Enantioselective synthesis of trans-aryl-and-heteroaryl-substituted cyclopropylboronates by copper (I)-catalyzed reactions of allylic phosphates with a diboron derivative

Article abstract of DOI:10.1021/ja103783p

A new asymmetric route for the synthesis of trans-2-aryl- and -heteroaryl-substituted cyclopropylboronates has been developed. (Z)-3-arylallylic phosphates were converted to the optically active products with high yield and diastereo- and enantioselectivity through a copper(I)-catalyzed reaction with a diboron derivative. Under mild reaction conditions, the reaction affords the arylcyclopropane products with a functional group and a heteroaromatic group in a highly enantioselective manner. When (E)-allylic phosphates were used as substrates, a ligand-controlled product switch between the trans and cis configurations was observed.

Full text of DOI:10.1021/ja103783p

Published on Web 08/04/2010
Enantioselective Synthesis of trans-Aryl- and -Heteroaryl-Substituted
Cyclopropylboronates by Copper(I)-Catalyzed Reactions of Allylic Phosphates
with a Diboron Derivative
Chongmin Zhong,† Shun Kunii,† Yuki Kosaka,† Masaya Sawamura,† and Hajime Ito*,†,‡
Department of Chemistry, Faculty of Science, Hokkaido UniVersity, Sapporo 060-0810, Japan, and PRESTO, Japan
Science and Technology Agency (JST), Honcho, Kawaguchi, Saitama 332-0012, Japan
Received May 3, 2010; E-mail: hajito@sci.hokudai.ac.jp
The reaction conditions were optimized, and the best result was
Abstract: A new asymmetric route for the synthesis of trans-2-aryl-
and -heteroaryl-substituted cyclopropylboronates has been devel-
obtained using a bulky phosphate leaving group, as shown in Table
1.8 With the catalyst system of 10 mol % CuCl, 12 mol % (R,R)-
oped. (Z)-3-arylallylic phosphates were converted to the optically
i-Pr-DuPhos, and 1.0 equiv of K(O-t-Bu), (Z)-1a, the phosphate
active products with high yield and diastereo- and enantioselectivity
through a copper(I)-catalyzed reaction with a diboron derivative.
Under mild reaction conditions, the reaction affords the arylcyclo-
propane products with a functional group and a heteroaromatic group
in a highly enantioselective manner. When (E)-allylic phosphates
were used as substrates, a ligand-controlled product switch between
the trans and cis configurations was observed.
with 2-ethylhexyl groups, reacted with bis(pinacolato)diboron (3)
to produce (1R,2R)-2-phenylcyclopropylboronate [(1R,2R)-4a] in
71% yield with 94% ee and excellent diastereoselectivity (trans/
cis ) 99:1; entry 1). Decreasing the catalyst loading resulted in an
improved yield (89%; entry 2). We found that (R,R)-i-Pr-DuPhos
was superior to other chiral ligands in yield and enantioselectivity
(entries 4-8). Using the isopropyl phosphate (Z)-2a rather than
the 2-ethylhexyl phosphate resulted in a low yield (entry 9).8 No
desired product (4a) was obtained in the absence of the ligand (entry
10). The stereochemical outcome indicates that this reaction of a
Optically active cyclopropane structural moieties are found in a
wide range of naturally occurring compounds and pharmaceuticals.
Z-configured substrate proceeds in a manner similar to those for
In recent years, substantial effort has been put into the enantiose-
the silyl-substituted compounds that we previously reported.9
lective synthesis of cyclopropanes.1 Chirally substituted cyclopro-
pylboronates are attractive building blocks for the synthesis of
cyclopropane-containing compounds.2 A number of methods have
been developed for the synthesis of cyclopropylboronic derivatives.3
Many examples that employ stoichiometric optically active groups
on the boron atom as the chiral auxiliary have also been reported
for the preparation of optically active cyclopropylboronates.4
However, only two reported examples that have taken advantage
of metal-catalyzed asymmetric methods have been reported, one
by us and one by other group.5 The asymmetric synthesis of
optically active cyclopropylboronates with high enantiomeric purity
remains a difficult synthetic challenge. We recently reported the
synthesis of optically active allylboronates using copper(I)-catalyzed
SN2′ substitution of allylic carbonates with a diboron compound.6
When the allylic carbonates have a silyl group at the γ-position of
the leaving group, optically active trans-silyl-substituted cyclopro-
pylboronates were obtained with high enantio- and diastereoselec-
tivity (up to 98% ee, trans/cis ) 99:1).5b More recently, silyl- or
aryl-substituted homoallylic methanesulfonates were found to be
converted to racemic cyclobutane analogues in the presence of an
achiral copper(I) catalyst.7 We propose that the anomalous product
switch from allylboronates to cyclic boronates can be attributed to
the reverse regioselectivity of the Cu-B addition to the CdC double
bond induced by the electronic directing effect of the silyl or aryl
substituent. These results prompted us to develop a direct methodol-
ogy for the synthesis of substituted cyclopropylboronates. We report
herein that trans-aryl- and -heteroaryl-substituted cyclopropylbo-
ronates can be synthesized with high enantio- and diastereoselec-
tivity through a copper(I)-catalyzed reaction. Furthermore, ligand-
dependent stereoselectivity switching between the cis and trans
isomers is also reported.
Table 1. Optimization of Reaction Conditions for the Synthesis of
Optically Active trans-4aa
entry substrate
ligand
temp (°C) time (h) yield (%)b
ee (%)c
1
(Z)-1a (R,R)-i-Pr-DuPhos
0
0
36
45
17
17
17
18
17
17
17
25
71
89
76
35
55
32
34
23
49
0
94
94
91
2d (Z)-1a (R,R)-i-Pr-DuPhos
3
4
5
6
(Z)-1a (R,R)-i-Pr-DuPhos
(Z)-1a (R,R)-Me-DuPhos
(Z)-1a (R,R)-QuinoxP*
(Z)-1a (R)-Segphos
rt
rt
rt
rt
rt
rt
rt
rt
80 (1S,2S)
91 (1S,2S)
81 (1S,2S)
35
7e (Z)-1a (S,S)-DIOP
8
9
(Z)-1a (R,R)-BDPP
(Z)-2a (R,R)-QuinoxP*
27
92 (1S,2S)
-
10 (Z)-1a none
a Conditions: (Z)-1a or 2a (0.2 mmol), 3 (0.3 mmol), CuCl (0.02
mmol), ligand (0.024 mmol), K(O-t-Bu) (1.2 M in THF, 0.2 mmol),
toluene (0.6 mL). b The yield and cis/trans ratio were determined by
GC. c Determined by HPLC. d CuCl (5 mol %, 0.01 mmol),
(R,R)-i-Pr-DuPhos (6 mol %, 0.012 mmol), 3 (1.2 equiv, 0.24 mmol).
e The trans/cis ratio was >30:1.
Under the optimized conditions, allylic phosphates with diverse
aryl and heteroaryl groups were subjected to the copper(I)-catalyzed
enantioselective synthesis of cyclopropylboronates (Table 2).
Substrates with a range of substituents on the benzene ring afforded
the corresponding products with high trans selectivity (entries 1-9).
Generally, substrates with electron-donating substituents on the
benzene ring resulted in higher enantioselectivity (94% ee; entries
1, 5, and 7) than those with electron-withdrawing groups (64-86%
ee; entries 2-4 and 6). A substrate with a 1-naphthyl group was
converted to the product with a high ee value and the highest
† Hokkaido University.
‡ Japan Science and Technology Agency.
9
11440 J. AM. CHEM. SOC. 2010, 132, 11440–11442
10.1021/ja103783p  2010 American Chemical Society

C O M M U N I C A T I O N S
isolated yield (90% yield, 92% ee; entry 10). We further found
that cyclopropylboronates with an aromatic heterocyclic group can
also be furnished with high enantioselectivity (92% ee; entries 11
and 12). Various functional groups such as chloro, ether, ester,
BocNR2, and acetal were tolerated in this reaction (entries 1, 2, 4, 8,
9, and 11), whereas the presence of ketone and bromo groups led to
diminished yields (entries 13 and 14). The substrate with an alkenyl
substituent did not undergo the cyclopropanation reaction (entry 15).
QuinoxP* showed a stereoselective feature (see the Supporting
Information). This catalyst-dependent stereospecificity/selectivity
switching is unique among the analogous copper(I)/diboron catalyst
systems; the cyclopropanation from silyl-substituted allylic carbon-
ates is a stereoselective reaction (trans product only), and the
cyclobutane synthesis reaction from homoallylic sulfonates showed
stereospecific features (from E substrate to cis product and vice
versa).5b,7 The detailed rationale for these differences requires
further mechanistic studies.
Table 2. Substrate Scope and Limitation for the Synthesis of
Optically Active Cyclopropylboronatesa
Scheme 1. Ligand-Controlled Product Switch with (E)-1a
Scheme 2. Explanation for the Formation of trans- and cis-4a
In conclusion, we have described a highly enantioselective
copper(I)-catalyzed synthesis of trans-aryl- and -heteroaryl-
substituted cyclopropylboronates from (Z)-allylic phosphates and
a diboron derivative. The reaction shows excellent diastereoselec-
tivity and good functional group compatibility. When (E)-allylic
phosphates were used as the substrate, the products switched from
the trans configuration in the presence of (R,R)-QuinoxP* to the
cis configuration in the presence of (R,R)-i-Pr-DuPhos. These
reactions offer a new, efficient route to chirally substituted
cyclopropylboronates.
Acknowledgment. This work was supported by the PRESTO
Program (JST) and a Grant-in-Aid for Scientific Research (B)
(JSPS). C.Z. was supported by GCOE (Catalysis as the Basis for
Innovation in Materials Science, Hokkaido University).
a Conditions: 1 (0.4 mmol), 3 (0.48 mmol), CuCl (0.02 mmol), ligand
(0.024 mmol), K(O-t-Bu) (1.2 M in THF, 0.4 mmol), toluene (1.2 mL).
b Isolated yield. c Determined by 1H NMR analysis. d Determined by
HPLC. e Reaction was carried out at -10 °C.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
In the process of ligand screening using (E)-allylic phosphates,
we were surprised to find that the diastereoselectivity of the product
could be drastically switched by using different ligands (Scheme
1). In contrast to the observation that the cis product (cis-4a) was
produced with excellent yield (96% GC yield) when the (R,R)-i-
Pr-DuPhos ligand was used, the trans product [(1R,2R)-4a] was
obtained in the presence of (R,R)-QuinoxP*.10
References
(1) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
2003, 103, 977. (b) Pietruszka, J. Chem. ReV. 2003, 103, 1051. (c) Rubin,
M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117. (d) Salaun,
J. Top. Curr. Chem. 2000, 207, 1. (e) Donaldson, W. A. Tetrahedron 2001,
57, 8589.
(2) (a) Hildebrand, J. P.; Marsden, S. P. Synlett 1996, 893. (b) Charette, A. B.;
De Freitas-Gil, R. P. Tetrahedron Lett. 1997, 38, 2809. (c) Zhou, S.-M.;
Deng, M.-Z.; Xia, L.-J.; Tang, M.-H. Angew. Chem., Int. Ed. 1998, 37,
2845. (d) Chen, H.; Deng, M.-Z. J. Org. Chem. 2000, 65, 4444. (e) Chen,
H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649. (f) Yao, M.-L.; Deng, M.-Z. J.
Org. Chem. 2000, 65, 5034. (g) Bubnov, Y. N.; Nesmeyanova, O. A.;
Rudashevskaya, T. Y.; Mikhailov, B. M.; Kazansky, B. A. Tetrahedron
Lett. 1971, 12, 2153. (h) Pietruszka, J.; Solduga, G. Synlett 2008, 1349. (i)
Pietruszka, J.; Solduga, G. Eur. J. Org. Chem. 2009, 5998.
(3) (a) Utimoto, K.; Tamura, M.; Tanouti, M.; Sisido, K. Tetrahedron 1972,
28, 5697. (b) Fontani, P.; Carboni, B.; Vaultier, M.; Carrie´, R. Tetrahedron
Lett. 1989, 30, 4815. (c) Priestley, E. S.; Decicco, C. P. Org. Lett. 2000,
2, 3095. (d) Fujioka, Y.; Amii, H. Org. Lett. 2008, 10, 769.
A possible explanation for the product switching is shown in
Scheme 2. In the case of the reaction with the (R,R)-i-Pr-DuPhos
ligand, the addition product5b,11 generated from the reaction between
the borylcopper(I) intermediate and the (E)-allylic substrate un-
dergoes intramolecular substitution with retention of the stereo-
chemistry at the R-carbon atom on the copper(I) center to form
cis-4a. Contrary to this, the substitution reaction in the presence of
(R,R)-QuinoxP* would proceed with inversion of the stereochem-
istry, affording trans-4a.
(4) (a) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem. 1990, 55, 4986. (b) Luithle,
J. E. A.; Pietruszka, J.; Witt, A. Chem. Commun. 1998, 2651. (c) Luithle,
J. E. A.; Pietruszka, J. J. Org. Chem. 1999, 64, 8287. (d) Luithle, J. E. A.;
In other words, the reaction with (R,R)-i-Pr-DuPhos proceeded
in a stereospecific manner, whereas the reaction with (R,R)-
9
J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11441

C O M M U N I C A T I O N S
Pietruszka, J. Eur. J. Org. Chem. 2000, 2557. (e) Pietruszka, J.; Witt, A.
J. Chem. Soc., Perkin Trans. 1 2000, 4293. (f) Garcia, P. G.; Hohn, E.;
Pietruszka, J. J. Organomet. Chem. 2003, 680, 281. (g) Hohn, E.; Pietruszka,
J. AdV. Synth. Catal. 2004, 346, 863. (h) Hohn, E.; Pietruszka, J.; Solduga,
G. Synlett 2006, 1531. (i) Hohn, E.; Palecek, J.; Pietruszka, J.; Frey, W. Eur.
J. Org. Chem. 2009, 3765. (j) Zimmer, L. E.; Charette, A. B. J. Am. Chem.
Soc. 2009, 131, 15624. (k) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem.
2000, 65, 9194.
(7) Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990.
(8) The substrates with a carbonate leaving group, which is operative in the
γ-silyl substrates (see ref 5b), generally gave low yields (<50%; see Table
S4). The impacts of solvents, copper salts, base additives, and diverse
ligands were also further investigated (see the Supporting Information for
details).
(9) See the Supporting Information for the detailed explanation.
(10) The absolute configuration of cis-4a could not be determined.
(11) For related studies on borylcopper(I) addition to aromatic alkenes, see: (a)
Laitar, D.; Tsui, E.; Sadighi, J. Organometallics 2006, 25, 2405. (b) Dang,
L.; Zhao, H.; Lin, Z.; Marder, T. Organometallics 2007, 26, 2824. (c)
Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160.
(5) (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125,
7198. (b) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M.
Angew. Chem., Int. Ed. 2008, 47, 7424.
(6) (a) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem.
Soc. 2007, 129, 14856. (b) Ito, H.; Kawakami, C.; Sawamura, M. J. Am.
Chem. Soc. 2005, 127, 16034. (c) Ito, H.; Okura, T.; Matsuura, K.;
Sawamura, M. Angew. Chem., Int. Ed. 2010, 49, 560. (d) Ito, H.; Sasaki,
Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774.
JA103783P
9
11442 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010