Model Studies towards Functionalized Bisbenzannulated [5,6]-Spiroketals

Article abstract of DOI:10.1002/ejoc.201501586

Following up on our previous model studies on the synthesis of simple bisbenzannulated [5,6]-spiroketals we here report the preparation of new examples of this entity with a variation in their substitution pattern. The regioselective introduction of functional groups in the C-3 or C-3′ positions (rubromycin numbering) may either take place prior to the spiroketalization by α-functionalizations of the ketone moiety of the precursor or in a subsequent step by the nucleophilic substitution of the benzylic hydroxy group of the previously described C-3-hydroxylated spiroketal. By applying these methods we could synthesize new methyl-substituted, hydroxylated, halogenated and amino-substituted bisbenzannulated [5,6]-spiroketals in good overall yields. C-1 or C-3? By applying suitable methods new functionalized [5,6]-spiroketals were regioselectively generated as model compounds for rubromycin-type natural products.

Full text of DOI:10.1002/ejoc.201501586

DOI: 10.1002/ejoc.201501586
Full Paper
Spiroketals
Model Studies towards Functionalized Bisbenzannulated [5,6]-
Spiroketals
Michael Wilsdorf,[a] Dieter Lentz,[a] and Hans-Ulrich Reissig*[a]
Dedicated to Professor Horst Kunz on the occasion of his 75th birthday
Abstract: Following up on our previous model studies on the cursor or in a subsequent step by the nucleophilic substitution
synthesis of simple bisbenzannulated [5,6]-spiroketals we here
report the preparation of new examples of this entity with a
variation in their substitution pattern. The regioselective intro-
duction of functional groups in the C-3 or C-3′ positions (rubro-
mycin numbering) may either take place prior to the spiroketali-
zation by α-functionalizations of the ketone moiety of the pre-
of the benzylic hydroxy group of the previously described C-3-
hydroxylated spiroketal. By applying these methods we could
synthesize new methyl-substituted, hydroxylated, halogenated
and amino-substituted bisbenzannulated [5,6]-spiroketals in
good overall yields.
Introduction
building block[2] and furnishes a set of differently substituted
spiroketals, which all possess a benzylic hydroxy group at their
C-3 position (rubromycin numbering; see Figure 1a). As the
spiroketal scaffold has been recognized as crucial pharmaco-
phore for the biological activity of the rubromycins (e.g. to in-
hibit human telomerase and HIV reverse transcriptase),[3] these
small molecules are therefore attractive targets in their own
right.[4] In this report, we would like to summarize some of our
recent efforts towards the synthesis of simple bisbenzannulated
[5,6]-spiroketals with a variation of the substitution pattern of
their spiroketal core. As a viable model substrate we sought
after the preparation of the simple ketone 1, which may then
be functionalized in its α-positions through regioselective enol-
ate formation in order to introduce additional functional groups
(Figure 1c).
In our previous study towards bisbenzannulated [5,6]-spiroket-
als we established a robust and modular entry to this unique
class of molecules that represent the key structural feature of
the rubromycin natural product family.[1] This highly convergent
approach utilizes lithiated methoxyallene as a signature C3-
Results and Discussion
As illustrated in Scheme 1 the synthesis to the key intermediate
ketone 1 commenced with the preparation of the known arene-
carbaldehyde 3. In modification of the original procedure,[5] the
required Dakin oxidation of dimethoxybenzaldehyde 2 was
achieved with 30 % aq. H2O2 in the presence of catalytic
amounts of SeO2 (Syper modification) instead of m-CPBA.[6] The
replacement of the peracid by aq. H2O2 as stoichiometric oxid-
ant greatly facilitated the preparation of the corresponding
phenol, especially when the reaction was conducted on a larger
scale (0.1 mol). Next, the alkylation of the phenol with MOMCl
was followed by ortho-formylation to furnish 3, which was then
carried on to the benzylic bromide 4. Its substitution with lithi-
ated methoxyallene was followed by mild acidic hydrolysis of
the primary allenyl adduct with dilute aq. H2SO4 to cleanly af-
ford the enone 5. This enone served as acceptor for the CuI-
mediated conjugate addition of simple aryl Grignard reagents
Figure 1. (a) Our previous methoxyallene-based approach towards simple bis-
benzannulated [5,6]-spiroketals. (b) Heliquinomycinone, as an example of a
rubromycin natural product. (c) Envisaged α-functionalizations of
ketone 1 for the introduction of functional groups.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
http://www.bcp.fu-berlin.de/en/chemie/chemie/forschung/OrgChem/reissig/
index.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501586.
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such as 6,[7] which were conveniently prepared from their par-
ent aryl iodides by a fast and clean magnesium/halogen ex-
change reaction according to a protocol of the Knochel
group.[8] For the conjugate addition, best results were still ob-
tained in the presence of 2.4 equiv. of HMPA and 2.0 equiv. of
TMSCl in THF (–40 °C → room temp.) with a 1.2-fold excess of
the aryl Grignard reagent 6. Subsequent slightly acidic workup
with saturated aq. NH4Cl solution readily hydrolyzed the inter-
mediate silyl enolether and reliably provided ketone 1 even on
a multi-gram scale. Additionally, a brief survey of applicable
substitutes for the carcinogenic HMPA revealed the analogous
pyrrolidino derivative TPPA[9] to be almost equally efficient,
whereas LiBr[10] gave the desired product only in minute
amounts, and TMEDA[11] completely failed to promote the reac-
tion.
Scheme 2. Synthesis of spiroketal 7 under mild acid conditions and formation
of compound 9 as side product.
Next, we focused on the regioselective introduction of alkyl
groups (e.g. methyl groups) at the C-3 and C-3′ positions of the
spiroketal by α-alkylation of the parent ketone 1. Sequential
treatment of 1 with LiHMDS and MeI at low temperature
(–78 °C) in THF cleanly furnished the C-1-methylated ketone 11,
which was further converted into spiroketal 12 with a prefer-
ence for the trans-configured diastereoisomer as determined by
1H NMR spectroscopy. A switch in regioselectivity for the α-
alkylation of ketone 1 was efficiently achieved by the presence
of HMPA, which led to the C-3-methylated ketone 13 along
with ca. 10 % of its regioisomer 11. Here, the acid-mediated
spiroketalization gave the spiroketal 14 as a 1.2:1 mixture of
inseparable isomers with essentially no stereoselection
(Scheme 3).
Scheme 1. Scalable route to ketone 1 and brief screening of various additives
as replacement for HMPA.
First we evaluated conditions for the conversion of 1 into the
simple and unfunctionalized [5,6]-spiroketal 7, which represents
the key structural feature of the natural product γ-rubro-
mycin.[12] It has already been recognized that ketones such as
1 are highly susceptible to an irreversible ꢀ-elimination/aroma-
tization process under strongly acidic or basic conditions.[13]
Hence, a careful evaluation of the reaction conditions, including
the screening of various Lewis and Brønsted acids as well as
solvents, eventually identified catalytic amounts of triflic acid
(10 mol-% TfOH) in MeCN as optimal to achieve a smooth con-
version of 1 to spiroketal 7 with the formation of the undesired
benzofuran derivative 8 being sufficiently suppressed.[14] Still,
for optimal results the temperature profile (–25 to –10 °C) had
to be accurately monitored as we observed the generation of a
1:1 mixture of diastereomeric diarylmethanes 9 at temperatures
above –5 °C. Undoubtedly, its formation results from an initial
Friedel–Crafts-type reaction of 7 with the electrophilic oxo-
carbenium ion 10 to form an intermediate ortho-quinone meth-
Scheme 3. Regioselective access to the C-3- and C-3′-methyl-substituted bis-
benzannulated [5,6]-spiroketals 12 and 14.
As the base was employed in excess (2.0 equiv.) and as the
ide, which is immediately trapped by a second equivalent of 7. order of addition of the reagents (base to the ketone or ketone
The highly reactive species 10 is generated as by-product from to the base) did not noticeably affect the outcome of the regio-
the acid-induced fragmentation of the MOM groups and could selectivity, we assume that the deprotonation of 1 with LiHMDS
in principle be scavenged by the addition of competing nucleo- to deliver the putative lithium enolate 15 had to occur relatively
philic reagents such as 1,2,4-trimethoxybenzene (Scheme 2).[15] slow at –78 °C in THF. With ketone 1 still present in the reaction
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mixture, the thermodynamic enolate 16 [(E)/(Z) < 30:1] may be
formed by equilibration within 30 min prior to its trapping with
electrophiles. With the presence of HMPA in the reaction mix-
ture, however, the deprotonation of 1 may be drastically accel-
erated, thus securing the kinetically controlled lithium enolate
15. The enolate geometries as illustrated in Scheme 4 were de-
1
termined by H NMR spectroscopy of the respective silyl enol-
ethers (see the Supporting Information).
Scheme 5. Attempts of α-hydroxylations of the C-1 and C-3 position via the
enolates of ketone 1.
isolated as trans-configured diastereomer solely (trans/cis
> 98:2), thus reflecting the thermodynamically equilibrated
product ratio. In our previous model study we already found
that for substrates with a benzylic hydroxy group slight heating
was necessary – not only to achieve conversion, but also to
accelerate the cis/trans equilibration.[1a] Importantly, under
these conditions no ꢀ-elimination to the corresponding benzo-
furanone derivative 25 occurred, presumably due to an advan-
tageous allylic strain (1,3A) that is exerted by the adjacent
methoxy group on the aryl moiety. This effectively prevents the
intermediate oxocarbenium ion to undergo aromatization. In
contrast to ketones such as 1 that are unsubstituted at C-1,
the additional hydroxy group generally allows harsher reaction
conditions to be employed for the crucial spiroketalization.
Moreover, the use of MOM protecting groups and also reverting
to a CuI-mediated strategy to assemble the two halves of the
molecule, considerably shortened the route from arenecarbal-
dehyde 2 to the spiroketal 24 to a total of 9 steps in compari-
son to 14 steps in our previous study (Scheme 6).
Scheme 4. Additive-controlled regioselective formation of enolates 15 or 16
by starting from ketone 1.
With a relatively good control over the regioselectivity for
the α-functionalization of ketone 1 we considered the use of
chiral electrophilic oxygen-transfer reagents to allow the rea-
gent-controlled enantioselective introduction of hydroxy
groups at the C-1 or C-3 positions.[16] Unfortunately, the se-
quential treatment of 1 with base and, e.g., camphorsulfonic
acid derived oxaziridines completely failed to yield any C-1-
oxidized ketone 18. Some conversion could be achieved with
the achiral and sterically less demanding Davis oxaziridine
17,[17] but this required the warming up to room temperature
and also resulted in a significant degree of unspecific decompo-
sition of the substrate. The reluctance towards oxidation in the
C-1 position with oxaziridines has also been recognized by the
Kozlowski group during their studies towards purpuromycin.[18]
A plausible explanation might be the effective shielding of the
enolate faces by the two bulky ortho substituents (OMe and
OMOM) at the adjacent aryl moiety. In contrast to this, the oxid-
ation of the C-3 position of 1 went remarkably well to give 19;
however, this substrate then failed to undergo the spiroketal-
ization to 20 under a variety of conditions and only resulted in
a rapid decomposition. We speculate that a dehydration to an
enone or its respective conjugated oxocarbenium ion may oc-
cur, which then is not capable to effectively engage in a
spiroketalization anymore (Scheme 5).
With these results in mind we reverted to our initial strategy
for the assembly of 3-hydroxylated spiroketals, which included
the addition of lithiated methoxyallene to the arenecarbalde-
hyde 3 to give the α-hydroxy enone 21.[1a] The temporary silyl-
ation of the benzylic hydroxy group with TESCl was necessary
to allow the assembly of ketone 23 by CuI-mediated conjugate
Scheme 6. Improved route to the 3-hydroxy-substituted trans-configured
spiroketal 24 via ketone 23.
The benzylic hydroxy group of 24 can also serve as handle
addition of aryl Grignard reagent 6. The spiroketalization of 23 for diversification. First, the inversion of the 3-hydroxy configu-
to 24 was routinely carried out in the presence of catalytic ration was examined, which was readily achieved by oxidation
amounts of concentrated aq. hydrochloric acid (HCl) with iPrOH with Dess–Martin periodinane (DMP) to give the intermediate
as solvent at elevated temperature (50 °C). The spiroketal was ketone. Its reduction with sterically demanding borohydride re-
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agents (e.g. L-selectride) exclusively led to the cis-configured moderate preference for the trans-configured spiroketal sug-
spiroketal 26. Both diastereoisomers are readily distinguishable gests the intermediacy of a resonance-stabilized oxocarbenium
1
by comparison of diagnostic signals in their respective H and ion at C-3 during the substitution process. Accordingly, deoxy-
13C NMR spectra, with significant differences in their chemical halogenations were readily achieved by treatment of alcohol
shifts of the 3-hydroxy hydrogen signals and those of the qua- 24 with methanesulfonyl chloride (MsCl) or nonaflyl fluoride
ternary ketal carbon atom C-2. The downfield-shifted and (NfF)[23] to afford the corresponding chloro- and fluoro-substi-
broadened signal of the 3-hydroxy group of 26 is also indicative tuted spiroketals 28 and 29, respectively, in moderate yields
of a hydrogen-bonding interaction between this group and the and diastereoselectivities (Scheme 8).
dihydropyran ketal oxygen atom in solution. Further elucidation
of the structure of 26 was provided by an X-ray crystal-structure
analysis[19] that again highlights the almost planar structure of
the dihydrobenzofuran moiety known for these entities
(Scheme 7).[20] In the solid state two molecules of 26 are associ-
ated by two hydrogen bonds [O–O 3.013(2) Å; Figure 2].
Scheme 8. Conversion of 24 into the amino-, chloro- and fluoro-substituted
spiroketals 27–29.
Next, we investigated the introduction of the second
hydroxy group in C-3 position that would provide an oxidation
pattern as it was found in the spiroketal core of the natural
Scheme 7. Inversion of configuration at C-3 of compound 24 leading to cis-
configured spiroketal 26.
product heliquinomycinone (Figure 1b). Therefore, directing a
gentle stream of gaseous molecular oxygen (O2) through a solu-
tion of the sodium enolate of protected ketone 23 in the pres-
ence of triethyl phosphite efficiently afforded the dihydroxyl-
ated ketone 30 as an inseparable 3.3:1 mixture of syn/anti dia-
steromers in 84 % yield (Scheme 9).[24]
Scheme 9. Electrophilic hydroxylation of 23 leading to dihydroxylated ketone
30, its conversion into acetonide 31, and assignment of the relative configu-
ration.
Figure 2. Molecular structure[21] of 26 displaying the hydrogen bonds. The
second molecule is generated by the crystallographic inversion center.
A subsequent formation of the corresponding acetonide 31
allowed the assignment of their relative configurations: the
chemical shifts for the axial and equatorial acetonide methyl
Some examples for the diversification at the C-3 position are groups in the respective 13C NMR spectra as well as key NOE
shown in Scheme 8. For instance, we converted 24 into its azide correlations are in agreement with the assigned syn configura-
employing Mitsunobu conditions (Bose modification),[22] which tion for the major isomer.[25] The origin of the observed moder-
was then reduced (Pd/C, H2) to furnish a separable mixture of ate diastereoselectivity is still unclear, but it may arise from a
diastereomeric benzylic amines 27 (trans/cis = 2.6:1). The rela- facial discrimination of the sodium (Z)-enolate by the adjacent
tive configurations were tentatively assigned according to the bulky OTES group. It is still unclear why in this particular case
chemical shift of the quaternary ketal carbon atom C-2. The the sterically more demanding Davis oxaziridine 17 cleanly led
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to a 1:1 mixture of syn/anti-30, with no stereoselection at all Experimental Section
(Scheme 9).
General Information: See the Supporting Information.
Typical Experimental Procedures
With α,α′-dihydroxy-substituted ketone 30 in hand we next
looked into its ketalization to the spiroketal 31. Unfortunately,
treatment of 30 with acid did not lead to the desired spiroketal
1-[3,6-Dimethoxy-2-(methoxymethoxy)phenyl]but-3-en-2-one
31, and the reaction was predominately characterized by un- (5): To a cold (–78 °C) solution of methoxyallene (3.21 g, 45.8 mmol)
in THF (50 mL) was added nBuLi (15.3 mL, 38.3 mmol, ca. 2.5
M in
specific decomposition. We could isolate a product in small
amounts that we assigned as the atropisomeric naphthalene
derivative 32, which was found to be relatively labile and sensi-
tive towards autoxidation in air. We speculate that the putative
hemiketal A readily suffers an acid-mediated dehydration to
produce the resonance-stabilized C-3 carbenium ion B followed
by an intramolecular Friedel–Crafts alkylation to C and a second
dehydration to D (or vice versa) to eventually form 32. Strain
release and tautomerization to the aromatic naphthalene por-
hexane). After 15 min at this temperature, benzylic bromide 4
(4.44 g, 15.3 mmol in 10 mL of THF) was added. The mixture was
warmed up and stirred at room temperature for 2 h. Then dilute
H2SO4 (5 % aq., 50 mL) and EtOAc were sequentially added. The
layers were separated, and the aqueous phase was extracted three
times with EtOAc. The combined organic layers were washed with
satd. NaCl solution (aq.), dried with Na2SO4, filtered, and concen-
trated. Column chromatography (hexanes/EtOAc = 6:1) provided
2.92 g (72 %) of enone 5 as pale yellow oil. 1H NMR (500 MHz,
tion may account as driving forces to favor this competing reac- CDCl3): δ = 3.50, 3.71, 3.79 (3 s, 3 H each, OMe), 3.98 (s, 2 H, 1-H),
tion pathway (Scheme 10).[26]
5.07 (s, 2 H, OCH2), 5.74 (dd, J = 1.5, 10.4 Hz, 1 H, 4-H), 6.29 (dd, J =
1.5, 17.5 Hz, 1 H, 4-H), 6.41 (dd, J = 10.4, 17.5 Hz, 1 H, 3-H), 6.58,
6.79 (2 d, J = 8.9 Hz, 1 H each, Ar) ppm. 13C NMR (126 MHz, CDCl3):
δ = 36.5 (t, C-1), 55.8, 56.1, 57.5 (3 q, OMe), 99.0 (t, OCH2), 105.6,
111.1 (2 d, Ar), 118.5 (s, Ar), 127.7 (t, C-4), 135.5 (d, C-3), 145.3, 146.4,
152.1 (3 s, Ar), 197.8 (s, C-2) ppm. IR (ATR): ν = 3000–2835 (C–H),
˜
1690 (C=O), 1615, 1595 (C=C), 1490, 1465, 1400 cm–1. HRMS (ESI-
TOF): calcd. for [M + Na]+ 289.1052, found 289.1053. C14H18O5
(266.3): C 63.15, H 6.81; found C 63.07, H 6.95.
1-[3,6-Dimethoxy-2-(methoxymethoxy)phenyl]-4-[3-methoxy-2-
(methoxymethoxy)phenyl]butan-2-one (1): To a cold (–40 °C) and
well-stirred solution of 1-iodo-3-methoxy-2-(methoxymethoxy)-
benzene (2.04 g, 6.89 mmol) in THF (10 mL) was added iPrMgCl (ca.
1.7
M in THF, 3.75 mL, 6.35 mmol). This freshly prepared aryl Grig-
nard reagent was then rapidly transferred by cannula into a mixture
of enone 5 (1.41 g, 5.30 mmol), HMPA (2.20 mL, 12.7 mmol),
CuI·2LiCl (0.10
M in THF, 2.50 mL) and TMSCl (1.34 mL, 10.6 mmol)
in THF (30 mL) at –40 °C. The cooling bath was immediately re-
moved and the mixture stirred at room temperature for 1 h. Then
satd. NH4Cl solution (aq.) and EtOAc were added. The layers were
separated, and the aqueous phase was extracted three times with
EtOAc. The combined organic layers were washed with satd. NaCl
solution (aq.), dried with Na2SO4, filtered, and concentrated. Column
chromatography (hexanes/EtOAc = 4:1 → 2:1) provided 1.98 g
(86 %) of ketone 1 as pale yellow oil. 1H NMR (500 MHz, CDCl3): δ =
2.77 (mc, 2 H, 3-H), 2.96 (mc, 2 H, 4-H), 3.50, 3.56, 3.71, 3.78, 3.81 (5
s, 3 H each, OMe), 3.80 (s, 2 H, 1-H), 5.06, 5.07 (2 s, 2 H each, OCH2),
6.56, 6.76 (2 d, J = 9.0 Hz, 1 H each, Ar), 6.75–6.78 (m, 2 H, Ar), 6.96
(t, J = 8.2 Hz, 1 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 24.5 (t,
C-4), 38.8 (t, C-1), 42.3 (t, C-3), 55.6, 55.7, 56.1, 57.3, 57.5 (5 q, OMe),
98.8, 99.0 (2 t, OCH2), 105.5, 110.2, 111.0 (3 d, Ar), 118.8 (s, Ar),
122.0, 124.1 (2 d, Ar), 135.6, 144.2, 145.3, 146.4, 152.0, 152.0 (6 s,
Scheme 10. Attempted spiroketalization of compound 30 and proposed reac-
tion pathway to naphthalene derivative 32.
Conclusions
This model study is a follow-up of our previous methoxyallene-
based approach to simple bisbenzannulated [5,6]-spiroketals.
An efficient CuI-mediated strategy for the assembly of the re-
quired basic spiroketalization precursors significantly improved
the overall efficiency to these entities and allowed the rapid
preparation of new spiroketals with different substitution pat-
terns. In principle, the introduction of a more diverse set of
substituents by α-functionalization of the key ketone 1 should
be possible. However, some substitutents in the C-3 position of
the spiroketalization precursors may not be well tolerated dur-
ing the subsequent spiroketalization event, in particular if these
substrates possess the propensity to undergo competing elimi-
nation reactions under acidic conditions. For that reason a sim-
ple spiroketal with two hydroxy groups (in C-3 and C-3′ posi-
tions) – as found in the core to the natural product heliquino-
mycinone – could not be accessed by this approach yet.
Ar), 208.0 (s, C-2) ppm. IR (ATR): ν = 2995–2780 (C–H), 1710 (C=O),
˜
1600, 1585, 1485, 1440 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
457.1838, found 457.1846. C23H30O8 (434.5): calcd. C 63.58, H 6.96;
found C 63.65, H 7.01.
4,7,8′-Trimethoxy-3H-spiro[benzofuran-2,2′-chroman] (7): To a
cold (–25 °C) solution of ketone 1 (109 mg, 0.25 mmol) in MeCN
(12.5 mL) was added TfOH (20 μL of a freshly prepared 1.3
M stock
solution of TfOH in MeCN, 25 μ ). The mixture was warmed up to
M
–10 °C over 15 min. Then satd. Na2CO3 solution (aq. 1 mL), water,
and EtOAc were sequentially added. The layers were separated, and
the aqueous phase was extracted three times with EtOAc. The com-
bined organic layers were washed with satd. NaCl solution (aq.),
dried with Na2SO4, filtered, and concentrated. Column chromatog-
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raphy (hexanes/EtOAc = 4:1) provided 69 mg (84 %) of spiroketal 7
as colorless solid. M.p. 118–122 °C. H NMR (500 MHz, CDCl3): δ =
2.17 (td, J = 5.8, 13.5 Hz, 1 H, 3′-H), 2.35 (ddd, J = 2.8, 5.8, 13.5 Hz,
2.32 (ddd, J = 2.4, 5.8, 13.4 Hz, 1 H, 3′-H), 2.83 (ddd, J = 2.4, 5.8,
16.5 Hz, 1 H, 4′-H), 3.30 (mc, 1 H, 4′-H), 3.72, 3.73 (2 s, 3 H each,
OMe), 3.76 (q, J = 7.3 Hz, 1 H, 3-H), 3.80 (s, 3 H, OMe), 6.36, 6.68 (2
1
1 H, 3′-H), 2.79 (ddd, J = 2.8, 5.6, 16.5 Hz, 1 H, 4′-H), 3.26, 3.57 (AB d, J = 8.9 Hz, 1 H each, 5-H, 6-H), 6.70–6.75 (m, 2 H, Ar), 6.83 (t, J =
system, J = 16.8 Hz, 1 H each, 3-H), 3.29 (mc, 1 H, 4′-H), 3.76, 3.78,
3.79 (3 s, 3 H each, OMe), 6.35 (d, J = 8.9 Hz, 1 H, 5-H), 6.69–6.76
(m, 3 H, 6-H, Ar), 6.84 (t, J = 7.9 Hz, 1 H, Ar) ppm. 13C NMR (126 MHz,
CDCl3): δ = 21.8 (t, C-4′), 30.6 (t, C-3′), 40.1 (t, C-3), 55.5, 55.9, 56.6
(3 q, OMe), 102.8, 109.9 (2 d, C-5, C-6), 110.2 (s, C-2), 112.6 (d, Ar),
7.8 Hz, 1 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.0 (q, Me),
21.6 (t, C-4′), 25.9 (t, C-3′), 45.0 (d, C-3), 55.4, 56.0, 56.6 (3 q, OMe),
103.1 (d, C-5), 110.2 (d, Ar), 111.7 (s, C-2), 112.5 (d, C-6), 120.2 (s,
Ar), 120.3, 121.0 (2 d, Ar), 122.8, 139.0, 142.1, 146.1, 148.4, 150.7 (6
s, Ar) ppm. cis/trans-12: IR (ATR): ν = 3000–2835 (C–H), 1735, 1605,
˜
114.0 (s, Ar), 120.5, 121.0 (2 d, Ar), 122.4, 138.9, 141.9, 147.3, 148.4, 1585, 1510, 1485, 1460 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
150.4 (6 s, Ar) ppm. IR (ATR): ν = 3000–2835 (C–H), 1610, 1585, 365.1365, found 365.1375. C20H22O5 (342.4): calcd. C 70.16, H 6.48;
˜
1510, 1480, 1460, 1440 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
351.1208, found 351.1224. C19H20O5 (328.4): calcd. C 69.50, H 6.14;
found C 69.54, H 6.23.
found C 70.14, H 6.51.
Acknowledgments
4-[3,6-Dimethoxy-2-(methoxymethoxy)phenyl]-1-[3-methoxy-2-
(methoxymethoxy)phenyl]pentan-3-one (11): To a cold (–78 °C) Financial support by Bayer HealthCare AG is gratefully acknowl-
solution of ketone 1 (87 mg, 0.20 mmol) in THF (5 mL) was added
dropwise LiHMDS (1.0 in THF/ethylbenzene, 0.40 mL, 0.40 mmol).
edged. We thank Dr. Cengiz Azap for preliminary experiments.
M
The mixture was stirred at this temperature for 30 min. Then methyl
iodide (142 mg in 0.50 mL of THF, 1.00 mmol) was added. The
mixture was warmed up and stirred at room temperature for
30 min. Then satd. NH4Cl solution (aq.) and EtOAc were added. The
layers were separated, and the aqueous phase was extracted three
times with EtOAc. The combined organic layers were washed with
satd. NaCl solution (aq.), dried with MgSO4, filtered, and concen-
trated. Column chromatography (hexanes/EtOAc = 3:1) provided
83 mg (93 %) of 11 as pale yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 1.35 (d, J = 6.7 Hz, 3 H, Me), 2.55 (mc, 2 H, 3-H), 2.90 (mc, 2 H,
4-H), 3.52, 3.54, 3.66, 3.78, 3.78 (5 s, 3 H each, OMe), 4.02 (q, J =
6.7 Hz, 1 H, 1-H), 5.00, 5.02 (AB system, JAB = 5.8 Hz, 1 H each,
OCH2), 5.08, 5.10 (AB system, JAB = 6.0 Hz, 1 H each, OCH2), 6.52,
6.74 (2 d, J = 9.2 Hz, 1 H each, Ar), 6.69–6.70 (m, 2 H, Ar), 6.91 (t,
J = 8.0 Hz, 1 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.5 (q,
Me), 24.8 (t, C-4), 40.3 (t, C-3), 43.8 (t, C-1), 55.4, 55.5, 56.0, 57.3, 57.4
(5 q, OMe), 98.7, 99.1 (2 t, OCH2), 105.8, 110.0, 110.8, 121.9, 124.0
(5 d, Ar), 125.5, 135.9, 144.1, 144.7, 146.4, 151.4, 152.0 (7 s, Ar), 210.2
Keywords: Benzofuran · Ketals · Ketones · Pyran ·
Rubromycin · Spiro compounds
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˜
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M stock solution of TfOH in MeCN, 50 μM). The mixture
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1
products as colorless solids in a combined yield of 78 %. cis-12: H
NMR (500 MHz, CDCl3): δ = 1.51 (d, J = 7.2 Hz, 3 H, Me), 2.06 (mc,
1 H, 3′-H), 2.28 (ddd, J = 2.9, 5.7, 13.5 Hz, 1 H, 3′-H), 2.77 (ddd, J =
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Eur. J. Org. Chem. 2016, 1555–1561
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Full Paper
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Received: December 10, 2015
Published Online: February 16, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim