Enantioimpure Chiral Auxiliaries
J. Am. Chem. Soc., Vol. 121, No. 40, 1999 9305
nonlinear effects in asymmetric catalysis.27,29 A modeling of
the abnormal behavior in KR (asymmetric amplification or
depletion) has been performed and will be reported soon.31
Kinetic resolution has been carried out on two types of reactions
(oxidation of racemic sulfoxides and diethylzinc addition on
hydratropaldehyde). We found evidence for both abnormal
behavior (asymmetric amplification) and normal behavior,
according to the nature of the catalyst. Kinetic resolution itself
is a way to amplify chirality by means of a partial conversion
of a racemic mixture. It is interesting to note that superimposi-
tion of an asymmetric amplification in a KR leads to an overall
double amplification of chirality.32
organic phases were combined and vigorously stirred with NaOH (15
mL, 2 M) solution for 1 h. After separation of the phases the aqueous
phase was washed with ether (3 × 15 mL). The organic extracts were
combined, dried (MgSO4), and evaporated to dryness to give the crude
product. The crude product was purified by column chromatography
(eluent: ethyl acetate) to give enantiomerically enriched sulfoxide 1a.
The sulfoxide was analyzed by HPLC on a Chiralcel OD-H column
(eluent: hexane:2-propanol (98:2); flow rate: 0.5 mL/min; λ: 254 nm;
Rt-(R): 28.2 min; Rt-(S): 38.2 min).
Kinetic Resolution of Sulfoxide 1b. Ti(O-iPr)4 (0.41 mL, 1.5 mmol)
was added dropwise to a stirred solution of (R,R)-DET (0.5 mL, 3.0
mmol) in 5 mL of CH2Cl2 at 20 °C. The resulting solution was stirred
for 20 min then water (27 µL, 1.5 mmol) was added dropwise over 45
s. After being stirred for an additional 20 min stirring was stopped and
the reaction cooled to -24 °C. After 20 min a solution of sulfoxide 1b
(230 mg, 1.5 mmol) in 1 mL of CH2Cl2 and CHP, precooled to -24
°C (0.44 mL, 3.0 mmol), were added. The reaction was quenched after
16-48 h by pouring into a solution of ferrous sulfate heptahydrate (1
g, 5.4 mmol) and citric acid (330 mg, 1.6 mmol) in water (15 mL).
Ether (15 mL) and 1,4-dioxane (7 mL) were added and the resulting
biphasic mixture was vigorously stirred for 15 min. The phases were
separated and the aqueous phase washed with ether (3 × 15 mL). The
organic phases were combined and vigorously stirred with NaOH (15
mL, 2 M) solution for 1 h. After separation of the phases the aqueous
phase was washed with ether (3 × 15 mL). The organic extracts were
combined, dried (MgSO4), and evaporated to dryness to give the crude
product. The crude product was purified by column chromatography
(eluent: ethyl acetate) to give enantiomerically enriched sulfoxide 1b.
The sulfoxide was analyzed by HPLC on a Chiracel OD-H column
(eluent: hexane:2-propanol (98:2); flow rate: 0.5 mL/min; λ: 254 nm;
Rt-(R): 28.9 min; Rt-(S): 33.9 min).
Catalytic Oxidation of Sulfide 5 (NLE Studies). Ti(O-iPr)4 (0.81
mL, 3.0 mmol) was added dropwise to a stirred solution of (R,R)-DET
(1.0 mL, 6.0 mmol) in 9 mL of CH2Cl2 at 20 °C. The resulting solution
was stirred for 20 min then water (54 µL, 3.0 mmol) was added
dropwise over 90 s. After being stirred for an additional 20 min a
solution of sulfide 5 (0.4 mL, 3.0 mmol) in 1 mL of CH2Cl2 was added
in one portion. On completion of the addition stirring was stopped and
the reaction cooled to -24 °C. After 20 min CHP, precooled to -24
°C (0.89 mL, 6.0 mmol), was added. The reaction was quenched after
16-20 h by pouring into a solution of ferrous sulfate heptahydrate (3
g, 10.8 mmol) and citric acid (1 g, 4.8 mmol) in water (30 mL). Ether
(20 mL) and 1,4-dioxane (15 mL) were added and the resulting biphasic
mixture was vigorously stirred for 15 min. The phases were separated
and the aqueous phase washed with ether (3 × 20 mL). The organic
phases were combined and vigorously stirred with NaOH (15 mL, 2
M) solution for 1 h. After separation of the phases the aqueous phase
was washed with ether (3 × 20 mL). The organic extracts were
combined, dried (MgSO4), and evaporated to dryness to give the crude
product. The crude product was purified by column chromatography
(eluent: ethyl acetate) to give sulfoxide 1b. The sulfoxide was analyzed
as previously described above. (R,R)-DET of eeaux ) 100%, 75%, 50%,
and 25% gave 1b with ee values of respectively 83.8%, 64.0%, 40.5%,
and 22.0%.
Experimental Section
The curves in the various schemes were computed by Mathematica
and Excel and graphics were obtained using Kaleida Graph. All the
reactions were performed under an argon atmosphere using standard
Schlenk techniques. The Schlenks and stirring bars were oven dried.
Measurements of ee’s were made by HPLC analyzed on a Spec-
troseries P100 pump module with a Spectroseries UV100 detector and
a Daicel Chiralcel OD-H column. Measurements of ee’s by chiral GC
were made on a Fisons GC9000 series gas chromatography with an
ASTEC B-PM (â-cyclodextrin, permethylated) 50 m column. Deter-
minations for conversions were made on a Fisons GC8000 series gas
chromatograph with a J&W Scientific DB-1 30 m column. Column
chromatography was performed using silica gel 60 Å (35-70 µm)
purchased from SDS.
Chemicals. Dichloromethane was distilled from calcium hydride.
Diethyl tartrate and titanium tetraisopropoxide were distilled using a
Vigreux column before use. The commercially available cumene
hydroperoxide (80% in cumene alcohol) was purchased from Aldrich
and used without purification. The active free peroxide was determined
by iodometric titration. Racemic sulfoxides were prepared as described
by Ali et al.33 The synthesis of (-)-PDB has been previously described
by Oguni et al.24 Hexane was distilled from sodium benzophenone ketyl
under argon. Diethylzinc and 2-phenylpropanal were purchased from
Fluka and the latter was distilled before use.
Kinetic Resolution of Sulfoxide 1a. Ti(O-iPr)4 (0.20 mL, 0.71
mmol) was added dropwise to a stirred solution of (R,R)-DET (0.49
mL, 2.85 mmol) in 8 mL of CH2Cl2 at 20 °C. The resulting solution
was stirred for 20 min then 2-propanol (0.22 mL, 2.85 mmol) was added
dropwise over 30 s. After being stirred for an additional 20 min a
solution of sulfoxide 1a (100 mg, 0.7 mmol) in 2 mL of CH2Cl2 was
added in one portion. On completion of the addition stirring was stopped
and the reaction cooled to -24 °C. After 20 min CHP, precooled to
-24 °C (0.13 mL, 0.86 mmol), was added. The reaction was quenched
after 16-20 h by pouring into a solution of ferrous sulfate heptahydrate
(1 g, 5.4 mmol) and citric acid (330 mg, 1.6 mmol) in water (15 mL).
Ether (20 mL) and 1,4-dioxane (7 mL) were added and the resulting
biphasic mixture was vigorously stirred for 15 min. The phases were
separated and the aqueous phase washed with ether (3 × 15 mL). The
(27) For definition of indexes of asymmetric amplification in asymmetric
catalysis see the discussion in ref 28.
(28) Kagan, H. B.; Fenwick, D. R. Asymmetric Amplification. In Topics
in Stereochemistry; Denmark, S., Ed.; John Wiley & Sons: New York,
1999; Vol. 22, pp 257-296.
(29) The rate dependency with eeaux has been discussed by D. Blackmond
for MLn models in asymmetric catalysis,30a and for kinetic implications of
NLEs in asymmetric synthesis.30b The same concepts should apply to kinetic
resolution.
(30) (a) Blackmond, D. J. Am. Chem. Soc. 1997, 119, 12934-12939.
(b) Blackmond, D. J. Am. Chem. Soc. 1998, 120, 13349-13353.
(31) Luukas, T. O.; Girard, C.; Fenwick, D.; Kagan H. B. Manuscript in
preparation.
(32) For eeaux values <1 the s′ or eesm values can be higher than expected,
but never higher than the final value of s or eemax (for eeaux ) 1). As
predicted for (+)-NLEs in asymmetric catalysis (see ref 11), one may
envisage s′ or eesm values higher than s or eemax for eeaux < 1. There are,
as yet, no described examples of such situations. We are presently
investigating these cases by both modeling and experiment.31
(33) Ali, M.; Stevens, W. Synthesis 1997, 764-768.
Kinetic Resolution of Racemic Aldehyde 3 with (-)-PDB.
Naphthalene (100 mg), to act as an internal standard, was added to a
stirred solution of (-)-PDB (0.15 mmol) in 15 mL of dry, degassed
hexane. The solution was cooled to 0 °C and diethylzinc (8.2 mmol)
was added in one portion. The temperature was allowed to rise to 17
°C over 30 min then cooled to -20 °C. Racemic 2-phenylpropanal 3
(7.45 mmol) was added dropwise and stirring was continued for an
additional 16-20 h. HCl (20 mL, 1 M) was added and the resulting
mixture was extracted with ether (3 × 35 mL). The organic extracts
were combined, dried (MgSO4), and evaporated to dryness. The
components of the residue were isolated using flash chromatography
(eluent 12:1 n-hexane:ethyl acetate). The ee values of the diastereomers
of 2-phenylpentan-3-ol 4 were determined by GC analysis on a chiral
B-PM column (Rt-anti: 151 min (2R,3S), 154 min (2S,3R); Rt-syn: 171
min (2S,3S), 174 min (2R,3R); isotherm 100 °C).
The unreacted aldehyde 3 was reduced with an excess of LiAlH4
(28 mg, 0.74 mmol) in diethyl ether (5 mL) to give (S)-2-phenylpro-