Design and synthesis of modular oxazoline ligands for the enantioselective chromium-catalyzed addition of allyl bromide to ketones

Article abstract of DOI:10.1021/ja068915m

By systematically evaluating ligand diastereomers using a modular oxazoline template, a new ligand has been identified leading to the discovery of the first example of a chromium-catalyzed enantioselective allylation of ketones using allylic bromides. Cop

Full text of DOI:10.1021/ja068915m

Published on Web 02/20/2007
Design and Synthesis of Modular Oxazoline Ligands for the Enantioselective
Chromium-Catalyzed Addition of Allyl Bromide to Ketones
Jeremie J. Miller and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112
Received December 13, 2006; E-mail: sigman@chem.utah.edu
The catalytic asymmetric addition of allyl fragments to carbonyl
substrates has proven to be a powerful method for the synthesis of
enantiomerically enriched homoallylic alcohols.1 While many
successful variants of this transformation have been reported for
aldehyde allylation,2 only recently has carbonyl allylation been
extended to ketones. This is presumably due to the inherent
difficulty in differentiation of the enantiotopic faces of a ketone as
compared to those of an aldehyde. In recently reported examples,
a range of nucleophilic allyl sources can be used including boranes,3
stannanes,4 and silanes.5 However, there are no catalytic examples
using allylic halides,6 which are generally the synthetic precursors
to these nucleophilic allyl sources. Herein we report the discovery
of a chromium-catalyzed enantioselective ketone allylation reaction
where allylic bromides are used directly.
On the basis of our success using oxazoline ligands of type 1 in
the chromium-catalyzed enantioselective addition of allylic halides
to aldehydes (Nozaki-Hiyama-Kishi reaction),7 we chose to
explore this ligand template for enantioselective ketone allylation
reactions (Figure 1).8 These ligands contain an oxazoline, amide,
and proline module and can be readily synthesized using R-amino
acid derivatives allowing for rapid and systematic optimization of
the ligand structure.9 The optimal ligand for aldehyde allylation
1a was initially probed for ketone allylation using acetophenone
Figure 1. Evaluation of ligand diastereomers and truncation of the ligand
structure in the enantioselective allylation of acetophenone.
as the model substrate. Excitingly, a 68:32 enantiomeric ratio (ER)
of the tertiary alcohol product was observed (Figure 1, ligand 1a)
without modification to the original aldehyde allylation conditions.8
On the basis of our previous studies, we anticipated that the most
significant changes in enantiomeric ratio as a function of ligand
structure would be observed when altering ligand relative stereo-
chemistry. Therefore, all four diastereomers of ligand 1 were
synthesized and evaluated for acetophenone allylation. The relative
configuration of the chiral centers on the ligand has a significant
effect on the enantiomeric ratio and absolute configuration of the
product. Specifically, the configuration of the proline module
directly influences the facial selectivity of the reaction. For example,
comparing the use of ligand 1a versus 1c, where the proline
configuration is inverted, results in the opposite facial selection. A
similar effect is observed comparing ligands 1b and 1d, although
in this case, the configuration of proline remains constant and the
other two centers are inverted. In contrast, the chiral center on the
oxazoline ring only subtly impacts the enantioselective outcome.
For example, inverting the chiral center on the oxazoline module
in 1a as compared to 1d results in only a 4% ee difference. This
observation is intriguing considering the oxazoline substituent
dramatically effects both the absolute configuration and enantio-
meric ratio of the product in aldehyde allylation.8
derivative 3 and proline derivative 4 (Scheme 1). After peptide
coupling10 and nucleophilic addition of glycinol to the resulting
ester 5, oxazoline formation was accomplished under Mitsunobu-
type conditions.11 This synthetic sequence is significantly more
efficient than our previous method for synthesizing ligand 1a.8
To our delight, evaluation of the truncated ligand 2a revealed
an increase in the enantiomeric ratio of the acetophenone allylation
product (ER ) 91:9). The diastereomer of ligand 2a, ligand 2b,
was then synthesized and evaluated to obtain information on the
relative stereochemistry of the two chiral centers in the truncated
ligand framework. Again, the relative stereochemistry of the proline
and the amide modules had a considerable effect on the ER (2a,
91:9 vs 2b, 63.5:36:5).
Optimization of the catalyst system using ligand 2a and ac-
etophenone led to the use of 4 equiv of TMSCl,12 which increases
the isolated yield with no detrimental effects on ER. Lowering the
reaction temperature from room temperature to 0 °C enhanced the
ER to 96:4 (Table 1, entry 1). Using these optimal conditions, the
scope was evaluated. We found that aryl ketones are excellent
substrates for the transformation, as is highlighted by a 95% yield
and a 96:4 ER for the allylation of 2-acetonaphthone (entry 6).
The nature and placement of the substituent on the aryl ring has
little effect on the enantioselective outcome of the reaction (entries
2-6) though R-tetralone is a poor substrate using this system (entry
7). Additionally, halide-containing compounds are tolerated, provid-
ing an additional synthetic handle for further functionalization and
showcasing the chemoselective nature of the Nozaki-Hiyama-
Kishi reaction (entries 2, 9, and 10). As can be seen in entries 8-10,
Considering the present results from acetophenone allylation, it
was hypothesized that the oxazoline substituent is not an important
structural feature for affecting asymmetric induction. Therefore, a
truncated ligand, with the chiral center on the oxazoline module
removed, was synthesized in a three-step process starting with valine
9
2752
J. AM. CHEM. SOC. 2007, 129, 2752-2753
10.1021/ja068915m CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Synthesis of Truncated Ligand 2aa
allylic halides, methylallyl and crotylbromide, were successfully
added to acetophenone in similar enantiomeric ratios to that of allyl
bromide (entries 13 and 14). A modest diastereoselection is
observed for the addition of crotylbromide favoring the anti isomer
(3.8:1).
In summary, by using a modular catalyst design, key structural
features responsible for improving asymmetric induction were
systematically tested. Evaluating ligand relative stereochemistry
revealed that the oxazoline module had little effect on asymmetric
catalysis. Therefore, a truncated ligand was synthesized and found
to be highly effective for the first example of a chromium-catalyzed
enantioselective addition of allylic bromides to aryl ketones.
Currently, we are applying this approach to further explore and
understand the influence of systematic structural changes on
enantioselective outcomes and applying this knowledge to improv-
ing the scope of enantioselective ketone allylation as well as
investigating other synthetically useful transformations.
a Reagents and conditions: (a) isobutyl chloroformate, NMM, CH2Cl2
(95%); (b) glycinol, PhCH3/THF, reflux (95%); (c) PPh3, DIAD, CH2Cl2
(85%).
Table 1. Substrate Scope
Acknowledgment. This work was supported by the National
Science Foundation through a CAREER award to M.S.S. (CHE-
0132905). M.S.S. thanks the Dreyfus Foundation (Teacher-Scholar)
and Pfizer for their support.
Supporting Information Available: Ligand synthesis, catalytic
procedures, and enantiomeric excess determination. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews of enantioselective carbonyl allylation, see: (a) Yamamoto,
Y. Acc. Chem. Res. 1987, 20, 243-249. (b) Marshall, J. A. Chem. ReV.
1996, 96, 31-47. (c) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-
2793.
(2) For examples of enantioselective aldehyde allylation, see: (a) Costa, A.
L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am.
Chem. Soc. 1993, 115, 7001-7002. (b) Keck, G. E.; Tarbet, K. H.; Geraci,
L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468. (c) Yanagisawa, A.;
Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
4723-4724. (d) Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc.
2003, 125, 1140-1141. (e) Xia, G.; Yamamoto, H. J. Am. Chem. Soc.
2006, 128, 2554-2555.
(3) For examples of enantioselective ketone allylation using boranes, see: (a)
Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910-8911. (b) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem.
Soc. 2006, 128, 12660-12661.
(4) For examples of enantioselective ketone allylation using stannanes, see:
(a) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061-
1063. (b) Hamasaki, R.; Chounan, Y.; Horino, H.; Yamamoto, Y.
Tetrahedron Lett. 2000, 41, 9883-9887. (c) Kamble, R. M.; Singh, V.
K. Tetrahedron Lett. 2001, 42, 7525-7526. (d) Waltz, K. M.; Gavenonis,
J.; Walsh, P. J. Angew. Chem., Int. Ed. 2002, 41, 3697-3699. (e)
Cunningham, A.; Mokal-Parekh, V.; Wilson, C.; Woodward, S. Org.
Biomol. Chem. 2004, 2, 741-748. (f) Kim, J. G.; Waltz, K. M.; Garcia,
I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580-
12585. (g) Teo, Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743-
2745. (h) Liu, L.-Y.; Tang, L.; Yu, L.; Chang, W.-X.; Li, J. Tetrahedron
2005, 61, 10930-10934. (i) Lu, J.; Hong, M.-L.; Ji, S.-J.; Teo, Y.-C.;
Loh, T.-P. Chem. Commun. 2005, 4217-4218. (j) Wooten, A. J.; Kim, J.
G.; Walsh, P. J. Org. Lett. 2007, 9, 381-384.
(5) For examples of enantioselective ketone allylation using silanes, see: (a)
Tietze, L. F.; Schiemann, K.; Wegner, C. J. Am. Chem. Soc. 1995, 117,
5851-5852. (b) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 6536-6537. (c) Wadamoto, M.;
Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556-14557.
(6) For examples of stoichiometric enantioselective ketone allylations using
allylic halides, see: (a) Loh, T.-P.; Zhou, J.-R.; Li, X.-R. Tetrahedron
Lett. 1999, 40, 9333-9336. (b) Yamada, K.; Tozawa, T.; Nishida, M.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1997, 70, 2301-2308.
(7) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
a Average of at least two experiments. b Determined either by GC or
HPLC equipped with a chiral stationary phase. c Ethyl levulinate was used
as the ketone substrate.
(8) Lee, J.-Y.; Miller, J. J.; Hamilton, S. S.; Sigman, M. S. Org. Lett. 2005,
7, 1837-1839.
(9) Rajaram, S.; Sigman, M. S. Org. Lett. 2002, 4, 3399-3401.
(10) Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am. Chem. Soc.
1967, 89, 5012-5017.
(11) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267-6270.
(12) See Supporting Information for details.
changing the nature of the non-aryl substituent does not erode the
observed enantioselectivity and the highest ER is observed in
entry 8. In contrast, poor enantiomeric ratios are observed for
aliphatic ketones (entries 11 and 12) though it is important to
highlight that the facial selection in these cases is reversed.12 Other
JA068915M
9
J. AM. CHEM. SOC. VOL. 129, NO. 10, 2007 2753