New stereospecific synthesis of Tesaglitazar and Navaglitazar precursors

Article abstract of DOI:10.1016/j.tetasy.2009.10.027

A new synthetic route of to pharmaceutical intermediates (S)-1a-b and (S)-14 is reported. The reaction pathway is based on the baker's yeast-mediated reduction of the α-alkoxy cinnamaldehydes 9a-c to give the corresponding (S)-alcohols in good yields and

Full text of DOI:10.1016/j.tetasy.2009.10.027

Tetrahedron: Asymmetry 20 (2009) 2694–2698
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New stereospecific synthesis of Tesaglitazar and Navaglitazar precursors
*
Elisabetta Brenna, Claudio Fuganti, Francesco G. Gatti , Fabio Parmeggiani
Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘G. Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic route of to pharmaceutical intermediates (S)-1a–b and (S)-14 is reported. The reaction
Received 22 September 2009
Accepted 23 October 2009
Available online 22 November 2009
pathway is based on the baker’s yeast-mediated reduction of the
a-alkoxy cinnamaldehydes 9a–c to give
the corresponding (S)-alcohols in good yields and excellent ee.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Alternatively, the baker’s yeast reduction of (Z)-a-alkoxy cinn-
amaldehydes 9a–b gave excellent results in terms of yield and
selectivity (Scheme 2). Substrates 9a–b were easily prepared by a
four-step sequence as shown in Scheme 2, avoiding unpractical
chromatographic purifications. Firstly, the Claisen condensation
Recently we reported a new synthesis for the enantiomerically
pure forms of chiral ethyl
a-alkoxy phenyl propanoate esters (S)-
1a and (S)-1b,1 which are the key intermediates of several drugs
such as the Tesaglitazar 2 and Navaglitazar 3 (Fig. 1).2
Our strategy was based on a resolution approach consisting of a
highly stereoselective
a-chymotrypsin-catalysed hydrolysis of
O
O
racemic esters 4a–b (Fig. 1). However, the general disadvantages
of the resolution approach are well known: the maximum yield
cannot exceed 50%, and the remaining enantiomer has to be
discarded.
In addition, the only reported stereoselective synthesis of 1a–b,
based on the metal-catalysed asymmetric hydrogenation of a-eth-
oxy cinnamic acid derivatives (5a–b) (Fig. 1) was insufficiently effi-
cient in terms of enantioselectivity (20–92% ee) and practicality
(high pressure vessel reactors 200–700 psi).3 Thus, in view of this
we looked at the baker’s yeast-mediated reduction as an alterna-
tive and valuable method.4
OH
OH
O
O
O
O
O
O
O
S
O
O
2, Tesaglitazar
3, Navaglitazar
O
2. Results and discussion
OEt
Since it is known that the baker’s yeast-mediated reduction of
ethyl 3-phenyl pyruvate gives the corresponding (R)-hydroxy ester
with discrete ee (67%)5 and that the chain length extension of keto
esters usually reverts the stereochemistry,6 we envisaged the octyl
3-(4-methoxyphenyl)pyruvate 7 as a good starting material. The
latter was prepared by the addition of p-methoxybenzyl magne-
sium chloride to dioctyl oxalate 6 according to a previously re-
ported procedure.7 Thus, the ester was submitted to the standard
microbial reduction in fermenting baker’s yeast (Scheme 1). The at-
tended inversion of stereoselectivity did not take place, since the
(R)-hydroxy ester (R)-8 was obtained (Scheme 1). The yield was
also very low (8%) and the selectivity was not sufficient (55% ee
by HPLC of methyl ester derivative).1
OR
HO
(S)-1a, R=Et
(S)-1b, R=Me
H2 (500 psi)
chiral cat.
ref. (3)
α-chymotrypsin
ref. (1)
O
O
OH
OEt
OR
OR
BnO
MeO
5a, R=Et
5b, R=Me
4a, R=Et
4b, R=Me
Figure 1. Reported preparations of the key intermediates 1a–b of Tesaglitazar and
Navaglitazar based on the enzyme-mediated resolution or stereospecific
hydrogenation.
* Corresponding author. Tel.: +39 02 23993072; fax: +39 02 23993080.
E-mail address: Francesco.Gatti@polimi.it (F.G. Gatti).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.027

E. Brenna et al. / Tetrahedron: Asymmetry 20 (2009) 2694–2698
2695
O
O
i
ii
Cl
O
7
O
7
O
OH
MeO
MeO
MeO
7
(R)-8 (55.2% ee)
distomer
Scheme 1. Reagents and conditions: (i) Mg, Et2O, dioctyl oxalate 6; and (ii) baker’s yeast, H2O, glucose.
O
H
PPh3 Cl
ref. (15)
MeO
MeO
iii
i
O
O
O
iv
ii
OR'
OH
H
OR
OR
OR
MeO
MeO
MeO
9a, R=Et
9b, R=Me
9c, R=All
10a, R=Et
10b, R=Me
11a, R=Et, R'=Et
11b, R=Me, R'=Et
11c, R=All, R'=All
v
O
vi
OH
OH
OR
OR
MeO
MeO
(S)-12a, R=Et (99% ee)
(S)-12b, R=Me (93% ee)
(S)-12c, R=All (>99.9% ee)
(S)-13a, R=Et
(S)-13b, R=Me
OH
vii
OH
(S)-14
MeO
Tesaglitazar
Navaglitazar
(+)-epi-Cytoxazone
Scheme 2. Reagents and conditions: (i) (a) ethyl chloroacetate, RONa, ROH; (b) NaOH/H2O; (c) HCl/H2O; (ii) EtBr, TBAI, K2CO3, acetone; (iii) n-BuLi, THF, 0 °C, diallyl oxalate
15; (iv) (a) LiAlH4, Et2O, 0 °C; (b) MnO2, CH2Cl2; (v) (a) baker’s yeast, H2O, glucose, XAD 1180; (b) MnO2, CH2Cl2; (vi) BAIB, cat. TEMPO, CH2Cl2/H2O, 2:1; and (vii) cat. PdCl2,
AcOH, AcONa.
of anisaldehyde with ethyl chloroacetate in the presence of EtONa
or MeONa followed by alkaline hydrolysis gave the (Z)- -alkoxy
mers the reduction proceeded with high ee. This is likely due to the
fact that the (E)-isomers were not reduced by the baker’s yeast; in-
deed, the GC analysis of the the partially reduced allyl alcohols
showed a substantial enrichment of the (E)-isomers.
a
cinnamic acids 10a–b, which were easily isolated by simple
crystallisation.8 The acids were then quantitatively converted into
esters 11a–b under mild conditions (EtBr, K2CO3 and TBAI in ace-
tone).9 The latter were reduced with LiAlH4 to give the correspond-
ing allyl alcohols, which in turn were oxidised with MnO2 in CH2Cl2
to give the enriched (Z)-aldehydes 9a–b (Z/E ꢀ9:1 by 1H NMR)10 in
an overall yield of 63% and 61%, respectively.
Thus, both aldehydes were submitted to the microbial reduc-
tion (Scheme 2).11 However, in order to achieve a high yield and
enantioselectivity together with a practical work up, we adsorbed
the starting materials on non-polar resins (XAD 1180).12 Indeed,
after just 3–4 days, a mixture composed mainly of the saturated
alcohol (S)-12a–b (over 85% by GC), together with the starting
material and the corresponding allylic alcohol, was separated from
the biomass by filtering and washing the resins with EtOAc. This
mixture was submitted to MnO2 oxidation in such a way to recon-
vert the residual allyl alcohol into the corresponding aldehyde 9a–
b, allowing an easy separation of the latter from the alcohol by col-
umn chromatography. The yeast-mediated reduction of the double
bond of these aldehydes furnished the corresponding alcohols (S)-
12a–b (vide infra for the attribution of stereochemistry) in high
yields (about 78% for the isolated products) with excellent ee
(99% and 95% for (S)-12a and (S)-12b, respectively, by HPLC). It is
noteworthy that even if the starting aldehydes were not single iso-
To the best of our knowledge, this is the first example of baker’s
yeast reduction performed on
a-enol ether aldehydes. Moreover,
the typical slightly acidic environment of fermenting yeast is com-
patible with the acid labile enol ether functionality.
Next, the optically active alcohols (S)-12a–b were oxidised
with BAIB in the presence of a catalytic amount of TEMPO to the
corresponding acids (S)-13a {99% ee by HPLC of the methyl ester
derivative,
½
a 2D0
ꢁ
¼ ꢂ17:9 (c 1.04, CHCl3) versus lit. 93% ee,
½
a 2D0
ꢁ
¼ ꢂ16:6 (c 1.21, CHCl3)1} and (S)-13b {95% ee by HPLC of
the methyl ester derivative, ½a D20
¼ ꢂ23:9 (c 1.11, CHCl3) versus
ꢁ
lit. 99% ee, ½a 2D0
ꢁ
¼ ꢂ25:2 (c 1.40, CHCl3)1} in quantitative yield
and without loss of enantiomeric purity.13
Next, (S)-13a–b were transformed into (S)-1a–b following our
previously reported procedure.1
Finally, these results prompted us to submit the a-allyloxy alde-
hyde 9c to the same microbial reduction, which once reduced to
the corresponding alcohol (S)-12c might give access to diol (S)-
14, an important precursor of (+)-epi-cytoxazone.14 Initially, we at-
tempted to prepare the corresponding allyloxy acid following the
same synthetic route adopted for acids 10a–b. However, the isola-
tion of the acid by crystallisation or of the ethyl ester derivative by
column chromatography was unsuccessful.

2696
E. Brenna et al. / Tetrahedron: Asymmetry 20 (2009) 2694–2698
Instead, the Wittig reaction of the ylide of p-methoxybenzyltri-
100 mL), aq NaHCO3 (satd, 100 mL) and brine (2 ꢃ 100 mL), and
dried over Na2SO4. The solvent and residual alcohols were removed
by vacuum distillation.
phenylphosponium chloride15 with diallyl oxalate 15 gave ester
(Z)-11c in 75% yield (Z/E 20:1) after column chromatography.16
The ester was converted into aldehyde 9c following the same route
adopted before. The baker’s yeast reduction of 9c afforded the
allyloxy alcohol (S)-12c in 70% yield and excellent ee (>99.9% by
HPLC). Next, the latter was converted to the diol (S)-14
4.2.1. Dioctyl oxalate 6
Yellow oil; 41.9, 89% yield; 98% purity by GC (tR 25.31 min); 1H
NMR (400 MHz, CDCl3) d 4.27 (t, J = 6.8, 4H), 1.71 (m, J = 6.8, 4H),
1.20–1.42 (m, 20H), 0.88 (t, J = 7.1, 6H); 13C NMR (100.6 MHz,
CDCl3) d 158.5, 67.4, 32.1, 29.5, 28.7, 26.1, 23.0, 14.4. MS: m/z (%)
315 [M+1]+ (1), 157 (39), 112 (19), 83 (19), 71 (98), 57 (100).
{½a 2D0
ꢁ
¼ ꢂ12:7 (c 0.93, CHCl3) versus lit. 98% ee, ½a D20
¼ ꢂ12:9 (c
ꢁ
2.0, CHCl3)14a} by PdCl2-catalysed cleavage of the O-allyl ether in
89% yield.17
4.2.2. Diallyl oxalate 15
3. Conclusion
Yellow oil; 23.2 g, 91% yield; 94% purity by GC (tR 9.86 min); 1H
NMR (400 MHz, CDCl3) d 5.92 (ddt, J = 16.9, 10.6, 6.1, 2H), 5.40 (m,
2H), 5.31 (m, 2H), 4.76 (dt, J = 5.9, 1.4, 4H); 13C NMR (100.6 MHz,
CDCl3) d 157.2, 130.4, 119.8, 67.1; MS: m/z (%) 170 [M]+ (5), 57
(9), 41 (100).
In conclusion, we have disclosed a new and efficient enantio-
specific synthesis of the important pharmaceutical intermediates
(S)-1a and (S)-1b in an overall yield of 32% and 31%, respectively
(starting from anisaldehyde). This synthetic route compares well
in terms of selectivity with the metal-catalysed asymmetric hydro-
genation3 approach (92% ee vs 99% ee for 1a), which, however re-
quires non-standard high pressure equipment. Moreover, the
biocatalysed reduction approach proved to be superior in terms
of diastereoselectivity, since it does not seem to require extremely
pure (Z) isomers as starting materials, which are usually difficult to
access. Concerning the stereoselectivity of baker’s yeast towards
these aldehydes, it seems to increase by lengthening the alkoxy
chain.
In addition, we have devised a new route to diol (S)-14, a key
intermediate of (+)-epi-cytoxazone.
Finally, it is noteworthy that the baker’s yeast exhibits a stere-
odivergence with respect to the kind of substrates (7 vs 9c), which
gives access to both the enantiomers of diol 14 by means of a few
simple manipulations.
4.3. Octyl 3-(4-methoxyphenyl)pyruvate 7
To an ice-cold suspension of Mg turnings (20.0 g) in well dried
Et2O (40 mL), was added dropwise a solution of 4-methoxybenzyl-
chloride (14.8 g, 95 mmol) in Et2O (80 mL) over 1 h. Once the Grig-
nard reaction had started, it was important to keep the
temperature below 5 °C to minimize Wurtz coupling. Then, the
reaction mixture was cannulated into a solution of 6 (32 g,
104 mmol) in Et2O (100 mL) at ꢂ30 °C. Then, the reaction mixture
was left to reach room temperature, poured into ice-cold HCl aq
solution (0.5 M, 100 mL) and extracted with Et2O (2 ꢃ 200 mL).
The combined organic layers were dried over Na2SO4 and the sol-
vent was removed under reduced pressure. Column chromatogra-
phy on a pad of silica gel (n-hexane/EtOAc 9:1) gave a yellow oil,
which was triturated with cold n-hexane to afford a white powder;
8.4 g, 29% yield; 94% purity by 1H NMR; 1H NMR (400 MHz, CDCl3)
d 7.75 (d, J = 8.6, 2H), 6.92 (d, J = 8.6, 2H), 6.50 (br s, 1H), 6.33 (s,
1H), 4.30 (t, J = 6.8, 2H), 3.84 (s, 3H), 1.76 (m, J = 6.8, 2H), 1.20–
1.48 (m, 10H), 0.90 (t, J = 7.1, 3H); 13C NMR (100.6 MHz, CDCl3) d
166.8, 159.7, 138.2, 131.7, 127.3, 114.3, 111.0, 66.9, 55.6, 32.1,
29.5, 29.4, 28.3, 26.2, 22.9, 14.4. MS: m/z (%) 306 [M]+ (10), 207
(18), 148 (32), 121 (100).
4. Experimental
4.1. General
GC–MS analyses were performed on an Agilent HP 6890 gas-
chromatograph equipped with a 5973 mass-detector, using an Agi-
lent HP-5MS column (30 m ꢃ 0.25 mm ꢃ 0.25
lm). The following
temperature programm was employed: 60 °C (1 min)/6 °C/min/
150 °C (1 min)/12 °C/min/280 °C (5 min). 1H and 13C NMR spectra
were recorded on a Bruker ARX 400 spectrometer (400 MHz 1H,
100.6 MHz 13C) in CDCl3 solution at rt, using TMS as internal stan-
dard for 1H and CDCl3 for 13C; chemical shifts d are expressed in
parts per million (ppm) relative to TMS, J values are given in hertz.
Optical rotations were determined on a Dr. Kernchen Propol digital
automatic polarimeter. Chiral HPLC analyses were performed on a
Merck-Hitachi L-4250 chromatograph equipped with a Chiralcel
OD column and UV detector (210 nm); mobile phase: n-hexane/i-
PrOH 99:1 for the methyl esters of 13a and 13b and 98:2 for the
other compounds; flow rate: 0.6 mL/min. TLC analyses were per-
formed on Merck Kieselgel 60 F254 plates. All the chromatographic
separations were carried out on silica gel columns. All reagents and
solvents were purchased from Fluka or Aldrich and used without
any further purification.
4.4. Octyl (R)-2-hydroxy-3-(4-methoxyphenyl) propanoate (R)-8
To a mechanically stirred mixture of baker’s yeast (450 g) in tap
water (2.0 L) at 30 °C, was added a solution of glucose (25 g) in
water (50 mL). After 1 h was added a solution of 7 (2.93 g,
9.6 mmol) in EtOH (40 mL). The vigorous stirring was continued
for 4 days. During this time, more baker’s yeast (250 g) and glucose
(20 g) were added after 24 and 48 h. Then, the mixture was filtered
on a Celite pad and the aq phase was extracted with EtOAc
(3 ꢃ 0.75 L). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure. Column chromatogra-
phy purification (n-hexane/EtOAc, 9:1) gave a yellow oil; 0.23 g,
8% yield; 94% purity by 1HNMR; 1H NMR (400 MHz, CDCl3) d 7.12
(d, J = 8.5, 2H), 6.92 (d, J = 8.5, 2H), 4.30 (dd, J = 6.4, 4.6, 1H), 4.14
(t, J = 7.1, 2H), 3.78 (s, 3H), 3.10–2.85 (mAB, 1H), 1.63 (m, 2H),
1.20–1.48 (m, 10H), 0.88 (t, J = 7.1, 3H); 13C NMR (100.6 MHz,
CDCl3) d 173.7, 159.1, 131.2, 130.3, 114.3, 71.4, 61.5, 55.2, 41.2,
32.4, 29.8, 29.7, 29.2, 26.5, 23.2, 14.6.
4.2. General procedure for the preparation of dialkyloxalates
To a well stirred ice-cold solution of the alcohol (0.30 mol) and
Et3N (43.4 mL, 0.31 mol) in CH2Cl2 (200 mL) was added dropwise a
solution of oxalyl chloride (12.6 mL, 0.15 mol) in CH2Cl2 (100 ml).
After 5 h the mixture was poured into ice (300 g) and aq NH4Cl
solution (satd, 50 mL), and extracted with CH2Cl2 (2 ꢃ 100 mL).
The reunited organic phase was washed with aq HCl (1 M,
4.5. (Z)-2-Methoxy-3-(4-methoxyphenyl)acrylic acid 10b
To an ice-cold stirred solution of NaOMe in MeOH (prepared by
dissolving 19.4 g, 842 mmol of sodium in 400 mL of MeOH), a solu-
tion of ethyl chloroacetate (89 mL, 842 mmol) in MeOH (60 mL)
was slowly added over for about 30 min. After the addition the

E. Brenna et al. / Tetrahedron: Asymmetry 20 (2009) 2694–2698
2697
reaction mixture was warmed to 25 °C, stirred for 1 h and then
cooled again to 0 °C. Solid NaOMe (52.7 g, 977 mmol) was added
portionwise to the slurry over 1 h. Keeping the temperature below
5 °C were subsequently added additional MeOH (20 mL), diethyl
carbonate (62 mL, 512 mmol) and slowly anisaldehyde (45 mL,
359 mol) over 2 h. The mixture was warmed to 25 °C and stirred
J = 8.6, 2H), 7.02 (s, 1H), 6.89 (d, J = 8.6, 2H), 6.01–5.95 (m,
1H+1H), 5.42–5.32 (m, 1H+1H), 5.28 (ddd, J = 1.3, 2.6, 10.2, 1H),
5.23 (ddd, J = 0.9, 2.5, 10.2, 1H), 4.73 (dt, J = 5.7, 1.4, 2H), 4.48 (dt,
J = 5.9, 1.4, 2H), 3.83 (s, 3H); MS: m/z (%) 274 [M]+ (9), 233 (4),
205 (3), 161 (100), 146 (8), 121 (10).
for
a
further 10 h. Next, H2O (100 mL) and NaOH solution
4.8. General procedure for the synthesis of the
aldehydes 9
a-alkoxy
(110 mL, 1.1 mol, 10 M) were added under stirring and, after 2 h,
the slurry was concentrated under reduced pressure. To the ice-
cold slurry HCl (179 mL, 2.15 mol, 12 M) was slowly added over
1 h. The mixture was then stirred at rt for 2 h and filtered. The filter
cake was washed with H2O (4 ꢃ 300 mL) and dried under vacuum
at 55 °C, yielding the pure acid 10b. White crystalline solid; 55.9 g,
75% yield; >99% purity by 1H NMR; 1H NMR (400 MHz, CDCl3) d
7.74 (d, J = 8.6, 2H), 7.12 (s, 1H), 6.91 (d, J = 8.7, 2H), 3.84 (s, 3H),
3.79 (s, 3H); 13C NMR (100.6 MHz, CDCl3) d 169.7, 160.6, 143.2,
132.1, 126.2, 125.8, 114.1, 59.2, 55.3; HRMS (ESI) calcd for
C11H12O4 208.0736, found 208.0744.
To an ice-cold solution of ester (23.0 mmol) in Et2O (80 mL) was
added portionwise LiAlH4 (0.45 g, 11.8 mmol). After complete con-
version of ester checked by TLC, the reaction mixture was
quenched with a saturated solution of NH4Cl (50 mL) and filtered
on a Celite pad. Then, the organic phase was washed with brine
(2 ꢃ 50 mL) and dried over Na2SO4. Concentration under reduced
pressure gave a white yellowish solid, which was triturated in cold
n-hexane/Et2O (9:1) to afford the alcohol as a white powder of suf-
ficient purity for the next step. To a well stirred and ice-cold sus-
pension of MnO2 (60.0 g) in CH2Cl2 (200 mL) was added dropwise
a solution of alcohol (21.0 mmol) in CH2Cl2 (20 mL). After 1 h, the
suspension was filtered over a Celite pad, and concentrated under
reduced pressure to give the aldehyde as a yellow oil of satisfactory
purity.
4.6. General procedure for the esterification of acids 10a–b
To a solution of acid (6.9 mmol) in dry acetone (80 mL) were
added anhydrous K2CO3 (1.10 g, 7.9 mmol), TBAI (1.00 g, 2.7 mmol)
and EtBr (0.59 mL, 7.9 mmol). The white suspension was stirred at
rt until complete consumption of the acid, which was checked by
TLC. Then, the suspension was concentrated under reduced pres-
sure, diluted with n-hexane/Et2O (100 mL, 9:1) and filtered over
a Celite pad, which was washed several times. Concentration under
reduced pressure gave the corresponding ester of sufficient purity
for the next step.
4.8.1. (Z)-2-Ethoxy-3-(4-methoxyphenyl)acrylaldehyde 9a
Yellow oil; 2.98 g, 63% yield, 93% purity by GC (tR 21.59 min); Z/
E 9:1 by 1H NMR; 1H NMR (400 MHz, CDCl3) d 9.30 (s, 1H), 7.82 (d,
J = 8.8, 2H), 6.93 (d, J = 8.9, 2H), 6.52 (s, 1H), 4.23 (q, J = 7.1, 2H),
3.85 (s, 3H), 1.37 (t, J = 7.1, 3H); 13C NMR (100.6 MHz, CDCl3) d
189.4, 161.0, 152.1, 134.7, 132.0, 126.3, 114.14, 66.8, 55.3, 15.7;
MS: m/z (%) 206 [M]+ (65), 162 (58), 149 (47), 121 (100), 91 (21),
77 (21). HRMS (ESI) calcd for C12H14O3 206.0943, found 206.0950.
4.6.1. Ethyl (Z)-2-ethoxy-3-(4-methoxyphenyl)acrylate 11a
Yellow oil; 1.66 g, 96% yield, 97% purity by GC (tR 23.35 min); 1H
NMR (400 MHz, CDCl3) d 7.75 (d, J = 8.8, 2H), 6.96 (s, 1H), 6.89 (d,
J = 8.9, 2H), 4.29 (q, J = 7.1, 2H), 3.99 (q, J = 7.1, 2H), 3.83 (s, 3H),
1.36 (t+t, J = 7.1, 7.1, 3H+3H); 13C NMR (100.6 MHz, CDCl3) d
165.2, 160.3, 143.4, 132.0, 126.8, 124.2, 114.2, 67.8, 61.3, 55.6,
15.8, 14.6; MS: m/z (%) 250 [M]+ (100), 193 (37), 148 (94), 121
(36), 91 (16), 77 (12); HRMS (ESI) calcd for C14H18O4 250.1205,
found 250.1209.
4.8.2. (Z)-2-Methoxy-3-(4-methoxyphenyl)acrylaldehyde 9b
Yellow oil; 2.69 g, 61% yield, 94% purity by GC (tR 20.84 min); Z/
E 9:1 by 1H NMR; 1H NMR (400 MHz, CDCl3) d 9.30 (s, 1H), 7.78 (d,
J = 8.9, 2H), 6.93 (d, J = 8.9, 2H), 6.51 (s, 1H), 3.93 (s, 3H), 3.85 (s,
3H); 13C NMR (100.6 MHz, CDCl3) d 189.2, 161.0, 152.9, 134.4,
132.1, 126.1, 114.2, 58.6, 55.3; MS: m/z (%) 192 [M]+ (100), 161
(18), 149 (39), 121 (81), 91 (20), 77 (21). HRMS (ESI) calcd for
C11H12O3 192.0786, found 192.0779.
4.6.2. Ethyl (Z)-2-methoxy-3-(4-methoxyphenyl)acrylate 11b
Yellow oil; 1.55 g, 95% yield, 98% purity by GC (tR 22.92 min); 1H
NMR (400 MHz, CDCl3) d 7.72 (d, J = 8.6, 2H), 6.96 (s, 1H), 6.90 (d,
J = 8.9, 2H), 4.30 (q, J = 7.1, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 1.37 (t,
J = 7.1, 3H); 13C NMR (100.6 MHz, CDCl3) d 164.7, 160.1, 144.1,
131.8, 126.2, 123.8, 114.0, 61.0, 59.0, 55.3, 14.3; MS: m/z (%) 236
[M]+ (100), 193 (29), 148 (27), 137 (16), 121 (26). HRMS (ESI) calcd
for C13H16O4 236.1049, found 236.1042.
4.8.3. (Z)-2-Allyoxy-3-(4-methoxyphenyl)acrylaldehyde 9c
Yellow oil; 2.91 g, 58% yield; 91% purity by GC (tR 18.96 min); Z/E
8:1 by 1H NMR; 1H NMR (400 MHz, CDCl3) d 9.3 (s, 1H), 7.82 (d, J = 8.6,
2H), 6.92 (d, J = 8.6, 2H), 6.56 (s, 1H), 6.01 (m, 1H), 5.37 (ddd, J = 1.3,
2.5, 10.5, 1H), 5.22 (ddd, J = 1.6, 3.2, 17.2, 1H), 4.73 (dt, J = 6.0, 1.3, 2H),
3.85 (s, 3H); 13C NMR (100.6 MHz, CDCl3) d 189.8, 161.6, 152.0, 135.7,
134.3, 132.7, 126.7, 118.8, 114.7, 72.2, 55.9; MS: m/z (%) 218 [M]+
(11), 161 (100), 146 (10), 121 (13), 91 (14).
4.7. Allyl (Z)-2-allyloxy-3-(4-methoxyphenyl)acrylate 11c
4.9. Baker’s yeast reduction of a-alkoxy aldehydes 9
To a mechanically stirred ice-cold suspension of p-methoxyben-
zylphosphonium chloride (50.1 g, 0.12 mol) in dry THF (300 mL)
was added dropwise n-BuLi (10 M, 12 mL, 0.12 mol) under an N2
atmosphere. After 1 h a solution of 15 (22.1 g, 0.12 mol) in dry
THF was added dropwise. Then, after 24 h, the reaction mixture
was quenched with NH4Cl solution (satd, 100 mL) and ice
(100 g), and concentrated under reduced pressure. The aqueous
phase was extracted with CH2Cl2 (2 ꢃ 200 mL) and the combined
organic phase was dried over Na2SO4 and concentrated under re-
duced pressure to give a crude yellowish paste. The latter was trit-
urated in cold n-hexane/Et2O 9:1, filtered and concentrated.
Column chromatography purification (eluent n-hexane/EtOAc
9:1) afforded 11c as a yellow oil; 24.1 g, 75% yield; 97% purity by
GC (tR 23.09 min); Z/E 20:1; 1H NMR (400 MHz, CDCl3) d 7.75 (d,
To a mechanically stirred mixture of commercial baker’s yeast
(250 g) in tap water (0.7 L) at 30 °C, was added a solution of glu-
cose (25 g) in water (50 mL). After 1 h was added in one portion
the aldehyde (9.6 mmol) adsorbed on the resin XAD 1180 (20 g).
The vigorous stirring was continued for 4 days. During this time
more baker’s yeast (50 g) and glucose (10 g) were added after 24
and 48 h. Then, the mixture was filtered on a sintered glass funnel
(porosity 0, >165 lm) and the aq phase was extracted again with
other resins (50 g). The combined resin crops were washed with
acetone (50 mL) and EtOAc (4 ꢃ 100 mL). The combined organic
phase was concentrated under reduced pressure to give an oil
which was dissolved in CH2Cl2 (100 mL). To this solution, after
washing with brine (2 ꢃ 50 mL) and drying over Na2SO4, was

2698
E. Brenna et al. / Tetrahedron: Asymmetry 20 (2009) 2694–2698
added MnO2 (20 g) which was filtrated and concentrated under re-
duced pressure after complete conversion of the residual allylic
alcohol to the corresponding aldehyde. The residue was submitted
to column chromatography purification using n-hexane/EtOAc
(9:1) as eluent to give, in order of elution, the starting aldehyde
and the saturated alcohol.
½
a 2D0
ꢁ
¼ ꢂ23:9 (c 1.11, CHCl3) versus lit. 99% ee, ½a D20
¼ ꢂ25:2 (c
ꢁ
1.40, CHCl3), Ref. 1; 1H and 13C NMR data are consistent with
the literature, Ref. 1; HRMS (ESI) calcd for C11H14O4 210.0892,
found 210.0898.
4.11. (S)-3-(4-Methoxyphenyl)-1,2-propandiol (S)-14
4.9.1. (S)-2-Ethoxy-3-(4-methoxyphenyl)-1-propanol (S)-12a
Yellow oil; 1.57 g, 78% yield, 99% purity by GC (tR 20.31 min);
To a stirred solution of 13c (0.22 g, 0.9 mmol) in AcOH (4 mL)
and water (1 mL) were added PdCl2 (0.07 g) and NaOAc (0.1 g).
After complete cleavage of O-allyl group the reaction mixture
was concentrated under reduced pressure. The residual solid was
dissolved in EtOAc (30 mL) and the solution was washed with
NaHCO3 solution (satd, 2 ꢃ 30 mL) and brine (20 mL). The organic
phase was dried over Na2SO4 and concentrated under reduced
pressure. Column chromatography purification (n-hexane/EtOAc
7:3) afforded pure diol (S)-14.
99% ee by HPLC (tR 34.2 min (R) and 38.4 min (S)); ½a D20
¼ þ4:0 (c
ꢁ
3.52, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.12 (d, J = 8.5, 2H),
6.83 (d, J = 8.6, 2H), 3.79 (s, 3H), 3.65–3.40 (m, 5H), 2.85–2.65
(mAB, 2H), 1.19 (t, J = 7.0, 3H); 13C NMR (100.6 MHz, CDCl3) d
158.0, 130.2, 130.1, 113.7, 81.1, 65.2, 63.6, 55.2, 36.4, 15.5; MS:
m/z (%) 224 [M]+ (23), 194 (100), 165 (79), 151 (50), 137 (25),
121 (85), 91 (37), 77 (24); HRMS (ESI) calcd for C12H18O3
210.1256, found 210.1252.
Brownish oil; 145 mg, 89% yield; 89% purity by GC (tR
20.64 min);
½
a 2D0
ꢁ
¼ ꢂ12:7 (c 0.93, CHCl3) versus lit. 98% ee
4.9.2. (S)-2-Methoxy-3-(4-methoxyphenyl)-1-propanol (S)-12b
Yellow oil; 1.52 g, 81% yield; 98% purity by GC (tR 19.56 min);
½
a 2D0
ꢁ
¼ ꢂ12:9 (c 2.0, CHCl3), Ref. 14a; 1H NMR data are consistent
with the literature, Ref. 18; 13C NMR (100.6 MHz, CDCl3) d 158.4,
130.2, 129.6, 114.1, 73.1, 66.0, 55.3, 38.9; MS: m/z (%) 182 [M]+
(5), 164 (3), 148 (8), 121 (100).
95% ee by HPLC (tR 39.9 min (R) and 49.6 min (S)); ½a D20
¼ ꢂ3:4 (c
ꢁ
1.16, EtOH); 1H NMR (400 MHz, CDCl3) d 7.12 (d, J = 8.7, 2H),
6.83 (d, J = 8.7, 2H), 3.79 (s, 3H), 3.68–3.56 (m, 1H), 3.49–3.42
(mAB
, 1H), 3.40 (s, 3H), 2.88–2.65 (mAB,
2H); 13C NMR
(100.6 MHz, CDCl3) d 158.2, 130.2, 129.2, 113.9, 82.9, 63.3, 57.4,
55.2, 35.9; MS: m/z (%) 196 [M]+ (25), 165 (26), 121 (100), 75
(15); HRMS (ESI) calcd for C11H16O3 196.1099, found 196.1102.
Acknowledgements
We thank Dr. M. Hedberg of AstraZeneca for providing a sample
of 10a. We are grateful for the generous financial support from the
E.U. INTENANT project.
4.9.3. (S)-2-Allyoxy-3-(4-methoxyphenyl)-1-propanol (S)-12c
Yellowish oil; 1.49 g, 70% yield; 98% purity by GC (tR
21.45 min); >99.9% ee by HPLC (tR 29.7 min (R) and 36.6 min (S));
a 2D0
ꢁ
¼ ꢂ2:9 (c 1.16, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.11 (d,
References
½
J = 8.9, 2H), 6.83 (d, J = 8.9, 2H), 5.90 (m, 1H), 5.26 (ddd, J = 1.4,
1. Brenna, E.; Fuganti, C.; Gatti, F. G.; Parmeggiani, F. Tetrahedron: Asymmetry
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3.2,16.9, 1H), 5.18 (ddd, J = 1.4, 2.8, 10.4, 1H), 4.09–3.98 (mAB
,
2H), 3.80 (s, 3H), 3.66–3.58 (m, 1H+1H), 3.48 (dd, J = 5.9, 11.0,
1H), 2.88–2.67 (mAB, 2H); 13C NMR (100.6 MHz, CDCl3) d 158.2,
134.8, 130.3, 130.0, 117.1, 113.9, 80.8, 70.8, 63.7, 55.2, 36.5; MS:
m/z (%) 222 [M]+ (10), 191 (7), 121 (100).
2. (a) Anderson, K. PCT Appl. WO 99/62872.; (b) Martin, J. A.; Brooks, D. A.; Prieto,
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1 by catalytic reduction of a-ethoxy
4.10. General procedure for the oxidation of alcohols 12
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To a well stirred solution of alcohol (9.9 mmol) in CH2Cl2/H2O
(2:1, 60 ml) were added TEMPO (0.46 g, 3.0 mmol) and BAIB
(6.37 g, 19.8 mmol). After complete oxidation of the alcohol is ver-
ified by TLC, the reaction mixture was quenched with Na2S2O3 solu-
tion (10% in water, 350 mL). Then, the mixture was washed with a
saturated solution of NaHCO3 (2 ꢃ 100 mL). The combined aq phase
was washed with EtOAc (1 ꢃ 50 mL) and acidified with HCl (3 M,
100 mL). The aq solution was washed with EtOAc (3 ꢃ 100 mL).
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centrated under reduced pressure to give the pure corresponding
acid.
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a,b-unsaturated
4.10.1. (S)-2-Ethoxy-3-(4-methoxyphenyl)propanoic acid (S)-13a
Pale yellow oil; 2.22 g, 100% yield; 99% purity by GC (of methyl
ester derivative, tR 20.71 min); 99% ee by HPLC (of methyl ester
aldehydes adsorbed on solid support see: (a) D’Arrigo, P.; Fuganti, C.; Pedrocchi
Fantoni, G.; Servi, S. Tetrahedron 1998, 54, 15017–15026; (b) Fuganti, C.; Serra,
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Fuganti, C. Eur. J. Org. Chem. 2008, 1036–1037.
derivative, tR 14.8 min (R) and 16.7 min (S)); ½a D20
¼ ꢂ17:9 (c
ꢁ
13. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
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1.04, CHCl3) versus lit. 93% ee, ½a D20
¼ ꢂ16:6 (c 1.21, CHCl3), Ref.
ꢁ
1; 1H and 13C NMR data are consistent with the literature, Ref. 1;
HRMS (ESI) calcd for C12H16O4 224.1049, found 224.1043.
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4.10.2. (S)-2-Methoxy-3-(4-methoxyphenyl)propanoicacid (S)-13b
Pale yellow oil; 2.02 g, 97% yield; 97% purity by GC (of
methyl ester derivative, tR 20.08 min); 95% ee by HPLC (of
methyl ester derivative, tR 22.3 min (R) and 25.9 min (S));