Aza-cope rearrangement-Mannich cyclizations for the formation of complex tricyclic amines: Stereocontrolled total synthesis of (±)-gelsemine

Article abstract of DOI:10.1021/ja055710p

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0^2,8] decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0^2,8]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0^2,8]decanone 18, a central intermediate in our total of (±)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.

Full text of DOI:10.1021/ja055710p

Published on Web 12/06/2005
Aza-Cope Rearrangement-Mannich Cyclizations for the
Formation of Complex Tricyclic Amines: Stereocontrolled
Total Synthesis of (()-Gelsemine
William G. Earley,1a Jon E. Jacobsen,1b Andrew Madin,1c G. Patrick Meier,1d
Christopher J. O’Donnell,1e Taeboem Oh,1f David W. Old,1g Larry E. Overman,* and
Matthew J. Sharp1h
Contribution from the Department of Chemistry, UniVersity of California, IrVine,
516 Rowland Hall, IrVine, California 92697-2025
Received August 30, 2005; E-mail: leoverma@uci.edu
Abstract: A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences
for assembling the azatricyclo[4.4.0.02,8]decane core of gelsemine is described. Iminium ions and
N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines
do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroiso-
quinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place
to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions
to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones
prepared in this way efficiently assembles the azatricyclo[4.4.0.02,8]decane unit of gelsemine. Using a
sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities
of azatricyclo[4.4.0.02,8]decanone 18, a central intermediate in our total of (()-gelsemine, were prepared
from 3-methylanisole in 12 steps and 16% overall yield.
Background
The genus Gelsemium (Loganiaceae) is comprised of three
species, of which G. semperVirens (Carolina or yellow jasmine)
has been the most extensively investigated for the presence of
alkaloids.2 This particular plant is indigenous to the southeastern
United States and has a long history of medicinal applications.
Wormley first detected the presence of alkaloids in extracts of
G. semperVirens in 1870.3 In 1876, Sonnenschein isolated the
principal component of the species, gelsemine (1), as an
amorphous base (Figure 1).4 The correct molecular formula of
gelsemine, C20H22N2O2, was established in 1910 by Moore.5
More than 70 years of degradative studies failed to elucidate
the structure of gelsemine but demonstrated that gelsemine had
(1) Current addresses: (a) Albany Molecular Research, Inc., 21 Corporate
Circle, Albany, NY 12203. (b) Pfizer Inc., St. Louis Laboratories, 700
Chesterfield Parkway West, Chesterfield, MO 63017. (c) Merck Sharp &
Dohme Laboratories, Terlings Park, Harlow, Essex CM20 2QR, England.
(d) Medical University of South Carolina, Department of Medicinal
Chemistry, 171 Ashley Ave., Charleston, SC 29425. (e) Pfizer Inc., Groton/
New London Laboratories, Eastern Point Road, 8220-4044, Groton, CT
06340. (f) California State University Northridge, Department of Chemistry,
Northridge, CA 91330. (g) Allergan Inc., 2525 DuPont Dr., Irvine, CA
92623. (h) GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC
27709.
(2) For reviews of the literature concerning Gelsemium alkaloids, see: (a)
Saxton, J. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press:
New York, 1965; Vol. 8, pp 93-117. (b) Bindra, J. S. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol.14, pp 83-
121. (c) Liu, Z.-J.; Lu, R.-R. In The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, 1988; Vol. 33, pp 83-140. (d) Saxton, J. E. Nat. Prod.
Rep. 1992, 9, 393-446. (e) Takayama, H.; Sakai, S.-J. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: NY, 1997; Vol. 49, pp 1-78.
(3) Wormley, T. G. Am. J. Pharm. 1870, 42, 1-16.
Figure 1. Gelsemium alkaloids.
the same five functional groups that are present in strychnine.2
Finally, in 1959, the structure was solved independently by two
(4) Sonnenschein, F. L. Ber. 1876, 9, 1182-1186.
(5) Moore, C. W. J. Chem. Soc. 1910, 97, 2223-2233.
9
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Aza-Cope Rearrangement−Mannich Cyclizations
A R T I C L E S
laboratories: Lovell and co-workers used X-ray crystallography
to determine the structure of the hydrochloride and hydroiodide
salts of gelsemine,6 whereas Conroy and Chakrabarti derived
the same structure from a combination of biosynthetic rationale
(attributed to Woodward) and an early application of 1H NMR
spectroscopy for structure elucidation.7,8 Gelsemine’s presumed
biosynthesis from secologanin suggests the absolute configu-
ration depicted in Figure 1, a supposition verified in 2000 by
Fukuyama’s enantioselective total synthesis.9
Since these early reports, many structurally related Gelsemium
alkaloids have been reported (Figure 1).10-15 Among these,
gelsemicine (5) is the most toxic and appears to be largely
responsible for the CNS stimulant activity that is characteristic
of the Gelsemium extracts.12 Koumine (10), which has enjoyed
a long history of use in traditional Chinese medicine, is the most
abundant alkaloid found in G. elegans.16 Gelsemine (1),
gelsevirine (2), gelsedine (6), gelsenicine (9), gelsemine N-oxide,
19-(S)-hydroxydihydrogelsevirine, and 19-(R)-hydroxydihydro-
gelsevirine (11) are among the numerous alkaloids isolated from
G. elegans.17 The least studied species is G. rankinii, from which
rankinidine (14), 21-oxogelsevirine (4), 19-(R)-acetoxydihy-
drogelsevirine (12), and 19-(R)-hydroxydihydrogelsemine (13)
have been isolated.17a,18
Figure 2. Initial retrosynthetic analysis.
the spirooxindole unit of pentacyclic intermediate 15 could be
formed by cyclization of an appropriately functionalized R,â-
unsaturated amide such as 16. At the outset, we entertained the
(20) For model studies and syntheses of fragments of gelsemine, see: (a) Autrey,
R. L.; Tahk, F. C. Tetrahedron 1967, 23, 901-917. (b) Autrey, R. L.;
Tahk, F. C. Tetrahedron 1968, 24, 3337-3345. (c) Johnson, R. S.; Lovett,
T. O.; Stevens, T. S. J. Chem. Soc. C 1970, 6, 796-800. (d) Fleming, I.;
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M.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 1986, 349-359. (g) Stork,
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Tetrahedron 1987, 43, 5019-5030. (i) Clarke, C.; Fleming, I.; Fortunak,
J. M. D.; Gallagher, P. T.; Honan, M. C.; Mann, A.; Nubling, C. O.;
Raithby, P. R.; Wolff, J. J. Tetrahedron 1988, 44, 3931-3934. (j) Hiemstra,
H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882-3884. (k)
Choi, J.-K.; Ha, D.-C.; Hart, D. J.; Lee, C.-S.; Ramesh, S.; Wu, S. J. Org.
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Speckamp, W. N. J. Org. Chem. 1992, 57, 1059-1061. (o) Hart, D. J.;
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Soc., Perkin Trans. 1 1996, 883-893. (r) Ng, F.; Chiu, P.; Danishefsky,
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Cha, J. K. Synlett 1999, 561-562. (t) Avent, A. G.; Byrne, P. W.; Penkett,
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For total syntheses of (+)-gelsedine, see: (w) Beyersbergen van Hene-
gouwen, W. G.; Fieseler, R. M.; Rutjes, F. P. J. T.; Hiemstra, H. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2214-2217. (x) Beyersbergen van
Henegouwen, W. G.; Fieseler, R. M.; Rutjes, F. P. J. T.; Hiemstra, H. J.
Org. Chem. 2000, 65, 8317-8325. For total syntheses of (+)-koumine,
see: (y) Magnus, P.; Mugrage, B.; DeLuca, M.; Cain, G. A. J. Am. Chem.
Soc. 1989, 111, 786-789. (z) Magnus, P.; Mugrage, B.; DeLuca, M. R.;
Cain, G. A. J. Am. Chem. Soc. 1990, 112, 5220-5230. For formal total
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Tetrahedron Lett. 1991, 32, 3895-3898. (bb) Bailey, P. D.; McLay, N. R.
J. Chem. Soc., Perkin Trans. 1 1993, 441-449.
The six diverse rings of gelsemine (1) are assembled into a
compact cage. The unusual and densely functionalized nature
of this hexacyclic structure provoked intense efforts to synthesize
gelsemine.19 These studies stimulated the development of many
innovative synthetic methods,20,21 culminating in total syntheses
of (()-gelsemine by the groups of Johnson,22 Speckamp,23
Hart,24 Fukuyama,25 Overman,26 and Danishefsky27 and of (+)-
gelsemine by Fukuyama and co-workers.9
Initial Synthesis Planning
The retrosynthetic analysis that propelled our efforts to
synthesize gelsemine is outlined in Figure 2. We envisaged
forming the hydropyran ring last, for example, by intramolecular
etherification of an intermediate such as 15. It was hoped that
(6) Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 1
(4), 1-5.
(7) Conroy, H.; Chakrabarti, J. K. Tetrahedron Lett. 1959, 1 (4), 6-13.
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result, some of the original assignments have been revised. See: (a) Schun,
Y.; Cordell, G. A. J. Nat. Prod. 1985, 48, 969-971. (b) Wenkert, E.; Chang,
C.-J.; Clouse, A. O.; Cochran, D. W. J. Chem. Soc., Chem. Commun. 1970,
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Wenkert, E.; Chang, C.-J.; Cochran, D. W.; Pellicciari, R. Experientia 1972,
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(21) For early studies from our laboratories, see: (a) Abelman, M. M.; Oh, T.;
Overman, L. E. J. Org. Chem. 1987, 52, 4130-4133. (b) Earley, W. G.;
Jacobsen, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. Tetrahedron Lett.
1988, 29, 3781-3784. (c) Earley, W. G.; Oh, T.; Overman, L. E.
Tetrahedron Lett. 1988, 29, 3785-3788. (d) Madin, A.; Overman, L. E.
Tetrahedron Lett. 1992, 33, 4859-4862. (e) Overman, L. E.; Sharp, M. J.
J. Org. Chem. 1992, 57, 1035-1038.
(22) (a) Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem.
Commun. 1994, 763-764. (b) Dutton, J. K.; Steel, R. W.; Tasker, A. S.;
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766.
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(12) (a) Schwarz, H.; Marion, L. Can. J. Chem. 1953, 31, 958-975. (b)
Przybylska, M.; Marion, L. Can. J. Chem. 1961, 39, 2124-2127.
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C. L. J. Org. Chem. 1962, 27, 4123-4126.
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104, 87-98.
(15) Schun, Y.; Cordell, G. A. J. Nat. Prod. 1985, 48, 788-791.
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(23) (a) Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N.
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A R T I C L E S
Scheme 1
Earley et al.
Scheme 2
possibility that either radical-chain or metal-catalyzed processes
might accomplish this conversion. At the time our efforts began,
precedent that a sterically congested quaternary carbon center
such as C7 could be fashioned by either process was lacking.
Nonetheless, we adopted this strategy in part because it would
present opportunities for developing new methods to address
what still remains a challenging problem in organic synthesis:
stereocontrolled construction of quaternary carbon stereo-
centers.28 As it happened, the discovery that intramolecular Heck
reactions could solve this general problem with remarkable
facility is the most significant outcome of our endeavors in this
area.29
We anticipated that cyclization precursor 16 could be prepared
from the azatricyclo[4.4.0.02,8]decanone 17. This latter inter-
mediate encodes a 3-acylpyrrolidine unit, suggesting that it
might be available by aza-Cope-Mannich reaction of bicyclo-
[2.2.2]octyliminium ion 19.30,31 The projected aza-Cope-
Mannich transformation is outlined in more detail in Scheme
1. Although thermal Cope rearrangements of bicyclo[2.2.2]-
octenes bearing endo alkenyl substituents have high activation
barriers,32 these rearrangements and the corresponding oxy-Cope
rearrangements have been employed to prepare functionalized
cis-decalins.33 Because of the kinetic activation provided by the
positively charged nitrogen atom,31b we expected the conversion
of iminium cation 19 to cis-hydroisoquinolinium cation 21 to
occur at significantly lower temperatures than those required
for similar sigmatropic reorganizations of hydrocarbons. At the
outset, Mannich cyclization of iminium ion 21 to yield
azatricyclo[4.4.0.02,8]decanone 17 was viewed as the potentially
problematic step of this sequence for two reasons: (1) the ring
strain of the azatricyclo[4.4.0.02,8]decane ring system34 and (2)
the requirement that the tetrahydropyridinium ring adopt a boat
conformation (as depicted in conformer 22) to achieve accept-
able orbital overlap for the intramolecular Mannich reaction.31a,35
The intramolecular Mannich reaction depicted in Scheme 1
was without precedent; however, the literature provided ex-
amples of other cyclizations that form tricyclo[4.4.0.02,8]decane
ring systems.36 For example, closure of an analogous bond is
involved in a tosylate displacement reaction leading to sa-
tivene.37 A more relevant example of this bond construction is
found in Woodward’s base-promoted conversion of R-santonin
(23) to santonic acid, which is particularly germane as the
intramolecular Michael reaction involved in this sequence, like
the Mannich reaction, presumably is reversible (Scheme 2).38
With these considerations in mind, we set out to explore the
feasibility of the aza-Cope-Mannich reaction to prepare the
azatricyclo[4.4.0.02,8]decane ring system of gelsemine (1). At
the time our studies began, this cascade reaction had just been
invented30 and never had been examined in the bicyclo[2.2.2]-
octyl series or with a substrate as complex as 19. Although the
direct way to access azatricyclodecanone intermediate 17
depicted in Scheme 1 ultimately proved unworkable, a base-
promoted variant of aza-Cope-Mannich chemistry eventually
provided access to related intermediate 18 (Figure 2). Full details
of our investigations into iminium-ion transformations in the
bicyclo[2.2.2]octyl series and the development of a base-
promoted 2-aza-Cope rearrangement are the subject of this
(27) (a) Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J. Tetrahedron Lett. 2002,
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(28) For recent reviews of enantioselective generation of quaternary stereocenters,
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L. E.; Link, J. T. In Cross Coupling Reactions; Diederich, F.; Stang, P. J.,
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A R T I C L E S
Scheme 3
Scheme 4
rearrangement but rather aza-Prins cyclization at the proximal
terminus of the alkene double bond to generate tertiary
carbenium ion 31 and, ultimately, azatricyclodecane 32.
We hypothesized that the electron-releasing methyl group at
C5 of iminium-ion intermediate 30 was responsible for the
undesired cyclization to generate 32. As a substituent at C5 must
ultimately evolve to the angular vinyl group of gelsemine,
considerable variation in the electronic properties of this group
would be permitted. Therefore, we turned to explore the
chemistry of related bicyclo[2.2.2]octenyl formaldiminium ions
having less electron-rich carbon-carbon double bonds.
The outcome of generating a formaldiminium ion from a
bicyclo[2.2.2]octenylamine having an unsubstituted double bond
was explored first. The straightforward preparation of such a
precursor, bicyclo[2.2.2]octenylamine 35, from acid 3344 is
summarized in Scheme 4. Exposing bicyclooctenylamine 35 to
paraformaldehyde and camphorsulfonic acid in acetonitrile or
methanol at 100 °C resulted in no reaction. Heating these
reactants to 200 °C in toluene in a sealed tube also returned the
starting secondary amine 35, together with its N,N-dimethy-
lamine congener. As we had recorded considerable success in
initiating other aza-Cope-Mannich transformations of form-
aldiminium ions from cyanomethylamine precursors,31,45 octe-
nylamine 35 was allowed to react with formalin and potassium
cyanide to give cyanomethylamine 36. Heating this precursor
with camphorsulfonic acid and paraformaldehyde also failed
to affect the desired aza-Cope-Mannich reaction. The formation
of the corresponding N,N-dimethylamine product confirmed that
a formaldiminium ion was being generated; however, aza-Cope
rearrangement or Mannich cyclization of this intermediate was
slower than its reduction.46
account.39 The development of Heck cyclization chemistry to
prepare spirooxindoles and the endgame strategy that ultimately
led to (()-gelsemine (1) are presented in the accompanying
paper.40
Results and Discussion
Attempted Construction of Azatricyclo[4.4.0.02,8]decane
Intermediates by Cationic Aza-Cope-Mannich Cyclizations.
Bicyclooctenylamine 29 was chosen for our inaugural investiga-
tions of the projected aza-Cope-Mannich transformation (Scheme
3). The synthesis of this amine commenced with the reaction
of cyclohexadiene 24, the Birch-reduction product of 3-methy-
lanisole, with methyl acrylate in the presence of a catalytic
amount of dichloromaleic anhydride to provide a separable 2.7:1
mixture of endo, 25, and exo, 26, adducts.41 The methyl ester
of the endo product 25 was saponified, and the resulting acid
was converted to carbamate 28 by a standard Curtius-rearrange-
ment sequence.42 Reduction of this product with alane43 provided
bicyclooctenylamine 29 in 45% overall yield from Diels-Alder
product 25.
With amine 29 in hand, we turned to examine the proposed
cationic aza-Cope-Mannich transformation. Reaction of bicy-
clooctenylamine 29 with paraformaldehyde and camphorsulfonic
acid (CSA) in refluxing benzene for extended periods of time
resulted only in the recovery of starting material. The use of
higher boiling solvents such as toluene or chlorobenzene was
also unsuccessful, as paraformaldehyde sublimed from these
reaction mixtures. However, heating bicyclooctenylamine 29
with 1.1 equiv of paraformaldehyde, 0.98 equiv of camphor-
sulfonic acid, and a slight excess of sodium sulfate in acetonitrile
at 100 °C provided one major product, which was isolated in
76% yield. The presence of exomethylene and methoxy groups,
As N-acyloxyiminium ions are more reactive than iminium
ions and are readily generated by the acid-promoted reaction
of formaldehyde with secondary carbamates,47,48 we also
examined the direct reaction of bicyclooctenyl carbamate 34
with paraformaldehyde. When this condensation was carried out
1
readily apparent in H and 13C NMR spectra, established that
this product was not the desired azatricyclo[4.4.0.02,8]decanone
but rather the 10-methylene-4-azatricyclo[4.3.1.03,7]decane 32.
Iminium-ion intermediate 30 had not undergone aza-Cope
(44) (a) Alfaro, I.; Ashton, W.; McManus, L. D.; Newstead, R. C.; Rabone, K.
L.; Rogers, N. A. J.; Kernick, W. Tetrahedron 1970, 26, 201-218. (b)
The endo and exo isomers are misassigned in this paper; see: Jacobsen,
E. J. Ph.D. Dissertation, University of California, Irvine, 1983.
(45) Overman, L. E.; Jacobsen, E. J. Tetrahedron Lett. 1982, 23, 2741-2744.
(46) Presumably from Eschweiler-Clarke reduction by contaminating amounts
of formic acid.
(39) Portions of this work have appeared in preliminary communications.21b,c
(40) See the following paper in this issue.
(41) (a) Monti, S. A.; Chen, S.-C.; Yang, Y.-L.; Yuan, S.-S.; Bourgeois, O. P.
J. Org. Chem. 1978, 43, 4062-4069. (b) Birch, A. J.; Shoukry, E. M. A.;
Stansfield, F. J. Chem. Soc. 1961, 5376-5380.
(47) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1047-
1082.
(48) For an example of generating an N-acyloxyiminium ion in this fashion,
see: Kano, S.; Yokomatsu, T.; Yuasa, Y.; Shibuya, S. Tetrahedron Lett.
1983, 24, 1813-1814.
(42) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Organic Syntheses;
Wiley: New York, 1988; Collect. Vol. VI, pp 95-101.
(43) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1464-1472.
9
J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18049

A R T I C L E S
Scheme 5
Earley et al.
Figure 3. Transition structure of the cationic aza-Cope rearrangement of
43 and the steric energies of related tricyclodecanes.
3). A simplified model for this transition structure would be
tricyclo[4.4.0.00,0]decane (47, twistane). Molecular mechanics
calculations predict that this hydrocarbon is 2.2 kcal/mol higher
in energy than tricyclo[4.3.1.03,7]decane (46).34 Thus, the greater
strain of the twistane tricyclodecane skeleton provides a rationale
why the iminium- and N-acyloxyiminium-ion intermediates
generated in the reactions summarized in Schemes 3-5 cyclize
to generate 4-azatricyclo[4.3.1.03,7]decyl carbenium ion inter-
mediates rather than undergo aza-Cope rearrangements.
We hypothesized that a potential way to relieve the constraints
imposed by the rigid bicyclo[2.2.2]octenyl ring system would
be to alter the electronic nature of the rearranging system in
such a way to advance bond cleavage relative to bond formation
in the sigmatropic reorganization. The seminal contributions of
Evans and Goddard50 to the origin of base acceleration51 in the
oxy-Cope rearrangement suggested that an analogous base-
promoted oxy-aza-Cope rearrangement would have a less
constrained transition structure than that of the cationic rear-
rangement depicted in Figure 3.
Ultimately Successful Synthesis of Azatricyclo[4.4.0.02,8]-
decane 18. Although rarely used, base-promoted aza-Cope-
Mannich reactions are known.52 To explore this transformation
in the azabicyclo[2.2.2]octene ring system, we needed to
assemble bicyclo[2.2.2]oct-5-ene-2-amines in which the bridge-
head C1 substituent is hydroxyl in order for the powerful
activating effect of an alkoxide substituent51 to be brought into
play. Initially we examined demethylation of Diels-Alder
products 28 and 29 (see Scheme 3) to gain access to such
substrates. However, all attempts to remove the methyl group
from these precursors with trimethylsilyl iodide, boron tribro-
mide, or boron trifluoride/ethanethiol failed to give the corre-
sponding alcohols.
in formic acid at 50 °C using 1.3 equiv of paraformaldehyde,
azatricyclo[4.3.1.03,7]decyl formate 37, the product of aza-Prins
cyclization, was produced in high yield.
We turned next to explore whether introduction of an electron-
withdrawing group at C5 of the bicyclooctenylamine precursor
might prevent iminium ion-alkene (aza-Prins) cyclization, thus
allowing the desired sigmatropic reorganization to be realized.
The synthesis of such a precursor, ester 40, began with selenium
dioxide oxidation of bicyclo[2.2.2]octenyl carbamate 28 in
refluxing dioxane to form aldehyde 38 in 89% yield (Scheme
5). Sodium chlorite oxidation of this intermediate provided acid
39 in 83% yield, which, upon reaction with methyl iodide and
potassium carbonate, delivered methyl ester 40 in 89% yield.
A new reaction manifold was revealed when carbamate ester
40 was allowed to react at room temperature with paraformal-
dehyde in trifluoroacetic acid (TFA), a reaction that produced
one major tricyclic product, trifluoroacetate 42. Single-crystal
X-ray analysis established that this crystalline product had a
rearranged carbon skeleton. Tricyclic diester 42 likely arises
by initial aza-Prins cyclization to generate carbocation inter-
mediate 41, which undergoes Wagner-Meerwein rearrangement
and trapping of the resulting carbocation with trifluoroacetic
acid.
Construction of Azatricyclo[4.4.0.02,8]decanes by Sequen-
tial Base-Promoted Aza-Cope Rearrangement and Iminium
Ion Cyclization. General Considerations. The failure to realize
the desired aza-Cope reorganization in the bicyclo[2.2.2]octenyl
series, even with intermediates having an electron-withdrawing
group at C5 of the bicyclooctenylamine precursor, forced us to
consider other options.49 As a result of the high electrophilicity
of the iminium ion and N-acyloxyiminium ion functional groups,
bond formation is likely advanced with respect to bond cleavage
in iminium ion and N-acyloxyiminium ion [3,3]-sigmatropic
rearrangements. In the mechanistic limit, these rearrangements
could occur by a stepwise cyclization-Grob fragmentation
sequence. Thus, the energy of the transition state of the cationic
aza-Cope rearrangement of 43 f 45 is expected to be influenced
strongly by the stability of the tricyclic ring system defined by
the sigmatropic rearrangement transition structure 44 (Figure
We were able to prepare hydroxyl bicyclooctenylamine 53
quite smoothly by a Diels-Alder strategy using a triisopropyl-
silyl (TIPS) group to protect what will become the C1 hydroxyl
substituent of the bicyclo[2.2.2]octenylamine (Scheme 6). This
sequence began with kinetic deprotonation of â,γ-unsaturated
ketone 4853 with lithium diisopropylamide at -78 °C, followed
by quenching with triisopropylsilyl trifluoromethanesulfonate
to give siloxy diene 49 in 92% overall yield from 3-methylani-
sole, the precursor of enone 48. Diels-Alder cycloaddition of
(50) Steigerwald, M. L.; Goddard, W. A., III; Evans, D. A. J. Am. Chem. Soc.
1979, 101, 1994-1997.
(51) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765-4766.
(52) (a) Kakimoto, M.; Okawara, M. Chem. Lett. 1979, 1171-1174. (b) Okazaki,
M. E. Ph.D. Dissertation, University of California, Irvine, 1986.
(53) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1977, 42, 1051-1056.
(49) Attempted cationic aza-Cope rearrangement of substrates in which the
methoxy group was replaced by a free hydroxy group led only to formation
of the corresponding oxazolidine.
9
18050 J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005

Aza-Cope Rearrangement−Mannich Cyclizations
A R T I C L E S
Scheme 6
formalin and KCN in aqueous THF. Exposure of this product
to an excess of KH at room temperature in THF affected the
desired base-promoted oxy-aza-Cope rearrangement to generate
cis-hydroisoquinoline alkoxide 56. Upon aqueous workup, the
corresponding ketone 57, albeit impure, was isolated in low
yield. We soon discovered that quenching the basic reaction at
low temperature with an aqueous HCN/KCN buffer solution
allowed the cis-3-cyanohydroisoquinolone 58 to be isolated in
67% yield.57
We had succeeded in promoting the desired sigmatropic
rearrangement; however, alkoxide imine 56 did not cyclize to
generate an azatricyclo[4.4.0.02,8]decane product. This outcome,
which contrasts with the formation of 3-acylpyrrolidine and
hydroindolone conjugate bases from related base-promoted aza-
Cope-Mannich transformations,52 likely reflects the strain of
the azatricyclo[4.4.0.02,8]decane ring system. The increase in
basicity that would result when a potassium enolate is trans-
formed to a potassium amide renders the cyclization of imine
enolate 56 much less favorable than the related junction of
iminium ion and enol functional groups (classical Mannich
cyclization).
Scheme 7
Decoupling the base-promoted sigmatropic reorganization and
the Mannich cyclization step finally allowed the long-sought
azatricyclo[4.4.0.02,8]decanones to be constructed. To eventually
facilitate the Mannich cyclization, cis-3-cyanohydroisoquinolone
58 was converted to its tertiary amine congener 59 by reaction
with methyl methanesulfonate and diisopropylethylamine in
refluxing chloroform (Scheme 7). To our delight, exposure of
this intermediate to excess HCl in methanol at 95 °C brought
about the desired intramolecular Mannich reaction to generate
azatricyclo[4.4.0.02,8]decanone 61. This product, whose structure
was secured readily by NMR and mass spectrometric analysis,
was isolated in 44% yield.
With the successful sequential base-promoted oxy-aza-Cope-
Mannich sequence developed, we turned to examine the related
process with intermediates that contained functionality that
plausibly could be employed to fashion the terminal vinyl and
hydropyran fragments of gelsemine. We began by examining a
sequence in which the hydroxymethylene unit of gelsemine
would be present from the outset. This study commenced with
the Diels-Alder cycloaddition of siloxy diene 49 with methyl
(E)-4-benzyloxy-2-butenoate (62) (Scheme 8). When conducted
in the presence of AlCl3 at -78 °C, this reaction delivered a
7:1 mixture of endo and exo cycloadducts in 71% yield, from
which the endo epimer 63 was separated readily by chroma-
tography. Allylic oxidation of adduct 63 with selenium dioxide
gave aldehyde 64, which upon standard Wittig methylenation
provided diene 65 in 68% yield for the two steps. Saponification
of the methyl ester of 65, Curtius rearrangement of the derived
acid, and alkaline hydrolysis of the resulting isocyanate delivered
primary amine 67 in 60% overall yield. The cyanomethyl group
was introduced next by reaction of 67 with chloroacetonitrile
in the presence of tetrabutylammonium iodide to deliver amino
nitrile 68 in 65% yield. Finally the silyl protecting group was
removed using TBAF giving the oxy-aza-Cope precursor 69 in
91% yield. However, exposing 69 to KH to initially form
formaldimine alkoxide 70 did not effect the desired anionic aza-
Cope rearrangement; when this reaction was quenched with
diene 49 with methyl acrylate at -78 °C in the presence of
AlCl3 provided an 8:1 mixture of endo/exo cycloadducts in
nearly quantitative yield. The major epimer 50 was separated
by chromatography and saponified to yield acid 51. Curtius
rearrangement of 51, with trapping of the resulting isocyanate
by ethanol, provided bicyclooctenyl carbamate 52 in 68%
yield.54 Removal of the alcohol protecting group from this
intermediate with tetrabutylammonium fluoride, followed by
cleavage of the carbamate with potassium hydroxide, delivered
the hydroxyl bicyclooctenylamine 53 in 64% yield for the two
steps.
With hydroxyl bicyclo[2.2.2]octenylamine 53 in hand, we
turned to investigate the projected base-promoted aza-Cope-
Mannich sequence (Scheme 7). A method for generating the
labile formaldehyde imine derivative of 5355 under strongly basic
conditions that would also deprotonate the bridgehead alcohol
was required. Such a method was available, as we had shown
earlier that formaldehyde imines could be generated in situ by
base-promoted fragmentation of secondary cyanomethylamines.56
Cyanomethylamine 54 was prepared conveniently in 84% yield
by reaction of the hydrochloride salt of primary amine 53 with
(54) Attempted alkaline hydrolysis of the isocyanate to directly produce the
amine resulted in formation of substantial amounts of the dimeric urea.
(55) Formaldehyde imines, unless substituted with extremely bulky substituents
on nitrogen, cannot be isolated as they rapidly trimerize to form hexahydro-
1,3,5-triazines.56a
(56) (a) Overman, L. E.; Burk, R. M. Tetrahedron Lett. 1984, 25, 1635-1638.
(57) The relative configuration of the cyano substituent was established by single-
(b) Overman, L. E.; Osawa, T. J. Am. Chem. Soc. 1985, 107, 1698-1701.
crystal X-ray analysis of the N-benzoyl derivative.
9
J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18051

A R T I C L E S
Scheme 8
Earley et al.
Scheme 9
methyl chloroformate, only the tricyclic oxazolidine 71 was
isolated (43% yield).
Presumably the benzyloxymethyl side chain of 70 is respon-
sible for imine-alkoxide 70 failing to undergo [3,3]-sigmatropic
rearrangement. As depicted in Scheme 1, this substituent would
emerge after [3,3]-sigmatropic rearrangement on the congested
concave face of the cis-hydroisoquinoline product. Presumably
this extra steric encumbrance is sufficient to prevent the
sigmatropic reorganization. We had no choice but to postpone
installation of the hydroxymethyl group until after the base-
promoted oxy-aza-Cope rearrangement/Mannich cyclization
sequence. Bromoazatricyclodecane 18 (Figure 2) emerged as a
logical target, foreseeing the exo-oriented bromine at C16 as a
handle for eventual installation of the hydroxymethyl group.
The ultimately successful synthesis of rearrangement substrate
77 began with the 8:1 mixture of Diels-Alder cycloadducts
50, which was prepared on a large scale in 90% overall yield
from 3-methylanisole (see Scheme 6). Allylic oxidation of 50
provided a mixture of epimeric enals. These products could be
separated on a large scale by flash chromatography to provide
the required endo epimer 72 in 80% yield (Scheme 9). Wittig
methylenation of aldehyde 72, followed by saponification of
the diene product delivered acid 74 in 86% yield for the two
steps. Curtius rearrangement of acid 74 was effected using
triphenylphosphoryl azide in refluxing toluene, and the resulting
isocyanate was trapped at room temperature with 4-methoxy-
benzyl alcohol to give the p-methoxybenzyl carbamate (Moz)
75 in 72% yield. Exposure of 75 to trifluoroacetic acid at room
temperature in the presence of anisole cleaved the carbamate
to provide the corresponding primary amine in high yield.54
Reaction of this crude primary amine with formalin and KCN
in a pH 7 buffer solution then delivered cyanomethylamine 76
in 81% yield for the two steps. Finally, liberation of the hydroxyl
group of 76 using TBAF provided the crystalline aza-Cope
rearrangement precursor 77 in 90% yield.
was initiated by base-promoted aza-Cope rearrangement brought
about by exposing 77 to excess potassium hydride and 18-
crown-6 at room temperature in THF. Quenching the resulting
rearrangement product with methyl chloroformate provided a
mixture of regioisomeric carbamate enecarbonates 78. Selective
cleavage of the carbonate functionality of this crude product
with methanolic KOH at room temperature gave cis-hydroiso-
quinoline enecarbamate 79 in 81% overall yield from cyanom-
ethylamine 77. Incorporation of the bromine substituent was
realized without complications by reaction of enecarbamate 79
with 1.1 equiv of bromine and excess 1,2,2,6,6-pentamethylpi-
peridine (PMP) to generate â-bromo enecarbamate 80. This
product was not purified but directly heated at reflux in
trifluoroacetic acid to provide azatricyclo[4.4.0.02,8]decanone 18
as a single stereoisomer in 67% overall yield from enecarbamate
79.58 1H NMR NOE studies suggested that the bromine
substituent was oriented on the exo face of the azatricyclic ring
system, a conclusion that was confirmed by single-crystal X-ray
analysis of ethylene ketal derivative 82. After extensive
optimization, the sequence summarized in Scheme 9 allowed
gram quantities of azatricyclo[4.4.0.02,8]decanone 18 to be
prepared from commercially available 3-methylanisole in an
overall yield of 16% for the 12 steps.
The configuration of the bromine substituent in azatricyclic
product 18 deserves comment. We assume that â-bromo
enecarbamate 80 kinetically protonates from the convex face
to deliver initially N-acyloxyiminium-ion epimer 83 (Scheme
10). However, Mannich cyclization of this epimer is not
(58) The formyl analogues (79 and 80 with R ) CHO), which are available
from the reaction of 79 with Vilsmeier reagent, do not cyclize under these
conditions.
Azatricyclo[4.4.0.02,8]decanone 18 was assembled from bi-
cyclooctenylamine 77 in three additional steps. The sequence
9
18052 J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005

Aza-Cope Rearrangement−Mannich Cyclizations
A R T I C L E S
Scheme 10
advanced with respect to bond cleavage in this sigmatropic
rearrangement, and the tricyclo[4.4.0.00,0]decane-like pericyclic
transition state being of high energy.32,34 However, the analogous
base-promoted oxy-aza-Cope rearrangement does take place,
which we associate with bond cleavage being advanced over
bond formation in this anionic sigmatropic rearrangement.50
Moreover we demonstrated for the first time that the azatricyclo-
[4.4.0.02,8]decane core fragment and the C5-C6 bond of
gelsemine can be formed by Mannich cyclization of a cis-
hydroisoquinolone precursor.59 Using a sequential base-
promoted oxy-aza-Cope rearrangement-Mannich cyclization
sequence,26,40 gram quantities of azatricyclo[4.4.0.02,8]decanone
18, a central intermediate in our total synthesis of (()-
gelsemine,40 was prepared from 3-methylanisole in 12 steps and
16% overall yield.
Acknowledgment. This work was supported by the National
Institute of Health (HL-25854). C.J.O. gratefully acknowledges
the American Cancer Society for postdoctoral fellowship support
(PF-98-002-01). We also thank Dr. John Greaves and Mr. John
Mudd of the UCI mass spectroscopy facility, Dr. Joseph Ziller
of the UCI X-ray crystallography laboratory, and Dr. Jiejun Wu
of the UCI NMR spectroscopy facility for their technical
support.
observed because the boat conformation of the azacyclic ring
that would be required to achieve proper overlap in the
cyclization step thrusts the bulky bromine substituent directly
under the carbocyclic ring. Thus, 83 equilibrates by way of 80
with epimer 84, the latter undergoing Mannich cyclization as
depicted in transition structure 81 to deliver azatricyclodecanone
18.
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data for new compounds and
1H NMR spectra of selected compounds (42 pages, print/PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Conclusion
Iminium ions and N-acyloxyiminium ions derived from endo-
oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-eny-
lamines do not undergo cationic aza-Cope rearrangement to form
cis-hydroisoquinolinium ions (e.g., 19 f 21, Scheme 1), a
failure that we ascribe to two factors: bond formation being
JA055710P
(59) Johnson subsequently employed a Mannich cyclization of a more advanced
intermediate to form this bond of gelsemine in his inaugural total synthesis
of (()-gelsemine.22
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J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18053