Enantioselective total synthesis and absolute configuration of the alleged structure of crassinervic acid

Article abstract of DOI:10.1016/j.tet.2011.06.015

An enantioselective synthesis of the structure reported for the natural antifungal compound, (-)-crassinervic acid (1), has been achieved starting from geraniol and p-hydroxybenzoic acid. The key chirality-inducing step is a Sharpless asymmetric epoxidation of an allylic alcohol, on the basis of which the S configuration can be assigned to the (-) natural enantiomer. The discrepancies between the spectroscopic data for synthetic and natural crassinervic acid cast some doubts on the structure assigned to the natural compound. A possible revised structure is discussed.

Full text of DOI:10.1016/j.tet.2011.06.015

Tetrahedron 67 (2011) 6300e6307
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective total synthesis and absolute configuration of the alleged
structure of crassinervic acid
*
Jyotsna N. Chakor , Lucio Merlini, Sabrina Dallavalle
ꢀ
Dipartimento di Scienze Molecolari Agroalimentari, Universita di Milano, Via Celoria 2, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective synthesis of the structure reported for the natural antifungal compound, (ꢀ)-cras-
sinervic acid (1), has been achieved starting from geraniol and p-hydroxybenzoic acid. The key chirality-
inducing step is a Sharpless asymmetric epoxidation of an allylic alcohol, on the basis of which the S
configuration can be assigned to the (ꢀ) natural enantiomer. The discrepancies between the spectro-
scopic data for synthetic and natural crassinervic acid cast some doubts on the structure assigned to the
natural compound. A possible revised structure is discussed.
Received 18 March 2011
Received in revised form 16 May 2011
Accepted 6 June 2011
Available online 14 June 2011
Keywords:
Antifungal
Ó 2011 Elsevier Ltd. All rights reserved.
Natural products
Enantioselective
Synthesis
1. Introduction
development of an enantioselective synthesis could also allow as-
signment of the absolute configuration at C-30 of the natural
Piperaceae species have been extensively investigated as
a source of new natural products with potential antitumor, anti-
microbial, antifungal, and insecticidal activities.1 The phytochemi-
cal profile in Piper species is characterized by the production of
classes of compounds, such as amides, benzoic acids, and chro-
menes in addition to lignans, neolignans, and a few alkaloids.2
Crassinervic acid (1) was isolated from leaves of Piper crassiner-
vium by Kato and co-workers.3 Crassinervic acid shows antifungal
activity mainly against Cladosporium cladosporioides and Clado-
sporium sphaerospermum.
As part of our studies on natural compounds with antifungal
activity, we became interested in developing a general method for
synthesizing 1 (Fig. 1), which might also be amenable to the syn-
thesis of analogues. As the absolute stereochemistry of (ꢀ)-crassi-
nervic acid was not determined in the isolation report, the
product.
2. Results and discussion
We first planned to synthesize racemic 1, by an aldol reaction
between 3-acetyl-4-hydroxybenzoic acid methyl ester and com-
mercially available 6-methyl-5-hepten-2-one, followed by ester
hydrolysis under basic conditions to obtain (ꢁ)-1, then to extend
the synthesis to the enantioselective case.
3-Acetyl-4-hydroxybenzoic acid (2), obtained by Fries rear-
rangement of 4-acetoxybenzoic acid, was selectively methylated
with MeOH/H2SO4, to give the acetophenone derivative 3. Aldol
reaction of 3 with commercially available 6-methyl-5-hepten-2-
one by using LDA afforded
b-hydroxyketone 4. However depro-
tection of the carboxyl group using a variety of acidic conditions
(TFA; AlCl3/DMA,4 BBr35) gave complex mixtures possibly including
a product of cyclization of the tertiary alcohol onto the double
bond6 instead of the expected compound 1. Hydrolysis by using
LiOH$H2O caused retro-aldol reaction to give the starting ketone 2.
Thus, in order to overcome these difficulties, we reduced the ketone
group to the corresponding diol 5 by NaBH4/MeOH in 83% yield,
which was then hydrolyzed to give acid 6. Oxidation of the benzylic
alcohol was successfully accomplished using IBX in DMSO, to ob-
tain the desired racemic 1 (Scheme 1).
OH O
OH
COOH
1
Fig. 1. Structure of crassinervic acid.
We then focused our attention on the synthesis of enantiopure
crassinervic acid by using the same route described above. The key
step of our synthetic approach was the aldol addition to a ketone.
* Corresponding author. Tel.: þ39 0250316818; fax: þ39 0250316801; e-mail
address: jnchakor@gmail.com (J.N. Chakor).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.015

J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
6301
O
O
OP
OH O
HO
H
O
b
a
OH O
OH
+
COOH
OH O
2
COOH
OH O
COOH
1
OH
OP
Br
OH
c
COOCH3
CH2OP
Scheme 2. Retrosynthetic analysis of (ꢀ)-crassinervic acid 1.
COOCH3
COOCH3
e
4
d
3
The chiral fragment 11 was obtained by modification of
a reported procedure,16 using as a key step the Sharpless epoxi-
dation of commercially available geraniol, followed by a reductive
ring opening. This method has the advantage of providing access to
both enantiomers of 11, if the appropriate tartrate is used.
OH O
OH
OH OH
OH
Initially, we decided to prepare the enantiomer with absolute
configuration 30(S). Thus, asymmetric epoxidation of geraniol using
L
COOH
rac-1
COOCH3
f
5
-(þ)-diisopropyl tartrate (DIPT)17 was carried out to give the ep-
oxide 7. The enantiomeric excess was determined to be 93% by
comparing its optical rotation with the data reported in the liter-
ature.16 Regioselective ring opening of 7 using sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) as a reducing agent18
led to the chiral diol 8 in quantitative yield and without any loss
g
OH OH
OH
25
25
of optical purity [
a]
þ2.7 (c 2.5, CHCl3); {lit.,17
[
a
]
þ2.1 (c 3,
COOH
D
D
6
CHCl3)}. Protection of both the hydroxy groups with TBSOTf, gave
diprotected diol 9. It was then selectively deprotected with p-TSA/
MeOH to obtain the monoprotected diol 10. Oxidation of the pri-
mary alcohol 1016 furnished aldehyde 11 (Scheme 3).
Scheme 1. Reagents and conditions: (a) AlCl3, 160 ꢂC, 5 h, 80%; (b) Concd H2SO4,
MeOH, reflux, 1 h, 65%; (c) LDA, THF, ꢀ78 ꢂC, 1 h; CH3CO(CH2)2CH]C(CH3)2, THF,
ꢀ78 ꢂC, 3 h, 56%; (d) LiOH$H2O, THF/H2O, rt or AlCl3/DMA or BBr3, CH2Cl2 or TFA; (e)
NaBH4, MeOH, 0 ꢂC to rt, 2 h, 83%; (f) LiOH$H2O, THF/H2O, reflux, 9 h, 66%; (g) IBX,
DMSO, rt, 3 h, 71%.
b
d
a
O
HO
HO
HO
The aldol reaction is one of the most important CeC bond-forming
reactions and, therefore, there is widespread interest in developing
asymmetric variants of this transformation. Reports on the asym-
metric aldol condensations using ketones both as aldol acceptors
and donors are scarce and so far limited to the use of pyruvates7 or
HO
8
7
c
e
TBSO
O
TBSO
HO
TBSO
TBSO
10
9
11
other activated ketones, such as 1,3-dioxan-5-one derivatives,
a-
i
ꢁ
Scheme 3. Reagents and conditions: (a) L-(þ)-DIPT, MS 4 A, Ti(O Pr)4, TBHP, CH2Cl2,
ꢀ23 ꢂC, 4 h, 94%; (b) Red-Al, THF, 0 ꢂC to rt, 4 h, 100%; (c) TBSOTf, 2,6-Lutidine, CH2Cl2,
12 h, 100%; (d) pTSA, MeOH, 0 ꢂC, 30 min, 100%; (e) SO3$Py, TEA, DMSO, rt, 3 h, 92%.
diketones, -ketonitriles, and
a
a
-keto lactams.8e11
Notwithstanding the discouraging lack of precedent, it was
deemed worthwhile to test different conditions and catalysts to see
whether these could be successful in the case of our substrate. We
attempted to use chiral lithium amide bases, instead of bonding
covalently a chiral auxiliary, which requires removal later on. The
use of chiral lithium amides as enantioselective agents for proton
removal represents one of the most prominent recent advances in
aldol reactions.12 In principle, treatment of achiral, Cs symmetric
ketones with chiral lithium amides leads to the formation of non-
racemic lithium enolates. The base discriminates between two
enantiotopic protons, and the resulting enolate could be trapped
with electrophiles yielding ultimately an enantiomerically enriched
chiral product. The potential of this approach has been exploited by
numerous research groups.12
The synthesis of the aromatic fragment 14 is summarized in
Scheme 4. Bromination of methyl 4-hydroxybenzoate gave in 95%
yield the bromoderivative 12,19 that was converted into alcohol 13
using DIBAL as a reducing agent (Scheme 4).
OR
OH
OH
OH
Br
Br
Br
a
b
c
CH2OR'
COOCH3
CH2OH
COOCH3
14a: R = R' = TBDMS
14b: R = H, R'= TBDMS
14c: R = R' = SEM
13
12
Attempts using different lithium amides, such as those from
(þ)-bis[(R)-1-phenylethyl]amine,13 and the tetradentate (R)-N-[2-(2-
methoxyethoxy)ethyl]-1-phenyl-2-piperidinoethylamine,14 failed to
give the desired product. The use of an alkyllithium in tandem with
a chiral ligand (BuLi/sparteine and LDA/sparteine) gave only racemic
material.15
These failures in enantioselective aldol reaction forced us to look
for another route for obtaining enantiopure crassinervic acid. The
retrosynthetic approach is depicted in Scheme 2. It was envisioned
to proceed via a condensation of the monoterpene aldehyde de-
rivative and the bromo arene unit, which could be synthesized from
commercially available geraniol and methyl 4-hydroxybenzoate,
respectively.
Scheme 4. Reagents and conditions: (a) Br2, CH2Cl2, 0 ꢂC to rt, 24 h, 95%; (b) DIBAL,
CH2Cl2, ꢀ78 ꢂC, 1 h, 68%; (c) TBDMSCl, imidazole, THF, rt, 12 h, 87% (14a); TBDMSCl,
TEA, DMAP, CH2Cl2, rt, 12 h, 86% (14b); SEMCl, DIPEA, CH2Cl2, 0 ꢂC to rt, 12 h, 87% (14c).
Protection of one or both the benzylic and phenolic function-
alities as silyl ethers was effected using TBDMSCl, to give com-
pounds 14a,b. Disappointingly, the alkylation reaction with
aldehyde 11 by using t-BuLi, failed to give the expected product.
Eventually, we found that the protection of both the hydroxy
functionalities as SEM-ethers (14c) followed by treatment with t-
BuLi (Scheme 5) gave the expected coupling product 15 as a mix-
ture of diastereoisomers in a satisfying 64% yield. However,
deprotection of this compound was troublesome, an attempt to

6302
J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
remove both SEM and TBS protecting groups with an excess of
tetrabutyl ammonium fluoride (TBAF) in THF did not remove the
benzylic SEM. This was accomplished with an excess of tetrabutyl
Unfortunately, we were not able to obtain either a sample or
copies of the spectra of natural crassinervic acid (M.J. Kato, personal
communication, 2010). As the analytical data reported in the iso-
lation paper could also match with the structure of the isomer 20,
we prepared this compound following the route described in
Scheme 6. However, not even the spectroscopic NMR data for 20
match with those reported for natural crassinervic acid. As the most
striking difference was the chemical shift of C10 (207.1 ppm vs 191.5
of the reported compound), we reasoned that the carbonyl group in
the natural compound could not be involved in an intramolecular
hydrogen bond. This pointed to the possibility of the cyclic struc-
ture 22, supported by comparison with spectroscopic NMR data for
a farnesyl-derived analogue.21 Thus, compound 22 was synthesized
following the sequence described in Scheme 7. As hypothesized, the
NMR spectra of the new derivative completely matched those
reported for crassinervic acid. However, the true structure of the
natural compound remains open to question, because the mass
spectrometric data are consistent with structure 1, whereas the
NMR data correspond to structure 22. In absence of a direct com-
parison we may only hypothesize that, if the natural compound is 1,
the reported NMR data were measured on an artifact perhaps due
to an acid/base treatment.
ꢁ
ammonium fluoride (TBAF), 4 A molecular sieves, and DMPU as
solvent.20 The addition of 4 A molecular sieves (crushed, activ-
ꢁ
ated) was needed to reduce the formation of the corresponding
ethoxymethyl ether and to increase the rate of the reaction.
SEMO OH
OSEM
Br
OTBS
TBSO
O
a
+
CH2OSEM
CH2OSEM
15
11
14c
b
OH O
OH O
CHO
OH
OH
OH OH
OH
c
d
COOH
S-1
17
16
CH2OH
Scheme 5. Reagents and conditions: (a) t-BuLi, THF, ꢀ78 ꢂC, 2 h, 64%; (b) TBAF, DMPU,
reflux, 7 h, 78%; (c) IBX, DMSO, rt, overnight, 65%; (d) NaClO2, NaH2PO4$H2O, t-BuOH,
H2O, 2-methyl-2-butene, 3 h, 75%.
Finally, oxidation of 16 with IBX in DMSO gave the ketoaldehyde
17, which, by treatment with sodium chlorite furnished (ꢀ)-1 in
75% yield.
OH
O
O
OH
OH
a,b
c,d
Synthetic 1 showed the same (ꢀ) sign of specific rotation
reported for natural crassinervic acid. As the absolute configuration
at C-30 stereogenic center of synthetic 1 is S, due to Sharpless
enantioselective epoxidation mechanism, we may safely deduce
that the absolute configuration of the natural compound is S.
Most of the spectroscopic data of synthetic (ꢀ)-1 (1H, 13C NMR
and MS) matched those reported for the natural product,3 except
for the signals of H-20 and C10, C30, and C40, that showed remarkable
discrepancies in chemical shift (Table 1).
HO
HO
HO
COOCH3
COOH
COOCH3
20
19
18
Scheme 6. Reagents and conditions: (a) LDA, THF/heptane, ꢀ78 ꢂC, 4 h, 59%; (b)
NaBH4, MeOH, 2 h, rt, 70%; (c) THF/H2O, LiOH$H2O, 4 h, reflux, 95%; (d) IBX, DMSO, 3 h,
rt, 61%.
O
OH O
OH O
OH O
OH
O
b
a
+
COOH
22
COOCH3
COOCH3
COOCH3
4
21b
21a
Scheme 7. Reagents and conditions: (a) TEA, SOCl2, DCM, 0 ꢂC, 2 h, 80%; (b) NaOH,
H2O, rt, overnight, quantitative.
Table 1
1H and 13C chemical shifts for natural crassinervic acid,3 and compounds 1, 20, and 22
3. Conclusion
OH O
O
In conclusion, the first stereoselective total synthesis of the
structure reported3 for (ꢀ)-crassinervic acid 1 was accomplished in
12 steps in 12% overall yield. Crucial steps for our strategy included
an enantioselective Sharpless epoxidation of easily available gera-
niol, followed by a regioselective reduction of the corresponding
epoxyalcohol, and a condensation of the monoterpene fragment
with lithiated a 4-hydroxymethylphenol. The successful coupling of
the two moieties required a careful choice of the protecting groups.
The absolute configuration of 1 was assigned as S. However, the
differences in spectroscopic data for 1 and those reported for
crassinervic acid,3 in absence of a direct comparison, cast doubts on
the structure assigned to crassinervic acid. The chromanone ana-
logue 22, whose NMR data are consistent with those reported for
the natural compound, was synthesized.
OH
OH
20
4
3
1'
5'
3'
O
2'
4'
6'
2
HO
O
1
22
1
COOH
COOH
COOH
Positiona Nat.
1
20
22
Position Nat.
compd
1
20
22
compd
OH
H-2
H-6
H-5
H-60
H-20a
H-20b
H2-50
12.3
12.06 11.18 12.76 C-1
119.9 119.0 118.5 120.0
129.9 132.0 132.1 130.1
122.1 119.9 132.0 122.0
163.7 166.8 166.3 163.9
118.8 119.1 129.3 118.9
137.3 137.8 136.0 137.4
191.5 207.1 199.6 191.6
8.56 8.56 8.54 8.64 C-2
8.11 8.20 8.14 8.18 C-3
6.93 7.06 7.08 7.01 C-4
4.98 5.09 5.09 5.06 C-5
2.77 3.30
2.64 3.18
3.18
3.07
2.85
2.71
C-6
C-10
2.03 2.11 1.98 2.01 C-20
e2.18 e2.18 e2.18
1.70 1.65 1.58 1.61 C-30
47.2
46.9 46.5 47.3
The synthetic routes developed here could potentially be ap-
plied to the synthesis of analogues and other related natural
products. Further synthetic studies and the evaluation of biological
activity are in progress.
H2-40
82.3
72.2 72.8 82.5
e1.68 e1.71 e1.85
H3-80
H3-90
H3-100
1.58 1.64 1.65 1.66 C-40
39.3
22.2
41.8 42.0 39.4
22.6 22.9 22.3
1.50 1.60 1.61 1.57 C-50
1.37 1.35 1.34 1.44 C-60
122.9 123.7 124.2 123.0
132.5 133.6 132.3 132.7
4. Experimental
4.1. General
C-70
C-80
25.6
17.5
23.9
27.0 27.0 25.7
17.5 17.7 17.7
25.5 25.7 24.1
C-90
C-100
C-110
170.6 170.0 172.5 171.1
All reagents and solvents were reagent grade or were purified by
standard methods before use. Melting points were determined in
open capillaries. IR spectra were recorded on a PerkineElmer 177
a
For sake of clarity the same numbering was given to the structurally corre-
sponding atoms.

J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
6303
spectrophotometer. NMR spectra were recorded at 300 MHz. Mass
1380, 1280, 1230, 1120, 980, 780 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d:
spectra were recorded with a Fourier transform ion cyclotron res-
onance (FT-ICR) mass spectrometer. Solvents were routinely dis-
tilled prior to use; anhydrous tetrahydrofuran (THF) and ether
(Et2O) were obtained by distillation from sodiumebenzophenone
ketyl; dry dichloromethane was obtained by distillation from
phosphorus pentoxide. All reactions requiring anhydrous condi-
tions were performed under a positive nitrogen flow, and all
glassware were oven dried and/or flame dried. Isolation and puri-
fication of the compounds were performed by flash column chro-
matography on silica gel 60 (230e400 mesh). Analytical thin-layer
chromatography (TLC) was conducted on TLC plates (silica gel 60
F254, aluminum foil) visualized by UV light and spraying with
phosphomolybdic acid and p-anisaldehyde.
12.61 (s, 1H), 8.50 (d, J 2.2 Hz, 1H), 8.18 (dd, J 2.2, 8.8 Hz, 1H), 7.02 (d,
J 8.8 Hz,1H), 5.06 (m,1H), 3.95 (s,1H), 3.30 (d, J 16.6 Hz,1H), 3.20 (d,
J 16.6 Hz, 1H), 2.10 (m, 2H), 1.80e1.55 (m, 8H), 1.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) d: 207.2, 166.0, 165.6, 137.3, 132.6, 131.9, 123.7,
120.9, 119.2, 118.8, 72.0, 52.0, 46.8, 41.8, 26.9, 25.4, 22.5, 17.4. HRMS
(ESIþ) calcd for C18H24O5Naþ343.15159, found 343.15882.
4.2.4. 3-(10,30-Dihydroxy-30,70-dimethyl-oct-60-enyl)-4-
hydroxybenzoic acid methyl ester (5). 4-Hydroxy-3-(30-hydroxy-
30,70-dimethyl-oct-60-enoyl)benzoic acid methyl ester 4 (0.110 g,
0.34 mmol) was dissolved in MeOH (2.5 mL) and then cooled to 0 ꢂC
NaBH4 (0.039 g, 0.10 mmol) was added portionwise and the reaction
mixture was slowly (without removing ice bath) warmed to room
temperature. After 2 h from addition of NaBH4, MeOH was evapo-
rated under vacuo. The residue was diluted with ethyl acetate, fol-
lowed by addition of a saturated aqueous NH4Cl solution. The
organic layer was separated, dried over anhydrous Na2SO4, filtered,
and concentrated to afford 5 as a sticky solid (0.091 g, 83%). [Found:
C, 67.13; H, 8.19. C18H26O5 requires C, 67.07; H, 8.13]; Rf 0.40 (ethyl
acetate/hexane 1:1). IR nmax (liquid film) 3380, 3080, 2990, 1715,
4.2. Synthesis
4.2.1. 3-Acetyl-4-hydroxybenzoic acid22 (2). 4-Acetoxy-benzoic acid
(0.350 g, 1.95 mmol) and anhydrous AlCl3 (0.800 g, 6.02 mmol)
were mixed and heated at 155e160 ꢂC (oil bath temperature) for
5 h (after 1 h a solid, brown foamy mass formed and stirring was no
longer possible). After cooling (ice bath), the reaction mixture was
treated with 6.5 mL of 2 N HCl. The acidified reaction mixture was
extracted with ethyl acetate (3ꢃ10 mL). The combined organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated to
afford a yellow solid (0.280 g, 80%), which was used without any
further purification.
1430, 1275, 755 cmꢀ1
astereomers ratio 50:50)
;
1H NMR (300 MHz, CDCl3) (mixture of di-
: 9.69 (0.5H, s), 9.62 (0.5H, s), 7.90 (dd, J 1.7,
d
8.6 Hz, 1H), 7.65 (d, J 1.7 Hz, 1H), 6.90 (d, J 8.6 Hz, 1H), 5.75 (s, 0.5H),
5.70 (s, 0.5H), 5.45e5.35 (m,1H), 5.25e5.19 (m, 0.5H), 5.15e5.05 (m,
0.5H),3.90 (s, 3H), 2.20e1.50 (m, 15H). 13C NMR (75 MHz, CDCl3)
(mixture of diastereomers, some signals overlapped) d: 166.9,161.0,
132.9,130.6,128.7,126.7,123.6,121.7,117.4, 75.3, 73.9, 73.6, 51.7, 47.4,
46.9, 44.4, 39.6, 29.7, 29.1, 25.6, 23.3, 22.4, 17.7.
4.2.2. 3-Acetyl-4-hydroxybenzoic acid methyl ester2 3
(3). Concentrated H2SO4 (5 drops) was added to a suspension of
3-acetyl-4-hydroxybenzoic acid 2 (0.250 g, 1.38 mmol) in 12 mL of
MeOH at room temperature. The resulting reaction mixture was
heated at reflux for 1 h, then it was cooled to room temperature and
neutralized using 2 N NaOH. The mixture was allowed to stand for
15 min, before being poured onto an iced H2O beaker and made up
to 42 mL with H2O. The white precipitate was filtered and dried.
The crude product was purified by flash column chromatography
(ethyl acetate/hexane 13:87) to give the title compound as a white
crystalline solid (0.175 g, 65%). Mp 101e102 ꢂC; [Found: C, 61.80; H,
5.21. C10H10O4 requires C, 61.85; H, 5.19]; Rf 0.62 (ethyl acetate/
4.2.5. 3-(10,30-Dihydroxy-30,70-dimethyl-oct-60-enyl)-4-
hydroxybenzoic acid (6). 3-(10,30-dihydroxy-30,70-dimethyl-oct-60-
enyl)-4-hydroxybenzoic acid methyl ester 5 (0.085 g, 0.26 mmol)
was taken in THF/H2O (3:1) (1.5 mL:0.5 mL), followed by addition of
LiOH$H2O (33 mg, 0.79 mmol). The resulting reaction mixture was
refluxed for 9 h and then cooled to room temperature. THF was
evaporated and the remaining aqueous layer was cooled to 0 ꢂC and
acidified to pH 3 by cold 2 N HCl. The resulting white precipitate
was filtered, washed with H2O and dried to afford the acid 6 as
a sticky solid (0.051 g, 66%). This crude product was used further
without any purification. IR nmax (liquid film) 3400, 3080, 1950,
hexane 35:65); 1H NMR (300 MHz, CDCl3)
d: 12.65 (s, 1H), 8.48 (d, J
1.7 Hz, 1H), 8.21 (dd, J 1.7, 8.6 Hz, 1H), 7.01 (d, J 8.6 Hz, 1H), 3.90 (s,
1690, 1600, 1430, 1280, 910, 750 cmꢀ1
(mixture of diastereomers ratio 50:50)
;
d
1H NMR (300 MHz, CDCl3)
: 9.80 (br s, 0.5H), 9.75 (br s,
3H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3)
136.9, 133.0, 120.8, 118.9, 118.4, 51.9, 26.5.
d: 204.3, 165.7 (ꢃ2),
0.5H), 7.92 (dd, J 1.7, 8.6 Hz, 0.5H), 7.85 (dd, J 1.7, 8.6 Hz, 0.5H), 7.70
(d, J 1.7 Hz, 1H), 6.90 (d, J 8.6 Hz, 1H), 5.45 (t, J 6.0 Hz, 0.5H), 5.40 (t, J
6.0 Hz, 0.5H), 5.25e5.21 (m, 0.5H), 5.10e4.99 (m, 0.5H), 4.12e4.00
(m, 0.5H), 3.55e3.45 (m, 0.5H), 2.30e1.20 (m, 15H). 13C NMR
(75 MHz, CDCl3) (mixture of diastereomers, some signals over-
4.2.3. 4-Hydroxy-3-(30-hydroxy-30,70-dimethyl-oct-60-enoyl)benzoic
acid methyl ester (4). A solution of LDA was prepared by adding
a 2.7 M solution of n-BuLi in heptane (0.595 mL, 1.61 mmol) to
a solution of diisopropylamine (0.227 mL, 1.61 mmol) in 4 mL of
THF, stirring at 0 ꢂC under argon atmosphere. After 30 min, the
solution was cooled to ꢀ78 ꢂC and added slowly with a solution of
3-acetyl-4-hydroxybenzoic acid methyl ester (3) (0.125 g,
0.64 mmol) in THF (1 mL) over 10 min. The resulting solution was
stirred for 1 h at ꢀ78 ꢂC (in order to secure the complete formation
of the corresponding enolate) prior to slow addition of 6-methyl-5-
hepten-2-one (0.143 mL, 0.97 mmol). Stirring was continued for 3 h
at ꢀ78 ꢂC and then the reaction was quenched with a saturated
aqueous NH4Cl solution. The reaction mixture was allowed to reach
room temperature. The layers were separated and the aqueous
layer was extracted with diethyl ether (3ꢃ5 mL). The combined
organic layer was dried over anhydrous Na2SO4, filtered, and con-
centrated. The residue was purified by flash column chromatogra-
phy (ethyl acetate/hexane 15:85) to afford the aldol product 4 as
a viscous oil (0.115 g, 56%). [Found: C, 67.45; H, 7.52. C18H24O5 re-
quires C, 67.48; H, 7.55]; Rf 0.74 (ethyl acetate/hexane 1:1); IR nmax
(liquid film) 3510, 3080, 2950, 2850, 1720, 1640, 1590, 1480, 1440,
lapped) d: 171.3, 161.6, 133.5, 131.4, 129.4, 126.5, 123.4, 120.5, 117.6,
75.5, 74.0, 73.6, 46.7, 44.2, 39.2, 29.0, 25.8, 25.4, 23.2, 22.4, 17.6.
4.2.6. 4-Hydroxy-3-(30-hydroxy-30,70-dimethyl-oct-60-enoyl)-benzoic
acid (rac 1). To a stirred solution of IBX (136 mg, 0.49 mmol) in
DMSO (1.5 mL), 3-(10,30-dihydroxy-30,70-dimethyl-oct-60-enyl)-4-
hydroxybenzoic acid 6 (0.051 g, 0.16 mmol) in 1 mL DMSO was
added dropwise at 0 ꢂC under argon atmosphere. The reaction
mixture was warmed to room temperature and stirred for 3 h, then
H2O (2 mL) was added. Stirring was continued for further 10 min.
The reaction mixture was filtered through a pad of Celite and the
residue was washed with ethyl acetate. The resulting filtrate and
washings were combined and dried over anhydrous Na2SO4, fil-
tered, and concentrated. The crude product was purified by reverse
phase column chromatography (RP-18) (water/methanol 35:65) to
afford rac 1 as a white solid (0.036 g, 71%). Mp 148 ꢂC; Rf 0.65
(CH2Cl2/MeOH 9:1); IR nmax (Nujol) 3450, 3080, 2980, 1690, 1640,
1432, 1270, 750, 710 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d: 12.06 (s,

6304
J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
1H), 8.56 (d, J 1.7 Hz, 1H), 8.20 (dd, J 1.7, 8.9 Hz, 1H), 7.06 (d, J 8.9 Hz,
1H), 5.09 (t, J 7.2 Hz, 1H), 3.30 (d, J 16.6 Hz, 1H), 3.18 (d, J 16.6 Hz,
1H), 2.11 (m, 2H), 1.68 (m, 2H), 1.64 (s, 3H), 1.60 (s, 3H), 1.35 (s, 3H);
concentrated under reduced pressure. The residue was purified by
flash column chromatography (ethyl acetate/petroleum ether
12:88) to afford 10 as a colorless liquid (0.232 g, 100%). [Found: C,
67.09; H, 11.99. C16H34O2Si requires C, 67.07; H, 11.96.]; Rf 0.49
13C NMR (75 MHz, CDCl3)
d: 207.1, 170.0, 166.8, 137.8, 133.6, 132.0,
123.7, 119.9, 119.1, 119.0, 7ꢀ2.2, 46.9, 41.8, 27.0, 25.5, 22.6, 17.5. HRMS
(ethyl acetate/petroleum ether 15:85); [
a
]
D
20 þ4.13 (c 3, CHCl3); IR
(ESIꢀ) calcd for C17H21O5 305.13945, found 305.13967.
nmax (liquid film) 3405, 3080, 2965, 2940, 2870, 1630, 1460, 1380,
1360, 1275, 1150, 1097, 842, 750 cmꢀ1
: 5.08 (t, J 7.1 Hz, 1H), 3.80 (t, J 5.7 Hz, 2H), 2.72 (t, J 5.7 Hz, 2H),
1.97 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.80e1.50 (m, 2H), 1.20 (s,
3H), 0.87 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3)
: 131.7,
;
1H NMR (300 MHz, CDCl3)
4.2.7. (2S-trans)-3-Methyl-3-(40-methyl-pent-30-enyl)oxir-
d
ꢁ
anylmethanol (7). A mixture of powdered, activated 4-A molecular
sieves (0.040 g) and CH2Cl2 (2 mL) was cooled to 0 ꢂC (þ) diiso-
propyl tartrate (0.016 mL, 0.08 mmol) and Ti(OiPr)4 (0.015 mL,
0.05 mmol) were added sequentially. After the mixture was cooled
to ꢀ10 ꢂC t-BuOOH (0.274 mL, 1.51 mmol) was added and the
resulting mixture was stirred for 20 min. The mixture was cooled to
ꢀ23 ꢂC and geraniol (0.176 mL, 1.0 mmol) was added at a rate
sufficient to ensure that the temperature remained below ꢀ20 ꢂC.
The mixture was stirred at ꢀ23 ꢂC for an additional 4 h and water
was added with vigorous stirring. After 30 min a 30% aqueous so-
lution of NaOH saturated with NaCl was added, and the mixture
was stirred at room temperature for an additional 25 min until
a phase separation was observed. The suspension was filtered then
over a Buchner funnel to separate the residues of the molecular
sieves from the solution. After separating the liquid phases, the
cloudy, aqueous phase was extracted CH2Cl2 (3ꢃ5 mL), the com-
bined organic phases were dried over anhydrous Na2SO4, filtered,
and the solvent removed in vacuo. The residue was purified by flash
column chromatography (ethyl acetate/hexane 35:65) to afford 7 as
a colorless liquid (0.161 g, 94%). [Found: C, 70.52; H, 10.68. C10H18O2
requires C, 70.55; H, 10.66]; Rf 0.51 (ethyl acetate/petroleum ether
d
124.3, 77.3, 60.0, 42.9, 42.8, 27.8, 26.0, 25.8, 25.4, 25.3, 23.4, 18.2,
17.7, ꢀ1.3.
4.2.11. (3S)-3-(tert-Butyldimethylsilanyloxy)-3,7-dimethyl-oct-6-
enal (11). The compound was prepared following the procedure
described in Ref. 16.
4.2.12. 3-Bromo-4-hydroxybenzoic acid methyl ester (12). The
compound was prepared following the procedure described in
Ref. 19.
4.2.13. 2-Bromo-4-hydroxymethylphenol24 (13). To a solution of 12
(0.185 g, 0.80 mmol) in dry CH2Cl2 (14 mL), a solution of DIBAL-H in
THF (1.0 M) (1.92 mL, 1.92 mmol) was added at ꢀ78 ꢂC. The solution
was stirred for 1 h and then it was quenched by addition of MeOH
and water. A saturated solution of Naþ and Kþ tartrate was added;
the mixture was stirred for an additional hour and the aqueous
layer was extracted with ethyl acetate (3ꢃ20 mL). The organic
layers were combined and washed with a 10% aqueous solution of
NaHCO3 and water, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash column chroma-
tography (ethyl acetate/hexane 1:1) to afford 13 as white solid
(0.111 g, 68%). Mp 125 ꢂC; [Found: C, 41.45; H, 3.42. C7H7BrO2 re-
quires C, 41.41; H, 3.48]; Rf 0.6 (ethyl acetate/hexane 65:35); IR nmax
(Nujol) 3510, 3060, 2982, 1610, 1505, 1425, 1270, 905, 750,
1:1); [
a
]
20 ꢀ5.4 (c 3, CHCl3); {lit.,16
[
a
]
25 ꢀ5.3 (c 3, CHCl3)}; IR nmax
D
D
(liquid film) 3420, 3000, 2980, 2860, 1680, 1450, 1380, 1220, 1190,
1040, 870 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 5.08 (t, J 7.1 Hz, 1H),
3.83 (dd, J 3.8, 11.6 Hz, 1H), 3.68 (dd, J 11.6, 6.9 Hz, 1H), 2.97 (dd, J
3.81, 6.9 Hz, 1H), 2.10e1.98 (m, 2H),1.68 (s, 3H), 1.61 (s, 3H),
1.40e1.70 (m, 2H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3)
d: 132.3,
123.4, 63.0, 61.6, 61.3, 38.6, 25.7, 23.8, 17.7, 16.8.
710 cmꢀ1; 1H NMR (300 MHz, DMSO-d6)
d: (s, 1H), 7.38 (d, J 2.0 Hz,
1H), 7.08 (dd, J 2.0, 8.2 Hz, 1H), 6.87 (d, J 8.2 Hz, 1H), 5.07 (t, J 5.7 Hz,
4.2.8. (3S)-3,7-Dimethyl-oct-6-ene-1,3-diol (8). The compound was
1H), 4.34 (d, J 5.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d: 153.3,
prepared following the procedure described in Ref. 17.
135.4, 131.6, 127.6, 116.5, 109.4, 62.5.
4.2.9. (6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-2,6-dimethyl-oct-
2-ene (9). To an ice-cold stirred solution of 8 (0.145 g, 0.84 mmol)
in CH2Cl2 (5 mL), 2,6-lutidine (0.390 mL, 3.36 mmol) and TBSOTf
(0.464 mL, 2.02 mmol) were added at 0 ꢂC. The resulting mixture
was warmed to room temperature and stirred for 12 h, then water
(3 mL) was added. The aqueous layer was extracted with CH2Cl2
(3ꢃ5 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. The
crude mixture was purified by flash column chromatography (ethyl
acetate/hexane 98:2) to obtain 9 as a viscous oil, (0.337 g, 100%).
4.2.14. 2-Bromo-4-(tert-butyldimethylsilyloxymethylphenoxy)(tert-
butyl)dimethylsilane (14a). To a solution of 13 (0.100 g, 0.49 mmol)
in THF (3.0 mL) at 0 ꢂC, imidazole was added in one portion fol-
lowed by addition of TBDMSCl (0.192 mL, 1.08 mmol). The
resulting reaction mixture was warmed to room temperature and
stirred for 12 h, then the reaction mixture was diluted with water
and extracted with ethyl acetate (3ꢃ5 mL). The organic layers
were combined and dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash column chroma-
tography (ethyl acetate/petroleum ether 3:97) to afford 14a as
colorless thick oil (0.370 g, 87%). [Found: C, 52.92; H, 8.19.
C19H35BrO2Si2 requires C, 52.88; H, 8.17]; Rf 0.81 (ethyl acetate/
petroleum ether 30:70); IR nmax (liquid film) 3050, 2950, 2850,
[Found: C, 65.90; H, 12.11. C22H48O2Si2 requires C, 65.93; H, 12.07];
20
Rf 0.89 (ethyl acetate/petroleum ether 5:95); [
a
]
þ1.3 (c 3,
D
CHCl3); IR nmax (liquid film) 3000, 2960, 2920, 2905, 2860, 1610,
1540, 1495, 1465, 1410, 1360, 1240, 1100, 990, 840 cmꢀ1 1H NMR
(300 MHz, CDCl3) : 5.08 (t, J 6.7 Hz, 1H), 3.71 (t, J 7.4 Hz, 2H),
;
1600, 1495, 1300, 1250, 1090, 930, 850, 760 cmꢀ1
(300 MHz, CDCl3) : 7.46 (d, J 2.2 Hz, 1H), 7.09 (dd, J 2.2, 8.2 Hz),
6.81 (d, J 8.2 Hz), 4.62 (s, 2H), 1.02 (s, 9H), 0.92 (s, 9H), 0.22 (s, 6H),
0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
: 151.5, 135.7, 131.2, 126.1,
;
1H NMR
d
d
2.10e1.90 (m, 2H),1.80e1.65 (m, 5H),1.60 (s, 3H),1.50e1.35 (m, 2H),
1.21 (s, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.07 (s, 6H), 0.05 (s, 6H); 13C
d
NMR (75 MHz, CDCl3)
26.0, 25.8, 23.1, 18.4, 17.7, ꢀ1.9, ꢀ5.5.
d
: 131.2, 124.8, 74.9, 60.0, 45.0, 43.1, 28.0, 26.1,
120.0, 115.1, 64.1, 26.0, 25.8, 18.4, 16.6, ꢀ5.1, ꢀ4.1.
4.2.15. 2-Bromo-4-(tert-butyldimethylsilyloxymethyl)phenol
4.2.10. (3S)-3-(tert-Butyldimethylsilanyloxy)-3,7-dimethyl-oct-6-en-
1-ol16 (10). An ice-bath cooled solution of the bis-TBS ether 9
(0.325 g, 0.81 mmol) in MeOH (4 mL) was treated with p-TsOH
(0.019 g, 0.10 mmol) as a solid. The reaction mixture was stirred at
the same temperature for 30 min. The reaction mixture was
quenched with solid NaHCO3 and filtered. The filtrate was
(14b). To a solution of 13 (0.150 g, 0.74 mmol) in CH2Cl2 (5.0 mL) at
0
0.04 mmol) followed by slow addition of TBDMSCl (0.111 g,
0.74 mmol). The resulting reaction mixture was warmed to room
temperature and stirred for 12 h. After 12 h, a saturated aqueous
NH4Cl solution was added to the reaction mixture, followed by
ꢂC, was added TEA (0.154 mL, 1.11 mmol) and DMAP (0.005 g,

J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
6305
extraction with ethyl acetate (3ꢃ5 mL). The organic layers were
combined and dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by flash column chromatography
(ethyl acetate/petroleum ether 25:75) to afford 14b as a colorless oil
(0.200 g, 86%). [Found: C, 49.27; H, 6.65. C13H21BrO2Si requires C,
49.21; H, 6.67]; Rf 0.40 (ethyl acetate/petroleum ether 30:70); IR
nmax (liquid film) 3500, 3045, 2960, 2920, 1605, 1495, 1260, 1100,
room temperature, and the contents diluted with diethyl ether
and poured onto water. The solution was extracted with diethyl
ether (3ꢃ10 mL). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated. The resulting oil
was washed with hexane to remove residual DMPU and sub-
jected to flash column chromatography (ethyl acetate/petroleum
ether 80:20) to afford 16 as a colorless liquid (0.056 g, 78%).
[Found: C, 69.39; H, 8.86. C17H26O4 requires C, 69.36; H, 8.90]; Rf
0.54 (ethyl acetate/petroleum ether 90:10); IR nmax (liquid film)
845 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d: 7.53 (d, J 1.7 Hz, 1H), 7.16
(dd, J 1.7 Hz, 8.2 Hz), 6.85 (d, J 8.2 Hz, 1H), 4.59 (s, 2H), 1.04 (s, 9H),
0.24 (s, 6H).
3480, 3080, 2980, 1440, 1270 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
: 8.90 (br s, 1H), 7.11 (dd,
(mixture of diastereomers ratio 60:40)
d
4.2.16. 2-(20-Bromo-40-(200-(trimethylsilylethoxymethoxymethyl)-
phenoxy)methoxyethyl)trimethyl silane (14c). To a solution of 13
(0.100 g, 0.49 mmol) in CH2Cl2 (3.5 mL) at 0 ꢂC, N,N0-diisopropy-
lethylamine (0.683 mL, 3.9 mmol) was added dropwise, followed
by slow addition of 2-trimethylsilanylethoxymethoxy chloride
(0.192 mL, 1.08 mmol). The resulting reaction mixture was warmed
to room temperature and stirred for 12 h, then it was diluted with
water. The organic layer was separated, washed with H2O and dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography (ethyl acetate/hexane
6:96) to afford 14c as colorless thick liquid (0.198 g, 87%). [Found: C,
49.28; H, 7.66. C19H35BrO4Si2 requires C, 49.23; H, 7.61]; Rf 0.62
(Ethyl acetate/hexane 10:90); IR nmax (liquid film) 3080, 2950, 1650,
J 2.0, 8.7 Hz, 1H), 6.92 (d, J 2.0 Hz, 1H), 6.82 (d, J 8.7 Hz, 1H),
5.35e5.15 (m, 2Hþ0.6H), 5.12e5.02 (m, 0.4H) 4.55 (s, 2H),
2.25e2.00 (m, 2H), 1.85e1.55 (m, 13H), 13C NMR (75 MHz, CDCl3)
(mixture of diastereomers, some signals overlapped)
d: 155.9,
132.9, 132.1, 127.9, 127.1, 126.0, 125.9, 123.7, 117.5, 75.2, 75.1, 74.0,
73.5, 65.2, 47.1, 46.7, 44.3, 39.6, 29.8, 29.0, 25.8, 25.5, 23.3, 22.5,
17.9. HRMS (ESIþ) calcd for C17H26O4Naþ317.17233, found
317.17645.
4.2.19. (30S)-4-Hydroxy-3-(30-hydroxy-30,70-dimethyl-oct-60-enoyl)-
benzaldehyde (17). Alcohol 16 (0.050 g, 0.17 mmol) was dissolved in
DMSO (1 mL), and IBX (0.119 g, 0.424 mmol) was added. The
resulting mixture was stirred overnight at room temperature;
added with water and stirred for 5 min. The precipitate was filtered
through a Celite pad and the filtrate was extracted with ethyl ac-
etate (3ꢃ5 mL). The combined organic layer was dried over anhy-
drous Na2SO4, filtered, and concentrated. The crude was purified by
flash chromatography (ethyl acetate/hexane 35:65) to afford 17
(0.032 g, 65%) as a colorless liquid; [Found: C, 52.83; H, 8.11.
1490, 1250, 1100, 840 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 7.55 (d, J
2.0 Hz, 1H), 7.22 (dd, J 2.0, 8.4 Hz, 1H), 7.14 (d, J 8.4 Hz, 1H), 5.28 (s,
2H), 4.73 (s, 2H), 4.51 (s, 2H), 3.79 (t, 2H), 3.65 (t, J 8.5 Hz, 2H),
0.90e1.00 (m, 4H), 0.03 (s, 9H), 0.00 (s, 9H); 13C NMR (75 MHz,
CDCl3) d: 157.0, 153.6, 133.0, 128.2, 116.1, 112.8, 97.6, 94.2, 93.7, 68.3,
66.7, 65.4, 18.1, ꢀ1.3.
C17H22O4 requires C, 52.88; H, 8.17]; Rf 0.67 (ethyl acetate/petro-
20
4.2.17. (3S)-3-(tert-Butyldimethylsilyloxy)-3,7-dimethyl-1-[20-200-
(trimethylsilylethoxymethoxy)-50-200-(trimethylsilylethoxyethoxy-
methyl)-phenyl]-oct-6-en-1-ol (15). To a solution of 14c (0.190 g,
0.40 mmol) in THF (4 mL) 1.7 M t-BuLi (0.264 mL, 0.45 mmol) was
added at ꢀ78 ꢂC under argon atmosphere. Aldehyde 11 (0.117 g,
0.40 mmol) was added immediately to the above solution. After
additional 2 h at ꢀ78 ꢂC, a saturated aqueous NH4Cl solution was
added and the reaction mixture was allowed to reach room tem-
perature. The product was extracted by diethyl ether (3ꢃ10 mL).
The combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash col-
umn chromatography (diethyl ether/petroleum ether 12:88) to
afford 15 (0.175 g, 64%) as a colorless thick liquid. [Found: C, 65.21;
H, 10.25. C30H56 O5Si2 requires C, 65.17; H, 10.21]; Rf 0.47 (diethyl
ether/petroleum ether 20:80); IR nmax (liquid film) 3470, 3050,
leum ether 1:1); [
a]
ꢀ12.0 (c 0.15, CHCl3); IR nmax (liquid film)
D
3380, 3080, 2950, 1700, 1640, 1270, 750 cmꢀ1; 1H NMR (300 MHz,
CDCl3) : 12.74 (s, 1H), 9.90 (s, 1H), 8.31 (d, J 2.1 Hz, 1H), 8.08 (dd, J
d
2.1, 8.7 Hz, 1H), 7.11 (d, J 8.7 Hz, 1H), 5.12e5.04 (m, 1H), 3.29 (d, J
16.6 Hz, 1H), 3.17 (d, J 16.6 Hz, 1H), 2.18e1.98 (m, 2H), 1.75e1.55 (m,
2H), 1.64 (s, 3H), 1.60 (s, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3)
d: 207.4, 189.7, 167.6, 137.3, 133.5, 132.3, 128.3, 124.0, 119.9, 72.4,
47.4, 42.2, 27.3, 25.7, 22.8, 17.8.
4.2.20. (30S)-4-Hydroxy-3-(30-hydroxy-30,70-dimethyl-oct-60-enoyl)-
benzoic acid (S-1). To a solution of 17 (0.020 g, 0.07 mmol) in
t-BuOH (1.0 mL) and 2-methyl-2-butene (0.033 mL, 0.31 mmol)
was added a solution of NaH2PO4$H2O (0.02 g, 0.14 mmol) in water
(0.5 mL) and NaClO2 (0.019 g, 0.21 mmol). The reaction was stirred
for 3 h at room temperature. The reaction was then quenched by
dropwise addition of saturated aqueous NH4Cl solution. The
aqueous layer was extracted with ethyl acetate (3ꢃ5 mL), washed
with brine, and dried over anhydrous Na2SO4, filtered and con-
centrated. The crude product was purified by reverse phase col-
umn chromatography (water/methanol 35:65) to afford the title
compound as a white solid (0.016 g, 75%). Mp 148 ꢂC; Rf 0.65
2950, 1500, 1250, 1100, 1070, 980, 850 cmꢀ1
CDCl3) (mixture of diastereomers ratio 60:40)
;
d
1H NMR (300 MHz,
: 7.58 (s, 1H), 7.18 (d,
J 8.5 Hz, 1H), 7.06 (d, J 8.5 Hz, 0.6H), 7.02 (d, J 8.5 Hz, 0.4H),
5.40e5.35 (m, 1H), 5.21 (s, 2H), 5.20e5.15 (m, 0.6H), 5.01e4.95 (m,
0.4H), 4.74 (s, 2H), 4.56 (br s, 0.6H), 4.55 (s, 2H), 4.24 (br s, 0.4H),
3.69e3.65 (m, 4H), 2.05e1.95 (m, 2H), 1.78e1.55 (m, 16H),
0.99e0.85 (m, 13H), 0.18 (s, 6H), 0.03 (s, 9H), 0.02 (s, 9H); 13C NMR
(75 MHz, CDCl3) (mixture of diastereomers, some signals over-
(CH2Cl2/MeOH 9:1); [
a
]
25 ꢀ10.6 (c 0.15, CHCl3); {lit.,3 [
a
]
25 ꢀ6.70 (c
D
D
0.15, CHCl3); IR nmax (Nujol) 3450, 3080, 2980, 1690, 1640, 1432,
lapped)
d
:153.0, 134.0, 131.7, 131.2, 127.6, 126.4, 124.2, 124.1, 113.3,
1270, 750, 710 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d: 12.06 (s, 1H),
94.1, 92.8, 78.8, 78.4, 69.3, 66.3, 66.2, 66.0, 65.2, 47.7, 44.6, 41.0, 27.0,
26.1, 26.0, 25.7, 23.8, 23.1, 18.2, 18.1, 17.7, ꢀ1.3.
8.56 (d, J 1.7 Hz, 1H), 8.20 (dd, J 1.7, 8.9 Hz, 1H), 7.06 (d, J 8.9 Hz,
1H), 5.09 (t, J 7.2 Hz, 1H), 3.30 (d, J 16.6 Hz, 1H), 3.18 (d, J 16.6 Hz,
1H), 2.18e2.11 (m, 2H), 1.68e1.65 (m, 2H), 1.64 (s, 3H), 1.60 (s, 3H),
4.2.18. (30S)-1-(20-Hydroxy-50-hydroxymethylphenyl)-3,7-dimethyl-
oct-6-ene-1,3-diol (16). A solution of tetrabutyl ammonium fluo-
ride in THF (1 M, 3.70 mL, 3.70 mmol) was added to the SEM
protected compound 15 (0.165 g, 0.25 mmol) and the solution
was concentrated in vacuo. The resulting oil was dissolved in
1.35 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
: 207.1, 170.0, 166.8, 137.8,
133.6, 132.0, 123.7, 119.9, 119.1, 119.0, 72.2, 46.9, 41.8, 27.0, 25.5,
22.6, 17.5. {lit.,3 1H NMR (500 MHz, CDCl3)
: 12.3 (s, 1H), 8.56 (d, J
d
2.4 Hz, 1H, H-2), 8.11 (dd, J 2.4, 8.9 Hz, 1H, H-6), 6.93 (d, J 8.9 Hz,
1H, H-5), 4.98 (t, J 7.2 Hz, 1H, H-60), 2.77 (d, J 16.5 Hz, 1H, H-20a),
2.64 (d, J 16.5 Hz, 1H, H-20b), 2.03 (m, 2H, H-50), 1.70 (m, 2H, H-40),
1.58 (br s, 3H, H-80), 1.50 (br s, 3H, H-90); 1.37 (s, 3H, H-100) 13C
ꢁ
anhydrous DMPU (1.5 mL). Powdered activated 4 A molecular
sieves were added (ca. 0.160 g), and the resultant suspension was
heated to 80 ꢂC for 7 h. Then the reaction mixture was cooled to
NMR (125 MHz, CDCl3) d: 191.5, 170.6, 163.7, 137.3, 132.5, 129.9,

6306
J.N. Chakor et al. / Tetrahedron 67 (2011) 6300e6307
122.9, 122.1, 119.9, 118.8,ꢀ82.3, 47.2, 39.3, 25.6, 22.2 17.5}. HRMS
17.1 Hz, 1H), 3.07 (d, J 17.1 Hz, 1H), 2.18e1.98 (m, 2H), 1.71e1.58 (m,
(ESIꢀ) calcd for C17H21O5 305.13945, found 305.13967.
2H), 1.65 (s, 3H), 1.61 (s, 3H), 1.34 (s, 3H). 13C NMR (75 MHz, CDCl3)
d: 199.6, 172.5, 166.3, 136.0, 132.3, 132.1, 132.0, 129.3, 124.2, 118.5,
4.2.21. 5-(10,30-Dihydroxy-30,70-dimethyl-oct-60-enyl)-2-hydroxy-
benzoic acid methyl ester (19). Under argon atmosphere, LDA
(1.8 M in THF/heptane, 21.4 mL, 0.038 mol) was added to solution
of 5-acetyl-2-hydroxybenzoic acid methyl ester (3.000 g,
0.015 mol) in dry THF (100 mL) at ꢀ78 ꢂC. The resulting solution
was stirred for 30 min at ꢀ78 ꢂC, followed by addition of 6-
methyl-5-hepten-2-one (2.921 g, 0.023 mol). Stirring was contin-
ued for 4 h at ꢀ78 ꢂC, then the reaction was quenched with sat-
urated aqueous NH4Cl. The reaction mixture was allowed to reach
room temperature. The layers were separated and the aqueous
phase was extracted with diethyl ether (3ꢃ80 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash column chroma-
tography (ethyl acetate/hexane 12:88) to afford 2-Hydroxy-5-(30-
hydroxy-30,70-dimethyl-oct-60-enoyl)-benzoic acid methyl ester as
a sticky solid (4.911 g, 59%); [Found: C, 67.45; H, 7.58. C18H24O5
requires C, 67.48; H, 7.55]; Rf 0.7 (ethyl acetate/hexane 1:1); IR
72.8, 46.5, 42.0, 27.0, 25.7, 22.9, 17.7. HRMS (ESIꢀ) calcd for
C17H21O5ꢀ 305.13945, found 305.13911.
4.2.23. E,Z 3-(30,70-Dimethyl-octa-20,60-dienoyl)-4-hydroxybenzoic
acid methyl ester (21). To an ice-cooled solution of 4 (0.425 g,
1.326 mmol) and TEA (0.424 g, 0.580 mL, 4.190 mmol) in dry DCM
(5 mL) thionyl chloride (0.289 g, 0.178 mL, 2.430 mmol) was added
dropwise during 30 min under a nitrogen atmosphere. The mixture
was stirred for 2 h, poured onto crushed ice and extracted with
ethyl acetate (3ꢃ20 mL). The combined organic layers were washed
with cold 1 M HCl, a saturated NaHCO3 solution and brine, then it
was dried and concentrated under vacuum. The residue was puri-
fied by flash column chromatography (ethyl acetate/hexane 4:96)
to afford 21 as a sticky solid (0.318 g, 80%); [Found: C, 71.52; H, 7.28.
C18H22O4 requires C, 71.50; H, 7.33]; Rf 0.51; 0.42 (ethyl acetate/
hexane 1:9). IR nmax (liquid film) 3080, 2980, 1720, 1635,1580, 1485,
1440, 1370, 1270, 1220, 750, 710 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
nmax (Nujol) 3420, 3045, 2965, 2220, 1680, 1440, 1380, 1270 cmꢀ1
;
(mixture of diastereomers 50:50) : 13.35 (s, 1H), 8.52 (d, J 1.7 Hz,
d
1H NMR (300 MHz, CDCl3)
d
: 11.28 (s, 1H), 8.47 (d, J 1.7 Hz, 1H),
0.5H), 8.50 (d, J 1.7 Hz, 0.5H), 8.09 (dd, J 1.7, 8.9 Hz, 1H), 6.99 (d, J
8.9 Hz, 1H), 5.20e5.05 (m, 1H), 3.91 (s, 3H), 2.72e2.61 (m, 1H),
2.39e2.20 (m, 3H), 2.21 (s, 1.5H), 2.08 (s, 1.5H), 1.71 (s, 3H), 1.64 (s,
3H). 13C NMR (75 MHz, CDCl3) (mixture of diastereomers, some
signals overlapped) d: 198.2, 195.9, 177.2, 177.1, 167.1, 166.3, 163.6,
143.2, 136.6, 136.2,133.1,132.3, 122.8, 120.7,120.2,119.6,119.0,118.7,
52.2, 42.0, 31.2, 29.8, 26.3, 25.8, 20.4, 17.9.
8.08 (dd, J 1.7, 8.9 Hz, 1H), 7.05 (d, J 8.9 Hz, 1H), 5.14e5.04 (m, 1H),
4.01 (s, 3H), 3.13 (d, J 17.1 Hz, 1H), 3.03 (d, J 17.1 Hz, 1H), 2.18e1.99
(m, 2H), 1.71e1.60 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H), 1.30 (s, 3H).
The above compound (0.500 g, 1.560 mmol) was dissolved in
MeOH (12 mL) and then cooled to
0
ꢂC NaBH4 (0.171 g,
4.535 mmol) was added portionwise and the reaction was warmed
to room temperature. After 2 h MeOH was evaporated under
vacuo. The residue was diluted with ethyl acetate, followed by
addition of a saturated aqueous NH4Cl solution. The organic layer
was separated, dried over anhydrous Na2SO4, filtered, and con-
centrated. The residue was purified by flash column chromatog-
raphy (ethyl acetate/hexane 15:85) to afford 19 as a sticky solid
(0.350 g, 70%); [Found: C, 67.04; H, 8.10. C18H26O5 requires C,
67.06; H, 8.13]; Rf 0.5 (ethyl acetate/hexane 1:1). 1H NMR
4.2.24. 2-Methyl-2-(40-methyl-pent-30-enyl)-4-oxo-chroman-6-
carboxylic acid (22). Compound 21 (0.058 g, 0.192 mmol) was
added with NaOH 2.5 N in H2O (1.5 mL). The reaction mixture was
stirred overnight at room temperature, then it was acidified to pH 3
by addition of an ice-cooled solution of 2 N HCl. The aqueous phase
was extracted with ethyl acetate (3ꢃ5 mL). The collected organic
extracts were dried and evaporated to give a pale yellow solid
(0.054 g, quantitative). Mp 128e131 ꢂC; [Found: C, 70.77; H, 7.02.
C17H20O4 requires C, 70.81; H, 6.99]; Rf 0.78 (ethyl acetate/hexane
75:25). IR nmax (Nujol) 3350, 3040, 2850, 1695, 1620, 1420, 1280,
(300 MHz, CDCl3) (mixture of diastereomers ratio 60:40) d: 10.72
(s, 0.4H), 10.69 (s, 0.6H), 7.85 (d, J 1.7 Hz, 0.6H), 7.82 (d, J 1.7 Hz,
0.4H), 7.45 (dd, J 1.7, 8.9 Hz, 1H), 6.96 (d, J 8.9 Hz, 1H), 5.21e4.96
(m, 2H), 3.95 (s, 3H), 2.15e1.99 (m, 2H), 2.20e1.20 (m, 15H).
1140, 750 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 12.76 (s, 1H), 8.64 (d, J
2.1 Hz, 1H), 8.18 (dd, J 2.1, 8.7 Hz, 1H), 7.01 (d, J 8.7 Hz, 1H), 5.06 (t, J
7.2 Hz, 1H), 2.85 (d, J 16.3 Hz, 1H), 2.71 (d, J 16.3 Hz, 1H), 2.18e2.00
(m, 2H), 1.85e1.61 (m, 2H), 1.66 (s, 3H), 1.57 (s, 3H), 1.44 (s, 3H). 13C
4.2.22. 2-Hydroxy-5-(30-hydroxy-30,70-dimethyl-oct-60-enoyl)-ben-
zoic acid (20). Compound 19 (0.350 g,1.080 mmol) was dissolved in
THF/H2O (3:1), then LiOH$H2O (0.136 g, 3.241 mmol) was added. The
resulting reaction mixture was refluxed for 4 h and then cooled to
room temperature. THF was evaporated and the remaining aqueous
layer was cooled to 0 ꢂC and acidified to pH 3 by 2 N HCl. The
resulting precipitate was taken in ethyl acetate. The organic layer
was dried on anhydrous Na2SO4 and concentrated to afford 5-(10,30-
dihydroxy-30,70-dimethyl-oct-60-enyl)-2-hydroxy-benzoic acid as
a semisolidproduct (0.320 g, 95%). Rf 0.25 (ethylacetate/hexane 1:1).
This crude product was used without any further purification.
The above acid (0.050 g, 0.162 mmol) dissolved in DMSO (1 mL)
was added dropwise at 0 ꢂC, under argon atmosphere, to a stirred
solution of IBX (0.068 g, 0.243 mmol) in DMSO (1 mL). The reaction
mixture was warmed to room temperature and stirred for 3 h, then
it was filtered through a pad of Celite. The residue was washed with
ethyl acetate. The resulting filtrate and washings were combined
and dried over anhydrous Na2SO4, filtered, and concentrated. The
crude product was purified by reverse phase column chromatog-
raphy (water/methanol 60:40) to afford rac-20 as a faint brownish
solid (0.030 g, 61%). Mp 97 ꢂC; [Found: C, 66.61; H, 7.26. C17H22O5
requires C, 66.65; H, 7.24]; Rf 0.6 (CH2Cl2/MeOH 9:1); IR nmax (Nujol)
NMR (75 MHz, CDCl3) d: 191.6, 171.1, 163.9, 137.4, 132.7, 130.1, 123.0,
122.0,120.0,118.9, 82.5, 47.3, 39.4, 25.7, 24.1, 22.3, 17.7. HRMS (ESIꢀ)
calcd for C17H19O4ꢀ 287.12888, found 287.12859.
Acknowledgements
Financial support from University of Milan is gratefully ac-
knowledged. We thank Mr. Sachin Aiwale for the synthesis of
compounds 19 and 20.
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