Synthesis of enantiomeric bridgehead substituted bisnoradamantane derivatives

Article abstract of DOI:10.1016/j.tet.2007.05.061

The preparation of (+)- and (-)-12 by resolution of (±)-12 with (R)-N-phenylpantolactam, (R)-13, is described. From (+)- and (-)-12 a series of chiral bisnoradamantane derivatives, whose chirality stems from substitution at the bridgehead positions, have

Full text of DOI:10.1016/j.tet.2007.05.061

Tetrahedron 63 (2007) 8027–8036
Synthesis of enantiomeric bridgehead substituted
bisnoradamantane derivatives
b
b
a,
Carles Ayats,a Pelayo Camps,a, Merce Font-Bardia, Xavier Solans and Santiago Vazquez
*
*
ꢀ
ꢁ
aLaboratori de Quꢁımica Farmaceꢀutica (Unitat Associada al CSIC), Facultat de Farmaꢀcia, Universitat de Barcelona,
Av. Diagonal, 643, Barcelona E-08028, Spain
bServeis Cientifico-Teꢀcnics, Universitat de Barcelona, Av. Martꢁı Franqueꢀs, s/n, Barcelona E-08028, Spain
Received 28 March 2007; revised 11 May 2007; accepted 16 May 2007
Available online 21 May 2007
Abstract—The preparation of (+)- and (ꢀ)-12 by resolution of (ꢁ)-12 with (R)-N-phenylpantolactam, (R)-13, is described. From (+)- and
(ꢀ)-12 a series of chiral bisnoradamantane derivatives, whose chirality stems from substitution at the bridgehead positions, have been
obtained in both enantiomeric forms.
Ó 2007 Elsevier Ltd. All rights reserved.
CH2
O
1. Introduction
CO2H
H
a
b
Tricyclo[3.3.0.03,7]octane, also called bisnoradamantane or
natane, is an aesthetically pleasing, high-symmetry cage-
shaped molecule with achiral D2d symmetry.1 The molecular
geometry of bisnoradamantane results in two sets of homo-
topic methylene groups, and the sets are in turn enantiotopic.
The molecule can be desymmetrized by differentiation of
one set of enantiotopic methylene groups from the other
set and a variety of bisnoradamantane derivatives have
been prepared in an optically active form.
( )-1
(−)-2
(−)-3
O
O
CO2H
(−)-4
R
R
(−)-5, R = Me
(−)-7, R = i-Pr
(−)-6, R = CH2
(+)-8, R = CMe2
H
H
HO2C
HO2C
H
HO2C
The most simple chiral bisnoradamantane derivatives are
monosubstituted such as 1, 2, and 3. Naemura and
Nakazaki’s group achieved the resolution of (ꢁ)-1, from
which (ꢀ)-2 and (ꢀ)-3 were obtained.2 Some disubstituted
enantiopure bisnoradamantane derivatives have also been
synthesized. For example, starting from enantiopure (ꢀ)-4,
oxetanes (ꢀ)-5 and (ꢀ)-7 were prepared, and treatment
with LiNEt2 followed by oxidation led to (ꢀ)-6 and (+)-8,
respectively.3 Finally, coaxially disubstituted derivatives
were also prepared in optically active form. Optical resolu-
tion of (ꢁ)-9 was accomplished via the (+)-2-(1-amino-
ethyl)naphthalene salt to furnish (ꢀ)-9, which was
converted into (ꢀ)-10 (Scheme 1).4
c
a
O
(−)-10
( )-9
(−)-9
Scheme 1. Several chiral bisnoradamantanes. (a) O3, then Zn/H3O+. (b)
LiNEt2, benzene, D; then, CrO3, pyridine. (c) Resolution.
correspond to the bridgehead positions. However, in a more
simple way, they can be considered as having a chiral axis
passing by the middle of the C1–C5 and C3–C7 bonds. Their
chirality could then be defined as R or S, in the same way as
for chiral allenes, and requires only different substitutions at
the vicinal bridgehead positions.
Worthy of note, substituted bisnoradamantanes of general
structure 11 are chiral tricyclo[3.3.0.03,7]octane derivatives
(Fig. 1). All of them contain four stereogenic centers, which
Although several bridgehead substituted chiral bisnorada-
mantanes are known,5 efforts directed toward their prepara-
tion as single enantiomers have not been described.
* Corresponding authors. Tel.: +34 934024536; fax: +34 934035941 (P.C.);
tel.: +34 934024533; fax: +34 934035941 (S.V.); e-mail addresses:
camps@ub.edu; svazquez@ub.edu
In this paper, we report the preparation of (+)- and (ꢀ)-12
from racemic (ꢁ)-12 by using (R)-N-phenylpantolactam,
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.061

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C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
8
2. Results and discussion
R'
6
R
R
R
R
R'
R'
1
2
7
5
Reaction of the easily available (ꢁ)-12,5c with (R)-N-phenyl-
pantolactam, 13, gave a diastereomeric mixture of diesters
14, from which diesters (+)-14 and (ꢀ)-14 were isolated
and fully characterized after column chromatography. The
absolute configuration of (ꢀ)-14 was established as
(1S,3S,5S,7S,30R,300R)-14 by X-ray diffraction analysis
(Fig. 2), thus allowing us to establish also the absolute config-
uration of (+)-14 as (1R,3R,5R,7R,30R,300R)-14 (Scheme 2).7
3
R'
4
( )-11
Figure 1. Bridgehead substituted chiral bisnoradamantanes.
13, a chiral auxiliary developed by our group.6 From
(+)- and (ꢀ)-12 a series of enantiomeric bisnoradamantane
derivatives have been prepared.
Figure 2. X-ray diffraction structure (ORTEP) of (1S,3S,5S,7S,30R,300R)-14.
(CH3)α
OH
(CH3)β
Hβ
I
Hα
Hα
CO2R*
Hβ
I
Hα
I
I
CO2H
CO2H
*RO2C
7
5
1
3
O
a
Hβ
N
+
+
I
CO2R*
*RO2C
I
(1R,3R,5R,7R,3'R,3''R)-14
(1S,3S,5S,7S,3'R,3''R)-14
(R)-13
( )-12
R*OH = (R)-13
Hα
MeO2C
Hα
MeO2C
Hβ
I
Hβ
Hα
I
Hβ
MeO2C
I
MeO2C
I
(–)-15 [or (+)-15]
( )-15
(–)-16 [or (+)-16]
( )-16
(–)-17 [or (+)-17]
( )-17
c
e
c
Hα
Hβ
Hα
Hα
Hβ
I
Hβ
NC
*RO2C
*RO2C
I
I
HO2C
HO2C
d
f
b
NC
HO2C
I
HO2C
(–)-12 [or (+)-12]
and ( )-12
(–)-18 [or (+)-18]
( )-18
(–)-19 [or (+)-19]
( )-19
(1S,3S,5S,7S,3'R,3''R)-14
h
[or (1R,3R,5R,7R,3'R,3''R)-14]
g
g
Hα
Br
Hβ
I
Hα
O2N
Hβ
Hα
Br
Hβ
i
Br
I
O2N
Br
(–)-20 [or (+)-20]
( )-20
(–)-21 [or (+)-21]
(–)-22 [or (+)-22]
( )-22
( )-21
Scheme 2. Synthesis of enantiopure bridgehead substituted bisnoradamantanes. (a) DCC, DMAP, anhydrous THF, 0 ꢂC–rt, 21 h, 27% of
(1R,3R,5R,7R,30R,300R)-14; 30% of (1S,3S,5S,7S,30R,300R)-14, after silica gel column chromatography. (b) LiOH$H2O, H2O2, THF, 0 ꢂC–rt, 48 h, 87% of
(ꢀ)-12, 92% of (+)-12. (c) MeOH, H2SO4, D, 18 h, 86% of (ꢀ)-15, 89% of (+)-15, 90% of (ꢁ)-17, 88% of (ꢀ)-17, 86% of (+)-17. (d) Li, t-BuOH, D, 6 h,
75% of (ꢀ)-18, 65% of (+)-18. (e) IBDA, I2, acetonitrile, hn, 20 h, 57% of (ꢀ)-16, 56% of (+)-16. (f) Acetonitrile, H2SO4, D, 6 h, 38% of (ꢁ)-19, 26% of
(ꢀ)-19, 29% of (+)-19. (g) HgO, Br2, CH2Br2, D, 3 h, 88% of (ꢁ)-20, 94% of (ꢀ)-20, 88% of (+)-20, 53% of (ꢁ)-21, 71% of (ꢀ)-21, 71% of (+)-21. (h)
SOCl2, D, 2 h; then NaN3, H2O, acetone, 0 ꢂC–rt, 3 h; then anhydrous toluene, D, 5 h; then DMD, H2O, acetone, rt, 12 h, 48% of (ꢁ)-22, 41% of (ꢀ)-22,
44% of (+)-22. (i) H2, Pd/C, MeOH, H2O, approx. 83% of (ꢁ)-21, approx. 79% of (ꢀ)-21, approx. 85% of (+)-21.

C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
8029
Worthy of note, attempted resolution of diacid (ꢁ)-18 as
described for (ꢁ)-12, failed.
oxidation with an acetone solution of dimethyldioxirane
(DMD) to give the dinitroderivative (ꢁ)-22 in 67% yield.
Hydrolysis of (ꢀ)-14 gave the enantiopure diacid (ꢀ)-12 in
87% yield, while hydrolysis of (+)-14 gave diacid (+)-12 in
92% yield. The absolute configuration of (ꢀ)-12 must be
(1S,3S,5S,7S). As a compound having a chiral axis, it would
be more easily defined as (S)-12.
More conveniently, (ꢁ)-22 was prepared in 48% yield by
oxidation of the corresponding diisocyanate, (ꢁ)-23, with
dimethyldioxirane in wet acetone (Scheme 3), following
a procedure first reported by Eaton in the synthesis of 1,4-
dinitrocubane.11
OCN
a or
Very recently, we have described that reduction of (ꢁ)-12
with Li/t-BuOH gave the diacid (ꢁ)-18,5b whose double
iododecarboxylation led to racemic (ꢁ)-16 in 76% yield.5d
Starting from (ꢀ)-12, and following the aforementioned
procedures, (ꢀ)-18 and (ꢀ)-16 were obtained in high yields.
( )-18
b
c
OCN
( )-23
d
H2N
2HCl·
e
( )-22
On the other hand, esterification of (ꢀ)-12 with methanol led
to the diester (ꢀ)-15 in 86% yield. Racemic (ꢁ)-15, had
been previously obtained by our group following a different
synthetic approach.5c Similarly, (+)-15, (+)-16, and (+)-18
were obtained from (+)-12 (Scheme 2).
H2N
( )-24·HCl
Scheme 3. Synthesis of (ꢁ)-22. (a) SOCl2, D, 2 h; then NaN3, H2O, acetone,
0 ꢂC–rt, 3 h; then anhydrous toluene, D, 5 h. (b) (C6H5O)2PON3, Et3N, tol-
uene, D, 3 h. (c) 6 N HCl, D, 24 h, 22% from (ꢁ)-18. (d) DMD, acetone,
H2O, rt, 12 h, 48% of (ꢁ)-22 from (ꢁ)-18. (e) DMD, acetone, rt, 16 h, 67%.
In order to further explore the chemistry of enantiomeric
bridgehead substituted bisnoradamantanes we envisaged
the new compounds 17 and 19–22. Firstly, the synthesis of
these compounds was planned as racemic mixtures start-
ing from (ꢁ)-12. Thus, double bromodecarboxylation of
(ꢁ)-12 and (ꢁ)-18 using HgO/Br2 in CH2Br2 led to
(ꢁ)-20 and (ꢁ)-21 in 88 and 53% yields, respectively.
Both new compounds were fully characterized and the struc-
ture of (ꢁ)-20 was unequivocally established by X-ray dif-
fraction analysis (Fig. 3).8
Following the aforementioned procedures in the racemic
series and starting from enantiopure diacid (ꢀ)- or (+)-12,
enantiopure (ꢀ)- or (+)-17, 19–22, respectively, were pre-
pared and fully characterized.
The enantiopurity of (+)- and (ꢀ)-19 and of (+)- and (ꢀ)-21
was established by chiral GC/MS using a 30-m column con-
taining permethylated b-cyclodextrine as the chiral station-
ary phase. Only one stereoisomer was observed in each
case. The enantiopurity of (+)- and (ꢀ)-19, implies also
that of their precursors, (+)-12 and (+)-18, and (ꢀ)-12 and
(ꢀ)-18, respectively. We were not able to resolve esters
(ꢁ)-15 and (ꢁ)-17, and compounds (ꢁ)-20 and (ꢁ)-22 by
chiral GC. However, chemoselective hydrogenation of
(ꢀ)- and (+)-20 in alkaline methanol led to enantiopure
(ꢀ)- and (+)-21, respectively, thus establishing the enantio-
purity of the first compounds.
While Fischer esterification of (ꢁ)-18 with methanol gave
(ꢁ)-17 in 90% yield, obtention of (ꢁ)-19 from (ꢁ)-18 was
troublesome. Initial attempts to obtain (ꢁ)-19 from (ꢁ)-18
by using Barton’s decarboxylative cyanation met with fail-
ure.9 Also, a one-pot three-step procedure involving conver-
sion of (ꢁ)-18 into the corresponding bisacyl chloride,
diamide formation and dehydration gave (ꢁ)-19 in very
low yield. Fortunately, reaction of (ꢁ)-18 with H2SO4 in
´
acetonitrile, conditions very recently applied by Mlinaric-
Since esterification of 12 and 18 and the conversion of 18 to
22 are not expected to take place with racemization, the
enantiopurity of compounds (+)-15, (+)-17, and (+)-22
must be the same as their common precursor (+)-12. The
same is true in the enantiomeric series.
Majerski and co-workers to adamantane-1,3-dicarboxylic
acid, led to (ꢁ)-19 in 38% yield.10
Although application of Yamada’s modification of the classi-
cal Curtius reaction to (ꢁ)-18 gave the dihydrochloride of di-
amine (ꢁ)-24$2HCl in only 22% yield, we carried out its
It should be noted that the density of (ꢁ)-22 is quite high,
1.46 g mLꢀ1, as determined from its X-ray diffraction anal-
ysis (Fig. 4).12 Polynitro cage compounds have raised inter-
est as high-energetic materials as has beautifully been
illustrated by Eaton13 and Marchand.14
Figure 3. X-ray diffraction structure (ORTEP) of (ꢁ)-20.
Figure 4. X-ray diffraction structure (ORTEP) of (ꢁ)-22.

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C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
Taking into account the high density of (ꢁ)-22, we
attempted the obtention of 1,3,5,7-tetranitrotricyclo-
[3.3.0.03,7]octane from the known tricyclo[3.3.0.03,7]-
octane-1,3,5,7-tetracarboxylic acid,5c following a synthetic
sequence similar to that shown in Scheme 3 for (ꢁ)-22.
However, a complex mixture of products not containing
the expected tetranitro derivative was obtained.
30R,300R)-14 and (1S,3S,5S,7S,30R,300R)-14. Dicyclohexyl-
carbodiimide (DCC, 1.84 g, 8.92 mmol) was added in
portions to a solution of (ꢁ)-12 (2.0 g, 4.46 mmol) in anhy-
drous THF (15 mL) at 0 ꢂC and the mixture was stirred at
this temperature for 30 min. A solution of (R)-3-hydroxy-
4,4-dimethyl-1-phenylpyrrolidin-2-one [(R)-13, 1.83 g,
8.92 mmol] in anhydrous THF (15 mL) and 4-(dimethylami-
no)pyridine (DMAP, 30 mg, 0.24 mmol) was added and the
mixture was stirred at room temperature for 21 h. The
precipitated dicyclohexylurea (DCU) was filtered through
CeliteÒ washing the solid with CH2Cl2 (5ꢃ10 mL). The
combined filtrate and washings were concentrated under
reduced pressure, H2O (150 mL) and brine (30 mL) were
added and the mixture was extracted with CH2Cl2
(3ꢃ150 mL). The combined organic extracts were dried (an-
hydrous Na2SO4) and concentrated under reduced pressure
to give a diastereomeric mixture of (1R,3R,5R,7R,30R,300R)-
and (1S,3S,5S,7S,30R,300R)-14 (4.72 g, dr¼50:50, by 1H
NMR), which was submitted to flash column chromato-
graphy [silica gel, (480 g), 8 cm internal diameter of the
column, mixture hexane/AcOEt (3:1)] obtaining in order
of elution: (1R,3R,5R,7R,30R,300R)-14 (1.62 g), which after
recrystallization from EtOH (4 mL) gave the analytical sam-
3. Conclusions
In conclusion, an easy entry to unprecedented enantiomeric
bridgehead substituted bisnoradamantane derivatives by
resolution of diacid (ꢁ)-12 via diastereomeric esters of
(R)-N-phenylpantolactam has been developed. These com-
pounds constitute particular cases of axial chirality.
4. Experimental section
4.1. General methods
Melting points were determined in open capillary tubes. Un-
less otherwise stated, NMR spectra were recorded in CDCl3:
1H NMR (500 MHz), 13C NMR (75.4 MHz). Chemical
shifts (d) are reported in parts per million related to internal
tetramethylsilane (TMS). Assignments given for the NMR
spectra are based on DEPT, COSY 1H/1H, HETCOR
1H/13C (HSQC and HMBC sequences for one bond and
long range 1H/13C heterocorrelations, respectively), and
NOESY experiments for selected compounds. Diastereo-
topic methylene protons in tricyclo[3.3.0.03,7]octane deri-
vatives are referred as Ha and Hb as shown in the
1
ple (1.00 g, 27% yield from (ꢁ)-12, dr >98, by H NMR)
and (1S,3S,5S,7S,30R,300R)-14 (1.69 g), which was washed
with hot EtOH (8 mL) to give the analytical sample (1.09 g,
30% yield from (ꢁ)-12, dr >98, by 1H NMR), both as white
solids. (1R,3R,5R,7R,30R,300R)-14: mp 124–125 ꢂC (EtOH);
TLC (silica gel), Rf 0.61 [hexane/AcOEt (1:1)]; [a]2D0 +22.7
(CH2Cl2, c 0.50); IR (KBr) n 2964, 2931, 2875, 1741, 1717,
1598, 1500, 1481, 1409, 1385, 1324, 1264, 1217, 1158,
1124, 1100, 1075, 759, 691 cmꢀ1; 1H NMR d: 1.23 [s, 6H,
40(400)-a-CH3], 1.42 [s, 6H, 40(400)-b-CH3], 2.35 [dm, J¼
10.3 Hz, 2H, 4(8)-Hb], 2.46 [br s, 2H, 2-H2], 2.66 [br s,
2H, 6-H2], 2.69 [dm, J¼10.3 Hz, 2H, 4(8)-Ha], 3.54 [d, J¼
9.5 Hz, 2H, 50(500)-Ha], 3.65 [d, J¼9.5 Hz, 2H, 50(500)-Hb],
5.54 [s, 2H, 30(300)-H], 7.17 [tt, J¼7.5 Hz, J0¼1.0 Hz, 2H,
Ar–Hpara N-phenyl], 7.37 [m, 4H, Ar–Hmeta N-phenyl],
7.62 [m, 4H, Ar–Hortho N-phenyl]. 13C NMR d: 21.5
[CH3, 40(400)-a-CH3], 24.9 [CH3, 40(400)-b-CH3], 27.8 [C,
C5(7)], 37.4 [C, C40(400)], 51.0 [CH2, C2], 57.7 [CH2,
C50(500)], 60.6 [CH2, C4(8)], 61.2 [C, C1(3)], 69.0 [CH2,
C6], 78.9 [CH, C30(300)], 119.4 [CH, Ar–Cortho N-phenyl],
124.9 [CH, Ar–Cpara N-phenyl], 128.9 [CH, Ar–Cmeta
N-phenyl], 138.9 [C, Ar–Cipso N-phenyl], 168.2 [C,
C20(200) and 1(3)-CO2]; MS (EI), m/z (%): 695 ([MꢀI]+,
1), 568 ([Mꢀ2I]ꢄ+, 1), 362 ([MꢀIꢀHIꢀC12H15NO2]+, 6),
285 ([MꢀIꢀ2C12H15NO2]+, 11), 206 (17), 188 (18), 174
(14), 158 ([Mꢀ2Iꢀ2C12H15NO2]ꢄ+, 17), 131 (11), 127 (12),
119 (13), 106 (21), 105 (26), 104 (42), 103 (17), 77 (41), 69
(100). Anal. Calcd for C34H36I2N2O6 (822.47): C 49.65, H
4.41, N 3.41, I 30.86. Found: C 49.54, H 4.34, N 3.38, I
30.77. (1S,3S,5S,7S,30R,300R)-14: mp 278–279 ꢂC (EtOH);
TLC (silica gel), Rf 0.47 [hexane/AcOEt (1:1)]; [a]D20
ꢀ23.0 (CH2Cl2, c 0.55); IR (KBr) n 2962, 2929, 1741,
1716, 1699, 1626, 1599, 1500, 1488, 1411, 1388, 1345,
1325, 1304, 1286, 1264, 1223, 1157, 1125, 1079, 757,
1
corresponding structures. H NMR and 13C NMR spectra
are given only for the new racemic compounds, while only
the 300 MHz 1H NMR spectra are given for the enantiomer-
ic compounds. For the routine MS and GC/MS analyses the
sample was introduced directly or through a gas chromato-
graph. For achiral GC/MS analyses a 30-m column [5% di-
phenyl-95% dimethylpolysiloxane, conditions: 10 psi,
initial temperature: 35 ꢂC (2 min), then heating at a range
of 8 ꢂC minꢀ1 till 300 ꢂC, then isothermic at 300 ꢂC] was
used. For chiral GC/MS analyses a 30-m (0.25 mm internal
diameter) chiral column [containing permethylated b-cyclo-
dextrine as the chiral stationary phase, conditions: 10 psi,
initial temperature: 50 ꢂC (2 min), then heating at a range
of 10 ꢂC minꢀ1 till 240 ꢂC, then isothermic at 240 ꢂC] was
used. In both cases, the electron impact (70 eV) or chemical
ionization (CH4) techniques were used. Only significant ions
are given: those with higher relative abundance, except for
the ions with higher m/z values. Accurate mass measure-
ments were obtained using EI, CI or ESI techniques.
Absorption values in the IR spectra are given as wave-
numbers (cmꢀ1). Rotatory powers were determined on a
polarimeter using 1-cm cells. Column chromatography was
˚
performed on silica gel 60 A (35–70 mesh). For the thin
layer chromatography (TLC) aluminum-backed sheets
with silica gel 60 F254 were used and spots were visualized
with UV light and/or 1% aqueous solutions of KMnO4.
1
688 cmꢀ1; H NMR d: 1.23 [s, 6H, 40(400)-a-CH3], 1.41 [s,
6H, 40(400)-b-CH3], 2.41 [br s, 2H, 2-H2], 2.44 [dm, J¼
10.5 Hz, 2H, 4(8)-Hb], 2.64 [br s, 2H, 6-H2], 2.66 [dm, J¼
10.5 Hz, 2H, 4(8)-Ha], 3.54 [d, J¼9.5 Hz, 2H, 50(500)-Ha],
3.64 [d, J¼9.5 Hz, 2H, 50(500)-Hb], 5.52 [s, 2H, 30(300)-H],
7.17 [tt, J¼7.5 Hz, J0¼1.0 Hz, 2H, Ar–Hpara N-phenyl],
4.1.1. Bis[(3R)-1-phenyl-4,4-dimethyl-2-oxopyrrolidin-3-
yl] (1R,3R,5R,7R)- and (1S,3S,5S,7S)-5,7-diiodotricy-
clo[3.3.0.03,7]octane-1,3-dicarboxylate, (1R,3R,5R,7R,

C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
8031
7.38 [m, 4H, Ar–Hmeta N-phenyl], 7.63 [m, 4H, Ar–Hortho
149 (25), 148 ([Mꢀ2IꢀHCO2H]ꢄ+, 57), 105 (29), 104 (38),
103 (62), 91 (26), 77 (54). Accurate mass measurement
(ESI+) calcd for [C10H10O4I2+Na]+: 470.85607. Found:
470.85657.
13
N-phenyl]. C NMR d: 21.4 [CH3, 40(400)-a-CH3], 24.8
[CH3, 40(400)-b-CH3], 27.6 [C, C5(7)], 37.4 [C, C40(400)],
51.2 [CH2, C2], 57.6 [CH2, C50(500)], 60.6 [CH2, C4(8)], 60.7
[C, C1(3)], 69.2 [CH2, C6], 79.0 [CH, C30(300)], 119.3 [CH,
Ar–Cortho N-phenyl], 124.9 [CH, Ar–Cpara N-phenyl],
128.9 [CH, Ar–Cmeta N-phenyl], 139.0 [C, Ar–Cipso N-
phenyl], 168.2 (C) and 168.4 (C) [C20(200) and 1(3)-CO2];
MS (EI), m/z (%): 568 ([Mꢀ2I]ꢄ+, 1), 362 (3), 285 (7), 206
(12), 188 (14), 174 (10), 158 (15), 131 (10), 127 (9), 119 (11),
106 (19), 105 (21), 104 (35), 103 (14), 77 (36), 69 (100).
Anal. Calcd for C34H36I2N2O6 (822.47): C 49.65, H 4.41,
N 3.41, I 30.86. Found: C 49.70, H 4.45, N 3.35, I 30.77.
4.1.4. (L)-Dimethyl (1S,3S,5S,7S)-5,7-diiodotricyclo-
[3.3.0.03,7]octane-1,3-dicarboxylate, (L)-15.5c A solution
of diiodo diacid (ꢀ)-12 (100 mg, 0.22 mmol) in anhydrous
MeOH (2 mL) and concd H2SO4 (0.2 mL) was heated under
reflux for 18 h. The mixture was allowed to cool to room
temperature and concentrated under reduced pressure to
remove MeOH. The residue was taken in CH2Cl2 (20 mL)
and the organic solution was washed with H2O (3ꢃ5 mL)
and saturated aqueous NaHCO3 solution (2ꢃ5 mL). Evapo-
ration of the solvent from the dried organic phase (anhydrous
Na2SO4) under reduced pressure gave a yellow oil, which
was washed with a small amount of n-pentane to give diiodo
diester (ꢀ)-15 (90 mg, 86% yield) as a white solid. The
analytical sample was obtained by crystallization from
AcOEt, mp 87–89 ꢂC; [a]D24 ꢀ21.1 (CH2Cl2, c 2.05); IR
(KBr) n 3000, 2952, 2899, 1734, 1479, 1435, 1315, 1268,
1226, 1158, 1125, 1057, 942 cmꢀ1; MS (EI), m/z (%): 349
([MꢀI]+, 8), 317 ([MꢀIꢀCH3OH]+, 49), 289([MꢀIꢀHCO2-
CH3]+, 61), 190 (38), 189 (31), 162 ([Mꢀ2IꢀHCO2CH3]ꢄ+,
95), 131 (28), 104 (30), 103 ([Mꢀ2IꢀHCO2CH3ꢀ
CO2CH3]+, 100), 102 (44), 91 (31), 78 (33), 77 (65), 59
([CO2CH3]+, 68). Accurate mass measurement (ESI+) calcd
for [C12H14O4I2+Na]+: 498.8874. Found: 498.8875.
4.1.2. (L)(1S,3S,5S,7S)-5,7-Diiodotricyclo[3.3.0.03,7]oc-
tane-1,3-dicarboxylic acid, (L)-12.5c To a cold (0 ꢂC) sus-
pension of (1S,3S,5S,7S,30R,300R)-14 (681 mg, 0.83 mmol)
in THF (15 mL), H2O2 30% w/v (0.8 mL, 7.06 mmol) and
LiOH$H2O (0.18 g, 4.30 mmol) were added and the mixture
was stirred at room temperature for 48 h. The suspension
was cooled in an ice-bath and aqueous Na2SO3 (1.5 N,
7 mL, pHz9) was added. The mixture was extracted with
AcOEt (3ꢃ60 mL) and the combined organic extracts
were dried (anhydrous Na2SO4) and concentrated under re-
duced pressure to give (R)-13 (340 mg, quantitative recov-
ery, >99% ee by chiral HPLC). The aqueous phase was
cooled in an ice-bath, made acidic to pHz1–2 with 5 N
HCl (4 mL) and the mixture was extracted with AcOEt
(5ꢃ60 mL). The combined organic extracts were dried (an-
hydrous Na2SO4) and concentrated under reduced pressure
to give diiodo diacid (ꢀ)-12 (322 mg, 87% yield) as a white
solid, mp >300 ꢂC (dec); [a]2D3 ꢀ24.0 (MeOH, c 2.06); IR
(KBr) n 3200–2200 (max. at 3007, 2919, 2712, 2599),
1713, 1698, 1472, 1421, 1327, 1306, 1269, 1235, 1173,
1119, 1058, 989, 963, 947, 899, 801, 750, 723, 701,
638 cmꢀ1; MS (EI), m/z (%): 448 (Mꢄ+, 2), 430 ([MꢀH2O]ꢄ+,
3), 321 ([MꢀI]+, 4), 304 (11), 303 ([MꢀIꢀH2O]+, 100), 277
(14), 275 ([MꢀIꢀHCO2H]+, 58), 176 ([Mꢀ2IꢀH2O]ꢄ+, 24),
149 (21), 148 ([Mꢀ2IꢀHCO2H]ꢄ+, 49), 105 (22), 104 (28),
103 (41), 77 (36); MS (CI), m/z (%): 449 ([M+H]+, 7), 448
(Mꢄ+, 1), 403 (35), 321 ([MꢀI]+, 41), 304 (30), 303 ([MꢀIꢀ
H2O]+, 92), 277 (82), 276 (91), 275 ([MꢀIꢀHCO2H]+, 100),
231 (43), 194 (25), 193 (61), 177 (30), 176 ([Mꢀ2IꢀH2O]ꢄ+,
59), 175 (42), 150 (34), 149 (82), 148 ([Mꢀ2IꢀHCO2H]ꢄ+,
66), 147 (22), 131 (20), 105 (37), 104 (38), 103 (39). Accu-
rate mass measurement (ESI+) calcd for [C10H10O4I2+H]+:
448.8741. Found: 448.8738.
4.1.5. (D)-Dimethyl (1R,3R,5R,7R)-5,7-diiodotricy-
clo[3.3.0.03,7]octane-1,3-dicarboxylate, (D)-15.5c This
reaction was carried out as described for the preparation of
diiodo diester (ꢀ)-15. From (+)-12 (102 mg, 0.23 mmol),
anhydrous MeOH (2 mL), and concd H2SO4 (0.2 mL),
diiodo diester (+)-15 (97 mg, 89% yield) was obtained as
a white solid. The analytical sample was obtained by crystal-
lization from AcOEt, mp 97–98 ꢂC; [a]D24 +21.0 (CH2Cl2,
c 1.00); IR (KBr) n 3002, 2953, 2851, 1733, 1724, 1480,
1435, 1316, 1269, 1227, 1126, 1058, 943 cmꢀ1; MS (EI),
m/z (%): 349 [(MꢀI)+, 8], 317 ([MꢀIꢀCH3OH]+, 42), 289
([MꢀIꢀHCO2CH3]+, 55), 190 (34), 189 (30), 162 ([Mꢀ2Iꢀ
HCO2CH3]ꢄ+, 93), 131 (28), 104 (30), 103 ([Mꢀ2Iꢀ
HCO2CH3ꢀCO2CH3]+, 100), 102 (45), 91 (31), 78 (32),
77 (68), 59 ([CO2CH3]+, 76). Accurate mass measurement
(ESI+) calcd for [C12H14O4I2+Na]+: 498.8874. Found:
498.8873.
4.1.6. (L)(1S,3S,5S,7S)-1,3-Diiodotricyclo[3.3.0.03,7]oc-
tane, (L)-16.5d A mixture of diacid (ꢀ)-18 (37 mg,
0.19 mmol), iodine (0.11 g, 0.45 mmol), and iodosobenz-
enediacetate (IBDA, 0.15 g, 98% content, 0.45 mmol) in an-
hydrous acetonitrile (4 mL) was irradiated under reflux with
a 100 W tungsten lamp in an argon atmosphere for 4 h. More
iodine (0.11 g, 0.45 mmol) and IBDA (0.15 g, 0.45 mmol)
were added and irradiation under reflux was continued for
20 h more. The resulting solution was distilled under atmo-
spheric pressure through a Vigreux column (10 cm). The
residue was taken in diethyl ether (10 mL) and the organic
solution was washed with aqueous Na2S2O3 solution
(10%, 3ꢃ10 mL), saturated aqueous NaHCO3 solution
(3ꢃ10 mL), and brine (2ꢃ10 mL). The organic phase was
dried (anhydrous Na2SO4) and the solvent was distilled
under atmospheric pressure through a Vigreux column
4.1.3. (D)(1R,3R,5R,7R)-5,7-Diiodotricyclo[3.3.0.03,7]-
octane-1,3-dicarboxylic acid, (D)-12.5c This reaction
was carried out as described for the preparation of diiodo
diacid (ꢀ)-12. From (1R,3R,5R,7R,30R,300R)-14 (816 mg,
0.99 mmol), H2O2 30% w/v (0.95 mL, 8.38 mmol), and
LiOH$H2O (0.22 g, 5.24 mmol) in THF (18 mL), (R)-13
(390 mg, 96% recovery, >99% ee by chiral HPLC) and
diiodo diacid (+)-12 (409 mg, 92% yield) were obtained
as white solids, mp >300 ꢂC (dec); [a]2D3 +27.9 (MeOH,
c 1.98); IR (KBr) n 3500–2200 (max. at 3008, 2920, 2714,
2599), 1713, 1698, 1472, 1421, 1328, 1305, 1269, 1235,
1173, 1119, 1058, 989, 963, 947, 899, 869, 801, 749, 723,
701, 638 cmꢀ1; MS (EI), m/z (%): 448 (Mꢄ+, 2), 430
([MꢀH2O]ꢄ+, 3), 321 ([MꢀI]+, 4), 303 ([MꢀIꢀH2O]+,
100), 275 ([MꢀIꢀHCO2H]+, 65), 176 ([Mꢀ2IꢀH2O]ꢄ+, 25),

8032
C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
(10 cm). Most of the iodobenzene formed in the reaction was
distilled using a rotary microdistillation equipment at 70–
80 ꢂC/30 Torr. The light yellow residue (128 mg) was sub-
mitted to column chromatography [silica gel (25 g),
hexane]. The solvent of the chromatographic fractions was
distilled off at atmospheric pressure through a Vigreux
column (10 cm) to afford diiodide (ꢀ)-16 (43 mg) as a light
yellow liquid, which was further purified by distillation on
a rotary microdistillation equipment at 100–110 ꢂC/30 Torr
to give pure (ꢀ)-16 (39 mg, 57% yield) as a colorless liquid;
[a]2D5 ꢀ40.4 (CH2Cl2, c 0.86); IR (NaCl) n 2992, 2940, 2893,
1477, 1282, 1266, 1249, 1209, 1195, 1067, 1000, 944, 921,
809 cmꢀ1; MS (EI), m/z (%): 360 [Mꢄ+, <1], 233 ([MꢀI]+,
22), 106 ([Mꢀ2I]ꢄ+, 100), 105 (48), 91 (41), 79 (28), 78
(32), 77 (19). Anal. Calcd for C8H10I2 (359.98): C 26.69,
H 2.80, I 70.51. Found: C 27.07, H 2.74, I 69.36.
was obtained as a white solid, mp 190–191 ꢂC (diethyl
ether); [a]2D5 +7.7 (CH3OH, c 2.03); IR (KBr) n 3500–2250
(max. at 2996, 2950, 2903, 2713, 2612), 1698, 1483, 1420,
1319, 1289, 1259, 1219, 1127, 1088, 887, 747 cmꢀ1; MS
(EI), m/z (%): 178 ([MꢀH2O]ꢄ+, 1), 150 ([MꢀHCO2H]ꢄ+,
19), 133 ([MꢀHCO2HꢀOH]+, 10), 132 (10), 111 (13), 110
(10), 106 (18), 105 (68), 104 ([Mꢀ2HCO2H]ꢄ+, 20), 103
(29), 93 (19), 91 (53), 79 (66), 78 (40), 77 (100), 67 (45),
66 (44), 65 (68). Accurate mass measurement (ESIꢀ) calcd
for [C10H12O4ꢀH]ꢀ: 195.06628. Found: 195.06665.
4.1.10. ( )-Dimethyl tricyclo[3.3.0.03,7]octane-1,3-dicarb-
oxylate, ( )-17. Thisreactionwas carried out as describedfor
the preparation of diiodo diester (ꢀ)-15. From (ꢁ)-18
(123 mg, 0.62 mmol), anhydrous MeOH (3 mL), and concd
H2SO4 (0.3 mL), diester (ꢁ)-17 (125 mg, 90% yield) was ob-
tained as a white solid, mp 42–43 ꢂC (n-pentane); IR (KBr) n
3002, 2951, 2902, 2849, 1726, 1483, 1460, 1436, 1333, 1318,
1280, 1251, 1229, 1215, 1205, 1120, 1105, 1090, 1068, 1050,
1004, 934, 886, 873, 808, 783, 752, 737 cmꢀ1; 1H NMR d:
1.64 [br s, 2H, 6-H2], 1.74 [dt, J¼9.5 Hz, J0¼2.0 Hz, 2H,
4(8)-Ha], 1.91 [dm, J¼9.5 Hz, 2H, 4(8)-Hb], 2.02 [t,
J¼2.0 Hz, 2H, 2-H2], 2.73 [m, 2H, 5(7)-H], 3.71 [s, 6H,
1(3)-CO2CH3]. 13C NMR d: 42.8 [CH, C5(7)], 46.5 [CH2,
C6], 50.5 [CH2, C4(8)], 51.7 [CH3, 1(3)-CO2CH3], 52.7 [C,
C1(3)], 53.7 [CH2, C2], 174.6 [C, 1(3)-CO2CH3]; MS (EI),
m/z (%): 192 ([MꢀCH3OH]ꢄ+, 33), 165 (26), 164
([MꢀHCO2CH3]ꢄ+, 61), 133 ([MꢀHCO2CH3ꢀCH3O]+,
66), 132 (24), 125 (63), 105 (100), 104 (31), 93 (73), 79
(40), 77 (25), 65 (25), 59 ([CO2CH3]+, 42). Anal. Calcd for
C12H16O4 (224.25): C 64.27, H 7.19. Found: C 64.11, H 7.13.
4.1.7. (D)(1R,3R,5R,7R)-1,3-Diiodotricyclo[3.3.0.03,7]oc-
tane, (D)-16.5d This reaction was carried out as described
for the preparation of diiodide (ꢀ)-16. From (+)-18
(70 mg, 0.36 mmol), iodine [2ꢃ(0.20 g, 0.78 mmol)], and
iodosobenzenediacetate [IBDA, 2ꢃ(0.26 g, 98% content,
0.78 mmol)] in anhydrous acetonitrile (7 mL), diiodide
(+)-16 (72 mg, 56% yield) was obtained as a colorless liquid;
[a]2D8 +41.2 (CH2Cl2, c 0.47); IR (NaCl) n 2992, 2940, 2893,
1477, 1282, 1252, 1208, 1196, 1067, 1000, 944, 921,
809 cmꢀ1; MS (EI), m/z (%): 360 (Mꢄ+, 2), 233 ([MꢀI]+,
39), 106 ([Mꢀ2I]ꢄ+, 100), 105 (40), 91 (39), 79 (24), 78
(27). Anal. Calcd for C8H10I2 (359.98): C 26.69, H 2.80, I
70.51. Found: C 27.17, H 2.82, I 70.45.
4.1.8. (L)(1S,3S,5S,7S)-Tricyclo[3.3.0.03,7]octane-1,3-
dicarboxylic acid, (L)-18.5d To a boiling solution of (ꢀ)-
12 (640 mg, 1.43 mmol) in a mixture of t-BuOH (8.2 mL,
86 mmol) and anhydrous THF (30 mL) kept under argon,
lithium in small pieces (600 mg, 86 mmol) was added, and
the mixture was heated under reflux for 6 h. The mixture
was allowed to cool to room temperature and poured onto
ice-water (70 g). The aqueous solution was washed with di-
ethyl ether (3ꢃ25 mL), cooled with an ice-water bath, made
acidic (pHz1–2) with aqueous 5 N HCl (35 mL), and ex-
tracted with AcOEt (5ꢃ25 mL). The combined organic
extracts were dried (anhydrous Na2SO4) and concentrated
under reduced pressure to give a light yellow residue
(280 mg), which was washed with a small amount of cold
diethyl ether to give (ꢀ)-18 (210 mg, 75% yield) as a white
solid, mp 189–190 ꢂC (diethyl ether); [a]D24 ꢀ8.0 (CH3OH,
c 0.44); IR (KBr) n 3500–2250 (max. at 2997, 2950, 2903,
2716, 2612), 1706, 1483, 1419, 1319, 1289, 1258, 1219,
1140, 1088, 1030, 887, 757, 748 cmꢀ1; MS (EI), m/z (%):
178 ([MꢀH2O]ꢄ+, 27), 150 ([MꢀHCO2H]ꢄ+, 100), 134 (29),
133 ([MꢀHCO2HꢀOH]+, 80), 132 (40), 123 (31), 111 (87),
110 (17), 106 (29), 105 (100), 104 ([Mꢀ2HCO2H]ꢄ+, 34), 103
(29), 93 (55), 91 (49), 83 (20), 79 (75), 78 (30), 77 (70), 67
(53), 66 (29), 65 (52). Accurate mass measurement (ESIꢀ)
calcd for [C10H12O4ꢀH]ꢀ: 195.06628. Found: 195.06587.
4.1.11. (L)-Dimethyl (1S,3S,5S,7S)-tricyclo[3.3.0.03,7]oc-
tane-1,3-dicarboxylate, (L)-17. This reaction was carried
out as described for the preparation of diiodo diester
(ꢀ)-15. From (ꢀ)-18 (25 mg, 0.13 mmol), anhydrous MeOH
(1 mL), and concd H2SO4 (0.1 mL), diester (ꢀ)-17 (25 mg,
88% yield) was obtained as a white solid, mp 45–46 ꢂC
(n-pentane); [a]2D5 ꢀ10.0 (CH2Cl2, c 0.60); IR (KBr) n 3002,
2951, 2902, 2848, 1726, 1483, 1436, 1420, 1333, 1318, 1279,
1251, 1228, 1205, 1120, 1090, 1069, 1050, 1004, 934, 887,
782 cmꢀ1; MS (EI), m/z (%): 192 ([MꢀCH3OH]ꢄ+, 18),
165 (16), 164 ([MꢀHCO2CH3]ꢄ+, 39), 133 ([MꢀHCO2-
CH3ꢀCH3O]+, 51), 132 (21), 125 (45), 105 (100), 104
(30), 93 (67), 79 (45), 77 (32), 65 (34), 59 ([CO2CH3]+,
48). Anal. Calcd for C12H16O4 (224.25): C 64.27, H 7.19.
Found: C 64.02, H 7.18.
4.1.12. (D)-Dimethyl (1R,3R,5R,7R)-tricyclo[3.3.0.03,7]-
octane-1,3-dicarboxylate, (D)-17. This reaction was car-
ried out as described for the preparation of diiodo diester
(ꢀ)-15. From (+)-18 (39 mg, 0.20 mmol), anhydrous
MeOH (2 mL), and concd H2SO4 (0.2 mL), diester (+)-17
(38 mg, 86% yield) was obtained as a white solid, mp 51–
52 ꢂC (n-pentane); [a]D25 +9.5 (CH2Cl2, c 0.78); IR (KBr)
n 2983, 2951, 2902, 2853, 1732, 1484, 1452, 1436, 1330,
1319, 1283, 1253, 1229, 1213, 1178, 1135, 1117, 1087,
1067, 1050, 874, 783 cmꢀ1; MS (EI), m/z (%): 192 ([Mꢀ
CH3OH]ꢄ+, 21), 165 (18), 164 ([MꢀHCO2CH3]ꢄ+, 42), 133
([MꢀHCO2CH3ꢀCH3O]+, 54), 132 (21), 125 (47), 105
(100), 104 (33), 93 (73), 79 (52), 77 (36), 65 (39), 59
([CO2CH3]+, 57). Anal. Calcd for C12H16O4 (224.25): C
64.27, H 7.19. Found: C 63.98, H 7.28.
4.1.9. (D)(1R,3R,5R,7R)-Tricyclo[3.3.0.03,7]octane-1,3-
dicarboxylic acid, (D)-18.5d This reaction was carried
out as described for the preparation of diacid (ꢀ)-18. From
(+)-12 (1.43 g, 3.19 mmol), t-BuOH (18.5 mL, 195 mmol),
anhydrous THF (65 mL), and lithium in small pieces
(1.33 g, 192 mmol), diacid (+)-18 (410 mg, 65% yield)

C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
8033
4.1.13. ( )-Tricyclo[3.3.0.03,7]octane-1,3-dicarbonitrile,
( )-19. To a suspension of diacid (ꢁ)-18 (150 mg,
0.76 mmol) in acetonitrile (7 mL), concd H2SO4 (0.8 mL)
was added dropwise and the mixture was heated under reflux
for 6 h. The mixture was allowed to cool to room tempera-
ture and was concentrated under reduced pressure. The resi-
due was taken in CH2Cl2 (30 mL) and H2O (30 mL), the
phases were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢃ30 mL). The combined organic phase and
extracts were washed with brine (2ꢃ30 mL), dried with an-
hydrous Na2SO4, and concentrated under reduced pressure
to give a colorless oil, which was subjected to column chro-
matography [flash silica gel (3 g), hexane/AcOEt]. On elu-
tion with hexane/AcOEt in the ratio of 5:1 (50 mL),
dinitrile (ꢁ)-19 (46 mg, 38% yield) was obtained as a white
solid. The analytical sample was obtained by crystallization
from diethyl ether/n-pentane (1:1), mp 120–121 ꢂC; IR
(KBr) n 3004, 2957, 2906, 2237, 1484, 1311, 1287, 1269,
4.1.16. ( )-1,3-Dibromo-5,7-diiodotricyclo[3.3.0.03,7]oc-
tane, ( )-20. To a stirred suspension of red HgO (140 mg,
0.65 mmol) in anhydrous CH2Br2 (15 mL) in a Dean–Stark
distillation system maintained under an argon atmosphere,
diiodo diacid (ꢁ)-12 (200 mg, 0.45 mmol) was added. The
mixture was heated while distilling part of the solvent
(5 mL). A solution of bromine (0.047 mL, 0.93 mmol) in an-
hydrous CH2Br2 (5 mL) was added and the mixture was
heated under reflux for 3 h. The mixture was allowed to
cool to room temperature and the suspension was filtered
through CeliteÒ washing the solid with CH2Cl2 (3ꢃ5 mL).
The combined filtrate and washings were washed with aque-
ous Na2S2O3 solution (10%, 3ꢃ5 mL), 2 N NaOH (3ꢃ
5 mL), and brine (2ꢃ5 mL). The organic phase was dried
(anhydrous Na2SO4) and the solvent was removed under
reduced pressure to give (ꢁ)-20 (205 mg, 88% yield) as
a yellow solid. The analytical sample of (ꢁ)-20 was obtained
by crystallization from CH2Cl2 to give (ꢁ)-20 as a white
solid, mp 232–233 ꢂC (CH2Cl2); IR (KBr) n 2996, 2941,
1471, 1265, 1242, 1230, 1126, 994, 963, 874, 787 cmꢀ1; 1H
NMR d: 2.52 [t, J¼2.5 Hz, 2H, 2-H2], 2.58 [dt, J¼10.0 Hz,
J0¼2.0 Hz, 2H, 4(8)-Ha], 2.64 [dt, J¼10.0 Hz, J0¼2.0 Hz,
2H, 4(8)-Hb], 2.71 [t, J¼2.5 Hz, 2H, 6-H2]. 13C NMR d:
36.3 [C, C5(7)], 60.5 [C, C1(3)], 64.0 [CH2, C2], 66.7
[CH2, C4(8)], 69.4 [CH2, C6]; MS (EI), m/z (%): 439 (3)
and 437 (3) ([MꢀBr]+), 393 (8), 391 (16) and 389 (8)
([MꢀI]+), 312 (37) and 310 (37) ([MꢀBrꢀI]ꢄ+), 266 (8),
264 (15) and 262 (8) ([Mꢀ2I]ꢄ+), 185 (58) and 183 (62)
([MꢀBrꢀ2I]) 104 (100), 103 (72), 78 (29), 77 (35); MS
(CI), m/z (%): 521 (2), 519 (4) and 517 (2) ([M+H]+), 439
(52) and 437 (54) ([MꢀBr]+), 393 (17), 391 (36) and 389
(19) ([MꢀI]+), 312 (53) and 310 (55) ([MꢀBrꢀI]ꢄ+), 311
(55) and 309 (50) ([MꢀHBrꢀI]+), 266 (11), 264 (21) and
262 (11) ([Mꢀ2I]ꢄ+), 265 (14), 263 (24) and 261 (12)
([MꢀHIꢀI]+), 231 ([Mꢀ2BrꢀI]+, 28), 186 (12), 185 (97)
and 183 (100) ([MꢀBrꢀ2I]+), 184 (30), 182 (18), 105
(16), 104 (28), 103 (18). Accurate mass measurement
(ESI+) calcd for [C8H879Br81BrI2+H]+: 518.714005. Found:
518.714032.
1
1025, 889, 778 cmꢀ1; H NMR d: 1.75 [quint, J¼2.0 Hz,
2H, 6-H2], 1.92 [dt, J¼10.0 Hz, J0¼2.0 Hz, 2H, 4(8)-Ha],
2.05 [dq, J¼10.0 Hz, J0¼2.0 Hz, 2H, 4(8)-Hb], 2.19 [t,
J¼2.0 Hz, 2H, 2-H2], 2.87 [q, J¼2.0 Hz, 2H, 5(7)-H]. 13C
NMR d: 35.4 [C, C1(3)], 44.4 [CH, C5(7)], 46.1 [CH2,
C6], 51.1 [CH2, C4(8)], 55.2 [CH2, C2], 120.1 [C, 1(3)-
CN]; MS (EI), m/z (%): 158 (Mꢄ+, 2), 157 ([MꢀH]+, 13),
131 ([MꢀHCN]ꢄ+, 8), 130 (12), 117 (15), 116 (17), 104
(10), 92 (100), 91 (14), 79 (24), 65 (27). Chiral GC/MS anal-
ysis (retention time): (+)-19 (40.34 min) and (ꢀ)-19
(40.59 min). Accurate mass measurement (ESI+) calcd for
[C10H10N2+H]+: 159.0922. Found: 159.0917.
4.1.14. (L)(1S,3S,5S,7S)-Tricyclo[3.3.0.03,7]octane-1,3-
dicarbonitrile, (L)-19. This reaction was carried out as de-
scribed for the preparation of dinitrile (ꢁ)-19. From (ꢀ)-18
(56 mg, 0.29 mmol), acetonitrile (3 mL), and concd H2SO4
(0.3 mL), dinitrile (ꢀ)-19 (12 mg, 26% yield) was obtained
as a white solid. The analytical sample of (ꢀ)-19 was ob-
tained by crystallization from diethyl ether/n-pentane
(1:1), mp 112–114 ꢂC; [a]D24 ꢀ17.7 (CH2Cl2, c 0.52); IR
(KBr) n 3004, 2954, 2926, 2906, 2854, 2236, 1482, 1302,
1268, 1212, 1055, 1030, 890, 799, 776 cmꢀ1; MS (EI), m/z
(%): 158 (Mꢄ+, 4), 157 [(MꢀH)+, 20], 130 (11), 130 (10),
116 (25), 104 (10), 92 (100), 86 (22), 84 (26). Chiral GC/
MS analysis (retention time): (ꢀ)-19 (40.59 min). Accurate
mass measurement (EI) calcd for [C10H10N2]ꢄ+: 158.0844.
Found: 158.0841.
4.1.17. (L)(1R,3R,5S,7S)-1,3-Dibromo-5,7-diiodo-
tricyclo[3.3.0.03,7]octane, (L)-20. This reaction was
carried out as described for the preparation of (ꢁ)-20.
From (ꢀ)-12 (195 mg, 0.44 mmol), red HgO (140 mg,
0.65 mmol) in anhydrous CH2Br2 (15 mL) and bromine
(0.047 mL, 0.93 mmol) in anhydrous CH2Br2 (5 mL),
(ꢀ)-20 (214 mg, 94% yield) was obtained as a yellow solid.
The analytical sample of (ꢀ)-20 was obtained by crystalliza-
tion from CH2Cl2, mp 233–234 ꢂC (CH2Cl2); [a]D24 ꢀ6.4
(CH2Cl2, c 2.00); IR (KBr) n 2995, 2935, 2888, 1470,
1265, 1242, 1230, 1125, 993, 963, 873, 860, 804, 785,
635 cmꢀ1; MS (EI), m/z (%): 393 (1), 391 (3) and 389 (1)
([MꢀI]+), 312 (10) and 310 (10) ([MꢀBrꢀI]ꢄ+), 266 (3),
264 (6) and 262 (3) ([Mꢀ2I]ꢄ+), 185 (33) and 183 (37)
([MꢀBrꢀ2I]+), 104 (100), 103 (71), 78 (33), 77 (46),
63 (23). Accurate mass measurement (EI) calcd for
[C8H879Br81BrI2]ꢄ+: 517.7062. Found: 517.7048.
4.1.15. (D)(1R,3R,5R,7R)-Tricyclo[3.3.0.03,7]octane-1,3-
dicarbonitrile, (D)-19. This reaction was carried out as de-
scribed for the preparation of dinitrile (ꢁ)-19. From (+)-18
(80.5 mg, 0.41 mmol), acetonitrile (4 mL), and concd
H2SO4 (0.4 mL), dinitrile (+)-19 (19 mg, 29% yield) was ob-
tained as a white solid. The analytical sample of (+)-19 was
obtained by crystallization from diethyl ether/n-pentane
(1:1), mp 116–117 ꢂC; [a]D24 +17.3 (CH2Cl2, c 0.95); IR
(KBr) n 3004, 2954, 2905, 2236, 1482, 1302, 1266, 1212,
1030, 890, 776 cmꢀ1; MS (EI), m/z (%): 158 (Mꢄ+, 8), 157
([MꢀH]+, 23), 149 (29), 130 (23), 129 (24), 117 (30), 116
(33), 109 (23), 106 (20), 105 (37), 104 (23), 98 (38), 97
(35), 92 (100), 85 (22), 84 (34), 83 (28), 78 (34), 77 (29),
71 (51), 63 (21). Chiral GC/MS analysis (retention time):
(+)-19 (40.34 min). Accurate mass measurement (EI) calcd
for [C10H10N2]ꢄ+: 158.0844. Found: 158.0840.
4.1.18. (D)(1S,3S,5R,7R)-1,3-Dibromo-5,7-diiodo-
tricyclo[3.3.0.03,7]octane, (D)-20. This reaction was car-
ried out as described for the preparation of (ꢁ)-20. From
(+)-12 (200 mg, 0.45 mmol), red HgO (140 mg, 0.65 mmol)
in anhydrous CH2Br2 (15 mL) and bromine (0.047 mL,

8034
C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
0.93 mmol) in anhydrous CH2Br2 (5 mL), (+)-20 (205 mg,
88% yield) was obtained as a yellow solid. The analytical
sample of (+)-20 was obtained by crystallization from
CH2Cl2, mp 232–233 ꢂC (CH2Cl2); [a]D24 +6.3 (CH2Cl2,
c 1.99); IR (KBr) n 2992, 2938, 1473, 1266, 1242,
4.1.20. (L)(1S,3S,5S,7S)-1,3-Dibromotricyclo[3.3.0.03,7]-
octane, (L)-21.
4.1.20.1. Method A. This reaction was carried out as
described for the preparation of dibromide (ꢁ)-21 (method
A). From (ꢀ)-18 (50 mg, 0.25 mmol), red HgO (78 mg,
0.36 mmol) in anhydrous CH2Br2 (8 mL) and bromine
(0.03 mL, 0.58 mmol) in anhydrous CH2Br2 (3 mL), dibro-
mide (ꢀ)-21 (47 mg, 71% yield) was obtained as a light
yellow liquid. The analytical sample of (ꢀ)-21 was obtained
by distillation on a rotary microdistillation equipment at 60–
70 ꢂC/30 Torr; [a]D25 ꢀ19.0 (CH2Cl2, c 0.54); IR (NaCl)
n 3000, 2946, 2898, 2858, 1480, 1284, 1256, 1211, 1004,
947, 933, 824 cmꢀ1; MS (EI), m/z (%): 226 (3), 224 (6)
and 222 (3) ([MꢀC3H6]ꢄ+), 187 (24) and 185 (25)
([MꢀBr]+), 145 (11), 106 ([Mꢀ2Br]ꢄ+, 34), 105 (100), 91
(23), 79 (47), 78 (20), 77 (30), 65 (38). Chiral GC/MS anal-
ysis (retention time): (ꢀ)-21 (22.34 min). Anal. Calcd for
C8H10Br2 (265.97): C 36.13, H 3.79, Br 60.08. Found: C
35.97, H 3.62, Br 60.26.
1230, 1125, 993, 963, 873, 860, 801, 785, 634 cmꢀ1
;
MS (EI), m/z (%): 439 (1) and 437 (1) ([MꢀBr]+), 393 (3),
391 (6) and 389 (3) ([MꢀI]+), 312 (13) and 310 (14)
([MꢀBrꢀI]ꢄ+), 266 (4), 264 (8) and 262 (4) ([Mꢀ2I]ꢄ+),
185 (38) and 183 (42) ([MꢀBrꢀ2I]+), 104 (100), 103 (69),
77 (48), 66 (23). Accurate mass measurement (EI) calcd
for [C8H879Br81BrI2]ꢄ+: 517.7062, found: 517.7075.
4.1.19. ( )-1,3-Dibromotricyclo[3.3.0.03,7]octane, ( )-21.
4.1.19.1. Method A. To a stirred suspension of red HgO
(320 mg, 1.47 mmol) in anhydrous CH2Br2 (30 mL) in
a Dean–Stark distillation system maintained under an argon
atmosphere, diacid (ꢁ)-18 (200 mg, 1.02 mmol) was added.
The mixture was heated and part of the solvent (10 mL) was
distilled off. A solution of bromine (0.11 mL, 2.10 mmol) in
anhydrous CH2Br2 (10 mL) was added and the mixture was
heated under reflux for 3 h. The mixture was allowed to cool
to room temperature and the suspension was filtered through
CeliteÒ washing the solid with CH2Cl2 (3ꢃ5 mL). The com-
bined filtrate and washings were washed with aqueous
Na2S2O3 solution (10%, 3ꢃ5 mL), 2 N NaOH (3ꢃ5 mL),
and brine (2ꢃ5 mL). The organic phase was dried (anhy-
drous Na2SO4) and the solvent was distilled under atmo-
spheric pressure through a Vigreux column (10 cm). The
oily residue (352 mg) was submitted to column chromato-
graphy [silica gel (50 g), hexane]. On elution with hexane
(60 mL), dibromide (ꢁ)-21 (145 mg, 53% yield) was ob-
tained as a light yellow liquid. The analytical sample of
(ꢁ)-21 was obtained by distillation on a rotary microdistilla-
tion equipment at 60–70 ꢂC/30 Torr; IR (NaCl) n 2999,
2946, 2898, 1480, 1284, 1256, 1211, 1204, 1004, 947,
4.1.20.2. Method B. This reaction was carried out as de-
scribed for the preparation of dibromide (ꢁ)-21 (method B).
From (ꢀ)-20 (42 mg, 0.081 mmol), 10% Pd/C (7 mg), and
NaOH (10 mg, 0.25 mmol) in MeOH (2 mL), dibromide
(ꢀ)-21 (17 mg, approx. 79% yield) was obtained as a color-
less liquid.
4.1.21. (D)(1R,3R,5R,7R)-1,3-Dibromotricyclo[3.3.0.03,7]-
octane, (D)-21.
4.1.21.1. Method A. This reaction was carried out as de-
scribed for the preparation of dibromide (ꢁ)-21 (method A).
From (+)-18 (99 mg, 0.51 mmol), red HgO (160 mg,
0.73 mmol) in anhydrous CH2Br2 (15 mL) and bromine
(0.054 mL, 1.05 mmol) in anhydrous CH2Br2 (5 mL), dibro-
mide (+)-21 (96 mg, 71% yield) was obtained as a light yel-
low liquid. The analytical sample of (+)-21 was obtained by
distillation on a rotary microdistillation equipment at
60–70 ꢂC/30 Torr; [a]D25 +19.4 (CH2Cl2, c 1.02); IR
(NaCl) n 3000, 2946, 2898, 1480, 1284, 1259, 1211,
1004, 949, 933, 824 cmꢀ1; MS (EI), m/z (%): 226 (3),
224 (6) and 222 (3) ([MꢀC3H6]ꢄ+), 187 (23) and 185 (23)
([MꢀBr]+), 106 ([Mꢀ2Br]ꢄ+, 34), 105 (100), 91 (23), 79
(47), 78 (20), 77 (30), 65 (38). Chiral GC/MS analysis (re-
tention time): (+)-21 (22.14 min). Anal. Calcd for C8H10Br2
(265.97): C 36.13, H 3.79, Br 60.08. Found: C 36.02, H
3.68, Br 60.12.
1
933, 824 cmꢀ1; H NMR d: 1.74 [quint, J¼2.0 Hz, 2H,
6-H2], 1.81 [dt, J¼9.5 Hz, J0¼2.0 Hz, 2H, 4(8)-Ha], 2.24
[dq, J¼9.5 Hz, J0¼2.0 Hz, 2H, 4(8)-Hb], 2.30 [t, J¼
2.0 Hz, 2H, 2-H2], 2.54 [q, J¼2.0 Hz, 2H, 5(7)-H]. 13C
NMR d: 46.4 [CH2, C6], 48.4 [CH, C5(7)], 52.9 [C,
C1(3)], 56.2 [CH2, C4(8)], 64.7 [CH2, C2]; MS (EI), m/z
(%): 187 (26) and 185 (27) ([MꢀBr]+), 106 (27), 105
([MꢀBrꢀHBr]+, 100), 91 (20), 79 (36), 78 (20), 77 (31),
65 (32); MS (CI), m/z (%): 187 (55) and 185 (57)
([MꢀBr]+), 107 (14), 106 (16), 105 ([MꢀBrꢀHBr]+, 100),
87 (18), 85 (28), 79 (36). Chiral GC/MS analysis (retention
time): (+)-21 (22.14 min) and (ꢀ)-21 (22.34 min). Anal.
Calcd for C8H10Br2 (265.97): C 36.13, H 3.79, Br 60.08.
Found: C 36.09, H 3.75, Br 59.77.
4.1.21.2. Method B. This reaction was carried out as de-
scribed for the preparation of dibromide (ꢁ)-21 (method B).
From (+)-20 (40 mg, 0.078 mmol), 10% Pd/C (7 mg), and
NaOH (10 mg, 0.25 mmol) in MeOH (2 mL), dibromide
(+)-21 (18 mg, approx. 85% yield) was obtained as a color-
less liquid.
4.1.19.2. Method B. A suspension of (ꢁ)-20 (42 mg,
0.08 mmol), 10% Pd/C (7 mg), and NaOH (10 mg,
0.25 mmol) in MeOH (2 mL) was hydrogenated at atmo-
spheric pressure for 16 h. The suspension was filtered
through CeliteÒ washing the solid with MeOH (1 mL).
Water (5 mL) was added to the combined filtrate and
washings and the mixture was extracted with CH2Cl2
(5ꢃ5 mL). The combined organic extracts were dried
(anhydrous Na2SO4) and the solvent was distilled under at-
mospheric pressure through a Vigreux column (10 cm), to
give dibromide (ꢁ)-21 (18 mg, approx. 83% yield) as a
colorless liquid.
4.1.22. ( )-1,3-Dinitrotricyclo[3.3.0.03,7]octane, ( )-22.
4.1.22.1. Method A. A suspension of diacid (ꢁ)-18
(100 mg, 0.51 mmol) in SOCl2 (2 mL) was heated under
reflux for 2 h. The mixture was allowed to cool to room
temperature and was concentrated under reduced pressure
to give a white solid (121 mg). To a cold (0 ꢂC) solution of
NaN3 (0.22 g, 3.37 mmol) in H2O (1.5 mL), a solution of
the above white solid (121 mg) in acetone (1.5 mL) was
added dropwise for 15 min and the mixture was stirred at

C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
8035
room temperature for 3 h. The mixture was diluted with H2O
(2 mL) and was extracted with AcOEt (3ꢃ5 mL). The com-
bined organic extracts were washed with aqueous NaHCO3
solution (5%, 2ꢃ5 mL) and H2O (2ꢃ5 mL), dried (anhy-
drous Na2SO4), and concentrated under reduced pressure
to give a colorless oil (114 mg). A solution of the above col-
orless oil (114 mg) in anhydrous toluene (2 mL) was added
for 30 min to anhydrous toluene (14 mL) under reflux and
the residue was stirred under reflux for 5 h. The mixture
was allowed to cool to room temperature and the solvent
was distilled under atmospheric pressure through a Vigreux
column (10 cm) to give (ꢁ)-23 (96 mg) as a yellow wax. To
(ꢁ)-23 (96 mg) a solution of dimethyldioxirane (DMD) in
acetone (0.073 N, 70 mL, 5.1 mmol) and H2O (13 mL)
was added and the mixture, protected from light, was stirred
under an argon atmosphere for 12 h at room temperature.
Acetone was removed in vacuo and the precipitated white
solid was filtered in vacuo and washed with H2O (2 mL) to
give (ꢁ)-22 (36 mg) as a white solid. The combined filtrate
and washings were extracted with CH2Cl2 (3ꢃ5 mL), dried
(anhydrous Na2SO4), and concentrated under reduced pres-
sure to give a yellow oil (34 mg), which was washed with
diethyl ether to give more (ꢁ)-22 (12 mg, global yield 48%),
mp 135–137 ꢂC (H2O); IR (KBr) n 3020, 2957, 2909, 1534,
1483, 1427, 1376, 1291, 1146, 1032, 900, 886, 806,
4.1.24. (D)(1R,3R,5R,7R)-1,3-Dinitrotricyclo[3.3.0.03,7]-
octane, (D)-22. This reaction was carried out as described
for the preparation of (ꢁ)-22 (method A). From (+)-18
(71 mg, 0.36 mmol), (+)-22 (31 mg, 44% yield) was ob-
tained as a white solid, mp 141–142 ꢂC (H2O); [a]D25 +3.4
(CH2Cl2, c 0.91); IR (KBr) n 3025, 2960, 2923, 2853,
1540, 1378, 1136, 1046, 884, 807 cmꢀ1; MS (EI), m/z (%):
152 ([MꢀNO2]+, 0.4), 151 (0.8), 121 (24), 107 (10), 105
(93), 104 (47), 103 (30), 94 (16), 93 (75), 92 (14), 91 (53),
80 (10), 79 (100), 78 (35), 77 (87), 65 (11). The molecular
ion was not observed. Accurate mass measurement (EI)
calcd for [C8H10NO2]+ corresponding to [MꢀNO2]+:
152.0712. Found: 152.0709.
4.1.25. ( )-Tricyclo[3.3.0.03,7]octane-1,3-diamine dihy-
drochloride, ( )-24$2HCl. To a solution of (ꢁ)-18
(200 mg, 1.02 mmol) in toluene (6 mL), Et3N (0.38 mL,
2.73 mmol) and (PhO)2P(O)N3 (0.67 mL, 3.0 mmol) were
added and the mixture was heated under reflux for 3 h.
The mixture was allowed to cool to room temperature and
was washed with 1 N HCl (10ꢃ10 mL) at 0 ꢂC. Then, 6 N
HCl (10 mL) was added to the organic phase and it was
heated under reflux for 24 h. The solution was allowed to
cool to room temperature and the phases were separated. The
aqueous layer was washed with diethyl ether (3ꢃ8 mL) and
the aqueous solution was concentrated under reduced pres-
sure to give a brown solid (239 mg), which was washed
with a small amount of hot 2-propanol to give (ꢁ)-
24$2HCl (150 mg) as a yellow solid. A solution of (ꢁ)-
24$2HCl (150 mg, 0.71 mmol) was added to an aqueous
solution of NaOH (0.70 N, 2 mL) and the solution was
extracted with AcOEt (10ꢃ20 mL). The combined organic
extracts were dried (anhydrous Na2SO4) and distilled under
atmospheric pressure through a Vigreux column (10 cm) to
a final volume of approx. 5 mL. Diethyl ether/HCl was
added (until no more precipitate was formed) and the mix-
ture was filtered to give (ꢁ)-24$2HCl (47 mg, 22% yield)
as a yellow solid, mp >300 ꢂC (dec); IR (KBr) n 3600–
2200 (max. at 3413, 2995, 2947, 2900, 2749, 2594), 1593,
1571, 1509, 1492, 1319, 1286, 1265, 1244, 1181, 1163,
780 cmꢀ1 1H NMR d: 2.01 [br s, 2H, 6-H2], 2.26 [dt,
;
J¼10.0 Hz, J0¼2.0 Hz, 2H, 4(8)-Ha], 2.54 [dm,
J¼10.0 Hz, 2H, 4(8)-Hb], 2.84 [t, J¼2.0 Hz, 2H, 2-H2],
3.14 [br s, 2H, 5(7)-H]. 13C NMR d: 44.4 [CH, C5(7)],
45.5 [CH2, C6], 51.0 [CH2, C4(8)], 54.7 [CH2, C2], 86.0
[C, C1(3)]; MS (CI), m/z (%): 180 ([MꢀHNO2+C2H5]+,
8), 169 (15), 153 (11), 152 ([MꢀNO2]+, 100), 106 (20),
105 (44), 93 (16), 91 (19), 79 (63); MS (EI), m/z (%): 198
(Mꢄ+, 0.3), 152 ([MꢀNO2]+, 2), 121 (29), 107 (15), 105
(87), 104 (50), 103 (35), 94 (22), 93 (61), 92 (20), 91 (54),
80 (15), 79 (100), 78 (39), 77 (71), 65 (15). Accurate mass
measurement (EI) calcd for [C8H10N2O4]ꢄ+: 198.0641.
Found: 198.0641.
4.1.22.2. Method B. To (ꢁ)-24$2HCl (10.4 mg,
0.049 mmol), a solution of dimethyldioxirane in acetone
(0.08 N, 12 mL, 0.96 mmol) was added and the mixture,
protected from light, was stirred under an argon atmosphere
for 16 h at room temperature. The solvent was removed in
vacuo to give a yellow wax (10 mg), which was washed
with CH2Cl2 (3ꢃ2 mL), filtered and the combined filtrate
and washings were concentrated under reduced pressure to
give a white solid (9 mg), which was washed with a small
amount of diethyl ether to give (ꢁ)-22 (6.5 mg, 67% yield)
as a white solid.
1086, 1055 cmꢀ1
;
1H NMR (CD3OD) d: 1.85 [m,
J¼2.0 Hz, 2H, 4(8)-Ha], 1.86 [m, 2H, 6-H2], 2.17 [m, 2H,
4(8)-Hb], 2.18 [m, 2H, 2-H2], 2.55 [br s, 2H, 5(7)-H], 4.86
(br s, mobile H). 13C NMR (100.6 MHz, CD3OD) d: 43.1
[CH, C5(7)], 46.6 [CH2, C6], 49.9 [CH2, C4(8)], 52.8
[CH2, C2], 60.1 [C, C1(3)]; MS (EI), m/z (%): 138 (5),
137 ([MꢀH]+, 36), 120 (32), 109 (100), 97 (21), 96 (94),
95 (41), 94 (27), 82 (39), 81 (99), 80 (86). Accurate mass
measurement (ESI+) calcd for [C8H14N2+H]+: 139.12297.
Found: 139.12245.
4.1.23. (L)(1S,3S,5S,7S)-1,3-Dinitrotricyclo[3.3.0.03,7]-
octane, (L)-22. This reaction was carried out as described
for the preparation of (ꢁ)-22 (method A). From (ꢀ)-18
(31 mg, 0.16 mmol), (ꢀ)-22 (13 mg, 41% yield) was ob-
tained as a white solid, mp 149–151 ꢂC (H2O); [a]D25 ꢀ3.6
(CH2Cl2, c 0.32); IR (KBr) n 3026, 2958, 2910, 1540,
1484, 1378, 1137, 1046, 808 cmꢀ1; MS (EI), m/z (%): 152
([MꢀNO2]+, 1), 121 (66), 107 (14), 105 (98), 104 (81), 103
(65), 94 (26), 93 (93), 92 (28), 91 (84), 80 (16), 79 (100),
78 (69), 77 (94), 65(18). The molecular ion was not observed.
Accurate mass measurement (EI) calcd for [C8H10NO2]+ cor-
responding to [MꢀNO2]+: 152.0712. Found: 152.0715.
Acknowledgements
Financial support from Ministerio de Ciencia y Tecnologꢁıa
(Project CTQ2005-02192) and Comissionat per a Universi-
tats i Recerca (Project 2005-SGR-00180) is gratefully
acknowledged. C.A. thanks the Generalitat de Catalunya
(Beca predoctoral). We thank the Serveis Cientꢁıfico-
Teꢀcnics of the University of Barcelona for the NMR and
ꢀ
MS facilities, and Ms. P. Domenech from the IIQAB
(CSIC, Barcelona, Spain) for carrying out the elemental
analyses.

8036
C. Ayats et al. / Tetrahedron 63 (2007) 8027–8036
P
2
2 2
was
wjjF0j ꢀjFcj j , where w¼[s2(I)+(0.1251P)2+
References and notes
2
2
2.1488P]ꢀ1, and P ¼ ðjF0j þ2jFcj Þ=3, f, f0, and f00 were taken
from International Tables of X-ray Crystallography.17 All H
atoms were computed and refined, using a riding model, with
an isotropic temperature factor equal to 1.2 times the equivalent
temperature factor of the atom to which it is linked. The final
1. (a) Naemura, K. Carbocyclic Cage Compounds: Chemistry and
Applications; Osawa, E., Yonemitsu, O., Eds.; VCH: New
York, NY, 1992; Chapter 2, pp 61–90; (b) Nakazaki, M. Top.
Stereochem. 1984, 15, 199–251.
2. Nakazaki, M.; Naemura, K.; Arashiba, N. J. Org. Chem. 1978,
43, 888–891.
3. Nakazaki, M.; Naemura, K.; Kondo, Y. J. Org. Chem. 1976, 41,
1229–1233.
4. Naemura, K.; Komatsu, M.; Chikamatsu, H. Bull. Chem. Soc.
Jpn. 1986, 59, 1265–1266.
2
R(on F) factor was 0.071, wR(on jFj )¼0.1160 and goodness
of fit¼1.088 for all observed reflections. Number of refined
parameters was 77. Max. shift/esd¼0.00, mean shift/esd¼
0.00. Max. and min. peaks in final difference synthesis were
0.698 and ꢀ1.065 eAꢀ3, respectively.18
˚
9. Barton, D. H. R.; Jaszberenyi, J. Cs.; Theodorakis, E. A.
Tetrahedron Lett. 1991, 32, 3321–3324.
5. See, for example: (a) Webster, O. W.; Sommer, L. H. J. Org.
Chem. 1964, 29, 3103–3105; (b) Vogt, B. R.; Suter, S. R.;
Hoover, J. R. E. Tetrahedron Lett. 1968, 1609–1612; (c)
Ayats, C.; Camps, P.; Font-Bardia, M.; Mun˜oz, M. R.; Solans,
´
´
10. Mlinaric-Majerski, K.; Margeta, R.; Veljkovic, J. Synlett 2005,
2089–2091.
11. Eaton, P. E.; Wicks, G. E. J. Org. Chem. 1988, 53, 5353–
5355.
ꢁ
X.; Vazquez, S. Tetrahedron 2006, 62, 7436–7444; (d) Ayats,
C.; Camps, P.; Fernandez, J. A.; Vazquez, S. Chem.—Eur. J.
12. A prismatic crystal (0.1ꢃ0.1ꢃ0.2 mm) was selected and
mounted on a MAR345 diffractometer with an image plate
detector. Unit-cell parameters were determined from 125 re-
flections (3<q<31ꢂ) and refined by least-squares method.
Intensities were collected with graphite monochromatized
Mo Ka radiation; 3697 reflections were measured in the range
3.60ꢅqꢅ29.92; 542 reflections were assumed as observed by
applying the condition I>2s(I). Three reflections were mea-
sured every two hours as orientation and intensity control, sig-
nificant intensity decay was not observed. Lorentz-polarization
but no absorption corrections were made. The structure was
solved by direct methods, using SHELXS computer program15
and refined by full-matrix least-squares method with SHELX-
97 computer program,16 using 619 reflections (very negative
ꢁ
ꢁ
2007, 13, 1522–1532.
ꢁ
6. (a) Camps, P.; Gimenez, S.; Font-Bardia, M.; Solans, X.
Tetrahedron: Asymmetry 1995, 6, 985–990; (b) Camps, P.;
ꢁ
Gimenez, S. Tetrahedron: Asymmetry 1995, 6, 991–1000; (c)
Camps, P.; Mun˜oz-Torrero, D. Curr. Org. Chem. 2004, 8,
1339–1380.
7. A prismatic crystal (0.1ꢃ0.1ꢃ0.2 mm) was selected and
mounted on an Enraf–Nonius CAD4 four-circle diffractometer.
Unit-cell parameters were determined from automatic centering
of 25 reflections (12<q<21ꢂ) and refined by least-squares
method. Intensities were collected with graphite monochromat-
ized Mo Ka radiation; 9861 reflections were measured in the
range 2.17ꢅqꢅ29.99; 7836 reflections were assumed as ob-
served by applying the condition I>2s(I). Three reflections
were measured every two hours as orientation and intensity
control, significant intensity decay was not observed. Lorentz-
polarization but no absorption corrections were made. The
structure was solved by direct methods, using SHELXS com-
puter program15 andrefined byfull-matrixleast-squares method
with SHELX-97 computer program,16 using 9861 reflections
intensities were not assumed). The minimized function was
2
P
2 2
wjjF0j ꢀjFcj j , where w¼[s2(I)+(0.1120P)2+0.0532P]ꢀ1
,
2
2
and P ¼ ðjF0j þ2jFcj Þ=3, f, f0, and f00 were taken from
International Tables of X-ray Crystallography.17 All H atoms
were computed and refined, using a riding model, with an iso-
tropic temperature factor equal to 1.2 times the equivalent tem-
perature factor of the atom to which it is linked. The final R(on
2
F) factor was 0.061, wR(on jFj )¼0.167 and goodness of
(very negative intensities were not assumed). The minimized
2
P
2 2
function was wjjF0j ꢀjFcj j , where w¼[s2(I)+(0.0524P)2+
fit¼1.079 for all observed reflections. Number of refined pa-
rameters was 66. Max. shift/esd¼0.00, mean shift/esd¼0.00.
Max. and min. peaks in final difference synthesis were 0.141
2
2
0.2022P]ꢀ1 and P ¼ ðjF0j þ2jFcj Þ=3, f, f0, and f00 were taken
from International Tables of X-ray Crystallography.17 All H
atoms were computed and refined, using a riding model, with
an isotropic temperature factor equal to 1.2 times the equivalent
temperature factor of the atom to which it is linked. The final
and ꢀ0.216 eAꢀ3, respectively.18
˚
13. (a) Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1421–
1436; (b) Lukin, K. A.; Li, J.; Eaton, P. E.; Kanomata, N.;
Hain, J.; Punzalan, E.; Gilardi, R. J. Am. Chem. Soc. 1997,
119, 9591–9602; (c) Zhang, M. X.; Eaton, P. E.; Gilardi, R.
Angew. Chem., Int. Ed. 2000, 39, 401–404.
2
R(on F) factor was 0.031, wR(on jFj )¼0.080 and goodness
of fit¼1.022 for all observed reflections. Number of refined pa-
rameters was 397. Max. shift/esd¼0.00, mean shift/esd¼0.00.
Max. and min. peaks in final difference synthesis were 0.696
14. Marchand, A. P. Tetrahedron 1988, 44, 2377–2395.
15. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
16. Sheldrick, G. M. SHELX-97: A Computer Program for
and ꢀ0.517 eAꢀ3, respectively.
˚
8. A prismatic crystal (0.1ꢃ0.1ꢃ0.2 mm) was selected and
mounted on a MAR345 diffractometer with an image plate
detector. Unit-cell parameters were determined from 2210 re-
flections (3<q<31ꢂ) and refined by least-squares method.
Intensities were collected with graphite monochromatized
Mo Ka radiation; 1679 reflections were measured in the range
3.35ꢅqꢅ29.99; 1479 reflections were assumed as observed by
applying the condition I>2s(I). Lorentz-polarization but no
absorption corrections were made. The structure was solved
by direct methods, using SHELXS computer program15 and
refined by full-matrix least-squares method with SHELX-97
computer program,16 using 1679 reflections (very nega-
tive intensities were not assumed). The minimized function
€
Determination of Crystal Structure; University of Gottingen:
Gottingen, Germany, 1999.
€
17. International Tables of X-ray Crystallography; Kynoch:
Birmingham, 1974; Vol. IV, pp 99–100 and 149.
18. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 641679 [(1S,3S,5S,7S,30R,300R)-
14], CCDC 641677 [(ꢁ)-20], and CCDC 641678 [(ꢁ)-22].
Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].