Highly stereoselective epoxidation of α-methyl-γ-hydroxy- α,β-unsaturated esters: Rationalization and synthetic applications

Article abstract of DOI:10.1021/jo0709955

(Chemical Equation Presented) The diastereoselectivity of the nucleophilic epoxidation of γ-hydroxy-α,β-unsaturated esters having a methyl substituent at the α- or β-position was investigated. Epoxidation of the α-methyl-substituted enoate was highly stereoselective, giving rise to the syn isomer. This finding was used to perform an enantioselective synthesis of a natural product having a β-hydroxy-α-methylene- γ-butyrolactone motif. The nucleophilic epoxidation of enoates was found to be irreversible. Models to explain the observed stereoselectivities are proposed.

Full text of DOI:10.1021/jo0709955

SCHEME 1. General Scheme of Reactions
Highly Stereoselective Epoxidation of
r-Methyl-γ-hydroxy-r,â-unsaturated Esters:
Rationalization and Synthetic Applications
Irakusne Lo´pez, Santiago Rodr´ıguez,* Javier Izquierdo, and
Florenci V. Gonza´lez*
Departament de Qu´ımica Inorga`nica i Orga`nica UniVersitat
Jaume I, 12080 Castello´, Spain
SCHEME 2. Preparation of Substrate 1
fgonzale@qio.uji.es
ReceiVed May 14, 2007
SCHEME 3. Preparation of Substrate 3
The diastereoselectivity of the nucleophilic epoxidation of
γ-hydroxy-R,â-unsaturated esters having a methyl substituent
at the R- or â-position was investigated. Epoxidation of the
R-methyl-substituted enoate was highly stereoselective, giv-
ing rise to the syn isomer. This finding was used to perform
an enantioselective synthesis of a natural product having a
â-hydroxy-R-methylene-γ-butyrolactone motif. The nucleo-
philic epoxidation of enoates was found to be irreversible.
Models to explain the observed stereoselectivities are
proposed.
the epoxidation of non-ene-branched enoates were unable to
propose kinetic models to explain the observed selectivities
because it was unknown whether the reaction was kinetically
or thermodynamically controlled. However, in the present study
the observed stereoselectivities can be rationalized through
models combining chelation and allylic strain.
The epoxidation reactions of the R-methyl- and â-methyl-
substituted unsaturated esters 1 and 3, respectively, were
assayed, and the resulting stereoselectivities were compared with
that of the nonsubstituted ester 2. The stereochemistries of the
R,â-epoxyesters were assigned by their derivatization into
R-sulfphenyl-γ-butyrolactones using thiophenol (Scheme 1).
Compound 1 was prepared from O-protected (S)-lactaldehyde
by a Horner-Emmons reaction using triethyl 2-phosphonopro-
pionate, which furnished 4 as a 3:2 mixture of E/Z isomers.
Upon desylilation of 4 and chromatographic separation, (E)-R-
methyl-γ-hydroxy-R,â-unsaturated ester 1 was obtained (Scheme
2).
Compound 2 was obtained readily by treatment of ethyl (E)-
4-oxo-2-butenoate2a with methylmagnesium bromide. Com-
pound 3 was prepared from acetoin by protection, Horner-
Emmons reaction, and deprotection (Scheme 3). Enoates 2 and
3 were obtained as racemates and used as such in the epoxidation
reactions.
Enoates were epoxidized using lithium tert-butylperoxide in
THF as the oxidizing reagent. For compound 3, the reaction
needed to take place at room temperature to proceed to
completion. The stereoselectivity of epoxidation of these
compounds was highly dependent on the substitution of the
Stereoselective synthesis of R,â-epoxyesters is of considerable
synthetic interest because a number of compounds can be
obtained by the opening of the oxirane ring.1 A convenient
method for the preparation of R,â-epoxyesters is via nucleophilic
epoxidation of γ-chiral R,â-unsaturated esters.2 We previously
reported the stereoselectivity of the epoxidation of nonsubstituted
γ-hydroxy-R,â-unsaturated esters,2 and we now report that the
stereoselectivity depends highly on the substitution of the double
bond and that high syn stereoselectivity (dr >19:1) is observed
for the R-methyl-substituted enoates. This finding has synthetic
applications and provided for the synthesis of a â-hydroxy-R-
methylene-γ-butyrolactone that is a natural product.
Furthermore, it was determined that the nucleophilic epoxi-
dation of enoates is an irreversible process. The enolization of
a â-peroxyester afforded the corresponding R,â-epoxyester but
not enoate or hydroperoxide. Our previous reports describing
(1) (a) Chong, J. M.; Sharpless, K. B. Tetrahedron Lett. 1985, 26, 4683-
4686. (b) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1987,
28, 4435-4436. (c) Saito, S.; Takahashi, N.; Ishikawa, T.; Moriwake, T.
Tetrahedron Lett. 1991, 32, 667-670. (d) Lanier, M.; Pastor, R. Tetrahedron
Lett. 1995, 36, 2491-2492. (e) Righi, G.; Rumboldt, G.; Bonini, C. J. Org.
Chem. 1996, 61, 3557-3560. (f) Concello´n, J. M.; Bardales, E. Org. Lett.
2002, 4, 189-191. (g) Concello´n, J. M.; Bardales, E.; Llavona, R. J. Org.
Chem. 2003, 68, 1585-1588 and refs cited therein.
(2) (a) Rodr´ıguez, S.; Vidal, A.; Monroig, J. J.; Gonza´lez, F. V.
Tetrahedron Lett. 2004, 45, 5359-5361. (b) Rodr´ıguez, S.; Izquierdo, F.;
Lo´pez, I.; Gonza´lez, F. V. Tetrahedron 2006, 62, 11112-11123.
10.1021/jo0709955 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/26/2007
6614
J. Org. Chem. 2007, 72, 6614-6617

SCHEME 4. Epoxidation of r,â-Unsaturated Esters
SCHEME 6. Mechanism of Nucleophilic Epoxidation of
Enoates
Epoxides 11 and 12 were separated by column chromatog-
raphy and derivatized into lactones 16 and 17, respectively.
Lactone 16 exhibited an NOE effect between H-2 and H-4,
whereas 17 did not (Scheme 5).
SCHEME 5. Derivatization of Epoxyesters
A nucleophilic epoxidation reaction is thought to proceed by
the addition of a tert-butylperoxy anion to the activated double
bond, giving rise to enolate 18 (Scheme 6). Upon elimination
of tert-butoxide from 18, the epoxide is furnished.7
To conduct a meaningful analysis of transition states, it was
necessary to determine whether the initial Michael addition of
the peroxy anion to the enoate is kinetic (irreversible) or
reversible. If the enolate intermediate is prepared by an alternate
route and enoate and/or tert-butylperoxy anion is detected, this
result would prove reversibility of the reaction.
tert-Butylperoxyether 19 was prepared from ethyl 3-hydroxy-
butanoate by a two-step sequence.8 Then, 19 was treated with
LDA or LHMDS to generate the desired enolate 18. Careful
analysis of the 1H NMR spectrum of the crude reaction mixture
showed (E)-ethyl 2-butenoate oxide 20 and (E)-tert-butyl-2-
butenoate oxide in a 3:1 ratio as the sole product of the reaction.9
The same result was obtained when ethyl trans-crotonate was
epoxidized by using lithium tert-butylperoxide (Scheme 7).
A competition experiment was performed to examine the
reversibility of the epoxidation reaction. The peroxide interme-
diate and a second, different enone/enoate acceptor were mixed
to determine whether the epoxide of the second unsaturated
acceptor is formed, which would definitively prove reversibility
of the reaction.
double bond: compound 1 afforded higher stereoselection than
2, with the syn isomer predominating in both cases3 (Scheme
4). If the reaction was carried out using lithium tert-butylper-
oxide in the presence of HMPA, then a better selectivity was
observed.2b On the other hand, compound 3 provided poor
stereoselectivity, with the anti isomer predominating.
The stereochemistries of epoxides were assigned by treatment
with sodium thiophenolate to afford the corresponding diaster-
eomeric γ-butyrolactones. Stereochemical assignment was
performed by NOE experiments (Scheme 5).
The syn epoxyester 7 was transformed into the lactone 13,
which exhibited an NOE effect between H-4 and the methyl
group in the 2-position. Compound 13 was then treated with
m-chloroperbenzoic acid, curiously furnishing sulfoxide 14 as
a single stereoisomer.4 Heating of the sulfoxide provided 15, a
natural product isolated from plants of the Lauraceae5 family.
The spectroscopic data for 15 were identical to those
described previously, showing a coupling constant J3,4 of 5.5
Hz that denoted relative syn stereochemistry. â-Hydroxy-R-
alkylidene-γ-butyrolactone motifs such as 15 are present in
many natural products with interesting biological properties.5,6
When peroxide 19 was subjected to basic treatment in the
presence of methyl acrylate or chalcone, (E)-2-butenoate oxides
were obtained, and methyl acrylate or chalcone was recovered.10
(4) This reaction had been previously conducted by C. Benezra et al.
(see ref 5e) reporting a mixture of sulfoxides; however, we observed only
one sulfoxide although, if the reaction is conducted with an excess of
oxidant, then a mixture of sulfoxide and sulfone is obtained.
(5) (a) Mart´ınez, J. C. V.; Yoshida, M.; Gottlieb, O. R. Phytochemistry
1981, 20, 459-464. (b) Mart´ınez, J. C. V.; Yoshida, M.; Gottlieb, O. R.
Tetrahedron Lett. 1979, 20, 1021-1024. (c) Niwa, M.; Iguchi, M.;
Yamamura, S. Chem. Lett. 1977, 581-582. (d) Takeda, K.; Sakurawi, K.;
Ishi, H. Tetrahedron 1972, 28, 3757-3766. For other syntheses of 15 see:
(e) Barbier, P.; Benezra, C. J. Org. Chem. 1983, 48, 2705-2709. (f) Adam,
W.; Klug, P. Synthesis 1994, 567-572.
(6) Hanson, R. L.; Lardy, H. A.; Kupchan, S. M. Science 1970, 168,
376-380.
(3) Similar selectivities have been reported in the conjugate addition of
amides to nonsubstituted and R-methyl-substituted γ-methoxyenoates: (a)
Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am.
Chem. Soc. 1992, 114, 7652-7660. (b) Asao, N.; Shimada, T.; Sudo, T.;
Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J.
Org. Chem. 1997, 62, 6274-6282.
(7) (a) Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc., Perkin
Trans. I 1988, 2663-2674. (b) Yang, N. C.; Finnegan, R. A. J. Am. Chem.
Soc. 1958, 5845-5848.
(8) Salomon, M. F.; Salomon, R. G.; Gleim, R. D. J. Org. Chem. 1976,
41, 3983-3987.
(9) Only trans-epoxyesters were observed.
J. Org. Chem, Vol. 72, No. 17, 2007 6615

SCHEME 7. Reversibility Experiment
geometry B less favorable than D, resulting in a slight preference
for the anti isomer.
In summary, the nucleophilic epoxidation of R-methyl-
substituted γ-hydroxy-R,â-unsaturated esters is a diastereose-
lective reaction that favors the syn isomer. In contrast, the
reaction of â-methyl-substituted γ-hydroxy-R,â-unsaturated
esters is less stereoselective, and the anti isomer predominates.
The nucleophilic epoxidation of enoates is an irreversible process
because the enolization of a â-peroxyester gives only the R,â-
epoxyester. The observed syn selectivity for epoxides 1 and 2
can be explained by a Felkin-Anh model assisted by chelation
with the nucleophile. The enantioselective synthesis of a natural
product having a â-hydroxy-R-methylene-γ-butyrolactone motif
was accomplished.
SCHEME 8. Kinetic Models to Explain Stereoselectivity
Experimental Section
General Experimental Procedure for the Epoxidation. To a
-78 °C cold THF (3.5 mL) was added TBHP (3.3 M in toluene)12
(2.2 mmol) and then ethyllithium (0.5 M in benzene/cyclohexane
(9/1)) (1.61 mmol). The resulting mixture was stirred at -78 °C
for 15 min, and then a solution of the unsaturated ester (1.46 mmol)
in THF (2 mL) was added dropwise; the mixture was than stirred
at the required temperature and time (see Scheme 4). Solid Na2-
SO3 (120 mg) was then added in one portion with stirring for 15
min, followed by dilution with saturated aqueous NH4Cl solution
and extraction with Et2O (3 × 30 mL). The organic layers were
washed (brine), dried (Na2SO4), and concentrated. The crude oil
was purified through chromatography (silica gel, hexanes/EtOAc
(7:3), (6:4), (1:1), (1:2) and EtOAc).
Spectroscopy data for 7 and 8: 1H NMR (500 MHz, CDCl3) δ
4.20 (2H, m, 7 and 8), 3.69 (1H, dq, J ) 8.5, 6.5 Hz, 7 and 8),
3.16 (1H, d, J ) 8.0 Hz, 7), 3.15 (1H, d, J ) 8.0 Hz, 8), 1.54 (1H,
s, 8), 1.53 (1H, s, 7), 1.28 (3H, t, J ) 7.5 Hz, 7 and 8), 1.27 (1H,
d, J ) 6.5 Hz, 7 and 8). 13C NMR (125 MHz, CDCl3) δ 170.5 (7
and 8), 69.4 (7), 66.4 (8), 65.7 (8), 61.9 (8), 61.0 (7), 19.6 (7),
19.2 (8), 14.1 (8), 13.8 (8), 12.8 (7). IR (NaCl) ν 3449, 2981, 2928,
1734, 1446, 1371, 1294, 1181, 1089, 1058, 1021, 930, 878, 760
cm-1. HRMS m/z calcd for C8H14O4Na [M + Na+]: 197.0790,
The epoxidation of the acrylate or the chalcone was never
observed, demonstrating the irreversibility of the reaction.
The synthesis of the peroxide and its transformation into an
epoxide represents a new approach to synthesizing R,â-
epoxyesters from â-hydroxyesters.
The stereoselectivity in epoxidation of compounds 1, 2, and
3 can be accounted for by a modified Felkin-Anh model3
(Scheme 8). We previously reported that O-protected γ-hydroxy-
R,â-unsaturated esters are less reactive and less selective than
unprotected esters.2b Thus, a free hydroxyl would chelate
lithium, thereby directing the attack of the nucleophile.
To explain the syn selectivity observed for 1 and 2, transition-
state geometry A (Scheme 8) would be electronically favored
because the hydroxyl group is anti. However, there is 1,3-allylic
strain between the inside methyl group and an olefinic hydrogen
(in 2) or a methyl group (in 1). The transition-state geometry B
might be the most favorable due both to the chelation factor
and minimal allylic strain. In the case of transition-state
geometry C, there is steric repulsion between the incoming
reagent and the methyl group. Transition-state geometry D
would be the most unfavorable due to 1,3-allylic strain between
the hydroxyl group and vinylic hydrogen group (in 2) or a
methyl group (in 1) and to the presence of the methyl group at
the anti position.
found: 197.0790. For 7: [R]25 ) -8.82 (c ) 5.4, CHCl3).
D
4-Hydroxy-3,5-dimethyl-3-phenylsulfanyl-dihydro-furan-2-
one, 13. An ice-bath cold suspension of sodium hydride (60% in
mineral oil) (60 mg, 1.50 mmol) in THF (12 mL) was treated with
thiophenol (308 µL, 3.0 mmol). The mixture was stirred at this
temperature for 15 min and then was cooled to -10 °C; a solution
of 7 (174 mg, 1.00 mmol) in THF (15 mL) was added dropwise,
and the mixture was stirred at -10 °C for 80 min. Then brine was
added and extracted with Et2O (3 × 20 mL), and the organic layers
were washed (brine), dried (Na2SO4), and concentrated. The crude
oil was purified through chromatography (silica gel, hexanes/EtOAc
(7:3), and ethyl acetate) to afford 175 mg (60%) of a white solid
1
(mp 102-104 °C); [R]25 ) -54.66 (c ) 1.1, CHCl3). H NMR
D
(500 MHz, CDCl3) δ 7.63-7.64 (m, 2H), 7.40-7.46 (m, 3H), 4.70
(1H, dq, J ) 7.0, 4.0 Hz), 3.93 (1H, t, J ) 3.5 Hz), 3.40 (1H, d,
J ) 3.0 Hz), 1.56 (3H, d, J ) 6.5 Hz), 1.5 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 175.4, 136.5, 129.9, 129.4, 127.8, 77.9, 74.9, 61.4,
21.1, 14.5. IR (NaCl) δ 3459, 2931, 1766, 1440, 1096, 945, 753,
692 cm-1. HRMS m/z calcd for C12H14O3SNa [M + Na+]:
261.0561, found: 261.0540.
The syn selectivity observed for compounds 1 and 2 would
be then explained by transition state B, and the higher syn
selectivity in 1 compared to 2 would be due to the different
size of R2 group (methyl in 1 and hydrogen in 2) making less
favored transition state D in 1 compared to that in 2.
For compound 3, the 1,2-allylic strain between the methyl
group in the â-position and the hydroxyl group would make
(3R,4R,5S)-Dihydro-4-hydroxy-3,5-dimethyl-3-(phenylsulfinyl)-
furan-2(3H)-one, 14. To a -10 °C cold solution of compound 13
(100 mg, 0.34 mmol) in CH2Cl2 (3 mL) was added a solution of
(11) The preparation of O-tert-butyldimethylsilyl lactaldehyde was
performed according to: Marshall, J. A.; Shiping, X. J. Org. Chem. 1995,
60, 7230-7237.
(12) Preparation of tert-butylhydroperoxide solution: Hill, J. G.; Rossiter,
B. E.; Sharpless, K. B. J. Org. Chem. 1983, 48, 3607-3608.
(10) In the presence of chalcone, a by-product (a mixture of isomers)
resulting from the conjugate addition of enolate to chalcone was also formed.
6616 J. Org. Chem., Vol. 72, No. 17, 2007

m-CPBA (77% pure) (76 mg, 0.34 mmol) in CH2Cl2 (2 mL). The
resulting mixture was stirred at -10 °C for 30 min, then was
quenched with a saturated aqueous solution of sodium bicarbonate,
and extracted with CH2Cl2 (3 × 15 mL); the organic layers were
subsequently washed with brine and a saturated aqueous solution
of sodium bicarbonate and water and were dried (Na2SO4) and
concentrated. The crude was directly purified through recrystalli-
zation from CH2Cl2/hexane to give colorless needles (73 mg, 84%)
(mp 171-173 °C); [R]20D ) -234.88 (c ) 1.3, CHCl3). 1H NMR
(500 MHz, CDCl3) δ 7.90-7.91 (m, 2H), 7.58-7.60 (m, 3H), 5.30
(br s, 1H), 4.66 (1H, dq, J ) 6.0, 3.5 Hz), 4.34 (1H, d, J ) 3.5
Hz), 1.54 (3H, d, J ) 6.5 Hz), 1.18 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 173.0, 137.4, 132.3, 129.0, 127.3, 78.9, 78.0, 67.9, 14.2,
13.8. IR (NaCl) δ 3406, 2976, 1759, 1639, 1442, 1389, 1337, 1303,
1264, 1194, 1156, 1080, 1050, 1031, 1006, 949, 878, 755, 741,
688 cm-1. HRMS m/z calcd for C12H14O4SNa [M + Na+]:
277.0510, found: 277.0544.
1.27 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.4, 68.0.2, 65.3,
61.5, 54.5, 18.4, 14.3, 13.6. IR (NaCl) δ 3484, 3063, 2981, 2937,
1762, 1584, 1481, 1441, 1385, 1324, 1256, 1172, 1090, 1064, 1016,
958, 914, 865, 795, 743, 692, 649 cm-1. HRMS m/z calcd for
C12H14O3SNa [M + Na+]: 261.0561, found: 261.0554.
(3S,4S,5S)-Dihydro-4-hydroxy-4,5-dimethyl-3-(phenylthio)fu-
ran-2(3H)-one, 17. An ice-bath cold suspension of sodium hydride
(60% in mineral oil) (95 mg, 2.38 mmol) in THF (16 mL) was
treated with thiophenol (489 µL, 4.76 mmol). The mixture was
stirred at this temperature for 30 min and was cooled to -20 °C.
Then a solution of 12 (276 mg, 1.59 mmol) in THF (6 mL) was
added dropwise, and the mixture was stirred at -20 °C for 3 h.
Then brine was added and extracted with Et2O (3 × 10 mL); the
organic layers were washed (brine), dried (Na2SO4), and concen-
trated. The crude oil was purified through chromatography (silica
gel, hexanes/EtOAc (7:3), (6:4) and EtOAc) to afford 250 mg (66%)
of an oil. Recrystallization from CH2Cl2/hexane gave a white solid
1
(4S,5S)-Dihydro-4-hydroxy-5-methyl-3-methylenefuran-2(3H)-
one, 15. A solution of sulfoxide 14 (62 mg, 0.24 mmol) in toluene
(4 mL) was refluxed for 30 min, and then the solvent was removed
under vacuum,The resulting crude oil was purified through chro-
matography (silica gel, hexanes/EtOAc (1:1), (1:2)) to afford 22
(mp 90-93 °C). H NMR (500 MHz, CDCl3) δ 7.58-7.62 (m,
2H), 7.25-7.35 (3H, m), 4.47 (1H, q, J ) 7.0 Hz), 3.78 (1H, s),
1.56 (3H, d, J ) 6.5 Hz), 1.50 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 172.7, 132.8, 132.7, 129.5, 128.6, 83.5, 77.0, 58.9, 21.6, 15.8.
IR (NaCl) δ 3468, 3059, 2927, 2855, 1769, 1580, 1478, 1440, 1383,
1345, 1323, 1158, 1091, 1049, 1024, 953, 924, 869, 808, 741, 690
cm-1. HRMS m/z calcd for C12H14O3SNa [M + Na+]: 261.0561,
found: 261.0569.
mg of a colorless oil (71%). [R]20 ) -97.26 (c ) 1.3, CHCl3).
D
1H NMR (300 MHz, CDCl3) δ 6.41 (1H, d, J ) 2.1 Hz), 5.97 (1H,
d, J ) 1.5 Hz), 4.83 (1H, d, J ) 5.7 Hz), 4.65 (1H, dq, J ) 6.0,
6.6 Hz), 1.34 (3H, d, J ) 6.6 Hz). 13C NMR (75 MHz, CDCl3) δ
168.9, 138.8, 126.3, 78.4, 69.7, 14.3. IR (NaCl) δ 3439, 3015, 2930,
1756, 1672, 1387, 1263, 1186, 1103, 1045, 958, 910, 861, 821,
784 cm-1. HRMS m/z calcd for C6H8O3Na [M + Na+]: 151.0371,
found: 151.0354.
Ethyl 3-(tert-Butylperoxy)butanoate, 19. A -20 °C cold
solution of ethyl 3-hydroxybutanoate (165 mg, 1.24 mmol) in
dichloromethane (2 mL) was treated with pyridine (121 µL, 1.50
mmol) and then with trifluoromethansulfonic anhydride (230 µL,
1.36 mmol). The resulting mixture was stirred at this temperature
for 35 min and then was quenched with water; the organic layer
was separated, dried (MgSO4), and concentrated. Then the crude
oil was solved in dichloromethane (2 mL), and the resulting mixture
was treated with sodium hydrogencarbonate (310 mg, 3.70 mmol)
and tert-butylhydroperoxide (5 M in decanes) (310 µL, 1.60 mmol)
and stirred at room temperature for 3.5 h and then was quenched
with water and extracted with dichloromethane (3 × 10 mL), dried
(Na2SO4), and concentrated. The crude oil was purified through
chromatography (silica gel, hexanes/EtOAc (8:2)) to afford 126 mg
(50%) of an oil. 1H NMR (300 MHz, CDCl3) δ 4.35 (1H, dq, J )
6.3 Hz), 4.02 (2H, q, J ) 7.2 Hz), 2.63 (1H, dd, J ) 6.3, 15.0 Hz),
2.22 (1H, dd, J ) 6.3, 15.0 Hz), 1.17 (3H, t, J ) 7.2 Hz), 1.14
(3H, d, J ) 6.3 Hz), 1.11 (9H, s). 13C NMR (75 MHz, CDCl3) δ
171.1, 79.8, 76.0, 60.1, 40.1, 26.1, 18.1, 14.0. HRMS m/z calcd
for C10H20O4Na [M + Na+]: 227.1259, found: 227.1246.
Spectroscopy data for 11: 1H NMR (300 MHz, CDCl3) δ 4.26
(2H, m), 3.66 (1H, q, J ) 6.6 Hz), 3.61 (1H, s), 2.60 (1H, s), 1.36
(3H, s), 1.31 (3H, t, J ) 7.0 Hz), 1.29 (1H, d, J ) 6.6 Hz). 13C
NMR (125 MHz, CDCl3) δ 168.4, 68.0.2, 65.3, 61.5, 54.5, 18.4,
14.3, 13.6. IR (NaCl) ν 3422, 2925, 1753, 1446, 1371, 1294, 1181,
1089, 1058, 1021, 930, 878, 760 cm-1. HRMS m/z calcd for
C8H14O4Na [M + Na+]: 197.0790, found: 197.0787.
Spectroscopy data for 12: 1H NMR (500 MHz, CDCl3) δ 4.26
(2H, m), 3.86 (1H, q, J ) 6.5 Hz), 3.64 (3H, s), 2.05 (1H, s), 1.36
(3H, s), 1.33 (3H, t, J ) 7.0 Hz), 1.27 (1H, d, J ) 6.5 Hz). 13C
NMR (125 MHz, CDCl3) δ 168.4, 68.0.2, 65.3, 61.5, 54.5, 18.4,
14.3, 13.6. IR (NaCl) ν 3490, 2982, 1751, 1384, 1298, 1199, 1033,
923, 873, 736 cm-1. HRMS m/z calcd for C8H14O4Na [M + Na+]:
197.0790, found: 197.0752.
(3R,4R,5S)-Dihydro-4-hydroxy-4,5-dimethyl-3-(phenylthio)-
furan-2(3H)-one, 16. An ice-bath cold suspension of sodium
hydride (60% in mineral oil) (44 mg, 1.10 mmol) in THF (7 mL)
was treated with thiophenol (225 µL, 2.19 mmol). The mixture was
stirred at this temperature for 30 min and then was cooled to -20
°C; then a solution of 11 (127 mg, 0.73 mmol) in THF (3 mL) was
added dropwise, and the mixture was stirred at -20 °C for 8 h.
Then brine was added and extracted with Et2O (3 × 15 mL), and
the organic layers were washed (brine), dried (Na2SO4), and
concentrated. The crude oil was purified through chromatography
(silica gel, hexanes/EtOAc (6:4), (1:1) and ethyl acetate) to afford
166 mg (96%) of a white solid. Recrystallization from hexanes/
EtOAc gave a white solid (mp 104-106 °C). 1H NMR (500 MHz,
CDCl3) δ 7.60-7.61 (m, 2H), 7.30-7.38 (m, 3H), 4.33 (1H, q, J
) 6.0 Hz), 3.91 (1H, s), 2.45 (1H, br s), 1.43 (3H, d, J ) 6.5 Hz),
Acknowledgment. This work was financed by Conselleria
d’Educacio´, Cultura i Cie`ncia de la Generalitat Valenciana
(GV05/071) and Bancaixa-UJI foundation (P1 1A2005-14). We
thank Serveis Centrals d’Instrumentacio´ Cient´ıfica de la Uni-
versitat Jaume I for technical support and especially Prof.
William R. Roush for helpful discussions.
Supporting Information Available: Description of the general
experimental procedures and graphical NMR spectra of all com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0709955
J. Org. Chem, Vol. 72, No. 17, 2007 6617