Synthesis of aculeatins A and B via iterative hydrolytic kinetic resolution

Article abstract of DOI:10.1055/S-0029-1218687

A simple and concise approach for the synthesis of aculeatins A and B starting from (±)-epichlorohydrin is described. The synthetic strategy features Jacobsen's hydrolytic kinetic resolution and a Linchpin coupling as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218687

PAPER
1479
Synthesis of Aculeatins A and B via Iterative Hydrolytic Kinetic Resolution
Synthesis of
A
cule
n
atins A and Band Harbindu, Pradeep Kumar*
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: pk.tripathi@ncl.res.in
Received 28 December 2009; revised 30 December 2009
performed using phenyliodine bis(trifluoroacetate)
(PIFA).
Abstract: A simple and concise approach for the synthesis of
aculeatins A and B starting from ( )-epichlorohydrin is described.
The synthetic strategy features Jacobsen’s hydrolytic kinetic resolu-
tion and a Linchpin coupling as key steps.
As part of our research program aimed at developing
enantioselective syntheses of biologically active products
Key words: hydrolytic kinetic resolution, Linchpin coupling, based on hydrolytic kinetic resolution (HKR),7 we be-
epoxide, spirocyclization, aculeatins
came interested in devising a simple and concise route to
aculeatins A and B. Herein, we report our successful en-
deavors toward the total syntheses of 1 and 2 employing
HKR8 and a Linchpin coupling9 as the key steps.
Aculeatins A (1) and B (2) (Figure 1) were isolated by
Heilmann and co-workers in 2000 from Amomum Aculea-
tum rhizomes.1 They were found to inhibit the growth of
human cancer KB cell lines and MFC-7 human breast
H
H
cancer cells.2In addition, they display antiprotozoal activ-
ity against Trypanosoma and both the NF54 and chloro-
quine-resistant K1 strains of the malarial parasite
Plasmodium falciparum. Interestingly, these compounds
are endowed with an unprecedented 1,7-dioxa-
dispiro[5.1.5.2]pentadecane tricyclic ring system which
makes them attractive synthetic targets. In view of their
important biological activity, and unusual and challenging
structural features, the aculeatins have attracted consider-
able attention from synthetic organic chemists.
N
O
N
O
Co
t-Bu
t-Bu
OAc
t-Bu
t-Bu
Figure 2 Structure of the (R,R)-(salen)Co(III)(OAc) catalyst
The HKR method involves a readily accessible cobalt-
based chiral salen complex, (R,R)-(salen)Co(III)(OAc), as
the catalyst (Figure 2), and water to resolve a racemic
epoxide into an enantiomerically enriched epoxide and a
diol. Typically, the products can serve as useful precur-
sors for the synthesis of compounds of biological impor-
tance.10
O
O
O
O
Our retrosynthesis of the target compounds 1 and 2 is
based on a convergent approach as delineated in
Scheme 1. We envisioned that the common precursor 3
could be prepared via Linchpin coupling of epoxide syn-4
and dithiane 5. The epoxide syn-4 could in turn be pre-
pared from ( )-epichlorohydrin, while the dithiane frag-
ment 5 could be obtained starting from p-anisaldehyde.
O
O
( )
( )12
12
OH
OH
1
2
Figure 1 Aculeatins A (1) and B (2)
As shown in Scheme 2, the synthesis of epoxide fragment
syn-4 started from commercially available ( )-epichloro-
hydrin which on ring-opening with dodecylmagnesium
bromide gave alcohol 6. Subsequent treatment with base
gave the epoxide 7 in 92% yield. The rac-epoxide 7 was
subjected to Jacobsen’s HKR, using the (R,R)-
(salen)Co(III)(OAc) catalyst, to give a mixture of enan-
tiopure epoxide (R)-8a11in 46% yield along with diol 8b
in 45% yield, which were separated by silica gel column
chromatography.
In 2002, Wong reported the first syntheses of racemic
aculeatin A (1) and B (2) in which the spiroketal tricyclic
framework was generated by intramolecular cyclization
initiated by phenolic oxidation.3 Marco and co-workers
prepared 1 and 2 in enantiomerically pure form, for the
first time, using an asymmetric allylation reaction.4 Mean-
while, several other reported asymmetric syntheses of the
aculeatins were based mainly on chiral pool starting ma-
terials, or via stereoselective methods to generate the ste-
reogenic centers;5 subsequent oxidative cyclization6 was
With enantiomerically pure epoxide (R)-8a in hand, our
next task was to establish the second stereogenic center
with the required stereochemistry. Thus epoxide 8a was
treated with vinylmagnesium bromide in the presence of
copper(I) iodide to give the homoallylic alcohol 9 in 89%
SYNTHESIS 2010, No. 9, pp 1479–1484
Advanced online publication: 24.02.2010
DOI: 10.1055/s-0029-1218687; Art ID: Z28109SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

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A. Harbindu, P. Kumar
PAPER
O
O
O
OH
( )11
a
b
O
Cl
( )
Cl
11
7
6
OH
c
O
O
O
+
O
O
( )
OH
( )
12
( )11
12
( )11
8a
8b
OH
( )11
OH
OH
2
OH
1
O
e
O
d
( )11
8a
( )
11
10
9
OTBS OH
path b
S
S
g
f
( )11
path a
3
OMe
OTBS
OTBS
h
O
( )
( )
S
11
OTBS
( )11
11
O
9a
path a: 4 (syn/anti = 1:1.5)
path b: 4 (syn/anti = 1.5:1)
S
OTBS
syn-4
5
i
OTBS OH
OH
OTBS
O
OMe
O
+
( )
( )
( )
11
11
11
O
11
4 (syn/anti = 1.5:1)
syn-4
OHC
Cl
OTBS OH
OTBS
O
j
OMe
OH
( )
( )
Scheme 1 Retrosynthesis of aculeatins A (1) and B (2)
11
11
11
syn-4
Scheme 2 Synthesis of epoxide syn-4. Reagents and conditions: (a)
dodecylmagnesium bromide, THF, CuI, –40 °C, 12 h, 84%; (b) KOH,
Et2O, r.t., 1 h, 92%; (c) (R,R)-(salen)Co(III)(OAc) (0.5 mol%), THF,
H2O (0.55 equiv), 0 °C, 14 h (46% for 8a, 45% for 8b); (d) vinylma-
gnesium bromide, THF, CuI, –20 °C, 12 h, 89%; (e) MCPBA,
CH2Cl2, 0 °C to r.t., 10 h, 96%; (f) TBDMSCl, imidazole, CH2Cl2, 0
°C to r.t., 3 h, 92%; (g) TBDMSCl, imidazole, CH2Cl2, 0 °C to r.t., 4
h, 95%; (h) MCPBA, CH2Cl2, 0 °C to r.t., 8 h, 95%; (i) (R,R)-(sa-
len)Co(III)(OAc) (0.5 mol%), THF, H2O (0.55 equiv), 0 °C, 24 h
(49% for syn-4, 37% for 11); (j) (i) PivCl, Et3N, cat. DMAP, r.t., 2 h;
(ii) MsCl, Et3N, DMAP, 0 °C to r.t., 1 h; (iii) K2CO3, MeOH, r.t.,
overnight (61% over 3 steps).
yield. We next proceeded to explore the stereoselective
outcome of the epoxidation reaction of 9 with and without
protection of the hydroxy group. To this end, the hydroxy
group of homoallylic alcohol 9 was protected as the tert-
butyldimethylsilyl ether, followed by epoxidation with m-
chloroperoxybenzoic acid (path a). The epoxide 4 thus ob-
tained was found to be a mixture of two diastereomers
(syn/anti = 1:1.5) with the desired syn-diastereomer
present as the minor component. In contrast, epoxidation
of unprotected homoallylic alcohol 9 gave compound 10
in favor of the desired syn-diastereomer (syn/anti = 1.5:1).
Protection of the hydroxy group of epoxide 10 as the cor-
responding tert-butyldimethylsilyl ether gave epoxides
syn-4/anti-4 as a 1.5:1 diastereomeric mixture (path b).
The two diastereomers could not be differentiated by thin
layer chromatography. In order to improve the diastereo-
selectivity, the mixture of epoxides produced via path b
was subjected to HKR using the (R,R)-
(salen)Co(III)(OAc) complex (0.5 mol%) and water (0.55
equiv) to afford the diastereomerically pure epoxide syn-
4 in good yield.
O
CHO
b
d
a
OEt
MeO
MeO
MeO
12
OH
c
O
MeO
S
14
13
As the HKR method provided the desired epoxide syn-4
along with unwanted diol 11 in similar amounts, we de-
cided to convert diol 11 into the required epoxide syn-4
via internal nucleophilic substitution of a secondary me-
sylate.12 Accordingly, chemoselective pivalation of diol
11 with pivaloyl chloride was followed by mesylation of
the secondary hydroxy group. Treatment of the crude me-
sylate with potassium carbonate in methanol led to depro-
tection of the pivaloyl ester and concomitant ring closure
via intramolecular SN2 displacement of the mesyl group to
furnish epoxide syn-4 in 61% overall yield.
S
MeO
5
Scheme 3 Synthesis of dithiane 5. Reagents and conditions: (a)
Ph3PCHCO2Et, toluene, reflux, 6 h, 86%; (b) (i) 10% Pd/C, H2 (60
psi), EtOAc, r.t., 1 h; (ii) LiAlH4, THF, r.t. to reflux, 12 h, (81% over
2 steps); (c) IBX, DMSO–THF (1:1), 0 °C to r.t., 6 h, 84%; (d) 1,3-
propanedithiol, cat. BF3·OEt2, CH2Cl2, 0 °C, 12 h, 88%.
Synthesis 2010, No. 9, 1479–1484 © Thieme Stuttgart · New York

PAPER
Synthesis of Aculeatins A and B
1481
All reactions were carried out under an inert atmosphere, unless oth-
erwise stated, following standard syringe–septa techniques. Sol-
vents were dried and purified by conventional methods prior to use.
The progress of all the reactions was monitored by TLC using glass
plates precoated 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 PE or a PE–EtOAc mixture as the eluent. Pe-
troleum ether (PE) refers to the fraction boiling in the 60–80 °C
range. Optical rotations were measured on a JASCO DIP-360 digi-
tal polarimeter at 25 °C. IR spectra were recorded on a Perkin-
Elmer FT-IR spectrophotometer. 1H and 13C NMR spectra were re-
corded in CDCl3 using Bruker AC-200 and AC-400 spectrometers
at 200 MHz or 400 MHz (1H) and 50 MHz or 100 MHz (13C); TMS
was used as the internal standard. ESI-MS were obtained using an
API-Q-Star Applied Biosystems spectrometer. Elemental analyses
were carried out on a Carlo Erba CHNS-O analyzer.
The synthesis of dithiane fragment 5 (Scheme 3) started
from commercially available p-anisaldehyde which on
two carbon homologation via Wittig reaction provided the
olefin 12 as a cis/trans mixture. Reduction of the double
bond was carried out under hydrogenation conditions us-
ing 10% palladium on charcoal. This was followed by es-
ter reduction with lithium aluminum hydride to afford the
alcohol 13 in 81% overall yield. The alcohol 13 was oxi-
dized using 2-iodoxybenzoic acid (IBX) to give the corre-
sponding aldehyde 14, which on subsequent treatment
with 1,3-propanedithiol in the presence of a catalytic
amount of boron trifluoride–diethyl ether complex,13 at
room temperature, furnished the dithiane fragment 5 in
excellent yield.
1-Chloropentadecan-2-ol (6)
S
To a stirred soln of ( )-epichlorohydrin (14.00 g, 152.3 mmol) and
CuI (2.90 g, 15.2 mmol) in anhyd THF (150 mL) was added drop-
wise, at –40 °C, a soln of dodecylmagnesium bromide, itself pre-
pared from dodecyl bromide (113.12 g, 453.9 mmol) and Mg
turnings (7.40 g, 304.6 mmol) in anhyd THF. The mixture was
warmed to –20 °C over 12 h and then poured onto sat. aq NH4Cl
soln. The organic layer was separated and the aqueous layer was ex-
tracted with EtOAc (3 × 100 mL). The combined solvent extract
was dried over Na2SO4, concd and purified by silica gel column
chromatography (EtOAc–PE, 1:9) to give 6; yield: 9.06 g (84%), as
a colorless oil.
OTBS
( )11
a
O
+
S
OMe
5
syn-4
OTBS OH
S
S
S
b
( )11
3
OMe
OH
OH OH
1
+
2
(44%)
(15%)
S
c
IR (neat): 3409, 2955, 1467, 1216 cm–1.
( )11
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 3.0 Hz, 3 H), 1.26 (s,
20 H), 1.43–1.64 (m, 4 H), 2.02 (s, 1 H), 3.75–3.89 (m, 1 H), 3.40–
3.55 ( m, 1 H), 3.57–3.77 (m, 1 H), 3.75–3.89 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 22.6, 25.4, 29.3–29.6 (br,
several overlapping signals), 31.8, 34.1, 50.4, 71.4.
15
Scheme 4 Synthesis of aculeatin A (1) and B (2). Reagents and con-
ditions: (a) n-BuLi, HMPA, THF, –78 °C, 1 h, 87%; (b) BBr3,
CH2Cl2, r.t. to –78 °C, 4 h; (c) PhI(O2CCF3)2, Me2CO–H2O (9:1), r.t.,
4 h, 64% (over 2 steps), 2.93:1 diastereomeric mixture of 1 and 2.
ESI–MS: m/z = 285 [M + Na+].
With substantial amounts of both the required fragments
in hand the coupling of epoxide syn-4 and dithiane 5 was
accomplished via the Linchpin protocol (Scheme 4). To-
ward this end, the lithiated anion of dithiane 5 was pre-
pared using n-butyllithium in tetrahydrofuran at –78 °C,
and then quenched with epoxide syn-4 to afford the cou-
pled product 3. One-pot cleavage of the methyl and tert-
butyldimethylsilyl groups using boron tribromide14 gave
triol 15. Finally, spirocyclization of crude 15 with phe-
nyliodine bis(trifluoroacetate) in acetone–water (9:1 v/v),6
at room temperature, furnished a diastereoisomeric mix-
ture of aculeatins A (1) and B (2) in the ratio 2.93:1; these
were separated by silica gel column chromatography.
Compounds 1 and 2 were fully characterized by IR, NMR
and mass spectroscopy data which were in accord with
those reported in the literature.4,5
2-Tridecyloxirane (7)
To a soln of crude 6 (8 g, 30.43 mmol) in Et2O (50 mL) was added
finely powdered KOH (5.12 g, 91.3 mmol). The mixture was stirred
vigorously for 6 h and then poured onto H2O (50 mL). The aqueous
layer was extracted with Et2O (3 × 150 mL) and the combined or-
ganic layers dried over Na2SO4. Evaporation of the solvent and sil-
ica gel column chromatographic purification (PE) of the residue
gave epoxide 7; yield: 6.35 g (92%), as a colorless liquid.
IR (CHCl3): 3018, 2952, 2929, 2862, 1472, 1466, 1379, 1260, 1022,
916, 828 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.26 (s,
20 H), 1.42–1.59 (m, 4 H), 2.46 (dd, J = 5.0, 2.8 Hz, 1 H), 2.75 (dd,
J = 5.0, 4.0 Hz, 1 H), 2.87–2.95 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.1, 22.6, 25.9, 29.3–29.6 (br,
several overlapping signals), 31.9, 32.5, 47.0, 52.3.
ESI–MS: m/z = 249 [M + Na+].
In conclusion, a short and efficient total synthesis of
aculeatins A (1) and B (2) in high enantioselectivities and
11.5% overall yield has been accomplished. The stereo-
centers were installed by means of iterative Jacobsen’s
hydrolytic kinetic resolution, and the final oxidative spi-
rocyclization step was achieved using phenyliodine
bis(trifluoroacetate). It is expected that this approach
would be suitable for the synthesis of other aculeatins, and
we are currently working toward this objective.
(2R)-2-Tridecyloxirane (8a)
A
soln of epoxide 7 (7.5 g, 33.13 mmol) and (R,R)-
(salen)Co(III)(OAc) (0.109 g, 0.17 mmol) in THF (0.5 mL) was
stirred at 0 °C for 5 min, and then distilled H2O (327 mL, 18.22
mmol) was added. After stirring for 24 h, the mixture was concd and
purified by silica gel column chromatography (PE) to afford 8a;
yield: 3.45 g (46%), as a yellow liquid. Further chromatographic pu-
rification (PE–EtOAc, 4:1) provided diol 8b; yield: 3.64 g (45%),
brown liquid, as a single diastereomer.
[a]D25 +6.54 (c 1.0, CHCl3).
Synthesis 2010, No. 9, 1479–1484 © Thieme Stuttgart · New York

1482
A. Harbindu, P. Kumar
PAPER
IR (neat): 3018, 2869, 1736, 1467, 1216, 915, 828 cm–1.
IR (CHCl3): 3088, 2929, 2896, 1642, 1255, 1129 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.26 (s,
20 H), 1.42–1.59 (m, 4 H), 2.45 (dd, J = 5.1, 2.8 Hz, 1 H), 2.77 (dd,
J = 5.1, 4.0 Hz, 1 H), 2.84–2.93 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 22.6, 25.9, 29.3–29.6 (br,
several overlapping signals), 31.9, 32.4, 46.9, 52.1.
1H NMR (200 MHz, CDCl3): d = 0.06 (s, 6 H), 0.90 (s, 9 H), 0.90
(merged t, 3 H), 1.27 (s, 22 H), 1.36–1.43 (m, 2 H), 2.18–2.25 (m,
2 H), 3.69 (quin, J = 5.7 Hz, 1 H), 4.99–5.01 (m, 1 H), 5.05–5.09
(m, 1 H), 5.73–5.93 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = –4.5, –4.3, 14.1, 18.1, 22.7, 25.3,
25.9, 29.4, 29.7, 31.9, 36.8, 41.9, 72.0, 116.4, 135.5.
ESI–MS: m/z = 249 [M + Na+].
ESI–MS: m/z = 391 [M + Na+].
(4R)-Heptadec-1-en-4-ol (9)
To a stirred soln of 8a (3.25 g, 14.36 mmol) and CuI (274 mg, 1.44
mmol) in anhyd THF (30 mL) was added dropwise a soln of vinyl-
magnesium bromide (3.07 g, 28.72 mmol, 28.72 mL, 1 M soln in
THF) over a period of 30 min at –20 °C. The resulting mixture was
stirred for 12 h and then allowed to warm to 0 °C before being
quenched with sat. aq NH4Cl soln (20 mL). The aqueous layer was
extracted with Et2O (3 × 50 mL), and the combined extracts washed
with brine (20 mL) and dried (Na2SO4). Evaporation of the solvent
and silica gel column chromatographic purification (EtOAc–PE,
1:19) of the residue gave alkene 9; yield: 3.24 g (89%), as a color-
less oil.
(2R)-2-[(tert-Butyldimethylsilyl)oxy]-1-[(2R/S)-oxiran-2-
yl]pentadecane (syn-4/anti-4)
Path a: To a stirred soln of alcohol 10 (2 g, 7.40 mmol) in CH2Cl2
(25 mL) was added imidazole (1.00 g, 14.81 mmol). TBDMSCl
(1.45 g, 9.63 mmol) was added at 0 °C and the reaction was stirred
at r.t. for 4 h. The reaction mixture was quenched with sat. aq NH4Cl
soln and extracted with CH2Cl2 (3 × 20 mL). The organic extract
was washed with brine (3 × 10 mL), dried over Na2SO4 and concen-
trated. Silica gel column chromatography (PE–EtOAc, 19:1) of the
residue provided syn-4/anti-4; yield: 2.72 g (95%), as a colorless
liquid.
[a]D25 +4.92 (c 1.0, CHCl3) [Lit.5e [a]D25 +5.0 (c 1.0, CHCl3)].
IR (CHCl3): 3372, 2955, 1640, 1467, 1216 cm–1.
Path b: syn-4/anti-4
IR (CHCl3): 3041, 2926, 2854, 1465, 1255, 1070, 835, 773 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H), 1.26 (s,
22 H), 1.44–1.46 (m, 2 H), 1.65 (s, 1 H), 2.05–2.21 (m, 1 H), 2.24–
2.38 (m, 1 H), 3.57–3.70 (m, 1 H), 5.08–5.19 (m, 2 H), 5.73–5.94
(m, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.1, 22.7, 25.7, 29.3–29.6 (br,
several overlapping signals), 31.9, 36.8, 41.9, 70.7, 118.0, 134.9.
1H NMR (400 MHz, CDCl3): d (1.5:1 mixture of diastereomers) =
0.06, 0.07 (2 s, 3.6 H), 0.09 (s, 2.4 H), 0.89 (t, J = 7.1 Hz, 3 H), 0.90
(s, 9 H), 1.26 (s, 22 H), 1.48–1.55 (m, 2 H), 1.60–1.64 (m, 1 H),
1.70–1.76 (m, 1 H), 2.46 (dd, J = 5.1, 2.7 Hz, 0.43 H), 2.48 (dd,
J = 5.1, 2.7 Hz, 0.57 H), 2.76 (t, J = 4.5 Hz, 0.43 H), 2.80 (t, J = 4.9
Hz, 0.57 H), 3.01–3.07 (m, 1 H), 3.84–3.91 (m, 1 H).
13C NMR (100 MHz, CDCl3): d (1.5:1 mixture of diastereomers) =
–4.7, –4.6, –4.5, –4.4, 14.9, 18.0, 22.7, 25.0, 25.4, 25.8, 29.3, 29.6
(br, several overlapping signals), 31.9, 37.1, 37.9, 40.1, 40.2, 46.8,
47.7, 49.5, 50.0, 70.1, 70.4.
ESI–MS: m/z = 277 [M + Na+].
(2R)-1-(Oxiran-2-yl)pentadecan-2-ol (10)
To a stirred soln of alkene 9 (2.5 g, 87.08 mmol) in CH2Cl2 (30 mL)
at 0 °C was added 50% MCPBA (5.10 g, 14.75 mmol). The reaction
mixture was stirred at r.t. for 10 h, quenched with sat. aq NaHCO3
soln and extracted with CH2Cl2 (3 × 30 mL). The combined organic
layer was washed with sat. aq NaHCO3 soln (3 × 10 mL) and brine
(3 × 10 mL), dried over Na2SO4, concentrated and purified by silica
gel column chromatography (PE–EtOAc, 9:1) to afford a diastereo-
meric mixture (1.5:1) of epoxide 10; yield: 2.55 g (96%), as a white
solid.
ESI–MS: m/z = 407 [M + Na+].
(2R)-2-[(tert-Butyldimethylsilyl)oxy]-1-[(2R)-oxiran-2-yl]pen-
tadecane (syn-4)
A soln of epoxide syn-4/anti-4 (prepared via path b) (2.5 g, 6.49
mmol) and (R,R)-(salen)Co(III)(OAc) (0.021 g, 0.32 mmol) in THF
(0.3 mL) was stirred at 0 °C for 5 min, and then distilled H2O (64 L,
3.57 mmol) was added. After stirring for 24 h, the reaction mixture
was concentrated and purified by silica gel column chromatography
(PE–EtOAc, 19:1) to afford syn-4; yield: 1.23 g (49%), as a yellow
liquid. Further chromatographic purification (PE–EtOAc, 3:2) pro-
vided diol 11; yield: 0.969 g (37%), brown liquid, as a single dia-
IR (CHCl3): 3436, 3192, 2968, 2932, 2852, 1471, 1379, 1265, 1206,
1101, 944, 878 cm–1.
1H NMR (200 MHz, CDCl3): d (1.5:1 mixture of diastereomers) =
0.88 (t, J = 6.8 Hz, 3 H), 1.26 (s, 22 H), 1.50–1.68 (m, 2 H), 1.79–
1.94 (m, 1 H), 2.52 (dd, J = 4.9, 2.8 Hz, 0.4 H), 2.64 (dd, J = 4.9,
2.9 Hz, 0.6 H), 2.79–2.87 (m, 1 H), 3.07–3.23 (m, 1 H), 3.78–3.97
(m, 1 H), 4.52 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d (1.5:1 mixture of diastereomers) =
14.1, 22.6, 25.4, 25.5, 29.3, 29.6 (br, several overlapping signals),
31.9, 37.4, 37.5, 38.8, 39.6, 46.6, 46.9, 50.3, 50.7, 69.3, 70.6.
stereomer. The diastereoselectivity was determined from 1H and 13
NMR spectral data.
C
[a]D25 –8.42 (c 1.0, CHCl3).
IR (CHCl3): 3041, 2926, 2854, 1465, 1255, 1070, 835, 773 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.88
(t, J = 7.0 Hz, 3 H), 0.90 (s, 9 H), 1.26 (s, 22 H), 1.51–1.54 (m, 2 H),
1.61 (dt, J = 13.8, 5.8 Hz, 1 H), 1.73 (dt, J = 13.8, 5.8 Hz, 1 H), 2.46
(dd, J = 5.0, 2.8 Hz, 1 H), 2.76 (t, J = 4.5 Hz, 1 H), 3.02–3.07 (m, 1
H), 3.85 (quin, J = 5.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –4.5, –4.6, 14.1, 18.0, 22.7, 25.8,
29.4, 29.6, 29.7, 31.9, 37.2, 40.1, 46.8, 49.6, 70.4.
ESI–MS: m/z = 407 [M + Na+].
ESI–MS: m/z = 293 [M + Na+].
(4R)-4-[(tert-Butyldimethylsilyl)oxy]heptadec-1-ene (9a)
To a stirred soln of alcohol 9 (1 g, 3.93 mmol) in CH2Cl2 (15 mL)
was added imidazole (0.53 g, 7.86 mmol). TBDMSCl (0.77 g, 5.10
mmol) was added at 0 °C and the reaction was stirred at r.t. for 3 h.
The reaction mixture was quenched with sat. aq NH4Cl soln and ex-
tracted with CH2Cl2 (3 × 20 mL). The organic extract was washed
with brine (3 × 10 mL), dried over Na2SO4 and concentrated. Silica
gel column chromatography (PE) of the residue provided silyl ether
9a; yield: 1.33 g (92%), as a colorless liquid.
Anal. Calcd for C23H48O2Si : C, 71.81; H, 12.58. Found: C, 71.78;
H, 12.53.
2-[2-(4-Methoxyphenyl)ethyl]-1,3-dithiane (5)
To a soln of aldehyde 14 (4.0 g, 24.09 mmol) in anhyd CH2Cl2 (40
mL) at 0 °C was added 1,3-propanedithiol (2.93 mL, 28.90 mmol)
[a]D25 +5.37 (c 1.0, CHCl3).
Synthesis 2010, No. 9, 1479–1484 © Thieme Stuttgart · New York

PAPER
Synthesis of Aculeatins A and B
1483
and a cat. amount of BF3·OEt2, and the reaction stirred at r.t. for 12
h. After completion (TLC), the reaction was quenched with sat. aq
NaHCO3 soln, diluted with H2O and extracted with EtOAc (3 × 30
mL). The combined organic layer was washed with brine (3 × 10
mL), dried over Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (PE–EtOAc, 1:4) to
afford dithiane 5; yield: 5.46 g (88%), as a white liquid.
dried over Na2SO4 and concentrated to give a crude mixture of ac-
uleatins A (1) and B (2) which was purified by flash silica gel col-
umn chromatography (gradient: 25–40% EtOAc–PE) to afford
aculeatin A (1); yield: 0.039 g (44%), and aculeatin B (2); yield:
0.013 g (15%).
Aculeatin A (1)
[a]D25 –5.3 (c 0.9, CHCl3).
IR (CHCl3): 2995, 2904, 2831, 1654, 1610, 1512, 1438, 1246, 1176,
1035, 908, 827 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.82–1.93 (m, 1 H), 2.04 (q,
J = 7.3 Hz, 2 H), 2.09–2.15 (m, 1 H), 2.78 (t, J = 7.7 Hz, 2 H),
2.83–2.86 (m, 4 H), 3.80 (s, 3 H), 3.98 (t, J = 7.0 Hz, 1 H), 6.84 (d,
J = 8.8 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 2 H).
IR (neat): 3491, 2934, 1673, 1622, 1516, 1463, 1099, 1053, 949,
846 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.27 (s,
21 H), 1.40–1.52 (m, 4 H), 1.80 (d, J = 14.0 Hz, 1 H), 1.93 (d,
J = 14.0 Hz, 1 H), 1.98–2.04 (m, 3 H), 2.24 (dd, J = 10.3, 7.3 Hz, 1
H), 2.33–2.43 (m, 1 H), 3.37 (d, J = 9.8 Hz, 1 H), 4.08–4.13 (m, 2
H), 6.11 (dd, J = 10.5, 1.9 Hz, 1 H), 6.15 (dd, J = 10.5, 1.9 Hz, 1 H),
6.76 (dd, J = 10.0, 3.1 Hz, 1 H), 6.85 (dd, J = 10.0, 2.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.9, 30.2, 31.5, 37.0, 46.4, 55.1,
113.7, 129.4, 132.8, 157.8.
(2R,4R)-4-[(tert-Butyldimethylsilyl)oxy]-1-{[2-(4-methoxyphe-
nyl)ethyl]-1,3-dithian-2-yl}heptadecan-2-ol (3)
13C NMR (100 MHz, CDCl3): d = 14.1, 22.6, 25.6, 29.3, 29.6 (br,
several overlapping signals), 31.9, 34.1, 35.8, 37.9, 39.0, 64.8, 65.3,
79.7, 109.0, 127.0, 127.3, 148.7, 150.8, 185.3.
A flame-dried round bottom flask was charged with dithiane 5 (0.71
g, 2.81 mmol), followed by anhyd THF (10 mL) and HMPA (1 mL).
The resulting soln was cooled to –78 °C and treated dropwise with
n-BuLi (0.24g, 3.74 mmol, 2.34 mL, 1.6 M soln in hexane). The
dark-brown reaction mixture was stirred for 30 min after which was
added dropwise, epoxide syn-4 (0.70 g, 1.87 mmol) in anhyd THF
(5 mL) containing HMPA (0.5 mL). The reaction mixture was
stirred for an additional 30 min, then quenched with sat. aq NH4Cl
soln, diluted with H2O (5 mL) and extracted with EtOAc (3 × 20
mL). The combined organic layer was washed with brine (3 × 10
mL), dried over Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (gradient: 10–20%
EtOAc–PE) to afford coupled product 3; yield: 1.25g (87%), as a
thick syrup.
ESI–MS: m/z = 441 [M + Na+].
Aculeatin B (2)
[a]D25 +47.2 (c 0.2, CHCl3).
IR (neat): 3486, 2952, 1671, 1635, 1461, 1078, 980, 868 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 6.5 Hz, 3 H), 1.26 (s,
21 H), 1.41–1.52 (m, 4 H), 1.56–1.64 (m, 2 H), 1.87–1.97 (m, 2 H),
2.01–2.11 (m, 2 H), 2.33 (td, J = 12.4, 7.4 Hz, 1 H), 2.69 (dd,
J = 13.1, 7.1 Hz, 1 H), 3.85–3.89 (m, 1 H), 4.37–4.39 (m, 1 H), 6.11
(dd, J = 10.5, 1.9 Hz, 1 H), 6.15 (dd, J = 10.5, 1.9 Hz, 1 H), 6.77
(dd, J = 10.5, 3.0 Hz, 1 H), 6.99 (dd, J = 10.5, 2.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.1, 22.6, 25.9, 29.3, 29.4, 29.6
(br, several overlapping signals), 31.9, 35.2, 35.3, 35.7, 37.9, 40.5,
65.1, 69.4, 77.5, 108.4, 127.1, 149.1, 152.2, 185.6.
[a]D25 –3.10 (c 1.0, CHCl3).
IR (CHCl3): 3485, 2987, 2924, 2852, 2360, 1612, 1512, 1448, 1246,
1055, 813, 767 cm–1.
ESI–MS: m/z = 441 [M + Na+].
1H NMR (200 MHz, CDCl3): d = 0.09 (s, 3 H), 0.11 (s, 3 H), 0.09
(t, J = 3.5 Hz, 3 H), 0.91 (s, 9 H), 1.26 (s, 22 H), 1.42–1.76 (m, 4 H),
1.90–2.12 (m, 3 H), 2.17–2.39 (m, 3 H), 2.59–2.99 (m, 6 H), 3.79
(s, 3 H), 3.88–4.00 (m, 1 H), 4.07–4.35 (m, 1 H), 6.83 (d, J = 8.7 Hz,
2 H), 7.14 (d, J = 8.7 Hz, 2 H).
Acknowledgment
A.H. thanks UGC, New Delhi for financial support in the form of a
SRF.
13C NMR (50 MHz, CDCl3): d = –4.5, –4.2, 14.1, 18.0, 22.7, 24.9,
25.1, 25.3, 25.9, 26.1, 26.2, 29.3, 29.6, 29.7, 29.8, 31.9, 37.2, 41.8,
44.7, 45.8, 52.1, 55.2, 66.9, 71.4, 113.8, 129.3, 133.9, 157.8.
References
ESI–MS: m/z = 661 [M + Na+].
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Helv. Chim. Acta 2000, 83, 2939. (b) Heilmann, J.; Brun,
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Anal. Calcd for C36H66O3S2Si: C, 67.65; H, 10.41; S, 10.03. Found:
C, 67.58; H, 10.39; S, 10.01.
(2) Chin, Y.-W.; Salim, A. A.; Su, B.-N.; Mi, Q.; Chai, H.-B.;
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(2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pen-
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(3) Wong, Y. S. Chem. Commun. 2002, 686.
A soln of compound 3 (0.50 g, 0.78 mmol) in anhyd CH2Cl2 (5 mL)
at –78 °C was added to a soln of BBr3 (0.79 g, 3.14 mmol, 3.14 mL,
1.0 M soln in CH2Cl2). After 2 h, the mixture was warmed to –25
°C. The reaction progress was monitored by TLC and was found to
be complete after 2 h. The reaction mixture was quenched with sat.
aq NaHCO3 soln (3 × 10 mL), extracted with CH2Cl2 (3 × 20 mL)
and washed with brine (3 × 10 mL), then the organic layer was dried
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of crude 15 (0.10 g, 0.196 mmol) in acetone–H2O (9:1, 5 mL) was
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reaction mixture stirred for 4 h at r.t. After completion of the reac-
tion, sat. aq NaHCO3 soln was added and the aqueous layer was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layer was
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Synthesis 2010, No. 9, 1479–1484 © Thieme Stuttgart · New York

1484
A. Harbindu, P. Kumar
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Synthesis 2010, No. 9, 1479–1484 © Thieme Stuttgart · New York