A versatile route to L-hexoses: Synthesis of L-mannose and L-altrose

Article abstract of DOI:10.1021/ol061916z

(Chemical Equation Presented) An efficient route for the synthesis of orthogonally protected L-sugars has been opened up, starting from the heterocyclic homologating agent 1 and 2,3-O-isopropylidene-L-glyceraldehyde (2). Our synthetic path enables the syn

Full text of DOI:10.1021/ol061916z

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4863-4866
A Versatile Route to
L
-Hexoses:
-Altrose
Synthesis of -Mannose and
L
L
Annalisa Guaragna,* Carmela Napolitano, Daniele D’Alonzo,
Silvana Pedatella, and Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, UniVersita` di Napoli Federico II,
Via Cynthia, 4 I-80126 Napoli, Italy
guaragna@unina.it
Received August 2, 2006 (Revised Manuscript Received September 15, 2006)
ABSTRACT
An efficient route for the synthesis of orthogonally protected
1 and 2,3-O-isopropylidene- -glyceraldehyde (2). Our synthetic path enables the synthesis of a 2,3-unsaturated-
suitably functionalized to afford the desired -hexoses. In this paper, we report the synthesis of -manno- and -altro-pyranosides. Moreover,
this strategy may be used to prepare all eight sugars and their derivatives in either enantiomeric form.
L
-sugars has been opened up, starting from the heterocyclic homologating agent
L
L
-pyranoside, which can be
L
L
L
The rare L-sugars1 are valuable compounds as precursors in
the synthesis of various chemicals and also as agents in a
wide range of crucial biological events. Although much less
common in nature than their D-counterparts, L-hexoses (in
their pyranosidic form) are key components of numerous
bioactive2 oligosaccharides, antibiotics, glycopeptides, and
terpene glycosides, as well as of steroid glycosides and other
clinically useful agents such as heparin.3 Some remarkable
examples are L-gulopyranoside-containing compounds such
Vibrio fibrisolVens strain CF3,6 and L-mannose has been
found in some steroidal glycosides.7 Its phenolic derivatives
are potent substrates for measuring the R-L-mannosidase
activity of commercial naringinase8 (Figure 1).
4
as the antitumor drug Bleomycin A2 and the nucleoside
antibiotic Adenomycin.5 Moreover, L-altrose is a typical
constituent of the extracellular polysaccharides from Butyri-
Figure 1. Bioactive L-sugars.
* Corresponding author. Phone: + 39 081 674 118. Fax: + 39 081
674 119.
(1) McNaught, A. D. Pure Appl. Chem. 1996, 68, 1919-2008.
(2) (a) Collins, P. M. Dictionary of Carbohydrates; Chapman and Hall:
London, 1987. (b) Lee, J.-C.; Chang, S.-W.; Liao, C.-C.; Chi, F.-C.; Chen,
C.-S.; Wen, Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.;
Hung, S.-C. Chem.-Eur. J. 2004, 10, 399-415.
(3) (a) Lane, D. A.; Lindahl, U. Heparin-Chemical and Biological
Properties Clinical Applications; Edward Arnold: London, 1989. (b)
Lindahl, U. Pure Appl. Chem. 1997, 69, 1897-1902. (c) Iozzo, R. V. Annu.
ReV. Biochem. 1998, 67, 609-652. (d) Rabenstein, D. L. Nat. Prod. Rep.
2002, 19, 312-331.
(4) (a) Burger, R. M. Chem. ReV. 1998, 98, 1153-1169. (b) Boger, D.
L.; Ramsey, T. M.; Cai, H.; Hoehn, S. T.; Stubbe, J. J. Am. Chem. Soc.
1998, 120, 9139-9148. (c) Katano, K.; An, H.; Aoyagi, Y.; Overhand,
M.; Sucheck, S. J.; Stevens, W. C.; Hess, C. D.; Zhou, X.; Hecht, S. M. J.
Am. Chem. Soc. 1998, 120, 11285-11296.
(5) Ogita, T.; Otake, N.; Miyazaki, Y.; Yonehara, H.; Macfarlane, R.
D.; McNeal, C. J. Tetrahedron Lett. 1980, 21, 3203-3206.
Not all L-hexoses are commercially available; this fact,
together with the practical difficulties in obtaining these
compounds from natural sources, has led chemists to develop
new, general, and convenient methods for their production.
Numerous approaches to L-pyranose preparation have been
reported, including homologation of shorter-chain sugars,9
epimerization of readily available D-sugars,10 and de novo
syntheses.11
(6) Stack, R. J. FEMS Microbiol. Lett. 1987, 48, 83-87.
(7) Kubelka, W. Phytochemistry 1974, 13, 1805-1808.
(8) Esaki, S.; Ohishi, A.; Katsumata, A.; Sugiyama, N.; Kamiya, S.
Biosci. Biotechnol. Biochem. 1993, 57, 2099-2103.
10.1021/ol061916z CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/26/2006

As part of our efforts working toward the synthesis of
bioactive polyhydroxylated compounds, we have explored
a general and efficient route for the preparation of L-hexoses
(as well as their D-enantiomers) starting from L-glyceralde-
hyde and the three-carbon homologating agent 1 (Scheme
1). The latter has recently been employed in a versatile
The synthesis started with the coupling reaction of 1,
prepared in a few steps from methyl pyruvate,15 with the
protected aldehyde 2 to obtain a diastereoisomeric mixture
of secondary alcohols 5 (Scheme 2). Oddly, our first attempts
Scheme 2. Three-Carbon Homologation
Scheme 1. Retrosynthetic Path
at using Ti(O-i-Pr)4 as the catalyst16 led only to the formation
of a small amount of the desired alcohols; in fact, once
formed, 5 readily changed, almost quantitatively and even
at low temperature, into the unexpected aldehyde 6.17
On the contrary, in the absence of catalysts, this side
reaction proceeded much more slowly and the alcohols 5
were obtained in an excellent yield (95%) and in an anti/
syn 4:6 diastereomeric ratio.18 The slight preference for the
syn compound is consistent with a nonchelation-controlled
reaction19 according to the Felkin-Anh model prediction
(Figure 2).
procedure to prepare both 4-deoxy-hexopyranoses12 and
1-deoxy-iminosugars13 belonging to the D- or L-series.
In this preliminary communication, we describe the prep-
aration of orthogonally protected L-altro- and L-manno-
pyranosides in enantiomerically pure form, testing, at the
same time, the breadth of our methodology.
As shown in the retrosynthetic path (Scheme 1), our
strategy comprises the following major steps: (i) preparation
of 3 by a three-carbon homologation reaction, employing
the heterocyclic system 1 and the well-known14 2,3-O-
isopropylidene-L-glyceraldehyde (2); (ii) synthesis of the 2,3-
unsaturated pyranoside 4 by carbon skeleton cyclization; (iii)
suitable double-bond functionalization by stereoselective
dihydroxylation of 4.
(9) Some recent examples of homologation of shorter-chain sugars: (a)
Takahashi, S.; Kuzuhara, H. J. Chem. Soc., Perkin Trans. 1 1997, 607-
612. (b) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1997, 62, 6261-
6267. (c) Lubineau, A.; Gavard, O.; Alais, J.; Bonnaffe´, D. Tetrahedron
Lett. 2000, 41, 307-311. (d) Ermolenko, L.; Sasaki, N. A. J. Org. Chem.
2006, 71, 693-703.
Figure 2. Felkin-Ahn models for the aldehyde 2.
(10) Some recent examples of C-5 epimerization of sugars: (a) Ojeda,
R.; de Paz, J. L.; Mart´ın-Lomas, M.; Lassaletta, J. M. Synlett 1999, 8, 1316-
1318. (b) Adinolfi, M.; Barone, G.; De Lorenzo, F.; Iadonisi, A. Synlett
1999, 3, 336-338. (c) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J.
Am. Chem. Soc. 2000, 122, 2995-3000. (d) Hung, S.-C.; Wang, C.-C.;
Thopate, S. R. Tetrahedron Lett. 2000, 41, 3119-3122. (e) Boulineau, F.
P.; Wie, A. Org. Lett. 2002, 4, 2281-2283.
(11) Some recent examples of de novo syntheses: (a) Ko, S. Y.; Lee,
A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B.; Walker, F. J.
Tetrahedron 1990, 46, 245-264. (b) Harris, J. M.; Kera¨nen, M. D.; Nguyen,
H.; Yong, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36. (c)
Honzumi, M.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2001, 3, 1355-
1358. (d) Hodgston, R.; Majid, T.; Nelson, A. J. Chem. Soc., Perkin Trans.
1 2002, 1444-1454. (e) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152-2154. (f)
Co´rdova, A.; Ibrahem, I.; Casas, J.; Sunde´n, H.; Engqvist, M.; Reyes, E.
Chem.-Eur. J. 2005, 11, 4772-4784.
After mixture separation by SiO2 flash chromatography,
the anti-5 diastereoisomer was chosen as a model to test the
whole synthetic path. Benzylation of the secondary hydroxyl
function, treating anti-5 with NaH and BnBr, afforded 7 in
almost quantitative yield (Scheme 3). Interestingly, if the
reaction was carried out in the presence of an excess of NaH,
the formation of an unexpected byproduct 8 in 20% yield20
was observed besides the benzylated product 7 (65%).
4-Methoxybenzyl protecting group removal was next
attempted by treating 7 with DDQ (1.2 equiv) in CH2Cl2/
(12) Caputo, R.; De Nisco, M.; Festa, P.; Guaragna, A; Palumbo, G.;
Pedatella, S. J. Org. Chem. 2004, 69, 7033-7037.
(13) Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo,
G., manuscript in preparation.
(14) Hubschwerlen, C.; Specklin, J.-L.; Higelin, J. Org. Synth. 1995, 72,
1-3.
(15) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem.
1997, 62, 9369-9371.
(16) According to standard procedures carried out on the same chiral
aldehyde 2; see: Suzuki, K.; Yuki, Y.; Mukaiyama, T. Chem. Lett. 1981,
1529-1532.
4864
Org. Lett., Vol. 8, No. 21, 2006

conversion of the formyl group into its di-O-methyl acetal,12
acetonide deprotection, and intramolecular transacetalation
to give the unstable bicyclic compound 11. After subsequent
acetylation of the crude residue, an R/â diastereomeric
mixture (85:15 dr) was obtained in 97% overall yield.
Recrystallization from methanol allowed separation of the
major R-anomer 12 from its â-form.
Scheme 3. Cyclization of the Carbon Skeleton
Desulfurization of the R-anomer 12 with Raney Ni in THF
at 0 °C for 2 h led to the unsaturated pyranosyl derivative
13 (75% yield). Moreover, when the dithiodimethylene
bridge removal was carried out with an excess of Raney Ni,
the overreduction product was obtained with satisfactory
yield (84%), affording the interesting 2,3-dideoxy-L-hexo-
pyranoside 14.21
To access the desired L-manno- and L-altropyranosides,
we next explored the stereoselective dihydroxylation of olefin
13. Under common Upjohn conditions (OsO4/NMO), the
L-mannopyranoside 15 was obtained as a single diastereomer
in 82% yield. This result concurred with earlier investi-
gations11d,22 into the dihydroxylation of allylic alcohol
derivatives: the osmylation reaction occurred anti to the
pseudoequatorial benzyloxy group.
With our successful synthesis of the protected L-mannose
15, we next attempted preparation of the L-altrose derivative
by introducing an epoxy functionality.23 For this, we treated
olefin 13 with in situ24 generated DMDO (Oxone/trifluoro-
acetone). The anti-epoxide 16 was obtained25 exclusively in
92% yield (Scheme 4). Subsequent ring opening of the 2,3-
H2O (18:1). As we have previously described,12,15 with
similar substrates, such removal conditions lead quantitatively
to the formation of a formyl function rather than to the
expected primary alcohol. To our regret, under the same
conditions, 7 is converted both into 10 and into the
corresponding alcohol 9 with an unsatisfactory overall yield
(48%) and in a 4:6 ratio. All attempts to obtain quantitatively
only the aldehyde 10 failed; therefore, a two-step reaction
sequence was preferred, first converting 7 into 9 and then
oxidizing 9 to 10. The complete conversion of 7 into 9 (70%
yield) was accomplished using DDQ in the presence of a
higher-water percentage; on the other hand, oxidation of the
primary hydroxyl function of 9 was easily performed by
treatment with PCC and Celite in pyridine to afford
quantitatively 10, which was directly used in the next
cyclization step.
Scheme 4. Dihydroxylation of the Unsaturated Derivative 13
Treatment of the aldehyde 10 in the presence of Amberlyst
15 in methanol allowed, in a one-pot simple procedure, the
(17) This product, whose structure was unambiguously confirmed by
spectroscopic data, seems to be formed by consumption of the coupling
product 5 (TLC monitoring). The mechanism of such a reaction has to be
proved, and it is still under investigation; nevertheless, we assume that it
proceeds via the titanium complex 5 [see ref 11a]:
anhydro derivative 16 either by acid-26 or by base-catalyzed27
hydrolysis afforded the L-altropyranoside 17 (95% and 90%
yield, respectively), with C-6 O-deacetylation being observed
under both conditions.
(20) The latter could presumably be generated by an allylic C-1 proton
abstraction with a subsequent electronic shift, to give the thermodynamically
stable 8.
(18) The C-4 absolute stereochemistry was clearly established in the
3
course of our synthesis on the basis of the J4,5 of the cyclic compounds
12, 15, and 16.
(19) As recently reported [Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas,
M. D.; D´ıez, R.; Ga´lvez, J. A. Eur. J. Org. Chem. 2003, 2268-2275], steric
and stereoelectronic interactions between the chiral aldehyde 2 and the
nucleophile across the two diastereotopic faces of the carbonyl group do
not play a significant role in determining the stereochemical outcome of
the reaction, a situation that allows the nucleophilic attack on the more
stable conformer leading to a slight preference for the syn compound.
(21) For examples of bioactive 2,3-dideoxy-L-hexopyranoside-based
compounds, see: Guppi, S. R.; Zhou, M.; O’Doherty, G. A. Org. Lett. 2006,
8, 293-296. For their enantiomers, see: Groebke, K.; Hunziker, J.; Fraser,
W.; Peng, L.; Diederichsen, U.; Zimmermann, K.; Holzner, A.; Leumann,
C.; Eschenmoser, A. HelV. Chim. Acta 1998, 81, 375-474.
Org. Lett., Vol. 8, No. 21, 2006
4865

It is noteworthy to recall the value of diene 8, obtained as
byproduct in Scheme 3, as a useful intermediate with the
purpose to prepare 4-deoxy-L-hexopyranosides. In fact,
following chromatographic purification, the compound 8
afforded quantitatively the aldehyde 18 (Scheme 5). When
ing to our previous results,12 to methyl 4-deoxy-L-lyxo-
hexopyranoside 22 as a single diastereomer.
In summary, we have developed a pratical approach to
the synthesis of orthogonally protected L-manno- and L-
altropyranosides 15 and 17. The versatility of our method
lies in producing an intermediate bearing a double bond in
C-2/C-3 positions (such as 13), which can be suitably
functionalized. We are currently investigating the appropriate
conditions to achieve the remaining epimers belonging to
the gluco-configuration. On the other hand, the use of a C-4
diastereomer of olefin 13 (coming from the syn-5 intermedi-
ate) enables the preparation of all four galacto-epimers.
Obviously, it would be possible to synthesize D-analogues
and their deoxy derivatives simply by replacing the chiral
electrophile with its ent-2.
Scheme 5. 4-Deoxy-L-sugar Preparation Starting from 8
Acknowledgment. 1H and 13C NMR spectra were per-
formed at Centro Interdipartimentale di Metodologie Chimico-
Fisiche (CIMCF), Universita` di Napoli Federico II. The
Varian Inova 500 MHz instrument is the property of
Consorzio Interuniversitario Nazionale La Chimica per
l’Ambiente (INCA) and was used in the frame of a project
by INCA and M.I.U.R. (L. 488/92, Cluster 11-A).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
this was submitted to the synthetic steps described above, it
gave the intermediate 20, which after desulfurization (76%
yield) and double-bond osmylation (86% yield) led, accord-
OL061916Z
(24) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
(25) For similar results, see: Kim, K. S.; Moon, C. W.; Park, J., II; Han,
S.-H. J. Chem. Soc., Perkin Trans. 1 2000, 1341-1343.
(26) Fieser, L. F.; Goto, T. J. Am. Chem. Soc. 1960, 82, 1693-1697.
(27) Barili, P. L.; Berti, G.; Catelani, G.; Colonna, F.; Mastrorilli, E. J.
Org. Chem. 1987, 52, 2886-2892.
(22) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247-
2255.
(23) In an initial experiment, the oxidation of 13 with m-CPBA resulted
in a lower yield (70%) and a 10:1 anti/syn dr.
4866
Org. Lett., Vol. 8, No. 21, 2006