Regiocontrolled rearrangement of isobenzofurans

Article abstract of DOI:10.1021/ol200498k

Regioselective alkylation and oxidative rearrangement of isobenzofurans has been achieved to generate substituted 4,8- ihydroxyisochromanones in good yields and with complete regiocontrol.

Full text of DOI:10.1021/ol200498k

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2086–2089
Regiocontrolled Rearrangement of
Isobenzofurans
Ben A. Egan,† Michael Paradowski,‡ Lynne H. Thomas,§ and Rodolfo Marquez*,†,
WestCHEM, University of Glasgow, Joseph Black Building, University Avenue,
Glasgow G12 8QQ, United Kingdom, Pfizer Global R&D, Sandwich, Kent CT13 9NJ,
United Kingdom, and Department of Chemistry, University of Bath, Bath BA2 7AY,
United Kingdom
r.marquez@chem.gla.ac.uk
Received February 23, 2011
ABSTRACT
The regioselective alkylation and oxidative rearrangement of isobenzofurans has been achieved to generate substituted 4,8-
dihydroxyisochromanones in good yields and with complete regiocontrol.
Isochroman-1-ones are pharmacophores present in a
number of natural products with therapeutic potential.1
The 4,8-dihydroxyisochroman-1-one motif is particularly
significant, as it is a key structural component in a number
of biologically active metabolites such as the ajudazols 1,2
acetoxygeranyloxymellein 2,3 thailandolide 3,4 the Hel-
minthosporium monoceras antifungal metabolite 4,5 and
(4R)-hydroxyochratoxin 5 (Figure 1).6
However, despite their potential as therapeutic leads, the
approaches currently available for the syntheses of sub-
stituted 4,8-dihydroxyisochroman-1-ones tend to be either
low yielding or not flexible enough for the efficient gen-
eration of analogues.
Figure 1. 4,8-Dihydroxyisochroman-1-one containing natural
products.
† University of Glasgow.
‡ Pfizer Global R&D.
§ University of Bath.
Ian Sword Reader of Organic Chemistry and EPSRC Leadership Fellow.
(1) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334.
(2) (a) Jansen, R.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org.
Chem. 2002, 917. (b) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H.
J. Antibiot. 2004, 57, 151.
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36, 531.
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Damas, A. M.; Silva, A. M. S.; Eaton, G.; Herz, W. J. Nat. Prod.
2007, 70, 1200.
Recently, we reported the fast and efficient synthesis of
simple 4-hydroxyisochroman-1-one units 7 through a
high-yielding four-step sequence starting from phthalan
6. The entire process requires minimal purification and
does not require the isolation of any of the intermediate
species (Scheme 1).7
Mechanistically, we believe that the phthalan unit 6 is
deprotonated with LDA to generate the unstable
(5) Arai, K.; Ooka, M.; Koizumi, F.; Koda, S.; Iwasaki, Y.;
Kanemoto, Y. U.S. Patent Int. 5,530,146, 1996.
(6) Zepnik, H.; Pahler, A.; Schauer, U.; Dekant, W. Toxicol. Sci.
2001, 59, 59.
(7) Hobson, S. J.; Parkin, A.; Marquez, R. Org. Lett. 2008, 10, 2813.
r
10.1021/ol200498k
Published on Web 03/23/2011
2011 American Chemical Society

It was decided to focus initially on the synthesis and
rearrangement of 4-methoxyisobenzofuran. The methoxy
group was chosen because of its likely stability to with-
stand the reaction conditions while simultaneously allow-
ing the assessment of the reliability and flexibility of the
oxidative rearrangement in the presence of a potentially
competing methyl enol ether.
Scheme 1
Our synthesis began with 2-methoxybenzoic acid 18,
which was converted to the diethylamide 19 in excellent
yield. Ortho-formylation of amide 19 cleanly generated the
desired aldehyde 20, which upon reduction followed by
acid treatment afforded lactone 21.8 Dibal reduction pro-
vided the desired lactol, which was then converted to the
key methyl acetal 22 in excellent yield (Scheme 4).
isobenzofuran unit 8 which is deprotonated to afford the
lithiated isobenzofuran 9. The isobenzofuran anion 9 is
then trapped with an aldehyde to generate the postulated
R-hydroxyisobenzofuran 10, which upon treatment with
m-CPBA undergoes a hydroxyl-directed epoxidation to
generate epoxide 11 that then rearranges to the desired
lactol 12. Oxidation of the lactol 12 to the lactone 13
followed by regioselective reduction completes the diaster-
eoselective synthesis of the isochromanone 7. The stereo-
chemical outcome of the reduction is dependent on the
nature of the alkyl side chain, with the syn diastereomer
being the preferred product. The relative stereochemistry
can be determined by 1H NMR analysis (Jab syn e 2.5 Hz;
Scheme 4
Jab anti g 6.0 Hz) (Scheme 2).
Scheme 2
Treatment of methyl acetal 22 under our rearrangement
conditions yielded the isochromanones 23A and 23B in
excellent yield and, significantly, as a 1:2 ratio of regioi-
somers. The regiochemistry of the isochromanones was
corroborated by X-ray crystallography (Figure 2).9
On the basis of our proposed mechanism, it was postu-
lated that if a C4-substituted isobenzofuran unit 14 could
be generated, then it would be possible to use the C4 group
to influence the subsequent deprotonation step. A regio-
selective deprotonation would then allow for the selective
formation of either the C5 17A or the C8-substituted
isochromanone 17B (Scheme 3). The ability to control
the regiochemistry of the deprotonation step is crucial if
substituted 4,8-dihydroxyisochromanones are to be ac-
cessed using this methodology.
Figure 2. Crystal structure of isochromanones 23A and 23B.
This result was consistent with the methoxy group
directing the deprotonation of the isobenzofuran unit to
the C1 position B over the C3 position A (Figure 3). This
highly encouraging result made us confident that a more
Scheme 3
(8) De Silva, S. O.; Reed, J. N.; Billedeau, R. J.; Wang, X.; Norris,
D. J.; Snieckus, V. Tetrahedron 1992, 48, 4863.
(9) The atomic coordinates for 23A, 23B, and 48B (CCDC deposition
nos. CCDC809799, CCDC809800, and CCDC813670) are available
upon request from the Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K.
The crystallographic numberingsystem differs from that used in the text;
therefore, any request should be accompanied by the full literature
citation of this paper.
Org. Lett., Vol. 13, No. 8, 2011
2087

sterically demanding group at the C7 position of the
phthalan starting material 22 would be able to further
influence the product ratio in favor of the desired C1
alkylation product.
proceeds through an isobenzofuran intermediate 31, re-
arrangement of the C4 silyloxy-substituted phthalan deri-
vative should yield the same isochromanones as the C7-
substituted phthalan 28 with the same regioisomeric selec-
tivity (Scheme 6).
Scheme 6
Figure 3. Methoxy-directed isobenzofuran deprotonation.
The synthesis of the C4 silyloxy-substituted phthalan 37
began with benzoic acid 32, which was converted into the
diethyl amide and then methylated to afford methyl ether
33. Regioselective formylation of amide 33 using Snieckus’
conditions afforded aldehyde 34, which upon reduction
and acid treatment afforded lactone 35 in good yield
(Scheme 7).
Deprotection of methoxy phthalide 21 with iodocyclo-
hexane afforded the free hydroxyl 24 in good yield. The
hydroxyl group was then capped as the benzyl and tert-
butyl dimethylsilyl ethers 25 and 26 in excellent yield
(Scheme 5). DIBAL reduction followed by treatment of
the resulting lactols with methanol under acidic conditions
generated the required phthalans 27 and 28.
Scheme 7
Scheme 5
Iodocyclohexane promoted deprotection followed by sily-
lation afforded the TBS ether 36. Reduction of lactone 36
followed by acidic methanol treatment resulted in the desired
TBS phthalan 37. Gratifyingly, treatment of phthalan 37
under our optimized conditions yielded the desired isochro-
manone 30B in 45% yield and as a single regioisomer.
We believe that the drop in yield observed in the case of the
C4 isomer is likely to be due to the steric hindrance provided
by the silyloxy group during the initial rate-determining
isobenzofuran formation. However, once the isobenzofuran
unit is generated, the same steric hindrance provided by the
TBS group controls the regiochemistry for alkylation.
Having shown the ability of using either a C7 or C4
phthalan substituent to control the regiochemistry of
isobenzofuran alkylation and subsequent rearrangement
to yield C8-substituted isochromanones exclusively, this
approach was applied to the synthesis of the isochroma-
none unit of the ajudazols
Treatment of phthalans 27 and 28 with LDA followed
by trapping with isobutyraldehyde and oxidative rearran-
gement of the resulting R-hydroxy isobenzofurans gener-
ated the desired lactol intermediates. At this point, it was
decided to replace the Jones oxidation step of the original
sequence with the milder TEMPO oxidation to avoid any
undesired loss of the C4 isobenzofuran protecting groups.
Regioselective reduction of the ketone unit then afforded
the isochromanones 29 and 30 in excellent overall yield.
As expected, introduction of the more sterically de-
manding benzyl ether at the C7 position of the starting
phthalan resulted in an improved ratio of regioisomeric
isochromanones 29A/29B (1:4) compared to that obtained
with the methoxy substituent.
The C7 OTBS-substituted phthalan 28 on the other
hand, afforded the desired isochromanone 30B as a single
product in excellent yield over the reaction sequence.
At this point, it was decided to explore the effects of C4
phthalan substituents on the regioselectivity of isochroma-
none formation. It was hypothesized that if the reaction
The ajudazols 1 are biologically active metabolites iso-
lated from the myxobacteria Chondromyces crocatus. Struc-
turally, the ajudazols showcase a number of highly unusual
features such as 4,8-dihydroxy-7-methylisochroman-1-one
and 3-methoxybutenoic acid methyl amide.6
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Org. Lett., Vol. 13, No. 8, 2011

Our synthesis of the ajudazols’ 4,8-dihydroxy-7-methyli-
sochroman-1-one subunit began with 3-methylsalicylic acid
38, which was converted into diethyl amide 39 (Scheme 8).
Directed ortho-formylation of amide 39 generated the corre-
sponding aldehyde, which upon reduction and acid treatment
yielded the desired lactone 40.8 Replacement of the methyl
protecting group for the required TBS unit proceeded cleanly
to yield lactone 41. Lactone reduction followed by metha-
nolic acid treatment afforded the required phthalan 42.
Scheme 9
Scheme 8
to generate 4,8-dihydroxyisochroman-1-ones regiose-
lectively and in excellent overall yield. Although the
reduction step of the rearrangement sequence yields
the syn relation exclusively, the analogous anti relation-
ship can be obtained by treatment of the isochromanone
product under Mitsunobu conditions as demonstrated
previously.7
Treatment of phthalan 42 under our optimized protocol
conditions afforded the desired 4,8-dihydroxy-7-methyliso-
chroman-1-one 43 in good yield and as a single regioisomer.
Having observed the ability of phthalan 42 to regiose-
lectively couple with a simple aldehyde, a more relevant
model system was envisioned which incorporated the
functionality present in the ajudazols.
Oxazole 44 was subjected to a Taylor tandem oxidationÀ
olefination to afford ester 45 in excellent yield.10 Hydrogena-
tion of ester 45 followed by DIBAL reduction afforded the
primary alcohol, which was resolved through the use of chiral
HPLC.11 The novel nature of the enantiomeric alcohols
obtained meant that one of the enantiomeric components
had to be arbitrarily chosen. TEMPO oxidation of the
enantiomerically pure alcohol yielded aldehyde 46. Reaction
of aldehyde 46 with the phthalan 42 derived isobenzofuran 47
produced the diastereomeric isochromanones 48A and 48B in
59% yield (Scheme 9). The regiochemical outcome of the
rearrangement as well as the absolute stereochemistry of the
isochromanone (and via infra that of aldehyde 46) were
corroborated by X-ray crystallographic analysis of the 4,8-
dihydroxyisochroman-1-one 48B (Figure 4).
Figure 4. 4,8-Dihydroxyisochroman-1-one 48B.
Crucially, however, the successful coupling of isobenzo-
furan 47 with aldehyde 46 demonstrates the ability of the
isobenzofuran rearrangement to take place in the presence
of potentially conflicting unsubstituted C2-oxazoles. Ef-
forts are currently underway to apply this methodology to
the total synthesis of the ajudazols.
Acknowledgment. We thank the EPSRC Pharma Synt-
hesis Network and Pfizer for postgraduate support (B.A.
E.). We also thank Dr. Ian Sword, the EPSRC, and Pfizer
for funding.
In conclusion, we have demonstrated the ability to
control the regiochemistry of isobenzofuran alkylation
Supporting Information Available.
Experimental
procedures and characterization data of the described
compounds and intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res.
2005, 38, 851.
(11) Each enantiomeric alcohol was obtainedin 49% yield and 99% ee.
Org. Lett., Vol. 13, No. 8, 2011
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