Kinetic resolution of racemic 1 -alkyl-2-methylenecyclopropanes via palladium-catalyzed silaborative C-C cleavage

Article abstract of DOI:10.1021/ol900829c

Kinetic resolution of racemic 1-alkyl-2-methylenecyclopropanes via silaborative C-C cleavage was efficiently catalyzed by a palladium complex bearing a chiral phosphoramidite, affording 2-boryl-3-silylmathy 1-1 -alkenes as major products with up to 92% ee

Full text of DOI:10.1021/ol900829c

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2880-2883
Kinetic Resolution of Racemic
1-Alkyl-2-methylenecyclopropanes via
Palladium-Catalyzed Silaborative C-C
Cleavage
Toshimichi Ohmura, Hiroki Taniguchi, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
suginome@sbchem.kyoto-u.ac.jp
Received April 16, 2009
ABSTRACT
Kinetic resolution of racemic 1-alkyl-2-methylenecyclopropanes via silaborative C-C cleavage was efficiently catalyzed by a palladium complex
bearing a chiral phosphoramidite, affording 2-boryl-3-silylmethyl-1-alkenes as major products with up to 92% ee. Enantioenrichment through
parallel kinetic resolution, where the slower reacting enantiomer was converted to the constitutional isomer of the major product, may be
involved as the crucial stereodiscriminating step.
Methylenecyclopropanes (MCPs) have become important
starting materials in organic synthesis because of the unique
reactivity with sufficient stability.1 A variety of reactions of
MCPs, including transition-metal-catalyzed bond formation
with or without opening of the cyclopropane ring, have been
developed,1b-d presenting a potential applicability of MCPs
in asymmetric synthesis. However, limited successes have
been achieved for asymmetric reactions utilizing MCPs.2
Kinetic resolution of racemic MCPs is an unexplored yet
potentially attractive method for obtaining enantioenriched
chiral products as well as for recovering highly enan-
tioenriched MCPs.3 During the course of our study on the
asymmetric silaboration of meso-MCPs,4,5 we became
interested in the possibility of the kinetic resolution of
racemic MCPs through a transition-metal-catalyzed reaction
with silylborane.6 In this paper, we describe a unique kinetic
resolution system with palladium-catalyzed silaborative C-C
(1) (a) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589. (b) Nakamura,
I.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344, 111. (c) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213. (d) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117.
(4) Ohmura, T.; Taniguchi, H.; Kondo, Y.; Suginome, M. J. Am. Chem.
Soc. 2007, 129, 3518
.
(5) For related studies on asymmetric silaboration, see: (a) Suginome,
M.; Ohmura, T.; Miyake, Y.; Mitani, S.; Ito, Y.; Murakami, M. J. Am.
Chem. Soc. 2003, 125, 11174. (b) Ohmura, T.; Suginome, M. Org. Lett.
2006, 8, 2503. (c) Ohmura, T.; Taniguchi, H.; Suginome, M. J. Am. Chem.
Soc. 2006, 128, 13682. For recent reviews on bismetallation of unsaturated
hydrocarbons, see: (d) Beletskaya, I.; Moberg, C. Chem. ReV. 2006, 106,
2320. (e) Suginome, M.; Matsuda, T.; Ohmura, T.; Seki, A.; Murakami,
M. In ComprehensiVe Organometallic Chemistry III; Crabtree, R. H.,
Mingos, D. M. P., Eds.; Ojima, I., Vol. Ed.; Elsevier: Oxford, 2007; Vol.
10, p 725. (f) Burks, H. E.; Morken, J. P. Chem. Commun. 2007, 4717. (g)
(2) (a) Takaya, H.; Hayashi, N.; Ishigami, T.; Noyori, R. Chem. Lett.
1973, 813. (b) Binger, P.; Scha¨fer, B. Tetrahedron Lett. 1988, 29, 529. (c)
Binger, P.; Brinkmann, A.; Roefke, P.; Scha¨fer, B. Liebigs Ann. Chem.
1989, 739. (d) Stolle, A.; Becker, H.; Salau¨n, J.; de Meijere, A. Tetrahedron
Lett. 1994, 35, 3521. (e) Scott, M. E.; Han, W.; Lautens, M. Org. Lett.
2004, 6, 3309. (f) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591.
(3) Reviews on kinetic resolution, see: (a) Kagan, H. B. Tetrahedron
2001, 57, 2449. (b) Dehli, J. R.; Gotor, V. Chem. Soc. ReV. 2002, 31, 365.
(c) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974. (d) Gansa¨uer,
A.; Fan, C.-A.; Keller, F.; Karbaum, P. Chem.sEur. J. 2007, 13, 8084.
Ohmura, T.; Suginome, M. Bull. Chem. Soc. Jpn. 2009, 82, 29
.
10.1021/ol900829c CCC: $40.75
Published on Web 06/10/2009
 2009 American Chemical Society

Table 1. Silaborative C-C Cleavage of 2a with 1 in the Presence of Pd/(S,S,S)-5 Catalysta
.
path selectivitiese
entry
equiv of 2a
% yield 3a+4ab
3a:4ac
% ee of 3ad
% ee of 4ad
I:II
a:b
a′:b′
1
2
1.0
1.5
3.0
3.0
84
93
96
62:38
70:30
76:24
78:22
71
82
88
91
70
51
30
39
59:41
71:29
80:20
81:19
90:10
90:10
89:11
92:8
78:22
78:22
77:23
81:19
3
4f
99 (90)g,h
a Pd(dba)2 (3 mol %), (S,S,S)-5 (3 mol %), 1 (0.2 mmol), and 2a (0.2-0.6 mmol) were reacted in toluene (0.1 mL) at 28 °C for 41-95 h. b GC yield
based on 1. c Determined by GC. d Determined after conversion to the corresponding ꢀ-silyl ketones that analyzed by HPLC with a chiral stationary-phase
column. e Calculated from the product distribution. See Scheme 1 and the Supporting Information. f Reaction carried out at 20 °C for 92 h in the presence
of 5 mol % of catalyst. g Isolated yield. h Containing dba (<5%) as an inseparable impurity.
cleavage of 1-alkyl-2-methylenecyclopropanes, which pro-
vides highly enantioenriched alkenylboronic acid derivatives.
Reaction of MePh2Si-B(pin) (1) with 1 equiv of 1-hexyl-
2-methylenecyclopropane (2a) was carried out in toluene at
28 °C in the presence of 3 mol % of Pd(dba)2 with chiral
phosphoramidite (S,S,S)-5 (entry 1, Table 1). Silaborative
C-C cleavage of 2a took place to give alkenylboranes 3a
and 4a, which were formed via cleavage of the less sterically
hindered C2-C3 bond and more hindered C2-C1 bond,
respectively, in 84% yield in a ratio of 62:38. The enantio-
meric excesses (ee’s) of 3a and 4a were determined to be
71% and 70%, respectively. These results suggested that one
enantiomer of 2a was selectively converted to 3a and the
other enantiomer to 4a.
resolution in the stage of ꢀ-carbon elimination of intermedi-
ates B and B′: The ꢀ-carbon elimination of B and B′ proceeds
preferentially at the C-C bonds a and a′, respectively, which
have a common spatial arrangement relative to the Pd-C
bond that is to be cleaved. This second resolution arises from
chiral induction by the ligand (S,S,S)-5, which preferably
induces ꢀ-carbon cleavage at the C-C bonds, corresponding
to a and a′, irrespective of the substituents in the cyclopro-
pane ring. Although neither the primary (I:II ) 3:2-4:1)
nor the secondary resolution (a:b ) ca. 9:1, a′:b′ ) ca. 8:2)
is very selective, their combination allows the formation of
an enantioenriched product with high ee.
The product distribution and enantioselectivity changed
significantly when the reaction was carried out with excess
amounts of 2a (entries 2 and 3). Use of 3 equiv of 2a
afforded 3a more selectively (3a:4a ) 76:24, entry 3), with
a higher ee (88% ee). We eventually found that 3a was
formed with 91% ee at 20 °C with an improved ratio of 3a:
4a (entry 4).
Scheme 1. Plausible Reaction Pathways [R ) n-C6H13, Si )
SiMePh2, B ) B(pin), L* ) (S,S,S)-5]
A plausible rationale for the observed enantioenrichment
is depicted in Scheme 1. The C-C double bond in (R)-2a
coordinates to the B-Pd-Si complex on the less sterically
congested π-face opposite to the hexyl group in the cyclo-
propane ring to form A. The intermediate A then undergoes
insertion of the CdC bond into the B-Pd bond to form the
(cyclopropylmethyl)palladium species B. Diastereomeric
intermediate B′ is similarly formed from (S)-2a. The
selectivity for path I over path II (I:II), which arises from
the primary kinetic resolution of (R)- and (S)-2a, is not very
high: around 3:2-4:1 (Table 1). The high enantiopurities of
the final product (S)-3a may be attributed to the secondary
(6) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 2000, 122,
11015.
Org. Lett., Vol. 11, No. 13, 2009
2881

Table 2. Comparison of Ligandsa
.
path selectivitiese
entry
ligand
% yield 3a+4ab
3a:4ac
% ee of 3ad
% ee of 4ad
I:II
a:b
a′:b′
1
2
3
4
5
6
7
8
(S,S,S)-5
(R)-6
(R,S,S)-5
(S,S)-7
(S)-8
(S)-9
(S)-10
(R,R)-11
92
76
96
90
71
70
83
51
67:33
54:46
55:45
60:40
46:54
46:54
55:45
69:31
75
89
-36
28
67
58
32
70
-26
12
48
42
70:30
58:42
46:54
56:44
52:48
52:48
47:53
32:68
84:16
88:12
38:62
69:31
73:27
70:30
69:31
39:61
72:28
93:7
31:69
51:49
84:16
80:20
58:42
17:83
18
-64
36
-26
a Pd(dba)2 (3 mol %), ligand (3 mol %), 1 (0.2 mmol), and 2a (0.3 mmol) were reacted in toluene (0.1 mL) at 50 °C for 18-50 h. b GC yield based on 1.
c Determined by GC. d Determined after conversion to the corresponding ꢀ-silyl ketones that were analyzed by HPLC with a chiral stationary phase column.
A negative value means major formation of the other enantiomer. e Calculated from the product distribution. See Scheme 1 and the Supporting Information.
(S)-9, and (S)-10 gave inferior results in terms of primary
resolution (I:II ) 47:53-56:44) as well as secondary
resolution (a:b and a′:b′ ) ca. 5:5-8:2) (entries 3-7). It
should be noted that TADDOL-derived (R,R)-11 gave
product selectivity comparable with (S,S,S)-5, despite low
product yield (entry 8).
Various racemic MCPs 2 were subjected to the kinetic
resolution using the Pd/(S,S,S)-5 catalyst at 20 °C (Table
3). Selective formation of 3b (90% ee) was realized with
high total yield (97%, 3b:4b ) 80:20) (entry 1). The reaction
of 2c-e bearing siloxyalkyl and acetoxypropyl groups also
gave 3c-e with 90-92% ee’s in high yields with good
product selectivity (entries 2-4). Products 3f (87% ee) and
Our kinetic resolution system may be regarded as a unique
parallel kinetic resolution system7 in which the total ef-
ficiency of the kinetic resolution also relies on the reactivity
difference between the enantiomeric reactants.8 It suggests
that even if each of the two chiral discriminations is not very
effective, their synergism in the catalytic cycle affords high
enantioselectivity.9
It was interesting to compare the characteristic catalyst
ability of Pd/(S,S,S)-5 with that of several other palladium
catalysts (Table 2). To enable comparison with some less
active catalysts, the reactions were carried out at 50 °C with
1.5 equiv of 2a. The reaction with Pd/(S,S,S)-5 catalyst gave
3a and 4a in a ratio of 67:33, with 75% and 32% ee,
respectively, indicating good path selectivities (I:II ) 70:
30, a:b ) 84:16, a′:b′ ) 72:28) (entry 1). Very different
results were obtained for the reaction with Pd/(R)-6, which
was the most effective catalyst for the asymmetric desym-
metrization of meso-MCPs (entry 2).4 Although the reaction
afforded 3a and 4a in a ratio of almost 1:1, the ee’s of the
products were 89 and 70%, respectively, indicating that the
(R)-6-based catalyst is more selective in the ꢀ-carbon elimination
step (a:b, a′:b′) but less selective in the primary stereodiscrimination
(I:II). Palladium catalysts bearing (R,S,S)-5, (S,S)-7, (S)-8,
Table 3. Kinetic Resolution of rac-2 via Pd/(S,S,S)-5-Catalyzed
Silaborative C-C Cleavagea
.
% yield
(3 + 4)b 3:4c
% ee of
3d
entry
2
(7) In this paper, we used the term “parallel kinetic resolution” for the
reaction in which each enantiomer of racemic substrate was separately
converted into constitutional isomers.
1
2
3
4
5
6
2b [R ) (CH2)2Ph]
97e
85e
97e
71e
69h
84
80:20 90f (3b)
86:14 92 (3c)
77:23g 90 (3d)
80:20 90 (3e)
77:23 87 (3f)
81:19 85 (3g)
2c [R ) CH2OSiMe2(t-Bu)]
2d [R ) (CH2)3OSiMe2(t-Bu)]
2e [R ) (CH2)2OAc]
(8) Examples of parallel kinetic resolution using chiral transition-metal
catalyst : (a) Hayashi, T.; Yamamoto, A.; Ito, Y. Chem. Lett. 1987, 177.
(b) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem.
Soc. 1994, 116, 4493. (c) Visser, M. S.; Hoveyda, A. H. Tetrahedron 1995,
51, 4383. (d) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.;
Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117, 11021.
(e) Bolm, C.; Schlingloff, G. J. Chem. Soc., Chem. Commun. 1995, 1247.
(f) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew.
Chem., Int. Ed. 2001, 40, 930. (g) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc.
2003, 125, 8078. (h) Pineschi, M.; Moro, F. D.; Crotti, P.; Bussolo, V. D.;
Macchia, F. J. Org. Chem. 2004, 69, 2099. (i) Tanaka, K.; Hagiwara, Y.;
Hirano, M. Angew. Chem., Int. Ed. 2006, 45, 2734. (j) Gansa¨uer, A.; Fan,
C.-A.; Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129, 3484. (k) Kumar,
C.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6542. (l) Webster, R.;
Bo¨ing, C.; Lautens, M. J. Am. Chem. Soc. 2009, 131, 444.
2f [R ) (CH2)3Cl]
2g [R ) (CH2)2N(phthaloyl)]
a Pd(dba)2 (5 mol %), (S,S,S)-5 (5 mol %), 1 (0.2 mmol), and 2 (0.6
mmol) were reacted in toluene (0.1 mL) at 20 °C for 72-99 h. b Isolated
yield. c Determined by GC. d Determined after conversion to the corre-
sponding ꢀ-silyl ketones that were analyzed by HPLC with a chiral
stationary-phase column. The ee’s of 4 were 6-55%. e Containing dba
(<5%) as inseparable impurity. f Determined by direct analysis of 3b.
g
Determined by H NMR. h Yield after conversion to the ꢀ-silyl ketone.
1
2882
Org. Lett., Vol. 11, No. 13, 2009

In conclusion, we have reported the kinetic resolution of
racemic MCPs via Pd-catalyzed silaborative C-C cleavage,
which may prompt further development of asymmetric
synthesis on the basis of kinetic resolution of MCPs.
Acknowledgment. H.T. acknowledges JSPS for financial
support.
Supporting Information Available: Experimental details
and characterization data of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
3g (85% ee) were obtained with comparable ee’s in the
reaction of 2f and 2g bearing chloro and phthalimido groups
at the termini of the alkyl chains (entries 5 and 6).10
The enantioenriched alkenylborane 3 would be a useful
intermediate in asymmetric synthesis. An example is shown
by the synthesis of ꢀ-silyl ketone (eq 1).11 A mixture of 3c
OL900829C
(9) The kinetic resolution system in which secondary selection is
operating synergistically has been reported recently in the ring opening of
unsymmetrically substituted cis-epoxides: Arai, K.; Lucarini, S.; Salter,
M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007,
129, 8103.
(10) The reactions of sterically demanding 2 (R ) Ph and cyclohexyl)
took place slowly under the same reaction conditions (63% conversion after
48 h, R ) cyclohexyl), although we have not been able to find conditions
for HPLC analysis with chiral stationary phase column.
(11) For a review on ꢀ-silyl carbonyl compounds, see: Fleming, I. In
Science of Synthesis; Fleming, I., Ed.; Thieme: Stuttgart, 2002; Vol. 4, p
927.
(12) Further synthetic applications of alkenylboronates 3 are being
undertaken in this laboratory. A preliminary attempt at Suzuki-Miyaura
coupling using a mixture of 3b and 4b (80:20) with ethyl 4-bromobenzoate
in 1,4-dioxane at 100 °C in the presence of Pd[P(t-Bu)3]2 (5 mol %) with
5 N NaOH (3 equiv) resulted in the formation of the corresponding coupling
products in 70% total yield after 6 h.
and 4c, which was obtained by the reaction of 1 with rac-
2c, was treated with basic hydrogen peroxide. Optically
active ꢀ-silyl ketone 12c (92% ee) was isolated in 70% yield
for the two steps.12
Org. Lett., Vol. 11, No. 13, 2009
2883