On the use of phosphoramidite ligands in copper-catalyzed asymmetric transformations with trialkylaluminum reagents

Article abstract of DOI:10.1021/ol061471e

Phosphoramidites based on BINOL readily react with trimethylaluminum in "noncoordinating" solvents, leading to the corresponding aminophosphine which is the real ligand in copper-catalyzed asymmetric transformations. This artifact explains the experimenta

Full text of DOI:10.1021/ol061471e

ORGANIC
LETTERS
2
006
Vol. 8, No. 16
581-3584
On the Use of Phosphoramidite Ligands
in Copper-Catalyzed Asymmetric
Transformations with Trialkylaluminum
Reagents
3
†
‡
†
‡
Chlo e´ e Bournaud, Caroline Falciola, Thomas Lecourt, St e´ phane Rosset,
Alexandre Alexakis,*,‡ and Laurent Micouin*,†
Laboratoire de Chimie Th e´ rapeutique, UMR 8638 associ e´ e au CNRS et a` l'UniVersit e´
Ren e´ Descartes, Facult e´ des Sciences Pharmaceutiques et Biologiques, 4 aV de
l'ObserVatoire, 75270 Paris Cedex 06, France, and Department of Organic Chemistry,
UniVersity of GeneVa, 30 Quai Ernest Ansermet, CH-1211 GeneVa, Switzerland
laurent.micouin@uniV-paris5.fr; alexandre.alexakis@chiorg.unige.ch
Received June 15, 2006
ABSTRACT
Phosphoramidites based on BINOL readily react with trimethylaluminum in “noncoordinating” solvents, leading to the corresponding
aminophosphine which is the real ligand in copper-catalyzed asymmetric transformations. This artifact explains the experimental differences
in the asymmetric ring opening of meso bicyclic hydrazines using dialkylzinc or trialkylaluminum reagents as nucleophiles.
9
Phosphoramidites are now well-established ligands for
numerous asymmetric transformations such as hydrogena-
stitutions. More recently, several examples of the use of
trialkylaluminum reagents as nucleophiles in copper-
catalyzed asymmetric transformations with phosphoramidite
tion,1 1,4-additions of dialkylzinc and boronic acids,
2
3
4
5
6
10
hydrovinylation, hydrosilylation, hydroboration, intramo-
ligands have been described. In our ongoing work on
asymmetric transformations using bicyclic hydrazines, we
7
8
11
lecular Heck reactions, hydroformylation, or allylic sub-
were particularly attracted by a recent report on the asym-
metric nucleophilic ring opening of these derivatives (Scheme
1).
†
UMR 8638, Paris.
University of Geneva, Geneva.
‡
1
2
(1) (a) Komarov, I. V.; B o¨ rner, A. Angew. Chem., Int. Ed. 2001, 40,
1
197. (b) Van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.;
Schudde, E. P.; Meetsma, A.; Feringa, B. L.; De Vries, A. H. M.; Maljaars,
C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J.
W.; De Vries, J. G. AdV. Synth. Catal. 2003, 345, 308. (c) Hua, Z.; Vassar,
V. C.; Choi, H.; Ojima, I. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5411.
(5) Jensen, J. F.; Svendsen, B. Y.; La Cour, T. V.; Pedersen, H. L.;
Johannsen, M. J. Am. Chem. Soc. 2002, 124, 4558.
(6) Alexakis, A.; Polet, D.; Bournaud, C.; Bonin, M.; Micouin, L.
Tetrahedron: Asymmetry 2005, 16, 3672.
(
2) (a) Ferringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Alexakis, A.;
Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
3) Boiteau, J.-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.
003, 5, 681.
4) (a) Francio, G.; Faraone, F. Leitner, W. J. Am. Chem. Soc. 2002,
1
2
(7) Imbos, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2002,
124, 184.
(8) Lambers-Verstappen, M. M. H.; De Vries, J. G. AdV. Synth. Catal.
2003, 345, 478.
(9) (a) Alexakis, A.; Polet, D. Org. Lett. 2005, 7, 1621. (b) Leitner, A.;
Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093. (c) Lipowsky, G.; Miller,
N. Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595.
(
2
(
24, 736. (b) Shi, W.-J.; Xie, J.-H.; Zhou, Q.-L. Tetrahedron: Asymmetry
005, 16, 705.
1
0.1021/ol061471e CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/13/2006

species. Second, the sense of chirality of the amine part of
the ligand proved to exert a major influence on the stereo-
chemical outcome of the reaction (Table 1, entries 3 and 4),
with an almost complete reversal of absolute configuration,
a result in strong contrast with the normal trend in which
the BINOL part controls the enantioselectivity in conjugate
additions. All these troublesome observations prompted us
to investigate more details of this transformation.
Scheme 1. Desymmetrization of Polycyclic Hydrazines with
Organometallic Reagents Reported by Pineschi et al.12
We first decided to follow the reaction by phosphorus
NMR in methylene chloride. As depicted in Figure 1, we
Although this transformation proved to be particularly
efficient, several points, outlined by the authors, were
intriguing. First, very different results were obtained using
Figure 1. Phosphorus NMR of ligands in CH Cl . (a) Black:
2
2
ligand 5 in CH
of AlMe . (c) Red: compound 6 isolated after methanolic quenching
and chromatography. (d) Green: dimethylaminophosphine in CH
Cl . (f) Brown: dimethylaminophosphine in the presence of an
excess of AlMe
2 2
Cl . (b) Blue: ligand 5 in the presence of an excess
3
2
-
2 3
Et Zn or Et Al as a nucleophile (Table 1, entries 1 and 2),
2
3
.
Table 1. Desymmetrization of Polycyclic Hydrazines with
Organometallic Reagents Reported by Pineschi et al.12
observed a complete disappearance of the characteristic signal
of ligand 5 as soon as a solution of AlMe was added in the
NMR tube, leading to a new species with a single signal at
5 ppm. Workup and chromatographic purification led to
the isolation of two compounds. The less polar one proved
to be BINOL, and the phosphoramide 6 was isolated as the
more polar compound, with a signal at 43 ppm. The
formation of this compound could result from the oxidation
of the corresponding aminophosphine 7 during isolation. An
authentic sample of 7 was then prepared (see below), but
this ligand gave a signal at 13 ppm. However, in the presence
3
entry
substrate
RM
yield (%)
ee (%)
1
2
3
1
1
3
3
Et2Zn
Et3Al
Me3Al
Me3Al
38a
80
90
3
3
66 (+)
86 (+)
64 (-)
b
c
4
>98
a
b
Conversion after 24 h. Reaction carried out with diastereomeric ligand
c
(
R,S,S)-5. Conversion after 4 h.
although organometallics are supposed to be mainly alkyl
donors for the in situ generation of the reactive organocopper
of an AlMe
observed, indicating that the species formed by mixing
phosphoramidite 5 and an AlMe solution is probably a
complex between 7 and AlMe
3
solution, a single signal at 35 ppm was again
(
10) Reactions in THF or Et2O: (a) Alexakis, A.; Albrow, V.; Biswas,
K.; d'Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun. 2005, 2843.
b) Polet, D.; Alexakis, A. Tetrahedron: Asymmetry 2005, 46, 1529. (c)
d'Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005, 44,
376. Reactions in toluene or CH2Cl2: (d) Pineschi, M.; Del Moro, F.; Di
3
3
.
(
The same transformation was observed when running
NMR studies in toluene, whereas no modification of the
phosphoramidite signal could be obserVed in THF or diethyl
ether.
The in situ formation of 7 can be tentatively explained by
the cleavage of the BINOL moiety by the organoaluminic
1
Bussolo, V.; Macchia, F. AdV. Synth. Catal. 2006, 348, 301. (e) Pineschi,
M.; Del Moro, F.; Gini, F.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2
1
004, 1244. (f) Equey, O.; Alexakis, A. Tetrahedron: Asymmetry 2004,
5, 1531. (g) Eilitz, U.; Lessmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 3095.
11) (a) P e´ rez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson,
(
H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George,
P. J. Org. Chem. 2002, 67, 3522. (b) P e´ rez Luna, A.; Bonin, M.; Micouin,
L.; Husson, H.-P. J. Am. Chem. Soc. 2002, 124, 12098. (c) P e´ rez Luna, A.;
Cesario, M.; Bonin, M.; Micouin, L. Org. Lett. 2003, 5, 4771. (d)
Bunlaksananusorn, T.; P e´ rez Luna, A.; Bonin, M.; Micouin, L.; Knochel,
P. Synlett 2003, 2240. (e) Bournaud, C.; Robic, D.; Bonin, M.; Micouin,
L. J. Org. Chem. 2005, 70, 3316 and ref 6.
reagent, triggered by a precoordination of this species
13
(Scheme 2). This reaction does not occur (or is much
slower) in more coordinating solvents such as THF or with
the less-oxophilic organozinc reagents.
(
12) (a) Pineschi, M.; Del Moro, F.; Crotti, P.; Macchia, F. Org. Lett.
005, 7, 3605. See also: (b) Pineschi, M.; Del Moro, F.; Crotti, P.; Macchia,
F. Pure Appl. Chem. 2006, 78, 463.
(13) For a closely related reactivity of the P-O bond in phosphine-
borane complexes, see: Jug e´ , S.; Stephan, M.; Merdes, R.; Genet, J.-P.;
Halut-Desportes, S. J. Chem. Soc., Chem. Commun. 1993, 6, 531.
2
3582
Org. Lett., Vol. 8, No. 16, 2006

Scheme 2. In-Situ Reaction of 5 with Trimethylaluminum
Scheme 4. Desymmetrization of Polycyclic Hydrazines with
Organometallic Reagents with Aminophosphines or
Phosphoramidites
We then prepared several dimethylaminophosphines to
evaluate their role as ligands in the asymmetric ring opening
of hydrazines 1 and 3 (Scheme 3).
Scheme 3. Synthesis of Aminophosphines 7 and 10b-d
whereas the use of the free amine 8a led to the substituted
cyclopentene 4 with 51% ee (entry 3). Structural variations
of the amine part of the ligands led to a strong effect on the
enantioselectivity (entries 4-7), delivering compound 2 with
an ee from 72% with ligand 7 to 85% with ligand 10d.15
Introduction of the ethyl group could also be performed
(entries 8 and 9) but with lower enantioselectivities and
conversion than those with ligand 5.
Table 2. Desymmetrization of Polycyclic Hydrazines with
Organometallic Reagents with Aminophosphines or
Phosphoramidites
entry
substrate
ligand
RM
yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
3
3
3
1
1
1
1
3
1
5 (S,S,S)
7 (S,S)
8a (S,S)
7 (S,S)
10b (R,R)
10c (S,S)
10d (R,R)
7 (S,S)
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
75
94
47
86
74
92
85
6
77 (-)
79 (-)
51 (-)
67 (-)
72 (+)
46 (-)
Although the reaction between dichlorophosphoramines
and methylmagnesium bromide seemed to be the simplest
access to these ligands, this route proved to be problematic,
leading to ligands 7 and 10b-d contaminated by traces of
amines 8a-d. We therefore developed a more convenient
three-step route, leading to the expected aminophosphines
after a simple filtration.14 These rather air-sensitive ligands
were rapidly used after isolation.
85 (+)
55b
Et Al
3
b
7 (S,S)
Et3Al
56
48
a
Determined by chiral SFC chromatography. Absolute configuration was
b
established by comparison with configurations described in ref 12. Ab-
solute configuration was not determined.
Desymmetrization of polycyclic hydrazines was then
investigated (Scheme 4 and Table 2). Compound 4 could be
obtained with the same enantioselectivity using either 5 or
In conclusion, we have shown that binol- or biphenol-
based phosphoramidites react readily in noncoordinating
solvents with trimethylaluminum, leading to the correspond-
ing dimethylaminophosphines. These species appeared to be
the real ligands in the copper-catalyzed nucleophilic ring
7
as the ligand under similar experimental conditions,
confirming that 7 is the operating ligand in this transforma-
tion (entries 1 and 2). The chemical yield was improved using
ligand 7. No reaction occurred in the absence of copper salt,
(
14) Phosphoramidites 5 and 9a-d were prepared according to reported
procedures: (a) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen,
F.; Benhaim, C. Synlett 2001, 9, 1375. (b) Alexakis, A.; Polet, D.; Benhaim,
C.; Rosset, S. Tetrahedron: Asymmetry 2004, 15, 2199. (c) Monti, C.;
Gennari, C.; Piarulli, U. Tetrahedron. Lett. 2004, 45, 6859.
(15) In our hands, enantiomeric excess slightly differed from the ones
reported in ref 12. This could be explained by the fact that the authors in
some cases measured the ee after crystallization (see Supporting Information
of ref 12a), leading to uncontrolled enantiomeric enrichment.
Org. Lett., Vol. 8, No. 16, 2006
3583

opening of bicyclic hydrazines. This study shows that
extreme care is required when using phosphoramidite ligands
in conjunction with organometallic nucleophiles and that the
selectivities observed could result from an experimental
artifact.
supported by a French-Swiss “Germaine de Staels” pro-
gram.
Supporting Information Available: Analytical data for
all new compounds and NMR spectra of all synthesized
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. C.B. thanks the MRT for a grant. We
thank the CNRS for financial support. This work was
OL061471E
3584
Org. Lett., Vol. 8, No. 16, 2006