A formal asymmetric synthesis of (-)-epibatidine using a highly diastereoselective hetero Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4020(00)00284-2

A formal asymmetric synthesis of (-)-epibatidine is reported. The key step of the synthesis is a regio- and diastereoselective cycloaddition of silyloxycyclohexadiene with the acylnitroso dienophite derived from (+)- camphorsultam. The resulting cycloadduct was readily transformed into the N- protected-7-azabicycto[2.2.1]heptan-2-one derivative which has previously been transformed into(-)-epibatidine. (C) 2000 Elsevier Science.

Full text of DOI:10.1016/S0040-4020(00)00284-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3763±3769
A Formal Asymmetric Synthesis of (2)-Epibatidine Using a
Highly Diastereoselective Hetero Diels±Alder Reaction1
a,b b,c
Isabelle Cabanal-Duvillard, Jean-FrancËois Berrien, Leon Ghosez,
b,d,²
Henri-Philippe Hussona
Â
and Jacques Royera,
*
a
  Á
Laboratoire de Chimie Therapeutique associe au CNRS et a l'Universite Rene Descartes (UMR 8638),
Â
 Â
Faculte de Pharmacie, Paris V, 4 av. de l'Observatoire, F-75270 Paris cedex 06, France
Â
b
Á Â
Laboratoire de Chimie Organique de Synthese, Universite Catholique de Louvain-la-Neuve,
Place Louis Pasteur, 1, B-1348 Louvain la Neuve, Belgique
Â
c
Ã
UPRES A 8076 Biocis, Faculte de Pharmacie Paris XI, F-92296 Chatenay-Malabry Cedex, France
dI.E.C.B., ENSCPB, avenue Pey Berland, BP 108, F-33402 Talence Cedex, France
Received 11 February 2000; revised 13 March 2000; accepted 30 March 2000
AbstractÐA formal asymmetric synthesis of (2)-epibatidine is reported. The key step of the synthesis is a regio- and diastereoselective
cycloaddition of silyloxycyclohexadiene with the acylnitroso dienophile derived from (1)-camphorsultam. The resulting cycloadduct was
readily transformed into the N-protected-7-azabicyclo[2.2.1]heptan-2-one derivative which has previously been transformed into (2)-epiba-
tidine. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
enantiomerically pure bicyclic 7-azabicyclo[2.2.1]heptane-
2-one 2 which had already been converted into 1 (Scheme
1).4 Such an approach presents the advantage of being
readily applicable to the synthesis of analogs of the natural
product.
(2)-Epibatidine 1 was extracted in 1992 from the skin of the
Ecuadorian frog Epipedobates tricolor.2a,b Because of its
paucity in nature, its absolute stereochemistry was only
established in 1994 as 1R,2R,4S3(Fig. 1).
(2)-Epibatidine 1 is a powerful non-morphinic analgesic
which acts as an agonist of the nicotinic acetylcholine
receptor in the central and autonomic nervous system.2 As
a compound showing interesting pharmacological proper-
ties and being scarce in nature, (2)-epibatidine has attracted
much interest from synthetic chemists.4,5 Among the
reported syntheses, however, only a few have furnished
the natural non-racemic (2)-epibatidine 1 in an asymmetric
way.6 We were particularly interested by the asymmetric
synthesis of (2)-epibatidine 1 reported by the group of
Kibayashi in which the key step was a cycloaddition of
2-chloro-5-(1,5-cyclohexadienyl)-pyridine with an acyl-
nitroso dienophile derived from (1S)-8-(2-naphtyl)-
menthol.6c,d However the cycloaddition gave a 2:1 mixture
of regioisomeric adducts. This report prompted us to
disclose our own approach towards (2)-epibatidine 1. It
involves the development of an ef®cient synthesis of the
Figure 1.
Keywords: (2)-epibatidine; asymmetric synthesis; acylnitroso compounds;
hetero Diels±Alder cycloaddition.
* Corresponding author. Tel.: 133-1-537-397-49; fax: 133-1-432-914-03;
e-mail: jacques.royer@pharmacie.univ-paris5.fr
Fax: 132-10-47-41-68; e-mail: ghosez@chor.ucl.ac.be
²
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00284-2

3764
I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
rationalized on the basis of two possible transition states
(Scheme 2) involving (a) an endo-approach of the diene
from the less-hindered face of the dienophile in a syn±syn
conformation or (b) an exo-approach of the diene from the
less-hindered face of the dienophile in an anti-syn confor-
mation.7c The model implied that the construction of the
adduct (1R,4S)-4 leading to natural (2)-epibatidine 1
required the use of an acylnitroso compound derived from
(1)-camphorsultam.
(1)-Camphorsultam (1)-7 was converted into the corre-
sponding hydroxamic acid (1)-8 by the method described
earlier for the synthesis of (2)-8 (Scheme 3).7
The corresponding acylnitroso compound 6 was generated
by oxidation of (1)-8 with tetraethylammonium periodate
in the presence of excess 2-t-butyldimethylsilyloxycyclo-
hexadiene 5.8 Flash chromatography yielded a single
1
cycloadduct (1S,4R)-4 as shown by H NMR analysis. The
regiochemistry of the cycloaddition was that expected from
earlier cycloaddition of 6.7c Compound 4 was somewhat
unstable and could never be obtained in a satisfactory
state of purity. We then converted the crude (1S,4R)-4
into enone (1)-9 by treatment with Mo(CO)6.9 Under
these conditions the reductive cleavage of the N±O bond
was accompanied by the hydrolysis of the silyl enol ether
function and subsequent elimination of a molecule of water.
Compound (1)-9 was obtained in 63% total yield from
hydroxamic acid (1)-8 as a single diastereomer. The
excellent stereo- and regioselectivities (.98%) of the
cycloaddition were evidenced by extensive NMR studies
of the crude mixture of adduct 4. Only two sets of signals
for the bridgehead protons H1 and H4 were observed. In the
1H NMR spectrum the H1 gave a signal at 4.9 ppm (ddd,
Scheme 2.
The key step of our synthetic route uses an asymmetric
hetero Diels±Alder cycloaddition of silyloxycyclohexa-
diene 5 with an acylnitroso reagent 6 derived from camphor-
sultam. The latter had been reported to cycloadd to dienes
with excellent regio- and diastereoselectivity.7 We describe
herein a practical asymmetric synthesis of the N-tosyl
derivative of 2.
Results and Discussion
Earlier results on the cycloadditions of 6 to dienes had been
Scheme 3. Reagents: (i) triphosgene, i-Pr2EtN, Et2O then NH2OH´HCl, K2CO3, H2O, 85%; (ii) Et4N1IO42, CH2Cl2, diene 5, 2788C to rt; (iii) Mo(CO)6,
CH3CN, H2O, D, 3.5 h, 63% (ii1iii); (iv) NaBH4, CeCl3´7H2O, MeOH, 95%; (v) KOH, MeOH, rt, 95%; (vi) H2, Rh/C, EtOAc, 3 h, rt, 95%.

I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
3765
yielded the corresponding bromohydrin (2)-14 as two
diastereomers (2)-14a and (2)-14b (14a/14bˆ80/20)
easily separated by column chromatography. Reductive
removal of bromine13 from compound (2)-14a followed
by hydrolysis of the oxazolidinone ring gave diol (1)-15
in 80% yield. Cyclization under Mitsunobu's conditions,14
yielded the bicyclic alcohol (2)-16 (90%). Swern oxidation
of (2)-16 gave the target ketone (2)-(1R,4S)-17 (88%
yield), the racemate of which had earlier been converted
into (^)-epibatidine 1.15
Scheme 4. Reagents: (i) HCl 6N, rfx, 2 h.
Optical purity was determined on amino-alcohol (2)-16.
Comparison of NMR spectra of racemic (^)-16 and
(2)-16 in the presence of an increasing amount of the
chiral NMR shift reagent Eu(tfc)3 allowed us to determine
the enantiomeric excess to be greater than 98%.
Jˆ1.6, 3.6 Hz (J±H1/H6) and Jˆ5.7 Hz (J±H1/H2)) while H4
gave a signal at 5.35 ppm (dd, Jˆ2.7 Hz and Jˆ6.6 Hz
(J±H4/H5)). This was further con®rmed by the conversion
of crude 4 into aminocyclohexenone derivative (1)-9. None
of the known epimer epi-(1)-9 could be detected in the
NMR spectrum. This epimer could be obtained by treatment
of (1)-9 with re¯uxing 6N HCl for 2 h, followed by
recrystallization from hexane/dichloromethane (Scheme
4). The high facial and regio-selectivities are superior to
those obtained in the work of Kibayashi,6c making our
method highly competitive. Compound (1)-9 was readily
converted into oxazolidinone (2)-11 (Scheme 3).
Conclusion
We have thus achieved a formal synthesis of (2)-epibati-
dine 1. Bicyclic ketone (2)-17 has been prepared in high
enantiomeric purity by a sequence of 8 steps. The total yield
was 18%. The bicyclic ketone could be a useful inter-
mediate for building combinatorial libraries of epibatidine
analogs.
Reduction of the carbonyl functionality of cyclohexenone
(1)-9 following Luche's procedure,10 gave a 9:1 mixture of
diastereomers (95% yield). The major cis-diastereomer
(1)-10 was readily isolated by chromatography (86%
yield). Treatment with base gave oxazolidinone (2)-11.
Further experiments showed that the minor (1)-trans-10
isomer did not cyclise under these conditions, making the
chromatographic separation unnecessary. As anticipated
(vide supra), oxazolidinone (2)-11 was shown to have the
(3aS,7aR) con®guration by comparison of its optical
rotation to its enantiomer (1)-11, which was reduced for
chemical correlation purposes into the corresponding
saturated known oxazolidinone (1)-12.11
Experimental
IR spectra were recorded with a Genesis Matteson infrared
spectrophotometer. H NMR spectra were recorded on a
1
Bruker AC 250 apparatus (250 MHz, dˆ0 (TMS), in
CDCl3 if not speci®ed otherwise, J in Hertz). 13C NMR
spectra were recorded at 62.5 MHz on a Bruker AC 300
apparatus (d in ppm relative to internal TMS, J in Hertz).
Samples were dissolved in CDCl3 unless stated. Multi-
plicities in the 13C spectra were determined by DEPT
experiments. Elemental analyses were performed by the
service of microanalyse, ICSN, CNRS, Gif-sur-Yvette.
Mass spectra were recorded with a AEI MS-50 (Electronic
Impact 50 eV) or AEI MS-9 (Chemical Ionisation with
isobutane as ionising gas). Optical rotations were measured
on polarimeter Perkin±Elmer 241 MC at a temperature
around 208C. Chromatographic solvents were distilled
Compound (2)-11 was then converted into bicyclic ketone
(2)-17, according to the sequence already described in the
racemic series (Scheme 5).12
N-Tosylation of (2)-11 gave (2)-13 (97% yield), which
upon treatment with aqueous bromine regioselectively
Scheme 5. Reagents: (i) NaH, TsCl, THF, rt, 97%; (ii) Br2, DME/H2O, 75%; (iii) AIBN, Bu3SnH, toluene 708C, 1 h; (iv) LiOH, MeOH, rt 80% (iii1iv); (v)
PPh3, DEAD, THF, rt, 90%; (vi) (COCl)2, DMSO, Et3N, 88%.

3766
I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
before use. Flash chromatographies were performed on
Merck 60 silica gel (230±400 mesh). TLC were performed
on Merck 60 F254 aluminium plates. All dry solvents were
distilled in vacuo. All the reactions were carried out under
inert atmosphere unless water was used as the solvent.
Solvents were distilled prior to use: CH3CN and CH2Cl2
over CaH2, THF and Et2O over Na, benzophenone, toluene
over P2O5. The other solvents were used in their commercial
quality grades.
(1R)-10,10-Dimethyl-3,3-dioxo-3l6-thia-4-aza-tricyclo-
[5.2.1.01,5]decane-4-carboxylic acid-(2-oxo-cyclohex-3-
enyl)-amide (1)-9. Cycloadduct 4 being unstable, with a
signi®cant loss of material during puri®cation, enone (1)-9
was prepared from crude product (1S,4R)-4. To a solution of
crude cycloadduct (1S,4R)-4 (29.56 mmol th.) in 270 mL of
a 15/1 solution of CH3CN/H2O9 was added 5.46 g
(20.7 mmol, 0.7 equiv.) of Mo(CO)6. The reaction was
heated to 808C and stirring was maintained until completion
of reaction (12 h). The mixture was ®ltered through a plug
of celite. After evaporation of the ®ltrate, the enone (1)-9
was puri®ed by ¯ash chromatography (cyclohexane/EtOAc
6/4); yield: 6.42 g, 63%; colourless crystals; recrystallized
from hexane/CH2Cl2; mp 1448C; IR (®lm, cm21): 3468,
(7S)-10,10-Dimethyl-3,3-dioxo-3l6-thia-4-azatricyclo-
[5.2.1.03,7]decane-4-hydroxamic acid (1)-8.7 To a solu-
tion of 10.21 g (47.49 mmol, 1 equiv.) of camphorsultam
(1)-7 and 24.8 mL (142.4 mmol, 3 equiv.) of iPr2EtN in
300 mL dry Et2O was added very slowly 14.09 g
(47.49 mmol, 1 equiv.) of triphosgene at 08C. The cooling
bath was removed and vigourous stirring was maintained for
18 h with the solution turning yellow. 16.5 g (237.4 mmol,
5 equiv.) of hydroxylamine hydrochloride and a solution of
K2CO3 (6.5 g, 3 equiv. in 45 mL H2O) were successively
added. Stirring was continued for 6 h. The organic layer
was separated and the aqueous layer was extracted 3 times
with 200 mL CH2Cl2. The organic layers were joined, dried
over Na2SO4 and the solvent evaporated under reduced
pressure. Hydroxamic acid (1)-8 was puri®ed by ¯ash
chromatography (CH2Cl2/EtOAc 7/3); yield: 11 g, 85%;
white solid; recrystallized from cyclohexane/CH2Cl2; mp
2508C; IR (®lm, cm21): 3260, 1658, 1360; 1H NMR
(300 MHz, CDCl3): 8.30 (1H, bs), 6.75 (1H, bs), 3.85
(1H, dd, Jˆ5.1, 7.8 Hz), 3.4 (2H, s), 2.1±2.1 (7H, m),
1.15 (3H, s), 0.95 (3H, s); 13C NMR (62.5 MHz, CDCl3):
152.9, 64.2, 51.7, 49.5, 47.9, 44.3, 37.3, 32.1, 26.6, 20.2,
19.8; m/z (E.I.): 274 (M1), 242; [a]Dˆ170.2 (cˆ1.1,
CHCl3). Starting from (2)-camphorsultam (2)-7, hydroxamic
acid (2)-8 was obtained in a similar way as (1)-8.
[a]Dˆ271 (cˆ0.8, CHCl3; lit.11 269 (cˆ1.05, CHCl3).
1
1689, 1529, 1417; H NMR (300 MHz, CDCl3): 7.0±6.8
(2H, m), 6.1 (1H, dd, Jˆ2.6, 10.0 Hz), 4.3 (1H, dt, Jˆ4.8,
13.8 Hz), 3.8 (1H, dd, Jˆ4.8, 7.8 Hz), 3.4 (2H, s), 2.85±
1.15 (11H, m), 1.1 (3H, s), 0.95 (3H, s); 13C NMR
(62.5 MHz, CDCl3): 195.2, 150.7, 150.6, 128.0, 64.2,
56.9, 51.8, 48.8, 47.8, 44.4, 37.7, 32.2, 30.2, 26.8, 25.8,
20.4, 19.9; m/z (C.I.): 381 (M129), 353 (MH1), 259, 216;
C17H24N2O4S: Calculated: C, 57.93; H, 6.86; N, 7.94,
Found: C, 57.66; H, 6.68; N, 7.86; [a]Dˆ171.2 (cˆ1.0,
CHCl3). Enone (2)-9 was obtained from (2)-8 in a similar
way as (1)-9. [a]Dˆ269.3 (cˆ0.8, CHCl3).
(1S)-10,10-Dimethyl-3,3-dioxo-3l6-thia-4-aza-tricyclo-
[5.2.1.01,5]decane-4-carboxylic acid-(2-oxo-cyclohex-3-
enyl)-amide epi-(1)-9. A solution of 60 mg (0.19 mmol,
1 equiv.) of enone (1)-9 in 0.570 mL of 6N HCl was heated
to the re¯ux temperature, until complete solubilization of
the enone. After 2 h stirring at 808C, a saturated aqueous
solution of NaHCO3 was added to pH 8±9. The aqueous
layer was extracted 3 times with 20 mL CH2Cl2, the organic
layers were joined, dried over Na2SO4 and the solvent
evaporated under reduced pressure. Enones 9 were puri®ed
by ¯ash chromatography (cyclohexane/ethylacetate 7/3);
yield: enone (1)-9, 25 mg (41 %); enone epi-(1)-9,
20 mg (33 %); white solid; recrystallized from hexane/
CH2Cl2; mp 928C; IR (®lm, cm21): 3400, 1693, 1510,
(1S,4R)-[5-(tert-Butyl-dimethyl-silyloxy)-2-oxa-3-aza-bi-
cyclo[2,2,2]oct-5-en-3-yl]-(3,3-dioxo-10,10-dimethyl-3l6-
thia-4-aza-tricyclo[5.2.1.01,5]dec-4-yl)-methanone (1S,
4R)-4. To a solution of 6.2 g (29.56 mmol, 1 equiv.)
of 2-(tert-Butyl-dimethyl-silyloxy)-cyclohexadiene 58 in
100 mL dry CH2Cl2 was added 9.91 g (30.85 mmol,
1.1 equiv.) of Et4NIO4 then the reaction was cooled to
±788C. A solution of 8.1 g (29.56 mmol, 1 equiv.) of hydro-
xamic acid (2)-8 in 100 mL CH2Cl2 was slowly added to
the mixture then the cooling bath was removed. After
addition of 100 mL of a 10% aqueous solution of
Na2S2O3, the organic phase was separated. The aqueous
layer was extracted with CH2Cl2, the organic layers joined,
dried over Na2SO4 and the solvents were evaporated under
reduced pressure. The cycloadduct (1S,4R)-4 was puri®ed
by ¯ash chromatography (heptane/ethylacetate 7/3); yield:
13.73 g, 64%; light brown foam; IR (®lm, cm21): 1707,
1
1335; H NMR (300 MHz, CDCl3): 7.0 (1H, m), 6.8 (1H,
d, Jˆ5.0 Hz), 6.1 (1H, dd, Jˆ1.6, 10.0 Hz), 4.4 (1H, dt,
Jˆ5.0, 13.9 Hz), 3.8 (1H, dd, Jˆ4.7, 7.8 Hz), 3.4 (2H, s),
2.6±2.4 (3H, m), 2.15±2.1 (8H, m), 1.1, 3H, s), 0.95 (3H, s);
13C NMR (50 MHz, CDCl3): 195.4, 150.9, 127.9, 64.1, 56.4,
51.8, 48.7, 47.9, 44.4, 37.6, 32.2, 30.2, 26.7, 25.7, 20.3,
19.9; m/z (C.I.): 353 (MH1), 259, 216; [a]Dˆ13.5
(cˆ0.9, CHCl3).
(1S,2R)-10,10-Dimethyl-3,3-dioxo-3l-thia-4-aza-tricyclo-
[5.2.1.01,5]decane-4-carboxylic acid-(2-hydroxy-cyclohex-
3-enyl)-amide (1)-cis-10 and (1S,2S)-10,10-dimethyl-3,3-
dioxo-3l6-thia-4-aza-tricyclo[5.2.1.01,5]decane-4-carboxylic
acid-(2-hydroxy-cyclohex-3-enyl)-amide (1)-trans-10.
To a solution of 400 mg (1.13 mmol, 1 equiv.) of enone
(1)-9 in 4 mL MeOH were added 424 mg (1.13 mmol,
1 equiv.) of CeCl3´7H2O10 and the reaction was cooled to
08C. A solution of 43 mg (1.13 mmol, 1 equiv.) of NaBH4 in
MeOH (2 mL) was slowly added to the mixture. After
30 min, the cooling bath was removed and stirring was
maintained for 20 min. After pouring a 5% HCl aqueous
solution (to pH 4±5), 15 mL of Et2O and 15 mL of H2O
were successively added. The organic layer was decanted,
1
1350. H NMR (250 MHz, CDCl3): 5.35 (1H, dd, Jˆ2.7,
6.6 Hz), 4.9 (1H, ddd, Jˆ1.6, 3.6, 5.7 Hz), 4.75 (1H, dd,
Jˆ2.9, 5.9 Hz), 4.00 (1H, dd, Jˆ4.4, 7.4 Hz), 3.4 (2H, s),
2.4±2.1 (2H, m), 1.9±1.3 (9H, m), 1.25 (3H, s), 0.95 (3H, s),
0.90 (9H, s), 0.20 (3H, s), 0.15 (3H, s); 13C NMR
(62.5 MHz, CDCl3): 154.7, 152.8, 102.4, 72.9, 64.7, 60.0,
54.8, 48.5, 47.9, 44.6, 37.3, 32.5, 26.8, 25.6, 25.1, 20.5,
19.9, 24.4, 24.7. Starting from (2)-8, (1R,4S)-4 was
obtained in a similar way as (1S,4R)-4.

I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
3767
1
and the aqueous layer was extracted 3 times with 10 mL
Et2O portions. The organic layers were joined, dried over
Na2SO4 and the solvents evaporated under reduced pressure.
The allylic alcohols (1)-cis-10 and (1)-trans-10 were
puri®ed by ¯ash chromatography (heptane/EtOAc 8/2);
yield: (1)-cis-10: 345 mg, 86%; (1)-trans-10: 35 mg,
9%; white foam; IR (®lm, cm21): 3300, 1690; m/z (C.I.):
355 (MH1), 337, 216; C17H26N2O4S: Calculated: C, 57.60;
H, 7.39; N, 7.90, Found: C, 57.95; H, 7.12; N, 7.89.
1729; H NMR (300 MHz, CDCl3): 5.4 (1H, bs), 4.6 (1H,
td, Jˆ6.8, 4.8 Hz), 3.75 (1H, q, Jˆ6.8 Hz), 2.10±1.10 (8H,
m). 13C NMR (75 MHz, CDCl3): 76.2, 51.8, 28.9, 26.8,
19.9, 19.6; m/z (C.I.): 142 (MH1); C7H11NO2: Calculated:
C, 59.56; H, 7.85; N, 9.92, Found: C, 59.18; H, 8.04; N,
9.79; [a]Dˆ127 (cˆ0.5, EtOH) lit.17 125 (cˆ1.0, EtOH).
(3aR,7aS)-3-Tosyl-3a,4,5,7a-tetrahydrobenzoxazolin-2-
one (2)-13. To a solution of 200 mg (1.43 mmol, 1 equiv.)
of oxazolidinone (2)-11 in 5 mL THF were slowly added
85 mg (3.57 mmol, 2.5 equiv.) of NaH at 08C. Stirring was
maintained for 20 min and 300 mg (1.57 mmol, 1.1 equiv.)
of freshly recrystallized tosylchloride were added. The
cooling bath was removed and stirring was maintained for
1 h. The mixture was neutralized by addition of a 1 M
aqueous solution of HCl (to pH 4±5). The aqueous layer
was then extracted 3 times with 10 mL Et2O portions. The
organic layers were joined, dried over Na2SO4 and the
solvents evaporated under reduced pressure. N-protected
oxazolidinone (2)-13 was obtained in excellent purity;
yield: 420 mg, 97%; colourless crystals; recrystallized
from Et2O; mp 108±1108C; IR (KBr, cm21): 1785, 1370,
Allylic alcohol (1)-cis-10: 1H NMR (250 MHz, CDCl3): 6.6
(1H, d, Jˆ7.7 Hz), 5.75±5.65 (2H, m), 3.9 (1H, t, Jˆ
4.0 Hz), 3.6 (2H, m), 3.35 (1H, d, Jˆ14.2 Hz), 3.30 (1H,
d, Jˆ14.2 Hz), 2.1±1.1 (11H, m), 1.05 (3H, s), 0.90 (3H s);
13C NMR (75 MHz, CDCl3): 152.6, 131.7, 128.4, 65.4, 64.9,
52.5, 52.1, 49.6, 48.9, 45.7, 38.7, 33.0, 27.5, 25.7, 24.4,
20.8, 20.1; [a]Dˆ1119.5 (cˆ1.1, CHCl3).
1
Allylic alcohol (1)-trans-10: H NMR (250 MHz, CDCl3):
5.8 (1H, d, Jˆ8.3 Hz), 5.75 (1H, bs), 5.65 (1H, dd, Jˆ5.6,
10.2 Hz), 4.1 (1H, d, Jˆ7.1 Hz), 3.8 (2H, m), 3.4 (2H, s), 3.1
(1H, bs), 2.1±1.1 (11H, m), 1.1 (3H, s), 0.9 (3H, s); 13C
NMR (75 MHz, CDCl3): 151.2, 128.5, 128.3, 70.3, 64.1,
53.6, 51.6, 48.5, 47.8, 44.2, 37.4, 31.9, 26.5, 25.9, 23.8,
20.2, 19.7; [a]Dˆ153.6 (cˆ0.9, CHCl3).
1
1173; H NMR (250 MHz, CDCl3): 8.0 (2H, d, Jˆ7.9 Hz),
7.25 (2H, d, Jˆ7.9 Hz), 6.2 (1H, m), 5.8 (1H, bs), 4.8 (1H,
m), 4.45 (1H, ddd, Jˆ4.5, 7.1, 11.7 Hz), 2.45 (3H, s),
2.3±2.1 (2H, m), 2.05±1.9 (1H, m), 1.6 (1H, m). 13C
NMR (75 MHz, CDCl3): 145.5, 135.5, 135.4, 129.8,
128.5, 121.2, 70.7, 56.9, 24.9, 21.8, 21.7; m/z (C.I.): 294
(MH1), 157, 140, 96; C14H15NO4S: Calculated: C, 57.32; H,
5.15; N, 4.77, Found: C, 57.59; H, 5.03; N, 4.61;
[a]Dˆ28.0 (cˆ1.4, CH2Cl2).
Allylic alcohols (2)-cis-10: ([a]Dˆ2122 (cˆ1.1, CHCl3))
and (2)-trans-10 ([a]Dˆ252 (cˆ1.1, CHCl3)) were
obtained from (2)-9 in a similar way as (1)-cis-10 and
(1)-trans-10.
(3aR,7aS)-3a,4,5,7a-Tetrahydrobenzoxazolin-2-one (2)-11.
To a solution of 70 mg (0.197 mmol, 1 equiv.) of diastereo-
mer (1)-cis-10 in 2 mL MeOH were added 56 mg (1 mmol,
5 equiv.) of KOH. The reaction was stirred at rt until
completion of reaction (1 h, TLC monitoring). After
evaporation of the solvent under reduced pressure, addition
of 15 mL CH2Cl2 and successive washing with 5 mL of
H2O, the organic layer was dried over Na2SO4 and the
solvent evaporated under reduced pressure. The oxazolidi-
none (2)-11 was puri®ed by ¯ash chromatography
(heptane/EtOAc 1/1); yield 26 mg, 95%; colourless crystals;
recrystallized from EtOAc/MeOH; mp 858C; IR (KBr,
cm21): 3250, 1750; 1H NMR (300 MHz, CD3OD): 6.1
(1H, dt, Jˆ3.8, 10.1 Hz), 5.7 (1H, ddt, Jˆ4.0, 10.1,
2.0 Hz), 4.95 (1H, dd, Jˆ2.0, 3.9 Hz), 3.95 (1H, dt,
Jˆ4.0, 7.6 Hz), 2.25±2.10 (1H, m), 2.0±1.8 (2H, m), 1.7±
1.5 (1H, m); 13C NMR (75 MHz, CD3OD): 172.9, 135.2,
123.8, 73.9, 52.3, 26.5, 21.5; m/z (C.I.): 140 (MH1);
C7H9NO2: Calculated: C, 56.69; H, 6.75; N, 9.40, Found:
C, 56.46; H, 6.68; N, 9.01; [a]Dˆ210.1 (cˆ0.5, CHCl3).
Oxazolidinone (1)-11 was obtained from diastereomer (2)-
cis-10 in a similar way as (2)-11. [a]Dˆ19.2 (cˆ0.5, CHCl3).
(3aR,6R,7S,7aS)-3-Tosyl-3a,4,5,6,7,7a-6-hydroxy-7-bromo-
hexahydrobenzoxazolin-2-one (2)-14a and (3aR,6S,7R,
7aS)-3-tosyl-3a,4,5,6,7,7a-6-hydroxy-7-bromo-hexahydro-
benzoxazolin-2-one (2)-14b. To a solution of 75 mg
(0.25 mmol, 1 equiv.) of N-tosyloxazolidinone (2)-13 in
DME/H2O (1/1, 5 mL) was added dropwise a solution of
26 mL (0.5 mmol, 2 equiv.) of Br2 in 2 mL DME, at rt
under vigourous stirring. After 15 min stirring, a 5%
aqueous solution of Na2S2O3 was added until the yellow
colour disappeared. The solution was extracted 3 times
with 10 mL CH2Cl2 portions. The organic layers were
joined, dried over Na2SO4 and the solvents evaporated
under reduced pressure. The bromhydrin (2)-14 was
puri®ed by ¯ash chromatography (heptane/EtOAc 1/1);
yield: 14a (60 mg, 60%), 14b (15 mg, 15%); white solids.
Compound 14a. Recrystallized from heptane/EtOAc; mp
1
130±1368C; IR (®lm, cm21): 3300, 1785, 1370, 1173; H
NMR (200 MHz, CDCl3): 7.95 (2H, d, Jˆ8.3 Hz), 7.45 (2H,
d, Jˆ8.3 Hz), 5.60 (1H, d, Jˆ5.5 Hz), 5.15 (1H, dd, Jˆ3.7,
5.8 Hz), 4.75 (1H, td, Jˆ5.9, 10.2 Hz), 4.35 (1H, dd, Jˆ3.7,
10.0 Hz), 3.70 (1H, ddt, Jˆ5.0, 5.3, 10.1 Hz), 2.50 (3H, s),
2.40±2.30 (1H, m), 1.90 (1H, m), 1.60±1.45 (1H, m), 1.45±
1.30 (1H, m); 13C NMR (50 MHz, CDCl3): 150.3, 145.5,
134.7, 129.8, 128.1, 78.8, 68.2, 57.2, 54.2, 29.4, 25.3,
21.1; m/z (C.I.): 392/390 (MH1), 238/236;. C14H16BrNO5S:
Calculated: C, 43.09; H, 4.13; N, 3.59, Found: C,43.25; H,
4.22; N, 3.40; [a]Dˆ2120 (cˆ0.5, CHCl3).
(3aS,7aR)-3a,4,5,6,7,7a-Hexahydrobenzoxazolin-2-one
(1)-12. To a solution of 45 mg (0.32 mmol, 1 equiv.) of
oxazolidinone (1)-11 in 5 mL EtOAc was added 10 mg
Rh/C and the reaction was stirred under H2 atmosphere
for 3 h at rt. The mixture was ®ltered and the solvent evapo-
rated under reduced pressure. The oxazolidinone (1)-12
was puri®ed by ®ltration on silica gel (EtOAc); yield:
38 mg, 85%; colourless crystals; recrystallized from
heptane/CH2Cl2; mp 90±928C; IR (KBr, cm21): 3260,
Compound 14b. IR (Film, cm21): 3330, 1788, 1370, 1164;
1H NMR (200 MHz, CDCl3): 8.00 (2H, d, Jˆ7.9 Hz), 7.60

3768
I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
(2H, d, Jˆ7.9 Hz), 5.60 (1H, d, Jˆ3.9 Hz), 5.05 (1H, t,
Jˆ7.3 Hz), 4.55 (1H, dt, Jˆ4.5, 6.4 Hz), 4.20 (1H, t,
Jˆ7.6 Hz), 3.80 (1H, m), 2.55 (3H, s), 2.45±1.60 (4H, m);
13C NMR (50 MHz, CDCl3): 150.8, 145.0, 133.2, 129.3,
127.5, 77.8, 67.7, 56.8, 55.9, 26.4, 21.6, 20.5; m/z (C.I.):
450/448 (M157), 392/390 (MH1); [a]Dˆ252 (cˆ0.7,
CHCl3).
3 mL CH2Cl2 were added, after 15 min stirring at 2788C,
50 mg (0.18 mmol, 1 equiv.) of bicyclic compound (2)-16.
Stirring was maintained for 30 min. 120 mL (0.81 mmol,
4.5 equiv.) of Et3N were then added and the cooling bath
was removed. After 1 h, the solution was treated with 5 mL
H2O and the aqueous layer was extracted 3 times with 5 mL
CH2Cl2 portions. The organic layers were joined, dried over
Na2SO4 and the solvent evaporated under reduced pressure.
Ketone (2)-17 was puri®ed by ¯ash chromatography
(heptane/EtOAc 7/3); yield: 42 mg, 88%; white crystals;
recrystallized from CH2Cl2/MeOH; mp 133±1358C; IR
(1S,2R,5R)-1,5-Dihydroxy-2-tosylamino-cyclohexane (1)-
15. To a solution of 120 mg (0.30 mmol, 1 equiv.) of
bromhydrin (2)-14 and 15 mg of AIBN in 10 mL of
degassed toluene were added 100 mL (0.36 mmol,
1.2 equiv.) of Bu3SnH at rt.13 The mixture was heated
rapidly to 708C. Stirring was maintained for 1 h at this
temperature then the heating bath was removed. Toluene
was evaporated and the residue was dissolved in 20 mL of
acetonitrile. After 3 times washing with 10 mL hexane
portions, the acetonitrile phase was evaporated under
reduced pressure and 110 mg of crude product were
obtained, together with stannic salts. To a solution of this
crude in 10 mL MeOH was then added 50 mg (0.9 mmol,
3 equiv.) of LiOH. After 20 min stirring the reaction was
complete and 10 mL of a saturated aqueous solution of
NH4Cl were added. The organic layer was decanted and
the aqueous layer was extracted 3 times with 10 mL
CH2Cl2 portions. The organic layers were joined, dried
over Na2SO4 and the solvent was evaporated under reduced
pressure. The diol (1)-15 was puri®ed by ¯ash chroma-
tography (EtOAc); yield: 69 mg, 80% overall); white
1
(®lm, cm21): 1762, 1157; H NMR (300 MHz, CDCl3):
7.8 (2H, d, Jˆ8.0 Hz), 7.4 (2H, d, Jˆ8.0 Hz), 4.6 (1H, t,
Jˆ4.6 Hz), 4.2 (1H, d, Jˆ5.1 Hz), 2.4 (3H, s), 2.3 (1H, m),
2.2 (1H, m), 2.1±1.8 (2H, m), 1.7±1.5 (2H, m); 13C NMR
(75 MHz, CDCl3) 133.7, 129.9, 65.3, 59.0, 44.5, 28.6, 24.3,
21.7; m/z: (C.I.): 266 (MH1); C13H15NO3S: Calculated: C,
58.85; H, 5.70; N, 5.28, Found: C, 58.73; H, 5.94; N, 5.06;
[a]Dˆ256 (cˆ1.1, CH2Cl2).
Acknowledgements
Á
This work was funded by the Ministere de l'Education et de
la Recherche Technologique (ICD), the University of
Á
Louvain and the Ministere de l'Education et de la Recherche
Â
Â
de la Communaute FrancËaise de Belgique (action concertee
96/01-197). We also are indebted to Marie-Elise Tran-
Uhuu-Dau for computer calculations.
1
solid; IR (®lm, cm21): 3330, 1164; H NMR (250 MHz,
CDCl3): 7.8 (2H, d, Jˆ8.2 Hz), 7.3 (2H, d, Jˆ8.2 Hz), 4.8
(1H, bs), 4.0 (2H, m), 3.2 (1H, m), 2.5 (3H, s), 2.2±1.3 (6H,
m); 13C NMR (62.5 MHz, CDCl3): 143.3, 137.7, 129.5,
126.6, 68.4, 64.3, 54.6, 39..8, 32.5, 24.8, 21.1; m/z (C.I.):
286 (MH1); C13H19NO4S: Calculated: C, 54.72; H, 6.71; N,
4.91, Found: C, 54.37; H, 6.57; N, 4.80; [a]Dˆ122 (cˆ1.3,
EtOH).
References
1. This work is part of the Ph.D thesis of I. Cabanal-Duvillard
Â
(Universite Paris-V, June 15, 1998).
2. (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,
114, 3475±3478. (b) Daly J. W. J. Nat. Prod. 1998, 61, 162±
172. (c) Qian, C.; Li, T.; Shen, T. Y.; Libetrine-Garahan, L.;
Eckman, J.; Biftu, T.; Ip, S. Eur. J. Pharmacol. 1993, 250, R13±
R14.
(1R,2S,4S)-7-Tosyl-7-azabicyclo[2.2.1]heptane-2-ol (2)-16.
To a solution of 90 mg (0.31 mmol, 1 equiv.) of diol (1)-15
and 225 mg (0.77 mmol, 2.5 equiv.) of PPh3 in 5 mL THF
were added 125 mL (0.77 mmol, 2.5 equiv.) of DEAD at
rt.14 Stirring was maintained for 30 min and 5 mL of H2O
were then added. The aqueous layer was extracted 3 times
with 10 mL CH2Cl2 portions. The organic layers were
joined, dried over Na2SO4 and the solvents were evaporated
under reduced pressure. Bicyclic compound (2)-16 was
puri®ed by ¯ash chromatography (heptane/EtOAc 8/2 then
7/3); yield: 75 mg, 90%; white crystals; recrystallized from
heptane/CH2Cl2; mp 124±1268C; IR (®lm, cm21): 3400,
1317, 1151; 1H NMR (300 MHz, CDCl3): 7.8 (2H, d,
Jˆ8.0 Hz), 7.3 (2H, d, Jˆ8.0 Hz), 4.25 (1H t, Jˆ4.3 Hz),
4.0 (1H, d, Jˆ4.1 Hz), 3.85 (1H ddd, Jˆ2.5, 7.5, 10.1 Hz),
2.6 (1H, d, Jˆ10.6 Hz), 2.5 (3H, s), 2.0±1.4 (6H, m); 13C
NMR (75 MHz, CDCl3): 144.0, 129.7, 127.7, 74.2, 66.1,
74.2, 66.1, 58.6, 44.0, 28.4, 24.5, 21.6; m/z (C.I.): 268
(MH1); C13H17NO3S: Calculated: 58.41; H, 6.41; N, 5.24,
Found: C, 58.34; H, 6.66; N, 5.44; [a]Dˆ213 (cˆ0.7,
CHCl3).
3. Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball,
R. G. J. Org. Chem. 1994, 59, 1771±1778.
4. For reviews see: (a) Dehmlow, E. V. J. Prakt. Chem. 1995, 337,
167±174. (b) Szantay, C.; Kardos-Balogh, Z.; Szantay Jr., C.
The Alkaloids, Cordell, G. A., Ed. 1995, 46, 95±125.
5. For more recent syntheses: (a) Albertini, E.; Barco, A.; Benetti,
S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Tetrahedron Lett. 1997,
38, 681±684. (b) Zhang, C.; Gyermek, L.; Trudell, M. L.
Tetrahedron Lett. 1997, 38, 5619. (c) Pavri, N. P.; Trudell, M. L.
Tetrahedron Lett. 1997, 38, 7993. (d) Jones, C. D.; Simpkins, N. S.;
Giblin, G. M. Tetrahedron Lett. 1998, 39, 1023±1024. (e)
Sirisoma, N. S.; Johnson, C. R. Tetrahedron Lett. 1998, 39,
2059±2062. (f) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J. Org.
Chem. 1998, 63, 760±768. (g) Clive, D. L. J.; Yeh, V. S. C.
Tetrahedron Lett. 1998, 39, 4789±4792. (h) Kasyan, A.; Wagner,
C.; Maier, M. E. Tetrahedron 1998, 54, 8047±8054. (i) Brieaddy,
L. E.; Liang, F.; Abraham, P.; Lee, J. R.; Carroll, F. I. Tetrahedron
Lett. 1998, 39, 5321±5322. ( j) Otten, A.; Namyslo, J. C.; Stoermer,
M.; Kaufmann D. E. Eur. J. Org. Chem. 1998, 1997±2001.
(k) Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.
Synthesis 1998, 1335±1338. (l) Maier, M. E.; Lapeva, T.
(1R,4S)-7-Tosyl-7-azabicyclo[2.2.1]heptane-2-one (2)-17.
To a solution of 40 mL (0.54 mmol, 3 equiv.) of DMSO
and 25 ml (0.27 mmol, 1.5 equiv.) of oxalyl chloride in

I. Cabanal-Duvillard et al. / Tetrahedron 56 (2000) 3763±3769
3769
Synlett 1998, 891±893. (m) Giblin, G. M. P.; Jones, C. D.;
Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1998, 3689±3697.
(n) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron
Lett. 1999, 40, 557±560.
S. J.; Mineur, C.; Belotti, D.; Dive, G.; Ghosez, L. Tetrahedron
1998, 54, 10537±10554.
8. Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1984, 25, 5953±
5956.
6. (a) Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485±
7488. (b) Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. J.
Chem. Soc. Chem. Commun. 1997, 1857±1858. (c) Aoyagi, S.;
Tanaka, R.; Naruse, M.; Kibayashi, C. Tetrahedron Lett. 1998,
39, 4513±4516. (d) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi,
C. J. Org. Chem. 1998, 63, 8397±8406. (e) Hall, A.; Bailey, P. D.;
Rees, D. C.; Wightman, R. H. Chem. Commun. 1998, 2251±2252.
(f) Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. Chem.
Commun. 1998, 2363±2364. (g) Nakashima, H.; Hiroya, K.;
Taniguchi, T.; Ogasawara, K. Synlett 1999, 1405±1406.
(h) Namyslo, J. C.; Kaufmann, D. Synlett 1999, 804±806.
9. Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982,
877±878.
Â
10. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454±5459.
11. (a) Remiszewski, S. W.; Yang, J.; Weinreb, S. M. Tetrahedron
Lett. 1986, 27, 1853±1856. (b) Kay, J. B.; Robinson, J. B. J. Chem.
Soc. Chem. Commun. 1969, 248±252.
12. Cabanal-Duvillard, I.; Berrien, J.-F.; Royer, J.; Husson, H.-P.
Tetrahedron Lett. 1998, 39, 5181±5184.
13. Bonini, C.; Righi, G.; Sotgiu, G. J. Org. Chem. 1991, 56,
6206±6209.
Â
(i) Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.; Peregrina,
J. M. Tetrahedron: Asymmetry 1999, 10, 3999±4007.
14. (a) Mitsunobu, O. Synthesis 1981, 1±28. (b) Grandel, R.;
Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009±8012.
15. Okabe, K.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1432±
1436.
7. (a) Gouverneur,V.; Dive, G.; Ghosez, L. Tetrahedron: Asym-
metry 1991, 2, 1173±1176. (b) Gouverneur, V. Ph.D thesis (1991).
UCL Louvain-la-Neuve, Belgique. (c) Gouverneur, V.; McCarthy,