Synthesis of spiroketals under neutral conditions via a type III ring-rearrangement metathesis strategy

Article abstract of DOI:10.1039/c1cc14329h

A conceptually novel approach to spiro- and dispiroketals of various ring-sizes under neutral conditions has been designed which complements the classical thermodynamically driven tactic. Key steps involved the formation of α-alkoxyfurans, their [4+2] or [4+3] cycloaddition reactions and the ring-rearrangement metathesis of the resulting oxabicycles.

Full text of DOI:10.1039/c1cc14329h

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COMMUNICATION
Synthesis of spiroketals under neutral conditions via a type III
ring-rearrangement metathesis strategyw
a
a
b
a
´ ´
Jeremie Mandel, Nathalie Dubois, Markus Neuburger and Nicolas Blanchard*
Received 18th July 2011, Accepted 4th August 2011
DOI: 10.1039/c1cc14329h
A conceptually novel approach to spiro- and dispiroketals of
various ring-sizes under neutral conditions has been designed
which complements the classical thermodynamically driven
tactic. Key steps involved the formation of a-alkoxyfurans, their
[4+2] or [4+3] cycloaddition reactions and the ring-rearrangement
metathesis of the resulting oxabicycles.
derivatives 3. We wish to report herein a general access to a
diversity of oxabicyclic derivatives 3 and their use in an
efficient RRM sequence. Spiroketals of various ring-sizes have
been synthesized in high yield and the method is amenable to
RCM-ROM-RCM as exemplified with the straightforward
elaboration of 1,7-dioxadispiroalkane derivatives.
It was envisaged that 1-alkoxy oxabicyclic derivatives 3
could be accessed through a [4+2] or [4+3] cycloaddition
reaction of the corresponding a-alkoxyfuran 4 (Scheme 1).
The latter species has been scarcely reported in the literature.
Indeed, the few reported syntheses rely on thermal rearrange-
ment of strained rings,6 trapping of a transient g-crotonolactone
enolate,7 oxidation of 2-lithiofuran,8 elimination of 2-substituted
2,5-dialkoxy-2,5-dihydrofuran,9 or nucleophilic aromatic substi-
tution of activated a-bromofurans with aliphatic sodium alkoxide
or phenoxide under pressure at 100 1C.10 These methods suffered
from either low yields or narrow scope thereby affording a unique
opportunity to develop a general methodology for the construc-
tion of these seemingly trivial heterocycles.
For the past few years, we have been interested in the ring
rearrangement metathesis1 (RRM) of strained heterobicycles
as an efficient strategy to access complex molecular scaffolds in
a single step.2 In connection with a total synthesis project ongoing
in our laboratories, we recently became interested in developing an
efficient strategy for the elaboration of spiroketal moieties 1 via the
RRM of oxabicyclic derivatives 3 (Scheme 1). This type III-RRM
tactic3 would proceed under neutral conditions thereby com-
plementing the classical and well-established thermodynamically-
driven acid-catalyzed condensation of dihydroxyketones.4 In
addition, the potential for the rapid increase in molecular
complexity and diversity combined with the general functional
group tolerance exhibited by metathesis catalysts would be of
high value to the synthetic chemist.
An efficient synthetic strategy of a-alkoxyfurans 4 was found,
based on the acid-catalysed transformation of commercially
available methyl 2,5-dimethoxy-2,5-dihydrofuranoate
6
Quite surprisingly however, such an approach has not been
reported to the best of our knowledge,5 certainly due to the
lack of practical and general access to 1-alkoxy oxabicyclic
(Scheme 2). At reflux in heptane with 5 mol% of p-TsOH, 6
is converted to a separable mixture of the desired a-alkoxyfurans
7 and 8a–j in 50–98% yield.11 Primary, secondary and
neopentylic alcohols were found to be excellent partners, with
secondary alcohols leading exclusively to a-alkoxyfurans 7
(see 7b, 7h and 7j, Scheme 2). Interestingly, unsaturated
alcohols such as but-3-enol or cyclopent-3-enol were also
tolerated which was of central importance in the context of
our RRM-based approach to spiroketals.12
Having in hand a straightforward synthesis of a-alkoxyfurans,
we investigated their reactivity in [4+2] and [4+3] cycloaddition
reactions (Scheme 3). [4+2] cycloaddition of furan derivatives
with vinylcyanoacetate 11a has a long standing history with
the seminal work of Katsuki and Nishizawa13 and Vogel and
Vieira14 who demonstrated that high pressure (15 kbars, 8 h)
or an external Lewis acid (ZnI2, 96 h) was required. In sharp
contrast, the cycloaddition reaction of dienophile 11a with the
electron rich a-alkoxyfuran 9 (obtained in two steps from
7i—or even from the 1 : 1 mixture of 7i and 8i—in 87% yield)
proceeded quite smoothly at 60 1C in the absence of solvent.15
A unique regioisomer was obtained in 80% yield.16 However,
the diastereoselectivity of this reaction was only moderate
Scheme 1 A type III-RRM tactic for spiroketal synthesis.
a
´
´
Universite de Haute-Alsace, Ecole Nationale Superieure de Chimie
de Mulhouse, Laboratoire de Chimie Organique et Bioorganique
EA4566, 3 rue A. Werner, 68093 Mulhouse Cedex, France.
E-mail: nicolas.blanchard@uha.fr
b Department of Chemistry, Universitat Basel, Spitalstrasse 51,
¨
CH-4056, Basel, Switzerland
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and NMR data. CCDC 835354. See
DOI: 10.1039/c1cc14329h
c
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Mann’s19 conditions leading to RRM precursors 17–19, the
structure of the latter being confirmed by X-ray diffraction studies
of the corresponding p-nitrobenzoate.16c
The reactivity of the [2.2.1] and [3.2.1]-oxabicycles 12, 14
and 17 in a RRM sequence was then evaluated (Scheme 4).
Much to our delight, a complete conversion of 12a to the
desired (5,6)-spiroketal 20a was observed under mild conditions
(Grubbs second generation catalyst [Ru]-2 10 mol%, CH2Cl2,
45 1C, 1 h). The RRM of the corresponding sulfone- or ester
substituted [2.2.1]-oxabicycles 12b and 12c proceeded equally
well delivering (5,6)-spiroketal derivatives 20b and 20c in 87
and 99% yield. It is of note that spiroketal 20b can be
smoothly desulfonylated to compound 21 by treatment with
sodium amalgam. Replacement of the butenyloxy moiety of
12a–c with a cyclopentenyloxy moiety as in oxabicycles 14b or
14c prevents any RRM sequence under the standard reaction
conditions or under an ethylene atmosphere. Only the ring
opening of the oxa-bridge of 14b was observed under forcing
conditions (1,2-DCE, 85 1C, 3 h), delivering cyclohexadienyl-
sulfone 22 in quantitative yield. Finally, the RRM of [3.2.1]-
oxabicycle 17 was studied. A good yield of the desired
(6,6)-spiroketal 23 could be obtained in 1 h under mild
conditions thus validating this straightforward strategy for
the rapid elaboration of polyfunctional spiroketal units.
A plausible sequence of events in this RRM approach to
spiroketals is a favorable initiation at the mono-substituted exo-
olefin of 12 followed by a RCM/ROM reaction. We thus
wondered whether the trapping of the last ruthenium alkylidene
by an internal olefin (instead of a bimolecular event with a
second [2.2.1]-oxabicycle) would generate the 1,7-dioxadispiro-
pentadecane tricyclic motif, a fascinating structural subunit
shared by several biologically relevant natural products such
as the aculeatins and aculeatols.20 To this end, [2.2.1]- and [3.2.1]-
oxabicycles 12a and 17 were converted to the corresponding
bis(alkenyl)ether through a high-yielding two-step sequence
involving silyl ether deprotection followed by a palladium-
catalyzed allylation reaction (Scheme 4).21 Under optimized
reaction conditions ([Ru]-2 10 mol%, toluene, 90 1C, 1 h), the
desired (6,5,6)- and (6,6,6)-dispiroketals 24 and 25 were
prepared in excellent yield demonstrating that a RCM/
ROM/RCM sequence is indeed possible for the elaboration
of complex spiroketals.
Scheme 2 A general synthesis of a-alkoxyfurans.
(12a/13a = 80 : 20) in agreement with related cycloaddition
reactions of 2-alkyl substituted furans.13,14a Two other dieno-
philes were evaluated in this [4+2] cycloaddition reaction,
phenylvinylsulfone 11b and ethyl acrylate 11c. In these two
cases, microwave irradiation proved beneficial to the rate and
yield of the reaction. Bicyclic adduct 12b was isolated as single
regio- and diastereomer in 75% yield.16b,c On the other hand,
two diastereomers were obtained in the cycloaddition reaction
of 9 with ethyl acrylate 11c (12c/13c = 80 : 20, 73% yield). We
next focused on a-alkoxyfuran 10 bearing a cyclopentenyloxy
motif (Scheme 3). [4+2] cycloaddition reactions with phenyl-
vinyl sulfone 11b and ethyl acrylate 11c proceeded in moderate
yield under microwave irradiation (2–4 h, 70 1C, 58 and 66%
yield respectively). Cycloadduct 14b was obtained as a single
regio- and diastereomer whereas the cycloaddition with 11c led
to two diastereomers in a 14c/15c = 80 : 20 ratio.16b,c
In the context of a RRM-based approach to spiroketal motifs,
a metathetic rearrangement of 1-alkoxy-1-oxabicylo[3.2.1]heptenes
3 (n = 2) (Scheme 1) would be of high interest, giving access to
(6,6)-spiroketals 2. Actually, we found that a-alkoxyfuran 9 is a
reactive partner in [4+3] cycloaddition17 under Noyori’s18 and
Scheme 3 [4+2] and [4+3] cycloaddition reactions of a-alkoxyfurans.
c
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(b) Determined by NOE experiments, 1H NMR chemical shifts
and/or J2, J3 coupling constants; (c) See ESIw for details.
Scheme 4 Synthesis of di- and trispiroketals under neutral conditions.
In conclusion, we have devised a conceptually novel approach
to spiro- and dispiroketals of various ring-sizes under neutral
conditions, which complements the classical thermodynamically
driven tactic. During this endeavour, a general access to
a-alkoxyfurans, versatile electron-rich heterocycles, has been
established and their use as dienophiles in [4+2] and [4+3]
cycloaddition reactions has been demonstrated.
´
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c
10286 Chem. Commun., 2011, 47, 10284–10286
This journal is The Royal Society of Chemistry 2011