Stereodivergent process for the synthesis of the decahydroquinoline type of dendrobatid alkaloids

Article abstract of DOI:10.1021/jo025929b

A flexible and stereodivergent synthesis of the cis- and trans-fused 2,5-disubstituted octahydroquinolinone ring systems bearing all four stereogenic centers for the synthesis of the decahydroquinoline type of dendrobatid alkaloids has been achieved. The strategy involves stereoselective and stereodivergent construction of 2,3,6-trisubstituted piperidine ring systems using the Michael type of conjugate addition reaction to the enaminoesters 1 and 3, the intramolecular aldol type of cyclization reaction of keto aldehydes 11 and 12, and ring-closing metathesis of 21 as key steps.

Full text of DOI:10.1021/jo025929b

Ster eod iver gen t P r ocess for th e Syn th esis of th e
Deca h yd r oqu in olin e Typ e of Den d r oba tid Alk a loid s
Naoki Toyooka,* Maiko Okumura, and Hideo Nemoto*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630,
Toyama 930-0194, J apan
toyooka@ms.toyama-mpu.ac.jp
Received May 13, 2002
A flexible and stereodivergent synthesis of the cis- and trans-fused 2,5-disubstituted octahydro-
quinolinone ring systems bearing all four stereogenic centers for the synthesis of the decahydro-
quinoline type of dendrobatid alkaloids has been achieved. The strategy involves stereoselective
and stereodivergent construction of 2,3,6-trisubstituted piperidine ring systems using the Michael
type of conjugate addition reaction to the enaminoesters 1 and 3, the intramolecular aldol type of
cyclization reaction of keto aldehydes 11 and 12, and ring-closing metathesis of 21 as key steps.
In tr od u ction
The neotropical dart poison frogs contain a remarkable
diversity of alkaloids, and the 2,5-disubstituted decahy-
droquinolines represent one of the major classes of these
amphibian alkaloids.1 Isolation of these alkaloids from
some ants strengthens a dietary hypothesis for the origin
of the above alkaloids that have been detected in extracts
of frog skin.2 In addition, these alkaloids contain both
cis and trans ring fusions, which have been identified as
well as diastereomers at C-2 and C-5 positions (Figure
1).
The structural diversity and pharmacological activity
associated with this class of alkaloids have stimulated
synthetic activity in numerous groups.3 However, the
route which can be applicable to the synthesis of both
cis- and trans-fused ring systems has been reported only
to a small extent.4 Moreover, no methodology for the
F IGURE 1.
(1) (a) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon
Press: New York, 1999; Vol. 13, pp 1-161. (b) Daly, J . W. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol.
50, pp 141-169.
divergent synthesis of the 2,8a-cis- and -trans-substituted
ring systems has been reported to date.
Here, we wish to describe the flexible and stereodiver-
gent route to the octahydroquinolinone ring core, which
contains all four stereogenic centers of target alkaloids.
The basic strategy we used involves three key reactions
(Figure 2).
The first key step is the highly stereoselective and
stereodivergent construction of a 2,3,6-trisubstituted
piperidine ring system using the Michael type of conju-
gate addition reaction of the cyclic enaminoesters (steps
A and B).5 The second key step is an intramolecular aldol
type of cyclization reaction6 of the keto aldehydes (steps
C and D) or ring-closing metathesis reaction7 of the vinyl
ketone (step E) derived from the above adducts, respec-
tively. The final key step is the stereoselective installa-
(2) Spande, T. F.; J ain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H.
J . C.; Daly, J . W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.; Torres,
J . A.; Snelling, R. R.; J ones, T. H. J . Nat. Prod. 1999, 62, 5-21.
(3) (a) Oppolzer, W.; Flaskamp, E.; Bieber, L. W. Helv. Chim. Acta
2001, 84, 141-145. (b) Akashi, M.; Sato, Y.; Mori, M. J . Org. Chem.
2001, 66, 7873-7874. (c) Riechers, T.; Krebs, H. C.; Wartchow, R.;
Habermehl, G. Eur. J . Org. Chem. 1998, 2641-2646. (d) Toyota, M.;
Asoh, T.; Fukumoto, K. Tetrahedron Lett. 1996, 37, 4401-4404. (e)
Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595-
1596. (f) Naruse, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994,
35, 9213-9216. (g) Naruse, M.; Aoyagi, S.; Kibayashi, C. J . Chem. Soc.,
Perkin Trans. 1 1996, 1113-1124. (h) Murahashi, S.; Sasao, S.; Saito,
E.; Naota, E. J . Org. Chem. 1992, 57, 2521-2523. (i) Murahashi, S.;
Sasao, S.; Saito, E.; Naota, E. Tetrahedron 1993, 49, 8805-8826 and
references therein.
(4) Comins’, Schultz’s, and Kunz’s approach could be applicable to
the divergent synthesis of cis- and trans-fused decahydroquinoline ring
systems. See: (a) Comins, D. L.; Dehghani, A. J . Chem. Soc., Chem.
Commun. 1993, 1838-1839. (b) Comins, D. L.; Dehghani, A. J . Org.
Chem. 1995, 60, 794-795. (c) Schultz, A. G.; McCloskey, P. J .; Court,
J . J . J . Am. Chem. Soc. 1987, 109, 6493-6502. (d) McCloskey, P. J .;
Schultz, A. G. J . Org. Chem. 1988, 53, 1380-1383. (e) Weymann, M.;
Schultz-Kukula, M.; Kunz, H. Tetrahedron Lett. 1998, 39, 7835-7838.
(5) (a) Momose, T.; Toyooka, N. J . Org. Chem. 1994, 59, 943-945.
(b) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J . W.; Garraffo, H. M.
Tetrahedron 1997, 53, 9553-9574. (c) Toyooka, N.; Fukutome, A.;
Nemoto, H.; Daly, J . W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T.
Org. Lett. 2002, 4, 1715-1717.
10.1021/jo025929b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002
6078
J . Org. Chem. 2002, 67, 6078-6081

Decahydroquinoline Type of Dendrobatid Alkaloids
F IGURE 2.
tion of the alkyl side chain at the C-5 position (step F)
by the conjugate addition reaction to the enone moiety.
anion attacks from the stereoelectronically preferred
â-axial direction9 to give rise to the adduct 4 exclusively
(Figure 3).
Resu lts a n d Discu ssion
The carbon chain at the R-positions on both adducts 2
and 4 was elongated by the Arndt-Eistert sequence to
provide the homologated esters 5 and 6. The esters 5 and
6 were transformed into the methyl ketones 9 and 10
via the Weinreb’s amides10 7 and 8.
Oxidative cleavage of the terminal olefins in 9 and 10
gave the keto aldehydes 11 and 12, which were subjected
to an intramolecular aldol type of cyclization to afford
the cis-fused quinolinone 13 selectively (cis/trans ) 6.5:
1, 52% isolated yield) or 14 exclusively (51% yield). The
stereochemistry of 13 and 14 was determined by NOE
experiments, as shown in Scheme 2.
Next, we examined the synthesis of a 4a,8a-trans-fused
ring system such as 18 using the same aldol type of
cyclization reaction of 17. The methyl ketone 9 was
converted to alcohol 15, which was treated with sodium
hydride to afford the oxazolizinone 16. The terminal
olefin in 16 was cleaved oxidatively to give rise to the
keto aldehyde 17 (Scheme 3). However, the aldol type of
cyclization reaction of 17 under the same reaction condi-
tions as those for 11 or 12 was very messy, and no
cyclized product was isolated.
The common starting material 15c was treated with
divinyllithium cuprate to afford the adduct 2 as a single
isomer. The stereoselectivity of this addition reaction can
be explained by A(1,3) strain8 and stereoelectronic effect,9
similar to the case for our recent investigations.5 On the
other hand, deprotection of the tert-butyldiphenylsilyl
group with tetrabutylammonium fluoride followed by
oxazolizinone ring formation using sodium hydride as a
base afforded the oxazolizinone 3. The conjugate addition
reaction of 3 proceeded smoothly to provide the adduct 4
as a single isomer again. The stereochemistry of 4 was
determined by the NOE between Ha and Hb and the half-
height width (W1/2, 11.5 Hz) of Hc in 4, as shown in
Scheme 1.
The stereoselectivity of this conjugate addition reaction
can be rationalized as follows. The conformation of 3 is
restricted to 3-A by the oxazolizinone ring, and the vinyl
(6) (a) Toyooka, N.; Okumura, M.; Takahata, H. J . Org. Chem. 1999,
64, 2182-2183. (b) Toyooka, N.; Okumura, M.; Takahata, H.; Nemoto,
H. Tetrahedron 1999, 55, 10673-10684.
(7) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3013-3043. (c) Wright, D. L. Curr. Org. Chem. 1999, 3, 211-
240. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(e) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-388.
(f) Blechert, S.; Schuster, M. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036-2056.
According to the above observation, we anticipate that
the aldol type of cyclization reaction of 11 should proceed
via aldehyde 11-E rather than trans-enone 13-T, as
shown in Figure 4.
(8) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(10) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983; pp 209-290.
(9) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1873.
J . Org. Chem, Vol. 67, No. 17, 2002 6079

Toyooka et al.
SCHEME 1a
a
Reagents and conditions: (a) (vinyl)2CuLi, Et2O, -78 to -30 °C (2, 96%; 4, 78%); (b) TBAF, THF, rt (90%); (c) NaH, THF, 0 °C (95%);
(d) LiOH, MeOH/H2O (3:1), reflux, then ClCO2Et, Et3N, THF, 0 °C, then CH2N2, Et2O, and then silver benzoate, Et3N, MeOH, rt (5, 80%;
6, 59%, four steps); (e) LiOH, MeOH/H2O (3:1), reflux, then 1,1′-carbonyldiimidazole, and then O,N-dimethylhydroxylamine‚HCl, Et3N,
CH2Cl2 (7, 81%; 8, 92%, two steps); (f) MeMgBr, THF, rt (9, 96%; 10, 93%); R ) TBDPS.
SCHEME 2a
a
Reagents and conditions: (a) OsO4, NaIO4, 1,4-dioxane/H2O
(1:1), rt (11, 79%; 12, 87%); (b) 4 equiv of DBU, benzene, reflux
(13, 52%; 14, 51%); R ) TBDPS.
F IGURE 4.
the alcohol 20. Swern oxidation of 20 followed by Grig-
nard reaction and PCC oxidation of the resulting second-
ary alcohol afforded the vinyl ketone 21. The ring-closing
methathesis reaction of 21 using Grubbs’ catalyst11 gave
rise to the trans-fused quinolinone 18 in good yield
(Scheme 4).
With the requisite enones 13, 14, and 18 in hand, we
F IGURE 3.
next examined the installation of the alkyl side chain at
the C-5 position. Thus, treatment of the above enones
with dimethyllithium cuprate afforded the adducts 22
and 24 exclusively or 25 selectively (R/â ) 3:1). The
stereochemistry of the adducts 22 and 24 was determined
to be a 4a,5-cis relationship by the NOE between Ha and
the methyl group on the C-5 position of 23 or between
We could not synthesize the 4a,8a-trans-fused enone
18 using the aldol type of cyclization reaction of 17. Thus,
we were forced to develop an alternative route to 18. We
designed the ring-closing methathesis reaction of diene
21. Deprotection of the tert-butyldiphenylsilyl (TBDPS)
group in 5 with TBAF followed by treatment of the
resulting alcohol with sodium hydride gave the oxazoliz-
inone 19. Reduction of 19 with Super-Hydride provided
(11) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
6080 J . Org. Chem., Vol. 67, No. 17, 2002

Decahydroquinoline Type of Dendrobatid Alkaloids
SCHEME 3a
a
Reagents and conditions: (a) TBAF, THF, rt (86%); (b) NaH, THF, 0 °C (78%); (c) OsO4, NaIO4, 1,4-dioxane/H2O (1:1), rt (63%); (d)
4 equiv of DBU, benzene, reflux.
SCHEME 4a
a
Reagents and conditions: (a) TBAF, THF, rt (80%); (b) NaH, THF, 0 °C (85%); (c) Super-Hydride, THF, 0 °C (97%); (d) Swern oxidn,
then vinylmagnesium bromide, THF, rt, then PCC, AcONa, CH2Cl2 (67%, three steps); (e) benzylidene bis(tricyclohexylphos-
phine)dichlororuthenium, CH2Cl2, rt (96%).
SCHEME 5a
a
Reagents and conditions: (a) Me2CuLi, Et2O, -78 to -30 °C (22, 96%; 24, 96%; 25, 60%; 26, 20%); (b) TBAF, THF, rt (67%); (c)
Me2CuLi, HMPA, TMSCl, THF, -78 °C then Pd(OAc)2, MeCN, rt (80%, two steps); (d) H2, Pd(OH)2, MeOH (quant).
Hb and the methyl group on the C-5 position of 24,
respectively. On the other hand, the stereochemistry of
the major product of the conjugate addition reaction of
18 was determined to be that of 25 by the large (13 Hz)
coupling constant of H-5 in the minor adduct 26, sug-
gesting the axial (R) position of this proton (Scheme 5).
The C-5 epimer of 22 was synthesized by means of
conjugate addition followed by Ito-Saegusa oxidation12
of the resulting silyl enol ether and catalytic hydrogena-
tion of the enone 27 to give rise to the epimeric octahy-
droquinolinone 28.
roquinolinone ring core starting from common precursor
1. In principle, any alkyl chain would be introduced on
the C-5 position. In addition, the carbon chain at the
2-position could be elongated by appropriated modifica-
tion of an oxygenated functional group. This route would
be applicable to the divergent synthesis of the cis- and
trans-fused or 2,8a-cis- and -trans-substituted decahy-
droquinoline type of dendrobatid alkaloids, shown in
Figure 1. Application of this methodology to the synthesis
of the above natural products is now under investigation.
Con clu sion s
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds, and
copies of 1H and 13C NMR spectra of synthetic compounds 13,
14, 18, 22, 24, 25, 26, and 28. This material is available free
of charge via the Internet at http://pubs.acs.org.
In summary, we have demonstrated a flexible and
stereodivergent route to the 2,5-disubstituted octahyd-
(12) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011-
1013.
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