Total Synthesis and Absolute Stereochemistry of Pentenocin B, a Novel Interleukin-1β Converting Enzyme Inhibitor

Article abstract of DOI:10.1021/jo035430x

Four possible diastereomers of pentenocin B were synthesized in a stereocontrolled manner, and the first total synthesis of a natural enantiomer of (+)-pentenocin B unequivocally established the absolute stereochemistry to be 4S,5R,6R.

Full text of DOI:10.1021/jo035430x

Tota l Syn th esis a n d Absolu te
Ster eoch em istr y of P en ten ocin B, a Novel
In ter leu k in -1â Con ver tin g En zym e
In h ibitor
Tsutomu Sugahara,* Hayato Fukuda, and
Yoshiharu Iwabuchi*
F IGURE 1. Four possible diastereomers of pentenocin B.
Graduate School of Pharmaceutical Sciences, Tohoku
University, Aobayama, Sendai 980-8578, J apan
natural pentenocin B. Because there are four possible
diastereomers of pentenocin B but eight stereoisomers
in total (including enantiomeric pairs) (Figure 1), we
synthesized the four possible racemic pentenocin B
diastereomers 3-6 to elucidate the relative configuration
of pentenocin B using racemic ketodicyclopentadiene
(KDP)4 7 as the common starting material.
iwabuchi@mail.pharm.tohoku.ac.jp
Received September 30, 2003
Abstr a ct: Four possible diastereomers of pentenocin B were
synthesized in a stereocontrolled manner, and the first total
synthesis of a natural enantiomer of (+)-pentenocin B
unequivocally established the absolute stereochemistry to
be 4S,5R,6R.
Thus, the 1,4-addition of vinylmagnesium bromide to
7 from its convex face afforded the vinyl ketone 8 in 91%
yield (Scheme 1). The vinyl ketone was transformed into
1,4-diketone by Wacker oxidation5 and was then oxidized
by DDQ6 to afford 9 in 71% yield for the two steps. The
reduction of 9 by DIBALH afforded the 1,4-diols 10a and
10b in 97% yield as an 86:14 mixture of diastereomers
at the stereogenic center on the side-chain alcohol, which
was fractionated by silica gel column chromatography.7
The major alcohol 10a was transformed into bromoether
by NBS, followed by the protection of the remaining side-
chain alcohol by MOMCl affording the MOM-ether 11a
in 63% yield for the two steps. The diastereoselective
dihydroxylation of 11a with OsO4 from its convex face
and the following treatment of the diols with 2,2-
dimethoxypropane afforded the acetonide 12a in 74%
yield for the two steps. The treatment of 12a with zinc
restored olefin-alcohol functionalities. The subsequent
oxidation of alcohol with PDC afforded the ketone 13a
in 74% yield for the two steps. The retro Diels-Alder
reaction of 13a was performed at 280 °C for 15 min in
Ph2O8 to afford the cyclopentenone 14a in 93% yield.
Although hydrolytic removal of the acetonide moiety
under conventional conditions, i.e., concentrated HCl in
MeOH or 5 N HCl in THF, suffered from complex
destructive reactions, the treatment of 14a with 90%
TFA9 at 0 °C for 2 h allowed us to isolate (()-pentenocin
B diastereomer 3 in a yield of 30%.
Interleukin-1â converting enzyme (ICE), also known
as caspase-1, is a unique cystein protease that cleaves
the inactive precursor of IL-1â into biologically active IL-
1â, a key mediator in the pathogenesis of acute and
chronic inflammation.1 Evidence that ICE is an excellent
target for therapeutic intervention has spurred much
research interest directed toward discovery of novel
small-molecule inhibitors.2
Pentenocins A (1) and B (2) were isolated by Oh mura
and co-workers in 1999 from the culture broth of Tricho-
derma hamatum FO-6903 as the active agent against
recombinant human ICE. The connectivity of novel,
highly oxygenated cyclopentenones containing quater-
nary centers were determined by detailed NMR spectral
analysis; however, the relative and absolute configura-
tions of these cyclopentenones have not been elucidated.3
In this paper, we report on the syntheses of the four
possible racemic pentenocin B diastereomers 3-6 and the
first synthesis of (+)-pentenocin B, as well as the deter-
mination of the relative and absolute configurations of
The minor alcohol 10b was transformed to (()-pen-
tenocin B diastereomer 4 by the same procedures as those
for the major alcohol 10a to (()-pentenocin B diastereo-
mer 3.
* Corresponding author.
(1) (a) Thornberry, N. A.; Bull, H. G.; Calaycay, J . R.; Chapman, K.
T.; Howard, A. D.; Kostura, M. J .; Miller, D. K.; Molineaux, S. M.;
Weidner, J . R.; Aunins, J .; Elliston, K. O.; Ayala, J . M.; Casano, F. J .;
Chin, J .; Ding, G. J .-F.; Egger, L. A.; Gaffney, E. P.; Limjuco, G.;
Palyha, O. C.; Raju, S. M.; Ronando, A. M.; Salley, J . P.; Yamin, T.-T.;
Lee, T. D.; Shively, J . E.; MacCross, M.; Mumford, R. A.; Schmidt, J .
A.; Tocci, M. J . Nature 1992, 356, 768. (b) Dinarello, C. A.; Wolff, S.
M. N. Engl. J . Med. 1993, 328, 6.
(2) (a) Koizumi, F.; Matsuda, Y.; Nakanishi, S. J . Antibiot. 2003,
56, 464. (b) Shahripour, A. B.; Plummer, M. S.; Lunney, E, A.; Sawyer,
T. K.; Stankovic, C. J .; Connolly, M. K.; Rubin, J . R.; Walker, N. P. C.;
Brady, K. D.; Allen, H. J .; Talanian, R. V.; Wong, W. W.; Humblet, C.
Bioorg. Med. Chem. Lett. 2001, 11, 2779. (c) Tanaka, T.; Tsukuda, E.;
Uosaki, Y.; Matsuda, Y. J . Antibiot. 1996, 49, 1085. (d) Tsukuda, E.;
Tanaka, T.; Ochiai, K.; Kondo, H.; Yoshida, M.; Agatsuma, T.; Saitoh,
Y.; Teshiba, S.; Matsuda, Y. J . Antibiot. 1996, 49, 333.
(4) Stork, G.; Nelson, G. L.; Rouessac, F.; Gringore, O. J . Am. Chem.
Soc. 1971, 93, 3091.
(5) Tsuji, J . Synthesis 1984, 369.
(6) Chai, K.-B.; Sampson, P. J . Org. Chem. 1993, 58, 6807.
(7) Although the stereochemistry of the side-chain alcohol of 10a
and 10b generated by the DIBALH reduction of 9 was assigned
tentatively as depicted in Scheme 1, the structure of the major alcohol
10a was confirmed by applying the modified Mosher method13 to the
advanced chiral synthetic intermediate (+)-22a and X-ray structure
of (+)-12a , as shown in Scheme 3.
(8) Takano, S.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1992,
33, 1909.
(3) (a) Matsumoto, T.; Ishiyama, A.; Yamaguchi, Y.; Masuma, R.;
Ui, H.; Shiomi, K.; Yamada, H.; Oh mura, S. J . Antibiot. 1999, 52, 754;
(b) 2003, 56, C2.
(9) (a) Verheyden, J . P. H.; Richardson, A. C.; Bhatt, R. S.; Grant,
B. D.; Fitch, W. L.; Moffatt, J . D. Pure Appl. Chem. 1978, 50, 1363. (b)
Pohmakotr, M.; Popuang, S. Tetrahedron Lett. 1991, 32, 275.
10.1021/jo035430x CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/31/2004
1744
J . Org. Chem. 2004, 69, 1744-1747

SCHEME 1a
a
Reagents and conditions: (a) vinyl magnesium bromide, CuI, THF, -30 °C, 91%; (b) O2, PdCl2, CuCl, DMF-H2O, 45 °C, 18 h, 97%;
(c) DDQ, p-TsOH, dioxane, reflux, 73%; (d) DIBALH, THF, -78 °C, 97%; (e) NBS, THF, -15 °C, 76%; (f) MOMCl, iPr2NEt, CH2Cl2, rt,
83%; (g) OsO4 (cat.), NMO, THF-H2O, 80%; (h) 2,2-dimethoxypropane, p-TsOH (cat.), 92%; (i) Zn, MeOH-AcOH, 80 °C, quant; (j) PDC,
CH2Cl2, 74%; (k) Ph2O, 280 °C, 15 min, 93%; (l) 90% TFA, 0 °C, 2 h, 30%.
SCHEME 2a
a
Reagents and conditions: (a) NBS, THF, -15 °C; (b) MnO2, CH2Cl2, 73% (2 steps); (c) 30% H2O2, 40% Triton B, MeOH, 0 °C, 97%; (d)
NH2NH2‚H2O, THF-MeOH, reflux, 95%; (e) Dess-Martin periodinane, CH2Cl2, 81%; (f) DIBALH, THF, -78 °C, 94%; (g) MOMCl, iPr2NEt,
CH2Cl2, 91%; (h) OsO4 (cat.), NMO, THF-H2O, quant; (i) 2,2-dimethoxypropane, p-TsOH (cat.), 85%; (j) Zn, MeOH-AcOH, 50 °C, 87%;
(k) PDC, CH2Cl2, 89%; (l) Ph2O, 280 °C,15 min, quant; (m) 90% aqueous TFA, 0 °C, 3 h, 35%.
To synthesize (()-pentenocin B diastereomer 5 or 6,
the mixture of the 1,4-diols 10a and 10b was treated with
NBS. The subsequent oxidation of the remaining side-
chain alcohol with MnO2 afforded the R,â-unsaturated
ketone 15 in 73% yield for the two steps (Scheme 2). The
epoxidation of 15 was performed with 30% H2O2 and 40%
Triton B from its convex face to afford the epoxy-ketone
16 in 97% yield, which was then transformed to an
inseparable 1:1 E,Z-mixture of the allylic alcohols 17a
and 17b with a Wharton rearrangement10 in 95% yield.
The Dess-Martin periodinane oxidation11 of 17a and 17b
afforded an E,Z-mixture of the R,â-unsaturated ketones
18a and 18b in 81% yield, respectively, which were
separated by silica gel column chromatography. The
stereochemistries of the E-olefin 18a and the Z-olefin 18b
1
were determined by H NMR analysis and NOE experi-
ments. The reduction of 18a by DIBALH from its convex
face afforded an allylic alcohol, which was then protected
as the MOM-ether 19a in 86% yield for the two steps.
The diastereoselective dihydroxylation of 19a with OsO4
(10) (a) Takano, S.; Inomata, K.; Takahashi, M.; Ogasawara, K.
Synlett 1991, 636. (b) Yu, W.; J in, Z. J . Am. Chem. Soc. 2002, 124,
6576.
(11) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
J . Org. Chem, Vol. 69, No. 5, 2004 1745

SCHEME 3a
a
Reagents and conditions: (a) vinylmagnesium bromide, CuI, THF, -30 °C, 91%; (b) O2, PdCl2, CuCl, DMF-H2O, 50 °C, 84%; (c)
DDQ, p-TsOH, dioxane, reflux, 73%; (d) DIBALH, THF, -78 °C, 77%; (e) NBS, THF, -15 °C, 97%; (f) (R)- or (S)-MTPACl, Et3N, DMAP,
i
CH2Cl2; (g) MOMCl, Pr2NEt, CH2Cl2, rt, 91%; (h) OsO4 (cat.), NMO, THF-H2O, 61%; (i) 2,2-dimethoxypropane, p-TsOH (cat.), CH2Cl2,
75%; (j) Zn, MeOH-AcOH, 50°C, quant; (k) Swern oxidation, -78 °C to rt, 99%; (l) Ph2O, 280 °C, 15 min, 98%; (m) 90% TFA, 0 °C, 2 h,
42%.
from its convex face and the subsequent protection of
diols as the acetonide afforded 20a in 85% yield for the
two steps. The treatment of 20a with zinc, followed by
PDC oxidation of the regenerated alcohol, afforded the
ketone 21a in 77% yield for the two steps. The retro
Diels-Alder reaction of the ketone 21a at 280 °C in Ph2O
afforded the cyclopentenone in a quantitative yield, which
was then treated with 90% TFA, affording (()-pentenocin
B diastereomer 5 in approximately 35% yield. The
Z-isomer 18b was transformed to (()-pentenocin B 6 by
the same procedures as those for 18a to 5.
of the secondary alcohol of 22a . 22a was subsequently
transformed into the protected trihydroxy bromoether
(+)-12a , [R]27 +4.6 (c 1.02, CHCl3), via the same three
D
steps used in the conversion of (()-10a to (()-12a by the
previous racemic synthesis. The X-ray crystal structure
of (+)-12a confirmed that the absolute configuration of
the side-chain alcohol was (R)-stereochemistry as deter-
mined by the modified Mosher method (see Supporting
Information).
The treatment of (+)-12a with zinc, followed by the
Swern oxidation of the regenerated alcohol, afforded the
ketone (-)-13a , [R]27 -228.1 (c 0.56, CHCl3). The retro
All of the pentenocin B diastereomers 3-6 were found
D
1
to have distinct H and 13C NMR spectra (see Supporting
Diels-Alder reaction of (-)-13a , followed by the depro-
tection of the resulting (-)-14a , afforded (+)-pentenocin
Information). Spectral data for one of the diastereomers,
compound 3, were confirmed to be identical with those
of natural pentenocin B,3 thereby establishing the rela-
tive configuration of pentenocin B as 4R*,5S*,6S*.
Having clarified the diastereoselective route to pen-
tenocin B diastereomers, we then conducted the enantio-
selective synthesis of such compounds to determine the
absolute stereochemistry of natural pentenocin B. (-)-
KDP (7)12 was transformed to the major diol (+)-10a ,
[R]28D +154.2 (c 0.15, CHCl3), and the minor diol (+)-10b,
B (3), [R]D +101 (c 1.0, H2O) (natural:14 [R]D +76 (c 1.0,
30
H2O ).
In conclusion, we have realized the first enantiocon-
trolled synthesis of (+)-pentenocin B and determined its
absolute stereochemistry to be 4S,5R,6R as shown by (+)-
3. Synthetic studies of pentenocin A (1) are now under
way and will be reported in due time.
Exp er im en ta l Section
[R]26 +146.5 (c 0.14, CHCl3), via (-)-8 and (+)-9 as
D
Com p ou n d (+)-22a . To a stirred solution of (+)-10a (201 mg,
1.05 mmol) in THF (5 mL) was added N-bromosuccinimide (280
mg, 1.57 mmol) at -15 °C. The reaction mixture was stirred at
-15 °C under dark for 15 min, quenched by addition of saturated
aqueous Na2S2O3 solution, and extracted with ether. The organic
extract was washed with brine, dried (MgSO4), and concentrated.
The residue was purified by silica gel column chromatography
(EtOAc-hexane 1:2) to give (+)-22a (274 mg, 1.01 mmol, 97%)
shown in Scheme 3 with the same procedures as those
described for the synthesis of the racemic pentenocin B
3. The major diol (+)-10a was transformed to the bro-
moether (+)-22a , [R]27D +87.7 (c 0.59, CHCl3), using NBS.
The absolute configuration of the remaining secondary
alcohol in 22a was determined using the modified Mosher
method.13 Thus, 22a was converted to both (R)- and (S)-
MTPA esters 22b and 22c, respectively. Selected 1H
NMR spectral data (that of CDCl3) indicated chemical
shift differences consistent with the (R)-stereochemistry
as a colorless oil: [R]27 +87.7 (c 0.59, CHCl3); IR (neat) 3390
D
cm-1; 1H NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 4.68 (dd, 1H, J
) 5.6, 2.4 Hz), 4.62 (d, 1H, J ) 4.9 Hz), 4.36 (q, 1H, J ) 6.6 Hz),
3.97 (d, 1H, J ) 2.2 Hz), 3.13 (ddd, 1H, J ) 8.8, 5.4, 5.3 Hz),
3.03 (dd, 1H, J ) 8.8, 3.9 Hz), 2.72-2.69 (m, 1H), 2.50 (s, 1H),
2.40 (d, 1H, J ) 11.0 Hz), 1.96 (d, 1H, J ) 11.0 Hz), 1.33 (d, 3H,
(12) (a) Ogasawara, K. Pure Appl. Chem. 1994, 66, 2119. (b)
Sugahara, T.; Ogasawara, K. Synlett 1999, 419 and references therein.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
(14) Private communication with Professor S. Oh mura.
1746 J . Org. Chem., Vol. 69, No. 5, 2004

J ) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 151.4, 127.9, 91.0,
84.9, 66.7, 55.0, 51.8, 50.3, 47.9, 47.2, 40.2, 22.0; MS (EI) m/z
191 (M+ - Br), 43 (100%); HRMS (EI) m/z calcd for C12H15O2
(M+ - Br) 191.1071, found 191.1052.
DMSO (0.165 mL, 2.32 mmol) dropwise at -78 °C. After 10 min,
the alcohol (60 mg, 0.194 mmol) in CH2Cl2 (1 mL) was added to
the solution. The mixture was stirred at -78 °C for 30 min, and
triethylamine (0.486 mL, 3.48 mmol) was added dropwise to the
reaction mixture. The mixture was stirred at room temperature
for 10 min and extracted with ether. The organic extract was
washed with brine, dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography
(EtOAc-hexane 1:2) to give (-)-13a (59 mg, 0.192 mmol, 99%)
as a colorless crystal: mp 79-80 °C (recrystallized from hexane);
Com p ou n d (+)-11a . To a stirred solution of (+)-22a (274 mg,
i
1.01 mmol) and Pr2NEt (0.88 mL, 5.05 mmol) in CH2Cl2 (5 mL)
was added MOMCl (0.23 mL, 3.03 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 10 h and then
poured into water and extracted with ether. The organic extract
was washed with brine, dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography
(EtOAc-hexane 1:4) to give (+)-11a (290 mg, 0.92 mmol, 91%)
[R]27 -228.1 (c 0.56, CHCl3); IR (Nujol) 1748 cm-1 1H NMR
;
D
(400 MHz, CDCl3) δ 6.21 (dd, 1H, J ) 5.6, 2.9 Hz), 6.15 (dd, 1H,
J ) 5.6, 2.4 Hz), 4.72 (d, 1H, J ) 7.1 Hz), 4.55 (d, 1H, J ) 6.8
Hz), 3.85 (s, 1H), 3.75 (q, 1H, J ) 6.3 Hz), 3.37 (s, 3H), 3.24
(brs, 1H), 3.20-3.17 (m, 1H), 3.04 (brs, 1H), 2.97 (dd, 1H, J )
8.5, 3.7 Hz), 1.62 (d, 1H, J ) 8.3 Hz), 1.49 (d, 1H, J ) 8.3 Hz),
1.47 (s, 3H), 1.37 (d, 3H, J ) 6.3 Hz), 1.25 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 219.0, 138.4, 133.9, 111.1, 95.0, 90.2, 83.8,
74.8, 55.7, 53.2, 52.0, 48.9, 46.1, 45.0, 29.1, 26.6, 15.0; MS (EI)
m/z 308 (M+), 153 (100%); HRMS (EI) m/z calcd for C17H24O5
308.1622, found 308.1646. Anal. Calcd for C17H24O5: C, 66.21;
H, 7.84. Found: C, 66.07; H, 7.70.
as a colorless oil: (+)-11a : [R]30 +145.0 (c 0.17, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 5.85 (d, 1H, J ) 2.2 Hz), 4.66 (dd,
1H, J ) 5.9, 2.4 Hz), 4.62 (d, 1H, J ) 4.9 Hz), 4.59 (s, 2H), 4.29
(q, 1H, J ) 6.6 Hz), 3.96 (d, 1H, J ) 2.2 Hz), 3.37 (s, 3H), 3.12
(ddd, 1H, J ) 8.8, 5.6, 5.4 Hz), 3.01 (dd, 1H, J ) 8.8, 3.9 Hz),
2.69 (ddd, 1H, J ) 5.1, 5.1, 1.2 Hz), 2.50-2.49 (m, 1H), 2.44 (d,
1H, J ) 10.7 Hz), 1.95 (dd, 1H, J ) 10.7, 1.5 Hz), 1.29 (d, 3H, J
) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 148.4, 130.3, 94.2, 91.0,
84.7, 70.5, 55.4, 55.0, 51.3, 50.3, 48.2, 47.1, 40.2, 19.6; MS (EI)
m/z 314 (M+), 45 (100%); HRMS (EI) m/z calcd for C14H19BrO3
314.0517, found 314.0529. Anal. Calcd for C14H19BrO3: C, 53.35;
H, 6.08; Br, 25.35. Found: C, 53.43; H, 6.12; Br, 25.42.
Com p ou n d (-)-14a . A mixture of (-)-13a (35 mg, 0.114
mmol) in Ph2O (1 mL) was heated at reflux for 15 min. After
cooling to room temperature, the reaction mixture was directly
purified by silica gel column chromatography (EtOAc-hexane
1:4) to give (-)-14a (27 mg, 0.112 mmol, 98%) as a colorless oil:
Com p ou n d (+)-12a . To a stirred solution of (+)-11a (70 mg,
0.223 mmol) and 4-methylmolpholine N-oxide (39 mg, 0.334
mmol) in THF (1.5 mL) and H2O (0.5 mL) was added OsO4
(0.197M in THF, 0.227 mL, 0.045 mmol) at room temperature.
The mixture was stirred at room temperature for 4 days,
quenched by addition of saturated aqueous Na2S2O3 solution,
and extracted with CHCl3. The organic extract was washed with
brine, dried (MgSO4), and concentrated. The residue was purified
by silica gel column chromatography (EtOAc-hexane 1:1) to give
the diol (47 mg, 0.135 mmol, 61%) as a colorless oil. A mixture
of the diol (43 mg, 0.123 mmol) and anhydrous p-toluenesulfonic
acid (2.3 mg, 0.013 mmol) in 2,2-dimethoxypropane (0.5 mL) was
stirred at room temperature for 17 h. The reaction mixture was
added to a saturated aqueous NaHCO3 solution and extracted
with ether. The organic extract was washed with brine, dried
(MgSO4), and concentrated. The residue was purified by silica
gel column chromatography (EtOAc-hexane 1:2) to give (+)-
12a (36 mg, 0.093 mmol, 75%) as a colorless crystal: mp 93 °C
(recrystallized from hexane); [R]27D +4.6 (c 1.02, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 4.76 (d, 1H, J ) 6.8 Hz), 4.62 (d, 1H, J )
6.8 Hz), 4.57 (s, 1H), 4.56 (d, 1H, J ) 6.1 Hz), 4.36 (d, 1H, J )
5.9 Hz), 3.68 (q, 1H, J ) 6.3 Hz), 3.61 (d, 1H, J ) 2.2 Hz), 3.35
(s, 3H), 3.16 (ddd, 1H, J ) 9.3, 5.9, 5.4 Hz), 2.87-2.78 (m, 1H),
2.64 (dd, 1H, J ) 9.5, 4.0 Hz), 2.32 (d, 1H, J ) 3.2 Hz), 2.28 (d,
1H, J ) 10.7 Hz), 1.71 (d, 1H, J ) 11.7 Hz), 1.46 (s, 3H), 1.37 (s,
3H), 1.29 (d, 3H, J ) 6.3 Hz); 13C NMR (100 MHz, CDCl3) δ
111.1, 95.4, 95.1, 92.2, 90.6, 89.2, 75.0, 56.3, 55.7, 55.0, 48.4,
47.8, 45.1, 37.6, 29.1, 27.2, 15.9; MS (EI) m/z 373 (M+ - Me),
299 (100%); HRMS (EI) m/z calcd for C16H22BrO5 (M+ - Me)
373.0650, found 373.0626. Anal. Calcd for C17H25BrO5 C, 52.45;
H, 6.47; Br, 20.53. Found: C, 52.25; H, 6.47; Br, 20.81.
[R]26 -10.9 (c 0.90, CHCl3); IR (neat) 1728 cm-1; 1H NMR (400
D
MHz, CDCl3) δ 7.56 (d, 1H, J ) 5.9 Hz), 6.27 (d, 1H, J ) 6.1
Hz), 4.71 (d, 1H, J ) 6.8 Hz), 4.63 (d, 1H, J ) 7.1 Hz), 4.28 (s,
1H), 4.05 (q, 1H, J ) 6.3 Hz), 3.35 (s, 3H), 1.46 (s, 3H), 1.33 (s,
3H), 1.23 (d, 3H, J ) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ
204.0, 161.8, 134.1, 115.6, 95.3, 90.9, 78.4, 73.9, 55.7, 28.3, 28.2,
15.8; MS (EI) m/z 227 (M+ - Me), 45 (100%); HRMS (EI) m/z
calcd for C11H15O5 227.0919, found 227.0917.
(+)-P en ten ocin B (3). A mixture of (-)-14a (33 mg, 0.136
mmol), H2O (0.02 mL), and trifluoroacetic acid (0.2 mL) was
stirred at 0 °C for 2 h. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (EtOAc-
MeOH 9:1) to give (+)-pentenocin B {(+)-3} (9.1 mg, 0.058 mmol,
42%) as a colorless resin: [R]30 +100.8 (c 1.0, H2O) {lit.14 [R]D
D
+76 (c 1.0, H2O)}; IR (neat) 3386, 1678 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 7.48 (d, 1H, J ) 6.1 Hz), 6.15 (d, 1H, J ) 6.1 Hz),
5.32 (d, 1H, J ) 7.3 Hz), 4.90 (s, 1H), 4.83 (d, 1H, J ) 5.1 Hz),
3.91 (d, 1H, J ) 7.3 Hz), 3.69 (qd, 1H, J ) 6.3, 5.6 Hz), 1.12 (d,
3H, J ) 6.3 Hz); 13C NMR (100 MHz, DMSO- d6) δ 208.1, 165.3,
131.6, 78.8, 70.7, 69.2, 18.0; MS (FAB) m/z 159 (MH+).
Ack n ow led gm en t. We are grateful to Professor S.
Oh mura of the Kitasato Institute, Tokyo for providing
the NMR spectral data and the value of the optical
rotation of natural pentenocin B. We thank Taisho
Pharmaceutical Co. J apan for X-ray structural analysis.
We also thank Emeritus Professor K. Ogasawara,
Tohoku University, for helpful discussions.
Com p ou n d (-)-13a . A mixture of (+)-12a (89 mg, 0.229
mmol) and activated Zn (375 mg, 5.73 mmol) in MeOH (2 mL)
and AcOH (0.2 mL) was stirred at 50 °C for 1 h and then filtered
through Celite. The filtrate was poured into saturated aqueous
NaHCO3 solution and extracted with ether. The organic extract
was washed with brine, dried (MgSO4), and concentrated. The
residue was purified by silica gel column chromatography
(EtOAc-hexane 1:2) to give the alcohol (71 mg, 0.229 mmol,
100%) as a colorless crystal. To a stirring solution of oxalyl
chloride (0.10 mL, 1.16 mmol) in CH2Cl2 (2 mL) was added
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all new compounds and experimental procedures,
including ORTEP and crystallographic details for (+)-12a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035430X
J . Org. Chem, Vol. 69, No. 5, 2004 1747