8-Azabicyclo[3.2.1]oct-3-en-2-ones via asymmetric 1,3-dipolar cycloaddition of a homochiral 3-oxidopyridinium betaine

Article abstract of DOI:10.1016/j.tetlet.2006.02.005

8-Azabicyclo[3.2.1]oct-3-en-2-ones were prepared by asymmetric 1,3-dipolar cycloadditions of homochiral pyridinium betaine 4. Excellent diastereofacial selectivity was achieved for the major 6-exo cycloadducts. The absolute stereochemistry of cycloadduct

Full text of DOI:10.1016/j.tetlet.2006.02.005

Tetrahedron Letters 47 (2006) 2635–2638
8-Azabicyclo[3.2.1]oct-3-en-2-ones via asymmetric 1,3-dipolar
cycloaddition of a homochiral 3-oxidopyridinium betaine
Neil R. Curtis,a,* Richard G. Ballb and Janusz J. Kulagowskia
aMerck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park,
Harlow, Essex CM20 2QR, UK
bMerck Research Laboratories, Rahway, NJ 07065, USA
Received 16 December 2005; revised 26 January 2006; accepted 1 February 2006
Available online 28 February 2006
Abstract—8-Azabicyclo[3.2.1]oct-3-en-2-ones were prepared by asymmetric 1,3-dipolar cycloadditions of homochiral pyridinium
betaine 4. Excellent diastereofacial selectivity was achieved for the major 6-exo cycloadducts. The absolute stereochemistry of cyclo-
adduct 7 was confirmed by a single-crystal X-ray diffraction study.
Ó 2006 Elsevier Ltd. All rights reserved.
We required access to homochiral 8-azabicyclo[3.2.1]-
oct-3-en-2-ones, as exemplified by structure 1 or its anti-
pode, to provide intermediates for a program of
chemical synthesis.
(R)-p-tolyl vinyl sulfoxide 24,5 or an acrylate derived
from (S)-methyl lactate 36 as the dipolarophile.
However, the latter novel approach (Scheme 1, Eq. 2)
was attractive to explore due to the versatility offered
by potential combination of a homochiral betaine with
a variety of dipolarophiles.
R2
An a-methylbenzyl substituent on the pyridinium bet-
aine was chosen as the auxilliary to investigate since this
would give a chiral controlling element close to the
reacting centres and would be easily removed. Thus,
synthesis of homochiral betaine 4 was performed in
three steps as outlined in Scheme 2. The key transforma-
tions were reductive amination of the hindered ketone 5,
using imine formation with (S)-a-methylbenzylamine
mediated by titanium(IV) isopropoxide followed by
sodium borohydride reduction,7 and oxidation of the
resultant furyl amine 6 (ca. 2:1 mixture of diastereoiso-
mers) with bromine in aqueous tetrahydrofuran.8
R1N
Ph
O
1
The construction of such bicyclic compounds in racemic
form utilised efficient 1,3-dipolar cycloaddition of
1-benzyl-2-phenyl-3-oxidopyridinium betaine and
a
dipolarophile bearing an electron-withdrawing group.1,2
It was envisaged that an asymmetric synthesis could be
accomplished by introducing
a chiral controlling
element to the dipolar cycloaddition.3 Two intermole-
cular approaches for asymmetric synthesis were
contemplated, either with a chiral auxilliary on the
dipolarophile (Scheme 1, Eq. 1), or on the nitrogen of
the betaine (Scheme 1, Eq. 2). Indeed, the feasibility of
the former methodology has been demonstrated using
Dipolar cycloaddition of homochiral betaine 4 with
excess tert-butyl acrylate was performed in toluene at
95 °C for 4 days to give a 70% overall yield of cyclo-
adducts with complete regioselectivity (Scheme 3). The
major 6-exo isomer 7 was formed with excellent diaste-
reofacial selectivity (7:8 96:4). As in the achiral cyclo-
addition
of
1-benzyl-2-phenyl-3-oxidopyridinium
Keywords: 8-Azabicyclo[3.2.1]oct-3-en-2-one; Asymmetric synthesis;
1,3-Dipolar cycloaddition; 3-Oxidopyridinium betaine; Diastereo-
selective; X-ray crystallography.
betaine with tert-butyl acrylate,2 a significant quantity
of 6-endo product were also formed (exo:endo ratio
1.8:1). Interestingly however, the 6-endo diastereoselec-
tivity was only moderate (9:10 67:33). The absolute
*
Corresponding author. Tel.: +44 0 1279 440570; fax: +44 0 1279
440390; e-mail: neil_curtis@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.005

2636
N. R. Curtis et al. / Tetrahedron Letters 47 (2006) 2635–2638
E*
E*
_
E*
O
and/or
(Eq. 1)
+
N
N
N
Ph
Ph
Ph
O
O
Ph
Ph
Ph
O
O
..
O
O
O
H3CO2C H
E*
S
p-Tol
O
O
N
N
e.g.
=
SO2
3
2
Ph
E
E
_
E
O
and/or
(Eq. 2)
+
N
N
N
Ph
Ph
Ph
O
O
R*
R*
R*
e.g.
R*
=
*
*
OR
Ph Me
Ph
Scheme 1. Potential approaches to asymmetric 1,3-dipolar cycloaddition, either with a chiral auxilliary on the dipolarophile (Eq. 1), or on the
nitrogen of the betaine (Eq. 2).
i
ii
Cl
Ph
Ph
Ph
O
O
O
O
O
O
HN
5
6
iii
_
X
O
O
Ph
Ph
X
+
Ph
X
N
Ph
N
HN
Ph
Ph
X = Br, OH
4
Scheme 2. Reagents and conditions: (i) NaBPh4, Pd(OAc)2, Na2CO3, acetone, rt (58%); (ii) (S)-(À)-a-methylbenzylamine, Ti(O-i-Pr)4, 80 °C then
NaBH4, MeOH, rt (95%); (iii) Br2, THF/H2O, 0 °C to rt (52%).
_
t-BuO2C
6
CO2t-Bu
CO2t-Bu
(20 eq.)
O
5
+
+
N
N
N
6-exo
toluene, 95 ˚C, 4 d
(70%)
Ph
Ph
Ph
Ph
O
O
9
Ph
Ph
(1S,5R,6S,9S)-7
(1R,5S,6R,9S)-8
4
(43%)
(<2%)
CO2t-Bu
t-BuO2C
exo selectivity
endo selectivity
96 : 4
67 : 33
+
+
N
N
6-endo
Ph
Ph
Ph
O
O
Ph
(1S,5R,6R,9S)-9
(1R,5S,6S,9S)-10
(17%)
(8%)
Scheme 3. Cycloaddition with tert-butyl acrylate.
stereochemistry of cycloadduct 7 was established by a
single-crystal X-ray diffraction study, as shown in Fig-
ure 1.9 Structural assignment of cycloadducts 8–10 was
made on the basis of NMR studies.10,11

N. R. Curtis et al. / Tetrahedron Letters 47 (2006) 2635–2638
2637
C28
C27
O26
C6
C5
C4
C29
C24
C3
C7
O25
C2
C30
O23
N8
C9
C1
C13
C12
C11
C17
C22
C14
C16
C15
C10
C18
Figure 2. Rationalisation of cycloaddition face selectivity.
C21
cycloadducts), was confirmed by a single-crystal X-ray
diffraction study. Asymmetric cycloadditions of homo-
chiral 1,3-dipoles, particularly nitrones and azomethine
ylides bearing a chiral substituent on nitrogen, are
well established.3 However, we believe that the work
described in this Letter represents the first application
of such methodology to cycloaddition of a homochiral
3-oxidopyridium betaine.
C19
C20
Figure 1. Perspective view of cycloadduct 7 generated by ORTEP3
from the crystallographic coordinates. The ellipsoids for the nonhy-
drogen atoms are drawn at the 50% level while the H atoms are a fixed
size.
Cycloaddition of betaine 4 with phenyl vinyl sulfone was
less efficient than previously observed with the corre-
sponding achiral N-benzyl betaine.2 Variation of solvent
and reaction temperature suggested that toluene at
90 °C for 4–5 days was the optimum conditions, giving
the major 6-exo isomer 11 with excellent diastereoselec-
tivity (>95:5) in 31% yield (48% based on recovered SM)
together with unreacted betaine 4 (34%) (Scheme 4).
Higher reaction temperatures failed to improve the yield
of cycloadduct 11, but instead gave significant amounts
of the O-a-methylbenzyl compound 12. The stereochemi-
Acknowledgements
We are indebted to Dr. Richard Herbert, for NMR
analysis and Drs. Piotr Raubo and Peter Hunt, for help-
ful discussions.
References and notes
1. (a) Katritzky, A. R.; Dennis, N. Chem. Rev. 1989, 89, 827–
861; (b) Ducrot, P.-H.; Lallemand, J. Y. Tetrahedron Lett.
1990, 31, 3879–3882; (c) Jung, M. E.; Longmei, Z.;
Tangsheng, P.; Huiyan, Z.; Yan, L.; Jingyu, S. J. Org.
Chem. 1992, 57, 3528–3530; (d) Kozikowski, A. P.; Araldi,
G. L.; Ball, R. G. J. Org. Chem. 1997, 62, 503–509; (e)
1
stry of cycloadduct 11 was assigned on the basis of H
NMR analysis,12 supported by the X-ray structure of 7.
The observed stereocontrol was rationalised by prefer-
ential approach of the dipolarophile from the b-face of
betaine 4 anti to the phenyl moiety of the a-methylbenz-
yl substituent as illustrated in Figure 2.
´
´
Estour, F.; Rezel, S.; Fraisse, D.; Metin, J.; Gaumet, V.;
Lartigue, C.; Miscoria, G.; Gueiffier, A.; Blache, Y.;
Teulade, J. C.; Chavignon, O. Heterocycles 1999, 50, 929–
945.
2. Curtis, N. R.; Kulagowski, J. J.; Huscroft, I. T.; Raubo, P.
A. US 20020193402, 2002; Chem. Abstr. 2002, 138, 39444.
3. Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863–909.
4. (a) Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu, H.;
Koizumi, T. Chem. Lett. 1989, 597–598; (b) Takahashi, T.;
Fujii, A.; Sugita, J.; Hagi, T.; Kitano, K.; Arai, Y.;
Koizumi, T.; Shiro, M. Tetrahedron: Asymmetry 1991, 2,
1379–1390.
The homochiral betaine 4 was efficiently prepared in
three steps from 2-furoyl chloride, using (S)-a-methyl-
benzylamine as the source of chirality. 1,3-Dipolar
cycloadditions proceeded in moderate to good yields,
with excellent diastereofacial selectivity achieved for
the major 6-exo cycloadducts. The absolute stereochem-
istry of cycloadduct 7, the major product from reaction
of 4 with tert-butyl acrylate (70% overall yield of
_
PhO2S
SO2Ph
(1.1 eq.)
O
O
Ph
4
+
+
N
N
toluene, 90 ˚C, 5 d
Ph
N
Ph
(34%)
Ph
O
Ph
12
Ph
(1S,5R,6S,9S)-11
4
(31%)
Scheme 4. Cycloaddition with phenyl vinyl sulfone.

2638
N. R. Curtis et al. / Tetrahedron Letters 47 (2006) 2635–2638
5. (a) Araldi, G. L.; Prakash, K. R. C.; George, C.;
appears as a doublet (coupling only to H-4, J4,5 typically
ca. 5.5 Hz).1a
Kozikowski, A. P. Chem. Commun. 1997, 1875–1876; (b)
Prakash, K. R. C.; Trzcinska, M.; Johnson, K. M.;
Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2000, 10,
1443–1446.
t-BuO2C
CO2t-Bu
6. Pham, V. C.; Charlton, J. L. J. Org. Chem. 1995, 60, 8051–
8055.
7. Shinohara, T.; Takeda, A.; Toda, J.; Terasawa, N.; Sano,
T. Heterocycles 1997, 46, 555–566.
N
N
Ph
Ph
O
O
Ph
Ph
13
14
8. Muller, C.; Diehl, V.; Lichtenthaler, F. W. Tetrahedron
¨
1998, 54, 10703–10712.
9. Crystallographic data for 7. C26H29NO3, Mr = 403.526,
11. 1H NMR (400 MHz, CDCl3) data for cycloadducts 7–10.
Compound 7: d 8.18 (2H, d, J 7.7 Hz), 7.37 (2H, t, J
7.7 Hz), 7.30–7.20 (6H, m), 6.74 (1H, dd, J 4.6, 9.7 Hz,
H-4), 5.98 (1H, d, J 9.7 Hz, H-3), 4.07 (1H, d, J 4.6 Hz,
H-5), 3.95 (1H, q, J 6.9 Hz, CHCH3), 2.94 (1H, dd, J 2.0,
14.4 Hz, H-7exo), 2.67 (1H, dd, J 1.9, 9.1 Hz, H-6), 2.42
(1H, dd, J 9.0, 14.4 Hz, H-7endo), 1.48 (9H, s, C(CH3)3),
0.85 (3H, d, J 6.9 Hz, CHCH3). Compound 8 (partial
data): d 6.18 (1H, d, J 9.8 Hz, H-3), 4.31 (1H, d, J 4.7 Hz,
H-5), 3.72 (1H, q, J 6.9 Hz, CHCH3), 3.26 (1H, dd, J 2.4,
14.5 Hz, H-7exo), 2.80 (1H, dd, J 2.4, 9.0 Hz, H-6), 2.22
orthorhombic, P212121, a = 10.415(2), b = 11.108(3),
3
˚
˚
c = 18.981(4) A, V = 2196(2) A , Z = 4, Dx = 1.220
g cmÀ3, monochromatized Mo radiation k = 0.71073 A,
˚
l = 0.07 mmÀ1
, F(000) = 864, T = 100 K. Data were
collected on a Bruker CCD diffractometer to a h limit of
26.36° which yielded 23,859 reflections. There are 4481
unique reflections with 4057 observed at the two sigma
level. The structure was solved by direct methods (SHELXS-
97) and refined using full-matrix least-squares on F2
(SHELXL-97). The final model was refined using 275
parameters and all 4481 data. All nonhydrogen atoms
were refined with anisotropic thermal displacements. The
final agreement statistics are: R = 0.029 (based on 4057
reflections with I P 2r(I)), wR = 0.069, S = 1.02 with (D/
r)max < 0.01. The maximum pÀea3k height in a final differ-
(1H, dd,
J 9.0, 14.5 Hz, H-7endo), 1.46 (9H, s,
C(CH3)3),1.23 (3H, d, J 6.9 Hz, CHCH3). Compound 9:
d 8.07 (2H, d, J 7.5 Hz), 7.38–7.24 (8H, m), 6.74 (1H, dd, J
4.6, 9.8 Hz, H-4), 6.12 (1H, d, J 9.8 Hz, H-3), 4.00 (1H, q,
J 6.9 Hz, CHCH3), 3.95 (1H, t, J 5.2 Hz, H-5), 3.52–3.46
(1H, m, H-6), 2.63–2.51 (2H, m, H-7exo/H-7endo), 1.37 (9H,
s, C(CH3)3), 0.85 (3H, d, J 7.0 Hz, CHCH3). Compound
10: d 7.58 (2H, d, J 7.3 Hz), 7.16–7.02 (7H, m), 6.96 (2H,
m), 6.21 (1H, d, J 9.8 Hz, H-3), 4.33 (1H, t, J 5.6 Hz, H-5),
3.79 (1H, q, J 6.9 Hz, CHCH3), 3.37–3.31 (1H, m, H-6),
2.71 (1H, dd, J 10.2, 14.2 Hz, H-7exo), 2.37 (1H, dd, J 6.8,
14.3 Hz, H-7endo), 1.42 (9H, s, C(CH3)3), 1.27 (3H, d, J
6.9 Hz, CHCH31).
˚
ence Fourier map is 0.129 e A and this peak is without
chemical significance. Crystallographic data (excluding
structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 287235. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. Compound 11: H NMR (400 MHz, CDCl3): d 8.15 (2H,
d, J 7.5 Hz), 7.82 (2H, m), 7.66 (1H, m), 7.52 (2H, m),
7.39–7.24 (8H, m), 6.61 (1H, dd, J 4.7, 9.7 Hz, H-4), 5.92
(1H, d, J 9.6 Hz, H-3), 4.28 (1H, d, J 4.7 Hz, H-5), 3.91
(1H, q, J 6.9 Hz, CHCH3), 3.35 (1H, dd, J 3.5, 9.4 Hz,
H-6), 2.90 (1H, dd, J 3.5, 15.2 Hz, H-7exo), 2.52 (1H, dd,
J 9.5, 15.2 Hz, H-7endo), 0.92 (3H, d, J 7.0 Hz, CHCH3).
10. Assignments made by analysis of 1H and COSY spectra of
1
cycloadducts 7–10, supported by H, COSY and NOESY
spectra of 13 and 14 (derived by hydrogenation of the
major 6-exo and 6-endo cycloadducts, 7 and 9, respec-
tively). It is known that 6-exo cycloadducts show no
coupling constant between H-5 and H-6endo so that H-5