A Heterodinuclear asymmetric catalyst for conjugate additions of α-hydroxyketones to β-substituted nitroalkenes

Article abstract of DOI:10.1021/ol062485n

(Chemical Equation Presented) The bis-ProPhenol ligand was designed to facilitate formation of hetereodinuclear complexes based upon the large difference in pK_a of the one phenolic OH group to the tertiary OH groups. In exploring the first exam

Full text of DOI:10.1021/ol062485n

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6003-6005
A Heterodinuclear Asymmetric Catalyst
for Conjugate Additions of
r
-Hydroxyketones to â-Substituted
Nitroalkenes
Barry M. Trost* and Soleiman Hisaindee
Department of Chemistry. Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received October 9, 2006
ABSTRACT
The bis-ProPhenol ligand was designed to facilitate formation of hetereodinuclear complexes based upon the large difference in pKa of the
one phenolic OH group to the tertiary OH groups. In exploring the first example of hydroxyacetophenones as donors in asymmetric Michael
reactions with nitroalkene acceptors, the best stereocontrol was observed with a zinc/magnesium dinuclear complex where enantiomeric
excesses ranged up to 92% for the major anti diastereomer.
The development of heterodinuclear complexes for catalysis
remains a scantily developed area.1 Particularly noteworthy
is the work of Shibasaki using heteropolynuclear complexes
for asymmetric catalysis.2 Our design of the bis-ProPhenol
ligands3 (eq 1) was meant to enable formation of heterodi-
nuclear complexes by virtue of the large difference in pKa
between the phenolic and tertiary alcohol hydroxy groups.
We began our studies of the prospect of forming heterobi-
metallic complexes for asymmetric catalysis in the context
of asymmetric conjugate additions,4 particularly of nitroalk-
enes because of the synthetic versatility of the nitro group
and of the versatility of the adducts.5,6 The juxtaposition of
functionality created by the use of R-hydroxyacetophenones
as donors focused our efforts on them since they have not
previously been reported with this class of Michael acceptors
to the best of our knowledge.7 Herein, we report the first
(5) For reviews, see: (a) Berner, O. M.; Livio, T.; Enders, D. Eur. J.
Org. Chem. 2002, 1877. (b) Barrett, A. G. M.; Graboski, G. G. Chem. ReV.
1986, 86, 751. For some recent reports, see: (c) Pansare, S. V.; Pandya, K.
J. Am. Chem. Soc. 2006, 128, 9624. (d) Luo, S.; Mi, X.; Zhang, L.; Liu, S.;
Xu, H.; Cheng, J. P. Angew. Chem., Int. Ed. 2006, 45, 3093. (e) Zhu, M.-
K.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron:
Asymmetry 2006, 17, 491. (f) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S. J.
Am. Chem. Soc. 2006, 128, 7418. (g) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84. (h) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119. (i) Wang, W.; Wang, J.; Li, H. Angew. Chem.,
Int. Ed., 2005, 44, 1369. (j) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M.
Angew. Chem., Int. Ed. 2005, 44, 4212. (k) McCooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed., 2005, 44, 6367 and earlier references cited.
(6) Hydroxyacetone as a donor has frequently given poor selectivities
or requires large excesses and long reaction times. See: (a) Andrey, O.;
Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559. (b) Betancourt,
J.M.; Sakthrivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C.F. III
Synthesis 2004, 1509. (c) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V.
Synlett 2005, 611. (d) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460. (e)
Wang, J; Li, H.; Low, B.; Zu, L.; Guo, H.; Wang, W. Chem.sEur. J. 2006,
12, 4321.
(1) Van Den Beuken, E. K.; Feringa, B. L. Tetrahedron 1998, 54, 12985.
(2) Shibasaki, M.; Kanai, M.; Matsunaga, S. Adrichimica Acta 2006,
39, 31.
(3) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b)
Trost, B.M.; Ito, H.; Silcoff, E. J. Am. Chem. Soc. 2001, 123, 3367.
(4) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. For recent reviews on the catalytic
asymmetric Michael reaction, see: (b) Krause, N.; Hoffman-Ro¨der, A.
Synthesis 2001, 171. (c) Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033.
(d) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley: New York, 2000; p 569. (e) Tomioka, K.; Nagaoka,
Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1.
10.1021/ol062485n CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/01/2006

example wherein a heterodinuclear complex from 1 functions
as an asymmetric catalyst.
magnesium rather than zinc gave a faster reaction with
somewhat better diastereomeric ratio (dr) but poorer ee (entry
5). The ligand design which consists of one phenolic OH
and two tertiary alcohols should allow installation of two
different metals because of the dramatic difference in pKa
of these two types of OH. Since magnesium gave better dr’s
than zinc and zinc gave better ee’s, we examined a mixed
metal Zn/Mg system (entries 6-10) wherein we add 1 equiv
each of diethylzinc and di-n-butylmagnesium per ligand
sequentially. The best results to date were indeed obtained
with this mixed system in a more polar toluene/hexanes/
acetonitrile solvent wherein the anti isomer was isolated in
67% yield and the dr determined by isolation of each pure
diastereomer.
In a test reaction, 1.1 equiv of phenylnitroalkene and 1.0
equiv of R-hydroxyacetophenone (0.6 M in ketone) were
mixed with 5 mol % of the standard Zn-Zn catalyst (2a) in
the stated solvent at +5 °C (eq 1).
Adopting entry 10 as the “standard” set of conditions,
because it was fastest and gave the best yield and selectivities
with a 5 mol % catalyst loading, we varied the donor by
using five-membered ring heterocycles (eq 2).
As summarized in Table 1, entries 1-4, in virtually every
solvent, the anti products showed high enantiomeric excesses
(ee’s), whereas the syn products were formed with poor ee’s.
The best ee’s were observed in the least Lewis basic solvents.
Unfortunately, the diastereoselectivities were poor.
While the furan 7a gave excellent results, there was a
diminishment in the ee with the thiophene derivative 7b,
which may derive from the thiophilicity of zinc. The anti
isomers of 8a and 8b can be isolated in 70 and 53% yields,
respectively, and the dr’s can be determined by isolation.
Thus, both five- and six-membered ring aromatic donors are
good partners.
Table 2 summarizes the variation of the nitroalkene (eq
3) using the standard conditions with 5 mol % of catalyst to
give the adducts 9. In virtually every case, the dr’s are higher
than those of the 2-nitrostyrene case. Five-membered ring
heterocycles as well as ortho-substituted six-membered aryl
rings give good selectivities. Interestingly, even a conjugated
alkyne gave only the simple conjugate adduct with good
selectivity (entry 7).
Table 1. Optimization of the Selectivities
time yield
% ee
entry
RnMa
(C2H5)2Zn/(C2H5)2Zn PhCH3
(C2H5)2Zn/(C2H5)2Zn CH2Cl2 44
solventb (h) (%)c anti:syn antid
1
2
3
4
5
6
7
8
9
44
89 1.3:1.0 99e
64 1.1:1.0 99
77 1.0:1.0 89
98 1.0:1.4 90
91 1.6:1.0 32f
89 2.1:1.0 90g
63 1.4:1.0 82
71 2.3:1.0 91
93 2.5:1.0 91
96 2.4:1.0 89h
83 1.0:1.0 81
(C2H5)2Zn/(C2H5)2Zn THF
(C2H5)2Zn/(C2H5)2Zn DME
(C4H9)2Mg/(C4H9)2Mg THF
(C2H5)2Zn/(C4H9)2Mg THF
(C2H5)2Zn/(C4H9)2Mg PhCH3
44
44
18
28
42
(C2H5)2Zn/(C4H9)2Mg CH2Cl2 32
(C2H5)2Zn/(C4H9)2Mg DME 21
10 (C2H5)2Zn/(C4H9)2Mg CH3CN 14
11 (C2H5)2Zn/(CH3)3Al
12 (CH3)3Al/(C4H9)2Mg THF
THF
18
18
72
4
a In each case, 2 equiv of total organometallic reagent per ligand was
employed. b (C2H5)2Zn is 1.1 M in PhCH3; (C4H9)2Mg is 1.0 M in heptanes.
c Total of the isolated yields for pure anti and syn. The diastereomers were
isolated by column chromatography with the fast eluting diastereomer being
the syn isomer and the slow eluting isomer anti. d The ee’s were determined
by chiral HPLC on a Chiracel OD column. e The syn isomer had an ee of
18%. f The syn isomer had an ee of 9%. g The syn isomer had an ee of
23%. h The syn isomer had an ee of 25%.
The relative stereochemistry being anti as drawn was
established by X-ray crystallography of the product 9c. The
absolute stereochemistry was established as shown in eq 4
by direct reduction to the amino diol 10 followed by
oxidative cleavage.
While we also examined some variation of the ligand with
no appreciable differences in the result, we considered an
alternative strategy involving change of metal. Use of
(7) In a different catalyst system, requirements for an ortho methoxy
group in the hydroxyacetophenone have been reported for Michael additions
to other acceptors for good enantioselectivities. See: (a) Matsunaga, S.;
Kimoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 7559. (b) Harada, S. Kumagai, N.; Kinoshita, T.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2582.
This known 2-substituted â-amino acid8 11 had a rotation
6004
Org. Lett., Vol. 8, No. 26, 2006

Table 2. Variation of the Acceptora
Scheme 1. Proposed Catalytic Cycle
a All reactions were performed with 1.0 equiv of hydroxyketone and
1.1 equiv of nitroolefin in acetonitrile at +5 °C with 5 mol % of catalyst
prepared from 5 mol % of ligand 1, 5 mol % of (C2H5)2Zn, and 5 mol %
of (C4H9)2Mg. b Sum of isolated yields with isolated yield of major
diastereomer given in parentheses. c Determined by isolation of anti and
syn isomers.
for the observed selectivity. This represents the first example
of a heterodinuclear complex with this ligand in an asym-
metric catalytic reaction. The reactions reported herein only
need equimolar ratios of reactants and reaction times of 18-
42 h to generate a highly differentially functionalized adduct
that permits selective manipulation of the functionalities. The
utility of the juxtaposition of the functionality is demonstrated
by the one-step asymmetric synthesis of pyrrolidines. The
benefit demonstrated herein of using two different metals
with the chiral scaffold 1 stimulates the broad exploration
of various metals that may expand the scope of asymmetric
catalytic processes possible.
corresponding to the S-enantiomer as depicted. Thus, this
also serves as an asymmetric route to such â-amino acids.9
These adducts also serve as a convenient intermediate for
the asymmetric synthesis of pyrrolidines, such as 12 as
illustrated in eq 5.
The stereochemistry is assigned as all cis based upon the
observed NOE effects of the three methine hydrogens (Figure
1).
Acknowledgment. We thank the National Science Foun-
dation for support of this work. S.H. thanks NSERC for
partial support as a NSERC Fellow.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062485N
(8) Ponsinet, R.; Chassaing, G.; Lavielle, S. Tetrahedron: Asymmetry
1998, 9, 865.
Figure 1. NOE data for pyrrolidine 12.
(9) For some reviews, see: (a) Juaristi, E. In EnantioselectiVe Synthesis
of â-Amino Acids; Wiley-VCH: New York, 1997. (b) Liu, M. L.; Sibi, M.
P. Tetrahedron 2002, 58, 7991. (c) Park, K.-H.; Kurth, M. Tetrahedron
2002, 58, 8629. (d) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794.
(10) Xiao, Y.; Wang, Z.; Ding, K. Chem.sEur. J. 2005, 11, 3668.
Scheme 1 proposes a catalytic cycle based upon the X-ray
structure of the homodinuclear zinc complex10 that accounts
Org. Lett., Vol. 8, No. 26, 2006
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