A straightforward and versatile synthetic approach to 1-azabicyclic alkaloids

Article abstract of DOI:10.1021/jo049003a

A very straightforward route to 1-azabicyclo alkaloid scaffolds with several ring sizes is reported. The final bicyclic structures were built through a synthetic scheme that involved (i) the construction of dienic 4-piperidone systems by an imino-Diels-Al

Full text of DOI:10.1021/jo049003a

A Str a igh tfor w a r d a n d Ver sa tile Syn th etic Ap p r oa ch to
1-Aza bicyclic Alk a loid s
J ose´ Barluenga,* Carlos Mateos, Fernando Aznar, and Carlos Valde´s
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”, Unidad asociada al C.S.I.C.,
Universidad de Oviedo, 33071 Oviedo, Spain
barluenga@uniovi.es
Received J une 14, 2004
A very straightforward route to 1-azabicyclo alkaloid scaffolds with several ring sizes is reported.
The final bicyclic structures were built through a synthetic scheme that involved (i) the construction
of dienic 4-piperidone systems by an imino-Diels-Alder reaction between aminotrienes and N-ω-
vinylimines, in the presence of Yb(OTf)3, and (ii) the ring-closing metathesis reaction of these cyclic
dienes, under the influence of the first-generation Grubbs’ Ru-complex catalyst. During this
investigations, various polysubstituted azabicyclic ring skeletons, including several examples of
the quinolizidine alkaloids, are reported, and their relative stereochemistry is adequately discussed.
In tr od u ction
Indolizidine and quinolizidine skeletons can be found
in many important biological natural products.1 These
nitrogen derivatives occur in plants, insects, and amphib-
ians and exhibit notable biological activities.2 Therefore,
the stereoselective synthesis of these bicyclic skeletons
has become an important goal for synthetic chemists in
the recent years.
Among these derivatives, 5,8-disubstituted indoliz-
idines and 1,4-disubstituted quinolizidines, such as in-
dolizidine 209B and quinolizidine 207I, respectively,
constitute an important group that have received great
attention and study (Figure 1). These types of alkaloids
are isolated from skin extracts of neotropical members
of tropical amphibians and ants and possess interesting
features such as noncompetitive blockers for muscle-type
and ganglionic nicotinic receptor channels.3 Moreover, the
4-arylquinolizidine substructure is a characteristic struc-
tural motif present in the Lythraceae family of alkaloids.
Representative lythraceous alkaloids are lasubine I,
lasubine II,4 subcosine II,5 and the macrocycles lyth-
rancepine6 and vertaline7 (Figure 1).
F IGURE 1. Examples of natural “izidine-type” alkaloids.
Because of the importance of these natural products,
the synthesis of higher 1-azabicyclic analogues with
F IGURE 2. Examples of 1-azabicyclo[x.4.0]alkanes and con-
ventional numbering.
(1) For reviews, see: (a) Daly, J . W.; Garraffo H. M.; Spande, T. F.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: London, U.K.,
1993; Vol. 43, pp 185-288. (b) Daly, J . W.; Garraffo, H. M.; Spande,
T. F. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Pergamon: New York, 1999; Vol. 13, Chapter 1, pp 1-161.
(c) Michael, J . P. The Alkaloids 2001, 55, 91. (d) Michael, J . P. Nat.
Prod. Rep. 2003, 20, 458. (e) Michael, J . P. Nat. Prod. Rep. 2002, 19,
719. (f) Michael, J . P. Nat. Prod. Rep. 2001, 18, 520. (g) Michael, J . P.
Nat. Prod. Rep. 2000, 17, 579. (h) Michael, J . P. Nat. Prod. Rep. 1999,
16, 675. (i) Michael, J . P. Nat. Prod. Rep. 1998, 15, 571.
(2) For an example, see: Rolf, S.; Haverkamp, W.; Borggrefe, M.;
Musshoff, U.; Eckardt, L.; Mergenthaler, J .; Snyders, D. J .; Pongs, O.;
Speckmann, E.-J .; Breithardt, G.; Madeja, M. Naunyn-Schmiedeberg’s
Arch. Pharmacol. 2000, 362, 22.
various ring sizes would be of great interest (Figure 2).
Despite that, very little effort has been made toward this
aim, and the synthetic strategies published in the
literature are in general long, describe the preparation
(4) Some recent examples of the synthesis of lasubine I and II: (a)
Davis, F. A.; Rao, A.; Carroll, P. J . Org. Lett. 2003, 5, 3855. (b) Gracias,
V.; Zeng, Y.; Desai, P.; Aube, J . Org. Lett. 2003, 5, 4999. (c) Ma, D.;
Zhu, W. Org. Lett. 2001, 3, 3927. (d) Davis, F.; Chao, B. Org. Lett. 2000,
2, 2623 and references therein.
(3) Daly, J . W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.; Smith,
A. L.; Holmes, A. B.; Kibayashi, C.; Aronstam, R. S. Neurochem. Res.
1991, 16, 1213.
(5) For an asymmetric approach to lasubine I, II and subcosine II,
see: Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J .-C.
Tetrahedron: Asymmetry 1998, 9, 4361.
10.1021/jo049003a CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/18/2004
7114
J . Org. Chem. 2004, 69, 7114-7122

Synthetic Approach to 1-Azabicyclic Alkaloids
SCHEME 1. Syn th esis of In d olizid in es a n d
Qu in olizid in es
of slightly substituted scaffolds, and have not proven to
be sufficiently general.8
On the other hand, our research group has been
working for many years in the development of synthetic
applications of 2-amino-1,3-butadiene reagents. Thus, we
have demonstrated that these dienes are particularly
useful in imino-Diels-Alder cycloaddition with nonacti-
vated imines.9 This reaction furnishes, after hydrolysis
of the enaminic cycloadduct, polysubstituted 4-piperi-
dones with a high degree of stereoselectivity.10 Moreover,
we have recently implemented this process into the solid
phase.11
As a part of our investigation on the synthetic applica-
tions of the 2-aminodienes we have described the prepa-
ration of the natural indolizidine (-)-nupharamine by
derivatization of an enantiopure piperidone.12 More
recently, we disclosed a more concise and convergent
route to 5,8-disubstituted indolizidines and 1,4-disubsti-
tuted quinolizidines employing a synthetic strategy that
required three main stages: (i) stereoselective prepara-
tion of functionalized 4-piperidones 3 from 2-amino-1,3-
butadienes 1 and N-ω-vinylimines 2 by imino-Diels-
Alder reaction, (ii) transformation of the piperidones 3
into dienes 4, and (iii) ring-closing metathesis (RCM) of
4 to afford, after hydrogenation in an ultimate step, the
bicyclic saturated indolizidine and quinolizidine skeletons
5 (Scheme 1).13
This methodology demonstrated its potential for the
preparation of indolizidines (1-azabicyclo[4.3.0]nonanes)
and quinolizidines (1-azabicyclo[4.4.0]decanes) but failed
in the synthesis of 1-azabicyclo[5.4.0]undecene 6 as a
result of the known prevention of the RCM process to
yield a seven-membered ring from a disubstituted ole-
fin.14
for the synthesis of 1-azabicyclic skeletons based again
on the imino-Diels-Alder/RCM sequence. Herein, we
expound on our recent studies, which represent an
extension and improvement of our previous work and
which have resulted in a more general, straightforward,
and convergent synthetic methodology for the prepara-
tion not only of indolizidine and quinolizidine frameworks
but also of larger members of this class of bicyclic
alkaloids, with a high degree of diversity.
Resu lts a n d Discu ssion
Taking into account that the RCM of terminal unsub-
stituted alkenes is usually more favorable, we envisioned
the dienes II as the ideal precursors of bicyclic target I.
The synthesis of cyclic diene II would be easily achieved
by imino-Diels-Alder reaction of an aminotriene with
general structure III an the proper imine IV. Moreover,
the improved versatility of this route would permit
variations on the position of the ω-vinyl substituent in
both cycloaddition partners III and IV, giving rise to
different ring sizes and double bond positions in the final
bicyclic structure. In addition, variation in the substitu-
tion pattern on the reactants would furnish final products
with a higher degree of diversity and would be suitable
for the parallel synthesis of a series of these bicyclic
alkaloids (Scheme 2).
Syn th esis of Am in otr ien es III. The first step in the
synthetic route was the efficient preparation of 2-ami-
notrienes III, which could be achieved by hydroamina-
tion15 of the corresponding terminal dienynes V. To the
best of our knowledge, dienynes with the general struc-
ture V had not been previously reported, and therefore
a new synthetic strategy was urgent.
With this previous work in mind, we initiated a
research plan aimed at the development of a new route
(6) For references on the total syntheses of lythrancepine alka-
loids: (a) Hart D.; Hong, W.; Hsu, L. J . Org. Chem. 1987, 52, 4665. (b)
Hart, D., Hong, W. J . Org. Chem. 1985, 50, 3670.
(7) Total syntheses of Verltaline: (a) Shishido, K.; Tanaka, K.;
Fukumoto, K. Tetrahedron Lett. 1983, 24, 2783. (b) Hart, D.; Kanai,
K. J . Org. Chem. 1982, 47, 1555.
(8) (a) Diedrichs, N.; Westermann, B. Synlett 1999, 1127. (b)
Tehrani, K.; D’hooghe, M.; DeKimpe, N. Tetrahedron 2003, 59, 3099.
(c) Lindemann, U.; Wulff-Molder, D.; Wessig, P. Tetrahedron: Asym-
metry 1998, 9, 4459. (d) Zeng, Y.; Smith, B. T.; Hershberger, J .; Aube´,
J . J . Org. Chem. 2003, 68, 8065. (e) Haddad, M.; Ce´le´rier, J . P.; Haviari,
G.; Lhommet, G. Heterocycles 1990, 31, 1251. (f) Csendes, I. G.; Lee,
Y. Y.; Padgett, H. C.; Rapoport, H. J . Org. Chem. 1979, 44, 4173.
(9) For reviews, see: (a) Boger D. L.; Weinreb, S. M. Hetero Diels-
Alder Methodology in Organic Synthesis; Academic Press: San Diego,
1987; Chapter 2. (b) Waldmann, H. Synthesis 1994, 535. (c) Weinreb,
S. M. Acc. Chem. Res. 1985, 18, 16. (d) Waldmann, H. Synlett 1995,
133. (e) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 190. (f)
Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131. (g) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069. (h) Yao, S.; Saaby, S.; Hazell,
R. G.; J ørgensen, K. A. Chem. Eur. J . 2000, 6, 2435.
(10) (a) Barluenga, J .; Aznar F.; Valde´s, C.; Cabal M. P. J . Org.
Chem. 1993, 58, 3391. (b) Barluenga, J .; Aznar, F.; Valde´s, C.; Mart´ın,
A.; Garc´ıa-Granda, S.; Mart´ın, E. J . Am. Chem. Soc. 1993, 115, 4403.
(c) Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C.; Ferna´ndez, M.; Cabal,
M. P.; Trujillo J . Chem. Eur. J . 1996, 2, 805. (d) Barluenga, J .; Aznar,
F.; Valde´s, C.; Ribas, C. J . Org. Chem. 1998, 63, 3918.
The known alcohols 8 (Scheme 3) were chosen as the
starting point for the preparation of a series of dienynes.
Alcohols 8 were synthesized following published proce-
dures16 developed by the Trost research group, which
consisted of the addition of trimethylsilylacetylene to a
substituted propiolate 7, in the presence of Pd(OAc)2. The
(11) Barluenga, J .; Mateos, C.; Aznar, F.; Valde´s, C. Org. Lett. 2002,
4, 3667.
(12) Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C. J . Org. Chem.
1999, 64, 3736.
(13) Barluenga, J .; Mateos, C.; Aznar, F.; Valde´s, C. Org. Lett. 2002,
4, 1971.
(14) For effects of olefin substitution on RCM reactions, see: Kirk-
land, T. A.; Grubbs, R. H. J . Org. Chem. 1997, 62, 7310.
(15) (a) Barluenga, J .; Aznar, F.; Liz, R.; Cabal, M. P. J . Chem. Soc.,
Chem. Commun. 1985, 1375. (b) Barluenga, J .; Aznar, F.; Valde´s, C.;
Cabal, M. P. J . Org. Chem. 1991, 56, 6166.
J . Org. Chem, Vol. 69, No. 21, 2004 7115

Barluenga et al.
SCHEME 2. Retr osyn th etic Ap p r oa ch to
1-Aza bicyclic Sk eleton s I
SCHEME 4. Syn th esis of Oxy-Su bstitu ted
Dien yn esa
SCHEME 3. Syn th esis of Dien yn es 10 a n d 12a
a
(i) Allylmagnesium bromide, THF, 0 °C; (ii) Ac2O, pyridine,
rt; (iii) MeI, KOH, reflux; (iv) vinylmagnesium bromide, THF,
0 °C.
therefore, we chose the latter because of its lower cost.
The effect of the palladium catalyst was also studied in
the cross-coupling reaction, and the best results after
testing different complexes were achieved with a combi-
nation of 3 mol % (CH3CN)2PdCl2 and 1.5 mol % PPh3.
The optimized reaction conditions for the synthesis of
methyl-substituted dienyne 12 are shown in Scheme 3.
An alternative method, suitable for synthesizing func-
tionalized dienynes, involves the addition of ω-vinyl
Grignard reagents to aldehydes 9. Thus, the reaction
between conjugated aldehydes 9 and allylmagnesium
bromide afforded allyllic alcohols 13, which were subse-
quently protected as acetate 14 and methyl ether 15
(Scheme 4). On the other hand, to demonstrate the
versatility of this approach, dienyne 17 was prepared by
a similar procedure, by addition of vinylmagnesium
bromide to aldehyde 9a followed by methylation of the
resulting alcohol 16. It is noteworthy that the present
methodology would allow for the straightforward prepa-
ration of larger alkyl chain dienynes, by exposing alde-
hydes 9 to longer chain ω-vinylmagnesium halides in a
similar manner as described above.
a
(i) Trimethylsilylacetylene, Pd(OAc)2, TDMPP, THF, rt; (ii)
DIBAL-H, toluene, -80 °C; (iii) Dess-Martin periodinane, DCM,
rt; (iv) methyltriphenylphosphorane, DCM, -40 °C; (v) CBr4, PPh3,
CH3CN; (vi) Sn(CHdCH2)4, 3 mol % (CH3CN)2PdCl2, 1.5 mol %
PPh3, CHCl3, 60 °C.
resulted unsaturated ester was then reduced with
DIBAL-H to yield the enyne 8. This protocol turned out
to be very useful as it allows for the introduction of
different substitution in the enyne 8 by changing the
substituents in the starting ethynyl ester 7.
Finally, alcohol 8a was readily transformed into di-
enyne 10 by smooth oxidation using Dess-Martin perio-
dinane17 followed by Wittig olefination of aldehyde in-
termediate 9a .
On the other hand, alcohols 8 served also as the
starting materials for the preparation of the homologous
dienyne 12 (Scheme 3), which was prepared via a Stille
cross-coupling reaction of the correspondent allyl bromide
11.18 Compound 11 was synthesized upon treatment of
alcohol 8a with CBr4 and PPh3.19 Two different vinyltin
reagents were tested in the cross-coupling step: tetrabu-
tylvinyltin and tetravinyltin, providing similar results;
With a series of structurally diverse dienynes in hand
we studied the hydroamination of the triple bond in order
to synthesize the required 2-aminotrienes III. Mercury-
catalyzed hydroamination of the triple bond represents
a very efficient method for the synthesis of 2-amino-1,3-
butadiene derivatives but implies the existence of a
(18) (a) Stille, J . Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Kosugui, M.; Miyajima, Y.; Nakanishi, H.; Sano, H.; Migita, T. Bull.
Chem. Soc. J pn. 1989, 62, 3383. (c) Shindo, M.; Matsumoto, K.; Mori,
S.; Shishido, K. J . Am. Chem. Soc. 2002, 124, 6840. (d) Sheffy, F. K.;
Godschalx, J . P.; Stille, J . K. J . Am. Chem. Soc. 1984, 106, 4833.
(19) (a) Lee, J . B.; Downie, I. M. Tetrahedron 1967, 23, 359. (b)
Friederang A. W.; Tarbell, D. S. J . Org. Chem. 1968, 33, 3797. (c) Kim,
S.; Lee, J .; Lee, T.; Park, H.-G.; Kim, D. Org. Lett. 2003, 5, 2703.
(16) (a) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter,
G. J . Am. Chem. Soc. 1997, 117, 698. (b) Trost, B. M.; McIntosh, M.
Tetrahedron Lett. 1997, 38, 3207.
(17) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Herlem, D.; Khuong-Huu, F.; Kende, A. S. Tetrahedron Lett. 1993, 34,
5587.
7116 J . Org. Chem., Vol. 69, No. 21, 2004

Synthetic Approach to 1-Azabicyclic Alkaloids
SCHEME 5. Syn th esis of Am in otr ien es 18
TABLE 1. Am in otr ien es 18 P r ep a r ed fr om Sch em e 5
F IGURE 3. Imines 19 prepared.
SCHEME 6. Syn th esis of 1-Aza bicyclic Alk a loid s
22 th r ou gh th e Cycloa d d ition -RCM Sequ en cea
a
(i) 20 mol % Yb(OTf)3, THF, rt; (ii) 2% TFA/DCM, rt; (iii) 3.5
mol % Cl2(PCy3)2RudCHPh, 10-2 M, DCM, 40 °C.
inefficient process in some cases, as a result of the vola-
tility of the resulting terminal alkynes. To avoid this
problem, a one-pot procedure of deprotection followed by
hydroamination was devised. Thus, the dienynes were
exposed to a minimized quantity of 40 mol % TBAF in
THF, and after tracing the transformation until comple-
tion by TLC, the standard protocol for the hydroamina-
tion with N-methylaniline was followed in the same
reaction flask. Finally, isolation following published pro-
cedures gave the desired aminotrienes 18 in a comparable
yield with the two-step process (Scheme 5, Table 1).
Under the standard conditions discussed previously,
dienynes 10, 12, 14, 15, and 17 were transformed into
the correspondent aminotrienes 18 with moderate yields.
Although the hydroamination of dienynes 10 and 12
occurred at room temperature, in the case of the prepara-
tion of 18c-e the reaction temperature had to be
increased to THF reflux to reach completion.
Im in e Syn th esis. Imine formation was achieved from
correspondent aldehydes and amines employing tri-
methylorthoformate as dehydrating agent.21 The synthe-
sized imines include examples derived from electron-
donating as well as electron-withdrawing aromatics and
also from ethyl glyoxylate (Figure 3).22
Im in o-Diels-Ald er a n d RCM Rea ction s. The gen-
eral procedure to access the bicyclic scaffolds is depicted
in Scheme 6. The imino-Diels-Alder reaction between
aminotrienes 18 and imines 19 consisted of a modified
a
b
Hydroamination carried out at room temperature. Hydro-
amination carried out at THF reflux.
(20) Barluenga, J .; Aznar, F.; Liz, R.; Rodes, R. J . Chem. Soc., Perkin
Trans. 1 1983, 1087.
(21) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937.
(22) Our study did not include C-alkyl-substituted imines, because
usually these systems provide poor results in the imino-Diels-Alder
reactions with 2-aminodienes.
terminal alkyne.20 However, the procedures outlined
above afforded trimethylsilylated species that should be
desilylated. The deprotection step resulted in a very
J . Org. Chem, Vol. 69, No. 21, 2004 7117

Barluenga et al.
TABLE 2. Cycloa d d ition Rea ction s of Dien es 18 a n d Im in es 19 a n d RCM of th e Resu ltin g Cyclic Dien es; Syn th esis of
Str u ctu r a lly Diver se Bicyclic F r a m ew or k s 22
a
b
After chromatographic purification. Product obtained as a 5:1 mixture of diastereoisomers. c Yield of the reaction. Both diastereoi-
somers were subsequently separated.
7118 J . Org. Chem., Vol. 69, No. 21, 2004

Synthetic Approach to 1-Azabicyclic Alkaloids
SCHEME 7. Syn th esis of En a m in e-Con ta in in g
Aza bicyclesa
the process. Nevertheless, the mixture of diastereoiso-
mers was subjected to the RCM conditions to furnish the
expected unsaturated quinolizidines 22e and 22f with
very high yield (entries 5 and 6).
Interestingly, the choice of acetoxy-substituted ami-
notriene 18d permitted the synthesis of 4-piperidone 21g,
isolated again as a 5:1 mixture of diastereoisomers. This
underwent ring closure to 1-azabicyclo[7.4.0]tridecene
22g, which features the piperidone fused to a nine-
membered ring, with quantitative yield (entry 7).
In the context of constructing large rings by RCM,23
concentration of reactants must be taken into account.
It is known that in the formation of macrocycles by RCM,
secondary dimerization products are often isolated,24 it
being necessary to employ high dilute solutions. However,
we obtained the desired compounds with no byproducts
using a concentration of 10-2 M in all cases. Additionally,
as Grubbs’ first-generation carbene is reported to be
moderately thermally unstable,25 the catalyst had to be
added in two portions to reach completion of the reaction.
Optimized cyclization conditions were 3.5 mol % Grubbs’
catalyst, 40 °C, DCM, 8 h.
As shown in Table 2, a variety of imines can be
employed in the cycloaddition-RCM process. Noticeably,
the overall yields showed no dependence on the imine
nature, with similar values in all cases. Interestingly, the
use of imino ester 19e allows for the preparation of
bicyclic derivatives of the R-amino acid pipecolic acid26
and may also permit further elaboration of the side chain
(entry 2).
a
(i) 20 mol % Yb(OTf)3, THF, rt; (ii) 2% TFA/DCM, rt; (iii) 3.5
mol % (PCy3)2Cl2RudCHPh, 10-2 M, DCM, 40 °C.
method to that reported previously.13 The correspondent
imine was exposed to an equimolecular amount of the
aminotriene in the presence of 20 mol % Yb(OTf)3. Then,
to prevent problems during purification, crude enaminic
cycloadducts 20 were hydrolyzed with TFA 2% in DCM
to give dienic 4-piperidones 21 in moderate yields. These
new dienes 21 were treated with Grubbs’ first-generation
catalyst to afford the desired azabicycles 22 in nearly
quantitative yields. The results of both cycloaddition and
RCM reactions are represented in Table 2.
The cycloaddition reaction under the conditions de-
scribed above proceeded with total diastereoselectivity
when dienes 18a and 18b were employed, to afford the
adducts 21a -d , which bear the substituents in positions
2 and 6 in a cis relationship (entries 1-4). The diastereo-
isomer obtained corresponds to an endo approach of the
substituent attached at the carbon atom of the imine in
a formal [4 + 2] cycloaddition, a general trend in the
aza-Diels-Alder reactions of 2-amino-1,3-butadienes.10
The dienic 4-piperidones subjected to the RCM process
with the Grubbs’ first-generation Ru-complex as catalyst
afforded unsaturated bicyclic structures in nearly quan-
titative yields. Thus, substituted unsaturated quinolizi-
dines 22a and 22b were obtained with total diastereo-
selectivity from aminotriene 18b and N-allylimines
19c and 19e, respectively, after the cycloaddition-RCM
sequence (entries 1 and 2).
Different combinations of dienes and imines allow for
the construction of various bicyclic frameworks. For
instance, 1-azabicyclo[5.4.0]undecene 22c could be ac-
cessed with total diastereoselectivity and very high yield
from aminotriene 18a and imine 19f after RCM of the
dienic 4-piperidone 21c (entry 3). The 1-azabicyclo-
[6.4.0]dodecene 22d homologous was formed following the
identical method starting from aminotriene 18b and
imine 19f (entry 4).
On the other hand, the use of methoxy-substituted
2-aminotriene 18c would lead to bicyclic structures with
an additional stereocenter. However, the cycloaddition
reaction with N-allylimines 19a ,b gave rise to a mixture
of two diasteromeric cycloadducts in a 5:1 relationship
as a result of the moderate facial diastereoselectivity of
It must be mentioned that the stereochemical integrity
of the stereocenters remained unaltered during the
transformation of dienic compounds to bicyclic systems.
The sterochemistry of all of the products was deduced
1
by H NMR and qualitative NOESY experiments.
On the other hand, the reaction of phenyl-substituted
aminotriene 18e with imine 19d afforded a 5:1 mixture
of diasteromeric enamines 23a and 23b, which unlike the
previous examples did not undergo hydrolysis of the
enamine moiety under the standard conditions (2% TFA/
DCM). Despite that, we decided to perform further with
the enamine. Both isomers reacted successfully with
Grubbs’ catalyst to provide bicyclic enamines 24a and
24b, respectively, in quantitative yield (Scheme 7).
Interestingly, the presence of the enamine functionality
did not diminish the activity of the Grubbs’ catalyst,
which performed equally efficiently.27 This remarkable
result opens the door to the preparation of diverse amine-
substituted bicyclic structures, simply by employing
different secondary amines in the aminodiene synthesis.
Con clu sion
In summary, we have described the general prepara-
tion of polysubstitued 1-azabicycloalkenes by a imino-
(23) For a review on the preparation of medium-sized rings by RCM,
see: Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073.
(24) See the following for preparation of macrocycles by RCM: (a)
Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 3942. (b)
Fu¨rtsner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005.
(25) Ulman, M.; Grubbs, R. H. J . Org. Chem. 1999, 64, 7202.
(26) Barluenga, J .; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Tetra-
hedron Lett. 2002, 43, 8159.
(27) For an example of participation of â-carboline and isoquinoline
enamines in RCM processes, see: Evans, P.; Grigg, R.; York, M.
Tetrahedron Lett. 2000, 41, 3967.
J . Org. Chem, Vol. 69, No. 21, 2004 7119

Barluenga et al.
of alcohol 8a (3 mmol) in CH3CN (15 mL) was added PPh3
(1.2 g, 4.5 mmol), and the resulting mixture was cooled to 0
°C. Then CBr4 (1.5 g, 4.5 mmol) was added in little portions,
and the suspension was stirred for 1 h. After this period of
time, CH3CN was evaporated under reduced pressure. Puri-
fication by column chromatography (silica gel, hexanes) af-
forded dienyne 11 as a colorless oil in 81% yield: bp 60 °C
(0.1 mmHg), Rf ) 0.42 (Hex) KMnO4. 1H NMR (CDCl3, 300
Diels-Alder/RCM sequence in a highly concise and
convergent manner. The process can be carried out with
a variety of aminotrienes and imines to provide the
bicyclic structures carrying different substituents. More-
over, by variation of both cycloaddition partners, bicyclic
frameworks featuring a piperidine ring fused to a ring
of various sizes (six- to nine membered) can be accessed
with a high degree of diversity and through a common
and very short synthetic route. Therefore, the strategy
described herein represents a very versatile approach to
1-azabicyclic skeletons which could be adapted to parallel
synthesis. The implementation of this methodology into
the solid phase, and the development of an enantiose-
lective version are our current goals in this area, and our
progress will be reported in due course.
4
MHz): 6.16 (tq; 3J ) 8.5, J ) 1.5; 1H), 4.02 (d; 3J ) 8.5; 2H),
1.92 (d; 4J ) 1.5; 3H), 0.25 (s: 9H). 13C NMR (CDCl3, 75
MHz): 132.3 (CH), 124.1 (C), 106.7 (C), 94.7 (C), 27.3 (CH2),
16.9 (CH3), -0.1 (CH3). HRMS (EI) calcd for C9H15BrSi:
230.0130, found 230.0130.
Stille Cr oss-Cou p lin g of Allylic Br om id e 11. P r ep a r a -
tion of th e Dien yn e Tr im eth yl ((E)-3-Meth ylh ep ta -3,6-
d ien -1-yn yl)sila n e 12. PPh3 (23 mg, 0.09 mmol, 1.5 mol %)
was added to a pressure Schlenk containing a solution of (CH3-
CN)2PdCl2 (45 mg, 0.18 mmol, 3 mol %) in chloroform (30 mL).
The resulting mixture was stirred until a homogeneous
solution was formed. Then, allylic bromide 11 (1.4 g, 6 mmol)
and tetravinyltin (1.3 g, 6 mmol) were added, and the resulting
mixture was heated to 60 °C for 2 h. TBME (50 mL) was added,
and the solution was washed with aqueous KF 10% (4 × 10
mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by column chromatography
(silica gel, hexanes) afforded dienyne 12 as a colorless oil in
74% yield: Rf ) 0.43 (Hex) KMnO4. 1H NMR (CDCl3, 300
MHz): 5.91-5.77 (m; 1H), 5.72 (t; 3J ) 7.4; 1H), 5.09 (d; 3J trans
Exp er im en ta l Section
Gen er a l Meth od s. The same experimental techniques were
used as previously reported.13 The starting materials were
obtained following literature procedures: imines 19a -f,21
N-pent-4-en-1-amine,28 and enynes 8a and 8b.16
Gen er a l P r oced u r e for th e Dess-Ma r tin Oxid a tion of
Allylic Alcoh ols 8a a n d 8b. A solution of the correspondent
enyne (3 mmol) in de DCM (5 mL) was treated at room
temperature with a solution of Dess-Martin periodinane (8.5
g, 15% in DCM, 3 mmol). After stirring for 1 h, the resulting
mixture was poured into an Erlenmeyer flask containing ether
(50 mL), and NaOH 3 N (10 mL) was added. After 15 min of
stirring, the aqueous phase was extracted with ether (20 mL).
The combined organic phases were washed with water and
brine, dried over anhydrous Na2SO4, and then concentrated
cautiously at room temperature under reduced pressure. The
oil obtained is essentially pure aldehyde that can be further
purified by distillation under 8 mbar vacuum.
3
3
) 17.6; 1H), 5.01 (d; J cis ) 10.1; 1H), 3.09 (t; J ) 7.1; 2H),
1.85 (s; 3H), 0.22 (s; 9H). 13C NMR (CDCl3, 75 MHz): 136.1
(CH), 136.0 (CH), 119.0 (C), 115.1 (CH2), 104.3 (C), 97.9 (C),
35.1 (CH2), 22.8 (CH3), 0.1(CH3). HRMS (EI) calcd for
C
11H18Si: 178.1178, found 178.1177.
Gen er a l P r oced u r e for th e Ad d ition of Gr ign a r d
Rea gen ts to Ald eh yd es 9a a n d 9b. To a solution of the
aldehyde (5.4 mmol) in ether (20 mL) cooled to 0 °C was added
dropwise the correspondent Grignard reagent (vinylmagne-
sium bromide or allylmagnesium bromide) (6.5 mL, 1 M
solution in THF, 6.5 mmol). The resulting mixture was stirred
for 10 min at 0 °C. Then, a saturated aqueous solution of NH4-
Cl (5 mL) was added, and the aqueous mixture was extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting oil was
purified by column chromatography.
(E)-3-Meth yl-5-(tr im eth ylsilyl)p en t-2-en -4-yn a l 9a . Pre-
pared from alcohol 8a . Obtained as a colorless liquid, 92%
yield: bp 70 °C (8 mbar), Rf ) 0.15 (Hex/EtOAc 20:1) KMnO4.
1H NMR (CDCl3, 300 MHz): 10.05 (d; J ) 8.0; 1H), 6.25 (dq;
4
J ) 8.0, J ) 1.4; 1H), 2.31 (d; 4J ) 1.4; 1H), 0.26 (s; 9H). 13C
NMR (CDCl3, 75 MHz): 190.3 (C), 140.1 (C), 134.1 (CH), 105.6
(C), 105.0 (C), 18.3 (CH3), -0.4 (CH3). HRMS (EI) calcd for
C9H14OSi-CH3: 151.0574, found 151.0574.
Wittig Meth ylen a tion of Ald eh yd e 9a . Tr im eth yl((E)-
3-m eth ylh exa -3,5-d ien -1-yn yl)sila n e 10. To a suspension
of triphenylphosphonium bromide (3 g, 8.5 mmol) in toluene
(20 mL) was added NaNH2 (1 g, 25 mmol), and the resulting
mixture was stirred overnight. The solution was filtered under
N2, and the filtrate was concentrated under high vacuum to
obtain methylentriphenylphosphorane as a yellow crystalline
solid (2.1 g, 7.3 mmol, 85%). This ylide was dissolved in THF
(10 mL) and was added dropwise to a -50 °C solution of
aldehyde 9a (800 mg, 4.9 mmol) in THF (10 mL). After the
mixture stirred for 10 min, water (0.2 mL) was added, and
the temperature was allowed to reach room temperature.
Then, the solution was dried over anhydrous Na2SO4 and
cautiously concentrated under reduced pressure without heat-
ing. Purification by column chromatography (silica gel, eluent
Hex/ether 10:1) afforded dienyne 10 as a colorless oil in 45%
yield: Rf ) 0.60 (Hex) KMnO4. 1H NMR (CDCl3, 300 MHz):
(E)-5-Met h yl-7-(t r im et h ylsilyl)h ep t a -1,4-d ien -6-yn -3-
ol 16. Prepared from conjugated aldehyde 9a . Obtained as a
colorless oil in 90% yield: Rf ) 0.13 (Hex/EtOAc 10:1) KMnO4.
1H NMR (CDCl3, 300 MHz): 5.84 (d; 3J ) 6.8; 1H), 5.82-5.77
3
3
(m; 1H), 5.25 (d; J ) 17.3; 1H), 5.12 (d; J ) 10.3; 1H), 4.86
3
(t; J ) 7.1; 1H), 1.85 (s; 3H), 0.32 (s; 9H). 13C NMR (CDCl3,
75 MHz): 138.2 (CH), 138.1 (CH), 120.1 (C), 115.2 (CH2), 107.2
(C), 92.3 (C), 69.5 (CH), 17.5 (CH3), -0.1 (CH3). HRMS (EI):
calcd for C11H18OSi-CH3: 179.0887, found 179.0888.
Gen er a l P r oced u r e for th e P r otection of Alcoh ols 13b
a n d 16 a s Meth yl Eth er s. To a flask containing the cor-
respondent alcohol (3 mmol) was added MeI (4 mL). To the
resulting mixture was added powdered KOH (0.5 g), and the
suspension was heated to reflux with stirring for 1 h. Then,
HCl 2 N (5 mL) and ether (10 mL) were added. The layers
were separated, and the aqueous phase was extracted with
ether (4 × 10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was generally pure enough for
most purpose.
((E)-5-Met h oxyh ep t a -3-m et h yl-3,6-d ien -1-yn yl)t r im e-
th ylsila n e 17. Prepared from alcohol 16. Obtained as a
colorless oil in 72% yield: Rf ) 0.43 (Hex/EtOAc 10:1) KMnO4.
1H NMR (CDCl3, 300 MHz): 5.84 (d; 3J ) 7.1; 1H), 5.82-5.69
(m; 1H), 5.28 (dd; 3J ) 17.0, 2J ) 1.5; 1H), 5.22 (dd; 3J ) 10.5,
2J ) 1.5; 1H), 4.37 (t; 3J ) 7.8; 1H), 3.31 (s; 3H), 1.85 (d; 4J )
1.4; 1H), 0.21 (s; 9H). 13C NMR (CDCl3, 75 MHz): 136.9 (CH),
3
3
6.65-6.52 (m; 1H), 6.42 (d; J ) 11.2; 1H), 5.27 (d; J trans
)
3
17.8; 1H), 5.16 (d; J cis ) 9.1; 1H), 1.88 (s, 3H), 0.22 (s; 9H).
13C NMR (CDCl3, 75 MHz): 137.1 (CH), 132.2 (CH), 119.5 (C),
119.2 (CH2), 108.6 (C), 93.7 (C), 17.4 (CH3), 0.0 (CH3). HRMS
(EI) calcd for C10H16Si: 164.1016, found 164.1012.
P r ep a r a tion of Allylic Br om id e 11. ((E)-5-Br om o-3-
m eth ylp en t-3-en -1-yn yl)tr im eth ylsila n e 11. To a solution
(28) (a) J acobson, M. A.; Williard, P. G. J . Org. Chem. 2002, 67,
3915. (b) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, H.;
Ikeda, M. J . Chem. Soc., Perkin Trans. 1 1992, 2399.
7120 J . Org. Chem., Vol. 69, No. 21, 2004

Synthetic Approach to 1-Azabicyclic Alkaloids
136.1 (CH), 121.1 (C), 116.7 (CH2), 107.2 (C), 92.1 (C), 78.6
column chromatography, affording the cycloaddition products
as pale yellow oils.
(CH3), 55.8 (CH), 17.7 (CH3), -0.1 (CH3). HRMS (EI) calcd for
C
12H20OSi-CH3: 193.1043, found 193.1037.
(2S*,3S*,6S*)-N,2-Diallyl-3-m eth yl-6-(4-m eth oxyph en yl)-
p ip er id in -4-on e 21a . Prepared from aminotriene 18b and
imine 19c. Obtained as a pale yellow oil in 55% yield: Rf )
0.38 (Hex/EtOAc 5:1) KMnO4. 1H NMR (CDCl3, 300 MHz):
7.45-7.33 (m; 3H), 6.92-7.03 (m; 2H), 6.21-6.07 (m; 1H),
5.93-5.81 (m; 1H), 5.23-5.06 (m; 4H), 3.91 (s; 3H), 4.12-4.02
Acetyla tion of Alcoh ol 13a . (E)-6-Meth yl-8-(tr im eth yl-
silyl)octa -1,5-d ien -7-yn -4-yl Aceta te 14. To a solution of
alcohol 13a (900 mg, 4.5 mmol) in pyridine (3 mL) and acetic
anhydride (500 mg, 5 mmol) were added. After the resulting
mixture stirred for 4 h, TBME (20 mL) was added, and the
organic layer was washed with HCl 1 N (4 × 10 mL), dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to afford acetate 14 pure enough for the next
transformation. This compound was obtained as a colorless
oil in 91% yield: Rf ) 0.32 (Hex/EtOAc 20:1) KMnO4. 1H NMR
(CDCl3, 300 MHz): 5.78 (d; 3J ) 9.4; 1H), 5.75-5.63 (m; 1H),
5.57-5.45 (m; 2H), 5.15-5.07 (m; 2H), 2.41-2.30 (m; 2H), 2.05
(s; 3H), 1.85 (s; 3H), 0.28 (s; 9H). 13C NMR (CDCl3, 75 MHz):
170.0 (C), 135.0 (CH), 132.5 (CH), 122.1 (C), 118.2 (CH2), 106.9
(C), 92.6 (C), 69.7 (CH), 38.6 (CH2), 21.0 (CH), 17.9 (CH3), -0.2
(CH3). HRMS (EI) calcd for C14H22O2Si: 250.1389, found
250.1395.
3
(m; 1H), 3.40 (dd; 3J gem ) 15.6, J ax-eq ) 6.8; 1H), 3.18 (dd; 3J
3
) 16.2, 3J ) 5.7; 1H), 2.81-2.63 (m; 3H), 2.42 (dd; J ax-ax
)
3
3
13.4, J ax-eq ) 3.4; 1H), 2.35-2.29 (m; 1H), 1.02 (d; J ) 6.0;
3H). 13C NMR (CDCl3, 75 MHz): 210.7 (C), 158.5 (C), 133.2
(C), 131.2 (CH), 128.4 (CH), 118.5 (CH2), 117.9 (CH2), 114.2
(CH), 113.9 (CH), 64.6 (CH3), 64.1 (CH), 60.8 (CH), 50.9 (CH2),
46.6 (CH2), 33.8 (CH2), 15.6 (CH), 11.0 (CH3). HRMS (EI) calcd
for C19H25NO2: 299.1879, found 299.1876.
Gen er a l P r oced u r e for th e RCM Rea ction . To a solution
of the correspondent diene 21 (0.2 mmol) in DCM (20 mL) (10-2
M) was added first-generation Grubbs catalyst (3 mg, 0.0035
mmol). The resulting solution was heated to gentle reflux, and
stirring was continued for 4 h. Subsequently, another portion
of the ruthenium catalyst was added (3 mg, 0.0035 mmol), and
stirring was continued for an additional 4 h. Then, the reaction
mixture was exposed to air and concentrated to afford the
crude bicyclic product 22, which was purified by flash column
chromatography.
Gen er a l P r oced u r e for P r ep a r a tion of Am in otr ien es
18. On e-P ot Dep r otection a n d Hyd r oa m in a tion of Silyl-
a ted Dien yn es 10, 12a , 14, 15, a n d 17. A modified procedure
from that previously published15b was employed. To a solution
of correspondent silylated enyne (3 mmol) in THF (20 mL) was
added TBAF (1.2 mmol, 40 mol %), and the resulting mixture
was stirred for 10 min. Then, Hg(OAc)2 (2.25 mmol, 75 mol
%) was added, and stirring was continued for an additional 5
min. The reaction mixture was then treated with NEt3 (0.8
mL, 600 mg, 6 mmol). After an additional 5 min, N-methyla-
niline (300 mg, 3 mmol) was added, and the reaction mixture
was heated to gently reflux overnight in the case of dienynes
14, 15, and 17 and at room temperature in the case of dienynes
10 and 12. Subsequently, the reaction mixture was concen-
trated under vacuum. The flask was filled with dry nitrogen,
and 30 mL of dry hexanes was added to the mixture. After
the suspension was stirred and shaken for 30 min, the solution
was filtered under a dry atmosphere, and the solid was washed
with additional dry hexanes (2 × 10 mL). The filtrates were
combined and concentrated under vacuum to afford the
correspondent essentially pure aminotriene 18 as a yellowish
oil.
(1S*,4S*,9R*,9a R*)-3,4,9,9a -Tet r a h yd r o-9-m et h oxy-1-
m eth yl-4-p h en yl-1H-qu in olizin -2(6H)-on e 22e. Prepared
from diene 21e. Obtained as a colorless oil in 93% yield: Rf )
0.24 (Hex/EtOAc 5:1) KMnO4. 1H NMR (CDCl3, 300 MHz):
3
7.45-7.28 (m; 5H), 6.10-6.00 (m; 1H), 5.90 (ddd; J ) 10.2,
3J ) 5.1, J ) 1.4; 1H), 3.81-3.76 (m; 1H), 3.55 (s; 3H), 3.33
(dd; 3J ax-ax ) 12.8, J ax-eq ) 2.6; 1H), 3.21-3.12 (m; 2H), 2.81
3
2
3
3
(dd; J gem ) 13.1, J ax-ax ) 12.8, J eq-eq ) 3.8; 1H), 2.45-2.35
(m; 3H), 1.13 (d, 3J ) 6.5; 3H). 13C NMR (CDCl3, 75 MHz):
210.2 (C), 142.1 (C), 130.2 (CH), 128.8 (CH), 127.7 (CH), 127.2
(CH), 122.0 (CH), 71.7 (CH3), 71.1 (CH), 69.8 (CH), 56.5 (CH),
53.2 (CH2), 50.0 (CH2), 44.7 (CH), 10.2 (CH3). HRMS (EI) calcd
for C17H21NO2: 271.1572, found 271.1560.
(1S*,4S*,9S*,9a R*)-4-(2-Br om op h en yl)-3,4,9,9a -tetr a h y-
dr o-9-m eth oxy-1-m eth yl-1H-qu in olizin -2(6H)-on e 22f. Pre-
pared from diene 21f. Obtained as a pale yellow oil in 97%
yield: Rf ) 0.23 (Hex/EtOAc 3:1) KMnO4. 1H NMR (CDCl3,
300 MHz): 7.61-7.51 (m; 2H), 7.39-7.31 (m; 1H), 7.19-7.11
N-Met h yl-N-((E)-3-m et h ylh exa -1,3,5-t r ien -2-yl)b en z-
en ea m in e 18a . Prepared from dienyne 10. Obtained as a
yellowish oil in 56% yield: 1H NMR (CDCl3, 300 MHz): 7.31-
7.22 (m; 3H), 6.85-6.73 (m; 2H), 6.70-6.60 (m; 1H), 6.49 (d;
J ) 11.4; 1H), 5.27 (d; 3J trans ) 16.8; 1H), 5.18 (d; 3J cis ) 11.7;
1H), 5.13 (s; 1H), 4.90 (s; 1H), 3.15 (s; 3H), 1.93 (s; 3H). 13C
NMR (CDCl3, 75 MHz): 155.9 (C), 149.2 (C), 134.1 (C), 133.2
(CH), 128.7 (CH), 122.4 (CH), 118.5 (CH2), 118.2 (CH2), 116.3
(CH), 105.8 (CH2), 39.8 (CH3), 14.4 (CH3). HRMS (EI) calcd
for C14H17N: 199.1355, found 199.1349.
3
(m; 1H), 6.11-6.01 (m; 1H), 5.86 (ddd; 3J ) 9.8, J ) 5.2, J )
3
3
1.1; 1H), 4.81 (dd; J ax-ax ) 9.6, J ax-eq ) 4.9; 1H), 3.68-3.63
(m; 1H), 3.41 (s; 3H), 3.15 (dd; 3J ax-ax ) 9.6, 3J eq-eq ) 3.8; 1H),
2
3
3.07 (dd; J gem ) 16.7; J eq-eq ) 4.9; 1H), 2.73-2.58 (m; 4H),
1.25 (d; J ) 6.0; 3H). 13C NMR (CDCl3, 75 MHz): 209.6 (C),
3
139.2 (C), 132.8 (CH), 131.1 (CH), 130.3 (CH), 129.0 (CH),
128.1 (CH), 125.0 (C), 124.0 (CH), 73.2 (CH3), 64.9 (CH), 59.7
(CH), 56.4 (CH). 51.7 (CH2), 48.0 (CH2), 43.7 (CH), 9.4 (CH3).
HRMS (EI) calcd for C17H20BrNO2: 349.0676, found 349.0675.
Gen er a l P r oced u r e for th e Im in o-Diels-Ald er Rea c-
tion . P r ep a r a tion of Dien ic P ip er id in es 21. To a solution
of Yb(OTf)3 (55 mg, 0.1 mol, 20 mol %) in THF (10 mL) was
added dropwise the correspondent imine 19 (0.50 mmol), and
the resulting mixture was stirred for 10 min. Subsequently, a
solution of correspondent aminotriene 18 (0.50 mmol) in THF
(5 mL) was added, and the reaction mixture stirred overnight.
Then, the reaction was quenched with a saturated aqueous
solution of NaHCO3, and the mixture was extracted with
EtOAc (20 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to afford a brown oil. The reaction
crude was dissolved in 2% TFA/DCM (5 mL), and the solution
was stirred for 15 min. The reaction mixture was then poured
over a saturated aqueous solution of NaHCO3 (sat) (10 mL).
The resulting mixture was extracted with EtOAc (2 × 20 mL),
and the combined organic phases were washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford a pale brown oil. The crude was purified by
(1S*,4S*,9R*,9aR*)-4-(2-Br om op h en yl)-3,4,9,9a -tetr a h y-
dr o-9-m eth oxy-1-m eth yl-1H-qu in olizin -2(6H)-on e 22f ′. Pre-
pared from diene 21f ′. Obtained as a pale yellow oil in 97%
yield: Rf ) 0.28 (Hex/EtOAc 3:1) KMnO4. 1H NMR (CDCl3,
300 MHz): 7.78 (dd; 3J ) 8.0, 4J ) 0.8; 1H), 7.54 (dd; 3J ) 7.9,
4J ) 0.7; 1H), 7.41-7.31 (m; 1H), 7.12-7.01 (m; 1H), 6.11-
3
3
6.01 (m; 1H), 5.90 (ddd; J ) 9.8, J ) 5.2, J ) 1.0; 1H), 4.02
3
(dd; 3J ax-ax ) 12.5, J ax-eq ) 3.3; 1H), 3.81-3.75 (m; 1H), 3.55
(s; 3H), 3.30-3.11 (m; 2H), 2.63-2.45 (m; 4H), 1.15 (d, 3J )
6.1; 3H). 13C NMR (CDCl3, 75 MHz): 209.3 (C), 140.6 (C), 132.8
(CH), 129.9 (CH), 129.0 (CH), 128.7 (CH), 128.2 (CH), 122.9
(C), 122.1 (CH), 71.6 (CH3), 69.2 (CH), 68.0 (CH), 56.4 (CH).
52.4(CH2), 47.9 (CH2), 44.3 (CH), 10.0 (CH3). HRMS (EI) calcd
for C17H20BrNO2: 349.0676, found 349.0675.
(1S*,4S*,9aS*)-3,4,9,9a-Tetr ah ydr o-4-(4-m eth oxyph en yl)-
1-m eth yl-1H-qu in olizin -2(6H)-on e 22a . Prepared from di-
ene 21a . Obtained as a pale yellow oil in 95% yield: Rf ) 0.16
(Hex/EtOAc 6:1) KMnO4. 1H NMR (CDCl3, 300 MHz): 7.35
3
3
(d; J ) 8.3; 2H), 6.94 (d; J ) 8.3; 2H), 5.81-5.72 (m; 1H),
J . Org. Chem, Vol. 69, No. 21, 2004 7121

Barluenga et al.
3
3
6.62-5.55 (m; 1H), 3.83 (s; 3H), 3.40 (dd; J ) 12.8, J ax-eq
)
) 6.8; 3H). 13C NMR (CDCl3, 75 MHz): 211.2 (C), 170.2 (C),
144.5 (C), 132.6 (CH), 128.4 (CH), 127.7 (CH), 127.5 (CH),
124.8 (CH), 73.2 (CH), 70.9 (C), 65.3 (CH), 63.6 (CH2), 47.3
(CH2), 42.7 (CH3), 29.2 (CH2), 28.3 (CH2), 23.1 (CH2), 20.7 (CH),
10.6 (CH3). HRMS (EI) calcd for C21H27NO3-C4H7: 341.1985,
found 341.1986.
2.8; 1H), 3.15-3.05 (m, 1H), 2.89 (dd; 3J ax-ax )12.8, J ) 12.8,
1H), 2.60-2.50 (m; 6H),1.16 (d; 3J ) 6.6; 3H). 13C NMR (CDCl3,
75 MHz): 208.9 (C), 159.1 (C), 128.3 (CH), 124.5 (C), 123.3
(CH), 114.1 (CH), 70.3 (CH3), 65.0 (CH), 55.3 (CH), 55.2 (C),
52.4 (CH2), 50.1 (CH2), 48.7 (CH), 33.3 (CH2), 10.1 (CH3).
HRMS (EI) calcd for C17H21NO2: 271.1567, found 271.1567.
Eth yl (1S*,4S*,9a S*)-2,3,4,6,9,9a -Hexa h yd r o-1-m eth yl-
2-oxo-1H-qu in olizin -4-ca r boxyla te 22b. Prepared from di-
ene 21b. Obtained as a pale yellow oil in 97% yield: Rf ) 0.33
(E)-(6R*,7S*,11S*)-11-(4-F lu or op h en yl)-6-m et h oxy-8-
p h en yl-9-(N-m et h ylb en zen ea m in o)-1-a za b icyclo[5.4.0]-
u n d ec-3,8-d ien e 24a . Prepared from diene 23a . Obtained as
a pale yellow oil in 94% yield: Rf ) 0.26 (Hex/EtOAc 3:1)
KMnO4. 1H NMR (CDCl3, 300 MHz): 7.39-7.19 (m; 8H), 7.08-
7.00 (m; 3H), 6.80-6.64 (m; 3H), 5.95-5.83 (m; 1H), 4.69 (dd;
1
(Hex/EtOAc 5:1) KMnO4. H NMR (CDCl3, 300 MHz): 6.85-
5.73 (m; 1H), 5.70-5.60 (m; 1H), 4.30 (q; 3J ) 6.4; 2H), 3.61-
3.49 (m; 1H), 3.25 (dd; 3J ax-ax ) 13.5, 3J ax-eq ) 3.2; 1H), 3.05-
2.83 (m; 3H), 2.63-2.41 (m; 4H), 1.35 (t; J ) 6.4; 3H), 1.12 (d;
3J ) 6.6; 3H). 13C NMR (CDCl3, 75 MHz): 208.7 (C), 173.5
(C), 135.8 (CH), 134.0 (CH), 64.2 (CH), 60.5 (CH2), 60.1 (CH),
57.0 (CH2), 46.5 (CH), 43.7 (CH2), 36.1 (CH2), 14.2 (CH3), 12.0
(CH3). HRMS (EI) calcd for C17H19NO3: 237.1359, found
237.1350.
3
3J ) 11.1, 6.0; 1H), 4.22 (dd; J ) 6.7, 5.6; 1H) 3.48 (dd; J )
11.1, 3.7; 1H), 3.35 (s; 3H), 3.22 (dd; J ) 14.8, 5.6; 1H), 2.73
(s; 3H), 2.72-2.48 (m; 2H), 2.45-2.20 (m; 2H). 13C NMR
(CDCl3, 75 MHz): 150.5 (C), 141.6 (C), 141.1 (C), 132.7 (C),
132.6 (C), 131.4 (CH), 130.7 (CH), 130.3 (C), 127.5 (CH), 127.3
(CH), 125.4 (CH), 124.2 (CH), 118.7 (CH), 117.5 (CH), 117.2
(CH), 115.6 (CH), 73.5 (CH), 70.5 (CH3), 59.5 (CH), 59.4 (CH),
51.1 (CH2), 39.5 (CH3), 32.1 (CH2), 31.3 (CH2). HRMS (EI) calcd
for C30H31FN2O: 454.2415, found 454.2415.
(7S*,8S*,11S*)-8-Meth yl-11-p h en yl-1-a za bicyclo[5.4.0]-
u n d ec-5-en -9-on e 22c. Prepared from diene 21c. Obtained
as a pale yellow oil in 95% yield: Rf ) 0.25 (Hex/EtOAc 5:1)
KMnO4. 1H NMR (CDCl3, 300 MHz): 7.47-7.30 (m; 5H), 5.83-
5.75 (m; 1H), 5.52 (ddd; J ) 11.4, 2.3, 2.1; 1H), 3.68 (dd; 3J ax-ax
(E)-(6S*,7S*,11S*)-11-(4-F lu or op h en yl)-6-m et h oxy-8-
p h en yl-9-(N-m et h ylb en zen ea m in o)-1-a za b icyclo[5.4.0]-
u n d ec-3,8-d ien e 24b. Prepared from diene 23b. Obtained as
a pale yellow oil in 96% yield: Rf ) 0.47 (Hex/EtOAc 3:1)
KMnO4. 1H NMR (CDCl3, 300 MHz): 7.38-7.19 (m; 9H), 7.05-
6.93 (m; 2H), 6.75-6.69 (m; 1H), 6.60 (d; 3J ) 7.7; 2H), 5.71-
3
3
) 11.7, J ax-eq ) 3.3; 1H), 3.10 (dd; J ) 10.5, J ) 4.3; 1H),
2.91-2.62 (m; 4H), 2.60-2.49 (m; 2H), 2.19-1.92 (m; 1H),
1.56-1.40 (m; 2H), 1.12 (d; J ) 6.6; 3H). 13C NMR (CDCl3,
3
3
75 MHz): 209.0 (C), 143.7 (C), 129.9 (CH), 128.7 (CH), 128.3
(CH), 127.5 (CH), 127.1 (CH), 72.8 (CH), 69.2 (CH), 50.7 (CH2),
49.8 (CH), 48.8 (CH2), 26.7 (CH2), 23.1 (CH2), 10.3 (CH3).
HRMS (EI) calcd for C17H21NO: 255.1618, found 255.1613.
(8S*,9S*,12S*)-9-Meth yl-12-p h en yl-1-a za bicyclo[6.4.0]-
d od ec-5-en -10-on e 22d . Prepared from diene 21d . Obtained
as a pale yellow oil in 97% yield: Rf ) 0.29 (Hex/EtOAc 10:1)
KMnO4. 1H NMR (CDCl3, 300 MHz): 7.48-7.28 (m; 5H), 5.97-
5.87 (m; 1H), 5.76-5.66 (m; 1H), 3.90 (dd; 3J ax-ax ) 11.1, 3J ax-eq
) 2.7; 1H), 2.71-2.51 (m; 4H), 2.38-2.22 (m; 2H), 2.22-2.11
(m; 2H), 1.91 (dd, J ) 6.3, 0.7; 1H), 1.56-1.44 (m; 1H), 1.13
(d; 3J ) 6.3; 3H). 13C NMR (CDCl3, 75 MHz): 210.8 (C), 140.6
(C), 132.6 (CH), 128.8 (CH), 128.2 (CH), 127.9 (CH), 127.5
(CH), 127.3 (CH), 69.4 (CH), 50.1 (CH2), 46.4 (CH), 30.6 (CH2),
29.9 (CH2), 29.7 (CH2), 26.3 (CH2), 10.8 (CH3). HRMS (EI) calcd
for C18H23NO: 269.1774, found 269.1776.
5.62 (m; 1H), 5.38-5.30 (m; 1H), 4.50 (s; 1H), 4.38 (dd; J )
3
3
9.4, 4.2; 1H), 3.78 (d; J ) 15.1; 1H), 3.45 (dd; J ) 6.6, 2.3;
1H) 3.18 (dd; 2J gem ) 17.1, 3J ax-eq ) 4.2; 1H), 3.04 (s; 3H), 2.73-
2.62 (m; 2H), 2.65 (s; 3H), 2.55-2.45 (m; 1H), 2.31 (ddd; 2J gem
3
) 17.1, J ) 9.4, 2.2; 1H). 13C NMR (CDCl3, 75 MHz): 147.5
(C), 139.0 (C), 138.9 (C), 134.2 (C), 129.8 (C), 129.7 (CH), 129.0
(CH), 128.2 (CH), 127.6 (C), 127.0 (CH), 126.9 (CH), 125.2
(CH), 116.7 (CH), 115.0 (CH), 114.7 (CH), 113.1 (CH), 83.9
(CH), 77.2 (CH), 67.5 (CH3), 57.1 (CH), 56.4 (CH), 49.1 (CH2),
37.1 (CH3), 35.3 (CH2), 29.9 (CH2). HRMS (EI) calcd for C30H31
FN2O: 454.2415, found 454.2408.
-
Ack n ow led gm en t. Financial support for this work
by was provided by the Direccio´n General de Investi-
gacio´n (DGI) of Spain (BQU-2001-3853) and the FICYT
of the Principado de Asturias (Spain) (PR-01-GE-09).
(8S*,9R*,10S*,13S*)-8-Acet yl-13-p h en yl-10-m et h yl-1-
a za bicyclo[7.4.0]tr id ec-5-en -11-on e 22g. Prepared from
diene 21g. Obtained as a colorless oil in 95% yield: Rf ) 0.19
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 9b, 13a ,b, 15, 18b-e, 22f, 21b-d , 21f,g,
and 23a ,b and copies of the 13C NMR spectra of all the
compounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
(Hex/EtOAc 6:1) KMnO4. H NMR (CDCl3, 300 MHz): 7.51-
7.29 (m; 5H), 5.62-5.48 (m; 2H), 5.00 (dt; 3J ) 10.7, 4.4; 1H),
3.95 (dd; 3J ax-ax ) 13.1, J ax-eq ) 3.1; 1H), 3.40-3.31 (m; 1H),
3
3.22-3.15 (m; 1H), 3.13-2.93 (m; 3H), 2.75-2.61 (m; 2H),
2.46-2.25 (m; 3H), 2.01 (s; 3H), 1.47-1.25 (m; 2H), 1,02 (d; 3J
J O049003A
7122 J . Org. Chem., Vol. 69, No. 21, 2004