Stereocontrolled synthesis of the aminocyclitol moiety of (+)-trehazolin via C-H insertion reaction of alkylidenecarbene

Article abstract of DOI:10.1016/j.tetlet.2004.07.087

The aminocyclitol moiety of (+)-trehazolin, a powerful trehalase inhibitor, was synthesized in a stereocontrolled manner from cis-2-butene-1,4-diol via C-H insertion reaction of the alkylidenecarbene, followed by regioselective opening of the epoxide ring

Full text of DOI:10.1016/j.tetlet.2004.07.087

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7133–7136
Stereocontrolled synthesis of the aminocyclitol moiety of
(+)-trehazolin via C–H insertion reaction of alkylidenecarbene
Megumi Akiyama, Toshiki Awamura, Kazuhito Kimura, Yoshimi Hosomi,
Ayako Kobayashi, Kazutaka Tsuji, Atsuhito Kuboki and Susumu Ohira*
Department of Biological Chemistry, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
Received 14 June 2004; revised 9 July 2004; accepted 21 July 2004
Available online 12 August 2004
Abstract—The aminocyclitol moiety of (+)-trehazolin, a powerful trehalase inhibitor, was synthesized in a stereocontrolled manner
from cis-2-butene-1,4-diol via C–H insertion reaction of the alkylidenecarbene, followed by regioselective opening of the epoxide
ring. It was obtained in an enantiomerically pure form by twice using Sharpless asymmetric epoxidation.
Ó 2004 Elsevier Ltd. All rights reserved.
Trehazolin (1) was isolated from a culture broth of
Micromonospora, strain SANK 62390 by Ando and
co-workers in 1991.1 This compound is a powerful treh-
alase inhibitor, whose structure was independently
determined through the synthetic work by Ogawa and
co-workers2 and Shiozaki and co-workers3 groups.
Structure–activity relationships were also studied exten-
sively by these groups based on their own synthetic
strategies for 1.4 After their seminal work, the unique
structure and biological activity attracted other syn-
thetic chemists, and many syntheses related to 15 and
its analogues were reported. The aminocyclitol part of
1 (2) or its hexaacetate (3) is the common target, which
is convertible to 1.3c The success of synthesizing 2 or 3 is
due to the effective construction of a skeleton with the
proper stereochemistry. As chiral sources, sugars or
amino acids were used in most previous chiral syntheses.
In this study, we describe the stereocontrolled asymmet-
ric synthesis of 3 starting from cis-2-butene-1,4-diol.
This investigation was pursuant to our continual interest
to use the C–H insertion reaction of the alkylidenecar-
bene to construct the functionalized cyclopentene6,7
(Fig. 1).
Figure 1.
intramolecular reactions, for example, [2+3] cyclo-
addition, pinacol coupling, RCM were applied for con-
struction of the five membered ring from the acyclic
intermediates. Our early plan for 3 was also along this
line, and direct synthesis of cyclopentene 6 was
attempted with acyclic ketone 4 derived from D-tartrate.
With the hope that the bulky protecting group of vicinal
diol would make each reaction sites close as described by
Saito et al.,8 4 was treated with lithiotrimethylsilyldiazo-
methane (TMSCLiN2)9 to generate the alkylidenecar-
bene. The main product obtained, however, was a
compound, which arose from the oxonium ylide inter-
mediate.10 The yield of 6 was only 5% at maximum.
To suppress formation of oxonium ylide, pivalate 5
was prepared and subjected to the same reaction,
although in this case only decomposition of 5 occurred
(Fig. 2).
Among the previous synthesis, the approaches via func-
tionalized acyclic intermediates derived from the chiral
pool looked most concise and efficient. Characteristic
After these preliminary studies, our attention turned to
the disubstituted epoxide 8 that seemed to be a good
precursor of trisubstituted epoxide 7. It was expected
that addition of oxygen nucleophile (R2OH) occurs at
Keywords: Trehazolin; C–H insertion; Alkylidenecarbene.
*
Corresponding author. Tel./fax: +81 862569425; e-mail: sohira@
dbc.ous.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.087

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M. Akiyama et al. / Tetrahedron Letters 45 (2004) 7133–7136
Figure 2.
Scheme 1. Reagents and conditions: (a) IBX, Py, DMSO, 45°C; (b)
Ph3PCH3Br, KHMDS, toluene, THF, ꢀ20°C to rt (83% in two steps);
(c) OsO4, NMO, THF–H2O, rt (95%); (d) TBSCl, imidazole, DMF, rt
(88%); (e) Dess–Martin periodinane, CH2Cl2, rt (85%); (f) TMSCLiN2,
DME, 0°C to rt (51%).
Figure 3.
the allylic position of 8, and resulting substituents
around the cyclopentene ring possibly assist the diastereo-
selective epoxidation. Epoxide 8 was presumably obtain-
able from ketone 9 by C–H insertion of alkylidene-
carbene without oxonium ylide formation7d and prefer-
able orientation of the alkoxy group of 8 on the convex
face was anticipated in view of our observation with the
bicyclo [3.3.0] system6d (Fig. 3).
however, demethylation was unsuccessful at any stage.
Thus, we decided to abandon the substrate-controlled
epoxidation and to turn to the asymmetric epoxidation.
Since the Shiozaki group reported effective Sharpless ep-
oxidation with a similar system,3c we expected that the
undesired enantiomer of 16 (6%, calculated from ee of
10) would be removable as a minor diastereomer after
the second asymmetric epoxidation.
According to the procedure by Trost et al., cis-2-butene-
1,4-diol was converted into epoxide 10 via Sharpless
asymmetric epoxidation with 88% ee.11 Oxidation of
10 with IBX, followed by a Wittig reaction with methyl-
triphenylphosphonium bromide and KHMDS produced
a good yield of olefin 11. The use of another base, such
as BuLi or NaH in DMSO, considerably lowered the
yield. Dihydroxylation of the double bond of 11 with
OsO4 furnished the diol 12 and the primary hydroxyl
group was protected as TBS ether. Oxidation of the sec-
ondary alcohol of 13 with Dess–Martin periodinane
produced the epoxy ketone 9, a precursor of the alkyl-
idenecarbene. The reaction between TMSCLiN2 and 9
in DME was conducted at 0°C. Warming the reaction
mixture to an ambient temperature (20–25°C) produced
the cyclized product 8 as a single diastereomer with a
51% yield. The stereochemistry of the C-5 position of
8 was deduced based on the correlation between the
C-4 proton and benzyl protons of the PMB group in
its NOESY spectra.12 To improve the yield, this reaction
was attempted under various reaction conditions, how-
ever, a better yield was not obtained probably due to
the instability of 8 under these reaction conditions
(Scheme 1).
Removal of the TBS group using TBAF in THF pro-
duced the desired diol 16.13 Sharpless epoxidation of
diol 16 and purification by silica gel chromatography
produced the desired epoxide 19 as a single isomer.
Minor diastereomers included in crude by-products
could not be isolated. 1H NMR spectra of (S)- and
(R)-MTPA esters of 19 indicated that both are single
diastereomers, namely, 19 is enantiomerically pure.
After protecting two hydroxyl groups of 19 as MOM
ether, the allyl group of 20 was removed cleanly with
PdCl2 in acetic acid14 and the resulting hydroxyl group
was protected as MOM ether. Epoxide opening of 21
with sodium azide and ammonium chloride and the sub-
sequent removal of the PMB group using DDQ followed
by the reduction of the azido group of 22 provided a
good yield of amino diol 23. Direct conversion of 22 to
23 was attempted using H2 over Pd/C, but the reaction
was incomplete and gave a low yield. Treatment of 23
with methanolic hydrogen chloride and acetylation of
the crude product resulted in a complex mixture contain-
ing hexaacetate 3, therefore, the amino group of 23 was
acetylated at this stage. Acetamide 24 was subjected to
deprotection followed by acetylation to provide a good
1
yield of the final compound 3. The H NMR spectra of
Opening of the epoxide ring of 8 was successful with
methanol or allyl alcohol under acidic conditions to pro-
vide 14 or 15. Using acetic acid and benzyl alcohol, the
corresponding alcohol was produced in a much lower
yield. Epoxidation of 14 with m-CPBA gave the desired
epoxide 17 and its isomer with a 2.5:1 ratio with an 88%
combined yield. Although epoxidation of 15 gave epox-
ide 18 stereoselectively (3.5:1), the yield was less than
10% due to the competitive reaction with the allyl group.
Methyl ether 17 was elaborated to some later stages,
the synthetic sample of 3 were identical with those of
the Shiozaki groupÕs sample, and the other physical
properties were identical with those reported3c,5h,15
(Scheme 2). Therefore, synthesis of hexaacetate 3, which
means the formal total synthesis of (+)-trehazolin (1),
was completed in 20 steps.
Although circumvention of the direct construction of
the vicinal trans oxygenated cyclopentene apparently

M. Akiyama et al. / Tetrahedron Letters 45 (2004) 7133–7136
7135
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Scheme 2. Reagents and conditions: (a) MeOH or allyl alcohol, p-
TsOH, ꢀ78 to 0°C; (b) TBAF, THF, rt (69% in two steps); (c) L-(+)-
DET, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ20°C (73%); (d) MOMCl, iPr2NEt,
CH2Cl2, rt (87%); (e) PdCl2, NaOAc, AcOH, H2O, rt (85%); (f)
MOMCl, iPr2NEt, CH2Cl2, rt (86%); (g) NaN3, NH4Cl, DMF–
ethylene glycol, 120°C (78%); (h) DDQ, CH2Cl2–H2O, rt (87%); (i)
10%Pd–C, H2, EtOAc, rt (97%); (j) Ac2O, MeOH, rt (quant.); (k)
AcCl, MeOH, rt; (l) Ac2O, DMAP, Py, rt (40% in two steps).
reduced the total efficiency of the synthesis, it is notable
that C–H insertion of alkylidenecarbene is still useful for
the synthesis of such an oxygenated cyclopentene and its
related natural product.
Acknowledgements
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We thank Dr. Masao Shiozaki, ChemTech Lab Co.,
Ltd, for providing us with H NMR spectra of hexaac-
etate 3 as well as with derivative samples of 2.
1
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J = 2.4Hz) 3.81 (s, 3H), 3.94 (t, 1H, J = 2.6Hz), 4.38–4.41
(m, 3H), 4.60 (d, 2H, J = 6.4Hz), 5.87 (d, 1H, J = 2.1Hz),
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20
1
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3H), 4.15 (ddt, 1H, J = 1.4Hz, 5.6Hz, 12.9Hz), 4.18–4.29
(m, 6H), 4.55 (d, 1H, J = 11.5Hz), 4.63 (d, 1H,
J = 11.5Hz), 5.21 (ddd, 1H, J = 1.3Hz, 2.8Hz, 10.4Hz),
5.31 (ddd, 1H, J = 1.6Hz, 3.2Hz, 17.2Hz), 5.77 (br s, 1H),
5.95 (ddt, 1H, J = 5.4Hz, 10.6Hz, 17.2Hz), 6.89 (d, 1H,
J = 8.6Hz), 7.30 (d, 1H, J = 8.6Hz); 13C NMR (CDCl3)
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d 55.29, 60.27, 70.95, 71.30, 86.25, 86.27, 87.26,
113.95, 117.26, 126.22, 129.45, 130.38, 134.90, 144.17,
159.34.

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M. Akiyama et al. / Tetrahedron Letters 45 (2004) 7133–7136
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5.24 (t, 1H, J = 5.2Hz), 5.33 (dd, 1H, J = 8.3Hz, 9.4Hz),
5.38 (dd, 1H, J = 4.8Hz, 7.8Hz), 5.81 (d, 1H, J = 5.5Hz),
5.89 (d, 1H, J = 9.5Hz); 13C NMR (CDCl3) d 20.55, 20.65,
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86.61, 168.91, 168.94, 169.52, 169.74, 169.90, 170.39.
20
15. ½aꢁD þ 4 (c 0.13, CHCl3); 1H NMR (CDCl3) d 2.02 (s, 3H),
2.07 (s, 3H), 2.08 (s, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.14
(s, 3H), 4.56 (d, 1H, J = 12.2Hz), 4.63 (d, 1H, J = 12.2Hz),