Total synthesis of TMS-ent-bisabolangelone

Article abstract of DOI:10.1016/j.tet.2017.04.042

The absolute configuration of bisabolangelone has been established by an eleven step total synthesis of the corresponding TMS protected antipode starting from (R)-(+)-pulegone. Comparison of the TMS-derivatives by GC on a chiral column, allowed us to assign the absolute configuration of the synthetic compound and thus of the corresponding natural product. The latter has been confirmed by the Mosher's ester analysis of the known secondary carbinol derivative.

Full text of DOI:10.1016/j.tet.2017.04.042

Tetrahedron xxx (2017) 1e11
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of TMS-ent-bisabolangelone*
Bernard Riss*, Marion Garreau, Prisca Fricero, Patricia Podsiadly, Nicolas Berton,
Sophie Buchter
Novartis Pharma AG, Chemical and Analytical Development, CH-4056 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The absolute configuration of bisabolangelone has been established by an eleven step total synthesis of
the corresponding TMS protected antipode starting from (R)-(þ)-pulegone. Comparison of the TMS-
derivatives by GC on a chiral column, allowed us to assign the absolute configuration of the synthetic
compound and thus of the corresponding natural product. The latter has been confirmed by the Mosher's
ester analysis of the known secondary carbinol derivative.
Received 11 January 2017
Received in revised form
12 April 2017
Accepted 18 April 2017
Available online xxx
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Bisabolangelone
Sesquiterpene
Bisabolane
Configuration
Perhydrobenzofuran
MTPA-ester
1. Introduction
limited availability. Isolation from natural sources is cumbersome,
and the total syntheses15,16 disclosed so far, were lengthy and
Bisabolangelone 11 (Angelikoreanol, Ligustilone2), a bisabolane-
type sesquiterpene3 present in Angelica species4 known for their
therapeutic values,5 belongs to a very small family of related
compounds with a poly-hydroxylated perhydro-benzofuran core
and a rare conjugated exo-cyclic enol-ether moiety (Fig. 1). Bisa-
bolangelone was found together with Osterivolones A-C6 in An-
gelica koreana. Liginvolones A-D7 were found in Ligusticum
involucratum, and Ashitabaol A8 in Angelica keiskei. Bisabolangelone
is known for a variety of biological activities such as anti-microbi-
al,9 insecticidal,10 anti-feeding,11 and many pharmacological12
properties such as: neuroprotective, anti-tumor, antioxidant and
anti-inflammatory. It has been identified as an anti-melanogenesis
factor,13 and derivatives14 are investigated as pharmaceutical drug
candidates. Unfortunately, a broad evaluation is hampered by its
delivered the target molecule in racemic form and low yield. In
order to enable a broader evaluation, we focused our attention on
the development of a practical synthesis. Although further efforts
are required to achieve our goal, we considered worth publishing
our first results about the synthesis of TMS-ent-bisabolangelone,
which enabled us to assign the absolute configuration of
(þ)-bisabolangelone, which was ambiguous considering the cor-
responding CAS number,17 and those of related derivatives.
2. Results and discussion
Among potential routes considered for the total synthesis of
bisabolangelone
1 (considering the abs. config. assigned to
CAS:30557-81-4), we focused our approach on the perhydro-
benzofuran intermediate 6b and the precursor (R)-5-
methylcyclohexenone 3b, readily available from (R)-(þ)-pulegone
(Scheme 1).
In order to develop the chemistry considered to build our target
molecule, we used the hemi-acetal 4a (Scheme 2a) reported by
Saimoto et al.,18 as a model substrate. The latter is formed by an
oxa-Michael addition of 1,3-dihydroxy-acetone 2a (DHA) with
*
This work is dedicated to Prof. Dr. Bernard Muckensturm for his great support
during my (BR) PhD thesis and his enthusiasm for natural product chemistry, which
remained with me my whole life.
* Corresponding author. Novartis campus, Lichtstrasse 35, CH-4056 Basel,
Switzerland.
E-mail address: bernard.riss@novartis.com (B. Riss).
http://dx.doi.org/10.1016/j.tet.2017.04.042
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
Fig. 1. Related bisabolane sesquiterpenes (stereochemistry drawn according to SciFinder).
Scheme 1. Retrosynthetic analysis.
a
b
Scheme 2. a. Reagents and conditions: (i) 1 eq. dihydroxyacetone (dimer), 0.05 eq. NaOH, water, 0e20 ꢀC, 20h (82%); (ii) 1 eq. NaBH4, water, 0 ꢀC, 2h (>99%); (iii) 2 eq. NaIO4, water,
0e20 ꢀC, 5 h (76%); (iv) HOCH2CH2OH, MsOH, 20 ꢀC, 0.5 h (92%). b. Reagents and conditions: (i) 2 eq. H2O2, 0.2 eq. LiOH, methanol/water 20 ꢀC, 20h, (100%); (ii) 1.2 eq. NaSPh, Me-THF
60 ꢀC, 15 h (81%); (iii) 1 eq. NaBO3, AcOH, 20 ꢀC, 2 h (93%); (iv) excess CaCO3, tetraglyme 140 ꢀC, 50 mbar, cold trap, (91%); (v) aq. H2SO4, trimethylcetylammonium chloride (90%);
(vi) Br2, water, acetic acid (100%); (vii) MgO, n-butylpyrrolidone, 120 ꢀC (57%, ee > 99%); (viii) dihydroxyacetone (dimer, 0.5 eq), NaOH (0.1 eq), water, 0 ꢀC, 20h; (ix) NaBH4 (1 eq)
water, 0 ꢀC, 4h; (x) NaIO4 (2 eq) water, 0e20 ꢀC, 15 h (91% from 3b,
a/b 15:85).
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
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Scheme 3. Reagents and conditions: (i) TBS-triflate, imidazole, THF, rt (99%); (ii) LDA (1.1 eq), prenal (1.2 eq), THF -78 ꢀC (84% for 11a and 55% for 11b); (iii) Trifluoroacetic anhydride
(3 eq), Et3N (6 eq). DMAP (0.1 eq), DCM, 35h, rt (85% for 12a and 86% for 12b).
unsaturated carbonyls, such as cyclohexenone 3a, and might be
extended to organo catalyzed enantioselective approaches.19 We
found that compound 4a can be readily converted to compound 5a
by reduction with NaBH4 in water,20 and to 4-hydroxy-perhydro-
benzofuran-3-one 6a by a subsequent treatment with sodium
periodate. Conversely, the dioxolane 9a,16 could not be obtained
from 4a and ethylene glycol under acidic conditions, despite the
facile formation of the mixed acetal 8a, emphasizing the stability of
the intra molecular hemi-acetal bond. It is noteworthy that 6a can
equally be obtained by using (L)-(þ)-erythrulose 2b instead of
DHA.21
Under optimized conditions, a one-pot telescoped reaction,
which consist in stirring an alkaline solution of cyclohexenone
and DHA at 0 ꢀC in water until full conversion, neutralizing the
solution with acetic acid, adding sodium borohydride, neutral-
izing again with acetic acid and adding sodium periodate, pro-
vided after an extractive work up, the compound 6a as the main
product in ~62% yield, together with minor amounts of the cor-
responding C-4 epimer and the dehydrated by-product 7a.22
Although each epimer can be obtained in pure form by chro-
matographic purification, this opportunity is of limited interest,
since the hydroxyl group of the minor isomer, which is anti-
periplanar to the hydrogen on carbon-3a, is quite labile and
prone to elimination.
particular, by NOESY correlations between the axial hydrogens on
carbons 2, 3, and carbon 6, which abs. config. (R) is derived from
pulegone. The absolute configuration, was confirmed by the
anomalous X-ray diffractions analysis of the corresponding
crystalline acetate (section 4.6). Notable is, that the correspond-
ing enantiomer, can be obtained from (S)-5-methyl-cyclo-
hexenone accessible by known methods,25 in particular from (S)-
5-methyl-cyclohexanone, available by resolution of the racemic
mixture with cholic acid (guest/host inclusion with >90% ee)
according to Bertolasi et al.26
With the central core in place, we followed our goal to syn-
thesize bisabolangelone, taking advantage of the methodologies
established, reducing however the number of protecting groups to
a strict minimum. We tried therefore, to introduce the prenyl side
chain by an aldol reaction directly on the unprotected hydroxy-
ketone 6a/6b, expecting high selectivity27 and enhanced stability.
Unfortunately, this approach failed due to by-products formation
by retro-aldol reaction and homo-coupling. Consequently, we
introduced the TBS protecting group on the labile hydroxyl. To our
delight, TBS-triflate reacted preferentially with the main isomer,
providing compounds 10a/10b in pure form by simple silica gel
filtration in about 80% isolated yield from 3a/3b (ee >96% for 10b).
The introduction of the prenyl side chain was performed in analogy
to Cossy et al.,16 by deprotonation with LDA at low temperature, and
subsequent addition of senecialdehyde, providing compounds 11a/
11b as a mixture of diastereomers in 84% and 55% yield respectively.
Subsequent treatment with trifluoroacetic anhydride, DMAP and
triethylamine, provided the desired compounds 12a/12b in 85e86%
yield28 (Scheme 3).
With the method to synthesize 6a in place, we turned our
attention to compound 6b required for the synthesis of bisabo-
langelone (Scheme 2b). The latter can be obtained in ~80% yield
by a telescoped sequence starting from 5-methyl-cyclohexenone
3b, which can be obtained in enantiomerically pure form from
(R)-(þ)-pulegone by known methods.23,24 The relative configu-
ration of the stereogenic centers in the intermediate 4b obtained
this way, was established by proton NMR investigations. In
With the diene structural feature in place, introduction of the
methyl group in position 3, was achieved stereoselectively with
methyl-magnesium bromide in the presence of anhydrous
Scheme 4. Reagents and conditions: (i) CeCl3 (1.5 eq), MeMgBr (3 eq), THF 0 ꢀC (52% for 13b); (ii) tetrabutylammonium fluoride (3 eq), THF, rt (90%); (iii) TPAP/NMO, CH2Cl2, 4 Å
molecular sieves (50%); (iv) TMS-Cl, TMS-imidazole, imidazole, DMF (>99%); (v) LDA, N-tert-butylbenzenesulfinimidoyl chloride, THF -78 ꢀC (20%).
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
cerium chloride, providing 13a/13b in 52% yield (Scheme 4). The
TBS protecting group, was smoothly removed with tetrabuty-
lammonium fluoride, providing the corresponding diols 14a/14b
in >90% yield. Selective oxidation of 14b by means of the Ley-
Griffith method (TPAP/NMO),29 provided ketone 15 in 50% iso-
lated yield, while other methods such as TEMPO/bleach, Saegusa-
Ito, failed. The modest yield is mainly due to the facile dehy-
dration of ketone 15, since compound 18 forms readily under
slightly acidic conditions. Notably, compound 14b and ketone 15
are diastereomers of 5,6-dihydro-bisabolangelol 1930 and 5,6-
dihydro-bisabolangelone 2031 respectively, both derivatives of
the natural product 1, distinguishable by their physical and
spectroscopic properties.
After silylation of the labile hydroxyl group (>99% yield with
TMS-imidazole, imidazole and cat. amounts of TMS-Cl in DMF),32
formation of the enone 17 succeeded under the remarkable
Mukaiyama-Matsuo conditions33 (generation of the lithium
enolate with LDA and quench with N-tert-butylbenzenesulfini-
midoyl chloride at ꢁ78 ꢀC). However, the conversion was low
(20% yield), likely due to the poor quality of the hygroscopic re-
agent. The identity of compound 17 obtained in this way was
ascertained by NMR/MS signals and comparison with an
authentic sample of TMS-bisabolangelone 21.34 Moreover, GC on
a chiral column35 (Fig. 2), showed that compound 17 did not
match with the TMS derivative of natural bisabolangelone, but
was superimposable with one of the two peaks of the corre-
sponding racemate obtained by synthesis from rac. 5-
methylcyclohexenone. According to these results, compound 17
is the enantiomer of the derivative 21. We can therefore conclude,
that the absolute configuration of the natural product (þ)-bisa-
bolangelone is: 3R, 3aR, and 7aS.
2.1. Material and conditions
GC apparatus HP6890, FID detector, 1.5 mL/min hydrogen flow,
1
mL
injection, split 1:10. Column HYDRODEX-g-TBDAc
(25 m ꢂ 0.25 mm) at 140 ꢀC isotherm. Sample 1: racemic TMS-
bisabolangelone obtained by synthesis from 5-methyl-cychlohex-
enone; Sample 2: mixture of racemic TMS-bisabolangelone and
compound 17; Sample 3: mixture of compound 17 (chiral) and
(þ)-TMS-bisabolangelone 21 (from natural source); Sample 4:
(þ)-TMS-bisabolangelone 21; Sample 5: compound 17 (chiral);
Sample 6: mixture of racemic TMS-bisabolangelone and (þ)-TMS-
bisabolangelone 21.
In order to confirm our finding, we performed the advanced
Mosher-Kusumi analysis36 of the MTPA esters 22(R) and 22(S), of
the secondary carbinol 19,30,31 obtained by reduction of natural
(þ)-bisabolangelone 1, with sodium borohydride (Scheme 5, Fig. 3).
Scheme 5. Reagents and conditions: (i) TMS-imidazole, Imidazole, TMS-Cl, DMF, 1h, RT
(99%); (ii) 1.5 eq. NaBH4, MeOH, 4h, 0 ꢀC (32%); (iii) MTPA-Cl (R/S) pyridine, rt (99%).
Fig. 2. GC overlays.
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
5
commercial suppliers and used without further purification.
Organic solutions were concentrated under reduced pressure on a
Büchi rotary evaporator. Reactions were monitored by thin-layer
chromatography (TLC) on silica gel coated glass plates (0.25 mm
thickness, 60F-254, E. Merck). Chromatograms were visualized by
fluorescence quenching with UV light at 254 nm or by staining with
vanillin/sulfuric acid/ethanol solution. 1H and 13C NMR spectra
were recorded in deuterated solvents on Bruker DPX-300, AV-400
and 600 spectrometers. Chemical shifts (d ppm) are relative to the
solvent used. 1H NMR data are reported as follows: chemical shift,
multiplicity (s ¼ singlet, d ¼ doublet, q ¼ quartet, m ¼ multiplet),
coupling constants in hertz (Hz). Molecular mass (LC/Ms-ToF), were
obtained on a Bruker maXis. LC-method: 1% acetonitrile þ0.1%
HCOOH to 99% acetonitrile þ0.1% HCOOH within 4 min, flow rate
0.4 mL/min, UV detector at 210 nm. Temperature 30 ꢀC. Optical
rotations were measured on an Autopol® V PLUS polarimeter
(Rudolph Research Analytical). Gas chromatography (GC) was
performed on HP6850 with a HP-5 capillary column (phenyl methyl
siloxane 30 m ꢂ 320 ꢂ 0.25), and a time program beginning with
1 min at 80 ꢀC, followed by a 12 min ramp to 280 ꢀC, column flow:
2 mL helium/min. Chiral GC analysis of 3-methyl-cychlohexanone,
5-methyl-cychlohex-2-enone and TMS-(ent)-bisabolangelone were
performed on a GC apparatus HP6890 with a FID detector, on a
Fig. 3. Drawing of the MTPA-esters 22. Dd
¼
d(S)-MTPA-22(S) - d(R)-MTPA-22(R).
3. Conclusion
In the present work, we describe the total synthesis of enantio-
merically pure TMS-ent-bisabolangelone in eleven steps and e2%
overall yield, starting from (R)-5-methyl-cyclohexenone obtained
from (R)-(þ)-pulegone (Scheme 6). The synthesis relies on the
stereoselective and straightforward access to the central perhydro-
benzofuran core, which allowed us to establish without ambiguity
the absolute configuration of the natural product, confirmed by the
MTPA-ester analysis of a known derivative. Despite additional im-
provements to the prior art, further effort will be devoted to syn-
thesize (þ)-bisabolangelone in an efficient and practical manner.
HYDRODEX-
g
-TBDAc column (25 m ꢂ 0.25 mm) at 100 ꢀC isotherm
(140 ꢀC for TMS-bisabolangelone), 1.5 mL/min hydrogen flow, 1
mL
injection, split 1:10. Monoisotopic mass were calculated with
ChemCalc.37
4.2. (R)-3-methylcyclohexanone38
Practical (R)-(þ)-pulegone (250 g, 1.64 mol, 92% from ABCR,
½
a 2D0
ꢃ
þ22.3ꢀ neat) was added dropwise at 80 ꢀC to a well stirred
solution of sulfuric acid (552 g, 5.63 mol), water (1.2 L) and cetyl-
pyridinium chloride (5.0 g, 14.7 mmol) in a 3 L double-jacketed
vessel equipped with an overhead stirrer. After 15 h, the reaction
mixture was cooled to 25 ꢀC and phases were separated. The
organic phase was washed with brine (20 mL) and neutralized with
NaHCO3. After drying with MgSO4, the crude brownish oil (184 g)
4. Experimental part
4.1. General methods
Unless otherwise stated, all reagents were purchased from
Scheme 6. Synthesis overview of TMS-ent-bisabolangelone.
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
was purified by distillation under reduced pressure (52 ꢀC,
5.6 mbar) providing a colorless liquid (110 g, 96% purity by GC).
Additional 43 g were obtained from the aqueous phase (via steam
distillation) increasing the overall yield to 90%.
aliph.) 1458, 1441 cmꢁ1; 1H NMR (600 MHz, DMSO-d6),
d ppm 5.55
(s, 1H) 5.30 (s, 1H) 4.10e4.06 (m, 1H) 3.96 (dd, J1 ¼ 8.5 Hz e
J2 ¼ 2.4 Hz, 1H) 3.88 (d, J ¼ 8.7 Hz, 1H) 3.79 (d, J ¼ 8.5 Hz, 1H) 3.46
(dd, J1 ¼ 8.7 Hz e J2 ¼ 2.4 Hz, 1H) 2.06 (d, J ¼ 6.9 Hz, 1H) 1.86 (dd,
J1 ¼13.7 Hz e J2 ¼ 2.5 Hz,1H) 1.77 (dd, J1 ¼14.2 Hz e J2 ¼ 2.5 Hz,1H)
1.74e1.67 (m,1H) 1.17e1.06 (m, 2H) 0.82 (d, J ¼ 6.7 Hz, 3H). 13C NMR
(151 MHz, DMSO-d6), ppm 104.36, 87.68, 79.12, 78.00, 77.04, 57.10,
44.39, 36.48, 22.59, 21.44.
½
a 2D0
ꢃ
þ12.1ꢀ (neat), lit.39 þ12.7ꢀ (neat). Enantiomeric purity
>99% (according to GC on a HYDRODEX-g
-TBDAc column, 100 ꢀC
isotherm, RT: 6.7 min for R and 6.3 min for S). 1H NMR (400 MHz,
Chloroform-d)
d
ppm 2.40e2.29 (m, 2H), 2.22 (dddd, J ¼ 14.1, 12.4,
6.2, 1.4 Hz, 1H), 2.08e2.00 (m, 1H), 1.97 (dd, J ¼ 13.4, 1.3 Hz, 1H),
1.94e1.80 (m, 2H), 1.65 (dtdd, J ¼ 13.5, 12.1, 4.8, 3.5 Hz, 1H), 1.32
(dddd, J ¼ 13.3, 12.0, 10.4, 3.6 Hz, 1H), 1.00 (d, J ¼ 6.3 Hz, 3H).
4.6. (2aR,4aS,6R,7aR,7bS)-4a-Hydroxy-6-methylhexahydro-2H-
furo[4,3,2-cd][1]benzofuran-2a(3H)-yl acetate
4.3. (5R)-2-bromo-5-methylcyclohexanone (isomeric mixture)
Bromine (157 g, 980 mmol) was added dropwise at 5 ꢀC to a
stirred solution of (R)-3-methylcyclohexanone (100 g, 892 mmol)
in water (400 mL) and acetic acid (10 g). During the addition, the
color of the solution changed from colorless to orange and later to
red. After full addition, the temperature was raised to 18 ꢀC within
1 h and stirring was continued overnight. After that time, the
organic layer was separated, and the aqueous phase extracted with
dichloromethane (DCM, 2 ꢂ 50 mL). The combined organic layers
were washed with a diluted solution of sodium bisulfite (20 mL,
5%), NaHCO3 (2 ꢂ 30 mL), and water (30 mL). The organic phase was
dried over MgSO4 and the solvent removed under reduced pres-
sure, leaving a purple liquid (180 g) as a mixture of isomers
(32:14:19:32 according to GC). The latter was used as is in the next
step without further purification.
A solution of hemiacetal 4b (2.0 g), THF (20 mL), pyridine (3.1 g 4
eq.), dimethylaminopyridine (DMAP, 0.06 g, 0.05 eq.) and acetic
anhydride (3.0 g, 3 eq.) was stirred overnight at RT. Next day, TLC
(heptane/MTBE, 50/50) showed full conversion. The reaction was
diluted with ethyl acetate (50 mL) and quenched with water
(50 mL). After phase split and wash with sat. NaHCO3, the org.
phase was dried over Na2SO4 and concentrated to dryness. The
crude solid was purified by column chromatography on silica gel
(eluent heptane/MTBE 100/0 to 30/70) leaving 1.6 g of pure acetate
which was crystallized from ethyl acetate/heptane providing
crystals suitable for X-ray analysis (fig. above). X-ray parameters,
temperature: 100(2)ꢀK, wavelength: 1.54178 Å, crystal system:
4.4. (R)-5-methylcyclohex-2-enone (3b)
The isomeric mixture of (5R)-2-bromo-5-methylcyclohexanone
(82.3 g, 0.43 mol) diluted in N-methyl-pyrrolidone (NMP, 55 mL),
was added dropwise at 110 ꢀC to a stirred suspension of MgO
(27.0 g, 0.67 mol) in NMP (200 mL). After 50 min stirring, the crude
product was isolated by distillation under reduced pressure
(5 mbar, jacket 120 ꢀC). The clear distillate (80 g) is a mixture of
desired product 3b, 3-methyl isomer and NMP, with a ratio of
33:18:49. (57% yield by NMR quantification with 1,3,5-trimethoxy-
benzene as internal standard and >99% ee according to GC on a
monoclinic, unit cell dimensions, a ¼ 17.818(9) Å (
a
¼ 90ꢀ),
b ¼ 16.961(9) Å (
b
¼ 107.080(16) ꢀ), c ¼ 8.195(4) Å (
g
¼ 90ꢀ), volume
2367(2) Å3, theta range for data collection: 3.68e66.58ꢀ, reflections
collected: 24150, refinement method: full-matrix least-squares on
F2, goodness-of-fit on F2: 1.059, final R indices [I > 2sigma(I)],
R1 ¼ 0.0286, wR2 ¼ 0.0736, R indices (all data), R1 ¼ 0.0288,
wR2 ¼ 0.0737. Absolute structure parameter 0.02(10), largest diff.
HYDRODEX-g
-TBDAc column, 100 ꢀC isotherm, RT: 10.4 min for R
and 10.0 min for S). Further purification can be performed by
fractionate distillation under reduced pressure or by column
chromatography (eluent: methyl acetate/pentane 1:9).
peak and hole 0.180 and ꢁ0.252 e.Åꢁ3
.
½
a 2D0
ꢃ
þ3.57ꢀ (c 2, MeOH); mp 151e152 ꢀC; HRMS calcd for
C
12H18O5Na [MþNa]þ 265.10519, found 265.10472; 1H NMR
4.5. (2aR,4aS,6R,7aR,7bS)-6-Methyltetrahydro-2H-furo[4,3,2-cd]
[1]benzofuran-2a,4a(3H,5H)-diol (4b)
(400 MHz, CDCl3)
d
ppm 0.96 (d, J ¼ 6.78 Hz, 3 H) 1.26 (ddd,
J ¼ 14.68, 12.17, 3.51 Hz, 1 H) 1.37 (dd, J ¼ 13.43, 12.42 Hz, 1 H) 1.60
(s, 2 H) 1.91e2.02 (m, 1 H) 2.02e2.09 (m, 1 H) 2.13 (s, 3 H) 2.72 (d,
J ¼ 6.78 Hz, 1 H) 3.02 (s, 1 H) 3.70 (ddd, J ¼ 9.54, 2.76, 0.70 Hz, 1 H)
4.22 (ddd, J ¼ 6.65, 3.89, 2.26 Hz,1 H) 4.27 (dd, J ¼ 9.64, 2.76 Hz,1 H)
4.38 (d, J ¼ 9.64 Hz, 1 H) 4.51 (d, J ¼ 9.54 Hz, 1H) ppm; 13C NMR
Sodium hydroxide (1.2 g, 30% solution, 9.4 mmol) was added at
0e2 ꢀC to a solution of dihydroxy-acetone dimer (DHA, 8.5 g,
47 mmol), water (440 mL) and (R)-5-methylcyclohex-2-enone 3b
(10.3 g, 94 mmol according to NMR quantification). After 15 h at
0e2 ꢀC (pH occasionally adjusted to 10e11 with NaOH), the tem-
perature was allowed to rise to RT. Once TLC analysis (EtOAc/MeOH
90/10, stained with vanillin/sulfuric acid in ethanol) showed full
conversion, acetic acid (about 0.5 mL) was added to set the pH to
5e6. The solution was evaporated to dryness (jacked 35 ꢀC), and the
crude oil was purified by silica gel chromatography (160 g). Elution
with EtOAc/MeOH gradient 95/5 to 50/50, provided 4b in pure form
(16.5 g, 88% isolated yield). The stereochemistry has been estab-
lished by proton NMR, thanks to NOE correlations between the
axial proton on carbon 2, 3 and carbon 6 (which configuration is R,
as it is the case for (þ)-pulegone).
(101 MHz, CDCl3)
d ppm 171.14, 104.87, 93.12, 78.39, 77.90, 77.36,
76.36, 55.01, 44.24, 36.50, 22.96, 21.42, 21.13.
4.7. (3S,3aS,4R,6S,7aR)-3-(hydroxymethyl)-6-
methyloctahydrobenzofuran-3,4-diol (5b)
Sodium borohydride (0.43 g) was added portionwise at 0 ꢀC to an
aq. solution of compound 4b (prepared from 1.2
g (R)-5-
methylcyclohex-2-enone and DHA, and neutralisation with acetic
acid). After 3 h stirring at 0e2 ꢀC and full conversion according to
NMR and TLC, acetic acid (about 1 g) was added to destroy the
excess of reagent. The resulting mixture was concentrated to
½
a 2D0
ꢃ
þ8.33ꢀ (c 1.9, MeOH); HRMS calcd for C11H17O6 [MþHCOO]-
245.10251, found 245.10306; IR: 3390 n(OH) 2953, 2929, 2871 n(CH
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B. Riss et al. / Tetrahedron xxx (2017) 1e11
7
dryness leaving 2.3 g of a yellowish residue. The latter was purified
by silica gel chromatography (150 g), eluted with ethyl acetate/
methanol 90/10, providing compound 5b (1.6 g, 74%) as a colorless
solid.
purified through a pad of silica gel (200 g) eluted with heptane/
ethyl acetate 8:2, providing 12.8 g of 10b as a colorless oil (about
80% overall yield from 3b, ee > 96% according to GC on a 25 m
HYDRODEX-b
-TBDMS column, gradient: 80e200 ꢀC in 60 min. RT:
½
a 2D0
ꢃ
ꢁ8.17ꢀ (c 2.6, MeOH); HRMS calcd for C11H19O6 [MþHCOO]-
40.7 min for 10b and 41.8 min for the enantiomer).
247.11816, found 247.11876; 1H NMR (600 MHz, DMSO-d6) ppm:
5.01 (s, 1H) 4.67 (s, 1H) 4.65 (s, 1H) 4.31e4.27 (m, 1H) 3.70 (d,
J ¼ 9.4 Hz, 1H) 3.62 (d, J ¼ 11.6 Hz, 1H) 3.48e3.44 (m, 2H) 3.31e3.27
(m, 1H) 1.82e1.76 (m, 1H) 1.74e1.70 (m, 1H) 1.60e1.51 (m, 2H) 1.03
(td, 1H) 0.85 (d, J ¼ 6.6 Hz, 3H) 0.84e0.77 (m, 1H); 13C NMR
(151 MHz, DMSO-d6), ppm: 77.69, 75.25, 69.80, 66.79, 64.94, 54.76,
43.05, 36.34, 24.95, 21.73.
½
a 2D0
ꢃ
ꢁ11.5 (c 2, acetonitrile); HRMS calcd for C15H29O3Si [MH]þ
285.18859; found 285.18850. 1H NMR (400 MHz, CDCl3)
d ppm 0.02
(d, J ¼ 2.01 Hz, 6 H) 0.89 (s, 9 H) 0.98 (d, J ¼ 6.53 Hz, 3 H) 1.08 (ddd,
J ¼ 13.00, 12.50, 11.30 Hz, 1 H) 1.26 (ddd, J ¼ 15.30, 12.00, 3.00 Hz,
1 H) 1.80e1.95 (m, 2 H) 1.96e2.07 (m, 1 H) 2.15 (dd, J ¼ 9.29,
4.27 Hz, 1 H) 3.77 (ddd, J ¼ 11.11, 9.10, 4.14 Hz, 1 H) 3.85 (d,
J ¼ 17.07 Hz, 1 H) 4.18 (d, J ¼ 17.32 Hz, 1 H) 4.26e4.32 (m, 1 H). 13
C
NMR (101 MHz, CDCl3)
d
ppm ꢁ4.98, ꢁ4.69, 17.75, 21.70, 25.50,
25.60, 35.49, 42.75, 54.76, 67.69, 71.16, 78.26, 213.59.
4.8. (3aS,4R,6S,7aR)-4-hydroxy-6-methyl-hexahydro-benzofuran-
3(2H)-one (6b and minor isomer)
4.10. (2R,3aR,4R,6R,7aR)-4-((tert-butyldimethylsilyl)oxy)-2-(1-
hydroxy-3-methylbut-2-en-1-yl)-6-methyl-hexahydrobenzofuran-
3(2H)-one (11b)
A solution of (R)-5-methylcyclohex-2-enone (5.7 g, 25.4 mmol),
DHA (4.6 g, 50.8 mmol) and NaOH (0.2 g, 0.1 eq) in water (250 mL),
was hold ca. 20 h at 0 ꢀC. After full conversion according to NMR,
acetic acid (0.25 mL) was added, followed by NaBH4 (0.97 g). Again,
after 4 h stirring at 0 ꢀC and full conversion according to NMR, acetic
acid (3.5 mL) was added to destroy the excess of reagent. Then after
neutralisation with NaOH (4 mL 10% solution, pH 7), sodium peri-
odate (3.9 g) was added portionwise in such a way to keep the
temperature between 15e25 ꢀC. After 15 h at 20 ꢀC and full con-
version according to NMR and TLC, the solid formed was removed by
filtration, and washed with ethyl acetate (50 mL). After phase split,
and three additional extraction with ethyl acetate (30 mL each), the
organic phase was evaporated to dryness leaving 7.9 g of a viscous oil
(91% yield, as an 85:15 mixture of diastereomers). An aliquot (0.7 g)
was submitted to a silica gel chromatography (75 g SiO2, eluent
heptane/MTBE: 50/50), providing the two isomers of compound 6b
in pure form.
Compound 10b (3.0 g) in anhydrous THF (6 mL) was added
dropwise at ꢁ78 ꢀC to a solution of LDA (prepared with 1.7 g diiso-
propylamine in 30 mL THF and 7.4 mL n-butyl-lithium 1.6 M in hex-
ane). After 10 min at ꢁ78 ꢀC, freshly distilled senecialdehyde (1.4 mL)
diluted in THF (5 mL) was added dropwise within 10 min, in such a
way to keep the temperature below ꢁ75 ꢀC. After 20 min stirring,
acetic acid (16.7 g, 5% in water) was added rapidly, and the solution
was allowed to warm to RT. After removal of the THF by distillation
under reduced pressure and extraction with MTBE (3 ꢂ 50 mL), pu-
rification of the crude oil by column chromatography (120 g SiO2,
eluent heptane/ethyl acetate 95:5, 750 mL, then 90:10, 750 mL) left
2.0 g of a clear colorless oil (55% as a 1:1 isomeric mixture).
HRMS calcd for C20H33O3Si [MH-(H2O-H2)]þ 349.2198, found
349.2577; 1H NMR (400 MHz, CDCl3)
d ppm 0.01 (m, 6 H) 0.86e0.88
Main isomer (4R-epimer): 0.56 g, crystalline solid (needle
(m, 9 H) 0.96 (dd, J ¼ 6.53, 2.26 Hz, 3 H) 0.98e1.13 (m,1 H) 1.17e1.33
(m, 2 H) 1.69 (dd, J ¼ 11.30, 1.00 Hz, 3 H) 1.73 (s, 3 H) 1.77e1.91 (m,
1 H) 1.93e2.09 (m, 1 H) 2.17e2.24 (m, 1 H) 3.69e3.79 (m, 1 H)
3.97e4.01 and 4.06e4.10 (m, 1 H) 4.44e4.50 and 4.69e4.76 (m, 1 H)
4.57e4.64 (m, 1 H) 5.30 [(dt, J ¼ 9.03, 1.38 Hz) þ 5.39 (ddt, J ¼ 9.10,
2.82, 1.32, 1.32 Hz), 1 H].
shaped) mp 80e82 ꢀC; ½a D20
ꢃ
þ6.46ꢀ (c 1.9, MeOH); HRMS calcd for
C9H14O3Na [MþNa]þ 193.0840, found 193.085; 1H NMR (600 MHz,
DMSO-d6) ppm: 4.86 (s, 1H) 4.25 (dd, J ¼ 3.4 Hz, 1H) 4.16 (d,
J ¼ 16.9 Hz, 1H) 3.76 (d, J ¼ 16.9 Hz, 1H) 3.53e3.46 (m, 1H) 2.00 (dd,
J1 ¼ 9.7 Hz, J2 ¼ 4.3 Hz, 1H) 1.87e1.82 (m, 1H) 1.79e1.75 (m, 1H)
1.75e1.66 (m, 1H) 1.20 (td, J1 ¼14.6 Hz, J2 ¼ 12.2 Hz, J3 ¼ 3.7 Hz, 1H)
0.93 (q, J ¼ 11.8 Hz, 1H) 0.90 (d, J ¼ 6.6 Hz, 3H). 13C NMR (151 MHz,
DMSO-d6), ppm: 214.5, 77.66, 70.70, 65.55, 53.99, 42.67, 35.33,
25.57, 21.77.
4.11. (3aR,4R,6R,7aR,Z)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-
2-(3-methylbut-2-en-1-ylidene)-hexahydro-benzofuran-3(2H)-one
(12b)
Minor isomer (4S-epimer): 57 mg (gel) ½a D20
ꢃ
þ68.09ꢀ (c 2.4,
methanol). 1H NMR (400 MHz, D2O) ppm: 0.81 (t, J ¼ 7.53 Hz, 1H)
0.87 (d, J ¼ 6.53 Hz, 3H) 1.14e1.20 (m, 1H) 1.21e1.38 (m, 1H)
1.39e1.48 (m, 1H) 1.73e1.81 (m, 1H) 2.46 (t, J ¼ 5.27 Hz, 1H) 3.51 (t,
J ¼ 6.65 Hz, 1H) 3.87 (d, J ¼ 17.32 Hz, 1H) 3.97 (d, J ¼ 17.57 Hz, 1H)
4.21e4.26 (m, 1H) 4.35e4.40 (m, 1H).
A solution of trifluoroacetic anhydride (3.8 mL, 26.9 mmol, 3 eq.)
in dichloromethane (30 mL) was added dropwise within 1 h at 0 ꢀC
to a solution of compound 11b (3.3 g, 8.9 mmol, 1 eq.), dichloro-
methane (60 mL), triethylamine (7.5 mL, 53.7 mmol, 6 eq.) and
DMAP (109 mg, 0.9 mmol, 0.1 eq.). The mixture was heated to 24 ꢀC
and stirred for 38 h. After full conversion according to GC, NaHCO3
(50 mL) and MTBE (30 mL) was added, and the layers were sepa-
rated. The organic layer was washed with distilled water
(2 ꢂ 50 mL) and concentrated under vacuum. The crude oil was
purified through a pad of silica gel, eluted with heptane/ethyl ac-
etate 8:2, providing 12b (2.8 g, 86%) as a yellowish oil.
4.9. (3aR,4R,6R,7aR)-4-((tert-butyldimethylsilyl)oxy)-6-
methylhexahydrobenzofuran-3(2H)-one (10b)
Tert-butyldimethylsilyl-trifluoromethane-sulfonate (19.3 g,
73 mmol, 1.1 eq.) was added dropwise at 0 ꢀC to a crude mixture of
compound 6b (11.3 g, isomeric ratio 85:15, 66 mmol of 6b) anhy-
drous THF (120 mL) and imidazole (11.3 g, 165 mmol, 2.5 eq.). After
2 h at 0 ꢀC, sodium bicarbonate (50 mL, 10% solution) was added
and the mixture was partially concentrated under reduced pressure
to remove the THF. The resulting mixture was extracted with ethyl
acetate (3 ꢂ 150 mL) and the combined organic layers were washed
with water (2 ꢂ 50 mL), dried over sodium sulfate and concentrated
under reduced pressure, leaving 35 g of an orange oil. The latter was
HRMS calcd for C20H35O3Si [MH]þ 351.2355, found 351.2354; 1H
NMR (400 MHz, CDCl3)
d ppm 0.00 (s, 3 H) 0.03 (s, 3 H) 0.88e0.90
(m, 9 H) 0.99 (d, J ¼ 6.50 Hz, 3 H) 1.05e1.16 (m, 2 H) 1.30e1.40 (m,
2 H) 1.86 (dd, J ¼ 13.30, 1.00 Hz, 6 H) 2.13 (ddt, J ¼ 15.03, 3.61, 1.98,
1.98 Hz, 1 H) 2.36 (dd, J ¼ 8.53, 5.02 Hz, 1 H) 3.71 (ddd, J ¼ 10.48,
8.60, 4.27 Hz, 1 H) 4.53 (ddd, J ¼ 5.33, 3.45, 2.51 Hz, 1 H) 6.12 (dq,
J ¼ 12.05,1.25 Hz,1 H) 6.27 (d, J ¼ 12.05 Hz,1 H). 13C NMR (101 MHz,
CDCl3) ppm: ꢁ4.72, ꢁ4.62, 17.98, 18.84, 21.86, 25.80, 25.87, 26.64,
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8
B. Riss et al. / Tetrahedron xxx (2017) 1e11
31.89, 35.56, 42.15, 54.21, 69.01, 78.45, 103.34, 118.41, 142.91, 199.23.
suspension was filtered through a pad of silica gel, eluted with ethyl
acetate and concentrated under vacuum, providing 50 mg (50%) of
compound 15 as a yellowish solid.
4.12. (3S,3aR,4R,6R,7aR,Z)-4-((tert-butyldimethylsilyl)oxy)-3,6-
dimethyl-2-(3-methylbut-2-en-1-ylidene)-octahydrobenzofuran-3-
ol (13b)
½
a 2D0
ꢃ
þ28 (c 0.25, acetonitrile); mp 99e100 ꢀC; HRMS calc for
C
15H22O3Na [MþNa]þ 273.1466, found 273.1461; 1H NMR (400 MHz,
CDCl3)
d
ppm 1.06 (d, J ¼ 6.53 Hz, 3 H) 1.46 (d, J ¼ 0.75 Hz, 3 H) 1.66
Methylmagnesium-bromide (5.7 mL, 1.6 M in Et2O, 17.1 mmol, 3
eq.) was added dropwise at 0 ꢀC to a slurry of compound 12b (2 g,
5.7 mmol, 1 eq.) and cerium chloride (2.1 g, 17.1 mmol, 1.5 eq.
weighted in a glove box under an inert and dry atmosphere) in
anhydrous tetrahydrofuran (80 mL) previously stirred 1 h at RT
before being cooled to 0 ꢀC. After 45 min and full conversion ac-
cording to GC and TLC, the reaction was quenched by addition of a
10% solution of NaHCO3 (30 mL). THF was removed under vacuum
and the aqueous residue was extracted with MTBE (3 ꢂ 100 mL).
The combined organic layers were washed with distilled water
(2 ꢂ 30 mL) and concentrated under vacuum, leaving 2.1 g of a
yellowish oil which was purified by flash chromatography on silica
gel (75 g) eluted with heptane/ethyl acetate 95:5, providing 1.5 g
(72%) of a pale yellow oil.
(ddd, J ¼ 14.62, 11.11, 3.64 Hz, 1 H) 1.72 (d, J ¼ 0.75 Hz, 3 H) 1.78 (s,
3 H) 2.01e2.09 (m, 1 H) 2.19e2.28 (m, 1 H) 2.28e2.36 (m, 1 H) 2.42
(ddd, J ¼ 13.43, 3.39, 2.01 Hz, 1 H) 2.55 (d, J ¼ 5.27 Hz, 1 H) 4.77 (dt,
J ¼ 5.08, 3.48 Hz, 1 H) 5.34 (d, J ¼ 0.75 Hz, 1 H) 5.40 (d, J ¼ 11.54 Hz,
1 H) 5.97 (ddt, J ¼ 11.45, 2.79, 1.29, 1.29 Hz, 1 H). 13C NMR (101 MHz,
CDCl3)
d ppm 18.19, 21.50, 26.00, 27.58, 28.39, 36.12, 50.19, 55.92,
77.23, 78.87, 93.66, 109.98, 117.83, 131.63, 213.85.
4.15. (3S,3aS,6R,7aR,Z)-3,6-dimethyl-2-(3-methylbut-2-en-1-
ylidene)-3-((trimethylsilyl)oxy)hexahydro -benzofuran-4(2H)-one
(16)
1-(Trimethylsilyl)imidazole (0.07 mL) and TMS-Chloride (4 mL)
was added to a solution of compound 15 (4 mg) and imidazole
(18.3 mg) in dimethylformamide (0.7 mL). After 1 h stirring at RT,
and full conversion (TLC, LC/MS), the solution was diluted with
ethyl acetate (10 mL) and treated with sat. sodium bicarbonate
(10 mL). After phase split, the org. phase was diluted with n-hep-
tane (5 mL) and washed with water (2 ꢂ 10 mL). Concentration to
dryness, left 5 mg (>99%) of a colorless residue which crystallized
on the recipient walls.
½
a 2D0
CH3]þ 351.2355, found 351.2360; 1H NMR (400 MHz, BENZENE-d6)
ꢃ
ꢁ1.57 (c 1, acetonitrile); HRMS calcd for C20H35O3Si [M-
d
ppm 0.02 (d, J ¼ 2.76 Hz, 6 H) 0.78 (s, 9 H) 0.86 (d, J ¼ 6.78 Hz, 3 H)
0.91 (q, J ¼ 12.00 Hz, 1 H) 1.01e1.10 (m, 1 H) 1.36 (br s, 3 H) 1.47 (s,
1 H) 1.63 (br s, 3 H) 1.66 (dd, J ¼ 9.28, 4.26 Hz, 1 H) 1.68 (s, 3 H)
1.73e1.81 (m, 1 H) 2.00 (ddt, J ¼ 14.81, 3.83, 1.98, 1.98 Hz, 1 H) 3.86
(ddd, J ¼ 11.80, 9.29, 4.27 Hz, 1 H) 4.02 (s, 1 H) 4.28e4.33 (m, 1 H)
5.29 (d, J ¼ 11.54 Hz,1 H) 5.92 (ddt, J ¼ 11.45, 2.73,1.32,1.32 Hz,1 H).
1H NMR (400 MHz, CDCl3)
d ppm 0.03 (s, 9 H) 0.90 (d,
13C NMR (101 MHz, BENZENE-d6)
d
ppm ꢁ4.55, ꢁ2.92, 17.73, 17.85,
J ¼ 7.28 Hz, 3 H) 1.67 (d, J ¼ 0.75 Hz, 3 H) 1.75 (s, 3 H) 1.92 (br dd,
J ¼ 13.30, 6.02 Hz,1 H) 2.02e2.11 (m, 2 H) 2.33 (br d, J ¼ 3.51 Hz,1 H)
2.46 (dd, J ¼ 16.44, 5.40 Hz, 1 H) 2.64 (d, J ¼ 8.78 Hz, 1 H) 4.67 (td,
J ¼ 8.91, 6.27 Hz, 1 H) 5.23 (d, J ¼ 11.0 Hz, 1 H) 5.97 (dm, J ¼ 11.0 Hz,
1 H).
21.44, 25.18, 25.65, 25.80, 29.02, 36.28, 42.45, 54.19, 70.97, 77.81,
79.40, 94.20, 119.56, 128.58,160.35.
4.13. (3S,3aS,4R,6S,7aR,Z)-3,6-dimethyl-2-(3-methylbut-2-en-1-
ylidene)octahydrobenzofuran-3,4-diol (14b)
4.16. (3S,3aS,7aR,Z)-3,6-dimethyl-2-(3-methylbut-2-en-1-ylidene)-
3-((trimethylsilyl)oxy)-3,3a,7,7a-tetrahydro-benzofuran-4(2H)-one
(TMS-ent-bisabolangelone, 17)
Tetra-n-butylammonium fluoride (2.9 mL, 1 M in THF, 1.2 eq.)
was added to a solution of compound 13b (0.9 g, 1 eq.) in anhydrous
THF (50 mL) at 0 ꢀC under an inert atmosphere. After 30 min stir-
ring at 0 ꢀC, NaHCO3 (30 mL, 10% solution) was added. THF was
removed by distillation under reduced pressure, and the aqueous
residue extracted with MTBE (2 ꢂ 100 mL). The combined organic
layers were washed with water (2 ꢂ 20 mL) and concentrated
under vacuum to afford 1.4 g of a brownish oil, which was purified
by column chromatography, eluted with heptane/ethyl acetate 8:2
to 6:4 providing 0.5 g (90%) of a colorless solid.
A solution of compound 16 (5 mg, 1 eq.) in anhydrous THF
(0.5 mL) was added dropwise at ꢁ78 ꢀC to a solution of LDA, pre-
pared by addition of nBuLi (1 M in hexane, 2.2 eq.) to a solution of
diisopropylamine (2.4 eq.) in anhydrous THF (0.5 mL) at 0 ꢀC under
argon. After 10 min stiring at ꢁ78 ꢀC, a solution of N-tert-butyl-
benzenesulfinimidoyl chloride (3 eq.) in anhydrous THF (0.5 mL)
was added dropwise and the mixture kept stirring for
50 min at ꢁ78 ꢀC. The reaction was quenched by addition of a
saturated solution of NH4Cl and ethyl acetate. The layers were
separated, washed with water and concentrated under vacuum. LC/
MS, GC and TLC showed that only 20% conversion took place. The
crude residue was passed through a pad of silica gel (0.5 g), eluted
with heptane/ethyl acetate 8:2. Despite poor separation of the
excess of reagent, LC/MS, GC and NMR (same retention time and
NMR signals as (þ)-TMS-bisabolangelone 21 described ibid) led to
the conclusion that the desired enone 17 has been formed. Unfor-
tunately, unsufficient material was available for full characterisa-
½
a 2D0
ꢃ
ꢁ28 (c 0.5, acetonitrile); mp 84e85 ꢀC; HRMS calcd for
C
15H25O3 [MH]þ 253.1803, found 253.1797; 1H NMR (400 MHz,
CDCl3)
d
ppm 0.86 (m, 1H) 0.97 (d, J ¼ 6.53 Hz, 3 H) 1.00 (q,
J ¼ 12 Hz,1 H) 1.18 (m, 1 H) 1.52 (s, 3 H) 1.73 (d, J ¼ 0.75 Hz, 3 H) 1.76
(dd, J ¼ 9.28, 4.26 Hz, 1 H) 1.78 (s, 3 H) 1.87 (m, 1 H) 2.13 (m, 1 H)
2.84 (s, 1 H) 3.09 (s, 1 H) 3.77 (dddd, J ¼ 11.80, 9.30, 4.30, 1.20 Hz,
1 H) 4.38 (m, 1 H) 5.32 (d, J ¼ 11.29 Hz, 1 H) 6.01 (ddt, J ¼ 11.23, 2.82,
1.38, 1.38 Hz, 1 H). 13C NMR (101 MHz, CDCl3)
d ppm 18.20, 21.61,
25.27, 25.97, 28.42, 36.46, 40.55, 54.54, 68.61, 78.58, 80.77, 93.57,
117.85, 131.18, 159.87.
tion, but, GC on a chiral columns HYDRODEX-g-TBDAc and LIPODEX
4.14. (3S,3aS,6R,7aR,Z)-3-hydroxy-3,6-dimethyl-2-(3-methylbut-2-
en-1-ylidene)hexahydro-benzo-furan-4(2H)-one (15)
E, allowed us to attribute compound 17 and (þ)-TMS-bisabo-
langelone (section 4.19) to one distinct peak of a racemic sample,
obtained by synthesis from rac. 5-methylcyclohexenone.
A solution of compound 14b (100 mg, 2 mmol) in acetonitrile
(1 mL) was added to a suspension of tetra-n-propylammonium
perruthenate (TPAP, 28 mg, 0.08 mmol), N-Methyl-morpholine N-
oxide (NMO, 93 mg, 0.8 mmol) and 4 Å powdered molecular sieves
(0.4 g) in dichloromethane (5 mL) stirred under an inert atmo-
sphere. After 1 h and full conversion according to GC and TLC, the
4.17. (R)-3,6-dimethyl-2-(3-methylbut-2-en-1-yl)-6,7-
dihydrobenzofuran-4(5H)-one (18)
Trimethylsilyl-chloride (0.35 mL, 3 eq.) was added at 0 ꢀC to a
suspension of compound 16 (230 mg, 1 eq.) imidazole (187 mg, 3
Please cite this article in press as: Riss B, et al., Total synthesis of TMS-ent-bisabolangelone, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.04.042

B. Riss et al. / Tetrahedron xxx (2017) 1e11
9
eq.) and DMF (0.3 mL) in acetonitrile (5 mL) under an inert atmo-
sphere of argon. The mixture was stirred 1 h at 0 ꢀC and 3 h at RT,
and quenched subsequently by addition of a saturated solution of
NaHCO3 (5 mL). Acetonitrile was removed by distillation under
reduced pressure and the aqueous layer was extracted with ethyl
acetate (3 ꢂ 20 mL). The combined organic layers were washed
with water (2 ꢂ 10 mL) and concentrated under vacuum. The crude
oil was purified over a pad of silica gel, eluted with heptane/ethyl
acetate 1:1, providing 75 mg (35%) of compound 18 as yellowish oil,
which solidified on standing.
Material
Bisabolangelone (area %)
Bisabolangelone (weight %)
Seeds
Stem
Leaves
Roots
2.4
1.4
0.02
0.3
3.17
14.7
8.6
0.06
4.19. (3R,3aR,7aS,Z)-3,6-dimethyl-2-(3-methylbut-2-en-1-
ylidene)-3-((trimethylsilyl)oxy)-3,3a,7,7a -tetra-hydrobenzofuran-
4(2H)-one, (þ)-TMS-bisabolangelone (21)
HRMS calcd for C15H21O2 [MH]þ 233.1541, found: 233.1536; 1H
NMR (600 MHz, CDCl3)
d
ppm 1.15 (d, J ¼ 6.60 Hz, 3 H) 1.72 (d,
J ¼ 7.34 Hz, 6 H) 2.14 (s, 3H) 2.15e2.23 (m, 1 H) 2.35e2.43 (m, 1H)
2.44e2.52 (m, 2 H) 2.88 (dd, J ¼ 16.69, 4.95 Hz, 1 H) 3.25 (br d,
J ¼ 7.34 Hz, 2 H) 5.20e5.26 (m, 1 H). 13C NMR (151 MHz, CDCl3)
Bisabolangelone (10 mg) and imidazole (5 mg) were dissolved in
dimethylformamide (1 mL). TMS-imidazole (0.1 mL) and TMS-Cl
(0.01 mL) were added subsequently at RT. After 30 min stirring LC/
MS, GC and TLC showed full conversion. After dilution with ethyl
acetate, quench with water (10 mL), phase split, wash with sat.
NaHCO3 and brine (5 mL each), provided after concentrated to dry-
ness 12 mg (93%) of a yellowish oil which crystallized from heptane.
d
ppm 8.65, 17.61, 20.95, 24.54, 25.50, 30.69, 31.44, 46.63, 112.04,
119,29, 120.52, 133,51, 150.39, 165.02, 195.22.
4.18. Isolation of bisabolangelone from Angelica silvestris L.
Mp 95e96 ꢀC, ½a 2D0
þ82.5 (c 1, acetonitrile); HRMS calcd for
ꢃ
C
18H28NaO3Si [MþNa]þ 343.1705, found 343.1698; 1H NMR
Fruits, leaves and roots from Angelica silvestris, were harvested
August 1st, 2014, along the Rhine river banks between Basel's
border and Huningue's pedestrian bridge in France. 400 g fresh
seeds (fruits) were dried in a vacuum oven at 40 ꢀC and 50 mbar
during 3 days, leaving about 123 g of dry material. This substrate
was subsequently powdered with a kitchen mixer to yield a fine
brownish powder. 100 g seed powder, suspended in 500 g aceto-
nitrile (HPLC grade), was submitted to ultra-sonication at
20e30 ꢀC and alternate stirring for 6 h. The solid was separated by
filtration, and submitted to a second extraction with 250 g
acetonitrile. After a second round of sonication, the clear green
filtrate was extracted twice with 200 g heptane fractions. Both
layers were concentrated separately leaving: 3.6 g of an oily res-
idue for the heptane fraction which contains little bisabolange-
lone, and 7.6 g for the acetonitrile fraction which contains about
25% bisabolangelone (HPLC A%). The solid residue from acetoni-
trile was subsequently dissolved in 50 mL MTBE, and aged at 5 ꢀC
for 48 h. After this time the solid formed was collected leaving
1.58 g of crude bisabolangelone (70% content). The later was dis-
solved in 5 g methanol under reflux, filtered for clarity and let
crystallize at RT. The solid formed was collected by filtration,
washed with cold methanol and dried under vacuum, leaving
0.44 g colorless crystals of bisabolangelone (>98% purity by HPLC
A%).
(400 MHz, BENZENE-d6)
d ppm 0.07 (s, 9 H) 1.35 (s, 3 H) 1.68 (d,
J ¼ 3.26 Hz, 6 H) 1.74 (s, 3 H) 2.18 (dd, J ¼ 17.57, 7.53 Hz, 1 H) 2.43 (d,
J ¼ 8.78 Hz, 1 H) 2.56 (ddt, J ¼ 17.47, 8.63, 1.25, 1.25 Hz, 1 H) 4.39 (q,
J ¼ 8.20 Hz, 1 H) 5.44 (d, J ¼ 11.04 Hz, 1 H) 5.91 (s, 1H) 6.52 (dm,
J ¼ 11.46 Hz, 1 H). 13C NMR (151 MHz, BENZENE-d6)
d ppm 1.75,
2.32, 18.45, 24.07, 25.03, 26.53, 36.87, 57.23, 77.72, 81.35, 96.35,
119.85, 131.75, 157.32, 158.51, 194.25.
4.20. Chiral GC conditions
GC apparatus HP6890, injector 260 ꢀC, detector 200 ꢀC, H2 flow
1.5 mL min, pressure 0.52 bar, mode: split 1:10, injection 1
Column HYDRODEX-
ml.
g
-TBDAc (Macherey-Nagel), 25 m ꢂ 0.25 mm,
temperature program: 140 ꢀC for 130 min then 200 ꢀC within
12 min. Diluted samples (ca. 0.1% in MTBE) of compound 17,
racemic mixture (obtained by synthesis starting with rac. 5-
methyl-cyclohexenone) and TMS-bisabolangelone 21, were injec-
ted single or mixed accordingly to check the increase of the cor-
responding peak.
4.21. (3R,3aR,4R,6S,7aS,Z)-3,6-dimethyl-2-(3-methylbut-2-en-1-
ylidene)octa-hydrobenzofuran-3,4-diol, 5,6-dihydro-bisabolangelol
(19)
Spectral data's were consistent with those previously reported.1
LC/MS [MH]þ 249; UV max. 248 nm, ½a 2D0
ꢃ
þ148 (c 1, acetonitrile),
Sodium borohydride (80 mg) was added in small portions
within 30 min to a cold solution (0 ꢀC) of bisabolangelone (250 mg)
dissolved in anhydrous methanol (15 mL). After 3 h, the reaction
was over according to HPLC (one peak) and TLC (two spots). After
acidification with acetic acid and work up with MTBE/NaHCO3, we
got after concentration to dryness 200 mg of a residue which was
purified by column chromatography (10 g SiO2, eluent Heptane/
MTBE 3:2), providing 31 mg (12%) of a less polar compound
(amorphous solid) which correspond to the 1,2-reduction product
(obtained by Chen et al.30 as the main product) and 81 mg (32%) of
compound 19 obtained as a colorless solid.
½
a 2D0
ꢃ
þ85 (c 1, CHCl3), lit.31
½
a 2D0
ꢃ
þ111 (c 1.1, CHCl3). The discrep-
ancies between the opt. rotations in chloroform may be explained
by the rapid decomposition of bisabolangelone in this solvent. The
content of bisabolangelone has been determined by HPLC in
different parts of the plant (table below). Equipment: Agilent 1200,
column: Waters Acquity BEH Phenyl, particle size: 1.7 mm, length:
50 mm internal diameter: 2.1 mm, column temperature: 45 ꢀC;
mobile phase A: water/acetonitrile/TFA: 95/5/0.05 (v), B: water/
acetonitrile/TFA: 5/95/0.05 (v). Gradient: T0 5% B, T0.75 5% B, T4.75
60% B, T5.75 95% B, T6.51 5% B, T7.50 5% B. Flow rate: 0.6 mL/min. Run
time: 7.5 min. Injection volume: 1
ml. Detection: UV, wavelength
HRMS calcd for C15H25O3 [MH]þ 253.1803, found 253.1797, calcd
220 nm. Sample preparation: 1 g dry powdered material (seeds,
stem pieces, leaves and roots) were subjected to ultra-sonication
with 10 mL THF for 5 min. 1 mL supernatant was transferred in
an HPLC vial, and injected as it. Quantification was made by com-
parison with a reference solution of bisabolangelone in acetonitrile
for
C
15H24NaO3 [MþNa]þ 275.1623, found 275.1618; mp
142e143 ꢀC (lit.30 140e142 ꢀC, lit.31 135e137 ꢀC). Notice, the opt.
rotation could not be measured with accuracy. The value: ꢁ11.6ꢀ
obtained, is not reliable due to the fast decomposition of the sub-
strate in chloroform. Lit.31
DMSO-d6)
½
a D
ꢃ
20 -3.7 (c 1, CHCl3). 1H NMR (600 MHz,
(5.6 mg in 5 mL, inj. 1
m
L, RT 4.3 min).
d
ppm 0.89 (br d, J ¼ 6.05 Hz, 3 H) 1.28e1.43 (m, 2 H) 1.50
Please cite this article in press as: Riss B, et al., Total synthesis of TMS-ent-bisabolangelone, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.04.042

10
B. Riss et al. / Tetrahedron xxx (2017) 1e11
(s, 3 H) 1.51e1.62 (m, 2 H) 1.64 (s, 3 H) 1.69 (br d, J ¼ 5.14 Hz, 1 H)
1.72 (s, 3 H) 2.18 (br t, J ¼ 6.97 Hz, 1 H) 3.92 (dq, J ¼ 11.39, 5.74 Hz,
1 H) 4.29 (dt, J ¼ 10.09, 6.97 Hz, 1 H) 4.47 (br d, J ¼ 5.69 Hz,1 H) 4.49
(s, 1 H) 5.14 (d, J ¼ 11.19 Hz, 1 H) 5.91 (br d, J ¼ 11.37 Hz, 1 H) 13C
(m, 2 H) 2.31 (t, J ¼ 7.03 Hz, 1 H) 3.21 (d, J ¼ 1.51 Hz, 1 H) 3.63 (s, 3 H)
4.35e4.45(m,1 H)5.23(d, J ¼ 11.29 Hz,1 H)5.41 (dt, J ¼ 11.54, 5.77 Hz,
1 H) 6.00 (br dd, J ¼ 11.29, 1.25 Hz, 1 H) 7.35e7.42 (m, 3 H) 7.52e7.59
(m, 2 H) 13C NMR (101 MHz, CDCl3)
d ppm 18.14, 21.52, 25.99, 26.34,
NMR (151 MHz, DMSO-d6)
d
ppm 18.19, 22.28, 26.13, 29.11, 37.89,
26.98, 28.51, 35.86, 37.18, 47.29, 55.68, 74.61, 78.23, 79.21, 94.94,
118.14, 127.03, 128.37, 129.57, 132.05, 160.26, 165.91.
40.16, 49.54, 68.97, 79.74, 92.91, 119.72.
NMR signals (HSQC) of tetrahydrobisabolangelol 19 and the corresponding MTPA-esters 22 (R and S)
Sample
Position
19
(R)-MTPA-ester, 22-(R)
(S)-MTPA-ester, 22-(S)
D d SꢁR
Hz
1H NMR
13C NMR30
21.8 ppm
1H NMR
d
ppm/Hz
388.8
13C NMR
1H NMR
d
ppm/Hz
398.8
13C NMR
6-CH3
7-H
5/7 ax
6-H
5/7 eq
5-H eq
3-CH3
19-CH3
18-CH3
4-OH
0.99 ppm
1.35
1.42
1.50
1.86
1.95
1.64
1.73
1.79
2.04
2.07
2.46
4.41
5.34
4.14
6.06
0.97
21.09 ppm
1.00
21.14 ppm
þ10.0
1.46
1.50
1.92
563.2
600.1
764.9
36.76
25.89
36.35
1.44
1.50
1.93
579.6
601.8
771.8
36.98
26.40
36.91
þ16.4
þ1.7
þ6.9
26.0
37.5
30.6
18.2
26.1
1.37
1.69
1.78
548.5
677.7
711.4
29.24
17.34
25.89
1.09
1.68
1.77
435.6
675.3
709.3
28.04
16.60
25.89
ꢁ113
ꢁ2.4
ꢁ2.1
3-OH
3a-H
7a-H
3.22
2.43
4.42
5.29
5.41
6.02
3.50
7.39
7.41
7.52
3.22
2.31
4.40
5.23
5.41
6.00
3.63
7.30
7.39
7.56
48.8
79.1
94.5
70.4
118.3
971.0
47.27
79.01
95.11
74.53
119.5
55.31
128.92
128.93
127.21
924.0
47.08
78.87
94.64
73.99
117.80
55.27
123.55
128.55
126.88
ꢁ47.0
ꢁ7.0
1768.5
2118.3
2165.4
2410.6
1401.8
2957.6
2963.5
3007.9
1762.0
2093.0
2166.0
2402.3
1451.4
2409.7
2963.4
3007.9
CH¼
ꢁ25.3
þ0.6
4-H
CH¼
ꢁ8.3
O-CH3
Ar. para
Ar. ortho
Ar.ortho
4.22. (3R,3aS,4R,6R,7aS,Z)-3-hydroxy-3,6-dimethyl-2-(3-
Acknowledgements
methylbut-2-en-1-ylidene)octahydro-benzofuran-4-yl (R)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate, (R)-MTPA ester 22(R)
The author's thanks Dr. Daniel Kaufmann, the heads of Chemical
and Analytical Development, for their encouragements and funding
of internships (NB, PF, SB, PP, and MG), those contributions were
essential to achieve this endeavor. We also express our deep grat-
itude to Regis Denay and Angelique Schneider for NMR in-
vestigations, Philippe Piechon and Trixie Wagner for X-Ray,
Christian Guena and Evelyne Muller for MS, Profs. Robert Boeck-
man, Dieter Seebach, Herbert Waldmann and my colleagues and
friends Fabrice Gallou, Benjamin Martin and Michael Parmentier
for their suggestions, helpful discussions and proof reading of this
manuscript.
(S)-MTPA-Cl (20
mL) was added to 7 mg diol 19 dissolved in
0.5 mL pyridine. The clear yellowish solution was kept at RT for 8 h.
After that time, HPLC showed full conversion. The solution was
quenched with diluted sodium bicarbonate solution (5 mL, 10%)
and extracted with MTBE (10 mL). After a second wash with water,
the org. phase was concentrated to dryness leaving about 12 mg of
the corresponding ester, which was used for HSQC-NMR in-
vestigations (caution: the S-Mosher acid chloride gives rise to the R-
Mosher ester, since there is a change in relative priority: CF3 is
lower than COCl but higher than COOR. The product was purified
afterwards by flash chromatography (1 g SiO2, eluent MTBE/Hep-
tane 2:8) providing 9 mg of a waxy solid.
References
1H NMR (400 MHz, CDCl3)
d
ppm 0.97 (d, J ¼ 6.02 Hz, 3 H) 1.37 (s,
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1H NMR (400 MHz, CDCl3)
d
ppm 1.00 (d, J ¼ 6.00 Hz, 3 H) 1.09 (d,
J ¼ 1.00 Hz, 3 H) 1.37e1.55 (m, 3 H) 1.68 (s, 3 H) 1.77 (s, 3 H) 1.89e1.97
Please cite this article in press as: Riss B, et al., Total synthesis of TMS-ent-bisabolangelone, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.04.042

B. Riss et al. / Tetrahedron xxx (2017) 1e11
11
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presence of triethylamnine (explaining the retrieval of SM after quench), and
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since carbon 3 is reported (S). This configuration matches with other related
natural products such as phyllaemblic acida (which configuration has been
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-bisabololb (determined by derivati-
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Universite Louis Pasteur (Strasbourg, France), 1988.
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acetonitrile instead of DMF (due to the poor solubility of imidazole in this
solvent).
20. The
a
/b
ratio of the hydroxyl group in position 4, is affected by the method of
ratio of 1:4, and RedAl, DIBAH
ratio of 4:1.
þ1.0. (c 7, methanol), was not further
reduction, with NaBH4 in water resulting in a
a/b
or super hydride in THF resulting in a
a
/b
33. Mukaiyama T, Matsuo J-I, Kitagawa H. A new and one-pot synthesis of a,b-
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ꢃ
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river Rhine between Basel (Switzerland) and Huningue (France), and TMS
protected with TMS-Cl/TMS-imidazole in dimethylformamide in presence of
excess imidazole. Bisabolangelone can be recovered in nearly quantitative
yield by removal of the TMS-protecting group under mild conditions (acetic
acid/THF/Water 1:1:1, 24 h at RT), which is a great improvement towards the
conditions applied for triethylsilyl-bisabolangelone,15 which require harsh
conditions (HF/pyridine) to be released.
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be performed with great care. Heating and concentration to dryness should be
avoided, since the residue of concentration, has an energy of decomposition
(DSC measurement) of approx. -95 kJ/kg starting at ca. 60ꢀC as well as a second
enthalpy of decomposition (approx. -75 kJ/kg) starting above 195ꢀC. The same
remark applies for the sulfoxide, which should not be heated “neat” as
mentioned by the authors. It is preferable to dilute it with a high boiling sol-
vent like tetraglyme or N-butyl-pyrrolidone as we did. At 140ꢀC, 50 mbar, the
desired cychohexenone can be recovered by distillation from the reaction
mixture leaving the sulphenic acid dimers in solution.
24. The synthesis of (R)-5-methyl-cyclohexenone has been addressed intensively
in our lab., without major breakthrough. None of the route described so far, are
suitable for scale up. Organocatalysis require high loading of expensive cata-
lyst. Use of a cheap chiral auxiliary (menthol) to build on an advanced inter-
mediate already used by Myersa and Colletb is lengthy and resolution by
crystallization tricky. Lipase desymetrisation of meso-cyclohexandiol was
attractive, but access to the required diol is not easy and isolation of the pure
cis isomer failed. Finally we developed the well-known chemistry based on the
35. The analysis was performed on a chiral column HYDRODEX-g-TBDAc, isotherm
at 140 ꢀC (RT: 117.2 and 118.8 min) and LIPODEX E, isotherm at 180 ꢀC
(inversed retention times at 34.2 and 34.6 min).
36. a) Ohtani I, Kusumi T, Kashman Y, Kakisawa H. A new aspect of the high-field
NMR application of Mosher's method. The absolute configuration of marine
triterpene sipholenol A. J Org Chem. 1991;56:1296e1298;
b) Hoye TR, Jeffrey CS, Shao F. Mosher ester analysis for the determination of
absolute configuration of stereogenic (chiral) carbinol carbons. Nature Pro-
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Please cite this article in press as: Riss B, et al., Total synthesis of TMS-ent-bisabolangelone, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.04.042