Synthesis of 7-azabicyclo[2.2.1]heptane derivatives via bridgehead radicals

Article abstract of DOI:10.1016/S0040-4020(01)01222-4

This report shows the versatility and synthetic potential of 7-azabicyclo[2.2.1]heptane-1-carboxylic acid (Ahc) to obtain several bridgehead 1-substituted-7-azabicyclo[2.2.1]heptane derivatives, including halogen derivatives, via bridgehead radical reactions, proving the existence of the bridgehead radical in 7-azabicyclo[2.2.1]heptane systems. Moreover, we have obtained the interesting compound N-benzoyl-7-azabicyclo[2.2.1]heptane, a precursor of epibatidine.

Full text of DOI:10.1016/S0040-4020(01)01222-4

TETRAHEDRON
Pergamon
Tetrahedron 58 02002) 1193±1197
Synthesis of 7-azabicyclo[2.2.1]heptane derivatives via
bridgehead radicals
a,p
Alberto Avenoza, Jesus H. Busto, Carlos Cativiela and Jesus M. Peregrina
a
b
a,p
Â
Â
a
  Â
Departamento de Quõmica, Grupo de Sõntesis Quõmica de La Rioja, Universidad de La Rioja, UA-CSIC, 26006 Logrono, Spain
b
  Â
Departamento de Quõmica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza-CSIC,
50009 Zaragoza, Spain
Received 12 November 2001; accepted 13 December 2001
AbstractÐThis report shows the versatility and synthetic potential of 7-azabicyclo[2.2.1]heptane-1-carboxylic acid 0Ahc) to obtain several
bridgehead 1-substituted-7-azabicyclo[2.2.1]heptane derivatives, including halogen derivatives, via bridgehead radical reactions, proving
the existence of the bridgehead radical in 7-azabicyclo[2.2.1]heptane systems. Moreover, we have obtained the interesting compound
N-benzoyl-7-azabicyclo[2.2.1]heptane, a precursor of epibatidine. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The reaction of O-acyl thiohydroxamates 0Barton esters) to
give free-radicals was achieved in 1983 by the Barton
group1 and has many useful modi®cations. This type of
chemistry has developed as an important source of radicals
for decarboxylations, decarboxylative halogenations or to
trap them with double bonds.2 There are some examples
of a-amino-substituted radicals generated from oxidative
Figure 1. Several 7-azabicyclo[2.2.1]heptane derivatives.
decarboxylation of a-amino acids3 as well as of bridgehead
bicyclo[2.2.1]heptane-1-carboxylic acid 0Ahc) is particu-
radicals from carboxylic acids.4 However, there are very
few examples including both aspects, the bridgehead
a-amino-substituted radicals. Moreover, there are few
reactions in which these a-amino-substituted radicals
generated from oxidative decarboxylation of a-amino
acids are captured with halogens to afford a-haloamino-
derivatives -N,X-acetals-. To the best of our knowledge,
this fact is only possible in special situations as the
generation of 2-haloaziridinyl derivatives.3
larly interesting, since it can be regarded as
a
conformationally constrained proline. In fact, it has been
introduced in two biomolecules as a proline analogue.7,8
In the structure block, we show several related structures
that have been already synthesized.9±12
In the course of our investigations, we have developed a
new and versatile method to obtain the Ahc.9 Now, our
goal is to obtain different 1-substituted-7-azabicyclo[2.2.1]
heptane derivatives, including halogen derivatives due to
the dif®culty of its synthesis, via bridgehead radical carbon
and starting from the Barton ester of Ahc. A retrosynthesis
of these compounds is shown in Scheme 1.
In this context, Rapoport and co-workers used the Barton
procedure to achieve the decarboxylation of a quaternary
and bridgehead amino acid 01S,4R)-N-0benzyloxycar-
bonyl)-7-azabicyclo[2.2.1]heptan-3-one-1-carboxylic acid,
in a formal synthesis of epibatidine.5 The interest in this
7-azabicyclo[2.2.1]heptane system as important biomolecu-
lar substructure is due to its presence in the epibatidine
skeleton 0Fig. 1). Because of this, the synthesis of different
7-azabicyclo[2.2.1]heptane derivatives has been the subject
of numerous synthetic studies.6 In addition, the 7-aza-
Keywords: bicyclic heterocyclic compounds; radicals and radical reactions;
amino acids and derivatives; halogenation; X-ray crystal structures.
p
Corresponding authors. Tel.: 134-941-299655; fax: 134-941-299621;
e-mail: alberto.avenoza@dq.unirioja.es
Scheme 1. Retrosynthetic analysis of 1-substituted-7-azabicyclo[2.2.1]
heptane systems.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)0 1222-4

1194
A. Avenoza et al. / Tetrahedron 58 32002) 1193±1197
2. Results and discussion
1,1,1-tri¯uoro-2-iodoethane4 to give a 37% yield of 4c
0Scheme 3). In order to explore the capability of Barton
ester 3 to generate C±C bonds, we tried its reaction with
methyl acrylate, as terminal ole®n.14 The reaction was
carried out in toluene at re¯ux to give 59% of methyl
ester compound 4d. Moreover, we also created a double
carbon±carbon bond by the reaction of ester 3 with
propynoic acid methyl ester, in the same conditions
described earlier, to produce a 62% yield of 4e 0Scheme 3).
2.1. Synthesis of 1-substituted-7-azabicyclo[2.2.1]
heptane derivatives
Our starting material was compound 1, an intermediate
obtained in the synthesis of Ahc.9 From this compound
and by treatment with LiOH´H2O in methanol, acid 2 was
obtained in a good yield. The O-acyl thiohydroxamate can
be prepared by reaction of N-hydroxypyridine-2-thione with
an activated acyl derivative from acid 2 or using coupling
reagents. First, we tried the use of N,N0-bis02-oxo-3-oxa-
zolidinyl)phosphinic chloride 0BOPCl) combined with
diisopropylethylamine 0DIEA), a very useful procedure
for hindered amino acids synthesis,13 and we achieved a
satisfactory yield of the yellow ester 3, which was puri®ed
through a ¯ash chromatography. Nevertheless, the coupling
of the acid chloride of 2 0obtained by treatment of 2 with
oxalyl chloride) with N-hydroxypyridine-2-thione in the
presence of TEA gave ester 3 in a better and excellent
yield and was used for the next reaction without any further
puri®cation 0Scheme 2).
In the case of 4b and 4c, we could obtain two single crystals
and it was possible to determine by X-ray diffraction the
de®ned structures and the non-planarity of the amide
groups. The planarity of amide nitrogen can be represented
by two angle parameters, the summation of the three
valence angles around the nitrogen 0uˆ3608) and the out-
of-plane angle of the N-substituents 0aˆ08). The single
crystal structures of 4b and 4c 0Fig. 2) revealed signi®cant
pyramidalization of the amide nitrogen: uˆ335.8, 330.08
and aˆ41.4, 37.08, respectively, as referenced for other
N-acyl-7-azabicyclo[2.2.1]heptane systems.15,16
The chlorination of 3 was then carried out using neat tetra-
chloromethane as solvent and reagent. The mixture was
irradiated with a 200 W tungsten lamp and after stirring
for 6 h, the solvent was evaporated and the residue was
puri®ed by chromatography to obtain 4a in a 23% yield.
The bromo was introduced using neat bromotrichloro-
methane to give an 85% yield of 4b. Finally, to get the
iodo derivative we used dichloromethane as a solvent and
Figure 2. ORTEP diagrams for 4b and 4c.
The amide bond is the crucial linkage in the structures of
proteins and the isomerization between planar cis and trans
amide conformations is essential for protein folding and for
many other processes.17 This isomerization probably
involves a transition state with a pyramidal nitrogen. In
this sense, the knowledge of new compounds, which present
distorted amides, will help to understand the isomerization
process of amides. Therefore and taking into account that
the pyramidal nitrogen of amides plays an important role in
the chemical and biological processes17 and it is still an
exceptional phenomenon due to the few examples
reported, the structures of 4b and 4c reported here
constitute additional examples of the intrinsic pyramidal
nitrogen of N-acyl-7-azabicyclo[2.2.1]heptanes, suggested
by Ohwada.15,16
Scheme 2. Method A: BOPCl, DIEA, CH2Cl2, N-hydroxypyridine 2-thione,
rt, 16 h. Method B: 0a) Oxalyl chloride, dichloroethane, DMF, rt, 3 h;
0b) TEA, THF, N-hydroxypyridine-2-thione, rt, 1 h.
2.2. Formal synthesis of epibatidine
Since the isolation of epibatidine,18 N-benzoyl-7-aza-
bicyclo[2.2.1]heptane 04f) and its derivatives have
attracted the attention of the chemists in the last years.
Recently, both Hassner,19 from a monoprotected 1,4-cyclo-
hexanedione, and Olivo,20 from trans-4-aminocyclo-
hexanol, have reported the synthesis of several N-alkyl-7-
Scheme 3. 0a) CCl4, 200 W, 6 h, 23%. 0b) BrCCl3 200 W, 6 h, 85%.
0c) CF3CH2I, CH2Cl2, 200 W, 6 h, 37%. 0d) CH2vCHCO2Me, toluene,
re¯ux, 59%. 0e) CHuCCO2Me, toluene, re¯ux, 62%.

A. Avenoza et al. / Tetrahedron 58 32002) 1193±1197
1195
azabicyclo[2.2.1]heptane systems. We could obtain 4f by
simple decarboxylation of thiohydroxamic ester 3, using
tributyltin hydride 0Bu3SnH) as a source of hydrogen
radical. As the epibatidine has been obtained from 4f by
microbial oxidation,21 we can therefore consider the
synthesis of 4f as a formal synthesis of epibatidine
0Scheme 4).
1.75±1.94 0m, 4H), 2.23±2.36 0m, 2H), 4.200`t', 1H,
Jˆ4.2 Hz), 7.30±7.50 0m, 3H), 7.55±7.65 0m, 2H). 13C
NMR 0CDCl3) d 29.9, 32.3, 62.3, 68.1, 128.2, 128.4,
131.4, 134.2, 172.2, 173.1.
4.1.2. N-Benzoyl-7-azabicyclo[2.2.1]heptane-1-carboxylic
acid 2-thioxo-2H-pyridin-1-yl ester )3). Method A.
BOPCl 0115 mg, 0.45 mmol) and DIEA 00.26 mL,
1.48 mmol) were added into a mixture of N-hydroxypyri-
dine-2-thione 050mg, 0.45 mmol) and carboxylic acid
2
092 mg, 0.37 mmol) in dichloromethane at 08C with protec-
tion against light. The reaction was stirred at rt for 16 h and
the solvent was then evaporated and the residue puri®ed by
¯ash column chromatography using hexane/ethyl acetate
1:1, with protection against light, to obtain a yellow
compound, which was used in the following step without
further puri®cation. Method B. To a suspension of acid 2
093 mg, 0.38 mmol) in dichloroethane 06 mL), DMF 03 mL,
0.129 mmol) and oxalyl chloride 084 mL, 0.95 mmol) were
added. The mixture was stirred for 3 h at rt and evaporated.
The residue was dissolved, in the dark, in THF 05 mL) and
cooled to 08C, N-hydroxypyridine-2-thione 089 mg,
0.80 mmol) and TEA 0116 mL, 0.84 mmol) in THF 04 mL)
were then added. The mixture was stirred for 1 h at rt and
®ltered. The residue was washed with cooled THF and the
solvent was evaporated with protection against the light to
obtain a yellow compound, which was used in the following
step without puri®cation.
Scheme 4. Synthesis of epibatidine from Barton ester 3 via 4f.
3. Conclusion
We have showed the versatility and synthetic potential of
the azabicycle 1 to obtain several bridgehead 1-substituted
compounds, including halogen derivatives, via radical
reactions, proving the existence of the bridgehead radical
in 7-azabicyclo[2.2.1]heptane systems. Moreover, we have
obtained the interesting compound 4f, a precursor of
epibatidine. In future, we wish to extend this methodology
to other azabicycles and to use the halogen derivatives to try
some coupling reactions.
4.1.3.
N-Benzoyl-1-chloro-7-azabicyclo[2.2.1]heptane
)4a). The yellow solid 3 0starting from 0.37 mmol of 2,
Method A) was dissolved in tetrachloromethane and
irradiated with a 200 W tungsten lamp at rt for 6 h. The
solvent was eliminated and the residue puri®ed by column
chromatography using hexane/ethyl acetate 8:2 to give
20mg of 4a as a white solid 023% yield). Mp 155±1588C.
4. Experimental
4.1. General
Melting points are uncorrected. All the manipulations with
air-sensitive reagents were carried out under a dry argon
atmosphere using standard Schlenk techniques. Solvents
were puri®ed according to standard procedures. The
chemical reagents were purchased from Aldrich Chemical
Co. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using
Kieselgel 60023±0400mesh). Organic solutions were
1
IR 0CH2Cl2, cm21): 1718. H NMR 0CDCl3) d 1.52±1.67
0m, 2H), 1.98±2.15 0m, 4H), 2.30±2.39 0m, 2H), 4.21 0`t',
1H, Jˆ4.5 Hz), 7.36±7.52 0m, 3H), 7.65±7.73 0m, 2H). 13C
NMR 0CDCl3) d 29.9, 38.7, 59.7, 81.8, 128.2, 128.6, 131.4,
135.6, 173.2. ESI1 0m/z)ˆ236 03), 238 01). Anal. Calcd for
C13H14ClNO: C, 66.24; H, 5.99; N, 5.94. Found: C, 66.15;
H, 6.07; N, 5.82.
dried over anhydrous Na2SO4 and, when necessary, concen-
trated under reduced pressure using a rotary evaporator.
4.1.4.
N-Benzoyl-1-bromo-7-azabicyclo[2.2.1]heptane
n
max 0cm21) of IR spectra are given for the main absorption
)4b). The yellow solid 3 0starting from 0.59 mmol of 2,
Method B) was dissolved in bromotrichloromethane and
irradiated with a 200 W tungsten lamp at rt for 6 h. The
solvent was eliminated and the residue puri®ed by column
chromatography using hexane/ethyl acetate 9:1 to give
117 mg of 4b as a white solid 085% yield). Mp 56±588C.
bands. NMR spectra were recorded at 300 MHz 01H) and at
75 MHz 013C) and are reported in ppm down®eld from TMS.
Mass spectra were obtained by electrospray ionization
0ESI).
IR 0CH2Cl2, cm21): 1665. H NMR 0CDCl3) d 1.45±1.57
1
4.1.1. N-Benzoyl-7-azabicyclo[2.2.1]heptane-1-carboxylic
acid )2). Compound 1 0760mg, 2.93 mmol) was dissolved
in a mixture of MeOH/H2O 3:2 050mL) and LiOH´H 2O
01.23 g, 29.30mmol) was added. The reaction was stirred
at rt for 48 h and the solvent was then evaporated in vacuo.
The residue was diluted with H2O 030mL) and washed with
dichloromethane 02£20mL). The aqueous phase was acidi-
®ed with a 2N HCl solution and extracted with dichloro-
methane 02£20mL). The organic layer was dried, ®ltered
and evaporated to give 711 mg of a residue corresponding to
compound 2, which was used in the following step without
puri®cation 099%). 1H NMR 0CDCl3) d 1.44±1.56 0m, 2H),
0m, 2H), 1.90±2.17 0m, 4H), 2.38±2.51 0m, 2H), 4.06 0`t',
1H, Jˆ5.1 Hz), 7.35±7.53 0m, 3H), 7.67±7.75 0m, 2H). 13C
NMR 0CDCl3) d 30.9, 40.0, 59.9, 70.9, 128.3, 128.8, 131.6,
135.5, 173.4. ESI1 0m/z)ˆ28001), 282 01). Anal. Calcd for
C13H14BrNO: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.91;
H, 5.16; N, 5.12.
4.1.5. N-Benzoyl-1-iodo-7-azabicyclo[2.2.1]heptane )4c).
The yellow solid 3 0starting from 0.40 mmol of 2, Method
B) was dissolved in dichloromethane and 1,1,1-tri¯uoro-2-
iodoethane 01.77 g, 4.49 mmol) was added and the mixture

1196
A. Avenoza et al. / Tetrahedron 58 32002) 1193±1197
was then irradiated with a 200 W tungsten lamp at rt for 6 h.
The solvent was eliminated and the residue puri®ed by
column chromatography using hexane/ethyl acetate 7:3 to
give 49 mg of 4c as a white solid 037% yield). Mp 85±878C.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.25; H, 7.37; N, 6.82.
4.2. X-Ray structure analysis
1
IR 0CH2Cl2, cm21): 1660. H NMR 0CDCl3) d 1.39±1.51
0m, 2H), 1.84±1.96 0m, 2H), 2.03±2.15 0m, 2H), 2.45±2.57
0m, 2H), 3.81 0`t', 1H, Jˆ5.4 Hz), 7.35±7.53 0m, 3H), 7.67±
7.74 0m, 2H). 13C NMR 0CDCl3) d 32.1, 42.7, 43.0, 58.6,
128.2, 128.8, 131.6, 135.3, 173.3. ESI1 0m/z)ˆ328. Anal.
Calcd for C13H14INO: C, 44.73; H, 4.31; N, 4.28. Found: C,
44.98; H, 4.46; N, 4.12.
Crystals of 4b and 4c were obtained by slow evaporation
from a mixture of hexane/dichloromethane.
4.2.1. Crystal data of 4b. C13H14BrNO, Mwˆ280.26,
colourless crystal of 0.4£0.35£0.25 mm3, Tˆ293 K,
Ê
triclinic, space group P 21, Zˆ4, aˆ9.740102) A, bˆ
Ê
Ê
Ê 3
11.434403) A, cˆ12.073803) A, Vˆ1232.1605) A , dcalc
ˆ
1.510g cm 23, F0000)ˆ568, lˆ0.71070 A 0Mo Ka), mˆ
3.315 mm21, Nonius kappa CCD diffractometer, u range
2.49±27.488, 5606 collected re¯ections, 5606 unique, full-
Ê
4.1.6. 3-)N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)-2-)2-
pyridylthio)-propionic acid methyl ester )4d). The yellow
solid 3 0starting from 0.60 mmol of 2, Method B) was
dissolved in degassed and dry toluene and methyl acrylate
00.54 mL, 6.00 mmol) was added. Then, the mixture was
heated at re¯ux for 15 h. The solvent was eliminated and
the residue puri®ed by column chromatography using
hexane/ethyl acetate 6:4 to give 140mg of 4d as a yellow
matrix
least-squares
0SHELXL9722),
R1ˆ0.0567,
wR2ˆ0.0966, 0R1ˆ0.1130, wR2ˆ0.1078 all data), goodness
of ®tˆ1.529, residual electron density between 0.571 and
Ê 23
20.634 e A . Hydrogen atoms ®tted at theoretical posi-
tions.
1
oil 059% yield). IR 0CH2Cl2, cm21): 1734, 1634. H NMR
0CDCl3) d 1.40±1.48 0m, 2H), 1.62±2.05 0m, 6H), 2.96 0dd,
1H, Jˆ6.0, 14.7 Hz), 3.31 0dd, 1H, Jˆ8.1, 14.7 Hz), 3.700s,
3H), 4.02±4.06 0m, 1H), 4.78 0`t', 1H, Jˆ7.2 Hz),
6.94±7.02 0m, 1H), 7.16±7.23 0m, 1H), 7.31±7.55 0m,
6H), 8.37±8.42 0m, 1H). 13C NMR 0CDCl3) d 29.8, 33.7,
34.3, 36.5, 43.6, 52.5, 61.0, 67.7, 119.9, 122.3, 127.6, 128.1,
130.3, 136.1, 137.2, 149.3, 157.0, 171.1, 173.3. ESI1
0m/z)ˆ397. Anal. Calcd for C22H24N2O3S: C, 66.64; H,
6.10; N, 7.07; S, 8.09. Found: C, 66.91; H, 6.26; N, 7.12;
S, 8.21.
4.2.2. Crystal data of 4c. C13H14INO, Mwˆ327.15, colour-
less crystal of 0.67£0.25£0.25 mm3, Tˆ293 K, ortho-
Ê
rhombic, space group P, b, c, a, Zˆ8, aˆ9.177002) A,
Ê
Ê
Ê 3
bˆ13.517003) A, cˆ20.260005) A, Vˆ2513.1605) A ,
dcalc
ˆ
1.729 g cm23
,
F0000)ˆ1280,
lˆ0.71070 A
Ê
0Mo Ka), mˆ2.528 mm21, Nonius kappa CCD diffract-
ometer, u range 2.86±27.478, 2868 collected re¯ections,
2868 unique, full-matrix least-squares 0SHELXL9722),
R1ˆ0.0436, wR2ˆ0.0969, 0R1ˆ0.0687, wR2ˆ0.1077 all
data), goodness of ®tˆ1.397, residual electron density
Ê 23
between 0.409 and 21.714 e A . Hydrogen atoms ®tted
4.1.7. 3-)N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)-2-)2-
pyridylthio)-acrylic acid methyl ester )4e). The yellow
solid 3 0starting from 0.61 mmol of 2, Method B) was
dissolved in degassed and dry toluene and propynoic acid
methyl ester 00.56 mL, 6.10 mmol) was added. Then, the
mixture was heated at re¯ux for 6 h. The solvent was elimi-
nated and the residue puri®ed by column chromatography
using hexane/ethyl acetate 7:3 to give 140mg of 4e as a
at theoretical positions.
5. Supplementary material
Further details on the crystal structures 4b and 4c are
available on request from Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, UK on quoting
the depository numbers CCDC 173438 and 173439,
respectively.
1
white oil 062% yield). IR 0CH2Cl2, cm21): 1723, 1644. H
NMR 0CDCl3) d 1.48±1.600m, 2H), 1.80±1.92 0m, 3H),
2.03±2.32 0m, 3H), 3.66 0s, 3H), 4.10±4.17 0m, 1H),
6.93±7.01 0m, 1H), 7.26±7.49 0m, 5H), 7.52±7.67 0m,
3H), 8.35±8.400m, 1H). 13C NMR 0CDCl3) d 30.4, 33.0,
52.3, 61.2, 67.9, 119.9, 120.2, 121.4, 128.2, 128.3, 131.2,
135.6, 136.6, 148.8, 149.3, 159.6, 167.2, 172.9. ESI1
0m/z)ˆ395. Anal. Calcd for C22H22N2O3S: C, 66.98; H,
5.62; N, 7.10; S, 8.13. Found: C, 66.91; H, 5.76; N, 7.22;
S, 8.21.
Acknowledgements
Â
We thank Ministerio de Educacion y Cultura 0project
2FD97-1530), Gobierno de La Rioja 0ACPI-2000) and
Universidad de La Rioja 0project API-00/B02).
4.1.8. N-Benzoyl-7-azabicyclo[2.2.1]heptane )4f). The
yellow solid 3 0starting from 0.38 mmol of 2, Method B)
was dissolved in THF and Bu3SnH 0204 mL, 0.76 mmol)
was added. Then, the mixture was irradiated with a 200 W
tungsten lamp at rt for 6 h. The solvent was eliminated and
the residue puri®ed by column chromatography using
hexane/ethyl acetate 6:4 to give 47 mg of 4f as a white
solid 061% yield). Mp 73±768C. IR 0CH2Cl2, cm21): 1624.
1H NMR 0CDCl3) d 1.34±1.55 0m, 4H), 1.70±2.00 0m, 4H),
4.09±4.13 0m, 1H), 4.72±4.76 0m, 1H), 7.32±7.45 0m, 3H),
7.50±7.57 0m, 2H). 13C NMR 0CDCl3) d 28.7, 30.4, 53.6,
58.7, 127.6, 128.2, 130.3, 136.2, 168.6. ESI1 0m/z)ˆ202.
References
1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 939±941.
2. Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413±1432.
3. Renaud, P.; Giraud, L. Synthesis 1996, 913±926.
4. Della, E. W.; Tsanaktsidis, J. Aust. J. Chem. 1989, 42, 61±69.
5. Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313±
6325.
6. Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179±1193.
7. Han, W.; Pelletier, J. C.; Hodge, C. N. Bioorg. Med. Chem.
Lett. 1998, 8, 3615±3620.

A. Avenoza et al. / Tetrahedron 58 32002) 1193±1197
1197
8. Han, W.; Pelletier, J. C.; Mersinger, L. J.; Kettner, C. A.;
Hodge, C. N. Org. Lett. 1999, 1, 1875±1877.
9. Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.;
16. Ohwada, T. Yakugaku Zasshi 2001, 121, 65±77.
17. Shao, H.; Jiang, X.; Gantzel, P.; Goodman, M. Chem. Biol.
1994, 1, 231±234.
Â
Fernandez-Recio, M. A.; Rodrõguez, F. Tetrahedron 2001,
Â
18. 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.
57, 545±548.
10. Badio, B.; Garraffo, H. M.; Plummer, C. V.; Padgett, W. L.;
Daly, J. W. Eur. J. Pharmacol. 1997, 321, 189±194.
11. Xu, Y.-Z.; Choi, J.; Calaza, M. I.; Turner, S.; Rapoport, H.
J. Org. Chem. 1999, 64, 4069±4078.
19. Hassner, A.; Belostotskii, A. M. Tetrahedron Lett. 1995, 36,
1709±1712.
20. Olivo, H. F.; Hemenway, M. S.; Gezginci, M. H. Tetrahedron
Lett. 1998, 39, 865±868.
12. Fletcher, S. R.; Baker, R.; Chambers, M. S.; Hobbs, S. C.;
Mitchell, P. J. J. Chem. Soc., Chem. Commun. 1993, 1216±
1218.
21. Olivo, H. F.; Hemenway, M. S. J. Org. Chem. 1999, 64, 8968±
8969.
22. Sheldrick, G. M. SHELXL97. Program for the re®nement of
13. Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243±2266.
È È
crystal structures; University of Gottingen: Gottingen,
Germany, 1997.
14. Barton, D. H. R.; Crich, D.; Kretzschmar, G. J. Chem. Soc.,
Perkin Trans. 1 1986, 39±53.
15. Ohwada, T.; Achiwa, T.; Okamoto, I.; Shudo, K. Tetrahedron
Lett. 1998, 39, 865±868.