Enzyme-catalysed approach to the preparation of triazole antifungals: synthesis of (-)-genaconazole

Article abstract of DOI:10.1016/j.tetasy.2009.09.024

The work describes a new enzyme-mediated approach to optically active epoxide (2R,3S)-6, which is an important key intermediate in the preparation of single enantiomers of chiral azole antifungals. The conversion of (2R,3S)-6 into (-)-genaconazole is reported as an example of its synthetic relevance.

Full text of DOI:10.1016/j.tetasy.2009.09.024

Tetrahedron: Asymmetry 20 (2009) 2413–2420
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzyme-catalysed approach to the preparation of triazole antifungals:
synthesis of (À)-genaconazole
a
a
b
Daniela Acetti a, Elisabetta Brenna a, , Claudio Fuganti , Francesco G. Gatti , Stefano Serra
*
a Politecnico di Milano, Dipartimento di Chimica, Materiali, Ingegneria Chimica, Via Mancinelli 7, I-20131 Milano, Italy
b Istituto CNR per la Chimica del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The work describes a new enzyme-mediated approach to optically active epoxide (2R,3S)-6, which is an
important key intermediate in the preparation of single enantiomers of chiral azole antifungals. The con-
version of (2R,3S)-6 into (À)-genaconazole is reported as an example of its synthetic relevance.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 September 2009
Accepted 25 September 2009
Available online 23 October 2009
1. Introduction
N
N
N
OH
N
OH
F
N
N
N
The need for effective treatments for fungal infections has be-
come more urgent over the last decade by the growing increase
of immuno-compromised patients, suffering from AIDS, or sub-
jected to transplantations or anti-cancer therapy. Although a major
breakthrough has been brought about by the licensing of potent
azoles, that is, fluconazole,1 voriconazole2 and posaconazole3
(Scheme 1), some therapeutic problems still remain, particularly
related to the appearance of new pathogenic fungal species, and
to the development of significant drug resistance.4
Several azole agents have been investigated, most of which show
the core structure I (Scheme 2), such as (À)-1,5 the active enantiomer
of racemicgenaconazole, albaconazole 2, ravuconazole 3,6 and many
new structures 47 and 58 that are currently being introduced.
The key structural motif I can be obtained in the correct abso-
lute configuration by ring opening of epoxide (2R,3S)-6 by means
of a suitable nucleophilic reagent (Scheme 3). We have developed
a lipase-mediated preparation of (2R,3S)-6, and employed it to pre-
pare the azole antifungal (À)-1, that is, the eutomer of genaconaz-
ole, as a demonstration of its synthetic utility.
N
F
N
N
N
F
F
F
fluconazole
voriconazole
Et
OH
O
N
N
N
N
N
N
O
F
N
F
O
N
posaconazole
Scheme 1.
2. Results and discussion
triol (2R,3R)-9,11a,14 or epoxy alcohol (2R,3S)-10.11b Diastereoiso-
meric purity was achieved by crystallisation of diol (2R,3R)-8,9,12
and by means of diastereoselective reactions for triol (2R,3R)-9,14
and epoxy alcohol (2R,3S)-10.11b In a completely different approach,
a Sharpless–Katsuki epoxydation was employed to prepare epoxy
alcohol (2R,3S)-10 with moderate enantiomeric purity.15
Slightly different procedures were then exploited to convert
(2R,3R)-8, (2R,3R)-9 and (2R,3S)-10 into the desired epoxide.
We devised an alternative synthetic sequence to (2R,3S)-6: the
key step being the lipase-mediated acetylation of racemic triol
(2RS,3RS)-9a, which was obtained according to a new synthetic
procedure as reported in Scheme 4, from commercial 2,4-difluoro-
The preparation of epoxide (2R,3S)-6 reported in the literature
employed compound (R)-7 as a key intermediate (Scheme 3). This
latter was obtained either from (R)-9,10 or (S)-lactic acid,11 or by
enantioselective hydroxylation of the corresponding ketone12 with
camphorsulfonyl oxaziridines, or by enzymatic resolution of the hy-
droxy ketone mediated by lipases.13 The second stereogenic centre
was created by conversion of (R)-7 into either diol (2R,3R)-8,9,10,12
* Corresponding author. Tel.: +39 02 23993077; fax: +39 02 23993180.
E-mail address: elisabetta.brenna@polimi.it (E. Brenna).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.024

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D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
N
HO
N
N
R
F
CN
F
I
N
S
1
R = SO2CH3
O
SCH 42427
3 R =
ravuconazole
O
Ar
n
4
R =
2 R =
albaconazole
Cl
N
O
Z
N
Z = S, CH2
O
O
X
Ar
5
R =
S
X = electron withdrawing group
Scheme 2.
O
F
OAc
N
O
HO
HO
O
N
O
O
N
Nu
F
F
F
F
F
iv
i, ii
iii
F
11
F
12
F
13
F
(2R,3S)-6
O
O
O
O
F
O
HO
HO
HO
O
O
O
O
O
O
O
HO
N
OTHP
F
OH
F
OH
F
N
OH
F
OH
F
F
v
vi
F
F
+
N
+
F
F
F
(2R,3R)-9
F
F
15a
3
F
15b
1
F
14a
1.5
(R)-7
(2R,3R)-8
(2R,3S)-10
14b
1
Scheme 3.
HO
OH
F
HO
vii
acetophenone 11, and brought to diastereoisomeric purity by frac-
tional crystallisation.
Compound 11 was carefully brominated and then reacted with
sodium acetate in DMF, to afford acetoxy ketone 12. The latter was
treated with vinyl magnesium bromide in THF to give diol 13,
which was protected as an acetonide and submitted to epoxidation
with m-chloroperbenzoic acid, to afford a 1:1.3 mixture of epox-
ides 14a and 14b. Column chromatography allowed us to enrich
this mixture into the desired diastereoisomer 14a (14a/14b 1.5/
1). Lithium aluminium hydride reduction and a further enrichment
by column chromatography afforded compound 15 as a 3/1 mix-
ture of diastereoisomers 15a and 15b. These latter derivatives were
deprotected to give triols 9a and 9b; the desired isomer, (2RS,3RS)-
9a, could be obtained with de = 99% (1H NMR) by crystallisation
from hexane/diethyl ether 8/2.
F
(2RS,3RS) - 9a
Scheme 4. i. Br2, AcOH; ii. AcONa, DMF; iii. vinylmagnesium bromide, THF; iv. 2,2-
dimethoxypropane, acetone, PPTS; v. m-chloroperbenzoic acid, CH2Cl2; column
chromatography; vi. LiAlH4, THF; column chromatography; vii. HCl, AcOH, THF;
crystallisation from hexane-diethylether.
The lipase-mediated acetylation of the primary OH moiety of
compound 16 was characterised by very modest enantioselectivity,
and by a different stereochemical course according to the lipase,
which was employed as
a catalyst. Lipase PS gave (S)-18
(ee = 15%, of the corresponding alcohol), while either PPL (Porcine
pancreatic lipase) or CRL (Candida rugosa lipase) afforded (R)-18
(ee = 37% and 23% of the corresponding alcohol, respectively).
The biocatalytic transesterification of the 1:1 mixture of diaste-
reoisomers 17a and 17b was found to be characterised by high val-
ues of enantio- and diastereoselectivity, when lipase PS was
employed as a catalyst: acetate (+)-19b16 was obtained with
The choice of triol 9a as the best intermediate for this sequence
to be submitted to biocatalytic kinetic resolution was the result of
an investigation which was developed as follows; we first studied
the behaviour under the conditions of lipase-mediated transesteri-
fication of model compounds 16 and 17a,b (Scheme 5) with no
fluorine atoms on the aromatic ring, which could be easily pre-
pared from the largely available acetophenone.

D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
2415
OH
OAc
OAc
O
F
O
O
O
O
HO
HO
HO
i, iii, iv
OAc
F
O
F
OAc
F
NO2
i,ii
16
18
O2N
F
F
(2S,3S) - 24a
(+)-22b
23
O
O
O
O
O
O
R
S
Scheme 6. i. KOH, MeOH; ii. DIAD, PPh3, 3,5-dinitrobenzoic acid, THF; iii. HCl,
OH
OH
X'
OAc
X'
AcOH, THF; iv. Ac2O, pyridine.
X'
tion of acetate (+)-22b was determined to be (R,S) by chemical cor-
relation, according to the procedure shown in Scheme 6. A sample
of (+)-22b was submitted to saponification and a Mitsunobu ester-
ification with 3,5-dinitrobenzoic acid, to give ester 23. Compound
23 was hydrolysed and acetylated to afford diacetate (2S,3S)-24a,
thus confirming the preference of Lipase PS for the acetylation of
(R)-stereogenic centres.16
X''
X''
X''
X' = X'' = H
X' = H, X'' = F
17b X' = X'' = H
20b X' = H, X'' = F (+)-21b
15b
(R,S)-(+)-22b
(+)-19b
X' = X'' = H
X' = H, X'' = F
X' = X'' = F
17a
20a
15a X' = X'' = F
X' = X'' = F
Scheme 5.
The results of the kinetic resolution of 15a,b prompted us to
move the enzymatic resolution step further along the synthetic
procedure. The only other possible candidate to be resolved by en-
zyme-catalysed acetylation was triol 9 (Scheme 7).
When a 1:1 mixture of the diastereoisomeric diols 9a and 9b
was treated either with CRL or Lipase PS for 96 h in t-butylmethyl
ether in the presence of vinyl acetate, a 1:1 mixture of the two
enantiomerically pure diacetates 24a and 24b was recovered, in
17% and 34% isolated yields, respectively. When PPL was employed
as the catalyst a complex mixture of regioisomeric and stereoiso-
meric monoacetates was obtained, in addition to the unreacted
starting triols 9a and 9b.
The kinetic resolution of triol 9 showed no diastereoselectivity,
thus diastereoisomer separation had to be performed by means of
fractional crystallisation of the mixture 9a–b from 8:2 hexane/
diethyl ether (Scheme 7). Diacetate (2R,3R)-24a was then obtained
from racemic (RS,RS)-9a by Lipase PS mediated acetylation with
ee = 99% and de = 99%, and then hydrolysed to known (2R,3R)-9a.
A known procedure was then employed to convert triol (2R,3R)-
9a into epoxide (2R,3S)-6, which involved the treatment with me-
syl chloride in pyridine, and subsequent reaction with the sodium
salt of 1,2,4-triazole and NaH in DMF solution. Ring opening pro-
moted by sodium thiomethylate gave a sulfide intermediate, which
was oxidised to (À)-1, the most active enantiomer of genaconazole.
ee = 99%, and de = 91% (Table 1). The diastereoselectivity was
slightly lower when C. rugosa lipase was used, and acetate (+)-
19b was obtained with ee = 97% and de = 69%. No acetylation
was observed with PPL as a catalyst. We also investigated the
course of the lipase-mediated acetylation of racemic diastereoiso-
mers 20a and 20b, which showed one fluorine atom on the aro-
matic ring.
When the 1:1 mixture of the two racemic diastereoisomers 20a
and 20b (Table 1) was submitted to lipase PS-catalysed transeste-
rification, only acetate (+)-21b16 was obtained, showing ee = 99%
and de = 87%. When CRL was employed, diastereoisomeric acetate
(+)-21b was produced with ee = 94% and de = 33%. PPL gave mod-
est values of stereoselectivity, with a slight preference for the other
diastereoisomer: acetate 21a was obtained with de = 59% (the ee
could not be determined).
As for the kinetic resolution of 15a and 15b (Table 1), only li-
pase PS proved to be successful in the production of an acetate
derivative: acetate (+)-22b was obtained as a single enantiomeri-
cally pure diastereoisomer. Unfortunately 22b was the wrong dia-
stereoisomer for our synthetic sequence: after saponification and
acetal hydrolysis, diol 9b was recovered. The absolute configura-
Table 1
Lipase-mediated acetylation of the mixtures of 17a–b, 20a–b, and 15a–b
Acetate derivative
Unreacted alcohol
17a–b
Lipase PS
19b: ee = 99%, de = 91%
(first eluting enantiomer in GC)
19b: ee = 97%, de = 69%
(first eluting enantiomer in GC)
—
17b: ee = 31% (second eluting enantiomer in
GC as acetate derivative); 17b/17a = 2.9/7.1
17b: ee = 17%, (second eluting enantiomer in
GC as acetate derivative); 17b/17a = 4.3/5.7
—
CRL
PPL
20a–b
Lipase PS
21b: ee = 99%, de = 87%
(first eluting enantiomer in GC)
21b: ee = 94%, de = 33%
(first eluting enantiomer in GC)
21a: ee = not determined, de = 59% 21b:
ee = 40% (first eluting enantiomer in GC)
20b: ee = 99% (second eluting enantiomer in
GC as acetate derivative; 20b/20a = 3.3/6.6
20b: ee = 3.7% (second eluting enantiomer in
GC as acetate derivative); 20b/20a = 4.5/5.5
20a: ee = not determined; 20b: ee = 1.8% (second
eluting enantiomer in GC as acetate derivative); 20b/20a = 5.4/4.6
CRL
PPL
15a–b
Lipase PS
22b: ee = 99%, de = 99%
15b: ee = 10%; 15b/15a = 0.9/1.0
(first eluting enantiomer in GC)
CRL
PPL
—
—
—
—

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D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
CH3
OH
CH3
OH
CH3
OAc
CH3
OAc
HO
HO
HO
HO
HO
AcO
AcO
HO
F
F
F
F
i
+
+
F
F
F
F
(2RS,3RS) - 9a
(2RS,3SR) - 9b
(2R,3R) - 24a
(2S,3R) - 24b
ii
CH3
CH3
CH3
O
CH3
HO
N
N
HO
HO
HO
N
F
N
OAc
F
SO2CH3
OH
F
N
AcO
N
F
iii, iv, v
vi, vii
i
F
F
F
F
(2RS,3SR) - 9a
(2R,3R) - 24a
(2R,3S) - 6
(-)-genaconazole
Scheme 7. i. Lipase PS, t-butylmethylether, vinyl acetate; ii. crystallisation from hexane-diethyl ether; iii. KOH, MeOH; iv. mesyl chloride, pyridine; v. 1,2,4-triazole, NaH,
DMF; vi. CH3SNa, CH3OH; vii. m.-chloroperbenzoic acid, CH2Cl2.
exothermic reaction took place with concomitant decolouration.
After 30 min, sodium acetate (42.0 g, 0.512 mol) was added and
the reaction mixture was concentrated under reduced pressure.
Next, DMF (300 mL) was added, and the mixture was stirred at
room temperature for 2 h. The reaction mixture was poured into
water and extracted with diethyl ether. The combined organic
phases were washed with water, dried on sodium sulfate and con-
centrated under reduced pressure to give a solid residue, from
which compound 12 was recovered by crystallisation from hexane:
(35.1 g, 64%); dH (400 MHz; CDCl3): 2.21 (3H, s, COCH3), 5.19 (2H, d,
J 3.8 Hz, CH2), 6.91 (1H, m, aromatic H), 7.01 (1H, m, aromatic H),
8.02 (1H, m, aromatic H); dC (100.61 MHz, CDCl3): 20.4, 68.8 (d),
104.7 (ddt), 112.7 (dd), 119.2 (dd), 132.8 (dd), 163.3 (dd), 166.6
(dd), 170.2, 189.0 (d); GC/MS tR 14.91 min, m/z 214 (M+, 1), 172
(1), 154 (3), 141 (100).
3. Conclusions
The work highlights the great versatility of lipases in the catal-
ysis of transesterification reactions. The best results were achieved
by using lipase PS: the kinetic resolution of secondary alcohols
17a–b, 20a–b, and 15a–b proved to be enantiospecific and totally
diastereoselective; the acetylation of triols 9a–b was enantiospec-
ific, but not diastereoselective. The synthetic route we have de-
vised for optically active epoxide (2R,3S)-6 is characterised by
interesting key intermediates that can be enriched in the desired
diastereoisomer either by column chromatography (i.e., epoxides
14 and alcohols 15) or by crystallisation (triols 9). The procedure
is well suited for investigating the possibility of integrating the
physical methods of diastereoisomer separation with chemical
techniques of optical activation, in order to enhance the production
yield of the desired stereoisomer. The synthetic target, epoxide
(2R,3S)-6, is a valuable chiral structural moiety, whose synthesis
is worth being optimised, as it plays a central role in the prepara-
tion of relevant antifungal drugs.
4.2. 2-(2,4-Difluorophenyl)but-3-ene-1,2-diol 13
To a solution of vinyl magnesium bromide in THF, obtained by
the addition of vinyl bromide (78.8 g, 0.736 mol) to a suspension
of magnesium turnings (25.4 g, 1.10 mol) in THF (500 mL), com-
pound 12 (35.0 g, 0.164 mol) was added dropwise. After 30 min,
the reaction mixture was poured into a saturated NH4Cl water
solution, and extracted with diethyl ether. The organic phase was
dried and concentrated under reduced pressure, to obtain a residue
which was chromatographed on silica gel with hexane–ethyl ace-
tate 9:1, affording derivative 13 (23.3 g, 71%): dH (400 MHz;
CDCl3): 3.85 (2H, s, CH2), 5.24 (1H, d, J 10.5 Hz, @CHH), 5.35 (1H,
d, J 17.3 Hz, @CHH), 6.22 (1H, ddd, J = 2.2, 10.8, 17.3 Hz, CH@),
6.77 (1H, m, aromatic H), 6.87 (1H, m, aromatic H), 7.62 (1H, m,
aromatic H); dC (100.61 MHz, CDCl3): 67.8 (d), 76.3 (d), 104.2 (t),
111.1 (dd), 115.8, 125.5 (dd), 129.1 (dd), 138.9 (d), 159.5 (dd),
162.5 (dd); GC/MS tR 14.19 min, m/z 200 (M+, 2), 182 (1), 169
(100), 151 (17), 141 (26).
4. Experimental
The enantiomeric excess values were determined either by GC
or HPLC analysis: (a) GC analysis was performed using a Chirasil
DEX CB, 25 m  0.25 mm (Chrompack) column, installed on a DANI
HT 86.10 gas chromatograph; (b) HPLC analyses were performed
using a Chiralcel OD column, installed on a Merck-Hitachi l-7100
instrument with a Merck-Hitachi L-4250 UV–vis detector. The GC
and HPLC analyses conditions and the observed retention times
are hereafter reported:
(a) Compound 19b: GC temperature programme 60 °C (3 min)—
1.5 °C minÀ1—180 °C; tR = 36.5 min, 36.8 min.
(b) Compound 21b: GC temperature programme 60 °C (3 min)—
1.5 °C minÀ1—180 °C; tR = 37.5 min, 38.0 min.
4.3. 4-(2,4-Difluorophenyl)-2,2-dimethyl-4-vinyl-1,3-dioxolane
(c) Compound 22b: GC temperature programme 60 °C (3 min)—
1.5 °C minÀ1—180 °C; tR = 33.9 min, 34.9 min.
Compound 13 (23.0 g, 0.115 mol) was treated with dimethoxy-
propane (10 ml), in acetone solution (200 mL), in the presence of
a catalytic amount of pyridinium p-toluenesulfonate, to afford the
corresponding acetonide derivative (24.0 g, 87%): dH (400 MHz;
CDCl3): 1.38 (3H, s, CCH3), 1.55 (3H, s, CCH3), 4.20 (1H, dd, J 1.2,
8.9 Hz, CHH), 4.35 (1H, dd, J 2.8, 8.9 Hz, CHH), 5.09 (1H, dd, J
0.6, 10.6 Hz, @CHH), 5.17 (1H, d, J 17.0 Hz, @CHH), 6.12 (1H,
ddd J 1.2, 10.6, 17.0 Hz, CH@), 6.77 (1H, m, aromatic H), 6.86
(1H, m, aromatic H), 7.61 (1H, m, aromatic H); dC (100.61 MHz,
(d) Compound 24a: HPLC, 1.0 ml/min, 254 nm, 99:1 hexane/iso-
propanol, tR = 16.3 min, 20.8 min.
(e) Compound 24b: HPLC, 1.0 ml/min, 254 nm, 99:1 hexane/iso-
propanol, tR = 24.7 min, 29.7 min.
4.1. 2-(2,4-Difluorophenyl)-2-oxoethyl acetate 12
To a solution of 2,4-difluoroacetophenone (40.0 g, 0.256 mol) in
acetic acid (500 mL), bromine (41.0 g, 0.256 mol) was added: an

D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
2417
CDCl3): 25.8, 26.7, 74.5 (d), 82.5 (d), 103.8 (t), 110.3, 111.0 (dd),
114.0, 126.9 (dd), 128.5 (dd), 139.9, 159.0 (dd), 162.7 (dd); GC/
MS tR 13.63 min, m/z 240 (M+, 4), 225 (68), 210 (52), 182 (33),
165 (59), 151 (100).
4.6. (2RS,3RS)-2-(2,4-Difluorophenyl)butane-1,2,3-triol (2RS,-
3RS)-9a and (2RS,3SR)-2-(2,4-difluorophenyl)butane-1,2,3-triol
(2RS,3SR)–9b
The 3:1 mixture of derivatives 15a and 15b (13.8 g, 0.053 mol)
was dissolved in THF (100 mL), then a few drops of acetic acid and
of HCl 37% were added. The mixture was heated at 40 °C for 3 h,
then concentrated under reduced pressure, poured into a saturated
NaHCO3 solution, and extracted with ethyl acetate. The organic
phase was dried over Na2SO4, and concentrated under reduced
pressure to afford a residue, which was chromatographed on silica
gel. From the first eluted fraction, two crystallisations from hex-
ane/ethyl ether 8:2 allowed the isolation of triol 9a as a pure crys-
talline solid (4.62 g, 40%). From the last eluted fractions, diol 9b
(2.31 g, 20%) was recovered.Data of 9a: dH (400 MHz; acetone-
d6): 0.88 (3H, d, J 6.2 Hz, CH3CH), 3.81 (1H, d, J 11.1 Hz, CHH),
4.11 (1H, dd, J 1.7, 11.1 Hz, CHH), 4.33 (1H, m, CHOH), 6.91 (1H,
m, aromatic H), 6.98 (1H, m, aromatic H), 7.78 (1H, m, aromatic
H); dC (100.61 MHz, CDCl3): 19.2, 69.6 (d), 71.7 (d), 79.5 (d),
105.4 (m), 112.6 (m), 128.0 (d), 132.6 (m), 161.1 (dd), 163.9
(dd).Data of 9b: dH (400 MHz; CDCl3): 1.12 (3H, d, J 6.4 Hz, CH3CH),
3.94 (1H, d, J 11.4, CHH), 4.01 (1H, q, J 6.4 Hz, CHCH3), 4.06 (1H, dd,
J = 2.2, 11.4 Hz, CHH), 6.7586 (1H, m, aromatic H), 6.86 (1H, m, aro-
matic H), 7.56 (1H, m, aromatic H); 13C NMR (100.61 MHz,CDCl3):
17.0, 64.4 (d), 71.9 (d), 78.5 (d), 104.1 (dd), 111.1 (dd), 124.5 (dd),
130.6 (dd), 159.3 (dd), 162.4 (dd).
4.4. 4-(2,4-Difluorophenyl)-2,2-dimethyl-4-(oxiran-2-yl)-1,3-
dioxolane 14a and 4-(2,4-difluorophenyl)-2,2-dimethyl-4-
(oxiran-2-yl)-1,3-dioxolane 14b
m-Chloroperbenzoic acid (20.5 g, 0.119 mol) was added at 0 °C
to a solution of the acetonide derivative of compound 13 (23.8 g,
0.0991 mol) in methylene chloride (300 mL) under stirring. After
2 h at room temperature, the reaction mixture was poured into
water, and extracted with methylene chloride. The organic phase
was washed with a saturated sodium pyrosulfite solution, dried
on sodium sulfate and concentrated under reduced pressure, to
give a residue, which was chromatographed on a silica gel column,
eluting with hexane and increasing amount of ethyl acetate. The
main fraction (19.8 g, 78%) consisted of a 1.5:1 mixture of epoxide
derivatives 14a and 14b. The following data were obtained for en-
riched samples of the two diastereoisomers.
Data of 14a: dH (400 MHz; CDCl3): 1.34 (3H, s, CCH3), 1.51 (3H, s,
CCH3), 2.60 (1H, dd, J 3.9, 5.4 Hz, OCHH oxirane ring), 2.74 (1H, dd, J
2.5, 5.7 Hz, OCHH oxirane ring), 3.24 (1H, m, CHO oxirane ring),
4.22 (1H, dd, J 1.7, 9.1 Hz, CHH), 4.56 (1H, dd, J 2.5, 9.1 Hz, CHH),
6.82 (1H, m, aromatic H), 6.89 (1H, m, aromatic H), 7.59 (m, 1H,
aromatic H); dC (100.61 MHz, CDCl3): 25.8, 25.9, 43.5, 54.5 (d),
72.3 (d), 80.3 (d), 103.9 (t), 110.6, 111.3 (dd), 124.9 (dd), 129.2
(dd), 158.9 (dd), 162.7 (dd); GC/MS tR 17.43 min, m/z 256 (M+, 1),
241 (16), 213 (100), 181 (14), 155 (53).Data of 14b: dH (400 MHz;
CDCl3): 1.33 (3H, s, CCH3), 1.56 (3H, s, CCH3), 2.64 (1H, m, OCHH
oxirane ring), 2.75 (1H, m, OCHH oxirane ring), 3.25 (m, 1H, CHO
oxirane ring), 4.16 (1H, dd, J 1.7, 9.1 Hz, CHH), 4.41 (1H, dd, J 2.8,
9.1 Hz, CHH), 6.79 (1H, m, aromatic H), 6.89 (1H, m, aromatic H),
7.61 (1H, m, aromatic H); dC (100.61 MHz, CDCl3): 25.4, 26.4,
44.3 (d), 55.2, 71.1 (d), 81.2 (d), 103.9 (t), 110.3, 111.1 (dd),
124.4 (dd), 129.3 (dd), 159.0 (dd), 162.6 (dd); GC/MS tR
17.79 min, m/z 256 (M+, 1), 241 (17), 213 (100), 181 (15), 155 (66).
4.7. (2R,3R)-2-(2,4-Difluorophenyl)-2-hydroxybutane-1,3-diyl
diacetate (À)-24a
From triol 9a (4.5 g, 0.0206 mol) with lipase PS after 96 h, diac-
etate (À)-24a was recovered (1.92 g, 31%): [ D = À22.6 (c 0.93,
a]
CHCl3); ee = 99% (HPLC on a chiral column, tR = 16.3 min); dH
(400 MHz; CDCl3): 1.04 (3H, d, J 6.4 Hz, CH3CH), 1.93 (3H, s,
COCH3), 2.12 (3H, s, COCH3), 4.47 (1H, dd, J = 1.2, 11.5 Hz, CHH),
4.56 (1H, dd, J 1.2, 11.8 Hz, CHH), 5.47 (1H, dq, J 1.6, 6.4 Hz,
CHOAc), 6.80 (1H, m, aromatic H), 6.91 (1H, m, aromatic H), 7.69
(1H, m, aromatic H); dC (100.61 MHz, CDCl3): 14.4, 20.4, 21.0,
67.9 (d), 72.4 (d), 77.05, 104.0 (t), 111.3 (dd), 122.9 (dd), 130.2
(dd), 159.0 (dd), 162.8 (dd), 169.9, 171.6; GC/MS tR 20.61 min, m/
z 242 (M+À60, 1), 229 (40), 215 (71), 187 (45), 173 (100).
4.5. 1-(4-(2,4-Difluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethanol 15a and 1-(4-(2,4-difluorophenyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethanol 15b
4.8. (2R,3R)-2-(2,4-Difluorophenyl)butane-1,2,3-triol (+)-9a
The 1.5:1 mixture of epoxides 14a–14b (19.7 g, 0.077 mol) was
reduced with LiAlH4 (1.46 g, 0.038 mol) in refluxing THF solution
(200 mL). After the usual work-up, column chromatography elut-
ing with hexane and with increasing amounts of ethyl acetate al-
lowed the isolation of a fraction (13.9 g, 70%) consisting of a 3:1
mixture of derivatives 15a and 15b. The following data were ob-
tained for the enriched samples of the two diastereoisomers.Data
of 15a: dH (400 MHz; CDCl3): 0.94 (3H, dd, J 1.1, 6.2 Hz, CHCH3),
1.31 (3H, s, CCH3), 1.57 (3H, s, CCH3), 3.95 (1H, m, CHOH), 4.16
(1H, dd, J 2.2, 8.8 Hz, CHH), 4.58 (1H, dd, J 2.5, 9.1 Hz, CHH), 6.78
(1H, m, aromatic H), 6.88 (1H, m, aromatic H), 7.58 (1H, m, aro-
matic H); dC (100.61 MHz, CDCl3): 17.9, 25.2, 26.6, 70.5, 72.1 (d),
85.5 (d), 103.8 (t), 110.1, 111.1 (dd), 125.7 (dd), 130.1 (dd), 159.4
(dd), 162.3 (dd); GC/MS tR 16.91 min, m/z 243 (M+À15, 10), 213
(100), 183 (13), 155 (91), 141 (14).Data of 15b: dH (400 MHz;
CDCl3): 1.16 (3H, dd, J 1.1, 6.2 Hz, CHCH3), 1.22 (3H, s, CCH3),
1.55 (3H, s, CCH3), 3.88 (1H, dq, J 1.1, 6.2 Hz, CHOH), 4.18 (1H,
dd, J 1.9, 9.4 Hz, CHH), 4.42 (1H, dd, J 2.8, 9.4 Hz, CHH), 6.78 (1H,
m, aromatic H), 6.87 (1H, m, aromatic H), 7.58 (1H, m, aromatic
H); dC (100.61 MHz, CDCl3): 16.9, 24.8, 26.1, 70.4 (d), 71.7, 85.5
(d), 103.9 (t), 109.8, 110.9 (dd), 124.1 (dd), 129.1 (dd), 158.9
(dd), 162.3 (dd); GC/MS tR 17.45 min, m/z 243 (M+À15, 9), 213
(100), 183 (11), 155 (90), 141 (13).
Saponification of diacetate (À)-24a (1.85 g, 6.13 mmol) with
KOH (0.411 g, 7.35 mmol) in methanol (20 mL) gave (+)-9a
(1.19 g, 89%):
[a]
[a]D = +5.74 (c 0.88, acetone), lit. Ref. 11a
D = +11.4 (c 1.11, CHCl3); 1H and 13C NMR spectra were in accor-
dance with those of the racemic compound.
4.9. (2R,3R)-2-(2,4-Difluorophenyl)-2-hydroxybutane-1,3-diyl
dimethanesulfonate
Triol 9a (1.10 g, 5.04 mmol) was dissolved in pyridine (10 mL)
and mesyl chloride (12.1 mmol, 1.29 g) was added at 0 °C. After
stirring for 2 h at room temperature, the reaction mixture was
poured into water, and extracted with ethyl acetate. The organic
phase was washed with HCl 1%, and dried over Na2SO4, to afford
a residue (1.71 g, 91%), which was submitted without any further
purification to the following reaction step: dH (400 MHz; CDCl3):
1.26 (3H, d, J 6.4 Hz, CHCH3), 2.97 (3H, s, SO2CH3), 3.11 (3H, s,
SO2CH3), 4.65 (1H, d, J 11 Hz, CHHOMs), 4.70 (1H, d, J 11 Hz,
CHHOMs), 5.26 (1H, q, J 6.4 Hz, CHOMs), 6.82 (1H, m, aromatic
H), 6.94 (1H, m, aromatic H), 7.75 (1H, m, aromatic H). GC/MS tR
20.61 min, m/z 278 (M+À96, 3), 251 (36), 169 (32), 155 (42), 141
(100).

2418
D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
4.10. 1-(((2R,3S)-2-(2,4-Difluorophenyl)-3-methyloxiran-2-yl)-
methyl)-1H-1,2,4-triazole (2R,3S)–6
compound 12 from 2,4-difluoroacetophenone: dH (400 MHz; CDCl3):
2.22 (3H, s, COCH3), 5.32 (s, 2H), 7.49 (2H, m, aromatic H), 7.61 (1H, m,
aromatic H), 7.92 (2H, m, aromatic H); dC (100.61 MHz, CDCl3): 20.8,
66.3, 128.0, 129.21, 134.1, 134.54, 170.6, 192.1.
A solution of triazole (2.03 g, 29.4 mmol) in DMF (5 mL) was
dropped into a suspension of sodium hydride (60% dispersion in
mineral oil, 1.03 g, 25.7 mmol) in DMF (20 mL) at 0 °C. When
hydrogen evolution was ceased, a solution of the dimesyl deriva-
tive of triol (+)-9a (1.60 g, 7.34 mmol) in DMF (5 mL) was added.
The reaction mixture was stirred at 70 °C for 2 h, then cooled and
poured into water and extracted with ethyl acetate. The organic
phase was washed with brine, dried over Na2SO4 and concentrated
under reduced pressure to afford a residue, which was purified by
column chromatography to afford oxirane (À)-6 (0.719 g, 67%):
4.14. 2-(4-Fluorophenyl)-2-oxoethyl acetate19
This was prepared (16.8 g, 59%) from 4-fluoroacetophenone
(20.0 g, 0.145 mol) according to the same procedure described for
obtaining compound 12 from 2,4-difluoroacetophenone: dH
(400 MHz; CDCl3): 2.21 (3H, s, COCH3), 5.29 (2H, s, CH2OAc), 7.15
(2H, m, aromatic H), 7.94 (2H, m, aromatic H); GC/MS tR
16.30 min, m/z 196 (M+, 1), 154 (1), 136 (2), 123 (100), 95 (18).
[a
]
D = À12.2 (c 0.96, CHCl3), lit. Ref. 11a [ D = À7.55 (c 1.06,
a
]
4.15. 2-Phenylbut-3-ene-1,2-diol 1620
CHCl3); dH (400 MHz; CDCl3): 1.64 (3H, d, J 5.4 Hz, CHCH3), 3.19
(1H, q, J 5.4 Hz, CHO oxirane ring), 4.44 (1H, d, J 14.7 Hz, CHH),
4.87 (1H, d, J 14.4 Hz, CHH), 6.68–6.81 (2H, m, aromatic H), 7.02
(1H, m, aromatic H), 7.80 (1H, s, triazole H), 7.96 (1H, s, triazole
H); dC (100.61 MHz, CDCl3): 13.9, 51.6, 59.7, 60.4, 103.8 (t), 111.6
(dd), 121.0 (dd), 129.4 (dd), 143.6, 151.9, 162.7 (dd), 163.2 (dd);
GC/MS tR 20.59 min, m/z 236 (M+À15, 6), 220 (1), 206 (1), 153
(12), 141 (40), 96 (100).
This was prepared (13.8 g, 74%) from 2-oxo-2-phenylethyl ace-
tate (20.3 g, 0.114 mol), according to the same procedure described
for obtaining compound 13 from 12; dH (400 MHz; CDCl3): 3.71 (2H,
s, CH2OH), 5.22 (1H, d, J 10.8 Hz, @CHH), 5.32 (1H, d, J 17.1 Hz,
@CHH), 6.09 (1H, dd, J 10.8, 17.1 Hz, CH@), 7.23 (1H, m, aromatic
H), 7.31 (2H, m, aromatic H), 7.41 (2H, m, aromatic H); dC
(100.61 MHz, CDCl3): 69.2, 77.3, 115.3, 125.6, 127.2, 128.2, 140.5,
142.4; GC/MS tR 15.38 min, m/z 164 (M+, 1), 133 (100), 115 (8).
4.11. (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylthio)-1-(1H-
1,2,4-triazol-1-yl)butan-2-ol
4.16. 2-(4-Fluorophenyl)but-3-ene-1,2-diol
A solution of compound (À)-6 (0.600 g, 2.39 mmol) in DMSO
(5 mL) was added to a solution of sodium thiomethylate (0.250 g,
3.58 mmol)inDMSO(5 mL). Afterstirringat25 °Cfor2 h, thereaction
mixture was poured into water and extracted with ethyl acetate. The
organic phase was washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure to afford a residue which was purified
by column chromatography to afford the title compound (0.493 g,
This was prepared (11.6 g, 75%) from 2-(4-fluorophenyl)-2-oxo-
ethyl acetate (16.7 g, 0.0852 mol), according to the same procedure
describedfor obtainingcompound 13 from 12: dH (400 MHz; CDCl3):
3.75 (2H, s, CH2OH), 5.29 (1H, d, J 10.8 Hz, @CHH), 5.36 (1H, d, J
17.4 Hz, @CHH), 6.12 (1H, dd, J 10.8, 17.4 Hz, CH@), 7.03 (2H, m, aro-
matic H), 7.42 (2H, m, aromatic H); dC (100.61 MHz, CDCl3): 69.3,
77.0, 115.2 (d), 115.7, 127.5 (d), 138.2 (d), 140.5, 162.2 (d); GC/MS
tR 15.54 min, m/z 182 (M+, 2), 164 (1), 151 (100), 133 (16).
69%): [
a
]
D = À125.2 (c 0.87, MeOH), lit. Ref. 17 [ D = À126.7 (c 0.5,
a
]
CHCl3); dH (400 MHz; CDCl3): 1.16 (3H, d, J 7.1 Hz, CHCH3), 2.26 (3H,
s, SCH3), 3.21 (1H, q, J 7.1 Hz, CHSCH3), 4.87 (1H, d, J 14.1 Hz, CHH-tri-
azole), 5.06 (1H, d, J 14.1 Hz, CHH-triazole), 6.69–6.77 (2H, m, aro-
matic H), 7.37 (1H, m, aromatic H), 7.76 (1H, s, triazole H), 7.81 (1H,
s, triazole H); dC (100.61 MHz, CDCl3): 14.3, 16.2, 47.5 (d), 56.7 (d),
79.3 (d), 103.9 (dd), 111.5 (dd), 124.3 (dd), 130.5 (dd), 143.8, 151.8,
157.8 (dd), 162.7 (dd); GC/MS tR 23.91 min, m/z 234 (M+À65, 3),
224 (100), 155 (3), 141 (15), 127 (17).
4.17. 2,2-Dimethyl-4-phenyl-4-vinyl-1,3-dioxolane
This was prepared (14.5 g, 85%) from 16 (13.7 g, 0.0835 mol)
according to the same procedure described for obtaining 4-(2,4-
difluorophenyl)-2,2-dimethyl-4-vinyl-1,3-dioxolane from 13; dH
(400 MHz; CDCl3): 1.41 (3H, s, CCH3), 1.54 (3H, s, CCH3), 4.16
(1H, d, J 8.5 Hz, CHH), 4.26 (1H, d, J 8.5 Hz, CHH), 5.15 (1H, dd, J
1.1, 10.8 Hz, @CHH), 5.21 (1H, dd, J 10.5, 17.1 Hz, @CHH), 6.11
(1H, dd, J 1.1, 17.1 Hz, CH@), 7.21–7.41 (m, 5H, Ar); GC/MS tR
14.86 min, m/z 204 (M+, 4), 189 (12), 146 (50), 129 (100).
4.12. (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfonyl)-1-(1H-
1,2,4-triazol-1-yl)butan-2-ol
4.18. 4-(4-Fluorophenyl)-2,2-dimethyl-4-vinyl-1,3-dioxolane
m-Chloroperbenzoic acid (0.575 g, 3.34 mmol) was added at
0 °C to
a
solution of the (À)-methylthioderivative (0.400 g,
This was prepared (11.4 g, 81%) from 2-(4-fluorophenyl)but-3-
ene-1,2-diol (16.5 g, 0.0632 mol) according to the same procedure
described for obtaining 4-(2,4-difluorophenyl)-2,2-dimethyl-4-vi-
nyl-1,3-dioxolane from 13: dH (400 MHz; CDCl3): 1.40 (3H, s,
CCH3), 1.52 (3H, s, CCH3), 4.13 (1H, d, J 8.5 Hz, CHH), 4.24 (1H, d,
J 8.5 Hz, CHH), 5.16 (1H, d, J 10.8 Hz, @CHH), 5.18 (1H, d, J
17.1 Hz, @CHH), 6.08 (1H, dd, J = 10.8, 17.1 Hz, CH@), 7.01 (2H,
m, aromatic H), 7.35 (2H, m, aromatic H); dC (100.61 MHz, CDCl3):
26.3, 26.7, 74.4, 84.4, 110.6, 114.5, 114.9 (d), 127.3 (d), 138.9 (d),
141.4, 161.9; GC/MS tR 14.73 min, m/z 222 (M+, 4), 207 (12), 192
(13), 164 (51), 147(95), 72 (100).
1.34 mmol) in CH2Cl2 (10 mL). After stirring at room temperature
for 2 h, the reaction mixture was poured into a saturated NaHCO3
solution, and extracted with CH2Cl2. The organic phase was dried
over Na2SO4 and concentrated under reduced pressure to afford
(À)-1 (0.256 g, 58%); [
a]D = À36.9 (c 0.98, MeOH); lit. Ref. 17
[a]D = À38.5 (c 1, MeOH); dH (400 MHz; CDCl3): 1.27 (3H, d, J
7.3 Hz, CHCH3), 3.11 (3H, s, SO2CH3), 3.61 (1H, q, J 7.3 Hz, CH),
5.01 (1H, d, J 14.4 Hz, CHH), 5.43 (1H, d, J 14.4 Hz, CHH), 6.71–
6.82 (2H, m, aromatic H), 7.29 (1H, m, aromatic H); dC
(100.61 MHz, CDCl3): 12.5, 40.1, 55.7 (d), 64.7, 76.7, 104.3 (t),
111.9 (dd), 123.1 (dd), 129.6 (dd), 143.9, 151.5, 157.6 (dd), 163.1
(dd); GC/MS tR 26.20 min, m/z 331 (M+, 1), 252 (27), 249 (44),
224 (14), 141 (67), 83 (100).
4.19. (RS)-2,2-Dimethyl-4-((RS)-oxiran-2-yl)-4-phenyl-1,3-di-
oxolane and (RS)-2,2-dimethyl-4-((SR)-oxiran-2-yl)-4-phenyl-
1,3-dioxolane
4.13. 2-Oxo-2-phenylethyl acetate18
These compounds were prepared (10.7 g, 70%) from 2,2-di-
This was prepared (20.5 g, 69%) from acetophenone (20.0 g,
0.167 mol) according to the same procedure described for obtaining
methyl-4-phenyl-4-vinyl-1,3-dioxolane
(14.3 g,
0.0701 mol)

D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
2419
according to the same procedure described for obtaining 14a and
4.22. (RS)-1-((RS)-4-(4-Fluorophenyl)-2,2-dimethyl-1,3-dioxo-
14b from 4-(2,4-difluorophenyl)-2,2-dimethyl-4-vinyl-1,3-dioxo-
lane. The following spectral data were obtained for enriched sam-
ples of the two diastereoisomers:Data of the first eluted
diastereoisomer: dH (400 MHz; CDCl3): 1.37 (3H, s, CCH3), 1.51
(3H, s, CCH3), 2.69 (1H, dd, J 3.9, 5.4 Hz, CHO oxirane ring), 2.86
(1H, dd, J 2.5, 5.4 Hz, OCHH oxirane ring), 3.12 (1H, dd, J 2.5,
3.9 Hz, OCHH oxirane ring), 4.04 (1H, d, J 8.8 Hz, CHH), 4.32
(1H, d, J 8.8 Hz, CHH), 7.25–7.40 (5H, m, aromatic H); GC/MS tR
18.49 min, m/z 220 (M+, 1), 205 (17), 177 (100), 119 (62).Data
of the second eluted diastereoisomer: dH (400 MHz; CDCl3): 1.37
(3H, s, CCH3), 1.58 (3H, s, CCH3), 2.37 (1H, dd, J 2.5, 4.8 Hz, OCHH
oxirane ring), 2.73 (1H, dd, J 3.9, 4.8 Hz, CHO oxirane ring), 3.25
(1H, dd, J 2.5, 3.9 Hz, OCHH oxirane ring), 4.08 (1H, d, J 8.5 Hz,
CHH), 4.33 (1H, d, J = 8.5 Hz, CHH), 7.24–7.40 (5H, m, aromatic
H); GC/MS tR 18.55 min, m/z 220 (M+, 1), 205 (18), 177 (100),
119 (65).
lan-4-yl)ethanol 20a and (RS)-1-((SR)-4-(4-fluorophenyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)ethanol 20b
These compounds were prepared (4.48 g, 74%) from (RS)-4-(4-
fluorophenyl)-2,2-dimethyl-4-((RS)-oxiran-2-yl)-1,3-dioxolane
and
(RS)-4-(4-fluorophenyl)-2,2-dimethyl-4-((SR)-oxiran-2-yl)-
1,3-dioxolane (6.0 g, 0.0252 mol) according to the same procedure
described for obtaining 15a and 15b from 14a and 14b. The follow-
ing spectral data were obtained for enriched samples of the two
diastereoisomers.Data of the first eluted diastereoisomer: dH
(400 MHz; CDCl3): 1.01 (3H, d, J 6.4 Hz, CHCH3), 1.21 (3H, s,
CCH3), 1.51 (3H, s, CCH3), 3.84 (1H, m, CHOH), 4.20 (1H, d, J
8.6 Hz, CHH), 4.42 (1H, d, J 8.6 Hz, CHH), 7.03 (2H, m, aromatic
H), 7.37 (2H, m, aromatic H); dC (100.61 MHz, CDCl3): 17.2, 25.9,
26.7, 70.1, 71.9, 86.9, 110.1, 114.8 (d), 128.1 (d), 137.6 (d), 162.2
(d); GC/MS tR 17.97 min, m/z 225 (M+À15, 4), 195 (95), 137
(100), 109 (100).Data of the last eluted diastereoisomer: dH
(400 MHz; CDCl3): 0.95 (3H, d, J 6.4 Hz, CHCH3), 1.29 (3H, s,
CCH3), 1.55 (3H,s, CCH3), 3.81 (m, 1H, CHOH), 4.12 (1H, d, J
8.0 Hz, CHH), 4.47 (1H, d, J 8.0 Hz, CHH), 7.02 (2H, m, aromatic
H), 7.28 (2H, m, aromatic H); dC (100.61 MHz, CDCl3): 17.8, 25.6,
26.7, 72.2, 72.3, 86.8, 110.3, 114.7 (d), 127.3 (d), 138.6 (d), 162.2
(d); GC/MS tR 18.13 min, m/z 225 (M+À15, 6), 195 (100), 137
(94), 109 (95).
4.20. (RS)-4-(4-Fluorophenyl)-2,2-dimethyl-4-((RS)-oxiran-2-
yl)-1,3-dioxolane and (RS)-4-(4-fluorophenyl)-2,2-dimethyl-4-
((SR)-oxiran-2-yl)-1,3-dioxolane
These compounds were prepared (8.84 g, 73%) from 4-(4-fluo-
rophenyl)-2,2-dimethyl-4-vinyl-1,3-dioxolane
(11.3 g,
0.0509 mol) according to the same procedure described for
obtaining 14a and 14b from 4-(2,4-difluorophenyl)-2,2-di-
methyl-4-vinyl-1,3-dioxolane. The following spectral data were
obtained for enriched samples of the two diastereoisomers:Data
of the first eluted diastereoisomer: dH (400 MHz; CDCl3): 1.36
(3H, s, CCH3), 1.50 (s, 3H, CCH3), 2.71 (1H, dd, OCH oxirane ring),
2.83 (1H, dd, J 2.5, 5.4 Hz, OCHH oxirane ring), 3.08 (1H, dd, J 2.8,
3.8 Hz, OCHH oxirane ring), 3.98 (1H, d, J 8.9 Hz, CHH), 4.27 (1H,
d, J 8.9 Hz, CHH), 7.04 (2H, m, aromatic H), 7.41 (2H, m, aromatic
H); dC (100.61 MHz, CDCl3): 26.0, 26.7, 44.2, 55.2, 71.0, 82.2,
110.8, 115.2 (d), 127.0 (d), 138.0 (d), 162.5; GC/MS tR
18.32 min, m/z 238 (M+, 1), 223 (11), 195 (100), 163 (11), 137
(61).Data of the last eluted diastereoisomer: dH (400 MHz; CDCl3):
1.36 (3H, s, CCH3), 1.57 (3H, s, CCH3), 2.30 (1H, dd, J 2.5, 4.7 Hz,
OCHH oxirane ring), 2.72 (1H, dd, J 3.8, 4.7 Hz, OCH oxirane ring),
3.22 (1H, dd, J 2.5, 3.8 Hz, OCHH oxirane ring), 4.05 (1H, d, J
8.5 Hz, CHH), 4.34 (1H, d, J 8.5 Hz, CHH), 7.02 (2H, m, aromatic
H), 7.33 (2H, m, aromatic H); dC (100.61 MHz, CDCl3): 25.8,
26.7, 44.4, 55.6, 72.2, 82.9, 110.7, 114.9 (d), 127.4 (d), 136.2 (d),
162.5; GC/MS tR 18.34 min, m/z 238 (M+, 1), 223 (11), 195
(100), 163 (11), 137 (57).
4.23. General procedure for lipase-mediated acetylations
In a typical experiment, a solution of the suitable alcohol deriv-
ative (1.0 g) in vinyl acetate/tert-butyl methyl ether (1:2, 15 mL),
was stirred with the chosen lipase (1.0 g) at room temperature.
The filtered solution was concentrated, and the residue was chro-
matographed with increasing amounts of ethyl acetate in hexane.
Under these conditions, the following results were obtained.
4.24. (À)-(S)-2-Hydroxy-2-phenylbut-3-enyl acetate (À)-18
From racemic 16 (20.0 g, mol), with Lipase PS after 24 h, (À)-18
(10.3 g, 41%) was obtained: [
a
]D = À6.0 (c 2.5, EtOH); dH (400 MHz;
CDCl3): 4.30 (1H, d, J 11.4 Hz, CHHOAc), 4.42 (1H, d, J 11.4 Hz,
CHHOAc), 5.25 (1H, dd, J 0.8, 10.7 Hz, @CHH), 5.38 (1H, d, J 0.8,
17.3 Hz, @CHH), 6.14 (1H, dd, J 10.7, 17.3 Hz, CH@), 7.27 (1H, m,
aromatic H), 7.34 (2H, m, aromatic H), 7.46 (2H, m, aromatic H);
dC (100.61 MHz, CDCl3): 20.7, 70.0, 76.1, 115.1, 125.5, 127.5,
128.3, 140.2, 141.9, 170.9; GC/MS tR 17.68 min, m/z 146 (M+À60,
22), 133 (100), 115 (10).
Saponification of (À)-18 ([
MeOH gave (À)-(S)-16: [ D = À7.1 (c 1.1, EtOH), ee = 15%, lit. Ref.
20 [ D = +47.3 (c 1.2, EtOH) for (R)-16 and Ref. 21 [
a
]
D = À6.0 (c 2.5, EtOH)) with KOH in
4.21. (RS)-1-((RS)-2,2-Dimethyl-4-phenyl-1,3-dioxolan-4-yl)-
ethanol 17a and (RS)-1-((SR)-2,2-dimethyl-4-phenyl-1,3-dioxo-
lan-4-yl)ethanol 17b
a]
a]
a]D = À43.4 (c
0.20, EtOH) for (S)-16; spectral data were in accordance with those
of the racemic compound.
These compounds were prepared (4.11 g, 68%) from (RS)-2,2-di-
methyl-4-((RS)-oxiran-2-yl)-4-phenyl-1,3-dioxolane and (RS)-2,2-
4.25. (+)-(R)-1-((S)-4-(2,4-Difluorophenyl)-2,2-dimethyl-1,3-
dimethyl-4-((SR)-oxiran-2-yl)-4-phenyl-1,3-dioxolane
(6.0 g,
dioxolan-4-yl)ethyl acetate (+)-22b
0.0273 mol) according to the same procedure described for obtain-
ing 15a and 15b from 14a and 14b. The following spectral data
were obtained for enriched samples of the two diastereoiso-
mers.Data of the first eluted diastereoisomer: dH (400 MHz, CDCl3):
0.95 (3H, d, J 6.5 Hz, CHCH3), 1.30 (3H, s, CCH3), 1.57 (3H, s,
CCH3), 3.84 (1H, m, CHOH), 4.15 (1H, d, J 8.2 Hz, CHH), 4.50 (1H,
d, J 8.2 Hz, CHH), 7.22–7.42 (5H, m, aromatic H).Data of the last
eluted diastereoisomer: dH (400 MHz, CDCl3): 1.04 (3H, d, J 6.2 Hz,
CHCH3), 1.21 (3H, s, CCH3), 1.52 (3H, s, CCH3), 3.86 (1H, m, CHOH),
4.26 (1H, d, J 8.5 Hz, CHH), 4.43 (1H, d, J 8.5 Hz, CHH), 7.25–7.42
(5H, m, aromatic H).
From a 1:1 mixture of alcohols 15a and 15b (5.0 g, 0.019 mol),
with Lipase PS after 48 h, (+)-22b (0.46 g, 8%) was obtained:
[a]D = +54.3 (c 0.6, CHCl3); ee = 99%, de = 99% (GC on a chiral col-
umn); dH (400 MHz; CDCl3): 1.22 (3H, d, J 6.54 Hz, CHCH3), 1.24
(3H, s, CCH3), 1.58 (3H, s, CCH3), 1.84 (3H, s, COCH3), 4.16 (dd,
1H, J 1.2, 9.6 Hz, CHH), 4.39 (1H, dd, J 3.2, 9.6 Hz, CHH), 5.22 (1H,
q, J = 6.51 Hz, CHOAc), 6.77 (1H, m, aromatic H), 6.86 (1H, m, aro-
matic H), 7.58 (1H, m, aromatic H); dC (100.61 MHz, CDCl3): 14.3,
20.8, 24.9, 26.3, 71.8 (d), 72.8, 83.7 (d), 103.8 (t), 110.5 (dd),
110.6 (d), 125.1 (dd), 130.0 (dd), 158.9 (dd), 162.7 (dd), 170.5;

2420
D. Acetti et al. / Tetrahedron: Asymmetry 20 (2009) 2413–2420
GC/MS tR 19.22 min, m/z 285 (M+À15, 11), 213 (100), 183 (33), 155
H), 9.28 (2H, d, J 1.9 Hz, aromatic H); GC/MS tR 29.92 min, m/z
437 (M+À15, 5), 213 (100), 155 (56), 127 (44). Compound 23 was
treated first with KOH (0.019 g, 0.34 mmol) in MeOH (10 mL), then
with acetic anhydride (2 mL) in pyridine (2 mL). The usual work
(89), 141 (11).
4.26. (+)-1-(2,2-Dimethyl-4-phenyl-1,3-dioxolan-4-yl)ethyl
acetate (+)-19b
afforded compound (+)-(2S,3S)-24 (0.031 g, 46%): [a]D = +20.7 (c
0.75, CHCl3); ee = 99% (HPLC on a chiral column, tR = 20.8 min);
NMR and GC/MS data were in accordance with those of the
enantiomer.
From a 1:1 mixture of alcohols 17a and 17b (5.0 g, 0.022 mol),
with lipase PS after 48 h, (+)-19b (1.12 g, 19%) was obtained:
[a]D = +34.4 (c 1.20, CHCl3); ee = 99%, de = 91% (GC on a chiral col-
umn); dH (400 MHz, CDCl3): 1.12 (3H, d, J 6.2 Hz, CHCH3), 1.27 (3H,
s, CCH3), 1.54 (3H, s, CCH3), 1.93 (3H, s, OAc), 4.17 (1H, d, J 8.8 Hz,
CHH), 4.31 (1H, d, J 8.8 Hz, CHH), 5.12 (1H, q, J 6.2 Hz, CHOAc),
7.23–7.41 (5H, m, aromatic H); dC (100.61 MHz, CDCl3): 14.8,
20.9, 25.6, 26.6, 71.9, 73.9, 85.4, 110.6, 126.2, 127.2, 127.7, 141.7,
169.7.
Acknowledgements
This work was in part supported by the research project INTEN-
ANT (‘Integrated synthesis and purification of single enantiomers’)
financed by the European Commission within the seventh frame-
work programme.
4.27. (+)-1-(4-(4-Fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl acetate (+)-21b
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[a]D = +29.7 (c 1.16, CHCl3); ee = 99%, de = 87% (GC on a chiral col-
umn); dH (400 MHz; CDCl3): 1.10 (3H, d, J 6.1 Hz, CHCH3), 1.27 (3H,
s, CCH3), 1.53 (3H, s, CCH3), 1.96 (3H, s, COCH3), 4.13 (1H, d, J 8.6 Hz,
CHH), 4.29 (1H, d, J 8.6 Hz, CHH), 5.08 (1H, q, J 6.1 Hz, CHOAc), 7.02
(2H, m, aromatic H), 7.36 (2H, m, aromatic H); dC (100.61 MHz,
CDCl3): 14.8, 20.9, 25.7, 26.6, 72.2, 73.9, 85.1, 110.8, 114.6 (d),
127.9 (d), 137.5 (d), 162.0 (d), 169.8; GC/MS tR 19.87 min, m/z
267 (M+À15, 6), 195 (100), 165 (28), 137 (91), 109 (71).
4.28. Determination of the absolute configuration of acetate
(+)-22b
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4.28.1. (+)-1-(4-(2,4-Difluorophenyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethanol (+)-15b
A sample of acetate (+)-22b (0.200 g, 0.67 mmol) was treated
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those of racemic 15b.
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4.29. (2S,3S)-2-(2,4-Difluorophenyl)-2-hydroxybutane-1,3-diyl
diacetate (+)-(2S,3S)-24
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Alcohol (+)-15b (0.120 g, 0.46 mmol) was submitted to a Mits-
unobu esterification with 3,5-dinitrobenzoic acid (0.475 g,
2.24 mmol) in THF (10 mL), in the presence of diisopropylazodicar-
boxylate (0.452 g, 2.24 mmol) and triphenylphosphine (0.586 g,
2.24 mmol). The nitro ester 23 was thus recovered (0.101 g, 49%),
after column chromatography eluting with hexane/ethyl acetate
97/3: dH (400 MHz; CDCl3): 1.25–1.30 (9H, m, CHCH3 + 2CCH3),
4.14 (1H, dd, J 8.6, 1.6 Hz, CHH), 4.53 (1H, dd, J 8.6, 3.8 Hz, CHH),
5.45 (1H, m, CHOAr), 6.84 (1H, m, aromatic H), 6.98 (1H, m, aro-
matic H), 7.70 (1H, m, aromatic H), 9.23 (1H, t, J 1.9 Hz, aromatic
20. Agami, C.; Couty, F.; Lequesne, C. Tetrahedron 1995, 51, 4043–4056.
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Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2003, 14, 3225–3232.