Improved synthesis and application of conjugation-amenable polyols from d-mannose

A series of polyhydroxyl sulfides and triazoles was prepared by reacting allyl and propargyl d-mannose derivatives with selected thiols and azides in thiol–ene and Huisgen click reactions. Conformational analysis by NMR spectroscopy proved that the intrinsic rigidity and linear conformation of the mannose derived polyol backbone is retained in the final click products in solution. Single crystal X-ray structure determination of one of the compounds prepared further verified that the linear conformation of the polyol segment is also retained in the solid state. In addition, an improved method for direct Barbier-type propargylation of unprotected d-mannose is reported. The new reaction protocol, involving tin-mediated propargylation in an acetonitrile-water mixture, provides access to multigram quantities of the desired, valuable alkyne polyol without relying on protecting group manipulations or chromatographic purification.


Introduction
We have previously reported that the major diastereomer formed in the metal-mediated allylation of mannose (compound 1, Fig. 1) aggregates from aqueous solution upon stirring. 1,2 This counter-intuitive, self-assembling behavior was shown to originate from the linear, planar zigzag conformation of the polyol backbone, retained both in the solid state and in solution, allowing the formation of highly ordered hydrogen bonded networks resulting in rod-like packing in the crystal lattice. 1,2 Furthermore, both the propargylated analogue (compound 2, Fig. 1) and the hydrogenated congener of 1 exhibit similar behavior, likewise adopting linear solution and, as determined for compound 2, also solid state conformations. 2 In contrast, as shown in the earlier study, the corresponding allylated D-glucose and D-galactose analogues adopted nonlinear solution conformations without spontaneous aggregation, further manifesting the congurational uniqueness of the mannose derivative 1. 1 The earlier conformational investigations also suggest that the linearity of the polyol backbone of these mannose-derived compounds is mainly responsible for the observed self-assembling and self-aggregating solution and solid-state behavior. Consequently, a relevant research question is whether the hydrophobic end of compounds 1 and 2 could be further derivatized, without affecting the intrinsic linear conformation and hydrogen-bonding properties of the polyol part of the molecule. This, in turn, would open the possibilities to utilize these mannose derived polyols as rigid and compact linear rods in various polymer science and material applications, tentatively, for example, in rod-coil block copolymers or liquid crystal systems. 3 Click chemistry is a term coined by Sharpless in the early 2000s. 4 Click reactions are characterized by high yields, insensitivity to water and oxygen, wide scope, regio-and stereo-specicity, simple workup and high atom economy. Among the most well known click-type reactions are the thiol-ene coupling and the Huisgen 1,3-dipolar cycloaddition reaction. Due to their inherent simplicity and versatility, these reactions have been extensively used in a wide range of applications, including medicinal chemistry, biochemistry and material sciences. 5 En route to developing novel functional materials based on the mannose-derived, self-assembling linear rods, we report here our initial investigation on the utilization of the unsaturated functionalities of compounds 1 and 2 in clickreactions and the preparation and characterization of a series of their thiol and triazole derivatives. By NMR-spectroscopic conformational analysis, further supported by X-ray structure While the preparation of allylated carbohydrate derivatives through metal-mediated Barbier-type reaction was reported almost three decades ago, 6 the corresponding propargylation is less straightforward. Metal-mediated propargylation in general typically results in mixtures of the propargylic and allenic products due to facile rearrangement of the triple bond. 7 While different reaction protocols for selective propargylation of carbonyl compounds have been developed previously, 7 to our knowledge, successful methods for direct metal-mediated propargylation of C1 in unmodied monosaccharides have not been described. For propargylation of D-mannose, all earlier reported methods are suboptimal, involving either complex isolation procedures, multiple steps and protecting groups, or expensive chiral ligands. 2,8 For applying the Huisgen 1,3-cycloaddition click reaction to the propargylated mannose derivative in gram scale, an efficient synthesis procedure becomes essential.
For optimization of our earlier reported method, 2 various reaction conditions (solvent, metal, temperature, reaction time, optimization is shown in Table S1 in ESI †) for Barbier-type, metal-mediated propargylation of D-mannose were screened. It was found that conducting the reaction with fresh reagents in degassed AcCN : H 2 O 9 : 1, under argon atmosphere, produces the diastereomerically pure propargylated compound 2 in 20% isolated yield (Scheme 1). The seemingly low yield is, however, well compensated by the simplicity of the synthesis protocol which allows to isolate the desired compound 2 in pure form, in multigram scale, by simple crystallization from water, and without any protecting group manipulations or chromatographic purication. Unfortunately, even at longer reaction times, complete conversion of the starting material is not achieved with the NMR spectra of the crude reaction product showing a complex mixture of multiple products and possible degradation. Also a small amount of the allenic analogue forms during the reaction and co-precipitates with the desired propargylated product (see peaks at approximately 5.4, 4.9 and 4.5 ppm in the 1 H-NMR spectrum in ESI †). This is, however, not a critical issue for further use of the propargylic product in copper-catalyzed Huisgen 1,3-cycloaddition reaction, as the allene derivative is inactive in such reactions and can be removed at the work-up stage by simple washing of the triazol products with water.
In the rst stage of the click-reaction screening, suldes 3-9 ( Fig. 2) were prepared in good to excellent isolated yields via the UV-initiated thiol-ene reaction (Scheme 2).  conversions were typically obtained within 60 minutes. The work-up procedure was notably easy: the products were puried by washing the solid crude products with suitable solvents in order to remove excess starting materials and initiator residuals, followed by centrifugation/decantation and freeze-drying. For full experimental procedures and spectral data, see Experimental section and ESI. † Next, the propargylated mannose derivative 2 was coupled to a series of azides via the copper-catalyzed Huisgen 1,3-cycloaddition reaction (Scheme 2) to form the triazoles 10-13 (Fig. 3). The coupling reactions were carried out in H 2 O, H 2 O/THF or DMF/H 2 O mixtures at 55 C. The work-up was conducted in a similar manner as for the suldes, by washing with suitable organic solvent and water, followed by centrifugation/ decantation and freeze-drying. Although full conversions were typically reached, the isolated yields were only moderate due to the relatively high solubility of the products in water, causing partial dissolution of the reaction products and material losses upon removing the salts formed. For full experimental details, see Experimental section and ESI. † To reassure that no changes in the conformation of the polyol backbone occurs upon chain elongation, all prepared compounds underwent conformational analysis by NMR spectroscopy. The relationship between the size of the vicinal 3 J H,H couplings and the conformation of acyclic polyols has been thoroughly elucidated in previous literature. 9 For polyol compounds in linear conformation, the 3 J H,H couplings should be either small (<3 Hz), corresponding to a dihedral angle of 60 , or large (7-10 Hz), corresponding to a dihedral angle of 180 , consistent with linearity. Intermediate 3 J H,H couplings (3)(4)(5)(6)(7) instead indicate that the carbon chain is twisted rather than linear. All prepared compounds were fully characterized by NMR spectroscopy, and the 1 H-1 H coupling constant patterns were compared with the corresponding data for the original polyols 1 and 2. 1,2 In our earlier studies, it was shown that the vicinal coupling constants for linear mannose-based polyols follow a regular pattern, being either small (#1.6 Hz) when the neighboring protons are in gauche conguration, or large (8.3-9.5 Hz) when the neighboring protons are in anti conguration. 1,2 The suldes and triazoles prepared in this work did not exhibit any signicant changes in the coupling constant pattern of the polyol backbone (see Table 1), consistent with the linear conformation of the polyol part indeed being retained also with longer, exible chains attached to the molecules. Similar to the starting polyols, the linearity of the suldes and triazoles does not appear to be solvent-dependent, being retained both in D 2 O and in d 6 -DMSO. 2 In addition, the single crystal X-ray structure of compound 11 was determined. Compound 11 crystallizes in a triclinic crystal system in chiral space group P1, with one molecule in the asymmetric unit (Fig. 4). In solid state, the carbohydrate backbone of 11 adopts a linear conformation similar to the previously reported structures of the allylated (1) and propargylated (2) derivatives of D-mannose, 1,2 as can be observed from the well Scheme 2 Synthesis of sulphides and triazoles from mannose derivatives by thiol-ene and Huisgen click reactions.    Table S3, ESI †), thereby arranging the individual molecules in the same way, side by side along the a-and b-axes resulting in head to tail order along the c- bonding occurs between the hydroxyl groups (O1, O2, O3, O4 and O5) of adjacent carbohydrate backbone hydroxyl groups. The C-H/N hydrogen bond is manifested between two adjacent triazole groups (C12-H12/ N10) and O-H/N between a hydroxyl (O6) group and a triazole ring nitrogen (N9). The molecular packing and hydrogen bond network are illustrated in Fig. S2, ESI. † It can also be observed that the phenyl group is disordered over to equally occupied sites (shown in orange in Fig. 4). This is manifested in the packing scheme as an orientation of two adjacent phenyl groups in a manner of weak phase-to-edge p-p interaction. Although the actual distances between the phenyl ring centroids ($4.8-5.3Å, vs. mainly <5.5Å) are within the generally accepted p-p interaction distance, the somewhat too low contact angle ($40 vs. mainly >60 ) between the ring planes indicates weak interaction.

Instrumentation and chemicals
All NMR spectra were recorded at 298 K on a Bruker Avance-III HD 500 MHz spectrometer equipped with a Bruker SmartProbe™. Deuterated DMSO with 0.03% tetramethylsilane (TMS) as internal standard or D 2 O were used as solvents.
Coupling constants were solved with Chemadder/SpinAdder soware, The Spin Discoveries Ltd. 10 HRMS were recorded with a Bruker Daltonics micro-QToF instrument in positive or negative mode using ESI-ionization. All UV-induced reactions were conducted in a 75 ml immersion well reactor equipped with a 125 W lamp emitting UV light at 365 nm wavelength. The reactor system was purchased from Photochemical Reactors LTD. The reactor setup is shown in Fig. S1, ESI. † All chemicals and solvents were purchased from commercial vendors and were used as such without purication.

Conclusions
To conclude, an improved method for preparation of propargylated D-mannose has been developed. This method provides access to larger quantities of the desired product, enabling more extensive utilization of this linear mannose-derived molecule in click reaction based applications. In addition, efficient synthesis protocols for mannose-derived suldes and triazoles have been developed. Notably, based on 1 H-1 H NMR spectroscopic coupling constant analysis and single crystal Xray diffraction, the linear conformation of the polyol backbone remains unaffected by the chain-elongation, indicating that these mannose derived polyols could be used as stiff, hydrogen bond-forming building blocks in polymer and other material science applications.
Future studies will focus on further application of the developed protocols by covalently linking the mannosederivatives to larger molecular architectures, such as polymers, dendrimers, silica and other surfaces.

Conflicts of interest
There are no conicts to declare.