The stereoselective total synthesis of aculeatin A and B via prins cyclization

Article abstract of DOI:10.1055/s-0029-1217144

The total synthesis of aculeatins A and B is described proving the versatility of Prins cyclization in natural product synthesis. The approach is convergent and highly stereoselective. Morpholine amide coupling with an alkyne and PIFA-mediated oxidative spirocyclization were utilized as key steps. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217144

PAPER
431
The Stereoselective Total Synthesis of Aculeatin A and B via Prins Cyclization
S
tereosele
.
ctive
Total
S
S
ynthesis of
A
c
.
uleatin Aan
Y
d
B
adav,* N. Thrimurtulu, M. Venkatesh, A. R. Prasad
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 26 August 2009; revised 14 September 2009
the synthesis of various polyketide intermediates and ap-
Abstract: The total synthesis of aculeatins A and B is described
proving the versatility of Prins cyclization in natural product syn-
thesis. The approach is convergent and highly stereoselective. Mor-
pholine amide coupling with an alkyne and PIFA-mediated
oxidative spirocyclization were utilized as key steps.
plied it in the synthesis of some natural products.5 As a
part of this ongoing program, we have accomplished a ste-
reoselective total synthesis of the aculeatin A and B via
Prins cyclization.
Key words: aculeatins, Prins cyclization, morpholine amide,
PIFA-mediated oxidative spirocyclization
Before the synthesis, a careful examination was made on
retrosynthetic analysis (Scheme 1). We have simplified
the molecule into an aliphatic fragment 13 and an aromat-
ic fragment 16. The aliphatic part is envisaged to be con-
Aculeatins A–D (1–4) (Figure 1) were isolated from the
petroleum ether extract of the rhizomes of Amomum
aculeatum by Heilmannin in 2000–2001.1 Aculeatin A (1)
was found to be amongst the most cytotoxic of the com-
pounds tested and was further evaluated in an in vivo hol-
low fiber assay. It was found to be active against MCF-7
(human breast cancer) cells implanted intraperitoneally at
doses of 6.25, 12.5, 25, and 50 mg/kg.2 However, when 1
was tested using P388 lymphocytic leukemia and human
A2780 ovarian carcinoma in vivo models, it was deemed
to be inactive at the doses used.2
O
O
O
O
O
O
12
12
HO
HO
O
1
2
O
HO
As aculeatins have a novel framework and significant an-
tiprotozoal, antibacterial, and antitumoral activities, sev-
eral schools of chemistry started synthetic investigations
on these compounds.3 Inspired by the cytotoxic effects
and having been fascinated by the spiroacetal framework
in the structure we investigated the synthesis of aculeatin
A and B via Prins cyclization.4 Our group has made a sig-
5
O
10
O
O
O
O
O
12
OH
HO
3
4
nificant effort to explore the utility of Prins cyclization in Figure 1 Aculeatins A–D (1–4)
O
O
OTBS
OTBS
O
+
+
BnO
N
11
14
O
O
O
17
O
O
12
12
OTBS OTBS
HO
aculeatin A (1)
HO
aculeatin B (2)
11
11
OH
OH
5
OH
+
OH
tetradecanal
O
11
6
Scheme 1
SYNTHESIS 2010, No. 3, pp 0431–0436
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1217144; Art ID: Z18009SS
© Georg Thieme Verlag Stuttgart · New York

432
J. S. Yadav et al.
PAPER
OH
O
OTBS
OH
O
OTBS
a
b
c
d
e
OH
OH
OTs
OTs
I
O
O
12
12
12
12
OH
5
6
7
8
9
OH OTBS
TBS
O
OTBS
O
TBS
O
OTBS
OH
OTBS
TBSO
g
h
i
j
12
O
N
10
12
f
TBSO
12
12
12
O
12
13
14
11
OH
OTBS
O
O
O
OTBS
TBS
l
k
1
+
2
2
12
OBn
15
16
Scheme 2 Reagents and conditions: a) tetradecanal, TFA, CH2Cl2, 0 °C to r.t., 3 h, then K2CO3, MeOH, r.t., 30 min, 52%; b) TsCl, Et3N,
CH2Cl2, 0 °C to r.t., 3 h, 85%; c) TBDMSCl, imidazole, DMAP, CH2Cl2, 0 °C to r.t., 6 h, 92%; d) NaI, acetone, reflux, 24 h, 90%; e) Zn, EtOH,
reflux, 2 h, 96%; f) p-NO2C6H4CO2H, TPP, DEAD, then K2CO3, MeOH, 1 h, 86%; g) TBDMSCl, imidazole, CH2Cl2, 0 °C to r.t., 3 h, 92%; h)
i. O3, Ph3P, CH2Cl2, –78 °C, ii. NaClO4, NaH2PO4, i) morpholine, DIC, DMAP, CH2Cl2, 0 °C to r.t., 3h, 85%; j) 4-BnOC6H4C≡CH, n-BuLi,
BF3·Et2O, –78 °C, 77%; k) Pd/C, MeOH, H2, 6 h, 88%; l) i. TBAF, THF, 0 °C, ii. PhI(OOCCF3)2, acetone–H2O (9:1) r.t., 30 min, 77% (overall
yield for the two steps).
structed from 11, which in turn could be obtained from carbodiimide (DIC).9 Treatment of 14 with lithiated 4-
pyranylmethanol 6. Pyranylmethanol 6 could be easily benzyloxyphenylacetylene10 furnished alkynone11 15,
constructed via Prins cyclization between 5 and tetradeca- which on further catalytic hydrogenolysis with 10% Pd/C-
nal following our recently developed methodology.6
H2 in methanol gave 16 in 88% yield. The latter was de-
silylated with TBAF and directly treated with phenyliodo-
nium(III) bis(trifluoroacetate)12,13 in acetone–water (9:1)
to produce a mixture of aculeatins A and B in a ratio of
2.5:1 (Scheme 2), which were smoothly separated by col-
umn chromatography. Synthetic compounds 1 and 2 have
shown spectral and analytical data (1H NMR, 13C NMR,
IR, Rf, and [a]D) identical to the previously synthesized
samples.3
In view of the above importance of aculeatin A and B we
attempted and completed its stereoselective total synthe-
sis (Scheme 2). The synthesis commenced from chiral
homoallyl alcohol (HAA) 5. Copper-mediated regioselec-
tive opening5 of S-(–)-benzylglycidyl ether with vinyl-
magnesium bromide followed by debenzylation with Li or
Na in liquid ammonia produced HAA 5. Prins cyclization
of HAA 5 with tetradecanal in the presence of TFA fol-
lowed by hydrolysis of the resulting trifluoroacetate gave In conclusion, we have proved the versatility of the Prins
trisubstituted pyran 6 in 52% yield.6
cyclization in natural product synthesis by achieving the
stereoselective synthesis of aculeatins A (1) and B (2) in a
13-step sequence. Further applications of the Prins cy-
clization in the synthesis of natural products are in
progress and will be disclosed in due course.
Stereochemistry was assumed to be in anticipated line as
it was well examined and established previously.4–6 How-
ever, it was proved after elaborating the compound 6 to
the target molecule, which in all respects was identical
with the reported one. Tosylation with 1.1 equivalents of
tosyl chloride in the presence of triethylamine in dichlo-
romethane produced the corresponding primary tosylate 7
in 85% yield.7 Protection of the secondary alcohol func-
tion in 7 with TBSCl in the presence of DMAP and imida-
zole provided the corresponding TBS ether 8. Treatment
of 8 with NaI in refluxing acetone gave the corresponding
iodo compound 9. Iodo compound 9 on exposure to unac-
All reactions were carried out under inert atmosphere, unless other-
wise mentioned, 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 0.5 mm
(Merck). Column chromatography was performed on silica gel (60
mesh) and neutral alumina using Et2O, EtOAc, and hexane as the
eluents. Optical rotations were measured with a Perkin-Elmer P241
tivated Zn in refluxing ethanol furnished the key open polarimeter and JASCO DIP-360 digital polarimeter at 25 °C. IR
spectra were recorded on a Perkin-Elmer FT-IR spectrophotometer.
chain intermediate (4S,6S)-10 in 96% yield. Alcohol
(4S,6S)-10 when subjected to standard Mitsunobu inver-
1H and 13C NMR spectra were recorded on a Varian Gemini 200
MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian
Inova 500 MHz spectrometer using TMS as an internal standard in
CDCl3. Mass spectra were recorded on Micro mass VG-7070H for
sion conditions (DEAD, PPh3, p-nitrobenzoic acid in
THF, then K2CO3, MeOH)8 yielded (4S,6R)-11 in 86%
yield. This was followed by secondary alcohol protection
with TBSCl in the presence of DMAP and imidazole to
give the corresponding bis-TBS ether 12. Ozonolytic
cleavage of the olefinic bond of 12 followed by further ox-
idation afforded acid 13, which was converted to the
amide 14 by treatment with morpholine and diisopropyl-
EI and VG Autospec M for FABMS.
(2S,4R,6S)-2-(Hydroxymethyl)-6-tridecyltetrahydro-2H-pyr-
an-4-ol (6)
Trifluoroacetic acid (43.78 mmol) was added slowly to a solution of
the homoallylic alcohol 5 (3.00 g, 29.4 mmol) and tetradecanal
(3.87 g, 88.12 mmol) in CH2Cl2 (90 mL) at 25 °C under N2. The re-
Synthesis 2010, No. 3, 431–436 © Thieme Stuttgart · New York

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Stereoselective Total Synthesis of Aculeatin A and B
433
action mixture was stirred for 3 h and then sat. aq NaHCO3 (200
mL) was added and the pH was adjusted to >7 by addition of Et3N.
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (4 × 70 mL). The organic layers were combined and the sol-
vent was removed under reduced pressure. The trifluoroacetate ob-
tained was directly used in the next reaction without purification.
The residue was dissolved in MeOH (40 mL) and stirred with solid
K2CO3 (8.11 g) for 0.5 h. The MeOH was then removed under re-
duced pressure and H2O (30 mL) was added. The mixture was ex-
tracted with CH2Cl2 (3 × 30 mL), the combined organic layers were
dried (Na2SO4), and the solvent was removed under reduced pres-
sure. Purification of the crude product by column chromatography
on silica gel yielded 6 (4.8 g, 52%) as a colorless liquid; Rf = 0.3
(silica gel, 60% EtOAc in hexane); [a]D25 +13.8 (c 1.0, CHCl3).
3.46 (m, 1 H), 3.24–3.14 (m, 1 H), 2.46 (s, 3 H), 1.80–1.67 (m, 2 H),
1.54–1.14 (m, 29 H), 0.86 (s, 9 H), 0.03 (s, 6 H).
13C NMR (300 MHz, CDCl3): d = 144.07, 129.65, 128.18, 72.93,
71.90, 68.44, 41.54, 37.73, 35.84, 32.08, 29.84, 29.45, 22.85, 25.99,
25.58, 21.78, 18.17, 14.17, 14.35, –4.28.
LCMS: m/z = 605 (M+ + 23).
tert-Butyl[(2S,4R,6S)-2-(iodomethyl)-6-tridecyltetrahydro-2H-
pyran-4-yloxy]dimethylsilane (9)
NaI (6.06 g, 40.4 mmol) was added to a solution of 8 (3.80 g, 8.08
mmol) in acetone (70 mL) and the mixture was heated to reflux for
24 h. Acetone was removed under reduced pressure. To the residue
was added H2O (10 mL) and CH2Cl2 (3 × 25 mL) and the organic
layer was separated, dried (Na2SO4), concentrated, and chromato-
graphed to afford 9 (3.33 g, 90%) as a colorless liquid; Rf = 0.8 (sil-
ica gel, 10% EtOAc in hexane); [a]D20 +10.8 (c 1.65, CHCl3).
IR (neat): 3367, 2919, 2850, 1660, 1633 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.83–3.73 (m, 1 H), 3.60–3.55 (m,
1 H), 3.44–3.38 (m, 1 H), 3.34–3.27 (m, 1 H), 1.94–1.78 (m, 2 H),
1.65–1.09 (m, 26 H), 0.89 (t, J = 6.83, 13.66 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 75.79, 76.06, 68.13, 65.95, 41.47,
37.17, 36.16, 32.09, 29.84, 29.53 (br, several overlapped signals),
25.73, 22.86, 14.35.
IR (neat): 3383, 2923, 2853, 1729, 1611, 1513 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.81–3.69 (m, 1 H), 3.36–3.21 (m,
2 H), 3.19–3.09 (m, 2 H), 2.06–1.90 (m, 2 H), 1.75–1.38 (m, 2 H),
1.35–1.10 (m, 27 H), 0.89 (s, 9 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 79.92, 76.01, 68.77, 62.25, 41.65,
41.52, 36.15, 32.12, 27.41, 26.08, 22.88, 21.64, 21.10, 8.59, –4.16.
ESI-MS: m/z = 314 [M]+.
LCMS: m/z = 539 [M + H]+.
(2S,4R,6S)-4-Hydroxy-6-tridecyltetrahydro-2H-pyran-2-
yl)methyl 4-Methylbenzenesulfonate (7)
(4S,6S)-4-(tert-Butyldimethylsilyloxy)nondec-1-en-6-ol (10)
To the iodide 9 (2.20 g, 5.94 mmol) in EtOH (80 mL) was added
commercial Zn dust (5.82 g, 89.10 mmol). The mixture was re-
fluxed for 1 h and then cooled to 25 °C. Addition of solid NH4Cl
(8.17 g) and Et2O (120 mL) followed by stirring for 5 min gave a
gray suspension. The suspension was filtered through Celite and the
filtrate was concentrated in vacuo. Purification by flash chromatog-
raphy gave the product 10 (2.19 g, 96%) as a colorless liquid;
Rf = 0.4 (silica gel, 10% EtOAc in hexane); [a]D +6.0 (c 1.0,
CHCl3).
IR (neat): 3452, 2942, 1640, 1098, 1034, 916, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.80–5.67 (m, 1 H), 5.10–5.02 (m,
2 H), 4.05–3.98 (m, 1 H), 3.96–3.88 (m, 1 H), 3.14 (br, 1 H), 2.34
(t, J = 6.59, 13.18 Hz, 3 H), 1.60–1.51 (m, 2 H), 1.47–1.17 (m, 27
H), 0.89 (s, 9 H), 0.09 (d, J = 8.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 134.68, 117.33, 71.24, 68.20,
41.06, 37.98, 29.34, 25.79, 25.57, 17.94, 16.94, 14.10, –4.54, –4.84.
To a solution of diol 6 (4.0 g, 13.7 mmol) in anhyd CH2Cl2 (15.0
mL) was added Et3N (3.81 mL, 27.4 mmol) at 0 °C. Then tosyl
chloride (2.86 g, 15.04 mmol) was added over 2 h. The reaction
mixture was allowed to warm to r.t. and stirred for 3 h. The mixture
was treated with aq 1 N HCl (10 mL) and extracted with CH2Cl2
(3 × 30 mL). The combined organic layers were washed with sat. aq
NaHCO3 (15 mL) and H2O (15 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure.
Flash chromatography of the crude afforded tosylate 7 (5.01 g,
85%) as a gummy liquid; Rf = 0.5 (silica gel, 80% EtOAc in hex-
ane); [a]D25 +34.8 (c 3.0, CHCl3).
25
IR (neat): 3582, 2921, 2851, 1742, 1599 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.83–7.75 (d, J = 6.61 Hz, 2 H),
7.39–7.27 (d, J = 5.87 Hz, 2 H), 3.98 (d, J = 4.40 Hz, 2 H), 3.87–
3.63 (m, 1 H), 3.61–3.43 (m, 1 H), 3.32–3.16 (m, 1 H), 2.46 (s, 3 H),
2.08–1.81 (m, 2 H), 1.56–1.02 (m, 29 H), 0.90 (t, J = 5.87, 8.08 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 129.75, 127.96, 75.87, 72.76,
72.01, 67.71, 40.71, 37.01, 35.77, 31.90, 29.66 (br, several over-
lapped signals), 25.39, 22.67, 21.62, 14.10.
LCMS: m/z = 413 [M + H]+.
(4S,6R)-4-(tert-Butyldimethylsilyloxy)nondec-1-en-6-ol (11)
To a stirred mixture of 10 (4.0 g, 9.6 mmol), Ph3P (8.10 g, 31.0
mmol), and p-nitrobenzoic acid (3.16 g, 21.6 mmol) in anhyd THF
(10 mL) at 0 °C was added diethyl azodicarboxylate (5.39 g, 31.0
mmol) via a syringe. The reaction mixture was then stirred for 0.5 h
at r.t., diluted with H2O (10 mL), and extracted with EtOAc (2 × 15
mL). After removing the solvent, the crude was dissolved in MeOH
(10 mL) and mixed with solid K2CO3 (1.99 g, 19.2 mmol). After
stirring the mixture for 4 h at r.t., it was diluted with H2O (15 mL)
and extracted with CH2Cl2 (3 × 10 mL). Removal of solvent under
reduced pressure followed by flash chromatography afforded 11
(3.0 g, 75%) as a colorless liquid; Rf = 0.4 (30% EtOAc in hexane);
[a]D25 –19.6 (c 1.0, CHCl3).
LCMS: m/z = 469 [M + H]+.
(2S,4R,6S)-4-(tert-Butyldimethylsilyloxy)-6-tridecyltetrahydro-
2H-pyran-2-yl)methyl 4-Methylbenzenesulfonate (8)
To alcohol 7 (3.80 g, 10.67 mmol) in anhyd CH2Cl2 (30 mL) at 0 °C
were added TBSCl (1.93 g, 12.8 mmol), DMAP (cat.), and imida-
zole (2.9 g, 42.6 mmol) successively. The mixture was stirred for 3
h at 25 °C, then quenched by adding H2O (10 mL), and extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated under
pressure to remove the solvent and the crude was purified by col-
umn chromatography to afford the pure product 8 (4.57 g, 92%) as
25
IR (neat): 3452, 2942, 1640, 1098, 1034, 916, 702 cm–1.
a colorless liquid; Rf = 0.8 (silica gel, 10% EtOAc in hexane); [a]D
+23.3 (c 3.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 5.88–5.70 (m, 1 H), 5.12–5.01 (m,
2 H), 4.01–3.92 (m, 1 H), 3.79–3.67 (m, 1 H), 2.33–2.22 (t, J = 5.85,
12.84 Hz, 2 H), 1.67–1.20 (m, 29 H), 0.91 (s, 9 H), 0.12 (d, J = 2.45
Hz, 6 H).
IR (neat): 2926, 2854, 1598, 1463, 1367, 1254 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.78 (d, J = 8.12 Hz, 2 H), 7.31 (d,
J = 8.12 Hz, 2 H), 4.00–3.89 (m, 2 H), 3.76–3.73 (m, 1 H), 3.55–
Synthesis 2010, No. 3, 431–436 © Thieme Stuttgart · New York

434
J. S. Yadav et al.
PAPER
13C NMR (300 MHz, CDCl3): d = 134.05, 117.47, 72.82, 71.08,
37.73, 31.90, 29.65, 29.33, 25.79, 25.39, 22.67, 17.90, 14.09, –4.75,
–4.01.
at r.t. DMAP (0.06 g, 0.53 mmol) was added after stirring the mix-
ture at the same temperature and the stirring was continued for 3 h.
To the reaction mixture was added H2O (5 mL) and CH2Cl2 (3 × 20
mL) and the organic layer was separated, dried (Na2SO4), concen-
trated, and chromatographed to afford 14 (0.88 g, 85%) as a color-
less oil; Rf = 0.2 (silica gel, 20% EtOAc in hexane); [a]D20 –81.0 (c
0.75, CHCl3),
LCMS: m/z = 413 (M + H) +.
(5S,7R)-5-Allyl-2,2,3,3,9,9,10,10-octamethyl-7-tridecyl-4,8-di-
oxa-3,9-disilaundecane (12)
To alcohol 11 (3.80 g, 10.67 mmol) in anhyd CH2Cl2 (30 mL) at
0 °C were added TBSCl (1.93 g, 12.8 mmol), DMAP (cat.), and im-
idazole (2.9 g, 42.6 mmol) successively and the mixture was stirred
for 3 h at 25 °C. The mixture was then quenched by adding H2O (10
mL) and extracted with CH2Cl2 (3 × 20 mL). The organic extracts
were washed with brine (10 mL), dried (Na2SO4), and concentrated
under vacuum. The crude product was purified by column chroma-
tography to afford the pure 12 (1.76 g, 92%) as a colorless liquid;
IR (neat): 3168, 2928, 1732, 1631, 1384, 1244, 1154 cm–1.
1H NMR (200 MHz, CDCl3,): d = 4.37–4.13 (m, 1 H), 3.83–3.43 (m,
9 H), 32.61–2.26 (m, 2 H), 1.69–1.55 (m, 2 H), 1.52–1.12 (m, 27 H),
0.88 (s, 9 H), 0.86 (s, 9 H), 0.07 (d, J = 3.67 Hz, 6 H), 0.03 (d,
J = 5.14 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 169.57, 154.24, 69.97, 69.30,
46.46, 43.82, 36.95, 31.89, 29.63, 25.80, 25.0, 22.80, 21.67, 18.0,
14.08, –4.35, –4.29.
25
Rf = 0.8 (silica gel, 10% EtOAc in hexane); [a]D –4.1 (c 0.5,
ESI-MS: m/z = 568 [M + H]+.
CHCl3).
IR (neat): 3443, 2927, 2855, 1640 cm–1.
(5R,7R)-1-[4-(Benzyloxy)phenyl]-5,7-bis(tert-butyldimethyl-
silyloxy)icos-1-yn-3-one (15)
1H NMR (300 MHz, CDCl3): d = 5.93–5.66 (m, 1 H), 5.12–4.95 (m,
2 H), 3.86–3.63 (m, 2 H), 2.30–2.13 (m, 2 H), 1.64–1.47 (m, 2 H),
1.47–1.09 (m, 27 H), 0.87 (s, 18 H), 0.05 (d, J = 3.67 Hz, 12 H).
13C NMR (300 MHz, CDCl3): d = 135.07, 116.77, 70.11, 69.79,
44.93, 42.50, 37.84, 31.91, 25.92, 25.65, 25.86, 22.66, 18.06, 14.10,
–3.95, –4.19.
n-BuLi (7.5 mL, 1.6 M solution in hexane, 12 mmol) was added to
a solution of alkyne 17 (0.5 g, 12 mmol) in THF (40 mL) and
BF3·Et2O at –78 C. After stirring for 30 min, a solution of 14 (2.69
g, 6 mmol) in THF (15 mL) was added. The resulting mixture was
warmed to 0 °C and stirred for 1 h. The mixture was poured onto sat.
aq NH4Cl (50 mL) and extracted with Et2O (3 × 60 mL). The com-
bined organic extracts were washed with brine (60 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by silica gel chromatography to afford 15 (0.49 g,
LCMS: m/z = 550 (M + Na)+.
(3R,5R)-3,5-Bis(tert-butyldimethylsilyloxy)octadecanoic Acid
(13)
25
77%); [a]D –12 (c 1.0, CHCl3); Rf = 0.25 (silica gel, 30% EtOAc
Ozone was bubbled through a solution of 12 (1.5 g, 2.84 mmol) in
CH2Cl2 (2 mL) at –78 °C until no unreacted starting material was
observed on TLC. The reaction mixture was purged with N2 to re-
move the excess of ozone and cooled to 0 °C. Ph3P (1.48 g, 5.68
mmol) was added and the mixture was stirred for 2 h and concen-
trated in vacuo. After adding hexane (20 mL), the mixture was fil-
tered through a Celite pad. Then the residue was washed with
hexane (50 mL) and the filtrate was dried (Na2SO4). The solvent
was removed under reduced pressure and the crude aldehyde was
subjected to the next reaction without further purification. To a
stirred solution of the crude aldehyde in t-BuOH (1 mL) was added
methylbut-2-ene (0.5 mL) in t-BuOH (0.5 mL). The reaction mix-
ture was cooled to 0 °C and treated with a solution of NaClO2 (0.086
g, 0.95 mmol) and NaH2PO4 (0.344 g, 2.87 mmol) in H2O (1 mL).
After 1.5 h, the mixture was partitioned between brine (3 mL) and
Et2O (3 mL). The organic phase was separated and the aqueous
phase was extracted with Et2O (3 × 10 mL). The combined organic
phases were washed with brine (8 mL), dried (Na2SO4), concentrat-
ed in vacuo, and purified by flash chromatography (Et2O) to afford
the acid 13 (1.39 g, 90%); Rf = 0.25 (silica gel, 30% EtOAc in hex-
ane); [a]D25 –23.3 (c 2.5, CHCl3).
in hexane).
IR (neat): 3035, 2926, 2855, 2196, 1731, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.23 (m, 7 H), 6.89–6.82 (d,
J = 8.32 Hz, 2 H), 5.05 (s, 2 H), 4.21–4.11 (m, 1 H), 3.72–3.61 (m,
1 H), 2.53–2.91 (m, 3 H), 1.62–1.44 (m, 3 H), 1.41–1.16 (m, 23 H),
0.86 (s, 18 H), 0.09 (d, J = 5.67 Hz, 6 H), 0.07 (d, J = 1.46 Hz, 6 H).
13C NMR (300 MHz, CDCl3): d = 209.6, 127.42, 127.80, 128.49,
128.7, 128.6, 114.65, 69.99, 67.31, 51.02, 45.75, 44.13, 37.61,
31.88, 29.55 (br, several overlapped signals), 27.92, 25.77, 25.86,
25.48, 24.93, 22.66, 22.25, 14.08, 13.81, –4.13, –4.48.
LCMS: m/z = 736 (M + H)+.
(5R,7R)-5,7-Bis(tert-butyldimethylsilyloxy)-1-(4-hydroxyphe-
nyl)icosan-3-one (16)
To solution of compound 15 (300 mg, 0.54 mmol) in EtOAc (10
mL) was added 10% Pd/C (50 mg) and the mixture was stirred un-
der H2 atmosphere for 7 h. After completion, the reaction mass was
filtered through Celite and the solvent was removed under reduced
pressure to give crude 16. Purification by column chromatography
on silica gel (hexane–EtOAc, 4:1) afforded the pure 16 (222 mg,
88%) as a colorless solid; [a]D25 –4.5 (c 1.0, CHCl3).
IR (neat): 3457, 2926, 2855, 1712 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.25–4.11 (m, 1 H), 3.79–3.66 (m,
1 H), 2.66–2.41 (m, 2 H), 1.76–1.58 (m, 2 H), 1.47–1.17 (m, 29 H),
0.87 (s, 18 H), 0.09 (d, J = 3.67 Hz, 6 H), 0.06 (d, J = 1.46 Hz, 6 H).
13C NMR (300 MHz, CDCl3): d = 176.58, 70.05, 67.63, 45.20,
42.98, 37.66, 31.91, 29.31 (br, several overlapped signals), 22.66,
24.93, 25.86, 25.71, 18.03, 17.89, 14.10, –4.04, –4.65, –4.36, –4.30.
IR (neat): 3386 (OH), 2929, 1724, 1257, 1076 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.04 (d, J = 8.49 Hz, 2 H), 6.74 (d,
J = 8.68 Hz, 2 H), 4.25–4.14 (m, 1 H), 3.74–3.60 (m, 1 H), 2.86–
2.67 (m, 4 H), 2.61–2.42 (m, 2 H), 1.69–1.50 (m, 7 H), 1.34–1.21
(m, 27 H), 0.87 (s, 9 H), 0.85 (s, 9 H), 0.07 (s, 6 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.0, 133.6, 129.3, 115.2, 71.1,
70.5, 42.9, 39.5, 37.3, 36.2, 31.9, 30.7, 30.2, 29.6 (br, several over-
lapped signals), 29.5, 29.3, 24.9, 22.6, –4.16, –4.28.
LCMS: m/z = 545 (M + H)+.
(3R,5R)-1-Morpholino-3,5-bis(tert-butyldimethylsilyloxy)octa-
decan-1-one (14)
To a solution of morpholine (0.20 g, 1.06 mmol) in CH2Cl2 (10 mL)
ESI-MS: m/z = 649 [M + H]+.
was added acid 13 (1.0 g, 1.16 mmol) and DIC (0.24 g, 1.16 mmol)
Synthesis 2010, No. 3, 431–436 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Aculeatin A and B
435
(2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pen-
tadeca-9,12-dien-11-one (Aculeatin A, 1) and (2R,4R,6S)-4-Hy-
droxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-9,12-dien-
11-one (Aculeatin B, 2)
Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod. 2008, 71,
390. (b) Peuchmaur, M.; Saïdani, N.; Botte, C.; Marechal,
E.; Vial, H.; Wong, D. Y. J. Med. Chem. 2008, 51, 4870.
(3) (a) Wong, Y. S. Chem. Commun. 2002, 686. (b) Falomir,
E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J. A.
To a stirred solution of ketone 16 (150 mg, 0.32 mmol) in anhyd
THF (2 mL) was added TBAF (0.3 mL, 0.3 mmol) and the mixture
was stirred for 2 h at 0 °C. The reaction mixture was quenched with
H2O (3 mL) and extracted with EtOAc (2 × 2 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo. To
the crude in acetone–H2O mixture (9:1, 10 mL) was added
PhI(OCOCF3)2 (412 mg,0.96 mmol) in a single portion. The mix-
ture was stirred for 4 h at 25 °C in the dark. After completion of the
reaction, H2O (2 mL) was added and extracted with EtOAc (3 × 5
mL). The combined organic layers were dried (Na2SO4) and con-
centrated to give a crude mixture of aculeatin A (1) and aculeatin B
(2), which was purified on silica gel column eluting with hexane–
EtOAc to yield 1 (50 mg) and 2 (27 mg).
Tetrahedron Lett. 2005, 46, 8407. (c) Baldwin, J. E.;
Adlington, R. M.; Sham, V. W. W.; Marquez, R.; Bulger, P.
G. Tetrahedron 2005, 61, 2353. (d) Alvarez-Bercedo, P.;
Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62,
9641. (e) Euchmaur, M.; Wong, Y. S. J. Org. Chem. 2007,
72, 5374. (f) Chandrasekhar, S.; Rambabu, C.;
Shyamsunder, T. Tetrahedron Lett. 2007, 48, 4683.
(g) Ramana, C. V.; Srinivas, B. J. Org. Chem. 2008, 73,
3915. (h) Zhen, Z.; Gao, J.; Wu, S. J. Org. Chem. 2008, 73,
7310. (i) Suresh, V.; Selvam, J.; Rajesh, K.; Venkateswarlu,
Y. Tetrahedron: Asymmetry 2008, 19, 1509.
(4) For the Prins cyclization, see for example: (a) Barry, C. St.
J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001,
66, 739. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew.
Chem. Int. Ed. 2005, 44, 3485. (d) Barry, C. S.; Bushby, N.;
Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683.
(e) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407. (g)Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919. (h) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(i) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679. (j) Kopecky, D. J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2001, 123, 8420. (k) Rychnovsky, S. D.;
Thomas, C. R. Org. Lett. 2000, 2, 1217. (l) Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
3022. (m) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425. (n) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.;
Gunasekar, D. Synthesis 2001, 885. (o) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. S.; Niranjan, N. J. Mol. Catal. A: Chem.
2004, 210, 99. (p) Yadav, J. S.; Reddy, B. V. S.; Reddy, M.
S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779.
(5) (a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4397. (b) Yadav, J. S.; Reddy,
M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4937.
(c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133. (d) Yadav, J. S.; Reddy, M. S.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4995. (e) Yadav, J. S.;
Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049.
(f) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad,
A. R. Tetrahedron Lett. 2007, 48, 1469. (g) Yadav, J. S.;
Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron
2006, 63, 2689. (h) Rao, A. V. R.; Reddy, E. R.; Joshi, B. V.;
Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497. (i) Yadav, J.
S.; Sridhar Reddy, M.; Rao, P. P.; Prasad, A. R. Synlett 2049,
2007. (j) Yadav, J. S.; Issana, A.; Gayathri, K. U.; Rao, N.
V.; Prasad, A. R. Synthesis 2008, 3945.
Aculeatin A (1)
Oil; [a]D25 –52 (c 0.8, CHCl3).
IR (neat): 3417 (OH), 2925, 1512, 1671, 1630, 1512, 1461, 1099
cm–1.
1H NMR (300 MHz,CDCl3): d = 6.85 (dd, J = 9.82, 3.02 Hz, 1 H),
6.78 (dd, J = 9.82, 3.02 Hz, 1 H), 6.14 (dd, J = 9.82, 1.51 Hz, 1 H,),
6.09 (dd, J = 10.5, 2.26 Hz, 1 H), 4.05–4.15 (m, 2 H), 3.32 (br s, 1
H), 2.38 (m, 1 H), 2.24 (m, 1 H), 1.93–2.04 (m, 3 H), 1.94 (br d,
J = 14.3 Hz, 1 H), 1.76 (br d, J = 13.5 Hz, 1 H), 1.60–1.40 (br m, 4
H), 1.21–1.37 (br m, 21 H), 0.87 (t, J = 6.79 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 185.3, 150.9, 148.8, 127.4, 127.2,
109.1, 79.8, 65.4, 64.9, 39.2, 38.0, 35.9, 34.2, 32.0, 29.7 (br, several
overlapped signals), 29.6, 29.4, 25.7, 22.7, 14.1.
EIMS: m/z = 441.29 [M + Na].
Aculeatin B (2)
Oil; [a]D25 +54 (c 0.4, CHCl3).
IR (neat): 3417 (OH), 2925, 2854, 1671, 1630, 1512, 1461, 1099
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.99 (dd, J = 9.80, 3.02 Hz, 1 H),
6.78 (dd, J = 9.80, 3.02 Hz, 1 H), 6.14 (dd, J = 9.82, 1.61 Hz, 1 H),
6.09 (dd, J = 9.82, 1.61 Hz, 1 H), 4.36 (app quint, J = 3.1 Hz, 1 H),
3.87 (m, 1 H), 2.68 (br dd, J = 12.8, 7.2 Hz, 1 H), 2.30 (td, J = 12.3,
7.2 Hz, 1 H), 2.10–2.00 (m, 2 H), 1.95–1.84 (m, 2 H), 1.60–1.40 (br
m, 8 H), 1.40–1.20 (br m, 19 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 185.5, 151.0, 148.5, 127.5, 127.3,
109.3, 79.9, 65.5, 65.0, 39.3, 38.2, 36.1, 34.4, 32.1, 29.9 (br, several
overlapped signals), 29.8, 29.5, 25.8, 22.9, 14.3.
EIMS: m/z = 441.29 [M + Na].
Acknowledgment
N.T. and M.V. thank CSIR, New Delhi for the award of fellowships
and DST for the financial assistance under the J. C. Bose fellowship
scheme.
(6) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.;
Colobert, F.; Solladie, G. Tetrahedron Lett. 2003, 44, 2695.
(7) (a) Yadav, J. S.; Thrimurtulu, N.; Gayathri, U. K.;
Subba Reddy, B. V.; Prasad, A. R. Tetrahedron Lett. 2008,
49, 6617. (b) Yadav, J. S.; Sridhar Reddy, M.;
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