Intramolecular aldol cyclization of L-lyxo-hexos-5-ulose derivatives: A new diastereoselective synthesis of D-chiro-inositol

Article abstract of DOI:10.1016/S0960-894X(02)00692-3

The DBU-promoted intramolecular aldol condensation of two partially protected L-lyxo-hexos-5-ulose derivatives (8 and 9), in turn obtained starting from methyl β-D-galactopyranoside, takes place with fairly good yield and complete diastereoselectivity to

Full text of DOI:10.1016/S0960-894X(02)00692-3

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3313–3315
Intramolecular Aldol Cyclization of L-lyxo-Hexos-5-ulose
Derivatives: A New Diastereoselective Synthesis of
D-chiro-Inositoly
Giorgio Catelani,a,* Antonino Corsaro,b Felicia D’Andrea,a Manuela Mariania
and Venerando Pistarab
a
`
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita degli Studi di Pisa, Via Bonanno, 33, I-56126 Pisa, Italy
b
`
Dipartimento di Scienze Chimiche, Universita degli Studi di Catania, Viale A. Doria, I-95125 Catania, Italy
Received 10 May 2002; revised 6 August 2002; accepted 14 August 2002
Dedicated to the memory of Professor Serena Catalano
Abstract—The DBU-promoted intramolecular aldol condensation of two partially protected l-lyxo-hexos-5-ulose derivatives (8
and 9), in turn obtained starting from methyl b-d-galactopyranoside, takes place with fairly good yield and complete diastereo-
selectivity to give 2l-(2,3,6/4,5)-pentahydroxycyclohexanone derivatives, 10 and 11. The stereoselective reduction of inosose 10 with
sodium triacetoxyborohydride leads, after catalytic debenzylation, to d-chiro-inositol (1), while the sodium borohydride reduction
furnishes, with opposite stereoselectivity, a derivative of allo-inositol.
# 2002 Elsevier Science Ltd. All rights reserved.
d-chiro- (1) and l-chiro-inositol, the sole couple of
optically active members of the inositol family, have
attracted a great deal of attention because of their bio-
logical interest.1 The potentiality of d-chiro-inositol (1)
in the treatment of polycystic ovary syndrome2 has been
recognized. 1l-chiro-Inositol 2,3,5-triphosphate was
postulated to act as an inhibitor of the enzymes
involved on the 1d-myo-inositol 1,4,5-triphosphate
metabolism.3
Although d-chiro-inositol (1) is available from natural
sources as the antibiotic kasugamycin4 or the 4-O-
methyl ether, (+)-pinitol, a component of the sugar
pine extracts,5 several chemical or chemo-enzymatic
synthetic efforts have been made, using, with different
efficiency, a broad range of starting materials. The most
exploited synthetic ways include: (a) the stereoselective
epimerization of readily available myo-inositol,6 (b) the
Ferrier-II reaction of hex-5-enopyranosides,7 (c) the
Scheme 1.
yPart 16 of the series: Chemical Valorization of Milk-Derived Sugars. This series title replaces the previous one: Rare and Complex Saccharides from
d-Galactose and Other Milk-Derived Sugars. For part 15, see ref 21.
*Corresponding author. Tel.: +39-050-44074; fax: +39-050-43321; e-mail: giocate@farm.unipi.it
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00692-3

3314
G. Catelani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3313–3315
enantio- and regioselective functionalization of cyclo-
hexene8 or halobenzenes.9 In this context, we have been
attracted by the routes involving as the final step a dia-
stereoselective hydride reduction of an appropriately
protected b-hydroxyinosose,7a,9 owing to our recent
findings on the highly diastereoselective preparation of
such types of intermediates through a base-promoted
intramolecular aldol cyclization of hexos-5-ulose deriv-
atives.10 We have, thus, developed the idea retro-
synthetically depicted in Scheme 1, that, starting from
methyl b-d-galactopyranoside (4) provides the prepara-
tion of l-lyxo-hexos-5-ulose derivatives 3,11 their intra-
molecular aldol condensation to inososes 2 and, finally,
their stereoselective reduction followed by deprotection
to 1.
course of the intramolecular aldol condensation of 8
and 9 is identical to that we previously found for the
same reaction of 2,6-di-O-benzyl-l-arabino-hexos-5-
ulose,10 the two new stereogenic centres being formed in
a cis orientation each other and trans with respect to the
substituent of the contiguous stereocentre (C-2of the
parent dicarbonyl precursor).
The treatment of inosose 10 with NaBH4 in EtOH at
ꢁ78 ꢀC gave with good yields (78%) a crude product
constituted by a main component, which, after catalytic
debenzylation [H2–Pd(C)/MeOH] and subsequent
acetylation (Ac2O/Py), led to the previously reported16
hexa-O-acetyl allo-inositol (13). The high stereo-
selectivity of this reaction, close to that previously
found10 for the same reaction of the C-5 epimeric ino-
sose, is in accordance with the prevalence of the steric
effects in the reductions with NaBH4, the hydride attack
being inferred from the a face, anti to the substituents at
the two contigous carbons.
The starting material of our synthesis (Scheme 2) was
the 1,5-bis-methyl glycoside 5,12 masked form of 2,6-di-
O-benzyl-l-arabino-hexos-5-ulose recently10 used for
the diastereoselective preparation of epi-inositol. The
preparation of two hexos-5-uloses of the l-lyxo series,
811 and 9 was achieved by acid hydrolysis of the bis-
glycosides 6 and 7, respectively, in turn obtained by
epimerization through a sequence of oxidation and
stereoselective reduction13 of the 4-O-acetate or the 4-O-
benzyl ether of 5.14 The treatment of crude 8 and 9 with
a catalytic amount of DBU in toluene–CH2Cl2 at 0 ꢀC
gave with high diastereoselectivity the b-hydroxy-
inososes 10 and 11, obtained pure15 through flash chro-
matography with 67 and 58% isolated yield over two
steps from 6 and 7, respectively. Furthermore, their
structure was confirmed by transformation into the
known inosose 12,9 through catalytic debenzylation
[H2–Pd(C)/MeOH]. Interestingly, the stereochemical
The stereochemical course of the inosose reductions
could be, however, inverted using reagents able to give
intramolecular hydride delivery,17 taking advantage
from the presence of a free b-hydroxy substituent.
Although in our case the presence of two free b-hydroxy
groups having an opposite relative orientation (OH-3
and OH-5) could not ensure a firm prevision of the
steric course of the reaction, 10 was treated with NaB-
H(OAc)3 under standard conditions,7a,17 (room temp,
CH3CN and AcOH). A smooth reduction took place
giving, after 45 min, a crude product (about 95%)
containing a sole di-O-benzyl inositol, which was sub-
jected to catalytic debenzylation [H2–Pd(C)/MeOH,
Scheme 2. Reagents and conditions: (1) (a) BnBr–NaH/DMF; (b) TPAP–NMO/CH2Cl2; (c) NaBH4/MeOH; (ii) CF3COOH–H2O/CH3CN; (iii)
DBU/C6H5CH3–CH2Cl2; (iv) (a) NaBH(OAc)3–AcOH/CH3CN; (b) H2–Pd(C)/MeOH; (v) (a) NaBH4/EtOH; (b) H2–Pd(C)/MeOH; (c) Ac2O/Py.

G. Catelani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3313–3315
3315
Scheme 3.
90%] to give the known,4ꢁ9 completely deprotected
d-chiro-inositol (1).
4. Umezawa, H.; Okami, Y.; Hashimoto, T.; Suhara, Y.;
Hamada, M.; Takeuchi, T. J. Antibiot. (Tokyo) Ser. A 1965,
18, 101.
5. Anderson, A. B. Ind. Eng. Chem. 1953, 593.
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K.; Ito, N.; Takita, T.; Takeuchi, T.; Miyake, T. Tetrahedron
Lett. 2001, 42, 1053. (b) Chung, S.-K.; Kwon, Y.-U. Bioorg.
Med. Chem. Lett. 1999, 9, 2135. (c) Berlin, W. K.; Zhang,
W.-S.; Shen, T. Y. Tetrahedron 1991, 47, 1.
7. (a) Takahashi, H.; Kittaka, H.; Ikegami, S. J. Org. Chem.
2001, 66, 2705. (b) Jaramillo, C.; Chiara, J.-L.; Martin-Lomas,
M. J. Org. Chem. 1994, 59, 3135.
8. Kim, K. S.; Park, J. I.; Moon, H. K.; Yi, H. Chem. Com-
mun. 1998, 1945.
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1 1993, 741. (b) Mandel, M.; Hudlicky, T. J. Org. Chem. 1993,
58, 2331.
10. Pistara, V.; Barili, P. L.; Catelani, G.; Corsaro, A.;
D’Andrea, F.; Fisichella, S. Tetrahedron Lett. 2000, 41, 3253.
11. Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.; De
Rensis, F.; Goracci, G. J. Carbohydr. Chem. 1998, 17, 1167.
12. Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F. Gazz.
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13. The stereoselectivity of the reductions of the 3-ulose
intermediates was very high, if not complete. A discussion of
this point will be given in the full paper.
14. The 4-O-acetate of 5 was obtained, as previously reported,11
by acid hydrolysis (aq AcOH) of orthoester intermediates,
while the 4-O-benzyl ether was formed in high yield (80%) by
direct benzylation of 5 with 1 equiv of benzyl bromide either
with NaH–DMF or KOH/18-crown-6/THF.
A tentative explanation of this satisfactory result could
take in account the conformational features of inosose 10.
A high preference of the conformation 10A (Scheme 3)
could be anticipated on the basis of the presence of an
unfavourable 1,3-syn-diaxial interaction between a ben-
zyloxy and a hydroxy group in the alternative conforma-
tion 10B. Furthermore, NMR18 analysis confirms this
hypothesis, as evidenced by the presence of a long-range
coupling between the two a hydrogens (J2,6=1.4 Hz)
which, owing to the high vicinal coupling constant of one
of them (J5,6=9.9 Hz), may necessarily be both axially
oriented, as it is in the conformation 10A. The internal
hydride transfer involves, thus, an intermediate having a
b-alkoxydiacetoxyborohydride group axially oriented in
position 3 and, for these reasons, it is directed on the b
face, leading to the observed diastereoselectivity.
A final point of interest arising from our approach is the
possible extension of the same intramolecular carbacy-
clization-stereoselective reduction sequence to hexos-5-
uloses of the d-lyxo series available from recent litera-
ture reports,19,20 opening the way to an effective syn-
thesis of biologically relevant l-chiro-inositol. Our next
synthetic efforts will be directed in this direction.
15. All new compounds have been fully characterized with
satisfactory elemental analyses and through analysis of routine
mono- and bi-dimensional NMR spectra.
Acknowledgements
16. Motherwell, W. B.; Williams, A. S. Angew. Chem. I.E.E.
1995, 34, 2031.
17. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3560.
18. 2,4-Di-O-benzyl-2l-(2,3,6/4,5)-pentahydroxycyclohexanone
(10): mp 89–91 ꢀC (EtOAc–hexane); [a]2D5=+ 15.1 (c 0.96,
CHCl3); selected NMR data (CD3CN): dH (200 MHz): 4.42
(dd, 1H, J2,3=3.4 Hz, H-2), 4.30 (dd, 1H, J3,4=4.0 Hz, H-3),
4.29 (dd, 1H, J5,6=9.9 Hz, J2,6=1.4 Hz, H-6), 3.90 (dd, 1H,
J4,5=3.3 Hz, H-4), 3.78 (dd, 1H, H-5); dC (50 MHz): 206.39
(C-1), 80.91 (C-2), 79.64 (C-4), 77.60 (C-6), 75.46 (C-5), 71.56
(C-3).
This work was performed with funds provided by Con-
sorzio Interuniversitario Nazionale ‘La Chimica per
l’Ambiente’ within the project ‘Ambiente Terrestre: Chi-
mica per l’Ambiente’ financed by M.U.R.S.T. in accor-
dance with Law no. 488/92. Partial support to G.C. from
University of Pisa and M.U.R.S.T. is also acknowledged.
References and Notes
1. Berridge, M. J. Nature 1989, 341, 197. Billington, D. C. The
Inositols Phosphates—Chemical Synthesis and Biological
Significance; VCH: Weinheim, 1993.
19. Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni, L.
Tetrahedron Lett. 1998, 39, 2021.
2. Nestler, J. E.; Jakubowicz, D. J.; Reamer, P.; Gunn, R. D.;
Allan, G. J. N. Engl. J. Med. 1999, 340, 1314.
3. Liu, C.; Nahorski, S. R.; Potter, B. V. L. Carbohydr. Res.
1992, 234, 107.
20. O’Brien, J. L.; Tosin, M.; Murphy, P. V. Org. Lett. 2001,
3, 3353.
21. Attolino, E.; Catelani, G.; D’Andrea, F.; Puccioni, L.
Carbohydr. Res. 2002, 337, 991.