Chelation-Assisted C-O Bond Cleavage of Ortho Esters. A Convenient Synthesis of myo-Inositol Derivatives Having Free Hydroxy Group(s) at Specific Position(s)

Article abstract of DOI:10.1021/jo970606e

Reactions of ortho esters of myo-inositol 8 or 10 with 1-2 equiv of Grignard reagents in benzene-ether yield regio- and stereoselectively the corresponding ring opening products having a free hydroxy group at C-1. The regioselectivity is rationalized owing to the presence of the 2-methoxy group which will serve as an auxiliary to form a chelation complex 12 with magnesium. Inositol derivatives having two free hydroxy group at C-1 and C-3 positions can be achieved from reactions of 6 or 8 with excess Grignard reagents or under more drastic conditions. The reaction of 8b with excess LiAlH₄/AlCl₃, on the other hand, yields the corresponding 1,5-diol 19.

Full text of DOI:10.1021/jo970606e

J . Org. Chem. 1997, 62, 8315 8318
8315
Ch ela tion -Assisted C O Bon d Clea va ge of Or th o Ester s. A
Con ven ien t Syn th esis of m yo-In ositol Der iva tives Ha vin g F r ee
Hyd r oxy Gr ou p (s) a t Sp ecific P osition (s)
Sue-Min Yeh, Gene Hsiang Lee, Yu Wang, and Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Republic of China
Received April 2, 1997X
Reactions of ortho esters of myo-inositol 8 or 10 with 1 2 equiv of Grignard reagents in benzene
ether yield regio- and stereoselectively the corresponding ring opening products having a free
hydroxy group at C-1. The regioselectivity is rationalized owing to the presence of the 2-methoxy
group which will serve as an auxiliary to form a chelation complex 12 with magnesium. Inositol
derivatives having two free hydroxy group at C-1 and C-3 positions can be achieved from reactions
of 6 or 8 with excess Grignard reagents or under more drastic conditions. The reaction of 8b with
excess LiAlH4/AlCl3, on the other hand, yields the corresponding 1,5-diol 19.
Inositol derivatives are important biologically.1 Tre-
mendous efforts have been endeavored in synthesizing
partially protected inositols having the free hydroxy
group(s) at specific position(s). Acetal functionalities are
most commonly used to protect vicinal hydroxy groups
in inositols.1,2 To illustrate this, acetals 1 to 4 have
widely been employed as the starting materials for the
synthesis of various derivatives of myo-inositols.3,4 How-
ever, multistep synthesis and tedious separation of
regioisomers are frequently required to access 2 4. More
recently, Kishi and several other groups have employed
orthoformate of myo-inositol 5 for the preparation of
certain inositol derivatives having one to three free
hydroxy groups.3
nard reagents (eq 2).4d,e We felt that this reaction can
be extended to the ortho esters of inositols to selectively
give inositol derivatives having one or two free hydroxy
groups at certain specific position(s).
Inositol derivative 8a was treated with MeMgI (2
equiv) in refluxing benzene ether (10:3) for 16 h to give
the corresponding ring opening derivative 9a in 83%
yield.5 Similar reactions with EtMgBr and PhMgBr
gave 9b and 9c in 68% yield each (eq 3).5 When more
reactive 8b was employed, the reaction was carried out
at room temperature in the same medium to afford 9d
in 57% yield.5 The stereochemistry was determined by
2D NOESY experiments and by the X-ray structure of
9d .8 The nucleophile apparently attacks from the op-
posite site to the C O bond being cleaved. Presumably,
due to the rigidity of the skeleton of 6 or 8, cleavage of
the C O bond with inversion of configuration was
observed.
It is well documented that nucleophiles can react with
acetals to give the corresponding alkoxy alcohols.4 Reac-
tion of 6 with Me3Al has been shown to afford 7
selectively (eq 1).3e,f We recently uncovered a chelation-
assisted regioselective ring opening of acetals with Grig-
(3) (a) Vogl, O.; Anderson, B. C.; Simons, D. M. J . Org. Chem. 1969,
34, 204. (b) Lee, H. W.; Kishi, Y.; J . Org. Chem. 1985, 50, 4402. (c)
Billington, D. C.; Baker, R. J . Chem. Soc., Chem. Commun. 1987, 1011.
(d) Baudin, G.; Gla¨nzer, B. I.; Swaminathan, K. S.; Vasella, A. Helv.
Chim. Acta 1988, 71, 1367. (e) Gilbert, I. H.; Holmes, A. B.; Young, R.
C. Tetrahedron Lett. 1990, 31, 2633. (f) Gilbert, I. H.; Holmes, A. B.;
Pestchanker, N. J .; Young, R. C. Carbohyd. Res. 1992, 234, 117. (g)
Andersch, P.; Schneider, M. P. Tetrahedron: Asymmetry 1993, 4, 2135.
(h) Li, C.; Vasella, A. Helv. Chim. Acta 1993, 76, 211. (i) Banerjee, T.;
Srikantiah, S. M. Tetrahedron Lett. 1994, 35, 8053. (j) Ozaki, S.; Koya,
Y.; Ling, L.; Watanabe, Y.; Kimura, Y.; Hirata, M. Bull. Chem. Soc.,
J pn. 1994, 67, 1058.
(4) For reviews, see: (a) Trofimov, B. A.; Korostova, S. E. Russ.
Chem. Rev. 1975, 44, 41. (b) Mukaiyama T.; Murakami, M. Synthesis
1987, 1043. (c) Alexakis A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477. (d) Luh, T.-Y. Pure Appl. Chem. 1996, 68, 635. (e) Luh,
T.-Y. Synlett 1996, 201.
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) For reviews, see: (a) David, S.; Hanessian, S. Tetrahedron 1985,
41, 643. (b) Billington, D. C. Chem. Soc. Rev. 1989, 18, 83. (c) Potter,
B. V. L. Nat. Prod. Rep. 1990, 1. (d) Beaucage, S. L.; Iyer, R. P.
Tetrahedron 1993, 49, 10441. (e) Billington, D. C. The Inositol
Phosphate Chemical-Synthesis and Biological Significance; VCH: New
York, 1993. (f) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1933. (g) Kiddle, J . J . Chem. Rev. (Washington, D.C.) 1995,
95, 2189. (h) Hudlicky, T.; Cebulak, M. Cyclitols And Their Deriva-
tives: A Handbook of Physical, Spectral, and Synthetic Data; VCH:
New York, 1993.
(2) (a) Greene, T. A.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Kocienski, P. J .
Protective Groups; Thieme: New York, 1994.
(5) These products were obtained as racemic mixture.
S0022-3263(97)00606-3 CCC: $14.00 © 1997 American Chemical Society

8316 J . Org. Chem., Vol. 62, No. 24, 1997
Yeh et al.
Compounds 15 appeared to be important intermediates
to furnish various inositol derivatives having one to three
free hydroxy group at different positions. For example,
diacetate 16 was transformed upon hydrogenolysis into
17 in 86% yield.
Treatment of 10 with MeMgI under the same condi-
tions gave racemic 11a as the sole product (eq 4). The
benzylic acetal moiety in 10 remained intact under these
conditions. The structure of 11a was proved by the X-ray
crystallography of the corresponding ether 11b.5
Although the 1,5-dihydroxy derivative can be obtained
from 9 by protection of the hydroxy group followed by
hydrolysis of the acetal moiety (e.g. 9a to 18, eq 6), a more
direct synthesis would be desirable. The strategy was
based on our previous work using LiAlH4/AlCl3 to effect
regioselective ring opening of acetals.7 Thus, reaction of
8b with an excess of LiAlH4/AlCl3 for 16 h afforded 19 in
49% yield (eq 7). The 13C NMR spectrum of 19 exhibited
10 signals due to absorptions of sp3 carbons which is
consistent with the structure with free hydroxy groups
at C1 and C5. The discrepancy in regioselectivity between
the Grignard reagent and the aluminum hydride reagent
in these ring opening reactions, however, remains un-
clear.
It is noteworthy that the reaction is both regio- and
diastereoselective. The regioselectivity of this reaction
is understandable owing to the presence of the 2-methoxy
group which will serve as an auxiliary to form a chelation
complex 12 with magnesium such that selective ring
opening is expected. We have tested this viewpoint by
investigating the related reaction of scyllo-inositol deriva-
tive 13 with MeMgI at room temperature. A diastereo-
meric mixture of 14 (2:1) was obtained in 56% yield. No
C
O bond cleavage at the ortho ester moiety in 13 was
observed. The methoxy group in 13 apparently directs
the selectivity of the ring opening reaction at the ben-
zylidene moiety. Interestingly, the reaction is nonste-
reoselective and is compatible with our earlier work on
the alkylative ring opening of acetals with the methyl
Grignard reagent.6
In summary, we have demonstrated a useful method
for the selective ring opening of ortho esters of myo-
inositol derivatives. The procedure described here can
serve as a convenient route for the synthesis of myo-
inositol derivatives having one hydroxy group at C-1 or
C-5, and two hydroxy groups at C-1,3 and at C-1,5. Other
derivatives could easily be accessed from these interme-
diates.
Acetal functionality are known to undergo chelation-
assisted regioselective ring opening reactions with Grig-
nard reagents.4d,e,6 The products shown in eqs 3 and 4
contain such acetal group. We felt that a one-pot process
may be developed such that a convenient synthesis of
inositol derivatives having two free hydroxy group at C-1
and C-3 positions can be achieved from 6 or 8. Accord-
ingly, treatments of 6 with 3 equiv of MeMgI and with
an excess amount of PhMgBr at refluxing benzene
temperature yielded the corresponding diols 15a and 15b
in 69% and 72% yields, respectively. Compound 8a
behaved similarly to give 15c in 60% yield (eq 5). 13C
NMR data (8 signals for 15a and 7 signals for 15b,c due
to the absorptions of sp3 carbons) for 15 are consistent
with a Cs symmetry.
Exp er im en ta l Section
exo-3,5-O-E t h ylid en e-2,4,6-t r i-O-m et h yl-m yo-in osit ol
(9a ). Compound 8a (3.58 g, 15.4 mmol) in benzene (50 mL)
was treated with MeMgI (15 mL in 2.05 M ether solution, 30.8
mmol). The mixture was heated at ca. 60 °C for 16 h, cooled,
(7) Yuan, T.-M.; Hsieh, Y.-T.; Yeh, S.-M.; Shyue, J .-J .; Luh, T.-Y.
Synlett 1996, 53.
(8) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(6) Yuan, T.-M.; Yeh, S.-M.; Hsieh, Y.-T.; Luh, T.-Y. J . Org. Chem.
1994, 59, 8192.

Chelation-Assisted C O Bond Cleavage of Ortho Esters
J . Org. Chem., Vol. 62, No. 24, 1997 8317
diluted with ether, and washed with saturated NH4Cl. The
organic layer was washed with brine and dried (MgSO4). The
solvent was removed in vacuo to give the residue which was
chromatographed (silica gel, 30% EtOAc/hexane) to afford
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 21.6, 57.5, 59.4, 63.9,
67.3, 69.4, 72.1, 73.0, 78.6, 90.6, 92.5, 126.1, 128.5, 129.5, 137.4;
HRMS Calcd for C17H22O6: 322.1416. Found: 322.1414. Anal.
Calcd C, 63.33%; H, 6.88%. Found: C, 63.22%; H, 6.85%.
3-O-Meth yl-5-O-(1′-p h en yleth yl)-2,4,6-O-m eth ylid yn e-
scyllo-in ositol (14). In a manner similar to that described
in 9a , 13 (51.7 mg, 0.18 mmol) in benzene (2 mL) was treated
with MeMgI (0.5 mL in 2 M ether solution, 1.0 mmol) at rt for
16 h to afford a mixture of inseparable diasteromers 14 (34.0
1
racemic 9a as an oil (3.15 g, 83%): IR (neat) ν 3503 cm 1; H
NMR (400 MHz, CDCl3) δ 1.20 (d, J
4.8 Hz, 3 H), 3.14 (d, J
5.6 Hz, 1 H), 3.33 (s, 3 H), 3.47 (s, 3 H), 3.49 (s, 3 H), 3.48
4.50 (m, 1 H), 3.73 (dt, J
1.2, 4.4 Hz, 1 H), 3.79 (dd, J
6.4,
7.8 Hz, 1 H), 4.15 4.20 (m, 2 H), 4.41 (ddd, J
2.0, 4.4, 6.4
Hz, 1 H), 5.22 (q, J 4.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 21.0, 56.8, 58.0, 58.6, 67.7, 67.9, 71.2, 73.8, 74.9, 84.5, 90.7;
HRMS Calcd for C11H20O6: 248.1260. Found: 248.1263.
exo-3,5-O-P r op ylid en e-2,4,6-t r i-O-m et h yl-m yo-in osi-
tol (9b). In a manner similar to that described above, 8a (0.49
g, 2.11 mmol) in benzene (20 mL) was treated with EtMgBr
(2.2 mL in 2.5 M ether solution, 5.50 mmol) at 65 °C for 16 h
1
mg, 56%, dr 2:1). The major isomer exhibited H NMR (300
MHz, CDCl3) at δ 1.42 (d, J 6.4 Hz, 3 H), 3.52 (s, 3 H), 4.07
4.57 (m, 6 H), 4.67 (q, J
6.4 Hz, 1 H), 5.40 (s, 1 H), 7.25
7.38 (m, 5 H). The minor isomer showed characteristic 1H
NMR absorptions at δ 1.43 (d, J
H).
6.4 Hz, 3H) and 3.47 (s, 3
5-O-Isop r op yl-2,4,6-tr i-O-ben zyl-m yo-in ositol (15a ). In
a manner similar to that described in 9a , 6 (0.14 g, 0.30 mmol)
in benzene (3 mL) was treated with MeMgI (0.45 mL in 2 M
to afford racemic 9b as an oil (0.38 g, 68%): IR (neat) ν 3511
1
cm 1; H NMR (200 MHz, CDCl3) δ 0.88 (t, J
7.5 Hz, 3 H),
1.51 (dq, J 5.0, 7.5 Hz, 2 H), 3.05 (br s, 1 H), 3.34 (s, 3 H),
ether solution, 0.90 mmol) under reflux for 16 h to afford 15a
1
(0.11 g, 69%): IR (neat) ν 3455 cm
;
1H NMR (400 MHz,
5.4 Hz, 2 H),
2.4, 5.6, 9.6 Hz, 2 H),
3.71 (dt, J
4.14 4.22 (m, 2 H), 4.45 (ddd, J
(t, J
56.8, 58.0, 58.5, 67.5, 68.1, 71.4, 73.9, 75.1, 84.5, 94.3; HRMS
Calcd for C10H17O6 (M 43): 233.1025. Found: 233.1028.
1.0, 4.2 Hz, 1 H), 3.82 (dd, J
6.5, 7.7 Hz, 1 H),
1.8, 4.2, 6.5 Hz, 1 H), 4.97
CDCl3) δ 1.23 (d, J
6.0 Hz, 6 H), 2.25 (d, J
5.0 Hz, 1 H); 13C NMR (50 MHz, CDCl3) δ 8.0, 27.9,
3.36 (t, J
3.68 (t, J
9.6 Hz, 1 H), 3.50 (ddd, J
9.6 Hz, 2 H), 3.96 (t, J
2.4 Hz, 1 H), 4.10 (sept,
J
9.6 Hz, 1 H), 4.74 (d, J
11.2 Hz, 2 H), 4.77 (s, 2 H), 4.93
exo-3,5-O-Ben zylid en e-2,4,6-t r i-O-m et h yl-m yo-in osi-
tol (9c). In a manner similar to that described above, 8a (1.51
g, 6.51 mmol) in benzene (30 mL) was treated with PhMgBr
(4.0 mL in 2.1 M ether solution, 8.4 mmol) at 65 °C for 16 h to
(d, J
11.2 Hz, 2 H), 7.28 7.40 (m, 15 H); 13C NMR (75 MHz,
CDCl3) δ 22.7, 72.6, 73.1, 75.2, 75.8, 78.8, 79.6, 82.3, 127.7,
127.8, 128.0, 128.4, 128.5, 138.5, 138.6; HRMS Calcd for
C30H36O6: 492.2512. Found: 492.2510.
afford racemic 9c as an oil (1.32 g, 68%): IR (neat) ν 3526
5-O-Ben zh yd r yl-2,4,6-tr i-O-ben zyl-m yo-in ositol (15b).
In a manner similar to that described in 9a , 6 (0.32 g, 0.70
mmol) in benzene (7 mL) was treated with PhMgBr (1.7 mL
1
cm 1; H NMR (400 MHz, CDCl3) δ 3.25 (d, J
6.4 Hz, 1 H),
6.4 Hz, 1 H), 3.90 4.01
3.40 (s, 3 H), 3.53 (s, 3 H), 3.69 (d, J
(m, 2 H), 4.26 4.31 (m, 1 H), 4.35 4.42 (m, 1 H), 4.62 (ddd, J
1.8, 4.4, 6.4 Hz, 1 H), 6.07 (s, 1 H), 7.31 7.38 (m, 3 H), 7.43
7.47 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 57.0, 58.1, 58.6,
68.1, 68.2, 71.9, 73.9, 75.0, 84.4, 93.3, 126.2, 128.3, 129.0, 138.1;
HRMS Calcd for C16H22O6: 310.1416. Found: 310.1421.
exo-1′-P h en yl-3,5-O-eth ylid en e-2,4,6-tr i-O-m eth yl-m yo-
in ositol (9d ). In a manner similar to that described above,
8b (0.47 g, 1.52 mmol) in benzene (15 mL) was treated with
MeMgI (8.8 mL in 2 M ether solution, 9.6 mmol) at 15 °C for
16 h to afford racemic 9d (0.28 g, 57%): mp 102 104 °C; IR
(neat) ν 3561 cm 1; 1H NMR (300 MHz, CDCl3) δ 1.73 (s, 3 H),
in 2 M ether solution, 3.40 mmol) and was refluxed for 16 h to
1
yield 15b (0.32 g, 72%): mp 115 117 °C; IR (neat) ν 3558 cm
;
1H NMR (300 MHz, CDCl3) δ 2.24 (d, J
5.3 Hz, 2 H), 3.48
9.2 Hz, 1 H), 3.83
2.8 Hz, 1 H), 4.73 (s, 4 H),
(ddd, J
(t, J
2.8, 5.3, 9.2 Hz, 2 H), 3.58 (t, J
9.2 Hz, 2 H), 3.94 (t, J
4.76 (s, 2 H), 6.13 (s, 1 H), 7.18 7.39 (m, 25 H); 13C NMR (75
MHz, CDCl3) δ 72.6, 75.2, 75.5, 78.3, 78.7, 82.4, 83.5, 127.3,
127.4, 127.8, 128.0, 128.1, 128.2, 128.5, 138.4, 142.6; HRMS
Calcd for C40H42O6: 618.2981. Found: 525.2232 (M
93).
Anal. Calcd C, 77.63%; H, 6.85%. Found: C, 77.54%, H,
6.51%.
5-O-Ben zh yd r yl-2,4,6-tr i-O-m eth yl-m yo-in ositol (15c).
In a manner similar to that described in 9a , 8a (0.36 g, 1.53
mmol) in benzene (15 mL) was treated with PhMgBr (3.1 mL
2.84 (d, J
(m, 1 H), 3.81 (dd, J
5.9, 9.0 Hz, 1 H), 4.45 4.52 (m, 1 H), 4.56 4.65 (m, 1 H), 4.73
9.0 Hz, 1 H), 3.43 (s, 3 H), 3.45 (s, 6 H), 3.66 3.71
1.5, 5.9 Hz, 1 H), 4.07 (ddd, J 2.7,
(br d, J
5.6 Hz, 1 H), 7.19 7.32 (m, 3 H), 7.47 7.51 (m, 2
in 2.0 M ether solution, 6.2 mmol) under reflux for 16 h to
H); 13C NMR (75 MHz, CDCl3) δ 33.6, 56.8, 57.6, 58.7, 68.1,
68.9, 70.7, 72.6, 74.9, 86.0, 98.9, 124.2, 127.7, 128.1, 146.0;
Anal. Calcd C, 62.95%; H, 7.46%. Found: C, 62.59%; H,
7.18%.
give 15c (0.24 g, 60%): mp 89 90 °C; IR (neat) ν 3420 cm
;
1
1H NMR (300 MHz, CDCl3) δ 2.39 (d, J
5.1 Hz, 2 H), 3.29
2.52 (m, 5 H), 3.48 (s, 6 H), 3.63 (s, 3 H), 3.67 (t, J
2.5 Hz,
1 H), 5.95 (s, 1 H), 7.18 7.39 (m, 10 H); 13C NMR (75 MHz,
CDCl3) δ 61.3, 61.7, 72.6, 78.4, 80.4, 83.8, 84.0, 127.3, 127.4,
128.1, 142.7; HRMS Calcd for C22H28O6: 388.1886. Found:
388.1885. Anal. Calcd C, 68.01%; H, 7.27%. Found: C,
67.74%; H, 7.15%.
en d o-4,6-O-Ben zylid en e-exo-3,5-eth ylid en e-2-O-m eth -
yl-m yo-in ositol (11a ). In a manner similar to that described
above, 10 (0.40 g, 1.37 mmol) in benzene (23 mL) was treated
with MeMgI (2.8 mL in 2 M ether solution, 5.6 mmol) at 55
°C for 16 h to afford racemic 11a (0.20 g, 47%): IR (neat) ν
1,3-O-Dia cetyl-5-O-ben zh yd r yl-2,4,6-tr i-O-m eth yl-m yo-
in ositol (16). A benzene solution (10 mL) of 15c (0.97 g, 2.49
mmol), Ac2O (0.58 mL), and pyridine (0.5 mL) was refluxed
for 5 h. The mixture was cooled, diluted with ether, and
washed with 10% HCl and saturated NaCl. The organic
solution was dried (MgSO4), filtered, and concentrated. The
residue was chromatographed (silica gel, 30% EtOAc/hexane)
to afford 16 (0.84 g, 71%): mp 135 137 °C; IR (neat) ν 1751
cm 1; 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 6H), 3.35 (s, 6 H),
1
3457 cm 1; H NMR (200 MHz, CDCl3) δ 1.26 (d, J
4.7 Hz,
4.9, 7.4 Hz, 1
7.4 Hz, 1 H), 4.52 4.59 (m, 2 H), 4.63 (dt, J
3H), 2.99 (br, 1 H), 3.54 (s, 3 H), 4.16 (dd, J
H), 4.44 (d, J
1.7, 5.2 Hz, 1 H), 4.81 4.90 (m, 1 H), 5.69 (q, J
4.7 Hz, 1
H), 6.04 (s, 1 H), 7.34 7.41 (m, 5 H); 13C NMR (50 MHz, CDCl3)
δ 21.4, 57.4, 64.2, 67.2, 67.7, 68.8, 72.9, 74.2, 90.9, 92.8, 126.2,
128.5, 129.4, 137.4.
en d o-4,6-O-Ben zylid en e-exo-3,5-et h ylid en e-1,2-d i-O-
m eth yl-m yo-in ositol (11b). To a mixture of 11a (0.19 g, 0.62
mmol) and solid KOH (0.14 g, 2.50 mmol) in DMSO (5 mL)
was added MeI (0.08 mL, 1.3 mmol) dropwise and the mixture
was stirred at rt overnight, poured into water, and extracted
with CH2Cl2. The organic layer was washed with water and
brine and dried (MgSO4). The solvent was removed in vacuo
to give the residue which was chromatographed (silica gel, 20
30% EtOAc/hexane) to give racemic 11b (0.19 g, 94%): mp
3.42 (t, J
9.0 Hz, 1 H), 3.47 (s, 3 H), 3.64 (dd, J
2.5 Hz, 1 H), 4.67 (dd, J
9.1, 10.1
Hz, 2 H), 3.71 (t, J
2.5, 10.1 Hz,
2 H), 5.94 (s, 1 H), 7.17 7.39 (m, 10 H); 13C NMR (75 MHz,
CDCl3) δ 20.9, 60.9, 61.3, 73.5, 78.0, 78.8, 81.1, 84.4, 127.2,
127.3, 128.0, 142.7, 169.9; HRMS Calcd for C26H32O8: 472.2097.
Found: 472.2109. Anal. Calcd C, 66.09%; H, 6.83%. Found:
C, 66.06%; H, 6.83%.
1,3-O-Dia cetyl-2,4,6-tr i-O-m eth yl-m yo-in ositol (17). A
methanolic solution (100 mL) of 16 (0.42 g, 0.89 mmol) in the
presence of Pd/C (5%, 83 mg) was treated with H2 at 1 atm
for 4 h. The mixture was filtered on Celite, and the filtrate
was evaporated in vacuo to give the residue which was
chromatographed (silica gel, 50% EtOAc/hexane) to afford 17
118 119 °C; 1H NMR (300 MHz, CDCl3) δ 1.25 (d, J
Hz, 3 H), 3.51 (s, 3 H), 3.58 (s, 3 H), 3.91 (d, J 7.5 Hz, 1 H),
4.25 (dd, J 4.7, 7.4 Hz, 1 H), 4.49 (t, J 4.7 Hz, 1 H), 4.52
2.0, 5.0 Hz, 1 H), 4.90 (br t, J 5.0
4.9 Hz, 1 H), 6.08 (s, 1 H), 7.34 7.39
4.9
4.59 (m, 1 H), 4.61 (td, J
Hz, 1 H), 5.85 (q, J

8318 J . Org. Chem., Vol. 62, No. 24, 1997
Yeh et al.
1
(0.23 g, 86%): mp 113 114 °C; IR (neat) ν 3561, 1746 cm
;
3 H), 3.40 (s, 3 H), 3.59 (t, J
2.4 Hz, 1 H); 13C NMR (100
1H NMR (300 MHz, CDCl3) δ 2.14 (s, 6 H), 2.65 (d, J
2.4
MHz, DMSO-d6) δ 57.9, 59.8, 59.9, 70.9, 73.9, 79.4, 81.4, 82.9,
83.5; HRMS Calcd for C10H20O6: 236.1260. Found: 236.1264.
3-O-Ben zyl-2,4,6-tr i-O-m eth yl-m yo-in ositol (19). Com-
pound 8b (1.14 g, 3.70 mmol) in CH2Cl2 (10 mL) was treated
with LiAlH4 (0.17 g) in the presence of a catalytic amount of
AlCl3 (ca. 50 mg) in Et2O (30 mL). The mixture was refluxed
for 16 h, diluted with ether, washed with saturated NaCl, dried
(MgSO4), filtered, and concentrated. The residue was chro-
matographed (silica gel, 30 50% EtOAc/hexane) to afford
Hz, 1 H), 3.40 3.56 (m, 4 H), 3.47 (s, 3 H), 3.54 (s, 3 H), 3.76
(t, J 2.8 Hz, 1 H), 4.75 (dd, J
2.4, 9.6 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ 21.0, 60.8, 61.6, 73.3, 74.2, 78.4, 80.2,
169.9; HRMS Calcd for C13H22O8: 306.1315. Found: 306.1317.
Anal. Calcd C, 50.96%; H, 7.24%. Found: C, 51.15%; H,
7.30%.
2,3,4,6-Tetr a -O-m eth yl-m yo-in ositol (18). To a mixture
of 9a (1.09 g, 4.40 mmol) and solid KOH (1.01 g, 18.0 mmol)
in DMSO (20 mL) was added MeI (0.7 mL, 11.2 mmol)
dropwise, and the mixture was stirred at rt overnight, poured
into water, and extracted with CH2Cl2. The organic layer was
washed with water and brine and dried (MgSO4). The solvent
was removed in vacuo to give the residue which was chro-
matographed (silica gel, 50% EtOAc/hexane) to give the
corresponding ether as an oil: 1H NMR (300 MHz, CDCl3) δ
racemic 19 (0.57 g, 49%): mp 124 125 °C; IR (neat) ν 3428
1
cm 1; H NMR (300 MHz, CDCl3) δ 2.46 (d, J
6.0 Hz, 1 H),
2.67 (br, 1 H), 3.26 3.39 (m, 4 H), 3.44 3.51 (m, 1 H), 3.63 (s,
3 H), 3.64 (s, 3 H), 3.65 (s, 3 H), 3.73 (t, J
2.3 Hz, 1 H), 4.67
(s, 2 H), 7.27 7.35 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 60.8,
61.4, 61.5, 72.1, 72.6, 74.6, 79.2, 80.7, 82.6, 82.8, 127.6, 127.8,
128.4, 138.0; HRMS Calcd for C16H24O6: 312.1573. Found:
312.1578. Anal. Calcd C, 61.52%; H, 7.74%. Found: C,
61.27%; H, 7.74%.
1.21 (d, J
4.8 Hz, 3 H), 3.35 (s, 3 H), 3.47 (s, 6 H), 3.49 (s, 3
H), 3.57 (d, J
6.9 Hz, 1 H), 3.70 3.74 (m, 1 H), 3.82 (t, J
7.5 Hz, 1 H), 3.93 (dd, J
3.5 Hz, 1 H), 4.46 (ddd, J
6.9, 7.5 Hz, 1 H), 4.16 (dd, J
1.8, 4.0, 6.3 Hz, 1 H), 5.19 (q, J
1.8,
Ack n ow led gm en t. This work was supported by the
National Science Council of the Republic of China.
4.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 20.7, 56.9, 57.8,
58.1, 58.6, 67.8, 71.9, 72.2, 75.0, 76.6, 82.5, 90.7; HRMS Calcd
for C12H22O6: 262.1416. Found: 262.1410.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
9a d , 11a , 11b, 15a c, and 16 19 and ORTEP of 9d and
11b (14 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
A mixture of the ether (0.32 g, 1.23 mmol) and TsOH (58
mg, 0.20 mmol) in MeOH (10 mL) was stirred at rt for 6 h
and then treated with solid K2CO3. After filtration, the filtrate
was concentrated, and the racemic 18 was crystallized from
the filtrate (0.24 g, 76%): mp 144 146 °C; IR (neat) ν 3451
cm 1; 1H NMR (400 MHz, D2O DMSO-d6) δ 2.95 3.11 (m, 4
H), 3.20 3.23 (dd, J
2.4, 9.6 Hz, 1 H), 3.29 (s, 3 H), 3.37 (s,
J O970606E