Facile ring transformation from gluconolactone to cyclitol derivative via spiro sugar ortho ester

Article abstract of DOI:10.1021/ol9913035

(Formula presented) A short step preparation of cyclitol derivative 8 which is a versatile synthon for the synthesis of valiolamine and its related compounds is described. Key steps in this preparation are a novel enol ether formation from spiro sugar ortho esters with AIMe₃ and an intramolecular Aldol condensation of alkyl enol ethers catalyzed by ZnCl₂ in THF-H₂O. With these reactions, gluconolactone derivative 1 was efficiently converted into 8 in short steps.

Full text of DOI:10.1021/ol9913035

ORGANIC
LETTERS
2000
Vol. 2, No. 4
457-460
Facile Ring Transformation from
Gluconolactone to Cyclitol Derivative via
Spiro Sugar Ortho Ester
Hiro Ohtake and Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo UniVersity, Sagamiko,
Kanagawa 199-0195, Japan
shi-ike@pharm.teikyo-u.ac.jp
Received December 2, 1999
ABSTRACT
A short step preparation of cyclitol derivative 8 which is a versatile synthon for the synthesis of valiolamine and its related compounds is
described. Key steps in this preparation are a novel enol ether formation from spiro sugar ortho esters with AlMe3 and an intramolecular Aldol
condensation of alkyl enol ethers catalyzed by ZnCl2 in THF−H O. With these reactions, gluconolactone derivative 1 was efficiently converted
2
into 8 in short steps.
Carbasugars and carbaaminosugars have attracted much
attention due to their activities as glycosidase inhibitors,
whose potential use as therapeutic agents against HIV
infection and diabetes was recently recognized.1 Various
methods for the synthesis of these molecules have been
developed, and the use of carbohydrates as synthetic precur-
sors for cyclitol derivatives has been widespread.2,3 In this
paper, we report a novel and facile procedure for the effective
conversion of gluconolactone to the cyclitol derivative 8,4
which is a versatile synthon for the synthesis of valiolamine,5-7
and its derivatives including voglibose.8 Compound 8 was
(4) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3642.
(5) (a) Kameda, Y.; Asano, M.; Yoshikawa, M.; Takeuchi, M.; Yamagu-
chi, T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1984, 37, 1301. (b)
Horii, S.; Fukase, H.; Kameda, Y. Carbohydr. Res. 1985, 140, 185.
(6) Total syntheses of valiolamine: (a) Ogawa, S.; Shibata, Y. Chem.
Lett. 1985, 1581. (b) Hayashida, M.; Sakairi, N.; Kuzuhara, H. J. Carbohydr.
Chem. 1988, 7, 83. (c) Shing, T. K. M.; Wan, L. H. J. Org. Chem. 1996,
61, 8468. (d) See ref 8a.
(7) Total syntheses of related valienamine: (a) Sakairi, N.; Kuzuhara,
H. Tetrahedron Lett. 1982, 23, 5327. (b) Ogawa, S.; Chida, N.; Suami, T.
J. Org. Chem. 1983, 48, 1203. (c) Schmidt, R. R.; Ko¨hn, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 482. (d) Yoshikawa, M.; Cha, B. C.; Nakae, T.;
Kitagawa, I. Chem. Pharm. Bull. 1988, 36, 3714. (e) Nicotra, F.; Panza,
L.; Ronchetti, F.; Russo, G. Gazz. Chim. Ital. 1989, 119, 577. (f) Park, T.
K.; Danishefsky, S. J. Tetrahedron Lett. 1994, 35, 2667. (g) Paulsen, H.;
Heiker, F. R. Liebigs Ann. Chem. 1981, 2180. (h) Ogawa, S.; Shibata, Y.;
Nose, T.; Suami, T. Bull. Chem. Soc. Jpn. 1985, 58, 3387. (i) Ogawa, S.;
Iwasawa, Y.; Nose, T.; Suami, T.; Ito, M.; Saito, Y. J. Chem. Soc., Perkin
Trans. 1 1985, 903. (j) Knapp, S.; Naughton, A. B. J.; Dhar, T. G. M.
Tetrahedron Lett. 1992, 33, 1025. (k) Trost, B. M.; Chupak, L. S.; Lu¨bbers,
T. J. Am. Chem. Soc. 1998, 120, 1732.
(1) (a) Truscheit, E.; Frommer, W.; Junge, B.; Mu¨ller, L.; Schmidt, D.
D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 744. (b) Ganem,
B. Acc. Chem. Res. 1996, 29, 340. (c)Humphries, M. J.; Matsumoto, K.;
White, S. L.; Olden, K. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1752. (d)
Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.;
Petursson, S.; Namgoong, S. K.; Ramsdem, N. G.; Smith, P. W.; Son, J.
C.; Wilson, F.; Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett.
1988, 237, 128. (e) Montefiori, D. C.; robinson, W. E.; Mitchell, W. M.
Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9248.
(2) Recent reviews: (a) Nicotra, F. In Carbohydrate Chemistry; Boons,
G.-J., Ed.; Blackie Academic & Professional: London, 1998; p 384. (b)
Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779. (c) Chida, N.;
Ogawa, S. Chem. Commun. 1997, 807.
(3) (a) Iimori, T.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 1996,
37, 649. (b) Takahashi, H.; Kittaka, H.; Ikegami, S. Tetrahedron Lett. 1998,
39, 9703.
10.1021/ol9913035 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/21/2000

recently synthesized by Fukase and Horii on the basis of
the intramolecular Aldol condensation of the R,R-bis-
(methylthio)- or R,R-dichlorocarbonyl compound; however,
a desulfurization or dechlorination step was necessary to
accomplish the preparation of this molecule using their
method. In the procedure presented here, the alkyl enol ether
compound that was prepared directly from a spiro sugar ortho
ester by a novel methyl anion insertion and a subsequent
ring opening reaction was used as the key intermediate,
which shortened the steps for the preparation of 8 and
improved the yield.
with a smaller amount of aluminum reagent, ketal 4 was also
detected as a product. TLC analysis revealed that 5 was
formed via 4 under these conditions. Actually, isolated 4 was
smoothly converted into 5, by treatment with AlMe3. These
results indicated that the first step of this reaction was the
cleavage of a pyran ring of the sugar moiety caused by the
insertion of a methyl anion from AlMe3 and the second step
was cleavage of a dioxane ring accompanied by proton
elimination.12 The first step ring opening which was caused
by the two-faced character of AlMe3 was presumed to be
assisted by the π-electrons of two oxygen atoms of a dioxane
ring.13
As the resulting enol compound seemed to be a suitable
precursor for the preparation of cyclitols based on the
intramolecular Aldol condensation, we planned to develop
a new method for the synthesis of these molecules and
prepared a 5-keto species from 5 according to the conditions
shown in Scheme 2. Treatment of 5 with TBDMSCl (2
Recently, we have thoroughly explored the reactivity of
sugar ortho esters for the purpose of developing the reductive
glycosylation methods by which the glycosyl linkages are
formed as the result of hydride anion attack to the spiro
carbon atoms of the ortho ester molecules.9 As an extension
of this study, we investigated the reactivity of the methyl
anion to sugar ortho esters and revealed that gluconolactone
ortho ester was smoothly converted into an enol ether
compound by treatment with AlMe3. As shown in Scheme
1, ortho ester 3 which was prepared from lactone 110 and
Scheme 2
Scheme 1
equiv), Et3N (5 equiv), and DIMAP (0.2 equiv) in DMF
provided the silyl-protected compound 6 in 91% yield,14
which was converted into the keto derivative 7 by exposure
to excess Ac2O/DMSO. The yield of 7 was increased by
changing the ratio between Ac2O and DMSO to 1:4 from
the usual 1:1; however, the keto product was partially
decomposed during column chromatography to reduce the
yield to 82%.
While the aldol condensation with silyl enol ethers15 has
been frequently used in products syntheses, there have been
few reports on the related reaction with alkyl enol ethers
recently.16 Thus, the conditions for the cyclization of 7 were
next investigated. As shown in Table 1, hydrolysis product
9 was the main product instead of the desired compound 8
2,2-dimethylpropanediol 2 in 94% yield according to the
method previously reported11 was treated with 5 equiv of
AlMe3 (1.0 M n-hexane solution) in CH2Cl2 for 2 h at room
temperature to afford enol ether 5 in 93% yield. In the case
(11) Yoshimura and co-workers previously reported the synthesis of
interglycosidic spiro ortho esters (ref 11a) from sugar lactones and silylated
diols using TMSOTf as the catalyst in a modification of Noyori’s method
(ref 11b). We also modified the process for ortho ester preparation (ref
11c) considering the acetal synthesis by Kurihara and Miyata (ref 11d). (a)
Yoshimura, J.; Tamaru, M. Carbohydr. Res. 1979, 72, C9. (b) Tsunoda,
T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357. (c) References
9a and 9c. (d) Kurihara, M.; Miyata, N. Chem. Lett. 1995, 263.
(12) Naruse, Y.; Yamamoto, H. Tetrahedron Lett. 1986, 27, 1363.
(13) Deslongchamps, P.; Che´nevert, R.; Taillefer, R. J.; Moreau, C.;
Saunders J. K. Can. J. Chem. 1975, 53, 1601.
(8) (a) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3651. (b) Horii, S.;
Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. J. Med. Chem.
1986, 29, 1038.
(9) (a) Ohtake, H.; Iimori, T.; Ikegami, S. Tetrahedron Lett. 1997, 38,
3413. (b) Iimori, T.; Ohtake, H.; Ikegami, S. Tetrahedron Lett. 1997, 38,
3415. (c) Ohtake, H.; Iimori, T.; Shiro, M.; Ikegami, S. Heterocycles 1998,
47, 685. (d) Ohtake, H.; Iimori, T.; Ikegami, S. Synlett 1998, 1420.
(10) (a) Kuzuhara, H.; Fletcher, Jr., H. G. J. Org. Chem. 1967, 32, 2531.
(b) Hanessian, S.; Ugolini, A. Carbohydr. Res. 1984, 130, 261.
(14) Chaudhary, S. K.; Hernandez, O.Tetrahedron Lett. 1979, 99.
(15) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503.
458
Org. Lett., Vol. 2, No. 4, 2000

Table 1. Intramolecular Aldol Condensation of 7 with Acid Catalysts
% yieldc
entry
reagent
PPTS
BF3‚Et2O
ZnCl2
ZnCl2
ZnCl2
ZnCl2
HCl
La(OTf)3
YbCl2‚6H2O
reagent/7
additive
temp
rt
rt
rt
rt
rt
reflux
time
18 h
15 mim
18 h
18 h
18 h
4 h
30 min
18 h
8
9
7 (recovery)
1a
2a
3a
4b
5b
6b
7b
8b
9b
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.0
1.0
28
69
68
28
43
90
4
51
1
ndd
nd
nd
67
50
nd
nd
84
91
nd
nd
nd
nd
62
nd
nd
H2O
H2O
H2O
H2O
H2O
H2O
rt
rt
rt
9
24 h
tracee
a Reactions were carried out in THF. b Reactions were carried out in THF/H2O (19:1). c Isolated yields based on 7. d Not detected. e <0.5%.
when PPTS was used as an acid catalyst (entry 1). With
ZnCl2 or BF3‚Et2O in nonaqueous solvent (entries 2 and 3),
Scheme 3
the formation of 9 was suppressed; however, the yield of 8
was less than 70% because of the undesired side reaction
and product decomposition. Remarkably, it was revealed that
the addition of water improved the product selectivity in the
ZnCl2-catalyzed cyclization of 7 (entries 4 and 5). Although
the rate of the reaction was reduced by the additon of water
(entry 4 vs 3), the reaction with 2 equiv of the catalyst under
reflux conditions proceeded efficiently to afford 8 in 90%
yield (entry 6). Since the product distribution in the reaction
with HCl was far different from that in the case with ZnCl2
(entry 7 vs 5), it seemed rational to assume that the zinc
complex catalyzed the reaction instead of a proton in aqueous
solvent. Water might change the reactivity of ZnCl2 by
coordination to a metal center or might assist the reaction
by providing an excess amount of hydroxy units. Recently,
aldol condensation of silyl enol ethers with various metal
catalysts in aqueous THF was reported.17 As shown in entries
practically, oxidation of 5 followed by cyclization of the
crude oxidation products according to the same procedure
used for the silyl-protected enol ether 6 afforded 8 in 73%
yield based on 5 (Scheme 3). The main product of the
oxidation of 5 was the dioxo species 10 which was generated
by the oxidation of both of 1°- and 2°-alcohols. The 5-keto
species with a methylthiomethyl functionality on the 1°-
alcohol whose type of byproduct was often detected in Ac2O/
DMSO oxidation was also obtained. Fortunately, the enol
ether moiety of 10 selectively reacted with ketone in sugar
under the above conditions to afford 8 in 83% yield (Scheme
3); thus the desired product was obtained in good yield
directly from 5. The process presented here with few steps
and a 64% total yield based on 1 provides a facile and
efficient method for the synthesis of 8 and may be a new
practical entry for the preparation of cyclitols. Extension of
this study is now under investigation in this laboratory.
8 and 9, La(OTf)3 or YbCl3‚6H2O, which were efficient
catalysts for the reaction with silyl enol ethers, were not as
effective as ZnCl2 for this cyclization (entries 8 and 9 vs 4),
which might be explained by considering the steric hindrance
of large lanthanide complexes.
As described above, the 5-keto enol ether 7 was not stable
in a silica gel column; however, it was revealed that column
purification of 7 was not necessary for efficient cyclization
under the above conditions. After the usual workup (washing
with H2O), crude 7 was treated with ZnCl2 in THF/H2O and
converted into 8 in 80% yield based on 6 (Scheme 3). More
(16) Reaction with acetals or ketals: (a) Effenberger, F. Angew. Chem.,
Int. Ed. Engl. 1969, 8, 295. (b) Isler, O.; Lindlar, H.; Montavon, M.; Ru¨egg,
R.; Zeller, P. HelV. Chim. Acta 1956, 39, 249. (c) Fishman, D.; Klug, J. T.;
Shani, A. Synthesis 1981, 137. (d) von der Bru¨ggen, U.; Lammers, R.; Mayr,
H. J. Org. Chem. 1988, 53, 2920.
(17) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998,
120, 8287.
Org. Lett., Vol. 2, No. 4, 2000
459

Acknowledgment. We are grateful to Misses J. Shimode,
J. Nonobe, and M. Kitsukawa for spectroscopic measure-
ments. Partial financial support for this research from the
Ministry of Education, Science, Sports and Culture of Japan
is gratefully acknowledged.
OL9913035
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