Combining two-directional synthesis and tandem reactions: Synthesis of trioxadispiroketals

Article abstract of DOI:10.1021/ol0479702

(Chemical Equation Presented) A tandem bromonium ion-promoted cyclization of two pendant hydroxyl groups onto a central furan core provides a highly direct route to both the [5,5,5]- and the [6,5,6]-trioxadispiroketal ring systems.

Full text of DOI:10.1021/ol0479702

ORGANIC
LETTERS
2005
Vol. 7, No. 1
27-29
Combining Two-Directional Synthesis
and Tandem Reactions: Synthesis of
Trioxadispiroketals
Paul J. McDermott and Robert A. Stockman*
School of Chemical Sciences and Pharmacy, UniVersity of East Anglia,
Norwich, NR4 7TJ, UK
r.stockman@uea.ac.uk
Received October 4, 2004
ABSTRACT
A tandem bromonium ion-promoted cyclization of two pendant hydroxyl groups onto a central furan core provides a highly direct route to
both the [5,5,5]- and the [6,5,6]-trioxadispiroketal ring systems.
The trioxadispiroketal functionality is present in a number
of biologically active marine natural products such as the
spirolides,1 the pinnatoxins2 2, the pteriatoxins3 3, and the
azaspiracids4 1 (Figure 1), as well as the antibiotic polyether
ionophores.5 As such, this functionality is of synthetic
interest. However, due to its low occurrence relative to other
spirocyclic groups, limited research has been carried out into
the assembly of such structures. Our group has a continuing
interest in combining two-directional synthesis with tandem
reactions to create efficient strategies for the synthesis of
complex molecules, as exemplified by our recent syntheses
of perhydrohistrionicotoxin6 and hippodamine.7 With the aim
of developing efficient synthetic routes to the aforementioned
marine natural products, we herein report the development
of a novel trioxadispiroketalization procedure. Our methodol-
ogy employs a bromonium source to effect an oxidative
tandem cyclization of two proximal hydroxyl groups onto a
central furan core8 allowing direct access to the [5,5,5]-
trioxadispiroketal 8 and the [6,5,6]-trioxadispiroketal 14 ring
systems (Schemes 1 and 2).
To begin our synthesis of the [5,5,5]-trioxoxadispiroketal
analogue, 5-hydroxymethyl-2-furaldehyde 4 was subjected
to Taylor’s tandem oxidation/Wittig procedure.9 Stirring
compound 4 with 2.4 equiv of (methoxycarbonylmethylen)-
triphenylphosphorane 5 and 10 equiv of manganese(iv) oxide
at room temperature for 4 days gave diester 6 as a 6.6:1
mixture of (E,E)- and (E,Z)-isomers in 87% yield overall
after column chromatography. Reduction of the R,â-unsatur-
ated ester functionalities in compound 6 using 20 equiv of
lithium borohydride,10 which was generated in situ from
lithium chloride and sodium borohydride, gave a complex
mixture of diols that were shown by NMR to contain
(1) (a) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, M.
A.; Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun.
1995, 2159. (b) Hu, T.; Curtis, J. M.; Walter, M. A.; Wright, J. L. C.
Tetrahedron Lett. 1996, 37, 7671. (c) Hu, T.; Burton, I. W.; Cembella, A.;
Curtis, J. M.; Quilliam, M. A.; Walter, M. A.; Wright, J. L. C. Nat. Prod.
2001, 64, 308.
(2) Chou, T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett.
1996, 37, 4027.
(3) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495.
(6) Stockman, R. A.; Sinclair, A. S.; Arini, L. G.; Szeto, P.; Hughes, D.
L. J. Org. Chem. 2004, 69, 1598.
(7) Rejzek, M.; Stockman, R. A.; Hughes, D. L. Org. Biomol. Chem.
2005, in Press (DOI: 10.1039/B413052A).
(8) Wu has reported an acid-catalyzed synthesis of a monospiroketal by
the nucleophilic cyclization of a pendant hydroxy group onto an R-hydroxyl
furan core. Gao, Y.; Wu, W.-L.; Wu, Y.-L.; Ye, B.; Zhou, R. Tetrahedron
1998, 54, 12523.
(9) Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 616.
(10) Ramesh, C.; Anand.; Vimal. Tetrahedron Lett. 1998, 39, 917.
(4) (a) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.;
McMahon, T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967.
(b) Nicoloau, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada, Y. M. A.; Ling,
T.; Chen, D. Y.-K.; Tang, W.; Petrovic, G.; Frederick, M. O.; Li, Y.; Satake,
M. Angew. Chem., Int. Ed. 2004, 43, 4312. (c) Nicoloau, K. C.; Koftis, T.
V.; Vyskocil, K. S.; Petrovic, G.; Ling, T.; Yamada, Y. M. A.; Tang, W.;
Frederick, M. O. Angew. Chem., Int. Ed. 2004, 43, 4318.
(5) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat. Prod. Rep. 1995, 12,
165.
10.1021/ol0479702 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/09/2004

Scheme 2. Synthesis of the 6,5,6-Trioxadispiroketal Analogue
dispiroketal 8 as an inseparable 1:1 mixture of cisoidal and
transoidal isomers in 28.4% yield over three steps.
It was envisaged that the synthesis of [6,5,6]-trioxa-
dispiroketal 14 could be achieved via an analogous strategy
(Scheme 2). Oxidation of 5-hydroxymethyl-2-furaldehyde 4
using pyridinium chlorochromate gave 2,5-difuraldehyde 9
in 65% yield. Wittig olefination of this compound with 2
equiv of phosphonium ylide 10 homologated both side chains
in one efficient step to give diolefin 11 in 54% yield.
Hydrogenation of compound 11 was then achieved using a
hydride transfer reduction procedure,12 by stirring compound
11 in a suspension of palladium black and 1,4-cyclohexadiene
in ethanol for 2 h to give compound 12 in 98% yield.
Desilylation of this compound was effected by stirring in
THF in the presence of 2.2 equiv of TBAF to give our
desired diol cyclization precursor 13 in 54% yield. A solution
of diol 13 in a (3:1) THF/H2O solvent system was then
treated with 1.2 equiv of N-bromosuccinimide at 0 °C to
produce dispiroketal 14 as a 1:1 mixture of cisoidal and
transoidal isomers in 65% yield. The two isomers were found
to be separable by column chromatography; however,
reequilibration was noted after a period of several hours in
solution.
Figure 1. Naturally occurring trioxadispiroketals.
Scheme 1. Synthesis of the 5,5,5-Trioxadispiroketal Analogue
significant olefin character. Subsequent hydrogenation of this
mixture under standard conditions achieved complete con-
version of the diol mixture to give saturated cyclization pre-
cursor 7 in 71% overall yield from diester 6 after column
chromatography. A solution of diol 7 in a (3:1) THF/H2O
solvent system was then treated with 1.2 equiv of N-bromo-
succinimide at 0 °C11 to effect oxidative cyclization, giving
(11) Kocienski, P. J.; Brown, R. C. D.; Pommier, A.; Procter, M.;
Schmidt, B. J. Chem. Soc., Perkin Trans. 1 1998, 9.
(12) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194.
28
Org. Lett., Vol. 7, No. 1, 2005

group in the side chain, followed by loss of a proton, forms
the first spirocenter and gives intermediate 16. Consequent
E2′ elimination of the bromine substituent via the 5,4-central
ring double bond reveals a second oxonium ion that under-
goes an analogous nucleophilic attack from the remaining
hydroxyl group in 17. The loss of a proton completes the
formation of the trioxadispiroketal ring system 14.
In conclusion, the combination of two-directional synthesis
building from a central furan core combined with a bromo-
nium ion-mediated tandem spirocyclization has resulted in
a very concise entry to trioxadispiroketal synthesis. Work
directed at the application of this strategy for total synthesis
is ongoing in these laboratories, and our results will be
published in due course.
Scheme 3. Mechanism
Acknowledgment. The authors thank the EPSRC for
funding this research (P.J.M.). They also thank AstraZeneca
for their generous unrestricted funding and the EPSRC Mass
Spectrometry Service at the University of Wales, Swansea,
for carrying out high-resolution mass spectroscopy. The
authors also acknowledge the use of the EPSRC’s Chemical
Database Service at Daresbury.
Supporting Information Available: Experimental pro-
cedures, full characterization, and 1H NMR and 13C
NMR spectra for compounds 6-8 and 11-14. This material
is available free of charge via the Internet at http://pubs.acs.org.
A postulated mechanism for the tandem cyclization is
shown in Scheme 3. It is proposed that the process begins
with an electrophilic bromination of the central furan ring
of 13, thus revealing an electrophilic oxonium ion 15.
Subsequent nucleophilic attack from the proximal hydroxyl
OL0479702
Org. Lett., Vol. 7, No. 1, 2005
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