Catalytic enantioselective boron conjugate addition to cyclic carbonyl compounds: A new approach to cyclic β-hydroxy carbonyls

Article abstract of DOI:10.1039/b914207j

The highly enantioselective conjugate boration of six-membered and seven-membered cyclic enones and unsaturated esters was achieved by the use of a copper-(R,S)-Taniaphos complex with up to 99% ee under optimal conditions. The Royal Society of Chemistry 2

Full text of DOI:10.1039/b914207j

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Catalytic enantioselective boron conjugate addition to cyclic carbonyl
compounds: a new approach to cyclic b-hydroxy carbonylsw
Xinhui Feng and Jaesook Yun*
Received (in Cambridge, UK) 15th July 2009, Accepted 2nd September 2009
First published as an Advance Article on the web 17th September 2009
DOI: 10.1039/b914207j
The highly enantioselective conjugate boration of six-membered
and seven-membered cyclic enones and unsaturated esters was
achieved by the use of a copper–(R,S)-Taniaphos complex with
up to 99% ee under optimal conditions.
conversion when L6 or L7 were used. When the amount of
alcohol was limited to 1 equiv. relative to the cyclic enone, the
conversion was not complete (B80%) in 24 h although the
enantioselectivity did not change significantly.10
Chiral b-hydroxy carbonyl compounds are useful building
blocks and a successful enantioselective b-boration–oxidation
sequence for cyclic carbonyl compounds can provide an easy
route to the synthesis of such compounds. In contrast to
acyclic b-hydroxy carbonyls, enantiomerically enriched cyclic
b-hydroxy carbonyl compounds are not easily accessible by
either aldol reaction or direct oxy-Michael reactions.11
Enantioselective epoxidation–regioselective ring opening is
another interesting option.12 In this context, the conjugate
boration of several cyclic enones was examined with the
established, optimal reaction conditions using ligand L7 and
methanol (Table 2).
Catalytic boration reactions of unsaturated C–C bonds with
diboron reagents have emerged as a novel synthetic tool to
afford a variety of organoboron compounds.1 In particular,
the conjugate addition of a diboron reagent to a,b-unsaturated
carbonyl compounds provides ready access to functionalized
organoboron compounds by incorporating a boron group at
the b-position to the carbonyl. This transformation has been
studied with transition metals such as Pt,2 Rh,3 Cu,4 Ni5 and
very recently, with N-heterocyclic carbenes.6 However, there
are only a few reports on asymmetric conjugate boration
reactions4f,7 and the enantioselective boration of cyclic
substrates has not been reported yet.8
Herein, we report a highly enantioselective copper–boryl
(Cu–B) catalyst system effective for the boration of cyclic
carbonyl compounds. Cyclic substrates including enones and
unsaturated lactones served as good substrates for the copper-
catalyzed boration, and b-boryl cyclic compounds were
obtained with a high level of enantioselectivity up to 99% ee.
In initial experiments, a series of copper(I)–chiral phosphine
catalysts were generated in situ by combining a chiral
bisphosphine, CuCl and NaOt-Bu in THF. Their catalytic
efficiency and enantioselectivity were screened using cyclo-
hexenone as substrate using bis(pinacolato)diboron as reagent.
As shown in Table 1, full conversion of the starting cyclic
enone was obtained with all the ligands screened. However,
only low to moderate enantioselectivities were obtained with
the axially chiral bisphosphine ligands (BINAP, p-tol-BINAP,
SEGPHOS), the Duphos and Tangphos ligands (entries 1–5).
The Josiphos ligand (L5), which was quite effective for acyclic
substrates in our previous studies,7a,7b gave the lowest ee of all
for the reaction of cyclohexenone (entry 6). We were pleased to
obtain high levels of enantioselectivity with the copper–Walphos
(L6) and copper–Taniaphos (L7) complexes. When L7 was
employed as the ligand, the resulting boronate product was
produced with particularly high enantiomeric purity (98% ee)
and determined to have the (R) configuration9 (entry 8). The
addition of 2 equiv. of MeOH was necessary for complete
Table 1 Ligand screening.
Entry Ligand
Conditiona Time/h Yield (%) ee (%)b
1
2
3
4
5
6
7
8
(S)-BINAP
A
A
A
A
B
A
B
B
2
2
2
2
24
4
93
93
93
94
91
92
90
92
40 (R)
63 (S)
43 (S)
53 (R)
38 (S)
13 (S)
90 (S)
98 (R)
L1
L2
L3
L4
L5
L6
L7
24
24
a
Condition A: CuCl (3 mol%), NaOt-Bu (3 mol%), ligand (3 mol%)
and MeOH (1 equiv.); condition B: CuCl (2 mol%), NaOt-Bu (3
mol%), ligand (4 mol%) and MeOH (2 equiv.) with 1.1 equiv. B2pin2
b
in THF. Determined by chiral HPLC analysis of the corresponding
b-hydroxy naphthoate derivative.
Department of Chemistry and Institute of Basic Science,
Sungkyunkwan University, Suwon 440-746, Korea.
E-mail: jaesook@skku.edu; Fax: +82-31-290-7075;
Tel: +82-31-299-4561
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all products. See DOI:
10.1039/b914207j
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Table 2 Asymmetric conjugate boration of cyclic enones with (R,S)-
Taniaphos (L7)
Conversion Yield
Substrate
Entry
1
(%)a
(%)b
ee (%)c
100
93 (70)d 98
Scheme 1 Catalytic b-boration of other cyclic carbonyl compounds.
reacted with the copper-L7 catalyst, produced the desired
product 2g with a modest level of enantioselectivity (entry 8).
The optimized reaction protocol was employed with
unsaturated lactone substrates (Scheme 1). Pentenolide 3
produced the boronate ester product in high yield and ee.
Also, initial studies on the formation of chiral tertiary C–B
centers were conducted with b-methylcyclohexenone.
Complete conversion of the starting enone was obtained only
with L3 or L4 among the ligands tested in Table 1.14 However,
the enantioselectivities achieved with these ligands were only
modest and are yet to be improved.
2
83
78
95
88
3e
1b
100
94 (75)
4
5
96
0
92 (72)
499
—
—
In summary, copper–boryl complexes coordinated with
the Taniaphos ligand is an efficient catalyst system for the
asymmetric conjugate boration of six- and seven-membered
unsaturated cyclic carbonyl compounds. Efficient enantio-
selective formation of secondary C–B bonds was achieved in
good yields and with excellent enantioselectivity. This method
also provides a new catalytic synthetic route to chiral cyclic
b-hydroxy ketones, which are difficult to access otherwise.
This work was supported by a Korea Science and Engineering
Foundation (KOSEF) grant funded by the Korea government
(MEST) (No. R01-2008-000-20332-0). We are grateful to
Solvias for a generous gift of (R,S)-Taniaphos.
dr = 43 : 57
96, 499
6
7
100
93 (79)
100
100
95
76
90
74
8
a
Conversion was determined on the basis of consumed starting
b
material by GC analysis with an internal standard. Isolated yield
c
of 2. Determined by chiral GC or HPLC analysis. See ESI for
d
Notes and references
details.w Yield in parentheses corresponds to that of b-hydroxy
ketone obtained via
(NaBO3 in THF–H2O). L1 was used instead of L7.
a sequential boration–oxidation reaction
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e
Cyclohexenones having different substitution patterns were
generally good substrates, giving the corresponding borylated
products 2 with excellent enantioselectivities over 95% ee.13
However, the reaction of 1b, bearing two methyl groups at the
a0-position, had a slower rate of reaction, giving 83% conver-
sion with the Taniaphos ligand (entry 2). The copper-L1
complex was more catalytically active for the reaction of 1b
but the enantioselectivity obtained was slightly lower (88% ee;
entry 3). Cyclic enone 1d with two substituents at the g-
position showed no reactivity. This is probably due to too
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scope of the current catalytic system. Reaction of the benzyl-
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boronate products in a 1 : 1.3 ratio, with excellent ee values
of 96% and 499%, respectively (entry 6). The conjugate
boration of cycloheptenone also produced the desired product
in high yield and ee (entry 7). However, cyclopentenone, when
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´
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´ ´ ´ ´
´
8 After the submission of this manuscript, a copper-catalyzed
asymmetric conjugate boration of b-substituted cyclic enones was
reported by Shibasaki and co-workers: I-H. Chen, L. Yin,
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9 The absolute configuration was assigned by comparison of optical
rotation of the corresponding TBS-protected hydroxy derivative of
the boronate product with known literature data: M. A. Arai,
14 Complete conversion was obtained with use of 1 equiv. of
MeOH. For the effect of alcohol additives on conversion and ee,
see ref. 7b.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6577–6579 | 6579