Synthesis of chiral 2-hydroxy-1-methylpropanoates by rhodium-catalyzed stereoselective hydrogenation of α-(hydroxymethyl)-acrylate derivatives

Article abstract of DOI:10.1002/adsc.200800525

The synthesis of chiral 3-hydroxy-2-methylpropanoic acid esters (e.g., "Roche ester" 3a) based on the rhodium-catalyzed stereoselective hydrogenation of Baylis-Hillman reaction products was investigated. Full conversions and enantioselectivities of up to 99% at a substrate/catalyst ratio of up to 500/1 were achieved by application of bisphospholanes of the catASium M series as ancillary ligands. An interesting kinetic resolution was observed by the diastereoselective hydroxy-directed hydrogenation of related racemic β-branched precursors affording mainly anti-isomers with up to 96%ee.

Full text of DOI:10.1002/adsc.200800525

FULL PAPERS
DOI: 10.1002/adsc.200800525
Synthesis of Chiral 2-Hydroxy-1-methylpropanoates by Rhodium-
Catalyzed Stereoselective Hydrogenation of a-(Hydroxymethyl)-
acrylate Derivatives
Jens Holz,a,* Benjamin Schꢀffner,a Odalys Zayas,b Anke Spannenberg,a
and Armin Bçrnera,b,*
a
Leibniz-Institut fꢁr Katalyse an der Universitꢀt Rostock e.V., A.-Einstein-Str. 29a, 18059 Rostock, Germany
Fax : (+49)-381-1281-51202; e-mail: jens.holz@catalysis.dearmin.boerner@catalysis.de
Institut fꢁr Chemie, Universitꢀt Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
b
Received: August 22, 2008; Published online: November 4, 2008
Abstract: The synthesis of chiral 3-hydroxy-2-methyl- esting kinetic resolution was observed by the diaste-
propanoic acid esters (e.g., “Roche ester” 3a) based reoselective hydroxy-directed hydrogenation of relat-
on the rhodium-catalyzed stereoselective hydrogena- ed racemic b-branched precursors affording mainly
tion of Baylis–Hillman reaction products was investi- anti-isomers with up to 96%ee.
gated. Full conversions and enantioselectivities of up
to 99% at a substrate/catalyst ratio of up to 500/1
were achieved by application of bisphospholanes of Keywords: asymmetric catalysis; hydrogenation; ki-
the catASium M series as ancillary ligands. An inter- netic resolution; phospholanes; rhodium
Introduction
in the synthesis of (+)-13-deoxytedanolide,[1] (À)-dic-
tyostatin,[2] spiculoic acid A,[3] and discodermolide,[4]
Enantiomerically pure 3-hydroxy-2-methylpropio- respectively. In spite of their huge synthetic potential,
nates of the general formula 3 (Scheme 1, R=H, the number of synthetic venues is strongly limited.[5]
alkyl) represent versatile C4-building blocks for the Recently, Ratovelomanana-Vidal and GenÞt showed
synthesis of natural products as well as for the con- that the homogeneous enantioselective hydrogenation
struction of other biologically active compounds. of the unsaturated precursor a-(hydroxymethyl)-
These compounds have seen, for example, application
ACHTUNGTRENaNUGN crylic acid ester (2) represents a synthetic methodol-
Scheme 1. Synthesis of functionalized olefins 2 and 4 by Baylis–Hillman reaction and their subsequent stereoselective hydro-
genation.
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Jens Holz et al.
FULL PAPERS
ogy of high potential. By using
a chiral Ru-
AHCTUNGTREG(NNUN SYNPHOS) hydrogenation catalyst pertinent chiral
esters yielded by up to 94% ee.[5,6] Interestingly, only
two example exist in the literature which are con-
cerned with the use of rhodium complexes. Thus,
Reek et al. achieved up to 98% ee with an INDOL-
PHOS ligand with TOFs over 5500 hÀ1 by application
of low temperatures (À408C).[7] Saito and co-workers
reported 90% ee with DuPHOS and BeePHOS as
chiral ligands.[8] The latter belong to the large family
of bisphospholanes.[9]
Inspired by these investigations and taking our own
observations in mind that small changes in the struc-
ture of bisphospholane ligands may cause dramatic ef-
fects in the outcome of the asymmetric hydrogena-
tion,[10] herein we report our results on the Rh-cata-
lyzed asymmetric hydrogenation of a-(hydroxymeth-
AHCTUNGTRENNUNG
yl)acrylates (2) with catASium M ligands.[11] These bi-
sphospholanes belong to
a
large family of
commercially available and strongly related ligands.
Therefore, fine tuning of the reaction can be easily
achieved. The required prochiral olefins 2 are avail-
able by Baylis–Hillman reaction of the corresponding
acrylates 1 with formaldehyde.[12a] Moreover, this syn-
thetic approach also allows the preparation of racemic
(a-branched hydroxymethyl)acrylates of type 4 which
are highly challenging substrates for the diastereose-
lective hydrogenation of the olefinic group.
Results and Discussion
In order to identify the most efficient ligand types for
the asymmetric transformation in the beginning of
our research we screened the hydrogenation of sub-
strate 2a with rhodium catalysts bearing ferrocene li-
gands JOSIPHOS,[13] DPPFtBP[13] and BoPHOZ[14] as
well as the atropisomeric ligand SYNPHOS.[15] Re-
quired cationic precatalysts of the type [RhACTHNUTRGENNU(G COD)ACHTUNGTRENNUNG(P–
P)]BF4 were prepared prior to the asymmetric reac-
tion. The hydrogenations were carried out with a
ratio of substrate/catalyst of 100:1 at 25 or 50 bar ini-
tial H2 pressure at 258C over a period of 12 h. The re-
sults (Table 1) show that full conversion, but disap-
pointingly low ee values were achieved. Only the cata-
lyst based on JOSIPHOS gave the so-called “Roche
ester” 3a as well as t-butyl ester 3b (entry 2) with
moderate ee values (33–77%).
Next, we turned our attention to the use of the of
catASium ligands 6–11 (Figure 1).[11b] Differences in
the substitution pattern and ring size of the backbone
of the ligands should provide some information about
electronic and/or steric effects. The results are sum-
marized in Table 2.
In most reactions full conversion was achieved in
less than 90 min. The ee values are in the range from
0–98%. Our results clearly evidence that the ring size
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Synthesis of Chiral 2-Hydroxy-1-methylpropanoates
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In methanol the Rh catalysts based on ligand 10 bear-
ing an anhydride structure in the backbone showed
varying results in dependence on the time of pretreat-
ment. Thus, after stirring of the precatalyst
[RhACTHNUTRGNEU(GN COD)(10)]BF4 in methanol for one hour the
enantioselectivity differed from the values noted by
using the same precatalyst without preformation (en-
tries 10/26 vs. entries 11/27). This result might be at-
tributed to the ring opening reaction and transesterifi-
cation with methanol.[17]
In general, hydrogenation at elevated H2 pressure,
which proceeded faster than at 1 bar, is recommended
in order to avoid the formation of traces of by-prod-
ucts due to oligomerization of the starting olefin and
dehydroxylation of the product. In regard to enantio-
selectivity the pressure effect is small. In some exam-
ples a slight increase (entries 8, 15) or a slight de-
Figure 1. Structures of ligands 6–11.
of the ligand backbone does not dramatically influ- crease was observed (e.g., entries 1, 2, 9, 17). In meth-
ence the stereodifferentiating properties of the cata- anol the influence of the applied pressure is more
lyst.[16] Also, the replacement of the 2,5-dimethyl sub- pronounced than in aprotic solvents (entries 10, 14,
stituents at the phospholane by ethyl groups (ligands 26).
9 vs. 11) did not strongly affect the enantioselectivi-
ties.
In the next step of our optimization approach we
investigated the influence of the initial hydrogen pres-
A much stronger effect can be attributed to the sol- sure and the substrate:catalyst ratio on the asymmet-
vent (e.g.. entries 14/30 vs. 16/32). In general, the use ric hydrogenation using the precatalyst based on
of aprotic solvents (tetrahydrofuran, dichlorome- ligand 11. All reactions were carried out at 258C in
thane) was superior in comparison to methanol. In THF and conducted over a period of two hours. The
the latter several hours were required to achieve full results in Table 3 illustrate that a decrease of the pres-
conversion. It is remarkable to note that the catalysts sure influences the ee values in the product only mar-
derived from the fluorinated ligand 7 gave nearly rac- ginally. The reactions can be carried out even with
emic mixtures of 3a or 3b in methanol (entries 3 and higher ratios of substrate to catalyst (entries 5 and 7).
19) whereas in aprotic solvents 90–98% ee resulted However to our surprise in the hydrogenation of sub-
(entries 4, 5, 20, 21). The reason for this disparate be- strate 2b with an S/C ratio of 500 only traces of the
haviour is not clear and currently under investigation. desired product were formed (entries 14 and 16).
Table 2. Results of the asymmetric hydrogenation of 2a, b (1 and 50 bar, up to 90 min).[a]
2a
2b
Entry
Ligand
Solvent
ee [%] at 1 bar
ee [%] at 50 bar
Entry
ee [%] at 1bar
ee [%] at 50 bar
1
2
3
4
5
6
7
8
6
6
7
7
7
8
8
9
THF
90 (S)
92 (S)
racemic
91 (S)
94 (S)
93 (S)
95 (S)
89 (S)
97 (S)
79 (S)
–
92 (S)
95 (S)
40 (R)
88 (R)
93 (R)
84 (S)
85 (S)
racemic
90 (S)
95 (S)
95 (S)
94 (S)
95 (S)
91 (S)
84 (S)
79 (S)[b]
93 (S)
93 (S)
80 (R)
94 (R)
95 (R)
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
95 (S)
93 (S)
28 (S)
96 (S)
98 (S)
97 (S)
95 (S)
97 (S)
97 (S)
93 (S)
–
96 (S)
95 (S)
61 (R)
99 (R)
94 (R)
81 (S)
89 (S)
19 (S)
97 (S)
98 (S)
95 (S)
92 (S)
96 (S)
96 (S)
77 (S)
92 (S)[b]
95 (S)
95 (S)
57 (R)
95 (R)
93 (R)
CH2Cl2
MeOH
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
MeOH
MeOH
THF
9
9
10
11
12
13
14
15
16
10
10
10
10
11
11
11
CH2Cl2
MeOH
THF
CH2Cl2
[a]
For other reactions conditions and analytics of the reaction product, see Table 1.
[b]
The precatalyst with ligand 10 was stirred in MeOH for 60 min. Under these conditions the anhydride was opened quanti-
tatively.[16]
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Table 3. Influence of reaction conditions on the hydrogenation with ligand 11 in THF.[a]
2a
2b
Entry
S:C
pH2 [bar]
ee [%]
Entry
S:C
pH2 [bar]
ee [%]
1
2
3
4
5
6
7
100
100
100
250
500
250
500
90
60
30
50
50
25
25
96 (R)
93 (R)
92 (R)
94 (R)
93 (R)
95 (R)
96 (R)
10
11
12
13
14
15
16
100
100
100
250
500
250
500
90
60
30
50
50
25
25
95 (R)
94 (R)
93 (R)
97 (R)
n. d.[b]
97 (R)
n. d.[b]
[a]
For other conditions and analytics of the reaction products, see Table 1.
Only traces of the product were formed.
[b]
As announced in the introduction, in order to When a chiral RhACTHNUTRGENNGU AHCUTNGTREN(NUNG BINAP) cat-
(DiPAMP)[19a–c] or Ru
extend the range of substrates, we also used as sub- alyst[21] was employed diastereoselective hydrogena-
strates olefins 4a–e which are likewise available by tion could be achieved caused by different reaction
Baylis–Hillman reaction of aromatic aldehydes and rates of the enantiomeric substrates.[22]
methyl acrylate.[12] Among others, products of the hy-
In order to confirm these pioneering results we hy-
drogenation have importance in drugs with antiproli- drogenated the olefins with an initial H2 pressure at
ferative activity.[18] Due to the already established 20 bar in methanol at room temperature. In first trials
stereocentre in the substrate the hydrogenation with substrates 4a–e were reduced until full conversion
chiral catalysts should provide interesting information (20 h). By application of the achiral precatalyst
as to whether the stereochemistry in the final product [RhACHTNUTRGNENUG(dppb)ACHTUGNTREN(NUGN COD)]BF4 the racemic mixtures of the
is governed by the substrate or by the catalyst. Princi- diastereomers anti-5a,c,d,e were obtained in a anti/syn
pally, the hydrogenation of racemic 4 with an achiral ratio of > 90/10. Exceptionally, under these condi-
rhodium catalyst may afford a mixture of two pairs of tions the hydrogenation of 4b afforded not only 5b.
racemic diastereomers 5 where hydroxy group and As a side product the corresponding aniline derivative
the newly created methyl substituent are placed anti-5b’ was formed as a result of the reduction of the
either in a synACHTUNGTRENNUNG(erythro)- or an antiACHTUNGTRENNUNG
(Scheme 2).
The hydrogenation of 4a was already investigated analysis (Figure 2).[23]
by Brown et al. with the homogeneous Rh catalyst in
The application of Pd on charcoal as a heterogene-
hand.[19] It was found that in methanol the anti-prod- ous catalyst at ambient pressure in THF led predomi-
uct was preferentially formed. This preference was at- nantly to the formation of the aniline derivative 5b’,
tributed to attractive stereodirecting interactions be- but under these conditions significant hydrogenolysis
tween hydroxy group in the substrate and the metal of the benzylic alcohol took place to give 5b’’
centre during the transfer of hydrogen. Protection of (Scheme 3). The compound anti-5b’ was detected as a
the polar group led to a significant decrease of the an- by-product in the homogeneous hydrogenation of rac-
ti:syn ratio.[20] In contrast, by application of a hetero- emic mixture of 4b.
geneous Pd catalyst the anti/syn ratio was diminished.
Scheme 2. Possible hydrogenation products derived from 4a–e.
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Synthesis of Chiral 2-Hydroxy-1-methylpropanoates
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tives is larger than for the corresponding syn-isomer
(~8 Hz vs. 4 Hz).
In general, by employment of the chiral Rh cata-
lysts based on ligands 6, 8–10 or 11 only poor ee
values were noted (Table 4). This observation gives
proof that the stereodifferentiating addition of H2 is
dominated by the adjacent chiral centre in the sub-
strate and not by the chiral catalyst. Also under our
conditions the syn-products were formed in less than
4%. Surprisingly in the hydrogenation of the (2-pyrid-
yl)-substituted derivative 4e with the achiral
Scheme 3. Products of the heterogeneous Pd-catalyzed hy-
drogenation of 4b.
[RhACHTNUTRGENNUG(dppb)ACHTUNGTRENN(UGN COD)]BF4 and the chiral Rh catalyst of 9
we observed an increase in the formation of the syn-
over the anti-compound (79:21 and 68:32, respective-
ly). This change nicely illustrates that the decisive sec-
ondary interaction of the substrate with the Rh centre
is now governed by the pyridine nitrogen instead of
the hydroxy group.
Under the precondition evidenced above, that the
stereochemical course of the hydrogenation is domi-
nated by the chiral substrate, interruption of the hy-
drogen uptake at ca. 50% conversion opens up the
opportunity of a diastereoselective reaction provided
a highly stereoselective catalyst can be found which
reacts much faster with one enantiomer of the race-
mic substrate. In this case the classical situation of a
kinetic resolution is established.[26] In order to test
this hypothesis we stopped the reaction of 4a with cat-
Figure 2. X-ray structural analysis of anti-5b. The thermal el-
lipsoids correspond to 30% probability.
The anti-geometry for the other main products 5a, alysts based on ligands 9 and 11 after varying periods
c–e could be established by comparison of the NMR of hydrogen uptake and determined conversion
spectra.[24] Thus, the signal of the CHO proton is shift- (NMR, HPLC) as well as enantiomeric composition
ed downfield for the syn-isomer (region of 4.95 to of the reaction mixture (HPLC). From Figure 3 it is
5.15 ppm vs. 4.60 to4.85 ppm for the anti-isomer). apparent that during the first half of the reaction (ca.
Also the relevant coupling constant of the anti-deriva- 50% conversion) mainly anti-product 5a was formed.
Table 4. Results of the asymmetric hydrogenation of 4a–e at room temperature.[a]
Entry
Substrate
Ligand
Solvent
pH2 [bar]
ee [%][25]
1
2
3
4
5
6
7
8
4a
4b
4b
4b
4b
4b
4b
4b
4c
4c
4d
4e
4e
9
6
8
9
10
10
11
11
9
11
11
9
MeOH
THF
THF
THF
MeOH
THF
MeOH
THF
THF
THF
THF
1
17 (+)[b]
9 (+)
2 (+)
1 (+)
27 (+)
4 (+)
50
50
50
50
50
50
50
1
2 (À)
5 (À)
9
8 (+)
10
11
12
13
50
50
1
7 (À)
7 (À)
MeOH
THF
25(À)/90(+)[c]
9
1
47(À)/94(+)[d]
[a]
Conditions: 0.33 mmol substrate, 0,0033 mmol Rh catalyst, 5 mL solvent, 258C, 120 min (50 bar) or until completion of
hydrogen consumption (1 bar). For other reaction conditions and analytics of the hydrogenation products, see Experimen-
tal Section.
[b]
[c]
[d]
(+)=(2S,3R)-configuration, (À)=(2R,3S)-configuration.
syn/anti=76:24; absolute configuration could not be determined.
syn/anti=68:32; absolute configuration could not be determined.
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A similar behaviour was found in other solvents
(MeOH, CH2Cl2), with substrates 4b–e (Table 5).
Obviously the difference in the hydrogenation rates
of the enantiomeric starting products is large enough
to allow for a good stereodifferentiation. Proof for
this assumption can be easily derived from the hydro-
gen uptake curves (Figure 4), which are clearly sepa-
rated into two parts. Figure 4 a and b (bold lines) il-
lustrates the hydrogen consumption in the reaction
with 4a and 4c under ambient reaction conditions
(258C, 1 bar) using [Rh(9)ACHTNUGTRENUNG(COD)]BF4. In the first
part, for example, after ca. 50% of required H2
volume uptake, the preferred (S)-enantiomers are
consumed rapidly followed by a slow reaction of the
less-favored (R)-enantiomers. A different behaviour
is noted in the hydrogenation of the 2-pyridyl-substi-
tuted substrate 4e (Figure 4 b, empty squares). This
&
*
Figure 3. Selective hydrogenation of 4a (&/ ) to anti-5a ( /
*
* *
) with [Rh(9)
A
ACHTUNGTNER(NUNG COD)]BF4
*
hydrogenation is characterized by
a continuous
uptake of hydrogen without deceleration after ca.
50% conversion. Apparently, both the hydroxy group
In this stage the product was generated with nearly and the 2-pyridyl group compete for coordination
constant enantiomeric excess and the starting product with the rhodium centre. Therefore both enantiomeric
4a became enantiomerically enriched with the less substrates are hydrogenated by the same catalyst with
favoured enantiomer. The maximum ee value of both similar rates and kinetic resolution is impossible. The
enantiomeric compounds was found around a conver- predominant formation of the syn-isomer of 5e (e.g.,
sion of 48–52%. As expected in the second half of the anti-isomer relative to the pyridyl group) indicates
reduction also the less favoured enantiomeric starting that the coordinating ability of the 2-pyridyl group is
product reacts to give the anti-product with the oppo- stronger.
site configurations, hence in the end nearly racemic
product is obtained.
In a preparative trial we interrupted the hydrogena-
tion reaction of 4a with ligand 9 at ca. 50% conver-
Table 5. Chiral composition of mixtures after ca. half conversion of 4a–e.[a]
Entry
Substrate
Ligand
Solvent
Conversion [%]b
anti:syn[b]
eeEduct [%][c]
eeProduct [%][d]
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
9
9
9
11
11
11
9
THF
52
53
47
51
53
49
51
54
40
52
52
48
49
50
58
59
98:2
98:2
>99:1
97:3
97:3
96 (À)
85 (À)
77 (À)
88 (+)
91 (+)
83 (+)
93 (À)
94 (À)
54 (+)
88 (+)
95 (À)
82 (+)
85 (À)
73 (+)
10 (+)[f]
14 (À)[f]
91 (+)
80 (+)
93 (+)
MeOH
CH2Cl2
THF
MeOH
CH2Cl2
THF
MeOH
THF
MeOH
THF
88 (À)
82(À)
99:1
89 (À)
4b[e]
4b[e]
4b[e]
4b[e]
4c
>99:1
>99:1
>99:1
>99:1
98:2
98:2
99:1
97:3
32:68
29:71
92 (+)
9
82 (+)
9
11
11
9
11
9
11
9
11
88 (À)
10
11
12
13
14
15
16
84 (À)
89 (+)
4c
4d
4d
4e
THF
THF
THF
THF
90 (À)
84 (+)
84 (À)
99 (+)/54 (À)[f]
99 (À)/40 (+)[f]
4e
THF
[a]
Reaction conditions: H2 (1 bar, isobar), 0.5 mmol substrate, 0.005 mmol precatalyst, 7.5 mL solvent, 258C.
Conversion was determined by H NMR spectroscopy and/or HPLC.
[b]
[c]
[d]
[e]
[f]
1
(+)=(S)-configuration, (À)=(R)-configuration.
(+)=(2S,3R)-configuration, (À)=(2R,3S)-configuration.
Less than 4% of anti-5b’ was formed.
anti/syn; absolute configurations could not be determined. Conclusions by comparison with optical rotations of the relat-
ed anti- and syn-derivatives of 5a–d may fail due to the unique hydrogenation mechanism, which covers competitive inter-
actions of pyridyl and hydroxy group with Rh.
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Synthesis of Chiral 2-Hydroxy-1-methylpropanoates
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Figure 4. Consumption of hydrogen during the reaction of a) 4a with [Rh(9)ACTHNURTGNENG(U COD)]BF4 and b) 4c (bold line, continued up
to 17 h with 11.5 mL H2 consumption) and 4e (&) with [Rh(9)ACTHNUGRTNEUNG(COD)]BF4 [S/C=100, 258C, H2 (1 bar, isobar), 10 mL THF].
sion (nearly half of H2 consumption; additionally con- resolution is possible under the conditions that the
firmed by NMR and HPLC analysis) in order to gen- hydrogenation is stopped after ca. 50% conversion.
erate a mixture consisting of (R)-4a (93.9% ee) and Starting products and hydrogenation products can be
(2S,3R)-5a (91.5% ee) as described above (Scheme 4). obtained by this methodology in high enantioselectivi-
Both compounds could be separated by flash chroma- ty. In general, with the exception of a pertinent pyri-
tography. Subsequently compound (R)-4a was individ- dine derivative the steric course is governed by the
ually hydrogenated with [Rh(11)
ACHTUNGTRNE(NUGN COD)]BF4 bearing hydroxy group in the chiral substrate and not by the
a ligand with opposite configuration in comparison to chiral catalyst. It proceeds in an anti-manner. By sep-
ligand 9 to produce (2R,3S)-5a in 94.4% ee.
aration of enantiomerically enriched starting product
and hydrogenation product after ca. half conversion
and subsequent individual hydrogenation of the
former with a catalyst of opposite chirality both enan-
tiomers could be produced in >91% ee.
Conclusions
The Rh-catalyzed enantioselective hydrogenation of
a-(hydroxymethyl)acrylates proceeds with up to
>99% ee with bisphospholanes of the catASium M
family as ancillary ligands, which are the highest
enantioselectivities reported up to now. Moreover, in
the diastereoselective hydrogenation of related race-
mic b-hydroxy-b-aryl-substituted precursors kinetic
Experimental Section
General Remarks
Solvents were dried and freshly distilled under argon before
use. All reactions were performed under an argon atmos-
Scheme 4. Production of both enantiomers of 5a by two consecutive diastereoselective hydrogenations with different chiral
catalysts.
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Jens Holz et al.
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phere. Thin layer chromatography was performed on pre-
coated TLC plates (silica gel). Flash chromatography was
carried out with silica gel 60 (particle size 0.040–0.063 mm).
Melting points are uncorrected. NMR spectra were recorded
at a Bruker ARX 400 spectrometer at the following fre-
quencies: 400.13 MHz (1H) and 100.63 MHz (13C). Chemical
shifts of 1H and 13C NMR spectra are reported in ppm
downfield from TMS as internal standard. Signals are
quoted as s (singlet), d (doublet), br (broad) and m (multip-
let).
(m, 1H, =CH), 5.55 (d, J=5.6, 1H, CHO), 3.71 (s, 3H,
OCH3), 3.14 (d, J=5.6 Hz, 1H, OH); 13C NMR (CDCl3):
d=166.7 (C=O), 141.9 (=C), 141.2 (arom. =C), 128.4 (arom.
=CH), 127.8 (arom. =CH), 126.5 (arom. =CH), 126.0 (=
CH2), 73.1 (CHO), 51.9 (OCH3); HPLC analysis: Reprosil
100 NR 8 mm (250ꢃ4.6 mm), flow rate 1.25 mL/min; eluant
hexane/2-propanol=95:5, tR =7.7 min (R)-(À)-4a and tR =
9.3 min (S)-(+)-4a at 210, 215 and 225 nm.
rac-Methyl
2-[hydroxy(4-nitrophenyl)methyl]acrylate
(4b): Yield: 2.75 g (77%); mp 72–748C; yellow solid by crys-
1
tallization from ether; H NMR (CDCl3): d=8.17 (m, 2H,
arom. H), 7.55 (m, 2H, arom. H), 6.38 (m, 1H, =CH), 5.86
(m, 1H, =CH), 5.61 (d, br, 1H, CHO), 3.72 (s, 3H, OCH3),
3.14 (d, br, 1H, OH); 13C NMR (CDCl3): d=166.4 (C=O),
148.6 (arom. =C), 147.4 (arom. =C), 140.9 (=C), 127.3
(arom. =CH), 127.3 (=CH2), 123.6 (arom. =CH), 72.7
(CHO), 52.2 (OCH3); HPLC analysis: Chiralpak AS-H
(150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant hexane/2-
propanol=85:15, tR =5.9 min (R)-(À)-4b and tR =17.2 min
(S)-(+)-4b at 210, 240 and 255 nm.
General Procedures for the Synthesis of 2-Hydroxy-
methylacrylates 2a, b and 4b, e
Following the procedure of Hu et al.[12a] relevant aldehydes
(30 mmol), acrylates 1 (90 mmol) and DABCO (30 mmol)
were dissolved in 300 mL of 1,4-dioxane/water (1:1 v/v) and
the mixture was stirred at ambient temperature. After com-
pletion of the reaction MTBE (500 mL) and water (250 mL)
were added to the mixture. After phase separation the or-
ganic layer was washed with brine (2ꢃ100 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by distillation (3a,
b) and crystallization (4b from ethanol) to yield the desired
product.
rac-Methyl
2-[hydroxy(4-methylphenyl)methyl]acrylate
(4c): Yield: 2.87 g (93%); colourless oil by column chroma-
tography (heptane/AcOEt=4:1; Rf =0.55); 1H NMR
(CDCl3): d=7.24 (m, 2H, arom. H), 7.14 (m, 2H, arom. H),
6.31 (m, 1H, =CH), 5.84 (m, 1H, =CH), 5.51 (d, J=5.4 Hz,
1H, CHO),3.70 (s, 3H, OCH3), 3.05 (d, J=5.4 Hz, 1H,
OH), 2.33 (s, 3H, CH3); 13C NMR (CDCl3): d=166.7 (C=
O), 142.0 (=C), 138.3 (arom. =C), 137.4 (arom. =C), 129.0
(arom. =CH), 126.5 (arom. =CH), 125.7 ( =CH2), 72.9
(CHO), 51.8 (OCH3), 21.0 (CH3); HPLC analysis: Reprosil
100 NR 8 mm (250ꢃ4.6 mm), flow rate 1.00 mL/min; eluant
hexane/2-propanol=90:10, tR =7.7 min (R)-(À)-4c and tR =
9.5 min (S)-(+)-5c at 210, 215 and 220 nm.
rac-Methyl 2-[hydroxy(4-methoxyphenyl)methyl]acrylate
(4d): Yield: 2.90 g (87%); mp 62–638C; white solid by
column chromatography (heptane/AcOEt=4:1; Rf =0,15);
1H NMR (CDCl3): d=7.20 (m, 2H, arom. H), 6.78 (m, 2H,
arom. H), 6.23 (m, 1H, =CH), 5.77 (m, 1H, =CH), 5.44 (d,
J=5.3 Hz, 1H, CHO),3.71 (s, 3H, OCH3), 3.63 (s, 3H,
OCH3), 2.89 (d, J=5.4 Hz, 1H, OH); 13C NMR (CDCl3):
d=166.7 (C=O), 159.2 (arom. =C), 142.2 (=C), 133.5 (arom.
=C), 127.9 (arom. =CH), 125.5 (=CH2), 113.8 (arom. =CH),
72.6 (CHO), 55.2 (OCH3), 51.8 (OCH3); Chiralpak AD-H
(150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant hexane/2-
propanol=95:15, tR =11.6 min (S)-(+)-4d and tR =12.7 min
(R)-(À)-4d at 210, 215 and 220 nm.
General Procedures for Synthesis of Methyl 2-Aryl-2-
hydroxymethylacrylates 4a, c, d
According to the method of Zheng et al.[12b] methyl acrylate
(1a) (1.61 g, 18.7 mmol), the corresponding aromatic alde-
hyde (15 mmol) and DABCO (1.68 g, 15 mmol) were stirred
without any solvent for 24 h at room temperature. After di-
lution with diethyl ether (200 mL) the mixture was washed
with HCl, NaHCO3 and water. The organic phase was dried
(Na2SO4) and concentrated to remove the solvent and the
excess of methyl acrylate. The yielded crude products were
purified by chromatography to yield the desired racemic
mixtures of 4a, c, d.
Methyl (2-hydroxymethyl)acrylate (2a): Yield: 2.4 g
(69%); colourless oil; bp 60–628C/2 mbar; 1H NMR
(CDCl3): d=6.21 (m, 1H, =CH), 5.81 (m, 1H, =CH), 4.27
(m, 2H, CH2O), 3.73 (s, 3H, OCH3), 2.82 (s, br), 1H, OH);
13C NMR (CDCl3): d=166.7 (C=O), 139.4 (=C), 125.6 (=
CH2), 62.1 (CH2O), 51.8 (OCH3); HPLC analysis: Chiralcel
OD-H (150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant
hexane/2-propanol=97:3, tR =7.6 min at 210, 215 and
225 nm.
rac-Methyl 2-[hydroxy(2-pyridyl)methyl]acrylate (4e):
Yield: 3.42 g (59%); mp 50–518C; pale yellow solid by
column chromatography (heptane/AcOEt=1:1; Rf =0.45);
1H NMR (CDCl3): d=8.52 (m, 1H, arom. H), 7.66 (m, 1H,
arom. H), 7.40 (m, 1H, arom. H), 7.17 (m, 1H, arom. H),
6.33 (m, 1H, =CH), 5.94 (m, 1H, =CH), 5.60 (s, br, 1H,
CHO), 2.89 (s, br, 1H, OH), 3.72 (s, 3H, OCH3); 13C NMR
(CDCl3): d=166.4 (C=O), 159.5 (arom. =C), 148.2 (arom. =
C), 141.6 (=C), 136.7 (arom. =CH), 125.5 (=CH2), 122.5
(arom. =CH), 121.1 (arom. =CH), 72.0 (CHO), 51.7
(OCH3); Chiralpak OD-H (150ꢃ4.6 mm), flow rate
1.30 mL/min; eluant hexane/2-propanol=97:3, tR =9.1 min
syn-(+)-4e and tR =11.8 min syn-(À)-4e at 215, 255 and
270 nm.
tert-Butyl (2-hydroxymethyl)acrylate (2b): Yield: 8.8 g
(56%); colourless oil; bp 728C/2 mbar or purification by
colum chromatography (heptane/AcOEt=2:1, Rf =0.25);
1H NMR (CDCl3): d=6.12 (m, 1H, =CH), 5.72 (m, 1H, =
CH), 4.25 (m, 2H, CH2O), 2.51 (t, J=6.5 Hz, 1H, OH); 1.48
(s, 9H, CH3); 13C NMR (CDCl3): d=165.7 (C=O), 140.8 (=
À
C), 124.7 (=CH2), 81.3 (O C), 62.6 (CH2O), 28.0 (CH3);
HPLC analysis: Chiralcel OD-H (150ꢃ4.6 mm), flow rate
1.20 mL/min; eluant hexane/2-propanol=99:1, tR =8.0 min
at 210, 215 and 225 nm.
rac-Methyl
2-[hydroxy
G
(4a):
Yield: 2.70 g (94%), colourless oil by colum chromatography
1
(heptane/AcOEt=8:1 to 2:1; Rf =0.25); H NMR (CDCl3):
d=7.24–7.43 (m, 5H, arom. H), 6.34 (m, 1H, =CH), 5.84
2540
asc.wiley-vch.de
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2533 – 2543

Synthesis of Chiral 2-Hydroxy-1-methylpropanoates
FULL PAPERS
7.2 Hz, 3H, CH3); 13C NMR (CDCl3): d=175.5 (C=O),
148.9 (arom. =C), 147.4 (arom. =C), 127.4 (arom. =CH),
123.5 (arom. =CH), 75.0 (CHO), 52.0 (OCH3), 46.7 (CH),
14.1 (CH3); MS (EI, 70 eV): m/z=239 [M+, 2], 152
[C7H6NO3 , 21]; 88 [C4H8O2 , 100], HPLC analysis: Chiral-
pak AS-H (150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant
hexane/2-propanol=85:15, tR =6.8 min (2S,3R)-(+)-5b and
tR =9.2 min (2R,3S)-(À)-5b at 210, 240 and 270 nm.
General Procedure for Synthesis of Racemates of 3a,
b and 4a-e
A solution of substrates 2a, b or 4a–e (0,5 mmol) and achiral
[RhACHTUNGTRENNUNG(dppb)ACHTUNGTRENNUNG(COD)]BF4 (3.5 mg, 0.005 mmol) in methanol
+
+
(7.5 mL) was stirred at ambient temperature under a hydro-
gen pressure of 60 bar for 20 h. After decompression the
mixture was directly used for HPLC analysis and the residue
after evaporation was investigated by NMR. In all cases full
conversion was observed.
anti-5b’: mp 1548C; Rf =0.13 (heptane:AcOEt=2:1);
1H NMR (CDCl3): d=7.11 (m, 2H, arom. H), 6.65 (m, 2H,
arom. H), 4.63 (d, J=9.0 Hz, 1H, CHO), 3.73 (s, 3H,
OCH3), 3.67 (s, br, 1H, OH), 2.76 (m, 1H, CH), 0.95 (d, J=
7.2 Hz, 3H, CH3); 13C NMR (CDCl3): d=176.5 (C=O),
146.3 (arom. =C), 131.5 (arom. =C), 127.8 (arom. =CH),
115.0 (arom. =CH), 76.3 (CHO), 51.9 (OCH3), 47.2 (CH),
14.5 (CH3); MS (EI, 70 eV): m/z=209 [M+, 8], 191
[(MÀH2O, 40)+ 122 [C7H8NO+, 100]; HPLC analysis: Chir-
alpak AS-H (150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant
hexane/2-propanol=85:15, tR =11.9 min (2S,3R)-(+)-5b’ and
tR =15.6 min (2R,3S)-(À)-5b’ at 210, 240 and 270 nm.
1
rac-Methyl 3-hydroxy-2-methyl-propanoate (3a): H NMR
(CDCl3): d=3.68 (m, 2H, CH2O), 3.68 (s, 3H, OCH3), 2.65
(m, 1H, CH), 2.50 (s, br, 1H, OH), 1.14 (d, J=7.2 Hz, 3H,
CH3; 13C NMR (CDCl3): d=176.1 (C=O), 64.5 (CH2O), 51.8
(OCH3), 41.6 (CH), 13.4 (CH3); HPLC analysis: Chiralcel
OD-H (150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant
hexane/2-propanol=97:3, tR =5.8 min (R)-3a and tR =
6.6 min (S)-3a at 210, 215 and 225 nm.
rac-tert-Butyl
3-hydroxy-2-methyl-propanoate
(3b):
1H NMR (CDCl3): d=3.63 (m, 2H, CH2O), 2.55 (m, 1H,
CH), 2.44 (s, br, 1H, OH), 1.44 (s, 9H, CH3),1.11 (d, J=
7.2 Hz, 3H, CH3); 13C NMR (CDCl3): d=175.1 (C=O), 80.8
(C-O), 64.6 (CH2O), 42.4 (CH), 28.0 (CH3), 13.5 (CH3);
HPLC analysis: Chiralcel OD-H (150ꢃ4.6 mm), flow rate
1.20 mL/min; eluant hexane/2-propanol=99:1, tR =5.5 min
(R)-3b and tR =6.1 min (S)-3b at 210, 215 and 225 nm.
Application of Pd/C (5%) as catalyst (1 bar, 90 min, S:C=
100:1, THF, 258C) leads to the predicted formation of a
mixture of the anti-5b’ and syn-5b’ diastereomers with a
ratio of 56:44 (84%). In contrast to the observation of
Coelho et al.[17a] we observed also the hydrogenolysis of the
À
C OH bond to form the racemic methyl 3-(4-aminophenyl)-
2-methylpropanoate (5b’’) (16%). All products could be sep-
arated by colum chromatography (heptane:AcOEt=2:1).
syn-5b’: mp 898C; Rf =0.16 (heptane:AcOEt=2:1);
1H NMR (CDCl3): d=7.07 (m, 2H, arom. H), 6.60 (m, 2H,
arom. H), 4.88 (d, J=4.7 Hz, 1H, CHO), 3.60 (s, 3H,
OCH3), 3.60 (s, br, 1H, OH), 2.72 (m, 1H, CH), 1.13 (d, J=
6.7 Hz, 3H, CH3); 13C NMR (CDCl3): d=176.0 (C=O),
145.7 (arom. =C), 131.6 (arom. =C), 127.0 (arom. =CH),
114.9 (arom. =CH), 73.8 (CHO), 51.7 (OCH3), 46.7 (CH),
11.3 (CH3); HPLC analysis: Chiralpak AS-H (150ꢃ4.6 mm),
flow rate 1.20 mL/min; eluant hexane/2-propanol=85:15,
tR =8.5 min (S,S)-(À)-5b’ and tR =13.7 min (R,R)-(+)-5b’ at
210, 240 and 270 nm;
rac-Methyl 3-Hydroxy-2-methyl-3-phenyl-propanoate
(5a) [anti:syn=90:10]
1
anti-5a: H NMR (CDCl3): d=7.23–7.38 (m, 5H, arom. H),
4.72 (d, J=8.8 Hz, 1H, CHO), 3.70 (s, 3H, OCH3), 3.09 (s,
br, 1H, OH), 2.80 (m, 1H, CH), 0.97 (d, J=7.2 Hz, 3H,
CH3); 13C NMR (CDCl3): d=176.3 (C=O), 145.6 (arom. =
C), 128.4 (arom. =CH), 128.0 (arom. =CH), 126.6 (arom.=
CH), 76.4 (CHO), 51.9 (OCH3), 47.1 (CH), 14.4 (CH3);
HPLC analysis: Reprosil 100 NR 8 mm (250ꢃ4.6 mm), flow
rate 1.00 mL/min; eluant hexane/2-propanol=95:5, tR =
8.8 min (2R,3S)-(À)-5a and tR =10.5 min (2S,3R)-(+)-5a at
210, 215 and 225 nm.
rac-5b’’: oil; Rf =0.32 (heptane:AcOEt=2:1); 1H NMR
(CDCl3): d=6.93 (m, 2H, arom. H), 6.60 (m, 2H, arom. H),
3.62 (s, 3H, OCH3), 3.57 (s, br, 1H, OH), 2.90 (dd, J=13.2,
6.6 Hz, 1H, Hb-CH2), 2.65 (m, 1H, CH), 2.54 (dd, J=13.2,
7.6 Hz, 1H, Ha-CH2),1.11 (d, J=6.8 Hz, 3H, CH3);
13C NMR (CDCl3): d=176.8 (C=O), 144.6 (arom. =C), 129.7
(arom. =CH), 129.3 (arom. =C), 115.1 (arom. =CH), 51.5
(OCH3), 41.7 (CH), 38.9 (CH2), 16.6 (CH3); MS (EI, 70 eV):
m/z=193 [M+, 12], 106 [C7H8N+, 100]; HPLC analysis:
Chiralpak AS-H (150ꢃ4.6 mm), flow rate 1.20 mL/min;
eluant hexane/2-propanol=85:15, tR =4.3 min rac-5b’’ at
220, 240 and 255 nm and Chiralcel OD-H (150ꢃ4.6 mm),
flow rate 1.20 mL/min, eluant hexane/2-propanol=85:15,
tR =8.8 min (S)-(+)-5b’’ and tR =11.0 min (R)-(À)-5b’’ at
220, 240 and 255 nm.
syn-5a: 1H NMR (CDCl3): d=7.23–7.38 (m, 5H, arom.
H), 5.06 (d, J=4.3 Hz, 1H, CHO), 3.64 (s, 3H, OCH3), 3.09
(s, br, 1H, OH), 2.80 (m, 1H, CH), 1.11 (d, J=7.2 Hz, 3H,
CH3); 13C NMR (CDCl3): d=176.1 (C=O), 141.4 (arom. =
C), 128.2 (arom. =CH), 127.4 (arom. =CH), 125.9 (arom. =
CH), 73.6 (CHO), 51.8 (OCH3), 46.4 (CH), 10.7 (CH3);
HPLC analysis: Reprosil 100 NR 8 mm (250ꢃ4.6 mm), flow
rate 1.00 mL/min; eluant hexane/2-propanol=95:5, tR =
7.6 min and tR =8.0 min syn-5a at 210, 215 and 225 nm.
Racemic anti-Methyl 3-Hydroxy-2-methyl-3-(4-nitro-
phenyl)propanoate (5b), rac-Methyl 3-(4-
Aminophenyl)-3-hydroxy-2-methylpropanoate (5b’)
and rac-Methyl 3-(4-Aminophenyl)-2-
methylpropanoate (5b’’) [anti-5b:anti-5b’=89:11]
rac-Methyl 3-Hydroxy-2-methyl-3-(4-methyl-
phenyl)propanoate (5c) [anti:syn=97:3]
Separation by chromatography (eluant heptane:AcOEt=
2:1 to 1:1).
anti-5b: mp 1058C; Rf =0.32 (heptane:AcOEt=2:1);
1H NMR (CDCl3): d=8.13 (m, 2H, arom. H), 7.45 (m, 2H,
arom. H), 4.81 (d, J=7.7 Hz, 1H, CHO), 3.67 (s br, 1H,
OH), 3.64 (s, 3H, OCH3), 2.76 (m, 1H, CH), 1.00 (d, J=
1
anti-5c: H NMR (CDCl3): d=7.19 (m, 2H, arom. H), 7.13
(m, 2H, arom. H), 4.67 (d, J=8.5 Hz, 1H, CHO), 3.70 (s,
3H, OCH3), 3.04 (s, br, 1H, OH), 2.77 (m, 1H, CH), 2.32 (s,
3H, CH3), 0.95 (d, J=7.2 Hz, 3H, CH3); 13C NMR (CDCl3):
Adv. Synth. Catal. 2008, 350, 2533 – 2543
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2541

Jens Holz et al.
FULL PAPERS
d=176.3 (C=O), 138.6 (arom. =C), 137.7 (arom. =C), 129.1
(arom. =CH), 126.5 (arom. =CH), 76.2 (CHO), 51.8
(OCH3), 47.1 (CH), 21.0 (CH3), 14.3 (CH3); HPLC analysis:
Reprosil 100 NR 8 mm (250ꢃ4.6 mm), flow rate
1.00 mL/min; eluant hexane/2-propanol=90:10, tR =7.2 min
(2R,3S)-(À)-5c and tR =8.5 min (2S,3R)-(+)-5c at 210, 215
4.6 mm), flow rate 1.00 mL/min; eluant hexane/2-propa-
nol=97:3, tR =8.6 min syn-(+)-5e and tR =11.9 min syn-(À)-
5e at 215, 255 and 270 nm.
and 220 nm.
1
syn-5c: H NMR (CDCl3): d=7.19 (m, 2H, arom. H), 7.13 Acknowledgements
(m, 2H, arom. H), 5.00 (d, J=4.5 Hz, 1H, CHO), 3.62 (s,
3H, OCH3), 3.04 (s, br, 1H, OH), 2.77 (m, 1H, CH), 2.32 (s,
3H, CH3), 1.11 (d, J=7.2 Hz, 3H, CH3); 13C NMR (CDCl3)
d 176.0 (C=O), 138.6 (arom. =C), 137.7 (arom. =C), 128.8
(arom. =CH), 125.8 (arom. =CH), 73.6 (CHO), 51.7
(OCH3), 46.5 (CH), 21.0 (CH3), 10.9 (CH3); HPLC analysis:
not detectable.
We are grateful to Mrs. H. Borgwaldt for skilled technical as-
sistance. B. S. acknowledges a grant from the graduate school
1213 of the Deutsche Forschungsgemeinschaft DFG.
References
rac-Methyl 3-Hydroxy-2-methyl-3-(4-methoxy-
phenyl)propanoate (5d) [anti:syn=96:4]
[1] A. B. Smith III, C. M. Adams, S. A. Lodise Barbosa,
A. P. Degnan, Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
12042–12047.
1
anti-5d: H NMR (CDCl3): d=7.22 (m, 2H, arom. H), 6.86
(m, 2H, arom. H), 4.67 (d, J=8.7 Hz, 1H, CHO), 3.77 (s,
3H, OCH3), 3.70 (s, 3H, OCH3), 2.89 (s, br, 1H, OH), 2.75
(m, 1H, CH), 0.95 (d, J=7.2 Hz, 3H, CH3); 13C NMR
(CDCl3): d=176.3 (C=O), 159.3 (arom. =C), 133.7 (arom. =
C), 127.8 (arom. =CH), 113.8 (arom. =CH), 75.9 (CHO),
55.2 (OCH3), 51.8 (OCH3), 47.2 (CH), 14.4 (CH3); Chiral-
pak AD-H (150ꢃ4.6 mm), flow rate 1.20 mL/min; eluant
hexane/2-propanol=95:15, tR =16.7 min (2S,3R)-(+)-5d and
tR =17.8 min (2R,3S)-(À)-5d at 210, 215 and 220 nm.
[2] Y. Shin, J.-H. Fournier, Y. Fukui, A. M. Brꢁckner, D. P.
Curren, Angew. Chem. 2004, 116, 4734–4737; Angew.
Chem. Int. Ed. 2004, 43, 4634–4637.
[3] J. E. D. Kirkham, V. Lee, J. E. Baldwin, Chem.
Commun. 2006, 2863–2865.
[4] a) A. B. Smith III, T. J. Beauchamp, M. J. LaMarche,
M. D. Kaufman, Y. Qiu, H. A. D. R. Jones, K. Kobaya-
shi, J. Am. Chem. Soc. 2000, 122, 8654 À8664; b) I. Pa-
terson, G. J. Florence, Eur. J. Org. Chem. 2003, 2193–
2208; c) S. J. Mickel, G. H. Sedelmeier, D. Niederer, R.
Daeffler, A. Osmani, K. Schreiner, M. Seeger-Weibel,
B. Bꢄrod, K. Schaer, R. Gamboni, Org. Proc. Res. Dev.
2004, 8, 92–100 (see also Parts 2–5 Org. Proc. Res.
Dev. 2004, 8, 101–133); d) I. Paterson, O. Delgado,
G. J. Florence, I. Lyothier, M. OꢅBrien, J. P. Scott, N.
Sereinig, J. Org. Chem. 2005, 70, 150–160.
syn-5d: 1H NMR (CDCl3): d=7.22 (m, 2H, arom. H),
6.86 (m, 2H, arom. H), 4.97 (d, J=4.8 Hz, 1H, CHO), 3.77
(s, 3H, OCH3), 3.62 (s, 3H, OCH3), 2.89 (s, br, 1H, OH),
2.75 (m, 1H, CH), 1.13 (d, J=7.1 Hz, 3H, CH3); 13C NMR
(CDCl3): d=176.0 (C=O), 159.3 (arom. =C), 133.7 (arom. =
C), 127.1 (arom. =CH), 113.6 (arom. =CH), 73.5 (CHO),
55.2 (OCH3), 51.7 (OCH3), 46.6 (CH), 11.1 (CH3); HPLC
analysis: Chiralpak AD-H (150ꢃ4.6 mm), flow rate
1.20 mL/min; eluant hexane/2-propanol=95:15, tR =9.3 min
and tR =10.2 min at 210, 215 and 220 nm.
[5] S. Jeulin, T. Ayad, V. Ratvelomanana-Vidal, J.-P.
GenÞt, Adv. Synth. Catal. 2007, 349, 1592–1596, and
references cited therein.
[6] Y. Keiji, N. Koichi, (Nippon Shokubai Co Ltd.), Japa-
nese Patent 2000128832, 2000.
[7] J. Wassenaar, M. Kuil, J. N. H. Reek, Adv. Synth. Catal.
2008, 350, 1610–1614.
rac-Methyl 3-Hydroxy-2-methyl-3-(2-pyridyl)-
propanoate (5e) [anti:syn=21:79]
1
anti-5e: H NMR (CDCl3): d=8.47 (m, 1H, arom. H), 7.63
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(m, 1H, arom. H), 7.26 (m, 1H, arom. H), 7.14 (m, 1H,
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3H, OCH3), 2.96 (m, 1H, CH), 1.05 (d, J=7.2 Hz, 3H,
CH3); 13C NMR (CDCl3): d=175.3 (C=O), 159.8 (arom. =
C), 148.5 (arom. =CH), 136.5 (arom. =CH), 122.6 (arom. =
CH), 121.3 (arom. =CH), 75.2 (CHO), 51.6 (OCH3), 46.2
(CH), 13.5 (CH3); HPLC analysis: Chiralpak AS-H (150ꢃ
4.6 mm), flow rate 1.00 mL/min; eluant hexane/2-propa-
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M and DuPHOS-ligands, see: J.
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syn-5e: 1H NMR (CDCl3): d=8.47 (m, 1H, arom. H),
7.63 (m, 1H, arom. H), 7.30 (m, 1H, arom. H), 7.14 (m, 1H,
arom. H), 5.30 (m, 1H, CHO), 4.42 (s, br, 1H, OH), 3.64 (s,
3H, OCH3), 2.89 (m, 1H, CH), 0.97 (d, J=7.2 Hz, 3H,
CH3); 13C NMR (CDCl3): d=175.2 (C=O), 159.7 (arom. =
C), 148.2 (arom. =CH), 136.6 (arom. =CH), 122.4 (arom. =
CH), 120.6 (arom. =CH), 73.1 (CH), 51.7 (OCH3), 45.7
(CHO), 10.0 (CH3); HPLC analysis: Chiralpak AS-H (150ꢃ
2542
asc.wiley-vch.de
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2533 – 2543

Synthesis of Chiral 2-Hydroxy-1-methylpropanoates
FULL PAPERS
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[22] When the reaction was quenched after a conversion of
65–70% the starting unsaturated ester displayed >90%
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drogenation product.
[23] Crystal data for anti-5b: C11H13NO5, Mr =239.22, mono-
clinic, space group P21/n, a=6.6231(5), b=8.2144(9),
c=21.614(2) ꢆ, b=95.306(7)8, V=1170.8(2) ꢆ3, Z=4,
1calcd =1.357 gcmÀ3, 18909 reflections measured, 2684
independent reflections and 1883 were observed [I>
2s(I)], R1 =0.0450, wR2 (all data)=0.1378, 158 parame-
ters. Data were collected on a STOE IPDS diffractom-
eter using graphite-monochromated Mo Ka radiation.
The structure was solved by direct methods [SHELXS-
97: G. M. Sheldrick, University of Gçttingen, Germany,
1997] and refined by full-matrix least-squares tech-
niques on F2 [SHELXL-97: G. M. Sheldrick, University
of Gçttingen, Germany, 1997]. XP (Bruker AXS) was
used for graphical representation. CCDC 698748 con-
tains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax.: (internat.) + 44 1223/336–033; e-mail: depos-
it@ccdc.cam.ac.uk].
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[25] The absolute configuration was determined by using a
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that the enantiomers of 4a–d with negative optical rota-
tion values correspond to (R)-enantiomers {e.g., (R)-4a
[a]D: À1118 (c 1.11; CHCl3) or ethyl ester of (S)-4b
[a]D: +948 (c 1; MeOH)}; diastereomers (2S,3R)-5a
{[a]D: +538 (c 1.05; CHCl3)} and the (2S,3R)-ethyl
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[16] This conclusion could also be drawn from a trial with
(S,S)-methyl-DuPHOS as ligand where at 50 bar H2
pressure 95% ee were observed.
[17] The 31P NMR spectrum showed a change of the origi-
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(JRh,P =151 Hz) to two double doublets with d=
93.9 ppm (JRh,P =152 Hz, JP,P =22 Hz) and d=94.0 ppm
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Adv. Synth. Catal. 2008, 350, 2533 – 2543
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2543