Synthesis of (-)-sordarin

Article abstract of DOI:10.1021/ja060408h

The first total synthesis of (-)-sordarin (1) was accomplished exploiting the following key reactions: (i) Ag(I)-catalyzed oxidative radical cyclization of a cyclopropanol derivative leading to a bicyclo-[5.3.0]decan-3-one skeleton; (ii) Pd(0)-catalyzed i

Full text of DOI:10.1021/ja060408h

Published on Web 05/05/2006
Synthesis of (-)-Sordarin
Shunsuke Chiba, Mitsuru Kitamura,† and Koichi Narasaka*
Contribution from the Department of Chemistry, Graduate School of Science,
The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received January 25, 2006; E-mail: narasaka@chem.s.u-tokyo.ac.jp
Abstract: The first total synthesis of (-)-sordarin (1) was accomplished exploiting the following key
reactions: (i) Ag(I)-catalyzed oxidative radical cyclization of a cyclopropanol derivative leading to a bicyclo-
[5.3.0]decan-3-one skeleton; (ii) Pd(0)-catalyzed intramolecular allylation reaction resulting in the entire
strained bicyclo[2.2.1]heptan-2-one framework of sordaricin (2); (iii) selective dihydroxylation of terminal
alkenes by the combined use of OsO4 and PhB(OH)2; and (iv) â(1,2-cis)-selective glycosidation via a 1,3-
anchimeric assistance from a 4-methoxybenzoyl group.
Introduction
Sordarin (1), isolated in 1971 as a metabolite of the fungus
Sordaria araneosa,1 is a potent and selective inhibitor of fungal
protein synthesis.2 Despite the high-sequence homology between
the fungal and mammalian protein synthesis mechanisms,
sordarin is able to selectively form the stable complex of fungal
elongation factor 2 (EF-2)/a ribosomal stalk protein (P0) and
prevent the release of EF-2 in the course of translation.3 This
compound exhibits potent in vitro antifungal activity against
several fungi such as Candida albicans.4
As shown in Figure 1, the structure of sordarin (1)5 contains
a diterpene aglycon, sordaricin (2),6 which has a unique
tetracyclic diterpene core containing a bicyclo[2.2.1]heptene
framework (norbornene system) with three successive quaternary
carbon centers (C-5, C-6, C-7).7 The molecule also has an
unusual 6-deoxy-glycoside residue, which is bonded with
sordaricin (2) through a â(1,2-cis)-glycoside linkage.
Figure 1. Molecular structures of sordarin (1) and sordaricin (2).
We have recently communicated a racemic synthesis of
sordaricin (2),10 based on the construction of the highly strained
substituted norbornene system by a Pd(0)-catalyzed intramo-
lecular allylation reaction.11 Because of the interesting biological
activities of sordarin (1), we turned our attention to the synthesis
of natural sordarin and its structural analogues as well as the
improvement of the synthetic route to sordaricin (2). Herein,
we wish to report the full details of our total synthesis of (-)-
sordarin (1).
The characteristic biological activity and the challenging
molecular architecture of sordarin (1) have stimulated synthetic
efforts directed toward its total synthesis. While there are no
reports of the synthesis of sordarin (1), syntheses of sordaricin
(2)8 have been accomplished by employing the postulated
biogenetic intramolecular [4+2]-cycloaddition9 to form the
polysubstituted norbornene system.
Results and Discussion
1. Synthetic Plan. The retrosynthetic analysis for the
synthesis of (-)-sordarin (1) is outlined in Scheme 1. The
structure of sordarin (1) is composed of two distinct domains,
sordaricin (2) and an unusual 6-deoxy-glycoside residue, which
are linked by a â(1,2-cis)-glycosidic bond. Our strategy relied
on the â(1,2-cis)-selective glycosidation of sordaricin ethyl ester
3 with fluoro sugar 4 having an acyloxy group at C-3 with the
aid of a 1,3-anchimeric assistance. In turn, sordaricin ethyl ester
3 was envisaged to arise from bicyclo[2.2.1]heptan-2-one
derivative 5 via the introduction of an isopropyl unit and
† Current address: Department of Applied Chemistry, Faculty of
Engineering, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku,
Kitakyushu-shi, Fukuoka 804-8550, Japan.
(1) Hauser, D.; Sigg, H. P. HelV. Chim. Acta 1971, 54, 1178-1190.
(2) Protein synthesis is considered as one of the most attractive targets for
developing novel antimicrobial agents, see: Hall, C. C.; Bertasso, A. B.;
Watkins, J. D.; Georgopapadakou, N. H. J. Antibiot. 1992, 45, 1697-1699.
(3) Justice, M. C.; Hsu, M. J.; Tse, B.; Ku, T.; Balkovec, J.; Schmatz, D.;
Nielsen, J. J. Biol. Chem. 1998, 273, 3148-3151.
(8) (a) Mander, L. N.; Thomson, R. J. J. Org. Chem. 2005, 70, 1654-1670.
(b) Mander, L. N.; Thomson, R. J. Org. Lett. 2003, 5, 1321-1324. (c)
Kato, N.; Kusakabe, S.; Wu, X.; Kamitamari, M.; Takeshita, H. J. Chem.
Soc., Chem. Commun. 1993, 1002-1004.
(4) DiDomenico, B. Curr. Opin. Microbiol. 1999, 2, 509-515 and references
therein.
(5) Vasella, A. T. Ph.D. Dissertation, Eidgenossischen Technischen Hochschule,
Zurich, 1972.
(9) Borschberg, H. J. Ph.D. Dissertation, ETH, Zurich, Switzerland, 1975. For
a review of the biogenetic intramolecular [4+2]-cycloaddition, see: (a)
Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078-
3115. (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668-1698.
(6) It has recently become apparent that several sordaricin derivatives exhibit
antifungal activities, see: Quesnelle, C. A.; Gill, P.; Dodier, M.; Laurent,
D. S.; Serrano-Wu, M.; Marinier, A.; Martel, A.; Mazzucco, C. E.; Stickle,
T. M.; Barrett, J. F.; Vyas, D. M.; Balasubramanian, B. N. Bioorg. Med.
Chem. Lett. 2003, 13, 519-524.
(10) Kitamura, M.; Chiba, S.; Narasaka, K. Chem. Lett. 2004, 33, 942-943.
(11) (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140-145. (b) Tsuji, J.
Tetrahedron 1986, 42, 4361-4401. (c) Tsuji, J. Acc. Chem. Res. 1969, 2,
144-152.
(7) The numbers on each carbon atom of intermediates 8, 13, 14, 18, 19, 20,
21, 33, and 34 correspond to those of sordaricin (2).
9
10.1021/ja060408h CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 6931-6937
6931

A R T I C L E S
Chiba et al.
Scheme 1. Retrosynthetic Analysis of Sordarin (1)
oxidative cleavages of two vinyl groups. It was anticipated that
5 would be prepared from tricyclic compound 6 by Pd(0)-
catalyzed intramolecular allylation of a π-allylpalladium inter-
mediate. Tricyclic compound 6 could be derived from bicyclic
ketone 8, which itself is prepared by the Ag(I)-catalyzed
oxidative radical cyclization of cyclopropanol derivative 9 as
developed in our laboratory.12 Compound 9 was anticipated to
arise from optically active (+)-4-tert-butyldimethylsilyloxy-2-
cyclohexen-1-one (10).
Scheme 2. Stereoselective Synthesis of
Bicyclo[5.3.0]decan-3-one 8a
2. Stereoselective Synthesis of Bicyclo[5.3.0]decan-3-one
Compound 8. Optically active bicyclic compound 8, incorpo-
rating the three successive chiral centers (C-10, C-9, C-13) of
the trans-perhydroindene part of sordaricin (2), was prepared
from optically active (+)-4-tert-butyldimethylsilyloxy-2-cyclo-
hexen-1-one (10)13 as summarized in Scheme 2. Thus, treatment
of cyclohexenone 10 with 3-butenylmagnesium bromide in the
presence of a catalytic amount of CuBr‚SMe2, TMSCl, and
HMPA in THF at -78 °C14 produced the corresponding silyl
enol ether 11 as a single stereoisomer. Cyclopropanation of this
silyl enol ether 11 was carried out by using diethylzinc and
diiodomethane,15 and the resulting TMS-protected cyclopropanol
was successively deprotected with a catalytic amount of
potassium carbonate in methanol to afford cyclopropanol 9. In
our previous syntheseis of (()-sordaricin (2),10 bicyclo[5.3.0]-
decan-3-one derivative 8 was prepared by the oxidative radical
cyclization of 9 with a stoichiometric amount of manganese-
(III) tris(2-pyridinecarboxylate) [Mn(pic)3]. Recently, we up-
graded this stoichiometric reaction to a catalytic process by the
use of a AgNO3-(NH4)2S2O8-pyridine system.12 Treatment of
9 with a catalytic amount of AgNO3, (NH4)2S2O8 as a reoxidant,
and pyridine in the presence of 1,4-cyclohexadiene in DMF gave
optically active 8 stereoselectively via the cyclization of â-keto
radical intermediate 12.
a Reagents and conditions: (a) 3-butenylmagnesium bromide (1.5 equiv),
CuBr‚SMe2 (0.1 equiv), TMSCl (2.0 equiv), HMPA (2.4 equiv), THF, -78
°C, 1 h, 91%; (b) Et2Zn (1.5 equiv), CH2I2 (2.3 equiv), Et2O, reflux, 13 h;
(c) K2CO3 (0.03 equiv), MeOH, room temperature, 1 h, 82% (two steps);
(d) AgNO3 (0.1 equiv), (NH4)2S2O8 (2.4 equiv), pyridine (2.0 equiv), 1,4-
cyclohexadiene (3.0 equiv), DMF, 20-25 °C, 4 h, 85%. THF ) tetrahy-
drofuran; TMS ) trimethylsilyl; HMPA ) hexamethylphosphoramide; DMF
) N,N-dimethylformamide.
Previously, we found that treatment of ketone 8 with LDA,
followed by the addition of TMSCl, gave a regioisomeric
mixture (1:1) of silyl enol ethers.16 This problem was solved
by applying N,N-dimethylhydrazone for stereo- and regiose-
lective allylation at C(3) of 8 via the three-step sequence:17 (i)
conversion to N,N-dimethylhydrazone 13, (ii) allylation of the
hydrazone using LDA and allyl bromide, and (iii) hydrolysis
of the hydrazone to ketone 14. Dihydroxylation of the vinyl
group of 14 using osmium tetroxide, followed by NaIO4-induced
oxidative cleavage, provided the corresponding aldehyde 15,
which was then converted into â-keto ester 16 by reaction with
ethyl diazoacetate in the presence of tin(II) chloride.18 Dehy-
3. Synthesis of Tricyclic Compound 6. The synthetic route
leading to tricyclic compound 7 is shown in Scheme 3.
(12) Chiba, S.; Cao, Z.; El Bialy, S. A. A.; Narasaka, K. Chem. Lett. 2006, 35,
18-19.
(13) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans.
1 2001, 166-173.
(14) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron
1989, 45, 349-362.
(16) Iwasawa, N.; Funahashi, M.; Hayakawa, S.; Ikeno, T.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1999, 72, 85-97.
(17) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 3-6.
(15) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323-5324.
9
6932 J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006

Synthesis of (−)-Sordarin
A R T I C L E S
Scheme 3. Construction of Tricyclic Compound 7a
Scheme 5. Synthesis of Compound 6 for Palladium-Catalyzed
Allylationa
a Reagents and conditions: (a) N,N-dimethylhydrazine (2.0 equiv), AcOH
(5 drops), EtOH, room temperature; (b) LDA (1.1 equiv), then allylbromide
(2.0 equiv), THF, -78 °C, 0.5 h; (c) AcOH-THF-H2O-NaOAc (5:2:2:1
by weight), room temperature, 3 h, 85% (three steps); (d) OsO4 (0.005
equiv), NMO (1.2 equiv), THF-H2O, room temperature, 22 h; (e) NaIO4
(2.0 equiv), THF-H2O, room temperature, 1 h, 96% (two steps); (f) SnCl2
(0.09 equiv), ethyldiazoacetate (1.6 equiv), CH2Cl2, room temperature, 4.5
h, then reflux, 2 h, 93%; (g) EtONa (0.3 equiv), EtOH, 0 °C, 0.5 h, 76%.
LDA ) lithium diisopropylamide; NMO ) N-methylmorpholine N-oxide.
a Reagents and conditions: (a) vinylmagnesium chloride (1.6 equiv),
CuBr‚SMe2 (0.15 equiv), TMSCl (2.0 equiv), HMPA (4.3 equiv), THF,
-78 °C, 1 h; (b) Ac2O (2.0 equiv), DMAP (trace amounts), pyridine, room
temperature, 0.5 h, 97% (two steps); (c) TsOH‚H2O (0.1 equiv), THF-
H2O, 60 °C, 15 h; (d) PCC (2.0 equiv), Celite, CH2Cl2, room temperature,
3 h, 90% (two steps); (e) vinylmagnesium chloride (1.9 equiv), THF, -78
°C, 1 h; (f) NaOEt (1.1 equiv), EtOH, 0 °C, 0.5 h; (g) TBSCl (1.2 equiv),
Et3N (3.0 equiv), DMAP (trace amounts), CH2Cl2, room temperature, 5 h,
89% (three steps); (h) LDA (1.5 equiv), ClCO2Et (1.6 equiv), THF, -78
to 0 °C, 89%; (i) TBAF (1.0 equiv), THF, 0 °C, 0.5 h, quant. DMAP )
4-dimethyl-aminopyridine; PCC ) pyridinium chlorochromate; TBS ) tert-
butyldimethylsilyl; TBAF ) tetrabutylammonium fluoride.
Scheme 4. Construction of Tricyclic Compound 7a
with 6-bromomethyl-2,2-dimethyl-1,3-dioxin-4-one 17.19 After
cleavage of the N,N-dimethylhydrazone, the resulting ketone
18 was treated with sodium ethoxide in ethanol to give tricyclic
keto ester 7 via deprotection of the acetonide group and
successive condensation.
For the transformation of 7 to 6, the precursor for the Pd-
catalyzed intramolecular allylation, two vinyl groups were
introduced as equivalents of the hydroxy methyl and formyl
parts of sordaricin (2) (Scheme 5). Construction of the quater-
nary center at C(7) was accomplished via the 1,4-addition of
vinylmagnesium chloride in the presence of CuBr‚SMe2 and
TMSCl. Successive acetylation of the resulting enol afforded
enol acetate 19. Next, the TBS group of 19 was removed under
acidic conditions, and the liberated secondary alcohol was
oxidized with pyridinium chlorochromate (PCC) to ketone 20.
Addition of vinyl Grignard to the carbonyl at C(5) of 20
proceeded smoothly at -78 °C to give an allylic alcohol, and
subsequent replacement of the acetyl group with TBS provided
21. Ethoxy carbonylation of 21 and desilylation of resulting 22
with tetrabutylammonium fluoride (TBAF) gave 6.
a Reagents and conditions: (a) N,N-dimethylhydrazine (2.0 equiv), AcOH
(5 drops), EtOH, room temperature; (b) LDA (1.1 equiv), then 17 (2.0
equiv), THF, -78 °C, 1 h; (c) AcOH-THF-H2O-NaOAc (5:2:2:1 by
weight), room temperature, 3 h, 60% (three steps); (d) EtONa (2.0 equiv),
EtOH, 60 °C, 0.5 h, 70%.
4. Construction of the Basic Framework of Sordaricin (2)
and Synthesis of Various Bicyclo[2.2.1]heptan-2-one Deriva-
tives. As shown in Scheme 6, construction of the bicyclo[2.2.1]-
heptan-2-one framework was successfully achieved from 6 by
drative condensation of 16 catalyzed by sodium ethoxide in
ethanol gave tricyclic compound 7.
To simplify the synthesis of 7, an alternative route was
developed (Scheme 4). This improved sequence began with the
reaction of lithium aza-enolate of N,N-dimethylhydrazone 13
(18) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-3260.
(19) Jones, R. C. F.; Tankard, M. J. Chem. Soc., Perkin Trans. 1 1991, 240-
241.
9
J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006 6933

A R T I C L E S
Chiba et al.
Scheme 6. Construction of Sordaricin Precursor 5
Table 1. Pd(0)-Catalyzed Synthesis of
Bicyclo[2.2.1]heptan-2-ones
a slight modification of the original Tsuji-Trost allylation
conditions.11 When 6 was exposed to a catalytic amount of Pd-
(PPh3)4 and NaH, the desired intramolecular allylation furnished
sordaricin precursor 5 in 92% yield along with 5% yield of
â-hydride elimination product 23 as a byproduct.20 The presence
of NaH was essential for this cyclization. â-Hydride elimination
product 23 was formed exclusively in the absence of NaH (the
standard Tsuji-Trost reaction conditions in the case of using
allylic carbonates). The structure of 5, which contains all of
the stereogenic centers of sordaricin (2), was secured by X-ray
crystallographic analysis.21
Generally, bicyclo[2.2.1] systems are constructed by [4+2]-
cycloadditions (Diels-Alder reactions) between cyclopentadiene
derivatives and alkenes. This catalytic method has found some
applicabilities as depicted in Table 1.22 Thus, this catalytic
reaction would provide a general method for the synthesis of
highly substituted bicyclo[2.2.1]heptan-2-one derivatives.23 The
cyclization, however, did not proceed in a stereospecific manner,
because 25b was obtained as an exo/endo 5:1 mixture, even
though it was carried out by using a single diastereomer of 24b
(run 3).
a Configuration of allylic carbon in 24 was not determined. b Isolated
yield as endo-exo mixture. c Stereochemistry of 25 (exo-endo) was
assigned by NOESY spectroscopy.
5. Synthesis of (-)-Sordaricin. To complete the synthesis
of sordaricin (2) from 5, we first adopted the strategy involving
oxidative cleavage of two terminal vinyls, followed by introduc-
tion of an isopropyl unit (Scheme 7).24 Thus, ozonolysis of (()-5
followed by reduction of the resulting dialdehyde proceeded
smoothly to afford the corresponding diol. The resulting two
hydroxy groups were protected as MOM (methoxymethyl)
ethers to give 26, and then the ketone was converted into enol
triflate 27. We attempted to introduce an isopropyl group onto
27 using the higher order cuprate25 derived from lithium
2-thienylcyanocuprate [(2-Th)Cu(CN)Li]26 and isopropylmag-
nesium chloride, or by Pd(0)-catalyzed cross-coupling with
isopropylmagnesium chloride.27 However, the enol triflate was
very unreactive, giving back only the starting material 27. 1,2-
Addition of isopropylmagnesium chloride or isopropyllithium
to ketone 26 in the presence of cerium chloride28 did not proceed
at all.
(20) The structure of 23 was confirmed by the 1H and 13C NMR analysis of its
acetate 49.
We assumed that these unsuccessful results with 26 and 27
were due to the steric and electronic repulsion around the
carbonyl group and the enol triflate moiety. To circumvent this
problem, introduction of an isopropyl group using enol triflate
28 was examined as shown in Scheme 8. When 28 was treated
(21) CCDC-295066 contains the supplementary crystallographic data for
compound 5. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Center, 12 Union Road, Cambridge, CB21 EZ, U.K.; fax
(+44)1223-336-033; or deposit@cdc.cam.ac.uk).
(22) Synthetic schemes of the substrate 24 were depicted in the Supporting
Information.
(23) There are some reports on the transition-metal catalyzed construction of
bicyclo[2.2.1]heptan-2-one derivatives, see: (a) Langer, P.; Holtz, E.; Saleh,
N. N. R. Chem.-Eur. J. 2002, 8, 917-928. (b) Miura, T.; Nakazawa, H.;
Murakami, M. Chem. Commun. 2005, 2855-2856. (c) Miura, T.; Sasaki,
T.; Nakazawa, H.; Murakami, M. J. Am. Chem. Soc. 2005, 127, 1390-
1391.
(25) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313-4316.
(26) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987, 28,
945-948.
(27) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu,
K. J. Am. Chem. Soc. 1984, 106, 158-163.
(28) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J.
Am. Chem. Soc. 1989, 111, 4392-4398.
(24) This approach was carried out on racemic 5.
9
6934 J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006

Synthesis of (−)-Sordarin
A R T I C L E S
Scheme 7. Unsuccessful Attempt To Introduce an Isopropyl Unita
Scheme 9. Synthesis of (-)-Sordaricin (2)a
a Reagents and conditions: (a) O3, then Me2S (13 equiv), MeOH-
CH2Cl2, -78 °C to room temperature, 96%; (b) NaBH3CN (2.5 equiv),
THF-AcOH (10:1), room temperature, 3 h, 92%; (c) MOMCl (5.2 equiv),
i-Pr2NEt (6.0 equiv), CH2Cl2, room temperature, 2 h, 86%; (d) LDA (1.5
equiv), then PhNTf2 (1.2 equiv), THF, -78 to 0 °C, 88%; (e) (2-
Th)Cu(CN)Li (3.0 equiv), i-PrMgCl (3.0 equiv), THF-HMPA, -78 °C to
room temperature, 0%; (f) PdCl2(dppf) or Pd(PPh3)4 (0.1 equiv), i-PrMgCl
(2.0 equiv), THF or Et2O, room temperature to reflux, 0%; (g) i-PrMgCl
or i-PrLi (2.0 equiv), CeCl3 (2.0 equiv), THF, room temperature to reflux,
0%. MOM ) methoxymethyl; Tf ) trifluoromethanesulfonyl; Th ) thienyl;
dppf ) diphenylphosphino ferrocene.
a Reagents and conditions: (a) OsO4 (0.056 equiv), NMO (3.0 equiv),
PhB(OH)2 (3.8 equiv), CH2Cl2, room temperature, 12 h; (b) NaIO4 (11
equiv), THF-H2O (1:1), 50 °C, 2 h, 53% (two steps); (c) NaBH4 (3.0 equiv),
EtOH, room temperature, 1 h, 95%; (d) TBSCl (1.1 equiv), imidazole (3.0
equiv), DMF, 0 °C, 3 h, 90%; (e) Dess-Martin periodinane (1.3 equiv),
NaHCO3 (2.3 equiv), CH2Cl2, room temperature, 5.5 h; (f) TsOH‚H2O (0.14
equiv), THF-H2O (10:1), 50 °C, 12 h, 90% (two steps); (g) n-PrSNa,
HMPA, room temperature, 12 h, 89%.
Scheme 8. Introduction of an Isopropyl Unita
resulting phenylboronic esters with NaIO4 in aqueous THF
afforded dialdehyde 32 in 53% yield (two steps). Reduction of
32 with NaBH4 to the corresponding diol 33 and subsequent
selective protection of the less hindered C(19)-hydroxy group
with TBS afforded 34. Dess-Martin oxidation31 of the C(17)-
hydroxy group to an aldehyde, followed by desilylation with
TsOH, provided sordaricin ethyl ester 3. Finally, deethylation
of ester 3 with propanethiolate32 gave (-)-sordaricin (2).
6. Construction of the Carbohydrate Unit 4. The carbo-
hydrate fragment 4 of sordarin was prepared from D-mannose
via dehydroxylation of the C-6 hydroxy and inversion of the
configuration at C-3 as depicted in Schemes 10 and 11. The
known tosylate 35 synthesized from D-mannose33 was reduced
with LiAlH4, and the triisopropylsilyl (TIPS) was removed.
Methylation of resulting alcohol led to methyl ether 36, from
which the acetonide was removed by treatment with TsOH in
MeOH to give diol 37. Tin-acetal allylation34 of the less hindered
C-3 hydroxy provided the desired C-3 allyl ether 38. The
remaining C-2 hydroxy was converted into p-methoxybenzyl
ether 39, and then the allyl group was removed by sequential
treatment with RhCl(PPh3)3 and OsO4/NMO furnishing alcohol
40. Inversion at the C-3 center was realized by a two-step
sequence: (i) conversion of 40 into ketone 41 by Dess-Martin
oxidation and (ii) NaBH4 reduction.35
a Reagents and conditions: (a) LDA (1.2 equiv), then N-(5-chloro-2-
pyridyl)triflimide (1.1 equiv), THF, -78 °C, 95%; (b) (2-Th)Cu(CN)Li (3.0
equiv), i-PrMgCl (3.0 equiv), THF-HMPA, -78 to -20 °C, 12 h, 86%
(29) and 11% (30).
with the same higher order cuprate in the presence of HMPA,29
the desired product 29 was isolated in 86% yield with a small
amount of reduction product 30 in 11% yield.
The remaining obstacle for the synthesis of (-)-sordaricin
was selective oxidative cleavage of the two vinyl groups of 29.
Ozonolysis and OsO4-NaIO4 oxidation of 28 gave complex
mixtures probably due to overoxidation of the highly reactive
norbornene unit. Previously, we reported the dihydroxylation
of alkenes by the combined use of OsO4 and PhB(OH)2.30 It
was assumed that if the two vinyl groups were converted into
bulky phenylboronic esters, the remaining norbornene part
would be shielded from the overoxidation. As depicted in
Scheme 9, after treatment of 29 with a catalytic amount of OsO4,
PhB(OH)2, and NMO as a reoxidant, the 1H NMR spectrum of
the crude mixture exhibited the formation of the desired
bisphenylboronic ester 31. Successive oxidative cleavage of the
The resulting alcohol 42 led to benzoyl ester 43a, 4-meth-
oxybenzoyl ester 43b, 2,4-dimethoxybenzoyl ester 43c, and TBS
(31) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(32) Bartlett, P. A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459-4462.
(33) Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; Suzuki, H.; Flyaktakidou,
K. C.; Baudoin, O.; van Delft, F. L. Chem.-Eur. J. 2000, 6, 3095-3115.
(34) David, S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1981,
1976-1801.
(29) In the absence of HMPA, the desired 29 was obtained only in 58% yield
along with 35% yield of the hydride adduct 30.
(30) Iwasawa, N.; Kato, T.; Narasaka, K. Chem. Lett. 1988, 1721-1724.
9
J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006 6935

A R T I C L E S
Chiba et al.
Scheme 10. Construction of Carbohydrate Part 4a
Scheme 12. 1,3-Anchimeric Assistance
Table 2. Glycosidation of Neopentyl Alcohol (45)
a Reagents and conditions: (a) LiAlH4 (1.3 equiv), THF, reflux, 7 h; (b)
TBAF (1.1 equiv), THF, room temperature, 1 h; (c) NaH (1.2 equiv), MeI
(3.0 equiv), DMF, room temperature, 2 h, 87% (three steps); (d) ethylene
glycohol (1.4 equiv), TsOH‚H2O (0.1 equiv), MeOH, 50 °C, 12 h, 87%;
(e) Bu2SnO (1.1 equiv), toluene, reflux, 3 h; allylBr (1.5 equiv), Bu4NI
(0.2 equiv), reflux, 3 h, 95%; (f) NaH (1.1 equiv), PMBCl (1.3 equiv),
Bu4NI (0.2 equiv), DMF, 50 °C, 1 h, 93%; (g) RhCl(PPh3)3 (0.03 equiv),
DABCO (1.5 equiv), EtOH-H2O (10:1) reflux, 1 h, then OsO4 (0.05 equiv),
NMO (1.2 equiv), acetone-H2O (10:1), room temperature, 2 h, 82% (two
steps); (h) Dess-Martin periodinane (1.5 equiv), NaHCO3 (2.5 equiv),
CH2Cl2, room temperature, 4 h, 81%; (i) NaBH4 (1.2 equiv), MeOH, 0 °C,
0.5 h, 76% (dr ) 25:1); DABCO ) 1,4-diazabicyclo[2.2.2]octane.
Scheme 11. Construction of Carbohydrate Parts 4a
a Three equivalents of neopentyl alcohol and 1.1 equiv of SnCl2 and
AgClO4 were used. b Isolated yield. c Determined by NOESY measurement.
Mukaiyama conditions38 (SnCl2, AgClO4 in Et2O) (Table 2).
In the case of glycosyl fluoride 4a having a benzoyl group at
C-3 (run 1), the coupling reaction proceeded smoothly to afford
â- and R-anomers 46a in 92% yields with 2.5:1 (â:R) selectivity.
a Reagents and conditions: (a) BzCl (2.0 equiv), DMAP (trace amounts),
pyridine, room temperature, 2 h, 92%; (b) 4-MeO-BzCl (3.0 equiv), DMAP
(trace amounts), pyridine, room temperature, 2 h, 99%; (c) 2,4-(MeO)2-
BzCl (2.0 equiv), DMAP (trace amounts), pyridine, room temperature, 12
h, 81%; (d) TBSOTf (1.5 equiv), 2,6-lutidine (3.0 equiv), room temperature,
2 h, 98%; (e) NBS (1.5 equiv), acetone-H2O (10:1), room temperature, 1
h, 95% (44a), 96% (44b), 68% (44c), and 95% (44d); (f) DAST (1.5 equiv),
CH2Cl2, 0 °C, 0.2 h. NBS ) N-bromosuccinimide; DAST ) (diethylami-
no)sulfur trifluoride.
(35) The hydride attack occurred from the opposite side of the bulky thiophenyl
group at C-1, which occupies an axial position (shown below). The
configuration of 42 was readily assigned by inspection of the 1,2-coupling
constant.
ether 43d, respectively (Scheme 11). Phenyl thioglycosides
43a-d were converted into lactols 44a-d by the action of NBS
in aqueous acetone, and then exposure to (diethylamino)sulfur
trifluoride (DAST) led to the rapid conversion to the desired
glycosyl fluorides 4a-d.
7. â(1,2-cis)-Selective Glycosidation: Model Study. We
expected that the desired â-selective glycosidation would be
realized by a 1,3-anchimeric assistance36,37 from the acyloxy
group at C-3 (Scheme 12).
(36) There are some reports on the synthesis of â-2-deoxyribonucleosides using
the 1,3-anchimeric assistance, see: (a) Mukaiyama, T.; Uchiro, H.; Hirano,
N.; Ichikawa, T. Chem. Lett. 1996, 629-630. (b) Mukaiama, T.; Hirano,
N.; Nishida, M.; Uchiro, H. Chem. Lett. 1996, 99-100. (c) Young, R. J.;
Shaw-Ponter, S.; Hardy, G. W.; Mills, G. Tetrahedron Lett. 1994, 35, 8687-
8690. (d) Lavallee, J. F.; Just, G. Tetrahedron Lett. 1991, 32, 3469-3472.
(e) Ichikawa, Y.; Kubota, H.; Fujita, K.; Okauchi, T.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1989, 62, 845-852.
(37) Wiesner et al. reported the synthesis of â-2-deoxyglycosides by the
anchimeric assistance of a N-methylurethane group and a 4-methoxybenzoyl
group, see: Wiesner, K.; Tsai, T. Y. R.; Jin, H. HelV. Chim. Acta 1985,
68, 300-314. However, Binkley et al. suggested that the anchimeric
assistance from the C-3 position was not the dominating characteristic of
glycosyl donors having an acyloxy group at the C-2 position, see: Binkley,
R. W.; Koholic, D. J. J. Carbohydr. Chem. 1988, 7, 487-489.
A model reaction was examined with neopentyl alcohol (45)
as the glycosyl acceptor and glycosyl fluorides 4 under
(38) Mukaiyama, T.; Murai, Y.; Sonoda, S. Chem. Lett. 1981, 431-432.
9
6936 J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006

Synthesis of (−)-Sordarin
A R T I C L E S
Scheme 13. Synthesis of (-)-Sordarin (1)a
a Reagents and conditions: (a) 4b (1.5 equiv), AgClO4 (1.6 equiv), SnCl2 (1.6 equiv), MS 4A, Et2O, room temperature, 4 h; (b) DDQ (1.5 equiv),
CH2Cl2-H2O (10:1), room temperature, 2 h, 79% (â-47) and 12% (r-47) (two steps); (c) EtONa (1.0 equiv), EtOH, room temperature, 4 h, 97%; (d)
n-PrSNa, HMPA, room temperature, 12 h, 95%.
A slight improvement of the selectivity (â:R ) 3:1) was
observed by using 4-methoxybenzoate 4b (run 2).39,40 Introduc-
tion of a 2,4-dimethoxybenzoyl group lowered the yield (69%)
and the â:R ratio (2.5:1) (run 3). Glycosidation with the
comparatively bulky TBS-protected donor 4d (run 4) gave low
selectivity (â:R ) 1.5:1).
8. Total Synthesis of Sordarin. Completion of the total
synthesis of sordarin (1) is shown in Scheme 13. â(1,2-cis)-
Selective glycosidation of sordaricin ethyl ester 3 with glycosyl
fluoride 4b by the Mukaiyama’s method gave the desired
coupling products with good selectivity (â:R ) 6.5:1) judged
by 1H NMR spectroscopy of the diastereomeric mixtures.
Successive deprotection of the PMB ether by treatment with
DDQ led to the isolation of â- and R-anomers 47 in 79% and
12% yields, respectively. This better selectivity was probably
due to not only 1,3-anchimeric assistance from the 4-methoxy-
benzoyl group, but also the steric effect of the rather bulky
sordaricin ethyl ester 3. Finally, removing the 4-methoxybenzoyl
group of â-47 using EtONa in EtOH, followed by deethylation
of sordarin ethyl ester 48 with propanethiolate, gave sordarin
(1). The physical and spectroscopic data (1H NMR, 13C NMR,
IR, [R]D, Rf, and HRMS) and biological activity41 of synthetic
sordarin matched those of an authentic sample.
Acknowledgment. This work was supported by the Grant-
Aid for The 21st Century COE program for Frontiers in
Fundamental Chemistry from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. S.C. thanks JSPS for
a predoctoral fellowship. We thank Dr. N. Kano (Department
of Chemistry, Graduate School of Science, The University of
Tokyo) for assistance in X-ray crystallographic analysis. We
thank Sankyo Co. Ltd. for providing samples of natural sordarin
and Astellas Pharm Inc. for biological tests of our synthetic
sordarin.
(39) When this reaction was examined in CH3CN instead of Et2O, r-47b was
preferentially obtained in 46% yield with 1:3 (â:R) selectivity.
(40) Interestingly, in the case of trichloroimidate 4b′ as a glycosyl donor,
R-selective glycosidation proceeded to give 46b in 80% yield with 1:20
(â:R) selectivity.
Supporting Information Available: Experimental procedures,
1
compound characterization, H NMR spectra of selected com-
pounds, and a CIF file giving crystallographic data for com-
pound 5. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA060408H
(41) Synthetic sordarin was tested for fungal growth inhibition in C. albicans,
C. glabrata, C. parapsilosis, and C. neoformans.
9
J. AM. CHEM. SOC. VOL. 128, NO. 21, 2006 6937