Enzymatic Acylation and Ring-Closing Olefin Metathesis: A Convenient Strategy for the Lactone Moiety of Compactin and Mevinolin

Full text of DOI:10.1021/jo000528m

J . Org. Chem. 2000, 65, 4779-4781
4779
En zym a tic Acyla tion a n d Rin g-Closin g
Olefin Meta th esis: A Con ven ien t Str a tegy
for th e La cton e Moiety of Com p a ctin a n d
Mevin olin
Arun K. Ghosh* and Hui Lei
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
arunghos@uic.edu
F igu r e 1.
Received April 10, 2000
Sch em e 1a
Compactin (1) and mevinolin (2) are potent inhibitors
of HMG-CoA reductase, the rate-limiting enzyme in-
volved in cholesterol biosynthesis.1 Both of these com-
pounds have been shown to reduce serum cholesterol
levels in animals as well as in humans.2 The therapeutic
efficacy of mevinolin has been well documented.3 One of
the key structural features of these fungal metabolites
is the presence of a (4R,6R)-tetrahydro-2-pyrone unit that
is essential for their biological properties.4 As a conse-
quence, a great deal of synthetic studies have been
devoted to the optically active synthesis of the â-hydroxy-
δ-lactone, as well as on the replacement of the complex
hexahydronaphthalene moieties of compactin or mevi-
nolin.5 This effort has resulted in the discovery of
numerous very potent and selective HMG-CoA reductase
inhibitors in which the δ-lactone moiety has been at-
tached to simpler aromatic fragments.6 As part of our
interest in the enzymatic methodologies for 1,3-diol
synthons, we have developed an enantioselective syn-
thesis of the δ-lactone unit of mevinolin (Figure 1).
Herein, we report a convenient synthesis of (4R,6S)-
tetrahydro-2-pyrone derivative 3 in high enantiomeric
excess, utilizing an immobilized lipase catalyzed selective
acylation of (()-1-(benzyloxy)-4-penten-2-ol and a ring-
closing olefin metathesis with Grubbs’ catalyst as the key
steps.
The key starting material, racemic homoallylic alcohol
5, was prepared in multigram quantities by treatment
of commercial benzyloxyacetaldehyde with allyltrimeth-
ylsilane in the presence of TiCl4 in CH2Cl2 at -78 °C for
30 min. Enzymatic acylation of the racemic alcohol 5 with
immobilized lipase PS-30 (25 wt % with respect to lipase
PS-30) in the presence of isopropenyl acetate in dimethoxy-
a
(a) immobilized lipase PS-30, CH2dC(Me)OAc, DME, 37 °C,
36 h; (b) LiOH, THF-H2O (1:4), 23 °C, 12 h; (c) p-NO2PhCO2H,
Ph3P, EtO2C-NdN-CO2Et, 23 °C, 12 h (91%); (d) CH2dCHCOCl,
Et3N, DMAP (cat.), -15 °C, 30 min (75%); (e) (PCy3)2Cl2RudCHPh
(10 mol %), Ti(OiPr)4 (0.3 equiv), CH2Cl2, 40 °C, 15 h (91%); (f)
aq. NaOH, H2O2, MeOH, 23 °C (81%); (g) PhSeSePh, NaBH4,
iPrOH, AcOH, 0 °C (93%); (h) PhSeSePh, NaBH4, iPrOH, 23 °C
(90%); (i) H2, Pearlman’s catalyst, EtOAc, 5 h, 23 °C (70%).
(1) (a) Brown, A. G.; Smale, T. C.; King, T. J .; Hasenkamp, R.;
Thompson, R. H. J . Chem. Soc., Perkin Trans. 1 1976, 1165. (b) Endo,
A.; Kuroda, M.; Tsujita, Y. J . Antibiot. 1976, 26, 1346. (c) Alberts, A.
W.; Chen, J .; Kuron, G.; Hunt, V.; Huff, J .; Hoffman, C. H.; Rothrock,
J .; Lopez, M.; J oshua, H.; Haris, E.; Patchett, A. A.; Monaghan, R.;
Currie, S.; Stapley, E.; Albers-Scho¨nberg, G.; Hensens, O.; Hirschfield,
J .; Hoogsteen, K.; Liesch, J . Proc. Nat. Acad. Sci. U.S.A. 1980, 77, 3957.
(2) Mol, M. J . T. M.; Erkelenz, D. W.; Gevers Leuven, J . A.; Schouten,
J . A. Lancet 1986, 936.
ethane at 37 °C for 36 h afforded the optically active
alcohol ent-5 (44% yield) and the acylated alcohol 6 (50%
yield), which were separated by silica gel chromatography
(Scheme 1).7 The optical purity of ent-5 (95% ee, [R]23
D
+2.1 (c 1.25, CHCl3) was determined by formation of the
Mosher ester and 19F NMR analysis.8 The control experi-
ment without the enzyme proved that the nonenzymatic
(3) Vega, L.; Grundy, S. J . Am. Med. Assoc. 1987, 257, 33 and
references therein.
(4) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J .;
Deana, A. A.; Gilfilan, J . L.; Huff, J . W.; Novello, F. C.; Prugh, J . D.;
Smith, R. L.; Willard, A. K. J . Med. Chem. 1985, 28, 347.
(5) For an excellent review of the synthesis of mevinic acids, see:
Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909.
(6) J endralla, H.; Granzer, E.; von Kerekjarto, B.; Krause, R.;
Schacht, U.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.;
Kesseler, K.; Wess, G.; Chen, L.-J .; Granata, S.; Herchen, J .; Kleine,
H.; Schu¨ssler, H.; Wagner, K. J . Med. Chem. 1991, 34, 2962 and
references therein.
(7) (a) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 505. (b)
Ghosh, A. K.; Kincaid, J . F.; Walters, D. E.; Chen, Y.; Chaudhuri, N.
C.; Thompson, W. J .; Culberson, C.; Fitzgerald, P. M. D.; Lee, H. L.;
McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J . A.;
Schleif, W. A.; Axel, M. G.; Lin, J .; Huff, J . R. J . Med. Chem. 1996, 39,
3278.
(8) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
10.1021/jo000528m CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

4780 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
reaction was extremely slow (only a trace amount of
acylated product after 48 h at 37 °C). The acetate 6 can
be readily converted to 2-(S)-1-benzyloxy-4-penten-2-ol
ent-5 in a three-step sequence involving (1) saponification
of 6 with aqueous lithium hydroxide at 23 °C for 12 h;
(2) Mitsunobu inversion9 of the resulting 2-(R)-alcohol
with Ph3P, p-NO2-benzoic acid in the presence of diethy-
lazodicarboxylate at 23 °C for 12 h; and (3) aqueous
lithium hydroxide promoted saponification of the result-
ing benzoate derivative. The (S)-alcohol ent-5 thus ob-
tained (79% overall in three steps) has shown high optical
purity (>96% ee) after formation of the Mosher ester and
19F NMR analysis. The represented absolute configura-
tions of the resolved alcohols were assigned on the basis
of comparison of optical rotation with the literature
data.10
noteworthy. Further application of this methodology in
synthesis is currently underway.
Exp er im en ta l Section
Melting points were recorded and are uncorrected. Anhydrous
solvents and reagents were obtained as follows: tetrahydrofuran
and diethyl ether, distillation from sodium/benzophenone; me-
thylene chloride, distillation from CaH2; triethylamine, distil-
lation from CaH2. All other solvents were HPLC grade. Column
chromatography was performed with Whatman 240-400 mesh
silica gel under low pressure of 5-10 psi. Thin-layer chroma-
tography (TLC) was carried out with E. Merck silica gel 60 F-254
plates.
1-(Ben zyloxy)-4-p en ten -2-ol [(()-5]. To a stirred solution
of benzyloxyacetaldehyde (2.5 g, 16.6 mmol) in dichloromethane
(200 mL) was added titanium tetrachloride (1.8 mL, 16.6 mmol)
at -78 °C. The resulting mixture was stirred for 10 min,
allyltrimethylsilane (3.2 mL, 20 mmol, precooled to -78 °C) was
added, and the mixture was stirred at -78 °C for 30 min. The
reaction was then quenched with H2O (50 mL). The layers were
separated, and the aqueous layer was extracted with diethyl
ether (2 × 100 mL). The combined organic layers were succes-
sively washed with saturated aqueous NaHCO3 solution and
brine and dried over anhydrous MgSO4. Evaporation of the
solvent under reduced pressure provided a residue that was
purified by column chromatography on silica gel (10% EtOAc in
hexanes as the eluent) to afford the title alcohol (()-5 (2.7 g,
Optically active homoallylic alcohol ent-5 was con-
verted to acrylate ester 4 by reaction with acryloyl
chloride and Et3N in the presence of a catalytic amount
of DMAP in CH2Cl2 at -15 °C for 30 min. The acrylate
ester 4 was isolated in 75% yield after silica gel chroma-
tography. Olefin metathesis of 4 with commercially
available Grubbs’ catalyst (10 mol %) in the presence of
Ti(OiPr)4 (0.3 equiv) in refluxing CH2Cl2 for 15 h fur-
nished the R,â-unsaturated δ-lactone 7 in 91% yield.11
The ring-closing metathesis of acrylates utilizing Grubbs’
catalyst thus provides a convenient access to various R,â-
unsaturated γ- and δ-lactones.12 Epoxidation of the
unsaturated δ-lactone 7 with alkaline hydrogen peroxide
in methanol at 23 °C for 30 min furnished the epoxide 8
as a single isomer in 81% yield after silica gel chroma-
tography.13 Treatment of 8 with diphenyldiselenide and
sodium borohydride in 2-propanol at 23 °C in the absence
of acetic acid furnished the isopropyl ester 9 exclusively
in 90% yield after silica gel chromatography. Compound
9 consists of an important syn-1,3-diol subunit that is
inherent to numerous biologically active natural prod-
ucts.14 Exposure of the epoxide 8 to diphenyldiselenide
and sodium borohydride in 2-propanol at 0 °C in the
presence of acetic acid, however, afforded the â-hydroxy-
lactone 3 in 93% yield after silica gel chromatography.15
The removal of the benzyl protecting group was effected
by catalytic hydrogenation of 3 over Pearlman’s catalyst
in ethyl acetate to furnish the compactin lactone 10
([R]23 +1.8, c 0.18, MeOH; lit.15a [R]23 +1.81, c 0.992,
1
84%) as an oil: IR (film) 3433, 2905, 1641 cm-1; H NMR (400
MHz, CDCl3) δ 2.25-2.28 (m, 2H), 3.40 (dd, 1H, J ) 9.7, 3.3
Hz), 3.52 (dd, 1Η, J ) 9.7, 7.5 Hz), 3.91 (m, 1H), 4.56 (s, 2H),
5.05-5.15 (m, 2H), 5.88 (m, 1H), 7.29-7.40 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 37.9, 69.7, 73.3, 73.9, 117.6, 127.7, 128.4,
134.2, 137.9; MS (CI) m/z 193 (M+ + H).
(R)-1-(Ben zyloxy)-4-p en ten -2-oyl a ceta te [6] a n d (S)-1-
(Ben zyloxy)-4-p en ten -2-ol [(+)-5]. To a stirred solution of
alcohol (()-5 (2.35 g, 12.2 mmol) in a mixture of isopropenyl
acetate (60 mL) and 1,2-dimethoxyethane (60 mL) was added
immobilized lipase PS-30 (2.3 g). The resulting mixture was
stirred at 37 °C for 36 h. The mixture was cooled to 23 °C and
filtered. After removal of the solvent under reduced pressure,
silica gel chromatography (5% EtOAc in hexanes) afforded the
ester 6 (1.45 g, 50%): [R]23D -5.43 (c 3.13, CHCl3); IR (film) 2920,
2861, 1739, 1372, 1239 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.06
(s, 3H), 2.37-2.41 (m, 2H), 3.52 (d, 2H, J ) 4.8 Hz), 4.54 (ABq,
2H, ∆νAB) 28.9, J ) 12.1 Hz), 5.07-5.11 (m, 3H), 5.69 (m, 1H),
7.29-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 21.2, 35.4, 70.5,
71.9, 73.1, 118.0, 127.6, 127.7, 128.4, 133.2, 138.0, 170.6.
Optically pure alcohol (+)-5 (1.03 g, 44%): [R]23 +2.08 (c 1.25,
D
23
CHCl3); lit.10 [R]D +1.96 (c 2.3, CHCl3); MS (CI) m/z 193 (M+
+ H).
(R)-1-(Ben zyloxy)-4-p en ten -2-ol [(-)-5]. To a stirred solu-
tion of ester 6 (1.25 g, 5.4 mmol) in THF (5 mL) and H2O (20
mL) was added LiOH‚H2O (0.45 g, 18.8 mmol). The solution was
stirred at room temperature for 12 h and was quenched by
saturated NH4Cl (30 mL). The mixture was concentrated under
reduced pressure, and the residue was extracted with EtOAc (2
× 50 mL) and dried over anhydrous Na2SO4. The solvent was
D
D
MeOH).
In conclusion, lipase PS-catalyzed acylation and ring-
closing olefin metathesis strategy provides convenient
access to the lactone moiety of compactin in optically
active form. Chemoselective reduction of the epoxylactone
to the 1,3-diol subunit and the hydroxylactone unit is also
removed in vacuo to give the pure alcohol (918 mg, 90%): [R]23
-2.20 (c 2.64, CHCl3).
D
(S)-1-(Ben zyloxy)-4-p en ten -2-oyl p-Nitr oben zoa te. To a
stirred solution of the alcohol (-)-5 (482 mg, 2.51 mmol),
triphenylphosphine (3.29 g, 12.6 mmol), and p-nitrobenzoic acid
(1.84 g, 11.0 mmol) in dry benzene (80 mL) at 23 °C was added
dropwise diethylazodicarboxylate (1.94 mL, 12.6 mmol). After
12 h, the mixture was concentrated in vacuo, and the residue
was purified by silica gel chromatography (2.5% EtOAc in
(9) (a) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017.
(b) Mitsunobu, O. Synthesis 1981, 1 and references therein.
(10) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1997, 75, 12.
(11) For an excellent recent review, see: R. H. Grubbs, S. Chang,
Tetrahedron 1998, 54, 4413 and references therein.
(12) (a) Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J .; van Delft,
F. L. Angew. Chem., Int. Ed. Engl 1998, 37, 1874. (b) Ghosh, A. K.;
Cappiello, J .; Shin, D. Tetrahedron Lett. 1998, 39, 4651. (c) Cossy, J .;
Bauer, D.; Bellosta, V. Tetrahedron Lett. 1999, 40, 4187 and references
therein.
hexanes) to give the ester (786 mg, 91%): [R]23 +3.51 (c 2.51,
D
CHCl3); IR (film) 1724, 1526, 1348, 1273, 1103 cm-1; H NMR
1
(400 MHz, CDCl3) δ 2.52-2.57 (m, 2H), 3.68 (d, 2H, J ) 4.4 Hz),
4.57 (ABq, 2H, ∆νAB ) 28.9, J ) 12.2 Hz), 5.08 (dd, 1H, J )
10.1, 0.8 Hz), 5.14 (dd, 1H, J ) 17.1, 1.6 Hz), 5.39 (m, 1H), 5.79
(m, 1H), 7.29-7.32 (m, 5H), 8.24 (ABq, 4H, ∆νAB) 35.0, J ) 7.0
Hz); 13C NMR (100 MHz, CDCl3) δ 35.4, 70.4, 73.2, 73.6, 118.6,
123.5, 127.6, 127.8, 128.4, 130.8, 132.7, 135.8, 137.8, 150.5, 164.2.
Con ver sion of p-Nitr oben zoa te to (S)-1-(Ben zyloxy)-4-
p en ten -2-ol [(+)-5]. To a stirred solution of the above ester (761
(13) (a) Miyashita, M.; Suzuki, T.; Yoshikoshi, A. Tetrahedron Lett.
1987, 28, 4293. (b) Miyashita, M.; Hoshino, M.; Suzuki, T.; Yoshikoshi,
A. Chem. Lett. 1988, 507.
(14) Oishi, T.; Nakata, T. Synthesis 1990, 635.
(15) (a) Takano, S.; Shimazaki, Y.; Sekiguchi, Y.; Ogasawara, K.
Synthesis 1989, 539. (b) Hirota, K.; Onogi, S.; Maki, Y. Chem. Pharm.
Bull. J pn. 1991, 39, 2702. (c) McCague, R.; Olivo, H. F.; Roberts, S.
M. Tetrahedron Lett. 1993, 34, 3785.

Notes
J . Org. Chem., Vol. 65, No. 15, 2000 4781
mg, 2.22 mmol) in THF (20 mL) and H2O (80 mL) was added
LiOH‚H2O (326 mg, 7.8 mmol). The solution was stirred at room
temperature for 4 h and was quenched by saturated NH4Cl (30
mL). The mixture was concentrated under reduced pressure, and
the residue was extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried over anhydrous Na2SO4. The
solvent was removed in vacuo to give pure alcohol (+)-5 (412
m/z 235 (M+ + H); HRMS (EI) m/z calcd for C13H14O4 (M+)
234.0892, found 234.0883.
(3R,5S)-6-Ben zyloxy-3,5-d ih yd r oxyh exa n oic Acid Iso-
p r op yl Ester [9]. To a stirred suspension of diphenyl diselenide
(1.58 g, 5.06 mmol) in iPrOH (30 mL) was added NaBH4 (383
mg, 10.1 mmol) at 23 °C. The resulting mixture was stirred for
1 h, and a solution of epoxy lactone 8 (790 mg, 3.37 mmol) in
iPrOH (10 mL) was added dropwise. After stirring for an
additional 1 h, the mixture was diluted with EtOAc (30 mL),
and the organic layer was washed with brine and dried over
MgSO4. Evaporation of the solvent under reduced pressure
provided a residue that was purified by silica gel chromatogra-
phy (50% EtOAc in hexanes as the eluent) to give the pure ester
9 (891 mg, 90%) as a white solid (mp 56-57 °C): [R]23D -12.8 (c
mg, 97%): [R]23 +2.16 (c 2.59, CHCl3).
D
(S)-1-(Ben zyloxy)-4-p en ten -2-ol Acr yloyl Ester [4]. To a
stirred solution of alcohol (+)-5 (886 mg, 4.61 mmol) and
4-(dimethylamino)pyridine (56 mg, 0.46 mmol) in dichloro-
methane (60 mL) was added triethylamine (1.93 mL, 13.8 mmol).
The mixture was cooled to -15 °C, and acryloyl chloride (0.56
mL, 6.9 mmol) was added slowly. After stirring for 30 min, the
reaction was quenched with aqueous NaHCO3 solution. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and evaporated under reduced
pressure. Silica gel chromatography (5% EtOAc in hexanes) gave
the ester 4 as an oil (850 mg, 75%): [R]23D +1.58 (c 1.27, CHCl3);
1.92, CHCl3); IR (film) 3411, 2982, 2910, 1709, 1453, 1375 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.24 (d, 6H, J ) 6.4 Hz), 1.60-
1.66 (m, 2H), 2.42-2.47 (m, 2H), 3.42-3.45 (m, 2H), 4.07 (m,
1H), 4.27 (m, 1H), 4.56 (s, 2H), 5.05 (m, 1H), 7.29-7.37 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 21.8, 38.9, 41.8, 68.2, 68.3, 70.5,
73.4, 74.1, 127.8, 127.8, 128.5, 137.9, 172.0; HRMS (EI) m/z calcd
for C16H24O5 (M+) 296.1624, found 296.1639.
IR (film) 3068, 3031, 2906, 2863, 1724, 1630, 1405, 1269 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.39-2.49 (m, 2H), 3.58 (d, 2H, J
) 4.9 Hz), 4.55 (ABq, 2H, ∆νAB ) 28.4, J ) 12.4 Hz), 5.06 (dd,
1H, J ) 10.5, 1.4 Hz), 5.10 (dd, 1H, J ) 17.5, 1.4 Hz), 5.17 (m,
1H), 5.74 (m, 1H), 5.83 (dd, 1H, J ) 10.5, 1.6 Hz), 6.14 (dd, 1H,
J ) 17.5, 10.5 Hz), 6.42 (dd, 1H, J ) 17.5, 1.6 Hz), 7.28-7.37
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 35.3, 70.4, 72.0, 73.1,
118.0, 127.5, 127.6, 128.3, 128.5, 130.7, 133.1, 137.9, 165.6; MS
(CI) m/z 247 (M+ + H); HRMS (EI) m/z calcd for C15H18O3 (M+)
246.1256, found 246.1251.
(4R,6S)-6-(Ben zyloxy)m et h yl-4-h yd r oxy-t et r a h yd r o-2-
p yr on e [3]. To a stirred suspension of diphenyl diselenide (150
mg, 0.48 mmol) in 2-propanol (5 mL) was added NaBH4 (36 mg,
0.96 mmol) at 23 °C. The resulting mixture was stirred for 2
min, and AcOH (0.13 mL, 2.24 mmol) was added. After stirring
for an additional 5 min, the mixture was cooled to 0 °C, and a
solution of the epoxy lactone 8 (74.4 mg, 0.32 mmol) in iPrOH
(4 mL) was added dropwise to the mixture. The resulting
mixture was stirred for 30 min at 0 °C and then diluted with
EtOAc (30 mL). The organic layer was washed with brine and
dried over MgSO4. Evaporation of the solvent under reduced
pressure gave a residue that was purified by silica gel chroma-
tography (70% EtOAc in hexanes as the eluent) to furnish 3 (70
(S)-6-Ben zyloxym eth yl-5,6-d ih yd r o-2-p yr on e [7]. To a
stirred solution of ester 4 (694 mg, 2.82 mmol) in dichloro-
methane (180 mL) was added titanium isopropoxide (0.25 mL,
0.85 mmol). The resulting mixture was heated at 40 °C for 1 h,
and then Grubbs’ catalyst (230 mg, 0.28 mmol) dissolved in
dichloromethane (10 mL) was added dropwise to the mixture.
The mixture was heated at 40 °C for 15 h. After this period, the
solution was cooled to room temperature and concentrated under
reduced pressure. The residue was purified by silica gel chro-
matography (30% EtOAc in hexanes) to give the lactone 7 (562
mg, 93%) as a colorless oil: [R]23 +6.8 (c 0.4, CHCl3); IR (film)
D
3423, 2920, 2867, 1720 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.90-
1.96 (m, 2H), 2.55-2.66 (m, 2H), 3.59 (dd, 1H, J ) 10.7, 4.4 Hz),
3.68 (dd, 1H, J ) 10.7, 3.7 Hz), 4.34 (m, 1H), 4.55 (s, 2H), 4.84
(m, 1H), 7.26-7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 31.8,
38.4, 62.1, 71.6, 73.4, 75.2, 127.6, 127.7, 128.4, 137.6, 170.9;
HRMS (FAB) m/z calcd for C13H17O4 (M+ + H) 237.1127, found
237.1123.
mg, 91%) as an oil: [R]23 -116 (c 1.3, CHCl3); IR (film) 3061,
D
3031, 2913, 2867, 1724, 1386, 1247 cm-1
;
1H NMR (400 MHz,
CDCl3) δ 2.37-2.60 (m, 2H), 3.70 (d, 2H, J ) 4.8 Hz), 4.58-
4.63 (m, 3H), 6.02 (ddd, 1H, J ) 9.8, 2.9, 1.0 Hz), 6.89 (ddd, 1H,
J ) 9.8, 5.9, 2.5 Hz), 7.29-7.36 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 26.1, 70.7, 73.6, 76.5, 121.1, 127.6, 127.8, 128.4, 137.6,
144.8, 163.6; HRMS (EI) m/z calcd for C13H14O3 (M+) 219.1021,
found 219.1004.
(4R ,6S )-4-H y d r o x y -6-h y d r o x y m e t h y lt e t r a h y d r o -2-
p yr on e [10]. To a stirred solution of the benzyl ether 3 (40.8
mg, 0.17 mL) in EtOAc (3 mL) containing 5 drops of CHCl3 was
added Pd(OH)2 (6.9 mg); the resulting solution was placed under
a H2 balloon and stirred at 23 °C for 5 h. The mixture was
filtered through Celite, and the filtrate was evaporated under
reduced pressure. The residual oil was purified by silica gel
chromatography (EtOAc) to give pure 10 (17.2 mg, 70%) as a
colorless oil: [R]23 +1.8 (c 0.18, MeOH); lit.15a [R]23 +1.81 (c
(3R,4R,6S)-6-(Ben zyloxy)m et h yl-3,4-ep oxy-t et r a h yd r o-
2-p yr on e [8]. To a stirred solution of the R,â-unsaturated
lactone 7 (368 mg, 1.69 mmol) in MeOH (15 mL) was added 30%
aqueous H2O2 (0.65 mL, 5.69 mmol) and 6 N aqueous NaOH
(0.17 mL, 1 mmol) at 23 °C. After stirring for 1 h, the mixture
was diluted with Et2O (50 mL) and H2O (20 mL), and the
solution was acidified to pH 3-4 by addition of concentrated HCl.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were
washed with brine, dried over MgSO4, and evaporated under
reduced pressure, and the residual oil in benzene (15 mL) was
heated at reflux with azeotropic removal of water. After removal
of the solvent under reduced pressure, the residue was purified
by silica gel chromatography (30% EtOAc in hexanes as the
eluent) to give pure 8 (342 mg, 81%) as colorless oil: [R]D23 +46.7
D
D
0.992, MeOH); IR (film) 3377, 2930, 1712 cm-1
;
1H NMR (400
MHz, CDCl3) δ 1.90-2.04 (m, 4H), 2.68-2.76 (m, 2H), 3.68 (dd,
1H, J ) 12.4, 4.6 Hz), 3.93 (dd, 1H, J ) 12.4, 2.8 Hz), 4.48 (m,
1H), 4.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 31.3, 38.5, 62.7,
64.5, 76.2, 169.6; MS (CI) m/z 147 (M+ + H); HRMS (EI) m/z
calcd for C6H9O3 (M+ - OH) 129.0552, found 129.0545.
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health (GM 55600) is
gratefully acknowledged.
1
(c 1.3, CHCl3); IR (film): 2924, 2866, 1743 cm-1; H NMR (400
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3-10. This material is available free
of charge via the Internet at http://pubs.acs.org.
MHz, CDCl3) δ 2.21 (m, 1H), 2.35 (m, 1H), 3.54-3.64 (m, 3H),
3.68 (m, 1H), 4.59 (ABq, 2H, ∆νAB ) 17.9, J ) 12.0 Hz), 4.65 (m,
1H), 7.28-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 25.7, 49.0,
52.0, 70.4, 73.0, 73.4, 127.6, 127.8, 128.4, 137.5, 167.2; MS (CI)
J O000528M