Ti(III)-promoted radical cyclization of epoxy enones. total synthesis of (+)-paeonisuffrone

Full text of DOI:10.1021/jo8026033

Ti(III)-Promoted Radical Cyclization of Epoxy
Enones. Total Synthesis of (+)-Paeonisuffrone
Mar´ıa Mart´ın-Rodr´ıguez, Raquel Gala´n-Ferna´ndez,
Andre´s Marcos-Escribano, and Francisco A. Bermejo*
Departamento de Qu´ımica Orga´nica, UniVersidad de
Salamanca, 37008 Salamanca, Spain
fcobmjo@usal.es
ReceiVed NoVember 24, 2008
FIGURE 1. Monoterpenes from Chinese paeony.
Mateos by developing the chemistry of epoxy ketones and epoxy
aldehydes,6 epoxy nitriles,7 and epoxy esters.8
Moreover, chiral tertiary alcohols are important structural
subunits in chemical building blocks and biologically active
compounds;9 for example, (-)-paeoniflorin (1), the ꢀ-glucoside
of paeoniflorigenin (2), (-)-paeonisuffrone (3a), (-)-paeonisuf-
frone monoacetate (3b), and (-)-paeonisuffrone diacetate (3c)
are novel complex terpenoids from the roots of the Chinese
paeony, Paeonia albiflora Pallas and Paeonia suffruticosa
Andrews (Paeoniaceae),10 that are widely used in traditional
Chinese medicine.11 They all include a cyclobutyl tertiary
alcohol within a compact polyoxygenated structure (Figure 1).
Pioneering synthetic work in this field was reported by
Takano,12 Corey,13 and Hatakeyama.14 Furthermore, the total
synthesis of (-)-paeonisuffrone (3a) was reported by Hatakeya-
ma in 1995. The synthesis of enantiomerically pure 3a required
The total synthesis of (+)-paeonisuffrone starting from (+)-
10-hydroxycarvone is described. The key step of our
synthetic strategy is a titanium-catalyzed stereoselective
cyclization initiated by epoxide opening through electron
transfer. This reaction stereoselectively affords the highly
oxygenated pinane skeleton present in the target molecule
and opens a new and effective approach to the synthesis of
the complex, biologically active terpenoids isolated from the
roots of the Chinese paeony (Paeonia albiflora Pallas and
Paeonia suffruticosa Andrews).
(5) For examples of enantioselective syntheses of natural products, see: (a)
Trost, B. M.; Shen, H. C.; Surivet, J.-P. Angew. Chem. 2003, 115, 4073–4077.
Angew. Chem., Int. Ed. 2003, 42, 3943-3947. (b) Banerjee, B.; Roy, S. C.
Synthesis 2005, 2913–2919. (c) Barrero, A. F.; Herrador, M. M.; Qu´ılez del
Moral, J. F.; Arteaga, P.; Arteaga, J. F.; Piedra, M.; Sa´nchez, E. M. Org. Lett.
2005, 7, 2301–2304. (d) Bermejo, F. A.; Mateos, A. F.; Marcos-Escribano, A.;
Mart´ın-Lago, R.; Mateos-Buro´n, L.; Rodr´ıguez-Lo´pez, M.; Rubio-Gonza´lez, R.
Tetrahedron 2006, 62, 8933–8942. (e) Justicia, J.; Campan˜a, A. G.; Bazdi, B.;
Robles, R.; Cuerva, J. M.; Oltra, J. E. AdV. Synth. Catal. 2008, 4, 571–576. (f)
Arteaga, J. F.; Domingo, V.; Qu´ılez del Moral, J. F.; Barrero, A. F. Org. Lett.
2008, 10, 1723–1726.
(6) (a) Ferna´ndez Mateos, A.; Mart´ın de la Nava, E.; Pascual Coca, G.; Ramos
Silvo, A.; Rubio Gonza´lez, R. Org. Lett. 1999, 1, 607–609. (b) Mateos, A. F.;
Mateos-Buro´n, L.; De la Nava, E. M.; Rabanedo-Clemente, R.; Rubio-Gonza´lez,
R. Synlett 2004, 2553–2557.
(7) (a) Mateos, A. F.; Herrero-Teijo´n, P.; Rabanedo-Clemente, R.; Rubio-
Gonza´lez, R.; Sanz-Gonza´lez, F. Synlett 2007, 2718–2722. (b) Mateos, A. F.;
Herrero-Teijo´n, P.; Mateos-Buro´n, L.; Rabanedo-Clemente, R.; Rubio-Gonza´lez,
R. J. Org. Chem. 2007, 72, 9973–9982.
The homolytic opening of epoxides using bis(cyclopentadi-
enyl) titanium chloride (Cp2TiCl) was first reported in 1988 by
Nugent and RajanBabu.1 Furthermore, the catalytic versions
reported by Gansa¨uer2 in 1998 and by Oltra3 in 2003 contributed
strongly to extending the scope of radical cyclizations, and the
total syntheses of numerous terpenoids in racemic form were
reported.4 However, Cp2TiCl has found little application in the
enantioselective synthesis of natural products.5 Further applica-
tions to intramolecular processes were found by Ferna´ndez-
(1) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8562–
8564. (b) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1989, 111, 4525–
4527. (c) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem. Soc.
1990, 112, 6408–6409. (d) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc.
1994, 116, 986–997.
(8) Mateos, A. F.; Herrero-Teijo´n, P.; Rabanedo-Clemente, R.; Rubio-
Gonza´lez, R. Tetrahedron Lett. 2006, 47, 7755–7758.
(9) For the enantioselective formation of tertiary alcohols, see: Garc´ıa, C.;
Martin, V. S. Curr. Org. Chem. 2006, 10, 1849–1889.
(2) (a) Gansa¨uer, A.; Bluhm, H. Chem. Commun. 1998, 2143–2144. (b)
Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem. 1998, 110, 107–109. (c)
Friedrich, J.; Walczak, K.; Dolg, M.; Piestert, F.; Lauterbach, T.; Worgull, D.;
Gansa¨uer, A. J. Am. Chem. Soc. 2008, 130, 1788–1796, and references therein.
(3) (a) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
2003, 5, 1935–1938. (b) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Gansa¨uer,
A.; Oltra, J. E. Tetrahedron Lett. 2003, 44, 1079–1082.
(4) (a) Clive, D. L. J.; Magnuson, S. R.; Manning, H. W.; Mayhew, D. L. J.
Org. Chem. 1996, 61, 2095–2108. (b) Gansa¨uer, A.; Bluhm, H. Chem. ReV.
2000, 2771–2788. (c) Gansa¨uer, A.; Lauterbach, T.; Narayan, S. Angew. Chem.
2003, 42, 5556–5573. (d) Cuerva, J. M.; Justicia, J.; Oller-Lo´pez, J. L.; Oltra,
J. E. Top. Curr. Chem. 2006, 264, 63–91. (e) Barrero, A.; Qu´ılez del Moral,
J. F.; Sa´nchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641. (f)
Gansa¨uer, A.; Fan, C.; Justicia, J.; Worgull, D.; Piestert, F. Top. Curr. Chem.
2007, 279, 25–52.
(10) (a) Shibata, S.; Nakahara, M. Chem. Pharm. Bull. 1963, 11, 372–378.
(b) Aimi, N.; Inaba, M.; Watanabe, M.; Shibata, S. Tetrahedron 1969, 25, 1825–
1838. (c) Kaneda, M.; Iitaka, Y.; Shibata, S. Tetrahedron 1972, 28, 4309–4317.
(d) Yoshikawa, M.; Harada, E.; Kawaguchi, A.; Yamahara, J.; Murakami, N.;
Kitagawa, I. Chem. Pharm. Bul.l 1993, 41 (3), 630–632. (e) Murakami, N.; Saka,
M.; Shimada, H.; Matsuda, H.; Yamahara, J.; Yoshikawa, M. Chem. Pharm.
Bull. 1996, 44 (6), 1279–1281.
(11) (a) Hikino, H. In Economic and Medicinal Plant Research; Wagner,
H., Hikino, H., Farnsworth, N. R., Eds.; Academic Press, Inc.: London, 1985;
pp 55-85. (b) Fujiwara, M. Jpn. J. Neurophsychopharmacol. 1990, 12, 217–
226. (c) Yoshikawa, M.; Ohta, T.; Kawaguchi, A.; Matsuda, H. Chem. Pharm.
Bull 2000, 48 (9), 1327–1331.
(12) Hatakeyama, S.; Kawamura, M.; Shimanuki, E.; Saijo, K.; Takano, S.
Synlett 1992, 114–116.
(13) Corey, E. J.; Wu, Y-J. J. Am. Chem. Soc. 1993, 115, 8871–8872.
1798 J. Org. Chem. 2009, 74, 1798–1801
10.1021/jo8026033 CCC: $40.75 2009 American Chemical Society
Published on Web 01/20/2009

SCHEME 1. Synthesis of Epoxy Enones 7a,b and Ti(III)-
Induced Radical Cyclizationsa
FIGURE 2. Observed ROESY correlations on diols 8a,b and 9a,b.
afforded a mixture of two diastereomeric alcohols 8a,b and 9a,b
in moderate yields and low stereoselectivies (the diols 8a,b were
always obtained as the major products in the reaction mix-
tures).16 No change in stereoselectivity was observed by reverse
addition (Method B), although for the case of 7b a small increase
in the elimination product, 5, was observed.
The reaction, which afforded mixtures of diols 8a,b and 9a,b,
is a chemo- and regioselective radical 4-exo cyclization process
onto a carbonyl function conjugated with a double bond, as has
been observed in previous work carried out at our laboratory.5d
The addition of triethylamine to the reaction mixture was
performed to suppress the rearranged side products (mostly
aldehydes), promoted by Lewis acid catalysis (zinc dihalide)
(Table 1, entries 3 and 7).17 However, under these conditions
the stereoselectivities obtained were very similar, but the reaction
yields were lower.
The structural assignments of diol diastereomers 8a,b and
9a,b were based on complete NMR studies. ROESY experi-
ments were relevant to prove the vicinity between the cyclobutyl
exo proton and the methylene group belonging to the exo side
chain present in both types of diastereomers (Figure 2).
The same reaction performed under the catalytic conditions
described by Gansäuer2 yielded higher stereoselectivities but
lower yields (Table 1, entries 4 and 8).
a Reactions and conditions: (i) mCPBA, CH2Cl2, Na2CO3, rt, 15 h, 60%;
(ii) iPr2EtN, C6H5CH2OCH2Cl, THF, 4 days, rt, 85% (for 7a); ClCOtBu,
pyr, CH2Cl2, 15 h, rt, 80% (for 7b); (iii) Cp2TiCl2, Zn, THF rt, 15 h (see
Table 1).
TABLE 1. Radical Cyclizations of Epoxy Enones 7a,ba
starting
material
yield (%)b
8 + 9
entry
method
8:9c ratio
5 (%)
1
2
3
4
5
6
7
8
A
B
A
A(cat)
A
B
A
A(cat)
7a
50
47
45
46
70
62
58
65
1.1:1
1:1
1:1
1.2:1
2:1
1.5:1
1.75:1
2.5:1
7a
7ad
7a
7b
7b
7bd
7b
8
15
5
6
a All reactions were run under an argon atmosphere at room
temperature overnight (12 h). In the cases of catalyzed reactions (entries
4 and 8), full conversions were observed after 20 h (7a) and 24 h (7b).
b Isolated yields. c Determined by either 1H NMR or HPLC. d TEA was
added as an additive.
The diol 8b was obtained from the epoxy pivalate 7b under
either stoichiometric or catalytic conditions,2,3 with similar
isolated yields (47% and 46%, respectively), to complete the
synthesis of (+)-paeonisuffrone.18
Protection of the diol 8b by treatment with benzaldehyde
dimethyl acetal (BDMA) and PPTS afforded the benzylidene
acetal 10 in 80% isolated yield (Scheme 2).
the resolution of a racemic intermediate via the O-methyl
mandelate and unambigously established the absolute config-
uration of natural paeonisuffrone.14a
The synthesis of functionalized pinanes by means of the
Ti(III)-promoted radical cyclization of epoxy derivatives of
carvone seemed to be an appropriate method to access the
polyoxygenated cagelike pinane skeleton present in paeony
monoterpenes (1-3). Here we describe a new synthetic approach
to synthesize the highly oxygenated pinane (+)-paeonisuffrone
(4), the enantiomer of the natural monoterpene (3a). Our strategy
is based on the Cp2TiCl-catalyzed reductive C-C bond forma-
tion, leading to a tertiary cyclobutyl alcohol after regioselective
homolytic epoxide opening of the epoxy pivalate 7b.
The preparation of (+)-10-hydroxycarvone 515 (Scheme 1)
followed by epoxidation and protection of the hydroxy function
under basic conditions allowed us to isolate the benzyloxymethyl
(BOM) ether 7a and the pivalate 7b as mixtures of diastereomers
at the C-8 center with 37% and 30% overall yields, respectively,
from S-(+)-carvone.
Allylic oxidation of 10 was performed by treatment with CrO3
and dimethyl pyrazole in dichloromethane at -20 °C to afford
a mixture of the enone 11 and the benzylic alcohol 12 with
63% yield and 25% isolated yields, respectively.
Conversion of the enone 11 to the paeonisuffrone intermediate
13 required the hydrolysis of the pivalate functionality and
conjugate addition (oxa-Michael addition)19 of the hydroxy-
methyl side chain to the enone.
Our first effort was performed under the conditions described
by Snider on occasion of the biomimetic synthesis of poly-
galolides A and B by stirring 11 with Cs2CO3 in 1:1 THF-H2O
at 50 °C.20 Unfortunately, no cyclization product was obtained
after 7 h of heating the reaction mixture.
(16) The formation of 5 starting from 7b would require the activation of an
acyloxy elimination step, which is faster than the titanoxy elimination reaction,
both triggered off from the same Ti-carbanion intermediate.
(17) (a) Hilt, G.; Bolze, P.; Kieltsch, I. Chem. Commun. 2005, 1996–1998.
(b) Hilt, G.; Bolze, P.; Harms, K. Chem. Eur. J. 2007, 13, 4312–4325.
(18) The stoichiometric method required considerable amounts of Cp2TiCl2
to obtain acceptable yields of 8c. Thus, the catalytic method is the best choice
for isolating 8c and carrying out the total synthesis of enantiomerically pure
4.
We studied the Ti(III)-promoted cyclization reaction of the
epoxides 7a,b under standard conditions (Table 1).2 Addition
of the reagent Cp2TiCl to the epoxide solution (Method A)
(14) (a) Hatakeyama, S.; Kawamura, M.; Takano, S. J. Am. Chem. Soc. 1994,
116, 4081–4082. (b) Hatakeyama, M.; Kawamura, Y.; Mukugi, Y.; Irie, H.
Tetrahedron Lett. 1995, 36, 267–268. .
(15) Weinges, K.; Schwartz, G. Liebigs Ann. Chem. 1993, 811–814. (b)
Hegde, S. G.; Wolinsky, J. J. Org. Chem. 1982, 47, 3148–3150.
(19) Nising, C. F.; Bra¨se, S. Chem. Soc. ReV. 2008, 37, 1218–1228.
(20) Snider, B. B.; Wu, X.; Nakamura, S.; Hashimoto, S. Org. Lett. 2007, 9,
873–874.
J. Org. Chem. Vol. 74, No. 4, 2009 1799

SCHEME 2. Synthesis of (+)-Paeonisuffrone (4)a
(CDCl3) δ 16.8, 27.7, 29.9, 30.5, 38.9, 39.9, 48.9, 62.9, 64.2, 77.8,
117.6, 145.7, 179.4 ppm. Anal. Calcd for C15H24O4: C, 67.14, H,
9.01. Found: C, 67.32, H, 9.36. HRMS-EI (M+ + Na) calcd for
C15H24O4Na 291.1567, found 291.1553.
Diol 9b. Rf ) 0.50 (hexane-ethyl acetate 1:1); [R]20 -26.18
D
(c 0.615, CHCl3); IR (film) ν 3432, 2959, 1716, 1462, 1288, 1165,
1
1026 cm-1. H NMR (CDCl3) δ 1.22 (s, 9H), 1.69 (d, J ) 9 Hz,
1H), 1.80 (s, 3H), 1.9-2.4 (m, 5H), 2.41 (t, J ) 7 Hz, 1H), 3.51
(d, J )11.3 Hz, 1H), 3,72 (d, J ) 11.3 Hz, 1H), 4.56 (d, J ) 11.9
Hz, 1H), 4.67 (d, J ) 11.9 Hz, 1H), 5.31 (s, 1H) ppm. 13C NMR
(CDCl3) δ 16.9, 27.2 (3×), 29.9, 30.6, 39.0, 39.9, 50.5, 60. 2, 62.8,
64.4, 117.6, 145.3, 179.5 ppm. Anal. Calcd for C15H24O4: C, 67.14,
H, 9.01. Found: C, 67.38, H, 9.24. HRMS-EI (M+ + H) calcd for
C15H24O4 269.1747, found 269.1740.
Benzylidene Acetal 10. A solution of 9c (0.2 g, 0.4 mmol) in
15 mL of dichloromethane was placed in a two-necked 50-mL
round-bottomed flask equipped with a magnetic stirrer. Then,
benzaldehyde dimethyl acetal (0.3 mL, 0.4 mmol) and pyridinium
p-toluenesulfonate (cat.) were added under an argon atmosphere,
and the reaction mixture was stirred at room temperature for 24 h.
When the reaction was finished, a solution of saturated sodium
bicarbonate (10 mL) was added, the reaction mixture was extracted
with ethyl acetate, the combined organic layers were washed with
brine and dried on anhydrous sodium sulfate, and the solvent was
removed at reduced pressure to afford a crude (0.5 g), which was
fractionated by flash column on silica gel. By elution with
hexane-ethyl acetate (95:5), the acetal 10 (0.210 g, 80%) was
a Reactions and conditions: (i) BDMA, PPTS, CH2Cl2, 24 h, 80%; (ii)
CrO3, DMP, CH2Cl2, -20°C, 11 (63%), 12 (25%); (iii) 10 N NaOH,
CH3OH, 85%; (iv) H2, Pd (C), AcOEt, 90%.
However, treatment of a methanolic solution of 11 with
aqueous 10 N NaOH at room temperature led to quantitative
transformation into the tetracyclic ketone 13, whose structural
assignment was based on complete spectroscopic analysis.
Catalytic hydrogenolysis of 13 with palladium on carbon (5%)
led to (+)-paeonisuffrone 4, with spectroscopic properties
identical to those described for the natural enantiomer.10
The synthesis of (+)-paeonisuffrone 4 was achieved based
on a new strategy that allows access to the functionalized pinane
intermediate 8b. The key step in our strategy was the Ti(III)-
catalyzed reductive C-C formation of a cyclobutyl tertiary
alcohol after Ti(III)-catalyzed epoxide opening of epoxypivalate
7b. Transformation of the dihydroxy pivalate 8b into (+)-
paeonisuffrone 4 can be achieved in four steps, with 38% yield.
obtained. Rf ) 0.45 (hexane-ethyl acetate 95:5); [R]20 -75° (c
D
0.60, CHCl3); IR (film) ν 2968, 1728, 1479, 1453, 1393, 1228,
1
1072, 750 cm-1. H NMR (CDCl3) δ 1.18 (s, 9H), 1.59 (d, J ) 9
Hz, 1H), 1.81 (s, 3H), 2.1-2.4 (m, 5H), 3.24 (t, J ) 9 Hz, 1H),
4.22 (d, J ) 12 Hz, 1H), 4.23 (d, J ) 12 Hz, 1H), 4.33 (d, J )
11.5 Hz, 1H), 4.44 (d, J ) 12 Hz, 1H), 5.32 (s, 1H), 5.93 (s, 1H),
7.36 (m 3H), 7.50 (m, 2H) ppm. 13C NMR (CDCl3) δ 16.4, 27.2
(3×), 30.1, 30.5, 32.4, 38.9, 41.1, 62.8, 70.2, 96.1, 117.5, 126.3,
128.1, 128.8, 138.5, 144.1, 178.6 ppm. Anal. Calcd for C22H28O4,
C, 74.13, H, 7.92. Found: C, 74.37, H, 8.16. HRMS-EI (M++ Na)
calcd for C22H28O4Na 379.1880, found 379.1883.
Experimental Section
Enones 11 and 12. A suspension of chromium oxide (1.15 g,
12 mmol) in dry dichloromethane (25 mL) was placed in a two-
necked 50-mL round-bottomed flask equipped with a magnetic
stirrer. The reaction mixture was cooled to -20 °C, and dimeth-
ylpyrazole (1.1 g, 12 mmol) was added in one portion under an
argon atmosphere. After 15 min a solution of the acetal 10 (0.36
g, 1mmol) in dichloromethane (20 mL) was added dropwise, and
the reaction mixture was stirred for 4 h, maintaining the temperature
between -10 and -20 °C. A sodium hydroxide solution (2 mL, 5
N) was then added, and the reaction mixture was stirred at 0 °C
for 1 h. The two phases were separated, and the combined organic
layers were washed with dilute hydrochloric acid to remove the
DMP. The organic layers were washed with a saturated NaCl
solution, dried over Na2SO4, and evaporated at reduced pressure
to afford a crude product (0.4 g), which was fractionated by flash
chromatography on silica gel. By elution with hexane-ethyl acetate
(8:2), the enones 11 (233 mg, 63%) and 12 (93 mg, 25%) were
Ti-Promoted Cyclization of 7b. Solution A: In a 25-mL round-
bottomed flask equipped with a magnetic stirrer were placed Zn
(195 mg, 3.0 mmol) and Cp2TiCl2 (313 mg, 1.25 mmol) under an
argon atmosphere. Deoxygenated and freshly distilled tetrahydro-
furan (2.5 mL) was added, and the reaction mixture was stirred
until the green color persisted. Solution B: In a two-necked 25-mL
round-bottomed flask equipped with a magnetic stirrer was placed
a solution of the epoxy enone 7b (200 mg, 0.75 mmol) in THF (5
mL) under an argon atmosphere.
Method A. Solution A was added very slowly to solution B,
and the reaction mixture was stirred overnight at room temperature.
Method B. Solution B was added dropwise to solution A, and
the reaction mixture was stirred overnight at room temperature.
Workup and Isolation of 8b and 9b. When the reaction mixture
turned from deep green to red, saturated solutions of NaH2PO4 (75
mL) and NaCl (75 mL) were successively added to the reaction
mixture. Stirring was maintained for 5 h, and the reaction mixture
was filtered. The filtrate was extracted with ether (3 × 25 mL),
and the combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed at reduced pressure to yield
the crude product. Fractionation of the crude by flash silica gel
chromatography eluting with hexane-ethyl acetate (9:1) yielded
8b (93 mg, 47%), 9b (46.5 mg, 23%), and 515 (10 mg, 8%) (Method
A) and 8b (75 mg, 37%), 9b (50 mg, 25%), and 5 (19 mg, 15%)
(Method B).
isolated. Enone 11: Rf ) 0.50 (hexane-ethyl acetate 8:2); [R]20
D
) -84.4 (c 0.97 CHCl3); IR (film) ν 2960, 2923, 2853, 1728, 1688,
1457, 1227 cm-1; UV (EtOH) λmax ) 205 (ε 12024); λmax ) 254
1
nm (ε 4780). H NMR (CDCl3) δ 1.15 (s, 9H), 2.10 (s, 3H); 2.46
(d, J ) 10 Hz, 1H); 2.81 (d, J ) 5 Hz, 1H); 3.68 (dd, J1 ) 5 Hz,
J2 ) 10 Hz, 1H); 4.23 (d, J ) 12 Hz, 1H), 4.40 (d, J ) 12 Hz,
1H), 4.46 (s, 2H), 5.79 (s, 1H), 6.02 (s, 1H), 7.39 (m, 3H); 7.49
(m, 2H) ppm. 13C NMR (CDCl3) δ 17.5, 27.1 (3×), 38.9, 42.4,
46.4, 54,6, 63.0, 69.8, 96.7, 121.1, 126.2, 128.3, 129.2, 137.3, 169.1,
178.2, 198.6 ppm. Anal. Calcd for C22H26O5: C, 71.33, H, 7.07.
Found: C, 71.52, H, 7.34. HRMS-EI (M++ Na) calcd for
C22H26O5Na 393.1672, found 393.1667. Enone 12: Mp 160-161
°C. Rf ) 0.25 (hexane-ethyl acetate 8:2); [R]20D ) -31.22 (c 0.6
CHCl3); IR (film) ν 3441, 2970, 2921, 1725, 1677, 1271 cm -1. 1H
Diol 8b. Rf ) 0.60 (hexane-ethyl acetate 1:1); [R]20D +14.4 (c
0.25, CHCl3); IR (film) ν 3418, 2964, 2363, 1726, 1711, 1296,
1
1172 cm-1. H NMR (CDCl3) δ 1.20 (s, 9H), 1.71 (d, J ) 9 Hz,
1H), 1.78 (s, 3H), 2.05-2.25 (m, 5H), 2.44 (t, J ) 9 Hz, 1H), 3.86
(d, J ) 12 Hz, 1H), 4.15 (d, J ) 11.5 Hz, 1H), 4.16 (d, J ) 12 Hz,
1H), 4.46 (d, J ) 11.5 Hz, 1H), 5.30 (s, 1H) ppm. 13C NMR
1800 J. Org. Chem. Vol. 74, No. 4, 2009

NMR (CDCl3) δ 1.18 (s, 9H), 2.14 (s, 3H), 2.60 (d, J ) 9 Hz,
1H), 2.93 (m, 2H), 4.13 (d, J ) 12 Hz, 1H), 4.43 (d, J ) 12 Hz;
1H), 4.67 (d, J ) 12 Hz 1H), 4.83 (d, J ) 12 Hz, 1H), 5.81 (s,
1H), 7.46 (m, 2H), 7,58 (m, 1H), 8.02 (m, 2H) ppm. 13C NMR
(CDCl3) δ 18.3, 27.1 (3×), 38.9, 46.6, 48.1, 62.8 (2×), 62.9, 77.6,
121.1, 128.5, 129.3, 129.7, 133.5, 166.8, 171.1, 178.1, 199.5 ppm.
Anal. Calcd for C22H26O6: C, 68.38, H, 6.78. Found: C, 68.52, H,
6.96. HRMS-EI (M++ Na) calcd for C22H26O6Na 409.1622, found
409.1617.
flask equipped with a magnetic stirrer. A solution of 13 (0.143 g,
0.5 mmol) in ethyl acetate (1.5 mL) was added dropwise, and the
reaction mixture was stirred under hydrogen for 4 h. at room
temperature. Filtration of the reaction product through celite and
evaporation of the solvent afforded 4 (0.09 g, 90%). Mp 163-164
°C. Rf ) 0.50 (hexane-ethyl acetate 1:1); [R]20D ) +17.34°(c 0.8,
CH3OH); IR (film) ν 3372, 1727, 1458, 1240, 1166, 1052, cm-1
.
1H NMR (CD3OD) δ 1.31 (s, 3H), 2.20 (d, J )11 Hz, 1H), 2.31
(d, J )18 Hz, 1H), 2.46 (dd, J1 ) 7 Hz, J2 )11 Hz, 1H), 2.85 (d,
J ) 7 Hz, 1H) 2.91 (d, J )18 Hz, 1H), 3.57 (d, J ) 10 Hz, 1H),
3.83 (d, J ) 12 Hz, 1H), 3.88 (d, J ) 10 Hz, 1H), 3.89 (d, J1 ) 12
Hz, 1H) ppm. 13C NMR (CD3OD) δ 19.2, 31.7, 49.5, 49.8, 62.7,
63.0, 71.7, 82.2, 87.6, 212.9 ppm. Anal. Calcd for C10H14O4: C,
60.59, H, 7.12. Found: C, 60.72, H, 7.30. HRMS-EI (M++ Na)
calcd for C10H14O4Na 221.0784, found 221.0787.
Tetracyclic Ketone 13. A solution of 11 (0.185 g, 0.5 mmol)
in methanol (2 mL) was placed in a two-necked 50-mL round-
bottomed flask equipped with a magnetic stirrer. Sodium hydroxide
(0.01 mL, 10N) was added and the reaction mixture was stirred
for 24 h at room temperature. Evaporation of the solvent was
followed by the addition of water (5 mL) and extraction of the
aqueous phase with dichloromethane. The organic layers were
washed with saturated sodium chloride and dried on anhydrous
sodium sulfate to yield a crude product (0.17 g), which was
fractionated by flash chromatography on silica gel. By elution with
hexane-ethyl acetate (8:2) the tricyclic ketone 13 (0.122 g, 85%)
was isolated. Rf ) 0.50 (hexane-ethyl acetate 8:2); [R]20D ) +0.88
(c 1.13, CHCl3); IR (film) ν 2960, 2924, 2855, 1729, 1144, 1014
Acknowledgment. We thank the Spanish Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica (MEC CTQ2005-05026/
BQU) and the Junta de Castilla y Leo´n (SA079A06) for
providing financial support for this work. R.G.-F. wishes to
thank the Junta de Castilla y Leo´n (Consejer´ıa de Educacio´n)
for financial aid (EDU/ I 486/2008). We also wish to thank Dr.
Anna M. Lithgow Bertelloni (Servicios Generales USAL) for
recording the NMR spectra.
1
cm-1. H NMR (CDCl3) δ 1.47 (s, 3H), 2.14 (d, J ) 12 Hz, 1H),
2.59 (d, J ) 18 Hz, 1H), 2.80 (d, J ) 7 Hz, 1H) 2.85 (d, J ) 18
Hz, 1H), 3.13 (dd, J1 ) 7.0 Hz, J2 ) 12 Hz, 1H), 3.87 (d, J )10
Hz, 1H), 4.15 (d, J )10 Hz, 1H), 4.16 (d, J ) 12 Hz, 1H), 4.31 (d,
J ) 12 Hz, 1H), 5.88 (s, 1H), 7.39 (m, 3H), 7.54 (m, 2H) ppm. 13
C
Supporting Information Available: Experimental proce-
dures for the preparation and characterization of 6, 7a, 7b, 8a,
and 9a and spectral data of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
NMR (CDCl3) δ 18.1, 25.2, 49.0, 49.1, 51.8, 68.2, 70.7, 79.8, 86.7,
96.8, 126.4, 128.3, 129.3, 137.4, 208.3 ppm. Anal. Calcd for
C17H18O4: C, 71.31, H, 6.34. Found: C, 71.56, H, 6.58. HRMS-EI
(M++ Na) calcd for C17H18O4Na 309.1097, found 309.1091.
(+)-Paeonisuffrone 4. Palladium on carbon (5%) was suspended
in ethyl acetate (2 mL) in a two-necked 50-mL round-bottomed
JO8026033
J. Org. Chem. Vol. 74, No. 4, 2009 1801