Synthesis of natural α-methylene butyrolactones via tungsten-π-allyl complexes. Total synthesis of (-)-methylenolactocin

Full text of DOI:10.1021/jo9814142

9122
J . Org. Chem. 1998, 63, 9122-9124
Syn th esis of Na tu r a l r-Meth ylen e
Bu tyr ola cton es via Tu n gsten -π-Allyl
Com p lexes. Tota l Syn th esis of
(-)-Meth ylen ola ctocin
Malapaka Chandrasekharam† and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University,
Hsinchu, 30043 Taiwan, ROC
Received J uly 20, 1998
The synthesis of optically pure R-methylene butyro-
lactones has received considerable attention because of
their wide occurrence in bioactive natural products.1 This
structural unit is also synthetically interesting as it is a
useful building block for natural products such as alka-
loids, macrocyclic antibiotics, and pheromones.2 Numer-
ous synthetic methods1,2 have been developed for the
synthesis of chiral R-methylene butyrolactones. We
recently reported3 the synthesis of racemic R-methylene
butyrolactones via tungsten-π-allyl compounds 1a as
shown in Scheme 1 (eq 1). Ligand substitution of this
dicarbonyl π-allyl complex with NO+ and X- generated
a reactive allyl species4 (1b) which reacted with R′′CHO
to yield trans-methylenebutyrolactones in high yields.3b,4
This synthetic method starts with cheap and easily
prepared chloropropargyl derivatives.4 In this paper, we
report application of this method for the synthesis of
natural (-)-methylenolactocin 2, which was first isolated
from the culture filtrate of Penicillium sp. in 1988.5 Its
enantioselective synthesis6 is currently receiving consid-
erable attention because of its antibacterial and anti-
tumor activities.
F igu r e 1. Molecular structure of optically active tungsten-
π-allyl complex 8.
Sch em e 1
prepared from Sharpless asymmetric epoxidation of
2-octenol.7 After fractional crystallization, the ee value
of compound 3 is estimated to be 98% according to GC
analysis of its Mosher ester derivative. This alcohol is
subsequently transformed into alkyn-3-ol 4 in 56% yield
according to the method reported by Takano.8 Treatment
of 4 with TBSCl and imidazole in DMF gave the 3-si-
loxyalkyne 5 in 93% yield. Alkylation of 5 with paraform-
aldehyde followed by tosylation gave an 83% yield of
propargyl tosylate 6. Metalation of compound 6 with
NaCpW(CO)3 proceeded smoothly at 23 °C to yield chiral
tungsten-propargyl complex 7 in 91% yield. Acidifica-
tion of 7 with CF3SO3H catalyst (0.20 equiv) in cold CH2-
Cl2 (-20 °C) led to intramolecular alkoxycarbonylation,
giving chiral tungsten-syn-π-allyl complex 8 in 70%
yield. The syn-configuration of this π-allyl complex was
indicated3b by the coupling constant J 34 ) 3.6 Hz and
further confirmed by X-ray diffraction study;9 its ORTEP
drawing is shown in Figure 1. The C(12) carbon config-
uration of 8 revealed that the intramolecular alkoxycar-
bonylation for conversion of 7 to 8 proceeded with
retention of stereochemistry. Substitutiion of the two
Our synthetic protocol is depicted in Scheme 2. The
starting (2S-trans)-3-pentyloxiranemethanol 3 is readily
† Present address: Indian Institute of Chemical Technology, Hy-
derabad-500007, India.
(1) For review papers, see: (a) Grieco, P. A. Synthesis 1975, 67. (b)
Hoffman, H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl. 1985, 24,
94. (c) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J . Synthesis 1986,
157. (d) Dictionary of Organic Compounds: Chapman and Hall: New
York, 1982. (e) Comprehensive Medicinal Chemistry; Hansch, C., Ed.;
Pergamon Press: Oxford, U.K., 1990. (f) Connolly, J . D.; Hill, R. A.
Dictionary of Terpenoids; Chapman and Hall: London, 1991; Vol. 1,
pp 476-541.
(2) (a) Lee, E.; Lim, J . L.; Yoon, C. H.; Sung, Y. S.; Kim, Y. K. J .
Am. Chem. Soc. 1997, 119, 8391. (b) Aziza, J .; Font, J .; Ortuno, R. M.
Tetrahedron Lett. 1990, 46, 1931. (c) Koch, S. C.; Chamberlin, A. R. J .
Org. Chem. 1993, 58, 2725. (d) Menges, M.; Bruckner, R. Synlett 1993,
901. (e) Ando, M.; Ibayashi, K.; Minami, N.; Nakamura, T.; Isogai, K.;
Yoshimura, H. J . Nat. Prod. 1994, 57, 433. (f) Nagao, Y.; Dai, W.;
Ochiai, M.; Shiro, M. J . Org. Chem. 1989, 54, 5211.
(3) (a) Lin, S.-H.; Vong, W.-J .: Liu, R.-S. Organometallics 1995, 14,
1619. (b) Chen, C.-H. Fan, J .-S. Lee, G.-H., Shieh, S.-J ., Wang, S.-L.;
Peng S.-M.; Liu, R.-S. J . Am. Chem. Soc. 1996, 118, 9279. (c) Shiu, L.
H.; Wang S.-L.; Wu M.-J .; Liu R. S. J . Chem. Soc., Chem. Commun.
1997, 2055.
(4) (a) Faller, J . W.; Linebarrier D. L. J . Am. Chem. Soc. 1989, 111,
1939. (b) Faller, J . W.; J ohn, J . A.; Mazzier, M. R. Tetrahedron Lett.
1989, 31, 1769.
(5) Park, B. K.; Nakagara, M.; Hirota, A.; Nakakayama, M. J .
Antibiot. 1988, 41, 751.
(6) For total synthesis of methylenolactocinin in enantiomeric6a-c
and racemic forms,6d-g see: (a) Zhu, G.; Lu, X. J . Org. Chem. 1995,
60, 1087. (b) Martin, T.; Rodriguez, C. M.; Martin, V. C. J . Org. Chem.
1996, 61, 6450 (c) Azevedo, de M. B.; Murta, M. M.; Greene, A. E. J .
Org. Chem. 1992, 57, 4567. (d) Mandal, P. K.; Maiti, G.; Roy, S. C. J .
Org. Chem. 1998, 63, 2829. (e) Vaupel, A.; P. Knochel, P. Tetrahedron
Lett. 1995, 36, 231 (f) Ghosh, B.; Sakar, S. Tetrahedron Lett. 1996, 37,
4809. (g) Saicic, R. N.; Zair, S. Z. J . Chem. Soc., Chem. Commun. 1996,
14.
(7) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(8) Takano, S.; Samizu, K.; Sugihara, T.; Ogawawara, K. J . Chem.
Soc., Chem. Commun. 1989, 1344.
(9) Compound 8 crystallizes in the monoclinic space group P212121,
orthorhombic, a ) 7.2500(1) Å, b ) 11.0386(2) Å, c ) 21.4606(2) Å, V
) 1717.5(6) Å3, Z ) 4. Data were collected on a Siemens R3m/V
diffractometer, using Mo KR radiation. Final R ) 0.0268, Rw ) 0.0250
for 9202 reflections >3.0σ(I) out of 10 107 unique reflections.
10.1021/jo9814142 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

Notes
J . Org. Chem., Vol. 63, No. 24, 1998 9123
Sch em e 2
carbonyls of 8 via sequential treatment with NOBF4 and
NaI in CH3CN (0 °C) generated the corresponding CpW-
(NO)I(π-allyl)3,4 derivative 9 which was used in situ to
achieve better yields of reaction products. Compounds
such as 9 can undergo highly diastereoselective conden-
sation with aldehydes and ketones.3b,4 Attempts to
perform carboxylation of species 9 with flowing CO2 were
unsuccessful, and no (-)-methylenolactocin could be
found over the temperature ranges -40 to 23 °C.
Exp er im en ta l Section
Unless otherwise noted, all reactions were carried out under
nitrogen atmosphere in oven-dried glassware using standard
syringe, cannula, and septa apparatus. Benzene, diethyl ether,
tetrahydrofuran, and hexane were dried with sodium benzophe-
none and distilled before use. Dichloromethane was dried over
CaH2 and distilled before use. W(CO)6, sodium, dicyclopenta-
diene, tosyl chloride, triflic acid, tert-butyl hydroperoxide, Ti-
(OPri)4, (+)-diethyl tartarate, 2-octenol, and sodium were ob-
tained commercially and used without purification. NaCpW(CO)3
was prepared12 by stirring of [CpW(CO)3]2 with sodium amalgam
in THF for 8 h and it was used in situ. The syntheses of organic
substrates 3-5 followed the methods in the literature reports,7,8
and spectral data were identical to those of the authentic
samples.
To circumvent this synthetic problem, species 9 was
treated with TBSOCH2CHO in CH3CN at 23 °C (6 h) to
yield trans-R-methylenebutyrolactone 10 as a single
stereoisomer in 67% yield. The trans-configuration of 10
was determined by a proton NOE experiment. Although
the CH(OH) configuration of 10 is not determined, it is
presumbly to have anti configuration according to our
previous studies on closely related system.3a-c The
reaction of this type has been elucidated to involve a
chairlike transition state to control the stereochemistry
of the products.3a-c,4 Desilylation of compound 10 was
achieved in the presence of Bu4NF to give the diol 11 in
89% yield, and J ones oxidation of 11 effected oxidative
cleavage10 of the 1,2-diol 11 to form (-)-methylenolactocin
(4S)-1-Tolu en e-p -su lfon yloxy-4-(ter t-b u t yld im et h ylsil-
oxy)n on -2-yn e (6). To a cold (-78 °C) stirred solution of
compound 5 (2.80 g, 20.0 mmol) in THF (15.0 mL) was added
BuLi (12.5 mL, 1.60 M solution in hexane, 20.0 mmol) under
N2, and the mixture was stirred for 30 min. To this solution
was added paraformaldehyde (1.20 g, 40.0 mmol) in THF (10
mL), and the mixture was warmed to 23 °C and stirred for an
additional 45 min. The resulting mixture was filtered through
a Celite pad, and to the filtrate was added brine (10 mL). The
organic layer was separated, and the aqueous layer was ex-
tracted with Et2O (3 × 20 mL). The combined organic layer was
dried (MgSO4) and concentrated to afford a crude alcohol as a
yellow oil (4.59 g, 85%) which was subjected to tosylation without
further purification. The above alcohol in acetone (10 mL) was
added to a solution of TsCl (3.2 g, 17.1 mmol) dissolved in 25
mL of acetone. To the resulting cooled (0 °C) solution was added
slowly a solution of KOH (1.42 g, 25.5 mmol) dissolved in 3 mL
of H2O; stirring was continued for 6 h. The solvent was removed
in vacuo, and the residue was dissolved in Et2O (50 mL), washed
with brine (2 × 20 mL), dried (MgSO4), and concentrated. The
resulting crude solid was purified by silica gel chromatography
2 in 81% yield. Spectral data of 2 {[R]25 ) -6.77 (c )
D
0.52, MeOH)} in this synthesis are virtually identical to
those of the authentic sample {[R]25 ) -6.8 (c ) 0.5,
D
MeOH)} reported in the literature.5,6
In conclusion, we have demonstrated that tungsten-
π-allyl complexes can be used for total synthesis of
natural (-)-methylenolactocin 2. This route proves to be
efficient because only a few steps were involved based
on chiral propargyl tosylate that was easily prepared
according to literature papers.8,11 The key step in this
synthesis relies on intramolecular alkoxycarbonylation
of tungsten-propargyl compounds to yield chiral tungsten-
π-γ-lactonyl complex, ultimately preceding to (-)-meth-
ylenolactocin according to chemistry of tungsten-π-allyl
compounds.
using hexane/ether (9/1) as eluent to afford 6 (7.03 g, 83%): [R]22
D
) -29.0 (c 0.82; CHCl3); IR (neat) 2112 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.76 (d, J ) 8.1 Hz, 2 H), 7.30 (d, J ) 8.1 Hz, 2 H),
4.70 (d, J ) 1.4 Hz, 2 H), 4.19 (t, J ) 6.4 Hz, 1 H), 2.41 (s, 3 H),
1.47 (m, 2 H), 1.35-1.15 (m, 6 H), 1.84 (m, 12 H), 0.02 (s, 3 H),
0.01 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 144.8, 133.1, 129.7,
127.9, 91.1, 75.4, 62.5, 58.0, 38.0, 31.2, 25.6, 24.6, 22.4, 21.5,
18.0, 13.9, -4.6, -5.2; HRMS calcd for C22H36O4SSi 424.2103,
found 424.2108.
Tu n gsten -η1-P r op a r gyl Com p ou n d (7). To a THF (50
(10) Epifanio, R. A.; Camargo, W.; Pinto, A. C. Tetrahedron Lett.
1988, 29, 6403.
(11) (a) Midland, M. M. In Asymmetric Synthesis; Morrison, J . D.,
Ed.; 1983; Vol. 2, part A, pp 45-69. (b) Yadav, J . Y.; Chander, M. C.;
J oshi, B. V. Tetrahedron Lett. 1988, 29, 2737. (c) Soai, K.; Niwa, S.
Chem. Lett. 1989, 481.
mL) solution of CpW(CO)3Na12 (5.0 mmol) was slowly added
(12) Eisch, J . J .; King, R. B., Eds. Organometallic Synthesis;
Academic: New York, 1965; Vol. 1, pp 114-116.

9124 J . Org. Chem., Vol. 63, No. 24, 1998
Notes
compound 6 (2.12 g, 5.0 mmol) in THF (5 mL). The mixture
was stirred for 5 h at 23 °C. The solution was evaporated to
dryness, and the resulting residue was chromatographed over
a short neutral alumina column under medium pressure to yield
compound 7 as a yellow oil (2.66 g, 91%): [R]21D ) -30.5 (c 0.74;
CHCl3); IR (neat) 2015, 1915 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.47 (s, 5 H), 4.35 (t, J ) 6.6 Hz, 1H), 1.99 (s, 2 H), 1.68-1.53
(m, 2 H), 1.48-1.20 (m, 6 H), 0.89 (m, 12 H), 0.11 (s, 3 H), 0.08
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 229.3, 216.4, 216.3, 93.2,
92.7, 82.3, 63.7, 39.6, 31.6, 25.8, 25.1, 22.7, 16.3, 14.1, -4.3, -4.9,
Dep r otection of TBS Eth er . Syn th esis of Dih yd r oxy-
la cton e (11). To a stirring THF (5 mL, 0 °C) solution of 10
(0.68 g, 2.0 mmol) was added dropwise a 1 M THF solution of
Bu4NF (2.4 mL, 2.4 mmol). Stirring is continued for 1.5 h. The
resulting solution was concentrated, and the residue was dis-
solved in EtOAc, washed with H2O and brine, dried (MgSO4),
filtered, and concentrated. The crude compound was chromato-
graphed on silica column (diethyl ether/hexane ) 1/1) to give
11 as a light yellow oil (0.40 g, 89%): [R]24 ) -5.2 (c 0.36;
D
CHCl3); IR (neat) 3450 (br), 1770, 1470 cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.28 (d, J ) 1.9 Hz, 1 H), 5.75 (d, J ) 1.9 Hz, 1H), 4.39
(m, 1 H), 3.78-3.42 (m, 5 H), 2.80 (m, 1 H), 1.65-1.49 (m, 2 H),
1.48-1.12 (m, 6 H), 0.85 (t, J ) 6.4 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 170.9, 135.1, 125.5, 80.6, 72.9, 63.4, 47.0, 36.1, 31.4,
24.4, 22.4, 13.9; HRMS calcd for C12H20O4 228.1361, found
228.1367.
-32.1; MS (75 eV, m/e) 586 (M+). Anal. Calcd for C23H34
-
WSiO4: C, 47.09; H, 5.85. Found: C, 47.13; H, 5.87.
Syn th esis of Cp W(CO2)(π-γ-la cton yl) Com p ou n d (8). To
a CH2Cl2 (20 mL) solution of 7 (2.90 g, 5.0 mmoL) at -40 °C
was slowly added CF3SO3H (0.09 mL, 1.0 mmol), and the
mixture was stirred for 1 h before the temperature was raised
to 0 °C. To the resulting solution was added a saturated
NaHCO3 solution (3 mL). The organic layer was separated, and
the aqueous layer was extracted with dichloromethane (3 × 20
mL). The combined organic layer was dried (MgSO4), concen-
trated, and eluted through a silica column (diethyl ether/hexane
(-)-Meth ylen ola ctocin (2). A solution of the dihydroxylac-
tone 11 (0.22 g, 1.0 mmol) in acetone (4 mL) was treated with
freshly prepared J ones reagent at 40 °C until a persistent orange
color was observed. After the solution was stirred for 5 min
(TLC) and cooled to room temperature, 2-propanol was added
to destroy the excess reagent. The reaction mixture was diluted
with water (2 mL), and acetone was removed under reduced
pressure. The residue was extracted with CH2Cl2 (3 × 5 mL).
The organic extract was washed with brine (4 mL) and dried
(MgSO4). Evaporation of the solvent afforded a residue which
was purified by a short column of silica gel (diethyl ether/hexane
) 1/2) to give 8 as a yellow solid (1.65 g, 70%): [R]26 ) +68.6°
D
(c 1.12; CHCl3); IR (Nujol) 1950, 1867, 1750 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.35 (s, 5 H), 5.03 (m, 1 H), 3.68 (d, J ) 3.2 Hz,
1H), 3.07 (d, J ) 3.5 Hz, 1 H), 1.78-1.22 (m, 9 H), 0.91 (t, J )
6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 224.5, 219.7, 175.5,
93.3, 80.7, 70.0, 69.3, 38.5, 31.3, 25.4, 22.2, 19.5, 13.7; MS (75
eV, m/e) 472 (M+). Anal. Calcd for C17H20WO4: C, 43.21; H,
4.27. Found: C, 43.25; H, 4.32.
) 4/1) to give (-)-methylenolactocin 2 (0.17 g, 81%): [R]24 ) -
D
6.77 (c 0.52, MeOH); IR (neat) 3460, 1750, 1660, 1460 cm-1; 1H
NMR (600 MHz, CDCl3) δ 6.44 (d, J ) 2.9 Hz, 1H), 6.00 (d, J )
2.9 Hz, 1H), 4.78 (m, 1 H), 3.61 (m, 1 H), 1.73 (m, 2 H), 1.52-
1.20 (m, 6 H), 0.86 (t, J ) 3.4 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 173.8, 168.2, 132.4, 125.8, 78.8, 49.5, 35.6, 31.3, 24.4,
22.3, 13.6; HRMS calcd for C11H16O4 212.1048, found 212.1052.
Con d en sa tion of π-Allyl Com p lex 8 w ith 2-(ter t-bu -
tyld im eth ylsiloxy)a ceta ld eh yd e. To a stirring CH3CN (7
mL) solution of π-allyl compound 8 (1.41 g, 3.0 mmol) was slowly
added a CH3CN (2 mL) solution of NOBF4 (0.38 g, 3.3 mmol) at
0 °C. After 30 min, NaI (0.90 g, 6.0 mmol) was added, and the
mixture was stirred for additional 30 min and treated with
TBSOCH2CHO (0.57 g, 3.3 mmol) at 0 °C. The solution was
warmed to 23 °C and stirred for 4 h to produce a dark orange
precipitate. The solution was treated with NaHCO3, concen-
trated, and eluted on a preparative TLC plate (diethyl ether/
hexane ) 7/1) to give compound 10 as a yellow oil (0.68 g, 67%):
Ack n ow led gm en t. The authors wish to thank the
National Science Council, Taiwan, for support of this
work.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
all new compounds; tables of crystal data and thermal
parameters and ORTEP drawing of compound 8 (28 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
[R]24 ) -5.4° (c 0.58; CHCl3); IR (neat) 3450 (br), 1770, 1470
D
cm-1 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J ) 2.4 Hz, 1 H),
;
5.79 (d, J ) 2.4 Hz, 1 H), 4.43 (m, 1 H), 3.68-3.45 (m, 3 H), 2.91
(m, 1 H), 1.63-1.22 (m, 8 H), 0.88 (13H, 2s + m), 0.07 (6H, s);
13C NMR (100 MHz, CDCl3) δ 170.1, 135.3, 124.8, 79.5, 72.7,
63.5, 46.9, 36.3, 31.5, 31.3, 25.7, 25.5, 24.4, 22.4, 18.1, 13.8, -5.4;
HRMS calcd for C18H34SiO4 342.2226, found 342.2231.
J O9814142