Synthesis and transformation of novel cyclic β-amino acid derivatives from (+)-3-carene

Article abstract of DOI:10.1016/j.tetasy.2003.10.001

The regio- and stereoselective addition of chlorosulfonyl isocyanate to (+)-3-carene 1 resulted in β-lactam 2, which was converted to N-Boc-β-amino acid 4, β-amino ester 7, and carboxamide derivatives 18 and 20 via N-Boc activation and mild ring opening.

Full text of DOI:10.1016/j.tetasy.2003.10.001

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3965–3972
Synthesis and transformation of novel cyclic b-amino acid
derivatives from (+)-3-carene
Szilvia Gyo´nfalvi, Zsolt Szakonyi and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary
Received 17 September 2003; accepted 1 October 2003
Abstract—The regio- and stereoselective addition of chlorosulfonyl isocyanate to (+)-3-carene 1 resulted in b-lactam 2, which was
converted to N-Boc-b-amino acid 4, b-amino ester 7, and carboxamide derivatives 18 and 20 via N-Boc activation and mild ring
opening. The corresponding b-amino ester 7 was transformed to 2-thioxopyrimidin-4-one 11 and 2,4-pyrimidinedione 13. LAH
reduction of 5 and 7 resulted in amino alcohols 6 and 8. The reaction of 8 with phenyl isothiocyanate, followed by cyclisation,
furnished 1,3-oxazine 15.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ity.15,16 (1R,2S)-2-Amino-4-methylenecyclopentanecar-
boxylic acid (BAY 10-8888) possesses antifungal
activity against Candida albicans, and clinical studies
are in progress.17,18 b-Amino acids can also be used as
building blocks of modified analogues of pharmacologi-
cally active peptides.19–23 Conformational studies of
b-amino acid oligomers are currently at the focus of
interest.24–26
The readily available homochiral terpenes and their
derivatives are widely used as chiral auxiliaries in enan-
tioselective transformations.1 Various amino alcohol
catalysts derived from monoterpenes such as (+)-pule-
gone,2 b-pinene,3 nopinone,4 fenchone-camphor,5
limonene6 and recently (+)-3-carene7 have been
reported to have been used successfully in enantioselec-
tive syntheses. Derivatives of a-pinene such as 2-
hydroxypinan-3-one8 and the enantiomerically pure
3-amino-2-hydroxypinane9 have also served as useful
chiral reagents. Monoterpene-fused 1,3-oxazines have
been applied as catalysts for enantioselective allylic
substitutions.10 In an earlier publication, we reported
the transformations of enantiomerically pure a-pinene
to b-amino acid derivatives and monoterpene-fused sat-
urated 1,3-heterocycles.11
Our present aim was the synthesis and transformation
of homochiral b-amino acid derivatives prepared from
(+)-3-carene,
a commercially available homochiral
source. The ring opening reactions of the corresponding
b-lactam 3 to give novel homochiral b-amino acid
derivatives were studied; and some cyclisation reactions
of the resulting compounds were carried out to produce
monoterpene-fused saturated 1,3-heterocycles.
b-Amino acids and their derivatives, such as amino
esters, amides or 1,3-amino alcohols, can serve for the
synthesis of a wide range of saturated heterocycles.12–14
Besides their chemical importance,12 b-amino acids and
their derivatives possess noteworthy pharmacological
effects; for example, (1R,2S)-2-aminocyclopentanecar-
boxylic acid (cispentacin) and 2-aminocyclohexenecar-
2. Results and discussion
The synthetic route to the novel homochiral b-amino
acid derivatives is shown in Scheme 1. The reaction of
chlorosulfonyl isocyanate (CSI) with a cycloalkane is a
well-known procedure for the synthesis of cycloalkane-
fused b-lactams. There are several examples in the
literature concerning the regio- and stereoselectivity of
the cycloaddition, which proceeds in accordance with
the Markovnikov orientation of CSI addition.27
boxylic acid (originally designed as
a pyridoxal
phosphate suicide inhibitor) have antifungal activ-
Starting from commercially available (+)-3-carene 1, the
cycloaddition of CSI furnished the enantiomeric b-lac-
* Corresponding author. Tel./fax: 36 62 545 564/36 62 545 705;
e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.001

3966
S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
Scheme 1. Reagents and conditions: (i) CSI, Et2O, 9 h, rt, 76%; (ii) Na2SO3, then KOH; (iii) Boc2O, Et3N, DMAP/THF, rt, 2 h,
82%; (iv) LiOH/H2O, THF, rt, 7 h, 94%; (v) cat. NaOMe/MeOH, rt, 2 h, 89%; (vi) CH2N2/Et2O, rt, 2 h, 98%; (vii) LiAlH4/THF,
rt, 2 h, 6: 95%, 8: 85%; (viii) TFA/CH2Cl2, rt, 2 h, 96%; (ix) dioxane/H2O, reflux, 48 h, 88%.
tam 2 in a regio- and stereoselective reaction. The exo
stereoselectivity of the cycloaddition was earlier
reported by Sasaki et al.28 The CSI addition proceeded
at room temperature in good yield (76%). There are
several methods in the literature for the ring opening of
azetidinones.14,29,30 Our first attempt was the ring open-
ing of 2 by refluxing with ethanol containing HCl to
obtain the corresponding amino ester.11 Hydrolysis of
the b-lactam ring of 2 to the amino acid was also
attempted with aqueous HCl.31 None of the applied
methods resulted in the expected compounds: only a
mixture of several decomposed products was obtained
under the given conditions. These results suggested that
the strongly constrained carene ring system decomposes
under highly acidic conditions. Activation of the car-
boxamide bond of azetidinone 2 therefore seemed
necessary.
Treatment of the b-lactam 2 with di-tert-butyl dicarbon-
ate resulted in N-Boc b-lactam 3, which was readily
opened under mild conditions. The reaction of 3 with
aqueousLiOHinTHF32 gavehomochiralN-Bocb-amino
acid 4 in excellent yield (98%). The N-Boc amino ester
was prepared in different ways. Either the ring opening
of N-Boc b-lactam 3 in the presence of a catalytic amount
of sodium methoxylate in dry methanol or the esterifica-
tion of N-Boc b-amino acid 4 with diazomethane in dry
diethyl ether gave 5 in excellent yield.
N-Boc amino ester 5 was reduced by lithium aluminium
hydride to N-methyl amino alcohol 6, and, after the
deprotection of 5, to the corresponding amino alcohol 8.
b-Amino ester 7 was transformed to b-amino acid 9 by
refluxing in a dioxane:water=1:1 mixture33 for 2 days
(Scheme 1).
Scheme 2. Reagents and conditions: (i) PhNCS/toluene, rt, 5 h, 91%; (ii) NH3/MeOH, rt, 11: 95%, 13: 93%; (iii) PhNCO/toluene,
rt, 5 h, 76%.

S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
3967
Scheme 3. Reagents and conditions: (i) PhNCS/toluene, rt, 5 h, 91%; (ii) MeI/MeOH, 15°C, 3 h, then KOH/MeOH, rt, 4 h, 90%;
(iii) HCl/EtOH, reflux, 1 h.
Scheme 4. Reagents and conditions: (i) NH3/MeOH, 4°C, 12 h, 60%; (ii) TFA/CH2Cl2, 0°C, 2 h, 18: 77%, 20: 65%; (iii)
PhCH2NH2, KCN, DMF, 40°C, 24 h, 78%.
When b-amino ester 7 was reacted with phenyl isothio-
cyanate or phenyl isocyanate, the corresponding
thiourea 10 or urea 12 was obtained. Compounds 10
and 12 were easily converted to 2-thioxo-4-pyrimidi-
none 11 and 2,4-pyrimidindione 13 by base-catalysed
ring closure,11 using methanol containing a catalytic
amount of NH3 (Scheme 2).
on a CHIRASIL-DEX CB column by GC. There was
no sign of the presence of any other diastereomer in the
spectra of the prepared compounds.
3. Conclusions
The regio- and stereoselective addition of CSI to (+)-3-
carene resulted in enantiomerically pure b-lactam 2,
which was activated with a tert-butoxycarbonyl group.
In contrast with b-lactam 2, the N-Boc b-lactam was
easily transformed to homochiral b-amino acid, amino
ester, 1,3-amino alcohol and carboxamide derivatives.
Starting from the amino ester, ring closure gave 2,4-
pyrimidinedione and 2-thioxo-4-pyrimidinone. The use
of 1,3-amino alcohol as starting material resulted in the
saturated 1,3-oxazine.
With phenyl isothiocyanate, amino alcohol 8 resulted in
the thiourea adduct 14, which was transformed to
2-phenylimino-1,3-oxazine 15. Preparation of the corre-
sponding thiazine 16 was not successful when HCl-con-
taining ethanol was used;34 only several decomposed
products were observed (Scheme 3).
The nucleophilic ring opening of N-Boc-b-lactam 3 was
also performed with amines such as NH3 and benzyl-
amine, resulting in N-Boc amides 17 and 19. Both 17
and 19 were deprotected with trifluoroacetic acid35 and
gave the expected amides 18 and 20 (Scheme 4).
The prepared b-amino acid derivatives may serve as
chiral building blocks in the asymmetric synthesis of
potential pharmacons, b-amino acid oligomers and
modified analogues of natural peptides. They can also
be used as chiral auxiliaries and catalysts in enantiose-
lective syntheses.
The compounds prepared have four stereogenic centres.
Accordingly, the diastereomeric and hence the enan-
tiomeric purity was proved by NMR spectroscopy and

3968
S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
4. Experimental
(1H, dd, J=8.5, 16.6 Hz, H-5), 0.72 (1H, dd, J=9.0,
17.6 Hz, H-3), 0.89 (1H, q, J=9.0 Hz, H-6), 0.95 (3H,
s, Me-4), 1.01 (3H, s, Me-4), 1.05 (1H, m, J=4.5, 9.1
Hz, H-2), 1.44 (3H, s, Me-7), 1.49 (9H, s, tert-butyl),
2.16 (1H, ddd, J=2.5, 8.0, 15.1 Hz, H-2), 2.46 (1H, q,
1H and 13C NMR spectra were recorded on a Bruker
Avance DRX 400 spectrometer (400 MHz, l=0
(TMS)), in CDCl3, with the exceptions of compounds 9
and 20 (D2O) and 18 (DMSO). Chemical shifts are
expressed in ppm (l) relative to TMS as internal refer-
ence. J values are given in Hz. FT-IR spectra were
recorded on a Perkin–Elmer model 1000 spectrophoto-
meter. Microanalyses were performed on a Perkin–
Elmer 2400 elemental analyser. GC measurements were
made on a Crompack CP-9002 system, consisting of a
Flame Ionization Detector 901A and a Maestro II
Chromatography data system (Chrompack Interna-
tional B.V., Middelburg, The Netherlands). The
column used for direct separation was a CHIRASIL-
DEX CB column (2500×0.25 mm I.D.) at 160°C, 80
kPa for 2. Optical rotations were obtained with a
Perkin–Elmer 341 polarimeter. Melting points were
determined on a Kofler apparatus and are uncorrected.
J=8.0 Hz, H-6), 2.74 (1H, dd, J=2.5, 4.5 Hz, H-1); 13
C
NMR (CDCl3) l (ppm): 15.6, 17.4, 17.9, 18.3, 18.4,
24.4, 26.2, 28.7, 28.8, 55.0, 58.8, 83.2, 148.3, 169.2.
Anal. calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01.
Found: C, 68.56; H, 9.16; N, 5.13%.
4.3. (1R,3R,4S,6S)-4-tert-Butoxycarbonylamino-4,7,7-
trimethylbicyclo[4.1.0]heptane-3-carboxylic acid 4
N-Boc-lactam 3 (2.0 g, 7.17 mmol) was dissolved in
THF (50 mL) and treated with aq. LiOH (0.9 g in 20
mL of water) at room temperature. The mixture was
stirred at room temperature for 7 h. The THF was
removed in vacuo and, after the addition of water (10
mL), the solution was acidified to pH 3.5–4.0 with
acetic acid and extracted with ethyl acetate (3×30 mL).
The combined organic phase was dried (Na2SO4),
filtered and concentrated in vacuo to give a white
crystalline product, 4 (2.0 g, 94% yield); mp 135–139°C;
[h]2D0=+31.3 (c 1, MeOH); IR=1686, 1729, 2977 cm−1;
1H NMR (CDCl3) l (ppm): 0.58–0.75 (3H, m, H-6,
H-1, H-5), 0.85 (3H, s, Me-7), 0.95 (3H, s, Me-7), 1.27
(3H, s, Me-3), 1.38 (9H, s, tert-butyl), 1.80 (1H, dd,
J=7.1, 14.1 Hz, H-2), 1.90 (1H, dd, J=6.6, 11.6 Hz,
H-5), 2.02–2.13 (1H, m, H-2), 2.96 (1H, dd, J=7.6,
13.6 Hz, H-3), 5.37 (1H, bs, NH); 13C NMR (CDCl3) l
(ppm): 15.8, 17.9, 18.1, 18.5, 21.0, 25.6, 29.1, 29.3, 30.8,
50.4, 51.8, 79.9, 156.0, 181.4. Anal. calcd for
C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C,
64.45; H, 8.96; N, 3.96%.
4.1. (1R,3R,5S,7S)-4,4,7-Trimethyl-8-azatricyclo-
[5.2.0.03,5]nonan-9-one 2
A mixture of 2.72 g (20.0 mmol) of (+)-(1S,6R)-3-
carene 1 (Aldrich Chemical Co., 90% purity, 98% ee)
and 2.84 g (20.0 mmol) of CSI was stirred in dry diethyl
ether (50 mL) at room temperature for 9 h. Na2SO3
(3.78 g) in water (50 mL) was then cautiously added
dropwise to the solution. The pH was held at 7–8 by
the addition of 20% aqueous KOH. After separation of
the organic phase, the aqueous layer was extracted with
diethyl ether (2×50 mL). The combined organic layer
was dried (Na2SO4) and evaporated, and the resulting
white crystalline product was recrystallized from hexane
to give 2 (2.72 g, 76% yield); mp 108–111°C (lit.17
111–114°C); [h]2D0=+56.9 (c 1, MeOH); IR=1769, 3233
4.4. Methyl (1R,3R,4S,6S)-4-tert-butoxycarbonylamino-
4,7,7-trimethylbicyclo[4.1.0]heptane-3-carboxylate 5
cm−1; H NMR (CDCl3) l (ppm): 0.66 (1H, dd, J=8.0,
1
16.6 Hz, H-5), 0.76 (1H, dd, J=8.5, 17.1 Hz, H-3), 0.97
(3H, s, Me-4), 1.04 (3H, s, Me-4), 1.00–1.11 (2H, m,
H-6, H-2), 1.36 (3H, s, Me-7), 1.99 (1H, dd, J=8.0,
15.6 Hz, H-6), 2.15 (1H, ddd, J=2.5, 10.5, 15.6 Hz,
H-2), 2.72 (1H, dd, J=2.5, 4.5 Hz, H-1), 5.91 (1H, bs,
NH); 13C NMR (CDCl3) l (ppm): 17.3, 24.2, 26.3, 28.9,
54.9, 58.9, 77.7, 83.1, 148.3. Anal. calcd for C11H17NO:
C, 73.70; H, 9.56; N, 7.81. Found: C, 74.05; H, 9.33; N,
7.96%.
Method A: To a stirred solution of N-Boc amino acid
4 (3.0 g, 10 mmol) in dry diethyl ether (30 mL), an
ethereal solution of diazomethane was added dropwise
at room temperature until the yellow colour remained.
After stirring for 1 h, the diethyl ether was evaporated
off and a yellow oil was obtained. The resulting crude
product was used in the next step without further
purification.
4.2. (1R,3R,5S,7S)-N-tert-Butoxycarbonyl-4,4,7-tri-
Method B: To a stirred solution of N-Boc lactam 3
(9.70 g, 35 mmol) in dry methanol (50 mL), NaOMe
was added in catalytic amount at room temperature.
After stirring for 2 h (the reaction was monitored by
TLC), the solution was evaporated. Water (30 mL) was
added to the oily residue, followed by extraction with
CHCl3 (3×30 mL). The organic phase was dried
(Na2SO4) and evaporated. 5 was formed as a yellow oil
(Method A: 3.10 g, 98% yield, method B: 9.57 g, 89%
methyl-8-azatricyclo[5.2.0.03,5]nonan-9-one 3
To a stirred solution of 2.0 g (11.2 mmol) of azetidi-
none 2 in dry THF (20 mL), triethylamine (0.32 mL,
22.4 mmol), di-tert-butyl dicarbonate (4.89 g, 22.4
mmol) and a catalytic amount of 4-dimethylamino-
pyridine were added. After stirring for 2 h at room
temperature (the reaction was monitored by means of
TLC), the mixture was evaporated to dryness. The oily
residue obtained was purified by flash chromatography
on a silica gel column (hexane:ethyl acetate=9:1),
resulting in a white crystalline product, 3 (2.56 g, 82%
yield); mp 107–112°C; [h]2D0=+29.7 (c 1, MeOH); IR=
1708, 1792, 2936 cm−1; 1H NMR (CDCl3) l (ppm): 0.53
1
yield); [h]2D0=−22.3 (c 1, MeOH); H NMR (CDCl3) l
(ppm): 0.79–0.64 (3H, m, H-6, H-1, H-5), 0.91 (3H, s,
Me-7), 1.00 (3H, s, Me-7), 1.24 (3H, s, Me-3), 1.44 (9H,
s, tert-butyl), 1.79 (1H, dd, J=7.1, 14.6 Hz, H-2), 1.95
(1H, dd, J=7.1, 12.1 Hz, H-5), 2.11 (1H, ddd, J=8.06,
14.6, 20.1 Hz, H-2), 3.12 (1H, t, J=10.6 Hz, H-3), 3.70

S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
3969
1
(3H, s, COO-Me), 5.48 (1H, bs, NH); 13C NMR
(CDCl3) l (ppm): 15.8, 17.9, 18.0, 18.6, 21.0, 25.6, 29.1,
29.2, 30.1, 50.2, 51.8, 52.4, 79.1, 156.9, 177.2. Anal.
calcd for C17H29NO4: C, 65.57; H, 9.39; N, 4.50.
Found: C, 65.34; H, 9.18; N, 4.64%.
oil (0.73 g, 85% yield); [h]2D0=+10.1 (c 1, MeOH); H
NMR (CDCl3) l (ppm): 0.61–0.69 (1H, dd, J=3.0, 11.1
Hz, H-6), 0.77 (1H, t, J=8.5 Hz, H-1), 0.84–0.91 (1H,
m, H-5), 0.90 (3H, s, Me-7), 1.03 (3H, s, Me-7), 1.20
(3H, s, Me-4), 1.23 (1H, d, J=4.5 Hz, H-2), 1.56–1.71
(2H, m, H-5, H-2), 2.28 (1H, ddd, J=8.1, 15.1, 20.6
Hz, H-3), 3.00 (2H, bs, NH2), 3.34 (1H, dd, J=2.0, 11.1
Hz, CH2-OH), 4.11 (1H, dd, J=3.0, 11.1 Hz, CH2-
OH); 13C NMR (CDCl3) l (ppm): 15.5, 18.1, 18.3, 19.4,
19.5, 27.7, 29.6, 37.9, 41.3, 51.2, 65.1. Anal. calcd for
C11H21NO: C, 72.08; H, 11.55; N, 7.64. Found: C,
71.95; H, 11.42; N, 7.53%.
4.5. (1R,3R,4S,6S)-(4,7,7-Trimethyl-4-methylamino-
bicyclo[4.1.0]hept-3-yl)methanol 6
To a slurry of LiAlH4 (0.36 g, 9.48 mmol) in dry THF
(20 mL), amino ester 5 (1.0 g, 3.21 mmol) in THF (5
mL) was added dropwise at 0°C. After stirring for 2 h
at room temperature (the reduction was monitored by
means of TLC), the mixture was decomposed with
water (1.0 mL) in THF (10 mL) under ice cooling. The
inorganic material was filtered off and washed with
THF (3×20 mL). Drying (Na2SO4) and evaporation
gave 7 as a yellow oil (0.60 g, 95% yield); [h]2D0=+11 (c
4.8. (1R,3R,4S,6S)-4-Amino-4,7,7-trimethylbicyclo-
[4.1.0]heptane-3-carboxylic acid 9
Amino ester 7 (0.55 g, 2.60 mmol) was dissolved in a
mixture of dioxane and water (1:1, 10 mL). After
stirring and refluxing for 2 days (the reaction was
monitored by means of TLC), the mixture was evapo-
rated to dryness and the resulting white crystalline
product was filtered off and washed with acetone to
furnish 9 (0.45 g, 88% yield); mp 273–275°C; [h]2D0=+23
1
1, MeOH); H NMR (CDCl3) l (ppm): 0.52–0.59 (1H,
m, H-6), 0.72 (1H, t, J=8.1 Hz, H-1), 0.78 (1H, dd,
J=5.0, 15.1 Hz, H-5), 0.85–0.93 (1H, m, H-2), 0.91
(3H, s, Me-7), 1.03 (3H, s, Me-7), 1.15 (3H, s, Me-4),
1.58 (1H, dd, J=7.05, 15.11 Hz, H-5), 2.13–2.25 (2H,
m, H-2, H-3), 2.26 (3H, s, NH-Me), 3.30 (1H, dd,
J=1.5, 11.1 Hz, CH2-OH), 4.13 (1H, dd, J=2.5, 10.6
Hz, CH2-OH); 13C NMR (CDCl3) l (ppm): 15.5, 17.8,
18.1, 18.9, 19.1, 23.8, 28.0, 28.1, 29.5, 42.9, 54.1, 63.3.
Anal. calcd for C12H23NO: C, 73.04; H, 11.75; N, 7.10.
Found: C, 73.15; H, 11.68; N, 6.90%.
1
(c 1, MeOH); H NMR (D2O) l (ppm): 0.74–0.83 (2H,
m, H-6, H-1), 0.97 (3H, s, Me-7), 1.03 (3H, s, Me-7),
1.31 (3H, s, Me-4), 1.36 (1H, d, J=4.0 Hz, H-5),
1.85–2.02 (2H, m, H-2, H-5), 2.08–2.20 (2H, m, H-2,
H-3); 13C NMR (D2O) l (ppm): 14.3; 15.9, 17.8, 18.0,
20.3, 23.9, 28.2, 29.9, 48.6, 52.6, 183.2. Anal. calcd for
C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C,
66.75; H, 9.45; N, 6.85%.
4.6. Methyl (1R,3R,4S,6S)-4-amino-4,7,7-trimethyl-
bicyclo[4.1.0]heptane-3-carboxylate 7
4.9. Thiourea derivative 10
To a stirred solution of N-Boc amino ester 5 (0.20 g,
0.64 mmol) in dry CH2Cl2 (10 mL), trifluoroacetic acid
(0.50 mL) was added at 0°C. After stirring for 2 h, the
solution was neutralized with saturated aq. NaHCO3
solution and extracted with CH2Cl2 (2×30 mL). The
combined organic phase was dried (Na2SO4) and evap-
orated to give 6 as a yellow oil product (0.13 g, 96%
Phenyl isothiocyanate (0.60 g, 4.40 mmol) was added to
a solution of 0.80 g (3.80 mmol) of amino ester 7 in dry
toluene (30 mL). After stirring for 5 h at room temper-
ature (the reaction was monitored by means of TLC),
the solution was evaporated to dryness and the
obtained white crystalline product was recrystallized
from diisopropyl ether to give 10 (1.10 g, 84% yield);
mp 142–145°C; [h]2D0=−26.7 (c 1, MeOH); IR=1723,
1
yield); [h]2D0=−26.7 (c 1, MeOH); H NMR (CDCl3) l
(ppm: 0.67–0.77 (2H, m, H-6, H-1), 0.93 (3H, s, Me-7),
1.02 (6H, s, Me-7, Me-4), 1.06 (1H, dd, J=4.5, 14.6 Hz,
H-5), 1.85 (2H, ddd, J=9.6, 14.6, 24.1 Hz, H-2, H-5),
2.03 (1H, dd, J=6.5, 12.1 Hz, H-2), 2.14 (1H, ddd,
J=7.5, 12.1, 19.6 Hz, H-3), 3.66 (3H, s, COO-Me); 13C
NMR (CDCl3) l (ppm): 15.3, 17.8, 17.9, 18.3, 20.8,
28.6, 29.3, 33.5, 49.2, 50.2, 51.6, 177.1. Anal. calcd for
C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.04; H, 9.82; N, 6.52%.
1
2955, 3333 cm−1; H NMR (CDCl3) l (ppm): 0.54 (1H,
t, J=8.6 Hz, H-6), 0.72 (1H, dd, J=5.6, 15.1 Hz, H-1),
1.03 (3H, s, Me-7), 1.50 (3H, s, Me-7), 1.66 (3H, s,
Me-4), 1.77 (2H, dd, J=7.1, 15.1 Hz, H-5, H-2), 1.95
(2H, dd, J=7.6, 12.1 Hz, H-5, H-2), 3.54 (3H, s,
COO-Me), 4.20 (1H, dd, J=9.6, 15.1 Hz, H-3), 7.23-
7.39 (5H, m, Ph); 13C NMR (CDCl3) l (ppm): 15.8,
17.7, 18.2, 18.7, 21.1, 24.1, 28.9, 29.1, 51.2, 52.5, 55.8,
126.5, 127.8, 130.4, 137.0, 176.7, 180.1. Anal. calcd for
C19H26N2O2S: C, 65.86; H, 7.56; N, 8.08. Found: C,
65.75; H, 7.45; N, 7.85%.
4.7. (1R,3R,4S,6S)-(4-Amino-4,7,7-trimethylbicyclo-
[4.1.0]hept-3-yl)methanol 8
To a slurry of LiAlH4 (0.36 g, 9.48 mmol) in dry THF
(20 mL), amino ester 7 (1.0 g, 4.74 mmol) in THF (5
mL) was added dropwise at 0°C. After stirring for 2 h
at room temperature (the reduction was monitored by
means of TLC), the mixture was decomposed by the
cautious addition of water (2.0 mL) dissolved in THF
(10 mL) under ice cooling. The inorganic material was
filtered off and washed with THF. Drying (Na2SO4)
and evaporation of the solvent resulted in 8 as a yellow
4.10. (1aR,2aR,6aS,7aS)-1,1,6a-Trimethyl-4-phenyl-5-
thioxodecahydro-4,6-diazacyclopropa[b]naphthalen-3-one
11
The appropriate thiourea derivative 10 (0.50 g, 1.45
mmol) was dissolved in methanol (10 mL). Five drops
of methanol containing 25% NH3 were added to the
solution. After standing for 1 day at room temperature,
the solution was evaporated to give 11 as a crystalline

3970
S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
product (0.50 g, 95% yield); mp 293–296°C; [h]2D0=
+49.3 (c 1, MeOH); IR=1189, 1713, 2921, 3254 cm−1;
1H NMR (CDCl3) l (ppm): 0.73–0.82 (1H, m, H-7a),
0.87 (1H, d, J=8.1 Hz, H-1a), 0.91 (3H, s, Me-1), 1.06
(3H, s, Me-1), 1.24 (1H, dd, J=4.0, 15.6 Hz, H-7), 1.41
(3H, s, Me-6a), 1.95–2.06 (1H, m, H-2), 2.10–2.21 (2H,
m, H-2, H-7), 2.28 (1H, ddd, J=1.5, 8.1, 10.1 Hz,
H-2a), 7.15 (2H, d, J=7.1 Hz, Ph), 7.39–7.50 (3H, m,
Ph), 7.54 (1H, bs, NH); 13C NMR (CDCl3) l (ppm):
15.8, 16.5, 18.6, 18.8, 20.4, 27.4, 28.9, 30.3, 45.3, 52.3,
129.3, 129.6, 129.8, 172.0, 182.6. Anal. calcd for
C18H22N2OS: C, 68.75; H, 7.05; N, 8.91. Found: C,
68.65; H, 6.96; N, 8.85%.
TLC), the solution was evaporated and resulted in 14 as
a white crystalline product (0.16 g, 91% yield); mp
157–160°C; [h]2D0=−80 (c 1, MeOH); IR=1551, 3236,
1
3399 cm−1; H NMR (CDCl3) l (ppm): 0.73–0.83 (2H,
m, H-6, H-1), 0.91 (3H, s, Me-7), 1.02 (3H, s, Me-7),
1.47 (2H, dd, J=7.1, 15.1, H-5, H-2), 1.64 (3H, s,
Me-4), 1.68–1.80 (2H, m, H-5, H-2), 3.32 (1H, dd,
J=3.0, 11.1 Hz, CH2-OH), 3.81 (1H, dd, J=11.1, 16.6
Hz, H-4), 3.91 (1H, dd, J=3.0, 11.1 Hz, CH2-OH),
7.12–7.53 (5H, m, Ph); 13C NMR (CDCl3) l (ppm):
15.8, 18.2, 18.7, 19.2, 19.6, 24.2, 29.3, 31.4, 45.6, 57.4,
63.2, 126.8, 127.8, 130.4, 137.2, 180.1. Anal. calcd for
C18H26N2OS: C, 67.88; H, 8.23; N, 8.80. Found: C,
67.65; H, 8.16; N, 8.68%.
4.11. Urea derivative 12
4.14. (1aR,2aR,6aS,7aS)-Phenyl-(1,1,6a-trimethylocta-
hydro-4-oxa-6-azacyclopropa[b]naphthalen-5-ylidene)-
amine 15
Phenyl isocyanate (0.24 g, 2.04 mmol) was added to a
solution of 0.40 g (1.89 mmol) amino ester 7 in toluene
(30 mL). After stirring for 5 h at room temperature (the
reaction was monitored by TLC), the solution was
evaporated to dryness, resulting in 12 as a crystalline
product (0.45 g, 76% yield); mp 179–182°C; [h]2D0=
+60.9 (c 1, MeOH); IR=1727, 3315, 3406 cm−1; 1H
NMR (CDCl3) l (ppm): 0.59–0.65 (1H, m, H-6), 0.75–
0.87 (2H, m, H-1, H-2), 0.91 (3H, s, Me-7), 1.00 (3H, s,
Me-7), 1.32 (3H, s, Me-4), 1.78–1.87 (1H, m, H-5),
1.92–2.06 (2H, m, H-2, H-5), 3.34 (1H, dd, J=8.6, 13.6
Hz, H-3), 3.66 (3H, s, COO-Me), 5.71 (1H, bs, NH),
6.28 (1H, bs, NH), 7.02–7.09 (1H, m, Ph), 7.28–7.34
(4H, m, Ph); 13C NMR (CDCl3) l (ppm): 15.8, 17.9,
18.1, 18.8, 21.2, 25.8, 29.2, 30.1, 50.1, 52.5, 52.6, 121.4,
124.0, 129.8, 139.7, 155.9, 177.7. Anal. calcd for
C19H26N2O3: C, 69.06; H, 7.93; N, 8.48. Found: C,
68.85; H, 7.96; N, 8.65%.
To a stirred solution of 0.50 g (1.57 mmol) of thiourea
derivative 14 in 15 mL of methanol, 0.54 mL (8.64
mmol) of iodomethane was added and the solution was
stirred at 15°C for 3 h. After evaporation of the sol-
vent, the residue was stirred in 15 mL of 2.5 N KOH in
methanol for 4 h. The solution was then evaporated,
and the residue was dissolved in water (30 mL) and
extracted with chloroform (3×30 mL). After drying
(Na2SO4) and evaporation of the organic layer, the
crystalline product was recrystallized from hexane,
which resulted in oxazine 15 (0.40 g, 90% yield); mp
132–134°C; [h]2D0=+29.7 (c 1, MeOH); IR=1669, 2921
1
cm−1; H NMR (CDCl3) l (ppm): 0.60–0.82 (2H, m,
H-7a, H-1a), 0.92 (3H, s, Me-1), 0.95 (1H, m, H-7),
1.03 (3H, s, Me-1), 1.21 (3H, s, Me-6a), 1.26–1.38 (1H,
m, H-2), 1.62–1.92 (3H, m, H-2a, H-2, H-7), 3.97 (1H,
dd, J=3.5, 10.1 Hz, H-3), 4.30 (1H, dd, J=4.0, 10.6
Hz, H-3), 6.89–7.27 (5H, m, Ph); 13C NMR (CDCl3) l
(ppm): 15.3, 17.9, 18.1, 19.1, 19.4, 21.4, 25.9, 28.7, 31.9,
34.2, 70.5, 121.6, 122.6, 124.2, 129.4, 148.3. Anal. calcd
for C18H24N2O: C, 76.02; H, 8.51; N, 9.85. Found: C,
75.95; H, 8.26; N, 9.75%.
4.12. (1aR,2aR,6aS,7aS)-1,1,6a-Trimethyl-4-phenylocta-
hydro-4,6-diazacyclopropa[b]naphthalene-3,5-dione 13
The appropriate urea derivative 12 (0.50 g, 1.52 mmol)
was dissolved in 20 mL of methanol. Five drops of
methanol containing 25% NH3 were added to the solu-
tion. After standing for 4 days at room temperature,
the solution was evaporated and resulted in 13 as a
white crystalline product (0.42 g, 93% yield); mp 191–
196°C; [h]2D0=+51.3 (c 1, MeOH); IR=1713, 2920, 3254
4.15. tert-Butyl (1R,3R,4S,6S)-(3-aminocarbonyl-4,7,7-
trimethylbicyclo[4.1.0]hept-4-yl)-carbamate 17
1
cm−1; H NMR (CDCl3) l (ppm): 0.68–0.77 (1H, m,
N-Boc-b-lactam 3 (2.0 g, 7.17 mmol) was dissolved in
20 mL of a 25% solution of NH3 in dry methanol. The
reaction mixture was allowed to stand at 4°C for 12 h.
After evaporation (first at room temperature and then
on a 60°C water bath), the white crystalline product
was purified by flash chromatography on a silica gel
column (hexane:ethyl acetate=4:1) to give 17 (1.27 g;
H-7a), 0.80–0.89 (1H, m, H-1a), 0.92 (3H, s, Me-1),
1.06 (3H, s, Me-1), 1.26 (1H, dd, J=4.5, 16.1 Hz, H-7),
1.38 (3H, s, Me-6a), 1.97–2.17 (3H, m, 2×H-2, H-7),
2.20–2.28 (1H, m, H-2a), 5.25 (1H, bs, NH), 7.13–7.20
(2H, m, Ph), 7.35–7.50 (3H, m, Ph); 13C NMR (CDCl3)
l (ppm): 17.9, 18.1, 18.8, 21.4, 25.8, 29.2, 30.1, 50.5,
52.6, 52.8, 121.7, 124.3, 129.8, 139.4, 177.8. Anal. calcd
for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.35; H, 7.26; N, 9.25%.
1
60% yield); mp 81–85°C; [h]2D0=+33 (c 1, MeOH); H
NMR (CDCl3) l (ppm): 0.64.0.79 (3H, m, H-6, H-1,
H-5), 0.90 (3H, s, Me-7), 1.01 (3H, s, Me-7), 1.29 (3H,
s, Me-4), 1.43 (9H, s, tert-butyl), 1.58–1.63 (1H, m,
H-2), 1.75 (1H, dd, J=7.1, 15.1 Hz, H-5), 2.10 (1H, dd,
J=9.6, 15.6 Hz, H-2), 3.15–3.21 (1H, m, H-3), 3.96
(1H, bs, NH); 13C NMR (CDCl3) l (ppm): 16.1, 17.9,
18.1, 18.7, 21.4, 25.6, 29.2, 30.2, 30.3, 38.4, 51.0, 51.7,
79.1, 155.9, 178.9. Anal. calcd for C16H28N2O3: C,
64.83; H, 9.52; N, 9.45. Found: C, 64.76; H, 9.38; N,
9.27%.
4.13. (1S,3S,4R,6R)-1-(4-Hydroxymethyl-3,7,7-tri-
methylbicyclo[4.1.0]hept-3-yl)-3-phenylthiourea 14
Phenyl isothiocyanate (0.04 g, 0.29 mmol) was added to
a solution of 0.10 g (0.54 mmol) of amino alcohol 8 in
10 mL of dry toluene. After stirring for 3 h at room
temperature (the reaction was monitored by means of

S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
3971
4.16. (1R,3R,4S,6S)-4-Amino-4,7,7-trimethylbicyclo-
[4.1.0]heptane-3-carboxamide 18
Anal. calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78.
Found: C, 75.22; H, 8.99; N, 9.61%.
To a stirred solution of N-Boc carboxamide 17 (0.20 g,
0.67 mmol) in dry CH2Cl2 (10 mL), trifluoroacetic acid
(0.50 mL) was added at 0°C. After stirring for 2 h, the
trifluoroacetic acid was neutralized with saturated
aqueous NaHCO3, and the phases were separated. The
aqueous phase was extracted with CH2Cl2 (2×20 mL).
The combined organic phase was dried (Na2SO4) and
evaporated to give 18 as a yellow oil product (0.10 g,
77% yield); [h]D20=+36.2 (c 1, MeOH); 1H NMR
(DMSO) l (ppm): 0.63 (1H, dd, J=5.0, 9.6 Hz, H-6),
0.74 (1H, d, J=7.6 Hz, H-1), 0.93 (3H, s, Me-7), 1.00
(3H, s, Me-7), 1.09 (1H, dd, J=4.5, 15.6 Hz, H-5), 1.18
(3H, s, Me-4), 1.82 (1H, dd, J=6.0, 13.6 Hz, H-2),
1.94–2.08 (2H, m, H-5, H-2), 2.12 (1H, dd, J=9.6, 15.6
Hz, H-3), 3.93 (2H, bs, NH2); 13C NMR (DMSO) l
(ppm): 14.8, 15.9, 17.6, 17.9, 19.6, 23.9, 28.6, 30.2, 44.4,
51.7, 176.6. Anal. calcd for C11H20N2O: C, 67.31; H,
10.27; N, 14.27. Found: C, 67.12; H, 10.09; N, 14.11%.
Acknowledgements
Financial support from the National Scientific Research
Foundation, Hungary (OTKA, T-04888, TS 040888, T
034901 and F 032828) is gratefully acknowledged.
References
1. Ho, T.-L. Enantioselective Synthesis of Natural Products
from Chiral Terpenes; John Wiley: New York, 1992.
2. He, X. C.; Eliel, E. L. Tetrahedron 1987, 43, 4979–4987.
3. Posner, T.; Sears, P. T.; Nugent, W. A.; Blackmond, D.
G. Org. Lett. 2000, 2, 2511–2513.
4. Goralski, C. T.; Chrisman, W.; Hasha, D. L.; Nicholson,
L. W.; Rudolf, P. R.; Zakett, D.; Singaram, B. Tetra-
hedron: Asymmetry 1997, 8, 3863–3871.
4.17. tert-Butyl (1R,3R,4S,6S)-(3-benzylaminocarbonyl-
4,7,7-trimethylbicyclo[4.1.0]hept-4-yl)-carbamate 19
5. Goldfuss, B.; Steigelman, M.; Khan, S. I.; Houk, K. N. J.
Org. Chem. 2000, 65, 77–82.
N-Boc-b-lactam 3 (0.28 g, 1.0 mmol) was dissolved in
dry DMF (10 mL) under a N2 atmosphere. Benzyl-
amine (0.21 g, 2.0 mmol) and 0.05 g of KCN were
added. After stirring for 24 h at 40°C (the reaction was
monitored by means of TLC), diethyl ether (20 mL)
was added to the solution and the mixture was washed
in turn with brine (2×20 mL), 1N HCl (20 mL) and
saturated aqueous NaHCO3 (20 mL). After drying
(Na2SO4) and evaporation of the organic phase, the
white crystalline product obtained was purified by flash
chromatography on a silica gel column (hexane:ethyl
acetate=4:1) to give 19 (0.29 g, 78% yield); mp 182–
184°C; [h]2D0=+31.5 (c 1, MeOH); IR=1716, 2934, 3284
6. Steiner, D.; Sethofer, S. D.; Goralski, C. T.; Singaram, B.
Tetrahedron: Asymmetry 2002, 13, 1477–1483.
7. Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry
2003, 14, 1763–1766.
8. Solladie-Cavallo, A.; Koessler, J. L. J. Org. Chem. 1994,
59, 3240–3242.
9. Masui, M.; Shioiri, T. Tetrahedron 1995, 51, 8363–8370.
10. Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37,
9143–9146.
11. Szakonyi, Z.; Martinek, T.; Hete´nyi, A.; Fu¨lo¨p, F. Tetra-
hedron: Asymmetry 2000, 11, 4571–4579.
12. Juaristi, E. Enantioselective Synthesis of i-Amino Acids,
New York, 1997.
1
cm−1; H NMR (CDCl3) l (ppm): 0.61–0.79 (4H, m,
13. Fu¨lo¨p, F. In Studies in Natural Product Chemistry; Atta-
ur-Rahman, Ed.; Elsevier, 2000; Vol. 22, pp. 273–306.
14. Fu¨lo¨p, F. Chem. Rev. 2001, 101, 2181–2204 and refer-
ences cited therein.
15. Knapp, S. Chem. Rev. 1995, 95, 1859–1876 and references
cited therein.
16. Kunisch, F.; Babczinski, P.; Arlt, D.; Plempel, M. Ger.
Offen. DE 4,028,046; Chem. Abstr. 1992, 117, 20486a.
17. Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.;
Schmidt, A.; Scho¨nfeld, W. Bioorg. Med. Chem. Lett.
2003, 13, 433–436.
H-6, H-1, H-5, H-2), 0.87 (3H, s, Me-7), 1.25 (3H, s,
Me-7), 1.43 (9H, s, tert-butyl), 1.52 (3H, s, Me-3), 1.72
(2H, dd, J=7.1, 15.1 Hz, CH2-Ph), 2.25 (1H, ddd,
J=8.06, 14.6, 19.6 Hz, H-2), 3.20 (1H, dd, J=9.1, 14.6
Hz, H-5), 4.43 (1H, d, J=6.0 Hz, H-3), 6.25 (1H, bs,
NH), 7.22-7.38 (5H, m, Ph); 13C NMR (CDCl3) l
(ppm): 16.1, 17.9, 18.2, 18.7, 21.7, 25.7, 26.3, 28.8, 29.2,
30.1, 44.3, 52.1, 79.0, 128.4, 128.5, 129.5, 138.4, 156.0,
176.2. Anal. calcd for C23H34N2O3: C, 71.47; H, 8.87;
N, 7.25. Found: C, 71.12; H, 8.59; N, 7.11%.
18. Mittendorf, J.; Benet-Buchholz, J.; Fey, P.; Mohrs, K.-L.
4.18. (1R,3R,4S,6S)-N-Benzyl-4-amino-4,7,7-trimethyl-
bicyclo[4.1.0]heptane-3-carboxamide 20
Synthesis 2003, 1, 136–140.
19. Bozo´, B.; Fu¨lo¨p, F.; To´th, G. K.; To´th, G.; Szucs, M.
Neuropeptides 1997, 31, 367–372.
The Boc group of the N-benzyl derivative of 19 (1.0 g,
2.59 mmol) was removed according to Section 4.17 to
give benzylamide 20 as a yellow oil (0.48 g, 65% yield);
20. Porter, E. A.; Wang, X.; Lee, H.; Weisblum, B.; Gellman,
S. H. Nature 2000, 404, 565.
21. Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.;
Aquilar, M. I. Curr. Med. Chem. 2002, 9, 811–822.
22. Park, J. S.; Lee, H. S.; Lai, J. R.; Kim, B. M.; Gellman,
S. H. J. Am. Chem. Soc. 2003, 125, 8539–8545.
23. Langenhan, J. M.; Guzei, I. A.; Gellman, S. H. Angew.
Chem., Int. Ed. 2003, 42, 2402–2405.
1
[h]2D0=+34.3 (c 1, MeOH); H NMR (D2O) l (ppm):
0.34–0.52 (2H, m, H-6, H-1), 0.70 (6H, s, Me-7, Me-7),
0.75 (3H, s, Me-4), 1.47 (2H, m, H-5, H-2), 1.62 (1H,
dd, J=6.0, 11.6 Hz, H-5), 1.83 (2H, m, H-2, H-3), 4.03
(2H, s, CH2-Ph), 6.95–7.19 (5H, m, Ph); 13C NMR
(D2O) l (ppm): 15.6, 18.0, 18.1, 18.7, 21.6, 29.3, 29.8,
35.2, 42.7, 49.1, 49.1, 127.6, 128.1, 129.1, 140.4, 176.3.
24. Gademann, K.; Hane, A.; Rueping, M.; Jaun, B.; See-
bach, D. Angew. Chem., Int. Ed. 2003, 42, 1534–1537.

3972
S. Gyo´nfal6i et al. / Tetrahedron: Asymmetry 14 (2003) 3965–3972
25. Glatti, A.; Daura, X.; Seebach, D.; van Gunsteren, W. F.
J. Am. Chem. Soc. 2002, 124, 12972–12978.
26. Martinek, T. A.; To´th, G. K.; Vass, E.; Hollo´si, M.;
Fu¨lo¨p, F. Angew. Chem., Int. Ed. 2002, 41, 1718–1721.
27. Kamal, A.; Sattur, P. B. Heterocycles 1987, 26, 1051–
1076.
31. Szakonyi, Z.; Fu¨lo¨p, F.; Berna´th, G.; Evanics, F.; Rid-
dell, F. G. Tetrahedron 1998, 54, 1013–1020.
32. Furet, P.; Garc´ıa-Ecchever´ıa, C.; Gay, B.; Schoepfer, J.;
Zeller, M.; Rahuel, J. J. Med. Chem. 1999, 42, 2358–
2363.
33. Tamagnan, G.; Gao, Y.; Baldwin, R. M.; Zoghbi, S. S.;
Neumeyer, J. L. Tetrahedron Lett. 1996, 37, 4353–
4356.
28. Sasaki, T.; Eguchi, S.; Yamada, H. J. Org. Chem. 1973,
38, 679–686.
34. Berna´th, G.; Szakonyi, Z.; Fu¨lo¨p, F.; Soha´r, P. Hetero-
cycles 1994, 37, 1687–1694.
35. Csomo´s, P.; Berna´th, G.; Fu¨lo¨p, F. Monatsh. Chem.
29. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Synlett 2001, 12, 1813–1826.
30. Parsons, P. J.; Camp, N. P.; Edwards, N.; Sumoreeah, L.
2002, 133, 1077–1084.
R. Tetrahedron 2000, 56, 309–315.