An organocatalytic enantioselective synthesis of (+)-duryne

Article abstract of DOI:10.1016/j.tetasy.2012.04.004

An efficient enantioselective synthesis of the potent anticancer agent (+)-duryne was achieved by the use of a one-pot organocatalyzed hydroxylation/Ohira-Bestmann and Grubbs cross-metathesis/selective cis-Wittig reaction. This new approach is envisioned to facilitate the synthesis of every representative member of the family.

Full text of DOI:10.1016/j.tetasy.2012.04.004

Tetrahedron: Asymmetry 23 (2012) 587–593
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An organocatalytic enantioselective synthesis of (+)-duryne
⇑
Gullapalli Kumaraswamy , Kadivendi Sadaiah, Nimmakayala Raghu
Organic & Biomolecular Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient enantioselective synthesis of the potent anticancer agent (+)-duryne was achieved by the use
of a one-pot organocatalyzed hydroxylation/Ohira–Bestmann and Grubbs cross-metathesis/selective cis-
Wittig reaction. This new approach is envisioned to facilitate the synthesis of every representative mem-
ber of the family.
Received 19 March 2012
Accepted 5 April 2012
Available online 10 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
(+)-duryne 1a and established the central olefin geometry as well
as the absolute configuration of stereogenic centers to be
Enantioenriched propargylic alcohols are key structural units of
many natural products isolated from various marine sponges such
as Cribrochalina dura, Diplastrella, Petrosia, and Haliclona.1 Mole-
cules derived from these marine sponges were reported to be en-
dowed with potent cytotoxicity toward tumor cell lines.2 The
exceedingly cytotoxic property was attributed to the occurrence
of the enantioenriched propargylic alcohol motif. Among the first
one reported was the highly cytotoxic duryne molecule 1a, isolated
from Cribrochalina dura, which inhibits several human tumor cell
lines, in particular against p388 murine leukemia with an IC50 of
(15Z,3S,28S) (Fig. 1). In all of the previous syntheses of (+)-duryne,
the stereogenic centers were determined by enzymatic kinetic
resolution of the respective racemic substrates. In view of the
exceptional pharmacological profile coupled with low natural
abundance, we herein report an alternative strategy for the synthe-
sis of 1a.
With our continued interest in developing catalytic routes to
bioactive small molecules,9 we recently developed a flexible
organocatalytic enantioselective synthesis of heptadeca-1-ene-
4,6-diyne-(3S,8R,9S,10S)-tetrol and its congeners using the
proline-catalyzed aminoxylation as the key step.10 As a logical
extension, we herein report the enantioselective synthesis of the
natural product (+)-duryne, which relies on two catalytic steps;
0.07 l
g/mL.3
The (+)-duryne molecule possesses C2 symmetry, encompassing
a terminal propargylic alcohol linked by a trans double bond with a
pendant C9 long chain carbon unit and the same fragment con-
nected to each side of a cis double bond. The structurally related
petrosynol 1b has been isolated from the Red Sea sponge Petrocia
sp. and was synthesized due to its inhibitory activity of the reverse
transcriptase of the human immunodeficiency virus (HIV).4 Novel
brominated polyacetylenic diols diplynes C 1c has been isolated
along with several related family members via an inhibitory activ-
ity guided screening and their absolute configurations estab-
lished.1d,5 A C-17 polyacetylenic diol falcarindiol 1d has also been
isolated as an algicidal principle against the harmful red tide dino-
flagellate6 (Fig. 1).
(a)
a one-pot organocatalyzed hydroxylation/Ohira–Bestmann
reaction11 and (b) a Grubbs cross-metathesis. Our retrosynthetic
approach is shown in Scheme 1. We envisioned that 1a could be
obtained by a cis-Wittig reaction between fragments (S)-2 and
(S)-3, which in turn could be derived from a common advanced
intermediate (S)-2. The crucial synthone (S)-2 could be generated
via a cross metathesis between MOM-protected allyl substrate
(S)-4 and a terminal olefin C12 carbinol 5. The MOM-protected allyl
substrate (S)-4 could be obtained from the substituted propargyl
alcohol (S)-6, which in turn could be synthesized by a one-pot
organocatalyzed hydroxylation/Ohira–Bestmann reaction.
Our initial interest was focused on the synthesis of crucial
synthon (S)-6 and terminal olefin C12 carbinol 5. The synthesis of
5 began with diol 7. The monobromination of 7 yielded 8, and
was followed by protection of the primary alcohol to its TBS ether
to yield 9. Base induced dehydrobromination of 9 and subsequent
cleavage of the silyl group gave 5 in 60% overall yield (Scheme 2).
We envisaged that a one-pot reaction could be used to install a
hydroxyl stereogenic center as well as the propargyl functionality
2. Results and discussion
Due to the interesting biological activities of 1a, many synthetic
approaches have been recorded.7 Recently, Gung et al.8 achieved
the unambiguous total synthesis of natural polyacetylenic alcohol
to give (S)-6. Initially,
a
proline-catalyzed
a-aminoxylation
⇑
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
strategy12 was adopted for 11 to give labile
a-aminoxy aldehyde
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.004

588
G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
OH
OH
7
7
OH
OH
OH
Br
1a
(+)-duryne
4
1c
diplyne C
4
4
OH
HO
OH HO
petrosynol 1b
5
OH
1d
(+)-falcarindiol
Figure 1. Natural polyacetylenic alcohols 1a–d.
Organo-catalyzed hydroxylation
Grubbs cross-metathesis
C2-symmetry
7
7
OH
OH
1a
cis-wittig reaction
Ohira-Bestmann
reaction
O
PMBO
PMBO
PPh3I
+
8
7
OMOM
(S)-2
OMOM
(S)-3
PMBO
+
OH
8
OMOM
(S)-4
5
PMBO
OH
(S)-6
Scheme 1. Retrosynthetic analysis of (+)-duryne.
and attempted to capture the labile aminoxylated aldehyde by a
Wittig reaction under various conditions. Unfortunately, we could
not succeed to generate the anticipated compound (S)-12. The la-
The desired transformation was eventually achieved by evapo-
ration of the original acetonitrile solvent and the resulting residue
was dissolved in MeOH followed by the addition of an Ohira–Best-
mann reagent/base and stirring for 24 h at ambient temperature.
The desired compound (S)-613 was obtained in 64% yield with
97% enantiomeric purity, while avoiding an O–N cleavage step.
With (S)-6 in hand, we next determined the enantiomeric purity
and the absolute configuration of the new stereogenic center in
bile
a-aminoxy aldehyde was also subjected to the Ohira–Best-
mann reaction in situ in order to convert the aldehyde to a
terminal acetylene using different reaction conditions, such as
DMSO12a or CHCl3,12b however no trace of the desired compound
(S)-6 was observed.
48% HBr
i) TBDMSCl
HO
Br
HO
OH
toluene
Δ
8
8
Imidazole, DCM
7
8,
87%
tBuOK
THF, rt
PTSA
Br
TBSO
HO
TBSO
8
8
8
MeOH
0C to rt
0
9, 96%
5,
95%
10,
75%
Scheme 2. Synthesis of terminal olefin C12 carbinol 5.

G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
589
(S)-6. Hence, the terminal acetylene in (S)-6 was reduced to an ole-
fin under Lindlar conditions to provide (S)-12 in 98% yield and 97%
ee. The enantiomeric purity and absolute configuration of the new
stereogenic center in (S)-12 were determined by comparing the
specific rotation data reported in the literature.10 Protection of
the secondary alcohol with MOM-Cl under basic conditions fur-
nished (S)-13 in 85% yield (Scheme 3). At first, we attempted to
carry out a cross metathesis between (S)-12 and olefin 10 using a
second-generation Grubbs catalyst. However, when this reaction
was carried out, no trace of the required product (S)-14a was ob-
served (Table 1, entry 1). The MOM ether (S)-13 and 10 were sub-
jected to a cross-metathesis reaction under otherwise similar
conditions. However, this reaction also failed to give the antici-
pated product (S)-14b (Table 1, entry 2). Eventually the cross
metathesis reaction between (S)-13 and tethered alcohol olefin 5
was carried out by using 10 mol % of second-generation Grubbs
catalyst to give (S)-14c in moderate yield (Table 1, entry 3). After
substantial experimentation, by varying the stoichiometry of the
coupling partners of (S)-13 and 5 (Table 1, entries 4 and 5), we
found that using 8 mol % of second-generation Grubbs catalyst re-
sulted in the formation of (S)-14c (76%) with an E/Z ratio of 9:1 (1H
NMR) (Table 1, entry 6).14
trace amounts of the required product (S,S)-16 were isolated. Next
we screened conditions for the Wittig reaction to access the
symmetrical Z-olefination. Thus, the reaction of (S)-2 and (S)-3 in
the presence of the Rochow base (NaHMDS) in THF at 0 °C gave
(S,S)-16 as a detectable isomer in 60% yield with >99% diastereose-
lectivity (assessed by 1H NMR).16 Oxidative deprotection of PMB
resulted in diol (S,S)-17. The terminal acetylenic functionality
was installed by a two step sequence. Diol (S,S)-17 was subjected
to oxidation using DMP in DCM and the resulting crude aldehyde
was then reduced with an Ohira–Bestmann reagent under basic
conditions in MeOH to give MOM protected C2 symmetric (+)-dur-
yne (S,S)-18.17
The deprotection of the MOM group in (S,S)-18 using acidic re-
agents gave us cause for concern. None of the mineral acids (1 M
HCl in THF or MeOH or MeCN) were able to give us the required
deprotection. Eventually, the (S,S)-18 to 1a transformation was
achieved by using PTSA in MeOH at ambient temperature to give
1a in 72% yield (Scheme 5). The optical and spectroscopic data of
1a {½a 2D3
ꢀ
¼ þ24:8 (c 1.8, CHCl3), lit.8 ½a D23
¼ þ25 (c 1.4, CHCl3)} were
ꢀ
in full accordance with those reported in the literature.8
3. Conclusion
i) 20 mol%
L-proline
In conclusion, we have developed a concise enantioselective
route for the synthesis of natural product (+)-duryne. The salient
features of this concise synthesis are; (i) the genesis of chirality
through an organocatalytic reaction; (ii) the two critical intermedi-
ates are generated from the same synthon, which in turn can be
obtained by two catalytic reactions. The advanced intermediates
generated in this protocol by a one-pot organocatalyzed hydroxyl-
ation/Ohira–Bestmann reaction circumvent the need for an O–N
cleavage step. This advanced intermediate can facilitate the syn-
thesis of each representative member of the Haplosclerid and
Spira-strellid sponges.
PhN
O
O
P
PMBO
PMBO
O
O
OH
11
ii)
OMe
OMe
(S)-6, 64%,
97%ee
N2
K2CO3
MOMCl
H2, balloon
PMBO
PMBO
DIEPA
THF
Lindler catalyst
EtOAc, rt
OH
OMOM
(S)-13, 85%
(S)-12, 98%
4. Experimental
4.1. General
97%ee
Scheme 3. Organo-catalyzed synthesis of 13.
All reactions were conducted under an atmosphere of nitrogen
(IOLAR, Grade I). The apparatus used for the reactions were oven
dried and THF was distilled over sodium benzophenone ketyl be-
fore use. All other chemicals used were commercially available.
The progress of the reactions was monitored by TLC on Silica Gel
60 F-254 pre-coated. Evaporation of the solvents was performed
at reduced pressure on a rotary evaporator. Column chromatogra-
phy was carried out with silica gel grade 60–120, 100–200 mesh.
1H NMR spectra were recorded at 300 and 500 MHz and 13C
NMR at 75 MHz in CDCl3. J values were recorded in Hertz and
Having obtained compound (S)-14c in substantial amounts, we
generated the two crucial intermediates 2 and 3 from the same
synthon. Accordingly, the primary alcohol of (S)-14c was converted
into iodo (S)-15 in the presence of iodine, triphenylphosphine, and
imidazole. Refluxing the corresponding iodo compound (S)-15 with
triphenylphosphine in acetonitrile resulted in Wittig salt (S)-3 and
the crude salt was subjected to further reaction. The IBX oxidation
of (S)-14c also furnished aldehyde (S)-2 in 90% isolated yield
(Scheme 4). Primarily, we adopted an auto oxidation process under
salt free conditions15 using phosphonium salt (S)-3. However, only
Table 1
Stoichiometry variation in the Grubbs cross metathesis reaction
PMBO
PMBO
OR'
OR'
8
8
Entry
Catalyst mol %
Yield %a
OR
OR
(S)-14a-cb
1
2
3
4
5
6
(S)-12, R = H (1 equiv)
10, R0 = TBDMS (1.5 equiv)
10, R0 = TBDMS (1.5 equiv)
5, R0 = H (1.5 equiv)
5, R0 = H (1 equiv)
10
10
10
10
(S)-14a, R = H, R0 = TBDMS
NR
NR
60
65
76
76
(S)-13, R = MOM (1 equiv)
(S)-13, R = MOM (1 equiv)
(S)-13, R = MOM (1 equiv)
(S)-13, R = MOM (1.5 equiv)
(S)-13, R = MOM (1.5 equiv)
(S)-14b, R = MOM, R0 = TBDMS
(S)-14c, R = MOM, R0 = H
(S)-14c, R = MOM, R0 = H
(S)-14c, R = MOM, R0 = H
(S)-14c, R = MOM, R0 = H
5, R0 = H (1 equiv)
10
5, R0 = H (1 equiv)
8 (5+3)c
bMajor E-isomer and E/Z (9:1) ratio established by 1H NMR.
a
Isolated yield of the purified material.
Catalyst was added in two portions.
c

590
G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
i) TPP, I2
PMBO
OH
PMBO
I
8
8
Imidazole
OMOM
OMOM
(S)-14c
(S)-15, 95%
ii) Ph3P
MeCN
PMBO
PPh3I
8
OMOM
(S)-3
i) IBX
DMSO:DCM
rt
PMBO
OH
PMBO
8
O
8
OMOM
OMOM
(S)-14c
(S)-2, 90%
Scheme 4. Synthesis of aldehyde (S)-2 and Wittig salt (S)-3.
PMBO
PMBO
O
8
OMOM
NaHMDS
THF, 0 0
C
(S)-2
+
PMBO
OPMB
7
7
OMOM
OMOM
(S,S)-16, 60%
PPh3I
8
>99% ds
OMOM
(S)-3
i) Dess-Martin periodinane,
DCM
DDQ
DCM
HO
OH
OMOM
7
7
O
O
P
OMOM
(S,S)-17, 85%
OMe
ii)
OMe
N2
K2CO3, MeOH
Cat.PTSA.H2O
MeOH,
0
7
7
oC to rt, 6h
72%
7
7
OMOM
OMOM
(S,S)-18, 85%
OH
OH
1a
85%
Scheme 5. Synthesis of natural molecule (+)-duryne 1a.
the abbreviations used are s-singlet, d-doublet, t-triplet, q-quartet,
m-multiplet, and br-broad. Chemical shifts (d) are reported relative
to TMS (d = 0.0) as the internal standard. IR spectra were recorded
on FT/IR-5700. Mass spectral data were compiled using MS (ESI)
and HRMS mass spectrometers. Optical rotations were recorded
on high sensitive polarimeter with a 10 mm cell.
(7:3) to provide 8 as a pale yellow oil (32.0 g, 87%). 1H NMR
(300 MHz, CDCl3): d 3.64 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H),
1.89–1.80 (m, 2H), 1.61–1.51 (m, 2H), 1.44–1.27 (m, 16H); 13C
NMR (75 MHz, CDCl3): d 62.8, 33.9, 32.7, 32.6, 29.5, 29.4, 29.3,
28.7, 28.1, 25.6; IR (neat): 3358, 2923, 2362,1740,1515,
1052 cmꢁ1; ESI-MS: m/z 365 (M+H)+.
4.1.1. 12-Bromododecan-1-ol 8
4.1.2. (12-Bromododecyloxy)(tert-butyl)dimethylsilane 9
To a solution of diol 7 (28 g, 0.14 mol) in toluene (600 mL) was
added concentrated HBr [27.5 mL of a 48% (9 M) aqueous solution,
0.162 mol]. The heterogeneous mixture was heated at reflux for
36 h, after which TLC analysis showed that 20% of the diol still re-
mained. Thus, a further quantity of HBr (10 mL, 0.09 mol) was
added, and the mixture was heated at reflux for a further 12 h, after
which TLC analysis showed no diol remaining. The reaction mix-
ture was allowed to return to room temperature, and the phases
were separated. The organic layer was diluted with ether
(200 mL) and washed with 1 M NaOH solution (200 mL) and brine
solution (300 mL). Drying over anhydrous Na2SO4, filtration and
concentration of the organic layer gave a yellow oil, which was
purified by column chromatography using hexane/ether as eluent
To a solution of bromo alcohol 8 (2.0 g, 7.55 mmol) in dichloro-
methane (25 mL), imidazole (0.62 g 9.06 mmol), followed by TBSCl
(1.25 g, 8.30 mmol) were added at 0 °C. This reaction mixture was
allowed to stir at room temperature for 2 h. The reaction mixture
was quenched with cold water (25 mL), and the phases were
separated. The organic layer was washed with brine (25 mL), dried
over anhydrous Na2SO4 and concentration of the organic layer gave
a yellow oil, which was purified by column chromatography using
hexane as eluent to provide title compound 9 as a colorless oil
(2.74 g, 96%). 1H NMR (300 MHz, CDCl3): d 3.57 (t, J = 6.4 Hz, 2H),
3.37 (t, J = 6.8 Hz, 2H), 1.90–1.80 (m, 2H), 1.51–1.41 (m, 4H),
1.34–1.24 (m, 14H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3): d
63.3, 33.9, 32.9, 32.8, 29.6, 29.5, 29.4, 28.8, 28.2, 26.0, 25.8, 18.4,

G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
591
-5.3; IR (neat): 2927, 2333, 1516, 1099, 837 cmꢁ1; ESI-MS: m/z 379
(M+H)+; ESI-HRMS: calcd for C18H40OSiBr 379.2031, found
379.2015.
4.1.6. (S)-1-(4-Methoxybenzyloxy)but-3-en-2-ol (S)-12
To a stirred solution of (S)-6 (70 mg, 0.109 mmol) in ethyl
acetate (3 mL) were added sequentially quinoline (17 mL,
0.131 mmol) and Lindlar’s catalyst (15 mg). The solution was
placed under an atmosphere of H2 and allowed to stir for 6 h at
room temperature. The solution was filtered through a small plug
of Celite and further washed with EtOAc. The filtrate was concen-
trated under reduced pressure and the crude residue was purified
by column chromatography using hexane/ethyl acetate (7:1) as
4.1.3. tert-Butyl(dodec-11-enyloxy)dimethylsilane 10
To a solution of alkyl bromide 9 (4.36 g, 11.5 mmol) in THF
(60 mL), t-BuOK (3.86 g, 34.4 mmol) was added in one portion at
0 °C under nitrogen atmosphere. The reaction mixture was then al-
lowed to stir at room temperature. After completion of the reaction
(monitored by TLC 1 h), ice cubes were added and extracted with
ether (3 ꢂ 50 mL). The combined organic layers were washed with
brine (50 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The crude residue was subjected
to column chromatography using hexane as the eluent to afford
olefin 10 as a colorless oil (2.57 g, 75%). 1H NMR (300 MHz, CDCl3):
d 5.83–5.70 (m, 1H), 4.99–4.88 (m, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.03
(q, J = 7.0 Hz, 2H), 1.49 (t, J = 6.2 Hz, 2H), 1.32–1.23 (m, 14H), 0.03
(s, 6H); 13C NMR (75 MHz, CDCl3): d 139.2, 114.1, 63.32, 33.8, 32.9,
29.6, 29.5, 29.4, 29.1, 28.9, 26.0, 25.8, 18.4, -5.3; IR (neat): 2926,
2362, 11646, 1099, 774 cmꢁ1; ESI-MS: m/z 299 (M+H)+.
eluent to give (S)-12 (0.068 g, 98%) as a colorless oil. ½a D24
¼ ꢁ2:0
ꢀ
(c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.26 (d, J = 8.5 Hz,
2H), 6.89 (d, J = 8.5 Hz, 2H), 5.83 (ddd, J = 16.4, 10.4, 5.5 Hz, 1H),
5.35 (d, J = 17.4 Hz, 1H), 5.19 (d, J = 10.6 Hz, 1H), 4.50 (s, 2H),
4.33 (br s, 1H), 3.81 (s, 3H) 3.52 (dd, J = 9.6, 3.4 Hz, 1H), 3.44 (dd,
J = 9.4, 7.9 Hz, 1H), 2.45 (br s, 1H); 13C NMR (75 MHz, CDCl3) d
159.1, 136.5, 129.7, 129.3, 116.2, 113.7, 73.6, 72.8, 55.1, 25.5; IR
(neat) 3448, 2860, 2362, 1613, 1462, 1096, 820 cmꢁ1; ESIMS (m/
z): 231 (M+Na)+; HRMS calcd for C12H16O3Na 231.0997, found
231.1000.
4.1.7. (S)-1-Methoxy-4-((2-(methoxymethoxy) but-3-enyloxy)
methyl) benzene (S)-13
4.1.4. Dodec-11-en-1-ol 5
At first, MOM-Cl (2.71 mL, 35.68 mmol) was added to a solution
of alcohol (S)-12 (2.47 g, 11.9 mmol) and diisopropyl ethylamine
(26.8 mL) in dichloromethane (30 mL) at 0 °C. This resultant reac-
tion mixture was stirred at 0 °C to room temperature for 2 h. Then
the reaction was quenched with water (20 mL). The organic layer
was separated and the aqueous layer extracted with dichlorometh-
ane (2 ꢂ 20 mL). The combined organic layers were washed with
brine (30 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The resultant residue was purified
by silica gel column chromatography using hexane/ethyl acetate
(7:1) as eluent to give title compound (S)-13 as a pale yellow oil
At first, PTSA (0.464 g, 2.44 mmol), was added to a solution of
TBS–ether 10 (7.3 g, 24.4 mmol) in methanol (75 mL) at 0 °C. The
reaction mixture was allowed to stir at 0 °C to room temperature
for 1 h. The solvent was then removed under reduced pressure.
The resultant residue was dissolved in ether (100 mL), and satd
NaHCO3 (50 mL) and brine (50 mL) washes were applied, after
which the residue was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was sub-
jected to column chromatography using hexane/ethyl acetate (9:1)
as eluent to afford alcohol 5 as a colorless oil (4.27 g, 95%). 1H NMR
(500 MHz, CDCl3): d 5.85–5.77 (m, 1H), 5.00–4.91 (m, 2H), 3.63 (t,
J = 6.9 Hz, 2H), 2.03 (q, J = 6.9 Hz, 2H), 1.59–1.53 (m, 2H), 1.38–1.22
(m, 14H); 13C NMR (75 MHz, CDCl3): d 139.2, 114.0, 62.9, 33.8,
32.7, 29.5, 29.4, 29.1, 28.9, 25.7; IR (neat): 3334, 2924, 2362,
1645, 1462, 909 cmꢁ1; ESI-MS: m/z 185 (M+H)+.
(2.85 g, 85%). ½a D24
ꢀ
¼ þ12:4 (c 1.9, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz), 5.80 (ddd,
J = 7.0 Hz, J = 10.4 Hz, J = 17.4 Hz, 1H), 5.32 (d, J1 = 17.9 Hz, 1H),
5.25 (d, J = 10.4 Hz, 1H), 4.68 (dd, J = 6.6 Hz, J = 22.5 Hz, 2H), 4.51
(s, 3H), 4.26 (dd, J = 6.0 Hz, J = 11.7 Hz, 1H), 3.80 (s, 3H), 3.54–
3.48 (m, 2H), 3.38 (s, 3H); 13C NMR (75 MHz, CDCl3): d 158.9,
135.1, 129.3, 129.0, 117.9, 113.7, 113.5, 94.0, 75.8, 72.7, 72.4,
55.1, 55.0; IR (neat): 2925, 2333, 1612, 1513, 1248, 1099,
4.1.5. (S)-1-(4-Methoxybenzyloxy)but-3-yn-2-ol (S)-6
Compound 11 (160 mg, 0.82 mmol) was dissolved in acetoni-
;
821 cmꢁ1 ESI-MS: m/z 270 (M+NH4)+; ESI-HRMS: calcd for
trile (5 mL) and cooled to ꢁ20 °C. To this,
L-proline (19 mg,
0.16 mmol) was added followed by nitroso benzene (88 mg,
0.82 mmol). The resultant reaction mixture was stirred for 24 h
during which time, the acetonitrile solvent evaporated and the
residue was redissolved in methanol (8 mL). Next, the Ohira–
Bestmann reagent (236 mg, 1.23 mmol) in methanol (8 mL) and
K2CO3 (226 mg, 1.64 mmol) were added sequentially. The reaction
mixture was allowed to stir for 8 h at 0 °C. The reaction mixture
was quenched by satd NH4Cl (10 mL) and the combined contents
were stirred for an additional 24 h at ambient temperature. The or-
ganic solvent was removed under reduced pressure and the aque-
ous layer was extracted with ethyl acetate (3 ꢂ 10 mL). The
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The resultant residue was purified by silica gel column
chromatography using hexane/ethyl acetate (7:1) as eluent to give
title compound (S)-6 as a pale yellow oil (108 mg, 64% for three
C14H20O4Na 275.1259, found 275.1251.
4.1.8. (S,E)-14-(4-Methoxybenzyloxy)-13-(methoxymethoxy)
tetradec-11-en-1-ol (S)-14c
To a solution of the cross metathesis partners [dodecenol 5,
1.33 g, 7.23 mmol; olefin (S)-13, 2.19 g, 8.67 mmol] in dichloro-
methane (25 mL) was added Grubbs 2nd generation catalyst
(600 mg, 0.71 mmol) at room temperature. Then, the reaction
was heated at reflux for 6 h. The TLC analysis indicated that
ꢃ20% of starting materials still remained. Thus, a further quantity
of (146 mg, 0.17 mmol) Grubbs 2nd generation catalyst was added,
and the reaction mixture was heated at reflux for a further 4 h. The
solvent was then removed under reduced pressure, and the residue
was purified by column chromatography using hexane/ethyl ace-
tate (6:1) as eluent to afford title compound (S)-14c as a brown
oil (2.24 g, 76%, 9:1 E/Z) ½a D24
ꢀ
¼ þ29:6 (c 1.4, CHCl3); 1H NMR
conversions).
½
a 2D4
ꢀ
¼ þ4:8 (c 1.9, CHCl3) 97% ee; 1H NMR
(300 MHz, CDCl3): d 7.20 (t, J = 8.4 Hz, 2H), 6.83–6.80 (m, 2H),
5.72–5.64 (m, 1H), 5.45–5.28 (m, 1H), 4.70–4.55 (m, 2H), 4.48–
4.44 (m, 2H), 4.23–4.09 (m, 1H), 3.80 (s, 3H), 3.60 (t, J = 7.3 Hz,
2H), 3.48–3.39 (m, 2H), 3.34 (s, 3H), 2.06–2.02 (m, 2H), 1.57–1.52
(m, 2H),1.43–1.25 (m, 14H); 13C NMR (75 MHz, CDCl3): d 159.1,
130.8, 130.2, 129.1, 126.4, 113.6, 94.2, 94.1, 74.9, 74.9, 72.8, 72.5,
55.3, 55.2, 32.7, 32.2, 29.6, 29.5, 29.4, 29.3, 29.0, 28.9, 25.7; IR
(neat): 3565, 2852, 2362, 1513, 1246, 1099, 1101 cmꢁ1; ESI-MS:
(300 MHz, CDCl3): d 7.28–7.25 (m, 2H), 6.90–6.87 (m, 2H), 4.54
(d, J = 3.02 Hz, 2H), 3.80 (s, 3H), 3.64–3.52 (m, 2H), 2.46 (d,
J = 2.26 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 159.2, 129.5, 128.6,
114.0, 73.6, 73.1, 73.0, 65.0, 61.4, 55.3; IR (neat): 3402, 3280,
2118, 1615, 1514, 1466, 1363, 1303, 1246, 1177, 1101, 1088,
1029, 925, 816 cmꢁ1; ESI-MS (m/z): 229 (M+Na)+; HRMS calcd for
C12H14O3Na 229.0835, found 229.0828.

592
G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
m/z 431 (M+Na)+ ESI-HRMS: calcd for C24H40O5Na 431.2773, found
purified over silica gel column chromatography using hexane/ethyl
431.2783.
acetate (7:1) to give (S,S)-16 as a pale yellow oil (250 mg, 60%,
>99% diastereoselectivity). ½a D24
ꢀ
¼ þ21:3 (c 3.8, CHCl3); 1H NMR
4.1.9. (S,E)-1-((14-Iodo-2-(methoxymethoxy) tetradec-3-
enyloxy) methyl)-4methoxybenzene (S)-15
(300 MHz, CDCl3): d 7.21 (d, J = 8.3 Hz, 4H), 6.81 (d, J = 9.1 Hz,
4H), 5.74–5.64 (m, 2H), 5.34–5.26 (m, 4H), 4.67 (d, J = 6.0 Hz,
2H), 4.54 (d, J = 6.8 Hz, 2H), 4.48 (s, 4H), 4.19–4.13 (m, 2H), 3.79
(s, 6H), 3.49–3.38 (m, 4H), 3.34 (s, 6H), 2.07–1.96 (m, 8H), 1.39–
1.26 (m, 28H); 13C NMR (75 MHz, CDCl3): d 159.1, 135.9, 130.4,
129.8, 129.1, 126.4, 113.7, 93.5, 75.6, 72.9, 72.8, 55.2, 32.3, 29.8,
29.7, 29.6, 29.4, 29.3, 29.1, 29.0, 27.2; IR (neat): 2923, 2852,
To a solution of alcohol (S)-14c (1 g, 2.45 mmol) in dichloro-
methane (30 mL), triphenyl phosphine (707 mg, 2.7 mmol) fol-
lowed by imidazole (333 mg, 4.9 mmol) were added at room
temperature, then the reaction temperature was decreased to
0 °C and I2 (686 mg, 2.7 mmol) was added. This reaction mixture
was allowed to stir at 0 °C to room temperature for 1 h. The reac-
tion was diluted with dichloromethane (20 mL), then washed with
satd NaHCO3 (30 mL), sodium thiosulfate (30 mL), and brine
(30 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by sil-
ica gel column chromatography using hexane/ethyl acetate (11:1)
as eluent to give iodide (S)-15 as a pale yellow oil (1.2 g, 95%).
2362, 1709,1513, 1248, 1030, 821 cmꢁ1
; ESI-MS: m/z 799
(M+NH4)+; ESI-HRMS: calcd for C48H76O8Na 803.5437, found
803.5462.
4.1.12. (2S,3E,14Z,25E,27S)-2,27-Bis(methoxymethoxy)octacosa-
3,14,25-triene-1, 28-diol (S,S)-17
To a stirred solution of (S,S)-16 (320 mg, 0.41 mmol) in dichlo-
romethane/water (19:1, 10 mL), DDQ (140 mg, 0.62 mmol) was
added at 0 °C. The reaction mixture was stirred at 0 °C to room
temperature for 1 h, and then the reaction was diluted with dichlo-
romethane (10 mL) and quenched with satd NaHCO3 solution
(10 mL). The organic layer was separated and the aqueous layer
was extracted with dichloromethane (3 ꢂ 10 mL). The combined
organic layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The resulting crude residue was purified by silica gel column chro-
matography using hexane/ethyl acetate (3:1) to give title com-
½
a 2D4
ꢀ
¼ þ11:6 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.26 (d,
J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.77–5.67 (m, 1H), 5.37–
5.30 (m, 1H), 4.73 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 1H), 4.51
(s, 2H), 4.24 4.18 (m, 1H), 3.80 (s, 3H), 3.52–3.44 (m, 2H), 3.37 (s,
3H), 3.18 (t, J = 7.0 Hz, 2H), 2.03 (q, J = 7.0 Hz, 2H),1.86–1.76 (m,
2H), 1.42–1.26 (m, 14H); 13C NMR (75 MHz, CDCl3): d 159.0,
135.8, 130.4, 129.1, 126.4, 113.6, 93.6, 75.5, 72.9, 72.8, 55.2, 33.5,
32.3, 30.4, 29.6, 29.4, 29.1, 29.0, 28.5; IR (neat): 2925,2853, 2362,
1647, 1515, 1248, 1034 cmꢁ1; ESI-MS: m/z 536 (M+NH4)+; ESI-
HRMS: calcd for C24H39O4NaI 541.1790, found 541.1771.
pound (S,S)-17 as a pale yellow oil (188 mg, 85%). ½a D24
¼ þ34:6
ꢀ
4.1.10. (S,E)-14-(4-Methoxybenzyloxy)-13-(methoxymethoxy)
tetradec-11-enal (S)-2
(c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.79–5.73 (m, 2H),
5.37–5.29 (m, 4H), 4.74 (d, J = 7.0 Hz, 2H), 4.61 (d, J = 6.0 Hz, 2H),
4.11–4.07 (m, 2H), 3.61–3.54 (m, 4H), 3.40 (s, 6H), 2.08–1.96 (m,
8H), 1.38–1.2 (m, 28H); 13C NMR (75 MHz, CDCl3): d 136.5,
129.8, 125.8, 94.1, 78.8, 65.7, 55.4, 35.0, 29.7, 29.5, 29.4, 29.3,
29.1, 29.0, 27.2; IR (neat): 3449, 2925, 2854, 2362, 1709, 1693,
1516, 1034 cmꢁ1; ESI-MS: m/z 563 (M+Na)+; ESI-HRMS: calcd for
Dichloromethane (20 mL) was added to a mixture of alcohol (S)-
14c (1.1 g, 2.7 mmol), IBX (1.51 g, 5.4 mmol), and DMSO (2 mL) un-
der nitrogen atmosphere. The reaction mixture was stirred for 6 h
at room temperature, and then the solvent was removed, adsorbed
on silica gel and purified by column chromatography using hex-
ane/ethyl acetate (9:1) as eluent to give aldehyde (S)-2 as a color-
C32H60O6Na 563.4287, found 563.4306.
less oil (0.99 g, 90%). ½a D24
ꢀ
¼ þ40:6 (c 0.75, CHCl3); 1H NMR
(300 MHz, CDCl3): d 9.75 (s, 1H), 7.25 (d, J = 8.3 Hz, 2H), 6.86 (d,
J = 8.3 Hz, 2H), 5.76–5.66 (m, 1H), 5.37–5.29(m, 1H), 4.72 (d,
J = 6.8 Hz, 1H), 4.59 (d, J = 6.8 Hz, 1H),4.50 (s, 2H), 4.23–4.17 (m,
1H), 3.80 (s, 3H), 3.58–3.44 (m, 2H), 3.36 (s, 3H), 2.41 (t,
J = 6.8 Hz, 2H), 2.06–1.99 (m, 2H), 1.70–1.57 (m, 2H), 1.43–1.15
(m, 14H); 13C NMR (75 MHz, CDCl3): d 202.9, 159.0, 135.8, 130.4,
129.1, 126.5, 113.6, 93.6, 75.5, 72.9, 72.8, 55.2, 43.8, 32.3, 29.3,
29.1, 29.0, 22.0; IR (neat): 2925, 2362,1724, 1514, 1247, 1096.
cmꢁ1; ESI-MS: m/z 429 (M+Na)+.
4.1.13. (6E,17Z,28E)-5,30-Diethynyl-2,4,31,33-tetraoxatetra-
triaconta-6,17,28-triene (S,S)-18
To a solution of diol (S,S)-17 (167 mg, 0.31 mmol) in dichloro-
methane (8 mL) was added DMP (394 mg, 0.93 mmol) at 0 °C.
The resulting reaction mixture was stirred at room temperature
for 1 h, and then the reaction mixture was further diluted with
dichloromethane (10 mL) and washed with satd NaHCO3 (4 mL),
sodium thiosulfate (4 mL), and brine (4 mL) and dried over anhy-
drous Na2SO4. The contents were filtered and concentrated under
reduced pressure. The resultant crude residue was passed through
a small plug of silica gel using ether as eluent. Removal of the ether
solvent under reduced pressure afforded the aldehyde, which was
immediately dissolved in anhydrous MeOH (6 mL). To this reaction
mixture, Ohira–Bestmann reagent (178 mg, 0.93 mmol) and K2CO3
(171 mg, 1.24 mmol) were sequentially added at 0 °C. After 4 h of
stirring, the solvent was evaporated under reduced pressure. To
the resulting residue, satd NH4Cl solution (5 mL) was added and
the aqueous layer extracted with ethyl acetate (3 ꢂ 10 mL). The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The resultant crude residue was purified over silica gel column
chromatography eluting with hexane/ethyl acetate (11:1) to give
4.1.11. (6E,17E,28E)-5,30-Bis((4-methoxybenzyloxy)methyl)-
2,4,31,33-tetraoxatetratriaconta-6,17,28-triene (S,S)-16
To a solution of iodide (S)-15 (302 mg, 0.58 mmol) in dry aceto-
nitrile (15 mL) triphenylphosphine (229 mg, 0.87 mmol) was
added at room temperature and the contents were refluxed for
12 h. The solvent was removed under reduced pressure, and the
resultant material (S)-3 was washed with hexane (2 ꢂ 5 mL) and
dried under vacuum. The crude salt (S)-3 was dissolved in dry
THF (5 mL) and to this, a 1 M solution of NaHMDS in THF
(0.55 mL) was added at 0 °C. The resulting red brown reaction mix-
ture was allowed to stir at room temperature for 45 min, thereaf-
ter, after which the temperature was shifted to 0 °C. Next,
aldehyde (S)-2 (214 mg, 0.53 mmol) in THF (2 mL) was added
slowly. After the addition, the reaction contents were allowed to
stir from 0 °C to room temperature over a period of 45 min. The
reaction mixture was quenched with water, and extracted with
ethyl acetate (3 ꢂ 5 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
(S,S)-18 as a pale yellow oil (139 mg, 85%). ½a D24
¼ ꢁ14:0 (c 0.8,
ꢀ
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.97–5.87 (m, 2H), 5.57–
5.49 (m, 2H), 5.34 (t, J = 4.7 Hz, 2H), 4.86 (d, J = 6.8 Hz, 2H), 4.79
(d, J = 6.6 Hz, 2H), 4.65 (d, J = 7.0 Hz, 2H), 3.39 (s. 6H), 2.53 (d,
J = 2.3 Hz, 2H), 2.11–1.98 (m, 8H), 1.42–1.22 (m, 28H); 13C NMR
(100 MHz, CDCl3): d 135.9, 129.8, 126.0, 93.5, 81.3, 74.4, 65.7,
55.6, 32.0, 29.8, 29.6, 29.5, 29.3, 29.2, 28.8, 27.2; IR (neat): 2926,

G. Kumaraswamy et al. / Tetrahedron: Asymmetry 23 (2012) 587–593
593
2854, 2362, 1741, 1693, 1516, 1029, 671 cmꢁ1; ESI-MS: m/z 551
(M+Na)+; ESI-HRMS: calcd for C34H56O4Na 551.4076, found
551.4066.
2. (a) Zhou, G.-X.; Molinski, T. F. Mar. Drugs 2003, 1, 46–53; (b) Ko, J.; Morinaka, B.
I.; Molinski, T. F. J. Org. Chem. 2011, 76, 894–901.
3. Wright, A. E.; McConnell, O. J.; Kohmoto, S.; Lui, M. S.; Thompson, W.; Snader, K.
M. Tetrahedron Lett. 1987, 28, 1377–1379.
4. (a) Fusetani, N.; Shiragaki, T.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett.
1987, 28, 4313–4314; (b) Isaacs, S.; Kashman, Y.; Loya, S.; Hizi, A.; Loya, Y.
Tetrahedron 1993, 49, 10435–10438.
5. (a) Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2004, 15, 3973–
3977; (b) Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16,
3107–3114.
6. (a) Nitz, S.; Spraul, M. H.; Drawert, F. J. Agric. Food Chem. 1990, 38, 1445–1447;
(b) Alamsjah, M. A.; Hirao, S.; Ishibashi, F.; Oda, T.; Fujita, Y. J. Appl. Phycol.
2008, 20, 713–720.
7. (a) Deshpande, V. H.; Upadhye, B. K.; Wakharkar, R. D. Tetrahedron Lett. 1989,
30, 1991–1992; (b) Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1998, 63, 6128–
6131.
8. Gung, B. W.; Omollo, A. O. J. Org. Chem. 2008, 73, 1067–1070.
9. (a) Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73, 5198–5201; (b)
Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Jagadeesh, B.; Sridhar, B. J. Org.
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10. Kumaraswamy, G.; Sadaiah, K. Tetrahedron 2012, 68, 262–271.
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K. A. J. Am. Chem. Soc. 2010, 132, 9188–9196. and references therein; (b) Jensen,
K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jørgensen, K. A. Org. Lett. doi:
http://dx.doi.org/10.1021/ol3002514.; (c) Hayashi, Y.; Shoji, M.; Ishikawa, H.;
Yamaguchi, J.; Tamara, T.; Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada,
H. Angew. Chem., Int. Ed. 2008, 47, 6657–6660.
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4.1.14. (+)-Duryne 1a
To a methanolic (2 mL) solution of MOM protected (S,S)-18
(31 mg, 0.059 mmol) was added PTSAꢄH2O (2.3 mg, 0.012 mmol)
at 0 °C. The resulting reaction mixture was warmed to ambient
temperature (6 h), and then solid NaHCO3 (excess) was added,
followed by silica adsorption and purified by silica gel column
chromatography using hexane/ethyl acetate (7:3) as eluent to give
(+)-duryne, 1a as
a low melting white solid (18 mg, 72%).
½
a 2D4
ꢀ
¼ þ24:8 (c 1.8, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.87
(dt, J = 15.1, 6.8 Hz, 2H), 5.56 (dd, J = 15.5, 6.8 Hz, 2H), 5.30 (t,
J = 4.5 Hz, 2H), 4.77 (d, J = 5.8, 2H), 2.48 (d, J = 1.9 Hz, 2H), 2.10–
1.96 (m, 8H), 1.72–1.20 (m, 28H); 13C NMR (100 MHz, CDCl3): d
134.6, 129.9, 128.3, 83.3, 73.9, 62.8, 32.6, 31.9, 29.74, 29.68, 29.5,
29.4, 29.3, 29.2, 28.8, 27.2; IR (neat): 3357, 2922, 2859, 2367,
1740, 1696, 1316, 1021 cmꢁ1; ESI-MS: m/z 463 (M+Na)+; ESI-
HRMS: calcd for C30H48O2Na 463.3552, found 463.3568.
Acknowledgments
We are grateful to Dr. J. S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New
Delhi, India (Grant No.: SR/S1/OC-08/2011) and the UGC (New
Delhi) is gratefully acknowledged for awarding fellowship to K. S.
and N.R. Thanks are also due to Dr. G. V. M. Sharma for his support.
15. Poulain, S.; Noiret, N.; Patin, H. Tetrahedron Lett. 1996, 37, 7703–7706.
16. (a) White, J. D.; Kim, T. S.; Nambu, M. J. Am. Chem. Soc. 1997, 119, 103–111; (b)
Ainai, T.; Matsuumi, M.; Kobayashi, Y. J. Org. Chem. 2003, 68, 7825–7832; (c)
Hoemann, M. Z.; Agrios, K. A.; Aubé, J. Tetrahedron Lett. 1996, 37, 953–956.
17. In addition to 18, we also isolated a minor compound which was tentatively
References
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found to be
a minor geometrical isomer derived from the Grubbs cross
metathesis reaction. At this juncture, we may not rule out the product arising
from the Wittig olefination. The isolated compound was not sufficient for
further characterization.