Stereoselective Synthesis of a cis-Cedrane-8,9-diol as a Key Intermediate for an Amber Odorant

Article abstract of DOI:10.1021/acs.oprd.0c00423

The naturally occurring (-)-α-cedrene exhibits a weak woody and cedarlike odor. In contrast, cis-cedrene acetonide, which is a derivative of cedrene, is an extremely powerful semisynthetic aroma molecule. The current process starting from cedrene yields cis-cedrene acetonide in an overall yield of <20%. Herein, we report two synthetic pathways toward this valuable product starting either by isomerization of commercially available cedrene epoxide or by photo-oxidation of (-)-α-cedrene to an allylic intermediate. The key step of the synthesis is the epoxidation of the protected or even unprotected allyl alcohol followed by the reductive opening of the epoxide. This reaction sequence leads to the respective cis-diol with the correct stereochemistry. Subsequent acetalization gives cis-cedrene acetonide in up to 78% overall yield. We also report our attempt to prepare the cis-diol with inverted stereochemistry. In this context, we inverted the configuration of the allylic alcohol via a Mitsunobu reaction. However, only the acetyl-protected alcohol could be epoxidized, leading the undesired trans-product in >99% yield.

Full text of DOI:10.1021/acs.oprd.0c00423

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Article
Stereoselective Synthesis of a cis-Cedrane-8,9-diol as a Key
Intermediate for an Amber Odorant
Vivian Stefanow, Aiga Grandane, Marcus Eh, Johannes Panten, Anke Spannenberg,
and Thomas Werner*
Cite This: https://dx.doi.org/10.1021/acs.oprd.0c00423
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ABSTRACT: The naturally occurring (−)-α-cedrene exhibits a weak woody and cedarlike odor. In contrast, cis-cedrene acetonide,
which is a derivative of cedrene, is an extremely powerful semisynthetic aroma molecule. The current process starting from cedrene
yields cis-cedrene acetonide in an overall yield of <20%. Herein, we report two synthetic pathways toward this valuable product
starting either by isomerization of commercially available cedrene epoxide or by photo-oxidation of (−)-α-cedrene to an allylic
intermediate. The key step of the synthesis is the epoxidation of the protected or even unprotected allyl alcohol followed by the
reductive opening of the epoxide. This reaction sequence leads to the respective cis-diol with the correct stereochemistry.
Subsequent acetalization gives cis-cedrene acetonide in up to 78% overall yield. We also report our attempt to prepare the cis-diol
with inverted stereochemistry. In this context, we inverted the configuration of the allylic alcohol via a Mitsunobu reaction. However,
only the acetyl-protected alcohol could be epoxidized, leading the undesired trans-product in >99% yield.
KEYWORDS: cedrene, terpenes, ambrocenide, stereoselective synthesis, natural resources
compounds of its class, used in various applications, with an
annual production of several tons.12
INTRODUCTION
■
Extracts and secretions of animals and plants have been widely
used for perfumery and flavor purposes since early antiquity.1,2
The number of potential fragrance chemicals has expanded
continually ever since as a result of the systematic investigation
of essential oils and odoriferous compounds.1,3,4 Therefore,
chemical synthesis is an important tool to address the growing
demand for substances with improved properties, e.g.,
enhanced odor quality, increased stability in technical
applications, and skin compatibility.5 The increasing global
demand for odorous substances cannot be covered by
feedstock originating from plants or animals.6 Therefore, the
development of technical processes for the synthesis of
fragrance materials is of crucial relevance. A prominent
example for the industrial production of a naturally occurring
compound used in fragrance and flavor applications is the
synthesis of linalool from different feedstocks like 6-methyl-5-
hepten-2-one (BASF-process)7 or as practiced by Symrise
company from α-pinene originating from crude sulfate
turpentine (CST).8
The current technical synthesis is starting from (−)-α-
cedrene (1) within three reaction steps (Scheme 1). First,
cedrene (1) is epoxidized via a Prilezhaev reaction using
peracetic acid. The obtained cedrene epoxide (2) is
subsequently hydrolyzed in the presence of diluted sulfuric
acid and a phase transfer catalyst (PTC) to give cedrene-8,9-
diol (3) as a mixture of stereoisomers. During this reaction,
significant amounts of the corresponding ketone cedralon (4)
are formed as a byproduct. The formation of cedralon (4) from
2 under acidic conditions has been reported previously.14,15
Subsequent acetalization of the diol mixture using acetone
gives the corresponding acetonide 5 as a mixture of
diastereomers that contains cis-5a, in which the dioxolane
ring is orientated exo with respect to the methylene bridge, as
the major component. The moderate yield of 45% in this step
can be attributed to the formation of by-products, e.g., due to
elimination in the conversion of acid-sensitive diol 3 with
acetone under acidic reaction conditions. The overall yield of
this sequence is below 20%.5
(−)-α-Cedrene (1) is one of the main components in the
essential oil of cedar wood, a natural product that can be
obtained from various cedar wood types such as the American
cedar, Juniperus virginiana, the Spanish cedar, Juniperus
thurifera, or originally the Lebanon cedar, Cedrus libani.9,10
This compound and various derivatives are known to have a
woody scent, and as a consequence, they are valuable
ingredients for perfumes.1 cis-Cedrene acetonide is a semi-
synthetic product derived from (−)-α-cedrene (1) that
exhibits an extremely powerful and long-lasting woody-ambery
note and at the same time intensifies and prolongs different
fragrance notes.11−13 It is one of the most important
Notably, compound cis-5a is the key component in the
resulting mixture. In addition, diastereomer cis-5b, in which the
dioxolane ring is cis with respect to the methylene bridge, does
not contribute to the intense scent of the final fragrance
Received: September 24, 2020
https://dx.doi.org/10.1021/acs.oprd.0c00423
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© XXXX American Chemical Society
A

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Article
a
Scheme 1. Current Synthesis of Amber Odorant 5
a
Reaction conditions: (i) MeCO3H (40% in H2O), NaOAc, Et2O, 20−25 °C, 3 h (93%); (ii) H2SO4 (10% in H2O), Aliquat R336, 20−25 °C, 2 h
(38%); and (iii) acetone, p-TSA, toluene, 20−25 °C, 24 h (45%).5
Scheme 2. Retrosynthesis for the Stereoselective Preparation of cis-3a
compound, although it is formed during the synthesis.15,16
Hence, a stereoselective and more efficient route to obtain cis-
5a is desirable. Straightforward access to cis-5a could be the
wood oil containing at least 75% of (−)-α-cedrene. cis-Cedrene
EXPERIMENTAL SECTION
■
(−)-α-Cedrene (1) was received from Symrise AG as a cedar
catalytic cis-dihydroxylation of cedrene (1) followed by
acetalization. Various methods for the conversion of olefins
to the corresponding cis-diols have been reported.17,18
However, only the dihydroxylation using osmium tetroxide
proved to be feasible to obtain cis-3.19 Nevertheless, the use of
expensive and toxic transitional metals in the synthesis of cis-5a
is undesirable. Especially in industrial chemistry, the use of
OsO4 is restricted due to its high toxicity and costs.20,21
Herein, we report our effort in the development of an
alternative route for the stereoselective preparation of cis-5a.
As mentioned above, cis-5a should be readily available from the
corresponding diol cis-3 via acetalization. Therefore, the key
step is a stereospecific synthesis of diol cis-3 (Scheme 2). We
envisioned introducing the correct stereo information starting
from cedrene (1) or cis-cedrene epoxide (cis-2) that are
converted to the corresponding allyl alcohol 6. The subsequent
stereoselective epoxidation of the exocyclic double bond
followed by the reduction of epoxide cis-7 should lead to
diol cis-3.
epoxide (cis-2) was received from Symrise AG as well with a
purity of 95%. Anhydrous solvents were ordered from Acros
Organics with a purity of >99% in a septum flask and stored
over molecular sieves. All other chemicals were purchased from
commercially available sources and used without further
purification. Phosphonium salt-based catalysts used in the
organocatalytic variant of the isomerization of cedrene oxide to
the allylic alcohol were prepared as reported earlier.22,23
Infrared (IR) spectra were recorded on a Nicolet iS10 MIR
FT-IR-spectrometer from Thermo Fisher Scientific. High-
resolution mass spectra (HRMS) were obtained either from a
MAT 95 XP by Thermo Fisher Scientific (EI) or an HPLC
system 1200 and downstream ESI-TOF-MS 6210 by Agilent
(ESI). Mass spectra were obtained from a mass spectrometer
MAT 95 XP by Thermo Fisher Scientific. Optical rotation
analysis was carried out at a Polarimeter MCP 200 by Anton
Paar using glass cuvettes d = 10 or 100 mm. Optical rotation
concentrations are given as g·100 mL−1. The specific optical
rotation [α]2D0 is expressed in °·cm3·g−1·dm−1. Deuterated
chloroform was ordered from euriso-top and Deutero. NMR
B
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spectra were recorded using either a Burker 300 Fourier,
Burker AV300, or Burker AV400 spectrometer. The chemical
shifts are reported in ppm using the residue signal of the
solvent as an internal standard, which is 7.26 ppm for CDCl3.
Coupling constants are expressed in hertz (Hz). The following
abbreviations are used to describe the multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, dd =
doublet of doublets, and ddt = doublet of doublet of triplets.
Thin-layer chromatography (TLC) was performed using TLC
plates with fluorescence indication (silica type 60, F254) from
Merck. Visualization of the spot was done by the use of
phosphomolybdic acid or p-anisaldehyde stain. Column
chromatography was performed using silica with a grain size
of 40−63 μm from Macherey-Nagel.
with Et2O (4 × 10 mL). The combined organic layers were
washed with brine (20 mL) and dried over Na2SO4. All
volatiles were evaporated under reduced pressure. The crude
product was purified by recrystallization from EtOAc/cHex
yielding 6 (4.47 g, 20.3 mmol, 89%) as colorless needles. Rf
(SiO2, cHex/EtOAc, 3:1) = 0.71. 1H NMR (300 MHz,
CDCl3) δ = 0.87 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 8.7 Hz, 6H),
1.11−1.64 (m, 6H), 1.69−1.93 (m, 4H), 2.08−2.19 (m, 1H),
2.35 (d, J = 4.1 Hz, 1H), 4.34 (ddt, J = 10.2, 7.7, 2.5 Hz, 1H),
4.75 (ddt, J = 2.5, 1.9, 0.6 Hz, 1H), 4.99 (dd, J = 2.4, 1.9 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3) δ = 15.6, 26.0 (CH2),
26.3, 26.8, 36.8 (CH2), 41.7, 42.4 (Cq), 45.1 (2 CH2), 55.0
(Cq), 57.1, 60.5, 70.3, 106.6 (CH2), 154.3 (Cq) ppm. To
obtain crystals suitable for X-ray crystal structure analysis, the
product was crystalized from cHex/EtOAc.
epi-β-Cedren-9-ol (epi-6). Compound epi-10 (785 mg,
2.12 mmol, 1 equiv) was suspended in tBuOH (20 mL), and
KOH (360 mg, 6.37 mmol, 3 equiv) dissolved in H2O (5 mL)
was added. After stirring at 21 °C for 16 h, the mixture was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with sat. NH4Cl (20 mL), followed by H2O
(20 mL). It was dried over Na2SO4 and all volatiles were
evaporated under reduced pressure. Product 6 (416 mg, 1.89
mmol, 89%) was obtained as a yellow oil without further
purification. Rf (SiO2, cHex/EtOAc 3:1) = 0.74. 1H NMR (300
MHz, CDCl3): δ = 0.85 (d, J = 7.1 Hz, 3H), 0.98 (s, 3H), 1.06
(s, 3H), 1.09−1.23 (m, 1H), 1.27−1.94 (m, 9H), 2.26−2.41
(m, 2H), 4.44 (d, J = 7.1 Hz, 1H), 4.87−4.96 (m, 1H), 4.98−
5.05 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.6,
25.4 (CH2), 26.6, 28.3, 36.0 (CH2), 42.0, 42.3 (CH2), 43.2
(C), 43.4 (CH2), 53.6 (Cq), 54.3, 59.6, 69.6, 114.9 (  CH2),
154.7 (Cq) ppm. IR (ATR): λ−1 = 3399 (m, vb), 3066 (w),
2938 (vs), 2902 (s), 2869 (s), 1637(w), 1461 (m), 1409 (w),
1384 (m), 1364 (m), 1312 (m), 1226 (w), 1196 (w), 1164
(w), 1107 (w), 1061 (m), 1039 (s), 989 (s), 960 (m), 940
(w), 902 (vs), 887 (s), 843 (m), 780 (w), 749 (w), 719 (w),
653 (w), 582 (w), 468 (w), 432 (w) cm−1 MS (EI): m/z (%):
220 (6) [M+], 202 (6), 177 (23), 159 (44), 145 (18),135 (31),
118 (47), 105 (32), 95 (30) 91 (68), 79 (46), 69 (100), 55
(59), 41 (87), 29 (18). [α]2D2 = −51.0 (c = 1.0, CHCl3).
HRMS (EI): m/z calcd for C15H24O: 220.1821 found:
220.1822.
β-Epoxy Cedrenyl Acetate (cis-7). β-Cedrenyl acetate (8,
700 mg, 2.67 mmol) was dissolved in CH2Cl2 (10 mL), and m-
CPBA (986 mg, 4.00 mmol) was added in portions. After the
reaction was stirred at 21 °C for 20 h, CH2Cl2 (15 mL) was
added. The mixture was washed with sat. aq. KHCO3 (2 × 7
mL), and the organic layer was dried over Na2SO4. All volatiles
were evaporated under reduced pressure. The crude product
was purified by column chromatography (SiO2, cHex/EtOAc
20:1) to yield cis-7 (657 mg, 2.36 mmol, 88%) as a colorless
solid. Rf (SiO2, cHex/EtOAc, 3:1) = 0.47. 1H NMR (300 MHz,
CDCl3): δ = 0.88 (d, J = 7.0 Hz, 3H), 0.97 (s, 3H), 1.17 (s,
3H), 1.33−1.37 (m, 1H), 1.42−1.63 (m, 4H), 1.69−1.74 (m,
2H), 1.75−1.95 (m, 2H), 1.95−2.03 (m, 2H), 2.07 (s, 3H),
2.60 (d, J = 4.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 1H), 5.48 (dd, J =
10.9, 7.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.6
(CH2), 21.2 (CH2), 25.8 (CH2), 26.0, 27.1 (CH2), 36.9, 38.4,
41.3 (Cq), 41.6, 41.8 (CH2), 51.2, 54.4 (Cq), 56.7 (CH2), 58.7
(CH2), 59.9 (Cq), 67.9 (CH2), 170.9 (CO) ppm. IR
(ATR): λ−1 = 2954 (s), 2871 (m), 1728 (vs), 1470 (w), 1372
(s), 1292 (w), 1230 (vs), 1197 (m), 1168 (w), 1139 (w), 1113
(w), 1060 (w), 1040 (m), 1016 (m), 974 (s), 941 (m), 925
cis-Cedrene-8,9-diol (cis-3).19 LiAlH4 (120 mg, 3.16
mmol) was added in portions to a solution of cis-7 (280 mg,
1.01 mmol) in anhydrous tetrahydrofuran (THF) (4 mL)
under Ar at 0 °C. After the reaction was stirred for 2 h at 0 °C,
the resulting mixture was quenched with 1 M aq. HCl (10
mL). The aqueous phase was extracted with EtOAc (3 × 7
mL), and the combined organic layers were washed with H2O
(1 × 10 mL) and dried over Na2SO4. All volatiles were
evaporated under reduced pressure to yield cis-3 (234 mg,
0.982 mmol, 98%) as a colorless solid without further
1
purification. Rf (SiO2, cHex/EtOAc, 3:1) = 0.18. H NMR
(300 MHz, CDCl3): δ = 0.85 (d, J = 7.1 Hz, 3H), 1.01 (s, 3H),
1.13 (s, 3H), 1.39 (s, 3H), 1.22−1.62 (m, 4H), 1.61−1.97 (m,
7H), 3.68 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ =
15.7, 25.7 (CH2), 26.9, 28.8, 29.3, 36.8 (CH2), 39.1 (CH2),
40.7 (CH2), 41.4, 41.7 (C), 53.5 (Cq), 57.2, 60.8, 72.3, 74.4
(Cq) ppm. [α]2D0 = −15.6 (c = 1.8, MeOH). Crystals suitable
for X-ray crystal structure analysis were obtained by vapor
diffusion of pentane into a saturated solution of cis-3 in CHCl3.
cis-Cedrene Acetonide (cis-5a).5 Under Ar compound,
cis-3 (250 mg, 1.05 mmol) was dissolved in anhydrous CH2Cl2
(5 mL). 2,2-Dimethoxypropane (546 mg, 5.24 mmol) and p-
TSA (20 mg, 0.10 mmol) were added and stirred at 21 °C for
10 h. The mixture was diluted with CH2Cl2 (10 mL) and
washed with aq. NaOH (2 M, 2 × 5 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried over Na2SO4, and all volatiles were
evaporated under reduced pressure (40 °C, 100 mbar). After
purification via column chromatography (cHex/EtOAc 3:1),
product cis-5a (262 mg, 0.941 mmol, 90%) was obtained as a
1
colorless solid. Rf (SiO2, cHex/EtOAc, 3:1) = 0.83. H NMR
(300 MHz, CDCl3) δ = 0.80 (dd, J = 7.1, 0.9 Hz, 3H), 1.02 (s,
3H), 1.14 (s. 3H), 1.19−1.36 (m, 1H), 1.33−1.48 (m, 1H),
1.43−1.51 (m, 6H), 1.51 (s, 3H), 1.49−2.05 (m, 9H), 4.00−
4.08 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ = 15.5, 25.5
(CH2), 27.7, 28.9, 29.8, 30.4, 31.2, 36.0 (CH2), 38.6 (CH2),
41.1 (CH2), 42.0, 42.6 (Cq), 52.5 (Cq), 57.5, 58.7, 78.9, 85.1
(Cq), 109.0 (Cq) ppm.
β-Cedren-9-ol (6).14 Under an argon atmosphere,
diisopropylamine (6.40 mL, 4.61 g, 45.5 mmol) was dissolved
in anhydrous THF (20 mL) and cooled to 0 °C. n-BuLi (18.2
mL, 2.5 M in hexane, 45.5 mmol) was added dropwise. After
the addition was completed, the mixture was stirred for 10 min
and subsequently cooled to −78 °C. This solution was added
dropwise via a double-tipped needle to a solution of cedrene
epoxide (2, 5.00 g, 22.7 mmol) in anhydrous THF (20 mL) at
−78 °C. The resulting mixture was stirred 1.5 h at −78 °C and
afterward 48 h at 21 °C. The reaction was quenched by the
dropwise addition of THF/H2O (1:1, 10 mL) and extracted
C
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(w), 907 (w), 888 (m), 805 (m), 769 (w), 742 (w), 687 (m),
653 (w), 623 (m), 559 (m), 502 (m), 480 (s), 434 (w) cm−1.
MS (EI, 70 eV): m/z (%): 236 (7) [M − Ac], 218 (20), 206
(100), 190 (23), 175 (28), 163 (33), 147 (34), 136 (51), 121
(46), 105 (76), 91 (61), 79 (41), 69 (55), 55 (33), 43 (81).
[α]2D0 = −5.6 (c = 1.0, MeOH). HRMS (ESI): m/z calcd. for
C17H26O3 [M + Na] 301.1774 found: 301.1776.
Na2SO4 and evaporation of all volatiles under reduced
pressure, epi-8 (160 mg, 0.610 mmol, 88%) was obtained as
a colorless oil without further purification. Rf (SiO2, cHex/
1
EtOAc, 20:1) = 0.74. H NMR (300 MHz, CDCl3): δ = 0.83
(d, J = 7.1 Hz, 3H), 0.98 (s, 3H), 1.04 (s, 3H), 1.18 (d, J =
11.7 Hz, 1H), 1.23−2.01 (m, 8H), 2.04 (s, 3H), 2.16−2.29
(m, 1H), 2.29 (d, J = 4.3 Hz, 1H), 4.97 (dd, J = 2.1, 0.6 Hz,
1H), 5.10 (dd, J = 2.0, 0.9 Hz, 1H), 5.59 (d, J = 7.2 Hz, 1H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 15.6, 22.0, 25.4
(CH2), 26.7, 27.6, 36.1 (CH2), 40.9 (CH2), 41.9, 43.2 (Cq),
43.6 (CH2), 53.5 (Cq), 54.2, 59.8, 70.9, 117.9 (CH2), 149.2
(Cq), 170.4 (Cq) ppm. IR (ATR): λ−1 = 2941.70 (m), 2870.50
(m), 1733 (s), 1639.17 (w), 1460.01 (w), 1368.60 (m),
1226.99 (s), 1197.34 (w), 1166.32 (w), 1141.39 (w), 1102.93
(w), 1067.83 (w), 1012.30 (m), 983.45 (w), 956.83 (m),
909.91 (m), 876.45 (w), 820.64 (w), 784.65 (w), 751.82 (w),
718.59 (w), 604.12 (w), 579.29 (w), 477.51 (w), 448.74 (w)
cm−1. MS (EI, 70 eV): m/z (%): 263 (0.42) [M + H], 220
(100), 202 (28), 187 (19), 177 (98), 159 (179), 145 (23), 131
(36), 118 (90), 105 (38), 91 (89). [α]2D0 = +2.1 (c = 1.0,
CHCl3). HRMS (EI): m/z calcd for C17H26O2 262.1927
found: 262.1931.
trans-β-Epoxy Cedrenyl Acetate (trans-7). epi-β-Ce-
drenyl acetate (epi-8, 160 mg, 0.610 mmol) was dissolved in
CH2Cl2 (10 mL), and m-CPBA (158 mg, 0.915 mmol) was
added in portions and subsequently stirred at 21 °C for 26 h.
Afterward, the reaction mixture was diluted with CH2Cl2 (15
mL) and washed with sat. NaHCO3 (2 × 15 mL). After
extraction with CH2Cl2 (2 × 15 mL), the combined organic
layers were dried over Na2SO4 and all volatiles were
evaporated under reduced pressure. The crude mixture was
purified via column chromatography (SiO2, cHex/EtOAc,
20:1) yielding compound trans-7 (170 mg, 0.610 mmol,
>99%) as a colorless solid. Rf (SiO2, cHex/EtOAc, 20:1) =
1
0.29. H NMR (400 MHz, CDCl3): δ = 0.84 (d, J = 7.0 Hz,
3H), 0.96 (s, 3H), 1.21 (s, 3H), 1.34 (m, 1H), 1.47 (m, 1H),
1.53−1.68 (m, 3H), 1.73−1.91 (m, 4H), 1.97−2.05 (m, 1H),
2.06 (s, 3H), 2.22−2.30 (m, 1H), 2.71 (d, J = 4.6 Hz, 1H),
2.83 (d, J = 4.6 Hz, 1H), 4.71 (d, J = 7.3 Hz, 1H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 15.5, 21.7, 25.5 (CH2), 26.6,
27.0, 36.0 (CH2), 39.4 (CH2), 41.6 (CH2), 41.9, 42.6 (Cq),
52.9, 53.1 (CH2), 54.0 (Cq), 58.1, 61.0 (Cq), 74.5, 169.8 (Cq)
ppm. [α]2D0 = −60.3 (c = 1.0, CHCl3).
β-Epoxy Cedren-9-ol (cis-9).25 A two-necked flask was
charged with β-cedren-9-ol (6, 111 mg, 0.50 mmol), 1,1′-
sulfonyldiimidazole (198 mg, 1.00 mmol) and H2O2 (30%,
0.41 mL, 4.00 mmol) dissolved in MeOH (4 mL). The mixture
was cooled to 5 °C (cHex/dry ice). NaOH (160 mg, 4.00
mmol, 2 M in H2O) in MeOH (10 mL) was added slowly via a
syringe pump with a flow rate of 5 mL·h−1 over a period of 2 h.
The reaction was quenched by adding ice water (20 mL), and
the mixture was extracted with Et2O (3 × 15 mL). The
combined organic layers were washed with aq. NaHCO3 (15
mL), H2O (15 mL), and brine (15 mL); dried over Na2SO4;
and evaporated under reduced pressure. After purification of
the crude product via column chromatography (cHex/EtOAc
5:1), product cis-9 was obtained as a colorless solid (115 mg,
0.487 mmol, 97%). 1H NMR (300 MHz, CDCl3): δ = 0.88 (d,
J = 7.0 Hz, 3H), 0.97 (s, 3H), 1.11 (s, 3H), 1.24 (dd, J = 12.3,
10.4 Hz, 1H), 1.27−1.50 (m, 2H), 1.56 (s, 3H), 1.55−1.95
(m, 5H), 2.16 (ddd, J = 12.3, 7.2, 2.7 Hz, 1H), 2.64 (d, J = 4.7
Hz, 1H), 3.07 (d, J = 4.7 Hz, 1H), 4.08 (td, J = 10.6, 7.2 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.6, 25.7, 25.9
(CH2), 26.9, 36.7 (CH2), 41.5 (CH2), 41.7, 41.8 (Cq), 43.2
(CH2), 51.9 (CH2), 54.4 (Cq), 56.4, 57.7, 61.7 (Cq), 65.9
ppm. [α]2D0 = 4.22 (c = 1.0 CHCl3).
β-Cedrenyl Acetat (8).24 β-Cedren-9-ol (6, 800 mg, 3.63
mmol) and DMAP (22 mg, 0.18 mmol) were dissolved in
anhydrous CH2Cl2 (8 mL). Subsequently, Ac2O (556 mg, 5.45
mmol, 0.51 mL) was added dropwise at 21 °C. After the
reaction mixture was stirred for 17 h, CH2Cl2 (4 mL) was
added. The reaction was carefully quenched with H2O (4 mL).
The organic phase was washed with sat. aq. KHCO3 (4 mL)
and dried over Na2SO4. After the removal of all volatiles under
reduced pressure, product 8 (909 mg, 3.46 mmol, 95%) was
obtained as a colorless oil without further purification. Rf
(SiO2, cHex/EtOAc, 3:1) = 0.68. 1H NMR (300 MHz,
CDCl3): δ = 0.85 (d, J = 7.0 Hz, 3H,), 0.98 (s, 3H), 0.99 (s,
3H), 1.24−1.49 (m, 4H), 1.53−1.65 (m, 1H), 1.70−1.93 (m,
4H), 2.02−2.12 (m, 1H), 2.13 (s, 3H), 2.35−2.38 (m, 1H),
4.71−4.73 (m, 2H), 5.56 (ddt, J = 10.3, 7.8, 2.5 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.6 (CH2), 21.3 (CH2),
26.1, 26.4 (CH2), 26.8 (CH2), 36.9, 40.7, 41.9 (CH2), 42.4
(C), 44.8, 54.8 (Cq), 57.0 (CH2), 60.7 (CH2), 72.0 (CH2),
107.0 (C(O)−CH3), 148.9 (C), 170.6 (CO) ppm. IR
(ATR): λ−1 = 2942(m), 2870 (m), 1738 (s), 1647 (w), 1456
(w), 1375 (m), 1233 (vs), 1167 (w), 1131 (w), 1086 (w),
1039 (m), 1026 (m), 984 (w), 892 (m), 638 (w), 604 (w),
549 (w), 472 (w) cm−1. MS (EI, 70 eV): m/z (%):262 (3)
[M+], 220 (7), 202 (31), 187 (12), 177 (70), 159 (59), 145
(20), 131 (33), 118 (100), 105 (32), 91 (76), 79 (23), 69
(86), 55 (26), 43 (54). [α]2D2 = +20.4 (c = 1.0, MeOH).
HRMS-ESI (m/z) calcd for C17H26O2 [M + Na]+ 285.1825,
found 285.1826.
β-Cedrenyl p-Nitrobenzoate (10). Under Ar, β-cedren-9-
ol (6, 200 mg, 0.908 mmol) was dissolved in anhydrous
CH2Cl2 (6 mL), Et3N (0.190 mL, 1.38 mmol) was added, and
the mixture was cooled to 0 °C. p-Nitrobenzoyl chloride (185
mg, 0.998 mmol) was slowly added, and the mixture was
stirred at 21 °C for 24 h. Subsequently, the mixture was
washed with sat. KHCO3 (5 mL) and brine (5 mL). After
drying over Na2SO4 and evaporation under reduced pressure,
the crude product was purified via column chromatography
using cHex/EtOAc (20:1) as an eluent mixture. Product 10
(176 mg, 0.476 mmol, 52%) was obtained as a pale orange
1
epi-β-Cedrenyl Acetate (epi-8). Under argon, epi-6 (153
mg, 0.694 mmol) and DMAP (4 mg, 0.03 mmol) were
dissolved in anhydrous CH2Cl2 (4 mL). Afterward, Ac2O (106
mg, 1.04 mmol) was added, and the resulting mixture was
stirred at 21 °C for 24 h. The reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with sat. aq. NaHCO3 (10 mL)
and H2O (10 mL). After drying of the organic layer over
solid. Rf (SiO2, cHex/EtOAc, 20:1) = 0.9. H NMR (400
MHz, CDCl3): δ = 0.88 (d, J = 7.0 Hz, 3H), 1.02 (s, 3H), 1.06
(s, 3H), 1.29−1.54 (m, 4H), 1.57−1.70 (m, 1H), 1.71−2.01
(m, 4H), 2.21 (ddd, J = 10.9, 7.7, 2.6 Hz, 1H), 2.44 (d, J = 4.2
Hz, 1H), 4.76−4.79 (m, 2H), 5.85 (ddt, J = 10.2, 7.7, 2.4 Hz,
1H), 8.26−8.32 (m, 4H) ppm. 13C NMR (101 MHz,CDCl3):
δ = 15.6, 26.1 (CH2), 26.5, 26.8, 37.0 (CH2), 40.7 (CH2), 41.9
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Scheme 3. Synthesis of β-Cedrene-9-ol (6) by Photo-oxidation Starting from (−)-α-Cedrene (1) and by Isomerization of cis-
a
Cedrene Epoxide (cis-2)
a
Reaction conditions: (i) (a) O2, rose bengal, hν, CH3CN, 40 °C, 4.5 h; (b) PPh3, CH3CN, 21 °C, 16 h. (ii) LDA, THF, −78 °C, 48 h.
(CH2), 42.5, 44.8 (CH2), 54.9 (Cq), 57.2, 60.7, 73.8, 77.4
(Cq), 107.5 (CH2), 123.7, 130.9, 136.0 (Cq), 148.4 (Cq) ppm.
epi-β-Cedrenyl p-Nitrobenzoate (epi-10). β-Cedren-9-
ol (6, 2.0 g, 9.1 mmol), p-nitrobenzoic acid (1.97 g, 11.8
mmol), and triphenyl phosphine (2.6 g, 10 mmol) were
dissolved in a mixture of anhydrous toluene (5 mL) and
anhydrous THF (2 mL). The mixture was cooled to 0 °C.
Diisopropyl azodicarboxylate (DIAD) (2.0 g, 10 mmol) was
added dropwise at 0 °C without letting the temperature exceed
10 °C. After complete addition, the mixture was stirred at 21
°C for 42 h. Subsequently, all volatiles were removed under
reduced pressure. The residue was carefully overlaid with Et2O
and after leaving it in the fridge overnight a colorless solid
precipitated. The suspension was sonicated while dropwise
adding cHex. The precipitate was filtered off and washed
thoroughly with cHex/Et2O (1:1). This was repeated three
times. Afterward, the solvent was removed under reduced
pressure to give a yellow oil, which was further purified via
column chromatography (SiO2, cHex/EtOAc, 50:1). The
resulting solid was recrystallized from MeOH to give epi-10
(2.91 g, 7.87 mmol, 87%) as colorless crystals suitable for X-ray
crystal structure analysis. Rf (SiO2, cHex/EtOAc, 3:1) = 0.77.
1H NMR (300 MHz, CDCl3): δ = 0.85 (d, J = 7.0 Hz, 3H),
1.04 (s, 3H), 1.14 (s, 3H), 1.20−1.97 (m, 8H), 2.08 (dd, J =
14.9, 7.3 Hz, 1H), 2.24−2.36 (m, 1H), 2.39 (d, J = 4.2 Hz,
1H), 5.09 (d, J = 1.8 Hz, 1H), 5.23 (dd, J = 1.9, 0.9 Hz, 1H),
5.91 (d, J = 7.4 Hz, 1H), 8.14−8.24 (m, 2H), 8.24−8.36 (m,
2H). ppm. 13C NMR (101 MHz, CDCl3): δ = 15.6, 21.8, 25.6
(CH2), 26.6, 28.0, 36.1 (CH2), 41.2 (CH2), 41.9, 43.4 (CH2),
43.5 (Cq), 53.5 (Cq), 54.8, 59.7, 73.0, 74.5, 119.4 (CH2),
123.7, 130.8, 136.5 (Cq), 148.5 (Cq), 150.5 (Cq), 164.3 (Cq)
ppm. IR (ATR): λ−1 = 3112 (w), 2942 (m), 2871 (m) 1711
(s), 1638 (w), 1606 (m), 1521 (s), 1458 (w), 1409 (w), 1382
(w), 1346 (s), 1320 (w), 1270 (s), 1197 (w), 1170 (w), 1117
(m), 1101 (s)1061 (w), 1012 (m), 1028 (m), 984 (m), 967
(w), 927 (m), 907 (m), 874 (s), 855 (m), 826 (m), 785 (m),
717 (s), 653 (w), 590 (w), 505 (w), 483 (w), 436 (w) cm−1.
MS (EI, 70 eV): m/z (%): 369 (4) [M+], 284 (50), 253 (5),
202 (18), 187 (8), 159 (38), 150 (42) 91 (100). [α]2D2 = −20.0
(c = 1.0, CHCl3). HRMS (EI): m/z calcd for C22H27NO4
369.1935; found: 369.1932.
isolated in 43% yield. The isomerization of cis-cedrene epoxide
(cis-2), which is readily available from 1, is an attractive
alternative route to allyl alcohol 6. In this regard, we studied
the use of NbCl5, aminophenols, and bifunctional phospho-
nium salts as catalysts for the isomerization of epoxide cis-2
under various reaction conditions.26 Besides the desired
product 6, usually significant amounts of cedralon (4) were
formed. The best result was obtained using NbCl5 (0.5 mol %)
with Bu4NBr (5 mol %) as a cocatalyst. After 24 h at 100 °C,
the desired product alcohol 6 was isolated in 42% yield.
Venturello and co-workers described the isomerization of
epoxidized monoterpenes in the presence of lithium
diisopropylamide (LDA).27 We adopted this protocol for the
conversion of cis-cedrene epoxide (cis-2). Under slightly
modified conditions, 6 was obtained in 87% on a multigram
scale.26
As outlined above, the correct stereochemistry of the allylic
alcohol is crucial for the subsequent selective synthesis of cis-3.
The stereochemistry of the allyl alcohol synthesized by photo-
oxidation was determined using NOESY experiments. The
LDA-mediated isomerization gave crystals suitable for X-ray
crystallographic studies, and the stereochemistry of 6 was
confirmed at the newly formed chirality center C9 (Figure
1).26
Figure 1. ORTEP representation of β-cedrene-9-ol (6). Displacement
ellipsoids correspond to 30% probability.28
The preparation of 1,2-diols from allylic alcohols or acetates
with exocyclic double bonds has been previously de-
scribed.29−32 Based on a report from Ogawa and co-workers
on the epoxidation of methylene cyclohexyl acetate derivatives,
we envisioned that the epoxidation of acetyl-protected β-
cedrene-9-ol 8 should lead to the desired epoxide cis-7. Thus,
initially, allyl alcohol 6 was converted into the corresponding
acetate 8 in an excellent yield of 95%, following a modified
protocol reported by Tomi et al. using DMAP as an acylation
catalyst in the absence of an additional base (Scheme 4).26,33
Subsequently, epoxidation with m-CPBA at 100 °C gave β-
RESULTS AND DISCUSSION
■
As outlined in the retrosynthetic analysis for the stereoselective
preparation of cis-3 in Scheme 2, we started our studies with
the evaluation of synthetic routes toward allyl alcohol 6
(Scheme 3). Zhang and co-workers reported photocatalyzed
oxidation of cedrene (1) to 6 using molecular oxygen as the
oxidant.14 In our hands, the reaction showed insufficient
conversion under the reported conditions, which might be due
to differences in the reaction set up. After reduction of the
hydroperoxide with triphenylphosphane, compound 6 was
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a
Scheme 4. Synthetic Pathway toward cis-5a Starting from Allyl Alcohol 6
a
Reaction conditions: (i) DMAP (5 mol %), Ac2O, CH2Cl2, 21 °C, 17 h; (ii) m-CPBA, CH2Cl2, 21 °C, 20 h; (iii) 1,1’-sulfonyldiimidazol, NaOH,
MeOH, H2O2, 5 °C, 3 h; (iv) LiAlH4, CH2Cl2, 0 °C, 2 h; (v) 2,2’-dimethoxypropane, p-TSA (10 mol %), CH2Cl2, 21 °C, 10 h.
epoxy cedrenyl acetate (cis-7) in 59% yield. When the reaction
was conducted at ambient temperature, an increased yield of
88% was obtained.
to give cis-5a in 90% yield. To reduce the reaction time, the
temperature was increased to 40 °C. However, after 4 h, cis-5
was obtained only in a moderate yield of 38% and significant
amounts (45%) of the isomerization product cedralon (4)
were formed. Compared to the current route (Scheme 1), this
approach allows the selective synthesis of acetonide cis-5a.
Additionally, the overall yield is significantly improved from 17
to 66%, starting from cis-cedrene epoxide (cis-2). When
starting from the also commercially available β-cedrene-9-ol
(6), the overall yield is 74%. Even shorter access to cis-5a can
be realized by the direct epoxidation of allyl alcohol 6,
following the procedure reported by Schulz.25 In this case, 1,1′-
sulfonyldiimidazol in combination with H2O2 is used as an
epoxidation reagent and cis-9 is obtained in 97% yield.
Interestingly, attempts to epoxidize cis-9 with m-CPBA failed.
Following the reduction protocol for cis-7 with LiAlH4, epoxide
cis-9 was directly reduced, yielding cis-3 in >99% yield. We also
evaluated the possibility to reduce cis-9 with molecular
hydrogen instead of LiAlH4.26 Even though considerable
efforts were made in this regard, the desired product cis-3
could not be obtained. However, the sequence via the direct
epoxidation of 6 allowed the further improvement of the
overall yield of cis-5a starting from cis-cedrene epoxide (cis-2)
to 78%. Although this route seems to be less attractive for
industry due to the formation of imidazole and imidazole
sulfonic acid as by-products as well as the much higher prize of
1,1′-sulfonyldiimidazole compared to m-CPBA.
To obtain the desired product cis-5a, it is crucial that the
epoxidation occurs in cis orientation with respect to the acetate
group. The compound cis-7 was reduced using LiAlH4. The
hydride opens the epoxide regioselectively to the tertiary
alcohol. Additionally, the acetate group is cleaved off. The
cedrene diol (cis-3) was obtained in an excellent yield of 98%.
We confirmed the desired cis-configuration at C8 and C9 via a
NOESY experiment as well as X-ray analysis (Figure 2). The
crystal structure of cis-3 was also previously reported by Song
and co-workers.26,34
Figure 2. ORTEP representation of cedrene diol (cis-3). Displace-
ment ellipsoids correspond to 30% probability.28
In olfactory research knowledge about structure−odor
relationships can facilitate the design of novel fragrance
ingredients.38−40 Thus, studies on such structure−activity
relationships are of general interest. Hence, we were also
interested in the synthesis of diastereomeric cis-cedrene
acetonide cis-5a. We envisioned that the reaction sequence
to access cis-5 via ester 8 might also allow the stereoselective
synthesis of diastereomer cis-5a by inverting the stereo-
chemistry of allylic alcohol 6 by a Mitsunobu reaction
Subsequently, the diol cis-3 was converted into the desired
acetal cis-5a. Performing an acetalization with acetone in the
presence of sulfuric acid as a catalyst gave complete conversion
to the ketone cedralon (4).35−37 However, in the presence of
p-TSA (10 mol %) and an excess of 2,2-dimethoxypropane,
substrate exo-5 was converted at ambient temperature for 10 h
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a
Scheme 5. Mitsunobu Reaction of 6 and Following Conversion of epi-10
a
Reaction conditions: (i) p-nitrobenzoic acid, PPh3, DIAD, toluene/THF, 0 °C → 21 °C, 96 h; (ii) KOH, tBuOH/H2O, 21 °C, 16 h; (iii) Ac2O,
DMAP (5 mol %), CH2Cl2, 21 °C, 24 h; and (iv) m-CPBA, CH2Cl2, 21 °C, 26 h.
simultaneously forming an ester. Therefore, 6 was converted in
a Mitsunobu reaction using p-nitrobenzoic acid under
conditions known to be suitable for sterically demanding
substrates (Scheme 5).41−44 Under the conditions reported by
Dodge et al., the desired product epi-β-cedrenyl p-nitro-
benzoate (epi-10) was obtained in 88% using a large excess of
p-nitrobenzoic acid, PPh3, and diisopropyl azodicarboxylate
(DIAD). Notably, further optimization of the solvent mixture
and reaction conditions allowed to significantly reduce the
amounts of the required reagents, leading to a comparable
yield. In the presence of p-nitrobenzoic acid (1.3 equiv), PPh3
(1.1 equiv), and DIAD (1.1 equiv), ester epi-10 was isolated in
87% yield.26
We were able to isolate crystals of epi-9 suitable for X-ray
crystallographic analysis. The molecular structure of epi-9
indicates the expected inversion of the stereochemistry at C9
(Figure 3). This was also confirmed by comparison of the
NOESY spectra of epi-9 and 9, which were prepared via
esterification of 6 using p-nitrobenzoic acid chloride.26
were tested. However, in all cases, low conversions were
obtained and the desired epoxide was not detected.
Consequently, allyl alcohol epi-6 was converted to the
corresponding acetate epi-8, which was then epoxidized with
m-CPBA. We were delighted to obtain the epoxidized product
in >99% yield. However, analysis by NMR spectroscopy
revealed that epoxidation occurred trans with respect to the
acetate functionality and product trans-7 was obtained. The
stereoselectivity of the epoxidation is obviously controlled by
the substrate that favors the oxidation trans with respect to the
2-propylidene bridge. The stereochemistry of the epoxide was
confirmed by NOE experiments.26 We proposed to prepare
trans-diol trans-3 from epoxide trans-7 following the above-
established protocol for the reduction of exo-8a. However, the
reduction of exo-8a using LiAlH4 to obtain trans-3 only led to
the formation β-cedrenone. Other attempts to reduce trans-7
to e.g., using DIBAL-H or Li in EDA48,49 were unsuccessful.
CONCLUSIONS
■
In summary, we herein reported a synthetic pathway toward
cis-cedrene diol and cis-cedrene acetonide. The achieved
overall yield was significantly improved compared to the
current technical synthesis. Starting from commercially
available cedrene epoxide isomerization under basic conditions
led to the respective allylic alcohol in 89% yield. Notably, this
reaction was performed on a multigram scale. The photo-
oxidation of natural occurring (−)-α-cedrene gave only 43% of
this key intermediate. After esterification and subsequent
epoxidation of the exocyclic double bond the obtained epoxide
was converted with LiAlH4. This led to the ring opening of the
epoxide and simultaneous reductive cleavage of the ester.
Subsequent acetalization led to the desired product as a single
diastereomer in an overall yield of 66%, starting from cedrene
epoxide. When allyl alcohol β-ceden-9-ol is directly epoxidized
without the protection of the hydroxyl group, the overall yield
was improved to 74%. To selectively prepare the cis-diol with
inverted stereochemistry, we successfully converted the allyl
alcohol β-cedren-9-ol in a Mitsunobu reaction yielding 89% of
the Mitsunobu ester with inverted stereochemistry, which was
confirmed by X-ray crystal structure analysis. Notably, only the
acetyl-protected alcohol could be epoxidized, leading the
undesired trans-product in >99% yield.
Figure 3. ORTEP representation of β-cedrenyl p-nitrobenzoate (epi-
10). Only one of the two molecules of the asymmetric unit is
depicted. Displacement ellipsoids correspond to 30% probability.
Hydrogen atoms are omitted for clarity.28
Epoxidation of epi-9 using m-CPBA under the conditions
used for 8 led to decomposition of the starting material. Thus,
we prepared epi-6 by saponification of epi-10. Subsequent
conversion of alcohol epi-6 with H2O2 in the presence of 1,1′-
sulfonyldiimidazole led to decomposition, and a complex
reaction mixture was obtained. We also attempted the
epoxidation of epi-6 by the Sharpless epoxidation45,46 as well
as a modified variant using hydride and silica47 as additives.
Both enantiomers of diethyl tartrate as well as the racemate
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̈
(12) Holscher, B. Cyclic Acetals and Ketals and Their Use thereof as
Fragrances. WO2014/183883 A12014.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00423.
(13) Betzer, M.; Lambrecht, S.; Eh, M. Use of Ambrocenide for
Intensifying a Lily of the Valley Scent. WO2017/174827 A12017.
(14) Wu, W.; An, F.; Geng, Z.; Zhang, R.; Jiang, Z. Novel and
Versatile Photosensitized Oxygenation Reaction of α-Cedrene. Lett.
Org. Chem. 2013, 10, 223−227.
(15) Schatkowski, D.; Knoop, D.; Lambrecht, S. New Mixtures
Containing (4aR,5R,7aS,9R)-Octahydro-2,2,5,8,8,9a-hexamethyl-4H-
4a,9-methanoazuleno(5,6-d)-1,3-dioxol) (ambrocenide ). WO2015/
176833 A12015.
Additional screening experiments, additional procedures,
NOESY spectra of selected compounds, H and 13C
1
NMR spectra of all synthesized compounds, and
crystallographic details (PDF)
(16) Eh, M.; Lambrecht, S. Blends Containing Enantiomerically
Pure Ambrocenide. WO2017/186973 A22017.
AUTHOR INFORMATION
■
Corresponding Author
(17) Zaitsev, A. B.; Adolfsson, H. Recent Developments in
Asymmetric Dihydroxylations. Synthesis 2006, 2006, 1725−1756.
(18) Schroeder, M. Osmium tetraoxide cis hydroxylation of
unsaturated substrates. Chem. Rev. 1980, 80, 187−213.
(19) Song, Y.; Ding, Z.; Wang, Q.; Tao, F. Preparation of
Cedranediol Boronic Esters. Synth. Commun. 1998, 28, 3757−3764.
(20) Gadamasetti, K.; Braish, T. Process Chemistry in the
Pahrmaceutical Industry. In Challenges in Ever-Changing Climates;
CRC Press: Boca Raton, 2007; Vol. 2.
Thomas Werner − Leibniz Institute for Catalysis at the
University of Rostock, 18059 Rostock, Germany;
orcid.org/0000-0001-9025-3244;
Email: thomas.werner@catalysis.de
Authors
Vivian Stefanow − Leibniz Institute for Catalysis at the
University of Rostock, 18059 Rostock, Germany
Aiga Grandane − Leibniz Institute for Catalysis at the
University of Rostock, 18059 Rostock, Germany
Marcus Eh − Symrise AG, 37603 Holzminden, Germany
Johannes Panten − Symrise AG, 37603 Holzminden,
Germany
(21) Griffith, W. P. Osmium Tetroxide and Its Applications.
Platinum Met. Rev. 1974, 18, 94−96.
̈
(22) Buttner, H.; Steinbauer, J.; Wulf, C.; Dindaroglu, M.; Schmalz,
H. G.; Werner, T. Organocatalyzed Synthesis of Oleochemical
Carbonates from CO2 and Renewables. ChemSusChem 2017, 10,
1076−1079.
Anke Spannenberg − Leibniz Institute for Catalysis at the
University of Rostock, 18059 Rostock, Germany
(23) Werner, T.; Buttner, H. Phosphorus-based Bifunctional
̈
Organocatalysts for the Addition of Carbon Dioxide and Epoxides.
ChemSusChem 2014, 7, 3268−3271.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00423
(24) Goel, D.; Singh, V.; Ali, M.; Mallavarupu, G. R.; Kumar, S.
Essential oils of petal, leaf and stem of the antimalarial plant Artemisia
annua. J. Nat. Med. 2007, 61, 187−191.
Notes
(25) Kluge, R.; Schulz, M.; Liebsch, S. Diastereoselective
Epoxidation of Olefins by Organo Sulfonic Peracids, II. Tetrahedron
1996, 52, 2957−2976.
The authors declare no competing financial interest.
(26) See Supporting Information for further details.
ACKNOWLEDGMENTS
■
(27) Deagostino, A.; Tivola, P. B.; Prandi, C.; Venturello, P.
Lithium-potassium superbases as key reagents for the base-catalysed
isomerisation of some terpenoids. J. Chem. Soc., Perkin Trans. 1 2001,
2856−2860.
(28) CCDC 2023906−2023908 contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service www.
ccdc.cam.ac.uk/structures. Selected crystallographic details are also
given in the Supporting Information (see Table S8).
We thank Fabian Fischer and Dr. Ralf Jackstell for their
support.
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