Short access to (+)-lupinine and (+)-epiquinamide via double hydroformylation

Article abstract of DOI:10.1021/ol902718q

[Chemical equation presented] Short and efficient access to (+)-lupinine and (+)-epiquinamide by means of an unprecedented double hydroformylation of a bis-homoallylic azide followed by a tandem catalytic hydrogenatlon/reductive bis-amination is reported.

Full text of DOI:10.1021/ol902718q

ORGANIC
LETTERS
2010
Vol. 12, No. 3
528-531
Short Access to (+)-Lupinine and
(+)-Epiquinamide via Double
Hydroformylation†
Etienne Airiau,‡ Thomas Spangenberg,‡,§ Nicolas Girard,‡ Bernhard Breit,*,§ and
Andre´ Mann*,‡
Faculte´ de Pharmacie, UMR 7200, CNRS-UniVersite´ de Strasbourg, Laboratoire
d’InnoVation The´rapeutique, 74 route du Rhin, F-67401 Illkirch, France, and Institut
fu¨r Organische Chemie und Biochemie, Albert-Ludwigs-UniVersita¨t Freiburg,
Albertstrasse 21, D-79104 Freiburg, Germany
andre.mann@pharma.u-strasbg.fr; bernhard.breit@chemie.uni-freiburg.de
Received November 25, 2009
ABSTRACT
Short and efficient access to (+)-lupinine and (+)-epiquinamide by means of an unprecedented double hydroformylation of a bis-homoallylic
azide followed by a tandem catalytic hydrogenation/reductive bis-amination is reported.
In recent years, synthetic strategies toward piperidine- and
pyrolidine-containing alkaloids have often implemented
transition-metal-catalyzed transformations. In this regard, the
ring closing metathesis (RCM) has found its way for the
construction of many alkaloids,1 but a prerequisite for
performing a RCM is the presence of two olefinic partners
in the substrate to be heterocyclized, one of them being
generally a homoallylamine. As an alternative, a homoally-
lamine could also be identified as an ideal substrate for
performing a hydroformylation.2 This atom-economic pro-
cess3 consists of a formal addition of H2/CO across an olefin
catalyzed by Rh(I) and has recently emerged as a powerful
method in the synthesis of alkaloids.4 Thus, if the introduc-
tion of the aldehyde function occurs regioselectively at the
terminal carbon atom of the alkene function, the presence
of the nucleophilic nitrogen atom in the allylamine will allow
us to form an internal imine directly amenable to a six-
membered N-heterocycle.
Combining hydroformylation and heterocycle syntheses,
we recently disclosed the hydroformylation of homoallylic
azides5 as a highly efficient way to construct the piperidine
nucleus thus offering a new tactic for the construction of
alkaloids. Indeed, the reaction proceeded with a very good
† This paper is dedicated to Christian Marazano.
‡ CNRS-Universite´ de Strasbourg.
§ Albert-Ludwigs-Universita¨t Freiburg.
(1) For selected examples or reviews, see: (a) Niethe, A.; Fischer, D.;
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2007, 16, 2599. (d) Compain, P. AdV. Synth. Catal. 2007, 349, 1829, and
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Biera¨ugel, H. Eur. J. Org. Chem. 1999, 5, 959. (f) Gaich, T.; Mulzer, J.
Curr. Org. Chem. 2005, 5, 1473. (g) Brenneman, J. B.; Martin, S. F. Curr.
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(4) For selected examples, see: (a) Airiau, E.; Girard, N.; Mann, A.;
Salvadori, J.; Taddei, M. Org. Lett. 2009, 11, 5314. (b) Spangenberg, T.;
Airiau, E.; Bui The Thuong, M.; Donnard, M.; Billet, M.; Mann, M. Synlett
2008, 18, 2859. (c) Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder,
A.; Salvadori, J.; Taddei, M.; Mann, A. Chem.sEur. J. 2008, 14, 10938.
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Eilbracht, P.; Schmidt, A. M. Top. Organomet. Chem. 2006, 18, 65.
(5) Spangenberg, T.; Breit, B.; Mann, A. Org. Lett. 2009, 11, 261.
10.1021/ol902718q  2010 American Chemical Society
Published on Web 12/28/2009

catalyst-based regiocontrol in favor of the linear aldehyde
employing a biphephos/rhodium(I) catalyst (see Scheme 1).6
Additionally, we have recently shown that instead of the
amine function one could employ as an amine surrogate the
azido function. This functional group remains intact during
the hydroformylation reaction thus enabling a range of
subsequent chemoselective transformations (e.g., Schmidt
rearrangement, aza-Wittig reaction, Staudinger reaction).7 To
further extend our strategy, the syntheses of naturally
occurring quinolizidine alkaloids (+)-lupinine 1a and (+)-
epiquinamide 1b have now been considered (Figure 1).
azide reduction/reductive bis-amination process8 took place
to form the desired quinolizidine 1c exclusively.9
Next, (+)-lupinine 1a (Scheme 2), a quinolizidine alkaloid
from Lupinus spp.,10 was selected as a target to explore our
new bidirectional hydroformylation/tandem hydrogenation-
reductive bis-amination strategy. Previously, Ma et al.11
reported the access to all four epimers of lupinine via a
double RCM reaction of nitrogen-containing tetraenes.
Scheme 2. Synthesis of (+)-Lupinine, 1a
Figure 1. Strategy for the formation of quinolizidine alkaloids.
From a retrosynthetic point of view, the quinolizidine ring
system is attainable by a double reductive amination of two
equidistant aldehydes smoothly generated by a regioselective
bidirectional hydroformylation of an appropriate chiral bis-
homoallylic amine which might be generated in situ through
catalytic reduction of the azide function.
Scheme 1. Model Reaction
Interestingly, a similar intermediate (9) could be used for
our purposes. However, for the preparation of 9, we chose
a different path.
Our synthesis commenced with the Evans aldol reaction12
between commercially available oxazolidinone 4 and freshly
(8) (a) Gradnig, G.; Berger, A.; Grassberger, V.; Stu¨tz, A. E. Tetrahedron
Lett. 1991, 32, 4889. (b) Schaller, C.; Vogel, P. Synlett 1999, 8, 1219.
(9) 1H NMR yield.
(10) (a) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458. (b) Michael, J. P.
Nat. Prod. Rep. 2008, 25, 139. (c) Abdel Halim, O. B.; El Gammal, A. A.;
Abdel Fatta, H.; Takeya, K. Phytochemistry 1999, 51, 5.
(11) (a) Ma, S.; Ni, B. Chem.sEur. J. 2004, 10, 3286. For other synthesis
of optically active lupinine, see: (b) Noe¨l, R.; Fargeau-Bellassoued, M.-C.;
Vanucci-Bacque´, C.; Lhommet, G. Synthesis 2008, 12, 1948. (c) Agami,
C.; Dechoux, L.; Hebbe, S.; Me´nard, C. Tetrahedron 2004, 60, 5433. (d)
Ledoux, S.; Marchalant, E.; Ce´le´rier, J.-P.; Lhommet, G. Tetrahedron Lett.
2001, 42, 5397. (e) Mangeney, P.; Hamon, L.; Raussou, S.; Urbain, N.;
Alexakis, A. Tetrahedron 1998, 54, 10349. (f) Morley, C.; Knight, D. W.;
Share, A. C. J. Chem. Soc., Perkin Trans. 1 1994, 20, 2903. (g) Hua, D. H.;
Miao, S. W.; Bravo, A. A.; Takemoto, D. J. Synthesis 1991, 11, 970.
(12) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047. (b) Nerz-Stormes, M.; Thornton, E. R. J. Org.
Chem. 1991, 56, 2489. (c) Bonner, M. P.; Thornton, E. R. J. Am. Chem.
Soc. 1991, 113, 1299. (d) Crimmins, M. T.; King, B. W.; Tabet, E. A.
J. Am. Chem. Soc. 1997, 119, 7883. (e) Crimmins, M. T.; Choy, A. L.
J. Am. Chem. Soc. 1999, 121, 5653. (f) Crimmins, M. T.; King, B. W.;
Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894. (g) Crimmins,
M. T.; Tabet, E. A. J. Org. Chem. 2001, 66, 4012. (h) Sakaguchi, H.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635.
To explore the feasibility of this approach, we subjected
the bis-homoallylic azide 2 to the conditions of a regiose-
lective hydroformylation employing the biphephos/rhod-
ium(I) catalyst (Scheme 1). The bisaldehyde 3 was formed
smoothly in high regioselectivity and good yield. After
subjection of the azide to the conditions of catalytic
hydrogenation employing Pearlman’s catalyst, a clean tandem
(6) (a) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. U.S. Patents
4,668,651, 1987, and 4,769,498, 1988. (b) Cuny, G. D.; Buchwald, S. L.
J. Am. Chem. Soc. 1993, 115, 2066.
(7) For a review on the chemistry of azides, see: Bra¨se, V.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
Org. Lett., Vol. 12, No. 3, 2010
529

prepared 3-butenal13 5. Employing DIPEA as the base to
form the chlorotitanium enolate via soft enolization of 4,
the syn-aldol product 6 was obtained as a single diastereomer
in 77% yield. Reductive removal of the chiral auxiliary with
lithium borohydride, in THF with some methanol, furnished
the diol 7 in 80% yield. The primary alcohol was protected
as a TBS ether, and the secondary alcohol was activated as
its mesylate and displaced with the azide function upon
reaction with sodium azide in DMF to give the desired bis-
homoallylic azide 10. Subjection of 10 to the conditions of
a hydroformylation employing the biphephos/rhodium system
furnished the azido-bis-δ,δ′-aldehyde 11 in very good yield
(76%). Azido and subsequent imine reduction gave in one
pot the desired quinolizidine core 12 in 87% yield; treatment
of compound 12 with TBAF resulted in the formation of
(+)-lupinine 1a. Finally, the present route to (+)-lupinine
features 8 steps (from 4) with an overall yield of 15%.
group can be introduced from a anti-1,2 amino alcohol 16
generated by chelation-controlled reduction of the corre-
sponding homoallylic ketone 14. The latter may be easily
obtained from inexpensive amino acid Cbz-L-methionine via
the Weinreb amide and an allyl-Grignard, introducing the
second essential alkene function.
Initially, Cbz-L-vinylglycine was considered in our strat-
egy, but as epimerization was a concern, the olefin was kept
in its hidden form (dialkylsulfide) until reaching 17 (Scheme
4), a compound not prone to epimerization.16
Scheme 4. Synthesis of (+)-Epiquinamide, 1b
In a second part, we focused on the total synthesis of (+)-
epiquinamide 1b (Scheme 3), an alkaloid isolated from the
rainforest frog Epipedobates tricolor along with Epibatidine
and that has a relevant activity on nicotinic receptors.14
Scheme 3. Retrosynthetic Analysis for (+)-Epiquinamide
(+)-Epiquinamide 1b has attracted considerable attention
from the synthetic community. Interestingly, most of the
reported strategies used RCM as the key reaction.15
Following our key strategy (Scheme 1), the access to the
enantiopure bis-homoallylic azide 18 from the chiral pool
has been envisaged. Indeed, one olefin (vide supra) may be
obtained by syn-elimination of the corresponding sulfoxide
16 obtained from a former methionine derivative. The azido
It should be mentionned that the choice of the N-protecting
group is not trivial as it is decisive for the chelation-controlled
reduction. It must be stable for the thermal elimination and
ideally removable during the final hydrogenolysis. As a
consequence, we selected the benzylcarbamate (Cbz) as a
suitable protecting group.
Practically, Weinreb amide 13 was obtained from Cbz-L-
methionine using standard coupling conditions (Scheme 4),
and subsequent treatment with allylmagnesium chloride
afforded the corresponding homoallylic ketone 14 in excel-
lent yields (97% over 2 steps) along with a negligible amount
of isomerized product.17 At this point, three reducing
conditions were evaluated (see Supporting Information for
details) to obtain the desired anti amino alcohol 15 with high
diastereoselectivity. The best result was obtained with lithium
(13) See Supporting Information for the preparation of 5.
(14) (a) Fitch, R. W.; Garrafo, H. M.; Spande, T. F.; Yeh, H. J. C.;
Daly, J. W. J. Nat. Prod. 2003, 66, 1345. (b) Fitch, R. W.; Sturgeon, G. D.;
Patel, S. R.; Spande, T. F.; Garrafo, H. M.; Daly, J. W.; Blaauw, R. H. J.
Nat. Prod. 2009, 72, 243.
(15) Recent syntheses of optically active epiquinamide using RCM: (a)
Kumar Srivastava, A.; Kumar Das, S.; Panda, G. Tetrahedron 2009, 65,
5322. (b) Gosh, S.; Shashidhar, J. Tetrahedron Lett. 2009, 50, 1177. (c)
Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8, 4541. (d) Wijdeven,
M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes,
F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005. For other methods, see:
(e) Voituriez, A.; Ferreira, F.; Pe´rez-Luna, A.; Chemla, F. Org. Lett. 2007,
9, 4705. (f) Huang, P.-Q.; Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8, 1435.
(16) Afzali-Ardakani, A.; Rapoport, H. J. Org. Chem. 1980, 45, 4817.
(17) Liu, J.; Ikemoto, N.; Petrillo, D.; Amstrong, J. D., III. Tetrahedron
Lett. 2002, 43, 8223.
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Org. Lett., Vol. 12, No. 3, 2010

tris-tert-butoxy aluminum hydride furnishing the desired anti
alcohol in excellent yield and diastereoselectivity.18 Subse-
quent oxidation of the sulfide was achieved quantitatively
with sodium meta-periodate producing a ∼1:1 mixture of
sulfoxide diastereomers (16). Thermal treatment of 16 in the
presence of calcium carbonate19 initiated a clean syn-
elimination to yield the desired bis-homoallylic alcohol 17
in a very good overall yield. Noteworthy is that only two
purification steps were needed from Cbz-L-methionine.
to preclude cyclohydrocarbonylation.22 In our hands, acy-
lation under basic conditions was found to be problematic
as only low conversions were obtained (LiHMDS, AcCl,
THF, -10 to 0 °C, 14%, 89% based on recovered starting
material, see Supporting Information). Gratifyingly, the
reaction proceeded under mild acidic conditions with pTSA
in isopropenylacetate23 as solvent to yield the desired N-Cbz,
N-acylated product 19 in 80% yield.
Finally, applying to 19 the previously developed hydro-
formylation conditions furnished the azido-bis-δ,δ′-aldehyde
20 in 67% yield. The latter was subjected to hydrogenation
in the presence of Pearlman’s catalyst allowing four reductive
reactions in one pot: the azido group was converted into a
free amine, two reductive aminations produced the bicyclic
quinolizidine ring, and the cleavage of the Cbz protecting
group afforded 1b with consistent analytical data (NMR,
HRMS, and optical rotation) in 83% yield.
Scheme 5. Determination of the Relative Stereochemistry
In conclusion, we successfully realized the total syntheses
of two quinolizidine alkaloids, (+)-lupinine 1a (8 steps,
overall yield 15% from 4) and (+)-epiquinamide 1b (9 steps,
overall yield 29% from Cbz-L-methionine), using a bidirec-
tional regioselective hydroformylation of chiral bis-homoal-
lylic azides as a key step followed by a highly efficient
tandem catalytic azide reduction/reductive bis-amination
process. Taking advantage of the exceptional stability of
azides during the hydroformylation process, the proposed
methodology is well suited for the preparation of quinolizi-
dine alkaloids. Moreover, the use of methylsulfide com-
pounds as a hidden terminal alkene function may be an
attractive strategy for subsequent hydroformylation. Applying
the hydroformylation reaction in the synthesis of other
alkaloids is currently underway in our laboratories.
Moreover, the anti relationship in 17 could be secured by
NOE experiments performed on the corresponding cyclic
carbamate 21 (Scheme 5). The observed vicinal coupling
constant (J ) 8 Hz) is consistent with a cis stereochemistry
of oxazolidinone 21.20
Next, a Mitsunobu reaction enabled the introduction of
the azido function to give 18 in 84% yield setting the desired
stereochemistry for 1b.21
Anticipating a possible trapping of one aldehyde during
the hydroformylation process with the secondary carbamate
to form an enamide, acylation of intermediate 18 was decided
In our group, we are currently applying this hydroformy-
lation strategy for the synthesis of other alkaloids.
(18) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572. (b) Datta, A.; Kumar, J. S.; Roy, S. Tetrahedron 2001, 57, 1169.
(c) Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31, 19. (d)
Toumi, M.; Couty, F.; Evano, G. Tetrahedron Lett. 2008, 49, 1175.
(19) Krebs, A.; Ludwig, V.; Pfizer, J.; Durner, G.; Gobel, M. W.
Chem.sEur. J. 2004, 10, 544 NB: Overheating during syn-elimination led
to cyclized product 21.
Acknowledgment. This work was supported by the
Ministe`re de´le´gue´ a` l’Enseignement Supe´rieur et a` la
Recherche (EA, TS).
(20) Barrett, A. G. M.; Seefeld, M. A.; White, J. P.; Williams, D. J. J.
Org. Chem. 1996, 61, 2677.
Supporting Information Available: Detailed experimen-
tal procedures and spectral and analytical data for all the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Mesylation of alcohol 17 followed by treatment with sodium azide
gave also compound 18 in 81% (over two steps).
(22) (a) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995,
60, 7078. (b) Ojima, I.; Iula, D. M.; Tzamarioudaki, M. Tetrahedron Lett.
1998, 39, 4599.
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J. M. Heterocycles 1987, 11, 2911.
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