Synthesis of dimethyl gloiosiphone A by way of palladium-catalyzed domino cyclization

Article abstract of DOI:10.1021/jo062546v

(Chemical Equation Presented) The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear 7-methylene-2,10- undecadienyl acetate is described. The π-allylpalladium intermediate underwent intramolecular alkene ins

Full text of DOI:10.1021/jo062546v

Synthesis of Dimethyl Gloiosiphone A by Way of
Palladium-Catalyzed Domino Cyclization
Takayuki Doi, Yusuke Iijima, Masaru Takasaki, and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama,
Meguro, Tokyo 152-8552, Japan
ttak@apc.titech.ac.jp
ReceiVed December 12, 2006
The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear
7-methylene-2,10-undecadienyl acetate is described. The π-allylpalladium intermediate underwent
intramolecular alkene insertion with high intraannular diastereoselectivity, followed by intramolecular
Heck-type cyclization, leading to a spiro[4.4]nonane system. Oxidation of the allylic ether moiety and
transformation of the vinyl group to an exo-methylene unit provided 3, which is the known synthetic
intermediate of dimethyl gloiosiphone A (2).
Introduction
fused system from a linear alkenyl-allenyl-allylic acetate via
six consecutive carbon-carbon bond formations under carbo-
nylation conditions.6 Few examples using the intramolecular
alkene insertion to a π-allylpalladium complex in the formation
of a spiro ring system have been reported, although the Heck-
type polyene cyclizations were demonstrated.7-10 We wish to
report palladium-catalyzed domino cyclization of a 7-methylene-
2,10-undecadienyl acetate derivative providing a spiro[4.4]-
Reactions of π-allylpalladium complexes with various nu-
cleophiles are important for carbon-carbon bond formations.1
Since Oppolzer reported that palladium-catalyzed cyclization
of 2,7-octadienyl acetate in acetic acid provides 1-methylene-
2-vinylcyclopentane,2 intramolecular insertion of alkene, alkyne,
and allene moieties to the π-allylpalladium complex3 has been
applied to the construction of not only five- and six-membered
rings but also fused ring systems.4 We have already demon-
strated that palladium-catalyzed domino cyclization of 6-vinyl-
2,8-nonadienyl acetate formed a trans fused bicyclo[3.3.0]octane
system.5 It was further applied to the construction of a four ring
(4) Takahashi, T.; Doi, T. Allylpalladation and Related Reactions of
Alkenes, Alkynes, Dienes, and other π-Compounds. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., de Meijere,
A., Eds.; Wiley-Interscience: New York, 2002; Vol. 1, pp 1449-1462.
(5) Doi, T.; Yanagisawa, A.; Takahashi, T.; Yamamoto, K. Synlett 1996,
145-146.
(6) (a) Doi, T.; Yanagisawa, A.; Nakanishi, S.; Yamamoto, K.; Takahashi,
T. J. Org. Chem. 1996, 61, 2602-2603. (b) Doi, T.; Takasaki, M.;
Nakanishi, S.; Yanagisawa, A.; Yamamoto, K.; Takahashi, T. Bull. Chem.
Soc. Jpn. 1998, 71, 2929-2935.
(7) Grigg, R.; Sridharan, V.; Stevenson, P.; Worakun, T. J. Chem. Soc.,
Chem. Commun. 1986, 1697-1699.
(1) (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144-152. (b) Tsuji, J. Palladium
Reagents and Catalysts; Wiley: Chichester, UK, 2004; pp 438-469. (c)
Michelet, V.; Geneˆt, J.-P.; Savignac, M. Synthesis of Natural Products and
Biologically Active Compounds via Allylpalladium and Related Derivatives.
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., de Meijere, A., Eds.; Wiley-Interscience: New York, 2002; Vol. 2, pp
2027-2117.
(2) (a) Oppolzer, W.; Gaudin, J.-M. HelV. Chim. Acta 1987, 70, 1477-
1481. (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 38-52.
(3) (a) Go´mez-Bengoa, E.; Cuerva, J. M.; Echavarren, A. M.; Martorell,
G. Angew. Chem., Int. Ed. Engl. 1997, 36, 767-769. (b) Ca´rdenas, D. J.;
Alcam´ı, M.; Coss´ıo, F.; Me´ndez, M.; Echavarren, A. M. Chem.sEur. J.
2003, 9, 96-105.
(8) (a) Abelman, M. M.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
2328-2329. (b) Overman, L. E.; Abelman, M. M.; Kucera, D. J.; Tran,
V. D.; Ricca, D. J. Pure Appl. Chem. 1992, 64, 1813-1819.
(9) Wu, G.; Lamaty, F.; Negishi, E. J. Org. Chem. 1989, 54, 2507-
2508.
(10) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421-9438.
10.1021/jo062546v CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/12/2007
J. Org. Chem. 2007, 72, 3667-3671
3667

Doi et al.
SCHEME 1. Palladium-Catalyzed Domino Cyclization of 5
FIGURE 1. Synthetic strategy of dimethyl gloiosiphone A (2).
Results and Discussion
A linear precursor 5 (R ) MPM) was prepared by palladium-
catalyzed one-pot sequential allylation of bis(phenylsulfonyl)-
methane (7) (Scheme 1).15 A suspension of 7 (2 equiv) and an
excess amount of NaH (4.4 equiv) were treated with 2-substi-
tuted allyl acetate 8 (1 equiv) in the presence of a palladium
catalyst. In the first allylation, 2 equiv of 7 was used to avoid
diallylation of 7. After the reaction was complete, cis-4-bromo-
2-butenyl acetate (9) (4.4 equiv) was added to the reaction
mixture in one pot. It is theoretically essential to add 4 equiv
of NaH and 9 to complete the second allylation and to consume
remaining 7. Although it was necessary to add an additional
amount of the palladium catalyst to complete the second
allylation, the bromo group in 9 was selectively displaced by
forming a π-allylpalladium intermediate to provide (E)-5 in 74%
overall yield.16 The product 5 was isolated by silica gel column
chromatography, whereas the diallylation product of 7 with 9
was also obtained.
The palladium-catalyzed domino cyclization of 5 was inves-
tigated by tuning ligands and reaction temperature (Table 1).
The reaction proceeded at 90 °C better than at the lower
temperature (entry 3 vs entries 1 and 2).6b Addition of
triphenylphosphine provided better results than other ligands,
such as tri(2-furyl)phosphine (38% in entry 4) and o-tolylphos-
phine (40% in entry 5). The desired spiro[4.4]nonane 10 was
obtained as a 60:40 diastereomer mixture in 66% yield (entry
3). Deprotection of the MPM group in 10, followed by oxidation,
FIGURE 2. HMBC analysis of compound 12.
nonane system and its application to a formal total synthesis of
dimethyl gloiosiphone A (2).
Gloiosiphone A (1), isolated from Gloiosiphonia Verticillaris,
exhibits antimicrobial activity against several Staphylococcus,
Bacillus, and Salmonella species.11 Since 1 is not stable, the
structure was proved as its di-O-methylated derivative 2. These
compounds have a highly oxygenated spiro[4.4]nonenedione
system. Three total syntheses of dimethyl gloiosiphone A (2)
utilizing unique construction of the spiro[4.4]nonane system
have been reported.12-14 Our synthetic strategy for 2 is illustrated
in Figure 1. Spiro[4.4]nonane 4 can be constructed from a linear
precursor 5 by way of palladium-catalyzed domino cyclization,
such as intramolecular alkene insertion to a π-allylpalladium
intermediate 6, followed by Heck-type cyclization. Oxidative
transformation of the allylic ether moiety in 4 would form 2,3-
dimethoxy-2-cyclopentenone, and the vinyl moiety in 4 can be
converted to a methylene unit to provide 3, which is the known
synthetic intermediate in the total synthesis of 2.13
(11) Chen, J. L.; Moghaddam, M. F.; Gerwick, W. H. J. Nat. Prod. 1993,
56, 1205-1210.
(12) (a) Paquette, L. A.; Sturino, C. F.; Doussot, P. J. Am. Chem. Soc.
1996, 118, 9456-9457. (b) Sturino, C. F.; Doussot, P.; Paquette, L. A.
Tetrahedron 1997, 53, 8913-8926.
(13) (a) Sha, C.-K.; Ho, W.-Y. Chem. Commun. 1998, 2709-2710. (b)
Sha, C.-K.; Ho, W.-Y. J. Chin. Chem. Soc. 1999, 46, 469-475.
(14) Hashizume, Y.; Maki, S.; Ohashi, M.; Niwa, H. Synlett 1998, 1357-
1358.
(15) Ferroud, D.; Gaudin, J. M.; Genet, J.-P. Tetrahedron Lett. 1986,
27, 845-846.
(16) Nystro¨m, J.-E.; Ba¨ckvall, J.-E. J. Org. Chem. 1983, 48, 3947-3950.
3668 J. Org. Chem., Vol. 72, No. 10, 2007

Dimethyl Gloiosiphone A by Pd-Catalyzed Domino Cyclization
TABLE 1. Palladium-Catalyzed Domino Cyclization of 5 to 10
SCHEME 2. Formal Total Synthesis of Dimethyl
Gloiosiphone A (2)
Pd(OAc)2 (10 mol %) +
yield (%)
of 10
entry
ligand (40 mol %)
temp (°C)
1
2
3
4
5
PPh3
PPh3
PPh3
P(2-furyl)3
P(o-tol)3
70
80
90
90
90
58
57
66
38
40
provided 12 as a single product, whose structure was determined
by analysis of H-H COSY, HMBC (Figure 2), and HMQC
spectra and NOE measurement. The results exhibited that this
system exclusively controlled the intraannular diastereoselection
in the Pd(0)-catalyzed cyclization via 6A, and the resulting
σ-palladium intermediate 11 underwent the intramolecular Heck
reaction, followed by â-hydride elimination, leading to the
formation of a spiro compound 10.17 On the other hand,
diastereoselectivity induced from the stereogenic center of the
methoxyphenylmethyloxy (OMPM) substituent was not high.
Removal of the phenylsulfonyl groups in 10 with Mg,18
ozonolysis of the two alkene moieties, and selective reduction
of the resulting aldehyde with LiAlH(O-tBu)3 provided 13. The
primary alcohol in 13 was converted into a phenylselenyl
group19 by displacement of its tosylate.20 Oxidative â-hydride
elimination of the phenylselenyl group afforded 14 in 61%
overall yield. Removal of the MPM group, followed by
oxidation of the resulting alcohol with SO3•Py afforded 15,
which was in equilibrium with 1,2-diketone. After O-methyla-
tion, R-hydroxyketone 16 was prepared by treatment with
KHMDS and the Davis reagent.21 Base treatment of 16 provided
the thermodynamically stable 2-hydroxy-3-methoxy-6-
methylenespiro[4.4]non-2-en-1-one, which was immediately
converted to 3 by O-methylation in 76% overall yield. The
spectral data of 3 were identical to those reported by Sha and
Ho, who have demonstrated the total synthesis of 2 from 3 in
three steps.13 Thus, this synthesis constitutes a formal total
synthesis of dimethyl gloiosiphone A (2) (Scheme 2).
mmol), and triphenylphosphine (689 mg, 2.63 mmol) in THF (20
mL) was added at room temperature and stirred at reflux for 3 h.
A solution of (Z)-4-bromo-2-butenyl acetate (9) (4.19 g, 28.9 mmol),
palladium acetate (148 mg, 0.657 mmol), and triphenylphosphine
(689 mg, 2.63 mmol) in THF (20 mL) was added at room
temperature and stirred under reflux for another 1 h. The reaction
mixture was poured into 1 M HCl at 0 °C. The aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with saturated aqueous NaHCO3 solution and brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by chromatography on silica gel (25% ethyl acetate in hexane) to
give (E)-9-(4-methoxybenzyloxy)-7-methylene-5,5-di(phenylsulfo-
nyl)-2,10-undecadienyl acetate (5) (3.11 g, 4.86 mmol, 74%): 1H
NMR (400 MHz, CDCl3) δ 7.96-8.00 (m, 4H), 7.65-7.69 (m,
2H), 7.49-7.54 (m, 4H), 7.20-7.22 (m, 2H), 6.86-6.88 (m, 2H),
5.86-5.94 (m, 1H), 5.65-5.73 (m, 2H), 5.17-5.21 (dd, J ) 17.5,
10.2 Hz), 5.10 (s, 1H), 5.08 (s, 1H), 4.44-4.49 (m, 3H), 4.21 (d,
1H, J ) 11.1 Hz), 3.80-3.88 (m, 4H), 3.12 (d, 2H, J ) 6.3 Hz),
3.01 (s, 2H), 2.32-2.41 (m, 2H), 2.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.8, 159.2, 138.4, 137.4, 137.3, 134.6, 131.8, 130.7,
129.4, 129.3, 128.6, 127.6, 120.7, 117.4, 113.8, 91.7, 79.6, 69.9,
64.5, 55.4, 43.9, 36.0, 33.4, 21.0; IR (neat) 1739, 1514, 1448, 1311,
1247, 1144, 1077, 725, 689, 572 cm-1; HRMS (ESI-TOF) calcd
for [C34H38O8S2 + Na]+ 661.1906, found 661.1900.
7-(4-Methoxybenzyloxy)-8-methylene-3,3-di(phenylsulfonyl)-
1-vinylspiro[4.4]nonane (10). To a solution of (E)-9-(4-methoxy-
benzyloxy)-7-methylene-5,5-di(phenylsulfonyl)-2,10-undecadie-
nyl acetate (5) (2.50 g, 3.92 mmol) in acetic acid (15 mL) were
added palladium acetate (88 mg, 0.392 mmol) and triphenylphos-
phine (411 mg, 1.57 mmol) at room temperature. After being stirred
at 90 °C for 2 h, the reaction mixture was concentrated in vacuo.
The residue was purified by chromatography on silica gel (7% ethyl
acetate in toluene) to give 7-(4-methoxybenzyloxy)-8-methylene-
3,3-di(phenylsulfonyl)-1-vinylspiro[4.4]nonane (10) (1.50 g, 2.60
mmol, 66%, dr ) 60:40). The diastereomers were separated by
HPLC (20% ethyl acetate in hexane, 3.00 mL/min, RT ) 19.5 min
(minor isomer), 20.7 min (major isomer)). Major isomer: 1H NMR
(400 MHz, CDCl3) δ 8.02-8.06 (m, 4H), 7.69-7.72 (m, 2H),
7.56-7.59 (m, 4H), 7.19-7.22 (m, 2H), 6.84-6.87 (m, 2H), 5.57-
5.66 (m, 1H), 4.98-5.09 (m, 4H), 4.47 (d, 1H, J ) 11.1 Hz), 4.36
(d, 1H, J ) 11.6 Hz), 4.09-4.13 (m, 1H), 3.81 (s, 3H), 2.77 (d,
In conclusion, we have demonstrated palladium-catalyzed
domino cyclization of 5, synthesized by a one-pot two-step
allylation, which stereoselectively provides a spiro[4.4]nonane
skeleton. Oxidation of the allylic ether moiety and transforma-
tion of the vinyl group to an exo-methylene unit furnished the
desired 6-methylene-2,3-dimethoxyspiro[4.4]non-2-en-1-one (3).
Experimental Section
(E)-9-(4-Methoxybenzyloxy)-7-methylene-5,5-di(phenylsulfo-
nyl)-2,10-undecadienyl acetate (5). To a suspension of sodium
hydride (1.26 g, 28.9 mmol, 55%, washed with dry hexane) in THF
(10 mL) was added bis(phenylsulfonyl)methane (7) (3.89 g, 13.1
mmol) in THF (10 mL) at 0 °C. When gas evolution was complete,
a solution of 4-(4-methoxybenzyloxy)-2-methylene-5-hexenyl ac-
etate (8) (1.91 g, 6.57 mmol), palladium acetate (148 mg, 0.657
(17) After conversion of 10 to exo-methylene 14, a diastereomer mixture
was still observed though the stereogenic center at the vinyl group in 10
was lost in 14. This result also proved the high intraannular diastereose-
lectivity.
(18) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749-1750.
(19) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697-
2699.
(20) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183-2192.
(21) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M. J. Org. Chem.
1984, 49, 3241-3243. (b) Vishwakarma, L. C.; Stringer, O. D.; Davis,
F. A. Org. Synth. 1987, 66, 203-211.
J. Org. Chem, Vol. 72, No. 10, 2007 3669

Doi et al.
1H, J ) 16.4 Hz), 2.70 (d, 1H, J ) 16.4 Hz), 2.46-2.63 (m, 5H),
2.26 (d, 1H, J ) 16.9 Hz), 1.90-1.95 (m, 1H), 1.78-1.82 (m,
1H); 13C NMR (67.8 MHz, CDCl3) δ 159.0, 150.7, 137.0, 136.2,
135.3, 134.5, 134.4, 131.4, 131.3, 130.7, 129.1, 128.7, 128.6, 118.2,
113.8, 110.7, 93.0, 79.7, 69.9, 55.3, 51.9, 51.8, 45.3, 44.2, 38.5,
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (30%
ethyl acetate in hexane) to give 3-(4-methoxybenzyloxy)-6-
(hydroxymethyl)spiro[4.4]nonan-2-one (13) (1.67 g, 5.50 mmol,
92%, diastereomer mixture). Major isomer: 1H NMR (400 MHz,
CDCl3) δ 7.30-7.27 (m, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.78 (d,
J ) 11.1 Hz, 2H), 4.61 (d, J ) 11.6 Hz, 2H), 3.91 (dd, J ) 9.2,
8.7 Hz, 1H), 3.80 (s, 3H), 3.68 (dd, J ) 10.6, 6.8 Hz, 1H), 3.59
(dd, J ) 10.6, 6.3 Hz, 1H), 2.43 (d, J ) 17.8 Hz, 1H), 2.18-1.87
(m, 5H), 1.69-1.57 (m, 4H), 1.37-1.32 (m, 1H); 13C NMR (67.8
MHz, CDCl3) δ 216.2, 159.4, 129.7, 129.6, 113.8, 78.9, 72.0, 63.7,
55.3, 49.5, 44.1, 43.5, 41.5, 40.5, 27.7, 22.0; IR (neat) 3463, 2951,
1744, 1612, 1586, 1513, 1466, 1399, 1302, 1248, 1174, 1034, 822,
754, 518 cm-1; HRMS (ESI-TOF) calcd for [C18H24O4 + Na]+
327.1567, found 327.1564.
3-(4-Methoxybenzyloxy)-6-methylenespiro[4.4]nonan-2-one (14).
To a solution of 3-(4-methoxybenzyloxy)-6-(hydroxymethyl)spiro-
[4.4]nonan-2-one (13) (175 mg, 0.569 mmol), trimethylamine
hydrochloride (5 mg, 0.0569 mmol), and triethylamine (0.16 mL,
1.14 mmol) in dichloromethane (3 mL) was added p-toluenesulfonyl
chloride (163 mg, 0.853 mmol) at 0 °C. After being stirred at the
same temperature for 30 min, the reaction mixture was quenched
with 1 M HCl. The aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (15% ethyl acetate in hexane) to give
3-(4-methoxybenzyloxy)-6-(p-toluenesulfonyloxymethyl)spiro[4.4]-
nonan-2-one (247 mg, 0.539 mmol, 95%, diastereomer mixture).
Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J ) 7.7
Hz, 2H), 7.36-7.26 (m, 4H), 6.87 (d, J ) 8.7 Hz, 2H), 4.75 (d,
J ) 11.6 Hz, 1H), 4.58 (d, J ) 11.6 Hz, 1H), 4.01-3.80 (m, 6H),
2.44 (s, 3H), 2.23-1.24 (m, 11H); 13C NMR (100 MHz, CDCl3) δ
215.0, 159.4, 145.0, 132.7, 130.0, 129.6, 127.9, 113.9, 78.6, 72.0,
70.7, 55.3, 46.1, 44.0, 43.3, 41.3, 39.7, 27.6, 21.8, 21.6; IR (neat)
2957, 1749, 1613, 1598, 1515, 1464, 1361, 1249, 1176, 1097, 955,
817, 667, 555 cm-1; HRMS (ESI-TOF) calcd for [C25H30O6S +
Na]+ 481.1655, found 481.1656.
37.1; IR (neat) 1613, 1514, 1448, 1328, 1310, 1144, 1078 cm-1
;
HRMS (ESI-TOF) calcd for [C32H34O6S2 + Na]+ 601.1694, found
601.1689.
3-Methylene-8,8-di(phenylsulfonyl)-6-vinylspiro[4.4]nonan-2-
one (12). To a solution of 7-(4-methoxybenzyloxy)-8-methylene-
3,3-di(phenylsulfonyl)-1-vinylspiro[4.4]nonane (10) (685 mg, 1.18
mmol) in dichloromethane (3.8 mL) and water (0.2 mL) was added
DDQ (537 mg, 2.37 mmol) at 0 °C. After being stirred at room
temperature, the reaction mixture was diluted with diethyl ether
and quenched with saturated aqueous NaHSO3 solution and
saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with diethyl ether. The combined organic layers were
washed with saturated aqueous NaHCO3 solution and brine, dried
over MgSO4, and concentrated in vacuo. The crude 3-methylene-
8,8-di(phenylsulfonyl)-6-vinylspiro[4.4]nonan-2-ol (399 mg, 0.869
mmol) was used in the next reaction without further purification.
To a solution of 2-hydroxy-3-methylene-8,8-di(phenylsulfonyl)-
6-vinylspiro[4.4]nonane (399 mg, 0.869 mmol) and NMO (204 mg,
1.74 mmol) in dichloromethane (5 mL) was added TPAP (15 mg,
0.0435 mmol). After being stirred at room temperature, the reaction
mixture was directly subjected to silica gel chromatography (25%
ethyl acetate in hexane) to give 3-methylene-8,8-di(phenylsulfonyl)-
6-vinylspiro[4.4]nonan-2-one (12) (196 mg, 0.429 mmol, 36%, two
steps): 1H NMR (400 MHz, CDCl3) δ 8.02-8.09 (m, 4H), 7.73-
7.76 (m, 2H), 7.60-7.65 (m, 4H), 5.99 (s, 1H), 5.53-5.62 (m,
1H), 5.34 (s, 1H), 5.02-5.12 (m, 2H), 2.53-2.82 (m, 7H), 2.39
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 203.9 (C), 144.3 (C,), 136.7
(C, Ph), 135.9 (C, Ph), 135.0 (CH, Ph), 134.9 (CH, Ph), 134.2 (CH),
131.6 (CH, Ph), 131.4 (CH, Ph), 129.0 (CH, Ph), 128.9 (CH, Ph),
119.8 (CH2), 118.2 (CH2), 92.4 (C), 52.0 (CH), 49.8 (CH2), 48.1
(C), 43.0 (CH2), 37.3 (CH2), 37.0 (CH2); IR (solid) 1727, 1638,
1447, 1309, 1143, 1075, 920, 731, 689, 552, 511, 483, 466 cm-1
.
3-(4-Methoxybenzyloxy)-6-(hydroxymethyl)spiro[4.4]nonan-
2-one (13). Into dry methanol (100 mL) was added activated
magnesium turnings (washed with 0.1 M HCl, water, methanol,
and diethyl ether and heated at 100 °C) (1.25 g, 51.6 mmol). The
mixture was stirred at 50 °C. When gas evolution started, a solution
of 7-(4-methoxybenzyloxy)-8-methylene-3,3-di(phenylsulfonyl)-1-
vinylspiro[4.4]nonane (10) (1.20 g, 2.06 mmol) in THF (5 mL)
was added at the same temperature. After being stirred for 3 h, the
reaction mixture was quenched with 3 M HCl at 0 °C. The aqueous
layer was extracted with diethyl ether. The combined organic layers
were washed with saturated aqueous NaHCO3 solution and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by chromatography on silica gel (5% ethyl acetate in
hexane) to give 2-(4-methoxybenzyloxy)-3-methylene-6-vinylspiro-
[4.4]nonane (489 mg, 1.63 mmol, 79%, diastereomer mixture).
Ozone was bubbled into a solution of 2-(4-methoxybenzyloxy)-
3-methylene-6-vinylspiro[4.4]nonane (230 mg, 0.770 mmol) in
dichloromethane (2 mL) and methanol (2 mL) at -78 °C. The
solution was purged by bubbling nitrogen to remove excess ozone,
and the ozonide was reduced by addition of dimethyl sulfide (225
µL, 3.08 mmol) at the same temperature. The reaction mixture was
allowed to gradually warm to room temperature and diluted with
diethyl ether. The organic layer was washed with 1 M HCl and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by chromatography on silica gel (20% ethyl acetate
in hexane) to give 3-(4-methoxybenzyloxy)-6-formylspiro[4.4]-
nonan-2-one (177 mg, 0.586 mmol, 76%, diastereomer mixture).
To a solution of 3-(4-methoxybenzyloxy)-6-formylspiro[4.4]-
nonan-2-one (1.80 g, 5.95 mmol) in THF (25 mL) was added LiAl-
(Ot-Bu)3H (0.5 M in diglyme, 13.1 mL, 6.55 mmol) at -78 °C.
The reaction mixture was quenched with a 10% aqueous solution
of potassium sodium tartrate at -78 °C. The aqueous layer was
To a solution of diphenyl diselenide (27 mg, 0.0876 mmol) in
THF (1 mL) and methanol (1 mL) was added sodium borohydride
(6.6 mg, 0.175 mmol) at 0 °C. The reaction mixture was allowed
to warm to room temperature and stirred for 30 min. A solution of
3-(4-methoxybenzyloxy)-6-(p-toluenesulfonyloxymethyl)spiro[4.4]-
nonan-2-one (57.4 mg, 0.125 mmol) in THF (1 mL) was added
and stirred at reflux. The reaction mixture was diluted with ethyl
acetate and washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (20% ethyl acetate in hexane) to give 3-(4-methoxy-
benzyloxy)-6-(phenylselenylmethyl)spiro[4.4]nonan-2-one (47 mg,
0.106 mmol, 85%, diastereomer mixture).
To a solution of 3-(4-methoxybenzyloxy)-6-(phenylselenylmethyl)-
spiro[4.4]nonan-2-one (390 mg, 0.879 mmol) in THF (5 mL) was
added hydrogen peroxide (107 µL, 1.06 mmol) at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred for
1 h. The reaction mixture was concentrated in vacuo. The residue
was purified by chromatography on silica gel (20% ethyl acetate
in hexane) to give 3-(4-methoxybenzyloxy)-6-methylenespiro[4.4]-
nonan-2-one (14) (190 mg, 0.663 mmol, 75%, diastereomer
1
mixture): H NMR (270 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 6.91-
6.84 (m, 2H), 4.99-4.77 (m, 3H), 4.66-4.55 (m, 1H), 4.08-3.94
(m, 1H), 3.80 (s, 3H), 2.49-2.18 (m, 4H), 2.04-1.56 (m, 6H); IR
(neat) 3070, 2956, 1748, 1651, 1613, 1586, 1515, 1465, 1398, 1302,
1248, 1174, 1112, 1036, 881, 821 cm-1
.
3-Hydroxy-6-methylenespiro[4.4]non-3-en-2-one (15). To a
solution of 3-(4-methoxybenzyloxy)-6-methylenespiro[4.4]nonan-
2-one (14) (215 mg, 0.751 mmol) in dichloromethane (3.3 mL)
and water (0.18 mL) was added DDQ (256 mg, 1.13 mmol) at
0 °C. After being stirred at room temperature, the reaction mixture
was diluted with diethyl ether and quenched with a saturated
3670 J. Org. Chem., Vol. 72, No. 10, 2007

Dimethyl Gloiosiphone A by Pd-Catalyzed Domino Cyclization
aqueous solution of NaHSO3 and a saturated aqueous solution of
NaHCO3. The aqueous layer was extracted with diethyl ether. The
combined organic layers were washed with a saturated aqueous
solution of NaHCO3 and brine, dried over MgSO4, and concentrated
in vacuo. The residue was purified by chromatography on silica
gel(20%ethylacetateinhexane)togive3-hydroxy-6-methylenespiro-
[4.4]nonan-2-one (100 mg, 0.602 mmol, 80%, diastereomer mix-
ture).
To a solution of 3-hydroxy-6-vinylspiro[4.4]nonan-2-one (22.8
mg, 0.126 mmol) and triethylamine (87 µL, 0.630) in DMSO (1
mL) was added sulfur trioxide pyridine complex (60 mg, 0.379
mmol) in one portion at room temperature. After being stirred at
the same temperature for 10 min, the reaction mixture was quenched
with 1 M HCl at 0 °C. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by chromatography on silica gel (15% ethyl acetate in hexane) to
give 3-hydroxy-6-methylenespiro[4.4]non-3-en-2-one (15) (21.6 mg,
0.121 mmol, 96%): 1H NMR (400 MHz, CDCl3) δ 6.30 (s, 1H),
5.60 (s, 1H), 4.89 (t, J ) 1.9 Hz, 1H), 4.76 (t, J ) 2.4 Hz, 1H),
2.58-2.35 (m, 4H), 1.89-1.69 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 204.1, 157.4, 151.1, 136.1, 106.1, 49.3, 48.8, 40.7, 32.2,
23.4; IR (neat) 3344, 2955, 2871, 1702, 1655, 1625, 1401, 1256,
1201, 1108, 887 cm-1; HRMS (ESI-TOF) calcd for [C10H12O2 +
Na]+ 187.0730, found 187.0725.
1-Hydroxy-3-methoxy-6-methylenespiro[4.4]non-3-en-2-one
(16). To a solution of 3-hydroxy-6-methylenespiro[4.4]non-3-en-
2-one (15) (23 mg, 0.139 mmol) in DMF (0.7 mL) were added
potassium carbonate (23 mg, 0.167 mmol) and methyl iodide (13
µL, 0.209 mmol) at room temperature. After being stirred for 2 h,
the reaction mixture was quenched with 1 M HCl at 0 °C. The
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (20% ethyl acetate in hexane) to give 3-methoxy-6-
methylenespiro[4.4]non-3-en-2-one (24.3 mg, 0.136 mmol, 98%):
1H NMR (400 MHz, CDCl3) δ 6.13 (s, 1H), 4.89 (s, 1H), 4.76 (s,
1H), 3.75 (s, 3H), 2.58-2.34 (m, 4H), 1.85-1.69 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 202.2, 157.9, 155.7, 133.3, 105.8, 57.0,
49.7, 49.0, 41.1, 32.1, 23.3; IR (neat) 3071, 2955, 1720, 1650, 1625,
1453, 1405, 1347, 1290, 1221, 1121, 986, 885 cm-1; HRMS (ESI-
TOF) calcd for [C11H14O2 + Na]+ 201.0886, found 201.0884.
To a solution of KHMDS (0.5 M in toluene, 1.56 mL, 0.779
mmol) in THF (0.5 mL) was added a solution of 3-methoxy-6-
methylenespiro[4.4]non-3-en-2-one (92.5 mg, 0.519 mmol) in THF
(1 mL) at -78 °C and stirred 1 h. To the reaction mixture was
added a solution of (()-trans-2-(phenylsulfonyl)-3-phenyloxaziri-
dine (272 mg, 1.04 mmol) in THF (1 mL) at -78 °C. The mixture
was gradually allowed to warm to room temperature. The reaction
mixture was quenched with 1 M HCl at 0 °C. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (20%
ethylacetateinhexane)togive1-hydroxy-3-methoxy-6-methylenespiro-
[4.4]non-3-en-2-one (16) (61.2 mg, 0.315 mmol, 61%): 1H NMR
(400 MHz, CDCl3) δ 6.10 (s, 1H), 5.07 (s, 1H), 4.83 (t, J ) 2.4
Hz), 4.09 (s, 1H), 3.74 (s, 3H), 2.89 (br s, 1H), 2.59-2.40 (m,
2H), 2.13-2.07 (m, 1H), 1.91-1.59 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 202.7, 158.2, 153.4, 132.8, 107.1, 81.0, 56.7, 53.8, 35.8,
33.1, 23.8; IR (neat) 3430, 2957, 1722, 1620, 1453, 1354, 1081,
1066 cm-1; HRMS (ESI-TOF) calcd for [C11H14O3 + Na]+
217.0835, found 217.0835.
2,3-Dimethoxy-6-methylenespiro[4.4]non-2-en-1-one (3). To
a solution of 1-hydroxy-3-methoxy-6-methylenespiro[4.4]non-3-
en-2-one (16) (14.3 mg, 0.0736 mmol) in THF (0.5 mL) and
methanol (0.5 mL) was added sodium methoxide (6 mg, 0.110
mmol). After being stirred for 1 h at room temperature, the reaction
mixture was quenched with 1 M HCl at 0 °C. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The crude 2-hydroxy-3-methoxy-6-methylenespiro[4.4]non-2-en-
1-one was used in the next reaction without further purification.
To a solution of the crude 2-hydroxy-3-methoxy-6-methylenespiro-
[4.4]non-2-en-1-one were added potassium carbonate (15 mg, 0.110
mmol) and methyl iodide (9 µL, 0.147 mmol) at room temperature.
After being stirred for 2 h, the reaction mixture was quenched with
1 M HCl at 0 °C. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by chromatography on silica gel (15% ethyl acetate in hexane) to
give 2,3-dimethoxy-6-methylenespiro[4.4]non-2-en-1-one (3)13b
(11.7 mg, 0.0562 mmol, two steps, 76%): 1H NMR (400 MHz,
CDCl3) δ 4.93 (t, J ) 2.4, 1.9 Hz, 1H), 4.75 (t, J ) 2.4 Hz, 1H),
4.06 (s, 3H), 3.83 (s, 3H), 2.57 (d, J ) 16.9 Hz, 1H), 2.49 (d, J )
16.9 Hz, 1H), 2.60-2.45 (m, 2H), 2.19-2.16 (m, 1H), 1.99-1.84
(m, 1H), 1.69-1.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 202.3,
170.0, 156.8, 134.3, 105.2, 59.3, 58.1, 54.5, 40.9, 38.2, 33.8, 24.1;
IR (neat) 2954, 1705, 1633, 1463, 1342, 1132 cm-1; HRMS (ESI-
TOF) calcd for [C12H16O3 + Na]+ 231.0992, found 231.0991.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (No. 17035026)
from MEXT.
1
Supporting Information Available: Experimental details, H
and 13C NMR spectra of 5, 10, 12, 13, 15, 16, and 3, and HMBC
and HMQC spectra of 12. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO062546V
J. Org. Chem, Vol. 72, No. 10, 2007 3671