A new synthetic route to β-unsubstituted β-lactones by intramolecular cyclization

Article abstract of DOI:10.1016/S0040-4020(00)00313-6

When carboxylic acids β-substituted by a tert-butoxy group were treated with thionyl chloride, an intermediate acyl chloride β-substituted by a hydroxyl group was likely formed. Its subsequent intramolecular cyclization produced novel β-lactones in one step. Two enantiomerically enriched lactones could be prepared via intermediates obtained by enzymatic hydrolysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00313-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3921±3926
A New Synthetic Route to b-Unsubstituted b-Lactones by
Intramolecular Cyclization
*
 Â
FrancËois-Rene Alexandre, Stephanie Legoupy and FrancËois Huet
Á Â Â
Laboratoire de Synthese Organique, UPRES A CNRS 6011, Faculte des Sciences, Universite du Maine, Avenue Olivier Messiaen,
F-72085 Le Mans Cedex 9, France
Received 16 November 1999; accepted 25 April 2000
AbstractÐWhen carboxylic acids b-substituted by a tert-butoxy group were treated with thionyl chloride, an intermediate acyl chloride
b-substituted by a hydroxyl group was likely formed. Its subsequent intramolecular cyclization produced novel b-lactones in one step. Two
enantiomerically enriched lactones could be prepared via intermediates obtained by enzymatic hydrolysis. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
several results in obtaining such compounds were pointed
out in the case of spiro b-lactones,4 serine b-lactones5 and
some simple b-lactones.6 We then envisaged the possibility
of preparing racemic lactones 3 in several steps starting
from 2 via a cyclization to generate the lactone moiety.
Extension to the non-racemic series should also be worth
studying.7
We recently obtained good results for the conjugate nucleo-
philic addition to diethyl methylenemalonate.1 Compounds
such as 1 thus became easily available. Several of these
products could be reduced into diols then subjected to
enzyme catalyzed acylation.2 We also prepared 2 by alkyl-
ation of 1 with methyl iodide (Scheme 1).2
As b-lactones are compounds with versatile applicability,3
we envisaged using 2 in preparation of functionalized
compounds 3 with several centers likely to react with
nucleophiles. Such `polyalkylating agents' could ®nd appli-
cations in organic synthesis. Their biological properties
should also be evaluated (Scheme 2).
Results and Discussion
Saponi®cation of 2 gave hemiester 4 and we were pleased to
observe that when the latter was treated with thionyl
chloride in re¯uxing CH2Cl2 the cyclization product 5 was
obtained. This preparation of lactone 5, in one step, involves
nearly concomitant formation of an acid chloride moiety
and deprotection of the tert-butoxy ether. Several experi-
mental conditions were tested with the aim of minimizing
While numerous b-lactones can be obtained, the ones which
are unsubstituted a to the oxygen are fairly scarce although
Scheme 1.
Scheme 2.
Keywords: b-lactones; cyclization; reduction; enzymatic hydrolysis.
* Corresponding author. Tel.: 133-2-43-83-3338; fax: 133-2-43-83-3366; e-mail: fhuet@aviion.univ-lemans.fr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00313-6

3922
F.-R. Alexandre et al. / Tetrahedron 56 (2000) 3921±3926
Scheme 3.
formation of the unwanted diastereomeric compounds 6 and
of 7. Finally when 2 equiv. of thionyl chloride were quickly
added to a 1.7 M solution of 4 in re¯uxing CH2Cl2, a 54%
yield was attained after 10 h at re¯ux (Scheme 3). This
moderate yield is however interesting when taking into
account the fact that such cyclizations to b-lactones
unsubstituted a to the oxygen are usually very dif®cult,
albeit possible in some cases via a Mitsunobu reaction.5a,6c
On the other hand cyclization of compounds substituted by
alkyl or aryl groups leads to good results by the usual
methods due to the `gem-dialkyl effect'.8 Attempts to
cyclize 9, which is available from 2 by acidic treatment
providing 8, followed by saponi®cation, did not lead to 5
by reaction with PhSO2Cl/pyridine4b,c,9 and using MsCl/
to the last one, depending on the experimental conditions.
Fortunately when a solution of 12 in CHCl31SOCl2 was
added to re¯uxing SOCl2 in the presence of a small amount
of MeOH to acidify the reaction mixture, 13 was obtained in
a reasonable yield after 16 h heating. Debenzylation gave
lactone 14 (Scheme 4).
To extend our results to non-racemic products, we subjected
2 to PLE enzymatic hydrolysis. We thus obtained (1)-R-4
in 87% yield and 89±92% ee (there were little variations of
this ee according to the experimental conditions) measured
1
by chiral gas phase chromatography or by H NMR of the
ammonium salt with (1)-R-a-methylbenzylamine. This
result is comparable to the one obtained by Luyten et al.
from the dimethyl ester.14 The absolute con®guration was
assessed by chemical correlation leading to the known 1614
(Scheme 5).
10
Na2CO3 in CH2Cl2 mainly yielded unidenti®ed products
together with a very small amount of lactone 5. This new
method then appeared as complementary to the already
known ones.
Both enantiomers of lactone 14 could be obtained from a
sample of (1)-R-4 of 89% ee. The S-lactone was prepared
through the b-hydroxyester, as in the racemic synthesis,
whereas obtaining the R-lactone involved reduction of the
ester group. We ®rst used BH3/Me2S in THF as the reducing
agent.15 However, we obtained mixtures of b-hydroxyacid
and of diol. We then replaced it by Ca(BH4)2 in EtOH16 and
we could thus prepare (2)-R-17 in nearly quantitative yield
(Scheme 6).
The good result with 4 prompted us to pursue our work
towards preparation of lactones such as 3 but with the
leaving group replaced by a hydroxyl group. Therefore
compound 10 was prepared by reduction of a mixed
anhydride.11 Its benzylation with NaH/BnBr in THF led to
poor results (30% yield) but use of benzyl 2,2,2-trichloro-
acetamidate in acidic medium12 gave 11 in good yield.
Saponi®cation with LiOH, H2O/THF or 1 M aq. NaOH/
EtOH failed, probably because the molecule is too sterically
crowded. Therefore 11 was saponi®ed according to
Gassman et al. conditions.13 The ®rst attempts of obtaining
13 by treatment with SOCl2 led to a mixture of the expected
product and of anhydride corresponding to 12, or even only
b-Lactones 5, 13 and 14 were characterized by the spectral
data and in particular by IR absorptions at 1813±1830 cm21
(n CvO). Dif®culty of access to this kind of compounds is
not due to their instability and these lactones could be kept
Scheme 4. (a) ClCO2/Et3N; (b) NaBH4, MeOH; (c) CCl3CNHOBn, CF3SO3H; (d) 8.0 equiv. of tBuOK, 2 H2O, Et2O; (e) SOCl2; (f) H2, 10% Pd/C.
Scheme 5.

F.-R. Alexandre et al. / Tetrahedron 56 (2000) 3921±3926
3923
Scheme 6. (a) ClCO2Me/Et3N; (b) NaBH4, MeOH; (c) CCl3CNHOBn, CF3SO3H; (d) 8 tBuOK, 2 H2O, Et2O; (e) SOCl2; (f) H2, 10% Pd/C; (g) Ca(BH4)2, EtOH;
(h) EtOH, SOCl2.
for several weeks at low temperature without decomposi-
tion.
(CH2), 65.1 (CH2), 74.2 (quat. C), 171.4 (CO), 174.6
(CO); IR (®lm) cm21 3500±2500, 2979, 2937, 1747 (br.),
1365, 1302, 1257, 1193, 1083, 1025; anal. calcd. for
C11H20O5´0.4H2O: C, 55.12; H, 8.68, found: C, 55.14; H,
8.62. The optically active monoester (1)-R-4 was obtained
by enzymatic hydrolysis of diester 2 (3.102 g, 11.9 mmol)
which was added to a pH 7 phosphate buffer (0.1 M
KH2PO4, 30 mL). After adding of a 1 M NaOH aqueous
solution to attain pH 7.2, then of PLE (250 mL, 937.5
units), the reaction mixture was stirred at 388C overnight
with maintaining pH at 7.2 by using a pH-stat to control
addition of a 1 M NaOH aqueous solution. Extraction with
ether (3£50 mL), acidi®cation to pH 1±2 with a 10% HCl
solution, another extraction with ether (3£100 mL), drying
of the last organic phases (MgSO4) and evaporation yielded
(1)-R-(4) as an oil (2.523 g, 81%). This experiment led to a
89% ee. However, a 92% ee ([a]2D0 14.1 (cˆ4.0, MeOH))
was obtained another time when working at a lower scale.
Finally this new one step cyclization method was successful
for obtaining several new b-lactones. It also could be
applied to the synthesis of optically active compounds with-
out damage to the enantiomeric excess.
Experimental
NMR spectra were recorded on a Bruker AC 400 instrument
1
at 400 and 100.6 MHz for H and 13C, respectively, in
CDCl3 and using TMS as the internal reference. Multi-
plicities in the 13C spectra were determined by DEPT
experiments. Optical rotations were measured with a
Perkin±Elmer 343 polarimeter. Chromatographic analyses
were performed with a Hewlett±Packard HP 6890 apparatus
equipped with a 30 m Restek b-DEX-sm column. IR spectra
were recorded with a Genesis Matteson infrared spectro-
photometer. Melting points were measured on a Reichert
apparatus and are uncorrected. Elemental analyses were
performed by the service de microanalyse, CNRS, ISCN,
Gif-sur-Yvette. Mass spectra were obtained by GPC/MS
(Varian 3300 DB5 sm/ITD 800 Finnigan MAT). High-
resolution mass measurements were performed at the
CRMPO, Rennes.
(^)-Ethyl 3-methyl-2-oxetanone-3-carboxylate (5). A
solution of monoester 4 (199 mg, 0.86 mmol) in CH2Cl2
(0.5 mL) was heated to re¯ux under argon then SOCl2
(124 mL, 1.7 mmol) was added through a septum. The reac-
tion was stirred overnight at the same temperature. Cooling
and evaporation left an oil. Puri®cation by column chroma-
tography on silica gel (cyclohexane/AcOEt 8:2) yielded
1
pure 5 as a colorless oil (73 mg, 54%). H NMR d 1.32 (t,
3H, Jˆ7.1 Hz), 1.71 (s, 3H), 4.13 (d, 1H, Jˆ5.1 Hz), 4.28
(q, 2H, Jˆ7.1 Hz), 4.67 (d, 1H, Jˆ5.1 Hz); 13C NMR d 14.0
(CH3), 16.9 (CH3), 62.3 (quat. C), 62.5 (CH2), 69.3 (CH2),
167.29 (CO), 167.31 (CO); IR (®lm) cm21 2989, 1830,
1733, 1286, 1159, 1097; GPC/MS (EI) m/z (rel. int) 159
(MH1, 5), 129 (9), 115 (14), 99 (23), 86 (27), 69 (100),
41 (88); anal. calcd. for C7H10O4: C, 53.16, H, 6.37,
found: C, 53.42, H, 6.48.
2-(tert-Butoxymethyl)-3-ethoxy-2-methyl-3-oxopropanoic
acid (4 and (1)-R-4). Preparation of the racemic monoester
4 was carried out by adding at room temperature a 1 M
NaOH aqueous solution (5.9 mL) to a solution of diester
22 (1.400 g, 5.38 mmol) in ethanol (3.5 mL). The reaction
mixture was stirred overnight then ethanol was evaporated.
The aqueous phase was extracted with ether (2£10 mL),
acidi®ed with a 10% HCl solution then extracted again
with ether (3£15 mL). The last organic phases were dried
(MgSO4) and evaporated to afford the pure monoester 4 as a
colorless oil (1.053 g, 84%). 1H NMR d 1.21 (s, 9H), 1.29 (t,
3H, Jˆ7.1 Hz), 1.46 (s, 3H), 3.63 (d, 1H, Jˆ8.4 Hz), 3.80
(d, 1H, Jˆ8.4 Hz), 4.24 (q, 2H, Jˆ7.1 Hz); 13C NMR d 13.9
(CH3), 18.3 (CH3), 27.1 (3C, CH3), 54.5 (quat. C), 61.7
(^)-Ethyl 3-chloro-2-[(chlorosul®nyl)oxy]methyl-2-methyl-
3-oxopropanoate (6) (both diastereomers). A mixture of
monoester 4 (258 mg, 1.11 mmol) and of SOCl2 (800 mL,
11.1 mmol) was heated to re¯ux under argon and without
solvent and stirred at this temperature for 18 h. Cooling then
evaporation left a yellow oil mainly consisting of crude 6

3924
F.-R. Alexandre et al. / Tetrahedron 56 (2000) 3921±3926
(229 mg, 74%). 1H NMR d 1.33 (t, 3H, Jˆ7.1 Hz), 1.66 (s, 3H,
(dia 1)), 1.68 (s, 3H, (dia 2)), 4.31 (q, 2H, (dia 1), Jˆ7.1 Hz),
4.32 (q, 2H, (dia 2), Jˆ7.1 Hz), 4.63 (d, 1H, (dia 1),
Jˆ10.5 Hz), 4.71 (d, 1H, (dia 1), Jˆ10.5 Hz), 4.90 (d, 1H,
(dia 2), Jˆ10.3 Hz), 4.96 (d, 1H, (dia 2), Jˆ10.3 Hz); 13C
NMR d 13.8 (CH3), 18.5 (CH3), 62.8 (quat. C (dia 1)), 62.9
(quat. C (dia 2)), 63.2 (CH2), 66.5 (CH2 (dia 1)), 66.6 (CH2 (dia
2)), 166.5 (CO), 170.5 (CO); IR (®lm) cm21 2987, 1799, 1745,
1226, 962, 813.
1.93 mmol) in EtOH (20 mL). The mixture was cooled to
08C then a suspension of NaBH4 (439 mg, 11.61 mmol) in
EtOH (4 mL) was added with stirring. The reaction was
allowed to proceed for 17 h at room temperature then cooled
to 08C. Addition of a 10% HCl solution at the same tempera-
ture to attain pH 2±3, evaporation of EtOH, adding of water
(10 mL), saturation with NaCl, extraction with CH2Cl2
(3£20 mL), drying (MgSO4) then evaporation provided
practically pure (2)-R-17 as an oil that crystallized slowly
on standing (358 mg, 97%), 89% ee, [a]2D0 22.2 (cˆ21.7,
1
(^)-Ethyl 2-(tert-butoxymethyl)-3-chloro-2-methyl-3-oxo-
propanoate (7). A solution of monoester 4 (1.022 g,
4.4 mmol) in CH2Cl2 (4.4 mL) was heated to re¯ux under
stirring then a solution of SOCl2 (950 mL, 13.2 mmol) in
CH2Cl2 (2.6 mL) was added quickly. After 16 h stirring at
the same temperature cooling then evaporation left a yellow
oil mainly consisting of crude 7 (1.048 g, 95%). 1H NMR d
1.17 (s, 9H), 1.29 (t, 3H, Jˆ7.1 Hz), 1.57 (s, 3H), 3.65 (d, 1H,
Jˆ8.7 Hz), 3.92 (d, 1H, Jˆ8.7 Hz), 4.23 (m, 2H); 13C NMR
d 14.1 (CH3), 18.9 (CH3), 27.2 (3C, CH3), 62.1 (CH2), 64.4
(CH2), 64.5 (quat. C), 73.4 (quat. C), 168.6 (CO), 171.7 (CO);
IR (®lm) cm21 2977, 2940, 1799, 1747, 1365, 1257, 1195,
1087.
CHCl3). Mp 50.2±51.08C, H NMR d 1.20 (s, 3H, H-5),
1.24 (s, 9H), 3.57 (d, 1H, Jˆ8.9 Hz), 3.60 (d, 1H,
Jˆ8.9 Hz), 3.68 (d, 1H, Jˆ11.4 Hz), 3.80 (d, 1H,
Jˆ11.4 Hz); 13C NMR d 18.1 (CH3), 27.2 (3C, CH3), 47.9
(quat. C), 66.0 (CH2), 67.1 (CH2), 74.7 (quat. C), 178.6
(CO); IR (nujol) cm21 3500±2500, 3311, 1698, 1463,
1365, 1195, 1085, 1031; anal. calcd. for C9H18O4: C,
56.82; H, 9.54, found: C, 56.64; H, 9.51.
Ethyl 3-(tert-butoxy)-2-(hydroxymethyl)-2-methylpro-
panoate (10, (1)-S-10, (2)-R-10). Et3N (945 mL,
6.82 mmol) was added at 08C under argon to a stirred solu-
tion of 4 (1.535 g, 6.62 mmol) in THF (14 mL) then methyl
chloroformate (525 mL, 6.82 mmol) was introduced drop-
wise at the same temperature. The reaction was allowed to
proceed for 1 h then the reaction mixture was ®ltered and
the precipitate was washed with cooled THF. Filtrate was
cooled to 2788C, NaBH4 (500 mg, 13.23 mmol) was intro-
duced portionwise and methanol (2.7 mL) was added drop-
wise over 30 min. After 1 h more at the same temperature
the cooling bath was removed then a 10% HCl solution
(25 mL) was added slowly. Evaporation of THF, extraction
with CH2Cl2 (3£20 mL), drying (MgSO4), evaporation, and
column chromatography on silica gel (cyclohexane/AcOEt
8:2), provided 10 as a colorless oil (1.35 g, 94%). 1H NMR
d 1.15 (s, 3H), 1.17 (s, 9H), 1.27 (t, 3H, Jˆ7.1 Hz), 2.98 (dd,
1H, OH, Jˆ7.6, 5.4 Hz), 3.35 (d, 1H, Jˆ8.4 Hz), 3.70 (dd,
1H, Jˆ11.1, 7.6 Hz), 3.71 (d, 1H, Jˆ8.4 Hz), 3.82 (dd, 1H,
Jˆ11.1, 5.4 Hz), 4.18 (m, 2H); 13C NMR d 14.1 (CH3), 17.9
(CH3), 27.2 (3C, CH3), 48.1 (quat. C), 60.6 (CH2), 66.3
(CH2), 67.4 (CH2), 73.2 (quat. C), 175.4 (CO); IR (®lm)
cm21 3484, 2975, 2937, 1729, 1365, 1234, 1197, 1083,
1045; GPC/MS (EI) m/z (rel. int.) 203 (M1±Me, 3), 185
(3), 163 (100), 145 (21), 132 (17), 100 (18), 71 (18), 57
(51), 41 (61); GPC/MS (CI) m/z (rel. int.) 219 (MH1, 0.1),
163 (100); anal. calcd. for C11H22O4´0.15H2O: C, 59.73; H,
10.09, found: C, 59.68; H, 10.01. The same reaction from a
89% ee sample of (1)-R-4 (1.876 g, 8.08 mmol) provided
(1)-S-10 (1.589 g, 88%), [a]2D0 10.8 (cˆ1.9, CHCl3), 89%
ee. Preparation of (2)-R-10 was carried out starting from
a solution of (2)-R-17 (344 mg, 1.81 mmol) in EtOH
(1.8 mL) that was added dropwise, at 08C and under argon
to a stirred mixture of SOCl2 (200 mL, 2.71 mmol) and of
EtOH (4.5 mL). The reaction mixture was stirred for 20 h at
room temperature, EtOH was evaporated, ether was added
(20 mL), this solution was successively washed with a satu-
rated solution of NaHCO3 then with brine, dried (MgSO4), and
evaporated to afford practically pure (2)-R-10 as a colorless
oil which was used without further puri®cation in the following
step (336 mg, 85%). [a]2D0 0.5 (cˆ2.0, CHCl3), 89% ee.
(^)-Diethyl 2-(hydroxymethyl)-2-methylmalonate (8).
18 M H2SO4 (1.15 mL) was added dropwise with stirring
to a solution of 2 (1.915 g, 7.36 mmol) in EtOH (20 mL).
After 17 h re¯uxing the cooled solution was evaporated.
Adding of water (10 mL), neutralization to pH 7 by adding
of a saturated solution of NaHCO3, extraction with ether
(3£30 mL), drying (MgSO4) and evaporation left practically
pure 8 as a colorless oil which was used without further
puri®cation in the following step (1.397 g, 93%). This
compound is also available by aldol condensation between
diethyl methyl malonate and formaldehyde.18 1H NMR d
1.28 (t, 6H, Jˆ7.1 Hz), 1.44 (s, 3H), 2.88 (t, 1H,
Jˆ7.1 Hz), 3.85 (d, 2H, Jˆ7.1 Hz), 4.23 (q, 4H,
Jˆ7.1 Hz); 13C NMR d 13.9 (2 CH3), 17.5 (CH3), 55.8
(quat. C), 61.5 (2 CH2), 66.7 (CH2), 171.6 (CO); IR (®lm)
cm21 3507, 2983, 1729, 1303, 1253, 1120, 1052; GPC/MS
(EI) m/z (rel. int.) 205 (MH1, 100), 187 (9), 175 (42), 174
(55), 129 (52), 115 (31), 100 (31), 100 (47), 85 (48), 57 (42).
(^)-3-Ethoxy-2-(hydroxymethyl)-2-methyl-3-oxopropa-
noic acid (9). A 1 M NaOH aqueous solution (1.22 mL) was
added to a solution of 8 (250 mg, 1.22 mmol) in EtOH
(1 mL). The reaction mixture was stirred at room tempera-
ture for 18 h. Ethanol was then evaporated and the aqueous
phase was extracted with ether (2£5 mL), acidi®ed with a
10% HCl solution then extracted again with ether (3£5 mL).
The last organic phases were dried (MgSO4) and evaporated
to afford practically pure 9 as a colorless oil which was used
without further puri®cation in the following step (158 mg,
73%). 1H NMR d 1.30 (t, 3H, Jˆ7.1 Hz), 1.48 (s, 3H), 3.89
(d, 1H, Jˆ11.4 Hz), 3.93 (d, 1H, Jˆ11.4 Hz), 4.26 (q, 2H,
Jˆ7.1 Hz); 13C NMR d 14.0 (CH3), 17.6 (CH3), 45.8 (quat.
C), 62.1 (CH2), 66.5 (CH2), 171.6 (CO), 176.2 (CO); IR (®lm)
cm21 3477, 3400±2600; 2987, 1712, 1253, 1126, 1045.
3-(tert-Butoxy)-2-(hydroxymethyl)-2-methylpropanoic
acid ((2)-R-17). A solution of KOH (239 mg, 4.26 mmol)
and of CaCl2 (945 mg, 8.51 mmol) in EtOH (5.5 mL) was
mixed to a solution of monoester (R)-4 of 89% ee (449 mg,
Ethyl 3-(benzyloxy)-2-(tert-butoxymethyl)-2-methylpro-
panoate (11, (1)-S-11 and (2)-R-11). To a stirred solution

F.-R. Alexandre et al. / Tetrahedron 56 (2000) 3921±3926
3925
of alcohol 10 (277 mg, 1.27 mmol) and of benzyl 2,2,2-
trichoroacetamidate (472 mL, 2.54 mmol) in CH2Cl2
(2.5 mL), was added at 08C a catalytic amount of trifuoro-
methanesulfonic acid (11 mL, 0.13 mmol). After stirring for
1 h, a saturated solution of NaHCO3 (10 mL) was added.
Extraction with CH2Cl2 (2£10 mL) then drying (MgSO4)
and evaporation of the organic layer left a residue. Adding
of pentane, ®ltration, evaporation then column chromato-
graphy on silica gel (cyclohexane/ AcOEt 95/5) gave 11
for 16 h then cooling, evaporation and column chromato-
graphy on silica gel (CH2Cl2) led to 13 as a colorless oil
(48 mg, 55%). 1H NMR d 1.39 (s, 3H), 3.46 (d, 1H,
Jˆ9.8 Hz), 3.64 (d, 1H, Jˆ9.8 Hz), 4.03 (d, 1H, Jˆ
4.9 Hz), 4.48 (d, 1H, Jˆ4.9 Hz), 4.55 (d, 1H, Jˆ12.3 Hz),
4.62 (d, 1H, Jˆ12.3 Hz), 7.29±7.38 (m, 5H); 13C NMR d
16.1 (CH3), 58.2 (quat. C), 69.1 (CH2), 69.8 (CH2), 73.3
(CH2), 127.6 (2C, CH), 127.8 (CH), 128.4 (2C, CH),
137.4 (quat. C), 173.3 (CO); IR (®lm) cm21 3051, 2977,
2864, 1824, 1101, 916, 738, 700; GPC/MS (EI) m/z (rel.
int) 207 (MH1, 2), 205 (3), 161 (7), 136 (7), 117 (5), 107
(21), 105 (18), 91 (100), 79 (21), 77 (15), 65 (27), 51 (19);
anal. calcd. for C12H14O3: C, 69.88, H, 6.84, found: C,
70.15, H, 6.86. The same reaction from a 89% ee sample
of (1)-S-12 (1.120 g, 3.98 mmol) provided (1)-S-13
(437 mg, 53%), [a]D20 111.0 (cˆ7.3 CHCl3), 89% ee.17
The same reaction from a 89% ee sample of (2)-R-12
(159 mg, 0.57 mmol) provided (2)-R-13 (58 mg, 50%),
[a]2D0 211.5 (cˆ5.0 CHCl3), 89% ee.17
1
as a colorless oil (339 mg, 87%). H NMR d 1.13 (s, 9H),
1.19 (s, 3H), 1.23 (t, 3H, Jˆ7.1 Hz); 3.44 (d, 1H, Jˆ8.2 Hz),
3.48 (d, 1H, Jˆ8.2 Hz), 3.58 (s, 2H), 4.14 (q, 2H,
Jˆ7.1 Hz), 4.52 (s, 2H), 7.25±7.32 (m, 5H); 13C NMR d
14.2 (CH3), 17.9 (CH3), 27.4 (3C, CH3), 48.1 (quat. C), 60.2
(CH2), 63.7 (CH2), 72.2 (quat. C), 72.4 (CH2), 73.2 (CH2),
127.3 (3C, CH), 128.4 (2C, CH), 138.7 (quat. C), 175.0
(CO); IR (®lm) cm21 3029, 2974, 2873, 1730, 1363, 1234,
1197, 1082, 736, 698; GPC/MS (EI) m/z (rel. int.) 253
(MH1±tBu, 17), 251 (20), 145 (29), 91 (100), 57 (29), 41
(28); GPC/MS (CI) m/z (rel. int.) 253 (MH1±tBu, 100), 161
(76), 131 (29), 91 (13); anal. calcd. for C18H28O4: C, 70.10;
H, 9.15, found: C, 70.29; H, 9.11. The same reaction from a
89% ee sample of (1)-S-10 (1.589 g, 7.15 mmol) provided
(1)-S-11 (2.102 g, 94%), [a]2D0 11.3 (cˆ12.0 CHCl3), 89%
ee. The same reaction from a 89% ee sample of (2)-R-10
(336 mg, 1.54 mmol) provided (2)-R-11 (406 mg, 86%),
[a]2D0 21.6 (cˆ1.9 CHCl3), 89% ee.
3-(Hydroxymethyl)-3-methyl-2-oxetanone (14). A solu-
tion of 13 (48 mg, 0.23 mmol) in AcOEt (6 mL) was hydro-
genated for 18 h under pressure (5 bars), at 408C and with
stirring in presence of 10% Pd on activated carbon (a few
mg). Filtration, washing with AcOEt and evaporation left 14
as an oil (24.5 mg, 91%). 1H NMR d 1.41 (s, 3H), 2.6±3.0
(br s, 1H), 3.65 (d, 1H, Jˆ11.6 Hz), 3.89 (d, 1H, Jˆ
11.6 Hz), 4.08 (d, 1H, Jˆ4.8 Hz), 4.50 (d, 1H, Jˆ4.8 Hz);
13C NMR d 15.7 (CH3), 59.6 (quat. C), 62.9 (CH2), 68.8
(CH2), 171.1 (CO); IR (®lm) cm21 3454, 2975, 2937, 2879,
1813, 1159, 1101, 1051, 910. The same reaction from a 89%
ee sample of (1)-S-13 (286 mg, 1.24 mmol) provided, after
column chromatography on silica gel (cyclohexane/AcOEt
1:1), (1)-S-14 (135 mg, 94%) HRMS Calcd for C4H5O2:
(M±CH2O)1 86.0367. Found: 86.0358, [a]2D0 17.3 (cˆ1.0
CHCl3), 89% ee. The same reaction from a 89% ee sample
of (2)-R-13 (50 mg, 0.24 mmol) provided (2)-R-14
(27 mg, 96%), [a]D20 29.0 (cˆ3.0 CHCl3), 89% ee.17
3-(Benzyloxy)-2-(tert-butoxymethyl)-2-methylpropanoic
acid (12, (1)-S-12 and (2)-R-12). Water (42 mL,
2.32 mmol) was added under argon to a stirred suspension
of potassium tert-butoxide (1.046 g, 9.32 mmol) in dry ether
(18 mL), cooled to 08C. This slurry was stirred for 5 min,
then 11 (359 mg, 1.16 mmol) in dry ether (3 mL) was added.
After 5 h stirring at room temperature the reaction mixture
was quenched by adding cooled water until obtaining two
clear layers. The aqueous phase was extracted with ether
(2£10 mL), acidi®ed with a 50% HCl solution and re-
extracted with ether (3£15 mL). Drying of the last organic
layers (MgSO4), evaporation and column chromatography
on silica gel (cyclohexane/AcOEt 8:2) provided 12 as a
R-1-Ethyl-3-methyl-2-(tert-butoxymethyl)-2-methyl-
malonate (R-15). A sample of R-14 of 92% ee (89 mg,
0.38 mmol) in ether (5 mL) was esteri®ed by adding a solu-
tion of diazomethane until obtaining a yellow solution then
excess of diazomethane was destroyed by adding acetic acid
until discoloration. Evaporation left pure R-15 as a colorless
1
white solid (267 mg, 82%). Mp 72.6±76.88C; H NMR d
1.20 (s, 9H), 1.24 (s, 3H), 3.47 (d, 1H, Jˆ8.6 Hz), 3.54 (d,
1H, Jˆ8.9 Hz), 3.57 (d, 1H, Jˆ8.6 Hz), 3.64 (d, 1H,
Jˆ8.9 Hz), 4.54 (s, 2H), 7.25±7.32 (m, 5H); 13C NMR d
18.2 (CH3), 27.3 (3C, CH3), 47.6 (quat. C), 63.8 (CH2), 72.3
(CH2), 73.5 (CH2), 74.1 (quat. C), 127.5 (2C, CH), 127.6
(CH), 128.3 (2C, CH), 138.1 (quat. C), 178.0 (CO); IR (®lm)
cm21 3400±2600, 3066, 2971, 2877, 1712, 1456, 1363,
1251, 1197, 1087, 735, 698; GPC/MS (EI) m/z (rel. int)
281 (MH1, 8), 223 (14), 107 (29), 91 (100); anal. calcd.
for C16H24O4: C, 68.54; H, 8.63, found: C, 68.43; H, 8.59.
The same reaction from a 89% ee sample of (1)-S-11
(2.102 g, 6.82 mmol) provided (1)-S-12 (1.539 g, 80%),
[a]2D0 12.4 (cˆ1.0 CHCl3), 89% ee. The same reaction
from a 89% ee sample of (2)-R-11 (409 mg, 1.33 mmol)
provided (2)-R-12 (320 mg, 86%), [a]2D0 23.1 (cˆ1.1
CHCl3), 89% ee.
1
oil (91 mg, 97%). H NMR d 1.14 (s, 9H), 1.24 (t, 3H,
Jˆ7.1 Hz), 1.48 (s, 3H), 3.70 (s, 2H), 3.72 (s, 3H), 4.18
(d, 2H, Jˆ7.1 Hz); 13C NMR d 14.0 (CH3), 18.4 (CH3),
27.3 (3C, CH3), 52.2 (CH3), 54.8 (quat. C), 61.1 (CH2),
64.7 (CH2), 72.9 (quat. C), 170.9 (CO), 171.4 (CO); IR
(®lm) cm21 2976, 1739, 1259, 1221, 1196, 1120, 1087.
R-1-Ethyl-3-methyl-2-(hydroxymethyl)-2-methylmalo-
nate (R-16). Tri¯uoracetic acid (150 mL) was added drop-
wise at 08C to a solution of (R)-15 (64 mg, 0.26 mmol) in
CH2Cl2 (1.5 mL). After 1 h stirring at room temperature,
adding of CH2Cl2 (15 mL), washings with a saturated solu-
tion of NaHCO3 (1 mL) then with brine (1 mL), drying
(MgSO4) and evaporation yielded practically pure R-16 as
a colorless oil (40 mg, 81%). 1H NMR d 1.28 (t, 3H,
Jˆ7.1 Hz), 1.45 (s, 3H), 2.85 (t, 1H, OH, Jˆ7.1 Hz), 3.77
(s, 3H), 3.86 (d, 2H, Jˆ7.1 Hz), 4.23 (d, 2H, Jˆ7.1 Hz); 13C
NMR d 13.9 (CH3), 17.5 (CH3), 52.6 (CH3), 55.8 (quat. C),
3-[(Benzyloxy)methyl]-3-methyl-2-oxetanone (13).
A
solution of 12 (118 mg, 0.42 mmol) in CHCl3 (0.5 mL)
was added under argon to a re¯uxing solution of SOCl2
(1 mL) acidi®ed with methanol (7 mL). Re¯ux was pursued

3926
F.-R. Alexandre et al. / Tetrahedron 56 (2000) 3921±3926
6. (a) Testa, von E.; Fontanella, L.; Cristiani, G. F.; Mariani, L.
Liebigs Ann. Chem. 1961, 639, 166±180. (b) Hmamouchi, M.;
Prud'homme, R. E. J. Polym. Sci.: Part A: Polym. Chem. 1988,
26, 1593±1607. (c) Dollinger, L. M.; Howell, A. R. J. Org. Chem.
1996, 61, 7248±7249.
61.6 (CH2), 66.7 (CH2), 171.5 (CO), 172.1 (CO); IR (®lm)
cm21 3498, 2987, 2956, 1730, 1303, 1253, 1214, 1120,
1051; GPC/MS (EI) m/z (rel. int) 191 (MH1, 5), 160 (61),
132 (14), 131 (17), 129 (17), 128 (18), 116 (19), 115 (55),
101 (34), 100 (36), 88 (29), 85 (100), 83 (46); [a]2D0 12.2
(cˆ3.7 CHCl3) and [a]D20 21.0 (cˆ3.7 MeOH) 92% ee. Lit14
[a]2D0 10.95 (cˆ2.2, MeOH) for the S-16 of 95% ee.
7. Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403±6434.
8. Wedler, C.; Kleiner, K.; GruÈndemann, E.; Schick, H. J. Chem.
Soc., Perkin Trans. 1 1997, 1963±1967 (and references therein).
9. Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94,
2000±2006.
Acknowledgements
10. Mageswaran, S.; Sultanbawa, M. U. S. J. Chem. Soc., Perkin
Trans 1 1976, 884±890. Campi, E. M.; Dyall, K.; Fallon, G.;
Jackson, W. R.; Perlmutter, P.; Smallridge, A. J. Synthesis 1990,
855±856.
We thank the local section of Sarthe of the Ligue Nationale
contre le Cancer for a fellowship to F.-R. A. and M. Y.
Â
Buzare for his participation on this project during a stay in
our laboratory.
11. Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647±
648.
References
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Â
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17. ee of (1)-S-13 and of (2)-R-13 were measured by chiral gas
phase chromatography; ee of (1)-S-14 and of (2)-R-14 were
assumed to be identical to those of (1)-S-13 and of (2)-R-13,
respectively.
5. See for instance (a) Ramer, S. E.; Moore, R. N.; Vederas, J. C.
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È
18. Guzaev, A.; Lonnberg, H. Synthesis 1997, 1281±1284.