Palladium-catalyzed cyclization of unsaturated β-amino alcohols: A new access to enantiopure bicyclic oxazolidines

Article abstract of DOI:10.1021/ol901375w

Image Presented Chiral unsaturated β-amino alcohols possessing a dialkylamino function cyclize in the presence of Pd(II) catalysts and reoxidants to afford enantiopure bicyclic oxazolidines with total regio- and stereocontrol. The scope and limitations of

Full text of DOI:10.1021/ol901375w

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3746-3749
Palladium-Catalyzed Cyclization of
Unsaturated ꢀ-Amino Alcohols: A New
Access to Enantiopure Bicyclic
Oxazolidines
Jeanne Alladoum, Emmanuel Vrancken, Pierre Mangeney, Sylvain Roland,* and
Catherine Kadouri-Puchot*
UniVersite´ Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique
IPCM-UMR 7201, 4 place Jussieu, case courrier 47, 75252 Paris cedex 05, France
cathy.kadouri-puchot@upmc.fr; sylVain.roland@upmc.fr
Received June 18, 2009
ABSTRACT
Chiral unsaturated ꢀ-amino alcohols possessing a dialkylamino function cyclize in the presence of Pd(II) catalysts and reoxidants to afford
enantiopure bicyclic oxazolidines with total regio- and stereocontrol. The scope and limitations of this transformation have been studied.
Bicyclic oxazolidines are important intermediates in both
synthetic and pharmaceutical chemistry. These compounds
are interesting building blocks for the construction of
nitrogen-containing heterocycles that constitute a tremendous
class of biologically active compounds.1,2
new asymmetric syntheses of such products. In a previous
paper, we reported the diastereoselective synthesis of various
ꢀ-amino alcohols via addition of methoxyallyl anions on (S)-
phenylglycinol-derived oxazolidines.6 ꢀ-Amino alcohols 1,
obtained by addition of methoxyallyllithium, cyclized spon-
taneously in acidic medium to give bicyclic oxazolidines 2.
These appeared as good substrates for the asymmetric
synthesis of proline derivatives 3 (eq 1).7 On the other hand,
addition of methoxyallylzinc bromide provided ꢀ-amino
alcohols 4 bearing a terminal alkene function. We anticipated
that 4 might cyclize in the presence of palladium(II)
complexes and reoxidants to give trisubstituted bicyclic
oxazolidines 5 (eq 2). Herein we describe our results
concerning the development of this reaction and its applica-
tion to a series of unsaturated ꢀ-amino alcohols.
The methodologies reported by Husson,3 Katritzky,4 and
Higashiyama,5 using bicyclic oxazolidines as key intermedi-
ates, have allowed enantioselective syntheses of many natural
or unnatural derivatives containing a piperidine or a pyrro-
lidine framework and showed the relevance of developing
(1) For the pioneering work in this field, see:(a) Meyers, A. I.; Harre,
M.; Garland, R. J. Am. Chem. Soc. 1984, 106, 1146. (b) Meyers, A. I.;
Lefker, B. A.; Sowin, T. J.; Westrum, L. J. J. Org. Chem. 1989, 54, 4243
.
(2) Kadouri-Puchot, C.; Agami, C. Asymmetric Synthesis of Nitrogen
Heterocycles; Royer, J., Ed.; Wiley-VCH, 2009; p 223, and references cited
therein.
(3) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383.
(4) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem.
1999, 64, 1979.
(6) Alladoum, J.; Roland, S.; Vrancken, E.; Kadouri-Puchot, C.;
Mangeney, P. Synlett 2006, 1855.
(5) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50,
1083.
(7) Alladoum, J.; Roland, S.; Vrancken, E.; Mangeney, P; Kadouri-
Puchot, C. J. Org. Chem. 2008, 73, 9771.
10.1021/ol901375w CCC: $40.75
Published on Web 07/24/2009
 2009 American Chemical Society

°C) (Table 1). This procedure proved to be efficient for the
cyclization of 4a-d and led to the formation of the expected
oxazolidines 5 and/or pyrroles 6 with complete conversions
(Table 1, entries 1-4). However, the pyrroles 6 were
obtained as the major products together with a maximum of
30% of 5. We assumed that the in situ formation of 6 could
be favored by the presence of HCl, which is released during
the reaction.
Since the pioneering works of Hegedus and co-workers,8
the palladium-catalyzed intramolecular cyclization of unsat-
urated amines is a well-known method to synthesize aza-
heterocycles.9 To the best of our knowledge, this reaction
was not investigated with ꢀ-amino alcohols such as 4 having
a homoallylic secondary amino group.10 We expected that
the enamine I or the aldehyde II could be obtained from 4
by an aza-Wacker or a Wacker reaction, respectively, and
lead to the formation of the iminium ion III, which is a direct
precursor of 5 (eq 3).11 Examples of aza-Wacker reactions
involving primary or secondary amino groups are relatively
scarce.12 Less basic acylated, tosylated, or aromatic amines
are usually used for this transformation.9 In the case where
a Wacker reaction would be involved (formation of II), the
oxidation must take place at the external terminal carbon of
the double bond. It is known that oxidations of terminal
alkenes under Wacker-type conditions generally afford the
methyl ketone.13 However, the preferential formation of the
aldehyde was observed in some cases.9c For example,
Nokami and co-workers obtained γ-butyrolactols through a
regioselective oxidation of substituted 1-alken-4-ols at the
terminal position of the alkene.14
Table 1. Cyclization of Compounds 4 in the Wacker-Type
Conditions: Effect of Bases on the Product Distribution
4/6/5 (%)a b
,
entry
sm
base (equiv)
none
none
none
solvent
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4b
4b
4b
4b
4b
4c
4d
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
THF
THF
0/100/0
0/90/10
0/85/15
0/70/30
100/0/0
0/48/52
15/5/80
0/5/95
none
NaOH 2 M (5)
AcONa 1 M (5)
AcONa 2 M (3)
NaHCO3 sat.
NaHCO3 sat.
NaHCO3 sat.
NaHCO3 sat.
0/0/100 (35%)c
0/0/100 (62%)c
0/0/100 (54%)c
10
11
a Conditions: PdCl2 10 mol %, CuCl2, O2, 20 °C, 15 h. b Determined
by H NMR of the crude mixture c Isolated yield after chromatography.
1
A second set of experiments was then performed with 4b
in the same conditions by adding various bases (Table 1,
entries 5-8). The reaction was completely inhibited in the
presence of NaOH (entry 5), but the use of sodium acetate
allowed the yield of 5b to increase significantly and limited
the formation of the pyrrole 6b (entries 6 and 7). The best
results were obtained when an aqueous NaHCO3 solution
was added to the reaction mixture. In this case, a 95:5 ratio
of 5b/6b was obtained (entry 8). Finally, changing the solvent
from DMF to THF afforded exclusively the expected
oxazolidine 5b (entry 9). This protocol proved to be also
efficient for the transformation of 4c-d into the oxazolidines
5c-d (entries 10 and 11). The expected oxazolidines 5b-d
were isolated in 35-62% yields. A single diastereoisomer
This prompted us to study the cyclization of 4 under
similar conditions (PdCl2 10 mol %, CuCl2, O2, DMF, 20
(8) (a) Hegedus, L. S. Organometallic in Synthesis; Schlosser, M., Ed.;
John Wiley& Sons, 2002; p 1137. (b) Hegedus, L. S.; McKearin, J. M.
J. Am. Chem. Soc. 1982, 104, 2444. (c) Harrington, P. J.; Hegedus, L. S.
J. Org. Chem. 1984, 49, 2657. (d) Harrington, P. J.; Hegedus, L. S.;
McDaniel, K. F. J. Am. Chem. Soc. 1987, 109, 4355.
(9) For recent reviews on aminopalladation, see:(a) Zeni, G.; Larock,
R. C. Chem. ReV. 2004, 104, 2285. (b) Minatti, A.; Mun˜iz, K. Chem. Soc.
ReV. 2007, 36, 1142. (c) Beccali, E. M.; Broggini, G.; Martinelli, M.;
Sottocornolla, S. Chem. ReV. 2007, 107, 5318.
1
is detectable by H NMR of the crude reaction mixtures.
(10) Cyclizations of ꢀ-amino alcohols having an allylic amine moiety
have been reported. In this case, cyclic acetals or hemiacetals are obtained
through nucleophilic attack of the hydroxy group at the double bond. See:
Lai, J.-Y.; Shi, X.-X; Gong, Y.-S.; Dai, L.-X. J. Org. Chem. 1993, 58,
4775.
The configurations of bicyclic oxazolidine 5b were estab-
1
lished from the DIFNOE H NMR data which demonstrate
that the three substituents i-Pr, Ph, and H are located in the
same half-space. The relative configuration of compound 5d
was assigned from an X-ray analysis. Surprisingly, a cis
relationship between the three substituents i-Pr, Ph, and H
was also found in this case indicating that an inversion of
configuration at the carbon bearing the methoxy substituent
occurred during the reaction.15,16
(11) Several strategies, reported in the literature for the synthesis of
bicyclic oxazolidines, are based on the transient formation of cyclic iminium
ions. For a review, see :Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004,
104, 2311–2352.
(12) Pugin, B.; Venanzi, L. M. J. Am. Chem. Soc. 1983, 105, 6877.
(13) For a recent review of the Wacker oxidation, see:Cornell, C. N.;
Sigman, M. S. Inorg. Chem. 2007, 46, 1903.
(14) Nokami, J.; Ogawa, H.; Miyamoto, S.; Mandai, T.; Wakabayashi,
S.; Tsuji, J. Tetrahedron Lett. 1988, 29, 5181.
Org. Lett., Vol. 11, No. 16, 2009
3747

Encouraged by these results, we decided to study the scope
and the limitations of this reaction. A series of chiral ꢀ-amino
alcohols 7-9 without a methoxy group at the allylic position
were synthesized. These compounds differ in the length of
the chain bearing the double bond and in the nature of the
R-group. The cyclizations of 7-9 were performed using two
catalytic systems: the classic Wacker-type conditions (condi-
tions A) and conditions using PdCl2(CH3CN)2 as the catalyst,
reported by Hegedus, which proved to be efficient for the
intramolecular amination of olefins (conditions B).8
Hegedus conditions led to comparable or significantly higher
yields than the Wacker-type conditions (entries 2, 3, and 7).
Conditions B applied to 7-9 afforded the oxazolidines in
65-89% isolated yields (entries 2-9). For n ) 1 and 2, the
reaction gave in good yields, respectively, the bicyclic
oxazolidines 5/5 10 and 5/6 11 containing an angular methyl
group. These cyclizations occurred with total stereoselec-
tivity: substituents R, R′, and Ph are in a cis-position.15
To illustrate the efficiency of this cyclization, we synthe-
sized (2R,6S)-isosolenopsine A17 in two steps from amino
alcohol 12 (Scheme 1). Treatment of 12 with catalytic
PdCl2(CH3CN)2 in the presence of benzoquinone and LiCl
produced the bicyclic oxazolidine 13 with an excellent
diastereoselectivity (de > 93%) and in 75% yield. Hydro-
genolysis with the Pearlman catalyst led to isosolenopsine
14 in an enantiomerically pure form.
Table 2. PdII-Catalyzed Cyclization of ꢀ-Amino Alcohols 7, 8,
and 9
Scheme 1. Asymmetric Synthesis of (-)-Isosolenopsine A 14
Although our data cannot clearly establish the mechanism
of these transformations (Wacker or aza-Wacker-type reac-
tions), a route involving the preferential formation of the
iminium ions (A, B, and C) leading to the more stable
bicyclic oxazolidines (respectively, 2, 10, and 11), can
account for the regio- and stereoselectivity of these cycliza-
tions (Scheme 2).
Concerning the regioselectivity, five-membered rings (imi-
niums A and B, respectively from 7 and 8 leading to [5,5]
oxazolidines 2 and 10) and six-membered rings (iminium C
from 9 leading to [5,6] oxazolidine 11) are likely favored.
The stereoselective formation of the stereocenter at the ring
junction leads also to the more stable bicyclic oxazolidines
where the carbon-oxygen bond is formed in an anti position
relative to the phenyl and R substituents.11
b
,
entry
amino alcohol
oxazolidine
yielda
2ac d
traces
,
1
2
3
4
5
6
7
8
9
7a
7b
7d
8b
8c
8d
9b
9c
9d
2b
2d
58d, 89e
84d, 75e
75e
10b
10c
10d
11b
11c
11d
86e
65e f
,
32d, 80e
77e
76e
a After purification by flash silica gel chromatography. b Only one
1
diastereoisomer was observed by H NMR spectra of the crude mixture.
c A complex mixture was obtained in which 2a and 7a were detectable.
d Conditions A: PdCl2 (0.1 equiv), CuCl2 (1 equiv), AcONa 2 M (3 equiv),
DMF, rt, 15 h. e Conditions B: [PdCl2(CH3CN)2] (0.1 equiv), benzoquinone
(1 equiv), LiCl (10 equiv), THF, reflux, 4 h. f Isolated together with 8% of
a nonidentified byproduct (not separable).
Scheme 2
.
Iminium Ions Probably Involved in the Cyclization
Reactions
The results, presented in Table 2, show the importance of
the R substituent. No selectivity was observed when the
cyclization was performed from 7a (R ) H, entry 1). On
the other hand, the methoxy group initially present in 4 is
not essential. When R is an alkyl or aryl group, the bicyclic
oxazolidines 2, 10, and 11 were obtained in 32-89% yields
as single diastereomers (entries 2-9). Comparison of the two
catalytic systems using 7b, 7d, and 9b showed that the
(15) CCDC719372 for 5d and CCDC719373 for 10b contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(16) A reversible ꢀ-elimination involving the hydrogen atom on the
carbon bearing the methoxy group and leading finally to the more stable
oxazolidine 5d could explain the epimerization observed during the
cyclization of 4d.
In summary, the catalyzed reactions described herein
provide access to valuable structures with total control of
(17) For examples, see:(a) Singh, O.; Han, V. H. Org. Lett. 2004, 6,
Org. Lett., Vol. 11, No. 16, 2009
3748

selectivity. Further explorations of this palladium chemistry
and studies on the synthetic applications of the bicyclic
oxazolidines are actively in progress.
Acknowledgment. We thank Dr. Patrick Herson (Uni-
versite´ Pierre et Marie Curie-Paris 6, IPCM-UMR 7201) for
X-ray analyses of compounds 5d and 10b.
Supporting Information Available: Experimental pro-
cedure and characterization data of amino alcohols and
bicyclic oxazolidines. This material is available free of charge
via the Internet at http://pubs.acs.org.
3067. (b) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919. (c) Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.;
Remuson, R. Tetrahedron: Asymmetry 2005, 16, 1025. (d) Wang, X.; Dong,
Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem. 2005, 70, 1897. (e)
Gonza´lez-Go´mez, J. C.; Foubelo, F.; Yus, M. Synlett 2008, 2777. (f) Ciblat,
S.; Besse, P.; Papastergiou, G. I.; Veschambre, H.; Canet, J. -L.; Troin, Y.
Tetrahedron: Asymmetry 2000, 11, 2221.
OL901375W
Org. Lett., Vol. 11, No. 16, 2009
3749