Asymmetric bisboranes as bidentate catalysts for carbonyl substrates

Article abstract of DOI:10.1021/ol802793k

(Chemical Equation Presented) A new class of C₂ symmetric bisoxazaborolidinone compounds is described which exhibits bidentate binding to carbonyl substrates. Using the Diels-Alder reaction as a model system, the catalytic activity of these bis

Full text of DOI:10.1021/ol802793k

ORGANIC
LETTERS
2009
Vol. 11, No. 3
713-715
Asymmetric Bisboranes as Bidentate
Catalysts for Carbonyl Substrates
Andrew A. Rodriguez, Carrie Zhao, and Kenneth J. Shea*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
IrVine, California 92697-2025
kjshea@uci.edu
Received December 3, 2008
ABSTRACT
A new class of C2 symmetric bisoxazaborolidinone compounds is described which exhibits bidentate binding to carbonyl substrates. Using
the Diels-Alder reaction as a model system, the catalytic activity of these bis-Lewis acids is probed. Reaction rates and selectivities are
observed that are higher than the corresponding mono-Lewis acids. This novel system offers a potentially powerful new approach to asymmetric
Lewis acid catalysis.
Bimetallic catalysts have received considerable attention in
recent years.1 Drawing inspiration from bimetallic enzymes,2
these catalysts incorporate two metal atoms positioned to
act cooperatively on substrate molecules. Bimetallic catalysts
are grouped in two major subsets: (i) bifunctional compounds
that activate both the electrophile and nucleophile of a
reaction3 and (ii) bis-Lewis acids (BLA) that strongly activate
electrophiles through cooperative binding.4,5 Although con-
siderable progress has been made in the former category,
(1) Shibasaki, M.; Yamamoto, Y. Multimetallic Catalysts in Organic
Synthesis; Wiley-VCH: Weinheim, 2004.
(2) (a) Mitic, N.; Smith, S. J.; Neves, A.; Guddat, L. W.; Gahan, L. R.;
Figure 1. Bidentate interaction achieves greater organization than
Schlenk, G. Chem. ReV. 2006, 106, 3338–3363. (b) Wilcox, D. E. Chem.
monodentate and lowers substrate LUMO to a greater extent.
ReV. 1996, 96, 2435–2458.
(3) (a) Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc. Jpn. 2008, 81,
60–75. (b) Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566–
4583.
examples of the latter are less common,4 and asymmetric
examples of BLA catalysts remain rare.5
(4) (a) Ooi, T.; Takahashi, M.; Yamada, M.; Tayama, K.; Omoto, K.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 1150–1160. (b) Saito, A.; Yanai,
H.; Taguchi, T. Tetrahedron Lett. 2004, 45, 9439–9442. (c) Saito, A.; Ito,
H.; Taguchi, T. Org. Lett. 2002, 4, 4619–4621. (d) Abe, N.; Hanawa, H.;
Maruoka, K. Tetrahedron Lett. 1999, 40, 5369–5372. (e) Ooi, T.; Saito,
Asymmetric Lewis acid catalysts are commonly employed
to activate carbonyl substrates such as aldehydes, ketones,
and esters by binding one of the carbonyl oxygen’s lone pair
electrons while creating a chiral microenvironment for the
substrate. Since, in most cases, the carbonyl oxygen has two
nonequivalent lone pair electrons, preorganization of the
A.; Maruoka, K. Tetrahedron Lett. 1998, 39, 3745–3748
.
(5) (a) Hashimoto, T.; Omote, M.; Kano, T.; Maruoka, K. Org. Lett.
2007, 9, 4805–4808. (b) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 1708–1709. (c) Oh, T.; Lopez, P.; Reilly, M. Eur.
J. Org. Chem. 2000, 2901–2903. (d) Reilly, M.; Oh, T. Tetrahedron Lett.
1995, 36, 221–224
.
10.1021/ol802793k CCC: $40.75
Published on Web 12/29/2008
2009 American Chemical Society

Figure 2. Modular bisoxazaborolidinone design.
Figure 3.
Plot of DMF carbonyl carbon 13C NMR shift vs relative
Lewis acid concentration.
catalyst and substrate often requires the use of modified
substrates that incorporate auxiliaries to chelate the Lewis
acid (i.e., oxazolidinones)6 or secondary interactions as
proposed in oxazaborolidinone catalysts.7 Both strategies can
add steps to a reaction sequence and/or limit substrate scope.
An approach that does not rely on these constraints could
offer a more general method for controlling product stereo-
chemistry even for the most challenging substrates such as
internal carbonyl groups.8
computational9 and experimental studies.10 We describe a
new family of asymmetric BLAs prepared from readily
available starting materials. The molecules are designed to
bind carbonyl substrates by simultaneous binding to both
electron lone pairs. The bisoxazaborolidinone design posi-
tions two Lewis acidic boron atoms to form a six-membered
ring chelate with carbonyl substrates (Figure 2). Asymmetry
is derived from R-amino acids and is transmitted to the boron
atoms upon complexation to a carbonyl substrate. The Lewis
acidity of the structure can be fine-tuned by choice of the
tether “X” and boron substituent “R”. The steric environment
can be optimized by choice of substituents “Y” and “R”.
The L-valine derivative 4 incorporating a sulfone one-atom
linker and phenyl substituent on boron is a representative of
this catalyst family. Its synthesis is illustrated in Scheme 1.
Condensation of 2 equiv of L-valine methyl ester 1 with
sulfuryl chloride gave diester 2. Alkaline hydrolysis afforded
diacid 3. Two equivalents of phenyldichloroborane followed
by treatment with polymer-bound hindered base furnished
bisoxazaborolidinone 4 in nearly quantitative yield.
Scheme 1. Synthesis of Bisoxazaborolidinone 4
The coordination behavior of BLA 4 with carbonyl
substrates was studied by NMR spectroscopy. Monoox-
azaborolidinone 5 was used11 for comparison. Following a
modified form of Maruoka’s procedure,4a the carbonyl carbon
of dimethylformamide (DMF) was monitored by 13C NMR
in the presence of varying amounts of each Lewis acid. The
data (Figure 3) show a steady downfield shift of the carbonyl
signal that plateaus at 1:1 equivalency in both cases.
Additional Lewis acid had no further effect on the carbonyl
shift. Importantly, there was a larger downfield shift for
bisoxazaborolidinone 4 compared to monooxazaborolidinone
5, supporting a bidentate mode of binding for the former.
With evidence of bidentate binding by BLA 4, a compu-
tational study was performed to determine the preferred
binding configuration. There are four possible bidentate
binding geometries for a C2-symmetric BLA with a carbonyl
substrate, two anti modes and two syn modes (Figure 4a).
Formaldehyde was chosen as a carbonyl donor to simplify
the system by merging both syn modes. The antiexo,
antiendo, and syn conformations of the 4-formaldehyde
complex were modeled and the ground-state energies deter-
The chelation of both carbonyl lone pair electrons with a
BLA offers a potential solution to this challenge. Simulta-
neous coordination enforces the s-trans conformation, and
it has been proposed that BLA coordination of carbonyl
compounds results in enhanced activation compared to mono-
Lewis acids (Figure 1).9,10 Support for this has come from
(6) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt,
P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos,
K. R. J. Am. Chem. Soc. 1999, 121, 7582–7594.
(7) (a) Singh, R. S.; Harada, T. Eur. J. Org. Chem. 2005, 3433–3435.
(b) Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527–538.
(8) Examples of asymmetric Diels-Alder reactions of simple R,ꢀ-
unsaturated ketones and esters: (a) Singh, R. S.; Adachi, S.; Tanaka, F.;
Yamauchi, T.; Inui, C.; Harada, T. J. Org. Chem. 2008, 73, 212–218. (b)
Futatsugi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 1484–1487.
(c) Hawkins, J. M.; Nambu, M.; Loren, S. Org. Lett. 2003, 5, 4293–4295.
(d) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992–9993. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 2458–2460.
(9) Ab initio calculations (6-31g*) have indicated that double coordina-
tion of BH3 to CH2O in the gas phase is exothermic: LePage, T. J.; Wiberg,
K. B. J. Am. Chem. Soc. 1988, 110, 6642–6650
.
(10) (a) Wuest, J. D. Acc. Chem. Res. 1999, 32, 81–89. (b) Tshinkl,
M.; Schier, A.; Riede, J.; Gabbai, F. P. Organometallics 1999, 18, 1747–
1753. (c) Vaugeois, J.; Wuest, J. D. J. Am. Chem. Soc. 1998, 120, 13016–
13022. (d) Vaugeois, J.; Simard, M.; Wuest, J. D. Coord. Chem. ReV. 1995,
145, 55–73. (e) Sharma, V.; Simard, M.; Wuest, J. D. J. Am. Chem. Soc.
(11) Harada, T.; Yamamoto, Y.; Kusukawa, T. Chem. Commun. 2005,
859–861.
1992, 114, 7931–7933
.
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Org. Lett., Vol. 11, No. 3, 2009

Figure 5. Proposed transition state model to explain enantioselec-
tivity for the Diels-Alder reaction of cinnamaldehyde and cyclo-
pentadiene catalyzed by BLA 4. The model incorporates the antiexo
structure.
Figure 4. (a) Computed bidentate adducts 4/CH2O at the B3LYP
respectively). Returning to low temperature, the use of ether
as solvent increased the yield somewhat but with lowered
selectivity. In toluene, BLA 4 provided high conversion and
moderate ee. In contrast, under these optimized conditions,
monoborane 5 resulted in only 21% conversion and poor
selectivity.
In all cases, the endo cycloadduct predominated, and one
enantiomer was formed in excess. The absolute configuration
of this enantiomer was established to be endo-2R by comparison
with a known enantioenriched sample.14 Importantly, the endo-
2R enantiomer would be expected to arise from the antiexo
binding mode between catalyst and substrate, as shown in Figure
5. In the proposed interaction, the boronic phenyl ring positioned
above the substrate alkyl group blocks the Si-face of the
dienophile, allowing approach of the diene only from the Re-
face. This finding lends further support to the antiexo bidentate
binding mode proposed previously.
6-31g* level of theory. (b) Lowest-energy conformer (antiexo)
shown in 3-D without and with LUMO.
mined at the B3LYP 6-31g* level of theory.12 Of the three,
the antiexo mode, was found to have the most stable
conformation by 9.9 kcal/mol. Further analysis revealed the
lowest (most electrophilic) LUMO is associated with this
antiexo isomer (Figure 4b) and that the orbital is localized
on the carbonyl π* orbital. Taken together, the computational
data indicate that the antiexo adduct is the most stable isomer
and imparts the strongest activation of a carbonyl substrate.
Table 1. Optimization of Diels-Alder Reaction Conditions
These studies provide the first example of a new class of
bisoxazaborolidinone catalyst. Computational and experi-
mental results have shown that these BLAs, represented by
4, form bidentate complexes with carbonyl substrates and
that a single isomeric catalyst-substrate complex is strongly
favored. The catalyst displays greater activity than the
corresponding mono-Lewis acid and leads to products with
predictable stereochemistry. It works as designed.
entry
cat.
solvent
emp.
yielda
endo:exo
eeb
1
2
3
4
5
6
4
4
4
4
4
5
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
toluene
toluene
-78 °C
-34 °C
0 °C
-78 °C
-78 °C
-78 °C
11%
54%
91%
32%
96%
21%
94:6
85:15
83:17
92:8
95:5
91:9
73%
31%
13%
33%
76%
31%
a Yields were determined by 1H NMR using naphthalene asan internal
standard. b ee’s determined by NaBH4 reduction of aldehyde products to
the corresponding alcohol and analysis by chiral HPLC.
Current efforts are focused on modifying the catalyst structure
and optimizing its performance as well as expanding the
substrate scope. Further results will be presented in due course.
Acknowledgment. This work was supported by a grant
from the NIH. A.R. is grateful for a departmental dissertation
fellowship. C.Z. is grateful for support from the University
Research Opportunities program.
The catalytic activity of BLA 4 was evaluated for the
Diels-Alder cycloaddition of cinnamaldehyde and cyclo-
pentadiene (Table 1). This choice was influenced in part by
the absence of thermal reaction under the conditions stud-
ied.13 At -78 °C in methylene chloride, 10 mol % of BLA
4 resulted in 11% conversion, indicating the absence of
turnover. Increasing the temperature to -34 or 0 °C led to
the onset of turnover (up to 91% yield) but at the expense
of both endo:exo selectivity and ee (down to 83:17 and 13%,
Supporting Information Available: Experimental pro-
cedures, computational data, and spectral data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802793K
(14) Enantioenriched sample prepared using MacMillan’s catalyst and
compared to our sample by chiral HPLC (Chiralcel AS column): Ahrendt,
K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243–4244.
(12) See Supporting Information for all complete computational data.
(13) Kelly, T. R.; Maity, S. K.; Meghani, P.; Chandrakumar, N. S.
Tetrahedron Lett. 1989, 30, 1357–1360.
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