A diastereoselective radical cyclization approach to substituted quinuclidines

Article abstract of DOI:10.1021/jo060349q

A new, concise, and flexible approach to novel quinuclidines has been developed, which employs a phosphorus hydride mediated radical addition/cyclization reaction in the key step. 1,7-Diene 5 reacts with diethyl thiophosphite in an efficient and diastereo

Full text of DOI:10.1021/jo060349q

treatment of Alzheimer’s dementia,5 eating disorders, sexual
behavior and stress,9 depression,10 and cholesterol blood levels.8
Recently, 2,5-disubstituted quinuclidines11 have been used as
chiral ligands in asymmetric reactions.12 The development of a
new, general, and convergent method for the synthesis of
substituted quinuclidines is therefore important to further exploit
the important properties of this class of molecules.
A Diastereoselective Radical Cyclization
Approach to Substituted Quinuclidines
Thomas A. Hunt,† Andrew F. Parsons,*,† and Robert Pratt‡
Department of Chemistry, UniVersity of York, Heslington, York,
YO10 5DD, U.K. and Vernalis Research Ltd, Oakdene Court,
613 Reading Road, Winnersh, Wokingham, RG41 5UA, U.K.
Building on our earlier research into the phosphorus hydride
mediated radical cyclization of dienes,13 we embarked on a
diastereoselective synthesis of 2,5-disubstituted quinuclidines,
of type 2, that would be amenable to a synthesis of (-)-quinine
1 (Scheme 1).14 It is envisaged that the HWE-type reaction of
unstabilized phosphonothioate 3 with ketones would give access
to a diverse library of quinuclidines. Construction of phos-
phonothioate 3 is to be achieved by an SN2-type cyclization of
phosphonothioate 4, which is to be synthesized by a diastereo-
selective phosphorus hydride mediated radical cyclization of
diene 5. Known iodide 615 will be used to construct diene 5
and the oxazolidinone ring will act as a N- and O-protecting
group.
afp2@york.ac.uk
ReceiVed February 20, 2006
A new, concise, and flexible approach to novel quinuclidines
has been developed, which employs a phosphorus hydride
mediated radical addition/cyclization reaction in the key step.
1,7-Diene 5 reacts with diethyl thiophosphite in an efficient
and diastereoselective radical addition/cyclization reaction
to give trisubstituted piperidines 4ab. Piperidines 4ab are
subsequently converted into 2,5-disubstituted quinuclidines
using SN2-type cyclizations. Finally, the resulting quinucli-
dines are shown to undergo novel Horner-Wadsworth-
Emmons-type (HWE-type) reactions to give unsaturated
quinuclidines 21a and 21b, which have structures similar to
that of (-)-quinine 1.
Elaboration of substrates such as iodide 6 can be difficult
due to the presence of a â-heteroatom.16 However, it has been
shown that iodide 6 readily forms an organozinc reagent, which
reacts with a range of electrophiles.17 The synthesis of diene 5
began with an organozinc/copper coupling reaction of iodide 6
(Scheme 2). Insertion of activated zinc (Zn*)18 into the C-I
bond in 6, followed by transmetalation to copper, gave an
(7) Swain, C. J.; Fong, T. M.; Haworth, K.; Owen, S. N.; Seward, E.
M.; Strader, C. D. Bioorg. Med. Chem. Lett. 1995, 5, 1261-1264.
(8) Brown, G. R.; Foubister, A. J.; Freeman, S.; McTaggart, F.; Mirrlees,
D. J.; Reid, A. C.; Smith, G. J.; Taylor, M. J.; Thomason, D. A.; Whittamore,
P. R. O. Bioorg. Med. Chem. Lett. 1997, 7, 197-600.
(9) Rosen, T.; Nagel, A. A.; Rizzi, J. P. Synlett 1991, 213-221.
(10) Mantyh, P. W. J. Clin. Psych. 2002, 63, 6-10.
(11) 2,5-Disubstituted quinuclidines (quincorine and quincoridine) are
available from the degradation of (-)-quinine 1 and quinidine: Hoffmann,
H. M. R.; Plessner, T.; von Riesen, C. Synlett 1996, 690-692.
(12) (a) Hartikka, A.; Modin, S. A.; Andersson, P. G.; Arvidsson, P. I.
Org. Biomol. Chem. 2003, 1, 2522-2526. (b) Pellet-Rostaing, S.; Saluzzo,
C.; Halle, R. T.; Breuzard, J.; Vial, L.; Guyader, F. Le; Lemaire, M.
Tetrahedron: Asymmetry 2001, 12, 1983-1985. (c) Saluzzo, C.; Breuzard,
J.; Pellet-Rostaing, S.; Vallet, M.; Guyader, F. Le; Lemaire, M. J.
Organomet. Chem. 2002, 643, 98-104.
(13) (a) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D.
Tetrahedron Lett. 2003, 44, 479-483. (b) Jessop, C. M.; Parsons, A. F.;
Routledge, A.; Irvine, D. J. Tetrahedron Lett. 2004, 45, 5095-5098. (c)
Healy, M. P.; Parsons, A. F.; Rawlinson, J. G. T. Org. Lett. 2005, 7, 1597-
1600.
(14) (a) For a review on the synthesis of (-)-quinine 1, see: Kaufman,
T. S.; Ru´veda, E. A. Angew. Chem., Int. Ed. 2005, 44, 854-885. For
stereoselective syntheses of (-)-quinine 1, see: (b) Stork, G.; Niu, D.;
Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Drake, G. R. J. Am.
Chem. Soc. 2001, 123, 3239-3242. (c) Raheem, I. T.; Goodman, S. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706-707. (d) Igarashi, J.;
Katsukawa, M.; Wang, Y.-G.; Acharya, H. P.; Kobayashi, Y. Tetrahedron
Lett. 2004, 45, 3783-3786. (e) Igarashi, J.; Kobayashi, Y. Tetrahedron
Lett. 2005, 46, 6381-6384.
Quinuclidines are an important class of molecules found in
many natural products1,2 including (-)-quinine 1, which is one
of the most important naturally occurring alkaloids because of
its role in treating malaria.3 (-)-Quinine 1 is a member of the
cinchona family of alkaloids, and these compounds and their
derivatives have been used in a wide range of synthetic
applications.4 Various quinuclidines have also been shown to
be inhibitors of the muscarinic (M1),5 serotonin-3 (5-HT3),6 and
neurokinin (NK1)7 receptors and also as squalene synthase
inhibitors.8 The inhibition of these targets is important in the
† University of York.
‡ Vernalis Research Ltd.
(1) Turner, R. B.; Woodward, R. B. The Chemistry of the Cinchona
Alkaloids in The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New
York, 1953; Vol. 3, Chapter 16.
(2) Kitajima, M.; Takayama, H.; Sakai, S.-i. J. Chem. Soc., Perkin Trans.
1 1991, 1773-1779.
(3) Caseel, D. A. Quinine has been claimed “to have relieved more human
suffering than any other in history”. In Burger’s Medicinal Chemistry and
Drug DiscoVery, 5th ed.; Wolff, M. E., Ed.; John Wiley: New York, 1997;
Vol. 5, Chapter 59, p 16.
(4) For recent reviews, see: (a) Kacprzak, K.; Gawronski, J. Synthesis
2001, 961-998. (b) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.;
Deng, L. Acc. Chem. Res. 2004, 37, 621-631. (c) OÄ Da´laigh, C. Synlett
2005, 875-876.
(5) (a) Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.; Iverson,
L. L.; Kneen, C.; Macleod, A. M.; Merchant, K. J.; Snow, R. J.; Baker, R.
J. Med. Chem. 1990, 33, 1128-1138. (b) Baker, R.; Street, L. J.; Reeve,
A. J.; Saunders, J. J. Chem. Soc., Chem. Commun. 1991, 760-762.
(6) Clark, R. D.; Weinhart, K. K.; Berger, J.; Lee, C.-H.; Leung, E.;
Wong, E. H. F.; Smith, W. L.; Eglen, R. M. Bioorg. Med. Chem. Lett.
1993, 3, 1375-1378.
(15) Jackson, R. F. W.; Perez-Gonzalez, M. Org. Synth. 2005, 81, 77-
88.
(16) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417-
4422 and references therein.
(17) For recent reviews, see: (a) Rilatt, I.; Caggiano, L.; Jackson, R. F.
W. Synlett 2005, 2701-2719. (b) Knochel, P.; Singer, R. D. Chem. ReV.
1993, 93, 2117-2188.
(18) Activated zinc was prepared using dibromoethane and TMSCl; see
Supporting Information for further details. For alternative methods of
forming activated zinc see ref 17b.
10.1021/jo060349q CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
3656
J. Org. Chem. 2006, 71, 3656-3659

SCHEME 1. Retrosynthetic Analysis of Substituted Quinuclidine 2
SCHEME 2. Synthesis of Diene 5
SCHEME 3. Radical Cyclization of Diene 5 (Relative
Stereochemistry is Indicated)
organozinc/copper reagent.19 This reagent reacted with alkynyl
iodide 7 (formed in 96% yield in one step from the previously
reported tert-butyl(diphenyl)(2-propynyloxy)silane)20,21 to give
alkyne 8 in good yield on a multigram scale. Reduction of
alkyne 8 with Pd/BaSO4 (Rosenmund’s catalyst)22 gave the most
reliable partial hydrogenation of the CtC bond in 8, but the
purity of Z-alkene 9 was judged to be only 70% (the 1H NMR
spectrum indicated ca. 30% of alkane 11, which is formed by
further reduction of the CdC bond in 9).23 Unfortunately, alkene
9 and alkane 11 were inseparable by column chromatography.
Alternative conditions and catalysts (e.g., use of quinoline and
sulfur as catalyst poisons or Lindlar reduction) gave lower yields
of alkene 9.
Reduction of the ester group in 9 required only mild
conditions and gave alcohol 10 in excellent yield (containing
ca. 30% of alkane 12 derived from ester 11).23 Conversion of
alcohol 10 into diene 5 was accomplished in 23% yield over
two steps; however, a telescoped, one-pot cyclization and
N-allylation of alcohol 10 gave diene 5 in an improved 58%
yield (the purity was judged to be 75% as diene 5 contained
ca. 25% of alkene 13 carried through from over-reduction of
alkyne 8).24
1
product 4 (Scheme 3). The H and 13C NMR spectra of the
product indicated that the cyclization was diastereoselective,
producing an inseparable mixture of only two of the four
possible diastereomers. The efficiency and diastereoselectivity
of the cyclization was not significantly affected by the reaction
conditions. For example, using AIBN as initiator (in cyclohex-
ane, 80 °C) afforded 4a and 4b in a combined 56-75% yield
(dr 1:1.7-2.2),23 whereas the use of Et3B/O2 as initiator (in
cyclohexane, rt) afforded 4a and 4b in a combined 47-68%
yield (dr 1:1.5-2.0).23 NOESY experiments in vide showed that
the major diastereomer 4b had the same relative stereochemistry
as (-)-quinine 1 with the minor diastereomer 4a being epimeric
at C-6. In addition, a byproduct was also isolated in 99% yield
(based on alkene 13), which was consistent with phosphono-
thioate 14, derived from addition of diethyl thiophosphite to
the CdC bond in alkene 13.
Radical cyclization of diene 5 with diethyl thiophosphite13
proceeded with complete regioselectivity for the 6-exo-trig
(19) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger, S.;
Knochel, P. Tetrahedron 1994, 50, 2415-2432.
(20) See Supporting Information for further details.
(21) Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 68, 5962-5970.
(22) (a) Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1956, 78, 2518-
2524. (b) Nicolau, K. C.; Li, J.; Zenke, G. HelV. Chim. Acta 2000, 83,
1977-2006.
(23) As judged from the 1H NMR spectrum; see Supporting Information
for further details.
(24) For a related example see: Huwe, C. M.; Blechert, S. Tetrahedron
Lett. 1994, 35, 9533-9536.
J. Org. Chem, Vol. 71, No. 9, 2006 3657

SCHEME 4. Transition States Leading to
Phosphonothioates 4a and 4b (Relative Stereochemistry is
Indicated)
proceeded to give 21a in (unoptimized) 42% yield and 21b in
93% yield.13c NOESY NMR experiments indicated that the
major diastereomer 21b had the same relative stereochemistry
as (-)-quinine 1 and the minor diastereomer was the C-5 epimer
(Figure 1).20 Removal of the DPS group from 21b with TBAF
gave alcohol 22b (Scheme 7).
In conclusion, a short and reasonably efficient synthesis of
diene 5 has been developed starting from iodide 6 (four steps
and 24% yield). Phosphorus hydride mediated radical cyclization
of diene 5 was shown to proceed efficiently and diastereose-
lectivity to give trisubstituted piperidines 4a and 4b that were
efficiently converted into quinuclidines. Novel HWE-type
reactions of unstabilized quinuclidinyl methylphosphonothioates
20a and 20b were demonstrated to give excellent yields of
alkenyl-substituted quinuclidines 21a and 21b. Quinuclidine 21b
was shown to have the same relative stereochemistry as (-)-
quinine 1, and current research is exploring adapting this
approach to a stereoselective synthesis of (-)-quinine 1.
The selective formation of phosphonothioates 4a and 4b can
be explained by the transition states adopted in the radical
cyclization of diene 5. 6-Exo-trig radical cyclizations are known
to proceed via “chairlike” transitions states,25 and the thermo-
dynamically most favored transition state, 15b, has all substit-
uents in pseudo-equatorial positions, which leads to the major
diastereomer 4b (Scheme 4). The minor diastereomer 4a is
formed from transition state 15a that places the methylphospho-
nothioate group axially, so incurring one unfavorable 1,3-diaxial
interaction. The relative stereochemistry at C-7 is fixed due to
the presence of the oxazolidinone ring26 and the Z-geometry of
the acceptor alkene.27
Conversion of phosphonothioates 4a and 4b into quinuclidines
required opening of the oxazolidinone ring, but the hydrolysis
conditions were incompatible with the DPS ether in 4ab.
Therefore, the DPS ether was removed and primary alcohol 16
was reprotected to give trityl ether 17 in good yield (Scheme
5). The oxazolidinone ring in 17 was then hydrolyzed using
aqueous sodium hydroxide and the primary alcohol was
protected as its DPS ether to give piperidines 18a and 18b
(separable by column chromatography, dr ) 1:1.3). The trityl
ether in 18a and 18b was selectively cleaved under acidic
conditions in the presence of thiophenol (in the absence of
thiophenol the separation of amino alcohols 19a and 19b from
trityl alcohol was problematic).28
Experimental Section20
O,O-Diethyl [rel-(6S,7R,8aS)-7-(2-{[tert-Butyl(diphenyl)silyl]-
oxy}ethyl)-3-oxohexahydro-[1,3]oxazolo[3,4-a]pyridin-6-yl]-
methylphosphonothioate 4a and O,O-Diethyl [rel-(6R,7R,8aS)-
7-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-3-oxohexahydro[1,3]-
oxazolo[3,4-a]pyridin-6-yl]methyl-phosphonothioate 4b. To a
solution of diene 5 (0.20 g containing 25% alkene 13 as judged
from the 1H NMR spectrum, 0.35 mmol) in degassed cyclohexane
(15 mL) was added diethyl thiophosphite (0.14 g, 0.92 mmol) and
AIBN (8 mg, 0.046 mmol). The reaction was heated to reflux for
12 h during which time further portions of AIBN (6 × 8 mg, 0.28
mmol) were added. The reaction mixture was concentrated in vacuo,
and the residue was purified by flash column chromatography on
silica using petroleum ether/EtOAc (9:1 to 1:1) as eluent to afford
phosphonothioates 4a and 4b (0.16 g, 75%) as a 1:2 mixture of
diastereomers as indicated from the 1H NMR spectrum (by
comparison of the integral values of the signals at 4.39 and 4.32
ppm). Rf 0.3 (petroleum ether/Et2O 1:2); IR (CH2Cl2) νmax 2959,
2932, 2859, 1753, 1473, 1427, 1390, 1111, 1049, 1025, 959 cm-1
;
1H NMR (400 MHz, CDCl3) δH 7.66-7.63 (m, 4H), 7.46-7.36
(m, 6H), 4.39 and 4.32 (2 × t, J ) 8.5, 1H), 4.24-3.99 (m, 5H),
3.83-3.45 (m, 3H), 2.87 and 2.50 (d, J ) 12.5 Hz and dd J )
13.0, 10.5 Hz, 1H), 2.30-2.19 (m, 1H), 2.00-1.36 (m, 8H), 1.32,
1.28 and 1.26 (3 × t, J ) 7.0 Hz, 6H), 1.05 (9H, s); 13C NMR
(100 MHz, CDCl3) δC 157.3 (C), 156.3 (C), 135.5 (CH), 135.43
(CH), 135.41 (CH), 133.6 (C), 133.5 (C), 133.4 (C), 129.64 (CH),
129.61 (CH), 127.62 (CH), 127.59 (CH), 68.0 (CH2), 67.6 (CH2),
62.61 (d, JCP ) 7.0 Hz, CH2), 62.63 (d, JCP ) 7.0 Hz, CH2), 62.5
(d, JCP ) 7.0 Hz, CH2), 62.4 (d, JCP ) 7.0 Hz, CH2), 60.7 (CH2),
60.6 (CH2), 54.4 (CH), 53.6 (CH), 46.4 (d, JCP ) 2.5 Hz, CH2),
45.5 (d, JCP ) 1.5 Hz, CH2), 36.2 (d, JCP ) 15.0 Hz, CH), 35.8 (d,
JCP ) 1.5 Hz, CH2), 35.6 (d, JCP ) 112.0 Hz, CH2), 35.5 (CH2),
35.3 (d, JCP ) 3.0 Hz, CH), 34.9 (CH2), 34.6 (d, JCP ) 13.5 Hz,
CH), 31.5 (d, JCP ) 2.5 Hz, CH), 31.2 (CH2), 29.9 (d, JCP ) 112.0
Hz, CH2), 26.79 (CH3), 26.76 (CH3), 19.1 (C), 19.0 (C), 16.12 (d,
Using the conditions developed by Stork,14b the amino
alcohols 19a and 19b were selectively O-mesylated without the
need for temporary N-protection (Scheme 6). The crude
mesylates then underwent cyclization on heating in acetonitrile
to give quinuclidines 20a and 20b in good yield. It was found
that reducing the amount of MsCl (1.05 to 0.6 equiv) gave
improved yields of the quinuclidine 20a (from 31% to 92%).
Novel HWE-type reactions of unstabilized quinuclidinyl
methylphosphonothioates 20a and 20b with benzophenone
JCP ) 7.0 Hz, CH3), 16.10 (d, JCP ) 7.0 Hz, CH3), 16.06 (d, JCP
)
(25) (a) Curran, D. P.; Porter, N. A. Stereochemistry of Radical Reactions;
Giese, B., Ed.; Wiley-VCH: New York, 1996. (b) Parsons, A. F. An
Introduction to Radical Chemistry; Blackwell Science: Oxford, 2000.
(26) For examples of oxazolidinones affecting the diastereoselectivity
of radical cyclizations, see: (a) Baldwin, J. E.; Moloney, M. G.; Parsons,
A. F. Tetrahedron 1990, 46, 7263-7282. (b) Baldwin, J. E.; Li, C.-S. J.
Chem. Soc., Chem. Commun. 1988, 261-263. (c) Lee, E.; Kang, T. S.;
Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C. K. Tetrahedron Lett. 1995, 36,
417-420.
7.0 Hz, CH3), 16.04 (d, JCP ) 7.0 Hz, CH3); LRMS (CI, NH3) m/z
590 ([M + H]+, 14%), 512 (100); HRMS (CI, NH3) m/z [M +
H]+ found 590.2525, calcd 590.2525 for C30H44NO5PSSi.
rel-(2S,4R,5R)-2-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-5-
(2,2-diphenylvinyl)-1-azabicyclo[2.2.2]octane 21a. A solution of
phosphonothioate 20a (72 mg, 0.13 mmol) was dissolved in
anhydrous THF (6 mL) and cooled to -78 °C. sBuLi (0.33 mL of
a 0.80 M solution in cyclohexane, 0.26 mmol) was added and after
0.1 h of stirring at -78 °C, benzophenone (48 mg, 0.26 mmol)
was added. The reaction was allowed to warm slowly to room
temperature and was stirred at this temperature for 16 h before being
quenched with NH4Cl (saturated aqueous solution) and then
(27) For an example of alkene geometry affecting the diastereoselectivity
of 6-exo-trig radical cyclizations, see: Hannessian, S.; Dhanoa, D. S.;
Beaulieu, P. L. Can. J. Chem. 1987, 65, 1859-1866.
(28) Masui, Y.; Chino, N.; Sakakibara, S. Bull. Chem. Soc. Jpn. 1980,
53, 464-468.
3658 J. Org. Chem., Vol. 71, No. 9, 2006

SCHEME 5. Synthesis of Amino Alcohols 19a and 19b (Relative Stereochemistry is Indicated)
SCHEME 6. Synthesis of Quinuclidines 21a and 21b (Relative Stereochemistry is Indicated)
SCHEME 7. Formation of Amino Alcohol 22b
rel-(2S,4R,5S)-2-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-5-
(2,2-diphenylvinyl)-1-azabicyclo[2.2.2]octane 21b. A solution of
phosphonothioate 20b (20 mg, 0.037 mmol) was dissolved in
s
anhydrous THF (2 mL) and cooled to -78 °C. BuLi (0.092 mL
of a 0.80 M solution in cyclohexane, 0.073 mmol) was added and
after 0.1 h of stirring at -78 °C, benzophenone (13 mg, 0.078
mmol) was added. The reaction was allowed to warm slowly to
room temperature and was stirred at this temperature for 2 h before
being quenched with NH4Cl (saturated aqueous solution) and then
extracted with Et2O. The combined organic phases were dried
(MgSO4), filtered, and evaporated to give a yellow oil that was
purified by flash column chromatography on silica (using petroleum
ether/Et2O/Et3N (67:33:1) to (33:67:1) as eluent) to afford quinu-
clidine 21b (20 mg, 93%) as a colorless oil. Rf 0.4 (petroleum ether/
Et2O 1:2); IR (neat) νmax 3057, 2929, 2860, 1599, 1493, 1471, 1427,
1265, 1228, 1198, 1113, 1076 cm-1; 1H NMR (400 MHz, CDCl3)
δH 7.71-7.66 (m, 4H), 7.43-7.21 (m, 14H), 7.15-7.13 (m, 2H),
6.18 (d, J ) 10.0 Hz, 1H), 3.79 (dd, J ) 10.0, 5.5 Hz, 1H), 3.73
(dd, J ) 10.0, 7.0 Hz, 1H) 3.08 (dd, J ) 13.5, 10.0 Hz, 1H) 3.07-
2.91 (m, 2H), 2.69 (dd, J ) 13.5, 4.5 Hz, 1H), 2.58-2.49 (m, 1H),
2.43-2.36 (m, 1H), 2.08-2.01 (m, 1H), 1.78-1.74 (m, 1H), 1.46-
1.36 (m, 2H), 1.32-1.22 (m, 1H), 1.07 (s, 9H); 13C NMR (100
MHz, CDCl3) δC 142.7 (C), 141.9 (C), 140.1 (C), 135.6 (CH), 133.6
(C), 133.5 (C), 132.9 (CH), 129.8 (CH), 129.6 (CH), 128.2 (CH),
128.1 (CH), 127.6 (CH), 127.3 (CH), 127.0 (CH), 66.7 (CH2), 57.9
(CH2), 57.6 (CH), 42.0 (CH2), 35.9 (CH), 27.9 (CH), 27.4 (CH2),
26.9 (CH3), 25.3 (CH2), 19.3 (C); LRMS (CI, NH3) m/z 558 ([M
+ H]+, 100%); HRMS (CI, NH3) m/z [M + H]+ found 558.3197,
calcd 558.3192 for C38H43NOSi.
extracted with Et2O. The combined organic phases were dried
(MgSO4), filtered, and evaporated to give a yellow oil. Purification
by flash column chromatography on silica, eluting with a solvent
gradient of petroleum ether/Et2O (1:1) to petroleum ether/Et2O/
Et3N (33:67:1), afforded quinuclidine 21a (31 mg, 42%) as a
colorless oil. Rf 0.2 (petroleum ether/Et2O 1:2); IR (CH2Cl2) νmax
2958, 2931, 2860, 1603, 1493, 1471, 1444, 1427, 1315, 1279, 1113
cm-1; 1H NMR (400 MHz, CDCl3) δH 7.60-7.63 (m, 4H), 7.41-
7.32 (m, 9H), 7.27-7.20 (m, 5H), 7.15-7.13 (m, 2H), 6.20 (d, J
) 10.0 Hz, 1H), 3.71 (d, J ) 6.0 Hz, 2H), 3.11-3.00 (m, 2H),
2.85-2.74 (m, 2H), 2.62 (dd, J ) 13.5, 7.0 Hz, 1H), 2.50-2.43
(m, 1H), 1.93-1.81 (m, 1H), 1.80-1.75 (m, 1H), 1.65-1.57 (m,
1H), 1.45-1.33 (m, 2H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3)
δC 142.6 (C), 142.4 (C), 140.1 (C), 135.6 (CH), 133.5 (C), 133.4
(C), 131.7 (CH), 129.7 (CH), 129.6 (CH), 128.2 (CH), 128.1 (CH),
127.62 (CH), 127.59 (CH), 127.3 (CH), 127.1 (CH), 127.0 (CH),
66.2 (CH2), 56.7 (CH2), 56.4 (CH), 43.1 (CH2), 35.4 (CH), 30.2
(CH2), 28.4 (CH), 26.8 (CH3), 21.5 (CH2), 19.2 (C); LRMS (CI,
NH3) m/z 558 ([M + H]+, 100%); HRMS (CI, NH3) m/z [M +
H]+ found 558.3196, calcd 558.3192 for C38H43NOSi.
Acknowledgment. We thank Vernalis Research Ltd and the
EPSRC for financial support.
Supporting Information Available: Experimental procedures,
1
spectroscopic data, and H and 13C NMR spectra for compounds
4, 5, 7-10 and 16-22b; 2D HSQC, COSY and NOESY spectra
for compounds 21a, 21b and 22b. This material is available free
of charge via the Internet at http://pubs.acs.org.
FIGURE 1. Key NOESY correlations for quinuclidine 21a and
quinuclidine 21b.
JO060349Q
J. Org. Chem, Vol. 71, No. 9, 2006 3659