Concise stereocontrolled formal synthesis of (±)-quinine and total synthesis of (±)-7-hydroxyquinine via merged Morita-Baylis-Hillman-Tsuji- Trost cyclization

Article abstract of DOI:10.1021/jo802165k

(Chemical Equation Presented) Concise stereoselective syntheses of (±)-quinine and (±)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophili

Full text of DOI:10.1021/jo802165k

Concise Stereocontrolled Formal Synthesis of (()-Quinine and Total
Synthesis of (()-7- Hydroxyquinine via Merged
Morita-Baylis-Hillman-Tsuji-Trost Cyclization
Peter Webber and Michael J. Krische*
UniVersity of Texas at Austin Department of Chemistry and Biochemistry Austin, Texas 78712, USA
mkrische@mail.utexas.edu
ReceiVed October 2, 2008
Concise stereoselective syntheses of (()-quinine and (()-7-hydroxyquinine are achieved using a catalytic
enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and
the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the
product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr)
followed by exchange of the N-protecting group provides the saturated N-Boc-protected methyl ketone 19,
which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine.
Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the
allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by
N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17
provides (()-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal.
Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-
asymmetric induction events. Deoxygenation of the N-Cbz-protected allylic acetate 22 provides olefin 23,
which previously has been converted to quinine. Thus, (()-quinine is accessible in 16 steps and 4% overall
yield from commercial aminoacetaldehyde diethyl acetal.
Introduction
connectivity of quinine was proposed in 1908 by Rabe, who in
1918 reconstructed quinine via degradation, thereby establishing
the veracity of his structural assignment.4 The first total synthesis
of quinine was reported by Woodward in 1944.5 A “formal total
synthesis,” Woodward’s approach is based on the interception
Over three centuries ago, Jesuit monks found the essence of
cinchona bark to be a powerful therapeutic agent in the treatment
of malaria,1 which remains the foremost cause of death among
human beings since recorded history.2 Nearly two centuries have
elapsed since the active constituent of cinchona bark, quinine
1, was isolated in 1820 by Pelletier and Caventou.3 The proper
(2) For reviews on malaria, see: (a) Greenwood, B.; Mutabingwa, T. Nature
2002, 415, 670. (b) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem., Int. Ed. 2003, 42, 5274.
(3) (a) Pelletier, P. J.; Caventou, J.-B. Ann. Chim. Phys. 1820, 15, 291. (b)
Pelletier, P. J.; Caventou, J.-B. Ann. Chim. Phys. 1820, 15, 337.
(4) Rabe, P.; Kindler, K. Ber. Dtsch. Chem. Ges. 1918, 51, 466.
(1) For an authoritative review on quinine, including previous syntheses, see:
Kaufman, T. S.; Ru´veda, E. A. Angew. Chem., Int. Ed. 2005, 44, 854.
10.1021/jo802165k CCC: $40.75
Published on Web 11/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9379–9387 9379

Webber and Krische
SCHEME 1a
ratio after epimerization of an initially formed 1:1.7 mixture
favoring the undesired isomer. Finally, in a recent effort to
prepare quinine, Williams disclosed the synthesis of 7-hydrox-
yquinine in 27 steps which took advantage of a unique C-3 to
C-4 bond construction.9 Despite these enormous advances, a
concise route to quinine that addresses both relative and absolute
stereocontrol remains absent (Scheme 1, bottom).
Here, we report a highly stereoselective formal synthesis of
(()-quinine in 16 steps and 4% overall yield from aminoac-
etaldehyde diethyl acetal employing a novel cycloallylation
methodology developed in our laboratory, wherein the nucleo-
philic features of the Morita-Baylis-Hillman reaction and the
electrophilic features of the Tsuji-Trost reaction are com-
bined.10 To our knowledge, this route represents the most
concise synthetic approach to quinine reported to date. Ad-
ditionally, we report a stereoselective route to (()-7-hydrox-
yquinine in 13 steps and 11% overall yield from aminoacetal-
dehyde diethyl acetal, wherein highly stereoselective formation
of five contiguous stereocenters is achieved through a series of
1,2-asymmetric induction events.
a (Top) Strategic Bond Constructions in Prior Syntheses and Synthetic
Approaches to Quinine. (Bottom) Key Amine-Epoxide Cyclization De-
veloped by Uskokovic´.
Results and Discussion
Quinine can be envisioned to arise by way of compound
4 via amine-glycidic epoxide cyclization. Cyclization would
furnish 7-hydroxyquinine 3, which upon C-7 deoxygenation
would deliver quinine. The N-protected glycidic epoxide 4
may be obtained via aldol dehydration of piperidine 5 and
6-methoxyquinoline-4-carbaldehyde, followed by diastereo-
selective 1,2-reduction and hydroxy-directed epoxidation of
the resulting allylic alcohol. Finally, the requisite cis-1,2-
disubstituted piperidine 5 is potentially accessible through
merged Morita-Baylis-Hillman-Tsuji-Trost reaction of
enone-allyl carbonate 6 followed by diastereoselective con-
jugate reduction. In accordance with this approach, all five
stereocenters of glycidic epoxide 4, 7-hydroxyquinine 3 and,
ultimately, the relative stereochemistry embodied by quinine
itself, would be controlled through a series of 1,2-asymmetric
induction events, relayed from the initially formed stereo-
center bearing the vinyl moiety, which arises at the stage of
cycloallylation (Scheme 2).
Efforts toward quinine began with the preparation of enone-
allyl carbonate 6, the substrate for merged Morita-Baylis-
Hillman-Tsuji-Trost cycloallylation. Sulfonylation of com-
mercially available aminoacetaldehyde diethyl acetal 7 with
either p-toluenesulfonyl chloride or 2,4,6-trisopropylbenzene-
sulfonyl chloride provides the crude sulfonamides which under
Mitsunobu conditions couple to (Z)-4-hydroxy-2-butenyl methyl
carbonate11 to furnish the products of N-allylation 8 and 9 in
excellent yields over two steps. Hydrolysis of acetal 8 and 9
mediated by trifluoroacetic acid followed by Wittig olefination
of the resulting aldehyde delivers enone-allyl carbonates 10
and 11 in 69 and 68% yields over two steps, respectively
(Scheme 3).
of quinotoxine 2, a compound that was converted to quinine in
three manipulations by Rabe.4 Recently, Williams and co-
workers validated the three-step “Rabe protocol” for the
conversion of quinotoxine 2 to quinine 1,6 and in doing so ended
the controversy surrounding the Woodward-Doering claim of
the first “total synthesis” of quinine (Scheme 1, top).7
Subsequent to Woodward’s seminal work, total syntheses of
quinine 1 were reported by Uskokovic´, Gates, Taylor, Stork,
Jacobsen, and Kobayashi.8 Uskokovic and co-workers at
Hoffman-La Roche developed four different routes to quinine.
Although the group at Hoffman-La Roche was unable to
develop a highly stereoselective approach, many of their
discoveries, especially the N-1 to C-8 amine-epoxide cycliza-
tion strategy and the diastereoselective C-9 hydroxylation, have
been utilized in subsequent syntheses. In 2001, Stork reported
the first stereoselective synthesis of quinine 1 in 20 steps from
trans-butene-1,4-diol employing a novel N-1 to C-6 discon-
nection strategy. Completion of this synthesis resulted in
optimization of the Hoffman-La Roche C-9 hydroxylation. In
2004, Jacobsen and Kobayashi published synthetic approaches
relying on the N-1 to C-8 amine-epoxide cyclization initially
reported by Hoffman-La Roche. These syntheses cleverly
provide access to both quinine 1 and quinidine. Jacobsen’s
catalytic asymmetric synthesis of quinine 1 is achieved in 17
steps from N-(chloroacetyl)-benzamide but is not fully stereo-
controlled. The C-3 stereocenter is obtained in a 3:1 epimeric
(5) (a) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66, 849.
(b) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1945, 67, 860.
(6) Smith, A. C.; Williams, R. M. Angew. Chem., Int. Ed. 2008, 47, 1736.
(7) Seeman, J. I. Angew. Chem., Int. Ed. 2007, 46, 1378.
(8) (a) Uskokovic´, M.; Gutziller, J.; Henderson, T. J. Am. Chem. Soc. 1970,
92, 203. (b) Gutzwiller, J.; Uskokovic´, M. J. Am. Chem. Soc. 1970, 92, 204. (c)
Gutzwiller, J.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 576. (d) Grethe,
G.; Lee, H. L.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978, 100, 581.
(e) Grethe, G.; Lee, H. L.; Mitt, T.; Uskokovic´, M. R. J. Am. Chem. Soc. 1978,
100, 589. (f) Gates, M.; Sugavanam, B.; Schreiber, W. L. J. Am. Chem. Soc.
1970, 92, 205. (g) Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1972, 94,
6218. (h) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata,
J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239. (i) Raheem, I. T.;
Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706. (j) Igarashi,
J.; Katsukawa, M.; Wang, Y.-G.; Acharaya, H. P.; Kobayashi, Y. Tetrahedron
Lett. 2004, 45, 3783. (k) Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2005, 46,
6381.
With the requisite cycloallylation substrate in hand, the
merged Morita-Baylis-Hillman-Tsuji-Trost cycloallylation
of the N-Ts protected enone-allyl carbonate 10 was explored.
Applying standard conditions,10 which involve exposure of
(9) Johns, D. M.; Mori, M.; Williams, R. M. Org. Lett. 2006, 8, 4051.
(10) (a) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 7758. For a related cycloallylation methodology see: (b) Krafft, M. E.;
Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168.
(11) Oppolzer, W.; Fu¨rstner, A. HelV. Chim. Acta 1993, 76, 2329.
9380 J. Org. Chem. Vol. 73, No. 23, 2008

Merged Morita-Baylis-Hillman-Tsuji-Trost Cyclization
SCHEME 2. Retrosynthetic Analysis of Quinine via Merged Morita-Baylis-Hillman-Tsuji-Trost Cycloallylation
TABLE 1. Selected Experiments in the Optimization of the
Merged Morita-Baylis-Hillman-Tsuji-Trost Reaction of
Enone-Allyl Carbonates 10 and 11a
SCHEME 3. Preparation of Enone-Allyl Carbonates 10
and 11
R
Pd(PPh3)4
Phosphine
Solvent
T °C Yield
Ts 1.0 mol% PBu3 (100 mol%) t-BuOH, 0.1 M
Ts 5.0 mol% PBu3 (100 mol%) t-BuOH, 0.1 M
Ts 5.0 mol% PBu3 (100 mol%) t-BuOH, 0.1 M
60 °C 3%
60 °C 13%
35 °C 46%
Ts 5.0 mol% PBu3 (100 mol%) t-AmOH, 0.1 M 25 °C 62%
Ts 5.0 mol% PBu3 (100 mol%) t-AmOH, 0.1 M 0 °C 55%
substrate to Pd(PPh3)4 (1 mol%), PBu3(100 mol%) in tert-
butanol (0.1 M) at 60 °C, only a 3% isolated yield of cyclization
product 12 was obtained. This result is attributed to the
sulfonamide moiety, which enhances the electrophilicity of the
enone such that anionic polymerization becomes problematic.
Intramolecular capture of the phosphonio-enolate is facilitated
by increasing the loading of palladium (5 mol%) and by
conducting the reaction at ambient temperature. Under these
conditions, the N-Ts protected substrate 10 undergoes cyclization
to furnish 12 in 62% isolated yield. A major side-product in
the cyclization of 10 is the ꢀ,γ-unsaturated piperidine. This
material is not produced upon reexposure of piperidine 12 to
the reaction conditions, suggesting it is formed upon E2-
elimination of the ꢀ-phosphonium intermediate. The corre-
sponding N-Trs (Trs ) 2,4,6-trisopropylphenyl sulfonyl) de-
rivative 11, should be resistant to deprotonation at the γ-position
after cyclization. Further, the N-Trs moiety of 11 may facilitate
cyclization through the Thorpe-Ingold effect.12 In practice, the
steric demand of the N-Trs moiety mandated use of a smaller
phosphine, trimethylphosphine, which upon substoichiometric
loading (80 mol%) provided the N-Trs protected piperidine 13
in 68% isolated yield (Table 1).
Ts 5.0 mol% PMe3 (100 mol%) t-AmOH, 0.1 M 25 °C 39%
Trs 5.0 mol% PBu3 (100 mol%) t-AmOH, 0.1 M 25 °C 27%
Trs 5.0 mol% PMe3 (100 mol%) t-AmOH, 0.1 M 25 °C 63%
Trs 5.0 mol% PMe3 (80 mol%) t-AmOH, 0.1 M 25 °C 68%
Trs 5.0 mol% PMe3 (65 mol%) t-AmOH, 0.1 M 25 °C 60%
Trs 2.5 mol% PMe3 (80 mol%) t-AmOH, 0.1 M 25 °C 57%
Trs 5.0 mol% PMe3 (80 mol%) t-AmOH, 0.05 M 25 °C 27%
a Isolated yields of material purified by silica gel chromatography.
In our hands, reductive removal of the N-sulfonyl protecting
group could not be performed in the presence of the quinoline.
Hence, N-Trs protected cis-piperidine 14 was converted to the
corresponding N-Boc derivative 18. Exposure of 14 to sodium
naphthalenide in DME at -78 °C resulted in cleavage of the
sulfonyl moiety. However, to avoid epimerization to the trans-
piperidine, quenching of the reaction mixture at -78 °C using
saturated aqueous ammonium chloride was required. Treatment
of the crude amine with Boc2O delivers the N-Boc protected
cis-piperidine 18 in 76% isolated yield over these two manipula-
tions (Scheme 4).
Introduction of the quinoline moiety was accomplished using
an aldol addition-dehydration protocol employing N-Boc pro-
tected cis-piperidine 18 and 6-methoxyquinoline-4-carbaldehyde.
To avoid epimerization of the cis-piperidine, carefully controlled
conditions were required. Regioselective deprotonation at the
methyl group of the acetyl moiety is accomplished by treating
cis-piperidine 18 with one equivalent of LHMDS at -78 °C in
THF solvent. After stirring for one hour, 6-methoxyquinoline-
4-carbaldehyde14 was added. The reaction mixture was quenched
at -78 °C with acetic anhydride and warmed to -40 °C, at
which point DBU was added. Quenching of the reaction mixture
at -40 °C using saturated aqueous ammonium chloride was
Elaboration of the cyclization product 13 to quinine requires
diastereoselective conjugate reduction to establish appropriate
relative stereochemistry at C-3 and C-4. Using a modification
of the copper-hydride mediated 1,4-reduction developed by
Tsuda and Saegusa,13 the cis-piperidine 14 was formed as a
single diastereomer, as established 1H NMR analysis. The
relative stereochemistry of piperidine 14 was corroborated by
single crystal X-ray diffraction analysis. Interestingly, the
corresponding N-Ts derivative 12 forms an equimolar mixture
of diastereomers upon exposure to identical conjugate reduction
conditions. cis-Piperidine 14 requires careful handling, as rapid
isomerization to trans-piperidine epi-14 occurs upon exposure
to acid or base (Scheme 5).
(14) (a) Este´vez, C.; Venemalm, L.; Alvarez, M.; Joule, J. Tetrahedron 1994,
50, 7879. (b) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron 2004, 60, 3017. (c) Biot, C.; Delhaes, L.; Maciejewski, L. A.;
Mortuaire, M.; Campus, D.; Dive, D.; Brocard, J. S. Eur. J. Med. Chem. 2000,
35, 707.
(12) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735.
(13) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J. Org.
Chem. 1986, 51, 537.
J. Org. Chem. Vol. 73, No. 23, 2008 9381

Webber and Krische
SCHEME 4. Stereoselective Conversion of Cycloallylation Product 13 to (()-7-Hydroxyquinine Involving a Series of
1,2-Asymmetric Induction Events
SCHEME 5. Epimerization to Thermodynamically
Preferred trans-Piperidine 14 and 18
Validating the superiority of the bis(hydroxamate) catalyst,
epoxidation of allylic alcohol 16 under identical conditions
employing VO(acac)2 as catalyst results in a substantial decline
in stereoselectivity (6:1 dr). The stereochemical assignment of
glycidic alcohol 17 was confirmed by single crystal X-ray
diffraction analysis.
Removal of the N-protecting group of glycidic alcohol 17
was accomplished upon treatment of 17 with trifluoroacetic acid
in dichloromethane. The resulting crude amine underwent
intramolecular cyclization when exposed to Zn(OTf)2 in reflux-
ing MeCN to provide 7-hydroxyquinine 3 in 70% yield. At this
point, several different strategies to deoxygenate 7-hydroxyqui-
nine 3 were explored. Selective functionalization of the C-9
hydroxyl is readily achieved, as demonstrated by formation of
the p-methoxybenzyl ether 24 and methoxymethyl ether 25
(Scheme 7). Having differentiated the alcohol functionalities,
the Barton-McCombie deoxygenation was first investigated.19
This strategy appeared quite attractive, as deoxygenation of the
epimeric C-7 hydroxyl had been accomplished in a quinine
model study.20 The C-7 hydroxyl of 24 and 25, however, proved
to be especially resistant to the action of external reagents.
Treatment of 24 and 25 with thiocarbonyldiimidazole under a
range of conditions provided none of the desired thiocarbamate.
Attempted xanthate formation also failed. Protocols for the
radical deoxygenation of tertiary alcohols and hindered second-
ary alcohols are reported by Barton, which involve formation
of mixed oxalates,21 thioformates22 and phenylselenocarbon-
ates.23 These too were ineffective.
required to avoid epimerization. Using this procedure, the N-Boc
protected aldol adduct 15, which retains the cis-piperidine, is
obtained in 70% isolated yield. Thus, in eight manipulations
from commercially available aminoacetaldehyde diethyl acetal,
the carbon framework of quinine is assembled (Scheme 4).
With clear evidence for the thermodynamic preference of a
trans-relationship about the piperidine of enone 15, immediate
reduction of the ketone was imperative. Upon exposure of enone
15 to L-selectride at -78 °C in THF, allylic alcohol 16 is formed
1
as a single stereoisomer, as determined by H NMR analysis
(>20:1 dr). This transformation removed the threat of epimer-
ization, while introducing functionality required for hydroxyl-
directed diastereoselective epoxidation. However, under standard
conditions developed by Sharpless employing VO(acac)2 (5
mol%) as precatalyst and TBHP as terminal oxidant in toluene
at 50 °C,15 the glycidic alcohol 17 is formed in 98% yield in a
3:1 diastereomeric ratio. Such modest stereoselectivity is
presumed to arise in response to the relatively low levels of
allylic strain embodied by the trans-1,2-disubstituted olefin of
16.16
The remarkable resistance of alcohols 24 and 25 toward
derivatization is underscored by their reluctance to react with
ketene, neat acetic anhydride or acetyl chloride. The singular
method identified for derivation of alcohols 24 and 25 involves
mesylation, which likely occurs through the intervention of
sulfene (H2CdSO2). Mesylates 26 and 27 were treated with a
range of hydride sources, molten thiolate, various iodide sources
and hydrazines, however, mesylates 26 and 27 proved to be
quite impervious. Presumably, an appropriate trajectory for SN2
displacement cannot be attained due to the position of the C-3
vinyl moiety. In the hope of exploiting the C-3 vinyl moiety as
a directing group, the reaction of mesylates 26 and 27 with low
Hydroxamates are effective ligands in asymmetric oxovana-
dium catalyzed epoxidations of allylic alcohols.17 Upon screen-
ing a number of achiral hydroxamic acids, that derived from
N-methyl hydroxylamine and pivaloyl chloride, when complexed
to VO(acac)2 in situ, promoted greater levels of diastereose-
lection (6:1 dr). It was found that preformation of the oxova-
nadium bis(hydroxamate) complex was required to suppress a
less selective background reaction promoted by VO(acac)2.18
After extensive optimization, it was found that exposure of 16
to VO[tBuCO(MeNO)]2 (5 mol%) and TBHP (1000 mol%) in
dichloromethane at 4 °C promotes formation of epoxide 17 in
91% isolated yield as a 17:1 ratio of diastereomers. In this way,
highly stereoselective formation of five contiguous stereocenters
is achieved through a series of 1,2-asymmetric induction events.
(19) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574.
(20) Stotter, P. L.; Friedman, M. D.; Minter, D. E. J. Org. Chem. 1985, 50,
29.
(15) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.
(16) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(17) (a) Michaelson, R. C.; Palermo, R. E.; Sharpless, K. B. J. Am. Chem.
Soc. 1977, 99, 1990. (b) Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000,
122, 10452. (c) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H.
Angew. Chem., Int. Ed. 2005, 44, 4389.
(21) (a) Barton, D. H. R.; Crich, D. J. Chem. Soc., Chem. Commun. 1984,
774. (b) Barton, D. H. R.; Crich, D. J. Chem. Soc. Perkin Trans. 1 1986, 1603.
(22) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc. Perkin Trans. 1
1975, 1574. (b) Barton, D. H. R.; Hartwig, W.; Motherwell, R. S. H.; Motherwell,
W. B.; Stange, A. Tetrahedron Lett. 1982, 23, 2019.
(23) Pfenninger, J.; Heuberger, C.; Graf, W. HelV. Chim. Acta 1980, 63,
2328.
(18) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1059.
9382 J. Org. Chem. Vol. 73, No. 23, 2008

Merged Morita-Baylis-Hillman-Tsuji-Trost Cyclization
SCHEME 6. Formal Synthesis of (()-Quinine 1 via Conversion of cis-Piperidine 14 to Diene 23
SCHEME 7. Selective Functionalization of
7-Hydroxyquinine 3
Baylis-Hillman reaction and the electrophilic features of the
Tsuji-Trost reaction. In accordance with this strategy, quinine
is accessible in 16 steps and 4% overall yield from commercial
aminoacetaldehyde diethyl acetal, making it the most concise
approach to quinine, to date. Additionally, 7-hydroxyquinine
is prepared in 13 steps and 11% overall yield from aminoac-
etaldehyde diethyl acetal through a sequence wherein five
contiguous stereocenters are formed with high levels of relative
stereocontrol through a series of 1,2-asymmetric induction
events. This route delivers 7-hydroxyquinine in less than half
the number of manipulations previously reported.9
Among the challenges that remain, control of absolute
stereochemistry and the identification of an effective method
for C-7 deoxygenation of 7-hydroxyquinine figure prominently.
With regard to the former issue, it is interesting to note that the
N-2,4,6-triisopropylbenzenesulfinyl derivative of compound 6
engages in cyclization with only modest levels of diastereose-
lection (2:1), presumably as highly diastereoselective cyclization
requires high levels of diastereofacial selectivity at the stage of
phosphine conjugate addition and enolate allylation.
Quinine, which has been known since the very inception of
organic chemistry as a science, may be viewed as a barometer
of the state-of-the-art. Hence, it is remarkable that, to date, a
highly step-economic route to quinine that completely addresses
both relative and absolute stereochemistry remains absent. The
present study has evoked effective new strategies for controlling
the relative stereochemistry of quinine via substrate direction.
However, it is but one of many small steps toward the distant
goal of devising an ideal synthesis.
valent metals was explored. However, the Collman reagent24
(Na2Fe(CO)4), Rieke manganese25 and conditions developed by
Yus26 for the deoxygenation of hindered sulfonates also were
ineffective.
Given the difficulties encountered in the deoxygenation of
7-hydroxyquinine, an alternate strategy was pursued involving
C-7 deoxygenation in advance of amine-epoxide cyclization.
Thus, in analogy to the preparation of the corresponding N-Boc
protected allylic alcohol 16, cis-piperidine 14 was converted to
the N-Cbz derivative 19, which was transformed to the quinoline
containing enone 20 Via aldol coupling-dehydration to 6-meth-
oxyquinoline-4-carbaldehyde. Exposure of enone 20 to L-
selectride in THF solvent at -78 °C resulted in 1,2-reduction
to furnish allylic alcohol 21 as a single diastereomer, as
1
determined by H NMR analysis (>20:1 dr). Conversion of
allylic alcohol 21 to the corresponding acetate 22 followed by
palladium-catalyzed, formate-mediated reduction delivers the
product of C-7 deoxygenation 23 as a single alkene regio- and
stereoisomer (Scheme 6).27
Experimental Section
General. All reactions were run under an atmosphere of argon
when exclusion of water or oxygen was deemed appropriate.
Anhydrous solvents were transferred by an oven-dried syringe.
Diene 23 is an intermediate in Jacobsen’s synthesis of quinine
1. Although Jacobsen’s approach provides diene 23 in optically
enriched form, the C-3 stereocenter is initially formed as a 1:1.7
mixture favoring the undesired isomer, which after epimerization
is converted to a 3:1 mixture favoring the desired isomer. Our
route to racemic diene 23 is accomplished in two less manipula-
tions and with complete control of relative stereochemistry.
t
t
i
Dichloromethane (DCM), BuOH, AmOH, MeCN, Pr2NH, and
HMPA were dried by distillation over CaH2. Et2O, DME, THF,
and toluene were dried by distillation over sodium benzophenone.
DMF and pyridine were stored over molecular sieves and KOH
respectively. Chemical reagents were used as received without
further purification unless otherwise stated. Flasks were flame-dried
and cooled under a stream of argon. Analytical thin-layer chroma-
tography (TLC) was carried out using 0.2 mm commercial silica
get plates. Flash chromatography was performed on silica gel 60
(200-400 mesh) according to the method of Still. Solvents for
chromatography are listed as volume:volume ratios.
Proton nuclear magnetic resonance (1H NMR) spectra were
obtained at either 500, 400, or 300 MHz, as indicated. Chemical
shifts are reported in delta (µ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are reported
in Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR)
spectra were obtained at either 125, 100, or 75 MHz, as indicated.
Summary
Concise stereoselective syntheses of (()-quinine and (()-7-
hydroxyquinine are reported using a catalytic enone cycloally-
lation that combines the nucleophilic features of the Morita-
(24) Collman, J. P. Acc. Chem. Res. 1975, 8, 342.
(25) Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 1999, 40, 4931.
(26) Radivoy, G.; Alonso, F.; Moglie, Y.; Vitale, C.; Yus, M. Tetrahedron
2005, 61, 3859.
(27) Hutchins, R. O.; Learn, K.; Fulton, R. P. Tetrahedron Lett. 1980, 21,
27.
J. Org. Chem. Vol. 73, No. 23, 2008 9383

Webber and Krische
Chemical shifts are reported in delta (µ) units, parts per million
(ppm) relative to the residual solvent. 13C NMR spectra were
routinely run with broadband decoupling. Vanadium-51 nuclear
magnetic resonance (51V NMR) spectra were obtained at 131 MHz.
Chemical shifts are reported in delta (µ) units, parts per million
(ppm) relative to the singlet at 2.0 ppm for VOCl3. High-resolution
mass spectra (HRMS) are reported m/z (relative intensity). Accurate
masses are reported for the molecular ion (M + 1) or a suitable
fragment ion. Melting points were obtained in open capillaries and
are uncorrected.
Conversion of Aminoacetaldehyde Diethyl Acetal 7 to
Enone 10. To a solution of aminoacetaldehyde diethyl acetal 7 (5.07
mL, 34.9 mmol, 100 mol%) in DCM (55.8 mL, 0.63 M) at 0 °C
was added Et3N (6.46 mL, 46.4 mmol, 133 mol%) and tosyl
chloride (8.85 g, 46.4 mmol, 133 mol%). The reaction mixture was
allowed to slowly warm to room temperature with stirring over
20 h, at which point the reaction mixture was quenched with water
and extracted with DCM with the aid of a separatory funnel. The
combined organic layers were washed with saturated Cu2SO4 (aq.),
brine, dried (Na2SO4), filtered and concentrated in Vacuo to furnish
the crude sulfonamide.
Conversion of Aminoacetaldehyde Diethyl Acetal 7 to
Enone 11. To a solution of aminoacetaldehyde diethyl acetal 7 (11.7
mL, 80.7 mmol, 100 mol%) in DCM (129 mL, 0.63 M) at 0 °C
was added Et3N (13.8 mL, 99.0 mmol, 120 mol%) and 2,4,6-
triisopropylbenzenesulfonyl chloride (25 g, 82.6 mmol, 102 mol%).
The reaction mixture was allowed to slowly warm to room
temperature over 22 h with stirring, at which point the reaction
mixture was poured into H2O and extracted with DCM with the
aid of a separatory funnel. The combined organic extracts were
washed with 5% Cu2SO4 (aq.), brine, dried (Na2SO4), filtered, and
concentrated in Vacuo to furnish the crude sulfonamide.
The crude sulfonamide (32.25 g) was dissolved in THF (269
mL, 0.3 M) and the solution was cooled to 0 °C with stirring. The
known allylic alcohol11 (17.67 g, 121.1 mmol, 150 mol%), DIAD
(25.4 mL, 129.1 mmol, 160 mol%), and PPh3 (34.04 g, 121.1 mmol,
160 mol%) were added to the reaction vessel. The reaction mixture
was allowed to slowly warm to room temperature with stirring over
20 h, at which point the reaction mixture was concentrated in Vacuo.
The crude residue was purified by flash column chromatography
(SiO2/hexanes/EtOAc, 15:1 to 3:1) to provide compound 9 (42.59
1
g, 26.9 mmol) as a thick yellow oil in 100% yield. H NMR (400
MHz, CDCl3): δ 7.16 (s, 2 H), 5.78-5.72 (m, 1 H), 5.63-5.56
(m, 1 H), 4.66 (dd, 2 H, J ) 6.8, 1.0 Hz), 4.53 (t, 1 H, J ) 5.3
Hz), 4.15-4.07 (m, 2 H), 4.04 (d, 2 H, J ) 7.2 Hz), 3.76 (s, 3 H),
3.68-3.60 (m, 2 H), 3.52-3.44 (m, 2 H), 3.26 (d, 2 H, J ) 5.5
Hz), 2.89 (hp, 1 H, J ) 6.8 Hz), 1.25 (dd, 18 H, J ) 6.9, 1.1 Hz),
1.18 (t, 6 H, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3): δ 155.4,
153.1, 151.2, 131.2, 129.5, 127.5, 123.8, 102.3, 63.0, 63.0, 54.6,
47.1, 43.6, 34.0, 29.1, 24.6, 23.4, 15.1; IR (film): 2962, 2872, 1752,
1601, 1445, 1425, 1365, 1012, 940 cm-1; HRMS (CI) calcd for
C27H44NO7S [M - 1]: 526.2839, found: 526.2845.
Compound 9 (29.38 g, 55.70 mmol, 100 mol%) was dissolved
in CHCl3 (137 mL, 0.4 M) and H2O (68 mL) at 0 °C. Trifluoroacetic
acid (68 mL, 915 mmol, 1640 mol%) was added and the reaction
mixture was allowed to slowly warm to ambient temperature with
stirring over 20 h, at which point solid NaHCO3 was added and
the reaction mixture was poured into H2O, and extracted with DCM
with the aid of a separatory funnel. The combined organic extracts
were washed with saturated NaHCO3 (aq.), brine, dried (Na2SO4),
filtered, and concentrated in Vacuo to provide the crude aldehyde
(24.01 g) as a yellow oil.
The crude sulfonamide (10.76 g) was dissolved in THF (116
mL, 0.3 M) and the solution was cooled to 0 °C with stirring. The
known allylic alcohol11 (5.72 g, 39.1 mmol, 110 mol%), DIAD
(8.32 mL, 42.3 mmol, 120 mol%), and PPh3 (11.1 g, 42.3 mmol,
120 mol%) were added to the reaction vessel. The reaction mixture
was allowed to slowly warm to room temperature with stirring over
20 h, at which point the reaction mixture was concentrated in Vacuo.
The crude residue was purified by flash column chromatography
(SiO2: hexanes:EtOAc, 10:1 to 2:1) to provide 8 (12.47 g) as a
thick yellow oil.
Compound 8 (12.47 g) was dissolved in CHCl3 (74 mL, 0.32
M) and H2O (36 mL) at 0 °C. Trifluoroacetic acid (36 mL, 492
mmol, 1410 mol%) was added and the reaction mixture was allowed
to slowly warm to room temperature with stirring over 20 h, at
which point it was quenched with solid NaHCO3, poured into H2O,
and extracted with DCM with the aid of a separatory funnel. The
combined organic extracts were washed with saturated NaHCO3
(aq.), brine, dried (Na2SO4), filtered and concentrated in Vacuo. The
crude residue was purified by flash column chromatography (SiO2:
hexanes:EtOAc, 5:1 to 1:1) to provide the aldehyde (8.07 g, 23.7
1
mmol) as a yellow oil in 68% over 3 steps. H NMR (300 MHz,
To a solution of the crude aldehyde in DCM (520 mL, 0.1 M)
at ambient temperature was added the known Wittig reagent28
(19.73 g, 61.98 mmol, 110 mol%). The reaction mixture was
allowed to stir for 18 h, at which point the reaction mixture was
concentrated in Vacuo. The crude residue was purified by flash
column chromatography (SiO2:/hexanes/EtOAc, 5:1 to 3:1) to
provide compound 11 (18.70 g, 37.88 mmol, 68%) as a white solid.
CDCl3): δ 9.56 (s, 1 H), 7.69 (d, 2 H, J ) 8.2 Hz), 7.33 (d, 2 H,
J ) 8.2 Hz), 5.78-5.70 (m, 1 H), 5.61-5.53 (m, 1 H), 4.55 (d, 2
H, J ) 6.7 Hz), 3.94 (d, 2 H, J ) 6.9 Hz), 3.86 (s, 2 H), 3.74 (s,
3 H), 2.43 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ 197.7, 155.5,
144.1, 135.5, 129.9, 128.9, 128.5, 127.3, 62.3, 56.1, 54.9, 45.8,
21.5; IR (film): 2958, 1598, 1445, 1345, 1267, 1161, 763 cm-1
;
1
HRMS (CI) calcd. for C15H20NO6S [M + 1]: 342.1011, found:
342.1011
M.P.: 42 °C; H NMR (400 MHz, CDCl3): δ 7.18 (s, 2 H), 6.65
(dt, 1 H, J ) 16.1, 6.4 Hz), 6.14 (d, 1 H, J ) 16.1 Hz), 5.79-5.73
(m, 1 H), 5.68-5.62 (m, 1 H), 4.56 (d, 2 H, J ) 6.8 Hz), 4.10 (hp,
2 H, J ) 6.8 Hz), 3.97 (dd, 2 H, J ) 5.2, 1.0 Hz), 3.89 (d, 2 H, J
) 7.2 Hz), 3.77 (s, 3 H), 2.90 (hp, 1 H, J ) 6.8 Hz), 2.23 (s, 3 H),
1.26 (dd, 18 H, J ) 6.8, 1.4 Hz); 13C NMR (75 MHz, CDCl3): δ
197.5, 155.3, 153.5, 151.4, 141.0, 133.3, 130.3, 129.1, 127.6, 124.0,
70.9, 62.4, 54.8, 46.6, 42.8, 36.2, 34.0, 29.2, 28.5, 26.9, 24.7, 23.4;
IR (film): 2960, 2931, 2871, 1601, 1384, 1107, 1072, 1060, 703
cm-1; HRMS (CI) calcd for C26H40NO6S [M + 1]: 494.2576, found:
494.2579.
To a solution of the aldehyde (0.26 g, 0.75 mmol, 100 mol%) in
DCM (7.5 mL, 0.1 M) at ambient temperature was added the known
Wittig reagent28 (0.24 g, 0.75 mmol, 100 mol%). The reaction
mixture was allowed to stir for 20 h, at which point the reaction
mixture was concentrated in Vacuo. The crude residue was purified
by flash column chromatography (SiO2/hexanes/EtOAc, 5:1 to 2:1)
to provide 10 (0.20 g, 0.52 mmol) as a yellow oil in 69% yield. 1H
NMR (400 MHz, CDCl3): δ 7.64 (d, 2 H, J ) 8.2 Hz), 7.27 (d, 2
H, J ) 7.9 Hz), 6.51 (dt, 1 H, J ) 16.1 Hz), 6.06 (dt, 1 H, J )
16.4, 1.4 Hz), 5.66-5.60 (m, 1 H), 5.49-5.42 (m, 1 H), 4.51 (dd,
2 H, J ) 6.8, 1.0 Hz), 3.86 (m, 4 H), 3.69 (s, 3 H), 2.37 (s, 3 H),
2.14 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 197.4, 155.2, 143.7,
141.1, 136.2, 132.4, 129.7, 129.1, 127.2, 127.0, 62.3, 54.6, 48.2,
44.6, 26.9, 21.2; IR (film): 3055, 2985, 1599, 1422, 1265, 741,
706 cm-1; HRMS (CI) calcd for C18H24NO6S [M + 1]: 382.1324,
found: 382.1329.
1-[1-(Toluene-4-sulfonyl)-3-vinyl-1,2,3,6-tetrahydro-pyridin-
4-yl]-ethanone (12). To a degassed solution of enone 10 (83 mg,
t
0.20 mmol, 100 mol%) in AmOH (2.0 mL, 0.1 M) at ambient
temperature was added Pd(PPh3)4 (13 mg, 0.01 mmol, 5 mol%) and
freshly distilled PBu3 (50 µL, 0.2 mmol, 100 mol%). The reaction
mixture was allowed to stir at ambient temperature for 20 min, at which
point the reaction mixture was concentrated in Vacuo. The crude residue
was purified by flash column chromatography (SiO2: hexanes:EtOAc,
5:1 to 2:1) to provide the title compound (42 mg, 0.12 mmol) as a
yellow oil in 62% yield. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, 2 H,
(28) Kuroda, H.; Hanaki, E.; Izawa, H.; Kano, M.; Itahasi, H. Tetrahedron
2004, 60, 1913.
9384 J. Org. Chem. Vol. 73, No. 23, 2008

Merged Morita-Baylis-Hillman-Tsuji-Trost Cyclization
J ) 8.2 Hz), 7.32 (d, 2 H, J ) 8.2 Hz), 6.72 (t, 1 H, J ) 3.5 Hz), 5.83
(ddd, 1 H, J ) 17.1, 10.3, 6.8 Hz), 5.12-5.07 (m, 2 H), 4.20 (dd, 1
H, J ) 19.0, 3.8 Hz), 3.74 (dd, 1 H, J ) 11.6, 2.1 Hz), 3.51 (br s, 1
H), 3.36 (dt, 1 H, J ) 19.1, 2.4 Hz), 2.54 (dd, 1 H, J ) 11.5, 3.8 Hz),
2.42 (s, 3 H), 2.26 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 196.4,
143.9, 139.2, 136.6, 134.0, 132.8, 129.7, 127.6, 116.9, 47.2, 44.8, 36.8,
25.6, 21.5; IR (film): 2924, 2854, 1674, 1597, 1354, 1166, 1093, 668
cm-1; HRMS (CI) calcd for C16H20NO3S [M + 1]: 306.1164, found:
306.1173.
reaction mixture was filtered with the aid of CHCl3, and concen-
trated in Vacuo.
The crude amine was dissolved in DCM (79 mL, 0.1 M), and the
solution was cooled to 0 °C. To the stirred solution was added Et3N
(3.0 mL, 21.52 mmol, 270 mol%), Boc2O (8.66 g, 39.68 mmol, 500
mol%), and DMAP (0.98 g, 8.02 mmol, 101 mol%). The reaction
mixture was allowed to slowly warm to ambient temperature with
stirring over 18 h, at which point the reaction mixture was quenched
with saturated NH4Cl (aq.) and extracted with DCM with the aid of a
separatory funnel. The combined organic extracts were washed with
brine, dried (Na2SO4), filtered and concentrated in Vacuo. The crude
residue was purified by flash column chromatography (SiO2/hexanes/
EtOAc, 5:1) to provide the title compound (1.52 g, 6.03 mmol) as a
colorless oil in 76% yield. 1H NMR (500 MHz, d6-DMSO, 90 °C): δ
5.65 (ddd, 1 H, J ) 17.3, 10.5, 2.8 Hz), 5.11 (ddd, 1 H, J ) 17.3 Hz,
1.8 Hz, 1.2 Hz), 5.03 (ddd, 1 H, J ) 10.6, 1.7, 1.0 Hz), 3.93 (ddd, 1
H, J ) 13.2 Hz, 3.5 Hz, 1.6 Hz), 3.95-3.88 (m, 1 H), 3.11 (dd, 1 H,
J ) 13.2 Hz, 3.3 Hz), 2.85-2.80 (m, 2 H), 2.77 (dt, 1 H, J ) 10.7
Hz, 4.2 Hz), 2.07 (s, 3 H), 1.62-1.59 (m, 1 H), 1.58-1.52 (m, 1 H),
1.39 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 208.8, 154.7, 134.8,
117.2, 79.4, 79.3, 52.3, 40.6, 28.4, 28.2, 28.1, 22.5; IR (neat): 2976,
2930, 2854, 1478, 1464, 1423, 1366, 1241, 1164, 1119 cm-1; HRMS
(CI) calcd for C14H24NO3 [M + 1]: 254.1756, found: 254.1757.
4-[3-(6-Methoxy-quinolin-4-yl)-acryloyl]-3-vinyl-piperidine-
1-carboxylic acid tert-butyl ester (15). To a solution of methyl
ketone 14 (0.11 g, 0.44 mmol, 100 mol%) in THF (1.4 mL, 0.3 M) at
-78 °C was rapidly added LHMDS (1.0 M in THF, 0.53 mL, 0.53
mmol, 120 mol%). The reaction mixture was stirred at -78 °C for
1 h, at which point the quinoline-bearing aldehyde14 (0.11 g, 0.57
mmol, 130 mol%) was added as a solution in THF (0.3 mL). The
reaction mixture was allowed to stir at -78 °C for 45 min, at which
point Ac2O (80 µL, 0.89 mmol, 200 mol%) and DMAP (54 mg, 0.44
mmol, 100 mol%) were added. The reaction was allowed to stir at
-78 °C for an additional 45 min, at which point it was allowed to
reach -40 °C (MeCN/solid CO2) and was allowed to stir for 30 min.
To the reaction mixture was added DBU (0.34 mL, 2.27 mmol, 520
mol%) at -40 °C. The reaction mixture was allowed to stir for 15
min at -40 °C, at which point it was quenched with saturated NH4Cl
(aq.) and was extracted with Et2O with the aid of a separatory funnel.
The combined ethereal extracts were washed with brine, dried
(Na2SO4), filtered and concentrated in Vacuo. The crude residue was
purified by flash column chromatography (SiO2/hexanes/EtOAc, 1:1
to 1:3) to provide the title compound (0.13 g, 0.31 mmol) as a yellow
1-[1-(2,4,6-Triisopropyl-benzenesulfonyl)-3-vinyl-1,2,3,6-tet-
rahydro-pyridin-4-yl]-ethanone (13). To a degassed solution of
enone 11 (0.50 g, 1.0 mmol, 100 mol%) in tAmOH (10.0 mL, 0.1 M)
at ambient temperature was added Pd(PPh3)4 (59 mg, 0.05 mmol, 5
mol%) and PMe3 (1.0 M in toluene, 0.82 mL, 0.8 mmol, 80 mol%).
The reaction mixture was allowed to stir for 30 min, at which point
the reaction mixture was poured into water and extracted with DCM
with the aid of a separatory funnel. The combined organic extracts
were washed with brine, dried (Na2SO4), filtered and concentrated in
Vacuo. The crude residue was purified by flash column chromatography
(SiO2/hexanes/EtOAc, 10:1 to 5:1) to provide the title compound (0.29
1
g, 0.68 mmol) as a yellow oil in 68% yield. H NMR (400 MHz,
CDCl3): δ 7.18 (s, 2 H), 6.80 (t, 1 H, J ) 3.6 Hz), 5.70 (ddd, 1 H, J
) 17.1, 10.3, 6.8 Hz), 5.03-4.96 (m, 2 H), 4.12 (hp, 2 H, J ) 6.8
Hz), 3.93 (dd, 1 H, J ) 18.7, 4.0 Hz), 3.80 (dt, 1 H, J ) 18.7, 2.6
Hz), 3.68 (dd, 1 H, J ) 12.2, 2.6 Hz), 3.55 (br s, 1 H), 3.04 (dd, 1 H,
J ) 12.0, 3.8 Hz), 2.90 (hp, 1 H, J ) 6.8 Hz), 2.29 (s, 3 H), 1.26-1.23
(m, 18 H); 13C NMR (100 MHz, CDCl3): δ 196.5, 153.5, 151.8, 139.3,
136.9, 134.4, 129.4, 123.9, 116.7, 45.6, 43.8, 36.8, 34.1, 29.4, 28.5,
25.6, 25.0, 24.7, 23.4, 23.4; IR (film): 3068, 2962, 2870, 2823, 2255,
1674, 1601, 1562, 1462, 1385, 1152, 918 cm-1; HRMS (CI) calcd
for C24H36NO3S [M + 1]: 418.2410, found: 418.2407.
cis-1-[1-(2,4,6-Triisopropyl-benzenesulfonyl)-3-vinyl-piperi-
din-4-yl]-ethanone (14). To a solution of CuI (2.92 g, 15.37 mmol,
110 mol%) in THF (480 mL) at -60 °C was added MeLi (1.6 M in
Et2O, 10.8 mL, 17.3 mmol, 125 mol%), HMPA (59.3 mL, 340.8 mmol,
2500 mol%), and DIBAL (1.0 M in cyclohexane, 69 mL, 69 mmol,
500 mol%). The resulting mixture was allowed to stir between -60
°C and -55 °C for 1.5 h and was then cooled to -78 °C. Enone 13
(5.74 g, 13.76 mmol, 100 mol%) in THF (19 mL, 0.72 M) was added
to the reaction mixture at -78 °C. The reaction mixture was allowed
to stir for 10 min, at which point the reaction mixture was quenched
with 2 M HCl (aq.) at -78 °C and the cooling bath was removed.
The reaction mixture was allowed to reach room temperature, at which
point the reaction mixture was poured into H2O and extracted with
Et2O with the aid of a separatory funnel. The combined organic layers
were washed with brine, dried (Na2SO4), filtered and concentrated in
Vacuo. The crude residue was purified by flash column chromatography
(SiO2/hexanes/EtOAc, 5:1 to 4:1) to provide the title compound (4.47
g, 10.60 mmol) as a white solid in 77% yield exclusively as the cis-
diastereomer. M.P.: 112-113 °C; 1H NMR (400 MHz, CDCl3): δ 7.16
(s, 2 H), 5.83 (ddd, 1 H, J ) 17.2, 10.5, 8.7 Hz), 5.30-5.06 (m, 2 H),
4.16-4.07 (m, 2 H), 3.78-3.73 (m, 1 H), 3.44-3.40 (m, 1 H), 3.12
(dd, 1 H, J ) 11.8, 3.3 Hz), 2.94-2.84 (m, 3 H), 2.66 (dt, 1 H, J )
10.3, 4.4 Hz), 2.12 (s, 3 H), 1.88-1.79 (m, 2 H), 1.24 (dt, 18 H, J )
6.9, 1.5 Hz); 13C NMR (100 MHz, CDCl3): δ 208.5, 153.4, 151.8,
135.0, 129.6, 123.9, 117.7, 51.6, 48.4, 43.9, 40.4, 34.1, 31.6, 29.4,
28.6, 25.1, 24.7, 23.5, 22.6, 22.6, 14.1; IR (film): 2959, 2929, 2869,
1711, 1601, 1276, 1261, 1151, 764, 750 cm-1; HRMS (CI) calcd for
C24H38NO3S [M + 1]: 420.2572, found: 420.2585.
1
foam in 70% yield. H NMR (500 MHz, d6-DMSO, 90 °C): δ 8.76
(d, 1 H, J ) 4.5 Hz), 8.18 (d, 1 H, J ) 15.8 Hz), 7.99 (dd, 1 H, J )
6.8 Hz, 3.1 Hz), 7.74 (d, 1 H, J ) 4.5 Hz), 7.48-7.45 (m, 2 H), 7.23
(d, 1 H, J ) 15.8 Hz), 5.72 (ddd, 1 H, J ) 17.3, 10.6, 2.8 Hz),
5.11-5.07 (m, 1 H), 5.05-5.02 (m, 1 H), 3.98-3,92 (m, 2 H), 3.97
(s, 3 H), 3.31-3.24 (m, 2 H), 2.98-2.95 (m, 2 H), 1.84-1.76 (m, 1
H), 1.71-1.66 (m, 1 H), 1.41 (s, 9 H); 13C NMR (100 MHz, CDCl3):
δ 199.0, 170.6, 158.0, 154.5, 146.9, 144.5, 138.1, 136.6, 134.6, 131.3,
128.7, 127.1, 122.1, 117.9, 117.1, 100.6, 79.3, 55.3, 55.3, 51.0, 40.5,
28.0, 22.6; IR (film): 2974, 1690, 1619, 1506, 1472, 1429, 1366, 1318,
1227, 1165 cm-1; HRMS (CI) calcd for C25H31N2O4 [M + 1]:
423.2284, found: 423.2284.
4-[1-Hydroxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-pip-
eridine-1-carboxylic acid tert-butyl ester (16). To a solution of
enone 15 (0.98 g, 2.33 mmol, 100 mol%) in THF (65.8 mL, 0.04 M)
at -78 °C was added dropwise L-Selectride (1.0 M in THF, 3.1 mL,
3.07 mmol, 130 mol%). The reaction mixture was allowed to stir for
5 min, at which point saturated NH4Cl (aq.) was added and the reaction
mixture was extracted with Et2O with the aid of a separatory funnel.
The combined ethereal extracts were washed with brine, dried
(Na2SO4), filtered and concentrated in Vacuo. The crude residue was
purified by flash column chromatography (SiO2/hexanes/EtOAc, 1:1
to 1:3) to provide the title compound (0.93 g, 2.19 mmol) as a white
cis-4-Acetyl-3-vinyl-piperidine-1-carboxylic acid tert-butyl
ester (18). To a solution of naphthalene (9.57 g, 74.64 mmol, 940
mol%) in DME (22.8 mL) at room temperature was added freshly
cut sodium (1.42 g, 61.72 mmol, 780 mol%). The resulting green
solution of the anion radical was stirred for 2 h, at which point it
was added dropwise to a solution of N-trisyl piperidine 14 (3.33 g,
7.94 mmol, 100 mol%) in DME (50 mL, 0.16 M) at -78 °C. Once
the green color of the anion radical persisted for 10 s, saturated
NH4Cl (aq.) was added immediately. The crude reaction mixture
was allowed to reach ambient temperature, at which point the
1
solid in 94% yield as a single diastereomer. M.P.: 148-149 °C; H
NMR (500 MHz, d6-DMSO, 90 °C): δ 8.66 (d, 1 H, J ) 4.5 Hz),
7.92 (d, 1 H, J ) 9.2 Hz), 7.51 (d, 1 H, J ) 4.7 Hz), 7.48 (d, 1 H, J
J. Org. Chem. Vol. 73, No. 23, 2008 9385

Webber and Krische
1
) 2.7 Hz), 7.40 (dd, 1 H, J ) 9.2, 2.8 Hz), 7.24 (d, 1 H, J ) 15.3
Hz), 6.49 (dd, 1 H, J ) 15.8, 7.0 Hz), 5.93 (ddd, 1 H, J ) 17.4, 10.5,
2.3 Hz), 5.22 (ddd, 1 H, J ) 17.4, 2.4, 1.1 Hz), 5.16 (dd, 1 H, J )
10.9, 1.9 Hz), 4.73 (brs, 1 H), 4.08-4.02 (m, 3 H), 3.94 (s, 3 H), 2.90
(dd, 1 H, J ) 13.2, 3.0 Hz), 2.79 (brs, 1 H), 2.70 (td, 1 H, J ) 12.4,
3.0 Hz), 1.77-1.71 (m, 1 H), 1.45-1.41 (m, 1 H), 1.40 (s, 9 H),
1.36-1.33 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 157.5, 154.9,
147.0, 144.0, 141.2, 138.4, 135.4, 130.8, 126.9, 125.6, 121.7, 117.5,
101.2, 79.3, 73.5, 65.7, 55.3, 55.3, 45.2, 39.1, 28.2, 23.8, 15.1; IR
(film): 3630, 3264, 2359, 2341, 2018, 1693, 1620, 1392, 1366, 1230,
1164, 1138, 1034 cm-1; HRMS (CI) calcd for C25H33N2O4 [M + 1]:
425.2440, found: 425.2441.
VO(hydroxamate)2. To a solution of the known hydroxamic
acid29 (1.00 g, 7.64 mmol, 160 mol%) in H2O (12 mL) at ambient
temperature was added Na2CO3 (0.80 g, 7.52 mmol, 150 mol%)
and VO(SO)4µH2O (0.80 g, 4.89 mmol, 100 mol%) in H2O (12
mL, 0.4 M). The reaction mixture, which immediately turned purple,
was allowed to stir for 5 min, at which point the reaction mix-
ture was cooled to 0 °C and VO(hydroxamate)2 (0.32 g, 1.27 mmol)
was collected by filtration with the aid of a Hirsch funnel, washed
with cold H2O and dried in Vacuo to provide the title compound as
a light purple solid in 26% yield. M.P.: 134-135 °C; 51V NMR
(130 MHz, C6D6): δ -375.3, -412.7, -492.4, -552.0; IR (film):
2978, 2939, 2361, 1572, 1483, 1422, 1368, 1111, 983, 956, 718,
606 cm-1; HRMS (CI) calcd for C12H25N2O5V [M + 1]: 328.1203,
found: 328.1206.
4-{Hydroxy-[3-(6-methoxy-quinolin-4-yl)-oxiranyl]-methyl}-
3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (17). To a
solution of allylic alcohol 16 (1.00 g, 2.27 mmol, 100 mol%) in DCM
(22.3 mL, 0.1 M) at 4 °C was added VO(hydroxamate)2 (38 mg, 0.11
mmol, 5 mol%) and TBHP (5.0 M in decane, 4.4 mL, 22.2 mmol,
980 mol%). The reaction mixture was allowed to stir at 4 °C for 71 h,
at which point the reaction mixture was concentrated in Vacuo. The
crude residue was purified by flash column chromatography (SiO2/
hexanes/EtOAc, 1:1 to 1:2) to provide the title compound (0.91 g,
2.07 mmol) as a white foam in 91% yield as a 17:1 ratio of separable
diastereomers. 1H NMR (500 MHz, d6-DMSO, 90 °C): δ 8.69 (d, 1
H, J ) 4.4 Hz), 7.96 (d, 1 H, J ) 2.7 Hz), 7.44 (dd, 1 H, J ) 9.2, 2.8
Hz), 7.28 (d, 1 H, J ) 4.4 Hz), 5.88 (ddd, 1 H, J ) 17.4, 10.5, 2.3
Hz) 5.25 (ddd, 1 H, J ) 17.4, 2.3, 1.1 Hz), 5.15 (dd, 1 H, J ) 10.5,
2.3 Hz), 4.96 (dd, 1 H, J ) 6.2, 2.1 Hz), 4.42 (d, 1 H, J ) 2.0 Hz),
4.10-4.05 (m, 2 H), 3.95 (s, 3 H), 3.23 (ddd, 1 H, J ) 12.6, 9.5, 6.4
Hz), 3.01-2.99 (m, 1 H), 2.91 (dd, 1 H, J ) 13.0, 2.8 Hz), 2.75-2.70
(m, 2 H), 1.91-1.85 (m, 1 H), 1.65 (dd, 1 H, J ) 13.6, 2.9 Hz), 1.40
(s, 9 H), 1.39-1.34 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 158.1,
154.9, 147.4, 143.3, 141.6, 135.1, 131.2, 127.2, 122.0, 118.1, 116.8,
109.7, 100.9, 79.6, 70.5, 63.3, 55.7, 52.1, 44.7, 39.4, 29.7, 28.3, 22.9;
IR (film): 2975, 2932, 2858, 2358, 2338, 2029, 1689, 1621, 1429,
1238, 1167, 1147, 853 cm-1; HRMS (CI) calcd for C25H33N2O5 [M
+ 1]: 441.2389, found: 441.2383.
7-Hydroxy-quinine (3). To a solution of epoxide 17 (53 mg, 0.12
mmol, 100 mol%) in DCM (1.2 mL, 0.1 M) at 0 °C was added
trifluoroacetic acid (0.30 mL, 3.90 mmol, 3300 mol%). The reaction
mixture was allowed to stir at 0 °C for 1 h, at which point the reaction
mixture was concentrated in Vacuo. Toluene (2 mL) was then added
to the flask and the mixture was concentrated again in Vacuo. The
yellow residue was dissolved in MeCN (3 mL, 0.04 M) and Na2CO3
(64 mg, 0.60 mmol, 500 mol%) and Zn(OTf)2 (65 mg, 0.18 mmol,
150 mol%) were added. The reaction mixture was allowed to stir at
80 °C for 41 h, at which point the reaction mixture was allowed to
cool to ambient temperature. The reaction mixture was poured into
H2O and was extracted with DCM with the aid of a separatory funnel.
The combined organic extracts were washed with brine, dried
(Na2SO4), filtered and concentrated in Vacuo. The crude residue was
purified by flash column chromatography (SiO2/DCM/MeOH, 20:1
to 15:1) to provide the title compound (28 mg, 0.084 mmol) as a white
solid in 70% yield. M.P.: 196 °C (decomp.); H NMR (400 MHz,
d6-DMSO): δ 8.69 (d, 1 H, J ) 4.8 Hz), 7.91 (d, 1 H, J ) 9.2 Hz),
7.59 (d, 1 H, J ) 2.7 Hz), 7.51 (d, 1 H, J ) 4.4 Hz), 7.37 (dd, 1 H,
J ) 9.2, 2.7 Hz), 5.99-5.90 (m, 1 H), 5.60 (dd, 1 H, J ) 9.4, 4.3
Hz), 5.46 (d, 1 H, J ) 4.1 Hz), 5.07-5.01 (m, 2 H), 4.81 (d, 1 H, J
) 2.4 Hz), 4.26-4.23 (m, 1 H), 3.89 (s, 3 H), 3.14-3.02 (m, 2 H),
2.65 (dd, 1 H, J ) 13.2, 10.1 Hz), 2.49-2.24 (m, 3 H), 2.08-1.99
(m, 2 H), 1.18-1.11 (m, 1 H); 13C NMR (100 MHz, d6-DMSO): δ
156.6, 148.9, 147.5, 144.0, 142.0, 131.0, 127.8, 120.9, 120.0, 114.5,
102.8, 66.9, 64.9, 63.8, 55.4, 54.5, 48.6, 41.4, 34.3, 20.0; IR (film):
3310, 2918, 2868, 2216, 2159, 2035, 1622, 1509, 1476, 1275, 1261,
1242, 1094, 1025, 750 cm-1; HRMS (CI) calcd for C20H25N2O3 [M
+ 1]: 341.1865, found: 341.1863.
cis-4-Acetyl-3-vinyl-piperidine-1-carboxylic Acid Benzyl
Ester (19). To a solution of naphthalene (0.57 g, 4.45 mmol, 1850
mol%) in DME (1.35 mL) at ambient temperature was added freshly
cut sodium (0.90 g, 3.8 mmol, 1580 mol%). The resulting green
solution of anion radical was allowed to stir for 2 h, at which point it
was added dropwise to a solution of N-trisyl piperidine 14 (0.10 g,
0.24 mmol, 100 mol%) in DME (1.42 mL, 0.17 M) at -78 °C. Once
the green color of the anion radical persisted for 10 s, saturated NH4Cl
(aq.) was added. The crude reaction mixture was filtered through a
pipet packed with Na2SO4 with the aid of CHCl3 and the filtrate was
concentrated. The residue was dissolved in DCM (2.4 mL, 0.1 M)
and the solution was cooled to 0 °C, at which point Et3N (0.20 mL,
1.43 mmol, 600 mol%) and CbzCl (0.11 mL, 0.78 mmol, 330 mol%)
were added. The reaction mixture was allowed to slowly warm to
ambient temperature with stirring over 18 h, at which point saturated
NH4Cl (aq.) was added and the reaction mixture was extracted with
DCM with the aid of a separatory funnel. The combined organic
extracts were washed with brine, dried (Na2SO4), filtered and con-
centrated in Vacuo. The crude residue was purified by flash column
chromatography (SiO2/hexanes/EtOAc, 3:1) to provide the title com-
pound (41 mg, 0.15 mmol) as a colorless oil in 61% yield. 1H NMR
(500 MHz, d6-DMSO, 90 °C): δ 7.37-7.28 (m 5 H), 5.65 (ddd, 1 H,
J ) 17.3, 10.5, 2.7 Hz), 5.12-4.99 (m, 4 H), 4.01-3.94 (m, 2 H),
3.21 (dd, 1 H, J ) 13.3, 3.5 Hz), 2.97-2.91 (m, 1 H), 2.85-2.83 (m,
1 H), 2.80 (dt, 1 H, J ) 10.6, 4.2 Hz), 2.08 (s, 3 H), 1.71-1.58 (m,
2 H); 13C NMR (125 MHz, d6-DMSO): δ 208.5, 154.5, 136.9, 135.6,
128.3, 128.3, 127.7, 127.6, 127.4, 117.0, 66.1, 51.0, 47.6, 42.6, 28.1,
22.0; IR (film): 2923, 2361, 2340, 1717, 1700, 1696, 1684, 1653, 1559,
1437, 1233, 668 cm-1; HRMS (CI) calcd for C17H22NO3 [M + 1]:
288.1600, found: 288.1599.
4-[3-(6-Methoxy-quinolin-4-yl)-acryloyl]-3-vinyl-piperidine-
1-carboxylic Acid Benzyl Ester (20). To a stirred solution of methyl
ketone 19 (42 mg, 0.15 mmol, 100 mol%) in THF (0.54 mL, 0.28 M)
at -78 °C was rapidly added LHMDS (0.9 M in methylcyclohexane,
0.19 mL, 0.17 mmol, 110 mol%). The reaction mixture was allowed
to stir at -78 °C for 1 h, at which point the quinoline bearing
aldehyde14 (39 mg, 0.21 mmol, 140 mol%) was added. The reaction
mixture was allowed to stir at -78 °C for 1 h, at which point Ac2O
(30 µL, 0.32 mmol, 210 mol%) and DMAP (18 mg, 0.14 mmol, 90
mol%) were added. The reaction was allowed to stir at -78 °C for an
additional 45 min, at which point the reaction mixture was allowed to
reach -40 °C (MeCN/solid CO2) and was allowed to stir for 30 min.
DBU (0.11 mL, 0.74 mmol, 500 mol%) was added to the reaction
mixture at -40 °C. The reaction mixture was stirred for 15 min at
-40 °C, at which point it was quenched with saturated NH4Cl (aq.)
and extracted with Et2O with the aid of a separatory funnel. The
combined ethereal extracts were washed with brine, dried (Na2SO4),
filtered and concentrated in Vacuo. The crude residue was purified by
flash column chromatography (SiO2/hexanes/EtOAc, 1:1 to 1:3) to
1
afford 20 (43 mg, 0.10 mmol, 64%) as a yellow oil. H NMR (500
MHz, d6-DMSO, 90 °C): δ 8.78 (d, 1 H, J ) 4.6 Hz), 8.19 (d, 1 H,
J ) 15.9 Hz), 8.02-8.00 (m, 1 H), 7.78 (d, 1 H, J ) 4.4 Hz),
7.50-7.47 (m, 2 H), 7.38-7.29 (m, 5 H), 7.24 (d, 1 H, J ) 15.9 Hz),
5.71 (ddd, 1 H, J ) 17.3, 10.5, 2.7 Hz), 5.13-5.00 (m, 4 H), 4.04-3.98
(m, 2 H), 3.97 (s, 3 H), 3.38-3.31 (m, 2 H), 3.12-3.07 (m, 1 H),
3.02-2.99 (m, 1 H), 1.88-1.80 (m, 1 H), 1.75-1.70 (m, 1 H); 13C
(29) (a) Lin, X.; Artmant, G. D., III; Stien, D.; Weinreb, S. M. Tetrahedron
2001, 57, 8779. (b) Grigat, H.; Zinner, G. Arch. Pharm. 1986, 1037.
9386 J. Org. Chem. Vol. 73, No. 23, 2008

Merged Morita-Baylis-Hillman-Tsuji-Trost Cyclization
NMR (125 MHz, d6-DMSO): δ 199.8, 157.8, 154.5, 147.5, 144.4,
138.2, 137.0, 135.8, 135.3, 131.3, 130.4, 128.3, 127.8, 127.4, 126.8,
122.1, 118.7, 117.0, 66.1, 55.6, 49.4, 42.4, 30.4; IR (film): 2960, 2360,
2340, 1700, 1695, 1684, 1617, 1506, 1436, 1227, 668 cm-1; HRMS
(CI) calcd for C28H29N2O4 [M + 1]: 457.2122, found: 457.2128.
4-[1-Hydroxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-pip-
eridine-1-carboxylic Acid Benzyl Ester (21). To a solution of enone
20 (27 mg, 0.065 mmol, 100 mol%) in THF (1.8 mL, 0.04 M) at -78
°C was added dropwise L-Selectride (1.0 M in THF, 70 µL, 0.070
mmol, 110 mol%). The reaction mixture was stirred for 5 min at which
time it was quenched with saturated NH4Cl (aq.) and extracted with
Et2O with the aid of a separatory funnel. The combined ethereal extracts
were washed with brine, dried (Na2SO4), filtered and concentrated in
Vacuo. The crude residue was purified by flash column chromatography
(SiO2/hexanes/EtOAc, 1:2 to 1:3) to provide the title compound (29
mg, 0.062 mmol) as a clear oil in 96% yield as a single diastereomer.
1H NMR (500 MHz, d6-DMSO, 90 °C): δ 8.66 (d, 1 H, J ) 4.6 Hz),
7.93 (d, 1 H, J ) 9.3 Hz), 7.51 (d, 1 H, J ) 4.4 Hz), 7.48 (d, 1 H, J
) 2.7 Hz), 7.40 (dd, 1 H, J ) 9.1, 2.8 Hz), 7.37-7.28 (m, 5 H), 7.25
(d, 1 H, J ) 15.6 Hz), 6.49 (dd, 1 H, J ) 15.7, 7.0 Hz), 5.92 (ddd, 1
H, J ) 17.3, 10.5, 2.2 Hz), 5.28-5.24 (m, 1 H), 5.14 (dd, 1 H, J )
10.6, 2.3 Hz), 5.10 (d, 1 H, J ) 12.9 Hz), 5.06 (d, 1 H, J ) 12.9 Hz),
4.76 (brs, 1 H), 4.15-4.12 (m, 2 H), 4.06-4.03 (m, 1 H), 3.93 (s, 3
H), 3.00 (dd, 1 H, J ) 13.2, 2.9 Hz), 2.84-2.78 (m, 2 H), 1.80-1.74
(m, 1 H), 1.50-1.40 (m, 2 H); 13C NMR (125 MHz, CDCl3): δ 157.3,
154.6, 147.5, 144.2, 140.8, 139.6, 137.0, 135.7, 130.9, 128.3, 127.7,
127.4, 126.7, 124.7, 121.6, 117.4, 117.1, 101.9, 79.1, 72.3, 66.0, 55.6,
44.6, 43.6, 38.1, 30.4; IR (film): 2927, 2360, 2340, 1700, 1695, 1684,
1507, 1472, 1436, 1231, 668, 417 cm-1; HRMS (CI) calcd for
C28H31N2O4 [M + 1]: 459.2284, found: 459.2280.
2.8 Hz), 7.39-7.28 (m, 5 H), 7.16 (d, 1 H, J ) 15.6 Hz), 6.56-6.50
(m, 1 H), 5.87 (ddd, 1 H, J ) 17.3, 10.4, 2.1 Hz), 5.20-5.05 (m, 4
H), 4.02-3.98 (m, 1 H), 3.93 (s, 3 H), 3.17 (dd, 1 H, J ) 13.2, 3.2
Hz), 3.02-2.97 (m, 1 H), 2.48-2.45 (m, 1 H), 2.37-2.24 (m, 2 H),
1.97-1.91 (m, 1 H), 1.60 (dd, 1 H, J ) 13.4, 3.7 Hz), 1.50-1.42 (m,
1 H), 1.26 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 157.6, 155.4,
147.3, 144.3, 142.0, 136.8, 135.4, 131.1, 128.3, 127.8, 127.7, 127.0,
126.6, 121.7, 117.5, 117.4, 101.4, 66.9, 55.4, 49.0, 48.5, 43.9, 42.5,
38.9, 37.3, 27.2; IR (film): 2928, 2360, 2340, 1695, 1619, 1506, 1470,
1432, 1365, 1229 cm-1; HRMS (CI) calcd for C28H30N2O3 [M + 1]:
443.2335, found: 443.2332.
7-Hydroxy-9-(4-methoxybenzyloxy)-quinine (24). To a solution
of KH (30% in oil, 47 mg, 0.35 mmol, 120 mol%) in DMF (2.9 mL,
0.1 M) at 0 °C was added diol 3 (100 mg, 0.30 mmol, 100 mol%).
The reaction mixture stirred at 0 °C for 35 min, at which point PMBCl
(40 µL, 0.42 mmol, 140 mol%) was added and the mixture was
warmed to 4 °C. After 46 h at 4 °C, the reaction mixture was poured
into H2O and extracted with Et2O with the aid of a separatory funnel.
The combined ethereal extracts were washed with water, dried
(Na2SO4), filtered and concentrated in Vacuo. The crude residue was
purified by flash column chromatography (SiO2/DCM/MeOH, 40:1
to 30:1) to provide the title compound (0.11 g, 0.23 mmol) as a white
foam in 78% yield. 1H NMR (400 MHz, d6-DMSO): δ 8.71 (d, 1 H,
J ) 4.4 Hz), 7.95 (d, 1 H, J ) 8.9 Hz), 7.55 (m, 1 H), 7.49 (d, 1 H,
J ) 4.4 Hz), 7.41 (dd, 1 H, J ) 9.2, 2.7 Hz), 7.18 (d, 2 H, J ) 8.5
Hz), 6.88 (d, 2 H, J ) 8.5 Hz), 5.91-5.82 (m, 1 H), 5.13 (brs, 1 H),
4.98-4.91 (m, 2 H), 4.30 (d, 1 H, J ) 10.9 Hz), 4.20 (d, 1 H, J )
10.9 Hz), 3.86 (s, 3 H), 3.72 (s, 3 H), 3.13 (m, 2 H), 2.88-2.72 (m,
1 H), 2.42-2.32 (m, 2 H), 2.17 (m, 1 H), 1.83 (m, 1 H), 1.72 (m, 1
H), 1.60-1.59 (m, 2 H), 1.42 (m, 1 H); 13C NMR (100 MHz, d6-
DMSO): δ 158.6, 156.4, 147.5, 142.2, 141.9, 131.2, 131.0, 130.9,
130.3, 130.1, 129.4, 129.2, 129.0, 121.0, 114.4, 113.6, 71.5, 70.8, 70.1,
63.0, 55.3, 55.0, 54.4, 34.6, 30.5; IR (film): 2931, 2360, 2340, 1684,
1618, 1518, 1543, 1363, 1240, 1036 cm-1; HRMS (CI) calcd for
C28H33N2O4 [M + 1]: 461.2440, found: 461.2442.
7-Hydroxy-9-(methoxymethyloxy)-quinine (25). To a solution
of KH (30% in oil, 47 mg, 0.35 mmol, 120 mol%) in DMF (2.9 mL,
0.1 M) at 0 °C was added diol 3 (100 mg, 0.30 mmol, 100 mol%).
The reaction mixture stirred at 0 °C for 35 min at which time MOMCl
(30 µL, 0.39 mmol, 130 mol%) was added and the mixture was
warmed to 4 °C. After 45 h at 4 °C, the reaction mixture was poured
into H2O, and extracted with Et2O with the aid of a separatory funnel.
The combined ethereal extracts were washed with water, dried
(Na2SO4), filtered and concentrated in Vacuo. The crude residue was
purified by flash column chromatography (SiO2/DCM/MeOH, 40:1
to 30:1) to provide the title compound (60 mg, 0.17 mmol) as a
colorless oil in 58% yield. 1H NMR (400 MHz, CDCl3): δ 8.74 (brs,
1 H), 8.02 (d, 1 H, J ) 9.2 Hz), 7.46 (brs, 1 H), 7.38-7.35 (m, 2 H),
5.92-5.79 (m, 1 H), 5.07-5.04 (m, 2 H), 4.57 (d, 1 H, J ) 5.8 Hz),
4.40 (m, 1 H), 3.94 (s, 3 H), 3.68-3.52 (m, 1 H), 3.36 (s, 3 H),
3.30-3.16 (m, 1 H), 2.79 (m, 1 H), 2.52-2.43 (m, 3 H), 2.23-2.19
(m, 3 H), 1.28-1.17 (m, 3 H); 13C NMR (125 MHz, d6-DMSO): δ
156.6, 156.5, 147.5, 142.2, 131.1, 131.0, 120.8, 120.7, 114.7, 114.4,
102.8, 95.9, 79.1, 55.4, 55.3, 54.3, 41.7, 34.6, 32.6, 30.4, 29.0, 20.4;
IR (film): 3246 (br), 2929, 2361, 2340, 1622, 1508, 1473, 1244, 1101,
1032, 668 cm-1; HRMS (CI) calcd for C22H29N2O4 [M + 1]: 385.2127,
found: 385.2124.
4-[1-Acetoxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-pip-
eridine-1-carboxylic Acid Benzyl Ester (22). To a solution of allylic
alcohol 21 (22 mg, 0.052 mmol, 100 mol%) in DCM (0.87 mL, 0.6
M) at 0 °C was added Et3N (40 µL, 0.29 mmol, 560 mol%), Ac2O
(30 µL, 0.32 mmol, 620 mol%), and DMAP (1.2 mg, 0.01 mmol, 20
mol%). The reaction mixture was stirred for 45 min, at which point it
was poured into H2O and extracted with DCM with the aid of a
separatory funnel. The combined organic extracts were washed with
brine, dried (Na2SO4), filtered and concentrated in Vacuo. The crude
residue was purified by flash column chromatography (SiO2/hexanes/
EtOAc, 1:1 to 1:2) to provide the title compound (21 mg, 0.042 mmol)
1
as a white foam in 81% yield. H NMR (500 MHz, d6-DMSO, 90
°C): δ 8.70 (d, 1 H, J ) 4.4 Hz), 7.97 (d, 1 H, J ) 8.0 Hz), 7.56 (d,
1 H, J ) 4.6 Hz), 7.46-7.42 (m, 2 H), 7.37-7.28 (m, 6 H), 6.41 (dd,
1 H, J ) 15.6, 7.6 Hz), 5.89 (ddd, 1 H, J ) 17.1, 10.5, 1.5 Hz),
5.19-5.05 (m, 5 H), 4.17-4.14 (m, 1 H), 4.10-4.07 (m, 1 H), 3.94
(s, 3 H), 3.08 (dd, 1 H, J ) 13.4, 2.9 Hz), 2.89-2.83 (m, 1 H),
2.69-2.66 (m, 1 H), 2.16-2.09 (m, 1 H), 2.08 (s, 3 H), 1.56-1.48
(m, 2 H); 13C NMR (125 MHz, d6-DMSO): δ 169.5, 157.6, 154.5,
146.8, 143.1, 140.9, 137.0, 135.1, 133.8, 130.2, 128.3, 128.3, 127.7,
127.4, 126.7, 122.2, 117.7, 117.5, 102.0, 79.1, 75.5, 66.1, 55.6, 43.3,
41.8, 40.1, 38.9, 20.8; IR (film): 3009, 2931, 2863, 2360, 2340, 1734,
1700, 1696, 1685, 1617, 1507, 1231, 1027 cm-1; HRMS (CI) calcd
for C30H33N2O5 [M + 1]: 501.2389, found: 501.2391.
4-[3-(6-Methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-car-
boxylic Acid Benzyl Ester (23). To a solution of allylic acetate 22
(50 mg, 0.13 mmol, 100 mol%) in THF (1.0 mL, 0.13 M) at ambient
temperature was added Pd(PPh3)4 (3 mg, 0.003 mmol, 2.5 mol%),
freshly distilled PBu3 (20 µL, 0.08 mmol, 60 mol%), Et3N (90 µL,
0.65 mmol, 500 mol%), and formic acid (88% in H2O, 20 µL, 0.53
mmol, 400 mol%). The reaction mixture was stirred for 4 h, at which
point it was poured into H2O and extracted with Et2O with the aid of
a separatory funnel. The combined ethereal extracts were washed with
brine, dried (Na2SO4), filtered and concentrated in Vacuo. The crude
residue was purified by flash column chromatography (SiO2/hexanes/
EtOAc, 1:1 to 1:2) to provide the title compound (42 mg, 0.10 mmol)
Acknowledgment. Acknowledgment is made to the Research
Corporation Cottrell Scholar Program, the Sloan Foundation,
the Dreyfus Foundation, Eli Lilly, Johnson & Johnson, the
Robert A. Welch Foundation and the NSF (CHE-0749016) for
partial support of this research.
Supporting Information Available: Spectral data for all new
compounds. Single crystal X-ray diffraction data for piperidine
14 and glycidic alcohol 17. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
as a colorless oil in 78% yield. H NMR (500 MHz, d6-DMSO, 90
°C): δ 8.65 (d, 1 H, J ) 4.6 Hz), 7.92 (d, 1 H, J ) 9.3 Hz), 7.51 (d,
1 H, J ) 4.6 Hz), 7.46 (d, 1 H, J ) 2.7 Hz), 7.40 (dd, 1 H, J ) 9.1,
JO802165K
J. Org. Chem. Vol. 73, No. 23, 2008 9387