Synthesis and transformations of enantiomeric 1,2-disubstituted monoterpene derivatives

Article abstract of DOI:10.1016/S0957-4166(00)00435-3

Regio- and stereospecific addition of chlorosulfonyl isocyanate to (+)- and (-)-α-pinene 1 resulted in enantiomerically pure β-lactams 2, which were converted to enantiomeric β-amino esters 3 and 1,3-amino alcohols 4 and 6 with ee >99%. The resulting 1,3-

Full text of DOI:10.1016/S0957-4166(00)00435-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4571–4579
Synthesis and transformations of enantiomeric
1,2-disubstituted monoterpene derivatives†
Zsolt Szakonyi, Tama´s Martinek, Anaszta´zia Hete´nyi and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged POB 121, Hungary
Received 16 October 2000; accepted 2 November 2000
Abstract
Regio- and stereospecific addition of chlorosulfonyl isocyanate to (+)- and (−)-a-pinene 1 resulted in
enantiomerically pure b-lactams 2, which were converted to enantiomeric b-amino esters 3 and 1,3-amino
alcohols 4 and 6 with ee >99%. The resulting 1,3-difunctional compounds 3, 4 and 6 were transformed to
fused saturated 1,3-heterocycles such as tetrahydro-1,3-oxazines 7 and 9, 2,4-pyrimidinedione 11 and
2-thioxopyrimidin-4-one 13 enantiomers. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The readily available chiral terpenes and their derivatives are chiral auxiliary materials that
are widely used in enantioselective transformations.1 a-Pinene is a useful chiral source because
both of its enantiomers are available commercially. Its derivatives, such as pinanediol,2
2-hydroxypinan-3-one3 and B-isopinocampheyl-9-borabicyclo[3.3.1]nonane (Alpine-Borane®),4
have been widely utilized as chiral reagents in asymmetric syntheses. The preparation and some
synthetic applications of enantiomerically pure 3-amino-2-hydroxypinane have also been
reported by several authors.5–7 As an example, the Eliel synthon (a 1,3-amino alcohol prepared
from (+)-pulegone) has been successfully applied for the enantioselective synthesis of primary
and secondary amines, a-hydroxy acids, isoxazolines, etc.8–11
Our aim was the preparation and some transformations of chiral b-lactams and b-amino acid
derivatives, derived from chiral terpenes. Besides the chemical interest of b-amino acids,12,13
some of them exert significant pharmacological effects, for example the antifungal antibiotic
(1R,2S)-2-aminocyclopentanecarboxylic acid (cispentacin).14 They can be also used as building
blocks for the preparation of modified analogues of pharmacologically active peptides.15
Conformational studies of helix-forming b-amino acid oligomers are currently at the focus of
interest.16
* Corresponding author. Tel: +36 62 545564; fax: +36 62 545705; e-mail: fulop@pharma.szote.u-szeged.hu
†
Dedicated to Professor Kalevi Pihlaja on the occasion of his 60th birthday.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00435-3

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We additionally planned the synthesis and transformations of 1,3-amino alcohols, starting
from (+)- and (−)-a-pinene to prepare cycloalkane-fused saturated 1,3-heterocycles.12
2. Results and discussion
The synthetic route for azetidinone 2 is shown in Scheme 1. Although both enantiomers were
prepared, the scheme mentions only the compounds derived from (+)-a-pinene. The reaction of
chlorosulfonyl isocyanate (CSI) with a cycloalkene is a well-known procedure for the synthesis
of cycloalkane-fused b-lactams.17–21 There are several examples in the literature concerning the
regio- and stereospecificity of the cycloaddition, which proceeds in accordance with the
Markovnikov orientation of CSI addition.21–24
Scheme 1. (i) CSI, 1 h, rt, 76%; (ii) KOH, then Na2SO3; (iii) 22% HCl/EtOH, reflux, 60%; (iv) LiAlH4/THF, reflux,
4: 85%, 6: 79%; (v) ClCOOEt, 10% NaOH/benzene, 81%
Starting from commercially available (+)- and (−)-a-pinene 1, the cycloaddition of CSI
furnished the enantiomeric b-lactam 2 in a regio- and stereospecific reaction. In contrast with the
literature data (−60 to −73°C, 3 h, 40–52% overall yield, the enantiomer purity was not
mentioned),17–19 the cycloaddition proceeded with excellent yield (76%) at room temperature
within 1 h (ee >99%). The exo stereoselectivity of the CSI cycloaddition was earlier proved
through the application of Eu(dpm)3, an NMR shift reagent, by Sasaki et al.17
The reaction of the azetidinone 2 with ethanol containing HCl resulted in b-amino ester 3,
which was converted to the corresponding amino alcohol 4 by lithium aluminium hydride
(LAH) reduction. When amino ester 3 was treated with ethyl chloroformate, the N-ethoxycar-
bonyl derivative 5 was formed, which was reduced to the N-methyl amino alcohol 6 (Scheme 1).
Starting from 4 and 6, the N-methyl-1,3-oxazine 7 was prepared in two independent ways:
from 6 with aqueous formaldehyde, or from 4 with a formaldehyde/formic acid mixture, when
ring closure and N-methylation took place.25
With phenyl isothiocyanate, 4 gave the thiourea adduct 8, which was transformed to the
2-phenylimino-1,3-oxazine 9 with methyl iodide, followed by alkaline methyl mercaptan elimina-
tion (Scheme 2).

Z. Szakonyi et al. / Tetrahedron: Asymmetry 11 (2000) 4571–4579
4573
Scheme 2. (i) HCOOH, CH2O/H2O, reflux, 51%; (ii) CH2O/H2O, rt, 65%; (iii) PhNCS/benzene, rt, 92%; (iv)
MeI/MeOH, rt; (v) KOH/MeOH, rt, 60%
When amino ester 3 was reacted with phenyl isocyanate, urea derivative 10 was obtained,
which was converted to the pyrimidinedione 11 by base-catalyzed ring closure (Scheme 3).
Scheme 3. (i) PhNCO/benzene, rt, 89%; (ii) NH3/MeOH, rt, 87%; (iii) PhNCS/benzene, rt, 83%
The reaction of 3 and phenyl isothiocyanate resulted in the corresponding 2-thioxopyrimidin-
4-one 13: the thiourea intermediate 12 cyclized spontaneously even at room temperature
(Scheme 3). All of the NMR signals of 2, 7, 9 and 13 were assigned. The relative configurations
of the 1,2-disubstituted monoterpene derivatives were established on the basis of NOESY
experiments, which revealed the cis relationship of Me-2 and H-7 (7, 9, 13) or H-5 (2).
3
Conformational flexibility is possible in 7 and 9. The J(H-6, H-7) couplings reveal a predomi-
3
nantly gauche conformation for 9 (2.1, 9.1 Hz). The J(H-6, H-7) couplings (6.0, 6.3 Hz) of 7
are indicative of considerable conformational flexibility of the heterocyclic ring.
The enantiomeric excesses were proved in 2, 3 and 5 (ee >99%). There was no sign of the
presence of any other diastereomer in the NMR spectra of the crude products 4 and 6–13,
consistent with a high enantiomeric excess of 4 and 6–13.

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3. Conclusions
Starting from (+)- and (−)-a-pinene, the regio- and stereoselective addition of CSI resulted in
enantiomerically pure b-lactams, which were converted to chiral b-amino esters and 1,3-amino
alcohols. The 1,3-difunctional compounds prepared were transformed to chiral fused saturated
1,3-heterocycles, such as 1,3-oxazines, 2,4-pyrimidinediones and 2-thioxo-4-pyrimidinones.
The resulting b-amino acid derivatives and 1,3-amino alcohols may serve as chiral building
blocks for the synthesis of potential drugs, b-amino acid oligomers and modified analogues of
natural peptides. They may also be used as chiral auxiliaries for further enantioselective
syntheses.
4. Experimental
1H and 13C NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer (400
MHz, l=0 (TMS), in CDCl3). Chemical shifts are expressed in ppm (l) relative to TMS as
internal reference: J values are given in Hz.
GC measurements were performed on a Chrompack 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 130°C, 80 kPa for 2 and at 100°C, 80 kPa
for 3 and 5. Optical rotations were obtained with a Perkin–Elmer 341 polarimeter. Melting
points were determined on a Kofler apparatus and are uncorrected.
4.1. (1S,2S,5R,7S)-2,8,8-Trimethyl-3-azatricyclo[5.1.1.02,5]nonan-4-one 2‡
A mixture of 13.6 g (100.0 mmol) of (+)-(1R,5R)-a-pinene 1 and 14.30 g (101.2 mmol) of CSI
was stirred in 300 ml of dry diethyl ether for 1 h. Sodium sulfite (20.4 g) in 140 ml water was
then cautiously added dropwise to the solution. The pH was held at 7–8 by the addition of 20%
aqueous potassium hydroxide. After separation of the organic phase, the aqueous layer was
extracted with diethyl ether (2×100 ml). The combined organic layer was dried (Na2SO4) and
evaporated, and the white crystalline product was recrystallized from isopropyl ether.
Compound 2 (13.6 g, 76%; mp: 144–147°C (lit.:17–19 146–148°C); [h]D20=+96.5 (c=0.1,
MeOH); ee >99%). Analysis: calculated for C11H17NO: C, 73.70; H, 9.56; N, 7.81; found: C,
1
74.05; H, 9.33; N, 7.96. H NMR (CDCl3) l (ppm): 0.91 (3H, s, Me-8), 1.32 (3H, s, Me-8), 1.47
(3H, s, Me-2), 1.53 (1H, d, H-9, J=11.08 Hz), 1.83–1.93 (1H, m, H-6), 1.94–1.98 (1H, m, H-7),
2.09 (1H, dd, H-1, J=4.66, 6.04 Hz), 2.12–2.21 (2H, m, H-6, H-9), 2.86 (1H, d, H-5, J=10.32
Hz), 6.12 (1H, s, NH). 13C NMR (CDCl3) l (ppm): 23.4, 25.1, 25.6, 25.7, 27.8, 42.3, 50.3, 50.4,
59.2, 173.8.
The (1R,2R,5S,7R)-enantiomer of 2 was prepared from (−)-(1S,5S)-a-pinene as described
above; [h]2D0=−96 (c=0.1, MeOH); ee >99%; the spectroscopic data and mp were similar to
those for 2. Analysis: found: C, 74.15; H, 9.26; N, 7.71.
‡ Although there is no change in the (1R,5R) configuration of (+)-a-pinene, the configuration of the corresponding
atoms in the products 2–13 is (S,S), due to the changes in CIP priority.

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4.2. Ethyl (1S,2S,3R,5S)-2-aminopinane-3-carboxylate 3
Azetidinone 2 (13.5 g, 75.3 mmol) was dissolved in 80 ml of ethanol containing 10%
hydrochloric acid. After refluxing for 12 h, the mixture was evaporated to dryness in vacuo. The
residue was dissolved in water, basified with cold saturated sodium hydrogencarbonate solution
and extracted with diethyl ether (3×50 ml). The combined organic phase was dried (Na2SO4),
filtered and evaporated. The oily residue obtained was purified by flash chromatography on a
silica gel column (toluene:ethanol=9:1).
Compound 3 (10.2 g, 60%; [h]2D0=−28 (c=0.29, EtOH); ee >99%). Analysis: calculated for
1
C13H23NO2: C, 69.29; H, 10.29; N, 6.22; found: C, 69.43; H, 10.05; N, 6.47. H NMR (CDCl3)
l (ppm): 1.02 (3H, s, Me-6), 1.22 (1H, d, H-4, J=10.58 Hz), 1.26 (3H, s, Me-6), 1.31 (3H, t,
CH2-CH3, J=7.05 Hz), 1.36 (3H, s, Me-2), 1.78 (1H, t, H-1, J=5.29 Hz), 1.89–2.00 (2H, m,
H-4, H-5), 2.17–2. 26 (1H, m, H-7), 2.29–2.39 (1H, m, H-7), 3.01 (1H, dd, H-3, J=7.05, 10.07
Hz), 4.19 (2H, q, CH2-CH3, J=7.05 Hz). 13C NMR (CDCl3) l (ppm): 14.8, 24.0, 28.4, 28.7,
29.3, 31.6, 39.7, 40.3, 47.0, 55.4, 56.4, 60.6, 175.6.
The (1R,2R,3S,5R)-enantiomer of 3 was prepared as described above; [h]2D0=+26 (c=0.29,
EtOH); ee >99%; the spectroscopic data and mp were similar to those for 3. Analysis: found: C,
69.39; H, 10.35; N, 6.29.
4.3. (1S,2S,3R,5S)-2-Amino-3-hydroxymethylpinane 4
To a slurry of LiAlH4 (3.19 g, 15 mmol) in 150 ml of dry THF, amino ester 3 (10.14 g, 45.0
mmol) in 20 ml of THF was added dropwise at 0°C. After stirring and refluxing for 2 h (the
reduction was monitored by means of TLC), the mixture was decomposed with 6.5 ml of water
under ice cooling. The inorganic material was filtered off and washed with THF. After drying
(Na2SO4) and evaporation, a pale-yellow oil was obtained. The prepared amino alcohol was
purified as the hydrochloride. The base liberated for spectroscopic purposes was a viscous oil.
Compound 4 (7.0 g, 85%; [h]2D0=−11 (c=0.2, MeOH)). Analysis: calculated for C11H21NO: C,
1
72.08; H, 11.55; N, 7.64; found: C, 72.36; H, 11.52; N, 7.39. H NMR (CDCl3) l (ppm): 1.02
(3H, s, Me-6), 1.05 (1H, d, H-4, J=10.32 Hz), 1.24 (3H, s, Me-6), 1.27 (3H, s, Me-2), 1.31–1.41
(1H, m, H-3), 1.65 (1H, t, H-1, J=5.79 Hz), 1.85–1.97 (2H, m, H-5, H-7), 2.05–2.23 (2H, m,
H-4, H-7), 3.47 (1H, dd, CH2-OH, J=9.06, 11.03 Hz), 3.62 (1H, dd, CH2-OH, J=4.53, 11.58
Hz). 13C NMR (CDCl3) l (ppm): 23.8, 28.0, 28.4, 28.8, 29.7, 38.8, 39.4, 40.4, 52.1, 63.0, 63.6.
The (1R,2R,3S,5R)-enantiomer of 4 was prepared as described above; [h]2D0=+10 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 4. Analysis found: C, 72.29; H,
11.50; N, 7.43.
4.4. Ethyl (1S,2S,3R,5S)-2-(ethoxycarbonylamino)pinane-3-carboxylate 5
To a stirred solution of b-amino ester 3 (4.17 g, 18.8 mmol) and sodium hydrogencarbonate
(1.59 g, 18.9 mmol) in 10 ml of water, ethyl chloroformate (1.99 ml, 20.9 mmol) was added
dropwise at 0°C. The mixture was stirred for 1 h at 0°C. After standing overnight at room
temperature, the precipitated oil was extracted with ethyl acetate (3×50 ml), and the organic
phase was dried (Na2SO4) and evaporated. The product was purified by flash chromatography
on a silica gel column (toluene:ethanol=19:1).

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Compound 5 (4.5 g, 81%; [h]=−23 (c=0.17, EtOH); ee >99%). Analysis: calculated for
1
C16H27NO4: C, 64.62; H, 9.15; N, 4.71; found: C, 64.73; H, 9.35; N, 4.47. H NMR (CDCl3) l
(ppm): 1.07 (3H, s, Me-6), 1.19 (3H, t, NHCOO-CH2-CH3, J=7.05 Hz), 1.29 (3H, t, CH2-
CH3, J=7.05 Hz), 1.29 (3H, s, Me-6) 1.63 (3H, s, Me-2), 1.96–2.02 (1H, m, H-5), 2.07 (1H, m,
H-4), 2.10–2.13 (1H, m, H-4), 2.20–2.28 (1H, m, H-7), 2.34–2.37 (1H, m, H-7), 2.65 (1H, t,
H-1, J=5.54 Hz), 3.12 (1H, t, H-3, J=9.57 Hz), 3.98 (2H, q, NHCOO-CH2-CH3, J=7.05
Hz), 4.15–4.25 (2H, m, CH2-CH3), 5.91 (1H, s, NH). 13C NMR (CDCl3) l (ppm): 14.6, 14.9,
23.8, 27.0, 29.2, 29.9, 31.2, 38.8, 40.5, 46.3, 51.9, 58.3, 60.4, 61.5, 155.3, 175.9.
The (1R,2R,3S,5R)-enantiomer of 5 was prepared as described above; [h]2D0=+22 (c=0.17,
EtOH); ee >99%; the spectroscopic data and mp were similar to those for 5. Analysis found:
C, 64.50; H, 9.23; N, 4.41.
4.5. (1S,2S,3R,5S)-2-Methylamino-3-hydroxymethylpinane 6
Amino ester 5 was reduced with LAH according to Section 4.3.
Compound 6 (6.7 g, 79%; [h]=−9 (c=0.2, MeOH)). Analysis: calculated for C12H23NO: C,
1
73.04; H, 11.75; N, 7.10; found: C, 72.95; H, 11.52; N, 7.28. H NMR (CDCl3) l (ppm): 1.11
(3H, s, Me-6), 1.32 (3H, s, Me-6), 1.52–1.61 (4H, m, Me-2, H-4), 1.73 (1H, dd, H-1, J=8.31,
11.58 Hz), 1.92–2.05 (3H, m, H-3, H-5, H-7), 2.22–2.32 (1H, m, H-7), 2.52 (4H, m, N-Me,
H-4), 3.94 (1H, dd, CH2-OH, J=4.03, 11.58 Hz), 4.25 (1H, dd, CH2-OH, J=8.56, 11.58 Hz).
13C NMR (CDCl3) l (ppm): 23.6, 25.2, 27.4, 27.9, 28.7, 29.7, 39.0, 39.9, 40.5, 49.4, 62.6, 66.5.
The (1R,2R,3S,5R)-enantiomer of 6 was prepared as described above; [h]2D0=+8.2 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 6. Analysis: found: C, 73.34;
H, 11.61; N, 7.33.
4.6. (1S,2S,7R,9S)-2,3,10,10-Tetramethyl-5-oxa-3-azatricyclo[7.1.1.02,7]undecane 7
Method A: Amino alcohol 6 (0.48 g, 2.43 mmol) was stirred with 10 ml of 33% aqueous
formaldehyde at room temperature for 1 h. The mixture was made alkaline with 10% aqueous
potassium hydroxide and extracted with diethyl ether (3×30 ml). The combined organic phase
was dried (Na2SO4) and evaporated to give an almost colorless oil, which was purified as the
hydrochloride. The base liberated for spectroscopic purposes was a viscous oil.
Method B: Amino alcohol 4 (0.38 g, 2.07 mmol) was dissolved in a mixture of 5 ml of 33%
aqueous formaldehyde and 5 ml of formic acid. After stirring and refluxing for 1 h, the
solution was cooled, basified with 10% KOH solution and extracted with chloroform (3×30
ml). The combined organic phase was dried (Na2SO4) and evaporated to give an almost
colorless oil, which was purified as the hydrochloride.
Compound 7 (Method A: 65%, Method B: 51%; mp: 147–150°C; [h]2D0=−9 (c=0.2,
MeOH)). Analysis: calculated for C13H24ClNO: C, 63.53; H, 9.84; N, 5.70; found: C, 63.92; H,
1
9.72; N, 5.96. H NMR (CDCl3) l (ppm): 1.05 (3H, s, Me-10), 1.06 (3H, s, Me-10), 1.29 (3H,
s, Me-2), 1.50–1.60 (1H, m, H-8), 1.71 (1H, d, H-11, J=9.32 Hz), 1.86–1.98 (6H, m, H-1,
N-Me, H-8, H-9), 1.99–2.10 (2H, m, H-7, H-11), 3.62 (1H, dd, H-6, J=6.29, 10.83 Hz), 3.73
(1H, dd, H-6, J=6.04, 10.83 Hz), 4.13 (1H, d, H-4, J=6.04 Hz), 4.23 (1H, d, H-4, J=6.04
Hz). 13C NMR (CDCl3) l (ppm): 16.7, 24.5, 27.8, 30.2, 31.9, 32.0, 37.8, 38.9, 40.8, 52.3, 58.2,
69.2, 81.9.

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4577
The (1R,2R,7S,9R)-enantiomer of 7 was prepared as described above; [h]2D0=+9 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 7. Analysis found: C, 63.97; H,
9.65; N, 5.61.
4.7. Thiourea derivative 8
Phenyl isothiocyanate (0.48 g, 3.55 mmol) was added to a solution of 0.6 g (3.27 mmol) of
amino alcohol 4 in 40 ml of toluene. After stirring for 3 h at room temperature (the reaction was
monitored by means of TLC), the solution was evaporated and the pale-yellow crystalline
product was recrystallized from isopropyl ether.
Compound 8 (1.04 g, 92%; mp: 119–121°C; [h]=−111 (c=0.2, MeOH)). Analysis: calculated
for C18H26N2OS: C, 67.88; H, 8.23; N, 8.80; found: C, 67.72; H, 8.39; N, 8.56. 1H NMR (CDCl3)
l (ppm): 0.94 (1H, d, H-4, J=10.83 Hz), 1.05 (3H, s, Me-6), 1.29 (3H, s, Me-6), 1.66–1.89 (6H,
m, H-1, Me-2, H-3, H-7), 1.89–1.97 (1H, m, H-5), 2.12–2.20 (1H, m, H-4), 2.20–2.39 (1H, m,
H-7), 3.48 (1H, dd, CH2-OH, J=4.28, 10.07 Hz), 3.69 (1H, dd, CH2-OH, J=2.01, 11.08 Hz),
7.21–7.30 (2H, m, Ph), 7.38 (3H, t, Ph, J=7.30 Hz). 13C NMR (CDCl3) l (ppm): 23.9, 29.2,
29.8, 30.0, 38.9, 40.4, 42.0, 62.1, 65.4, 127.5, 129.9, 180.6.
The (1R,2R,3S,5R)-enantiomer of 8 was prepared as described above; [h]2D0=+105 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 8. Analysis: found: C, 67.97;
H, 8.11; N, 8.72.
4.8. (1S,2S,7R,9S)-4-Phenylimino-2,10,10-trimethyl-5-oxa-3-azatricyclo[7.1.1.02,7]undecane 9
To a stirred solution of 0.4 g (1.26 mmol) of thiourea derivative 8 in 15 ml of methanol, 0.43
ml (6.9 mmol) of iodomethane was added and the solution was stirred at 15°C for 3 h. After
evaporation of the solvent, the residue was stirred in 15 ml of 2.5N methanolic potassium
hydroxide 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 resulting oxazine was recrystallized from hexane.
Compound 9 (0.22 g, 60%; mp: 70–73°C; [h]D20=+245 (c=0.2, MeOH)). Analysis: calculated
1
for C18H24N2O: C, 76.02; H, 8.51; N, 9.85; found: C, 76.33; H, 8.52; N, 9.61. H NMR (CDCl3)
l (ppm): 1.04 (3H, s, Me-10), 1.13 (1H, d, H-11, J=6.04 Hz), 1.24–1.33 (6H, m, Me-2, Me-10),
1.69–1.72 (2H, m, H-1, H-8), 1.96 (1H, s, H-9), 2.08–2.18 (1H, m, H-8), 2.18–2.33 (2H, m, H-7,
H-11), 3.86 (1H, dd, H-6, J=2.27, 10.58 Hz), 4.18 (1H, d, H-6, J=8.31 Hz), 6.96 (1H, t, Ph,
J=7.05 Hz), 7.09 (1H, s, Ph), 7.20–7.29 (3H, m, Ph). 13C NMR (CDCl3) l (ppm): 24.2, 28.3,
28.7, 31.2, 32.0, 34.6, 40.4, 55.02, 57.8, 68.2, 109.7.
The (1R,2R,7S,9R)-enantiomer of 9 was prepared as described above; [h]2D0=−250 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 9. Analysis: found: C, 76.27;
H, 8.72; N, 9.93.
4.9. Urea derivatives 10
Phenyl isocyanate (0.17 g, 1.42 mmol) was added to a solution of 0.3 g (1.33 mmol) of amino
ester 4 in 30 ml of toluene. After stirring for 5 h at room temperature, the solution was
evaporated and the crystalline product obtained was recrystallized from isopropyl ether.
Compound 10 (0.41 g, 89%; mp: 127–128°C; [h]2D0=−23 (c=0.2, MeOH)). Analysis: calculated
1
for C20H28N2O3: C, 69.74; H, 8.19; N, 8.13; found: C, 69.89; H, 8.01; N, 8.35. H NMR (CDCl3)

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l (ppm): 1.07 (3H, s, Me-6), 1.21–1.31 (7H, m, H-5, Me-6, CH2-CH3), 1.72 (3H, s, Me-2),
1.95–2.01 (1H, m, H-7), 2.02–2.16 (2H, m, H-4, H-4), 2.22–2.32 (1H, m, H-7), 2.86 (1H, t, H-1,
J=5.79 Hz), 3.14 (1H, t, H-3, J=9.32 Hz), 4.07–4.20 (2H, m, CH2-CH3), 5.96 (1H, s, C2-NH),
6.29 (1H, s, NH-Ph), 6.99–7.08 (1H, m, Ph), 7.24–7.30 (4H, m, Ph). 13C NMR (CDCl3) l (ppm):
14.6, 23.9, 27.5, 29.2, 30.2, 31.3, 38.9, 40.5, 46.6, 52.1, 59.3, 61.6, 121.2, 123.8, 129.4, 139.3,
154.9, 176.6.
The (1R,2R,3S,5R)-enantiomer of 10 was prepared as described above; [h]2D0=+23 (c=0.2,
MeOH); the other physical, analytical and spectroscopic data and mp were similar to those for
10. Analysis: found: C, 69.55; H, 8.13; N, 8.02.
4.10. (1S,2S,7R,9S)-4,6-Dioxo-5-phenyl-2,10,10-trimethyl-3,5-diazatricyclo[7.1.1.02,7]-
undecane 11
The appropriate urea derivative 10 (0.4 g, 1.16 mmol) was dissolved in 20 ml of methanol.
Five drops of methanol containing 25% ammonia were added to the solution and, after standing
for 1 day at room temperature, the solution was evaporated and the crystalline product was
recrystallized from isopropyl ether/ethyl acetate.
Compound 11 (0.3 g, 87%; mp: 205–207°C; [h]2D0=−27 (c=0.2, MeOH)). Analysis: calculated
1
for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39; found: C, 72.15; H, 7.59; N, 9.71. H NMR (CDCl3)
l (ppm): 1.11 (3H, s, Me-10), 1.33 (3H, s, Me-10), 1.38 (1H, d, H-11, J=10.83 Hz), 1.46 (3H,
s, Me-2), 1.91 (1H, t, H-1, J=5.54 Hz), 1.98 (1H, ddd, H-8, J=2.01, 8.31, 13.85 Hz), 2.08–2.14
(1H, m, H-9), 2.31–2.40 (1H, m, H-11), 2.59–2.69 (1H, m, H-8), 3.26 (1H, dd, H-7, J=8.81,
10.32 Hz), 5.39 (1H, s, H-3), 7.16–7.20 (2H, m, Ph), 7.36–7.41 (1H, m, Ph), 7.42–7.48 (2H, m,
Ph). 13C NMR (CDCl3) l (ppm): 23.9, 28.8, 30.8, 32.1, 33.4, 38.9, 40.6, 41.0, 53.3, 55.8, 128.8,
129.2, 129.5, 135.5, 152.9, 173.2.
The (1R,2R,7S,9R)-enantiomer of 11 was prepared as described above; [h]2D0=+26 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 11. Analysis found: C, 72.27;
H, 7.31; N, 9.47.
4.11. (1S,2S,7R,9S)-6-Oxo-5-phenyl-4-thioxo-2,10,10-trimethyl-3,5-diazatricyclo[7.1.1.02,7]-
undecane 13
Phenyl isothiocyanate (0.31 g, 2.3 mmol) was added to a solution of 0.5 g (2.2 mmol) of
amino ester 3 in 40 ml of toluene. After stirring for 6 h at room temperature, the solution was
evaporated and the crystalline product obtained was recrystallized from isopropyl ether/ethyl
acetate.
Compound 13 (0.57 g, 83%; mp: 264–267°C; [h]2D0=−8 (c=0.2, MeOH)). Analysis: calculated
for C18H22N2OS: C, 68.76; H, 7.05; N, 8.91; found: C, 69.05; H, 7.26; N, 8.73. 1H NMR (CDCl3)
l (ppm): 1.09 (3H, s, Me-10), 1.31–1.36 (4H, m, Me-10, H-11), 1.51 (3H, s, Me-2), 1.98 (1H, ddd,
H-8, J=2.01, 8.31, 14.1 Hz), 2.04 (1H, t, H-1, J=5.29 Hz), 2.09–2.15 (1H, m, H-9), 2.37–2.45
(1H, m, H-11) 2.60–2.69 (1H, m, H-8), 3.34 (1H, dd, H-7, J=9.57 Hz), 7.15–7.23 (2H, m, NH,
Ph), 7.39–7.50 (3H, m, Ph), 7.39–7.51 (1H, m, Ph). 13C NMR (CDCl3) l (ppm): 24.2, 28.8, 31.0,
31.2, 33.5, 39.1, 40.4, 40.8, 52.8, 60.1, 139.3, 169.9.
The (1R,2R,7S,9R)-enantiomer of 13 was prepared as described above; [h]2D0=+7 (c=0.2,
MeOH); the spectroscopic data and mp were similar to those for 13. Analysis found: C, 68.89;
H, 7.31; N, 8.56.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 11 (2000) 4571–4579
4579
Acknowledgements
Financial support from the National Scientific Research Foundation, Hungary (OTKA,
F 032828) and the Foundation for Hungarian Research and Higher Education (AMFK) is
gratefully acknowledged. We express our special thanks to Lonza Ltd for providing chlorosul-
fonyl isocyanate.
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