A convenient chiron approach to (4R,5R)-5-hydroxyalkylbutan-4-olides and the corresponding 7-oxa analogues from d-(+)-mannitol via an advanced common precursor: Syntheses of (-)-muricatacin, 7-oxa-(-)-muricatacin, (4R,5R)-(-)-5-hydroxy-4-decanolide, and (4R,5R)-(-)-7-oxa-5-hydroxy-4-dodecanolide

Article abstract of DOI:10.1016/j.tetasy.2014.11.001

An efficient and concise chiron approach toward the synthesis of (-)-muricatacin and its unnatural 7-oxa analogue starting from commercially available and inexpensive d-(+)-mannitol via an advanced common chiral precursor has been described. In addition, (4R,5R)-(-)-5-hydroxy-4-decanolide and (4R,5R)-(-)-7-oxa-5-hydroxy-4-dodecanolide were also synthesized to show the versatility of this synthetic strategy. The methodology involves the conversion of a common chiral intermediate, prepared from d-(+)-mannitol in six steps, to a variety of target molecules in only two steps.

Full text of DOI:10.1016/j.tetasy.2014.11.001

Tetrahedron: Asymmetry 25 (2014) 1624–1629
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A convenient chiron approach to (4R,5R)-5-hydroxyalkylbutan-4-
olides and the corresponding 7-oxa analogues from D-(+)-mannitol
via an advanced common precursor: syntheses of (À)-muricatacin,
7-oxa-(À)-muricatacin, (4R,5R)-(À)-5-hydroxy-4-decanolide, and
(4R,5R)-(À)-7-oxa-5-hydroxy-4-dodecanolide
⇑
Sandip Chatterjee, Avrajit Manna, Tanurima Bhaumik
Department of Chemistry, Jadavpur University, Jadavpur, Kolkata 700032, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2014
Accepted 3 November 2014
An efficient and concise chiron approach toward the synthesis of (À)-muricatacin and its unnatural 7-oxa
analogue starting from commercially available and inexpensive D-(+)-mannitol via an advanced common
chiral precursor has been described. In addition, (4R,5R)-(À)-5-hydroxy-4-decanolide and (4R,5R)-(À)-7-
oxa-5-hydroxy-4-dodecanolide were also synthesized to show the versatility of this synthetic strategy.
The methodology involves the conversion of a common chiral intermediate, prepared from
tol in six steps, to a variety of target molecules in only two steps.
D-(+)-manni-
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
revealed that the length of the side chain is vital. Decreasing the
length of the alkyl side chain leads to reduced activity, while
increasing the chain length does not show any enhanced activ-
ity.2a,3,4 Its importance has stimulated significant interest in its
synthesis.5,9b
Chiral hydroxylactones are important bio-active molecules and
are useful synthetic intermediates in total synthesis. One example
of such a group of molecules is the 5-hydroxyalkylbutan-4-olides
of general structure 1. These are widely distributed in Nature, show
diverse biological activities and many of these are often used as
synthons in the synthesis of more complex and biologically impor-
tant natural products.1 Some of these compounds are known to
have insect anti-feedant activity2c and some are cytotoxic to
human tumor cells.2a The short chain homologues are important
flavor constituents in wine, sherry, and tobacco smoke.2b,d–f
O
HO
O
9
(-)-muricatacin 2
In 2007, Ruther et al. reported that a mixture of (4R,5R)-(À)-5-
hydroxy-4-decanolide 3 and its diastereoisomer (4R,5S)-(À)-5-
hydroxy-4-decanolide was released occasionally in the abdomens
of male jewel wasps, Nasonia vitripennis Walker and attracted vir-
gin females, but not males. This was the first identification of a
male sex pheromone in the parasitic Hymenoptera.6
O
HO
5
O
1
2
4
R
3
1
One such molecule that has gained much interest since its iso-
lation is the acetogenin derivative muricatacin, which was isolated
several years ago by McLaughlin et al. from the seeds of Annona
Muricata.3 Both (+)- and (À)-enantiomers, ent-2 and 2, respectively,
can be found in Nature and both exhibit the same potent cytotox-
icity toward several human tumor cell lines. Biological studies
O
HO
O
2
(4R,5R)-(-)-5-hydroxy-4-decanolide 3
In 1982, Gräfe7 isolated (4S,5R)-(+)-5-hydroxy-4-decanolide
and its (4S,5S)-(+)-diastereoisomer, known as L-factors, from a
⇑
Corresponding author. Tel.: +91 033 2457 2504; fax: +91 033 2414 6414.
E-mail address: tanurimabhaumik@gmail.com (T. Bhaumik).
http://dx.doi.org/10.1016/j.tetasy.2014.11.001
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

S. Chatterjee et al. / Tetrahedron: Asymmetry 25 (2014) 1624–1629
1625
culture of Streptomyces griseus. These two occur temporarily before
the production of the anthracycline antibiotic leukaemomycin dur-
ing the fermentation of Streptomyces griseus. Since then, a number
of publications toward the syntheses of all four stereoisomers of 5-
hydroxy-4-decanolide have been reported in the literature.8
Apart from these naturally occurring molecules, unnatural ana-
logues have also been synthesized and evaluated for their antitu-
mor activities. Among them 7-oxa-(À)-muricatacin 4 was the
most significant. It was designed as a possible muricatacin bioiso-
stere and was found to have more potent and selective antitumor
activity than muricatacin.9b,c Until today, only two groups5q,9a,c
have developed synthetic strategies for this bioactive unnatural
molecule.
moiety. We assumed that the key intermediate 7 could be easily
prepared from commercially available C2 symmetric -(+)-manni-
tol 8 via an easy reaction sequence. The approach was based on
D
the fact that the stereochemistry inherited from C-3 and C-4 of
D-(+)-mannitol could be translated into the desired stereochemis-
try at C-4 and C-5 of the target molecules. This type of chiron
approach is one of the most widely used approaches toward the
total synthesis of natural products in which chiral templates such
as amino acids, carbohydrates, hydroxy acids, and terpenes are
used as starting materials. Herein we report the results of our
investigation based on this concept.
O
HO
n
O
O
O
O
HO
O
X
O
O
COOEt
6
7
9
X= CH2, O
7-oxa-(-)-muricatacin 4
OH
OH
Herein we report a general but simple, short, and flexible
approach to give access to not only various enantiopure (4R,5R)-
5-hydroxyalkylbutan-4-olides but also their 7-oxa analogues start-
OH
HO
OH
OH
ing from
sive molecule from the chiral pool, via ethyl 3-((4R,5S)-5-formyl-
2,2-dimethyl-1,3-dioxolan-4-yl)propanoate 7, common key
D
-(+)-mannitol 8, a commercially available and inexpen-
8
Scheme 1. Retrosynthetic analysis.
a
intermediate. Our approach here is exemplified by the total syn-
thesis of naturally occurring (À)-muricatacin 2 and (4R,5R)-(À)-
5-hydroxy-4-decanolide 3 as well as by the synthesis of unnatural
3. Results and discussion
For entry into both (4R,5R)-5-hydroxyalkylbutan-4-olides and
the corresponding 7-oxa analogues 6, aldehyde–ester 7 is required
7-oxa-(À)-muricatacin
4 and a hitherto unknown c-lactone,
(4R,5R)-(À)-7-oxa-5-hydroxy-4-dodecanolide, 5. The publication
of a general synthetic approach5q for the enantiodivergent formal
synthesis of the muricatacins and the preparation of enantiomeri-
(Scheme 2). Toward this end, D-(+)-mannitol 8 was converted into
glycol 10 by following the literature procedure.10 Here we would
like to state that while the yield of the acetonide protection reac-
tion was very good (90–95%), the yield obtained in the selective
cally pure 7-oxa-muricatacins starting from
publication of an article5k describing a strategy, which is applicable
to the preparation of diverse enantiomerically pure -lactones
including (À)-muricatacin and is based upon the desymmetriza-
tion of a -mannitol or tartaric acid derived C2 symmetric dienedio-
D-xylose, as well as
c
D
OH
OH
O
O
O
ate by monodihydroxylation as well as elaboration of the hydroxy
alkyl side chains on an aldehyde intermediate that is structurally
close to our key intermediate 7 have encouraged us to report our
findings on this subject.
OH
a
a
HO
OH
OH
O
O
O
8
9
O
HO
O
O
O
O
O
O
O
b
4
O
(4R,5R)-(-)-7-oxa-5-hydroxy-4-dodecanolide 5
O
O
HO
OH
O
10
11
2. Retrosynthetic analysis
O
O
O
O
O
O
d
c
We envisaged that (4R,5R)-5-hydroxyalkylbutan-4-olides and
the corresponding 7-oxa analogues of general structure 6 would
easily be obtained from an advanced common precursor 7, an
aldehyde–ester (Scheme 1). The aldehyde functionality present
in the key intermediate 7 could be used for the elaboration of
various alkyl side chains of (4R,5R)-5-hydroxyalkylbutan-4-olides
6 (X = CH2) via Wittig olefination followed by catalytic hydrogena-
tion. Moreover, the aldehyde functionality in 7 could also be used
to introduce a range of alkoxy side chains present in the corre-
sponding 7-oxa analogues 6 (X = O) via chemoselective reduction
of aldehyde functionality followed by alkylation of the newly gen-
COOEt
COOEt
HO
OH
13
O
12
O
O
O
e
O
COOEt
COOEt
HO
OH
14
7
erated primary hydroxyl group. In addition, a masked
ester such as 7 could readily undergo spontaneous lactonization
during ketal hydrolysis to serve as a precursor for the -lactone
c-hydroxy-
Scheme 2. Reagents and conditions: (a) Ref. 10; (b) NaIO4, MeCN–H2O, 0 °C–rt, 6 h,
then TEPA, satd K2CO3, 0 °C–rt, 12 h, 88%; (c) CuCl2Á2H2O, MeCN, 20–25 °C, 3 h, 55–
65%; (d) H2/Pd–C, MeOH, rt, 24 h, 88%; (e) NaIO4, MeOH–H2O, 0 °C to rt, 6 h, 99%.
c

1626
S. Chatterjee et al. / Tetrahedron: Asymmetry 25 (2014) 1624–1629
hydrolysis reaction was poor (20–30%). However, it was encourag-
ing that this inefficient hydrolysis reaction could be carried out on
a large scale and almost all of the unreacted starting materials
could be recovered in a pure state. The Horner–Wadsworth–
Emmons reaction on aldehyde 11 furnished almost exclusively
completion of the synthesis, a methanolic solution of olefin 15 was
hydrogenated using palladium on charcoal to furnish the saturated
ester 17. Without isolating this expected hydrogenated product 17
after completion of the reaction, as indicated by TLC, the resulting
methanolic solution was treated with inorganic acid. This led to an
acid-induced deketalization of 17 followed by a spontaneous con-
comitant acid promoted lactonization of the in situ generated
deketalized product, a dihydroxyester, to afford the desired chiral
the
a
,b-unsaturated ester 12 (determined by 1H NMR spectros-
copy). Aldehyde 11 was indeed generated in situ by periodate
cleavage of glycol 10. The major product 12 was isolated in 88%
yield after column chromatography. The E-configuration at the
newly formed C@C bond in this major product 12 was confirmed
by the large coupling constant between the two olefinic hydrogens,
hydroxylactone (À)-muricatacin 2, [
a
]
25 = À21.8 (c 1.06, CHCl3)
D
{lit.5k
to the
[a]
25 = À22.10 (c 0.64, CHCl3)}, in 91% yield. The ring closure
D
c
-lactone occurs immediately according to Baldwin’s rules.12
Jtrans (H,H) = 15.7 Hz. Selective hydrolysis of the terminal acetonide
The 1H and 13C NMR spectra of the sample obtained in this way
were closely comparable to those reported in the literature.5k Fol-
lowing the same one-pot protocol as mentioned above, (4R,5R)-
in the diacetonide 12 using an equivalent amount of CuCl2Á2H2O
at 20–25 °C generated diol 13 in moderate yield (55–65%) along
with the starting material.11 This unsaturated product 13 was
allowed to undergo hydrogenation reaction in the presence of
10% Pd–C to afford the expected saturated compound 14 in 88%
yield. Oxidative cleavage of the saturated glycol-ester 14 gave
our desired aldehyde–ester 7, the divergent intermediate for the
syntheses of both (4R,5R)-5-hydroxyalkylbutan-4-olides and the
corresponding 7-oxa analogues. This aldehyde 7, after having been
(À)-5-hydroxy-4-decanolide 3, [
a
]
D
25 = À32.4 (c 0.33, CHCl3) {lit.8q
[a]
25 = À33.1 (c 1.64, CHCl3)}, was subsequently obtained from ole-
D
fin 16 in 91% yield. The procedure involved catalytic hydrogenation
of olefin 16 followed by acid-induced deketalization of the result-
ing saturated compound 18 and finally a spontaneous lactonization
of the deketalized product to give the desired chiral c
-lactone 3. 1H
and 13C NMR spectral data of compound 3 prepared in this way
were also as good as those reported in the literature.5y
prepared from D-mannitol 8 in only six steps, was subjected to var-
ious reactions as per the requirement of our synthetic plan without
further purification.
Aldehyde 7 can also be employed for the synthesis of the 7-oxa
analogues of (4R,5R)-5-hydroxyalkylbutan-4-olides, 6 (X = O) in a
highly efficient two-step procedure as shown in Scheme 4. While
the first step is the sodium borohydride reduction of aldehyde 7
to afford the corresponding primary alcohol 19 in 79% yield, the
final step is the treatment of the resulting primary alcohol 19 with
appropriate alkyl bromides in the presence of silver oxide and
silver triflate in refluxing ether. The latter transformation gave rise
to the desired 7-oxa analogues of 5-hydroxyalkylbutan-4-olides 6
(X = O) in a tandem etherification-ketal hydrolysis-lactonization
After successful synthesis of aldehyde 7, we focused on its
transformation to both (À)-muricatacin
2
and (4R,5R)-(À)-5-
hydroxy-4-decanolide 3. This was achieved in only two steps as
delineated in Scheme 3. At this stage, alkyl side chains of various
lengths, the typical feature of the target molecules (4R,5R)-5-
hydroxyalkylbutan-4-olides 6 (X = CH2), were introduced. For this
purpose, aldehyde 7 was treated with the appropriate ylides pre-
pared from suitable phosphonium salts with different alkyl groups
to provide the corresponding olefins. In fact, Wittig olefination of
the key aldehyde 7 in THF with the appropriate C-11 ylide (unde-
cylphosphonium bromide/nBuLi) gave rise to the corresponding
unsaturated compound 15 as a mixture of E- and Z-isomers in
68% yield. No effort was made to determine the relative ratio of
the two isomers in the mixture as well as their separation since
in the next step, this mixture of two diastereoisomeric olefins
was going to be hydrogenated in the presence of 10% Pd–C to give
a single isomer of the saturated compound 17. However, 1H and
13C NMR spectra of the mixture showed the predominance of the
Z-isomer (Jcis (H,H) ꢀ 10 Hz) over the other. A similar result was
obtained when the THF solution of aldehyde 7 was treated with
butylphosphonium bromide/nBuLi. This led to formation of unsat-
urated compound 16 as a mixture of E- and Z-isomers in 70% yield,
(here also the Z-isomer was the major isomer in the mixture). For
step. The use of decyl bromide in the final step produced 7-oxa-
25
(À)-muricatacin 4,
[
a]
25 = À32.5 (c 0.80, CHCl3) {lit.9c
[a
]
D
=
D
À33.0 (c 0.8, CHCl3)}, in 89% yield. The 1H and 13C NMR spectral
data of this were comparable to those reported in the literature.9c
To show the versatility of this synthetic methodology for the easy
preparation of a variety of 7-oxa analogues of (4R,5R)-5-hydrox-
yalkylbutan-4-olides for biological evaluation, another relatively
smaller alkyl bromide, pentyl bromide, was used in the ultimate
step, which led to the isolation of the expected hitherto unknown
chiral
c
-lactone (4R,5R)-(À)-7-oxa-5-hydroxy-4-dodecanolide 5,
[a]
25 = À29.5 (c 0.3, CHCl3), in 86% yield.
D
O
O
O
O
O
a
b
O
HO
COOEt
COOEt
7
19
O
O
O
O
a
b
O
HO
O
COOEt
COOEt
n
O
7
15
, n = 9
16, n = 2
n
4
, n = 9
5
, n = 4
O
O
O
HO
O
Scheme 4. Reagents and conditions: (a) NaBH4, MeOH, rt, 10 h, 79%;
(b) CH3(CH2)nBr, AgOTf, Ag2O, Et2O, reflux, 7 h, 89% for 4, 86% for 5.
COOEt
n
n
2, n = 9
17, n = 9
18, n = 2
3
, n = 2
4. Conclusion
Scheme 3. Reagents and conditions: (a) [CH3(CH2)nCH2PPh3]Br, nBuLi, dry THF,
À10 °C–rt, 3 h, 68% for 15, 70% for 16; (b) H2/Pd–C, MeOH, rt, 24 h then concd HCl
(cat.), rt, 12 h, 91% for 2, 91% for 3.
We have successfully developed a new, simple, concise, effi-
cient, general, and flexible chiron approach that provides access

S. Chatterjee et al. / Tetrahedron: Asymmetry 25 (2014) 1624–1629
1627
to both (4R,5R)-5-hydroxyalkylbutan-4-olides and their corre-
sponding 7-oxa analogues in enantiomerically pure forms from a
was decanted off from the top and the solid mass was washed
thoroughly with diethyl ether. The combined liquid was finally
extracted with diethyl ether (3 Â 20 mL). The resulting combined
organic layer was washed with water, brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off to give
the crude product 12 as a viscous liquid with negligible amount
of the possible cis-isomer (as evident from 1H and 13C NMR spectra
of the crude product). It was further purified by column chroma-
tography using ethyl acetate–hexane (1:9) as eluent to afford pure
D
-mannitol derived enantiomerically pure advanced common pre-
cursor. It uses inexpensive reagents and a readily available starting
material and involves conversion of the common intermediate,
prepared from D-(+)-mannitol in six steps, to a variety of desired
target molecules in only two steps. Almost all of the steps are mod-
erate to high yielding. Flexibility is built into the synthesis and a
large number of derivatives are available by a slight modification
to these procedures. Using the above strategy, the total synthesis
of naturally occurring (À)-muricatacin and (4R,5R)-(À)-5-
hydroxy-4-decanolide has been accomplished. This approach has
also been applied for the preparation of unnatural 7-oxa-(À)-muri-
catacin, which shows powerful antiproliferative activities against
some malignant cells and even found to have more potent and
selective antitumor activity than the naturally occurring murica-
tacins. The synthesis of a hitherto unknown compound, (4R,5R)-
(À)-7-oxa-5-hydroxy-4-dodecanolide has also been reported.
Hence, the synthetic methodology is suitable for the easy and
efficient preparation of libraries of (4R,5R)-5-hydroxyalkylbutan-
4-olides and their corresponding 7-oxa analogues for biological
evaluation. Further application of this strategy for the synthesis
a
,b-unsaturated ester 1215 (20.15 g, 88%) as a colorless viscous
liquid: [
a]
D
25 = À2.95 (c 0.60, CHCl3);
m
max/cmÀ1 (KBr) 1724.1,
1663.3; dH (CDCl3, 300 MHz) 1.29 (3H, t, J 7.2 Hz, CH3), 1.35 (3H,
s, CH3), 1.41 (6H, s, CH3), 1.43 (3H, s, CH3), 3.68 (1H, t, J 7.6 Hz,
OCH2), 3.95 (1H, dd, J 10.9, 6.9 Hz, OCH2), 4.10–4.16 (1H, m,
OCH), 4.17–4.24 (3H, m, OCH2, OCH), 4.54 (1H, ddd, J 6.1, 4.5,
1.5 Hz, OCH), 6.16 (1H, dd, J 15.7, 1.5 Hz, @CH), 7.01 (1H, dd, J
15.7, 4.5 Hz, @CH); dC (CDCl3, 75 MHz) 14.0 (CH3), 25.0 (CH3),
26.5 (2Â CH3), 26.8 (CH3), 60.2 (OCH2), 67.3 (OCH2), 76.6 (OCH),
78.8 (OCH), 81.0 (OCH), 109.6 (C), 110.0 (C), 121.2 (@CH), 144.9
(@CH), 166.0 (CO); HRMS (ESI) calcd for C15H24O6Na [M+Na]+,
323.1417; found, 323.1417.
of
a
number of bio-active lactones such as the phytotoxic
5.1.2. (E)-Ethyl 3-((4R,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)acrylate 13
(4R,5R)-(À)-sapinofuranone B13,14 is currently being investigated
in our laboratory.
To a magnetically stirred ice-cold solution of 12 (14.9 g,
49.61 mmol) in acetonitrile (11.4 mL) was added CuCl2Á2H2O
(8.44 g, 49.61 mmol). After stirring the resulting reaction mixture
at 20–25 °C for 3 h, it was quenched with aqueous saturated
sodium bicarbonate solution and extracted with ethyl acetate
(3 Â 20 mL). The combined organic layer was washed with water,
brine, and dried over anhydrous sodium sulfate. The removal of
the solvent was followed by column chromatography. The use of
ethyl acetate–hexane as eluent in a 1:9 ratio led to the isolation
of unreacted starting material 12 (5.16 g) while that of ethyl
acetate–hexane as eluent in a 1:1 ratio furnished the pure diol
5. Experimental
5.1. General
1H NMR spectra were recorded in a Bruker 500/300 (500/
300 MHz, respectively) spectrometer as a solution in deuteriochlo-
roform (CDCl3) unless stated otherwise. Chemical shifts are
expressed in parts per million (ppm, d) and with tetramethylsilane
or chloroform as the internal standard. The coupling constants are
absolute values and are expressed in Hz. Signal description: s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet
of doublet, dt = doublet of triplet, br s = broad singlet. 13C NMR
spectra were recorded in a Bruker 500/300/200 (125/75/50 MHz,
respectively) spectrometer as a solution in deuterated chloroform
(CDCl3) solution unless stated otherwise with complete decoupling
of the proton. Chemical shifts are expressed in parts per million
(ppm, d) and are referred to chloroform as the internal standard.
High-resolution mass spectra (HRMS) were recorded on a TOF
spectrometer using the simultaneous electrospray (ESI) method.
Routine monitoring of reactions were carried out with pre-coated
Al plates, which were analyzed with iodine. THF was dried by
refluxing with metallic sodium prior to use. All solvents were dis-
tilled normally before use. Column chromatographic purifications
were carried out with silica gel 60–120 until stated otherwise.
All of the moisture sensitive reactions were performed using oven
dried glassware and under an inert gas atmosphere.
13 (8.36 g, 65%) as a viscous liquid: [
a]
25 = +4.65 (c 0.50, CHCl3);
D
m
max/cmÀ1 (KBr) 3439.4, 1721.6, 1660.5; dH (CDCl3, 300 MHz)
1.32 (3H, t, J 7.1 Hz, CH3), 1.44 (3H, s, CH3), 1.47 (3H, s, CH3),
2.11 (1H, br s, OH), 2.64 (1H, br s, OH), 3.70–3.75 (1H, m, OCH),
3.81–3.85 (3H, m, OCH, OCH2), 4.23 (2H, q, J 7.1 Hz, OCH2),
4.62–4.66 (1H, m, OCH), 6.19 (1H, d, J 15.6 Hz, @CH), 7.01 (1H,
dd, J 15.6, 4.8 Hz, @CH); dC (CDCl3, 75 MHz) 14.1 (CH3), 26.6
(CH3), 26.9 (CH3), 60.7 (OCH2), 63.7 (OCH2), 73.0 (OCH), 78.2
(OCH), 80.3 (OCH), 110.1 (C), 121.4 (@CH), 145.7 (@CH), 166.7
(CO); HRMS (ESI) calcd for C12H20O6Na [M+Na]+, 283.1158; found,
283.1157.
5.1.3. Ethyl 3-((4R,5R)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)propanoate 14
A solution of the a,b-unsaturated ester 13 (2.0 g, 7.64 mmol) in
methanol (1 mL) containing a catalytic amount of Pd–C (10%) was
stirred under a hydrogen atmosphere at room temperature for
24 h. The catalyst was then filtered off and the solvent was evapo-
rated to yield the crude product. Column chromatography using
ethyl acetate–hexane (1:1) as eluent produced the product 14
5.1.1. (E)-Ethyl 3-((4R,5S)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)2,2-dimethyl-1,3-dioxolan-4-yl)acrylate 12
a]
25 = +16.4 (c 3.72,
D
To
a magnetically stirred ice-cold solution of 10 (20 g,
(1.77 g, 88%) as a colorless viscous liquid: [
max/cmÀ1 (KBr) 3443.9, 1732.0; dH (CDCl3, 300 MHz)
76.25 mmol) in 60% acetonitrile–water (200 mL) was added
sodium metaperiodate (24.46 g, 114.46 mmol) portionwise.
Stirring was continued at room temperature for approximately
6 h, until the disappearance of the starting material (checked by
performing TLC). Then to the ice-cold reaction mixture triethyl
phosphonoacetate (TEPA) (15.2 mL, 76.25 mmol) was added drop-
wise followed by the addition of a saturated aqueous solution of
potassium carbonate (200 mL). The resulting mixture was stirred
for 12 h. The solid mass was then allowed to settle. The liquid layer
CHCl3);
m
1.28 (3H, t, J 7.1 Hz, CH3), 1.38 (3H, s, CH3) 1.41 (3H, s, CH3), 1.69
(1H, br s, OH), 1.87–1.92 (1H, m, CH2), 2.10–2.15 (1H, m, CH2),
2.50–2.57 (2H, m, CH2), 2.87 (1H, br s, OH), 3.68–3.82 (4H, m,
OCH, OCH2), 4.00–4.06 (1H, m, OCH), 4.16 (2H, q, J 7.1 Hz, OCH2);
dC (CDCl3, 75 MHz) 14.1 (CH3), 27.0 (CH3), 27.2 (CH3), 29.0 (CH2),
30.6 (CH2), 60.5 (OCH2), 64.0 (OCH2), 73.1 (OCH), 78.7 (OCH),
80.3 (OCH), 109.0 (C), 173.9 (CO); HRMS (ESI) calcd for C12H22O6Na
[M+Na]+, 285.1314; found, 285.1312.

1628
S. Chatterjee et al. / Tetrahedron: Asymmetry 25 (2014) 1624–1629
5.1.4. Ethyl 3-((4R,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl)
propanoate 7
(OCH), 79.8 (OCH), 108.5 (C), 126.2 (@CH), 136.3 (@CH), 173.1
(CO); HRMS (ESI) calcd for C15H26O4Na [M+Na]+, 293.1729; found,
293.1726.
To a magnetically stirred ice-cold solution of diol 14 (1.61 g,
6.14 mmol) in 60% methanol–water (2 mL) was added sodium
metaperiodate (1.97 g, 9.21 mmol) portionwise. Stirring was con-
tinued until the disappearance of the starting material (checked
by performing TLC). The reaction mixture was then filtered
through CeliteÒ to remove the solids. The solid in turn was washed
thoroughly with diethyl ether. The combined organic layer was
washed with water, brine, and dried over anhydrous sodium sul-
fate. The solvent was evaporated to afford aldehyde 716 (1.40 g,
99%) as a viscous liquid which was used for the next step without
5.1.7. Ethyl 3-((4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)propanoate 19
To a magnetically stirred ice-cold solution of aldehyde 7 (1.26 g,
5.47 mmol) in methanol (7 mL) under an argon atmosphere was
added sodium borohydride (0.41 g, 10.94 mmol) in small portions.
After stirring the reaction mixture for 10 h at room temperature, it
was quenched with a saturated aqueous ammonium chloride
solution. The aqueous layer was extracted with ethyl acetate
(3 Â 2 mL) and the combined organic layer was washed with
water, brine, and dried over anhydrous sodium sulfate. The residue
obtained by evaporation of the solvent was purified by performing
column chromatography using ethyl acetate–hexane (1:1) as elu-
further purification: m
max/cmÀ1 (KBr) 1737.3; dH (CDCl3, 500 MHz)
1.25 (3H, t, J 8.8 Hz, CH3), 1.40 (3H, s, CH3) 1.47 (3H, s, CH3),
1.93–1.98 (1H, m, CH2), 2.05–2.08 (1H, m, CH2), 2.43–2.49 (2H,
m, CH2), 3.97 (1H, d, J 9.0 Hz, OCH), 4.07–4.16 (3H, m, OCH,
OCH2), 9.73 (1H, s, CHO); dC (CDCl3, 125 MHz) 14.2 (CH3), 26.2
(CH3), 27.1 (CH3), 28.5 (CH2), 30.2 (CH2), 60.6 (OCH2), 76.0 (OCH),
84.6 (OCH), 111.2 (C), 172.8 (CO), 201.0 (CHO); HRMS (ESI) calcd
for C11H18O5Na [M+Na]+, 253.1052; found, 253.1056.
ent to give pure 1916 (1.0 g, 79%) as a viscous liquid: [
a]
25 = +24.9
D
(c 0.60, CHCl3);
m
max/cmÀ1 (KBr) 3476.6, 1737.3; dH (CDCl3,
300 MHz), 1.20 (3H, t, J 7.13 Hz, CH3), 1.33 (3H, s, CH3), 1.34 (3H,
s, CH3), 1.74–1.86 (1H, m, CH2), 1.87–1.93 (1H, m, CH2),
2.38–2.47 (2H, m, CH2), 2.73 (1H, br s, OH), 3.57–3.62 (1H, m,
OCH2), 3.67–3.74 (2H, m, OCH, OCH2), 3.80–3.87 (1H, m, OCH),
4.07 (2H, q, J 7.1 Hz, OCH2); dC (CDCl3, 75 MHz) 14.2 (CH3), 27.0
(CH3), 27.2 (CH3), 28.0 (CH2), 30.6 (CH2), 60.5 (OCH2), 61.9
(OCH2), 76.2 (OCH), 81.1 (OCH), 108.9 (C), 173.3 (CO); HRMS
(ESI) calcd for C11H20O5Na [M+Na]+, 255.1208; found, 255.1207.
5.1.5. Ethyl 3-((4R,5R)-5-(dodec-1-enyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)propanoate 15
To
a cooled suspension of undecylphosphonium bromide
(0.85 g, 1.71 mmol) in dry THF (15 mL) at À10 °C was added nBuLi
(0.8 mL of 1.6 M solution in THF) dropwise. The resulting orange
red mixture was then allowed to return to room temperature
and stirred for 3 h. The freshly prepared aldehyde 7 (0.22 g,
0.85 mmol) in dry THF (6 mL) was added slowly to the resulting
solution at À10 °C. It was then stirred for 3 h at room temperature.
The reaction was quenched with a saturated aqueous solution of
ammonium chloride at 0 °C and the resulting mixture was
extracted with diethyl ether (3 Â 5 mL). The combined organic
layer was washed with water, brine, dried over anhydrous sodium
sulfate, and evaporated under reduced pressure. The crude product
thus obtained was subjected to column chromatography using
ethyl acetate–hexane (1:9) as eluent to isolate the E–Z mixture of
5.1.8. (À)-Muricatacin 2
A solution of the E–Z mixture of the unsaturated ester 15 (0.2 g,
0.54 mmol) in methanol (0.5 mL) containing a catalytic of amount
of Pd–C (10%) was stirred under a hydrogen atmosphere at room
temperature for 24 h. To the resulting reaction mixture was added
a catalytic amount of concentrated hydrochloric acid at 0 °C and
was again stirred for 12 h. The reaction was quenched with satu-
rated aqueous sodium bicarbonate solution and extracted with
ethyl acetate (3 Â 2 mL). The combined organic layer was washed
with water, brine, and dried over anhydrous sodium sulfate. The
residue obtained after removal of the solvent was purified by col-
umn chromatography using ethyl acetate–hexane (3:2) as eluent
to afford compound 2 as a white crystalline solid (0.14 g, 91%) with
the alkenes 15 (0.24 g, 68%) as a viscous liquid: m
max/cmÀ1 (KBr)
2927.2, 1740.0; dH (for the major isomer from the mixture) (CDCl3,
300 MHz) 0.90 (3H, t, J 6.3 Hz, CH3), 1.28 (17H, br s, CH3, CH2), 1.42
(6H, s, CH3), 1.57 (2H, s, CH2), 1.84–1.95 (2H, m, CH2), 2.08–2.20
(2H, m, CH2), 2.42–2.52 (2H, m, CH2), 3.65–3.70 (1H, m, OCH),
4.10–4.24 (2H, m, OCH2) 4.40 (1H, t, J 8.6 Hz, OCH), 5.36 (1H, t, J
10.1 Hz, @CH), 5.72 (1H, dt, J 10.7, 7.5, Hz, @CH); dC (for the major
isomer from the mixture) (CDCl3, 75 MHz) 14.1 (CH3), 14.2 (CH3),
22.6 (CH2), 26.8 (CH2), 27.1 (CH3), 27.2 (CH3), 27.8 (CH2), 29.2
(CH2), 29.3 (CH2), 29.4 (CH2), 29.55 (CH2), 29.58 (CH2), 29.61
(CH2), 30.8 (CH2), 31.9 (CH2), 60.3 (OCH2), 76.5 (OCH), 79.9
(OCH), 108.5 (C), 125.9 (@CH), 136.6 (@CH), 173.0 (CO); HRMS
(ESI) calcd for C22H40O4Na [M+Na]+, 391.2824; found, 391.2818.
a melting point of 70 °C (lit.5k mp 71 °C): [
CHCl3);
a]
25 = À21.8 (c 1.06,
D
m
max/cmÀ1 (KBr) 3398.1, 1743.4; dH (CDCl3, 300 MHz),
0.88 (3H, t, J 6.2 Hz, CH3), 1.26 (18H, s, CH2) 1.53 (5H, s, CH2,
OH), 2.05–2.31 (2H, m, CH2), 2.48–2.68 (2H, m, CH2), 3.57–3.58
(1H, m, OCH), 4.38–4.45 (1H, m, OCH); dC (CDCl3, 75 MHz), 14.1
(CH3), 22.7 (CH2), 24.1 (CH2), 25.5 (CH2), 28.7 (CH2), 29.3 (CH2),
29.50 (CH2), 29.56 (CH2), 29.62 (CH2), 29.64 (3Â CH2), 31.9 (CH2),
33.0 (CH2), 73.6 (OCH), 83.0 (OCH), 177.4 (CO); HRMS (ESI) calcd
for C17H32O3Na [M+Na]+, 307.2249; found, 307.2248.
5.1.9. (4R,5R)-(À)-5-Hydroxy-4-decanolide 3
Compound 3 (0.10 g, 91%) was prepared as a viscous liquid from
the olefin mixture 16 (0.16 g, 0.59 mmol) following the same pro-
5.1.6. Ethyl 3-((4R,5R)-2,2-dimethyl-5-(pent-1-enyl)-1,3-dioxo-
lan-4-yl)propanoate 16
cedure as used for the preparation of compound 2: [
a
]
D
25 = À32.4 (c
Compound 1617 (0.41 g, 70%) was prepared as a viscous liquid
from aldehyde 7 (0.5 g, 1.91 mmol) and butylphosphonium bro-
mide/nBuLi following the same procedure as used for the prepara-
0.33, CHCl3);
m
max/cmÀ1 (KBr) 3455.6, 1771.3; dH (CDCl3, 300 MHz),
0.89 (3H, t, J 6.2 Hz, CH3), 1.31 (6H, s, CH2), 1.53 (2H, s, CH2), 1.84
(1H, br s, OH), 2.09–2.28 (2H, m, CH2), 2.53–2.68 (2H, m, CH2),
3.55–3.60 (1H, m, OCH), 4.38–4.45 (1H, m, OCH); dC (CDCl3,
75 MHz) 14.0 (CH3), 22.5 (CH2), 24.1 (CH2), 25.1 (CH2), 28.7
(CH2), 31.7 (CH2), 32.9 (CH2), 73.6 (OCH), 83.0 (OCH), 177.4 (CO);
tion of compound 15: mmax (KBr) 2932.0, 1738.0, 1634.4; dH (for the
major isomer from the mixture) (CDCl3, 300 MHz) 0.93 (3H, t, J
7.3 Hz, CH3), 1.25 (3H, t, J 7.1 Hz, CH3), 1.40 (8H, s, CH3, CH2),
1.79–1.95 (2H, m, CH2), 2.06–2.17 (2H, m, CH2), 2.40–2.50 (2H,
m, CH2), 3.63–3.68 (1H, m, OCH), 4.08–4.17 (2H, m, OCH2), 4.39
(1H, t, J 8.6 Hz, OCH), 5.36 (1H, t, J 10.0 Hz, @CH), 5.70 (1H, dt, J
10.7, 7.6 Hz, @CH); dC (for the major isomer from the mixture)
(CDCl3, 75 MHz) 13.7 (CH3), 14.2 (CH3), 22.8 (CH2), 26.8 (CH2),
27.1 (CH3), 27.2 (CH3), 29.8 (CH2), 30.7 (CH2), 60.3 (OCH2), 76.5
HRMS (ESI) calcd for
209.1156.
C
10H18O3Na [M+Na]+ 209.1154; found,
5.1.10. 7-Oxa-(À)-muricatacin 4
To a stirred solution of alcohol 19 (0.1 g, 0.43 mmol) in dry
diethyl ether (1.2 mL) were added successively silver oxide

S. Chatterjee et al. / Tetrahedron: Asymmetry 25 (2014) 1624–1629
1629
5. For the recent synthesis of muricatacin, see: (a) González, M.; Gándara, Z.;
Martínez, A.; Gómez, G.; Fall, Y. Synthesis 2013, 45, 1693; (b) González, M.;
Gándara, Z.; Pazos, G.; Gómez, G.; Fall, Y. Synthesis 2013, 45, 625; (c) Sabitha,
G.; Chandrashekhar, G.; Reddy, D. V.; Yadav, J. S. Lett. Org. Chem. 2012, 9, 344;
(d) Tsai, Yow-Fu; Huang, Chien-Cheng; Lin, Shiau-Han; Su, Pei-Mei; Chen, Ying-
Ju; Wu, Tzong-Yuan Heterocycles 2012, 85, 299; (e) Srec´o, B.; Benedekovic´, G.;
(0.25 g, 1.08 mmol), silver triflate (0.02, 0.11 mmol), and undecyl
bromide (0.48 g, 2.15 mmol). The mixture was stirred at reflux
for 7 h and then filtered. The residue obtained by evaporation of
the solvent was purified by column chromatography using ethyl
acetate–hexane (3:2) as eluent to afford pure 4 (0.11 g, 89%) as a
ˇ ´
´
´
´
Popsavin, M.; Hadzic, P.; Kojic, V.; Bogdanovic, G.; Divjakovic, V.; Popsavin, V.
Tetrahedron 2011, 67, 9358; (f) González, M.; Gándara, Z.; Covelo, B.; Gómez, G.;
Fall, Y. Tetrahedron Lett. 2011, 52, 5983; (g) Srinivas, C.; Kumar, C. N. S. S. P.;
Raju, B. C.; Rao, V. J. Helv. Chim. Acta 2011, 94, 669; (h) Yaragorla, S.; Muthyala,
R. Arkivoc 2010, x, 178; (i) Kumarasway, G.; Ramakrishna, D.; Santhakumar, K.
Tetrahedron: Asymmetry 2010, 21, 544; (j) Ghosal, P.; Kumar, V.; Shaw, A. K.
Carbohydr. Res. 2010, 345, 41; (k) Barros, M. T.; Charmier, M. A. J.; Maycock, C.
D.; Michaud, T. Tetrahedron 2009, 65, 396; (l) Prasad, K. R.; Gandi, V.
Tetrahedron: Asymmetry 2008, 19, 2616; (m) Southard, J. M.; Sears, N. L. Texas
J. Sci. 2007, 59, 301; (n) Ferrié, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Synlett
2007, 2891; (o) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17,
2465; (p) Ahmed, M., Md.; Cui, H.; O’Doherty, G. A. J. Org. Chem. 2006, 71, 6686;
viscous liquid: [
a]
D
25 = À32.5 (c 0.80, CHCl3).
m
max/cmÀ1 (KBr)
3448.1, 1774.2; dH (CDCl3, 300 MHz), 0.88 (3H, t, J 6.0 Hz, CH3),
1.26 (14H, s, CH2), 1.55–1.59 (2H, m, CH2), 2.24–2.32 (2H, m,
CH2), 2.44–2.55 (2H, m, CH2), 2.61–2.72 (1H, m, OH), 3.44–3.49
(2H, m, OCH2), 3.50–3.58 (2H, m, OCH2), 3.81 (1H, dt, J 5.8,
3.25 Hz, OCH), 4.56 (1H, dt, J 6.9, 3.8 Hz, OCH); dC (CDCl3,
75 MHz) 14.1 (CH3), 22.6 (CH2), 23.8 (CH2), 26.0 (CH2), 28.4
(CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (3Â CH2), 31.9 (CH2), 71.2
(OCH2), 71.8 (OCH2), 72.1 (OCH), 79.9 (OCH), 177.6 (CO); HRMS
(ESI) calcd for C16H30O4Na [M+Na]+, 309.2042; found, 309.2044.
´
´
´
´
(q) Popsavin, V.; Krstic, I.; Popsavin, M.; Sreco, B.; Benedekovic, G.; Kojic, V.;
Bogdanovic´, G. Tetrahedron 2006, 62, 11044. and references therein; (r)
Dhotare, B.; Chattopadhyay, A. Tetrahedron Lett. 2005, 46, 3103; (s) Quinn, K.
J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143; (t) Popsavin, V.; Krstic´, I.;
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6. (a) Niehuis, O.; Buellesbach, J.; Gibson, J. D.; Pothmann, D.; Hanner, C.; Mutti, N.
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5.1.11. (4R,5R)-(À)-7-Oxa-5-hydroxy-4-dodecanolide 5
Compound 5 (0.08 g, 86%) was prepared as a viscous liquid from
the alcohol 19 (0.1 g, 0.43 mmol) following the same procedure as
used for the preparation of compound 4: [
CHCl3);
a]
25 = À29.5 (c 0.30,
D
m
max/cmÀ1 (KBr) 3436.30, 1773.10; dH (CDCl3, 300 MHz),
0.92 (3H, t, J 6.6 Hz, CH3), 1.31–1.41 (4H, m, CH2), 1.60 (2H, s,
CH2), 2.27–2.34 (2H, m, CH2), 2.46–2.58 (2H, m, CH2), 2.64–2.75
(1H, m, OH), 3.44–3.53 (2H, m, OCH2), 3.55–3.57 (2H, m, OCH2),
3.77–3.84 (1H, m, OCH), 4.58 (1H, dt, J 5.3, 3.0 Hz, OCH); dC (CDCl3,
50 MHz) 14.2 (CH3), 22.7 (CH2), 24.1 (CH2), 28.4 (CH2), 28.5 (CH2),
29.4 (CH2), 71.4 (OCH2), 72.0 (OCH2), 72.3 (OCH), 80.0 (OCH), 177.7
(CO); HRMS (ESI) calcd for C11H20O4Na [M+Na]+, 239.1159; found,
239.1157.
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1 2000, 2475; (c) Fadnavis, N. W.; Vadivel, S. K.; Sharfuddin, M.
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T.B. acknowledges Jadavpur University, Kolkata for providing
her research work initial financial support in the form of J.U.
Research Grant. S.C. and A.M. wish to thank UGC, New Delhi for
their Senior Research Fellowships.
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