Enantiodivergent synthetic entry to the quinolizidine alkaloid lasubine II

Article abstract of DOI:10.1021/ol2019967

Intramolecular cycloaddition of the syn- and the anti-nitrone 9 and 13 leads stereoselectively to the azabicyclic compounds 10 and 14 which may provide access to both enantiomers of the quinolizidine alkaloid lasubine II.

Full text of DOI:10.1021/ol2019967

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5128–5131
Enantiodivergent Synthetic Entry to the
Quinolizidine Alkaloid Lasubine II
Nemai Saha, Tanmoy Biswas, and Shital K Chattopadhyay*
Department of Chemistry, University of Kalyani, Kalyani-741235, West Bengal, India
skchatto@yahoo.com
Received July 24, 2011
ABSTRACT
Intramolecular cycloaddition of the syn- and the anti-nitrone 9 and 13 leads stereoselectively to the azabicyclic compounds 10 and 14 which may
provide access to both enantiomers of the quinolizidine alkaloid lasubine II.
The piperidine ring system constitutes part of many
naturally occurring and biologically interesting com-
pounds.1 In particular, 2,6-disubstituted piperidine deri-
vatives have attracted more attention because of their
frequent appearance in various naturally occurring ring
forms such as quinolizidines, indolizidines, and others.2,3
Most of these compounds are known to display a broad
range of useful biological activities. A major challenge in
their synthesis is the strategic placement of the ring func-
tionalities with the desired stereochemistry. As a conse-
quence, synthetic methodologies continue to be developed
for the stereoselective synthesis of both cis-4 and trans-2,6-
disubstituted piperidines.5
Among this class of compounds, the cis-2,6-disubsti-
tuted 4-piperidinol motif is present in important alkaloids
such as lasubine II,6 subcosine II,6 alkaloid 241D,7 and epi-
myrtine8 (Figure 1). Of these, lasubine II has received
considerable attention and its several elegant syntheses
have been reported. However, synthetic entry to both
enantiomers of lasubine II from a common source remains
(1) (a) Michael, J. P. Nat. Prod. Rep 2008, 25, 139 and earlier reports
in the series. (b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (c)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953. (d) Laschat, S.; Dickner, T. Synthesis
2000, 1781.
(2) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26, pp 89À183. (b) Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon,
Oxford, U.K., 1996; Vol. 10. (c) Baliah, V.; Jeyaraman, R.; Chandrase-
karan, L. Chem. Rev. 1983, 83, 379.
(3) (a) Acarya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223. (b)
Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org. Biol. Chem.
2010, 8, 1899. (c) Gnamn, C.; Krauter, C. M.; Brodner, K.; Helmchen,
G. Chem.;Eur. J. 2009, 15, 2050.
(4) (a) Wee, A. G. H.; Fan, G.-J. Org. Lett. 2008, 10, 3869. (b) Davis,
F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73, 9619.
(c) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006, 71,
8591. (d) Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2005, 70, 7342. (e)
Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27. (f) Shu, C.;
Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878. (g) Davis, F. A.;
Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759. (h) Ryckman, D. M.;
Stevens, R. V. J. Org. Chem. 1987, 52, 4274. (i) Munchhof, M. J.;
Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399.
(5) (a) Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067. (b) Davis, F. A.;
Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855. (c) Davis, F. A.; Xu, H.;
Zhang, J. J. Org. Chem. 2007, 72, 2046. (d) Guilloteau-Bertin, B.;
Compere, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J. Org. Chem.
2000, 1391. (e) Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72,
3853. (f) Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2003, 44, 527. (g)
Carruthers, W.; Williams, M. J. Chem. Commun. 1986, 1287. (h) Lathbury,
D.; Gallagher, T. Tetrahedron Lett. 1985, 26, 6249. (i) Wynne, E. L.;
Clarkson, G. J.; Shipman, M. Tetrahedron Lett. 2008, 49, 250. (j) Mix, S.;
Blechert, S. Adv. Synth. Catal. 2007, 349, 157.
r
10.1021/ol2019967
Published on Web 09/07/2011
2011 American Chemical Society

important.6c Herein, we report an enantiodivergent syn-
thetic route to lasubine II.
Scheme 1. Retrosynthetic Analysis of Lasubine II
We have recently reported9 a diastereoselective synthesis
of homoallylic amines by the addition of a suitable allyl
metal to an imine derived from R-2,3-O-cyclohexylidene-
glyceraldehyde (5, Scheme 2). We adopted this methodol-
ogy with some modifications to prepare the homoallylic
syn- and anti-amines 7 and 8 from the imine 6, obtained by
dehydrative condensation of 3,4-dimethoxybenzyl amine
with 5. Thus, addition of allylmagnesium bromide to 6
delivered a separable mixture of the major syn-isomer 7
and the minor anti-isomer whereas addition of allylzinc
bromide to 6 resulted in the formation of 8 as the major
product.
Figure 1. Selected natural products accommodating the cis-2,
6-disubstituted piperidine ring system.
Our retrosynthetic analysis (Scheme 1) of lasubine II
relied on using two simultaneous or sequential Mitsunobu
reactions involving hydroxyl group inversion and aza-
bicycle formation in either order leaving the substructure
II as the prime target. The desired stereochemistry in II as
well as the key ring formation from an acyclic precursor
was thought to be obtainable from the Intramolecular
Nitrone Cycloaddition (INC)10 of an optically pure ni-
trone of the type III.
(6) For previous synthesis of (À)-lasubine II, see: (a) Chou, S.-S. P.;
Chung, Y.-C.; Chen, P.-A.; Chiang, S.-L.; Wu, C.-J. J. Org. Chem. 2011,
76, 692. (b) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132,
12216. (c) Verkade, J. M. M.; van der Pijl, F.; Willems, M. M. J. H. P.;
Quaedflieg, P. J. L. M.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem.
2009, 74, 3207. (d) Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, Ch.
R. Tetrahedron Lett. 2009, 50, 5686. (e) Lim, J.; Kim, G. Tetrahedron
Lett. 2008, 49, 88. (f) Mancheno, O. G.; Arrayas, R. G.; Adrio, J.;
Carretero, J. C. J. Org. Chem. 2007, 72, 10294. (g) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 12370. (h) Back, T. G.; Hamilton, M. D.;
Lim, V. J. J.; Parvez, M. J. Org. Chem. 2005, 70, 967. (i) Zaja, M.;
Blechert, S. Tetrahedron 2004, 60, 9629. (j) Gracias, V.; Zeng, Y.; Desai,
P.; Aube, J. Org. Lett. 2003, 5, 4999. (k) Ma, D.; Zhu, W. Org. Lett. 2001,
3, 3927. (l) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623. (m) Pilli,
R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717. (n)
Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110,
7445. (o) Iida, H.; Tanaka, M.; Kibayashi, C. J. Org. Chem. 1984, 49,
1909.
Scheme 2. Preparation of the Homoallylic Amines 7 and 8
(7) Girard, N.; Hurvois, J.-P. Tetrahedron Lett. 2007, 48, 4097. (b)
Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503.
(8) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org. Chem. 2003, 68,
8061.
(9) Chattopadhyay, S. K.; Biswas, T.; Biswas, T. Tetrahedron Lett.
2008, 49, 1365.
(10) For some reviews, see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007,
63, 12247. (b) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol 2, pp 83À168. (c) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223. (d) Gothelf, K. V.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 863. (e) Jones, R. C. F.; Martin,
J. N. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A.; Pearson, W. H.,
Eds.; Wiley: New York, 2002; Chapter 1, pp 1À81.
Org. Lett., Vol. 13, No. 19, 2011
5129

refluxing toluene to give a single isolable product in 81%
yield, but examination of the crude mixture by HPLC-MS
indicated the possibility of the existence of an isomeric
compound (7%) whichcouldnotbeobtained inpure form.
The major product was assigned structure 10 based on
the assumption that an endo approach of the double bond
to the Re face of the nitrone would be favorable.13 Hydro-
lytic removal of the cyclohexylidene moiety followed by a
two-step conversion of the resulting diol 11 involving
oxidative cleavage of the diol unit and subsequent reduc-
tion of the resultingformyl group tothe primaryalcohol 12
proceeded smoothly under conventional conditions.
Similarly, the anti-amine derivative 8 produced the
corresponding nitrone 13 also as the Z-isomer. Cycloaddi-
tion of 13 in refluxing toluene proceeded smoothly to
deliver the cycloadduct 14 formed in an analogous manner
by Re face addition to the nitrone in an endo approach.
Compound 14 was then converted to the bicyclic piper-
idine derivative 16 following the three-step conversion
detailed above for the conversion 10f12, i.e. acid
mediated opening to the diol 15 followed by its redox
manipulation leading to the primary alcohol 16. Com-
pound 16 was found, as expected, to be enantiomeric to
compound 12 from spectroscopic and optical measure-
ment data.
Scheme 3. Enantiodivergent Synthesis of the
Azabicyclic Compounds 12 and 16
Scheme 4
Intramolecular 1,3-dipolar cycloaddition of N-alkenyl
nitrones has been used11 in the stereoselective preparation
of various heterocyclic systems including piperidine deri-
vatives. We therefore explored the utility of the chiral
homoallylic amines 7 and 8 in the stereoselective construc-
tion of piperidine derivatives related to the synthesis of
lasubine II. The syn-amine 7 was converted to the corre-
sponding nitrone 9 (Scheme 3) using a hydrogen perox-
ideÀsodium tungstate combination.12 Compound 9 was
obtained in high yield and as a single isomer assigned as the
thermodynamically more stable Z-isomer. This assign-
ment was further supported by NOESY experiments
which revealed a correlation between the CR-proton
(δ3.89) and the azomethine proton (δ 8.41). Intramole-
cular cycloaddition of the nitrone 9 proceeded smoothly in
Having established an enantiodivergent route to the all
cis-2,4,6-trisubstituted piperidine derivatives 12 and 16
(ent-12), we focused on the conversion of 11 to lasubine
II along the projected pathway. Thus, the diol 11 was
oxidatively cleaved to the aldehyde 17, which was used
without purification in the subsequent three-carbon Wittig
homologation with the salt 18 to obtain the cis-olefin 19 as
the only isomer in an overall yield of 86% over two steps
(Scheme 4). Catalytic hydrogenation of the latter effected
the desired three reductions to directly yield the amino-diol
20 in good yield. However, attempts to cyclize this to
(11) For some reports on INC-mediated stereoselective synthesis of
heterocyclic systems, see: (a) Gribble, G. W.; Barden, T. C. J. Org. Chem.
1985, 50, 5900. (b) Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988, 53,
4074. (c) Hems, W. P.; Tan, C.-H.; Stork, T.; Feeder, N.; Holmes, A. B.
Tetrahedron Lett. 1999, 40, 1393. (d) Jones, R. C. F.; Martin, J. N.;
Smith, P. Synlett 2000, 967. (e) White, J. D.; Hansen, J. D. J. Am. Chem.
Soc. 2002, 124, 4950. (f) Jeong, J.; Weinreb, S. M. Org. Lett. 2006, 8,
2309. (g) Merino, P.; Mannucci, V.; Tejero, T. Eur. J. Org. Chem. 2008,
3943. (h) Flick, A. C.; Caballero, M. J. A.; Padwa, A. Org. Lett. 2008, 10,
1871. (i) Chiacchio, U.; Padwa, A.; Romeo, G. Curr. Org. Chem. 2009,
13, 422. (j) Piperno, A.; Giofre, S. V.; Iannazzo, D.; Romeo, R.; Romeo,
G.; Chiacchio, U.; Rescifina, A.; Piotrowska, D. G. J. Org. Chem. 2010,
75, 2798.
(13) This was supported by theoretical calculations as well as by
X-ray analysis of model compound (27); CCDC No. 835450.
(12) Murahashi, S.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J.
Org. Chem. 1990, 55, 1736.
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Org. Lett., Vol. 13, No. 19, 2011

epi-lasubine 21 involving displacement of the derived
primary OTs group by a ring nitrogen,6d or by Mitsuno-
bu-type cyclization, proved to be unsuccessful; the solubi-
lity of compound 20 in the desired solvents was the major
impediment.
protected as its OTBS-derivative 24 under conventional
conditions. Hydrogenolytic removal of the benzyl group
followed by cyclization of the resulting alcohol 25 under a
Mitsunobu protocol proceeded in a facile manner leading
to the formation of the quinolizidine derivative 26 in good
yield. Removal of the OTBS group in the latter using
Et3NÀHF then provided 2-epi-lasubine II (21) in an over-
all yield of 14% over 11 steps in a convenient manner.
Conversion of 21 to lasubine II was achieved using a
second Mitsunobu reaction as described previously.6k
Compounds 21 and 1 (overall yield 9% over 12 steps)
showed spectroscopic and optical rotation data in close
agreement with those reported for 2-epi-lasubine II6j and
(À)-lasubine II respectively.6k,l,14
Scheme 5. Synthesis of (À)-Lasubine II
In conclusion, we have developed an enantiodiver-
gent approach to the quinolizidine ring system culmi-
nating in the total synthesis of the alkaloid (À)-lasubine
II. Although ent-lasubine II was not synthesized, it
could be achieved starting with the diol 15. The meth-
odology may prove to be useful for the preparation of
related compounds.
Acknowledgment. We are thankful to DST, Govt. of
India for support (Grant No. SR/S1/OC-35/2009) and
CSIR, New Delhi for fellowships.
In an alternative approach (Scheme 5), selective hydro-
genation of the olefinic bond in 19 leading to 22 and its
subsequent Zn-mediated opening of the bicyclic ring de-
livered the 4-hydroxypiperidine derivative 23, which was
Supporting Information Available. Experimental pro-
cedures, characterization data and copies of H and 13
NMR spectra for all new compounds, and ORTEP
diagram of model compound 27 are provided in the
Supporting Information files. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
C
(14) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C.
Tetrahedron: Asymmetry 1998, 9, 4361.
Org. Lett., Vol. 13, No. 19, 2011
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