A concise synthesis of (-)-conduritol F from L-quebrachitol via AlCl3-n-Bu4NI mediated demethylation

Article abstract of DOI:10.1016/0040-4039(91)80092-K

(-)-Conduritol F was prepared starting from naturally occurring cyclitol, L-quebrachitol, in 5 steps via AlCl₃-Bu₄NI mediated chemoselective demethylation of the methyl ether. A preparation of (+)-conduritol B was also described.

Full text of DOI:10.1016/0040-4039(91)80092-K

Tetrahedron Letters, Vo132, No 40, pp 5593-5596, 1991
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A Concise Synthesis Of (-)-Conduritol F
From L-Quebrachitol
Via AIC13-n-Bu4NI Mediated Demethylation
Takahiko AKIYAMA,* Itiroaki SHIMA, and Shoichiro OZAKI*
Department of Applied Chemistry, Facultyof Engineenng,
Ehime University, Bunkyo-cho, Matsuyama 790, Japan
Keywords: (-)-cunduritol F; (+)-conduritoi B; L-quebrachitol; dernethylation; A1C13
A b s t r a c t : (-)-Conduritol F was prepared starting from naturally occunqng cyelitol, L-quebracbitol, in 5 steps via
AICI3-Bu4NI mechated chemoselective demethylation of the methyl ether. A preparation o[(+)-condu~tol B was also
descffbed
There is currently considerable interest in the synthesis of conduritols, cyclohex-5-ene-1,2,3,4-tetrol,1
since these compounds are useful precursors in the preparation of cyclitols such as myo-inositol phosphates,
and pseudo-sugars, and also because their derivatives present interesting biological activities.2 Concise chiral
syntheses of conduritols are hence desired. There are, however, few reports on the subject though chiral
syntheses of conduritols via microbial oxidation of benzene have been recently reported.3 As part of our
continuing effort to explore the utility of L-quebrachitol (1L-2-O-methyl- ch/ro-inositol),4,5,6 we wish to report a
concise preparation of (-)-conduritol F,7 the antipode of naturally occurring (+)-leucanthemitol, from L-
quebrachitol via A1C13-n-Bu4NI mediated ehemoselective demethylation of the methyl ether, and also describe a
first synthesis of (+)-conduritol B.
OCH3
o ,oH
.,OH
HO'
~
OH
"OH
HO" _v: "OH
OH
HO" _-v_ ~'OH
OH
L-Quebrachitol
(-)-ConduritoFl
(+)-ConduritolB
We reported, in a previous paper,8 that a combined system ofAICl3 and NaI9 cleaved methyl ethers with
vicinal OH group in preference to the c/s cyclohexylidene moieties. Our strategy for the synthesis of(-)-
5593

5594
R10~ ~R2,Q
c
~
_
.,,O
4
O"
~
~ (-)-Conduritol F
~ 1 , R,=H, R2=CH3
2, RI=R2=H
)
a
b
3, RI=R2-'- C=S
a) See text, b)N,N'-thiocarbonyldiimidazole, acetone, reflux, 9 h, 90%,
Scheme 1
c) P(OCH3)3, reflux, 6 h, d) 80%trifluoroacetlc acid in methanol, 90% from 3.
Table 1 Demethylation of 1 by means of AlCl3 and iodide ion.a}
Run Equiv. of AICI3 MetalIodide (Equiv) Time / h Yield of 2/% Recovery of 1/%
1
10
20
Nal (10)
KI (20)
20
34
57
41
13
37
2
3
4
10
10
Ld (10)
22
26
59
78
25
12
n-Bu4NI (10)
a) Reactions were carried out in the presence of pyridine(10 eq ) in CH3CN at room
temperature
conduritol F involves AICI3 mediated chemoselective demethylation as outlined in Scheme 1. Treatment of 1,
which was prepared in one step from L-quebrachitol, with A1C13 ( 10 equiv) and NaI ( 10 equiv) in the presence
ofpyridine (10 equiv) in CH3CN gave 2 in 57% yield. 1° Concurrent cleavage of cyclohexylidene moieties
took place in the system and chemoselective demethylation in preference to the trans cyclohexylidene group was
difficult with the system. In order to overcome the difficulty, iodide source was examined and the results are
shown in Table 1. Marked effect of the counter cations was observed and a use oftetrabutylammonium iodide
instead of Nai11 suppressed the cleavage of cyclohexylidene moiety and 2 was obtained in 78% yield. 12
Advantage of AlCl3-n-Bu4NI over A1C13-NaI is also demonstrated in the demethylation of 5 and 8, m which
case the presence ofpyridine is not necessary. On treatment of 5 and 8 with AIC13-n-Bu4NI in CH3CN,
O_CH3
OH
OCH3
H o ~ O B z
AICI3 (10 eq) ~
H o ~ , O B z
H O ~ O B z
O" =~y~" OBz
MI (10 eq)
CH3CN
O" "y".-~" OBz
HO" ~-~_- " OBz
~
8
~ - ( 3
OH
5
6
7
M = n-Bu4N
M = Na
0 °C, 2 h
0 "C, 3 h
88%
54%
0%
17%

5595
OCH3
OH
BzO,, ~ O H
BzO,~ ~ O H
""
'
AICI3 (10 eq) - MI (10 eq)
~
"
'
O"' V= ' O H
O"' v. "OH
r.t. ovemight
M = n-Bu4N
M= Na
83%
58%
8
9
chemoselecfive demethylation took place without concurrent cleavage of the acetal groups, giving 6 and 9 in
high yields respectively. AICI3-n-Bu4NI was thus found to be much superior to AICI3-NaI for the
chemoselective demethylation of the methyl ethers although both reagents system showed similar reaction rote.
Treatment of 2 with N,N'-thiocarbonyldiimidazole gave a cyclic thiocarbonate 3, which was treated with
tdmethylphosphite to furnish 4. Deprotection of the cyclohexylidene groups afforded (-)-conduritol F as
crystals. 13 Thus, (-)-conduritol F was synthesized in 5 steps starting from L-quebmchitol. Although several
reports appeared on the syntheses ofit, our present method is the most straightforward and practical.
OBz
OBz
BzO,, ~ , O B z
b
BzO,, ~ O B z
c
r
~
(+)-Conduritol B
RO"' v . " OBz
OR
"
~
~OBz
12
10, R= H
~--~ 11; R= C=S
a
Scheme 2. a) N,N'-thiocarbonyldiimidazole, acetone, reflux, 5 h, 91%,
b) P(OCH3)3, reflux, 5 h, 97%, c) NaOMe, MeOH, r.t. overnight,
Finally, we prepared (+)-conduritol B starting from a diol 10, which was readily available from L-
quebmchitol.4 Although recemic and (-)-condudtol B have been already synthesized, 7 no preparation of(+)-
conduritol B has been reported so far. Treatment of 10 with N,N'-thiocarbonyldiimidazole gave cyclic
thiocarbonate 11, which was treated with trimethylphosphite to give 12. Deprotection of the benzoyl groups
afforded (+)-condudtol B quantitatively.14
In conclusion, we found that a combined system ofAlCl3 and n-Bu4NI selectively cleaved methyl ether in
preference to the cyclohexylidene moieties and accomplished a short step synthesis of (-)-conduritol F from L-
quebmchitol, and also a first synthesis of(+)-condudtol B. The present demethylation method will be a useful
tool in manipulating naturally occurring cyclitols bearing methyl ethers such as L-quebrachitol and pinitolllb
and will expand the utility of the eyclitols as chiml synthon in natural product syntheses.
Acknowledgment: The authors wish to express our gratitude to Yokohama Rubber Co. Ltd. (Tokyo Japan) for
the kind gift of L-quebmchitol.
REFERENCES AND NOTES
1.
Fora review, see: Balci, M., Siitbeyaz, Y.; Se(;en, H. Tetrahedron, 1990, 46, 3715-3742.

5596
2.
3.
4.
5.
6.
Legler, G.; Bause, E.; Carbohydr. Res., 1973, 28, 45-52. Legler, G.; Lotz, W. Z. Physiol. Chem.,
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Hudlicky, T.; Price, J. D.; Luna, H.; Andersen, C. M. Synlett., 1990, 30%310: Carless, H. A. J.; Oak,
O. Z. Tetrahedron Lett., 1991,32, 1671-1674.
A synthesis of D-myo-inositol 1-phosphate, see: Akiyama, T.; Takechi, N.; Ozaki, S. Tetrahedron Lett.,
1990, 31, 1433-1434.
Asymmetric reduction employing L-quebrachitol as a chiral auxiliary group, see: Akiyama, T.;
Nishimoto, H.; Ozaki, S. Tetrahedron Lett., 1991,32, 1335-1338.
Other syntheses of natural products utilizing L-quebrachitol as a starting material, see: a)Angyal, S. J.;
Hoskinson, R. M. Methods in Carbohydr. Chem., 1963, 2, 87-89; b) Mercier, D.; Barnett, J. E. G.;
Gero, S. D. Tetrahedron, 1969, 25, 5681-5687. c) Paulsen, H.; Heiker, F. R. Justus Liebigs Ann.
Chem., 1981, 2180-2203:d) Paulsen, H.; Deyn, W. ibid., 1987,125-131; Kozikowski, A. P.; Fauq,
A. H.; Rusnak, J. M.; Tetrahedron Lett., 1989, 30, 3365-3368. e) Tegge, W.; Ballou, C. E. Proc.
Natl. Acad. Sci. U.S.A., 1989, 86, 94-98. f) Kozikowski, A. P.; Fauq, A. H.; Powis, G.; Meilder, D.
C.; J. Am. Chem. Soc., 1990, 112, 4528-4531 g) Chida, N; Suzuki, M.; Suwama, M.; Ogawa, S. J.
Carbohydr. Chem., 1989, 8,319-332. h) Chida, N :Tobe, T.; Suwama, M.; Ohtsuka, M.; Ogawa, S.
J. Chem. Soc., Chem. Commun., 1990, 994-995. i) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron
Lett., 1991, 32, 1063-1066.
a) (-+)-Conduritol F and (-+)-conduritol B: Seqen, H.; Siatbeyaz, Y.; Balci, M. Tetrahedron Lett., 1990,
31, 1323-1326. b) (+) and (-)-conduritol F: Ley, S. V.; Redgrave, A. J. SJmletL, 1990,393-394. c) (-)-
conduritol F and (-)-conduritol B: Paulsen, H.; R6ben, W.; Heiken, F. R. Chem. Bet., 1981, 114,
3242-3252. d) (+-)-conduritol B: Carless, H. J.; Busia, K.; Tetrahedron Lett., 1990, 31, 3449-3452, e)
(-+)-conduritol B epoxide: Lee, K. J ; Boyd, S. A.; Radin, N. S. Carbohydr. Res., 1985, 144, 148-
154. f) (+)-conduritol F and (-)-conduritol B: Drian, C. L.; Vionnet, J-P.; Vogel, P HeN Chim. Acta.,
1990, 73, 161-168.
7.
8.
9.
Akiyama, T.; Takechi, N.; Shima, H.; Ozakl, S. Chem. Lett., 1990, 1433-1436.
Node, M.; Ohta, K.; Kajimoto, T.; Nishide, K.; Fujita, E; Fuji, K. Chem. Pharm. Bull., 1983, 31,
4178-4180.
10. We would like to correct the reported8 yield (39%) of this demethylation.
11. Demethylation of methyl ethers employing BF3OEt2-n-Bu4NI was already reported, but comparison of
NaI and n-Bu4NI was not studied: a) Mandal, A. K. N.; Soni, R.; Ratman, K. R. Synthesis, 1985,
274-275. b) Ley, S. V.; Sternfeld, F. Tetradedron, 1989, 45, 3463-3476.
12. A typical experiment procedure of the demethylation is as follows: To a solution of I (306 rag, 0.864
retool), n-Bu4NI (3.2 g, 8.6 mmol), and pyridine (0.69 ml, 8.6 retool) in CH3CN (9.0 ml) was added
AIC13 (1.15 g, 8.6 mmol) at 0 *C. Stirring was continued for 26 h at room temperature. The reaction
mixture was quenched by addition ofwater (30 ml) and the aqueous layer was extracted with CH2C12 (3
x 15 ml). The combined organic layers were successively washed with 10% Na2SO3 solution and brine,
dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The remaining
residue was dissolved in small amount of CH2C12 and Et20 was added. The precipitate thus formed was
filtered offand the filtrate was concentrated and purified by preparative TLC (CHCI3 : Et20 (v/v) = 3:1)
to afford 2 (229 mg, 78%).
13. (-)-Conduritol F; [~]D22 = -70.7° (c 0.75, CH3OH), lit.7c [Ct]D20 = -70.5* (c 0.75, CH3OH)~ mp 131-
132 "C, lit.7f [(+)-isomer] 129-130 °C.
14. (+)-Conduritol B; [t~]D22 = 191° (c 1.26, CH3OH), lit.7f(-)-isomer [~t]D20 = -179" (c 1.2, CH3OH), mp
177-178 °C, lit.7c[(-)-isomer] 179"C.
(Received xn Japan 12 June 1991)