Key words aldehydes - boron - carbohydrates - cycloaddition - sulfur
There are several sulfur-containing sugars found in nature.[
1
] Among them, angucycline class of compounds, BE-7585A[
2
] and rhodonocardins,[
3
] are the only reported natural products containing a 2-thioglucose. However, in the
field of synthetic organic chemistry, 2-thioaldoses have been of much interest for
decades and a wide range of synthetic studies has been reported.[
4
] For instance, some oligomers of saccharides with sulfur in the glycosidic linkage
have been synthesized as potential glycosidase inhibitors[
5
] or potentially stable immunogens.[
6
] 2-Thioaldose derivatives have also been used as synthetic equivalents of 2-deoxyglycosyl
donors in the stereocontrolled synthesis of 2-deoxyglycosides.[7 ]
[8 ] In this strategy, the sulfur-containing group controls the glycosylation stereochemistry
by acting as a neighboring participation group, and is then removed by reductive desulfurization
after the glycoside formation, stereoselectively furnishing the corresponding 2-deoxyglycosides.
In these synthetic studies, 2-thioaldoses are usually prepared by an SN 2 displacement reaction involving a sulfur-containing nucleophile at C-2[
9
] or by anti -addition of an electrophilic sulfur species to the double bonds of glycals in the
presence of alcohols.[
10
] It is anticipated that an alternative approach, via carbon elongation reactions,
would be useful for obtaining a variety of 2-thioaldose derivatives, but to the best
of our knowledge, such an approach to the synthesis of 2-thioaldoses has not been
reported to date. We previously reported a novel method for the two-carbon elongation
of aldose derivatives based on [2+3]-type cycloaddition reactions of 1-alkenyl ethers
with 2,3-O -isopropylidene derivatives of aldehydo -aldoses.[
11
] This synthetic strategy enabled stereocontrolled installation of two stereogenic
centers at C-2 and C-3 in a single step, and the synthesis of several 2-subsituted
or 2,2-disubstituted 2-deoxy-d -gluco -hexose derivatives was achieved in a highly stereoselective manner. As part of a
study to examine the use of these cycloaddition products as synthetic intermediates,
we now report the synthesis of 2-thioaldoses using the strategy outlined in Scheme
[1 ]. We envisioned that a range of 2-(aryl- or alkylthio)aldofuranoses could be readily
accessed via the cycloaddition of β-methoxyvinyl sulfides with 2,3-O -isopropylidene-aldehydo -aldose derivatives.
β-Methoxyvinyl sulfides 3a –c were prepared as the trans form by a two-step reaction of bromoacetaldehyde dimethyl acetal with benzenethiol,
2-naphthalenethiol, and benzyl mercaptan, according to the literature method[
12
] with minor modifications (Scheme [2 ]).
Scheme 1 Scheme for synthesis of 2-thioaldose using BF3 -promoted cycloaddition reaction
Scheme 2 Preparation of β-methoxyvinyl sulfides 3a –c
With β-methoxyvinyl sulfides 3a –c in hand, the cyclization reaction was then investigated using 2,3;4,5-di-O -isopropylidene-aldehydo -d -arabinose (4 ). The reaction was carried out using 1.5 equivalents of 3a –c in the presence of 1.2 equivalents of BF3 ·OEt2 at –78 °C in CH2 Cl2 , affording the desired furanoside derivatives 5a –c
[13 ]
[14 ] with high diastereoselectivities (>95%). The vinyl sulfides employed in this study
underwent cycloaddition to give adducts in good yields and diastereoselectivities,
regardless of the steric and electronic properties of the substituents on the sulfur
(Table [1 ], entries 1–3). The newly formed stereogenic centers, C-1, C-2, and C-3, were proved
to have 1,2-cis –2,3-trans –3,4-cis relationships, using NMR spectroscopy (vide infra).
Table 1 Cycloaddition of β-Methoxyvinyl Sulfides 3a –c with Aldehyde 4
Entry
Sulfide
Reaction time (h)
Product
Yield (%)a
1
3a
2
5a
98
2
3b
3
5b
84
3
3c
2
5c
84
a Isolated yield.
Encouraged by the above results, we next embarked on the synthesis of 2-thioglucose.
Starting from 2,3-O -isopropylidene derivatives of aldehydo -d -erythrose, the addition of β-methoxyvinyl sulfides 3 to the carbonyl group, followed by cyclization, proceeded in a similar stereochemical
fashion, affording 2-thio-d -glucofuranoside derivatives stereoselectively. We investigated the reactions of aldehydes
6a and 6b , derived from d -erythrose, with vinyl sulfide 3c under the same reaction conditions. As a result, the desired cycloadducts 7a and 7b
[
15
] were again respectively obtained as the sole diastereomers, although the yield of
7a was somewhat lower, probably due to instability of the silyl-protecting group under
the reaction conditions (Table [2 ]).
Table 2 Cycloaddition of β-Methoxyvinyl Sulfide 3c with Aldehydes 6a and 6b
Entry
Aldehyde
Reaction time (h)
Product
Yield (%)a
1
6a
2
7a
62
2
6b
2
7b
82
a Isolated yield.
The furanoside 7a was converted into the corresponding methyl pyranoside 8
[
16
] in good yield as an inseparable 5:1 (α/β) mixture (Scheme [3 ]) by treatment with an ion-exchange resin (DOWEX-50W, H+ -form) in absolute methanol under reflux, followed by treatment with acetic anhydride
in pyridine. The anomeric configuration of the major isomer was confirmed as α-gluco by the 1 H NMR J values of the C-2 axial proton (3.2 Hz and 11.5 Hz).
Scheme 3 Transformation to methyl 2-thio-d -glucopyranoside 8
Detailed structural and conformational elucidations of the cycloadducts were achieved
by NMR spectroscopic analysis. As a result of the fixed bicyclic structure of the
furanoside, the coupling constants and NOE effects are very distinctive. Furanosides
5 and 7 both show relatively large coupling constants of J
1,2 = 5.0–5.5 Hz, indicating cis vicinal protons. In addition, furanoside 5 has a typical trans vicinal coupling constant, J
2,3 = 0.0 Hz, indicating that the dihedral angle between 2-H and the axial 3-H is near
90°, whereas furanoside 7 has J
2,3 = 4.6 Hz, probably as a result of a larger dihedral angle between 2-H and the equatorial
3-H than that in 5 . Moreover, the results of detailed NOE studies are in good accordance with this conformational
analysis, based on a fixed bicyclic structure, as illustrated in Figure [1 ].
Figure 1 Structural comparison of cycloadducts 5 and 7
The exclusive formation of a single diastereomer in all the reactions can be explained
by the open transition-state model A , as depicted in Scheme [1 ], which serves to minimize steric interactions between the nucleophile R′S and the
aldehyde substituents and allows an antiperiplanar arrangement of the C=O and C=C.
Subsequent ring closure of the resulting addition intermediate B is postulated to occur through the attack of the oxygen at C4 on the oxocarbenium
ion with the sterically favorable arrangement of the methoxy substituent, forming
the cyclization product.
In conclusion, we have successfully developed a facile method for the synthesis of
2-thioaldose derivatives using a BF3 -promoted cyclization reaction between β-methoxyvinyl sulfides and 2,3-isopropylidene
derivatives of aldehydo -aldoses. The reaction proceeded in a highly stereoselective manner to afford the
corresponding methyl furanoside derivatives with 1,2-cis –2,3-trans –3,4-cis relationships. The applicability of this approach was demonstrated by the preparation
of methyl 2-thioglucopyranoside, in which the newly formed stereogenic centers at
C-2 and C-3 were installed in a completely stereocontrolled manner.
