Bisoxazolidine-catalyzed enantioselective reformatsky reaction

Article abstract of DOI:10.1021/jo200774e

A readily available chiral bisoxazolidine catalyzes the asymmetric Reformatsky reaction between ethyl iodoacetate and aldehydes. In the presence of 10 mol % of the ligand, dimethylzinc, and air, this method produces ethyl 3-hydroxy-3-(4-aryl)propanoates in high yields and in 75 to 80% ee at room temperature within 1 h. In contrast to aromatic substrates, relatively low ee's are obtained with aliphatic aldehydes.

Full text of DOI:10.1021/jo200774e

NOTE
pubs.acs.org/joc
Bisoxazolidine-Catalyzed Enantioselective Reformatsky Reaction
Christian Wolf * and Max Moskowitz
Department of Chemistry, Georgetown University, Washington, D.C. 20057, United States
S Supporting Information
b
ABSTRACT: A readily available chiral bisoxazolidine catalyzes the asym-
metric Reformatsky reaction between ethyl iodoacetate and aldehydes. In the
presence of 10 mol % of the ligand, dimethylzinc, and air, this method
produces ethyl 3-hydroxy-3-(4-aryl)propanoates in high yields and in 75 to
80% ee at room temperature within 1 h. In contrast to aromatic substrates,
relatively low ee’s are obtained with aliphatic aldehydes.
he classical Reformatsky reaction produces β-hydroxy esters
through insertion of zinc into R-halo esters and subsequent
Scheme 1. Asymmetric Reformatsky Reaction Using 1 and 2
T
nucleophilic addition of the zinc enolate to aldehydes or ketones.
Since its introduction in 1887, this reaction has become one of
the most successful carbonÀcarbon bond formation methods,
and it has found numerous synthetic applications which can
certainly be attributed to the remarkable functional group
tolerance and generally mild reaction conditions.1 The advance
of procedures that generate zinc enolates under homogeneous
conditions, for example in the presence of dimethylzinc, set the
stage for asymmetric variants.2 Until recently, few examples of
diastereoselective3 and enantioselective4 Reformatsky reactions
were known, and ee’s obtained were generally low unless
stoichiometric amounts of chiral ligands were used. A break-
through in the development of catalytic enantioselective proce-
dures was made in 2008 when Cozzi and Feringa reported that
ephedrine and BINOL derivatives 1 and 2 effectively catalyze the
Me2Zn-promoted addition of ethyl iodoacetate to aromatic
aldehydes in the presence of air or tert-butyl hydroperoxide
whichaccelerate the zincenolate generation.5 Employing 25 mol %
of N-pyrrolidinylephedrine and catalytic amounts of triphenyl-
phosphine oxide in the Reformatsky reaction between ethyl
iodoacetate and benzaldehyde, Cozzi’s group obtained ethyl
3-hydroxy-3-(4-bromophenyl)propanoate, 3, in 40% yield and
84% ee after 100 h. Feringa et al. were able to produce 3 in the
presence of 20 mol % of 2 in 70% yield and 80% ee (Scheme 1).6
A few years ago, we reported the synthesis of bisoxazolidine 4
from aminoindanol and cyclohexadione, and since then we have
shown several applications of this C2-symmetric N,O-diketal in
asymmetric catalysis (Figure 1).7 This ligand catalyzes the
dimethylzinc-mediated enantioselective alkynylation of a wide
range of aldehydes toward propargylic alcohols with excellent
yields and ee’s.8 It has also been used successfully in the alkylation
of aldehydes with Me2Zn and Et2Zn,9 and in the asymmetric
Henry reaction which can be performed either in the presence of
excess of dimethylzinc or catalytic amounts of copper(I)
acetate.10 Most recently, we have demonstrated the useful-
ness of ligand 4 in the nitroaldol reaction of trifluoromethyl
Figure 1. Structure of bisoxazolidine 4.
ketones and R-keto esters and an asymmetric FriedelÀCrafts
reaction.11
On the basis of the success with asymmetric reactions invol-
ving organozinc species, we decided to introduce 4 to the
Reformatsky reaction. During optimization, we realized that
4-bromobenzaldehyde is significantly less prone to decomposi-
tion than benzaldehyde and therefore a better choice for method
Received: April 13, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200774e J. Org. Chem. 2011, 76, 6372–6376
|

The Journal of Organic Chemistry
NOTE
1À11). Aliphatic substrates gave good yields but low to moderate
ee’s even at reduced temperatures and at higher catalyst
loading, entries 12À14. The results obtained with both linear
and branched aldehydes are comparable with those reported by
Cozzi and Feringa.5
In summary, the bisoxazolidine-catalyzed asymmetric Reformatsky
reaction produces 3-hydroxy-3-(4-aryl)propanoates in high yields
and in 75 to 80% ee at room temperature within 1 h. Our method
requires only 10 mol % of 4, and the results compare well with
previously reported procedures. However, effective asymmetric
induction with aliphatic substrates remains a challenge, and
future work is needed to further improve ee’s.
Figure 2. Radical generation and subsequent formation of the methyl-
zinc enolate.
’ EXPERIMENTAL SECTION
All commercially available reagents and solvents were used without
further purification. NMR spectra were obtained at 400 MHz (1H NMR)
and 100 MHz (13C NMR). Chemical shifts are reported in ppm relative
to TMS. Reaction products were purified by column chromatography on
silica gel (particle size 32À63 μm). Aldehydes were purified prior to use
by distillation under reduced pressure or by flash chromatography on
silica gel using 4% ethyl acetate in hexanes as mobile phase.
Scheme 2. Bisoxazolidine-Catalyzed Reformatsky Reaction
with Bromobenzaldehyde
General ReactionProcedure. A 150mLthree-neck flaskwas fitted
with a CaCl2 drying tube sealed with a stopper. Bisoxazolidine 4 (9.6 mg,
0.024 mmol) was dissolved in 5.0 mL of anhydrous Et2O at room
temperature and transferred into the flame-dried flask, and the solution
was stirred for 5 min under inert atmosphere until ethyl iodoacetate (59.1 μL,
0.50 mmol) was added. After 5 min, B(OMe)3 (27.9 μL, 0.25 mmol) was
added. Then, the reaction was opened to the atmosphere by removing the
stopper from the CaCl2 drying tube. After another 5 min, 1.2 M Me2Zn in
toluene (0.85 mL, 1.0 mmol) was added at once followed immediately by
dropwise addition of the substrate (0.25 mmol) in 1.0 mL of anhydrous
Et2O using a syringe pump(10 μL drops over 10 min). After 4 min, within
the automated addition, another portion of 1.2 M Me2Zn in toluene
(0.85 mL, 1.0 mmol) was added to the reaction flask. The reaction was
allowed to proceed for 1 h and was quenchedwith 10 mLof1 M HCl. The
mixture was extracted with three portions of Et2O and dried over MgSO4,
and solvents were removed in vacuo. The product was purified by flash
chromatography on silica gel as described below.
development. The Reformatsky reaction proved to be very
sensitive to unusual parameters, such as the size of the flask
used, the timing of the exposure to air, and the addition sequence
of dimethylzinc. It is generally assumed that dimethylzinc and
oxygen generate a methyl radical which initiates the formation of
the Reformatsky reagent (Figure 2).12 Because the oxygen has to
diffuse into the reaction mixture to affect the radical process, the
subsequent production of the intermediate methylzinc enolate is
dependent on several parameters including flask size and reaction
volume which determine the surface area at the gasÀliquid
interface. We found that a change in the parameters mentioned
above and in the rate of addition of the aldehyde or in the amount
of ethyl iodoacetate strongly affect yields. For example, when the
amount of ethyl iodoacetate was reduced from 2 to 1 equiv, no
product was isolated. Addition of stoichiometric amounts of
trimethoxyborane led to a 10% increase in yield which may be
attributed to formation of a borate complex with the Reformatsky
product. This transmetalation process should facilitate catalyst
turnover and avoid interference of the alkoxide formed with the
catalytically active zinc complex. By contrast, we observed that
the enantioselectivity of this reaction is considerably less sensi-
tive, and variation of the reaction temperature between 0 and
35 °C did not change ee’s.
Careful optimization of solvent, catalyst loading, introduction
of air, concentration of ethyl iodoacetate, amount of dimethyl-
zinc and trimethoxyborane, and the addition sequence of the
latter and the substrate resulted in a procedure that gives ethyl
3-hydroxy-3-(4-bromophenyl)propanoate, 3, in 90% yield and
78% ee (Scheme 2). Our method involves only 10 mol % of the
ligand and is completed at room temperature within 1 h.
However, a decrease in the temperature did not improve ee’s
any further.
We then continued with the screening of various aldehyde
substrates (Table 1). Benzaldehyde gave ethyl 3-hydroxy-3-(4-
bromophenyl)propanoate, 5, in 79% yield and 77% ee (entry 1),
and similar results were obtained with a range of other
aromatic aldehydes. In general, yields up to 94% were achieved
with this method while ee’s varied between 75 and 80% (entries
Ethyl 3-(4-Bromophenyl)-3-hydroxypropanoate, 3.5a Fol-
lowing the general procedure described above, 3 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH
=
300:100:4) as a colorless oil (90% yield, 76% ee). 1H NMR (400
MHz, CDCl3) δ = 1.26 (t, J = 7.2 Hz, 3H), 2.65À2.74 (m, 2H), 3.46
(bs, 1H), 4.17 (q, J = 7.2 Hz, 2H), 5.08 (m, 1H), 7.25 (d, J = 8.3 Hz, 2H),
7.47 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 13.1, 42.1,
60.0, 68.6, 120.6, 126.4, 130.6, 140.5, 171.2. Ee determination by chiral
HPLC analysis on Chiralpak AS using hexanes:i-PrOH (98:2) as mobile
phase; retention times: t1 (minor) = 11.3 min, t2 (major) = 13.4 min.
Ethyl 3-Hydroxy-3-phenylpropanoate, 5.5a Following the
general procedure described above, 5 was obtained after purification
by flash chromatography (pentane:Et2O:EtOH = 300:100:4) as a
1
colorless oil (79% yield, 77% ee). H NMR (400 MHz, CDCl3) δ =
1.25 (t, J = 7.1 Hz, 3H), 2.67À2.79 (m, 2H), 3.31 (d, J = 3.5 Hz, 1H),
4.17 (q, J = 7.1 Hz, 2H), 5.12 (m, 1H), 7.25À7.39 (m, 5H). 13C NMR
(100 MHz, CDCl3) δ = 14.1, 43.3, 60.8, 70.2, 125.6, 127.7, 128.5, 142.5,
172.4. Ee determination by chiral HPLC analysis on Chiralcel OD using
hexanes:i-PrOH (90:10) as mobile phase; retention times: t1 (major) =
13.8 min, t2 (minor) = 15.6 min.
Ethyl 3-(4-Fluorophenyl)-3-hydroxypropanoate, 6.13 Fol-
lowing the general procedure described above, 6 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH
=
300:100:4) as a colorless oil (70% yield, 76% ee). 1H NMR (400
MHz, CDCl3) δ = 1.26 (t, J = 7.2 Hz, 3H), 2.64À2.76 (m, 2H), 3.39 (bs,
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NOTE
Table 1. Bisoxazolidine-Catalyzed Enantioselective Reformatsky Reactiona
a General reaction conditions: Ethyl iodoacetate (59.1 μL, 0.50 mmol) was added to a solution of bisoxazolidine 4 (9.6 mg, 0.024 mmol) in 5.0 mL of
anhydrous Et2O. After 5 min, B(OMe)3 (27.9 μL, 0.25 mmol) and 1.2 M Me2Zn in toluene (0.85 mL, 1.0 mmol) were added at once, followed by
dropwise addition of the aldehyde (0.25 mmol) in 1.0 mL of anhydrous Et2O over 10 min. Within 4 min of the substrate addition, another portion of 1.2
M Me2Zn in toluene (0.85 mL, 1.0 mmol) was added, and the reaction was stirred for 1 h. b Isolated yields. c Determined by chiral HPLC on Chiralcel
OD and Chiralpak AS or by GC on 6-O-TBDMS-2,3-di-O-methyl-β-cyclodextrin and Lipodex E. Absolute configurations were determined as described
in the literature.5a
1H), 4.18 (q, J = 7.1 Hz, 2H), 5.09 (m, 1H), 7.03 (dd, J = 8.6 Hz, 8.6 Hz,
2H), 7.34 (dd, J = 5.6 Hz, 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ = 14.1, 43.3, 60.9, 69.6, 115.3 (d, JCÀF = 21.4 Hz), 127.3 (d, JCÀF = 8.1
Hz), 138.3 (d, JCÀF = 3.1 Hz), 162.2 (d, JCÀF = 245.7 Hz), 172.2. Ee
determination by chiral HPLC analysis on Chiralpak AS using hexanes:i-
PrOH (98:2) as mobile phase; retention times: t1 (minor) = 10.5 min, t2
(major) = 12.1 min.
Ethyl 3-Hydroxy-3-(4-isopropylphenyl)propanoate, 8.5a
Following the general procedure described above, 8 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH = 300:
1
100:4) as a colorless oil (82% yield, 79% ee). H NMR (400 MHz,
CDCl3) δ = 1.24 (d, J = 6.9 Hz, 6H), 1.26 (t, J = 7.1 Hz, 3H), 2.66À2.80
(m, 2H), 2.90 (sept, J = 6.9 Hz,1H), 3.18 (d, J = 3.3 Hz, 1H), 4.18 (q, J =
7.1 Hz, 2H), 5.11 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H) 7.30 (d, J = 8.0 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 23.9, 33.8, 43.3, 60.8, 70.2,
125.7, 126.6, 139.9, 148.5, 172.4. Ee determination by chiral HPLC
analysis on Chiralpak AS using hexanes:i-PrOH (96:4) as mobile phase;
retention times: t1 (minor) = 20.1 min, t2 (major) = 22.7 min.
Ethyl 3-(4-Chlorophenyl)-3-hydroxypropanoate, 7.5a Fol-
lowing the general procedure described above, 7 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH = 300:
1
100:4) as a colorless oil (86% yield, 78% ee). H NMR (400 MHz,
Ethyl 3-(4-tert-Butylphenyl)-3-hydroxypropanoate, 9.5a
Following the general procedure described above, 9 was obtained after
CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.65À2.74 (m, 2H), 3.44 (bs, 1H),
4.18 (q, J = 7.1 Hz, 2H), 5.10 (m, 1H), 7.21 - 7.41 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ = 14.1, 43.2, 61.0, 69.6, 127.0, 128.6, 133.4, 141.0,
172.2. Ee determination by chiral HPLC analysis on Chiralpak AS using
heptanes:i-PrOH (95:5) as mobile phase; retention times: t1 (minor) =
21.1 min, t2 (major) = 26.4 min.
purification by flash chromatography (pentane:Et2O:EtOH
=
300:100:4) as a colorless oil (79% yield, 79% ee). 1H NMR (400
MHz, CDCl3) δ = 1.26 (t, J = 7.2 Hz, 3H), 1.31 (s, 9H), 2.67À2.80 (m,
2H), 3.17 (d, J = 3.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.11 (m, 1H), 7.31
6374
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NOTE
(d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ = 14.1, 31.3, 34.5, 43.2, 60.8, 70.1, 125.4, 139.5, 150.7, 172.4.
Ee determination by chiral HPLC analysis on Chiralpak AS using
hexanes:i-PrOH (96:4) as mobile phase; retention times: t1 (minor) =
18.3 min, t2 (major) = 20.8 min.
NMR (100 MHz, CDCl3) δ = 14.1, 17.7, 18.3, 33.1, 38.4, 60.6, 72.6,
173.4. Ee determination bychiral GC analysis onLipodexE (25 m  0.25
mm). Initial temperature 50 °C for 60 min, then 10 °C/min until 70 °C,
then 70 °C for 20 min; retention times: t1 (major) = 69.3 min, t2 (minor)
= 69.9 min.
Ethyl 3-Cyclohexyl-3-hydroxypropanoate, 16.5c Following
the general procedure described above, 16 was obtained after purifica-
tion by flash chromatography (pentane:Et2O:EtOH = 500:100:6) as a
Ethyl 3-Hydroxy-3-(4-tolyl)propanoate, 10.13 Following the
general procedure described above, 10 was obtained after purification by
flash chromatography (pentane:Et2O:EtOH = 300:100:4) as a colorless
oil (83% yield, 78% ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.1
Hz, 3H), 2.34 (s, 3H), 2.66À2.74 (m, 2H), 3.22 (bs, 1H), 4.17 (q, J = 7.1
Hz, 2H), 5.08 (m, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ = 14.1, 21.1, 43.3, 60.8, 70.2, 125.6,
129.2, 137.4, 139.6, 172.4. Ee determination by chiral HPLC analysis on
Chiralpak AS using hexanes:i-PrOH (95:5); retention times: t1 (minor) =
18.4 min, t2 (major) = 21.1 min.
1
colorless oil (86% yield, 36% ee). H NMR (400 MHz, CDCl3) δ =
0.96À1.31 (m, 5H), 1.27 (t, J = 7.2 Hz, 3H), 1.38 (m, 1H), 1.62À1.71
(m, 2H), 1.71À1.81 (m, 2H), 1.86 (m, 1H), 2.41 (dd, J = 9.5 Hz, 16.3
Hz, 1H), 2.51 (dd, J = 2.9 Hz, 16.3 Hz, 1H), 2.87 (d, J = 3.8 Hz, 1H),
3.78 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ = 14.1, 26.0, 26.1, 26.4, 28.2, 28.8, 38.6, 43.0, 60.6, 72.1, 173.5. Ee
determination by chiral GC analysis on 6-O-TBDMS-2,3-di-O-methyl-
β-cyclodextrin (5 m  0.25 mm). Temperature at 60 °C; retention
times: t1 (major) = 150 min, t2 (minor) = 175 min.
Ethyl 3-Hydroxy-3-(4-methoxyphenyl)propanoate, 11.5a
Following the general procedure described above, 11 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH = 300:100:4)
as a colorless oil (77% yield, 77% ee). 1H NMR (400 MHz, CDCl3) δ =
1.26 (t, J = 7.2 Hz, 3H), 2.64À2.79 (m, 2H), 3.19 (d, J = 3.1 Hz, 1H), 3.81
(s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 5.08 (m, 1H), 6.88 (d, J = 8.7 Hz, 2H),
7.30 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.3,
55.2, 60.8, 69.9, 113.9, 126.9, 134.7, 159.2, 172.4. Ee determination by
chiral HPLC analysis on Chiralpak AS using hexanes:i-PrOH (95:5);
retention times: t1 (minor) = 10.4 min, t2 (major) = 14.6 min.
Ethyl 3-Hydroxy-3-(2-naphthyl)propanoate, 12.5a Follow-
ing the general procedure described above, 12 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH = 300:
Ethyl 3-Hydroxy-5-phenylpentanoate, 17.16 Following the
general procedure described above, 17 was obtained after purification by
flash chromatography (pentane:Et2O:EtOH = 500:100:6) as a colorless
oil (75% yield, 26% ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.2
Hz, 3H), 1.74 (m, 1H), 1.85 (m, 1H), 2.44 (dd, J = 8.6 Hz, 16.6 Hz, 1H),
2.50 (dd, J = 3.5 Hz, 16.5 Hz, 1H), 2.70 (m, 1H), 2.83 (m, 1H), 3.09 (bs,
1H), 4.02 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 7.16À7.20 (m, 3H),
7.25À7.30 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 31.7, 38.1,
41.3, 60.7, 67.1, 125.9, 128.3, 128.4, 141.7, 173.0. Ee determination by
chiral HPLC analysis on Chiralcel OD using heptanes:i-PrOH (90:10);
retention times: t1 (major) = 12.1 min, t2 (minor) = 14.2 min.
1
100:4) as a colorless oil (89% yield, 79% ee). H NMR (400 MHz,
CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.76À2.86 (m, 2H), 3.44 (s, 1H),
4.18 (q, J = 7.1 Hz, 2H), 5.29 (m, 1H), 7.46À7.48 (m, 3H), 7.81À7.83
(m, 4H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.3, 60.9, 70.4, 123.7,
124.4, 125.9, 126.2, 127.6, 128.0, 128.3, 133.0, 133.2, 139.9, 172.4. Ee
determination by chiral HPLC analysis on Chiralpak AS using hexanes:i-
PrOH (95:5); retention times: t1 (minor) = 29.8 min, t2 (major) =
34.6 min.
’ ASSOCIATED CONTENT
S
Supporting Information. General procedures and NMR
b
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
Ethyl 3-Hydroxy-3-(1-naphthyl)propanoate, 13.14 Following
the general procedure described above, 13 was obtained after purification
by flash chromatography (pentane:Et2O:EtOH = 300:100:4) as a color-
less oil (94% yield, 80% ee). 1H NMR (400 MHz, CDCl3) δ = 1.27 (t, J =
7.1 Hz, 3H), 2.79À2.92 (m, 2H), 3.44 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H),
5.91 (m, 1H), 7.45À7.53 (m, 3H), 7.69 (d, J = 7.1 Hz, 1H) 7.78 (d, J = 8.2
Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ = 14.2, 42.7, 61.0, 67.3, 122.8, 122.9, 125.5, 125.6, 126.2,
128.2, 129.0, 130.0, 133.7, 138.0, 172.7. Ee determination by chiral HPLC
analysis on Chiralcel OD using heptanes:i-PrOH (90:10); retention
times: t1 (major) = 16.2 min, t2 (minor) = 21.3 min.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cw27@georgetown.edu.
’ ACKNOWLEDGMENT
Funding from the National Science Foundation (CHE-0848301)
is gratefully acknowledged.
Ethyl 3-Hydroxy-3-(thiophen-2-yl)propanoate, 14.5a Fol-
lowing the general procedure described above, 14 was obtained after
purification by flash chromatography (pentane:Et2O:EtOH = 300:
’ REFERENCES
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1
100:4) as a colorless oil (77% yield, 75% ee). H NMR (400 MHz,
CDCl3) δ = 1.27 (t, J = 7.2 Hz, 3H), 2.82À2.91 (m, 2H), 3.47 (d, J = 4.2
Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 5.37 (m, 1H), 6.95À6.98 (m, 2H),
7.25 (m, 1H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.1, 66.5, 69.1,
123.6, 124.8, 126.7, 146.2, 171.9. Ee determination by chiral HPLC
analysis on Chiralcel OD using heptanes:i-PrOH (90:10); retention
times: t1 (major) = 11.7 min, t2 (minor) = 30.3 min.
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Ethyl 3-Hydroxy-4-methylpentanoate, 15.15 Following the
general procedure described above, 15 was obtained after purification
by flash chromatography (pentane:Et2O:EtOH = 500:100:6) as a color-
less oil (89% yield, 51% ee). 1H NMR(400 MHz, CDCl3) δ = 0.92 (d, J =
6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.71 (m,
1H), 2.40 (dd, J = 9.5 Hz, 16.3 Hz, 1H), 2.50 (dd, J = 2.8 Hz, 16.3 Hz,
1H), 2.89 (d, J = 3.2 Hz, 1H), 3.78 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H). 13C
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The Journal of Organic Chemistry
NOTE
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’ NOTE ADDED AFTER ASAP PUBLICATION
This paper was published ASAP on June 22, 2011. The title
was updated. The revised paper was reposted on June 24, 2011.
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