A new stereoselective approach to a selectively protected derivative of d-pinitol and its evaluation as α-l-rhamnopyranose mimetic

Article abstract of DOI:10.1016/j.tetlet.2008.05.040

The synthesis of 3,5-di-O-benzyl-d-pinitol has been stereoselectively accomplished through intramolecular aldolization of 2,6-di-O-benzyl-4-O-methyl-l-lyxo-hexos-5-ulose followed by reduction with NaBH(OAc)₃. Computational analysis [DFT calculations at the B3LYP/6-31G(d) level] suggests that d-pinitol in water largely prefers the conformation corresponding to the ¹C₄ one of a α-l-rhamnopyranoside unit, being thus a good candidate for its mimicking.

Full text of DOI:10.1016/j.tetlet.2008.05.040

Tetrahedron Letters 49 (2008) 4534–4536
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new stereoselective approach to a selectively protected derivative of
I
D-pinitol and its evaluation as a-L-rhamnopyranose mimetic
a
a
a
b
b,
*
Giorgio Catelani a, , Felicia D’Andrea , Alessio Griselli , Lorenzo Guazzelli , Laura Legnani , Lucio Toma
*
a Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, I-56126 Pisa, Italy
b Dipartimento di Chimica Organica, Università di Pavia, Via Taramelli 10, I-27100 Pavia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 3,5-di-O-benzyl-
ular aldolization of 2,6-di-O-benzyl-4-O-methyl-
D
-pinitol has been stereoselectively accomplished through intramolec-
-lyxo-hexos-5-ulose followed by reduction with NaB-
Received 2 April 2008
Revised 28 April 2008
Accepted 7 May 2008
Available online 11 May 2008
L
H(OAc)3. Computational analysis [DFT calculations at the B3LYP/6-31G(d) level] suggests that
D
-pinitol
in water largely prefers the conformation corresponding to the 1C4 one of a a-
L-rhamnopyranoside unit,
being thus a good candidate for its mimicking.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
D-Pinitol
a- -Rhamnopyranose mimetic
L
Intramolecular aldol condensation
Computational analysis
D-Pinitol is an interesting member of the natural methoxylated
a-
L-rhamnopyranose unit (2), that is present in several bio-active
inositol family and has been recognized for its anti-diabetic prop-
erties,1 and, more recently, for the ability to modulate the immune
response by interacting with dendritic cells (DCs) maturation.2
complex saccharides as, for instance, the capsular polysaccharide
repeating unit of some Pneumococcus strains.8
Before planning the synthesis of suitably protected
D-pinitol
Furthermore, the access to selectively protected
D
-pinitol deriva-
derivatives, a preliminary computational exploration of the confor-
mational space of 1 and 2 was carried out through DFT calculations
at the B3LYP/6-31G(d) level.9 A high number of starting geometries
was prepared, taking into consideration all the degrees of confor-
mational freedom of the molecules. In particular, in the case of 2,
the two chair pyranose forms 1C4 and 4C1 were investigated (Chart
1), together with the different orientations of the four hydroxyl
groups, with particular attention to the formation of intramolecu-
lar hydrogen bonds.
Also for compound 1 ring inversion was investigated consider-
ing the 1C4-like and 4C1-like conformations (Chart 1). In this case,
in addition to the orientation of the hydroxyl groups, the confor-
mational preferences of the methoxy group were considered
through the evaluation of its three different gauche and anti orien-
tations. The energies of the optimized conformers were recalcu-
lated in water by single point calculations, at the same level as
above, using the polarizable continuum model PCM10 to take into
account the influence of the solvent and their percentage contribu-
tion to the overall population was determined at 298 K through the
Boltzmann equation. The conformations of each compound were
grouped into two families, characterized by the ring geometry;
the global minimum of compounds 2 and 1 was a member of
the 1C4 and the 1C4-like families, respectively, while the lowest
energy inverted conformation resulted higher in energy by about
3 and 4 kcal/mol, respectively. Considering the entire families,
tives represents an important task in view of the synthesis of
potential antitumor agents as (+)-pancratistatin3 and some carbo-
cyclic azole nucleoside analogues.4 Owing to the formal analogy
between inositol derivatives and monosaccharides, it could also
be possible to substitute a specific member of one family with an
appropriate one of the other family, maintaining not only the over-
all structural requirements but also the biological properties. In
fact, some examples are reported in which modified monosaccha-
rides, easily available in pure enantioform, have been used to sub-
stitute
D
-myo-inositol frames.5 However, to the best of our
knowledge, the reverse replacing possibility has not yet been
exemplified although the class of carbasugars,6 in which a methyl-
ene group replaces the ring oxygen atom, constitutes one of the
most popular type of carbohydrate mimetics.7
Looking to the relative orientation of
D-pinitol (1) hydroxyl
groups, we suppose 1 to be a possible candidate for mimicking a
q
Part 23 of the series ‘Chemical Valorisation of Milk-Derived Carbohydrates’. For
Part 22 see Ref. 17.
* Corresponding authors. Tel.: +39 050 2219678; fax: +39 050 2219660 (G.C.);
tel.: +39 0382 987843; fax: +39 0382 987323 (L.T.).
E-mail addresses: giocate@farm.unipi.it (G. Catelani), lucio.toma@unipv.it
(L. Toma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.040

G. Catelani et al. / Tetrahedron Letters 49 (2008) 4534–4536
4535
OH
OH
OH
OH
OH
OH
OH
O
O
MeO
HO
HO
OH
OH
OH
HO
HO
OMe
OH
OH
OH
OH
1-1C4-like
1-4C1-like
2-1C4
2-4C1
Chart 1.
L
-rhamnopyranose (2) showed a complete preference for the 1C4
geometry, being the overall population of the 4C1 family <1%. Ana-
logously,
-pinitol (1) showed a high preference for the 1C4-like
dicarbonylic derivative 6 as a complex mixture of tautomeric
forms. Although the NMR spectra of this compound were not inter-
preted, its structure was firmly proved by the next reaction. Crude
6 was subjected to an intramolecular aldol condensation under
conditions (0.2 equiv of DBU in CH2Cl2) analogous to those previ-
ously reported for similar reactions of 5-ketoaldohexoses,11 giving
with complete diastereoselectivity inosose 7 isolated after flash
chromatography in 51% yield. Interestingly, when the intramole-
cular aldolization was performed with Et3N in the presence of
Yb(OTf)3 in CH2Cl2 the isolated yield of 7 increased to 62%. Inosose
7 was then reduced with NaBH(OAc)3 under standard condition
D
geometry which resulted populated for >98%.
Considering these conformational results, we approached the
synthesis of 1 through a sequence (Scheme 1) based on the
intramolecular aldol condensation of a partially protected aldo-
hexos-5-ulose, that was recently used11 successfully for the stere-
oselective synthesis of protected inositol derivatives. Starting
material for the synthesis was the known 1,5-methyl bis-glycoside
3, masked form of the 2,6-di-O-benzyl-
readily obtained from commercially available methyl b-
L-arabino-hexos-5-ulose,
D-galacto-
(CH3CN, AcOH) and brought to the expected di-O-benzyl-D-pinitol
pyranoside through a previously described synthetic route.12
The transformation of compound 3 into 4, having the sole OH-3
group in the free form, was achieved efficiently with a three-step
strategy (88% overall yield) involving: (1) the preliminary protec-
tion of the equatorial OH-3 group of 3 through a regioselective
stannylidene acetal-mediated naphthylmethylation (Bu2SnO,
PhCH3 under azeotropic anhydrification followed by NAPBr and
Bu4NBr); (2) the methylation of OH-4 (CH3I, DMF, NaH); and (3)
the final selective removal of the naphthylmethyl group with
DDQ in CH3CN–H2O.
derivative 8 in 76% yield. This complete stereoselectivity takes
place through an internal hydride delivery as described by Evans
for b-hydroxy ketones.13
Compounds 4–5 and 7–8 were characterized and their analyti-
cal14 and NMR data,15 determined by 1D and 2D (COSY and HET-
COR) NMR experiments, were in agreement with the proposed
structures. Finally, the D-pinitol (1) was obtained in nearly quanti-
tative yield by hydrogenolysis of 8 over 10% palladium on charcoal
in MeOH. The physico-chemical properties and NMR data of 1 were
identical to those reported.16 The high field (600 MHz) 1H NMR
spectrum in D2O confirms the calculated conformational prefer-
ences of the compound; in particular, the high value of the J1,2
(9.9 Hz), J1,6 (9.6 Hz), and J5,6 (9.9 Hz) and the low value of the
J2,3 (2.8 Hz) and J4,5 (2.9 Hz) establish four substituents in equato-
rial position for the preferred conformer.
The C-4 epimerization of the derivative 4 was made with a two-
step procedure requiring first the oxidation with the TPAP-NMO
system in CH2Cl2 followed by the crude uloside intermediate
reduction (NaBH4/MeOH, rt). The 1,5-bis-methyl glycoside 5,
masked form of the 2,6-di-O-benzyl-4-O-methyl-L-lyxo-hexos-5-
ulose 6, was obtained in high yield after chromatographic purifica-
tion (84% yield over two steps). The complete diastereoselectivity
of the reaction could be reasonably attributed to the presence of
the axial 5-OMe, which allows the hydride to attack only on the
b face shielding the a one. The bis-glycoside 5 was then submitted
to acid hydrolysis (CF3COOH, in 4:1 CH3CN–H2O) giving the 1,5-
Our next efforts will be oriented to understand if
D-pinitol
is truly able to mimic a a- -rhamnopyranose unit, in view of
L
the synthesis of pseudotrisaccharide derivatives of the struc-
ture b-d-ManNAcp-ð1 ! 4Þ-a-d-Glcp-ð1 ! 4Þ-d-pinitol-3-O-PO32ꢀ
,
representing a chemically more stable mimic of the capsular
polysaccharide repeating unit of Streptococcus pneumoniae 19F.
OMe
OBn
OH
OBn
OMe
OBn
OMe
OBn
O
O
O
O
OMe
OMe
a
b
OMe
c
HO
HO
CHO
OBn
OBn
OBn
OBn
OMe
OH
OMe
OMe
OH
4
3
5
6
d
OH
OH
OH
OH
OH
1
OH
OBn
O
OBn
HO
2
MeO
HO
3
e
HO
MeO
f
HO
MeO
5
MeO
6HO
4
OH
OH
OH
OH
OBn
OBn
8
7
1 (D-pinitol)
Scheme 1. Reagents and conditions: (a) (1) Bu2SnO, NAPBr, CH3Ph; (2) CH3I, DMF, NaH; (3) DDQ, CH3CN–H2O (88%, overall yield). (b) (1) TPAP, NMO, CH2C12; (2) NaBH4,
MeOH, (84%, over two steps), (c) 90% aq CF3COOH/ 4:1 CH3CN–H2O. (d) DBU, CH2C12, 51% or Et3N, Yb(OTf)3, CH2Cl2, 62%. (e) NaBH(OAc)3, CH3CN–AcOH, 75%. (f) H2, Pd/C,
MeOH, quantitative yield.

4536
G. Catelani et al. / Tetrahedron Letters 49 (2008) 4534–4536
12. Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F. Gazz. Chim. Ital. 1992, 48, 135–
Acknowledgment
142.
13. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560–
3578.
This research was supported by a grant from MiUR (Ministero
dell’Università e della Ricerca, Roma) in the frame of the national
project COFIN 2006.
14. Compound 4: syrup, (Found: C, 66.34; H, 7.37; C23H30O7 requires: C, 66.01; H,
7.23); Rf 0.26 (7:3 hexane/EtOAc); [a]D ꢀ34.6 (c 1.2, CHCl3); compound 5:
syrup, (Found: C, 66.25; H, 7.34; C23H30O7 requires: C, 66.01; H, 7.23); Rf 0.16
(7:3 hexane/EtOAc); [a]D ꢀ58.5 (c 1.2, CHCl3); compound 7: white solid,
(Found: C, 67.88; H, 6.63; C21H24O6 requires: C, 67.73; H, 6.50); mp 113–115 °C
(EtOAc); Rf 0.22 (4:6 hexane/EtOAc); [a]D ꢀ1.7 (c 1.1, CHCl3); compound 8:
white solid, (Found: C, 67.51; H, 7.09; C21H26O6 requires: C, 67.36; H, 7.00); mp
91–94 °C (EtOAc); Rf 0.14 (2:8 hexane/EtOAc); [a]D +12.3 (c 1.1, CHCl3).
15. Selected NMR data: compound 4: dH (CD3CN, 250 MHz) 4.39 (d, 1H,
J1,2 = 7.6 Hz, H-1), 3.86 (ddd, 1H, J2,3 = 9.8 Hz, J3,4 3.4 Hz, J3,OH = 6.7 Hz, H-3),
3.58, 3.53 (AB syst., 2H, JA,B = 10.3 Hz, H-6a, H-6b), 3.48, 3.45 (2s, each 3H,
OMe-1, OMe-4), 3.43 (d, 1H, H-4), 3.33 (dd, 1H, H-2), 3.23 (s, 3H, OMe-5), 3.12
(d, 1H, OH-3); dC (CD3CN, 62.9 MHz) 101.6 (C-1), 101.5 (C-5), 80.7 (C-4), 80.6
(C-2), 71.5 (C-3), 66.4 (C-6), 61.9 (OMe-4), 57.1 (OMe-1), 48.5 (OMe-5);
compound 5: dH (CD3CN, 250 MHz) 4.72 (d, 1H, J1,2 = 8.1 Hz, H-1), 4.12 (dt, 1H,
J3,4 = J2,3 = 3.5 Hz, J3,OH = 9.1 Hz, H-3), 3.55 (s, 2H, H-6a, H-6b), 3.49 (s, 3H,
OMe-1), 3.41 (d, 1H, H-4), 3.38 (dd, 1H, H-2), 3.35 (s, 3H, OMe-4), 3.32 (s, 3H,
OMe-5), 3.31 (d, 1H, OH-3); dC (CD3CN, 62.9 MHz) 103.4 (C-5), 98.2 (C-1), 78.9
(C-4), 76.2 (C-2), 73.9, 68.5 (C-3), 66.9 (C-6), 59.4 (OMe-4), 56.1 (OMe-1), 48.8
(OMe-5); compound 7: dH (CD3CN, 250 MHz) 4.37 (dd, 1H, J2,3 = 3.5 Hz,
J2,6 = 1.1 Hz, H-2), 4.28 (q sl, 1H, J3,4 = 3.5 Hz, J3,OH = 3.4 Hz, H-3), 3.98 (dd, 1H,
J5,6 = 9.7 Hz, H-6), 3.90 (dd, 1H, J4,5 = 3.4 Hz, H-4), 3.83 (ddd, 1H, J5,OH = 6.7 Hz,
H-5), 3.53 (d, 1H, OH-3), 3.44 (s, 3H, OMe), 3.43 (d, 1H, OH-5); dC (CD3CN,
62.9 MHz) 204.6 (C-1), 86.2 (C-6), 81.1 (C-2), 79.4 (C-4), 73.5 (C-5), 71.3 (C-3),
59.4 (OMe); compound 8: dH (CDCl3, 250 MHz) 4.65, 4.55, 3.98 (t, 1H,
J2,3 = J3,4 = 3.1 Hz, H-3), 3.88 (m, 2H, H-4, H-5), 3.80 (t, 1H, J1,2 = J1,6 = 9.2 Hz,
H-1), 3.61 (s, 3H, OMe), 3.60 (dd, 1H, H-2), 3.30 (t sl, 1H, J5,6 = 9.0 Hz, H-6); dC
(CDCl3, 62.9 MHz) 83.2 (C-6), 79.4 (C-2), 78.8 (C-4), 72.0 (C-1), 70.5 (C-5), 66.8
(C-3), 60.5 (OMe).
References and notes
1. (a) Fonteles, M. C.; Huang, L. C.; Larner, L. J. Diabetol. 1996, 39, 731–734; (b)
Ortmeyer, H. K.; Huang, L. C.; Zhang, L.; Hansen, B. C.; Larner, L. Endocrinology
1993, 132, 646–651.
2. Lee, J. S.; Jung, I. D.; Jeong, Y.-I.; Lee, C.-M.; Shin, Y. K.; Lee, S.-Y.; Suh, D.-S.;
Yoon, M.-S.; Lee, K.-S.; Choi, Y. H.; Chung, H. Y.; Park, Y.-M. Int. Immunopharm.
2007, 7, 791–806.
3. Li, M.; Wu, A.; Zou, P. Tetrahedron Lett. 2006, 47, 3707–3710.
4. Zhan, T.; Lou, H. Carbohydr. Res. 2007, 342, 865–869.
5. (a) Moitessier, N.; Chrétien, F.; Chapleur, Y.; Humeau, C. Tetrahedron Lett. 1995,
36, 8023–8026; (b) Roussel, F.; Hilly, M.; Chrétien, F.; Mauger, J.-P.; Chapleur, Y.
J. Carbohydr. Chem. 1999, 18, 697–707; (c) Chrétien, F.; Roussel, F.; Hilly, M.;
Mauger, J.-P.; Chapleur, Y. J. Carbohydr. Chem. 2005, 24, 549–581; (d) Dinev, Z.;
Gannon, T. C.; Egan, C.; Watt, J. A.; McConville, M. J.; Williams, S. J. Org. Biomol.
Chem. 2007, 5, 952–959; (e) Rosenberg, H. J.; Riley, A. M.; Marwood, R. D.;
Correa, V.; Taylor, C. W.; Potter, B. V. L. Carbohydr. Res. 2001, 332, 53–66; (f)
Abe, H.; Shuto, S.; Matsuda, A. J. Org. Chem. 2000, 65, 4315–7325.
6. Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–
2036.
7. (a) Carbohydrate Mimics: Concepts and Method; Chapleur, Y., Ed.; Wiley-VCH,
1998; (b) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2301–2324.
8. (a) Jennings, H. J. Adv. Carbohydr. Chem. Biochem. 1983, 41, 155; (b) Pozsgay, V.
Adv. Carbohydr. Chem. Biochem. 2001, 56, 153.
9. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652; (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1988, 37, 785–789.
16. (a) Mondal, D. N.; Barik, B. R.; Dey, A. K.; Kundu, A. B.; Banerji, A.; Maiti, S. J.
Indian Chem. Soc. 1993, 70, 651–652; (b) Sridhar, C.; Krishnaraju, A. V.;
Subbaraju, G. V. Indian J. Pharm. Sci. 2006, 68, 111–114.
17. Attolino, E.; Bonaccorsi, F.; Catelani, G.; D’Andrea, F.; Krenek, K,; Bezouska, K.;
Kren, V. J. Carbohydr. Chem. 2008, 27, 000.
10. Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404–417.
11. (a) Pistarà, V.; Barili, P. L.; Catelani, G.; Corsaro, A.; D’Andrea, F.; Fisichella, S.
Tetrahedron Lett. 2000, 41, 3253–3256; (b) Catelani, G.; Corsaro, A.; D’Andrea,
F.; Mariani, M.; Pistarà, V. Bioorg. Med. Chem. Lett. 2002, 12, 3313–3315.