.27, 1.33
ꢁ1.75
1.82, 1.90
r
r
r
r
6.14
4.55
5.21
4.35
4.35
2.02, 2.19
1.75, 2.20
1.22, 2.05
1.23, 2.07
ꢁ2.45
2.36
ꢁ2.45
r
r
2.54
2.59
2.52
2.54
1
1
2.35
a
ꢂ1
In KBr discs (cm ); further bands, ꢂOH band: ꢁ3345 (9), 3460 (11), ꢂNH band: ꢁ3230 (2), 3247
þ
(
(
3), 3318 (5), coalesced ꢂOH (acidic & alcoholic) and=or ꢂN H bands: 3250–2250 (4), 3600–3250
3
8), 3500–2500 (9, 11), ꢂC–O: 1014 (2), 1167 (3), 1108 (4), 1182 and 1047 (5), 1184 and 1060 (7),
b
185 and 1155 (11); in CDCl solution (D O for 4 and DMSO-d for 8, 9, and 11) at 500 MHz;
1
3
2
6
c
chemical shifts in ppm (ꢃTMS ¼ 0 ppm), coupling constants in Hz; assignments were supported by
HMQC (except for 2), for 5, 7, 9, and 11 by HMBC, and for 8 and 11 also by DIFFNOE measurements;
d
e
urethane group (2, 3), ꢂC¼N band (7); COOH (1, 4, 8, and 9), lactone (2 and 3), COOEt (5, 7, and
f
1); 3H (5, 7, and 8); ethyl group, J: 7.1; Intensity 1H (2, 3, 5, and 9), 2H (8), coalesced signal of
g
h
1
þ
the acidic protons and the solvent (4), or the amide-NH and COOH (8), or the OH and NH3 groups
k
(
i
11), d (J: 6.5, 5); ꢁt (2, 4, and 7), ꢁs (9) with coalesced lines, t (J: 4.7 for 3), d (J: 4.5 for 11); dd,
l
J: 10.3 and 4.7 (2–4), ꢁdd (5), ddd (7), td (8) with coalesced lines, d, J: 4.3 (9), 5.1 (11); broad m (2),
m
ꢁ
t(3), ꢁd, J: 9.3 (4), 4.3 (9), dt, J: 8.9 ad 3.5 (5), m (7, 8, and 11); signals with coalesced lines, m (2,
n
5
, and 8), ꢁs (3, 4, and 9), ꢁ t (7 and 11); broad m (1H) for 2 and 7–9, dd, J: 5.6 and 2.9 (5), m (2H)
o
for 3, 2ꢃm (2ꢃ1H) for 4, m for 11; d (1H), J: 5.0 (2), m (2H, 3), t (1H), J: 6.3 (4), dd (1H), J: 5.6
p
and 3.0 (5), 2ꢃm (2ꢃ1H, 7–9, and 11); AB-type multiplet, 2ꢃd (2ꢃ1H), J: 11.8 (2 and 4), 11.2 (3),
9
.0 (5), 10.8 (7 and 8), ꢁ10 (9), 11.5 (11), further split by long-range couplings of downfield=upfield d
, r
to td (2=7), both doublets to dd (9) and downfield d to m (7 and 8), respectively; overlapping signals

2
054
M. Palk o´ et al.
and 10 were proved indirectly. The stereostructures of 8 and 11 being demonstrated
using the DIFFNOE technique and also by chemical transformation: esterification
of 9 led to hydroxylated amino ester 11, whereas after acetic acid treatment 10
gave an N-acetyl derivative. The NMR spectrum of the resulted compound was
identical with that of all-endo-3-acetylamino-5-hydroxybicyclo[2.2.1]heptane-2-
carboxylic acid (8).
The constitutions and stereostructure of the new compounds 2–5 and 7–11
1
13
were determined by IR, H, and C NMR spectroscopy. The spectral data are
self-explanatory; only a few additional remarks are necessary. It should be noted
that, for easier comparison of analogous spectral data, the numbering of 1 given in
Scheme 1 will be used for all compounds in this section and also in the experi-
mental part.
1
) The di-endo arrangement of the 2,3-substituents in 2–5, 7, and 8 follows from
ꢄ
our ‘‘splitting rule’’ [17, 18]. In consequence of the dihedral angles of ca. 90 ,
the 1,2- and 3,4-vicinal H,H-couplings do not cause double spliting of the H–2
and H–3 signals in the di-exo compounds, whereas these couplings lead to a
well-detectable split by 2–4 Hz in the case of the di-endo anellated molecules,
1
Table 2. C NMR chemical shifts of compounds 2–5, 7–9, and 11
3
a
b
c
d
e
f
Compound
CH3
CH2
Cquat or CH3
OC¼O
C¼O or C¼N
2
3
4
5
7
8
9
28.7
28.7
–
–
81.0
80.4
–
176.6
178.1
179.9
173.8
172.2
172.0
174.8
173.5
155.8
155.9
–
–
–
14.5
14.7
–
60.9
60.3
–
23.8
21.9
19.9
–
170.1
156.6
171.1
–
–
–
1
1
14.9
61.5
–
–
g
Norbornane=ene moiety
Compound
C–1
C–2
C–3
54.6
C–4
C–5
C–6
CH (7)
2
2
3
4
5
7
8
9
51.4
47.8
48.4
47.6
34.5
34.7
42.7
42.8
41.8
43.4
42.1
47.7
50.1
48.9
51.3
51.2
48.2
40.7
39.7
47.4
36.8
36.9
43.3
43.3
24.5
32.5
31.1
134.3
73.4
79.3
72.6
72.5
89.6
81.1
35.6
35.6
35.3
48.0
37.9
36.1
35.2
35.2
54.1
53.9
52.5
50.3
46.1
54.7
54.8
83.1
137.6
33.2
32.6
40.2
40.1
h
h
h
h
h
1
1
a
In ppm (ꢃTMS ¼ 0 ppm) at 125.7 MHz, solvent: CDCl (for 4 D O, for 8, 9, and 11 DMSO-d );
3
2
6
b
assignments were supported by DEPT, HMQC (except for 2), and for 5, 7, 9, and 11 also by HMBC
c
measurements; t-butyl (2, 3) or ethyl (5, 7, and 11); quaternary carbon (t-butyl, 2 and 3), methyl
d
e
acetyl, 5 and 8 or oxazoline 7); lactone (2, 3), carboxyl (4, 8, and 9), ester (5, 7, and 11);
(
f
g
carbamoyl (2, 3), amide (5, 8), C¼N for 7; for the numbering used in tables and in the spectro-
h
scopic part of the text, see 1 (Scheme 1); interchangeable assignments

3
-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid
2055
ꢄ
where the dihedral angles are ca. 30 . Hence, as a consequence of the H–2, H–3
interaction, H–2 and H–3 exhibit doublets in the di-exo derivatives and double
doublet signals in the di-endo analogues. The H–2,3 coupling results in a
ꢄ
7
ellated compounds [17], while this coupling constant is expected to be smaller
–11 Hz split due to the dihedral angle of 0 for the di-endo and di-exo an-
ꢄ
(
ca. 4–6 Hz) for exo–endo derivatives [19], where the dihedral angle is ca. 109 .
Thus, the dd (2–4), dt (5), ddd (7), or td (8) split of the H–2 (2–5) or H–3 (7, 8)
signal confirms the 2,3-di-endo configuration. Higher than dd splits are due to
1
3
couplings with the NH (5) or H–7 (exo) (7, 8). The similar C NMR chemical
shifts in 3 and 4 demonstrate the unaltered all-endo orientation of the three
substituents in 4 as compared with 3.
1
In the H NMR spectrum of 9, the H–2 and H–3 signals are doublets, split by
4
.3 Hz, and consequently this molecule must have the endo–exo configuration. In
accordance, the C–1 and C–4 chemical shifts in 9 are dramatically higher (by
.0 and 8.6ppm) because of the absence of a field effect [20] causing opposite
8
shifts to those in 8, due to very strong hindrance between the three endo sub-
stituents. Hence, during the acidic hydrolysis of 8, endo ! exo isomerisation
occurred, probably in position 2, via the enolic form of the carboxyl group.
1
3
The practically identical C NMR chemical shifts of 9 and 11 confirm
analogous stereostructures for these molecules. For 11, DIFFNOE measure-
ments unambiguously proved the 2-exo-3-endo configuration. On saturation
of the H–2 doublet (at 2.59 ppm), for example the H–6(exo) signal (at
1.24 ppm) responded, while for the H–7(endo) signal an intensity enhancement
was not observed. The DIFFNOE measurements together with the HMQC and
HMBC spectra also furnished proof of the assignments.
1
3
2
) In the C NMR spectrum of 2 the very characteristic upfield-shifted line of
iodo-substituted carbon (C–5) [20] appears at 24.5 ppm. The ꢁ-effect of the
iodo substituent [20] is revealed in a downfield shift by 7.5 and 8.5 ppm of
the C–4 and C–6 lines as compared with 3. An anisotropic neighbouring
deshielding effect of the iodine atom is also observable on the H–7 signals in
1
the H NMR spectrum, which are downfield-shifted in 2 (by 0.36 and 0.61 ppm)
as compared with 3. This supports the ab ovo more probable exo position
of the iodine atom [to avoid the steric interaction between 2(endo)-I and
O–4(endo)].
1
3
4
5
) The H NMR signal (a singlet of 9H intensity) of the methyl group and its car-
1
3
bon line in C NMR spectrum, together with the line of the quaternary carbon
atom, are proof of the presence of the t-But group in 2 and 3.
) The position of the hydroxy group in 4 follows from the structures of 2 and 3
containing a ꢀ-lactone ring, the presence of which is proven by the high IR
ꢂ1
carbonyl frequency [23] (1788 and 1775 cm in 2 and 3).
1
13
) In the spectra of 5, 7, and 11 all the IR, H, and C NMR signals of the COOEt
group appear and the rigid structure of 7 results in a series of long-range
couplings, which lead to higher multiplicities of all signals observed in this
case only in the H NMR spectrum.
) The downfield shift of the methyl (Ac) signal (by 0.49 ppm) in the H NMR
1
1
6
spectrum of 8 relative to 5 is noteworthy; this is caused by the anisotropic effect
[
20] of the endo-OH group.

2
056
M. Palk o´ et al.
Experimental
Melting points were determined on a Kofler micro melting point apparatus. Elemental analyses were
conducted with a Perkin-Elmer CHNS-2400 Ser II Elemental Analyser; the results were found to be in
good agreement (ꢅ0.2%) with the calculated values. Merck Kieselgel 60F plates were used for
2
54
1
13
TLC: the eluent was toluene:MeOH¼ 4:1. The H and C NMR spectra were recorded in CDCl
3
1
solution in 5 mm tubes at room temperature, on a Bruker DRX 500 spectrometer at 500.13 ( H) and
1
25.76 ( C) MHz, with the deuterium signal of the solvent as the lock and TMS as internal standard.
3
1
ꢄ
DEPT spectra were run in a standard manner, using only the Y ¼ 135 pulse to separate CH=CH and
3
CH lines phased ‘‘up’’ and ‘‘down’’. The HMQC and HMBC spectra were obtained by using the
2
standard Bruker pulse programs.
ꢀ
carboxylic acid (1) [22]
ꢀ
ꢀ
ꢀ
(
1S ,2R ,3S ,4R )-3-tert-Butoxycarbonylaminobicyclo[2.2.1]hept-5-ene-2-
3
To a solution of 3.1 g 3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid (20 mmol) [23] in 60 cm
3
of a 2:1 dioxane:H O mixture 20 cm 1 M NaOH were added. The solution was cooled to 0 C in an
ꢄ
2
ꢄ
ice bath and di-tert-butyl dicarbonate was added slowly. The mixture was stirred at 0 C for 30 min
3
and then warmed to room temperature and stirred for 4 h. The solvent was concentrated to 20 cm
on a rotatory evaporator, the pH was then adjusted to 2.5 with 10% H SO , and the resulting
2
4
3
solution was extracted with EtOAc (3ꢃ50 cm ). The combined extracts were dried (Na SO ), and
2
4
evaporated, to give 1 as a white solid, which was recrystallized from iPr O. Yield 3.59 g (75%);
2
ꢄ
ꢄ
mp 183–187 C (Ref. [24] 126–127 C).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
;7
ꢀ
(
1S ,2S ,3S ,6R ,7R ,9S )-9-tert-Butoxycarbonylamino-2-iodo-4-
3
oxatricyclo[4.2.1.0 ]nonan-5-one (2, C H INO )
1
3
18
4
3
3
To a solution of 2.25 g 1 (11.5 mmol) in 100 cm CH Cl , 70 cm NaHCO solution (0.5 N), 11.62 g KI
2
2
3
ꢄ
70 mmol), and 5.84g I (23 mmol) were added at 0 C. The reaction mixture was stirred at room
2
(
3
temperature for 20 h and then poured into 50 cm 10% aqueous Na S O solution. The reaction
2
2 3
3
3
mixture was extracted with 3ꢃ20 cm CH Cl and the combined extract was washed with 20cm
2
2
brine, dried (Na SO ), and evaporated. The residue was recrystallized from iPr O. Yield 3.66 g (84%);
2
4
2
ꢄ
mp 183–187 C.
ꢀ
ꢀ
ꢀ
ꢀ
-one (3, C H NO )
ꢀ
3;7
(
1R ,3R ,6R ,7R ,9S )-9-tert-Butoxycarbonylamino-4-oxatricyclo[4.2.1.0 ]nonan-
5
1
3
19
4
3
Bu SnH (4.8 cm , 18 mmol) was added to a solution of 4.41 g iodolactone 2 (9 mmol) in 65 cm
3
3
ꢄ
dry CH Cl under Ar. After stirring for 20 h, at 40 C, the solvent was evaporated and the resi-
2
2
due was crystallized from n-hexane, and recrystallized from iPr O-EtOAc. Yield 1.26 g (55%);
2
ꢄ
mp 145–150 C.
ꢀ
hydrochloride (4, C H ClNO )
ꢀ
ꢀ
ꢀ
ꢀ
(
1R ,2R ,3S ,4R ,6R )-3-Amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid
8
14
3
3
Compound 3 (1.01 g, 4 mmol) was dissolved in 20 cm aqueous HCl (20%) and the solution was stirred
at room temperature for 10h. The solvent was next evaporated and the residue was recrystallized from
ꢄ
H O-acetone. Yield 0.70 g (84%); mp 220–222 C.
2
ꢀ
17
ꢀ
ꢀ
ꢀ
Ethyl (1S ,2R ,3S ,4R )-3-acetylaminobicyclo[2.2.1]hept-5-ene-2-carboxylate
5, C H NO )
(
1
2
3
To a suspension of 2.17 g ethyl 3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylate hydrochloride [25]
3
10 mmol) in 40 cm toluene, 2.04g triethylamine (20mmol), and 0.94 g acetyl chloride (12 mmol)
(
were added and the reaction mixture was stirred at room temperature for 2 h, and then washed with
3
3
2
ꢃ10 cm H O. The aqueous layer was extracted with 3ꢃ20cm EtOAc. The combined organic layer
2

3
-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid
2057
was dried (Na SO ) and evaporated. The residue was recrystallized from n-hexane-iPr O. Yield 1.67g
2
4
2
ꢄ
(
75%); mp 64–67 C.
Ethyl (1R ,2R ,3R ,7S ,8R ,10R )-2-iodo-5-methyl-4-oxa-6-azatricyclo[5.2.1.03;8]dec-
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5
-ene-10-carboxylate (6a, C H INO ) and Ethyl(1R ,2R ,3R ,7S ,8R ,10R )-2-bromo-
12 16 3
5
-methyl-4-oxa-6-azatricyclo[5.2.1.03 ]dec-5-ene-10-carboxylate (6b, C H BrNO )
3
A solution of 1.67 g 5 (7.5mmol) in 80cm CH Cl was treated with 1.68 g N-iodosuccinimide
;8
1
2
16
3
2
2
(
7.5mmol) or 1.34 g NBS (7.5mmol) and subsequently stirred for 14h at room temperature. When
3
the reaction was completed, the mixture was washed with 3ꢃ10cm 10% NaOH solution. The aqueous
3
solution was extracted with 3ꢃ40 cm CH Cl the organic phase was dried (Na SO ), and evaporated.
2
2,
2
4
The oily products (6a: 1.92 g (73%); 6b: 2.07 g (91%)) were sensitive to air; they were therefore used
without purification in the next step.
ꢀ
ꢀ
carboxylate (7, C H NO )
ꢀ
ꢀ
ꢀ
3;8
Ethyl (1S ,3S ,7S ,8S ,10R )-5-methyl-4-oxa-6-azatricyclo[5.2.1.0 ]dec-5-ene-10-
1
2
17
3
3
Bu SnH (2.9 cm , 11mmol) was added to a solution of iodo- or bromooxazine 6a or 6b (5.5mmol) in
ꢄ
5cm dry CH Cl under Ar. After stirring for 20 h at 40 C, the solvent was evaporated and the residue
2 2
3
3
6
was purified by column chromatography on silica gel (n-hexane:EtOAc¼ 10:1) to afford 7 as an oil
(0.82 g (67%) from 6a; and 0.84 g (69%) from 6b).
ꢀ
ꢀ
ꢀ
ꢀ
carboxylic acid (8, C H NO )
ꢀ
(
1S ,2R ,3S ,4S ,5R )-3-Acetylamino-5-hydroxybicyclo[2.2.1]heptane-2-
1
0
15
4
3
A solution of 0.67g 7 (3mmol) in 20 cm 20% aq. HCl was stirred for 2 h. The solvent was then
evaporated to afford crude 8, which was recrystallized from H O-acetone. Yield 0.51g (80%);
2
ꢄ
mp 225–235 C (dec).
ꢀ
ꢀ
ꢀ
ꢀ
hydrochloride (9, C H ClNO )
ꢀ
(
1S ,2S ,3S ,4S ,5R )-3-Amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid
8
14
3
3
A solution of 0.4 g 8 (1.8mmol) in 20cm 20% aq. HCl was refluxed for 30h. The solvent was
then evaporated to afford crude 9, which was recrystallized from EtOH-Et O. Yield 0.21g (55%);
2
ꢄ
mp 240–245 C (dec).
ꢀ
ꢀ
ꢀ
10, C H NO )
ꢀ
ꢀ
(
1S ,2R ,3S ,4S ,5R )-3-Amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid
(
8
13
3
The mother liquor of 9 was evaporated and the residue was dissolved in dry EtOH. To this
solution, 10 equivalents of propylene oxide were added. After stirring and refluxing for 2 h the
mixture was evaporated to afford a mixture of 10:9 ¼ 8:2 as solid crystals. Yield 0.1 g (32%);
ꢄ
mp 230–235 C (dec).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
hydrochloride (11, C H ClNO )
Ethyl (1S ,2R ,3S ,4S ,5R )-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylate
1
0
18
3
3
3
ꢄ
Thionyl chloride (0.5cm , 7 mmol) was added dropwise with stirring to 5 cm dry EtOH at ꢂ15 C. To
ꢄ
this mixture 0.21 g 9 (1mmol) were added in one portion, which was then stirred for 30 min at 0 C.
After standing for 3 h at room temperature, the mixture was refluxed for a further 1 h and then
ꢄ
evaporated. The residue was recrystallized from EtOH-Et O. Yield 0.22 g (93%); mp 210–211 C.
2
Acknowledgements
The authors thank the Hungarian Research Foundation (OTKA grants T-043634, TS-040888, TS-
040732, and TS-44742) for financial support.

2
058
M. Palk o´ et al.: 3-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid
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