Desymmetrization of meso 7-aza-2,3-bis(phenylsulfonyl) bicyclo[2.2.1]hept-2-ene: a re-examination. Kinetic resolution of racemic 3-arylsulfonyl-7-aza-2-bromobicyclo[2.2.1]hepta-2,5-dienes

Article abstract of DOI:10.1016/j.tetlet.2006.04.014

The inexpensive large scale preparation of N-methoxycarbonyl-7-aza-2,3-bis(phenylsulfonyl)bicyclo[2.2.1]hept-2-ene and the re-examination of its stereoselective desymmetrization are reported. Moreover, the kinetic resolution of N-protected 3-arylsulfonyl-

Full text of DOI:10.1016/j.tetlet.2006.04.014

Tetrahedron Letters 47 (2006) 4015–4018
Desymmetrization of meso 7-aza-2,3-bis(phenylsulfonyl)
bicyclo[2.2.1]hept-2-ene: a re-examination. Kinetic
resolution of racemic 3-arylsulfonyl-7-aza-
2-bromobicyclo[2.2.1]hepta-2,5-dienes
Sergio Cossua,* and Paola Pelusob
a
`
Dipartimento di Chimica, Universita Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
bIstituto di Chimica Biomolecolare ICB CNR, sezione di Sassari, Trav. La Crucca 3, Reg. Baldinca, I-07040 Li Punti, Sassari, Italy
Received 7 February 2006; revised 5 April 2006; accepted 5 April 2006
Abstract—The inexpensive large scale preparation of N-methoxycarbonyl-7-aza-2,3-bis(phenylsulfonyl)bicyclo[2.2.1]hept-2-ene and
the re-examination of its stereoselective desymmetrization are reported. Moreover, the kinetic resolution of N-protected 3-arylsulfo-
nyl-7-aza-2-bromobicyclo[2.2.1]hepta-2,5-dienes promoted by (R,R)-hydrobenzoin is described, representing a new tool to fix the
absolute stereochemistry of the 7-azabicyclo[2.2.1] skeleton.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Since Daly’s pioneering work, Epibatidine 1 {exo-2-
Cl
(20-chloro-50-pyridinyl)-7-azabicyclo[2.2.1]heptane}, has
attracted intense synthetic interest because of its
important biological properties.1 In fact, this natural
alkaloid shows exceptional non-opioid antinociceptive
property and high binding affinity to nicotinic acetyl-
choline receptors.1,2 The natural scarcity of epibatidine
has prompted synthetic efforts devoted to its total syn-
thesis both as racemate3 and in optically active form;4,5
because 1 exhibits high toxicity preventing its therapeu-
tic use,6 the preparation of structural analogues of
epibatidine has been also extensively investigated.7
Some strategies are based on the construction of racemic
7-azabicyclo[2.2.1]heptane-2-one 23a,b,7a,8 and, in this
context, Trudell’s work evidences the importance of
N-protected-7-aza-2-arylsulfonylbicyclo[2.2.1]heptane-
3-one 3 as the key precursor of 1 (Scheme 1).3b,7a–c,8a
PG
H
PG
N
N
N
N
O
O
(-)-1
(-)-2
3
SO2Ph
PG
PG
a) x = CH2, PG = BOC;
b) x = CH, PG = BOC;
c) x = CH2, PG = -CO2Me;
d) x = CH; PG = -CO2Me
N
N
SO2Ph
SO2Ph
x
x
x
x
SO2Ph
4a-d
5a-d
Scheme 1.
Although compound 4 could be achieved through the
cycloaddition between bis(arylsulfonyl)ethyne and the
proper protected pyrrole, the objective problems con-
cerning the large scale preparation of the dienophile dra-
matically limit the synthetic use of this procedure.8b
Moreover the reaction between the same pyrroles and
either (E)- or (Z)-1,2-bis(phenylsulfonyl)chloroethylene,
which have proven to be cheap synthetic equivalents of
bis(arylsulfonyl)ethyne for [4+2] cycloadditions,10 was
unsuccessful. We also carried out a relevant number of
experiments to prepare 4 by the b-metallation of sulfone
5 and the subsequent quenching of the vinyl anion with
phenylsulfonylfluoride under the reported11 as well as
On the basis of our experience, we have explored the
possibility to fix the absolute stereochemistry of the 7-
azabicyclo[2.2.1] skeleton by the stereoselective desym-
metrization of 4, promoted by chiral diolates, according
to our previously reported strategy.9
Keywords: Desymmetrization; Kinetic resolution; Epibatidine; 7-Aza-
bicyclo[2.2.1]heptane; Sulfones.
*
Corresponding author. Tel.: +39 (0)41 2348647; fax: +39 (0)41
2348517; e-mail: cossu@unive.it
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.014

4016
S. Cossu, P. Peluso / Tetrahedron Letters 47 (2006) 4015–4018
under different reaction conditions. Nevertheless we
were unable to prepare 4 by this route, observing the
quick and complete conversion of the polycyclic reagent
to unidentified by-products whose NMR spectra suggest
that an open-chain reaction is operative. Taking into ac-
count that Simpkins also encountered a similar difficulty
attempting to metallate 5b,8b we concluded that the
preparation of 4 from 5 could not be easily realized.11
Therefore, according to a protocol developed by our
group, we conceived a strategy suitable for the prepara-
tion of alkenes 4 (Scheme 2) based on the efficient phen-
ylsulfonylation of 2-bromo-3-phenylsulfonyl bridged
alkenes 6.12 The preparation of reagents 6b,d, which
was adjusted over the Trudell’s protocol,8a was realized
by the [4+2] cycloaddition between N-protected pyrrole
and 1-bromo-2-phenylsulfonylethyne in 65–70% average
yield (after chromatographic purification). The N-Boc
protected derivative 6b revealed to be rather unstable
under chromatographic conditions either on silica gel
or on alumina, so we continued the research only con-
sidering the N-methoxycarbonyl substituted adduct
6d.13 The reaction between 6d and an equivalent of
freshly prepared thiophenol sodium salt in dry THF
afforded 7,13 which was purified (flash chromatography)
and collected in almost quantitative yield. The oxidation
of 7 to 4d, carried out under mild reaction conditions
(TEBA–OXONE) in order to preserve the 5-double
bond, requires very long reaction time (weeks) and the
frequent renewal of the oxidizing reagent. In addition,
compound 7 is strongly resistant to hydrogenation.
More conveniently, 6d was quantitatively hydrogenated
to 813 (H2, 5% Pd/C, AcOEt, 1 h, rt), which was in turn
transformed to 913 (PhSH, NaH, THF) and finally oxi-
dized to 4c13 (m-CPBA), which was collected in 80%
overall yield.
COOMe
N
SO2Ph
SO2Ph
4c
(R,R)-hydrobenzoin
NaH, THF
Ph
H
Ph
H
MeOOC
MeOOC
5'
5'
O
3
O
N
N
1
H
H
4
2
4
5
6
5
3
Ph
Ph
2
4'
4'
O
O
6
H
1
SO2Ph
H
SO2Ph
endo-(1S,4R)-10
exo-(1S,4R)-10
8
2
Scheme 3.
pletely unresolved NMR spectra of the crude,
consequently, it has been impossible to attribute the sig-
nals as well as to correlate the pattern of signals to any
structure. The phenomenon, frequently observed for
polycyclic azasubstituted compounds, suggests a poor
conformational stability due to the presence of the ami-
dic moiety in apical position. Differently, the use of
other solvents more polar than deuterochloroform, such
as DMSO-d6, gave a solution to this problem providing
perfectly understandable spectra. By dissolving the sam-
ples in DMSO-d6, all signals have been well resolved.
Because of the difficulties to obtain suitable crystals
for an X-ray structure determination, we chose to estab-
lish the absolute stereochemistry by NMR (COSY,
NOESY, HMQC, HMBC), using the chiral 1,3-dioxol-
anic portion of absolute configuration (40R,50R) known
as the intramolecular stereochemical marker. It should
be noted, relatively to H2 of structures exo-10 and
endo-10 that the NMR signal does not show a measur-
able J coupling with the bridgehead H1 either in CDCl3
or as well in DMSO-d6 solution. Consequently, the
structure determination of exo-1011 cannot be based
on the observation of a missed coupling between H2
and H1. The NOESY map of exo-(1S,4R)-10 shows a
number of particularly diagnostic interactions involving,
for instance, the aromatic proton (d, 7.94 ppm) at the
position ortho to the sulfonyl group, which presents
intense NOE allowing to unambiguously recognize both
H1 (br s, 4.57 ppm) and H2 (br s, 4.14 ppm) as well as
to discriminate H4 (br s, 4.39 ppm) from H1. Most
importantly, the aforementioned aromatic proton shows
The desymmetrization step (Scheme 3) has been realized
by adding a THF solution of an equivalent of (R,R)-
hydrobenzoin sodium salt to a THF solution of 4c stir-
red at ꢀ78 ꢁC under argon and at rt for an additional
4 h.
Among four possible stereoisomers, the NMR of the
crude reveals the diastereoselective formation of
(1S,4R)-10 in an 8:2 endo/exo ratio (82% yield).13 Deu-
terochloroform solution of 1011 has furnished com-
0
NOE with the dioxolanic H5 (d, 4.25 ppm). Being
COOMe
PG
COOMe
N
N
N
connected to the dioxolanic carbon of absolute known
configuration (5R), H5 is oriented towards the exo face
SO2Ph
SO2Ph
SO2Ph
PhSH
NaH
0
TEBA-
Oxone
of the norbornanic skeleton. Consequently, the latter
interaction can be only justified by the phenylsulfonyl
group oriented to the exo position, while H2 occupies
the endo one; this interpretation is also supported by
the COSY map, which shows the complete absence of
spin–spin correlation between H1 and H2 as it is
expected, accordingly to the Karplus rules, taking into
account the dihedral angle value between vicinal pro-
tons. Moreover, coherently with the proposed structure,
a very diagnostic NOE between the bridgehead H4 and
6b,d
4d
7
SO2Ph
Br
SPh
H2, Pd/C
COOMe
COOMe
COOMe
N
N
N
SO2Ph
SO2Ph
PhSH
NaH
SO2Ph
m-CPBA
8
SPh
Br
SO2Ph
9
4c
80% yield
b) PG= -BOC; d) PG= -COOMe
0
the dioxolanic H4 is observed. It has been also noted
Scheme 2.
the unfrequent NOE of the methoxy group in apical

S. Cossu, P. Peluso / Tetrahedron Letters 47 (2006) 4015–4018
4017
position with H1, H4 as well as with the previously cited
aromatic proton; this effect is not observed considering
H5 and H6. On these basis, seems reliable the propensity
of the amidic groups to occupy the most hindered face.
Based on similar consideration it was established the
absolute configuration of the epimer at C2 endo-
(1S,4R)-10. In the present case the exo oriented position
of H2, which does not present measurable J coupling
with H1, was established by evaluating the COSY
map, which shows the spin–spin correlation between
H1 and H2. In addition, having at our disposal all the
stereoisomers of 10 we have studied their chromato-
graphic analytical separation by HPLC on a XTerra
RP18 column (5 lm, 4.6 · 250 mm) (Waters) (CH3CN–
H2O = 60/40, flow rate 0.8 mL/min, detection 254 nm)
measuring for exo-10 and endo-10 tR1 = 12.3 min and
tR2 = 13.3 min, respectively (for exo-10: lit.11 tR = 3.56
min).
starting material 34% (1R), recovered chiral auxiliary
34%]. On the basis of NMR maps, the reaction products
are established to be a diastereoisomeric mixture of
endo-(1R,4S)-110d,e and endo-(1S,4R)-11d,e in a 3:1
ratio (by the NMR spectra of the crude). We have estab-
lished the absolute stereochemistry of products 11d,e
and 110d,e by NMR spectroscopy13 (DMSO-d6) as pre-
viously described. The reaction mixture of dioxolanic
derivatives 11d,e and 110d,e has been separated by flash
chromatography (silica gel, gradient of n-hexane–AcOEt
up to 95:5 ratio, 65% yield). Under these conditions
endo-(1R,4S)-110d,e as well as endo-(1S,4R)-11d,e
partially epimerize at the phenylsulfonyl substituted
position 2 affording exo-(1R,4S)-110d,e and exo-(1S,4R)-
11d,e, respectively. All stereoisomers of 11d and 110d
were analyzed by HPLC as previously described: tR
(endo-110d) 11.1 min, tR (exo-110d) 12.0 min, tR (exo-
11d) 12.6 min, tR (endo-11d) 14.2 min.
Then this re-examined protocol represents a safe, quick
and reproducible methodology useful for the multigram
scale preparation (5 g) of 10, in which the absolute con-
figuration of (ꢀ)-epibatidine 1 is fixed. We have not fur-
ther investigated both on the deprotection and the
desulfonylation steps of 10 giving (ꢀ)-2, precursor of
(ꢀ)-epibatidine.4b,5e
Concerning the stereoselective aspects, it is noted that
(R,R)-hydrobenzoin reacts with 6 showing opposite
selectivity with respect to the reaction carried out on
2,3-bis(phenylsulfonyl) substituted 4c. Furthermore, 1-
bromo-2-phenylsulfonyl 6d is, as expected, less reactive
than the parent bis(phenylsulfonyl)substituted 4c,
requiring in fact longer reaction times (24 h vs 4 h) to
reach completion, probably as the consequence of the
changed steric and electronic situations (bromine vs
PhSO2– group). In addition, the impossibility to stabilize
transient species through p–p interactions involving the
aromatic rings of both the chiral auxiliary and the phen-
ylsulfonyl group,9d makes the reaction of bromo deriva-
tives less stereoselective. The comparison between 4c
and 6d takes into account that the desymmetrization
processes of 2,3-bis(phenylsulfonyl)bicyclo[2.2.1] sys-
tems are not influenced by the remote substituents at
the positions 5,6.
Successively, we resonated that a meso compound could
be considered as an internal racemate, whereas the race-
mic mixture could represent a meso form in which the
symmetry plane is external to the molecules.14 From a
kinetic point of view, the desymmetrization of a meso
compound constitutes an internal resolution process.
Based on these considerations we have explored on the
kinetic resolution of racemic N-protected 3-arylsulfo-
nyl-7-aza-2-bromobicyclo[2.2.1]hepta-2,5-dienes 6d,e,
constituting a promising strategy to prepare an optically
active 7-azabicyclo[2.2.1] skeleton. Racemic mixtures
of 6d,e are prepared in multigram scale by [4+2] cyclo-
addition of N-CO2Me protected pyrrole to 1-bromo-
2-phenylsulfonyl-ethyne or 1-bromo-2-tolylsulfonyl-
ethyne, respectively.8a The crude reaction mixtures were
always carefully purified prior to its successive use as a
standard practice (flash chromatography on silica gel,
65–70% yields). The kinetic resolution has been realized
by treating a THF solution of 6d,e with a THF solution
of (R,R)-hydrobenzoin sodium salt (1:1 molar ratio) at
ꢀ78 ꢁC, then stirring under argon at rt for 24 h (Scheme
4). All reagents 6d,e have shown to react in an almost
identical fashion independently of the nature of the aryl-
sulfonyl groups [conversion 66%, yield 98%, recovered
Taking into account that racemic 6d has proved to be
itself a precursor of racemic ketosulfone 3,8a the
described asymmetric transformation of 6d appears
as a parallel kinetic resolution process, in which the
recovered starting material 1R-6d (95 ee%, HPLC,
Chiralcel OD-H) can be transformed8a to enantiopure
N-protected-3 (Scheme 5).
( )-6d
1. (R,R)-hydrobenzoin
2. flash chromatography
CO2Me Ph
O
CO2Me
1
CO2Me
N
N
N
4
PG
SO2Ph
Br
Ph
HO
HO
Ph
Ph
N
Ph
PG
O
SO2Ar
O
N
O
SO2Ph
SO2Ph
Ph
O
O
Ph
:
6d,e
O
+
NaH, THF
Ph
O
11'd (49%)
(1R,4S)-6d (34%)
11d (16%)
Ph
SO2Ar
11d,e
11'd,e
Ph
(1R,4S)
ref. 8a
(1S,4R)
absolute
stereochemistry
1
3
d) PG = -CO2Me; Ar = Ph
e) PG = -CO2Me; Ar = p-Tolyl conversion 66%; yield 98%
absolute
stereochemistry
(1S,4R)-3
Scheme 4.
Scheme 5.

4018
S. Cossu, P. Peluso / Tetrahedron Letters 47 (2006) 4015–4018
1
13. Compound 6d: mp 154–155 ꢁC (Et2O–CH2Cl2); H NMR
(300 MHz, CDCl3) 3.70 (br s, 3H, OMe), 5.21 (s, 1H, H4),
5.69 (s, 1H, H1), 6.97 (br s, 2H, H5, H6), 7.56–7.59, 7.63–
7.69, 7.89–7.91 (series of m, 5H, Ar); 13C NMR (75 MHz,
CDCl3) 53.2 (OMe), 69.3 (C1), 75.4 (C4), 127.7, 129.4,
134.1, 139.8, 154.6. Compound 7: mp 162–163 ꢁC (Et2O–
CH2Cl2); 1H NMR (300 MHz, CDCl3) 3.38 (br s, 3H,
OMe), 4.80 (br s, 1H, H4), 5.37 (br s, 1H, H1), 6.65 (dd,
J = 5.3, 2.6, 1H, H5), 6.88 (dd, J = 5.3, 2.2, 1H, H6), 7.43–
7.67, 7.96–7.98 (series of m, 10H, Ar); 13C NMR (75 MHz,
CDCl3) 52.9, 69.1, 71.4, 127.2, 129.2, 130.2, 133.5, 134.7,
138.5. 143.1. Compound 8: mp 134–135 ꢁC; 1H NMR
(300 MHz, CDCl3) 1.24–1.50 (m, 2H, H5endo, H6endo),
1.95–2.03 (m, 2H, H5exo, H6exo), 4.76 (br s, 1H, H1), 4.96
(br s, 1H, H4), 3.47 (br s, 3H, OMe), 7.52–7.69, 7.95–7.98
(series of m, 5H, Ar); 13C NMR (75 MHz, CDCl3) 24.1
(C6), 26.6 (C5), 53.0 (OMe), 63.8 (C1), 69.7 (C2), 127.7,
129.4 (2C), 134.1, 134.3, 140.0. Compound 9: 1H NMR
(300 MHz, CDCl3) 1.25–1.39, 1.45–1.58, 1.77–1.85, 1.98–
2.00 (series of m, 4H, H5exo, H5endo, H6exo, H6endo), 3.36 (s,
3H, OMe), 4.38 (br s, 1H, H3), 4.92 (br s, 1H, H2), 7.42–
7.54, 7.59–7.71, 7.99–8.02 (series of m, 10H, Ar); 13C
NMR (75 MHz, CDCl3, 2C omitted) 25.0, 27.7, 52.6, 64.1,
65.8, 127.2, 127.7, 129.2, 129.3, 129.6, 129.7 (2C), 133.5,
134.1 (2C), 141.2. Compound 4c: mp 159–160 ꢁC (n-
hexane–AcOEt); 1H NMR (300 MHz, CDCl3) 1.35 (d, 2H,
H5exo, H6exo), 2.08 (d, 2H, H5endo, H6endo), 3.38 (s, 3H,
OMe), 5.10 (br s, 2H, H1, H4), 7.58 (t, J = 7.6 Hz, 4H, Ar),
7.70 (t, J = 7.6 Hz, 2H, Ar), 8.02 (d, J = 7.6 Hz, 4H, Ar);
13C NMR (75 MHz, CDCl3) 25.1 (C5, C6), 53.0 (OMe),
65.7 (C1, C4), 128.2 (4Ar C o- to SO2), 129.4 (4Ar C m- to
SO2), 134.6 (2Ar C p- to SO2), 139.3 (2Ar C–SO2), 155.3
Acknowledgements
`
This work has been supported by Universita Ca’ Foscari
di Venezia (ex 60% funds). Thanks are due to Dr. P. Vol-
pato and Dr. A. Migatta for preliminary experiments.
References and notes
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(C@O). Compound exo-10: H NMR (300 MHz, DMSO-
d6) 1.60–1.90 (series of m, 4H, H5, H6), 3.57 (s, 3H, OMe),
4.14 (br s, 1H, H2), 4.25 (d, 1H, 1/2 AX system,
0
J = 9.2 Hz,H5 ), 4.39 (br s, 1H, H4), 4.57 (br s, 1H, H1),
0
´
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J = 7.5 Hz, Ar, meta to SO2), 7.73 (d, 1H, J = 7.5 Hz, Ar,
para to SO2), 7.94 (d, 2H, J = 7.1 Hz, Ar, ortho to SO2).
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1.65–1.85 (series of m, 4H, H5,H6), 3.57 (s, 3H, OMe),
6. Badio, B.; Garraffo, H. M.; Plummer, C. V.; Padgett, W.
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4.25 (d, 1H, 1/2 AX system, J = 9.2 Hz, H5 ), 4.40 (br s,
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7.13–7.15, 7.30–7.33, 7.62–7.72, 7.93–7.96 (series of m,
15H, Ar); 13C NMR (75 MHz, DMSO-d6, mixture of exo–
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74.7, 84.7, 86.5, 127.4, 127.6, 128.9, 129.0, 129.1, 129.4,
129.6, 134.2, 135.1, 136.9, 140.0, 177.0. Compound endo-
1
110d: H NMR (300 MHz, DMSO-d6) 3.53 (s, 3H, OMe),
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8709; (c) Cossu, S.; De Lucchi, O.; Peluso, P.; Volpicelli,
R. Tetrahedron Lett. 2000, 41, 7263–7266; (d) Cossu, S.;
Peluso, P. Org. Chem.: Indian J. 2005, 1, 1–17.
10. Cossu, S.; De Lucchi, O. Gazz. Chim. Ital. 1990, 120, 569–
576.
3.79 (s, 1H, H2), 4.78 (d, 1H, 1/2 AX system, J = 9.0 Hz,
0
H5 ), 4.85 (br s, 2H, H1, H4), 5.09 (d, 1H, 1/2 AX system,
0
J = 9.0 Hz, H4 ), 6.63 (m, 1H, H5), 6.72 (m, 1H, H6), 7.20–
7.47 (series of m, 10H, Ar), 7.52 (t, 2H, J = 7.4 Hz, Ar,
meta to SO2), 7.68 (d, 1H, J = 7.4 Hz, Ar, para to SO2),
7.89 (d, 2H, J = 7.4 Hz, Ar, ortho to SO2). Compound
endo-11d: 1H NMR (300 MHz, DMSO-d6) 3.50 (s, 3H,
OMe), 4.30 (br s, 1H, H1), 4.83 (d, 1H, 1/2 AX system,
0
J = 9.0 Hz, H4 ), 5.04 (br s, 1H, H4), 5.07 (d, 1H, 1/2 AX
0
system, J = 9.0 Hz, H5 ), 6.63 (m, 1H, H5), 6.80 (m, 1H,
H6), 7.01–7.11, 7.13–7.20, 7.32–7.40 (series of m, 10H, Ar),
7.75 (t, 2H, J = 7.6 Hz, Ar, meta to SO2), 7.83 (d, 1H,
J = 7.6 Hz, Ar, para to SO2), 8.05 (d, 2H, J = 7.6 Hz, Ar,
ortho to SO2).
11. Pandey, G.; Tiwari, S. K.; Singh, R. S.; Mali, R. S.
Tetrahedron Lett. 2001, 42, 3947–3949.
12. Peluso, P.; Greco, C.; De Lucchi, O.; Cossu, S. Eur. J.
Org. Chem. 2002, 4024–4031.
14. Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096–
1109.