A concise synthesis of (±)-pseudodeflectusin, an antitumor isochroman derivative isolated from Aspergillus sp.

Article abstract of DOI:10.1016/j.tet.2007.07.020

A novel and concise synthesis of (±)-pseudodeflectusin (1), an antitumor isochroman derivative isolated from the culture broth of Aspergillus pseudodeflectus, was accomplished by starting from 4-(tert-butyldimethylsilyloxy)-1-pentyne (3) and diethyl 3-oxo

Full text of DOI:10.1016/j.tet.2007.07.020

Tetrahedron 63 (2007) 9333–9337
A concise synthesis of ( )-pseudodeflectusin, an antitumor
isochroman derivative isolated from Aspergillus sp.
Makiko Tobe,a Takuya Tashiro,b Mitsuru Sasakia and Hirosato Takikawaa,
*
aDepartment of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai 1-1, Nada-ku,
Kobe 657-8501, Japan
bGlycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology,
Hirosawa 2-1, Wako, Saitama 351-0198, Japan
Received 21 June 2007; revised 9 July 2007; accepted 9 July 2007
Available online 13 July 2007
Abstract—A novel and concise synthesis of (ꢀ)-pseudodeflectusin (1), an antitumor isochroman derivative isolated from the culture broth of
Aspergillus pseudodeflectus, was accomplished by starting from 4-(tert-butyldimethylsilyloxy)-1-pentyne (3) and diethyl 3-oxopentanedicarb-
oxylate (5).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
were in good agreement with each other. It meant that pseu-
dodeflectusin and aspergione B should be the same com-
pound, and either of the proposed structures might be in
error. Kobayashi and his co-workers have clarified this prob-
lem by their first syntheses of (+)-1 and (ꢀ)-2, and proven
that 1 is correct.3 They were also able to determine the
absolute stereochemistry of the naturally occurring 1 as
shown in Figure 1.
In 2004, Mizushina and his co-workers isolated pseudo-
deflectusin from the culture broth of Aspergillus pseudo-
deflectus.1 Pseudodeflectusin is an isochroman derivative
exhibiting cytotoxicity against several human cancer cell
lines such as HeLa-S3, HL-60, etc., and its LD50 value for
HL-60 cells was reported to be 39 mM. The originally pro-
posed structure for pseudodeflectusin (1, in Fig. 1) was
just a planar structure, and the absolute configurations of
two stereogenic centers were not determined. On the other
hand, Proksch and his co-workers reported the isolation of
aspergione B from Aspergillus versicolor in 2003.2 The
proposed structure for aspergione B (2) was identical with
1 concerning isochromanol framework but different from 1
in the northwestern portion. However, both the NMR spec-
tral data reported for pseudodeflectusin and aspergione B
We became interested in the biological activities and the
unique structure of 1 and undertook a project to synthesize
it. Although the absolute configuration of the natural 1 was
unknown at the beginning, the first enantioselective synthe-
sis was reported last year as mentioned above.3 Therefore,
we turned to focus on the development of a new and concise
synthetic route to (ꢀ)-1. Herein, we report a short-step and
straightforward synthesis of (ꢀ)-pseudodeflectusin (1) in
detail.
1
2
OH
OH
9
O
O
O
OH
2. Results and discussion
3
O
O
8
7
O
O
O
O
Our basic strategy is shown in Scheme 1. One of the crucial
points in the synthesis of 1 should be the construction of
the 2-isopropylidenefuran-3-one portion. For this point, we
assigned the intermediate A as an appropriate precursor,
because an isopropylidene moiety was preparable from a
carboxylate group by nucleophilic dimethylation followed
by dehydration. For the construction of the furan-3-one
framework of A, we envisioned adopting Dieckmann con-
densation,4 which was also employed in Kobayashi’s synthe-
sis.3 In our strategy, the envisaged intermediates A and B
4
6
5
(+)-1 (natural)3
Proposed structure for
Proposed structure
pseudodeflectusin (1)1
for aspergione B (2)2
Figure 1. Structure of pseudodeflectusin.
Keywords: Isochroman; Antitumor; Aspergillus pseudodeflectus; Cyclocon-
densation.
* Corresponding author. Tel./fax: +81 78 803 5958; e-mail: takikawa@
kobe-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.020

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M. Tobe et al. / Tetrahedron 63 (2007) 9333–9337
prepared an aldehyde 46c (¼D) from the starting alkyne 3
EtO2C
O
according to the conventional manner. The next key cyclo-
condensation of 4 with 5 (¼E) was performed based on the
reported procedure.8 Our first trial of this cyclocondensation
was not so successful under the originally reported condi-
tions: NaH, THF, room temperature, affording the cycload-
duct 6 in 36% yield. Although the use of K2CO3 as a base
made the yield worse (19%), the improved yield (54%)
was observed by changing a base to Cs2CO3. Very recently,
we have realized that the identical cyclocondensation was
reported by McClay and his co-workers independently,6c,9
but our modified method was more efficient than theirs in
yield.10 The cycloadduct 6 was then converted to the corre-
sponding lactone 7 (83%; ¼C) by treatment with p-TsOH.
We then intended to obtain 7 from 4 in one-pot process.
This attempt was achieved by the cyclocondensation of 4
with 5 in the presence of Cs2CO3 and the following acidic
work-up to give the desired 7 in 43% yield.
OH
+ 2×Me
- H2O
OR
O
O
Dieckmann
O
O
O
A
1
OH OR
OH
O
O
Chemoselective
Reduction
RO2C
RO2C
O
B
C
O
OHC
OR
Cyclocondensation
RO2C
CO2R
+
D
E
(R = H, alkyl or protecting group)
Scheme 1. Synthetic plan for (ꢀ)-1.
The next step was the crucial chemoselective reduction of
the lactone functionality in 7 leaving the ester intact. This
chemoselective reduction was successfully performed by
treatment with DIBAL in toluene at ꢁ78 ꢂC to furnish the
desired lactol 8 (¼B) in 15–67% yield.11 The lactol 8 was
then treated with p-TsOH in MeOH to give the correspond-
ing methyl acetal 9 (91%). However, this reduction was
somewhat problematic, and the isolated yield fluctuated con-
siderably from case to case. Because this fluctuation might
depend mainly on work-up and/or isolation processes but
not on reduction itself, we endeavored to obtain 9 directly
from 7 by skipping the isolation of 8. As a result, the desired
9 was successfully obtained in 58% yield (based on the
recovered SM) by quenching with MeOH–AcOH. On the
were not lactones but acetals. That was the key point of our
synthetic plan. Because we were worried that reduction of
the lactone to the corresponding lactol in the later stage
might be problematic, we ventured on the chemoselective
reduction of C to B. In other words, another crucial point
was this chemoselective reduction. For the synthesis of C,
we were purposed to establish a new route to C based on the
cyclocondensation of D with E, although C has already re-
ported as not only racemic5 but also optically active3,6 forms.
Scheme 2 shows our synthetic route to (ꢀ)-1. Our starting
material was the known alkyne 3, which was easily prepared
from commercially available 4-pentyn-2-ol.7 First, we
O
OH
EtO2C
CO2Et
OH
O
R
OTBS
CO2Et
OTBS
EtO2C
EtO2C
5 (= E)
O
b, c or d
3 R = H
a
4 R = CHO (= D)
7 (= C)
6
OH OR
OH O
EtO2C
1
O
HO
O
+
e, f or g
3
8 (R = H)
9 (R = Me)
10
(= B)
EtO2C
HO
EtO2C
EtO2C
O
OMe
OMe
O
O
h
i
j
O
12 (= A)
11
EtO2C
MOMO
HO
MOMO
OMe
O
O
OMe
O
OH
O
O
k
l
O
O
( )-1
13
14
Scheme 2. Synthesis of (ꢀ)-1. Reagents and conditions: (a) n-BuLi, THF, DMF (91%); (b) Cs2CO3, THF (54% for 6); (c) p-TsOH, EtOH (83% for 6/7);
(d) Cs2CO3, THF, then dil HCl (43% for 4/7); (e) DIBAL, toluene, ꢁ78 ꢂC (15–67% for 7/8); (f) p-TsOH, MeOH (91% for 8/9); (g) DIBAL, toluene,
ꢁ78 ꢂC, then MeOH, AcOH (58% for 7/9); (h) BrCH2CO2Et, K2CO3, acetone, reflux (90%); (i) t-BuOK, THF (93%); (j) MOMCl, DBU, CH2Cl2; (k) MeLi,
THF; (l) p-TsOH, aq THF (43% based on 12 in 3 steps).

M. Tobe et al. / Tetrahedron 63 (2007) 9333–9337
9335
other hand, the undesired product 10 was also yielded (19%).
Both 8 and 9 were isolated as a single diastereomer, respec-
tively, in these reactions. Even though their relative configu-
rations between OH or OMe at C-1 and Me at C-3 were not
carefully examined, these were tentatively assigned as trans
based on the spectral similarity to the reported 1.12
a JEOL JMS-SX102A or a HITACHI M-80B spectrometer.
Column chromatography was carried out on Kanto Chemi-
cal Co., Inc. Silica Gel 60N (spherical, neutral, 63–
210 mm). TLC analyses were performed on Merck silica
gel plates 60 F254
.
4.1.1. 5-tert-Butyldimethylsilyloxy-2-hexynal (4). To a
solution of 3 (228 mg, 1.15 mmol) in dry THF (10 mL), n-
BuLi (2.66 M in hexane, 0.52 mL, 1.4 mmol) was added at
ꢁ78 ꢂC under Ar. After stirring for 30 min at 0 ꢂC, DMF
(0.13 mL, 1.7 mmol) was added dropwise. After stirring
for 10 min, the reaction mixture was quenched with satd
aq NH4Cl and extracted with EtOAc. The organic layer
was washed with brine, dried with MgSO4, and concentrated
under reduced pressure. The residue was purified by silica
gel chromatography to give 4 (237 mg, 91%) as a colorless
For the construction of the benzofuranone portion of 12
(¼A) employing Dieckmann condensation,4 the phenolic
hydroxyl group of 9 was etherified with BrCH2CO2Et in
the presence of K2CO3 to give 11 (90%). The diester 11
was subjected to Dieckmann condensation by treatment
with t-BuOK in THF to afford the adduct 12 (93%). It should
be mentioned that the keto–enol equilibrium was observed
as a matter of course, and the enol form was predominant.
The next and remaining subject was the construction of
the isopropylidenefuranone framework. In other words, the
final crucial step was conversion of the ethoxycarbonyl
group of 12 into the isopropylidene group. Our initial at-
tempts to convert 12 to 1 by treatment with excess MeLi
and the following acidic work-up did not work.13 Thus, we
turned to prepare the corresponding MOM enol ether 13.14
The MOM ether 13, prepared by treatment with MOMCl
and DBU in CH2Cl2, was exposed to excess MeLi to give
the tertiary alcohol 14. The resulting unstable alcohol 14
was finally treated with p-TsOH in aq THF to give (ꢀ)-1
(43% based on 12 in 3 steps). The various spectral data of
synthetic (ꢀ)-1 were in good accord with those of the re-
ported.1,3 The overall yield was 8.2% in 8 steps based on
the starting alkyne 3.
1
oil: H NMR d 0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H),
1.25 (d, J¼6.0 Hz, 3H), 2.48 (dd, J¼17.1, 6.3 Hz, 1H),
2.56 (dd, J¼17.1, 6.0 Hz, 1H), 4.04 (m, 1H), 9.18 (br s, 1H).
4.1.2. Diethyl 4-(2-tert-butyldimethylsilyloxy)propyl-2-
hydroxyisophthalate (6). To a stirred and ice-cooled
mixture of 5 (10.0 g, 49.5 mmol) and Cs2CO3 (18.2 g,
55.9 mmol) in dry THF (110 mL), a solution of 4 (8.26 g,
36.5 mmol) in dry THF (20 mL) was added dropwise under
Ar. After stirring at room temperature for 2 days, the reaction
mixture was quenched with satd aq NH4Cl and extracted
with hexane. The organic layer was washed with water
and brine, dried with MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give 6 (8.07 g, 54%) as a pale yellow
1
oil: H NMR d ꢁ0.21 (s, 3H), ꢁ0.08 (s, 3H), 0.83 (s, 9H),
3. Conclusion
1.15 (d, J¼6.0 Hz, 3H), 1.39 (t, J¼7.2 Hz, 3H), 1.41 (t,
J¼7.2 Hz, 3H), 2.72 (d, J¼6.3 Hz, 2H), 4.00–4.13 (m,
1H), 4.35–4.48 (m, 4H), 6.79 (d, J¼8.1 Hz, 1H), 7.77 (d,
J¼8.1 Hz, 1H), 11.20 (s, 1H); 13C NMR d ꢁ5.1, ꢁ4.9,
14.1, 14.2, 18.0, 24.1, 25.8, 44.1, 61.4, 61.6, 68.9, 110.9,
122.2, 123.8, 130.1, 145.1, 158.7, 167.3, 169.8. This was
immediately used for the next step.
In conclusion, a novel and concise synthesis of (ꢀ)-pseudo-
deflectusin (1) was completed in 8 steps from the known
alkyne 3 with an overall yield of 8.2%. An alkynal–acetone
dicarboxylate cyclocondensation, a chemoselective reduc-
tion, and an isopropylidenation have been employed as the
key steps. The total number of steps and the overall yield
of our synthesis are shorter and better than the reported
synthesis (11 steps; 2.0%).
4.1.3. 7-Ethoxycarbonyl-8-hydroxy-3-methyl-1-isochro-
manone (7). (a) Conversion of 6 to 7: a solution of 6
(8.07 g, 19.7 mmol) and p-TsOH$H2O (0.1 g, 0.5 mmol)
in EtOH (150 mL) was stirred at room temperature over-
night. After removal of the solvent under reduced pressure,
the residue was diluted with water and extracted with
EtOAc. The organic layer was washed with satd aq NaHCO3
and brine, dried with MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica gel chro-
matography to give 7 (4.09 g, 83%) as a pale yellow solid:
mp 96–98 ꢂC; IR (Nujol) 1710 (s, C]O), 1665 (s, C]O),
It is also obvious that the enantiospecific synthesis of 1 is
possible according to our developed synthetic route, because
not only the starting material (¼3) but also the key inter-
mediate C are known to be in optically active form.6,15
4. Experimental
4.1. General
1
1610 (m, C]C) cmꢁ1; H NMR d 1.39 (t, J¼7.2 Hz, 3H),
1.52 (d, J¼6.3 Hz, 3H), 2.95 (d, J¼7.2 Hz, 2H), 4.39 (q,
J¼7.2 Hz, 2H), 4.69 (m, 1H), 6.73 (d, J¼7.8 Hz, 1H), 8.01
(d, J¼7.8 Hz, 1H), 12.13 (s, 1H); 13C NMR d 14.2, 20.6,
35.1, 61.3, 75.3, 110.2, 117.0, 117.4, 137.6, 145.2, 162.6,
166.1, 167.7; HRMS (EI) m/z calcd for C13H14O5:
250.0890, found: 250.0833.
Melting points were measured with YANAKO MP-S9
micro-melting point apparatus. IR spectra were recorded
with a Shimadzu IR-408 spectrophotometer. 1H NMR spectra
were recorded at 300 MHz on a JEOL JNM-AL300 spec-
trometer. The peak for CHCl3 in CDCl3 (d 7.26) was used
as the internal standard. Chemical shifts are reported in parts
per million on the d scale and J-values are given in hertz. 13C
NMR spectra were recorded at 75 MHz on a JEOL JNM-
AL300 spectrometer. The peak for CDCl3 (d 77.0) was used
as the internal standard. Mass spectra were measured with
(b) Conversion of 4 to 7: to a stirred and ice-cooled mixture
of 5 (265 mg, 1.31 mmol) and Cs2CO3 (750 mg, 2.30 mmol)
in dry THF (5 mL), a solution of 4 (237 mg, 1.05 mmol) in
dry THF (5 mL) was added dropwise under Ar. After stirring

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M. Tobe et al. / Tetrahedron 63 (2007) 9333–9337
at room temperature overnight, the reaction mixture was
quenched with 1 M HCl (20 mL). This mixture was stirred
for 2 days and extracted with ether. The organic layer was
washed with water and brine, dried with MgSO4, and con-
centrated under reduced pressure. The residue was purified
by silica gel chromatography to give 7 (112 mg, 43%).
4.1.6. Ethyl (1S*,3R*)-8-(ethoxycarbonyl)methoxy-1-
methoxy-3-methylisochroman-7-carboxylate (11). To a
solution of 9 (293 mg, 1.10 mmol) in acetone (50 mL),
K2CO3 (182 mg, 1.32 mmol) and BrCH2CO2Et (220 mg,
1.32 mmol) were added. After stirring under reflux for 2
days, the reaction mixture was concentrated under reduced
pressure, diluted with water and extracted with EtOAc.
The organic layer was washed with brine, dried with
MgSO4, and concentrated under reduced pressure. The resi-
due was purified by silica gel chromatography to give 11
(348 mg, 90%) as a white solid: mp 45–47 ꢂC; IR (Nujol)
1720 (s, C]O), 1605 (m, C]C) cmꢁ1; 1H NMR d 1.30 (t,
J¼7.2 Hz, 3H), 1.33 (t, J¼7.2 Hz, 3H), 1.33 (d, J¼6.0 Hz,
3H), 2.61 (dd, J¼11.1, 17.1 Hz, 1H), 2.70 (dd, J¼4.2,
17.1 Hz, 1H), 3.46 (s, 3H), 4.18–4.35 (m, 1H), 4.28 (q,
J¼7.2 Hz, 2H), 4.31 (dq, J¼1.8, 7.2 Hz, 2H), 4.61 (d,
J¼15.0 Hz, 1H), 4.74 (d, J¼15.0 Hz, 1H), 5.78 (s, 1H),
6.92 (d, J¼8.1 Hz, 1H), 7.77 (d, J¼8.1 Hz, 1H); 13C NMR
d 14.1, 14.2, 21.0, 35.2, 54.6, 60.8, 61.0, 61.8, 71.6, 95.1,
122.4, 124.5, 129.4, 131.4, 141.3, 156.3, 165.1, 169.1;
HRMS (FAB) m/z calcd for C18H24O7Na: 375.1420, found:
375.1420.
4.1.4. Ethyl (1S*,3R*)-1,8-dihydroxy-3-methylisochro-
man-7-carboxylate (8). To a stirred solution of 7 (84 mg,
0.34 mmol) in dry toluene (10 mL), DIBAL (0.99 M in tol-
uene, 0.71 mL, 0.70 mmol) was added dropwise at ꢁ78 ꢂC
under Ar. After stirring for 30 min at ꢁ78 ꢂC, the reaction
mixture was quenched with MeOH. This was then diluted
with satd aq Rochelle’s salt and extracted with EtOAc.
The organic layer was washed with brine, dried with
MgSO4, and concentrated under reduced pressure. The resi-
due was purified by silica gel chromatography to give the
recovered 7 (14 mg, 17%) and 8 (47 mg, 56%, 67% based
on the recovered SM): mp 135–137 ꢂC; IR (Nujol) 3350
(m, O–H), 1665 (s, C]O), 1620 (s, C]C) cmꢁ1 1H
;
NMR d 1.38 (d, J¼6.0 Hz, 3H), 1.41 (t, J¼7.2 Hz, 3H),
2.56–2.75 (m, 2H), 3.18 (d, J¼3.3 Hz, 1H), 4.33–4.48 (m,
3H), 6.20 (d, J¼3.3 Hz, 1H), 6.65 (d, J¼8.1 Hz, 1H), 7.74
(d, J¼8.1 Hz, 1H), 11.33 (s, 1H); 13C NMR d 14.2, 21.1,
35.8, 61.4, 62.7, 88.4, 110.5, 119.1, 123.4, 129.2, 142.8,
159.0, 170.2; HRMS (EI) m/z calcd for C13H16O5:
252.0995, found: 252.0991.
4.1.7. Ethyl (7R*,9S*)-3-hydroxy-9-methoxy-7-methyl-
6,9-dihydro-7H-furo[3,2-h]isochromen-2-carboxylate
(12). To a stirred and ice-cooled solution of 11 (37 mg,
0.11 mmol) in dry THF (10 mL), t-BuOK (30 mg,
0.27 mmol) was added portionwise. After stirring for
5 min, the reaction mixture was diluted with satd aq
NH4Cl and extracted with EtOAc. The organic layer was
washed with brine, dried with MgSO4, and concentrated un-
der reduced pressure. The residue was purified by silica gel
chromatography to give 12 (30 mg, 93%) as a white solid:
mp 88–93 ꢂC; IR (Nujol) 3340 (m, O–H), 1655 (s, C]O),
1605 (m, C]C) cmꢁ1; 1H NMR d 1.41 (d, J¼6.0 Hz, 3H),
1.45 (t, J¼7.2 Hz, 3H), 2.68–2.83 (m, 2H), 3.66 (s, 3H),
4.34 (m, 1H), 4.46 (q, J¼7.2 Hz, 2H), 5.90 (s, 1H), 7.02
(d, J¼8.1 Hz, 1H), 7.59 (d, J¼8.1 Hz, 1H), 8.18 (br s,
1H); 13C NMR d 14.4, 21.1, 35.5, 55.5, 61.1, 63.0, 94.6,
118.6, 119.3, 120.3, 123.7, 126.3, 136.3, 146.7, 151.1,
162.5; HRMS (EI) m/z calcd for C16H18O6: 304.1103,
found: 306.1104.
4.1.5. Ethyl (1S*,3R*)-8-hydroxy-1-methoxy-3-methyl-
isochroman-7-carboxylate (9). (a) Conversion of 8 to 9:
a solution of 8 (47 mg, 0.17 mmol) and p-TsOH$H2O
(5 mg, 0.03 mmol) in MeOH (20 mL) was stirred at room
temperature for 2 h. This mixture was diluted with water
and extracted with EtOAc. The organic layer was washed
with satd aq NaHCO3 and brine, dried with MgSO4, and con-
centrated under reduced pressure to give 9 (45 mg, 91%.) as
a white solid: mp 69–70 ꢂC; IR (Nujol) 3350 (w, O–H), 1665
(s, C]O), 1620 (s, C]C) cmꢁ1 1H NMR d 1.37 (d,
;
J¼6.0 Hz, 3H), 1.39 (t, J¼7.2 Hz, 3H), 2.62 (dd, J¼10.5,
17.4 Hz, 1H), 2.71 (dd, J¼4.5, 17.4 Hz, 1H), 3.59 (s, 3H),
4.30 (m, 1H), 4.38 (q, J¼7.2 Hz, 2H), 5.66 (s, 1H), 6.62
(d, J¼8.1 Hz, 1H), 7.73 (d, J¼8.1 Hz, 1H), 11.24 (s, 1H);
13C NMR d 14.2, 21.1, 35.7, 55.4, 61.3, 62.0, 95.0, 110.4,
118.9, 122.5, 129.3, 142.9, 159.3, 170.1; HRMS (EI) m/z
calcd for C14H18O5: 266.1153, found: 266.1162.
4.1.8. (7R*,9S*)-9-Methoxy-3-methoxymethoxy-7-meth-
yl-6,9-dihydro-7H-furo[3,2-h]isochromen-2-carboxylate
(13). To a solution of 12 (11.3 mg, 36.9 mmol) in dry CH2Cl2
(10 mL), DBU (15 mg, 97 mmol) and MOMCl (6.0 mg,
75 mmol) were added. After stirring at room temperature
for 20 min, the reaction mixture was diluted with satd aq
NH4Cl and extracted with EtOAc. The organic layer was
washed with brine, dried with MgSO4, and concentrated
under reduced pressure to give the crude 13 (10.2 mg) as
a white solid: 1H NMR d 1.35–1.45 (m, 6H), 2.77 (m, 2H),
3.59 (s, 3H), 3.67 (s, 3H), 4.22–4.50 (m, 3H), 5.39 (m,
2H), 5.94 (s, 1H), 7.03 (d, J¼8.1 Hz, 1H), 7.65 (d,
J¼8.1 Hz, 1H). This was used for the next step without
purification.
(b) Conversion of 7 to 9: to a stirred solution of 7 (58 mg,
0.23 mmol) in dry toluene (15 mL), DIBAL (0.99 M in
toluene, 0.49 mL, 0.49 mmol) was added dropwise at
ꢁ78 ꢂC under Ar. After stirring for 15 min at ꢁ78 ꢂC, the
reaction mixture was quenched by the successive addition
of MeOH (15 mL) and AcOH (10 mL). After stirring at
room temperature for 2 h, this mixture was neutralized
with satd aq NaHCO3 and extracted with ether. The organic
layer was washed with brine, dried with MgSO4, and
concentrated under reduced pressure. The residue was puri-
fied by silica gel chromatography to give 9 (30 mg, 49%,
58% based on the recovered SM), 7 (7 mg, 12%), and 10
(9 mg, 19%).
4.1.9. 2-{(7R*,9S*)-9-Methoxy-3-methoxymethoxy-7-
methyl-6,9-dihydro-7H-furo[3,2-h]isochromen-2-yl}-2-
propanol (14). To a solution of 13 (11.2 mg) in dry THF
(5 mL), MeLi (1.04 M in ether; 0.22 mL, 0.23 mmol) was
added dropwise at ꢁ78 ꢂC under Ar. After stirring for
1
10: H NMR d 1.53 (d, J¼6.6 Hz, 3H), 2.92 (d, J¼6.9 Hz,
2H), 4.55–4.80 (m, 3H), 6.69 (d, J¼7.5 Hz, 1H), 7.44 (d,
J¼7.5 Hz, 1H), 11.39 (s, 1H).

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2. Lin, W.; Brauers, G.; Ebel, R.; Wray, V.; Berg, A.; Sudarsone;
Proksch, P. J. Nat. Prod. 2003, 66, 57–61.
3. Saito, F.; Kuramochi, K.; Nakazaki, A.; Mizushina, Y.;
Sugawara, F.; Kobayashi, S. Eur. J. Org. Chem. 2006, 4796–
4799.
4. (a) Dieckmann, W. Chem. Ber. 1894, 27, 102–103 and 965–
966; (b) Schaefer, J. P.; Bloomfield, J. J. Org. React. 1967,
15, 1–203.
5. Kraus, G. A. J. Org. Chem. 1981, 46, 201–202.
6. (a) Sasaki, Y.; Fujita, T.; Okazaki, K.; Kamata, K.; Tobinaga, S.
Heterocycles 1992, 33, 357–374; (b) Donner, C. D.; Gill, M.
Aust. J. Chem. 2002, 55, 213–217; (c) McClay, A.; Van Den
Berg, H.; Johnston, P.; Watters, W.; McGarell, K.; Waugh,
D.; Armstrong, P.; Delbederi, Z.; Higgins, C.; Mills, T.
PCT Int. Appl. WO2006046071, 2006; Chem. Abstr. 2006,
144, 450616 and others cited therein.
30 min, the reaction mixture was quenched with satd aq
NH4Cl and extracted with EtOAc. The organic layer was
washed with brine, dried with MgSO4, and concentrated
under reduced pressure to give the crude 14 (11.5 mg) as
1
a white solid: H NMR d 1.40 (d, J¼6.3 Hz, 3H), 1.68 (s,
6H), 2.74 (m, 2H), 3.13 (br s, 1H), 3.60 (s, 3H), 3.64 (s,
3H), 4.32 (m, 1H), 5.13 (s, 2H), 5.85 (s, 1H), 6.95 (d,
J¼7.8 Hz, 1H), 7.46 (d, J¼7.8 Hz, 1H). This was used for
the next step without purification.
4.1.10. (7R*,9S*)-9-Hydroxy-7-methyl-2-(methylethyl-
idine)-6,9-dihydro-7H-furo[3,2-h]isochromen-3-one;
( )-pseudodeflectusin (1). The mixture of 14 and
p-TsOH$H2O (20 mg, 0.11 mmol) in THF (2 mL) and H2O
(2 mL) was stirred at room temperature for 2 days. The reac-
tion mixture was diluted with water and extracted with
EtOAc. The organic layer was washed with brine, dried
with MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography to
give (ꢀ)-1 (4.1 mg, 43%) as a white solid: mp 169–
170 ꢂC; IR (Nujol) 3380 (s, O–H), 1695 (s, C]O), 1650
7. Lin, C. H.; Alexander, D. L. J. Org. Chem. 1982, 47, 615–620.
ꢀ
8. Covarrubias-Zꢀun˜iga, A.; Rıos-Barrios, E. J. Org. Chem. 1997,
62, 5688–5689.
9. They reported the preparation of dimethyl or methyl esters
corresponding to 6 and 7 based on the same strategy.8
10. The reported yield of the cyclocondensation was 19%.
11. It was noted that this chemoselective DIBAL reduction was
unsuccessful in THF.
12. Our conformational analyses based on MM and MOPAC
(PM3) calculations using SpartanÒ ’04 also suggested
that the trans-diastereomers were more favorable than the
cis-isomers.
(s, C]C), 1610 (s, C]C), 1590 (s, C]C) cmꢁ1 1H
;
NMR d 1.40 (d, J¼6.0 Hz, 3H), 2.12 (s, 3H), 2.36 (s, 3H),
2.71 (dd, J¼10.2, 17.4 Hz, 1H), 2.80 (dd, J¼3.9, 17.4 Hz,
1H), 2.99 (d, J¼3.6 Hz, 1H), 4.46 (m, 1H), 6.28 (d,
J¼3.6 Hz, 1H), 6.88 (d, J¼7.8 Hz, 1H), 7.61 (d, J¼7.8 Hz,
1H); 13C NMR d 17.4, 20.4, 21.1, 35.9, 62.9, 87.8, 119.4,
122.0, 122.6, 123.7, 132.5, 143.8, 145.2, 162.0, 183.3;
HRMS (EI) m/z calcd for C15H16O4: 240.1045, found:
260.1046.
13. (a) Coates, R. M.; Shaw, J. E. J. Am. Chem. Soc. 1970, 92,
5657–5664; (b) Goldsmith, D. J.; Sakano, I. J. Org. Chem.
1976, 41, 2095–2098.
14. It should be noted that the corresponding TMS and TBS enol
ethers could not be prepared, probably due to their instabilities.
15. (a) Rzasa, R. M.; Romo, D. Tetrahedron Lett. 1995, 36, 5307–
5310; (b) Dimitriadis, C.; Gill, M.; Harte, M. F. Tetrahedron:
Asymmetry 1997, 8, 2153–2158; (c) Sells, P.; Lett, R.
Tetrahedron Lett. 2002, 43, 4621–4625.
References and notes
1. Ogawa, A.; Murakami, C.; Kamisuki, S.; Kuriyama, I.;
Yoshida, H.; Sugawara, F.; Mizushina, Y. Bioorg. Med.
Chem. Lett. 2004, 14, 3539–3543.