Chiral amplification based on enantioselective dual-phase distribution of a scalemic bisoxazolidine catalyst

Article abstract of DOI:10.1021/ol070915j

A readily available bisoxazolidine ligand was found to catalyze the asymmetric alkylation of aldehydes with Et₂Zn and less reactive Me2Zn, providing high yields and ee's in both reactions. The bisoxazolidine-catalyzed alkylations and alkynylation of benzaldehyde show a positive nonlinear effect that cannot be accounted for by Kagan's ML_n model. The chiral amplification originates from selective phase distribution favoring enrichment of the major enantiomer of the scalemic catalyst in solution.

Full text of DOI:10.1021/ol070915j

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2965-2968
Chiral Amplification Based on
Enantioselective Dual-Phase Distribution
of a Scalemic Bisoxazolidine Catalyst
Shuanglong Liu and Christian Wolf*
Department of Chemistry, Georgetown UniVersity, Washington, DC 20057
cw27@georgetown.edu
Received April 19, 2007
ABSTRACT
A readily available bisoxazolidine ligand was found to catalyze the asymmetric alkylation of aldehydes with Et2Zn and less reactive Me2Zn,
providing high yields and ee’s in both reactions. The bisoxazolidine-catalyzed alkylations and alkynylation of benzaldehyde show a positive
nonlinear effect that cannot be accounted for by Kagan’s MLn model. The chiral amplification originates from selective phase distribution
favoring enrichment of the major enantiomer of the scalemic catalyst in solution.
The enantioselective alkylation of aldehydes with organozinc
reagents has emerged as one of the most extensively studied
carbon-carbon bond formations.1 This reaction produces
chiral secondary alcohols, which are popular synthetic
building blocks,2 and it is commonly used to test the potential
of new chiral ligand designs and high-throughput screening
methods.3 Numerous amino alcohols,4 diols,5 and diamine
derivatives6 that effectively catalyze the asymmetric addition
of diethylzinc to aldehydes are known. However, few
examples of reactions with dimethylzinc have been reported,
which can be partly attributed to its inherently low reactivity.7
We have recently introduced bisoxazolidine 1 and de-
monstrated the use of this new class of C2-symmetric
catalysts for asymmetric alkynylation of aldehydes.8 The
bisoxazolidine ligand can be prepared in a single step from
cis-1-amino-2-indanol and 1,2-cyclohexanedione in the pres-
ence of catalytic amounts of formic acid and is readily
available in both enantiomeric forms (Scheme 1). Compari-
son with mono-oxazolidines revealed that the N,O-diketal
structure is crucial for both catalytic activity and enantiose-
lectivity. We now report that bisoxazolidine 1 catalyzes the
asymmetric reaction of aldehydes with both Et2Zn and Me2-
Zn. Importantly, we found that the addition of saturated
organozinc and alkynylzinc reagents to benzaldehyde in the
presence of this catalyst proceeds with a positive nonlinear
(1) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
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5467-5480. (c) Trost, B. M.; Krische, M. J. J. Am. Chem. Soc. 1999, 121,
6131-6141. (d) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Org. Lett. 2000,
2, 2149-2152.
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Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028-4036. (c) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 9800-9809. (d) Wolf, C.; Hawes, P. A. J. Org.
Chem. 2002, 67, 2727-2729. (e) Kozlowski, M. C.; Dixon, S. L.; Panda,
M.; Lauri, G. J. Am. Chem. Soc. 2003, 125, 6614-6615. (f) Yoon, T. P.;
Jacobsen, E. N. Science 2003, 299, 1691-1693.
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Soc. 1986, 108, 6071-6072. (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa,
K. J. Am. Chem. Soc. 1987, 109, 7111-7115. (c) Wolf, C.; Francis, C. J.;
Hawes, P. A.; Shah, M. Tetrahedron: Asymmetry 2002, 13, 1733-1741.
(5) (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30,
1321-1323. (b) Harada, T.; Kanda, K. Org. Lett. 2006, 8, 3817-3819. (c)
Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org. Chem. 2006, 71, 6474-
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4842. (b) Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68, 7505-
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1989, 111, 4028-4036.
(8) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996-10997.
10.1021/ol070915j CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/30/2007

Optimization of catalyst loading and solvents showed that
the reaction proceeds in the presence of 2 mol % of
bisoxazolidine 1 using hexanes and toluene (4:1 v/v) as
solvent at room temperature. This procedure is suitable to
aldehydes bearing electron-donating and -withdrawing sub-
stituents, and the corresponding chiral alcohols were isolated
in up to 99% yield and 96% ee (entries 2-11).
Scheme 1. Synthesis of Bisoxazolidine (+)-1 from
(1R,2S)-Aminoindanol and 1,2-Cyclohexanedione
Despite the excellent results generally obtained with Et2Zn,
this reaction often proceeds with unsatisfactory yield and
enantioselectivity when Me2Zn is used.9 Significant progress
has been achieved with chiral chromium,10 titanium,11 and
osmium12 complexes, but the development of a methylation
method that resembles the high yield, enantioselectivity, and
operational simplicity of ligand-catalyzed Et2Zn addition is
still desirable. We were pleased to find that the use of 5
mol % of 1 in apolar solvents provides a viable alternative
when aromatic aldehydes are employed (Figure 1). Our
effect that originates from an unexpected solid-liquid phase
behavior which cannot be accounted for by Kagan’s MLn
model.
Encouraged by the high yields and enantiomeric excess
of propargylic alcohols obtained by bisoxazolidine-catalyzed
alkynylation of aldehydes, we decided to employ 1 in the
reaction of diethylzinc with several aldehydes (Table 1).
Table 1. Bisoxazolidine-Catalyzed Asymmetric Addition of
Et2Zn to Aldehydes.
Figure 1. Structures of chiral alcohols obtained by bisoxazolidine-
catalyzed addition of Me2Zn to aldehydes.
method affords 1-phenylethanol, 4a, in 92% yield and 88%
ee, and similar results were obtained with other aromatic
aldehydes. Bisoxazolidine-catalyzed ethylation and methyl-
ation of cyclohexcanecarboxaldehyde, 21, furnished alcohols
3l and 4h in high yields and ee’s, but alkylation of linear
aldehydes showed only moderate enantioselectivity (entry
12 in Table 1, Figure 1, and Supporting Information).
Following the seminal work from Oguni’s and Noyori’s
groups, many examples of positive deviations from a linear
relationship between the enantiopurity of chiral amino
alcohols or other precatalysts and the enantiomeric excess
of 1-arylpropanols obtained by asymmetric addition of
(9) (a) Prieto, O.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2000,
11, 1629-1644. (b) Dangel, B. D.; Polt, R. Org. Lett. 2000, 2, 3003-
3006. (c) Yus, M.; Ramon, D. J.; Oscar, P. Tetrahedron: Asymmetry 2002,
13, 1573-1579. (d) Garcia-Delgado, N.; Fonts, M.; Pericas, M. A.; Riera,
A.; Verdaguer, X. Tetrahedron: Asymmetry 2004, 15, 2085-2090. (e)
Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem. 2004, 69, 6666-
6673.
(10) Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940-
4941.
(11) (a) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron 1998,
54, 8275-8319. (b) Blay, G.; Fernandez, I.; Hernandez-Olmos, V.; Marco-
Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, 1953-
1958.
a Isolated yields. b Determined by HPLC on Chiralcel OD, OB-H, and
Chiralpak AD. c Determined by GC on octakis(6-O-methyl-2,3-di-O-pentyl)-
γ-cyclodextrin.
(12) Muniz, K. Tetrahedron Lett. 2003, 44, 3547-3549.
2966
Org. Lett., Vol. 9, No. 16, 2007

diethylzinc to aromatic aldehydes have been reported.7,13 This
positive nonlinear effect (NLE) has been explained by
predominant formation of thermodynamically favored, het-
erochiral zinc complexes in solution. The organozinc adduct
of the minor enantiomer is thus trapped in a catalytically
inactive form while the surplus of the organozinc adduct of
the major enantiomer is available to catalyze the reaction.
Because heterochiral recognition and association generates
an enantiomerically enriched or enantiopure monomeric
catalytic species, the enantiomeric excess of the reaction
product can exceed the ee of the precatalyst employed.14
Positive and negative nonlinear effects have been observed
in a variety of asymmetric reactions and are generally
explained with Kagan’s MLn model, which is based on the
assumption that a scalemic catalyst is in equilibrium with
homochiral and heterochiral adducts exhibiting different
catalytic activity.15
a mixture containing (+)-1 in 50% ee in toluene and hexanes
(1:4 v/v) for 12 h. The precipitate was isolated, and the
enantiomeric composition of 1 in the solid state and in
solution was determined.
Unfortunately, screening of several HPLC columns did
not provide a chromatographic method for direct enantio-
separation of 1. We therefore decided to subject the bis-
oxazolidine mixtures to hydrolysis and derivatization to
afford N-t-Boc-aminoindanol 7, which can be resolved by
chiral HPLC on Chiralcel OD (Scheme 2). Gravimetric and
Scheme 2. Hydrolysis and Derivatization of Ligand 1 for
Chiral HPLC Analysis
Analysis of the enantioselective alkylation of benzaldehyde
with diethylzinc in the presence of scalemic mixtures of 1
revealed a positive nonlinear effect (Figure 2). For example,
chromatographic analysis showed that the crystalline material
was almost racemic and corresponded to 47% of the
originally used bisoxazolidine. By contrast, the supernatant
contained the remaining 53% of 1 in 89% ee.16 The same
results were obtained when the experiment was conducted
in the presence of 150 equiv of diethylzinc. Upon mixing of
solutions containing a large excess of Et2Zn and either
enantiopure (+)-1 or (-)-1 to afford 50% ee, a precipitate
formed which contained nearly racemic 1 (4.5% ee) but no
trace of Et2Zn. NMR analysis of mixtures of 1 and Me2Zn
revealed that complexation occurs without concomitant
deprotonation. This shows that 1 is not a precatalyst and
unlike amino alcohols does not require 1 equiv of R2Zn to
form a catalytically active species.17 Accordingly, alkylation
of 2a proceeds with high yield and enantioselectivity when
equimolar amounts of 1 and Et2Zn are used; see the
Supporting Information.
Figure 2. Nonlinear effects in the bisoxazolidine-catalyzed enan-
tioselective ethylation, methylation, and alkynylation of benzalde-
hyde with organozinc reagents (from left to right). See the
Supporting Information for reaction conditions.
Apparently, the positive nonlinear effect observed in the
bisoxazolidine-catalyzed reaction between benzaldehyde and
diethylzinc is a result of the inherently low solubility of
racemic 1 in apolar organic solvents. This unexpected solid-
liquid phase behavior of scalemic 1 selectively increases the
purity of the major enantiomer in solution and gives rise to
a positive NLE that cannot be described by Kagan’s MLn
model.18 In our case, chiral amplification originates from
thermodynamically controlled crystallization of racemic 1,
whereas the enantiomeric surplus remains in solution and is
available for asymmetric catalysis (Scheme 3). As expected,
no NLE was observed when the reaction was carried out in
toluene and dichloromethane (1:1 v/v) because racemic 1 is
soluble in this solvent mixture (Figure 2).
1-phenylpropanol is obtained in 94% yield and 96% ee in
the presence of 2 mol % of 1 having 50% ee. During our
studies, we noticed that the solubility of the ligand signifi-
cantly decreases as the enantiopurity of the bisoxazolidine
is reduced. When scalemic 1 was used, the catalyst could
not be fully dissolved, and we suspected that this might
account for the NLE observed. We found that the solubility
of enantiopure 1 in toluene and hexanes (1:4 v/v) is 10.5
mg/mL, whereas only 1.4 mg/mL of racemic 1 dissolves in
the same solvent mixture. To prove our hypothesis, we stirred
(13) (a) Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988,
110, 7877-7878. (b) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49-69.
(14) Kagan, H. B. AdV. Synth. Catal. 2001, 343, 227-233.
(15) (a) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108, 2353-2357. (b) Mikami, K.; Motoyama,
Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812-2820. (c) Evans, D.
A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell,
B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685. (d) Chen, Y.
K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc. 2001, 123, 5378-5379.
(e) Yuan, Y.; Li, X.; Sun, J.; Ding, K. J. Am. Chem. Soc. 2002, 124, 14866-
14867. (f) Qin, Y.-C.; Liu, L.; Pu, L. Org. Lett. 2005, 7, 2381-2383. (g)
Reetz, M. T.; Meiswinkel, A.; Mehler, G.; Angermund, K.; Graf, M.; Thiel,
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10313.
To date, only a few examples of enantioenrichment of
chiral catalysts and chiral amplification based on solid-
(16) The ee of the precipitate was determined as 6%. We found that the
ee of the solid formed decreases further when the precipitate is washed
more thoroughly, but less material is recovered in these cases.
(17) Organozinc reagents have been reported to not deprotonate secondary
amino groups. See ref 4c.
(18) (a) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108, 2353-2357. (b) Girard, C.; Kagan, H.
B. Angew. Chem. Int. Ed. 1998, 37, 2922-2959.
Org. Lett., Vol. 9, No. 16, 2007
2967

Scheme 3. Enantioenrichment and Solid-Liquid Phase
Behavior of Scalemic 1 Resulting in a Positive Nonlinear Effect
Figure 3. Single-crystal structure of racemic 1.
solution equilibration have been reported.19 Bolm et al.
observed precipitation of a heterochiral meso zinc complex
upon treatment of a bipyridine-derived precatalyst exhibiting
50% ee with 5 equiv of diethylzinc.20 A small amount of
the major enantiomer was found to be enriched to 84% ee
in solution while the precipitate contained 74% of the ligand
in 44% ee. Importantly, the enantioenrichment of bisoxazo-
lidine 1 does not require the presence of a reagent or chiral
additive, and we therefore anticipated that the unique solid-
liquid-phase behavior of scalemic 1 would also afford a
positive NLE in other reactions. In fact, precipitation of
racemic ligand resulting in chiral amplification was observed
when scalemic mixtures of bisoxazolidine 1 were applied in
the methylation and alkynylation of benzaldehyde following
a previously reported procedure (Figure 2 and Supporting
Information).8
Slow evaporation of a diluted solution of (+)-1 exhibiting
50% ee in toluene and hexanes produced a single-crystal
suitable to X-ray diffraction; see the Supporting Information
for details. In accordance with our findings that racemic 1
is significantly less soluble than the enantiopure form,
crystallographic analysis confirmed formation of racemic
single crystals while conglomerates were not observed
(Figure 3). The melting point ranges of enantiopure and
racemic 1 were determined as 135-137 °C and 208-210
°C, respectively. Noteworthy, many attempts to grow a single
crystal from a solution of enantiopure 1 in toluene and
hexanes were unsuccessful, while racemic crystals were
easily prepared from scalemic mixtures in the same solvents.
It is quite possible that enantioenrichment of chiral catalysts
and nonlinear effects due to formation of a thermodynami-
cally favored racemic crystal lattice is a common phenom-
enon when asymmetric reactions are carried out in biphasic
systems. Our studies coincided with Blackmond’s recent
findings that enantioenrichment of proteinogenic amino acids
and chiral amplification observed in proline-mediated aldol-
type reactions are directly related to the phase behavior of
the catalyst and may explain the evolution of biomolecular
homochirality in Nature.21 A clear distinction between
nonlinear effects that originate from a physical phase
behavior similar to that of bisoxazolidine 1 and chiral
amplification that can be explained by Kagan’s MLn model
is important, in particular, when NLEs are used as mecha-
nistic probes.22
In conclusion, bisoxazolidine 1 has been successfully
applied in the catalytic asymmetric alkylation of aldehydes
with organozinc reagents. The high yield, enantioselectivity,
and operational simplicity generally encountered in nucleo-
philic additions of Et2Zn to aromatic aldehydes has been
extended to less reactive Me2Zn. The bisoxazolidine-
catalyzed alkylation and alkynylation of benzaldehyde
studied show a positive nonlinear effect that is not related
to the reaction mechanism but a result of a dual-phase
behavior favoring enrichment of the major enantiomer of
scalemic 1 in solution. This enantioselective phase distribu-
tion does not require the presence of any additives, and
stereochemical and crystallographic analysis confirmed that
the chiral amplification originates from crystallization of
racemic 1. These observations cannot be accounted for by
Kagan’s model, and it is possible that our results have
important implications for the interpretation of nonlinear
effects obtained with other catalytic systems.
Supporting Information Available: Synthetic proce-
dures, NLE analysis, X-ray diffraction data and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070915J
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Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621-
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G. Angew. Chem., Int. Ed. 2006, 45, 7985-7989. (c) Klussmann, M.;
Mathew, S. P.; Iwamura, H.; Wells, D. H., Jr.; Armstrong, A.; Blackmond,
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