Asymmetric allylboration of ketones catalyzed by chiral diols

Article abstract of DOI:10.1021/ja0651308

Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of ketones. The reaction requires 15 mol % of 3,3′-Br₂-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in

Full text of DOI:10.1021/ja0651308

Published on Web 09/13/2006
Asymmetric Allylboration of Ketones Catalyzed by Chiral Diols
Sha Lou, Philip N. Moquist, and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment at Boston UniVersity,
Life Science and Engineering Building, Boston UniVersity, 24 Cummington Street, Boston, Massachusetts 02215
Received July 18, 2006; E-mail: seschaus@bu.edu
Table 1. Asymmetric Allylboration Catalyzed by Chiral Diolsa
The asymmetric allylation reaction is a powerful method for the
construction of chiral building blocks for use in synthesis.1 Many
useful and innovative methods exist for the allylation of aldehydes;2
however, the enantioselective allylation of ketones to yield chiral
tertiary homoallylic alcohols remains a challenge for asymmetric
methods.3 Notable advances in this area include the use of chiral
allylsilanes,4 chiral allylboranes,5 and boronates,6 the asymmetric
entry
catalyst
boronate
temp (
°
C)
solvent
% yieldb
erc
allylation of ketones using allyl stannanes,7 the asymmetric Cu(I)-
catalyzed allylboration reaction,8 and the Ag(I)-catalyzed asym-
metric Sakurai-Hosomi reaction of ketones with allyl silanes.9 In
developing an asymmetric allylation reaction of ketones, we
considered two key observations. First, recent reports illustrate that
the addition of allylboronates to aldehydes is accelerated by the
use of Lewis acids10 or strong Brønsted acids.11 The observed rate
acceleration is presumably due to Lewis acid activation of the boron
atom via coordination to the boronate alkoxy ligand.12 Second, we
sought to capitalize on the facility with which acyclic dialkoxybo-
ranes undergo ligand exchange.13 We postulated that chiral diols
could act as catalytic promoters of asymmetric allylboration
reactions (eq 1): exchangeable chiral ligands with Brønsted acidic
characteristics. Herein, we report the first example of a highly
enantioselective asymmetric allylboration of ketones using chiral
BINOL-derived catalysts and allyldiisopropoxyborane.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
0
0
0
0
0
0
0
0
0
PhCH3
13
54
19
21
58
35
82
78
68
76
72
47
89
83
1
2
3
4
5a
5b
5c
6a
6b
7
5b
5b
5b
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCF3
PhCH3:PhCF3
1:3
PhCH3:PhCF3
1:3
PhCH3:PhCF3
1:3
50:50
50:50
55:45
50:50
72:28
83:17
82:18
55:45
71:29
68:32
95:5
0
0
-35
-25d
-35
94.5:5.5
97:3
15
16
5b
8
10b
10a
-35
-35
0
25
53:47
a Reactions were run with 0.25 mmol boronate, 0.375 mmol acetophe-
none, and 15 mol % of catalyst in organic solvent (0.1 M) for 15 h under
Ar, followed by flash chromatography on silica gel. b Isolated yield.
c Enantiomeric ratios determined by chiral HPLC analysis. d Freezing point
of PhCF3 is -29 °C.
We initiated our investigation by evaluating the reaction of
allyldiisopropoxyborane 10a with acetophenone in toluene at 0 °C
(Table 1, entry 1). The uncatalyzed reaction afforded the product
11a in only 13% yield. However, when 15 mol % of (+)-TADDOL
1 was included in the reaction, a greater yield of the tertiary alcohol
was obtained (entry 2, 54% yield) but in racemic form. Other chiral
diols, such as (S,S)-1,2-diphenylethane diol 2 and (-)-diethyl tartrate
3, gave only modest increases in yield over the uncatalyzed reaction
(entries 3 and 4). Alternatively, (S)-BIPHEN 4 and (S)-BINOL 5a
both gave increases in yield over the uncatalyzed reaction (entries
5 and 6), and (S)-BINOL afforded 11a in an enantiomeric ratio
(er) of 72:28. Encouraged by this result, we evaluated other BINOL-
derived catalysts in the reaction. Catalysts with substitution at the
3,3′-positions (catalysts 5b,c) gave higher enantioselectivities, and
the H8-BINOL catalyst 6b (entries 7-10) with 3,3′-Br2-BINOL 5b
afforded the product in the highest er (83:17). The isomeric 6,6′-
Br2-BINOL catalyst afforded 11a in an er of only 68:32 (entry 11).
Using catalyst 5b, we optimized the reaction for enantioselectivity
using temperature and solvent (entries 12-14). Higher er’s were
achieved at lower temperatures but at a reduced rate (entry 12).
Using solvents, such as CH2Cl2 and THF, gave lower er’s, but
R,R,R-trifluorotoluene (PhCF3) gave comparable er’s and higher
yields at -25 °C as did toluene (PhCH3) at -35 °C (entry 13), the
limitation of PhCF3 being that it freezes at -29 °C. A mixture of
Figure 1. Chiral diols.
PhCF3 and PhCH3 was the most effective solvent system at -35
°C, affording the tertiary homoallylic alcohol in 83% yield and 97:3
er (entry 14). Interestingly, the use of allylpinacol boronate 10b as
the nucleophile under catalytic conditions resulted in no conversion
to the product (entry 15), most likely due to the stability of the
cyclic boronate. Also of note was the reaction using methyl ether
8 (entry 16); the removal of one hydroxyl group on the catalyst
9
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J. AM. CHEM. SOC. 2006, 128, 12660-12661
10.1021/ja0651308 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Allylboration of Ketonesa
Figure 2. Proposed transition state.
ration reaction catalyzed by 5b. A positive nonlinear effect was
observed when we examined the effect of catalyst er on the
enantioselectivity of the reaction.15 However, the yield of the
reaction diminished linearly with catalyst er. The reaction was also
found to be first order in catalyst. We attributed the observed
nonlinear effect to racemate catalyst aggregation.16 On the basis of
these experiments, we propose a model of selectivity in which the
5b‚boronate complex imparts selectivity by activation of the alkoxy
ligand via hydrogen bonding17 leading to si facial attack on the
ketone in a chair-like TSq (Figure 2).
entry
ketone
product
% yieldb
erc
1d
2d
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
83
81
86
89
83
81
87
88
83
76
88
87
83
91
93
97:3
95.5:4.5
99.5:0.5
95.5:4.5
99.5:0.5
96.5:3.5
97:3
97:3
97.5:2.5
98:2
96.5:3.5
97.5:2.5
96:4
96.5:3.5
95:5
9d
10
11
12
13
14
15d
In summary, we have developed a highly enantioselective and
diastereoselective allylboration of ketones catalyzed by chiral
BINOL-derived catalysts. Ongoing studies include expansion of
the scope and utility of the reaction.
Acknowledgment. S.L. gratefully acknowledges a graduate
research fellowship from Merck Research Laboratories, Boston.
This research was supported by a gift from Amgen, Inc., an NSF
CAREER grant (CHE-0349206), and the NIH (P50 GM067041).
a Reactions were run with 0.125 mmol 10a, 0.19 mmol ketone, and 15
mol % of catalyst in a PhCF3:PhCH3 (3:1) mixture (0.1 M) for 15 h under
Ar, followed by flash chromatography on silica gel. b Isolated yield.
c Determined by chiral HPLC and chiral GC analysis. d Reactions were run
with 0.5 mmol 10a and 0.75 mmol acetophenone.
Supporting Information Available: Experimental procedures and
HPLC separations for compounds 11a-11o, 13a, and 13b. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 1. Asymmetric Crotylboration of Acetophenone
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Preliminary mechanistic experiments indicate a catalyst-associ-
ated boronate complex.14 Rapid exchange of one isopropoxy ligand
was observed by 1H NMR in the reaction of 5b with 10a. A similar
observation was made when we monitored the asymmetric allylbo-
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J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006 12661