Asymmetric synthesis of 4,8-dihydroxyisochroman-1-one polyketide metabolites using chiral hypervalent iodine(III)

Article abstract of DOI:10.1021/ol300185u

Stereoselective oxylactonization of ortho-alkenylbenzoate with chiral hypervalent iodine is applied to the asymmetric synthesis of 4-oxyisochroman-1-one polyketide metabolites including 4-hydroxymellein (1), a derivative of fusarentin 2, monocerin (3), and an epimer of monocerin epi-3.

Full text of DOI:10.1021/ol300185u

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1294–1297
Asymmetric Synthesis of 4,8-
Dihydroxyisochroman-1-one Polyketide
Metabolites Using Chiral Hypervalent
Iodine(III)
Morifumi Fujita,* Kazuhiro Mori, Mio Shimogaki, and Takashi Sugimura
Graduate School of Material Science, University of Hyogo, Kohto, Kamigori, Hyogo
678-1297, Japan
fuji@sci.u-hyogo.ac.jp
Received January 23, 2012
ABSTRACT
Stereoselective oxylactonization of ortho-alkenylbenzoate with chiral hypervalent iodine is applied to the asymmetric synthesis of 4-oxyisochroman-
1-one polyketide metabolites including 4-hydroxymellein (1), a derivative of fusarentin 2, monocerin (3), and an epimer of monocerin epi-3.
The 4-oxyisochroman-1-one motif is present in some
types of natural products such as 1À8 illustrated in Figure 1,
which includes a number of bioactive polyketide metabolites.1
Owing to their biological and pharmacological potential,
these compounds have attracted considerable attention.1À5
From a synthetic viewpoint, the 4-hydroxyisochroman-1-one
structure has been strategically approached in the following
two ways: (1) hetero-DielsÀAlder cycloaddition of ortho-
quinone dimethides followed by oxidation;4 (2) oxidative
rearrangement of isobenzofurans followed by reduction.5
However, enantiomeric control and the total synthesis of
this class of natural products are still challenging issues.
Oxidative lactonization of ortho-alkenylbenzoates could
be an alternative and efficient route toward the 4-
hydroxyisochroman-1-one motif, if it proceeds with endo-
selectivity. Unfortunately, the oxidative lactonization
using conventional oxidizing reagents yielded a phthalide
product because of exo selectivity.6,7 In contrast, endo selec-
tive oxylactonization was achieved by using hypervalent
(1) (a) (3R,4R)-1: Aldridge, D. C.; Galt, S.; Giles, D.; Turner, W. B.
J. Chem. Soc. (C) 1971, 1623. Garson, M. J.; Staunton, J.; Jones, P. G. J.
Chem. Soc., Perkin Trans. 1 1984, 1021. (b) (3S,4S)-1:Izawa, Y.; Hirose, T.;
Shimizu, T.; Koyama, K.; Natori, S. Tetrahedron 1989, 45, 2323. (c) 2:
Zhang, W.; Krohn, K.; Draeger, S.; Schulz, B. J. Nat. Prod. 2008, 71, 1078.
Tianpanich, K.; Prachya, S.; Wiyakrutta, S.; Mahidol, C.; Ruchirawat, S.;
Kittakoop, P. J. Nat. Prod. 2011,74,79. (d)3: Aldridge, D. C.; Turner, W. B.
J. Chem. Soc. (C) 1970, 2598. (e) 4: Isaka, M.; Yangchum, A.; Intamas, S.;
Kocharin, K.; Jones, E. B. G.; Kongsaeree, P.; Prabpai, S. Tetrahedron 2009,
65, 4396. Xu, L.; Xue, J.; Wei, X.; He, Z.; Chen, X. J. Nat. Prod. 2010, 73,
885. (f) 5: Nonaka, G.; Sakai, T.; Mihashi, K.; Nishioka, I. Chem. Pharm.
Bull. 1991, 39, 884. (g) 6: Ritzau, M.; Vettermann, R.; Fleck, W. F.; Gutsche,
W.; Dornberger, K.; Graefe, U. J. Antibiot. 1997, 50, 791. (h) 7: Li, S.;
Marquardt, R. R.; Frohlich, A. A. Food Chem. Toxicol. 2000, 38, 141. (i) 8:
Arai, K.; Yoshimura, T.; Itatani, Y.; Yamamoto, Y. Chem. Pharm. Bull.
1983, 31, 925.
(2) Monocerine (3) has been synthesized by taking advantage of the
tetrahydrofuran framework; see: Mori, K.; Takaishi, H. Tetrahedron
1989, 45, 1639. Dillon, M. P.; Simpson, T. J.; Sweeney, J. B. Tetrahedron
Lett. 1992, 33, 7569. Mallareddy, K.; Rao, S. P. Tetrahedron 1996, 52,
8535. Cassidy, J. H.; Farthing, C. N.; Marsden, S. P.; Pedersen, A.;
Slater, M.; Stemp, G. Org. Biomol. Chem. 2006, 4, 4118. Kwon, H. K.;
Lee, Y. E.; Lee, E. Org. Lett. 2008, 10, 2995.
(4) Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 1937.
(5) Hobson, S. J.; Parkin, A.; Marquez, R. Org. Lett. 2008, 10, 2813.
Egan, B. A.; Paradowski, M.; Thomas, L. H.; Marquez, R. Org. Lett.
2011, 13, 2086.
(6) Berti, G. J. Org. Chem. 1959, 24, 934 and references herein.
Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni, P.; Benaglia, M.
Tetrahedron 1991, 47, 5737. Denieul, M.-P.; Laursen, B.; Hazell, R.;
Skrystrup, T. J. Org. Chem. 2000, 65, 6052. Ohzeki, T.; Mori, K. Biosci.
Biotechnol. Biochem. 2003, 67, 2240. Cottrell, I. F.; Cowley, A. R.; Croft,
L. J.; Hymns, L.; Moloney, M. G.; Nettleton, E. J.; Smithies, H. K.;
Thompson, A. L. Tetrahedron 2009, 65, 2537.
(3) For synthesis of 5, see: Deffieux, D.; Natangelo, A.; Malik, G.;
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r
10.1021/ol300185u
Published on Web 02/15/2012
2012 American Chemical Society

iodine(III) as an oxidizing reagent.9 Here, we describe the
asymmetric synthesis of 4-oxyisochroman-1-one polyketide
metabolites, containing 4-hydroxymellein (1), a derivative of
fusarentin 2, monocerin (3), and an epimer of monocerin epi-
3 by oxylactonization with hypervalent iodine.
hypervalent iodine based on a lactate motif is one of the
most attractive reagents for this process because of its
short-step access.9,10cÀ10g,11e The lactate-derived reagents
9À10 (Figure 2) were used for a key step in the asymmetric
synthesis of oxyisochromanones. In particular, the three
targets, 2, ent-3, and epi-3, were divergently provided from
a single (R,E)-2-(4-oxyhept-1-enyl)benzoate substrate. Se-
lective formation of one of these targets was achieved
through judicious choice of the oxy-functional group in
the substrate and the stereochemistry of the chiral hyper-
valent iodine reagent employed.
Figure 2. Chiral hypervalent iodine(III).
For the asymmetric synthesis of 4-hydroxymellein (1),
acetoxy-protected propenylbenzoate 11d was employed as
a substrate of oxylactonization with enantiomerically pure
hypervalent iodine (Scheme 1). The enantioselective oxy-
lactonization of 11d with 10 gave 12d in 68% isolated yield
with 96% ee of the (3S,4S)-isomer. Hydrolysis of the
acetoxy product 12d successfully yielded the target com-
pound (3S,4S)-1 (13d) in 61% yield. Details are summa-
rized in Tables S1 and S2 (Supporting Information (SI)),
along with the results of model compounds 11aÀ11c.13
Figure 1. Natural products containing hydroxyisochromanone.
Asymmetric oxidation with chiral hypervalent iodine
has attracted considerable attention owing to its high
enantioselectivity in metal-free oxidation.8À12 The chiral
(7) Oxidative lactonization of aryl-substituted substrates such as
2-(2-phenylethenyl)benzoic acid gave isochromanone products. The
endo- vs exo-selectivity may be controlled by an electron-donating aryl
group; see: Berti, G. Tetrahedron 1958, 4, 393. Clive, D. L. J.; Russel,
C. G.; Chittattu, G.; Singh, A. Tetrahedron 1980, 36, 1399. Izumi, T.;
Morishita, N. J. Heterocycl. Chem. 1994, 31, 145. Shahzad, S. A.; Venin,
C.; Wirth, T. Eur. J. Org. Chem. 2010, 3465.
Scheme 1. Synthesis of 4-Hydroxymellein and Analogs
(8) For recent highlights on asymmetric oxidation with chiral hyper-
valent iodine, see: Ngatimin, M.; Lupton, D. W. Aust. J. Chem. 2010, 63,
653. Liang, H.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2011, 50, 11849.
(9) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura, T.
Angew. Chem., Int. Ed. 2010, 49, 7068.
(10) For enantioselective oxidation of alkene with chiral hypervalent
iodine(III), see: (a) Hirt, U. H.; Spingler, B.; Wirth, T. J. Org. Chem.
1998, 63, 7674. (b) Hirt, U. H.; Schuster, M. F. H.; French, A. N.; Wiest,
O. G.; Wirth, T. Eur. J. Org. Chem. 2001, 1569. (c) Fujita, M.; Okuno, S.;
Lee, H. J.; Sugimura, T.; Okuyama, T. Tetrahedron Lett. 2007, 48, 8691.
(d) Fujita, M.; Ookubo, Y.; Sugimura, T. Tetrahedron Lett. 2009, 50,
1298. (e) Fujita, M.; Wakita, M.; Sugimura, T. Chem. Commun. 2011, 47,
In order to identify suitable conditions for the synthesis
of 2 and 3, the simplified model substrates 16Sa and 16Ha
were subjected to oxylactonization with hypervalent io-
dine. The yield and selectivity of the model reactions are
summarized in Tables 1 and 2. The reaction of the silyl
ether substrate 16Sa yielded dihydrofuran-fused isochro-
manones 17a and 18a, but no acetoxy product (an analog
of 19a), as shown in Table 1. In contrast, the acetoxy
€
ꢀ
3983. (f) Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.;
~
Muniz, K. Angew. Chem., Int. Ed. 2011, 50, 9478. (g) After submission
of this manuscript a related report on intramolecular oxyamination was
published: Farid, U.; Wirth, T. Angew. Chem., Int. Ed., DOI: 10.1002/
anie.201107703.
(11) For catalytic use of chiral hypervalent iodine generated in situ,
see: (a) Richardson, R. D.; Page, T. K.; Altermann, S.; Paradine, S. M.;
French, A. N.; Wirth, T. Synlett 2007, 538. (b) Dohi, T.; Maruyama, A.;
Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer,
S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787. (c) Quideau, S.;
Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-Beaudenon, A.;
ꢀ
ꢀ
Buffeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem., Int. Ed.
(13) Rearranged γ-lactone 14 was often obtained in the hydrolysis
(Table S2). The rearrangement to thermodynamically stable γ-lactone
may take place via hydrolysis of the δ-lactone moiety. The rate for the
hydrolysis of the δ-lactone moiety must be affected by the electronic
property of a substituent on the benzene ring: the acetoxy group at the
8-position of 12c,d may be hydrolyzed to an electron-donating hydroxy
group to decrease the rate for hydrolysis of the lactone moiety. Thus,
selectivity in the hydrolysis products 13/14 is controlled by the sub-
stituent on the benzene moiety as well as basicity of the reaction
conditions. Nonsubstituted 13a was obtained under mild basic condi-
tions with K2CO3 (entry 2 in Table S2).
€
2009, 48, 4605. (d) Farooq, U.; Schafer, S.; Shah, A. A.; Freudendahl,
D. M.; Wirth, T. Synthesis 2010, 1023. (e) Uyanik, M.; Yasui, T.;
Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175.
(12) For reactions featuring metal-free conditions, see: Kang, Y.-B.;
Gade, L. H. J. Am. Chem. Soc. 2011, 133, 3658. Zhdankin, V. V. J. Org.
Chem. 2011, 76, 1185. Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed.
2011, 50, 1524. Silva, L. F., Jr.; Olofsson, B. Nat. Prod. Rep. 2011, 28,
1722. Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am. Chem.
Soc. 2009, 131, 1382. Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto,
A.; Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668.
Org. Lett., Vol. 14, No. 5, 2012
1295

product 19a was obtained with 17a and 18a in the reaction
of the hydroxyl substrate 16Ha (Table 2). These results
indicate that the silyloxy group does not act as a protect-
ing group but preferably enhances the electron-donating
ability14 of the oxy-group to promote nucleophilic oxy-
cyclization. The electron donation may be futhermore
(entries 4 and 5). Selective formation of 17a and 18a was
achieved in the reaction of (R)-16Sa with (R)-9 (entry 4) and
in that with (S)-9 (entry 5), respectively. The configuration
of the (2R)-17a product corresponds to that of the antipodal
enantiomer of monocerin (ent-3). Thus, a combination of
the (S)-isomer of the silyloxy substrate and (S)-reagentmust
be suitable conditions for the selective synthesis of 3.
enahanced by coordination of BF3 OEt2 to the silyl group.
3
The structure of target 2 corresponds with that of the
acetoxy product (R)-19a. The reaction of the hydroxyl
substrate 16Ha gave the acetoxy product 19a (Table 2).
The yield of 19a drastically decreased in the absence of
acetic acid (entry 2). The desired enantiomer (R)-19a was
obtained in the reaction of the (R)-hydroxyl substrate
(entries 4À6). Use of the (S)-iodine reagent increased the
selectivity of the acetoxy product (entry 5), while reaction
with the (R)-reagent gave an isomeric mixture (entry 6).
The above-mentioned results provide useful informa-
tion from mechanistic and synthetic viewpoints. The
mechanistic points are discussed as follows. A plausible
reaction mechanism for the double oxidative cyclization to
give 17 and 18 is proposed in Scheme 2. The oxidative
cyclization may be initiated by electrophilic addition of the
Table 1. Oxylactonization of Silyloxy Substrate
hypervalent iodine activated by BF3 OEt2 toward 16S.
3
a Product ratio determined by 1H NMR of a crude mixture. b Yield
for the product purified by column chromatography. c Enantiomer ratio
((2R)-17a/(2S)-17a or (2R)-18a/(2S)-18a) determined by GC analysis on
a chiral stationary phase. d Products were purified as a diastereomeric
mixture (17/18 = 43/57) in 74%.
Nucleophilic substitutions with the internal silyloxy and
methoxycarbonyl groups follow the electrophilic addition
and proceed with inversion of configuration to give 17 and
18. The product 17a with a (2R,3aS,9bS)-configuration is
formed via the Si-face attack, while 18a is formed via the Re-
face attack toward the (R)-alkene substrate. The 1/1 mix-
ture of 17/18 in the reaction with achiral reagent PhI(OAc)2
(entries 1 and 3, Table 1) indicates that the stereogenic
center of the silyloxy substrate 16Sa has little effect on the
diastereoface differentiation. The chirality of the hyper-
valent iodine reagent controls the diastereoface selectivity
well: the R-reagent preferentially attacks the Si-face to give
17a (entry 4, Table 1), and the S-reagent attacks the Re-face
to give 18a (entry 5, Table 1). In other words, the reaction of
the silyloxy substrate takes place under reagent control.
Table 2. Oxylactonization of Hydroxy Substrate
Scheme 2. Plausible Pathway
a Product ratio determined by 1H NMR of a crude mixture. b Yield for
the product purified by column chromatography. The value in parenthe-
ses is enantiomer ratio determined by GC analysis on a chiral stationary
phase; (2R)-17a/(2S)-17a, (2R)-18a/(2S)-18a, and (R)-19a/(S)-19a. c In
the absence of AcOH. d An unidentified product X was included in 12%
content. e Products were purified as a mixture of 17/18/19/X = 49/19/22/
10 in 88% yield. The enantiomeric ratio was not determined.
In the reaction of the silyl substrate (Table 1), an ∼1/1
mixture of 17a/18a was obtained (entries 1À3), unless both
substrate 16Sa and reagent 9 were enantiomerically pure
In contrast, the reaction of the hydroxyl substrate 16H
proceedsunder substrate control. The reaction of 16H with
the achiral reagent PhI(OAc)2 predominantly gives 18
and 19 (entries 1 and 4, Table 2). The acetoxy product 19
forms through the Re-face addition. This indicates that
electrophilic addition of the achiral iodine reagent
(14) A silyl group is inductively electon-donating; see: Bassindale,
A. R.; Taylor, P. G. In The Chemistry of Silicon Compounds; Patai, S.,
Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1989; Part 2, Chapter
14, pp 892À963.
1296
Org. Lett., Vol. 14, No. 5, 2012

preferentially takes place on the Re-face.15 That is, the
achiral reagent is able to differentiate the diastereoface of
the alkene during the electrophilic addition step. In other
words, the stereogenic center of the hydroxyl substrate
controls the diastereoface selectivity well.16 In addition to
thesubstratecontrol, the stereodifferentiating ability ofthe
chiral hypervalent iodine reagent also affects the product
distribution: the (R)-9 reagent favors the Si-face attack,
which is the reverse of the substrate control and, thus,
results in a decrease in diastereoface selectivity to afford
isomeric mixtures (entry 6, Table 2). In contrast to the
mismatched pair (the reaction of (R)-16Ha with (R)-9), the
reaction of (R)-16Ha with (S)-9 yielded only 18 and 19,
both of which were derived from the Re-face attack (entry
5, Table 2).17 These observations of the double asymmetric
induction are consistent with the kinetic resolution of
racemic 16Ha with (R)-9, where (R)-enriched 16Ha re-
mained (SI). This indicates that the reaction of (S)-16Ha
(the matched pair) is faster than that of (R)-16Ha (the
mismatched pair).
yield together with 18b. Thus, the acetoxy group of 16b
does not affect the selectivity of double asymmetric induc-
tion. Oxylactonization of the trioxy-substituted benzoate
substrate 16c proceeded with a selectivity similar to that of
16a and 16b. Fortunately, the electron-rich aromatic por-
tion of 16c was tolerated during the oxylactonization.
Syntheses of 2, ent-3, and epi-3 were completed through
hydrolysis under basic conditions. The desired enantiomer
of monocerin (3) was obtained in the oxylactonization of
(S)-16Sc with (S)-9 (48% yield) and following hydrolysis
(41% yield).
A catalytic variant of the oxylactonization isobtainedby
using chiral iodoarene 20 as an organocatalyst, m-CPBA
as a terminal oxidant, and trifluoroacetic acid as an
activator. Enantioselectivity in the catalytic variant was
examined in the reaction of achiral substrates 21aÀf
(Scheme 4; Table S3, SI). Double oxidative cyclization
preferentially took place in the reaction of the hydroxyl
substrate 21 to give the dihydrofuran-fused isochroma-
none 22 with up to 91% ee.
Scheme 4. Catalytic Enantioselective Oxylactonization
Scheme 3. Synthesis of 2 and 3
Based on the enantioselective catalytic reaction, mono-
cerin (3) was synthesized under the catalytic conditions as
follows. The substrate (S)-16Scwas used for the reaction in
the presence of (S,S)-20 as an organocatalyst to give a
mixture of (2S)-17c/(2S)-18c in a 9/1 ratio. These isomers
were separated by column chromatography with SiO2, and
(2S)-17c was isolated in 39% yield.
In conclusion, the first asymmetric syntheses of 4-hydro-
xymellein (1) and a derivative of fusarentin 2 were achieved
by using enantio- and diastereoselective acetoxylacton-
ization with chiral hypervalent iodine(III). Monocerin (3)
was also concisely prepared under both the stoichiometric
and catalytic conditions. These synthetic applications allow
the outstanding selectivity and synthetic capabilities of oxi-
dation mediated by hypervalent iodine to be demonstrated.
Based on the optimization of reaction conditions pre-
sented above, an advanced model substrate 16b was sub-
jected to oxylactonization (Scheme 3). An analog of
monocerin, (2R)-17b, was obtained in the reaction of the
silyl substrate (R)-16Sb with (R)-9 in 65% yield. The
reaction of the hydroxyl substrate (R)-16Hb with (S)-9
gave the 4-acetoxyisochromanone product 19b in 31%
(15) (a) The product distribution of 18/19 is determined by a nucleo-
philic displacement step at the benzylic position of the iodonium15b
derived from the Re-face electrophilic addition: the internal hydroxy
group attacks to give 18, and intermolecular substitution with AcOÀ or
AcOH gives 19. The competition may be affected by the steric effect of
the aryliodane moiety. (b) The three-membered ring structure of the
iodonium intermediate has previously been proposed judging from the
high enantioselectivity in oxylactonization of 2-ethenylbenzoic acid.9
(16) Association of hypervalent iodine with a hydroxy group has
been suggested; see: (a) Ding, H.; Chen, D. Y.-K. Angew. Chem., Int. Ed.
Acknowledgment. This research was supported by
KAKENHI (23550059) from JSPS. We thank Dr. Hiroki
Akutsu and Prof. Shin’ichi Nakatsuji (Hyogo) for their
assistance with X-ray crystallographic analyses.
ꢀ
2011, 50, 676. (b) Traore, M.; Maynedier, M.; Souard, F.; Choisnard, L.;
Supporting Information Available. Experimental pro-
cedures and data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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Vial, H.; Wong, Y.-S. J. Org. Chem. 2011, 76, 1409. (c) Pouysegu, L.;
Chassaing, S.; Dejugnac, D.; Lamidey, A.-M.; Miqueu, K.; Sotiropoulos,
J.-M.; Quideau, S. Angew. Chem., Int. Ed. 2008, 47, 3552. (d) Baldwin,
J. E.; Adlington, R. M.; Sham, V. W.-W.; Marquez, R.; Bulger, P. G.
Tetrahedron 2005, 61, 2353.
(17) The results of entry 3 in Table 2 are explained by a combination
of those of the matched and mismatched pairs because the substrate is a
racemic mixture.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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