Total synthesis of aculeatins A and B from d-glucose

Article abstract of DOI:10.1016/j.tetasy.2008.05.028

A simple and highly efficient total synthesis of cytotoxic dioxa-dispiroketals aculeatins A and B is disclosed. The key steps include alkynylation of a chiral aldehyde and in situ deprotection, spirocyclization of a 3,5-acetonide protected ketone.

Full text of DOI:10.1016/j.tetasy.2008.05.028

Tetrahedron: Asymmetry 19 (2008) 1509–1513
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of aculeatins A and B from D-glucose
*
Vangaru Suresh, Jondoss Jon Paul Selvam, Karuturi Rajesh, Yenamandra Venkateswarlu
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2008
Accepted 28 May 2008
A simple and highly efficient total synthesis of cytotoxic dioxa-dispiroketals aculeatins A and B is dis-
closed. The key steps include alkynylation of a chiral aldehyde and in situ deprotection, spirocyclization
of a 3,5-acetonide protected ketone.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
3
5
1 or 2
Several spirocyclic natural products possess interesting biolog-
ical properties.1 Among them epimeric dioxa-dispiroketals, aculea-
tins A–D2,3 and aculeatols4 isolated from the terrestrial plant
species Amomum aculeatum Roxb. (Fam. Zingiberaceae) exhibited
high cytotoxicity against the KB cancer cell lines as well as antipro-
tozoal activity against Plasmodium falciparum strains K1 and NF54.
The observed biological activity of the aculeatins may be allied to
the presence of a Michael acceptor moiety.5 In addition, aculeatin
A(1) was found to be active against MCF-7 (human breast cancer)
cells.6 The biological potential of these compounds has stimulated
significant interest in the synthesis of aculeatins A and B. First, a
synthesis of racemic aculeatins A 1 and B 2 was carried out by
Wong et al.7 Subsequently, these were synthesized in enantiome-
rically pure form by Marco et al.,8 Chandrasekhar et al.9a and Peu-
chmaur and Wong.9b
11
3
OH
O
O
O
3
5
+
H
OBn
4
11
5
O
O
11
O
O
O
6
O
O
O
O
-glucose
D
12
12
Scheme 1. Retrosynthesis of aculeatins A and B.
HO
HO
(1)
(2)
Herein, we report an efficient and practical total synthesis of the
aculeatins A and B from commercially available -glucose. From
2. Results and discussion
D
our retrosynthetic analysis of compound 1 (or) 2 (Scheme 1), we
envisaged that the key intermediate 3 can be derived from modi-
fied D-glucose 6 and 4-benzyloxy phenyl acetylene 5.
Our synthesis (Scheme 2) started from 3-deoxy-1,2:5,6-di-O-
isopropylidine- -glucofuranose 7, which was prepared from
commercially available -glucose following the reported proce-
a
-D
D
dure.10 Regioselective deprotection of the 5,6-O-isopropylidene
moiety of 7 with 0.8% H2SO4 in MeOH at ambient temperature
afforded diol 8 in 85% yield. Introduction of the n-tridecyl group
at the C-4 position was achieved in three steps: (i) oxidative
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.028

1510
V. Suresh et al. / Tetrahedron: Asymmetry 19 (2008) 1509–1513
HO
HO
O
O
O
O
O
Ref-9
a
b
O
O
10
D-glucose
O
O
O
O
9
7
8
O
O
OH OH
c
d
e
O
OH
OH
11
11
10
11
h
O
6
11
O
O
O
O
f
g
OH
11
11
12
13
O
O
OH
O
O
HO
j
i
15
11
11
OH
14
OBn
O
O
O
k
1
2
+
11
5:2
3
OH
Scheme 2. Reagents and conditions: (a) 0.8% aq H2SO4, MeOH, rt, 85%; (b) (i) NaIO4 on silica gel, CH2Cl2, 96%; (ii) n-C12H25P+Ph3Brꢀ, KOtBu, THF, 0 °C to rt, 75%; (c) 10% Pd–C,
H2, EtOAc, rt, 1 h, 98%; (d) (i) 4% aq H2SO4, THF, 60 °C, 4 h, 92%; (e) CH3PPh3I, KOtBu, THF, 0 °C, 5 h, 80%; (f) PTSA (cat), 2,2-dimethoxypropane, acetone, rt, 0.5 h, 98%; (g)
(Cy)2BH, THF, 0 °C, 97%; (h) (i) IBX, DMSO, CH2Cl2, rt, 4 h, 95%; (ii) 4-benzyloxyphenyl acetylene, n-BuLi, THF, ꢀ78 °C, 2 h, 85%; (i) 10% Pd–C, H2, EtOAc, rt, 5 h, 88%; (j) (COCl)2,
DMSO, CH2Cl2, ꢀ78 °C, then Et3N, ꢀ78 to 0 °C, 89%; (k) PhI(OOCCF3)2, 5 mol % CF3COOH, Me2CO/H2O (9:1), rt, 4 h, 72% overall, 5:2 mixture of aculeatins A and B.
cleavage of diol 8 using silica gel-supported NaIO4;11 (ii) a twelve
carbon homologation using n-dodecayltriphenylphosphonium bro-
mide and KOtBu in THF at 0 °C and (iii) followed by hydrogenation
using 10% Pd–C to afford 6 in 87% overall yield. Deprotection of the
1,2-O-isopropylidine group12 of 6 with 4% aqueous sulfuric acid in
THF at 60 °C gave the epimeric lactols 10 in 90% yield. This was
subjected to a Wittig olefination13 with in situ generated methy-
lene triphenyl phosphorane to afford 3,5-syn diol olefinic interme-
diate 11. Protection of the 1,3-syn diol intermediate 11 using 2,2-
dimethoxy propane, in acetone using p-TSA afforded 12 in 98%
yield, followed by selective hydroboration using dicyclohexyl bor-
ane in THF yielded alcohol 13 in 97% yield. This alcohol was oxi-
dized using IBX to furnish aldehyde 4 (not isolated), which was
subjected to reaction with lithiated 4-benzyloxyphenyl acetylene14
to yield the corresponding alkynols15 11 in 85% yield. Benzyl
deprotection of alkynols 11 using 10% Pd–C/H2 in ethyl acetate
gave a mixture of 12 in 88% yield. Alcohol 12 was oxidized under
Swern conditions to afford 3. In a previous report, the prolonged
reaction time of secondary acetonide deprotection and subsequent
phenolic oxidation and spiro acetalization16 of 37 using phenyliod-
onium(III) bis (trifluoroacetate) in acetone–H2O (9:1) gave aculea-
tins A and B in a 5.5: 1 ratio in 24 h. Here we reduced this reaction
time to 4 h by the addition of 5 mol % of CF3COOH and produced, in
almost equal selectivity, aculeatins A and B (5:2) in 70% yield. The
physical and spectroscopic data of compounds 1 and 2 were in
good agreement with the reported data of natural aculeatins A 1
and B 2.1 All the compounds were fully characterized by 1H
NMR, 13C NMR, mass and IR spectroscopy.
3. Conclusion
In conclusion, a simple, highly efficient and chiral pool approach
towards the total synthesis of aculeatins A and B has been devel-
oped using the alkynylation of a chiral aldehyde and rapid in situ
deprotection and phenolic oxidative spiroacetylation. In our syn-
thesis, 3,5-syn diols are taken from the chiron D-glucose.
4. Experimental
4.1. General methods
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used without
further purification. All column chromatographic separations were

V. Suresh et al. / Tetrahedron: Asymmetry 19 (2008) 1509–1513
1511
performed using silica gel (Acme’s, 60–120 mesh). Organic solu-
4.1.3. (3aR,5R,6aR)-2,2-Dimethyl-5-tridecylperhydrofuro[2,3-
d][1,3]dioxole 6
tions were dried over anhydrous Na2SO4 and concentrated below
40 °C in vacuo. 1H NMR (200 MHz and 300 MHz) and 13C NMR
(50 MHz and 75 MHz) spectra were measured with a Varian Gem-
ini FT-200 MHz spectrometer and Bruker Avance 300 MHz with
tetramethylsilane as the internal standard for solutions in deute-
riochloroform. J values are given in Hertz. IR spectra were recorded
on Perkin–Elmer IR-683 spectrophotometer with NaCl optics. Opti-
cal rotations were measured with JASCO DIP 300 digital polarime-
ter at 25 °C. Mass spectra were recorded on CEC-21-11013 or
Fannigan Mat 1210 double focusing mass spectrometers operating
at a direct inlet system or LC/MSD Trap SL (Agilent Technologies).
To a stirred solution of olefin 9 (932 mg, 2.88 mmol) in ethyl
acetate (5 mL) was added 10% Pd/C (50 mg) under hydrogen atmo-
sphere. After 1 h, the catalyst was filtered and removal of solvent
afforded 6, which was purified on silica gel column chromatogra-
phy (silica gel, 60–120 mesh; hexane/ethyl acetate = 9:1) to obtain
compound 6 (918 mg, 98% yield) as a yellow syrup; ½a D25
ꢂ
¼ ꢀ12:3 (c
1.7, CHCl3); IR (neat): 2925, 2854, and 1021 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 5.72 (1H, d, J = 3.7), 4.64 (1H, td, J = 4.53,
3.77), 4.1 (1H, m), 2.02–2.06 (1H, dd, J = 12.8, 3.7), 1.6 (1H, m),
1.47 (3H, s), 1.34–1.42 (2H, m), 1.28 (3H, s), 1.26 (19H, br s),
0.893 (3H, t, J = 7.5); 13C NMR (75 MHz, CDCl3): d 111, 106, 81,
78, 40, 35, 32, 30 (br, several overlapped signals), 27.5, 27, 23,
14; ESI-MS: m/z 344 [M+Na+].
4.1.1. (1S)-1-[(3aR,5R,6aR)-2,2-Dimethylperhydrofuro[2,3-d]-
[1,3]dioxol-5-yl] ethane-1,2-diol 8
To a stirred solution of compound 7 (1.44 g, 5.90 mmol) in
methanol (20 mL) was added 0.8% H2SO4 solution (5 mL). After
completion of the reaction, methanol was removed under reduced
pressure after which was added a saturated NaHCO3 (20 mL) solu-
tion. It was extracted into chloroform (5 ꢁ 50 mL) and dried over
anhydrous Na2SO4. The solvent was removed under vacuum, and
the residue purified by flash column chromatography (silica gel,
60–120 mesh; hexane/ethyl acetate = 1:9) to afford compound 8
as a white solid (1 g, 83% yield): IR (neat): 3423, 2985, 2934,
4.1.4. (3R,5R)-5-Tridecyltetrahydro-2,3-furandiol 10
To a solution of 6 (868 mg, 2.67 mmol) in tetrahydrofuran
(20 mL) was added 4% aq H2SO4 solution (2 mL) and then stirred
at 70 °C temperature for 6 h. After completion of the reaction, the
reaction mass was extracted into ethyl acetate (4 ꢁ 25 mL). The
combined organic layer was washed with saturated aq NaHCO3,
brine solution, and the organic layer dried over anhydrous Na2SO4.
Removal of the solvent gave epimeric lactols 10, which was puri-
fied on silica gel column chromatography (silica gel, 60–120 mesh;
hexane/ethyl acetate = 1:1) to obtain compound 10 (700 mg, 92%
1641, 1377, 1016 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.73 (d, 1H,
;
J = 3.77 Hz), 4.68 (m, 1H), 4.15 (m, 1H), 4.13 (td, 1H, J = 4.53,
5.28 Hz), 3.82 (m, 1H), 3.64 (dd, 1H, J = 3.02 Hz), 3.53 (dd, 1H,
J = 6.79 Hz), 3.18 (br s, 1H), 2.92 (br s, 1H), 2.02(dd, 1H, J = 4.53,
13.59 Hz), 1.79 (dd, 1H, J = 4.53, 3.02, 10.57, 6.04 Hz), 1.47 (s,
3H), 1.29 (s, 3H); 13C NMR (75 MHz, CDCl3): d 111.55, 105.0,
80.4, 78.3, 72.2, 64.1, 33.6, 26.4, 25.9; ESI-MS: m/z 227 [M+Na]+.
yield) as a white solid. ½a D25
ꢂ
¼ þ5 (c 0.5, CHCl3); IR (neat): 3423,
3353, 2919, 2848, 1460, 1081 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
5.27(d, 1H, J = 3.7), 4.2 (m, 2H), 1.92–1.60 (m, 2H), 1.26 (br s,
20H), 0.89 (t, 3H, J = 6,79); 13C NMR (75 MHz, CDCl3): d 102.7,
76.4, 71.9, 38.7, 37.8, 35.9, 31.9, 29.65, 29.62 (br, several over-
lapped signals), 26.21, 25.8, 22.69, 14.17; ESI-MS: m/z 286 [M],
304 [M+18]+.
4.1.2. (3aR,5S,6aR)-2,2-Dimethyl-5-[(Z)-1-tridecenyl]perhydro-
furo[2,3-d][1,3]dioxole 9. Preparation of silica gel-supported
NaIO4 reagent
4.1.5. (3R,5R)-1-Octadecene-3,5-diol 11
NaIO4 (2.57 g, 12.0 mmol) was dissolved in 5 mL of hot water
(70 °C) in a 25 mL round-bottomed flask. To the hot solution was
added silica gel (230–400 mesh, 10 g) with vigorous swirling and
shaking. The resultant silica gel coated with NaIO4 was in powder
form and free-flowing.
To a mixture of methyl triphenylphosphonium iodide (2.76 g,
6.84 mmol) and potassium tert-butoxide (639 mg, 5.69 mmol)
was added dry THF (50 mL) at room temperature and stirred under
N2 for 4 h, after which stirring was stopped and the solid was al-
lowed to settle. The clear supernatant orange-yellow liquid was
cannulated into the solution of compound 10 (650 mg, 2.28 mmol)
in dry THF (10 mL) at ꢀ78 °C. The reaction mixture was brought to
room temperature and stirred for 3 h. After completion of the reac-
tion, the reaction was quenched with saturated aq ammonium
chloride solution and extracted into ethyl acetate (3 ꢁ 40 mL).
The combined organic layer was dried over anhydrous Na2SO4
and the removal of solvent under reduced pressure gave crude
product 11 as a pale yellow syrup which was purified on silica
gel column chromatography (hexane/ethyl acetate = 1.2:1) to ob-
To a solution of the vicinol diol 8 (926 mg, 4.54 mmol) in CH2Cl2
(30 mL) was added this silica gel-supported NaIO4 reagent (9.0 g).
After completion of the reaction, the silica gel was filtered and
washed with dichloromethane (5 ꢁ 10 mL). Removal of the solvent
afforded the aldehyde (960 mg, 96% yield), which was used for the
next reaction without purification. To a stirred suspension of n-
dodecyl phosphonium bromide (6.12 g, 12.2 mmol) in dry THF
(50 mL) at 0 °C was added t-BuOK (1.15 g, 10.28 mmol) and the
solution was stirred for 2 h. To this, a solution of aldehyde
(642 mg, 4.11 mmol) in dry THF (10 mL) was added dropwise at
0 °C and slowly warmed to room temperature and stirred for 4 h.
After completion of the reaction, it was quenched with saturated
aq ammonium chloride (20 mL), extracted into ethyl acetate
(3 ꢁ 60 mL), washed with brine, dried over anhydrous Na2S2O4
and concentrated under reduced pressure. The crude product 9
was purified on silica gel column chromatography (silica gel, 60–
120 mesh; hexane/ethyl acetate = 9:1) to obtain pure compound
tain pure diol 11 (518 mg, 80% yield) as
¼ ꢀ3:2 (c 0.87, CHCl3); IR (neat): 3281, 2919, 2849, 1465,
1317, 1073 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.8 (m, 1H), 5.26
a white solid.
½ ꢂ
a 2D5
;
(dt, 1H, J = 17.18, 1.56), 5.03–5.18 (dt, 1H, J = 10.15), 4.33 (m,
1H), 3.83 (q, 1H, J = 2.34), 3.24 (br s, 2H), 1.59 (m, 2H), 1.25 (br s,
24H), 0.88 (t, 3H, J = 7.03); 13C NMR (75 MHz, CDCl3): d 141.1,
114.5, 96.5, 74.1, 72.7, 43.3, 38.5, 32.3, 30.0 (br, several overlapped
signals), 29.7, 25.7, 23.0, 14.5; ESI-MS: m/z 285, 307, 363 [M+39]+.
9 (1.0 g) in 75% yield as a colourless syrup. ½a D25
¼ ꢀ10:5 (c 0.82,
ꢂ
CHCl3); IR (film): 2925, 2854, 1459, 1375, 1019, 847, 759 cmꢀ1
;
4.1.6. (4R,6R)-2,2-Dimethyl-4-tridecyl-6-vinyl-1,3-dioxane 12
To a solution of compound 11 (500 mg, 1.76 mmol) in dry ace-
tone (15 mL) and 2,2-dimethoxypropane (0.36 mL, 3.52 mmol)
were added p-toluenesulfonic acid (30 mg, 0.17 mmol) and acti-
vated 3 Å molecular sieves (0.5 g) after which the reaction was stir-
red for 30 min at room temperature. After completion of the
reaction, the molecular sieves were filtered and aq saturated NaH-
CO3 solution (10 mL) was added and extracted into CH2Cl2
1H NMR (300 MHz, CDCl3): d 5.73 (d, 1H, J = 3.77), 5.49 (m, 1H),
5.29 (m, 1H), 4.87 (td, 1H J = 3.77, 4.53), 4.65 (t, 1H, J = 3.77),
2.06 (m, 3H), 1.49 (br s, 4H), 1.27 (br s, 7H), 1.24 (br s, 16H),
0.86 (t, 3H, J = 6.79); 13C NMR (75 MHz, CDCl3): d 134.1, 127.9,
111.85, 105.2, 80.6, 73.3, 39.7, 31.8, 29.5 (br, several overlapped
signals), 29.3, 29.1, 27.8, 26.7, 26.1, 22.6, 14.1 (br, several over-
lapped signals), 29, 25, 22.5, 20, 14; ESI-MS: m/z 284, 325 [M+1]+.

1512
V. Suresh et al. / Tetrahedron: Asymmetry 19 (2008) 1509–1513
(3 ꢁ 30 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to afford
crude compound 12 as a colourless syrup. Purification of the crude
product on silica gel column chromatography (hexane/ethyl ace-
tate = 9:1) gave 12 (559 mg, 98% yield) as a colourless liquid.
(1H, m), 3.81 (1H, m), 2.78 (OH, br s), 2.04 (1H, m), 1.86 (1H, m),
1.46 (3H, s), 1.39 (3H, s), 1.28 (27H, br s), 3.73 (3H), 2.4 (1H, br
s), 1.69 (2H, m), 1.45 (3H, s), 1.37 (3H, s), 1.27 (27 H, br s), 0.91
(3H, t, J = 6.7); 13C NMR (75 MHz, CDCl3): d 158.7, 136.6, 133.0,
128.5, 127.9, 127.2, 114.7, 98.4, 96.1, 88.5, 84.5, 69.85, 68.80,
68.16, 61.27, 44.10, 37.03, 36.39, 31.94, 30.26, 29.67 (several over-
lapped signals), 29.38, 22.69, 19.81, 14.20; EIMS: m/z 548 (Mꢀ1),
530 (Mꢀ18).
½
a 2D5
ꢂ
¼ þ1:25 (c 1.2, CHCl3); IR (neat): 3050, 2925, 2854, 1646,
1462 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.8 (m, 1H), 5.1–5.3 (m,
;
2H), 4.28 (m, 1H), 3.85 (m, 1H), 1.53 (s, 3H), 1.41 (s, 3H), 1.25 (br
s, 26H), 0.88 (t, 3H, J = 7.05); 13C NMR (75 MHz, CDCl3): d 138.9,
115.1, 98.5, 70.3, 68.7, 36.8, 36.4, 31.9, 30.2, 29.6 (br, several over-
lapped signals), 29.3, 24.9, 22.6, 19.7, 14.0; ESI-MS: m/z 325
[M+1]+.
4.1.9. (4S,6R)-4-[(R)-2-Hydroxy-4-(4-hydroxyphenyl)butyl]-2,2-
dimethyl-6-tridecyl-[1,3]dioxane 15
To a solution of compound 14 (300 mg, 0.54 mmol) in EtOAc
(10 mL) was added Pd–C 10% (50 mg) and stirred under an H2
atmosphere for 7 h. After completion, the reaction mass was fil-
tered through Celite and the solvent was removed under reduced
pressure to give crude product 15. Purification of the crude product
using column chromatography on silica gel (hexane–EtOAc, 4:1)
gave a mixture of alcohols 15 (222 mg, 88% yield) as a colourless
4.1.7. 2-[(4S,6R)-2,2-Dimethyl-6-tridecyl-1,3-dioxane-4-yl]-1-
ethanol 13
To a solution of cyclohexene (0.435 mL, 4.62 mmol) in THF
(20 mL) at 0 °C was added BH3–DMS (0.212 mL, 2.31 mmol). The
reaction mixture was warmed to room temperature and stirred
for 1 h at rt. To this, olefin 12 (500 mg, 1.54 mmol) in THF (5 mL)
was added at 0 °C and then stirred at 0 °C for 12 h. The reaction
mixture was oxidized by the addition of methanol (0.5 mL), 3 M
aq NaOH solution (1 mL) and 30% aq H2O2 solution (0.9 mL). After
stirring at room temperature for 10 h, water was added and the
organic layer was extracted into ethyl acetate (4 ꢁ l30 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
the solvent was removed under reduced pressure to give crude
product 13. The resulting crude product was purified on silica gel
column chromatography (hexane/ethyl acetate = 4:1) to afford
pure compound 13 (511 mg, 97% yield) as a colourless liquid.
solid; ½a 2D5
ꢂ
¼ ꢀ25 (c 0.4, CHCl3). IR (film): 3386 (OH), 2929, 1724,
1257, 1076 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 6.95 (d, 2H,
J = 8.59), 6.69 (d, 2H, J = 8.59), 4.06 (m, 1H), 3.81 (m, 2H), 2.61 (t,
2H, J = 8.59), 1.46–1.82 (m, 4H), 1,45 (s, 3H), 1.37 (s, 3H), 1.26 (br
s, 28H), 0.89 (t, 3H, J = 7.03); 13C NMR (75 MHz, CDCl3): d 154.0,
133.6, 129.3, 115.2, 98.6, 71.1, 70.5, 68.8, 42.9, 39.5, 37.3, 36.2,
31.9, 30.7, 30.2, 29.6 (br, several overlapped signals), 29.5, 29.3,
24.9, 22.6, 19.9, 14.1; ESI-MS: m/z 485.4 [M+Na]+.
4.1.10. 1-[(4R,6R)-2,2-Dimethyl-6-tridecyl-[1,3]dioxan-4-yl]-4-
(4-hydroxyphenyl)-butane-2-one 3
½
a 2D5
ꢂ
¼ ꢀ25 (c 0.68, CHCl3); IR (neat): 3314 (OH), 2919, 2850,
To a solution of oxalyl chloride (73.2
lL, 0.86 mmol) in dry
1196 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.08 (1H, m), 3.73 (3H,
;
CH2Cl2 (3 mL) under N2 was added DMSO (141
lL, 1.29 mmol) at
m), 2.4 (1H, br s, –OH), 1.69 (2H, m), 1.45 (3H, s), 1.37 (3H, s),
1.27 (26H, br s), 0.90 (3H, J = 7.55); 13C NMR (75 MHz, CDCl3): d
96.0, 69.7, 69.5, 61, 39, 37, 36, 32, 30.5, 29.5 (br, several overlapped
signals), 29, 25, 22.5, 20, 14; ESI-MS: m/z 365.3 [M+Na]+.
ꢀ78 °C. After 10 min, a solution of alcohol 15 (200 mg, 0.43 mmol)
in dry CH2Cl2 (5 mL) was added dropwise. The addition of Et3N
(0.3 mL, 2.15 mmol) was followed by stirring for 15 min at
ꢀ78 °C and for a further 1 h at 0 °C. After completion of the reac-
tion, the resulting mixture was extracted with CH2Cl2
(3 ꢁ 30 mL). The combined organic layer was dried over anhydrous
Na2SO4 and evaporated to give crude product 3 and the resulting
syrup was purified on silica gel column chromatography (hex-
ane/ethyl acetate = 7:3) to obtain the pure ketone 3 (177 mg, 89%
4.1.8. 4-[4-(Benzyloxy)phenyl]-1-[(4S,6R)-2,2-dimethyl-6-
tridecyl-1,3-dioxan-4-yl]-3-butyn-2-ol 14
To a stirred solution of 2-iodoxybenzoic acid (IBX) (573 mg,
2.04 mmol) in DMSO (2 mL) was added a solution of 13 (500 mg,
1.46 mmol) in THF (10 mL) at room temperature and stirred for
4 h. After completion of the reaction as monitored by TLC, water
(10 mL) was added to the reaction mixture, and the precipitated
solid was filtered off and the filtrate diluted with water (50 mL)
and extracted into ether (4 ꢁ 50 mL). The combined organic layer
was washed with aqueous NaHCO3, water, brine and dried over
Na2SO4. Removal of the solvent afforded aldehyde 4 (472 mg,
95% yield), which was used for the next reaction without purifica-
yield) as a colourless solid; ½a D25
ꢂ
¼ ꢀ4:0 (c 0.55, CHCl3). IR (film):
3395 (OH), 2919, 2851, 1703, 1614, 1514, 1381 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 6.98 (d, 2H, J = 8.30), 6.69 (d, 2H, J = 8.30),
5.19 (br s, 1H), 4.24 (m, 1H), 3.76 (m, 1H), 2.82–2.68 (br m, 4H),
2.63 (dd, 1H, J = 15.86, 7.55), 2.35 (dd, 1H, J = 15.8, 5.28), 1.49 (m,
1H), 1.39 (s, 3H), 1.31 (s, 3H), 1.26 (br m, 24H), 1.11 (q, 1H,
J = 11.33), 0.89 (t, 3H, J = 6.79); 13C NMR (75 MHz, CDCl3): d
208.5, 153.9, 133.0, 129.4, 115.2, 98.6, 68.8, 65.8, 49.4, 46.6, 36.8,
36.3, 31.9, 30.1, 29.6 (br, several overlapped signals), 29.5, 29.3,
28.6, 24.9, 22.6, 19.7, 14.1; HR EIMS m/z (rel. int.) 483.34 [M+Na].
tion. To
a solution of 1-(benzyloxy)-4-(1-ethynyl)benzene 5
(406 mg, 1.94 mmol) in THF (20 mL) at ꢀ78 °C was added n-BuLi
(1.21 mL of a 1.6 M solution in hexanes, 1.94 mmol) and stirred
20 min for anion generation. To this anion solution, aldehyde 4
(472 mg, 1.29 mmol) in THF (5 mL) was added slowly. The result-
ing solution was slowly warmed to ambient temperature over
2 h, and quenched by the addition of saturated aq ammonium
chloride solution (20 mL). The organic layer was extracted into
ethyl acetate (3 ꢁ 30 mL), and the combined organic layer was
washed with brine, and dried over anhydrous Na2SO4. Removal
of solvent under reduced pressure afforded the mixture of crude
products 14. The resulting syrup was purified on silica gel column
chromatography (hexane/ethyl acetate = 9:1) and gave racemic
alkynols in the ratio of 1:2 (from 1H NMR without separation) 14
4.1.11. (2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro-
[5.1.5.2]pentadeca-9,12-dien-11-one (aculeatin A) 1 and
(2R,4R,6S)-4-hydroxy-2-tridecyl-1,7-dioxadispiro-
[5.1.5.2]pentadeca-9,12-dien-11-one (aculeatin B) 2
To a solution of ketone 3 (150 mg, 0.32 mmol) in an acetone–
water mixture (9:1, 10 mL) was added PhI(OCOCF3)2 (412 mg,
0.96 mmol) in a single portion followed by the dropwise addition
of CF3COOH (1.2 lL, 0.0161 mmol). The reaction mixture was stir-
red for 4 h at room temperature in the dark. After completion of
the reaction, water was added and extracted into ethyl acetate
(3 ꢁ 25 mL). The combined organic layer was dried over anhydrous
sodium sulfate and concentrated to give crude mixture of aculeatin
A 1 and aculeatin B 2 which was purified on silica column eluting
with hexane–EtOAc to yield 1 (70 mg) and 2 (28 mg). Aculeatin A
(600 mg, 84% yield) as a colourless liquid. ½a D25
ꢂ
¼ ꢀ28 (c 0.68,
CHCl3); IR (neat): 3435 (OH), 2924, 2853, 1507, 1243 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 7.40 (5H, m), 7.32–7.35 (2H, d, J = 9.0),
6.86–6.89 (2H, d, J = 9.0), 5.06 (2H,s), 4.77 (1H, t, J = 6.7), 4.15
1: Oil; ½a 2D5
¼ ꢀ5:2 (c 0.73, CHCl3); IR (neat): 3417 (OH), 2925,
ꢂ

V. Suresh et al. / Tetrahedron: Asymmetry 19 (2008) 1509–1513
1513
2854, 1671, 1630, 1512, 1461, 1099 cmꢀ1 1H NMR (300 MHz,
;
3. Heilmann, J.; Brun, R.; Mayr, S.; Rali, T.; Sticher, O. Phytochemistry 2001, 57,
1281–1285.
4. Salim, A. A.; Su, B.-N.; Chai, H.-B.; Riswan, S.; Kardono, L. B. S.; Ruskandi, A.;
Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. Tetrahedron Lett. 2007, 48,
1849–1853.
5. Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C.-M.; Hwang, I.;
Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc.
2003, 125, 15694–15695.
6. Chin, Y. W.; Salim, A. A.; Su, B. N.; Chai, H. B.; Riswan, S.; Kardono, L. B. S.;
Ruskandi, A.; Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod.
2008, 71, 390.
CDCl3): d 6.85 (dd, 1H, J = 9.82, 3.02),6.78 (dd, 1H, J = 9.82, 3.02),
6.14 (dd, 1H, J = 9.82, 1.51), 6.09 (dd, 1H, J = 10.5, 2.26), 4.05–
4.15 (m, 2H), 3.32 (br s, 1H), 2.38 (m, 1H), 2.24 (m, 1H), 1.93–
2.04 (m, 3H), 1.94 (br d, 1H, J = 14.3), 1.76 (br d, 1H, J = 13.5),
1.60–1.40 (br m, 4H), 1.21–1.37 (br m, 21H), 0.87 (t, 3H, J = 6.79);
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; HR EIMS m/z (rel.
int.) 441.29 [M+Na].
7. Wong, Y.-S. Chem. Commun. 2002, 686–687.
8. (a) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J. A. Tetrahedron Lett.
2005, 46, 8407–8410; (b) Alvarez-Bercedo, P.; Falomir, E.; Carda, M.; Marco, J.
A. Tetrahedron 2006, 62, 9641–9649.
9. (a) Chandrasekhar, S.; Rambabu, Ch.; Shyamsundar, T. Tetrahedron Lett. 2007,
48, 4683–4685; (b) Peuchmaur, M.; Wong, Y.-S. J. Org. Chem. 2007, 72, 5374–
5379.
10. (a) Schmidt, O. T. In Methods in Carbohydrate Chemistry; Whistler, R. L.,
Wolfrom, M. L., Eds.; Academic: New York, 1963; Vol. 2, pp 318–325; (b)
Barton, D. H. R.; Mc Combie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–
1585.
11. Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622–2624.
12. Adiyaman, M.; John, A. L.; Hwang, S.-W.; Subhash, P.-K.; FitzGerald, G.-A.;
Rokach, J. Tetrahedron Lett. 1996, 37, 4849–4852.
AculeatinB 2: Oil;
½
a 2D5
ꢂ
¼ þ54 (c 0.2, CHCl3); IR (neat):
3417(OH), 2925, 2854, 1671, 1630, 1512, 1461, 1099 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 6.99 (dd, 1H, J = 9.80, 3.02), 6.78 (dd,
1H, J = 9.80, 3.02), 6.14 (dd, 1H, J = 9.82, 1.61), 6.09 (dd, 1H,
J = 9.82, 1.61), 4.36 (apparent quintuplet, J = 3.1), 3.87 (m, 1H),
2.68 (br dd, 1H, J = 12.8, 7.2 Hz), 2.30 (td, 1H, J = 12.3, 7.2), 2.10–
2.00 (m, 2H), 1.95–1.84 (m, 2H), 1.60–1.40 (br m, 8H), 1.40–1.20
(br m, 19H), 0.88 (t, 3H, J = 6.9); 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; HR EIMS m/z (rel. int.) 441.29 [M+Na].
13. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16,
1611–1614.
14. Furst, M.; Ruck-Braun, K. Synlett 2002, 1991–1994.
15. (a) Stephane, G.; Karen, P.; Banchet, A.; Liard, A.; Haudrechy, A. Chem. Rev.
2006, 106, 2355–2403; (b) Hanessian, S.; Sahoo, S. P.; Botta, M. Tetrahedron Lett.
1987, 28, 1143; (c) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41,
508.
16. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584; For more recent
developments, see: Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903; Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656–3665; For oxidations of phenolic
compounds with hypervalent iodine reagents, see: Moriarty, R. M.; Prakash,
O. Org. React. 2001, 57, 327–415; For reagents for oxidative spiroacetalizations
of arenes, including hypervalent iodine compounds, see: Rodriquez, S.; Wipf, P.
Synthesis 2004, 2767–2783.
Acknowledgements
The authors are thankful to UGC, CSIR, New Delhi, Ministry of
Earth Sciences (MoES), and Department of Biotechnology (DBT),
New Delhi, India, respectively, for financial support and Dr. J. S.
Yadav, Director, Indian Institute of Chemical Technology (IICT),
for his encouragement.
References
1. Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55, 7661–7706.
2. Helimann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. Helv. Chim. Acta 2000, 83,
2939–2945.