Unexpected stereocontrolled access to 1α,1′β-disaccharides from methyl 1,2-ortho esters

Article abstract of DOI:10.1021/jo202335n

Mannopyranose-derived methyl 1,2-orthoacetates (R = Me) and 1,2-orthobenzoates (R = Ph) undergo stereoselective formation of 1α,1′β-disaccharides, upon treatment with BF ₃?Et₂O in CH₂Cl₂, rather than the expected acid-catalyzed reaction leading to methyl glycosides by way of a rearrangement-glycosylation process of the liberated methanol.

Full text of DOI:10.1021/jo202335n

Note
pubs.acs.org/joc
Unexpected Stereocontrolled Access to 1α,1′β-Disaccharides
from Methyl 1,2-Ortho Esters
Clara Uriel,† Juan Ventura,† Ana M. Gomez,*,† J. Cristobal Lopez,*,† and Bert Fraser-Reid‡
́
́
́
†Instituto de Química Organ
́
ica General (IQOG-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
‡Natural Products and Glycotechnology Research Institute Inc. (NPG), 595F Weathersfield Road, Pittsboro, North Carolina 27312,
United States
S
* Supporting Information
ABSTRACT: Mannopyranose-derived methyl 1,2-orthoacetates (R =
Me) and 1,2-orthobenzoates (R = Ph) undergo stereoselective
formation of 1α,1′β-disaccharides, upon treatment with BF3·Et2O in
CH2Cl2, rather than the expected acid-catalyzed reaction leading to
methyl glycosides by way of a rearrangement−glycosylation process of
the liberated methanol.
lkyl 1,2-ortho esters, first introduced in glycosylation
studies by Kochetkov and co-workers,1−4 have been
completely stereocontrolled manner, to 1α,1′β-mannose
disaccharides rather than to the expected methyl mannopyrano-
sides.20 This unexpected outcome has been studied, and a
reaction pathway that accounts for the observed experimental
results is advanced.
In an attempt to prepare methyl mannopyranoside 6, we
treated the mannose-derived methyl 1,2-orthoacetate 4 with
BF3·Et2O. To our surprise, 1α,1′β-mannose disaccharide 5 was
isolated in 86% yield, and no significant amount (<5%) of
methyl mannopyranoside 6 could be observed (Scheme 2a).21
A
recently revitalized5 with the advent of n-pentenyl ortho esters
(NPOEs)6−8 and can be considered as valuable, multifaceted
substrates in oligosaccharide9 assembly.10,11
Alkyl 1,2-ortho esters (e.g., 1, Scheme 1a) undergo a facile
acid-catalyzed rearrangement to glycosides.12,13 In this context,
Scheme 1. Transformations Involving Alkyl 1,2-Ortho Esters
Scheme 2. Reaction of Methyl Ortho Esters 4 and 7 with
BF3·Et2O (3 equiv) in CH2Cl2 at −30 °C
n-pentenyl glycosides are routinely prepared in our laboratories
by acid-catalyzed rearrangement of NPOEs.14 However, their
use in “direct” glycosylation protocols15,16 is compromised by
the competing glycosylation issue depicted in Scheme 1b, where
the leaving group (OR) can compete with the glycosyl acceptor
(R2OH) to give a mixture of glycosides (e.g., 2 and 3, Scheme 1b).17
Along these lines, the success of NPOEs2 as glycosyl donors
rests in the fact that by way of halonium, rather than acid,
activation the pentenyloxy moiety (Scheme 1b, R = n-pentenyl)
is extruded as a non-nucleophilic 2-(halomethyl)-
tetrahydrofuran,18,19 thus reducing the amount of rearranged
glycoside (e.g., 2).
Along these lines, it could be anticipated that methyl 1,2-ortho
esters (1, R = Me) should be useful precursors for methyl
glycosides by acid-catalyzed rearrangement, i.e. 1 → 2 (R = Me).
In this paper we disclose that some methyl 1,2-mannopyranosyl
ortho esters lead upon treatment with BF3·Et2O in CH2Cl2, in a
In contrast, treatment of 1,2-orthobenzoate 7 with BF3·Et2O
did afford the methyl mannopyranoside 9 in 44% yield (Scheme 2b).
Received: November 13, 2011
Published: December 4, 2011
© 2011 American Chemical Society
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However, 1α,1′β-mannose disaccharide 8 was also observed
(36%), along with hemiacetal 10. The configurations at C-1
and C-1′ in compounds 5 and 8 were unambiguously assigned
hemiacetal species in the glycosylation events leading to 1,1′-
disaccharides in Scheme 2.
To gain insight into the formation of these 1,1′-disaccharides,
we examined the mannose ortho esters shown in Scheme 4.
on the basis of their JC1,H1 coupling constants.22,23
1
Several aspects of these transformations could be regarded as
remarkable: (i) the unexpected formation of 1,1′-disaccharides
5 and 8 in appreciable amounts, (ii) the complete stereocontrol
in their formation (along with the β stereochemistry on one of
the monosaccharide components), and (iii) the absence of
methyl mannopyranoside 6 in the reaction of methyl ortho
ester 4.
Scheme 4. Reaction of Ortho Esters 13−15 with BF3·Et2O
With respect to item ii, the α-anomeric configurations of
disaccharide products 5 and 8 are consistent with the well-
known 1,2-trans-directing effect of ortho ester glycosyl donors.
Because of the latter effect, the anomeric β configurations in 5
and 8 must be seen as “unusual”, therefore inviting speculation
that the β configuration was retained from the ortho ester
progenitor 4 or 7. Thus, a reaction pathway is suggested in
Scheme 3, where the ortho ester serves as both donor and
Scheme 3. Proposed Rationalization for the Entirely
Stereocontrolled Formation of 1α,1′β-Disaccharides from
1,2-Ortho Esters and a Supporting Experiment
There were striking differences in results obtained from the tri-
O-acetyl and tri-O-benzyl orthoacetate analogues 4 and 13,
respectively. With respect to the methyl orthoacetate 4
rearrangement products, compound 6 was “not observed” in
Scheme 2a, whereas the analogous compound 17a was the
major product in Scheme 4a. On the other hand, whereas
disaccharide 5 had been the major product in Scheme 2a,
analogue 1630 was a minor product in Scheme 4a.
The effect of the alkoxy moiety on the reaction was tested by
replacing methoxy with allyloxy in orthobenzoate 15 (Scheme 4c).
This change also resulted in a reduced yield of 1,1′ disaccharide
8 (compare Scheme 2b with Scheme 4c).
According to the results in Scheme 4, the protecting groups
in the pyranose ring and the nature of the alkoxy moiety of the
ortho ester play an important role in the formation of 1,1′-
disaccharides. Better yields are observed for methyl ortho esters
on acyl-substituted pyranoses.
We have also studied the effect of different acids on methyl
orthoacetate 4. Thus, treatment of 4 with Yb(OTf)3 and HgBr2
in acetonitrile led to hemiacetal 11 in 91% and 42% yields,
respectively, although in the latter case a considerable amount
of unreacted ortho ester 4 (45%) was also recovered (Scheme 5a,b).
The use of commercially available acid-washed molecular sieves
under microwave irradiation11,31 proved to be the method of
choice for the preparation of methyl mannopyranoside 6 (90%
yield, Scheme 5c). Finally, according to precedents,32 reaction
of 4 with TMSOTf led to a mixture of 6 (4.5%), and methyl di-
and trisaccharides 21 and 22 (46% and 21%, respectively)
(Scheme 5d).
As mentioned above, in addition to the unexpected
formation of 1α,1′β-disaccharide 5, an additional issue of
interest in the reaction of 4 was the fate of the “supposedly”
released methanol in the reaction medium, since no rearranged
methyl mannoside 615 had been observed (see Scheme 2a).
Our rationalization of these observations rests on the analysis
of the commonly accepted reaction pathway for the reaction of
acceptor, going through intermediates I and then II, establish-
ing inverted (α) and retained (β) configurations consecutively
in disaccharide products 5 and 8.24
In order to discard the formation of 1α,1′β-disaccharides by
direct glycosylation of an in situ formed hemiacetal (e.g., 10) by
the ortho ester,25 we conducted the experiment depicted in
Scheme 3b. Accordingly, methyl orthobenzoate 7 was treated
with BF3·Et2O in the presence of hemiacetal 11, to give a
mixture of 1α,1′β-disaccharide 8 and 1,1′-disaccharides 12 in 38
and 9% yield, respectively.26,27
The formation of 12 as an anomeric mixture, with the α,α′
isomer predominating, is in agreement with the stereochemical
preference for α orientation displayed by hemiacetal manno-
pyranose glycosyl acceptors in 1,1′-disaccharide formation.28,29
On the basis of this evidence, we rule out the participation of
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Note
found in the antibiotic everninomicin 13,384-1,38 which has
shown antibacterial properties against drug-resistant patho-
gens.39 On the other hand, a reaction pathway in which the
cyclic ortho ester acts as a nucleophile has been put forward to
account for the β-stereochemistry of one of the components.
A reaction course in which coordination of the 1,2-ortho ester
with the Lewis acid takes place at O-1, e.g. 25, rather than at the
exocyclic OR, e.g. 23, could explain this outcome. Synthetic
implications of these findings in glycosylation studies are under
consideration in our laboratories and will be reported in due
course.
Scheme 5. Reaction of Methyl Ortho Ester 4 under Different
Conditions
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR and 13C NMR spectra
were obtained for solutions in CDCl3 using a 300, 400, or 500 MHz
spectrometer. Optical rotations were determined for solutions in
chloroform at 25 °C. Column chromatography was performed on
silica gel (230−400 mesh). TLC was conducted in precoated Kieselgel
60 F254 (Merck). Detection was first by UV light (254 nm) and then
charring with a 1/20/4 solution of sulfuric acid/acetic acid/H2O. All
solvents were purified by distillation over drying agents or by elution
through a PURE SOLV purification system. Reactions requiring
anhydrous conditions were performed under argon. Anhydrous mag-
nesium sulfate was used for drying solutions. Microwave irradiation was
performed with a single-mode Discovery System from CEM Corp.
Methyl orthoacetate 440,41 and methyl orthobenzoates 742 and 1543 were
prepared from tetra-O-acetyl-α-D-mannopyranosyl bromide44 and tetra-O-
benzoyl-α-D-mannopyranosyl bromide12 following a published proce-
dure.41 Ortho esters 13 and 14 were prepared from 4 and 7,
respectively, as previously described.45
1,2-ortho esters with Lewis acids (Scheme 6).3,4,33−36
Accordingly, the formation of alkyl mannosides by rearrange-
Scheme 6. Proposed Reaction Pathway for the Formation of
1α,1′β-Disaccharides 5 and 8 from Ortho Ester 1
Reaction of Ortho Esters with BF3·OEt2: General Procedure. A
solution of the corresponding 1,2-ortho ester, in dry CH2Cl2 under
argon at −30 °C, was treated with BF3·Et2O. After 5−15 min, when all
the starting material had disappeared, Et3N was added and the
resulting mixture was vigorously stirred. The reaction mixture was then
concentrated, without heating, and the crude product was purified by
flash chromatography.
(2,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyl)-2,3,4,6-tetra-O-
acetyl-β-D-mannopyranoside (5). Following the general procedure,
the 1,2-ortho ester 4 (50 mg, 0.14 mmol) was treated with BF3·Et2O
(50 μL, 0.42 mmol). After 5 min, Et3N (59 μL, 0.42 mmol) was added,
and the residue was purified by flash chromatography (hexane/EtOAc,
1/1) to yield compound 5 (41 mg, 86%). Data for 5: [α]D = +15.6°
ment would invoke coordination of the Lewis acid (LA) with
OR (e.g., 1 → 23, Scheme 6), followed by bond cleavage to
dioxolenium 2437 and subsequent glycosylation of the extruded
ROH to give 2.
However, Lewis acid activation could also take place at O-1
(e.g., 1 → 25, Scheme 6),3,4,33−36 and the results obtained in
this work could be explained if BF3·Et2O activation of methyl
ortho esters proceeds through intermediate 25 and then
oxocarbenium ion 26, which is susceptible to reaction with an
“external nucleophile”. The methoxy residue (OR, R = Me) is
then extruded subsequently. As indicated by I (Scheme 2a), we
propose that the “external nucleophile” can be the anomeric
oxygen of an ortho ester.
We sought support of the foregoing analysis by treating
ortho ester 7 in the usual way, except that 1.0 equiv of CD3OD
was included, with the expectation that it could scavenge any
oxocarbenium ion 26. Indeed, deuteriomethyl mannopyrano-
side 9 was isolated (85% deuterium content) and formation of
the 1,1′-disaccharide 8 was thwarted.
In summary, some mannose-derived methyl 1,2-orthoace-
tates and 1,2-orthobenzoates react in the presence of BF3·Et2O
to give 1α,1′β-disaccharides in a completely stereocontrolled
manner. The construction of this type of saccharide bridge is a
challenging process, and this 1α,1′β-disaccharide unit has been
1
(c 0.3, CHCl3); H NMR (300 MHz, CDCl3) δ 1.99 (s, 3 H), 2.00
(s, 3 H), 2.04 (s, 3 H), 2.05 (s, 3 H), 2.10 (s, 3 H), 2.12 (s, 3 H), 2.16
(s, 3 H), 2.23 (s, 3 H), 3.69 (ddd, J = 9.8, 5.8, 2.5 Hz, 1 H), 4.09 (m,
1 H), 4.17 (dd, J = 12.3, 5.9 Hz, 1 H), 4.24 (dd, J = 12.3, 2.5 Hz, 1 H),
4.26−4.28 (m, 1 H), 4.28 (dd, J = 12.7, 2.8 Hz, 1 H), 4.87 (d, J =
1.3 Hz, 1 H), 5.05 (dd, J = 10.0, 3.4 Hz, 1 H), 5.09 (d, J = 1.8 Hz,
1 H), 5.17 (dd, J = 2.9, 1.9 Hz, 1 H), 5.22 (t, J = 9.9 Hz, 1 H), 5.33−
5.39 (m, 2 H), 5.49 (dd, J = 3.4, 1.2 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 20.7, 20.8 (×4), 20.9 (×2), 21.0, 62.0, 62.7, 65.6, 65.7, 68.7
(×2), 69.2, 69.6, 70.7, 73.2, 97.8 (dd, J = 157.4, 2.1 Hz, Cβ), 98.2 (dd,
J = 174.6, 4.3 Hz, Cα), 169.7 (×2), 169.9, 170.0, 170.1, 170.5, 170.8,
170.9; API-ES positive 701.1 (M + Na)+. Anal. Calcd for C28H38O19
(678.59): C, 49.56; H, 5.64; O, 44.80. Found: C, 49.47; H, 5.50.
(2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl)-2,3,4,6-tetra-O-
benzoyl-β-D-mannopyranoside (8). Following the general procedure,
a solution of the 1,2-ortho ester 7 (61.1 mg, 0.1 mmol) was treated with
BF3·Et2O (38 μL, 0.3 mmol). After 5 min, Et3N (42 μL, 0.3 mmol) was
added, and the residue was purified by flash chromatography (hexane/
EtOAc, 8/2) to yield the 1α,1′β-disaccharide 8 (21 mg, 36%), methyl
mannopyranoside 946 (27 mg, 44%), and hemiacetal 1047 (11 mg, 18%).
Data for 8: [α]D = −54.3° (c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 4.17 (m, 1 H), 4.34 (dd, J = 12.3, 2.4 Hz, 1 H), 4.44 (dd, J = 12.3,
4.0 Hz, 1 H), 4.55 (m, 1 H), 4.68 (dd, J = 12.4, 2.1 Hz, 1 H), 4.93 (dd,
J = 12.2, 2.3 Hz, 1 H), 5.36 (s, 1 H), 5.51 (s, 1 H), 5.67−5.70 (m, 3
H), 6.08−6.20 (m, 3 H), 7.20−8.15 (m, 40 H); 13C NMR (75 MHz,
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Note
CDCl3) δ 62.2, 62.3, 66.4 (×2), 69.7 (×2), 69.9, 70.0, 71.6, 73.3, 97.6
(d, J = 174.9 Hz, Cα), 98.1 (d, J = 158.4 Hz, Cβ), 128.3 (×3), 128.4
(×3), 128.5 (×3), 128.6 (×6), 128.7 (×3), 128.8, 128.9, 129.1, 129.2,
129.3, 129.5, 129.8 (×3), 129.9 (×3), 130.0 (×6), 130.1, 130.2 (×3),
133.1 (×2), 133.3, 133.4, 133.5 (×2), 133.6, 133.7, 165.1, 165.2, 165.3,
165.4, 165.6, 165.7, 166.1 (×2). ESI-HRMS: 1192.3578 (M+NH4)+;
Anal. Calcd for C68H54O19 (1174.32): C, 69.50; H, 4.63; O, 25.87;
Found C, 69.61; H, 4.67.
75.3, 78.3, 98.9, 127.5 (×2), 127.6 (×2), 127.7 (×4), 128.0 (×2),
128.1 (×2), 128.4 (×3), 128.5 (×4), 130.0, 133.2, 138.1, 138.5 (×2),
165.8; API-ES positive 591.3 (M + Na)+. Anal. Calcd for C35H36O7
(568.24): C, 73.92; H, 6.38; O, 19.69. Found: C, 73.87; H, 6.30. Data
for 19b: 3.74−3.83 (m, 2H), 3.96 (m, 1H), 4.09−4.19 (m, 2H), 4.53
(d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.58 (d, J = 12.0 Hz,
1H), 4.67 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.88 (d, J =
12.0 Hz, 1H), 5.35 (bs, 1H), 5.63 (dd, J = 1.9, 3.0 Hz, 1H), 7.18−8.08
(m, 20H); 13C NMR (125 MHz, CDCl3) δ 69.8 (×2), 71.8, 71.9, 73.7,
74.9, 75.3, 77.9, 92.8, 127.7 (×3), 127.8 (×3), 128.1 (×3), 128.4 (×4),
128.5 (×4), 130.1 (×3), 133.2, 138.3, 138.6, 138.7, 165.9; API-ES
positive 573.6 (M + Na)+. Anal. Calcd for C34H34O7 (554.62): C,
73.63; H, 6.18; O, 20.19. Found: C, 73.51; H, 6.12.
Allyl 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranoside (20). Fol-
lowing the general procedure, 1,2-ortho ester 15 (63.6 mg, 0.1 mmol)
was treated with BF3·Et2O (38 μL, 0.3 mmol). After 10 min, Et3N
(42 μL, 0.3 mmol) was added and the resulting residue was con-
centrated and purified by flash chromatography (hexane/EtOAc 7/3) to
yield allyl glycoside 2049 (40 mg, 63%), hemiacetal 10 (5 mg, 8%), and
1α,1β′-disaccharide 8 (2 mg, 2%).
Reaction of Methyl Ortho Ester 4 with Different Acids. Reac-
tion with Yb(OTf)3. To a stirred solution of methyl ortho ester 4 (100 mg,
0.28 mmol) in anhydrous CH2Cl2 (4 mL), at room temperature, was
added Yb(OTf)3 (515 mg, 0.83 mmol). After 51/2 h all the starting
material has disappeared and the reaction mixture was treated with
Et3N (700 μL). The crude mixture was concentrated and purified by
flash chromatography (hexane/EtOAc 7/3) to yield hemiacetal 11
(87 mg, 91%).
Reaction with HgBr2. Methyl ortho ester 4 (100 mg, 0.28 mmol)
in anhydrous CH3CN (4 mL) at room temperature was treated with
HgBr2 (302.4 mg, 0.84 mmol). After 12 h, the reaction mixture was
diluted with CH2Cl2 and quenched by addition of saturated aqueous
NaHCO3. The layers were separated, the aqueous phase was extracted
with CH2Cl2, and the combined organic layers were washed with
saturated aqueous NaCl. The resultant organic phase was dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
silica gel column chromatography (hexane/EtOAc 7/3) to yield
hemiacetal 11 (41 mg, 42%).
(2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl)-2,3,4,6-tetra-O-
acetyl-α-D-mannopyranoside and (2,3,4,6-Tetra-O-benzoyl-α-D-
mannopyranosyl)-2,3,4,6-tetra-O-acetyl-β-D-mannopyranoside
(12). To a stirred solution of the 1,2-ortho ester 7 (91.6 mg,
0.15 mmol) and hemiacetal 1148 (52.2 mg, 0.15 mmol) was added
BF3·Et2O (57 μL, 0.45 mmol). After 5 min, Et3N (63 μL, 0.45 mmol)
was added and the resulting residue was purified by flash
chromatography (hexane/EtOAc, 8/2 to 7/3) to give 8 (34 mg,
38%) and 1,1′-disaccharides 12 (1α, 1′α/1α, 1′β; 3.2/1 ratio) (12.4 mg,
9%) along with other compounds such as 2,3,4,6-tetra-O-benzoyl-α-D-
mannopyranosyl fluoride (14 mg, 16%), methyl glycoside 9 (29 mg,
32%), and unchanged starting material 11 (30 mg, 57%). Selected data
for 12 are as follows. Major isomer: 1α,1′α-disaccharide 1H NMR
(500 MHz, CDCl3) δ 5.27 (d, J = 1.3 Hz, 1H, H-1′), 5.46 (dd, J = 1.3,
3.5 Hz, 1H, H-2′), 5.46 (d, J = 1.8 Hz, 1H, H-1), 5.72 (dd, J = 1.8,
3.4 Hz, 1H, H-2); 13C NMR (125 MHz, CDCl3) δ 93.17 (d, J = 173.8
Hz, C-1α), 93.49 (d, J = 173.3 Hz, C-1′α). Minor isomer: 1α,1′β-
1
disaccharide H NMR (500 MHz, CDCl3) δ 5.01 (d, J = 1.2 Hz, 1H,
H-1′), 5.38 (d, J = 1.8 Hz, 1H, H-1), 5.60 (dd, J = 1.2, 3.3 Hz, 1H, H-
2′), 5.64 (d, J = 1.8, 3.3 Hz, 1H, H-2); 13C NMR (125 MHz, CDCl3):
δ 97.84 (d, J = 156.7 Hz, C-1′β), 98.10 (d, J = 175.3 Hz, C-1α). Anal.
Calcd for C48H46O19 (926.86): C, 62.20; H, 5.00; O, 32.80. Found: C,
62.30; H, 5.10.
(2-O-acetyl-3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-2-O-
acetyl-3,4,6-tetra-O-benzyl-β-D-mannopyranoside (16). Following
the general procedure, the 1,2-ortho ester 13 (50.6 mg, 0.1 mmol) was
treated with BF3·Et2O (38 μL, 0.3 mmol). After 10 min, Et3N (42 μL,
0.3 mmol) was added, and the residue was purified by flash chromato-
graphy (hexane/EtOAc 8/2), to yield 1α,1β′-disaccharide 16 (11 mg,
23%) along with methyl glycoside 17a (32 mg, 64%) and hemiacetal
17b (6 mg, 11%). Data for 16: [α]D = +19.3° (c 0.14, CHCl3);
1H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.07 (s, 3H), 3.38 (ddd,
J = 9.7, 4.3, 2.6 Hz, 1H), 3.52 (dd, J = 10.8, 1.9 Hz, 1H), 3.56 (dd, J =
9.3, 3.3 Hz, 1H), 3.58−3.68 (m, H), 3.86−3.92 (m, 2H), 3.99−4.02
(m, 1H), 4.25 (d, J = 12.1 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 4.39
(d, J = 15.0 Hz, 1H), 4.41 (d, J = 12.1 Hz, 1H), 4.43 (d, J = 15.0 Hz,
1H), 4.46 (d, J = 15.0 Hz, 1H), 4.49 (d, J = 15.0 Hz, 1H), 4.50 (d, J =
15.0 Hz, 1H), 4.61 (d, J = 11.4 Hz, 1H), 4.63 (d, J = 1.0 Hz, 1H), 4.67
(d, J = 11.4 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1H), 4.79 (d, J = 10.8 Hz,
1H), 5.04 (d, J = 1.8 Hz, 1H), 5.23 (dd, J = 1.9, 2.9 Hz, 1H), 5.53 (dd,
J = 1.0, 3.2 Hz, 1H), 7.08−7.25 (m, 30H); 13C NMR (125 MHz,
CDCl3) δ 21.2, 21.5, 68.0, 68.5, 68.7, 69.3, 71.7, 72.0, 72.4, 73.4, 73.5,
74.1, 74.2, 75.2, 75.3, 75.9, 77.8, 80.2, 98.2, 98.3, 127.6 (x2), 127.7
(×2), 127.8 (×3), 127.9 (×3), 128.0 (×3), 128.2 (×3), 128.3 (×2),
128.4 (×4), 128.5 (×4), 128.6 (×4), 137.6, 138.0, 138.3, 138.4, 138.5,
138.7, 170.5, 170.6; ESI-HRMS 989.4203 (M + Na)+. Anal. Calcd for
C58H62O13 (966.4190): C, 72.03; H, 6.46; O, 21.51. Found: C, 72.25;
H, 6.33.
Methyl 2-O-Benzoyl-3,4,6-tetra-O-benzyl-α-D-mannopyranoside
(19a) and 2-O-Benzoyl-3,4,6-tetra-O-benzyl-α-D-mannose (19b). Fol-
lowing the general procedure, the 1,2-ortho ester 14 (56.8 mg,
0.1 mmol) was treated with BF3·Et2O (38 μL, 0.3 mmol). After 10 min
Et3N (42 μL, 0.3 mmol) was added and the resulting residue was
concentrated and purified by flash chromatography (hexane/EtOAc
7/3) to yield methyl glycoside 19a (29 mg, 51%) and hemiacetal 19b
(17 mg, 30%). Data for 19a: [α]D = +1.9° (c 0.58, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 3.32 (s, 3H), 3.71 (dd, J = 1.5, 10.2 Hz, 1H),
3.76 (m, 1H), 3.81 (m, 1H), 3.99 (m, 2H), 4.46 (d, J = 10.9 Hz, 1H),
4.47 (d, J = 11.4 Hz, 1H), 4.48 (d, J = 11.4 Hz, 1H), 4.66 (d, J =
12.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 2.2 Hz, 1H), 4.80
(d, J = 10.2 Hz, 1H), 5.54 (bt, J = 2.2 Hz, 1H), 7.10−8.01 (m, 20H);
13C NMR (125 MHz, CDCl3) δ: 55.1, 69.0, 69.2, 71.5, 71.6, 73.5, 74.4,
Reaction with AW-300. A solution of methyl ortho ester 4 (50 mg,
0.14 mmol) in anhydrous CH2Cl2 (4 mL) was treated with acid
molecular sieves AW-300 (1.6 mm pellets, 1 g). After it was heated for
2 h at 50 °C under MW irradiation, the crude mixture was filtered and
the solvent was removed under reduced pressure. The residue was
purified by flash silica gel column chromatography (hexane/EtOAc
7/3) to afford methyl glycoside 6 (46 mg, 90%).
Reaction with TMSOTf. To a stirred solution of methyl ortho ester
4 (100 mg, 0.28 mmol) in anhydrous CH2Cl2 (4 mL) at −30 °C was
added TMSOTf (158 μL, 0.84 mmol). After 5 min, the reaction
mixture was diluted with CH2Cl2 and quenched by addition of
saturated aqueous NaHCO3. The layers were separated, the aqueous
phase was extracted with CH2Cl2, and the combined organic layers
were washed with saturated aqueous NaCl. The resultant organic
phase was dried over Na2SO4, filtered, and concentrated.
The resulting residue was purified by silica gel flash column
chromatography (hexane/EtOAc, 1/1) to yield methyl glycoside 6
(4.6 mg, 4.5%), methyl 3,4,6-tri-O-acetyl-2-O-(2,3,4,6-tetra-O-acetyl-α-
D-mannopyranosyl)-mannopyranoside 2150 (42.4 mg, 46%), and
trisaccharide 22 (19 mg, 21%). Data for 22: [α]D = +2.0° (c 0.64,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 2.00 (s, 3H), 2.02 (s, 3H),
2.03 (s, 6H), 2.05 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H),
2.13 (s, 3H), 2.15 (s, 3H), 3.41 (s, 3H), 3.89 (m, 1H), 4.01 (m, 1H),
4.06−4.19 (m, 8H), 4.23 (dd, J = 4.8, 12.0 Hz, 1H), 4.86 (bs, 1H),
4.94 (bs, 1H), 5.09 (d, J = 1.6 Hz, 1H), 5.24−5.32 (m, 6H), 5.38 (dd,
J = 3.2, 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 20.8 (×4),
20.9 (×4), 21.0 (×2), 55.4, 62.3, 62.4, 62.7, 66.3, 66.4, 68.5, 68.6, 69.4,
69.6, 69.7, 69.8, 70.5, 76.7, 77.4, 99.3, 99.5, 99.9, 169.5, 169.6 (×2),
169.8, 169.9, 170.2, 170.3, 170.6, 170.9, 171.0; ESI-HRMS 956.3215
(M + NH4)+. Anal. Calcd for C39H54O26 (938.8305): C, 49.89; H,
5.80; O, 44.31. Found: C, 49.71; H, 5.77.
798
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The Journal of Organic Chemistry
Note
Reaction of Methyl Ortho Ester 7 in the Presence of
CD3OD. Following the general procedure, to a solution of the 1,2-
ortho ester 7 (50 g, 0.08 mmol) in dry CH2Cl2 (3 mL), under argon
and cooled to −30 °C, was added CD3OD (3.33 μL, 0.08 mmol), and
this mixture was treated with BF3·Et2O (31 μL, 0.25 mmol). After
5 min, when all the starting material had disappeared, Et3N (1 mL)
was added and the resulting mixture was vigorously stirred. The
residue was concentrated and purified by flash chromatography
(hexane/EtOAc, 8/2) to yield deuteriomethyl mannopyranoside 9
(22 mg, 48% yield, 85% deuterium content) and hemiacetal 10
(12 mg, 24%).
chemistry, see: Jayaprakash, K. N.; Radhakrishnan, K. V.; Fraser-Reid,
B. Tetrahedron Lett. 2002, 43, 6953−6955.
(15) “Two-stage” glycosylation strategies that make use of ortho ester
intermediates have been described: Ogawa, T.; Beppu, K.;
Nakabayashi, S. Carbohydr. Res. 1981, 93, C6−C9.
(16) See also: Kong, F. Curr. Org. Chem. 2003, 7, 841−865, and
references cited therein.
(17) For early strategies to overcome this problem, see: Kochetkov,
N. K.; Bochkov, A. F.; Sokolovskaya, T. A.; Snyatkova, V. J. Carbohydr.
Res. 1971, 16, 17−27.
(18) Llera, J. M.; Lop
2997−2998.
́
ez, J. C.; Fraser-Reid, B. J. Org. Chem. 1990, 55,
ASSOCIATED CONTENT
(19) Propargyl ortho esters that also release a non-nucleophilic
species have been recently described: Vidadala, S. R.; Thadke, S. A.;
Hotha, S. J. Org. Chem. 2009, 74, 9233−9236, and references cited
therein.
■
S
* Supporting Information
Figures giving 1H NMR and 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
(20) Castillon and co-workers have reported the use BF3·Et2O in
CH2Cl2 to induce the rearrangement of ortho ester intermediates to
glycolipids; see: (a) Morales-Serna, J. A.; Boutureira, O.; Díaz, Y.;
AUTHOR INFORMATION
Matheu, M. I.; Castillon
(b) Morales-Serna, J. A.; Díaz, Y.; Matheu, M. I.; Castillon
Biomol. Chem. 2008, 6, 3831−3836.
́
, S. Org. Biomol. Chem. 2008, 6, 443−446.
■
́
, S. Org.
Corresponding Author
*E-mail: ana.gomez@csic.es (A.M.G.); jc.lopez@csic.es (J.C.L.)
(21) Careful inspection of a blowout of the anomeric region in the
1H NMR spectrum of the reaction of 4 with BF3·Et2O showed the
presence of some methyl mannopyranoside 6 (<5%), although it could
not be isolated.
ACKNOWLEDGMENTS
■
This research was supported with funds from the Ministerio de
Ciencia e Innovacion
CTQ2009-10343 and S2009/PPQ-1752, respectively. B.F.-R.
́
and Comunidad de Madrid, Grant Nos.
(22) Duus, J. Ø.; Gotfredsen, C. H.; Bock., K. Chem. Rev. 2000, 100,
4589−4614.
1
1
(23) JC1,H1 Coupling constants: 5, C-1α JC1,H1 = 174.6 Hz, C-1β
1JC1,H1 = 157.4 Hz; , C-1α 1JC1,H1 = 174.9 Hz, C-1β 1JC1,H1 = 158.4 Hz.
(24) In this context, Nicolaou et al. described a related stereo-
controlled construction of 1,1′-disaccharides comprising a β-manno-
side structure in which a five-membered-ring stannane was used to fix
the anomeric oxygen in the desired β configuration; see: Nicolaou, K.
C.; van Delf, F. L.; Conley, S. R.; Mitchell, H. J.; Jin, Z.; Rodríguez, R.
M. J. Am. Chem. Soc. 1997, 119, 9057−9058.
thanks the National Science Foundation, Grant No. CHE
́
0717702. We also thank Ms. Marina Rodriguez (IQOG) for
skillful technical support.
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