Stereoselective total synthesis of cananginones (D-I) using Ireland-Claisen rearrangement as a key step

Article abstract of DOI:10.1016/j.tet.2014.03.028

A strategy for stereoselective total synthesis of α-substituted γ-hydroxymethyl γ-butyrolactone containing bioactive natural products cananginones (D-I) has been developed using cheap and commercially available d-mannitol as a chiral pool. The Ireland-Cla

Full text of DOI:10.1016/j.tet.2014.03.028

Tetrahedron xxx (2014) 1e14
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Stereoselective total synthesis of cananginones (DeI) using
IrelandeClaisen rearrangement as a key step
*
Tapan Kumar Kuilya, Shamba Chatterjee, Rajib Kumar Goswami
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A strategy for stereoselective total synthesis of
a-substituted g-hydroxymethyl g-butyrolactone con-
Received 28 January 2014
Received in revised form 6 March 2014
Accepted 11 March 2014
Available online xxx
taining bioactive natural products cananginones (DeI) has been developed using cheap and commer-
cially available -mannitol as a chiral pool. The IrelandeClaisen rearrangement is utilized as a key step to
generate the -substituted chiral center of the core lactone moiety, while the elongation of aliphatic side
chain by different C-8 hydrocarbon groups have been achieved by alkylation, CadioteChodkiewicz, and
Sonogashira reactions.
D
a
Keywords:
Cananginones
Ó 2014 Elsevier Ltd. All rights reserved.
IrelandeClaisen rearrangement
CadioteChodkiewicz coupling
Sonogashira reaction
Lactonization
1. Introduction
trans-orientation (Fig. 1). Most of these compounds show cyto-
toxicity to human carcinoma cell lines KB, MCF7, and NCI-H187 in
micromolar range. In addition some of these members exhibit
moderate antimalarial and antifungal activities. Their potential as
therapeutic agents as well as the interesting architectural feature
Functionalized chiral
g
-butyrolactone1 is an important subunit
of biologically active compounds. Examples of natural products
having such g
-butyrolactone moiety include cananginones (AeI)2
(1e9), goniothalamusin3 (10), saccopetrin A4 (11), debilisones
(A-F)5 (12e17), and oropheolide6 (18), which belong to a family of
linear acetogenins7 (Fig. 1). The common skeleton of these type
(substituted chiral g-butyrolactone containing polyunsaturated
skeleton) of this class of linear acetogenins has rendered them at-
tractive targets for the synthetic organic chemistry community.8
natural products is most often characterized by
branched unsaturated fatty acid chain terminated with a saturated
-hydroxymethyl -butyrolactone. The substituted -butyr-
a
-substituted un-
A
common and very obvious approach8 to prepare this
a
-substituted
stereoselective alkylation at the enolizable
-lactone moiety by long chain aliphatic halide (Scheme 1). The
g
-hydroxymethyl
g
-butyrolactone skeleton involves
g
g
g
a
-position of the core
olactone groups in this class of natural products remains either in
cis- or trans-configuration. Cananginones (AeI) (1e9) were first
discovered by Kanokmedhakul and co-workers2 from crude hexane
extract of the stem bark of traditional Thai medicinal tree Cananga
g
inherent chirality derived from the substituted parent lactone
moiety usually plays a key role for this type diastereoselectivity.
Barua and co-workers8b adopted this strategy proficiently to pre-
pare debilisone5 C; a member of the same family (14) (Fig. 1). In
latifolia. Stereochemically, the embedded
a-substituted long ali-
phatic side chain and -hydroxymethyl group on lactone ring are in
g
debilisone C both
orientation. However, this synthetic route does not allow synthe-
sis of molecules (1e11, 18) where both the - and -substituents on
lactone ring are in trans-configuration. The major drawback8b of
this strategy is that the synthesis of trans- -substituted
-butyrolactone moiety offers low yield, due to the incomplete
a- and g-substituents specifically are in a cis-
a
g
Abbreviations: TBAI, tetrabutyl ammonium iodide; TMSI, trimethyl sulphonium
iodide; DCC, N,N0-dicyclohexylcarbodiimide; DMAP, 4-dimethylaminopyridine;
LiHMDS, lithium bis(trimethylsilyl)amide; DMPU, N,N0-dimethylpropylene urea;
HMPA, hexamethylphosphoramide; CH2N2, diazomethane; CSA, camphorsulfonic
acid; NaHMDS, sodium bis(trimethylsilyl)amide; KHMDS, potassium bis(-
trimethylsilyl)amide; LDA, lithium diisopropylamide; DIBAL-H, diisobutylalumi-
num hydride; TMS-acetylene, ethynyltrimethylsilane; TBAF, tetrabutyl ammonium
fluoride; DMP, DesseMartin periodinane.
a,g
g
consumption or decomposition of starting g-lactone and the poor
diastereoselectivity, due to inefficient chiral induction exerted by
remote -substituent of parent lactone moiety.
Thus the challenge is in the development of an effective route
for the synthesis of trans-substituted -butyrolactone skeleton. We
sought to pursue a very flexible strategy for the stereoselective
g
g
* Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805; e-mail
address: ocrkg@iacs.res.in (R.K. Goswami).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.028
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T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
Fig. 1. Natural products with a-substituted g-hydroxymethyl g-lactone moiety.
Scheme 1. Known strategy for synthesis of a-substituted g-hydroxymethyl g-butyrolactone.
synthesis of
g
-butyrolactone containing bioactive natural products
IrelandeClaisen rearrangement. Compound 26 then could be pre-
pared by esterification of the acid 27 using the allylic alcohol 28.
Both the acid 27 and the allylic alcohol 28 could be synthesized
using the IrelandeClaisen rearrangement9 as a key step. The ste-
reochemical outcome of this rearrangement can be ascertained by
the predictable relay of chirality of the allylic center (present in the
from a single chiral pool;
G) (6 and 7), we planned for a little alteration of above reaction
sequences to preclude epimerization of the -alkyl center during
D-mannitol. For the cananginones (F and
allylester surrogate) in an acyclic system through
a well-
understood transition state structure.9,10 Our continual interest11
in the asymmetric synthesis of bioactive natural products promp-
ted us to embark upon the total synthesis of cananginones. To the
best of our knowledge, total synthesis of any member of canangi-
nones has not been reported till the date. Herein we describe the
total synthesis of cananginones (DeI) for the first time (4e9). We
believe this strategy can be used for successful stereoselective
a
installation of the C-8 hydrocarbon part under basic conditions
(Scheme 2). Both the cananginone F (6) and its methylated ana-
logue cananginone G (7) could be prepared from the ester 29 by
acid catalyzed g-lactonization. The ester 29 in turn could be derived
from the alkyne 24 by alkylation with the alkyl iodide 30.
Our synthetic endeavor began with the preparation of known
acid 27 and allylic alcohol 28 from commercially available, and
synthesis of a large number of natural products having the trans-
a-
substituted -hydroxymethyl -butyrolactone core.
g
g
cheap,
D
-mannitol (Scheme 3). The known
a,b-unsaturated ester
31,14 derived from
D
-mannitol, was used to synthesize the epoxide
2. Results and discussion
32 in four steps. First, the ester (31) was reduced to a saturated
alcohol14b in the presence of NaBH4/LiCl, which was subsequently
benzylated with BnBr/NaH to get the corresponding benzyl ether.15
Then the resultant benzyl ether was treated with 80% AcOH/H2O to
deprotect the acetonide and finally reacted with tosyl-imidazole in
the presence of NaH16 to afford the known epoxide 3215,17a in good
overall yield. The epoxide 32 was then transformed to the known
allylic alcohol 28 by Me3SI/nBuLi following the literature pro-
cedure.17 The required acid 2718 was synthesized from the known
ester 31 in two steps: hydrogenation followed by saponification in
the presence of LiOH.
Retrosynthetic analysis of cananginones (DeI) is outlined in
Scheme 2. We envisaged that the cananginones (D, E, H, I) (4, 5, 8, 9)
could be derived from the g-lactones 22 and 23 by coupling it with
the corresponding C-8 hydrocarbon counterparts (19e21) using
CadioteChodkiewicz reaction12 or Sonogashira reaction.13 The
lactones 22 and 23 could be prepared from the intermediates 24
and 25, respectively, involving regioselective g-lactonization as one
of the key steps. The construction of the alkynes 24 and 25 could be
achieved from the common intermediate 26 utilizing the
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T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
3
Scheme 2. Retrosynthetic analysis of cananginones (DeI).
enolizable a-proton of the ester functionality. We varied the sol-
vent polarity as well as the nature of amide bases20 during our
optimization process. The rearrangement did not proceed with
NaHMDS in THF solvent even after 6 h at ꢀ78 ꢁC (Table 1, entry 1).
But the same base was effective in the presence of 20% polar aprotic
solvents (HMPA or DMPU) dissolved in THF. The use of dipolar
HMPA or DMPU solvent assisted the desired rearranged product
formation almost in identical diastereoselectivity (w6.6:1) but
with different yields (Table 1, entries 2 and 3). The presence of
a dipolar solvent seems to be essential for effective enolization.9c,21
Because the polar solvent helps to disintegrate the base from its
original oligomeric form (via solvation) and makes the active in-
gredient, the amidate anion, more accessible for the enolization
process.9c Enolization using KHMDS in THF/HMPA (Table 1, entry 4)
and THF/DMPU (Table 1, entry 5) was also separately attempted.
The changes of metal counter ion from sodium to potassium re-
duced the yield by a substantial amount in our case. It is necessary
to note that the choice of HMPA or DMPU in case of NaHMDS did
not result in such a big difference in diastereoselectivity. These
differences in results are consistent with the established Ireland
cyclic transition state model (Fig. 2).9b According to this model, the
abstraction of enolizable proton by amide base takes place through
a six-member chair like transition state (TS-I or TS-II). TS-I leads to
(E)-silyl ketene acetal via (Z)-enolate formation whereas TS-II fa-
cilitates (Z)-silyl ketene acetal through (E)-enolate formation
(Fig. 2).
Scheme 3. Synthesis of acid 27 and allylic alcohol 28. Reagents and conditions: (a) (i)
NaBH4/LiCl (1:1), THF/MeOH (1:1), 0 ꢁC to rt, 48 h, 78%; (ii) NaH, BnBr, TBAI, 0 ꢁC to rt,
3 h, 87%; (iii) 80% AcOH in H2O, 12 h, rt, 91%; (iv) tosyl-imidazole, NaH, THF, 0 ꢁC,
n
45 min, 75%; (b) Me3SI, BuLi, THF, ꢀ40 ꢁC to rt, 2 h, 85%; (c) (i) H2, Pd/C (10%), EtOAc
3 h, rt, quantitative; (ii) LiOH, MeOH: H2O (3:1), 0 ꢁC to rt, 14 h, 90%.
The synthesis of crucial a-substituted esters 33 & 33a is illus-
trated in Scheme 4. The acid 27 was esterified with the allylic al-
cohol 28 under Steglich condition19 (DCC/DMAP) to afford
compound 26 in very good yield. The stage was thus set to carry out
the IrelandeClaisen rearrangement to install the crucial
a-sub-
stituent in the lactone domain in a stereoselective manner. The
diastereoselectivity of this rearrangement is mainly controlled by
either the geometry of silyl ketene acetals (Z- or E-isomer) or the
transition structure (chair or boat).9,10 The selective formation of
the silyl ketene acetals or the adopted preference of the transition
geometry are closely dependent on several parameters like solvent
polarity, temperature, nature of the base, ester to base ratio, and
structure of substrates.9c,j Thus several experimental parameters
contribute to selectivity and yield of IrelandeClaisen rearrange-
ment reaction. Logically rigorous optimization of conditions is es-
sential to obtain the best yield and diastereoselectivity of the
desired product. Our efforts toward standardization of the Ire-
landeClaisen rearrangement on ester 26 are summarized in Table 1.
We had initially kept the ester to base ratio and reaction temper-
ature invariable during the optimization process. A higher base to
ester ratio of 4:1 was used to ensure the deprotonation of the
The metal ion in this transition state is coordinated by both the
carbonyl oxygen and the base nitrogen. The changes in size or in
degree of solvation of metal ion or both could and possibly would
affect the geometry of the transition structure.22 This would tune
the extent of interaction of metal ion with the reacting ester and the
base. Consequently this would exert an effect in the kinetics of
deprotonation22 and, subsequently, in the selectivity of TS-I versus
TS-II. Consequently the yield and diastereoselectivity of this rear-
rangement differ with variation in the base used and the polarity of
medium. Moreover, the degree of solvation of metal ion by dipolar
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4
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
Scheme 4. Synthesis of
a
-substituted esters 33 and 33a. Reagents and conditions: (a) 27, DCC, DMAP, CH2Cl2, 0 ꢁC to rt, 20 h, 78%; (b) (i) LiHMDS, TBSCl, THF/DMPU (4:1), ꢀ78 ꢁC,
4.5 h; (ii) CH2N2, Et2O, 0 ꢁC, 10 min, overall 85% after two steps [dr w12:1]; (c) CSA, MeOH, 0 ꢁC to rt, 3 h, 90% (combined); (d) H2, Pd/C (10%), EtOH, 4 h, rt, (90e92)%.
Table 1
solvents like HMPA or DMPU varies because of their effective
abundance in reaction medium at low temperature and also due to
Optimization of reaction conditions for IrelandeClaisen rearrangement of ester 26
Entry Base(equiv)/TBSCl (equiv) Solvents
Temp Time Yield dra
the differences in their steric requirements. Bulkier HMPA in THF at
(ꢁC) (h)
(%)
ꢀ78 ꢁC is heterogeneous due to its higher melting temperature (ca.
7
ꢁC) whereas the relatively smaller DMPU under the same con-
1
2
3
4
5
6
7
NaHMDS (4.0)/TBSCl (6.0) THF
ꢀ78
6
4
NRb
55
d
NaHMDS (4.0)/TBSCl (6.0) THF/HMPA (4:1) ꢀ78
NaHMDS (4.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
KHMDS (4.0)/TBSCl (6.0) THF/HMPA (4:1) ꢀ78
KHMDS (4.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
6.7:1
6.6:1
3.6:1
5.5:1
1:2
ditions is homogeneous due its low melting temperature (ca.
ꢀ20 ꢁC).9c It is likely that in the case of sodium, due to its smaller
size and tight association in transition state, the solvation of metal
ion either with HMPA or with DMPU has no substantial effect on
the fate of the reaction in our case. This is why we did not observe
any noticeable difference in the distribution of the products. But in
the case of KHMDS, the effect of polarity of solvent is prominent.
Due to the larger size of potassium ion, the chair like transition state
may not be very compact, which results an overall drop of dia-
stereoselectivity compared to NaHMDS. The extent of solvation of
potassium with DMPU is most likely better than the less abundant
(due to insolubility) and bulkier HMPA at low temperatures. As the
degree of solvation increases, the interaction of metal ion with base
and ester carbonyl decreases. As a result the severe 1,3-syn diaxial
5.5 66
6
5
18
30
61
48
LDA (4.0)/TBSCl (6.0)
LDA (4.0)/TBSCl (6.0)
THF/HMPA (4:1) ꢀ78 10
THF/HMPA (4:1) ꢀ78
5
1.3:1
to rt
8
9
10
11
LDA (4.0)/TBSCl (6.0)
THF/DMPU (4:1) ꢀ78 14
56
23
3:1
1:1.5
12:1
7:1
LiHMDS (4.0)/TBSCl (6.0) THF/HMPA (4:1) ꢀ78
LiHMDS (4.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
LiHMDS (4.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
to rt
9
4.5 85
3
4
70
67
12
LiHMDS (4.0)/TBSCl (6.0) THF/DMPU
(11:9)
ꢀ78
7.7:1
13
14
15
LiHMDS (1.5)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
LiHMDS (3.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
LiHMDS (6.0)/TBSCl (6.0) THF/DMPU (4:1) ꢀ78
8
6
4
61
74
75
5.9:1
7.2:1
8:1
a
strain, which exists in the TS-II is diminished whereas the TS-I still
Diastereomeric ratio of inseparable compounds 33 and 33a was determined
9b,c
from the integration of singlet methyl peaks of ester groups by 1H NMR.
suffer from A1,3-strain
.
Thus the population of TS-II definitely
b
NR¼no reaction.
is higher in the case of DMPU when compared with HMPA.
Fig. 2. Cyclic transition model for enolization of carbonyl ester with amide bases.
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T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
5
This provides a plausible mechanism for the observed differences in
the diastereoselectivity obtained using KHMDS in THF/DMPU (dr
w5.5:1, Table 1, entry 5) and in THF/HMPA (dr w3.6:1, Table 1, entry
4) solvent systems.
seen by NOE experiment. This thereby confirmed the stereo-
chemistry of major product from the IrelandeClaisen rearrange-
ment step.
We used the route outlined in Scheme 5 to construct the key
intermediates 22, 23, and 24. The mixture of compounds 33 and
33a was next reduced by DIBAL-H to get chromatographically
separable alcohols 36 as the major and 36a as the minor isomer. The
free alcohol of the required product 36 was masked as a TBS-ether
and subsequently hydrogenated to get the alcohol 37 in quantita-
tive yield. The alcohol was iodinated by Ph3P/I2 in the presence of
imidazole to get an iodide, which was next reacted with TMS-
acetylene in the presence of nBuLi to afford the TMS deprotected
alkyne 25 in situ in 74e75% overall yield in two steps. A negligible
amount of the terminal alkene, generated from the precursor io-
dide by elimination process, was also observed as a byproduct in
this reaction and was discarded during purification. The alkyne 25
was then converted to 23 in five steps. TBS was first deprotected by
TBAF to get an alcohol. Then the corresponding alcohol was oxi-
dized sequential by DMP and Pinnick oxidation23 conditions to get
an acid. The resulting acid was next esterified with diazomethane
and finally treated with CSA in MeOH to result in the lactone 23 as
a single regioisomer in very good overall yield. On the other hand,
we have proceeded from the same alcohol 37 to synthesize 38 in
three steps. A one pot Swern oxidation followed by concomitant
Wittig olefination using (carbethoxymethylene) triphenylphos-
We were interested to see the effect of smallest metal counter
ion containing bases like LDA or LiHMDS in this rearrangement. The
ester 26 was treated with LDA in the presence of THF/HMPA (Table
1, enties 6 and 7) or THF/DMPU (Table 1, entry 8) as solvents. The
yields were moderate but the diastereoselectivity was very low in
both the cases. Although the diastereoselectivity is poor, it is in-
teresting to notice that in the presence of weakly coordinating
bulky solvents, HMPA at ꢀ78 ꢁC, (Table 1, entry 6) the undesired
product is obtained in higher yields than the desired one (dr w1:2)
whereas in the presence of DMPU (Table 1, entry 8) the observed
diastereoselectivity favors the formation of the desired isomer (dr
w3:1). According to Ireland model (Fig. 2),9b the TS-I is likely to be
marginally favored in HPMA whereas TS-II is favored in DMPU. The
elevation of temperature from ꢀ78 ꢁC to room temperature re-
duced the selectivity significantly (dr w1:1) (Table 1, entry 7) as
may be expected. The use of LiHMDS in THF/HMPA solvent system
provided the rearranged products in very poor yield and diaster-
eoselectivity (Table 1, entry 9) similar to LDA in THF/HMPA (entry
6). Remarkably the variation of diisopropylamide to hexame-
thyldisilazide bases in THF/DMPU affected both the yield and dia-
stereoselectivity favoring the desired isomer (dr w12:1, Table 1,
entry 10). Li metal ion solvated with DMPU is likely to achieve the
optimal size, which is required to bind with the six-member tran-
sition state (Fig. 2) most tightly. More importantly as silicon is
larger than carbon in size, the NeSi bond in disilazide base is ex-
pected to be longer than NeC bond in diisopropylamide base.
Consequently the extent of 1,3-syn diaxial interaction in TS-II would
be less in LiHMDS when compared to LDA in same THF/DMPU
solvent system. This probably accounts the differences in observed
results. The rise of temperature from ꢀ78 ꢁC to room temperature
diminished the yield as well as the diastereoselectivity (Table 1,
entry 11).
phorane to get a a,b-unsaturated ester, which was reduced further
by NaBH4/LiCl combination to obtain the higher homologue 38 in
78e80% overall yield (Scheme 5). Utilizing the similar chemistry
described above, the alcohol 38 was iodinated and subsequently
reacted with TMS-acetylene/nBuLi to produce the alkyne 24, which
was finally converted to the lactone 22 in five steps with very good
overall yield (Scheme 5).
Having secured access to the lactone domains, we proceeded to
complete the synthesis of cananginones (D, E, H, I) (4, 5, 8, 9) as
summarized in Scheme 6. The key alkyne 22 was coupled sepa-
rately with bromo alkyne 1924 and vinyl iodide 2025 by Cadiote-
Chodkiewicz reaction12 and Sonogashira reaction13 to achieve
compound 39 and cananginone E (5), respectively, in good to
moderate yields. Methylation26 of free primary alcohol of lactone
39 by Me3OBF4 in the presence of a proton sponge successfully
facilitated the total synthesis of cananginone D (4). The physical
and spectroscopic data of the synthesized cananginone D were in
accordance with the literature data of the isolated natural product.2
Similarly another key alkyne 23 was subjected separately to
Sonogashira coupling with the vinyl iodides 2025 and 2127 to syn-
thesize successfully proposed cananginones H (8) and I (9) in good
yields, respectively. The spectral data (1H, 13C NMR, HRMS) and
optical rotations of synthesized cananginones E (5), H (8), and I
(9),28 measured immediately after their purification (vide infra), are
found to be in close agreement with the reported values of these
isolated natural products.2
We were next keen to see whether variations9c in the con-
centrations of DMPU used in reaction mixture or the ratio of
ester to base (LiHMDS) could improve the yield and diaster-
eoselectivity further. For this purpose, we carried out the rear-
rangement reaction by LiHMDS in the presence of 45% DMPU in
THF (Table 1, entry 12). But both the yield and diaster-
eoselectivity reduced substantially when compared to entry 10.
The use of more (Table 1, entry 15) or less amount (Table 1, en-
tries 13 and 14) of base compared to entry 10 was not fruitful to
improve either the yield or the diastereoselectivity. In our case
LiHMDS in THF/DMPU solvent system at low temperature (Table
1, entry 10) was the optimal condition for the rearrangement to
yield the desired isomer.
Exposure of ester 26 to LiHMDS/TBSCl in THF/DMPU (4:1) sol-
vent system at ꢀ78 ꢁC affected the expected IrelandeClaisen
rearrangement to deliver a pair of inseparable diastereomers 33
and 33a (dr w12:1) after methyl ester formation with diazo-
methane in 85% total yield. To reassure the stereochemical outcome
of this rearrangement the mixture of diastereomers 33 and 33a was
It is noteworthy to mention that the cis-enyne system of can-
anginones I (9) is susceptible to isomerization and it equilibrates
with the trans-enyne slowly under ambient conditions.29 The
isomerization of cananginones I (9) could be clearly understood
from the 1H NMR spectra recorded at different time intervals
(Fig. 3). The gradual increase of intensity of the new peaks at
further transformed to g-lactones 34 and 34a by CSA/MeOH and
separated easily by silica gel column chromatography. The stereo-
chemical assignments of both compounds 34 and 34a by extensive
1H NMR were unsuccessful due to overlapping of (H-9)b and (H-
3)allyl protons. Both compounds 34 and 34a were hydrogenated
separately to get compounds 35 and 35a, respectively. The NOESY
of both compounds were recorded and the characteristic correla-
tion between (H-9)b/(H-3) (Scheme 4) protons was observed only
in the major compound 35. The speculated correlations among the
protons (H-9)a/(H-11)2 (1.18% & 0.64%), (H-9)a/(H-2) (1.47%), (H-9)b/
(H-10) (2.63%), and (H-9)b/(H-3) (1.86%) in compound 35 were also
d
6.03 ppm at the expense of peaks at
(9), indicates the cis to trans isomerization of the olefin proton (H-
12, Fig. 1)
to the alkyne group. The downfield shift5,30 and large
d 5.78 ppm for cananginone I
b
coupling constant (dt, J¼15.8, 7.0 Hz) of H-12 proton support this
isomerization. The observed ratio of cis-enyne of cananginone I
versus its trans-enyne form was around 1.0:0.6 at equilibrium. On
the contrary the cananginones E (5) and H (8), with very similar cis-
enyne moiety of cananginone I (9), did not exhibit any noticeable
isomerization within days.31
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6
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
Scheme 5. Synthesis of Alkynes 22, 23, and 24. Reagents and conditions: (a) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 15 min, 92% (combined); (b) (i) TBSCl, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt, 1.5 h,
n
quantitative; (ii) H2, Pd/C (10%), EtOAc, rt, 4.5 h, quantitative; (c) (i) I2, Ph3P, imidazole, toluene, 0 ꢁC to rt, 3.5 h; (ii) TMS-acetylene, BuLi, THF: HMPA (5:1), ꢀ78 ꢁC to rt, 12 h,
(74e75)% in two steps; (d) (i) TBAF, THF, 0 ꢁC to rt, 6 h; (ii) DMP, NaHCO3, CH2Cl2, 0 ꢁC to rt, 2.5 h; (iii) NaClO2, NaH2PO4$2H2O, tert-butanol/2-methyl-2-butene (2:1), 0 ꢁC to rt, 5 h;
(iv) CH2N2, Et2O, 0 ꢁC, 10 min; (v) CSA, MeOH, 0 ꢁC to rt, 3 h (78e80)% overall yield in five steps; (e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to 0 ꢁC, 2 h; (ii) Ph3P]CHCOOEt, CH2Cl2, rt,
36 h; (iii) NaBH4/LiCl (1:1), THF/MeOH (1:1), 0 ꢁC to rt, 48 h, 80% in three steps.
Scheme 6. Completion of cananginones D (4), E (5), H (8), and I (9). Reagents and conditions: (a) 19, CuBr, Et3N, NH2OH$HCl, rt, 12 h, 72%; (b) Me3OBF4, proton sponge, CH2Cl2, 0 ꢁ
to rt, 42 h, 60%; (c) 20, Pd[(PPh3)2Cl2], CuI, Et3N, rt, 20 h, (65e68)%; (d) 21, Pd[(PPh3)2Cl2], CuI, Et3N, rt, 20 h, 70%.
C
For successful construction of cananginones F (6) and G (7), we
followed a slightly modified Scheme 7, because the installation of
C-8 hydrocarbon part had to be carried out under basic conditions.
The key alkyne 24 was subjected to alkylation with iodide 3032 in
the presence of nBuLi to achieve compound 40 in very good yield.
Rest of the steps was similar to the chemistry aforesaid in Schemes
5 and 6. Compound 40 was subjected to a three-step reaction
protocol: The alcohol was oxidized sequentially with DMP oxida-
tion followed by Pinnick oxidation23 to get an acid, which was next
treated with diazomethane to afford the methyl ester 29 in 88%
overall yield. The ester was then lactonized by CSA in MeOH to get
regioselectively cananginone F (6) in excellent yield. Methylation26
of free hydroxyl of cananginone F (6) by Me3OBF4 in the presence of
proton sponge facilitated finally cananginone G (7) in 65% yield. The
spectral data and optical rotation of synthesized cananginones F (6)
and G (7) are in good agreement with the reported values2 of
natural cananginones F and G.
3. Conclusions
In summary, a very flexible and highly stereoselective strategy
has been developed to efficiently access trans- -substituted
hydroxymethyl -butyrolactone containing bioactive natural
products cananginones (DeI) from -mannitol using Ire-
a
g-
g
D
landeClaisen as a key step. The various C-8 aliphatic parts have
been assembled with the key alkyne intermediates (22, 23, 24) to
construct the full length hydrocarbon side chain of cananginones
(DeI) by simple alkylation reaction or by CadioteChodkiewicz or
Sonogashira coupling reactions. The cananginones (D, E, F, G) have
been synthesized from known intermediates 27 and 28 in 17, 16, 15,
16 steps, respectively, with an overall yields of 11, 17, 17, 11%, re-
spectively, whereas cananginones H and I obtained in 14 steps from
same starting materials with overall yields of 21 and 22%, re-
spectively. The general strategy finally developed here can easily be
extended to efficiently synthesize a wide range of natural products
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T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
7
Fig. 3. Stacked 1H NMR (partial) spectra of synthesized cananginones I (9) recorded at different time intervals.
Scheme 7. Completion of cananginones F (6) and G (7). Reagents and conditions: (a) 30, nBuLi, THF/HMPA (5:1), 0 ꢁC to rt, 18 h; (ii) TBAF, THF, 0 ꢁC to rt, 2.5 h, 65% in two steps; (b)
(i) DMP, NaHCO3, CH2Cl2, 0 ꢁC to rt, 3 h; (iii) NaClO2, NaH2PO4$2H2O, tert-butanol/2-methyl-2-butene (2:1), 0 ꢁC to rt, 3 h; (iv) CH2N2, Et2O, 0 ꢁC, 10 min, 88% in three steps; (c) CSA,
MeOH, 0 ꢁC to rt, 3 h, 92%; (d) Me3OBF4, proton sponge, CH2Cl2, 0 ꢁC to rt, 48 h, 65%.
and their related analogues bearing a functionalized
g
-butyr-
atmosphere using dry, freshly distilled solvents prior to use unless
otherwise noted. Air- and moisture-sensitive liquids were handled
through gastight syringe and stainless-steel needle. Reactions were
monitored by thin layer chromatography (TLC) carried out on
0.25 mm silica gel plates with UV light, I2, 7% ethanolic phospho-
molybdic aciddheat and 2.5% ethanolic anisaldehyde (with 1%
AcOH and 3.3% concd H2SO4)dheat as developing agents. All
workup and purification procedures were carried out with reagent-
grade solvents under ambient atmosphere unless otherwise stated.
Flash chromatography was done using silica gel 100e200 unless
otherwise stated. Yields mentioned as chromatographically unless
olactone scaffold having and -substitutions in trans-
a
-
g
relationship with judicious selection of allylic ester in initial stage
and requisite manipulations to adjust the side chain in later stage.
4. Experimental section
4.1. General
All reactions were carried out in oven or flame-dried glassware
with Teflon coated magnetic stirring under argon or nitrogen
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8
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
otherwise stated. Optical rotations were measured using sodium
(m, 5H), 4.5 (s, 2H), 3.65 (m, 1H), 3.5 (d, J¼11.0 Hz, 1H), 3.50 (m, 2H),
3.39 (m,1H),1.76e1.66 (m, 2H),1.58e1.52 (m,1H),1.50e1.43 (m,1H);
(589, D line) lamp and are reported as follows: [
a
]
25 (c¼mg/100 mL,
D
solvent). IR spectra were recorded as neat liquids. High resolution
mass spectra were taken using Q-Tof-micro MS system using
electron spray ionization (ESI) techniques. CHN analyses were
carried out by frontal chromatographic techniques (thermal con-
ducting measurement). 1H NMR spectra were recorded on 300, 400,
and 500 MHz spectrometers in suitable solvents and calibrated
using residual undeuterated solvent as an internal reference, and
13C NMR (CDCl3, 125 MHz)
d 138.1, 128.5, 127.8, 127.7, 73.1, 72.0, 70.5,
66.7, 30.4, 26.1 ppm; HRMS (ESI) m/z calcd for C12H18O3Na [MþNa]þ
233.1154, found 233.1154.
To a stirred suspension of NaH (60% dispersion in mineral oil,
560 mg, 23.2 mmol) in anhydrous THF (50 mL) at 0 ꢁC, the diol from
the above step (1.94 g, 9.28 mmol) was added under argon atmo-
sphere. Tosyl-imidazole (4.0 g, 18.56 mmol) was then poured to the
reaction mixture and stirred for additional 45 min at the same
temperature. After completion of reaction, water was added and
extracted with EtOAc (2ꢂ100 mL). The combined organic extract was
washed with water, brine, dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was chromatographed (SiO2, 10e15% EtOAc/
hexane) to purify the epoxide 32 (1.34 g, 75%) as a liquid. Rf¼0.50
(10% EtOAc/hexane); data for epoxide 32: same as Refs. 15 and 17a.
the chemical shifts are shown in d ppm scales. Multiplicities of NMR
signals are designated as s (singlet), d (doublet), t (triplet), q
(quartet), br (broad), m (multiplet, for unresolved lines), etc. 13C and
2D NMR spectra were recorded on 75, 100, and 125 MHz
spectrometers.
4.2. (S)-2-(3-(Benzyloxy)propyl)oxirane (32)
To a solution of NaBH4 (26.92 g, 0.71 mol) in anhydrous EtOH
(450 mL) and THF (450 mL) at 0 ꢁC under argon atmosphere, dry
4.3. (S)-6-(Benzyloxy)hex-1-en-3-yl-3-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)propanoate (26)
LiCl (30.18 g, 0.71 mol) was added, and stirred for 10 min. The a,b-
unsaturated ester 3114 (19.0 g, 94.89 mmol) dissolved in anhydrous
THF (100 mL) was then cannulated to the reaction mixture and
stirring was continued further for 48 h at ambient temperature. The
reaction mixture was cooled again to 0 ꢁC and quenched cautiously
with slow addition of saturated aqueous solution of NH4Cl. The
organic solvent was evaporated in vacuo and extracted with EtOAc
(3ꢂ200 mL). The combined EtOAc extract was washed sequentially
with water, brine and dried over Na2SO4. The organic extract was
concentrated in vacuo and finally subjected to chromatographic
purification (SiO2, 30e35% EtOAc/hexane) to provide correspond-
DCC (7.15 g, 34.66 mmol) and DMAP (222 mg, 2.0 mmol) were
added to a solution of acid 2718 (5.75 g, 32.0 mmol) and allyl alcohol
2817 (5.5 g, 26.67 mmol) in anhydrous CH2Cl2 (150 mL) at 0 ꢁC
under argon atmosphere. The mixture was stirred at 0 ꢁC for 1 h and
then at room temperature for further 19 h. It was then filtered and
concentrated under reduced pressure. Flash column chromatogra-
phy of the crude residue (using SiO2, 5e10% EtOAc/hexane) gave the
ester 26 (7.54 g, 78%) as a colorless oil: Rf¼0.50 (20% EtOAc/hex-
27
ane); [
d
a]
ꢀ1.4 (c 6.5, CHCl3); 1H NMR (CDCl3, 500 MHz)
D
7.35e7.27 (m, 5H), 5.76 (m, 1H), 5.21 (m, 3H), 4.49 (s, 2H), 4.11 (m,
ing acetonide protected triol (11.85 g, 78%) as a colorless oil:
1H), 4.03 (m, 1H), 3.53 (t, J¼7.4 Hz, 1H), 3.47 (m, 2H), 2.50e2.37 (m,
28
Rf¼0.30 (30% EtOAc/hexane); [
a
]
þ8.0 (c 4.0, CHCl3); 1H NMR
2H), 1.89e1.84 (m, 2H), 1.74e1.70 (m, 2H), 1.67e1.61 (m, 2H), 1.40 (s,
D
(CDCl3, 500 MHz)
d
4.12 (m, 1H), 4.06 (m, 1H), 3.67 (m, 2H), 3.53 (t,
3H), 1.33 (s, 3H); 13C NMR (CDCl3, 125 MHz)
d
172.5, 138.6, 136.5,
J¼7.6 Hz, 1H), 1.67 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (CDCl3,
128.5, 127.7, 127.6, 116.9, 109.1, 75.0, 74.7, 73.0, 69.9, 69.2, 31.0, 30.7,
125 MHz)
d
109.1, 76.1, 69.5, 62.7, 30.3, 29.3, 27.0, 25.8 ppm; HRMS
28.8, 27.0, 25.7, 25.5 ppm; IR (neat) nmax 2935, 1734, 1251 cmꢀ1
;
(ESI) m/z calcd for C8H16O3Na [MþNa]þ 183.0997, found 183.0996.
The acetonide protected triol (5.0 g, 31.5 mmol) from the above
step was taken in anhydrous THF (100 mL) under argon atmosphere
and cooled to 0 ꢁC. NaH (60% dispersion in mineral oil, 1.51 g,
63.0 mmol) was added portion wise to the stirred reaction mixture.
After stirring for 15 min, BnBr (4.12 mL, 34.64 mmol) followed by
TBAI (582 mg, 1.57 mmol) was added to the reaction mixture and
stirred for 3 h at room temperature prior to quench with slow
addition of saturated aqueous solution of NH4Cl at 0 ꢁC. The re-
action mixture was extracted with EtOAc (2ꢂ100 mL). The com-
bined organic extract was washed with water and brine, dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by col-
umn chromatography (SiO2, 15% EtOAc/hexane) afforded corre-
sponding benzyl protected compound (6.85 g, 87%) as a colorless
HRMS (ESI) m/z calcd for C21H30O5Na [MþNa]þ 385.1991, found
385.1991.
4.4. (R,E)/(S,E)-Methyl 8-(benzyloxy)-2-(((S)-2, 2-dimethyl-1,3-
dioxolan-4-yl)methyl)oct-4-enoate (33, 33a)
LiHMDS (1.0 M in THF, 28.1 mL, 28.1 mmol) was added to
a mixture of anhydrous THF (45 mL) and DMPU (15 mL) at ꢀ78 ꢁC
under argon environment and stirred for 1 h. Then a solution of
TBSCl (6.36 g, 42.2 mmol) and the allylester 26 (2.55 g, 7.03 mmol)
dissolved in anhydrous THF (15 mL) was cannulated to the reaction.
The resulting mixture was stirred for 3.5 h at ꢀ78 ꢁC prior to
quench with saturated aqueous solution of NH4Cl at the same
temperature. The resulting mixture was stirred vigorously for an-
other 5 min at room temperature and extracted with Et2O
(5ꢂ75 mL). The organic layer was then washed with water, brine,
dried (Na2SO4), and concentrated in vacuo to get a mixture of acids,
which was taken forward without further characterizations.
The mixture of the crude acids from above step was next taken
in Et2O (50 mL) and cooled to 0 ꢁC. An ethereal solution of CH2N2
(prepared in Et2O using NMU and 50% aqueous KOH) was added to
it until the yellow color persisted and stirred for another 10 min.
Solvent was evaporated and the crude reaction mixture was tried to
purify by silica gel column chromatography using different solvent
systems (EtOAc/hexane, Et2O/hexane, iPrOH/hexane) to get 33 and
33a separately but we ended up with inseparable mixture of esters
(dr w12:1) (2.25 g) as an oil in 85% overall yield after two steps:
Rf¼0.50 (20% EtOAc/hexane); The major peaks in 1H NMR (CDCl3,
oil. Rf¼0.60 (10% EtOAc in hexane); [
a
]
28 þ6.7 (c 7.7, CHCl3); 1H NMR
D
(CDCl3, 500 MHz)
d
7.35e7.25 (m, 5H), 4.50 (s, 2H), 4.1 (quint,
J¼6.2 Hz, 1H), 4.02 (m, 1H), 3.51 (m, 3H), 1.74e1.60 (m, 4H), 1.40 (s,
3H), 1.3 (s, 3H); 13C NMR (CDCl3, 125 MHz)
d
138.7, 128.5, 127.7,
127.6, 108.8, 75.9, 73.0, 70.1, 69.5, 30.4, 27.1, 26.1, 25.8 ppm; HRMS
(ESI) m/z calcd for C15H22O3Na [MþNa]þ 273.1467, found 273.1476.
The benzyl protected compound from the above step (5.0 g,
19.97 mmol) was taken in a 100 mL round bottom flask and dissolved
in 80% AcOH (60 mL) and stirred for 12 h at room temperature. After
completion of the reaction, the AcOH was removed under vacuum
and the crude residue was extracted with EtOAc (3ꢂ100 mL). The
combined organic layers were washed with water, saturated aque-
ous solution of NaHCO3, brine, dried (Na2SO4), filtered, and con-
centrated in vacuo. Purification by flash column chromatography
(SiO2, 80% EtOAc/hexane) afforded corresponding acetonide depro-
tected diol (3.82 g, 91%) as a colorless oil. Rf¼0.30 (80% EtOAc/hex-
500 MHz)
d 7.35e7.27 (m, 5H), 5.46 (m, 1H), 5.33 (m, 1H), 4.49
(s, 2H), 4.05 (m, 1H), 4.01e3.98 (m, 1H), 3.66 (s, 3H), 3.49e3.44
(m, 3H), 2.64 (m, 1H), 2.33e2.27 (m, 1H), 2.22e2.17 (m, 1H), 2.07
ane); [
a
]
28 ꢀ1.1 (c 6.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 7.35e7.27
D
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T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
9
(q, J¼7.1 Hz, 2H), 1.89e1.83 (m, 1H), 1.69e1.64 (m, 3H), 1.38 (s, 3H),
1.32 (s, 3H). The major signals in 13C NMR (CDCl3, 125 MHz)
175.8,
138.7, 132.8, 128.4, 127.7, 127.6, 126.8, 109.0, 74.3, 74.1, 73.0, 69.8,
69.5, 51.6, 42.5, 36.1, 35.6, 29.6, 29.2, 27.0, 25.7 ppm; IR (neat) nmax
2937, 1735 cmꢀ1; HRMS (ESI) m/z calcd for C22H32O5Na [MþNa]þ
399.2147, found 399.2147.
25.6 ppm; IR (neat) nmax 3375, 2928, 1746 cmꢀ1; HRMS (ESI) m/z
calcd for C11H21O4 [MþH]þ 217.1440, found 217.1438.
d
4.8. (R,E)/(S,E)-8-(Benzyloxy)-2-(((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)oct-4-en-1-ol (36, 36a)
Diastereomeric mixture of esters 33, 33a (4.3 g, 11.42 mmol) was
taken in dry CH2Cl2 (50 mL), cooled to ꢀ78 ꢁC and DIBAL-H (1 M in
CH2Cl2, 34.26 mL, 34.26 mmol) was added drop wise to it. The re-
action mixture was stirred for 15 min at the same temperature. The
reaction was then quenched by slow addition of methanol and
warmed to room temperature. Saturated aqueous solution of so-
dium potassium tartrate was then added to the reaction mixture
and stirred until the two layers were separated. The reaction mix-
ture was extracted with EtOAc (2ꢂ100 mL). The combined organic
layers were washed with water, brine, dried (Na2SO4), filtered, and
concentrated in vacuo. Flash chromatography (SiO2, 20% EtOAc/
hexane) of the resulting residue provided colorless alcohols 36
(3.38 g) as major and 36a (280 mg) as minor products in 92%
combined yield.
4.5. (3R,5S)/(3S,5S)-3-((E)-6-(Benzyloxy)hex-2-enyl)-dihydro-
5-(hydroxymethyl)furan-2(3H)-one (34, 34a)
To a stirred solution of mixture of esters 33 and 33a (250 mg,
0.66 mmol) in MeOH (2 mL) at 0 ꢁC, CSA (8 mg, 0.03 mmol) was
added and stirred for 3 h at room temperature. The reaction was
then quenched with Et3N and evaporated in vacuo. The crude
residue was purified by column chromatography (SiO2, 8% EtOAc/
hexane) to get separately compounds 34 (168 mg) and 34a (14 mg)
as colorless liquids in 90% combined yield.
27
4.5.1. Data for 34. Rf¼0.2 (30% EtOAc/hexane); [
CHCl3); 1H NMR (CDCl3, 500 MHz)
a
]
D
þ13.8 (c 1.8,
d
7.36e7.28 (m, 5H), 5.54 (m,1H),
5.30 (m, 1H), 4.53 (m, 1H), 4.50 (s, 2H), 3.84 (d, J¼12.3 Hz, 1H), 3.62
(d, J¼12.1 Hz, 1H), 3.46 (t, J¼6.4 Hz, 2H), 2.77 (m, 1H), 2.47 (m, 1H),
2.25e2.17 (m, 2H), 2.13e2.09 (m, 2H), 2.04e1.99 (m, 1H), 1.71e1.65
27
4.8.1. Data for 36. Rf¼0.33 (20% EtOAc/hexane); [
CHCl3); 1H NMR (CDCl3, 400 MHz)
a
]
þ6.8 (c 1.3,
D
d
7.34e7.26 (m, 5H), 5.43e5.36
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d 179.2, 138.7, 133.8, 128.5,
(m, 2H), 4.49 (s, 2H), 4.18e4.12 (m, 1H), 4.08e4.03 (m, 1H),
3.64e3.58 (m, 1H), 3.51e3.44 (m, 4H), 2.11e2.05 (m, 2H), 2.04e1.94
(m, 2H), 1.71e1.59 (m, 4H), 1.50e1.44 (m, 1H), 1.41 (s, 3H), 1.36 (s,
127.8, 127.7, 126.0 78.7, 73.0, 69.7, 64.7, 39.8, 34.1, 29.5, 29.2,
28.7 ppm; IR (neat) nmax 3444, 2923, 1741, 1170 cmꢀ1; HRMS (ESI)
m/z calcd for C18H24O4Na [MþNa]þ 327.1572, found 327.1575.
3H); 13C NMR (CDCl3, 100 MHz)
d 138.7, 132.2, 128.4, 128.3, 127.7,
127.6, 109.4, 75.6, 73.0, 70.1, 69.8, 66.2, 39.9, 36.4, 35.8, 29.6, 29.2,
27.0, 26.0 ppm; IR (neat) nmax 3452, 2931, 1452 cmꢀ1; HRMS (ESI)
m/z calcd for C21H32O4Na [MþNa]þ 371.2198, found 371.2195.
4.5.2. Data for 34a. Rf¼0.19 (30% EtOAc/hexane); [
CHCl3); 1H NMR (CDCl3, 300 MHz)
a
]
27 þ30.0 (c 1.3,
D
d
7.38e7.27 (m, 5H), 5.57e5.48
(m, 1H), 5.42e5.32 (m, 1H), 4.50e4.43 (m, 3H), 3.88 (m, 1H),
3.64e3.56 (m, 1H), 3.48e3.44 (t, J¼6.4 Hz, 2H), 2.76e2.66 (m, 1H),
2.58e2.50 (m, 1H), 2.27e2.16 (m, 2H), 2.15e2.04 (m, 2H), 1.87e1.76
4.8.2. Data for 36a. Rf¼0.37 (20% EtOAc/hexane); [
CHCl3); 1H NMR (CDCl3, 400 MHz)
a
]
27 þ8.2 (c 0.7,
D
d
7.35e7.26 (m, 5H), 5.48e5.35
(m, 1H), 1.72e1.63 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d 178.2, 138.7,
(m, 2H), 4.49 (s, 2H), 4.13e4.10 (m, 1H), 4.04e3.92 (s, 2H), 3.63 (dd,
J¼11.3, 3.7 Hz, 1H), 3.53e3.51 (m, 1H), 3.49e3.43 (m, 2H), 2.11e2.06
(m, 2H), 2.03e1.98 (m, 2H), 1.96e1.90 (m, 1H), 1.71e1.64 (m, 3H),
1.48e1.42 (m, 1H), 1.35e1.33 (m, 6H); 13C NMR (CDCl3, 75 MHz)
133.4, 128.5, 127.8, 127.6, 126.2, 78.9, 73.0, 69.7, 63.9, 40.8, 33.2,
29.4, 29.2, 28.9 ppm. HRMS (ESI) m/z calcd for C18H24O4Na
[MþNa]þ 327.1572, found 327.1575.
d
138.7, 131.9, 128.4, 128.3, 127.7, 127.6, 109.1, 79.9, 72.9, 69.8, 67.8,
4.6. (3R,5S)-3-(6-hydroxyhexyl)-5-(hydroxymethyl) dihy-
drofuran-2(3H)-one (35)
66.1, 39.9, 36.6, 35.7, 29.6, 29.2, 26.7, 25.3 ppm; IR (neat) nmax 3461,
2931, 1454 cmꢀ1; HRMS (ESI) m/z calcd for C21H32O4Na [MþNa]þ
371.2198, found 371.2195.
The lactone 34 (8 mg, 0.037 mmol) was subjected to hydroge-
nation in EtOH (1 mL) in the presence of 10% Pd/C (5 mg) using
hydrogen-balloon at room temperature. The reaction was contin-
ued for 4 h after which it was filtered through a short pad of Celite
and the filter cake was washed with EtOAc. The organic layer was
evaporated in vacuum and finally passed through a short pad of
silica using EtOAc as eluent to furnish the title compound 35
4.9. (R)-8-((tert-Butyldimethylsilyl)oxy)-7-(((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)methyl)octan-1-ol (37)
Et3N (1.61 mL, 11.55 mmol) and TBDMSCl (1.40 g, 9.24 mmol)
were added sequentially to a solution of alcohol 36 (2.68 g,
7.69 mmol) in anhydrous CH2Cl2 (40 mL) at 0 ꢁC. After being stirred
for 15 min at the same temperature, DMAP (47 mg, 0.39 mmol) was
added and stirring was continued further for 1.5 h at room tem-
perature. The reaction mixture was then quenched with saturated
aqueous solution of NH4Cl and extracted with EtOAc (75 mL). The
organic extract was washed with water, brine, dried (Na2SO4), fil-
tered, and concentrated in vacuo. Purification of the residue by
column chromatography (SiO2, 2% EtOAc/hexane) provided corre-
sponding silyl ether (3.68 g) in quantitative yield: Rf¼0.76 (5%
(5.1 mg) in 90% yield. Rf¼0.5(EtOAc); [
a
]
28 þ20.5 (c 0.6, CHCl3); 1H
D
NMR (CDCl3, 500 MHz)
d
4.60 (m, 1H), 3.86 (dd, J¼12.3, 2.8 Hz, 1H),
3.66e3.62 (m, 3H), 2.71 (m, 1H), 2.33e2.28 (m, 1H), 2.03e1.97 (m,
1H), 1.87e1.80 (m, 1H), 1.59e1.54 (m, 2H), 1.49e1.34 (m, 7H); 13C
NMR (CDCl3, 75 MHz) d 180.0, 78.6, 64.7, 63.0, 39.6, 32.7, 31.3, 29.7,
29.1, 27.2, 25.6 ppm; IR (neat) nmax 3375, 2929, 1747 cmꢀ1; HRMS
(ESI) m/z calcd for C11H21O4 [MþH]þ 217.1440, found 217.1436.
4.7. (3S,5S)-3-(6-Hydroxyhexyl)-5-(hydroxymethyl) dihy-
drofuran-2(3H)-one (35a)
EtOAc/hexane); [
d
a
]
D
27 þ7.4 (c 1.1, CHCl3); 1H NMR (CDCl3, 500 MHz)
7.35e7.26 (m, 5H), 5.45e5.34 (m, 2H), 4.49 (s, 2H), 4.21e4.14 (m,
Following the same procedure as described for compound 35,
1H), 4.02 (dd, J¼8.0, 5.8 Hz, 1H), 3.53e3.45 (m, 5H), 2.10e1.96 (m,
alcohol 35a (2.6 mg, 92%) was prepared from compound 34a (4 mg,
4H), 1.70e1.61 (m, 3H), 1.56e1.53 (m, 2H), 1.39 (s, 3H), 1.34 (s, 3H),
27
0.02 mmol): Rf¼0.48 (EtOAc); [
a]
þ26.5 (c 0.2, CHCl3); 1H NMR
0.88 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d 138.8, 131.7,
D
(CDCl3, 500 MHz)
d
4.52e4.47 (m, 1H), 3.92 (dd, J¼12.6, 2.6 Hz, 1H),
128.6, 128.5, 127.7, 127.6, 108.7, 74.7, 73.0, 70.1, 69.9, 64.7, 38.1, 34.9,
34.8, 29.8, 29.3, 27.2, 26.0, 26.0, 18.4, ꢀ5.2 ppm; IR (neat) nmax 2931,
2856, 1469, 1251 cmꢀ1; HRMS (ESI) m/z calcd for C27H46O4SiNa
[MþNa]þ 485.3063, found 485.3064.
3.65e3.61 (m, 3H), 2.65 (m, 1H), 2.33 (m, 1H), 1.92 (m, 1H),
1.92e1.77 (m, 1H), 1.57 (m, 2H), 1.47e1.38 (m, 7H); 13C NMR (CDCl3,
75 MHz)
d 178.8, 78.7, 63.9, 63.0, 40.8, 32.7, 30.4, 29.7, 29.2, 27.3,
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028

10
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
The silyl ether (3.0 g, 6.48 mmol) from the above step, was sub-
it at 0 ꢁC in argon atmosphere. After 6 h stirring at room temper-
ature, the reaction was quenched with saturated aqueous solution
of NH4Cl and extracted with Et2O (30 mL). The organic phase was
washed with water, brine, dried (Na2SO4), and concentrated in
vacuo. Purification of the residue (SiO2, 8e10% EtOAc/hexane)
jected to hydrogenation in EtOAc (40 mL) in the presence of 10% Pd/C
(510 mg) using hydrogen-balloon at room temperature. After 4.5 h
the reaction mixture was filtered through a short pad of Celite and
the filter cake was washed with EtOAc. The organic layer was con-
centrated in vacuum and finally passed through a short pad of silica
using EtOAc as an eluent to afford the title compound 37 (2.40 g) as
afforded corresponding alcohol (378 mg, 98%) as a colorless oil:
26
Rf¼0.45 (20% EtOAc/hexane); [
a]
þ4.7 (c 1.0, CHCl3); 1H NMR
D
a colorless liquid in quantitative yield: Rf¼0.22 (20% EtOAc/hexane);
(CDCl3, 500 MHz) d 4.25e4.20 (m, 1H), 4.07e4.04 (m, 1H), 3.62 (dd,
26
[a]
þ8.8 (c 1.3, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
4.16 (m, 1H),
J¼11.5, 4.1 Hz, 1H), 3.57e3.49 (m, 2H), 2.20e2.16 (dt, J¼7.2, 2.5 Hz,
2H), 1.94 (t, J¼2.5 Hz, 1H), 1.74e1.69 (m, 1H), 1.67e1.59 (m, 2H),
1.55e1.49 (m, 2H),1.41e1.38 (m, 6H),1.36 (s, 3H),1.32e1.27 (m, 5H);
D
4.01 (m, 1H), 3.61 (t, J¼6.5 Hz, 2H), 3.52e3.44 (m, 3H),1.84 (br s, 1H),
1.56e1.51 (m, 5H), 1.38 (s, 3H), 1.35e1.24 (m, 11H), 0.86 (s, 9H), 0.01
(s, 6H); 13C NMR (CDCl3, 100 MHz)
d
108.6, 74.8, 70.1, 65.1, 63.0, 37.7,
13C NMR (CDCl3, 125 MHz)
d 109.2, 84.8, 73.5, 70.0, 68.2, 65.5, 37.8,
35.5, 32.8, 31.7, 29.8, 27.1, 26.9, 26.0, 25.9, 25.8, 18.4, ꢀ5.3 ppm; IR
35.3, 30.9, 29.4, 28.8, 28.5, 27.0, 25.9, 18.5 ppm; IR (neat) nmax 3433,
3307, 2929, 2115 cmꢀ1; HRMS (ESI) m/z calcd for C16H28O3Na
[MþNa]þ 291.1936, found 291.1934.
(neat) nmax 3452, 3431, 2927, 1585 cmꢀ1; HRMS (ESI) m/z calcd for
C
20H42O4SiNa [MþNa]þ 397.2750, found 397.2752.
The alcohol (350 mg, 1.3 mmol) from the above step was taken
in anhydrous CH2Cl2 (5 mL) under argon atmosphere and cooled to
4.10. ((R)-2-(((S)-2, 2-Dimethyl-1,3-dioxolan-4-yl) methyl)dec-
9-ynyloxy)(tert-butyl)dimethylsilane (25)
0
ꢁC. NaHCO3 (546 mg, 6.5 mmol) followed by DMP (830 mg,
1.95 mmol) was added to the reaction mixture and the reaction
mixture was allowed to attain the ambient temperature with
constant stirring. After 1.5 h, the reaction was quenched with sat-
urated aqueous solution of Na2S2O3 and NaHCO3 and diluted with
Et2O (30 mL) and stirred for another 1 h until the two phases were
separated. The mixture was then transferred to a separating funnel
and the organic extract was washed with water, brine, dried
(Na2SO4), and concentrated in vacuo. The residue was passed
through a short pad of silica (EtOAc as eluent) to obtain corre-
sponding aldehyde, which was used for the next step without
further characterization.
To a cool solution (0 ꢁC) of alcohol 37 (850 mg, 2.27 mmol) in
anhydrous toluene (15 mL), Ph3P (833 mg, 3.18 mmol) was added
under argon atmosphere and stirred for 5 min. Then iodine
(863 mg, 3.4 mmol) and imidazole (310 mg, 4.54 mmol) were
added and kept the reaction mixture at room temperature for 3.5 h
prior to extract with Et2O (50 mL). The organic layer was washed
with water, brine, dried (Na2SO4), and concentrated in vacuo. Flash
column chromatography of the residue (SiO2, 4% EtOAc/hexane)
afforded corresponding iodide (990 mg, 91%) as a light yellow oil:
28
Rf¼0.80 (10% EtOAc/hexane); [
a
]
þ6.8 (c 2.0, CHCl3); 1H NMR
D
(CDCl3, 400 MHz)
d
4.20e4.15 (m, 1H), 4.05e4.01(m, 1H), 3.55e3.45
An aqueous solution of NaClO2 (240 mg, 3.25 mmol) and
NaH2PO4$2H2O (507 mg, 3.25 mmol) was added to a solution of
(m, 3H), 3.18 (t, J¼7.02 Hz, 2H), 1.84e1.77 (m, 2H), 1.58e1.52 (m,
t
3H), 1.41e1.37 (m, 6H), 1.34 (s, 3H), 1.30e1.25 (m, 5H), 0.88 (s, 9H),
the above aldehyde (1.3 mmol) in BuOH (4 mL) and 2-methyl-2-
0.02 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d
108.7, 74.8, 70.2, 65.1, 37.8,
butene (2 mL) at 0 ꢁC. The resultant reaction mixture was left to
room temperature and stirred for 5 h. After completion of re-
action, the solvent was removed under reduced pressure and
extracted with EtOAc (3ꢂ20 mL) and the combined organic ex-
tracts were washed with water, brine, dried (Na2SO4), filtered,
and concentrated in vacuo to get an acid. The crude acid was
directly used in the next step without further purification and
characterization.
35.5, 33.6, 31.7, 30.6, 29.0, 27.2, 26.7, 26.0, 26.0, 18.4, 7.2, ꢀ5.2 ppm;
IR (neat) nmax 2927, 1251 cmꢀ1
C
; HRMS (ESI) m/z calcd for
20H41IO3SiNa [MþNa]þ 507.1767, found 507.1765.
To a solution of TMS-acetylene (0.35 mL, 2.44 mmol) in anhy-
drous THF (5 mL) under argon atmosphere at ꢀ78 ꢁC, nBuLi (2.5 M
in toluene, 0.9 mL, 2.25 mmol) was added drop wise and the re-
action mixture was stirred at the same temperature for 45 min.
HMPA (1.5 mL) was then added and stirred another 30 min before
addition of precursor iodide (910 mg, 1.88 mmol, dissolved in
2.5 mL of dry THF) from above step. The mixture was allowed to
warm to room temperature and stirred for 12h. The reaction was
quenched with saturated aqueous solution of NH4Cl and extracted
with Et2O (50 mL). The organic extract was washed with water,
brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, 230e400 mesh, 2%
EtOAc/hexane) to yield the target compound 25 (580 mg, 81%) as
a colorless liquid. The negligible amount of elimination product
(terminal alkene) of precursor iodide was also formed, which was
The crude acid from above step was next dissolved in Et2O
(10 mL) and cooled to 0 ꢁC and chilled ethereal solution of CH2N2
was added until the yellow color persisted. After 10 min, the solvent
was evaporated and the residue was chromatographed (SiO2, 3e4%
EtOAc/hexane) to afford ester (354 mg, 92%) as a colorless oil:
27
Rf¼0.45 (10% EtOAc/hexane); [
a
]
þ0.4 (c 2.9, CHCl3); 1H NMR
D
(CDCl3, 400 MHz)
d
4.07e3.98 (m, 2H), 3.68 (s, 3H), 3.53e3.47 (m,
1H), 2.63e2.56 (m, 1H), 2.17 (dt, J¼7.0, 2.6 Hz, 2H), 1.93 (t, J¼2.6 Hz,
1H), 1.92e1.85 (m, 1H), 1.70e1.59 (m, 2H), 1.54e1.46 (m, 3H), 1.39
(m, 5H), 1.32 (s, 3H), 1.31e1.23 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d
176.4, 109.0, 84.7, 74.4, 69.5, 68.2, 51.6, 42.3, 36.3, 33.1, 29.0, 28.6,
discarded during column purification: Rf¼0.40 (3% EtOAc/hexane);
28.4, 27.1, 27.0, 25.7, 18.4 ppm; IR (neat) nmax 3307, 2935, 2115,
1733 cmꢀ1; HRMS (ESI) m/z calcd for C17H28O4Na [MþNa]þ
319.1885, found 319.1887.
27
[
a]
þ2.7 (c 1.7, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 4.17 (m, 1H),
D
4.03 (m, 1H), 3.55e3.52 (m, 1H), 3.51e3.46 (m, 2H), 2.17 (dt, J¼7.0,
2.5 Hz, 2H), 1.93 (t, J¼2.5 Hz, 1H), 1.56e1.48 (m, 5H), 1.39 (br s, 6H),
1.34 (s, 3H), 1.29 (m, 5H), 0.88 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3,
Following the same procedure as described for lactone 34, the
title compound 23 (161 mg, 89%) was prepared from the above
ester (256 mg, 0.86 mmol) using CSA (20 mg, 0.086 mmol) in MeOH
100 MHz)
d 108.6, 84.8, 74.8, 70.2, 68.2, 65.1, 37.8, 35.5, 31.7, 29.5,
28.8, 28.6, 27.2, 26.8, 26.0, 26.0, 18.5, 18.4, ꢀ5.2 ppm; IR (neat) nmax
(3 mL): Rf¼0.25 (30% EtOAc/hexane); [
a
]
27 þ20.9 (c 1.5, CHCl3); 1H
D
3313, 2929, 2117, 1471, 1251 cmꢀ1; HRMS (ESI) m/z calcd for
NMR (CDCl3, 400 MHz)
d
4.61e4.58 (m, 1H), 3.87 (d, J¼12.2 Hz, 1H),
C
22H42O3SiNa [MþNa]þ 405.2801, found 405.2803.
3.64 (d, J¼12.2 Hz, 1H), 2.73e2.67 (m, 1H), 2.34e2.28 (m, 1H),
2.20e2.16 (m, 2H), 2.03e1.98 (m, 1H), 1.96e1.94 (m, 1H), 1.87e1.81
(m, 1H), 1.54e1.49 (m, 2H), 1.45e1.35 (m, 7H); 13C NMR (CDCl3,
4.11. (3R,5S)-Dihydro-5-(hydroxymethyl)-3-(oct-7-ynyl)furan-
2(3H)-one (23)
100 MHz)
d 180.0, 84.6, 78.7, 68.3, 64.6, 39.7, 31.3, 29.7, 28.9, 28.5,
28.4, 27.2, 18.4 ppm; IR (neat) nmax 3446, 3292, 2933, 2113,
1762 cmꢀ1; HRMS (ESI) m/z calcd for C13H20O3Na [MþNa]þ
247.1310, found 247.1313.
Compound 25 (550 mg, 1.44 mmol) was dissolved in anhydrous
THF (3 mL) and TBAF (1 M in THF, 1.73 mL, 1.73 mmol) was added to
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028

T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
11
4.12. (R)-10-((tert-Butyldimethylsilyl)oxy)-9-(((S)-2,2-di-
methyl-1,3-dioxolan-4-yl)methyl)decan-1-ol (38)
68.1, 65.1, 37.8, 35.5, 31.7, 30.0, 29.5, 29.2, 28.8, 28.6, 27.2, 26.9, 26.0,
26.0, 18.5, 18.4, ꢀ5.3 ppm; IR (neat) nmax 3313, 2929, 2856, 2117,
1251 cmꢀ1; HRMS (ESI) m/z calcd for C24H46O3SiNa [MþNa]þ
433.3114, found 433.3112.
To a solution of oxalyl chloride (0.66 mL, 7.6 mmol) in dry CH2Cl2
(20 mL) at ꢀ78 ꢁC, DMSO (1.15 mL, 16.2 mmol) was added slowly in
drop wise manner with constant stirring under argon atmosphere.
After 15 min, compound 37 (1.9 g, 5.07 mmol) dissolved in dry
CH2Cl2 (10 mL) was added to the reaction mixture. After 30 min of
stirring at ꢀ78 ꢁC, Et3N (3.54 mL, 25.35 mmol) was added and stirred
for another 30 min at same temperature. The reaction mixture was
then allowed to warm to room temperature slowly to get an alde-
hyde. To the crude aldehyde (confirmed through TLC) Ph3P]
CHCO2Et (3.53 g, 10.14 mmol) was added and stirred at ambient
temperature for 36 h. The reaction mixture was then quenched with
saturated aqueous solution of NH4Cl and the organic layers were
washed with water, brine, dried (Na2SO4), filtered, and concentrated
in vacuo. Purification by column chromatography (SiO2, 5% EtOAc/
4.14. (3R,5S)-3-(Dec-9-ynyl)-dihydro-5-(hydroxymethyl)fu-
ran-2(3H)-one (22)
The desilylated compound (578 mg, 96%) was synthesized from
silyl ether 24 (840 mg, 2.04 mmol) using TBAF (1M in THF, 2.45 mL,
2.45 mmol) in THF (6 mL) following the same procedure as de-
scribed before for the shorter homologue: Rf¼0.3 (20% EtOAc/
hexane); [
a
]
29 þ2.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 4.22
D
(m, 1H), 4.05 (m, 1H), 3.61 (m, 1H), 3.56e3.48 (m, 2H), 2.45 (br s,
1H), 2.17 (dt, J¼7.0, 2.3 Hz, 2H), 1.94 (m, 1H), 1.71e1.68 (m, 1H),
1.66e1.60 (m, 2H), 1.54e1.49 (m, 2H), 1.41e1.36 (m, 9H), 1.28 (m,
9H); 13C NMR (CDCl3, 75 MHz)
d 109.1, 84.8, 73.5, 69.9, 68.2, 65.4,
hexane) furnished corresponding a,b-unsaturated ester (1.99 g, 89%)
37.7, 35.3, 30.9, 29.9, 29.5, 29.1, 28.8, 28.5, 27.1, 27.0, 25.9, 18.4 ppm;
IR (neat) nmax 3434, 3309, 2927, 2115 cmꢀ1; HRMS (ESI) m/z calcd
for C18H32O3Na [MþNa]þ 319.2249, found 319.2251.
(mixture of cis/trans isomers) as a colorless liquid: Rf¼0.67 (10%
EtOAc/hexane). The major peaks in 1H NMR (CDCl3, 400 MHz)
d
6.98e6.91 (m, 1H), 5.82e5.78 (d, J¼15.6 Hz, 1H), 4.20e4.13 (m, 3H),
Following the same procedure as adopted for shorter homo-
logue, the corresponding ester (552 mg, 92%) was prepared from
4.04e4.01 (m, 1H), 3.55e3.45 (m, 3H), 2.21e2.15 (m, 2H), 1.55e1.54
(m, 3H), 1.46e1.43 (m, 2H), 1.39 (s, 3H), 1.34 (br s, 4H), 1.29e1.25 (m,
8H), 0.87 (s, 9H), 0.02 (s, 6H). The major signals 13C NMR (CDCl3,
the alkynyl alcohol (550 mg, 1.85 mmol) obtained from above step:
27
Rf¼0.5 (10% EtOAc/hexane); [
a
]
ꢀ2.7 (c 4.0, CHCl3); 1H NMR
D
100 MHz) d 166.9, 149.4, 121.4, 108.7, 74.8, 70.2, 65.1, 60.2, 37.8, 35.5,
(CDCl3, 500 MHz)
d
4.06e3.99 (m, 2H), 3.68 (s, 3H), 3.53e3.47 (m,
32.3, 31.7, 29.6, 28.1, 27.2, 26.7, 26.0, 26.0, 18.4, 14.4, ꢀ5.3 ppm;; IR
1H), 2.62e2.56 (m, 1H), 2.17 (dt, J¼7.0, 2.5 Hz, 2H), 1.93 (t, J¼2.4 Hz,
1H), 1.91e1.85 (m, 1H), 1.68e1.60 (m, 2H), 1.54e1.47 (m, 3H), 1.39
(m, 5H), 1.32 (s, 3H), 1.27 (m, 8H); 13C NMR (CDCl3, 125 MHz)
(neat) nmax 2929, 1722, 1255 cmꢀ1; HRMS (ESI) m/z calcd for
C
24H46O5Si Na [MþNa]þ 465.3012, found 465.3010.
Following the same procedure adopted in reduction of ester 31,
d
176.6, 109.0, 84.8, 74.4, 69.5, 68.2, 51.6, 42.3, 36.4, 33.2, 29.5, 29.4,
the saturated alcohol 38 (1.5 g, 90%) was prepared from the above
-unsaturated ester (1.83g, 4.13 mmol) as a colorless oil using LiCl
(1.3 g, 30.98 mmol) and NaBH4 (1.17 g, 30.98 mmol) in THF (100 mL)
29.1, 28.8, 28.6, 27.2, 27.1, 25.7, 18.5 ppm; IR (neat) nmax 3290, 2931,
2115, 1735 cmꢀ1; HRMS (ESI) m/z calcd for C19H32O4Na [MþNa]þ
347.2198, found 347.2195.
a,b
25
and MeOH (100 mL) in 48 h: Rf¼0.25 (10% EtOAc/hexane); [
a]
D
Following the same procedure as described for lactone 23, the
title compound 22 (171 mg, 88%) was prepared from the above
ester (250 mg, 0.77 mmol) using CSA (18 mg, 0.07 mmol) in MeOH
þ5.9 (c 2.3, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 4.17 (m, 1H), 4.03
(m, 1H), 3.63 (t, J¼6.6 Hz, 2H), 3.53 (dd, J¼10.0, 3.6 Hz, 1H),
3.49e3.46 (m, 2H), 1.57e1.54 (m, 5H), 1.39 (s, 3H), 1.34 (s, 3H),
1.32e1.24 (m, 12H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3,
(3 mL): Rf¼0.25 (30% EtOAc/hexane); [
a
]
27 þ13.9 (c 8.7, CHCl3); 1H
D
NMR (CDCl3, 500 MHz)
d
4.61e4.57 (m, 1H), 3.89e3.84 (m, 1H),
125 MHz)
d 108.6, 74.8, 70.2, 65.1, 63.2, 37.8, 35.5, 32.9, 31.7, 30.0,
3.66e3.62 (m, 1H), 2.73e2.67 (m, 1H), 2.51 (br s, 1H), 2.33e2.28 (m,
1H), 2.17 (dt, J¼7.0, 2.4 Hz, 2H), 2.04e1.97 (m, 1H), 1.94e1.93 (m,
1H), 1.86e1.74 (m, 1H), 1.54e1.49 (m, 2H), 1.47e1.37 (m, 5H), 1.30
29.6, 29.5, 27.2, 26.9, 26.0, 26.0 25.8, 18.4, ꢀ5.3; IR (neat) nmax 3407,
2929, 2856 cmꢀ1; HRMS (ESI) m/z calcd for C22H46O4SiNa [MþNa]þ
425.3063, found 425.3066.
(br s, 6H); 13C NMR (CDCl3, 100 MHz)
d 180.0, 84.8, 78.7, 68.2, 64.6,
39.7, 31.3, 29.7, 29.3, 29.0, 28.7, 28.5, 27.3, 18.4 ppm; IR (neat) nmax
4.13. ((R)-2-(((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)do-
dec-11-ynyloxy)(tert-butyl)dimethylsilane(24)
3294, 3444, 2929, 2856, 2115, 1770 cmꢀ1; HRMS (ESI) m/z calcd for
C
15H24O3Na [MþNa]þ 275.1623, found 275.1625.
The corresponding iodide (1.72 g, 92%) was synthesized starting
from precursor alcohol 38 (1.47 g, 3.65 mmol) using Ph3P (1.34 g,
5.11 mmol), imidazole (500 mg, 7.3 mmol) in toluene (20 mL) fol-
lowing the same procedure as described for the shorter homologue
4.15. (3R,5S)-Dihydro-5-(hydroxymethyl)-3-(octadeca-9,11-
diynyl)furan-2(3H)-one (39)
27
1
above. Rf¼0.5 (5% EtOAc/hexane); [
a
]
þ4.0 (c 2.1, CHCl3); H NMR
To a degassed solution of 22 (25 mg, 0.1 mmol) in Et3N (0.5 mL)
under argon atmosphere CuBr (3 mg, 0.02 mmol) and NH2OH$HCl
(2 mg, 0.028 mmol) were added sequentially. Alkynyl bromide 19
(19 mg, 0.1 mmol) dissolved in degassed Et3N (1 mL) was added
drop wise to the reaction mixture and stirred for 12 h at room
temperature. The reaction was quenched with water and extracted
with Et2O (10 mL).The organic layer was washed with water, brine,
dried (Na2SO4), and concentrated in vacuo. Purification by column
chromatography (SiO2, 30% EtOAc/hexane) furnished the coupled
product 39 (26 mg, 72%) as a colorless liquid: Rf¼0.56 (30% EtOAc/
D
(CDCl3, 500 MHz)
d
4.16 (m, 1H), 4.03 (m, 1H), 3.53 (m, 1H),
3.49e3.46 (m, 2H), 3.18 (t, J¼7.0 Hz, 2H),1.84e1.78 (m, 2H),1.59e1.55
(m, 3H) (merged with H2O), 1.39e1.34 (m, 9H), 1.27 (m, 9H), 0.88 (s,
9H), 0.02 (s, 6H); 13C NMR (CDCl3, 125 MHz)
d 108.6, 74.8, 70.2, 65.1,
37.8, 35.5, 33.7, 31.7, 30.6, 30.0, 29.5, 28.6, 27.2, 26.9, 26.0, 26.0, 18.4,
7.3, ꢀ5.3 ppm; IR (neat) nmax 2927, 2854, 1251 cmꢀ1; HRMS (ESI) m/z
calcd for C22H45IO3SiNa [MþNa]þ 535.2080, found 535.2079.
The titled alkyne 24 (859 mg, 80%) was prepared from the above
iodide (1.35 g, 2.63 mmol) using TMS alkyne (0.5 mL, 3.42 mmol)
and nBuLi (2.5 M in hexane, 1.26 mL, 3.15 mmol) in THF (10 mL) and
HMPA (2 mL) solvent system following the same procedure as
hexane); [
a
]
27 þ10.8 (c 1.6, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 4.58
D
(m, 1H), 3.87 (dd, J¼12.3, 2.8 Hz, 1H), 3.65 (dd, J¼12.3, 4.7 Hz, 1H),
2.70 (m, 1H), 2.30 (m, 1H), 2.24 (t, J¼6.9 Hz, 4H), 2.00 (m, 1H), 1.80
(m, 1H), 1.53e1.48 (m, 4H), 1.38 (br s, 7H), 1.29 (br s, 10H), 0.88 (t,
describe for compound 25: Rf¼0.50 (5% EtOAc/hexane); [
a
]
27 þ8.2
D
(c 3.3, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
4.17 (m, 1H), 4.02 (m,
1H), 3.54 (m, 1H), 3.50e3.46 (m, 2H), 2.17 (dt, J¼7.1, 2.3 Hz, 2H), 1.92
J¼6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 179.8, 78.6, 77.7, 77.6,
(m, 1H), 1.55e1.48 (m, 5H), 1.39e1.34 (m, 9H), 1.26 (br, 9H), 0.87 (s,
65.4, 65.3, 64.7, 39.7, 31.4, 31.3, 29.7, 29.3, 29.0, 28.8, 28.6, 28.4, 28.4,
9H), 0.02 (s, 6H); 13C NMR (CDCl3, 125 MHz)
d
108.6, 84.9, 74.8, 70.2,
27.3, 22.6, 19.3, 19.3, 14.1 ppm; IR (neat) nmax 3444, 2929, 2254,
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028

12
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
2160, 1770, 1458 cmꢀ1; HRMS (ESI) m/z calcd for C23H36O3Na
[MþNa]þ 383.2562, found 383.2560.
the lactone 23 (20 mg, 0.09 mmol) using vinyl iodide 20 (27 mg,
0.11 mmol), Pd(PPh3)2Cl2 (7.5 mg, 0.01 mmol), and CuI (5.1 mg,
0.03 mmol) in degassed Et3N (3 mL) in 20 h: Rf¼0.27 (25% EtOAc/
23
23
4.16. (3R,5S)-Dihydro-5-(methoxymethyl)-3-(octadeca-9,11-
diynyl)furan-2(3H)-one (4)
hexane); reported [
a]
þ14.0 (c 0.206, CHCl3); observed [
a]
D
D
þ14.7 (c 0.3, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 5.87e5.74 (m, 2H),
5.43 (d, J¼10.6 Hz, 1H), 5.03e4.91 (m, 2H), 4.60 (m, 1H), 3.86 (br d,
J¼12.4 Hz, 1H), 3.46 (dd, J¼12.3, 4.6 Hz, 1H), 2.7 (m, 1H), 2.35e2.24
(m, 5H), 2.07e2.02 (m, 2H), 2.00e1.95 (m, 1H), 1.83 (m, 1H),
Under the minimum exposure of light (covering the reaction
flask by carbon paper), to a solution of alcohol 39 (15 mg,
0.042 mmol) in anhydrous CH2Cl2 (2 mL), proton sponge (54 mg,
0.25 mmol) and Me3OBF4 (31 mg, 0.21 mmol, in two installments)
were added sequentially under argon atmosphere at 0 ꢁC. The
mixture was warmed to room temperature over 1 h and stirred for
24 h before addition of second installment of Me3OBF4. The re-
action was continued further for 17 h and quenched with saturated
NH4Cl solution. The reaction mixture was extracted with EtOAc
(5 mL) and washed with 1 N HCl, water, brine, dried (Na2SO4), and
concentrated in vacuum. Purification of the crude residue by col-
1.56e1.51 (m, 2H),1.42 (br s,11H); 13C NMR (CDCl3, 75 MHz)
d 179.7,
142.5, 139.1, 114.1, 109.6, 94.5, 78.5, 77.5, 64.8, 39.7, 33.7, 31.3, 29.9,
29.7, 29.0, 28.9, 28.8, 28.5, 28.4, 27.3, 19.6 ppm; IR (neat) nmax 3417,
2927, 2854, 2208, 1758, 1454 cmꢀ1; HRMS (ESI) m/z calcd for
C
C
21H32O3Na [MþNa]þ 355.2249, found 355.2248. Anal. Calcd for
21H32O3: C, 75.86; H, 9.70. Found: C, 75.53; H, 9.73.
4.19. (3R,5S)-3-((Z)-Hexadec-9-en-7-ynyl)-dihydro-5-(hydrox-
ymethyl)furan-2(3H)-one (9)
umn chromatography (SiO2, 15% EtOAc/hexane) afforded 4 (10 mg,
23
60%) as a colorless oil : Rf¼0.4 (20% EtOAc/hexane); reported [
a
]
Experimental procedure and purification process were same as
5. Compound 9 (21 mg, 70%) was prepared from lactone 23
(20.5 mg, 0.09 mmol) as a clear yellow oil using vinyl iodide 21
(26.1 mg, 0.11 mmol), Pd(PPh3)2Cl2 (6.3 mg, 0.01 mmol) and CuI
D
þ13.3 (c 0.206, CHCl3); observed [
(CDCl3, 500 MHz)
a]
23 þ8.9 (c 0.7, CHCl3); 1H NMR
D
d
4.58 (m, 1H), 3.55 (dd, J¼10.6, 3.4 Hz, 1H), 3.49
(dd, J¼10.6, 4.0 Hz,1H), 3.38 (s, 3H), 2.69 (m,1H), 2.31e2.26 (m,1H),
2.24 (t, J¼6.9 Hz, 4H), 2.02e1.96 (m, 1H), 1.83 (br s, 1H), 1.51 (m, 4H),
1.38 (br s, 7H), 1.29 (br s, 10H), 0.88 (t, J¼6.7 Hz, 3H); 13C NMR
(5.14 mg, 0.027 mmol) in degassed Et3N (3 mL) in 20 h: Rf¼0.27
23
(25% EtOAc/hexane); reported [
a
]
þ14.3 (c 0.206, CHCl3); ob-
D
28
(CDCl3, 125 MHz)
d
179.7, 77.7, 77.6, 76.9, 74.4, 65.4, 65.4, 59.6, 39.3,
served [
a
]
D
þ10.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz)
31.4, 31.3, 30.5, 29.4, 29.3, 29.1, 28.9, 28.6, 28.4, 28.3, 27.4, 22.6, 19.3,
19.3, 14.1 ppm; IR (neat) nmax 2929, 2856, 2212, 2160, 1772,
1456 cmꢀ1; HRMS (ESI) m/z calcd for C24H38O3Na [MþNa]þ
397.2719, found 397.2716. Anal. Calcd for C24H38O3: C, 76.96; H,
10.23. Found: C, 76.94; H, 10.25.
d
5.84e5.79 (m, 1H), 5.42 (br d, J¼10.7 Hz, 1H), 4.60e4.58 (m, 1H),
3.86 (m, 1H), 3.65 (m, 1H), 2.69 (m, 1H), 2.37e2.23 (m, 5H), 2.00 (m,
1H), 1.84 (m, 1H), 1.51e1.29 (m, 17H), 0.88 (m, 3H); 13C NMR (CDCl3,
75 MHz)
d 180.0, 142.8, 109.3, 94.3, 78.5, 77.6, 64.7, 39.7, 31.8, 31.3,
30.1, 29.7, 29.0, 28.9, 28.8, 28.7, 27.3, 22.7, 19.6, 14.2 ppm; IR (neat)
nmax 3444, 2927, 2856, 2208,1770,1460 cmꢀ1; HRMS (ESI) m/z calcd
for C21H34O3Na [MþNa]þ 357.2406, found 357.2404. Anal. Calcd for
4.17. (3R,5S)-3-((Z)-Heptadeca-11,16-dien-9-ynyl)-dihydro-5-
(hydroxymethyl)furan-2(3H)-one (5)
C21H34O3: C, 75.41; H, 10.25. Found: C, 75.15; H, 10.29.
To a solution of 22 (27 mg, 0.107 mmol) and vinyl iodide 20
(33 mg, 0.14 mmol) in freshly dried and degassed Et3N (1 mL),
Pd(PPh3)2Cl2 (7.5 mg, 0.01 mmol) and CuI (6.1 mg, 0.032 mmol)
were added and stirred for 20 h at room temperature. The reaction
mixture was poured into saturated aqueous solution of NaHCO3
(1 mL) and extracted with EtOAc (5 mL). The organic extract was
washed with water, brine, dried (Na2SO4), and concentrated in
vacuo. Purification of the crude product was done first by column
chromatography (SiO2, 25% EtOAc/hexanes) and later by pre-
4.20. (R)-2-(((S)-2,2-Dimethyl-1,3-dioxolan-4-yl) methyl)icos-
19-en-11-yn-1-ol (40)
To a stirred solution of compound 24 (260 mg, 0.63 mmol) in
anhydrous THF (1.5 mL) at 0 ꢁC, nBuLi (2.5 M in hexane, 0.33 mL,
0.82 mmol) was added under argon atmosphere. After stirring for
about 30 min at the same temperature, HMPA (0.5 mL) was added.
The mixture was stirred for another 30 min at same temperature
and the iodide 30 (226 mg, 0.95 mmol, dissolved in 1 mL THF) was
cannulated .The mixture was then allowed to warm to room tem-
perature and stirred for further 17 h before it was quenched with
saturated aqueous solution of NH4Cl. The mixture was extracted
with Et2O (25 mL).The organic phase was washed with water, brine,
dried (Na2SO4), and concentrated in vacuo. The inseparable mixture
of alkylated product with some unreacted starting material was
taken in next step without further characterization.
The crude mixture from above step was dissolved in anhydrous
THF (3 mL), cooled to 0 ꢁC, and TBAF (1M in THF, 0.76 mL,
0.76 mmol) was added to it under argon atmosphere. After 2.5 h the
reaction was quenched with saturated aqueous solution of NH4Cl
and extracted with Et2O (30 mL). The organic phase was washed
with water, brine, dried (Na2SO4), and evaporated in vacuo. Puri-
fication of the residue (SiO2, 10% EtOAc/hexane) afforded title
compound 40 {98 mg, 65% overall yield after two steps, based on
i
parative TLC (using 4% PrOH/hexane as mobile phase) gave com-
pound 5 (26.6 mg, 69%) as a clear yellow oil. The negligible amount
of corresponding trans-isomer originated from trans vinyl iodide
present as an inseparable impurity in synthesized cis-vinyl iodide
20 was discarded during this purification process: Rf¼0.3 (25%
23
EtOAc/hexane); reported [
a]
þ14.1 (c 0.206, CHCl3); observed
D
[
a]
23 þ11.3 (c 0.4, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 5.81 (m, 2H),
D
5.43 (d, J¼10.6 Hz, 1H), 5.02e4.91 (m, 2H), 4.62e4.55 (m, 1H),
3.91e3.83 (m, 1H), 3.68e3.60 (m, 1H), 2.69 (m, 1H), 2.34e2.24 (m,
5H), 2.07e2.01 (m, 2H), 2.00e1.94 (m, 1H), 1.86e1.80 (m, 1H), 1.50
(quint, J¼6.2 Hz, 2H), 1.41 (m, 8H), 1.30 (br s, 7H); 13C NMR (CDCl3,
75 MHz) d 179.8, 142.4, 139.1, 114.4, 109.6, 94.6, 78.6, 77.5, 64.8, 39.7,
33.7, 31.4, 29.9, 29.7, 29.4, 29.4, 29.2, 29.0, 28.5, 28.4, 27.3, 19.6 ppm;
IR (neat) nmax 3438, 2927, 2854, 2212, 1768, 1461 cmꢀ1; HRMS (ESI)
m/z calcd for C23H36O3Na [MþNa]þ 383.2562, found 383.2564.
Anal. Calcd for C23H36O3: C, 76.62; H, 10.06. Found: C, 76.84; H,
10.10.
corresponding silyl deprotected recovered starting material
27
(52 mg)} as a colorless liquid: Rf¼0.33 (20% EtOAc/hexane); [
a
]
D
þ1.9 (c 1.5, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 5.80 (m, 1H), 4.98
4.18. (3R,5S)-3-((Z)-Hexadeca-9,15-dien-7-ynyl)-dihydro-5-
(hydroxymethyl)furan-2(3H)-one (8)
(dd, J¼17.1, 1.4 Hz, 1H), 4.92 (d, J¼10.1 Hz, 1H), 4.22 (m, 1H), 4.05 (m,
1H), 3.62e3.49 (m, 3H), 2.12 (m, 4H), 2.03 (m, 2H), 1.70e1.58 (m,
4H), 1.46 (br s, 4H), 1.41e1.35 (br s, 13H), 1.27 (br s, 11H); 13C NMR
Experimental procedure and purification process were same as
5. Compound 8 (20 mg, 67%) was prepared as a clear yellow oil from
(CDCl3, 125 MHz)
37.8, 35.3, 33.8, 31.0, 30.0, 29.6, 29.3, 29.2, 29.0, 28.9, 28.8, 28.7, 27.2,
d 139.2, 114.3, 109.2, 80.4, 80.3, 73.5, 70.0, 65.5,
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028

T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
13
27.0, 25.9, 18.9 ppm; IR (neat) nmax 3434, 2927, 2854, 2169,
1369 cmꢀ1; HRMS (ESI) m/z calcd for C26H46O3H [MþH]þ 407.3525,
found 407.3522.
discussions. The financial support from Department of Science
and Technology, Ministry of Science and Technology
(_501100001409) (Project no. SR/FT/CS-157/2011) and Council of
Scientific and Industrial Research (Project no. 02(0119)/13/EMR-II)
to carry out this work is gratefully acknowledged.
4.21. (R)-Methyl 2-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)
methyl)icos-19-en-11-ynoate (29)
Supplementary data
The ester 29 (56 mg, 88%) was prepared from alcohol 40 (60 mg,
0.15 mmol) following three steps protocol as describe in above:
Preparation of compounds 20, 21 and DFT calculation of model
compounds. Copies of NMR (1H, 13C) and HRMS of representative
compounds. NOESY, COSY, HSQC spectrum of compound 35 and
35a. NOE spectrum of compound 35. These material can be found in
the online version. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.03.028.
ꢀ0.3 (c 1.3, CHCl3); 1H NMR
27
Rf¼0.5 (10% EtOAc/hexane); [
a
]
D
(CDCl3, 500 MHz)
d
5.80 (m, 1H), 4.98 (d, J¼17.1 Hz, 1H), 4.92 (d,
J¼10.1 Hz, 1H), 4.05e3.98 (m, 2H), 3.68 (s, 3H), 3.48 (t, J¼6.8 Hz,
1H), 2.58 (m, 1H), 2.12 (m, 4H), 2.03 (q, J¼6.9 Hz, 2H), 1.87 (m, 1H),
1.68e1.63 (m, 2H), 1.48e1.44 (m, 5H), 1.38e1.29 (m, 13H), 1.25 (br s,
9H); 13C NMR (CDCl3, 100 MHz)
d 176.6, 139.2, 114.3, 109.0, 80.3,
80.3, 74.4, 69.5, 51.6, 42.3, 36.3, 33.8, 33.3, 29.5, 29.4, 29.3, 29.2,
29.2, 28.9, 28.8,28.7, 27.3, 27.1, 25.7, 18.9 ppm; IR (neat) nmax 2929,
2856, 2171,1735, 1458,1251 cmꢀ1; HRMS (ESI) m/z calcd for
References and notes
C
27H46O4Na [MþNa]þ 457.3294, found 457.3297.
1. (a) Koch, S. S. C.; Chamberlin, A. R. J. Org. Chem. 1993, 58, 2725; (b) Koch, S. S. C.;
Chamberlin, A. R. Stud. Nat. Prod. Chem. 1995, 16, 687.
2. Wongsa, N.; Kanokmedhakul, S.; Kanokmedhakul, K. Phytochemistry 2011, 72,
1859.
3. Seidel, V.; Bailleul, F.; Watermana, P. G. Phytochemistry 1999, 52, 1101.
4. Wang, M. L.; Du, J.; Zhang, P. C.; Chen, R. Y.; Xie, F. Z.; Zhao, B.; Yu, D. Q. Planta
Med. 2002, 68, 719.
4.22. (3R,5S)-Dihydro-5-(hydroxymethyl)-3-(octadec-17-en-9-
ynyl) furan-2(3H)-one (6)
Following the same procedure as described for lactones 34, the
lactone 6 (27 mg, 92%) was prepared from the ester 29 (36 mg,
5. Panthama, N.; Kanokmedhakul, S.; Kanokmedhakul, K. J. Nat. Prod. 2010, 73,
1366.
6. Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Riswan, S.; Setyowati, F. M.;
Saribi, A. M.; Soejarto, D. D.; Farnsworth, N. R.; Falkinham, J. O., III; Kroll, D. J.;
Kinghorn, A. D.; Wani, M. C.; Oberlies, N. H. J. Nat. Prod. 2009, 72, 1949.
0.08 mmol) using CSA (2 mg, 0.008 mmol) in MeOH (2 mL): Rf¼0.4
23
(30% EtOAc/hexane); reported [
a
]
D
þ20.4 (c 0.206, CHCl3); ob-
23
þ16.2 (c 1.1, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 5.79
ꢀ
7. Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell, E.; Cortes, D.
served [
a
]
D
Nat. Prod. Rep. 2005, 22, 269.
(m, 1H), 4.98 (d, J¼17.1 Hz, 1H), 4.92 (d, J¼10.1 Hz, 1H), 4.57 (m, 1H),
3.85 (m, 1H), 3.64 (m, 1H), 2.69 (m, 1H), 2.29 (m, 1H), 2.13 (t,
J¼6.6 Hz, 4H), 2.06e1.93 (m, 3H), 1.82 (m, 1H), 1.46 (m, 4H), 1.36 (m,
€
8. (a) Harcken, C.; Bruckner, R.; Rank, E. Chem.dEur. J. 1998, 4, 2342; (b) Saikia, B.;
Devi, T. J.; Barua, N. C. Org. Biomol. Chem. 2013, 11, 905.
9. (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897; (b) Ireland, R. E.;
Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868; (c) Ireland, R. E.;
Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650; (d) Hong, S. P.; Lindsay, H.
A.; Yaramasu, T.; Zhang, X.; McIntosh, M. C. J. Org. Chem. 2002, 67, 2042; (e) Qin,
Y. C.; Stivala, C. E.; Zakarian, A. Angew. Chem., Int. Ed. 2007, 46, 7466; (f) Review:
Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133; (g) Review
Martin Castro, A. M. Chem. Rev. 2004, 104, 2939; (h) Review Chai, Y.; Hong, S.;
Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905; (i)
Feldman, K. S.; Selfridge, B. R. Tetrahedron Lett. 2012, 53, 825; (j) Gu, Z.; Herr-
mann, A. T.; Stivala, C. E.; Zakarian, A. Synlett 2010, 1717.
8H), 1.29 (m, 9H); 13C NMR (CDCl3, 100 MHz)
d 179.6, 139.2, 114.3,
80.3, 80.3, 78.5, 64.8, 39.7, 33.8, 31.4, 29.7, 29.4, 29.3, 29.2, 29.2,
29.0, 28.8, 28.7, 27.4, 18.9 ppm; IR (neat) nmax 3409, 2929, 2856,
2171, 1766, 1458 cmꢀ1; HRMS (ESI) m/z calcd for C23H38O3Na
[MþNa]þ 385.2719, found 385.2716. Anal. Calcd for C23H38O3: C,
76.20; H, 10.56. Found: C, 76.24; H, 10.52.
10. (a) Nagatsuma, M.; Shirai, F.; Sayo, N.; Nakai, T. Chem. Lett. 1984, 1393; (b)
Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N. J. Org. Chem. 2003, 68,
572.
4.23. (3R,5S)-Dihydro-5-(methoxymethyl)-3-(octadec-17-en-
9-ynyl)furan-2(3H)-one (7)
11. (a) Das, S.; Goswami, R. K. J. Org. Chem. 2013, 78, 7274; (b) Chakraborty, T. K.;
Goswami, R. K. Tetrahedron Lett. 2007, 48, 6463; (c) Chakraborty, T. K.; Goswami,
R. K.; Sreekanth, M. Tetrahedron Lett. 2007, 48, 4075; (d) Chakraborty, T. K.;
Goswami, R. K. Tetrahedron Lett. 2006, 47, 9373; (e) Chakraborty, T. K.; Goswami,
R. K. Tetrahedron Lett. 2004, 45, 7637.
Following the same procedure as described for lactone 4, the
lactone 7 (12 mg, 65%) was prepared in 48 h from compound 6
(19 mg, 0.05 mmol) using Me3OBF4 (39 mg, 0.26 mmol) and proton
sponge (67 mg, 0.31 mmol) in CH2Cl2 (3 mL): Rf¼0.4 (20% EtOAc/
12. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel
Dekker: New York, NY, 1969; pp 597e647.
hexane); reported [
a
]
D
23 þ18.0 (c 0.206, CHCl3); observed [
a
]
27 þ14.6
D
13. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.
14. (a) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 403;
(b) Kang, E. J.; Cho, E. J.; Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S. Y.; Chung, Y. K.;
Kim, J.-S.; Kim, H.-J.; Lee, S.-G.; Lah, M. S.; Lee, E. J. Org. Chem. 2005, 70, 6321.
(c 0.7, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 5.80 (m, 1H), 4.98 (d,
J¼17.1 Hz, 1H), 4.92 (d, J¼10.1 Hz, 1H), 4.58 (m, 1H), 3.55 (dd, J¼10.6,
3.5 Hz, 1H), 3.48 (dd, J¼10.6, 4.0 Hz, 1H), 3.37 (s, 3H), 2.68 (m, 1H),
2.27 (m, 1H), 2.12 (t, J¼6.1 Hz, 4H), 2.05e1.95 (m, 3H), 1.82 (m, 1H),
1.48e1.43 (m, 4H), 1.39e1.32 (m, 8H), 1.32e1.24 (m, 9H); 13C NMR
€
15. Kuhnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643.
16. Yadav, J. S.; Das, S. K.; Sabitha, G. J. Org. Chem. 2012, 77, 11109.
17. (a) Srihari, P.; Kumaraswamy, B.; Somaiah, R.; Yadav, J. S. Synthesis 2010, 1039;
(b) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
(CDCl3, 125 MHz)
d 179.7, 139.2, 114.3, 80.3, 80.3, 76.9,74.4, 59.6,
39.4, 33.8, 31.3, 30.5, 29.4, 29.3, 29.2, 29.2, 29.0, 28.8, 28.7, 27.4,
18.9 ppm; IR (neat) nmax 2929, 2856, 2160,1770, 1456 cmꢀ1; HRMS
(ESI) m/z calcd for C24H40O3Na [MþNa]þ 399.2875, found 399.2877.
Anal. Calcd for C24H40O3: C, 76.55; H, 10.71. Found: C, 76.33; H,
10.74.
18. Siddiqui, M. A.; Marquez, V. E.; Driscoll, J. S.; Barchi, J. J., Jr. Tetrahedron Lett.
1994, 35, 3263.
19. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
20. Some selected references for use of different bases in IrelandeClaisen re-
arrangement: (a) For NaHMDS see: Pal, U.; Ranatunga, S.; Ariyarathna, Y.; Del
Valle, J. R. Org. Lett. 2009, 11, 5298; (b) For KHMDS see: (i) Nogoshi, K.; Domon,
D.; Fujiwara, K.; Kawamura, N.; Katoono, R.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2013, 54, 676; (ii) Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. J. Org. Chem.
2004, 69, 8172; (c) For LDA related see: (i) Wuts, P. G. M.; Ritter, A. R.; Pruitt, L.
E. J. Org. Chem. 1992, 57, 6696; (ii) Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J.
Acknowledgements
ꢁ
Org. Chem. 2004, 69, 112; (iii) Araoz, R.; Servent, D.; Molgo, J.; Iorga, B. I.;
T.K.K. and S.C. thank to Council of Scientific and Industrial Re-
search (_501100001412), New Delhi, India, for research fellowships.
We are grateful to Prof. Kanokmedhakul (isolation group) for
providing us the copies of NMR spectra of all cananginones. We
sincerely thank Prof. Dipankar Datta, Department of Inorganic
Chemistry, IACS for his help with the DFT calculations and useful
Gaillard, C. F.; Benoit, E.; Gu, Z.; Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2011,
133, 10499; (d) For LiHMDS see: (i) Mulzer, J.; Mohr, J. T. J. Org. Chem. 1994, 59,
1160; (ii) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529; (iii) Magauer, T.; Martin,
H. J.; Mulzer, J. Chem.dEur. J. 2010, 16, 507.
21. Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe,
J. J. Org. Chem. 1980, 45, 1066.
22. Moreland, D. W.; Dauben, W. G. J. Am. Chem. Soc. 1985, 107, 2264.
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028

14
T.K. Kuilya et al. / Tetrahedron xxx (2014) 1e14
23. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
24. Nicolai, S.; Sedigh-Zadeh, R.; Waser, J. J. Org. Chem. 2013, 78, 378.
25. Please see Supplementary data for preparation of vinyl iodide 20.
26. Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995, 117,
3448.
27. Please see Supplementary data for preparation of vinyl iodide 21.
28. Personal communication with the isolation group2 revealed that there is a ty-
pographical mistake in the chemical shift of the olefinic proton of cananginone
minimize the exposure to light, which, we think, may enhance the rate of
isomerization. The Sonogashira reactions of alkynes 22 and 23 with the vinyl
iodides 20 and 21 have been carried out in the dark by covering the reaction
vessels by aluminum foil or by carbon paper. The purification and data re-
cording have been done very quickly in very low intensity light to minimize the
conversion to the trans-isomer.
30. For chemical shift of olefin proton
b to alkyne group in both cis- and trans-
enyne system see: Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. J. Org. Chem.
I (9). While it is experimentally observed at
6.03 ppm in the published paper.
29. For preparation of isomerically pure cananginones (E, H, I), we planned to in-
d 5.78 ppm, it has been mistyped as
2007, 72, 3868.
d
31. Please see Supplementary data for DFT calculation.
32. Johnson, D. K.; Donohoe, J.; Kang, J. Synth. Commun. 1994, 24, 1557.
stall a sensitive cis-enyne system as the last step of the synthetic route to
Please cite this article in press as: Kuilya, T. K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.028