A general strategy for the stereoselective synthesis of the furanosesquiterpenes structurally related to pallescensins 1-2

Article abstract of DOI:10.3390/md17040245

Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1-2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by means of the coupling of the C₁₀ cyclogeranyl moiety with the C₅ 3-(methylene)furan moiety. The key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers, their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group to afford the whole sesquiterpene framework. The enantioselective synthesis of the α-, 3,4-dehydro-γ- and γ-cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and different regioselective chemical transformations.

Full text of DOI:10.3390/md17040245

marine drugs
Article
A General Strategy for the Stereoselective Synthesis
of the Furanosesquiterpenes Structurally Related to
Pallescensins 1–2
Stefano Serra
Consiglio Nazionale delle Ricerche (C.N.R.) Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7,
20131 Milano, Italy; stefano.serra@cnr.it; Tel.: +39-02-2399 3076
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 22 March 2019; Accepted: 23 April 2019; Published: 25 April 2019
Abstract: Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes
structurally related to pallescensins 1–2. The stereoisomeric forms of the pallescensin 1, pallescensin
2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas
isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by
means of the coupling of the C10 cyclogeranyl moiety with the C5 3-(methylene)furan moiety. The
key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers,
their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation
with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group
to afford the whole sesquiterpene framework. The enantioselective synthesis of the
and -cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and
different regioselective chemical transformations.
α-, 3,4-dehydro-γ-
γ
Keywords:
pallescensin 1; pallescensin 2; dihydropallescensin 2; isomicrocionin-3;
pallescensone; furanosesquiterpenes; stereoselective synthesis; lipase-mediated resolution;
cyclogeranylsulfonylbenzene isomers
1. Introduction
The furanosesquiterpenes are a large family of terpenoids that have been isolated from different
natural sources. Among these compounds, those possessing a chemical framework consisting of a
mono-cyclofarnesyl moiety linked to the 3-furyl moiety (compounds of type
small subclass whose components occurs only in marine environments.
1, Figure 1) constitute a
The first studies of these natural products date back to 1970s when pallescensin-1 (
pallescensin-2 ( ) were isolated from the sponge Dysidea pallescens [ ], together with other structurally
related sesquiterpenes. Afterward, these compounds were also detected in other sponges [ ] and in
some nudibranchs that feed on sponges [ ]. Moreover, the pallescensin-1 isomers isomicrocionin-3
) [ ] and dihydropallescensin-2 ( ) [ ] were isolated contextually to the above-mentioned studies
as well as during the course of researches finalized to the characterization of metabolites derived
from marine organisms. In addition, the ketone derivative pallescensone ( ) was obtained from
], and later, from
2) and
4
1
2,3
4
(3
3
5 2,4–7
6
the dichloromethane extract of the New Zealand sponge Dictiodendrilla cavernosa [
8
different nudibranch species [9,10].
Almost immediately after their identification, both the chemical structure and the absolute
configuration of the pallescensin-1 ( ) and of the pallescensin-2 ( ) were confirmed by chemical
synthesis [11]. Thereafter, several new synthetic approaches [12 19] provided compounds , and
2
4
–
2
,
5
6
both in racemic and in enantioenriched forms. Curiously, isomicrocionin-3 (3) has not been prepared
yet, whereas pallescensis-2 (4) has been synthesized only in racemic form.
Mar. Drugs 2019, 17, 245; doi:10.3390/md17040245
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Figure 1. Representative examples of natural furanosesquiterpenes showing molecular framework of
type 1.
The reported syntheses were studied in order to confirm a proposed chemical structure or to assign
the absolute configuration to a given metabolite. Overall, the preparation of the sesquiterpenes
2–6
was studied on a case-by-case basis. Therefore, a reliable and general synthetic approach to this class
of compounds is still lacking. In addition, some of these sesquiterpenes have shown biological activity,
but the limited amount of the available natural material precluded their comprehensive evaluation.
For example, compounds
antifeedant activity against their predators [
the whole dichloromethane extract of the mollusks [10], thus the determination of the real antifeedant
contribute of each furanosesquiterpene could not be determined. Similarly, the antibacterial activity [
of the pallescensin-1 ( ) and the inhibitory activity against human tyrosine protein phosphatase
1B (hPTP1B) [ ] of the dihydropallescensin-2 ( ) were evaluated only for the natural occurring (S)
5
and
6
were isolated from nudibranch mollusks and are thought to possess
4–
10]. This ability was experimentally confirmed only on
3]
2
7
5
enantiomers. Since the enantiomeric composition of a given compound could affect its biological
properties, it is clear that the reported data are not enough to give a proper characterization of the
biological activity of these metabolites. Overall, the aforementioned considerations point to the need
of a general and stereoselective synthetic method for the preparation of all the isomeric forms of
these furanosesquiterpenes.
By taking advantage of our previously acquired expertise in the enantioselective synthesis of
monocyclofarnesyl terpenoids [20–23] and cyclogeraniol isomers [24], we decided to devise a synthetic
procedure that could comply with the above-described requirements.
Our synthetic plan is exemplified by the retrosynthetic analysis described in Figure 2. Accordingly,
we envisioned to prepare the target molecules of type
1
through the reductive cleavage of
, which can be in turn obtained by alkylation of the
with 3-(chloromethyl)furan . The latter lithium salt
the phenylsulfonyl derivatives of type
cyclogeranylsulfonylbenzene derivatives
7
8
9
can be prepared by reaction of a commercially available alkyllithium reagent (e.g., BuLi) with the
cyclogeranylsulfonylbenzene derivatives, in turn synthesizable from the corresponding enantiopure
cyclogeraniol isomers 10. Of course, none of the above-described chemical transformations should
involve side reactions, such as the double bond isomerization or the racemization, which could end up
with decreasing the isomeric purity of the chemical intermediates, and thus, of the target compounds 1.

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Figure 2.
The proposed retrosynthetic analysis for the stereoselective synthesis of the
furanosesquiterpenes possessing molecular framework of type 1.
Herein, we describe the accomplishment of this synthetic plan, whose effectiveness was confirmed
by the stereoselective preparation of some selected furanosesquiterpenes, namely (S)-pallescensin-1
(
−
)-
of the presented approach were also discussed as highlighted with the stereoselective synthesis of
(R)-pallescensone ( )-( ), which again required a building block of type 10 as starting material but
2
, isomicrocionin-3 (
3
), (R)-pallescensin-2 (
−
)-(
4
), and (R)-dihydropallescensis-2 (
−
)-(5). The limits
−
6
with the use of a different synthetic path.
2. Results and Discussion
According to our retrosynthetic analysis, we started with the stereoselective preparation of
the cyclogeraniol isomers 10. The
asymmetric synthesis [25] and resolution procedure [26]. Since racemic
α
-cyclogeraniol enantiomers were already prepared using both
-cyclogeraniol is easily
α
synthesizable from ethyl geraniate [24], the lipase-mediated resolution procedure is the most suitable
approach for the preparation of both the enantiomeric forms (Figure 3) of the alcohol 10a.
In order to find out a proper enzyme to be employed in this process, we investigated the reactivity
of ( )-10a toward irreversible acetylation using vinyl acetate as acyl donor in the presence of lipase
±
catalyst. We checked three different commercial enzymes, namely porcine pancreatic lipase (PPL),
Candida rugosa lipase (CRL), and lipase from Pseudomonas sp., (lipase PS). These preliminary experiments
indicated that only lipase PS catalyzed the esterification reaction with an enantioselectivity acceptable
to perform a proper enantiomers separation (enantiomeric ratio E = 9.2). Our findings agree with
previous reported studies on the same enzymatic transformation [26], which assessed an enantiomeric
ratio of 12.9 for lipase PS.
Accordingly, our resolution procedure furnished the enantioenriched alcohols (S)-(+)-10a and
(R)-(
−
)-10a that were converted in the corresponding sulfones (S)-(+)-11a and (R)-( )-11a, respectively.
−
This chemical transformation was accomplished by means of a high yielding, three steps procedure [27],
consisting of the reaction of alcohol 10a with tosyl chloride, nucleophile substitution of the obtained
tosylate with potassium thiophenate in dry DMF, followed by sodium molybdate catalysed oxidation of
the resulting sulfide using an excess of hydrogen peroxide in methanol. Other synthetic methods, usually
employed for the transformation of a hydroxyl functional group into a phenylsulfonyl group, afford
sulfones 11 in inferior yields. For example, the reaction of the diphenyldisulfide/tributylphosphine
reagent [28] with 3,4-dehydro-γ-cyclogeraniol or with γ-cyclogeraniol give the expected sulfide
derivatives close to a significant amount of elimination side products. For this reason, we decided to
employ exclusively the above-described thiophenate displacement procedure for the synthesis of the
four sulfones 11a–d.
Concerning
aldehyde is commercially available since it is employed both as building block for carotenoids
synthesis and as flavor ingredient [29 30]. The reduction of 12 with NaBH4 in methanol afforded
quantitatively -cyclogeraniol 10b that was converted into sulfone 11b according to the general
β-cyclogeraniol, we selected β-cyclocitral 12 as starting compound. The latter
,
β
procedure described above.
For the stereoselective synthesis of γ-isomers 11c and 11d, we used diol 13 as a common starting
compound. According to our previous studies [24], the latter racemic diol is preparable in high

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diastereoisomeric purity starting from
α
-cyclogeraniol. The following lipase PS mediated resolution
procedure afforded diols (4R,6S)-( )-13 and (4S,6R)-(+)-13 in high enantiomeric purity. Each one of
−
these two enantiomers was transformed into the corresponding enantiomeric forms of the acetates 14
and 15. Accordingly, the chemical acetylation of the diol 13 enantiomers afforded the corresponding
diacetates that were submitted to two different chemical reactions, aimed to the cleavage of the
secondary allylic acetate group. The regioselective elimination of the latter group was accomplished
refluxing the diacetates in dioxane, in presence of calcium carbonate and palladium acetate catalyst [31].
This process allow the conversion of the diols (
)-14, respectively. Similarly, the diacetate derivatives of the diols (
using triethylammonium formate, in refluxing tetrahydrofuran (THF) and in presence of the palladium
catalyst to afford -cyclogeraniol acetate enantiomers (+)-15 and ( )-15, respectively [24]. It is worth
−
)-13 and (+)-13 into diene derivatives (+)-14 and
(−
−
)-13 and (+)-13 were reduced
γ
−
noting that both reactions proceeded without appreciable formation of other isomers deriving from
double bonds isomerization.
Figure 3. Synthesis of the stereoisomeric forms of the cyclogeranylsulfonylbenzene derivatives 11a-d
starting from the racemic cyclogeraniol derivatives 10a and 13 and from
conditions: ( ) TsCl, Py, CH2Cl2, DMAP catalyst, rt (room temperature), 4 h; (
rt, 12 h; (
) H2O2, MeOH, (NH4)2MoO4 catalyst, 0 ◦C then rt, 8 h; ( ) NaBH4, MeOH, 0 ◦C; (
Py, DMAP catalyst, rt, 8 h; ( ) CaCO3, PPh3, Pd(OAc)2 catalyst, dioxane, reflux, 5 h; ( ) HCOOH, Et3N,
(PPh3)2PdCl2 catalyst, PPh3, THF, reflux, 6 h; (h) NaOH, MeOH, reflux.
β
-cyclocitral 12. Reagents and
) K2CO3, DMSO, PhSH,
) Ac2O,
a
b
c
d
e
f
g

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This aspect is of pivotal relevance in natural product synthesis, where the biological activity
of a given product is often dependent on its isomeric composition. Finally, the obtained acetates
enantiomers (+)- and (
the obtained alcohols were transformed into sulfones (+)- and (
according to the general procedure used for the synthesis of compounds 11a and 11b.
The obtained sulfones were then used as chiral building blocks for the stereoselective synthesis of
the marine furanosesquiterpenes structurally related to pallescensins. Although we prepared both
−
)-14, (+)- and (
−
)-15 were hydrolyzed using sodium hydroxide in methanol, and
)-11c, (+)- and ( )-11d, respectively,
−
−
enantiomers of the compounds 11a
available in higher enantiomeric purity, according to the resolution procedures of alcohol 10a and diol
13. Therefore, we decided to use the latter sulfone enantiomers for the furanosesquiterpenes synthesis.
,
11c, and 11d, the isomers (
−
)-11a, (
−
)-11c, and ( )-11d were those
−
As described in the retrosynthetic analysis, compounds (
were treated with n-butyllithium (nBuLi) and the resulting lithium salts were alkylated using
−
)-11a
,
11b, (
−
)-11c, and (
−
)-11d
3-(chloromethyl)furan
lithium naphthalenide at low temperature (
through its regioselective reduction. Both alkylation step and phenylsulfonyl group cleavage proceeded
with high chemical yields and compounds ( )-11a 11b, ( )-11c, and ( )-11d were efficiently and
stereoselectively converted into ( )-pallescensin-1 ( ), isomicrocionin-3 ( ), ( )-pallescensin-2 ( ), and
(−)-dihydropallescensin-2 (5), respectively (Figure 4).
9
. The obtained derivatives 7a-d were not isolated and were treated with
◦
−
70 C) in order to remove the phenylsulfonyl group
−
,
−
−
−
2
3
−
4
Figure 4. Use of the cyclogeranylsulfonylbenzene derivatives 11a
–
d
in the stereoselective synthesis
), ( )-pallescensin-2 ( ), and
) nBuLi, THF dry, in DMPU,
60 ◦C, then
of the furanosesquiterpenes (
−
)-pallescensin-1 (
2
), isomicrocionin-3 (
3
−
4
(
−)-dihydropallescensis-2 (
5). Reagents and conditions: (
a
−
9
rt, 2 h; (b) lithium naphthalenide, THF dry, Et2NH, −75 ◦C, 1 h.
The proposed synthesis of compounds
2, 4, and 5 compare favorably over the previously reported
stereoselective methods [11 15 18 19] since the overall yields are higher, the approach is operationally
,
,
,
simple, and it afforded the target compounds in high stereoisomeric purity.
Isomicrocionin-3 was not synthesized before. Therefore, the comparison of the analytical data of
synthetic
us confirming the chemical structure previously assigned to isomicrocionin-3.
Furthermore, as mentioned in the introduction, pallescensis-2 ( ) was synthesized only in racemic
form [11] and the (S) absolute configuration was tentatively assigned to the dextrorotatory isomer.
This assumption is based on the observation that both (+)-pallescensin-2 and ( )-pallescensin-1 were
isolated from the same sponge (Dysidea pallescens) and the absolute configuration of ( )-pallescensin-1
was already assigned by chemical correlation with (S)-( )- -cyclocitral. (S)-( )- and (+)- most likely
3 with those recorded for the natural sesquiterpene isolated from Fasciospongia sp. [3] allows
4
−
−
−
α
−
2
4
possess the same absolute configuration because they were formed through a common biosynthetic
pathway. According to our synthetic procedure, we established a chemical correlation between
(4S,6R)-4-hydroxy-γ-cyclogeraniol (+)-13 and (−)-pallescensin-2 (4), thus confirming unambiguously
that (−)-pallescensin-2 (4) possesses (R) absolute configuration.

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The very good results described above prompted us to investigate a possible exploitation of the
sulfone alkylation approach for the synthesis of pallescensone ( ), a sesquiterpene ketone structurally
related to dihydropallescensin-2 ( ). As described previously [27 32], the lithium salt of a given
6
5
,
phenylsulfonyl derivative can be acylated using anhydrous magnesium bromide and the alkyl ester
of the corresponding acyl moiety. The following cleavage of the phenylsulfonyl group by means of
lithium naphthalenide at low temperature provides the acylated derivative. Unfortunately, we found
that the reaction of phenylsulfone 11d with 3-furoic acid methyl ester afforded the acylated sulfone in
very low yield.
This disappointing result is most likely due to the steric hindrance around the new formed bond,
which does not allow phenylsulfonyl and ketone functional groups to adopt vicinal conformation with
formation of the magnesium complex, whose chemical stability secure the product formation.
For that reason, we decided to study a different approach for the stereoselective synthesis of
ketone
-cyclogeraniol derivatives (Figure 3), we selected the enantiomeric forms of compound 15 as chiral
building blocks for pallescensone synthesis. More enantiopure isomer ( )-15 was used as starting
6. Taking advantage of the above-described process for the preparation of the enantioenriched
γ
−
compound (Figure 5) and the devised synthetic procedure provided pallescensone (
good overall yield (43%).
6) after six steps, in
O
OAc
CN
CHO
e, f
a-c
d
6
O
( )-
85%
51%
16
( )-
15
( )-
17
( )-pallescensone
Figure 5. Stereoselective synthesis of (
Reagents and conditions: ( ) NaOH, MeOH, reflux; (
NaCN, DMSO dry, 80–90 ◦C, 5 h; (
) DIBAL, toluene,
dry, 20 min; (f) IBX, DMSO dry, 40 ◦C, 4 h.
−
)-pallescensone (
) TsCl, Py, CH2Cl2, DMAP catalyst, rt, 4 h; (
70 ◦C, 30 min; ( 70 ◦C, THF
) 3-furyllithium,
6
) starting from
γ
-cyclogeraniol acetate (
−
)-15.
c)
a
b
−
d
e
−
Accordingly, acetate (
−
)-15 was hydrolyzed using sodium hydroxide in methanol and the obtained
γ
-cyclogeraniol was treated with tosyl chloride and pyridine, in presence of the DMAP catalyst. The
nucleophilic substitution of the tosyl functional group with the cyanide group was performed by
reaction with sodium cyanide in dimethylsulfoxide (DMSO), heating at 80–90 ◦C to afford cyanide
(+)-16 in 85% overall yield. The latter compound was then reduced at low temperature (
70 ◦C) using
−
DIBAL in toluene. The resulting aldehyde 17 was not purified and was treated with freshly prepared
3-furyllithium in THF. The obtained crude carbinol was dissolved in dry DMSO and was treated with
an excess of IBX [33] to afford (−)-(R)-pallescensone (6) in 51% overall yield from 16.
The 1H- and 13C-NMR spectroscopic data of the synthesized compound
6
were superimposable
with those reported for the synthetic [18
,
19] and the natural [
8
] sesquiterpene, whereas the measured
20
optical rotation value, [
α
]
= −34.4 (c 1.1, CH2Cl2), show comparable value and opposite sign of the
D
naturally occurring (S)-pallescensone, [α]20D = +36 (c 1.0, CHCl3).
Finally, it should be considered that the enantiomeric forms of γ-homocyclogeranial 17 were used
as a chiral building blocks not only for the synthesis of pallescensone, but also for the preparation of
other sesquiterpenes [18 34] or sesquiterpene analogues [35], thus expanding the prospective utility of
,
this synthon in natural products synthesis.
3. Materials and Methods
3.1. Materials and General Methods
All moisture- and air-sensitive reactions were carried out using dry solvents under a static
atmosphere of nitrogen.

Mar. Drugs 2019, 17, 245
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All solvents and reagents were of commercial quality and were purchased from Sigma-Aldrich (St.
Louis, MO, USA) with the exception of -cyclogeraniol, 3-(chloromethyl)furan and IBX. -Cyclogeraniol
was prepared by reduction of -cyclogeranial using NaBH4 in methanol. 3-(Chloromethyl)furan was
obtained starting from furan-3-carboxylic acid by means of reduction with LiAlH4 and reaction of the
β
β
β
obtained carbinol with mesyl chloride in presence of s-collidine and LiCl [36
starting from o-iodobenzoic acid, according to the literature [33].
,37]. IBX was prepared
Lipase from Pseudomonas cepacia (PS), 30 units/mg, was purchased from Amano Pharmaceuticals
Co., Tokyo, Japan. Enantioenriched -cylogeraniol 10a and cis-4-hydroxy- -cyclogeraniol 13 were
α
γ
prepared by means of the lipase PS-mediated resolution of the corresponding racemic compounds, as
previously described by Vidari [26] and Serra [24], respectively.
3.2. Analytical Methods and Characterization of the Chemical Compounds
1H and 13C-NMR spectra and DEPT (Distortionless enhancement by polarization transfer)
experiments: CDCl3 solutions at room temperature using a Bruker-AC-400 spectrometer (Billerica,
MA, USA) at 400, 100, and 100 MHz, respectively; 13C spectra are proton-decoupled; chemical shifts in
ppm relative to internal SiMe4 (0 ppm).
Thin-layer chromatography (TLC) involved the use of Merck silica gel 60 F254 plates (Merck
Millipore, Milan, Italy), while column chromatography involved the use of silica gel.
Melting points were measured on a Reichert apparatus equipped with a Reichert microscope and
are uncorrected.
Optical rotations were measured on a Jasco-DIP-181 digital polarimeter (Jasco, Tokyo, Japan).
Mass spectra were recorded on a Bruker ESQUIRE 3000 PLUS spectrometer (ESI detector, Billerica,
MA, USA) or by GC-MS analyses.
GC-MS analyses involved the use of an HP-6890 gas chromatograph equipped with a 5973 mass
detector, using an HP-5MS column (30 m
×
0.25 mm, 0.25-µm film thickness; Hewlett Packard, Palo
Alto, CA, USA) with the following temperature program: 60◦ (1 min), then 6◦/min to 150◦ (held at
1 min), then 12◦/min to 280◦ (held 5 min); carrier gas: He; constant flow 1 mL/min; split ratio: 1/30; tR
given in minutes.
The values of tR for each compound are as follows: tR(
) 21.81, tR( ) 3.90, tR(10a) 10.59, tR(10b) 11.32, tR(11a) 25.85, tR(11b) 26.03, tR(11c) 25.71, tR(11d
25.86, tR(14) 14.02, tR(15) 13.86, tR(16) 14.71.
2) 18.70, tR(3) 19.14, tR(4) 18.47, tR(5) 18.48,
tR(
6
9
)
3.3. Stereoselective Preparation of (R) and (S) Enantiomers of 3,4-Dehydro-γ-cyclogeraniol Acetate 14 and
γ-Cyclogeraniol Acetate 15
3.3.1. (R)-3,4-Dehydro-γ-cyclogeraniol Acetate (−)-14
20
A sample of diol (+)-13, (0.5 g, 2.9 mmol; [
α
]
= +29.5 (c 2.8, CHCl3); 98% ee by chiral GC)
D
was converted to the corresponding diacetate by treatment with pyridine (10 mL), DMAP (50 mg, 0.4
mmol) and Ac2O (10 mL) at rt for 8 h. After removal of the solvents, the crude diacetate was dissolved
in dioxane (20 mL) and treated under N2 with Pd(OAc)2 (50 mg, 0.2 mmol), CaCO3 (1 g, 10 mmol), and
PPh3 (270 mg, 1 mmol). The resulting heterogeneous mixture was stirred under reflux for 5 h (TLC
monitoring). The mixture was then cooled to room temperature, diluted with diethyl ether (100 mL), and
filtered. The filtrate was washed successively with saturated aqueous NaHCO3 solution (50 mL) and
brine, dried (Na2SO4), and evaporated. The residue was purified by chromatography (n-hexane/Et2O
95:5–8:2) and bulb-to-bulb distillation to give pure 3,4-dehydro-
(R)-(6,6-dimethyl-2-methylenecyclohex-3-enyl)methyl acetate (480 mg, 84% yield) as a colourless oil;
γ
-cyclogeraniol acetate ( )-14 =
−
20
[
α
]
= δ 6.08 (d, J =
69.9 (c 3.3, CHCl3); 99% of chemical purity by GC. 1H NMR (400 MHz, CDCl3)
−
D
9.8 Hz, 1H), 5.70-5.63 (m, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 4.23 (dd, J = 10.7, 4.6 Hz, 1H), 3.93 (dd, J = 10.7,
9.1 Hz, 1H), 2.21 (dd, J = 9.1, 4.6 Hz, 1H), 2.05 (d, J = 18.6 Hz, 1H), 2.02 (s, 3H), 1.83 (dd, J = 18.6, 5.2 Hz,
1H), 1.02 (s, 3H), 0.92 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 171.0 (C), 143.3 (C), 127.5 (CH), 127.3 (CH),

Mar. Drugs 2019, 17, 245
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114.2 (CH2), 64.2 (CH2), 50.0 (CH), 37.0 (CH2), 31.8 (C), 28.4 (Me), 27.3 (Me), 21.0 (Me). GC-MS m/z (rel
intensity) 134 ([M − AcOH]+, 52), 119 (100), 105 (24), 91 (54), 77 (17), 65 (6), 53 (5).
3.3.2. (S)-3,4-Dehydro-γ-cyclogeraniol Acetate (+)-14
20
The reaction sequence described above was repeated using sample of diol (
−
)-13, ([
α
]
= 26.8
−
D
(c 2.5, CHCl3); 90% ee by chiral GC) to afford pure 3,4-dehydro-
γ
-cyclogeraniol acetate (+)-14
=
20
(S)-(6,6-dimethyl-2-methylenecyclohex-3-enyl)methyl acetate (81% yield) as a colorless oil; [
α
]
=
D
+61.1 (c 3.0, CHCl3); 96% of chemical purity by GC. 1H-NMR, 13C-NMR and GC-MS superimposable
to those described for (R)-isomer.
3.3.3. (R)-γ-Cyclogeraniol Acetate (−)-15
20
A sample of diol (+)-13, (0.9 g, 5.3 mmol; [
α
]
= +29.5 (c 2.8, CHCl3); 98% ee by chiral GC)
D
was treated with pyridine (10 mL), DMAP (50 mg, 0.4 mmol) and Ac2O (10 mL) and set aside at rt
until acetylation was complete (8 h). The obtained diacetate was dissolved in dry THF (30 mL) and
refluxed under a static nitrogen atmosphere in the presence of formic acid (0.75 g, 16.3 mmol), Et3N
(1.65 g, 16.3 mmol), (PPh3)2PdCl2 (140 mg, 0.2 mmol) and triphenylphosphine (0.25 g, 0.9 mmol).
After the reaction was complete (6 h, TLC analysis), the mixture was diluted with ether (100 mL) and
washed with water (50 mL), 5% HCl (50 mL), satd. aq NaHCO3 (50 mL), and brined. The organic
phase was concentrated under reduced pressure and the residue was purified by chromatography
(n-hexane/AcOEt 95:5–8:2) and bulb-to-bulb distillation to afford pure (R)-
γ-cyclogeraniol acetate
(
[
−
)-15 = (R)-(2,2-dimethyl-6-methylenecyclohexyl)methyl acetate (0.81 g, 78% yield) as a colorless oil;
20
α
]
=
−
10.1 (c 3.8, CHCl3); 96% diastereoisomeric purity, 99% of chemical purity by GC. 1H NMR
(400 MHz, CDCl3) 4.75 (s, 1H), 4.53 (s, 1H), 4.19 (dd, J = 11.0, 5.3 Hz, 1H), 4.15 (dd, J = 11.0, 9.2 Hz,
D
δ
1H), 2.16–2.06 (m, 2H), 2.03–1.92 (m, 1H), 1.94 (s, 3H), 1.54–1.44 (m, 2H), 1.42–1.32 (m, 1H), 1.29–1.20
(m, 1H), 0.91 (s, 3H), 0.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.0 (C), 147.0 (C), 109.7 (CH2), 62.7
(CH2), 52.1 (CH), 37.8 (CH2), 34.2 (C), 33.3 (CH2), 28.6 (Me), 25.0 (Me), 23.3 (CH2), 20.9 (Me). Lit. for
1H and 13C NMR [38
79 (33), 69 (49), 55 (9), 43 (50).
,
39]. GC-MS m/z (rel intensity) 136 ([M
−
AcOH]+, 80), 121 (100), 107 (43), 93 (89),
3.3.4. (S)-γ-Cyclogeraniol Acetate (+)-15
20
The reaction sequence described above was repeated using sample of diol (
−
)-13, ([
α
]
=
=
D
−
26.8 (c 2.5, CHCl3); 90% ee by chiral GC) to afford pure (S)-
γ
-cyclogeraniol acetate (+)-15
20
(S)-(2,2-dimethyl-6-methylenecyclohexyl)methyl acetate (74% yield) as a colorless oil; [
α
]
D = +9.1
(c 3.1, CHCl3); 96% diastereoisomeric purity, 95% of chemical purity by GC. 1H-NMR, 13C-NMR and
GC-MS superimposable to those described for (R)-isomer.
3.4. Synthesis of the Enantiomeric Forms of the Cyclogeranylsulfonylbenzene Derivatives 11a–d
3.4.1. General Procedure
A solution of p-toluenesulfonyl chloride (1.5 g, 7.9 mmol) in CH2Cl2 (4 mL) was added dropwise
to a stirred solution of the suitable cyclogeraniol isomer (0.9 g, 5.8 mmol), DMAP (50 mg, 0.4 mmol)
and pyridine (2 mL) in CH2Cl2 (4 mL). After 4 h, the mixture was diluted with ether (100 mL) and then
was washed with 1 M aqueous HCl solution (50 mL), saturated NaHCO3 solution (50 mL), and brined.
The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in dry
DMSO (5 mL) and added dropwise to a suspension of K2CO3 (3.2 g, 23.1 mmol) and thiophenol (1.7 g,
15.4 mmol) in DMSO (20 mL). The resulting mixture was stirred vigorously at rt (room temperature)
until the starting tosylate was no longer detectable by TLC analysis (12 h). The reaction was partitioned
between water (150 mL) and ether (100 mL). The aqueous phase was extracted again with ether (100 mL)
and the combined organic phases were washed with an aqueous solution of NaOH (10% w/w, 50 mL)
and brined, dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in methanol (50 mL)

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and was treated at 0 ◦C with (NH4)2MoO4 (80 mg, 0.4 mmol) followed by the dropwise addition of a
solution of H2O2 (35% wt. in water, 10 mL). The solution was then warmed to rt while stirring was
continued for a further 8 h. The reaction was cooled again and a saturated solution of Na2SO3 was
added to destroy excess oxidant. The main part of the methanol was removed under reduced pressure
and the residue extracted with AcOEt (3
concentrated, and the residue purified by chromatography using n-hexane/AcOEt (95:5–8:2) as eluent
to afford the suitable cyclogeranylsulfonylbenzene derivative.
×
100 mL). The combined organic layers were dried (Na2SO4),
3.4.2. (S)-((2,6,6-Trimethylcyclohex-2-enyl)methylsulfonyl)benzene (−)-11a
According
to
the
general
procedure,
(S)-
α
-cyclogeraniol
(
−
)-10a
=
20
(S)-(2,6,6-trimethylcyclohex-2-en-1-yl)methanol ([
chemical purity) was transformed into (S)-((2,6,6-trimethylcyclohex-2-enyl)methylsulfonyl)benzene
α
]
=
−
102.1 (c 2.4, EtOH); 90% ee; 97%
D
20
(−
)-11a (85% yield); [
CDCl3)
15.2, 3.9 Hz, 1H), 2.25 (s, 1H), 2.06–1.84 (m, 2H), 1.62 (br s, 3H), 1.23–1.16 (m, 2H), 0.91 (s, 6H). 13
α
]
=
83.9 (c 2.1, CH2Cl2); 96% of chemical purity by GC. 1H NMR (400 MHz,
−
D
δ
7.97–7.90 (m, 2H), 7.68–7.52 (m, 3H), 5.33 (s, 1H), 3.23 (dd, J = 15.2, 4.3 Hz, 1H), 2.91 (dd, J =
C
NMR (100 MHz, CDCl3)
δ 140.4 (C), 134.8 (C), 133.5 (CH), 129.2 (CH), 128.1 (CH), 121.8 (CH), 58.6
(CH2), 42.9 (CH), 32.2 (C), 31.3 (CH2), 27.0 (Me), 26.2 (Me), 22.8 (CH2), 22.5 (Me). Lit. for 1H and 13
C
NMR [25]. MS (ESI): 301.1 [M + Na]+.
3.4.3. (R)-((2,6,6-Trimethylcyclohex-2-enyl)methylsulfonyl)benzene (+)-11a
According
to
the
general
procedure,
(R)-
α
-cyclogeraniol
(+)-10a
=
20
(R)-(2,6,6-trimethylcyclohex-2-en-1-yl)methanol, ([
α
]
= +96.7 (c 2.7, EtOH); 85% ee; 97%
D
chemical purity) was transformed into (R)-((2,6,6-trimethylcyclohex-2-enyl)methylsulfonyl)benzene
20
(+)-11a (81% yield), [
α
]
= +77.8 (c 2.8, CH2Cl2), 98% of chemical purity by GC. 1H-, 13C-NMR and
D
MS superimposable to those described for (S)-isomer.
3.4.4. 2,6,6-((Trimethylcyclohex-1-enyl)methylsulfonyl)benzene 11b
According
to
the
general
procedure,
β-cyclogeraniol
=
((2,6,6-trimethylcyclohex-1-en-1-yl)methanol (96% chemical purity) was transformed into
((2,6,6-trimethylcyclohex-1-enyl)methylsulfonyl)benzene 11b (82% yield) as a colorless oil,
97% of chemical purity by GC. 1H NMR (400 MHz, CDCl3)
δ
7.97–7.90 (m, 2H), 7.67–7.51 (m, 3H), 3.97
(s, 2H), 2.06 (t, J = 6.3 Hz, 2H), 1.68–1.58 (m, 2H), 1.67 (s, 3H), 1.52–1.46 (m, 2H), 1.04 (s, 6H). 13C NMR
(100 MHz, CDCl3)
δ 141.7 (C), 139.2 (C), 133.2 (CH), 129.1 (CH), 127.8 (CH), 125.9 (C), 57.7 (CH2), 39.5
(CH2), 34.4 (C), 33.3 (CH2), 28.8 (Me), 21.8 (Me), 18.9 (CH2). Lit. for 1H and 13C NMR [40]. GC-MS m/z
(rel intensity) 278 (M+, 1), 137 (100), 121 (10), 107 (6), 95 (45), 81 (28), 69 (8), 55 (6).
3.4.5. (R)-((2,2-Dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene (−)-11c
(
−
)-
γ
-3,4-dehydrocyclogeraniol acetate = (R)-(6,6-dimethyl-2-methylenecyclohex-3-en-1-yl)methyl
20
acetate ([
α
]
= −69.9 (c 3.3, CHCl3); 98% ee; 99% chemical purity) was hydrolyzed using NaOH
D
in methanol, at reflux. After work-up, the obtained crude alcohol was submitted to the general
procedure to give (R)-((6,6-dimethyl-2-methylenecyclohex-3-enyl)methylsulfonyl)benzene (75% yield)
20
as a colorless oil; [
α
]
=
89.2 (c 3.7, CHCl3); 96% of chemical purity by GC. 1H NMR (400 MHz,
−
D
CDCl3)
δ
7.92–7.86 (m, 2H), 7.66–7.60 (m, 1H), 7.58–7.51 (m, 2H), 5.96 (d, J = 9.9 Hz, 1H), 5.65–5.58
(m, 1H), 4.82 (s, 2H), 3.22 (dd, J = 14.6, 2.4 Hz, 1H), 3.04 (dd, J = 14.6, 8.1 Hz, 1H), 2.53 (dm, J = 8.1
Hz, 1H), 1.90 (dm, J = 18.7 Hz, 1H), 1.79 (dd, J = 18.7, 5.0 Hz, 1H), 0.91 (s, 3H), 0.85 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 143.1 (C), 140.3 (C), 133.4 (CH), 129.1 (CH), 128.1 (CH), 127.4 (CH), 127.1 (CH),
115.0 (CH2), 56.7 (CH2), 44.8 (CH), 36.3 (CH2), 32.7 (C), 27.2 (Me), 26.7 (Me). MS (ESI): 299.1 [M + Na]+,
315.1 [M + K]+.

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3.4.6. (S)-((2,2-Dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene (+)-11c
The reaction sequence described above was repeated using (+)-
= (S)-(6,6-dimethyl-2-methylenecyclohex-3-en-1-yl)methyl acetate ([
γ
-3,4-dehydrocyclogeraniol acetate
20
α
]
= +61.1 (c 3.0, CHCl3); 96%
D
of chemical purity) to afford (S)-((6,6-dimethyl-2-methylenecyclohex-3-enyl)methylsulfonyl)benzene
20
1
(74% yield), colorless oil; [
α
]
= +78.8 (c 3.1, CHCl3); 96% of chemical purity by GC. H-NMR,
D
13C-NMR and GC-MS superimposable to those described for (R)-isomer.
3.4.7. (R)-((2,2-Dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene (−)-11d
20
(
−
)-
10.1 (c 3.8, CHCl3); 96% diastereoisomeric purity; 99% chemical purity by GC) was hydrolysed using
NaOH in methanol, at reflux. After work-up, the obtained crude alcohol was submitted to the general
γ
-Cyclogeraniol acetate = (R)-(2,2-dimethyl-6-methylenecyclohexyl)methyl acetate (([
α
]
=
D
−
procedure to give (
−
)-(R)-((2,2-dimethyl-6-methylenecyclohexyl(methylsulfonyl)benzene (89% yield)
20
as a colorless oil; [
α
]
=
−
11.7 (c 3.7, CHCl3); 96% diastereoisomeric purity, 95% of chemical purity
7.92–7.85 (m, 2H), 7.67–7.49 (m, 3H), 4.74 (s, 1H), 4.56 (s, 1H), 3.35
(dd, J = 14.7, 9.4 Hz, 1H), 3.24 (dd, J = 14.7, 2.5 Hz, 1H), 2.44 (dm, J = 9.4 Hz, 1H), 2.07–1.93 (m, 2H),
1.55–1.44 (m, 2H), 1.35–1.28 (m, 2H), 0.90 (s, 3H), 0.78 (s, 3H). 13C NMR (100 MHz, CDCl3)
145.6 (C),
D
by GC. 1H NMR (400 MHz, CDCl3)
δ
δ
140.0 (C), 133.4 (CH), 129.0 (CH), 128.2 (CH), 110.9 (CH2), 54.4 (CH2), 47.8 (CH), 37.2 (CH2), 35.3 (C),
32.9 (CH2), 27.8 (Me), 24.9 (Me), 23.2 (CH2). Lit. for 1H and 13C NMR [41]. MS (ESI): 301.2 [M + Na]+.
3.4.8. (S)-((2,2-Dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene (+)-11d
The reaction sequence described above was repeated using (+)-
γ
-cyclogeraniol
+9.1 (c 3.1,
20
acetate
=
(S)-(2,2-dimethyl-6-methylenecyclohexyl)methyl acetate ([
α
]
=
D
CHCl3); 96% diastereoisomeric purity, 95% of chemical purity by GC) to afford
20
(S)-((2,2-dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene (84% yield); ([
α
]
D = +9.8 (c 2.4,
CHCl3); 97% of chemical purity by GC. 1H-NMR, 13C-NMR and GC-MS superimposable to those
described for (R)-isomer.
3.5. Synthesis of the Furanosesquiterpenes (
and (−)-Dihydropallescensis-2 (5)
−
)-Pallescensin-1 (
2
), Isomicrocionin-3 (
3
), ( )-Pallescensin-2 (4),
−
3.5.1. General Procedure
nBuLi (1 mL of a 2.5 M solution in hexane) was added dropwise under nitrogen to a cooled
◦
(−
60 C) solution of the suitable cyclogeranylsulfonylbenzene derivative (2.2 mmol) in dry THF
(10 mL). The resulting orange solution was stirred at this temperature for 15 min and then a solution of
3-(chloromethyl)furan (260 mg, 2.23 mmol) in dry DMPU (1 mL) was added dropwise. The reaction was
allowed to reach room temperature and after two hours at this temperature, and it was quenched by the
addition of a saturated solution of NH4Cl aqueous (50 mL). The resulting mixture was extracted with
diethyl ether (3
vacuo. The crude product was dissolved in dry THF (15 mL) containing dry Et2NH (1 mL). The mixture
was cooled (
75 ◦C) and was treated under nitrogen with freshly prepared lithium naphthalenide
×
50 mL) and the combined organic phases was dried (Na2SO4) and concentrated in
−
(8 mL of a 0.72 M solution). When the staring material could no longer be detected by TLC analysis
(1 h), the reaction was quenched by the addition of a saturated solution of NH4Cl aqueous (50 mL)
and diluted with diethyl ether (80 mL). The organic phase was separated and the aqueous phase
was extracted with ethyl ether (50 mL). The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. A large part of the naphthalene content was
removed by crystallization from hexane. The liquid phase was then purified by chromatography
(hexane/diethyl ether 99:1–95:5) to afford the desired furanosesquiterpene.

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3.5.2. Synthesis of (−)-Pallescensin-1 (2)
According
to
the
general
procedure,
the
alkylation/reduction
83.9 (c
of
2.1,
) =
93.2
20
((2,6,6-trimethylcyclohex-2-enyl)methylsulfonyl)benzene
CH2Cl2); 90% ee, 96% of chemical purity by GC) afforded (
3-(2-(2,6,6-trimethylcyclohex-2-enyl)ethyl)furan (73% yield) as a colorless oil; [
(c 3.2, CHCl3); 94% of chemical purity by GC; Lit. [10] for synthetic
([
α
]
=
−
D
−
)-pallescensin-1 (
2
−
20
α
]
=
D
20
2
: [
α
]
=
−
89.5 (CHCl3); Lit. [
3]
D
20
1
for natural
2
: [α
]
=
−
23.5 (c 0.07, CHCl3). H NMR (400 MHz, CDCl3)
δ
7.34 (t, J = 1.7 Hz, 1H),
D
7.23–7.20 (m, 1H), 6.27 (br s, 1H), 5.31 (br s, 1H), 2.50–2.40 (m, 2H), 2.01–1.91 (m, 2H), 1.76–1.63 (m,
1H), 1.69–1.66 (m, 3H), 1.62–1.39 (m, 3H), 1.19–1.10 (m, 1H), 0.95 (s, 3H), 0.88 (s, 3H). 13C NMR (100
MHz, CDCl3)
31.6 (CH2), 31.6 (CH2), 27.52 (Me), 27.46 (Me), 25.5 (CH2), 23.5 (Me), 23.0 (CH2). Lit. for 1H and 13
NMR [
δ 142.6 (CH), 138.6 (CH), 136.5 (C), 125.6 (C), 120.2 (CH), 111.0 (CH), 49.0 (CH), 32.6 (C),
C
3
]. GC-MS m/z (rel intensity) 218 (M+, 8), 203 (2), 162 (3), 147 (15), 133 (13), 121 (14), 109 (26), 95
(41), 81 (100), 67 (7), 53 (13).
3.5.3. Synthesis of Isomicrocionin-3 (3)
According
to
the
general
procedure,
the
alkylation/reduction
of
((2,6,6-trimethylcyclohex-1-enyl)methylsulfonyl)benzene (97% of chemical purity by GC) afforded
isomicrocionin-3 = 3-(2-(2,6,6-trimethylcyclohex-1-enyl)ethyl)furan (78% yield) as a colorless oil; 99%
of chemical purity by GC. 1H NMR (400 MHz, CDCl3)
7.34 (t, J = 1.7 Hz, 1H), 7.24–7.22 (m, 1H), 6.30
(br s, 1H), 2.50–2.42 (m, 2H), 2.27–2.19 (m, 2H), 1.93 (t, J = 6.2 Hz, 2H), 1.64 (s, 3H), 1.63–1.55 (m, 2H),
1.47–1.41 (m, 2H), 1.02 (s, 6H). 13C NMR (100 MHz, CDCl3)
142.6 (CH), 138.4 (CH), 136.9 (C), 127.6
(C), 125.7 (C), 110.9 (CH), 39.8 (CH2), 34.9 (C), 32.8 (CH2), 29.5 (CH2), 28.6 (Me), 25.6 (CH2), 19.8 (Me),
19.5 (CH2). Lit. for 1H and 13C NMR [ ]. GC-MS m/z (rel intensity) 218 (M+, 64), 203 ([M Me]+, 47),
3
δ
δ
3
−
185 (4), 175 (10), 162 (18), 149 (25) 137 (77), 121 (18), 109 (20), 95 (100), 81 (85), 67 (15), 53 (16).
3.5.4. Synthesis of (−)-Pallescensin-2 (4)
According
to
the
general
procedure,
the
alkylation/reduction
of
89.2
20
(R)-((6,6-dimethyl-2-methylenecyclohex-3-enyl)methylsulfonyl)benzene
(c 3.7, CHCl3); 96% of chemical purity by GC) afforded
([α
]
=
−
D
(−
)-pallescensin-2
(
4
)
=
(R)-3-(2-(6,6-dimethyl-2-methylenecyclohex-3-enyl)ethyl)furan (79% yield) as a colorless oil;
[α]20D = −65.1 (c 2.9, CHCl3); 96% of chemical purity by GC; Lit. [1] for natural 4: [α]20D = +39.5.
1H NMR (400 MHz, CDCl3)
δ 7.33 (m, 1H), 7.19 (s, 1H), 6.25 (m, 1H), 6.03 (dd, J = 9.8, 1.8 Hz, 1H),
5.69–5.59 (m, 1H), 4.91 (s, 1H), 4.74 (s, 1H), 2.53–2.42 (m, 1H), 2.33–2.22 (m, 1H), 2.05 (d, J = 18.5 Hz,
1H), 1.81–1.67 (m, 3H), 1.35–1.23 (m, 1H), 0.96 (s, 3H), 0.86 (s, 3H). 13C NMR (100 MHz, CDCl3)
145.6
δ
(C), 142.6 (CH), 138.8 (CH), 127.8 (CH), 127.3 (CH), 125.4 (C), 112.8 (CH2), 111.0 (CH), 51.1 (CH), 36.4
(CH2), 32.6 (C), 28.3 (CH2), 28.2 (Me), 27.6 (Me), 23.0 (CH2). Lit. for 1H NMR [13]. GC-MS m/z (rel
intensity) 216 (M+, 8), 201 ([M
(10), 65 (4), 53 (5).
−
Me]+, 2), 173 (2), 157 (2), 145 (2), 131 (2), 122 (55), 107 (100), 91 (17), 81
3.5.5. Synthesis of (−)-Dihydropallescensis-2 (5)
According to the general
procedure,
the
alkylation/reduction
of
20
(
−
)-(R)-((2,2-dimethyl-6-methylenecyclohexyl)methylsulfonyl)benzene ([
3.7, CHCl3); 95% of chemical purity by GC) afforded (
(R)-3-(2-(2,2-dimethyl-6-methylenecyclohexyl)ethyl)furan (71% yield) as a colorless oil; [
α
]
=
−
11.7 (c
D
−
)-dihydropallescensis-2 (
5
α
) =
20
]
D
= 7.1 (c 2.5, CHCl3); 94% of chemical purity by GC; Lit. [15] for synthetic dextrorotatory isomer:
−
20
20
1
[
α
]
D = +4.55 (c 0.1, CHCl3); Lit. [
CDCl3) 7.34 (m, 1H), 7.19 (s, 1H), 6.26 (m, 1H), 4.80 (s, 1H), 4.57 (d, J = 1.9 Hz, 1H), 2.45–2.34 (m, 1H),
2.25–1.92 (m, 3H), 1.81–1.40 (m, 6H), 1.30–1.17 (m, 1H), 0.91 (s, 3H), 0.84 (s, 3H). 13C NMR (100 MHz,
CDCl3) 149.1 (C), 142.6 (CH), 138.7 (CH), 125.5 (C), 111.0 (CH), 109.1 (CH2), 53.5 (CH), 36.2 (CH2),
2] for natural 5: [α] D = +6.0 (c 0.3, CHCl3). H NMR (400 MHz,
δ
δ

Mar. Drugs 2019, 17, 245
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1
34.8 (C), 32.4 (CH2), 28.3 (Me), 26.7 (CH2), 26.3 (Me), 23.7 (CH2), 23.3 (CH2). Lit. for H and 13C
NMR [15]. GC-MS m/z (rel intensity) 218 (M+, 72), 203 ([M Me]+, 14), 189 (6), 175 (10), 162 (5), 147
(12) 133 (13), 124 (13), 109 (85), 95 (65), 81 (100), 69 (49), 53 (21).
−
3.6. Synthesis of (−)-Pallescensone (6) Starting from (R)-γ-Cyclogeraniol Acetate
3.6.1. Synthesis of (R)-2-(2,2-Dimethyl-6-methylenecyclohexyl)acetonitrile (+)-16
(
−
)-
γ
-Cyclogeraniol acetate = (R)-(2,2-dimethyl-6-methylenecyclohexyl)methyl acetate 380 mg,
20
1.94 mmol, ([
α
]
= −10.1 (c 3.8, CHCl3); 98% ee; 99% chemical purity) was hydrolysed using NaOH
D
in methanol, at reflux. After work-up, a solution of p-toluenesulphonyl chloride (570 mg, 3 mmol) in
CH2Cl2 (3 mL) was added dropwise to a stirred solution of the obtained crude alcohol and DMAP
(20 mg, 0.16 mmol) in pyridine (2 mL). After 4 h, the mixture was diluted with ether (60 mL) and
washed in turn with a 1 M aqueous HCl solution (50 mL), saturated NaHCO3 solution (30 mL), and
brined. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in
dry DMSO (20 mL) and treated with NaCN (1 g, 20 mmol) stirring at 80–90 ◦C until the starting tosylate
could no longer be detected by TLC analysis (5 h). The mixture was diluted with ether (80 mL) and
was washed in turn with water and brine. The organic phase was dried (Na2SO4) and concentrated in
vacuo. The residue was then purified by chromatography eluting with hexane/ethyl acetate (95:5–8:2)
as eluent to afford pure (R)-2-(2,2-dimethyl-6-methylenecyclohexyl)acetonitrile (+)-16 (270 mg, 85%
20
yield) as a colorless oil; [
α
]
D = +12.1 (c 2.2, CH2Cl2); 96% diastereoisomeric purity, 92% of chemical
4.96 (s, 1H), 4.75 (s, 1H), 2.56 (dd, J = 16.7, 4.4 Hz, 1H), 2.41
(dd, J = 16.7, 10.8 Hz, 1H), 2.26–2.15 (m, 2H), 2.14–2.02 (m, 1H), 1.70–1.50 (m, 2H), 1.50–1.31 (m, 2H),
1.00 (s, 3H), 0.81 (s, 3H). 13C NMR (100 MHz, CDCl3)
146.2 (C), 119.7 (C), 110.4 (CH2), 50.3 (CH), 37.7
purity by GC. 1H NMR (400 MHz, CDCl3)
δ
δ
(CH2), 35.0 (C), 33.5 (CH2), 28.6 (Me), 23.5 (Me), 23.2 (CH2), 16.4 (CH2). GC-MS m/z (rel intensity) 163
(M+, 3), 148 (7), 134 (1), 120 (21), 107 (9), 91 (11), 79 (18), 69 (100), 53 (11).
3.6.2. Synthesis of (−)-Pallescensone (6)
DIBAL (0.9 mL of a 25% wt. solution in toluene, 1.34 mmol) was added dropwise under nitrogen
to a cooled (
70 ◦C) solution of nitrile (+)-16 (200 mg, 1.23 mmol) in dry toluene (10 mL). The resulting
−
solution was stirred at this temperature for half an hour and then was allowed to reach rt. The reaction
was quenched by the carefully addition of diluted HCl aqueous (50 mL), followed by extraction with
diethyl ether (2
reduced pressure to a final volume of about 4 mL. The resulting solution was added under nitrogen to
a cooled (
70 ◦C) solution of 3-furyllithium (10 mL of a 0.25 M solution in THF), which was previously
×
50 mL). The combined organic phases were dried (Na2SO4) and concentrated under
−
prepared in situ by addition of nBuLi (2.5 M solution in hexane) to a solution of 3-bromofuran in dry
THF. The resulting mixture was stirred at this temperature for 20 min, then was quenched by adding
saturated aqueous NH4Cl (20 mL) and was extracted with ether (2
×
60 mL). The combined organic
phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in
dry DMSO (2 mL) and was added to a stirred solution of IBX (1 g, 3.5 mmol) in dry DMSO (6 mL). The
reaction was warmed at 40 ◦C for 4 h and then was diluted with diethyl ether (80 mL) and washed
with water (2
×
50 mL) and brine. The organic phase was concentrated in vacuo and the residue was
then purified by chromatography eluting with hexane/ethyl acetate (99:1–9:1) as eluent to afford pure
(−)-pallescensone 6 = (R)-2-(2,2-dimethyl-6-methylenecyclohexyl)-1-(furan-3-yl)ethan-1-one (145 mg,
20
51% yield) as a pale yellow oil that solidified on standing; [
α
]
= 34.4 (c 1.1, CH2Cl2); 97% of
−
D
20
chemical purity by GC; Lit. [18] for synthetic
6
: [
α
]
=
−
31.8 (c 0.57, CH2Cl2); Lit. [
8.05 (s, 1H), 7.44–7.42 (m, 1H), 6.77–6.75
8] for natural 6:
D
20
[
α
]
= +36 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3)
δ
D
(s, 1H), 4.71 (s, 1H), 4.44 (s, 1H), 2.91 (dd, J = 15.8, 9.8 Hz, 1H), 2.81 (dd, J = 15.8, 4.2 Hz, 1H), 2.66
(dd, J = 9.8, 4.2 Hz, 1H), 2.28–2.17 (m, 1H), 2.13–2.01 (m, 1H), 1.65–1.34 (m, 4H), 0.98 (s, 3H), 0.84 (s,
3H). 13C NMR (100 MHz, CDCl3)
δ
194.5 (C), 148.9 (C), 146.7 (CH), 144.1 (CH), 128.1 (C), 108.8 (CH),
108.5 (CH2), 48.7 (CH), 38.8 (CH2), 38.6 (CH2), 35.0 (C), 34.4 (CH2), 28.9 (Me), 23.8 (Me), 23.6 (CH2). Lit.

Mar. Drugs 2019, 17, 245
13 of 14
for 1H and 13C NMR [14,16,18]. GC-MS m/z (rel intensity) 232 (M+, 5), 217 (5), 199 (2), 189 (3), 176 (3),
163 (3), 137 (3), 122 (22), 107 (24), 95 (100), 81 (12), 69 (13), 55 (6).
Funding: This research received no external funding.
Conflicts of Interest: The author declare no conflict of interest.
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