Total synthesis and determination of the absolute configuration of (-)-idesolide

Article abstract of DOI:10.1021/ol9029676

(Chemical Equetion Presentation) The first total synthesis of (-)-idesolide was achieved via organocatalytic, enantioselective oxidative kinetic resolution (OKR) using (1S,4S)4-Bn-1-Bu-AZADO- and AZADO-catalyzed dimerization of (S)-(-)-methyl 1-hydroxy-6-

Full text of DOI:10.1021/ol9029676

ORGANIC
LETTERS
2010
Vol. 12, No. 5
980-983
Total Synthesis and Determination of
the Absolute Configuration of
(-)-Idesolide
Hiroyuki Yamakoshi, Masatoshi Shibuya, Masaki Tomizawa, Yuji Osada,
Naoki Kanoh, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received December 28, 2009
ABSTRACT
The first total synthesis of (-)-idesolide was achieved via organocatalytic, enantioselective oxidative kinetic resolution (OKR) using (1S,4S)-
4-Bn-1-Bu-AZADOH- and AZADO-catalyzed dimerization of (S)-(-)-methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate. The absolute configuration
of (-)-idesolide is determined to be 2R,2′S,3aS,7aR.
Dimerization is a ubiquitous process in nature to endow
molecule complexity and biological activity, and reproduc-
tion of the process often offers chemists significant chal-
lenges.1,2 In 2005, Kim and co-workers reported the isolation
of (-)-idesolide (1) from the fruit of Idesia polycarpa; this
compound effectively inhibits nitric oxide (NO) production
induced by lipopolysaccharide (LPS) in BV2 microglial cells
(Figure 1).3 The unprecedented structure of idesolide featur-
ing a tetrahydrobenzodioxole was confirmed by X-ray
Figure 1. Possible biogenesis of idesolide.
crystallography, but the absolute configuration remained
unknown.
The hemiketal/ketal functionality of idesolide leads to
a straightforward analysis that the natural product may
be formed from two identical molecules of an R-hydroxy
ketone,4 more specifically, optically identical methyl
1-hydroxy-6-oxo-2-cyclohexenecarboxylate (2).5 However,
Snider and co-workers reported that they could not observe
the formation of idesolide from either racemic or optically
enriched 2 under a variety of conditions.6
(1) For a review, see: Vrettou, M.; Gray, A. A.; Brewer, A. R. E.; Barrett,
A. G. M. Tetrahedron 2007, 63, 1487
.
(2) For leading references, see: (a) Snyder, S. A.; Kontes, F. J. Am.
Chem. Soc. 2009, 131, 1745. (b) Ondrus, A. E.; Movassaghi, M. Chem.
Commun. 2009, 4151. (c) Nicolaou, K. C.; Nold, A. L.; Milburn, R. R.;
Schindler, C. S.; Cole, K. P.; Yamaguchi, J J. Am. Chem. Soc. 2007, 129,
1760. (d) Shoji, M.; Hayashi, Y. Eur. J. Org. Chem. 2007, 3783. (e) Porco,
J. A., Jr; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem.,
(4) Dimerization of R-hydroxy ketones: (a) Creary, X.; Rollin, A J. J.
Org. Chem. 1977, 42, 4226. (b) Creary, X.; Rollin, A. J. J. Org. Chem.
1977, 42, 4231. (c) Banks, M. R.; Gosney, I.; Grant, K. J.; Reed, D.;
Hodgson, P. K. G. Magn. Reson. Chem. 1992, 30, 996. (d) Jauch, J.; Schurig,
V.; Walz, L. Zeit. Kristallograph. 1991, 196, 255.
Int. Ed 2006, 45, 5790
.
(3) Kim, S. H.; Sung, S. H.; Choi, S. Y.; Chung, Y. K.; Kim, J.; Kim,
Y. C. Org. Lett. 2005, 7, 3275.
10.1021/ol9029676  2010 American Chemical Society
Published on Web 02/05/2010

Fascinated with the exquisite structure coupled with the
interesting biological activity, we also embarked on the
synthetic journey to idesolide and encountered the same
difficulty as Snider’s team. Fortunately, an unexpected
discovery led to the completion of this synthesis. We herein
report the first total synthesis and determination of the
absolute configuration of (-)-idesolide, featuring a highly
enantioselective oxidative kinetic resolution (OKR) using a
chirally modified AZADO7 and AZADO-catalyzed dimer-
ization of the monomer 2.
The synthesis began with the Horner-Wadsworth-
Emmons reaction of glutaraldehyde (3) with trimethyl
phosphonoacetate to give cyclohexenol 4.8 The hydroxy
group of 4 was protected as an acetate ester, and the resulting
acetate 5 was subjected to catalytic dihydroxylation using
OsO4 and NMO to furnish diol 6 in a highly diastereose-
lective manner. After acetonide protection of the diol moiety
followed by methanolytic removal of the acetyl group, the
racemic alcohol 7 thus obtained was subjected to the OKR
using a chirally modified AZADO which had recently been
developed by our group (Scheme 1).7a
of 5 mol % of (1S,4S)-4-Bn-1-Bu-AZADOH and 2 equiv
NaHCO3 (solid), rac-7 was resolved to give (+)-ketone 8
in 37% yield with 95% ee, and (+)-alcohol 7 was recovered
in 59% yield with 63% ee10 (kR/kS ) 39).11 The absolute
configuration of recovered, enantiomerically enriched (+)-7
was established to be that of the (S)-alcohol by comparison
with the specific rotation of an authentic sample of (-)-7,
which was independently synthesized from known (R)-48 (see
the Supporting Information).
The highly enantiomerically enriched (+)-ketone 8
(95% ee) was converted to (-)-cyclohexene 9 via a
conventional sequence consisting of enol triflate forma-
tion and the subsequent palladium-catalyzed reduction
(Scheme 2). Treatment of acetonide 9 with p-TsOH in
Scheme 2. Synthesis of Monomer 2
Scheme 1. Oxidative Kinetic Resolution
THF-H2O-AcOH12 at ambient temperature allowed
selective hydrolysis of the acetonide to give cis-diol 10.
While oxidation of 10 to monomer 2 was somewhat
troublesome, the goal was achieved by AZADO catalysis
employing polymer-supported bis(acetoxy)iodobenzene13
(PS-BAIB) as the bulk oxidant. Note that the use of BAIB
as the bulk oxidant suffered from cleavage of the diol
moiety of 10. The spectral data for 2 were identical to
those of the isolated product and reported by Snider.6 The
[R]D value of our synthetic (-)-2 of -278 (c 1.0, CHCl3)
establishes that natural (-)-monomer 2 has the S-config-
uration.5a
Having secured the highly enantiomerically enriched
monomer, the stage was set for the crucial dimerization. We
confirmed that (-)-monomer 2 does not dimerize under
Upon treatment with 0.25 equiv of trichloroisocyanuric
acid (TCCA)7a,9 in CH2Cl2 at -40 °C for 3 h in the presence
(9) (a) Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
3041. (b) Luca, L. D.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org.
Chem. 2003, 68, 4999.
(5) Isolation of methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate: (a)
Rasmussen, B.; Nkurunziza, A.-J.; Witt, M.; Oketch-Rabah, H. A.;
Jaroszewski, J. W.; Stærk, D. J. Nat. Prod 2006, 69, 1300. (b) Kim, S. H.;
Jang, Y. P.; Sung, S. H.; Kim, Y. C. Planta Med. 2007, 73, 167. (c) Ekabo,
O. A.; Farnsworth, N. R. J. Nat. Prod. 1993, 56, 699.
(10) 99.5% ee of (+)-7 was obtained in 44% yield after 24 h reaction
under the same conditions, together with 77% ee of (+)-ketone 8 in 54%
yield. Oxidation of the highly enantiomerically enriched (+)-7 gave (-)-8
which was converted to unnatural idesolied (+)-1 (see the Supporting
Information).
(6) Richardson, A. M.; Chen, C.-H.; Snider, B. B. J. Org. Chem. 2007,
72, 8099.
(7) AZADO : (a) Tomizawa, M.; Shibuya, M.; Iwabuchi, Y. Org. Lett.
2009, 11, 1829. (b) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y.
J. Am. Chem. Soc. 2006, 128, 8412.
(11) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(12) Kaburagi, Y.; Osajima, H.; Shimada, K.; Tokuyama, H.; Fukuyama,
T. Tetrahedron Lett. 2004, 45, 3817.
(8) Yamane, T.; Ogasawara, K. Synlett 1996, 925.
(13) Togo, H.; Nogami, G.; Yokoyama, M. Synlett 1998, 534.
Org. Lett., Vol. 12, No. 5, 2010
981

neutral conditions: even ultrahigh pressure condition (0.8
GPa)14 did not give any detectable amount of the dimer.
Acidic conditions (cf. p-TsOH or BF3·OEt2)2a,6 gave methyl
salicylate as the only isolable product. Basic treatment of
(-)-2 using NaH,2a NaOMe, or DBU led to decomposition
or ring-opening of the ꢀ-ketoester moiety.6 After several
unsuccessful experiments, we eventually found that a small
amount of crystalline idesolide was formed in a stock flask
containing an oily, crude monomer contaminated with
AZADO. This observation prompted us to examine AZADO
as a possible promoter.
the sp3-nitrogen would play an essential role in this
particular dimerization process. Indeed, Et3N as well as
i-Pr2NEt were confirmed to promote the dimerization and
afforded idesolide (1) along with an unstable diastereomer
(entries 13 and 14).15-17 Interestingly, DMAPO and NMO
gave similar results with attenuated efficiencies (entries 15
and 16). The catalytic property of AZADO to promote the
dimerization of 2 would be attributable to the less-hindered,
basic nature of the N-oxyl moiety.18
Synthetic (-)-idesolide (1) was isolated in 34% yield
([R]25 ) -238.9 (c 0.27), lit.3 [R]25 ) -230.0 (c 1.0))
D
D
To our surprise, AZADO significantly promoted the
dimerization (Table 1). The yield of idesolide increased
from the oily mixture containing AZADO and (-)-
monomer 2 after a gel-filtration chromatograpy.15 The
structure of synthetic (-)-idesolide was unambiguously
confirmed by X-ray crystallography, thereby establishing
the absolute configuration of natural (-)-idesolide to be
2R,2′S,3aS,7aR.
Table 1. Dimerization of (-)-Monomer 2
In conclusion, we have achieved the first total synthesis
of (-)-idesolide (1) that establishes the absolute configuration
of the dimeric natural product. The successful enantioselec-
tive synthesis of monomer (-)-2 highlights the power of our
organocatalytic OKR methodology using chiral AZADOH.
Central to the completion of this synthesis was the seren-
.
yieldb (%)
solvent
(15) This diastereomer dissociated to the monomer 2 during silica
gel column chromatography. Although we could not isolate the diaste-
reomer, we obtained a mixture of the diastereomer and idesolide after
gel filtration chromatography. The 13C NMR spectrum (see the
Supporting Information) indicated that this diastereomer is the epimer
at the ketal carbon.
(16) AZADO-catalyzed dimerization of racemic monomer 2 gave
racemic idesolide (rac-1) along with the diastereomer (diastereomer-Rac)
consisting of (R)-2 and (S)-2. The structure of this diastereomer was
confirmed by X-ray crystallography (see the Supporting Information).
entry
additive (equiv)
none
(CDCl3) idesolide diastereomer
1
2
3
4
5
6
7
8
none
0.1 M
0.4 M
2 M
0
6
0
0
0
0
0
0
0
0
0
0
0
0
6
12
6
30
AZADO (1.0)
AZADO (1.0)
AZADO (1.0)
AZADO (1.0)
AZADO (1.0)
AZADO (0.1)
AZADOH (1.0)a
1-Me-AZADO (1.0)
TEMPO (1.0)
DMAP (1.0)
pyridine (1.0)
Et3N (1.0)
i-Pr2NEt (1.0)
DMAPO·H2O (1.0)a
NMO (1.0)a
35
62
68
73
38
38
63
0
65
0
65
50
22
11
10 M
none
none
none
none
none
none
none
none
none
none
none
9
10
11
12
13
14
15
16
(17) We found that some chiral tertiary amines induced the dimerization
of rac-2 to give an optically active diasetereomer-Rac consisting of (R)-2
and (S)-2, in which deMeQDAc19 brought about 45% ee (see the Supporting
Information).
(18) In light of the experimental results that the dimerization was
promoted either by tertiary alkylamines or tertiary amine N-oxide, we
speculate AZADO behaved as a possible general base.
a Additive did not dissolve completely. Calculated yield (1H NMR).
b
as the concentration of AZADO increased (entries 1-6).
Addition of 0.1 equiv of AZADO to (-)-monomer 2
yielded idesolide in 38%, indicating that AZADO acts as
a catalyst in this reaction (entry 7). Note that AZADOH
showed a considerably decreased productivity compared
with AZADO (entry 8). Interestingly, 1-Me-AZADO
showed an attenuated performance compared with AZA-
DO, and TEMPO did not give any detectable amount of
idesolide after 48 h, indicating the importance of less-
hinderd nature of the N-oxyl group on the promotion of
dimerization (entries 9 and 10). Eventually, we found that
DMAP promoted the desired dimerization of which the
efficiency was comparable with that AZADO (entry 11).
Pyridine did not give idesolide (entry 12), implying that
For hydrogen-bonding interactions between stable nitroxyl radical and ROH,
see: (a) Morishima, I.; Ishihara, K.; Tomishima, K.; Inubushi, T.; Yonezawa,
T J. Am. Chem. Soc. 1975, 97, 2749. (b) Otsuka, T.; Motozaki, W.;
Nishikawa, K.; Endo, K. J. Mol. Struct. 2002, 615, 147. (c) Russ, J. L.;
Gu, J.; Tsai, K.-H.; Glass, T.; Duchamp, J. C.; Dorn, H. C. J. Am. Chem.
Soc. 2007, 129, 7018.
(19) Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 12658.
(20) (a) Kinoshita, S.; Ohsaka, T.; Tokuda, K. Electrochem. Acta 2003,
48, 1589. (b) Sen, V. D.; Golubev, V. A. J. Phys. Org. Chem. 2009, 22,
138.
(14) Shimizu, T.; Hiramoto, K.; Nakata, T. Synthesis 2001, 1027.
982
Org. Lett., Vol. 12, No. 5, 2010

dipitous discovery that AZADO enables the dimerization of
the monomeric R-hydroxy ketone 2. Mechanistic studies to
elucidate the precise role of AZADO as well as to expand
the synthetic scope are now underway and will be reported
in due course.
pressure reaction apparatus and helpful discussions on the
dimerization chemistry.
Supporting Information Available: Detailed experimen-
tal procedures, copies of all spectral data, and full charac-
terization. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Mikiko Sodeoka and Dr.
Takeshi Shimizu (RIKEN) for the use of the ultrahigh
OL9029676
Org. Lett., Vol. 12, No. 5, 2010
983