Model studies for the synthesis of heliquinomycin: Preparation of new spiroketals

Article abstract of DOI:10.1055/s-0028-1083194

New model compounds were investigated within our efforts to synthesize the natural product heliquinomycin. We could provide good evidence that electronic effects prevent the spiroketal formation of compounds such as 5 incorporating an isocoumarin moiety. As a consequence, precursors 16 and 26 were prepared, which do not exert the strong electron-withdrawing effect of the methoxycarbonyl group present in 5. Dihydroisocumarin derivative 10 and phthalide 25 were coupled by Heck reactions with enone 4 to provide the required precursors 16 and 26. After reductive debenzylation the resulting intermediates were treated with anhydrous hydrochloric acid in alcohols to give spiroketals 18-20 and 28, 29 in reasonable yields. The spiroketalizations occur under thermodynamic control affording products with the hydroxyl group in a trans-relationship with respect to the pyran oxygen atom. Attempts to oxidatively convert dihydroisocumarin 19 into an isocoumarin derivative failed. In one attempt a ring contraction to new spiroketal 24 was observed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083194

PAPER
3605
Model Studies for the Synthesis of Heliquinomycin: Preparation of New
Spiroketals
Spiroketals
D
irec
h
ted Towards
e
the Synthe
l
sis of
H
v
eliquinomyc
a
in m Venkatesh, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 10 June 2008; revised 10 July 2008
O
O
MeO
Abstract: New model compounds were investigated within our ef-
OH
HO
O
forts to synthesize the natural product heliquinomycin. We could
provide good evidence that electronic effects prevent the spiroketal
formation of compounds such as 5 incorporating an isocoumarin
moiety. As a consequence, precursors 16 and 26 were prepared,
which do not exert the strong electron-withdrawing effect of the
methoxycarbonyl group present in 5. Dihydroisocumarin derivative
10 and phthalide 25 were coupled by Heck reactions with enone 4
to provide the required precursors 16 and 26. After reductive deben-
zylation the resulting intermediates were treated with anhydrous hy-
drochloric acid in alcohols to give spiroketals 18–20 and 28, 29 in
reasonable yields. The spiroketalizations occur under thermody-
namic control affording products with the hydroxyl group in a
trans-relationship with respect to the pyran oxygen atom. Attempts
to oxidatively convert dihydroisocumarin 19 into an isocoumarin
derivative failed. In one attempt a ring contraction to new spiroketal
24 was observed.
CO2Me
O
O
O
HO
OMe
O
OH
O
HO
heliquinomycin (1)
Figure 1 A prominent member of the rubromycin family: heliqui-
nomycin (1)
the ‘eastern side’, and the carbohydrate L-cymarose7d for
the ‘southern part’ of 5,6-spiroketal linkage. First model
studies were also carried out, initially to verify that the
spiroketalization of phenolic hydroxyl groups is a viable
strategy to obtain bis-benzannulated spiroketals.7e–f With
these preliminary studies and syntheses of various build-
ing blocks in hand, we wish to describe in the present re-
port the serious difficulties encountered during model
studies with isocoumarin building block 5, the identifica-
tion of various factors inhibiting spiroketalization, the
successful thermodynamically controlled spiroketaliza-
tion with the newly synthesized dihydroisocoumarin moi-
ety, and our endeavors to reinstall the double bond from
the dihydroisocoumarin unit at the last stage of the synthe-
sis. Finally, an alternative strategy employing a function-
alized phthalide intermediate is described. This moiety
should enable the construction of the isocoumarin ring in
the later stage of the synthesis.
Key words: acetals, spiro compounds, Heck reaction, natural prod-
ucts, heliquinomycin
Heliquinomycin (1), first isolated by Chino et al.1 from
Streptomyces sp. MJ 929-SF2, belongs to a family of nat-
ural metabolites called rubromycins, which exhibit anti-
biotic, cytostatic, and antimicrobial activity. The basic
structure of the rubromycin family2 consists of a highly
functionalized naphthoquinone moiety, which is linked to
an isocoumarin unit through a 5,6-spiroketal system
(Figure 1). Heliquinomycin (1) is a selective inhibitor of
human DNA-helicase3and unique from other members of
the rubromycin family by the fact that the 3¢-hydroxy
functionality is further linked to the rare carbohydrate L-
cymarose. In spite of these intriguing structural and bio-
logical activities of this molecule, apart from several mod-
el studies carried out by various research groups,4 only a
single total synthesis of the aglycon of racemic heliquino-
mycin has been reported in the literature.5 In addition to
this, the first total synthesis of g-rubromycin, was recently
completed by Kita and co-workers employing Pummerer-
type rearrangement reactions as key steps.6
OMe OMe
OBn
O
MeO
OBn
OMe
O
OMe OMe OSiEt3
2
O
a
7%
Ref. 7g
CO2Me
O
O
MeO
Our group has been actively involved for the past few
years in synthesizing various building blocks such as a
highly functionalized naphthaldehyde unit7a that may
serve as precursor to the ‘western hemisphere’ of the nat-
ural product, derivatized 6-iodoisocoumarin unit 57b,c for
OMe O
OMe O
CO2Me
MeO
O
O
OH
3
Dimethylated 3'-hydroxy-β-rubromycin
Scheme 1 Spiroketalization of the advanced intermediate 2.
Reagents and conditions: a) i: Pd/C, H2, MeOH, r.t., 2 d, ii: concd HCl
(cat.), i-PrOH, 40 °C, 2 d.
SYNTHESIS 2008, No. 22, pp 3605–3614
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1083194; Art ID: T10008SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

3606
C. Venkatesh, H.-U. Reissig
PAPER
In our earlier communication,7f we had described the suc- tempts to selectively prepare compounds such as 9 or 10
cessful spiroketalization of a bisphenolic ketone derived in high yields from 5 were not successful.
from the pentamethoxy-substituted naphthaldehyde and
– I effect
simple iodinated benzene derivatives, which confirmed
our strategy towards the planned total synthesis of heliqui-
nomycin (1). After completion of these model studies, the
OMe O
HO
O
O
advanced precursor 2 with the newly synthesized 6-iodo-
R
isocoumarin in the eastern part was investigated.7g Unfor-
OMe
tunately, the expected spiroketal 3 was isolated only in a
– M effect
very low yield of 7% (Scheme 1).
OMe OH
BnO
Reduction
OMe O
O
Certainly, the spiroketalization of 2 is not smooth and in-
hibited by unknown effects at this stage. Therefore, to as-
certain and overcome the factors inhibiting the
spiroketalization, once again we resumed our model stud-
O
I
BnO
I
9
O
OMe
OMe O
O
BnO
I
ies with a-siloxyenone
4
derived from 2,6-
O
OMe
Reduction
5
(dimethoxy)benzaldehyde7f as shown in Scheme 2. How-
ever, all our attempts to transform bisphenolic ketone 7
into spiroketal 8 under various reaction conditions using
Brønsted or Lewis acids resulted either in the recovery or
complete decomposition of 7 affording unidentifiable
mixtures.
O
OMe
10
Scheme 3 Electronic factors diminishing the nucleophilicity of the
phenolic hydroxyl group in the isocoumarin unit.
At this point, we developed an alternative strategy to re-
duce the double bond in the isocoumarin ring of 5 at an
earlier stage of our 6-iodoisocoumarin synthesis as shown
in Scheme 4. We assumed that the Wittig–Horner adduct
12 derived from highly functionalized carbaldehyde 11,
available from vanillin according to our earlier reported
procedure,7b can be desilylated under mild conditions to
provide enol 13, which on tautomerization should afford
a-keto ester 14. This intermediate should be reduced se-
lectively to the a-hydroxy ester 15 that can undergo lac-
tonization to 10 by acid- or base-catalyzed reaction.
Gratifyingly, the HW-adduct 12 was successfully desily-
lated within a few minutes to give the enol 13 by using a
mixture of TBAF/AcOH in 1:1 ratio at –78 °C. All our at-
tempts to isolate the desilylated adduct in its keto or enol
form resulted in the fast intramolecular cyclization to 6-
iodoisocoumarin 5. Therefore, we reduced the keto group
of a-keto ester 14 in situ directly after its generation by us-
ing sodium borohydride. This protocol afforded the a-hy-
droxy ester 15 in an overall yield of 71%. The
intramolecular lactonization required fine tuning of the re-
action conditions and after several trials we could success-
fully transform a-hydroxy ester 15 using p-
toluenesulfonic acid as catalyst to provide 6-iododihy-
droisocoumarin 10 in good yield (Scheme 4).
OMe
OMe
OBn
OBn
O
OBn
O
I
OMe
O
a
+
OBn
OMe
O
40%
OMe OSiEt3
OMe OSiEt3
O
O
CO2Me
4
5
6
CO2Me
b
quant.
O
OMe
OH
O
MeO
O
O
OMe
CO2Me
OH
O
OMe
O
c
OMe OH
OH
OMe
O
CO2Me
7
8
Scheme 2 Attempted spiroketalization with compound 7 containing
an isocoumarin fragment. Reagents and conditions: a) Pd(OAc)2 (10
mol%), NaHCO3, n-Bu4NCl, 3 Å MS, DMF, 60 °C, 17 h; b) Pd/C (10
mol%), H2 (1 atm), MeOH, r.t., 3 d; c) Brønsted or Lewis acids (p-
TsOH·H2O, MgSO4, Amberlyst-15, aq HCl, etc.).
Meanwhile Kozlowski et al.4f reported a failed attempt to
spiroketalize an advanced precursor with an isocoumarin
fragment in their endeavor towards the synthesis of pur-
puromycin. They concluded from their model studies that
the presence of electron-withdrawing groups in the iso-
coumarin unit dramatically diminishes the nucleophilicity
of the phenolic hydroxyl group engaged in the spiroketal-
ization. Our results are in complete agreement with
Kozlowski’s observation. The negative mesomeric and
inductive effects exerted by the functional groups present
in the isocoumarin ring dramatically decelerate the ring
closure (Scheme 3). Hence we wanted to increase the nu-
cleophilicity of the phenolic hydroxyl group by selective-
ly breaking the conjugation of an ester or lactone carbonyl
group using reducing agents. Disappointingly, all our at-
Spiroketal precursor 17 was prepared according to our
earlier standard conditions. Thus, TES-protected enone 4
was coupled with newly synthesized 6-iododihydroiso-
coumarin 10 under palladium catalysis8 to afford 16 in
good yield. A slight modification of the palladium-cata-
lyzed hydrogenation of 16 at 8 atmospheres decreased the
reaction time drastically from 3 days to 5 hours (compare
Scheme 2) without compromising the yield of bisphenolic
ketone 17 (Scheme 5). Due to the stereogenic center in the
isocoumarin part, the product was obtained as a 1:1 mix-
ture of two diastereomers. In one of our initial experi-
ments, the precursor 17, on treatment with anhydrous
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

PAPER
Spiroketals Directed towards the Synthesis of Heliquinomycin
3607
were completely characterized by spectroscopic tech-
niques and the diastereomeric ratio was found to be ap-
proximately 1:1. The diastereomeric mixture of 19 should
not pose serious threat to our synthetic endeavor since the
stereogenic center in the lactone ring will vanish when the
required double bond in the dihydroisocoumarin moiety is
reinstalled. With precursor 17 we performed the first suc-
cessful spiroketalization of a heliquinomycin model com-
pound including an isocoumarin derivative on the eastern
side.
OMe
OMe
BnO
I
CO2Me
CHO
BnO
I
CO2Me
OTBS
a
Ref. 7b
CO2Me
E:Z > 95:5
11
12
OMe
OMe
CO2Me
BnO
I
CO2Me
BnO
I
slow
O
OH
CO2Me
CO2Me
13
14
The next task in completing the model studies was the re-
generation of the double bond in the dihydroisocoumarin
moiety of spiroketals 18 and 19. In one of our preliminary
experiments, treatment of spiroketal 18 with DDQ in re-
fluxing chlorobenzene resulted in the oxidation of 3¢-hy-
droxyl group to afford the spiroketone 21 instead of the
expected dehydrogenation of the lactone ring (Scheme 6).
OMe O
OMe
CO2Me
OH
BnO
BnO
I
O
c
b
85%
3 steps
71%
I
CO2Me
CO2Me
15
10
Scheme 4 Synthesis of 6-iododihydroisocoumarin 10. Reagents
and conditions: a) TBAF/AcOH (1:1), THF, –78 °C, 5 min; b) NaBH4
(1.1 equiv), THF, –78 to –30 °C, 5 h; c) p-TsOH·H2O (1.0 equiv), to-
luene, 70 °C, 2 h.
O
O
MeO
O
O
MeO
O
O
OMe
OMe
OMe
OMe
CO2i-Pr
CO2i-Pr
O
O
hydrochloric acid, generated in situ from a mixture of
acetyl chloride and isopropyl alcohol, underwent sponta-
neous spiroketalization to afford the spiroketal 18 as a
mixture of diastereomers in 48% yield.
a
80%
OH
O
18
21
Scheme 6 Oxidation of 18 leading to compound 21. Reagents and
conditions: a) DDQ (6.0 equiv), PhCl, 140 °C, 16 h.
OMe
OBn
OMe
OBn
O
OBn
O
I
OMe
O
+
OBn
a
77%
OMe
O
Other test reactions to regenerate the double bond in
spiroketal 19 using N-bromosuccinimide bromination fol-
lowed by elimination resulted in an unidentifiable mixture
of products from which we could not detect the desired
product 22. Our oxidation experiments of spiroketals 19
or 20 with mild oxidizing agents such as DDQ, MnO2, and
IBX also resulted either in the recovery of starting materi-
al or in the complete decomposition of spiroketals 19 or
20 leading to unidentifiable products (Scheme 7).
OMe OSiEt3
O
OMe OSiEt3
CO2Me
O
4
10
16
CO2Me
b
75%
O
OMe
MeO
OMe
O
OH
O
CO2R2
OH
c
O
O
OMe
O
OMe OH
OR1
OMe
O
O
O
18 R1 = H, R2 = i-Pr; 48%, dr = 1:1
19 R1 = H, R2 = Me; 47%, dr = 1:1
20 R1 = R2 = Me; 10%, dr = 1:1
17 dr = 1:1
MeO
O
O
MeO
O
O
CO2Me
OMe
OMe
OMe
OMe
CO2Me
CO2Me
O
O
Scheme 5 Synthesis and spiroketalization of precursor 17 with a di-
hydroisocoumarin fragment. Reagents and conditions: a) Pd(OAc)2
(10 mol%), NaHCO3, n-Bu4NCl, DMF, 60 °C, 16 h; b) H2 (8 atm),
Pd/C (10 mol%), MeOH, r.t., 5 h; c) AcCl (10 equiv), i-PrOH or
MeOH, HC(OMe)3 (2 equiv), 60 °C, 16–48 h.
OR
OR
19, 20
R = H, Me
22
Scheme 7 Attempted experiments to regenerate the double bond in
19, 20 under various conditions. Reagents and conditions: a) R = H,
i: NBS, AIBN, CCl4, reflux, 3 h, ii: Et3N, reflux, 3 h; b) R = H, DDQ,
toluene, 100 °C, 24 h; c) R = Me, MnO2, THF, reflux, 22 h; d)
R = Me, IBX, PhF, 85 °C, 48 h.
As found in our earlier studies, the thermodynamically
more stable trans-5,6-spiroketal linkage was formed. Un-
der these reaction conditions, we also observed transester-
ification in the lactone ring of 18 to provide the isopropyl
ester (Scheme 5). Therefore, our subsequent spiroketal-
ization of 17 was carried out using methanol as solvent
and we were pleased to obtain the expected spiroketal 19
as a mixture of diastereomers in 47% yield along with an-
other product 20 in which the benzylic hydroxyl group at
C-3¢ of the spirolinkage was solvolytically displaced by
MeOH (also see ref.7f). The spiroketals 18, 19, and 20
Our final experiment to regenerate the double bond was
performed with triethylsilyl-protected spiroketal 23 by
deprotonation with lithium hexamethyldisilazane and (at-
tempted) selenylation. Unexpectedly, a ring contraction
afforded the a-hydroxycyclopentanone spiroketal 24 as a
1:1 mixture of diastereomers. Apparently, the intermedi-
ate ester enolate attacks the neighboring lactone carbonyl
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

3608
C. Venkatesh, H.-U. Reissig
PAPER
O
O
wards the phthalide moiety with highly functionalized
benzaldehyde intermediate 11. Reduction of this aldehyde
with NaBH4 in ethanol afforded directly 5-iodophthalide
25. a-Triethylsiloxy enone 4 was coupled with 25 by pal-
ladium-catalyzed Heck reaction under Jeffery’s ligand-
free conditions at 60 °C to provide the adduct 26 in 79%
yield. Hydrogenation of this compound to saturate the
double bond and to cleave all the protecting groups result-
ed in the formation of the desired spiroketalization precur-
sor bis(phenolic) hydroxyketone 27 in 70% yield.
Spiroketalization of this compound was performed fol-
lowing similar reaction conditions as described for the
model studies with the dihydroisocoumarin fragment.
Thus, mixing acetyl chloride with anhydrous methanol in
situ generates anhydrous hydrochloric acid, which cata-
lyzes the spiroketalization of precursor 27 to give 5,6-
spiroketals 28 and 29 in 42 and 19% yield, respectively.
MeO
O
MeO
O
O
OMe
OMe
OMe
OMe
CO2Me
CO2Me
O
O
O
a
81%
OH
OSiEt3
23
19
O
b
50%
MeO
O
OH
CO2Me
OMe
OMe
O
OSiEt3
24, dr = 1:1
Scheme 8 Unexpected ring contraction of lactone 23 to hydroxy
cyclopentanone 24. Reagents and conditions: a) Et3SiCl, i-Pr2NEt,
DMF, r.t., 15 h; b) i: LiHMDS (1.2 equiv), THF, –78 °C, 20 min; ii:
PhSeCl (1.5 equiv), THF, –78 to 0 °C, 4 h.
TLC analysis of the reaction mixture showed distinct
spots for both spiroketals 28 and 29 without any trace of
diastereomers. Compared to the synthesis of dihydroiso-
coumarin spiroketal 19 purification was simple in this
case and can be easily performed by column chromatog-
raphy without the need of HPLC. Also, NMR spectrosco-
py confirmed that only one diastereomer was formed,
which is predicted to be the thermodynamically more sta-
ble trans-5,6-spiroketal 28 according to our earlier pre-
liminary studies (Scheme 9). Starting from spiroketals
such as 28, the future task will be the construction of the
isocoumarin system from the five-membered lactone ring.
group leading to cyclopentanone derivative 24
(Scheme 8).
The model studies with the dihydroisocoumarin system
showed that the thermodynamically controlled spiroketal-
ization is feasible by fine tuning of electronic and nucleo-
philic factors present in the isocoumarin ring system.
Nevertheless, complications arose during purification
(formation of diastereomers) and in particular during at-
tempted regeneration of the double bond in spiroketals 18,
19, and 20. These problems urged us to conceive an alter-
native synthetic strategy. Based on our earlier experienc-
es, the proposed new approach should enable the
construction of a 5,6-spiroketal moiety without an addi-
tional stereogenic center and also provide a possible route
to regenerate the isocoumarin system in a later stage of the
synthesis. In our new approach via phthalide intermediate
25 we hoped to fulfill the necessary requirements
(Scheme 9).
In summary, we have confirmed that the ketalization to
construct the 5,6-spiroketal moiety was the crucial step to-
wards the total synthesis of heliquinomycin (1). Our ini-
tial model studies with isocoumarin fragment 5 on the
eastern hemisphere showed that the spiroketalization is ei-
ther inefficient or does not take place due to the strongly
decreased nucleophilicity of the phenolic hydroxyl group.
Breaking the conjugation by synthesizing dihydroisocou-
marin 10 enabled the spiroketalization successfully, but
the generation of an additional chiral center and the failure
to regenerate the double bond from the spiroketal 19 led
to abandon this dihydroisocoumarin approach. Another
promising strategy via a highly functionalized phthalide
intermediate 25, without the above mentioned complica-
tions, afforded 5,6-spiroketals 28 and 29 with exclusive
trans diastereoselectivity. The conversion of the five-
membered lactone ring into the six-membered isocou-
marin ring of 22 is currently in progress and construction
of the corresponding spiroketals with highly functional-
ized pentamethoxynaphthaldehyde will be reported in due
course.
Similar to the synthesis of isocoumarin and dihydroiso-
coumarin building blocks, we began our sequence to-
OMe
OMe
O
OBn
O
BnO
I
OBn
b, 4
a
O
OMe
O
11
79%
95%
OMe OSiEt3
25
26
O
c
70%
O
OMe
MeO
O
OH
O
OMe
d
OH
O
O
OMe
O
OMe OH
OR
OMe
Reactions involving moisture-sensitive reactants were performed in
flame-dried glassware under argon, reagents being added via a sy-
ringe. Purchased chemicals were used without further purification.
CH2Cl2, cyclohexane, PhCl, and MeCN were distilled from CaH2
and toluene over Na. THF was distilled from sodium benzophenone
ketyl. Anhyd DMF was purchased from Aldrich and stored over 4
Å molecular sieves. Products were purified by flash chromatogra-
phy on silica gel (230–400 mesh, Merck). Preparative HPLC was
O
28 R = H, 42%
29 R = Me, 19%
27
Scheme 9 Synthesis of phthalide spiroketals 28 and 29. Reagents
and conditions: a) NaBH4, EtOH, r.t., 1 h; b) Pd(OAc)2 (10 mol%),
NaHCO3, n-Bu4NCl, DMF, 60 °C, 12 h; c) H2 (8 atm), Pd/C (10
mol%), MeOH, r.t., 5 h; d) AcCl (10 equiv), MeOH, HC(OMe)3, 0 °C
to r.t., 25 h.
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

PAPER
Spiroketals Directed towards the Synthesis of Heliquinomycin
3609
carried out on a nucleosil 50–5 column (diameter 32 mm, length
250 mm) and detection was carried out with a Knauer visible UV-
detector (l = 254 nm) and a Knauer refractometer. NMR spectra
were recorded on Bruker (AC 250, AM 270, AC 500) and JEOL
(Eclipse 500) instruments. Chemical shifts are reported relative to
CHCl3 (1H: d = 7.24, 13C: d = 77.0), DMSO (1H: d = 2.49, 13C:
d = 39.7) and SiMe4 (1H: d = 0.00). The numbering of carbon atoms
for NMR assignments for the structures 6, 7, 15, 10, 16–21, 23–29
is depicted in Figure 2.
IR spectra were recorded on a Nicolet spectrometer (FTIR 5 SXC)
and MS spectra (EI, FAB) on Finnigan instruments (MAT 711,
MAT CH7A and CH5DF). CHN-analyses were performed on a
PerkinElmer elemental analyzer. Reported melting points (deter-
mined with a Büchi MP 510 apparatus) are uncorrected.
OMe
2"
OMe
OBn
O
OH
O
4"
5"
OBn
7
4"
OMe
1
OH
1'
4'
1'
OMe
O
3
O
I
CO2Me
OH
4'
OMe
O
8
5"
2'
OMe OSiEt3
5
OMe
OMe OH
5
3'
1
5
1'
1
O
O
O
4
3
6
7
15
CO2Me
CO2Me
OMe
2"
OMe
2"
OBn
O
OMe O
8a
4"
5"
OH
O
OBn
7
4"
5"
1
1'
7
OH
7
O
I
4'
OMe
O
1'
O
3
4'
OMe
O
OMe OSiEt3
CO2Me
4a
5
5
OMe OH
5
1
1
O
O
3
10
16
17
3
CO2Me
CO2Me
O
Me
Me
O
O
MeO
1
O
O
O
O
MeO
OMe
O
OMe
10
10
MeO
O
OMe
O
OMe
10
1'
1'
1
OMe
1'
1
O
O
O
6'
5'
O
6'
5'
O
6
6
6'
5'
O
6
5
5
5
3'
3'
3
3
3'
3
OMe
OH
OH
OMe
OMe
OMe
18
19
20
O
O
O
Me
MeO
O
OMe
O
MeO
OH
CO2Me
10
9
OMe
OMe
OMe
MeO
O
O
O
1'
1
O
1'
1
O
10
OMe
Me
6'
5'
O
1'
1
6'
5'
O
6
6
O
6'
5'
O
6
5
5
3
OSiEt3
5
3'
3'
3
OSiEt3
3'
3
OMe
O
OMe
21
23
24
OMe
5"
OMe
5"
OMe
7a
OH
O
OBn
O
O
OH
6
6
OBn
6
O
I
1'
1'
4'
1"
OMe
OMe
O 2
3"
3"
2'
3'
3a
4
OMe OH
4
OMe OSiEt3
O
1
4
O
1
O
3
O
3
25
26
27
O
O
MeO
9
O
OMe
OMe
MeO
1'
1
9
O
6
OMe
7'
1'
1
O
6
O
6'
5'
O
O
5
5
3'
3
5'
3'
OH
3
OMe
OMe
28
29
Figure 2 Numbering of carbon atoms for NMR assignments in structures 6, 7, 15, 10, 16–21, 23–29
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

3610
C. Venkatesh, H.-U. Reissig
PAPER
Methyl 7-Benzyloxy-6-[4-(2-benzyloxy-3,6-dimethoxyphenyl)-
3-oxo-4-(triethylsiloxy)but-1-enyl]-8-methoxy-1-oxo-1H-iso-
chromene-3-carboxylate (6)
under reduced pressure and the residue was purified by silica gel
column chromatography using hexane–EtOAc (4:1 to 3:2) as elu-
ent; yield: 2.32 g (71%); pale yellow viscous liquid; Rf = 0.35 (3:2
hexane–EtOAc).
To a solution of a-triethylsiloxyenone 4 (0.285 g, 0.644 mmol) and
6-iodoisocoumarin 5 (0.315 g, 0.676 mmol) in anhyd DMF (6 mL)
were added Pd(OAc)2 (0.014 g, 0.064 mmol), n-Bu4NCl (0.178 g,
0.644 mmol), MS 3Å (0.10 g), and NaHCO3 (0.14 g, 1.60 mmol).
The mixture was stirred at 60 °C under argon for 17 h. After cooling
the mixture to r.t., it was diluted with EtOAc (50 mL) and washed
with H2O (2 × 25 mL). The aqueous layer was extracted with
EtOAc (3 × 20 mL) and the combined organic extracts were washed
with brine (25 mL), and dried (MgSO4). The solvent was filtered,
evaporated under reduced pressure, and the crude residue was puri-
fied through silica gel column chromatography using hexane–
EtOAc (3:1) as eluent to afford the adduct 6; yield: 0.20 g (40%);
yellow foamy liquid; Rf = 0.20 (4:1 hexane–EtOAc).
IR (KBr): 3485 (O–H), 3030 (=C–H), 3000–2950 (C–H), 2870
(OCH3), 1735 (C=O), 1605–1555 (C=C), 1010 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 2.80 (dd, 2J = 14.2 Hz,
3J = 8.4 Hz, 1 H, 1¢-H), 3.07 (dd, 2J = 14.2 Hz, 3J = 4.1 Hz, 1 H, 1¢-
H), 3.20 (d, 3J = 6.2 Hz, 1 H, OH), 3.78, 3.88, 3.93 (3 s, 3 H each,
OMe), 4.37 (ddd, 3J = 8.4 Hz, 3J = 6.2 Hz, 3J = 4.1 Hz, 1 H, 2¢-H),
3
4.97 (s, 2 H, OCH2Ph), 7.34, 7.39 (2 t, J = 7.2 Hz, 1 H, 2 H, Ph),
7.49 (s, 1 H, 5-H), 7.55 (d, 3J = 7.2 Hz, 2 H, Ph).
13C NMR (126 MHz, CDCl3): d = 37.4 (t, C-1¢), 52.8, 52.9, 62.1 (3
q, OMe), 71.3 (d, C-2¢), 75.2 (t, OCH2Ph), 95.6 (s, C-4), 128.6,
128.7, 128.9 (3 d, Ph), 130.6 (s, C-6), 132.7 (s, C-1), 136.3 (d, C-5),
136.6 (s, Ph), 150.5 (s, C-2), 151.0 (s, C-3), 167.8 (s, CO2Me),
174.4 (s, C-3¢).
HRMS (ESI-TOF): m/z calcd for C20H21IO7 + Na+: 523.0229;
found: 523.0206.
IR (film): 3030 (=C–H), 2955–2835 (C–H), 2835 (OCH3), 1745
(C=O), 1690 (C=O), 1590 (C=C), 1490 cm–1 (C–C).
1H NMR (500 MHz, CDCl3): d = 0.61, 0.87 (q, t, 3J = 7.8 Hz, 6 H,
9 H, SiEt3), 3.76, 3.79, 3.96, 3.98 (4 s, 3 H each, OMe), 5.01, 5.05
(AB system, 2JA,B = 10.7 Hz, 2 H, OCH2Ph), 5.06, 5.11 (AB system,
2JA,B = 10.7 Hz, 2 H, OCH2Ph), 5.67 (s, 1 H, 4¢-H), 6.61, 6.87 (2 d,
3J = 9.1 Hz, 1 H each, 5¢¢-H, 4¢¢-H), 7.07 (s, 1 H, 4-H), 7.15, 7.22 (2
t, 3J = 7.4 Hz, 1 H, 2 H, Ph), 7.29, 7.33 (2 t, 3J = 7.3 Hz, 1 H, 2 H,
Ph), 7.39–7.45 (m, 6 H, Ph, 5-H, 2¢-H), 7.80 (d, 3J = 16.2 Hz, 1 H,
1¢-H).
13C NMR (126 MHz, CDCl3): d = 4.8, 6.8 (t, q, SiEt3), 52.9, 56.1,
56.5, 62.1 (4 q, OMe), 71.7 (d, C-4¢), 75.2, 76.4 (2 t, OCH2Ph),
106.5 (d, C-5¢¢), 112.2 (d, C-5), 113.5 (d, C-4¢¢), 117.1 (s, Ar), 121.2
(d, C-4), 125.4, 127.2 (2 s, Ph), 127.6, 128.0, 128.2, 128.55, 128.6,
128.9 (6 d, Ph), 131.9, 133.4 (2 d, C-2¢, C-1¢), 136.2, 137.9, 138.1,
142.6, 147.3, 147.4, 151.9, 152.9, 156.0 (9 s, Ph, Ar), 156.9 (s, C-
1), 160.8 (s, CO2Me), 200.6 (s, C-3¢).
Anal. Calcd for C20H21IO7 (500.0): C, 48.02; H, 4.23. Found: C,
48.11; H, 4.13.
Methyl 7-Benzyloxy-6-iodo-8-methoxy-1-oxo-isochromene-3-
carboxylate (10)
A solution of 15 (0.385 g, 0.77 mmol) in toluene (20 mL) was
stirred with p-TsOH·H2O (0.146 g, 0.77 mmol) at 70 °C under ar-
gon for 2 h and the reaction was monitored by TLC. The mixture
was cooled to r.t., washed with 5% aq NaHCO3 (20 mL) and brine
(20 mL). The aqueous layer was extracted with EtOAc (2 × 25 mL)
and the combined organic extracts were dried (MgSO4). After filtra-
tion, the organic solvent was evaporated under reduced pressure and
the residue was purified by silica gel column chromatography using
hexane–EtOAc (7:3) as eluent; yield: 0.306 g (85%); colorless sol-
id; mp 131–133 °C; Rf = 0.44 (3:2 hexane–EtOAc).
HRMS (ESI-TOF): m/z calcd for C44H48O11Si + Na+: 803.2858;
found: 803.2898.
IR (KBr): 2995 (=C–H), 2950–2930 (C–H), 2865–2850 (OCH3),
1770 (C=O), 1725 (C=O), 1675–1555 (C=C), 990–970 cm–1 (C–O).
Methyl 7-Hydroxy-6-[4-hydroxy-4-(2-hydroxy-3,6-dimethoxy-
phenyl)-3-oxobutyl]-8-methoxy-1-oxo-1H-isochromene-3-car-
boxylate (7)
2
1H NMR (500 MHz, CDCl3): d = 3.17, 3.32 (2 dd, J = 16.4 Hz,
3J = 5.3 Hz, 2 H, 4-H), 3.72, 3.95 (2 s, 3 H each, OMe), 5.01, 5.07
(AB system, 2JA,B = 10.3 Hz, 2 H, OCH2Ph), 5.06 (t, 3J = 5.3 Hz, 1
H, 3-H), 7.34, 7.39 (2 t, 3J = 7.1 Hz, 1 H, 2 H, Ph), 7.45 (s, 1 H, 5-
H), 7.54 (d, 3J = 7.1 Hz, 2 H, Ph).
Pd/C (0.010 g, 0.009 mmol) was suspended in MeOH (5 mL) and
H2 was bubbled via a needle through the suspension for 30 min. A
solution of the adduct 6 (0.070 g, 0.090 mmol) in MeOH (5 mL) was
added to the suspension and stirred under H2 atmosphere (1 atm) for
3 d. The mixture was filtered through a pad of Celite and washed
with anhyd MeOH (6 × 5 mL). The filtrate was concentrated under
reduced pressure and the crude product 7 was utilized for the at-
tempted spiroketalization without further purification; yield: 0.044
g (quant); yellow foamy liquid; Rf = 0.10 (1:1 hexane–EtOAc).
13C NMR (126 MHz, CDCl3): d = 30.5 (t, C-4), 53.2, 62.3 (2 q,
OMe), 74.5 (d, C-3), 75.5 (t, OCH2Ph), 101.1, 119.8 (2 s, C-6, C-
8a), 128.66, 128.7, 129.0 (3 d, Ph), 132.8 (d, C-5), 134.2, 136.5,
152.9, 155.3, 160.0, 169.3 (6 s, C-4a, Ph, C-7, C-8, C-1, CO2Me).
HRMS (ESI-TOF): m/z calcd for C19H17IO6 + H+: 469.0148; found:
469.0151.
1H NMR (250 MHz, CDCl3): d = 2.71–2.74, 2.94–3.01 (2 m, 2 H
each, CH2), 3.68, 3.78, 3.91, 3.93 (4 s, 3 H each, OMe), 5.28 (s, 1
H, OH), 5.54 (br s, 1 H, 4¢-H), 6.28, 6.71 (2 d, 3J = 8.5 Hz, 1 H each,
5¢¢-H, 4¢¢-H), 7.04, 7.28 (2 s, 1 H each, 4-H, 5-H).
Anal. Calcd for C19H17IO6 (468.0): C, 48.74; H, 3.66. Found: C,
48.64; H, 3.71.
Methyl (E)-7-(Benzyloxy)-6-[4-(2-(benzyloxy)-3,6-dimethoxy-
phenyl)-3-oxo-4-(triethylsiloxy)but-1-enyl]-8-methoxy-1-oxo-
isochromene-3-carboxylate (16)
Methyl 3-(Benzyloxy)-4-iodo-2-methoxy-6-(3-methoxy-2-hy-
droxy-3-oxopropyl)benzoate (15)
Under argon, the adduct 127c (4.00 g, 6.53 mmol) was dissolved in
THF (100 mL) and cooled to –78 °C. A freshly prepared 1:1 mix-
ture of TBAF (1 M in THF, 6.53 mL, 6.53 mmol) and glacial AcOH
(0.37 mL, 6.53 mmol) was added and the mixture was stirred for 5
min at the same temperature. Then NaBH4 (0.25 g, 6.53 mmol) was
added and stirring was continued for 5 h at –78 to –30 °C. The mix-
ture was quenched by the addition of sat. aq NH4Cl (20 mL) at
–30 °C and extracted with EtOAc (3 × 25 mL). The combined or-
ganic layers were washed with H2O (25 mL), brine (10 mL), and
dried (MgSO4). After filtration, the organic solvent was evaporated
To a solution of triethylsiloxyenone 4 (0.289 g, 0.655 mmol) and 6-
iododihydroisocoumarin 10 (0.279 g, 0.595 mmol) in DMF (5 mL)
were added Pd(OAc)2 (0.013 g, 0.0595 mmol), n-Bu4NCl (0.165 g,
0.595 mmol) and NaHCO3 (0.125 g, 1.49 mmol). The mixture was
stirred at 60 °C under argon for 16 h, then cooled to r.t., diluted with
EtOAc (25 mL). The organic phase was washed with H2O (2 × 15
mL), brine (15 mL), and dried (MgSO4). After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel column chromatography using hexane–EtOAc (3:2) as
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

PAPER
Spiroketals Directed towards the Synthesis of Heliquinomycin
3611
eluent to afford 16 as a 1:1 mixture of diastereomers; yield: 0.358 g
(77%); pale yellow foamy liquid; Rf = 0.35 (3:2 hexane–EtOAc).
(5 × 20 mL), brine (25 mL), and the organic phase was dried
(MgSO4). The solvent was filtered, concentrated under reduced
pressure to afford the residue, which was purified by silica gel col-
umn chromatography using MeOH–CH2Cl2 (1:99) as eluent to af-
ford spiroketals 18, 19, and 20 as a 1:1 mixture of diastereomers. A
final purification was performed by HPLC.
IR (film): 3030 (=C–H), 3000–2875 (C–H), 2835 (OCH3), 1760
(C=O), 1740 (C=O), 1555 (C=C), 1005 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 0.57, 0.84 (q, t, 3J = 7.8 Hz, 6 H,
9 H, SiEt3), 3.08–3.16, 3.24–3.29 (2 m, 1 H each, 4-H), 3.72, 3.74,
3.74, 3.75, 3.76, 3.78, 3.94, 3.94 (8 s, 1.5 H each, OMe), 4.88–4.95,
4.98–5.02, 5.05–5.08 (3 m, 5 H, 2 × OCH2Ph, 3-H), 5.64 (s, 1 H, 4¢-
H), 6.59, 6.60 (2 d, 3J = 9.0 Hz, 0.5 H each, 5¢¢-H), 6.81, 6.85 (2 br
d, 3J = 16.3 Hz, 0.5 H each, 2¢-H), 6.86 (d, 3J = 9.0 Hz, 1 H, 4¢¢-H),
7.14–7.22, 7.26–7.34, 7.39–7.43 (3 m, 3 H, 4 H, 4 H, Ph, 5-H, Ph),
7.77, 7.79 (2 d, 3J = 16.3 Hz, 0.5 H each, 1¢-H).
13C NMR (126 MHz, CDCl3): d = 4.9, 6.9 (t, q, SiEt3), 31.0 (t, C-4),
53.1, 56.2, 56.6, 62.1 (4 q, OMe), 71.8, 74.7 (2 d, C-4¢, C-3), 75.5,
76.2 (2 t, OCH2Ph), 106.6, 113.4 (2 d, C-5¢¢, C-4¢¢), 119.6 (s, C-8a),
120.5 (d, C-2¢), 125.5 (s, C-1¢¢), 126.2 (d, C-5), 128.2, 128.3, 128.4,
128.5, 128.7, 128.9 (6 d, Ph), 132.5 (s, C-4a), 134.0 (d, C-1¢), 136.0,
136.6, 138.0, 147.5, 151.5, 152.0, 156.2, 160.1, 169.4, 200.6 (10 s,
C-6, Ph, C-6¢¢, C-7, C-2¢¢, C-8, C-1, CO2Me, C-3¢); the two diaste-
reomers show only one set of 13C signals.
Spiroketal 18
According to the general procedure, AcCl (0.11 mL, 1.53 mmol)
was added dropwise to a solution of 17 (0.075 g, 0.153 mmol) and
HC(OMe)3 (0.033 mL, 0.306 mmol) in i-PrOH (25 mL) at r.t., and
stirred at 60 °C for 16 h and worked up as mentioned above to af-
ford 18; yield: 0.036 g (48%, after column chromatography, purity
ca. 90%, 1:1 mixture of diastereomers); pale yellow foamy liquid;
final HPLC purification: tR = 5.46 min (1:2.3 i-PrOH–hexane).
IR (film): 3490 (O–H), 2975–2835 (C–H), 1730, 1720 (C=O),
1610, 1510, 1375 (C–H), 1265 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 1.17–1.21, 2.17–2.25, 2.44–2.49
(3 m, 6 H, 1 H, 1 H, Me, 3-H), 2.86 (s, 0.5 H, 3¢-OH), 2.87–2.92 (m,
2
1 H, 4-H), 2.94 (s, 0.5 H, 3¢-OH), 3.11, 3.14 (2 dd, J ≈ 16.0 Hz,
3J ≈ 5.7 Hz, 0.5 H each, 6-H), 3.17–3.21 (m, 1 H, 4-H), 3.24, 3.27
(2 dd, 2J ≈ 16.0 Hz, 3J ≈ 5.7 Hz, 0.5 H each, 6-H), 3.68, 3.73, 3.85
(3 s, 3 H each, OMe), 4.94–5.04 (m, 2 H, 7-H, CHMe2), 5.34, 5.35
(2 s, 0.5 H each, 3¢-H), 6.41, 6.42, 6.80, 6.81 (4 d, 3J = 8.9 Hz, 0.5
H each, 5¢-H, 6¢-H), 6.73, 6.74 (2 s, 0.5 H each, 5-H).
MS (EI, 80 eV, 150 °C): m/z (%) = 782 (<1, [M]+), 419 (29), 387
(100), 267 (23), 91 (14, [C7H7]+).
Anal. Calcd for C44H50O11Si (782.3): C, 67.50; H, 6.44. Found: C,
67.09; H, 6.25.
13C NMR (126 MHz, CDCl3): d = 21.55, 21.58 (2 q, Me), 21.7 (t, C-
4), 21.88, 21.92 (2 q, Me), 23.9, 24.0 (2 t, C-3), 30.79, 30.84 (2 t, C-
6), 55.8, 56.9, 61.5 (3 q, OMe), 69.93, 69.96 (2 d, CHMe2), 74.80,
74.86 (2 d, C-7), 76.3 (d, C-3¢), 103.7 (d, C-5¢), 111.6, 111.7 (2 s,
Ar), 115.48, 115.52 (2 d, C-6¢), 116.5 (s, C-2), 117.2, 117.3 (2 s,
Ar), 122.6 (d, C-5), 129.3, 129.4, 130.0, 130.1, 139.25, 139.27,
145.8, 148.1, 150.66, 150.70, 151.27, 151.31 (12 s, Ar), 160.3,
168.6, 168.8 (3 s, C-9, CO2i-Pr).
Methyl 7-Hydroxy-6-[4-hydroxy-4-(2-hydroxy-3,6-dimethoxy-
phenyl)-3-oxobutyl]-8-methoxy-1-oxo-3,4-dihydro-1H-isochro-
mene-3-carboxylate (17)
A solution of the Heck adduct 16 (0.150 g, 0.192 mmol) in MeOH
(10 mL) was added to Pd/C (0.020 g, 0.019 mmol) in a Büchi high
pressure reaction bottle. The mixture was stirred under H2 (8 atm)
for 5 h. The Pd/C was filtered through a pad of Celite and washed
with anhyd MeOH (6 × 5 mL). The filtrate was concentrated and the
crude product was purified by silica gel column chromatography us-
ing MeOH–CH2Cl2 (1:19) as eluent to afford 17 as a 1:1 mixture of
diastereomers; yield: 0.070 g (75%); pale yellow-white foam;
Rf = 0.50 (1:19 MeOH–CH2Cl2).
HRMS (ESI): m/z calcd for C26H29O10 + H+: 501.1761; found:
501.1742.
Spiroketals 19 and 20
According to the general procedure, AcCl (0.29 mL, 4.08 mmol)
was added dropwise to a solution of 17 (0.20 g, 0.408 mmol) and
HC(OMe)3 (0.089 mL, 0.816 mmol) in MeOH (25 mL) at r.t. The
resulting solution was stirred at 60 °C for 48 h and worked up as
mentioned above to afford a mixture of 19 and 20.
IR (film): 3430 (O–H), 3000–2840 (C–H), 1755, 1725 (C=O),
1610, 1600, 1490 (C=C) 1460, 1440, 1430 (C=C), 1250, 1070, 1030
cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 2.61–2.71, 2.82–2.93 (2 m, 2 H
each, CH2), 3.07, 3.11 (2 dd, 2J ≈ 16.5 Hz, 3J ≈ 3.7 Hz, 0.5 H each,
2
3
Spiroketal 19
Yield: 0.090 g (47%, 1:1 diastereomers); colorless solid; mp 219–
220 °C; tR = 4.70 min (1:3 i-PrOH–hexane).
4-H), 3.26, 3.29 (2 dd, J ≈ 16.5 Hz, J ≈ 3.7 Hz, 0.5 each, 4-H),
3.67, 3.68, 3.69, 3.70, 3.80, 3.81, 3.90, 3.90 (8 s, 1.5 H each, OMe),
4.06–4.11, 5.03–5.06 (2 m, 1 H each, 4¢-OH, 3-H), 5.49, 5.51 (2 d,
2J = 4.2 Hz, 0.5 H each, 4¢-H), 6.15, 6.26 (br s, 2 H, ArOH), 6.30,
IR (KBr): 3510 (O–H), 2990–2835 (C–H), 1730 (C=O), 1510, 1365
(C–H), 1265 cm–1 (C–O).
3
6.32, 6.73, 6.74 (4 d, J = 9.0 Hz, 0.5 H each, 5¢¢-H, 4¢¢-H), 6.66,
6.69 (2 s, 0.5 H each, 5-H).
1H NMR (500 MHz, CDCl3): d = 2.18–2.22 (m, 1 H, 3-H), 2.24 (d,
13C NMR (126 MHz, CDCl3): d = 25.0, 35.5, 36.3 (3 t, C-2¢, C-4, C-
1¢), 52.9, 55.9, 56.6, 62.3 (4 q, OMe), 71.7, 74.8 (2 d, C-4¢, C-3),
101.6, 110.9 (2 d, C-5¢¢, C-4¢¢), 115.0 (s, Ar), 123.9 (d, C-5), 124.1,
128.1, 133.8, 141.4, 144.9, 147.1, 148.0, 152.2 (8 s, Ar, Ph), 160.3,
169.6 (2 s, C-1, CO2Me), 208.8 (s, C-3¢); the two diastereomers
show only one set of 13C signals.
2
3
3J = 4.6 Hz, 1 H, 3¢-OH), 2.47 (ddd, J = 14.1 Hz, J = 6.2 Hz,
3J = 2.5 Hz, 1 H, 3-H), 2.90 (ddd, 2J = 17.2 Hz, 3J = 6.2 Hz, 3J = 2.5
Hz, 1 H, 4-H), 3.16 (dd, 2J = 16.3 Hz, 3J = 5.5 Hz, 1 H, 6-H), 3.19–
3.23 (m, 1 H, 4-H), 3.27 (dd, 2J = 16.3 Hz, 3J = 5.5 Hz, 1 H, 6-H),
3.69, 3.71, 3.74, 3.85 (4 s, 3 H each, OMe), 5.03 (t, 3J = 5.5 Hz, 1
H, 7-H), 5.35 (d, 3J = 4.6 Hz, 1 H, 3¢-H), 6.41 (d, 3J = 8.9 Hz, 1 H,
5¢-H), 6.74 (s, 1 H, 5-H), 6.81 (d, 3J = 8.9 Hz, 1 H, 6¢-H); only one
set of 1H signals was observed.
HRMS (ESI-TOF): m/z calcd for C24H26O11 + Na+: 513.1372;
found: 513.1369.
13C NMR (126 MHz, CDCl3): d = 21.9, 23.9, 30.6 (3 t, C-4, C-3, C-
6), 52.9, 55.8, 56.9, 61.5 (4 q, OMe), 74.7, 76.3 (2 d, C-7, C-3¢),
103.7 (d, C-5¢), 111.6 (s, Ar), 115.5 (d, C-6¢), 116.5, 116.9 (2 s, C-
2, Ar), 122.6 (d, C-5), 129.3, 130.2, 139.3, 145.9, 148.1, 150.8,
Spiroketals 18, 19, and 20; General Procedure
AcCl (10 equiv) was added dropwise to a solution of 17 (1 equiv)
and HC(OMe)3 (2 equiv) in i-PrOH or MeOH (25 mL) at r.t. The re-
sulting solution was further stirred at 60 °C under argon for the time
indicated in the individual experiment. Sat. aq NaHCO3 (10 mL)
was added to the cooled reaction mixture and extracted with EtOAc
(4 × 50 mL). The combined EtOAc layers were washed with H2O
151.3 (7 s, Ar), 160.1, 169.7 (2 s, C-9, CO2Me); only one set of 13
C
signals was observed.
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

3612
C. Venkatesh, H.-U. Reissig
PAPER
MS (EI, 80 eV, 190 °C): m/z (%) = 472 (82, [M]+), 454 (50, [M –
quenched with sat. aq NaHCO3 (2 mL) and extracted with EtOAc
(5 × 10 mL). The combined organic layers were washed with H2O
(2 × 10 mL), brine (10 mL), and dried (MgSO4). The solvent was
filtered, evaporated under reduced pressure, and the residue was
chromatographed on silica gel using MeOH–CH2Cl2 (1:50) as elu-
ent to afford the spiroketal 23; yield: 0.020 g (81%, two diastere-
omers in a ratio of 85:15); colorless solid; mp 172–173 °C;
Rf = 0.50 (1:19 MeOH–CH2Cl2).
H2O] +), 266 (47), 207 (100).
Anal. Calcd for C24H24O10 (472.1): C, 61.01; H, 5.12. Found: C,
61.26; H, 5.26.
Spiroketal 20
Yield: 0.020 g (10%, 1:1 diastereomers); colorless solid; melting
range 175–190 °C; final HPLC purification: tR = 2.68 min (1:3
i-PrOH–hexane).
IR (KBr): 2955–2835 (C–H), 1750, 1740 (C=O), 1605, 1510, 1365
(C–H), 1265 cm–1 (C–O).
IR (KBr): 2955–2850 (C–H), 1750, 1730 (C=O), 1605, 1510, 1365
(C–H), 1265 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d (major diastereomer) = 0.65–0.71
(m, 6 H, SiEt3), 0.93 (t, 3J = 7.7 Hz, 9 H, SiEt3), 2.00–2.08 (m, 1 H,
3-H), 2.49 (ddd, 2J = 13.9 Hz, 3J = 6.0 Hz, 3J = 2.5 Hz, 1 H, 3-H),
1H NMR (500 MHz, CDCl3): d = 2.15–2.21, 2.47–2.50, 2.85–2.89
(3 m, 1 H each, 3-H, 4-H), 3.13–3.29 (m, 3 H, 4-H, 6-H), 3.52, 3.53,
3.64, 3.65, 3.70, 3.72, 3.73, 3.74, 3.84, 3.85 (10 s, 1.5 H each,
OMe), 4.94 (s, 1 H, 3¢-H), 4.99 (dd, 3J = 6.6 Hz, 3J = 5.0 Hz, 0.5 H,
7-H), 5.02 (t, 3J = 5.0 Hz, 0.5 H, 7-H), 6.42 (d, 3J = 9.1 Hz, 1 H, 5¢-
H), 6.73 (s, 1 H, 5-H), 6.80, 6.81 (2 d, 3J = 9.1 Hz, 0.5 H each, 6¢-
H).
13C NMR (126 MHz, CDCl3): d = 21.9, 22.0 (2 t, C-4), 24.0, 24.1 (2
t, C-3), 30.5, 30.6 (2 t, C-6), 52.8, 52.9, 55.7, 55.8, 56.9, 57.0, 58.5,
58.6, 61.3, 61.4 (10 q, OMe), 74.6, 74.7 (2 d, C-7), 83.4, 83.9 (2 d,
C-3¢), 103.7 (d, C-5¢), 111.1, 111.2 (2 s, Ar), 115.2 (s, C-2), 115.4,
115.6 (2 d, C-6¢), 116.8, 116.9 (2 s, Ar), 122.5, 122.6 (2 d, C-5),
129.3, 129.4, 130.31, 130.34, 139.3, 139.4, 145.8*, 148.5, 148.6,
150.7, 150.8, 151.8* (12 s, Ar), 160.0 (s, C-9), 169.4, 169.7 (2 s,
CO2Me); * signals with higher intensities.
2
3
3
2.86 (ddd, J = 17.2 Hz, J = 6.0 Hz, J = 2.5 Hz, 1 H, 4-H), 3.15
(dd, 2J = 16.2 Hz, 3J = 6.3 Hz, 1 H, 6-H), 3.18–3.21 (m, 1 H, 4-H),
3.25 (dd, 2J = 16.2 Hz, 3J = 5.0 Hz, 1 H, 6-H), 3.64, 3.73, 3.75, 3.80
(4 s, 3 H each, OMe), 5.00 (dd, 3J = 6.3 Hz, 3J = 5.0 Hz, 1 H, 7-H),
5.33 (s, 1 H, 3¢-H), 6.37 (d, 3J = 8.8 Hz, 1 H, 5¢-H), 6.74 (s, 1 H, 5-
H), 6.78 (d, 3J = 8.8 Hz, 1 H, 6¢-H).
13C NMR (126 MHz, CDCl3): d (major diastereomer) = 4.9, 6.9 (t,
q, SiEt3), 22.1, 22.4, 30.7 (3 t, C-4, C-3, C-6), 52.9, 54.9, 56.9, 61.5
(4 q, OMe), 74.7, 77.3 (2 d, C-7, C-3¢), 103.1 (d, C-5¢), 111.8 (s, Ar),
114.8 (d, C-6¢), 116.9, 117.1 (2 s, C-2, Ar), 122.6 (d, C-5), 129.3,
130.4, 139.2, 146.0, 148.1, 150.8, 151.2 (7 s, Ar), 160.1, 169.5 (2 s,
C-9, CO2Me).
1H NMR (500 MHz, CDCl3): d (minor diastereomer) = 5.31 (s, 1 H,
3¢-H), 6.36, 6.76 (2 d, 3J = 8.8 Hz, 1 H each, 5¢-H, 6¢-H).
HRMS (ESI-TOF): m/z calcd for C25H26O10 + Na+: 509.1424;
found: 509.1465.
MS (EI, 80 eV, 160 °C): m/z (%) = 586 (47, [M]+), 557 (15, [M –
C2H5]+), 454 (100, [M – Et3SiOH]+), 321 (87), 207 (100).
Oxidized Spiroketal 21
Anal. Calcd for C30H38O10Si (586.2): C, 61.41; H, 6.53. Found: C,
61.23; H, 6.27.
To a solution of 18 (5 mg, 0.009 mmol, mixture of diastereomers)
in anhyd chlorobenzene (2 mL) was added DDQ (13 mg,
0.06 mmol) and the mixture was heated to reflux at 140 °C for 16 h
under argon (TLC monitoring). Then the mixture was cooled to r.t.,
quenched with sat. aq NaHCO3 (2 mL) and extracted with CH2Cl2
(3 × 25 mL). The combined organic layers were washed with H2O
(25 mL), brine (20 mL), and dried (MgSO4). After filtration and
evaporation of solvent under reduced pressure, the residue was
chromatographed with silica gel using MeOH–CH2Cl2 (1:50) as
eluent to afford 21; yield: 4 mg (ca. 80%, 1:1 diastereomers); pale
yellow liquid; Rf = 0.40 (1:19 MeOH–CH2Cl2).
Ring Contracted Spiroketal 24
LiHMDS (0.1 M in THF, 0.41 mL, 0.041 mmol) was added drop-
wise to a solution of spiroketal 23 (0.020 g, 0.034 mmol) in THF (5
mL) at –78 °C under argon and stirred for 20 min resulting in the
formation of a yellow solution. A THF (3 mL) solution of PhSeCl
(9 mg, 0.0512 mmol) was added to the mixture at –78 °C and stirred
for further 4 h while the temperature was slowly warmed to 0 °C.
The mixture was quenched with sat. aq NH4Cl (1.0 mL) and extract-
ed with EtOAc (3 × 25 mL). The combined organic extracts were
washed with H2O (20 mL), brine (10 mL), and dried (MgSO4). Af-
ter filtration and evaporation of the solvent under reduced pressure,
the residue was purified by silica gel column chromatography using
MeOH–CH2Cl2 (1:99) as eluent.
1H NMR (500 MHz, CDCl3): d = 1.12–1.21 (m, 6 H, Me), 2.06–
2.12, 2.23–2.32, 2.91–2.95 (3 m, 1 H each, 3-H, 4-H), 3.13–3.31 (m,
3 H, 6-H, 4-H), 3.84, 3.85, 3.85, 3.86, 3.93, 3.94 (6 s, 1.5 H each,
3
OMe), 4.97–5.03 (m, 2 H, 7-H, CHMe2), 6.43, 6.44 (2 d, J = 8.8
Hz, 0.5 H each, 5¢-H), 6.74, 6.75 (2 s, 0.5 H each, 5-H), 7.14, 7.15
HRMS (ESI-TOF): m/z calcd for C30H39O10Si + H+: 587.2313;
found: 587.2337.
(2 d, 3J = 8.8 Hz, 0.5 H each, 6¢-H).
13C NMR (126 MHz, CDCl3): d = 21.59, 21.61 (2 q, Me), 21.70 (t,
C-4), 21.71, 21.9 (2 q, Me), 25.2, 25.3 (2 t, C-3), 30.79, 30.84 (2 t,
C-6), 56.3, 56.4, 57.02, 57.06, 61.74, 61.75 (6 q, OMe), 70.01,
70.04 (2 d, CHMe2), 74.75, 74.79 (2 d, C-7), 102.0, 102.1 (2 d, C-
5¢), 103.5, 109.25, 109.26 (3 s, Ar), 117.6, 117.8 (2 d, C-6¢), 122.3,
123.4 (2 d, C-5), 123.1, 123.2, 128.85, 128.9, 129.9, 130.0, 139.67,
139.69, 145.76, 145.81, 150.6, 150.7, 152.50, 152.51, 160.0, 160.1
(16 s, Ar), 160.18, 160.23 (2 s, C-9), 168.62, 168.63 (2 s, CO2i-Pr),
192.47, 192.49 (2 s, C-3¢).
The 1:1 mixture of diastereomers of 24 was separated by HPLC.
Diastereomer a of 24
Yield: 5 mg (25%); colorless liquid; tR = 3.76 min (1:19 i-PrOH–
hexane).
IR (film): 3465 (O–H), 2950–2830 (C–H), 1745, 1715 (C=O),
1610, 1510, 1265 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 0.64–0.74 (m, 6 H, SiEt3), 0.94 (t,
3J = 8.0 Hz, 9 H, SiEt3), 2.06–2.13 (m, 1 H, 3-H), 2.51 (ddd,
2J = 13.7 Hz, 3J = 6.2 Hz, 3J = 2.5 Hz, 1 H, 3-H), 2.95 (ddd,
2J = 17.4 Hz, 3J = 6.2 Hz, 3J = 2.5 Hz, 1 H, 4-H), 3.08 (d, 2J = 17.1
Hz, 1 H, 6-H), 3.31 (ddd, 2J = 17.4 Hz, 3J = 12.4 Hz, 3J = 6.2 Hz, 1
H, 4-H), 3.58 (d, 2J = 17.1 Hz, 1 H, 6-H), 3.69, 3.71, 3.72, 3.81 (4
s, 3 H each, OMe), 3.87 (s, 1 H, OH), 5.31 (s, 1 H, 3'-H), 6.37, 6.78
(2 d, 3J = 8.8 Hz, 1 H each, 5¢-H, 6¢-H), 6.93 (s, 1 H, 5-H).
HRMS (ESI-TOF): m/z calcd for C26H26O10 + Na+: 521.1424;
found: 521.1443.
Triethylsilyl Ether Protected Spiroketal 23
i-Pr2NEt (0.22 mL, 0.127 mmol) was added to a stirred solution of
19 (0.020 g, 0.042 mmol, mixture of 1:1 diastereomers) in DMF
(1 mL) under argon, followed by dropwise addition of Et3SiCl
(0.16 mL, 0.093 mmol) at r.t. The mixture was stirred for 15 h and
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

PAPER
Spiroketals Directed towards the Synthesis of Heliquinomycin
3613
13C NMR (126 MHz, CDCl3): d = 4.9, 6.9 (t, q, SiEt3), 22.9, 24.3,
37.9 (3 t, C-4, C-3, C-6), 53.4, 54.9, 57.0, 61.6 (4 q, OMe), 76.6 (d,
C-3¢), 81.4 (s, C-7), 103.1 (d, C-5¢), 111.9 (s, Ar), 115.2 (d, C-6¢),
117.3 (s, C-2), 120.7 (d, C-5), 124.2, 134.3, 139.3, 144.35, 144.36,
147.7, 148.1, 151.2 (8 s, Ar), 171.9, 197.8 (2 s, CO2Me, C-8).
1H NMR (500 MHz, CDCl3): d = 0.59, 0.86 (q, t, 3J = 8.0 Hz, 6 H,
9 H, SiEt3), 3.75, 3.79, 4.10 (3 s, 3 H each, OMe), 4.96 (AB system,
2JA,B = 10.8 Hz, 2 H, OCH2Ph), 5.07 (AB system, 2JA,B = 10.8 Hz, 2
H, OCH2Ph), 5.15 (s, 2 H, 3-H), 5.67 (s, 1 H, 4¢-H), 6.61 (d, 3J = 9.1
Hz, 1 H, 3¢¢-H), 6.86–6.88 (m, 2 H, 4¢¢-H, 4-H), 7.19 (t, 3J = 7.2 Hz,
1 H, Ph), 7.23 (t, 3J = 7.4 Hz, 2 H, Ph), 7.29 (t, 3J = 7.2 Hz, 1 H, Ph),
7.32–7.37 (m, 3 H, Ph), 7.41–7.45 (m, 4 H, 2¢-H, Ph), 7.85 (d,
3J = 16.2 Hz, 1 H, 1¢-H).
Diastereomer b of 24
Yield: 5 mg (25%); colorless liquid; tR = 4.15 min (1:19 i-PrOH–
hexane).
13C NMR (126 MHz, CDCl3): d = 4.8, 6.8 (t, q, SiEt3), 56.1, 56.5,
62.7 (3 q, OMe), 68.8 (t, C-3), 71.7 (d, C-4¢), 75.3, 76.5 (2 t,
OCH2Ph), 106.5 (d, C-3¢¢), 113.4 (d, C-4¢¢), 114.3 (d, C-4), 118.6,
125.5 (2 s, Ph), 126.3, 127.5, 128.15, 128.21, 128.5, 128.6, 128.8 (7
d, Ph, C-2¢), 134.5 (d, C-1¢), 136.4, 137.5, 138.0 142.5, 147.35,
147.40, 150.6, 151.9, 152.8 (9 s, Ar), 168.3 (s, C-1), 200.7 (s, C-3¢).
IR (film): 3460 (O–H), 2950–2835 (C–H), 1745, 1715 (C=O),
1610, 1510, 1265 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 0.66–0.71 (m, 6 H, SiEt3), 0.94 (t,
3J = 8.0 Hz, 9 H, SiEt3), 2.06–2.12 (m, 1 H, 3-H), 2.49 (ddd,
2J = 14.0 Hz, 3J = 6.0 Hz, 3J = 2.5 Hz, 1 H, 3-H), 2.93 (ddd,
2J = 17.3 Hz, 3J = 6.0 Hz, 3J = 2.5 Hz, 1 H, 4-H), 3.09 (d, 2J = 17.1
Hz, 1 H, 6-H), 3.31 (ddd, 2J = 17.3 Hz, 3J = 12.4 Hz, 3J = 6.0 Hz, 1
H, 4-H), 3.56 (d, 2J = 17.1 Hz, 1 H, 6-H), 3.73, 3.75, 3.76, 3.81 (4
s, 3 H each, OMe), 3.89 (s, 1 H, OH), 5.34 (s, 1 H, 3¢-H), 6.37, 6.78
(2 d, 3J = 8.8 Hz, 1 H each, 5¢-H, 6¢-H), 6.91 (s, 1 H, 5-H).
MS (EI, 80 eV, 240 °C): m/z (%) = 710 (7, [M]+), 387 (86), 267
(65), 91 (100, [C7H7]+).
Anal. Calcd for C41H46O9Si (710.3): C, 69.27; H, 6.52. Found: C,
68.86; H, 6.42.
13C NMR (126 MHz, CDCl3): d = 5.0, 6.9 (t, q, SiEt3), 22.9, 24.5,
38.0 (3 t, C-4, C-3, C-6), 53.5, 54.9, 56.8, 61.7 (4 q, OMe), 76.9 (d,
C-3¢), 81.3 (s, C-7), 103.0 (d, C-5¢), 112.1 (s, Ar), 114.7 (d, C-6¢),
117.1 (s, C-2), 120.7 (d, C-5), 124.2, 134.2, 139.2, 144.23, 144.28,
147.5, 148.1, 151.2 (8 s, Ar), 172.1, 197.9 (2 s, CO2Me, C-8).
6-Hydroxy-5-[4-hydroxy-4-(2-hydroxy-3,6-dimethoxyphenyl)-
3-oxobutyl]-7-methoxyisobenzofuran-1(3H)one (27)
Analogous to the procedure for the synthesis of 17, a solution of 26
(1.30 g, 1.83 mmol) was added to a suspension of Pd/C (0.194 g,
0.183 mmol) in MeOH (20 mL) and subjected to high pressure
(8 atm) hydrogenation; yield: 0.535 g (70%); pale yellow liquid;
Rf = 0.48 (3:7 hexane–EtOAc).
6-Benzyloxy-5-iodo-7-methoxy-2-benzofuran-1(3H)-one (25)
NaBH4 (0.043 g, 1.14 mmol) was added to a solution of aldehyde
117c (0.43 g, 1.00 mmol) in anhyd EtOH (20 mL) at r.t. and the mix-
ture was stirred for 1 h. A colorless precipitate appeared in the mix-
ture as the reduction progressed. The excess of EtOH was
evaporated under reduced pressure keeping the bath temperature at
30–40 °C. The colorless residue obtained was dissolved in CH2Cl2
(25 mL), and quenched with sat. aq NH4Cl (5 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 25 mL), and the combined or-
ganic layers were washed with H2O (25 mL), brine (25 mL), and
dried (MgSO4). After filtration and evaporation of the solvent, the
crude product 25 was purified by silica gel column chromatography
using hexane–EtOAc (3:2) as eluent; yield: 0.376 g (95%); color-
less crystals; mp 106–108 °C; Rf = 0.30 (4:1 hexane–EtOAc).
IR (film): 3405 (O–H), 3000–2840 (C–H), 1745, 1720 (C=O),
1615, 1600, 1490 (C=C), 1470, 1435, 1400 (C=C), 1250, 1055,
1025 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 2.71 (m, 2 H, 2¢-H), 2.97 (t,
3J = 7.1 Hz, 2 H, 1¢-H), 3.69, 3.80 (2 s, 3 H each, OMe), 4.10 (br s,
1 H, OH), 4.16 (s, 3 H, OMe), 5.12, 5.54 (2 s, 2 H, 1 H, 3-H, 4¢-H),
6.08, 6.15 (2 br s, 1 H each, OH), 6.30, 6.72 (2 d, 3J = 8.8 Hz, 1 H
each, 3¢¢-H, 4¢¢-H), 6.82 (s, 1 H, 4-H).
13C NMR (126 MHz, CDCl3): d = 25.3, 36.5 (2 t, C-2¢, C-1¢), 56.0,
56.5, 63.1 (3 q, OMe), 69.2 (t, C-3), 71.7 (d, C-4¢), 101.5, 111.0 (2
d, C-3¢¢, C-4¢¢), 112.8, 114.4 (2 s, Ar), 117.6 (d, C-4), 135.4, 138.8,
141.4, 144.4, 145.1, 146.5, 152.1 (7 s, Ar), 168.9 (s, C-1), 208.6 (s,
C-3¢).
IR (KBr): 3085–2845 (=C–H, C–H), 1750 cm–1 (C=O).
MS (EI, 80 eV, 160 °C): m/z (%) = 418 (16, [M]+), 183 (86), 154
(79), 139 (100), 111 (45), 55 (27).
1H NMR (500 MHz, CDCl3): d = 4.11 (s, 3 H, OMe), 5.05, 5.16 (2
s, 2 H each, OCH2Ph, 3-H), 7.35 (t, 3J = 6.9 Hz, 1 H, Ph), 7.39 (t,
3J ≈ 7.0 Hz, 2 H, Ph), 7.55 (d, 3J = 6.9 Hz, 2 H, Ph), 7.60 (s, 1 H, 4-
H).
Anal. Calcd for C21H22O9 (418.1): C, 60.28; H, 5.30. Found: C,
59.98; H, 5.54.
13C NMR (126 MHz, CDCl3): d = 62.9 (q, OMe), 67.9, 75.7 (2 t,
OCH2Ph, C-3), 102.5, 119.3 (2 s, Ar), 126.9 (d, C-4), 128.6*, 128.8
(2 d, Ph), 136.3, 144.5, 151.6, 151.7 (4 s, Ph, Ar), 167.8 (s, C-1); *
signal with higher intensity.
Spiroketals 28 and 29
To a solution of ketone 27 (0.520 g, 1.24 mmol) in MeOH (35 mL)
were added dropwise HC(OMe)3 (0.27 mL, 2.48 mmol) and AcCl
(0.88 mL, 12.4 mmol) at 0 °C over a period of 5 min. The reaction
mixture was then stirred at r.t. for 25 h. The excess of MeOH was
evaporated under reduced pressure and the residue was dissolved in
EtOAc (50 mL) and quenched with sat. aq NaHCO3 (10 mL). The
organic phase was washed with H2O (2 × 20 mL), brine (20 mL),
and dried (MgSO4). The solvent was filtered and concentrated to af-
ford the crude products 28 and 29, which were purified by silica gel
column chromatography using hexane–EtOAc (1:1 to 1:4) as elu-
ent.
MS (EI, 80 eV, 100 °C): m/z (%) = 395 (23, [M]+), 91 (100,
[C7H7]+).
Anal. Calcd for C16H13IO4 (395.9): C, 48.51; H, 3.31. Found: C,
49.30; H, 3.43.
5-{(1E)-4-[2-(Benzyloxy)-3,6-dimethoxyphenyl]-4-(triethyl-
siloxy)-3-oxo-but-1-enyl}-7-methoxy-6-(benzyloxy)-2-benzo-
furan-1(3H)one (26)
Analogous to the procedure for the preparation of 16, a mixture of
triethylsiloxyenone 4 (1.53 g, 3.47 mmol), 5-iodophthalide 25
(1.25 g, 3.16 mmol), Pd(OAc)2 (0.071 g, 0.316 mmol), n-Bu4NCl
(0.876 g, 3.16 mmol), and NaHCO3 (0.662 g, 7.87 mmol) in DMF
(16 mL) was used for the Heck reaction; yield: 1.77 g (79%); pale
yellow viscous liquid; Rf = 0.63 (2:3 hexane–EtOAc).
Spiroketal 28
Yield: 0.208 g (42%); colorless solid; mp 227–228 °C; Rf = 0.54
(1:4 hexane–EtOAc).
IR (KBr): 3525 (O–H), 3090, 3000 (=CH), 2975–2840 (C–H), 1765
(C=O), 1510, 1450 (C=C), 1375, 1365 (C–H), 1270 cm–1 (C–O).
IR (film): 3085–2835 (=C–H, C–H), 1760 cm–1 (C=O).
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York

3614
C. Venkatesh, H.-U. Reissig
PAPER
1H NMR (500 MHz, DMSO-d6): d = 2.11 (ddd, 2J = 14.0 Hz,
3J = 10.8 Hz, 3J = 8.0 Hz, 1 H, 4-H), 2.35 (dt, 2J = 14.0 Hz, 3J = 5.2
Hz, 1 H, 4-H), 3.05 (mc, 2 H, 3-H), 3.65, 3.67, 3.80 (3 s, 3 H each,
OMe), 5.00 (s, 1 H, 3¢-H), 5.21, 5.25 (AB system, 2JA,B = 16 Hz, 2
H, 6-H), 5.94 (s, 1 H, OH), 6.54, 6.92 (2 d, 3J = 8.8 Hz, 1 H each,
5¢-H, 6¢-H), 7.16 (s, 1 H, 5-H).
13C NMR (126 MHz, DMSO-d6): d = 22.6, 24.3 (2 t, C-3, C-4),
56.2, 56.8, 62.1 (3 q, OMe), 69.2 (t, C-6), 75.5 (d, C-3¢), 104.8 (d,
C-5¢), 112.1 (s, Ar), 115.3 (d, C-6¢), 116.1, 117.6 (2 s, C-2, Ar),
118.2 (d, C-5), 132.6, 139.4, 140.95, 145.2, 147.1, 148.0, 151.7 (7
s, Ar), 168.7 (s, C-8).
References
(1) (a) Chino, M.; Nishikawa, K.; Umekita, M.; Hayashi, C.;
Chigusa, Y. J. Antibiot. 1996, 49, 752. (b) Chino, M.;
Nishikawa, K.; Sawa, R.; Hamada, M.; Naganawa, H.
J. Antibiot. 1998, 51, 480.
(2) Review: Brasholz, M.; Sörgel, S.; Azap, C.; Reissig, H.-U.
Eur. J. Org. Chem. 2007, 3801.
(3) (a) Niedenzu, T.; Röleke, D.; Bains, G.; Scherzinger, E.;
Saenger, W. J. Mol. Biol. 2001, 306, 479. (b) Xu, H.;
Ziegelin, G.; Schröder, W.; Frank, J.; Ayora, S.; Alonso, J.
C.; Lanka, E.; Saenger, W. Nucleic Acids Res. 2001, 29,
5058. (c) Xu, H.; Frank, J.; Trier, U.; Hammer, S.; Schröder,
W.; Behlke, J.; Schäfer-Korting, M.; Holzwarth, J. F.;
Saenger, W. Biochemistry 2001, 40, 7211. (d) Ziegelin, G.;
Niedenzu, T.; Lurz, R.; Saenger, W.; Lanka, E. Nucleic
Acids Res. 2003, 31, 5917.
MS (EI, 80 eV, 180 °C): m/z (%) = 400 (49, [M]+), 382 (41, [M –
H2O]+), 207 (100), 181 (26).
Anal. Calcd for C21H20O8 (400.1): C, 63.00; H, 5.03. Found: C,
62.64; H, 5.39.
(4) (a) Capecchi, T.; de Koning, C. B.; Michael, J. P.
Tetrahedron Lett. 1998, 39, 5429. (b) Capecchi, T.; de
Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1
2000, 2681. (c) Thrash, T. P.; Welton, T. D.; Behar, V.
Tetrahedron Lett. 2000, 41, 29. (d) Waters, S. P.;
Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567.
(e) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661.
(f) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett.
2006, 8, 3243. (g) Lowell, A. N.; Fennie, M. W.; Kozlowski,
M. C. J. Org. Chem. 2008, 73, 1911. (h) Tsang, K. Y.;
Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 5, 4425.
(i) Brimble, M. A.; Flowers, C. L.; Trzoss, M.; Tsang, K. Y.
Tetrahedron 2006, 47, 3349. (j) Lindsey, C. C.; Wu, K. L.;
Pettus, T. R. R. Org. Lett. 2006, 8, 2365. (k) Marsini, M.
A.; Huang, Y.; Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R.
Org. Lett. 2008, 10, 1477. (l) Zhou, G.; Zheng, D.; Da, S.;
Xie, Z.; Li, Y. Tetrahedron Lett. 2006, 47, 3349. (m) Zhou,
G.; Zhu, J.; Xie, Z.; Li, Y. Org. Lett. 2008, 10, 721.
(5) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S.
J. Angew. Chem. Int. Ed. 2001, 40, 4709; Angew. Chem.
2001, 113, 4845. (b) Siu, T.; Qin, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4713; Angew. Chem. 2001,
113, 4849.
Spiroketal 29
Yield: 0.097 g (19%); pale yellow solid; mp 166–168 °C; Rf = 0.68
(1:4 hexane–EtOAc).
IR (KBr): 2935–2835 (C–H), 1755 (C=O), 1510, 1450 (C=C), 1365
(C–H), 1265 cm–1 (C–O).
1H NMR (500 MHz, CDCl3): d = 2.22 (ddd, 2J = 13.6 Hz, 3J = 12.4
3
2
3
Hz, J = 6.2 Hz, 1 H, 4-H), 2.50 (ddd, J = 13.6 Hz, J = 6.2 Hz,
3J = 3.0 Hz, 1 H, 4-H), 2.96 (ddd, 2J = 17.3 Hz, 3J = 6.2 Hz, 3J = 3.0
Hz, 1 H, 3-H), 3.29 (ddd, 2J = 17.3 Hz, 3J = 12.4 Hz, 3J = 6.2 Hz, 1
H, 3-H), 3.53, 3.73, 3.78, 3.85 (4 s, 3 H each, OMe), 4.95 (s, 1 H,
3¢-H), 5.12, 5.15 (AB system, 2JA,B = 15.6 Hz, 2 H, 6-H), 6.43, 6.81
(2 d, 3J = 8.8 Hz, 1 H each, 5¢-H, 6¢-H), 6.89 (s, 1 H, 5-H).
13C NMR (126 MHz, CDCl3): d = 22.6, 24.0 (2 t, C-3, C-4), 55.7,
56.9, 58.5, 61.9 (4 q, OMe), 68.3 (t, C-6), 83.8 (d, C-3¢), 103.7 (d,
C-5¢), 111.3 (s, Ar), 115.1 (s, C-2), 115.4 (d, C-6¢), 115.9 (s, Ar),
116.4 (d, C-5), 132.1, 139.3, 139.5, 144.9, 147.6, 148.5, 151.7 (7 s,
Ar), 168.7 (s, C-8).
MS (EI, 80 eV, 130 °C): m/z (%) = 414 (74, [M]+), 382 (100, [M –
MeOH]+), 221 (85).
Anal. Calcd for C22H22O8 (414.1): C, 63.76; H, 5.35. Found: C,
63.48; H, 5.55.
(6) Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi,
T.; Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem.
Int. Ed. 2007, 46, 7458; Angew. Chem. 2007, 119, 7602.
(7) (a) Sörgel, S.; Azap, C.; Reissig, H.-U. Eur. J. Org. Chem.
2006, 4405. (b) Brasholz, M.; Reissig, H.-U. Synlett 2004,
2736. (c) Brasholz, M.; Luan, X.; Reissig, H.-U. Synthesis
2005, 3571. (d) Brasholz, M.; Reissig, H.-U. Angew. Chem.
Int. Ed. 2007, 46, 1634; Angew. Chem. 2007, 119, 1659.
(e) Azap, C. Ph.D. Thesis; Freie Universität Berlin:
Germany, 2004. (f) Sörgel, S.; Azap, C.; Reissig, H.-U. Org.
Lett. 2006, 8, 4875. (g) Sörgel, S. Ph.D. Thesis; Freie
Universität Berlin: Germany, 2006.
Acknowledgment
The authors thank the Alexander von Humboldt Foundation (post-
doctoral fellowship for CV), the Fonds der Chemischen Industrie,
and the Bayer Schering Pharma AG for generous support. We also
thank Dr. R. Zimmer for his suggestions during the preparation of
this manuscript, and D. Przyrembel and S. Duric for their experi-
mental contributions.
(8) (a) Jeffery, T. Tetrahedron 1996, 52, 10113. (b) Jeffery, T.
J. Chem. Soc., Chem. Commun. 1984, 1287. (c) Jeffery, T.
Tetrahedron Lett. 1985, 26, 2667.
Synthesis 2008, No. 22, 3605–3614 © Thieme Stuttgart · New York