Enantioselective organocatalytic intramolecular aza-Michael reaction: A concise synthesis of (+)-sedamine, (+)-allosedamine, and (+)-coniine

Article abstract of DOI:10.1021/ol702447y

(Chemical Equation Presented) The intramolecular aza-Michael reaction of carbamates bearing remote α,β-unsaturated aldehydes under organocatalytic conditions took place with good yields and excellent ee's when Jorgensen catalyst IV was used in the process, giving rise to the enantioselective formation of several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.

Full text of DOI:10.1021/ol702447y

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5283-5286
Enantioselective Organocatalytic
Intramolecular Aza-Michael Reaction:
a Concise Synthesis of ( )-Sedamine,
+
(
+
)-Allosedamine, and (+)-Coniine
Santos Fustero,*,†,‡ Diego Jime´nez,† Javier Moscardo´,† Silvia Catala´n,† and
Carlos del Pozo†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot,
Spain, and Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe
Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
Received October 9, 2007
ABSTRACT
The intramolecular aza-Michael reaction of carbamates bearing remote
r,â-unsaturated aldehydes under organocatalytic conditions took place
with good yields and excellent ee’s when Jørgensen catalyst IV was used in the process, giving rise to the enantioselective formation of
several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.
In the past decade, organocatalysis has emerged as a powerful
synthetic tool,1 one that is complementary to transition metal-
based catalysis in asymmetric synthesis. The success of this
methodology is based on several factors: (1) organocatalysts
are available (or easily synthesized) in both enantiomerically
pure forms, (2) they are moisture stable so that reactions
can be conducted under air atmosphere and, in some cases,
in water, (3) generally, reactions are operationally simple
(practically mix and stir), (4) and most importantly, excellent
or moderate to excellent results are obtained in terms of both
enantioselectivity and yield.
interesting methods in C-N bond formation because the
resulting â-amino carbonyl adducts are privileged structures
that are present in natural products and used in pharmaceuti-
cal agents.2 Despite the importance of this methodology,
catalyzed enantioselective aza-Michael reactions remain
elusive and can thus be considered as a challenging task.3
In fact, only very recently have several organocatalyzed
nucleophilic nitrogen addition reactions to R,â-unsaturated
carbons been presented in their intermolecular version.4 Most
of these reactions take advantage of the enhancement of
nucleophilicity produced by the presence of a heteroatom in
the R-position relative to the nitrogen-centered nucleophile
(R-effect).5
Conjugate addition of amines or their synthetic equivalents
to R,â-unsaturated compounds constitutes one of the most
Encouraged by our recent results in aza-Michael reactions,6
we decided to explore the organocatalytic version of this
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) See, for example: (a) Gaunt, M. J.; Johansson, C. C. C.; McNally,
A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8. (b) Gillena, G.; Ramo´n,
D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693. (c) Marcia de
Figueiredo, R.; Christmann, M. Eur. J. Org. Chem. 2007, 2575. (d) Dalko,
P. I. EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, Germany,
2007. (e) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79.
(2) EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.; Juaristi, E.
C., Soloshonok, V. A., Eds.; Wiley-VCH Ltd.: New York, 2005.
(3) For recent reviews see: (a) Vicario, J. L.; Badia, D.; Carrillo, L.
Synthesis 2007, 2065. (b) Vicario, J. L.; Carrillo, L.; Etxebarria, J.; Reyes,
E.; Ruiz, N. Org. Prep. Proced. Int. 2005, 37, 513. (c) Xu, L.-W.; Xia,
C.-G. Eur. J. Org. Chem. 2005, 633.
10.1021/ol702447y CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/07/2007

reaction.7 Herein, we describe a very high enantioselective
organocatalytic intramolecular aza-Michael reaction (IMAMR)
of carbamates bearing remote R,â-unsaturated aldehydes as
Michael acceptors (Scheme 1). The application of this
out with catalyst I and lasted 120 h with temperatures ranging
from -20° to 15 °C. After reduction of the corresponding
aldehyde, amino alcohol 3a was isolated in 60% yield,
although with less than 5% ee (Table 2, entry 1). Catalyst
Scheme 1. Synthetic Strategy
Table 2. Catalyst Screening and Optimization Reaction
Conditionsa
strategy for the synthesis of three piperidine alkaloids is also
presented.
Starting amines 2 were assembled through a cross-
metathesis reaction of the corresponding unsaturated amines
18 with acrolein catalyzed by second-generation Hoveyda-
Grubbs catalyst [Cl2(IMes)RudCH(o-i-PrOC6H4)]. The reac-
tion proceeded in DCM at room temperature, affording the
desired products in general good yields (Table 1).
entry cat. additive temp (°C) time (h) yield (%) ee (%)b
1
2
3
4
5
6
7
I
II
HCl
TFA
-20
-20
-20
-30
-40
-50
-60
120
7
7
22
22
22
45
60
73
78
71
74
71
67
<5
27
40
75
79
93
93
III PhCO2H
III PhCO2H
IV
IV
IV
PhCO2H
PhCO2H
PhCO2H
Table 1. Preparation of the Starting Amines 2
a In all cases 0.2 equiv of catalyst and additive was used in 0.1 M solution.
b Determined by means of chiral-phase HPLC analysis.
entry
1
PG
X
n
2
yield (%)
II proved to be a great deal more reactive, and when it was
used at -20 °C for 7 h, 3a was isolated in 73% yield and
with 27% ee (Table 2, entry 2). Under the same conditions,
catalyst III (20 mol %) afforded the desired product in 78%
yield and with 40% ee (Table 2, entry 3).
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Boc
Cbz
Boc
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
CH2
CH2
CH2
CH2
O
1
1
2
2
1
2
1
2
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
81
83
60
70
56
84
43
44
87
60
An important improvement in ee (75%) was achieved
when the reaction was performed at -40 °C (Table 2, entry
4), but at lower temperatures, the addition did not take place.
We then decided to use Jørgensen catalyst IV (20 mol %)
since good results for organocatalyzed conjugated additions
to R,â-unsaturated aldehydes with this catalyst had previously
been described.9 To our delight, when the reaction was
carried out at -50 °C for 22 h, the desired amino alcohol
3a was isolated in 71% yield and with 93% ee (Table 2,
entry 6). When lower temperatures were used, however, no
O
N-Cbz
N-Cbz
S
10
1j
S
2j
In order to find optimum conditions and catalysts, substrate
2a was subjected to the intramolecular protocol under
different reaction conditions. The initial attempt was carried
(4) With carbamates as nitrogen nucleophiles: (a) Ibrahem, I.; R´ıos, R.;
Vesely, J.; Zhao, G.-L.; Co´rdova, A. Chem. Commun. 2007, 849. (b) Vesely,
H.; Ibrahem, I.; Zhao, G.-L.; R´ıos, R.; Co´rdova, A. Angew. Chem., Int. Ed.
2007, 46, 778. (c) Sunde´n, H.; R´ıos, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson,
L.; Co´rdova, A. AdV. Synth. Catal. 2007, 349, 827. (d) Vesely, J.; Ibrahem,
I.; R´ıos, R.; Zhao, G.-L.; Xu, Y.; Co´rdova, A. Tetrahedron Lett. 2007, 48,
2193. (e) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang,
W. Org. Lett. 2007, 9, 965. (f) Chen, Y. K.; Yoshida, M.; McMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 9328. With azides as nitrogen
nucleophiles: (g) Horstmann, T. E.; Guerin, D. J.; Miller, S. C. Angew.
Chem., Int. Ed. 2000, 39, 3635. (h) Guerin, D. J.; Miller, S. C. J. Am. Chem.
Soc. 2002, 124, 2134. With hydrazones as nitrogen nucleophiles: (i)
Perdicchia, D.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 3565. With triazols
as nitrogen nucleophiles: (j) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (k) Wang, J.; Li, H.; Zu, L.;
Wang, W. Org. Lett. 2006, 8, 1391.
(6) (a) Fustero, S.; Chiva, G.; Piera, J.; Volonterio, A.; Zanda, M.;
Gonza´lez, J.; Ramallal, A. M. Chem. Eur. J. 2007, 13, 8530. (b) Fustero,
S.; Jime´nez, D.; Sa´nchez-Rosello´, M.; del Pozo, C. J. Am. Chem. Soc. 2007,
129, 6700. (c) Sani, M.; Bruche´, L.; Chiva, G.; Fustero, S.; Piera, J.;
Volonterio, A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42, 2060.
(7) Only one example of organocatalytic intramolecular aza-Michael
reaction has been described before, using amides as nitrogen nucleophiles,
although with poor levels of enantioselectivity: Takasu, K.; Maiti, S.; Ihara,
M. Heterocycles 2003, 59, 51.
(8) For the preparation of amines 1, see Supporting Information.
(9) (a) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Marigo, M.; Bertelsen, S.;
Landa, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475. (c) Wang,
W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (d)
Marigo, M.; Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 15710.
(5) Heaton, M. M. J. Am. Chem. Soc. 1978, 100, 2004.
5284
Org. Lett., Vol. 9, No. 25, 2007

found that the reaction was highly efficient when either Boc
or Cbz were used as protecting groups (Table 3, entries 1,
2). The formation of the derivatives 3c and 3d, both
containing a six-membered ring, also took place with
excellent ee (Table 3, entries 3, 4). We then decided to extend
this methodology to the preparation of other substrates
containing different heteroatoms within the alkyl chain since
the resulting reaction products could be potentially valuable
heterocycles to use in medicinal chemistry. The organocata-
lytic intramolecular aza-Michael reaction led to the formation
of the corresponding five- and six-membered ring hetero-
cycles containing oxygen, nitrogen, and sulfur in yields
ranging from 30 to 80% and with excellent ee (up to 96%)
(Table 3, entries 5-10).
Table 3. Scope of the Organocatalytic Intramolecular
Aza-Michael Reaction
The absolute configuration of the newly created stereo-
center was determined to be R by comparing the [R]D values
and NMR data of compound 3a with those described in the
literature11 (see experimental section in Supporting Informa-
tion). Identical stereochemical development was assumed for
all the substrates.
The mechanism commonly invoked to rationalize the
organocatalytic conjugate additions of nitrogen nucleophiles
to R,â-unsaturated carbonyl compounds involves activation
of the substrate by the catalyst through the iminium ion
mechanism, thereby facilitating the intramolecular addition
of the nucleophile to the â-carbon atom. The si face of the
E-diene intermediate is shielded by the chiral group of the
catalyst, approaching the nitrogen atom on the re face. When
X ) O, S, or N-PG, the priority of the substituents is
reversed, and the approach in these cases is on the si face
(Scheme 2).
Scheme 2. Plausible Reaction Pathway for the Organocatalytic
Reaction
a Determined by means of chiral-phase HPLC analysis.
improvement in the final ee was observed (Table 2, entry
7).10
Having determined the optimal reaction conditions (Table
2, entry 6), we turned our attention to the scope of the
process. We first evaluated the influence of the nitrogen-
protecting group on the selectivity of the final product and
As mentioned above, the previously described examples
of the organocatalytic intermolecular aza-Michael reaction
take advantage of the presence of one heteroatom in the
R-position relative to the nitrogen-centered nucleophile, thus
Org. Lett., Vol. 9, No. 25, 2007
5285

allowing the reaction to occur at room temperature. It is
noteworthy that in the intramolecular version described
herein, no R-effect is necessary to enhance the nucleophilicity
of the nitrogen, carrying out the addition at a much lower
temperature.
Scheme 4. Synthesis of (+)-Coniine 7
Finally, we decided to apply our newly developed meth-
odology to the total synthesis of three piperidine alkaloids.12
When piperidine 4c (obtained from 2c) was treated with
phenyl magnesium bromide, a 3:2 mixture of diastereoiso-
mers was obtained in the secondary alcohol. After chro-
matographic separation and reduction of the Boc nitrogen-
protecting group with lithium aluminum hydride, (+)-
sedamine 5 and (+)-allosedamine 6 were obtained (Scheme
3).13 Wittig reaction and hydrogenation of the double bond
reaction of carbamates containing pendant conjugated alde-
hydes which proceeds in good yields and high enantiose-
lectivities. The process, efficiently catalyzed by prolinol
derivative IV, is useful for the enantioselective preparation
of several five- and six-membered ring heterocycles. Finally,
the synthetic utility of the novel organocatalytic reaction was
confirmed by the concise synthesis of three piperidine
alkaloids. The application of this methodology to the total
synthesis of several other alkaloids is currently underway.
Scheme 3. Synthesis of (+)-Sedamine 5 and (+)-Allosedamine
6
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462) and the Generalitat Valenciana
(GV/2007/013) of Spain for their financial support. D.J., S.C.,
and J.M. express their thanks for predoctoral fellowships,
and C.P., for a Ramo´n y Cajal contract.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for 1-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL702447Y
generated from 4d gave rise to (+)-coniine 714 in a very
simple manner (Scheme 4).15
(13) For recent synthesis of sedamine and allosedamine see: (a)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 3734. (b) Zheng, G.; Dwoskin, L. P.; Crooks, P. A. J. Org.
Chem. 2004, 69, 8514. (c) Angoli, M.; Barilli, A.; Lesma, L.; Passarella,
D.; Riva, S.; Silvani, A.; Danielli, B. J. Org. Chem. 2003, 68, 9525.
(14) For recent synthesis of coniine see: (a) Lebrun, S.; Couture, A.;
Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473. (b) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2006, 128, 9646.
In conclusion, we have developed a very high enantiose-
lective organocatalytic intramolecular aza-Michael addition
(10) The use of other solvents did not improve the final ee; thus, when
substrate 2a was subjected to the reaction conditions described in Table 2
(entry 6) but using toluene as solvent, compound 3a was obtained in 72%
yield and 68% ee.
(11) Deng, X.; Many, N. S. Tetrahedron: Asymmetry 2005, 16, 661.
(12) Reynolds, T. Phytochemistry 2005, 66, 1399.
(15) The preparation of these piperidine alkaloids is an additional
confirmation of the absolute stereochemistry of the newly created stereo-
center.
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Org. Lett., Vol. 9, No. 25, 2007