Enantioselective synthesis of multisubstituted biaryl skeleton by chiral phosphoric acid catalyzed desymmetrization/kinetic resolution sequence

Article abstract of DOI:10.1021/ja311902f

Described herein is the enantioselective synthesis of multisubstituted biaryl derivatives by chiral phosphoric acid catalyzed asymmetric bromination. Two asymmetric reactions (desymmetrization and kinetic resolution) proceeded successively to afford chiral biaryls in excellent enantioselectivities (up to 99% ee). Both experimental and computational studies suggested that this excellent selectivity could be achieved via a highly organized hydrogen bond network among a substrate, a catalyst (chiral phosphoric acid), and a brominating reagent (N-bromophthalimide).

Full text of DOI:10.1021/ja311902f

Article
pubs.acs.org/JACS
Enantioselective Synthesis of Multisubstituted Biaryl Skeleton by
Chiral Phosphoric Acid Catalyzed Desymmetrization/Kinetic
Resolution Sequence
Keiji Mori,† Yuki Ichikawa,† Manato Kobayashi,† Yukihiro Shibata,‡ Masahiro Yamanaka,‡
and Takahiko Akiyama*,†
†Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
‡Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
S
* Supporting Information
ABSTRACT: Described herein is the enantioselective synthesis of
multisubstituted biaryl derivatives by chiral phosphoric acid catalyzed
asymmetric bromination. Two asymmetric reactions (desymmetriza-
tion and kinetic resolution) proceeded successively to afford chiral
biaryls in excellent enantioselectivities (up to 99% ee). Both
experimental and computational studies suggested that this excellent
selectivity could be achieved via a highly organized hydrogen bond
network among a substrate, a catalyst (chiral phosphoric acid), and a
brominating reagent (N-bromophthalimide).
INTRODUCTION
■
Chiral biaryl skeletons are prevalent in useful organic
molecules, such as biologically active compounds,1 chiral
ligands,2 and chiral Brønsted acid catalysts.3 In relation to
this, much effort has been devoted to the development of new
strategies for the construction of chiral biaryl scaffolds.4
Diastereo- or enantioselective coupling is the simplest and
most straightforward method for the construction of chiral
biaryl scaffolds.5 The chemical yields of this method, however,
are not always satisfactory due to the difficulty of connecting
the two bulky aromatic moieties. From a practical point of view,
Bringmann’s asymmetric ring-opening strategy6 is highly
reliable and widely employed as a key step in the total
synthesis of biologically active compounds, furnishing various
tetrasubstituted biaryls with good to excellent enantioselectivi-
Figure 1. Sequential asymmetric bromination reaction.
ties.1e,7
The desymmetrization of Cs-symmetric compounds has
recently attracted much attention because it enables easy
preparation of target molecules in a few steps. A wide range of
important chiral substructures, such as chiral cyclohexenone8
and trans-1,2-diamine,9 have been synthesized with excellent
selectivities. Nevertheless, to the best of our knowledge, this
method has not been applied to the asymmetric construction of
chiral biaryls except for the works of Hayashi,10 Matsumoto,11
and Alexakis group.12 Although this method furnished chiral
biaryls with excellent selectivities, the enantioselective synthesis
of sterically encumbered, tetrasubstituted chiral biaryls remains
a daunting task.5,13
of chiral phosphoric acid: (1) desymmetrization of a Cs-
symmetric biphenol moiety by chiral phosphoric acid catalyzed
asymmetric bromination, and (2) chiral phosphoric acid
induced kinetic resolution in the subsequent (second)
bromination. The high selectivity in the first asymmetric
reaction (desymmetrization) is further enhanced by the
subsequent asymmetric reaction (kinetic resolution) to afford
chiral biaryls with excellent selectivities (up to 99% ee).14
RESULTS AND DISCUSSION
Development of Sequential Asymmetric Bromination
Reaction (Desymmetrization/Kinetic Resolution Se-
■
We report herein the enantioselective construction of
tetrasubstituted chiral biaryls by the desymmetrization strategy
(asymmetric bromination strategy, Figure 1). This strategy
consists of consecutive asymmetric transformations by means
Received: December 6, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
quence). We initiated our study with the design of a substrate
because the control of atropisomerism with an organocatalyst is
still an underdeveloped and challenging area.15 Generally, the
high stability of the transition state structure and the high
reactivity to induce a low-temperature reaction are indispen-
sable to achieve excellent enantioselectivity. Under such
circumstances, we envisaged that Cs-symmetric biaryl A with
two hydroxy groups would be a suitable structural motif
because of two reasons (Figure 2): (1) a hydrogen bond
ee).19,20 A further interesting feature of this methodology is its
prominent kinetic resolution: treatment of racemic-3a with 0.50
equiv of NBP under the optimal conditions gave dibromide 4 in
45% yield, accompanied by unreacted 3a in 49% yield in an
optically active form (87% ee) in favor of the R-isomer, which is
the major enantiomer in the desymmetrization reaction. The
selectivity factor (s-value) was 31.5, which was sufficiently high
for synthetic use.21
The results strongly suggest that sequential asymmetric
reactions (desymmetrization/kinetic resolution) can provide
chiral biaryls in excellent optical yields, i.e., the selectivity in the
chiral phosphoric acid catalyzed desymmetrization (first
asymmetric bromination) can be further improved by the
second asymmetric bromination (kinetic resolution) with slight
sacrifice of the chemical yield, as depicted in Figure 1.
As expected, the planned desymmetrization/kinetic reso-
lution sequence worked well: subjection of 2a and a slight
excess of NBP (1.1 equiv) under the optimal conditions
furnished monobromide 3a with excellent enantioselectivity,
accompanied by a slight loss of chemical yield (88%, 97% ee,
entry 1 in Table 1). The substrate scope of this reaction is listed
in Table 1. In all cases, good to excellent selectivities were
achieved in desymmetrization (81−93% ee) and kinetic
resolution (63−96% ee, s-value: 6.1−97.3), and the successive
asymmetric bromination reaction realized excellent selectivities
(≥91% ee). Benzyloxy analogue 3b was obtained with complete
enantioselectivity (99% ee, entry 2).22,23 The electronic factor
of the lower aromatic moiety was negligible in this trans-
formation. Both substrates with electron-donating groups
(methoxy and methyl) and the substrate with an electron-
withdrawing group (fluoro) afforded corresponding mono-
bromides (3a−d) with excellent selectivities (≥94% ee, entries
1−4). Excellent selectivities were also achieved when sterically
encumbered, 2′,3′,6′-substituted substrates 2e and 2f were
employed (≥96% ee, entries 5 and 6). Naphthyl-type substrates
also participated in this reaction, affording 3g and 3h in 82%
yield with 95% ee and in 90% yield with 95% ee, respectively
(entries 7 and 8). This method was applicable to trisubstituted
biaryls as well (entries 9−11). Various trisubstituted biaryls
(3i−k) were obtained in excellent enantioselectivities (≥91%
ee).24
Figure 2. Design of the starting material.
network would be formed among the phenolic hydroxy group
(substrate), phosphoric acid (catalyst), and the brominating
reagent (such as NBS),16 and (2) the intramolecular hydrogen
bond between the phenolic hydroxy group and the OR group
(light blue) would enhance not only reactivity but also
structural rigidity.
The designed substrate provided another advantage: the
facile connection of the two aryl portions. Due to the small size
of the OR group, the Suzuki coupling of o-dialkoxy arylboronic
acid and iodobenzene derivatives proceeded smoothly to afford
the desired Cs-symmetric biphenol in good yield (not shown,
see Supporting Information).
Hydrogenated phosphoric acid (R)-1 bearing 9-anthryl
groups turned out to be the most effective for the
enantioselective bromination reaction of designed substrate
2a (Figure 3a).17,18 When a solution of 2a in CH2Cl2/toluene
(v/v = 1/1) was treated with 1.0 equiv of N-bromophthalimide
(NBP) in the presence of 1 and MS13X, the desired
asymmetric bromination reaction (desymmetrization) pro-
ceeded smoothly (within 0.5 h) to afford monobromide 3a in
excellent yield with satisfactory enantioselectivity (97%, 93%
The important feature of the present method is that the
selectivity could be further enhanced by tuning the amount of
the brominating reagent: e.g., excellent selectivity of 92% ee in
3i (entry 9) was achieved by employing 1.2 equiv of NBP,
whereas selectivity was 88% ee when the amount of NBP was
reduced (1.1 equiv, 88% chemical yield). The absolute
configurations of these products were surmised as depicted in
Table 1 by analogy to 3c, 3g, and 3h, whose absolute
stereochemistries were unambiguously established by single-
crystal X-ray analysis.25
Clarification of Transition State Model Based on
Supporting Experiments and Computational Results.
To clarify the reaction mechanism, additional experiments were
conducted. The simple resorcinol moiety (upper aromatic part)
and the alkoxy group at C6′-position in the lower aromatic part
were found to be responsible for the excellent enantioselectivity
(Figure 4a). 4-Methyl-substituted monobromide 3l was
obtained in good chemical yield (80%), but its selectivity was
as low as 44% ee. The alkoxy group at C6′-position played a
crucial role in the selectivity. In the case of substrate 2m that
had an ethyl group in place of a methoxymethyl group, the
selectivity completely disappeared and corresponding mono-
Figure 3. Desymmetrization and kinetic resolution.
B
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 1. Substrate Scope of the Sequential Bromination
a
Reaction
Figure 4. Examination for clarifying the transition state model.
bromide 3m was obtained in racemic form (0% ee). The same
situation was noted in vinyl (π-donor moiety) analogue 3n
(84%, 2% ee).
To confirm the importance of the hydrogen bond network,
masked substrate (dimethoxy analogue) 2o was subjected to
the optimal reaction conditions (Figure 4b). Corresponding
product 3o was obtained in low yield (14%) even though the
reaction was prolonged (14.5 h). In addition, the selectivity
significantly dropped to 17% ee. The results strongly suggest
the important role of the free hydroxy group in both reactivity
and selectivity, and that this reaction proceeds via the expected
hydrogen bond network: i.e., the Brønsted acidic part of the
catalyst activates the carbonyl oxygen of NBP and the
phosphoryl oxygen coordinates to the phenolic hydroxy
group.26,27
To gain further insight into the origin of the high
enantioselectivity and the substituent effects of biaryls,
theoretical calculations of the detailed transition state (TS)
models were conducted. The bromination reaction consists of
the nucleophilic attack of an aryl group on a brominating
reagent and the subsequent proton transfer. It is widely
accepted that the first nucleophilic attack is the rate-
determining step and the subsequent proton transfer is a fast
process.28 The enantiotopic discrimination of the asymmetric
bromination reaction of biaryls should be determined in the
first step. On the basis of the bifunctional nature of the
phosphoric acid16 and the experimental results for masked
substrate 2o, cyclic TS through a two-point interaction at the
Brønsted acidic and Lewis basic sites of the phosphoric acid was
predicted.29 Whereas one of the enantiotopic phenolic hydroxy
groups of biaryl coordinates to the Lewis basic site of the
catalyst (e.g., phosphoryl oxygen), the other phenolic hydroxy
group intramolecularly coordinates to the OMe or CH2OMe
group. The Brønsted acidic site (e.g., proton) activates the
brominating reagent (e.g., NBS)30 through hydrogen bonding
interaction. To elucidate the major factor contributing to the
high enantioselectivity in this asymmetric bromination
(desymmetrization), the possible TSs for both R- and S-
products were addressed. Four possible TSs corresponding to
two different conformations for the intramolecular hydrogen
bonding in biaryl (TS2, TS4, OMe coordination; TS1, TS3,
CH2OMe coordination) and two different approaches to NBS
(TS1, TS2, front of OMe; TS3, TS4, back of OMe) were
investigated for each TS affording R- or S-product (TSr or TSs)
a
Unless otherwise noted, all reactions were conducted with 0.1 mmol
of biphenol 2 and NBP (1.1 equiv) in the presence of 10 mol % of 1
and MS13X in CH2Cl2/toluene (1.0 mL, v/v = 1/1) at −20 °C for 0.5
b
h. Enantiomeric ratio was determined by the chiral stationary phase.
c
d
e
CH2Cl2 was employed as the reaction solvent. At −40 °C. 4 mL of
f
CH2Cl2 was employed. 4 mL of CH2Cl2/toluene (v/v = 1/1) was
g
employed. 1.2 equiv of NBP was employed.
C
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 5. Examination for clarifying the transition state model.
(Figure 5b,c). All calculations were performed with the
Gaussian 03 package.31 To reduce computational cost,
geometries were fully optimized and characterized by frequency
calculation using the ONIOM (M05-2X/6-31G*:HF/3-21G)
method (black, higher level layer; gray, lower level layer, Figure
5a).32−34 Single-point energy calculations were evaluated at the
M05-2X/6-31G* level35,36 for the ONIOM-optimized struc-
tures. Free energies were also computed for the gas phase.
Focusing on the 3,3′-substituent effect of 1, the relative
energy and the structural difference between the energetically
lowest TSr and TSs were first investigated in the case of 2a
(Figure 6). In agreement with the experimental result, the
lowest TS for R-product (TSr1a) is 4.1 kcal/mol lower in
energy than the lowest TS for S-product (TSs4a). TSr1a has a
similar structure to TSs4a with respect to the hydrogen bond
network. The chiral pocket of 1 enforces the binding
orientation of NBS and 2a conformationally fixed by the
intramolecular hydrogen bonding interaction. In the energeti-
cally disfavored TSs4a, the CH2OMe group, which is bulkier
than the OMe group, is located at the sterically demanding 9-
anthryl group positioned in the upper left-hand quadrant and
thereby leads to steric repulsive interaction (purple curved
lines). Therefore, the major factor affecting the stereochemical
outcome in this asymmetric bromination would be explained by
the steric interaction between the 3,3′-positioned 9-anthryl
group of 1 and the biaryl substituent group.
Next, we investigated the origin of the substituent effect of
biaryls on the stereochemical outcome. Experiments showed
that the enantioselectivity significantly decreased by using 2l
and 2n. The small energy difference between the lowest TSr
and TSs was responsible for the decrease in enantioselectivity.
In the case of 2l, the relative energy difference between the
lowest TSr and TSs decreased to 1.1 kcal/mol (Figure 7a).
TSs3l as the lowest TSs would be destabilized by the steric
repulsion between the CH2OMe group of 2l and the 9-anthryl
group of 1 positioned in the upper left-hand quadrant (purple
curved lines). On the other hand, TSr1l would be also
destabilized by the steric repulsion between the additional
methyl group of 2l and the 9-anthryl group of 1 positioned in
the lower right-hand quadrant (purple curved lines). These
steric effects resulted in the small energy difference of the
diastereomeric transition structures in the case of 2l. In a
manner similar to 2l, the 1.5 kcal/mol difference in energy
between the lowest TSr and TSs was also obtained for 2n
(Figure 7b). In the case of TSs4n as the lowest TSs, the
destabilization effect caused by the steric repulsion between the
vinyl group of 2n and the 9-anthryl group of 1 would be small
because the vinyl group was smaller than the CH2OMe group.
On the other hand, the intramolecular hydrogen bonding of the
biaryl unit disappeared in TSr1n. Therefore, TSr1n would be
destabilized and the relative energy difference between the
lowest TSr and TSs also decreased for 2n. These calculation
results rationally explained the substituent effects of the
phosphoric acid catalyst at 3,3′-positions and the biaryls on
the enantioselectivity.
Figure 6. 3D structures of TSr1a and TSs4a and relative energies
(kcal/mol) based on single-point energy calculations using M05-2X/6-
31G* for the ONIOM (M05-2X/6-31G*:HF/3-21G)-optimized
structures.
D
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 7. 3D structures and relative energies (kcal/mol) based on single-point energy calculations using M05-2X/6-31G* for the ONIOM(M05-
2X/6-31G*:HF/3-21G)-optimized structures of (a) TSr1l and TSs3l and (b) TSr1n and TSs4n.
In summary, we have developed a strategy for the
enantioselective construction of sterically encumbered biaryls,
which involves the chiral phosphoric acid catalyzed asymmetric
bromination of Cs-symmetric biphenols. The interesting feature
of the present strategy is the combination of two chiral
transformations (desymmetrization/kinetic resolution). A
range of substrates were employed in this transformation, i.e.,
various biphenyl derivatives with electron-donating and -with-
drawing groups, and some arylnaphthalenes afforded mono-
brominated biaryls with excellent enantioselectivities (up to
99% ee). The experimental and computational results suggest
that the highly organized hydrogen bond network among the
substrate, the catalyst, and the brominating reagent plays a key
role in attaining the excellent selectivities. Further investigations
of its application to natural product synthesis are under way in
our laboratory.
REFERENCES
■
(1) For recent reviews on axially chiral biaryls, see: (a) Bringmann,
G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384. (b) Boudoin, O.
Eur. J. Org. Chem. 2005, 4223. (c) Kozlowski, M. C.; Morgan, B. J.;
Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193. (d) Tanaka, K. Chem.
Asian J. 2009, 4, 508. (e) Bringmann, G.; Gulder, T.; Gulder, T. A. M.;
Breuning, M. Chem. Rev. 2011, 111, 563.
(2) For selected reviews, see: (a) Tang, W.; Zhang, X. Chem. Rev.
2003, 103, 3029. (b) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41,
581.
(3) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356. For reviews on chiral phosphoric acid catalysis, see:
(a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
(b) Akiyama, T. Chem. Rev. 2007, 107, 5744. (c) Connon, S. J. Angew.
Chem., Int. Ed. 2006, 45, 3909. (d) Terada, M. Chem. Commun. 2008,
4097. (e) Terada, M. Synlett 2010, 1929. (f) Zamfir, A.; Schenker, S.;
Freund, M.; Tsogoeva, S. M. Org. Biomol. Chem. 2010, 8, 5262.
(g) Terada, M. Curr. Org. Chem. 2011, 15, 2227. (h) Rueping, M.;
Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. See also
references cited therein.
(4) For selected examples of chiral biaryls via the [2 + 2 + 2]
cycloaddition reaction, see: (a) Nishida, G.; Noguchi, K.; Hirano, M.;
Tanaka, K. Angew. Chem., Int. Ed. 2007, 46, 3951. (b) Heller, B.;
Gutnov, A.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Redkin, D.;
Sundermann, C.; Sundermann, B. Chem.Eur. J. 2007, 13, 1117.
(c) Shibata, T.; Chiba, T.; Hirashima, H.; Ueno, Y.; Endo, K. Heteroat.
Chem. 2011, 22, 363. (d) Mori, F.; Fukawa, N.; Noguchi, K.; Tanaka,
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical and spectroscopic data for
new compounds, copies of NMR and HPLC spectra, and
crystallographic data for s53, 3g, and 3h (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
K. Org. Lett. 2011, 13, 362.
Tsuchikama, K. Org. Biomol. Chem. 2008, 1317. (f) Shibata, Y.;
For reviews, see: (e) Shibata, T.;
takahiko.akiyama@gakushuin.ac.jp
Tanaka, K. Synthesis 2012, 323.
Notes
(5) For selected examples of chiral biaryls via the biaryl coupling
reaction, see: (a) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada, Y.
M. A. Angew. Chem., Int. Ed. 2008, 48, 2708. (b) Egami, H.; Katsuki, T.
J. Am. Chem. Soc. 2009, 131, 6082. (c) Huang, S.; Petersen, T. B.;
Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 14021. (d) Shen, X.;
Jones, G. O.; Watson, D. A.; Bhayana, B.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 11278. (e) Egami, H.; Matsumoto, K.; Oguma, T.;
Kunisu, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 13633.
(f) Yamamoto, T.; Akai, Y.; Nagata, Y.; Suginome, M. Angew. Chem.,
Int. Ed. 2011, 50, 8844. (g) Yamaguchi, K.; Yamaguchi, Y.; Studer, A.;
Itami, K. Chem. Sci. 2012, 3, 2165. (h) Wu, W.; Wang, S.; Zhou, Y.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Trans-
formation by Organocatalysis” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and a Grant-in
Aid for Scientific Research from the Japan Society for the
Promotion of Science.
E
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
He, Y.; Zhuang, Y.; Li, L.; Wan, P.; Wang, P.; Zhou, Z.; Qiu, L. Adv.
Synth. Catal. 2012, 353, 2395. (i) Wang, S.; Li, J.; Miao, T.; Wu, W.;
Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org. Lett. 2012, 14, 1966.
(6) Bringmann’s asymmetric ring opening methodology: (a) Bring-
mann, G.; Hartung, H. Tetrahedron 1993, 49, 7891. (b) Bringmann,
G.; Kraus, J.; Breuning, M.; Tasler, S. Synthesis 1999, 525.
(7) Representative examples of application of asymmetric ring
opening concept to the total synthesis of natural products:
(a) Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.; Peters, K.;
Peters, E.-M. Synthesis 2001, 155. (b) Bringmann, R.; Menche, D.
Angew. Chem., Int. Ed. 2001, 40, 1687. (c) Bringmann, G.; Menche, D.;
(16) For theoretical studies on phosphoric acid catalysts as acid/base
bifunctional catalysts, see: (a) Yamanaka, M.; Itoh, J.; Fuchibe, K.;
Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756. (b) Simon, L.;
́
Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741. (c) Akiyama, T.;
Morita, H.; Bachu, P.; Mori, K.; Yamanaka, M.; Hirata, T. Tetrahedron
2009, 65, 4950. (d) Yamanaka, M.; Hirata, T. J. Org. Chem. 2009, 74,
3266. (e) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J.
Am. Chem. Soc. 2009, 131, 13819. (f) Shi, F.-Q.; Song, B.-A. Org.
Biomol. Chem. 2009, 7, 1292. (g) Simn, L.; Goodman, J. M. J. Org.
Chem. 2010, 75, 589. (h) Zheng, C.; Sheng, Y.-F.; Li, Y.-X.; You, S.-L.
Tetrahedron 2010, 66, 2875. (i) Xu, S.; Wang, Z.; Li, Y.; Zhang, X.;
Wang, H.; Ding, K. Chem.Eur. J. 2010, 16, 3021. (j) Hirata, T.;
Yamanaka, M. Chem.Asian J. 2011, 6, 510. (k) Simon, L.; Goodman,
J. M. J. Org. Chem. 2011, 76, 1775. (l) He, L.; Chen, X.-H.; Wang, D.-
N.; Luo, S.-W.; Zhang, W.-Q.; Yu, J.; Ren, L.; Gong, L.-Z. J. Am. Chem.
Soc. 2011, 133, 13504. (m) Grayson, M. N.; Pellegrinet, S. C.;
Goodman, J. M. J. Am. Chem. Soc. 2012, 134, 2716.
Kraus, J.; Muhlbacher, J.; Peters, K.; Peters, E.-M.; Brun, R.; Bezabih,
̈
M.; Abegaz, B. M. J. Org. Chem. 2002, 67, 5595. (d) Ohmori, K.;
Tamiya, M.; Kitamura, M.; Kato, H.; Ohrui, M.; Suzuki, K. Angew.
Chem., Int. Ed. 2005, 44, 3871. (e) Tamiya, M.; Ohmori, K.; Kitamura,
M.; Arai, T.; Kato, H.; Oorui, M.; Suzuki, K. Chem.Eur. J. 2007, 13,
9791.
(8) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615. (c) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.;
Poland, L. A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem.
1975, 40, 675. (d) Hajos, Z. G.; Parrish, D. R. Organic Syntheses;
Wiley: New York, 1990; Collect Vol. VII, p 363. (e) Zhong, G.;
Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas, C. F., III. J. Am.
Chem. Soc. 1997, 119, 8131. (f) List, B.; Lerner, R. A.; Barbas, C. F.,
III. Org. Lett. 1999, 1, 59. (g) Zhou, J.; Wakchaure, V.; Kraft, P.; List,
B. Angew. Chem., Int. Ed. 2008, 47, 7656. (h) Mori, K.; Katoh, T.;
Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew. Chem., Int. Ed.
2009, 48, 9652.
(17) For recent examples of asymmetric bromination, see: (a) Cai,
Y.; Liu, X.; Hui, Y.; Jiang, J.; Wang, W.; Chen, W.; Lin, L.; Feng, X.
Angew. Chem., Int. Ed. 2010, 49, 6160. (b) Murai, K.; Matsushita, T.;
Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem.,
Int. Ed. 2010, 49, 9174. (c) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.;
Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474. (d) Cai, Y.; Liu, X.;
Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2011, 133, 5536.
(e) Rueping, M.; Ieawsuwan, W. Chem. Commun. 2011, 47, 11450.
(f) Chen, Z.-M.; Zhang, Q.-W.; Chen, Z.-H.; Li, H.; Tu, Y.-Q.; Zhang,
F.-M.; Tian, J.-M. J. Am. Chem. Soc. 2011, 133, 8818. (g) Li, H.; Zhang,
F.-M.; Tu, Y.-Q.; Zhang, Q.-W.; Chen, Z.-M.; Chen, Z.-H.; Li, J. Chem.
Sci. 2011, 2, 1839. (h) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett.
2011, 13, 2738. (i) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2011, 133, 9164. (j) Huang, D.; Wang, H.; Xue, F.; Guan,
H.; Li, L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350. (k) Denmark, S.
E.; Burk, M. T. Org. Lett. 2012, 14, 256. (l) Chen, J.; Zhou, L.; Tan, C.-
K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999. (m) Alix, A.; Lalli, C.;
Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012, 134, 10389.
(n) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J.
Am. Chem. Soc. 2012, 134, 11128. (o) Wang, Y.-W.; Wu, J.; Hoong, C.;
Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 12928.
(18) Hennecke’s group recently achieved the desymmetrization-type
asymmetric bromination catalyzed by chiral sodium phosphate:
́
(9) (a) Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1,
1611. (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 6312. (c) Mita, T.; Fukuda, N.; Roca, F. X.;
Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259. (d) Rowland, E. B.;
Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 12084.
For the enantioselective desymmetrization of meso-
aziridines with various alcohols, see: (e) Hamilton, G. L.; Kanai, T.;
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984. With TMSSPh and
TMSCN, see: (f) Sala, D. K.; Lattanzi, A. Org. Lett. 2009, 11, 3330.
(g) Miti, T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2005, 127, 11252. With ArSH, see: (h) Larson, S. E.;
Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 5186. With
TMSCl or TMSBr, see: (i) Ohmatsu, K.; Hamajima, Y.; Ooi, T. J. Am.
Chem. Soc. 2012, 134, 8794.
Hennecke, U.; Muller, C. H.; Frohlich, R. Org. Lett. 2011, 13, 860.
̈
̈
(19) For details of the screening for catalysts and reaction conditions,
see Supporting Information.
(10) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y.
(20) We assumed that molecular sieve 13X trapped some impurities
(such as HBr, which might be released from NBP, and water), thereby
suppressing the formation of the hydrogen bond network. Actually, the
addition of H2O (10 mol %) to the reaction media decreased the
selectivity.
(21) Kagan, H. B.; Fiaud, J. C. Kinetic resolution. In Topics in
Stereochemistry; John Wiley & Sons, Inc.: New York, 1988; p 249.
(22) The benzyl group was easily deprotected under standard
hydrogenation conditions (Pd/C, H2, MeOH/EtOAc) without
sacrificing the bromo atom and axial chirality. For details, see
Supporting Information.
J. Am. Chem. Soc. 1995, 117, 9101.
(11) (a) Matsumoto, T.; Konegawa, T.; Nakamura, T.; Suzuki, K.
Synlett 2002, 122. (b) Okuyama, K.; Shingubara, K.; Tsujiyama, S.;
Suzuki, K.; Matsumoto, T. Synlett 2009, 941.
(12) Perron, Q.; Alexakis, A. Adv. Synth. Catal. 2010, 352, 2611.
(13) Recent examples of stereoselective synthesis of tetra-ortho-
substituted biaryls: (a) Meyers, A. I.; Nelson, T. D.; Moorlag, H.;
Raeson, D. J.; Meier, A. Tetrahedron 2004, 60, 4459. (b) Aoyama, H.;
Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora, Y.; Tsuji, Y. J. Am.
Chem. Soc. 2005, 127, 10474. (c) Nishida, G.; Suzuki, N.; Noguchi, K.;
Tanaka, K. Org. Lett. 2006, 8, 3489. (d) Bringmann, G.; Scharl, H.;
Maksimenka, K.; Radacki, K.; Braunschweig, H.; Wich, P.; Schmuck,
C. Eur. J. Org. Chem. 2006, 4349. (e) Ashizawa, T.; Tanaka, S.;
Yamada, T. Org. Lett. 2008, 10, 2521. (f) Guo, F.; Konkol, L. C.;
Thomson, R. J. J. Am. Chem. Soc. 2011, 133, 18. (g) Konkol, L. C.;
Guo, F.; Sarjeant, A. A.; Thomson, R. J. Angew. Chem., Int. Ed. 2011,
50, 9931. (h) Nushiro, K.; Kikuchi, S.; Yamada, T. Chem. Lett. 2013,
42, 165.
(14) Miller’s group recently reported the enantioselective synthesis of
biaryls by peptide-catalyzed asymmetric bromination: Gustafson, J. L.;
Lim, D.; Miller, S. J. Science 2010, 328, 1251.
(15) (a) Brandes, S.; Bella, M.; Kjarsgaard, A.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 1147. (b) Shirakawa, S.; Liu, K.;
Maruoka, K. J. Am. Chem. Soc. 2012, 134, 916.
(23) The methoxymethyl analogue exhibited low selectivity (59%
ee).
(24) The axial chirality of 3i, having the lowest configurational
stability in the series of 3, is fairly stable at room temperature. No
appreciable racemization was observed even after 10 days.
(25) See Supporting Information for details.
(26) The observation of linear effect suggests that a single molecule
of the catalyst is involved in this asymmetric reaction. See Supporting
Information for details.
(27) The employment of THF (polar solvent) in place of CH2Cl2/
toluene dramatically decreased the selectivity to less than 10%. This
result strongly supported the importance of the hydrogen bond
network in this asymmetric reaction.
F
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(28) (a) Zollinger, H. Adv. Phys. Org. Chem. 1964, 2, 163. (b) Mo, F.;
Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed.
2010, 49, 2028.
(29) As a preliminary mechanistic study, the reaction mechanism of
the chiral phosphoric acid catalyzed bromination was investigated by
using small models (see Supporting Information for details).
(30) NBS exhibited similar tendency to NBP in terms of selectivity in
most cases (3a: 79% ee, 3l: 39% ee, 3n: 13% ee).
(31) Frisch, M. J.; et al.. Gaussian 03, Revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004.
(32) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput.
2006, 2, 364.
(33) M05-2X is a good level of theory for studying organocatalysis,
̀
see: Simon, L.; Goodman, J. M. Org. Biomol. Chem. 2011, 9, 689−700.
(34) Svensson, M.; Humbel, S.; Morokuma, K. J. Chem. Phys. 1996,
105, 3654.
(35) Dapprich, S.; Komaromi, I.; Byun, K. S.; Morokuma, K.; Frisch,
M. J. THEOCHEM 1999, 461.
(36) Vreven, T.; Morokuma, K. J. Comput. Chem. 2000, 21, 1419.
G
dx.doi.org/10.1021/ja311902f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX