Unambiguous characterization of the sesquiterpene (7R,9E)-1,2,11- trihydroxy-1,3,5,9-bisabolatetraene through its enantioselective synthesis

Article abstract of DOI:10.1002/ejoc.201200620

The bisabolane sesquiterpene (7R,9E)-1,2,11-trihydroxy-1,3,5,9- bisabolatetraene previously extracted from Commiphora kua resins was prepared by enantioselective synthesis using an enzyme-mediated resolution procedure as the key step. Both the chemical st

Full text of DOI:10.1002/ejoc.201200620

Job/Unit: O20620
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Date: 16-07-12 10:20:43
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201200620
Unambiguous Characterization of the Sesquiterpene (7R,9E)-1,2,11-
Trihydroxy-1,3,5,9-bisabolatetraene through Its Enantioselective Synthesis
Stefano Serra*[a] and Giovanni Fronza[a]
Keywords: Natural products / Terpenoids / Configuration determination / Chiral resolution / Enzymes
The bisabolane sesquiterpene (7R,9E)-1,2,11-trihydroxy-
1,3,5,9-bisabolatetraene previously extracted from Commi-
phora kua resins was prepared by enantioselective synthesis
using an enzyme-mediated resolution procedure as the key
step. Both the chemical structure and the absolute configura-
tion were unambiguously assigned, although the comparison
of the obtained analytical data with those previously reported
for the isolated terpene indicated a possible error in the char-
acterization of the natural product. A further study on the
chemical stability of the aforementioned compound revealed
that it is very unstable in an acidic environment, where it
cyclizes readily to give the corresponding chromane deriva-
tives.
aforementioned studies left the absolute configuration of
the identified sesquiterpenes unassigned, as a reliable chem-
ical conversion into a compound of known configuration
was unavailable. More recently, 1,2,11-trihydroxy-1,3,5,9-
bisabolatetraene[5] (1c) was isolated from the resins of the
plant Commiphora kua, and its configuration was tenta-
tively assigned as R on the basis of its CD spectrum. None
of the sesquiterpenes described above have been prepared
before by chemical synthesis. This means that both the con-
firmation of their chemical structure and the unambiguous
assignment of their absolute configuration are still lacking.
Introduction
The phenolic sesquiterpenes of the bisabolane family
have been isolated from many different natural sources.
They display a wide range of biological activities, which are
strictly related to their chemical structures. In particular,
minor modification of the molecular framework or switch-
ing of the absolute configuration might result in a dramatic
change in their activity. Most of these compounds possess
a benzylic asymmetric center whose stereoselective intro-
duction is especially demanding from a synthetic point of
view. Therefore, only a few of the reported synthetic ap-
proaches to these compounds are enantioselective,[1] and
the assignment of the absolute configuration of a newly iso-
lated natural product belonging to this class is often tricky,
especially if a straightforward chemical conversion into a
known compound is not available. To this end, circular di-
chroism (CD), biosynthetic considerations, or comparison
of the sign of optical rotation with those of structurally sim-
ilar terpenes might help with the tentative assignment of the
configuration. Phenolic sesquiterpenes with the structural
framework 1 (Figure 1) are quite rare, and to the best of
our knowledge, their occurrence in nature is restricted to
the three structures 1a–c. Compounds 1a were first isolated
from the aerial part of the plants Wedelia regis[2] (angeloyl
derivatives) and Rutidosis murchisonii[3] (senecioyl deriva-
tives), whereas the bioactive diol parahigginol D[4] (1b) was
isolated from a marine sponge Parahigginsia sp. All the
[a] C.N.R., Istituto di Chimica del Riconoscimento Molecolare,
Via Mancinelli, 7, 20131 Milano, Italy
Fax: +39-02-2399-3180
Figure 1. Structure and numbering of the phenolic 1,2-dihydroxy-
bisabolane sesquiterpenes.
E-mail: stefano.serra@cnr.it
Taking advantage of our previous experience[6–10] in the
enantioselective synthesis of phenolic sesquiterpenes, we de-
cided to investigate a synthetic approach to 1c, which seems
stefano.serra@polimi.it
Homepage: http://www.icrm.cnr.it/serra.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200620.
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FULL PAPER
to be the most well-characterized compound among the be efficiently resolved by this protocol, since its aromatic
aforementioned class of terpenes. In this paper, we describe substitution pattern fulfills all the requirements described
the accomplishment of this plan by reporting the first enan- above.
tioselective synthesis of (–)-1c. The comparison of the ana-
Thus, we devised a large-scale preparation of racemic 5
lytical data obtained with those previously reported indi- starting from commercially available 1,2-dimethoxy-3-
cated a possible error in the characterization of the natural methylbenzene (2). Dimethyl ether 2 was metalated[11] re-
product. A further study involving degradation of the ses- gioselectively at position 6 of the aromatic ring by reaction
quiterpene was thus undertaken. This revealed that 1c is with
butyllithium
and
tetramethylethylenediamine
very unstable in an acidic environment, cyclizing readily to (TMEDA) in hexane at room temperature. The aryllithium
give chromane derivative 12, whose analytical data could derivative was then quenched with CO2 at low temperature,
account for some of the discrepancies observed.
and the resulting benzoic acid (i.e., 3) was converted in the
corresponding methyl ester by treatment with methanol and
concentrated H2SO4. The ester was treated with excess
methylmagnesium bromide, and the resulting crude di-
methyl alcohol was dehydrated by heating in refluxing benz-
ene in the presence of a catalytic amount of para-tolu-
enesulfonic acid (PTSA). The resulting styrene derivative 4
was hydroborated by reaction with BH3·SMe2. The organo-
borane intermediate was then oxidized in situ with H2O2 in
the presence of NaOH to give alcohol 5 in very good yield
and with almost complete regioselectivity.
The reactivity of this substrate in the PPL-mediated
irreversible acetylation was tested by treatment of the
alcohol with vinyl acetate in tert-butyl methyl ether in the
presence of the enzyme at room temperature. In a prelimi-
nary experiment, the reaction was interrupted at a conver-
sion of about 50%, and the acetate product had 76%ee.
This data allowed the calculation of the enantiomeric ratio
(E)[12] of the reaction, and the value of 17 is in good agree-
ment with results previously obtained with structurally
analogous substrates.
In order to obtain both enantiomeric forms of 5 in high
ee, we prolonged the reaction time until the acetylation
reached about 60% conversion. The unreacted alcohol [i.e.,
(+)-5, 94%ee, 38% yield] was separated by chromatography.
Acetate (+)-6 was hydrolyzed and the resulting enantiomer-
ically enriched alcohol was submitted again to the PPL-
mediated acetylation process until a conversion of about
60% was reached. Chromatographic separation gave (+)-6
(96%ee, 35% yield). By this protocol, we obtained both the
isomeric forms of 5 in high enantiomeric purity. Even
though PPL usually catalyzes the acetylation of S-config-
ured 2-aryl propanols, the absolute configuration of acetate
(+)-6 had to be unambiguously assigned. Thus, we de-
graded acetate (+)-6 into methyl 3-acetoxy-2-methylpro-
panoate (–)-7 (Scheme 2). A sample of (+)-6 (70%ee) was
oxidized with sodium periodate in the presence of a cata-
lytic amount of ruthenium trichloride,[13,14] and the re-
Results and Discussion
A reliable synthesis of a natural product to be used in
structural determination should give the desired compound
as a single isomer. For 1c, two challenging aspects of the
synthesis are the enantioselective preparation of the R-con-
figured benzylic stereocenter, and the avoidance of the for-
mation of other isomers (regioisomers and/or geometrical
isomers) during the construction of the molecular frame-
work. Recently, we developed a chemo-enzymatic process[10]
that allows the resolution of 2-arylpropanols. The key step
of the method is the irreversible lipase-mediated acetylation
of the primary alcohol, and the enantioselectivity of this
step is strongly dependent on the substitution pattern of the
aromatic ring. We found porcine pancreatic lipase (PPL) to
be the most enantioselective catalyst suitable for this pur-
pose, preferentially acetylating the S enantiomers. Substitu-
ents in the position para to the aliphatic chain and methoxy
substituents both greatly increased the selectivity of the en-
zyme. We envisaged that 2-arylpropanol 5 (Scheme 1) could
Scheme 1. Synthesis and enzyme-mediated resolution of 2-(2,3-di-
methoxy-4-methylphenyl)propan-1-ol. Reagents and conditions:
(a) BuLi, TMEDA, hexane, r.t., 24 h, then CO2, –78 °C; (b) MeOH,
conc. H2SO4, reflux, 4 h; (c) MeMgBr, THF; (d) cat. PTSA, benz-
ene, reflux; (e) BH3·SMe2, THF, r.t., 2 h, then NaOH/H2O2;
(f) PPL, vinyl acetate, tBuOMe, then chromatographic separation;
(g) NaOH, MeOH, reflux.
Scheme 2. Chemical degradation of acetate (+)-6 into (–)-(R)-3-
acetoxy-2-methylpropanoate (7). Reagents and conditions:
(a) NaIO4, CH3CN/CCl4, H2O, cat. RuCl3·nH2O, 48 h; (b) CH2N2,
Et2O, 0 °C, 1 h.
2
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Synthesis of (7R,9E)-1,2,11-Trihydroxy-1,3,5,9-bisabolatetraene
sulting acid was treated with diazomethane. This degrad- sure gave (+)-10 in good yield. This compound was reduced
ative procedure afforded (–)-7 of known[15] R absolute con- with diisobutylaluminum hydride (DIBALH; 2 equiv.) at
figuration, thus confirming our assumption about the lipase low temperature (–78 °C) to give the corresponding lactol.
enantioselectivity.
This intermediate was not isolated, but was treated with an
As a result, we used (+)-6 as a chiral building block for excess of (carbethoxymethylene)triphenylphosphorane to
the synthesis of 1c (Scheme 3). The acetate was homolo- give ester (–)-11 as an inseparable 9:1 mixture of E/Z iso-
gated to acid (–)-9 by a four-step process. Compound (+)-6 mers. Since the natural terpene consists of the E isomer
was hydrolyzed, and the resulting alcohol was converted only, we had to remove the unwanted compound (Z)-11.
into the corresponding tosylate. This was heated with Luckily, we found that chromatographic purification of the
NaCN in DMSO, and the nucleophilic substitution reac- crude target compound obtained in the following step al-
tion afforded cyano derivative (+)-8, which was hydrolyzed lowed the isolation of 1c in isomerically pure form. There-
with NaOH in diethylene glycol/water at reflux. The re- fore, we treated impure (–)-11 with an excess of methyllith-
sulting acid [i.e., (–)-9] was treated with boron tribromide ium, and then proceeded with the chromatographic pro-
in dichloromethane, which allowed the deprotection of the cedure to obtain pure (–)-1c in good yield. The chemical
1
two methyl ether groups, and simultaneous lactone ring clo- structure of the resulting compound was confirmed by H-
and 13C NMR spectroscopic analysis, whose complete spec-
tral assignment was performed by HSQC and HMBC ex-
periments (see Table 1).
Thus, our chemical synthesis unambiguously assigns the
R
absolute configuration to (–)-(E)-1,2,11-trihydroxy-
1,3,5,9-bisabolatetraene 1c, confirming the previously re-
ported results based on CD study. In spite of this fact, we
have to report a number of discrepancies between our ana-
lytical data and those recorded in the natural product study.
First of all, we measured an optical rotation value of –4.5
(c = 1.6, CH2Cl2) for a sample of 1c with 96%ee, whereas
the isolated natural compound had an optical rotation
value of –35 (c = 1.0, CH2Cl2). In addition, although our
NMR spectroscopic data were, for the most part, in good
agreement with those reported for the natural product,
there are three 13C NMR signals described in the latter
study (Table 1) that do not match our data, and neither do
they match the data from a simulated 13C NMR spectrum.
These signals are due to carbons 7, 8 and 15 of the bis-
abolane framework, and are all in allylic or benzylic posi-
tions. This points to the possibility of a 1,3-allylic transposi-
tion of the oxygen atom and thus of the formation of a
Scheme 3. Stereoselective synthesis of sesquiterpene (–)-(7R,9E)-
1,2,11-trihydroxy-1,3,5,9-bisabolatetraene (1c). Reagents and con-
ditions: (a) NaOH, MeOH, reflux; (b) TsCl, Py, CH2Cl2; (c) NaCN,
DMSO, 80 °C, 3 h; (d) NaOH, diethylene glycol, H2O, reflux, 2 h;
(e) BBr3, CH2Cl2, r.t., 3 h; (f) DIBALH, toluene, –78 °C then 0 °C,
1 h; (g) Ph3PCHCO2Et, CH2Cl2, reflux 3 h; (h) MeLi, diethyl ether,
0 °C then r.t., 2 h.
Table 1. NMR spectroscopic data of synthetic and natural (–)-(7R,9E)-1,2,11-trihydroxy-1,3,5,9-bisabolatetraene (1c) and cyclized com-
pound 12.
Position[a] Synthetic 1c
δC (CDCl3)
Natural 1c[b]
δC (CDCl3)
100 MHz
12[c]
δC (CDCl3)
125 MHz
δH ([D6]benzene)
400 MHz
δH ([D6]benzene)
400 MHz
125 MHz
1
2
3
4
5
6
7
141.6
142.2
122.0
122.2
118.2
131.3
32.9
5.76 and 5.50
(2 br. s, OH)
141.4
142.0
122.0
123.5
118.2
131.4
39.3
7.20 (s, 2 H)
141.5
143.0
121.5
122.0
117.2
124.8
29.5
6.66 (s, 2 H)
6.85 (d, J = 7.5 Hz, 1 H)
7.02 (d, J = 7.5 Hz, 1 H)
3.26–3.12 (m, 1 H)
2.70 (tq, J = 6.9, 6.9 Hz, 1 H)
8
9
40.1
2.38–2.18 (m, 2 H)
5.57 (dt, J = 15.6, 7.1 Hz, 1 H)
5.44 (br. d, J = 15.6 Hz, 1 H)
37.5
not reported
5.50 (ddd, J = 15.5, 6.5, 6 Hz, 1 H) 74.0
5.46 (br. d, J = 15.5 Hz, 1 H)
38.2
126.0
139.2
71.2
124.7
138.2
72.6
29.4
30.1
22.0
18.7
10
11
12
13
14
15
124.9
137.3
25.8
18.5
20.3
15.3
29.6[d]
29.7[d]
20.4
1.12 and 1.08 (2s, 3 H each)
1.20 (s, 6 H)
1.25 (d, J = 7.0 Hz, 3 H)
2.09 (s, 3 H)
1.25 (d, J = 6.6 Hz, 3 H)
2.10 (s, 3 H)
15.6
[a] Bisabolane numbering. [b] Data reported in ref.[5] [c] Data of the major diastereoisomer. [d] These NMR signals could be switched.
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S. Serra, G. Fronza
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degradation product during acquisition of the 13C NMR
spectra. In order to test our theory, we checked the acid-
catalyzed degradation of 1c. A sample of (–)-1c was dis-
solved in CHCl3 and treated at room temperature with a
catalytic amount of PTSA (Scheme 4).
(6) = 20.60, tR (7) = 8.06, tR (8) = 20.49, tR (9) = 21.53, tR (10) =
20.51, tR (11) = 24.46, tR (12) = 23.40 (minor diastereoisomer)
and 23.67 (major diastereoisomer); mass spectra: m/z (%); Mass
spectrum of compound 1c was recorded with a Bruker ESQUIRE
3000 PLUS spectrometer (ESI ionization). Chiral HPLC analysis:
Merck–Hitachi L-7100 equipped with a Merck–Hitachi L-4250
UV/Vis detector, constant flow, detector 210 nm, tR given in min;
with the following elution conditions: compound 6: flow 1 mL/min,
eluent hexane/iPrOH, 99:1 tR [(S)-(+)-6] = 8.6, tR [(R)-(–)-6] = 9.2.
Optical rotations: Jasco-DI-181 digital polarimeter. 1H and 13C
NMR spectra: recorded at room temperature; Bruker AC-400 spec-
trometer at 400 and 100 MHz, respectively; chemical shifts in ppm
relative to internal SiMe4 (0 ppm), J values in Hz. The complete
13C NMR signal assignment for compounds 1c and 12 was per-
formed by HSQC (heteronuclear single quantum coherence) and
HMBC (heteronuclear multiple-bond correlation) experiments
using a Bruker AC-500 spectrometer at 500 and 125 MHz. Melting
points were measured with a Reichert apparatus, equipped with a
Reichert microscope.
Scheme 4. Acid-catalyzed cyclization of (–)-(7R,9E)-1,2,11-tri-
hydroxy-1,3,5,9-bisabolatetraene (1c). Reagents and conditions:
(a) cat. PTSA, CHCl3, r.t., 30 min.
We observed the rapid and quantitative formation of bi-
cyclic ether (–)-12 as a 2:1 mixture of diastereoisomers. This
experiment confirms the chemical instability of 1c in an
acidic environment. Even though the 13C NMR spectrum
of compound 12 (Table 1) does not account for the mislead-
ing signals described for the natural product, we measured
an optical rotation value of –31.5 (c = 2, CH2Cl2) for the
mixture of diastereoisomers of 12 that might explain the
difference between our data and that previously reported
for 1c. It is possible that the isolated natural sample was
impure (thus explaining the misleading signals), and it may
have slowly degraded after the NMR spectroscopic analysis
had been performed. Nevertheless, none of these sensible
considerations can allow a definitive statement on the
chemical and optical purity of the natural compounds
whose unambiguous determination requires further investi-
gation.
Lipase-Mediated Resolution of Racemic 2-(2,3-Dimethoxy-4-meth-
ylphenyl)propan-1-ol (5): A solution of racemic 2-(2,3-dimethoxy-
4-methylphenyl)propan-1-ol (6.3 g, 30 mmol), PPL (5 g), vinyl acet-
ate (15 mL), and tBuOMe (60 mL) was stirred at room tempera-
ture, and the formation of acetylated compounds was monitored
by TLC analysis. The reaction was stopped when the acetylation
had reached a conversion of about 65% (GC analysis), by filtration
of the enzyme and evaporation of the solvent at reduced pressure.
The residue was then purified by chromatography using hexane/
diethyl ether (95:5–3:1) as eluent. The resulting alcohol (R)-(+)-5
(2.40 g, 38%) gave the following analytical data: 97% purity by
GC, 94%ee by chiral HPLC. [α]2D0 = +14.8 (c = 2.2, CHCl3). The
resulting acetate (+)-6 was treated with NaOH (2 g, 50 mol) in
MeOH (40 mL) at reflux for 1 h. After work-up, the resulting
alcohol was submitted again to the resolution procedure, allowing
the acetylation reaction to reach a conversion of about 60%. The
resulting acetate (S)-(+)-6 (2.65 g, 35%) gave the following analyti-
cal data: 99% purity by GC, 96%ee by chiral HPLC; colorless oil.
Conclusions
1
[α]2D0 = +24.9 (c = 2.6, CHCl3). H NMR (400 MHz, CDCl3): δ =
We report here the first enantioselective synthesis of
(–)-(E)-1,2,11-trihydroxy-1,3,5,9-bisabolatetraene (1c) and
the unambiguous assignment of its absolute configuration
as R. Careful comparison of the obtained analytical data
with those reported for the isolated terpene indicated a pos-
sible error in the characterization of the natural product.
Studying the acid-catalyzed degradation of synthetic 1c re-
vealed that this sesquiterpene is very unstable, cyclizing
readily to give chromane derivative 12, whose analytical
data could account for some of the discrepancies observed.
6.87 (dd, J = 8.0, 0.4 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 4.19–4.09
(m, 2 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.54–3.43 (m, 1 H), 2.24 (d,
J = 0.4 Hz, 3 H), 2.00 (s, 3 H), 1.25 (d, J = 7.0 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.9, 151.4, 151.1, 134.8, 130.5,
125.6, 121.7, 69.0, 60.6, 59.8, 31.8, 20.8, 17.8, 15.6 ppm. GC–MS
(EI): m/z (%) = 252 (16) [M]+, 192 (39), 179 (90), 177 (100), 164
(65), 149 (21), 135 (5), 119 (10), 105 (5), 91 (14), 77 (7).
Hydrolysis of (+)-6 (using NaOH in MeOH) afforded (–)-5, which
gave the following analytical data: 99% purity by GC, 96%ee by
chiral HPLC; colorless oil. [α]2D0 = –15.4 (c = 3.8, CHCl3).
(R)-3-(2,3-Dimethoxy-4-methylphenyl)butanenitrile (8): A solution
of p-toluenesulfonyl chloride (3 g, 15.7 mmol) in CH2Cl2 (10 mL)
Experimental Section
was added dropwise to a stirred solution of alcohol (–)-5 {[α]2D0
=
General Methods: All moisture-sensitive reactions were carried out
under a static atmosphere of nitrogen. All reagents were of com-
mercial quality. Lipase from porcine pancreas (PPL) type II, Sigma,
147 units/mg was used in this work. TLC: Merck silica gel 60 F254
plates. Column chromatography: silica gel. GC–MS analysis: HP-
6890 gas chromatograph equipped with a 5973 mass detector, using
a HP-5MS column (30 mϫ 0.25 mm, 0.25 μm film thickness; Hew-
lett–Packard) with the following temperature program: 60 °C
(1 min), then 6 °C/min to 150 °C (1 min), then 12 °C/min to 280 °C
(5 min); carrier gas, He; constant flow 1 mL/min; split ratio, 1:30;
tR given in min: tR (3) = 20.11, tR (4) = 13.64, tR (5) = 18.70, tR
–15.4 (c = 3.8, CHCl3), 98%ee, 2.6 g, 12.4 mmol} in pyridine
(5 mL). After 4 h, the mixture was diluted with diethyl ether
(100 mL), and washed in turn with 1 n aq. HCl solution (100 mL),
saturated NaHCO3 solution (50 mL) and brine. The organic phase
was dried (Na2SO4) and concentrated in vacuo. The residue was
dissolved in dry DMSO (40 mL) and treated with NaCN (3.1 g,
63.3 mmol), stirring at 80–90 °C until the starting tosylate could
no longer be detected by TLC analysis (3 h). The mixture was di-
luted with diethyl ether (100 mL), and washed in turn with water
and brine. The organic phase was dried (Na2SO4) and concentrated
in vacuo. The residue was then purified by chromatography eluting
4
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Synthesis of (7R,9E)-1,2,11-Trihydroxy-1,3,5,9-bisabolatetraene
with n-hexane/diethyl ether (95:5–8:2) to afford pure (+)-8 (2.49 g,
3.15 (m, 1 H), 2.61–2.51 (m, 1 H), 2.46–2.34 (m, 1 H), 2.21 (s, 3
H), 1.26 (t, J = 7.1 Hz, 3 H), 1.25 (d, J = 7.0 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.8, 147.9, 141.8, 141.5, 130.2,
122.4, 121.8, 121.7, 118.3, 60.2, 39.5, 32.1, 20.2, 15.3, 14.2 ppm.
GC–MS (EI): m/z (%) = 264 (98) [M]+, 218 (8), 203 (15), 190 (7),
175 (50), 161 (45), 150 (100), 133 (7), 121 (9), 105 (4), 91 (10), 77
(11).
1
92%) as a colorless oil. [α]2D0 = +25.7 (c = 2.7, CHCl3). H NMR
(400 MHz, CDCl3): δ = 6.89 (d, J = 8.0 Hz, 1 H), 6.85 (d, J =
8.0 Hz, 1 H), 3.88 (s, 3 H), 3.81 (s, 3 H), 3.56–3.44 (m, 1 H), 2.63
(dd, J = 16.6, 6.1 Hz, 1 H), 2.53 (dd, J = 16.6, 7.8 Hz, 1 H), 2.24
(s, 3 H), 1.40 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.4, 150.6, 134.4, 131.4, 125.8, 121.1, 118.8, 60.6,
59.8, 30.0, 25.3, 19.9, 15.6 ppm. GC–MS (EI): m/z (%) = 219 (41)
[M]+, 179 (100), 164 (39), 149 (9), 136 (2), 119 (6), 103 (2), 91 (10),
77 (6).
(7R,9E)-1,2,11-Trihydroxy-1,3,5,9-bisabolatetraene or (R,E)-3-(6-
hydroxy-6-methylhept-4-en-2-yl)-6-methylbenzene-1,2-diol
(1c):
MeLi (4 mL of 1.6 m solution in diethyl ether) was added dropwise
under nitrogen to a vigorously stirred solution of (–)-11 (0.6 g,
2.3 mmol) in dry diethyl ether (20 mL). The reaction mixture was
kept cool (0 °C) until complete addition of the reagents, after which
it was left to reach room temperature, and stirring was continued
for a further 2 h. The mixture then was poured onto crushed ice
and a saturated aqueous solution of NH4Cl (40 mL). The pH was
adjusted to 6.5 by addition of dilute HCl, and the mixture was
extracted with EtOAc (3ϫ60 mL). The organic phase was washed
with brine, dried with Na2SO4 and concentrated under reduced
pressure. The residue was purified by chromatography eluting with
hexane/EtOAc (9:1–7:3) to afford pure 1c (0.39 g, 68%) as a color-
less oil. [α]2D0 = –4.5 (c = 1.6, CH2Cl2). 1H NMR and 13C NMR
spectroscopic data are reported in Table 1. MS (ESI): m/z = 273.2
[M + Na]+.
(R)-3-(2,3-Dimethoxy-4-methylphenyl)butanoic Acid (9): Nitrile (+)-
8 (1.1 g, 5 mmol) was heated with NaOH (2 g, 50 mmol) in diethyl-
ene glycol/water, 2:1 (30 mL) at reflux for 2 h. After cooling, the
mixture was diluted with water and extracted with diethyl ether.
The organic phase was discarded, and the aqueous phase was acidi-
fied with 5 n aq. HCl solution and then extracted with CH2Cl2.
Removal of the solvent in vacuo left a thick oil, which was purified
by chromatography, eluting with n-hexane/ethyl acetate (9:1–7:3) to
afford pure acid (–)-9 (1.05 g, 88%). [α]2D0 = –14.0 (c = 3.3, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.86 (d, J = 8.0 Hz, 1 H), 6.81
(d, J = 8.0 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.67–3.56 (m, 1
H), 2.67 (dd, J = 15.5, 6.5 Hz, 1 H), 2.54 (dd, J = 15.5, 8.4 Hz, 1
H), 2.23 (s, 3 H), 1.27 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.3, 151.4, 150.6, 137.0, 130.4, 125.6,
121.3, 60.5, 59.8, 41.6, 29.6, 21.3, 15.6 ppm. GC–MS (EI): m/z (%)
= 238 (56) [M]+, 205 (6), 192 (4), 179 (100), 164 (39), 149 (10), 135
(5), 119 (8), 105 (4), 91 (14), 77 (6).
(4R)-4,7-Dimethyl-2-(2-methylprop-1-enyl)chroman-8-ol (12):
A
sample of (–)-1c (0.1 g, 0.4 mmol) was dissolved in CHCl3 (5 mL)
and treated with p-toluenesulfonic acid monohydrate (5 mg,
0.03 mmol). After 30 min, the solvent was removed under reduced
pressure, and the residue was purified by chromatography eluting
with hexane/diethyl ether (95:5–8:2) to afford pure 12 (85 mg,
91%). Colorless oil, 2:1 mixture of diastereoisomers (by GC analy-
sis). [α]2D0 = –31.5 (c = 2, CH2Cl2). Data for the major diastereoiso-
mer: 1H NMR (400 MHz, CDCl3): δ = 6.72–6.62 (m, 2 H), 5.62
(br. s, 1 H), 5.34 (double m, J = 8.3 Hz, 1 H), 4.76 (ddd, J = 11.4,
8.3, 1.9 Hz, 1 H), 3.08–2.97 (m, 1 H), 2.21 (s, 3 H), 2.00–1.91 (m,
1 H), 1.80 (d, J = 1.4 Hz, 3 H), 1.73 (d, J = 1.4 Hz, 3 H), 1.70–
1.53 (m, 1 H), 1.30 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR spectro-
scopic data are reported in Table 1. GC–MS (EI): m/z (%) = 232
(25) [M]+, 217 (6), 199 (2), 189 (4), 175 (7), 163 (7), 150 (100), 131
(5), 121 (3), 107 (5), 91 (9), 77 (13), 67 (12).
(R)-8-Hydroxy-4,7-dimethylchroman-2-one (10): Acid (–)-9 (0.72 g,
3 mmol) was dissolved in dry dichloromethane (40 mL) at 0 °C,
and BBr3 (1.7 g, 6.8 mmol) was added under a nitrogen atmo-
sphere. The reaction mixture was allowed to warm to ambient tem-
perature, and stirred for further 3 h. The reaction was quenched
by the addition of water (100 mL), and the resulting mixture was
extracted with CH2Cl2 (2ϫ60 mL). The combined organic extracts
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by chromatography eluting with hexane/diethyl
ether (9:1–2:1) to afford pure (+)-10 (0.43 g, 75%), which solidified
on standing. Colorless crystals; m.p. 83–85 °C. [α]2D0 = +20.1 (c =
1
2, CHCl3). H NMR (400 MHz, CDCl3): δ = 6.88 (d, J = 7.8 Hz,
1 H), 6.65 (d, J = 7.8 Hz, 1 H), 5.60 (s, 1 H), 3.21–3.10 (m, 1 H),
2.84 (dd, J = 15.8, 5.4 Hz, 1 H), 2.57 (dd, J = 15.8, 7.5 Hz, 1 H),
2.25 (s, 3 H), 1.32 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.4, 141.9, 138.4, 126.1, 125.6, 124.4, 116.4, 37.0,
29.5, 19.8, 15.3 ppm. GC–MS (EI): m/z (%) = 192 (45) [M]+, 177
(4), 164 (3), 150 (100), 131 (6), 121 (5), 107 (4), 91 (6), 77 (7).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 3–5 and 7, and copies of the 1H NMR and 13C NMR
spectra for compounds 4–12 and 1c.
[1] M. C. Pirrung, A. T. Morehead in The Total Synthesis of Natu-
ral Products (Ed.: D. Goldsmith), Wiley, New York, 1997, vol.
10, pp. 29–44.
[2] F. Bohlmann, T. Gerke, J. Jakupovic, N. Borthakur, R. M.
King, H. Robinson, Phytochemistry 1984, 23, 1673–1676.
[3] C. Zdero, F. Bohlmann, R. M. King, H. Robinson, Phytochem-
istry 1987, 26, 1759–1762.
[4] C.-Y. Chen, Y.-C. Shen, Y.-J. Chen, J.-H. Sheu, C.-Y. Duh, J.
Nat. Prod. 1999, 62, 573–576.
[5] L. O. A. Manguro, I. Ugi, P. Lemmen, Chem. Pharm. Bull.
2003, 51, 479–482.
[6] C. Fuganti, S. Serra, Synlett 1998, 1252–1254.
[7] C. Fuganti, S. Serra, J. Org. Chem. 1999, 64, 8728–8730.
[8] S. Serra, Synlett 2000, 890–892.
[9] C. Fuganti, S. Serra, J. Chem. Soc. Perk. Trans. 1 2000, 3758–
3764.
[10] S. Serra, Tetrahedron: Asymmetry 2011, 22, 619–628.
[11] J. A. Gainor, S. M. Weinreb, J. Org. Chem. 1982, 47, 2833–
2837.
(R)-Ethyl
5-(2,3-Dihydroxy-4-methylphenyl)hex-2-enoate
(11):
DIBALH (1.7 m in toluene, 3.1 mL) was added dropwise under ni-
trogen to a stirred solution of lactone (+)-10 (0.9 g, 4.7 mmol) in
dry toluene (20 mL) at –78 °C. The reaction mixture was stirred at
0 °C for 1 h, then diluted with diethyl ether (40 mL), and quenched
with a saturated aqueous solution of NH4Cl (50 mL). The mixture
was extracted with diethyl ether (2ϫ100 mL), and the combined
organic phases were concentrated under reduced pressure. The resi-
due was dissolved in CH2Cl2 (30 mL), and treated with
Ph3PCHCO2Et (3 g, 8.6 mmol), stirring at reflux for 3 h. The sol-
vent was removed under reduced pressure, and the residue was then
purified by chromatography eluting with n-hexane/diethyl ether
(95:5–8:2) to afford (–)-11 (0.8 g, 64%) as a colorless oil, with an
E/Z ratio of 9:1 (by NMR spectroscopic analysis). [α]2D0 = –2.9 (c
= 2, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.91 (ddd, J = 15.6,
7.7, 6.9 Hz, 1 H), 6.63 (s, 2 H), 5.81 (dt, J = 15.6, 1.5 Hz, 1 H),
5.49, 5.12 (two br. s, each 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.26–
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O20620
/KAP1
Date: 16-07-12 10:20:43
Pages: 7
S. Serra, G. Fronza
FULL PAPER
[12] C. S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem.
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[15]
T. Matsumoto, S. Imai, S. Miuchi, H. Sugibayashi, Bull. Chem.
Soc. Jpn. 1985, 58, 340–345.
Received: May 10, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20620
/KAP1
Date: 16-07-12 10:20:43
Pages: 7
Synthesis of (7R,9E)-1,2,11-Trihydroxy-1,3,5,9-bisabolatetraene
Natural Product Synthesis
S. Serra,* G. Fronza ......................... 1–7
Unambiguous Characterization of the
Sesquiterpene (7R,9E)-1,2,11-Trihydroxy-
1,3,5,9-bisabolatetraene through Its En-
antioselective Synthesis
The enantioselective synthesis of the bis-
abolane sesquiterpene (7R,9E)-1,2,11-tri-
hydroxy-1,3,5,9-bisabolatetraene was ac-
complished using an enzyme-mediated res-
olution procedure and a number of stereo-
selective chemical reactions. Both the
chemical structure and the absolute con-
figuration of the natural product were thus
unambiguously assigned.
Keywords: Natural products / Terpenoids /
Configuration determination / Chiral resol-
ution / Enzymes
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