Facile and practical synthesis of optically pure 1D-chiro-inositol from myo-inositol

Article abstract of DOI:10.1016/S0040-4039(00)02178-X

Optically pure 1D-chiro-inositol (DCI) has been synthesized from optically inactive myo-inositol practically in four steps. The crystalline nature of most intermediates and the utilization of inexpensive reagents facilitate the economical mass production of DCI, which is expected to be used in the future for treatment of Type 2 diabetes and polycystic ovary syndrome (PCOS).

Full text of DOI:10.1016/S0040-4039(00)02178-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1053–1056
Facile and practical synthesis of optically pure 1
D-chiro-inositol
from myo-inositol
Yoshiaki Takahashi,a Hitoshi Nakayama,a Keiki Katagiri,a Kumi Ichikawa,a Nobuhiro Ito,a
Tomohisa Takita,b Tomio Takeuchib and Toshiaki Miyakea,*
aInstitute of Bioorganic Chemistry, MCRF, 3-34-17 Ida, Nakahara-ku, Kawasaki 211-0035, Japan
bInstitute of Microbial Chemistry, MCRF, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
Received 12 October 2000; revised 21 November 2000; accepted 24 November 2000
Abstract—Optically pure 1D-chiro-inositol (DCI) has been synthesized from optically inactive myo-inositol practically in four
steps. The crystalline nature of most intermediates and the utilization of inexpensive reagents facilitate the economical mass
production of DCI, which is expected to be used in the future for treatment of Type 2 diabetes and polycystic ovary syndrome
(PCOS). © 2001 Elsevier Science Ltd. All rights reserved.
Kasugamycin,1 discovered by Umezawa et al. in 1965,
has been used as an agricultural antibiotic. While its
constituent cyclitol, 1D-chiro-inositol (DCI), is expected
As shown in Scheme 1, we chose inexpensive and
readily available myo-inositol as the starting com-
pound. First, myo-inositol was converted into its 2,3-
(+)-camphor acetal (1) in 63% yield (43% after recrys-
tallization in MeOH–H2O) by modifying the methods
described in recent papers.13–15 The mixture of
byproduct acetals was readily hydrolyzed in an acidic
solution to recover myo-inositol.
to have potential to treat Type 2 (adult-onset) dia-
betes,2 it was reported3 that the Phase II clinical trials
of DCI for women with polycystic ovary syndrome
(PCOS), the most common female endocrine disorder
that affects up to 6 million women in the United
States,4 had been successfully conducted. These signifi-
cant results put kasugamycin in the spotlight as the
natural source of DCI, but its present fermentation
scale is too small to meet the expected demand.
Although 4-O-methyl-DCI, (+)-pinitol, has been found
in the extract of sugar pine,5 its limited availability
hinders its use for the production of DCI on a large
scale. Other reported methods to yield DCI or pro-
tected DCI include enzymatic conversion from myo-
In order to introduce a leaving group at the C-1
position, compound 1 was treated with Tf2O in pyri-
dine–CH2Cl2 (1:1) at −20°C to give unstable 1-triflate
(2a)16 as the main product. Similar selectivity was
observed on treatment with TsCl to give 1-tosylate
(2b)17 in 85% yield. This higher reactivity of the 1-
hydroxyl group may be attributed to its intramolecular
hydrogen bonding with cis-vicinal oxygen at C-2.18
Suami and co-workers reported19 an analogous selectiv-
ity in tosylation of 1,2-O-cyclohexylidene-DL-myo-inos-
itol by obtaining the 3-tosylate.
inositol6 or
D
-chiro-3-inosose,7 a combination of a
biocatalytic approach and chemical modification start-
ing from halobenzene,7,8 and chemical synthesis from
methyl a-D
-glucoside via 6-O-acetyl-5-enopyranoside9
Treatment of 2a with BzOLi in DMF afforded anhy-
drides 320 and 4,21 instead of forming a benzoyl deriva-
tive with inversion of the stereochemistry at C-1. The
structures of 3 and 4 were unambiguously confirmed by
X-ray diffraction. These two compounds were also
obtained from 1-tosylate (2b) (Table 1, entries 1 and 2).
It was concluded, therefore, the oxygen anions at 4 or
6 intramolecularly attacked the C-1 more easily than
the benzoyloxy anion under these conditions. Forma-
tion of similar anhydrides was also observed22 when
1,2-O-cyclohexylidene-3- or 3,4-di-O-tosyl-DL-myo-
inositol was treated with MeONa in MeOH.
or via 5-enopyranoside,10 from myo-inositol,11 and
from cyclohexene.12 In the light of the anticipated
problems such as cost, purity and availability associ-
ated with the above processes, it was deemed worth-
while to investigate a new synthetic route applicable to
the mass production of DCI.
Keywords: inositols; cyclitols; resolution; sulfonyl compounds; inver-
sion reactions; 1D-chiro-inositol; diabetes.
* Corresponding author. Tel.: +81 44 788 6821; fax: +81 44 755 3099;
e-mail: tomiyake@mx1.alpha-web.ne.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02178-X

1054
Y. Takahashi et al. / Tetrahedron Letters 42 (2001) 1053–1056
For suppression of these undesirable attacks of the
oxygen anions, the remaining three hydroxyl groups of
2a were protected by addition of Ac2O into the reaction
mixture of sulfonylation, after monitoring disappear-
ance of 1 on a TLC plate, to yield triacetate (5a).23
Compound 5b24 was also produced from 1 in a similar
manner.
A few representative results of inversion reactions at
C-1 of 5a and 5b are summarized in Table 1. Our
concern that a muco-inositol would be formed25 by the
neighboring group participation fortunately proved to
be groundless, and these two compounds successfully
underwent displacement by the benzoate or acetate
anion to give 6a26 and 6b,27 respectively (entries 3–9),
OH OH
3
2
OH
1
O
O
O
O
O
O
a, b
c
4
+
3
2
2
1
OH
5
2 OR
1
1
6
O
HO
3
3
OH
OH
OH
OH
HO
HO
O
myo-inositol
OH
OH
1
R = H
3
4
2a R = Tf
2b R = Ts
d
OH OH
2
1
O
O
O
O
e
f
3
6
OR
2
OH
4
1
5
HO
OH
OH
3
OAc
OAc
AcO
AcO
OR
OAc
1D-chiro-inositol
(DCI)
OAc
5a R = Tf
5b R = Ts
6a R = Bz
6b R = Ac
g
f
O
O
O
O
O
O
O
O
+
+
+
2
1
3
OAc
OAc
OH
OAc
AcO
OH
OAc
AcO
OAc
OH
AcO
OAc
HO
OAc
OAc
OAc
7a
7d
7b
7c
Scheme 1. Reaction conditions: (a) 1. (1R)-(+)-camphor dimethyl acetal, H2SO4, DMSO, 70°C, 3 h, 2. MeONa, 3. p-TsOH,
CHCl3–MeOH–H2O, 17 h, 63%; (b) Tf2O (or TsCl), pyr–CH2Cl2, −20°C, 2 h (or 20 h), 76% (or 85%); (c) see Table 1; (d) Ac2O,
pyr–CH2Cl2; (e) see Table 1; (f) 1. MeONa, MeOH, 1 h, 2. 50% AcOH–H2O, 80°C, 0.5 h, 88–93%; (g) see Table 1.

Y. Takahashi et al. / Tetrahedron Letters 42 (2001) 1053–1056
1055
Table 1. Inversion reactions of the 1-hydroxyl group of myo-inositol derivatives
Entry
Substrate
Reagent
Solvent
Temp. (°C)
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
2a
2b
5a
5b
5b
5b
5a
5b
5b
5a
5b
BzOLi
BzOLi
BzOLi
BzOLi
BzONa
BzOK
AcOK
AcOK
AcOK
NaF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMSO
80
120
80
Reflux
Reflux
Reflux
80
150
140
1
3
2
20
10
5
1
8
3
2
3, 4 (1:6)
3, 4 (1:2)
6a
6a
6a
6a
6b
6b
61
52
83
51
57
56
81
57
57
56
65
9
10
11
6b
100
170
7a, 7b, 7c (1:1.5:0.1)
7a, 7b, 7c, 7d (1:1:0.7:0.4)
NaF
15
a From 1 after purification by silica-gel chromatography.
which have the same configuration as DCI. The rate of
displacement by the benzoate anion depends on its
counter cations (K+>Na+>Li+, entries 4–6). Moreover,
using DMSO instead of DMF for a solvent gave the
same yield of 6b at lower temperature in a shorter time
(entries 8 and 9). Optimization of the reaction condi-
tions is now under study.
References
1. Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.;
Hamada, M.; Takeuchi, T. J. Antibiot. (Tokyo) Ser. A
1965, 18, 101–103.
2. Kennington, A. S.; Hill, C. R.; Craig, J.; Bogardus, C.;
Raz, I.; Ortmeyer, H. K.; Hansen, B. C.; Romero, G.;
Larner, J. N. Engl. J. Med. 1990, 323, 373–378.
3. Nestler, J. E.; Jakubowicz, D. J.; Reamer, P.; Gunn, R.
D.; Allan, G. J. N. Engl. J. Med. 1999, 340, 1314–1320.
When 5a was treated with NaF, the desired inversion
products (7a, 7b, 7c) were also obtained by participa-
tion of the adjacent 6-acetoxyl group followed by
hydrolysis and acetyl migration (entry 10).28 Treatment
of 5b with NaF in DMSO gave 7a–c accompanied with
7d, which was produced by rather drastic conditions to
complete the inversion at C-1 (entry 11).
4. Web
www.insmed.com).
5. Anderson, A. B. Ind. Eng. Chem. 1953, 593–596.
site
of
Insmed
Incorporated
(http://
6. Pak, Y.; Huang, L. C.; Larner, J. FASEB 1992, A1629,
Abstr. No. 4008.
7. Mandel, M.; Hudlicky, T.; Kwart, L. D.; Whited, G. M.
J. Org. Chem. 1993, 58, 2331–2333.
8. Mandel, M.; Hudlicky, T. J. Chem. Soc., Perkin Trans 1
Finally, compounds 6a, 6b and the mixture of 7a–c(d)
were respectively deprotected in a basic, and subse-
quently acidic, medium to give DCI almost quantita-
tively. DCI thus obtained showed the same specific
rotation, [h]2D5+64 (c 1, H2O), (lit.7 +63.2), and NMR
spectra as those of authentic DCI from kasugamycin.
1993, 741–743.
9. Takahashi, H.; Kittaka, H.; Ikegami, S. Tetrahedron Lett.
1998, 39, 9703–9706 and 9707–9710.
10. Jaramillo, C.; Chiara, J.-L.; Martin-Lomas, M. J. Org.
Chem. 1994, 59, 3135–3141.
In conclusion, we have successfully developed a new
synthetic route to optically pure 1D-chiro-inositol
11. Berlin, W. K.; Zhang, W.-S.; Shen, T. Y. Tetrahedron
1991, 47, 1–20.
(DCI) from optically inactive myo-inositol, in total 47%
(via 5a and 6a), 33% (via 5b and 6a) and 36% (via 5b
and 7a–d) yields, practically in four steps: (1) selective
monoacetalization with chiral ketone and resolution;
(2) selective introduction of a leaving group at C-1 and
subsequent esterification of the remaining hydroxyl
groups; (3) inversion at C-1; (4) deprotection. The total
yields become higher when myo-inositol recovered in
the first step is taken into the calculation. The crys-
talline nature of most intermediates, the utilization of
inexpensive reagents and the environmentally-friendly
recycling of the undesired acetal isomers, (1R)-(+)-cam-
phor, and solvents facilitate the economical mass pro-
duction of DCI. We believe the above synthetic route
will meet the great demand for manufacturing DCI,
which is expected to be used in the future for treatment
of Type 2 diabetes and polycystic ovary syndrome
(PCOS).
12. Kim, K. S.; Park, J. I.; Moon, H. K.; Hann, Y. J. Chem.
Soc., Chem. Commun. 1998, 1945–1946.
13. Bruzik, K. S.; Salamonczyk, G. M. Carbohydr. Res. 1989,
195, 67–73.
14. Salamonczyk, G. M.; Pietrusiewicz, K. M. Tetrahedron
Lett. 1991, 32, 4031–4032.
15. Bruzik, K. S.; Tsai, M.-D. J. Am. Chem. Soc. 1992, 114,
6361–6374.
1
16. Compound 2a: H NMR (500 MHz, CDCl3) l 0.84, 0.87
and 0.97 (s, Me each), 3.39 (t, J=10 Hz, H-5), 3.61 (dd,
J=7, 10 Hz, H-4), 3.95 (dd, J=5.5, 7 Hz, H-3), 3.99 (t,
J=10 Hz, H-6), 4.47 (apparent t, J=5, 5.5 Hz, H-2), 4.94
(dd, J=5, 10 Hz, H-1).
17. Compound 2b: colorless needles (from CHCl3–n-hexane);
mp 143–144°C; [h]D21 −32 (c 1, CHCl3); 1H NMR (500
MHz, DMSO-d6) l 0.73, 0.81 and 0.85 (s, Me each), 2.41
(s, Me of Ts), 3.02 (dt, J=5, 9.5, 9.5 Hz, H-5), 3.17 (ddd,
J=5, 7, 9.5 Hz, H-4), 3.42 (dt, J=5, 9.5, 9.5 Hz, H-6),

1056
Y. Takahashi et al. / Tetrahedron Letters 42 (2001) 1053–056
3.73 (dd, J=6, 7 Hz, H-3), 4.06 (dd, J=4.5, 6 Hz, H-2),
4.62 (dd, J=4.5, 9.5 Hz, H-1), 4.93 (d, J=5 Hz, HO-4),
4.95 (d, J=5 Hz, HO-5), 5.24 (d, J=5 Hz, HO-6).
J=5, 6.5 Hz, H-3), 4.58 (dd, J=4, 6.5 Hz, H-2), 5.07 (dd,
J=6, 8 Hz, H-5), 5.12 (dd, J=4, 10.5 Hz, H-1), 5.16 (dd,
J=5, 6 Hz, H-4), 5.61(dd, J=8, 10.5 Hz, H-6). Anal.
calcd for C23H31F3O11S: C, 48.25; H, 5.46. Found: C,
48.07; H, 5.38.
18. Chung, S.-K.; Ryu, Y. Carbohydr. Res. 1994, 258, 145–
167.
19. Suami, T.; Ogawa, S.; Tanaka, T.; Otake, T. Bull. Chem.
24. Compound 5b: colorless needles (from CHCl3–n-hexane);
mp 226–227°C; [h]D23 −36 (c 1, CHCl3); 1H NMR (500
MHz, CDCl3) l 0.85, 0.91 and 0.96 (s, Me each), 1.89,
1.99 and 2.06 (s, Me of Ac each), 2.44 (s, Me of Ts), 4.05
(t, J=6 Hz, H-3), 4.42 (dd, J=4, 6 Hz, H-2), 4.91 (dd,
J=4, 10.5 Hz, H-1), 5.00 (t, J=8 Hz, H-5), 5.12 (dd,
J=6, 8 Hz, H-4), 5.44 (dd, J=8, 10.5 Hz, H-6). Anal.
calcd for C29H38O11S: C, 58.57; H, 6.44. Found: C, 58.71;
H, 6.50.
Soc. Jpn. 1971, 44, 835–841.
20. Compound 3: colorless columns (from CHCl3–n-hexane);
mp 136–137°C; [h]D24 −22 (c 1, CHCl3); 1H NMR (500
MHz, CDCl3) l 0.84, 0.86 and 1.01 (s, Me each), 2.67 (d,
J=11 Hz, HO-3), 3.12 (d, J=11 Hz, HO-4), 3.26 (H-6),
3.52 (H-5), 4.08 (H-3), 4.19 (dt, J=3, 3, 11 Hz, H-4), 4.26
(H-2), 4.63 (d, J=6 Hz, H-1). Some signals were col-
lapsed with long-range couplings between H-1 and 5, H-2
and 6 and H-3 and 5. Anal. calcd for C16H24O5: C, 64.84;
H, 8.16. Found: C, 64.92; H, 8.08.
25. Suami, T.; Ogawa, S.; Oki, S.; Sato, H. Bull. Chem. Soc.
Jpn. 1974, 47, 1731–1736.
21. Compound 4: colorless columns (toluene–n-hexane); mp
26. Compound 6a: colorless needles (from n-hexane); mp
138–139°C; [h]2D3 +64 (c 1, CHCl3);1H NMR (500 MHz,
CDCl3) l 0.87, 0.99 and 1.00 (s, Me each), 1.98, 2.04 and
2.10 (s, Me of Ac each), 4.21 (t, J=6.5 Hz, H-2), 4.33
(dd, J=3, 6.5 Hz, H-1), 5.25 (dd, J=6.5, 7.5 Hz, H-3),
5.40 (dd, J=3, 9 Hz, H-5), 5.43 (dd, J=7.5, 9 Hz, H-4),
5.81 (t, J=3 Hz, H-6). Anal. calcd for C29H36O10: C,
63.96; H, 6.66. Found: C, 63.70; H, 6.60.
1
180–181°C; [h]2D4 −11 (c 1, CHCl3); H NMR (500 MHz,
CDCl3) l 0.87, 0.98 and 1.02 (s, Me each), 2.09 (d, J=6.5
Hz, HO-5), 4.17 (dddd, J=1.5, 2.5, 5, 11.5 Hz, H-4), 4.26
(d, J=11.5 Hz, HO-4), 4.39 (broad d, 5 Hz, H-6), 4.41 (t,
J=5 Hz, H-3), 4.47 (dd, 2.5, 6.5 Hz, H-5), 4.67 (dddd,
J=1, 1.5, 5, 8.5 Hz, H-2), 4.72 (dd, J=5, 8.5 Hz, H-1).
The 2D-COSYLR spectrum showed long-range correla-
tions between H-1 and 3, H-1 and 5, H-2 and 4, H-2 and
6, H-3 and 5 and H-4 and 6. Anal. calcd for C16H24O5: C,
64.84; H, 8.16. Found: C, 64.88; H, 8.10.
27. Compound 6b: [h]2D1 +46 (c 1, CHCl3);1H NMR (500
MHz, CDCl3) l 0.86, 0.94, 0.97 (s, Me each), 2.01, 2.03,
2.07 and 2.13 (s, Me of Ac each), 4.14 (t, J=6.5 Hz,
H-2), 4.18 (dd, J=3, 6.5 Hz, H-1), 5.17 (apparent t, J=7,
8 Hz, H-3), 5.25 (dd, J=2.5, 8 Hz, H-5), 5.28 (t, J=8 Hz,
H-4), 5.56 (apparent t, J=2.5, 3.5 Hz, H-6).
22. Suami, T.; Ogawa, S.; Oki, S.; Ohashi, K. Bull. Chem.
Soc. Jpn. 1972, 45, 2597–2602.
23. Compound 5a: colorless needles (from CHCl3–n-hexane);
mp 121–122°C (decomp.); [h]2D3 −42 (c 1, CHCl3); 1H
NMR (500 MHz, CDCl3) l 0.88, 0.99 and 1.02 (s, Me
each), 2.04, 2.08 and 2.10 (s, Me of Ac each), 4.18 (dd,
28. Mercier, D.; Barnett, J. E. G.; Gero, S. D. Tetrahedron
1969, 25, 5681–5687.
.