Synthesis of W-propionylated (S)-(-)-2-(pyrrolidin-2-yl)propan2-ol and its use as a chiral auxiliary and selectivity marker in asymmetric aldol reactions

Article abstract of DOI:10.1039/b001730m

The N-propionylated pyrrolidine derivative and chiral auxiliary, (S)-(-)-2-(pyrrolidin-2-yl)propan-2-ol, was synthesised and used in stereoselective aldol reactions with benzaldehyde. Differences in stereoselectivity were investigated as a function of temperature, solvent, chelating agent and the amount of the chelating agent used by monitoring the ¹H NMR spectra of the aldol adducts that were obtained. Among the additives that were investigated, Cp₂ZrCl₂ induced higher syn-selectivity, while SnCl₂ induced higher syn-selectivity respectively. TMSCl was found to induce high selectivity for one syn- and one anti-diastereomer. Varying the ligand sets on titanium additives was found to induce differences in selectivity, with (i-PrO)₃TiCl exhibiting syn-selectivity and Cp₂TiCl₂ exhibiting anti-selectivity. Differences in reactivity and stereoselectivity were also found to depend upon the amount of Lewis acid that was added. Methods for removal of the auxiliary were also investigated. Acidic hydrolysis was used successfully to obtain the desired 3-hydroxy-2-methyl-3-phenylpropionic acids, but was found to give low yields and resulted in a large amount of epimerisation. Furthermore, the ethyl esters of these hydroxy acids are easy to separate into pure syn- and anti-diastereomers by LC. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b001730m

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Synthesis of N-propionylated (S)-(؊)-2-(pyrrolidin-2-yl)propan-
2-ol and its use as a chiral auxiliary and selectivity marker in
asymmetric aldol reactions
1
Erik Hedenström,*a Fredrik Anderssona and Mats Hjalmarssonb
a Department of Chemistry and Process Technology, Mid Sweden University,
SE-851 70 Sundsvall, Sweden
b AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden
Received (in Lund, Sweden) 20th December 1999, Accepted 9th March 2000
Published on the Web 19th April 2000
The N-propionylated pyrrolidine derivative and chiral auxiliary, (S)-(Ϫ)-2-(pyrrolidin-2-yl)propan-2-ol, was
synthesised and used in stereoselective aldol reactions with benzaldehyde. Differences in stereoselectivity were
investigated as a function of temperature, solvent, chelating agent and the amount of the chelating agent used
by monitoring the 1H NMR spectra of the aldol adducts that were obtained. Among the additives that were
investigated, Cp2ZrCl2 induced higher anti-selectivity, while SnCl2 induced higher syn-selectivity respectively.
TMSCl was found to induce high selectivity for one syn- and one anti-diastereomer. Varying the ligand sets on
titanium additives was found to induce differences in selectivity, with (i-PrO)3TiCl exhibiting syn-selectivity and
Cp2TiCl2 exhibiting anti-selectivity. Differences in reactivity and stereoselectivity were also found to depend upon the
amount of Lewis acid that was added. Methods for removal of the auxiliary were also investigated. Acidic hydrolysis
was used successfully to obtain the desired 3-hydroxy-2-methyl-3-phenylpropionic acids, but was found to give low
yields and resulted in a large amount of epimerisation. Furthermore, the ethyl esters of these hydroxy acids are easy
to separate into pure syn- and anti-diastereomers by LC.
1
The crude aldol adduct mixture was analysed by H NMR
spectroscopy (250 MHz) which made it possible to simul-
taneously measure both the conversion and the ratio of the
diastereomers that were obtained (syn-2R, syn-2S, anti-2R and
anti-2S). The chemical shifts for the methyl groups located next
to the tertiary alcohol appeared as singlets and varied signifi-
cantly between the hydroxyamide and the four aldol adducts; in
the hydroxyamide 1 they were found at 1.05 ppm, while in syn-
2R, syn-2S, anti-2R and anti-2S they showed up at 1.03, 0.87,
1.02 and 0.74 ppm, respectively (see Fig. 1). Therefore, this
Introduction
Numerous examples can be found in the literature involving the
construction of new asymmetric C–C bonds via aldol addition
reactions.1 The asymmetric induction may be derived from
pre-existing chirality in one of the reaction partners in the con-
struction event (diastereoselective reactions) e.g., when a chiral
auxiliary is used in stoichiometric quantities.2 Several papers
have reported the successful application of proline-derived
auxiliaries and ligands in diastereoselective aldol reactions.3 In
this paper, however, we report the synthesis and utilisation of
an N-propionylated chiral auxiliary, (S)-(Ϫ)-2-(pyrrolidin-2-
yl)propan-2-ol4 1, in aldol reactions with benzaldehyde.
Results and discussion
The amino alcohol, (S)-(Ϫ)-2-(pyrrolidin-2-yl)propan-2-ol
was synthesised in optically pure form according to the liter-
ature5 (see Scheme 1). Accordingly, (S)-(Ϫ)-proline was
reacted with gaseous HCl in MeOH to produce a methyl ester
hydrochloride in quantitative yield. Then, after treatment with
Et3N the free amine was N-benzyl protected in order to give a
tertiary alcohol when reacted with 2.4 equivalents of MeMgI.
Removal of the benzyl protection with hydrogen, catalysed by
Pd/C, gave the aminoalcohol as white crystals in excellent yield.
Crystallisation from hexane gave this very hygroscopic amino-
alcohol in optically pure form, which after propionylation6 with
propionic anhydride afforded the hydroxyamide 1 in excellent
yield.
The general method (see Experimental section) for the aldol
reaction involved addition of the hydroxyamide 1 to freshly
prepared LDA in order to give the Z-lithium amide enolate.7
Benzaldehyde was then added to the enolate, or alternatively an
additive (cf. Table 1) was introduced before adding the benz-
aldehyde. This reaction resulted in the four diastereomers syn-
2R, syn-2S, anti-2R and anti-2S (see Scheme 1).
Fig. 1 The methyl region of the 250 MHz 1H NMR spectrum of
N-propionylated (S)-(Ϫ)-2-(pyrrolidin-2-yl)propan-2-ol 1 and the four
aldol diastereomers that were produced: syn-2R, syn-2S, anti-2R and
anti-2S.
DOI: 10.1039/b001730m
J. Chem. Soc., Perkin Trans. 1, 2000, 1513–1518
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Scheme 1 The synthesis of the N-propionylated (S)-(Ϫ)-2-(pyrrolidin-2-yl)propan-2-ol 1 and the procedure for the aldol reactions which resulted
in one or more of the four possible diastereomers: syn-2R, syn-2S, anti-2R and anti-2S.
proline-derived auxiliary is not only useful as a chiral auxiliary,
but also as a selectivity marker when studying aldol reactions.
The results of the stereoselective aldol reactions are summar-
ised in Table 1. Comparing entries 1 and 2 shows that the
modest syn:anti ratio increased from 54:46 to 66:34 when the
solvent was changed from THF to Et2O; the amount of anti-2S
was also somewhat decreased relative to anti-2R. Lowering the
temperature (entry 3) resulted in a lower syn:anti ratio and
almost the same distribution among the four diastereomers
with respect to entry 2.
In an effort to improve the stereoselectivity of the reaction,
different additives were investigated that had been used in the
literature in similar aldol reactions. When (i-PrO)3TiCl was
added (entry 4), a moderate syn-selectivity was still obtained,
but the amounts of syn-2S and anti-2S increased, indicating a
2S selectivity. However, when Cp2TiCl2 (cf. Procter et al.8) was
used as an additive (entry 9), an anti-selectivity resulted (e.g.
28:72), mostly because of an increase of anti-2R and a decrease
of syn-2S, despite the decrease of anti-2S. Procter et al.8 studied
the aldol reaction of the non-chelating N-propionylpyrrolidine
with benzaldehyde using Cp2TiCl2 as an additive and reported
a similar increase in anti-selectivity (syn:anti 2:98).
with SnCl2 as an additive and all of these cases exhibit increased
conversion with modest and almost identical syn:anti ratios
(e.g. 65:35), though some changes in the selectivity were regis-
tered when Et2O (entry 6) was used instead of THF (entry 5).
The solvent change to Et2O resulted in an increased 2S prefer-
ence, with the ratio of the two anti-isomers anti-2R and anti-2S
becoming inverted and the amount of syn-2S increasing at the
expense of syn-2R. The opposite preference is obtained when
SnCl2 is not added (cf. entry 1 and entry 2), indicating that in
this case the 2S products are disfavoured with Et2O as the sol-
vent. In THF, the amount of added SnCl2 was found to influ-
ence the outcome of the reaction: increasing the amount of
SnCl2 from 1.1 eq. (entry 7) to 2.1 eq. (entry 5) lowered the
amounts of syn-2S and anti-2S that were produced, while
increasing the amount of SnCl2 to 5 eq. caused an inversion in
the anti-2S:anti-2R ratio.
Using Cp2ZrCl2 as an additive (entries 10 and 11) resulted in
anti-selectivity (29:71 and 27:73 respectively), which is oppos-
ite to the report by Evans and McGee9 in which high syn-
selectivity was obtained using N-propionylpyrrolidine as an
auxiliary.
Use of TMSCl as an additive (entry 12) resulted in a modest
anti-selectivity and a very high 2S preference, giving high theor-
etical ee values for the hydroxy acids that would be obtained
after removal of the chiral auxiliary (95% for syn-2S and 98%
for anti-2S respectively, see Table 1). The syn-2S product
probably forms via the non-chelated chair transition state,2a
while the anti-2S product most likely forms via either the non-
Use of SnCl2 as an additive (entry 5) resulted in the highest
syn:anti ratio obtained in this study (73:27), but the conversion
was rather low. The majority of the product consisted of the
syn-2R adduct, corresponding to a hydroxy acid (that would be
obtained after removal of the chiral auxiliary) with a theor-
etical ee value of 84%. Entries 6–8 include varying conditions
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chelated boat or the twist-boat transition state2a respectively.
To fully understand and interpret the outcome of these asym-
metric aldol reactions a proline derivative without the possibil-
ity of chelating to the additives is now in production in our
laboratory. However, the conversion was rather low (entry 12)
and did not increase with longer reaction times. Dichloro-
dimethylsilane was utilised instead of TMSCl in an effort to
produce a bicyclic dimethylsiloxane similar to that which was
obtained when primary (S)-prolinol propionamide was used.3b
However, no such product was formed in this case. From the
various mixtures of diastereomers (see Table 1), each of the
four aldol products syn-2R, syn-2S, anti-2R and anti-2S can be
isolated in stereoisomerically pure form by repeated LC (see
Experimental section).
In order to obtain either 3-hydroxy-2-methyl-3-phenyl-
propionic acids or the corresponding diols, four different
methods of hydrolysis were tested. Acidic hydrolysis4 gave
somewhat low yields 52–55% of the hydroxy acids and
hydrolysis of the stereoisomerically pure aldol product syn-2R
resulted in epimerisation; this was evident from the change in
the syn:anti ratio to 58:42 following hydrolysis. The epimeris-
ation probably occurs at the α-carbon, since Katsuki and
Yamaguchi3c reported no epimerisation at the β-carbon when
hydrolysing an aldol product without an α-methyl substituent
under similar conditions. Basic hydrolysis using 2.5 M KOH
(10% H2O in MeOH) resulted in a retro aldol process which
gave the starting materials, the hydroxyamide 1 and benzalde-
hyde instead of the desired acids. The reductive hydrolysis,10
using a borane–lithium pyrrolidine complex did not under-
go appreciable conversion to the desired diols and basic
hydrolysis11 using H2O2 (30%) and LiOH in a THF–H2O
mixture also showed no conversion to the acids. The chiral aux-
iliary (S)-(Ϫ)-2-(pyrrolidin-2-yl)propan-2-ol was recoverable
as the hydroxyamide 1 in optically pure form from the acidic
hydrolysis mixture in good yield according to the literature.4
The aldol product from entry 12 (syn:anti ratio 38:62) con-
tained >97% of syn-2S- and anti-2S-aldol products which after
acidic hydrolysis gave a syn:anti mixture (42:58) of 3-hydroxy-
2-methyl-3-phenylpropionic acids. The acids in the mixture
were then converted to their ethyl esters and then separated
by LC into pure syn- and anti-forms.12 The optical rotation for
the ethyl ester obtained from syn-2S corresponded well to ethyl
(2S,3S)-3-hydroxy-2-methyl-3-phenylpropionate.12 Based on
the sign of optical rotation for the ester obtained from anti-2S,
this ester corresponds to ethyl (2S,3R)-3-hydroxy-2-methyl-3-
phenylpropionate although the difference from the literature
value for the enantiomer12 is significant.
This work represents the first time that this proline-derived
chiral auxiliary has been used in asymmetric aldol reactions
and it was found to be useful as a selectivity marker when study-
ing such reactions. We are currently investigating the scope and
further applications of this chiral auxiliary and its derivatives in
asymmetric syntheses.
Experimental
Unless otherwise stated starting materials and solvents were
used as received from commercial suppliers. Dry THF (benzo-
phenone and potassium), Et2O (LiAlH4), diisopropylamine
(CaH2), benzaldehyde and TMSCl (CaH2) were distilled from
the indicated drying agents and either used immediately or
stored under argon. SnCl2 was oven dried before use. NMR
spectra were recorded on a JEOL JNM-EX 270 FT-NMR (270
1
1
MHz H) or a Bruker DMX 250 (250 MHz H and 62.9 MHz
13C) instrument, using CDCl3 as the solvent, Si(CH3)4 as the
internal standard; all shifts are reported in ppm. GC analyses
were carried out using a Varian 3300 or a Varian STAR 3400
CX with a 30 m × 0.25 mm id capillary column coated with
HP-5, df = 0.25 µm, carrier gas: He (12 psi), split ratio: 1:20 or
a 30 m × 0.25 mm id capillary column coated with VA-1, df =
J. Chem. Soc., Perkin Trans. 1, 2000, 1513–1518
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0.25 µm, carrier gas: He (12 psi), split ratio: 1:20 respectively.
GC-MS were recorded using a Varian SATURN 2000 GC/MS
with a 30 m × 0.25 mm id capillary column coated with DB-5,
df = 0.25 µm, carrier gas: He (10 psi), split ratio: 1:20. Optical
rotations were carried out on a Perkin-Elmer 241 Polarimeter
and are reported in units of 10Ϫ1 deg cm2 gϪ1. Merck Silica gel
60 (0.040–0.063 mm, 230–400 mesh ASTM) was used in LC
separations. TLC (thin layer chromatography) was performed
on silica gel plates (Merck 60, pre-coated aluminium foil) eluted
with EtOAc (100%), and developed in UV-light and sprayed
with vanillin in sulfuric acid or phosphomolybdic acid in
aqueous sulfuric acid followed by heating with a heat gun. Boil-
ing points are not corrected and the bulb-to-bulb distillations
were performed in a Büchi GKR-51 apparatus. The HRMS
measurements were taken on a VG-70E mass spectrometer.
(S)-(؊)-2-(Pyrrolidin-2-yl)propan-2-ol
(S)-(Ϫ)-2-(N-Benzylpyrrolidin-2-yl)propan-2-ol (41.2 g, 0.188
mol) and Pd/C (2.9 g, 10%) were stirred in methanol (200 ml)
for three days under 1 atm of hydrogen. The catalyst was fil-
tered off and the solvent removed by rotary evaporation to give
a golden oil that crystallised upon standing (23.3 g, 0.180 mol,
96%). The crude product was crystallised twice from hexane
and dried over phosphoric pentaoxide in a vacuum desiccator
to yield the optically pure aminoalcohol (6.52 g, 0.052 mol).
Mp = 37–39 ЊC, lit.4 mp = 37–38 ЊC, [α]D25 Ϫ35.8 (c 1.1, MeOH),
lit.4 [α]D20 Ϫ35.8 (c 1.1, MeOH). 1H NMR (270 MHz): δ 1.13 (3H,
s), 1.17 (3H, s), 1.53–1.79 (4H, m), 2.69 (2H, two overlapping br
s, disappeared on shaking with D2O), 2.87–3.05 (3H, m) ppm.
(S)-(؊)-2-(N-Propionylpyrrolidin-2-yl)propan-2-ol, 1
Methyl (S)-(N-benzylpyrrolidin-2-yl)methanoate
To the aminoalcohol (2.72 g, 21.1 mmol, from above), prop-
ionic anhydride (3.01 g, 23.2 mmol) was added drop by drop
(0.3 h) with stirring under an argon atmosphere. The mixture
was heated at 70 ЊC (0.5 h), then cooled and basified to pH 10
with NaOH (aq. 30%) and stirred for an additional 1.5 h. The
organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (5 × 20 ml). The combined organic
phases were washed with 10% aq. HCl (20 ml), brine (40 ml)
and finally dried (MgSO4). Evaporation of the solvent and
bulb-to-bulb distillation (162–163 ЊC/0.5 mbar) gave the optic-
ally pure hydroxyamide 1 (3.78 g, 20.4 mmol). [α]D25 Ϫ96.5 (c 5.4,
MeOH), lit.4 [α]D20 Ϫ93.2 (c 5.4, MeOH). 1H NMR (270 MHz):
δ 1.05 (3H, s), 1.17 (3H, t, J = 7.4 Hz), 1.19 (3H, s), 1.57–2.15
(4H, m), 2.39 (2H, q, J = 7.4 Hz), 3.32–3.43 (1H, m), 3.62–3.70
(1H, m), 4.13 (1H, apparent t, J = 7.6 Hz), 5.90 (1H, br s, dis-
appeared on shaking with D2O). 13C NMR (62.9 MHz): δ 9.14,
23.18, 24.47, 27.80, 28.64, 28.71, 48.81, 68.13, 73.48, 175.75
ppm. MS (EI) m/z (relative intensity): 186 (25%, MHϩ), 168 (5),
127 (67), 98 (31), 70 (100), 57 (9).
HCl(g) was bubbled through a solution of (S)-(Ϫ)-proline (103
g, 0.90 mol) in methanol (700 ml, p.a.) at Ϫ5 ЊC until no more
HCl(g) was taken up (3.5 h). The solvent was removed by rotary
evaporation, the residue treated with CH2Cl2 (300 ml) and the
CH2Cl2 subsequently removed in vacuo. This process was
repeated 3 times to remove the water formed. The residue was
then dissolved in CH2Cl2 (300 ml), dried (MgSO4) and evapor-
ated to give the title compound (149 g, 0.90 mol). The hydro-
chloride was checked by 1H NMR spectroscopy and used in the
next step without further purification.
The (S)-proline methyl ester hydrochloride (130 g, 0.785 mol)
was dissolved in methanol (180 ml, p.a.) and cooled to 0 ЊC
when dry Et3N (120 ml, 0.858 mol) was added drop by drop
(0.7 h). Et2O (1650 ml, p.a.) was added and after 0.5 h the
triethylammonium chloride formed was filtered off. Removal
of the solvent gave the free base (74.7 g, 0.579 mol). This was
immediately dissolved in dry toluene (150 ml) and added to a
suspension of NaHCO3 (53.4 g, 0.636 mol) and a few crystals
of KI in dry toluene (750 ml). Benzyl bromide (69.4 ml, 0.578
mol) was then added. The mixture was heated to reflux until
10 ml of water had been collected (2 h). After cooling, the sol-
vent was evaporated off and the residue distilled (102 ЊC/0.10
mmHg) to yield the title compound (118 g, 0.538). [α]D20 Ϫ73.6
Aldol reactions: general procedure
To a cooled solution (0 ЊC) of diisopropylamine (0.510 g,
5.0 mmol) in either THF or Et2O (4 ml) under an argon
atmosphere in a two-necked flask (50 ml) was added 1.6 M
n-butyllithium in hexane (2.75 ml, 4.4 mmol). The mixture was
stirred at 0 ЊC (1 h), and to this solution of LDA was added
dropwise a solution of hydroxyamide 1 (0.371 g, 2.0 mmol)
dissolved in THF or Et2O (4 ml). After stirring at 0 ЊC (1 h) the
solution was cooled to Ϫ78 ЊC followed by addition of benz-
aldehyde (0.255 g, 2.4 mmol) in THF or Et2O (4 ml). The mix-
ture was then stirred at Ϫ78 ЊC (2 h) and slowly warmed to
room temperature (2 h).
1
(c 1.2, methanol). H NMR (250 MHz): δ 1.70–2.21 (4H, m),
2.34–2.44 (1H, m), 3.01–3.09 (1H, m), 3.19–3.27 (1H, m), 3.57
(1H, d, J = 12.7 Hz), 3.64 (3H, s), 3.88 (1H, d, J = 12.7 Hz),
7.19–7.35 (5H, m) ppm. 13C NMR (62.9 MHz): δ 22.92,
29.33, 51.71, 53.26, 58.75, 65.29, 127.07, 128.14 (2 C), 129.22
(2 C), 138.20, 174.56 ppm. MS (EI) m/z (relative intensity):
220 (27%, MHϩ), 219 (7, Mϩ), 218 (29, Mϩ Ϫ H), 160 (100),
142 (3), 91 (3).
Alternatively. before the addition of benzaldehyde a Lewis
acid was added (1.1–5.0 eq.) neat (Cp2TiCl2, (i-PrO)3TiCl and
TMSCl) or dissolved in either THF or Et2O (10–17 ml). The
reaction mixture was stirred at low temperature (0.2–0.5 h)
followed by warming to 0 ЊC or to room temperature (0.5–
2.0 h). The mixture was again cooled to Ϫ78 ЊC for 0–1 h,
followed by addition of benzaldehyde (0.255 g, 2.4 mmol, 1.2
eq.) in THF or Et2O (4 ml). For exact equivalents of Lewis acid,
reaction temperatures and times etc., see Table 1. The reaction
mixture was quenched by dropwise addition of aqueous satur-
ated NH4Cl (20–30 ml). Precipitated materials were filtered off
and the organic phase was separated. The aqueous phase was
extracted with CH2Cl2 (5 × 25 ml) and the combined organic
phases were dried (MgSO4). (In the case of remaining precip-
itated material the combined organic phases were washed with
brine and water before drying.) Concentration by evaporation
afforded the crude aldol products.
(S)-2-(N-Benzylpyrrolidin-2-yl)propan-2-ol
To the methyl Grignard reagent prepared from magnesium
chips (30.2 g, 1.147 mol) the methyl ester from above (104 g,
0.478 mol) in dry Et2O (450 ml) was added dropwise at 0–7 ЊC.
The mixture was heated to reflux (2 h) and then stirred at ambi-
ent temperature overnight before quenching with aqueous
saturated NH4Cl (1000 ml). The organic phase was separated
and the aqueous phase extracted with Et2O (4 × 300 ml). The
pooled organic phases were dried (MgSO4) and the solvent
evaporated off to give the alcohol after distillation (97–99.5 ЊC/
0.10 mmHg) as a light brown oil (79.7 g, 0.371 mol). [α]D20 Ϫ49.3
1
(c 0.9, methanol). H NMR (250 MHz): δ 1.17 (3H, s), 1.26
(3H, s), 1.64–1.96 (4H, m), 2.37–2.47 (1H, m), 2.66 (1H, br s,
disappeared on shaking with D2O), 2.73–2.78 (1H, m), 2.85–
2.94 (1H, m), 3.59 (1H, d, J = 13.9 Hz), 4.14 (1H, d, J = 13.9
Hz), 7.20–7.39 (5H, m) ppm. 13C NMR (62.9 MHz): δ 25.16,
25.20, 27.76, 28.66, 55.36, 63.14, 72.69, 72.92, 126.80, 128.05
(2 C), 128.30 (2 C), 140.51. MS (EI) m/z (relative intensity): 220
(31%, MHϩ), 219 (8, Mϩ), 218 (22, Mϩ Ϫ H), 202 (20), 160
(100), 142 (1), 91 (3).
For entry 12 (cf. Table 1) the silyl ether was formed and had
to be removed in order to afford the desired aldol product. The
crude product was dissolved in MeOH (30 ml) and TsOH (10
mg) was added. After stirring overnight at room temperature,
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MeOH was evaporated off and the residue dissolved in CH2Cl2
(30 ml) and washed with Na2CO3 (aq. 10%, 10 ml). The organic
phase was separated and the aqueous phase was extracted with
CH2Cl2 (20 ml). The combined organic phases were dried
(MgSO4) and evaporation afforded the crude aldol product.
The crude product was adsorbed on SiO2 (approx. 5 times the
weight of the crude product) and applied to the top of a column
(id 12.5 mm) with SiO2 (approx. 30 times the weight of the
crude product in SiO2). Eluting with EtOAc in cyclohexane, 0,
1.25, 2.5, 5, 10, 20, 40, 80, 100% and MeOH in EtOAc, 1.25,
2.5, 5, 10, 20%, gave after one repetition of this procedure pure
syn-2R as determined by 1H NMR spectroscopy.
scopy) was dissolved in 1,4-dioxane (14 ml) and 3 M aq. HCl
(14 ml). The solution was stirred at 90–95 ЊC (43 h). After cool-
ing to room temperature, the hydrolysis mixture was extracted
with CH2Cl2 (4 × 25 ml). The combined organic phases were
treated with aqueous saturated Na2CO3 (50 ml). Acidification
of the aqueous phase with 6 M HCl to pH 1–2, extraction with
CH2Cl2 (5 × 25 ml) and drying (MgSO4) gave after evaporation
of the solvent a mixture of acids (0.252 g, 1.40 mmol). Purifi-
cation by bulb-to-bulb distillation (205 ЊC/0.3 mbar) gave 0.195
g (1.08 mmol) of the acids with >94.7% purity by GC. The
1
syn:anti ratio for the mixture was determined by H NMR
spectroscopy to be 48:52. [α]D25 ϩ4.4 (c 0.90, CH2Cl2), lit.13 for
(2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid [α]D Ϫ29.3
(c 0.80, CHCl3) and lit.13 for (2S,3R)-3-hydroxy-2-methyl-3-
phenylpropionic acid [α]D ϩ17.8 (c 2.0, CHCl3). 1H NMR (250
MHz): δ 1.04 (3H, d, J = 7.3 Hz, anti isomers), 1.16 (3H, d, J =
7.3 Hz, syn isomers), 2.81–2.92 (1H, m), 4.77 (1H, d, J = 8.9 Hz,
anti isomers), 5.18 (1H, d, J = 4.0 Hz, syn isomers), 7.26–7.42
(5H, m). MS (EI) m/z (relative intensity): 180 (3%, Mϩ), 162
(5), 133 (7), 117 (38), 107 (73), 91 (25), 77 (100), 51 (34), 45 (15).
Hydrolysis of the pure aldol product syn-2R (0.155 g, 0.53
1
Spectroscopic data for syn-2R. H NMR (250 MHz): δ 1.03
(3H, s), 1.17 (3H, d, J = 7.0 Hz), 1.19 (3H, s), 1.50–1.69 (2H,
m), 1.80–2.13 (2H, m), 2.86 (1H, dq, J = 7.0, 3.6 Hz), 3.22–3.35
(1H, m), 3.55–3.65 (1H, m), 4.14 (1H, apparent t, J = 7.3 Hz),
4.24 (2H, two overlapping br s), 5.09 (1H, d, J = 3.6 Hz), 7.21–
7.40 (5H, m) ppm. 13C NMR (62.9 MHz): δ 10.79, 23.30, 24.40,
27.76, 28.56, 44.94, 49.07, 68.15, 73.16, 73.54, 125.97, 127.31,
128.18, 141.63, 178.44 ppm. MS (EI) m/z (relative intensity):
292 (68%, MHϩ), 274 (23), 256 (3), 233 (8), 218 (5), 185 (4), 167
(3), 126 (100), 107 (8), 70 (36). HRMS (EI, 28 eV): (MHϩ)
292.1904 and (MHϩ Ϫ C3H7O) 233.1400. C17H26NO3 and
C14H19NO2 require 292.1913 and 233.1416 respectively.
1
mmol, 100% purity by H NMR spectroscopy) yielded a syn:
anti mixture (58:42) of acids (0.050 g, 0.28 mmol) as deter-
1
mined by H NMR spectroscopy. [α]D25 Ϫ2.6 (c 0.90, CH2Cl2),
lit.13 for (2R,3R)-2-methyl-3-hydroxy-3-phenylpropionic acid
[α]D ϩ28.5 (c 1.12, CHCl3), and lit.13 for (2R,3S)-2-methyl-3-
hydroxy-3-phenylpropionic acid [α]D Ϫ17.5 (c 2.3, CHCl3).
1
Spectroscopic data for syn-2S. H NMR (250 MHz): δ 0.87
(3H, s), 1.13 (3H, d, J = 7.0 Hz), 1.16 (3H, s), 1.54–1.78 (2H, m),
1.84–2.15 (2H, m), 2.84 (1H, dq, J = 7.0, 4.1 Hz), 3.25–3.37 (1H,
m), 3.62–3.71 (1H, m), 4.09 (1H, apparent t, J = 7.6 Hz), 4.71
(2H, two overlapping br s), 5.04 (1H, d, J = 4.1 Hz), 7.21–7.40
(5H, m) ppm. 13C NMR (62.9 MHz): δ 10.34, 23.02, 24.40,
27.77, 28.67, 44.91, 48.94, 68.15, 73.32, 73.99, 126.25, 127.40,
128.23, 141.64, 178.09 ppm. MS (EI) m/z (relative intensity):
292 (16%, MHϩ), 274 (5), 233 (31), 218 (27), 185 (14), 167 (3),
126 (100), 107 (13), 70 (75). HRMS (EI, 28 eV): (MHϩ Ϫ
C3H7O) 233.1576 and (MHϩ Ϫ C10H14O2) 126.0961. C14H19NO2
and C7H12NO require 233.1416 and 126.0919 respectively.
Ethyl (2S,3S)- and (2S,3R)-3-hydroxy-2-methyl-3-phenyl-
propionate
Hydrolysis of a mixture of aldol products (76 mg, 0.26 mmol,
syn-2S:anti-2S = 32:68, 100% pure by 1H NMR spectroscopy)
by the same procedure as above yielded a yellow oil (46 mg).
The crude product of the acids was dissolved in EtOH (99.5%,
10 ml), and H2SO4 (conc., 2 drops) was added. After refluxing
(21 h) the reaction mixture was poured into H2O (20 ml) and
extracted with pentane (5 × 20 ml). The combined organic
phases were washed with aqueous saturated Na2CO3 (2 × 20
ml), brine (20 ml) and finally dried (MgSO4). Evaporation of
the solvent gave a yellow oil (30 mg, 0.14 mmol). Separation by
LC (using the same procedure as for the separation of aldols,
see above) gave 6 mg of (2S,3S)-3-hydroxy-2-methyl-3-phenyl-
propionate and 14 mg of ethyl (2S,3R)-3-hydroxy-2-methyl-3-
phenylpropionate both with 100% purity by GC.
Spectroscopic data for ethyl (2S,3S)-3-hydroxy-2-methyl-3-
phenylpropionate obtained from aldol product syn-2S: [α]D25
Ϫ23.4 (c 0.36, CHCl3), lit.12 [α]D17 Ϫ22.0 (c 0.87, CHCl3). MS (EI)
m/z (relative intensity): 208 (7%, Mϩ), 191 (5), 163 (3), 135 (5),
117 (7), 107 (47), 102 (100), 77 (74), 74 (81), 57 (23).
Spectroscopic data for ethyl (2S,3R)-3-hydroxy-2-methyl-3-
phenylpropionate obtained from aldol product anti-2S: [α]D25
ϩ47.1 (c 1.12, CHCl3), lit. for ethyl (2R,3S)-3-hydroxy-2-
methyl-3-phenylpropionate12 [α]D17 Ϫ15.3 (c 1.11, CHCl3). MS
(EI) m/z (relative intensity): 208 (3%, Mϩ), 191 (37), 163 (3), 135
(37), 117 (7), 107 (46), 102 (100), 77 (38), 74 (42), 57 (20).
1
Spectroscopic data for anti-2R. H NMR (250 MHz): δ 1.02
(3H, s), 1.18 (3H, s), 1.20 (3H, d, J = 7.0 Hz), 1.35–1.64 (2H,
m), 1.72–2.08 (2H, m), 3.01 (1H, dq, J = 7.0, 6.4 Hz), 3.17–3.28
(1H, m), 3.49–3.58 (1H, m), 4.10 (1H, apparent t, J = 7.7 Hz),
4.29 (2H, two overlapping br s), 4.79 (1H, d, J = 6.4 Hz),
7.22–7.43 (5H, m) ppm. 13C NMR (62.9 MHz): δ 15.52, 23.22,
24.21, 27.71, 28.55, 45.45, 49.07, 67.96, 73.44, 76.43, 126.15,
127.72, 128.39, 142.55, 177.55 ppm. MS (EI) m/z (relative inten-
sity): 292 (76%, MHϩ), 274 (24), 256 (5), 233 (11), 218 (4), 185
(4), 167 (4), 126 (100), 107 (11), 70 (57). HRMS (EI, 28 eV):
(MHϩ Ϫ C3H7O) 233.1594 and (MHϩ Ϫ C10H14O2) 126.0953.
C14H19NO2 and C7H12NO require 233.1416 and 126.0919
respectively.
1
Spectroscopic data for anti-2S. H NMR (250 MHz): δ 0.74
(3H, s), 1.12 (3H, s), 1.20 (3H, d, J = 7.0 Hz), 1.53–1.77 (2H,
m), 1.85–2.10 (2H, m), 2.99 (1H, dq, J = 7.0, 5.9 Hz), 3.22–3.40
(1H, m), 3.62–3.71 (1H, m), 4.07 (1H, apparent t, J = 7.5 Hz),
4.71 (2H, two overlapping br s), 4.80 (1H, d, J = 5.9 Hz),
7.22–7.43 (5H, m) ppm. 13C NMR (62.9 MHz): δ 14.61, 22.86,
24.29, 27.71, 28.67, 45.35, 49.05, 68.28, 73.52, 76.56, 126.01,
127.17, 127.47, 128.36, 142.70, 177.28 ppm. MS (EI) m/z
(relative intensity): 292 (45%, MHϩ), 274 (12), 233 (18), 218 (5),
185 (5), 167 (4), 126 (100), 107 (14), 70 (61). HRMS (EI, 28 eV):
(MHϩ Ϫ C3H7O) 233.1526 and (MHϩ Ϫ C10H14O2) 126.0954.
C14H19NO2 and C7H12NO require 233.1416 and 126.0919
respectively.
Acknowledgements
Financial support from the City of Sundsvall (Sundsvalls
Kommun), Swedish Natural Science Research Council (NFR)
and the Swedish Council for Forestry and Agricultural
Research (SJFR) is gratefully acknowledged. We thank Pierre
Ljungquist at STFI (Swedish Pulp and Paper Research
Institute) for performing HRMS measurements.
References
(2S,3S) and (2S,3R)-3-Hydroxy-2-methyl-3-phenylpropionic
acids. Hydrolysis general method
1 For some examples, see: (a) S. G. Nelson, Tetrahedron: Asymmetry,
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A diastereomeric mixture of aldol products (0.538 g, 1.85
mmol, syn:anti = 65:35, determined by 1H NMR spectro-
J. Chem. Soc., Perkin Trans. 1, 2000, 1513–1518
1517

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