Asymmetric cyclopropanation catalyzed by C2-symmetric bi(oxazolines)

Article abstract of DOI:10.1016/S0040-4039(99)02220-0

C₂-symmetric bi(oxazolines) 3a-e were prepared in three steps based on a tartaric-derived vicinal diamine as common precursor. These chiral ligands were studied with respect to their directive influence on the enantioselective copper catalyzed

Full text of DOI:10.1016/S0040-4039(99)02220-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1023–1026
Asymmetric cyclopropanation catalyzed by C2-symmetric
bi(oxazolines)
Rachel Boulch,a Andreas Scheurer,a,b Paul Mosset a,∗ and Rolf W. Saalfrank b,∗
aLaboratoire de Synthèses et Activations de Biomolécules, Ecole Nationale Supérieure de Chimie de Rennes et CNRS,
Avenue du Général Leclerc, F-35700 Rennes, France
bInstitut für Organische Chemie der Universität Erlangen-Nürnberg, Henkestraße 42, D-91054 Erlangen, Germany
Received 21 October 1999; accepted 26 November 1999
Abstract
C2-symmetric bi(oxazolines) 3a–e were prepared in three steps based on a tartaric-derived vicinal diamine as
common precursor. These chiral ligands were studied with respect to their directive influence on the enantioselec-
tive copper catalyzed cyclopropanation of 1,1-diphenylethylene and styrene. The highest enantioselectivities (79%
ee) were achieved with bi(oxazoline) 3e, bearing bulky adamantyl groups even using commercial CuOTf. The
presence of desiccants such as molecular sieves or magnesium sulfate was found to be crucial for high yields and
reproducibility. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric reactions; copper; copper compounds; cyclopropanation; alkenes.
Within the last decade, numerous spectacular advances in the field of asymmetric catalysis have been
reported. For instance, metal complexes of chiral oxazolines and particularly C2-symmetric bisoxazo-
lines, proved to be efficient stereoselective catalysts for a wide range of reactions. Prominent examples are
the metal complexes of bisoxazolines 1 and 2 with methylene or 2,6-pyridinediyl spacer groups (Scheme
1).1 Typically, the chiral oxazolines were prepared from enantiomerically pure aminoalcohols, generated
from the corresponding α-amino acids. In this context, we were interested in other C2-symmetric ligands
such as bi(oxazolines) 3 derived from tartaric acid. While literature bisoxazolines such as 1 and 2 required
the distinct chiral aminoalcohol for their preparation, great benefit can be drawn from the fact that the
structure of bi(oxazolines) 32 can be easily modulated. In order to test the influence of the R group on
the stereoselectivity of the copper-catalyzed asymmetric cyclopropanation of alkenes, a series of such
ligands was prepared and the bi(oxazolines) 3a–e (Scheme 2) proved to be the most representative.
Although Pfaltz et al. briefly reported the use of 3a as ligand for this reaction,3 we found that the new
bi(oxazoline) 3e4 with bulky adamantyl groups afforded noticeably better enantioselectivities. Herein,
we also report that the addition of a desiccant was found to be crucial.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02220-0
tetl 16148

1024
Scheme 1.
As shown previously, L-tartaric acid 4 can easily be transformed to (2S,3S)-1,4-bis(benzyloxy)-2,3-
diaminobutane 5.5 Starting from this vicinal diamine, bi(oxazolines) 3a–e were prepared efficiently via a
three-step sequence using known methodology: amidation, debenzylation6 and cyclization7 (Scheme 2).
It is noteworthy that easy modulation of the R group was realized at the amidation step by use of RCO2H
or RCOCl.
Scheme 2. a: R=tert-butyl, b: R=cyclohexyl, c: R=phenyl, d: R=2,6-dichlorophenyl, e: R=1-adamantyl. Reagents, conditions
and yields. (i) Method A: NEt3 (4 equiv.), RCOCl (3 equiv.), CH2Cl2, 3 h, 0°C, 81% for 6a, 85% for 6c, 79% for 6d. Method B:
DMAP (0.4 equiv.), DCC (3.2 equiv.), RCO2H (2.6 equiv.), CH2Cl2, 16 h, ca. 20°C, 88% for 6b, 87% for 6e. (ii) BCl3·Me2S
(8 equiv.), CH2Cl2, −40°C and then 6 h, ca. 20°C, 83% for 7a, 80% for 7b, 85% for 7c, 85% for 7d, 91% for 7e. (iii) MsCl
(2.4 or 2.8 equiv.), NEt3 (6 equiv.), DMF for 7b or THF for 7a and 7c–e, 0°C and then 16 h, ca. 20°C followed by 20% aqueous
NaOH, 30 min, 87% for 3a, 3b, 3c and 3e, 82% for 3d
Initially, catalytic cyclopropanation experiments of 1,1-diphenylethylene 8 with ethyl diazoacetate 9
afforded only low yields of cyclopropane (S)-10, probably due to traces of water. Therefore, several
desiccants such as CaSO4 and MgSO4 were tested and the highest yields were obtained with a molecular
sieve (3Å MS). Consequently, the cyclopropanation of 1,1-diphenylethylene 8 with ethyl diazoacetate 9
was performed by addition of 2 mol% of the chelates formed from Cu(I)-triflate and the bi(oxazolines)
3a–e and optimized in the presence of the molecular sieve.8,9 The reaction is basically temperature-
and solvent-independent. The stereoselectivity could not be improved by the use of more hindered
diazoacetates.
In summary, the best chemical yields and the highest ee values for cyclopropane (S)-10 were achieved
with the adamantyl substituted bi(oxazoline) 3e (Table 1).
Cyclopropanation of styrene 11 with ethyl diazoacetate 9, 2 mol% of Cu-catalyst [CuOTf,
bi(oxazolines) 3a–e] and molecular sieve lead to mixtures of cis- and trans-ethyl cyclopropane
carboxylates (1S,2R)-12 and (1S,2S)-13 (Table 2).9
Again, the highest ee values for cyclopropanes (1S,2R)-12 and (1S,2S)-13 were obtained with the
adamantyl substituted bi(oxazoline) 3e however with moderate chemical yield (Table 2). The major
enantiomers of 10, 12 and 13 obtained with bi(oxazolines) 3a–e were of opposite absolute configuration
compared to those obtained with bisoxazoline 1 [except for 12 in the case of bi(oxazoline) 3b].
Furthermore, in contrast to reported results,1 we obtained higher amounts of the cis-isomer 12.10 In
the case of the bi(oxazolines) 3a and 3b, 12 was even the major product. Finally, it is noteworthy that
these results were obtained with commercial CuOTf. In contrast, the use of freshly prepared CuOTf
in asymmetric cyclopropanation reactions with bisoxazolines such as 1 and 2 seems to be an essential
prerequisite to obtain good results.

1025
Table 1
Influence of bi(oxazoline) structure on the enantioselectivity of the copper-catalyzed asymmetric
cyclopropanation of 1,1-diphenylethylene 8 with ethyl diazoacetate 9
Table 2
Diastereoselectivities and enantioselectivities of the asymmetric cyclopropanation of styrene 11 with
ethyl diazoacetate 9 catalyzed by CuOTf and bi(oxazolines) 3a–e
In conclusion, the C2-symmetric bi(oxazolines) 3a–e, derived from L-tartaric acid, present markedly
different reactivities in the asymmetric copper-catalyzed cyclopropanation compared with the bisoxazo-
lines 1 and 2. The highest enantioselectivities were obtained with adamantyl substituted bi(oxazoline) 3e
in the presence of a desiccant even with commercial grade reagents.

1026
Acknowledgements
Financial support by CNRS, MENRT and DFG is gratefully acknowledged for grants respectively to
R.B. and A.S. Dr. R. Grée is thanked for helpful discussions.
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9. A typical experimental procedure for the asymmetric cyclopropanation: CuOTf.1/2 C6H6 (0.02 mmol, purchased from Fluka)
was complexed by a bi(oxazoline) 3 (0.03 mmol) in anhydrous CH2Cl2 (3.4 mL) (1 h, rt). The resulting filtered solution was
transferred to alkene 8 or 11 (7.9 mmol) and additive (1 g) in CH2Cl2 (1 mL). A solution of ethyl diazoacetate (1 mmol) in
CH2Cl2 (1 mL) was added during 5 h at 0°C and stirring was continued for 16 h at ca. 20°C.
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