2-(Trimethylsilyloxy)furan as a dianion equivalent: A two-step synthesis of functionalized spirocyclic butenolides

Article abstract of DOI:10.1021/ol061284g

The use of 2-(trimethylsilyloxy)furan derivatives as dianion equivalents leads to a general and connective spiroannulation protocol for the efficient preparation of spirocyclic butenolides.

Full text of DOI:10.1021/ol061284g

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3705-3707
2-(Trimethylsilyloxy)furan as a Dianion
Equivalent: A Two-Step Synthesis of
Functionalized Spirocyclic Butenolides
Nuno Maulide and Istva´n E. Marko´*
UniVersite´ catholique de LouVain, De´partement de Chimie, 1 Place Louis Pasteur,
B-1348 LouVain-la-NeuVe, Belgium
marko@chim.ucl.ac.be
Received May 26, 2006
ABSTRACT
The use of 2-(trimethylsilyloxy)furan derivatives as dianion equivalents leads to a general and connective spiroannulation protocol for the
efficient preparation of spirocyclic butenolides.
Among the plethora of heterocyclic subunits present in
biologically active natural or synthetic products, spirobuteno-
lides of the general formula 1 (Figure 1) occupy a cardinal
position. The number of strategies reported in the literature
for their assembly is a clear testimony to their importance.1
In addition, the unusually high number of molecules dis-
playing useful biological activities and embodying the basic
structure of 1 further illustrates the unique properties of this
class of compounds. Representative examples including man-
made molecules, such as the remarkably active acaricides
and insecticides spirodiclofen (2) and spiromesifen (3),2 the
spirocyclic neuropeptide Y antagonist (4),3 and naturally oc-
curring substances, such as spirofragilide (5)4 or the recently
isolated lambertellol A (6),5 are collected in Figure 1.
The ubiquitous presence of this subunit coupled with its
interesting biological properties triggered our interest, and
the possibility of assembling spirocyclic butenolides 1 in a
connective manner was envisioned. Moreover, we were par-
ticularly intrigued by the likelihood of generating more richly
functionalized analogues of 1, such as 7 (Scheme 1). Indeed,
a literature survey revealed that most of the procedures
employed to date either relied upon multistep sequences or
allowed little functionalization of the final adducts.
Guided by our previous experience in the preparation of
carbospirocycles,6 we envisaged the use of 2-(trimethylsi-
lyloxy)furan (9, R ) H) as the template upon which a novel
spiroannulation strategy could be implemented. Our proposed
approach is presented in Scheme 1. It was anticipated that
adducts 8, available through Lewis acid mediated condensa-
(1) (a) Langer, P.; Albrecht, U. Synlett 2002, 11, 1841. (b) Wenderborn,
S.; Binot, G.; Nina, M.; Winkler, T. Synlett 2002, 10, 1683. (c) Rauter, A.
P.; Figueiredo, J.; Ismael, M.; Canda, T.; Font, J.; Figueredo, M.
Tetrahedron: Asymmetry 2001, 12, 1131. (d) Paquette, L. A.; Owen, D.
R.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.; Lanter, J. C.; Corral, M.
A. J. Org. Chem. 2001, 66, 2828. (e) Michaut, M.; Santelli, M.; Parrain,
J.-L. J. Organomet. Chem. 2000, 606, 93. (f) Hoffmann, H. M. R.;
Wulferding, A. Synlett 1993, 6, 415. (g) Orduna, A.; Gerardo Zepeda, L.;
Tamariz, J. Synthesis 1993, 4, 375. (h) Black, T. H.; McDermott, T. S.;
Brown, G. A. Tetrahedron Lett. 1991, 32, 6501. (i) Ortuno, R. M.; Corbera,
J.; Font, J. Tetrahedron Lett. 1986, 27, 1081. (j) Canonne, P.; Belanger,
D.; Lemay, G. J. Org. Chem. 1982, 47, 3953. (k) Caine, D.; Smith, T. L.
Synth. Commun. 1980, 10, 751. (l) Iwai, K.; Kosugi, H.; Miyazaki, A.;
Hisashi, U. Synth. Commun. 1976, 6, 357 and references therein. For a
recent example of the synthesis of aza-spirobutenolides through an unusual
strategy, see: (m) Guindeuil, S.; Zard, S. Z. Chem. Commun. 2006, 665.
(2) Liu, T.-X. Crop Prot. 2004, 23, 505.
(3) Iida, T.; Satoh, H.; Maeda, K.; Yamamoto, Y.; Asakawa, K.-i.;
Sawada, N.; Wada, T.; Kadowaki, C.; Itoh, T.; Mase, T.; Weissman, S. A.;
Tschaen, D.; Krska, S.; Volante, R. P. J. Org. Chem. 2005, 70, 9222.
(4) Reddy, N. S.; Venkatesham, U.; Rao, T. P.; Venkateswarlu, Y. Ind.
J. Chem., Sect. B 2000, 39, 393.
(5) Murakami, T.; Morikawa, Y.; Hashimoto, M.; Okuno, T.; Harada,
Y. Org. Lett. 2004, 6, 157.
10.1021/ol061284g CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

derivatives.10 Despite all these potential pitfalls, we now wish
to report the successful application of this simple strategy
for the efficient preparation of spirobutenolides, as depicted
in Scheme 1.
We had previously shown that compounds such as 8a
could be readily produced, in one step and in high yields,
through the ZnCl2-promoted condensation of trimethylsilyl-
oxy furan 9a with ortho-ester 10a.7 With these substrates in
hand, we next investigated their reactivity under basic
conditions. To our disappointment, initial treatment of
chlorinated 8a with a variety of bases led only to the recovery
of the starting material (Scheme 2).
Scheme 2. Initial Results on the Base-Promoted
Spiroannulation of Butenolides 8a,b
Figure 1. Representative compounds bearing the spirobutenolide
structure 1.
tion of ortho-esters 10 with 2-(trimethylsilyloxy)furan de-
rivatives 9,7 could serve as substrates for a base-mediated
cyclization to spirobutenolides 7. Such a strategy would
imply the formal use of trimethylsilyloxy furan as the C-5
dianionic synthon 11.8
Scheme 1. Proposed Retrosynthetic Analysis of
Functionalized Spirobutenolides 7
Interestingly, when iodinated derivatives 8b,c were treated
with base, rapid and complete transformation of these sub-
strates into new products of similar polarity (TLC analysis)
was observed. Following conventional aqueous workup, two
new compounds, lacking the characteristic H-5 signal in their
1H NMR spectrum and bearing a new quaternary carbon
resonance at 94-95 ppm (APT/DEPT NMR), were obtained
in excellent yields and without the need for further purifica-
tion (Scheme 2). Extensive spectroscopic studies provided
compelling evidence for the formation of the spirocyclic
compounds 7b and 7c. Further investigations revealed
NaHMDS and t-BuOK to be the most suitable bases for this
reaction.
It is noteworthy that cyclization of butenolides 8 proceeds
smoothly and in good yields regardless of the size of the
ring being generated (five- vs six-membered). This observa-
tion is in sharp contrast to similar spiroannulations of the
carbocyclic analogues of 8 for which the final cyclization is
highly ring-size dependent.6
Though attractive due to its simplicity and convergency,
this approach did, however, raise some concerns. Indeed,
from the onset, we were surprised at the lack of literature
precedent on spirocyclization of compounds analogous to
8.9 Furthermore, Pelter et al. had previously shown that,
under strongly basic conditions, adducts similar to 8 (R′ )
Me) underwent alkoxy group elimination to form dienol ether
Subsequently, the scope and limitations of this novel
approach toward spirobutenolides were investigated. Some
(6) (a) Marko´, I. E.; Vanherck, J.-C.; Ates, A.; Tinant, B.; Leclercq, J.-
P. Tetrahedron Lett. 2003, 44, 3333. For an application to total synthesis,
see: (b) Maulide, N.; Vanherck, J.-C.; Marko´, I. E. Eur. J. Org. Chem.
2004, 3962.
(7) Maulide, N.; Marko´, I. E. Chem. Commun. 2006, 1200.
(8) For reviews on the chemistry of trimethylsilyloxyfuran derivatives,
see: (a) Casiraghi, G.; Rassu, G. Synthesis 1995, 607. (b) Bur, S. K.; Martin,
S. F. Tetrahedron 2001, 57, 3211.
(9) For a rare example of aldol-mediated spirocyclization, see: (a) Kende,
A. S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron 2002, 58, 61. For
Mannich-based spirocyclizations, see: (b) Tokumaru, K.; Arai, S.; Nishida,
A. Org. Lett. 2006, 8, 27. (c) Martin, S. F.; Bur, S. K. Tetrahedron Lett.
1997, 38, 7641. For a related cyclization, see: (d) Kobayashi, K.; Itoh, M.;
Suginome, H. Tetrahedron Lett. 1987, 28, 3369.
(10) Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.; Pardasani,
P.; Hansel, R. J. Chem. Soc., Perkin Trans. 1 1987, 4, 717.
3706
Org. Lett., Vol. 8, No. 17, 2006

Table 1. Direct Spiroannulation of Butenolidesa
Scheme 3. Functionalization of Spirocyclic Butenolides
7b and 7c proved to be quite efficient providing diols 13b
and 13c, again as the sole products, following extractive
workup.12 These diastereomerically pure diols, obtained in
only three steps, could be interesting scaffolds en route to
spiro-constrained DNA building blocks, popularized through
the recent work of Paquette et al.13
In summary, we have successfully developed a concise
and efficient access to the spirobutenolide framework. This
new methodology hinges upon the use of 2-(trimethylsilyl-
oxy)furan derivatives 9 as a synthon for dianions such as
11, enabling this unprecedented, direct spiroannulation. The
adducts thus obtained hold considerable potential as building
blocks in synthesis. Current work focuses on the function-
alization of these adducts, the establishment of an asymmetric
version of this procedure, and its application to the stereo-
controlled synthesis of biologically relevant substances. The
results obtained during these investigations will be reported
in due course.
a All reactions performed in the presence of 1.3 equiv of t-BuOK or
NaHMDS, in THF, from 0 °C to room temperature. b All yields refer to
pure, isolated products.
pertinent examples are collected in Table 1. Interestingly,
3,5-disubstituted butenolides bearing a dioxolane protecting
group are viable substrates, affording the annelated products
7d and 7e in good yields (entries 1 and 2). The smooth
generation of spirobutenolides 7f-i from diethyl- and
dimethylketals 8f-i was a pleasant surprise (entries 3-6).
Indeed, not only did trimethylsilyloxyfuran derivatives
condense efficiently with the triethyl- and trimethyl-
substituted ortho-esters 10 (in stark contrast to other cyclic
silyl enol ethers that afforded mostly, if not exclusively, the
corresponding enol ester) but also the adducts 8f-i under-
went preferential cyclization rather than elimination of EtOH
or MeOH, a process previously described by Pelter et al.
Finally, interesting spirotetronic acid derivatives could be
obtained by application of our protocol (entries 5 and 6).
The spirocyclic butenolides thus obtained proved surpris-
ingly inert toward a wide variety of reagents (e.g., OsO4,
cuprates, high-order cuprates, cyanide, and malonate anions,
etc.). However, simple though valuable synthetic transforma-
tions can be accomplished on these adducts provided a
judicious choice of reaction conditions is made. Selected
results are displayed in Scheme 3.
Acknowledgment. We are grateful to Prof. Reinhard
Bruckner (Albert-Ludwigs-Universita¨t Freiburg) for experi-
mental details concerning the preparation of 2-trimethylsi-
lyloxyfuran. Financial support of this work by the Universite´
catholique de Louvain, the Fonds pour la Recherche dans
l’Industrie et l’Agriculture (F.R.I.A., studentship to N.M.),
the Fond National de la Recherche Scientifique (N.M.,
Aspirant F.N.R.S.), Merck, Sharp and Dohme (Merck
Academic Development Award to I.E.M.), and SHIMADZU
Benelux (financial support for the acquisition of a FTIR-
8400S spectrometer) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all spirocyclic products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061284G
(11) (a) Khurana, J. M.; Sharma, P. Bull. Chem. Soc. Jpn. 2004, 549.
(b) George, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173.
(12) (a) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.;
Jiang, Q. Chem.-Eur. J. 1996, 2, 50. See also: (b) Paquette, L. A.;
Seekamp, C. K.; Kahane, A. L.; Hilmey, D. G.; Galucci, J. J. Org. Chem.
2004, 69, 7443.
Thus, saturation of the butenolide C-C double bond could
be smoothly accomplished through the use of NiCl2/NaBH4
and the spirocyclic γ-butyrolactones 12b and 12c were
obtained in quantitative yields.11 Similarly, the ruthenium-
catalyzed dihydroxylation of the conjugated double bond of
(13) Dong, S.; Paquette, L. A. J. Org. Chem. 2006, 71, 1647 and
references therein.
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