Formal synthesis of aspergillide A from tri-O-acetyl-d-glucal

Article abstract of DOI:10.1055/s-0030-1260203

We describe an efficient synthesis of a key intermediate in the synthesis of aspergillide A from a commercially available, chiral starting material. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260203

PAPER
3301
Formal Synthesis of Aspergillide A from Tri-O-acetyl-D-glucal
Formal Synthesis
o
n
f
A
spergillide A from Tr
r
i-
O
-ace
t
e
yl-
D
-glucala Zúñiga, Manuel Pérez, Maria González, Generosa Gómez,* Yagamare Fall*
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(986)812262; E-mail: yagamare@uvigo.es; E-mail: ggomez@uvigo.es
Received 27 June 2011; revised 26 July 2011
13
Abstract: We describe an efficient synthesis of a key intermediate
in the synthesis of aspergillide A from a commercially available,
chiral starting material.
O
O
O
O
O
O
9
1
8
Key words: Claisen rearrangement, allylic alcohol, stereoselective
synthesis, tri-O-acetyl-D-glucal, aspergillide A
O
H
O
H
O
H
3
7
H
H
H
4
HO
HO
HO
1
2
3
Aspergillides A (1), B (2) and C (3) are novel 14-mem-
bered macrolides recently isolated by Kusumi and co-
workers1 from a culture of Aspergillus ostianus strain
01F313 in bromine-modified 1/2PD medium. These com-
pounds show significant cytotoxic activity against the mu-
rine leukemia cell line L1210, with IC50 values ranging
from 2.0–71 mg/mL. The structure originally proposed for
aspergillide C (3) has been confirmed by synthesis,2 while
the structures of aspergillides A (1) and B (2) have been
revised in the light of X-ray crystallography results.3 The
corrected structures are shown in Figure 1.
Figure 1 Structures of aspergillides A (1), B (2) and C (3)
The starting compound, tri-O-acetyl-D-glucal (7), was
chosen because it already contains stereocenters 2 and 3
of compound 4, and because it was envisaged as giving
access to compound 6 through the very efficient Claisen
rearrangement previously employed in our synthesis of
(+)-isolaurepan.7
As hoped, compound 6 was readily obtained from known
aldehyde 10,7 as shown in Scheme 2. Compound 87 was
prepared from triacetate 7 as per Mori and Hayashi8a and
Hoberg8b in two steps and 91% yield. The mercury(II) ac-
etate catalyzed reaction of allylic alcohol 8 with ethyl vi-
nyl ether then afforded enol ether 97 (80%), and Claisen
rearrangement9 of the latter in toluene at 185 °C gave a
95% yield of aldehyde 10. Finally, hydrogenation of 10,
followed by sodium borohydride reduction, afforded a
90% yield of alcohol 6, which possesses the stereocenters
corresponding to C3, C4 and C7 of the target molecule.
Because of their unique pharmaceutical profiles and in-
triguing structural features, these macrolides have attract-
ed much interest in the synthetic chemistry community.
To date, however, only a relatively small number of actual
or formal total syntheses have been reported: nine for 1,4
nine for 24b,c,e,i,5 and three for 3.2,6
Here, we describe a formal total synthesis of aspergillide
A (1) from the relatively inexpensive, commercially avail-
able product tri-O-acetyl-D-glucal. The retrosynthetic ba-
sis is outlined in Scheme 1. Since the conversion of 4 and
5 into 1 has already been reported in the literature,4a we
describe only the preparation of compound 4.
The transformation of compound 6 into compound 4 was
carried out as shown in Scheme 3. First, alcohol 6 was
easily converted into iodide 11 in 80% yield.10 Reaction of
11 with potassium tert-butoxide followed by tetrabutyl-
HO
O
O
AcO
AcO
O
OH
O
O
t-Bu
t-Bu
Si
2
13
O
OAc
3
TBSO
O
4
6
7
O
9
1
8
7
O
H
3
H
4
HO
HO
1
5
Scheme 1 Retrosynthetic analysis of aspergillide A (1)
SYNTHESIS 2011, No. 20, pp 3301–3306
x
x.
x
x
.
2
0
1
1
Advanced online publication: 02.09.2011
DOI: 10.1055/s-0030-1260203; Art ID: Z64511SS
© Georg Thieme Verlag Stuttgart · New York

3302
A. Zúñiga et al.
PAPER
O
followed by TEMPO/BAIB oxidation in aqueous acetoni-
trile, afforded the target acid 4 in 61% yield (two steps).
O
O
AcO
ii
i
t-Bu
t-Bu
Si
O
Sabitha and co-workers4a have published syntheses of
acid 4 from chiral epoxides prepared by Sharpless epoxi-
dation or by hydrolytic kinetic resolution of terminal ep-
oxides catalyzed by a chiral (salen)Co(III) complex. Our
synthesis of 4 compares favorably with those described so
far in that it starts from a chiral compound that is commer-
cially available and relatively inexpensive, and involves
high-yielding reactions that can be carried out on a multi-
gram scale.
AcO
OH
OAc
8
7
O
O
O
H
iii
iv
O
t-Bu
t-Bu
Si
t-Bu
t-Bu
O
Si
O
O
O
O
10
9
In conclusion, we have developed a practical, efficient
synthesis of acid 4, an intermediate in a known synthesis
of aspergillide A, and have hence achieved a new formal
total synthesis of aspergillide A. Work is now in progress
on the synthesis of new aspergillide A analogues with a
view to their biological evaluation.
O
OH
t-Bu
t-Bu
Si
O
6
Scheme 2 Reagents and conditions: (i) (a) K2CO3, MeOH; (b)
t-Bu2Si(OTf)2, DMF, pyridine, –30 °C, 91% (two steps);8 (ii) ethyl
vinyl ether, Hg(OAc)2, 65 °C, 80%;7 (iii) toluene, 185 °C, 5 h, 95%;
(iv) (a) H2, Pd/C, MeOH; (b) NaBH4, MeOH, 90% (two steps).
Solvents were purified and dried by standard procedures before use.
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on a Bruker ARX-400 spectrometer (400 MHz, 1H; 100.61
MHz, 13C) using TMS as internal standard (chemical shifts in d val-
ues, J in Hz). Mass spectrometry was carried out with a Hewlett
Packard 5988A spectrometer. Specific rotations were recorded on a
Jasco P-1020 polarimeter. Flash chromatography was performed on
silica gel (Merck 60, 230–400 mesh); analytical TLC was per-
formed on plates precoated with silica gel (Merck 60 F254, 0.25 mm).
ammonium fluoride afforded diol 12 in 79% overall yield
(two steps). Unfortunately, the interesting one-step silyl-
deprotection procedure described by Pagenkopf and co-
workers11 could not be used in this case because reaction
of 11 with potassium tert-butoxide afforded a mixture of
alkenes with di- and monoprotected hydroxy groups,
which was then treated with tetrabutylammonium fluoride
to yield 12. Protection of the hydroxy groups of diol 12,
followed by selective deprotection of the primary hy-
droxy, gave alcohol 14, which was uneventfully convert-
ed into nitrile 16 in 63% yield by tosylation followed by
displacement of tosylate with sodium cyanide. Finally, re-
duction of nitrile 16 with diisobutylaluminum hydride,
(4aR,8R,8aS)-2,2-Di-tert-butyl-4,4a,8,8a-tetrahydropyrano[3,2-
d][1,3,2]dioxasilin-8-ol (8)
To a soln of tri-O-acetyl-D-glucal (7; 14 g, 51.4 mmol) in MeOH
(50 mL) was added K2CO3 (100 mg), and the mixture was stirred at
r.t. for 12 h. The MeOH was removed, the crude material was dilut-
ed with CHCl3 and the solvent was evaporated to eliminate all traces
of MeOH. The resulting solid was dissolved in DMF (40 mL), py-
OH
O
O
I
O
O
ii
i
t-Bu
t-Bu
t-Bu
t-Bu
Si
Si
O
THF
O
6
11
O
O
O
HO
TBSO
TBSO
HO
iii
iv
TBSO
HO
12
13
14
O
O
NC
TsO
v
vi
TBSO
TBSO
16
15
HO
O
vii
O
TBSO
4
Scheme 3 Reagents and conditions: (i) I2, Ph3P, imidazole, THF, 80%; (ii) (a) t-BuOK, THF; (b) TBAF, THF, 79% (two steps); (iii) TBSCl,
imidazole, DMAP, THF, 92%; (iv) PPTS, MeOH, 84%; (v) p-TsCl, pyridine, CH2Cl2, 95%; (vi) NaCN, DMSO, 66%; (vii) (a) DIBAL-H,
CH2Cl2; (b) TEMPO, BAIB, MeCN, H2O, 61% (two steps).
Synthesis 2011, No. 20, 3301–3306 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of Aspergillide A from Tri-O-acetyl-D-glucal
IR (NaCl): 1728 cm–1.
3303
ridine (20 mL, 257.1 mmol) was added and the mixture was cooled
to –30 °C. Then, t-Bu2Si(OTf)2 (18.3 mL, 56.6 mmol) was slowly
added and the resulting mixture was allowed to warm to r.t. over 1.5
h. EtOAc (30 mL) was added to the mixture, and the organic phase
was washed with 10% aq CuSO4 (2 × 30 mL), H2O (3 × 30 mL) and
brine (3 × 30 mL). The organic phase was dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc–hexane, 1:19) to
afford 8; yield: 13.4 g (91%).
White solid; mp 84–85 °C; [a]D23 –16.3 (c 1.46, CHCl3); Rf = 0.71
(EtOAc).
IR (NaCl): 3440, 3074, 2939, 2889, 2862, 1647 cm–1.
1H NMR (CDCl3): d = 6.25 (dd, J = 6.1, 1.8 Hz, 1 H, H-6), 4.74 (dd,
J = 6.1, 1.9 Hz, 1 H, H-7), 4.31–4.26 (m, 1 H, H-8), 4.16 (dd,
J = 10.2, 4.9 Hz, 1 H, H-4), 3.98–3.88 (m, 2 H, H-4, H-8a), 3.85–
3.78 (m, 1 H, H-4a), 2.66 (s, 1 H, OH), 1.05 [s, 9 H, C(CH3)3], 0.98
[s, 9 H, C(CH3)3].
13C NMR (CDCl3): d = 143.49 (CH-6), 103.07 (CH-7), 77.27 (CH-
8a), 72.20 (CH-4a), 70.01 (CH-8), 65.63 (CH2-4), 27.36 [C(CH3)3],
26.84 [C(CH3)3], 22.65 [C(CH3)3], 19.75 [C(CH3)3].
1H NMR (CDCl3): d = 9.75 (t, J = 2.06 Hz, 1 H, CHO), 5.93 (d,
J = 10.34 Hz, 1 H, H-8¢), 5.68–5.61 (m, 1 H, H-7¢), 4.77–4.67 (m, 1
H, H-6¢), 4.43–4.36 (m, 1 H, H-8a¢), 4.16 (dd, J = 9.97, 5.05 Hz, 1
H, H-4¢), 3.84 (t, J = 10.24 Hz, 1 H, H-4¢), 3.54 (ddd, J = 10.34,
8.52, 5.08 Hz, 1 H, H-4a¢), 2.57 (dd, J = 6.05, 2.06 Hz, 2 H,
CH2CHO), 1.05 [s, 9 H, C(CH3)3], 0.99 [s, 9 H, C(CH3)3].
13C NMR (CDCl3): d = 200.40 (C=O), 131.22 (C-8¢), 127.80 (C-7¢),
74.67 (C-4a¢), 70.94 (C-6¢), 69.96 (C-8a¢), 66.99 (C-4¢), 48.26
(CH2CHO), 27.45 [C(CH3)3], 27.04 [C(CH3)3], 22.67 [C(CH3)3],
20.04 [C(CH3)3].
MS (FAB+): m/z (%) = 313 (6) [M + H]+, 312 (7) [M+], 311 (21) [M
– H]+, 283 (11) [M – CHO]+, 270 (23), 269 (100) [M – CH2CHO]+,
268 (13), 267 (15), 255 (17) [M – t-Bu]+, 239 (20), 213 (21), 211
(19), 201 (27).
HRMS (FAB+): m/z calcd for C16H29O4Si: 313.1757; found:
313.1790.
2-[(4aR,6R,8aS)-2,2-Di-tert-butylhexahydropyrano[3,2-
d][1,3,2]dioxasilin-6-yl]ethanol (6)
To a soln of aldehyde 10 (10.2 g, 32.69 mmol) in MeOH (60 mL)
was carefully added 10% Pd/C (0.35 g, 0.33 mmol), and the mixture
was stirred under H2 atmosphere overnight. The solution was fil-
tered over Celite®, which was then washed with CH2Cl2, and the re-
sulting solution was concentrated under reduced pressure. The
resulting residue (10.56 g, 33.63 mmol) was dissolved in MeOH (20
mL) and cooled to 0 °C. NaBH4 (1.9 g, 50.44 mmol) was added in
8 portions, then the mixture was allowed to reach r.t. over 3 h. The
solvent was evaporated, the residue was dissolved in EtOAc (20
mL), and the organic layer was washed with H2O (2 × 15 mL) and
brine (2 × 15 mL). The organic phase was dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc–hexane, 1:9) to
give the desired alcohol 6; yield: 9.64 g (90%).
MS (FAB+): m/z (%) = 287 (7) [M + H]+, 286 (12) [M+], 285 (18)
[M – H]+, 269 (100) [M – OH]+, 229 (43) [M – t-Bu]+.
HRMS (FAB+): m/z calcd for C14H26O4Si: 286.1632; found:
286.1647.
(4aR,8R,8aS)-2,2-Di-tert-butyl-8-(vinyloxy)-4,4a,8,8a-tetrahy-
dropyrano[3,2-d][1,3,2]dioxasiline (9)
A soln of alcohol 8 (5.2 g, 18.2 mmol) and Hg(OAc)2 (1.74 g, 5.46
mmol) in ethyl vinyl ether (40 mL) was heated to 65 °C in a sealed
tube for 4 d, during which time Hg(OAc)2 (5.46 mmol) was added
every 24 h. Then, the organic solution was washed with H2O (3 × 35
mL) and brine (3 × 35 mL). The volatiles were removed under re-
duced pressure and the resulting residue was chromatographed on
silica gel (EtOAc–hexane, 2:98), which afforded recovered starting
material (0.51 g, 10%) and 9; yield: 4.55 g (80%).
23
White solid; mp 89 °C; [a]D –17.20 (c 2.09, CHCl3); Rf = 0.35
(EtOAc–hexane, 3:7).
Colorless liquid; [a]D23 –77.3 (c 0.042, MeOH); Rf = 0.63 (EtOAc–
hexane, 3:7).
IR (NaCl): 3384, 2960, 2935, 2859 cm–1.
1H NMR (CDCl3): d = 4.07 (dd, J = 10.12, 4.78 Hz, 1 H, H-4¢), 3.81
(t, J = 10.40 Hz, 1 H, H-4¢), 3.78–3.70 (m, 3 H, H-1, H-8a¢), 3.67–
3.60 (m, 1 H, H-6¢), 3.35 (td, J = 9.70, 4.90 Hz, 1 H, H-4a¢), 2.35 (s,
1 H, OH), 2.17–2.10 (m, 1 H, H-8¢), 1.75–1.68 (m, 3 H, H-2, H-7¢),
1.55–1.47 (m, 2 H, H-7¢, H-8¢), 1.05 [s, 9 H, C(CH3)3], 1.00 [s, 9 H,
C(CH3)3].
13C NMR (CDCl3): d = 77.70 (CH-6¢), 77.59 (CH-4a¢), 73.66 (CH-
8a¢), 67.05 (CH2-4¢), 60.98 (CH2-1), 37.63 (CH2-2), 32.41 (CH2-8¢),
31.08 (CH2-7¢), 27.47 [C(CH3)3], 27.09 [C(CH3)3], 22.64
[C(CH3)3], 19.93 [C(CH3)3].
IR (NaCl): 2893, 1639 cm–1.
1H NMR (CDCl3): d = 6.53 (dd, J = 14.00, 6.44 Hz, 1 H, H-1¢), 6.32
(dd, J = 6.03, 1.24 Hz, 1 H, H-6), 4.78 (dd, J = 6.03, 1.88 Hz, 1 H,
H-7), 4.43–4.36 (m, 2 H, H-8, H-2¢), 4.18 (dd, J = 10.30, 4.94 Hz, 1
H, H-4), 4.13 (dd, J = 10.30, 7.08 Hz, 1 H, H-8a), 4.03 (dd, J = 6.44,
1.35 Hz, 1 H, H-2¢), 3.98 (t, J = 10.30 Hz, 1 H, H-4), 3.90–3.81 (m,
1 H, H-4a), 1.06 [s, 9 H, C(CH3)3], 1.00 [s, 9 H, C(CH3)3].
13C NMR (CDCl3): d = 151.22 (C-1¢), 144.67 (C-6), 100.58 (C-7),
88.90 (C-2¢), 77.39 (C-8), 75.16 (C-8a), 72.49 (C-4a), 65.86 (C-4),
27.34 [C(CH3)3], 26.90 [C(CH3)3], 22.67 [C(CH3)3], 19.81
[C(CH3)3].
MS (FAB+): m/z (%) = 313 (4) [M + H]+, 312 (3) [M+], 311 (9) [M
– H]+, 270 (23), 269 (100) [M – OCHCH2]+, 268 (8), 255 (7) [M –
t-Bu]+, 213 (8), 201 (5).
HRMS (FAB+): m/z calcd for C16H29O4Si: 313.1757; found:
313.1790.
MS (FAB+): m/z (%) = 339 (12) [M + Na]+, 317 (100) [M + H]+.
HRMS (FAB+): m/z calcd for C16H33O4Si: 317.2143; found:
317.2143.
(4aR,6R,8aS)-2,2-Di-tert-butyl-6-(2-iodoethyl)hexahydropyra-
no[3,2-d][1,3,2]dioxasiline (11)
To a soln of 6 (9.64 g, 30.49 mmol) in THF (40 mL) were added
Ph3P (9.6 g, 36.59 mmol) and imidazole (6.23 g, 91.47 mmol). Once
the mixture became homogeneous, I2 (8.50 g, 33.54 mmol) was add-
ed at 0 °C. The solution was stirred at r.t. for 3 h and then sat. aq
NaHCO3 (15 mL) was added. The resulting mixture was extracted
with EtOAc (2 × 15 mL), and the combined organic phases were
washed with 10% aq Na2S2O4 (2 × 20 mL) and brine (2 × 20 mL),
then dried (Na2SO4). The solvents were removed under reduced
pressure. The residue was chromatographed on silica gel (EtOAc–
hexane, 2:98) to afford 11; yield: 10.39 g (80%).
2-{(4aR,6S,8aS)-2,2-Di-tert-butyl-4,4a,6,8a-tetrahydropyra-
no[3,2-d][1,3,2]dioxasilin-6-yl}acetaldehyde (10)
A soln of 9 (4.2 g, 13.46 mmol) in toluene (40 mL) was heated to
185 °C in a sealed tube for 5 h. Then, the solvent was evaporated
and the residue was chromatographed on silica gel (EtOAc–hexane,
2:98) to furnish the aldehyde 10; yield: 4 g (95%).
20
White solid; mp 68 °C; [a]D +31.4 (c 0.026, MeOH); Rf = 0.6
(EtOAc–hexane, 3:7).
Synthesis 2011, No. 20, 3301–3306 © Thieme Stuttgart · New York

3304
A. Zúñiga et al.
PAPER
Brown oil; [a]D22 +0.40 (c 6.36, CHCl3); Rf = 0.68 (EtOAc–hexane,
IR (NaCl): 3377, 2938, 2862, 2360, 2340 cm–1.
3:7).
1H NMR (CDCl3): d = 5.87–5.77 (m, 1 H, H-1¢), 5.23 (d,
Jtrans = 17.29 Hz, 1 H, H-2¢), 5.11 (d, Jcis = 10.40 Hz, 1 H, H-2¢),
3.88–3.70 (m, 4 H, OH, H-1¢¢, H-6), 3.58–3.49 (m, 1 H, H-3), 3.33–
3.20 (m, 2 H, OH, H-2), 2.14–2.07 (m, 1 H, H-4), 1.79–1.73 (m, 1
H, H-5), 1.57–1.40 (m, 2 H, H-4, H-5).
13C NMR (CDCl3): d = 138.20 (CH-1¢), 115.60 (CH2-2¢), 81.36
(CH-2), 77.98 (CH-6), 66.76 (CH-3), 63.05 (CH2-1¢¢), 32.14 (CH2-
4), 30.81 (CH2-5).
IR (NaCl): 2962, 2934, 2859, 2360, 2342 cm–1.
1H NMR (CDCl3): d = 4.08 (dd, J = 10.40, 5.06 Hz, 1 H, H-4), 3.79
(t, J = 10.12 Hz, 1 H, H-4), 3.71 (td, J = 9.42, 4.07 Hz, 1 H, H-8a),
3.50–3.43 (m, 1 H, H-6), 3.31 (td, J = 9.42, 4.92 Hz, 1 H, H-4a),
3.24 (t, J = 7.03 Hz, 2 H, H-2¢), 2.18–2.08 (m, 1 H, H-8), 2.00–1.89
(m, 2 H, H-1¢), 1.75–1.69 (m, 1 H, H-7), 1.59–1.36 (m, 2 H, H-7, H-
8), 1.05 [s, 9 H, C(CH3)3], 1.00 [s, 9 H, C(CH3)3].
13C NMR (CDCl3): d = 77.46 (CH-4a), 77.05 (CH-6), 73.84 (CH-
8a), 67.09 (CH2-4), 39.47 (CH2-1¢), 32.40 (CH2-8), 30.51 (CH2-7),
27.52 [C(CH3)3], 27.15 [C(CH3)3], 22.67 [C(CH3)3], 19.94
[C(CH3)3], 2.36 (CH2-2¢).
MS (FAB+): m/z (%) = 182 (8) [M + H + Na]+, 181 (100) [M + Na]+,
180 (4), 159 (3) [M + H]+.
HRMS (FAB+): m/z calcd for C8H14NaO3: 181.0835; found:
181.0837.
MS (FAB+): m/z (%) = 445 (19), 427 (100) [M + H]+, 391 (5), 301
(3).
tert-Butyl{[(2R,3S,6R)-3-(tert-butyldimethylsilyloxy)-6-vinyl-
tetrahydro-2H-pyran-2-yl]methoxy}dimethylsilane (13)
To a soln of diol 12 (1.32 g, 8.35 mmol) in THF (20 mL) were added
imidazole (3.4 g, 50.1 mmol), a catalytic amount of DMAP and
TBSCl (3.0 g, 20.04 mmol), and the mixture was stirred at r.t. for 15
h. The volatiles were evaporated, H2O (15 mL) was added and the
product was extracted with CH2Cl2 (4 × 20 mL). The organic phase
was dried (Na2SO4) and filtered, and the solvent was evaporated un-
der reduced pressure. The residue was purified by chromatography
on silica gel (EtOAc–hexane, 2:98) to afford 13; yield: 2.97 g
(92%).
HRMS (FAB+): m/z calcd for C16H32IO3Si: 427.1160; found:
427.1163.
(4aR,6R,8aS)-2,2-Di-tert-butyl-6-vinylhexahydropyrano[3,2-
d][1,3,2]dioxasiline (A)
To a soln of iodide 11 (10.39 g, 24.39 mmol) in THF (30 mL)
cooled to 0 °C was added t-BuOK (2.74 g, 24.39 mmol), and the
mixture was stirred at r.t. for 14 h. Then, t-BuOK (1.37 g, 12.2
mmol) was added at 0 °C and the mixture was stirred for a further 6
h at r.t. The reaction was quenched with sat. aq NH4Cl (20 mL) and
the mixture was extracted with CH2Cl2 (3 × 20 mL). The organic
phases were dried (Na2SO4) and filtered, and the solvent was evap-
orated under reduced pressure. The residue was chromatographed
on silica gel (CH2Cl2) to afford A [yield: 2.4 g (33%)] and a mixture
of alcohols B and C [yield: 4.09 g (56%)].
22
Colorless oil; [a]D +35.62 (c 11.10, CHCl3); Rf = 0.71 (EtOAc–
hexane, 3:7).
IR (NaCl): 2953, 2931, 2885, 2857, 2360, 2341 cm–1.
1H NMR (CDCl3): d = 5.91–5.81 (m, 1 H, H-1¢), 5.26 (d,
Jtrans = 17.15 Hz, 1 H, H-2¢), 5.07 (d, Jcis = 10.68 Hz, 1 H, H-2¢),
3.89–3.76 (m, 3 H, H-1¢¢, H-6), 3.58 (td, J = 9.70, 4.78 Hz, 1 H, H-
3), 3.20–3.15 (m, 1 H, H-2), 2.06–1.99 (m, 1 H, H-4), 1.76–1.70 (m,
1 H, H-5), 1.56–1.39 (m, 2 H, H-4, H-5), 0.91 [s, 9 H, SiC(CH3)3],
0.90 [s, 9 H, SiC(CH3)3], 0.09 [s, 6 H, Si(CH3)2], 0.08 [s, 6 H,
Si(CH3)2].
Compound A: White solid; mp 82 °C; [a]D23 –2.79 (c 4.71, CHCl3);
Rf = 0.53 (EtOAc–hexane, 1:9).
IR (NaCl): 2962, 2935, 2860, 2360, 2341 cm–1.
1H NMR (CDCl3): d = 5.85–5.75 (m, 1 H, H-1¢), 5.23 (d,
Jtrans = 17.43 Hz, 1 H, H-2¢), 5.11 (d, Jcis = 10.54 Hz, 1 H, H-2¢),
4.12 (dd, J = 10.40, 4.92 Hz, 1 H, H-4), 3.92–3.82 (m, 2 H, H-4, H-
6), 3.79–3.72 (m, 1 H, H-8a), 3.37 (td, J = 9.42, 5.06 Hz, 1 H, H-
4a), 2.19–2.13 (m, 1 H, H-8), 1.82–1.76 (m, 1 H, H-7), 1.58–1.48
(m, 2 H, H-7, H-8), 1.05 [s, 9 H, C(CH3)3], 1.00 [s, 9 H, C(CH3)3].
13C NMR (CDCl3): d = 138.04 (CH-1¢), 115.54 (CH2-2¢), 78.14
(CH-4a), 77.44 (CH-6), 73.60 (CH-8a), 67.13 (CH2-4), 32.45 (CH2-
8), 30.95 (CH2-7), 27.51 [C(CH3)3], 27.14 [C(CH3)3], 22.65
[C(CH3)3], 19.95 [C(CH3)3].
13C NMR (CDCl3): d = 139.02 (CH-1¢), 114.22 (CH2-2¢), 83.00
(CH-2), 77.46 (CH-6), 66.42 (CH-3), 63.21 (CH2-1¢¢), 33.28 (CH2-
4), 31.20 (CH2-5), 25.99 [SiC(CH3)3], 25.79 [SiC(CH3)3], 18.49
[SiC(CH3)3], 17.95 [SiC(CH3)3], –4.25, –4.91, –5.16
[2 × Si(CH3)2].
MS (FAB+): m/z (%) = 410 (18) [M + H + Na]+, 409 (100) [M +
Na]+, 387 (92) [M + H]+, 255 (9).
HRMS (FAB+): m/z calcd for C20H43O3Si2: 387.2745; found:
387.2742.
MS (FAB+): m/z (%) = 299 (100) [M + H]+, 282 (6).
HRMS (FAB+): m/z calcd for C16H31O3Si: 299.2037; found:
299.2035.
[(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-vinyltetrahydro-
2H-pyran-2-yl]methanol (14)
To a soln of 13 (2.3 g, 5.95 mmol) in MeOH (15 mL) was added a
catalytic amount of PPTS at 0 °C, and the mixture was stirred at
0 °C for 15 h. Then, a catalytic amount of PPTS was again added
and stirring was continued for an additional 7 h at r.t. The reaction
was quenched with Et3N (1 mL), the volatiles were evaporated and
the residue was chromatographed on silica gel (2% EtOAc–hexane
→ 10% EtOAc–hexane) to provide the alcohol 14; yield: 1.36 g
(84%).
Colorless oil; [a]D22 +51.58 (c 12.36, CHCl3); Rf = 0.5 (EtOAc–hex-
ane, 3:7).
IR (NaCl): 3482, 2952, 2931, 2857, 2360, 2341 cm–1.
(2R,3S,6R)-2-(Hydroxymethyl)-6-vinyltetrahydro-2H-pyran-3-
ol (12)
To a soln of compound A (1.65 g, 5.53 mmol) in THF (10 mL) was
added 1.0 M TBAF in THF (6.64 mL, 6.64 mmol) at r.t., and the
mixture was stirred at r.t. for 48 h. Then, the solvent was evaporated
and the residue was chromatographed on silica gel (20% EtOAc–
hexane → 50% EtOAc–hexane → 100% EtOAc) to provide the diol
12; yield: 0.726 mg (83%).
To a soln of the mixture of alcohols B and C (4.09 g, 13.7 mmol) in
THF (40 mL) was added 1.0 M TBAF in THF (16.44 mL, 16.44
mmol) at r.t., and the mixture was stirred at r.t for 48 h. Then, the
solvent was evaporated and the residue was chromatographed on
silica gel (20% EtOAc–hexane → 50% EtOAc–hexane → 100%
EtOAc) to afford diol 12; yield: 1.92 g (88%).
1H NMR (CDCl3): d = 5.89–5.79 (m, 1 H, H-1¢), 5.25 (dd,
Jtrans = 17.15 Hz, Jgem = 1.12 Hz, 1 H, H-2¢), 5.12 (dd, Jcis = 10.68
Hz, Jgem = 1.12 Hz, 1 H, H-2¢), 3.91–3.81 (m, 2 H, H-1¢¢), 3.68–3.61
(m, 1 H, H-6), 3.55–3.47 (m, 1 H, H-3), 3.30–3.24 (m, 1 H, H-2),
Colorless oil; [a]D22 +25.32 (c 3.18, CHCl3); Rf = 0.09 (EtOAc).
Synthesis 2011, No. 20, 3301–3306 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of Aspergillide A from Tri-O-acetyl-D-glucal
3305
2.18 (s, 1 H, OH), 2.07–2.00 (m, 1 H, H-4), 1.77 (d, J = 12.79 Hz,
1 H, H-5), 1.59–1.42 (m, 2 H, H-4, H-5), 0.89 [s, 9 H, SiC(CH3)3],
0.08 [s, 6 H, Si(CH3)2].
13C NMR (CDCl3): d = 138.37 (CH-1¢), 115.18 (CH2-2¢), 81.95
(CH-2), 77.74 (CH-6), 67.53 (CH-3), 63.00 (CH2-1¢¢), 33.04 (CH2-
4), 30.92 (CH2-5), 25.73 [SiC(CH3)3], 17.89 [SiC(CH3)3], –4.16, –
4.94 [Si(CH3)2].
(m, 1 H, H-4), 1.81–1.75 (m, 1 H, H-5), 1.59–1.45 (m, 2 H, H-4, H-
5), 0.89 [s, 9 H, SiC(CH3)3], 0.11, 0.10 [2 × s, 2 × 3 H, Si(CH3)2].
13C NMR (CDCl3): d = 137.67 (CH-1¢), 117.48 (CN), 115.37 (CH2-
2¢), 78.06 (CH-6), 77.41 (CH-2), 69.83 (CH-3), 32.79 (CH2-4),
30.70 (CH2-5), 25.70 [SiC(CH3)3], 21.46 (CH2-1¢¢), 17.82
[SiC(CH3)3], –3.97, –4.87 [Si(CH3)2].
MS (FAB+): m/z (%) = 305 (15) [M + H + Na]+, 304 (100) [M +
MS (FAB+): m/z (%) = 311 (28), 295 (100) [M + Na]+, 273 (43) [M
Na]+, 299 (11), 282 (51) [M + H]+.
+ H]+, 271 (38) [M – H]+.
HRMS (FAB+): m/z calcd for C15H28NO2Si: 282.1884; found:
282.1885.
HRMS (FAB+): m/z calcd for C14H29O3Si: 273.1880; found:
273.1881.
2-[(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-vinyltetrahy-
dro-2H-pyran-2-yl]acetic Acid (4)
[(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-vinyltetrahydro-
2H-pyran-2-yl]methyl 4-Methylbenzenesulfonate (15)
To a soln of nitrile 16 (0.103 g, 0.366 mmol) in CH2Cl2 (4 mL),
cooled to –78 °C, was added dropwise 1.0 M DIBAL-H in hexane
(0.55 mL, 0.55 mmol), and the mixture was stirred for 1 h. Then, the
temperature was allowed to warm to –40 °C and stirring was con-
tinued for 4 h. The reaction was quenched with sat. aq NH4Cl (5
mL) and the mixture was extracted with CH2Cl2 (5 × 4 mL). The or-
ganic phases were dried (Na2SO4) and the solvent was evaporated
under reduced pressure. The residue (0.11 mg, 0.38 mmol) was dis-
solved in a mixture of MeCN–H2O (1:1, 6 mL), and TEMPO (0.012
g, 0.075 mmol) and BAIB (0.266 g, 0.827 mmol) were added; the
mixture was stirred at r.t. for 7 h. The reaction was quenched with
1.0 M aq Na2S2O3 (1 mL), then the mixture was diluted with CH2Cl2
(10 mL) and filtered through Celite®. The solvents were evaporated
and the resulting solid was chromatographed on silica gel (2%
EtOAc–hexane → 20% EtOAc–hexane) to afford the desired acid
4; yield: 0.067 g (61%, two steps).
To a soln of alcohol 14 (1.11 g, 4.1 mmol) in CH2Cl2 (8 mL) at 0 °C
were added dropwise pyridine (2 mL) and p-TsCl (1.56 g, 8.2
mmol). The mixture was stirred at r.t. for 20 h and then H2O (5 mL)
was added. The aqueous phase was extracted with EtOAc (2 × 10
mL). The combined organic phases were washed with 10% aq
Cu2SO4 (2 × 10 mL), H2O (10 mL) and brine (10 mL), then dried
(Na2SO4). The solvent was evaporated under reduced pressure. The
residue was purified by chromatography on silica gel (EtOAc–hex-
ane, 1:99) to afford 15; yield: 1.65 g (95%).
Colorless oil; [a]D21 +43.94 (c 1.98, CHCl3); Rf = 0.49 (CH2Cl2).
IR (NaCl): 2953, 2930, 2857, 2360, 2341 cm–1.
1H NMR (CDCl3): d = 7.76 (d, J = 8.04 Hz, 2 H, o-HTs), 7.28 (d,
J = 8.15 Hz, 2 H, m-HTs), 5.76–5.66 (m, 1 H, H-1¢), 5.12 (dd,
Jtrans = 17.29 Hz, Jgem = 1.12 Hz, 1 H, H-2¢), 5.01 (dd, Jcis = 10.82
Hz, Jgem = 1.12 Hz, 1 H, H-2¢), 4.22 (d, J = 10.26 Hz, 1 H, H-1¢¢),
4.14–4.08 (m, 1 H, H-1¢¢), 3.77–3.70 (m, 1 H, H-6), 3.43 (td,
J = 9.56, 4.64 Hz, 1 H, H-3), 3.33–3.28 (m, 1 H, H-2), 2.40 (s, 3 H,
ArCH3), 2.03–1.96 (m, 1 H, H-4), 1.69 (dd, J = 12.93, 2.67 Hz, 1 H,
H-5), 1.52–1.30 (m, 2 H, H-4, H-5), 0.81 [s, 9 H, SiC(CH3)3], 0.03,
0.01 [2 × s, 2 × 3 H, Si(CH3)2].
13C NMR (CDCl3): d = 144.50 (CTs), 138.01 (CH-1¢), 133.17 (CTs),
129.69 (m-CHTs), 127.98 (o-CHTs), 114.65 (CH2-2¢), 79.69 (CH-2),
77.44 (CH-6), 70.06 (CH2-1¢¢), 66.65 (CH-3), 33.05 (CH2-4), 30.61
(CH2-5), 25.68 [SiC(CH3)3], 21.53 (ArCH3), 17.75 [SiC(CH3)3], –
4.03, –5.03 [Si(CH3)2].
Colorless oil; [a]D21 +20.84 (c 3.32, CHCl3); Rf = 0.52 (EtOAc–hex-
ane, 3:7).
IR (NaCl): 2930, 2858, 1715 cm–1.
1H NMR (CDCl3): d = 5.87–5.77 (m, 1 H, H-1¢), 5.24 (dd,
Jtrans = 17.43 Hz, Jgem = 1.41 Hz, 1 H, H-2¢), 5.11 (dd, Jcis = 10.96
Hz, Jgem = 1.41 Hz, 1 H, H-2¢), 3.93–3.85 (m, 1 H, H-6), 3.65 (td,
J = 9.14, 3.09 Hz, 1 H, H-2), 3.41–3.32 (m, 1 H, H-3), 2.87 (dd,
J = 15.74, 3.23 Hz, 1 H, H-1¢¢), 2.45 (dd, J = 15.60, 8.85 Hz, 1 H,
H-1¢¢), 2.08–2.00 (m, 1 H, H-4), 1.82–1.75 (m, 1 H, H-5), 1.63–1.43
(m, 2 H, H-4, H-5), 0.89 [s, 9 H, SiC(CH3)3], 0.08 [s, 6 H, Si(CH3)2].
13C NMR (CDCl3): d = 176.84 (CO2H), 137.95 (CH-1¢), 115.25
(CH2-2¢), 78.80 (CH-2), 77.85 (CH-6), 70.57 (CH-3), 37.91 (CH2-
1¢¢), 33.09 (CH2-4), 30.88 (CH2-5), 25.73 [SiC(CH3)3], 17.88
[SiC(CH3)3], –4.01, –4.79 [Si(CH3)2].
MS (FAB+): m/z (%) = 450 (18) [M + H + Na]+, 449 (92) [M + Na]+,
444 (25), 428 (19) [M + 2 H]+, 427 (100) [M + H]+.
HRMS (FAB+): m/z calcd for C21H35O5SSi: 427.1969; found:
427.1972.
MS (FAB+): m/z (%) = 339 (4), 324 (15) [M + H + Na]+, 323 (100)
[M + Na]+, 301 (4) [M + H]+, 199 (5).
2-[(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-vinyltetrahy-
dro-2H-pyran-2-yl]acetonitrile (16)
HRMS (FAB+): m/z calcd for C15H28NaO4Si: 323.1649; found:
To a soln of tosylate 15 (0.405 g, 0.95 mmol) in DMSO (8 mL) was
added NaCN (0.145 g, 2.85 mmol), and the mixture was stirred at
50 °C for 7 h. The reaction was quenched with H2O (8 mL) and the
mixture was extracted with EtOAc (2 × 10 mL). The organic layers
were washed with H2O (2 × 10 mL) and brine (2 × 10 mL), then
dried (Na2SO4). The solvent was evaporated under reduced pres-
sure. The residue was chromatographed on silica gel (100% hexane
→ 2% EtOAc–hexane) to furnish the nitrile 16; yield: 0.176 g
(66%).
323.1648.
Acknowledgment
This work was supported financially by the Spanish Ministry of
Foreign Affairs and Cooperation (PCI A/030052/10) and the Xunta
de Galicia (INCITE845B-2010/020, INCITE08PXIB314255PR).
The work of the NMR and MS divisions of the research support ser-
vices of the University of Vigo (CACTI) is also gratefully acknow-
ledged. M.P. thanks the Xunta de Galicia for an Angeles Alvariño
contract.
Colorless oil; [a]D21 +42.26 (c 1.62, CHCl3); Rf = 0.54 (EtOAc–hex-
ane, 3:7).
IR (NaCl): 2942, 2858, 2360, 2251 cm–1.
1H NMR (CDCl3): d = 5.88–5.78 (m, 1 H, H-1¢), 5.30–5.24 (m, 1 H,
H-2¢), 5.14–5.09 (m, 1 H, H-2¢), 3.91–3.85 (m, 1 H, H-6), 3.50–3.42
(m, 1 H, H-3), 3.41–3.35 (m, 1 H, H-2), 2.74 (dd, J = 16.87, 3.65
Hz, 1 H, H-1¢¢), 2.62 (dd, J = 16.73, 5.76 Hz, 1 H, H-1¢¢), 2.10–2.03
References
(1) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.;
Kusumi, T. Org. Lett. 2008, 10, 225.
(2) Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761.
Synthesis 2011, No. 20, 3301–3306 © Thieme Stuttgart · New York

3306
A. Zúñiga et al.
PAPER
(3) Ookura, R.; Kito, K.; Saito, Y.; Kusumi, T.; Ooi, T. Chem.
Lett. 2009, 38, 384.
(6) (a) Panarese, J. D.; Waters, S. P. Org. Lett. 2009, 11, 5086.
(b) Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron
Lett. 2011, 52, 1372.
(4) (a) Sabitha, G.; Reddy, D. V.; Rao, A. S.; Yadav, J. S.
Tetrahedron Lett. 2010, 51, 4195. (b) Fuwa, H.;
Yamaguchi, H.; Sasaki, M. Tetrahedron 2010, 66, 7492.
(c) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010,
12, 1848. (d) Diaz-Oltra, S.; Angulo-Pachon, C. A.; Murga,
J.; Carda, M.; Marco, J. A. J. Org. Chem. 2010, 75, 1775.
(e) Nagasawa, T.; Kuwahara, S. Tetrahedron Lett. 2010, 51,
875. (f) Kanematsu, M.; Yoshida, M.; Shishido, K. Angew.
Chem. Int. Ed. 2011, 50, 2618. (g) Izuchi, Y.; Kanomata,
N.; Koshino, H.; Hongo, Y.; Nakata, T.; Takahashi, S.
Tetrahedron: Asymmetry 2011, 22, 246. (h) Nagasawa, T.;
Nukada, T.; Kuwahara, S. Tetrahedron 2011, 67, 2882.
(i) Diaz-Oltra, S.; Angulo-Pachon, C. A.; Murga, J.;
Falomir, E.; Carda, M.; Marco, J. A. Chem. Eur. J. 2011, 17,
675.
(5) (a) Liu, J.; Xu, K.; He, J.; Zhang, L.; Pan, X.; She, X. J. Org.
Chem. 2009, 74, 5063. (b) Nagasawa, T.; Kuwahara, S.
Biosci., Biotechnol., Biochem. 2009, 73, 1893. (c) Diaz-
Oltra, S.; Angulo-Pachon, C. A.; Kneeteman, M. N.; Murga,
J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2009, 50,
3783. (d) Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009,
50, 189. (e) Mueller Hendrix, A. J.; Jennings, M. P.
Tetrahedron Lett. 2010, 51, 4260.
(7) Gonzalo, P.; Pérez, M.; Gándara, Z.; Gómez, G.; Fall, Y.
Tetrahedron Lett. 2009, 50, 5285.
(8) (a) Mori, Y.; Hayashi, H. J. Org. Chem. 2001, 66, 8666.
(b) Hoberg, J. O. Carbohydr. Res. 1997, 300, 365.
(9) (a) Chen, C.-L.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11,
409. (b) Wallace, G. A.; Scott, R. W.; Heathcock, C. H.
J. Org. Chem. 2000, 65, 4145. (c) Ireland, R. E.; Wuts, P. G.
M.; Ernst, B. J. Am. Chem. Soc. 1981, 103, 3205. For
reviews related to the Claisen rearrangement in natural
product synthesis, see: (d) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 3003. (e) Hewlett, N. M.; Hupp, C. D.;
Tepe, J. J. Synthesis 2009, 2825. (f) Rosenberg, S.; Leino,
R. Synthesis 2009, 2651. (g) Marcelli, T.; Hiemstra, H.
Synthesis 2010, 1229. (h) Dömling, A.; Huang, Y. Synthesis
2010, 2859.
(10) Pérez-Sestelo, J.; Mascareñas, J. L.; Castedo, L.; Mouriño,
A. J. Org. Chem. 1993, 58, 118.
(11) Yu, M.; Lynch, V.; Pagenkopf, B. L. Org. Lett. 2001, 3,
2563.
Synthesis 2011, No. 20, 3301–3306 © Thieme Stuttgart · New York