Preparation and use of enantioenriched 2-aryl-propylsulfonylbenzene derivatives as valuable building blocks for the enantioselective synthesis of bisabolane sesquiterpenes

Article abstract of DOI:10.1016/j.tetasy.2014.10.016

We have demonstrated that different enantioenriched 2-arylpropylsufonylbenzene derivatives are very useful building blocks for the synthesis of aromatic bisabolane sesquiterpenes. Their preparation and the exploitation of their chemical reactivity have been comprehensively investigated. Accordingly, the naturally occurring bisabolane sesquiterpenes (-)-curcuphenol, (-)-xanthorrhizol, (+)-glandulone A, (+)-curcudiol, (+)-turmerone and (+)-curcudiol-10-one were synthesized in high enantiomeric purity. It is worth noting that the compounds (+)-curcudiol-10-one and (+)-glandulone A were prepared in enantioenriched form for the first time. Through the proposed synthetic approaches, we were able to confirm both chemical structures and the absolute configurations previously assigned to the two aforementioned sesquiterpenes.

Full text of DOI:10.1016/j.tetasy.2014.10.016

Tetrahedron: Asymmetry 25 (2014) 1561–1572
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation and use of enantioenriched 2-aryl-
propylsulfonylbenzene derivatives as valuable building blocks for the
enantioselective synthesis of bisabolane sesquiterpenes
⇑
Stefano Serra
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2014
Accepted 23 October 2014
We have demonstrated that different enantioenriched 2-arylpropylsufonylbenzene derivatives are very
useful building blocks for the synthesis of aromatic bisabolane sesquiterpenes. Their preparation and
the exploitation of their chemical reactivity have been comprehensively investigated. Accordingly, the
naturally occurring bisabolane sesquiterpenes (À)-curcuphenol, (À)-xanthorrhizol, (+)-glandulone A,
(+)-curcudiol, (+)-turmerone and (+)-curcudiol-10-one were synthesized in high enantiomeric purity. It
is worth noting that the compounds (+)-curcudiol-10-one and (+)-glandulone A were prepared in
enantioenriched form for the first time. Through the proposed synthetic approaches, we were able to
confirm both chemical structures and the absolute configurations previously assigned to the two
aforementioned sesquiterpenes.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
R''
The aromatic bisabolane sesquiterpenes are a family of natural
compounds that can be isolated from many different sources and
are characterized by their great structural diversity. They feature
a functionalized aromatic ring bearing a benzylic stereocenter
and often possess specific biological activities, which are strictly
related to their stereochemical structures. As a consequence, much
effort has been spent both for their chemical characterization and
for their stereoselective synthesis. From a synthetic standpoint, the
general difficulties related to the selective construction of the
benzylic stereocenter have made these sesquiterpenes a popular
target, many of which have been singled out and synthesized in
order to prove the effectiveness of a proposed method of asymmet-
ric synthesis.
OH
R''
R'
(R)-1
R
R
OH
R'
PPL
OAc
R''
1
)-
(
R
OAc
(S)-2
a) R, R' and R''=H
b) R=OMe, R' and R''=H
c) R and R''=H, R'=OMe
d) R=H, R' and R''=OMe
e) R and R'=OMe, R''=H
R'
Figure 1. Porcine pancreatic lipase-mediated resolution of 2-aryl-propanol
derivatives.
In this context, we have already reported on different synthetic
approaches to this class of compounds, based on either
a
benzannulation reaction of substituted 3,5-hexadienoic acids,1–3
enantioselective baker’s yeast reduction of substituted (E)-3-aryl-
2-butenals4–6 or lipase-mediated resolution of 2-aryl-propanol
derivatives.7,8 The latter studies proved that both enantiomeric
forms of substituted 2-aryl-propanols of type 1 (Fig. 1) can be con-
veniently obtained through porcine pancreatic lipase-mediated
resolution of the corresponding racemic alcohol.8 Since the afore-
mentioned compounds are easily prepared, this method provides
a reliable source of chiral building blocks to be used for bisabolane
synthesis.
Herein we report the result of a new study, which describes the
development of a general process for the transformation of enan-
tioenriched 2-aryl-propanols into the corresponding 2-aryl-pro-
pylsulfonylbenzene derivatives as well as the exploitation of the
latter derivatives for the stereoselective synthesis of the naturally
⇑
Tel.: +39 02 2399 3076; fax: +39 02 2399 3180.
E-mail addresses: stefano.serra@cnr.it, stefano.serra@polimi.it
http://dx.doi.org/10.1016/j.tetasy.2014.10.016
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1562
S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
occurring bisabolane sesquiterpenes (À)-curcuphenol, (À)-xan-
thorrhizol, (+)-glandulone A, (+)-curcudiol, (+)-turmerone and
(+)-curcudiol-10-one.
to 50% of the iodide 5 close to the desired product 4. The use of
bromide-based reagents such as LiBr or NBS/Ph3P gave the
rearranged halide in a minor but yet significant amount. The
described transposition was previously observed12,13 with other
reactions involving substituted 2-aryl-propanols. Our experimen-
tal results substantiate the transposition mechanism suggested
by Cram13 who postulated the formation of a bicyclic phenonium
ion as an intermediate in the intramolecular rearrangement. The
latter carbocation can be greatly stabilized by the presence of
o-methoxy and p-methyl electron donating groups, thus justifying
the larger amount of the rearranged products 5.
Overall, these results indicate that these approaches are
unsuitable for the synthesis of sesquiterpenes. Thus we looked
for a different nucleophile to be used in reactions with tosylates.
Taking inspiration from two previous works14,15 in which the
transformation of enantioenriched 2-aryl-propanols into 2-aryl-
propylsulfonylbenzene derivatives were described, we investi-
gated the conversion of alcohols of type 1 into the corresponding
thiophenyl ethers. We found that the nucleophilic displacement
of the tosylates with sodium thiophenate proceeded smoothly
and did not afford any detectable amount of isomerized products
(Scheme 2). It is worth noting that the use of the tributylphos-
phine/diphenyldisulfide reagent16 required that the reactions were
performed in pyridine. Without this precaution, partial isomeriza-
tion takes place, thus affecting the usefulness of the reaction.
2. Results and discussion
2.1. Exploitation of enantioenriched 2-aryl-propanols: synthesis
of 2-aryl-propylsulfonylbenzene derivatives
As mentioned earlier, we searched for a reliable synthetic
procedure that would allow a straightforward transformation of
enantioenriched 2-aryl-propanol into bisabolane sesquiterpenes.
As a preliminary investigation of this process, we accomplished
the enantioselective synthesis of different phenolic sesquiter-
penes7,8 and trinorsesquiterpenes.9 According to these studies,
we transformed the enantiopure alcohols of type 1 into the corre-
sponding 3-aryl-butanenitrile derivatives, which were then used
for the synthesis of the desired terpenes. The latter C1-homologa-
tion step proceeds straightforwardly when it is performed through
the transformation of compounds 1 into the corresponding tosy-
lates followed by nucleophilic substitution with sodium cyanide.
In order to prepare additional sesquiterpenes, we investigated
further general approaches for the construction of the bisabolane
aliphatic chain, not necessarily involving a sequential homologa-
tion procedure.
The first approach tested was based on the oxidation of the
alcohol functional group to give the corresponding aldehyde
followed by a Wittig reaction (Scheme 1).
R''
R''
*
*
OH
SO2Ph
76-92%
overall
i, ii
iv
or v
or iii
R
R
OH
R'
R'
CO2Et
i, ii, iii
1a-d
6a-d
95% ee
25% ee
(R)-1a
(S)-3
Scheme 2. Synthesis of enantioenriched 2-aryl-propylsulfonylbenzene derivatives
6a–d starting from the corresponding 2-aryl-propanol derivatives 1a–d. Reagents
and conditions: (i) TsCl, Py, CH2Cl2; (ii) PhSH, K2CO3, DMSO; (iii) Bu3P, Ph2S2, Py;
(iv) mCPBA, CH2Cl2, 0 °C; (v) H2O2, MeOH, (NH4)2MoO4 cat., 0 °C then rt.
OMe
OMe
OMe
OH
I
iv, v
+
I
As a result, the intermediate sulfides were oxidized either using
mCPBA or hydrogen peroxide in presence of catalytic ammonium
molibdate17 to afford the corresponding phenylsulfonyl derivatives
6a–d in good overall yields.
(S)-1b
(S)-4
5
Scheme 1. The synthetic exploitation of enantioenriched 2-aryl-propanol deriva-
tives: some unsuccessful approaches. Reagents and conditions: (i) PySO3, DMSO,
Et3N, rt; (ii) Ph3PCHCO2Et, CH2Cl2, rt; (iii) H2, 10% Pd/C cat., EtOAc, atmospheric
pressure; (iv) TsCl, Py, CH2Cl2; (v) NaI, acetone, reflux.
2.2. Enantioenriched 2-aryl-propylsulfonylbenzene derivatives
and their synthetic exploitation
Accordingly, enantioenriched (95% ee) alcohol (R)-1a was
oxidized with the Py–SO3 complex and the crude aldehyde was
immediately treated with an excess of (ethoxycarbonylmethylene)
triphenylphosphorane. The unsaturated ester obtained was hydro-
genated and the specific optical rotation of the purified compound
3 was compared with that reported10 for the enantiopure material.
The aforementioned compounds turned out to be very flexible
chiral building blocks that could be used for the synthesis of differ-
ent bisabolane sesquiterpenes. The methylenic groups of the sulf-
ones 6a–d are readily deprotonated using an equimolar amount
of nBuLi at À50 °C in THF solution to give the corresponding
monolithium salts. We planned to employ the latter reactive
intermediates for different types of chemical reactions.
As shown in Figure 2, the C15 bisabolane framework can be built
up via the reaction of the sulfone lithium salts with different C5
electrophiles. The most obvious electrophiles are substituted pre-
nyl bromides of type 7, whose alkylation affords sulfones of type 8.
Alternatively, a two step homologation can be performed via
the conjugate addition of sulfone anions to the very reactive acry-
late 9. The obtained C13 derivatives of type 10 require further
homologation step, which is viable by exploitation of the ester
group reactivity. On the other hand, the sulfone anions can be acyl-
ated with C5 acyl derivatives of type 11 or can be used as nucleo-
philes in the ring opening of C5 epoxides 13 to afford derivatives
12 and 14, respectively. Lastly, their reaction with C5 substituted
The result was disappointing, indicating that
3 had a low
enantiomeric purity. Most likely, the intermediate aldehyde under-
went rapid racemization even when using an oxidising reagent
specially selected11 for the synthesis of epimerization-sensitive
a-methyl-aldehydes.
As a second approach we sought a procedure that would invert
the polarity at the carbon atom bearing the hydroxyl group. To this
end we planned to transform enantioenriched into the
1
corresponding tosylates, which could be converted into substituted
2-aryl-propylmagnesium halides through the intermediates of the
corresponding halides. In this case, the results were also unsatis-
factory since the nucleophilic substitution of the tosylates invari-
ably afforded mixtures of the desired halides with inseparable
methyl-rearranged isomers. The methoxy-derivative 1b gave up

S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
1563
R''
R'
OMe
R''
16
OMe
OH
*
SO2Ph
*
CO2Et
Br
R'''
SO2Ph
R'''
8
SO2Ph
6b
(-)-
SO2Ph
10
8b
i, ii
83%
R
R
R'
OMe
iii
iv
CO2Et
Br
9
7
(-)-18
(-)-17
56%
68%
R''
R'
R''
R'
(R)-curcuphenol
*
*
SO2Ph
BuLi
R'''CHO
R'''
6a-d
Li
16
R
R
15
SO2Ph
Br
SO2Ph
O
(-)-6c
i, ii
85%
8c
O
OMe
OMe
OH
R'''
X
R'''
O
13
R''
11
R''
R'
iv
v
R'''
*
*
(-)-20
(-)-19
86%
R'''
SO2Ph
84%
OH
SO2Ph
OMe
(R)-xanthorrhizol
R
R
12
14
R'
Scheme 3. Synthesis of enantioenriched (R)-curcuphenol (À)-18 and (R)-xanthor-
rhizol (À)-20 starting from enantioenriched 2-aryl-propylsulfonylbenzene deriva-
tives (À)-6b and (À)-6c. Reagents and conditions: (i) nBuLi, THF, À50 °C; (ii) 16,
DMPU; (iii) Na(Hg), NaH2PO4, THF/MeOH, 0 °C; (iv) EtSNa, DMF, reflux; (v) Lithium
naphthalenide, THF, Et2NH, À78 °C.
Figure 2. The synthetic potential of enantioenriched 2-aryl-propylsulfonylbenzene
derivatives.
aldehydes gives the corresponding carbinol derivatives whose
phenylsulfonyl groups can be removed by means of a Julia–Lythgoe
reaction to afford unsaturated compounds of type 15.
All of the synthetic pathways described above require further
chemical reactions to transform the intermediates of type 8, 10,
12, 14 and 15 into the desired sesquiterpenes. These synthetic
steps comprise the reductive cleavage of the phenylsulfonyl groups
as well as other functional group manipulations, whose specific
experimental procedures can be selected on a case by case basis.
sluggishly, especially for the reduction of compound 8c, which
required a large excess of the reagents to achieve a satisfactory
conversion. Otherwise, we found that lithium naphthalenide
reduces the latter sulfone even at low temperature (À78 °C).
According to our previous study,22 the reaction was carried out
in THF solution in the presence of an excess of Et2NH. Using these
experimental conditions, compound (À)-19 was obtained in very
good yield and without any detectable side product.
As previously reported,5 the demethylation of the phenol ethers
(À)-17 and (À)-19 was performed using sodium ethanethiolate in
refluxing DMF to give curcuphenol (À)-18 and xanthorrhizol (À)-
20 in good yield. The latter sesquiterpenes showed NMR data
and specific rotation data in good agreement with those reported
for the natural (R)-(À)-enantiomers.
2.3. Alkylation of the 2-aryl-propylsulfonylbenzene derivatives:
synthesis of (R)-(À)-curcuphenol, (R)-(À)-xanthorrhizol and (S)-
(+)-glandulone A
The first procedure investigated involves the alkylation of the
aforementioned sulfones anions with two different prenyl bromide
derivatives. Prenyl bromide 16 was employed for the synthesis of
the phenolic sesquiterpenes curcuphenol 18 and xanthorrhizol
20 (Scheme 3). The latter compounds occur in Nature18–21 either
as (R)- or (S)-enantiomers depending upon their source of extrac-
tion and have different biological properties that are also related
to their absolute configuration. For example (R)-curcuphenol has
been isolated from the gorgonian coral Pseudopterogorgia rigida18
and possesses antibacterial properties whereas (S)-curcuphenol,
extracted from the marine sponge Didiscus flavus,19 shows antitu-
moral activity.
Furthermore, the alkylation reaction of enantioenriched sulfone
(+)-6d with substituted prenyl bromide 23 was used for the syn-
thesis of compound (+)-26 (Scheme 4). The latter sesquiterpene
possesses antimicrobial activity and was isolated23 from noncapi-
tate glandular hairs of the common sunflower Helianthus annuus.
For this reason, it was given the name glandulone A. More recently,
the synthesis of its racemic form24 confirmed the chemical struc-
ture previously assigned to the natural product. Nevertheless, its
absolute configuration was tentatively assigned as (S) by compar-
ison of its specific rotation sign with that of structurally analogous
sesquiterpenes.
Since the enantioselective synthesis of glandulone A was still
lacking, we decided to prepare the (S)-enantiomer of this com-
pound in order to unambiguously confirm its absolute configura-
tion. Accordingly, we prepared bromide 23 starting from the
commercially available (E)-ethyl-3-formyl crotonate 21 through a
number of regioselective reactions. The starting unsaturated alde-
hyde was reduced using NaBH4 in methanol and the resulting alco-
hol was protected as a TBDPS ether. The ethyl ester functional
group was reduced using DIBALH and the obtained carbinol 22
Since we have already reported5 on the stereoselective synthe-
sis of the (S) stereoisomers of curcuphenol and xanthorrhizol, we
singled out the sulfones (À)-6b and (À)-6c in order to synthesize
their (R)-enantioforms as well.
Accordingly, the lithium salts of the latter sulfones were
efficiently alkylated by bromide 16 in the presence of DMPU as
co-solvent to give derivatives 8b and 8c, respectively. The follow-
ing reductive removal of the phenylsulfonyl group was performed
using either Na(Hg) or lithium naphthalenide to afford phenol
ethers (À)-17 and (À)-19, respectively. As previously indicated,14
the use of sodium amalgam in presence of NaH2PO4 cleaved the
sulfone functional group without any detectable side products. In
spite of this fact, we observed that the latter reactions proceeded
Et2NH does not quench lithium naphthalenide at low temperature (À78 °C).
Instead it acts as a scavenger of the alkyl lithium side products that could be produced
during the reaction and thus prevents the substrate degradation.

1564
S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
OMe
OMe
i, ii, iii
83%
iv
O
EtO2C
OTBDPS
SO2Ph
CO2Et
HO
70%
i, ii
iii
21
23
22
6b
(+)-
10b
SO2Ph
67%
(from 6b)
OTBDPS
Br
OMe
OMe
OH
OH
iv
OMe
OMe
28
(+)-
SO2Ph 27
64%
SO2Ph
OTBDPS
v, vi
vii
71%
SO2Ph
OH
(+)-6d
72%
8d
OH
v
OMe
OMe
OMe
viii
29
(+)-
85%
OMe
OMe
(S)-curcudiol
OH
OTBDPS
Scheme 5. Synthesis of (S)-curcudiol starting from enantioenriched 2-aryl-propyl-
sulfonylbenzene derivatives (+)-6b. Reagents and conditions: (i) nBuLi, THF, À50 °C;
(ii) ethyl acrylate, THF, À78 °C then NH4Cl aq; (iii) MeLi, THF, 0 °C, then NH4Cl aq;
(iv) Na(Hg), NaH2PO4, THF/MeOH, 0 °C; (v) EtSNa, DMF, reflux.
93%
(+)-25
24
(+)-
OMe
O
O
that this kind of approach is very effective, provided that the
reaction is performed at low temperature using only a slight excess
of acrylate 9. The addition proceeds rapidly and the resulting
anionic species can give polymeric side products.
ix, x
83%
26
(+)-
(S)-glandulone A
O
According to these experimental conditions, the lithium salt of
the enantioenriched sulfone (+)-6b reacted quickly with ethyl
acrylate 9. Although the resulting ester 10b was contaminated
with trace amounts of polymeric materials, the following reaction
with an excess of methylithium gave carbinol 27 in good overall
yield. The phenylsulfonyl group was then removed using sodium
amalgam in the presence of NaH2PO4 to afford compound (+)-28.
The demethylation of the phenol ether functional group was
accomplished using sodium ethanethiolate in refluxing DMF to
give curcudiol (+)-29 in good yield, whose analytical data were in
good agreement with those previously reported.
Scheme 4. Synthesis of (S)-glandulone A starting from enantioenriched 2-aryl-
propylsulfonylbenzene derivative (+)-6d. Reagents and conditions: (i) NaBH4,
MeOH, 0 °C; (ii) TBDPSCl, DMF, imidazole, DMAP cat., rt; (iii) DIBALH, toluene,
THF, À50 °C; (iv) NBS, Me2S, CH2Cl2, À20 °C; (v) nBuLi, THF, À50 °C; (vi) 23, DMPU;
(vii) lithium naphthalenide, THF, Et2NH, À78 °C, then NH4Cl aq; (viii) TBAF, THF, rt;
(ix) MnO2, CH2Cl2, reflux; (x) (NH4)2Ce(NO3)6, CH3CN/H2O.
was converted into the corresponding bromide using NBS and
Me2S, according to the procedure proposed by Corey.25 Compound
23 was obtained in high isomeric purity (98% chemical purity, 95%
of the E-isomer) and was used for the alkylation of the lithium salt
of enantioenriched sulfone (+)-6d (94% ee). Next, the phenylsulfo-
nyl group of the resulting alkylated derivative 8d was reductively
removed using lithium naphthalenide in the presence of Et2NH
to give compound (+)-24 in good yield. The following deprotection
of the TBDPS ether with TBAF in THF afforded allyl alcohol (+)-25 in
nearly quantitative yield. The oxidation of the alcohol functional
group with MnO2 followed by the oxidation of the hydroquinone
dimethylether moiety using (NH4)2Ce(NO3)6 in CH3CN/H2O gave
glandulone A (+)-26, whose NMR data were in good agreement
with those previously reported. Moreover, we recorded a specific
rotation value of +47.1 (c 3.2, MeOH) for a sample of glandulone
A with 94% chemical purity and 94% ee, thus corroborating the
absolute configuration of the natural product. It should be noted
that a specific rotation value of +142.5 (c 0.12, MeOH)23 was
obtained for the natural glandulone A. Although we are not able
to give a sensible explanation for this discrepancy, we can affirm
that the first enantioselective synthesis of glandulone A was
accomplished, confirming the absolute configuration previously
assigned.
2.5. Acylation of the 2-aryl-propylsulfonylbenzene derivatives:
synthesis of (S)-(+)-turmerone
According to the synthetic plan outlined in Figure 2, we also
examined the effectiveness of the acylation reaction using our
enantioenriched 2-aryl-propylsulfonylbenzene derivatives as sub-
strates. To this end, we selected (S)-turmerone 31 as synthetic tar-
get (Scheme 6). The latter sesquiterpene is a flavour component of
different Curcuma species36 and has been the subject of a number
of synthetic studies.6,37–42
O
SO2Ph
i, ii, iii
O
77%
SO2Ph
(+)-6a
12a
MeO
30
O
iv
2.4. Conjugate addition of the 2-aryl-propylsulfonylbenzene
derivatives: synthesis of (S)-(+)-curcudiol
85%
31
(+)-
(S)-turmerone
As mentioned earlier, the sulfone anions can give conjugated
addition to very reactive acrylates such as ethyl acrylate 9. The reac-
tion was studied using enantioenriched sulfone (+)-6b in order to
prepare the naturally occurring enantiomer of the sesquiterpene
curcudiol (+)-29 (Scheme 5). The latter phenol has been isolated
from different species of sponge19,26–29 and has antifungal19 and
antifouling30 properties. Although a number of enantioselective
syntheses of this compound have been described,31–35 none of them
are based on the conjugate addition of sulfone anions. We found
Scheme 6. Synthesis of (S)-turmerone starting from enantioenriched 2-aryl-
propylsulfonylbenzene derivatives (+)-6a. Reagents and conditions: (i) nBuLi, THF,
À50 °C; (ii) MgBr2-Et2O, 0 °C, 10 min; (iii) 30, À78 °C then rt, NH4Cl aq; (iv) lithium
naphthalenide, THF, Et2NH, À78 °C, then NH4Cl aq.
Inspired by work that exploited the acylation of structurally dif-
ferent sulfones,43 we treated the lithium salt of compound (+)-6a
with magnesium bromide-diethyl ether. The derived magnesium

S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
1565
complex was treated with 3,3-dimethylacrylic acid methyl ester 30
to give unsaturated ketone 12a in good yield. The following cleav-
age of the phenylsulfonyl group was performed using lithium
naphthalenide in the presence of Et2NH at low temperature
(À78 °C) to give (S)-turmerone (+)-31, in good yield and without
any significant amount of other reduction side products. The latter
ketone appeared as a colorless oil and possessed a subtle odour
reminiscent of turmeric and had analytical data in perfect agree-
ment with those previously reported.
The chemical synthesis of 35 has not been reported yet and the
inherent instability of its -hydroxy-ketone moiety make it a suit-
a
able target to check the flexibility of synthetic approaches based on
the use of building blocks 6a–d. Hence, we selected compound (+)-
6b (95% ee) as common starting material. With regards to the first
path, we added the lithium salt of (+)-6b to racemic aldehyde 32.
The crude carbinol was acetylated using acetic anhydride and pyr-
idine and then submitted to a Julia–Lythgoe reactionà to afford
compound 15b in good overall yield and as a 4:1 E/Z isomeric
mixture. The following hydrogenation reaction was performed at
atmospheric pressure using Pd/C as catalyst to give ketal 33, which
is a common precursor of the two planned synthetic pathways.
Treatment of compound (+)-6b with an excess of LDA in the pres-
ence of TMEDA followed by the addition of epoxide 36 afforded
derivative 14b which was reduced using lithium naphthalenide in
the presence of Et2NH at low temperature (À78 °C) to give diol 37.
Since the latter compound unexpectedly reacted with sodium ethan-
ethiolate to afford thioether derivatives, the diol functional group
was protected as a ketal derivative by treatment with 2,2-dime-
thoxypropane in the presence of catalytic PTSA. The methyl ether
group of the obtained compound 33 was then replaced by an acetate
group through sequential reaction with sodium ethanethiolate in
refluxing DMF followed by acetylation of the resulting phenol by
acetic anhydride and pyridine. The ketal protecting group was finally
removed by heating the crude acetate at 60 °C in aqueous acetic acid.
The obtained diol 34 was readily oxidized with IBX in DMSO and
cautious hydrolysis of the acetate group with NaOH in methanol
afforded (+)-curcudiol-10-one 35 in good overall yield.
2.6. The use of 2-aryl-propylsulfonylbenzene derivatives for
epoxides ring opening and Julia–Lythgoe olefination
The chemical reactivity of the enantioenriched 2-aryl-propyl-
sulfonylbenzenes 6a–d was studied by means of two other types
of reaction. The lithium derivatives of the aforementioned sulfones
can lead to nucleophilic addition to the carbonyl group of the C5
aldehydes and the resulting b-hydroxy-sulfones can undergo to
Julia–Lythgoe reaction to give olefins of type 15 (Fig. 2). Moreover,
the same lithium salts are able to give nucleophilic ring opening of
epoxides of type 13 to afford
c-hydroxy-sulfone of type 14. In
order to substantiate the potential of these methods, we selected
the sesquiterpene curcudiol-10-one 35 as a prospective target to
be synthesized through a convergent approach, which can use both
types of reactions as key steps (Scheme 7).
OMe
SO2Ph
The aforementioned sesquiterpene appeared as colorless oil
whose NMR data were in good agreement with those reported. A
minor discrepancy concerning the specific rotation value was
observed. We recorded a value of +19.1 (c 2.2, CHCl3) for a sample
of 35 prepared starting from (+)-6b with 95% ee whereas curcudi-
ol-10-one produced by Aspergillus alliaceus was reported to possess
a specific rotation of +40.5 (c 0.6, CHCl3). Since the reactions
employed for the synthesis of (+)-35 do not involve racemization,
we supposed that either an error of measurement or the presence
of optically active impurities had affected one of the two specific
rotation values.
(+)-6b
O
O
OH
O
36
O
32
i, ii, iii, iv
78%
x
87%
OMe
OMe
OMe
OH
OH
OH
O
15b
OH
O
O
SO2Ph
14b
3. Conclusion
v
91%
80%
xi 89%
Enantioenriched 2-aryl-propanols are easily preparable by
enzyme mediated resolution of the corresponding racemic materi-
als. Herein we have reported on how they can be effectively trans-
formed into the related 2-aryl-propylsulfonylbenzene derivatives,
which are very useful chiral building blocks for the synthesis of
aromatic bisabolane sesquiterpenes.
More specifically, the latter sulfones reacted efficiently with
nBuLi and the resulting lithium salts were used to accomplish
different types of reactions comprising of alkylations, acylations,
conjugated additions, additions to aldehydes followed by Julia–
Lythgoe olefinations and regioselective epoxide ring openings.
Through these approaches, different outcomes were achieved. First
and foremost, we have proposed a new stereoselective synthesis of
the naturally occurring bisabolane sesquiterpenes (À)-curcuphe-
nol, (À)-xanthorrhizol, (+)-glandulone A, (+)-curcudiol, (+)-turmer-
one and (+)-curcudiol-10-one. Our approach compares favorably
over the previous asymmetric syntheses of the latter compounds,
is reliable, is of general applicability and does not require demand-
ing experimental conditions. In addition, (+)-glandulone A and
OMe
xii
O
37
33
34
OH
95%
vi, iii, vii
OAc
OH
OH
viii, ix
83%
35
(+)-
OH
O
(S)-curcudiol-10-one
Scheme 7. Synthesis of (+)-curcudiol-10-one starting from enantioenriched 2-aryl-
propylsulfonylbenzene derivatives (+)-6b. Reagents and conditions: (i) nBuLi, THF,
À50 °C; (ii) 32, THF, À50 °C, then NH4Cl aq; (iii) Ac2O, Py, cat. DMAP, rt; (iv) Na(Hg),
NaH2PO4, THF/MeOH, À10 °C then NH4Cl aq; (v) H2, AcOEt, 1 atm, rt; (vi) EtSNa,
DMF, reflux; (vii) AcOH, H2O, 60 °C, 6 h; (viii) IBX, DMSO, rt; (ix) NaOH, MeOH; (x)
LDA, THF, TMEDA, À50 °C, then 36, 0 °C, 5 h; (xi) lithium naphthalenide, THF, Et2NH,
À78 °C, then NH4Cl aq; (xii) 2,2-dimethoxypropane, acetone, cat. PTSA, rt.
The (S)-enantiomer of the latter phenol was isolated only
recently27 during a study aimed at identifying metabolites derived
by the microbial transformation of marine sesquiterpenes. The
incubation of (+)-curcuphenol with Aspergillus alliaceus afforded
(S)-curcudiol-10-one 35, alongside other hydroxylated derivatives.
à
A similar approach was studied for the synthesis of helibisabonols (Ref. 44) but
the authors reported that Julia–Lythgoe reaction performed on benzoyl derivatives
gave only poor yields of the corresponding olefins.

1566
S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
(+)-curcudiol-10-one were prepared in enantioenriched form for
the first time, allowing us to confirm both the chemical structures
and the absolute configurations previously assigned to these
sesquiterpenes. As a final point, it is worth noting that the starting
2-aryl-propanols are available in both enantiomeric forms and our
synthetic approach represents a formal enantioselective synthesis
of the opposite enantiomeric form of each one of the aforemen-
tioned sesquiterpenes.
washed with an aq solution of NaOH (10% w/w, 50 mL) and brine,
dried (Na2SO4) and concentrated in vacuo. The residue was dis-
solved in CH2Cl2 (40 mL) and treated with m-chloroperbenzoic acid
(6.8 g of a 77% w/w powder, 30.3 mmol) stirring at 0 °C until com-
pletion of the reaction (TLC monitoring). The m-chlorobenzoic acid
formed was removed by filtration and the liquid phase was washed
in turn with aq NaSO3 (10% w/w), aq NaHCO3 (saturated solution)
and brine. The organic phase was dried (Na2SO4), concentrated
and the residue was purified by chromatography using n-hexane/
AcOEt (95:5–7:3) as eluent to afford (R)-1-methyl-4-(1-(phenylsul-
fonyl)propan-2-yl)benzene (+)-6a (2.51 g, 76% yield) as a colorless
4. Experimental
4.1. General
oil which solidified upon standing. Mp 75–76 °C; [a]
20 = +7.8 (c
D
2.1, CHCl3), 99% of chemical purity by GC. 1H NMR (400 MHz, CDCl3)
d 1.42 (d, J = 6.8 Hz, 3H), 2.27 (s, 3H), 3.27–3.45 (m, 3H), 6.96 (d,
J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 7.44–7.50 (m, 2H), 7.55–
7.61 (m, 1H), 7.77–7.83 (m, 2H). 13C NMR (100 MHz, CDCl3) d
140.9, 139.9, 136.4, 133.3, 129.3, 129.0, 127.8, 126.5, 63.4, 34.6,
22.1, 20.9. GC–MS m/z (rel intensity) 274 (M+, <1), 242 (<1), 165
(2), 132 (100), 105 (62), 91 (27), 77 (40), 51 (12).
All moisture-sensitive reactions were carried out under a static
atmosphere of nitrogen. All solvents and reagents were of commer-
cial quality with the exception of sodium amalgam, lithium napht-
halenide, o-iodoxybenzoic acid (IBX) and 3-methylbut-2-enyl
4-nitrobenzoate. The amalgam was prepared by dissolving sodium
metal in mercury and the obtained solid was finely ground. Lith-
ium naphthalenide (0.72 M in THF) was prepared by dissolving
small pieces of lithium metal (0.75 g, 108.1 mmol) in a cooled
(0 °C) solution of naphthalene (15 g, 117 mmol) in dry THF (final
volume 150 mL) under a static atmosphere of nitrogen. The deep
green solution obtained was stored under nitrogen at 0 °C and
was used within 12 h. IBX and 3-methylbut-2-enyl 4-nitrobenzo-
ate were prepared according to the procedure described in Refs.
45 and 46, respectively. TLC: Merk silica gel 60 F254 plates. Column
chromatography (CC): silica gel. GC–MS analyses: HP-6890 gas
chromatograph equipped with a 5973 mass detector, using a HP-
According to the procedure outlined for the synthesis of com-
pound (+)-6a, alcohol (+)-(R)-1b (95% ee, 98 % chemical purity)
gave, in 84% yield, sulfone (R)-2-methoxy-4-methyl-1-(1-(phenyl-
sulfonyl)propan-2-yl)benzene (+)-6b as a colorless oil, which solid-
ified upon standing. Mp 60–62 °C; [a]
20 = +13.8 (c 2, CHCl3), 99% of
D
chemical purity by GC. 1H NMR (400 MHz, CDCl3) d 1.40 (d,
J = 7.0 Hz, 3H), 2.26 (s, 3H), 3.29 (dd, J = 13.9, 7.5 Hz, 1H), 3.47–
3.64 (m, 2H), 3.61 (s, 3H), 6.47 (s, 1H), 6.64 (d, J = 7.7 Hz, 1H),
6.92 (d, J = 7.7 Hz, 1H), 7.40–7.47 (m, 2H), 7.52–7.58 (m, 1H),
7.74–7.81 (m, 2H). 13C NMR (100 MHz, CDCl3) d 156.5, 140.0,
137.9, 132.9, 128.7, 128.4, 127.9, 127.8, 121.1, 111.5, 61.7, 54.8,
30.4, 21.2, 19.8. GC–MS m/z (rel intensity) 304 (M+, 15), 162 (83),
147 (100), 135 (33), 119 (15), 105 (25), 91 (17), 77 (19), 65 (4).
According to the procedure outlined in the synthesis of com-
pound (+)-6a, alcohol (À)-(S)-1b (98% ee, 97% chemical purity)
gave, in 82% yield, sulfone (S)-2-methoxy-4-methyl-1-(1-(phenyl-
sulfonyl)propan-2-yl)benzene (À)-6b as a colorless oil which solid-
5MS column (30 m  0.25 mm, 0.25
lm film thickness; Hewlett
Packard) with the following temp. program: 60° (1 min)–6°/min–
150° (1 min)–12°/min–280° (5 min); carrier gas, He; constant flow
1 ml/min; split ratio, 1/30; tR given in min: tR(3) 19.91, tR(4) 20.50,
tR(5) 20.27, tR(6a) 26.59, tR(6b) 27.97, tR(6c) 27.78, tR(6d) 28.76,
tR(8b) 28.10 and 28.24, tR(8c) 30.26 and 30.42; tR(10b) 30.97 and
31.2, tR(15b-Z isomers) 23.03, 23.10, tR(15b-E isomers) 23.42 and
23.47, tR(17) 19.89, tR(18) 20.64, tR(19) 20.17, tR(20) 21.08, tR(25)
24.78, tR(26) 23.89, tR(27) 30.25 and 30.49, tR(28) 22.15, tR(29)
23.07, tR(31) 20.70, tR(32), 4.76, tR(33) 22.97 and 23.05, tR(35)
23.61, tR(36) 5.00, tR(37) 23.77. Mass spectra of compounds 8d,
12a, 22, 23, 24, 26, 27 and 34 were recorded on a Bruker ESQUIRE
3000 PLUS spectrometer (ESI detector). Optical rotations: Jasco-
DIP-181 digital polarimeter. 1H and 13C Spectra and DEPT experi-
ments: CDCl3 solutions at rt using a Bruker-AC-400 spectrometer
at 400, 100 and 100 MHz, respectively; chemical shifts in ppm
rel to internal SiMe4 (=0 ppm), J values in Hz. Melting points were
measured on a Reichert apparatus, equipped with a Reichert
microscope, and are uncorrected.
ified upon standing. Mp 60–62 °C; [
of chemical purity by GC.
a]
20 = À13.9 (c 2.2, CHCl3), 96%
D
4.2.2. Via the use of diphenyldisulfide/Bu3P
At first, Bu3P (4.8 g, 23.7 mmol) was added dropwise, under
nitrogen, to a stirred solution of enantioenriched alcohol (À)-(S)-
1c (2.50 g, 13.9 mmol, 95% ee, 97% chemical purity) and diphenyl
disulfide (5.8 g, 26.6 mmol) in dry pyridine (10 mL) at 0 °C. After
the addition was complete, the reaction was stirred at rt for a fur-
ther 2 h and then diluted with ether (100 mL) and quenched with
water (50 mL). The organic phase was washed with aq NaOH (10%
w/w, 2 Â 30 mL), brine, dried (Na2SO4) and concentrated in vacuo.
The residue was then dissolved in MeOH (40 mL) and the resulting
solution was treated with (NH4)2MoO4 (120 mg, 0.6 mmol) and
with a solution of H2O2 (35% wt. in water, 10 mL) stirring at 0 °C.
The solution was then warmed to rt while stirring was continued
for a further 8 h. The reaction was then cooled and a saturated
solution of Na2SO3 was added to destroy any excess oxidant. The
main part of the methanol was removed under reduced pressure
and the residue was extracted with AcOEt (3 Â 100 mL). The com-
bined organic layers were dried (Na2SO4), concentrated and the
residue was purified by chromatography using n-hexane/AcOEt
(95:5–7:3) as eluent to afford sulfone (S)-2-methoxy-1-methyl-4-
(1-(phenylsulfonyl)propan-2-yl)benzene (À)-6c (3.88 g, 92% yield)
as a colorless oil which solidified upon standing. Mp 66–69 °C;
4.2. Preparation of 2-aryl-propenylbenzene derivatives 6a–d
4.2.1. Via tosylate derivatives
A solution of p-toluenesulfonyl chloride (2.85 g, 15 mmol) in
CH2Cl2 (5 mL) was added dropwise to a stirred solution of enantio-
enriched alcohol (+)-(R)-1a (1.8 g, 12 mmol, 96% ee) and DMAP
(50 mg, 0.4 mmol) in pyridine (5 mL). After 4 h, the mixture was
diluted with ether (100 mL) and then washed with 1 M aq HCl solu-
tion (100 mL), saturated NaHCO3 solution (50 mL) and brine. The
organic phase was dried (Na2SO4) and concentrated in vacuo. The
residue was dissolved in dry DMSO (10 mL) and added dropwise
to a suspension of K2CO3 (6.2 g, 44.8 mmol) and thiophenol (3.3 g,
30 mmol) in DMSO (20 mL). The resulting mixture was stirred vig-
orously at rt until the starting tosylate was no longer detectable
by TLC analysis. 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
[
a
]
20 = À2.1 (c 3.2, CHCl3), 94% of chemical purity by GC. 1H NMR
D
(400 MHz, CDCl3) d 1.43 (d, J = 6.8 Hz, 3H), 2.12 (s, 3H), 3.28–3.45
(m, 3H), 3.74 (s, 3H), 6.49 (d, J = 1.7 Hz, 1H), 6.56 (dd, J = 7.6,
1.7 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 7.42–7.49 (m, 2H), 7.53–7.60
(m, 1H), 7.77–7.82 (m, 2H). 13C NMR (100 MHz, CDCl3) d 157.8,

S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
1567
142.9, 140.1, 133.2, 130.7, 129.0, 127.8, 125.2, 118.2, 108.6, 63.6,
55.2, 35.1, 22.1, 15.7. GC–MS m/z (rel intensity) 304 (M+, 8), 162
(100), 147 (9), 135 (10), 122 (4), 105 (4), 91 (6), 77 (7).
4.3.2. Preparation of 2,2,5,5-tetramethyl-1,3-dioxolane-4-carbal
dehyde 32
A
solution of 3-methylbut-2-enyl 4-nitrobenzoate46 (10 g,
According to the procedure outlined for the synthesis of com-
pound (À)-6c, alcohol (+)-(R)-1d (94% ee, 97% chemical purity)
gave, in 81% yield, sulfone (R)-1,4-dimethoxy-2-methyl-5-(1-
(phenylsulfonyl)propan-2-yl)benzene (+)-6d as a colorless thick
42.5 mmol) in acetone/water (85:15, 120 mL) was treated with
NMO47 (50% wt. in H2O, 14 g, 59.7 mmol) and catalytic K2OsO4-
Á2H2O (74 mg, 0.2 mmol) and stirred under nitrogen at rt until
the starting olefin could not be detected by TLC analysis (48 h).
The reaction was then quenched by the addition of an aqueous
solution of sodium hydrosulfite (5% wt., 100 mL) and the acetone
was evaporated under vacuum. The pH of the resulting aqueous
solution was adjusted to pH 5 by the careful addition of diluted
HCl aq and the mixture was extracted with EtOAc (3 Â 100 mL).
The combined organic phases were dried (Na2SO4) and concen-
trated in vacuo. The residue was dissolved in acetone (80 mL)
and treated with 2,2-dimethoxypropane (20 mL) and toluene-4-
sulfonic acid (0.5 g, 2.6 mmol) and then stirred at rt for 8 h. Next,
Et3N (5 mL) was added and the solvents were removed under
reduced pressure. The residue was partitioned between EtOAc
and water and the organic phase was washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue consisted of a
pale yellow oil (10.9 g, 83% yield), which solidified upon standing.
A solution of the above described ester (10.6 g, 34.3 mmol) in
methanol (80 mL) was treated with NaOH (20% w/w in water,
50 mL) stirring at rt until complete hydrolysis (1 h). Afterward, the
reaction mixture was extracted with diethyl ether (3 Â 100 mL)
and the combined organic phases were washed with water, brine,
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography using n-hexane/EtOAc (8:2–1:1) as eluent to
oil. [
for the opposite enantiomer [
a]
20 = +5.4 (c 2.5, CHCl3), 98% of chemical purity by GC, lit.44
D
a]
20 = À6.6 (c 1.2, CHCl3). 1H NMR
D
(400 MHz, CDCl3) d 1.42 (d, J = 7.0 Hz, 3H), 2.13 (s, 3H), 3.32 (dd,
J = 14.2, 7.5 Hz, 1H), 3.46–3.56 (m, 1H), 3.58 (s, 3H), 3.64 (dd,
J = 14.2, 5.7 Hz, 1H), 3.74 (s, 3H), 6.46 (s, 1H), 6.53 (s, 1H), 7.40–
7.47 (m, 2H), 7.52–7.58 (m, 1H), 7.74–7.80 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 151.6, 150.4, 140.0, 132.9, 129.0, 128.7,
127.9, 125.8, 114.0, 111.1, 61.7, 56.1, 55.5, 31.1, 19.9, 15.9. GC–
MS m/z (rel intensity) 334 (M+, 57), 192 (100), 177 (48), 163
(14), 149 (10), 135 (8), 105 (5), 91 (11), 77 (12).
4.3. Preparation of the C5 building blocks 23, 32 and 36
4.3.1. Preparation of (E)-(4-bromo-2-methylbut-2-enyloxy) (tert-
butyl)diphenylsilane 23
Ethyl-3-formyl crotonate 21 (4 g, 28.2 mmol) in methanol
(30 mL) was treated with NaBH4 (0.5 g, 13.2 mmol) at 0 °C. After
complete reduction (30 min), the reaction was diluted with water,
acidified with diluted aq HCl and extracted with CH2Cl2. The
organic phases were washed in turn with water and brine, dried
(Na2SO4) and concentrated in vacuo. The residue was then dis-
solved in dry DMF (30 mL) and treated with imidazole (2.1 g,
30.8 mmol), DMAP (0.1 g, 0.8 mmol) and tert-butylchlorodiphenyl
silane (8.3 g, 30.2 mmol) stirring at rt for 3 h. The reaction was then
quenched by the addition of a saturated solution of NaHCO3
(100 mL) and extracted with diethyl ether (2 Â 100 mL). The com-
bined organic phases were dried and concentrated under reduced
pressure. The residue was dissolved in dry THF (60 mL) and the
resulting solution was cooled (À50 °C) and treated under a static
atmosphere of nitrogen with DIBALH (40 mL of 1.49 M solution
in toluene). After 2 h, the reaction was heated to 0 °C, quenched
with a saturated aq solution of NH4Cl (60 mL), acidified with aq
HCl and diluted with ethyl acetate (100 mL). The organic phase
was separated and the aqueous phase was extracted with ethyl
acetate (100 mL). The combined organic layers were washed with
brine, dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by chromatography eluting with hex-
ane/ethyl acetate (9:1–3:1) as eluent to afford pure (E)-4-(tert-
butyldiphenylsilyloxy)-3-methylbut-2-en-1-ol 22 (7.9 g, 83%
yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) d 1.08 (s, 9H),
1.42 (br s, 1H), 1.62 (s, 3H), 4.08 (s, 2H), 4.18 (d, J = 6.8 Hz, 2H),
5.72 (tm, J = 6.8 Hz, 1H), 7.32–7.45 (m, 6H), 7.64–7.73 (m, 4H).
13C NMR (100 MHz, CDCl3) d 137.7, 135.5, 133.7, 129.6, 127.6,
122.8, 68.2, 58.9, 26.8, 19.2, 13.4. MS (ESI): 363.1 (M++Na).
Methyl sulfide (0.6 mL, 8.2 mmol) was added dropwise to a stir-
red solution of N-bromosuccinimide (1.42 g, 8 mmol) in CH2Cl2
(10 mL) at 0 °C. The reaction was cooled to À20 °C and then alcohol
22 (1.7 g, 5 mmol) in CH2Cl2 (4 mL) was added slowly. The mixture
was stirred 5 h at 0 °C, diluted with hexane and quenched with
crushed ice. The organic phase was washed with brine, dried (Na2-
SO4) and concentrated under reduced pressure. The residue was
purified by chromatography eluting with hexane/ethyl acetate
(95:5–8:2) as eluent to afford pure (E)-(4-bromo-2-methylbut-2-
enyloxy)(tert-butyl)diphenylsilane 23 (1.42 g, 70% yield) as a color-
less oil. 1H NMR (400 MHz, CDCl3) d 1.07 (s, 9H), 1.66 (s, 3H), 4.06
(d, J = 8.5 Hz, 2H), 4.09 (s, 2H), 5.93 (tm, J = 8.5 Hz, 1H), 7.34–7.46
(m, 6H), 7.64–7.70 (m, 4H). 13C NMR (100 MHz, CDCl3) d 141.4,
135.5, 133.4, 129.7, 127.7, 119.4, 67.7, 28.6, 26.8, 19.2, 13.1. MS
(ESI): 425.4 and 427.4 (M++Na), 441.3 and 443.3 (M++K).
afford
pure
(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)methanol
(4.9 g, 89% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) d
1.12 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 1.44 (s, 3H), 2.03 (br s, 1H),
3.64 (dd, J = 11.4, 3.8 Hz, 1H), 3.76 (dd, J = 11.4, 7.5 Hz, 1H), 3.90
(dd, J = 7.5, 3.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 107.7, 83.7,
79.5, 61.7, 28.5, 27.0, 26.8, 23.0.
A sample of the above described alcohol (4 g, 25 mmol) in CH2-
Cl2 (10 mL) was added under stirring at À60 °C to the heteroge-
neous mixture previously prepared through the dropwise
addition of a solution of DMSO (4.7 g, 60.2 mmol) in CH2Cl2
(10 mL) to a solution of (COCl)2 (4.1 g, 32.3 mmol) in CH2Cl2
(30 mL) at the same temperature. After one hour, Et3N (14 mL,
0.1 mol) was added, and the reaction was allowed to reach rt, after
which it was quenched by the addition of brine and dilution with
CH2Cl2 (40 mL). The organic phase was washed with water, brine,
dried (Na2SO4) and concentrated in vacuo. The residue consists of
almost pure 2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde 32
(3.41 g, 86% yield) as an unstable colorless oil (92% purity by GC
analysis) which was used immediately without any further purifi-
cation. GC–MS m/z (rel intensity) 143 (M+-Me, 65), 129 (47), 115
(4), 101 (7), 85 (86), 71 (17), 59 (74), 43 (100).
4.3.3. Preparation of 2-(oxiran-2-yl)propan-2-ol 36
Trifluoroacetic anhydride (54 g, 257 mmol) was added dropwise
at 0 °C to a stirred suspension of hydrogen peroxide-urea adduct
(25 g, 266 mmol) in CH3CN (80 mL).48 As soon as the solid dissolved,
the resulting solution was added dropwise, within 5 min, to a
mechanically stirredmixtureof K2CO3 (100 g, 724 mmol), 2-methyl-
but-3-en-2-ol (20 g, 232 mmol) and CH2Cl2 (200 mL), cooled at
À30 °C. The reaction was allowed to reach rt and stirred for a further
12 h. The organic phase was separated from the viscous-solid salt
mixture by filtration and washed in turn with sodium metabisulfite
(5% w/w aqueous solution), saturated NaHCO3 solution (50 mL),
brine and concentrated under reduced pressure. The residue was
distilled (bp 60 °C, 30 mmHg) to give pure 2-(oxiran-2-yl)propan-
2-ol 36 (14.1 g, 59% yield). 1H NMR (400 MHz, CDCl3) d 1.22 (s, 3H),
1.32 (s, 3H), 2.11 (br s, 1H), 2.72 (dd, J = 5.1, 3.8 Hz, 1H), 2.79 (dd,
J = 5.1, 2.8 Hz, 1H), 2.94 (dd, J = 3.8, 2.8 Hz, 1H). 13C NMR

1568
S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
(100 MHz, CDCl3) d 67.5, 58.4, 44.0, 27.4, 24.7. GC–MS m/z (rel inten-
7.56–7.68, 7.71–7.76 and 7.79–7.85 (4 m, 15H). 13C NMR
(100 MHz, CDCl3) d 151.7, 151.6, 150.6, 150.5, 140.6, 140.5,
136.2, 135.5, 133.8, 133.8, 133.8, 133.8, 132.8, 132.7, 129.6,
129.6, 129.5, 129.0, 128.6, 128.5, 128.3, 128.1, 127.6, 127.5,
125.8, 125.5, 121.7, 119.8, 113.6, 112.1, 111.5, 68.8, 68.7, 67.8,
67.0, 56.2, 56.0, 55.6, 55.5, 34.6, 32.3, 26.9, 26.8, 26.7, 22.2, 19.3,
19.2, 17.2, 16.0, 15.9, 13.5, 13.3, 13.2. MS (ESI): 679.7 (M++Na),
695.6 (M++K).
sity) 102 (M+, <1), 87 (M+-Me, 14), 71 (5), 59 (100), 43 (77), 31 (17).
4.4. Alkylation procedure. Synthesis of compounds 8b–d
At first, BuLi (1 mL of a 2.5 M solution in hexane) was added
dropwise under nitrogen to a cooled (À50 °C) solution of sulfone
(À)-6b (98% ee, 0.62 g, 2.04 mmol) in dry THF (10 mL). The result-
ing orange solution was stirred at this temperature for half an hour
and then a solution of bromide 16 (0.33 g, 2.2 mmol) in dry DMPU
(1 mL) was added dropwise. The reaction was allowed to reach rt
and after two hours at this temperature it was quenched by the
addition of a saturated solution of NH4Cl aq (50 mL). The resulting
mixture was extracted with CH2Cl2 (3 Â 60 mL) and the organic
phase was dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by chromatography using n-hexane/EtOAc
(9:1–7:3) as eluent to afford pure 2-methoxy-4-methyl-1-((2S)-
6-methyl-3-(phenylsulfonyl)hept-5-en-2-yl)benzene 8b (0.63 g,
83% yield) as a colorless thick oil, which consisted of a 1:1 mixture
of diastereoisomers. 1H NMR (400 MHz, CDCl3) d 1.25, 1.35, 1.39
and 1.54 (4 s, 6H); 1.41 and 1.56 (2 d, J = 7.2 Hz, 3H); 2.19–2.42
and 2.60–2.72 (2 m, 2H); 2.28 (s, 3H); 3.48–3.86 (m, 2H); 3.64
and 3.72 (2 s, 3H); 4.67 and 4.89 (2 t, J = 7.0 Hz, 1H); 6.53 (s, 1H),
6.64 and 6.70 (2 d, J = 7.7 Hz, 1H); 7.01 and 7.03 (2 d, J = 7.7 Hz,
1H); 7.40–7.47 (m, 1H); 7.48–7.64 (m, 2H); 7.73–7.78 (m, 1H);
7.85–7.90 (m, 1H). 13C NMR (100 MHz, CDCl3) d 156.6, 156.3,
140.4, 137.7, 137.5, 133.6, 132.9, 132.8, 132.8, 128.8, 128.6,
128.5, 128.4, 128.2, 127.8, 127.7, 121.4, 121.1, 120.9, 119.9,
111.2, 111.1, 68.0, 66.9, 54.9, 54.9, 33.7, 31.2, 27.2, 25.7, 25.5,
22.3, 21.3, 21.3, 17.4, 17.3, 12.7. GC–MS m/z (rel intensity)
tR(28.10): 372 (M+, 2), 230 (100), 215 (81), 199 (10), 187 (46),
175 (9), 149 (91), 135 (19), 119 (9), 105 (9), 91 (13), 69 (12);
tR(28.24): 372 (M+, 4), 230 (78), 215 (66), 199 (9), 187 (37), 175
(9), 149 (100), 135 (22), 119 (9), 105 (9), 91 (11), 69 (15).
According to the procedure outlined for the synthesis of com-
pound 8b, the alkylation of sulfone (À)-6c (95% ee) with bromide
16 gave, in 85% yield, 2-methoxy-1-methyl-4-((2S)-6-methyl-3-
(phenylsulfonyl)hept-5-en-2-yl)benzene 8c as a colorless thick
oil, which consisted of a 2:1 mixture of diastereoisomers. 1H
NMR (400 MHz, CDCl3) d 1.18, 1.39, 1.40 and 1.49 (4 s, 6H); 1.44
and 1.56 (2 d, J = 7.1 Hz, 3H); 2.10–2.33, 2.41–2.51 and 2.56–2.67
(3 m, 2H); 2.14 and 2.16 (2 s, 3H); 3.24–3.32, 3.50–3.59 and
3.69–3.79 (3 m, 2H); 3.76 and 3.80 (2 s, 3H); 4.61 and 4.77 (2 t,
J = 7.0 Hz, 1H); 6.55 and 6.72 (2 s, 1H), 6.62 and 6.69 (2 dd,
J = 7.6, 1.5 Hz, 1H); 6.97 and 7.01 (2 d, J = 7.6 Hz, 1H); 7.46–7.53
(m, 2H); 7.55–7.61 (m, 1H); 7.81–7.87 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 157.7, 157.6, 142.5, 141.6, 140.2, 140.2,
133.9, 133.4, 133.1, 133.1, 130.4, 130.3, 128.8, 128.5, 128.5,
125.1, 125.0, 120.9, 120.1, 119.7, 119.4, 110.5, 109.6, 70.8, 70.6,
55.3, 38.6, 36.8, 26.8, 25.5, 25.4, 23.1, 20.6, 17.5, 17.5, 15.7, 15.7,
14.4. GC–MS m/z (rel intensity) tR(30.26, minor isomer): 372 (M+,
1), 230 (88), 215 (54), 199 (7), 187 (100), 175 (12), 149 (54), 135
(18), 109 (53), 91 (20), 69 (19); tR(30.42, major isomer): 372 (M+,
2), 230 (81), 215 (56), 199 (6), 187 (100), 173 (11), 149 (59), 135
(16), 109 (22), 91 (17), 69 (23).
4.5. Conjugate addition of sulfone 6b to ethyl acrylate. Synthesis
of compound 27
At first, BuLi (1 mL of a 2.5 M solution in hexane) was added
dropwise under nitrogen to a cooled (À50 °C) solution of sulfone
(+)-6b (95% ee, 0.62 g, 2.04 mmol) in dry THF (10 mL). The result-
ing orange solution was stirred at this temperature for half an hour
and then cooled at À78 °C after which ethyl acrylate (0.23 g,
2.3 mmol) in dry THF (1 mL) was added quickly with vigorous stir-
ring. After 15 min the reaction was quenched by the addition of a
saturated solution of NH4Cl aq (50 mL). The resulting mixture
was warmed to rt, extracted with EtOAc (2 Â 60 mL) and the
organic phase was dried (Na2SO4) and concentrated in vacuo. The
crude product was roughly purified by chromatography using
n-hexane/EtOAc (9:1–1:1) as eluent to afford sulfone 10b (0.81 g)
as a 2:1 mixture of diastereoisomers (by GC analysis) contami-
nated with polymeric impurities.
All of the aforementioned compound was dissolved in dry THF
(15 mL) and treated at 0 °C with MeLi (5.2 mL of a 1.6 M solution
in diethyl ether) stirring under a static atmosphere of nitrogen for
2 h. The reaction was then quenched with a saturated aq solution
of NH4Cl (60 mL) and diluted with ethyl acetate (100 mL). The
organic phase was separated and the aqueous phase was extracted
with ethyl acetate (50 mL). The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by chromatography eluting with
hexane/ethyl acetate (9:1–2:1) as eluent to afford pure (6R)-6-(2-
methoxy-4-methylphenyl)-2-methyl-5-(phenylsulfonyl)heptan-2-
ol 27 (0.53 g, 67% yield) as a 2:1 mixture of diastereoisomers. 1H
NMR (400 MHz, CDCl3) d 0.90, 0.92, 1.03 and 1.07 (4 s, 6H); 1.10–
1.44, 1.44–1.60, 1.62–1.69, 1.70–1.87 and 2.02–2.18 (5 m, 5H);
1.38 and 1.50 (2 d, J = 7.0 Hz, 3H); 2.27 and 2.28 (2 s, 3H); 3.45–
3.64 (m, 2H); 3.54 and 3.73 (2 s, 3H); 6.48 and 6.56 (2 s, 1H);
6.65–6.72 (m, 1H); 6.99–7.05 (m, 1H); 7.44–7.66, 7.78–7.85 and
7.87–7.93 (3 m, 5H). 13C NMR (100 MHz, CDCl3) d 156.6, 156.3,
140.4, 139.7, 137.9, 137.8, 133.0, 132.9, 128.9, 128.8, 128.7, 128.5,
128.2, 128.2, 127.6, 127.5, 121.2, 121.0, 111.5, 111.2, 70.6, 70.2,
68.2, 66.5, 55.0, 54.8, 42.3, 40.4, 34.3, 31.8, 29.3, 28.9, 28.4, 28.4,
23.3, 21.3, 18.4, 17.9, 12.6. MS (ESI): 413.2 (M++Na).
4.6. Acylation of sulfone 6a
At first, BuLi (4 mL of a 2.5 M solution in hexane) was added
dropwise under nitrogen to a cooled (À50 °C) solution of sulfone
(+)-6a (96% ee, 2.4 g, 8.76 mmol) in dry THF (20 mL). The resulting
orange solution was cooled at À78 °C and a magnesium bromide-
diethyl ether complex (5.3 mL of a 2 M solution in diethyl ether)
was slowly added. The resulting heterogeneous mixture was
warmed at 0 °C for 10 min then cooled again at À78 °C before
the addition of 3,3-dimethylacrylic acid methyl ester (1.3 g,
11.4 mmol) in dry THF (2 mL). The mixture was allowed to slowly
reach to rt, and then was quenched by the addition of a saturated
solution of NH4Cl aq (80 mL) and diluted with ethyl acetate
(100 mL). The organic phase was separated and the aqueous phase
extracted with ethyl acetate (80 mL). The combined organic layers
were washed with brine, dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by chromatography
According to the procedure outlined for the synthesis of
compound 8b, the alkylation of sulfone (+)-6d (94% ee) with
bromide 23 gave, in 71% yield, tert-butyl((6R,E)-6-(2,5-dime-
thoxy-4-methylphenyl)-2-methyl-5-(phenylsulfonyl)hept-2-enyl-
oxy)diphenylsilane 8d as a colorless thick oil, which consisted of a
2:1 mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) d 1.01
and 1.05 (2 s, 9H); 1.26 and 1.39 (2 s, 3H); 1.44 and 1.58 (2 d,
J = 7.2 Hz, 3H); 2.03–2.37, 2.39–2.53 and 2.67–2.80 (3 m, 2H);
2.13 (s, 3H); 3.56, 3.60, 3.70 and 3.74 (4 s, 6H); 3.56–3.65 and
3.71–3.84 (2 m, 2H); 3.79 and 3.90 (2 br s, 2H); 5.12 and 5.31 (2
t, J = 7.1 Hz, 1H); 6.47, 6.60 and 6.65 (3 s, 2H); 7.30–7.54,

S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
1569
eluting with hexane/ethyl acetate (9:1–2:1) as eluent to afford
pure (6R)-2-methyl-5-(phenylsulfonyl)-6-p-tolylhept-2-en-4-one
12a (2.39 g, 77% yield, 1:1 mixture of diastereoisomers by NMR
analysis) as a colorless oil, that solidified upon standing. Mp
112–115 °C. 1H NMR (400 MHz, CDCl3) d 1.20 and 1.61 (2 d,
J = 7.0 Hz, 3H); 1.56, 1.66, 1.97, 2.17 (4 d, J = 1.0 Hz, 6H); 2.24 and
2.25 (2 s, 3H); 3.55–3.70 (m, 1H); 4.29 (d, J = 11.0 Hz) and 4.30
(d, J = 10.3 Hz) 1H; 5.86 and 6.38 (2 m, 1H); 6.87–7.04 (m, 4H);
7.22–7.30, 7.41–7.54, 7.57–7.65 and 7.84–7.90 (4 m, 5H). 13C
NMR (100 MHz, CDCl3) d 190.9, 190.6, 160.4, 158.5, 139.9, 139.3,
138.9, 138.5, 136.6, 136.5, 133.8, 132.8, 129.2, 129.2, 129.1,
128.8, 128.4, 128.4, 127.6, 127.5, 124.0, 123.3, 82.3, 82.1, 39.3,
39.1, 28.0, 27.4, 21.7, 21.4, 20.9, 20.8, 20.5. MS (ESI): 379.5
(M++Na); 395.4 (M++K).
27.3, 26.9, 26.8, 26.2, 22.8, 21.3, 21.2, 21.0. GC–MS m/z (rel inten-
sity) 306 (M+, 4), 291 (M+-Me, 15), 249 (10), 230 (6), 215 (5), 190
(4), 175 (21), 165 (88), 149 (100), 135 (11), 127 (27), 119 (11), 105
(10), 91 (16), 71 (11).
5-((S)-3-(2-Methoxy-4-methylphenyl)butyl)-2,2,4,4-tetramethyl-
1,3-dioxolane 33 was also prepared starting from (6S)-6-(2-meth-
oxy-4-methylphenyl)-2-methylheptane-2,3-diol 37 by reaction
with 2,2-dimethoxypropane in acetone in the presence of a
catalytic amount of PTSA (95% yield).
4.8. Nucleophilic opening of epoxide 36 using sulfone 6b
Freshly prepared LDA (32 mL of a 0.9 M solution in THF) was
added to a cooled (À50 °C) solution of sulfone (+)-6b (95% ee,
2.2 g, 7.23 mmol) and dry tetramethylethylene diamine (5 mL) in
dry THF (10 mL), and stirred under a static atmosphere of nitrogen.
Immediately after, 2-(oxiran-2-yl)propan-2-ol 36 (1.48 g,
14.5 mmol) was added dropwise, then the mixture was allowed
to slowly reach 0 °C and stirring was continued for 5 h. The reac-
tion was then quenched by the addition of a saturated solution
of NH4Cl aq (100 mL) and diluted with ethyl acetate (100 mL).
The organic phase was separated and the aqueous phase was
extracted with ethyl acetate (100 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by chromatogra-
phy eluting with hexane/ethyl acetate (7:3–1:1) as eluent to afford
pure (6R)-6-(2-methoxy-4-methylphenyl)-2-methyl-5-(phenylsul-
fonyl)heptane-2,3-diol 14b (2.55 g, 87% yield) as a colorless thick
oil. MS (ESI): 429.5 (M++Na), 445.4 (M++K) and 835.0 (2M++Na).
4.7. Julia–Lythgoe olefination using sulfone (+)-6b and aldehyde
32
At first, BuLi (4.3 mL of a 2.5 M solution in hexane) was added
dropwise under nitrogen to a cooled (À50 °C) solution of sulfone
(+)-6b (95% ee, 3 g, 9.87 mmol) in dry THF (20 mL). 2,2,5,5-Tetra-
methyl-1,3-dioxolane-4-carbaldehyde 32 (1.72 g, 10.9 mmol) in
dry THF (5 mL) was added to the resulting orange solution and the
mixture was vigorously stirred for one hour. The reaction was then
quenched by the addition of a saturated solution of NH4Cl aq
(80 mL) and diluted with ethyl acetate (100 mL). The organic phase
was separated and the aqueous phase extracted with ethyl acetate
(100 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was dissolved in pyridine (10 mL) and treated with acetic
anhydride (10 mL) and DMAP (0.1 g, 0.8 mmol). The mixture was
left for 5 h and then concentrated under reduced pressure as long
as both pyridine and the anhydride were completely removed.
The residue was dissolved in methanol–THF (1:1, 40 mL), cooled
(À10 °C) and treated under vigorous stirring with finely ground
NaH2PO4 (6 g, 50 mmol) followed by the portionwise addition of
sodium amalgam (6.1% w/w, 12 g, 31.5 mmol). Stirring was pro-
longed until the starting carbinol could no longer be detected by
TLC analysis (7 h). The mixture was diluted with ether (100 mL),
quenched by the addition of a saturated solution of NH4Cl aq and
washed in turn with water and brine. The organic phase was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
chromatography eluting with hexane/ethyl acetate (9:1–7:3) as
eluent to afford pure 15b (2.35 g, 78% yield) as a colorless oil. The
GC analysis of the latter oil showed the presence of four peaks cor-
responding to the 12%, 10%, 38% and 40% of the mixture. The NMR
analysis indicated the presence of the E/Z isomers in a 4:1 ratio,
respectively. As a consequence, the mixture consisted of four diaste-
reoisomers: two Z-isomers (22%) and two E-isomers (78%).
4.9. Reductive cleavage of the phenylsulfonyl group
A solution of 2-methoxy-4-methyl-1-((2S)-6-methyl-3-(phen-
ylsulfonyl)hept-5-en-2-yl)benzene 8b (0.8 g, 2.15 mmol) in
methanol-THF (1:1, 30 mL) was cooled (0 °C) and treated under
vigorous stirring with finely ground NaH2PO4 (4 g, 33.3 mmol) fol-
lowed by addition of sodium amalgam (6.1 % w/w, 4 g, 10.6 mmol).
Stirring was prolonged for 12 h during which time further portion-
wise additions (overall 2 g, 5.3 mmol) of sodium amalgam were
added. The mixture was then diluted with ether (100 mL), the
organic phase was decanted, and washed in turn with water and
brine and dried (Na2SO4). The solvents were removed in vacuo
and the residue was purified by chromatography eluting with
hexane/ethyl acetate (9:1–7:3) as eluent to afford recovered 8b
(0.22 g, 0.59 mmol) and pure (R)-2-methoxy-4-methyl-1-(6-meth-
ylhept-5-en-2-yl)benzene (À)-17 (curcuphenol methylether,
0.28 g, 1.21 mmol, 56% yield, 84% yield vs reacted 8b) as a colorless
oil. [
a
]
20 = À7.5 (c 2, CHCl3), 99% of chemical purity by GC, lit.5 for
D
the opposite enantiomer
[a]
20 = +7.8 (c 1, CHCl3). 1H NMR
D
A sample of the aforementioned ketal (2.1 g, 6.9 mmol) was dis-
solved in EtOAc (50 mL), treated with Pd/C (10% w/w, 100 mg) and
hydrogenated at rt and atmospheric pressure until 1.05 equiv of
hydrogen were adsorbed (12 h). The catalyst was removed by filtra-
tion, the organic phase was concentrated in vacuo and the residue
was purified by chromatography eluting with hexane/ethyl acetate
(9:1–7:3) as eluent to afford pure 5-((S)-3-(2-methoxy-4-methyl-
phenyl)butyl)-2,2,4,4-tetramethyl-1,3-dioxolane 33 (1.92 g, 91%
yield) as a colorless oil, which consisted of a 1:1 mixture of diaste-
reoisomers (GC–MS and NMR analysis). 1H NMR (400 MHz, CDCl3)
d 1.02, 1.03, 1.18, 1.19, 1.30, 1.32, 1.38 and 1.39 (8 s, 12H); 1.20
(d, J = 7.0 Hz, 3H); 1.10–1.85 (m, 4H); 2.32 (s, 3H); 3.07–3.26 (m,
1H); 3.62 (dd, J = 8.3, 4.4 Hz) and 3.68 (dd, J = 8.6, 4.4 Hz) 1H; 3.79
and 3.79 (2 s, 3H); 6.66 (br s, 1H); 6.73 (d, J = 7.8 Hz, 1H); 7.04
(dd, J = 7.8, 2.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 157.0, 156.9,
136.4, 136.4, 132.5, 132.3, 126.7, 126.6, 121.2, 111.6, 111.6, 106.3,
106.3, 83.6, 83.2, 80.1, 55.3, 55.3, 34.2, 33.9, 32.1, 31.3, 28.6, 27.8,
(400 MHz, CDCl3) d 1.17 (d, J = 7.0 Hz, 3H), 1.46–1.70 (m, 2H),
1.53 (s, 3H), 1.66 (m, 3H), 1.80–2.01 (m, 2H), 2.32 (s, 3H), 3.08–
3.18 (m, 1H), 3.79 (s, 3H), 5.11 (tm, J = 7.0 Hz, 1H), 6.66 (s, 1H),
6.73 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 157.0, 136.2, 132.9, 131.0, 126.6, 124.9,
121.1, 111.5, 55.3, 37.2, 31.5, 26.3, 25.7, 21.3, 21.1, 17.6. GC–MS
m/z (rel intensity) 232 (M+, 22), 217 (3), 189 (2), 175 (7), 162
(12), 149 (100), 135 (19), 115 (12), 105 (13), 91 (21), 69 (7).
According to the procedure outlined for the synthesis of
compound (À)-17, the reduction of (6R)-6-(2-methoxy-4-methyl-
phenyl)-2-methyl-5-(phenylsulfonyl)heptan-2-ol 27 gave (S)-6-
(2-methoxy-4-methylphenyl)-2-methylheptan-2-ol (+)-28 (64%
yield and 88% yield versus reacted 27) as a colorless thick oil.
[a]
20 = +7.5 (c 2, CHCl3), 98% of chemical purity by GC. 1H NMR
D
(400 MHz, CDCl3) d 1.16 (s, 6H), 1.17 (d, J = 7.0 Hz, 3H), 1.17–1.38
(m, 3H), 1.38–1.54 (m, 3H), 1.55–1.69 (m, 1H), 2.32 (s, 3H), 3.09–
3.20 (m, 1H), 3.79 (s, 3H), 6.66 (s, 1H), 6.73 (d, J = 7.7 Hz, 1H),

1570
S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
7.03 (d, J = 7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 156.9, 136.2,
132.9, 126.5, 121.2, 111.6, 71.0, 55.4, 44.0, 37.7, 31.5, 29.2, 29.1,
22.4, 21.3, 21.0. GC–MS m/z (rel intensity) 250 (M+, 5), 232
(M+-H2O, 15), 217 (3), 175 (6), 162 (9), 149 (100), 135 (8), 119
(7), 105 (6), 91 (8).
3.31–3.41 (m, 1H); 3.79 and 3.80 (2 s, 3H); 6.66 and 6.67 (2 s,
1H); 6.73 and 6.74 (2 d, J = 7.7 Hz, 1H); 7.04 and 7.05 (2 d,
J = 7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 156.9, 156.7, 136.4,
136.4, 132.7, 132.3, 126.6, 126.4, 121.4, 121.3, 111.7, 111.6, 78.7,
78.6, 73.0, 73.0, 55.4, 55.4, 34.5, 34.1, 31.4, 31.3, 29.6, 29.6, 26.4,
23.3, 23.3, 21.5, 21.3, 20.7. GC–MS m/z (rel intensity) 266 (M+, 4),
248 (M+-H2O, 6), 208 (5), 189 (11), 162 (18), 149 (100), 135 (5),
119 (7), 105 (5), 91 (9), 77 (3).
Freshly prepared lithium naphthalenide (5.2 mL of a 0.72 M solu-
tion in THF) was added dropwise under nitrogen to a stirred solution
of 2-methoxy-1-methyl-4-((2S)-6-methyl-3-(phenylsulfonyl)hept-
5-en-2-yl)benzene 8c (0.45 g, 1.21 mmol) and dry Et2NH (1 mL) in
dry THF (10 mL) at À78 °C. When the staring material could no
longer be detected by TLC analysis, the reaction was quenched by
the addition of a saturated solution of NH4Cl aq (50 mL) and diluted
with diethyl ether (100 mL). The organic phase was separated and
the aqueous phase was extracted with ethyl ether (50 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
chromatography eluting with hexane/ethyl acetate (95:5–9:1) as
eluent to afford pure (R)-2-methoxy-1-methyl-4-(6-methylhept-
5-en-2-yl)benzene (À)-19 (xanthorrhizol methylether, 235 mg,
4.10. Synthesis of (À)-curcuphenol, (À)-xanthorrhizol, (+)-curcudiol
Ethanethiol (2 mL, 27 mmol) was added dropwise to a suspen-
sion of NaH (1.2 g, 60% in mineral oil, 30 mmol) in dry DMF
(30 ml) under nitrogen. The reaction temperature was kept below
20 °C by external cooling and after the addition was completed, the
mixture was stirred for 30 min at rt. Methyl ether (À)-17 (1.4 g,
6 mmol) in dry DMF (4 mL) was then added and the reaction
heated at reflux for 5 h. After cooling the mixture was diluted with
water (100 mL), neutralized with concentrated HCl, and extracted
with diethyl ether (2 Â 100 mL). The organic phase was dried
(Na2SO4) and concentrated. The residue was purified by chroma-
tography to give pure (R)-5-methyl-2-(6-methylhept-5-en-2-
yl)phenol (À)-18 (curcuphenol) as a pale yellow oil (0.89 g, 68%
84% yield) as a colorless oil. [
a]
20 = À41.9 (c 2.2, CHCl3), 94% of chem-
D
ical purity by GC, lit.5 for the opposite enantiomer [
a]
20 = +42.5 (c 2,
D
CHCl3). 1H NMR(400 MHz, CDCl3) d 1.23 (d, J = 7.0 Hz, 3H), 1.50–1.71
(m, 2H), 1.53 (s, 3H), 1.67 (s, 3H), 1.81–1.99 (m, 2H), 2.18 (s, 3H),
2.58–2.72 (m, 1H), 3.82 (s, 3H), 5.10 (tm, J = 7.1 Hz, 1H), 6.64 (s,
1H), 6.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 157.7, 146.8, 131.3, 130.4, 124.6, 123.9, 118.8,
109.1, 55.3, 39.6, 38.5, 26.2, 25.6, 22.4, 17.7, 15.7. GC–MS m/z (rel
intensity) 232 (M+, 37), 217 (1), 189 (3), 175 (7), 162 (17), 150
(100), 135 (61), 119 (9), 105 (7), 91 (16), 77 (6), 69 (5), 55 (5).
According to the procedure outlined for the synthesis of
compound (À)-19, the reduction of tert-butyl((6R,E)-6-(2,5-dime-
thoxy-4-methylphenyl)-2-methyl-5-(phenylsulfonyl)hept-2-enyl-
oxy)diphenylsilane 8d gave, in 72% yield, (S,E)-tert-butyl(6-(2,
5-dimethoxy-4-methylphenyl)-2-methylhept-2-enyloxy)diphenylsi-
yield). [
a]
20 = À23.2 (c 2.9, CHCl3), 94% chemical purity by GC,
D
lit.5 for the opposite enantiomer [
a]
D
20 = +24.8 (c 1, CHCl3). 1H
NMR and EI-MS superimposable to those previously reported for
the (S)-(+)-isomer.
According to the procedure outlined for the synthesis of com-
pound (À)-18, the reaction of methyl ether (À)-19 gave, in 86%
yield, (R)-2-methyl-5-(6-methylhept-5-en-2-yl)phenol (À)-20
(xanthorrhizol) as a pale yellow oil. [
a
]
20 = À41.3 (c 2.5, acetone),
D
97% of chemical purity by GC, lit.5 for the opposite enantiomer
[a]
20 = +47.6 (c 2, acetone). 1H NMR and EI-MS superimposable to
D
those previously reported for the (S)-(+)-isomer.
lane (+)-24 as a colorless thick oil. [
a]
20 = +16.7 (c 2.2, CHCl3). 1H
According to the procedure outlined for the synthesis of com-
pound (À)-18, the reaction of methyl ether (+)-28 gave, in 85%
D
NMR (400 MHz, CDCl3) d 1.06 (s, 9H), 1.20 (d, J = 7.0 Hz, 3H), 1.44–
1.73 (m, 2H), 1.54 (s, 3H), 1.88–2.06 (m, 2H), 2.20 (s, 3H), 3.10–
3.22 (m, 1H), 3.73 (s, 3H), 3.77 (s, 3H), 4.04 (br s, 2H), 5.43 (tq,
J = 7.3, 1.3 Hz, 1H), 6.67 (s, 2H), 7.31–7.43 (m, 6H), 7.64–7.73 (m,
4H). 13C NMR (100 MHz, CDCl3) d 152.0, 151.0, 135.6, 134.1, 133.9,
133.8, 129.5, 127.5, 124.9, 124.3, 114.4, 110.1, 69.2, 56.3, 56.2,
37.0, 32.0, 26.9, 25.8, 21.2, 19.3, 16.0, 13.4. MS (ESI): 539.6 (M++Na).
According to the procedure outlined for the synthesis of
compound (À)-19, the reduction of (6R)-2-methyl-5-(phenylsulfo-
nyl)-6-p-tolylhept-2-en-4-one 12a gave, in 85% yield, (S)-2-
methyl-6-p-tolylhept-2-en-4-one (+)-31 (turmerone) as a colorless
yield,
(S)-2-(6-hydroxy-6-methylheptan-2-yl)-5-methylphenol
(+)-29 (curcudiol) as a colorless thick oil. [a]
20 = +11.3 (c 2.9,
D
CHCl3), 96% of chemical purity by GC, lit.31 20 = +10.7 (c 5,
[a]
D
CHCl3). 1H NMR (400 MHz, CDCl3) d 1.16 (s, 3H), 1.18 (s, 3H),
1.22 (d, J = 7.0 Hz, 3H), 1.18–1.39 (m, 3H), 1.39–1.58 (m, 3H),
1.59–1.72 (m, 1H), 2.25 (s, 3H), 3.01–3.12 (m, 1H), 5.34 (br s,
1H), 6.56 (s, 1H), 6.70 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H).
13C NMR (100 MHz, CDCl3) d 153.0, 136.4, 130.5, 126.8, 121.6,
116.3, 71.4, 43.4, 37.7, 31.4, 29.5, 28.9, 22.2, 20.9, 20.8. GC–MS
m/z (rel intensity) 236 (M+, <1), 218 (M+-H2O, 25), 203 (3), 175
(2), 161 (10), 148 (32), 135 (100), 121 (15), 91 (12), 77 (3).
oil. [
[a]
D
a]
20 = +71.0 (c 3, hexane), 95% chemical purity by GC, lit.6
D
20 = +62.7 (c 1.25, hexane). 1H NMR (400 MHz, CDCl3) d 1.24
(d, J = 6.9 Hz, 3H), 1.84 (d, J = 1.2 Hz, 3H), 2.10 (d, J = 1.2 Hz, 3H),
2.30 (s, 3H), 2.59 (dd, J = 15.6, 8.4 Hz, 1H), 2.70 (dd, J = 15.6,
6.1 Hz, 1H), 3.23–3.34 (m, 1H), 6.01 (m, 1H), 7.04–7.13 (m, 4H).
13C NMR (100 MHz, CDCl3) d 199.7, 154.8, 143.7, 135.4, 129.0,
126.6, 124.1, 52.7, 35.3, 27.5, 21.9, 20.9, 20.6. GC–MS m/z (rel
intensity) 216 (M+, 37), 201 (M+-Me, 29), 173 (4), 159 (4), 145
(4), 132 (24), 119 (83), 105 (13), 98 (5), 91 (17), 83 (100), 77 (6),
65 (4), 55 (16).
According to the procedure outlined for the synthesis of
compound (À)-19 and using 5 equiv of lithium naphthalenide,
the reduction of (6R)-6-(2-methoxy-4-methylphenyl)-2-methyl-
5-(phenylsulfonyl)heptane-2,3-diol 14b gave, in 89% yield, (6S)-
6-(2-methoxy-4-methylphenyl)-2-methylheptane-2,3-diol 37 as a
colorless thick oil, which consisted of a 6:4 mixture of diastereoi-
somers (NMR analysis). 1H NMR (400 MHz, CDCl3) d 1.07, 1.10,
1.12 and 1.14 (4 s, 6H); 1.20 (d, J = 7.0 Hz, 3H); 1.01–1.36, 1.37–
1.49, 1.53–1.70, 1.70–1.79 and 1.80–1.92 (5 m, 4H); 1.97 and
2.05 (2 br s, 2H); 2.32 and 2.32 (2 s, 3H); 3.10–3.24 (m, 1H);
4.11. Synthesis of (+)-glandulone A
At first, TBAF (0.6 g of the trihydrate salt, 1.9 mmol) was added
portionwise at rt to a stirred solution of ether (+)-24 (0.46 g,
0.89 mmol) in THF (10 mL). When the silyl ether was completely
cleaved (4 h), the reaction was diluted with diethyl ether (60 mL)
and quenched with water (30 mL). The aqueous phase was then
extracted with ether (30 mL) and the combined organic phases
were washed with brine, dried and concentrated in vacuo. The res-
idue was purified by chromatography using hexane-diethyl ether
(95:5–7:3) as the eluent to afford pure (S,E)-6-(2,5-dimethoxy-4-
methylphenyl)-2-methylhept-2-en-1-ol (+)-25 (230 mg, 93%
yield). [a]
20 = +31.6 (c 3, CHCl3), 97% of chemical purity by GC. 1H
D
NMR (400 MHz, CDCl3) d 1.19 (d, J = 6.9 Hz, 3H), 1.30 (br s, 1H),
1.53–1.74 (m, 2H), 1.57 (s, 3H), 1.89–2.06 (m, 2H), 2.20 (s, 3H),
3.09–3.21 (m, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 3.95 (br s, 2H), 5.38
(tq, J = 7.1, 1.3 Hz, 1H), 6.66 (s, 1H), 6.67 (s, 1H). 13C NMR
(100 MHz, CDCl3) d 152.0, 151.0, 134.6, 133.8, 126.7, 124.4,

S. Serra / Tetrahedron: Asymmetry 25 (2014) 1561–1572
1571
114.5, 110.0, 69.1, 56.4, 56.2, 36.9, 31.9, 25.9, 21.3, 15.9, 13.5. GC–
MS m/z (rel intensity) 278 (M+, 37), 260 (M+-H2O, 2), 205 (3), 192
(4), 179 (100), 164 (16), 152 (13), 135 (3), 117 (3), 91 (5), 77 (4).
A solution of alcohol (+)-25 (0.4 g, 1.44 mmol) in CH2Cl2 (20 mL)
was treated with MnO2 (3 g, 34.5 mmol) stirring at reflux until the
starting alcohol could no longer be detected by TLC analysis (2 h).
The reaction was then filtered and the organic phase was concen-
trated under reduced pressure. The residue was dissolved in CH3CN
(10 mL) and treated with a solution of ceric ammonium nitrate
(1.6 g, 2.92 mmol) in water (6 mL), and stirred at rt until the com-
plete transformation of the starting aldehyde (10 min). Next, the
reaction was diluted with water and extracted with CH2Cl2
(3 Â 60 mL) and the organic phase was dried (Na2SO4) and concen-
trated in vacuo. The residue was purified by chromatography using
n-hexane/EtOAc (95:5–8:2) as eluent to afford pure (S,E)-2-
methyl-6-(4-methyl-3,6-dioxocyclohexa-1,4-dienyl)hept-2-enal
(+)-26 (glandulone A) as a pale yellow oil (295 mg, 83% yield).
white precipitate formed. The aqueous phase was extracted with
EtOAc (2 Â 80 mL) and the combined organic phases were washed
with water, brine, and concentrated in vacuo. The residue was dis-
solved in methanol (10 mL) and treated with a solution of NaOH
(0.5 g, 12.5 mmol) in methanol (5 mL). As soon as the acetate
was completely hydrolysed, the reaction was quenched by dilution
with water (60 mL) and extraction with EtOAc (2 Â 80 mL). The
combined organic phases were washed with water, brine, dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by chromatography using n-hexane/EtOAc (9:1–7:3)
as eluent to afford pure (S)-2-hydroxy-6-(2-hydroxy-4-methyl-
phenyl)-2-methylheptan-3-one (+)-35 (curcudiol-10-one) as a col-
orless oil (0.31 g, 83% yield). [
chemical purity by GC, lit.27 20 = +40.5 (c 0.6, CHCl3). 1H NMR
[a]
D
a]
20 = +19.1 (c 2.2, CHCl3), 97% of
D
(400 MHz, CDCl3) d 1.25 (d, J = 6.9 Hz, 3H), 1.33 (s, 3H), 1.34 (s,
3H), 1.72–1.83 (m, 1H), 1.88–1.99 (m, 1H), 2.26 (s, 3H), 2.48–
2.63 (m, 2H), 2.94–3.06 (m, 1H), 3.76 (br s, 1H), 6.11 (br s, 1H),
6.63 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) d 216.1, 153.5, 137.0, 128.6, 126.3, 121.4,
116.5, 76.4, 33.3, 31.2, 30.9, 26.5, 26.5, 20.9, 20.1. GC–MS m/z (rel
intensity) 250 (M+, 5), 232 (M+-H2O, 3), 192 (26), 174 (9), 161
(7), 148 (54), 135 (100), 121 (27), 99 (14), 91 (21), 77 (8), 59 (51).
[
[
a
a
]
]
20 = +47.1 (c 3.2, MeOH), 94% chemical purity by GC, lit.23
D
20 = +142.5 (c 0.12, MeOH). 1H NMR (400 MHz, CDCl3) d 1.17
D
(d, J = 6.9 Hz, 3H), 1.56–1.67 (m, 1H), 1.69–1.81 (m, 1H), 1.71
(s, 3H), 2.04 (d, J = 1.6 Hz, 3H), 2.25–2.43 (m, 2H), 2.91–3.04 (m,
1H), 6.43 (tq, J = 7.2, 1.3 Hz, 1H), 6.53 (d, J = 1.0 Hz, 1H), 6.60 (q,
J = 1.6 Hz, 1H), 9.38 (s, 1H). 13C NMR (100 MHz, CDCl3) d 194.8,
188.1, 187.1, 153.2, 152.9, 145.4, 139.8, 133.7, 131.4, 34.5, 31.4,
26.8, 19.1, 15.2, 9.2. MS (ESI): 269.3 (M++Na); 247.3 (M++H+) by
addition of HCOOH.
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