Practical and robust method for the preparation of Seebach and Frater's chiral template, cis-2-substituted 5-methyl(or phenyl)-1,3-dioxolan-4-ones

Article abstract of DOI:10.1055/s-2006-950295

A practical and highly stereoselective method for the preparation of three cis-2-substituted 5-methyl (orphenyl)-1,3-dioxolan-4-ones 3a and 7a (Seebach and Frater's chiral template), and a new modified analogue 7b has been developed. The present robust me

Full text of DOI:10.1055/s-2006-950295

PRACTICAL SYNTHETIC PROCEDURES
3915
Practical and Robust Method for the Preparation of Seebach and Fráter’s
Chiral Template, cis-2-Substituted 5-Methyl(or Phenyl)-1,3-dioxolan-4-ones
C
hiral Template,
y
cis-2-Substi
o
tuted 5-Meth
h
yl (or Pheny
e
l)-1,3-dioxo
i
lan-4-ones Nagase, Yumiko Oguni, Tomonori Misaki, Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University,
2-1 Gakuen, Sanda, Japan
Fax +81(79)5659077; E-mail: tanabe@kwansei.ac.jp
PSP
Received 26 May 2006; revised 4 July 2006
No72
Abstract: A practical and highly stereoselective method for the preparation of three cis-2-substituted 5-methyl (or phenyl)-1,3-dioxolan-
4-ones 3a and 7a (Seebach and Fráter’s chiral template), and a new modified analogue 7b has been developed. The present robust method
utilized reactive 2-methoxy-1,3-dioxolane intermediate 4 and the reaction proceeded more smoothly under milder reaction conditions than
in previously reported methods. Desired products 3a, 7a, and 7b were easily purified by distillation or recrystallization, i.e. column chro-
matographic purification, was not necessary.
Key words: (S)-lactic acid, (S)-mandelic acid, cyclocondensation, acid catalyst, 2,5-disubstituted-1,3-dioxolan-4-ones
NHR4
O
O
R3
R1
R3
R1
O
O
O
O
R2
A
E
R2
R3X
NR4
R3
H
O
R1
5
O
O
2
B
D
O
R3
O
R1
R2
HO
R4
O
1
R3COR4
R3M
OH
R3
R1
O
O
O
R2
C
R3
R4
R2
O
R4
R1
O
R3
O
O
R2
Scheme 1 Synthetic applications of cis-2,5-disubstituted 1,3-dioxolan-4-ones 1
cis-2,5-Disubstituted 1,3-dioxolan-4-ones 1,1 the so- main: (i) 1,3-dioxolan-4-ones 1 are unstable under acidic
called Seebach and Fráter’s chiral template, serve as use- conditions, the production and purification procedures re-
ful chiral synthons for a number of syntheses using some quire careful technique; (ii) due to the low reactivity of
stereocontrolled reactions: (A) alkylation,1 (B) aldol addi- these substrates, a long reaction period is generally re-
tion,1a,2 (C) Michael addition,3 (D) nucleophilic addition,4 quired; and (iii) trans isomeric products are thermody-
and (E) Mannich reaction5 (Scheme 1). These methods namically stable, these tedious procedures repress the cis-
have been successfully applied for total syntheses of nat- selectivity.
ural products and pharmaceuticals. The general method
for the preparation of 1 utilizes cyclocondensation of a-
Recently, three improved methods for the cis-selective
preparation of phenyl analogues 3a,b were disclosed
hydroxycarboxylic acids with aldehydes or ketones pro-
(Scheme 2). The first is a simple and direct method for ob-
moted by acid catalysts. Some problems, however, still re-
taining 3a using (S)-mandelic acid (2) with t-BuCHO pro-
moted by a TfOH catalyst.2e A major drawback of this
method is the use of highly volatile pentane (bp 35 °C)
SYNTHESIS 2006, No. 22, pp 3915–3917
x
x
.x
x
.
2
0
0
6
solvent, which is undesirable for industrial scale produc-
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950295; Art ID: F08706SS
© Georg Thieme Verlag Stuttgart · New York
tion (process chemistry).6 The second is Banyu’s and

3916
R. Nagase et al.
PRACTICAL SYNTHETIC PROCEDURES
Merck’s groups’ indirect method utilizing a dioxolane in-
termediate derived from (i-PrO)3CH/catalytic PTS for
large scale production of 3a.3a The third is our recent im-
provement of the second method for a smoother prepara-
tion of 3b (a novel analogue) using cost-effective
substrates, (MeO)3CH and 1-naphthoaldehhyde.7
O
CO2H
(MeO)3CH/c-Hex
O
65–80 °C
O
OH
OMe
azeotropic removal
of MeOH
(S)-lactic acid (5)
6
A
O
O
RCHO [a; R = t-Bu or b; 4-ClC6H4]
acid catalyst [a; PTS or b; CSA)
Ph
5
5
Ph
CO2H
B
C
O
2
O
O
O
OH
toluene or heptane
2
0–5 °C
R
R
2
3a : R = t-Bu
3b : R = 1-Naph
7a : R = t-Bu; 71% yield, 96% de
7b : R = 4-ClC6H4; 62% yield, >99% de
A: t-BuCHO, cat. TfOH/pentane
B: i) (i-PrO)3CH/toluene, ii) t-BuCHO, cat. TsOH/toluene
C: i) (MeO)3CH/cyclohexane, ii) 1-Naphthaldehyde, cat. CSA/toluene
Scheme 4 Preparation of cis-2-substituted-5-methyl-1,3-dioxolan-
4-ones 7a,b
Scheme 2 Reported methods for the preparation of cis-2-substituted
5-phenyl-1,3-dioxolan-4-ones 3a,b
The third was the related reaction using 5 and a cost-effec-
tive substrate, 4-chlorobenzaldehyde instead of t-BuCHO.
As expected, the reaction successfully produced the newly
designed 4-chlorophenyl analogue 7b, which solidified
(mp 73–75 °C). Compound 7b was easily purified up to
>99% ee by simple recrystallization (hexane).8 In con-
trast, the 1-naphthyl cis-analogue produced by the reac-
tion between 5 and 1-naphthaldehyde was an oily
compound (cis/trans = 70:30).
As an extension of the study, we report herein a practical
and robust method for the preparation of three cis-2-sub-
stituted 5-methyl-1,3-dioxolan-4-ones 3a, 7a, and 7b (a
new modified analogue). The advantages are as follows:
(i) the desired products 3a, 7a, and 7b were prepared with
a shorter reaction period due to higher reactivity of 2-
methoxy-1,3-dioxolane intermediates 4 and 6 under mild
conditions; (ii) 3a, 7a, and 7b were purified by distillation
or recrystallization (column chromatography was not nec-
essary); and (iii) the reaction proceeded with consistent
high cis-selectivity.
In conclusion, we have achieved a practical and highly
stereoselective method for the preparation of three cis-2-
(tert-butyl)-5-methyl (or phenyl)-1,3-dioxolan-4-ones.
The present robust method provides facile access to See-
bach and Fráter’s chiral template and its modified ana-
logue, in view of the process chemistry.
First, we describe the reaction using (S)-mandelic acid (2)
and t-BuCHO. As shown in Scheme 3, 2 was smoothly
converted into intermediate 4 by the reported procedure
using (MeO)3CH.7 Then, 4 was transformed into cis-2-
(tert-butyl)-5-phenyl-1,3-dioxolan-4-one (3a) as crystals
(mp 142–144 °C) with excellent stereoselectivity (> 99%
de).
Melting points were determined on a hot stage microscope appara-
tus (Yanagimoto) and are uncorrected. NMR spectra were recorded
on a JEOL DELTA 300 spectrometer, operating at 300 MHz for 1H
NMR and 75 MHz for 13C NMR. Chemical shifts (d ppm) in CDCl3
1
were reported downfield from TMS for H NMR. For 13C NMR,
chemical shifts were reported in the scale relative to CDCl3 (77.00
ppm) as an internal reference. IR spectra were recorded on a JASCO
FT/IR-5300 spectrophotometer. Optical rotations were measured
on a JASCO DIP-370 (D = 589 nm) spectrometer. (S)-Mandelic
acid (2) was purchased from Tokyo Chemical Industry, Co. Ltd.
(S)-lactic acid (5) was purchased from Aldrich.
O
(MeO)3CH/c-Hex
Ph
CO2H
Ph
65–80 °C
O
OH
O
O
azeotropic removal
of MeOH
2
OMe
4
Ph
(2S,5S)-2-(tert-Butyl)-5-phenyl-1,3-dioxolan-4-one (3a)
5
t-BuCHO, cat. PTS/toluene
A solution of (S)-mandelic acid (2; 7.61 g, 50.0 mmol) and
(MeO)3CH (7.96 g, 75.0 mmol) in cyclohexane (50 mL) was stirred
at 65–80 °C using a Dean–Stark apparatus with continual azeotro-
pic removal of MeOH–cyclohexane mixture (ca. 20 mL) for 1 h un-
der argon. After cooling to r.t., the remaining cyclohexane and
(MeO)3CH were removed under reduced pressure at 35–45 °C us-
ing a rotary evaporator. Toluene (25 mL) was added to the resultant
residue (not viscous oil), which was cooled to 0–5 °C. After the ad-
dition of p-TsOH·H2O (285 mg, 1.5 mmol), a solution of t-BuCHO
O
87% yield
99% de
O
20–25 °C
2
t-Bu
3a
Scheme 3 Preparation of cis-2-(tert-butyl)-5-phenyl-1,3-dioxolan-
4-one (3a)
The second reaction used (S)-lactic acid (5) and t-BuCHO
(Scheme 4). In a similar manner to the above-mentioned (4.74 g, 55.0 mmol) in toluene (3.5 mL) was added dropwise to the
mixture in ca. 20 min. After ca. 5 min, a white precipitate appeared,
which increased in volume. The slurry was stirred at 20–25 °C for
2 h, and quenched with aq 5% K2CO3 solution (25 mL), which was
extracted with EtOAc (40 mL) at 40–45 °C (necessary for clear
case, the reaction using 5 proceeded smoothly through a
related reactive intermediate 6 to give cis-2-(tert-butyl)-5-
methyl-1,3-dioxolan-4-one (7a), which was easily puri-
fied by distillation (bp 69–73 °C/15 mmHg).
Synthesis 2006, No. 22, 3915–3917 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
cis-2-Substituted 5-Methyl(or Phenyl)-1,3-dioxolan-4-ones
3917
phase separation). The separated organic layer was concentrated in
vacuo to give the desired product (9.58 g, 87%, 99% de based on 1H
NMR measurement). The obtained crude solid was sufficiently pure
for the practical use (recrystallization not required); colorless crys-
1H NMR (300 MHz, CDCl3): d = 1.59 (3 H, d, J = 6.9 Hz), 4.53 (1
H, q, J = 6.9 Hz), 6.35 (1 H, s), 7.38–7.51 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 16.33, 71.93, 102.16, 128.05,
128.97, 132.99, 136.62, 173.16.
25
tals; mp 142–144 °C; [a]D27 +83.4 (c = 0.95, CHCl3) {Lit.2b [a]D
Anal. Calcd for C10H9ClO3: C, 56.49; H, 4.27. Found: C, 56.2; H,
4.1.
+88.7 (c = 1.20, CHCl3)}.
IR (KBr): 2980, 2961, 1800, 1275, 1213, 1090, 1053, 976, 760, 696
cm–1.
1H NMR (300 NHz, CDCl3): d = 1.08 (9 H, s), 5.23 (1 H, d, J = 1.4
Hz), 5.32 (1 H, d, J = 1.4 Hz), 7.34–7.50 (5 H, m).
Acknowledgment
This research was partially supported by Grant-in-Aids for Scienti-
fic Research on Priority Areas (A) ‘17035087’, Basic Areas (B)
‘18350056’, and Exploratory Research ‘17655045’ from the Mini-
stry of Education, Culture, Sports, Science and Technology
(MEXT).
13C NMR (75 MHz, CDCl3): d = 23.61, 34.46, 77.00, 109.30,
127.02, 128.70, 129.16, 133.50, 171.80.
(2S,5S)-2-(tert-Butyl)-5-methyl-1,3-dioxolan-4-one (7a)
A solution of (S)-lactic acid (5; 85% in H2O, 7.95 g, 75.0 mmol) and
(MeO)3CH (15.9 g, 150.0 mmol) in cyclohexane (100 mL) was
stirred at 65–80 °C using a Dean–Stark apparatus with continual
azeotropic removal of MeOH–cyclohexane mixture (ca. 50 mL) for
1 h under argon. After cooling to r.t., the remaining cyclohexane
and (MeO)3CH were removed under reduced pressure at 20–25 °C
using a rotary evaporator. Heptane (50 mL) was added to the result-
ant residue (not viscous oil), which was cooled to 0–5 °C. After the
addition of p-TsOH·H2O (285 mg, 1.5 mmol), a solution of t-Bu-
CHO (4.31 g, 50.0 mmol) in heptane (10 mL) was added dropwise
to the mixture in ca. 15 min. The mixture was stirred at 20–25 °C
for 2 h, and quenched with aq sat. NaHCO3 solution (100 mL), and
extracted with EtOAc (2 × 50 mL). The combined organic phases
were washed with brine and concentrated in vacuo. The obtained
crude oil (98% de based on 1H NMR measurement) was purified by
distillation to give the desired product (5.64 g, 71%, 96% de based
References
(1) (a) Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
(b) Fráter, G.; Müller, U.; Günther, W. Tetrahedron Lett.
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Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (d) Clayden,
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(2) (a) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
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Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.;
Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.;
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J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775. (b) Blay,
G.; Fernández, I.; Monje, B.; Pedro, J. R.; Ruiz, R.
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(4) (a) Heckmann, B.; Mioskowski, C.; Yu, J.; Falck, J. R.
Tetrahedron Lett. 1992, 33, 5201. (b) Heckmann, B.;
Mioskowski, C.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett.
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1
on H NMR measurement); colorless oil; bp 69–73 °C/15 mmHg;
27
20
[a]D +47.1 (c = 1.11, CHCl3) {Lit.2b [a]D +44.8 (c = 1.83,
CHCl3)}.
IR (neat): 2969, 1802, 1487, 1408, 1366, 1302, 1202, 1111, 1086,
970 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.98 (9 H, s), 1.48 (3 H, d, J = 6.5
Hz), 4.36 (1 H, dq, J = 1.4, 6.5 Hz), 5.14 (1 H, d, J = 1.4 Hz).
13C NMR (75 MHz, CDCl3): d = 16.16, 23.36, 34.17, 71.45, 109.30,
174.06.
(2S,5S)-2-(4-Chlorophenyl)-5-methyl-1,3-dioxolan-4-one (7b)
Intermediate 6 was prepared first by a similar procedure as de-
scribed for 7a. Toluene (50 mL) was added to the resultant residue
(not viscous oil), which was cooled to 0–5 °C. After addition of 10-
camphorsulfonic acid (CSA, 348 mg, 1.5 mmol), a solution of 4-
chlorobenzaldehyde (7.03 g, 50.0 mmol) in toluene (25 mL) was
added dropwise to the mixture in ca. 10 min. The mixture was
stirred at 20–25 °C for 20 h, and quenched with aq 5% K2CO3 solu-
tion (100 mL), which was extracted with EtOAc (ca. 50 mL). The
organic phase was washed with brine and concentrated in vacuo to
give the crude product (8.30 g, 70–75% de based on 1H NMR mea-
surement). This was purified by recrystallization from hexane (20
mL) to give the desired product (6.50 g, 61%, >98% de based on 1H
(5) (a) Barbaro, G.; Battaglia, A.; Guerrini, A.; Bertucci, C.
Tetrahedron: Asymmetry 1997, 8, 2527. (b) Barbaro, G.;
Battaglia, A.; Guerrini, A. J. Org. Chem. 1999, 64, 4643.
(6) In our hands, comparable experiments using pentane and
heptane (bp 98 °C) as solvents revealed that they have a
significant effect on the stereoselectivity; cis/trans = 97:3
(pentane) and 54:46 (heptane). The direct method largely
depends on the reaction temperature of azeotropic boiling
points.
27
NMR measurement); colorless crystals; mp 73–75 °C; [a]D +7.6
(7) Misaki, T.; Ureshino, S.; Nagase, R.; Oguni, Y.; Tanabe, Y.
Org. Process Res. Dev. 2006, 10, 500.
(c = 0.99, CHCl3).
(8) Related method using crystalline dioxolane in
diastereomerically pure form was reported: Ortholand, J.-Y.;
Vicart, N.; Greiner, A. J. Org. Chem. 1995, 60, 1880.
Note: The use of p-TsOH·H2O as catalyst resulted in no reaction.
IR (KBr): 2937, 1788, 1421, 1379, 1225, 1196, 1092, 1076, 963,
945 cm–1.
Synthesis 2006, No. 22, 3915–3917 © Thieme Stuttgart · New York