Selectivity in reduction of natural furanoheliangolides with Stryker's reagent

Article abstract of DOI:10.1039/c1ob05734k

Reduction of the natural sesquiterpene lactones furanoheliangolides with Stryker's reagent is an effective process for producing eremantholides through a biomimetic pathway. Other reduction products are also formed. Oxygenated functions at C-15 of the fur

Full text of DOI:10.1039/c1ob05734k

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PAPER
Selectivity in reduction of natural furanoheliangolides with Stryker’s reagent†
Daiane C. Sass,a Vladimir C. G. Heleno,b Gustavo O. Morais,*b Joa˜o L. C. Lopes,c Norberto P. Lopes*c and
Mauricio G. Constantino*a
Received 10th May 2011, Accepted 6th June 2011
DOI: 10.1039/c1ob05734k
Reduction of the natural sesquiterpene lactones furanoheliangolides with Stryker’s reagent is an
effective process for producing eremantholides through a biomimetic pathway. Other reduction
products are also formed. Oxygenated functions at C-15 of the furanoheliangolide produce an increase
in the velocities of the reactions and reduce the chemoselectivity of the reagent.
Furanoheliangolides and eremantholides (Fig. 1) are natural
sesquiterpene lactones1 that show a number of interesting biolog-
ical activities, e.g. trypanocidal, antibacterial, antiinflammatory,
antitumor, etc.2 Several compounds of this class have been isolated
from Brazilian plants.3
lactone function were shown to be toxic for clinical use. However,
the eremantholides maintain these activities despite the absence
of an a-methylene lactone, and are more selective and, thus, less
toxic.6
Due to their importance, several research groups have proposed
total syntheses or structural modifications of those substances.7
Some papers reported chemical transformations in furanohelian-
golides of type 4 with several reducing agents such as NaBH4,
Bu3SnH, H2/Pd/C and H2/Wilkinson’s catalyst,7d,7e attempting to
selectively reduce these compounds to prepare more rare natural
products or derivatives with enhanced biological activity.
We have been particularly interested in biomimetically8 trans-
forming furanoheliangolides (found in larger amounts in plants)
into eremantholides, which would require a reducing agent capable
of selectively delivering a hydride to the conjugated system a-
methylene-g-lactone producing an enolate that would attack the
nearby carbonyl of the ester group.
Fig. 1 Examples of eremantholides and furanoheliangolides.
A review of the available methods of selective reduction revealed
that Stryker’s reagent [Ph3PCuH]6 is highly regioselective and
It is believed that these biological activities are mediated
chemically by a,b-unsaturated carbonyl structures, such as an
a-methylene-g-lactone, an a,b-unsaturated cyclopentenone or a
conjugated ester.1a,4 Kupchan has shown that for many antitumor
active sesquiterpenoids having an a-methylene-g-lactone function,
activity is associated with the ability of this group to accept nucle-
ophilic attack by sulfhydryl groups, in a Michael-type addition
reaction.5 The sesquiterpenoids presenting this a-methylene-g-
9
chemoselective in conjugate reductions of various a,b-unsaturated
carbonyl derivatives, including unsaturated ketones, esters and
aldehydes. These reductions can usually be carried out under
very mild reaction conditions.10 In the presence of additional
electrophilic centers, this reagent can also promote, after the 1,4-
reduction, a second reaction consisting of an inter- or intramolec-
ular addition.11
So we have decided to investigate the use of Stryker’s reagent in
reduction reactions with these sesquiterpene lactones, and verify
how selective it can be in the presence of their several electrophilic
centers, which include unsaturated ketones and esters.
We have recently published a preliminary study conducted
with a sample of the natural product 15-deoxygoyazensolide (4)
(Scheme 1).12 Stryker’s reagent showed very high chemoselectivity:
we could find only products from the reduction of the a-methylene-
lactone; the unsaturated ketone of the furanone ring, as well as
the unsaturated ester, remained untouched. In this reaction we
obtained eremantholide C (1) and the reduced product a-methyl-
lactone 7.
aDepartamento de Qu´ımica, Faculdade de Filosofia, Cieˆncias e Letras de
Ribeira˜o Preto, Universidade de Sa˜o Paulo, Av. Bandeirantes 3900, 14040-
901, Ribeira˜o Preto–SP, Brazil. E-mail: mgconsta@usp.br
bNu´cleo de Pesquisas em Cieˆncias Exatas e Tecnolo´gicas, Universidade de
Franca, Avenida Dr Armando de Salles Oliveira, 201, 14404-600, Franca–
SP, Brazil. E-mail: vheleno_05@yahoo.com.br
cDepartamento de F´ısica e Qu´ımica, Faculdade de Cieˆncias Farmaceˆuticas de
Ribeira˜o Preto, Universidade de Sa˜o Paulo, Avenida do Cafe´ s/n, 14040-903,
Ribeira˜o Preto–SP, Brazil. E-mail: npelopes@fcfrp.usp.br
† Electronic supplementary information (ESI) available: Copies of NMR
(1H and 13C, including some gCOSY, gHMQC, gHMBC and NOESY)
analyses of compounds 1, 2, 3, 7, 10, 11, 12, 13, 14, 15 and 16. See DOI:
10.1039/c1ob05734k
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Table 1 Reactions of C-15-non-oxygenated sesquiterpene lactones (4 and
6) with [Ph3PCuH]6
SM
T/◦C
Consumed SM
Products and yields
4
0
25
72%
87%
44%
49%
32%
36%
6
Scheme 1 Transformation of 15-deoxygoyazensolide (4) into ereman-
tholide C (1).
Encouraged by this favorable result, we decided to extend our
studies to other furanoheliangolides. We now report the results of
this research.
0
25
48%
75%
—
15%
77%
63%
When we treated compounds 4, 5, 6, 8 and 9 (Fig. 2) wi◦th
Stryker’s reagent (0.5 equiv.) at two different temperatures (0 C
and 25 ◦C) for a period of 2 h, we found that the reducing agent
was still selective, but we obtained a larger variety in the results.
Table 2 Reactions of C-15-oxygenated sesquiterpene lactones (5, 8 and
9) with [Ph3PCuH]6
SM T/◦C Consumed SM Products and yields
5
2
Fig. 2 Derivatives prepared from goyazensolide (5).
0
25
100%
100%
45% 41%
48% 37%
—
5%
Though rather confusing at first sight, this variety can be better
understood if we consider that an oxygenated function at C-
15 has a strong influence on the behavior of Stryker’s reagent,
producing two remarkable changes: (1) the velocity of the reactions
is increased; (2) the a,b,g,d-unsaturated system of the furanone can
now be also reduced.
8
Two of our substrates, the natural products 15-
deoxygoyazensolide (4) and lychnopholide (6), contained
no oxygen at C-15 and gave similar results (Table 1). The reactions
were relatively slow, as evidenced by the recovery of starting
material, and the reagent attacked only the a-methylene-g-lactone,
producing the corresponding eremantholide by cyclization and
the corresponding a-methyl-g-lactone by quenching before
the intermediate enolate could cyclize (Scheme 1). From the
yields in Table 1, calculated based on the transformed starting
material, we can easily observe that the cyclization of the enolate
is considerably faster for the substrate 4 than for 6. This is
possibly due to an increased steric hindrance in 6 produced by the
additional methyl group in the ester moiety.
0
25
88%
100%
32%
28%
48%
62%
9
0
25
100%
100%
46%
39%
Complex mixture
In all cases (except for substrate 9 at 25 ◦C, which gave a complex
The other substrates, 5, 8 and 9, contain oxygenated functions
at C-15 and gave more complex results. Compound 5 is the natural
sesquiterpene lactone goyazensolide, and 8 and 9 are simple
derivatives, acetate and triisopropylsilyl ether, prepared from 5.
The increase in the velocity of all reactions is evident by the high
consumption of the starting materials, quantitative in all cases
except one. We can also observe that the amounts of a-methyl-
g-lactones is much smaller in Table 2 than in Table 1, indicating
that there was an increase also in the velocity of cyclization of the
intermediate enolates.
mixture) the expected eremantholide was formed in reasonable
yield (2 from 5, 13 from 8, 15 from 9). In all cases were also
obtained products of reduction of the allylic system conjugated
with the furanone.
These results can be explained by assuming that a complexation
of the Stryker’s reagent with the allylic oxygen at C-15 would
somehow enhance the reactivity of the reagent, of the substrate
or both. This complexation would also force the proximity of the
reactants in such a way that the reduction of the allylic system
would become an important process.
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Depending on the oxygenated group at C-15, this reduction
can occur in one of two ways. If the oxygen group in C-15 is a
part of a good leaving group (e.g. acetate, as in compound 8),
the oxygenated function can be reduced first, possibly through
an allylic rearrangement, forming an intermediate that can accept
conjugate addition of a hydride, giving a reduced product without
oxygen in C-15 (product 14), as suggested in Scheme 2. It is also
possible that 14-a is formed by 1,6-conjugate addition of hydride
followed by elimination of acetate.
Scheme 4 Control experiment showing that 14 can be reduced.
the appropriate relative stereochemistry at C-6, C-7, C-8) with
Stryker’s reagent is an efficient method for preparing ereman-
tholides. When the substrate furanoheliangolide is oxygenated
at C-15, the reactions are faster and the eremantholides are still
obtained in acceptable yield, but other reduction products are also
formed. This is an inconvenience from the point of view of classical
synthetic methods, but can also be regarded as an advantage for
applying the methodology of biological activity screening usually
associated with combinatorial synthesis.
Scheme 2 Proposed mechanism for formation of compound 14.
On the other hand, if the oxygen in C-15 is a part of a bad
leaving group (e.g. triisopropylsilyl ether, as in compound 9), the
conjugate addition of hydride to the conjugated system becomes
the main process, forming products still containing oxygen in C-
15 (e.g. 16), as suggested in Scheme 3. It is not possible to decide
if this reduction took place before or after the reduction of the
a-methylene-g-lactone and cyclization to form the eremantholide
moiety.
Experimental
General methods
Reagents and starting materials were purchased from commercial
sources and used as received or were synthesized when convenient.
Natural products starting materials were isolated from natural
sources as described in the literature. If necessary, solvents were
purified following standard literature procedures. The reactions
were carried out under an atmosphere of argon as specified in
the experimental procedures. The NMR spectra were recorded
1
using a Bruker DPX-500 instrument (500 MHz H NMR and
125 MHz 13C NMR); CDCl3 and mixtures of CDCl3 and DMSO-
d6 were used as solvent with TMS as internal standard. IR
spectra were measured with a Perkin-Elmer Spectrum RX IFTIR
System. High resolution mass spectra (HRMS) were obtained
on an ESI-TOF Mass Spectrometer. TLC was performed on
precoated silica gel 60 F254 plates (0.25 mm thick, Merck),
and silica gel 60 (70–230 mesh, Merck) was used for column
chromatography.
Scheme 3 Proposed mechanism for formation of compound 16.
The OH group of goyazensolide (5) is, like the triisopropylsilyl
ether, a bad leaving group, and the still oxygenated eremantholide
11 is the major of the two products that had the conjugated
furanone system reduced. However, under the more strained
conditions (25 ◦C), a small amount of 12 was also formed,
suggesting that the complexation with Stryker’s reagent could have
transformed the OH into a somewhat better leaving group.
The formation of compound 14 in the reduction of 8 is rather
surprising, because our experimental results indicate clearly that
the a-methylene-g-lactone is the more reactive group of these
molecules. It is possible that this methylene-lactone has withstood
reduction because in the reaction medium the furanone function
was in its enolate form. In fact, in a control experiment we found
that pure compound 14 is easily reduced to give 12 together with
the corresponding eremantholide 1713 when treated with Stryker’s
reagent under the same reaction conditions used in this paper
(25 ◦C) (Scheme 4).
Synthesis of Stryker’s reagent [PPh3CuH]6
This was performed, with some modifications, as described in the
literature.8 Copper(I) chloride (0.9930 g, 10.03 mmol), potassium
t-butoxide (1.124 g, 10.02 mmol) and triphenylphosphine (2.623 g,
20.00 mmol) were weighed into a dry septum-capped round-
bottomed flask inside a dry-box. The flask was charged with 50 mL
toluene (distilled from CaH2 and degassed for 20 min) and the
contents were stirred for 40 min under argon to produce a slightly
cloudy, yellow solution. 1,1,2,2-Tetramethyl-disiloxane (1.84 mL,
10.0 mmol) was then added by syringe. The colour of the reaction
mixture changed from yellow to very dark red. After stirring for
2 h, the mixture was transferred to a large Schlenk filter containing
1 cm Celite via cannula. The red filtrate was concentrated in vacuo
to about 15 mL. Dry degassed acetonitrile (40 mL) was slowly
layered onto the top of the toluene solution via cannula to induce
crystallization of the product. After standing overnight, the red
crystals thus obtained were isolated by filtration, washed with 3 ¥
10 mL dry acetonitrile and dried under vacuum to give 2.1 g (64%)
Conclusions
In conclusion we can say that, considering the complexity of
these substrates, the reduction of furanoheliangolides (having
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+
of bright to dark red crystals. 1H NMR (500 MHz, C6D6) d (ppm):
7.65 (36H, t, J = 8.1 Hz), 6.93 (18H, t, J = 7.3 Hz), 6.72 (36H, t, J
= 7.5 Hz), 3.49 (6H, br s).
1665; 1576 cm-1. HRMS (ESI-TOF): calcd for C19H23O6 (MH+)
347.1495, found 347.1501.
(2aS,3R,4aS,6R,11aR,11bR)-3-Hydroxy-2a,6,10-trimethyl-3-
[(1Z)-1-methylprop-1-en-1-yl]-2a,3,5,6,11a,11b-hexahydro-2H-
6,9-epoxy-1,4-dioxacyclodeca[cd]pentalene-2,7(4aH)-dione (3)
General procedure for reduction of sesquiterpene lactones with
Stryker’s reagent
A 9.5 ¥ 10-3 M solution of the sesquiterpene lactone (n mmol) in
toluene and recently prepared Stryker’s reagent (n/2 mmol), were
mixed together and stirred at room temperature or 0 C for 2 h.
Obtained from reduction of 6. Purified by column chromatography
in silica gel using a 9 : 1 mixture of toluene/ethyl acetate as eluent.
Colourless oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.17 (3H,
s); 1.42 (3H, s); 1.70–1.71 (3H, m); 1.76 (3H, br.s); 1.97–2.02 (4H,
m); 2.39 (1H, dd, J = 13.6, 2.4 Hz); 2.75 (1H, dd, J = 7.2, 4.4 Hz);
2.88 (1H, br.s); 4.07–4.09 (1H, m); 4.90–4.91 (1H, m); 5.25–5.55
(2H, m); 5,96 (1H, br.s). 13C NMR (CDCl3, 125 MHz), d (ppm):
15.3 (CH3); 20.3 (CH3); 20.5 (CH3); 21.4 (CH3); 21.9 (CH3); 43.7
(CH2); 61.2 (C); 62.0 (CH); 78.9 (CH), 81.4 (CH); 90.0 (C); 104.5
(CH); 127.9 (CH); 130.1 (C); 131.7 (C); 134.8 (CH); 175.6 (C O);
187.0 (C); 205.4 (C O). IR nmax (liquid film): 3402; 2960; 2926;
2855; 1773; 1733; 1699; 1585 cm-1. HRMS (ESI-TOF): calcd for
C20H24O6Na+ (MNa+) 383.1460, found 383.1476.
◦
The reaction was quenched with saturated ammonium chloride
solution. The mixture was stirred for 1 h. During this period a
white precipitate was formed. The reaction mixture was filtered
and the residue was washed with ethyl acetate. The organic phase
was separated and the aqueous phase was extracted with ethyl
acetate. The combined organic phases were dried with MgSO4 and
the solvent was removed under vacuum. The residue was purified
by column chromatography on silica gel. The yields are shown in
Tables 1 and 2.
(2aS,3R,4aS,6R,11aR,11bR)-3-Hydroxy-3-isopropenyl-2a,6,10-
trimethyl-2a,3,5,6,11a,11b-hexahydro-2H-6,9-epoxy-1,4-
dioxacyclodeca[cd]pentalene-2,7(4aH)-dione (eremantholide C) (1)
(3R,3aR,4S,6R,11aR)-3,6,10-Trimethyl-2,7-dioxo-
2,3,3a,4,5,6,7,11a-octahydro-6,9-epoxycyclodeca[b]furan-4-yl
(2Z)-2-methylbut-2-enoate (10)
Obtained from reduction of 4. Purified by column chromatography
in silica gel using a 9 :◦1 mixture of toluene/ethyl acetate as eluent.
White solid, mp (229 C - 230 ◦C). 1H NMR (CDCl3, 500 MHz), d
(ppm): 1.19 (3H, s); 1.49 (3H, s); 1.90 (3H, dd, J = 1.5, 0.9 Hz); 2.06
(1H, dd, J = 13.6, 11.9 Hz); 2.06 (3H, dd, J = 2.4, 1.6 Hz); 2.41 (1H,
dd, J = 13.6, 2.6 Hz); 2.57 (1H, br.s); 2.85 (1H, dd, J = 7.0, 4.2 Hz);
4.14 (1H, dddd, J = 11.9, 4.2, 2.6, 0.6 Hz); 4.98 (1H, dddq, J = 7.0,
2.7, 2.4, 0.6 Hz); 5.08 (1H, dd, J = 2.0, 1.5 Hz); 5.33 (1H, dd, J =
2.0, 0.9 Hz); 5.62 (1H, s); 6.03 (1H, dq, J = 2.7, 1.6 Hz). 13C NMR
(CDCl3, 125 MHz), d (ppm): 18.9 (CH3); 20.3 (CH3); 20.6 (CH3);
21.9 (CH3); 43.7 (CH2); 59.8 (C); 62.5 (CH); 78.5 (CH), 81.5 (CH);
89.9 (C); 104.5 (CH); 106.2 (C); 116.1 (CH2); 130.2 (C); 134.6
(CH); 142.0 (C); 175.4 (C O); 186.8 (C); 205.2 (C O). IR nmax
(liquid film): 3395; 2973; 2923; 1775; 1699; 1659; 1585 cm-1. HRMS
(ESI-TOF): calcd for C19H22O6Na+ (MNa+) 369.1308, found
369.1304.
Obtained from reduction of 6. Purified by column chromatography
in silica gel using a 9 : 1 mixture of toluene/ethyl acetate as eluent.
Yellow oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.26 (3H, d, J =
7.0 Hz); 1.44 (3H, s); 1.78 (3H, s); 1.91 (3H, d, J = 7.0 Hz); 2.05
(3H, s); 2.10–2.13 (1H, m); 2.26–2.33 (2H, m); 2.89–2.94 (1H, m);
4.85–4.87 (1H, m); 5.02–5.04 (1H, m); 5.71 (1H, s); 5.93 (1H, br.s);
6.10–6.15 (1H, m). 13C NMR (CDCl3, 125 MHz), d (ppm): 15.4
(CH3); 15.9 (CH3); 20.3 (CH3); 20.5 (CH3); 21.6 (CH3); 38.4 (CH);
44.9 (CH2); 55.1 (CH); 67.1 (CH); 80.4 (CH), 89.0 (C); 105.1 (CH);
133.2 (CH); 141.6 (CH); 166.6 (C O); 176.8 (C O); 187.0 (C);
204.2 (C O). IR nmax (liquid film): 2983; 2934; 1770; 1732; 1682;
1574 cm-1. HRMS (ESI-TOF): calcd for C20H24O6Na+ (MNa+)
383.1460, found 383.1469.
(2aS,3R,4aS,6R,11aR,11bR)-3-Hydroxy-10-(hydroxymethyl)-3-
isopropenyl-2a,6-dimethyl-2a,3,5,6,11a,11b-hexahydro-2H-6,9-
epoxy-1,4-dioxacyclodeca[cd]pentalene-2,7(4aH)-dione
(15-hydroxy-eremantholide C) (2)
(3R,3aR,4S,6R,11aR)-3,6,10-Trimethyl-2,7-dioxo-
2,3,3a,4,5,6,7,11a-octahydro-6,9-epoxycyclodeca[b]furan-4-yl
2-methylacrylate (7)
Obtained from reduction of 4. Purified by column chromatography
in silica gel using a 9 : 1 mixture of toluene/ethyl acetate as eluent.
Colourless oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.34 (3H, d,
J = 6.7 Hz); 1.50 (3H, s); 1.91 (3H, dd, J = 1.45, 0.8 Hz); 2.12 (3H,
dd, J = 2.4, 1.7 Hz); 2.19 (1H, dd, J = 13.4, 1.4 Hz); 2.35 (1H, dd,
J = 13.4, 11.6 Hz); 2.40 (1H, dq, J = 11.6, 6.7 Hz); 3.00 (1H, ddd,
J = 11.6, 9.2, 2.2 Hz); 4.92 (1H, dddd, J = 11.6, 2.2, 1.4, 0.6 Hz);
5.05 (1H, dddq, J = 9.2, 2.9, 2.4, 0.6 Hz); 5.63 (1H, q, J = 1.4 Hz);
5.78 (1H, s); 5.99 (1H, dq, J = 2.9, 1.7 Hz); 6.09 (1H, dq, J = 1.4,
0.8 Hz). 13C NMR (CDCl3, 125 MHz), d (ppm): 15.4 (CH3); 18.1
(CH3); 20.5 (CH3); 21.6 (CH3); 38.4 (CH); 44.8 (CH2); 55.2 (CH);
67.9 (CH); 80.3 (CH), 88.9 (C); 105.1 (CH); 126.9 (CH2); 128.6
(C); 133.2 (CH); 135.3 (C); 166.3 (C O); 176.6 (C O); 186.8
(C); 203.9 (C O). IR nmax (liquid film): 2979; 2941; 1779; 1716;
Obtained from reduction of 5. Purified by column chromatography
in silica gel using a 1 : 1 mixture of hexane/ethyl acetate as eluent.
Colourless oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.20 (3H,
s); 1.50 (3H, s); 1.90 (3H, br.s); 2.05–2.10 (1H, m); 2.42 (1H, dd,
J = 13.7, 2.3 Hz); 2.68 (1H, br.s); 2.91 (1H, dd, J = 7.3, 4.1 Hz);
4.17–4.19 (1H, m); 4.36–4.42 (2H, m); 5.05–5.06 (1H, m); 5.08
(1H, br.s); 5.33 (1H, br.s); 5.72 (1H, s); 6.31 (1H, br.s). 13C NMR*
(CDCl3, 125 MHz), d (ppm): 19.1 (CH3); 20.7 (CH3); 21.8 (CH3);
43.8 (CH2); 62.1 (CH); 63.3 (CH2); 78.3 (CH), 81.3 (CH); 90.1
(C); 106.4 (CH); 106.8 (C); 116.1 (CH); 116.2 (CH2); 134.5 (C);
135.3 (CH); 141.7 (C); 175.3 (C O); 184.0 (C); 205.0 (C O).
IR nmax (liquid film): 3422; 2979; 2930; 1778; 1713; 1659; 1584;
1451; 1377; 918 cm-1. HRMS (ESI-TOF): calcd for C19H22O7Na+
(MNa+) 385.1258, found 385.1269.
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(2aS,3R,4aS,6R,10S,11aR,11bR)-3-Hydroxy-10-
(hydroxymethyl)-3-isopropenyl-2a,6-dimethyl-
2a,3,5,6,10,11,11a,11b-octahydro-2H-6,9-epoxy-1,4-
dioxacyclodeca[cd]pentalene-2,7(4aH)-dione (11)
(3aS,4S,6R,10R,11aR)-6,10-Dimethyl-3-methylene-2,7-dioxo-
2,3,3a,4,5,6,7,10,11,11a-decahydro-6,9-epoxycyclodeca[b]furan-4-
yl 2-methylacrylate (14)
Obtained from reduction of 8. Purified by column chromatography
in silica gel using a 8 : 2 mixture of toluene/ethyl acetate as eluent.
Yellow oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.36 (3H, d, J =
7.0 Hz); 1.42 (3H, s); 1.75 (3H, br.s); 2.05–2.07 (1H, m); 2.27–2.30
(1H, m); 2.38–2.43 (2H, m); 2.95–3.01 (1H, m); 3.28–3.30 (1H,
m); 4.26–4.29 (1H, m); 4.42–4.45 (1H, m); 5.37–5.38 (1H, m); 5.46
(1H, br.s); 5.62 (1H, br.s); 5.93 (1H, br.s); 6.12 (1H, d, J = 3.1 Hz).
13C NMR (CDCl3, 125 MHz), d (ppm): 16.5 (CH3); 17.9 (CH3);
21.2 (CH3); 31.2 (CH); 41.4 (CH2); 45.4 (CH2); 54.7 (CH); 72.0
(CH), 80.2 (CH); 89.7 (C); 104.7 (CH); 124.3 (CH2); 126.4 (CH2);
133.9 (C); 135.6 (C); 166.8 (C O); 168.9 (C O); 193.8 (C); 205.1
(C O). IR nmax (liquid film): 2959; 2931; 2854; 1774; 1709; 1588;
1455; 1377; 1242; 1141; 1041; 944; 817 cm-1. HRMS (ESI-TOF):
calcd for C19H22O6Na+ (MNa+) 369.1309, found 369.1308.
Obtained from reduction of 5. Purified by column chromatography
in silica gel using a 1 : 1 mixture of hexane/ethyl acetate as eluent.
1
Yellow oil. H NMR (CDCl3 + 10% DMSO-d6, 500 MHz), d
(ppm): 1.16 (3H, s); 1.44 (3H, s); 1.87 (3H, br.s); 2.04 (1H, dd,
J = 14.0, 11.7 Hz); 2.24–2.31 (1H, m); 2.35 (1H, dd, J = 14.0,
2.3 Hz); 2.41–2.44 (1H, m); 2.54 (1H, dd, J = 6.7, 4.3 Hz); 2.99–
3.04 (1H, m); 3.80 (1H, dd, J = 10.5, 6.4 Hz); 3.92 (1H, dd, J =
10.5, 6.7 Hz); 3.98–4.01 (1H, m); 4.32–4.36 (1H, m); 5.01 (1H,
br.s); 5.26 (1H, br.s); 5.67 (1H, br.s); 5.71 (1H, br.s). 13C NMR
(CDCl3 + 10% DMSO-d6, 125 MHz), d (ppm): 18.6 (CH3); 20.7
(CH3); 22.0 (CH3); 36.0 (CH2); 38.5 (CH); 43.7 (CH2); 59.9 (C);
60.8 (CH2); 66.2 (CH), 75.9 (CH); 80.1 (CH); 88.5 (C); 104.1 (CH);
105.8 (C); 114.3 (CH2); 142.2 (C); 175.9 (C O); 190.4 (C); 205.5
(C O). IR nmax (liquid film): 3445; 1762; 1681; 1583; 1049; 1025;
997; 827; 765 cm-1. HRMS (ESI-TOF): calcd for C19H24O7Na+
(MNa+) 387.1414, found 387.1412.
(2aS,3R,4aS,6R,11aR,11bR)-3-Hydroxy-3-isopropenyl-2a,6-
dimethyl-10-{[(triisopropylsilyl)oxy]methyl}-2a,3,5,6,11a,11b-
hexahydro-2H-6,9-epoxy-1,4-dioxacyclodeca[cd]pentalene-
2,7(4aH)-dione (15)
(3R,3aS,4S,6R,10R,11aR)-3,6,10-Trimethyl-2,7-dioxo-
2,3,3a,4,5,6,7,10,11,11a-decahydro-6,9-epoxycyclodeca[b]furan-4-
yl 2-methylacrylate (12)
Obtained from reduction of 9. Purified by column chromatog-
raphy in silica gel using a 5 : 1 : 4 mixture of chloroform/ethyl
1
acetate/hexane as eluent. Colourless oil. H NMR (CDCl3, 500
Obtained from reduction of 5. Purified by column chromatography
in silica gel using a 1 : 1 mixture of hexane/ethyl acetate as eluent.
Colourless oil. 1H NMR (CDCl3, 500 MHz), d (ppm): 1.33 (3H,
d, J = 6.7 Hz); 1.42 (3H, d, J = 7.3 Hz); 1.45 (3H, s); 1.91 (3H,
br.s); 2.16–2.40 (5H, m); 2.50–2.55 (1H, m); 3.06–3.08 (1H, m);
4.37–4.40 (1H, m); 4.77–4.80 (1H, m); 5.62 (1H, br.s); 5.73 (1H,
br.s); 6.07 (1H, br.s). 13C NMR (CDCl3, 125 MHz), d (ppm): 16.0
(CH3); 16.1 (CH3); 18.1 (CH3); 20.7 (CH3); 31.3 (CH); 38.5 (CH);
41.5 (CH2); 46.5 (CH2); 59.4 (CH); 68.2 (CH), 79.2 (CH); 88.4 (C);
104.8 (CH); 126.9 (CH2); 135.4 (C); 166.3 (C O); 177.1 (C O);
194.1 (C); 204.9 (C O). IR nmax (liquid film): 2961; 2926; 2853;
1773; 1718; 1707; 1591; 1261; 1191; 805 cm-1. HRMS (ESI-TOF):
calcd for C19H24O6Na+ (MNa+) 371.1465, found 371.1483.
MHz), d (ppm): 1.00 (18H, d, J = 6.7 Hz); 1.04–1.09 (3H, m); 1.13
(3H, s); 1.40 (3H, s); 1.83 (3H, br.s); 1.97–2.02 (1H, m); 2.35 (1H,
dd, J = 13.5, 2.3 Hz); 2.65 (1H, br.s); 2.84 (1H, dd, J = 7.3, 4.2 Hz);
4.07–4.11 (1H, m); 4.34–4.41 (2H, m); 4.98–5.01 (2H, m); 5.26 (1H,
br.s); 5.61 (1H, s); 6.20 (1H, br.s). 13C NMR (CDCl3, 125 MHz),
d (ppm): 11.9 (CH–Si); 17.9 (CH3); 18.9 (CH3); 20.5 (CH3); 21.8
(CH3); 43.7 (CH2); 59.8 (C); 62.3 (CH); 63.7 (CH2); 78.4 (CH), 81.6
(CH); 90.1 (C); 106.2 (C); 106.4 (CH); 116.0 (CH2); 133.4 (CH);
134.4 (C); 142.1 (C); 175.5 (C O); 184.8 (C); 205.3 (C O). IR
nmax (liquid film): 3376; 2960; 2926; 2866; 1779; 1699; 1576; 1457;
1378; 1260; 1099; 1024; 919; 798 cm-1. HRMS (ESI-TOF): calcd
for C28H42O7SiNa+ (MNa+) 541.2592, found 541.2597.
(2aS,3R,4aS,6R,10S,11aR,11bR)-3-Hydroxy-3-isopropenyl-2a,6-
dimethyl-10-{[(triisopropylsilyl)oxy]methyl}-
[(2aS,3R,4aS,6R,11aR,11bR)-3-Hydroxy-3-isopropenyl-2a,6-
dimethyl-2,7-dioxo-2a,3,4a,5,6,7,11a,11b-octahydro-2H-6,9-
epoxy-1,4-dioxacyclodeca[cd]pentalen-10-yl]methyl acetate (13)
2a,3,5,6,10,11,11a,11b-octahydro-2H-6,9-epoxy-1,4-
dioxacyclodeca[cd]pentalene-2,7(4aH)-dione (16)
Obtained from reduction of 9. Purified by column chromatog-
raphy in silica gel using a 5 : 1 : 4 mixture of chloroform/ethyl
acetate/hexane as eluent. Yellow oil. 1H NMR (CDCl3, 500 MHz),
d (ppm): 1.00 (18H, d, J = 6.2 Hz); 1.04–1.10 (3H, m); 1.14 (3H,
s); 1.39 (3H, s); 1.82 (3H, br.s); 1.94–1.99 (1H, m); 2.21–2.27 (2H,
m); 2.33–2.36 (1H, m); 2.39–2.41 (1H, m); 2.50 (1H, dd, J = 6.5,
4.7 Hz); 3.90–3.99 (3H, m); 4.33–4.37 (1H, m); 4.99 (1H, br.s);
5.25 (1H, br.s); 5.64 (1H, br.s). 13C NMR (CDCl3, 125 MHz), d
(ppm): 11.8 (CH–Si); 18.0 (CH3); 18.9 (CH3); 21.2 (CH3); 22.6
(CH3); 36.8 (CH2); 39.2 (CH); 44.0 (CH2); 60.2 (C); 63.1 (CH2);
66.4 (CH); 77.0 (CH), 80.7 (CH); 89.1 (C); 104.8 (CH); 106.4 (C);
115.9 (CH2); 142.2 (C); 175.8 (C O); 190.4 (C); 205.9 (C O). IR
nmax (liquid film): 3396; 2926; 2866; 1771; 1740; 1695; 1586; 1456;
1373; 1242; 1107; 917; 882; 804; 683 cm-1. HRMS (ESI-TOF):
calcd for C28H44O7SiNa+ (MNa+) 543.2748, found 543.2748.
Obtained from reduction of 8. Purified by column chromatography
in silica gel using a 8 : 2 mixture of toluene/ethyl acetate as eluent.
1
Yellow oil. H NMR (CDCl3, 500 MHz), d (ppm): 1.19 (3H, s);
1.48 (3H, s); 1.88 (3H, br.s); 1.99–2.06 (1H, m); 2.10 (3H, s); 2.41
(1H, dd, J = 13.5, 2.5 Hz); 2.78 (1H, br.s); 2.89 (1H, dd, J = 7.1, 4.1
Hz); 4.10–4.17 (1H, m); 4.76 (2H, br.s); 5.02–5.07 (2H, m); 5.31
(1H, br.s); 5.70 (1H, s); 6.32–6.33 (1H, m). 13C NMR (CDCl3, 125
MHz), d (ppm): 18.9 (CH3); 20.5 (CH3); 21.7 (CH3); 22.7 (CH3);
43.7 (CH2); 59.7 (C); 62.0 (CH); 63.5 (CH2); 78.3 (CH), 81.2 (CH);
90.2 (C); 106.2 (C); 106.5 (CH); 116.2 (CH2); 129.6 (C); 138.0
(CH); 141.8 (C); 170.2 (C O); 175.2 (C O); 183.1 (C); 205.0
(C O). IR nmax (liquid film): 3412; 2961; 2925; 2855; 1767; 1746;
1712; 1589; 1449; 1373; 1259; 1097; 1046; 812 cm-1. HRMS (ESI-
TOF): calcd for C21H24O8Na+ (MNa+) 427.1363, found 427.1368.
6152 | Org. Biomol. Chem., 2011, 9, 6148–6153
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Acknowledgements
The authors thank FAPESP, CNPq and CAPES for financial
support of this research.
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