Total synthesis of (±)-scirpene

Article abstract of DOI:10.1021/ol9901164

(Equation presented) The racemate of scirpene, 12,13-epoxytrichothec-9-ene, was synthesized from 3-methoxyacetophenone. The key step in the synthesis is the palladium-mediated ring expansion reaction of the vinylcyclobutanol derivative, prepared via the o

Full text of DOI:10.1021/ol9901164

ORGANIC
LETTERS
1999
Vol. 1, No. 3
517-519
Total Synthesis of (±)-Scirpene
,†
Hideo Nemoto,* Eiki Takahashi, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received June 2, 1999
ABSTRACT
The racemate of scirpene, 12,13-epoxytrichothec-9-ene, was synthesized from 3-methoxyacetophenone. The key step in the synthesis is the
palladium-mediated ring expansion reaction of the vinylcyclobutanol derivative, prepared via the oxidative ring expansion reaction of the
cyclopropylidene. (3S*)-3-[(1S*,6S*)-3-Methyl-9-oxabicyclo[4.3.0]non-2-en-6-yl]-3-methyl-2-methylenecyclo-pentan-1-one formed from the reaction
was converted into (±)-scirpene through the ring opening of tetrahydrofuran part, followed by cyclization for construction of the desired
skeleton.
Trichothecanes have attracted great attention from synthetic
chemists1 because of significant biological activities such as
Scheme 1
antifungal, antibacterial, antiviral, and antitumor activities2
and unique structural features. We have been studying
syntheses of natural products employing key reactions
participating cyclobutanone3 and achieved a total synthesis
of (()-4-deoxyverrucarol, a trichothecane-type sesquiterpe-
noid, by their application.4 As an extension of this study, an
alternative route to a trichothecane has been designed as
shown in Scheme 1. Namely, the synthetic precursor 2 of
12,13-epoxytrichothec-9-ene (1),5,6 scirpene7 could be pre-
pared by the palladium-catalyzed ring expansion reaction of
3. The vinylcyclobutanol 3 would be transformed from the
† Present address: Faculty of Pharmaceutical Sciences, Toyama Medical
and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan.
(1) (a) Kupchan, S. M.; Jarvis, B. B.; Dailey, R. G., Jr.; Bright, W.;
Bryan, R. F.; Shizuri, Y. J. Am. Chem. Soc. 1976, 98, 7092-7093. (b)
Ueno, Y. TrichothecenessChemical, Biological and Toxicological Aspects,
DeVelopments in Food Science 4; American Elsevier: New York, 1983.
(c) Iida, A.; Konishi, K.; Kubo, H.; Tomioka, K.; Tokuda, H.; Nishino, H.
Tetrahedron Lett. 1996, 37, 9219-9220.
cyclobutanone 4, obtainable from 5. We now communicate
a total synthesis of (()-1 based on this strategy.
(2) Ishihara, J.; Nonaka, R.; Terasawa, Y.; Shiraki, R.; Yabu, K.; Kataoka,
H.; Ochiai, Y.; Tadano, K. J. Org. Chem. 1998, 63, 2678-2688 and
references therein.
(3) Nemoto, H.; Fukumoto, K. Synlett 1997, 863-875.
(4) Nemoto, H.; Miyata, J.; Ihara, M. Tetrahedron Lett. 1999, 40, 1933-
1936.
(5) Isolation: Machida, Y.; Nozoe, S. Tetrahedron 1972, 28, 5113-
5117.
(6) Synthesis: (a) Fujimoto, Y.; Yokura, S.; Nakamura. T.; Morikawa,
T.; Tatsuno, T. Tetrahedron Lett. 1974, 2523-2526. (b) Masuoka, N.;
Kamikawa, T. Tetrahedron Lett. 1976, 1691-1694. (c) Hua, D. H.;
Venkataraman, S.; King, R. C.-Y.; Paukstelis, J. V. J. Am. Chem. Soc. 1988,
110, 4741-4748.
10.1021/ol9901164 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

The cyclopropylidene 6, derived from 5, was subjected to
the oxidative ring expansion reaction using m-CPBA to
afford 4 in 84% yield (Scheme 2). Reduction of 4 with
resulting ketone provided the cyclobutanol 12 as a single
stereoisomer (Scheme 3). However, the palladium(II)-medi-
ated ring expansion reaction of 12 to 13 failed, probably due
to the existence of the double bond close to the reaction site.
Scheme 2a
Scheme 3a
a Reagents and conditions: (a) NaBH4, 100%; (b) MOMCl, iso-
Pr2NEt, 100%; (c) TBAF, 99%; (d) DMSO, (COCl)2; Et3N, 96%;
(e) vinylmagnesium bromide, CeCl3, 91%.
The introduction of one carbon unit accompanied by the
transposition of the double bond converted 11, in two steps,
into the tertiary alcohol 14 as a 1:1 stereoisomeric mixture
(Scheme 4). Exposure of 14 to acid produced 15 in a high
yield. Ring-expansion reaction of 16, prepared from 15 in a
stereoselective manner, was examined under various condi-
tions as shown in Table 1.
a Reagents and conditions: (a) cyclopropyltriphenylphosphonium
bromide, NaH, 92%; (b) m-CPBA, NaHCO3, 84%; (c) NaBH4,
100%, (9:1 ds); (d) TBDMSCl, imidazole, 99%; (e) Na, liquid NH3,
EtOH; (CO2H)2, MeOH, 50% of 8 and 16% of 9; (f) CrO3, 3,5-
DMP, 4 Å molecular sieves, 60%; (g) NaBH4, CeCl3‚7H2O, MeOH,
100% (1:1 ds); (h) ethyl vinyl ether, Hg(OCOCF3)2; Et3N-toluene
(1:4 v/v), 200 °C, 74%.
NaBH4 gave a 9:1 mixture of the corresponding alcohols,
the major of which was converted into the TBDMS ether 7.
Birch reduction of 7, followed by acidic and basic treatments,
provided the enone 8 in 50% overall yield together with the
overreduced product 9 in 16% yield. The latter was convert-
ible into 8 in 60% yield by oxidation with CrO3 and 3,5-
dimethylpyrazole.8 Introduction of an alkyl group at the
â-position of the enone 9 was performed in two steps
although the diastereoselectivity was unsatisfactory. Thus,
reduction of 9 with NaBH4 and CeCl3‚7H2O in MeOH
afforded a 1:1 mixture of the alcohols, which was trans-
formed into the aldehydes 10, via [3,3]-sigmatropic rear-
rangement. The two stereoisomers 10a and 10b were
separated by column chromatography on silica gel.
Scheme 4a
After transformation of the required stereoisomer 10a9 into
the MOM ether 11, the deprotection of the TBDMS group,
followed by oxidation and addition of vinyl group to the
a Reagents and conditions: (a) CrCO3, 3,5-DMP, 4 Å molecular
sieves, 82%; (b) MeLi, 100% (1.2:1 ds); (c) dilute HCl, 91%; (d)
DMSO, (COCl)2; Et3N, 93%; (e) vinylmagnesium bromide, CeCl3,
97%.
(7) Anderson, W. K.; Lee, G. E. J. Med. Chem. 1980, 23, 96-97.
(8) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978,
43, 2057-2059.
(9) Stereochemistries of two isomers were tentatively assigned by NOE
experiments after their conversions into 27 and 28, respectively.
The desired reaction did not proceed with Pd(OAc)2 (entry
1), but the target compound 17 was obtained by the use of
PdCl2(MeCN)2 (entry 2). It is interesting that the acetyl-
cyclobutene 18 was produced as a byproduct, although the
mechanism of the reaction is obscure. The yield of 17 was
improved to 62% by the presence of an oxidizing agent in
dimethylacetamide (DMA) (entry 3).10 It is noteworthy that
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Org. Lett., Vol. 1, No. 3, 1999

Table 1. Reaction of 16 with Pd(II)
the reaction has taken place by a catalytic amount of PdCl2-
(MeCN)2 in the presence of p-quinone or CuCl2 (entries 4
or 5).
With the ring-expanded compound in hand, the ring
opening of the tetrahydrofuran part was then investigated.
Fortunately, the process could be performed after reduction
of the carbonyl group of 17. Namely, 17 was reduced with
DIBALH to give a 1.5:1 epimeric mixture of 21 (Scheme 5).
Treatment of 21 with TBDMSOTf in the presence of 2,6-
lutidine caused the ring-opening reaction to afford 22.
Subsequent removal of one of the TBDMS groups of 22
provided, in 95% overall yield for two steps, a 1.5:1 mixture
of 23,11 separable by chromatography. Protection of the
primary hydroxyl group of the major product 23 with a
pivaloyl group, followed by the action of 10-camphorsulfonic
acid (CSA) in MeOH, quantitatively furnished the tricyclic
compound 24. Removal of one carbon unit was carried out
in three steps through the aldehyde 25 to afford 26, spectral
data of which were consistent with the reported ones.6c Since
26 had been converted into scirpene (1) by epoxidation with
m-CPBA,6c the total synthesis of (()-1 has been accomplished.
OL9901164
Scheme 5a
(10) Procedure for the Ring Expansion Reaction (Table 1, entry 3).
To a stirred mixture of 16 (24.9 mg, 0.100 mmol) and p-quinone (27.7 mg,
0.201 mmol) in DMA (3 mL) was added PdCl2(MeCN)2 (26.0 mg, 0.100
mmol), and the mixture was stirred for 0.5 h at ambient temperature. After
addition of MgSO4 and Celite, filtration followed by concentration of the
filtrate gave a residue, which was chromatographed on silica gel. Elution
with hexanes-AcOEt (9:1 v/v) provided 17 (15.3 mg, 62%), 18 (8.4 mg,
34%), and 19 (1.0 mg, 4%). 17: IR (neat) 1710 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.29 (3H, s), 1.71 (3H, s), 1.62-1.86 (5H, m), 2.03-2.26 (3H,
m), 2.38-2.46 (2H, m), 3.69 (1H, dd, J ) 8.9 Hz), 3.80 (1H, dt, J ) 4.2
and 8.9 Hz), 4.31 (1H, m), 5.28-5.30 (1H, m), 5.41 (1H, s), 6.14 (1H, s);
13C NMR (75 MHz, CDCl3) δ 23.3, 26.0, 26.6, 28.5, 31.4, 31.7, 36.0, 49.0,
50.1, 65.5, 77.2, 119.7, 122.5, 139.6, 152.6, 208.8; MS m/z 246 (M+). Anal.
Calcd for C16H22O2: C, 78, 01; H, 9.00%. Found: C, 77.63; H, 9.34%.
(11) Procedure for the Conversion of 21 into 23. To a stirred solution
of 21 (15.1 mg, 0.061 mmol) and 2,6-lutidine (0.04 mL, 0.304 mmol) in
dry CH2Cl2 (5 mL) at 0 °C was added TBDMSOTf (0.06 mL, 0.243 mmol),
and the mixture was stirred for 1 h at 0 °C. The mixture was partitioned
between H2O and Et2O. The combined organic layers were washed with
saturated NaCl, dried (MgSO4), and evaporated. The products 22 were
treated with AcOH-THF-H2O (3:1:1 v/v/v, 5 mL) for 3 h at ambient
temperature. After addition of H2O, the mixture was extracted with Et2O
three times. The combined organic layers were washed with saturated
NaHCO3 and saturated NaCl, dried (MgSO4), and evaporated. Column
chromatography on silica gel eluting with hexanes-AcOEt (96:4 v/v)
provided 23 (12.4 mg, 56%) and its epimer (8.6 mg, 39%). 23: IR (neat)
3300 cm-1; 1H NMR (300 Mz, CDCl3) δ 0.07 (3H, s), 0.08 (3H, s), 0.88-
(9H, s), 1.04 (3H, s), 1.26-2.39 (11H, m), 3.69 (2H, t, J ) 7.6 Hz), 4.35
(1H, br s), 4.77 (1H, s), 4.82 (1H, s), 5.09 (1H, s), 5.17 (1H, s), 5.88 (1H,
d, J ) 10.0 Hz), 6.25 (1H, d, J ) 10.0 Hz); 13C NMR (75 MHz, CDCl3)
δ -4.7, -4.5, 18.1, 25.8, 26.0, 28.0, 30.5, 32.7, 34.9, 40.3, 42.2, 51.1,
61.8, 78.7, 110.9, 112.0, 130.0, 135.4, 142.4, 161.2; MS m/z 362 (M+).
Anal. Calcd for C22H38O2Si: C, 72.87; H, 10.56%. Found: C, 72.73; H,
10.52%.
a Reagents and conditions: (a) DIBALH, 86% (1.5:1 ds); (b)
TBDMSOTf, 2,6-lutidine; (c) AcOH-H2O-THF (3:1:1 v/v/v),
95% for two steps; (d) PivCl, pyridine, DMAP, 99%; (e) CSA,
100%; (f) DIBALH, 93%; (g) DMSO, (COCl)2; Et3N, 100%; (h)
Rh(Ph3)3Cl, toluene, reflux, 70%.
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