Preparation of versatile synthetic precursors of optically active 5a-carba-sugars from (-)-vibo-quercitol

Article abstract of DOI:10.1081/CAR-200064653

The spiro-epoxide derived from (-)-2-deoxy-scyllo-inosose was converted into the iodide 2, which was directly subjected to elimination conditions, affording the key methylene compound 4. Successive cyclohexylidenation of the tetrol obtained from 4, select

Full text of DOI:10.1081/CAR-200064653

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Preparation of Versatile Synthetic
Precursors of Optically Active
5a‐Carba‐sugars from (-)‐vibo‐Quercitol
Seiichiro Ogawa a , Miwako Asada a , Yoriko Ooki b , Midori Mori b
Masayoshi Itoh b & Takashi Korenaga b
,
a Department of Biosciences and Informatics, Faculty of Science and
Technology , Keio University , Hiyoshi, Kohoku‐ku, Yokohama, Japan
b Department of Chemistry , Tokyo Metropolitan University ,
Minami‐Ohsawa, Hachioji, Tokyo, Japan
Published online: 20 Aug 2006.
To cite this article: Seiichiro Ogawa , Miwako Asada , Yoriko Ooki , Midori Mori , Masayoshi
Itoh & Takashi Korenaga (2005) Preparation of Versatile Synthetic Precursors of Optically Active
5a‐Carba‐sugars from (-)‐vibo‐Quercitol, Journal of Carbohydrate Chemistry, 24:7, 677-683
To link to this article: http://dx.doi.org/10.1081/CAR-200064653
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Journal of Carbohydrate Chemistry, 24:677–683, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200064653
Preparation of Versatile
Synthetic Precursors of
Optically Active 5a-Carba-
sugars from (2)-vibo-
Quercitol
Seiichiro Ogawa and Miwako Asada
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio
University, Hiyoshi, Kohoku-ku, Yokohama, Japan
Yoriko Ooki, Midori Mori, Masayoshi Itoh, and Takashi Korenaga
Department of Chemistry, Tokyo Metropolitan University, Minami-Ohsawa, Hachioji,
Tokyo, Japan
The spiro-epoxide derived from (2)-2-deoxy-scyllo-inosose was converted into the iodide
2, which was directly subjected to elimination conditions, affording the key methylene
compound 4. Successive cyclohexylidenation of the tetrol obtained from 4, selective ben-
zoylation, and conventional tosylation gave the homoallyl tosylate 11, which would be a
versatile intermediate for preparation of biologically active 5a-carbahexopyranosyl-
amines and their unsaturated congeners.
Keywords Cyclitols, Inositols, Bioconversion, Carbohydrate mimics, Carba-sugars,
Carba-glycosylamines
INTRODUCTION
We have been engaged in developing effective routes to connect readily avail-
able myo-inositol to optically active carba-sugars[1] of biologic interest. Practi-
cally, a number of carba-glycosylamines can be furnished[2] by chemical
Received January 11, 2005; accepted April 6, 2005.
Address correspondence to Seiichiro Ogawa, Department of Biosciences and Infor-
matics, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan. E-mail: ogawa@bio.keio.ac.jp
677

S. Ogawa et al.
678
degradation and/or biogenesis of antibiotic validamycins. In recent years opti-
cally active carba-sugars have been totally synthesized[3] starting from common
hexopyranose derivatives, (2)-shikimic acid, and so on. However, no process
has been successfully employed for the production of large quantities of
desired carba-sugars.
In a preceding paper,[4] we documented transformation of (2)-2-deoxy-
scyllo-inosose derived by bio-oxidation of (2)-vibo-quercitol[5] into a single
crystalline spiroepoxide, from which (2)-b-valiol[6] and clinically important
(2)-valiolamine[7] were prepared, thus establishing a link between cyclitols
and chiral carba-sugars. This process might also be applicable for provision
of branched-chain cyclitol derivatives and carba-sugars.
We report here ready synthesis of a key intermediate, 1L-(1,3/2,4)-5-
methylene-1,2,3,4-cyclohexanetetrol (2,3,4-tri-O-acetyl-5-deoxy-5a-carba-b-D-
xylo-5-enopyranose acetate)[8] (4), to provide 5a-carba-hexopyranoses as well
as valienamine type unsaturated 5a-carba-hexopyranosylamines[9,10] of
biological importance (Sch. 1).
Scheme 1: Synthetic routes to biologically interesting 5a-carba-sugar derivatives from
myo-inositol.

Synthetic Precursors of Carba-sugars
679
RESULTS AND DISCUSSION
Conversion of the spiro-epoxide[4] into the exo-methylene compound 4 was
attempted through an elimination reaction of the halides obtained from it
(Sch. 2). Thus, treatment of the epoxide with 20% HBr-AcOH at 508C gave
the 7-bromide 1 selectively in 80% yield, which was then subjected to conven-
tional elimination conditions[11] with zinc powder in refluxing acetic acid.
However, a major product was shown to be penta-O-acetyl-(2)-b-valiol 3
(58%), resulting from substitution at C-7 with an acetate ion. Alternatively,
the epoxide was treated with concd. hydroiodic acid in acetic acid at rt to
give the iodide 2 (ꢀ100%). Interestingly, under similar elimination conditions
as above, compound 2 was converted into the desired exo-methylene compound
4 preferentially in 85% yield. The structure of 4 was confirmed by its 1H NMR
spectrum, with signals due to H-4 and H-5a protons as a doublet (J ¼ 9.8 Hz)
Scheme 2: Synthesis of the key intermediates 4 and 11 from the spiro-epoxide. Conditions
and reagents: (a) 20% HBr-AcOH, 508C (!1); HI (2 molar equiv.), AcOH, r.t. (!2); (b) Zn
powder, AcOH, 2 hr, reflux temp; (c) NaOMe, MeOH; a,a-dimethoxycyclohexane (ꢀ10 molar
.
equiv.), TsOH H2O (0.2 molar equiv.), DMF, 8 hr, rt; (d) Ac2O, pyridine, rt; (e) benzoic acid (1.2
.
molar equiv.), Et3N (1.2 molar equiv.), EDC HCl (1.2 molar equiv.), DMAP (0.2 molar equiv.),
CH2Cl2, 2 days, rt; (f) TsCl, DMAP, pyridine.

S. Ogawa et al.
680
and two resonated doublets of doublets (J ¼ 5.4, 13.2 Hz and J ¼ 11.7, 13.2 Hz)
at d 5.39, 2.82, and 2.25, respectively.
Compound 4 was O-deacetylated with methanolic sodium methoxide, and
the resultant tetrol was allowed to react with 1,1-dimethoxycyclohexane (23
.
molar equiv.) in DMF in the presence of TsOH H2O (0.2 molar equiv.) at rt to
give, after fractionation over a column of silica gel, the 1,2-, 2,3-, and 3,4-O-cyclo-
hexylidene derivativesa 5a, 6a, and 7a in 13%, 53%, and 17% yields, respectively.
Their structures were clearly established on the basis of 1H NMR spectral data of
their respective di-O-acetyl derivatives 5b, 6b, and 7b. For example, the struc-
ture of 6b was assigned on the basis of its spectrum, which indicated signals
due to H-1 and H-4 as a doublet of doublets of doublets (J ¼ 5.4, 9.9, 10.0 Hz)
and a doublet (J ¼ 10.5 Hz) at d 4.86 and 5.41, respectively. Practically, the
tetrol obtained by hydrolysis of compounds 5a and 7a was again subjected to
cyclohexylidenation conditions to improve the yield of 6a.
Next, selective benzoylation of 6a was attempted by treatment with benzoic
acid (1.2 molar equiv.) in the presence of 1-ethyl-3-(30-dimethylaminopropyl)car-
.
bodiimide hydrochloride (EDC HCl, 1.2 molar equiv.), Et3N (1.2 molar equiv.),
and DMAP (0.2 molar equiv) in CH2Cl2 for two days at 2308C to room tempera-
ture to afford, after fractionation over a silica gel column, the 1-O-, 4-O-, and 1,4-
di-O-benzoyl derivatives 8, 9, and 10 in 13%, 35%, and 27% yields, respectively.
On conventional tosylation, the major benzoate 9 was converted into reactive
intermediate tosylate 11 (ꢀ100%), the structure of which was established by its
1H NMR spectrum, exhibiting a signal due to H-4 as a doublet (J ¼ 10.6 Hz) at
d 5.62. This compound is equivalent to the corresponding 1-bromide that was
effectively utilized[12] as the intermediate for preparation of b-valienamine and
its 4-epimer. To improve the practical yield of 9, compounds 8 and 10 were
readily convertible into 6a by O-debenzoylation with MeONa in MeOH.
Reactivity of the homoallyl tosylate 11 toward common nucleophiles was
first studied to assess reaction conditions to facilitate elimination and/or substi-
tution reactions as selectively as possible (Sch. 3). Treatment of 11 with a large
excess of lithium chloride (30 molar equiv.) in DMF in the presence of
triethylamine was carried out at 858C to afford the chloride 12 (62%) and the
elimination product 14 (15%). The structure of the chloride 12 was assigned
1
by the H NMR signals for H-2 and H-3 at d 3.58 and 4.25 as doublets of
doublets (J ¼ 3, 9.5 Hz) and (J ¼ 9.5, 10.3 Hz), respectively. The structure of
the alkadiene 14 was also assigned by the 1H NMR spectrum, which contained
a doublet (J ¼ 8.4 Hz) and a doublet of doublets (J ¼ 8.4, 11.2 Hz) at d 4.43 and
3.93 due to H-2 and H-3 signals, respectively. Alternatively, azidolysis of 11 with
10 molar equiv. of sodium azide in DMF at 858C produced the a-azide 13 (77%)
aAll compounds 4–14 are designated the derivatives of 5a-carba-hexopyranose.

Synthetic Precursors of Carba-sugars
681
Scheme 3: Reactions of the tosylate 11. Conditions and reagents: (a) LiCl (30 molar equiv.),
Et3N, DMF, 858C (11 ! 12); NaN3 (10 molar equiv.), DMF, 858C (11 ! 13).
1
along with 14 (12%). The H NMR spectrum of 13 contained two resonated
doublets of doublets at d 3.86 (J ¼ 2.7, 9.3 Hz) and 4.14 (J ¼ 9.3, 10.4 Hz),
attributable to H-2 and H-3, confirming the assigned structure. These results
indicated 11 as a nice candidate for direct nucleophilic substitution at C-1.
Compound 12 is considered to be equivalent to the a-anomer of 11, which
would produce the b-azide by azidolysis. All reaction conditions have not been
optimized yet. The alkadiene 14, obtainable mainly by treatment of 11 with
DBU in toluene, offered a key intermediate[13] for preparation of b-valienamine
derivatives. Selected 1H NMR data for key compounds are presented below.b
Recently, the 1L-(1,2/3,4)-isomer of 5-methylene-1,2,3,4-cyclohexanetetrol
was prepared[14] from a D-mannitol derivative through a multistep sequence
and demonstrated to be utilized as a versatile intermediate for preparation
of 5a-carbafucopyranose. In conclusion, the optically active 1L-(1,3/2,4)-isomer
1
1
bSpecific rotations and H NMR data follow 4: [a]D22 ¼ þ 5.58 (c ¼ 1.8, CHCl3); H NMR
(300 MHz, CDCl3): d 5.39 (d, 1H, J3,4 9.8 Hz, H-4), 5.28 (dd, 1H, J1,2 ¼ J2,3 9.8 Hz, H-2),
5.05 (m, 3H, H-3, 2 ꢀ H-6), 4.82 (ddd, 1H, J1,5a(eq) 5.4 Hz, J1,2 9.8 Hz, J1,5a(ax) 11.7 Hz,
H-1), 2.82 [dd, 1H, J1,5a(eq) 5.4 Hz, J5agem 13.2 Hz, H-5a(eq)], 2.25 (dd, 1H, J1,5a(ax) 11.7 Hz,
J5agem 13.2 Hz, H-5a(ax)], 2.12, 2.03, 2.02, 2.01 (4 s, each 3H, 4 ꢀ OAc). 6b: [a]2D2 ¼ 2 278
(c ¼ 0.52, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.41 (d, 1H, J3,4 10.5 Hz, H-4), 5.08, 4.95
(2 s, each 1H, 2 ꢀ H-6), 4.86 (ddd, 1H, J1,5a(eq) 5.4 Hz, J1,2 9.9 Hz, J1,5a(ax) 10.0 Hz, H-1),
3.76 (dd, 1H, J2,3 9.3 Hz, J1,2 9.9 Hz, H-2), 3.48 (dd, 1H, J2,3 9.3 Hz, J3,4 10.5 Hz, H-3),
2.92 [dd, 1H, J1,5a(eq) 5.4 Hz, J5agem 13.9 Hz, H-5a(eq)], 2.14 [m, 1H, H-5a(ax)], 2.21, 2.11
(2 s, each 3H, 2 ꢀ OAc), 1.67 (m, 10 H, C6H10). 11 [a]2D0 ¼ 2158 (c ¼ 2.8, CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.12–7.26 (m, 9H, Ph), 5.62 (d, 1H, J3.4 10.6 Hz, H-4), 5.11, 5.05 (2 s,
each 1H, 2 ꢀ H-6), 4.57 (ddd, 1H, J1,5a(eq) 5.4 Hz, J1,2 9.8 Hz, J1,5a(ax) 10.3 Hz, H-1), 3.74
(dd, 1H, J2,3 9.3 Hz, J1,2 9.6 Hz, H-2), 3.51 (dd, 1H, J2,3 9.3 Hz, J3,4 10.6 Hz, H-3), 3.01 [dd,
1H, J1,5a(eq) 5.4 Hz, J5agem 14.4Hz, H-5a(eq)], 2.51 [dd, 1H, J1,5a(ax) 10.3 Hz, J5agem
14.4 Hz, H-5a(ax)], 2.44 (s, 3H, PhCH3), 1.32 (m, 10 H, C6H10). 13: [a]2D0 ¼ 2 9.68 (c ¼ 1.1,
CHCl3); 1H NMR (300 MHz, CDCl3): d 8.16 (m, 2 H, Ph), 7.54 (m, 3H, Ph), 5.65 (d, 1H, J3,4
10.4 Hz, H-4), 5.09 (br s, 2 H, 2 ꢀ H-6), 4.29 (m, 1H, H-1), 4.14 (dd, 1H, J2,3 9.3 Hz, J3,4
10.4 Hz, H-3), 3.86 (dd, 1H, J1,2 2.7 Hz, J2,3 9.3 Hz, H-2), 2.54 [m, 2 H, H-5a(ax), H-5a(eq)],
1
1.71 (m, 10 H, C6H10). 14: [a]2D0 ¼ þ 478 (c ¼ 0.13, CHCl3); H NMR (300 MHz, CDCl3): d
8.14 (m, 2 H, Ph), 7.62–7.45 (m, 3H, Ph), 6.13 (m, 3H, H-1, H-4, H-5a), 5.25, 5.12 (2 s,
each 1H, 2 ꢀ H-6), 4.43 (d, 1H, J2,3 8.4Hz, H-2), 3.93 (dd, 1H, J2,3 8.4 Hz, J3,4 11.2 Hz,
H-3), 1.64 (m, 10 H, C6H10).

S. Ogawa et al.
682
4, obtained directly from myo-inositol through bioconversion combined with
conventional synthetic procedures, promises to be a key compound convertible
to quantities of optically pure carba-sugars, allowing us readily to design and
synthesize biologically active carba-sugar derivatives with ease.
ACKNOWLEDGMENTS
The authors sincerely thank Dr. Atsushi Takahashi (Hokko Chemical Industry,
Co. Ltd, Atsugi, Japan) for helpful discussions and provision of (2)-2-deoxy-
scyllo-inosose, and Ms. Miki Kanto for her assistance in preparing this
manuscript.
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