A versatile and general one-pot method for synthesizing bis-spiroketal motifs

Article abstract of DOI:10.1021/ol060558x

A versatile and general method for the biomimetic construction of [5,5,5]- and [6,5,6]-bis-spiroketals, starting from easily accessible furan nuclei, by means of a powerful one-pot singlet oxygen-mediated cascade sequence is reported.

Full text of DOI:10.1021/ol060558x

ORGANIC
LETTERS
2
006
Vol. 8, No. 9
945-1948
A Versatile and General One-Pot Method
for Synthesizing Bis-spiroketal Motifs
1
Thomas Georgiou, Maria Tofi, Tamsyn Montagnon, and
Georgios Vassilikogiannakis*
Department of Chemistry, UniVersity of Crete, Vasilika Vouton,
71003 Iraklion, Crete, Greece
Vasil@chemistry.uoc.gr
Received March 7, 2006
ABSTRACT
A versatile and general method for the biomimetic construction of [5,5,5]- and [6,5,6]-bis-spiroketals, starting from easily accessible furan
nuclei, by means of a powerful one-pot singlet oxygen-mediated cascade sequence is reported.
Nature has seen fit to include the delicate bis-spiroketal
functionality in a wide range of interesting natural products.
Several different classes of marine toxins including the
this approach has on rare occasions been successsful in
producing a cascade reaction capable of zipping up the three
rings simultaneously, more often than not it has required
7
1
2
3
4
spirolides, pinnatoxins, pteriatoxins, and the azaspiracids
two independent cyclization steps separated by at least one
6
contain this motif. It is also a subunit present in certain
deprotection and/or oxidation reaction(s). Furthermore, as
5
terrestrially derived ionophore antibiotics. Since interest in
a strategy it always requires both the engineering of a
complex linear precursor and the difficult orchestration of
multiple oxidations and protecting group manipulations in
order to prepare the requisite oxygen functionalities for
the syntheses of these architecturally complex molecules
abounds, much work has already been undertaken directed
toward finding elegant ways to synthesize the bis-spiroketal
moiety in its various forms. Not surprisingly the majority of
existing research in this field has focused on using acid-
6
participation in the envisaged cyclisations. Aside from this
not unproblematic ketalization strategy, several other spiro-
cycle formation reactions of note have been employed.6
Brimble et al. have used an elegant oxidative cyclization
procedure wherein hypervalent iodine, molecular iodine, and
light are comandeered to assist in forming a plethora of
different bis-spiroketals; again this approach requires several
6
catalyzed ketalization reactions to achieve the goal. While
(
1) (a) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A. S.; Walter, J.
A.; Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun.
995, 2159-2169. (b) Hu, T.; Burton, I. W.; Cembella, A. D.; Curtis, J.
M.; Quilliam, M. A. S.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 2001,
4, 308-312.
2) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
1
6
6,8
steps to affect the desired double cyclization. Alternatively,
a small number of strategies reliant on the oxidation of a
furan nucleus have appeared in the literature sporadically
over the past 4 decades. Indeed, the first reported synthesis
(
Zeng, S.-Z.; Chen, H.-S. J. Am. Chem. Soc. 1995, 117, 1155-1156. (b)
Chou, T.; Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023-4026.
(c) Chou, T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996,
3
7, 4027-4030. (d) Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.;
Nagatsu, A.; Haino, T.; Yamada, K.; Uemura, D. Tetrahedron Lett. 2001,
2, 3491-3494.
3) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495-3497.
4) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Fruey, A.; McMahon,
T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967-9968.
5) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod. Rep. 1995, 12,
65-181.
6) For a review of bis-spiroketal syntheses, see: Brimble, M. A.; Far e` s,
F. A. Tetrahedron 1999, 55, 7661-7706.
4
(7) For selected examples, see: (a) McGarvey, G. J.; Stepanian, M. W.
Tetrahedron Lett. 1996, 37, 5461-5464. (b) McGarvey, G. J.; Stepanian,
M. W.; Bressette, A. R.; Ellena, J. F. Tetrahedron Lett. 1996, 37, 5465-
5468. (c) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38,
7379-7382. (d) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke,
S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-
7648.
(
(
(
1
(
(8) For a recent application of this method, see: Meilert, K.; Brimble,
M. A. Org. Lett. 2005, 7, 3497-3500.
1
0.1021/ol060558x CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/25/2006

of a bis-spiroketal ring system used electrochemistry to
oxidize a simple furan bearing pendant hydroxyl groups to
yield the corresponding bis-spiroketal in one step. Later
Scheme 1. Outline of Our Concept for the One-Pot Formation
9
of Bis-spiroketals
1
0
11
12
Albizati, Kocienski, and Stockman all deployed elec-
trophilic bromine as the oxidant to transform various furans
into the corresponding bis-spiroketal moiety. Only in the
1
2
latter case were both spiroketals formed in a single step.
After surveying the methods reported for the formation
of bis-spiroketals, we were left in no doubt that there was a
pressing need for a more direct and general method for the
one-pot formation of these spirocycles from simple precur-
1
sors. Our experience in using singlet oxygen ( O
2
) as a
13
biomimetic synthetic tool (especially for synthesizing
14
spirocyclic compounds ) led us to believe that this objective
could be readily attained by the deft application of some
1
powerful O
2
chemistry. Furthermore, given that naturally
1
2
occurring furans are known and that O is readily available
in the natural environment as a result of the existence of
ideal conditions for its generation (abundant molecular
oxygen, visible spectrum light, and sensitizers such as
tannins, poryphrins, and chlorophylls), we felt that it was
highly possible that our postulate was biomimetic. Our
ambitious blueprint for the syntheses of these compounds
was devoid of cumbersome intermediary protection and
oxidation steps and was one wherein broad variation in the
cyclization precursors could be readily entertained. Herein,
we report our success in employing this design, involving a
highly efficient cascade reaction sequence initiated by the
To begin our investigation, we took the simple diester 2
(made previously for the purposes of a different project) and
reduced it with LAH to form the corresponding diol 3 in
1
good yield (82%). This diol 3 was then subjected to the O
2
3,14
oxidation conditions routinely used in our laboratories1
to affect such transformations: oxygen was bubbled through
-
4
the reaction solution, 10 M Methylene Blue was added as
sensitizer, and the solution was irradiated with visible
spectrum light until complete consumption of the starting
material was observed by TLC (2 min). After the addition
of dimethyl sulfide as in situ reductant and passing of the
crude material through a short pad of silica, we were most
gratified to observe the formation of the sought after [5,5,5]-
[
4 + 2]-cycloaddition between an easily accessible furan
1
15
nucleus and O
2
, for the synthesis of various bis-spiroketals.
The elegant concept that we were able to successfully
implement, wherein the [4 + 2]-cycloaddition is followed
by two succesive intramolecular trapping reactions in order
to furnish both of the targeted spiroketal rings in one
synthetic operation, is detailed in Scheme 1. Thus, our
1
2
bis-spiroketal 4 (80%) as a 1:1 mixture of diastereoisomers
1
3
(measured by H NMR, taken in CDCl ). It should be noted
that retrospective study of this reaction revealed that the
desired bis-spiroketal product 4 could be formed directly
from the hydroperoxide intermediate (not shown) upon
analysis can be summarized as follows: we proposed that
1
the product of the cycloaddition between O
2
and furans of
3
standing in CDCl , without the need to employ dimethyl
type A, endoperoxide B, might be the subject of an
intramolecular attack16 by a suitably positioned pendant
hydroxyl group to afford the spiroketal hydroperoxide C.
Hydroperoxide C might then be reduced in situ to yield the
corresponding hemiketal, which could, in turn, be coaxed
into cyclizing under the influence of traces of acid to furnish
the desired bis-spiroketal D.
sulfide.
Having obtained the exciting proof of principle for this
attractive cascade sequence, we set about devising a faster
and more efficient means by which to access the furan
Scheme 2. Proof of Principle: Successful One-Pot Formation
of the [5,5,5]-Bis-spiroketal 4 from Dihydroxyfuran 3
(9) Ponomarev, A. A.; Markushina, I. A. Zh. Obshch. Khim. 1963, 33,
3
955-3961.
(
10) Perron, F.; Albizati, K. F. J. Org. Chem. 1989, 54, 2044-2047.
(11) For selected examples, see: (a) Kocienski, P. J.; Fall, Y.; Whitby,
R. J. Chem. Soc., Perkin Trans. 1 1989, 841-844. (b) Brown, R. C. D.;
Kocienski, P. J. Synlett 1994, 415-417; 417-419.
(
(
12) McDermott, P. J.; Stockman, R. A. Org. Lett. 2005, 7, 27-29.
13) (a) Vassilikogiannakis, G.; Stratakis, M. Angew. Chem. 2003, 115,
5
620-5622. (b) Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.;
Stratakis, M. Chem. Eur. J. 2005, 11, 5899-5907. (c) Vassilikogiannakis,
G.; Margaros, I.; Montagnon, T. Org. Lett. 2004, 6, 2039-2042.
(14) Sofikiti, N.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G.;
Stratakis, M. Org. Lett. 2005, 7, 2357-2359.
15) For a review of photooxygenations of furan, see: Feringa, B. L.
Recl. TraV. Chim. Pays-Bas 1987, 106, 469-488.
16) For a similar intramolecular nucleophilic opening of an ozonide,
see: Feringa, B. A.; Butselaar, R. J. Tetrahedron Lett. 1982, 23, 1941-
942.
(
(
1
1946
Org. Lett., Vol. 8, No. 9, 2006

Scheme 3. Successful One-Pot Formation of the
6,5,6]-Bis-spiroketal 9 from Dihydroxyfuran 8
Scheme 4. Problems Encountered When Attempting To
[
Include a Furylic Olefin in the Oxidation Substrate
oxidation precursors. To this end, we sought to implement
a simple strategy in which two successive alkylations of
appropriate furyllithium anions with suitable alkyl iodides
would provide the desired compounds (Scheme 3). Starting
from furan itself and using n-BuLi as base, this procedure
could readily be employed to furnish first monosubstituted
furan 7 and then diol 8 (after TBAF-mediated deprotection)
in an overall yield of 62% (over three steps). The alkylating
agent, iodide 6, had been made in one step from tetrahy-
drofuran, using NaI and TBSCl, by following a literature
1
7
1
2
procedure. Upon subjection of this diol 8 to the O -
mediated oxidation and in situ reduction conditions described
above, once again the double spirocycle formation cascade
proceeded smoothly, successfully providing the desired
Indeed, when a double deprotection using TBAF was
attempted, formation of a complex mixture of unidentified
byproducts was observed. In an attempt to circumvent this
issue of substrate instability, we moved toward the introduc-
tion of just one trisubstituted double bond into the oxidation
substrate, as required for the synthesis of the natural products
of interest. To this end, the lithium anion of furan (5) was
[6,5,6]-bis-spiroketal product 9 (77%, as a 55:45 mixture of
diastereoisomers).
In order for our method to be more generally applicable
to complex natural product synthesis as we desired, we next
looked at synthesizing differentially substituted furans,
bearing suitable handles for further manipulations, to test as
reaction substrates. We deemed that introducing a trisubsti-
tuted double bond into the oxidation substrates would furnish
us with the most useful handle for the introduction of the
requisite tertiary alcohol present in the natural products of
interest (vide supra). To this end, a simple Wittig reaction
was employed to append an unsaturated side chain onto
1
8
first alkylated with bromide 12 (Scheme 4B). This alky-
lation was followed by the same acylation/Wittig sequence
that had previously been employed in the synthesis of 11.
Thus, unsaturated furan 13 was formed in an overall yield
of 43% with a ratio of Z:E geometric double bond isomers
of 4:1. The fate of 13, upon column chromatography after
TBAF-mediated deprotection, confirmed our suspicions
regarding the source of furan 11’s instability (i.e., degradation
via formation of the furylic cation). For when 13 was exposed
to the Lewis acidic conditions of column chromatography,
the sole product isolated was tetrahydrofuran 14. This
unwanted product was assumed to arise by intramolecular
trapping of the readily formed and highly stabilized furylic
cation E under the mildly acidic conditions of the column.
Given our experience regarding the instability of furans 11
and 13 upon deprotection, we felt that the inclusion of
trisubstituted double bonds or tertiary furylic alcohols (also
suitable for the targeted natural products but even more
susceptible to furylic cation formation) in these substrates
was going to be problematic, but we also felt that this
obstacle was not insurmountable. If acidic conditions,
including column chromatography, could be avoided or
postponed, the desired cyclization precursors might be
attainable.
2-furaldehyde (1, Scheme 4A). The lithium anion of the
product of this reaction was then acylated using the com-
mercially available Weinreb amide, N-methoxy-N-methyl-
acetamide. The resulting methyl ketone was subjected to a
second Wittig reaction employing the same phosphonium
salt 10.18 This facile reaction sequence yielded the bis-
unsaturated furan 11 (81:19 desired geometric isomer:other
isomers) in 51% overall yield starting from 2-furaldehyde
(1, three steps). The cis,cis-configuration of the major isomer
was unambiguously confirmed by NOE studies. Unfortu-
nately, the bis-unsaturated furan proved to be a labile
compound exhibiting a strong tendency toward degradation.
(
17) Nystr o¨ m, J.-E.; McCanna, T. D.; Helquist, P.; Amouroux, R
Synthesis 1988, 56-58.
18) Cushman, M.; Golebiewski, W. M.; McMahon, J. B.; Buckheit, R.
(
W., Jr.; Clanton, D. J.; Weislow, O.; Haugwitz, R. D.; Bader, J. P.; Graham,
L.; Rice, W. G. J. Med. Chem. 1994, 37, 3040-3050.
Org. Lett., Vol. 8, No. 9, 2006
1947

To test this postulate we reverted to the use of 2-substituted
furan 7 as a starting material. This furan was further
functionalized using the, by now, standard reaction sequence
to furnish diol 15 in an overall yield of 52% and as a mixture
of geometric isomers (85:15 Z:E, confirmed by NOE studies,
Scheme 5). To avoid unwanted degradation, we took the
silica). Hemiketal 17 had to be exposed to catalytic amounts
of p-TsOH before it could be coaxed into cyclizing to form
the desired [6,5,6]-bis-spiroketal 18 (1:1 mixture of diaste-
1
reoisomers, H NMR in C
D
6 6
) in 80% yield (from diol 15,
yield based on only the Z-isomer of 15 reacting in this
sequence). The regiochemistry of hemiketal 17 was deduced
1
on the basis of the coupling pattern seen in H NMR for the
vinylic proton; in the oxidation precursor 15 the vinylic
proton had appeared as a triplet, but in the hemiketal 17 it
was present as a broad doublet. It should be noted that it
was not necessary to isolate hemiketal 17, the whole double
cyclization cascade sequence could be done in one pot if
p-TsOH was added after the reduction was shown to be
complete by TLC.
Scheme 5. Successful One-Pot Synthesis of a Suitably
Functionalized [6,5,6]-Bis-spiroketal 18 from Dihydroxyfuran 15
With the highly successful cyclization of diol 15 to yield
bis-spiroketal 18 now accomplished, we were afforded with
further proof that the method we had developed for the
formation of variable bis-spiroketal ring systems was general
and amenable to incorporation of suitable handles potentially
allowing for its ready application to the synthesis of certain
natural products. In summary, the work described in this
communication meets the rigorous goals we had designated
at the outset of our investigation. In short, a method was
developed that (1) accomplished the facile one-pot formation
of both spiroketal rings of various bis-spiroketal units, (2)
was devoid of complex functional group manipulations and
cumbersome cyclization precursor syntheses, and (3) em-
1
ployed one of nature’s favorite synthetic tools, O
2
, in an
elegant and highly efficient biomimetic cascade reaction
sequence.
Acknowledgment. The project was cofunded by the
European Social Fund and National Resources (Pythagoras
program). The research was also supported by a Marie Curie
Intra-European Fellowship (TM) within the 6th European
Community Framework Programme and the European Sci-
ence Foundation (Cost D-28 program).
precaution of not attempting to purify the product of the
TBAF-mediated deprotection step; instead the diol 15 was
used crude. When diol 15 was subjected to the established
cascade reaction conditions, after the reduction step mediated
by dimethysulfide, the hemiketal 17 (2:1 mixture of diaste-
reoisomers) could be isolated, purified, and fully character-
ized (proving that the intramolecular trapping reaction was
completely regioselective). The relative stability of hemiketal
Supporting Information Available: Experimental pro-
1
13
cedures and H and C spectra for all relevant compounds
plus HRMS for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
17 provided a stark contrast to the previously encountered
hemiketals, which were all transient species that snapped shut
immediately on being exposed to any form of acid (including
OL060558X
1948
Org. Lett., Vol. 8, No. 9, 2006