Synthesis of trans-β-Elemene

Article abstract of DOI:10.1002/ejoc.201800800

Highly efficient syntheses of the anti-cancer agent trans-β-elemene have been achieved by using the readily available (±)-limonene as starting material. The syntheses were achieved in only nine to eleven steps with good overall yields. The key step in these reaction sequences is a stereoselective radical cyclization, induced by titanocene chloride.

Full text of DOI:10.1002/ejoc.201800800

DOI: 10.1002/ejoc.201800800
Full Paper
Natural Product Synthesis
Synthesis of trans-ꢀ-Elemene
D. Benito Iglesias,[a] P. Herrero Teijón,[a] Rosa Rubio González,[a] and A. Fernández-Mateos*[a]
Abstract: Highly efficient syntheses of the anti-cancer agent achieved in only nine to eleven steps with good overall yields.
trans-ꢀ-elemene have been achieved by using the readily avail- The key step in these reaction sequences is a stereoselective
able ( )-limonene as starting material. The syntheses were radical cyclization, induced by titanocene chloride.
Introduction
rect position. The last stage involves an elongation of one
carbon atom.
Elemanes are a family of sesquiterpenes and are minor compo-
nents of the essential oils of numerous plants widely occurring
in nature. From a bioactive point of view, (–)-trans-ꢀ-elemene
(1; see Scheme 1) is the most important member of the ele-
mane group, owing to its extensive and potent antineoplastic
activity against a wide variety of tumours, including brain,
breast, liver, lung and prostate as well as other tumours resist-
ant to traditional drugs. This topic has been extensively re-
viewed by Adio.[1]
Despite the wide range of bioactivity of this sesquiterpene
family, there are few references regarding its synthesis, most of
which use related naturally occurring compounds as starting
materials.[1] In the case of ꢀ-elemene (1), some studies on its
synthesis have been reported,[2] however, most of these refer
to a Cope–Claisen rearrangement as the critical step.
Scheme 1. Retrosynthetic analysis of ꢀ-elemene (1).
In this paper we describe a convenient method for synthesis-
ing elemane 1 by using ( )-limonene (2) as the starting mate-
rial. This method can also be extended to the synthesis of other
elemanes, by using many available compounds related to
limonene as starting materials.
Results and Discussion
The first step was carried out by a selective reaction using
ozone at –78 °C in dichloromethane, followed by treatment of
the intermediate ozonide with methyl sulfide.[3] The yield of the
resulting ketoaldehyde 3 was 80 % (Scheme 2).
Retrosynthetic analysis, summarized in Scheme 1, suggests a
four-step sequence from the target molecule ꢀ-elemene (1) to
limonene (2), which is a readily available and affordable starting
material. In this approach, radical cyclization, promoted by
titanocene chloride, is the key step in the construction of the
elemane skeleton. According to the analysis, the draft synthesis
would consist of four general stages starting from limonene (2).
The first stage would involve the selective cleavage of one of
the double bonds, followed by an elongation of three carbon
atoms and transformation of the functional groups. The third
stage, which is decisive for the completion of this project,
would consist of a 6-exo radical cyclization, followed by elimina-
tion of the hydroxy group, promoted by titanocene chloride, to
generate cyclohexane and a terminal double bond in the cor-
Scheme 2. Reagents and conditions: i) O3, –78 °C, CH2Cl2; ii) Me2S, CH2Cl2,
80 %.
The second general stage was achieved by using a five-step
sequence starting from the ketoaldehyde 3: a) chemoselective
reduction with sodium borohydride, b) methylenation using the
Corey–Chaykovsky method, c) oxidation with pyridinium
chlorochromate (PCC), d) Horner–Wadsworth–Emmons elonga-
tion and e) reduction with LiAlH4. The overall yield for the series
of reactions was 50 % (Scheme 3).
[a] Departmento de Química Orgánica, Universidad de Salamanca,
Plaza de los Caídos s/n, 37008 Salamanca, Spain
E-mail: afmateos@usal.es
http://fcquimicas.usal.es
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800800.
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the reagent was added dropwise to the substrate over different
periods of time and at different temperatures.[5]
In all cases a mixture of cyclized and non-cyclized products
was obtained. The structure of the major compound isolated
has been identified as the alcohol 13 presented in Scheme 5.
Scheme 3. Reagents and conditions: a) NaBH4, –10 °C, 76 %; b) Me2SOCH2Na,
DMSO, 50 °C, 95 %; c) PCC, CH2Cl2, 89 %; d) (EtO)2POCNa(CH3)COOEt, Tol, 0 °C,
63 %; e) LiAlH4, Et2O, 0 °C, 87 %.
Scheme 5. Reaction of 8 with TiIII.
Although the overall yield was similar for all reaction condi-
tions, the shortest experiment gave the best yield of the cy-
clized product 13 (45 %). The spectroscopic analysis of this
product indicated that it is comprised of a mixture of two iso-
mers in a ratio of 5:1.
Conformational analysis of the cyclization of epoxy alcohol
8 showed that the most favourable intermediate, according to
bibliographic precedents, should be 8A,[6] which leads to the
unsaturated cyclic alcohol 13a as the major product
(Scheme 6). The minor isomer 13b must be generated from
the intermediate 8B. In both isomers there are three equatorial
substituents on the cyclohexane. The relative configuration of
the 13a isomer was confirmed by its conversion into ꢀ-ele-
mene.
The unsaturated epoxy alcohol 8 was also prepared by an
alternative route consisting of five steps from the ketoaldehyde
3: a) Horner–Wadsworth-Emmons chemoselective reaction,
b) reduction with lithium aluminium hydride, c) chemoselective
acetylation, d) oxidation with pyridinium chlorochromate and
e) methylenation. The overall yield of this series of reactions
was 66 % (Scheme 4).
Although the sequence shown in Scheme 6 provides the cy-
clic intermediate with the suitable configuration for obtaining
ꢀ-elemene (1), the yield of the titanocene-induced radical cycli-
zation was relatively low, which instigated the search for a more
efficient alternative, maintaining the strategy of the proposed
synthesis.
Radicals produced by the opening of epoxides with TiIII are
nucleophilic in nature, so double bonds conjugated to an elec-
tron-withdrawing group undergo addition more quickly and
more efficiently.[7] This induced us to test the unsaturated
epoxy ester 7 as a substrate for the cyclization reaction.
Cyclization of the epoxy ester 7 was affected by the addition
Scheme 4. Reagents and conditions: a) (EtO)2POCNa(CH3)COOEt, Tol, 0 °C,
92 %; b) LiAlH4, Et2O, 0 °C, 87 %; c) ClCOCH3, DMAP, pyr, 0 °C, 63 %; d) PCC,
CH2Cl2, 98 %; e) i. KOH, MeOH, room temp., ii. Me2SOCH2Na, DMSO, 90 %.
In both sequences, in all compounds the geometry of the of 2.2 equivalemts of titanocene chloride to 1 equivalent of
C=C double bond is represented as the E isomer. This assign- substrate for 1 minute at room temperature. The reaction mix-
ment is based on numerous precedents of Horner–Wadsworth- ture was treated with a saturated NaH2PO4 aqueous solution to
Emmons reactions with aldehydes as well as on the 1H NMR allow for ester hydrolysis and subsequent cyclization to give a
spectra.[4]
The third stage is key in the synthesis of ꢀ-elemene (1) by
this approach. It was carried out by starting with the unsatu-
rated epoxy alcohol 8 and titanocene chloride as promoter of
the cyclization under different reaction conditions. All reactions
were carried out in tetrahydrofuran by adding 3.3 equivalents
lactone mixture with a 96 % yield. The mixture could not be
resolved by chromatography. Spectroscopic analysis of the
crude product showed it to be comprised of a mixture of dia-
stereoisomers, with lactone 15 representing 75 % of the total
product (Scheme 7).
Conformational analysis of the cyclization of epoxy ester 7
of Cp2TiCl to 1.0 equivalent of the epoxy alcohol 8. In all cases showed that the most favourable intermediate, according to
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Scheme 6. Cyclization intermediates.
Scheme 8. Reagents and conditions: a) LiAlH4, Et2O, 0 °C, 81 %; b) MsCl, Et3N,
CH2Cl2, 86 %; c) i. tBuOK, tBuOH, 80 °C%; ii. KOH, MeOH, 81 %.
Scheme 7. Reaction of 7 with TiIII.
bibliographical precedents,[6] must be 7A, which leads to unsat-
urated lactone 15 as the major product.
The relative configuration of the lactone 15 was determined
by spectroscopy and its subsequent conversion into ꢀ-elemene
(1).
The transformation of lactone 14 into alcohol 13 was carried
out in three stages: reduction, mesylation and elimination, with
an overall yield of 43 % (Scheme 8).
To complete the synthesis of ꢀ-elemene (1) from alcohol 13,
only two reactions were necessary: alcohol oxidation and Wittig
condensation. The first reaction was performed with PCC in di-
chloromethane at room temperature and the second with
methylenetriphenylphosphorane in THF. The overall yield of the
two reactions was 67 % (Scheme 9).
Scheme 9. Reagents and conditions: a) PCC, CH2Cl2, 82 %; b) BuLi, Ph3PCH2Br,
–78 °C, 82 %.
Conclusions
ꢀ-Elemene (1) has been synthesized from limonene by three
reaction sequences of nine, nine and eleven steps with overall
yields of 12, 15 and 17 %.
The key step of all the synthetic sequences is a radical cycli-
zation, induced by titanocene chloride. In these cyclization
The spectroscopic properties of the product obtained by this processes two stereocentres are created selectively with yields
synthetic procedure coincide with those of the ꢀ-elemene (1) close to 45 % in the cyclization of epoxy alcohol 8 and 70 % in
described in the literature.[2c,8]
the cyclization of epoxy ester 7.
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(3R*)-4-Methyl-3-[2-(2-methyloxiran-2-yl)ethyl]pent-4-en-1-ol
(5): Me3SOI (2.7 g, 12.4 mmol) was added portionwise to a suspen-
sion of NaH (449 mg, 11.8 mmol) in DMSO (12 mL). The reaction
mixture was stirred under argon for 1 h. Then a solution of 4 (1.00 g,
5.9 mmol) in DMSO (2 mL) was added and the resulting mixture
was vigorously stirred under argon for 3 h at 50 °C. A 10 % NaHCO3
aqueous solution (20 mL) was added and the resulting heterogene-
ous mixture was vigorously stirred for 25 min. The organic layer was
separated and the aqueous phase was extracted with Et2O. The
combined organic extracts were washed with a 5 % NaHCO3 aque-
ous solution and brine, and then dried (Na2SO4). Removal of the
solvent furnished (3R*)-4-methyl-3-[2-(2-methyloxiran-2-yl)ethyl]-
The relative configuration of the major products resulting
from these cyclizations promoted by titanocene chloride coin-
cides with that of ꢀ-elemene, with one axial and three equato-
rial substituents on cyclohexane, as demonstrated by NMR
spectroscopy.
Experimental Section
General Methods: 1H NMR spectra were measured at either 200 or
400 MHz, and 13C NMR were measured at 50 or 100 MHz in CDCl3
and referenced to TMS (1H) or solvent (13C), unless indicated other-
wise. IR spectra were recorded of neat samples on NaCl plates, un-
less otherwise noted. Standard mass spectra were acquired by GC–
MS in EI mode with a maximum m/z range of 600. When required,
all solvents and reagents were purified by standard techniques: THF
was purified by distillation from sodium and benzophenone and
degassed before use. All reactions were conducted under a positive
pressure of argon, using standard benchtop techniques for the han-
dling of air-sensitive materials. Chromatographic separations were
carried out under pressure on silica gel by using flash column chro-
matography on Merck silica gel 60 (0.040–0.063 mm). The yields
reported are for chromatographically pure isolated products unless
otherwise mentioned.
pent-4-en-1-ol (5; 952 mg, 95 %) as a colourless oil. IR (neat): ν =
˜
1
3072, 2927, 2718 cm–1. H NMR (200 MHz, CDCl3): δ = 1.25 (s, 3 H),
1.36 (m, 6 H), 1.54 (s, 3 H), 1.55 (m, 1 H), 2.14 (br. s, 1 H), 2.52 (m, 2
H), 3.50 (m, 2 H), 4.67 (s, 1 H), 4.70 (s, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 17.8 (CH3), 21.2 (CH3), 28.7 (CH2), 34.6 (CH2), 36.3 (CH2),
44.2 (CH), 54.1 (CH2), 57.2 (C), 61.2 (CH2), 112.6 (CH2), 146.9 (C) ppm.
HRMS (ESI): calcd. for C11H20O2Na 207.1361; found 207.1360.
(3R*)-4-Methyl-3-[2-(2-methyloxiran-2-yl)ethyl]pent-4-enal (6):
A solution of the alcohol 5 (950 mg, 5.16 mmol) in dry CH2Cl2
(20 mL) was added to a stirred suspension of PCC (1.33 g, 6.2 mmol)
in dry CH2Cl2 (20 mL). The reaction mixture was vigorously stirred
at room temp. under argon for 3 h. Then Et2O (40 mL) was added
and the mixture was filtered. Removal of the solvent afforded a
crude residue, which was purified by flash chromatography (hex-
ane/diethyl ether, 1:1) to furnish (3R*)-4-methyl-3-[2-(2-methyl-
oxiran-2-yl)ethyl]pent-4-enal (6; 836 mg, 89 %) as a colourless oil. IR
(3R*)-6-Oxo-3-(prop-1-en-2-yl)heptanal (3): A solution of limon-
ene (2; 5 g, 37.5 mmol) in MeOH (40 mL) was cooled to –78 °C
under argon. Then O3 (50 L/h, 90 % conversion) was bubbled
through the solution for 150 min. After the reaction was complete,
excess ozone was removed by purging with argon (10 min) and
dimethyl sulfide (20 mL) was slowly added. Stirring was continued
for 1 h at this temperature and for 2 h at room temp. Then a satu-
rated Na2CO3 solution (50 mL) was added. The organic layer was
separated and the aqueous phase was extracted with hexane. The
combined organic extracts were washed with brine and then dried
(Na2SO4). Removal of the solvent afforded a crude residue, which
was purified by flash chromatography (hexane/diethyl ether, 7:3) to
furnish (3R*)-6-oxo-3-(prop-1-en-2-yl)heptanal (3; 5.04 g, 80 %) as a
(neat): ν = 3074, 2936, 2720, 1726, 1275 cm–1 1H NMR (200 MHz,
.
˜
CDCl3): δ = 1.25 (s, 3 H), 1.3–1.5 (m, 4 H), 1.58 (m, 1 H), 1.58 (s, 3
H), 2.52 (m, 2 H), 2.60 (m, 2 H), 4.70 (s, 1 H), 4.76 (s, 1 H), 9.51 (s, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 18.7 (CH3), 21.2 (CH3), 28.4
(CH2), 34.2 (CH2), 41.5 (CH), 47.6 (CH2), 53.9 (CH2), 58.9 (C), 113.1
(CH2), 145.5 (C), 202.3 (CH) ppm. HRMS (ESI): calcd. for C11H18O2Na
205.1204; found 205.1207.
Ethyl (5R*,E)-2,6-Dimethyl-5-[2-(2-methyloxiran-2-yl)ethyl]-
hepta-2,6-dienoate (7): Triethyl 2-phosphonopropionate (1.1 mL,
5.2 mmol) was added to a suspension of NaH (208 mg, 55 % mineral
oil, 5.2 mmol) in toluene (4 mL) at 0 °C. After 30 min a solution of
6 (950 mg, 5.2 mmol) in toluene (3 mL) was added dropwise and
the reaction mixture was stirred under argon at that temperature
for 3 h and then diluted with diethyl ether and a saturated aqueous
NH4Cl solution. The organic layer was separated and the aqueous
phase was extracted with Et2O. The combined organic extracts were
washed with brine and then dried (Na2SO4). Removal of the solvent
furnished ethyl (5R*,E)-2,6-dimethyl-5-[2-(2-methyloxiran-2-
yl)ethyl]hepta-2,6-dienoate (7; 873 mg, 63 %) as a colourless oil. IR
colourless oil. IR (neat): ν = 3080, 2938, 2720, 1721 cm–1 1H NMR
.
˜
(200 MHz, CDCl3): δ = 1.63 (s, 3 H), 1.70 (m, 2 H), 2.09 (s, 3 H), 2.41
(m, 4 H), 2.65 (m, 1 H), 4.74 (s, 1 H), 4.80 (s, 1 H), 9.63 (s, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 18.5 (CH3), 26.6 (CH2), 30.2 (CH3), 40.9
(CH), 41.1 (CH2), 47.6 (CH2), 113.5 (CH2), 145.2 (C), 202.0 (CH), 208.4
(C) ppm. HRMS (ESI): calcd. for C10H16O2Na 181.1150; found
181.1145.
(5R*)-5-(2-Hydroxyethyl)-6-methylhept-6-en-2-one (4): NaBH4
(284 mg, 7.5 mmol) was added to a solution of 3 (2.5 g, 14.8 mmol)
in MeOH (10 mL) at 0 °C under argon. The mixture was stirred for
3 h at this temperature and water (5 mL) was added dropwise.
MeOH was evaporated and diethyl ether (20 mL) was added. The
organic layer was separated and the aqueous phase was extracted
with Et2O. The combined organic extracts were washed with brine
and then dried (Na2SO4). Removal of the solvent afforded a crude
residue, which was purified by flash chromatography (hexane/di-
ethyl ether, 6:4) to furnish (5R*)-5-(2-hydroxyethyl)-6-methylhept-6-
(neat): ν = 2938, 1713, 1275 cm–1 1H NMR (200 MHz, CDCl3): δ =
.
˜
1.29 (s, 3 H), 1.2–1.6 (m, 7 H), 1.59 (s, 3 H), 1.80 (s, 3 H), 1.85 (m, 1
H), 2.20 (m, 2 H), 2.54 (m, 2 H), 4.15 (m, 2 H), 4.68 (s, 1 H), 4.76 (s,
1 H), 6.68 (t, J = 6 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 12.7
(CH3), 14.5 (CH3), 18.6 (CH3), 21.2 (CH3), 28.3 (CH2), 33.1 (CH2), 34.5
(CH2), 46.8 (CH), 54.0 (CH2), 57.1 (C), 60.6 (CH2), 112.7 (CH2), 128.5
(C), 140.5 (CH), 146.2 (C), 168.3 (C) ppm. HRMS (ESI): calcd. for
C16H26O3Na 289.1779; found 289.1780.
en-2-one (4; 1.88 g, 75 %) as a colourless oil. IR (neat): ν = 3321,
˜
3074, 2916, 1720 cm–1. H NMR (200 MHz, CDCl3): δ = 1.42 (s, 3 H), (5R*,E)-2,6-Dimethyl-5-[2-(2-methyloxiran-2-yl)ethyl]hepta-2,6-
1
1.5–1.8 (m, 4 H), 1.94 (s, 3 H), 2.02 (m, 1 H), 2.19 (t, J = 7.5 Hz, 2 H), dien-1-ol (8): LiAlH4 (150 mg, 6.0 mmol) was added to a solution
3.07 (br. s, 1 H), 3.37 (m, 2 H), 4.54 (s, 1 H), 4.61 (s, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 17.7 (CH3), 26.7 (CH2), 30.1 (CH3), 36.1
(CH2), 41.5 (CH2), 43.3 (CH), 60.7 (CH2), 112.4 (CH2), 146.4 (C), 209.5
(C) ppm. HRMS (ESI): calcd. for C10H18O2Na 193.1204; found
193.1202.
of 7 (1.07 g, 4.0 mmol) in diethyl ether (10 mL) at 0 °C. The reaction
mixture was vigorously stirred at room temperature under argon
for 45 min, after which it was quenched with Na2SO4·10H2O (5 g)
and stirred for an additional 45 min. The resulting mixture was fil-
tered and then the filtrate was washed with Et2O. Removal of the
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solvent afforded a crude residue, which was purified by flash chro-
matography (hexane/diethyl ether, 9:1) to furnish (5R*,E)-2,6-di-
methyl-5-[2-(2-methyloxiran-2-yl)ethyl]hepta-2,6-dien-1-ol (8;
(CH3), 28.8 (CH2), 32.0 (CH2), 37.3 (CH2), 47.4 (CH), 68.3 (CH), 70.5
(CH2), 112.0 (CH2), 123.3 (CH), 130.4 (C), 147.1 (C), 171.2 (C) ppm.
HRMS (ESI): calcd. for C15H26O3Na 277.1779; found 277.1776.
682 mg, 87 %) as a colourless oil. IR (neat): ν = 3370, 3049, 2929,
˜
1
2853, 2375 cm–1. H NMR (200 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.3–
(5R*,E)-2-Methyl-8-oxo-5-(prop-1-en-2-yl)non-2-en-1-yl Acetate
(12): A solution of the alcohol 11 (3.90 g, 15.4 mmol) in dry CH2Cl2
(60 mL) was added to a stirred suspension of PCC (4.01 g,
18.6 mmol) in dry CH2Cl2 (60 mL). The reaction mixture was vigor-
ously stirred at room temp. under argon for 3 h. Then Et2O 100 mL
was added and the mixture was filtered. Removal of the solvent
afforded a crude residue, which was purified by flash chromatogra-
1.5 (m, 4 H), 1.51 (s, 3 H), 1.61 (s, 3 H), 1.94 (m, 1 H), 2.03 (m, 2 H),
2.54 (m, 2 H), 3.94 (s, 2 H), 4.63 (s, 1 H), 4.71 (s, 1 H), 5.30 (m, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.0 (CH3), 18.5 (CH3), 21.3
(CH3), 28.2 (CH3), 31.9 (CH2), 34.7 (CH2), 47.4 (CH), 54.1 (CH2), 57.4
(C), 69.0 (CH2), 112.1 (CH2), 124.5 (CH), 135.6 (C), 147.0 (C) ppm.
HRMS (ESI): calcd. for C14H24O2Na 247.1674; found 247.1671.
phy (hexane/diethyl ether, 7:3) to furnish 12 (3.78 g, 98 %) as a
Ethyl (5R*,E)-2-Methyl-8-oxo-5-(prop-1-en-2-yl)non-2-enoate
(9): Triethyl 2-phosphonopropionate (5.5 mL, 26.0 mmol) was
added to a suspension of NaH (1.04 g, 55 % mineral oil, 26.0 mmol)
in toluene (20 mL) at 0 °C. After 30 min a solution of 3 (4.36 g,
26.0 mmol) in toluene (12 mL) was added dropwise and the reac-
tion mixture was stirred under argon at that temperature for 3 h
and then diluted with diethyl ether and a saturated aqueous NH4Cl
solution. The organic layer was separated and the aqueous phase
was extracted with Et2O. The combined organic extracts were
washed with brine and then dried (Na2SO4). Removal of the solvent
1
colourless oil. IR (neat): ν = 3321, 3074, 2916, 1732, 1713 cm–1. H
˜
NMR (200 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.61 (s, 3 H), 1.4–1.8 (m, 5
H), 2.07 (s, 3 H), 2.16 (s, 3 H), 2.38 (t, J = 8 Hz, 2 H), 4.40 (s, 2 H),
4.64 (s, 1 H), 4.74 (s, 1 H), 5.36 (m, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 14.3 (CH3), 18.3 (CH3), 21.7 (CH3), 26.4 (CH2), 30.2 (CH3),
32.0 (CH2), 41.7 (CH2), 47.1 (CH), 70.4 (CH2), 112.6 (CH2), 128.6 (CH),
130.9 (C), 146.5 (C), 171.2 (C), 209.2 (C) ppm. HRMS (ESI): calcd. for
C15H24O3Na 275.1623; found 275.1621.
(5R*,E)-2,6-Dimethyl-5-[2-(2-methyloxiran-2-yl)ethyl]hepta-2,6-
dien-1-ol (8): KOH (3 M) (10 mL, 30 mmol) was added to a solution
furnished 9 (6.00 g, 92 %) as a colourless oil. IR (neat): ν = 3321,
˜
3074, 2916, 1720, 1713 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.19
of 12 (3.78 g, 15 mmol) in MeOH (20 mL) and the mixture was
stirred for 1 h at room temp. Then the mixture was diluted with
Et2O and quenched with an aqueous solution of NH4Cl. The organic
layer was washed with 10 % NaHCO3 and brine and then dried
(Na2SO4). Removal of the solvent furnished a crude residue, which
was used without further purification. Me3SOI (2.7 g, 12.4 mmol)
was added portionwise to a suspension of NaH (2.00 g, 47.0 mmol)
in DMSO (12 mL) and the reaction mixture was stirred under argon
for 1 h. Then the crude residue previously obtained (15.0 mmol) in
DMSO (2 mL) was added and the resulting mixture was vigorously
stirred under argon for 13 h at 75 °C. A 10 % NaHCO3 aqueous
solution (20 mL) was added and the resulting heterogeneous mix-
ture was vigorously stirred for 25 min. The organic layer was sepa-
rated and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with 5 % NaHCO3 and brine
and then dried (Na2SO4). Removal of the solvent furnished 8 (3.00 g,
90 %) as a colourless oil.
(m, 3 H), 1.43 (m, 2 H), 1.54 (s, 3 H), 1.75 (s, 3 H), 2.04 (s, 3 H), 1.40–
2.20 (m, 5 H), 2.30 (m, 2 H), 4.11 (q, J = 8 Hz, 2 H), 4.65 (s, 1 H), 4.75
(s, 1 H), 6.63 (t, J = 6 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
12.6 (CH3), 14.2 (CH3), 18.3 (CH3), 26.5 (CH2), 30.1 (CH3), 33.0 (CH2),
41.4 (CH2), 46.3 (CH), 60.5 (CH2), 113.0 (CH2), 128.5 (C), 140.3 (CH),
145.8 (C), 168.1 (C), 206.6 (C) ppm. HRMS (ESI): calcd. for C15H24O3Na
275.1623; found 275.1620.
(5R*,E)-2-Methyl-5-(prop-1-en-2-yl)non-2-ene-1,8-diol (10): Li-
AlH4 (945 mg, 33.0 mmol) was added to a solution of 9 (5.67 g,
22.5 mmol) in diethyl ether (50 mL) at 0 °C. The reaction mixture
was vigorously stirred at room temp. under argon for 45 min, after
which it was quenched with Na2SO4·10H2O (15 g) and stirred for a
further 45 min. The resulting mixture was filtered and then the
filtrate was washed with Et2O. Removal of the solvent afforded a
crude residue, which was purified by flash chromatography (hex-
ane/diethyl ether, 6:4) to furnish 10 (3.80 g, 87 %) as a colourless
1
oil. IR (neat): ν = 3402, 3077, 2938 cm–1. H NMR (200 MHz, CDCl3):
˜
(1R*,2S*,4R*)-1-Methyl-2,4-di(prop-1-en-2-yl)cyclohexylmeth-
anol (13): A mixture of Cp2TiCl2 (3.30 mmol) and Zn (6.60 equiv.)
in rigorously deoxygenated THF (10 mL) was stirred at a determined
temperature until the red solution turned green. In a separate flask,
the epoxy compound 8 (224 mg, 1 mmol) was dissolved in rigor-
ously deoxygenated THF (10 mL). The green TiIII solution was slowly
added through a cannula to the epoxide solution. After 60 min, an
excess of saturated NaH2PO4 was added and the mixture was stirred
for 20 min. The mixture was filtered to remove insoluble titanium
salts. The product was extracted into diethyl ether and the com-
δ = 1.14 (d, J = 8 Hz, 3 H), 1.58 (s, 3 H), 1.63 (s, 3 H), 1.1–2.20 (m, 9
H), 3.70 (m, 1 H), 3.96 (s, 2 H), 4.70 (s, 1 H), 4.75 (s, 1 H), 5.32 (m, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.1 (CH3), 18.6 (CH3), 23.7
(CH3), 28.6 (CH2), 32.0 (CH2), 37.0 (CH2), 47.7 (CH), 68.0 (CH), 68.5
(CH2), 111.8 (CH2), 124.7 (CH), 135.5 (C), 147.5 (C) ppm. HRMS (ESI):
calcd. for C13H24O2Na 235.1674; found 235.1673.
(5R*,E)-8-Hydroxy-2-methyl-5-(prop-1-en-2-yl)non-2-en-1-yl
Acetate (11): ClCOCH3 (10.5 mL, 147.0 mmol) and a catalytic
amount of 4-(dimethylamino)pyridine (DMAP) was added at 0 °C to
a solution of 10 (2.88 g, 14.7 mmol) in pyridine (5.8 mL). The reac- bined organic layers were washed with saturated NaHCO3 and
tion mixture was vigorously stirred at this temperature under argon
for 72 h, after which it was quenched with iced-water and stirred
for a further 1 h. The organic layer was separated and the aqueous
phase was extracted with Et2O. The combined organic extracts were
washed with 10 % NH4Cl, 10 % NaHCO3 and brine and then dried
(Na2SO4). Removal of the solvent afforded a crude residue, which
was purified by flash chromatography (hexane/diethyl ether, 7:3) to
brine, dried (Na2SO4) and filtered. After removal of the solvent, the
crude product was purified by flash chromatography (hexane/di-
ethyl ether, 8:2) to furnish a diastereomeric mixture of alcohols
(94 mg, 0.45 mmol, 45 %) as a colourless oil in which alcohol
(1R*,2S*,4R*)-1-methyl-2,4-di(prop-1-en-2-yl)cyclohexylmethanol
(13) predominates. IR (neat): ν = 3380, 3074, 2938 cm–1 1H NMR
.
˜
(200 MHz, CDCl3): δ = 0.95 (s, 3 H), 1.1–1.8 (m, 6 H), 1.78 (s, 6 H),
furnish 11 (873 mg, 63 %) as a colourless oil. IR (neat): ν = 3395,
1.90 (m, 2 H), 3.35 (m, 2 H), 4.69 (s, 4 H), 4.76 (s, 1 H), 4.83 (s, 1
˜
1
3067, 2923, 1732 cm–1. H NMR (200 MHz, CDCl3): δ = 1.20 (s, 3 H), H) ppm. 13C NMR (50 MHz, CDCl3): δ = 22.8 (CH3), 22.9 (CH3), 26.2
1.56 (s, 3 H), 1.59 (s, 3 H), 1.1–2.20 (m, 7 H), 2.01 (s, 3 H), 3.67 (m, 1
H), 4.39 (s, 2 H), 4.63 (s, 1 H), 4.71 (s, 1 H), 5.36 (m, 1 H) ppm. 13C (CH2), 108.5 (CH2), 113.0 (CH2), 149.1 (C), 150.4 (C) ppm. HRMS (ESI):
NMR (50 MHz, CDCl3): δ = 14.3 (CH3), 18.5 (CH3), 21.5 (CH3), 23.6 calcd. for C14H24ONa 231.1724; found 231.1720.
(CH3), 26.7 (CH2), 33.0 (CH2), 36.8 (CH2), 45.7 (CH), 50.1 (CH), 72.3
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(4aS*,6R*,8aR*)-4,8a-Dimethyl-6-(prop-1-en-2-yl)hexahydro-
1H-isochromen-3(4H)-one (15): A mixture of Cp2TiCl2 (3.97 mmol)
and Zn (24.0 mmol) in rigorously deoxygenated THF (18 mL) was
stirred at a room temperature until the red solution turned green.
In a separate flask, the epoxy compound 7 (480 mg, 1.8 mmol) was
dissolved in rigorously deoxygenated THF (18 mL). The green TiIII
solution was slowly added through a cannula to the epoxide solu-
tion. After 60 min, an excess of saturated NaH2PO4 was added and
was added at room temperature to a solution of 1 M tBuOK in
tBuOH (2.2 mL, 2.2 mmol). The reaction mixture was heated to 80 °C
and stirred under argon for 6 h. Then the mixture was cooled to
room temperature and quenched with water (40 mL). The organic
layer was separated and the aqueous phase was extracted with
diethyl ether. The combined organic extracts were washed with sat.
NaHCO3 and brine, dried (Na2SO4) and filtered. Removal of the sol-
vent afforded a crude residue, which was dissolved in MeOH
the mixture was stirred for 20 min. The mixture was filtered to re- (1.68 mL). Then 5
move insoluble titanium salts. The product was extracted into di- mixture was stirred for 1 h under argon. Then the mixture was
ethyl ether and the combined organic layers were washed with diluted with diethyl ether and a saturated aqueous NH4Cl solution.
saturated NaHCO3 and brine, dried (Na2SO4) and filtered. After re- The organic layer was separated and the aqueous phase was ex-
moval of the solvent, the crude product was purified by flash chro- tracted with Et2O. The combined organic extracts were washed with
matography (hexane/diethyl ether, 8:2) to furnish a diastereomeric brine and then dried (Na2SO4). Removal of the solvent afforded a
mixture of lactones (383 mg, 1.7 mmol, 96 %) in which the lactone crude residue, which was purified by flash chromatography (hex-
(4aS*,6R*,8aR*)-4,8a-dimethyl-6-(prop-1-en-2-yl)hexahydro-1H-iso- ane/diethyl ether, 8:2) to furnish a diastereomeric mixture of alco-
M KOH (, 0.3 mL, 1.41 mmol) was added and the
chromen-3(4H)-one (15) predominates (75 %) as a colourless oil. IR
hols (106 mg, 81 %) in which alcohol 13 predominates as a colour-
less oil.
1
(neat): ν = 2931, 1733 cm–1. H NMR (200 MHz, CDCl3): δ = 1.00 (s,
˜
3 H), 1.09 (s, 3 H), 1.20 (d, J = 6 Hz, 3 H)*, 1.23 (d, J = 6 Hz, 3 H),
1.0–1.6 (m, 14 H), 1.69 (s, 3 H)*, 1.70 (s, 3 H), 1.90 (m, 2 H), 2.17 (m,
2 H), 3.81 (m, 2 H)*, 4.07 (m, 2 H), 4.65 (s, 2 H)*, 4.69 (s, 2 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.3 (2 CH3), 15.1 (2 CH3), 21.0 (2
CH3), 25.6 (2 CH2), 30.5 (2 CH2), 32.7 (2 CH2), 34.5 (2 C), 38.5 (2 CH),
45.3 (2 CH), 46.1 (2 CH), 80.8 (2 CH2), 108.6 (CH2)*, 109.3 (CH2), 149.5
(C), 150.5 (C)*, 174.2 (2 C) ppm. HRMS (ESI): calcd. for C14H22O2Na
245.1517; found 245.1514.
(1R*,2S*,4R*)-1-Methyl-2,4-di(prop-1-en-2-yl)cyclohexanecarb-
aldehyde (18): A solution of the alcohol 13 (100 mg, 0.5 mmol) in
dry CH2Cl2 (6 mL) was added to a stirred suspension of PCC (1.26 g,
0.6 mmol) in dry CH2Cl2 (6 mL). The reaction mixture was vigorously
stirred at room temperature under argon for 3 h. Then Et2O 10 mL
was added and the mixture was filtered and then immediately puri-
fied by flash chromatography (hexane/diethyl ether, 1:1) to furnish
a diastereomeric mixture of aldehydes (98 mg, 82 %) as a colourless
2-[(1S*,2R*,5R*)-2-(Hydroxymethyl)-2-methyl-5-(prop-1-en-2-
yl)cyclohexyl]propan-1-ol (16): LiAlH4 (38 mg, 1.35 mmol) was
added to a solution of 15 (200 mg, 0.9 mmol) in diethyl ether (5 mL)
at 0 °C. The reaction mixture was vigorously stirred at room temper-
ature under argon for 45 min, after which it was quenched with
Na2SO4·10H2O (1.0 g) and stirred for a further 45 min. The resulting
mixture was filtered and then the filtrate was washed with Et2O.
Removal of the solvent afforded a crude residue, which was purified
by flash chromatography (hexane/diethyl ether, 8:2) to furnish a
diastereomeric mixture of diols (141 mg, 0.73 mmol, 81 %) in which
oil in which aldehyde 18 predominates. IR (neat): ν = 2916, 2720,
˜
1
1725 cm–1. H NMR (200 MHz, CDCl3): δ = 0.95 (s, 3 H), 1.1–1.6 (m,
6 H), 1.54 (s, 3 H), 1.65 (s, 3 H), 1.92 (m, 2 H), 4.64 (m, 4 H), 9.38 (s,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.2 (CH3), 23.4 (CH3), 25.5
(CH3), 28.5 (CH2), 31.4 (CH3), 31.5 (CH3), 31.5 (CH2), 33.1 (CH2), 45.0
(CH), 47.4 (CH), 50.0 (C), 109.0 (CH2), 113.5 (CH2), 145.9 (C), 206.6
(CH) ppm. HRMS (ESI): calcd. for C14H22ONa 229.1568; found
229.1564.
trans-ꢀ-Elemene (1): A three-necked round-bottomed flask was fit-
ted with a reflux condenser, an addition funnel, a mechanical stirrer
and a gas inlet tube. A gentle flow of Ar through the apparatus
was maintained throughout the reaction. An ethereal solution of n-
butyllithium (2.4 mmol) and anhydrous THF (5 mL) was added to
the flask. The solution was stirred and cooled to –75 °C. Then tri-
phenylmethylphosphonium bromide (3.59 mmol) was added cau-
tiously over 5 min and the solution was stirred for 15 min at room
temperature. After cooling the mixture to –75 °C, (1R*,2S*,4R*)-1-
methyl-2,4-di(prop-1-en-2-yl)cyclohexanecarbaldehyde (17;
100 mg, 0.49 mol) was added dropwise. The solution turned colour-
less and a white precipitate separated. The mixture was stirred for
30 min, allowed to warm to room temperature and the precipitate
removed by suction filtration. The precipitate was washed with di-
ethyl ether (100 mL) and the combined ethereal filtrates were ex-
tracted with 100 mL portions of NH4Cl until neutral and then the
combined organic extracts were washed with 10 % NaHCO3 and
brine and then dried (Na2SO4). Removal of the solvent afforded a
crude residue, which was purified by flash chromatography (hex-
ane/diethyl ether, 95:5) to furnish a diastereomeric mixture of tri-
enes (81 mg, 82 %) as a colourless oil in which triene 1 predomi-
diol 15 predominates as a colourless oil. IR (neat): ν = 3400, 3080,
˜
1
2936 cm–1. H NMR (200 MHz, CDCl3): δ = 0.8–1.9 (m, 8 H), 0.75 (s,
3 H), 1.01 (d, J = 6 Hz, 3 H), 1.82 (m, 1 H), 1.72 (s, 3 H), 3.38 (m, 2
H), 3.68 (m, 2 H), 4.68 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
13.3 (CH3), 16.4 (CH3), 21.2 (CH3), 27.7 (CH2), 28.5 (CH2), 32.9 (CH),
36.3 (CH2), 37.8 (C), 39.0 (CH), 45.3 (CH), 67.6 (CH2), 69.9 (CH2), 108.3
(CH2), 151.0 (C) ppm. HRMS (ESI): calcd. for C14H26O2Na 249.1830;
found 245.1827.
2-[(1S*,2R*,5R*)-2-Methyl-2-(methylsulfonyloxymethyl)-5-
(prop-1-en-2-yl)cyclohexyl]propyl Methanesulfonate (17): Meth-
anesulfonyl chloride (0.2 mL, 1.9 mmol) was added to a stirred solu-
tion of the alcohol 16 (200 mg, 0.9 mmol) in CH2Cl2 (1 mL) and
Et3N (0.35 mL) at 0 °C . The reaction mixture was stirred under
argon for 12 h and then diluted with diethyl ether and saturated
aqueous Na2CO3. The organic layer was separated and the aqueous
phase was extracted with diethyl ether. The combined organic ex-
tracts were washed with sat. NaHCO3 and brine, dried (Na2SO4) and
filtered. Removal of the solvent afforded a crude residue of 16
(265 mg, 0.76 mmol, 86 %) as a colourless oil. 1H NMR (200 MHz,
CDCl3): δ = 0.8–2.2 (m, 8 H), 0.93 (s, 3 H), 1.10 (d, J = 6 Hz, 3 H),
1.71 (s, 3 H), 2.99 (s, 6 H), 3.8–4.4 (m, 4 H), 4.69 (s, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 13.0 (CH3), 16.5 (CH3), 21.2 (CH3), 27.0
(CH2), 27.5 (CH2), 31.8 (CH), 36.6 (CH2), 36.7 (2 CH3), 37.8 (CH), 39.8
(C), 45.1 (CH), 74.0 (CH2), 76.4 (CH2), 108.8 (CH2), 149.9 (C) ppm.
nates. IR (neat): ν = 3080, 2916, 2820 cm–1 1H NMR (200 MHz,
.
˜
CDCl3): δ = 1.4–1.8 (m, 6 H), 1.01 (s, 3 H), 1.70 (s, 3 H), 1.72 (s, 3 H),
1.99 (m, 2 H), 4.6–5.0 (m, 6 H), 5.83 (dd, J1 = 6, J2 = 12 Hz, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 16.8 (CH3), 21.2 (CH3), 25.0 (CH3), 27.0
(CH2), 33.1 (CH2), 40.0 (C), 40.1 (CH2), 45.9 (CH), 52.9 (CH), 108.3
(CH2), 110.5 (CH2), 112.2 (CH2), 147.3 (C), 150.5 (CH), 150.6 (C) ppm.
HRMS (ESI): calcd. for C15H24Na 227.1878; found 227.1875.
(1R*,2S*,4R*)-1-Methyl-2,4-di(prop-1-en-2-yl)cyclohexylmeth-
anol (13): A solution of 17 (292 mg, 0.9 mmol) in tBuOH (0.88 mL)
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Acknowledgments
Financial support from the Regional Government of Castile and
Leon is gratefully acknowledged. D. B. I. and P. H. T. thank the
Regional Government of Castille and Leon and the University
of Salamanca for fellowships that have allowed them to carry
out this work.
Keywords: Terpenoids · Radicals · Natural products ·
Titanium
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Received: May 24, 2018
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Natural Product Synthesis
D. Benito Iglesias,
P. Herrero Teijón, R. Rubio González,
A. Fernández-Mateos* ...................... 1–8
Synthesis of trans-ꢀ-Elemene
Highly efficient syntheses of the anti- only nine to eleven steps with good
cancer agent trans-ꢀ-elemene have overall yields. The key step in these re-
been achieved by using the readily action sequences is a stereoselective
available ( )-limonene as starting ma- radical cyclization, induced by titan-
terial. The syntheses were achieved in ocene chloride.
DOI: 10.1002/ejoc.201800800
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