Synthesis of (+)-coronafacic acid

Article abstract of DOI:10.1021/jo802493k

An enantioselective synthesis of (+)-coronafacic acid has been achieved. Rhodium-catalyzed cyclization of an a-diazoester provided the intermediate cyclopentanone in high enantiomeric purity. Subsequent Fe-mediated cyclocarbonylation of a derived alkenyl

Full text of DOI:10.1021/jo802493k

Synthesis of (+)-Coronafacic Acid
Douglass F. Taber,* Ritesh B. Sheth, and Weiwei Tian
Department of Chemistry & Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed NoVember 7, 2008
An enantioselective synthesis of (+)-coronafacic acid has been achieved. Rhodium-catalyzed cyclization
of an R-diazoester provided the intermediate cyclopentanone in high enantiomeric purity. Subsequent
Fe-mediated cyclocarbonylation of a derived alkenyl cyclopropane gave a bicyclic enone that then was
hydrogenated and carried on to the natural product.
SCHEME 1
Introduction
Bicyclic and polycyclic ring systems are common in structur-
ally complex and physiologically active natural products.
Although there are many methods of preparing such ring
systems, the number of approaches to carbopolycyclic scaffolds
is more limited. Corey demonstrated the utility of an enzyme
to convert 20,21-dehydro-2,3-oxidosqualene to a dehydropro-
tosterol. Hajos2 employed a catalytic amount of (S)-(-)-proline
in an asymmetric aldol condensation to form optically pure
bicyclic intermediates. We3 were able to demonstrate that a
single stereogenic center on the bridge between the diene and
dienophile could set the absolute center of an intramolecular
Diels-Alder reaction leading to a carbobicyclic 6,6-system.
Corey4 reported examples of catalytic enantioselective [2 + 2]
cycloaddition catalyzed by chiral aluminum bromide complexes
to form 5,4-, 6,4-, and 7,4-carbobicyclic systems. We5 also
reported another approach to enantioselective polycyclic con-
struction, utilizing Shi epoxidation followed by selective ring
opening, and then intramolecular alkylation to set the stereogenic
centers. We6 further showed in our synthesis of (+)-sulcatine
G that enantiospecific C-H insertion, followed by intramo-
lecular alkylation, could also be applied to carbobicycle
construction. Schaus7demonstrated the utility of the Morita-
Baylis-Hillman reaction, coupled with the Hosomi-Sakauri
reacton, to construct 6,6-bicyclic systems. Gaunt8 reported a
strategy using oxidative dearomatization and amine-catalyzed
enantioselective desymmetrizing Michael reaction to form 6,6-
carbobicycles. In the Phillips9 synthesis of (+)-cyanthiwigin U,
tandem metathesis was used to enantioselectively construct the
polycarbocycle. Recently, Ishihara10 utilized enantioselective
Robinson annulation and cycloaddition reactions catalyzed by
chiral Lewis acids for polycarbocycle construction.
We had developed (Scheme 1) a general route to enantio-
merically pure 5,3- and 6,3-carbobicyclic scaffolds by cycliza-
tion of menthyl esters such as 1 to the cyclopentanone 2.11a
Nakada11l,r,s later reported an enantioselective preparation of
similar carbocyclic esters and sulfones by copper-catalyzed
(1) Corey, E. J.; Lin, K.; Yamamoto, H. J. Am. Chem. Soc. 1969, 91, 2132.
(2) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(3) Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979, 101, 3992.
(4) Corey, E. J.; Canales, E. J. Am. Chem. Soc. 2007, 129, 12686.
(5) Taber, D. F.; He, T.; Xu, M. J. Am. Chem. Soc. 2004, 126, 13900.
(6) Taber, D. F.; Frankowski, K. J. J. Org. Chem. 2005, 70, 6417.
(7) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334.
(8) Rodgen, S. A.; Schaus, S. E. Angew Chem., Int Ed. 2006, 45, 4929.
(9) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. I. J. Am. Chem. Soc.
2008, 130, 404.
(10) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532.
10.1021/jo802493k CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2433–2437 2433

Taber et al.
TABLE 1. Cyclization of Diazo Menthyl Ester 1
asymmetric intramolecular cyclopropanation. We have improved
upon our intramolecular cyclization11a by increasing the selec-
tivity and preparative yield of the cyclization. We anticipated
that we could convert the ester to the alkenyl cyclopropane 3.
We speculated12 that Fe-mediated cyclocarbonylation of the
alkenyl cyclopropane could deliver the bicyclic enone 4. If this
were successful, the enone 4 could then be transformed in a
few steps to the natural product (+)-coronafacic acid 5.
rhodium
ligand
diastereoselectivity yielda
entry
solvent
T (°C)
(2:8)
(%)
1
2
3
4
5
6
7
8
pivb
CH2Cl2
PhCH3
C6H12
25
25
25
25
-78
25
25
25
25
25
25
25
25
25
2.5:1
1.5:1
1.2:1
1.2:1
3.0:1
0.9:1
1.2:1
0.7:1
1.0:1
1.3:1
1.7:1
1.3:1
1.7:1
1.5:1
95
91
80
70
90
70
89
75
80
88
71
82
91
89
pivb
pivb
pivb
CCl4
pivb
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
tfac
octd
e
Ph3CCO2
OAcf
Espg
R-ptpah
R-pttli
S-dospj
S-tbspk
Background and Results
9
Coronatin 6 (eq 1) is a phytotoxin produced by Pseudomonas
syringae. Its structure is composed of coronafacic acid 5, a
bicyclic core with three stereogenic centers, and coronamic acid
7, a cyclopropane amino acid derived from isoleucine. Both
coronatin and coronafacic acid have been reported to mimic
jasmonic acid. All three compounds induce tubers, induce cell
expansion, inhibit cell division, and promote senescence in
plants.13 While there were 15 previous total syntheses of
coronafacic acid,14 only one enantioselective route had been
reported.14m
10
11
12
13
14
a Yields reported are for the isolated mixture of the two
diastereomers. b See ref 15a. c See ref 15b. d See ref 15c. e See ref 15d.
f See ref 15e. g See ref 15f. h See ref 15g. i See ref 15h. j See ref 15i.
k See ref 15j.
SCHEME 2
Intramolecular Cyclopropanation. Dirhodium tetracarboxy-
late catalysts are known to cyclize R-diazo esters, such as 1. We
had previously cyclized 1 to a 1:1 mixture of 2 and 8 (eq 2) using
a copper bronze catalyst.11a We separated the menthyl esters 2 and
8 by column chromatography, leading to pure 2 in 21% yield. We
have investigated a diverse selection of dirhodium tetracarboxylate
catalysts to improve upon those earlier results.
We have found (Table 1) that, by using Rh(II) catalysts, we
could induce some diastereoselectivity in this cyclization. We
found that dirhodium pivalate at room temperature provided the
best preparative yield, 63%, of the desired cyclopentanone 2.
Preparation of Alkenyl Cyclopropane 6. With the initial
two stereocenters set, we protected (Scheme 2) the ketone as
the ketal 9. Attempts to reduce the ester directly to the aldehyde
with less than 1 equiv of lithium aluminum hydride or with
DIBAL delivered a mixture of alcohol, aldehyde, and the starting
ester. We found that completely converting the ester 2 to the
alcohol followed by oxidization to aldehyde 10 with Dess-Martin
(12) For the development of Fe-mediated cyclocarbonylation, see: (a) Victor,
R.; Ben-Shoshan, R.; Sarel, S. J. Org. Chem. 1978, 43, 4971. (b) Taber, D. F.;
Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc. 2000, 122, 6807. (c) Taber,
D. F.; Bui, G.; Chen, B. J. Org. Chem. 2001, 66, 3423. (d) Taber, D. F.; Joshi,
P. V.; Kanai, K. J. Org. Chem. 2004, 69, 2268. (e) Taber, D. F.; Sheth, R. B. J.
Org. Chem. 2008, 73, 8030.
(11) For previous preparations of cyclohexanones and cyclopentanones via
intramolecular cyclopropanation, see: (a) Taber, D. F.; Saleh, S. A.; Korsmeyer,
R. W. J. Org. Chem. 1980, 45, 4699. (b) Taber, D. F.; Malcolm, S. C. J. Org.
Chem. 1998, 63, 3717. (c) Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng,
H. P. Tetrahedron Lett. 1990, 31, 6969. (d) Pique, C.; Fahndrich, B.; Pfaltz, A
Synlett 1995, 491. Special Issue: (e) Park, S.-W.; Son, J.-H.; Kim, S.-G.; Ahn,
K. H. Tetrahedron: Asymmetry 1999, 10, 1903. (f) Kim, S. G.; Cho, C. W.;
Ahn, K. H. Tetrahedron 1999, 55, 10079. (g) Barberis, M.; Estevan, F.; Lahuerta,
P.; Perez-Prieto, J.; Sanau, M. Inorg. Chem. 2001, 40, 4226. (h) Barberis, M.;
Prieto, J.; Stiriba, S.-E.; Lahuerta, P. Org. Lett. 2001, 3, 3317. (i) Saha, B.;
Uchida, T.; Katsuki, T. Chem. Lett. 2002, 8, 846. (j) Barberis, M.; Perez-Prieto,
J.; Herbst, K.; Lahuerta, P. Organometallics 2002, 21, 1667. (k) Saha, B.; Uchida,
T.; Katsuki, T. Tetrahedron: Asymmetry 2003, 14, 823. (l) Honma, M.; Sawada,
T.; Fujisawa, Y.; Utsugi, M.; Watanabe, H.; Umino, A.; Matsumura, T.; Hagihara,
T.; Takano, M.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 2860. (m) Honma,
M.; Nakada, M. Tetrahedron Lett. 2003, 44, 9007. (n) Wong, A.; Welch, C. J.;
Kuethe, J. T.; Vazquez, E.; Shaimi, M.; Henderson, D.; Davies, I. W.; Hughes,
D. L. Org. Biomol. Chem. 2004, 2, 168. (o) Estevan, F.; Lahuerta, P.; Lloret, J.;
Perez-Prieto, J.; Werner, H. Organometallics 2004, 23, 1369. (p) Estevan, F.;
Lahuerta, P.; Lloret, J.; Penno, D.; Sanau, M.; Ubeda, M. A. J. Organomet.
Chem. 2005, 690, 4424. (q) Uchida, T.; Katsuki, T. Synthesis 2006, 1715. (r)
Ida, R; Nakada, M. Tetrahedron Lett. 2007, 48, 4856. (s) Takeda, H.; Honma,
M.; Ida, R.; Sawada, T.; Nakada, M. Synlett 2007, 4, 579.
(13) For a recent review of chemistry and biological properties of coronatin
and coronafacic acid: Mitchell, R. E. Chem. N. Z. 2004, 68, 24.
(14) For previous coronafacic acid syntheses, see: (a) Ichihara, A.; Kimura,
R.; Moryasu, K.; Sakamura, S. Tetrahedron Lett. 1977, 18, 4331. (b) Jung, M. E.;
Hudspeth, J. P. J. Am. Chem. Soc. 1980, 102, 2463. (c) Ichihara, A.; Kimura,
R.; Moryasu, K.; Sakamura, S. J. Am. Chem. Soc. 1980, 102, 6353. (d) Tsuji, J.
Pure Appl. Chem. 1981, 53, 2371. (e) Jung, M. E.; Halweg, K. M. Tetrahedron
Lett. 1981, 22, 2735. (f) Nakayama, M.; Ohira, S.; Okamura, Y.; Soga, S. Chem.
Lett. 1981, 731. (g) Nakayama, M.; Ohira, S. Agric. Biol. Chem. 1983, 47, 1689.
(h) Liu, H. J.; Brunet, M. L Can. J. Chem. 1984, 62, 1747. (i) Bhamare, N. K.;
Granger, T.; Macas, T. S.; Yates, P. J. Chem. Soc., Chem. Commun. 1990, 739.
(j) Mehta, G.; Praveen, M. J. Chem. Soc., Chem. Commun. 1993, 1573. (k)
Hoelder, S.; Blechert, S. Synlett 1996, 505. (l) Nara, S.; Toshima, H.; Ichihara,
A. Tetrahedron Lett. 1996, 37, 6745. (m) Nara, S.; Toshima, H.; Ichihara, A.
Tetrahedron 1997, 53, 9509. (n) Sono, M.; Hashimoto, A.; Nakashima, K.; Tori,
M. Tetrahedron Lett. 2000, 41, 5115. (o) Mehta, G.; Reddy, D. S. J. Chem.
Soc., Perkin Trans. 1 2001, 10, 1153. (p) Moreau, B.; Ginisty, M.; Alberico,
D.; Charette, A. B. J. Org. Chem. 2007, 72, 1235.
2434 J. Org. Chem. Vol. 74, No. 6, 2009

Synthesis of (+)-Coronafacic Acid
reagent was more effective. We were then able to perform a
Wittig reaction on aldehyde 10 to give alkenyl cyclopropane 3.
Preparation of Enone 9. We12b-d previously reported the
preparation of 2,5- and 5-substituted cyclohexenones via Fe-
mediated cyclocarbonylation. More recently, we found that we
could couple the Wittig reaction with Fe-mediated cyclocarbo-
nylation to convert aldehydes to 2-substituted cyclohexenones.12e
Sarel12a demonstrated the photochemical expansion of a meth-
ylene spiroalkane 11 to the bicyclic enones 12 and 13 in his
studies of (+)-R-thujene (eq 3). The cyclocarbonylation to a
bicyclic enone from a 5,3- or 6,3-ring fused alkenyl cyclopro-
pane such as 3 had not yet been reported.
diastereomer. Carbomethoxylation followed by reduction with
sodium borohydride gave the alcohol 12 as a mixture of
diastereomers. Dehydration of the mixture by mesylation and
subsequent addition of DBU gave the ketal-protected coronafacic
methyl ester 13 as a single diastereomer. Deprotection and ester
hydrolysis were then completed in one step with aqueous HCl
at reflux to give the natural product 5. The physical data,
including optical rotation (obsd [R]20 +104; lit.14o [R]20
D
D
+105), were consistent with those previously reported for (+)-
coronafacic acid.
Conclusion
We have completed an enantioselective synthesis of (+)-
coronofacic acid. We were able to set the initial two stereogenic
centers utilizing rhodium-catalyzed intramolecular cyclopropa-
nation. We were then able to expand the cyclopropane utilizing
Fe-mediated cyclocarbonylation. We expect that this will be a
general route to enantiomerically pure 6,5- and 6,6-carbobicyclic
systems.
We found (eq 4) that UV irradiation of 3 in the presence of
Fe(CO)5 converted the alkenyl cyclopropane 3 to the bicyclic
cyclohexenone 4 in low yield with accompanying deketalization.
We found that by adding K2CO3 to the irradiation, the reaction
was buffered and ketal deprotection was avoided. The use of
tetrahydrofuran, rather than 2-propanol,12b-e as the reaction
solvent doubled the conversion of 3 to 4. We found it practical
to run the cyclocarbonylation to about 40% conversion (TLC),
as longer irradiation led to diminished yield. The unreacted
starting material was easily separated and recycled.
Experimental Section
(1S,2R,5S)-5-Methyl-2-(propan-2-yl)cyclohexyl 2-Oxobicyclo-
15a
[3.1.0]hexane-1-carboxylate 2 and 8. Rh2(Piv)4
(5 mg) was
added to R-diazoester 111a (6.12 g, 20 mmol) in 20 mL of dry
CH2Cl2 (1.0 M) at rt. The solution was stirred at rt for 1 h, and
then additional Rh2(Piv)4 (5 mg) was added and the reaction allowed
to stir for an additional 2 h. The mixture was concentrated and the
residue chromatographed using 94:6 hexanes/EtOAc as elution
solvent to give the cyclopentanone 2 (3.61 g, 63% yield) and 8
(1.78 g, 32% yield) as an oil. Cyclopentanone 2 was then
crystallized at -78 °C in petroleum ether (5 mL) to give 2 (3.49 g,
62% as a white crystalline solid: mp ) 34-36 °C; [R]20D +47.2 (c
) 1.0, CH2Cl2); TLC Rf ) 0.27 (9:1 hexanes/EtOAc); 1H NMR δ
4.71 (dt, J ) 4.9, 11.5 Hz, 1H), 2.54 (m, 1H), 2.22 (m, 3H), 2.01
(m, 4H), 1.68 (d, J ) 12.1 Hz, 2H), 1.34-1.48 (m, 3H), 0.88-1.05
(m, 9H), 0.75 (d, J ) 7.6 Hz, 3H); 13C NMR δ u16 207.0, 167.6,
40.6, 37.8, 34.2, 33.5, 21.4, 21.0; d 74.9, 46.8, 32.4, 31.3, 25.8,
23.1, 21.9, 20.8, 16.0; IR 2952, 1736, 1454, 1383, 1311 cm-1; MS
m/z 279 (M + H, 100), 263 (48), 141 (98), 123 (79); HRMS calcd
for C17H27O3 (M + H) 279.1960, obsd 279.1967. For cyclopen-
tanone 8: (1.45 g, 27% as an oil, [R]20D -47.0 (c ) 1.0, CH2Cl2);
TLC Rf ) 0.25 (9:1 hexanes/EtOAc); 1H NMR δ 4.65 (dt, J ) 4.9,
11.5 Hz, 1H), 2.49 (m, 1H), 2.16 (m, 3H), 1.93 (m, 3H), 1.75 (m,
1H), 1.60 (d, J ) 12.1 Hz, 2H), 1.34-1.48 (m, 3H), 0.88-1.05
(m, 9H), 0.67 (d, J ) 7.6 Hz, 3H); 13C NMR δ u 207.0, 167.6,
The kinetic product from the cyclocarbonylation was the ꢀ,γ-
unsaturated ketone. This was not purified but was converted to
the desired R,ꢀ-unsaturated ketone 4 by stirring for 1 h at room
temperature with DBU.
Synthesis of (+)-Coronafacic Acid. Pd-mediated hydroge-
nation of the cyclohexenone 4 (Scheme 3) at ambient temper-
ature and pressure provided the bicyclic ketone 11 as a single
SCHEME 3
(15) For rhodium (II) complexes, see: (a) piv ) pivalate: Handa, M.; Takata,
A.; Nakao, T.; Kasuga, K.; Mikuriya, M.; Kotera, T. Chem. Lett. 1992, 10, 2085.
(b) tfa ) trifluoroacetate: Duddeck, H.; Ferguson, G.; Kaitner, B.; Kennedy,
M.; McKervey, M. A.; Maguire, A. R J. Chem. Soc., Perkin Trans. 1 1990, 4,
1055. (c) oct ) octanoate: Giroud-Godquin, A. M.; Marchon, J. C.; Guillon,
D.; Skoullos, A. J. Phys. Chem. 1986, 90, 5502. (d) Ph3CO2 ) triphenylacetate:
Hashimoto, S.; Watanabe, N.; Ikegami, S Tetrahedron Lett. 1992, 33, 2709. (e)
OAc ) aceto Rempel, G. A.; Legzdins, P.; Smith, H.; Wilkinson, G. Inorg.
Synth. 1971, 13, 90. (f) Esp ) bis[rhodium (R,R,R′,R′-tetramethyl-1,3-benzene-
dipropionate)]: Espino, C. G.; Flori, K. W.; Kim, M.; Du Bois, J. D. J. Am.
Chem. Soc. 2004, 126, 15378. (g) R-ptpa ) dirhodium tetrakis[N-phthaloyl-
(R)-phenylalaninate]: Okada, Y.; Minami, Y.; Miyamoto, M.; Otaguro, T.;
Sawasaki, S.; Ichikawa, J. Heteroatom Chem. 1995, 6, 195. (h) R-pttl )
dirhodium tetrakis[(2R)-3,3-dimethyl-2-(phthalimido)butanoate]: Tsutsui, H.;
Yamaguchi, Y.; Kitagaki, S.; Nakamora, S.; Anada, M.; Hashimoto, S.
Tetrahedron: Asymmetry 2003, 14, 817. (i) S-dosp ) dirhodium tetrakis[(S)-
(-)-N-p-dodecylphenylsulfonyl)prolinate]: Davies, H. M. L.; Bruzinkski, P.;
Hutcheson, D. K.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897. (j)
S-tbsp ) dirhodium tetrakis[1-[(4-tert-butylphenyl)sulfonyl]-(2S)-pyrrolidin-
ecarboxylate], see ref 14i.
(16) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d” and
for methylene and quaternary carbons as “u”.
J. Org. Chem. Vol. 74, No. 6, 2009 2435

Taber et al.
40.7, 37.7, 34.2, 33.6, 21.6, 20.7; d 74.9, 46.8, 32.2, 31.3, 26.2,
23.4, 22.0, 20.9, 16.3; IR 2950, 1735, 1454, 1384, 1311 cm-1; MS
m/z 279 (M + H, 100), 263 (49), 141 (98), 123 (79); HRMS calcd
for C17H27O3 (M + H) 279.1960, obsd 279.1967.
Rayonet apparatus (300 nm) set for autocooling. The reaction was
halted every hour to agitate the tube inside the larger tube, after
which photolysis was restarted. At the end of the irradiation, DBU
(304 mg, 2.0 mmol) was added, and the mixture was stirred at room
temperature for 1 h under nitrogen. The mixture was diluted with
40 mL of EtOAc and filtered through a small pad of packed silica
gel. The eluate was concentrated and the residue was chromato-
graphed to give 152 mg of unreacted 3 and 90 mg of 4 (98% yield
Ketal 9. 2,2-Dimethyl-1,3-propanediol (2.11 g, 24 mmol),
p-toluenesulfonic acid monohydrate (5 mg, 0.02 mmol), and
cyclopentanone 2 (3.33 g, 12 mmol) were combined in 24 mL of
dry toluene. The solution was maintained at reflux for 8 h. The
reaction was concentrated, and the residue was chromatographed
to give the ketal 6 (3.89 g, 89% yield) as a white solid: mp )
based on 3 not recovered) as an oil: [R]20 +102.5 (c ) 1.0,
D
CH2Cl2); TLC Rf ) 0.30 (8:2 petroleum ether/MTBE); 1H NMR δ
6.45 (s, 1H), 3.45 (m, 4H), 2.95 (br s, 1H), 2.64 (m, 1H), 2.41 (m,
2H), 2.17 (m, 2H), 1.70- 1.97 (m, 3H), 1.35 (m, 1H), 0.95 (m,
6H), 0.85 (m, 3H); 13C NMR δ u 198.4, 140.7, 108.2, 71.4, 70.7,
39.9, 30.5, 29.3, 25.0, 21.7; d 138.9, 45.0, 33.1, 21.5, 21.3, 12.1;
IR 2952, 1672, 1493, 1312, 1153 cm-1; HRMS calcd for C16H24O3
264.1725, obsd 264.1731.
97-99 °C; [R]20 +32.1 (c ) 1.0, CH2Cl2); TLC Rf ) 0.49 (8:2
D
1
petroleum ether/MTBE); H NMR δ 4.69 (dt, J ) 4.9, 11.5 Hz,
1H), 3.62 (d, J ) 11.2 Hz, 1H), 3.47 (m, 3H), 2.43 (dd, J ) 8.2,
13.6 Hz, 1H) 1.87-2.10(m, 4H), 1.66-1.74 (m, 3H), 1.39-1.48
(m, 5H), 1.14 (m, 2H), 1.06 (m, 3H), 0.868-1.05 (m, 7H), 0.74
(m, 6H); 13C NMR δ u 170.6, 107.1, 73.2, 71.7, 40.7, 37.0, 34.5,
30.2, 25.2, 23.6, 23.3, 23.0, 16.8; d 74.3, 47.0, 31.4, 26.0, 24.6,
22.1, 22.0, 20.8, 16.4; IR 2950, 1705, 1455, 1384, 1309 cm-1; MS
m/z 365 (M + H, 87), 279 (7), 227 (100), 209 (63), 182 (36), 141
(65), 128 (60); HRMS calcd for C22H36O4 364.2614, obsd 364.2623.
(1S,5R)-5′,5′-Dimethyl-1H-spiro[bicyclo[3.1.0]hexane-2,2′-[1,3]di-
oxane]-1-carbaldehyde 10. LiAlH4 (1.0 M solution in THF, 12 mL,
12 mmol) was added over 10 min to ketal 9 (3.64 g, 10 mmol) in
10 mL (1.0 M) of dry THF at rt. The solution was stirred at rt for
2 h. Ethyl acetate (5 mL) was added dropwise over 30 min followed
by sodium sulfate decahydrate (3.2 g, 10 mmol). The mixture was
stirred at rt for 2 h and then filtered through a pad of silica gel
with ethyl acetate (20 mL) and concentrated. The residue was
chromatographed to give the crude alcohol. Dess-Martin perio-
dinane (4.24 g, 11 mmol) was added to the alcohol in 10 mL of
dry dichloromethane at rt. The mixture was concentrated, and the
residue was chromatographed to give the aldehyde 10 (1.62 g, 77%
yield from 9) as an oil: TLC Rf ) 0.34 (8:2 petroleum ether/MTBE);
[R]20D -59.1 (c ) 1.0, CH2Cl2); 1H NMR δ 10.36 (s, 1H), 3.72 (d,
J ) 11.2 Hz, 1H), 3.54 (d, J ) 11.2 Hz, 1H), 3.48 (s, 2H), 2.47
(dd, J ) 8.6, 14.3 Hz, 1H), 2.07 (m, 1H), 1.90 (m, 1H), 1.79 (m,
1H), 1.49 (dd, J ) 5.2, 13.0 Hz, 1H), 1 30 (m, 3H), 1.17 (m, 2H),
0.77 (s, 3H); 13C NMR δ u 107.7, 73.3, 71.6, 44.8, 30.0, 25.6,
24.2, 18.6; d 201.1, 30.5, 22.9, 22.0; IR 2953, 1700, 1467, 1335,
1116 cm-1; MS m/z 211 (M + H, 58), 181 (55), 141 (67), 123
(100); HRMS calcd for C12H18O3 210.1256, obsd 210.1262.
(1S,5R)-1-[(1Z)-But-1-en-1-yl]-5′,5′-dimethylspiro[bicyclo[3.1.0]-
hexane-2,2′-[1,3]dioxane] 3. Potassium tert-butoxide (1.0 M solution
in THF, 20 mL, 20 mmol) was added over 20 min to a suspension
of propyltriphenylphosphonium bromide (3.50 g, 9 mmol) in 20
mL of dry THF at 0 °C. The external cooling was removed, and
the mixture was stirred for 30 min. The aldehyde 10 (1.57 g, 7.5
mmol) was added, and the mixture was stirred at rt for 1 h. The
mixture was quenched with water (50 mL) and then partitioned
between water and EtOAc. The combined organic extract was dried
(MgSO4) and concentrated. The residue was chromatographed to
(3a′R,6′R,7a′S)-6′-Ethyl-5,5-dimethylhexahydrospiro[1,3-dioxane-
2,1′-inden]-5′(4′H)-one 14. Pd/C (5 wt%, 10 mg) was added to the
bicyclic enone 4 (85 mg, 0.32 mmol) in 5 mL of methanol. The
reaction vessel was purged with hydrogen, a hydrogen balloon was
attached, and the mixture was stirred at rt for 4 h until the TLC
indicated disappearance of the UV absorbent spot. The mixture was
filtered through a plug of Celite and concentrated. The residue was
chromatographed to give 11 (81 mg, 95% yield) as an oil: [R]20
D
+124.6 (c ) 1.0, CH2Cl2), TLC Rf ) 0.30 (8:2 petroleum ether/
1
MTBE); H NMR δ 3.48 (m, 4H), 2.62 (m, 1H), 2.51 (m, 2H),
2.25 (dd, J ) 5.6, 14.4 Hz, 1H), 2.15 (m, 1H), 2.00 (m, 3H), 1.82
(m, 2H), 1.46 (m, 1H), 1.24 (m, 2H), 1.04 (m, 3H), 0.91 (m, 6H);
13C NMR δ u 214.2, 109.6, 72.4, 71.5, 43.8, 30.7, 30.0, 28.3, 26.6,
22.3; d 49.2, 44.3, 37.1, 22.5, 11.6; HRMS calcd for C16H26O3
266.1882, obsd 266.1880.
Methyl (3a′S,5′S,6′R,7a′S)-6′-Ethyl-5′-hydroxy-5,5-dimethyloc-
tahydrospiro[1,3-dioxane-2,1′-indene]-4′-carboxylate 15. Sodium
hydride (60%, 24 mg, 0.6 mmol) and dimethyl carbonate (3 mL,
35 mmol) were heated to reflux for 20 min. A drop of methanol
was added via an addition funnel over a condenser and stirred at
reflux for 5 min. Bicyclic ketone 14 (80 mg, 0.3 mmol) in 1 mL
dry toluene was added via an addition funnel over a condenser,
and the mixture was stirred at reflux for 3 h. The mixture was cooled
to rt and quenched with saturated aqueous NH4Cl and then
partitioned between water and EtOAc. The combined organic extract
was dried (MgSO4) and concentrated. The residue was dissolved
in methanol (5 mL), and NaBH4 (19 mg, 0.5 mmol) was added.
The mixture was stirred at rt for 2 h. The mixture was concentrated
and the residue was chromatographed to give alcohol 15 (44 mg,
45% yield) as an oil: [R]20 +10.4 (c ) 1.0, CH2Cl2); TLC Rf )
D
1
0.19 (8:2 petroleum ether/MTBE); H NMR δ 4.17 (s, 1H), 3.72
(s, 3H), 3.50 (s, 2H), 3.42 (s, 2H), 2.64 (m 1H), 2.56 (m, 1H), 2.21
(m, 2H), 2.01 (m, 1H), 1.92 (m, 1H), 1.56 (m, 3H), 1.38 (m, 4H),
0.95 (m, 9H); 13C NMR δ u 176.1, 109.5, 72.7, 71.0, 31.6, 30.1,
30.0, 25.3, 22.3; d 67.6, 51.7, 46.8, 44.5, 42.0, 36.5, 22.5, 11.7; IR
3488, 2913, 1713, 1289, 1152 cm-1; MS m/z 327 (M + H, 6), 141
(100); HRMS calcd for C18H30O5 326.2093, obsd 326.2095.
Methyl (3a′S,6′R,7a′S)-6′-Ethyl-5,5-dimethyl-2′,3′,3a′,6′,7′,7a′-
hexahydrospiro[1,3-dioxane-2,1′-indene]-4′-carboxylate 16. Meth-
anesulfonyl chloride (60 mg, 0.36 mmol) was added slowly to
alcohol 12 (40 mg, 0.12 mmol) and triethylamine (1 mL, 7.2 mol)
in 1 mL of dichloromethane at 0 °C. The solution was stirred to rt
over 2 h. DBU (2 mL, 2.04 g, 14 mmol) was added, and the solution
was stirred at rt for 18 h. The solution was filtered through a pad
of silica gel with EtOAc and concentrated. The residue was
chromatographed to give ketal ester 15 (21 mg, 56% yield) as an
oil: [R]20D +25.5 (c ) 1.0, CH2Cl2); TLC Rf ) 0.44 (8:2 petroleum
ether/MTBE); 1H NMR δ 6.84 (s, 1H), 3.72 (s, 3H), 3.52 (s, 2H),
3.45 (d, J ) 4.4 Hz, 2H), 2.95 (m 1H), 2.34 (m, 1H), 2.12 (m,
3H), 1.84 (m, 2H), 1.47 (m, 4H), 0.98 (m, 9H); 13C NMR δ u 185.1,
133.3, 109.5, 72.9, 71.2, 31.2, 30.1, 28.2, 27.7, 25.9; d: 143.2, 51.8,
42.8, 38.1, 36.0, 22.5, 11.3; IR 2958, 1714, 1440, 1249 cm-1; MS
m/z 309 (M + H, 8), 279 (7), 237 (12), 222 (94), 209 (37), 165
give the alkenyl cyclopropane 3 (1.84 g, 78% yield) as an oil: [R]20
D
+20.8 (c ) 1.0, CH2Cl2); TLC Rf ) 0.74 (8:2 petroleum ether/
1
MTBE); H NMR δ 5.70 (d, J ) 8.0 Hz, 1H), 5.48 (m, 1H), 3.56
(d, J ) 11.6 Hz, 1H), 3.43 (d, J ) 11.6 Hz, 1H), 3.40 (s, 2H),
2.18-2.29 (m, 3H), 1.93 (m, 1H), 1.72 (dd, J ) 8.0, 12.0 Hz, 1H),
1.41 (m, 1H), 1.17 (m, 4H), 0.95 (t, J ) 7.2 Hz, 3H), 0.85 (m,
1H), 0.71 (s, 3H), 0.65 (dd, J ) 4.2, 7.2 Hz, 1H); 13C NMR δ u
110.0, 73.1, 71.4, 33.2, 30.1, 24.7, 24.6, 21.8, 14.7; d 136.6, 125.5,
22.7, 22.5, 22.1, 14.3; IR 2950, 2859, 1211, 1153, 1117 cm-1; MS
m/z 237 (M + H, 18), 201 (100), 183 (54), 141 (71); HRMS calcd
for C15H24O2 236.1776, obsd 236.1767.
(3a′R,7a′R)-6′-Ethyl-5,5-dimethyl-2′,3′,3a′,7a′-tetrahydrospiro[1,3-
dioxane-2,1′-inden]-5′(4′H)-one 4. To the alkenyl cyclopropane 3
(236 mg, 1.0 mmol) and potassium carbonate (280 mg, 2.0 mmol)
in 10 mL of 2-propanol and 5 mL of tetrahydrofuran (0.075 M)
was added Fe(CO)5 (392 mg, 2.0 mmol). The Pyrex reaction vessel
was purged with CO, a CO balloon was attached, and the mixture
was irradiated for 4 h at room temperature as a thin film in a
2436 J. Org. Chem. Vol. 74, No. 6, 2009

Synthesis of (+)-Coronafacic Acid
(55), 141 (100), 119 (99); HRMS calcd for C18H29O4 (M + H)
309.2066, obsd. 309.2066.
Acknowledgment. We thank John Dykins for high-resolution
mass spectrometry under the financial support of NSF 054177.
We thank the NIH (GM060287) for financial support of this
work.
(+)-Coronafacic Acid 5. Hydrochloric acid (20% aqueous, 2
mL) was added to ketal ester 16 (11 mg, 0.07 mmol). The mixture
was heated to reflux for 4 h. The solution was allowed to cool to
rt and then partitioned between water and EtOAc. The combined
organic extract was dried (MgSO4) and concentrated. The residue
was chromatographed to give 5 (7 mg, 55% yield) as an oil: TLC
Supporting Information Available: General experimental
procedures, details of the photochemical apparatus, preparation
of 1, and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Rf ) 0.25 (7:3 petroleum ether/EtOAc); [R]20 +104 (c ) 0.1,
D
MeOH) (lit.14o [R]20D +105). The spectroscopic data of the natural
product 5 were compared with those of earlier syntheses14o and
found to be identical.
JO802493K
J. Org. Chem. Vol. 74, No. 6, 2009 2437