Oxidative rearrangements of isobenzofurans: Studies toward the synthesis of the ajudazols

Article abstract of DOI:10.1021/ol8009336

(Chemical Equation Presented) We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This methodology has been successfully applied toward the synthesis of ajudazol A.

Full text of DOI:10.1021/ol8009336

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2813-2816
Oxidative Rearrangements of
Isobenzofurans: Studies toward the
Synthesis of the Ajudazols
Stephen J. Hobson, Andrew Parkin,† and Rodolfo Marquez*,‡
WestCHEM, UniVersity of Glasgow, Joseph Black Building, UniVersity AVenue,
Glasgow G12 8QQ, U.K.
r.marquez@chem.gla.ac.uk
Received April 23, 2008
ABSTRACT
We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This
methodology has been successfully applied toward the synthesis of ajudazol A.
As part of our efforts toward the synthesis of biologically
active natural products, we have become interested in the
development of new approaches toward the efficient synthesis
of isochromanones.
Isochromanones are biologically relevant building blocks
which are present in a significant number of biologically
active compounds such as the ajudazols 1,1 (4R)-hydroxyo-
chratoxin A 2,2 acetoxy-geranyloxymellein 3,3 thailandolide
B 4,4 bergenin 5,5 and the Helminthosporium monoceras
antifungal metabolite monocerin 66 (Figure 1).
Isobenzofurans 7 were conceived originally by Wittig and
Pohmer7 and were later validated by Fieser and Haddadin
as highly reactive intermediates through exquisite trapping
studies.8
† Author to whom crystallographic data questions should be addressed.
‡ Ian Sword Lecturer of Organic Chemistry.
(1) (a) Jansen, R.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org.
Figure 1. Isochromone-containing natural products.
Chem. 2002, 917. (b) Reichenbach, H. J. Ind. Microbiol. Biotechnol. 2001,
27, 149. (c) Kunze, B.; Rolf, J. A.; Hofle, G.; Reichenbach, H. J. Antibiot.
2004, 57, 151.
(2) Zepnik, H.; Pahler, A.; Schauer, U.; Dekant, W. Toxicol. Sci. 2001,
59, 59.
Although a significant amount of time and effort has been
dedicated to the development of excellent methods for the
generation of isobenzofuran and its derivatives, their synthetic
(3) Appendino, G.; Ozen, H. C.; Jakupovic, J. Phytochemistry 1994,
36, 531.
(4) Dethoup, T.; Manoch, L.; Kijjoa, A.; Pinto, M.; Gales, L.; Damas,
A. M.; Silva, A. M. S.; Eaton, G.; Herz, W. J. Nat. Prod. 2007, 70, 1200.
(5) Takahashi, H.; Kosada, M.; Watanabe, Y.; Nakade, K.; Fukuyawa,
Y. Bioorg. Med. Chem. 2003, 11, 1781.
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Y. U.S. Patent Int. 5,530,146, 1996.
10.1021/ol8009336 CCC: $40.75
Published on Web 06/03/2008
2008 American Chemical Society

application has been mostly limited to function as dienes in
Diels-Alder and singlet oxygen cycloaddition reactions
(Scheme 1).9,10
Scheme 3
Scheme 1. Traditional Use of Isobenzofuran Units
We would now like to report the novel oxidative rear-
rangement of R-hydroxyisobenzofurans 10, which radically
expands the use and scope of isobenzofurans 9 as synthetic
intermediates and permits the fast and efficient generation
of isochroman-1-ones 11 (Scheme 2).
We believe that the oxidation mechanism is analogous to
that postulated by Achmatowicz for the oxidative rearrange-
ment of simple furfuryl alcohols and amines.12 Hence, it
would be reasonable to expect the hydroxyl group to direct
the epoxidation to generate epoxide 19 (Scheme 4). Zwit-
terion formation followed by ring opening generates aldehyde
21, which can cyclize to generate the unstable lactols 17R/
ꢀ. However, the lactol intermediates can be isolated as the
corresponding acetates 22R/ꢀ. As expected, the R-anomer
is the dominant species.
Scheme 2. Proposed Approach to Isobenzofurans
In our approach to the synthesis of isochroman-1-ones,
commercially available phthalide 12 was reduced and the
resulting lactol 13 was methylated to generate acetal 14.11
Reaction of acetal 14 with methyllithium and diisopropy-
lamine then generated the isobenzofuran anion 15, which
was trapped with isobutyraldehyde to produce the highly
reactive R-hydroxyisobenzofuran 16. The key R-hydroxy-
isobenzofuran 16 was then successfully rearranged under
oxidative conditions to generate the labile lactols 17R/ꢀ,
which upon oxidation then generated the desired keto lactone
18 in excellent yield from methyl acetal 14 and with no need
of purification (Scheme 3).
Scheme 4
(7) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334.
(8) (a) Fieser, L. F.; Haddadin, M. J. J. Am. Chem. Soc. 1964, 86, 2081.
(b) Fieser, L. F.; Haddadin, M. J. Can. J. Chem. 1965, 43, 1599. (c)
Haddadin, M. J. Heterocycles 1978, 9, 865. (d) Friedrichsen, W. AdV.
Heterocycl. Chem. 1980, 26, 135. (e) Wiersum, U. E. Aldrichim. Acta 1981,
14, 53.
The methodology was applied successfully to a number
of substrates to generate the desired keto lactones 18 and
23-32 in excellent yield. Surprisingly, a phenyl substituent
(entry 9) can be tolerated under the reaction conditions
without detrimental effect (Scheme 5).
(9) (a) Wiersum, U. E.; Mijs, W. J. J. Chem. Soc., Chem. Commun.
1972, 347. (b) Plaumann, H. P.; Smith, J. G.; Rodrigo, R. J. Chem. Soc.,
Chem. Commun. 1980, 354. (c) Tobia, D.; Rickborn, B. J. Org. Chem. 1986,
51, 3849. (d) Hamaguchi, M.; Ibata, T. Chem. Lett. 1976, 287. (e) Hayakawa,
K.; Yamaguchi, Y.; Kanematsu, K. Tetrahedron Lett. 1985, 26, 2689. (f)
Mikami, K.; Ohmura, H. Org. Lett. 2002, 4, 3355.
(10) (a) Friedrichsen, W. AdV. Heterocycl. Chem. 1999, 73, 1. (b) Reck,
S.; Friedrichsen, W. Prog. Heterocycl. Chem. 1997, 9, 117. (c) Rodrigo,
R. Tetrahedron 1988, 44, 2093. (d) Wege, D. AdV. Theor. Interesting Mol.
1998, 4, 1. (e) Rainbolt, J. E.; Miller, G. P. J. Org. Chem. 2007, 72, 3020.
(f) Chan, C. W.; Wong, H. N. C. J. Am. Chem. Soc. 1988, 110, 462.
(11) Crump, S. L.; Rickborn, B. J. Org. Chem. 1984, 49, 304.
(12) (a) Hobson, S. J.; Marquez, R. Org. Biomol. Chem. 2006, 4, 3808.
(b) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.;
Zamojski, A. Tetrahedron 1971, 27, 1973. (c) Ciufolini, M. A.; Hermann,
C. Y. W.; Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998,
105. (d) Harris, J. M.; Padwa, A. Org. Lett. 2002, 4, 2029.
Having successfully achieved the synthesis of the key keto
lactone core unit, conditions for the selective reduction of
the ketone unit were investigated. Treatment of the keto
lactones 18 and 23-32 under Luche conditions proceeded
to generate the desired isochroman-1-one units 33-43 with
complete regioselectivity and in good yield (Scheme 6).
As expected, the stereochemical outcome of the reduction
is highly dependent on the nature of the alkyl side chain,
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Org. Lett., Vol. 10, No. 13, 2008

Scheme 5a,b
Figure 2. Crystal structure of isochromone 39.
rearrangement and to determine the scope of the rearrange-
ment in the presence of more complicated aldehyde systems,
the synthesis of the ajudazol A western section model system
44 was undertaken (Figure 3).
aCompounds could be taken on without purification. bIsolated as a 1.6:
1.0 mixture of diastereomers.
Scheme 6
Figure 3. Ajudazol western section model system.
Chondromyces strains have long been recognized as a
significant source of biologically active natural products
including the crocacins and the chondramines.1 Ajudazols
A and B are two of the latest biologically active metabolites
to be isolated from the myxobacteria Chondromyces croca-
tus.
Structurally, the ajudazols showcase a number of highly
unusual features such as 4,8-dihydroxy-7-methylisochroman-
1-one and 3-methoxybutenoic acid methyl amide. Biologi-
cally, the ajudazols have been identified as inhibitors of the
bacterial mitochondrial electron transport chain at low
nanomolar concentrations.1c
The combination of novel structural features together with
their biological potential makes the ajudazols attractive
synthetic targets. Although a total synthesis of either ajudazol
has yet to be achieved, Taylor and Rizzacasa have reported
their respective approaches to the eastern portion of ajudazol
A.14,15
Our synthesis began with serine methyl ester 45, which
was rapidly converted to oxazole 46 in acceptable yield. Ester
reduction followed by a Swern oxidation then afforded the
oxazole aldehyde 47 in reasonable yield (Scheme 7).16,17
Olefination of aldehyde 47 under stabilized Wittig conditions
with the syn diastereomer being the preferred product. The
relative stereochemistry was determined through H NMR
analysis (Jab syn e 2.5 Hz; Jab anti g 6.0 Hz) and further
corroborated through X-ray crystallography in the case of
compound 39 (Figure 2).13
1
In a desire to further investigate the synthetic potential of
our newly developed R-hydroxyisobenzofuran oxidative
(14) Krebs, O.; Taylor, R. J. K. Org. Lett. 2005, 7, 1063
(15) Ganame, D.; Quach, T.; Poole, C.; Rizzacasa, M. A. Tetrahedron
Lett. 2007, 48, 5841
(16) Benoit, G.-E.; Carey, J. S.; Chapman, A. M.; Chima, R.; Hussain,
N.; Popkin, M. E.; Roux, G.; Tavassoli, B.; Vaxelaire, C.; Webb, M. R.;
.
(13) The atomic coordinates for 39 (CCDC deposition no. CCDC676871)
are available upon request from the Cambridge Crystallographic Centre,
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW,
U.K. The crystallographic numbering system differs from that used in the
text; therefore, any request should be accompanied by the full literature
citation of this paper.
.
Whatrup, D. Org. Process Res. DeV. 2008, 12, 88
.
(17) We are grateful to Dr. J. Carey for generous amounts of aldehyde
47.
Org. Lett., Vol. 10, No. 13, 2008
2815

Scheme 7
Figure 4. Crystal structure of isochromone 53.
then produced the required conjugated ester 48 in high yield
and complete E selectivity. Ester reduction followed by
alkene hydrogenation and Swern oxidation produced the
pivotal aldehyde 49 in high yield over the three-step
sequence.
Treatment of iso-chromone 53 under Mitsunobu conditions
successfully produced the benzoate ester 55 matching the
stereochemistry present in the western section of the ajuda-
zols.
Coupling of aldehyde 49 with isobenzofuran anion 15
(generated under the same conditions previously described)
followed by oxidative rearrangement of the carbinol inter-
mediate and Jones oxidation of the resulting lactols 50R/ꢀ
generated the desired keto lactones 51 and 52 in good yield
over the entire sequence and as a 3:2 mixture of diastereo-
mers (Scheme 8).
In conclusion, we have developed a convergent and
versatile approach to the synthesis of isochroman-1-ones
from simple phthalides through a completely novel applica-
tion of isobenzofurans 9 as synthetic intermediates. The
synthetic methodology is concise, efficient, and amenable
to being scaled up and can tolerate diverse range of alde-
hyde coupling partners as demonstrated by our synthesis of
the ajudazol-derived isochromone derivatives 53 and 55. We
are currently in the process of investigating enantioselective
versions of this novel rearrangement.19
Scheme 8
Interestingly, we have recently become aware that Ko¨nig
and co-workers have recently reported the isolation of
phthalide 56 and 4-hydroxymellein 57 from the algicolous
marine fungus Epicoccum sp.20 This finding raises the
possibility that phthalide 56 or a derivative of it might be a
precursor in the biosynthesis of isochromone 57 (Figure 5).
Figure 5. Epicoccum sp. metabolites.
Acknowledgment. We thank the BBSRC for a postgradu-
ate studentship (S.J.H.). We also thank Dr. Ian Sword and
the University of Glasgow for funding. We thank Rigaku
for the loan of an R-AXIS RAPID image plate diffractometer
and Oxford Cryosystems for the loan of a low-temperature
device.
Luche reduction of the diastereomeric mixture of keto
lactones 51 and 52 proceeded in good yield and with
complete facial selectivity to afford the isochromones 53 and
54 which could be separated by selective crystallization of
the major diastereomer 53 (Figure 4).18
Supporting Information Available: Experimental pro-
cedures and characterization data of the described compounds
and intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) The atomic coordinates for 53 (CCDC deposition no. CCDC676872)
are available upon request from the Cambridge Crystallographic Centre,
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW,
U.K. The crystallographic numbering system differs from that used in the
text; therefore, any request should be accompanied by the full literature
citation of this paper.
OL8009336
(19) Furstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906.
(20) Abdel-Lateff, A.; Fisch, K. M.; Wright, A. D.; Ko¨nig, G. M. Planta
Med. 2003, 69, 831.
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