NAP ether mediated intramolecular aglycon delivery: A unified strategy for 1,2-cis-glycosylation

Article abstract of DOI:10.1002/ejoc.200800249

A methodology directed towards the stereoselective construction of 1,2-cis-glycosides through naphthylmethyl (NAP) ether mediated intramolecular aglycon derivery (IAD) has been developed. Stereospecific constructions of various 1,2-cis linkages, as in β-mannopyrano-, β-arabinofurano-, and α-glucopyranosides, were achieved through NAP-IAD. This methodology was successfully applied to the synthesis of Glcα(1→2)- Glcα(1→3)-Glcα(1→3)Man (Glc₃Man₁), the nonreducing terminal structure of the tetradecasaccharide Glc ₃Man₉GlcNAc₂, a common precursor of all N-linked glycans. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800249

FULL PAPER
DOI: 10.1002/ejoc.200800249
NAP Ether Mediated Intramolecular Aglycon Delivery: A Unified Strategy for
1,2-cis-Glycosylation
Akihiro Ishiwata,*[a,b] Yuichi Munemura,[a] and Yukishige Ito*[a,b]
Keywords: 1,2-cis-Glycosides / Intramolecular aglycon delivery (IAD) / Stereoselective synthesis / Glycosylation / Oligo-
saccharides
A methodology directed towards the stereoselective con-
struction of 1,2-cis-glycosides through naphthylmethyl (NAP)
ether mediated intramolecular aglycon derivery (IAD) has
been developed. Stereospecific constructions of various 1,2-
cis linkages, as in β-mannopyrano-, β-arabinofurano-, and α-
glucopyranosides, were achieved through NAP-IAD. This
methodology was successfully applied to the synthesis of
Glcα(1Ǟ2)-Glcα(1Ǟ3)-Glcα(1Ǟ3)Man (Glc3Man1), the non-
reducing terminal structure of the tetradecasaccharide
Glc3Man9GlcNAc2, a common precursor of all N-linked gly-
cans.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ids,[2] proteoglycans,[3] microbial polysaccharides,[4] and bio-
Introduction
1,2-cis Glycoside linkages, as found in β-mannopyranos- active natural products.[5] Stereoselective synthesis of 1,2-
ide, β-arabinofuranoside, and α-glucopyranoside, are preva- cis-glycosides is potentially problematic.[6] Although the key
lent in natural glycans, including glycoproteins,[1] glycolip- factors that control the stereoselectivity of glycosylation
Figure 1. Intramolecular aglycon delivery using NAP ether protected glycosyl donors.
have largely been elucidated, exclusive formation of the de-
sired isomer is generally difficult. To achieve this, a number
of strategies directed towards 1,2-cis-glycosides have been
explored.[7] Among them, approaches based on intramolec-
ular aglycon delivery (IAD) are of special promise, because
they would be expected to ensure the exclusive formation
of 1,2-cis-glycosides.[8]
[a] RIKEN (The Institute of Physical and Chemical Research),
2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Fax: +81-48-462-4680
E-mail: aishiwa@riken.jp
yukito@riken.jp
[b] CREST, Japan Science and Technology Agency (JST),
Kawaguchi, Saitama 332-0012, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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NAP Ether Mediated Intramolecular Aglycon Delivery
The concept of IAD was first proposed by Baressi and our synthetic studies directed towards mycobacterial arab-
Hindsgaul,[9] who employed an isopropylidene mixed acetal inan,[26,27] we faced a difficulty in constructing the nonre-
as a tether for β-mannopyranosylation. Subsequent work ducing terminal β-Araf-(1,2)-Araf linkage. Our former at-
by Stork et al.[10] explored the use of silaketals[11,12] for sim- tempt to solve this problem had met with partial success
ilar purposes. Following these pioneering reports, newer through the choice of appropriate protecting groups,[26] es-
versions of IAD using various types of tethers have been pecially 3,5-O-tetraisopropyldisiloxanylidene (TIPDS).[27]
developed.[13] Our approach[14] took advantage of the spe- The stereoselectivity of the glycosylations was highly de-
cial reactivity of p-methoxybenzyl (PMB) ethers (Fig- pendent upon the structure of the acceptor.
ure 1).[15,16] Namely, a 2-O-PMB-protected mannosyl donor
In the case of β-mannopyranosylation, the stereochemi-
(Da) was cleanly converted into the mixed acetal (MAa) cal outcome of IAD is obvious: the pathway directed
upon oxidative activation with DDQ. Subsequent activation towards the corresponding α-glycosides is essentially pro-
of the thioglycosidic linkage initiated the rearrangement of hibited. Namely, the axial orientation of the NAP ether at
an aglycon from the p-methoxybenzylidene acetal moiety to the C-2 position (MA1) guarantees the formation of the β-
give a desired β-mannopyranoside (Manp, P). The practi- glycoside (Figure 2). Although the pathway directed
cality of this approach was shown in the syntheses of high- towards α-Araf through IAD is also disfavored, because it
mannose-type[17] and complex-type[18] N-glycans.
requires the intermediacy of a trans-fused bicyclo[5.5.0] sys-
Since the 2-naphthylmethyl (NAP) group[19] has proper- tem (MA2), we employed the perdeuterated benzyl-pro-
ties similar to those of PMB,[20] being removable with tected ([D7]Bn) Araf derivative 7 as an acceptor to allow
DDQ,[21] it was expected that IAD with a 2-O-NAP-pro- critical evaluation of the stereochemical homogeneity of the
tected donor (Db Ǟ MAb Ǟ P) should be possible (Fig- product (Scheme 2).[28,29]
ure 1).[22] In fact, NAP-assisted IAD turned out to be
highly versatile, giving various types of 1,2-cis-glycosides in
high yields.
Results and Discussion
As we had already established the protocol for β-Manp
formation through PMB-assisted IAD, we attempted a sim-
ilar reaction with the 2-O-NAP-protected thiomannoside
1.[23] As shown in Scheme 1, the formation of MA 5 pro-
ceeded quantitatively, and subsequent IAD (MeOTf–
DTBMP[24]) cleanly gave β-Manp 6 after acetylation.
Figure 2. 1,2-cis induction via mixed acetals.
In fact, formation of the mixed acetal 8 from Araf donor
2
[23] and acceptor 7[23] proceeded cleanly to give 8 as a 3.4:1
As in the case of the 2-O-PMB-substituted donor, the mixture of diastereomers. Subsequent IAD provided 9 in
MA 5 was stereochemically homogeneous, most likely hav- satisfactory yield after acidic workup and acetylation. The
ing the (S) configuration.[14b] Obviously, the efficiency of anomeric configuration was assigned by 1H NMR spec-
NAP-assisted IAD was even higher than that of its PMB- troscopy: The signal of 1-H of β-Araf appeared as a singlet
assisted counterpart, requiring only 1.05 equiv. of the donor at δ = 4.93 ppm.
1 to give 6 in 90% yield.
On the other hand, the stereochemical outcome of the α-
Having observed the efficacy of NAP-IAD β-mannosyl- glucopyranoside (α-Glc) formation is less obvious (Fig-
ation, we turned our attention to β-arabinofuranoside ure 2). In this case, the NAP ether at the C-2 position is
(Araf) formation.[16] β-Araf has also been considered a dif- equatorially oriented, and IAD directed towards 1,2-trans-
ficult linkage in oligosaccharide synthesis.[25] In fact, during β-Glc may not be completely prohibited (MA3). In order
Scheme 1. NAP-IAD for β-mannopyranoside; reagents and conditions: (a) DDQ, MS (4 Å), (CH2Cl)2, room temp., quant. (single isomer);
(b) (i) MeOTf, DTBMP, (CH2Cl)2, r.t.; (ii) Ac2O, pyridine, 90% (only β-isomer).
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A. Ishiwata, Y. Munemura, Y. Ito
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Scheme 2. NAP-IAD for β-arabinofuranoside; reagents and conditions: (a) DDQ, MS (4 Å), (CH2Cl)2, quant. (3.40:1); (b) (i) MeOTf,
DTBMP, (CH2Cl)2, r.t.; (ii) TFA; (iii) Ac2O, pyridine, 77% (β-9).
to examine the stereospecificity of α-Glc formation through
In our synthetic study on glucose-branched high-man-
IAD, the mixed acetal 13 was prepared. As shown in nose-type N-glycans, the construction of α-Glc(1Ǟ2)-α-
Scheme 3, smooth formation of 13 from 3a[23] and 10[29] Glc(1Ǟ3)-α-Glc(1Ǟ3)Man (Figure 3) is problematic.[28,29]
(route A) took place (diastereomers 3.18:1). The same 13 We thought that the 1,2-cis-α-glucosylation through NAP-
was also prepared from 2-O-unprotected donor 11[23] and mediated IAD could be applicable to the synthesis of struc-
2-O-NAP acceptor 12[23] (route B). Interestingly, the dia- ture 21, with three continuous α-Glc units.[13d,13e,13h,31,32]
stereomeric composition according to route B (1:4.17) was For the synthesis of this structure, it would be necessary to
the opposite of that according to route A. The subsequent retain cyclohexylidene acetals on the IAD product to afford
intramolecular glycosylation of 13 afforded the desired 1,2- 22. We found that the addition of (TMS)3SiH[33] was effec-
cis-glycoside in good yield as pentaacetate 14 after acidic tive for the reductive in situ trapping of benzylic cation 20,
treatment and acetylation.[30]
generated from an activated 19 at the last stage of IAD
Scheme 3. NAP-IAD for α-glucosides; reagents and conditions: (a) DDQ, MS (4 Å), CH2Cl2, room temp., 96% (3.18:1) from 3a (route A);
93% (1:4.17) from 11 (route B); 84% (Ͼ10:1) from 3b; (b) (i) MeOTf, DTBMP, (CH2Cl)2, r.t.; (ii) TFA; (iii) Ac2O, pyridine, 72% (α-14);
(c) MeOTf, DTBMP, (TMS)3SiH, (CH2Cl)2, room temp., 73% (α-15) and 16% (α-16); 82% (α-18); (d) DDQ, 85% (16) in two steps from
13.
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NAP Ether Mediated Intramolecular Aglycon Delivery
Figure 3. Triglucosylated high-mannose-type N-glycan.
Scheme 4.
Figure 4. α-Glucosylation via NAP-IAD.
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(Scheme 4). Interestingly, IAD of 3b[23] with 10 gave NAP Table 1. NAP-IAD for various α-glucosides; yields for formation
of MA and glycosylation.[a]
ether 18 (82%) as sole product. The advantage of IAD with
the reducing additive is the regeneration of the NAP ether
in the product; this can be used not only as the orthogonal
protective group but also as the key functionality of a sub-
sequent NAP-IAD for further elongation. IAD of 13 in the
presence of (TMS)3SiH also afforded NAP ether 15 (73%),
together with 16 (16%) (Scheme 3). The crude mixture (15
and 16) was immediately treated with DDQ to give the sole
product 16, with the desired α-stereochemistry.[34]
Entry
D
A
MA (%, dr[b]
)
Glucoside (%)
1
2
3
4
5
6
3a
3c
3a
3b
3a
3b
23
10
28
28
33
33
24 (91, 2.32:1)
26 (94, 3.11:1)
29 (97, 3.00:1)
30 (84, 11.1:1)
34 (97, 3.11:1)
35 (84, 14.3:1)
25[c] (63, α)
27[c] (77[d]
)
31[c] (89, α)
32 (83, α)
36[c] (74, α)
37 (86, α)
[a] MeOTf, DTBMP, and (TMS)3SiH were used for intramolecular
glycosylation. [b] Diastereomer ratio. [c] DDQ workup. [d] α/β =
2.17:1.
NAP-IAD of 3a with 23[23] as primary alcohol afforded
the desired α-25[23] as a single isomer through 24 (Figure 4,
Table 1, Entry 1). IAD of 3c[23] with 10, however, gave a
mixture of anomers (Entry 2). It is therefore clear that the
cyclic protection at the 4,6-positions[14g] of the donor forded acceptor 39 in good yield. In the second IAD of 39
seemed to be important for control of the 1,2-cis stereo- with 3a, formation of a MA 40 followed by intramolecular
selectivity.
glycosylation resulted in a stereoselective formation of 42
For the synthesis of 21, NAP-IAD of glucose and man- via acetate 41 in good yield. In the third NAP-IAD, how-
nose acceptors (28, 33) with cyclohexylidene-protected do- ever, mixed acetalization between 42 with 3a (route A) af-
nors (3a, 3b) were examined through MAs (29, 30 and 34, forded 44 in low yield (50%). In route B, treatment of 11
35) (Figure 4, Table 1, Entries 3–6). In all cases, the desired with 43, prepared from 40 (76%), resulted in almost quanti-
α-isomers (31, 32 and 36, 37) were obtained in high yields tative conversion into MA 44.[35] Intramolecular glycosyla-
with complete stereoselectivity.
tion of 44 gave 22 as sole product in 77% yield. After con-
Finally, NAP-IAD was applied to the construction of 21 ventional deprotection, the synthesis of Glc3Man1-OMP
with the iterative α-glucosidic linkages (Scheme 5). Three- (21) was accomplished in high yield and with complete
step conversion of 37, obtained by NAP-IAD (Table 1), af- stereoselectivity.
Scheme 5. Synthesis of Glc3Man1-OMP 21; reagents and conditions: (a) DDQ, NaHCO3, (CH2Cl)2, 86%; (b) [D7]BnBr, NaH, DMF;
then TBAF, THF, 75% in two steps; (c) DDQ, MS (4 Å), CH2Cl2, 96% (2.72:1) (40), 47% (2.33:1) (44) from 42 (route A), 97% (3.43:1)
(44) from 43 (route B); (d) (i) MeOTf, DTBMP, MS (4 Å), (CH2Cl)2; (ii) Ac2O pyridine, 85% (41); (iii) NaOMe, MeOH, 88% (42); (e)
MeOTf, DTBMP, (TMS)3SiH, MS (4 Å), (CH2Cl)2, 76% (43) and 6% (42); (f) (i) MeOTf, DTBMP, (TMS)3SiH, CH2Cl2; (ii) DDQ,
NaHCO3, (CH2Cl)2, 77%; (g) TFA; (h) Pd(OH)2, H2, MeOH/H2O (2:1), quant. in two steps.
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NAP Ether Mediated Intramolecular Aglycon Delivery
Compound 5: For analytical measurements, the residue was sepa-
rated by gel filtration (SX-3, toluene/EtOAc, 1:1). 1H NMR
(CDCl3, 400 MHz): δ = 0.87–1.13 (m, 21 H, TIPS), 1.48–1.75 (m,
9 H, cyclohexyl), 2.15 (s, 3 H, SMe), 2.42–2.50 (m, 1 H, cyclohexyl),
3.68 (s, 3 H, OMe), 3.68–3.75 (m, 1 H, C5-HGlcNp), 3.81 (d, J =
11.2 Hz, 1 H, C6-HGlcNp), 3.90–3.96 (m, 2 H, C6-HGlcNp, C2-
HManp), 4.00 (dd, J = 10.0, 4.8 Hz, 1 H, C6-HManp), 4.05–4.12 (m,
1 H, C5-HManp), 4.19 (dd, J = 9.6, 2.4 Hz, 1 H, C3-HManp), 4.25
(t, J = 10.0 Hz, 1 H, C6-HManp), 4.37 (t, J = 10.0 Hz, 1 H, C3-
HGlcNp), 4.47–4.53 (m, 2 H, C2-HGlcNp, C4-HGlcNp), 4.58 (t, J =
9.2 Hz, 1 H, C4-HManp), 4.68 (d, J = 12.4 Hz, 1 H, Bn), 4.85 (d, J
= 12.4 Hz, 1 H, Bn), 4.90 (d, J = 12.8 Hz, 1 H, Bn), 5.18 (d, J =
12.8 Hz, 1 H, Bn), 5.71 (d, J = 8.8 Hz, 1 H, C1-HGlcNp), 5.89 (s, 1
H, C1-HManp), 5.99 (s, 1 H, CH Naph), 6.69–7.86 (m, 21 H, MP,
Naph, Bn ϫ2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 12.3, 13.6,
17.8, 17.9, 22.5, 22.6, 25.8, 27.9, 38.0, 43.4, 55.4, 55.7, 61.7, 66.5,
67.7, 70.4, 70.6, 73.8, 74.5, 75.2, 76.2, 76.6, 78.7, 82.8, 97.7, 99.8,
101.6, 114.1, 118.6, 123.0, 124.3, 125.9, 126.1, 126.2, 127.0, 127.5,
127.67, 127.73, 127.88, 127.92, 128.1, 128.2, 128.4, 131.6, 132.6,
133.5, 133.6, 135.6, 137.5, 138.3, 150.6, 155.1, 167.1, 167.5 ppm.
MALDI TOF MS: calcd. for C68H81NNaO13SSi [M + Na]+ 1202.5;
found 1202.5.
Compound 6: [α]2D9 = 24.8 (c = 1.0, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 0.96–1.10 (m, 21 H, TIPS), 1.48–1.75 (m, 9 H, cy-
clohexyl), 2.12 (s, 3 H, Ac), 2.28–2.35 (m, 1 H, cyclohexyl), 2.97
(ddd, J = 10.8, 9.2, 5.6 Hz, 1 H, C5-HManp), 3.50 (t, J = 10.8 Hz,
1 H, C6-HManp), 3.60–3.80 (m, 5 H, C5-HGlcNp, C6-HGlcNp, C3-
HManp, C4-HManp, C6-HManp), 3.84 (dd, J = 11.2, 3.2 Hz, 1 H, C6-
HGlcNp), 4.16 (dd, J = 10.0, 8.4 Hz, 1 H, C4-HGlcNp), 4.27 (dd, J =
10.8, 8.4 Hz, 1 H, C3-HGlcNp), 4.37 (dd, J = 10.8, 8.4 Hz, 1 H, C2-
HGlcNp), 4.39 (d, J = 12.4 Hz, 1 H, Bn), 4.51 (d, J = 12.4 Hz, 1 H,
Bn), 5.68 (d, J = 0.8 Hz, 1 H, C1-HManp), 4.73 (d, 1 H, Bn), 4.82
(d, J = 12.4 Hz, 1 H, Bn), 5.32 (dd, J = 2.8, 0.8 Hz, 1 H, C2-
HManp), 5.56 (d, J = 8.0 Hz, 1 H, C1-HGlcNp), 6.65–7.65 (m, 18 H,
MP, NPhth, Bn ϫ2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 12.3,
14.1, 17.9, 21.0, 22.2, 22.4, 25.5, 27.7, 37.8, 55.3, 55.4, 60.2, 60.9,
Conclusions
We have developed a methodology directed towards the
stereoselective construction of 1,2-cis-glycosides through
the use of NAP ether mediated IAD. It was applied with
high generality to the construction of various 1,2-cis link-
ages, such as β-Manp, β-Araf, and α-Glcp. The complete
stereoselective synthesis of a Glc3Man1 derivative contain-
ing three continuous 1,2-cis linkages in a high-mannose-
type N-glycan was successfully achieved. This clearly sug-
gests that this novel stereospecific IAD methodology is
highly efficient, useful, and practical.[36]
Experimental Section
General Methods: All reactions sensitive to air and/or moisture
were carried out under nitrogen or argon in anhydrous solvents.
Column chromatography was performed on silica gel 60N, 100–
210 mesh (Kanto Kagaku Co., Ltd.). Preparative TLC was per-
formed on silica gel 60 F254, 0.5 mm (E. Merck). Gel filtration was
performed on Sephadex LH-20 (Pharmacia). All other reagents
were purchased from Wako Pure Chemical Industries Ltd., Kanto
Chemicals Co. Inc., Tokyo Kasei Kogyo Co. and Aldrich Chemical
Company. Optical rotations were measured with a JASCO DIP 370
polarimeter. 1H NMR spectra were recorded at 400 MHz with a
JEOL JNM-AL 400 or an ECX 400 spectrometer, and chemical
shifts are referred to internal tetramethylsilane (δ = 0 ppm), CDCl3
(δ = 7.24 ppm), or CD3OD (δ = 3.30 ppm). 13C NMR spectra were
recorded at 100 MHz with the same instruments, and chemical
shifts are referred to internal CDCl3 (δ = 77.0 ppm), C6D6 (δ =
128.0 ppm), or CD3OD (δ = 49.0 ppm). MALDI-TOF mass spec-
tra were recorded with a Shimadzu Kompact MALDI AXIMA-
CFR spectrometer with 2,5-dihydroxybenzoic acid as the matrix.
ESI-TOF mass spectra were recorded with a JEOL AccuTOF
JMS-T700LCK with CF3CO2Na as the internal standard.
67.9, 68.2, 70.3, 71.1, 72.3, 73.2, 74.4, 74.6, 76.9, 78.9, 97.4 (JC–H
=
Methoxyphenyl 2-O-Acetyl-4,6-O-cyclohexylidene-3-O-triisopropyl-
163.4 Hz, C1β-GlcNp), 99.5 (JC–H = 161.7 Hz, C1β-Manp), 99.6, 114.1,
118.3, 123.0, 126.9, 127.4, 127.5, 127.7, 128.2, 131.3, 137.7, 138.3,
150.5, 155.0, 167.2, 167.9, 169.7 ppm. MALDI TOF MS: calcd. for
C58H73NNaO14Si [M + Na]+ 1058.5; found 1058.7. HRMS ESI-
TOF: calcd. for C58H73NNaO14Si [M + Na]+ 1058.4698; found
1058.4702.
silyl-β-
D-mannopyranosyl-(1Ǟ4)-3,6-di-O-benzyl-2-deoxy-2-phthal-
imido-β-
D-glucose (6): DDQ (609 mg, 2.91 mmol) was added under
Ar at room temperature to a mixture of acceptor 4[37] (1.4476 g,
2.43 mmol), donor 1[23] (1.5028 g, 2.56 mmol), and dried powdered
MS (4 Å, 2.0 g) in dry CH2Cl2 (10 mL). The mixture was stirred at
the same temperature for 2 h, quenched with aqueous ascorbate
buffer [-ascorbic acid (0.7 g), citric acid monohydrate (1.2 g), and
NaOH (0.92 g) in H2O (100 mL)], and filtered through Celite. The
filtrate was extracted with CHCl3 and washed with satd. aq. α-
NaHCO3 and brine. The combined organic layers were dried with
Na2SO4, and the solvents were evaporated in vacuo. The crude
mixed acetal 5 (one isomer) was used without further purification.
2-Naphthaldehyde ([D7]Benzyl 3,5-O-bis[D7]benzyl-α-
anosid-2-yl) [Methyl 3,5-O-(tetraisopropylsiloxane-1,3-diyl)-1-thio-
-arabinofuranosid-2-yl] Acetal (8): DDQ (10.3 mg, 49.7 µmol)
D-arabinofur-
D
was added under Ar at room temperature to a mixture of acceptor
7[23] (21.0 mg, 47.6 µmol), donor 2[23] (29.5 mg, 52.4 µmol), and
dried powdered MS (4 Å, 250 mg) in dry CH2Cl2 (2.0 mL). The
DTBMP (2.10 g, 10.3 mmol) and MS (4 Å) in dry (CH2Cl)2 mixture was stirred at the same temperature for 48 h, and further
(200 mL) were added to 5 at room temperature under Ar. MeOTf
(937 µL, 8.30 µmol) was then added to the mixture, which was
stirred at 40 °C for 48 h. After cooling to room temperature, the
reaction mixture was quenched with triethylamine, diluted with
EtOAc, and filtered through Celite. Pyridine (20 mL), Ac2O
(3.0 mL), and a catalytic amount of DMAP were added to the fil-
trate. The mixture was stirred overnight at room temperature and
concentrated in vacuo. The residue was diluted with EtOAc and
washed with satd. aq. NaHCO3 and brine. The washed organic
layer was dried with Na2SO4, and the solvents were evaporated in
vacuo. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 50:1 to 1:1) to give the product
(2.266 g, 90%, β) as the acetate.
DDQ (10.3 mg) was added. The mixture was stirred for 24 h,
quenched with aqueous ascorbate buffer, and filtered through Ce-
lite. The filtrate was extracted with CHCl3 and washed with satd.
aq. NaHCO3 and brine. The combined organic layers were dried
with Na2SO4, and the solvents were evaporated in vacuo. The crude
product was purified by gel filtration chromatography (SX-3;
EtOAc/toluene, 1:1) to give the mixed acetal (49.2 mg, quant.,
3.44:1). 1H NMR (CDCl3, 400 MHz) of the major isomer: δ =
0.87–1.17 (m, 28 H, TIPDS), 2.08 (s, 3 H, SMe), 3.58 (dd, J = 10.8,
5.6 Hz, 1 H, C5-HAraf2), 3.63 (dd, J = 10.8, 3.2 Hz, 1 H, C5-HAraf2),
3.85–4.20 (m, 4 H, C2-HAraf1, C3-HAraf2, C5-HAraf1), 4.18–4.26 (m,
1 H, C4-HAraf2), 4.32–4.36 (m, 2 H, C3-HAraf1, C4-HAraf1), 4.48 (d,
J = 3.2 Hz, 1 H, C2-HAraf2), 5.12 (s, 1 H, C1-HAraf2), 5.28 (d, J =
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A. Ishiwata, Y. Munemura, Y. Ito
FULL PAPER
4.0 Hz, 1 H, C1-HAraf1), 5.80 (s, 1 H, CH Naph), 7.18–7.84 (m, 7 128.9, 132.7, 133.5, 136.9, 150.2, 154.7 ppm. MALDI-TOF MS:
H, Naph) ppm. 13C NMR (CDCl3, 100 MHz): δ = 12.6, 12.9, 13.1,
13.5, 14.3, 17.0, 17.1, 17.3, 17.3, 17.5, 61.1, 69.8, 75.4, 79.8, 80.7,
83.7, 84.4, 86.9, 88.1, 102.5, 105.6, 124.3, 126.2, 126.4, 126.7, 127.0,
127.5, 127.6, 128.2, 128.3, 132.7, 133.7, 134.7, 126–137 ([D7]Bn)
ppm. MALDI TOF MS: calcd. for C55H51D21NaO10SSi [M +
Na]+ 1024.6; found 1024.9.
calcd. for C57H52D14NaO12S [M + Na]+ 1011.5; found 1011.7.
HRMS ESI-TOF: calcd. for C57H52D14NaO12S [M + Na]+
1011.5051; found 1011.5050.
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-β-D-glucopyranosid-2-yl) (Methyl 3-O-[D7]benzyl-4,6-O-
cyclohexylidene-1-thio-β-
D
-glucopyranosid-2-yl) Acetal (13); 11 + 12
Ǟ 13 (Route B): Compound 13 was synthesized from 11[23] and
[D7]Benzyl 2-O-Acetyl-3,5-O-(tetraisopropylsiloxane-1,3-diyl)-β-
D-
12[23] by the procedure used for the synthesis of 13 from 3a and 10
arabinofuranosyl-(1Ǟ2)-3,5-di-O-[D7]benzyl-α- -arabinofuranoside
D
1
(93%, 1:4.17). H NMR (CDCl3, 400 MHz) of the major isomer:
(9): DTBMP (19.8 mg, 96.4 µmol) and MS (4 Å) in dry (CH2Cl)2
(2.41 mL) were added at room temperature under Ar to the mixed
acetal 8 (24.2 mg, 24.1 µmol). MeOTf (9.3 µL, 81.9 µmol) was then
added to the mixture, which was stirred at the same temperature
for 48 h. The reaction mixture was quenched with triethylamine,
diluted with EtOAc, and filtered through Celite. The filtrate was
washed with satd. aq. NaHCO3 and brine. The washed organic
layer was dried with Na2SO4, and the solvents were evaporated in
vacuo. TFA (200 µL) was added at 0 °C to the mixture in CH2Cl2
(2.0 mL), which was stirred at the same temperature for 30 min.
Pyridine (2.0 mL) and Ac2O (200 µL) were added, and the mixture
was stirred at room temperature for 12 h. After concentration, the
residue was diluted with EtOAc and washed with satd. aq.
NaHCO3 and brine. The washed organic layer was dried with
Na2SO4, and the solvents were evaporated in vacuo. The crude
product was purified by PTLC (hexane/EtOAc, 3:1) to give the
product (15.9 mg, 77%, β) as the acetate. [α]2D9 = –42.5 (c = 0.40,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.87–1.25 (m, 28 H,
TIPDS), 1.97 (s, 3 H, Ac), 3.52–3.61 (m, 2 H, C5-HAraf1), 3.75–
3.92 (m, 4 H, C3-HAraf1, C4-HAraf2, C5-HAraf2), 4.23 (dt, J = 5.2,
4.0 Hz, 1 H, C4-HAraf1), 4.27 (d, J = 2.4 Hz, 1 H, C2-HAraf1), 4.27
(d, J = 8.4, 6.0 Hz, 1 H, C3-HAraf2), 4.74 (d, J = 8.4, 4.8 Hz, 1 H,
C2-HAraf2), 4.93 (s, 1 H, C1-HAraf1), 5.25 (d, J = 4.8 Hz, 1 H, C1-
HAraf2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 12.5, 12.8, 13.3,
13.4, 16.95, 16.97, 16.99, 17.40, 17.48, 17.52, 17.60, 20.5, 65.5, 69.8,
75.2, 76.7, 79.1, 80.6, 81.2, 84.0, 86.3, 98.6 (JC–H = 174.0 Hz, C1β-
Araf), 105.4 (JC–H = 170.8 Hz, C1α-Araf), 126–137 ([D7]Bn),
170.4 ppm. MALDI TOF MS: calcd. for C45H43D21NaO11Si2 [M
+ Na]+ 880.5; found 880.4. HRMS ESI-TOF: calcd. for
C45H43D21NaO11Si2 [M + Na]+ 880.5203; found 880.5243.
δ = 1.30–1.61 (m, 20 H, cyclohexyl), 2.04 (m, 3 H, SMe), 2.20 [s, 1
H, SMe (minor)], 2.92 (m, 2 H, C5-HGlcp1, C4-HGlcp2), 3.16–4.03
(m, 18 H, C2-HGlcp1, C3-HGlcp1, C4-HGlcp1, C6-HGlcp1, C2-HGlcp2
,
C3-HGlcp2, C5-HGlcp2, C6-HGlcp2), 4.22 (d, J = 10.4 Hz, 1 H, C1-
HGlcp2), 4.99 (d, J = 8.0 Hz, 1 H, C1-HGlcp1), 6.13 (s, 1 H, CH
Naph), 6.33 (s, 0.3 H, CH Naph), 6.84 (d, J = 9.2 Hz, 2 H, Ar),
6.99 (d, J = 8.8 Hz, 2 H, Ar), 7.43–7.86 (m, 7 H, Ar) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 13.6, 22.4, 22.5, 22.9, 25.5, 25.6,
27.6, 37.96, 38.01, 55.5, 61.4, 61.5, 66.3, 71.3, 72.9, 73.5, 78.3, 79.9,
80.6, 81.7, 86.7, 99.3, 100.5, 107.3, 113.9, 114.2, 117.4, 117.9, 124.3,
125.2, 125.8, 125.9, 127.7, 128.1, 128.3, 129.0, 132.9, 133.6, 137.3,
149.9, 154.8 ppm. MALDI-TOF MS: calcd. for C57H52D14NaO12S
[M + Na]+ 1011.5; found 1011.7. HRMS ESI-TOF: calcd. for
C57H52D14NaO12S [M + Na]+ 1011.5051; found 1011.5035.
4-Methoxyphenyl 3-O-[D7]Benzyl-4,6-di-O-acetyl-α-
D-glucopyrano-
syl-(1Ǟ2)-3-O-[D7]benzyl-2,4,6-tri-O-acetyl-β- -glucopyranoside
D
(14): MeOTf (16.7 µL, 148 µmol), diluted with dry 1,2-dichloroeth-
ane (1.0 mL), was added under Ar at room temperature to a solu-
tion of mixed acetal 13 (41.7 mg, 42.2 µmol), DTBMP (34.6 mg,
169 µmol), and dried powdered MS (4 Å, 1.0 g) in dry 1,2-dichloro-
ethane (6.0 mL). The mixture was stirred at room temperature for
21 h and then quenched with triethylamine, diluted with EtOAc,
and filtered through Celite. The filtrate was washed with satd. aq.
NaHCO3 and brine and dried with Na2SO4, and the solvents were
evaporated in vacuo. TFA (200 µL) was added at 0 °C to the mix-
ture in CH2Cl2 (2.0 mL), which was stirred at the same temperature
for 3 h. Pyridine (5.0 mL), Ac2O (500 µL), and a catalytic amount
of DMAP were added. The mixture was stirred at room tempera-
ture for 12 h and then concentrated in vacuo. The residue was di-
luted with EtOAc, washed with satd. aq. NaHCO3 and brine and
dried with Na2SO4, and the solvents were evaporated in vacuo. The
crude product was purified by gel filtration chromatography (SX-
3; EtOAc/toluene, 1:1) to give product 14 (72%, 25.8 mg) as the
pentaacetate. [α]2D6 = +11.2 (c = 0.50, CHCl3). 1H NMR (C6D6,
400 MHz): δ = 1.55 (s, 3 H, Ac), 1.85 (s, 3 H, Ac), 1.97 (s, 3 H,
Ac), 1.99 (s, 3 H, Ac), 2.06 (s, 3 H, Ac), 3.59 (dd, J = 12.4, 3.6 Hz,
1 H, C6-HGlcp1), 3.67 (dd, J = 12.4, 2.0 Hz, 1 H, C6-HGlcp1), 3.70–
3.78 (m, 2 H, C5-HGlcp2, C3-HGlcp2), 3.74 (s, 3 H, OMe), 3.90 (t, J
= 10.4 Hz, 1 H, C3-HGlcp1), 3.93 (dd, J = 10.4, 8.0 Hz, 1 H, C2-
HGlcp2), 4.05 (ddd, J = 10.4, 3.6, 2.0 Hz, 1 H, C5-HGlcp1), 4.12 (dd,
J = 12.8, 2.0 Hz, 1 H, C6-HGlcp2), 4.22 (dd, J = 12.4, 6.0 Hz, 1 H,
C6-HGlcp1), 4.94 (d, J = 10.4 Hz, 1 H, C1-HGlcp2), 4.98 (dd, J =
10.0, 3.6 Hz, 1 H, C2-HGlcp1), 5.02 (t, J = 8.8 Hz, 1 H, C4-HGlcp1),
5.02 (t, J = 10.0 Hz, 1 H, C4-H), 5.69 (d, J = 3.6 Hz, 1 H, C1-
HGlcp1), 6.80 (d, J = 8.8 Hz, 2 H, Ar), 7.87 (d, J = 8.8 Hz, 2 H,
Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 20.3, 20.7, 20.74 (ϫ2),
20.8, 22.7, 59.2, 61.1, 62.3, 67.9, 69.0, 70.5, 72.0, 72.2, 75.3, 80.5,
95.3 (C1Glcp2), 101.3 (C1Glcp1), 114.6, 117.0, 150.5, 155.3, 169.1,
169.5, 169.6, 170.70 (ϫ 2). MALDI-TOF MS: calcd. for
C43H36D14NaO17 [M + Na]+ 875.4; found 875.7. HRMS ESI-TOF:
calcd. for C43H36D14NaO17 [M + Na]+ 875.3824; found 875.3831.
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-β-D-glucopyranosid-2-yl) (Methyl 3-O-[D7]benzyl-4,6-O-
cyclohexylidene-1-thio-β-
D-glucopyranosid-2-yl) Acetal (13); 3a + 10
Ǟ 13 (Route A): DDQ (32.4 mg, 0.143 mmol) was added under Ar
at room temperature to a mixture of acceptor 10[29] (38.9 mg,
0.0840 mmol), 3a[23] (57.6 mg, 0.109 mmol), and dried powdered
MS (4 Å, 1.0 g) in dry CH2Cl2 (5.0 mL). The mixture was stirred
at the same temperature for 17 h, quenched with aqueous ascorbate
buffer, and filtered through Celite. The filtrate was extracted with
EtOAc and washed with satd. aq. NaHCO3 and brine and dried
with Na2SO4, and the solvents were evaporated in vacuo. The crude
product was purified by gel filtration chromatography (SX-3;
EtOAc/toluene, 1:1) to give the mixed acetal 13 (80.0 mg, 96%,
3.18:1). 1H NMR (CDCl3, 400 MHz) of the major isomer: δ =
1.32–1.62 (m, 28 H, cyclohexyl), 2.35 (s, 3 H, SMe), 3.31–3.87 (m,
18 H, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C2-
HGlcp1, C3-HGlcp1, C4-HGlcp1, C5-HGlcp1, C6-HGlcp1), 4.42 (d, J =
9.6 Hz, 1 H, C1-HGlcp2), 4.88 (d, J = 7.6 Hz, 1 H, C1-HGlcp1), 6.14
[s, 0.35 H, CH Naph (minor)], 6.34 (s, 1 H, CH Naph), 6.37–7.72
(m, 20 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.5, 13.7,
21.5, 22.4, 22.5, 22.9, 25.6, 27.7, 38.0, 55.5, 61.4, 61.5, 66.3, 66.7,
71.2, 72.9, 73.4, 76.3, 78.9, 79.9, 80.6, 81.7, 83.0, 86.3, 86.7, 99.3,
99.5, 100.5, 101.3, 106.0, 107.3, 113.9, 114.2, 117.4, 117.9, 124.3,
4-Methoxyphenyl 3-O-[D7]Benzyl-4,6-O-cyclohexylidene-2-O-(2-
124.6, 125.2, 125.6, 125.9, 126.2, 127.4, 127.9, 128.08, 128.12, naphthylmethyl)-α-
D-glucopyranosyl-(1Ǟ2)-3-O-[D7]benzyl-4,6-O-
4256
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4250–4263

NAP Ether Mediated Intramolecular Aglycon Delivery
cyclohexylidene-β-
O-[D7]Benzyl-4,6-O-cyclohexylidene-α-
O-[D7]benzyl-4,6-O-cyclohexylidene-β-
D
-glucopyranoside (15) and 4-Methoxyphenyl 3- HGlcp2), 4.81 (d, J = 8.4 Hz, 1 H, C1-HGlcp1), 6.09 (s, 1 H, CH
D
-glucopyranosyl-(1Ǟ2)-3-
Naph), 6.10 (d, J = 8.8 Hz, 2 H, Ar), 6.32 (d, J = 9.2 Hz, 2 H, Ar),
7.37–7.71 (m, 7 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ =
13.6, 14.4, 18.4, 22.3, 22.4, 22.7, 22.8, 25.5, 25.7, 27.6, 37.8, 37.9,
55.5, 61.2, 61.4, 66.5, 71.2, 72.8, 74.2, 77.7, 80.3, 80.7, 86.7, 99.4,
99.4, 101.0, 106.8, 113.6, 117.1, 124.6, 125.5, 125.7, 126.2, 127.4,
127.8, 128.0, 132.7, 133.4, 137.3, 139.4, 149.8, 154.5 ppm. MALDI-
TOF MS: calcd. for C59H73D7NaO12SSi [M + Na]+ 1070.5; found
1070.7. HRMS ESI-TOF: calcd. for C59H73D7NaO12SSi [M +
Na]+ 1070.5477; found 1070.5516.
D
-glucopyranoside (16): Me-
OTf (12.7 µL, 112 µmol) was added under Ar at room temperature
to a solution of mixed acetal 13 (31.7 mg, 32.0 µmol), DTBMP
(26.3 mg, 128 µmol), tris(trimethylsilyl)silane (49.4 µL, 160 µmol),
and dried powdered MS (4 Å, 1.0 g) in dry 1,2-dichloroethane
(8.0 mL). The mixture was stirred at room temperature for 17 h
and then quenched with triethylamine, diluted with EtOAc, and
filtered through Celite. The filtrate was diluted with EtOAc, washed
with satd. aq. NaHCO3 and brine and dried with Na2SO4, and the
solvents were evaporated in vacuo. The crude product was purified
by gel filtration chromatography (SX-3; EtOAc/toluene, 1:1) and
by PTLC (EtOAc/hexane, 1:6) to give product 15 (73%, 22.0 mg)
as the NAP ether and 16 (4.7 mg, 16%). DDQ treatment of the
crude mixture without any purification was carried out to give 16
(85%) as described for the synthesis of 11 from 3a.
4-Methoxyphenyl 4,6-O-Cyclohexylidene-2-O-(2-naphthylmethyl)-3-
O-triisopropylsilyl-α-
O-cyclohexylidene-β-
D
-glucopyranosyl-(1Ǟ2)-3-O-[D7]benzyl-4,6-
-glucopyranoside (18): DTBMP (33.5 mg,
D
163 µmol), MS (4 Å, 1.0 g), and tris(trimethylsilyl)silane (63.0 µL,
204 µmol) in dry 1,2-dichloroethane (10 mL) were added under Ar
at room temperature to mixed acetal 17 (42.8 mg, 40.8 µmol). Me-
OTf (16.2 µL, 143 µmol) was then added to the mixture, which was
stirred at room temperature. for 14 h The reaction mixture was
quenched with TEA, diluted with EtOAc, and filtered through Ce-
1
Compound 15: [α]2D6 = +29.8 (c = 0.92, CHCl3). H NMR (C6D6,
400 MHz): δ = 1.27–1.76 (m, 20 H, cyclohexyl), 2.98 (td, J = 10.0,
5.6 Hz, 1 H, C5-HGlcp2), 3.22 (s, 3 H, OMe), 3.55 (t, J = 10.8 Hz, lite. The filtrate was extracted with EtOAc and washed with satd.
1 H, C6-HGlc2), 3.64–3.90 (m, 7 H, C3-HGlc2, C4-HGlc2, C6-HGlc2
,
aq. NaHCO3 and brine. The combined organic layers were dried
C2-HGlc1, C4-HGlc1, C6-HGlcp1), 4.06 (dd, J = 10.4, 5.2 Hz, 1 H, with Na2SO4. After filtration and concentration, the crude product
C6-HGlcp1), 4.19 (t, J = 8.0 Hz, 1 H, C2-HGlcp2), 4.31 (t, J = 9.2 Hz, was purified by gel filtration chromatography (SX-3; EtOAc/tolu-
1 H, C3-HGlcp1), 4.70 (d, J = 11.6 Hz, 1 H, NAP), 4.80 (m, 2 H,
ene, 1:1) and by PTLC (EtOAc/hexane, 1:6) to give the product as
C5-HGlcp1, NAP), 4.93 (d, J = 8.0 Hz, 1 H, C1-HGlcp2), 5.96 (d, J NAP ether 18 (33.2 mg, 82%). [α]2D7 = +24.3 (c = 2.76, CHCl3). 1H
= 3.6 Hz, 1 H, C1-HGlcp1), 6.58 (d, J = 8.8 Hz, 2 H, Ar), 6.91 (d,
NMR (C6D6, 400 MHz): δ = 1.28–1.72 (m, 41 H, cyclohexyl,
J = 8.8 Hz, 2 H, Ar), 7.22–7.62 (m, 7 H, NAP) ppm. 13C NMR TIPS), 2.92 (td, J = 10.0, 5.2 Hz, 1 H, C5-HGlcp2), 3.15 (s, 3 H,
(C6D6, 100 MHz): δ = 22.8, 23.0, 23.4, 23.5, 25.9, 26.2, 27.9, 28.2, OMe), 3.49–3.75 (m, 7 H, C2-HGlcp1, C4-HGlcp1, C6-HGlcp1, C3-
38.6, 38.7, 55.2, 61.6, 62.4, 64.1, 67.1, 73.5, 75.0, 75.2, 76.6, 77.9,
78.9, 80.5, 97.4 (C1Glcp2), 99.6, 99.7, 102.6 (C1Glcp1), 114.9, 118.6, HGlcp1), 3.64 (d, J = 8.4 Hz, 1 H, C2-HGlcp2), 4.56–4.73 (m, 4 H,
125.9, 126.1, 126.1, 126.4, 133.4, 133.8, 136.6, 151.1, 155.9 ppm.
C3-HGlcp1, C5-HGlcp1, NAP), 4.93 (d, J = 7.6 Hz, 1 H, C1HGlcp2),
MALDI-TOF MS: calcd. for C56H50D14NaO12 [M + Na]+ 965.5; 6.01 (d, J = 3.6 Hz, 1 H, C1-HGlcp1), 6.45 (d, J = 8.8 Hz, 2 H, Ar),
HGlcp2, C4-HGlcp2, C6-HGlcp2), 4.03 (dd, J = 10.4 Hz, 1 H, C6-
found 966.1. HRMS ESI-TOF: calcd. for C56H50D14NaO12 [M +
6.76 (d, J = 8.8 Hz, 2 H, Ar), 7.23–7.71 (m, 7 H, NAP) ppm. 13C
NMR (C6D6, 100 MHz): δ = 13.7, 18.8, 18.9, 22.8, 22.9, 23.2, 23.4,
25.9, 26.3, 27.9, 28.2, 38.6, 55.1, 61.6, 62.0, 64.2, 67.1, 72.1, 72.8,
74.55, 74.64, 76.4, 78.9, 81.7, 96.5 (C-1Glcp2), 99.6 (ϫ2), 102.2 (C-
1Glcp1), 114.8, 117.9, 125.4, 125.6, 125.8, 126.2, 133.3, 133.8, 136.4,
138.4, 150.7, 155.6 ppm. MALDI-TOF MS: calcd. for
C58H71D7NaO12Si [M + Na]+ 1024.6; found 1025.1. HRMS ESI-
TOF: calcd. for C58H71D7NaO12Si [M + Na]+ 1024.5600; found
1024.5578.
Na]+ 965.5174; found 965.5205.
1
Compound 16: [α]2D6 = +39.1 (c = 0.43, CHCl3). H NMR (C6D6,
400 MHz): δ = 1.21–1.89 (m, 20 H, cyclohexyl), 2.11 (br. s, 1 H,
OH), 3.05 (td, J = 10.0, 5.6 Hz, 1 H, C5-HGlcp2), 3.28 (s, 3 H,
OMe), 3.50 (t, J = 9.2 Hz, 1 H, C3-HGlcp2), 3.60–3.88 (m, 7 H, C2-
HGlcp2, C4-HGlcp2, C6-HGlcp2, C6-HGlcp2, C3-HGlcp1, C4-HGlcp1, C6-
HGlcp1), 3.93 (dd, J = 10.4, 5.6 Hz, 1 H, C6-HGlcp1), 4.00 (t, J =
9.2 Hz, 1 H, C2-HGlcp1), 4.51 (td, J = 10.4, 5.2 Hz, 1 H, C5-HGlcp1),
4.61 (d, J = 8.0 Hz, 1 H, C1-HGlcp2), 5.71 (d, J = 3.2 Hz, 1 H, C1- 2-Naphthaldehyde (4-Methoxyphenyl 2,3,4-tri-O-[D7]benzyl-β-
D-
HGlcp1), 6.73 (d, J = 8.8 Hz, 2 H, Ar), 7.03 (d, J = 8.8 Hz, 2 H,
Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 21.5, 22.8, 23.0, 23.4,
23.5, 25.9, 26.1, 27.9, 28.1, 38.6, 38.7, 55.2, 61.7, 62.1, 64.4, 67.4,
73.5, 74.5, 74.9, 77.9, 78.1, 79.8, 99.6 (C1Glcp2), 99.7 (ϫ2), 104.0
(C1Glcp1), 114.8, 120.3, 125.7, 151.6, 156.5 ppm. MALDI-TOF MS:
calcd. for C45H42D14NaO12 [M + Na]+ 825.5; found 825.6. HRMS
ESI-TOF: calcd. for C45H42D14NaO12 [M + Na]+ 825.4548; found
825.4536.
glucopyranosid-6-yl) (Methyl 3-O-[D7]benzyl-4,6-O-cyclohexylidene-
1-thio-β-D-glucopyranosid-2-yl) Acetal (24); 3a + 23 Ǟ 24: The title
compound was synthesized from 3a and 23[23] by the procedure
used for the synthesis of 16 (91 %, 2.32:1). 1H NMR (CDCl3,
400 MHz) of the major isomer: δ = 1.24–1.64 (m, cyclohexyl, 10
H), 2.29 (s, 3 H, SMe), 3.25–4.04 (m, 15 H, C2-HGlcp2, C3-HGlcp2
,
,
C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C6-HGlcp2, C2-HGlcp1, C3-HGlcp1
C4-HGlcp1, C5-HGlcp1, C6-HGlcp1, C6-HGlcp1, OMe), 4.49 (d, J =
9.2 Hz, 1 H, C1-HGlcp2), 4.85 (d, J = 8.0 Hz, 1 H, C1-HGlcp1), 6.16
[s, 1 H, CH Naph (major)], 6.22 [s, 0.43 H, CH Naph (minor)],
6.67–7.41 (m, 11 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ =
12.1, 21.5, 22.5, 23.0, 25.6, 27.7, 27.8, 38.0, 55.6, 61.4, 64.2, 71.4,
73.9, 74.8, 76.1, 77.6, 81.9, 83.5, 84.5, 85.1, 99.5, 102.3, 103.6,
114.6, 118.0, 124.8, 125.2, 125.9, 126.0, 126.1, 126.3, 127.6, 128.0,
128.1, 128.2, 128.9, 132.8, 133.4, 136.0, 151.4, 154.9 ppm. MALDI-
TOF MS: calcd. for C65H42D28NaO12S [M + Na]+ 1125.6; found
1125.3.
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-β-
4,6-O-cyclohexylidene-1-thio-β-
D
-glucopyranosid-2-yl) (Methyl 3-O-triisopropylsilyl-
-glucopyranosid-2-yl) Acetal (17);
D
3b + 10 Ǟ 17: The title compound was synthesized from 3b[23] and
10 by the procedure used for the synthesis of 13 (84%, Ͼ10.0:1).
1H NMR (CDCl3, 400 MHz) of the major isomer: δ = 0.94–1.58
(m, 41 H, cyclohexyl, TIPS), 2.21 (s, 3 H, SMe), 3.13 (td, J = 10.4,
5.2 Hz, 1 H, C5-HGlcp2), 3.22 (t, J = 9.6 Hz, 1 H, C6-HGlcp1), 3.28–
3.37 (m, 2 H, C4-HGlcp1, C5-HGlcp1), 3.58 (s, 3 H, OMe), 3.67–3.84
(m, 6 H, C3-HGlcp2, C6-HGlcp1, C4-HGlcp2, C6-HGlcp2), 3.89 (t, J = 4-Methoxyphenyl 4,6-O-Cyclohexylidene-3-O-[D7]benzyl-α-
8.0 Hz, 1 H, C2-HGlcp1), 3.98 (t, J = 8.8 Hz, 1 H, C3-HGlcp1), 4.28 pyranosyl-(1Ǟ6)-2,3,4-tri-O-[D7]benzyl-β-
-glucopyranoside (25):
(t, J = 8.8 Hz, 1 H, C2-HGlcp2), 4.48 (d, J = 8.8 Hz, 1 H, C1- Compound 25 was synthesized from 24 by the procedure used for
D-gluco-
D
Eur. J. Org. Chem. 2008, 4250–4263
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4257

A. Ishiwata, Y. Munemura, Y. Ito
FULL PAPER
the synthesis of 16 (12.4 mg, 63%). [α]2D7 = 50.0 (c = 0.06, CHCl3).
1H NMR (C6D6, 400 MHz): δ = 1.34–1.68 (m, 10 H, cyclohexyl),
2.32 (br. s, 1 H, OH), 3.26–3.33 (m, 4 H, C5-HGlcp1, OMe), 3.55–
Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 13.6, 21.5, 22.5, 22.8,
23.2, 23.4, 25.9, 25.9, 26.1, 26.4, 27.2, 28.0, 28.1, 30.6, 38.3, 38.5,
55.2, 61.8, 67.3, 71.6, 71.8, 73.7, 74.7, 75.6, 79.1, 80.2, 81.7, 82.3,
3.97 (m, 11 H, C2-HGlcp1, C3-HGlcp1, C4-HGlcp1, C6-HGlcp1, C6- 83.9, 87.0, 99.5, 99.6, 100.1, 103.9, 105.5, 106.4, 107.2, 114.8, 114.9,
HGlc1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C6-
HGlcp2), 4.84 (d, J = 7.6 Hz, 1 H, C1-HGlcp2), 4.87 (d, J = 3.6 Hz, 155.9 ppm. MALDI-TOF MS: calcd. for C57H52D14NaO12S [M +
119.2, 125.6, 126.1, 126.6, 126.9, 133.4, 134.0, 137.8, 139.5, 151.9,
1 H, C1-HGlcp1), 6.85 (d, J = 8.8 Hz, 2 H, Ar), 7.19 (d, J = 8.8 Hz,
Na]+ 1011.5; found 1011.7. HRMS ESI-TOF: calcd. for
2 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 22.9, 23.4, 26.1, C57H52D14NaO12S [M + Na]+ 1011.5051; found 1011.5050.
28.1, 38.5, 55.2, 62.2, 64.6, 67.1, 73.4, 74.4, 74.5, 77.7, 82.5, 84.9,
4-Methoxyphenyl 4,6-O-Cyclohexylidene-3-O-[D7]benzyl-α-
pyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
D
-gluco-
99.7 (C1Glcp2), 99.9, 103.8 (C1Glcp1), 115.1, 119.7, 152.0, 156.2 ppm.
MALDI-TOF MS: calcd. for C53H32D28NaO12 [M + Na]+ 939.6;
found 940.0. HRMS ESI-TOF: calcd. for C53H32D28NaO12 [M +
Na]+ 939.5740; found 939.5749.
D-gluco-
pyranoside (31): Compound 31 was synthesized from 29 by the pro-
cedure used for the synthesis of 16 (89%). [α]2D7 = +47.9 (c = 1.59,
1
CHCl3). H NMR (C6D6, 400 MHz): δ = 1.28–1.90 (m, 20 H, cy-
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-cyclohex- clohexyl), 2.71 (br. s, 1 H, OH), 3.05 (td, J = 10.0, 5.6 Hz, 1 H,
ylidene-β-
D
-glucopyranosid-2-yl) (Methyl 3,4,6-tri-O-[D7]benzyl-1-
C5-H Glcp2), 3.28 (s, 3 H, OMe), 3.51–3.74 (m, 7 H, C2-HGlcp2, C4-
HGlcp2, C6-HGlcp2, C6-HGlcp2, C3-HGlcp1, C4-HGlcp1, C6-HGlcp1),
3.82–3.87 (m, 3 H, C2-HGlcp1, C6-HGlcp1, C3-HGlcp2), 4.35 (td, J =
10.0, 5.2 Hz, 1 H, C5-HGlcp1), 4.79 (d, J = 7.6 Hz, 1 H, C1-HGlcp2),
5.51 (d, J = 2.8 Hz, 1 H, C1-H Glcp1), 6.71 (d, J = 8.8 Hz, 2 H, Ar),
7.01 (d, J = 8.8 Hz, 2 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ
= 22.7, 22.9, 23.2, 23.5, 25.9, 26.1, 28.0, 28.11, 38.3, 38.7, 55.2,
61.6, 62.2, 64.7, 67.1, 73.4, 74.0, 74.3, 79.2, 80.2, 80.4, 99.7, 100.1,
101.0 (C1Glcp2), 104.1 (C1Glcp1), 115.0, 151.7, 156.1 ppm. MALDI-
TOF MS: calcd. for C45H42D14NaO12 [M + Na]+ 825.5; found
thio-β-
D
-glucopyranosid-2-yl) Acetal (26); 3c + 10 Ǟ 26: The title
compound was synthesized from 3c[23] and 10 by the procedure
used for the synthesis of 13 (94 %, 3.11:1). 1H NMR (CDCl3,
400 MHz) of the major isomer: δ = 1.20–1.75 (m, 9 H, cyclohexyl),
2.04–2.12 (m, 1 H, cyclohexyl), 2.26 (s, 3 H, SMe), 3.19 (d, J =
9.6 Hz, 1 H, C4-HGlcp1), 3.33–4.02 (m, 14 H, C2-HGlcp1, C3-HGlcp1
,
,
C5-HGlcp1, C6-HGlcp1, C6-HGlcp1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2
C5-HGlcp2, C6-HGlcp2, C6-HGlcp2, OMe), 4.42 (d, J = 9.6 Hz, 1 H,
C1-HGlcp1), 4.92 (d, J = 7.6 Hz, 1 H, C1-HGlcp1), 6.19 [s, 0.44 H,
CH Naph (minor)], 6.27 [s, 1 H, CH Naph (major)], 6.75–8.01 (m, 825.5. HRMS ESI-TOF: calcd. for C45H42D14NaO12 [M + Na]+
11 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.4, 22.3, 22.8,
25.5, 27.5, 37.9, 55.5, 61.4, 66.6, 68.9, 72.4, 73.8, 76.8, 78.1, 79.1,
81.0, 85.6, 86.4, 99.5, 100.9, 106.4, 113.9, 117.3, 124.6, 125.6, 125.9,
127.0, 127.5, 128.0, 128.2, 129.0, 134.5, 136.4, 150.4, 154.7 ppm.
MALDI-TOF MS: calcd. for C65H42D28NaO12S [M + Na]+
1125.6; found 1125.4.
825.4548; found 825.4586.
2-Naphthaldehyde (4-Methoxyphenyl 2-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-β-
4,6-O-cyclohexylidene-1-thio-β-
D
-glucopyranosid-3-yl) (Methyl 3-O-triisopropylsilyl-
-glucopyranosid-2-yl) Acetal (30);
D
3b + 28 Ǟ 30: The title compound was synthesized from 3b and
28 by the procedure used for the synthesis of 13 (84%, 11.1:1). H
1
4-Methoxyphenyl 3,4,6-Tri-O-[D7]benzyl-α-
(1Ǟ2)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-β-
D
-glucopyranosyl-
-glucopyranoside
NMR (CDCl3, 400 MHz) of the major isomer: δ = 0.98–1.59 (m,
41 H, cyclohexyl, TIPS), 2.23 (s, 3 H, SMe), 3.25–3.89 (m, 13 H,
D
(27): Compound 27 was synthesized from 26 by the procedure used
C2-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C2-HGlcp1, C4-HGlcp1
,
for the synthesis of 16 (77%, 2.17:1). Major isomer: [α]2D7 = 42.0 (c
C5-HGlcp1, C6-HGlcp1, OMe), 4.08 (t, J = 8.4 Hz, 1 H, C3-HGlcp1),
4.27 (t, J = 8.0 Hz, 1 H, C3-HGlcp2), 4.57 (d, J = 8.0 Hz, 1 H, C1-
1
= 1.0, CHCl3). H NMR (C6D6, 400 MHz): δ = 1.10–1.95 (m, 10
H, cyclohexyl), 2.11 (d, J = 8.8 Hz, 1 H, OH), 3.12 (td, J = 10.0, HGlcp2), 4.98 (d, J = 8.8 Hz, 1 H, C1-HGlcp1), 6.14 (s, 1 H, CH
5.6 Hz, 1 H, C5-HGlcp1), 3.28 (s, 3 H, OMe), 3.48–3.54 (m, 2 H,
C3-HGlcp1, C6-HGlcp2), 3.58 (dd, J = 9.2, 2.8 Hz, 1 H, C6-HGlcp2), 7.44–7.84 (m, 7 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ =
Naph), 6.78 (d, J = 9.2 Hz, 2 H, Ar), 6.91 (d, J = 9.2 Hz, 2 H, Ar),
3.62–3.74 (m, 2 H, C4-HGlcp1, C6-HGlcp2), 3.78–3.95 (m, 2 H, C5-
13.6, 14.6, 18.5, 18.5, 21.5, 22.0, 22.4, 22.7, 25.2, 25.7, 26.4, 27.5,
HGlcp1, C6-HGlcp1), 3.94 (t, J = 10.4 Hz, 1 H, C4-HGlcp1), 4.02 (t, J 37.4, 37.8, 55.6, 61.3, 61.4, 66.9, 70.5, 72.8, 75.7, 80.9, 86.1, 99.4,
= 8.8 Hz, 1 H, C3-HGlcp1), 4.10 (t, J = 8.0 Hz, 1 H, C2-HGlcp2), 103.7, 104.8, 114.4, 118.4, 124.8, 125.2, 125.8, 125.8, 126.2, 127.6,
4.48 (br. d, J = 10.0 Hz, 1 H, C5-HGlcp1), 4.73 (d, J = 8.0 Hz, 1 H,
128.1, 132.7, 133.5, 137.8, 138.3, 138.9, 151.1, 155.3 ppm. MALDI-
C1-HGlcp2), 5.78 (d, J = 4.0 Hz, 1 H, C1-HGlcp1), 6.70–7.36 (m, 4 TOF MS: calcd. for C59H73D7NaO12SSi [M + Na]+ 1070.54; found
H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 22.5, 23.0, 25.5, 1070.69. HRMS ESI-TOF: calcd. for C59H73D7NaO12SSi [M +
27.6, 38.2, 54.8, 61.4, 67.2, 68.7, 71.3, 73.7, 74.3, 77.0, 77.8, 79.3,
83.4, 98.8 (C1Glcp2), 99.4, 103.8 (C1Glcp1), 114.8, 119.7, 126.0–129.0
(overlapped with C6D6 signal), 151.4, 156.2 ppm. MALDI-TOF
MS: calcd. for C53H32D28NaO12 [M + Na]+ 939.6; found 940.0.
HRMS ESI-TOF: calcd. for C53H32D28NaO12 [M + Na]+
939.5740; found 939.5713.
Na]+ 1070.5477; found 1070.5518.
4-Methoxyphenyl 4,6-O-Cyclohexylidene-2-O-(2-naphthylmethyl)-3-
O-triisopropylsilyl-α-
O-cyclohexylidene-α-
D
-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-
-glucopyranoside (32): Compound 32 was
D
synthesized from 30 by the procedure used for the synthesis of 18
(83%). [α]2D7 = +45.5 (c = 0.95, CHCl3). 1H NMR (C6D6,
400 MHz): δ = 1.23–1.76 (m, 41 H, cyclohexyl, TIPS), 3.12 (td, J
= 10.0, 5.6 Hz, 1 H, C5-HGlcp2), 3.27 (s, 3 H, OMe), 3.55 (t, J =
10.4 Hz, 1 H, C6-HGlcp2), 3.58 (dd, J = 10.4, 5.2 Hz, 1 H, C2-
HGlcp1), 3.64 (dd, J = 10.0, 5.6 Hz, 1 H, C6-HGlcp2), 3.70–3.84 (m,
4 H, C4-HGlcp1, C6-HGlcp1, C2-HGlcp2, C4-HGlpc2), 4.11 (dd, J =
10.0, 5.6 Hz, 1 H, C6-HGlcp1), 4.15 (t, J = 5.2 Hz, 1 H, C3-HGlcp2),
4.70 (d, J = 11.6 Hz, 1 H, NAP), 4.80 (d, J = 7.6 Hz, 1 H, C1-
HGlcp2), 5.12 (d, J = 11.2 Hz, 1 H, NAP), 5.98 (d, J = 3.6 Hz, 1 H,
C1-HGlcp1), 6.58 (d, J = 8.8 Hz, 2 H, Ar), 6.91 (d, J = 8.8 Hz, 2 H,
Ar), 7.22–7.62 (m, 7 H, NAP) ppm. 13C NMR (C6D6, 100 MHz):
δ = 13.6, 18.8, 18.8, 22.9, 23.2, 23.2, 25.8, 27.6, 28.2, 38.4, 55.2,
2-Naphthaldehyde (4-Methoxyphenyl 2-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-β-D-glucopyranosid-3-yl) (Methyl 3-O-[D7]benzyl-4,6-O-
cyclohexylidene-1-thio-β-
D
-glucopyranosid-2-yl) Acetal (29); 3a + 28
Ǟ29: The title compound was synthesized from 3a and 28[28] by
the procedure used for the synthesis of 13 (97%, 3.00:1). 1H NMR
(CDCl3, 400 MHz) of the major isomer: δ = 1.22–1.81 (m, 20 H,
cyclohexyl), 2.34 (s, 3 H, SMe), 3.22–4.38 (m, 25 H, C2-HGlcp1
,
,
C3-HGlcp1, C4-HGlcp1, C5-HGlcp1, C6-HGlcp1, C2-HGlcp2, C3-HGlcp2
C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, OMe), 4.44 (d, J = 9.6 Hz, 1 H,
C1-HGlcp2), 4.95 (d, J = 7.2 Hz, 1 H, C1-HGlcp1), 6.31 [s, 0.31 H,
CH Naph (minor)], 6.38 (s, 1 H, CH Naph), 6.38–8.33 (m, 25 H,
4258
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4250–4263

NAP Ether Mediated Intramolecular Aglycon Delivery
61.3, 62.1, 64.2, 67.1, 71.9, 72.5, 74.3, 74.6, 75.9, 80.6, 81.7, 96.9
(C1Glcp2), 99.6 (ϫ2), 103.8 (C1Glcp1), 114.9, 119.1, 125.3, 125.7,
126.0, 133.9, 136.6, 151.7, 156.0 ppm. MALDI-TOF MS: calcd. for
C58H71D7NaO12Si [M + Na]+ 1024.6; found 1024.9. HRMS ESI-
TOF: calcd. for C58H71D7NaO12Si [M + Na]+ 1024.5600; found
1024.5549.
HRMS ESI-TOF: calcd. for C59H73D7NaO12SSi [M + Na]+
1070.5477; found 1070.5481.
4-Methoxyphenyl 4,6-O-Cyclohexylidene-2-O-(2-naphthylmethyl)-3-
O-triisopropylsilyl-α-
O-cyclohexylidene-α-
D
-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-
-mannopyranoside (37): Compound 37 was
D
synthesized from 35 by the procedure used for the synthesis of 18
(86%). [α]2D6 = +104.8 (c = 0.92, CHCl3). 1H NMR (C6D6,
400 MHz): δ = 1.21–1.78 (m, 41 H, cyclohexyl, TIPS), 3.29 (s, 3 H,
2-Naphthaldehyde (4-Methoxyphenyl 2-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-α-
O-cyclohexylidene-1-thio-β-
D
-mannopyranosid-3-yl) (Methyl 3-O-[D7]benzyl-4,6-
-glucopyranosid-2-yl) Acetal (34); 3a +
D
OMe), 3.58–4.18 (m, 9 H, C2-HGlcp, C4-HGlcp, C5-HGlcp, C6-HGlcp
,
33 Ǟ34: The title compound was synthesized from 3a and 33[29] by
the procedure used for the synthesis of 13 (101.3 mg, 97%, 3.11:1).
1H NMR (CDCl3, 400 MHz) of the major isomer: δ = 1.22–1.81
(m, 20 H, cyclohexyl), 2.23 (s, 3 H, SMe), 3.34–3.38 (m, 1 H, C5-
HGlcp), 3.64–4.41 (m, 11 H, C2-HGlcp, C3-HGlcp, C4-HGlcp, C6-
HGlcp, C2-HManp, C4-HManp, C5-HManp, C6-HManp, OMe), 4.55 (d,
J = 9.6 Hz, 1 H, C1-HGlcp), 4.63 (dd, J = 10.0, 9.6 Hz, 1 H, C3-
HManp), 5.31 (d, J = 1.6 Hz, 1 H, C1-HManp), 6.24 [s, 0.22 H, CH
Naph (minor)], 6.43 (s, 1 H, CH Naph), 6.47–6.88 (m, 5 H, Ar),
7.44–7.86 (m, 11 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ =
13.0, 22.1, 22.4, 22.7, 22.9, 25.4, 25.5, 27.5, 27.7, 37.9, 37.9, 55.6,
61.4, 61.5, 65.4, 71.1, 74.3, 75.0, 83.0, 85.5, 98.5, 99.5, 99.8, 104.4,
114.4, 114.5, 117.6, 117.9, 124.7, 125.4, 125.7, 125.8, 127.5, 127.6,
128.1, 132.8, 133.3, 138.0, 149.9, 154.7 ppm. MALDI-TOF MS:
calcd. for C57H52D14NaO12S [M + Na]+ 1011.5; found 1011.3.
HRMS ESI-TOF: calcd. for C57H52D14NaO12S [M + Na]+
1011.5051; found 1011.5050.
C2-HManp, C5-HManp, C6-HManp), 4.54 (t, J = 9.2 Hz, 1 H, C3-
HGlcp), 4.65–4.75 (m, 3 H, C3-HManp, C4-HManp, NAP), 5.13 (d, J
= 11.6 Hz, 1 H, NAP), 5.52 (s, 1 H, C-1HManp), 5.90 (d, J = 3.6 Hz,
1 H, C1-HGlcp), 6.68 (d, J = 9.2 Hz, 2 H, Ar), 6.87 (d, J = 8.8 Hz,
2 H, Ar), 7.24–8.03 (m, 7 H, Ar) ppm. 13C NMR (C6D6, 100 MHz):
δ = 13.5, 18.8, 22.6, 22.9, 23.2, 23.2, 25.8, 26.2, 27.8, 28.2, 38.8,
55.2, 61.5, 62.2, 64.8, 66.7, 71.3, 71.7, 72.6, 73.5, 74.6, 79.3, 81.2,
97.9 (C1Glcp), 99.0 (C1Manp), 100.06 (ϫ2), 115.0, 118.2, 125.8,
126.1, 126.4, 133.4, 133.9, 136.6, 138.6, 150.3, 155.6 ppm. MALDI-
TOF MS: calcd. for C58H71D7NaO12Si [M + Na]+ 1024.6; found
1025.0. HRMS ESI-TOF: calcd. for C58H71D7NaO12Si [M + Na]+
1024.5600; found 1024.5601.
4-Methoxyphenyl 2-O-[D7]Benzyl-4,6-O-cyclohexylidene-α-
pyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
D
-gluco-
D-manno-
pyranoside (39): DDQ (22.3 mg, 98.5 µmol) was added at room
temperature to a solution of NAP ether 37 (32.9 mg, 32.8 µmol)
and NaHCO3 (27.6 mg, 328 µmol) in dry 1,2-dichloroethane
(3.0 mL). The mixture was stirred at room temperature for 14 h.
After addition of aqueous ascorbate buffer solution, the product
was extracted with EtOAc. The combined extracts were washed
with satd. aq. NaHCO3 and brine. The washed organic layer was
dried with Na2SO4. After filtration and concentration, the residue
was purified by PTLC (hexane/EtOAc, 5:1) to give 38 (24.2 mg,
86 %). NaH (16.0 mg, 40.0 µmol) and then [D7]BnBr (4.0 µL,
32.0 µmol) were added at 0 °C to a solution of alcohol 38 (23.0 mg,
26.7 µmol) in dry DMF (2.0 mL), and the mixture was stirred for
3 h, during which the temperature was allowed to rise to room tem-
perature. After addition of triethylamine and brine to the mixture,
the product was extracted with EtOAc. The combined extracts were
washed with brine and dried with Na2SO4. After filtration and con-
centration, the residue was used for the next reaction without fur-
ther purification. A TBAF solution in THF (1 , 80.0 µL,
80.0 µmol) was added at room temperature to a solution of the
mixture in dry THF (2.0 mL), and the mixture was stirred for 16 h.
After concentration, the residue was purified by PTLC (hexane/
EtOAc, 4:1) to give the title compound 39[29] (16.1 mg, 75% in two
4-Methoxyphenyl 4,6-O-Cyclohexylidene-3-O-[D7]benzyl-α-
D-gluco-
pyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
D-manno-
pyranoside (36): Compound 36 was synthesized from 34 by the pro-
cedure used for the synthesis of 16 (74%). [α]2D7 = +101.3 (c = 1.67,
1
CHCl3). H NMR (C6D6, 400 MHz): δ = 1.23–1.86 (m, 20 H, cy-
clohexyl), 3.00 (br. s, 1 H, OH), 3.29 (s, 3 H, OMe), 3.63–4.18
(m, 10 H, C2-HGlcp, C4-HGlcp, C5-HGlcp, C6-HGlcp, C6-HGlcp, C3-
HManp, C4-HManp, C5-HManp, C6-HManp, C6-HManp), 4.54 (t, J =
9.2 Hz, 1 H, C3-HGlcp), 4.42 (dd, J = 10.0, 3.6 Hz, 1 H, C2-HManp),
5.31 (d, J = 3.6 Hz, 1 H, C1-HGlcp), 5.47 (d, J = 1.2 Hz, 1 H, C1-
HManp), 6.70 (d, J = 8.8 Hz, 2 H, Ar), 6.89 (d, J = 8.8 Hz, 2 H,
Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 22.9, 23.2, 23.4, 25.9,
26.1, 28.1, 28.2, 38.5, 38.7, 55.20, 61.7, 62.3, 65.3, 66.5, 70.7, 74.0,
74.1, 77.2, 78.9, 80.3, 98.2 (C1Manp), 99.8, 100.6, 102.1 (C1Glcp),
115.0, 118.2, 150.3, 155.8 ppm. MALDI-TOF MS: calcd. for
C45H42D14NaO12 [M + Na]+ 825.5; found 825.8. HRMS ESI-TOF:
calcd. for C45H42D14NaO12 [M + Na]+ 825.4548; found 825.4534.
2-Naphthaldehyde (4-Methoxyphenyl 2-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-α-
4,6-O-cyclohexylidene-1-thio-β-
D
-mannopyranosid-3-yl) (Methyl 3-O-triisopropylsilyl-
D
-glucopyranosid-2-yl) Acetal (35); steps). [α]2D8 = –125.2 (c = 1.00, CHCl3). 1H NMR (C6D6,
3b + 33 Ǟ 35: The title compound was synthesized from 3b and
33 by the procedure used for the synthesis of 13 (90%, 14.3:1). H
400 MHz): δ = 1.00–2.10 (m, 20 H, cyclohexyl ϫ2), 2.48 (br. s, 1
H, OH), 3.29 (s, 3 H, OMe), 3.59 (dd, J = 9.2, 4.0 Hz, 1 H, C2-
HGlcp), 3.69 (t, J = 9.2 Hz, 1 H, C4-HGlcp), 3.73–3.79 (m, 2 H, C6-
HManp), 3.80 (t, J = 10.4 Hz, 1 H, C6-HGlcp), 3.98 (t, J = 1.2 Hz, 1
H, C2-HManp), 4.02 (dd, J = 10.4, 5.6 Hz, 1 H, C6-HGlcp), 4.04–
1
NMR (CDCl3, 400 MHz) of the major isomer: δ = 1.00–1.57 (m,
41 H, cyclohexyl, TIPS), 2.19 (s, 3 H, SMe), 3.25 (td, J = 10.0,
5.6 Hz, 1 H, C5-HGlcp), 3.64–3.90 (m, 13 H, C2-HGlcp, C3-HGlcp
,
C4-HGlcp, C6-HGlcp, C5-HManp, C6-HManp, OMe), 4.02–4.32 (m, 2 4.18 (m, 2 H, C5-HManp, C5-HGlcp), 4.39 (t, J = 9.2 Hz, 1 H, C3-
H, C4-HManp, C6-HManp), 4.23 (d, J = 2.0 Hz, 1 H, C2-HManp),
4.48 (dd, J = 10.0, 9.6 Hz, 1 H, C3-HManp), 4.57 (d, J = 8.4 Hz, 1
HGlcp), 4.65–4.73 (m, 2 H, C3-HManp, C4-HManp), 5.53 (d, J =
1.2 Hz, 1 H, C1-HMan), 5.82 (d, J = 4.0 Hz, 1 H, C1-HGlcp), 6.68–
H, C1-HGlcp), 5.37 (d, J = 2.0 Hz, 1 H, C1-HManp), 6.36 (s, 1 H, 6.90 (m, 4 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 22.4,
CH Naph), 6.79 (d, J = 9.2 Hz, 2 H, Ar), 6.89 (d, J = 9.2 Hz, 2 H,
Ar), 7.34–7.94 (m, 7 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 13.9, 14.1, 14.3, 18.3, 18.7, 22.0, 22.6, 22.7, 25.5, 25.8, 27.3, 37.8,
37.9, 55.7, 61.2, 61.6, 65.6, 70.7, 70.9, 73.1, 77.9, 78.1, 86.0, 98.3,
99.8, 103.7, 114.6, 117.6, 124.9, 125.8, 125.9, 126.2, 127.6, 127.8,
22.5, 22.85, 22.92, 25.6, 25.7, 27.7, 38.3, 38.4, 54.8, 61.3, 61.9, 64.3,
66.2, 70.8, 71.3, 73.3, 73.5, 78.8, 79.5, 97.9 (C1Glcp), 98.5 (C1Manp),
99.7, 99.8, 114.7, 118.0, 126.9–128.7 (overlapped with C6D6 signal),
138.2, 138.5, 150.1, 155.4 ppm. MALDI-TOF MS: calcd. for
C45H42D14NaO12 [M + Na]+ 825.45; found 825.50. HRMS ESI-
128.1, 132.8, 133.5, 137.8, 149.9, 154.9 ppm. MALDI-TOF MS: TOF: calcd. for C45H42D14NaO12 [M + Na]+ 825.4548; found
calcd. for C59H73D7NaO12SSi [M + Na]+ 1070.6; found 1070.7.
825.4565.
Eur. J. Org. Chem. 2008, 4250–4263
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4259

A. Ishiwata, Y. Munemura, Y. Ito
FULL PAPER
2-Naphthaldehyde (4-Methoxyphenyl 2-O-[D7]benzyl-4,6-O-cyclo-
C66H61D21NaO18 [M + Na]+ 1206.7; found 1207.1. HRMS ESI-
TOF: calcd. for C66H61D21NaO18 [M + Na]+ 1206.6717; found
1206.6736.
hexylidene-α-
clohexylidene-α-
4,6-O-cyclohexylidene-1-thio-β-
D
-glucopyranosyl-(1Ǟ3Ј)-2Ј-O-[D7]benzyl-4Ј,6Ј-O-cy-
-mannopyranosid-3-yl) (Methyl 3-O-[D7]benzyl-
-glucopyranosid-2-yl) Acetal (40):
D
D
4-Methoxyphenyl 3-O-[D7]Benzyl-4,6-O-cyclohexylidene-α-
pyranoside-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
D
-gluco-
-gluco-
DDQ (26.7 mg, 117 µmol) was added under Ar at room tempera-
ture to a mixture of acceptor 39 (55.5 mg, 69.1 µmol), donor 3a
(47.4 mg, 89.8 µmol), and dried powdered MS (4 Å, 500 mg) in dry
CH2Cl2 (3.0 mL). The mixture was stirred at same temperature for
23 h, quenched with aqueous ascorbate buffer (3.0 mL), and fil-
tered through Celite. The filtrate was extracted with EtOAc and
then washed with satd. aq. NaHCO3 and brine. The combined or-
ganic layers were dried with Na2SO4, and the solvents were evapo-
rated in vacuo. The crude product was purified by gel filtration
chromatography (SX-3; EtOAc/toluene, 1:1) to give mixed acetal
40 (88.0 mg, 96%). 1H NMR (CDCl3, 400 MHz) of the major iso-
mer: δ = 1.27–1.59 (m, 30 H, cyclohexyl), 2.18 (s, 3 H, SMe), 2.90
(td, J = 10.0, 5.2 Hz, 1 H, C5-HGlcp1), 3.20 (t, J = 9.6 Hz, 1 H, C6-
HGlcp2), 3.37–4.43 (m, 17 H, C2-HGlcp1, C3-HGlcp1, C4-HGlcp1, C6-
HGlcp1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C2-
HManp, C3-HManp, C4-HManp, C5-HManp, C6-HManp, OMe), 5.30 (s,
1 H, C1-HManp), 5.64 (d, J = 3.6 Hz, 1 H, C1-HGlcp2), 6.34 (s, 1 H,
CH Naph), 6.39 [s, 0.4 H, CH Naph (minor)], 6.75–7.76 (m, 11 H,
Ar, NAP) ppm. 13C NMR (CDCl3, 100 MHz): δ = 12.9, 21.5, 22.2,
22.5, 22.7, 22.9, 25.5, 27.3, 27.6, 27.8, 37.7, 38.0, 55.7, 60.5, 61.3,
61.4, 62.0, 63.8, 64.0, 65.6, 71.1, 71.4, 72.0, 73.5, 73.7, 82.6, 85.7,
97.4, 98.7, 99.2, 99.5, 99.8, 105.2, 114.2, 114.5, 117.8, 125.0, 125.2,
125.6, 125.8, 126.4, 127.6, 127.8, 128.0, 128.2, 129.0, 132.6, 133.6,
137.2, 149.8, 154.9, 177.7 ppm. MALDI-TOF MS: calcd. for
C76H69D21NaO17 [M + Na]+ 1350.7; found 1350.8. HRMS ESI-
TOF: calcd. for C76H69D21NaO17 [M + Na]+ 1350.7115; found
1350.7110.
D
pyranoside-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-D-manno-
pyranoside (42): NaOMe (30.0 mg) was added to the solution of
the resulting acetate 41 (above, 28.4 mg, 24.0 µmol) in methanol/
THF (5:1) until the mixture was alkaline, as indicated by phenol-
phthalein, and the mixture was stirred at 50 °C for 20 h.
Amberlyst 15H+ was added to the mixture to quench excess Na-
OMe. The resin was filtered off and concentrated. The residue was
purified by PTLC (SiO2; hexane/EtOAc, 5:1) to give title com-
1
pound 42[29] (20.0 mg, 88%). [α]2D7 = +126.0 (c = 0.47, CHCl3). H
NMR (C6D6, 400 MHz): δ = 1.22–1.90 (m, 30 H, cyclohexyl), 2.64
(d, J = 10.4 Hz, 1 H, OH), 3.29 (s, 3 H, OMe), 3.54 (dd, J = 9.2,
4.0 Hz, 1 H, C2-HGlcp1), 3.60–4.11 (m, 13 H, C4-HGlcp1, C5-HGlcp1
,
,
C6-HGlcp1, C6-HGlcp1, C2-HGlcp2, C4-H Glcp2, C5-HGlcp2, C6-HGlcp2
C6-HGlcp2, C2-HManp, C5-HManp, C6-HManp, C6-HManp), 4.41–4.46
(m, 2 H, C3-HGlcp1, C3-HGlcp2), 4.68–4.95 (m, 2 H, C3-HManp, C4-
HManp), 5.53–5.55 (m, 2 H, C1-HGlcp2, C1-HManp), 5.84 (d, J =
3.6 Hz, 1 H, C1-HGlcp1), 6.69 (d, J = 8.8 Hz, 2 H, Ar), 6.86 (d, J
= 9.6 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ = 22.8,
22.9, 23.2, 23.3, 23.5, 26.0, 26.1, 28.1, 28.2, 38.5, 38.7, 38.8, 55.2,
61.6, 62.1, 62.2, 64.3, 64.6, 66.6, 71.6, 73.6, 74.0, 74.4, 74.4, 76.3,
77.5, 79.0, 80.2, 97.9 (C1Glcp2), 98.6 (C1Manp), 99.6, 100.2, 100.4,
100.9 (C1Glcp1), 115.0, 118.3, 138.1, 138.2, 139.2, 150.3, 155.7 ppm.
MALDI-TOF MS: calcd. for C64H59D21NaO17 [M + Na]+ 1164.7;
found 1165.2. HRMS ESI-TOF: calcd. for C64H59D21NaO17 [M +
Na]+ 1164.6611; found 1164.6655.
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-O-cyclo-
4-Methoxyphenyl 2-O-Acetyl-3-O-[D7]benzyl-4,6-O-cyclohexylid-
hexylidene-α-
clohexylidene-α-
O-cyclohexylidene-α-
zyl-4,6-O-cyclohexylidene-1-thio-α-D
D
-glucopyranosyl-(1Ǟ3Ј)-2Ј-O-[D7]benzyl-4Ј,6Ј-O-cy-
-glucopyranosyl-(1ЈǞ3ЈЈ)-2ЈЈ-O-[D7]benzyl-4ЈЈ,6ЈЈ-
-mannopyranosid-2-yl) (Methyl 3-O-[D7]ben-
-glucopyranosid-2-yl) Acetal
ene-α-
ene-α-
D
-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylid-
-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylid-
-mannopyranoside (41): DTBMP (21.1 mg, 103 µmol) and
D
D
D
ene-α-
D
MS (4 Å, 1.0 g) in dry 1,2-dichloroethane (5.0 mL) were added un-
der Ar at room temperature to mixed acetal 40 (34.2 mg,
25.7 µmol). MeOTf (10.2 µL, 0.0901 mmol), diluted in dry 1,2-
dichloroethane (1.0 mL), was then added to the mixture, which was
stirred at room temperature for 7 h. The reaction mixture was
quenched with triethylamine, diluted with EtOAc, and filtered
through Celite. Pyridine (4.0 mL), Ac2O (300 µL), and a catalytic
(44) (Route A): DDQ (15.8 mg, 70.0 µmol) was added under Ar at
room temperature to a mixture of acceptor 42 (18.0 mg,
15.8 µmol), donor 3a (10.8 mg, 20.5 µmol), and dried powdered
MS (4 Å, 800 mg) in dry CH2Cl2 (4.0 mL). The mixture was stirred
at same temperature for 20 h, quenched with aqueous ascorbate
buffer (1.0 mL), and filtered through Celite. The filtrate was ex-
tracted with EtOAc and then washed with satd. aq. NaHCO3 and
amount of DMAP were added to the filtrate. The mixture was brine and dried with Na2SO4, and the solvents were evaporated in
stirred at room temperature for 14 h and concentrated in vacuo.
The residue was diluted with EtOAc, washed with satd. aq.
NaHCO3 and brine and dried with Na2SO4, and the solvents were
evaporated in vacuo. The crude product was purified by gel fil-
vacuo. The crude product was purified by gel filtration chromatog-
raphy (SX-3; EtOAc/toluene, 1:1) to give mixed acetal 44 (13.2 mg,
1
50%, 2.33:1). H NMR (CDCl3, 400 MHz) of the major isomer: δ
= 1.25–2.00 (m, 40 H, cyclohexyl), 2.35 (s, 3 H, SMe), 3.32–4.52
tration chromatography (SX-3; EtOAc/toluene, 1:1) to give the (m, 28 H, C1-HGlcp1, C2-HGlcp1, C3-HGlcp1, C4-HGlcp1, C5-HGlcp1
,
,
,
product (25.8 mg, 85%) as an acetate. [α]2D6 = +125.9 (c = 1.69,
C6-HGlcp1, C6-HGlcp1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2
C6-HGlcp2, C6-HGlcp2, C2-HGlcp3, C3-HGlcp3, C4-HGlcp3, C5-HGlcp3
1
CHCl3). H NMR (C6D6, 400 MHz): δ = 1.22–1.87 (m, 33 H, cy-
clohexyl, Ac), 3.29 (s, 3 H, OMe), 3.64–3.96 (m, 13 H, C4-HGlcp1
C5-HGlcp1, C6-HGlcp1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2
C6-HGlcp2, C5-HManp, C6-HManp), 4.21–4.71 (m, 4 H, C3-HGlcp1
,
,
,
C6-HGlcp3, C6-HGlcp3, C2-HManp, C3-HManp, C4-HManp, C5-HManp
,
C6-HManp, C6-HManp, OMe), 5.36 (d, J = 1.6 Hz, 1 H, C1-HManp),
5.61 (d, J = 3.6 Hz, 1 H, C1-HGlcp3), 5.69 (d, J = 3.2 Hz, 1 H, C1-
C2-HManp, C3-HManp, C4-HManp), 5.35 (dd, J = 3.6, 4.0 Hz, 1 H, HGlcp2), 6.25 (s, 1 H, CH Naph), 6.30 [s, 0.4 H, CH Naph (minor)],
C2-HGlcp1), 5.53 (s, 1 H, C1-HManp), 5.87 (d, J = 3.6 Hz, 1 H, C1-
6.80–7.77 (m, 16 H, Ar, NAP) ppm. 13C NMR (CDCl3, 100 MHz):
HGlcp2), 6.06 (d, J = 4.0 Hz, 1 H, C1-HGlcp1), 6.69 (d, J = 8.8 Hz, δ = 10.5, 22.3, 22.4, 22.6, 22.9, 23.0, 25.5, 25.7, 27.6, 27.9, 37.9,
2 H, Ar), 6.86 (d, J = 9.6 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 38.3, 55.7, 61.3, 63.7, 65.7, 70.9, 71.3, 71.8, 72.1, 74.2, 74.4, 74.7,
100 MHz): δ = 12.9, 21.5, 22.2, 22.5, 22.7, 22.9, 25.5, 27.3, 27.6,
27.8, 37.7, 38.0, 55.7, 60.5, 61.3, 61.4, 62.0, 63.8, 64.0, 65.6, 71.1,
75.1, 83.6, 84.5, 97.0, 98.6, 98.7, 99.1, 99.4, 99.6, 99.8, 114.5, 117.8,
125.2, 125.7, 125.9, 126.0, 127.2, 127.6, 128.1, 128.1, 129.0, 133.7,
71.4, 72.0, 73.5, 73.7, 82.6, 85.7, 97.4 (C1Glcp2), 98.7 (C1Manp), 99.2, 136.0, 137.5, 149.8, 154.9 ppm. MALDI-TOF MS: calcd. for
99.5, 99.8, 105.2 (C1Glcp1), 114.2, 114.5, 117.8, 125.0, 125.2, 125.6, C95H86D28NaO22S [M + Na]+ 1689.9; found 1690.5. HRMS ESI-
125.8, 126.4, 127.6, 127.8, 128.0, 128.2, 129.0, 132.6, 133.6, 137.2,
149.8, 154.9, 177.7 ppm. MALDI-TOF MS: calcd. for
TOF: calcd. for C95H86D28NaO22S [M + Na]+ 1689.9178; found
1689.9170.
4260
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4250–4263

NAP Ether Mediated Intramolecular Aglycon Delivery
4-Methoxyphenyl 3-O-[D7]Benzyl-4,6-O-cyclohexylidene-2-O-(2-
silyl)silane (22.0 µL, 71.0 µmol) in dry 1,2-dichloroethane (3.6 mL).
The mixture was stirred at room temperature for 14 h, quenched
with triethylamine, diluted with EtOAc, and filtered through Celite.
naphthylmethyl)-α-
D
-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-
cyclohexylidene-α-
cyclohexylidene-α-
0.174 mmol) was added at room temperature under Ar to mixed
D-glucopyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-
D
-mannopyranoside (43): MeOTf (20.0 µL, The filtrate was extracted with EtOAc, washed with satd. aq.
NaHCO3 and brine and dried with Na2SO4, and the solvents were
acetal 40 (66.0 mg, 0.0500 mmol), DTBMP (40.8 mg, 0.199 mmol), evaporated in vacuo. The residue was used for the next reaction
MS (4 Å, 2.0 g), and tris(trimethylsilyl)silane (76.6 µL, 0.248 mmol)
in dry 1,2-dichloroethane (12.0 mL). The mixture was stirred at
room temperature for 14 h, quenched with triethylamine, diluted
with EtOAc, and filtered through Celite. The filtrate was extracted
with EtOAc, washed with satd. aq. NaHCO3 and brine, and dried
with Na2SO4. After filtration and concentration, the residue was
purified by PTLC (EtOAc/hexane, 1:7) to give product 43 (48.0 mg,
76%) as the NAP ether, together with 42 (3.0 mg, 6%). NAP ether
without further purification. It was dissolved in dry 1,2-dichloroe-
thane (1.0 mL), and NaHCO3 (12.0 mg, 142 µmol) and DDQ
(9.6 mg, 42.6 µmol) were added at room temperature. The residue
was stirred at room temperature for 5 h. After addition of aqueous
ascorbate buffer solution (2.0 mL), the product was extracted with
EtOAc. The combined extracts were washed with satd. aq.
NaHCO3 and brine and dried with Na2SO4. After filtration and
concentration, the residue was purified by gel filtration chromatog-
raphy (SX-3; EtOAc/toluene, 1:1) to give product 22 (17.7 mg,
77%). [α]2D5 = +143.6 (c = 1.54, CHCl3). 1H NMR (C6D6,
400 MHz): δ = 0.90–2.00 (m, 40 H, cyclohexyl), 3.30 (s, 3 H, OMe),
3.45 (brd, J = 10.8 Hz, 1 H, C2-OHGlcp3), 3.59 (dd, J = 9.6, 3.6 Hz,
1
43: [α]2D7 = +103.0 (c = 0.47, CHCl3). H NMR (C6D6, 400 MHz):
δ = 1.25–1.86 (m, 30 H, cyclohexyl), 3.28 (s, 3 H, OMe), 3.54 (dd,
J = 9.2, 4.0 Hz, 1 H, C2-HGlcp1), 3.67–4.10 (m, 13 H, C4-HGlcp1
,
,
C5-HGlcp1, C6-HGlcp1, C2-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2
C2-HManp, C5-HManp, C6-HManp), 4.36 (t, J = 9.2 Hz, 1 H, C3- 1 H, C2-HGlcp1), 3.63–3.76 (m, 7 H, C6-HGlcp1, C6-HGlcp2, C2-
HGlcp2), 4.63–4.81 (m, 4 H, C3-HGlcp1, C5-HGlcp2, C3-HManp, C4-
HManp), 5.00 (s, 2 H, NAP), 5.30 (d, J = 1.6 Hz, 1 H, C1-HManp),
HGlcp3, C3-HGlcp3, C6-HGlcp3, C6-HManp, C6-HManp), 3.81 (t, J =
10.8 Hz, 1 H, C4-HGlcp2), 3.80–4.10 (m, 9 H, C4-HGlcp1, C6-HGlcp1
,
,
5.90 (d, J = 4.0 Hz, 1 H, C1-HGlcp2), 5.95 (d, J = 3.6 Hz, 1 H, C1- C2-HGlcp2, C3-HGlcp2, C6-HGlcp2, C4-HGlcp3, C6-HGlcp3, C2-HManp
HGlcp1), 6.68 (d, J = 8.8 Hz, 2 H, Ar), 6.86 (d, J = 9.6 Hz, 2 H,
C5-HManp), 4.15 (td, J = 10.0, 5.2 Hz, 1 H, C5-HGlcp2), 4.36 (td, J
Ar), 7.25–7.95 (m, 7 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ = 10.8, 5.6 Hz, 1 H, C5-HGlcp1), 4.46 (td, J = 10.8, 5.6 Hz, 1 H,
= 22.8, 22.8, 23.0, 23.3, 23.4, 23.5, 25.95, 26.03, 26.2, 27.9, 28.0, C5-HGlcp3), 4.60 (t, J = 9.6 Hz, 1 H, C3-HGlcp2), 4.65–4.74 (m, 2
28.3, 38.6, 38.75, 38.82, 55.2, 61.6, 62.0, 62.5, 63.9, 64.3, 66.6, 71.8, H, C3-HManp, C4-HManp), 4.81 (br. s, 1 H, C1-HGlcp3), 5.50 (d, J =
73.2, 73.4, 75.2, 75.4, 77.2, 78.9, 80.4, 97.6 (C1Glcp2), 97.9 (C1Glcp1),
98.8 (C1Manp), 99.5, 99.9, 100.1, 118.2, 125.7, 126.0, 126.1, 126.3,
133.4, 133.9, 136.9, 138.4, 139.7, 150.3, 155.6 ppm. MALDI-TOF
MS: calcd. for C75H67D21NaO17 [M + Na]+ 1304.7; found 1305.4.
HRMS ESI-TOF: calcd. for C75H67D21NaO17 [M + Na]+
1304.7237; found 1304.7255.
1.6 Hz, 1 H, C1-HManp), 5.79 (d, J = 3.2 Hz, 1 H, C1-HGlcp2), 5.84
(d, J = 3.6 Hz, 1 H, C1-HGlcp1), 6.70 (d, J = 9.2 Hz, 2 H, Ar), 6.88
(d, J = 9.2 Hz, 2 H, Ar) ppm. 13C NMR (C6D6, 100 MHz): δ =
22.77 (ϫ4), 23.2, 23.31 (ϫ3), 25.92 (ϫ4), 27.97 (ϫ3), 28.2, 38.3,
38.47 (ϫ2), 38.7, 55.1, 61.5, 61.9, 62.2, 64.0, 64.4, 66.4, 71.6, 73.3,
73.5, 74.4, 74.8, 75.3, 76.7, 79.1, 79.2, 80.9, 96.5 (C1Glcp2), 96.6
(C1Glcp3), 97.7 (C1Glcp1), 98.7 (C1Manp), 99.5, 99.7, 100.0, 100.2,
114.9, 118.2, 138.8, 138.9, 139.7, 150.3, 155.6 ppm. MALDI-TOF
MS: calcd. for C83H76D28NaO22 [M + Na]+ 1503.9; found 1504.4.
HRMS ESI-TOF: calcd. for C83H76D28NaO22 [M + Na]+
1503.8674; found 1503.8626.
2-Naphthaldehyde (4-Methoxyphenyl 3-O-[D7]benzyl-4,6-O-cyclo-
hexylidene-α-
cyclohexylidene-α-
4ЈЈ,6ЈЈ-O-cyclohexylidene-α-
[D7]benzyl-4,6-O-cyclohexylidene-1-thio-α-
D
-glucopyranosyl-(1Ǟ3Ј)-2Ј-O-[D7]benzyl-4Ј,6Ј-O-
-glucopyranosyl-(1ЈǞ3ЈЈ)-2ЈЈ-O-[D7]benzyl-
-mannopyranosid-2-yl) (Methyl 3-O-
-glucopyranosid-2-yl)
D
D
D
Acetal (44) (Route B): DDQ (7.5 mg, 33.0 µmol) was added under
Ar at room temperature to a mixture of 43 (33.4 mg, 25.2 µmol),
11 (7.5 mg, 1.94 µmol), and dried powdered MS (4 Å, 800 mg) in
dry CH2Cl2 (3.0 mL). The mixture was stirred at the same tempera-
ture for 15 h, quenched with aqueous ascorbate buffer (2.0 mL),
and filtered through Celite. The filtrate was extracted with EtOAc,
washed with satd. aq. NaHCO3 and brine and dried with Na2SO4,
and the solvents were evaporated in vacuo. The crude product was
purified by gel filtration chromatography (SX-3; EtOAc/toluene,
1:1) to give mixed acetal 35 (31.4 mg, 97 %, 3.43:1). 1H NMR
(CDCl3, 400 MHz): δ = 1.25–2.00 (m, 40 H, cyclohexyl), 2.35 (s, 3
4-Methoxyphenyl α-
D
-Glucopyranosyl-(1Ǟ2)-α-
D-glucopyranosyl-
(1Ǟ3)-α- -glucopyranosyl-(1Ǟ3)-α-
D
D-mannopyranoside (21): TFA
(200 µL) was added to a solution of compound 22 (6.8 mg,
4.59 µmol) in CH2Cl2 (2.0 mL), and the mixture was stirred at
room temperature for 2 h and then concentrated in vacuo, followed
by azetropic removal of TFA with toluene. Hydrogenolysis of the
resulting residue 45 was carried out in the presence of Pd(OH)2
(28.0 mg) in MeOH/H2O (1:1, 2.0 mL) at room temperature over
5 h. The mixture was filtered through Celite, and the filtrate was
concentrated in vacuo. The residue was purified by gel filtration
(Sephadex LH-20; MeOH/H2O, 1:1) to give title compound 21
H, SMe), 3.32–4.52 (m, 28 H, C1-HGlcp1, C2-HGlcp1, C3-HGlcp1
C4-HGlcp1, C5-HGlcp1, C6-HGlcp1, C6-HGlcp1, C2-HGlcp2, C3-HGlcp2
C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C6-HGlcp2, C2-HGlcp3, C3-HGlcp3
,
,
,
1
(3.5 mg, 100%). H NMR (CD3OD, 400 MHz): δ = 3.33–4.12 (m,
23 H, C2-HGlcp1, C3-HGlcp1, C4-HGlcp1, C5-HGlcp1, C6-HGlcp1, C6-
HGlcp1, C2-HGlcp2, C3-HGlcp2, C4-HGlcp2, C5-HGlcp2, C6-HGlcp2, C6-
HGlcp2, C2-HGlcp3, C3-HGlcp3, C4-HGlcp3, C5-HGlcp3, C6-HGlcp3, C6-
HGlcp3, C2-HManp, C3-HManp, C4-HManp, C6-HManp, C6-HManp),
4.24–4.26 (m, 1 H, C2-HManp), 5.04 (d, J = 3.6 Hz, 1 H, C1-HGlcp3),
5.19 (d, J = 4.0 Hz, 1 H, C1-HGlcp2), 5.32 (d, J = 2.0 Hz, 1 H, C1-
HManp), 5.42 (d, J = 3.6 Hz, 1 H, C1-HGlcp1), 6.82 (d, J = 9.2 Hz,
2 H, Ar), 7.03 (d, J = 9.2 Hz, 2 H, Ar) ppm. 13C NMR (CD3OD,
100 MHz): δ = 56.0, 62.5, 62.6, 67.2, 71.3, 71.6, 71.7, 72.7, 73.1,
73.3, 73.5, 73.6, 73.7, 73.8, 74.8, 75.2, 78.7, 81.8, 82.9, 98.4
(C1Glcp3), 98.7 (C1Glcp1), 101.2 (C1Manp2), 102.4 (C1Glcp2), 115.5,
119.2, 151.8, 156.5 ppm. MALDI-TOF MS: calcd. for
C31H48NaO22 [M + Na]+ 795.3; found 795.9. HRMS ESI-TOF
MS: calcd. for C31H48NaO22 [M + Na]+ 795.2535; found 795.2507.
C4-HGlcp3, C5-HGlcp3, C6-HGlcp3, C6-HGlcp3, C2-HManp, C3-HManp
,
C4-HManp, C5-HManp, C6-HManp, C6-HManp, OMe), 5.36 (d, J =
1.6 Hz, 1 H, C1-HManp), 5.61 (d, J = 3.6 Hz, 1 H, C1-HGlcp3), 5.69
(d, J = 3.2 Hz, 1 H, C1-HGlcp2), 6.25 (s, 1 H, CH Naph), 6.30 [s,
0.4 H, CH Naph (minor)], 6.80–7.77 (m, 11 H, Ar, NAP) ppm.
4-Methoxyphenyl 3-O-[D7]Benzyl-4,6-O-cyclohexylidene-α-
pyranosyl-(1Ǟ2)-3-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
pyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-
D-gluco-
D-gluco-
D-gluco-
pyranosyl-(1Ǟ3)-2-O-[D7]benzyl-4,6-O-cyclohexylidene-α-D-manno-
pyranoside (22): MeOTf (5.6 µL, 49.7 µmol) was added under Ar
at room temperature to mixed acetal 44 (23.7 mg, 14.2 µmol),
DTBMP (11.7 mg, 56.8 µmol), MS (4 Å, 1.0 g), and tris(trimethyl-
Eur. J. Org. Chem. 2008, 4250–4263
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4261

A. Ishiwata, Y. Munemura, Y. Ito
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Acknowledgments
This work was partly supported by the “Ecomolecular Science”
and “Chemical Biology” programs in RIKEN, and by a Grant-in-
Aid for Encouragement of Young Scientists from the Ministry of
Education, Culture, Sports, Science, and Technology (No.
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Eur. J. Org. Chem. 2008, 4250–4263

NAP Ether Mediated Intramolecular Aglycon Delivery
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diastereoselectivity (3.43:1) as that of 35 obtained from 33
(2.33:1) (route B). The anomeric configuration of NAP-pro-
Received: March 5, 2008
Published Online: June 5, 2008
Eur. J. Org. Chem. 2008, 4250–4263
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4263