Enantioselective Synthesis of (-)-Gilbertine via a Cationic Cascade Cyclization

Article abstract of DOI:10.1021/ja0399021

Described is the first enantioselective synthesis of (-)-gilbertine (2), a member of the uleine-type family, and the determination of the absolute configuration of this natural product is reported. The key step employs a cationic cascade reaction for a te

Full text of DOI:10.1021/ja0399021

Published on Web 03/02/2004
Enantioselective Synthesis of (-)-Gilbertine via a Cationic
Cascade Cyclization
Jan Jiricek and Siegfried Blechert*
Contribution from the Institut fu¨r Chemie, Technische UniVersita¨t Berlin,
Strasse des 17 Juni 135, 10623 Berlin, Germany
Received December 2, 2003; E-mail: Blechert@chem.tu-berlin.de
Abstract: Described is the first enantioselective synthesis of (-)-gilbertine (2), a member of the uleine-
type family, and the determination of the absolute configuration of this natural product is reported. The key
step employs a cationic cascade reaction for a tetrahydropyrane and piperidine ring formation and the
construction of the pentacyclic framework in one step. The synthetic strategy utilizes the Shibasaki reaction
to build up the first stereogenic center. A formylation reaction of a 3-substituted cyclohexanone derivative
was achieved, giving only the desired regioisomer. The Japp-Klingemann Fischer indole protocol was
used successfully as a convergent synthetic approach for the construction of the desired tetrahydrocarbazole
(20). Furthermore, an unexpected behavior of this 2,3-disubstituted cyclohexanone derivative during an
epimerization process was investigated, resulting in different chemical behavior of the enantiomers and
the racemate. The diastereomeric resolution was achieved via the cationic cascade reaction, demonstrating
the versatility of this approach. Significantly, the synthetic 17-step sequence was easy to execute, giving
(-)-gilbertine in 5.5% overall yield.
Chart 1
Introduction
Uleine-type indole alkaloids such as uleine (1) have been of
synthetic interest over the past few decades (Chart 1).1 There
have been a number of reports for racemic and enantioselective
syntheses of uleine and epi-uleine.2 However, syntheses of epi-
uleine are predominant in these series as a result of the
electrophilic C-21-C-7 cyclization approach.3 The iminium ion
used for this final ring formation is subjected to an imine-
enamine tautomerization resulting in an epimerization of the
ethyl group at C-20. Steric discrimination in the event of
cyclization leads to the epi derivative as the major product. This
is the main reason that the synthesis of the natural product is
more problematic than it is for the epi series. Our synthetic
approach to the uleine framework excludes epimer formation
by employing a nucleophilic N-C bond formation at C-21.
Herein we demonstrate the application of this strategy in the
first enantioselective synthesis of (-)-gilbertine (2), a member
of the uleine family.
Gilbertine was first isolated in 1982 from the Aspidosperma
gilbertii (A. P. Duarte), as well as uleine and a large number of
related indole alkaloids.4 The compact pentacyclic framework
and the additional stereogenic center at C-16 are unusual
structural features compared to the other members of the uleine
alkaloid group, which has resulted in gilbertine remaining a
synthetic challenge during the last 20 years. The following
enantioselective synthesis allows the determination of the
absolute configuration of the natural product and employs a
cationic domino process to build up the pentacyclic framework
in one step.
(1) For reviews see (a) Joule, J. A. In Indoles, The Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Series Eds.; Wiley: New York, 1983; Vol.
25, Part 4, Chapt. 6. (b) Alvarez, M.; Joule, J. A. In Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds;
Taylor, E. C., Series Ed.; Wiley: Chichester, U.K., 1994; Vol. 25, Suppl.
to Part 4, Chapt. 6. (c) Saxton, J. E. Nat. Prod. Rep. 1995, 12, 385.
(2) (a) Bu¨chi, G.; Gould, S. J.; Na¨f, F. J. Am. Chem. Soc. 1971, 93, 2492. (b)
Jackson, A.; Wilson, N. D. V.; Gaskell, A. J.; Joule, J. A. J. Chem. Soc. C.
1969, 2738. (c) Amat, M.; Sathyanarayana, S.; Hadida, S.; Bosch, J.
Tetrahedron Lett. 1994, 35, 7123. (d) Gracia, J.; Casamitjana, N.; Bonjoch,
J.; Bosch, J. J. Org. Chem. 1994, 59, 3939. (e) Blechert, S.; Schmitt, M.
H. Angew. Chem. 1997, 109, 1516. (f) Amat, M.; Hadida, S.; Pshenichnyi,
G.; Bosch, J. J. Org. Chem. 1997, 62, 3158. (g) Saito, M.; Kawamura, M.;
Hiroya, K.; Ogasawara, K. Chem. Commun. 1997, 8, 765-766.
Synthetic Strategy
Our strategy to the Aspidosperma pentacycle was based on a cationic
cascade reaction of the tetrahydrocarbazole 5.2e It was envisaged that
5 could give, upon treatment with acid, a carbocation that would
rearrange through intermediates 3 and 4, allowing the generation of
the pseudo-benzylic carbocation required for the final tetrahydropyrane
ring formation. One important requirement for the generation of the
pseudo-benzylic carbocation would be that the N-acetoxy group perform
as a leaving group in intermediate 4.
(3) (a) Kametani, T.; Suzuki, T. Chem. Pharm. Bull. 1971, 19, 1424. (b) Dolby,
L. J.; Biere, H. J. Org. Chem. 1970, 35, 3843. (c) Kametani, T.; Suzuki, T.
J. Org. Chem. 1971, 36, 1291-1293. (d) Natsume, M.; Kitegawa, Y.
Tetrahedron Lett. 1981, 22, 331. (e) Grierson, D. S.; Harris, M.; Husson,
H.-P. Tetrahedron 1983, 39, 3683.
(4) Miranda, E. C.; Blechert, S. Tetrahedron Lett. 1982, 23, 5395.
9
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J. AM. CHEM. SOC. 2004, 126, 3534-3538
10.1021/ja0399021 CCC: $27.50 © 2004 American Chemical Society

Enantioselective Synthesis of (−)-Gilbertine
Scheme 1. Retrosynthesis
A R T I C L E S
Scheme 2 a
a Reagents and conditions: (a) 1 mol % (R-AlB), KOtBu, dimethylmalonate, THF, 96%, >99% ee; (b) ethylene glycol, pTSOH, reflux, 99%; (c) DABCO,
H2O, toluene, reflux, 66%; (d) LAH, Et2O, reflux, 97%; (e) CH3CN, H2O, 1 N HCl, rt, 91%.
Tetrahydrocarbazole 5 could be synthesized by a convergent
approach by use of the Japp-Klingemann5 Fischer indole6 synthesis,
which would predict the highly substituted cyclohexanone 6 addressing
two of the four stereogenic centers (see Scheme 1). The allyl moiety
in 6 would allow the introduction of the hydroxylamine side chain via
an oxidative cleavage7 reductive amination8 protocol. The carbonyl
functionality would be suitable for the introduction of the methyl group,
and simple acetylation should give the cyclization precursor 5.
The Shibasaki asymmetric Michael addition could introduce the
hydroxyethyl side chain by use of 2-allylcyclohexenone 7, which could
be easily prepared from o-anisic acid under Birch conditions on a large
scale,9 and dimethylmalonate as a commercially available starting
material, allowing the synthesis on a molar scale.10a By use of Corey’s
protocol for the introduction of a formyl moiety, the highly substituted
cyclohexanone derivative 6 should be straightforwardly synthesized.11
The protection group (PG) should be easily cleaved under the acidic
cyclization conditions in the last step of the synthesis, but it should be
stable under the acidic Fischer cyclization conditions.
was isolated (Scheme 2). Evaluation of this reaction led to the
conclusion that 7 is not a Michael acceptor for the Shibasaki
reaction or any other base-catalyzed reaction conditions. Since
the Shibasaki reaction delivers high yields and excellent
enantiomeric excess, it was envisaged to introduce the allyl
moiety at a later step in the synthesis (Scheme 3). For the
optimization of the entire procedures, especially the introduction
of the allyl moiety, the racemate was synthesized in a parallel
manner. The asymmetric Michael addition of dimethyl malonate
with cyclohexenone in the presence of R-AlB was achieved in
96% yield with an excess of >99% ee, achieved by recrystalliza-
tion.10b To avoid a retro-Michael process under decarboxylation
conditions, ketone 9 was protected as a cyclic ketal 10. The
Krapcho decarboxylation12 procedure was replaced by a milder
procedure with DABCO in toluene and water, which afforded
11 in 66% yield. LAH reduction of the methyl ester and deke-
talization with 1 N HClaq in acetonitrile gave rise to hydroxyl-
ethylcyclohexanone 13. These reactions were easily carried out
on a molar scale and it is noteworthy that all intermediates could
be purified by distillation or used without purification.
At the planning stage of the synthesis it was envisaged that
a bulky protecting group (PG, Scheme 1) could effect the
formylation of hydroxyethylcyclohexanone in a regioselective
manner. This formylation11 would allow the introduction of the
allyl side chain by bisanion alkylation,13 which would be
stereoselectively influenced by the protected hydroxyethyl side
chain giving rise to the favored trans diastereomer. Therefore
we investigated the influence of the TPS protecting group, which
could be introduced in a 97% yield (Scheme 3). This TPS ether
Results and Discussion
Synthesis of Gilbertine. The Michael reaction with cyclo-
hexenone derivative 7 was not successful; only starting material
(5) Phillips, R. R. Org. React. 1959, 10, 144.
(6) (a) Robinson, B. The Fischer Indole Synthesis; Wiley: New York, 1982.
(b) Salituro, F. G.; Harrison, B. L.; Baron, B. M.; Philip, L.; Stewart, K.
T.; Kehne, J. H.; White, H. S.; McDonald, I. A. J. Med. Chem. 1992, 35,
1791.
(7) Lee, C. B.; Chou, T.-C.; Zhang, X.-G.; Wang, Z.-G.; Kuduk, S. D.; Mark,
D.; Stachel, S. J.; Danishefsky, S. J. J. Org. Chem. 2000, 65, 6525.
(8) Shishido, K.; Hiroya, K.; Komatsu, H.; Fukumoto, K.; Kametani, T. J.
Chem. Soc., Chem. Commun. 1986, 904.
(9) (a) Taber, D. F. J. Org. Chem. 1976, 41, 2649. (b) Fletcher, R.; Kizil, M.;
Lampard, C.; Murphy, J. A.; Roome, S. J. J. Chem. Soc., Perkin Trans. 1
1998, 2341.
(10) (a) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1998, 63, 7547. (b) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. 1997,
109, 1290. (c) Yamada, K.-I.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1998, 63, 3666. (d) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.;
Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
(12) (a) Krapcho, A. P.; Mundy, B. P. Tetrahedron 1970, 26, 5437. (b) Krapcho,
A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 12, 957. (c) Krapcho, A. P.
Synthesis 1982, 805.
(13) (a) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082. (b)
Boatman, S.; Harris, T. M.; Hauser, C. R. Org. Synth. 1968, 48, 40.
(11) Corey, E. J.; Cane, D. E. J. Org. Chem. 1971, 36, 3070.
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J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3535

A R T I C L E S
Jiricek and Blechert
Scheme 3 a
a Reagents and conditions: (a) imidazole, TBDPSCl, DMF, rt, 97%; (b) HCO2Et, NaH, THF, rt, 78%; (c) LDA, THF, -78 °C, and then allyl bromide,
-78 °C to room temperature, 75%; (d) aniline, HCl concd, NaNO2, H2O, 0 °C, and then NaOAc, addition of 16 in THF, 0 °C, 65-90%; (e) (1) CF3CO2H,
80 °C, 50%, (2) HCO2H, 80 °C, 65%, (3) pTSOH, toluene, reflux, 72%.
Scheme 4. Equilibration of the Allyl Moiety Adjacent to the Carbonyl Groupa
1
a Detection of the diastereomers and enantiomers was achieved by chiral HPLC, Chiralpak OD, and H NMR spectroscopy. Solvent system: hexane/2-
propanol 95:5, flow 1 mL/min., retention time(minutes): 20(S) trans diastereomer, 11.07; 20(S) cis diastereomer, 9.99; 20(R) trans diastereomer, 12.01;
20(R) cis diastereomer, 8.41.
moiety of 14 should fulfill the following demands: (1) it should
direct the formylation reaction, (2) it should be stable under
acidic Fischer indole synthesis, and (3) it should be cleavable
during the acidic cyclization procedure in the last synthetic step.
Gratifyingly, the regioselective and diastereoselective formyl-
ation was achieved in 89% yield on a 0.2 g scale, whereas a
scale-up to 10 g decreased the yield to 78%; however, only the
desired regioisomer was detected by 1H NMR. Bisanion
formation and allylation afforded the highly substituted ketone
16 in 75% yield. For the Japp-Klingemann reaction, we utilized
a modified protocol, in which the strongly acidic diazonium
salt solution was initially treated with sodium acetate and then
16, which increased the yield from 10% to 65-90% yield.
Which products were isolated from the Fischer indole reaction
depended strongly on both the solvent and the pKa of the acid
promoter. Pivalic acid gave no conversion, and formic acid
treatment resulted in deprotection of the alcohol and formation
of the formylester 19, whereas trifluoracetic acid gave the
deprotected hydroxyindole 18. p-Toluenesulfonic acid (pTSOH)
in THF gave only decomposition; however, in toluene the
desired indole 20 could be isolated in 72% yield. Unfortunately,
the acidic conditions resulted in a loss of the trans configuration
and a 2:1 (trans:cis) diastereomeric mixture of 20 was formed
diastereomeric ratio; even after treatment for 1 month, no
deviation from the equilibrium diastereomeric ratio was observed
(Scheme 4).
We decided to further investigate this rather rare appearing
phenomenon of different chemical behavior of the racemate and
the enantiomeric pure form. Therefore, we synthesized (+)-
20ent to have the series complete for experimental and analytical
data. All experiments were carried out under the exact same
reaction conditions in a parallel manner. In the racemate 20rac
a precipitate was formed during the epimerization process and
this showed the desired substitution pattern, whereas no change
was observed in (-)- and (+)-20ent. Deuterium exchange
experiments clearly demonstrated that enolate formation was
achieved in all cases. Therefore, we propose that the precipita-
tion process is the reason for the epimerization, which is
evidenced by the following experiment. The equilibrated race-
mate trans-20rac was suspended and treated under diluted
conditions, when all the solid material was dissolved and the
expected reequilibration to the equilibrium diastereomeric ratio
occurred after 2 weeks. We further proposed that the reequili-
bration process of trans-20rac must also be achieved under
acidic conditions. Treatment of a solution of equilibrated 20rac
in boiling toluene with pTsOH showed rapid reequilibration to
a 2:1 ratio with concurrent cleavage of the silyl ether after 10
min.
1
and determined by H NMR.
As mentioned earlier, the synthesis of 20 was performed in
the racemic and the enantiomeric pure form. An equilibration
of the racemate 20rac with sodium methoxide in methanol
resulted in the expected thermodynamic favored trans config-
uration. Surprisingly, the same reaction conditions used for the
enantiomeric pure form (-)-20ent resulted in no change of the
These experiments provide evidence for complex formation
of n‚[(+)-20-trans‚(-)-20-trans], which is less soluble than the
cis isomers; however, this complex formation is strictly de-
pendent on concentration. Furthermore, if precipitation via
complex formation is the reason for the epimerization, we would
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3536 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004

Enantioselective Synthesis of (−)-Gilbertine
A R T I C L E S
Scheme 5 a
Scheme 6 a
a Reagents and conditions: (a) TBAF, THF, rt, 93%; (b) Ac2O, pyridine,
rt, directly used in next step; (c) HCO2H, rt, directly used in next step; (d)
K2CO3, MeOH, rt, 100%, directly used in next step; (e) CF3CO2H, rt, 50%
overall yield; (f) CF3CO2H, 61%.
a Reagents and conditions: (a) (1) OsO4, NMO, acetone/water, rt, 90%,
(2) Pb(OAc)4, K2CO3, toluene, rt, 95%; (b) CH3NOH‚HCl, NaBH3CN,
2-propanol/water, rt, 90%; (c) MeLi, THF, -60 °C to room temperature,
82%; (d) Ac2O, pyridine, rt, 75%.
Scheme 7
expect that the addition of the same amount of (+)-20ent to
the (-)-20ent in solution would result in a precipitation of this
complex with the desired trans substitution pattern, which could
have been observed. All experiments indicated that there is no
energetic preference for the trans-substituted derivative. To
further confirm the experimental data, we have calculated the
stabilization energies of the stereoisomers and an energy
difference of 4.18 kJ/mol was found, a value too small for a
differentiation of the stereoisomers.14 Nevertheless, we predicted
that separation of the diastereomers will be achieved by the final
cyclization process, where only the trans diastereomer is capable
of forming the piperidine ring leading to (-)-gilbertine. Since
an equilibration of 25 was not expected during the cascade
reaction conditions, we considered the loss of the cis diaster-
eomer. Due to steric hindrance in the case of the cis diaster-
eomer, the cyclization process is disabled at the step of the
piperidine ring formation and the reaction cascade cannot
proceed further. Therefore, we accomplished the synthesis with
the diastereomeric mixture as shown in Scheme 5.
Oxidative cleavage of 20 gave rise to the aldehyde 22 in 86%
yield in a two-step procedure. Reductive amination was ac-
complished with cyanoborohydride and N-methylhydroxylamine
in 90% yield. Subsequent addition of methyllithium gave rise
to alcohol 24 in 82% yield. To provide the leaving groups for
the final cyclization reaction, subsequent peracetylation of the
hydroxy groups gave rise to the cyclization precursor 25.
Elimination of the tertiary acetate was observed as a side
reaction, but the resulting double bond should also be a source
for the acid-induced formation of the tertiary carbocation.
The cyclization was initially carried out in formic acid and a
1:1 mixture of dichloromethane/trifluoroacetic acid, but unfor-
tunately no natural product was formed and complete decom-
position was observed. We proposed that the bulky TPS group
could hinder the process and therefore the reaction was carried
out in a mixture of aqueous HCl in THF in order to ensure
cleavage of the silyl ether, resulting in decomposition. The
precursor of the known uleine cascade reaction2e differs only
in the additional hydroxy group, and therefore a change of the
protection group could indicate if the cascade reaction can take
place or if the cis diastereomer interacts with the cascade
intermediates. The TPS group was removed in 93% yield and
the hydroxy group was protected as an acetate (Scheme 6).
Treatment with formic acid resulted in the formation of the
desired hydroxyuleine acetate 29 in 50% yield. The acetate was
removed with K2CO3 in methanol and hydroxyuleine 30 was
converted quantitatively to gilbertine in the dichloromethane/
trifluoracetic acid solvent mixture used previously. On the basis
of this pathway, we thought that the unprotected tetrahydro-
carbazole 27 could give gilbertine directly and the cyclization
occurred in 61% yield. Gratifyingly, spectral and analytical data
for 2 were comparable with those reported in the literature [see
ref 4; reported [R]20 ) -149 (CHCl3), measured: [R]20
)
D
D
-143.8 (c ) 0.08, CHCl3)]. The comparison of both values
confirms the configuration of the natural product. On the basis
of the enantioselective Michael addition (Shibasaki procedure),
we assign the absolute configuration of (-)-gilbertine as shown
in Scheme 1.
Mechanism of the Cationic Cascade Reaction. We propose
(14) See Supporting Information (S17).
the mechanism of the cyclization outlined in Scheme 7. Loss
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J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004 3537

A R T I C L E S
Jiricek and Blechert
of the tertiary alcohol or protonation of the exomethylene double
bond affords a carbocation, which tautomerizes to the imini-
umsalt 32. Nucleophilic attack on the aza analogue Michael
system by the NOAc moiety gives rise to the ammonium acetate
33. An intramolecular substitution of the acetate gives rise to
the azacyclopropane derivative 34, which yields the iminium
ion 35 after fragmentation. Finally, after 35 tautomerizes to the
indole moiety, the tertiary cation is trapped intramolecularly
by the hydroxy group. Elimination could also afford hydroxy-
uleine, which would be in equilibrium with gilbertine in acidic
medium. However, only gilbertine 2 was isolated.
The possible intramolecular trapping of the initial tertiary
cation by the hydroxy group may occur; however, it would be
expected to be a reversible process under protic conditions and
it is believed that the cation release over the indole moiety occurs
faster than a SN1 process. Furthermore, reaction monitoring
indicated the formation of hydroxyuleine 30 as an intermediate,
underlining the proposed reaction pathway. Experiments with
uleine derivatives have shown further evidence of the proposed
mechanism.15
Conclusion
We have achieved the first enantioselective synthesis of (-)-
gilbertine, a member of the Aspidosperma alkaloids, in a 17-
step sequence with a 5.5% overall yield. The employment of
the cationic cascade reaction has shown to be highly stereose-
lective and furthermore useful for an additional diasteromeric
resolution. Further studies to synthesize other members of the
Aspidosperma alkaloid group in an epimeric pure form are in
progress.
Supporting Information Available: Experimental procedures
and spectral data (PDF). This information is available free of
charge via the Internet at http://pubs.acs.org.
JA0399021
(15) Blechert, S. Liebigs Ann. Chem. 1985, 2073.
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3538 J. AM. CHEM. SOC. VOL. 126, NO. 11, 2004