Stereochemical diversity in chiral ligand design: Discovery and optimization of catalysts for the enantioselective addition of allylic halides to aldehydes

Article abstract of DOI:10.1021/ol050528e

(Chemical Equation Presented) We have identified a new set of stereochemically diverse oxazoline ligands derived from simple amino acids that promote the Cr-catalyzed enantioselective addition of allylic halides to aldehydes in up to 95% ee. The Cr-cataly

Full text of DOI:10.1021/ol050528e

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1837-1839
Stereochemical Diversity in Chiral
Ligand Design: Discovery and
Optimization of Catalysts for the
Enantioselective Addition of Allylic
Halides to Aldehydes
Jae-Young Lee, Jeremie J. Miller, Steven S. Hamilton, and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112-085
sigman@chem.utah.edu
Received March 10, 2005
ABSTRACT
We have identified a new set of stereochemically diverse oxazoline ligands derived from simple amino acids that promote the Cr-catalyzed
enantioselective addition of allylic halides to aldehydes in up to 95% ee. The Cr-catalyzed allylation using ligand 1d is rather insensitive to the
nature of the allylic bromide (crotyl, allyl, and methallyl) in that >90% ee is observed for all three bromides evaluated in the addition to
benzaldehyde.
The versatility of Cr(II)-mediated carbon-carbon bond
formation in target-oriented and diverse chiral building block
synthesis provides for a compelling target in asymmetric
catalysis.1 The foundation for the development of such
catalytic systems was provided by Fu¨rstner and Shi when
they reported a method to render Cr(II)-mediated processes
catalytic in Cr with Mn(0) as the reductant and trimethylsilyl
chloride as the turnover agent.2 Since then, several enantio-
selective Cr(II)-catalyzed reactions have been reported with
variable success.3,4 Herein, we report a set of new catalysts
for the chromium-catalyzed enantioselective addition of allyl
fragments to aldehydes5 (Nozaki-Hiyama reaction) in which
ligand stereochemical diversity plays a vital role in catalyst
optimization.
(3) For salen-based systems, see: (a) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 1999, 38, 3357-
3359. (b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Chem. Commun.
2002, 919-927 and references therein. (c) For an application, see:
Lombardo, M.; Licciulli, S.; Morganti, S.; Trombini, C. Chem. Commun.
2003, 1762-1763. (d) Berkessel, A.; Menche, D.; Sklorz, C. A.; Schro¨der,
M.; Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032-1035. (e) Berkessel,
A.; Schro¨der, M.; Sklorz, C. A.; Tabanella, S.; Vogl, N.; Lex, J.; Neudo¨rfl,
J. M. J. Org. Chem. 2004, 69, 3050-3056. For an application, see: Paterson,
I.; Bergmann, H.; Menche, D.; Berkessel, A. Org. Lett. 2004, 6, 1293-
1295.
(4) For oxazoline-based systems, see: (a) Choi, H.-W.; Nakajima, K.;
Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett. 2002,
4, 4435-4438. (b) Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc.
2003, 125, 1140-1141. (c) Using modified catalytic conditions (Zr(Cp)2Cl2
instead of TMSCl), see: Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031-
5033. (d) For propargylation, see: Inoue, M.; Nakada, M. Org. Lett. 2004,
6, 2977-2980.
(1) For reviews, see: (a) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
(b) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1-36. (c) Nozaki, H.;
Takai, K. Proc. Jpn. Acad. 2000, 76, 123-131.
(2) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533-2534.
(b) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349-12357.
10.1021/ol050528e CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/24/2005

Recently, we disclosed the synthesis of a modular amine-
functionalized oxazoline core that incorporates stereochem-
ical diversity from naturally available chiral sources (Figure
1).6,7 The diversity is controlled by the introduction of up to
Figure 1. Modular approach to new oxazoline-based ligands.
three chiral centers on the core as well as derivatives off the
free amine group. Initial evaluation of ligands incorporating
a variety of capping groups for the Cr(II)-catalyzed addition
of allyl bromide to benzaldehyde revealed that proline amides
lead to excellent reactivity and measurable enantioselectivity.
After initial optimization of ligand substituents,8 ligand 1,
which is derived from phenylalanine, valine, and proline,
was found to be the most promising (Figure 2). Previous
studies on C1-symmetric ligands have shown that the relative
stereochemical orientations of the chiral elements play an
important role in enantioselection.9 Therefore, a complete
set of diastereomers of ligand 1 were synthesized and
evaluated for the allylation of benzaldehyde (Figure 2, entries
1-4). Ligand diastereomer 1d led to the best catalytic system
for the Cr(II)-catalyzed addition of allyl bromide to benzal-
dehyde, giving a 92% ee in 95% isolated yield (Figure 2,
entry 4). Other allylic halides led to poorer results in
allylation (entries 5 and 6). It is important to note that
changing the catalyst diastereomer has a profound effect on
the reaction outcome and is showcased in the evaluation of
ligand 1c where the facial selection is completely reversed
to give the product in 89% ee and a diminished yield (entry
3).
Figure 2. Identification and optimization of oxazoline-amide
ligands.
1, entries 7 and 8) and a 94% ee for 2-naphthaldehyde (entry
9). Additionally, an R,â-unsaturated aldehyde also proves
to be a good substrate for allylation with cinnamaldehyde
Table 1. Substrate Scope
To probe the initial scope of the allylation reaction, two
optimized procedures were established: (A) using catalytic
CrCl2 or (B) using catalytic CrCl3, a much easier to handle
and considerably cheaper source of Cr. Both cases led to
consistent reaction outcomes with little variation in observed
enantioselectivity. Aryl aldehydes prove to be excellent
substrates highlighted by a 92% ee for furylaldehyde (Table
(5) For reviews on asymmetric allylation, see: (a) Denmark, S. E.; Fu,
J. Chem. ReV. 2003, 103, 2763-2793. (b) Yanagisawa, A. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, pp 965-979.
(6) Rajaram, S.; Sigman, M. S. Org. Lett. 2002, 4, 3399-3401.
(7) For examples of the use of oxazoline amine cores in asymmetric
catalysis, see: (a) Pastor, I. M.; Adolfsson, H. Tetrahedron Lett. 2002, 43,
1743-1746. (b) Wipf, P.; Wang, X. Org. Lett. 2002, 4, 1197-1200. (c)
McManus, H. A.; Barry, S. M.; Andersson, P. G.; Guiry, P. J. Tetrahedron
2004, 60, 3405-3416.
a Method A: 5 mol% CrCl2, 10% 1d, 10 mol% TEA. Method B: 10
mol% CrCl3, 10 mol% 1d, 15 mol% TEA. b See Supporting Information
for enantiomeric excess and absolute configuration determination.
(8) See Supporting Information for details.
(9) For an example, see: Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 4901-4902.
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Org. Lett., Vol. 7, No. 9, 2005

leading to a 89% ee (entry 10). Mixed results are observed
for allylation of aliphatic aldehydes, with 2g and 2i leading
to poorer ee’s (entries 12, 13, and 16). To test if this is related
to the ligand structure, all ligand diastereomers were tested
for the allylation of 2g, with the results mimicking the
allylation results observed for benzaldehyde.10 However,
R-substitution on the aliphatic aldehyde leads to a significant
enhancement of enantioselectivity, with substrate 2h giving
89% ee (entries 14 and 15) and substrate 2j giving 77% ee
(entry 17). Of additional note, a reversal of facial selectivity
occurs for the aliphatic substrates 2i and 2j. In most cases,
good to excellent yields of the homoallylic alcohol are
observed.
for both diastereomers with 95% ee for the syn and 91% ee
for the anti diastereomer.8 To the best of our knowledge,
the observed enantiomeric excesses for each diastereomer
are the highest to date in an asymmetric crotylation using a
Cr(II)-based system. The same sense of aldehyde facial
selection is observed in both products. The relatively low
diastereoselection points toward an open transition state12
leading to a variety of intriguing mechanistic scenarios,
including bimetallic processes where both Cr and Mn may
play a role.13,14
In summary, we have identified a new set of stereochemi-
cally diverse oxazoline ligands derived from simple amino
acids that promote the Cr-catalyzed enantioselective addition
of allylic halides to aldehydes in up to 95% ee. The ligand
stereochemistry plays a vital role in the identification of the
optimal catalyst. Both aromatic and R-substituted aliphatic
aldehydes are excellent substrates for the enantioselective
addition. Crotylation of benzaldehyde leads to an anti to syn
ratio of 2.3 to 1 and >90% ee for both diastereomers. Of
additional note, the Cr-catalyzed allylation using ligand 1d
is rather insensitive to the nature of the allylic bromide
(crotyl, allyl, and methallyl) in that >90% ee is observed
for all three bromides evaluated. Elucidating the mechanistic
details of this complicated reaction, enhancing the diaste-
reoselection of aldehyde crotylation, and application of this
new, modular ligand class to other catalytic asymmetric
transformations are subjects of current and future research.
To further explore the substrate scope, methallyl bromide
and trans-crotyl bromide were evaluated as substrates in the
allylation of benzaldehyde (Scheme 1). The addition of
Scheme 1. Cr-Catalyzed Addition of Other Allylic Halides to
Benzaldehyde
Acknowledgment. This work was partially supported by
the National Science Foundation through a CAREER award
to M.S.S. (CHE-0132905). We thank Eri Yoshida for initial
ligand screening. M.S.S. thanks the Dreyfus foundation
(Teacher-Scholar) and Pfizer for their support.
Supporting Information Available: Catalyst optimiza-
tion, ligand synthesis, catalytic procedures, and enantiomeric
excess determination. This material is available free of charge
via the Internet at http://pubs.acs.org.
methallyl bromide proceeded smoothly leading to 4 in 91%
ee and 81% isolated yield. When using trans-crotyl bromide
for the crotylation of benzaldehyde, the observed diastereo-
selectivity of the crotylation is relatively low with a 2.3:1
ratio favoring the anti-product. This low diastereoselectivity
is similar to all reported asymmetric crotylations using
Fu¨rstner/Nozaki-Hiyama conditions.11 In contrast to these
reports, this crotylation leads to high enantiomeric excess
OL050528E
(12) When ligand-less conditions are utilized, Nakada4b and Fu¨rstner2a
see significantly higher anti:syn ratios consistent with a closed-transition
state.
(13) Cozzi and co-workers propose a bimetallic mechanism where Cr
and Mn salen derivatives are involved. See ref 3b for details.
(14) Use of (E)-crotyl bromide with Mn-graphite in the addition to
benzyaldehyde has been reported. The diastereoselectivity is 64:36 anti:
syn. See: Fu¨rstner, A.; Brunner, H. Tetrahedron Lett. 1996, 37, 7009-
7012.
(10) 1a, 24% ee (S); 1b, 4% ee (R); 1c, 1% ee (S); 1d, 48% ee (R).
(11) Enantiomeric excess was determined by GC analysis of the methyl
ether. Absolute configuration was determined by Mosher ester analysis.
Org. Lett., Vol. 7, No. 9, 2005
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