A divergent and stereoselective approach to phenolic 1,7-dihydroxy- bisabolane sesquiterpenes: Asymmetric total synthesis of (+)-curcutetraol, (+)-sydonol, (+)-sydonic acid, and (+)-7-O-methylsydonic acid

Article abstract of DOI:10.1016/j.tetasy.2013.07.011

The combined use of the Sharpless asymmetric epoxidation, a number of stereospecific chemical transformations, and the 3,5-hexadienoic acid benzannulation protocol allowed us to devise a new, divergent, and stereoselective approach to terpenes with a chir

Full text of DOI:10.1016/j.tetasy.2013.07.011

Tetrahedron: Asymmetry 24 (2013) 1110–1116
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A divergent and stereoselective approach to phenolic
1,7-dihydroxy-bisabolane sesquiterpenes: asymmetric total
synthesis of (+)-curcutetraol, (+)-sydonol, (+)-sydonic acid,
and (+)-7-O-methylsydonic acid
⇑
Stefano Serra , Alessandra A. Cominetti
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:
The combined use of the Sharpless asymmetric epoxidation, a number of stereospecific chemical trans-
formations, and the 3,5-hexadienoic acid benzannulation protocol allowed us to devise a new, divergent,
and stereoselective approach to terpenes with a chiral tertiary hydroxyl group at the ortho-position of a
phenol functional group. Accordingly, the natural occurring enantiomeric forms of the bisabolane sesqui-
terpenes (+)-curcutetraol, (+)-sydonol, (+)-sydonic acid, and (+)-7-O-methylsydonic acid were synthe-
sized with high enantiomeric purity starting from geraniol. The latter two acids were prepared in
enantioenriched form for the first time.
Received 17 June 2013
Accepted 10 July 2013
Available online 27 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
14
OR'
(bisabolane numbering)
9
5
2
10
4
7
Phenolic sesquiterpenes belonging to the bisabolane family of-
ten possess specific biological activities, which are strictly related
to their stereochemical structures. As a consequence, much effort
has been spent for their chemical characterization and for their
stereoselective synthesis. In spite of this fact, only a few investiga-
tions have concerned the bisabolane sesquiterpenes with the gen-
eral framework 11–13 (Fig. 1). Moreover, the main part of these
studies deals with their characterization and isolation from natural
sources without providing any suitable approach for their synthe-
sis. This is due to the general difficulties related to the selective
construction of the benzylic stereocentre, which become more
demanding when a potentially unstable quaternary carbinol has
to be synthesized. Therefore, these issues have hampered the
development of a reliable and general synthetic approach to com-
pounds of type 1.
6
8
R
11
OH
15
R=H, O or OH
R'=H or Me
1
HO
3
12
13
R
1
OH
OH
HO
OH
OH
HO
HO
(+)-curcutetraol 1a
(+)-sydonol 1b
OH
OMe
Some relevant examples of phenolic sesquiterpenes of this kind
concern benzylic alcohols curcutetraol 1a and sydonol 1b, which
were both isolated from microbial cultures. More specifically tetrol
(+)-1a was extracted4 from the marine bacterium CNH-741 and fun-
gus CNC-979 whereas triol 1b was isolated from a different strain of
Aspergillus sp. either as (+)-(S)-2,11 or (ꢀ)-(R)-10 isomeric forms.
It is noteworthy that the stereochemistry of these compounds
considerably affects their biological activity. Compound (+)-1b
HO
CO2H
HO
CO2H
(+)-sydonic acid 1c
(+)-7-O-methylsydonic acid 1d
Figure 1. General structure of the 1,7-dihydroxy-bisabolane framework and
structures of some relevant sesquiterpenes having the same skeleton.
exhibited antifungal activity against Cochliobolus lunata2 (IFO
6299) whereas (ꢀ)-1b revealed10 selective antibacterial properties.
Another interesting instance concerns acid 1c1,6–8,12 and 1d,9
which have chemical structures very close to those of 1a and 1b
⇑
Corresponding author. Tel.: +39 02 2399 3076; fax: +39 02 2399 3180.
E-mail addresses: stefano.serra@cnr.it, stefano.serra@polimi.it (S. Serra).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.011

S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
1111
and both were also isolated from microorganisms but display only
Geraniol
modest biological activities.
To the best of our knowledge, only one5 specific synthetic meth-
od allows for the enantioselective preparation of (+)-curcutetraol
and (+)-sydonol. In addition, the synthesis of sydonic acid was
accomplished13 merely for a racemic material, whereas the prepa-
ration of 7-O-methyl-sydonic acid is still lacking.
i
92%
O
O
O
ii
OH
Cl
OH
Cl
85%
(-)-2
(-)-3
As an extension of our program on the enantioselective synthe-
sis of phenolic sesquiterpenes,14–16 we devised a new and general
synthetic approach to compounds of type 1. The existing method5
bases the construction of the benzylic stereocentre on the diaste-
reoselective addition of an aryl Grignard reagent on a chiral
methoxycarbonyl aminal. We envisaged that an alternative ap-
proach could be the construction of the substituted phenol ring
starting from an aliphatic precursor bearing an existing quaternary
stereocentre. The latter method can overcome some of the above
described issues, as demonstrated previously17,18 through the syn-
thesis of different phenolic sesquiterpenes.
iii
iii
O
4
5
iv, v
81%
OH
iv, v
83%
OH
Herein we report the result of our studies, comprising of the
stereoselective synthesis of four compounds 1a–d as well as the
development of a general and reliable process for the preparation
of the components of this class of natural products.
OH
OH
OH
OH
(-)-6
(+)-7
vi 78%
OH
vi 74%
OH
2. Results and discussion
(+)-9
(+)-8
2.1. Preparation of the chiral synthons (S)-(E)-4,8-
dimethylnona-2,7-diene-1,4-diol and (S)-(E)-4,8-dimethylnon-
2-ene-1,4-diol
Scheme 1. Synthesis of the (S)-(E)-4,8-dimethylnona-2,7-diene-1,4-diol and of the
(S)-(E)-4,8-dimethylnon-2-ene-1,4-diol from geraniol. Reagents and conditions: (i)
(+)-DIPT, Ti(OiPr)4, TBHP, molecular sieves, CH2Cl2, ꢀ25 °C, 8 h; (ii) H2, 10% Pd/C
cat., EtOAc, atm. pressure; (iii) Ph3P, CCl4, reflux 5 h; (iv) BuLi, THF, ꢀ78 °C, 30 min
then rt; (v) CH2O, rt 2 h; (vi) NaAlH2(OCH2CH2OMe)2, Et2O, 0 °C, 30 min then 1 h at
rt.
We based our retrosynthetic plan on the benzannulation reac-
tion19 of a chiral aliphatic precursor. According to our expertise,
we looked for the preparation of a substituted 3,5-hexadienoic acid
that had a suitable quaternary stereocentre at the 7-position. The
cyclization of this can give the phenolic derivative with a chiral ter-
tiary hydroxyl group at the ortho-position of the phenol functional
group. Finally, functional group transformations can afford the
whole 1,7-dihydroxy-bisabolane framework and thus the target
compounds.
We previously demonstrated that the Denmark reduction pro-
tocol22 can be successfully applied to 4-alkoxy-propyn-1-ol deriv-
atives18,23 to give the corresponding (E)-4-alkoxy-propen-1-ol
derivatives. Therefore, we tried to adapt this synthetic method to
the reduction of our propargylic diols. Accordingly, diols (ꢀ)-6
and (+)-7 were treated with at least 2 equiv of sodium
bis(methoxyethoxy)aluminum hydride in dry diethyl ether to give
diols (+)-8 and (+)-9, respectively, in 78% and 74% yields.
Thus, the latter chiral building blocks have been exploited in the
synthesis of the target bisabolane sesquiterpenes. We used (+)-8 or
(+)-9 as the starting material, depending on whether the carbon at
the 11-position had to be functionalized with a hydroxyl group or
not.
We have previously established17,18 a synthetic path that allows
for the preparation of this type of dienic acid starting from allylic
alcohols with a stereocentre at the c-position. For this reason, we
selected ((2S,3S)-3-methyl-3-(4-methylpent-3-enyl)oxiran-2-yl)
methanol 2 (Scheme 1), as a chiral building block for the synthesis
of all of our target compounds. Both enantiomeric forms of the
epoxy-alcohol can be prepared20 with high enantiomeric purity
(95% ee) by Sharpless asymmetric epoxidation of geraniol. Further-
more, (ꢀ)-2 can be easily converted into (S)-dehydrolinalool,20,21
which could give access to propargylic alcohol derivatives of type
6 through exploitation of the acetylenic group.
2.2. Synthesis of (S)-(+)-curcutetraol
Accordingly, we synthesized epoxy-alcohol (ꢀ)-2 starting from
geraniol and epoxy-alcohol (ꢀ)-3 by means of atmospheric pres-
sure hydrogenation of (ꢀ)-2, using Pd/C as the catalyst. The follow-
ing transformation of the hydroxyl functional group into the
corresponding chloride group was performed by refluxing the
epoxy-alcohols (ꢀ)-2 and (ꢀ)-3 with triphenylphosphine in car-
bon tetrachloride to afford epoxy-chloride 4 and 5, respectively.
The latter compounds were then treated with at least 3 equiv of
BuLi at low temperature. Under these conditions, the epoxy-chlo-
ride moiety undergoes a base-mediated rearrangement to give
the corresponding 1-propyn-3-ol dilithium salt derivative. These
intermediates were treated in situ with formaldehyde (solid),
which reacts at room temperature to form a new hydroxy-methy-
lenic group. As a result, we converted epoxy-alcohols (ꢀ)-2 and
(ꢀ)-3 into diols (ꢀ)-6 and (+)-7, respectively, in 81% and 83% over-
all yields.
(S)-(E)-4,8-Dimethylnona-2,7-diene-1,4-diol (+)-8 was chosen
as the starting material for the synthesis of (+)-curcutetraol 1a.
As demonstrated by some preliminary experiments, the tertiary
hydroxyl group must be protected before the homologation step.
Hence, we looked for a suitable protecting group which could be
easily introduced/removed from this sterically hindered position.
After some disappointing results with acetyl and trimethylsilyl
groups, we finally selected triethylsilylchloride as a reagent of
choice for this step. Accordingly, the primary hydroxyl group of
(+)-8 was selectively acetylated using acetic anhydride and pyri-
dine and the crude monoacetate was treated with triethylsilylchlo-
ride and imidazole in the presence of a catalytic amount of DMAP
(Scheme 2).
The following reaction with methanolic NaOH allowed for the
cleavage of the ester functionality, leaving the silyl ether

1112
S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
OTES
2.3. Synthesis of (+)-sydonol and (+)-sydonic acid
OH
iv
i, ii, iii
93%
(+)-8
The above experimental procedure can be easily adapted to the
synthesis of sydonol and sydonic acid. Diol (+)-9 was acetylated
using acetic anhydride and pyridine. The crude monoacetate was
treated with triethylsilylchloride and imidazole in the presence
of a catalytic amount of DMAP followed by reaction with methano-
lic NaOH (Scheme 3). The obtained allylic alcohol (ꢀ)-14 was oxi-
dized with an excess of MnO2 in refluxing CH2Cl2 and the resulting
aldehyde was treated with ylide 11 to give acid (+)-15 in good
yield. As described earlier, the benzannulation reaction was
performed in THF, using 1.9 equiv of trifluoroacetic anhydride
and an excess of triethylamine as the base. The obtained phenol
(+)-16 is the direct precursor of both target compounds 1b and
1c. Treatment of the latter phenol with LiAlH4 in refluxing THF al-
lowed the reduction of the benzoate ester functional group to a
benzylic alcohol. Quenching the reaction mixture with dilute
hydrochloric acid hydrolyzed the triethylsilyl protecting group to
afford (+)-sydonol 1b in very good yield.
(-)-10
CO2H
CO2Et
(Ph)3P
CO2Et
OTES
11
CO2H
70%
(+)-12
v
OTES
vi
vii, viii, ix, x
81%
61%
HO
CO2Et
(+)-13
OH
In the same way, treatment of phenol (+)-16 with an excess of
sodium hydroxide in methanol followed by quenching with dilute
hydrochloric acid affected hydrolysis of both the ethyl ester and of
the triethylsilyl protecting group to afford (+)-sydonic acid 1c in
nearly quantitative yield.
(+)-curcutetraol 1a
HO
OH
HO
Scheme 2. Synthesis of (+)-curcutetraol starting from (S)-(E)-4,8-dimethylnona-
2,7-diene-1,4-diol. Reagents and conditions: (i) Ac2O, Py; (ii) Et3SiCl, THF, imidaz-
ole, DMAP cat., 60 °C, 3 h; (iii) NaOH, MeOH, 30 min rt; (iv) MnO2, CH2Cl2, reflux
4 h; (v) 11, toluene, 80 °C, 3 h; (vi) (CF3CO)2O, Et3N, THF, 0 °C, then rt 1 h; (vii) Ac2O,
Py, DMAP cat.; (viii) MCPBA, CH2Cl2, 0 °C; (ix) LiAlH4, THF, reflux 1 h; (x) HCl aq.
The spectroscopic data and specific rotation value that we re-
corded for both (+)-1b and (+)-1c were in good agreement with
those previously reported. However, we observed a discrepancy
concerning the melting points of sydonic acid (+)-1c. For this com-
pound we measured a value of 66–68 °C whereas for an enantioen-
riched sample6 and for a racemic sample,1 melting points of 85–86
and of 158–159 °C, respectively, were recorded. This case is note-
worthy as it demonstrates how a variation of the enantiomeric
unaffected. The allylic alcohol (ꢀ)-10 obtained was oxidized with
an excess of MnO2 in refluxing CH2Cl2 and the resulting aldehyde
was treated with ylide 1124 to give acid (+)-12 in good yield. It is
noteworthy that the latter Wittig reaction proceeded with very
high stereoselectivity and we were able to detect only the
(3E,5E)-isomeric form of the trienic acid in the crude reaction
mixture.
OTES
i, ii, iii
91%
iv
OH
(+)-9
The benzannulation of acid (+)-12 using trifluoroacetic anhy-
dride as an activating agent and triethylamine as a base provided
isomerically pure phenol (+)-13 in satisfactory yield. We found that
the best reaction conditions consisted of adding 1.5–2 equiv of
anhydride to a cooled (0 °C) solution of the acid and of the trieth-
ylamine (at least 4 equiv) in THF. Higher amounts of anhydride or
higher temperatures increased the formation of side products, such
as the trifluoroacetate of the phenol or unidentified degradation
derivatives. The use of only 1 equiv of activating agent or perform-
ing the reaction at a lower temperature (ꢀ20 °C or below) signifi-
cantly decreased the yield.
(-)-14
CO2H
CO2Et
(Ph)3P
CO2Et
OTES
11
CO2H
(+)-15
v
77%
OTES
vi
Starting from (+)-13, only a few high yielding functional group
interconversions allowed us to prepare curcutetraol without isola-
tion of the intermediates. Accordingly, phenol 13 was acetylated by
acetic anhydride and pyridine in the presence of a catalytic amount
of DMAP. The ester was then treated with MCPBA in CH2Cl2 in or-
der to epoxidize the C(10)–C(11) double bond. The crude epoxide
was dropped into a refluxing suspension of LiAlH4 in THF to allow
the simultaneous reduction of the benzoate ester, the cleavage of
the phenol acetate, and regioselective epoxide reduction. Careful
quenching of the reaction mixture with dilute hydrochloric acid
triggered the hydrolysis of the silyl ether. After work-up and chro-
matographic purification, (+)-curcutetraol 1a was isolated in
very good yield and its spectroscopic data were in good agreement
with those previously reported. Moreover, we recorded a specific
rotation value of +6.3 (c 2.2, MeOH), which corroborated both
the absolute configuration and the occurrence in enantioenriched
59%
HO
CO2Et
ix, viii
(+)-16
vii, viii
89%
94%
OH
OH
OH
HO
(+)-sydonol 1b
HO
(+)-sydonic acid 1c
CO2H
Scheme 3. Synthesis of (+)-sydonol and (+)-sydonic acid starting from (S)-(E)-4,8-
dimethylnon-2-ene-1,4-diol. Reagents and conditions: (i) Ac2O, Py; (ii) Et3SiCl, THF,
imidazole, DMAP cat., 60 °C, 3 h; (iii) NaOH, MeOH, 30 min rt; (iv) MnO2, CH2Cl2,
reflux 4 h; (v) 11, toluene, 80 °C, 3 h; (vi) (CF3CO)2O, Et3N, THF, 0 °C, then rt 1 h; (vii)
LiAlH4, THF, reflux 30 min; (viii) HCl aq; (ix) NaOH, MeOH, reflux 30 min.
form of the natural product, which showed ½a D20
¼ þ5:2 (c 0.74,
ꢁ
MeOH).4

S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
1113
composition of a given compound can markedly affect not only the
biological activity but also physical data.
absolute configuration of the natural product. Moreover, we mea-
sured a specific rotation value of +3.9 (c 1.9, MeOH) for our syn-
thetic material whereas
a value of +2 (c 1.9, MeOH) was
2.4. Synthesis of (+)-7-O-methylsydonic acid
reported9 for natural 1d. Due to the low magnitude of the specific
rotation and the resulting low accuracy in the measurement, we
can assert that the natural product is enantioenriched although
we have to leave some extent of uncertainty concerning its enan-
tiomeric purity.
The stereoselective preparation of the 7-O-methylsydonic acid
is strictly related to that of sydonic acid, although it exhibits a fur-
ther synthetic issue. The methylation of the tertiary hydroxyl
group has to be performed under harsh experimental conditions,
which require functionalization of the primary hydroxyl group
with a very stable and yet easily removable protecting group.
Therefore, we treated diol (+)-9 with tert-butylchlorodiphenyl si-
lane, imidazole, and catalytic DMAP in DMF, at rt (Scheme 4). Un-
der these experimental conditions, the tertiary hydroxyl group was
unaffected and the crude product obtained consisted of a single si-
lyl ether derivative (by NMR analysis).
3. Conclusion
Herein we have reported on a new stereoselective approach to
the phenolic 1,7-dihydroxy-bisabolane sesquiterpenes. The syn-
thetic method is divergent since all of the obtained compounds
were prepared starting from geraniol. The key synthetic steps com-
prise of a Sharpless asymmetric epoxidation, transformation of
((2S,3S)-3-methyl-3-(4-methylpent-3-enyl)oxiran-2-yl)methanol
(ꢀ)-2 into allylic diols (+)-8 and (+)-9, and benzannulation of the
3,5-hexadienoic acids (+)-12, (+)-15, and (ꢀ)-19. Overall, different
outcomes were achieved. We proposed an alternative approach
that allows the construction of substituted phenol rings with a chi-
ral tertiary hydroxyl group at the ortho position of the phenol func-
tional group starting from an aliphatic precursor bearing an
existing quaternary stereocentre. Since all of the described chemi-
cal transformations do not involve racemization, both the interme-
diates and the natural occurring enantiomeric forms of the
bisabolane sesquiterpenes (+)-curcutetraol 1a, (+)-sydonol 1b,
(+)-sydonic acid 1c, and (+)-7-O-methylsydonic acid 1d were syn-
thesized with high enantiomeric purity (ee 95%) and in good over-
all yields. Our approach compares favorably to the previous
asymmetric syntheses of (+)-1a and (+)-1b in terms of reliability
and general applicability. In addition, the acids (+)-1c and (+)-1d
were prepared in enantioenriched form for the first time. It is
worth noting that the Sharpless asymmetric epoxidation can afford
either (S)- or (R)-enantiomers with the same selectivity. The pres-
ent study also represents a formal enantioselective synthesis of
(ꢀ)-1a, (ꢀ)-1b, (ꢀ)-1c, and (ꢀ)-1d.
The latter material was thus used without further purification
in the next step. Treatment with BuLi in THF at low temperature
gave the corresponding lithium alkoxide, which reacted smoothly
at rt with MeI in the presence of DMPU as co-solvent. Although
the reaction needed a long reaction time (48 h), the methyl ether
derivative (+)-17 was obtained in good yield. The following depro-
tection of the primary hydroxyl group was performed using TBAF
in THF to give (ꢀ)-18 in nearly quantitative yield.
From this point onward, the synthetic steps were the same of
those described for the preparation of sydonic acid.
Allylic alcohol (ꢀ)-18 was oxidized with an excess of MnO2 in
refluxing CH2Cl2 and the resulting aldehyde was treated with ylide
11 to give acid (ꢀ)-19 in good yield. The benzannulation reaction
was performed using the experimental conditions described before
to give phenol (+)-20 in satisfactory yield. Treatment of the latter
phenol with an excess of sodium hydroxide in methanol followed
by quenching with dilute hydrochloric acid afforded (+)-7-O-meth-
ylsydonic acid 1d in nearly quantitative yield.
The spectroscopic data recorded for 1d were in good agreement
with those reported for extractive (+)-7-O-methylsydonic acid.
Therefore, we can confirm both the chemical structure and the
4. Experimental
4.1. General
OMe
OTBDPS
i, ii
iii
(+)-9
77%
91%
(+)-17
All moisture-sensitive reactions were carried out under a static
atmosphere of nitrogen. All solvents and reagents were of commer-
cial quality. TLC: Merk silica gel 60 F254 plates. Column chromatog-
raphy (CC): silica gel. GC–MS analyses: HP-6890 gas
chromatograph equipped with a 5973 mass detector, using a HP-
(Ph)3P
CO2Et
11
OMe
CO2H
80%
iv
OH
v
5MS column (30 m ꢂ 0.25 mm, 0.25
lm film thickness; Hewlett
(-)-18
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(2) 14.45, tR(3) 13.87,
tR(10) 22.92, tR(14) 23.20, tR(17) 29.50, tR(18) 16.71. Mass spec-
trum of compounds (ꢀ)-6, (+)-7, (+)-8, (+)-9, (+)-12, (+)-13, (+)-
1a, (+)-15, (+)-16, (+)-1b, (+)-1c, (ꢀ)-19, (+)-20 and (+)-1d were re-
corded on a Bruker ESQUIRE 3000 PLUS spectrometer (ESI detec-
tor). Optical rotations: Jasco-DIP-181 digital polarimeter. 1H and
13C Spectra and DEPT experiments: CDCl3 solutions at rt using a
Bruker-AC-400 spectrometer at 400, 100, and 100 MHz, respec-
tively; chemical shifts in ppm rel to internal SiMe4 (=0 ppm), J val-
ues in Hz. Melting points were measured on a Reichert apparatus,
equipped with a Reichert microscope, and are uncorrected.
CO2H
CO2Et
OMe
OMe
vi
68%
(-)-19
HO
CO2Et
(+)-20
OMe
vii
(+)-7-O-methylsydonic acid 1d
95%
HO
CO2H
Scheme 4. Synthesis of (+)-7-O-methylsydonic acid starting from (S)-(E)-4,8-
dimethylnon-2-ene-1,4-diol. Reagents and conditions: (i) TBDPSCl, DMF, imidazole,
DMAP cat., rt 3 h; (ii) BuLi, THF, ꢀ78 °C, 20 min then MeI and DMPU, rt 48 h; (iii)
TBAF, THF, rt 1 h; (iv) MnO2, CH2Cl2, reflux 4 h; (v) 11, toluene, 80 °C 3 h; (vi)
(CF3CO)2O, Et3N, THF, 0 °C, then rt 1 h; (vii) NaOH, MeOH, reflux 30 min.
4.2. Preparation of the epoxy-alcohols (ꢀ)-2 and (ꢀ)-3
((2S,3S)-3-Methyl-3-(4-methylpent-3-enyl)oxiran-2-yl)methanol
(ꢀ)-2 (ee 95%, 94% chemical purity by GC, 92% yield) was prepared

1114
S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
by Sharpless asymmetric epoxidation of geraniol according to a
previously reported20 experimental procedure.
wise to a cooled and stirred solution of sodium bis(methoxyeth-
oxy)aluminum hydride (26 mL of a 3.46 M solution in toluene) in
dry diethyl ether (50 mL). After the addition was complete, the
reaction was allowed to reach rt and then stirred at this tempera-
ture for 1 h. The mixture was then cooled to 0 °C and quenched by
the dropwise addition of a saturated solution of potassium sodium
tartrate (60 mL) and water (90 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with further ethyl ace-
tate (100 mL). The combined organic phases were washed with
brine (100 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure and the residue was purified by chromatography
eluting with hexane/EtOAc (9:1ꢀ6:4) as eluent to afford pure (S)-
(E)-4,8-dimethylnona-2,7-diene-1,4-diol (+)-8 (4.35 g, 78% yield).
A solution of ((2S,3S)-3-methyl-3-(4-methylpent-3-enyl)oxi-
ran-2-yl)methanol (ꢀ)-2 (17 g, 0.1 mol) in ethyl acetate (60 mL)
was hydrogenated at atmospheric pressure using Pd/C (10% w/w)
as the catalyst. After adsorbing 1.05 equiv of hydrogen, the catalyst
was removed by filtration, the solvent was evaporated under re-
duced pressure, and the residue was purified by chromatography
eluting with hexane/acetate (9:1ꢀ7:3) as eluent to afford pure
((2S,3S)-3-methyl-3-(4-methylpentyl)oxiran-2-yl)methanol (ꢀ)-3
(14.6 g, 85% yield) as a colorless oil. ½a D20
¼ ꢀ6:6 (c 3, CHCl3), 94%
ꢁ
of chemical purity by GC. Lit.25
½
a 2D0
ꢁ
¼ ꢀ7:1 (c 0.0195, CHCl3). 1H
NMR (400 MHz, CDCl3) d 0.88 (d, J = 6.6 Hz, 6H), 1.14–1.22 (m,
2H), 1.28 (s, 3H), 1.33–1.48 (m, 3H), 1.48–1.65 (m, 2H), 2.77 (br
t, J = 5.4 Hz, 1H), 2.96 (dd, J = 6.7, 4.4 Hz, 1H), 3.62–3.72 (m, 1H),
3.76–3.86 (m, 1H). 13C NMR (100 MHz, CDCl3) d 16.6, 22.4, 22.4,
22.7, 27.8, 38.6, 38.8, 61.2, 61.2, 63.0. GC–MS m/z (rel intensity)
172 (M+, <1), 157 (2), 129 (17), 115 (50), 111 (27), 95 (23), 85
(11), 71 (100), 69 (91), 55 (46), 43 (62).
½
a 2D0
ꢁ
¼ þ4:4 (c 2, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.29 (s, 3H),
1.51–1.66 (m, 3H), 1.60 (s, 3H), 1.68 (s, 3H), 1.71 (br s, 1H), 1.93–
2.12 (m, 2H), 4.17 (br s, 2H), 5.11 (br t, J = 7.3 Hz, 1H), 5.77 (d,
J = 15.9 Hz, 1H), 5.84 (dt, J = 15.9, 4.9 Hz, 1H). 13C NMR (100 MHz,
CDCl3) d 17.7, 22.8, 25.6, 27.9, 42.3, 63.1, 72.8, 124.3, 126.7,
131.9, 138.4. MS (ESI): 207.3 (M++Na).
The above described procedure was repeated starting from (S)-
4,8-dimethylnon-2-yne-1,4-diol (+)-7 (7 g, 38 mmol) to give pure
(S)-(E)-4,8-dimethylnon-2-ene-1,4-diol (+)-9 (5.2 g, 74% yield).
4.3. Preparation of the propargylic diols (ꢀ)-6 and (+)-7
A
mixture of ((2S,3S)-3-methyl-3-(4-methylpent-3-enyl)oxi-
½
a 2D0
ꢁ
¼ þ6:8 (c 4, CHCl3). 1H NMR (400 MHz, CDCl3) d 0.87 (d,
ran-2-yl)methanol (ꢀ)-2 (10 g, 58.8 mmol), Ph3P (16 g, 61 mmol),
NaHCO3 (1 g, 11.9 mmol), and CCl4 (100 mL) was heated at reflux
with stirring. When the starting alcohol could no longer be de-
tected by TLC analysis (8 h) the reaction was cooled to 0 °C and
the precipitated phosphine oxide was removed by filtration. The
solution was concentrated under reduced pressure and the residue
was purified by chromatography eluting with hexane/ether
(95:5ꢀ8:2) as the eluent. The oil obtained consisted of 3-(chloro-
methyl)-2-methyl-2-(4-methylpent-3-enyl)oxirane impure with
some residual Ph3P. The whole aforementioned material was dis-
solved in dry THF (80 mL) and cooled to ꢀ78 °C. Next, BuLi
(78 mL of a 2.5 M solution in hexane, 195 mmol) was added drop-
wise under a static atmosphere of nitrogen and the mixture was
stirred at this temperature for one additional hour. The reaction
was allowed to reach rt and then a slurry of paraformaldehyde
(9 g, 0.3 mol) in dry THF (20 mL) was added in a few portions.
After the exothermic reaction settled down, stirring was prolonged
for a further 2 h and then the obtained jelly mixture was poured
into a saturated solution of NH4Cl (100 mL). The reaction was ex-
tracted with diethyl ether (3 ꢂ 100 mL) and the combined organic
phases were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by chromatogra-
phy eluting with hexane/EtOAc (9:1ꢀ6:4) as eluent to afford pure
(S)-4,8-dimethylnon-7-en-2-yne-1,4-diol (ꢀ)-6 (8.7 g, 81% yield)
J = 6.6 Hz, 6H), 1.10–1.23 (m, 2H), 1.24–1.38 (m, 2H), 1.28 (s, 3H),
1.44–1.62 (m, 3H), 1.74 (br s, 1H), 1.92 (br s, 1H), 4.15 (br s, 2H),
5.74–5.86 (m, 2H). 13C NMR (100 MHz, CDCl3) d 21.7, 22.5, 22.5,
27.8, 27.9, 39.4, 42.9, 63.1, 72.7, 126.5, 138.7. MS (ESI): 209.4
(M++Na).
4.5. Synthesis of (+)-curcutetraol 1a
Acetic anhydride (10 mL) was added to a solution of (S)-(E)-4,8-
dimethylnona-2,7-diene-1,4-diol (+)-8 (5 g, 27.2 mmol) in pyridine
(10 mL). After 2 h at rt, the starting diol was completely acetylated
(TLC analysis) and both pyridine and acetic anhydride were re-
moved under reduced pressure. The residue was dissolved in dry
THF (40 mL) and treated with imidazole (2.9 g, 42.6 mmol), DMAP
(0.1 g, 0.8 mmol), and chlorotriethylsilane (6.2 g, 41.1 mmol). The
reaction mixture was heated at 60 °C under nitrogen for 3 h, then
was cooled to rt, diluted with water (100 mL), and extracted with
diethyl ether (2 ꢂ 100 mL). The combined organic phases were
washed with a saturated solution of NaHCO3 (60 mL) and were
concentrated in vacuo. The residue was treated with a solution of
NaOH (4 g, 0.1 mol) in MeOH (30 mL) while stirring at rt until
the starting acetate was no longer detectable by TLC analysis
(30 min). The reaction was then diluted with water (100 mL) and
extracted with diethyl ether (2 ꢂ 100 mL). The combined organic
phases were washed with brine and dried (Na2SO4). The solvent
was removed under reduced pressure and the residue was purified
by chromatography eluting with hexane–diethyl ether (95:5–8:2)
as eluent to afford pure (S,E)-4,8-dimethyl-4-(triethylsilyl-
oxy)nona-2,7-dien-1-ol (ꢀ)-10 (7.55 g, 93% yield) as a colorless
as a colorless oil. ½a D20
ꢁ
¼ ꢀ11:9 (c 1.9, CHCl3). 1H NMR (400 MHz,
CDCl3) d 1.48 (s, 3H), 1.64 (s, 3H), 1.69 (s, 3H), 1.59–1.76 (m, 2H),
2.09–2.32 (m, 2H), 2.52 (br s, 2H), 4.29 (s, 2H), 5.15 (br t,
J = 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 17.6, 23.6, 25.6,
29.7, 43.3, 50.9, 68.3, 81.7, 89.4, 123.7, 132.3. MS (ESI): 205.3
(M++Na).
oil. ½a 2D0
ꢁ
¼ ꢀ1:5 (c 2.1, CHCl3), 95% of chemical purity by GC. 1H
The above described procedure was repeated starting from
((2S,3S)-3-methyl-3-(4-methylpentyl)oxiran-2-yl)methanol (ꢀ)-3
(10 g, 58.1 mmol) to give pure (S)-4,8-dimethylnon-2-yne-1,4-diol
NMR (400 MHz, CDCl3) d 0.58 (q, J = 8.0 Hz, 6H), 0.95 (t,
J = 8.0 Hz, 9H), 1.30 (br s, 1H), 1.31 (s, 3H), 1.46–1.53 (m, 2H),
1.59 (s, 3H), 1.67 (s, 3H), 1.88–2.09 (m, 2H), 4.15 (br s, 2H), 5.04–
5.12 (m, 1H), 5.71 (d, J = 15.6 Hz, 1H), 5.77 (dt, J = 15.6, 5.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) d 6.8, 7.1, 17.6, 22.8, 25.6, 27.8,
44.0, 63.4, 74.7, 124.7, 126.3, 131.1, 139.3. GC–MS m/z (rel inten-
sity) 280 (M+ꢀH2O, 1), 267 (6), 215 (100), 199 (3), 185 (10), 166
(6), 159 (5), 149 (6), 135 (34), 115 (60), 103 (54), 87 (33), 75
(54), 69 (52), 59 (13).
(+)-7 (8.9 g, 83% yield). ½a D20
ꢁ
¼ þ2:6 (c 1.2, CHCl3). 1H NMR
(400 MHz, CDCl3) d 0.89 (d, J = 6.7 Hz, 6H), 1.20 (q, J = 7.5 Hz, 2H),
1.39–1.71 (m, 5H), 1.48 (s, 3H), 2.89 (bs s, 1H), 2.92 (br s, 1H),
4.28 (s, 2H). 13C NMR (100 MHz, CDCl3) d 22.4, 22.5, 22.5, 27.8,
29.5, 38.9, 43.7, 50.7, 68.1, 81.4, 89.5. MS (ESI): 207.4 (M++Na).
4.4. Preparation of allylic diols (+)-8 and (+)-9
A mixture of alcohol (ꢀ)-10 (3.4 g, 11.4 mmol), CH2Cl2 (40 mL),
and MnO2 (15 g, 173 mmol) was stirred at reflux until complete
oxidation to the aldehyde (4 h, TLC analysis). The reaction was then
filtered and the organic phase was concentrated under reduced
A solution of (S)-4,8-dimethylnon-7-en-2-yne-1,4-diol (ꢀ)-6
(5.5 g, 30.2 mmol) in dry diethyl ether (30 mL) was added drop-

S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
1115
pressure. The residue was dissolved in toluene (25 mL) and treated
4.6. Synthesis of (+)-sydonol 1b and (+)-sydonic acid 1c
with BHA (50 mg, 0.28 mmol) and ylide 11 (6.8 g, 16.7 mmol). The
heterogeneous mixture obtained was stirred under nitrogen at
80 °C until the starting aldehyde could not be detected by TLC anal-
ysis (3 h). The solvent was removed under reduced pressure and
the residue was purified by chromatography eluting with hex-
ane-ethyl acetate (9:1–7:3) as eluent to afford pure (S,3E,5E)-3-
(ethoxycarbonyl)-7,11-dimethyl-7-(triethylsilyloxy)dodeca-
3,5,10-trienoic acid (+)-12 (3.4 g, 70% yield) as a pale yellow oil.
According to the procedure described for the synthesis of (ꢀ)-
10, diol (+)-9 (8 g, 43 mmol) was transformed into triethylsilyl
derivative (ꢀ)-14 (11.7 g, 91% yield). ½a D20
¼ ꢀ3:1 (c 2.6, CHCl3),
ꢁ
95% of chemical purity by GC. 1H NMR (400 MHz, CDCl3) d 0.57
(q, J = 8.0 Hz, 6H), 0.86 (d, J = 6.7 Hz, 6H), 0.95 (t, J = 8.0 Hz, 9H),
1.08–1.18 (m, 2H), 1.20–1.41 (m, 3H), 1.29 (s, 3H), 1.42–1.60 (m,
3H), 4.11–4.17 (m, 2H), 5.68–5.79 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 6.9, 7.0, 21.8, 22.6, 22.6, 27.8, 27.9, 39.5, 44.3, 63.5, 74.9,
126.2, 139.6. GC–MS m/z (rel intensity) 285 (M+ꢀMe, 4), 271
(14), 253 (2), 243 (2), 215 (100), 187 (5), 159 (5), 115 (34), 103
(51), 95 (16), 87 (24), 75 (33).
½
a 2D0
ꢁ
¼ þ5:4 (c 2.7, CHCl3). 1H NMR (400 MHz, CDCl3) d 0.60 (q,
J = 8.0 Hz, 6H), 0.96 (t, J = 8.0 Hz, 9H), 1.30 (t, J = 7.2 Hz, 3H), 1.35
(s, 3H), 1.45–1.62 (m, 2H), 1.57 (s, 3H), 1.66 (s, 3H), 1.85–2.11
(m, 2H), 3.48 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 5.06 (br t, J = 7.0 Hz,
1H), 6.17 (d, J = 15.0 Hz, 1H), 6.46 (dd, J = 15.0, 11.6 Hz, 1H),
7.36 (d, J = 11.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 6.9, 7.0,
14.2, 17.6, 22.9, 25.6, 28.0, 32.4, 43.8, 61.0, 75.5, 121.9,
122.9, 124.4, 131.4, 141.1, 151.6, 167.5, 175.7. MS (ESI): 447.6
(M++Na).
According to the procedure described for the synthesis of (+)-
12, triethylsilyl derivative (ꢀ)-14 (6 g, 20 mmol) was transformed
into dienic acid (+)-15 (6.6 g, 77% yield). ½a D20
¼ þ6:5 (c 2.1, CHCl3).
ꢁ
1H NMR (400 MHz, CDCl3) d 0.59 (q, J = 8.0 Hz, 6H), 0.85 (d,
J = 6.7 Hz, 6H), 0.95 (t, J = 8.0 Hz, 9H), 1.07–1.17 (m, 2H), 1.18–
1.40 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.33 (s, 3H), 1.43–1.58 (m,
3H), 3.48 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 6.17 (d, J = 15.0 Hz, 1H),
6.45 (dd, J = 15.0, 11.6 Hz, 1H), 7.36 (d, J = 11.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 6.8, 7.0, 14.2, 21.8, 22.5, 22.6, 27.9, 27.9, 32.4,
39.4, 44.1, 61.0, 75.6, 121.7, 122.8, 141.2, 151.9, 167.4, 176.0. MS
(ESI): 449.6 (M++Na) and 427.6 (M+H+).
At first, (CF3CO)2O (1.4 mL, 10 mmol) was added dropwise at
0 °C to a stirred solution of acid (+)-12 (2.2 g, 5.2 mmol) and Et3N
(4 mL, 28.7 mmol) in dry THF (20 mL). The mixture was stirred at
room temperature for 1 h then water (50 mL) was added, and the
reaction was extracted with diethyl ether (2 ꢂ 60 mL). The organic
phase was washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by chromatogra-
phy eluting with hexane–diethyl ether (95:5–8:2) as eluent to
afford pure (S)-ethyl 3-hydroxy-4-(6-methyl-2-(triethylsilyl-
According to the procedure described for the synthesis of (+)-
13, dienic acid (+)-15 (3.5 g, 8.2 mmol) was transformed into phe-
nol (+)-16 (1.97 g, 59% yield). ½a D20
ꢁ
¼ þ3:9 (c 2.3, CHCl3). 1H NMR
oxy)hept-5-en-2-yl)benzoate (+)-13 (1.29 g, 61% yield). ½a D20
ꢁ
¼
(400 MHz, CDCl3) d 0.67 (q, J = 8.0 Hz, 6H), 0.79 (d, J = 6.7 Hz, 6H),
0.94 (t, J = 8.0 Hz, 9H), 1.02–1.31 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H),
1.39–1.52 (m, 1H), 1.73 (s, 3H), 1.76–1.85 (m, 2H), 4.34 (q,
J = 7.2 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.1, 1.7 Hz,
1H), 7.49 (d, J = 1.7 Hz, 1H), 9.16 (s, 1H). 13C NMR (100 MHz, CDCl3)
d 6.5, 6.7, 14.3, 22.0, 22.4, 22.5, 27.6, 27.7, 39.0, 44.4, 60.8, 81.8,
118.4, 120.2, 125.7, 130.9, 135.4, 156.3, 166.3. MS (ESI): 431.5
(M++Na).
þ15:4 (c 1.8, CHCl3). 1H NMR (400 MHz, CDCl3)
d 0.67 (q,
J = 8.0 Hz, 6H), 0.95 (t, J = 8.0 Hz, 9H), 1.37 (t, J = 7.2 Hz, 3H), 1.49
(s, 3H), 1.62 (s, 3H), 1.75 (s, 3H), 1.80–1.97 (m, 4H), 4.34 (q,
J = 7.2 Hz, 2H), 4.95–5.02 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 7.47
(dd, J = 8.1, 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 9.19 (s, 1H). 13C
NMR (100 MHz, CDCl3) d 6.4, 6.7, 14.3, 17.5, 23.1, 25.5, 27.6, 44.2,
60.8, 81.6, 118.4, 120.2, 123.4, 125.7, 130.9, 131.9, 135.1, 156.3,
166.3. MS (ESI): 429.5 (M++Na).
Phenol (+)-16 (0.9 g, 2.21 mmol) was dissolved in dry THF
(5 mL) and added dropwise to a stirred suspension of LiAlH4
(0.2 g, 5.3 mmol) in refluxing THF (20 mL). After 30 min, the reac-
tion was cooled (0 °C) and quenched by the dropwise addition of
dilute HCl (50 mL). The resulting mixture was extracted with ethyl
acetate (3 ꢂ 40 mL) and the combined organic phases were washed
with brine and dried (Na2SO4). The solvent was removed under re-
duced pressure and the residue was purified by chromatography
eluting with hexane–ethyl acetate (9:1–6:4) as eluent to afford
Acetic anhydride (5 mL) and DMAP (0.1 g, 0.8 mmol) were
added to a solution of compound (+)-13 (1.1 g, 2.7 mmol) in pyri-
dine (5 mL). After 3 h at rt, the starting phenol was completely
acetylated (TLC analysis) and both pyridine and the acetic anhy-
dride were removed under reduced pressure. The residue was dis-
solved in CH2Cl2 (15 mL) and
a solution of MCPBA (0.6 g,
3.48 mmol) in CH2Cl2 (5 mL) was added dropwise at 0 °C with stir-
ring. As soon as the epoxidation was complete, the reaction was di-
luted with CH2Cl2 (80 mL) and quenched by the addition of a 5% aq
solution of Na2SO3 (50 mL). The organic phase was separated and
pure (+)-1b (0.50 g, 89% yield), as a thick oil. ½a D20
ꢁ
¼ þ5:8 (c 2.0,
¼ þ8:6 (c 1,
¼ þ7:2 (c 1, MeOH).
MeOH), lit.11
½
a 2D0
ꢁ
¼ þ6:1 (c 0.53, CHCl3), lit.6
½ ꢁ
a 2D0
then washed in turn with
a
saturated solution of NaHCO3
MeOH), lit.5 ½a 2D0
ꢁ
¼ þ9:0 (c 1, MeOH), lit.2 ½a D20
ꢁ
(50 mL) and with brine. After drying (Na2SO4), the solvent was re-
moved under reduced pressure and the residue was dissolved in
dry THF (5 mL) and added dropwise to a stirred suspension of
LiAlH4 (0.3 g, 7.9 mmol) in refluxing THF (20 mL). After 1 h the
reaction was cooled (0 °C) and quenched by the dropwise addition
of dilute HCl (60 mL). The resulting mixture was extracted with
ethyl acetate (3 ꢂ 60 mL) and the combined organic phases were
washed with brine and dried (Na2SO4). The solvent was removed
under reduced pressure and the residue was purified by chroma-
tography eluting with hexane–ethyl acetate (9:1–1:1) as eluent
1H NMR (400 MHz, CDCl3) d 0.83 (d, J = 6.6 Hz, 6H), 1.10–1.21 (m,
2H), 1.23–1.38 (m, 2H), 1.43–1.56 (m, 1H), 1.62 (s, 3H), 1.73–
1.83 (m, 1H), 1.83–1.94 (m, 2H), 2.67 (s, 1H), 4.58 (s, 2H), 6.79
(dd, J = 8.5, 1.7 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.96 (d, J = 8.5 Hz,
1H), 9.20 (s, 1H). 13C NMR (100 MHz, CDCl3) d 21.7, 22.5, 22.5,
27.8, 29.0, 39.1, 43.0, 64.8, 78.7, 116.0, 117.9, 126.4, 129.1, 141.7,
156.2. MS (ESI): 275.4 (M++Na), 527.2 (2M++Na) and 251.2 (Mꢀ).
At first, NaOH (1 g, 25 mmol) in methanol (10 mL) was added to
a solution of phenol (+)-16 (0.7 g, 1.72 mmol) in methanol (5 mL).
The obtained mixture was stirred at reflux until the starting ester
was no longer detected by TCL analysis (approximately 30 min).
The reaction was then cooled to 0 °C, quenched with dilute HCl
aq (50 mL) and extracted with ethyl acetate (2 ꢂ 100 mL). The
combined organic phases were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue was
purified by chromatography eluting with hexane–ethyl acetate
(9:1–6:4) as eluent to afford pure (+)-1c (0.43 g, 94% yield), as a
white solid. mp 66–68 °C, lit.6 mp 85–86 °C, lit.1 mp 158–159 °C
to afford pure (+)-1a (0.59 g, 81% yield), as
a thick oil.
½
a 2D0
ꢁ
¼ þ6:3 (c 2.2, MeOH), lit.4
½
a 2D0
ꢁ
¼ þ5:2 (c 0.74, MeOH), lit.5
½
a 2D0
ꢁ
¼ þ5:9 (c 0.74, MeOH). 1H NMR (400 MHz, CDCl3) d 1.17 (s,
3H), 1.17 (s, 3H), 1.36–1.51 (m, 5H), 1.63 (s, 3H), 1.76–1.88 (m,
1H), 1.88–2.00 (m, 2H), 3.24 (s, 1H), 4.58 (s, 2H), 6.80 (dd, J = 8.0,
1.6 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 9.35
(s, 1H).13C NMR (100 MHz, CDCl3) d 18.7, 29.3, 29.3, 29.4, 43.1,
43.5, 64.8, 71.2, 78.6, 116.0, 117.9, 126.3, 129.0, 141.7, 156.2. MS
(ESI): 291.4 (M++Na) and 267.3 (Mꢀ).
(for the racemic acid) ½a D20
ꢁ
¼ þ1:5 (c 1.4, MeOH), lit.9
½
a 2D0
ꢁ
¼ þ2:0

1116
S. Serra, A. A. Cominetti / Tetrahedron: Asymmetry 24 (2013) 1110–1116
(c 2, MeOH), lit.6
½
a 2D0
ꢁ
¼ þ2:73 (c 2.3, MeOH). 1H NMR (400 MHz,
1H), 7.37 (d, J = 11.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 14.1,
21.3, 22.2, 22.5, 22.5, 27.9, 32.5, 39.4, 39.8, 50.2, 61.0, 77.4,
123.5, 123.9, 140.9, 149.1, 167.3, 175.8. MS (ESI): 349.5 (M++Na).
According to the procedure described for the synthesis of
(+)-13, dienic acid (ꢀ)-19 (2.5 g, 7.7 mmol) was transformed into
CD3OD) d 0.82 (d, J = 6.6 Hz, 6H), 1.08–1.17 (m, 2H), 1.17–1.26
(m, 1H), 1.26–1.41 (m, 3H), 1.42–1.55 (m, 1H), 1.60 (s, 3H), 1.79
(ddd, J = 13.8, 11.6, 4.7 Hz, 1H), 1.94 (ddd, J = 13.8, 11.9, 4.6 Hz,
1H), 7.25 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.44 (dd,
J = 8.1, 1.7 Hz, 1H). 13C NMR (100 MHz, CD3OD) d 22.9, 22.9, 23.0,
28.9, 29.0, 40.5, 43.8, 78.1, 118.7, 121.6, 127.8, 131.7, 138.0,
157.0, 169.9. MS (ESI): 555.2 (2M++Na) and 265.2 (Mꢀ).
phenol (+)-20 (1.60 g, 68% yield). ½a D20
ꢁ
¼ þ15:7 (c 2.4, CHCl3). 1H
NMR (400 MHz, CDCl3) d 0.82 (d, J = 6.6 Hz, 6H), 1.06–1.22 (m,
3H), 1.25–1.41 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.42–1.56 (m, 1H),
1.60 (s, 3H), 1.76–1.90 (m, 2H), 3.22 (s, 3H), 4.35 (q, J = 7.1 Hz,
2H), 7.06 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 1.7 Hz, 1H), 7.51 (d,
J = 1.7 Hz, 1H), 8.93 (s, 1H). 13C NMR (100 MHz, CDCl3) d 14.3,
21.5, 22.2, 22.4, 22.5, 27.7, 39.1, 39.9, 50.5, 60.8, 83.0, 118.0,
120.5, 127.3, 131.4, 132.8, 156.0, 166.3. MS (ESI): 331.5 (M++Na)
and 639.1 (2M++Na).
4.7. Synthesis of (+)-7-O-methylsydonic acid 1d
A solution of diol (+)-9 (5 g, 26.9 mmol), imidazole (3.5 g,
51.4 mmol), and DMAP (0.1 g, 0.8 mmol) in dry DMF (15 mL) was
treated with tert-butylchlorodiphenyl silane (8.1 g, 29.5 mmol)
with 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 ꢂ 100 mL). The combined organic phases
were dried and concentrated under reduced pressure. The residue
was dissolved in dry THF (50 mL), cooled at ꢀ78 °C, and treated un-
der nitrogen with BuLi (12 mL of a 2.5 M solution in hexane). The
reaction was kept at this temperature for 20 min., then MeI
(2.5 mL, 40.2 mmol) and DMPU (10 mL) were added, the tempera-
ture was allowed to reach rt and stirring was prolonged for 48 h.
Quenching was performed by the addition of a saturated solution
of NH4Cl (100 mL) followed by extraction with diethyl ether
(2 ꢂ 100 mL). The combined organic phases were dried, concen-
trated under reduced pressure, and the residue was purified by
chromatography eluting with hexane–diethyl ether (95:5–9:1) as
eluent to afford pure (+)-17 (9.1 g, 77% yield), as a colorless oil.
According to the procedure described for the synthesis of (+)-1c,
phenol derivative (+)-20 (0.8 g, 2.6 mmol) was transformed into
acid (+)-1d (0.69 g, 95% yield) as a colorless gum. ½a D20
¼ þ3:9 (c
ꢁ
1.9, MeOH), lit.9
½
a 2D0
ꢁ
¼ þ2 (c 1.9, MeOH). 1H NMR (400 MHz,
CDCl3) d 0.83 (d, J = 6.6 Hz, 6H), 1.06–1.22 (m, 3H), 1.23–1.41 (m,
1H), 1.42–1.56 (m, 1H), 1.62 (s, 3H), 1.76–1.92 (m, 2H), 3.24 (s,
3H), 7.10 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 (d,
J = 1.7 Hz, 1H), 9.00 (s, 1H). 13C NMR (100 MHz, CDCl3) d 21.5,
22.2, 22.4, 22.5, 27.7, 39.1, 39.8, 50.5, 83.1, 118.7, 121.2, 127.4,
130.1, 133.9, 156.1, 171.6. MS (ESI): 303.4 (M++Na) and 279.2
(Mꢀ).
Acknowledgments
The authors thank Regione Lombardia for the partial financial
support through the project ‘VeLiCa—From ancient crops, materials
and products for the future’ (protocol no 14840/RCC).
½
a 2D0
ꢁ
¼ þ2:5 (c 0.6, CHCl3), 93% of chemical purity by GC. 1H NMR
(400 MHz, CDCl3) d 0.87 (d, J = 6.6 Hz, 6H), 1.06 (s, 9H), 1.11–1.22
(m, 2H), 1.20 (s, 3H), 1.23–1.35 (m, 2H), 1.42–1.60 (m, 3H), 3.11
(s, 3H), 4.25 (br s, 2H), 5.65 (br s, 2H), 7.32-7.44 (m, 6H), 7.65–
7.71 (m, 4H). 13C NMR (100 MHz, CDCl3) d 19.3, 21.5, 22.0, 22.6,
22.6, 26.9, 28.0, 39.6, 40.3, 49.9, 64.3, 76.8, 127.6, 129.2, 129.6,
133.9, 134.9, 135.6. GC–MS m/z (rel intensity) 423 (M+ꢀMe, <1),
406 (2), 381 (9), 349 (17), 261 (9), 213 (100), 199 (64), 183 (23),
153 (40), 135 (20), 95 (18), 81 (7), 69 (8).
References
1. Hamasaki, T.; Nagayama, K.; Hatsuda, Y. Agric. Biol. Chem. 1978, 42, 37–40.
2. Nukina, M.; Sato, Y.; Ikeda, M.; Sassa, T. Agric. Biol. Chem. 1981, 45, 789–790.
3. Henne, P.; Thiericke, R.; Grabley, S.; Hütter, K.; Wink, J.; Jurkiewicz, E.; Zeeck, A.
Liebigs Ann. Chem. 1993, 565–571.
4. Mulhaupt, T.; Kaspar, H.; Otto, S.; Reichert, M.; Bringmann, G.; Lindel, T. Eur. J.
Org. Chem. 2005, 334–341.
At first, TBAF (6.4 g of the trihydrate salt, 20.3 mmol) was added
portionwise at rt to a stirred solution of ether (+)-17 (8.5 g,
19.4 mmol) in dry THF (40 mL). When the silyl ether was com-
pletely cleaved (1 h), the reaction was diluted with diethyl ether
(100 mL) and quenched with water (100 mL). The aqueous phase
was then extracted with ether (100 mL) and the combined organic
phases were washed with brine, dried, and concentrated in vacuo.
The residue was purified by chromatography eluting with hexane–
diethyl ether (95:5–8:2) as eluent to afford pure (ꢀ)-18 (3.55 g,
5. Ito, S.; Zhang, C.; Hosoda, N.; Asami, M. Tetrahedron 2008, 64, 9879–9884.
6. Kudo, S.; Murakami, T.; Miyanishi, J.; Tanaka, K.; Takada, N.; Hashimoto, M.
Biosci., Biotechnol., Biochem. 2009, 73, 203–204.
7. Wei, M. Y.; Wang, C. Y.; Liu, Q. A.; Shao, C. L.; She, Z. G.; Lin, Y. C. Mar. Drugs
2010, 8, 941–949.
8. Lu, Z.; Zhu, H.; Fu, P.; Wang, Y.; Zhang, Z.; Lin, H.; Liu, P.; Zhuang, Y.; Hong, K.;
Zhu, W. J. Nat. Prod. 2010, 73, 911–914.
9. Trisuwan, K.; Rukachaisirikul, V.; Kaewpet, M.; Phongpaichit, S.; Hutadilok-
Towatana, N.; Preedanon, S.; Sakayaroj, J. J. Nat. Prod. 2011, 74, 1663–1667.
10. Li, D.; Xu, Y.; Shao, C. L.; Yang, R. Y.; Zheng, C. J.; Chen, Y. Y.; Fu, X. M.; Qian, P.
Y.; She, Z. G.; de Voogd, N. J.; Wang, C. Y. Mar. Drugs 2012, 10, 234–241.
11. Sun, L. L.; Shao, C. L.; Chen, J. F.; Guo, Z. Y.; Fu, X. M.; Chen, M.; Chen, Y. Y.; Li, R.;
de Voogd, N. J.; She, Z. G.; Lin, Y. C.; Wang, C. Y. Bioorg. Med. Chem. Lett. 2012,
22, 1326–1329.
12. Wang, J.; Lu, Z.; Liu, P.; Wang, Y.; Li, J.; Hong, K.; Zhu, W. Planta Med. 2012, 78,
1861–1866.
13. Murali, D.; Rao, G. S. K. J. Indian Chem. B 1987, 26, 156–157.
14. Serra, S. Tetrahedron: Asymmetry 2011, 22, 619–628.
15. Serra, S.; Fronza, G. Eur. J. Org. Chem. 2012, 4838–4843.
16. Serra, S. Nat. Prod. Commun. 2012, 7, 455–458.
17. Fuganti, C.; Serra, S. J. Org. Chem. 1999, 64, 8728–8730.
18. Serra, S. Synlett 2000, 890–892.
19. Serra, S.; Fuganti, C.; Brenna, E. Chem. Eur. J. 2007, 13, 6782–6791.
20. Mohapatra, D. K.; Pramanik, C.; Chorghade, M. S.; Gurjar, M. K. Eur. J. Org. Chem.
2007, 5059–5063.
21. Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. Chem. Commun. 1989, 1344–
1345.
22. Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595–4597.
23. Fuganti, C.; Serra, S. Synlett 1999, 1241–1242.
91% yield), as a colorless oil. ½a D20
¼ ꢀ11:6 (c 2, CHCl3), 97% of
ꢁ
chemical purity by GC. 1H NMR (400 MHz, CDCl3) d 0.87 (d,
J = 6.6 Hz, 6H), 1.11–1.19 (m, 2H), 1.22–1.33 (m, 2H), 1.23 (s, 3H),
1.45–1.59 (m, 3H), 1.92 (br s, 1H), 3.14 (s, 3H), 4.16 (d, J = 5.4 Hz,
2H), 5.63 (dt, J = 16.0, 1.3 Hz, 1H), 5.74 (dt, J = 16.0, 5.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) d 21.3, 22.0, 22.5, 22.5, 27.8, 39.4,
40.0, 49.8, 63.2, 76.7, 129.3, 136.2. GC–MS m/z (rel intensity) 185
(M+ꢀMe, 3), 169 (5), 143 (2), 135 (1), 115 (100), 109 (4), 97 (19),
83 (44), 73 (43), 55 (44), 43 (13).
According to the procedure described for the synthesis of
(+)-12, allylic alcohol (ꢀ)-18 (3.1 g, 15.5 mmol) was transformed
into dienic acid (ꢀ)-19 (4.05 g, 80% yield). ½a D20
¼ ꢀ7:6 (c 2.3,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3) d 0.86 (d, J = 6.6 Hz, 6H), 1.10–
1.20 (m, 2H), 1.22–1.34 (m, 2H), 1.27 (s, 3H), 1.30 (t, J = 7.1 Hz,
3H), 1.45–1.61 (m, 3H), 3.16 (s, 3H), 3.50 (s, 2H), 4.24 (q,
J = 7.1 Hz, 2H), 6.10 (d, J = 15.4 Hz, 1H), 6.39 (dd, J = 15.4, 11.4 Hz,
24. Hudson, R. F.; Chopard, P. A. Helv. Chim. Acta 1963, 46, 2178–2185.
25. Mundal, D. A.; Avetta, C. T.; Thomson, R. J. Nat. Chem. 2010, 2, 294–297.