Enantioselective synthesis of amino acids from pentacyclo[5.4.0.02,6.03,10.05,9] undecane-8,11-dione

Article abstract of DOI:10.1016/S0040-4020(00)01140-6

Treatment of (+)-pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9] undecane-8-one with sodium cyanide and ammonium carbonate produced an optically active hydantoin of which the 4′-carbonyl group of the hydantoin ring is in the less sterically hindered equatorial position. Hydrolysis of the latter with barium hydroxide produced (-)-8-amino-pentacyclo [5.4.0.0^2,6.0^3,10.0^5,9]undecane-8-carboxylic acid which has the 1S,2R,3R,5R,6R,7S,8R,9R,10R configuration. In a similar way, (+)-6-amino-tetracyclo-[6.2.0.0^4,11.0^5,9] undec-2-ene-6-carboxylic acid with 1R,4R,5R,6R,8S,9S,11R configuration was obtained from (-)-tetracyclo[6.3.0.0^4,11.0^5,9]undec-2-ene-6-one. The latter was obtained from (-)-11-hydroxy-pentacyclo [5.4.0.0^2,6.0^3,10.0^5,9]undecan-8-one.

Full text of DOI:10.1016/S0040-4020(00)01140-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1601±1607
Enantioselective synthesis of amino acids from
pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione
Frans J. C. Martins,a,p Agatha M. Viljoen,a,p Hendrik G. Kruger,a Louis Fourie,a Justus Roscher,a
a
Andre J. Joubert and Philippus L. Wessels
b
Â
aDepartment of Chemistry, Potchefstroom University for CHE, Potchefstroom 2520, South Africa
bDepartment of Chemistry, University of Pretoria, Pretoria 0001, South Africa
Received 11 September 2000; revised 13 November 2000; accepted 30 November 2000
AbstractÐTreatment of (1)-pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8-one with sodium cyanide and ammonium carbonate produced an
optically active hydantoin of which the 40-carbonyl group of the hydantoin ring is in the less sterically hindered equatorial position.
Hydrolysis of the latter with barium hydroxide produced (2)-8-amino-pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8-carboxylic acid which
has the 1S,2R,3R,5R,6R,7S,8R,9R,10R con®guration. In a similar way, (1)-6-amino-tetracyclo-[6.2.0.04,11.05,9]undec-2-ene-6-carboxylic
acid with 1R,4R,5R,6R,8S,9S,11R con®guration was obtained from (2)-tetracyclo[6.3.0.04,11.05,9]undec-2-ene-6-one. The latter was obtained
from (2)-11-hydroxy-pentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-one. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
As part of a programme that is concerned with the synthesis
and chemistry of amino acids with cage carbon structures,
we sought to synthesise novel unsymmetrical a-amino acids
utilising pentacyclo[5.4.0.02,6.03,10,05,9]undecane-8,11-dione
(1) and derivatives thereof. The dione (1) is easily obtained
from the Diels±Alder adduct of cyclopentadiene and
p-benzoquinone by intramolecular photocyclisation.1 The
Strecker reaction would be the obvious method of choice
to convert polycyclic ketones into amino acids.
It was previously shown2 that 1 produces the dihydroxy
lactam derivative 2 upon treatment with one equivalent of
aqueous sodium cyanide. With an excess of sodium cyanide
the cyano hydroxy lactam derivative 3 is obtained,3 whereas
with Strecker reagents (mixture of ammonium chloride,
sodium cyanide and ammonium hydroxide) the amino
hydroxy lactam derivative 4 is produced.3 Attempts2,4 to
convert the mono keto derivatives 5, 6 and 7 into amino
acids via amino nitrile derivatives failed.
2. Results and discussion
In order to minimise steric hindrance it was decided
to
investigate
the
utilisation
of
pentacyclo-
[5.4.0.02,6.03,10.05,9]undecane-8-one (10) as the starting
material for the synthesis of a-amino acids. The ketone 10
can be obtained readily from the dione 1 as a racemic
mixture5 or in the optically active form (1)-106 by enantio-
selective microbial asymmetric reduction of the dione 1
with Baker's yeast7 or by horse liver alcohol dehydro-
genase-catalysed (HLADH catalysed) reduction of 1.6 In
the latter case (2)-8 was reported6 to form in 74% yield,
Keywords: cage compounds; amino acids; stereoselection.
Corresponding authors. Tel.: 118-299-2345; fax: 118-299-2350; e-mail:
chefjcm@puknet.puk.ac.za; cheamv@puknet.puk.ac.za
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01140-6

1602
F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
Scheme 1.
which was then converted into the optically active ketone
(1)-10 as outlined in Scheme 1.6
was argued that the presence of ammonium carbonate
could possibly trap the amino nitrile from the established
equilibrium. In order to verify this possibility, a mixture
of (1)-10, sodium cyanide, ammonium chloride, 25%
ammonia (aq) and ammonium carbonate was kept at 40±
608C for 10 h in a sealed glass tube. Extraction with
dichloromethane rendered a product of which the EI mass
spectrum exhibits a molecular ion at m/z 230, con®rming the
desired hydantoin formation. The infrared spectrum also
clearly shows the presence of two carbonylic absorption
bands at 1760 and 1715 cm21 and two different N±H
stretching vibration absorptions at 3280 and 3205 cm21 of
a hydantoin ring. However, two possible orientations of the
hydantoin ring can be obtained theoretically. The isomers
differ in having the 40-carbon atom of the hydantoin ring
The ef®ciency of this conversion was improved to a great
extent by using a more concentrated solution of reactants
and extended reaction times. It was possible to increase the
yield of 8 from the reported6 74% to a quantitative con-
version (95%). Huang±Minlon reduction8 of the latter
produced the alcohol (2)-9 in high yield (89%) compared
to the 68% yield reported6 for a Wolff±Kishner reduction of
(2)-8. Chromium trioxide oxidation of (2)-9 in acetic acid
produced (1)-10 as the sole product.
Although no amino nitrile could be isolated from a con-
ventional Strecker reaction on the monoketone (1)-10, it
Table 1. 1H and 13C NMR data of 11
a
dH (ppm)
Proton/carbon
J (Hz)
Db dH (ppm)
dCa (ppm)
1J (Hz)
139.4
145.0
142.1
130.9
.1J (Hz)
Dc dH (ppm)
1
2
3
4a
4s
5
6
7
8
2.838
2.652 q
2.273
1.243 d
1.640 d
2.989
0.45
0.50
0.29
0.28
0.28
35.40 Dm
41.30 D
46.00 Dm
33.82 T
0.13
0.10
0.09
0.08
6.8
10.8 (a,s)
10.8
42.41 Dd
41.19 D
41.40 D
68.52 S(br)
48.15 Dm
42.06 Dm
28.35 DD
139.1
145.0
146.0
8.4
0.16
0.15
0.30
0.07
0.28
0.12
0.15
2.752 q
2.591 t
7.1
6.6
0.58
0.64
9
10
2.324
2.528
1.267 dt
1.450 d
7.566
0.80
0.44
0.44
0.86
141.7
140.2
127.1;132.7
11a
11s
10-NH
30-NH
20-CO
40-CO
8.4, 3.4
13.7 (a,s)
10.525
157.29 S
178.70Sd
1.00
0.82
7.5
500 MHz for 1H and 125 MHz for 13C.
a
Solvent CDCl3. Symbols in capital letters refer to patterns resulting from directly bonded protons and lower case letters refer to (C,H)- couplings over more
than one bond. Sˆsinglet, D or dˆdoublet, T or tˆtriplet, dtˆdoublet of triplets, qˆquartet and mˆmultiplet. Where couplings are not speci®ed complex
coupling patterns are observed.
Induced shift after addition of Eu(fod)3-d30 to the sample in CDCl3. Values relative to that for H-5.
Induced shifts after addition of Eu(fod)3-d30 relative to that of 20 CO taken as 1.00.
b
c

F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
1603
equatorial in one isomer (11) and the more sterically
hindered axial orientation in the other (12), in reference to
the boat cyclohexane ring.
dC 33.82 and dC 28.35 and a methine carbon resonance
appears at dC 68.52. Some overlapping occurs for the
methine carbon resonances that complicates assignment to
certain nuclei. The assignments of the different resonance
1
signals in the H and 13C spectra of the hydantoin 11 to
certain nuclei were made from heteronuclear chemical
shift correlation (HETCOR)10 and proton±proton chemical
shift correlation (COSY)11 2D-experiments assisted by
hydrogen multiple quantum correlation (HMQC)12 and
hydrogen multiple bond correlation (HMBC)12 experiments.
The results of the HMBC experiments were used as cross
1
references for the H assignments made from COSY and
HMQC experiments, while identi®cation of overlapping
resonances in the 13C NMR spectrum followed from
HMBC experiments. The assignments are given in Table
1. The assignments of the methine cage protons were
made with COSY experiments starting from the methylene
protons on C-4, which show correlation peaks with the H-3
and H-5 protons. H-3 shows cross correlation peaks with
H-10 and the methylene protons on C-11. The assignment of
the methine protons followed from these allocations.
It is not possible to distinguish between the structural
1
isomers 11 and 12 from the H and 13C data given in
Table 1. Force ®eld calculations13,14 showed that the
hydantoin 11 is of lower steric energy than the hydantoin
12. The calculated distance between the proton on the
10-nitrogen atom in 11 and the Hs proton on C-11 is
Ê
The structure of the product (2)-11 was elucidated from an
1.98 A. These protons are close enough to experience a
extensive H and C NMR investigation. The H and 13C
NMR data are collected in Table 1.
nuclear Overhauser effect (NOE).15 Irradiation at the
10-NH signal should stimulate absorption and emission
processes for this proton, and this stimulation will be trans-
ferred through space to the relaxation mechanism of Hs-11.
The spin±lattice relaxation of Hs-11 will be speeded up,
leading to a net increase in the NMR absorption signal of
Hs-11. A rotating frame Overhauser (ROESY) experiment16
performed on a 300 MHz NMR instrument (mixing time
200 ms) indeed showed a strong NOE effect between
10-NH and Hs-11. This observation was veri®ed by an
NOE difference experiment in which a proton is irradiated
prior to detection of the spectrum. A second spectrum
without pre-irradiation is subtracted from the ®rst one, and
the process is repeated until the weak difference peaks are
clearly observed. A difference NOE experiment in which
the 10-NH proton was irradiated (irradiation time 1.5 s)
showed a strong NOE with Hs-11, con®rming the close
proximity effect between these protons. A much weaker
effect on H-9 and H-7 was observed. These observations
unambiguously assign structure 11 to the hydantoin.
1
1
1
The 500 MHz 1H NMR spectrum of the hydantoin 11
recorded in deuterated dimethyl sulfoxide [(CD3)2SO]
exhibits some resonance overlapping. Better resolved
spectra were obtained in deuterated trichloromethane
(CDCl3). The cage protons resonate between dH 1.0 and
dH 3.0 and are registered as a complex signal pattern. The
spectrum shows two AX spin systems that appear at high
®eld and are associated with two different methylene
groups. In order to distinguish between the chemical shifts
of the two methylene groups the geminal coupling constants
(2J values) were compared. It was previously observed that
the geminal coupling constants of the bridgehead methylene
protons (H-4) of pentacyclo-undecane derivatives are in the
order of 10 Hz.2,3,4,9 It can therefore be concluded that the
doublets at dH 1.243 and 1.640 (Ja,sˆ10.8 Hz) can be asso-
ciated with the methylene protons on C-4 and that the high
®eld chemical shifts at dH 1.267 (doublet of triplets;
Jˆ3.4 Hz) and dH 1.450 (doublet; Ja,sˆ13.7 Hz) can be
attributed to the protons H-11a and H-11s of the methylene
carbon atom C-11, respectively.
In no experiment could the presence of the hydantoin 12 be
detected. Force ®eld calculations on 12 showed an inter-
atomic distance of 2.15 A between the proton on 1 -NH
0
Ê Ê
and H-5, 2.94 A between 1 -NH and H-7, 2.95 A between
1 -NH and H-6 and 3.16 A between 1 -NH and H-9. An
NOE between 10-NH and H-5 should be observed if 12
was present in detectable quantities.
0
Ê
Two deuterium exchangeable protons are registered at dH
7.566 and dH 10.525. The sharp resonance signal at dH
7.566 can be assigned to the 10-nitrogen proton and the
broad signal registered at dH 10.525 to the 30-nitrogen
proton which is shifted to lower ®eld by the two adjacent
carbonyl groups. The 13C NMR spectrum of the hydantoin
11 exhibits two signals of carbonyl carbon atoms charac-
teristic of a carbonyl group coupled to a NH-group at dC
178.70 and a carbonyl group bearing two NH-groups at dC
157.29. Two methylene carbon resonances are registered at
0
0
Ê
The result of addition of Eu(fod)3-d30 to the CDCl3 solution
of the hydantoin 11 are also given in Table 1. Complexation
on both the NH±CO-groups occur as evidenced by the
large-induced 13C shifts observed for the carbonyl carbon
atoms. No extra resonances, which could be associated with

1604
F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
Scheme 2.
12, could be observed with the addition of Eu(fod)3-d30. The
purity of 11 could be claimed con®dently to be better than
95%.
ment of the latter with zinc in acetic acid produced the
optically pure enone (2)-16. A racemic mixture of the
two possible enantiomers of 16 was previously synthe-
sised18 from a racemic mixture of 15. The latter was
obtained from a different route.18
Hydrolysis of the hydantoin 11 with barium hydroxide17
produced the expected amino acid (2)-13 in 67% yield.
The pKa values of the amino acid was found to be
pKa1ˆ3.7^0.1 and pKa2ˆ9.4^0.1. The amino acid was
isolated at pHˆ6.5 and should therefore be in the zwitter-
ionic form.
Treatment of (2)-16 with a mixture of soduim cyanide,
ammonium chloride, 25% ammonia (aq) and excess ammo-
nium carbonate produced the hydantoin (1)-17. The assign-
ments of 1H and 13C resonance signals to certain nuclei were
made as described before and are given in Section 3.
distance between the proton on the
13,14
As expected a negative ion FAB MS analysis of the amino
acid 13 in a sodium hydroxide containing glycerol matrix
shows a strong molecular ion at m/z 204 ([M2H]2). A
strong molecular ion is obtained at m/z 206 ([M1H]1)
when a hydrochloric acid containing glycerol matrix is
used and recording is done in the positive ion mode.
T0he calculated
Ê
1 -nitrogen atom and H-3 for 17 is 2.10 A and are close
enough to experience an NOE effect.15 Irradiation of the
10-NH signal indeed showed a strong NOE with H-3
con®rming the close proximity between these protons. No
NOE with any of the protons 0H-7, H-5 and H-9 could be
Ê
observed. An NOE between 1 -NH and H-9 (2.15 A inter-
The infrared spectrum of the amino acid 13 exhibits a broad
complex absorption pattern of peaks between 2345 and
3630 cm21 typical of amino acids. A strong carbonylic
absorption peak appears at 1715 cm21. Further characteri-
sation of amino acid 13 was done by acetylation with acetic
anhydride and sodium acetate at room temperature whereby
the N-acetyl derivative 14 was obtained.
atomic distance) should be observed if the 10-NH group was
in the exo position in any detectable quantities. No extra
resonances, which should be associated with the latter
isomer, could be observed with the addition of Eu(fod)3-d30.
A similar regioselectivity was observed previously19±22 for
hydantoin formation on cyclohexanone derivatives in the
chair conformation where the 40-carbonyl group of the
hydantoin ring is directed towards the less sterically
hindered (equatorial) position when the ketone is treated
with sodium cyanide and ammonium carbonate.
The optically active keto alcohol (2)-8 was assigned6 the
1R,2R,3R,5S,6S,7S,9R,10S,11R con®guration. It can thus
be concluded that the amino acid (2)-13 has the
1S,2R,3R,5R,6R,7S,8R,9R,10R con®guration (referring to
the skeletal numbering given below).
Hydrolysis of (1)-17 in an autoclave at 1808C produced the
amino acid (1)-18 which was characterised by its FAB
mass spectra in positive and negative ion mode as described
above for 13 as well as conversion into the benzyloxy-
carbonyl derivative 19. As (1)-18 was derived from
(2)-8 with known con®guration6 a 1R,4R,5R,6R,8S,9S,11R
con®guration (referring to numbering in 17) could be
assigned to (1)-18.
The selectivity of hydantoin formation in cage structures
was also demonstrated for the enone 16. The latter was
obtained enantioselectively as shown in Scheme 2. Treat-
ment of (2)-8 with hydrobromic acid produced the bromo-
ketone (2)-15 in 68% yield. Since nucleophilic attack can
only occur from the exo-face2 no racemisation can occur and
only the exo-bromo derivative (2)-15 is obtained. Treat-

F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
1605
3. Experimental
pure (1)-10 as colourless needles (0.75 g, 76%, mp 194±
25
1958C, [a]D ˆ181.5 in chloroform, lit.6: mp 196±1978C,
[a]Dˆ181.6). The IR, MS and NMR data were identical to
those of the corresponding racemate prepared according to
the Dekker's procedures.5
3.1. General
Infrared spectra (KBr-disc) were recorded on a Nicolet 550
Magna-IR-spectrometer. EI mass spectra were obtained at
70 eV on a Micromass Autospec-Tof mass spectrometer.
FAB mass spectra were obtained by bombardment with a
1 mA beam of 8 keV accelerated neutral xenon atoms
produced by an Ion-Tech FAB gun ®tted to a VG 7070-E
mass spectrometer. NMR spectra were recorded on a
Brucker WM 500 FT and a Varian Gemini-300 spec-
trometer. Melting points are uncorrected.
3.1.4. Synthesis of the hydantoin (2)-11. A mixture of the
monoketone (1)-10 (1 g, 6.3 mmol), sodium cyanide (0.5 g,
10.2 mmol), ammonium chloride (0.5 g, 9.4 mmol), an
excess of ammonium carbonate (2 g) and ammonia
(10 cm3) was sealed in a glass tube. The solution was stirred
in a water bath at 40±608C for 10 h. The mixture was poured
into water (800 cm3) and the solution boiled until no more
ammonia vapours could be detected. The product was
extracted with dichloromethane (3£20 cm3). The organic
layer was dried (anhydrous sodium sulfate), ®ltered and
the excess solvent (50 cm3) removed under reduced
pressure. Upon cooling (08C), the product 11 (1.2 g, 83%,
3.1.1. Improved synthesis of (2)-8. The dione 1 (1.5 g,
23
È
8.6 mmol) in a Sorensen phosphate buffer solution
(100 cm3, pHˆ7) containing the reduced form of b-nico-
tineamide-adenine dinucleotide (NADH, 0.1 g, Boehringer
Manheim), ethanol (1 cm3) and horse liver alcohol dehydro-
genase (HLADH, 1 cm3, Boehringer Manheim) was stirred
at 258C for 5 d. Extraction of the product with dichloro-
methane (40 cm3), treatment with activated charcoal
(0.2 g) and removal of the excess solvent (35 cm3) by distil-
25
mp 2308C, [a]D ˆ23.5 in methanol) was obtained as
colourless crystals. IR (KBr-disc): nmax 3280, 3205,
2968, 1760, 1715, 1417, 1278, 1261, and 769 cm21;
EI MS: m/z 230 (M1), 202 (M12CO). Calcd for C13H14
N2O2: C, 67.83; H, 6.09, N, 12.17%. Found: C, 67.71; H,
6.02, N, 12.08%. See Table 1 for the NMR data of the
hydantoin 11.
lation under reduced pressure, produced the optically active
25
hydroxyketone (2)-8 (1.45 g, 95%, mp 2308C, [a]D
ˆ
212.4 in chloroform, lit.6: mp 230±232.58C, [a]Dˆ
212.4) as colourless crystals. The IR, MS and NMR data
were identical to those of the corresponding racemate
prepared according to the Dekker's procedures.5
3.1.5. Synthesis of 8-amino-pentacyclo[5.4.0.02,6.03,10.05,9]-
undecane-8-carboxylic acid (2)-13. The optically active
hydantoin (2)-11 (1 g, 4.3 mmol) was added to a clear 4%
aqueous solution of barium hydroxide (60 cm3) and re¯uxed
for 30 h.16 A drying tube ®lled with soda lime was placed on
the re¯ux condenser to prevent atmospheric carbon dioxide
entering the reaction ¯ask. The reaction mixture was trans-
ferred to a beaker and diluted with water (1000 cm3). An
excess of ammonium carbonate (5 g) was added to the
solution and then heated to boiling point with stirring. The
hot solution was ®ltered to remove the insoluble barium car-
bonate. The pH of the ®ltrate was adjusted to 6.5 byadditionof
hydrochloric acid (4 mol dm23). The aqueous solution was
evaporated on a steam bath to a small volume (^5 cm3) and
3.1.2. Huang±Minlon reduction of (2)-8. A mixture of the
hydroxyketone (2)-8 (1 g, 5.68 mmol) and hydrazine
hydrate (2 cm3, 98%) in diethylene glycol (20 cm3) was
maintained at 1208C for 1.5 h. The mixture was allowed
to cool down to 808C after which potassium hydroxide
(1 g, 25 mmol) was added. The excess hydrazine hydrate
and water was removed from the reaction mixture by distil-
lation. Distillation was terminated when the temperature
reached 1908C. The reaction mixture was re¯uxed for 3 h
at 1908C after which the product was separated from the
reaction mixture by steam distillation utilising steam from
an external source. The distillate was extracted with
dichloromethane (2£25 cm3). The organic layer was dried
(anhydrous sodium sulfate), ®ltered and the excess solvent
(40 cm3) removed under reduced pressure to produce the
alcohol (2)-9 as colourless crystals (0.82 g, 89%, mp
25
the amino acid (13, 0.6 g, 67%, mp 3258C dec., [a]D ˆ220.8
in 32% HCl) ®ltered off as a white solid. IR (KBr-disc) nmax
3460, 3402, 2959, 1713, 1630, 1606, 1540, 1458, 1409, 1368,
1261, 1196, 1114 and 794 cm21. FAB (glycerol1HCl matrix)
MS(positiveion), m/z 206 ([M1H]1). FAB (glycerol1NaOH
matrix) MS (negative ion), m/z 204 ([M2H]2). Calcd for
C12H15 NO2: C, 70.24; H, 7.32; N, 6.83%. Found: C, 69.98;
H, 7.23; N, 6.72%, pKa1ˆ3.7^0.1 and pKa2ˆ9.4^0.1 (deter-
minedfromthepHtitrationcurveobtainedfromthetitrationof
the protonated acidformof13withsodiumhydroxide). Due to
poor solubility in conventional NMR solvents no NMR data
was obtained.
25
208±2108C after sublimation, [a]D ˆ215.4 in chloroform,
lit.6: mp 209±2118C, [a]Dˆ215.4). The IR, MS and NMR
data were identical to those of the corresponding racemate
prepared according to Dekker's procedures.5
3.1.3. Oxidation of (2)-9. A solution (2)-9 (1.0 g,
6.2 mmol) in acetic acid (5 cm3) was added dropwise over
a period of 10 min with stirring to a mixture of chromium
trioxide (1.2 g, 12 mmol), acetic acid (15 cm3) and water
(2 cm3). The reaction mixture was stirred at 908C for 4 h,
cooled to room temperature and diluted with water
(60 cm3). The crude product was extracted with dichloro-
methane (3£20 cm3). The dichloromethane extract was
washed successively with water (2£25 cm3), saturated
aqueous sodium hydrogen carbonate (2£25 cm3) and
water (50 cm3). Removal of the solvent under reduced
pressure and recrystallisation from cyclohexane produced
3.1.6.
Synthesis
of
8-acetylamino-pentacyclo-
[5.4.0.02,6.03,10.05,9]undecane-8-carboxylic acid (14). A
solution of the amino acid 13 (0.5 g, 2.4 mmol) in acetic
anhydride (10 cm3) and sodium acetate (0.05 g, 0.6 mmol)
was stirred for 3 h at room temperature. 100 cm3 water was
added and the reaction mixture stirred for 5 h. The mono-
25
acetate (14, 0.4 g, 66%, mp 181±1838C, [a]D ˆ215.2)
precipitated and was ®ltered off. IR (KBr-disc) nmax 3420,
2959, 1715, 1631, 1573, 1278 cm21. EI MS, m/z 247 (M1),
202 (M12COOH). FAB (glycerol1HCl matrix) MS

1606
F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
(positive ion), m/z 248 ([M1H]1). Calcd for C14H17 NO3: C,
68.02; H, 6.88; N, 5.67%. Found: C, 67.94; H, 6.80; N,
5.52%. 13C NMR [(CD3)2SO, 75 MHz]: dC 174.59 (S,
COOH), 169.03 (S, CO of NHCOCH3), 64.10 (S, C-8),
47.56 (D, C-6), 46.22 (D, C-5), 42.39 (D, C-2), 42.28 (D,
C-3), 42.02 (D, C-10), 40.97 (D, C-9), 37.86 (D, C-7), 35.13
(D, C-1), 33.51 (T, C-4), 28.14 (T, C-11) and 22.46 (Q,
CH3). 1H NMR [(CD3)2SO, 300 MHz]: dH 11.80 (1H,
COOH), 8.46 (1H, NH), 3.17 (1H, m, H-7), 2.58 (1H, m,
H-1), 2.52 (1H, m, H-2), 2.51 (1H, m, H-9), 2.38 (1H, m,
H-10), 2.37 (1H, m, H-6), 2.19 (1H, m, H-5), 2.09 (1H, d,
Jˆ11.3 Hz, H-11s), 2.07 (1H, m, H-3), 1.78 (3H, s, CH3),
1.62 (1H, d, Jˆ9.9 Hz, H-4s), 1.14 (1H, d, Jˆ9.9 Hz, H-4a),
and 0.93 (1H, dt, Jˆ9.4, 3.2 Hz, H-11a).
55.02 (D, C-5), 51.24 (D, C-9), 46.87 (D, C-1), 46.80
(D, C-4), 41.85 (D, C-8), 39.22 (T, C-7) and 31.34 (T,
C-10). H NMR [(CD3)2SO, 300 MHz]: dH 10.5 (1H, br,
30 NH), 7.13 (1H, S, 10 NH), 6.45 (1H, m, H-3), 5.98
(1H, m, H-2), 3.04 (1H, m, H-9), 2.80 (1H, m, H-11), 2.47
(1H, m, H-1), 2.44 (1H, m, H-4), 2.14 (1H, m, H-8), 2.10
(1H, dt, Jˆ8.4, 3.2 Hz, H-7b), 2.05 (1H, m, H-5), 1.66 (1H,
d, Jˆ13.0 Hz, H-7a), and 1.48 (1H, H-10).
1
3.1.10. Synthesis of 6-amino-tetracyclo[6.3.0.04,11.05,9]-
undec-2-ene-6-carboxylic acid (1)-18. A mixture of
(1)-17 (1 g, 4.3 mmol) and a 4% barium hydroxide (60 cm3)
solution was stirred in an open beaker in an autoclave for 0.5 h
at 1808C. The reaction mixture was diluted with water
(1000 cm3) and an excess of ammonium carbonate (5 g) was
added to the mixture and which was then heated to boiling
point with stirring. The hot solution was ®ltered to remove the
insolublebariumcarbonate. ThepHofthe®ltratewasadjusted
to 6.5 by addition of hydrochloric acid (4 mol dm23) and
evaporated on a steam bath to a small volume (,5 cm3) and
3.1.7. Synthesis of the bromoketone (2)-15. The hydroxy
ketone (2)-8 (1 g, 5.68 mmol) was stirred for 3 h at 808C in
48% hydrogen bromide (10 cm3). The warm solution was
poured over crushed ice and the precipitate ®ltered off,
dissolved in acetone and treated with activated charcoal.
After ®ltration the ®ltrate was concentrated under vacuo
25
the amino acid (18, 0.75 g, 84%, [a]D ˆ115.2 in 32% HCl)
®ltered off as a white solid. IR (KBr-disc) nmax 3450, 2787,
2695, 2500, 1738, 1225, 1066, and 695 cm21. FAB (glycer-
ol1HCl matrix) MS (positive ion), m/z 206 ([M1H]1). FAB
(glycerol1NaOH matrix) MS (negative ion), m/z 204
([M2H]2). Calcd for C12H15 NO2: C, 70.24; H, 7.32; N,
6.83%. Found: C, 69.94; H, 7.26; N, 6.77%, pKa1ˆ2.6^0.1
and pKa2ˆ10.4^0.1 (determined from the pH titration curve
obtained from the titration of the protonated acid form of 18
with sodium hydroxide). Due to poor solubility in conven-
tional solvents no NMR data was obtained.
and the solid recrystallised from methanol to produce 15
(0.93 g, 68%, mp 84±858C, lit.18: 84.5±85.38C, [a]D
ˆ
25
259.0 in chloroform) as colourless crystals. The IR, MS
and NMR data of (2)-15 were identical to those of an
authentic sample18 of a racemic mixture.
3.1.8. Synthesis of the enone(2)-16. A mixture of the
bromoketone (2)-15 (1 g, 4.2 mmol), glacial acetic acid
(12 cm3) and an excess of zinc powder (1.6 g) was re¯uxed
for 8 h. The reaction mixture was cooled and the residue
®ltered off and washed with diethyl ether (10 cm3). The
®ltrate was neutralised with a saturated sodium bicarbo-
nate solution and the crude product was extracted with
diethyl ether (3£10 cm3). After removal of the solvent
under vacuo and chromatography with silica gel as
stationary phase and 1:1 n-hexane±ethyl acetate mixture
as eluant (2)-16 (0.48 g, 72%, mp 190±1918C, lit.18:
3.1.11. Synthesis of the benzyloxycarbonyl derivative 19.
A solution of benzyl chloroformate (0.418 g, 2.5 mmol) in
toluene (4 cm3) was added to a solution of 18 (0.5 g,
2.4 mmol) in 4 mol dm23 NaOH (20 cm3). The reaction
mixture was stirred for 0.5 h. Hydrochloric acid (20 cm3,
4 mol dm23) was added and the precipitated white solid
®ltered off. Recrystallisation from ethanol produced 19
(0.43 g, 88%, mp 80±818C) as colourless crystals (plates).
IR (KBr-disc) nmax 3420, 3330, 3270, 3195, 3035, 1690,
1695, 1620, 1610, 1445, 1403, 1344, 1092, 1070 and
730 cm21. FAB (glycerol1NaOH matrix) MS (negative
ion), m/z 338 ([M2H]2). Calcd for C20H21NO4: C, 70.79; H,
6.20; N, 4.13%. Found: C, 70.45; H, 6.12; N, 4.05%. 13C NMR
[(CD3)2SO, 75 MHz]: dC 176.45(S, COOH), 158.85(S, COof
NHCOOCH2Ph), 141.28 (D, C-3), 139.55(D, C-2), 136.45 (S,
Ph), 128.63 (D, Ph), 128 03 (D, Ph), 127.28 (D, Ph), 72.24 (T,
CH2Ph), 71.83 (S, C-6), 57.88(D, C-11), 54.86(D, C-5), 50.24
(D, C-9), 47.44 (D, C-1), 45.32 (D, C-4), 42.82 (D, C-8), 41.65
(T, C-7), 32.15 (T, C-10).). 1H NMR [(CD3)2SO, 300 MHz]:
dH 11.8 (br, COOH), 7.18±7.93 (5H, m, Ph), 6.45 (1H, m, H-
3), 6.16 (1H, br, NH), 5.88 (1H, m, H-2), 4.18 (2H, s, CH2Ph),
3.05 (1H, m, H-9), 2.83 (1H, m, H-11), 2.49(1H, m, H-1), 2.41
(1H, m, H-4), 2.19 (1H, dt, Jˆ8.2, 3.0 Hz, H-7b), 2.05 (1H, m,
H-8), 1.95 (1H, m, H-5), 1.75 (1H, d, Jˆ13.0 Hz, H-7a), 1.46
(2H, m, H-10).
25
192±1938C, [a]D ˆ 226.9 in acetone) was obtained as
colourless needles. The IR, MS and NMR data of (2)-16
were identical to that of an authentic sample18 of a racemic
mixture.
3.1.9. Synthesis of the hydantoin (2)-17. A mixture of the
enone (2)-16 (1 g, 6.3 mmol), sodium cyanide (0.5 g,
10.2 mmol), ammonium chloride (0.5 g, 9.4 mmol), an excess
of ammonium carbonate (2 g), and 25% ammonia (10 cm3)
and ethanol (5 cm3) was sealed in a glass tube. The mixture
was stirred in a water bath at 608C for 24 h. The reaction
mixture was poured into water (800 cm3) and boiled until no
more ammonia vapours could be detected. The reaction
mixture was cooled to room temperature and the product
extracted with dichloromethane (3£20 cm3). The combined
organic layers were washed with water, dried (anhydrous
sodium sulfate), ®ltered and the ®ltrate concentrated in
vacuo. The product 17 (1.33 g, 93%, mp 2438C,
[a]Dˆ182.58 in dimethylsulphoxide) crystallised out as
colourless needles. IR (KBr-disc): nmax 3290, 3230, 3065,
2965, 2940, 1780, 1715, 1410, 1285 and 780 cm21; EI MS:
m/z 230. Calcd for C13H14 N2O2: C, 67.83; H, 6.09; N, 12.17%.
Found: C, 67.75; H, 6.01; N, 12.09%. 13C NMR. [(CD3)2SO,
75 MHz]: dC 180.73 (S, 40 CO), 156.92 (S, 20 CO), 140.28 (D,
C-3), 138.80 (D, C-2), 70.71 (S, C-6), 58.75 (D, C-11),
Acknowledgements
The authors thank the National Research Foundation for
®nancial support.

F. J. C. Martins et al. / Tetrahedron 57 (2001) 1601±1607
1607
12. Martin, G. E.; Crouch, R. C. J. Nat. Prod. 1991, 54, 1±70.
13. Alchemy II, Molecular Modelling Software, Tripos Asso-
ciates Inc., St Louis, Missouri, 1991.
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