Preparation of (2-naphthyl)methylene acetals of glycosides and their hydrogenolytic transformation into 2-naphthylmethyl (NAP) ethers

Article abstract of DOI:10.1016/S0040-4039(00)00735-8

Dioxane- and dioxolane-type (2-naphthyl)methylene acetals of glycosides were prepared by acid-catalyzed transacetalization reactions. The acetals were cleaved using either AlH₃ (LiAlH₄:AlCl₃-3:1), NaCNBH₃-HCl or BH₃·Me₃N-AlCl₃ reagents. Reaction of the 4,6-O-acetals with AlH ₃ yielded 4-ONAP ethers whereas the other two reagents gave 6-ONAP derivatives with excellent regioselectivity. In dioxolane, type acetals the direction of the cleavage with all three reagents is determined by the stereochemistry of the acetal center; equatorial ONAP/axial-hydroxy derivatives are obtained from the exo-naphthyl isomers; endo-naphthyl acetals, on the other hand, give rise to the formation of axial ONAP/equatorial-hydroxy compounds. The NAP ether and the (2-naphthyl)methylene acetal protecting groups can both be readily removed by treatment with DDQ. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00735-8

Tetrahedron Letters 41 (2000) 4949±4953
Preparation of (2-naphthyl)methylene acetals of glycosides
and their hydrogenolytic transformation into
2-naphthylmethyl (NAP) ethersy
Andras Liptak,a,b,* Aniko Borbas,a Lorant Janossyb
and Laszlo Szilagyic
aResearch Group for Carbohydrates of the Hungarian Academy of Sciences, H-4010 Debrecen, PO Box 55, Hungary
bDepartment of Biochemistry, University of Debrecen, H-4010 Debrecen, Hungary
cDepartment of Organic Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
Received 6 April 2000; accepted 4 May 2000
Abstract
Dioxane- and dioxolane-type (2-naphthyl)methylene acetals of glycosides were prepared by acid-
catalyzed transacetalization reactions. The acetals were cleaved using either AlH3 (LiAlH4:AlCl3=3:1),
.
NaCNBH3±HCl or BH3 Me3N±AlCl3 reagents. Reaction of the 4,6-O-acetals with AlH3 yielded 4-ONAP
ethers whereas the other two reagents gave 6-ONAP derivatives with excellent regioselectivity. In dioxolane-
type acetals the direction of the cleavage with all three reagents is determined by the stereochemistry of the
acetal center; equatorial ONAP/axial-hydroxy derivatives are obtained from the exo-naphthyl isomers;
endo-naphthyl acetals, on the other hand, give rise to the formation of axial ONAP/equatorial-hydroxy
compounds. The NAP ether and the (2-naphthyl)methylene acetal protecting groups can both be readily
removed by treatment with DDQ. # 2000 Elsevier Science Ltd. All rights reserved.
The protecting group strategy is an essential component in the design and syntheses of complex
oligosaccharides.1 Acetals2 and easily removable ether3 groups are among those most frequently
used. The well-controlled transformation of benzylidene acetals into benzyl ethers4 8 by
hydrogenolysis has become an important route to prepare di€erentially substituted compounds.
The blocking group strategy based on benzyl ethers is well supplemented by the p-methoxy
counterpart.9
Although 2-naphthylmethyl (NAP) ethers have been previously described,10 12 their
preparative usefulness was rediscovered13,14 only very recently. It was shown that NAP ethers can
be hydrogenolyzed in the presence of benzyl ethers or esters,11 and they are less sensitive to acids
* Corresponding author. Tel: +36 52 316666, ext. 2256; fax: +36 52 512913; e-mail: liptaka@tigris.klte.hu
y
Dedicated to Prof. Ralf Miethchen on the occasion of his 60th birhday.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00735-8

4950
than p-methoxybenzyl ethers. The most important observation, however, is that NAP ethers can
easily be removed by DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) under conditions when
other usual protecting groups like acetyl, pivaloyl, phthalimido, benzyl and benzylidene survive.13,14
Although the NAP group can be removed from the anomeric position, it is, on the other hand,
stable under very di€erent glycosylation reaction conditions. Syntheses of very complex oligo-
saccharides, e.g. a branched hexasaccharide containing the NeuAca2,3(SO3Na-6)Galb1,3Gal-
NAca sequence, have also been accomplished.14
Because the hydrogenolysis of benzylidene acetals results in benzyl ethers4,5 and the direction of
ring opening is well documented, we were keen to gain insight into the behaviour of 2-naphthyl-
methylene acetals under di€erent hydrogenolytic conditions. To our knowledge, until now, only
the synthesis of n-pentenyl-[2,3-di-O-benzoyl-4,6-O-(2-naphthyl)methylene-b-d-galactopyrano-
syl]-(1!4)-2,3,6-tri-O-benzoyl-b-d-glucopyranoside has been reported.15 Methyl a-d-glucopyrano-
side (1) or its 2,3-di-O-benzyl derivative16 (2) reacted with 2-naphthaldehyde or with its di-O-
methyl acetal in DMF or MeCN/DMF in the presence of p-TSA to give crystalline dioxane-type
acetals (3 and 4) (Scheme 1). Benzoylation of 3 gave 5. In a similar way, two diastereoisomeric
forms of the 2,3-O-(2-naphthyl)methylene acetals (7exo and 7endo) were obtained from methyl
a-l-rhamnopyranoside (6). The 7exo-isomer crystallized spontaneously. The mixture of 7exo and
7endo was benzylated and the products could be separated using column chromatography (8exo
and 8endo). The 7exo-isomer was converted into 4-OTBDMS (tert-butyldimethylsilyl) ether
(9exo).
Scheme 1. Reaction conditions: (a) 2-(dimethoxymethyl)naphthalene (1.2 equiv.), pTSA, DMF, rt, overnight, or 2-
naphthaldehyde (1.5 equiv.), CH3CN±DMF, pTSA, 2 days (90±97%); (b) benzoyl chloride, pyridine; (c) DDQ (0.4
equiv.) in CH3CN:H2O (9:1), 2±3 h (95±97%); (d) benzyl bromide (1.1 equiv.), NaH (1.3 equiv.), DMF (98%); (e)
TBDMsCl (1.2 equiv.), imidazole (2.4 equiv.), DMF, overnight (89%)
The structures of the synthesized acetals were ascertained on the basis of NMR spectra.
Characteristic 1H and 13C NMR resonances were found to be between 5.6±5.8 and 101±102 ppm,
respectively, for the acetal protons and carbons in the dioxane-type acetals (3, 4 and 5). In the
dioxolane-type acetals, on the other hand, the corresponding resonances were at ꢀ6.3 and 103

4951
ppm, respectively, for the exo-naphthyl isomers and below 6.1 and above 104 ppm for the endo-
naphthyl isomers.
Three reagents are generally used for the ring-cleavage of dioxane-type acetals: (i) LiAlH4±
7
8
AlCl3;4,5 (ii) NaCNBH3±HCl (or other strong acids); and (iii) BH3 Me3N±AlCl3. The ®rst one
gives rise to the formation of 4-O-alkyl/aryl/6-OH products predominantly. Reagents (ii) and (iii)
induce reverse regioselectivity producing 4-OH/6-O-alkyl/aryl derivatives; the regioselectivity is,
however, strongly dependent on the solvent used.
.
Hydrogenolysis of compound 4 with AlH3 (LiAlH4:AlCl3, 3:1) reagent in ether:dichloro-
methane (1:1) at room temperature gave a 97:3 (HPLC) mixture of the methyl 2,3-di-O-benzyl-4-
O-(2-naphthyl)methyl-a-d-glucopyranoside (10) and its regioisomer, methyl 2,3-di-O-benzyl-6-O-
(2-naphthyl)methyl-a-d-glucopyranoside (11). The reaction required 2 h, and the main product
10 could be isolated in crystalline form (Scheme 2).
Scheme 2. Reaction conditions: (f) LiAlH4 (3 equiv.), AlCl3 (1 equiv.) CH2Cl2:Et2O (1:1), rt, 20 min±3 h (90±98%); (g)
.
NaCNBH3 (12 equiv.), HCl in THF or Me3N BH3 (6 equiv.), AlCl3 (6 equiv.), 4 A MS in THF, 3±4 h (90±97%)
Hydrogenolysis of compound 4 by NaCNBH3±HCl7 in THF at room temperature required 2 h
giving 10:11 in a ratio of 9:91; 11 was isolated by column chromatography as a syrupy
.
compound. A very similar product distribution was observed in the case of the BH3 Me3N±AlCl3
.
reagent. The ratio of 10±11 was 7:93. Treatment of compound 5 with BH3 Me3N±AlCl3 the
methyl 2,3-di-O-benzoyl-6-O-(2-naphthyl)methyl-a-d-glucopyranoside (12) was obtained with
74% yield.
The structures of 10, 11 and 12 are evident from 13C NMR data. In 10 the C-6 resonance at
61.8 ppm indicates the presence of a CH2±OH group, whereas in 11 and 12 the down®eld shifts
for C-6s (69.4 and 69.3 ppm, respectively) clearly demonstrate the presence of the NAP group in
position 6.
In the case of dioxolane-type acetals the direction of the ring-cleavage is determined by the
con®guration of the acetalic carbon. Equatorial ethers are obtained from the exo (alkyl, aryl)-
acetals; the endo-isomers, on the other hand, react in an opposite way and axial-ethers are
produced.7,17,18 This general rule was observed for all of the three reagents mentioned above.

4952
It was therefore interesting to investigate the ring-cleavage reaction of the new dioxolane-type
(2-naphthyl)methylene acetals.
The crystalline 7exo-isomer reacted with AlH3 to give 3-O-(2-naphthyl)methyl ether 13, the
amount of the 2-O-(2-naphthyl)methyl ether isomer (14) being less than 5%. Similarly, the 8exo
furnished 4-O-benzyl-3-O-(2-naphthyl)methyl ether 15, while 4-O-benzyl-2-O-(2-naphthyl)methyl
isomer 16 was the product of hydrogenolysis of the 8endo compound. Only the traces of the other
.
isomers could be detected. Using BH3 Me3N±AlCl3 in the presence of powdered molecular sieves
(4 A) complete stereoselectivity could be observed; in the case of the exo-naphthyl isomers the
reagent attacks at the axial oxygen of the dioxolane ring. With endo-naphthyl-isomers the place
of the attack is, however, at the equatorial oxygen. The ring cleavage reaction of the dioxolane-
type acetals proceeds under very mild conditions (rt, 15 min).
Compound 9exo, containing a silyl ether protecting group, also followed the rule observed
above: reaction with AlH3 resulted in the formation of 3-ONAP (17). Oxidation of compound 14
with NaIO4 indicated the presence of a vicinal diol and proved that it is a 2-ether derivative;
compound 13 was stable under these conditions. These analytical experiments proved not only
the structure of the two isomeric ethers (13 and 14) but, at the same time, attested to the stability
of the ONAP group in the presence of NaIO4. The 13C NMR spectra provided further proof for
the structure of the 2-ONAP derivatives 14 and 16: a ꢀ^2 ppm b-shift could be observed for the
anomeric carbon atom.
1
The 13C NMR a-shifts of ONAP ethers are generally ꢀ+7 ppm. Complete H and 13C NMR
assignments were accomplished for all new compounds. The characteristic NMR and physical
data are given in Ref. 19.
We also investigated the stability and the compatibility of the new acetals and of the NAP
groups with other generally used protecting groups. In the presence of the (2-naphthyl)methylene
acetals alkylation, acylation or silylation can be achieved with very high yield. The removal of
isopropylidene, benzylidene as well as dithioacetal protecting groups of sugars by DDQ has been
reported.20,21 The new acetal blocking group reported here can also be removed using DDQ at
room temperature within a relatively short reaction time (2±3 h), and the yields are nearly
quantitative. These reactions required 0.4 equivalents of freshly crystallized DDQ.
The NAP ethers can also be cleaved in the presence of a variety of blocking groups (acetyl,
pivaloyl, NPhth, Bn and benzylidene).13,14 We have found that DDQ smoothly removed the NAP
group while other protecting groups (benzoyl and TBDMS) survived. On the other hand, various
reactions, like acid hydrolysis of acetal groups (isopropylidene, benzylidene), acylation, alkylation,
glycosylation (under various conditions), 1-O-imidate formation or silylation of free OH groups,
can be performed in the presence of NAP.
In summary, we have demonstrated the usefulness of the preparation of (2-naphthyl)methylene
acetals and their transformation into NAP ethers by hydrogenolysis using three di€erent
reagents. These compounds can be regarded as challenging new protecting groups especially
suitable for the preparation of very valuable sugar derivatives.
Acknowledgements
This work was supported by grants from the Hungarian Academy of Sciences (A.L.), the
Hungarian Scienti®c Research Fund (OTKA T 25244) and the Ministry of Education (FKFP
500/97).

4953
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19. The NMR spectra were recorded with Bruker AM-360 and Bruker DRX-500 spectrometers in CDCl3. Optical
rotations were measured in CHCl3. All compounds gave satisfactory spectroscopic data. Selected spectroscopic
and physical data are the following: compound 3: mp 194ꢁC (EtOAc) [ꢀ]D +99.30 (c 0.50), 1H NMR ꢁ 5.61 (1H, s,
acetalic); 13C NMR ꢁ 101.89 (Cacetalic); compound 4: mp 118ꢁC (EtOH), [ꢀ]D ^54.80 (c 0.33), 1H NMR ꢁ 5.68 (1H,
s, acetalic); 13C NMR ꢁ 101.3 (Cacetalic); compound 5: mp 216ꢁC (EtOAc±nhexane), [ꢀ]D +35.61 (c 0.40), 1H NMR
ꢁ 5.74 (1H, s, acetalic); 13C NMR ꢁ 101.8 (Cacetalic); compound 7exo: mp 108ꢁC (EtOAc±nhexane), [ꢀ]D ^2.42 (c
0.28), 1H NMR ꢁ 6.31 (1H, s, acetalic); 13C NMR ꢁ 103.1 (Cacetalic); compound 8exo: mp 70ꢁC (EtOH), [ꢀ]D ^69.78
1
1
(c 0.44) H NMR ꢁ 6.14 (1H, s, acetalic); 13C NMR ꢁ 103.0 (Cacetalic); compound 8endo: [ꢀ]D ^21.30 (c 0.34), H
NMR ꢁ 6.08 (1H, s, acetalic); 13C NMR ꢁ 104.08 (Cacetalic); compound 9: [ꢀ]D ^14.83 (c 0.37), 1H NMR ꢁ 6.25 (1H,
s, acetalic); 13C NMR ꢁ 102.7 (Cacetalic); compound 10: mp 68±73ꢁC (chexane), [ꢀ]D +1.07 (c 0.37), 13C NMR ꢁ 61.8
(C-6); compound 11: [ꢀ]D +8.24 (c 0.53), 13C NMR ꢁ 69.4 (C-6); compound 12: [ꢀ]D +109.95 (c 0.67), 13C NMR ꢁ
69.3 (C-6); compound 13: mp 110ꢁC (EtOAc±nhexane), [ꢀ]D ^12.16 (c 0.11), 13C NMR ꢁ 100.4 (C-1), 79.8 (C-3),
67.8 (C-2); compound 14: [ꢀ]D +15.84 (c 0.53), 13C NMR ꢁ 99.1 (C-1), 78.1 (C-2), 71.5 (C-3); compound 15: [ꢀ]D
^30.29 (c 0.33); 13C NMR ꢁ 100.04 (C-1), 79.94 (C-3), 68.47 (C-2); compound 16: [ꢀ]D ^11.31 (c 0.30); compound
17: [ꢀ]D ^53.85 (c 0.40), 13C NMR ꢁ 100.1 (C-1), 80.4, 72.7, 68.4 (C-2, C-3, C-4).
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