Total synthesis of aculeatins A and B from (S)-malic acid

Article abstract of DOI:10.1016/j.tetasy.2009.12.005

A simple convergent approach towards the total synthesis of bioactive spiroacetals aculeatins A and B is described. The key features of the synthetic strategy include a syn-stereoselective 1,3-asymmetric reduction, epoxide ring opening and oxidative spiro

Full text of DOI:10.1016/j.tetasy.2009.12.005

Tetrahedron: Asymmetry 20 (2009) 2861–2865
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Tetrahedron: Asymmetry
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Total synthesis of aculeatins A and B from (S)-malic acid
*
Ahmed Kamal , Papagari Venkat Reddy, Singanaboina Prabhakar, Moku Balakrishna
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple convergent approach towards the total synthesis of bioactive spiroacetals aculeatins A and B is
described. The key features of the synthetic strategy include a syn-stereoselective 1,3-asymmetric reduc-
tion, epoxide ring opening and oxidative spirocyclization reaction by employing (S)-malic acid as the
starting material.
Received 22 October 2009
Accepted 10 December 2009
Available online 5 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
a literature procedure.6 The primary alcohol 3 was subjected to
a Swern’s oxidation7 to afford the aldehyde, which was taken
There has been considerable interest in spirocyclic natural
products from synthetic as well as bioorganic chemists, due to
their unique structural properties and promising biological activi-
ties. In particular, the epimeric dioxa-dispiroketals and aculeatins
A–D which were isolated1 from the petroleum ether extract of
the rhizomes of species Amomum aculeatum Roxb. (Fam Zingibera-
ceae), exhibit high cytotoxicity against the KB cancer cell lines as
well as antiprotozoal activity against Plasmodium falciparum
strains K1 and NF54. It is believed that the presence of a Michael
acceptor moiety in the aculeatins structure is responsible for their
biological activity.2 Aculeatin A 1 has been found to be active
against MCF-7 (human breast cancer) cells.3 In view of these inter-
esting biological activities, efforts have been made to develop some
new synthetic approaches for the preparation of these spirocyclic
natural products (Fig. 1).4
up for the Barbier reaction (Zn/allylbromide/aq NH4Cl/THF) to
provide the diastereomeric homoallyl alcohol 4 in 88% yields
(Scheme 2).
The diastereomeric ratio of the required compound 6 could be
improved upon by subjecting the diastereomeric homoallyl alcohol
4 to an oxidation and reduction protocol to provide the desired
diasteriomer 6. For this purpose compound 4 was subjected to
O
O
O
O
O
O
11
11
As part of our studies directed towards the synthesis of biolog-
ically active molecules,5 we herein report an efficient and practical
approach for the total synthesis of aculeatins A 1 and B 2 by
employing (S)-malic acid; an inexpensive and readily available
starting material. The retrosynthetic concept is outlined in
Scheme 1. Thus, the dispirocyclic framework of the aculeatins
can be created via phenolic oxidation of intermediate ketone 15,
which in turn can be obtained by the condensation of the aldehyde
of 11 and 4-benzyloxy-phenyl acetylene. Compound 11 can be
formed by the syn-stereoselective 1,3-asymmetric reduction of
ketone 5, which in turn can be obtained from S-malic acid.
OH
OH
1
2
aculeatin A
aculeatin B
O
O
O
O
O
O
O
O
11
11
2. Results and discussion
OH
6
OH
The synthesis of aculeatins A 1 and B 2 utilizes the known
alcohol 3, which was derived from (S)-malic acid according to
OH
aculeatin C
aculeatin D
* Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
Figure 1. Chemical structures of the aculeatins.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.005

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A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 2861–2865
OH OH
O
OR1 OR
1 and 2
+
11
11
OBn
11
15
OH
O
O
O
OH
S-Malic acid
O
O
5
6
Scheme 1. Retrosynthetic analysis of 1 and 2.
O
O
O
OH
O
Ref 6
a
c
b
(S)-Malic acid
O
O
O
OH
3
4
5
O
O
OR
OR
OH OR
OH OR
g
O
f
e
HO
11
R = Bn
R = Bn
9
R = Bn
10
R = H
6
d
8
R = Bn
7
m
OR1 OR
R = Bn
O
OR1 OR OH
OR1 OR
j
h
i
k
11
11
11
R = Bn
R1 = TBDMS
R = Bn
R1 = TBDMS
R1 =T BDMS
OBn
OBn
11
12
13
OR1 OH
O
OH OH
O
l
1 and 2
11
11
OH
R1 = TBDMS
OH
14
15
Scheme 2. Reagents and conditions: (a) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 3 h, (ii) Zn, allyl bromide, NH4Cl, THF, 0 °C to rt, 4 h; (b) IBX, DMSO, CH2Cl2, 3 h; (c) LiI–LiAlH4,
diethyl ether, ꢀ78 °C to ꢀ100 °C, 1 h; (d) NaH, BnBr, THF, 0 °C to rt, 8 h; (e) TFA (THF/H2O 9:1) 0 °C to rt, 6 h; (f) TsCl, Bu2SnO, Et3N, CH2Cl2, 0 °C to rt, 5 h then K2CO3, MeOH,
0 °C, 1 h; (g) C12H25MgBr, CuI (cat), THF, ꢀ35 °C, 3 h; (h) TBDMSCl, imidazole, CH2Cl2, 0 °C to rt, 12 h; (i) (i) OsO4–NaIO4, 2,6-lutidine, dioxane/water (3:1), 0 °C to rt, 12 h, (ii)
n-BuLi, 4-benzyloxyphenyl acetylene, THF, ꢀ78 °C, 4 h; (j) Dess–Martin periodinate, CH2Cl2, 0 °C to rt, 2 h; (k) Pd–C, H2, EtOAc, rt, 12 h; (l) (i) TBAF, THF, 0 °C to rt, 1 h, (ii)
PhI(OOCCF3)2, Me2CO–H2O (9:1), rt, 15 min, 5:2 mixture of aculeatins A and B; (m) NaH, TsCl, THF, 0 °C, 2 h.
oxidation with IBX and DMSO in CH2Cl2 to afford ketone 5, which
was taken up for the syn-stereoselective 1,3-asymmetric reduction
with LiI–LiAlH4 in ether at ꢀ100 °C to give the syn alcohol 6 in 75%
yield (95% de).8 Protection of the resulting secondary alcohol with
BnBr and NaH, in THF afforded 7, which upon subsequent cyclo-
hexylidene deprotection with TFA (THF/H2O 9:1) gave diol 8. Oxi-
rane formation can be achieved by two approaches. In the first
method, the selective tosylation of the primary hydroxyl group in
8 using standard conditions TsCl, Bu2SnO and trimethylamine9 in
CH2Cl2 affords an unstable monoprotected tosylated compound,
which without further purification was taken up for the cyclization
using K2CO3 in methanol to afford epoxide 9. In the second meth-
od, to the diol 8 (taken in THF) were added NaH and TsCl as de-
scribed in the previous one-pot method.10 The regioselective ring
opening of the epoxide with n-dodecyl magnesium bromide in
the presence of cuprous iodide in dry THF at ꢀ35 °C afforded the

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 2861–2865
2863
secondary alcohol 10 in 79%. Then the hydroxyl group of
4.3. (2S,4S)-4-(Benzyloxy)-6-heptene-1,2-diol 8
compound 10 was protected as the TBDMS ether using TBDMSCl
and imidazole to afford 11. The TBDMS ether was selected for
the protection of this hydroxyl as it could be easily cleaved before
the spiroacetalization step. The one-pot oxidative cleavage of the
terminal alkene in 11 using OsO4–NaIO4, 2,6-lutidine and diox-
ane/water (3:1) afforded the aldehedye,11 which was reacted with
lithiated 4-benzyloxyphenyl acetylene to give the corresponding
diastereomeric alkynol 12. Compound 12 upon oxidation using
Dess–Martin periodinate in CH2Cl2 afforded alkynone 13, which
underwent catalytic hydrogenation by using 10% Pd–C in EtOAc
to result in debenzylation as well as triple bond reduction to pro-
duce 14. Treatment of 14 with TBAF in THF formed keto-triol 15
(not isolated) and subsequent treatment with phenyliodoni-
um(III)bis(trifluoroacetate) (PIFA) in acetone/water (9:1) resulted
in phenolic oxidation as well as spiroacetalization12 to yield acule-
atins A 1 and B 2 in a 5:2 ratio in about 15 min, these were sepa-
rated by column chromatography. The spectroscopic and
analytical data were comparable to the previously reported data
in the literature.4b–f
To a stirred solution of the compound 7 (2.7 g, 8.5 mmol) in
THF/H2O (9:1; 30 mL), trifluoroacetic acid (1.26 mL, 17.0 mmol)
was added slowly at 0 °C and stirred for an additional 6 h at room
temperature. After completion of the reaction, it was quenched
with aqueous sodium bicarbonate solution. Next, the THF was
evaporated, extracted with EtOAc (2 ꢁ 25 mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 60–120 mesh, EtOAc/hex-
ane 45:55) to afford 8 (1.63 g, 81%) as a colourless syrup. ½a D25
¼
ꢂ
þ77:5 (c 1.1, CHCl3); IR (neat):
cmax: 3403, 2926, 2870, 1452,
1063, 741, 698 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.55–1.77 (m,
;
2H), 2.17 (br s, 1H), 2.33–2.41 (m, 2H), 3.36 (m, 1H), 3.48–3.56
(m, 2H), 3.7–3.84 (m, 2H), 4.55 (dd, J = 11.3 Hz, 2H), 5.11 (m, 2H),
5.71–5.84 (m, 1H), 7.29 (m, 5H); 13C NMR (75 MHz, CDCl3): 36.8,
37.8, 66.5, 70.7, 71.4, 78.3, 117.9, 127.9, 128.5, 133.5, 137.6; MS–
EIMS: m/z 237 (M+H)+; HR ESIMS: m/z calcd for C14H20O3Na:
259.1310; found: 259.1311.
4.4. (2S)-2-[(2S)-2-(Benzyloxy)-4-pentenyl]oxirane 9
3. Conclusion
To a stirred solution of diol 8 (1.4 g, 5.9 mmol) in dry CH2Cl2
(25 mL), were added Bu2SnO (catalytic), p-TsCl (1.13 g, 5.9 mmol)
and Et3N (0.99 mL, 7.1 mmol) at 0 °C and allowed to stir at room
temperature for 5 h. Later, the reaction mixture was extracted with
CH2Cl2 (2 ꢁ 25 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo to afford monotosylated product. This was used
for the next step. To a stirred solution of this monotosylated com-
pound taken in dry methanol (20 mL), was added solid K2CO3
(1.63 g, 11.8 mmol) at 0 °C and stirred at the same temperature
for 1 h. After completion of the reaction, K2CO3 was filtered
through a Celite pad. Methanol was evaporated and extracted with
CHCl3 (2 ꢁ 20 mL). The combined organic phases were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 5:95) to afford the compound 9 (0.95 g, 73%, over
In conclusion, we have developed a simple, convenient and effi-
cient convergent approach for the synthesis of naturally occurring
aculeatins A and B by using a syn-stereoselective 1,3-asymmetric
reduction and an oxidative spirocyclization reaction. Interestingly,
(S)-malic acid has been used as the starting material in this
protocol.
4. Experimental
4.1. General experimental
Reagents and chemicals were purchased from Aldrich. All sol-
vents and reagents were purified by standard techniques. THF
was freshly distilled from LiAlH4. Crude products were purified
by column chromatography on 60–120 silica gel. IR spectra were
recorded on Perkin–Elmer 683 spectrometer. Optical rotations
were obtained on a Horiba 360 digital polarimeter. 1H and 13C
NMR spectra were recorded in CDCl3 solution on a Varian Gemini
200, Bruker Avance 300. Chemical shifts are reported in ppm with
respect to the internal TMS. Mass spectra were recorded on VG
micromass-7070H (70 Ev)
two steps) as a liquid. ½a D25
ꢂ
¼ þ25:5 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): d 1.69–1.81 (m, 2H), 2.36–2.42 (m, 3H), 2.69
(t, 1H), 3.01 (m, 1H), 3.62 (m, 1H), 4.55 (dd, J = 12.1 Hz, 2H),
5.102 (m, 2H), 5.79–5.89 (m, 1H), 7.24–7.32 (m, 10H); 13C NMR
(75 MHz, CDCl3): 36.5, 38.2, 46.65, 49.4, 70.7, 76.2, 117.4, 127.4,
127.5, 128.2, 134.2, 138.4. MS–EIMS: m/z 219 (M+H)+; HR ESIMS:
m/z calcd for C14H18O2Na: 241.1204; found: 241.1203.
4.5. (4S,6R)-4-(Benzyloxy)-1-nonadecen-6-ol 10
4.2. (2S)-2-[(2S)-2-(Benzyloxy)-4-pentenyl]-1,4-dioxaspiro[4.5]-
decane 7
To a stirred solution of 9 (0.85 g, 3.89 mmol) and CuI (catalytic
amount) in dry THF (20 mL) was added slowly n-dodecyl magne-
sium bromide {freshly prepared with Mg (0.280 mg, 11.67 mmol),
dodecyl bromide (3.08 mL, 12.83 mmol) and I2 (5 mg) in dry THF
(20 mL)} at ꢀ35 °C under a nitrogen atmosphere. Then the reac-
tion mixture was stirred for 3 h at the same temperature. After
3 h the reaction was quenched with saturated NH4Cl solution
(20 mL) at 0 °C, after which the THF was evaporated and ex-
tracted with ethyl acetate (2 ꢁ 30 mL). The combined organic lay-
ers were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
60–120 mesh, EtOAc/hexane 10:90) to afford compound 10
To a stirred solution of the compound 6 (2.5 g, 11.0 mmol) in
dry THF (25 mL) were added sodium hydride (0.52 g, 13.3 mmol,
60%) and benzyl bromide (1.44 mL, 12.1 mmol) at 0 °C, and al-
lowed to stir at room temperature for 8 h. After completion of
the reaction, it was quenched with saturated NH4Cl solution
(20 mL). Next, the THF was evaporated, extracted with CHCl3
(2 ꢁ 40 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 60–120 mesh, EtOAc/hexane 5:95) to afford 7
(3.03 g, 86%) as a yellow oil. ½a D25
ꢂ
¼ þ4:5 (c 1.1, CHCl3); 1H NMR
(1.2 g, 79%) as a liquid. ½a D25
ꢂ
¼ þ53:5 (c 1.1, CHCl3); IR (neat):
(400 MHz, CDCl3): d = 1.38 (m, 2H), 1.56 (m, 8H), 1.66 (m, 1H),
1.92 (m, 1H), 2.36 (t, 2H), 3.43 (t, 1H), 3.51 (m, 1H), 3.89 (t, 1H),
4.16 (m, 1H), 4.49 (dd, 2H), 5.07 (m, 2H), 5.8 (m, 1H), 7.28 (m,
5H); 13C NMR (75 MHz, CDCl3): 23.9, 24.0, 25.2, 35.3, 36.65, 37.5,
38.1, 69.1, 70.7, 72.5, 75.5, 108.95, 117.3, 127.4, 127.6, 128.2,
134.3, 138.3; MS–EIMS: m/z 339 (M+Na)+; HR ESIMS: m/z calcd
for C20H28O3Na: 339.1936; found: 339.1945.
c
max: 3449, 2924, 2853, 1460, 1068, 738, 697 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H), 1.206 (m, 22H),
1.33–1.34 (m, 2H), 1.50–1.57 (m, 2H), 2.32 (m, 2H), 3.26 (br s,
1H), 3.59–3.65 (m, 1H), 4.54 (dd, J = 11.3 Hz, 2H), 5.06 (m, 2H),
5.72 (m, 1H), 7.25 (m, 5H); 13C NMR (75 MHz, CDCl3): 14.1,
22.7, 25.4, 29.3, 29.64 (br, several overlapped signals), 31.9,

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A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 2861–2865
37.7, 37.9, 40.8, 70.7, 71.6, 79.4, 117.7, 127.8, 128.5, 133.7, 137.7;
MS–EIMS: m/z 389 (M+H)+; HR ESIMS: m/z calcd for C26H44O2Na:
411.3239; found: 411.3230.
4.8. (5R,7R)-5-(Benzyloxy)-1-[4-(benzyloxy)phenyl]-7-[1-(tert-
butyl)-1,1 dimethylsilyl]oxy-1-icosyn-3-one 13
To a stirred solution of compound 12 (0.4 g, 0.56 mmol) in CH2Cl2
(10 mL), Dess–Martin periodinate (0.26 g, 0.62 mmol) was added at
0 °C and stirred for 2 h. After completion of the reaction, it was
quenched with aqueous sodium thiosulfate solution (5 mL) and sat-
urated aqueous sodium bicarbonate solution (2 mL). The reaction
mixture was extracted with CH2Cl2 (2 ꢁ 10 mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 60–120 mesh, EtOAc/hexane
4.6. [(1R,3S)-3-(Benzyloxy)-1-tridecyl-5-hexenyl]oxy(tert-
butyl)dimethylsilane 11
To a cooled (0 °C) solution of 10 (0.98 g, 2.31 mmol) in CH2Cl2
(15 mL), was added imidazole (0.19 g, 2.8 mmol) followed by
TBDMSCl (0.38 g, 2.5 mmol) and then stirred for 12 h at room
temperature. The reaction mixture was treated with saturated
aqueous NH4Cl solution (15 mL) and extracted with CH2Cl2
(2 ꢁ 20 mL), dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography (sil-
ica gel, 60–120 mesh, EtOAc/hexane 5:95) to afford 11 (1.03 g,
7:93) to afford 13 (0.35 g, 87%) as a yellow liquid. ½a D25
¼ þ4:5 (c
ꢂ
1.1, CHCl3); IR (neat): cmax: 2926.4, 2854.8, 2196.5, 1665.0, 1251.4,
1072.2, 834.4, 736.6, 697.6 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
0.032 (s, 3H), 0.045 (s, 3H), 0.857–0.926 (m, 12 H), 1.17–1.34 (m, 22
H), 1.36–1.45 (m, 2H) 1.54–1.65 (m, 1 H), 1.79–1.89 (m, 1 H), 2.8
(dd, J = 15.8 Hz, 1H), 2.92 (dd, J = 15.8 Hz, 1H), 3.74 (m, 1H), 4.12
(m, 1H), 4.52 (dd, J = 11.3 Hz, 2H), 5.08 (s, 2H), 6.91 (d, J = 9.1 Hz,
2H), 7.17–7.41 (m, 10 H), 7.44 (d, J = 9.1 Hz, 2H). 13C NMR (75 MHz,
CDCl3): ꢀ4.4, ꢀ4.3, 14.1, 18.0, 22.7, 25.1, 25.9, 29.3, 29.6 (br, several
overlapped signals), 29.76, 31.9, 37.1, 41.7, 50.8, 69.4, 70.1, 71.4,
72.9, 88.2, 92.2, 111.95, 115.1, 127.4, 127.5, 127.8, 128.2, 128.6,
135.1, 136.05, 138.3, 160.9, 185.9; MS–EIMS: m/z 711 (M+H)+; HR
ESIMS: m/z calcd for C46H66O4NaSi: 733.4628; found: 733.4618
81%) as a liquid. ½a D25
ꢂ
¼ þ14:5 (c 1.1, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.011 (s, 3H), 0.021 (s, 3H), 0.86–0.90 (m, 12H), 1.25–
1.35 (m, 24H), 1.48–1.56 (m, 1H) 1.69–1.76 (m, 1H), 2.25–2.35
(m, 2H), 3.5 (m, 1H), 3.72 (m, 1H), 4.48 (dd, J = 11.9 Hz, 2H)
5.06 (m, 2H), 5.81 (m, 1H), 7.19–7.31 (m, 5H); 13C NMR
(75 MHz, CDCl3): ꢀ4.42, ꢀ4.32, 14.1, 18.1, 22.7, 25.1, 25.9, 29.3,
29.66 (br, several overlapped signals), 29.78, 31.9, 37.2, 38.4,
41.5, 69.5, 70.6, 75.6, 117.1, 127.4, 127.7, 128.2, 134.8, 138.8;
MS–EIMS: m/z 503 (M+H)+; HR ESIMS: m/z calcd for C32H58O2Na-
Si: 525.4103; found: 525.41.
4.9. (5R,7R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-5-hydroxy-
1-(4-hydroxyphenyl)icosan-3-one 14
4.7. (5S,7R)-5-(Benzyloxy)-1-[4-(benzyloxy)phenyl]-7-[1-(tert-
butyl)-1,1dimethylsilyl]oxy-1-icosyn-3-ol 12
To a stirred solution of compound 13 (0.3 g, 0.42 mmol) in ethyl
acetate (5 mL) was added Pd-C (10%) (catalytic amount) under a
hydrogen atmosphere and stirred for 12 h. After completion of
the reaction, it was filtered through a Celite pad. Concentration
of the filtrate gives the crude product, which was purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc/hexane 35:
To a stirred solution of compound 11 (0.5 g, 0.99 mmol) in
dioxane/water (5 mL, 3:1) were added 2,6-lutidine (0.23 mL, 1.98
mmol), OsO4 (5 mL in toluene) and NaIO4 (0.426 g, 1.98 mmol)
at 0 °C and then the reaction mixture was stirred at room temper-
ature for 12 h. After completion of the reaction, water and CH2Cl2
were added. The organic layer was separated and the water layer
was extracted by CH2Cl2 (2 ꢁ 20 mL). The combined organic
phases were dried over anhydrous Na2SO4 and concentrated in
vacuo to afford the aldehyde, which were used for the next step
without further purification. To a stirred solution of 1-(benzyl-
oxy)-4-(1-ethynyl)benzene (0.62 g, 2.9 mmol) in dry THF (10 mL)
was added n-BuLi (1.55 mL of a 1.6 M solution in hexanes,
2.5 mmol) at ꢀ78 °C and stirred for 45 min for the anion genera-
tion. To this lithiated 4-benzyloxyphenyl acetylene solution, the
above crude aldehyde taken in THF (2 mL) was added dropwise
and stirred for 4 h at the same temperature. The reaction was then
quenched by the addition of saturated NH4Cl solution (5 mL).
Next, the THF was evaporated and extracted with ethyl acetate
(2 ꢁ 15 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane 10:90) to afford compound 12 (0.51 g, 72%, over
65) to afford 14 (0.18 g, 80%) as a yellow syrup. ½a D25
¼ ꢀ4:5 (c
ꢂ
1.1, CHCl3); IR (neat): cmax: 3385, 2926, 2855, 1706, 1515, 1254,
1079, 834, 720, 665 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.068 (s,
;
3H), 0.073 (s, 3H), 0.861–0.903 (m, 12 H), 1.25 (m, 22H), 1.41–
1.57 (m, 4H), 2.48 (t, J = 6.8 Hz, 2H), 2.67 (m, 2H), 2.79 (m, 2H),
3.38 (d, 1H), 3.88 (m, 1H), 4.1 (m, 1H), 4.9 (s, 1H), 6.67 (d,
J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
ꢀ4.6, ꢀ4.1, 14.1, 17.9, 22.6, 24.7, 25.8, 28.6, 29.3 (br, several over-
lapped signals), 29.6, 31.9, 37.5, 42.4, 45.4, 49.8, 66.98, 72.2, 115.3,
129.3, 132.4, 154.4, 210.4; MS–EIMS: m/z 535 (M+H)+; HR ESIMS:
m/z calcd for C32H58O4NaSi: 557.4002; found: 557.4001.
4.10. (2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro [5.1.5.2]-
pentadeca-9,12-dien-11-one (aculeatinA)1 and (2R,4R,6S)-4-hyd-
roxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-
one (aculeatin B) 2
Compound 14 (0.14 g, 0.26 mmol) was dissolved in dry THF
(10 mL), cooled to 0 °C and TBAF (0.86 mL, 0.86 mmol, 1 M in
THF) was slowly added. The reaction mixture was stirred for 1 h
at room temperature. After completion of the reaction, it was
quenched with water, then THF was evaporated, extracted with
CHCl3 (2 ꢁ 10 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure affords an oily compound 15, which was
used directly in the next step without purification. The above crude
material was dissolved in a 9:1 acetone/water (10 mL) system and
PhI(OOCCF3)2 (0.225 g, 0.52 mmol) was added. The reaction mix-
ture was stirred at room temperature for 15 min in the dark. After
completion of the reaction, water was added and extracted with
ethyl acetate. The combined organic layer was dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 60–120 mesh, EtOAc/hex-
ane 25:75) to yield 1 (0.049 g, 45%) and 2 (0.019 g, 17%).
two steps) as a yellow liquid. ½a D25
¼ ꢀ39:5 (c 1.1, CHCl3); IR
ꢂ
(neat):
cmax: 3425, 2926, 2854, 1507, 1461, 1247, 1060, 833,
774, 737, 697 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.044 (s, 3H),
;
0.049 (s, 3H), 0.865–0.906 (m, 12 H), 1.25 (br s, 22 H) 1.42–1.46
(m, 2H), 1.59–1.68 (m, 2H), 1.90–2.16 (m, 2H), 3.55
(d, J = 7.5 Hz, 1H), 3.68–3.78 (m, 1H), 4.04–4.17 (m, 1H), 4.45–
4.64 (m, 2H), 4.81 (td, J = 3.8, 7.5 Hz, 1H), 5.06 (s, 2H), 6.9 (d,
2H), 7.25–7.43 (m, 12H). 13C NMR (75 MHz, CDCl3): ꢀ4.4, ꢀ4.2,
14.0, 17.98, 22.7, 25.0, 25.9, 29.3, 29.64 (br, several overlapped
signals), 29.78, 31.9, 37.7, 41.1, 41.2, 60.0, 69.3, 69.9, 71.2, 75.1,
84.7, 88.7, 114.7, 127.4, 127.7, 127.8, 127.9, 128.04, 128.09,
128.47, 128.57, 133.1, 136.5, 137.99,158.7; MS–EIMS: m/z 713
(M+H)+; HR ESIMS: m/z calcd for C46H68O4NaSi: 735.4784; found:
735.4803.

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 2861–2865
2865
2. 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.
3. 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.
4.10.1. Aculeatin A 1
¼ ꢀ5:3 (c 1.1, CHCl3); IR (neat):
1673.0, 1632.7, 1099.3, 1000.8 cmꢀ1 1H NMR (300 MHz, CDCl3): d
½
a 2D5
ꢂ
cmax: 3552, 2925.2, 2853.8,
;
0.88 (t, J = 6.8 Hz, 3H), 1.22–1.36 (br m, 21H), 1.39–1.47 (br m, 4H),
1.75 (br d, J = 14.3 Hz, 1H), 1.93 (br m, J = 14.3 Hz, 1H), 1.94–2.03
(m, 3H), 2.22 (m, 1H), 2.36 (m, 1H), 3.2 (br s, 1H), 4.06–4.09 (m,
2H), 6.09 (dd, J = 2.26, 10.04 Hz, 1H), 6.13 (dd, J = 2.26, 10.04 Hz,
1H), 6.75 (dd, J = 3.02, 10.57 Hz, 1H), 6.82 (dd, J = 3.02, 10.6 Hz,
1H); 13C NMR (75 MHz, CDCl3): 14.07, 22.63, 25.59, 29.4, 29.7 (br,
several overlapped signals), 31.9, 34.1, 35.84, 37.9, 39.04, 64.8,
65.4, 79.78, 109.0, 127.01, 127.3, 148.7, 150.8, 185.3; MS–EIMS: m/
z 419 (M+H)+; HR ESIMS: m/z calcd for C26H42O4Na: 441.2980;
found: 441.2961.
4. For a racemic synthesis see: (a) Wong, Y. S. Chem. Commun. 2002, 686–687; For
an asymmetric synthesis see: (b) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.;
Marco, J. A. Tetrahedron Lett. 2005, 46, 8407–8410; (c) Alvarez-Bercedo, P.;
Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62, 9641–9649; (d)
Chandrasekhar, S.; Rambabu, Ch.; Shyamsundar, T. Tetrahedron Lett. 2007, 48,
4683–4685; (e) Peuchmaur, M.; Wong, Y. S. J. Org. Chem. 2007, 72, 5374–5379;
(f) Suresh, V.; Selvam, J. J. P.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron:
Asymmetry 2008, 19, 1509–1513; (g) Malathong, V.; Rychnovsky, S. D. Org. Lett.
2009, 11, 4220–4223.
5. (a) Kamal, A.; Reddy, P. V.; Prabhakar, S. Tetrahedron: Asymmetry 2009, 20,
1936–1939; (b) Kamal, A.; Reddy, P. V.; Prabhakar, S.; Suresh, P. Tetrahedron:
Asymmetry 2009, 20, 1798–1801; (c) Kamal, A.; Reddy, P. V.; Prabhakar, S.
Tetrahedron: Asymmetry 2009, 20, 1120–1124; (d) Kamal, A.; Krishnaji, T.;
Reddy, P. V. Tetrahedron: Asymmetry 2007, 18, 1775–1779; (e) Kamal, A.;
Krishnaji, T.; Reddy, P. V. Tetrahedron Lett. 2007, 48, 7232–7235.
6. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J. Chem. 1984, 62, 2146.
7. Mancuso, A. J.; Swern, D. Tetrahedron Lett. 1981, 35, 2473.
4.10.2. Aculeatin B 2
½
a 2D5
ꢂ
¼ þ53:5 (c 1.1, CHCl3); IR (neat):
cmax: 3552, 2925.2, 2853.8,
1673.0, 1632.7, 1099.3, 1000.8 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
0.88 (7, J = 6.7 Hz, 3H), 1.25–1.35 (br m, 19H), 1.42–1.66 (br m,
8H), 1.85–1.95 (m, 2H), 2.01–2.09 (m, 2H), 2.29 (td, J = 7.3, 12.4 Hz,
1H), 2.67, (br dd, J = 7.3, 13.1 Hz, 1H), 3.8 (m, 1H), 4.36 (apparent
quintuplet, J = 3.1, 6.4 Hz, 1H), 6.1 (dd, J = 9.7, 2.0 Hz, 1H), 6.13 (dd,
J = 9.7, 2.0 Hz, 1H), 6.77 (dd, J = 2.9, 10.2 Hz, 1H), 6.98 (dd, J = 2.9,
10.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): 14.08, 22.8, 25.9, 29.32,
29.5, 29.8, (br, several overlapped signals), 31.9, 35.26, 35.7, 37.9,
40.56, 65.08, 69.44, 77.54, 108.67, 127.1 (two signals), 149.4,
152.28, 185.66; MS–EIMS: m/z 419 (M+H)+; HR ESIMS: m/z calcd
for C26H42O4Na: 441.2980; found: 441.2961.
8. (a) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783–8788; (b) Sabitha, G.;
Sudhakar, K.; Reddy, N. M.; Rajkumar, M.; Yadav, J. S. Tetrahedron Lett. 2005, 46,
6567–6570.
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Vaidyanathan, R. Org. Lett. 1999, 1, 447–450; (b) Martinelli, M. J.; Vaidyanathan,
R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.;
Moher, E. D.; Van Khau, V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578–3585;
(c) Martinelli, M. J.; Vaidyanathan, R.; Van Khau, V. Tetrahedron Lett. 2000, 41,
3773–3776.
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12. Zhdankin, V. V.; Stang, P. J. Chem. Rev 2002, 102, 2523–2584; For more recent
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Angew. Chem., Int. Ed. 2005, 44, 3656–3665; For oxidations of phenolic
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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.
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