Stereoselective construction of a quaternary carbon substituted with multifunctional groups: Application to the concise synthesis of (+)-ethosuximide

Article abstract of DOI:10.1016/j.tetlet.2003.10.081

Synthetically useful β,γ-unsaturated carbonyl compounds having a quaternary carbon at the α-position were prepared with high stereoselectivity by the reaction of a dienolate anion derived from α,β-unsaturated imide having a chiral auxiliary and electrophiles (ethyl acetate and allyl iodide as the C₂ and C₃ unit, respectively). This method was applied to a short asymmetric synthesis of (+)-ethosuximide.

Full text of DOI:10.1016/j.tetlet.2003.10.081

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9303–9305
Stereoselective construction of a quaternary carbon substituted
with multifunctional groups: application to the concise synthesis
of (+)-ethosuximide
Tomoaki Abe, Tatsuo Suzuki, Kazuhiko Sekiguchi, Seijiro Hosokawa and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science, Frontier Research Center for Genomic Drug Discovery,
Tokyo University of Science, Yamazaki, Noda, Chiba 278-8510, Japan
Received 1 September 2003; revised 6 October 2003; accepted 10 October 2003
Abstract—Synthetically useful b,g-unsaturated carbonyl compounds having a quaternary carbon at the a-position were prepared
with high stereoselectivity by the reaction of a dienolate anion derived from a,b-unsaturated imide having a chiral auxiliary and
electrophiles (ethyl acetate and allyl iodide as the C and C unit, respectively). This method was applied to a short asymmetric
2
3
synthesis of (+)-ethosuximide.
2003 Elsevier Ltd. All rights reserved.
©
During the course of our total synthesis of madindoline
A, stereochemical control of the quaternary chiral
stereoselectivities were moderate, ranging from 6:1 to
11:1. In order to expand the scope of this methodol-
1
1
center in the cyclopentene moiety was achieved by
developing a highly diastereo- and regioselective a-alkyl-
ation of the a,b-unsaturated chiral imide (Scheme 1).
While a number of methodologies have been developed
ogy, it seemed necessary to demonstrate the reaction of
a,b-unsaturated chiral imide with other alkyl halides. In
this paper we wish to describe the alkylation with
iodoacetate and allyl iodide as the C and C units,
2
3
2
for the construction of a quaternary chiral center,
respectively.
efficient and general methods are still required. As
demonstrated by the successful total synthesis of
madindoline A, the resulting b,g-unsaturated imides are
considered valuable synthetic intermediates for the syn-
thesis of a variety of biologically significant compounds
utilizing both a carbon–carbon double bond and a
carboxyl group. The electrophiles employed in the pre-
vious investigation were limited to benzyloxymethyl
chloride (BOMCl) or methoxymethyl chloride
Our method to construct a quaternary chiral center is
shown in Scheme 2. The g-proton of a,b-unsaturated
imide 1 was deprotonated with sodium hexamethyldi-
silazide, and the resulting dienolate was reacted with
electrophiles at the a-position in a regio- and stereose-
1,3,4
lective manner.
At first, alkylation with allyl iodide was examined
5
(
MOMCl) aiming at the madindoline synthesis, and the
(Table 1). The alkylation proceeded regioselectively at
Scheme 1.
*
Corresponding author.
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.081

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T. Abe et al. / Tetrahedron Letters 44 (2003) 9303–9305
the a-position, and the corresponding a-allyl-b,g-unsat-
urated imides were obtained with high stereoselectivi-
ties. In the case of b,g-disubstituted products (entries
4
–6), only E-isomers were obtained. The b,g-disubsti-
tuted olefins (entries 5 and 6) were obtained in higher
yield than the bis(exo-olefin) products (entries 2 and 3).
The stereochemistry of the newly formed quaternary
center was determined as shown in Scheme 3. Thus, 5a
was transformed into the known 2-ethyl-2-methylpen-
6
tanoic acid 6 by hydrolysis and subsequent hydrogena-
tion. The absolute configuration of 5b was confirmed to
26
be R by correlating to the caboxyacetal 7 ([h]D +24.6°)
by a four-step sequence: (i) iodolactonization of unsatu-
rated imide; (ii) ozonolysis of the remaining car-
bonꢀcarbon double bond; (iii) acetalization of the
resulting aldehyde; and (iv) reductive elimination of
iodolactone. The carboxyacetal 7 was found to be
Scheme 3.
26
identical with the carboxyacetal 7 ([h] +23.2°) derived
D
from the stereochemically established 5a in a similar
sequence of reactions.
smoothly to afford a chiral quaternary center with
excellent stereoselectivity. Stereochemistry was tenta-
tively assigned as shown in analogy to the case of the
reaction with allyl iodide. In order to demonstrate the
usefulness of this methodology as well as to confirm the
stereochemistry, the product shown in entry 1 was
Next, we attempted the alkylation with ethyl iodoac-
etate as a C unit (Table 2). The reaction proceeded
2
7,8
converted to (+)-ethosuximide, commonly used in the
treatment of petit mal epilepsy. (Scheme 4). Heating a
mixture of imide 8 and urea without a solvent gave
cyclic imide 9 which was subjected to hydrogenation in
the presence of a Pt catalyst. Thus, only three-step
synthesis of (+)-ethosuximide from 1 was accomplished.
Table 2. Alkylation with ICH CO Et
2
2
Scheme 2.
Table 1. Alkylation with allyliodide
Entry
R
XN
Yield (%)
Selectivitya
1
2
3
H
H
Bu
Val
Ile
Ile
76
67
85
31:1
38:1
>50:1
a
Determined by 1H NMR.
Entry
R
XN
Solvent
Yield (%)
Selectivitya
1
2
3
4
5
6
H
H
H
Val
Val
Ile
Toluene
THF
THF
Toluene
THF
THF
27
61
62
30
76
71
42:1
27:1
19:1
29:1
22:1
29:1
Bu Val
Bu Val
Bu Ile
a
Determined by HPLC.
Scheme 4.

T. Abe et al. / Tetrahedron Letters 44 (2003) 9303–9305
9305
In conclusion, we were able to develop a concise and
highly stereoselective method for the construction of a
quaternary carbon and accomplish a short synthesis of
5. General procedure of the alkylation with allyl iodide was
as follows: To a solution of a,b-unsaturated chiral imide
(99.0 mg, 370 mmol) in THF (4.0 mL) was dropwise
added a solution of NaHMDS (1.0 M in THF, 0.75 mL,
750 mmol) at −78°C. After stirring for 90 min at −78°C,
allyl iodide (380 mL, 4.10 mmol) was dropwise added to
the mixture, which was stirred at −50°C for 6 h. The
(
+)-ethosuximide. The stereochemical course of the
present alkylation is the same in all cases. The present
methodology can provide a useful synthetic intermedi-
ate having a quaternary chiral carbon substituted with
multifunctional groups (vinyl, allyl, and acetate). Fur-
ther application of this methodology toward natural
products is now in progress.
reaction mixture was quenched with satd NH Cl, and
4
was extracted with AcOEt (×3). The combined organic
layer was washed with brine and dried over Na SO .
2
4
Evaporation and purification by SiO column chromatog-
2
raphy (hexane:ethyl acetate=10: 1) gave 5b 86.5 mg
Acknowledgements
(76%) as colorless syrup. 5b: R =0.76 (hexane:AcOEt=
f
24
1
2:1); [h]D +62.2 (c 1.65, CHCl3), H NMR (500 MHz,
This work was supported in part by the Fujisawa
Foundation (S.H.) and Grant-in-Aids for Scientific
Research from the Ministry of Education, Culture,
Sports, and, Science and Technology, Japan.
CDCl ): l (ppm) 0.87 (3H, t, J=6.4 Hz), 0.88 (3H, d,
3
J=6.7 Hz), 0.91 (3H, d, J=7.0 Hz) 1.24–1.34 (4H, m),
1.36 (3H, s), 1.97–2.03 (2H, m), 2.26–2.37 (1H, m), 2.52
(1H, dd, J=13.7, 7.1 Hz), 2.97 (1H, dd, J=13.7, 7.6 Hz),
4.16 (1H, dd, J=8.9, 2.8 Hz), 4.21 (1H, dt, J=8.3, 3.4
Hz), 5.06 (1H, d, J=10.1 Hz), 5.10 (1H, d, J=17.1 Hz),
5.31 (1H, dt, J=15.9, 7.1 Hz), 5.69–5.79 (1H, m), 5.81
References
13
(
1H, dt, J=15.9, 1.5 Hz). C NMR (125 MHz, CDCl3):
1
2
. (a) Hosokawa, S.; Sekiguchi, K.; Enemoto, M.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 6429–6433; (b)
Hosokawa, S.; Kobayashi, S. J. Synth. Org. Chem. Jpn.
l (ppm) 13.8, 14.7, 18.1, 22.1, 24.4, 28.5, 31.4, 32.2, 42.7,
49.4, 60.1, 62.9, 118.2, 129.6, 133.6, 134.0, 152.1, 175.8.
IR (neat) 3077, 2961, 2929, 2873, 1787, 1685, 1639, 1465,
1384, 1362, 1299, 1230, 1200, 1148, 1092, 1062, 992, 996,
2
001, 59, 1103–1108.
−
1
. For excellent reviews covering most methods for the
asymmetric creation of quaternary carbon centers: (a)
Fuji, K. Chem. Rev. 1993, 93, 2037–2066; (b) Corey, E.
J.; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl. 1998,
917 cm
The alkylation with ethyl iodoacetate was carried out in a
similar manner except for the reaction temperature.
6. Kogen, H.; Tishihama, S.; Koga, T.; Kitazawa, E.; Ser-
izawa, N.; Hamano, K. Eur. Pat. Appl. 1994, 154.
7. (a) Sorel, L. Acta Neurol. Psychiat. Belg. 1960, 60, 551–
559; (b) Hirai, T.; Ando, N.; Naoi, T.; Inoue, R.; Watan-
abe, H. Seishin Igaku 1965, 7, 142.
8. (a) Knabe, J.; Koch, W. Arch. Pharm. 1972, 305, 757–
765; (b) Knabe, J.; Plisch, J. Tetrahedron Lett. 1973, 14,
745–746; (c) Nishide, K.; Katoh, T.; Imazato, H.; Node,
M. Heterocycles 1998, 47, 839–845; (d) Katoh, T.;
Nishide, K.; Node, M.; Ogura, H. Heterocycles 1999, 48,
833–841.
3
7, 388–401.
3
. For alkylation affording a chiral tertiary carbon: (a)
Evans, D. A.; Ennis, M. D.; Mathre D. J. J. Am. Chem.
Soc. 1982, 104, 1737–1738; (b) Evans, D. A.; Takacs, J.
M. Tetrahedron Lett. 1980, 21, 4233–4236.
4
. For stereoselective alkylation of a,b-unsaturated car-
boxylic acid derivatives: (a) Tomooka, K.; Nagasawa, A.;
Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8895–
8
898; (b) Tomooka, K.; Nagasawa, A.; Nakai, T. Chem.
Lett. 1998, 1049–1050.