Synthesis of 4-alkyl-4-alkoxybutenolides having unsaturated side chains via chromium carbene complex photochemistry: (+)-cerulenin

Article abstract of DOI:10.1021/jo960664k

The photochemical reaction between optically active ene carbamates and chromium alkoxycarbene complexes containing unsaturated aliphatic side chains was further developed. Although remote olefinic groups, including conjugated dienes, were tolerated, a homoallylic side chain underwent intramolecular reaction to give a strained cyclobutanone. (+)-Cerulenin was synthesized utilizing the photochemical reaction of an alkynylcarbene complex with an optically active ene carbamate and the bis(π-crotyl)nickel halide alkylation of a vinyl bromide as key steps.

Full text of DOI:10.1021/jo960664k

J . Org. Chem. 1996, 61, 6121-6126
6121
Syn th esis of 4-Alk yl-4-a lk oxybu ten olid es Ha vin g Un sa tu r a ted Sid e
Ch a in s via Ch r om iu m Ca r ben e Com p lex P h otoch em istr y:
(+)-Cer u len in
Tracey E. Kedar, Michael W. Miller, and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received April 9, 1996X
The photochemical reaction between optically active ene carbamates and chromium alkoxycarbene
complexes containing unsaturated aliphatic side chains was further developed. Although remote
olefinic groups, including conjugated dienes, were tolerated, a homoallylic side chain underwent
intramolecular reaction to give a strained cyclobutanone. (+)-Cerulenin was synthesized utilizing
the photochemical reaction of an alkynylcarbene complex with an optically active ene carbamate
and the bis(π-crotyl)nickel halide alkylation of a vinyl bromide as key steps.
In tr od u ction
being determined by the oxazolidinone chiral auxilliary.
Since the successful synthesis of (-)-2 by this methodol-
ogy had demonstrated that remote olefinic groups were
tolerated, the approach appeared applicable to the syn-
thesis of (-)-3 as well.
Optically active butenolides 1-3 having a 5-alkoxy
substituent in addition to a long saturated or unsaturated
aliphatic side chain at the same position have been
isolated from the marine sponge Plakortis lita.1 The
related (racemic) butenolide 4 was used as a key inter-
mediate in the synthesis of (racemic) cerulenin 5,2 an
antifungal antibiotic. Synthetic approaches to optically
active 4-alkoxy-4-alkylbutenolides are somewhat limited
and involve either a resolution at some stage3 or the
oxidation of carbohydrate-derived furan derivatives.4 We
have recently developed a quite different approach to this
class of compounds5 and have used it to synthesize
optically active butenolides (-)-1 and (-)-2, as well as
(+)-tetrahydrocerulenin.6 Below we describe its use in
an approach to diene-containing butenolide (-)-3 and in
the total synthesis of (+)-cerulenin 5.
The conjugate diene side chain required for (-)-3 was
synthesized as shown in Scheme 1. (E,E)-2,4-Hexadienal
was complexed to iron carbonyl8 to allow clean reaction
at the aldehyde center, and the resulting complex 6 was
alkylated with the THP ether of 10-lithiodecanol (from
lithiation of the corresponding iodide). Reduction of the
allylic alcohol 7 followed by decomplexation gave the free
(E,E)-12,14-hexadienol 9. The requisite organolithium
reagent was prepared by mesylation followed by displace-
ment with iodide and halogen metal exchange with tert-
butyllithium. Reaction with chromium hexacarbonyl
followed by trimethyloxonium tetrafluoroborate produced
carbene complex 11. Photolysis of 11 in the presence of
(R)-ene carbamate 12 produced cyclobutanone 13 in fair
yield with g95% de. However, all attempts to effect a
Baeyer-Villiger oxidation to the lactone (m-CPBA,
tBuOOH/NaOH, H2O2/CF3CH2OH) resulted in competi-
tive to exclusive oxidation of the diene unit. Thus,
synthesis of (-)-3 was abandoned.
Resu lts a n d Discu ssion
The general approach to optically active 4-alkoxy-4-
alkylbutenolides involves the photochemical reaction of
chromium alkoxycarbene complexes with optically active
ene carbamates, followed by Baeyer-Villiger oxidation
of the resulting cyclobutanones and oxazolidine elimina-
tion (eq 1). The reaction is highly diastereoselective,
giving cyclobutanones having the large R group and the
oxazolidinone group syn,7 with the absolute configuration
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) DeGuzman, F. S.; Schmitz, F. J . J . Nat. Prod. 1990, 53, 926.
(2) Ohta, T.; Tsuchiyama, H.; Nozoe, S. Heterocycles 1986, 24, 1137.
(3) Maeba, I.; Suzuki, M.; Hara, O.; Takeuchi, T.; Iijima, T.;
Furukawa, H. J . Org. Chem. 1987, 52, 4521.
Since previous studies6 had shown that nonconjugate
alkenes in the side chain tolerated Baeyer-Villiger
oxidation, attention was turned to the synthesis of (+)-
(4) Lopez Aparicio, F. J .; Lopez Sastre, J . A.; Garcia, J . I.; Diaz, R.
R. Carbohydr. Res. 1984, 132, 19.
(5) (a) Hegedus, L. S.; Bates, R. W.; Soderberg, B. C. J . Am. Chem.
Soc. 1991, 113, 923. (b) Reed, A. D.; Hegedus, L. S. J . Org. Chem. 1995,
60, 3787.
(7) Valenti, E.; Pericas, M. A.; Moyano, A. J . Org. Chem. 1990, 55,
3582.
(8) Franck-Neumann, M.; Martina, D.; Heitz, M. P. Tetrahedron
Lett. 1982, 23, 3493.
(6) Miller, M. W.; Hegedus, L. S. J . Org. Chem. 1993, 58, 6779.
S0022-3263(96)00664-0 CCC: $12.00 © 1996 American Chemical Society

6122 J . Org. Chem., Vol. 61, No. 18, 1996
Sch em e 1. Attem p ted Syn th esis of (-)-3
Kedar et al.
was removed hydrogenolytically, preparatory to oxidation
to provide an aldehyde for the introduction of the side
chain by a Wittig reaction. However, upon deprotection,
the alcohol 19 spontaneously cyclized to a single diaste-
reoisomer of spiroketal 20, a process which precluded
further use.
cerulenin (5) via butenolide (+)-4. The requisite carbene
complex 14 was synthesized in the usual manner (eq 2).9
Photolysis of 14 in both the presence and absence of ene
carbamate 12 led to the same product, which was very
unstable and rearranged upon acid workup to give
cyclopentanone 15.10 This product resulted from the
internal alkene being close enough to intramolecularly
trap the photochemically generated ketene, producing the
unstable cyclobutanone, which subsequently underwent
an acid-catalyzed pinacol rearrangement, producing cy-
Finally, a successful route to (+)-cerulenin was devised
and carried out (Scheme 2), utilizing an alkynyl group
as a masked aldehyde. Although many of the steps are
straightforward, some warrant comment. Previous stud-
ies11 had shown that alkynes did not undergo photocy-
cloaddition with chromium carbene complexes, either
inter- or intramolecularly, and, as expected, the conver-
sion of alkynylcarbene complex 21 to cyclobutanone 22
went without interference from side chain reactivity.
Clean reduction of the alkyne 24 to the alkene 25 was
problematic, with overreduction occurring readily. The
use of Mn(II)-modified Lindlar’s catalyst12 provided the
best results. Ozonolysis was uneventful, and the chro-
mous chloride promoted iodomethylenation (26 f 27)
provided excellent yields of pure trans vinyl iodide. The
final olefinic portion of the side chain was appended using
(π-crotyl)nickel bromide complex chemistry.13 This little
used reagent is almost unique among crotyl metal
reagents in that coupling occurs almost exclusively at the
less substituted terminus, giving the required connectiv-
ity for cerulenin. As previously observed,2,6 epoxidation
of the butenolide was highly stereoselective (only a single
isomer was detected in the crude reaction mixture) but
proceeded in only modest yield and conversion. Treat-
ment of butenolide 29 with gaseous ammonia produced
(+)-cerulenin,14 in overall 11% yield from carbene com-
plex 21 (8% from butynol). This is comparable to three
of the four other published syntheses of (+)-cerulenin,
two from an intermediate (no yield or procedure reported)
clopentanone 15. Thus, although remote olefinic groups
were tolerated by the photochemical reaction, those
within “striking distance” of the photogenerated ketene
were not, necessitating the installation of the requisite
alkene after the photochemical reaction. To that end,
carbene complex 16 was photolyzed with ene carbamate
(S)-12 to give cyclobutanone 17 in fair yield and with good
diastereoselectivity (eq 3). Baeyer-Villiger oxidation
cleanly afforded butyrolactone 18. The O-benzyl group
(11) Soderberg, B. C.; Hegedus, L. S.; Sierra, M. A. J . Am. Chem.
Soc. 1990, 112, 4364.
(12) Rajaram, J .; Narula, A. P. S.; Chawla, H. P. S.; Dev, Sukh.
Tetrahedron 1983, 39, 2315.
(9) Corey, E. J .; Williams, D. R. Tetrahedron Lett. 1977, 3847.
(10) Moser, W. A.; Hegedus, L. S. J . Am. Chem. Soc. Submitted for
publication.
(13) For reviews, see: (a) Semmelhack, M. F. Org. React. 1972, 19,
115. (b) Billington, D. C. Chem. Soc. Rev. 1985, 14, 93.
(14) Arison, B. H.; Omura, S. J . Antibiot. Ser. A 1974, 27, 28.

Synthesis of (+)-Cerulenin
Sch em e 2. Syn th esis of (+)-Cer u len in
J . Org. Chem., Vol. 61, No. 18, 1996 6123
in δ relative to CDCl3 (δ 7.24 for 1H and δ 77.0 for 13C) unless
otherwise noted.
Ma ter ia ls. The following compounds were prepared ac-
cording to literature methods: (S)-phenylglycinol,21 [(methoxy)-
(methyl)carbene]pentacarbonyl chromium(0),22 3-vinyl-(S)-4-
phenyl-2-oxazolidinone (43),23 nickel bis(cyclooctadiene),24 and
(η3-crotyl)nickel bromide.25
((E,E)-2,4-Hexa d ien a l)ir on Tr ica r bon yl (6).8 (E,E)-2,4-
Hexadienal (1.9 g, 20 mmol) and Fe2(CO)9 (8.7 g, 24 mmol) in
Et2O (100 mL, degassed) were heated at 40 °C under argon
for 16 h, cooled, and filtered through basic Al2O3, and the
solvent was removed under reduced pressure. Purification via
Kugelrohr distillation gave 2.2 g (47%) of 6 as an orange oil:
1H NMR δ 1.23 (m, 1H), 1.48 (d, 3H, J ) 6.3 Hz), 1.67 (m,
1H), 5.27 (dd, 1H, J ) 5.0, 8.9 Hz), 5.74 (ddd, 1H, J ) 1.1, 4.9,
6.0 Hz), 9.23 (d, 1H, J ) 4.4 Hz).
Tetr a h yd r o-2-[(10-br om od eca n yl)oxy]-2H-p yr a n . 10-
Bromodecanol (5.0 g, 21 mmol), dihydropyran (2.3 mL, 25
mmol), and CH2Cl2 (50 mL) were cooled to 0 °C, and TsOH (5
mg) was added at 0 °C. The reaction mixture was stirred at
0 °C (15 min) and then warmed to 25 °C and stirred at 25 °C
for 1 h. The reaction mixture was washed with saturated
NaHCO3(aq), dried over MgSO4, filtered, and concentrated
under reduced pressure to give the crude bromide. Purification
via Kugelrohr distillation gave 6.7 g (100%) of the bromide as
a colorless oil, bp ) 120 °C (0.45 mmHg): 1H NMR δ 1.2-1.9
(m, 22H), 3.37 (m, 1H), 3.38 (t, 2H, J ) 6.5 Hz), 3.50 (m, 1H),
3.70 (m, 1H), 3.85 (m, 1H), 4.55 (t, 1H, J ) 2.8 Hz).
Alk yla tion of Dien a l Com p lex 6 To P r od u ce Com p lex
7. tert-Butyllithium (12 mL, 1.7 M in pentane) was added to
tetrahydro-2-[(10-bromodecanyl)oxy]-2H-pyran (3.4 g, 9.3 mmol)
and Et2O (90 mL) at -78 °C, and the mixture was stirred at
-78 °C (5 min) and then warmed to 25 °C and stirred at 25
°C (1 h). The resulting solution was transferred via a cannula
to a 200 mL Airless flask containing the Fe-dienal complex 6
(2.2 g, 9.3 mmol) in Et2O (30 mL) at -78 °C. The mixture
was stirred at -78 °C (0.5 h), warmed to 0 °C, and stirred at
that temperature (0.5 h). The mixture was partitioned
between NH4Cl(aq) (100 mL) and Et2O (100 mL), and the
organic layer was washed with brine and dried over MgSO4.
Filtration and concentration under reduced pressure gave the
crude complex. Purification via flash chromatography (3/1
hexanes/EtOAc, SiO2) gave 3.4 g (89%) of the complex 7 as an
orange oil: 1H NMR δ 1.1-1.9 (m, 27H), 1.38 (d, 3H, J ) 6.2
Hz), 3.4-3.5 (m, 3H), 3.69 (dt, 1H, J ) 6.9, 9.5 Hz), 3.85 (m,
1H), 4.55 (d, 1H, J ) 2.8 Hz), 5.02 (dd, 1H, J ) 5.0, 8.8 Hz),
5.19 (dd, 1H, J ) 4.9, 8.4 Hz).
derived from d-glucose in 6.7%15 and 8%16 yields, respec-
tively, and one from Sharpless epoxidation of cis-2-
butene-1,4-diol in 3.3% yield.17 The most efficient syn-
thesis remains that of Yoda18 from D-tartaric acid, in
overall 12.3% yield.
((E,E)-12,14-H exa d ien -1-ol)ir on Tr ica r b on yl (8).19
Lithium aluminum hydride (320 mg, 8.4 mmol) was added in
portions to AlCl3 (4.5 g, 33 mmol) in 150 mL of ether at 0 °C
in a 500 mL Airless flask. The grey mixture was stirred at 0
°C (15 min), and complex 7 (4.0 g, 8.3 mmol) in Et2O (30 mL)
was added to the reaction mixture and stirred at 0 °C (10 min).
The reaction was quenched with slow addition of H2O (10 mL)
at 0 °C. The organic layer was washed with saturated NH4-
Cl(aq) and brine and then dried over MgSO4. Filtration and
concentration under reduced pressure gave a dark orange oil.
Purification via flash chromatography (3/1 hexanes/EtOAc,
SiO2) gave 1.3 g (41%) of 8 as an orange oil: 1H NMR δ 1.0-
1.6 (m, 25H), 3.61 (q, 3H, J ) 4.8 Hz), 4.96 (d, 2H, J ) 7.6
Hz); 13C NMR δ 19.08, 25.69, 29.19, 29.37, 29.48, 29.52, 31.84,
32.10, 32.73, 34.16, 56.92, 62.92, 63.96, 83.68, 84.83, 212.79;
Exp er im en ta l Section
Gen er a l Meth od s. Optical rotations were obtained on a
Perkin-Elmer 24 polarimeter at a wavelength of 589 nm (Na
D line) with a 1.0 dm cell with a total volume of 1 mL. Specific
rotation ([R]D) was reported in degrees per decimeter at the
specified temperature and the concentration (c) given in grams
per 100 mL in the specified solvent. Photolysis reactions were
carried out in pressure tubes with size 15 Ace-Thread placed
at a distance of 10 cm from a Conrad-Hanovia 7825 medium
pressure mercury lamp operating at 450 W, which was placed
in a water-cooled immersion well (Pyrex). A Conrad-Hanovia
7830-C power supply was used for the mercury lamp. Reac-
tions which were run under CO pressure were saturated with
CO (three cycles, 50-80 psi) and were photolyzed under 60-
70 psi of CO. NMR spectra (300 MHz for 1H and 75 MHz for
13C) were recorded in CDCl3, and chemical shifts are reported
IR (film) ν 3361, 2039, 1964 cm-1
.
(E,E)-12,14-Hexa d ien -1-ol (9). Complex 8 (1.3 g, 3.4
mmol) was taken up in EtOH (30 mL) and cooled to -40 °C,
and ceric ammonium nitrate (7.50 g, 13.6 mmol) in H2O/EtOH
(30 mL, 1/1) was added to the mixture in portions at -40 °C.
When the color persisted, no more oxidant was added. The
(15) Sueda, N.; Ohrui, H.; Kuzuhara, H. Tetrahedron Lett. 1979,
2039.
(16) Pietraszkiewicz, M.; Sina¨y, P. Tetrahedron Lett. 1979, 4741.
(17) Morisaki, N.; Funabashi, H.; Furukawa, J .; Shimazawa, R.;
Kanematsu, A.; Ando, T.; Okuda, S.; Iwasaki, S. Chem. Pharm. Bull.
1992, 40, 2945.
(18) Yoda, H.; Katagiri, T.; Takabe, K. Tetrahedron Lett. 1991, 32,
6771.
(21) Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. J . Chem.
Soc., Perkin Trans. 1 1983, 1673.
(22) Hoye, T. R.; Chen, K.; Vyvyan, J . R. Organometallics 1993, 12,
2806.
(23) Montgomery, J .; Wieber, G. M.; Hegedus, L. S. J . Am. Chem.
Soc. 1990, 112, 6255.
(19) Graf, R. E.; Lillya, C. P. J . Organomet. Chem. 1976, 122, 377.
(20) Matsumoto, M.; Kobayashi, H. Heterocycles 1986, 24, 2443.
(24) Krysan, D. J .; Mackenzie, P. B. J . Org. Chem. 1990, 55, 4229.
(25) Semmelhack, M. F. Org. React. 1972, 19, 115.

6124 J . Org. Chem., Vol. 61, No. 18, 1996
Kedar et al.
reaction mixture was stirred for an additional 10 min and then
partitioned between saturated NaHCO3(aq) (100 mL) and Et2O
(100 mL), the aqueous layer was extracted with Et2O (2 × 100
mL), and the combined Et2O layers were washed with satu-
rated NaHCO3(aq) and brine and then dried over MgSO4.
Filtration and concentration under reduced pressure gave a
white solid. Purification via flash chromatography (2/1 hex-
anes/EtOAc, SiO2) gave 650 mg (80%) of 9 as a white solid:
1H NMR δ 1.24 (m, 16H), 1.55 (m, 2H),1 .71 (d, 3H, J ) 6.2
Hz), 2.00 (q, 2H, J ) 7.0 Hz), 3.62 (bt, 3H, J ) 5.4 Hz), 5.55
(m, 2H), 6.00 (m, 2H); 13C NMR δ 17.95, 25.71, 29.17, 29.40,
29.47, 29.54, 32.53, 32.78, 63.06, 126.60, 130.15, 131.70,
126.38, 126.53, 129.32, 129.49, 130.13, 131.68, 132.15, 138.73,
157.81, 205.67; IR (film) ν 1788, 1751 cm-1. Anal. Calcd for
C30H43NO4: C, 74.84; H, 8.93; N, 2.91. Found: C, 74.56; H,
9.02; N, 3.10.
[(Met h oxy)(1-(E,E)-3,6-oct a d ien yl)ca r b en e]p en t a ca r -
bon yl Ch r om iu m (0) (14) a n d P h otolysis To P r od u ce 15.
tert-Butyllithium (1.2 mL, 1.7 M in pentanes) was added
dropwise to (E,E)-1-iodo-3,6-octadiene9 (0.24 g, 1.00 mmol) in
1 mL of Et2O at -78 °C, and the yellow solution was stirred
at -78 °C for 40 min, warmed to room temperature, and
stirred at that temperature for 1 h. This solution was added
via a cannula to Cr(CO)6 (0.22 g, 1.00 mmol) and Et2O (5 mL).
The dark brown solution was stirred at room temperature for
3 h, and the volatiles were removed under reduced pressure.
The brown residue was taken up in H2O (15 mL), and
Me3OBF4 was added until the solution was acidic (pH ) 2).
The mixture was extracted with Et2O (5 × 10 mL), the
combined Et2O layers were dried over MgSO4, and filtration
and concentration under reduced pressure gave the crude
carbene complex. Purification via flash chromatography (9/1
hexanes/EtOAc, SiO2) gave 190 mg (54%) of 14 as an orange
oil: 1H NMR δ 1.63 (d, 3H, J ) 5.0 Hz), 2.16 (app q, 2H, J )
6.4, 14.4 Hz), 2.63 (m, 2H), 3.35 (t, 2H, J ) 7.6 Hz), 4.76 (s,
3H), 5.5 (m, 4H); 13C NMR δ 17.84, 29.34, 35.43, 62.52, 67.58,
125.75, 128.16, 129.21, 130.38, 216.32, 223.13, 362.95; IR (film)
132.18; IR (film) ν 3330 cm-1
.
(E,E)-1-Iod o-12,14-h exa d ien e (10). Alcohol 9 (650 mg, 2.7
mmol) and Et3N (0.43 mL, 3 mmol) in CH2Cl2 (50 mL), cooled
to 0 °C, and methanesulfonyl chloride (0.23 mL, 3.0 mmol)
were added. The mixture was warmed to 25 °C and stirred
at that temperature (2 h), washed with saturated NH4Cl(aq),
and dried over MgSO4. Filtration and concentration under
reduced pressure gave 780 mg (91%) of the mesylate as a white
solid: 1H NMR δ 1.24 (m, 16H), 1.72 (d, 3H, J ) 9.1 Hz), 1.75
(m, 2H), 2.01 (q, 2H, J ) 6.6 Hz), 2.97 (s, 3H), 4.19 (t, 2H, J )
6.6 Hz), 5.55 (m, 2H), 6.00 (m, 2H); 13C NMR δ 17.87, 25.29,
28.89, 29.00, 29.04, 29.13, 29.30, 29.35, 29.39, 32.43, 37.18,
70.13, 126.47, 130.09, 131.62, 132.03. This material was used
without further purification.
ν 2062, 1920 cm-1
. Photolysis of this complex, both in the
presence and absence of substrate, led to the same unstable
compound with an absorption in the infrared spectrum at ν
1792 cm-1, characteristic of cyclobutanones. Stirring an ether
solution of a small portion of this material with 5% aqueous
HCl converted it to a new compound (crude yield ≈ 80%),
assigned as 15 on the basis of spectral data and subsequent
studies:10 1H NMR δ 5.50 (m, 2H), 2.88 (br s, 1H), 2.26-2.11
(m, 4H), 1.87 (m, 2H), 1.65 (d, 3H, J ) 4.0 Hz), 1.62 (m, 1H),
1.34 (dt, 1H, J ) 4.1, 7.0 Hz); 13C NMR δ 213.4, 129.2, 125.9,
70.3, 32.7, 30.9, 30.3, 29.9, 21.6, 17.9; IR (film) ν 3366, 1718
cm-1; MS m/ e 166 (M+).
[(Me t h o x y )(3-(b e n zy lo x y )p r o p y l)c a r b e n e ]p e n t a c -
a r bon yl Ch r om iu m (0) (16). tert-Butyllithium (4.4 mL, 1.7
M in pentanes) was added to 3-(benzyloxy)iodopropane (1.0 g,
3.6 mmol) in 10 mL of ether at -78 °C, and the resulting
homogeneous, yellow solution was stirred at -78 °C (10 min)
and then warmed to 25 °C and stirred at that temperature (1
h). This solution was added via a cannula to Cr(CO)6 (0.79 g,
3.60 mmol) in Et2O (20 mL), and the yellow-brown solution
was stirred at 25 °C (16.5 h). H2O (10 mL) was added to the
mixture, and Me3OBF4 was added until the solution was acidic
(pH ) 2). The Et2O layer was separated, and the aqueous
layer was extracted with Et2O (2 × 10 mL). The combined
Et2O layers were washed with brine and dried over MgSO4.
Filtration and concentration under reduced pressure gave an
orange oil. Purification via flash chromatography (9/1 hex-
anes/Et2O, SiO2) gave 590 mg (43%) of 16 as an orange oil:
1H NMR (270 MHz, CDCl3) δ 1.79 (q, 2H, J ) 7.5 Hz), 3.42
(m, 4H), 4.47 (s, 2H), 4.73 (s, 3H), 7.30 (m, 5H). This material
was relatively unstable and was used immediately.
The mesylate (780 mg, 2.50 mmol) and NaI (4.0 g, 27 mmol)
were heated at reflux (14 h) in acetone. The mixture was
partitioned between hexanes and H2O, the aqueous layer was
extracted with hexanes, and the combined hexane layers were
washed with 10% Na2S2O3(aq) and brine and then dried over
MgSO4. Filtration and concentration under reduced pressure
gave 810 mg (86% from the alcohol) of 10 as a yellow oil: 1H
NMR δ 1.24 (m, 16H), 1.70 (d, 3H, J ) 6.3 Hz), 1.79 (quint,
2H, J ) 6.9 Hz), 2.01 (q, 2H, J ) 6.9 Hz), 3.16 (t, 2H, J ) 7.1
Hz), 5.55 (m, 2H), 5.95 (m, 2H); 13C NMR δ 7.16, 17.96, 28.49,
29.13, 29.37, 29.44, 29.48, 29.61, 30.46, 32.51, 33.52, 126.49,
130.15, 131.68, 132.07. This material was used without
further purification.
Dien yl Ca r ben e Com p lex 11. tert-Butyllithium (2.8 mL,
1.7 M in pentanes) was added to iodide 10 (0.81 g, 2.33 mmol)
at -78 °C in 25 mL of Et2O, and the resulting homogeneous,
yellow solution was stirred at -78 °C (0.5 h). The mixture
was warmed to 25 °C, stirred at that temperature (1 h), and
then added via a cannula to Cr(CO)6 (506 mg, 2.33 mmol) in
Et2O (40 mL). The yellow-brown solution was stirred at 25
°C (16 h). The solvent was removed under reduced pressure,
the residue was taken up in H2O (50 mL), and Me3OBF4 was
added until the solution was acidic (pH ) 2). The aqueous
layer was extracted with Et2O (3 × 50 mL), and the combined
Et2O layers were washed with brine and dried over MgSO4.
Filtration and concentration under reduced pressure gave an
orange oil. Purification via flash chromatography (9/1 hex-
anes/Et2O, SiO2) gave 720 mg (68%) of 11 as an orange oil:
1H NMR δ 1.21 (m, 16H), 1.4 (m, 2H), 1.70 (d, 3H, J ) 6.3
Hz), 2.01 (q, 2H, J ) 6.9 Hz), 3.27 (t, 2H, J ) 7.5 Hz), 4.74 (s,
3H), 5.55 (m, 2H), 5.95 (m, 2H); 13C NMR δ 17.92, 26.31, 29.19,
29.23, 29.38, 29.44, 29.53, 29.66, 32.55, 63.08, 67.48, 126.51,
130.23, 131.77, 132.10, 216.41, 223.13, 363.78; IR (film) ν 2062,
Cyclobu ta n on e 17. The carbene complex 16 (0.59 g, 1.53
mmol) and (S)-ene carbamate 12 (0.19 g, 1.00 mmol) in CH2Cl2
(20 mL) were photolyzed as above (19.75 h). Purification via
radial chromatography (2/1, hexanes/EtOAc, 2 mm SiO2) gave
0.22 g (54%) of cyclobutanone 17: 1H NMR δ 1.4-2.0 (m, 4H),
2.47 (dd, 1H, J ) 10.2, 18.0 Hz), 3.03 (dd, 1H, J ) 9.5, 17.9
Hz), 3.22 (s, 3H), 3.50 (t, 2H, J ) 5.8 Hz), 4.10 (dd, 1H, J )
4.4, 8.7 Hz), 4.45 (t, 1H, J ) 9.9 Hz), 4.47 (s, 2H), 4.61 (t, 1H,
J ) 8.6 Hz), 4.87 (dd, 1H, J ) 4.4, 8.4 Hz), 7.2-7.4 (m, 10H).
This was used without further purification.
1930 cm-1
.
Dien yl Cyclobu ta n on e 13. The dienyl carbene complex
11 (722 mg, 1.58 mmol) and (R)-ene carbamate 12 (150 mg,
0.79 mmol) in CH2Cl2 (15 mL) were placed in an Ace pressure
tube which was charged with CO (60 psi) and irradiated at 25
°C for 16.5 h. The solvent was removed under reduced
pressure, and Cr(CO)6 was recovered by sublimation from the
crude reaction mixture. Purification via flash chromatography
(4/1, 2/1 hexanes/EtOAc, SiO2) gave 190 mg (51%) of 13 as a
colorless oil which solidified upon standing: 1H NMR δ 1.24
(m, 18H), 1.70 (d, 3H, J ) 6.5 Hz), 1.82 (m, 2H), 2.02 (q, 2H,
J ) 6.9 Hz), 2.51 (dd, 1H, J ) 10.1, 17.9 Hz), 3.15 (s, 3H),
3.21 (dd, 1H, J ) 9.6, 18.1 Hz), 4.19 (dd, 1H, J ) 4.8, 8.7 Hz),
4.34 (t, 1H, J ) 9.7 Hz), 4.67 (t, 1H, J ) 8.6 Hz), 4.87 (dd, 1H,
J ) 4.9, 8.4 Hz), 5.54 (m, 2H), 5.98 (m, 2H), 7.25 (m, 2H), 7.39
(m, 3H); 13C NMR δ 17.92, 23.04, 29.13, 29.38, 29.44, 29.51,
29.76, 29.90, 32.49, 42.57, 47.30, 52.38, 61.55, 70.03, 98.75,
La cton e 18. Cyclobutanone 17 (140 mg, 0.35 mmol) and
H2O2 (30%, 90 µL) in CF3CH2OH (20 mL)20 were stirred for
24 h, followed by removal of the solvent under vacuum, to give
150 mg (100%) of 17 as a colorless solid: 1H NMR δ 1.5-1.7
(m, 2H), 1.83 (d, 1H, J ) 18.3 Hz), 1.89 (m, 1H), 2.28 (m, 1H),
2.73 (dd, 1H, J ) 8.2, 18.3 Hz), 3.28 (s, 3H), 3.52 (m, 2H), 3.97
(dd, 1H, J ) 2.5, 8.5 Hz), 4.33 (t, 1H, J ) 8.5 Hz), 4.46 (d, 1H,
J ) 11.7 Hz), 4.51 (d, 1H, J ) 11.7 Hz), 4.55 (dd, 1H, J ) 2.5,
8.3 Hz), 4.72 (d, 1H, J ) 8.0 Hz), 7.2-7.4 (m, 10H).
Sp ir ola ct on e 20. Lactone 18 (37 mg, 0.09 mmol) was

Synthesis of (+)-Cerulenin
J . Org. Chem., Vol. 61, No. 18, 1996 6125
taken up in THF (5 mL). PdCl2 (5 mg, 0.03 mmol) was added,
and the mixture was stirred at 25 °C under 1 atm H2 (16 h).
The palladium black was removed via filtration through Celite,
and the solvent was removed under reduced pressure. Puri-
fication via flash chromatography (1/1 hexanes/EtOAc, SiO2)
gave 14 mg (52%) of a single diastereoisomer of 20 as a
colorless oil which solidified upon standing: 1H NMR δ 1.9-
2.4 (m, 6H), 4.04 (dd, J ) 7.6, 7.6 Hz), 4.12 (dd, 1H, J ) 3.8,
8.5 Hz), 4.17 (ddd, J ) 4.3, 8.3, 8.3 Hz), 4.61 (t, 1H, J ) 8.6
Hz), 4.85 (dd, 1H, J ) 8.6, 11.3 Hz), 5.18 (dd, 1H, J ) 3.8, 8.7
Hz), 7.25 (m, 2H), 7.36 (m, 3H); 13C NMR δ 23.62, 31.64, 34.00,
53.33, 58.32, 70.18, 71.02, 115.92, 126.08, 129.30, 129.65,
transferred to an Airless flask containing Cr(CO)6 (1.10 g, 5.00
mmol) in Et2O (20 mL), via a cannula, resulting in an orange/
brown solution. This was stirred at 25 °C for 14 h, and then
-
H2O (15 mL) was added. Ethyl Meerwein salt (Et3O+BF4
)
was added to the solution until a pH of 2 was reached. The
aqueous layer was extracted with Et2O (3 × 50 mL), and the
organic layers were combined and washed with brine and then
dried over MgSO4. Filtration and concentration under reduced
pressure and then purification via flash chromatography
(hexanes, SiO2) gave 1.93 g (84%) of carbene 56 as an orange
oil: 1H NMR δ 1.02 (m, 21 H), 1.65 (t, 3 H, J ) 7.1 Hz), 2.41
(t, 2 H, J ) 6.9 Hz), 3.60 (t, 2 H, J ) 6.8 Hz), 5.11 (q, 2 H, J
) 7.1 Hz); 13C NMR δ 11.2, 14.8, 16.2, 18.5, 60.9, 78.2, 80.7,
106.6, 216.2, 223.0, 355.6; IR (film) ν 2063, 1938 cm-1. This
carbene was unstable and thus was used immediately upon
purification.
140.94, 158.65, 171.65; IR (film) ν 1786, 1750 cm-1
. Anal.
Calcd for C10H17NO9: C, 63.36; H, 5.65; N, 4.62. Found: C,
63.26; H, 5.69; N, 4.61.
1-(Tr im eth ylsiloxy)-3-bu tyn e. Trimethylsilyl chloride
(13.0 mL, 100 mmol) was added to 3-butyn-1-ol (6.7 g, 95
mmol) and triethylamine (15 mL, 105 mmol) in 150 mL of
CH2Cl2, at 0 °C. The resulting slurry was warmed to 25 °C
and stirred at that temperature for 1 h. The mixture was
washed with saturated NaHCO3(aq) and H2O and then dried
over MgSO4. Filtration and purification via distillation (ambi-
ent pressure) gave 11 g (85%) of the silyl ether as a colorless
oil, bp ) 125-128 °C: 1H NMR δ 0.11 (s, 9H), 1.95 (t, 1H, J
) 2.7 Hz), 2.39 (dt, 2H, J ) 2.7, 7.1 Hz), 3.69 (t, 2H, J ) 7.2
Hz); 13C NMR δ -0.59, 22.64, 61.04, 69.34, 81.28. This was
used without further purification.
Alk yn ylcyclobu ta n on e 22. Carbene complex 21 (2.49 g,
5.34 mmol, 1.5 equiv) and (S)-ene carbamate 12 (0.68 g, 3.62
mmol) were placed into an Ace pressure tube, dissolved in
degassed CH2Cl2 (15mL) and charged to 50-80 psi of CO (3
cycles), and then irradiated at 25 °C (20-25 h) at 60-70 psi.
The solvent was removed under reduced pressure, and the
Cr(CO)6 was recovered via sublimation. Purification via flash
chromatography (4/1 hexanes/EtOAc, SiO2) gave 1.32 g of 22
(76%) as a colorless viscous oil. Only a single diastereomer
was detected by NMR analysis: 1H NMR δ 1.06 (m, 24 H),
2.1-2.3 and 2.4-2.5 (m, 4 H), 2.56 (dd, 1 H, J ) 10.2, 18.0
Hz), 3.30 (dd, 1 H, J ) 9.5, 18.0 Hz), 3.32 (q, 2 H, J ) 6.9 Hz),
4.20 (dd, 1 H, J ) 5.1, 9.7 Hz), 4.35 (t, 1 H, J ) 9.8 Hz), 4.66
(t, 1 H, J ) 8.6 Hz), 4.90 (dd, 1 H, J ) 5.0, 8.4 Hz), 7.27 (m, 2
H), 7.42 (m, 3 H); 13C NMR δ 11.2, 14.4, 15.2, 18.6, 30.3, 42.4,
47.6, 60.6, 61.7, 70.1, 80.8, 97.5, 108.0, 126.5, 129.4, 129.6,
138.6, 157.9, 205.4; IR (film) ν 1790, 1732 cm-1; [R]D ) +51.8°
(c ) 0.714, CH2Cl2); MS (FAB) m/ e 483.3 (M) 484.3 (M + 1).
Alk yn yl La cton e 23. Cyclobutanone 22 (1.32 g, 2.73
mmol) was dissolved in CH2Cl2 (100 mL). m-Chloroperbenzoic
acid (0.85 g, 4.10 mmol, 1.5 equiv) and Na2HPO4 (0.78 g, 5.47
mmol, 2 equiv) were added to the mixture which was allowed
to stir at 25 °C for 8 h. A solution of 10% Na2S2O3(aq) was
then added to the mixture which was stirred for a further 0.5
h. The organic layer was washed with saturated NaHCO3-
(aq) (2 × 80 mL) and then dried over MgSO4. Filtration and
concentration under reduced pressure and then purification
via flash chromatography (3/1 hexanes/EtOAc, SiO2) gave 1.35
g (99%) of 23 as a white, sticky solid: 1H NMR δ 1.05 (m, 21
H), 1.10 (t, 3 H, J ) 6.9 Hz), 1.98 (m, 2H), 2.27 (m, 2H), 2.45
(m, 1H), 2.75 (dd, 1 H, J ) 8.2, 18.2 Hz), 3.57 (m, 2 H), 4.22
(dd, 1 H, J ) 2.2, 7.7 Hz), 4.60 (m, 3 H), 7.24 (m, 2 H), 7.39
(m, 3 H); 13C NMR δ 11.1, 13.8, 15.0, 18.5, 30.5, 32.0, 56.3,
58.3, 58.9, 70.8, 81.2, 106.8, 110.6, 126.5, 129.6, 139.0, 157.8,
173.8; IR (film) ν 1751, 1755 cm-1; [R]D ) +26.5° (c ) 1.16,
CH2Cl2); MS (FAB) m/ e 499.3 (M) 500.2 (M + 1).
Alk yn ylbu ten olid e 24. Lactone 23 (0.19 g, 0.39 mmol)
was dissolved in THF (50 mL) and cooled to 0 °C. Tetrabu-
tylammomium fluoride (TBAF) (0.98 mL, 0.97 mmol, 2.5 equiv,
1 M soln in THF) was added dropwise to the solution which
instantly turned an orange color. This was stirred at 0 °C for
3 h. The mixture was partitioned between Et2O (60 mL) and
saturated NH4Cl(aq) (60 mL), the layers were separated, and
the aqueous layer was washed with Et2O (2 × 60 mL). The
organic layers were combined, washed with brine, and then
dried over MgSO4. Purification via flash chromatography (3/1
hexanes/EtOAc, SiO2) gave 0.065 g (93%) of 24 as a colorless
oil: 1H NMR δ 1.14 (t, 3 H, J ) 7.0 Hz), 1.93 (t, 1 H, J ) 2.6
Hz), 2.11 (t, 2 H, J ) 7.6 Hz), 2.35 (m, 2 H), 3.29 (dq, 1 H, J
) 7.2, 9.0 Hz), 3.44 (dq, 1 H, J ) 7.2, 9.0 Hz), 6.16 (d, 1 H, J
) 5.7 Hz), 7.23 (d, 1 H, J ) 5.8 Hz); 13C NMR δ 13.0, 15.0,
36.6, 59.5, 69.3, 83.1, 109.8, 124.5, 153.5, 169.6; IR (film) ν
3290, 1771 cm-1; [R]D ) +76.8° (c ) 1.12, CH2Cl2). Anal.
Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.80; H,
6.51.
4-(Tr iisopr opylsilyl)-3-bu tyn ol. n-Butyllithium (32.7 mL,
1.6 M in hexanes) was added to 1-(triisopropylsiloxy)silyl-3-
butyne (6.96 g, 49.0 mmol) in 200 mL of Et2O at -40 °C, and
the mixture was stirred at -40 °C for 0.5 h. Triisopropylsilyl
trifluoromethanesulfonate (16.51 mL, 53.9 mmol) was added,
and the reaction was allowed to warm to 25 °C and stirred at
that temperature (7 h). The reaction mixture was washed with
H2O, the aqueous layer was extracted with Et2O, and the
combined Et2O layers were washed with 5% NaHCO3(aq) and
brine. Filtration and concentration under reduced pressure
gave the crude alkynol. This was taken up in THF (50 mL),
H2O (30 mL), and glacial acetic acid (30 mL), and the mixture
was stirred at 25 °C (6 h) and then neutralized with NH4OH-
(aq). The aqueous layer was extracted with Et2O (3 × 50 mL),
and the combined Et2O layers were washed with saturated
NH4Cl(aq) and brine and then dried over MgSO4. Filtration
and concentration under reduced pressure gave a yellow oil.
Purification via flash chromatography (5/1 hexanes/EtOAc,
SiO2) gave 10.05 g (91% from 1-(trimethylsiloxy)-3-butyne) of
the product as a colorless oil: 1H NMR δ 1.03 (m, 21H), 1.72
(bs, 1H), 2.52 (t, 2H, J ) 6.2 Hz), 3.70 (t, 2H, J ) 6.2 Hz); IR
(film) ν 3329 cm-1. This was used without further purification.
1-Iod o-4-(tr iisop r op ylsilyl)-3-bu tyn e. Methanesulfonyl
chloride (1.00 mL, 12.9 mmol) was added to 2.66 g (11.8 mmol)
of 4-(triisopropylsilyl)-3-butynol and 1.8 mL (12.9 mmol) of
triethylamine in 200 mL of CH2Cl2 at 0 °C. The mixture was
warmed to 25 °C and stirred at that temperature for 17 h and
then washed with saturated NH4Cl(aq) dried over MgSO4, and
the solvent was removed under vacuum to give 3.60 g (≈100%)
of the desired mesylate as a yellow oil: 1H NMR δ 1.04 (m,
21H), 2.71 (t, 2H, J ) 6.9 Hz), 3.02 (s, 3H), 4.28 (t, 2H, J )
7.0 Hz). This material (3.6 g) was heated at reflux in 60 mL
of acetone containing 18 g of NaI for 24 h, cooled, and
partitioned between hexanes and water. The combined hexane
layers were washed with 10% Na2S2O3(aq) and brine and then
dried over MgSO4. Filtration and concentration under reduced
pressure gave 3.6 g (91% from the alcohol) of the product as a
1
yellow oil: H NMR δ 1.04 (m, 21H), 2.80 (t, 2H, J ) 7.3 Hz),
3.20 (t, 2H, J ) 7.3 Hz); 13C NMR δ 1.61, 11.15, 18.56, 25.09,
82.75, 106.55; IR (film) ν 2173 cm-1. This material was used
without further purification.
[(Eth oxy)(4-(tr iisop r op ylsilyl)-3-bu tyn yl)ca r ben e]p en -
ta ca r bon yl Ch r om iu m (0) (21). A flame-dried 100 mL
Airless flask was charged with iodide 55 (1.68 g, 5.00 mmol)
and Et2O (50 mL), flushed with argon, and then cooled to -78
°C. tert-Butyllithium (6.20 mL, 10.5 mmol, 2.1 equiv 1.7 M
solution in pentanes) was added dropwise to the cooled
mixture, and the resulting solution was stirred at -78 °C for
0.5 h and then gradually warmed to 25 °C. This solution was
Alk en ylbu ten olid e 25. Alkynylbutenolide 24 (0.280 g,
12
1.56 mmol), Lindlar’s catalyst poisoned with MnCl2 (0.012
g), and quinoline (3 drops) were taken up in EtOAc (25 mL)
and stirred under an atmosphere of hydrogen for 1 h. The
mixture was filtered through Celite, washed with 1 M HCl (2

6126 J . Org. Chem., Vol. 61, No. 18, 1996
Kedar et al.
× 20 mL) and H2O (2 × 20 mL), and then dried over Na2SO4.
Purification via flash chromatography (2/1 hexanes/EtOAc,
SiO2) gave 0.264 g (93%) of 25 as a colorless oil: 1H NMR δ
1.16 (t, 3H, J ) 7.0 Hz), 1.97 (m, 2H), 2.15 (m, 2H), 3.32 (dq,
1H, J ) 7.0, 9.0 Hz), 3.47 (dq, 1H, J ) 7.0, 9.0 Hz), 4.95 (dd,
1H, J ) 1.0, 10.2 Hz), 5.02 (dd, 1 H, J ) 1.0, 17.4 Hz), 5.77
(ddt, 1H, J ) 6.4, 10.3, 17.1 Hz), 6.16 (d, 1H, J ) 5.7 Hz), 7.14
(d, 1H, J ) 5.6 Hz); 13C NMR δ 15.0, 27.4, 36.3, 59.3, 110.6,
The AgNO3-impregnated silica gel was prepared by dissolv-
ing AgNO3 (10% w/w of SiO2) in water and adding this to SiO2.
The mixture was thoroughly shaken and then the water
removed under reduced pressure. The silica gel was dried
overnight at 110 °C.
Ep oxid e 29. Butenolide 28 (0.05 g, 0.21 mmol) was
dissolved in a solution of Et2O/DMF (5 mL/5 mL) and cooled
to 0 °C. Sodium hypochlorite (0.31 mL, 0.72 mmol, 2 equiv,
10% solution in H2O) was added dropwise to the cooled solution
and after complete addition the mixture was stirred for 1 h at
0 °C. The reaction mixture was quenched with 10% Na2S2O3
(aq), and the aqueous layer was extracted with Et2O (2 × 10
mL). The combined organic layers were washed with brine
and dried over MgSO4. Filtration and concentration under
reduced pressure and purification via flash chromatography
(5/1 hexanes/Et2O, SiO2) gave 11 mg (21%) of the epoxide and
33 mg of recovered starting material which was resubjected
to the reaction conditions. Recycling the starting material
twice gave 20 mg (38%) of epoxide 29 as a colorless oil: 1H
NMR δ 1.20 (t, 3 H, J ) 7.0 Hz), 1.64 (d, 3 H, J ) 4.4 Hz),
1.82-2.21 (m, 4 H), 2.65 (m, 2 H), 3.62 (dq, 1 H, J ) 7.0, 8.9
Hz), 3.69 (dq, 1 H, J ) 7.0, 8.9 Hz), 3.77 (d, 1 H, J ) 2.5 Hz),
3.94 (d, 1 H, J ) 2.3 Hz), 5.43 (m, 4 H); 13C NMR δ 15.1, 17.9,
26.4, 31.0, 35.5, 50.1, 57.3, 58.7, 107.8, 125.8, 128.7, 129.2,
130.2, 169.1; IR (film) ν 1781 cm-1; [R]D ) +62.6° (c ) 0.8,
CH2Cl2).
(+)-Cer u len in (5). Epoxide 29 (8 mg, 0.03 mmol) was
dissolved in dry Et2O (4 mL) and cooled to 0 °C. Ammonia
gas was bubbled into the mixture for 25 min at 0 °C after
which the solution was allowed to stir for 2 h at 0 °C. The
solvent was removed under reduced pressure. The crude
mixture contained a 1/1 ratio of the linear and cyclic isomers.
Only partial equilibration was observed after 24 h in either
CD3OD or CDCl3. In CD3OD the cyclic isomer 5 was favored
and a mixture of 90% of this and 10% of (+)-5 was obtained.
The linear isomer (+)-5 was dominant in CDCl3, and purifica-
tion via flash chromatography (1/1 Et2O/CH2Cl2, SiO2) gave 6
mg of a mixture of 90% of (+)-5 and 10% of the cyclic isomer.
These were not able to be separated completely.
115.2, 124.3, 137.0, 153.8, 169.8; IR (film) ν 3082, 1770 cm-1
[R]D ) +68.1° (c ) 1.16, CH2Cl2); MS (EI) m/ e 182.1 (M+).
;
Ald eh yd e 26. Alkene 25 (0.20 g, 1.10 mmol) in methanol
(20 mL) was cooled to -78 °C, and ozone was bubbled through
the solution at -78 °C until a blue color persisted (∼5 min).
Then argon was bubbled through the solution until the blue
color disappeared. A mixture of thiourea (0.04 g, 0.55 mmol,
0.5 equiv) in methanol (2 mL) was added, and the resulting
mixture was stirred at -78 °C for 15 min and then warmed
to 0 °C and stirred for a further 1 h. The mixture was
concentrated under reduced pressure, and the resulting white
slurry was diluted with CH2Cl2 (10 mL), washed with 1%
NaHCO3(aq) (1 × 10 mL) and H2O (3 × 10 mL), and then dried
over Na2SO4. Filtration and concentration under reduced
pressure gave 0.19 g (94%) of 26 as a colorless oil. Purification
via flash chromatography (1/1 hexanes/EtOAc, SiO2) gave
0.17g (85%) of pure 26: 1H NMR δ 1.10 (t, 3H, J ) 7.0 Hz),
2.07 (ddd, 1H, J ) 6.6, 7.8, 14.4 Hz), 2.23 (ddd, 1H, J ) 6.6,
7.8, 14.4 Hz), 2.61 (m, 2H), 3.26 (dq, 1H, J ) 7.0, 9.0 Hz), 3.40
(dq, 1H, J ) 7.0, 9.0 Hz), 6.15 (d, 1H, J ) 5.7 Hz), 7.12 (d, 1H,
J ) 5.7 Hz), 9.71 (s, 1H); 13C NMR δ 14.8, 29.9, 37.6, 59.4,
109.6, 124.5, 153.4, 169.3, 200.4; IR (film) ν 1769, 1723 cm-1
;
[R]D ) +26.3° (c ) 0.72, CH2Cl2); MS (FAB) m/ e 184.1 (M),
185.1 (M + 1).
Vin yl Iod id e 27. Chromous (II) chloride (0.69 g, 5.36
mmol, 6 equiv) was weighed out in a glovebag, under an
atmosphere of argon, and suspended in freshly distilled THF
(10 mL). The green suspension was cooled to 0 °C under argon,
and to this was added dropwise a solution of aldehyde 26 (0.16
g, 0.89 mmol, 1 equiv) and iodoform (0.70 g , 1.79 mmol, 2
equiv) in THF (10 mL). The solution went from pale green to
deep orange. This was stirred at 0 °C for 3 h, after which the
mixture was poured into H2O (15 mL) and extracted with Et2O
(3 × 15 mL). The organic layers were combined and dried over
Na2SO4. Filtration and concentration under reduced pressure
and then purification via flash chromatography (1/1 hexanes/
EtOAc, SiO2) gave 0.23 g (85%) of 27 as a pale yellow oil: 1H
NMR δ 1.15 (t, 3H, J ) 7.0 Hz), 1.98 (m, 2H), 2.21 (m, 2H),
3.31 (dq, 1H, J ) 7.0, 9.0 Hz), 3.46 (dq, 1H, J ) 7.0, 9.0 Hz),
6.04 (d, 1H, J ) 14.8 Hz), 6.18 (d, 1H, J ) 5.6 Hz), 6.46 (dt,
1H, J ) 7.1, 14.3 Hz), 7.12 (d, 1H, J ) 5.6 Hz); 13C NMR δ
15.1, 29.9, 36.0, 59.4, 109.5, 124.6, 139.6, 144.6, 153.5, 169.4;
IR (film) ν 3085, 1769 cm-1; [R]D ) +28.3° (c ) 0.6, CH2Cl2);
MS (EI) m/ e 308.0 (M+).
(+)-5: 1H NMR δ 1.66 (d, 3H), 2.31 (q, 2H, J ) 7.0 Hz), 2.64
(m, 4H), 3.72 (d, 1H, J ) 5.0 Hz), 3.85 (d, 1H, J ) 5.0 Hz),
5.30-5.51 (m, 5H), 6.28 (bs, 1H); 13C NMR δ 17.9, 25.9, 29.7,
35.4, 40.8, 55.3, 58.4, 125.8, 127.7, 129.2, 130.7, 167.2, 202.0;
IR (film) ν 3382, 3202, 1720, 1663, 967 cm-1; [R]D ) +63.3°
(natural (+)-cerulenin, mixture of isomers +63°) (c ) 2.62,
MeOH for 24 h). Spectroscopic data are identical with reported
values.26
Cyclic isom er : 1H NMR (300 MHz, CD3OD) δ 1.63 (d, 3H,
J ) 7.0 Hz), 1.78 (m, 2H), 2.21 (m, 2H), 2.64 (m, 2H), 3.58 (d,
1H, J ) 3.0 Hz), 3.81 (d, 1H, J ) 3.0 Hz), 5.42 (m, 4H); 13C
NMR (75.5 MHz, CD3OD) δ 18.2, 28.1, 36.7, 53.3, 59.1, 87.1,
126.5, 130.7, 130.9, 131.2, 186.8.
Bu ten olid e 28. Bis(π-crotyl)nickel bromide (0.09 g, 0.71
mmol, 1.1 equiv) was dissolved in degassed DMF (10 mL). To
this was added a solution of vinyl iodide 27 (0.20 g, 0.65 mmol)-
in DMF (1 mL). The mixture was stirred at 25 °C until the
solution turned emerald green. This was washed with hexanes
(3 × 10 mL). The organic layers were combined and dried over
Na2SO4. Filtration and concentration under reduced pressure
gave 0.136 g (89%) of a 10/1 mixture of butenolide 28 and its
regioisomer. These were separated via flash chromatography
(10/1 hexanes/EtOAc) on SiO2 impregnated with 10% AgNO3:
1H NMR δ 1.16 (t, 3H, J ) 7.0 Hz), 1.62 (d, 3H, J ) 4.1 Hz),
1.88-2.14 (m, 4H), 2.63 (m, 2H), 3.32 (dq, 1H, J ) 7.0, 9.0
Hz), 3.47 (dq, 1H, J ) 7.0, 9.0 Hz), 5.38 (m, 4H), 6.15 (d, 1H,
J ) 5.7 Hz), 7.12 (d, 1H, J ) 5.7 Hz); 13C NMR δ 15.1, 17.8,
26.3, 35.4, 37.0, 59.4, 110.7, 124.3, 125.6, 128.9, 129.3, 129.8,
153.8, 169.9; IR (film) ν 3084, 3022, 1772 cm-1; [R]D ) +48.2°
(c ) 1.10, CH2Cl2); MS (EI) m/ e 236.1 (M+); EI cald for
C14H20O3 236.1412, found 236.1408.
Ack n ow led gm en t. Support for this research by
National Science Foundation Grant CHE-9224489 is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra (60 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O960664K
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