Letter Cite This: Org. Lett. 2018, 20, 1220−1223
pubs.acs.org/OrgLett
Synthesis of 5‑C‑Methylated D‑Mannose, D‑Galactose, L‑Gulose, and L‑Altrose and Their Structural Elucidation by NMR Spectroscopy Christoph Köllmann,† Peter G. Jones,‡ and Daniel B. Werz*,† †
Institute for Organic Chemistry and ‡ Institute for Inorganic and Analytical Chemistry, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany S Supporting Information *
ABSTRACT: C5/C6-Spirocyclopropanation of exocyclic enol esters followed by alkali ring-opening of the three-membered ring was used for the diastereoselective preparation of 5-C-methylated D-mannose, D-galactose, L-gulose, and L-altrose. Extensive NMR studies demonstrated an increase of furanose form by 5-C-methylation in almost all cases.
C
D-galactose, a possible synthesis has only been proposed but is still not realized.9 In this work, we present a synthetic concept to generate both D- and L-configured 5-C-methylated derivatives of different monosaccharides. We used an alkali ring-opening reaction of C5/C6 spirocyclopropanated pyranoses, which have been extensively studied in our group.10 As a starting material for the syntheses, we exclusively utilized the corresponding D‑configured natural abundant monosaccharides. Application of Swern conditions to alcohols 1 and 1011 generated the corresponding C6 aldehydes. A simple methylation of these aldehydes at C5 proved to be a very sluggish reaction, and only traces of the desired compounds were ever obtained. Thus, we converted these aldehydes to exocyclic enol ethers, following a modified Takahashi procedure, which involved use of isobutyric anhydride and potassium carbonate in acetonitrile.12 For D‑mannose as well as for D-galactose, the isobutyric enol esters were received as diastereomeric mixtures of E and predominantly Z. The Furukawa procedure of the Simmons−Smith reaction13 also worked for the enol esters of both D-mannose and D-galactose and afforded an inseparable diastereomeric mixture of spirocyclopropanated pyranoses 3 and 12. Considering D-mannose, saponification of the mixture of cyclopropanated isobutyric esters 3 yielded the aldehyde of 5‑C-methylated D-mannose 4 and L-gulose 7. Reduction of both aldehydes by treatment with NaBH4 afforded the primary alcohols 5 and 8 of the monosaccharide derivatives. Further debenzylation with palladium on charcoal led to the fully deprotected 5-C-methylated D-mannose 6 and the corresponding L-gulose 9 (Scheme 1 and 2). Interestingly, in the case of the D-galactose scaffold, alkali cleavage of the diastereomeric mixture 12 yielded an inseparable mixture of the corresponding aldehydes. Therefore,
arbohydrates are key structures for biological interactions on the cellular surface for intracellular vesicle transport or progression of bacterial and viral infections.1 The polyfunctionality of each monosaccharide leads to an enormous complexity of their possible oligo- and polymers.2 Because of their extensive biological activities, carbohydrates represent powerful tools for biology, medicinal chemistry, and application as therapeutics in medicine.3 Numerous modifications of monosaccharides are present in Nature to meet the demand of specificity in highly diverse biological processes.4 In many cases, subtle differences in the substitution pattern lead to large differences in the ratio of pyranoses and furanoses. Nevertheless, access to these derivatized monosaccharides often requires multistep syntheses, revealing a need for general synthetic approaches.5 In earlier work from our group, we explored the scope of monosaccharide and disaccharide derivatives featuring a quaternary stereocenter at C4.6 Alkylation was performed by nucleophilic addition of the alkyl moiety to the previously oxidized hydroxyl group of the pyranose. In the case of C5, this synthetic strategy is not applicable to pyranoses. Therefore, generation of quaternary stereocenters at C5 is still challenging. Davis et al. have shown that 5-C-methylated D-mannose, naturally not apparent in cell surface oligosaccharides, can be used to increase host−antigen interactions.7 This effect is presumably based on the higher hydrophobicity of the monosaccharide. These results make 5-C-methylation of pyranoses in general more rewarding and a synthetic access to 5-C-methylated monosaccharide derivatives necessary. Nevertheless, suitable synthetic approaches to 5-C-methylated carbohydrates, including the preparation of L-configured 5-Cmethylated monosaccharides, are still limited. Since the first preparation of 5-C-methylated D-glucose and L-idose in the early 1990s, less scope expansion of such modified monosaccharides has been achieved.8 In the case of 5-C-methylated © 2018 American Chemical Society
Received: January 13, 2018 Published: February 6, 2018 1220
DOI: 10.1021/acs.orglett.8b00144 Org. Lett. 2018, 20, 1220−1223
Letter
Organic Letters
yields. Immediate reductive conversions of the aldehydes to the corresponding alcohols 14 and 17 were performed in 91% and 78% yield over two steps, respectively. After deprotection by hydrogenolysis with palladium on charcoal, we secured the monosaccharide derivatives 15 and 18 quantitatively. Using the described procedure, we were also able to synthesize the already literature-known 5-C-methylated monosaccharides of D‑glucose 25 and L-idose 26 (see the Supporting Information). Additionally, an isopropylidene protection strategy led to an overall shortened synthesis of 5-C-methylated L-altrose. As a starting material, 1,2:5,6-di-O-isopropylidene-α-D-galacto-pyranose 19 was prepared in a single step from D-galactose.14 After application of the previously described reaction conditions, the spirocyclopropanated L-altrose scaffold was obtained. In contrast to the previously used benzyl protection strategy, fixation of O3 and O4 by an isopropylidene protecting group hampered formation of the cyclopropanated D-galactose scaffold (Scheme 3).
Scheme 1. Synthesis of 5-C-Methylated D-Mannose (6) and L-Gulose (9)
Scheme 3. Alternative Preparation of 5-C-Methylated L‑Altrose by Usage of 1,2:5,6-Di-O-isopropylidene Protection
Scheme 2. Synthesis of 5-C-Methylated L-Altrose (15) and a D‑Galactose (18)
After column chromatography, compound 21 was isolated as a single diastereomer. Alkali reaction conditions for ringopening yielded a chromatographically separable mixture of aldehyde 22 and the corresponding spirocyclopropanol 24 in 69% and 10% yield, respectively. Further preparation of 5-Cmethylated L-altrose proved to be possible via alcohol 23. Acidic hydrolysis using concentrated aqueous hydrochloric acid afforded the 5-C-methylated L-altrose in 80% yield. Isopropylidene protection of the L-altrose scaffold facilitated crystallization by increased rigidity of the monosaccharide ring system. Therefore, spirocyclopropanol 24 crystallized instantly after separation from slowly evaporating diethyl ether as colorless rhombs. Single-crystal X-ray analysis of spirocyclopropanol 24 finally allowed a verification of the diastereoselective outcome of the Simmons−Smith cyclopropanation. The described method generated exclusively a (5S,6R)-configured spirocyclopropane moiety in case of the isopropylidene protected galactose scaffold. Furthermore, the L-altrose derivative showed a weak intramolecular hydrogen bonding interaction between the α-configured anomeric oxygen atom O2 and the secondary alcohol at the spirocyclopropane (see the Supporting Information).
a Compound 16 shows slow decomposition in solution proven by 1H NMR spectroscopy.
we further modified the developed procedure to perform the saponification at lower temperature in order to prevent ringopening and enable separation of the cyclopropanols 13 and 16. Luckily, we isolated the two cyclopropanols after separation in 50% and 11% yield. Application of the reaction conditions for aldehyde formation to both cyclopropanols delivered the aldehyde of L-altrose and D-galactose in good to quantitative 1221
DOI: 10.1021/acs.orglett.8b00144 Org. Lett. 2018, 20, 1220−1223
Letter
Organic Letters In order to clarify the origin of transferred protons during the ring opening reaction, we used deuterated methanol and D2O as solvents. Cleavage of the isobutyric esters led to an alcoholate anion 28, which can undergo a ring-opening reaction by formation of the corresponding monodeuterated 5-C-methylated aldehydes 29 and 30 (Scheme 4).
Table 1. Anomeric Ratios of Aldopyranoses and Aldofuranoses of 5-C-Methylated D-Mannose (6), L-Gulose (9), L-Altrose (18), and D-Galactose (20) Determined by 1H NMR Spectroscopy and Comparison with their Nonmethylated Counterparts 6
Scheme 4. Formation of Monodeuterated Aldehydes 29 and 30 after Ring-Opening Reaction by Saponification of the Isobutyric Ester 27 in Deuterated Solvents
After having prepared six different 5-C-methylated aldohexoses, we became interested in elucidating what kind of ring structures (pyranoses vs furanoses, α vs β) they preferred. Figure 1 illustrates the major NOE interactions used for structural elucidation. Ratios of the anomeric configurations in aqueous solution were determined for all investigated monosaccharide derivatives by 1H NMR spectroscopy (Table 1). Measurement of 1JC−H coupling constants, obtained from
a
D-Man
17
D-Gul
9
α-p (%) β-p (%) α-f (%) β-f (%)
23.8 76.2
