Asymmetric routes to pentadec-1-en-4-ol: Application to the syntheses of aculeatins F and epi-F, (R)- and (S)-5-hexadecanolide and a formal synthesis of solenopsin

Article abstract of DOI:10.1016/j.tetasy.2013.02.005

A short and simple route to the synthesis of pentadec-1-en-4-ol, an important synthetic building block for the aculeatins F and epi-F, insect pheromone 5-hexadecanolide, solenopsin and various other natural products has been developed via proline-catalyze

Full text of DOI:10.1016/j.tetasy.2013.02.005

Tetrahedron: Asymmetry 24 (2013) 305–314
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric routes to pentadec-1-en-4-ol: application to the syntheses
of aculeatins F and epi-F, (R)- and (S)-5-hexadecanolide and a formal
synthesis of solenopsin
⇑
Anand Harbindu, Brijesh M. Sharma, Pradeep Kumar
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 December 2012
Accepted 7 February 2013
A short and simple route to the synthesis of pentadec-1-en-4-ol, an important synthetic building block
for the aculeatins F and epi-F, insect pheromone 5-hexadecanolide, solenopsin and various other natural
products has been developed via proline-catalyzed
a-aminoxylation of an aldehyde and hydrolytic
kinetic resolution of a terminal epoxide. While the synthesis of aculeatins F and epi-F has been accom-
plished using a PIFA promoted oxidative spirocyclization/dithiane deprotection reaction sequence and
linchpin coupling as key steps, the synthesis of hexadecanolide and a formal synthesis of solenopsin
was performed using ring-closing metathesis (RCM) as key step.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
(S)-5-Hexadecanolide 5, (Fig. 1) a natural pheromone was iso-
lated from the mandibular glands of the oriental hornet Vespa ori-
In the search for new anticancer agents of plant origin, Kinghorn
et al. reported the isolation of metabolites, called aculeatols A–D, in
2007. Subsequently, the isolation of the eleven carbon side chain
containing aculeatins A and D, named, respectively as aculeatins
F and E were reported from Amomum aculeatum Roxb. (Zingibera-
ceae),1 a herbaceous plant, distributed in Indonesia, Malaysia, and
Papua New Guinea, and used as a folk medicine in the treatment of
fever and malaria. Due to their promising biological activity as po-
tential cancer chemotherapeutic agents based on the unusual 1,7-
dioxodispiro[5.1.5.2]pentadecane architecture, this class of com-
pound has generated a great deal of interest among synthetic or-
ganic chemists worldwide as an attractive synthetic targets.
Ramana et al.2 reported the first total synthesis of aculeatin F
and epi-F (Fig. 1) using a convergent approach. In this approach
the central 1,3,5-triol unit with the requisite stereochemistry was
entals.4 It contains a six membered lactone and its unsaturated
analogue (6-substituted 5,6-dihydro-2H-pyran-2-one) is the key
synthon for several biologically important molecules.5
Various methods for the synthesis of (S)-5-hexadecanolide 5
and its enantiomer have been reported.6 Servi reported the first
synthesis of enantiomerically pure (5S)-hexadecanolide 5 in which
the stereogenic center was generated by enzyme catalysis.6h Singh
et al. reported its synthesis from chiral epoxides derived from a
chiral pool starting material such as mannitol or ascorbic acid.6b
Zhang et al. described the synthesis of target compound 5 in enan-
tiomerically pure form using an L-proline-catalyzed asymmetric al-
dol reaction.7 In another approach, the target molecule was
constructed via asymmetric allylboration of an appropriate alde-
hyde and ring closing metathesis.8
Solenopsin 6,9 the alkaloidal component of the fire ant (Solenop-
sis invicta) exhibited powerful hemolytic, necrotoxic, antibiotic,
and antifungal activities as well as anti-HIV properties.10 Recently
it was found that solenopsin is a naturally occurring inhibitor of
prepared from commercially available
a-D-glucoheptonic-c-lac-
tone and addition of both the terminal units (phenol and side
chain) was performed at an advanced stage. Selective O-debenzy-
lation during the hydrogenolysis of a diyne intermediate and a
one-pot phenolic oxidation with concomitant spiroketalization
were the key features of this synthesis. Many synthetic strategies
have been described in the literature3 for aculeatins A, B, and D
phosphatidylinositol-3-kinase signaling and angiogenesis.11
A
number of methods have been reported for the stereospecific syn-
thesis of the solenopsins.9 Many of these methods involve multi-
step routes or require expensive starting materials.
involving
a final key oxidative spirocyclization of phenolic
precursors.
2. Result and discussion
Despite the numerous strategies available to synthesize penta-
dec-1-en-4-ol 1, interest in new methods for its synthesis contin-
ues.12 As part of our research program aimed at developing
⇑
Corresponding author. Tel.: +91 020 25902050; fax: +91 020 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.005

306
A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
( )10
O
( )10
O
O
O
OH
OH
O
O
epi-aculeatin F 2a
2
aculeatin F
O
NHCOCH3
O
NHCHO
O
H2N
O
O
O
O
O
O
( )9
n-C6H13
( )9
n-C6H13
tetrahydroesterastin 3
4
OH
tetrahydrolipstatin
∗
( )9
1
O
O
O
O
( )9
(5R)-hexadecanolide ent-5
( )9
5
(5S)-hexadecanolide
O
O
( )9
( )9
N
H
N
H
( )9
OH
6
(2S,6S)-solenopsin A
(2R,6R)-solenopsin A 7
OH
(3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone 8
Figure 1. Some selected natural products derived from pentatec-1-en-4-ol.
enantioselective methodologies and syntheses of naturally occur-
ring lactones13 and spiroacetals,14 we have now developed asym-
metric routes to pentadec-1-en-4-ol 1 in which the stereogenic
centers were generated either via hydrolytic kinetic resolution15
ONHPh
or by proline-catalyzed a
-aminoxylation of an aldehyde.16 As out-
a (i)
O
a (ii)
(iii)
O
∗
( )
( )9
lined in Figure 1, pentadec-1-en-4-ol serves as a building block for
the synthesis of various natural products such as isosolenopsins,17a
tetrahydroesterastin,17b tetrahydrolipstatin,17b (3S,4R)-dihydro-
9
9
(6S)-undecyl-a
-pyranone12 and so on. We have used synthetic pre-
OR1
cursor 1 for the synthesis of natural aculeatin F 2 and its epimer 2a
using a linchpin coupling,18 oxidative double spirocyclization/
dithiane deprotection sequence using PIFA and also for insect pher-
omone (R)- and (S)-5-hexadecanolide, solenopsins,17a employing
ring-closing metathesis. We herein report our synthetic endeavors
toward the synthesis of 1 and its application toward the synthesis
of the title compounds.
OH
∗
c
b (i)
(ii)
OR2
OH
O
∗
( )
( )9
9
10
11, R1=Ts, R2=Bz
12, R1=H, R2=Ts
OH
d
∗
∗
( )9
( ) 9
2.1. Organocatalytic route to pentadec-1-en-4-ol
1
/ ent-1
>90% ee
13
/ ent-13
Recently, Zhong et al. have reported on a
rected tandem reaction catalyzed by proline.16 The O-amino-
substituted diol obtained from the proline catalyzed -aminoxyla-
tion of achiral aldehydes and in situ reduction using NaBH4 could
be converted into homo allylic alcohol using standard protocols,
and which serve as a useful precursor for the synthesis of a variety
of biologically useful molecules. As shown in Scheme 1, the synthe-
a-aminoxylation di-
a
Scheme 1. Organocatalytic route to pentadec-1-en-4-ol. Reagents and conditions:
(a) (i) -proline, DMSO, nitrosobenzene, 1 h, (ii) NaBH4, MeOH, (iii) H2/Pd–C, EtOAc,
60 psi, 6 h, 72% (over three steps); (b) (i) benzoyl chloride, Et3N, CH2Cl2, 0 °C, 2 h, (ii)
TsCl, Et3N, CH2Cl2, rt, 8 h, 84% (over two steps) or TsCl, Et3N, Bu2SnO, CH2Cl2, rt, 4 h,
85%; (c) K2CO3, MeOH, rt, 1 h, 81%; (d) vinylmagnesium bromide, THF, CuI, ꢀ20 °C,
5 h, 82%.
L

A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
307
sis of pentadec-1-en-4-ol 1 started from aldehyde 9 which was
subjected to -aminoxylation using -proline and subsequent
which upon ring opening with decylmagnesium bromide followed
by base treatment gave epoxide 16 in 92% yield.
a
L
in situ NaBH4 reduction followed by Pd/C reduction to furnish diol
1019 in 72% yield. Subsequently, the primary hydroxy group of diol
10 was protected as its benzoyl ether followed by secondary hy-
droxyl group protection as the tosyl to afford 11 in 84% yield over
two steps. Base treatment resulted in epoxide 13. For the prepara-
tion of ent-13, the primary hydroxyl of diol 10 was converted into
its tosyl derivative 12. Subsequent base treatment furnished the
desired epoxides by intramolecular nucleophilic displacement of
the tosyl group. Epoxide 13/ent-13 was opened with vinylmagne-
sium bromide to give the homoallylic alcohol 1/ent-1 in excellent
yields (Scheme 1). The enantiomeric excess of 1/ent-1 was deter-
mined by converting the chiral pentadec-1-en-4-ol into its Mosher
ester and analyzing the 19F spectrum.
The rac-epoxide 16 was subjected to Jacobsen’s HKR using (R,R)-
salen–Co(OAc) catalyst to give enantiopure epoxide (R)-13 in 45%
yield along with diol 13a in 44% yield, which were separated by sil-
ica gel column chromatography. Epoxide 13 was treated with
vinylmagnesium bromide in the presence of CuI to give penta-
dec-1-en-4-ol 1 in 89% yield; ½a D25
ꢁ
¼ þ5:5 (c 1.0, CHCl3) {Ref.20
½
a 2D5
ꢁ
¼ þ5:5 (c 1.05, CHCl3)}. In the 1H NMR spectrum the terminal
olefinic group of 1 and epi-1 showed peaks at d 5.91–5.73 (multi-
plet, 1H) and 5.18–5.09 (m, 2H). All other protons resonated at
the expected chemical shifts. The 13C NMR spectrum displayed
peaks at d 118.0 and d 134.9 corresponding to the olefinic carbons.
Having the synthetic precursor 1 in substantial amounts, we then
turned our attention towards the total synthesis of aculeatins F 2
and epi-F 2a, hexadecanolide 5, and solenopsin 6.
2.2. HKR route to pentadec-1-en-4-ol
Our retrosynthetic analysis of aculeatins F and epi-F is shown in
Scheme 3. Aculeatins F and epi-F could be synthesized by the linch-
pin coupling of epoxide 18 and dithiane fragment 19. Epoxide 18
could in turn be prepared from 1 derived either from inexpensive
rac-epichlorohydrin 14 or aldehyde 9.
As shown in Scheme 2, the synthesis of pentadec-1-en-4-ol
started from the commercially available ( )-epichlorohydrin 14,
The epoxidation of homoallylic alcohol 1, using m-CPBA pro-
duced epoxide 20 in favor of the desired syn-isomer (syn/anti
1.5:1). The two diastereomers of the epoxy alcohol could not be
differentiated by thin-layer chromatography. For the separation
of the diastereomers, the hydroxy-group of epoxide 20 was pro-
tected as the TBS ether but again there was no separation on
TLC. In order to obtain better diastereoselectivity, epoxide 21 was
again subjected to HKR with (R,R)-salen–Co(OAc) complex
(0.5 mol %) and water (0.55 equiv) to afford the diastereomerically
pure epoxide 18 as a single diastereomer in good yield (Scheme 4).
As the HKR method provided the desired epoxide along with the
corresponding diol 18a in almost equal amounts, we thought that
it would be appropriate to convert diol 18a into the required epox-
ide 18 via internal nucleophilic substitution of a secondary mesy-
late.21 Accordingly chemoselective pivalation of diol 18a with
pivaloyl chloride followed by mesylation of the secondary hydro-
xyl and treatment of the crude mesylate with K2CO3 in methanol
led to the deprotection of the pivaloyl ester. Concomitant ring clo-
sure via intramolecular SN2 displacement of the mesylate fur-
nished epoxide 18 in 65% overall yield.
OH
O
a
b
Cl
Cl
( )9
14
15
OH
O
O
c
+
OH
( )9
( )9
13
( )9
13a
16
OH
O
d
( )9
( )9
>95% ee
13
1
Scheme 2. HKR route to pentadec-1-en-4-ol. Reagents and conditions: (a) decyl-
magnesium bromide, THF, CuI, ꢀ40 °C, 12 h, 83%; (b) KOH, Et2O, rt, 6 h, 92%; (c)
(R,R)-salen–Co-(OAc) (0.5 mol %), THF, distd H2O (0.55 equiv), 0 °C, 14 h, (45% for
13, 44% for 13a); (d) vinylmagnesium bromide, THF, CuI, ꢀ20 °C, 5 h, 89%.
With sufficient amounts of epoxide fragment 18 and dithiane
19 (synthesized by the previously reported method),5 in hand,
C10H21
C10H21
O
TBS
O
HO
O
O
S
S
O
OH
( ) 9
17
OH
OCH3
O
O
2a
aculeatin F 2
epi-aculeatin F
MeO
+
S
OH
OTBS
S
O
( )9
( )9
19
1
18
Scheme 3. Retrosynthetic route to aculeatin F 2 and epi-F 2a.

308
A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
OTBS
OH
OH
O
O
b
a
( )9
( )9
( ) 9
21
20
1
dr=1.5:1 (syn:anti)
OTBS
OTBS
OH
OTBS
O
O
c
+
OH
( )9
( ) 9
( ) 9
18
18a
21
OTBS
O
OTBS
OH
d
OH
( )9
( )9
18
18a
Scheme 4. Synthesis of epoxide 18. Reagents and conditions: (a) m-CPBA, CH2Cl2,0 °C to rt, 10 h, 96%; (b) TBDMSCl, imidazole, CH2Cl2,0 °C to rt, 3 h, 90%; (c) R,R-salen-co-
(OAc) (0.5 mol %), THF, dist. H2O (0.55 equiv), 0 °C, 24 h (46%) for 18, 39% for 18a); (d) (i) PivCl, Et3N, catDmAp, rt, 2 h, (ii) MsCl, Et3N, DMAP, 0 °C to rt, 1 h, (iii) K2CO3, MeOH,
rt, overnight (65% for three steps).
our next task was to couple epoxide 18 and dithiane 19 using
linchpin coupling (Scheme 5). The generation of lithiated anion
of dithiane 19 was carried out using n-BuLi in THF at ꢀ78 °C, fol-
lowed by the addition of epoxide 18 to furnish the coupled product
17. Deprotection of the methyl and TBS groups using BBr3 provided
the product in low yield. In order to improve the yield, the coupled
product was subjected to treatment with EtSNa22 in DMF to give
the naked 1,3-polyol in excellent yield, which upon reaction with
PhI(OCOCF3)2 in CH3CN/H2O (9:1 v/v) at room temperature fur-
nished a mixture of aculeatins F 2 and epi-F 2a in a 3:1 ratio, which
were easily separated by silica gel column chromatography.
Compounds 2 and 2a were fully characterized by 1H NMR, 13C
NMR, mass and IR spectroscopy data and which were in accor-
dance with those described in the literature.1,2
Next we turned our attention towards the synthesis of target
molecule 5. Retrosynthetic analysis for the target compound 5
and ent-5 is shown in Scheme 6. 5-Hexadecanolide could be syn-
thesized by the reduction of dihydro-2H-pyran derivative which
in turn could be obtained from ring-closing metathesis of a diene
precursor 23/ent-23.
We envisioned that homoallylic alcohol 1/ent-1 required us to
construct 23/ent-23, which could be easily synthesized from alde-
hyde 9 or epoxide 16 by standard synthetic manipulations. Toward
the synthesis of target 5, the alcohol ent-1 was esterified using
acryloyl chloride in the presence of triethylamine in dry CH2Cl2
to afford ester ent-23. Ring closing metathesis23 of ent-23 using
Grubbs’ 1st generation catalyst afforded lactone 24 which was
S
OTBS
O
+
a
S
( )9
hydrogenated using Pd/C to furnish the hexadecanolide
5
18
(Scheme 7). The physical and spectroscopic data of 5 were in full
OMe
19
O
OTBS OH
S
S
OH
O
b
a
b
( )9
( )9
( )9
17
ent-23
OMe
c
ent-1
O
O
OH
OH
S
S
aculeatin F
+
(49%)
(16%)
O
O
c
( )9
aculeatin epi-F
( )9
(5S)-hexadecanolide
( )9
22
OH
24
5
Scheme 5. Synthesis of aculeatin F 2 and epi-F 2a. Reagents and conditions: (a) n-
BuLi, HMPA, THF, ꢀ78 °C, 1 h, 85%; (b) EtSH, NaH, DMF, 120 °C, 48 h; 80%; (c)
PhI(OCOCF3)2, Me2CO/H2O (9:1), rt, 30 min, 65%, 3:1 mixture of aculeatins F 2 and
epi-F 2a.
Scheme 7. Synthesis of (5S)-hexadecanolide 5. Reagents and conditions: (a)
acryloyl chloride, Et3N, CH2Cl2, 2 h, cat. DMAP, 86%; (b) Grubb’s 1st gen. cat.,
CH2Cl2, 12 h, reflux, 80%; (c) Pd/C, H2, balloon press., 4 h, 84%.
O
O
OH
O
O
∗
( )9
∗
∗
( )9
( )9
1 /
ent-1
5 / ent-5
23
/ ent-23
Scheme 6. Retrosynthetic route to hexadecanolide 5.

A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
309
agreement with the literature.6b A similar reaction sequence to
that described in Scheme 7 was followed which eventually led to
the formation of the target molecule ent-5 (Scheme 8). The physi-
cal and spectroscopic data of ent-5 were also in full agreement with
the literature.6b
reaction and converted into an amine which upon protection with
(Boc)2O led to 27 in 82% yield (two steps, one pot).
Compound 27 was then alkylated with allyl bromide in the
presence of NaH to produce 25 in 85% yield. Treatment of 25 with
the Grubbs’ first generation catalyst in dichloromethane furnished
the 3,4-dehydropiperidine 28 in 90% yield. Catalytic hydrogenation
using Pd/C in EtOAc afforded compound 29. The final stage of the
synthesis could be achieved through known procedures24 via
incorporation of the methyl group and Boc deprotection to give
(2S,6S)-solenopsin A 6.
O
OH
O
a
c
b
( )9
( )9
3. Conclusion
1
23
In conclusion, we have developed an asymmetric route to pen-
tadec-1-en-4-ol 1 and applied it to the synthesis of aculeatin F 2,
epi-F 2a using PIFA mediated oxidative cyclization/dithiane depro-
tection as key step. The synthesis of (S)-5-hexadecanolide 5, (R)-5-
hexadecanolide ent-5 and formal synthesis of (2S,6S)-solenopsin A
6 have also been accomplished using ring-closing metathesis as the
key step.
O
O
O
O
( )9
(5R)-hexadecanolide
( )9
ent-24
Scheme 8. Synthesis of (5R)-hexadecanolide ent-5. Reagents and conditions: (a)
acryloyl chloride, Et3N, CH2Cl2, 2 h, cat. DMAP, 88%; (b) Grubb’s 1st gen. cat., CH2Cl2,
12 h reflux, 78%; (c) Pd/C, H2, balloon press., 4 h, 89%.
4. Experimental
4.1. General
After the successful synthesis of target molecule 5, we then at-
tempted the formal synthesis of yet another target molecule, sole-
nopsin 6.
The reactions were monitored by TLC using glass plates pre-
coated with silica gel 60 F254 to a thickness of 0.25 mm (Merck).
Column chromatography was performed on silica gel (60 and
230 mesh) using EtOAc, and petroleum ether as the eluents. Optical
rotations were measured with a JASCO DIP-360 digital polarimeter
at 25 °C. IR spectra were recorded on a Perkin–Elmer FT-IR spectro-
photometer. 1H NMR spectra were recorded on AC-200 MHz and
13C NMR spectra were recorded on AC-50 spectrometer, using
TMS as an internal standard in CDCl3. EI Mass spectra were re-
corded on Finnigan MAT-1020 spectrometer at 70 eV using a direct
inlet system.
In our retrosynthetic analysis (Scheme 9) for the target com-
pound 6, we envisaged that the construction of the six membered
ring could be achieved by ring closing metathesis of the N-alkyl-
ated diene compound 25, which in turn could be synthesized from
synthetic precursor 1 by simple manipulations. As depicted in
Scheme 10, our synthesis of (2S,6S)-solenopsin A started from
homoallylic alcohol 1. The free hydroxy group of 1 was converted
into the desired azido derivative in 80% yield using DPPA under
Mitsunobu conditions. Azide 26 was then subjected to a Staudinger
Boc
OH
HN
( )9
N
( )9
( )9
1
6
25
Scheme 9. Retrosynthetic route to (2S,6S)-solenopsin A 6.
OH
N3
NHBoc
a
b (i)
(ii)
( )9
( )9
( )9
27
26
1
Boc
Boc
N
c
N
e
d
( )9
( )9
25
28
Boc
N
HN
( )9
Ref. 24
( )9
29
Scheme 10. Synthesis of (2S,6S)-solenopsin A 6. Reagents and conditions: (a) (i) DPPA, DIAD, PPh3, toluene, ꢀ20 °C to rt, 12 h, 80%; (b) (i) PPh3, THF:H2O, 12 h, rt, (ii) (Boc)2O,
dioxane:H2O, 0 °C, 12 h, 82%; (c) Allyl bromide, NaH, DMF, 4 h, 85%; (d) Grubb’s catalyst I, CH2Cl2, 12 h, 90%; (e) H2-Pd/C, EtOAc, balloon press., 92%.

310
A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
4.2. (R)-Tridecane-1,2-diol 10
monitored by TLC, after completion in 4 h the mixture was
quenched by adding water. The solution was extracted with CH2Cl2
(3 ꢂ 20 mL) and then the combined organic phase was washed
with water, dried (Na2SO4), and concentrated. Column chromatog-
raphy of crude product using petroleum ether:ethyl acetate (92:8)
gave the compound 12 (1.46 g, 85%) as a solid. Mp 70–71 °C.
To a stirred solution of aldehyde 9 (3.00 g, 15.12 mmol) and
nitrosobenzene (1.61 g, 15.12 mmol) in DMSO (27 mL) was added
-proline (0.70 g, 6.04 mmol) in one portion at 25 °C. After 1 h,
L
the temperature was lowered to 0 °C, followed by dilution with an-
hyd MeOH (30 mL) and careful addition of excess NaBH4 (2.29 g,
60.49 mmol). The reaction was quenched after 10 min by pouring
the reaction mixture into a vigorously stirred biphasic solution of
Et2O and aqueous HCl (1 M). The organic layer was separated,
and the aqueous phase was extracted with EtOAc (3 ꢂ 40 mL).
The combined organic phases were dried over anhyd Na2SO4, and
concentrated to give the crude aminoxy alcohol.
½
a 2D5
ꢁ
¼ ꢀ6:9 (c 1.1, CHCl3). IR (CHCl3, cmꢀ1): mmax 3550, 2922,
2852, 1470, 1348, 1174, 955, 817. 1H NMR (200 MHz, CDCl3): d),
7.70 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 4.06–3.99 (m, 1H),
3.94–3.79 (m, 2H), 2.45 (s, 3H), 1.48–1.33 (m, 2H), 1.24 (br s,
18H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (50 MHz, CDCl3): d 145.0,
132.6, 129.9, 127.9, 73.9, 69.4, 32.6, 31.8, 29.5–29.3 (br, several
overlapped signals), 25.1, 22.6, 21.6, 14.0. Calcd: C, 64.83; H,
9.25; S, 8.65. Found: C, 64.88; H, 9.31; S, 8.72. MS (ESI): m/z
393.15 (M+Na)+.
The aminoxy alcohol (4.65 g) was dissolved in methanol
(30 mL) and to the solution was added 10% Pd/C (0.050 g). The
reaction mixture was then stirred in a hydrogen atmosphere at
60 psi for 6 h. After completion of the reaction (monitored by
TLC), the reaction mixture was filtered through a Celite pad, con-
centrated, and the crude product was then purified by silica gel
chromatography using EtOAc:petroleum ether (40:60) as eluent
to give pure diol 10 as a white solid (1.52 g, 72%). Mp 68 °C,
4.5. (S)-1,2-Epoxyundecane ent-13
To a solution of compound 11 (2.00 g, 4.21 mmol) in MeOH at
0 °C, K2CO3 (1.75 g, 12.64 mmol) was added and the resultant mix-
ture was allowed to stir for 1 h at the same temperature. After
completion of the reaction (as indicated by TLC), the reaction
was quenched by the addition of ice pieces and methanol was
evaporated. The concentrated reaction mixture was then extracted
with ethyl acetate (3 ꢂ 30 mL), the combined organic layer was
washed with brine, dried (Na2SO4), and concentrated. Column
chromatography of crude product using petroleum ether:ethyl
acetate (98:2) gave the epoxide ent-13 (0.68 g, 81%) as a colorless
½
a 2D5
ꢁ
¼ þ10:0 (c 1.00, MeOH); Lit.6h
½
a 2D5
ꢁ
¼ þ10:1 (c 1.06, MeOH).
IR (CHCl3, cmꢀ1): mmax 3391, 2957, 2932, 2861, 1466, 1216, 1069,
869. 1H NMR (200 MHz, CDCl3): d 3.80–3.59 (m, 2H), 3.53–3.35
(m, 1H), 2.39–2.13 (m, 2H), 1.52–1.41 (m, 2H), 1.25 (s, 18H), 0.87
(t, J = 6.73 Hz, 3H). 13C NMR (50 MHz, CDCl3): d 72.2, 66.7, 33.2,
31.8, 29.6–29.3 (br, several overlapped signals), 25.5, 22.6, 14.1.
MS (ESI): m/z 239.1 (M+Na)+.
liquid. ½a 2D5
ꢁ
¼ ꢀ11:5 (c 1.1, THF). IR (CHCl3, cmꢀ1): mmax 3018,
4.3. (R)-2-(Tosyloxy)tridecyl benzoate 11
2952, 2929, 2862, 1472, 1466, 1379, 1260, 1022, 916, 828. 1H
NMR (200 MHz, CDCl3): d 2.94–2.88 (m, 1H) 2.75 (dd, J = 7.4 Hz,
1H), 2.46 (dd, J = 8.6 Hz, 1H), 1.58–1.44 (m, 2H), 1.26 (br s, 18H),
0.89 (t, J = 7.3 Hz, 3H). 13C NMR (50 MHz, CDCl3): d 52.3, 47.0,
32.4, 31.8, 29.6–29.3 (br, several overlapped signals), 25.9, 22.6,
14.0. Calcd: C, 78.72; H, 13.21. Found: C, 78.79; H, 13.27%.
To a mixture of diol 10 (1.50 g, 6.93 mmol) in dry CH2Cl2 (20 mL),
benzoyl chloride (0.80 mL, 6.93 mmol) and triethylamine (0.97 mL,
6.93 mmol) were added and the reaction was stirred at room tem-
perature under nitrogen. The reaction was monitored by TLC; after
completion, the mixture was quenched by adding water. The solu-
tion was extracted with CH2Cl2 (3 ꢂ 20 mL) and then the combined
organic phase was washed with water (2 ꢂ 20 mL), dried, (Na2SO4)
and concentrated. To this crude mixture (2.22 g) in dry CH2Cl2
(25 mL), p-toluenesulfonyl chloride (2.66 g, 8.31 mmol) and trieth-
ylamine (1.16 mL, 8.31 mmol) were added and the reaction was
then stirred at room temperature under nitrogen. After completion
of reaction in 8 h, the mixture was quenched by adding water. The
solution was extracted with CH2Cl2 (3 ꢂ 20 mL) and then the com-
bined organic phase was washed with water, dried (Na2SO4), and
concentrated. Column chromatography of crude product using
petroleum ether:ethyl acetate (95:5) gave the compound 11
4.6. (S)-Pentadec-1-en-4-ol ent-1
A round bottomed flask was charged with copper(I) iodide
(0.12 g, 0.61 mmol), gently heated under vacuum, and slowly
cooled with a flow of argon, after which dry THF (20 mL) was
added. This suspension was cooled to ꢀ20 °C and stirred vigor-
ously, after which vinylmagnesium bromide (1 M in THF,
12.1 mL, 12.1 mmol) was injected into it. A solution of epoxide
(S)-ent-13 (1.2 g, 6.05 mmol) in THF (10 mL) was added slowly to
the above reagent, and the mixture was stirred at ꢀ20 °C for 5 h.
The reaction mixture was quenched with a saturated aqueous solu-
tion of NH4Cl. The organic layer was washed with brine
(2 ꢂ 10 mL), dried (Na2SO4), and concentrated. Silica gel column
chromatography of the crude product using petroleum ether:E-
tOAc (9:1) as eluent gave ent-1 (1.12 g, 82%) as a colorless syrupy
(2.76 g, 84%) as a colorless solid. Mp 39–40 °C. ½a D25
¼ ꢀ9:8 (c 1,
ꢁ
CHCl3). IR (CHCl3): mmax 3436, 2924, 2853, 1715, 1636, 1353, 1269,
1174, 1119, 928 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.99–7.89 (m,
.
2H), 7.78 (d, J = 8.3 Hz, 2H), 7.64–7.52 (m, 1H), 7.50-7.37 (m, 2H),
7.21 (d, J = 8.3 Hz, 2H), 4.92–4.81 (m, 1H), 4.45–4.26 (m, 2H) 2.35
(s, 3H), 1.84–1.65 (m, 1H), 1.25 (br s, 18H), 0.89 (t, J = 7.0 Hz, 3H).
13C NMR (50 MHz, CDCl3): d 14.0, 21.5, 22.6, 24.6, 29.5–29.1 (br, sev-
eral overlapped signals), 31.6, 31.8, 65.2, 80.4, 127.6, 128.3, 129.4,
129.7 (br, two overlapped signals), 133.1, 134.1, 144.5, 166. Anal.
Calcd: C, 68.32; H, 8.07. Found: C, 68.41; H, 8.13. MS (ESI): m/z
497.23 (M+Na)+.
liquid. ½a 2D5
ꢁ
¼ ꢀ15:8 (c 0.8, CHCl3). IR (CHCl3, cmꢀ1): mmax 3412,
2932, 2868, 1652, 1584, 1451, 1243, 1187, 1126, 837. 1H NMR
(200 MHz, CDCl3): d 5.91–5.73 (m, 1H), 5.18–5.09 (m, 2H), 3.70–
3.58 (m, 1H), 2.37–2.28 (m, 1H), 2.25–2.10 (m, 1H), 1.52–1.44
(m, 2H), 1.26 (br s, 18H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR
(50 MHz, CDCl3): d 134.9, 118.0, 70.6, 41.9, 36.7, 31.8, 29.6–29.3
(br, several overlapped signals, 25.6, 22.6, 14.0. Anal. Calcd: C,
79.58; H, 13.36. Found: C, 79.73; H, 13.39%.
4.4. (R)-2-Hydroxytridecyl 4-methylbenzenesulfonate 12
4.7. 1,2-Epoxyundecane 16
To a mixture of diol 10 (1.00 g, 4.62 mmol), in dry CH2Cl2
(20 mL) dibutyltin oxide (catalytic) was added followed by the
addition of p-toluenesulfonyl chloride (0.88 g, 4.62 mmol) and tri-
ethylamine (0.64 mL, 4.62 mmol) after which the reaction was stir-
red at room temperature under nitrogen. The reaction was
To a solution of crude compound 15 (10 g, 42.59 mmol) derived
from 1414 in Et2O (60 mL) was added finely powdered KOH (7.17 g,
127.8 mmol). The mixture was stirred vigorously for 6 h and then
poured into 50 mL of water. After separation of the layers, the

A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
311
aqueous layer was extracted with Et2O (3 ꢂ 150 mL), and the com-
bined organic layers were dried over Na2SO4. Evaporation of the
solvent and silica gel column chromatographic purification (petro-
leum ether) of the crude product gave 16 (7.77 g, 92%) as a color-
less liquid. IR (CHCl3, cmꢀ1): mmax 3018, 2952, 2929, 2862, 1472,
1466, 1379, 1260, 1022, 916, 828.1H NMR (200 MHz, CDCl3): d
0.89 (t, J = 7.3 Hz, 3H), 1.27 (br s, 18H), 1.48–1.54 (m, 2H), 2.47
(dd, J = 8.7 Hz, 1H), 2.76 (dd, J = 7.4 Hz, 1H), 2.89–2.93 (m,
1H).13C NMR (125 MHz, CDCl3): d 13.9, 22.6, 25.9, 26.8, 29.3,
29.4, 29.5, 29.6, 31.6, 32.4, 46.9, 52.3. ESI-MS: m/z = 221 [M+Na]+.
(m, 4H), 2.50 (dd, J = 2.8, 4.9, 0.60 H), 2.62 (dd, J = 2.9, 4.9,
0.40H), 2.76–2.84 (m, 1H), 3.04–3.19 (m, 1H), 3.73–3.92 (m, 1H)
(mixture of diastereomers). 13C NMR (CDCl3, 50 MHz): d = 14.0,
22.6, 25.4, 25.5, 29.3, 29.6 (br, several overlapped signals), 31.9,
37.4, 37.5, 39.0, 39.6, 46.5, 46.8, 50.2, 50.6, 69.2, 70.5 (mixture of
diastereomers). ESI-MS: m/z = 265 [M+Na]+.
4.11. tert-Butyldimethyl(((2R)-1-(oxiran-2-yl)tridecan-2-
yl)oxy)silane 21
To a stirred solution of alcohol 20 (2.8 g, 11.56 mmol) in CH2Cl2
(40 mL) was added imidazole (1.57 g, 23.06 mmol). To this solu-
tion, t-butyl dimethylchlorosilane (2.26 g, 15.02 mmol) was added
at 0 °C and reaction was stirred at room temperature for 3 h. The
reaction mixture was quenched with a saturated aqueous solution
of NH4Cl and extracted with CH2Cl2 (3 ꢂ 30 mL). The extract was
washed with brine, dried (Na2SO4), and concentrated. Silica gel col-
umn chromatography of the crude product using petroleum ether:-
EtOAc (19:1) as eluent provided 21 as a colorless liquid (3.71 g,
4.8. (R)-1,2-Epoxyundecane 13
A solution of epoxide 16 (7.0 g, 35.29 mmol) and (R,R)-salen–
Co(III)–OAc (0.106 g, 0.18 mmol) in THF (0.5 mL) was stirred at
0 °C for 5 min, and then distilled water (350 lL, 19.41 mmol) was
added. After stirring for 14 h, it was concentrated and purified by
silica gel column chromatography using petroleum ether to afford
13 (3.15 g, 45%) as a yellow liquid. Continued chromatography
with petroleum ether:EtOAc (4:1) provided the diol 13a as a brown
90%). ½a 2D5
¼ ꢀ6:3 (c 2.0, CHCl3). IR (CHCl3): mmax 3043, 2924,
ꢁ
color liquid as a single enantiomer. ½a D25
¼ þ11:5 (c 1.1, THF);
ꢁ
2855, 1465, 1255, 1072, 837, 775 cmꢀ1. 1H NMR (200 MHz, CDCl3):
d = 0.06, 0.08 (2s, 6H), 0.88 (t, J = 7.0, 3H), 0.91 (s, 9H), 1.26 (s, 18H),
1.48–1.71 (m, 4H), 2.44–2.51 (m, 1H), 2.74–2.82 (m, 1H), 2.75 (m,
1H), 3.02–3.09 (m, 1H), 3.79–3.94 (m, 1H) (mixture of diastereo-
mers). 13C NMR (CDCl3, 50 MHz): d = ꢀ4.7, ꢀ4.6, ꢀ4.5, ꢀ4.4, 14.1,
18.0, 22.7, 24.9, 25.4, 25.8, 29.3, 29.6 (br, several overlapped sig-
nals), 31.9, 37.9, 40.1, 40.2, 46.8, 47.7, 49.5, 49.9, 70.1, 70.3 (mix-
ture of diastereomers). ESI-MS: m/z = 379 [M+Na]+.
lit.17b
½
a 2D5
ꢁ
¼ þ11:2 (c 1.1, Et2O), IR (CHCl3, cmꢀ1): mmax 3018,
2952, 2929, 2862, 1472, 1466, 1379, 1260, 1022, 916, 828. 1H
NMR (200 MHz, CDCl3): d 0.89 (t, J = 7.3 Hz, 3H), 1.26 (br s, 18H),
1.44–1.58 (m, 2H), 2.46 (dd, J = 8.6 Hz, 1H), 2.75 (dd, J = 7.4 Hz,
1H), 2.94–2.88 (m, 1H). 13C NMR (50 MHz, CDCl3): d 14.0, 22.6,
25.9, 29.6–29.3 (br, several overlapped signals), 31.8, 32.4, 47.0,
52.3. ESI-MS: m/z = 221 [M+Na]+.
4.9. (R)-Pentadec-1-en-4-ol 1
4.12. tert-Butyldimethyl(((R)-1-((R)-oxiran-2-yl)tridecan-2-
yl)oxy)silane 18
A round bottomed flask was charged with copper(I) iodide
(0.288 g, 0.10 mmol), gently heated under vacuum, and then
slowly cooled with a flow of argon, after which dry THF (60 mL)
was added. This suspension was cooled to ꢀ20 °C and vigorously
stirred, after which vinylmagnesium bromide (1 M in THF,
30.3 mL, 30.3 mmol) was injected into it. A solution of epoxide
(R)-16 (3.0 g, 15.13 mmol) in THF (20 mL) was added slowly to
the above reagent, and the mixture was stirred at ꢀ20 °C for 5 h.
The reaction mixture was quenched with a saturated aqueous solu-
tion of NH4Cl. The organic layer was washed with brine
(2 ꢂ 30 mL), dried (Na2SO4), and concentrated. Silica gel column
chromatography of the crude product using petroleum ether:E-
tOAc (9:1) as eluent gave 1 (3.05 g, 89%) as a colorless syrupy li-
A solution of epoxide 21 (3.5 g, 6.49 mmol) and (R,R)-salen–
Co(III)–OAc (0.030 g, 0.05 mmol) in THF (1 mL) was stirred at
0 °C for 5 min, and then distilled water (97 lL, 5.40 mmol) was
added. After stirring for 24 h, it was concentrated and purified by
silica gel column chromatography using petroleum ether:EtOAc
(19:1) to afford 18 (1.61 g, 46%) as a colorless liquid. Continued
chromatography with petroleum ether/EtOAc (3:2) provided diol
18a as a brown liquid as a single diastereomer. The diastereoselec-
tivity was determined from 1H NMR and 13C NMR spectroscopic
data. ½a 2D5
¼ ꢀ8:4 (c 1.0, CHCl3). IR (CHCl3): mmax 3041, 2927,
ꢁ
2854, 1465, 1255, 1071, 835, 773 cmꢀ1 1H NMR (CDCl3,
400 MHz): d = 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H),
0.90 (s, 9H), 1.26 (s, 18H), 1.52–1.76 (m, 4H), 2.46 (dd, J = 2.8,
5.1 Hz, 1H), 2.76 (t, J = 4.5 Hz, 1H), 3.02–3.07 (m,1H),3.85 (quintet,
J = 5.8, 11.6, 1H). 13C NMR (CDCl3, 100 MHz): d = ꢀ4.5, ꢀ4.6, 14.1,
18.0, 22.7, 25.4, 25.6, 29.3, 29.6, 29.7, 31.9, 37.1, 40.1, 46.8, 49.5,
70.3. Calcd: C, 70.72; H, 12.43. Found: C, 70.89; H, 12.65% ESI-
MS: m/z = 379 [M+Na]+.
quid. ½a 2D5
ꢁ
¼ þ5:5 (c 1.0, CHCl3); lit.17b
½
a 2D5
ꢁ
¼ þ6:0 (c 1.7, CHCl3).
IR (CHCl3, cmꢀ1): mmax 3412, 2932, 2868, 1652, 1584, 1451, 1243,
1187, 1126, 837. 1H NMR (200 MHz, CDCl3): d 0.88 (t, J = 7.0 Hz,
3H), 1.26 (br s, 18H), 1.44–1.52 (m, 2H), 2.10–2.25 (m, 1H), 2.28–
2.37 (m, 1H), 3.58–3.70 (m, 1H), 5.09–5.18 (m, 2H), 5.73–5.91
(m, 1H). 13C NMR (50 MHz, CDCl3): d 14.0, 22.6, 25.6, 29.3–29.6
(br, several overlapped signals), 31.8, 36.7, 41.9, 70.6, 118.0,
134.9. ESI-MS: m/z = 249 [M+Na]+.
4.13. (2R,4R)-4-((tert-Butyldimethylsilyl)oxy)-1-(2-(4-
methoxyphenethyl)-1,3-dithian-2-yl)pentadecan-2-ol 17
4.10. (2R)-1-(Oxiran-2-yl)tridecan-2-ol 20
A flame dried two necked round bottomed flask was charged
with dithiane 19 (1.43 g, 5.61 mmol) under nitrogen after which
were added 30 mL of anhydrous THF and 5 mL of HMPA. The solu-
tion was cooled to ꢀ78 °C and to this was added n-BuLi
(5.61 mmol, 3.51 mL of 1.6 M in hexane) dropwise. The dark brown
reaction mixture was stirred for 30 min and to this was added
epoxide 18 (1.00 g, 2.80 mmol) dissolved in 10 mL of anhydrous
THF and 1 mL of HMPA dropwise. The reaction mixture was stirred
for an additional 30 min, then quenched with a saturated solution
of NH4Cl, diluted with water (10 mL), and extracted with ethyl ace-
tate (3 ꢂ 30 mL). The combined organic layers were washed with
To a stirred solution of olefin 1 (3.0 g, 13.26 mmol) in CH2Cl2
(60 mL) at 0 °C was added m-CPBA (50%) (6.84 g, 19.89 mmol).
The reaction mixture was stirred at room temperature for 10 h
and then quenched by saturated NaHCO3 solution, extracted with
CH2Cl2, washed with satd NaHCO3 and brine, dried (Na2SO4), con-
centrated, and purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1) as eluent to yield epoxide 20 as a pale
yellow liquid as a diastereomeric mixture (1.5:1). Yield: 3.08 g,
96%. ½a 2D5
¼ ꢀ0:5 (c 0.6, CHCl3). IR (CHCl3): mmax 3436, 3193,
ꢁ
2967, 2932, 2853, 1474, 1380, 1263, 1105, 944 cmꢀ1 1H NMR
(200 MHz, CDCl3): d 0.87 (t, J = 6.8 3H), 1.25 (s, 18H), 1.42–1.57

312
A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
saturated brine solution, dried over anhydrous Na2SO4, concen-
trated in vacuo, and the residue was purified by silica gel column
chromatography using a gradient of (10 ? 20%) ethyl acetate
and light petroleum to afford the coupled product 17 (1.45 g,
1H), 3.84–3.90 (m, 1H), 4.37–4.40 (m, 1H), 6.11 (dd,
J = 2.0,9.5 Hz, 1H), 6.16 (dd, J = 2.0, 9.5 Hz, 1H), 6.78 (dd, J = 2.8,
9.7 Hz, 1H), 6.99 (dd, J = 2.9, 10.0 Hz, 1H). 13C NMR (CDCl3,
100 MHz): d = 14.1, 22.7, 25.9, 29.3, 29.4, 29.6 (br, several over-
lapped signals), 31.9, 35.2, 35.3, 35.7, 37.9, 40.5, 65.2, 69.4,
77.5, 108.4, 127.1, 149.1, 152.2, 185.7. ESI-MS: m/z = 413
[M+Na]+.
85%) as a thick syrup. ½a D25
¼ þ8:7 (c 0.8, CHCl3). IR (CHCl3): mmax
ꢁ
3487, 2987, 2926, 2853, 2360, 1614, 1511, 1449, 1246, 1056,
815, 767 cmꢀ1 1H NMR (CDCl3, 200 MHz): d = 0.09 (s, 3H), 0.11
.
(s, 3H), 0.89 (t, J = 3.6 Hz, 3H), 0.91 (s, 9H), 1.27 (s, 18H), 1.42–
1.57 (m, 2H), 1.66–1.81 (m, 2H), 1.87–2.13 (m, 3H), 2.17–2.39
(m, 3H), 2.61–2.99 (m, 6H), 3.80 (s, 3H), 3.88–4.00 (m, 1H), 4.07–
4.23 (m, 1H), 6.83 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H). 13C
NMR (CDCl3, 50 MHz): d = ꢀ4.6, ꢀ4.4, 14.1, 18.0, 22.6, 25.1, 25.3,
25.9, 26.1, 26.3, 29.3, 29.6, 29.8, 31.9, 37.2, 41.9, 43.7, 45.8, 55.2,
65.0, 70.1, 113.8, 129.3, 133.8, 157.8. Anal. Calcd: C, 66.83; H,
10.23; S, 10.49. Found: C, 66.75; H, 10.21; S, 10.36. ESI-MS: m/
z = 634 [M+Na]+.
4.15. (S)-Pentadec-1-en-4-yl acrylate ent-23
Acryloyl chloride (0.20 mL, 2.43 mmol) was added drop wise
under argon to a solution of ent-1 (0.5 g, 2.21 mmol), triethylamine
(0.62 mL, 4.42 mmol) and DMAP catalytic amount in dry CH2Cl2
(5 mL) at 0 °C. The mixture was stirred for 2 h at room tempera-
ture. The resulting mixture was filtered through a pad of celite
and poured into water and organic layer was separated. The aque-
ous layer was extracted with CH2Cl2 (3 ꢂ 30 mL) and combined or-
ganic layer was washed with brine (2 ꢂ 20 mL), dried (Na2SO4),
and concentrated. Purification of crude product by silica gel col-
umn chromatography using petroleum ether:EtOAc (19:1) as elu-
4.14. (2R,4R,6R)-4-Hydroxy-2-undecyl-1,7-
dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-one 2 (aculeatin F)
and (2R,4R,6S)-4-hydroxy-2-undecyl-1,7-
dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-one 2a (aculeatin
epi-F)
ent afforded ent-23 (0.53 g, 86%) as
a
colorless liquid.
½
a 2D5
ꢁ
¼ þ14:2 (c 0.7, CHCl3). IR (CHCl3, cmꢀ1): mmax 2945, 2921,
2864, 1741, 1719, 1645, 1622, 1554, 1421, 1283, 1249, 1065. 1H
NMR (200 MHz, CDCl3): d 6.43–6.34 (dd, J = 1.7, 17.1 Hz, 1H),
6.17–6.03 (dd, J = 10.1, 17.1 Hz, 1H), 5.82–5.76 (dd, J = 1.7,
10.1 Hz, 2H), 5.74–5.66 (m, 1H) 5.11–4.96 (m, 2H), 2.34 (t,
J = 6.6 Hz, 2H), 1.60–1.53 (m, 2H), 1.25 (br s, 18H), 0.87 (t,
J = 7.1 Hz, 3H).13C NMR (50 MHz, CDCl3): d 166.0, 133.8, 130.4,
129.0, 117.7, 73.7, 38.7, 33.7, 32.0, 29.7–29.6 (br, several over-
lapped signals), 25.4, 22.8, 14.2. Anal. Calcd: C, 77.09; H, 11.50,
Found: C, 77.28; H, 11.54%.
To a suspension of NaH (0.33 g, 8.15 mmol) in DMF (10 mL)
cooled to 0 °C was added EtSH (0.9 mL, 9.82 mmol). After stirring
at 0 °C for 30 min, 17 (1.00 g, 1.63 mmol) in DMF (10 mL) was
added. The solution was heated to 120 °C for 48 h and then cooled
to room temperature. The reaction mixture was quenched with
water. The aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
Na2S2O7, brine, dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc/hexanes = 2:3) to afford 22 (0.63 g, 80%) as a colorless
liquid.
4.16. (S)-5,6-Dihydro-6-undecylpyran-2-one 24
To a solution of product 22 (0.10 g, 0.21 mmol) in an acetoni-
trile and water mixture (9:1, 5 mL) was added PhI(OCOCF3)2
(0.22 g, 0.52 mmol) in a single portion. The reaction mixture
was stirred for 30 min. at room temperature. After completion
of the reaction, a saturated solution of NaHCO3 was added and
the organic layers extracted with ethyl acetate (3 ꢂ 20 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
concentrated to give crude mixture of aculeatin F 2 and aculeatin
epi-F 2a, which was purified by flash silica column chromatogra-
phy using a gradient of (24 ? 30%) ethyl acetate and light petro-
leum to afford aculeatin F 2 (0.026 g, 49%) and aculeatin epi-F 2a
(0.008 g, 16%).
Grubb’s catalyst 1st generation (0.146 g, 0.18 mmol) dissolved
in CH2Cl2 (20 mL) was added dropwise to a refluxing solution of
acrylate ent-20 (0.500 g, 1.78 mmol), Ti(i-PrO)4 (0.13 g, 0.45 mmol)
in dry CH2Cl2 (50 mL). Refluxing was continued for 12 h by which
time all of the starting material was consumed. The solvent was re-
moved under reduced pressure and the crude product was purified
by silica gel column chromatography using petroleum ether:EtOAc
(4:1) as eluent to afford 24 (0.36 g, 80%) as a solid compound.
½
a 2D5
ꢁ
¼ þ78:2 (c, 0.9, THF), lit.6b
½
a 2D5
ꢁ
¼ þ78:7 (c 1.0, THF). IR (CHCl3,
cmꢀ1): max 3060, 1720, 1256, 1187, 1040, 875. 1H NMR (200 MHz,
m
CDCl3): d 6.90–6.81 (m, 1H), 6.01–5.94 (dt, J = 2, 8 Hz, 1H), 4.45–
4.31 (m, 1H), 2.33–2.26 (m, 2H), 1.69–1.53 (m, 2H), 1.23 (br s,
18H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (50 MHz, CDCl3): d 164.6,
145.1, 121.4, 78.1, 34.9, 31.9, 29.6–29.4 (br, several overlapped sig-
nals), 24.8, 22.7, 14.1. Anal. Calcd: C, 76.14; H, 11.18. Found: C,
76.23; H, 11.13.
4.14.1. Aculeatin F 2
½
a 2D5
ꢁ
¼ ꢀ3:9 (c 0.6, CHCl3); lit.2½a D25
¼ ꢀ4:7 (c 2.0, CHCl3) IR
ꢁ
(neat): mmax 3492, 2927, 2853, 1673, 1622, 1516, 1463, 1099,
1053, 949, 851 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.89 (t, J = 6.8,
.
3H), 1.27 (s, 17H), 1.40–1.55 (m, 4H), 1.82 (br d, J = 13.4 Hz, 1H),
1.90–2.05 (m, 4H), 2.22–2.27 (m, 1H), 2.34–2.42 (m, 1H), 3.38 (d,
J = 10.2 Hz, 1H), 4.08–4.13 (m, 2H), 6.11(dd, J = 2.0,10.2 Hz, 1H),
6.16 (dd, J = 2.0, 10.1 Hz, 1H), 6.77 (dd, J = 2.8, 10.0 Hz, 1H), 6.86
(dd, J = 2.9, 10.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d = 14.1,
22.7, 25.6, 29.3, 29.6, 29.7, 31.9, 34.1, 35.9, 37.9, 39.1, 64.8, 65.3,
79.7, 109.1, 127.0, 127.3, 148.8, 150.9, 185.3. ESI-MS: m/z = 413
[M+Na]+.
4.17. (S)-Tetrahydro-6-undecylpyran-2-one 5
To a solution of 24 (0.2 g, 0.79 mmol) in ethyl acetate (5 mL)
was added a catalytic amount of 10% Pd/C. The reaction mixture
was stirred for 4 h under a balloon of H2 at room temperature
and filtered through a Celite pad. The filtrate was concentrated
and the residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9:1) as eluent to give 5 (0.17 g, 84%)
as a white solid. Mp 37–38 °C, lit.6e mp 37 °C. ½a D25
¼ ꢀ42:2 (c 1.2,
ꢁ
4.14.2. Aculeatin epi-F 2a
THF), lit.6e
½
a 2D5
ꢁ
¼ ꢀ40:2 (c 1.5, THF). IR (CHCl3, cmꢀ1): mmax 1740,
½
a 2D5
ꢁ
¼ þ44:2 (c 0.6, CHCl3); lit.2
½
a 2D5
ꢁ
¼ þ46:8 (c 1.0, CHCl3) IR
1240, 1050. 1H NMR (200 MHz, CDCl3): d 4.30–4.19 (m, 1H),
2.61–2.32 (m, 2H), 1.93–1.79 (m, 2H), 1.71–1.38 (m, 2H), 1.23 (br
s, 18H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (50 MHz, CDCl3): d 172.0,
80.5, 35.7, 31.7, 29.5–29.4 (br, several overlapped signals), 27.6,
24.8, 22.5, 18.0, 14.1%.
(neat): mmax 3524, 2916, 2852, 1671, 1635, 1461, 1078, 980,
869 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.89 (t, J = 6.8, 3H), 1.27
.
(s, 17H), 1.41–1.51 (m, 3H), 1.53–1.64 (m, 3H), 1.84–1.94 (m,
2H), 2.00–2.12 (m, 2H),2.28–2.36 (m, 1H), 2.69 (dd, J = 7.4, 12.1,

A. Harbindu et al. / Tetrahedron: Asymmetry 24 (2013) 305–314
313
4.18. (R)-Tetrahydro-6-undecylpyran-2-one ent-5
(dd, J = 5.5, 23.3 Hz, 1H), 3.78–4.19 (m, 1H), 4.93–5.21 (m, 2H),
5.59–5.95 (m, 4H). 13C NMR (50 MHz, CDCl3): d 14.1, 22.7, 26.4,
29.3–29.6 (br, several overlapped signals), 31.9, 32.7, 33.1, 38.1,
38.4, 45.4, 56.6, 55.4, 64.5, 64.3, 79.4, 115.8, 116.4, 135.8, 136.4,
155.9 (rotamers). Calcd: C, 75.56; H, 11.86; N, 3.83. Found: C,
75.59; H, 11.68; N, 3.87. ESI-MS: m/z = 388 [M+Na]+.
Prepared in a similar way as described for 5. Mp 37–38 °C, lit.6e
mp 37 °C. ½a 2D5
ꢁ
¼ þ41:8 (c 1.5, THF), lit.6e
½
a 2D5
ꢁ
¼ þ40:2 (c 1.7, THF).
4.19. (S)-4-Azidopentadec-1-ene 26
A solution of DIAD (1.04 mL, 5.28 mmol) in dry toluene (10 mL)
was added dropwise to a solution of 1 (1.0 g, 4.4 mmol) and tri-
phenylphosphine (1.38 g, 5.28 mmol) in dry toluene (50 mL) under
an N2 atmosphere at ꢀ20 °C. After 15 min, diphenylphosphoryl
azide (1.04 mL, 4.84 mmol) was added dropwise and the reaction
mixture was stirred at ambient temperature for 12 h. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography (silica gel, petroleum ether:ethyl ace-
4.22. (S)-tert-Butyl 6-undecyl-5,6-dihydropyridine-1(2H)-
carboxylate 28
To a solution of 25 (0.30 g, 0.82 mmol) in anhydrous CH2Cl2
(10 mL) was added a solution of Grubb’s first generation catalyst
(0.067 g, 0.08 mmol) in CH2Cl2 (2 mL) over 4 h at room tempera-
ture. The mixture was stirred for 12 h under reflux conditions
and then concentrated in vacuo. Silica gel column chromatography
(EtOAc:petroleum ether, 1:99) of the crude product gave com-
tate, 95:05) to yield 26 as a colorless oil (0.88 g, 80%); ½a D25
¼ ꢀ1:4
ꢁ
(c 3.5, CHCl3). IR (CHCl3, cmꢀ1):
m
max 3081, 2925, 2855, 2101, 1643,
pound 28 as a pale yellow liquid. (0.25 g, 90%). ½a D25
¼ ꢀ0:65 (c
ꢁ
1465, 1339, 1256. 1H NMR (200 MHz, CDCl3): d 0.88 (t, J = 6.4 Hz,
3H), 1.26 (br s, 18H), 1.45–1.53 (m, 2H), 2.29 (t, J = 6.8 Hz, 2H),
3.32 (quin, J = 6.3, 12.3 Hz, 1H), 5.10–5.19 (m, 2H), 5.71–5.92 (m,
1H). 13C NMR (50 MHz, CDCl3): d 14.0, 22.7, 26.0, 29.3–29.6 (br,
several overlapped signals), 31.9, 33.9, 38.8, 62.3, 117.9, 134.0.
Calcd: C, 71.66; H, 11.63; N, 16.71. Found: C, 71.68; H, 11.53; N,
16.78. ESI-MS: m/z = 274 [M+Na]+.
1.5, CHCl3). IR (CHCl3, cmꢀ1): mmax 3019, 2927, 2855, 1694, 1599,
1369, 1337, 1215, 1156. 1H NMR (200 MHz, CDCl3): d 0.87 (t,
J = 6.7 Hz, 3H), 1.24 (br s, 20 H), 1.46 (br s, 9H), 1.83 (br d,
J = 18.4 Hz, 1H), 2.36 (br d, J = 18.4 Hz, 1H), 3.38 (br d, J = 18.4 Hz,
1H), 4.15–4.27 (m, 2H), 5.57–5.74 (m, 2H). 13C NMR (50 MHz,
CDCl3): d 14.1, 22.7, 26.4, 28.4, 29.3–29.6 (br, several overlapped
signals), 31.5, 31.8, 39.2, 40.2, 47.4, 48.6, 55.4, 79.3, 123.3 (br sig-
nal), 128.4, 128.5, 132.0, 132.1, 155.1 (rotamers). Calcd: C, 74.72;
H, 11.65; N, 4.15. Found: C, 74.70; H, 11.78; N, 4.23. ESI-MS: m/
z = 360 [M+Na]+.
4.20. (S)-tert-Butyl pentadec-1-en-4-ylcarbamate 27
To a solution of azide 26 (0.80 g, 3.18 mmol) in THF (20 mL)/
water (1.0 mL) was added PPh3 (1.00 g, 3.82 mmol) and mixture
was stirred at room temperature for 12 h. The mixture was concen-
trated and then 1,4-dioxane (5 mL)/water (5 mL) and Na2CO3
(0.84 g, 7.95 mmol) were added and stirred for another 10 min at
0 °C. To this ice cold solution, (Boc)2O (1.09 mL, 4.77 mmol) was
added and the mixture stirred overnight at 0 °C to room tempera-
ture. The solvent was evaporated at reduced pressure and ex-
tracted with EtOAc (3 ꢂ 25 mL). The combined organic layer was
washed with brine, water, dried (Na2SO4), and concentrated. Silica
gel column chromatography of the crude product using
EtOAc:petroleum ether (1:99) gave compound 27 as a colorless li-
4.23. (S)-tert-Butyl 2-undecylpiperidine-1-carboxylate 29
To olefin 28 (0.2 g, 0.59 mmol) in ethyl acetate was added Pd–C
(10%) (0.050 g). The reaction mixture was allowed to stir overnight
under hydrogenation conditions. Upon completion of the reaction
(when 1H NMR analysis of the crude mixture indicated complete
conversion), the mixture was filtered through a pad of celite and
concentrated in vacuo to give a saturated piperidine. The crude
product was then purified by using flash column chromatography
using petroleum ether:EtOAc (99:1) as eluent to give 29 as a color-
less liquid. (0.185 g, 92%). ½a D25
¼ ꢀ25:6 (c 0.6, CHCl3); IR (CHCl3,
ꢁ
quid. (0.85 g, 82%). ½a D25
ꢁ
¼ ꢀ2:9 (c 1.6, CHCl3). IR (CHCl3, cmꢀ1):
cmꢀ1): mmax 3009, 2927, 2855, 1678, 1417, 1365, 1159. 1H NMR
(200 MHz, CDCl3): d 0.87 (t, J = 6.7 Hz, 3H), 1.25 (br s, 21H), 1.44
(br s, 9H), 1.48–1.55 (m, 5H), 2.74 (t, J = 16.4 Hz, 1H), 3.96 (br d,
J = 14.6 Hz, 1H), 4.18 (br s, 1H). 13C NMR (50 MHz, CDCl3): d 14.1,
19.0, 22.7, 25.8, 26.4, 28.5, 29.3–29.6 (br, several overlapped sig-
nals), 31.9, 38.6, 50.5, 78.9, 155.1. Calcd: C, 74.28; H, 12.17; N,
4.13. Found: C, 74.31; H, 12.15; N, 4.18 ESI-MS: m/z = 362 [M+Na]+.
mmax 3349, 2926, 2855, 1704, 1641, 1504, 1248, 1174. 1H NMR
(200 MHz, CDCl3): d 0.87 (t, J = 6.64 Hz, 3H), 1.24 (br s, 18H), 1.43
(br s, 11H), 2.07–2.31 (m, 2H), 3.60 (br s, 1H), 4.34 (br d,
J = 8.2 Hz, 1H), 5.02–5.11 (m, 2H), 5.66–5.87 (dddd, J = 4, 10,
18Hz, 1H). 13C NMR (50 MHz, CDCl3): d 14.1, 22.7, 25.9, 29.3–
29.6 (br, several overlapped signals), 31.9, 34.7, 39.5, 50.1, 78.9,
117.5, 134.6, 155.6. Calcd: C, 73.79; H, 12.08; N, 4.30. Found: C,
73.65; H, 11.91; N, 4.33. ESI-MS: m/z = 348 [M+Na]+.
Acknowledgment
4.21. (S)-tert-Butyl allyl(pentadec-1-en-4-yl)carbamate 25
A.H. and B.M.S. thank the UGC and the CSIR, New Delhi respec-
tively for financial support in the form of SRF and JRF.
To a solution of 27 (0.50 g, 1.54 mmol) in DMF (5 mL), NaH
(0.246 g of 60% dispersion in oil, 6.16 mmol) was added through
solid addition funnel at 0 °C. The mixture was stirred for 30 min
at 0 °C after which freshly distilled allyl bromide (0.53 mL,
6.16 mmol) was added dropwise. After 4 h at room temperature,
the reaction was quenched by the addition of ice pieces. The reac-
tion mixture was diluted with EtOAc (10 mL), and the aqueous
phase was extracted with EtOAc (3 ꢂ 20 mL). The combined organ-
ic phase was washed with water (20 mL) and brine (20 mL), dried
over NaSO4, and concentrated in vacuo. Silica gel column chroma-
tography (EtOAc:petroleum ether, 1:99) of the crude product gave
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rotation with the known literature value: ½a D25
¼ þ10:0 (c 1.00, MeOH). This
ꢁ
value was in good agreement with the literature:6h
MeOH).
½ ꢁ ¼ þ10:1 (c 1.06,
a 2D5
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