Total synthesis of (+)-seco-C-oleanane via stepwise controlled radical cascade cyclization

Article abstract of DOI:10.1021/jo201968t

An asymmetric concise total synthesis of the (+)-seco-C-oleanane 1 was accomplished. The successful route to this natural product involves as the key step a stepwise regio- and stereocontrolled catalytic radical polyene cascade cyclization from preoleanatetraene oxide (16), a process mediated by Cp ₂TiCl. The use of this single-electron-transfer complex permits mild cyclization conditions without using unnecessary prefunctionalizations and stops the process at the bicyclic level. Theoretical data revealed high activation energy for the third ring closure, which would account for the control of the cyclization. This process also led to natural (-)-achilleol B, camelliol A, and (+)-seco-β-amyrin as minor compounds.

Full text of DOI:10.1021/jo201968t

Article
pubs.acs.org/joc
Total Synthesis of (+)-seco-C-Oleanane via Stepwise Controlled
Radical Cascade Cyclization
Victoriano Domingo,† Jesus F. Arteaga,‡ Jose Luis Lopez Perez,§ Rafael Pelaez,§
́
́
́
́
́
,†
,†
́
Jose F. Quılez del Moral,* and Alejandro F. Barrero*
́
†Department of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain
‡Department of Chemical Engineering, Physical Chemistry and Organic Chemistry, University of Huelva, Campus el Carmen,
21071 Huelva, Spain
§Department of Pharmaceutical Chemistry, University of Salamanca, Campus M. Unamuno, 37007 Salamanca, Spain
S
* Supporting Information
ABSTRACT: An asymmetric concise total synthesis of the
(+)-seco-C-oleanane 1 was accomplished. The successful route
to this natural product involves as the key step a stepwise regio-
and stereocontrolled catalytic radical polyene cascade cycliza-
tion from preoleanatetraene oxide (16), a process mediated by
Cp2TiCl. The use of this single-electron-transfer complex per-
mits mild cyclization conditions without using unnecessary pre-
functionalizations and stops the process at the bicyclic level.
Theoretical data revealed high activation energy for the third
ring closure, which would account for the control of the cyclization. This process also led to natural (−)-achilleol B, camelliol A, and
(+)-seco-β-amyrin as minor compounds.
Scheme 1. Natural Triterpenes 1−4 and Their Proposed
INTRODUCTION
■
Biosynthetic Origin
The biosynthesis of β-amyrin, in which 2,3-oxidosqualene (OS)
possessing one stereogenic center is transformed into a
pentacyclic triterpene containing eight stereogenic centers,
constitutes one of the most impressive examples of efficiency in
biosynthesis. Over the last 20 years, remarkable progress has
been achieved in the understanding of the fascinating mecha-
nism of triterpene formation, although the degree of enzymatic
assistance still remains difficult to determine.1 The potential of
metabolic engineering to produce alternative natural products
or to increase the yields of those of “commercial value” has
renewed interest in these kinds of compounds.2 In this sense,
the recent report by Ebizuka et al. describing an OS cyclase
homologue that is capable of cleaving preformed ring systems,
in addition to produce polycyclic systems, further increases
the diversity of structures produced by OS cyclases.3 In
this context, some triterpenes from higher plants or muta-
genesis studies such as the seco-C-oleananes 14 and 2,3
achilleol B (3),5 and camelliol A (4)6 are proposed to derive
from the oleanyl cation which suffers retrocyclization
processes (Scheme 1).7
chemists' efforts to mimic the enzymatic cyclization of 2,3-(R)-OS
in tetra- and pentacyclic triterpenes in a single step have
culminated in a number of impressive syntheses of triterpenes,
most of them sharing a cation−olefin polyannulation strategy.11
Nevertheless, this synthetic strategy involves certain drawbacks,
such as the need to attach extra groups to the polyene substrate
During the writing of this paper, Hoshino et al. reported the
existence of achilleol B synthase, an enzyme encoded by
AK070534 gene from Oryza sativa.8 This seco-type triterpene
cyclase produces achilleol B (3) as the main product (ca. 90%).
RESULTS AND DISCUSSION
■
From the work of pioneers, including those of van Tamelen
Received: September 23, 2011
Published: December 5, 2011
and Johnson,9 to the recent progresses reported by Corey,10
© 2011 American Chemical Society
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to stabilize carbocationic intermediates and the control of
the termination steps.12 In contrast to these acid-catalyzed
cyclizations, other approaches using radical transformations
exploited successfully in several polycarbocyclizations have
received less attention.13 In this sense, the work reported by
Breslow some 40 years ago showing that terpene skeletons are
accessible by radical cyclizations deserved to be underlined.13j
More recently, it has been established that the Ti(III)-mediated
opening of epoxypolyprenesa strategy reported by our
group14amay well be efficiently used for the preparation of
polycyclic structures.14j−o Interested in the so-called “unusually
cyclized triterpenes”,7 we report herein the enantioselective
synthesis of the seco-C-oleanane 1, a metabolite isolated from
Stevia viscida and S. eupatoria,4 and collaterally those of seco-
triterpenes 2−4.
enamine 9. Finally, compound 8 was envisaged as being acces-
sible by C5 homologation of the C15 bicyclic compound result-
ing from the Ti(III)-mediated cyclization of the chiral mono-
epoxy derivative of farnesol 10, a transformation previously
reported by some of us.14o
In this regard, we obtained adequately the advanced tetra-
cyclic intermediate 7, but we failed in achieving the stereo-
selective conjugate reduction of the tetrasubstituted conjugated
enone to produce the desired cis-decalin (Scheme 3). This
substrate remained unaltered by a variety of reducing reagents
and conditions, including copper hydrides generated in situ,15
commercial Stryker's reagent,16 Raney nickel,17a Crabtree's
catalyst,17b and dozens of hydrogenations with varying loads of
catalyst (Pd or Pt), solvent, pH, or pressure.17c
Finally, after getting enough topological information from
our unsuccessful routes, we anticipated that target 1 could be
produced via cyclization of epoxypreoleanatetraene 16, assum-
ing that the process would stop after the second cyclization
(Scheme 4). Two reasons led us to envision this truncated
cyclization: on the one hand, the recently reported theoretical
calculations supporting the nonconcerted nature of the radical
cyclization of a C15-epoxypolyprene,18 and on the other, the
existence of different examples where the Ti(III)-promoted
cyclization failed when the acceptor double bond possessed a Z
geometry.14a In contrast to what we expected using radical
chemistry, at this point, it should be noted that Van Tamelen
et al. described the racemic epoxide 16, which was trans-
formed into dl-δ-amyrin by treatment with stannic chloride−
CH3NO2 at 0 °C.19 In the same sense, the transformation of 16
by a cyclase from Pysum sativum led directly to β-amyrin20
(Scheme 4). These results coincided with recent experi-
mental10a,b and theoretical21 data in that the carbocationic cycliza-
tion of polyprenes led to tricyclic structures without the
intermediacy of mono- or bicyclic carbocations. With all these
data in mind, the crux of our strategy was to know whether
the radical cyclization of key intermediate 16 would lead to the
desired bicyclization process or the cyclization would progress
to produce the pentacyclic oleanane skeleton (Scheme 4).
In order to gain more data to evaluate the feasibility of our
radical approach, theoretical studies were undertaken to pro-
vide reaction and activation energies of the radicals which are
intermediates along the pathway connecting the starting
bicyclic radical I, resulting from the Ti(III)-mediated homolytic
opening of the oxirane ring in 16, to the potential pentacyclic
radical IV.
In our efforts to synthesize 1, two “dead-end” routes were
tried prior to the successful approach (Scheme 2).
Scheme 2. Unsuccessful Approaches to (+)-seco-C-Oleanane (1)
Focusing on the third key radical cyclization, the computa-
tional studies showed not only that this process is thermo-
dynamically unfavorable by 6.7 kcal/mol but also that the
activation energy for cyclization is higher than 29 kcal/mol,
which is a considerable energetic barrier, not easily reachable at
room temperature. This high barrier is most likely due to an
important increase of the steric hindrance and steric congestion
when evolving from the most stable conformer of radical III to
pentacyclic radical IV. In this sense, it should be noted that
the approach of carbons 8 and 14 in the transition state
leading from III to IV forced a rotation of the C11−C12 bond
(Figure 1). Furthermore, the theoretical calculations also
showed a slight D-ring rotation in the transition state confor-
mation in comparison to that of IV, which results in a
destabilizing decrease in the Me-26−Me-28 distance (Figure 2).
At this point, we also examined the conformational strain in
the cations corresponding to III (IIIc), IV (IVc), and the
transition state (Figure 3). The data shown in Figure 3 indicate
The first route was based on the convergent coupling of two
C15 synthons, 5 and 6, which we previously prepared in an
enantiopure form.14o,n This strategy failed most likely due to
the large steric repulsions originating in the C11−C12
approach.
In order to overcome this steric hindrance posed by C11 and
C12 in the carbon−carbon coupling, we planned a second
route where the target seco-C-oleanane could be obtained from
ketone A, after incorporation of a methyl group from the
corresponding enol triflate. Ketone A would be produced after
stereoselective cis hydrogenation of enone 7. The construction
of the tetracyclic backbone in 7 would be the result of an
enantioselective variation of the Robinson annulation, employ-
ing bicyclic compound 8 as the chiral Michael acceptor and
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Scheme 3. Second Approach to (+)-seco-C-Oleanane
of the asymmetric intermediate 616 with acyclic moiety 19
afforded, gratifyingly, a diasteromeric mixture of sulfones which
after reductive desulphonation furnished 20 in 58% overall
yield. Deprotection of acetonide 20 under acidic conditions,
treatment of the corresponding diol with mesyl chloride, and
subsequent oxirane closure with base gave rise to enantiopure
preoleanatetraene oxide (16) in 60% global yield (Scheme 5).
With this polyprene precursor in our hands without the use
of further functionalizations to promote the radical cascade, we
proceeded to carry out the key Ti(III)-mediated cyclization.
Gratifyingly, exposure of 16 to 2 equiv of Cp2TiCl led to seco-
C-oleanane 1 as the major product (39%), along with the
minor tricyclic triterpenes achilleol B (3) and camelliol A (4) in
7 and 3% yields,23 respectively. The physical and spectral
properties of synthetic 1 turned out to be identical with those
of an authentic sample. The signs of the optical rotation [α]D of
both synthetic (+23°, c 1.0, CHCl3) and natural seco-C-
oleanane (+30°, c 1.0, CHCl3) matched, thus confirming the
absolute configuration of the natural compound. Achilleol B
(3) was first isolated by our group from Achillea odorata,5
whereas camelliol A (4) was identified from Camellia sasanqua.6
Both achilleol B (3) and camelliol A (4) were formed as a
consequence of a premature trapping of the achilleyl radical II
(Figure 1) by a second molecule of Cp2TiCl, followed by a
β-elimination process. Whereas previous to this work one
enantioselective synthesis of achilleol B (3) was reported,14n
the minor camelliol A (4) has not been prepared before.
At this point, the feasibility of overcoming the energy barrier
leading to the pentacyclic skeleton was tested by conducting
the cyclization reaction in refluxing THF−toluene. In this reac-
tion, no pentacyclic compound was detected, with the results
obtained being comparable to those obtained at room
temperature.
Scheme 4. Carbocationic versus Radical Cyclizations
Starting from 16
that the formation of the C ring is thermodynamically
unfavorable by about 2 kcal/mol, although in this case, this
cyclization was calculated to proceed with activation energies of
about 10 kcal/mol, thus suggesting that the cationic approach
may well lead to pentacyclic structures, as proven exper-
imentally by Van Tamelen.
Encouraged by the computational results, we went on to
address the experimental studies that should corroborate the
applicability of our synthetic proposal. In designing a synthetic
route toward key intermediate 16, we envisioned a convergent
approach based on the coupling of two chiral synthons, namely
bicyclic allyl bromide 6 and polyprenated (E)-allyl sulfone 19
(Scheme 5). The route to 19 commenced from commercially
available farnesol, which was protected as its acetate form and
exposed to asymmetric dihydroxylation conditions to afford the
corresponding chiral diol in a 43% yield, based on recovered
starting material (96% ee).14o After acetonide protection with
2,2-dimethoxypropene, exposure of 18 to palladium-catalyzed
allylic sulfonation conditions22 led to the formation of 19 as a
single isomer in 98% yield on a gram scale. Anionic alkylation
Bearing in mind that it has been reported that in some cases
the use of catalytic Ti(III) improved to some degree the results
obtained with the stochiometric protocol,14j−p,18 we decided to
treat epoxide 16 with 0.2 equiv of Cp2TiCl2 and Mn in excess
(8 equiv) in the presence of 7 equiv of the Ti(III) regenerator
TMSCl−collidine.14i Under these conditions, the efficiency of
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Figure 1. Energy profile of the radical cyclization reaction from bicyclic radical I to the oleanyl radical IV. Geometries were optimized by UB3LYP/
6-31+G(d) basis set. Energies relative to that of I (kcal/mol) including zero-point energy corrections are shown. Distances are given in Å.
acceptable considering the number of bonds and stereocenters
created. Together with 1, a minor isomer (8%), C-ring seco-β-
amyrin 2, was also obtained in the cyclization. Compound 2
was recently reported to be produced by a triterpene synthase
encoded by Atlg78500, one of the OSC homologous genes of
Arabidopsis thaliana.3 As was the case for compound 1, the sign
of the optical rotation [α]D of both synthetic (+10.1°, c 0.1,
CHCl3) and natural 2 (+12°, c 1.0, CHCl3) coincided. Thus,
the formation of 2 in the cyclization of epoxypolyprene 16 also
permitted us to confirm the structure and stereochemistry of
this seco-triterpene.
Figure 2. Superposition of radical IV (green) and the III to IV
transition state (pink) structures.
Finally, with the ultimate goal of confirming the differences
between the radical and cationic outcomes of the cyclization of
preoleanatetraene 16, we performed a preliminary test repeat-
ing the Van Tamelen experiment. In this reaction, treatment of
epoxide 16 with SnCl4 led to a complex mixture of compounds,
where no seco-C-oleananes were detected, which confirms the
different behavior of the corresponding cations and radicals.
CONCLUSION
■
We have achieved the first enantioselective synthesis of seco-C-
oleanane 1 and the related seco-triterpenes 2−4. The use of a
Ti(III)-mediated radical polyannulation reaction as the key step
to produce these molecules demonstrated the synthetic
efficiency of this strategy, whereas the cationic version of
these cyclizations or other approaches failed. In addition to a
minimal use of protecting group chemistry and high stereo-
control over the six stereocenters created, we supported these
results with radical computational calculations, which also
confirmed the nonconcerted nature of these radical cyclizations.
Figure 3. Energy profile of the cyclization reaction from cation IIIc to
EXPERIMENTAL SECTION
((2S,4aS,5S)-Decahydro-1,1,4a-trimethyl-6-methylene-5-
the oleanyl cation IVc. Geometries were optimized by the UB3LYP/6-
31+G(d) basis set. Energies relative to that of IIIc (kcal/mol)
including zero-point energy corrections are shown. Distances are given
in Å.
■
((phenylsulfonyl)methyl)naphthalen-2-yloxy)(tert-butyl)-
dimethylsilane (5). A mixture of alcohol 11 (529 mg, 1.5 mmmol)
and diphenyl disulfide (981 mg, 4.5 mmol) in pyridine (1.5 mL) was
stirred at room temperature for 1 h before tributylphosphine
(1.11 mL, 4.5 mmol) was added. After the mixture was stirred for
an additional 4 h, EtOAc (100 mL) and water (50 mL) were added
and the resulting layers separated. The organic layer was washed with
the cyclization increased and the targeted seco-C-oleanane 1
was obtained in 44% yield after TBAF-mediated desilylation
(Scheme 6), a yield that could be considered more than
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Scheme 5. Synthesis of (+)-seco-C-Oleanane and Related Triterpenes
Scheme 6. Synthesis of (+)-seco-C-Oleanane using Catalytic Ti(III)
10% HCl(aq) (25 mL), 10% NaOH(aq) (25 mL), and brine (25 mL),
dried (Na2SO4), and evaporated under vacuum. The resulting crude
product was purified by column chromatography on silica gel (5/1
hexane/t-BuOMe) to afford the corresponding sulfide (521 mg, 78%).
To a solution of this sulfide (215 mg, 0.484 mmol) in DCM (12 mL)
at −78 °C was added dropwise a 0.1 M solution of MCPBA (0.5 mL,
1.21 mmol). The resulting mixture was stirred for 45 min until starting
material consumption (TLC analysis). Then, the reaction mixture was
diluted with DCM and the organic layer was washed with NaHCO3
(3 × 80 mL) and brine (100 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The resulting crude product was
purified by column chromatography on silica gel (5/1 hexanes/t-
BuOMe) to afford the corresponding sulfone 5 (166 mg, 72%): white
foam, TLC (hexanes/t-BuOMe, 2/1 v/v) Rf = 0.62; [α]D = +15.2°
(c 1, CH2Cl2); IR (film) νmax 2948, 2855, 1737, 1648, 1472, 1446,
1
1307, 1252, 1144, 1100, 885, 774, 731, 688 cm−1; H NMR (CDCl3,
500 MHz) δ 7.87 (d, J = 8 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.48 (t,
J = 7.6 Hz, 2H), 4.73 (brs, 1H), 4.42 (br s, lH), 3.35 (dd, J = 14.6, 8.8
Hz, 1H), 3.23−3.16 (m, 2H), 2.37 (bt, J = 9.8 Hz, 1H), 1.97 (bt, J =
13.2, 4.6 Hz, 1H), 1.73 (dt, J = 13.2, 2.8 Hz, 1H), 1.59−1.52 (m, 4H),
1.38−1.21 (m, 2H), 1.15 (dd, J = 13.2, 2.8 Hz, 1H), 0.91 (s, 3H), 0.88
(s, 9H), 0.70 (s, 3H), 0.61 (s, 3H), −0.04 (s, 6H); 13C NMR (CDCl3,
125 MHz) δ 145.5, 140.3, 133.6, 129.2 (2C), 128.3 (2C), 108.0, 79.0,
54.4, 52.5, 50.6, 39.9, 39.6, 37.6, 36.7, 28.7, 28.1, 26.0 (3C), 23.8, 18.2,
345
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15.9, 15.2, −3.6, −4.8; HRFABMS calcd for C28H46NaO3SSi
[M + Na]+ 513.2835, found 513.2841.
(1.3 mL, 3.9 mmol) and 30% aqueous H2O2 (1.3 mL, 3.9 mmol). After
1 h at 0 °C, the reaction mixture was stirred for 3 h at room temper-
ature and quenched with saturated NH4Cl solution (25 mL). The
mixture was extracted with ethyl acetate (3 × 25 mL), and the
combined organic extracts were washed with brine (15 mL) and dried.
The solvent was evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel with t-BuOMe to
afford the corresponding hydroxy sulfone 14 (675 mg, 83%) as a white
foam: TLC (EtOAc/t-BuOMe, 1/1 v/v) Rf = 0.75; [α]D = +12.6° (c 1,
CH2Cl2); IR (film) 3453, 2931, 2854, 1642, 1469, 1447, 1304, 1145,
1085, 835, 772 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.90 (d, J = 7.3
Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.9 Hz, 2H), 3.54−3.48
(m, 2H), 3.22 (ddd, J = 13.7, 11.4, 5 Hz, 1H), 3.12 (dd, J = 10.8, 5.2,
1H), 2.96 (ddd, J = 13.7, 11.0, 4.9 Hz, 1H), 1.99−1.92 (m, 2H), 1.71−
1.45 (m, 7H), 1.36−1.27 (m, 2H), 1.23 (dt, J = 11.3, 4 Hz, 1H), 0.93
(dt, J = 12.8, 4.5 Hz, 1H), 0.76 (brd, J = 9.7 Hz, 1H), 0.87 (s, 12H),
0.70 (s, 3H), 0.67 (s, 3H), 0.01 (s, 6H); 13C NMR (CDCl3, 125 MHz)
δ 139.5, 133.7, 129.3 (2C), 128.0 (2C), 79.1, 61.3, 55.5, 55.3, 52.01,
39.6, 39.2, 37.8, 37.4, 29.5, 28.5, 27.7, 25.9 (3C), 18.7, 18.1, 17.6, 15.9,
15.7, −3.7, −4.9; HRFABMS calcd for C28H48NaO4SSi [M + Na]+
531.2940, found 531.2945.
Compound 15. Hydroxysulfone 14 (383 mg, 0.76 mmol) was
dissolved in 15.8 mL of CH2Cl2, and N,N-diisopropylethylamine (0.40
mL, 2.28 mmol) and MEMCl (0.23 mL, 1.98 mmol) were added at
0 °C. The mixture was stirred for 3 h at room temperature and then
partitioned between H2O (50 mL) and DCM (50 mL). The aqueous
layer was extracted with DCM (3 × 25 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2SO4), and
concentrated under reduced pressure. To a solution of the crude
residue obtained above in THF (6.7 mL) at −78 °C was added a
2.5 M solution of n-BuLi (0.5 mL, 0.84 mmol). The resulting yellow
mixture was stirred for 30 min, and then oxirane (30 equiv) was added.
The reaction mixture was stirred for 10 min and then quenched by the
dropwise addition of a saturated aqueous solution of NH4Cl (3 mL).
The reaction mixture was partitioned between EtOAc (50 mL) and
H2O (50 mL), and the aqueous layer was extracted with EtOAc (2 ×
50 mL). The combined organic layers were washed with brine
(20 mL) and dried (Na2SO4). Evaporation of the organic solvent gave
a mixture of diastereomers which was used directly without further
purification. A solution of lithium (9 mg, 1.2 mmol) in ethylamine
(10 mL) at −78 °C under argon was stirred for 30 min until the
solution turned dark blue. Then, the crude bis-homologated
compound obtained above in THF (6 mL) at −78 °C was added.
The mixture was stirred for 10 min (TLC monitoring), and then the
reaction was quenched by dropwise addition of a saturated aqueous
solution of NH4Cl (3 mL). The resulting mixture was extracted with
EtOAc (3 × 25 mL), and the combined organic layers were washed
with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (1/1 hexanes/t-BuOMe) to afford
the primary alcohol 15 (236 mg, 62%) as a colorless oil: TLC
(t-BuOMe) Rf = 0.50; [α]D = +14.3° (c 1, CH2Cl2); IR (film) 3422,
2933, 2856, 1461, 1253, 1095, 1053, 835, 772 cm−1; 1H NMR (CDCl3,
500 MHz) δ 4.71 (d, J = 6.8, 1H), 4.69 (d, J = 6.8, 1H), 3.73−3.55 (m,
7H), 3.44 (t, J = 9.7 Hz, 1H), 3.39 (s, 3H), 3.15 (dd, J = 11.1, 4.7 Hz,
1H), 1.96 (m, 2H), 1.64 (dt, J = 13.0, 3.3 Hz, 1H), 1.60−1.15 (m,
12H), 0.94 (dt, J = 13.1, 3.8 Hz, 1H), 0.88 (s, 3H), 0.87(s, 9H), 0.79
(brd, J = 9.2 Hz, 1H), 0.73 (s, 3H), 0.71 (s, 3H), 0.02 (s, 6H); 13C
NMR (CDCl3, 125 MHz) δ 95.6, 79.4, 71.9, 67.0, 66.7, 62.8, 59.1,
55.7, 52.9, 39.6, 37.6, 37.5, 36.1, 33.1, 30.1, 28.6, 27.9, 25.9 (3C), 25.2,
24.1, 18.2, 17.8, 15.9 (2C), −3.7, −4.8; HRFABMS calcd for
C28H56NaO5Si [M + Na]+ 523,3795, found 523.3799.
((2S,4aS,5S)-Decahydro-1,1,4a-trimethyl-6-methylene-5-((E)-
2-(phenylsulfonyl)vinyl)naphthalene-2-yloxy)(tert-butyl)-
dimethylsilane (12). Oxalyl chloride (3.8 mL, 2.0 M in CH2Cl2,
7.5 mmol) was added to a solution of dry DMSO (1.2 mL, 15 mmol)
in dry CH2Cl2 (27 mL) at −60 °C, under argon. The mixture was
stirred for 30 min, and a solution of alcohol 11 (880 mg, 2.5 mmol) in
CH2Cl2 (9 mL) was added. After additional stirring for 30 min at
−60 °C, Et3N (3.5 mL, 25 mmol) was added, and the mixture was
warmed to 0 °C. The reaction mixture was then poured into ice-cold
water, diluted with CH2Cl2 (150 mL), washed with brine (150 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give the corresponding crude product, which was directly
used in the next step. To a solution of diethyl (phenylsulfonylmethyl)-
phosphonate (870 mg, 3.0 mmol) in THF (7 mL) was added
n-butyllithium (2 M solution in hexanes, 1.5 mL, 3.0 mmol) at −78 °C.
The resulting yellow mixture was stirred for 10 min, and then a solu-
tion of the aldehyde in THF (7 mL) was added dropwise. The mixture
was stirred for 12 h until starting material consumption (TLC analysis)
and then diluted with t-BuOMe and quenched with NH4Cl (10 mL).
The layers were separated, and the aqueous layer was extracted with
t-BuOMe (3 × 80 mL). The combined organic layers were washed
with brine (100 mL), dried over Na2SO4, and concentrated under reduced
pressure. The resulting crude product was purified by column chro-
matography on silica gel (3/1 hexanes/t-BuOMe) to afford the
corresponding vinyl sulfone 12 (813 mg, 67%): white solid, TLC
(hexanes/t-BuOMe, 3/1 v/v) Rf = 0.50; [α]D = +31.5° (c 1, CH2Cl2);
1
IR (film) 2934, 2854, 1639, 1319, 1146, 1088, 835, 750 cm−1; H
NMR (CDCl3, 500 MHz) δ 7.87 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2
Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.04 (dd, J = 15.0, 10.6 Hz, 1H), 6.3
(d, J = 15.0 Hz, 1H), 4.78 (brs, 1H), 4.36 (brs, 1H), 3.17 (dd, J = 11.2,
4.4 Hz, 1H), 2.41 (bd, J = 11.2 Hz, 1H), 1.99 (dt, J = 13.8, 5.5 Hz,
1H), 1.70 (dt, J = 13.1, 2.6 Hz, 1H), 1.61−1.39 (m, 4H), 1.33 (dt, J =
13.3, 3.3 Hz, 1H), 1.08−0.98 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87
(s, 9H), 0.76 (s, 3H), 0.01 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ
147.2, 145.5, 140.8, 133.3, 132.7, 129.4 (2C), 127.6 (2C), 109.3, 79.2,
59.6, 53.7, 39.9, 39.2, 38.4, 28.7, 27.9, 25.9 (3C), 22.9, 18.1, 17.1, 16.1,
15.0, −3.7, −4.9.
((2S,4aR,5S)-Decahydro-1,1,4a-trimethyl-6-methylene-5-(2-
(phenylsulfonyl)ethyl)naphthalen-2-yloxy)(tert-butyl)-
dimethylsilane (13). A 1 M solution of LiBH(Et)3 in THF
(1.77 mL, 1.7 mmol) was added to a solution of vinyl sulfone 12
(702 mg, 1.4 mmol) in THF (40 mL) at 0 °C under argon, and then
the resulting yellow mixture was stirred for 3 h at room temperature
before quenching with water (50 mL). The resulting mixture was
extracted with CH2Cl2 (3 × 50 mL), and the combined organic layers
were washed with brine (100 mL), dried over Na2SO4, and con-
centrated under vacuum. The resulting crude was purified by flash
column chromatography on silica gel (3/1 hexanes/t-BuOMe) to
afford the corresponding sulfone 13 (634 mg, 96%) as a white foam:
TLC (hexanes/t-BuOMe, 3/1 v/v) Rf = 0.55; [α]D = +14.6° (c 1,
CH2Cl2); IR (film) 2952, 2934, 2854, 1641, 1461, 1307, 1150, 1088,
1
835, 773 cm−1; H NMR (CDCl3, 500 MHz) δ 7.82 (d, J = 7.4 Hz,
2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 4.70 (brs, 1H),
4.19 (brs, 1H), 3.18 (ddd, J = 14.4, 10.4, 4.4 Hz, 1H), 3.11 (dd, J = 9.6,
5.7, 1H), 2.81 (ddd, J = 14.1, 9.9, 6.0 Hz, 1H), 2.26 (ddd, J = 12.9, 4.0,
2.3 Hz, 1H), 1.89 (m, 1H), 1.80 (dt, J = 13.0, 5.0 Hz, 1H), 1.67−1.46
(m, 6H), 1.27 (dt, J = 12.7, 4.1 Hz, 1H), 1.09−1.03 (m, 1H), 0.94 (dd,
J = 12.5, 2.6 Hz, 1H), 0.80 (s, 9H), 0.81 (s, 3H), 0.64 (s, 3H), 0.57(s,
3H), −0.03(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 147.1, 139.9,
133.6, 129.3 (2C), 127.9 (2C), 107.0, 79.1, 55.3, 54.6, 39.7, 39.4, 37.9,
36.9, 28.7, 28.2, 27.0, 25.9 (3C), 24.1, 18.1, 17.1, 15.9, 14.3, −3.7,
−4.9; HRFABMS calcd for C28H46NaO3SSi [M + Na]+ 513.2835,
found 513.2841.
Compound 14. A solution of 13 (789 mg, 1.6 mmol) in
anhydrous THF (69 mL) was cooled to 0 °C under argon and treated
with BH3·THF (3.2 mL, 1 M in THF, 3.2 mmol). The reaction
mixture was warmed slowly to room temperature over 4 h. It was then
cooled to 0 °C and treated with a premixed solution of 3 M NaOH
Compound 8. Oxalyl chloride (0.76 mL, 2.0 M in CH2Cl2, 1.52
mmol) was added to a solution of dry DMSO (0.23 mL, 3.04 mmol)
in dry CH2Cl2 (5.4 mL) at −60 °C, under argon. The mixture was
stirred for 30 min, and a solution of alcohol 15 (254 mg, 0.50 mmol)
in CH2Cl2 (1.8 mL) was added. After additional stirring for 30 min at
−60 °C, Et3N (0.7 mL, 5 mmol) was added. The mixture was warmed
to 0 °C, poured into ice-cold water, diluted with CH2Cl2, and worked
up in the usual way to give the corresponding crude aldehyde, directly
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used in the next step. To a solution of the aforementioned aldehyde
dissolved in THF (4.4 mL) at 0 °C was added vinylmagnesium
bromide (0.557 mL) dropwise. The reaction mixture was stirred for
10 min at 0 °C and then quenched by dropwise addition of a saturated
aqueous solution of NH4Cl (2 mL). The aqueous layer was separated
and extracted with t-BuOMe (2 × 20 mL). The combined organic
layer was washed with brine (25 mL) and dried over Na2SO4 to give a
mixture of epimers, which were used in the next step without
purification. To a solution of the allylic alcohols in CH2Cl2 (16 mL)
was added Dess−Martin periodinane (299 mg, 0.70 mmol) at 0 °C.
The ice bath was removed and the solution was stirred at room
temperature while the reaction progress was monitored by TLC. After
TLC analysis indicated consumption of the starting alcohol (30 min),
the reaction mixture was quenched with a saturated solution of
Na2S2O3·NaHCO3 (5 mL) diluted in CH2Cl2 (20 mL) and the organic
layer was washed with a saturated solution of NaHCO3 (20 mL) and
brine (25 mL) and dried over Na2SO4. Volatiles were removed in
vacuo, and the crude material was purified by silica gel flash
chromatography (1/1 hexanes/t-BuOMe) to afford enone 8 (224
mg, 84%) as a yellowish oil: TLC (hexanes/t-BuOMe, 1/1 v/v) Rf =
0.55; [α]D = +10.9° (c 1, CH2Cl2); IR (film) 2932, 2853, 1640, 1461,
1252, 1111, 1087, 1052, 835, 773 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 6.33 (dd, J = 17.6, 10.5 Hz, 1H), 6.19 (dd, J = 17.6, 1.1 Hz, 1H), 5.79
(dd, J = 10.5, 1.1 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.8
Hz, 1H), 3.69−3.53 (m, 5H), 3.46 (t, J = 9.6 Hz, 1H), 3.38 (s, 3H),
3.14 (dd, J = 11.1, 4.9 Hz, 1H), 2.56 (dt, J = 7.5, 3.1 Hz, 2H), 1.96
(brt, J = 7.4 Hz, 2H), 1.75−1.68 (m, 1H), 1.60 (dt, J = 9.4, 3.5 Hz,
1H), 1.54−1.15 (m, 10 H) 0.94 (dt, J = 13.1, 3.9 Hz, 1H), 0.87
(s, 12H), 0.78 (brt, J = 5.8 Hz, 1H), 0.71 (s, 3H), 0.68 (s, 3H), 0.01
(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 201.5, 136.6, 127.9, 95.6,
79.3, 71.9, 66.9, 66.7, 59.1, 55.6, 52.9, 39.9, 39.6, 37.6, 37.5, 36.3, 31.5,
30.0, 28.6, 27.8, 25.9 (3C), 25.2, 22.6, 18.2, 17.7, 15.9, −3.7, −4.8.
Compound 7. To a solution of compound 8 (224 mg,
0.43 mmol) in THF (1.5 mL) was added imine 915 (207 mg, 0.85
mmol) at 0 °C. The resulting mixture was stirred for 17 h at the same
temperature and concentrated under reduced pressure. H2O (6.0 mL)
and AcOH (1.0 mL) were added to the residue at room temperature.
The mixture was then stirred for 4 h, poured into brine (25 mL), and
extracted with EtOAc (2 × 50 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was treated with a 30% w/w solution of NaOMe
(0.17 mL, 0.94 mmol) in MeOH (1 mL) at reflux for 5 h, while the
reaction progress was monitored by TLC. After TLC analysis indicated
consumption of the starting diketone, the solvent was removed in
vacuo and partitioned between saturated aqueous 2 N HCl (50 mL)
and t-BuOMe (50 mL) and the aqueous layer extracted with t-BuOMe
(2 × 25 mL). The combined organic layers were washed with a
saturated solution of NaHCO3 (50 mL) and brine (50 mL) and dried
over Na2SO4. Volatiles were removed under reduced pressure, and the
crude material was purified by silica gel flash chromatography (1/1
hexanes/t-BuOMe) to afford enone 7 (183 mg, 66% overall yield).
TLC (hexanes/t-BuOMe, 1/1 v/v): Rf = 0.45; [α]D = +0.3° (c 1,
CH2Cl2); IR (film) 2930, 2855, 1665, 1459, 1252, 1112, 1086, 1051,
(500 mg, 1.6 mmol) and catalytic p-TsOH in acetone (30 mL). The
reaction mixture was removed from the ice bath and stirred at room
temperature for 30 min. It was then quenched with saturated aqueous
NaHCO3. The resulting solution was poured into t-BuOMe (150 mL),
and the aqueous layer was extracted with t-BuOMe (2 × 50 mL). The
combined organic extract was washed with water (150 mL) and brine
(150 mL) and dried over Na2SO4. Volatiles were removed under
vacuum, and the crude material was purified by silica gel flash
chromatography (hexanes/t-BuOMe 1/2) to afford acetonide 17 (535
mg, 87%): TLC (hexanes/t-BuOMe, 1/1 v/v) Rf = 0.75; [α]D = +3.3°
(c 1, MeOH); IR (film) 2982, 1742, 1377, 1369, 1232, 1114, 1023,
1
1003 cm−1; H NMR (CDCl3, 500 MHz) δ 5.33 (dt, J = 7.1, 1.2 Hz,
1H); 5.14 (dt, J = 6.9, 1.1 Hz, 1H), 4.6 (d, J = 7.1 Hz, 2H), 3.65 (dd,
J = 9.2, 3.6 Hz, 1H), 2.22−1.98 (m, 6H), 2.05 (s, 3H), 1.70 (s, 3H),
1.64−1.57 (m, 1H), 1.61 (s, 3H), 1.49−1.43 (m, 1H), 1.41 (s, 3H),
1.32 (s, 3H), 1.24 (s, 3H), 1.09 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 171.2, 142.2, 134.9, 124.2, 118.4, 106.5, 82.9, 80.2, 61.5, 39.6, 36.7,
28.6, 27.8, 26.9, 26.3, 26.2, 23.0, 21.1, 16.6, 16.1.
(R)-2,2,4,4-Tetramethyl-5-((3E,7E)-3,7-dimethyl-9-
(phenylsulfonyl)nona-3,7-dienyl)-1,3-dioxolane (19). A solu-
tion of (Pd(π-allyl)Cl)2 (23 mg, 0.06 mmol) and dppf (102 mg,
0.18 mmol) in 3.5 mL of CH2Cl2 was added to a flask containing
NaSO2Ph (854 mg, 5.2 mmol), tetramethylammonium bromide
(42 mg, 0.27 mmol), and 17 (1.19 g, 3.06 mmol), in a mixture of
degassed water (10 mL) and CH2Cl2 (7 mL). The reaction was stirred
at room temperature for 2.5 h, at which time the layers were separated.
The aqueous layer was extracted three times with CH2Cl2. The
combined organic extract was dried over Na2SO4, concentrated under
reduced pressure, and purified via silica gel flash chromatography (2/1
hexanes/t-BuOMe) to afford the corresponding sulfone 18 (1.26 g,
98%): TLC (hexanes/t-BuOMe, 1/1 v/v) Rf = 0.62; [α]D = +0.63°
(c 1, CH2Cl2); IR (film) 2979, 2932, 2855, 1.447, 1371, 1234, 1150,
1128, 100, 740 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.84 (d, J = 7.4
Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 5.17 (t, J =
7.9 Hz, 1H), 5.07 (bt, J = 6.3 Hz, 1H), 3.77 (d, J = 7.9 Hz, 2H), 3.61
(dd, J = 9.3, 3.3 Hz, 1H), 2.20−2.15 (m, 1H), 2.03−1.96 (m, 5H),
1.61−1.53 (m, 1H), 1.58 (s, 3H), 1.47−1.41 (m, 1H), 1.39 (s, 3H),
1.29 (s, 6H), 1.21 (s, 3H), 1.07 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 146.3, 138.7, 135.1, 133.5, 129.0 (2C), 128.546 (2C), 123.7, 110.3,
106.4, 82.9, 80.1, 56.1, 39.6, 36.7, 28.6, 27.7, 26.9, 26.1, 26.0, 22.9,
16.2, 16.0; HRFABMS calcd for C24H36NaO4S [M + Na]+ 443.2232,
found 443.2235.
(R)-5-((3E,7E)-10-((4aS,8aR)-1,2,3,4,4a,5,6,8a-Octahydro-
2,2,4a,7-tetramethylnaphthalen-8-yl)-3,7-dimethyldeca-3,7-di-
enyl)-2,2,4,4-tetramethyl-1,3-dioxolane (20). To a solution of
sulfone 18 (850 mg, 2.02 mmol) in THF (9.6 mL) was added
n-butyllithium (2 M solution in hexane, 1.01 mL, 2.02 mmol) at −78
°C. The resulting yellow mixture was stirred for 10 min, and a solution
of bromide 6 (192 mg, 0.67 mmol) in THF (20 mL) was added
dropwise. The mixture was warmed for 4 h and then diluted with
t-BuOMe (100 mL) and quenched with water. The organic layer
was washed with brine (100 mL), dried over Na2SO4, and concen-
trated under reduced pressure. Purification by silica chromato-
graphy (hexane/t-BuOMe, gradient from 3/1 to 1/1) afforded the
corresponding epimeric mixture of sulfones (326 mg, 78%). To a
solution of Li (10 mg) in EtNH2 (15 mL) was added at −78 °C a
solution of the sulfones (326 mg, 0.522 mmol) in THF (8 mL). The
mixture was stirred for 20 min. Saturated NH4Cl was then added
slowly, and the mixture was further stirred for 10 min. The aqueous
layer was extracted with t-BuOMe (2 × 100 mL), and the combined
organic extract was washed with brine (100 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The crude material was purified by
silica gel flash chromatography (5/1 hexanes/t-BuOMe) to afford
acetonide 19 (187 mg, 74%): TLC (hexanes/t-BuOMe, 4/1 v/v) Rf =
0.85; [α]D = +5.3° (c 1, CH2Cl2); IR (film) 2969, 2914, 2857, 1458,
1
835, 773 cm−1; H NMR (CDCl3, 500 MHz) δ 4.79 (d, J = 6.7 Hz,
1H), 4.74 (d, J = 6.7 Hz, 1H), 3.77−3.54 (m, 6H), 3.4 (s, 3H), 3.15
(dd, J = 10.9, 5.2 Hz, 1H), 2.48 (dd, J = 14.5, 5.4 Hz, 1H), 2.45 (dd,
J = 14.5, 5.4 Hz, 1H), 2.40−2.31 (m, 2H), 2.03−1.96 (m, 4H), 1.79
(dt, J = 13.5, 4.2 Hz, 1H), 1.73 (ddd, J = 8.4, 5.3, 3.1 Hz, 1H), 1.66−
1.20 (m, 11 H), 1.19 (s, 3H), 1.05 (s, 3H), 1.01−0.94 (m, 1H) 0.89
(s, 3H), 0.88 (s, 3H), 0.87 (s, 9H), 0.82 (s, 3H), 0.72 (s, 3H), 0.67
(s, 3H), 0.02 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 198.5, 161.6,
135.3, 95.8, 79.4, 71.9, 67.3, 66.7, 59.1, 55.7, 53.7, 40.9, 39.6, 38.4,
37.8, 37.6, 37.5, 36.5, 35.6, 34.8, 34.2, 33.8, 32.5, 30.1, 28.6, 27.8, 26.0
(3C), 25.7, 25.1, 24.2, 22.7, 18.2, 17.8, 16.0, 15.9, −3.7, −4.8;
HREIMS (m/z) calcd for C39H70O5Si [M − H]+ 645.4993, found
645.4994.
1
1369, 1215, 1113, 1002 cm−1; H NMR (CDCl3, 500 MHz) δ 5.09
(t, J = 8.1 Hz, 1H), 5.08 (t, J = 7.3 Hz, 1H), 3.59 (dd, J = 9.2, 3.5 Hz,
1H), 2.17−2.10 (m, 2H), 2.04−1.77 (m, 10H), 1.66−1.56 (m, 2H),
1.55 (s, 3H), 1.54 (s, 3H), 1.50 (s, 3H), 1.45−1.36 (m, 3H), 1.35 (s,
3H), 1.32 (d, J = 2.5 Hz, 1H), 1.31 (d, J = 2.7 Hz, 1H), 1.30 (m, 1H),
(2E,6E)-3,7-Dimethyl-9-((R)-2,2,5,5-tetramethyl-1,3-dioxo-
lan-4-yl)nona-2,6-dienyl Acetate (18). 2,2-Dimethoxypropane
(2.9 mL, 24 mmol) was added to a cooled (0 °C) solution of 1614
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1.25 (s, 3H), 1.17 (s, 3H), 1.13 (t, J = 3.2 Hz, 1H), 1.03 (s, 3H), 0.89
(t, J = 13 Hz, 1H), 0.88 (d, J = 9.2 Hz, 1H), 0.82 (s, 3H), 0.80 (s, 3H),
0.75 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 134.8, 134.4, 133.8,
125.0, 124.9, 124.1, 106.6, 83.1, 80.2, 43.2, 42.6, 39.9, 36.8 (2C), 34.8,
32.3, 31.9, 31.6, 31.1, 29.7, 28.7, 28.0, 27.3, 27.1, 27.0, 26.8 (2C), 26.3,
24.4, 23.1, 18.7, 16.1 (2C); HREIMS (m/z) [M]+ calcd for C33H56O2
484.4280, found 484.4277.
seco-C-oleanane (1; 7 mg) and achilleol B (3; 2 mg) (tr = 25.3 and
26.2 min, respectively). seco-C-oleanane (1): colorless oil; [α]D = +23°
1
(c 1.0, CHCl3); IR (CHCl3) 3610, 3450, 1644, 1384, 892 cm−1; H
NMR (CDCl3, 500 MHz) δ 4.86 (1H, d, J = 1.5 Hz, H-26), 4.63 (1H, d,
J = 1.0 Hz, H-26′), 3.25 (1H, dd, J = 11.7, 4.4 Hz, H-3), 2.41 (1H, dq, J =
12.7, 2.4 Hz, H-7), 2.32 (1H, m, H-12), 1.99 (1H, m, H-7′), 1.99 (1H, m,
H-15), 1.88 (1H, m, H-15′), 1.89 (1H, m, H-16), 1.79 (1H, m, H-1),
1.75 (1H, m, H-6), 1.69 (1H, m, H-2), 1.60 (1H, m, H-9), 1.59 (1H,
m, H-2′), 1.55 (1H, m, H-18), 1.56 (3H, s, Me-27), 1.49 (1H, m,
H-11), 1.48 (1H, m, H-22), 1.47 (1H, m, H-12′), 1.38 (1H, m, H-6′),
1.33 (1H, m, H-11′), 1.33 (1H, m, H-21), 1.33 (1H, m, H-19), 1.21
(1H, m, H-22′), 1.17 (1H, m, H-1′), 1.12 (1H, m, H-21′),1.10 (1H, m,
H-5), 0.93 (1H, m, H-19′), 0.99 (3H, s, Me-23), 0.88 (3H, s, Me-30),
0.87 (3H, s, Me-29), 0.85 (3H, s, Me-28), 0.81 (1H, m, H-16′), 0.77
(3H, s, Me- 24), 0.67 (3H, s, Me-25); 13C NMR (CDCl3, 125 MHz) δ
148.3, 134.2, 123.5, 106.5, 78.9, 56.9, 54.6, 42.9, 42.9, 39.5, 39.1, 38.2,
36.8, 36.5, 34.5, 33.1, 31.5, 30.9, 30.8, 29.4, 28.3 27.9, 27.2, 26.4, 24.0,
24.0, 22.8, 18.7, 15.3, 14.4; HREIMS m/z 426.3868 (calcd for
C30H50O 426.3865). Achilleol B (3): [α]D = −10.9° (c 0.9, CHCl3);
IR (CHCl3) 3394, 3080, 1662, 1644, 1385, 1365, 1195, 1085, 892; 1H
NMR (500 MHz, CDCl3) δ 5.12 (1H, t, J = 7.0 Hz), 4.88 (1H, bs),
4.62 (1H, bs), 3.40 (1H, dd, J = 10.0, 4.5 Hz), 2.32 (1H, dt, J = 13.2,
4.5 Hz), 2.21 (1H, ddd, J = 13.1, 10.0, 6.6 Hz), 2.08 (1H, ddd, J =
13.2, 10.3, 3.8 Hz), 2.02−1.82 (7H, m), 1.80−1.44 (8H, m), 1.61 (3H,
s), 1.58 (3H, s), 1.39 (1H, ddd, J = 13.0, 3.7, 2.6 Hz), 1.35 (1H, dd, J =
13.8, 3.9 Hz), 1.23 (1H, dt, J = 13.3, 3.5 Hz), 1.12 (1H, m), 1.04 (3H,
s), 0.97 (1H, t, J = 13.0 Hz), 0.90 (3H, s), 0.88 (3H, s), 0.82 (3H, s),
0.82 (1H, m), 0.72 (3H, s); 13C NMR (125 MHz, CDCl3) δ 147.5,
135.2, 133.8, 124.8, 124.1, 108.6, 77.5, 51.3, 43.2, 42.5, 40.8, 38.9, 36.8,
34.8, 33.4, 33.3, 32.4, 31.9, 31.6, 31.2, 29.7, 27.4, 27.2, 26.7, 26.1, 24.4,
24.0, 18.9, 16.2, 15.7.
Preoleanatetraene Oxide (16). To a solution of 20 (127 mg,
0.26 mmol) and 80% aqueous AcOH (2.5 mL) in THF (4 mL) was
gradually added 2 M HCl (2 mL) at room temperature for 30 min, and
the whole mixture was stirred for 12 h at the same temperature. The
reaction mixture was diluted with brine and extracted with t-BuOMe
(100 mL). The combined organic extract was washed with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL) and dried over
Na2SO4. Evaporation of the organic solvent gave a residue, which was
chromatographed on silica gel (hexane/t-BuOMe, 2/1) to give the
corresponding diol (92 mg, 80%). To a solution of the aforementioned
diol (142 mg, 0.32 mmol) and catalytic DMAP in anhydrous pyridine
(5 mL), cooled to −12 °C under an argon atmosphere, was added
dropwise MsCl (0.15 mL, 1.92 mmol). After 40 min (TLC
monitoring), the mixture was diluted with t-BuOMe and treated
with saturated NaHCO3 solution. After an additional 15 min of stirring
at room temperature, the mixture was extracted with Et2O (3 ×
50 mL) and the organic layer was washed with 1 N HCl (1 × 50 mL)
and brine (1 × 50 mL), dried over anhydrous Na2SO4, and finally
concentrated under reduced pressure. The mesylated crude product
was dissolved in 5 mL of MeOH, and K2CO3 (176 mg, 1.25 mmol)
was added. After the mixture was stirred for 20 min, the formation of
epoxide was complete (TLC monitoring). Then, the reaction was
quenched by diluting with H2O and t-BuOMe. The organic layer wa
washed with 1 N HCl (2 × 50 mL), saturated NaHCO3 (2 × 50 mL),
and brine (50 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The resulting crude product was purified by
column chromatography on silica gel (hexane/t-BuOMe, 1/2) to
afford 101 mg of the corresponding epoxide 16 (74% yield over two
steps): colorless oil, TLC (hexanes/t-BuOMe, 1/2 v/v) Rf = 0.50;
[α]D = +2.9° (c 1, CH2Cl2); IR (film) 2944, 2917, 2858, 1451, 1377,
1121, 1033, 967, 749 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.16 (t, J =
6.6 Hz, 1H), 5.15 (t, J = 6.6 Hz, 1H), 2.69 (t, J = 6.3 Hz, 1H), 2.22−
1.83 (m, 14H), 1.73−1.64 (m, 3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.57 (s,
3H), 1.48 (dt, J = 13.7, 4.3 Hz, 1H), 1.41−1.33 (m, 2H), 1.29 (s, 3H),
1.25 (s, 3H), 1.23−1.09 (m, 1H), 0.95 (t, J = 13 Hz, 1H), 0.94 (d, J =
9.2 Hz, 1H), 0.89 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 134.6, 133.9, 133.5, 124.9, 124.7, 123.8, 64.1,
58.2, 42.9, 42.2, 39.6, 36.5, 36.3, 34.6, 33.1, 31.6, 31.4, 30.9, 29.5, 27.5,
27.1, 26.9, 26.6, 26.5, 24.9, 24.2, 18.7, 18.6, 16.0, 15.9; HREIMS (m/z)
[M + H]+ calcd for C30H50O 427.3861, found 427.3867.
seco-C-Oleanane (1), Achilleol B (3), and Camelliol A (4). A
mixture of Cp2TiCl2 (138 mg, 0.557 mmol) and Mn dust (61 mg, 1.11
mmol) in strictly deoxygenated THF (6 mL) under an Ar atmosphere
was stirred at room temperature until the red solution turned green.
Then, a solution of 119 mg (0.278 mmol) of preoleanatetraene oxide
in THF (6 mL) was added. The reaction mixture was stirred for
20 min (TLC monitoring), quenched with 1 N HCl, extracted with
t-BuOMe (50 mL), washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting
crude product was purified by column chromatography on silica gel
using mixtures of hexanes and t-BuOMe as eluent (gradient from
10/1 to 4/1 v/v hexanes/t-BuOMe) to afford 51 mg (49%) of an
inseparable mixture of triterpenes by classic chromatography, namely,
seco-C-oleanane (1), achilleol B (3), and camelliol A (4), in a 81/13/6
ratio, respectively, calculated by GC-MS analyses: TLC (hexanes/
t-BuOMe, 4/1 v/v) Rf = 0.30. This mixture was subjected to column
chromatography on AgNO3 (20%)−silica gel using mixtures of
hexanes and t-BuOMe as eluent (gradient from 5/1 to 2/1 hexanes/
t-BuOMe v/v) to afford two main fractions, the first (35 mg)
constituted by a mixture of the three triterpenes (hexanes/t-BuOMe,
3/1 v/v), and the second (15 mg) enriched in seco-C-oleanane (1)
and achilleol B (3) (hexanes/t-BuOMe, 2/1 v/v). The latter frac-
tion was subjected to HPLC (6/1 hexanes/t-BuOMe) to obtain pure
seco-C-oleanane (1) and C-Ring seco-β-Amyrin (2). A mixture
of Cp2TiCl2 (18 mg, 0.071 mmol) and Mn dust (104 mg, 1.896
mmol) in strictly deoxygenated THF (4 mL) under an argon atmo-
sphere was stirred at room temperature until the red solution
turned green. Then, a solution of 101 mg (0.237 mmol) of pre-
oleanatetraene oxide 16 and 2,4,6-collidine (0.220 mL, 1.659 mmol)
and Me3SiCl (0.12 mL, 0.946 mmol) were added. The reaction mixture
was stirred for 3.30 h (TLC monitoring), quenched with 1 N HCl,
extracted with t-BuOMe (50 mL), washed with brine (50 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was dissolved in THF (3 mL) and stirred with Bu4NF
(0.704 mL, 0.704 mmol) for 30 min. Then, THF was removed,
and the mixture was diluted with t-BuOMe (50 mL), washed with
brine (50 mL), and dried over anhydrous Na2SO4 and the solvent
was removed. The resulting crude product was purified by column
chromatography on silica gel using hexanes/t-BuOMe mixtures of
increasing polarity as eluents to afford 59 mg (51%) of the exo and
endo isomers seco-C-oleanane (1) and seco-β-amyrin (2) in a 7/1 ratio,
respectively (NMR integration): TLC (hexanes/t-BuOMe, 4/1 v/v)
Rf = 0.30. This mixture was subjected to column chromatography on
AgNO3 (20%)−silica gel using mixtures of hexanes and t-BuOMe as
eluent (gradient from 5/1 to 2/1 hexanes/t-BuOMe v/v) to obtain a
fraction enriched in seco-β-amyrin (2; 30 mg) (hexanes/t-BuOMe, 2/1
v/v) and 19 mg of 1 (hexanes/t-BuOMe, 2/1 v/v). A 15 mg amount
of the fraction enriched in seco-β-amyrin (2) was subjected to HPLC
(4/1 hexanes/t-BuOMe) to obtain 3 mg of pure seco-β-amyrin (2)
(tr = 17.3 min): [α]D = +10.1° (c 0.1, CHCl3); IR (CHCl3) 3610,
1
3450, 1644, 1384, 892 cm−1; H NMR (CDCl3, 500 MHz) δ 5.40
(1H, brs, H-7), 3.25 (1H, dd, J = 10.9, 4.9 Hz, H-3), 2.41 (1H, dt, J =
13.0, 5.8 Hz, H-12), 1.98 (1H, m, H-15), 1.97 (1H, m, H-6, H-6′), 1.92
(1H, m, H-1), 1.87 (1H, m, H-15′), 1.75 (3H, brs, Me-26), 1.70−1.55
(2H, m, H-2, H-2′), 1.63 (1H, m, H-18), 1.58 (1H, m, H-9), 1.58 (1H,
m, H-12′), 1.57 (3H, s, Me-27), 1.51 (1H, m, H-22), 1.42 (1H, m, H-
11), 1.38 (1H, m, H-19), 1.35 (1H, m, H-21), 1.23 (1H, m, H-
22′),1.20 (1H, m, H-5), 1.19 (1H, m, H-1′), 1.14 (1H, m, H-11′), 1.13
(1H, m, H-21′), 0.98 (1H, m, H-19′), 0.98 (3H, s, Me-23), 0.88 (3H, s,
Me-29), 0.88 (3H, s, Me-30), 0.86 (3H, s, Me-24), 0.84 (3H, s,
Me-28), 0.76 (3H, s, Me-25); 13C NMR (125 MHz, CDCl3) δ 135.40,
134.3, 123.6, 121.8, 79.2, 55.7, 49.7, 43.0, 42.8, 38.7, 37.2, 37.0, 36.5,
348
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Article
34.9, 34.6, 33.2, 31.5, 31.0, 29.4, 27.9, 27.5, 27.1, 26.5, 26.0, 24.0, 23.5,
22.1, 18.8, 15.1, 13.7. HREIMS m/z 426.3855 (calcd for C30H50O,
426.3862).
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Text, figures, and tables giving computational methods and H
and 13C NMR spectra of 1−5, 8, 9, 12−16, and 18−20. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: afbarre@ugr.es (A.F.B.); jfquilez@ugr.es (J.F.Q.d.M.).
■
ACKNOWLEDGMENTS
■
This research was supported by the Spanish Ministry of Science
and Technology, Project No. CTQ2010-16818 (BQU). V.D.
thanks the Spanish Ministry of Science and Technology for a
predoctoral grant enabling him to pursue these studies. We
thank Prof. P. Joseph-Nathan (Centro de Investigacion y de
Estudios Avanzados del IPN, Mexico) for providing NMR
spectra and a sample of seco-C-oleanane (1).
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