Synthesis of enantiopure 3-quinuclidinone analogues with three stereogenic centers: (1S,2R,4S)- and (1S,2S,4S)-2-(hydroxymethyl)-1-azabicyclo[2.2.2]octan-5-one and stereocontrol of nucleophilic addition to the carbonyl group

Article abstract of DOI:10.1021/jo9919815

The pseudoenantiomeric title compounds have been prepared from quincorine (QCI) and quincoridine (QCD), respectively, in enantiopure form following an efficient six-step pathway. Nucleophilic attack at the carbonyl group proceeds preferentially from the s

Full text of DOI:10.1021/jo9919815

3982
J . Org. Chem. 2000, 65, 3982-3996
Syn th esis of En a n tiop u r e 3-Qu in u clid in on e An a logu es w ith Th r ee
Ster eogen ic Cen ter s: (1S,2R,4S)- a n d
(1S,2S,4S)-2-(Hyd r oxym eth yl)-1-a za bicyclo[2.2.2]octa n -5-on e a n d
Ster eocon tr ol of Nu cleop h ilic Ad d ition to th e Ca r bon yl Gr ou p
J ens Frackenpohl and H. M. R. Hoffmann*
Department of Organic Chemistry, University of Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
Received December 28, 1999
The pseudoenantiomeric title compounds have been prepared from quincorine (QCI) and quinco-
ridine (QCD), respectively, in enantiopure form following an efficient six-step pathway. Nucleophilic
attack at the carbonyl group proceeds preferentially from the supposedly more hindered endo π-face,
giving quinuclidinols with natural configuration at C5 (up to 97%). π-Face selectivity is highest in
the QCD series with bulky O-protecting groups, involving an unprecedented 1,7-stereoinduction.
Sch em e 1. Selected Med icin a lly Releva n t
Com p ou n d s Der ived fr om Qu in u clid in -3-on e
In tr od u ction
Substituted quinuclidines possess interesting and di-
verse pharmacological activities (Scheme 1). Recent
examples include 3-substituted quinuclidines C, E, and
F which are among the most potent muscarinic agonists
and antagonists.1 The 1-azabicyclo[2.2.2]octane nucleus
has been found to be a good mimic for the quaternary
nitrogen in acetylcholine but, unlike acetylcholine, the
unprotonated form is able to cross the blood-brain
barrier.2 Selective muscarinic M1-type antagonists ca-
pable of penetrating the blood-brain barrier have thera-
peutic potential for the treatment of Alzheimer’s disease.
Quinuclidine derivatives with substituents in the
3-position are able to block 5-HT3 (B) and NK1-receptors
(A).3,4 Substance P is a peptide neurotransmitter that
binds to the neurokinin-1 receptor and is involved in pain
transmission and neurogenic inflammation. CP-96 345
A is the first nonpeptide substance P antagonist and has
shown to be effective in animal models of pain and
* To whom correspondence should be addressed.. Fax: Int + (0) 511
762 3011. E-mail: hoffmann@mbox.oci.uni-hannover.de.
(1) Saunders, J .; Cassidy, M.; Freedman, S. B.; Harley, E. A.;
Iversen, L. L.; Kneen, C.; Macleod, A. M.; Merchant, K. J .; Snow, R.
J .; Baker, R. J . Med. Chem. 1990, 33, 1128. Baker, R.; Street, L. J .;
Reeve, A. J .; Saunders, J . J . Chem. Soc., Chem. Commun. 1991, 760.
Ashwood, M. S.; Gibson, A. W.; Houghton, P. G.; Humphrey, G. R.;
Roberts, D. C.; Wright, S. H. B. J . Chem. Soc., Perkin Trans. 1 1995,
641; Nordvall, G.; Sundquist, S.; Nilvebrant, L.; Hacksell, U. Bioorg.
Med. Chem. Lett. 1994, 4, 2837. J ohansson, G.; Sundquist, S.; Nordvall,
G.; Nilsson, B. M.; Brisander, M.; Nilvebrant, L.; Hacksell, U. J . Med.
Chem. 1997, 40, 3804.
(2) Wadsworth, H. J .; J enkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark,
M. S. G.; Brown, F.; Riley, G. J .; Graves, D.; Hawkins, J .; Naylor, C.
B. J . Med. Chem. 1992, 35, 1280.
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D. W.; Leung, E.; Eglen, R. M. Bioorg. Med. Chem. Lett. 1996, 6, 477;
Clark, R. D.; Weinhardt, 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; Langlois, M.; Soulier, J . L.; Allainmat, M.; Shen, S.; Gallais, C.
Bioorg. Med. Chem. Lett. 1993, 3, 1555.
(4) Fong, T. M.; Cascieri, M. A.; Yu, H.; Bansai, A.; Swain, C.;
Strader, C. D. Nature 1993, 362, 350-353; Snider, R. M.; Constantine,
J . W.; Lowe, J . A., III; Longo, K. P.; Lebel, W. S.; Woody, H. A.; Drozda,
S. E.; Desai, M. C.; Vinick, F. J .; Spencer, R. W. Science 1991, 251,
435; McLean, S.; Ganong, A. H.; Seeger, T. F.; Bryce, D. K.; Pratt, K.
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Bordner, J . Bioorg. Med. Chem. Lett. 1991, 1, 129. Swain, C. J .; Fong,
T. M.; Haworth, K.; Owen, S. N.; Seeward, E. M.; Strader, C. D. Bioorg.
Med. Chem. Lett. 1995, 5, 1261.
inflammation.4 Quinuclidinol D is a squalene synthase
inhibitor.5 Protonated quinuclidine squalene synthase
inhibitors are carbocation mimics for key steps of the
farnesyl pyrophosphate (FPP) to squalene conversion.
The 3-phenylethynyl substituent in D is supposed to
interact with a lipophilic pocket on the enzyme in a
manner similar to isoprenyl subunits in a farnesyl chain.6
10.1021/jo9919815 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/02/2000

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3983
Sch em e 2. P r ep a r a tion of Key In ter m ed ia tesa
Tricyclic spiro derivatives of quinuclidine are also potent
selective muscarinic agonists.7 The various pharmaco-
logically active quinuclidines have generally been pat-
ented in racemic form although contrasting bioactivity
of single isomers and enantiomers is, of course, well-
known.
The synthetic methods most frequently used for the
preparation of 3-substituted quinuclidines have started
from 3-methoxy-carbonylquinuclidine8 and nucleophilic
additions to 3-quinuclidinone.
Resu lts a n d Discu ssion
We here report the convenient preparation of enan-
tiopure 2-hydroxymethyl-substituted quinuclidin-3-one
analogues from quincoridine, 1 (QCI) and quincorine, 29
(QCD). Oxidative degradation of the vinyl side chain was
carried out by (i) double bond shift and (ii) 1,2-dihydroxy-
lation and subsequent 1,2-diol cleavage.
Specifically, hydrobromination of the vinyl group of
unprotected â-amino alcohols 1 and 2 in HBr (62%)
afforded the alkyl bromides 3a and 4a in high yield (86-
96%), but the use of fuming HBr was essential. In
contrast to the hydrobromination of quinidine,10 the
formation of tricyclic ring ethers was not observed.
Selective formation of the trisubstituted Saytzeff olefins
5a and 6a under E1-like conditions proceeded via drop-
wise addition of a DMF solution of alkyl bromides 3a and
4a into a preheated mixture of DBU and DMF (100-
110 °C). Although acyl protection of the C9-OH group
by benzoylation improved the yield of the base-mediated
elimination (87% instead of 76%), reaction sequence 1
f 5a and 2 f 6a was generally carried out without
protecting group, since the additional steps gave no
overall improvement (Scheme 2). Bishydroxylation of
silylated trisubstituted Saytzeff olefins with catalytic
amounts of OsO4 under two-phase conditions11 furnished
the corresponding diols 7 and 8 as mixtures of four
diastereomers, respectively. Olefins 5 and 6 were pro-
tected with TBDMS and TBDPS protecting groups in
order to maintain sufficient solubility of the intermediate
diols in organic solvents and to ease handling. Because
of unsatisfactory yields on silylations of C9-OH groups
of various QCI and QCD derivatives, protection of trisub-
stituted olefins 5a and 6a was optimized. While the
TBDPS group was superior concerning yield (90-94%),
a
Reagents and conditions: (i) 1. HBr (62%), 2. KOH, NaHCO3,
4 d; (ii) 1.5 equiv BzCl, 1.8 equiv Et3N, CH2Cl2, 0 °C f rt, 16 h;
(iii) 1.3 equiv DBU, DMF, 110 °C, 3 h; (iv) 8 equiv K2CO3, MeOH,
r.t., 20 min; (v) 2.0 equiv Et3N, 0.1 equiv DMAP, 1.5 equiv
TBDMSCl, CH2Cl2, 0 °C f rt, 10 h; (vi) 2.0 equiv Et3N, 0.1 equiv
DMAP, 1.5 equiv TBDPSCl, CH2Cl2, 0 °C f rt, 10 h.
the TBDMS derivatives 5b and 6b were more stable, but
were formed in lower yield (69-73%). Cleavage of vicinal
diols 7 and 8 with NaIO4 in tert-BuOH/H2O provided the
protected C-5-ketones 9a ,b and 10a ,b in high yield (87-
93%)12 and desilylation with TBAF furnished parent
hydroxy amino ketones 9d and 10d . Unlike quinuclidin-
3-one, which contains a plane of symmetry and is achiral,
the two title azabicyclics 9d and 10d are nonracemic and
homochiral, with three stereogenic centers. The trans-
formation of QCI and QCD into their corresponding keto
analogues was carried out on a gram scale in 30-35%
overall yield. Separation of diastereomers is not required
(Scheme 3).
(5) 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, 597.
McTaggart, F.; Brown, G. R.; Davidson, R. G.; Freeman, S.; Holdgate,
G. A.; Mallion, K. B.; Mirrlees, D. J .; Smith, G. J .; Ward, W. H. J .
Biochem. Pharmacol. 1996, 51, 1477; Ward, W. H. J .; Holdgate, G. A.;
Freeman, S.; McTaggart, F.; Girdwood, P. A.; Davidson, R. G.; Mallion,
K. B.; Brown, G. R.; Eakin, M. A. Biochem. Pharmacol. 1996, 51, 1489.
(6) Brown, G. R.; Clarke, D. S.; Foubister, A. J .; Freeman, S.;
Harrison, P. J .; J ohnson, M. C.; Mallion, K. B.; McCormick, J .;
McTaggart, F.; Reid, A. C.; Smith, G. J .; Taylor, M. J . J . Med. Chem.
1996, 39, 2971-2979.
π-F a cia l Selectivity in Nu cleop h ilic Ad d ition s to
Ca r bon yl Gr ou p . As evident from Scheme 1, the new
azabicyclic hydroxy ketones 9d and 10d are promising
candidates and precursors for the synthesis of a wide
variety of simplified quinine and quinidine analogues.
Addition of vinylmagnesium bromide to the C3 carbonyl
group of quinidine-based rubanone provides the known
and major quinidine metabolite M directly.13 For the
(7) Bo¨s, M.; Canesso, R. Heterocycles 1994, 38, 1889. Bromidge, S.
M.; Cassidy, F.; Clark, M. S. G.; Eggleston, D. S.; Orlek, B. S. J . Chem.
Soc., Chem. Commun. 1994, 2189. Bromidge, S. M.; Brown, F.; Cassidy,
F.; Clark, M. S. G.; Dabbs, S.; Hadley, M. S.; Loudon, J . M.; Orlek, B.
S.; Riley, G. J . Bioorg. Med. Chem. Lett. 1992, 2, 787.
(8) Grob, C. A.; Renk, E. Helv. Chim. Acta 1954, 37, 1689.
(9) Hoffmann, H. M. R.; Plessner, T.; v. Riesen, C. Synlett 1996, 690.
QCI and QCD are available from Buchler GmbH, Harxbu¨tteler Str. 3,
D-38110 Braunschweig, fax: +(0)5307-931-31.
(10) von Riesen, C.; J ones, P. G.; Hoffmann, H. M. R. Chem. Eur. J .
1996, 2, 680; Braje, W. M.; Frackenpohl, J .; Langer, P.; Hoffmann, H.
M. R. Tetrahedron 1998, 54, 3495.
(11) Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(12) Kang, S. H.; Kim, W. J . Synlett 1991, 520. Wu¨nsch, B.; Zott,
M. Synthesis 1992, 927.

3984 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
Sch em e 3. P r ep a r a tion of En a n tiop u r e
Qu in u clid in -3-on e An a logsa
Sch em e 4. Esta blish in g th e Na tu r a l
Con figu r a tion a t Ca r bon C3 in Qu in id in ea
a
Note that the azabicyclic core of the natural cinchona
alkaloids is numbered according to Rabe, whereas QCI and QCD
derivatives are numbered systematically according to IUPAC.
Sch em e 5. Syn th esis of Su bstitu ted
2-Hyd r oxym eth yl Qu in u clid in -5-ols
a
Reagents and conditions: (i)3 equiv K2CO3, 3 equiv K3[Fe(CN)6],
0.01 equiv OsO4 (solid), t-BuOH/ H2O (1:1), 6 h, rt; (ii) 1.3 equiv
NaIO4, t-BuOH/H2O, 2 h, rt; (iii) 1.3 equiv TBAF, THF, 0 °C f rt,
12 h.
preparation of naturally configurated analogues of this
key metabolite, reaction of TBDMS-protected rubanone
with Grignard reagents is the method of choice. Interest-
ingly, the bulky silyl group on the C9 alcohol function of
Cinchona alkaloids does not block attack at the endo face,
but appears to actually pull in the nucleophile toward
the sterically more hindered carbonyl π-face leading to
diastereoselectivities up to 9:1 in rubanol R (Scheme 4;
see also O-trityl derivative 11d , Scheme 5, Table 1).13
In the case of enantiopure quinuclidin-3-one analogues
9 and 10, face selectivity of nucleophilic attack at carbon
C5 is crucial for obtaining enantiopure analogues of
squalene synthase inhibitor D (Scheme 1). Addition of
L-Selectride to the C5 carbonyl group of 9 and 10 can, in
principle, afford two diastereomeric secondary alcohols:
anti-11 and anti-12 (natural configuration at carbon C5,
corresponding to quinidine metabolite M in Scheme 4;
endo attack of nucleophile) and alcohols syn-11 and syn-
12 (nonnatural configuration at C5, exo attack of nucleo-
phile). Reaction of unprotected azabicyclic ketone 9d with
bulky L-Selectride gave an inseparable mixture of dia-
stereomeric alcohols anti-11e and syn-11e (51:49). In
lectivity in favor of the naturally configurated anti alco-
hols with up to 95% de (Scheme 5, entries 1-4, Table 1).
Increasing the size of silyl protecting group furnished
de’s up to 71%. Trityl protected azabicyclic ketone 9e,
however, provided almost diastereoselectively pure qui-
nuclidinol anti-11d (de > 95%, entry 4). A similar trend
was observed for nucleophilic attack by lithiated phen-
ylacetylene. Whereas unprotected ketone 9d gave a
nearly 1:1 mixture of alcohols anti-11k and syn-11k (4%
de, entry 16), silylated ketones 9a (TBDMS) and 9c
(TIPS) furnished anti-11l in 40% de and anti-11m in 70%
de, respectively (entries 17, 18). Again, trityl protected
ketone 9e reacted with high endo selectivity providing
anti-11n (86% de, entry 19). Although the sterically
demanding TBDPS protecting group induced high dias-
tereoselectivity, TBDMS- or TIPS-protected azabicyclic
ketones 9a and 9c were used mainly, because they were
more stable toward lithium nucleophiles.14 For example,
the TBDPS ether in protected ketone 9b was cleaved with
5-methylfuranyl-2-lithium, giving unprotected quinucli-
din-5,9-diol 11i with poor diastereoselectivity (16% de,
entry 13). Addition of other organolithium nucleophiles
striking contrast, reaction of L-Selectride (LiBHBus )
3
with C9-protected ketones 9a -c,e showed diastereose-
(13) Langer, P.; Hoffmann, H. M. R. Tetrahedron 1997, 53, 9151.
(14) Cunico, R. F.; Bedell, L. J . Org. Chem. 1980, 45, 4797.

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3985
Ta ble 1. Rea ction of C5-Keton es w ith Nu cleop h iles
a
b
de and dr determined by NMR and GC; de and dr refer to the excess of anti-11 and anti-12, respectively. anti-11b and syn-11b
c
could be separated after mesylation. TBDPS-protected ketone 9 was deprotected upon treatment with lithiated 2-methylfuran.
and Grignard reagents showed similar diastereoselec-
tivities except for vinylmagnesium bromide giving only
16% de in the reaction with TBDMS-protected ketone 9a
(entry 15). TBDMS-protected ketone 10a , with the more
remote side chain, showed lower diastereoselectivity
compared with QCD-derived ketone 9a . Reaction of
TBDMS-protected ketone 10a with phenylmagnesium
bromide furnished quinuclidin-5-ol 12d with only 22%
de (entry 11), whereas the corresponding reaction with
parent QCD-derived ketone 9a showed 46% de (entry 10).
Likewise, reactions with lithiated alkynes (QCI-derived
ketone, 34% de; QCD-derived ketone, 64% de), lithiated
furan derivatives (QCI, 18% de; QCD, 42% de) and
L-Selectride (QCI, 48% de; QCD, 62% de) showed the
general trend toward lower diastereoselectivities with
QCI-derived ketones 10a ,b. Thus, diastereoselectivity of

3986 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
Sch em e 6. X-r a y Diffr a ction of δ-br om o Keton e 9f
nucleophilic attack at C5 is not limited to QCD-derived
ketones, but appears in QCI-derived ketones, although
less so.
a n d Tor sion of th e Aza bicyclic Ca gea
The study of electronic effects in various sterically
unbiased trigonal carbon centers continues to attract
considerable theoretical and experimental attention and
has been treated in detail in a recent thematic issue of
Chemical Reviews.15 Among the many models, transition-
state hyperconjugation15-17 and electrostatic field inter-
action18,19 are two popular explanations for face selectiv-
ity. Extended studies of reactions of 5-substituted
adamantan-2-ones and their derivatives suggest that the
reagent prefers to attack the face antiperiplanar to the
more electron-rich vicinal bonds.20 π-Facial selectivities
of sterically unbiased systems have also been observed
in substituted carbocyclic bicyclo[2.2.2]octanones, which
are rigid models of our title ketones 9 and 10.21 A more
hindered approach was preferred in the lithium alumi-
num hydride reduction of substituted bicyclo[2.2.2]octan-
2-ones since an isopropyl group at the position adjacent
to the keto group seemed to attract the hydride attack
from the sterically more demanding endo face.22 This is
analogous to the predominance of the more hindered
approach in the LiAlH4 reduction of 4-tert-butylcyclo-
hexanone. Mehta et al. studied the facial selectivities of
5,6-endo,syn-disubstituted bicyclo[2.2.2]octan-2-ones.23
anti-Substituents have an effect on face selectivity in
nucleophilic additions to these ketones (syn:anti ) 50:
50 to 70:30). Addition of organometallic reagents to
benzobicyclo[2.2.2]octan-2-one also exhibited syn prefer-
ence.24 In the case of our ketones 9 and 10, however,
electronic effects cannot exclusively explain the diaste-
reoselectivity of nucleophilic attack, because one π-face
of the C5 carbonyl group is affected by hydroxy-
methyl substitution at C2 and, in particular, by C9-
hydroxy protecting groups.
a
Torsion angles not drawn to scale.
Sch em e 7. Str u ctu r a l Assign m en t of
F u n ction a lized a n ti- a n d syn -Qu in u clid in olsa
a
Reagents and conditions: (i) 3 equiv LiBHBus3, THF, -90 °C
f -78 °C, 4 h, 82%; (ii) MsCl, 2.0 equiv Et3N, DCM, 0 °C f rt, 12
h, 94%.
Chelation by R- and â-alkoxy substituents is well-
known to control nucleophilic attack at the carbonyl
group.25 A priori, high face selectivities in nucleophilic
attack at the C5 carbonyl group of QCD-derived ketones
9a -e may also be considered to be caused partially by
interaction of the boron hydride, organolithium and
Grignard reagent with the lone-pair electrons of the
remote and protected C9 oxygen. Chelation was indeed
considered as a simple explanation in our earlier work
on the preparation of Cinchona alkaloid derivatives by
reduction and alkylation of rubanone.13 Test experiments
with parent unprotected quinuclidinone 9d did not
provide significant face selectivities. However, diastereo-
selectivity is strongly influenced by the size of protecting
groups at C9-oxygen. Even sterically less demanding
δ-bromo ketone 9f (Scheme 6) provides a moderate
diastereomeric excess of 36% (68:32) in favor of endo-
attack (Scheme 7).
(15) Tsai, T. L.; Chen, W.-C.; Yu, C.-H.; le Noble, W. J .; Chung, W.-
S. J . Org. Chem. 1999, 64, 1099-1107. Bodepudi, V. R.; le Noble, W.
J . J . Org. Chem. 1994, 59, 3265. Kaselj, M.; Chung, W.-S.; le Noble,
W. J . Chem. Rev. 1999, 99, 1387.
(16) Halterman, R. L.; McCarthy, B. A.; McEvoy, M. A. J . Org. Chem.
1992, 57, 5585.
(17) Cieplak, A. S.; Trait, B. D.; J ohnson, C. R. J . Am. Chem. Soc.
1989, 111, 8447; Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540;
Cieplak, A. S. Chem. Rev. 1999, 99, 1265.
Twisting of the azabicyclic moiety, rather than chela-
tion of the reagent, is an important factor requiring
consideration. First of all, X-ray analyses of δ-bromo
ketone 9f and alcohols anti-11o and syn-11o support our
configurational assignments at carbon C5. Twisting of
the azabicyclic core is demonstrated in Scheme 6.26
Torsion angles R(N1-C6-C5-C4) ) 9.0°, R(N1-C7-
C8-C4) ) 9.1°, and R(N1-C2-C3-C4) ) 13.0° indicate
clockwise torsion of the azabicyclic cage favoring nucleo-
(18) Adcock, W.; Cotton, J .; Trout, N. A. J . Org. Chem. 1994, 59,
1867.
(19) Paddon-Row, M. N.; Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc.
1992, 114, 10638.
(20) Coxon, J . M.; Houk, K. N.; Luibrand, R. T. J . Org. Chem. 1995,
60, 418.
(21) Ohwada, T. Chem. Rev. 1999, 99, 1337.
(22) Varech, D.; J acques, J . Tetrahedron Lett. 1973, 4443. Brienne,
M. J .; Varech, D.; J acques, J . Tetrahedron Lett. 1974, 1233. Che´rest,
M. J .; Felkin, H.; Tacheau, P.; J acques, J .; Varech, D. J . Chem. Soc.,
Chem. Commun. 1977, 372.
(23) Ganguly, B.; Chandrasekhar, J .; Khan, F. A.; Mehta, G. J . Org.
Chem. 1993, 58, 1734. Mehta, G.; Khan, F. A.; Ganguly, B.; Chan-
drasekhar, J . J . Chem. Soc., Chem. Commun. 1992, 1711.
(24) Pudzianowski, A. T.; Barrish, J . C.; Spergel, S. H. Tetrahedron
Lett. 1992, 33, 293.
(25) Reetz, M. T. Angew. Chem. 1984, 96, 73. Reetz, M. T. Acc. Chem.
Res. 1993, 26, 462. Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.;
Morokuma, K. J . Am. Chem. Soc. 1995, 117, 5055. Martin, R.; Pascual,
O.; Romea, P.; Rovira, R.; Urpi, F.; Vilarrasa, J . Tetrahedron Lett. 1997,
38, 1633.
(26) For detailed X-ray diffraction data of compounds 9f, anti-11o,
and syn-11o, see: Wartchow, R.; Frackenpohl, J .; Hoffmann, H. M. R.
Z. Kristallogr., NCS, 2000. In press. For further crystal structures of
quincorine and quincoridine derivatives, see: Wartchow, R.; Schrake,
O.; Braje, W. M.; Hoffmann, H. M. R. Z. Kristallogr. NCS 1999, 214,
285. von Riesen, C.; Wartchow, R.; Hoffmann, H. M. R. Z. Kristallogr.
NCS 1998, 213, 483. Wartchow, R.; Frackenpohl, J .; Ro¨per, S.;
Hoffmann, H. M. R. Z. Kristallogr. NCS, 2000. In press.

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3987
Sch em e 8. X-r a y Str u ctu r e of δ-Br om o Qu in u clid in ols a n ti-11o a n d syn -11o
Ta ble 2. Tor sion An gles (in d egr ees) of C9-Br om in a ted Qu in u clid in e Der iva tives
torsion angles
bromoketone 9f
anti-quinuclidin-5-ol, anti-11o
syn-quinuclidinol, syn-11o
N1-C2-C3-C4
N1-C6-C5-C4
N1-C7-C8-C4
Σ (twisting)
13
9
9
12
17
18
47
-2
-11
-18
-31
31
philic attack from the endo face. Clockwise torsion of the
azabicyclo[2.2.2]octanone core is also observed in parent
Cinchona alkaloid ketones which as we have shown
previously exhibit fair endo diastereoselectivities.13,27 In
fact, we have now observed that clockwise twist domi-
nates nearly all crystal structures of quincorine and
quincoridine derivatives.26,27 Introduction of the bridge-
head nitrogen softens and distorts an otherwise rigid
bicyclic ketone, which in turn appears to affect the
stereochemical outcome of nucleophilic additions.28 While
the endo-preference (up to 78:22) of nucleophilic attack
to QCI-based ketone 10 (Scheme 5) finds a parallel in
the work of Mehta,23 the endo-preference to QCD-based
ketone 9 is unprecedented (Schemes 5 and 7). Moreover,
clockwise twist in the QCD-series is more developed than
in the QCI-series (X-ray evidence26).
Assign m en t of a n ti- a n d syn -Con figu r a tion of
F u n ction a lized 5-Hyd r oxy Qu in u clid in es. Because
of signal overlap NOE-measurements on quinuclidin-5-
ol 11b were not informative, and assignment of anti- and
syn-diastereomers was not straightforward initially.
However, the derived mesylates anti-13 and syn-13 were
readily separated by column chromatography. The con-
figuration of either diastereomer was assigned by NOE
and COSY measurements (Scheme 7). In the case of anti-
13, H-5 shows characteristic NOEs with H3endo (a 4.8%)
and H6endo (b 4.8%), whereas H-5 in syn-13 shows NOEs
with H6exo (b 9.8%) and H8exo (d 2.5%). Moreover, dia-
stereomeric quinuclidinols anti-13 and syn-13 can be
easily distinguished by the H6endo and H6exo signals, since
the H6endo signal of anti-13 is shifted downfield (δ 3.51)
relative to the corresponding signal of the exo epimer (δ
3.16). In contrast, the H6exo signal of the endo diastere-
omer anti-13 (δ 2.78) is shifted to higher field compared
with H6exo in syn-13 (δ 3.09). These effects were previ-
ously observed in spectroscopic work on parent Cinchona
alkaloid derivatives.13
Although brominated quinuclidin-5-ols anti-11o and
syn-11o were obtained as a chromatographically insepa-
rable mixture, we were able to separate syn-11o and anti-
11o via fractional crystallization and fully characterized
both diastereomers by X-ray structure analysis.26 Thus,
the NMR work is corroborated further. Like its parent
ketone 9f, the azabicyclic core of major diastereomer anti-
11o is twisted clockwise (Scheme 8, Table 2), whereas
syn-11o is twisted anticlockwise. A change of twist-sense
necessitates two full eclipsing interactions in the C2-
C3 and the C7-C8 bridge en route from starting bromo
ketone 9f to the minor product syn-11o. We suggest that
unfavorable eclipsing in the bridges is engendered by
nucleophilic attack from the exo-face. Hence, endo attack
is favored (Scheme 9) with formation of naturally con-
figured anti-alcohols.
Chromatographically separable mesylated quinuclidin-
5-ols anti-13 and syn-13 afford 1,2,4-triazole derivatives,
such as 14, without epimerization, upon treatment with
sodium 1,2,4-triazolate in DMF (Scheme 10). These
reactions are considered to be SN2-like, proceeding with
clean inversion of configuration (anti-13 f 14). Parent
triazole- and tetrazole-substituted quinuclidines derived
from quinuclidin-3-one are potent and selective musca-
rinic ligands. In some cases, high diastereomeric excess
of quinuclidin-5-ols is not decisive, since the stereogenic
center at carbon C5 is lost. The reaction of methylfuranyl-
substituted quinuclidin-5-ol 11i (16% de) with formic acid
provided the first enantiomerically pure analogue of
antimuscarinic quinuclidin-5-ene F (Scheme 1) contain-
ing three stereogenic centers and a hydroxymethyl group.
Phenylacetylene-substituted quinuclidinols 11m ,n not
only exhibit considerable structural similarity to squalene
synthase inhibitor D, but in contrast to lead structure
D, they contain four stereocenters centers and are
obtained in high diastereomeric excess.
(27) Braje, W. M. Ph.D. Thesis, Hannover, 1999. Frackenpohl, J .
Ph.D. Thesis, Hannover, 2000.
(28) Gung, B. W. Chem. Rev. 1999, 99, 1377, in particular 1379.
Hahn, J . M.; le Noble, W. J . J . Am. Chem. Soc. 1992, 114, 1916.

3988 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
Sch em e 9. New m a n -P r ojection of δ-Br om o
Qu in u clid in ols a n ti-11o (Clock w ise Tw ist) a n d
syn -11o (Cou n ter clock w ise Tw ist)a
attack is preferentially directed toward the supposedly
more hindered endo π-face of the carbonyl group, giving
functionalized quinuclidinols with natural configuration
at carbon C5 in diastereomeric excess up to 97%. π-Face
selectivity, especially in the QCD series, is unprecedented
and depends on the size of the remote O-protecting group
(1,7-induction). The origin of π-facial selectivity is sug-
gested to be due to torsional strain (exo-attack leading
to syn-product, Scheme 9) rather than electronic.
Exp er im en ta l Section
13C NMR assignments for each signal were established by
DEPT measurements; multiplicities are indicated by CH3
(primary), CH2 (secondary), CH (tertiary) or C (quaternary).
THF was distilled over sodium and benzophenone before use.
Dichloromethane (DCM) was distilled over CaH2 before use.
N,N-Dimethylformamide was dried and distilled over BaO and
stored over molecular sieves (4 Å). Ethyl acetate (EA), CCl4,
CHCl3, DBU, and methyl tert-butyl ether (MTBE) were
distilled before use.
Short procedure for the synthesis of azabicyclic ketones 9d
and 10d . QCD, 1, or QCI, 2 (1 equiv), was added to concen-
trated hydrobromic acid (62%) at 0 °C. The reaction mixture
was stirred for 4 days at room temperature (rt). After
neutralization with aq KOH (pH 9), the solution was extracted
with CHCl3. The combined organic layer was dried (over
MgSO4) and the solvent removed. Purification by column
chromatography (EA/MeOH 4:1) afforded the alkyl bromides
3a and 4a . DBU (1.2 equiv) was added dropwise to the alkyl
bromide 3a or 4a (1 equiv) in DMF at 100 °C under argon.
The mixture was stirred for 4 h at 110 °C. Solvent and base
were removed (Kugelrohr apparatus) and the residue dissolved
in CHCl3. After extraction (saturated aqueous NaHCO3), the
combined organic layer was dried (over MgSO4), evaporated,
and purified by chromatography (EA/MeOH 4:1) to furnish the
desired trisubstituted alkenes 5a and 6a . Et3N (1.3 equiv) was
added to 5a or 6a (1 equiv) in abs. CH2Cl2 at rt. After the
solution was stirred under argon for 15 min, DMAP (0.1 equiv)
and TBDMSCl (1.1 equiv) were added at 0 °C, and the mixture
was stirred for 16 h at rt, followed by extraction with saturated
aqueous NaHCO3. The organic layer was dried (MgSO4),
evaporated and purified by chromatography (EA/MeOH 20:1)
to yield silyl ethers 5b and 6b, respectively. Silylated iso-QCD,
5b , or iso-QCI, 6b ,c, was added to a two-phase system of
K2CO3 (3 equiv) and K3[Fe(CN)6] (3 equiv) in tert-BuOH/H2O
(1:1). After 45 min elapsed, solid OsO4 (0.01 equiv) was added.
The reaction mixture was stirred for 5 h at rt, followed by
extraction (saturated aqueous NaHCO3, aq NaHSO3). The
organic layer was dried (MgSO4), evaporated, and purified by
chromatography (EA/MeOH 4:1) to yield diols 7a and 8a . A
saturated solution of NaIO4 (1.3 equiv) in H2O was added to
the silylated diol (1 equiv) in tert-butanol. The mixture was
stirred vigorously for 2 h at rt, treated with saturated aqueous
NaHCO3, and extracted with CHCl3. After the mixture was
dried (over MgSO4), the crude product was purified by column
chromatography (EA/MeOH 20:1) to afford the silylated C5-
ketones 9a and 10a . A 1.0 M solution of TBAF in abs THF
(1.3 equiv) was added to C5 ketone 9a or 10a (1 equiv) in abs
THF at 0 °C. The reaction mixture was stirred for 10 h at rt,
followed by addition of CHCl3 and extraction (saturated
aqueous NaHCO3, saturated aqueous NaCl). The combined
organic layer was dried (MgSO4), evaporated and purified by
chromatography (EA/MeOH 6:1) to yield the title compounds
9d and 10d .
a
Bond angles and bond lengths not drawn to scale. Reagents
and conditions: (i) 3 equiv LiBHBus3, THF, -90 °C f -78 °C, 4
h, 85%.
Sch em e 10. Syn th esis of P oten tia l Lea d
Str u ctu r esa
a
Reagents and conditions: (i) 3 equiv 5-methyl-2-furanyl-
lithium, THF, -90 °C f -78 °C, 4 h; (ii) 1,2,4-sodium triazolate,
DMF, 100 °C, 8 h, 74%; (iii) HCOOH (99%), 2 h, 96%.
Con clu sion
We have prepared new 1-azabicyclic ketones 9 and 10
derived from quinidine and quinine. Our ketones are
single-isomer 1,2-amino alcohols containing three ste-
reogenic centers each, including the N-chiral 1S-configu-
rated bridgehead. Because of their low molecular weight
and their compact bicyclic structure, both 9 and 10 are
attractive homochiral building blocks for asymmetric syn-
thesis, pharmacology and combinatorial chemistry.9,29-31
Substrate control of stereochemistry in reactions of the
simple QCI and QCD derivatives is a challenge greater
than substrate control with the sterically more demand-
ing parent Cinchona alkaloids. Nonetheless, nucleophilic
(1S,2R,4S,5R,10R/S)-2-H yd r oxym et h yl-5-(10-b r om o-
eth yl)-1-a za bicyclo[2.2.2]octa n e (3a ) a n d (1S,2S,4S,5R,-
(29) Hoffmann, H. M. R.; Schrake, O. Tetrahedron: Asymmetry
1998, 9, 1051.
(30) Schrake, O.; Braje, W.; Hoffmann, H. M. R.; Wartchow, R.
Tetrahedron: Asymmetry 1998, 9, 3717.
(31) Schrake, O.; Rahn, V. S.; Frackenpohl, J .; Braje, W. M.;
Hoffmann, H. M. R. Org. Lett. 1999, 1, 1607.

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3989
10/R/S)-2-Hydr oxym eth yl-5-(10-br om oeth yl)-1-azabicyclo-
[2.2.2]octa n e (4a ). QCD, 1, (10.40 g, 62.28 mmol) and QCI,
2, respectively, (11.50 g, 68.26 mmol) were carefully added
within 15 min to concentrated hydrobromic acid (62%) at 0
°C. The homogeneous reaction mixture was stirred for 4 days
at ambient temperature. After neutralization with aq KOH
(pH 9), the solution was diluted with H2O and extracted with
CHCl3. The combined organic layer was dried (MgSO4) and
the solvent was removed under reduced pressure. Purification
by column chromatography (EA-MeOH 4:1) afforded the alkyl
bromides 3a (86%, 13.23 g, 53.56 mmol) and 4a (93%, 15.68
g, 63.48 mmol) as slightly yellow waxy solids and diastereo-
meric mixtures (3a 2.2:1, 4a 1.9:1). Data for 3a . IR (CHCl3)
1 H, H-7), 2.23-1.87 (m, 3 H, H-4, H-8, H-3), 1.77/1.75 (d, 3
H, J 6.5 Hz, H-11), 1.66-1.55 (m, 1 H, H-8), 1.31-1.23 (m, 1
H, H-3). 13C NMR (100 MHz) δ 166.39 (C, C-12), 133.13 (C,
C-13), 131.61 (CH, Ar-H), 129.95 (CH, Ar-H), 129.55 (CH,
Ar-H), 128.36 (CH, Ar-H), 127.89 (CH, Ar-H), 64.09 (CH2,
C-9), 55.58 (CH2, C-6), 54.56 (CH, C-2), 52.10 (CH, C-10), 44.05
(CH, C-5), 40.11 (CH2, C-7), 26.33 (CH2, C-8), 25.81 (CH, C-4),
24.88 (CH3, C-11), 23.16 (CH2, C-3). MS m/z: 353 (M+, 1), 351
(M+, 0.4), 272 (6), 136 (5), 105 (100). FAB-MS m/z: 354 (56),
352 (64), 272 (100). HRMS calcd for C17H22NO279Br: 351.0834;
found 351.0819. Anal. Calcd for C17H22NO2Br: C 57.96, H 6.29,
N 3.97; found C 58.19, H 6.14, N 3.82.
Gen er a l P r oced u r e for th e Elim in a tion of 3a ,b a n d
4a ,b. DBU (1.2 equiv) was added dropwise to a solution of the
alkyl bromide 3a ,b or 4a ,b (1 equiv) in anhydrous DMF at
100 °C under argon, and the mixture was stirred for 4 h at
110 °C. Solvent and base were removed (Kugelrohr apparatus),
and the residue was dissolved in CHCl3. After extraction with
saturated aqueous NaHCO3, the combined organic layer was
dried (MgSO4), evaporated, and purified by chromatography
(EA/MeOH 4:1 for 3a and 4a and EA/MeOH 10:1 for 3b and
4b, respectively) to furnish the desired trisubstituted alkenes
5a , 5d , 6a , and 6d as inseparable E/ Z mixtures.
1
(ν): 3416, 2944, 1452, 1412, 1260, 1228, 1024 cm-1. H NMR
(400 MHz) (δ): 4.11 (m, 1 H, H-10), 4.05 (m, 1 H, OH), 3.51
(m, 1 H, H-9), 3.42 (dd, 1 H, J 11, 5 Hz, H-9), 2.97-2.75 (4 H,
H-7, H-6, H-2), 2.70/2.49 (ddd, 1 H, J 14.2, 7.7, 2.1 Hz, H-6),
1.92-1.81 (m, 2 H, H-5, H-4), 1.71/1.67 (d, 3 H, J 6.5 Hz, H-11),
1.68-1.40 (m, 3 H, H-8, H-3), 1.00-0.95 (m, 1 H, H-3). 13C
NMR (100 MHz) (δ): 62.01 (CH2, C-9), 57.24 (CH, C-2), 55.18
(CH, C-10), 48.98 (CH2, C-6), 48.54 (CH2, C-7), 45.34 (CH, C-5),
27.12 (CH2, C-8), 25.21 (CH, C-4), 25.12 (CH3, C-11), 23.03
(CH2, C-3). MS m/z: 249 (M+, 1), 247 (M+, 1), 168 (100). HRMS
calcd for C10H18NO81Br: 249.2583; found: 249.2584. Data for
4a . IR (CHCl3) (ν): 3444, 2948, 1452, 1412, 1260, 1236, 1032
(1S,2R,4S)-2-Hyd r oxym eth yl-(E/Z)-5-eth ylid en e-1-a za -
bicyclo[2.2.2]octa n e (5a ). 3a (14.21 g, 57.30 mmol) was
allowed to react according to the general procedure to afford
5a (76%, 7.27 g, 43.55 mmol). IR (CHCl3) (ν): 3000, 2940, 1452,
1
cm-1. H NMR (400 MHz) (δ): 4.15 (m, 1 H, H-10), 3.85 (s, 1
H, OH), 3.49-3.42 (m, 2 H, H-9), 3.24-3.16 (dd, 1 H, J
14.1, 9.4 Hz, H-2), 3.02-2.89 (m, 2 H, H-7), 2.72-2.70 (m, 1
H, H-6), 2.65-2.58 (m, 1 H, H-6), 1.96-1.93 (m, 2 H, H-5,
H-4), 1.75/1.72 (d, 3 H, J 6.5 Hz, H-11), 1.67-1.58 (m, 1 H,
H-8), 1.56-1.41 (m, 2 H, H-8, H-3), 0.83-0.75 (m, 1 H, H-3).
13C NMR (100 MHz) δ 62.89 (CH2, C-9), 57.61 (CH2, C-6),
57.38 (CH, C-2), 56.98 (CH, C-10), 45.59 (CH, C-5), 39.93 (CH2,
C-7), 27.84 (CH2, C-8), 25.25 (CH, C-4), 25.02 (CH3, C-11),
23.72 (CH2, C-3). MS m/z: 249 (M+, 2), 247 (M+, 1), 168 (100),
138 (5). HRMS calcd for C10H18NO81Br: 249.2583; found:
249.2569.
1
1412, 1236, 1088, 1016 cm-1. H NMR (400 MHz) (δ): 5.19-
5.11 (m, 1 H, H-10), 3.71 (bs, 1 H, OH), 3.58-3.54 (d, 1 H, J
17.6 Hz, H-6), 3.50-3.38 (m, 2 H, H-9), 3.27-3.23 (d, 1 H, J
17.2 Hz, H-6), 3.08-2.98 (m, 1 H, H-7), 2.95-2.86 (m, 2 H,
H-7, H-2), 2.29-2.27 (m, 1 H, H-4), 1.82-1.75 (m, 1 H, H-3),
1.71-1.62 (m, 1 H, H-8), 1.58-1.55 (m, 1 H, H-8), 1.50-1.47
(d, 3 H, J 6.9 Hz, H-11), 1.05-1.00 (m, 1 H, H-3). 13C NMR
(100 MHz) δ 141.14/140.04 (C, C-5), 113.74/113.26 (CH, C-10),
62.84 (CH2, C-9), 57.61 (CH, C-2), 49.82/49.26 (CH2, C-6), 46.78
(CH2, C-7), 32.76 (CH, C-4), 30.62/29.38 (CH2, C-8), 27.49/26.65
(CH2, C-3), 12.58/12.27 (CH3, C-11). MS m/z 167 (M+, 100):
150 (76), 136 (96). HRMS calcd for C10H17NO: 167.1310; found
167.1310.
(1S,2R,4S,5R,10R/S)-2-(Ben zoyloxym et h yl)-5-(10-b r o-
m oeth yl)-1-a za bicyclo[2.2.2]octa n e (3b) a n d (1S,2S,4S,-
5R,10/R/S)-2-(Ben zoyloxym et h yl)-5-(10-b r om oet h yl)-1-
a za bicyclo[2.2.2]-octa n e (4b). Benzoyl chloride (6.5 mL, 56
mmol, 1.3 equiv) was added dropwise to a stirred solution of
3a (10.63 g, 43.03 mmol) or 4a (10.63 g, 43.03 mmol) and
triethylamine (11.9 mL, 86.1 mmol, 2.0 equiv) in abs CH2Cl2
(90 mL) at 0 °C. After the mixture was stirred under argon
for 14 h at rt, the mixture was diluted with CH2Cl2 and
extracted with saturated aqueous NaHCO3. The combined
organic layer was dried (MgSO4), evaporated, and chromato-
graphed (EA/MeOH 10:1) to yield 3b (86%, 12.99 g, 37.00
mmol) or 4b (88%, 13.29 g, 37.87 mmol), respectively.
Data for 3b. IR (CHCl3) (ν): 3008, 2948, 1716, 1600, 1452,
1272, 1224, 1116 cm-1. 1H NMR (400 MHz) (δ): 8.10-8.04 (m,
2 H, Ar-H), 7.91-7.88 (m, 3 H, Ar-H), 4.58-4.49 (dd, 1 H, J
12.2, 8.4 Hz, H-9), 4.39-4.34 (dd, 1 H, J 12.2, 4.7 Hz, H-9),
4.13-4.08 (dd, 1 H, J 11, 6.5 Hz, H-10), 3.49-3.46 (m, 1 H,
H-2), 3.42-3.36 (m, 1 H, H-6), 3.22-3.04 (m, 2 H, H-7), 2.81-
2.76 (ddd, 1 H, J 14.3, 8.2, 2.5 Hz, H-6), 2.45 (m, 1 H, H-5),
2.02-1.93 (m, 1 H, H-4), 1.83-1.70 (m, 3 H, H-8, H-3), 1.74
(d, 3 H, J 6.5 Hz, H-11), 1.49-1.42 (m, 1 H, H-3). 13C NMR
(100 MHz) δ 166.63 (C, C-12), 133.05 (C, C-13), 130.94 (CH,
Ar-H), 129.04 (CH, Ar-H), 128.80 (CH, Ar-H), 127.60 (CH,
Ar-H), 127.15 (CH, Ar-H), 64.63 (CH2, C-9), 55.72 (CH, C-2),
52.50 (CH, C-10), 48.52 (CH2, C-6), 46.92 (CH2, C-7), 45.33 (CH,
C-5), 27.21 (CH, C-4), 26.66 (CH2, C-8), 25.16 (CH3, C-11),
24.27 (CH2, C-3). MS m/z: 353 (M+, 1), 351 (M+, 1), 272 (21),
136 (20), 105 (100). FAB-MS m/z: 354 (100), 352 (98), 272 (54).
HRMS calcd for C17H22NO279Br: 351.0834; found 351.0837.
Data for 4b. IR (CHCl3) (ν): 2952, 1720, 1620, 1600, 1452,
1272, 1116, 1024 cm-1. 1H NMR (400 MHz) (δ): 8.12-8.04 (m,
2 H, Ar-H), 7.95-7.87 (m, 1 H, Ar-H), 7.50-7.42 (m, 2 H,
Ar-H), 4.56-4.51 (dd, 1 H, J 12.3, 8.5 Hz, H-9), 4.47-4.42
(dd, 1 H, J 12.3, 5.0 Hz, H-9), 4.16-4.12 (dd, 1 H, J 10.7, 6.6
Hz, H-10), 3.73-3.62 (m, 1 H, H-7), 3.58-3.52 (dd, 1 H, J 14.1,
9.9 Hz, H-6), 3.39-3.26 (m, 1 H, H-2), 3.18-3.07 (m, 1 H, H-5),
3.06-3.00 (ddd, 1 H, J 14.4, 8.3, 2.6 Hz, H-6), 2.57-2.47 (m,
(1S,2S,4S)-2-Hyd r oxym eth yl-(E/Z)-5-eth ylid en e-1-a za -
bicyclo[2.2.2]octa n e (6a ). 4a (17.00 g, 68.83 mmol) was
allowed to react according to the general procedure to afford
6a (77%, 8.85 g, 53.0 mmol). IR (CHCl3) (ν): 3000, 2940, 1436,
1
1412, 1228, 1072, 1028 cm-1. H NMR (400 MHz) (δ): 5.24-
5.17 (m, 1 H, H-10), 3.68 (bs, 1 H, OH), 3.59-3.32 (m, 4 H,
H-6, H-9, H-6), 3.08-2.98 (m, 1 H, H-7), 2.95-2.86 (m, 1 H,
H-7), 2.72-2.61 (m, 1 H, H-2), 2.29-2.26 (m, 1 H, H-4), 1.76-
1.68 (m, 1 H, H-3), 1.71-1.62 (m, 2 H, H-8), 1.51-1.48 (m, 3
H, H-11), 1.05-0.99 (m, 1 H, H-3). 13C NMR (100 MHz) (δ):
141.38/140.80 (C, C-5), 114.80/114.28 (CH, C-10), 62.84 (CH2,
C-9), 58.58 (CH, C-2), 57.63/55.96 (CH2, C-6), 41.78/40.77 (CH2,
C-7), 32.73 (CH, C-4), 31.02/30.11 (CH2, C-8), 28.05/26.81 (CH2,
C-3), 12.69/12.37 (CH3, C-11). MS m/z: 167 (M+, 91), 150 (72),
136 (100). HRMS calcd for C10H17NO: 167.1310; found 167.1295.
(1S,2R,4S)-2-(Ben zoyloxym eth yl)-(E/Z)-5-eth ylid en e-1-
a za bicyclo[2.2.2]octa n e (5d ). 3b (3.32 g, 9.46 mmol) was
allowed to react according to the general procedure to afford
5d (87%, 2.23 g, 8.23 mmol; E/ Z ratio: 3.1:1). IR (CHCl3) (ν):
3000, 2940, 1716, 1580, 1452, 1276, 1116, 1024 cm-1. 1H NMR
(400 MHz) (δ): 8.07-8.04 (m, 2 H, Ar-H), 7.56-7.51 (m, 1 H,
Ar-H), 7.45-7.39 (m, 2 H, Ar-H), 5.23-5.19 (m, 1 H, H-10),
4.43-4.37 (dd, 1 H, J 11.5, 8.0 Hz, H-9), 4.26-4.21 (dd, 1 H,
J 11.7, 5.5 Hz, H-9), 3.73-3.69 (m, 1 H, H-6), 3.42-3.30 (m, 2
H, H-6, H-7), 3.05-2.79 (m, 2 H, H-7, H-2), 2.37-2.35 (m, 1
H, H-4), 1.96-1.89 (m, 1 H, H-3), 1.75-1.64 (m, 2 H, H-8),
1.60/1.53 (m, 3 H, H-11), 1.40-1.35 (m, 1 H, H-3). 13C NMR
(100 MHz) (δ): 166.73 (C, C-12), 141.04/139.91 (C, C-5), 132.94/
131.18 (CH, Ar-H), 130.15 (C, C-13), 129.73 (CH, Ar-H),
128.29 (CH, Ar-H), 113.92/113.46 (CH, C-10), 65.98 (CH2,
C-9), 54.62 (CH, C-2), 49.98/49.61 (CH2, C-6), 48.01 (CH2, C-7),
32.85 (CH, C-4), 31.17/30.12 (CH2, C-8), 27.13/26.24 (CH2, C-3),
12.61/12.34 (CH3, C-11). MS m/z: 271 (M+, 25), 256 (5), 166
(25), 150 (76), 136 (67), 105 (100). HRMS calcd for
C
17H21N1O2: 271.1361; found 271.1401.

3990 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
(1S,2S,4S)-2-(Ben zoyloxym eth yl)-(E/Z)-5-eth ylid en e-1-
a za bicyclo[2.2.2]octa n e (6d ). 4b (7.40 g, 21.1 mmol) was
allowed to react according to the general procedure to afford
6d (85%, 4.87 g, 18.0 mmol). IR (CHCl3) (ν): 3008, 2944, 1716,
to react according to the general procedure to afford 5c (94%,
10.26 g, 25.33 mmol). IR (CHCl3) (ν): 3000, 2932, 1600, 1572,
1
1428, 1260, 1112, 1024 cm-1. H NMR (400 MHz) (δ): 7.72-
7.68 (m, 4 H, Ar-H), 7.46-7.37 (m, 6 H, Ar-H), 5.25-5.18/
5.14-5.06 (m, 1 H, H-10), 3.85-3.74 (m, 2 H, H-9), 3.71 (bs, 1
H, OH), 3.37-3.32 (d, 1 H, J 17.4 Hz, H-6), 3.09-2.95 (m, 2
H, H-7, H-6), 2.94-2.80 (m, 2 H, H-7, H-2), 2.40-2.36 (m, 1
H, H-4), 1.89-1.83 (m, 1 H, H-3), 1.79-1.63 (m, 3 H, H-8, H-3),
1.62-1.58/1.49-1.46 (m, 3 H, H-11), 1.09-1.05 (s, 9 H,
SiC(CH3)3). 13C NMR (100 MHz) (δ): 141.00/140.36 (C, C-5),
135.70 (CH, Ar-H), 133.49 (C, Ph-Si), 129.60 (CH, Ar-H),
127.67 (CH, Ar-H), 113.51/113.06 (CH, C-10), 66.28/65.97
(CH2, C-9), 57.37/57.20 (CH, C-2), 50.00/50.18 (CH2, C-6),
49.34/48.72 (CH2, C-7), 33.08 (CH, C-4), 30.80/29.97 (CH2, C-8),
27.70/26.29 (CH2, C-3), 26.91 (CH3, SiC(CH3)3), 19.26 (C,
SiC(CH3)3), 12.59/12.29 (CH3, C-11). MS m/z: 405 (M+, 8), 348
(100), 266 (7), 199 (29), 136 (7). HRMS calcd for C26H35NOSi:
405.2488; found 405.2489.
(1S,2S,4S)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-(E/Z)-
5-et h ylid en e-1-a za bicyclo[2.2.2]-oct a n e (6c). 6a (5.00 g,
29.9 mmol) and TBDPSCl (8.57 mL, 32.9 mmol) were allowed
to react according to the general procedure to afford 6c (90%,
10.91 g, 26.95 mmol). IR (CHCl3) (ν): 3000, 2932, 1600, 1472,
1428, 1260, 1112 cm-1. 1H NMR (400 MHz) (δ): 7.74-7.68 (m,
4 H, Ar-H), 7.47-7.34 (m, 6 H, Ar-H), 5.29-5.19 (m, 1 H,
H-10), 3.84-3.77 (m, 2 H, H-9), 3.53-3.47 (d, 1 H, J 18.3 Hz,
H-6), 3.43-3.37 (d, 1 H, J 18.3 Hz, H-6), 3.18-3.03 (m, 1 H,
H-7), 2.99-2.91 (m, 1 H, H-7), 2.74-2.62 (m, 1 H, H-2), 2.37-
2.33 (m, 1 H, H-4), 1.92-1.79 (m, 2 H, H-3, H-8), 1.69-1.57
(m, 2 H, H-8, H-3), 1.53-1.49 (d, 3 H, J 6.7 Hz, H-11), 1.10/
1.06 (s, 9 H, SiC(CH3)3). 13C NMR (100 MHz) (δ): 141.59 (C,
C-5), 135.90 (CH, Ar-H), 134.92 (CH, Ar-H), 133.47 (C, Ph-
Si), 129.64 (CH, Ar-H), 127.56 (CH, Ar-H), 114.66/114.45
(CH, C-10), 66.39 (CH2, C-9), 58.17/57.34 (CH, C-2), 55.59 (CH2,
C-6), 43.12/42.37 (CH2, C-7), 33.01 (CH, C-4), 31.31 (CH2, C-8),
27.69/27.35 (CH2, C-3), 26.67 (CH3, SiC(CH3)3), 19.27 (C,
SiC(CH3)3), 12.71/12.39 (CH3, C-11). MS m/z: 405 (M+, 3), 349
(5), 199 (100). HRMS calcd for C26H35NOSi: 405.2488; found
405.2476.
Gen er a l P r oced u r e for th e Bish yd r oxyla tion of Sily-
la ted iso-qu in cor id in es 5b-c a n d silyla ted iso-qu in co-
r in es 6b,c. Silylated iso-QCD 5b,c or silylated iso-QCI 6b,c,
respectively, was added to a vigorously stirred two-phase
system of K2CO3 (3 equiv) and K3[Fe(CN)6] (3 equiv) in tert-
butyl alcohol/H2O (1:1, 5 mL per mmol alkaloid). After 45 min
solid osmium(VIII)oxide (0.01 equiv) was added in small
portions, and the reaction mixture was stirred for 5 h under
argon at rt, followed by extraction with saturated aqueous
NaHCO3 and aq NaHSO3 (10%). The combined organic layer
was dried (MgSO4), evaporated, and purified by chromatog-
raphy (EA/MeOH 4:1) to yield the desired C10-C3 diols 7a ,b
and 8a ,b as inseparable mixtures of four possible diastereo-
mers. In most cases, only the one or two most intensive NMR
signals are given.
(1S,2R,4S,5R/S,10R/S)-2-(ter t-Bu t yld im et h ylsilyloxy-
m et h yl)-5-(5,10-d ih yd r oxyet h yl)-1-a za b icyclo[2.2.2]oc-
ta n e (7a ). 5b (3.00 g, 10.7 mmol) was allowed to react ac-
cording to the general procedure to afford 7a (73%, 2.45 g, 7.79
mmol). IR (CHCl3) (ν): 3436, 2952, 2932, 1460, 1256, 1120,
1000 cm-1. 1H NMR (400 MHz) (δ): 3.98-3.94 (dd, 1 H, J 12.4,
6.2 Hz, H-9), 3.89-3.84 (dd, 1 H, J 10.7, 4.4 Hz, H-9), 3.77-
3.74 (m, 1 H, H-10), 3.64-3.62 (m, 1 H, H-2), 2.97-2.93/2.88-
2.85 (d, 1 H, J 14.3 Hz, H-6), 2.90-2.69 (m, 2 H, H-7), 2.48-
2.43/2.44-2.41 (d, J 14.6 Hz, H-6), 2.18-2.12 (m, 1 H, H-4),
2.01-1.93/1.83-1.81 (m, 1 H, H-3), 1.62-1.33 (m, 3 H, H-8,
H-3), 1.16-1.13/1.09-1.08 (m/d, 3 H, J 6.3 Hz, H-11), 0.90/
0.89 (s, 9 H, SiC(CH3)3), 0.11-0.10/0.07-0.04 (m, 6 H, SiCH3).
13C NMR (100 MHz) (δ): 73.70 (C, C-5), 69.64/67.54 (CH, C-10),
66.74/65.83 (CH2, C-9), 56.32/55.72 (CH, C-2), 55.53/54.29
(CH2, C-6), 49.82/49.13 (CH2, C-7), 29.68/28.35 (CH, C-4), 25.36
(CH3, SiC(CH3)3), 25.27/24.75 (CH2, C-8), 21.79/20.55 (CH2,
C-3), 17.85 (C, SiC(CH3)3), 15.66/15.57 (CH3, C-11), -6.03 (CH3,
SiCH3). MS m/z: 315 (M+, 10), 300 (11), 258 (89), 170 (100);
FAB-MS 316 (M++1, 100). HRMS calcd for C16H33NO3Si:
315.2229; found 315.2228.
1600, 1448, 1276, 1116, 1024 cm-1 1H NMR (400 MHz) (δ):
.
8.08-8.04 (M, 2 H, Ar-H), 7.55-7.50 (m, 1 H, Ar-H), 7.45-
7.37 (m, 2 H, Ar-H), 5.28-5.21 (m, 1 H, H-10), 4.48-4.33/
4.47-4.42 (dd, 1 H, J 11.5, 8.2 Hz, H-9), 4.32-4.27/4.33-4.28
(dd, 1 H, J 11.5, 5.8 Hz, H-9), 3.56-3.53 (m, 1 H, H-7), 3.32-
3.23 (m, 1 H, H-6), 3.21-3.11 (m, 1 H, H-6), 2.87-2.78 (m, 2
H, H-7, H-2), 2.37-2.33 (m, 1 H, H-4), 1.94-1.85 (m, 1 H, H-3),
1.69-1.62 (m, 2 H, H-8), 1.61/1.53 (m, 3 H, H-11), 1.41-1.32
(m, 1 H, H-3). 13C NMR (100 MHz) (δ): 166.74 (C, C-12),
140.39/139.34 (C, C-5), 132.96 (CH, Ar-H), 130.13 (C, C-13),
129.51 (CH, Ar-H), 128.32 (CH, Ar-H), 114.94/ 114.49 (CH,
C-10), 65.85 (CH2, C-9), 57.79/55.51 (CH2, C-6), 55.50/55.21
(CH, C-2), 41.93 (CH2, C-7), 32.86 (CH, C-4), 31.63/30.75 (CH2,
C-8), 27.97/26.75 (CH2, C-3), 12.73/12.42 (CH3, C-11). MS m/z:
271 (M+, 37), 256 (5), 166 (20), 150 (62), 136 (45), 105 (100).
HRMS calcd for C17H21N1O2: 271.1572; found 271.1571.
Gen er a l P r oced u r e for t h e Silyla t ion of 5a a n d 6a .
Triethylamine (1.3 equiv) was added to a solution of 5a or 6a
(1 equiv) in abs CH2Cl2 at rt. After the mixture was stirred
under argon for 15 min, DMAP (0.1 equiv) and the correspond-
ing silyl chloride (1.1 equiv) were added at 0 °C, and the
homogeneous mixture was stirred for 16 h at rt, followed by
extraction with saturated aqueous NaHCO3. The combined
organic layer was dried (MgSO4), evaporated, and purified by
chromatography (EA/MeOH 20:1) to yield silyl ethers 5b,c and
6b,c, respectively, as inseparable E/ Z mixtures.
(1S,2R,4S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-(E/Z)-
5-eth ylid en e-1-a za bicyclo[2.2.2]-octa n e (5b). 5a (6.58 g,
39.4 mmol) and TBDMSCl (6.50 g, 43.3 mmol) were allowed
to react according to the general procedure to afford 5b (69%,
7.64 g, 27.2 mmol, E/ Z ratio 2.65:1). IR (CHCl3) (ν): 2952,
2928, 1464, 1256, 1104, 1028 cm-1 1H NMR (400 MHz) (δ):
.
5.18-5.12/5.11-5.06 (m, 1 H, H-10), 3.73-3.69/3.72-3.68 (dd,
1 H, J 10.1, 5.8 Hz, H-9), 3.60-3.52 (m, 2 H, H-9, OH), 3.29-
3.24/3.21-3.16 (d, 1 H, J 17.5 Hz, H-6), 2.95-2.74 (m, 4 H,
H-6, H-7, H-2), 2.33-2.28 (m, 1 H, H-4), 1.82-1.76 (m, 1 H,
H-3), 1.69-1.60 (m, 2 H, H-8), 1.59-1.56/1.49-1.46 (m, 3 H,
H-11), 1.46-1.39 (m, 1 H, H-3), 0.92-0.88 (s, 9 H, SiC(CH3)3),
0.08-0.04 (m, 6 H, SiCH3). 13C NMR (100 MHz) (δ): 142.35/
141.21 (C, C-5), 112.81/112.39 (CH, C-10), 65.91 (CH2, C-9),
57.35 (CH, C-2), 51.26/50.46 (CH2, C-6), 50.16/48.85 (CH2, C-7),
33.26 (CH, C-4), 31.48/30.49 (CH2, C-8), 27.54/26.66 (CH2, C-3),
25.98 (CH3, SiC(CH3)3), 25.81 (CH3, SiC(CH3)3), 25.78 (CH3,
SiC(CH3)3), 18.39/18.08 (C, SiC(CH3)3), 12.56/12.23 (CH3, C-11),
-3.42 (CH3, SiCH3), -5.33 (CH3, SiCH3). MS m/z: 281 (M+,
23), 266 (17), 224 (100), 149 (16), 136 (31). HRMS calcd for
C
16H31NOSi: 281.2174; found 281.2169.
(1S,2S,4S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-(E/Z)-
5-eth ylid en e-1-a za bicyclo[2.2.2]-octa n e (6b). 6a (8.80 g,
52.7 mmol) and TBDMSCl (8.69 g, 58.0 mmol) were allowed
to react according to the general procedure to afford 6b (73%,
10.81 g, 38.47 mmol, E/ Z ratio 5:1). IR (CHCl3) (ν): 2952, 2928,
1
1472, 1256, 1108, 1004 cm-1. H NMR (400 MHz) (δ): 5.34-
5.25 (m, 1 H, H-10), 4.01-3.96 (dd, 1 H, J 11.0, 5.0 Hz, H-9),
3.76-3.72 (dd, 1 H, J 11.0, 5.2 Hz, H-9), 3.67-3.62 (d, 1 H, J
18.7 Hz, H-6), 3.62-3.57 (m, 1 H, H-7), 3.42-3.33 (m, 1 H,
H-6), 3.12-3.03 (m, 1 H, H-2), 2.92-2.83 (m, 1 H, H-7), 2.45-
2.41 (m, 1 H, H-4), 1.81-1.60 (m, 4 H, H-3, H-8, H-3), 1.53-
1.51 (d, 3 H, J 6.9 Hz, H-11), 0.91-0.86 (s, 9 H, SiC(CH3)3),
0.09-0.05 (m, 6 H, SiCH3). 13C NMR (100 MHz) (δ): 144.23/
143.16 (C, C-5), 116.41/115.96 (CH, C-10), 64.18 (CH2, C-9),
58.64/58.33 (CH, C-2), 55.72 (CH2, C-6), 43.39 (CH2, C-7), 32.53
(CH, C-4), 29.53/28.73 (CH2, C-8), 26.66/25.13 (CH2, C-3), 25.93
(CH3, SiC(CH3)3), 25.74 (CH3, SiC(CH3)3), 25.59 (CH3, SiC-
(CH3)3), 18.29/18.04 (C, SiC(CH3)3), 12.76/12.55 (CH3, C-11),
-3.48 (CH3, SiCH3), -5.33 (CH3, SiCH3). MS m/z: 282 (M++1,
18), 281 (M+, 6), 266 (14), 224 (100), 149 (12), 136 (23). HRMS
calcd for C16H31NOSi: 281.2174; found 281.2175.
(1S,2R,4S)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-(E/Z)-
5-et h ylid en e-1-a za bicyclo[2.2.2]-oct a n e (5c). 5a (4.50 g,
27.0 mmol) and TBDPSCl (7.71 mL, 29.6 mmol) were allowed

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3991
(1S,2S,4S,5R/S,10R/S)-2-(ter t-Bu t yld im et h ylsilyloxy-
m e t h yl)-5-(5,10-d ih yd r oxye t h yl)-1-a za b icyclo[2.2.2]-
octa n e (8a ). 6b (6.00 g, 21.4 mmol) was allowed to react
according to the general procedure to afford 8a (79%, 5.31 g,
16.9 mmol). IR (CHCl3) (ν): 3420, 2956, 2928, 1472, 1256,
1120, 1092, 1052 cm-1. 1H NMR (400 MHz) (δ): 3.92-3.83 (m,
1 H, H-9), 3.73-3.61 (m, 2 H, H-9, H-10), 3.11-2.96 (m, 2 H,
H-7, H-2), 2.75-2.71 (d, 1 H, J 14.3 Hz, H-6), 2.57-2.45 (d, J
14.6 Hz, H-6), 2.49-2.43 (m, 1 H, H-7), 2.15-2.11 (m, 1 H,
H-4), 1.99-1.95 (m, 1 H, H-3), 1.84-1.72 (m, 1 H, H-8), 1.55-
1.40 (m, 1 H, H-8), 1.38-1.27 (m, 1 H, H-3), 1.19-1.14 (m, 3
H, H-11), 0.89 (s, 9 H, SiC(CH3)3), 0.07-0.04 (m, 6 H, SiCH3).
13C NMR (100 MHz) (δ): 73.39/73.14 (C, C-5), 69.38/68.52 (CH,
C-10), 65.90/65.59 (CH2, C-9), 61.56/61.41 (CH2, C-6), 57.18/
56.38 (CH, C-2), 41.97/41.84 (CH2, C-7), 29.54/29.16 (CH, C-4),
26.58/25.28 (CH2, C-8), 25.98 (CH3, SiC(CH3)3), 23.09/21.63
(CH2, C-3), 18.38 (C, SiC(CH3)3), 16.32/16.12 (CH3, C-11), -5.33
(CH3, SiCH3). MS m/z: 315 (M+, 10), 298 (16), 58 (100), 170
(73); FAB-MS 316 (M++1, 100), 298 (17). HRMS calcd for
C16H33NO3Si: 315.2229; found 315.2230.
2928, 1728, 1468, 1404, 1256, 1124, 1096, 1028 cm-1. 1H NMR
(400 MHz) (δ): 3.71-3.66 (dd, 1 H, J 19.5, 5.1 Hz, H-6), 3.69-
3.68 (d, 1 H, J 5.3 Hz, H-9), 3.68-3.67 (d, 1 H, J 5.3 Hz, H-9),
3.10-3.04 (d, 1 H, J 19.5 Hz, H-6), 3.07-3.02 (m, 1 H, H-7),
3.01-2.95 (m, 1 H, H-2), 2.91-2.83 (ddd, 1 H, J 14.7, 10.0,
7.1 Hz, H-7), 2.47-2.45 (m, 1 H, H-4), 2.09-2.00 (m, 1 H, H-3),
1.99-1.91 (m, 2 H, H-8), 1.90-1.84 (m, 1 H, H-3), 0.87 (s, 9
H, SiC(CH3)3), 0.04 (s, 3 H, SiCH3), 0.03 (s, 3 H, SiCH3). 13C
NMR (100 MHz) (δ): 219.76 (C, C-5), 65.52 (CH2, C-9), 58.83
(CH2, C-6), 56.28 (CH, C-2), 49.77 (CH2, C-7), 40.72 (CH, C-4),
27.90 (CH2, C-3), 25.87 (CH3, SiC(CH3)3), 25.04 (CH2, C-8),
18.26 (C, SiC(CH3)3), -5.51 (CH3, SiCH3). MS m/z: 269 (M+,
5), 254 (13), 241 (33), 212 (69), 184 (100), 156 (10); FAB-MS
270 (M++1, 100), 184 (25). HRMS calcd for C14H27NO2Si:
269.1811; found 269.1812.
(1S ,2S ,4S )-2-(t er t -Bu t yld im e t h ylsilyloxym e t h yl)-1-
a za bicyclo[2.2.2]octa n -5-on e (10a ). 8a (1.00 g, 3.17 mmol)
was allowed to react according to the general procedure to
afford 10a (87%, 0.740 g, 2.76 mmol). IR (CHCl3) (ν): 2956,
2928, 1728, 1472, 1408, 1256, 1116, 1048, 1004 cm-1. 1H NMR
(400 MHz) (δ): 3.79-3.76 (dd, 1 H, J 10.4, 5.9 Hz, H-9), 3.76-
3.72 (dd, 1 H, J 10.4, 5.9 Hz, H-9), 3.36-3.31 (d, 1 H, J 18.4
Hz, H-6), 3.29-3.24 (d, 1 H, J 18.4 Hz, H-6), 3.32-3.25 (m, 1
H, H-7), 2.99-2.90 (m, 1 H, H-2), 2.82-2.73 (m, 1 H, H-7),
2.46-2.42 (m, 1 H, H-4), 2.09-2.02 (m, 1 H, H-3), 1.96-1.87
(m, 2 H, H-8), 1.84-1.78 (ddd, 1 H, J 13.5, 7.6, 2.2 Hz, H-3),
0.90 (s, 9 H, SiC(CH3)3), 0.08 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3). 13C NMR (100 MHz) (δ): 219.89 (C, C-5), 65.36 (CH2,
C-9), 64.79 (CH2, C-6), 57.64 (CH, C-2), 41.79 (CH2, C-7), 40.45
(CH, C-4), 28.67 (CH2, C-3), 25.93 (CH3, SiC(CH3)3), 25.39
(CH2, C-8), 18.33 (C, SiC(CH3)3), -5.40 (CH3, SiCH3). MS m/z:
269 (M+, 5), 254 (13), 241 (38), 212 (60), 184 (100), 156 (11);
(1S,2R,4S,5R/S,10R/S)-2-(ter t-Bu t yld ip h en ylsilyloxy-
m e t h yl)-5-(5,10-d ih yd r oxye t h yl)-1-a za b icyclo[2.2.2]-
octa n e (7b). 5c (10.00 g, 24.69 mmol) was allowed to react
according to the general procedure to afford 7b (78%, 8.45 g,
19.3 mmol). IR (CHCl3) (ν): 3568, 2934, 1589, 1471, 1251,
1
1113, 997 cm-1. H NMR (400 MHz) (δ): 7.70-7.63 (m, 4 H,
Ar-H), 7.43-7.34 (m, 6 H, Ar-H), 3.84-3.70 (m, 2 H, H-9,
H-10), 3.60-3.55 (m, 1 H, H-9), 2.90-2.75 (m, 3 H, H-2, H-7),
2.65-2.61 (d, 1 H, J 14.7 Hz, H-6), 2.43-2.39 (d, 1 H, J 14.7
Hz, H-6), 2.11-2.05 (m, 1 H, H-4), 1.96-1.88 (m, 1 H, H-3),
1.69-1.59 (m, 1 H, H-8), 1.57-1.43 (m, 1 H, H-8), 1.39-1.29
(m, 1 H, H-3), 1.13-1.11/0.98-0.97 (d, 3 H, J 6.2 Hz, H-11),
1.07/1.05 (s, 9 H, SiC(CH3)3). 13C NMR (100 MHz) (δ): 135.71
(CH, Ar-H), 133.49 (C, Ar-Si), 129.67 (CH, Ar-H), 127.66
(CH, Ar-H), 73.27/72.68 (C, C-5), 69.53/67.56 (CH, C-10),
66.87/66.23 (CH2, C-9), 56.56/55.68 (CH, C-2), 55.00/54.13
(CH2, C-6), 49.61/49.05 (CH2, C-7), 29.67/28.90 (CH, C-4), 26.92
(CH3, SiC(CH3)3), 26.02/24.22 (CH2, C-8), 22.54/21.21 (CH2,
C-3), 19.24 (C, SiC(CH3)3), 16.26/16.19 (CH3, C-11). MS m/z:
439 (M+, 4), 421 (3), 382 (100), 364 (8), 170 (28). HRMS calcd
for C26H37NO3Si: 439.2542; found 439.2535.
FAB-MS 270 (M++1, 100), 184 (24). HRMS calcd for C14H27
NO2Si: 269.1811; found 269.1806.
-
(1S ,2R ,4S )-2-(t er t -Bu t yld ip h e n ylsilyloxym e t h yl)-1-
a za bicyclo[2.2.2]octa n -5-on e (9b). 7b (3.45 g, 7.86 mmol)
was allowed to react according to the general procedure to
afford 9b (93%, 2.87 g, 7.31 mmol). IR (CHCl3) (ν): 3052, 2956,
1
1728, 1471, 1427, 1265, 1113, 1026 cm-1. H NMR (400 MHz)
(δ): 7.69-7.65 (m, 4 H, Ar-H), 7.47-7.37 (m, 6 H, Ar-H),
3.79-3.75 (dd, 1 H, J 10.5, 5.5 Hz, H-9), 3.75-3.70 (dd, 1 H,
J 10.5, 5.5 Hz, H-9), 3.69-3.63 (dd, 1 H, J 19.3, 1.0 Hz, H-6),
3.11-3.06 (d, 1 H, J 18.8 Hz, H-6), 3.09-3.02 (m, 2 H, H-7),
2.92-2.84 (m, 1 H, H-2), 2.52-2.48 (m, 1 H, H-4), 2.13-2.07
(m, 1 H, H-3), 2.06-1.92 (m, 3 H, H-8, H-3), 1.07 (s, 9 H,
SiC(CH3)3). 13C NMR (100 MHz) (δ): 219.74 (C, C-5), 135.64
(CH, Ar-H), 133.27 (C, Ar-Si), 129.75 (CH, Ar-H), 127.75
(CH, Ar-H), 66.18 (CH2, C-9), 58.79 (CH2, C-6), 56.28 (CH,
C-2), 49.77 (CH2, C-7), 40.71 (CH, C-4), 28.02 (CH2, C-3), 26.84
(CH3, SiC(CH3)3), 25.17 (CH2, C-8), 19.22 (C, SiC(CH3)3). MS
m/z: 378 (M+-Me, 1), 365 (15), 336 (100), 308 (92), 199 (16),
183 (12); FAB-MS 394 (M++1, 65), 336 (100). HRMS calcd for
(1S,2S,4S,5R/S,10R/S)-2-(ter t-Bu t yld ip h en ylsilyloxy-
m e t h yl)-5-(5,10-d ih yd r oxye t h yl)-1-a za b icyclo[2.2.2]-
octa n e (8b). 6c (10.00 g, 24.69 mmol) was allowed to react
according to the general procedure to afford 8b (84%, 9.11 g,
20.7 mmol). IR (CHCl3) (ν): 3568, 2932, 1589, 1472, 1427,
1
1265, 1112, 998 cm-1. H NMR (400 MHz) (δ): 7.69-7.64 (m,
4 H, Ar-H), 7.42-7.34 (m, 6 H, Ar-H), 3.85-3.66 (m, 3 H,
H-9, H-10), 3.13-3.05 (m, 1 H, H-7), 3.02-2.93 (m, 1 H, H-2),
2.73-2.66 (m, 1 H, H-6), 2.52-2.48 (d, 1 H, J 14.3 Hz, H-6),
2.46-2.38 (m, 1 H, H-7), 2.12-2.07 (m, 1 H, H-4), 1.93-1.78
(m, 1 H, H-3), 1.54-1.35 (m, 2 H, H-8), 1.29-1.22 (m, 1 H,
H-3), 1.16-1.10 (m, 3 H, H-11), 1.05 (s, 9 H, SiC(CH3)3). 13C
NMR (100 MHz) (δ): 135.65 (CH, Ar-H), 133.75 (C, Ar-Si),
129.67 (CH, Ar-H), 127.68 (CH, Ar-H), 73.39/73.10 (C, C-5),
69.34/68.36 (CH, C-10), 66.69/66.48 (CH2, C-9), 61.56/61.42
(CH2, C-6), 57.02/56.28 (CH, C-2), 42.05/41.99 (CH2, C-7),
29.59/29.15 (CH, C-4), 26.90 (CH3, SiC(CH3)3), 26.84/25.52
(CH2, C-8), 23.13/21.59 (CH2, C-3), 19.27 (C, SiC(CH3)3), 16.29/
16.09 (CH3, C-11). MS m/z: 439 (M+, 2), 408 (8), 383 (36), 351
(100), 199 (14). HRMS calcd for C26H37NO3Si: 439.2542; found
439.2539.
C
24H31NO2Si-Me: 378.8189; found 378.8176.
(1S ,2S ,4S )-2-(t er t -Bu t yld ip h e n ylsilyloxym e t h yl)-1-
a za bicyclo[2.2.2]octa n -5-on e (10b). 8b (4.00 g, 9.11 mmol)
was allowed to react according to the general procedure to
afford 10b (90%, 3.22 g, 8.20 mmol). IR (CHCl3) (ν): 3072,
1
2958, 1729, 1589, 1472, 1428, 1230, 1113, 1046, 999 cm-1. H
NMR (400 MHz) (δ): 7.72-7.68 (m, 4 H, Ar-H), 7.48-7.39
(m, 6 H, Ar-H), 3.85-3.83 (dd, 1 H, J 10.5, 6.0 Hz, H-9), 3.84-
3.82 (dd, 1 H, J 10.5, 5.8 Hz, H-9), 3.40-3.35 (d, 1 H, J 18.6
Hz, H-6), 3.33-3.28 (d, 1 H, J 18.6 Hz, H-6), 3.32-3.23 (m, 1
H, H-7), 3.09-3.01 (m, 1 H, H-2), 2.87-2.78 (m, 1 H, H-7),
2.51-2.47 (m, 1 H, H-4), 2.15-2.07 (m, 1 H, H-3), 1.93-1.87
(m, 3 H, H-8, H-3), 1.09 (s, 9 H, SiC(CH3)3). 13C NMR (100
MHz) (δ): 218.57 (C, C-5), 135.62 (CH, Ar-H), 133.26 (C, Ar-
Si), 129.81 (CH, Ar-H), 127.77 (CH, Ar-H), 65.70 (CH2, C-9),
64.38 (CH2, C-6), 57.63 (CH, C-2), 41.70 (CH2, C-7), 40.31 (CH,
C-4), 28.57 (CH2, C-3), 26.88 (CH3, SiC(CH3)3), 25.07 (CH2,
C-8), 19.24 (C, SiC(CH3)3). MS m/z: 378 (M+-Me, 2), 365 (19),
336 (100), 308 (93), 183 (14); FAB-MS 394 (M++1, 100), 365
(20), 336 (41). HRMS calcd for C24H31NO2Si-Me: 378.8189;
found 378.8180.
General procedure for the diol cleavage of silylated diols
7a ,b and 8a ,b. A saturated solution of NaIO4 (1.3 equiv) in
H2O was added dropwise to a solution of the silyl-protected
diol (1 equiv) in tert-butanol. The mixture was stirred vigor-
ously for 2 h at rt under argon, treated with NaHCO3 and
extracted with CHCl3. After it was dried (over MgSO4), the
organic layer was concentrated, and the crude product was
purified by column chromatography (EA/MeOH 20:1) to yield
the desired C5-ketones 9a ,b and 10a ,b, respectively.
(1S ,2R ,4S )-2-(t er t -Bu t yld im e t h ylsilyloxym e t h yl)-1-
a za bicyclo[2.2.2]octa n -5-on e (9a ). 7a (630 mg, 2.00 mmol)
was allowed to react according to the general procedure to
afford 9a (91%, 489 mg, 1.82 mmol). IR (CHCl3) (ν): 2952,
(1S,2R,4S)-2-(Hydr oxym eth yl)-1-azabicyclo[2.2.2]octan -
5-on e (9d ). 9a (137 mg, 0.51 mmol) was allowed to react

3992 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
according to the general procedure to afford 9d (97%, 77 mg,
0.49 mmol). IR (CHCl3) (ν): 3360, 2964, 1728, 1456, 1404,
127.81 (CH, Ar-H), 127.02 (CH, Ar-H), 86.71 (C, Ph3CO),
65.38 (CH2, C-9), 58.15 (CH2, C-6), 55.05 (CH, C-2), 49.62 (CH2,
C-7), 40.58 (CH, C-4), 28.72 (CH2, C-3), 25.27 (CH2, C-8). MS
m/z: 397 (M+, 1), 369 (33), 243 (100), 187 (9), 136 (9). HRMS
calcd for C27H27NO2: 397.2042; found 397.2044.
1232, 1148, 1052, 1020 cm-1 1H NMR (400 MHz, CDCl3
. +
CD3OD) (δ): 3.50-3.38 (m, 2 H, H-9), 3.37-3.27 (m, 2 H, H-2,
OH), 3.15-2.98 (m, 3 H, H-6, H-7), 2.95-2.87 (m, 1 H, H-7),
2.44-2.40 (m, 1 H, H-4), 2.11-1.95 (m, 2 H, H-3, H-8), 1.66-
1.59 (m, 1 H, H-8), 1.44-1.34 (m, 1 H, H-3). 13C NMR (100
MHz, CDCl3 + CD3OD) (δ): 216.41 (C, C-5), 62.60 (CH2, C-9),
56.65 (CH, C-2), 56.46 (CH2, C-6), 49.20 (CH2, C-7), 40.21 (CH,
C-4), 27.56 (CH2, C-3), 25.31 (CH2, C-8). MS m/z: 155 (M+, 21),
127 (100), 110 (43). HRMS calcd for C8H13NO2: 155.0946;
found 155.0944. Anal. Calcd for C8H13NO: C 61.92, H 8.44, N
9.03; found C 62.08, H 8.59, N 9.25.
(1S,2R,4S)-2-(Br om om eth yl)-1-a za bicyclo[2.2.2]octa n -
5-on e (9f). Methanesulfonyl chloride (0.39 mL, 5.0 mmol, 1.3
equiv) was added to a solution of unprotected ketone 9d (600
mg, 3.88 mmol, 1.0 equiv) and Et3N (1.08 mL, 7.74 mmol, 2.0
equiv) in abs. CH2Cl2 (10 mL) at 0 °C. After having been stirred
for 10 h at rt, the reaction mixture was diluted with CH2Cl2
and extracted with saturated aqueous NaHCO3. The organic
layer was dried, the solvent evaporated, and the crude product
(83%, 748 mg, 3.21 mmol) dissolved in abs dioxan (5 mL).
Powdered lithium bromide (838 mg, 9.64 mmol, 3.0 equiv) was
added, and the mixture was refluxed for 24 h at 110 °C. After
addition of saturated aqueous NaHCO3, the aqueous layer was
extracted with CH2Cl2, and the combined organic layers were
dried (MgSO4) and evaporated. Purification by chromatogra-
phy (EA/MeOH 20:1) furnished the desired brominated ketone
9f (81%, 565 mg, 2.60 mmol) as a colorless crystalline solid.
(1S,2S,4S)-2-(Hydr oxym eth yl)-1-azabicyclo[2.2.2]octan -
5-on e (10d ). 10b (1.80 g, 4.58 mmol) was allowed to react
according to the general procedure to afford 10d (96%, 682
mg, 4.39 mmol). IR (CHCl3) (ν): 3380, 2964, 1732, 1456, 1408,
1264, 1232, 1080, 1032 cm-1 1H NMR (400 MHz, CDCl3
. +
CD3OD) (δ): 3.64-3.56 (m, 2 H, H-9), 3.39-3.32 (d, 1 H, J
17.8 Hz, H-6), 3.25-3.19 (d, 1 H, J 18.1 Hz, H-6), 3.18-3.12
(m, 1 H, H-7), 3.07-2.99 (m, 1 H, H-2), 2.79-2.71 (m, 1 H,
H-7), 2.42-2.39 (m, 1 H, H-4), 2.09-2.01 (m, 1 H, H-3), 1.90-
1.85 (m, 1 H, H-8), 1.68-1.61 (m, 1 H, H-8), 1.47-1.38 (m, 1
H, H-3). 13C NMR (100 MHz, CDCl3 + CD3OD) (δ): 218.60
(C, C-5), 64.17 (CH2, C-9), 62.48 (CH2, C-6), 57.72 (CH, C-2),
39.89 (CH, C-4), 39.64 (CH2, C-7), 28.53 (CH2, C-3), 25.21 (CH2,
C-8). MS m/z: 155 (M+, 17), 127 (100), 110 (42). HRMS calcd
for C8H13NO2: 155.0946; found 155.0947. Anal. Calcd for
C8H13NO: C 61.92, H 8.44, N 9.03; found C 62.16, H 8.53, N
9.31.
IR (CHCl3) (ν): 2963, 1732, 1473, 1457, 1230, 1083, 1032 cm-1
.
1H NMR (400 MHz) (δ): 3.57-3.52 (dd, 1 H, J 10.4, 8.2 Hz,
H-9), 3.49-3.45 (dd, 1 H, J 10.4, 7.2 Hz, H-9), 3.45-3.40 (d, 1
H, J 19.7 Hz, H-6), 3.34-3.28 (dd, 1 H, J 19.7, 2.3 Hz, H-6),
3.23-3.09 (m, 2 H, H-2, H-7), 2.89-2.81 (m, 1 H, H-7), 2.49-
2.45 (m, 1 H, H-4), 2.33-2.25 (m, 1 H, H-3), 1.98-1.92 (m, 2
H, H-8), 1.68-1.61 (ddd, 1 H, J 13.7, 7.5, 2.2 Hz, H-3). 13C
NMR (100 MHz) (δ): 218.42 (C, C-5), 64.69 (CH2, C-6), 57.55
(CH, C-2), 40.17 (CH, C-4), 39.76 (CH2, C-7), 34.15 (CH2, C-9),
31.81 (CH2, C-3), 25.37 (CH2, C-8). MS m/z: 219 (M+, 3), 217
(1S,2R,4S)-2-(Tr iisopr opylsilyloxym eth yl)-1-azabicyclo-
[2.2.2]octa n -5-on e (9c). Triethylamine (0.240 mL, 1.74 mmol,
1.5 equiv) was added to a solution of 9d (180 mg, 1.16 mmol,
1 equiv) in abs CH2Cl2 (5 mL) at rt. After the solution was
stirred under argon for 15 min, DMAP (14 mg, 0.12 mmol, 0.1
equiv) and triisopropylsilyl chloride (0.32 mL, 1.5 mmol, 1.3
equiv) were added at 0 °C, and the homogeneous mixture was
stirred for 16 h at rt, followed by extraction with saturated
aqueous NaHCO3. The combined organic layer was dried (over
MgSO4), evaporated, and purified by chromatography (EA/
MeOH 20:1) to yield silylated ketone 9c (91%, 329 mg, 1.06
mmol). IR (CHCl3) (ν): 2946, 1728, 1464, 1404, 1233, 1128,
(M+, 3), 191 (10), 189 (10), 110 (100). HRMS calcd for C8H12
NOBr: 217.0102; found 217.0103.
-
Gen er a l P r oced u r e for th e Red u ction of C5-k eton es
9a -e a n d 10a ,b with l-Selectr id e. A 1.0 M solution of
L-Selectride in THF (1.5 equiv) was added dropwise within 5
min to a solution of the C5-ketone (1 equiv) in abs THF at
-90 °C. After it was stirred for 2 h at -78 °C, the reaction
mixture was warmed to 0 °C within 4 h and then quenched
with saturated aqueous NaHCO3. The aqueous layer was
extracted with CHCl3, and the organic layer dried (MgSO4)
and evaporated. The resulting crude product was purified by
column chromatography (EA/MeOH 6:1) to yield the corre-
sponding quinuclidin-5-ols 11a -e and 12a ,b.
1
1068, 1029 cm-1. H NMR (400 MHz) (δ): 3.82-3.80 (d, 1 H,
J 5.2 Hz, H-9), 3.76-3.74 (d, 1 H, J 5.2 Hz, H-9), 3.76-3.70
(d, 1 H, J 19.7, H-6), 3.10-3.05 (d, 1 H, J 19.4 Hz, H-6), 3.09-
3.04 (m, 1 H, H-7), 3.04-2.98 (m, 1 H, H-2), 2.91-2.83 (m, 1
H, H-7), 2.50-2.45 (m, 1 H, H-4), 2.09-1.91 (m, 4 H, H-3, H-8,
H-3), 1.14-0.94 (m, 21 H, Si(CH(CH3)2)3). 13C NMR (100 MHz)
(δ): 219.85 (C, C-5), 66.10 (CH2, C-9), 59.09 (CH2, C-6), 56.46
(CH, C-2), 49.90 (CH2, C-7), 40.77 (CH, C-4), 27.96 (CH2, C-3),
25.16 (CH2, C-8), 17.99 (CH3, Si(CH(CH3)2)3), 11.88 (CH, Si-
(CH(CH3)2)3). MS m/z: 311 (M+, 17), 284 (19), 268 (71), 240
(100), 138 (6). HRMS calcd for C17H33NO2Si: 311.2280; found
311.2282.
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-1-
a za bicyclo[2.2.2]octa n -5-ol (11a ). 9a (158 mg, 0.590 mmol)
was allowed to react according to the general procedure to
afford anti-11a (87%, 138 mg, 0.510 mmol) with 62% de. IR
(CHCl3) (ν): 2956, 2932, 1460, 1432, 1256, 1128, 1016 cm-1
.
1H NMR (400 MHz) (δ): 4.19-4.16 (dd, 1 H, J 11.8, 3.2 Hz,
H-9), 4.15-4.09 (m, 1 H, H-5), 3.85-3.77 (m, 1 H, H-6), 3.72-
3.66 (dd, 1 H, J 11.8, 4.9 Hz, H-9), 3.40-3.18 (m, 3 H, H-7,
H-2), 3.14-3.09 (d, 1 H, J 13.7 Hz, H-6), 2.42-2.29 (m, 2 H,
H-4, H-3), 1.95-1.88 (m, 1 H, H-8), 1.78-1.62 (m, 2 H, H-8,
H-3), 0.86 (s, 9 H, SiC(CH3)3), 0.08 (s, 3 H, SiCH3), 0.06 (s, 3
H, SiCH3). 13C NMR (100 MHz) (δ): 63.91 (CH, C-5), 62.02
(CH2, C-9), 57.35 (CH, C-2), 53.09 (CH2, C-6), 49.30 (CH2, C-7),
27.79 (CH, C-4), 25.89 (CH3, SiC(CH3)3), 23.65 (CH2, C-8), 18.19
(C, SiC(CH3)3), 16.53 (CH2, C-3), -5.43 (CH3, SiCH3), -5.55
(CH3, SiCH3). MS m/z: 271 (M+, 6), 256 (9), 214 (100), 126 (14).
HRMS calcd for C14H29NO2Si: 271.1967; found 271.1965.
(1S,2R,4S,5S)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-1-
a za bicyclo[2.2.2]octa n -5-ol (11b). 9b (680 mg, 1.73 mmol)
was allowed to react according to the general procedure to
afford anti-11b (82%, 560 mg, 1.42 mmol) with 68% de. The
diastereomeric excess given refers to the excess of 5S-configu-
rated diastereomer. IR (CHCl3) (ν): 3053, 2933, 1589, 1471,
(1S,2R,4S)-2-(Tr iph en ylm eth yloxym eth yl)-1-azabicyclo-
[2.2.2]octa n -5-on e (9e). Triethylamine (0.21 mL, 1.5 mmol,
1.5 equiv) was added to a solution of 9d (155 mg, 1.00 mmol,
1 equiv) in abs CH2Cl2 (4 mL) at rt. After the solution was
stirred under argon for 15 min, DMAP (12 mg, 0.10 mmol, 0.1
equiv) and triphenylmethyl chloride (363 mg, 1.30 mmol, 1.3
equiv) were added at 0 °C, and the homogeneous mixture was
stirred for 16 h at rt, followed by extraction with saturated
aqueous NaHCO3. The combined organic layer was dried
(MgSO4), evaporated and purified by chromatography (EA/
MeOH 20:1) to afford protected ketone 9e (88%, 349 mg, 0.880
mmol). IR (CHCl3) (ν): 3062, 2999, 2950, 1729, 1597, 1449,
1
1230, 1080, 1033, 1001 cm-1. H NMR (400 MHz) (δ): 7.45-
1
7.42 (m, 6 H, Ar-H), 7.30-7.26 (m, 6 H, Ar-H), 7.24-7.19
(m, 3 H, Ar-H), 3.45-3.40 (d, 1 H, J 19.1, H-6), 3.28-3.23
(dd, 1 H, J 9.3, 6.8 Hz, H-9), 3.22-3.14 (m, 1 H, H-2), 3.12-
3.03 (m, 1 H, H-7), 3.09-3.04 (d, 1 H, J 18.8 Hz, H-6), 3.02-
2.97 (dd, 1 H, J 9.3, 5.5 Hz, H-9), 2.93-2.85 (m, 1 H, H-7),
2.47-2.42 (m, 1 H, H-4), 2.15-2.08 (m, 1 H, H-3), 2.01-1.92
(m, 2 H, H-8), 1.68-1.61 (m, 1 H, H-3). 13C NMR (100 MHz)
(δ): 219.67 (C, C-5), 143.81 (C, Ar-C), 128.65 (CH, Ar-H),
1428, 1239, 1113, 1019 cm-1. H NMR (400 MHz) (δ): 7.71-
7.62 (m, 4 H, Ar-H), 7.43-7.35 (m, 6 H, Ar-H), 4.33-4.19
(br. s, 1 H, OH), 3.95-3.83 (m, 2 H, H-9, H-5), 3.70-3.66 (dd,
1 H, J 11.2, 4.9 Hz, H-9), 3.63-3.57 (m, 1 H, H-6), 3.17-2.98
(m, 3 H, H-7, H-2), 2.85-2.80 (d, 1 H, J 14.3 Hz, H-6), 2.15-
2.06 (m, 2 H, H-4, H-3), 1.87-1.78 (m, 1 H, H-8), 1.58-1.46
(m, 2 H, H-8, H-3), 1.07/1.05 (s, 9H, SiC(CH3)3). 13C NMR (100
MHz) (δ): 135.68/134.89 (CH, Ar-H), 132.73 (C, Ar-Si),

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3993
129.95 (CH, Ar-H), 127.87/127.58 (CH, Ar-H), 64.84/65.63
(CH, C-5), 64.79/64.35 (CH2, C-9), 57.68/56.35 (CH, C-2), 53.24/
52.22 (CH2, C-6), 49.17/48.68 (CH2, C-7), 28.34 (CH, C-4), 26.87
(CH3, SiC(CH3)3), 25.86 (CH2, C-8), 19.20 (C, SiC(CH3)3), 17.23
(CH2, C-3). MS m/z: 395 (M+, 2), 338 (40), 199 (100), 167 (11),
149 (23). HRMS calcd for C24H33NO2Si: 395.2280; found
395.2282.
(C, SiC(CH3)3), -5.37 (CH3, SiCH3). MS m/z: 271 (M+, 7), 256
(8), 214 (100). HRMS calcd for C14H29NO2Si: 271.1967; found
271.1969.
(1S,2S,4S,5S)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-1-
a za bicyclo[2.2.2]octa n -5-ol (12b). 10b (770 mg, 1.96 mmol)
was allowed to react according to the general procedure to
afford anti-12b (80%, 619 mg, 1.57 mmol) with 55% de. IR
(CHCl3) (ν): 3317, 3073, 2961, 1589, 1471, 1428, 1240, 1113,
(1S,2R,4S,5S)-2-(Tr iisop r op ylsilyloxym et h yl)-1-a za -
bicyclo[2.2.2]octa n -5-ol (11c). 9c (103 mg, 0.330 mmol) was
allowed to react according to the general procedure to afford
anti-11c (79%, 82 mg, 0.26 mmol) with 71% de. IR (CHCl3)
1
1013 cm-1. H NMR (400 MHz) (δ): 7.68-7.62 (m, 4 H, Ar-
H), 7.44-7.35 (m, 6 H, Ar-H), 4.27-4.18 (m, 2 H, H-9, H-5),
3.73-3.64 (m, 2 H, H-9, H-7), 3.61-3.52 (m, 2 H, H-6, H-2),
3.32-3.10 (m, 2 H, H-6, H-7), 2.28-2.17 (m, 2 H, H-4, H-3),
1.88-1.65 (m, 3 H, H-8, H-3), 1.07 (s, 9 H, SiC(CH3)3). 13C NMR
(100 MHz) (δ): 135.65 (CH, Ar-H), 132.08/131.93 (C, Ar-Si),
130.24/130.14 (CH, Ar-H), 128.06 (CH, Ar-H), 63.54/63.33
(CH, C-5), 62.87 (CH2, C-9), 59.21/58.60 (CH2, C-6), 58.21/57.62
(CH, C-2), 42.98/42.24 (CH2, C-7), 27.69/27.24 (CH, C-4), 26.89
(CH3, SiC(CH3)3), 23.26/20.92 (CH2, C-8), 19.21/17.19 (CH2,
C-3), 19.18 (C, SiC(CH3)3). MS m/z: 395 (M+, 2), 364 (3), 338
(100), 199 (17). HRMS calcd for C24H33NO2Si: 395.2280; found
395.2281.
(ν): 2944, 1463, 1230, 1114, 1065, 1034 cm-1 1H NMR (400
.
MHz) (δ): 3.84-3.79 (m, 1 H, H-5), 3.78-3.74/3.72-3.68 (dd,
1 H, J 9.9, 5.1 Hz, H-9), 3.67-3.63/3.61-3.57 (dd, 1 H, J 9.9,
6.8 Hz, H-9), 3.38-3.32 (ddd, 1 H, J 14.6, 8.1, 1.5 Hz, H-6),
2.99-2.78 (m, 3 H, H-7, H-2), 2.51-2.45 (d, 1 H, J 14.6 Hz,
H-6), 1.95-1.87 (m, 2 H, H-4, H-3), 1.84-1.77 (m, 1 H, H-8),
1.43-1.34 (m, 2 H, H-8, H-3), 1.09-1.02 (m, 21 H, Si-
(CH(CH3)2)3). 13C NMR (100 MHz) (δ): 68.16 (CH, C-5), 66.34/
66.10 (CH2, C-9), 56.12/56.10 (CH, C-2), 53.98/53.86 (CH2, C-6),
49.96 (CH2, C-7), 29.35 (CH, C-4), 28.15 (CH2, C-8), 18.33 (CH2,
C-3), 18.05 (CH3, Si(CH(CH3)2)3), 11.96 (CH, Si(CH(CH3)2)3).
MS m/z: 313 (M+, 21), 295 (6), 271 (100), 139 (9). HRMS calcd
for C17H35NO2Si: 313.2437; found 313.2438.
General procedure for the reaction of C5-ketones 9a -e and
10a with organolithium or Grignard reagents. A 1.0 M solution
of the Grignard reagent (3 equiv) or the organolithium reagent
(3 equiv) in abs. THF was added dropwise within 5 min to a
solution of the C5-ketone (1 equiv) in abs THF at -90 °C. After
stirring for 2 h at -78 °C the reaction mixture was warmed
to 0 °C within 2 h and stirred for 1 h at 0 °C. The reaction
mixture was extracted (saturated aqueous NaHCO3 and
CHCl3). The combined organic layer was dried (MgSO4),
filtered and the solvent was removed in vacuo. The resulting
crude product was purified by column chromatography (EA/
MeOH 10:1) to yield the corresponding quinuclidin-5-ols 11f-n
and 12c-f.
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(14-h yd r oxy-p en t-10-yn yl)-1-a za bicyclo[2.2.2]octa n -5-ol
(11f). 9a (100 mg, 0.37 mmol) was allowed to react with bis-
lithiated pent-4-yn-1ol (0.10 mL, 1.1 mmol) according to the
general procedure to afford anti-11f (69%, 91 mg, 0.26 mmol)
with 65% de. IR (CHCl3) (ν): 3304, 2956, 2932, 1468, 1256,
1120, 1020 cm-1. 1H NMR (400 MHz) (δ): 3.94-3.90 (dd, 1 H,
J 10.5, 3.8 Hz, H-9), 3.79-3.75 (dd, 1 H, J 10.6, 5.1 Hz, H-9),
3.77-3.68 (m, 2 H, H-14, H-14), 3.33-3.29/3.15-3.01 (m, 1
H, H-6), 2.89-2.79 (m, 2 H, H-7, H-2), 2.76-2.70 (m, 1 H, H-7),
2.64-2.60 (d, 1 H, J 14.7 Hz, H-6), 2.35-2.31 (m, 1 H, H-4),
2.09-2.04 (m, 1 H, H-3), 1.87-1.84 (m, 1 H, H-8), 1.80-1.61
(m, 2 H, H-8, H-3), 1.59-1.43 (m, 2 H, H-12, H-12), 1.39-1.29
(m, 2 H, H-13, H-13), 0.94-0.89 (m, 9 H, SiC(CH3)3), 0.13-
0.10/0.09-0.06 (m, 6 H, SiCH3). 13C NMR (100 MHz) (δ): 83.21
(C, C-10), 70.58 (C, C-5), 67.97 (C, C-11), 66.68/65.54 (CH2,
C-9), 59.73/58.89 (CH2, C-14), 56.28/56.01 (CH, C-2), 49.41/
48.62 (CH2, C-6), 39.91 (CH2, C-7), 32.65 (CH, C-4), 26.05/25.99
(CH3, SiC(CH3)3), 25.04 (CH2, C-8), 23.29 (CH2, C-12), 23.02
(CH2, C-3), 18.54/18.43 (C, SiC(CH3)3), 14.13 (CH2, C-13), -5.37
(CH3, SiCH3), -5.42 (CH3, SiCH3). MS m/z: 327 (M+-C2H2,
4), 312 (3), 270 (28), 182 (100); FAB-MS 353 (M+, 18), 327 (M+-
C2H2, 100). HRMS calcd for C19H35NO3Si: 353.8404; found
353.8411.
(1S,2S,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(14-h yd r oxy-p en t-10-yn yl)-1-a za bicyclo[2.2.2]octa n -5-ol
(12c). 10a (100 mg, 0.37 mmol) was allowed to react with bis-
lithiated pent-4-yn-1ol (0.10 mL, 1.1 mmol) according to the
general procedure to afford anti-12c (66%, 87 mg, 0.25 mmol)
with 33% de. IR (CHCl3) (ν): 3304, 2956, 2928, 1468, 1256,
1116, 1056, 1032 cm-1. 1H NMR (400 MHz) (δ): 3.78-3.58 (m,
4 H, H-9, H-14, H-14), 3.10-2.94 (m, 2 H, H-6, H-7), 2.89-
2.72 (m, 3 H, H-7, H-2, H-6), 2.56-2.48 (m, 1 H, H-4), 2.34-
2.25/2.11-2.02 (m, 1 H, H-3), 1.85-1.72 (m, 1 H, H-8), 1.64-
1.46 (m, 2 H, H-8, H-3), 1.40-1.17 (m, 4 H, H-12, H-12, H-13,
H-13), 0.91-0.88 (m, 9 H, SiC(CH3)3), 0.08-0.05 (m, 6 H,
SiCH3). 13C NMR (100 MHz) (δ): 83.92 (C, C-10), 71.63/71.45
(C, C-5), 67.95 (C, C-11), 66.16/66.12 (CH2, C-9), 65.81/65.64
(CH2, C-14), 56.59 (CH, C-2), 42.09/41.71 (CH2, C-6), 40.64/
39.93 (CH2, C-7), 32.28/32.19 (CH, C-4), 27.12 (CH2, C-12),
25.98 (CH3, SiC(CH3)3), 25.13/23.74 (CH2, C-8), 23.24/21.49
(1S,2R,4S,5S)-2-(Tr ip h en ylm et h yloxym et h yl)-1-a za -
bicyclo[2.2.2]octa n -5-ol (11d ). 9e (110 mg, 0.28 mmol) was
allowed to react according to the general procedure to afford
anti-11d (91%, 101 mg, 0.250 mmol) with 95% de. IR (CHCl3)
1
(ν): 3062, 2932, 1599, 1449, 1230, 1153, 1089, 1034 cm-1. H
NMR (400 MHz, CDCl3, CD3OD) (δ): 7.45-7.42 (m, 6 H, Ar-
H), 7.32-7.28 (m, 6 H, Ar-H), 7.25-7.20 (m, 3 H, Ar-H),
3.83-3.79 (m, 1 H, H-5), 3.65-3.44 (bm, 1 H, OH), 3.41-3.39
(m, 1 H, H-9), 3.34-3.25 (m, 1 H, H-6), 3.24-3.08 (m, 3 H,
H-9, H-2, H-7), 3.05-2.96 (m, 1 H, H-7), 2.82-2.78 (d, 1 H, J
14.3 Hz, H-6), 2.11-1.99 (m, 2 H, H-4, H-3), 1.89-1.81 (m, 1
H, H-8), 1.52-1.43 (m, 1 H, H-3), 1.29-1.18 (m, 1 H, H-8). 13
C
NMR (100 MHz, CDCl3, CD3OD) (δ): 143.47 (C, Ar-C), 128.70
(CH, Ar-H), 127.96 (CH, Ar-H), 127.23 (CH, Ar-H), 87.46
(C, Ph3CO), 65.59 (CH, C-5), 63.96 (CH2, C-9), 55.35 (CH, C-2),
52.59 (CH2, C-6), 49.24 (CH2, C-7), 28.09 (CH, C-4), 26.78 (CH2,
C-8), 17.24 (CH2, C-3). MS m/z: 399 (M+, 4), 338 (9), 271 (5),
243 (100), 165 (31), 156 (91). HRMS calcd for C27H29NO2:
399.2198; found 399.2197.
(1S,2R,4S,5R/S)-2-(Hyd r oxym eth yl)-1-a za bicyclo[2.2.2]-
octa n -5-ol (11e). 9d (100 mg, 0.65 mmol) was allowed to react
according to the general procedure to afford 11e (85%, 86 mg,
0.55 mmol) with 2% de. IR (CHCl3) (ν): 3358, 2932, 1460, 1408,
1232, 1148, 1040, 1018 cm-1. 1H NMR (400 MHz, CDCl3, CD3-
OD) (δ): 4.15-3.98 (m, 2 H, OH), 3.86-3.82 (m, 1 H, H-5),
3.64-3.43 (m, 2 H, H-9), 3.39-3.26 (m, 2 H, H-2, H-7), 3.21-
3.09 (m, 1 H, H-6), 3.01-2.88 (m, 2 H, H-6, H-7), 2.19-2.07
(m, 2 H, H-4, H-3), 1.82-1.68 (m, 1 H, H-8), 1.58-1.44 (m, 1
H, H-8), 1.29-1.24 (m, 1 H, H-3). 13C NMR (100 MHz, CDCl3,
CD3OD) (δ): 65.41 (CH, C-5), 62.87 (CH2, C-9), 53.82 (CH, C-2),
52.10 (CH2, C-6), 49.78 (CH2, C-7), 27.83 (CH, C-4), 26.05 (CH2,
C-8), 17.59 (CH2, C-3). MS m/z: 157 (M+, 8), 129 (100), 110
(16). HRMS calcd for C8H15NO2: 157.1104; found 157.1102.
Anal. Calcd for C8H15NO2: C 61.12, H 9.62, N 8.91; found C
60.73, H 9.86, N 8.72.
(1S,2S,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-1-
a za bicyclo[2.2.2]octa n -5-ol (12a ). 10a (143 mg, 0.530 mmol)
was allowed to react according to the general procedure to
afford anti-12a (84%, 121 mg, 0.450 mmol) with 48% de. IR
(CHCl3) (ν): 2952, 2928, 1472, 1256, 1116, 1032 cm-1. 1H NMR
(400 MHz) (δ): 4.10-3.98 (bs, 1 H, OH), 3.85-3.82 (m, 1 H,
H-5), 3.69-3.62 (m, 2 H, H-9), 3.23-3.19/3.19-3.10 (dd, 1 H,
J 14.2, 8.0 Hz, H-6), 3.08-2.97 (m, 2 H, H-7, H-2), 2.74-2.69/
2.63-2.58 (m, 1 H, H-6), 2.52-2.45 (m, 1 H, H-7), 2.03-1.95/
1.84-1.81 (m, 1 H, H-3), 1.93-1.88 (m, 1 H, H-4), 1.63-1.54
(m, 1 H, H-8), 1.39-1.28 (m, 1 H, H-8), 1.24-1.17 (m, 1 H,
H-3), 0.89-0.86 (m, 9 H, SiC(CH3)3), 0.06-0.04 (m, 6 H,
SiCH3). 13C NMR (100 MHz) (δ): 67.04/66.99 (CH, C-5), 65.44
(CH2, C-9), 60.55/59.86 (CH2, C-6), 56.84/56.64 (CH, C-2),
42.47/41.40 (CH2, C-7), 29.69/28.86 (CH, C-4), 25.96 (CH3, SiC-
(CH3)3), 27.75/24.26 (CH2, C-8), 22.31/18.85 (CH2, C-3), 18.35

3994 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
(CH2, C-3), 18.39 (C, SiC(CH3)3), 14.10 (CH2, C-13), -5.34 (CH3,
SiCH3), -5.36 (CH3, SiCH3). MS m/z: 327 (M+-C2H2, 7), 312
(7), 182 (100); FAB-MS 353 (M+, 20), 327 (M+-C2H2, 100).
Anal. Calcd for C19H35NO3Si: C 64.49, H 9.97, N 3.96; found
C 64.03, H 9.88, N 4.18.
SiCH3), -5.42 (CH3, SiCH3). MS m/z: 351 (M+, 4), 335 (M+-
O, 4), 294 (8), 276 (3), 206 (100). HRMS calcd for C19H33NO2-
Si: 335.2281; found 335.2249. Anal. Calcd for C19H33NO3Si:
C 64.97, H 9.47, N 3.99; found C 65.28, H 9.60, N 3.83.
(1S,2R,4S,5S)-2-(Hydr oxym eth yl)-5-(13-m eth ylfu r an yl)-
1-a za bicyclo[2.2.2]octa n -5-ol (11i). 9b (200 mg, 0.51 mmol)
was allowed to react with 2-methylfuranyllithium (0.76 mmol,
1.5 equiv) according to the general procedure to afford anti-
11i (65%, 78 mg, 0.33 mmol) with 16% de. IR (CHCl3) (ν):
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
p h en yl-1-a za bicyclo[2.2.2]octa n -5-ol (11g). 9a (64 mg, 0.24
mmol) was allowed to react with phenylmagnesium bromide
(0.71 mL, 0.71 mmol) according to the general procedure to
afford anti-11g (77%, 64 mg, 0.18 mmol) with 46% de. IR
(CHCl3) (ν): 2956, 2928, 1599, 1464, 1256, 1120, 1080, 1020
1
2974, 1559, 1413, 1371, 1231, 1145, 1025 cm-1. H NMR (400
MHz) (δ): 6.16-6.14/6.11-6.09 (d, 1 H, J 3.1 Hz, H-11), 5.90-
5.87 (m, 1 H, H-12), 3.79-3.73 (m, 1 H, H-9), 3.52-3.46 (m, 1
H, H-9), 3.43-3.39/3.34-3.16 (m, 1 H, H-6), 3.12-3.07 (m, 1
H, H-2), 2.99-2.89 (m, 1 H, H-7), 2.86-2.81 (d, 1 H, J 14.9
Hz, H-6), 2.78-2.72 (m, 1 H, H-7), 2.30-2.20 (m, 1 H, H-4),
2.25-2.24/2.23-2.22 (d, 3 H, J 3.1 Hz, H-14), 1.82-1.75 (m, 1
H, H-3), 1.63-1.47 (m, 2 H, H-8, H-3), 0.98-0.87 (m, 1 H, H-8).
13C NMR (100 MHz) (δ): 155.80/155.14 (C, C-13), 151.99/
151.97 (C, C-10), 106.98/106.83 (CH, C-12), 106.16/106.08 (CH,
C-11), 69.69/69.05 (C, C-5), 62.16/62.01 (CH2, C-9), 61.97/61.82
(CH2, C-6), 57.68/57.23 (CH, C-2), 48.24/47.83 (CH2, C-7),
32.93/32.09 (CH, C-4), 25.51/22.50 (CH2, C-8), 22.38/19.96
(CH2, C-3), 13.61/13.58 (CH3, C-14). MS m/z: 237 (M+, 1), 226
(4), 206 (100), 199 (14), 137 (16); FAB-MS 238 (M++1, 100),
206 (52). Anal. Calcd for C13H19NO3: C 65.80, H 8.07, N 5.90;
found C 66.07, H 8.02, N 5.68.
1
cm-1. H NMR (400 MHz) (δ): 7.54-7.51/7.48-7.46 (m, 2 H,
Ar-H), 7.39-7.35/7.31-7.26 (m, 3 H, Ar-H), 4.06-4.02 (dd,
1 H, J 10.6, 3.7 Hz, H-9), 3.88-3.84 (dd, 1 H, J 10.5, 5.2 Hz,
H-9), 3.74-3.67/3.66-3.59 (m, 1 H, H-2), 3.55-3.49/3.16-3.12
(d, 1 H, J 15.2, H-6), 3.45-3.41/3.09-3.03 (d, 1 H, J 15.1 Hz,
H-6), 2.94-2.85 (m, 1 H, H-7), 2.84-2.79 (m, 1 H, H-7), 2.49-
2.45 (m, 1 H, H-4), 2.35-2.28 (m, 1 H, H-3), 2.19-2.15/1.88-
1.84 (m, 1 H, H-8), 1.75-1.66/1.64-1.57 (m, 1 H, H-8), 1.53-
1.46/1.45-1.39 (m, 1 H, H-3), 0.96/0.79 (s, 9 H, SiC(CH3)3),
0.17/-0.01 (s, 3 H, SiCH3), 0.16/-0.03 (s, 3 H, SiCH3). 13C NMR
(100 MHz) (δ): 145.44/145.37 (C, Ph), 128.56/128.23 (CH, Ph),
127.52/127.11 (CH, Ph), 125.96/125.94 (CH, Ph), 72.67/72.16
(C, C-5), 67.95/66.61 (CH2, C-9), 58.81/57.82 (CH2, C-6), 56.41/
56.22 (CH, C-2), 49.74/48.91 (CH2, C-7), 34.98/32.34 (CH, C-4),
26.08/25.86 (CH3, SiC(CH3)3), 25.03/22.82 (CH2, C-8), 22.41/
20.75 (CH2, C-3), 18.59/18.30 (C, SiC(CH3)3), -5.37 (CH3,
SiCH3), -5.52 (CH3, SiCH3). MS m/z: 347 (M+, 2), 332 (3), 290
(1S,2S,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(13-m et h ylfu r a n yl)-1-a za bicyclo[2.2.2]-oct a n -5-ol (12e).
10a (100 mg, 0.37 mmol) was allowed to react with 2-meth-
ylfuranyllithium (0.60 mmol, 1.6 equiv) according to the
general procedure to afford anti-12e (72%, 94 mg, 0.27 mmol)
with 18% de. IR (CHCl3) (ν): 2956, 2928, 1472, 1264, 1112,
(10), 202 (100), 184 (23). HRMS calcd for
347.2280; found 347.2281.
C20H33NO2Si:
(1S,2S,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
p h en yl-1-a za bicyclo[2.2.2]octa n -5-ol (12d ). 10a (116 mg,
0.43 mmol) was allowed to react with phenylmagnesium
bromide (1.29 mL, 1.29 mmol) according to the general
procedure to afford anti-12d (73%, 109 mg, 0.310 mmol) with
22% de. IR (CHCl3) (ν): 3060, 2956, 2928, 1600, 1472, 1256,
1
1028 cm-1. H NMR (400 MHz) (δ): 6.20-6.19/6.17-6.16 (d,
1 H, J 3.1 Hz, H-11), 5.92-5.89 (m, 1 H, H-12), 3.85-3.79 (m,
1 H, H-9), 3.74-3.68 (m, 1 H, H-9), 3.56-3.53/3.47-3.43 (d, 1
H, J 14.0 Hz, H-6), 3.28-3.19 (m, 1 H, H-7), 3.21-3.17/3.14-
3.10 (d, 1 H, J 14.2 Hz, H-6), 3.01-2.89 (m, 2 H, H-2, H-7),
2.68-2.64 (m, 1 H, H-4), 2.34-2.24 (m, 1 H, H-3), 2.28 (s, 3
H, H-14), 1.81-1.72 (m, 1 H, H-8), 1.52-1.41 (m, 2 H, H-8,
H-3), 0.91/0.89 (s, 9 H, SiC(CH3)3), 0.09/0.08 (s, 3 H, SiCH3),
0.07/0.05 (s, 3 H, SiCH3). 13C NMR (100 MHz) (δ): 155.73/
155.25 (C, C-13), 152.11 (C, C-10), 106.94/106.90 (CH, C-12),
106.17/106.14 (CH, C-11), 69.88/69.59 (C, C-5), 64.79/64.68
(CH2, C-9), 62.51/62.46 (CH2, C-6), 56.84/56.49 (CH, C-2),
42.31/41.70 (CH2, C-7), 33.17/32.74 (CH, C-4), 25.95 (CH3, SiC-
(CH3)3), 25.72/23.36 (CH2, C-8), 22.71/20.17 (CH2, C-3), 18.34
(C, SiC(CH3)3), 13.62 (CH3, C-14), -5.37 (CH3, SiCH3), -5.41
(CH3, SiCH3). MS m/z: 351 (M+, 2), 336 (4), 294 (11), 206 (100).
HRMS calcd for C19H33NO2Si: 335.2281; found 335.2185. Anal.
Calcd for C19H33NO3Si: C 64.97, H 9.47, N 3.99; found C 65.34,
H 9.58, N 3.79.
1
1116, 1028 cm-1. H NMR (400 MHz) (δ): 7.49-7.44 (m, 2 H,
Ar-H), 7.38-7.34 (m, 2 H, Ar-H), 7.29-7.26 (m, 1 H, Ar-
H), 3.71-3.69 (d, 1 H, J 5.8 Hz, H-9), 3.68-3.65 (dd, 1 H, J
6.1, 3.9 Hz, H-9), 3.56-3.52/3.39-3.35 (d, 1 H, J 14.3, H-6),
3.23-3.14/3.08-3.00 (m, 1 H, H-2), 3.13-3.08/3.06-3.02 (d, 1
H, J 14.1 Hz, H-6), 2.89-2.71 (m, 2 H, H-7), 2.53-2.46 (m, 1
H, H-4), 2.29-2.22 (m, 1 H, H-3), 2.19-2.15 (m, 1 H, H-8),
1.48-1.39 (m, 1 H, H-8), 1.38-1.29 (m, 1 H, H-3), 0.92/0.89
(s, 9 H, SiC(CH3)3), 0.09 (s, 3 H, SiCH3), 0.06/0.05 (s, 3 H,
SiCH3). 13C NMR (100 MHz) (δ): 146.06/145.95 (C, Ph), 128.36
(CH, Ph), 127.27 (CH, Ph), 126.03/125.98 (CH, Ph), 72.71/72.41
(C, C-5), 65.59/65.32 (CH2, C-9), 64.74/64.64 (CH2, C-6), 56.55/
56.49 (CH, C-2), 42.14/41.52 (CH2, C-7), 34.05/33.37 (CH, C-4),
26.06/24.92 (CH2, C-8), 25.99/25.57 (CH3, SiC(CH3)3), 23.04/
21.29 (CH2, C-3), 18.35 (C, SiC(CH3)3), -5.34 (CH3, SiCH3),
-5.37 (CH3, SiCH3). MS m/z: 347 (M+, 4), 332 (4), 290 (14),
202 (100), 184 (7). HRMS calcd for C20H33NO2Si: 347.2280;
found 347.2284.
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
vin yl-1-a za bicyclo[2.2.2]octa n -5-ol (11j). 9a (190 mg, 0.71
mmol) was allowed to react with vinylmagnesium bromide
(2.12 mL, 2.12 mmol) according to the general procedure to
afford anti-11j (84%, 176 mg, 0.590 mmol) with 16% de. IR
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(13-m eth ylfu r a n yl)-1-a za bicyclo[2.2.2]-octa n -5-ol (11h ).
9a (100 mg, 0.37 mmol) was allowed to react with 2-methyl-
furanyllithium (0.60 mmol, 1.6 equiv) according to the general
procedure to afford anti-11h (76%, 99 mg, 0.28 mmol) with
42% de. IR (CHCl3) (ν): 2956, 2928, 1472, 1388, 1264, 1112,
(CHCl3) (ν): 2954, 2930, 1471, 1257, 1120, 1079, 1020 cm-1
.
1H NMR (400 MHz) (δ): 6.15-6.08/6.04-5.96 (dd, 1 H, J 17.3,
10.8 Hz, H-10), 5.30-5.23 (ddd, 1 H, J 17.3, 9.3, 1.5 Hz, H-11),
5.12-5.09 (d, 1 H, J 10.8 Hz, H-11), 3.91-3.87 (dd, 1 H, J
10.4, 4.4 Hz, H-9), 3.79-3.74 (dd, 1 H, J 10.3, 5.3 Hz, H-9),
3.67-3.66 (d, 1 H, J 5.6 Hz, H-2), 3.22-3.18/3.10-3.05 (dd, 1
H, J 14.8, 1.5 Hz, H-6), 2.99-2.78 (m, 2 H, H-7), 2.88-2.84/
2.66-2.62 (d, 1 H, J 14.5 Hz, H-6), 2.10-2.04 (m, 1 H, H-4),
1.86-1.82/1.79-1.75 (m, 1 H, H-3), 1.71-1.61 (m, 1 H, H-8),
1.58-1.47 (m, 1 H, H-8), 1.44-1.37 (m, 1 H, H-3), 0.91/0.86
(s, 9 H, SiC(CH3)3), 0.09/0.08 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3). 13C NMR (100 MHz) (δ): 142.91/142.79 (CH, C-10),
113.07/112.85 (CH2, C-11), 71.64/71.03 (C, C-5), 66.42/65.25
(CH2, C-9), 57.39/57.04 (CH2, C-6), 56.29/56.07 (CH, C-2),
49.36/49.01 (CH2, C-7), 34.22/33.43 (CH, C-4), 26.05 (CH3, SiC-
(CH3)3), 25.97/22.85 (CH2, C-8), 22.62/20.51 (CH2, C-3), 18.51/
18.38 (C, SiC(CH3)3), -5.35 (CH3, SiCH3), -5.38 (CH3, SiCH3).
MS m/z: 298 (M++1, 12), 240 (30), 184 (5), 152 (100). HRMS
calcd for C16H31NO2Si: 297.2124; found 297.2124.
1
1024 cm-1. H NMR (400 MHz) (δ): 6.18-6.17/6.12-6.11 (d,
1 H, J 3.0 Hz, H-11), 5.93-5.90 (m, 1 H, H-12), 3.82-3.76 (m,
1 H, H-9), 3.70-3.64 (m, 1 H, H-9), 3.51-3.48/3.42-3.39 (d, 1
H, J 13.5 Hz, H-6), 3.23-3.14/3.27-3.19 (m, 1 H, H-2), 3.18-
3.14/3.11-3.08 (d, 1 H, J 13.6 Hz, H-6), 2.95-2.83 (m, 2 H,
H-7), 2.69-2.63 (m, 1 H, H-4), 2.33-2.25 (m, 1 H, H-3), 2.29-
2.26 (m, 3 H, H-14), 1.87-1.73 (m, 1 H, H-8), 1.56-1.38 (m, 2
H, H-8, H-3), 0.93/0.90 (s, 9 H, SiC(CH3)3), 0.09/0.08 (s, 3 H,
SiCH3), 0.05/0.02 (s, 3 H, SiCH3). 13C NMR (100 MHz) (δ):
155.64/155.03 (C, C-13), 151.87/151.53 (C, C-10), 106.96/106.51
(CH, C-12), 106.11/106.02 (CH, C-11), 69.72/69.25 (C, C-5),
64.87/64.36 (CH2, C-9), 62.44/61.89 (CH2, C-6), 57.01/56.47
(CH, C-2), 47.99/47.32 (CH2, C-7), 33.09/32.65 (CH, C-4), 25.70/
23.28 (CH2, C-8), 25.84 (CH3, SiC(CH3)3), 22.81/20.54 (CH2,
C-3), 18.32 (C, SiC(CH3)3), 13.63 (CH3, C-14), -5.35 (CH3,

Synthesis of Enantiopure 3-Quinuclidinone Analogues
J . Org. Chem., Vol. 65, No. 13, 2000 3995
(1S,2R,4S,5S)-2-(Hydr oxym eth yl)-5-(10-ph en yleth yn yl)-
1-a za bicyclo[2.2.2]octa n -5-ol (11k ). 9b (100 mg, 0.25 mmol)
was allowed to react with lithiated phenyl acetylene (1.12
mmol, 3 equiv) according to the general procedure to afford
anti-11k (67%, 44 mg, 0.17 mmol) with 3% de. IR (CHCl3) (ν):
Hz, H-6), 2.15-2.11 (m, 1 H, H-4), 2.05-1.97 (m, 1 H, H-3),
1.94-1.87 (m, 1 H, H-8), 1.77-1.71 (m, 1 H, H-8), 1.47-1.39
(m, 1 H, H-3). 13C NMR (100 MHz, CDCl3, CD3OD) (δ): 144.07
(C, Ph), 131.72 (CH, Ph), 128.74 (CH, Ph), 128.26 (CH, Ph),
127.86 (CH, Ph), 126.88 (CH, Ph), 122.66 (C, Ph), 93.01 (C,
C-10), 86.62 (C, Ph3CO), 83.64 (C, C-11), 67.71 (C, C-5), 65.56
(CH2, C-9), 59.50 (CH2, C-6), 54.59 (CH, C-2), 48.47 (CH2, C-7),
34.63 (CH, C-4), 28.15 (CH2, C-8), 19.21 (CH2, C-3). MS m/z:
499 (M+, 3), 370 (9), 256 (18), 243 (100), 212 (40). HRMS calcd
for C35H33NO2: 499.2511; found 499.2513. Anal. Calcd for
3421, 2999, 2971, 1599, 1443, 1412, 1236, 1143, 1024 cm-1
.
1H NMR (400 MHz) (δ): 7.41-7.39 (m, 2 H, Ar-H), 7.33-
7.26 (m, 3 H, Ar-H), 4.30-4.18 (bs, 1 H, OH), 3.76-3.70/3.64-
3.58 (m, 1 H, H-9), 3.53-3.46 (m, 2 H, H-9, H-7), 3.32-3.28/
3.02-2.98 (d, 1 H, J 14.4 Hz, H-6), 3.23-3.19/2.94-2.89 (d, 1
H, J 13.8 Hz, H-6), 3.10-2.85 (m, 2 H, H-7, H-2), 2.18-2.09
(m, 2 H, H-4, H-3), 1.81-1.64 (m, 2 H, H-8), 1.55-1.43 (m, 1
H, H-3). 13C NMR (100 MHz) (δ): 131.65 (CH, Ph), 128.52/
128.35 (CH, Ph), 122.46/ 122.34 (C, Ph), 92.65/92.26 (C, C-10),
84.15/84.08 (C, C-11), 67.19/66.73 (C, C-5), 62.05/ 61.99 (CH2,
C-9), 57.65/57.56 (CH2, C-6), 57.04/56.99 (CH, C-2), 48.09/47.88
(CH2, C-6), 34.53 (34.33 (CH, C-4), 26.01/22.98 (CH2, C-8),
21.52/19.05 (CH2, C-3). FAB-MS m/z: 258 (M++1, 100), 240
(8), 226 (18). HRMS calcd for C16H19NO2: 257.3316; found
257.3304. Anal. Calcd for C16H19NO2: C 74.68, H 7.44, N 5.44;
found C 74.55, H 7.31, N 5.79.
C
35H33NO2: C 84.14, H 6.66, N 2.80; found C 83.98, H 6.40, N
2.54.
(1S,2S,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(10-p h en ylet h yn yl)-1-a za bicyclo[2.2.2]-oct a n -5-ol (12f).
10a (100 mg, 0.37 mmol) was allowed to react with lithiated
phenyl acetylene (1.11 mmol, 3 equiv) according to the general
procedure to afford anti-12f (75%, 103 mg, 0.280 mmol) with
16% de. IR (CHCl3) (ν): 2972, 2932, 1488, 1264, 1144, 1020
cm-1 1H NMR (400 MHz) (δ): 7.49-7.40 (m, 2 H, Ar-H),
.
7.32-7.28 (m, 3 H, Ar-H), 3.61-3.49 (m, 2 H, H-9), 3.41-
3.37 (d, 1 H, J 14.0 Hz, H-6), 3.17-3.08 (m, 1 H, H-6), 3.02-
2.94 (m, 1 H, H-2), 2.82-2.68 (m, 2 H, H-7), 2.18-2.03 (m, 2
H, H-4, H-3), 1.58-1.51/1.36-1.28 (m, 1 H, H-8), 1.27 (m, 9
H, SiC(CH3)3), 1.09-1.02 (m, 1 H, H-8), 0.92-0.82 (m, 1 H,
H-3), 0.02-0.01 (m, 6 H, SiCH3). 13C NMR (100 MHz) (δ):
131.66 (CH, Ph), 128.48/128.34 (CH, Ph), 122.54/122.47 (C,
Ph), 92.82/92.77 (C, C-10), 84.27/83.92 (C, C-11), 67.82/67.51
(C, C-5), 66.47/66.31 (CH2, C-9), 62.72/62.59 (CH2, C-6), 56.69/
56.29 (CH, C-2), 39.51/39.31 (CH2, C-7), 34.87/34.46 (CH, C-4),
31.23 (CH3, SiC(CH3)3), 27.02/23.74 (CH2, C-8), 23.29/19.78
(CH2, C-3), 18.32 (C, SiC(CH3)3), -5.31 (CH3, SiCH3), -5.37
(CH3, SiCH3). FAB-MS 372 (M++1, 23), 282 (27), 258 (100).
HRMS calcd for C22H33NO2Si: 371.2281; found 371.2262.
(1S,2R,4S,5S)-2-(Br om om eth yl)-1-azabicyclo[2.2.2]octan -
5-ol (11o). 9f (102 mg, 0.47 mmol) was allowed to react with
L-Selectride (0.71 mL, 0.71 mmol) according to the general
procedure to afford diastereomeric alcohols anti-11o and syn-
11o (85%, 87 mg, 0.40 mmol) in a ratio of 2.2:1 (38% de). IR
(1S,2R,4S,5S)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-5-
(10-p h en yleth yn yl)-1-a za bicyclo[2.2.2]-octa n -5-ol (11l). 9a
(86 mg, 0.32 mmol) was allowed to react with lithiated phenyl
acetylene (0.96 mmol, 3 equiv) according to the general
procedure to afford anti-11l (71%, 84 mg, 0.23 mmol) with 39%
de. IR (CHCl3) (ν): 3000, 2972, 1464, 1324, 1236, 1144, 1068,
1
1024 cm-1. H NMR (400 MHz) (δ): 7.42-7.38 (m, 2 H, Ar-
H), 7.32-7.27 (m, 3 H, Ar-H), 3.70-3.64/3.60-3.54 (dd, 1 H,
J 11.6, 10.0 Hz, H-9), 3.49-3.39 (m, 2 H, H-9, H-6), 3.05-
2.82 (m, 4 H, H-7, H-2, H-7, H-6), 2.15-2.11 (m, 1 H, H-4),
2.09-2.03 (m, 1 H, H-3), 1.79-1.71/1.68-1.59 (m, 1 H, H-8),
1.53-1.37 (m, 2 H, H-8, H-3), 1.26 (m, 9 H, SiC(CH3)3), 0.04-
0.03 (m, 6 H, SiCH3). 13C NMR (100 MHz) (δ): 131.65 (CH,
Ph), 128.45/128.25 (CH, Ph), 122.73/122.47 (C, Ph), 93.03/92.67
(C, C-10), 84.06/84.00 (C, C-11), 67.69/67.24 (C, C-5), 62.31/
62.23 (CH2, C-9), 57.91/57.86 (CH2, C-6), 56.52/56.46 (CH, C-2),
48.31/48.10 (CH2, C-7), 34.82/34.51 (CH, C-4), 31.22 (CH3, SiC-
(CH3)3), 26.39/23.53 (CH2, C-8), 21.72/19.38 (CH2, C-3), 18.39
(C, SiC(CH3)3), -5.36 (CH3, SiCH3), -5.44 (CH3, SiCH3). MS
m/z: 371 (M+, 4), 343 (3), 314 (11), 226 (100), 198 (37). FAB-
(CHCl3) (ν): 3385, 2955, 2928, 1453, 1230, 1116, 1028 cm-1
.
1H NMR (400 MHz) (δ): 4.08-4.03 (m, 1 H, H-5), 3.85-3.81/
3.61-3.56 (m, 1 H, H-6), 3.74-3.71/3.42-3.35 (m, 2 H, H-7),
3.51-3.44/3.32-3.23 (m, 1 H, H-2), 3.15-3.07/3.04-2.97 (m,
1 H, H-9), 2.91-2.86 (d, 1 H, J 13.1 Hz, H-6), 2.14-2.10 (m, 1
H, H-4), 2.00-1.94/1.87-1.79 (m, 1 H, H-3), 1.76-1.67/1.63-
1.53 (m, 1 H, H-8), 1.43-1.36 (m, 2 H, H-8, H-3). 13C NMR
(100 MHz) (δ): 64.83/64.63 (CH, C-5), 58.02/56.76 (CH, C-2),
51.86/50.95 (CH2, C-6), 49.26/48.63 (CH2, C-7), 31.78/30.94
(CH2, C-9), 29.38/23.77 (CH2, C-8), 28.67/28.27 (CH, C-4),
21.57/16.72 (CH2, C-3). MS m/z: 222 (M++H, 8), 220 (M++H,
8), 140 (100), 126 (12). HRMS calcd for C8H14NOBr: 219.0259;
found 219.0258. Anal. Calcd for C8H14NOBr: C 43.65, H 6.41,
N 6.36; found C 43.86, H 6.58, N 6.09.
MS 371 (M+, 100): 313 (18), 257 (82). HRMS calcd for C22H33
NO2Si: 371.2281; found 371.2271.
-
(1S ,2R ,4S ,5S )-2-(Tr iisop r op ylsilyloxym e t h yl)-5-(10-
p h en yleth yn yl)-1-a za bicyclo[2.2.2]octa n -5-ol (11m ). 9c
(115 mg, 0.37 mmol) was allowed to react with lithiated phenyl
acetylene (1.11 mmol, 3 equiv) according to the general
procedure to afford anti-11m (65%, 99 mg, 0.24 mmol) with
69% de. IR (CHCl3) (ν): 2944, 1490, 1463, 1261, 1120, 1068,
1
1022 cm-1. H NMR (400 MHz) (δ): 7.43-7.40 (m, 2 H, Ar-
H), 7.32-7.29 (m, 3 H, Ar-H), 3.89-3.85/3.84-3.80 (dd, 1 H,
J 9.5, 5.1 Hz, H-9), 3.77-3.72/3.71-3.67 (dd, 1 H, J 9.4, 8.2
Hz, H-9) 3.49-3.44 (dd, J 14.7, 1.3 Hz, H-6), 2.99-2.86 (m, 4
H, H-6, H-7, H-2, H-7), 2.18-2.15 (m, 1 H, H-4), 2.08-1.99
(m, 1 H, H-3), 1.91-1.82 (m, 2 H, H-8, H-3), 1.48-1.40 (m, 1
H, H-8), 1.11-0.99 (m, 21 H, Si(CH(CH3)2)3). 13C NMR (100
MHz) (δ): 131.63 (CH, Ph), 128.24 (CH, Ph), 122.77 (C, Ph),
93.34 (C, C-10), 83.84/83.81 (C, C-11), 68.03 (C, C-5), 65.95/
65.74 (CH2, C-9), 60.04/59.96 (CH2, C-6), 56.20/56.18 (CH, C-2),
48.74 (CH2, C-7), 34.91/ 34.88 (CH, C-4), 27.89/27.80 (CH2,
C-8), 19.37/18.69 (CH2, C-3), 18.00 (CH3, Si(CH(CH3)2)3), 11.88
(CH, Si(CH(CH3)2)3). MS m/z: 413 (M+, 47), 371 (66), 343 (10),
226 (100). HRMS calcd for C25H39NO2Si: 413.2750; found
413.2752.
(1S,2R,4S,5S)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-5-
(m eth a n esu lfon yloxy)-1-a za bicyclo-[2.2.2]octa n e (a n ti-
13) a n d (1S,2R,4S,5R)-2-(ter t-Bu tyld iph en ylsilyloxym eth -
yl)-5-(m eth an e-su lfon yloxy)-1-azabicyclo[2.2.2]octan e (syn -
13). Methanesulfonyl chloride (1.3 equiv) was added to a
solution of 11b (560 mg, 1.42 mmol) and Et3N (2.0 equiv) in
abs CH2Cl2 at 0 °C. The reaction mixture was stirred for 8 h
at rt, treated with saturated aqueous NaHCO3, and extracted
with CH2Cl2. After the solution was dried (over MgSO4), the
crude product was purified by column chromatography (EA/
MeOH 40:1) and mesylates anti-13 (79%, 531 mg, 1.12 mmol)
and syn-13 (15%, 100 mg, 0.21 mmol) were separated. Data
for anti-13, IR (CHCl3) (ν): 3051, 2945, 1589, 1471, 1428, 1230,
(1S,2R,4S,5S)-2-(Tr ip h e n ylm e t h yloxym e t h yl)-5-(10-
ph en yleth yn yl)-1-azabicyclo[2.2.2]octan -5-ol (11n ). 9e (134
mg, 0.34 mmol) was allowed to react with lithiated phenyl
acetylene (1.02 mmol, 3 equiv) according to the general
procedure to afford anti-11n (79%, 133 mg, 0.270 mmol) with
87% de. IR (CHCl3) (ν): 3061, 2999, 2940, 1598, 1491, 1448,
1
1174, 1113 cm-1. H NMR (400 MHz) (δ): 7.69-7.66 (m, 4 H,
Ar-H), 7.47-7.38 (m, 6 H, Ar-H), 4.77-4.72 (m, 1 H, H-5),
3.72-3.67 (dd, 1 H, J 18.1, 15.5 Hz, H-9), 3.69-3.64 (dd, 1 H,
J 18.2, 15.7 Hz, H-9), 3.53-3.47 (dd, 1 H, J 15.4, 8.2 Hz,
H-6endo), 3.03 (s, 3 H, Me-SO2), 2.96-2.92 (m, 2 H, H-7), 2.91-
2.84 (m, 1 H, H-2), 2.79-2.75 (d, 1 H, J 15.3 Hz, H-6exo), 2.30-
2.25 (m, 1 H, H-4), 1.91-1.83 (m, 2 H, H-8, H-3), 1.52-1.43
(m, 2 H, H-8, H-3), 1.08 (s, 9H, SiC(CH3)3); NOE H-5 irradiated
H-6endo (4.8%), H-3endo (4.8%), H-4 (5.6%), H-6endo irradiated H-5
(4.9%), H-6exo (27.4%). 13C NMR (100 MHz) (δ): 135.61 (CH,
1230, 1070, 1025 cm-1 1H NMR (400 MHz, CDCl3, CD3OD)
.
(δ): 7.49-7.46 (m, 7 H, Ar-H), 7.34-7.27 (m, 5 H, Ar-H),
7.26-7.22 (m, 6 H, Ar-H), 7.20-7.16 (m, 2 H, Ar-H), 3.31-
3.23 (m, 2 H, H-9, H-6), 3.14-3.09 (m, 1 H, H-9), 3.08-3.02
(m, 1 H, H-2), 2.99-2.88 (m, 2 H, H-7), 2.89-2.85 (d, J 14.8

3996 J . Org. Chem., Vol. 65, No. 13, 2000
Frackenpohl and Hoffmann
Ar-H), 133.32 (C, Ar-Si), 129.74 (CH, Ar-H), 127.75 (CH,
Ar-H), 79.17 (CH, C-5), 66.11 (CH2, C-9), 55.67 (CH, C-2),
51.02 (CH2, C-6), 49.58 (CH2, C-7), 38.51 (CH3, Me-SO2), 27.57
(CH, C-4), 27.32 (CH2, C-8), 26.89 (CH3, SiC(CH3)3), 19.24 (C,
SiC(CH3)3), 18.09 (CH2, C-3). MS m/z: 473 (M+, 1), 440 (2), 416
(100), 394 (25), 320 (23). HRMS calcd for C25H35NO4SSi:
473.2056; found 473.2054. Data for syn-13, IR (CHCl3) (ν):
3072, 2944, 1589, 1471, 1428, 1231, 1175, 1113 cm-1. 1H NMR
(400 MHz) (δ): 7.73-7.69 (m, 4 H, Ar-H), 7.45-7.38 (m, 6 H,
Ar-H), 4.79-4.74 (m, 1 H, H-5), 3.79-3.76 (d, 2 H, J 6.1 Hz,
H-9), 3.16-3.13 (d, 1 H, J 14.7 Hz, H-6endo), 3.11-3.05 (m, 1
H, H-6exo), 2.97-2.85 (m, 2 H, H-7, H-2), 2.94 (s, 3 H, Me-SO2),
2.77-2.69 (m, 1 H, H-7), 2.24-2.21 (m, 1 H, H-4), 1.88-1.81
(m, 1 H, H-3), 1.80-1.72 (m, 1 H, H-8), 1.67-1.56 (m, 2 H,
H-8, H-3), 1.09 (s, 9H, SiC(CH3)3); NOE H-5 irradiated H-6exo
(9.8%), H-8exo (2.5%), H-4 (3.9%), H-6endo irradiated H-5 (9.8%),
H-6exo (16.3%), H-7exo (4.1%). 13C NMR (100 MHz) (δ): 135.65
(CH, Ar-H), 133.49 (C, Ar-Si), 129.77 (CH, Ar-H), 127.72
(CH, Ar-H), 78.58 (CH, C-5), 65.73 (CH2, C-9), 56.96 (CH, C-2),
49.90 (CH2, C-6), 48.92 (CH2, C-7), 38.55 (CH3, Me-SO2), 27.92
(CH, C-4), 26.87 (CH3, SiC(CH3)3), 23.96 (CH2, C-8), 21.68
(CH2, C-3), 19.27 (C, SiC(CH3)3). MS m/z: 473 (M+, 1), 416
(100), 394 (11), 320 (10). HRMS calcd for C25H35NO4SSi:
473.2056; found 473.2057.
(1S,2R,4S,5R)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-5-
(10,11,13-tr ia zolyl)-1-a za bicyclo-[2.2.2]octa n -5-ol (14). So-
dium triazolate (143 mg, 1.57 mmol, 4 equiv) was added to a
solution of anti-13 (186 mg, 0.390 mmol) in DMF at rt. The
heterogeneous reaction mixture was stirred for 8 h at 110 °C,
diluted with CH2Cl2 and extracted with saturated aqueous
NaHCO3. The organic layer was dried (over MgSO4), the
solvent evaporated in vacuo, and the residue purified by
column chromatography (EA/MeOH 20:1) to yield 14 (74%, 129
mg, 0.290 mmol). IR (CHCl3) (ν): 3072, 2999, 2952, 1602, 1472,
1427, 1230, 1113, 1011 cm-1. 1H NMR (400 MHz) (δ): 8.04 (s,
1 H, triazol-H), 7.92 (s, 1 H, triazol-H), 7.71-7.66 (m, 4 H,
Ar-H), 7.47-7.36 (m, 6 H, Ar-H), 4.34-4.30 (m, 1 H, H-5),
3.84-3.75 (m, 2 H, H-9), 3.46-3.40 (ddd, 1 H, J 14.6, 6.9, 2.2
Hz, H-6), 3.28-3.21 (dd, 1 H, J 14.6, 9.7 Hz, H-6), 3.06-3.93
(m, 2 H, H-7, H-2), 2.89-2.77 (m, 1 H, H-7), 2.32-2.26 (m, 1
H, H-4), 1.85-1.60 (m, 4 H, H-3, H-8, H-3), 1.04 (s, 9 H, SiC-
(CH3)3). 13C NMR (100 MHz) (δ): 151.41 (CH, triazol-H),
141.93 (CH, triazol-H), 135.68 (CH, Ar-H), 133.55 (C, Ar-
Si), 129.65 (CH, Ar-H), 127.63 (CH, Ar-H), 67.40 (C, C-5),
65.75 (CH2, C-9), 57.13 (CH, C-2), 49.02 (CH2, C-6), 47.95 (CH2,
C-7), 28.67 (CH, C-4), 26.91 (CH3, SiC(CH3)3), 25.55 (CH2, C-8),
23.47 (CH2, C-3), 19.26 (C, SiC(CH3)3). FAB-MS 447 (M++1,
53): 389 (29), 378 (100), 320 (18), 300 (8), 135 (7). HRMS calcd
for C26H34N4OSi: 446.6158; found 446.6152.
(1S,2R,4S)-2-(Hyd r oxym eth yl)-5-(13-m eth ylfu r a n yl)-1-
a za bicyclo[2.2.2]oct-5-en e (15). 11i (82 mg, 0.35 mmol) was
dissolved in HCOOH (99%, 2 mL), stirred for 4 h at 100 °C,
and neutralized with aq KOH. The aqueous layer was ex-
tracted with CH2Cl2. After it was dried (over MgSO4), the
resulting organic layer was concentrated in vacuo and the
residue purified by column chromatography (EA/MeOH 4:1)
to yield 15 (96%, 73 mg, 0.33 mmol). IR (CHCl3) (ν): 2999,
1
2957, 1591, 1412, 1284, 1134, 1023 cm-1. H NMR (400 MHz,
CDCl3, CD3OD) (δ): 6.64 (s, 1 H, H-6), 6.34-6.32 (d, 1 H, J
3.3 Hz, H-11), 5.90-5.87 (dd, 1 H, J 3.3, 1.0 Hz, H-12), 3.46-
3.39 (m, 1 H, H-2), 3.39-3.34 (m, 1 H, H-9), 3.33-3.17 (m, 2
H, H-9, H-7), 3.07-3.04 (bs, 1 H, H-4), 2.94-2.86 (m, 1 H, H-7),
2.31 (s, 3 H, J 3.1 Hz, H-14), 2.00-1.93 (m, 1 H, H-3), 1.87-
1.79 (m, 1 H, H-8), 1.69-1.61 (m, 1 H, H-8), 0.99-0.95 (m, 1
H, H-3). 13C NMR (100 MHz) (δ): 153.82 (C, C-13), 147.17 (C,
C-10), 137.18 (C, C-5), 123.66 (CH, C-6), 109.08 (CH, C-12),
107.54 (CH, C-11), 64.19 (CH2, C-9), 63.67 (CH, C-2), 50.43
(CH2, C-7), 28.22 (CH, C-4), 29.69 (CH2, C-3), 24.66 (CH2, C-8),
13.71 (CH3, C-14). MS m/z: 219 (M+, 87), 202 (15), 190 (25),
161 (100), 146 (27). HRMS calcd for C13H17NO2: 219.1259;
found 219.1259.
Ack n ow led gm en t. We thank Buchler GmbH-Chin-
infabrik Braunschweig for a generous gift of QCI and
QCD, Degussa AG Hanau for a generous gift of OsO4,
the Fonds der Chemischen Industrie for a Ph.D. fellow-
ship (J .F.), and Ulrike Eggert and Henning Stu¨ckmann
for their help.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for com-
1
pounds 9f, anti-11o, and syn-11o and H and 13C NMR spectra
for each new compound. This material is free of charge via
the Internet at http://pubs.acs.org.
J O9919815