Angewandte
Chemie
DOI: 10.1002/anie.201203092
Asymmetric Catalysis
Catalytic Asymmetric Claisen Rearrangement of Enolphosphonates:
Construction of Vicinal Tertiary and All-Carbon Quaternary Centers**
Jiajing Tan, Cheol-Hong Cheon, and Hisashi Yamamoto*
The development of a one-step catalytic method for the
enantioselective construction of contiguous tertiary and all-
carbon quaternary centers is a challenging task but of great
significance.[1,2] Among the limited number of available
approaches for the assembly of such sterically congested
structures by a single transformation, the Claisen rearrange-
rangement reactions (Scheme 1). Importantly, the corre-
sponding products, a-ketophosphonates, are well-known as
one of the most synthetically useful phosphorous motifs and
could undergo various transformations with ease and effi-
ciency.[9] Herein, we are glad to report the first catalytic
enantioselective Claisen rearrangement of enolphosphonates
À
ment, well-known as one of the most effective carbon
carbon bond-formation strategies, has shown promise.
Since its discovery one century ago,[3] the Claisen rear-
rangement has become a powerful method widely used by
synthetic organic chemists.[4] Despite many efforts made in
this field, the development of the catalytic asymmetric
Claisen rearrangement is still in the early stages. Until now,
only Hiersemannꢀs copper[5] and Jacobsenꢀs hydrogen- Scheme 1. Claisen rearrangement of enolphosphonates.
bonding catalysts[6] have been applied to catalytic versions
of asymmetric Claisen rearrangement. Both of these
methods are excellent but rely heavily on ketocarboxylic
acid derivatives as substrates, thus affording products with
limited generality that are in most cases difficult to further
functionalize. Moreover, there are only a few examples of the
use of these catalytic systems for the direct formation of
a quaternary carbon center in the presence of a vicinal tertiary
center, with moderate to good stereoselectivities. In this
regard, the development of a novel catalytic enantioselective
Claisen rearrangement as an alternative efficient method for
the rapid creation of vicinal tertiary and quaternary carbon
center motifs, which are widely present in complex natural
products as well as medicinal and biologically active mole-
cules, remains an important goal.[7]
Recently, many groups including our own have reported
that a phosphonate group on the substrate is able to tightly
coordinate to metal ions and provide excellent enantiocontrol
through chelation with an additional binding site, which is
adjacent to the phosphonate group, to chiral metal catalysts.[8]
We thus envisioned that enolphosphonates would be favor-
able bidentate substrates for metal-catalyzed Claisen rear-
for the synthesis of a wide range of a-ketophosphonate
derivatives with contiguous tertiary and quaternary carbon
centers in excellent yields and selectivities.
Initially, a convenient protocol was developed for sub-
strate preparation. These compounds could be simply
obtained by treating allylic bromides with a-ketophospho-
nates in the presence of DBU.[10] Next, based on our previous
success in the use of metal/TBOx complexes in catalytic
asymmetric reactions of ketophosphonates,[11] we investigated
the use of Al/TBOx complexes in the Claisen rearrangement
of enolphosphonate S1 (Table 1, entry 1).[12] However, no
rearrangement product was detected. When the Cu/TBOx
complex was used, the reaction proceeded slowly to give the
product with 70% yield but in racemic form (Table 1,
entry 2). Bidentate bisoxazoline ligands instead of tetraden-
tate TBOx ligands were then examined. To our delight, when
the (R,R)-PhBOX ligand (L1) was used the product was
obtained with 88% yield and 93% ee in 2 hours (Table 1,
entry 3).[13,14] When the aminoindanol-derived bisoxazoline
ligand L2 was used the rearrangement product was obtained
in 93% ee but with lower yield (Table 1, entry 4). Other metal
triflates and copper sources were also tested but none of them
gave more-satisfying results.[10] A screen of solvents indicated
that several solvents were suitable for this reaction and that
the enantioselectivity could be improved when the reaction
was performed in a dichloromethane/n-hexane (1:5) solvent
mixture (Table 1, entry 5).[10] The best results were achieved
when the catalyst loading was lowered to 5 mol% (Table 1,
entry 6). Unfortunately, the use of this dichloromethane/n-
hexane (1:5) solvent mixture failed to increase the enantio-
selectivity when ligand L2 was used (Table 1, entry 7).
Interestingly, in the presence of L1 the catalyst loading
could even be lowered to 0.1 mol% without significant
detrimental effect on the selectivity and yield, although
[*] J.-J. Tan, Prof. H. Yamamoto
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: yamamoto@uchicago.edu
Dr. C.-H. Cheon
Department of Chemistry, Korea University
145 Anam-ro, Seongbuk-gu, Seoul 136-701 (Korea)
[**] Support of this research was provided by the NSF (CHE-1049551)
and NIH (P50 GM086 145-01). We thank Dr. Antoni Jurkiewicz for
NMR, Dr. Ian M. Steele for X-ray analysis and Dr. Furong Sun
(UIUC) for MS data. Dr. David Dickson is acknowledged for his
original work for this project.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!