Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: Potential starting compounds for the synthesis of anatoxin-a

Article abstract of DOI:10.1016/S0957-4166(01)00100-8

9-Azabicyclo[6.2.0]-dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E = 94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at -15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4-6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.

Full text of DOI:10.1016/S0957-4166(01)00100-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 643–649
Preparation of (1R,8S)- and
(1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting
compounds for the synthesis of anatoxin-a
´
Eniko
3
Forro´, Judit Arva and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary
Received 23 January 2001; accepted 27 February 2001
Abstract—9-Azabicyclo[6.2.0]dec-4-en-10-one ( )-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was
N-hydroxymethylated to ( )-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the
(S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl
ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ]92%). Treatment of 3a and 3b with
NH4OH/MeOH afforded the corresponding b-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ]93%), potential starting compounds in
anatoxin-a synthesis. The ring opening of lactams ( )-2, ( )-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8
and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic b-amino acid derivatives. © 2001 Published by Elsevier Science Ltd.
1. Introduction
groups are subject to a wide variety of chemical
transformations.15
Anatoxin-a, a neurotoxic alkaloid, is one of the most
toxic of the cyanobacterial toxins, but a potent and
stereospecific agonist at nicotinic acetylcholine recep-
tors.1–3 It has been isolated from strains of Anabaena
flos aqua, a freshwater blue–green algae. The presence
of cyanobacteria in lakes and drinking water4,5 creates a
major problem worldwide. Intense pharmacological
interest3,6,7 has led to a number of syntheses of ana-
toxin-a in both racemic and enantiomerically pure
form.1,8–12 (+)-Anatoxin-a has been efficiently synthe-
sised from (−)-cocaine hydrochloride,8 whilst Trost and
Oslob reported a new synthetic route to (−)-anatoxin-a
Our aims in this study were to prepare the enantiomer-
ically pure alicyclic b-lactams 2a and 2b, potential
starting compounds for enantiopure anatoxin-a synthe-
sis, and to use b-lactam 2 for the synthesis of both
racemic and enantiomeric eight-membered cyclic b-
amino acids and esters.
2. Results and discussion
2.1. Synthesis of ( )-2 and its transformations into
racemic alicyclic b-amino acids
via a palladium-catalysed asymmetric cyclisation.9
A
recently published efficient total synthesis of ( )-ana-
toxin-a starts from b-lactam ( )-2.11 b-Lactam 2 can
also be a precursor to valuable b-amino acids. It is well
known that b-amino acids are important compounds
from both pharmacological and chemical aspects13 (e.g.
The racemic b-lactam 2 was prepared from cyclooctadi-
ene 1 by chlorosulfonyl isocyanate (CSI) addition.10 It
was transformed with paraformaldehyde under sonica-
tion into N-hydroxymethylated b-lactam ( )-3, the
starting material for the enzymatic resolution (Scheme
1). ( )-2 could then be transformed by ring opening
with HCl/EtOH into cis-amino ester ( )-4 or into cis-
amino acid ( )-6 with concentrated aqueous HCl. The
unsaturated cyclooctene derivatives ( )-2 and ( )-4
were reduced catalytically under H2 or in the presence
of cyclohexene as a hydrogen donor to cyclooctanes
( )-5 and ( )-7, respectively. It is important to note that
the synthesis starting from cyclooctadiene is more eco-
nomical as compared to that starting from cyclooctene.
(1R,2S)-aminocyclopentanecarboxylic
acid,
cis-
pentacin,14 an antifungal antibiotic); cyclic b-amino
acids can be used as building blocks in the synthesis of
biologically active peptides; the two functional
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705;
e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00100-8

644
E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
Scheme 1.
2.2. Enzymatic resolution of ( )-3 and transformations
of its enantiomers
one, -7-azabicyclo[4.2.0]oct-3-en-8-one and -7-azabi-
cyclo[4.2.0]oct-4-en-8-one), based on asymmetric acyla-
tion, were performed in acetone by using lipase PS as
catalyst and vinyl butyrate as the acyl donor (E>200).21
High selectivities (E>200) were observed for the lipase
PS- or lipase AK-catalysed asymmetric acylation of
3,4-benzo-6-hydroxymethyl-6-azabicyclo[3.2.0]heptan-7-
one.22 These previous results in the enzymatic resolu-
tion of alicyclic b-lactams suggested the possibility of
selective N-acylation of ( )-3 (Scheme 2).
Lipase PS (Pseudomonas cepacia) and lipase AK (Pseu-
domonas fluorescens) are the enzymes most commonly
used in the resolution of primary alcohols.16,17 In previ-
ous studies, both lipase PS and lipase AK proved to be
applicable for the asymmetric acylation of monocyclic
and bicyclic N-hydroxymethylated b-lactams.18–22 In
the lipase AK-catalysed acylation of N-hydroxymethyl-
6-azabicyclo[3.2.0]heptan-7-one, using vinyl butyrate in
acetone, the occurrence of the reverse enzymatic reac-
tion was observed, resulting in a considerable decrease
in enantioselectivity (E=90).20 Successful gram-scale
resolutions of some recently investigated related sub-
The lipase PS- and lipase AK-catalysed butyrylations of
( )-3 in acetone at 25°C did not lead to the same high
E values as those observed earlier for the six-membered
analogues21 and at conversions around 50% or higher,
they tended to drop dramatically (Table 1, rows 1 and
strates
(N-hydroxymethyl-7-azabicyclo[4.2.0]octan-8-
Scheme 2.

E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
645
Table 1. Effects of solvent, acyl donor (0.1 M), enzyme (30 mg mL−1) and temperature on the enantioselectivity in
acylation of (9)-3
Row
Enzyme
Acyl donor
Solvent
Reaction time (h)
e.e.s (%)
e.e.p (%)
Conv. (%)
1
2
3
Lipase PSa
Lipase PSa
Lipase PSa
VB
VB
VB
Acetoneb
7
81
88
78
93
8
rac
92
88
73
74
89
92
83
71
94
83
80
49
55
45
53
9
Di-iso-propyl etherb
Di-iso-propyl etherb
Et3N
0.75
0.25
0.75
72
72
1
4
5
6
Lipase PSa
Lipase PSa
Lipase PSa
VB
VB
VB
Acetonitrileb
Chloroformb
Tolueneb
91
43
77
91
74
86
50
67
49
45
55
52
3
7
8
Lipase PSa
Lipase PSa
VA
VA
Acetoneb
2.7
0.25
0.75
0.75
Di-iso-propyl etherb
9
Lipase PSa
Lipase PSa
Lipase PSa
Lipase PSa
Lipase PSa
Lipase PSa
Lipase PSa
VA
VA
VA
VA
Vpr
Vpiv
IA
Di-iso-propyl ether
Et3Nb
10
11
12
13
14
15
Di-iso-propyl etherc
1
1.5
1
2.5
0.5
1
0.25
0.75
53
89
91
88
95
36
62
72
89
71
94
64
82
30
50
36
66
87
rac
37
23
rac
41
60
91
84
94
93
61
58
90
69
82
62
88
55
33
32
84
84
50
49
52
48
51
37
52
44
56
46
60
42
60
48
61
30
44
64
Di-iso-propyl etherd
Tetrahydrofuranb
Di-iso-propyl etherb
Di-iso-propyl etherb
Di-iso-propyl etherb
96
2.25
4
16
17
18
19
Novozym 435
Novozym 435
Lipase AKa
Lipase AKa
VB
VB
VB
VB
Acetoneb
0.25
0.25
2.5
0.25
0.75
48
1.7
1.5
48
Di-iso-propyl etherb
Acetoneb
Di-iso-propyl etherb
20
21
22
23
24
CAL-Aa
CAL-Aa
PPL
VB
VB
VB
VB
VB
Acetoneb
Di-iso-propyl etherb
Di-iso-propyl etherb
Acetoneb
38
61
49
28
Lipolasea
Lipolasea
Di-iso-propyl etherb
0.25
0.75
61
41
40
59
a Contains 20% (w/w) lipase adsorbed on Celite in the presence of sucrose.
b 25°C.
c 0°C.
d −15°C.
VA, vinyl acetate; VB, vinyl butyrate; Vpr, vinyl propionate; Vpiv, vinyl pivalate; and IA, iso-propenyl acetate.
18). Accordingly, preliminary experiments were needed
to find the optimal conditions for gram-scale resolution.
The effects of enzyme, acyl donor, solvent and temper-
ature on the enantioselectivity were investigated (Table
1).
(Table 1, row 24) than did Novozym, which is more
frequently used for the esterification of primary and
secondary alcohols (Table 1, row 17).16,17
In an attempt to enhance the enantioselectivity, vinyl
butyrate was replaced by other vinyl esters (vinyl ace-
tate, vinyl propionate, vinyl pivalate and iso-propenyl
acetate). The acylation reactions performed in di-iso-
propyl ether at 25°C did not stop at 50% conversion.
Nearly the same E values were observed around 50%
conversion for the reactions and the e.e. values for
products 3a and 3b then began to drop dramatically in
all cases (Fig. 1). It was demonstrated earlier that in
transesterification reactions the water adsorbed on the
enzyme preparation can serve as a nucleophile, leading
to ester hydrolysis and considerably reducing the enan-
tioselectivity of the reaction.20 To demonstrate the
occurrence of ester hydrolysis, racemic butyrate was left
in di-iso-propyl ether in the presence of lipase PS,
Initially, we examined the butyrylation reactions with
vinyl butyrate in acetone and di-iso-propyl ether at
25°C in the presence of various commercially available
lipases, including Novozym 435 (lipase from Candida
antarctica B), CAL-A (lipase from Candida antarctica
A), PPL (porcine pancreatic lipase) and Lipolase (Ther-
momices lanuginosus). These lipases did not exhibit
higher selectivity than lipase PS; probably the reverse
enzymatic reaction yielded the products 3a and 3b with
enantiopurities that decreased rapidly with time. Acyla-
tion was not observed even after 24 h. It is notable that
Lipolase, a lipase for fat hydrolyses, catalysed the
butyrylation of ( )-3 in di-iso-propyl ether at higher E

646
E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
Fig. 1. Experimental e.e. values vs conversion for lipase PS-catalysed butyrylation of ( )-3 in di-iso-propyl ether at −15°C.
without any added nucleophile except for the water
adsorbed on the enzyme. The ester was found to be
reacted to alcohol (21% conversion in 15 min, 79%
conversion in 1.5 h; Eꢀ2).
The physical data on the enantiomers prepared are
reported in Table 2.
2.3. Absolute configurations
It is known that the nature of the solvent usually
influences the enantioselectivity of enzymatic reactions.
Ethereal solutions are generally preferable for work
with lipase PS.17,23 In order to find a solvent where the
enzymatic hydrolysis of the ester is minimised and
where the enzymatic acylation proceeds with high enan-
tioselectivity, several solvents were examined for the
lipase PS-catalysed acylation of ( )-3. Of the solvents
used (acetone, di-iso-propyl ether, acetonitrile, chloro-
form, tetrahydrofuran and toluene at 25°C) the enzyme
was practically inactive in chloroform (Table 1, entry
5), and with acetonitrile the reaction time was
extremely long (Table 1, entry 4). Low enantioselectiv-
ity was observed with tetrahydrofuran solvent (Table 1,
entry 12). Di-iso-propyl ether and toluene gave the best
results (Table 1, entries 2, 6 and 8) with e.e.s of 74–89%
with di-iso-propyl ether and 88–92% in the reactions
with toluene solvent. When a few drops of Et3N was
added to di-iso-propyl ether solvated reactions, the E
value was increased slightly at conversions close to 50%
(Table 1, entries 3 and 9).
The analysed chromatograms indicated the same enan-
tiopreference in the reactions of all of the lipases exam-
ined. With lipase PS catalysis, the corresponding
enantiomers of ( )-3 react similarly as in the case of the
homologue 7-hydroxymethyl-7-azabicyclo[4.2.0]oct-3-
en-8-one.21 The lipase-catalysed acylations of ( )-3
occurred at the (S)-stereocentre. Thus, the (1R,8S)-
configuration is accepted for the resulting ester 3a, and
the (1S,8R)-configuration is assigned to the unreacted
alcohol 3b.
3. Experimental
3.1. Materials and methods
Vinyl acetate and butyrate were purchased from Fluka,
vinyl propionate, pivalate and iso-propenyl acetate
from Aldrich Co., lipase PS and lipase AK from
Amano Pharmaceuticals, PPL (type II) from Sigma,
and CAL-A, Lipolase and Novozym 435 (as an immo-
bilised preparation) from Novo Nordisk. Before use
lipase PS, lipase AK, CAL-A and Lipolase (5 g) were
dissolved in Tris–HCl buffer (0.02 M; pH 7.8) in the
presence of sucrose (3 g), followed by adsorption on
Celite (17 g) (Sigma). The lipase preparations thus
obtained contained 20% (w/w) of lipase.
Manipulation of the enantioselectivity by decreasing
the reaction temperature of the enzyme-catalysed acyla-
tion proved possible (Table 1, entries 8, 10 and 11). The
E value for the lipase PS-catalysed acetylation with
vinyl acetate in di-iso-propyl ether was clearly enhanced
when the reaction was conducted at −15°C (Eapparent
102 at 51% conversion).
=
On the basis of the above results, the gram-scale resolu-
tion of ( )-3 was performed in di-iso-propyl ether with
lipase PS catalyst and vinyl acetate or vinyl butyrate as
acyl donor at −15°C. The results are presented in Table
2 and in the experimental section.
Table 2. Physical data on enantiomers prepared
Compound Abs. config. e.e. (%)
[h]2D0
2a
2b
3a
3b
3c
3d
4a
4b
5a
5b
(1R,8S)
(1S,8R)
(1R,8S)
(1S,8R)
(1R,8S)
(1R,8S)
(1R,2S)
(1S,2R)
(1R,2S)
(1S,2R)
93
99
92
97
83
90
81
98
86
97
+19.8 (c=0.35, MeOH)
−20.2 (c=0.35, MeOH)
−29.5 (c=1, MeOH)
−27.0 (c=1, MeOH)
−27.9 (c=1, MeOH)
+24.7 (c=1, MeOH)
−1.5 (c=1, EtOH)
+1.8 (c=1, EtOH)
+6.3 (c=0.5, EtOH)
−7.0 (c=0.5, EtOH)
Treatment of 3a and 3b with NH4OH/MeOH afforded
2a and 2b, potential starting compounds for enantio-
pure anatoxin-a synthesis. The ester 3a was trans-
formed with K2CO3/MeOH to alcohol 3d, the antipode
of 3b, obtained from the enzymatic reaction. Transfor-
mations of 3a and 3b by ring opening with HCl/EtOH
followed by catalytic reduction resulted in enantiomers
of b-amino acid esters 4a, 4b, 5a and 5b (Scheme 2).

E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
647
In a typical small-scale experiment, racemic 3 (0.1 M
solution) in an organic solvent (3 mL) was added to
the lipase tested (30 mg mL−1). A vinyl ester (0.2 M
in the reaction mixture) was added. The mixture was
shaken continuously at −15, 0 or 25°C. The progress
of the reaction was followed by taking samples from
the reaction mixture at intervals and analysing them
by gas chromatography. The e.e. values of the unre-
acted alcohol 3b and the ester enantiomers 3a or 3c
produced were determined by gas chromatography on
a Chrompack CP-Chirasil-DEX CB column (25 m).
Amino esters 4a, 4b, 5a and 5b were derivatised with
hexanoic anhydride in the presence of 4-dimethy-
laminopyridine and pyridine before gas chromato-
graphic analysis on a Chirasil-L-Val column (25 m).
C11H20ClNO2: C, 56.53; H, 8.62; N, 5.99. Found: C,
56.39; H, 8.68; N, 5.87%.
3.4. Racemic ethyl cis-2-aminocyclooctanecarboxylate
hydrochloride ( )-5
Palladium-on-carbon (0.1 g) was added to ethyl cis-2-
aminocyclooct-5-enecarboxylate hydrochloride 4 (0.5
g, 2.14 mmol) dissolved in methanol (20 mL) under a
H2 atmosphere. After stirring for 3 h, the catalyst
was filtered off and the filtrate evaporated to dryness.
The resulting white crystalline product was recrys-
tallised from di-iso-propyl ether (0.29 g, 58%); mp
91–94°C; 1H NMR (400 MHz, CDCl3) l (ppm):
1.27–1.31 (3H, t, J=7.1, CH3), 1.57–2.24 (12H, m,
6×CH2), 3.13–3.15 (1H, m, H-1), 3.73–3.75 (1H, m,
H-2), 4.23–4.24 (2H, m, CH2CH3), 8.41 (3H, bs, N+
H3). Anal. calcd for C11H22ClNO2: C, 56.04; H, 9.41;
N, 5.94. Found: C, 56.13; H, 9.46; N, 5.90%.
Specific optical rotations were measured with
a
1
Perkin–Elmer 341 polarimeter. H NMR spectra were
recorded on a Bruker Avance DRX 400 spectrometer.
Melting points were determined on a Kofler appara-
tus.
3.5. ( )-cis-2-Aminocyclooct-5-enecarboxylic acid
hydrochloride ( )-6
3.2. Racemic 9-azabicyclo[6.2.0]dec-4-en-10-one ( )-2
The b-Lactam ( )-2 (0.5 g, 3.3 mmol) was dissolved
in cc HCl (6 mL) and stirred under reflux for 2 h at
70°C. The solvent was evaporated off and the residue
was recrystallised from methanol/acetone affording
white crystals of ( )-6 (0.3 g, 44%); mp 218–220°C;
1H NMR (400 MHz, D2O) l (ppm): 1.80–2.52 (8H,
m, 4×CH2), 3.06–3.09 (1H, m, H-1), 3.80–3.89 (1H,
m, H-2), 5.69–5.79 (2H, m, CHCH). Anal. calcd for
C9H16ClNO2: C, 52.56; H, 7.84; N, 6.81. Found: C,
52.51; H, 7.84; N, 6.78%.
1,5-Cyclooctadiene (24.5 mL, 0.2 mol), anhydrous
Na2CO3 (3.2 g, 0.08 mol) and CH2Cl2 (15 mL) were
added to a flask equipped with an argon inlet adap-
tor and cooled to 0°C. Chlorosulfonyl isocyanate (17
mL, 0.2 mol) was added dropwise to the stirred reac-
tion mixture over 15 min. After stirring at 0°C for a
further 2 h, the mixture was allowed to warm to
room temperature overnight. The resulting liquid was
diluted with CH2Cl2 (25 mL) and then added drop-
wise to a vigorously stirred two-phased mixture of
Na2SO3 (73 g) and Na2HPO4 (82 g) in H2O (400 mL)
underlaid with CHCl3 (300 mL). The organic layer
was separated and the aqueous phase was extracted
with chloroform. The combined organic layers were
dried (Na2SO4) and, after filtration, concentrated. The
resulting white solid, racemic 2 (7.5 g, 24%), was
recrystallised from di-iso-propyl ether/acetone mp
109–113°C (lit.10 112–113°C); 1H NMR (400 MHz,
CDCl3) l (ppm): 1.91–2.09 and 2.37–2.42 (8H, m,
4×CH2), 3.28–3.29 (1H, m, H-1), 3.82–3.85 (1H, m,
H-8), 5.68–5.70 (2H, m, CHCH), 6.01 (1H, bs, NH).
Anal. calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.23; H, 8.59; N, 9.28%.
3.6. Racemic 9-azabicyclo[6.2.0]decan-10-one ( )-7
Palladium-on-carbon (0.3 g) was added to ( )-9-azabi-
cyclo[6.2.0]dec-4-en-10-one 2 (0.5 g, 3.3 mmol) dis-
solved in
a
mixture of MeOH (20 mL) and
cyclohexene (4 mL). The mixture was refluxed for 4 h
and the catalyst was then filtered off. After evapora-
tion, the white crystalline product was recrystallised
from n-hexane (0.24 g, 47%; mp 71–73°C), lit.24 mp
71–72°C; 1H NMR (400 MHz, CDCl3) l (ppm):
1.29–2.09 (12H, m, 6×CH2), 3.02–3.06 (1H, m, H-1),
3.63–3.68 (1H, m, H-8), 5.89 (1H, bs, NH). Anal.
calcd for C9H15NO: C, 70.55; H, 9.87; N, 9.14.
Found: C, 70.28; H, 9.88; N, 9.17%.
3.3. Racemic ethyl cis-2-aminocyclooct-5-enecarboxy-
late hydrochloride ( )-4
3.7. Racemic cis-2-aminocyclooctanecarboxylic acid
hydrochloride ( )-8
b-Lactam ( )-2 (2 g, 13.22 mmol) was stirred under
reflux in ethanol (25 mL) containing 22% dry hydro-
gen chloride for 10 h. The solvent was completely
evaporated and the resulting white crystals of ( )-4
were recrystallised from n-hexane/ethyl acetate (1.3 g,
b-Lactam ( )-7 (0.5 g, 3.26 mmol) was dissolved in cc
HCl (6 mL) with gently warming for 2 h. The solvent
was evaporated off and the residue was recrystallised
from H2O/acetone, affording white crystals of ( )-8
(0.28 g, 41%); mp 214–216°C; 1H NMR (400 MHz,
D2O) l (ppm): 1.52–1.97 (12H, m, 6×CH2), 3.06–3.10
(1H, m, H-1), 3.77–3.81 (1H, m, H-2). Anal. calcd for
C9H18ClNO2: C, 52.05; H, 8.74; N, 6.74. Found: C,
52.11; H, 8.59; N, 6.71%.
1
42%); mp 112–117°C; H NMR (400 MHz, CDCl3) l
(ppm): 1.30–1.33 (3H, t, J=7.1, CH3), 1.78–2.66 (8H,
m, 4×CH2), 3.21–3.23 (1H, m, H-1), 3.77–3.78 (1H,
m, H-2), 4.25–4.30 (2H, m, CH2CH3), 5.57–5.76 (2H,
m, CHCH), 8.42 (3H, bs, N+H3). Anal. calcd for

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E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
CH2OCOMe, J=11.3), 5.67–5.71 (2H, m, CHCH).
Anal. calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27.
Found: C, 64.33; H, 7.64; N, 6.31%.
3.8. Racemic 9-hydroxymethyl-9-azabicyclo[6.2.0]dec-4-
en-10-one ( )-3
9-Azabicyclo[6.2.0]dec-4-en-10-one ( )-2 (4 g, 26.45
mmol) was dissolved in THF (35 mL). Paraformalde-
hyde (0.8 g, 26.6 mmol), K2CO3 (0.22 g, 1.59 mmol)
and H2O (1.5 mL) were added. The solution was soni-
cated for 5 h. The solvent was evaporated off and the
residue was dissolved in ethyl acetate (50 mL). The
solution was dried (Na2SO4) and then concentrated.
The residue was recrystallised from di-iso-propyl ether
to afford a white crystalline product, ( )-3 (3 g, 62%);
3.10. Methanolysis of 3a to the corresponding alcohol
enantiomer 3d
A mixture of 3a (0.13 g, 0.52 mmol) and K2CO3 (0.17
g, 1.2 mmol) in MeOH (15 mL) was stirred for 6 h at
room temperature. After evaporation, the residue was
dissolved in H2O (20 mL) and extracted with diethyl
ether (3×30 mL). The organic phase was dried
(Na2SO4), filtered and evaporated. The product
(1R,8S)-3d was obtained as a slowly crystallising oil
(0.06 g, 63%; [h]2D5=+24.7 (c=1, MeOH); e.e.=90%).
1
mp 96–97°C; H NMR (400 MHz, CDCl3) l (ppm):
1.86–2.21 and 2.36–2.43 (8H, m, 4×CH2), 3.26–3.30
(1H, m, H-1), 3.70 (1H, bs, OH), 3.93–3.97 (1H, m,
H-8), 4.45–4.48 (1H, d, CH2OH, J=11.6), 4.74–4.77
(1H, d, CH2OH, J=11.6), 5.66–5.71 (2H, m, CHCH).
Anal. calcd for C10H15NO2: C, 66.27; H, 8.34; N, 7.73.
Found: C, 66.19; H, 8.33; N, 7.70%.
1H NMR (400 MHz, CDCl3) l (ppm) for 3d: similar to
that for ( )-3. Anal. calcd for C10H15NO2: C, 66.27; H,
8.34; N, 7.73. Found: C, 66.20; H, 8.25; N, 7.75%.
3.9. Gram-scale resolution of racemic 9-hydroxymethyl-
9-azabicyclo[6.2.0]dec-4-en-10-one ( )-3
3.11. (1R,8S)- and (1S,8R)-9-Azabicyclo[6.2.0]dec-4-en-
10-one 2a and 2b
Racemic 3 (1.5 g, 8.27 mmol), vinyl acetate (1.53 mL,
16.56 mmol), Et3N (a few drops) and Na2SO4 (0.3 g) in
di-iso-propyl ether (100 mL) were added to lipase PS (3
g, 30 mg mL−1) and the mixture was shaken at −15°C
for 3 h, the enzyme was filtered off at 53% conversion
(e.e.-3b=95%, e.e.-3c=83%). Di-isopropyl ether was
evaporated. The residue was chromatographed on sil-
ica, eluting with ethyl acetate; this afforded unreacted
(1S,8R)-3b [0.5 g, 34%; [h]2D5 =−27.0 (c=1, MeOH);
mp 48–49°C (recrystallised from di-iso-propyl ether);
e.e.=97%] and the ester (1R,8S)-3c (0.81 g, 44%;
[h]2D5=−27.9 (c=1, MeOH); e.e.=83%) as a pale-yellow
oil. The gram-scale resolution of ( )-3 (1.5 g) was
repeated with vinyl butyrate (1.89 mL, 16.56 mmol)
instead of vinyl acetate. Intense shaking (4 h) of the
mixture (conversion 51%) afforded the unreacted
(1S,8R)-3b (e.e.=96%) and the ester (1R,8S)-3a (e.e.=
92%). The column chromatographic separation on sil-
ica, eluting with ethyl acetate, furnished 3b (0.46 g,
31%; e.e.=97%) and 3a (0.9 g, 43%; [h]2D5=−29.5 (c=1,
MeOH); e.e.=92%) as a pale-yellow oil.
The ester (1R,8S)-3a (0.2 g, 0.79 mmol) was dissolved
in MeOH (10 mL), NH4OH (1 mL) was added and the
mixture was stirred at room temperature for 24 h. The
solvent was evaporated off, the residue was chro-
matographed on silica and elution with ethyl acetate
afforded white crystals of (1R,8S)-2a [0.08 g, 65%;
[h]2D5=+19.8 (c=0.35, MeOH); mp 117–119°C (recrys-
tallised from di-iso-propyl ether); e.e.=93%].
1H NMR (400 MHz, CDCl3) l (ppm) for 2a: similar to
that for ( )-2. Anal. calcd for C9H13NO: C, 71.49; H,
8.67; N, 9.26; found: C, 71.31; H, 8.62; N, 9.26%.
Similarly, (1S,8R)-3b (0.2 g, 1.1 mmol) afforded white
crystals of (1S,8R)-2b [0.12 g, 72%; [h]2D5=−20.2 (c=
0.35, MeOH); mp 122–123°C (recrystallised from di-
iso-propyl ether); e.e.=99%].
1H NMR (400 MHz, CDCl3) l (ppm) for 2b: similar to
that for ( )-2. Anal. calcd for C9H13NO: C, 71.49; H,
8.67; N, 9.26. Found: C, 71.43; H, 8.69; N, 9.30%.
1H NMR (400 MHz, CDCl3) l (ppm) for 3a: 0.93–0.97
(3H, t, J=7.6, CH3), 1.62–1.68 (2H, m, CH2CH2CH3),
1.81–2.42 (10H, m, CH2CH2CH3 and 4×CH2 from
ring), 3.29–3.32 (1H, m, H-1), 3.84–3.88 (1H, m, H-8),
5.04–5.06 (1H, d, CH2OCOPr, J=11.2), 5.12–5.15 (1H,
d, CH2OCOPr, J=11.2), 5.68–5.70 (2H, m, CHCH).
Anal. calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57.
Found: C, 67.13; H, 8.53; N, 5.51.
3.12. Ethyl (1R,2S)- and (1S,2R)-2-aminocyclooct-5-
enecarboxylate hydrochloride 4a and 4b
The ester (1R,8S)-3a (0.2 g, 0.79 mmol) was dissolved
in 22% HCl/EtOH (10 mL) and refluxed for 5 h at
70°C. The solvent was evaporated off and the product,
(1R,2S)-4a, was obtained as a pale-yellow oil (0.08 g,
43%; [h]2D5=−1.5 (c=1, EtOH); e.e.=81%).
1H NMR (400 MHz, CDCl3) l (ppm) for 3b: similar to
that for ( )-3. Anal. calcd for C10H15NO2: C, 66.27; H,
8.34; N, 7.73. Found: C, 66.39; H, 8.24; N, 7.73%.
1H NMR (400 MHz, CDCl3) l (ppm) for 4a: similar to
that for ( )-4. Anal. calcd for C11H20ClNO2: C, 56.53;
H, 8.62; N, 5.99. Found: C, 56.50; H, 8.72; N, 5.99%.
1H NMR (400 MHz, CDCl3) l (ppm) for 3c: 1.83–2.26
and 2.37–2.43 (8H, m, 4×CH2), 2.09 (3H, bs, CH3),
3.30–3.34 (1H, m, H-1), 3.84–3.89 (1H, m, H-8), 5.02–
5.05 (1H, d, CH2OCOMe, J=11.3), 5.12–5.15 (1H, d,
Similarly, (1S,8R)-3b (0.2 g, 1.1 mmol) afforded
(1S,2R)-4b as a pale-yellow oil (0.11 g, 43%; [h]2D5=+1.8
(c=1, EtOH); e.e.=98%).

E. Forro´ et al. / Tetrahedron: Asymmetry 12 (2001) 643–649
649
1H NMR (400 MHz, CDCl3) l (ppm) for 4b: similar to
that for ( )-4. Anal. calcd for C11H20ClNO2: C, 56.53;
H, 8.62; N, 5.99. Found: C, 56.41; H, 8.61; N, 6.09.
6. Durany, N.; Riederer, P.; Deckert, J. Alzheimers Rep.
1999, 2, 263.
7. Fawell, J. K.; Mitchell, R. E.; Hill, R. E.; Everett, D. J.
Hum. Exp. Toxicol. 1999, 18, 168.
3.13. Ethyl (1R,2S)- and (1S,2R)-2-aminocyclooctane-
carboxylate hydrochloride 5a and 5b
8. Wegge, T.; Schwarz, S.; Seitz, G. Tetrahedron: Asymme-
try 2000, 11, 1405.
9. Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999, 121,
3057.
10. Parsons, P. J.; Camp, N. P.; Underwood, J. M.; Harvey,
D. M. J. Chem. Soc., Chem. Commun. 1995, 1461; Tetra-
hedron 1996, 52, 11637.
11. Parsons, P. J.; Camp, N. P.; Edwards, N.; Sumoreeah, L.
R. Tetrahedron 2000, 56, 309.
12. Aggarwal, V. K.; Humphries, P. S.; Fenwick, A. Angew.
Chem., Int. Ed. 1999, 38, 1985.
13. Porter, E. A.; Wang, X.; Lee, H. S.; Weisblum, B.;
Gellman, S. H. Nature 2000, 404, 565.
14. Fu¨lo¨p, F. In Studies in Natural Product Chemistry; Atta-
ur-Rahman, Ed. The Chemistry of 2-Aminocyclopentane-
carboxylic Acid. Elsevier Science: New York, 2000; Vol.
22, pp. 273–306.
With the method described in Section 3.4, the ester
(1R,8S)-4a (0.08 g, 0.32 mmol) afforded the product
(1R,2S)-5a as white crystals [0.05 g, 62%; [h]2D5=+6.3
(c=0.5, EtOH); mp 101–105°C (recrystallised from n-
hexane/ethyl acetate); e.e.=86%].
1H NMR (400 MHz, CDCl3) l (ppm) for 5a: similar to
that for ( )-5. Anal. calcd for C11H22ClNO2: C, 56.04;
H, 9.41; N, 5.94. Found: C, 56.31; H, 9.40; N, 5.89.
Similarly, (1S,8R)-4b (0.1 g, 0.43 mmol) afforded
(1S,2R)-5b as white crystals [0.06 g, 59%; [h]2D5=−7.0
(c=0.5, EtOH); mp 111–115°C (recrystallised from n-
hexane/ethyl acetate); e.e.=97%].
15. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
16. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis; Wiley-VCH Verlag: Weinheim, 1999;
pp. 65–107.
1H NMR (400 MHz, CDCl3) l (ppm) for 5b: similar to
that for ( )-5. Anal. calcd for C11H22ClNO2: C, 56.04;
H, 9.41; N, 5.94; found: C, 56.11; H, 9.66; N, 5.94%.
17. (a) Forro´, E.; Lundell, K.; Fu¨lo¨p, F.; Kanerva, L. T.
Tetrahedron: Asymmetry 1997, 8, 3095; (b) Forro´, E.;
Kanerva, L. T.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 1998,
9, 513; (c) Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry
1999, 10, 1985; (d) Forro´, E.; Szakonyi, Z.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 1999, 10, 4619.
Acknowledgements
The authors thank OTKA (grant No. T 030452) and
ETT (32/2000) for financial support.
18. Nagai, H.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem.
Pharm. Bull. 1993, 41, 1933.
19. Hongo, H.; Iwasa, K.; Kabuto, C.; Matsuzaki, H.;
Nakano, H. J. Chem. Soc., Perkin Trans. 1 1997, 1747.
20. Csomo´s, P.; Kanerva, L. T.; Berna´th, G.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 1996, 7, 1789.
21. Ka´ma´n, J.; Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry
2000, 11, 1593.
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