Towards γ-Rubromycin: Model Studies, Development of a C3Building Block, and Synthesis of 4′-Silyl-γ-rubromycin

Article abstract of DOI:10.1002/ejoc.201601224

The human telomerase inhibitor γ-rubromycin belongs to a class of natural products, which features a rare [5,6]-bisbenzannulated spiroketal core as its central structural motif. Also termed “aromatic spiroketals”, these scaffolds pose great challenges to

Full text of DOI:10.1002/ejoc.201601224

DOI: 10.1002/ejoc.201601224
Full Paper
Rubromycins
Towards γ-Rubromycin: Model Studies, Development of a
C3 Building Block, and Synthesis of 4′-Silyl-γ-rubromycin
Michael Wilsdorf*[a] and Hans-Ulrich Reissig*[a]
Abstract: The human telomerase inhibitor γ-rubromycin be- strategy towards this class of natural products, that led to the
longs to a class of natural products, which features a rare [5,6]- identification of an electronically well-balanced spiroketaliza-
bisbenzannulated spiroketal core as its central structural motif. tion precursor and eventually culminated in the preparation of
Also termed “aromatic spiroketals”, these scaffolds pose great an unnatural 4′-silyl-substituted γ-rubromycin derivative in ra-
challenges to total synthesis. The ideal approach through an cemic form. In the course of this study, we additionally intro-
acid-mediated spiroketalization event is demanding, since this duced a new type of γ-silylated allylic phosphonate reagents
transformation is susceptible to even slight electronic altera- that served as valuable C3 building blocks to forge the spiro-
tions on the polyaromatic ring system. Herein, we report our ketalization precursor in a convergent manner.
Introduction
The rubromycins comprise a unique family of highly oxygen-
ated natural products that are of polyketide origin, first de-
scribed by Brockmann et al. with the isolation and characteriza-
tion of the parent compound γ-rubromycin (1).[1] Since
then, the isolation of several congeners has been reported, in-
cluding for instance heliquinomycin (2),[2] purpuromycin (3),[3]
griseorhodin A (4),[4] and most recently hyaluromycin (5).[5]
Structurally, all these natural products share a unique bisbenz-
annulated [5,6]-spiroketal core, which conjoints a naphtharazin
portion with an isocoumarin moiety and significantly varies in
the degree and pattern of oxygenation (Figure 1).
The biological evaluation of the rubromycins has revealed a
wide range of potential therapeutic attributes, including cyto-
toxic, antimicrobial, and antibacterial activities and also in-
hibitory effects towards human telomerase and HIV reverse
transcriptase.[6,7] In light of this promising biological profile and
Figure 1. Selected members of the rubromycin natural product family.
due to their attractive molecular architecture, several comple-
mentary approaches towards their synthesis have been re-
ported in recent years.[8] An initial accomplishment in the total
synthesis of these natural products was published by Dani-
shefsky et al. in 2001, who first disclosed the assembly of race-
mic heliquinomycinone, the aglycon of heliquinoymcin (2).[9]
Later, the laboratories of Kita (2007)[10] and Pettus (2011)[11] suc-
ceeded in the synthesis of ( )-γ-rubromycin (1), and formal total
syntheses of this natural product were reported by the groups
of Brimble (2009)[12] and Li (2012).[13]
Over the last few years, our group has constantly contributed
to this research area, mainly focusing on the assembly of model
substrates and of important molecule fragments.[14] In a contin-
ued effort to achieve the total synthesis of members of this
class of biologically active natural products, here we detail our
discoveries during our approach to bisbenzannulated [5,6]-
spiroketals. Based on these results an efficient and scalable
route to the natural product ( )-γ-rubromycin (1) was previ-
ously communicated.[15]
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Results and Discussion
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.201601224.
General Considerations
In the context of rubromycin synthesis, a straightforward way
to construct the pivotal spiroketal core would include acid-
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mediated ketal formation from dihydroxy ketone precursors propensity of this fragment to undergo unspecific oxidative de-
such as 6 (see Figure 2). Yet, neither of the previously known composition during this event. Hence, in line with our previous
two successful total syntheses of ( )-γ-rubromycin relied on this strategy, we pursued a convergent approach to the electroni-
kind of strategy, but rather devised elegant routes to circum- cally well-balanced key intermediate 10 and therefore dissected
vent this approach. Initially unexpectedly, compounds like 6 this target into two main halves, the naphthalene fragment 11
preferably undergo an irreversible ꢀ-elimination/aromatization and the functionalized aryl iodide 13, which would eventually
sequence (via 7) to the naphthofuran 8 instead of forming the be linked through lithiated methoxyallene 12[17] as a central C3
desired spiroketal 9. This tendency is even more pronounced building block (Figure 3).
for substrates, which possess a fully elaborated isocoumarin do-
main, a behavior that could experimentally be substantiated by
the group of Kozlowski[16] and by our group.[14c] Apparently,
intrinsic electronic properties are responsible for this observa-
tion as the phenolic oxygen atom of the isocoumarin portion
suffers from a markedly reduced nucleophilicity as a result of
its conjugation to the remote methoxycarbonyl moiety. The
spiroketalization outcome of “aromatic precursors” is particu-
larly sensitive towards alterations to the substitution pattern
of the aromatic portions. In extreme cases, as for instance for
compound 6, the spiroketalization event may even be com-
pletely shut down.
Figure 3. Retrosynthesis based on the use of lithiated methoxyallene 12 as
C3 building block (X = suitable nucleofuge).
Evaluation of the Spiroketalization/Lactonization
Sequence
In order to demonstrate the feasibility of the planned strategy,
we first prepared the functionalized aryl iodide 13, which was
readily accessed from vanillin (14) by a short route that was
previously described by our group.[18] Here, the introduction of
the methoxycarbonyl group at C-3 of vanillin required three
steps (by the site-selective metallation of the intermediate
acetal, not shown) to yield 15 after hydrolysis in moderate yield
(Scheme 1). Next, ortho-iodination and O-alkylation with
MOMCl led to compound 16, which in turn was subjected to
Horner–Wadsworth–Emmons (HWE) olefination employing
Figure 2. Spiroketalization versus ꢀ-elimination/aromatization pathway.
Aware of these synthetic challenges, we envisaged a late-
stage elaboration of the isocoumarin fragment after the crucial
acid-mediated spiroketalization as a viable solution, a strategy
that has also already been implemented by Brimble and Li in
their respective formal total syntheses of ( )-γ-rubromycin.
After reexamining our approach, we considered the replace-
ment of the isocoumarin fragment by a synthetic equivalent
that would possess attenuated electron-withdrawing proper-
ties, but that would already incorporate all functional groups
required for the late-stage construction of the isocoumarin do-
main. In addition, we intended to selectively oxidize the elec-
tron-rich naphthalene portion to the corresponding γ-naphtho-
quinone prior to the spiroketalization in order to mitigate the
Scheme 1. Synthesis of functionalized aryl iodide 13 starting from vanillin
(14).
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dimethyl phosphonate 17[19] to afford the desired building
block 13 on a multigram scale.
With sufficient quantities of aryl iodide 13 in hand, we next
focused on the assembly of a model substrate suitable for the
evaluation of the planned spiroketalization/lactonization se-
quence. As outlined in Scheme 2, a halogen/metal exchange
with iPrMgCl according to Knochel's procedure[20] conveniently
generated the aryl Grignard reagent 18, that was then added to
the methoxyallene-derived enone 20[14d] mediated by cuprous
iodide in the presence of the co-solvent HMPA and TMSCl.[21]
An ensuing hydrolysis of the intermediate trimethylsilyl enol
ether (not shown) with dilute sulfuric acid in THF afforded the
pure 1,4-addition product 21 on a gram scale in good yield. It
is worth noting that despite its high degree of functionalization
the magnesium reagent 18 displayed a remarkable stability (no
noticeable decomposition up to 0 °C in THF) presumably due
to the beneficial complexation of the metal atom by the MOM
group in the ortho position.
Scheme 3. Triflic-acid-mediated spiroketalization of 21 to 22 and subsequent
lactonization to the simplified and masked γ-rubromycin congener 24.
Towards the Naphthalene Portion of γ-Rubromycin
In order to apply this promising strategy to the synthesis of γ-
rubromycin, we first needed to access the highly oxygenated
naphthalene fragment of this molecule in the form of
the ethoxycarbonyl-substituted naphthalene derivative 29
(Scheme 4). For that purpose, we adopted a route previously
disclosed by the group of Kozlowski, starting from trimethoxy-
benzaldehyde 26.[23] This short sequence, which can be used
to yield multigram quantities of 29, includes a Stobbe conden-
sation with ethyl succinate followed by an intramolecular Frie-
del–Crafts-type acylation to build up the naphthalene scaffold
(26 → 27). Next, regioselective introduction of a methoxy
group by oxidative dearomatization with bis(trifluoroacetoxy)-
iodobenzene (PIFA) in methanol and subsequent base-induced
tautomerization led to the naphthol derivative 28. The oxid-
ation of this compound with 2-iodoxybenzoic acid (IBX) then
afforded an ortho-quinone (not shown), which was reduced to
its respective catechol with Na2S2O4 and further O-alkylated se-
quentially with MOMCl and MeI to yield 29.
Scheme 2. Assembly of the functionalized model substrate 21 from enone
20 and Grignard reagent 18.
The functionalized model substrate 21 was then subjected to
the crucial acid-mediated [5,6]-spiroketalization. In our previous
studies we had already identified that catalytic amounts of triflic
acid (TfOH) in MeCN at low temperatures could be used to
induce the spiroketalization (Scheme 3), while the prevalent
benzofuran formation (21 → 23) was sufficiently suppressed at
the same time.[14d,22] In this event, the cleavage of the MOM
ethers occurred chemoselectively, while the potentially acid-
labile TBS enol ether remained untouched, a prerequisite for
the success of this transformation. Subsequently, the advanced
spiroketal 22 was treated with potassium fluoride (KF) in a mix-
ture of THF/H2O (4:1) to trigger the lactonization to the simpli-
fied and masked γ-rubromycin congener 24. Rather unexpect-
edly, the use of TBAF (1
M in THF) partially led to the formation
of aryl aldehyde 25, presumably resulting from the conjugate
addition of water to the intermediate α-hydroxy enone during
aqueous workup, followed by a retro-aldol-type fragmentation
(not shown). Still, with the efficient preparation of compound
24, we established a robust route that we planned to utilize
Scheme 4. Nine-step synthesis of ethoxycarbonyl-substituted naphthalene
derivative 29. PIFA = bis(trifluoroacetoxy)iodobenzene; IBX = 2-iodoxybenzoic
acid.
As shown in Scheme 5, substrate 29 was readily reduced by
in the synthesis of γ-rubromycin during the next stage of our LiAlH4 to hydroxymethyl-substituted naphthalene derivative 30.
investigation.
However, despite extensive experimentation, the primary alco-
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hol 30 could not be converted into a compound with a suitable of methyl hemiketal 35, generated through interception of the
leaving group, which would be compatible with the intended intermediate oxocarbenium ion by the adjacent MOM group.
substitution reaction with lithiated methoxyallene (12). Unfor- Unfortunately, 35 was highly susceptible to oxidation and not
tunately, all attempts to convert 30 into the corresponding suitable for conversion into aldehyde 36 in order to perform
primary halides or different sulfonic acid esters, for instance, led the planned addition of the vinyl Grignard reagent followed by
to its immediate decomposition. It is plausible to assume a oxidation to yield 32.
facile heterolysis of the formed product as a result of the ex-
traordinarily electron-rich nature of the hexaalkoxy-substituted
naphthalene ring leading to a quinone-methide-like species (30
→ 31).
Introduction of Allylic Phosphonates as C3 Building Blocks
In light of the encouraging reactivity of aldehyde 33 in olefin-
ations and with the demand for a simple reagent – ideally a C3
building block – to access the required enone, we directed our
attention to the known α-methoxy-substituted allylic phos-
phonate 37 (Scheme 7).[25] If this reagent could successfully be
employed in an HWE-type olefination with aldehyde 33, the
resultant 2-methoxybutadiene derivative (not shown) should
give access to the desired enone 32 after hydrolysis of its enol
ether moiety.
Scheme 5. Reduction of ester 29 to alcohol 30 and failed attempted conver-
sions into activated derivatives resulting in inaccessibility of enone 32
through the methoxyallene approach.
The inaccessibility of enone 32 through a methoxyallene-
based route prompted us to explore various stepwise methods
towards this substrate. A promising approach, amongst others,
included the Wittig homologation of naphthaldehyde 33, read-
ily obtained by oxidation of 30 with IBX (Scheme 6). Its reaction
with the ylide derived from (methoxymethyl)triphenylphos-
phonium chloride[24] afforded the expected naphthyl-substi-
tuted enol ether 34 [(E)/(Z) = 5.7:1]. The intended synthesis of
aldehyde 36 by hydrolysis of the enol ether moiety of 34 (with
trichloroacetic acid, for instance) led to the undesired formation
Scheme 7. Reaction of lithiated 37 with aryl aldehyde 38 and preparation of
γ-trimethylsilyl-substituted allylic phosphonate 40.
The α-methoxy-substituted allylic phosphonate 37 is readily
metallated with LDA to generate an acceptor-stabilized ambi-
dent allylic anion, which in turn is preferentially quenched with
electrophiles at its γ-position (Scheme 7). The regioselectivity
of this reaction, however, may also depend on the nature of
the electrophile employed, taking steric and electronic factors
into account.[26] Not entirely unexpectedly, the trapping of
lithiated 37 with the sterically congested aryl aldehyde 38[27]
yielded less than 15 % of the desired 2-methoxybutadiene de-
rivative 39. An anticipated in situ transmetallation with
TiCl(OiPr)3 or TiCl2(OiPr)2 in order to control the regioselectivity
(as reported for similar phosphine oxides with simple aryl alde-
hydes)[28] just led to complete disintegration of the sensitive
aldehyde 38. We therefore envisaged a temporary, but robust,
blockage of the γ-site by, for instance, silylation with TMSCl,
leading to a new type of α-methoxy-γ-silyl-substituted allylic
phosphonate reagent 40.[29]
The applicability of the new reagent 40 in the context of our
strategy to γ-rubromycin was again first demonstrated with the
preparation of simple model spiroketals (Scheme 8). Thus, de-
protonation of phosphonate 40 with LiHMDS and subsequent
trapping with aryl aldehyde 38 afforded the expected 2-
methoxybutadiene 41 (50 % yield, not optimized). Hydrolysis
under mild acidic conditions furnished ꢀ-trimethylsilyl-substi-
Scheme 6. Attempted route towards stepwise elaboration of 32 through Wit-
tig homologation of 33. IBX = 2-iodoxybenzoic acid; TCA = trichloroacetic
acid.
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tuted enone 42 (Scheme 8), which served as suitable acceptor enable a late-stage Tamao–Fleming-type oxidation,[30] either to
for the cuprous iodide mediated conjugate addition of aryl introduce an oxygen atom at C-4′ [as is found in the natural
Grignard reagent 43 to give ketone 44. In spite of the additional product purpuromycin (3); see Figure 1] or to ensure a formal
steric demand exerted by the bulky silyl group at the ꢀ-carbon protodesilylation in a subsequent defunctionalization step lead-
atom, the merging of both halves of the molecule proceeded ing to γ-rubromycin (1). Thus, we started the synthetic se-
remarkably well. Triflic acid induced the spiroketalization, fur- quence by employing the dimethyl(phenyl)silyl-substituted all-
nishing the desired product 45 with a good degree of dia- ylic phosphonate 46 that was readily obtained on a decagram
stereoselection (dr = 5.7:1) in favor of the trans isomer. Compari- scale (Scheme 9). Metallation of 46 with KHMDS followed by
1
son of diagnostic H NMR signals and their coupling constants addition to aldehyde 33 afforded 2-methoxybuta-1,3-diene 47
allowed the stereochemical assignment of the diastereomers.
in 74 % yield, which was hydrolyzed to enone 48 in good yield.
We were pleased to find that the conjugate addition of the
previously utilized highly functionalized aryl Grignard reagent
18 to enone 48 proceeded smoothly to give after acidic hydrol-
ysis 49 in 87 % yield. In the next step, the oxidation of the
naphthalene portion with DDQ occurred regioselectively to af-
ford the respective γ-naphthoquinone derivative 50. This sub-
strate represents the initially anticipated electronically well-bal-
anced key intermediate (see Figure 3), albeit with an additional
silyl group attached. As expected, treatment of 50 with TfOH in
MeCN (–25 °C to 5 °C) cleanly afforded spiroketal 51 essentially
as a single diastereomer with no detectable formation of the
corresponding naphthofuran derivative. The α-siloxypropeno-
ate side chain of precursor 50 is probably twisted out of plane
for steric reasons and as a consequence the nucleophilicity of
the phenolic hydroxy group is sufficiently high to allow smooth
spirocyclization to 51.
The final steps that are needed to complete the synthesis
of γ-rubromycin would include lactonization to generate the
isocoumarin unit and a proto-desilylation reaction, expected to
be feasible through a two-step oxidation/deoxygenation se-
quence. We therefore treated compound 51 with an excess of
fluoroboric acid–diethyl ether in dichloromethane, leading to
the formation of spiroketal 53 in 71 % yield along with minor
amounts of naphthofuran derivative 54. Under these condi-
tions, the lactonization proceeded smoothly without the afore-
mentioned fragmentation of the silyl enol ether moiety (com-
pare the reaction 51 → 52 in the presence of TBAF); however,
the anticipated fluorodearylation reaction at the silicon atom
(as the initial step of an intended Tamao–Fleming oxidation)
did not occur. Surprisingly, the dimethyl(phenyl)silyl moiety re-
Scheme 8. Application of γ-trimethylsilyl-substituted allylic phosphonate 40
in the preparation of simple model [5,6]-spiroketal 45 via silylated enone 42
and characteristic 1H NMR signals of the two diastereomers.
With the use of phosphonate 40 we established a comple-
mentary approach towards functionalized [5,6]-spiroketals start-
ing from aryl aldehydes instead of benzylic alcohols. Conse-
quently, our studies focused on the elaboration of phosphonate
reagents that would finally provide a potential handle for fur- mained untouched, even under prolonged reaction times and
ther functionalizations at the pyran backbone of the spiroketal at elevated temperatures (50 °C, sealed tube). More excessive
moiety. The installation of an aryl-substituted silyl group should heating gradually led to the irreversible formation of 54. Never-
Scheme 9. Synthesis of the advanced “aromatic spiroketal” 51 via ketone 50 employing allylic phosphonate 46 as key C3 building block.
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theless, we could convert 53 into racemic 4′-silyl-γ-rubromycin Experimental Section
55 in moderate yield by treatment with boron tribromide
General: For general information, experimental details of all experi-
ments, and copies of NMR spectra see the Supporting Information.
(Scheme 10). This product represents the first synthetic example
of a derivative of this natural product class bearing a silyl group
attached to the [5,6]-spiroketal backbone. Despite this remark-
able achievement it seems unlikely to obtain γ-rubromycin (1)
itself from the intermediates described here, since the pivotal
silyl group could not be removed under sufficiently mild condi-
tions. Yet, based on the strategy developed in this account, we
could successfully accomplish the total synthesis of ( )-γ-rubro-
mycin (1) when we incorporated the more electron-rich di-
methyl(para-methoxyphenyl)silyl group into the allylic phos-
phonate reagent, as already reported in our previous communi-
cation.[15]
Methyl 6-{(E)-2-[(tert-Butyldimethylsilyl)oxy]-3-methoxy-3-oxo-
prop-1-en-1-yl}-4-{4-[3,6-dimethoxy-2-(methoxymethoxy)-
phenyl]-3-oxobutyl}-2-methoxy-3-(methoxymethoxy)benzoate
(21): To a cold (–40 °C) and well-stirred solution of aryl iodide 13
(1.36 g, 2.40 mmol) in THF (12 mL) was added iPrMgCl (ca. 1.7
M in
THF, 1.42 mL, 2.41 mmol). This freshly prepared aryl Grignard rea-
gent was rapidly transferred through a cannula to a mixture of en-
one 20[14d] (0.59 g, 2.20 mmol), HMPA (2.20 mL, 5.31 mmol),
CuI·2LiCl (0.10
M in THF, 2.20 mL), and TMSCl (0.56 mL, 4.43 mmol)
in THF (30 mL) at –40 °C. The cooling bath was immediately re-
moved, and the mixture was stirred at r.t. for 1 h. Then satd. NH4Cl
solution (aq.) and EtOAc were added. The layers were separated and
the aq. phase was extracted with EtOAc (3 ×). The combined or-
ganic layers were washed with satd. NaCl solution (aq.), dried with
Na2SO4, filtered, and concentrated. Column chromatography (silica
gel; hexanes/EtOAc, 4:1 → 2:1) provided ketone 21 (1.10 g, 71 %)
1
as colorless oil. H NMR (500 MHz, CDCl3): δ = 0.19, 0.95 (2 s, 6 H,
9 H, OSiMe2tBu), 2.68–2.72 (m, 2 H, 3-H), 2.87–2.90 (m, 2 H, 4-H),
3.49, 3.52, 3.53, 3.71, 3.77 (5 s, 3 H each, OMe), 3.79 (s, 2 H, 1-H),
3.81, 3.84 (2 s, 3 H each, OMe), 5.06, 5.07 (2 s, 2 H each, OCH2), 6.32
(d, J = 0.7 Hz, 1 H, 1′-H), 6.56, 6.76 (2 d, J = 9.1 Hz, 1 H each, Ar),
6.75 (s, 1 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = –5.0, 18.2, 25.5
(q, s, q, OSiMe2tBu), 24.2 (t, C-4), 38.8 (t, C-1), 42.0 (t, C-3), 51.6, 52.2,
55.7, 56.0, 57.47, 57.49, 61.3 (7 q, OMe), 99.0, 99.1 (2 t, OCH2), 105.5,
111.0 (2 d, Ar), 117.0 (d, C-1′), 118.7 (s, Ar), 126.1 (d, Ar), 126.5, 128.8,
137.3, 142.7, 145.3, 146.3, 147.4, 149.5, 151.9 (9 s, Ar, C-2′), 164.8,
167.4 (2 s, C=O), 207.5 (s, C-2) ppm. IR (ATR): ν = 3000–2835 (C–H),
˜
1725 (C=O), 1635 (C=C), 1595, 1560, 1490 cm–1. HRMS (ESI-TOF):
calcd. for [M + Na]+ 729.2918; found 729.2950. C35H50O13Si (706.8):
calcd. C 59.47, H 7.13; found C 59.41, H 7.14.
Methyl 6′-{(E)-2-[(tert-Butyldimethylsilyl)oxy]-3-methoxy-3-oxo-
prop-1-en-1-yl}-4,7,8′-trimethoxy-3H-spiro[benzofuran-2,2′-
chroman]-7′-carboxylate (22): To a cold (–25 °C) solution of ket-
one 21 (151 mg, 0.21 mmol) in MeCN (11 mL) was added TfOH
(20 μL of a freshly prepared 1.0
M stock solution of TfOH in MeCN,
20 μ ). The mixture was warmed up to –15 °C during 30 min. Then
M
Scheme 10. Formation of the isocoumarin-spiroketal 53 and subsequent O-
demethylation to 4′-silyl-γ-rubromycin 55 (reaction flask containing 36 mg of
nicely colored final product 55).
satd. Na2CO3 solution (aq., 1 mL), water, and EtOAc were sequen-
tially added. The layers were separated, and the aq. phase was ex-
tracted with EtOAc (3 ×). The combined organic layers were washed
with satd. NaCl solution (aq.), dried with Na2SO4, filtered, and con-
centrated. Column chromatography (silica gel; hexanes/EtOAc, 4:1)
provided spiroketal 22 (85 mg, 66 %) as a colorless solid. 1H NMR
(500 MHz, CDCl3): δ = 0.20, 0.97 (2 s, 6 H, 9 H, OSiMe2tBu), 2.20 (mc,
1 H, 3′-H), 2.36 (ddd, J = 2.6, 5.8, 13.3 Hz, 1 H, 3′-H), 2.79 (ddd, J =
Conclusions
In this account we disclose the development of a convergent
synthetic strategy that would eventually pave the way to the
natural product ( )-γ-rubromycin. Crucial to the success was the
adoption of a late-stage isocoumarin formation that occurred 2.4, 5.8, 16.7 Hz, 1 H, 4′-H), 3.24, 3.50 (AB system, JAB = 16.7 Hz, 1
H each, 3-H), 3.26 (mc, 1 H, 4′-H), 3.63, 3.69, 3.76, 3.81, 3.82 (5 s, 3
H each, OMe), 6.35 (s, 1 H, 1′′-H), 6.37, 6.71 (2 d, J = 8.9 Hz, 1 H
each, 5-H, 6-H), 6.76 (s, 1 H, 5′-H) ppm. 13C NMR (126 MHz, CDCl3):
δ = –4.90, –4.89, 18.2, 25.5 (2 q, s, q, OSiMe2tBu), 21.9 (t, C-4′), 30.1
(t, C-3′), 40.0 (t, C-3), 51.7, 52.1, 55.6, 56.8, 61.5 (5 q, OMe), 103.1 (d,
C-5), 110.1 (s, C-2), 113.0 (d, C-6), 113.9 (s, Ar), 117.4 (d, C-1′′), 124.2
(s, Ar), 124.7 (d, C-5′), 125.2, 126.3, 138.9, 142.4, 144.5, 145.5, 147.2,
after the pivotal spiroketalization step employing an electroni-
cally well-balanced key intermediate. For the construction of
this substrate, however, our first-choice approach via lithiated
methoxyallene – that worked remarkably well for the prepara-
tion of various simplified model compounds – had to be aban-
doned due to the intrinsic lability of the intermediate naphthyl-
methyl alcohol 30. The required adjustments to our synthetic
route finally led to the development of new γ-silylated allylic
phosphonate reagents (40 and 46), which perfectly comple-
150.4 (8 s, Ar, C-2′′), 165.0, 167.6 (2 s, C=O) ppm. IR (ATR): ν = 3000–
˜
2855 (C–H), 1730 (C=O), 1630, 1610 (C=C), 1570, 1510 cm–1. HRMS
(ESI-TOF): calcd. for [M + Na]+ 623.2288; found 623.2278.
ment methoxyallene as C3 building blocks. Their first applica- C31H40O10Si (600.7): calcd. C 61.98, H 6.71; found C 61.95, H 6.89.
tion finally resulted in the preparation of 4′-silyl-γ-rubromycin
55, but we also expect these reagents to be valuable for other
synthetic endeavors.
Methyl 4,7,10′-Trimethoxy-9′-oxo-4′,9′-dihydro-3H,3′H-
spiro[benzofuran-2,2′-pyrano[4,3-g]chromene]-7′-carboxylate
(24): To a cold (0 °C) solution of spiroketal 22 (80 mg, 0.13 mmol)
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in THF (2.5 mL) and water (0.6 mL) was added KF (30 mg,
0.53 mmol). The mixture was stirred at this temperature for 90 min.
Then water and EtOAc were sequentially added. The layers were
separated, and the aq. phase was extracted with EtOAc (3 ×). The
combined organic layers were washed with satd. NaCl solution (aq.),
layers were separated, and the aq. phase was extracted with EtOAc
(3 ×). The combined organic layers were washed with satd. NaCl
solution (aq.), dried with Na2SO4, filtered, and concentrated. Column
chromatography (silica gel; hexanes/EtOAc, 4:1) provided spiroketal
45 (34 mg, 85 %) as a mixture of diastereomers (trans/cis = 5.7:1)
dried with Na2SO4, filtered, and concentrated. Column chromatog- as a colorless oil. For analytical purposes, the diastereomers were
raphy (silica gel; hexanes/EtOAc, 1:1) provided spiroketal 24 (49 mg,
81 %) as a colorless solid. M.p. 207–209 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.26 (mc, 1 H, 3′-H), 2.43 (ddd, J = 2.0, 6.2, 13.6 Hz, 1 H,
3′-H), 2.95 (ddd, J = 2.0, 5.6, 16.9 Hz, 1 H, 4′-H), 3.30, 3.58 (AB system,
JAB = 16.9 Hz, 1 H each, 3-H), 3.42 (mc, 1 H, 4′-H), 3.73, 3.79, 3.81,
3.92 (4 s, 3 H each, OMe), 6.40, 6.72 (2 d, J = 8.9 Hz, 1 H each, 5-H,
6-H), 7.01 (s, 1 H, 5′-H), 7.30 (s, 1 H, 6′-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 22.4 (t, C-4′), 29.5 (t, C-3′), 39.9 (t, C-3), 52.7, 55.6, 56.7,
61.5 (4 q, OMe), 103.4 (d, C-5), 110.1 (s, C-2), 112.2 (d, C-6′), 112.8
(d, C-6), 113.6, 115.0 (2 s, Ar), 123.1 (d, C-5′), 128.9, 131.6, 138.9 (3
s, Ar), 141.6 (s, C-7′), 146.8, 148.1, 150.4, 150.6 (4 s, Ar), 157.0, 161.0
separated by HPLC (Merck LiChrosorb Diol-5μ; 32 × 125 mm, 5 %
iPrOH/hexanes, flow 28 mL min–1, 13 bar). HRMS (ESI-TOF): calcd.
for [M + Na]+ 401.1784; found 401.1793.
1
Isomer trans-45: H NMR (500 MHz, CDCl3): δ = 0.12 (s, 9 H, TMS),
2.01 (t, J = 13.7 Hz, 1 H, 3′-H), 2.30 (dd, J = 6.3, 13.7 Hz, 1 H, 3′-H),
2.86 (dd, J = 6.3, 13.7 Hz, 1 H, 4′-H), 3.26, 3.59 (AB system, JAB
=
16.7 Hz, 1 H each, 3-H), 3.72, 3.76, 3.80 (3 s, 3 H each, OMe), 6.34,
6.68 (2 d, J = 8.9 Hz, 1 H each, 5-H, 6-H), 6.66–6.67 (m, 1 H, Ar),
6.80–6.83 (m, 2 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = –1.7 (q,
TMS), 20.1 (d, C-4′), 33.5 (t, C-3′), 40.3 (t, C-3), 55.6, 55.9, 56.7 (3 q,
OMe), 102.7, 108.9 (2 d, Ar), 109.0 (s, C-2), 112.7 (d, Ar), 114.2 (s, Ar),
120.4, 120.5 (2 d, Ar), 125.4, 138.9, 141.7, 147.4, 148.9, 150.5 (6 s,
Ar) ppm.
(2 s, C=O) ppm. IR (ATR): ν = 3015–2840 (C–H), 1740 (C=O), 1645,
˜
1610 (C=C), 1555, 1510 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
477.1162; found 477.1160. C24H22O9 (454.4): calcd. C 63.43, H 4.88;
found C 63.32, H 4.76.
Isomer cis-45: 1H NMR (500 MHz, CDCl3): δ = 0.10 (s, 9 H, TMS),
2.31 (dd, J = 7.2, 13.6 Hz, 1 H, 3′-H), 2.37 (dd, J = 4.9, 13.6 Hz, 1 H,
1-[3,6-Dimethoxy-2-(methoxymethoxy)phenyl]-4-[3-methoxy-2-
(methoxymethoxy)phenyl]-4-(trimethylsilyl)butan-2-one (44):
To a cold (–40 °C) and well-stirred solution of 1-iodo-3-methoxy-2-
(methoxymethoxy)benzene (75 mg, 0.25 mmol) in THF (3 mL) was
3′-H), 2.51 (dd, J = 4.9, 7.2 Hz, 1 H, 4′-H), 3.19, 3.41 (AB system, JAB
=
16.9 Hz, 1 H each, 3-H), 3.74, 3.77, 3.78 (3 s, 3 H each, OMe), 6.34,
6.70* (2 d, J = 8.7 Hz, 1 H each, 5-H, 6-H), 6.64–6.66 (m, 1 H, Ar),
6.70* (m, 1 H, Ar), 6.82 (t, J = 7.9 Hz, 1 H, Ar) ppm; * signals are
overlapping. 13C NMR (126 MHz, CDCl3): δ = –1.4 (q, TMS), 23.9 (d,
C-4′), 33.1 (t, C-3′), 39.8 (t, C-3), 55.6, 55.9, 56.8 (3 q, OMe), 102.8,
108.5 (2 d, Ar), 110.5 (s, C-2), 112.7 (d, Ar), 114.0 (s, Ar), 119.9, 120.5
(2 d, Ar), 125.7, 139.2, 141.1, 147.6, 148.9, 150.4 (6 s, Ar) ppm.
added iPrMgCl (ca. 1.7
M in THF, 0.15 mL, 0.25 mmol). This freshly
prepared aryl Grignard reagent was rapidly added by syringe to a
mixture of enone 42 (60 mg, 0.18 mmol), HMPA (75 μL, 0.43 mmol),
CuI·2LiCl (0.10
M in THF, 0.20 mL), and TMSCl (45 μL, 0.35 mmol) in
THF (5 mL) at –40 °C. The cooling bath was immediately removed,
and the mixture was stirred at r.t. for 15 min. Then satd. NH4Cl
solution (aq.) and EtOAc were added. The layers were separated,
and the aq. phase was extracted with EtOAc (3 ×). The combined
organic layers were washed with satd. NaCl solution (aq.) and con-
centrated. The residual oil was dissolved in THF (5 mL), and H2SO4
(5 % aq., 0.5 mL) was added at r.t. After completion of the hydrolysis
of the silyl enol ether (ca. 15 min, according to TLC), water and
EtOAc were added. The layers were separated, and the aq. phase
was extracted with EtOAc (2 ×). The combined organic layers were
washed with satd. NaCl solution (aq.), dried with Na2SO4, filtered,
and concentrated. Column chromatography (silica gel; hexanes/
EtOAc, 4:1) provided ketone 44 (63 mg, 70 %) as a pale yellow oil.
1H NMR (500 MHz, CDCl3): δ = –0.07 (s, 9 H, TMS), 2.79 (dd, J = 5.1,
17.5 Hz, 1 H, 3-H), 3.00 (dd, J = 10.0, 17.5 Hz, 1 H, 3-H), 3.33 (dd, J =
5.1, 10.0 Hz, 1 H, 4-H), 3.41, 3.63, 3.64 (3 s, 3 H each, OMe), 3.74 (s,
2 H, 1-H), 3.77, 3.80 (2 s, 3 H each, OMe), 4.97, 4.98 (AB system,
JAB = 5.6 Hz, 1 H each, OCH2), 5.09, 5.11 (AB system, JAB = 5.0 Hz, 1
H each, OCH2), 6.53, 6.76 (2 d, J = 8.9 Hz, 1 H each, Ar), 6.57 (dd, J
≈ 1.4, 8.0 Hz, 1 H, Ar), 6.65 (dd, J ≈ 1.4, 8.2 Hz, 1 H, Ar), 6.94 (t, J ≈
8.0 Hz, 1 H, Ar) ppm. 13C NMR (126 MHz, CDCl3): δ = –2.9 (q, TMS),
22.8 (d, C-4), 39.0 (t, C-1), 42.1 (t, C-3), 55.5, 55.6, 56.2, 57.3, 57.4 (5
q, OMe), 98.4, 98.9 (2 t, OCH2), 105.5, 108.3, 111.1 (3 d, Ar), 118.91,
118.92 (s, d, Ar), 123.4 (d, Ar), 138.1, 142.6, 145.3, 146.4, 152.0, 152.6
Dimethyl [(E)-1-Methoxy-3-(trimethylsilyl)prop-1-en-1-yl]phos-
phonate (46): To a cooled (–78 °C) and well-stirred solution of diiso-
propylamine (iPr2NH, 14.8 mL, 105 mmol) in THF (100 mL) was
added nBuLi (2.5
M in hexanes, 42.0 mL, 105 mmol). After the mix-
ture had been kept at this temperature for 15 min, phosphonate
37 (17.2 g, 95 mmol) was added dropwise, resulting in a bright
orange-colored solution. After 15 min, chlorodimethyl(phenyl)silane
(18.8 g, 110 mmol) was added. Then, the mixture was warmed up
and stirred at r.t. for 1 h. Next, satd. NH4Cl solution (aq.), water, and
Et2O were added. The layers were separated and the aq. phase was
extracted with Et2O (2 ×). The combined organic layers were
washed with satd. NaCl solution (aq.), dried with Na2SO4, filtered,
and concentrated. The resulting residue (oil) was subjected to high-
vacuum distillation. One fraction (boiling range: 70–140 °C at
55 mTorr) was isolated that contained phosphonate 46 (25.0 g,
84 %) as a colorless liquid (nD19 = 1.513). 1H NMR (500 MHz, CDCl3):
4
δ = 0.33 (s, 6 H, SiMe2Ph), 1.94 (dd, JP, H = 2.3, J = 8.9 Hz, 2 H, 3-H),
4
3
3.53 (d, JP, H = 0.9 Hz, 3 H, 1-OMe), 3.67 (d, JP, H = 11.2 Hz, 6 H,
3
POMe), 6.10 (dd, J = 8.9, JP, H = 18.6 Hz, 1 H, 2-H), 7.33–7.35, 7.49–
7.51 (2 m, 3 H, 2 H, SiMe2Ph) ppm. 13C NMR (126 MHz, CDCl3): δ =
3
2
–3.2 (q, SiMe2Ph), 16.8 (dt, JP, C = 12.5 Hz, C-3), 52.3 (dq, JP, C
=
3
5.2 Hz, POMe), 59.4 (dq, JC,P = 2.1 Hz, 1-OMe), 127.8, 129.2 (2 d,
Ph), 131.2 (dd, 2JP, C = 34.8 Hz, C-2), 133.4 (d, Ph), 137.6 (s, Ph), 143.0
(d, JP, C = 215.8 Hz, C-1) ppm. 31P NMR (162 MHz, CDCl3): δ =
1
(6 s, Ar), 207.3 (s, C-2) ppm. IR (ATR): ν = 2995–2835 (C–H), 1715
˜
(C=O), 1595, 1580, 1490, 1475, 1440 cm–1. HRMS (ESI-TOF): calcd.
for [M + Na]+ 529.2234; found 529.2249. C26H38O8Si (506.7): calcd.
C 61.63, H 7.56; found C 61.48, H 7.57.
16.5 ppm. IR (ATR): ν = 3070–2850 (C–H), 1625 (C=C), 1460, 1430,
˜
1315, 1250 (P=O) cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
337.1001; found 337.0986. C14H23O4PSi (314.4): calcd. C 53.48, H
7.37; found C 53.49, H 7.37.
Trimethyl(4,7,8′-trimethoxy-3H-spiro[benzofuran-2,2′-
chroman]-4′-yl)silane (45): To a cold (–25 °C) solution of ketone
44 (49 mg, 0.10 mmol) in MeCN (4 mL) was added TfOH (7 μL of a
{(E/Z)-3-Methoxy-4-[1,4,5,6,8-pentamethoxy-3-(methoxy-
methoxy)naphthalen-2-yl]buta-1,3-dien-1-yl}dimethyl-
(phenyl)silane (47): To a cooled (–40 °C) solution of phosphonate
freshly prepared 1.3
M stock solution of TfOH in MeCN, 10 μM). The
mixture was warmed up to –15 °C during 20 min. Then satd. Na2CO3
solution (aq., 1 mL), water, and EtOAc were sequentially added. The
46 (0.79 g, 2.50 mmol) in THF (20 mL) was added KHMDS (0.70
in toluene, 3.60 mL, 2.50 mmol). The mixture was stirred at this
M
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temperature for 15 min, then cooled to –78 °C, and aldehyde 33
(0.73 g, 2.00 mmol, dissolved in 5 mL of THF) was added dropwise.
After 15 min, the cooling bath was removed, and the mixture was
stirred at r.t. for 1 h. Then satd. NH4Cl solution (aq.) and EtOAc were
added. The layers were separated, and the aq. phase was extracted
with EtOAc (2 ×). The combined organic layers were washed with
in THF (10 mL), and H2SO4 (5 % aq., 2 mL) was added at 0 °C. After
completion of the hydrolysis of the silyl enol ether (ca. 20 min,
according to TLC), water and EtOAc were added. The layers were
separated, and the aq. phase was extracted with EtOAc (2 ×). The
combined organic layers were washed with satd. NaCl solution (aq.),
dried with Na2SO4, filtered, and concentrated. Column chromatog-
satd. NaCl solution (aq.), dried with Na2SO4, filtered, and concen- raphy (silica gel; hexanes/EtOAc, 4:1 → 3:1) provided ketone 49
trated. Column chromatography (silica gel; hexanes/EtOAc, 3:1) pro- (443 mg, 87 %) as a pale yellow, highly viscous oil. 1H NMR
vided butadiene 47 [mixture of (E)/(Z) isomers, 0.82 g, 74 %] as a
(500 MHz, CDCl3): δ = 0.19, 0.20, 0.21 (3 s, 6 H, 3 H, 3 H, SiMe2Ph,
pale yellow oil. IR (ATR): ν = 3065–2840 (C–H), 1605 (C=C), 1565, OSiMe2tBu), 0.96 (s, 9 H, OSiMe2tBu), 2.77 (dd, J = 3.9, 17.7 Hz, 1 H,
˜
1455, 1430 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+ 577.2234;
found 577.2224. C30H38O8Si (554.7): calcd. C 64.69, H 6.90; found C
64.99, H 6.89.
3-H), 2.99 (dd, J = 10.7, 17.7 Hz, 1 H, 3-H), 3.33, 3.45 (2 s, 3 H each,
OMe), 3.53 (dd, J = 3.9, 10.7 Hz, 1 H, 4-H), 3.55, 3.60, 3.73, 3.76, 3.77
(5 s, 3 H each, OMe), 3.79 (s, 2 H, 1-H), 3.81, 3.90, 3.95 (3 s, 3 H each,
OMe), 5.09 (s, 4 H, OCH2), 6.37 (s, 1 H, 1′-H), 6.56 (s, 1 H, Ar), 6.61
(s, 1 H, Ar), 7.22–7.32 (m, 3 H, Ph), 7.36–7.41 (m, 2 H, Ph) ppm. 13C
NMR (126 MHz, CDCl3): δ = –5.7, –5.02, –4.99, –4.3 (4 q, OSiMe2tBu,
SiMe2Ph), 18.1, 25.4 (s, q, OSiMe2tBu), 22.9* (d, C-4), 39.4 (t, C-1),
41.9 (t, C-3), 51.6, 52.0, 56.66, 56.70, 57.3, 57.6, 61.3, 61.4, 61.7, 61.8
(10 q, OMe), 96.1 (d, Ar), 98.7, 99.5 (2 t, OCH2), 114.3 (s, Ar), 118.2
(d, C-1′), 119.7 (s, Ar), 122.7 (d, Ar), 124.7, 125.7 (2 s, Ar), 127.5 (d,
Ph), 128.9 (s, Ar), 129.1, 133.9 (2 d, Ph), 136.5 (s, Ar), 136.6 (s, Ph),
139.7, 142.3 (2 s, Ar), 142.4 (s, C-2′), 145.8, 147.5, 149.7, 150.2, 151.0,
152.8 (6 s, Ar), 164.4, 167.5 (2 s, C=O), 207.9 (s, C-2) ppm. IR (ATR):
Isomer (E)-47: 1H NMR (400 MHz, CDCl3): δ = 0.41 (s, 6 H, SiMe2Ph),
3.52, 3.53, 3.72, 3.84, 3.87, 3.96, 3.99 (7 s, 3 H each, OMe), 5.18 (s, 2
H, OCH2), 5.91 (s, 1 H, 4-H), 6.43, 6.53 (2 d, J = 18.6 Hz, 1 H each, 1-
H, 2-H), 6.66 (s, 1 H, Ar), 7.35–7.40 (m, 3 H, Ph), 7.45–7.60 (m, 2 H,
Ph) ppm.
Isomer (Z)-47: 1H NMR (400 MHz, CDCl3): δ = 0.28 (s, 6 H, SiMe2Ph),
3.49, 3.65, 3.83, 3.85, 3.96, 4.00 (6* s, 3 H each, OMe), 5.07 (s, 2 H,
OCH2), 5.79 (s, 1 H, 4-H), 6.46, 6.54 (2 d, J = 18.8 Hz, 1 H each, 1-H,
2-H), 6.67 (s, 1 H, Ar), 7.35–7.40 (m, 3 H, Ph), 7.45–7.60 (m, 2 H, Ph)
ppm; * one signal for OMe could not be assigned properly.
ν = 2975–2855 (C–H), 1730 (C=O), 1635, 1605 (C=C), 1560 cm–1
.
˜
HRMS (ESI-TOF): calcd. for [M + Na]+ 1003.3944; found 1003.3982.
50H68O16Si2 (981.2): calcd. C 61.20, H 6.99; found C 61.43, H 6.55.
(E)-4-[Dimethyl(phenyl)silyl]-1-[1,4,5,6,8-pentamethoxy-3-
(methoxymethoxy)naphthalen-2-yl]but-3-en-2-one (48): To a
cooled (0 °C) solution of butadiene 47 (0.68 g, 1.23 mmol) in CH2Cl2
(15 mL) was added trichloroacetic acid (TCA, 200 mg, 1.23 mmol).
The mixture was stirred at r.t. for 3 h. Then, satd. Na2CO3 solution
(aq.), water, and CH2Cl2 were added. The layers were separated, and
the aq. phase was extracted with CH2Cl2 (2 ×). The combined or-
ganic layers were dried with Na2SO4, filtered, and concentrated. Col-
umn chromatography (silica gel; hexanes/EtOAc, 3:1) provided en-
one 48 (0.46 g, 68 %) as a pale yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 0.42 (s, 6 H, SiMe2Ph), 3.47, 3.67, 3.78, 3.81, 3.95, 3.99 (6 s, 3 H
each, OMe), 4.16 (s, 2 H, 1-H), 5.20 (s, 2 H, OCH2), 6.653 (s, 1 H, Ar),
6.656, 7.29 (2 d, J = 19.1 Hz, 1 H each, 3-H, 4-H), 7.31–7.39 (m, 3 H,
Ph), 7.46–7.49 (m, 2 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ =
–3.2 (q, SiMe2Ph), 36.5 (t, C-1), 56.8*, 57.6, 61.6, 61.8, 62.3 (5 q, OMe),
96.2 (d, Ar), 99.8 (t, OCH2), 114.4, 119.8, 125.8 (3 s, Ar), 127.9, 129.4,
133.8 (3 d, Ph), 136.5 (s, Ph), 136.6, 142.5 (2 s, Ar), 142.9 (d, C-3),
144.3 (d, C-4), 147.8, 149.8, 151.2, 152.9 (4 s, Ar), 197.8 (s, C-2) ppm;
C
Methyl 6-{(E)-2-[(tert-Butyldimethylsilyl)oxy]-3-methoxy-3-oxo-
prop-1-en-1-yl}-4-{1-[dimethyl(phenyl)silyl]-3-oxo-4-[1,4,6-tri-
methoxy-3-(methoxymethoxy)-5,8-dioxo-5,8-dihydro-
naphthalen-2-yl]butyl}-2-methoxy-3-(methoxymethoxy)benzo-
ate (50): To a cooled (0 °C) solution of ketone 49 (440 mg,
0.45 mmol) in MeCN (10.0 mL) and H2O (2.5 mL) was added DDQ
(135 mg, 0.59 mmol) in one portion. After the mixture had been
kept at this temperature for 20 min, water and EtOAc were added.
The layers were separated, and the aq. phase was extracted with
EtOAc (3 ×). The combined organic layers were washed with satd.
NaCl solution (aq.), dried with Na2SO4, filtered, and concentrated.
The residue was filtered through a plug of Al2O3 with EtOAc as
eluent and concentrated to provide ketone 50 (388 mg, 91 %) as a
yellow/orange resin. 1H NMR (500 MHz, CDCl3): δ = 0.195, 0.198,
0.22, 0.25 (4 s, 3 H each, SiMe2Ph, OSiMe2tBu), 0.97 (s, 9 H,
OSiMe2tBu), 2.75 (dd, J = 4.0, 17.7 Hz, 1 H, 3-H), 3.03 (dd, J = 10.8,
17.7 Hz, 1 H, 3-H), 3.28, 3.47 (2 s, 3 H each, OMe), 3.53 (dd, J = 4.0,
10.8 Hz, 1 H, 4-H), 3.587, 3.593, 3.76 (3 s, 3 H each, OMe), 3.78* (2
s, 3 H, 2 H, OMe, 1-H), 3.81, 3.82 (2 s, 3 H each, OMe), 5.04, 5.05 (AB
system, JAB = 5.6 Hz, 2 H, OCH2), 5.06, 5.07 (AB system, JAB = 5.0 Hz,
2 H, OCH2), 5.95 (s, 1 H, 6′′-H), 6.35 (d, J = 0.7 Hz, 1 H, 1′-H), 6.62 (s,
1 H, Ar), 7.30–7.36 (m, 3 H, Ph), 7.42–7.46 (m, 2 H, Ph) ppm; * signals
are overlapping. 13C NMR (126 MHz, CDCl3): δ = –5.8, –4.99, –4.95,
–4.2 (4 q, OSiMe2tBu, SiMe2Ph), 18.2, 25.4 (s, q, OSiMe2tBu), 23.1*
(d, C-4), 39.1 (t, C-1), 42.6 (t, C-3), 51.6, 52.1, 56.2, 57.55, 57.57, 61.28,
61.31, 61.9 (8 q, OMe), 98.8, 99.6 (2 t, OCH2), 110.1 (d, C-6′′), 117.9
(d, C-1′), 120.2 (s, Ar), 122.8 (d, Ar), 124.5, 125.0, 126.8 (3 s, Ar), 127.7,
129.3 (2 d, Ph), 132.9 (s, Ar), 134.0 (d, Ph), 136.5 (s, Ph), 139.1 (s, Ar),
142.6 (s, C-2′), 146.1, 149.7, 150.2, 155.0, 155.7, 159.1 (6 s, Ar), 164.4,
167.4 (2 s, C=O), 178.9, 183.3 (2 s, C-8′′, C-5′′), 206.0 (s, C-2) ppm;
* signal of higher intensity. IR (ATR): ν = 3070–2840 (C–H), 1685
˜
(C=O), 1600 (C=C), 1455, 1440, 1425 cm–1. HRMS (ESI-TOF): calcd.
for [M + Na]+ 563.2077; found 563.2069. C29H36O8Si (540.7): calcd.
C 64.42, H 6.71; found C 64.45, H 6.79.
Methyl 6-{(E)-2-[(tert-Butyldimethylsilyl)oxy]-3-methoxy-3-oxo-
prop-1-en-1-yl}-4-{1-[dimethyl(phenyl)silyl]-3-oxo-4-[1,4,5,6,8-
pentamethoxy-3-(methoxymethoxy)naphthalen-2-yl]butyl}-2-
methoxy-3-(methoxymethoxy)benzoate (49): To a cooled
(–40 °C) and well-stirred solution of aryl iodide 13 (585 mg,
1.03 mmol) in Et2O (18.0 mL) and THF (4.5 mL) was slowly added
iPrMgBr (3.00
M in 2-Me-THF, 0.36 mL, 1.03 mmol). To redissolve
partially precipitated material, the mixture was quickly warmed to
–20 °C and then recooled to –40 °C. Then, a mixture of enone 48
(280 mg, 0.52 mmol dissolved in 5.5 mL of Et2O), HMPA (0.52 mL,
* broad signal. IR (ATR): ν = 3000–2855 (C–H), 1730 (C=O), 1680,
˜
2.97 mmol), CuI·2LiCl (0.10
M in THF, 0.77 mL), and TMSCl (0.27 mL,
1645, 1630 (C=C), 1590, 1555, 1460, 1435 cm–1. HRMS (ESI-TOF):
calcd. for [M + Na]+ 973.3474; found 973.3497. C48H62O16Si2 (951.2):
calcd. C 60.61, H 6.57; found C 60.70, H 6.66.
3.20 mmol) was rapidly added to the Grignard reagent. The cooling
bath was immediately removed, and the mixture was stirred at r.t.
for 30 min. Then satd. NH4Cl solution (aq.) and EtOAc were added.
The layers were separated, and the aq. phase was extracted with
EtOAc (2 ×). The combined organic layers were washed with satd.
NaCl solution (aq.) and concentrated. The residual oil was dissolved
Methyl 6-{(E)-2-[(tert-Butyldimethylsilyl)oxy]-3-methoxy-3-oxo-
prop-1-en-1-yl}-4-[dimethyl(phenyl)silyl]-4′,7′,8,9′-tetrameth-
oxy-5′,8′-dioxo-5′,8′-dihydro-3′H-spiro[chroman-2,2′-naphtho-
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[2,3-b]furan]-7-carboxylate (51): To a cooled (–25 °C) solution of
ketone 50 (385 mg, 0.41 mmol) in MeCN (22.5 mL) was added TfOH
(12 mg, 80 μmol). The mixture was warmed up to +5 °C over 2 h.
(99 mg), which contained spiroketal 53 (71 %) and naphthofuran
derivative 54 (12 %, tentatively assigned), as judged by 1H NMR
spectroscopy. Melting range: 110–130 °C. 1H NMR (500 MHz, CDCl3):
Then satd. Na2CO3 solution (aq.), water and EtOAc were added. The δ = 0.41 (s, 6 H, SiMe2Ph), 2.27 (dd, J ≈ 11.9, 14.3 Hz, 1 H, 3′-H), 2.43
layers were separated, and the aq. phase was extracted with EtOAc
(3 ×). The combined organic layers were washed with satd. NaCl
(dd, J ≈ 7.9, 14.3 Hz, 1 H, 3′-H), 3.19 (dd, J ≈ 7.5, 10.9 Hz, 1 H, 4′-H),
3.41, 3.71 (AB system, JAB = 17.6 Hz, 1 H each, 3-H), 3.60, 3.70, 3.82,
solution (aq.), dried with Na2SO4, filtered, and concentrated. Column 3.91, 3.92 (5 s, 3 H each, OMe), 5.95 (s, 1 H, 6-H), 6.91 (d, J = 1.1 Hz,
chromatography (silica gel; CH2Cl2/Et2O, 10:1) provided spiroketal 1 H, 5′-H), 7.08 (s, 6′-H), 7.40–7.47 (m, 3 H, Ph), 7.49–7.53 (m, 2 H,
51 (dr > 20:1, 280 mg, 82 %) as a yellow solid. M.p. 79–83 °C. 1H
NMR (500 MHz, CDCl3): δ = 0.17, 0.96 (2 s, 6 H, 9 H, OSiMe2tBu),
0.34, 0.43 (2 s, 3 H each, SiMe2Ph), 2.15 (t, J ≈ 13.7 Hz, 1 H, 3′-H),
2.26 (dd, J ≈ 7.2, 14.0 Hz, 1 H, 3′-H), 3.02 (dd, J ≈ 7.2, 12.3 Hz, 1 H,
4′-H), 3.32, 3.59 (AB system, JAB = 17.4 Hz, 1 H each, 3-H), 3.54, 3.60,
3.69, 3.79, 3.80, 3.87 (6 s, 3 H each, OMe), 5.93 (s, 1 H, 6-H), 6.33 (s,
Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = –4.7, –3.7 (2 q, SiMe2Ph),
21.7 (d, C-4′), 32.7 (t, C-3′), 39.7 (t, C-3), 52.8, 56.3, 60.8, 61.2, 61.7
(5 q, OMe), 109.5 (s, C-2), 109.9 (d, C-6), 112.2 (d, C-6′), 114.0, 119.6
(2 s, Ar), 122.3 (d, C-5′), 125.6, 127.1 (2 s, Ar), 128.4 (d, Ph), 129.4 (s,
Ar), 130.1, 133.8 (2 d, Ph), 135.3 (s, Ar), 136.0 (s, Ph), 141.7, 141.9 (2
s, Ar, C-7′), 147.1, 151.1, 153.0, 155.0 (4 s, Ar), 156.8 (s, C-9′), 159.2
1 H, 1′′-H), 6.72 (s, 1 H, 5′-H), 7.32–7.40 (m, 3 H, Ph), 7.47–7.51 (m, (s, C-7), 160.9 (s, C=O), 179.2 (s, C-8), 183.6 (s, C-5) ppm. IR (ATR):
2 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = –5.0, 18.2, 25.5 (q, s, ν = 3050–2850 (C–H), 1740 (C=O), 1680, 1645, 1625 (C=C),
˜
q, OSiMe2tBu), –4.2, –3.7 (2 q, SiMe2Ph), 20.3 (d, C-4′), 32.9 (t, C-3′), 1590 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+ 721.1717; found
39.7 (t, C-3), 51.5, 52.1, 56.2, 60.7, 61.0, 61.6 (6 q, OMe), 109.6 (s, C-
2), 109.8 (d, C-6), 117.9 (d, C-1′′), 119.2 (s, Ar), 124.2 (d, C-5′), 125.2,
125.3, 126.4, 127.2, 127.3 (5 s, Ar), 128.1, 129.6, 133.6 (3 d, Ph), 136.8
(s, Ph), 141.8 (s, Ar), 142.5 (s, C-2′′), 143.5, 146.2, 152.9, 155.1 (4 s,
Ar), 159.2 (s, C-7), 164.4, 167.3 (2 s, C=O), 179.2 (s, C-8), 183.7 (s, C-
721.1741. C37H34O12Si (698.7): calcd. C 63.60, H 4.90; found C 63.47,
H 4.96.
Methyl 4′-[Dimethyl(phenyl)silyl]-4,9,10′-trihydroxy-7-methoxy-
5,8,9′-trioxo-4′,5,8,9′-tetrahydro-3 H,3′H-spiro[naphtho-
[2,3-b]furan-2,2′-pyrano[4,3-g]chromene]-7′-carboxylate (55):
To a cooled (–78 °C) solution of spiroketal 53 (72 mg, 0.10 mmol)
5) ppm. IR (ATR): ν = 2950–2855 (C–H), 1730 (C=O), 1680, 1645,
˜
1635 (C=C), 1590 cm–1. HRMS (ESI-TOF): calcd. for [M + Na]+
867.2844; found 867.2884. C44H52O13Si2 (845.0): calcd. C 63.54, H
6.20; found C 63.05, H 6.30.
in CH2Cl2 (10 mL) was added BBr3 (1.0
M in CH2Cl2, 0.62 mL,
0.62 mmol). The mixture was warmed up to –30 °C over 90 min,
and water was added. The layers were separated, and the aq. phase
was extracted with CH2Cl2 (3 ×). The combined organic layers were
dried with Na2SO4, filtered, and concentrated. Column chromatog-
raphy (silica gel; CH2Cl2/Et2O, 3:1) provided spiroketal 55 (36 mg,
Methyl 4-(Dimethyl(phenyl)silyl)-6-formyl-4′,7′,8,9′-tetrameth-
oxy-5′,8′-dioxo-5′,8′-dihydro-3′H-spiro[chroman-2,2′-naphtho-
[2,3-b]furan]-7-carboxylate (52): To a cooled (–78 °C) solution of
spiroketal 51 (25 mg, 30 μmol) in THF (3.0 mL) was added TBAF
1
53 %) as a red solid. Melting range: 260–265 °C. H NMR (700 MHz,
CDCl3): δ = 0.41 (s, 6 H, SiMe2Ph), 2.22 (t, J ≈ 14.3 Hz, 1 H, 3′-H),
2.40 (dd, J ≈ 7.1, 14.0 Hz, 1 H, 3′-H), 3.26 (dd, J ≈ 7.1, 12.5 Hz, 1 H,
4′-H), 3.36, 3.72 (AB system, JAB = 18.2 Hz, 1 H each, 3-H), 3.90, 3.93
(2 s, 3 H each, OMe), 6.15 (s, 1 H, 6-H), 6.74 (s, 1 H, 5′-H), 7.16 (s, 1
H, 6′-H), 7.38–7.47 (m, 3 H, Ph), 7.52–7.57 (m, 2 H, Ph), 10.92, 12.24,
13.01 (3 s, each 1 H, OH) ppm. 13C NMR (176 MHz, CDCl3): δ = –4.5,
–3.3 (2 q, SiMe2Ph), 21.2 (d, C-4′), 33.0 (t, C-3′), 39.4 (t, C-3), 52.9 (q,
7-OMe), 56.7 (q, OMe), 105.6 (s, C-9a′), 106.3 (s, C-4a), 110.0 (d, C-
6), 110.3 (s, C-2), 112.9 (d, C-6′), 113.8 (s, Ar), 117.7 (d, C-5′), 123.0,
127.0 (2 s, Ar), 128.4, 130.0, 133.8 (3 d, Ph), 135.2 (s, Ar), 136.4 (s,
Ph), 141.0 (s, Ar), 141.1 (s, C-7′), 150.2 (s, Ar), 150.9 (s, C-10′), 153.6
(s, C-4), 159.0 (s, C-9′), 159.9 (s, C-7), 160.5 (s, C=O), 164.8 (s, Ar),
(50 μL, 50 μmol, 1.0
M in THF). The mixture was stirred at this tem-
perature for 15 min. The cooling bath was removed, and satd. NaCl
solution (aq.) and EtOAc were added. After the mixture was warmed
to r.t., the layers were separated, and the aq. phase was extracted
with EtOAc (2 ×). The combined organic layers were dried with
Na2SO4, filtered, and concentrated. Column chromatography (silica
gel; CH2Cl2/Et2O, 10:1) provided spiroketal 52 (10 mg, 51 %) as a
1
yellow solid. Melting range: 105–115 °C. H NMR (500 MHz, CDCl3):
δ = 0.41, 0.43 (2 s, 3 H each, SiMe2Ph), 2.21 (dd, J = 12.7, 14.1 Hz,
1 H, 3-H), 2.40 (dd, J = 7.2, 14.1 Hz, 1 H, 3-H), 3.12 (ddd, J = 0.7, 7.2,
12.7 Hz, 1 H, 4-H), 3.42, 3.66 (AB system, JAB = 17.5 Hz, 1 H each,
3′-H), 3.60, 3.68, 3.82, 3.90, 3.92 (5 s, 3 H each, OMe), 5.95 (s, 1 H,
6′-H), 7.25 (d, J = 1.0 Hz, 1 H, 5-H), 7.40–7.46 (m, 3 H, Ph), 7.53–7.56
(m, 2 H, Ph), 9.55 (s, 1 H, CHO) ppm. 13C NMR (126 MHz, CDCl3): δ =
–4.7, –3.7 (2 q, SiMe2Ph), 20.3 (d, C-4), 32.5 (t, C-3), 39.7 (t, C-3′),
52.8, 56.3, 60.9, 61.2, 61.9 (5 q, OMe), 109.5 (s, C-2), 109.8 (d, C-6′),
119.6, 125.7 (2 s, Ar), 126.3 (s, C-6), 126.9, 127.0, 127.5 (3 s, Ar), 127.9
(d, C-5), 128.4, 130.0, 133.9 (3 d, Ph), 136.4 (s, Ph), 141.8, 146.7,
149.7, 153.0, 154.9 (5 s, Ar), 159.3 (s, C-7′), 166.7 (s, C=O), 179.1 (s,
178.8 (s, C-8), 183.5 (s, C-5) ppm. IR (ATR): ν = 3050–2850 (C–H),
˜
1735 (C=O), 1685, 1610, 1430 cm–1. HRMS (ESI-TOF): calcd. for [M +
Na]+ 679.1248; found 679.1266. C34H28O12Si (656.7): calcd. C 62.19,
H 4.30; found C 62.19, H 4.30.
Acknowledgments
C-8′), 183.6 (s, C-5′), 189.2 (d, CHO) ppm. IR (ATR): ν = 3410 (OH,
Support of this work by Bayer HealthCare AG is most gratefully
acknowledged. The help of C. Groneberg for HPLC separations,
the NMR spectroscopy service team of Dr. A. Schäfer, and the
mass spectrometry team of Dr. A. Springer is also gratefully
acknowledged.
˜
hydrate), 3020–2850 (C–H), 1730 (C=O), 1465 cm–1. HRMS (ESI-TOF):
calcd. for [M + Na]+ 681.1768; found 681.1804. C35H34O11Si (658.7):
calcd. C 63.82, H 5.20; found C 63.40, H 5.15.
Methyl 4′-[Dimethyl(phenyl)silyl]-4,7,9,10′-tetramethoxy-5,8,9′-
trioxo-4′,5,8,9′-tetrahydro-3H,3′H-spiro[naphtho[2,3-b]furan-
2,2′-pyrano[4,3-g]chromene]-7′-carboxylate (53): To a solution of
51 (145 mg, 0.17 mmol) in dry CH2Cl2 (8.6 mL) in a 50 mL pressure
tube was added HBF4·Et2O (0.23 mL, 1.70 mmol). The mixture was
heated to 50 °C for 30 min. Then, satd. Na2CO3 solution (aq.), water,
and CH2Cl2 were added. The layers were separated, and the aq.
phase was extracted with CH2Cl2 (2 ×). The combined organic layers
were dried with Na2SO4, filtered, and concentrated. Column
chromatography (silica gel; CH2Cl2/Et2O, 5:1) provided a yellow solid
Keywords: Rubromycin · Total synthesis · Conjugate
addition · Spiroketals · Allylic phosphonates · C3 building
blocks · Spiro compounds · Natural products · Oxygen
heterocycles
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Received: September 29, 2016
Published Online: ■
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Full Paper
Rubromycins
Condense and merge! A concise strat-
egy for the highly convergent assem-
bly for rubromycin-type “aromatic”
spiroketals with the help of allylic
phosphonates as central C3 building
blocks is presented.
M. Wilsdorf,* H.-U. Reissig* .......... 1–11
Towards γ-Rubromycin: Model Stud-
ies, Development of a C3 Building
Block, and Synthesis of 4′-Silyl-γ-ru-
bromycin
DOI: 10.1002/ejoc.201601224
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim