Total synthesis of (+)-trans-195A

Article abstract of DOI:10.1021/ol0474610

(Chemical Equation Presented) The first enantioselective synthesis of (+)-trans-195A is described. The structure has been constructed by ring-rearrangement metathesis (RRM) and zirconium-mediated Negishi-coupling, used for the first time to prepare 6,6-membered heterocycles, as key steps. By comparison of the synthesized material with the isolated natural product, the absolute configuration of natural trans-195A was determined to be (2R,4aS,5R,8aS)-(-).

Full text of DOI:10.1021/ol0474610

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1227-1229
Total Synthesis of (+)-trans-195A
Nicole Holub, Ju1rgen Neidho1fer, and Siegfried Blechert*
Institut fu¨r Chemie, Technische UniVersita¨t Berlin, Strasse des 17. Juni 135,
D-10623 Berlin, Germany
blechert@chem.tu-berlin.de
Received December 10, 2004
ABSTRACT
The first enantioselective synthesis of (+)-trans-195A is described. The structure has been constructed by ring-rearrangement metathesis
(RRM) and zirconium-mediated Negishi-coupling, used for the first time to prepare 6,6-membered heterocycles, as key steps. By comparison
of the synthesized material with the isolated natural product, the absolute configuration of natural trans-195A was determined to be
(2R,4aS,5R,8aS)-(−).
A remarkably diverse array of biologically active compounds
occurs in amphibian skin.1 One of the major classes of these
alkaloids is the relatively untoxic decahydroquinolines, which
have proven to be noncompetitive blockers of nicotinic
receptor channels.2 In addition, an inhibitory effect against
sodium and potassium transport has been observed.3 Decahy-
droquinolines occur mainly in skin extracts of neotropical
frogs but were also isolated from bufanoid toads, marine
flatworms, and myrmicine ants.1 Since the discovery of the
and trans-fused decahydroquinolines have been found. trans-
195A was first isolated as a trace compound from dendro-
batid frogs of the species Epipedobates bassleri and later
also from Dendrobates imitator and Dendrobates Variabilis.5
Due to the limited amounts available from natural sources,
many structures are still tentative or incompletely defined.
Further research and synthesis is required to confirm the
configuration of the natural products by comparison with
the synthesized material. In the case of 1, whose structure
and relative configuration could be solved,6 the absolute
configuration still remained tentative.
The aim of this work was to construct the decahydro-
quinoline structure of 1 by two metal-catalyzed, stereose-
lective steps, starting from easy accessible material (Scheme
1). First, the zirconium-mediated Negishi-coupling7 of dienes
Figure 1. Structures of (+)-trans-195A 1 and pumiliotoxine C
(cis-195A) 2.
Scheme 1. Retrosynthetic Analysis for the Synthesis of 1
first representative, pumiliotoxine C 2 (Figure 1),4 both cis-
(1) (a) Daly, J. W.; Garaffo, H. M.; Spande, T. F. The Alkaloids, 1st
ed.; Wiley: New York, 1999; Vol. 13. (b) Garaffo, H. M.; Spande, T. F.;
Daly, J. W.; Baldessari, A.; Gros, E. G. J. Nat. Prod. 1993, 56, 357. (c)
Davis, R. A.; Carroll, R.; Quinn, J. J. Nat. Prod. 2002, 65, 454. (d) Kubanek,
J.; Williams, D. E.; Dilip de Silva, E.; Allen, T.; Andersen, R. J. Tetrahedron
Lett. 1995, 36, 6189. (e) Daly, J. W.; Garaffo, H. M.; Jain, P.; Spande, T.
F.; Snelling, R. R.; Jaramillo, C.; Rand, A. S. J. Chem. Ecol. 2000, 26, 73.
(2) (a) Daly, J. W.; Nishizawa, Y.; Edwards, M. W.; Waters, J. A.;
Aronstam, R. S. Neurochem. Res. 1991, 16, 489. (b) Daly, J. W.; Nishizawa,
Y.; Padgett, W. L.; Tokuyama, T.; McCloskey, P. J.; Waykole, L.; Aronstam,
R. S. Neurochem. Res. 1991, 16, 1207. (c) Aronstam, R. S.; Daly, J. W.;
Spande, T. F.; Narayanan, T. K.; Albuquerque, E. X. Neurochem. Res. 1986,
11, 1227.
was employed, leading stereoselectively to cis-1,2-disubsti-
tuted cyclohexanes.7a Successfully introduced into natural
product synthesis by Mori et al.8 to construct 5,6-membered
10.1021/ol0474610 CCC: $30.25
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rings, this coupling has not been used to synthesize 6,6-
annulated piperidines until now.
Following transformation to epoxide 9 and second ring-
opening with vinylmagnesium bromide gave (R)-hept-1-en-
4-ol (10) in 91% overall yield. Comparison of its optical
rotation with published data14 corresponded to an enantio-
meric excess of 98%.
After formation of the corresponding mesylate 11, sub-
stitution with sodium azide was carried out to yield 12.
Following reduction with LiAlH4 and in situ protection of
the corresponding amine intermediate with ortho-nitroben-
zenesulfonyl chloride (o-NsCl) gave 6 in 89% yield. The
o-Ns-group was chosen due to its electron-withdrawing
effect, advantageous for subsequent Mitsunobu reaction15 and
for the planned RRM process. Subjection of 6 to chiral HPLC
corresponded to an enantiomeric excess of 99%, which
confirms complete inversion of the configuration in the
transformation of 11 to 12.
For synthesis of (S)-cyclohex-2-enol (5), the asymmetric
CBS reduction of ketones, published first by Corey et al.,16
was employed. As a prochiral ketone, we chose 2-bromo-
cyclohex-2-en-1-one (13),17 which was already successfully
applied to synthesize ent-5.18 Following the literature pro-
cedure, (R)-Me-CBS 16 was initially used as a chiral catalyst
for the asymmetric reduction to yield 5 with only 70% ee.
Reduction of the reaction temperature to -20 °C improved
the enantiomeric excess to 83%. Lower temperatures,
however, led to a decreased conversion, and the published
96% ee could not be reproduced (Table 1).17 Due to these
As a second key step, the concept of ring-rearrangement
metathesis (RRM),9 already established in natural product
synthesis,10 was used to construct the 2,6-disubstituted
tetrahydropyridine derivative 3. In recent work, we reported
the enantioselective synthesis of R,R′-disubstituted pip-
eridines via RRM of easily available carbocyclic secondary
amines.11 Since complete transfer of chirality was observed
in this step, the enantiopure secondary amine 4 was chosen
as a precursor for the planned RRM process. 4 was
synthesized by Mitsunobu reaction12 of the easily accessible
compounds 5 and 6. In conclusion, the desired decahydro-
quinoline 1 was constructed in only a few steps through our
proposed strategy.
For synthesis of ent-6, we chose commercially available
(R)-epichlorohydrin (7) as a starting material. Double copper-
catalyzed epoxide ring-opening with Grignard reagents
should lead to the corresponding enantiopure alcohol 10.13
The first ring-opening was carried out with ethylmagnesium
Scheme 2. Synthetic Route to 6
Table 1. Application of CBS Reduction for the Synthesis of 5
bromide to afford 8 in quantitative yield (Scheme 2).
(3) Warnick, J. E.; Jessup, P. J.; Overman, L. E.; Eldefrawi, M. E.; Nimit,
Y.; Daly, J. W.; Albuquerque, E. X. Mol. Pharmacol. 1982, 22, 565.
(4) (a) Isolation: Daly, J. W.; Tokuyama, T.; Habermehl, G.; Karle, I.
L.; Witkop, B. Liebigs Ann. Chem. 1969, 729, 198. (b) Absolute config-
uration: Oppolzer, W.; Flashkamp, E. HelV. Chim. Acta 1977, 60, 204.
(5) Spande, T. F.; Poonam, J.; Garaffo, H. M.; Pannell, L. K.; Yeh, H.
J. C.; Daly, J. W. J. Nat. Prod. 1999, 62, 5.
(6) (a) Garaffo, H. M.; Simon, L. D.; Daly, J. W.; Spande, T. F.; Jones,
T. H. Tetrahedron 1994, 50, 11329. (b) Abe, K.; Tsugoshi, T.; Nakamura,
N. Bull. Chem. Soc. Jpn. 1984, 57, 3351.
(7) (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E.
Tetrahedron Lett. 1989, 38, 5105. (b) Negishi, E.; Cederbaum, F. E.;
Takahashi, T. Tetrahedron Lett. 1986, 25, 2829. (c) Negishi, E.; Swanson,
D. R.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1987, 9, 917. (d)
Nugent, W. A.; Taber, D. F. J. Am. Chem. Soc. 1989, 111, 6435. (e) Lim,
J. A., Louey; J. P.; Taber, D. F. Tetrahedron Lett. 1993, 34, 2243.
(8) Mori, M.; Uesaka, N.; Shibasaki, M. J. Org. Chem. 1992, 13, 3519.
(9) (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 6634. (b) Hoveyda, A. H.; Schrock, R. R.; Weatherhead,
G. S.; Ford, J. G.; Alexanian, E. J. J. Am. Chem. Soc. 2000, 122, 1828. (c)
Choi, T.-L.; Grubbs, R. H. Chem. Commun. 2001, 2648.
entry
catalyst
temp (°C)a
conversion (%)
ee (%)b
1
2
3
4
5
16c
16c
16c
17d
17d
-10
-20
-30
rt
100
100
40e
100
100
70
83
nd
90
99
0
a Temperature during addition of the ketone solution. b Detected by
HPLC, Chiracel OJ column, flow rate 1.0 mL/min, temp 20 °C, eluent
hexane/propan-2-ol (9/1), retention times (R)-15 5.73 min, (S)-15 6.58 min.
c X ) SMe2. d X ) diethylaniline. e Detected by 1H NMR spectroscopy of
the crude product.
insufficient results, we tested (R)-MeO-CBS 17 as an
oxazaborolidine system next, already used several times for
(10) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K.
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 166. (b) Burke, S. D.; Quinn, K.
J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626. (c) Wrobleski, A.;
Sahasrabudhe, K.; Aube´, J. J. Am. Chem. Soc. 2004, 126, 5475. (d) Stapper,
C.; Blechert, S. J. Org. Chem. 2002, 67, 6456. (e) Buschmann, N.; Ru¨ckert,
A.; Blechert, S. J. Org. Chem. 2002, 67, 4325. (f) Stragies, R.; Blechert, S.
Tetrahedron 1999, 55, 8179. (g) Stragies, R.; Blechert, S. J. Am. Chem.
Soc. 2000, 122, 9584.
(11) Voigtmann, U.; Blechert, S. Synthesis 2000, 893.
(12) Mitsunobu, O. Synthesis 1981, 1.
(13) (a) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem 2000,
65, 707. (b) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org.
Chem. 2000, 65, 7990.
(14) Julien, P. N.; Taylor, R. J. K. Org. Lett. 2002, 1, 119.
(15) Dodge, J. A.; Jones, S. A. Recent Res. DeV. Org. Chem. 1997, 1,
273.
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Org. Lett., Vol. 7, No. 7, 2005

enantioselective reductions19 but, to the best of our knowl-
edge, never to synthesize ent-5.
derivative 3a in 96% yield. The enantiomeric excess of 3a
was determined to be 98% by means of chiral HPLC analysis
with comparison to the racemic material.
Catalyst 17 was synthesized through in situ reaction of
(R)-R,R-diphenylprolinol with B(OMe)3 at room temperature.
Addition of BH3‚diethylaniline followed by dropwise addi-
tion of a solution of 13 in THF afforded 15 with remarkably
better enantiomeric excess. Carrying out the reaction at room
temperature gave 15 with 90% ee. Temperature reduction
to 0 °C, during addition of the ketone solution, finally yielded
15 with 99% ee. Subsequent dehalogenation was achieved
by halogen-metal exchange with tert-BuLi and subsequent
hydrolysis to give 5 in 96% yield.
Unfortunately, subsequent Negishi-coupling7 of 3a did not
lead to the desired cyclization product but resulted in
dimerization of the aromatic nitro group. However, changing
the protecting group to the corresponding N-benzyl derivative
3b, we succeeded in constructing the required decahydro-
quinoline structure 18. The cyclization reaction was carried
out with n-BuLi and Cp2ZrCl2 under an argon atmosphere
to afford 18 in 74% yield. Utilization of a nitrogen
atmosphere proved to be unsuccessful, presumably due to
the formation of an unreactive zirconium-nitrogen complex.21
Final deprotection of 18 by hydrogenation with Pd/C afforded
1 as a colorless solid in 90% yield with an optical rotation
of +27.4 (c 0.56, MeOH). Unfortunately, stereochemical
determination of the product from Negishi cyclization was
unsuccessful through NMR. Therefore, transformation of
rac-1 to the corresponding N-p-nitro-benzoate was carried
out to form a crystallizable derivative. Subsequent analysis
by X-ray crystallography,22 coupled with the knowledge of
the absolute configuration of the chiral precursor, indicates
the absolute stereochemistry of the decahydroquinoline ent-1
to be 2S,4aR,5S,8aR.
Synthesis of 4 was achieved by Mitsunobu reaction12 of
5 and 6 (Scheme 3). Employment of 1.3 equiv each of PPh3,
Scheme 3. Synthesis of 1
In cooperation with J. W. Daly et al. (Institutes of Health,
Maryland), our synthetic (+)-enantiomer was compared with
the isolated natural product by means of chiral GC. Both
derivatives showed different retention times, indicating that
natural trans-195A occurs as the (-)-enantiomer, whose
absolute configuration is 2R,4aS,5R,8aS.
In conclusion, we successfully applied the concept of a
stereoselective RRM and a diastereoselective Negishi cou-
pling of dienes to the first enantioselective synthesis of (+)-
trans-195A. Starting from (R)-epichlorohydrin 7 we synthe-
sized 1 in 11 steps and in 35% overall yield. Subjection of
1 to chiral GC followed by comparison with the isolated
natural product led to the determination of the absolute
configuration of natural trans-195A.
diisopropylazo dicarboxylate (DIAD), and 5 afforded 4 in
42% yield after 72 h. After testing different solvents, we
finally succeeded in optimizing the reaction by use of THF
and addition of an excess (2 equiv) of PPh3, DIAD, and 5 to
yield 4 in 83%. RRM of the obtained secondary amide 4
was undertaken with 5 mol % benzylidene-bis-(tricyclo-
hexylphosphine)-dichloro ruthenium (Grubbs I catalyst)20
under an ethylene atmosphere. The transformation resulted
in complete conversion of the starting material and afforded
stereoselectively the cis-2,6-disubstituted tetrahydropyridine
Acknowledgment. We would like to thank the work
group of J. W. Daly (Institutes of Health, Maryland),
especially Thomas F. Spande for the chiral GC measurements
of the synthesized material and for the provided chromato-
grams.
(16) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1, 3-6,
8-12, 15, and 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) (a) Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863. (b)
Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 7925.
(c) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.;
Minowa, N. J. Chem. Soc., Chem. Commun. 1993, 619.
(18) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. 1982,
47, 5088.
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Xu, J. X.; Wei, T. Z.; Xia, J. K.; Zhang, Q. H.; Wu, H. S. Chirality 2004,
16, 341. (c) Xu, J. X.; Wei, T. Z.; Zhang, Q. H. J. Org. Chem. 2003, 68,
10146. (d) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem.
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Chem. Soc. 1992, 114, 3974.
OL0474610
(21) (a) Cohen, J. D.; Mylvaganam, M.; Fryzuk, M. D.; Loehr, T. M. J.
Am. Chem. Soc. 1994, 116, 9529. (b) Cohen, J. D.; Fryzuk, M. D.; Loehr,
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(22) Crystallographic data have been deposited with the Cambridge
Crystallographic Data Center under desposition no. CCDC-239791.
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