First enantioselective synthesis of (+)-quinolizidine 207I: Determination of the absolute stereochemistry

Article abstract of DOI:10.1016/S0040-4039(02)02540-6

First enantioselective synthesis of quinolizidine 207I has been achieved and the absolute stereochemistry of natural quinolizidine 207I was determined to be 1S,4S,10S by the present chiral synthesis using GC analysis with β-dextrin chiral column on co-inj

Full text of DOI:10.1016/S0040-4039(02)02540-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 569–570
First enantioselective synthesis of (+)-quinolizidine 207I:
determination of the absolute stereochemistry
Naoki Toyooka* and Hideo Nemoto
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 7 October 2002; accepted 8 November 2002
Abstract—First enantioselective synthesis of quinolizidine 207I has been achieved and the absolute stereochemistry of natural
quinolizidine 207I was determined to be 1S,4S,10S by the present chiral synthesis using GC analysis with b-dextrin chiral column
on co-injection with racemate. © 2002 Elsevier Science Ltd. All rights reserved.
The 5,8-disubstituted indolizidines and 1,4-disubsti-
tuted quinolizidines are the more common structural
patterns found in amphibian skin.1 None of these
alkaloids has so far been reported from any other
source. These dart-poison frog alkaloids continue to
be of interest as synthetic targets2 due to their intrigu-
ing biological activities. In addition, the biological
activity of only a few 5,8-disubstituted indolizidines
has been investigated due to the isolation in minute
quantities from the skin. Among them, the relative
stereochemistry of quinolizidine 207I was anticipated
to be 1 by our chiral synthesis of 23 followed by
stereocontrolled synthesis of 1.4 A sample of synthetic
racemate of 1 had produced the best separations on
GC analysis with b-dextrin chiral column.4
lyzed Sonogashira-type of coupling reaction7 with
propagyl ether in good yield. Catalytic hydrogenation
of 4 over 5% Rh–C in EtOAc under the medium
pressure (4 atm) gave the desired reduction product 5
in 90% yield. The stereochemistry of 5 was determined
to be that of desired all cis-trisubstituted piperidine on
the basis of the observation of NOE on the oxazolizi-
none 6 as shown in Scheme 1. After deprotection of
silyl group with TBAF, carbon-chain at the 2 position
was homologated by Swern oxidation followed by
Wittig reaction of the resulting aldehyde to afford the
homologated ether 7. Hydrogenation and deprotection
of the tetrahydropyranyl group with PPTS gave rise to
alcohol 8. This was transformed into the terminal
olefin 9 using Sharpless’8 and Grieco’s9 procedure.
Finally, quinolizidine ring closure was performed by
three-step sequence to provide the quinolizidine (+)-
1.10
The GC analysis of our synthetic (+)-1 revealed that
the absolute stereochemistry of natural 207I is
1S,4S,10S as shown in Scheme 1. On the GC analysis
using a b-Dex-120 cyclodextrin-based column (Supelco
Inc., Bellefonte, PA; 30 m, 0.25 mm i.d., 25 mm film
thickness), synthetic (+)-1 was coeluted with shorter
retention time peak of racemate and natural product
coeluted with the longer retention time peak of race-
mate.
As part of a program directed at studying the synthe-
sis of biologically active alkaloids,5 we planed the
enantioselective synthesis of 1 to determine the abso-
lute stereochemistry of natural quinolizidine 207I.
The synthesis began with enantiomerically pure triflate
3,6 which was converted to 4 using palladium cata-
In summary, we achieved the first chiral synthesis of
quinolizidine 207I and its absolute stereochemitry was
determined to be 1S,4S,10S by the GC-coinjection
analysis of (+)-1, ( )-1, and natural product
unambiguously.
* Corresponding author.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02540-6

570
N. Toyooka, H. Nemoto / Tetrahedron Letters 44 (2003) 569–570
Scheme 1.
Acknowledgements
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We are grateful to Dr. Thomas F. Spande, NIH, for
measurement of the GC analysis with b-dextrin chiral
column, and to Professor Andre´ Rassat, Ecole Normale
Supe´rieure, for kindly providing us with racemic quino-
lizidine 207I.
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10. The spectral data for synthetic (+)-1 are as follows: IR (neat)
1
3071, 2929, 2862, 2786, 2757 cm−1; H NMR (500 MHz):
l 0.87 (3H, t, J=7.3 Hz), 1.25–1.66 (12H, br m), 1.73 (1H,
dm, J=12 Hz), 1.79 (1H, dm, J=12 Hz), 1.88 (1H, br m),
1.96 (1H, d-like, J=11 Hz), 2.15 (1H, m), 2.42 (1H, dm,
J=12 Hz), 3.33 (1H, dm, J=11 Hz), 5.03 (2H, m), 5.83
(1H, m); 13C NMR (75 MHz): l 12.53 (q), 18.46 (t), 25.06
(t), 26.28 (t), 26.34 (t), 27.17 (t), 31.09 (t), 38.36 (t), 40.62
(d), 53.10 (t), 64.24 (d), 66.75 (d), 115.98 (t), 136.35 (d); MS:
207 (M+), 167 (100); [h]D26 +29.5 (c 0.44, CHCl3).