Enhanced anti-diastereo- and enantioselectivity in alcohol-mediated carbonyl crotylation using an isolable single component iridium catalyst

Article abstract of DOI:10.1021/jo200068q

The cyclometalated iridium complex (S)-I derived from [Ir(cod)Cl] ₂, 4-cyano-3-nitrobenzoic acid, allyl acetate, and (S)-SEGPHOS is conveniently isolated by precipitation or through conventional silica gel flash chromatography. This single-component precatalyst allows alcohol mediated carbonyl crotylations to be performed at significantly lower temperature, resulting in enhanced levels of anti-diastereo- and enantioselectivity. Most significantly, the chromatographically isolated precatalyst (S)-I enables carbonyl crotylations that are not possible under previously reported conditions involving in situ generation of (S)-I.

Full text of DOI:10.1021/jo200068q

NOTE
pubs.acs.org/joc
Enhanced anti-Diastereo- and Enantioselectivity in Alcohol-Mediated
Carbonyl Crotylation Using an Isolable Single Component Iridium
Catalyst
Xin Gao, Ian A. Townsend, and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S Supporting Information
b
ABSTRACT: The cyclometalated iridium complex (S)-I derived from [Ir(cod)Cl]2,
4-cyano-3-nitrobenzoic acid, allyl acetate, and (S)-SEGPHOS is conveniently isolated
by precipitation or through conventional silica gel flash chromatography. This single-
component precatalyst allows alcohol mediated carbonyl crotylations to be performed
at significantly lower temperature, resulting in enhanced levels of anti-diastereo- and
enantioselectivity. Most significantly, the chromatographically isolated precatalyst
(S)-I enables carbonyl crotylations that are not possible under previously reported
conditions involving in situ generation of (S)-I.
n the course of developing C-C bond-forming hydrogena-
tions and transfer hydrogenations,1 it was found that ortho-
4-cyano-3-nitrobenzoic acid, and (S)-SEGPHOS, termed (S)-I,
is subject to conventional silica gel flash chromatographic purifica-
tion, and that use of (S)-I purified in this manner enables low-
temperature (60 °C) alcohol-mediated carbonyl crotylation, resulting
in enhanced levels of anti-diastereo- and enantioselectivity.
Purification of the ortho-cyclometalated iridium C,O-benzoate
precatalyst (S)-I by conventional flash silica gel chromatogra-
phically was motivated by the fact that isolation of (S)-I by direct
precipitation from the parent reaction mixture failed to exclude
small quantities of inorganic byproducts, which contribute to
batch dependent variability in catalytic performance. To remove
such inorganic impurities, the precatalyst (S)-I was subjected to
flash silica gel chromatographically and was found to exhibit
excellent chromatographic stability. Thus, using (S)-SEGPHOS
as the limiting reagent, the iridium precatalyst (S)-I is obtained in
85% isolated as a yellow powder after purification by silica gel
I
cyclometalated iridium C,O-benzoates serve as catalysts for
diverse carbonyl allylation processes wherein primary alcohol
dehydrogenation triggers reductive generation of allyliridium
nucleophiles from allylic carboxylates, thus enabling asymmetric
carbonyl allylation directly from the alcohol oxidation level.
Under nearly identical conditions, carbonyl allylation is achieved
from the aldehyde oxidation level employing 2-propanol as
terminal reductant.2 Notably, by harnessing the reductive
capability of alcohol mediated transfer hydrogenation, asym-
metric carbonyl allylation is achieved in the absence of stoichio-
metric allylmetal reagents or metallic reductants, representing
a significant departure from conventional carbonyl allylation
protocols.3-5
Our initial investigations into stereoselective carbonyl crotyla-
tion employing R-methyl allyl acetate as the crotyl donor were
achieved using the ortho-cyclometalated iridium C,O-benzoate
prepared in situ from [Ir(cod)Cl]2, allyl acetate, 4-cyano-3-
nitrobenzoic acid, and the chiral phosphine ligand (S)-
SEGPHOS.2c,6,7 Although in situ assembly of the catalyst proved
convenient and exceptional enantioselectivities typically were
observed (>95% ee), only moderate levels of anti-diastereoselec-
tivity were evident (5:1-11:1 dr). In subsequent work, condi-
tions for preparation of the discrete ortho-cyclometalated iridium
C,O-benzoate precatalyst and its isolation via precipitation
were identified.2d Notably, using such single-component pre-
catalysts, alcohol-mediated carbonyl allylation processes were
found to proceed at considerably lower temperatures. This fact
prompted the present reinvestigation of alcohol-mediated car-
bonyl crotylation. Here, we report that the ortho-cyclometalated
iridium C,O-benzoate derived from [Ir(cod)Cl]2, allyl acetate,
Scheme 1. Synthesis and Isolation of the Cyclometalated
Iridium Complex (S)-I
Received: January 13, 2011
Published: March 04, 2011
r
2011 American Chemical Society
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|

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Table 1. Enhanced Levels of anti-Diastereo- And Enantioselectivity in Alcohol-Mediated Carbonyl Crotylations Using the
Chromatographically Isolated Single Component Iridium Catalyst (S)-I.a
a Cited yields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary-phase HPLC analysis
through comparison of reaction products to racemic diastereomeric mixtures. For assignment of relative and absolute stereochemistry, see ref 2c. See the
Experimental Section for further details. b 70 °C.
chromatography and subsequent precipitation, as described in
the Experimental Section (Scheme 1).
the alcohol or aldehyde oxidation level. Most significantly, as
illustrated by the formation of adducts 4d and 4h, the chromato-
graphically isolated precatalyst (S)-I enables carbonyl crotyla-
tions that are not possible under previously reported conditions
involving in situ generation of (S)-I, perhaps due to thermal
instability of these particular aldehydes or cross reactivity of these
aldehydes with the catalyst at higher temperatures. As established
in prior mechanistic studies,2c diastereomeric ratios are generally
higher in crotylations conducted from the aldehyde oxidation
level, as capture of the kinetically formed (E)-σ-allyliridium via
carbonyl addition is more rapid due to higher concentrations of
aldehyde (Table 1).
The performance of the chromatographically isolated preca-
talyst (S)-I was evaluated in carbonyl crotylations from the
alcohol or aldehyde oxidation level via transfer hydrogenation,
and a comparison with results obtained in reactions involving
generation of (S)-I in situ was made.2c Whereas reaction
temperatures of 90 °C were necessary using the catalyst gener-
ated in situ, the chromatographically isolated precatalyst (S)-I
functioned at 60 °C without extending reaction time. A con-
siderable improvement in the level of anti-diastereoselectivity
(7:1 to >20:1 dr) was accompanied by a modest but consistent
improvement in enantioselectivity (93-99% ee). As demonstrated
by the conversion of alcohols 2a-i to adducts 4a-i and the
conversion of aldehydes 3a-i to adducts 4a-i, these favorable
trends in selectivity were evident in carbonyl crotylations from
In summary, we report that the iridium precatalyst (S)-I is
subject to chromatographic purification and that the single-
component precatalyst (S)-I promotes alcohol-mediated carbo-
nyl crotylation at significantly lower temperature, resulting in
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enhanced levels of anti-diastereo- and enantioselectivity.2c Fu-
ture studies will focus on the development of related C-C bond-
forming processes that occur in the absence of stoichiometric
organometallic reagents, including butadiene-mediated carbonyl
crotylations from the alcohol oxidation level.7
H/AS-H column, hexanes/i-PrOH = 98:2, 0.5 mL/min, 230 nm): tminor
= 27.9 min, tmajor = 31.8 min.
(1S,2S)-1-(4-Methoxyphenyl)-2-methylbut-3-en-1-ol, 4b.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the alcohol oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate/hexanes, 1:20 with 0.1% TEA) provided 4b (35.0 mg, 0.182
mmol) as a colorless oil in 91% yield (10:1 dr, 94% ee).
’ EXPERIMENTAL SECTION
(1S,2S)-1-(4-Methoxyphenyl)-2-methylbut-3-en-1-ol, 4b.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the aldehyde oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate: hexanes, 1:20 with 0.1% TEA) provided 4b (34.2 mg, 0.178
mmol) as a colorless oil in 89% yield (12:1 dr, 98% ee). TLC (SiO2): Rf =
0.4 (ethyl acetate/hexanes, 1:5). 1H NMR (400 MHz, CDCl3): δ 7.25
(d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 5.86-5.76 (m, 1H), 5.23-
5.16 (m, 2H), 4.29 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 2.48-2.42 (m, 1H),
2.15 (br s, 1H), 0.83 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ159.3, 141.2, 134.8, 128.2, 117.0, 113.9, 77.7, 55.5, 46.7, 16.8. HPLC
(Chiralpak AD-H/AD-H column, hexanes/i-PrOH = 95:5, 0.5 mL/min,
230 nm): tminor = 41.2 min, tmajor = 48.9 min.
Preparation of the Single-Component Iridium Precatalyst
(S)-I. To a mixture of [Ir(cod)Cl]2 (87.3 mg, 0.13 mmol, 100 mol %),
(S)-SEGPHOS (159 mg, 0.26 mmol, 200 mol %), Cs2CO3 (169 mg,
0.52 mmol, 400 mol %), 4-CN-3-NO2BzOH (100 mg, 0.52 mmol, 400
mol %), and allyl acetate (65 mg, 0.65 mmol, 500 mol %) in a sealed tube
under an atmosphere of N2 was added THF (2.6 mL, 0.05 M). The
reaction mixture was stirred for 30 min at ambient temperature and
heated for 1.5 h at 80 °C. Upon cooling to ambient temperature, the
reaction mixture was diluted with CH2Cl2 (10 mL), filtered through a
Celite plug, washed with CH2Cl2 (50 mL), and concentrated in vacuo.
The residue was purified by flash chromatography (SiO2, 20% Et2O/
CH2Cl2) and concentrated in vacuo. The light yellow gum was dissolved
in THF (3 mL). Rapid addition of hexanes (50 mL) to the stirred
solution resulted in precipitation of a bright yellow powder, which was
collected by gravity filtration. Removal of trace solvents in vacuo
delivered (S)-I (228 mg, 0.221 mmol) in 85% yield.
General Procedure for Carbonyl Crotylation from the
Alcohol Oxidation Level. An oven-dried sealed tube under an
atmosphere of N2 was charged with alcohols 2a-i, (S)-I (10.3 mg,
0.01 mmol, 5 mol %), K3PO4 (21.5 mg, 0.10 mmol, 50 mol %), THF
(0.1 mL, 2.0 M), and H2O (18 μL, 1.0 mmol, 500 mol %). But-3-en-2-yl
acetate 1 (45.6 mg, 0.40 mmol, 200 mol %) was added, and the mixture
was allowed to stir at ambient temperature for 0.5 h, at which point the
reaction vessel was placed in an oil bath at 60 °C and was allowed to stir
for 48 h. The reaction mixture was concentrated in vacuo. Purification of
the residue by column chromatography (SiO2; ethyl acetate: hexanes)
provided 4a-i.
General Procedure for Carbonyl Crotylation from the
Aldehyde Oxidation Level. An oven-dried sealed tube under an
atmosphere of N2 was charged with aldehydes 3a-i, (S)-I (10.3 mg, 0.01
mmol, 5 mol %), K3PO4 (21.5 mg, 0.10 mmol, 50 mol %), THF (0.1 mL,
2.0 M), 2-propanol (31 μL, 0.4 mmol, 200 mol %), and H2O (18 μL, 1.0
mmol, 500 mol %). But-3-en-2-yl acetate 1 (45.6 mg, 0.40 mmol, 200
mol %) was added, and the mixture was allowed to stir at ambient
temperature for 0.5 h, at which point the reaction vessel was placed in an
oil bath at 60 °C and was allowed to stir for 48 h. The reaction mixture
was concentrated in vacuo. Purification of the residue by column
chromatography (SiO2; ethyl acetate/hexanes, 1:20 with 0.1% TEA)
provided 4a-i.
(1S,2S)-1-(4-Bromophenyl)-2-methylbut-3-en-1-ol, 4a.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the alcohol oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate/hexanes, 1:20 with 0.1% TEA) provided 4a (37.6 mg, 0.156
mmol) as a colorless oil in 78% yield (16:1 dr, 95% ee).
Methyl 4-((1S,2S)-1-Hydroxy-2-methylbut-3-enyl)benzo-
ate, 4c. The reaction was performed in accordance with the general
experimental procedure for carbonyl crotylation from the alcohol
oxidation level. Purification of the residue by column chromatography
(SiO2; ethyl acetate/hexanes, 1:20 with 0.1% TEA) provided 4c (34.4 mg,
0.156 mmol) as a colorless oil in 78% yield (11:1 dr, 97% ee).
Methyl 4-((1S,2S)-1-Hydroxy-2-methylbut-3-enyl)benzo-
ate, 4c. The reaction was performed in accordance with the general
experimental procedure for carbonyl crotylation from the aldehyde
oxidation level. Purification of the residue by column chromatography
(SiO2; ethyl acetate/hexanes, 1:20 with 0.1% TEA) provided 4c (35.7 mg,
0.162 mmol) as a colorless oil in 81% yield (13:1 dr, 98% ee). TLC
1
(SiO2): Rf = 0.4 (ethyl acetate/hexanes, 1:5). H NMR (400 MHz,
CDCl3): δ 7.97 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.79-5.69
(m, 1H), 5.17-5.12 (m, 2H), 4.40 (d, J = 7.2 Hz, 1H), 3.88 (s, 3H),
2.49-2.36 (m, 2H), 0.86 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 167.2, 147.9, 140.1, 129.7, 129.6, 127.0, 117.5, 77.3, 52.3,
46.5, 16.6. HPLC (Chiralpak AD-H column, hexanes/i-PrOH = 95:5,
0.5 mL/min, 254 nm): tminor = 27.1 min, tmajor = 32.3 min.
(1S,2S)-1-(6-Bromopyridin-2-yl)-2-methylbut-3-en-1-ol, 4d.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the alcohol oxidation
level. Purification of the residue by column chromatography (SiO2;
ethyl acetate: hexanes, 1:20 with 0.1% TEA) provided 4d (24.2 mg,
0.100 mmol) as a colorless oil in 50% yield (14:1 dr, 98% ee).
(1S,2S)-1-(6-Bromopyridin-2-yl)-2-methylbut-3-en-1-ol, 4d.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the aldehyde oxidation
level. Purification of the residue by column chromatography (SiO2;
ethyl acetate: hexanes, 1:20 with 0.1% TEA) provided 4d (36.3 mg,
0.150 mmol) as a colorless oil in 75% yield (>20:1 dr, 97% ee). TLC
1
(SiO2): Rf = 0.3 (ethyl acetate/hexanes, 1:5). H NMR (400 MHz,
CDCl3): δ 7.53 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.25 (d, J =
8.0 Hz, 1H), 5.73 (dt, J = 17.2, 10.4, 1H), 5.10-4.99 (m, 2H), 4.58 (t, J =
5.2 Hz, 1H), 3.28 (d, J = 6.0 Hz, 1H), 2.72-2.64 (m, 1H), 1.06 (d, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 162.8, 141.0, 138.7, 138.6,
126.7, 120.0, 116.5, 44.6, 16.1. HPLC (Chiralcel OD-H column,
hexanes/i-PrOH = 95:5, 0.5 mL/min, 210 nm): tmajor = 12.1 min, tminor
= 16.8 min.
(1S,2S)-2-Methyl-1-(1-methyl-1H-indol-3-yl)but-3-en-1-ol, 4e.
The reaction was performed in accordance with the general experimental
procedure for carbonyl crotylation from the aldehyde oxidation level.
Purification of the residue by column chromatography (SiO2; ethyl
(1S,2S)-1-(4-Bromophenyl)-2-methylbut-3-en-1-ol, 4a.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the aldehyde oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate/hexanes, 1:20 with 0.1% TEA) provided 4a (39.5 mg, 0.164
mmol) as a colorless oil in 82% yield (17:1 dr, 98% ee). TLC (SiO2): Rf
= 0.4 (ethyl acetate/hexanes, 1:5). 1H NMR (400 MHz, CDCl3): δ 7.46
(d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.81-5.71 (m, 1H), 5.22-
5.16 (m, 2H), 4.32 (d, J = 7.6 Hz, 1H), 2.45-2.37 (m, 1H), 2.20 (br s,
1H), 0.87 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ141.4,
140.1, 131.3, 128.6, 121.4, 117.3, 77.1, 46.4, 16.4. HPLC (Chiralpak AS-
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NOTE
acetate: hexanes, 1:20 with 0.1% TEA) provided 4e (32.3 mg, 0.150
mmol) as a colorless oil in 75% yield (7:1 dr, 98% ee).
tert-Butyl (3R,4S)-3-Hydroxy-4-methylhex-5-enylcarba-
mate, 4h. The reaction was performed in accordance with the general
experimental procedure for carbonyl crotylation from the aldehyde
oxidation level. Purification of the residue by column chromatography
(SiO2; ethyl acetate: hexanes, 1:20 with 0.1% TEA) provided 4h (30.3 mg,
0.142 mmol) as a colorless oil in 66% yield (>20:1 dr, 99% ee). TLC
(1S,2S)-2-Methyl-1-(1-methyl-1H-indol-3-yl)but-3-en-1-ol, 4e.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the aldehyde oxida-
tion level. Purification of the residue by column chromatography
(SiO2; ethyl acetate: hexanes, 1:20 with 0.1% TEA) provided 4e
(31.9 mg, 0.148 mmol) as a colorless oil in 74% yield (10:1 dr, 98%
ee). TLC (SiO2): Rf = 0.4 (ethyl acetate/hexanes, 1:5). 1H NMR
(400 MHz, CDCl3): δ 7.62 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H),
7.26 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.48 (s, 1H), 5.98-5.88
(m, 1H), 5.33-5.25 (m, 2H), 4.60 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H),
2.86-2.78 (m, 1H), 2.22 (br s, 1H), 1.03 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 140.7, 140.3, 138.2, 127.5, 121.9, 120.9, 119.8,
117.4, 109.4, 100.8, 71.4, 44.3, 30.7, 17.5. HPLC (Chiralcel OJ-H
column, hexanes/i-PrOH = 93:7, 0.5 mL/min, 254 nm): tmajor = 53.3
min, tminor = 60.0 min
1
(SiO2): Rf = 0.5 (ethyl acetate/hexanes, 1:3). H NMR (400 MHz,
CDCl3): δ 5.76 (dtd, J = 17.2, 10.0, 0.4 Hz, 1H), 5.12-5.05 (m, 2H),
4.91 (br, 1H), 3.48-3.41 (m, 2H), 3.20-3.11 (m, 1H), 2.58 (d, J =
2.8 Hz, 1H), 2.30-2.17 (m, 1H), 1.72-1.64 (m, 1H), 1.54-1.45 (m,
1H), 1.44 (s, 9H), 1.03 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 156.7, 140.4, 116.1, 79.3, 72.6, 44.2, 37.7, 34.2, 28.4, 16.2.
HPLC enantiomeric excess was determined by HPLC analysis of the
4-nitrobenzoate derivative of the product (Chiralcel OJ-H column,
hexanes/i-PrOH = 98:2, 0.75 mL/min, 254 nm): tminor = 24.4 min,
tmajor = 28.1 min.
(3R,4S)-1-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-ol, 4i.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the alcohol oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate: hexanes, 1:20 with 0.1% TEA) provided 4i (38.1 mg, 0.152
mmol) as a colorless oil in 76% yield (15:1 dr, 97% ee).
(3R,4S,E)-4-Methyl-1-phenylhexa-1,5-dien-3-ol, 4f. The re-
action was performed in accordance with the general experimental
procedure for carbonyl crotylation from the alcohol oxidation level.
Purification of the residue by column chromatography (SiO2; ethyl
acetate/hexanes, 1:20 with 0.1% TEA) provided 4f (27.1 mg, 0.144
mmol) as a colorless oil in 72% yield (10:1 dr, 93% ee).
(3R,4S)-1-(4-Methoxybenzyloxy)-4-methylhex-5-en-3-ol, 4i.
The reaction was performed in accordance with the general experi-
mental procedure for carbonyl crotylation from the aldehyde oxidation
level. Purification of the residue by column chromatography (SiO2; ethyl
acetate: hexanes, 1:20 with 0.1% TEA) provided 4i (38.1 mg, 0.152
mmol) as a colorless oil in 76% yield (>20:1 dr, 99% ee). TLC (SiO2): Rf
(3R,4S,E)-4-Methyl-1-phenylhexa-1,5-dien-3-ol, 4f. The re-
action was performed in accordance with the general experimental
procedure for carbonyl crotylation from the aldehyde oxidation level.
Purification of the residue by column chromatography (SiO2; ethyl
acetate/hexanes, 1:20 with 0.1% TEA) provided 4f (29.0 mg, 0.154
mmol) as a colorless oil in 77% yield (10:1 dr, 98% ee). TLC (SiO2): Rf =
1
= 0.5 (ethyl acetate/hexanes, 1:4). H NMR (400 MHz, CDCl3): δ
1
7.26-7.24 (m, 2H), 6.90-6.86 (m, 2H), 5.80 (dt, J = 17.2, 10.0 Hz,
1H), 5.09-5.02 (m, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.71-3.61 (m,
3H), 2.79 (d, J = 2.8, 1H), 2.23 (qt, J = 6.8, 0.8 Hz, 1H), 1.74-1.70 (m,
2H), 1.03 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.2,
140.5, 130.1, 129.3, 115.4, 113.8, 74.3, 73.0, 68.9, 55.3, 44.0, 33.5, 15.8.
HPLC enantiomeric excess was determined by HPLC analysis of the
4-nitrobenzoate derivative of the product (Chiralcel AD-H column,
hexanes/i-PrOH = 98:2, 1.0 mL/min, 210 nm): tminor = 15.4 min, tmajor
= 24.8 min.
0.3 (ethyl acetate/hexanes, 1:10). H NMR (400 MHz, CDCl3): δ
7.41-7.23 (m, 5H), 6.61 (d, J = 16.0 Hz, 1H), 6.21 (dd, J = 16.0, 7.2 Hz,
1H), 5.88-5.78 (m, 1H), 5.21-5.16 (m, 2H), 4.06 (t, J = 6.8 Hz, 1H),
2.41-2.35 (m, 1H), 1.99 (br s, 1H), 1.06 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 140.4, 136.9, 132.0, 130.4, 128.8, 127.9,
126.8, 117.0, 76.4, 44.9, 16.3. HPLC (Chiralpak AS-H/AS-H
column, hexanes/i-PrOH = 98:2, 0.5 mL/min, 254 nm): tminor
26.8 min, tmajor = 31.5 min.
=
(3R,4S)-4-Methyl-1-phenylhex-5-en-3-ol, 4g. The reaction
was performed in accordance with the general experimental procedure
for carbonyl crotylation from the alcohol oxidation level. Purification of
the residue by column chromatography (SiO2; ethyl acetate: hexanes,
1:20 with 0.1% TEA) provided 4g (27.0 mg, 0.142 mmol) as a colorless
oil in 71% yield (>20:1 dr, 99% ee).
(3R,4S)-4-Methyl-1-phenylhex-5-en-3-ol, 4g. The reaction
was performed in accordance with the general experimental pro-
cedure for carbonyl crotylation from the aldehyde oxidation level.
Purification of the residue by column chromatography (SiO2; ethyl
acetate: hexanes, 1:20 with 0.1% TEA) provided 4g (27.0 mg, 0.142
mmol) as a colorless oil in 71% yield (>20:1 dr, 98% ee). TLC (SiO2):
Rf = 0.4 (ethyl acetate/hexanes, 1:5). 1H NMR (400 MHz, CDCl3): δ
7.31-7.17 (m, 5H), 5.80-5.70 (m, 1H), 5.15-5.10 (m, 2H), 3.43-
3.40 (m, 1H), 2.89-2.81 (m, 1H), 2.72-2.64 (m, 1H), 2.26-2.20 (m,
1H), 1.89-1.80 (m, 1H), 1.75-1.62 (m, 2H), 1.03 (d, J = 6.8 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 142.6, 140.4, 128.7, 128.6, 126.0,
116.8, 74.2, 44.6, 36.4, 32.4, 16.5. HPLC (Chiralcel OD-H column,
hexanes/i-PrOH = 97:3, 0.7 mL/min, 254 nm): tminor = 11.5 min, tmajor
= 18.7 min.
’ ASSOCIATED CONTENT
S
Supporting Information. Spectral data for adducts 4a-i,
b
including scanned images of 1H and 13C NMR spectra and chiral
stationary phase HPLC traces. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mkrische@mail.utexas.edu.
’ ACKNOWLEDGMENT
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038), the NIH-NIGMS (RO1-GM069445), the American
Chemical Society Green Chemistry Institute Pharmaceutical
Roundtable, and the University of Texas at Austin, Center for
Green Chemistry and Catalysis. Dr. Yasunori Ino, Dr. Wataru
Kuriyama, and Dr. Taichiro Touge of Takasago are thanked for
the generous donation of SEGPHOS.
tert-Butyl (3R,4S)-3-Hydroxy-4-methylhex-5-enylcarbamate,
4h. The reaction was performed in accordance with the general
experimental procedure for carbonyl crotylation from the alcohol
oxidation level. Purification of the residue by column chromatogra-
phy (SiO2; ethyl acetate: hexanes, 1:20 with 0.1% TEA) provided
4h (32.6 mg, 0.142 mmol) as a colorless oil in 71% yield (>20:1 dr,
96% ee).
’ REFERENCES
(1) For selected reviews on C-C bond-forming hydrogenation and
transfer hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische, M. J.
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The Journal of Organic Chemistry
NOTE
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(7) As illustrated in ref 2m, investigation into the use of butadiene as
a crotyl donor in iridium-catalyzed C-C bond-forming transfer hydro-
genation is ongoing.
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