Establishment of the structure of pinpollitol by total synthesis of the proposed putative structures

Article abstract of DOI:10.1055/s-2005-863752

Proposed structures of pinpollitol, namely 1,4-di-O-methyl-chiro-inositol and 1,3-di-O-methyl-chiro-inositol, have been synthesized from myo-inositol. Racemic 1,4-di-O-methyl-chiro-inositol has been synthesized from the readily available 1,2:4,5-di-O-isop

Full text of DOI:10.1055/s-2005-863752

LETTER
769
Establishment of the Structure of Pinpollitol by Total Synthesis of the
Proposed Putative Structures
E
K
stablishment of th
a
e
Structure
n
of
P
inpollit
a
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Fax +81(89)9279944; E-mail: wyutaka@dpc.ehime-u.ac.jp; E-mail: sureshankm@yahoo.co.in
Received 2 January 2005
liriodendritol. Since demethylation of pinpollitol provid-
ed D-chiro-inositol, it was concluded that (+)-pinpollitol
is a dimethyl ether of D-chiro-inositol. Of the possible
Abstract: Proposed structures of pinpollitol, namely 1,4-di-O-
methyl-chiro-inositol and 1,3-di-O-methyl-chiro-inositol, have
been synthesized from myo-inositol. Racemic 1,4-di-O-methyl-
chiro-inositol has been synthesized from the readily available nine structures for the dimethyl ether of chiro-inositol,
1
1
,2:4,5-di-O-isopropylidene-myo-inositol, in five steps while DL- based on the lack of symmetry in the NMR spectrum and
,3-di-O-methyl-chiro-inositol from myo-inositol 1,3,5-ortho-
correlation of chemical shifts of both pinpollitol and its
formate in nine steps. A comparison of the reported NMR data of
pinpollitol with those of synthetic dimethyl ethers revealed that
pinpollitol is D-1,4-di-O-methyl-chiro-inositol. Thus we have not
only confirmed the structure of pinpollitol unambiguously but also
achieved a rapid total synthesis of it from a cheaply available
starting material, myo-inositol, in just six steps.
tetraacetyl derivative with similar type of compounds, the
authors have tentatively proposed two probable structures
for pinpollitol; 1D-1,4-di-O-methyl-chiro-inositol (1) and
1
D-1,3-di-O-methyl-chiro-inositol (2). We herein report
the establishment of the absolute structure of pinpollitol
by total syntheses of both 1 and 2 (Figure 1).
Key words: natural product, total synthesis, inositol, cyclitol,
regioselectivity
Myo-inositol (3) was chosen as the synthon for the synthe-
sis of 1 and 2 for the following reasons: (a) myo-inositol
is inexpensive starting material compared to the chiro-
A great deal of attention has been paid to the inositol inositol; (b) since the selective protection–deprotection
4
chemistry since many of the family members are proved strategies for myo-inositol is well explored, access to the
1
to possess interesting biological significance. Of the nine required hydroxyl group(s) can be easily achieved by
possible isomers, myo-, D-chiro-, L-chiro-, scyllo-, neo- adopting the known methodologies; (c) since pinpollitol is
and muco-inositols are naturally occurring, myo-inositol a derivative of D-chiro-inositol, determination of relative
being the abundant. In animals these inositols occur in the position of two methyl ethers on racemic chiro-inositol
phosphorylated form while in plants they occur in phos- skeleton is sufficient enough to establish the absolute
phorylated, methylated or in free forms. One or more me- structure of pinpollitol.
thyl ethers of each of these naturally occurring inositols
For the synthesis of 1 from 3, inversion of configuration
have been isolated from plants. Most of these methyl
at C-3 and methylation of 3-OH and 6-OH are the essen-
2
ethers have been synthesized owing to the impractical
tial steps required. Inversion can be achieved by substitu-
isolation of these natural products.
tion of a sulfonate moiety with an oxygen nucleophile.
Since no manipulation is required at 1-, 2-, 4- and 5-posi-
OH
6
OH
6
OH
2
tions of myo-inositol, readily available 1,2:4,5-di-O-iso-
5
HO
OMe HO
OH HO
OMe HO
OH HO
OH
OH
propylidene-myo-inositol (4) was chosen as the ideally
5
4
1
1
2
5
4
3
4
1
6
protected starting material (Scheme 1). Use of diketal 4 as
2
synthon allows syntheses of optically active derivatives as
3
3
5
MeO
6
efficient methods are known for the optical resolution of
OH
OMe
2
OH
3
this diol. Enhanced reactivity of 3-OH in 4 towards elec-
trophilic reagents is an additional advantage for selective
introduction of a sulfonate group (for subsequent inver-
1
Figure 1
4
sion) at this position. It has been reported that 3-OH of
diol 4 is more reactive than 6-OH towards acylation,
alkylation, sulfonylation, etc. Regioselective sulfonyl-
ation of racemic diol 4 with 1.1 equivalents of triflic an-
hydride provided the monotriflate 5 (90%) as expected
with minor amounts of ditriflate, which could be removed
by washing with hexane. Nucleophilic substitution of
triflate 5 with KOAc in N,N-dimethylacetamide (DMA)
gave the racemic 1-O-acetyl-2,3:5,6-di-O-isopropyl-
idene-chiro-inositol (6) in quantitative yield. The most
downfield signal appeared as a triplet with a coupling
(
+)-Pinpollitol, a dimethyl ether of chiro-inositol was iso-
lated from the pollen and needles of the plant Pinus radi-
ata by Gallagher. (+)-Pinpollitol is the first di-O-methyl
inositol to be found in a gymnosperm and is the third di-
O-methyl inositols found in nature after dambonitol and
3
SYNLETT 2005, No. 5, pp 0769–0772
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863752; Art ID: U00105ST
2
1.
0
3.
2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

7
70
K. M. Sureshan et al.
LETTER
constant of 2.4 Hz confirming the chiro-configuration (ae termediates for the synthesis of 2. Access to 1-, 3- and 5-
and ee coupling). Later, this structural assignment was hydroxyl groups of myo-inositol can be achieved by tem-
confirmed by solving the single crystal X-ray structure of porary protection of these hydroxyls as orthoester fol-
7
(
–)-6 (Figure 2). No product with retention of configura- lowed by protection of 2-, 4- and 6-hydroxyl groups and
tion has been identified. The acetate 6 on methanolysis acid hydrolysis of the orthoester functionality. Also it is
provided the racemic 1,2:4,5-di-O-isopropylidene-chiro- known that 1- and 3-hydroxyl groups are more reactive
inositol (7) in 94% yield. Diol 7 on methylation provided than 5-OH. Hence initial protection of one of the two
(
±)-1,2:4,5-di-O-isopropylidene-3,6-di-O-methyl-chiro- equivalent hydroxyl groups (1-OH or 3-OH) provides
8
inositol (8) in good (99%) yield. The isopropylidene 1(3),5-diol. It is known that 1(3)-OH is relatively more re-
groups were removed by acid hydrolysis to provide (±)- active than 5-OH towards various electrophilic reagents.
9
1
,4-di-O-methyl-chiro-inositol (1, 73%), which was Since an inversion is inevitable at C-3 before methylation,
1
0
acetylated to get the tetraacetate 9 (93%).
3-OH can be sulfonylated selectively and inverted by SN2
substitution to have access to 1,3-diol with chiro-inositol
configuration.
Myo-inositol 1,3,5-orthoformate11 was converted to the
fully protected tribenzyl ether 10. Acid hydrolysis of 10
provided the meso triol 11. Regioselective benzylation of
O
O
O
OTf
O
O
OH
O
b
a
1
2
triol 11 gave the known tetrabenzyl ether 12. In triol 11,
-OH and 3-OH are identical due to the symmetry of the
HO
HO
1
O
5
molecule. Benzylation at 1(3)-OH give a dissymmetric
molecule while benzylation at 5-OH give another meso-
compound. Thus, the position of benzylation can easily be
understood based on the presence or lack of symmetry in
the NMR spectrum. Between the two hydroxyl groups of
O
4
OR
OR
O
OR1
RO
OMe
OR
O
1
2, the more reactive 3-OH was sulfonylated with triflic
anhydride to provide the triflate 13 (81%). The most
deshielded proton appeared as a dd with coupling con-
stants 7.6 and 2.0 Hz, which confirm the triflylation at O-
2
MeO
R O
O
O
3
. Also the remaining hydroxyl group showed coupling
R1 = Ac; R = H
R1 = R2 = H
R1 = R2 = Me
2
1 R = H
9 R = Ac
(J = 2.4 Hz) with H-5. The triflate 13 was acetylated to
give the monoacetate 14 (98%). The triflate 14 on nucleo-
philic substitution with KOAc in DMA provided racemic
6
7
8
c
e
f
d
1
3
,2,3,5-tetra-O-benzyl-4,6-di-O-acetyl-chiro-inositol (15,
0%) as a gum along with an unidentified product.
Scheme 1 (a) Tf O (1.1 equiv), pyridine, CH Cl , –20 °C; (b)
2
2
2
13
KOAc, DMA, 70 °C; (c) NaOMe, MeOH, reflux; (d) MeI, NaH,
DMF, r.t.; (e) TFA, H O, r.t.; (f) Ac O, pyridine, r.t.
Methanolysis of the diacetate 15 provided the diol 16 in
2
2
8
3% yield. Diol 16 on methylation formed the dimethyl
ether 17 (63%) as expected. Finally, the hydrogenolysis
of the benzyl ether moieties provided racemic 1,3-di-O-
1
4
methyl-chiro-inositol (2, 89%), which was acetylated to
15
the tetraacetate 18 in 93% yield (Scheme 2).
1
A comparison of H NMR of pinpollitol and its tetraace-
tate with that of dimethyl ethers (1 and 2) and their tetra-
acetates (9 and 18) revealed that pinpollitol is 1,4-di-O-
methyl-chiro-inositol. Since pinpollitol is known to be a
dimethyl ether of D-chiro-inositol, the absolute configura-
tion of pinpollitol is 1D-1,4-di-O-methyl-chiro-inositol.
In conclusion, we have reported efficient routes for the
syntheses of proposed structures of pinpollitol. This has
established the structure of pinpollitol unambiguously.
We hope the chemistry explored here will be of interest to
a wider cross section of organic chemists as inositol and
other cyclitols are increasingly being used as synthons for
Figure 2 ORTEP diagram of 6.
16
17
many natural products, metal complexing agents, gela-
For the synthesis of 2 from myo-inositol (3), inversion at
C-3 and methylation at 3-OH and 5-OH groups are the im-
portant steps to be considered. Since diketal derivatives of
myo-inositols have protected 5-OH, they are not ideal in-
tors,18 catalysts, supramolecular assemblies, chiral
auxiliary, etc.
19
20
2
1
Synlett 2005, No. 5, 769–772 © Thieme Stuttgart · New York

LETTER
Establishment of the Structure of Pinpollitol
771
OBn
OH
OBn
O
O
O
HO
OH
BnO
BnO
OH
a,b
c
BnO
d
3
BnO
OBn
BnO
OBn
OBn
OH
12
10
11
OBn
OBn
OR
BnO
OTf
BnO
BnO
OR
RO
RO
OMe
OR
j
e
g
BnO
f
OBn
OBn
OR
OR
OMe
1
1
1
5 R = Ac
6 R = H
7 R = Me
2 R = H
18 R = Ac
1
1
3 R = H
h
i
f
4 R = Ac
Scheme 2 (a) CH(OEt) , pTSA, DMF, 100 °C, 2 h; (b) BnBr, NaH, DMF, r.t.; (c) 1 M HCl, MeOH, reflux, 1 h; (d) BnBr, NaH, DMF, r.t.,
3
1
0 min; (e) Tf O, pyridine, 0 °C; (f) Ac O, pyridine, 0 °C; (g) KOAc, DMA, 70 °C; (h) Et N, MeOH, reflux, 1 h; (i) MeI, NaH, DMF, 0 °C;
2
2
3
(
j) Pd/C, H , MeOH, EtOAc, r.t.
2
Acknowledgment
(CH
3
), 27.10 (CH ), 27.80 (CH ), 58.50 (OCH ), 60.00
3 3 3
(
OCH ), 74.70, 74.73, 77.26, 78.01, 80.64 (C-3 or C-6),
3
We thank JSPS for a postdoctoral fellowship (KMS) and Grant-in-
aid (No. 02170). Also we thank Venture Business Laboratory and
Advanced Instrumentation Center for Chemical Analysis, Ehime
University for NMR and elemental analysis, respectively.
84.78 (C-6 or C-3), 109.24 (O-C-O), 111.34 (O-C-O).
1
(
9) Analytical data: mp 189–192 °C. H NMR (400 MHz, D O):
2
d = 3.33 (t, 1 H, J = 9.6 Hz, H-4), 3.43 (s, 3 H, CH ), 3.60 (t,
3
1
H, J = 9.6 Hz, H-3), 3.60 (s, 3 H, CH ), 3.64 (t, 1 H, J = 3.6
3
Hz, H-1), 3.74 (dd, 1 H, J = 9.6, 3.6 Hz, H-5), 3.81 (dd, 1 H,
1
3
J = 10.0, 3.6 Hz, H-2), 4.22 (t, 1 H, J = 3.6 Hz, H-6). ( C
References
NMR (100.4 MHz, D O, dioxane reference at 66.5 ppm):
2
d = 58.5, 59.6, 68.0, 69.8, 70.2, 72.3, 81.2, 82.5. Anal. Calcd
(
1) (a) Hinchliffe, K.; Irvine, R. Nature 1997, 390, 123.
b) Phosphoinositides: Chemistry, Biochemistry and
for C H O (%): C, 46.15; H, 7.75. Found: C, 46.09; H,
(
8
16
6
7
.59.
Biomedical Applications; Bruzik, K. S., Ed.; ACS
Symposium Series 718, Oxford University Press: Oxford,
1
(
10) Analytical data: H NMR (400 MHz, CDCl ): d = 2.06 (s, 3
3
H, COCH ), 2.08 (s, 6 H, 2 × COCH ), 2.13 (s, 3 H, COCH ),
1999. (c) Ferguson, M. A. J.; Williams, A. F. Annu. Rev.
3
3
3
3
.44 (s, 3 H, O-CH ), 3.50 (s, 3 H, O-CH ), 3.62 (t, 1 H, J =
Biochem. 1988, 57, 285.
3
3
10.3 Hz, H-4), 3.64 (t, 1 H, J = 3.4 Hz, H-1), 5.14 (dd, 1 H,
(
2) Pinitol: (a) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T.
J. Am. Chem. Soc. 1990, 112, 9439. (b) Ley, S. V.;
Sternfeld, F.; Taylor, S. Tetrahedron Lett. 1987, 28, 225.
J = 10.3, 3.4 Hz, H-2), 5.21 (dd, 1 H, J = 10.3, 3.4 Hz, H-5),
5
.43 (t, 1 H, J = 10.3 Hz, H-3), 5.51 (t, 1 H, J = 3.4 Hz, H-
1
3
6). C NMR (100.4 MHz, CDCl ): d = 20.8 (COCH ), 59.4
(
(
c) Ley, S. V.; Sternfeld, F. Tetrahedron 1989, 45, 3463.
d) Jung, P. M. J.; Motherwell, W. B.; Williams, A. S. Chem.
3
3
(
(
(
O-CH ), 59.8 (O-CH ), 67.6, 70.5, 71.1, 76.6, 78.5, 169.5
3 3
O-COCH ), 169.6 (O-COCH ), 169.8 (O-COCH ), 170.3
Commun. 1997, 1283. Ononitol: (e) Pietrusiewicz, K. M.;
Salamonczyk, G. M. Synth. Commun. 1995, 25, 1863.
Quebrachitol: (f) Carless, H. A. J.; Busia, K.; Oak, O. Z.
Synlett 1993, 672.
3
3
3
O-COCH3).
(
(
11) Lee, H. W.; Kishi, Y. J. Org. Chem. 1985, 69, 4402.
12) Westerduin, P.; Willems, H. A. M.; van Boeckel, C. A. A.
Tetrahedron Lett. 1990, 31, 6915.
(
(
3) Gallagher, R. T. Phytochemistry 1975, 14, 755.
4) Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Das, T.
Chem. Rev. 2003, 103, 4477.
1
(
13) Analytical data: H NMR (400 MHz, CDCl ): d = 1.93 (s, 3
3
H, COCH ), 2.01 (s, 3 H, COCH ), 3.71 (t, 1 H, J = 3.9 Hz,
3
3
H-1), 3.74–3.80 (2 × dd, 2 H, H-2 and H-5), 3.88 (t, 1 H, J =
(
(
(
5) Diketal 4 can be synthesized from myo-inositol in one step.
See: Gigg, J.; Gigg, R.; Payne, S.; Conant, R. Carbohydr.
Res. 1985, 142, 132.
9
.8 Hz, H-3), 4.31–4.89 (m, 8 H, 4 × CH ), 5.31 (t, 1 H, J =
2
9
.8 Hz, H-4), 5.35 (t, 1 H, J = 3.9 Hz, H-6), 7.20–7.40 (m, 20
1
3
H, Ph). C NMR (100.4 MHz, CDCl ): d = 20.90 (COCH ),
6) Sureshan, K. M.; Yamasaki, T.; Hayashi, M.; Watanabe, Y.
Tetrahedron: Asymmetry 2003, 14, 1771; and references
cited therein.
3
3
2
7
1
1
0.95 (COCH ), 67.3, 71.9, 73.1, 73.3, 73.6, 74.6, 74.7, 75.5,
7.2, 79.4, 79.4, 127.5, 127.6, 127.7, 127.8, 127.83, 127.9,
27.90, 127.92, 128.3, 128.4, 128.43, 137.8, 137.9, 138.1,
3
7) Crystallographic data are deposited as CCDC 236206. These
data can be obtained free of charge via
38.6, 169.8 (OCOCH ), 170.02 (OCOCH ). Anal. Calcd
3
3
for C H O ·0.5H O (%): C, 72.02; H, 6.52. Found C,
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
38 40
8
2
7
2.01; H, 6.89.
1
(
14) Analytical data: H NMR (400 MHz, D O): d = 3.28 (t, 1 H,
(
1223)336033, e-mail: deposit@ccdc.cam.ac.uk].
2
1
J = 9.4 Hz, H-3), 3.48 (s, 3 H, OCH ), 3.60 (s, 3 H, OCH ),
(
8) Analytical data: H NMR (400 MHz, CDCl ): d = 1.35 (s, 3
3
3
3
3
3
3
.63 (t, 1 H, J = 9.6 Hz, H-4), 3.64 (t, 1 H, J = 3.6 Hz, H-1),
H, CH ), 1.48 (s, 6 H, 2 × CH ), 1.50 (s, 3 H, CH ), 3.44 (dd,
3
3
3
.69 (dd, 1 H, J = 9.6, 3.6 Hz, H-5), 3.86 (dd, 1 H, J = 10.2,
1
3
H, J = 10.3, 5.9 Hz, H-3), 3.560 (s, 3 H, OCH ), 3.564 (s,
3
1
3
.6 Hz, H-2), 4.22 (t, 1 H, J = 3.6 Hz, H-6). C NMR (100.4
H, OCH ), 3.79 (dd, 1 H, J = 10.3, 2.4 Hz, H-5), 3.96 (t, 1
3
MHz, D O, dioxane reference at 66.5 ppm): d = 58.5, 59.8,
H, J = 10.3 Hz, H-4), 4.02 (t, 1 H, J = 2.4, 2.0 Hz, H-6), 4.14
2
6
7.8, 70.6, 71.9, 81.5, 83.0. Anal. Calcd for C H O ·1.4H O
(
1
t, 1 H, J = 5.9 Hz, H-2), 4.30 (dd, 1 H, J = 5.9, 2.0 Hz, H-
8 16 6 2
13
(%): C, 41.16; H, 8.12. Found: C, 41.08; H, 7.86.
). C NMR (100.4 MHz, CDCl ): d = 25.60 (CH ), 26.50
3
3
Synlett 2005, No. 5, 769–772 © Thieme Stuttgart · New York

7
72
K. M. Sureshan et al.
LETTER
1
(
15) Analytical data: H NMR (400 MHz, CDCl ): d = 1.99 (s, 3
(17) Sureshan, K. M.; Shashidhar, M. S.; Varma, A. J. J. Org.
Chem. 2002, 67, 6884; and references cited therein.
(18) (a) Hosoda, A.; Miyake, Y.; Nomura, E.; Taniguchi, H.
Chem. Lett. 2003, 32, 1042. (b) Watanabe, Y.; Miyasou, T.;
Hayashi, M. Org. Lett. 2004, 6, 1547. (c) Sureshan, K. M.;
Yamaguchi, K.; Sei, Y.; Watanabe, Y. Eur. J. Org. Chem.
2004, 4703.
3
H, COCH ), 2.08 (s, 3 H, COCH ), 2.14 (s, 6 H, 2 × COCH ),
.47 (s, 3 H, OCH ), 3.49 (s, 3 H, OCH ), 3.68 (t, 1 H, J =
.4 Hz, H-1), 3.68 (t, 1 H, J = 9.8 Hz, H-3), 5.12 (dd, 1 H,
J = 10.3, 2.9 Hz, H-2), 5.20 (dd, 1 H, J = 10.3, 3.4 Hz, H-5),
.34 (t, 1 H, J = 9.8 Hz, H-4), 5.49 (t, 1 H, J = 3.9 Hz, H-6).
C NMR (100.4 MHz, CDCl ): d = 20.65 (COCH ), 20.82
3
3
3
3
3
3
3
5
13
3
3
(
COCH ), 20.86 (COCH ), 21.02 (COCH ), 59.32 (OCH ),
(19) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.;
Yamaguchi, K. Chem. Commun. 2003, 1734.
(20) Sureshan, K. M.; Gonnade, R. G.; Shashidhar, M. S.;
Puranik, V. G.; Bhadbhade, M. M. Chem. Commun. 2001,
881.
(21) (a) Akiyama, T.; Nishimoto, H.; Ishikawa, K.; Ozaki, S.
Chem. Lett. 1992, 447. (b) Akiyama, T.; Horiguchi, N.; Ida,
T.; Ozaki, S. Chem. Lett. 1995, 975.
3
3
3
3
6
1
1
0.57 (OCH ), 67.24, 69.23, 71.26, 72.62, 76.55, 78.66,
3
69.73 (OCOCH ), 169.75 (OCOCH ), 170.04 (OCOCH ),
3
3
3
70.11 (OCOCH ). Anal. Calcd for C H O (%): C, 48.73;
3
16 26 11
H, 6.65. Found: C, 48.46; H, 6.30.
16) (a) Kwon, Y.-K.; Lee, C.; Chung, S.-K. J. Org. Chem. 2002,
7, 3327. (b) Suzuki, T.; Suzuki, S. T.; Yamada, I.; Koashi,
Y.; Yamada, K.; Chida, N. J. Org. Chem. 2002, 67, 2874.
c) Chida, N.; Ogawa, S. Chem. Commun. 1997, 807; and
(
6
(
references cited therein. (d)Suzuki, T.; Tanaka, S.; Yamada,
I.; Koashi, Y.; Yamada, K.; Chida, N. Org. Lett. 2000, 2,
1137. (e) Chida, N.; Yoshinaga, M.; Tobe, T.; Ogawa, S.
Chem. Commun. 1997, 1043. (f) Akiyama, T.; Ohnari, M.;
Shima, H.; Ozaki, S. Synlett 1991, 831.
Synlett 2005, No. 5, 769–772 © Thieme Stuttgart · New York