2,3,5-Tri-O-benzyl-d-xylofuranose
2,3,5-Tri-O-benzyl-d-xylofuranose
Taffoureau, Baptiste;Gillaizeau, Isabelle;Retailleau, Pascal;Nicolas, Cyril
2022-06-07 00:00:00
molbank Short Note 1 1 2 , 1 , Baptiste Taffoureau , Isabelle Gillaizeau , Pascal Retailleau * and Cyril Nicolas * Institut de Chimie Organique et Analytique (ICOA), UMR 7311 CNRS, Université d’Orléans, Pôle de Chimie, Rue de Chartres, BP 6759, 45067 Orléans CEDEX 2, France; baptiste.taffoureau@sigma-clermont.fr (B.T.); isabelle.gillaizeau@univ-orleans.fr (I.G.) Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette CEDEX, France * Correspondence: pascal.retailleau@cnrs.fr (P.R.); cyril.nicolas@univ-orleans.fr (C.N.); Tel.: +33-(0)-1-69-82-31-19 (P.R.); +33-(0)-2-38-49-26-46 (C.N.) Abstract: The synthesis and crystallization of 2,3,5-tri-O-benzyl-D-xylofuranose permitted us to isolate the alpha anomer with a small contamination of the beta form (ca 10%), whose first crystallo- graphic structure obtained in the P2 2 2 space group was determined at 100 K up to a resolution 1 1 1 of sin / = 0.71 Å and refined to an R1 value of 0.0171 with a Hirshfeld atom refinement max (HAR) approach. Keywords: 2,3,5-tri-O-benzyl-D-xylofuranose; synthesis; Hirshfeld atom refinement of X-ray structure; 3-D Hirshfeld surface; crystal packing 1. Introduction Carbohydrates are ubiquitous key biomolecules that are involved in numerous funda- mental biological events. They are an integral part of living cells acting as a vital source of energy, structural building blocks, and cell surface receptors or mediators [1]. Given the pivotal roles of mono-, oligo- and polysaccharides as well as glycoconju- Citation: Taffoureau, B.; Gillaizeau, I.; gates in the process of life, carbohydrate-mediated processes have therefore progressively Retailleau, P.; Nicolas, C. been labeled as promising targets in drug discovery [2]. However, sugar derivatives are typically not ideal candidates for therapeutic purposes, as they are mostly unstable and Molbank 2022, 2022, M1382. susceptible to hydrolysis [e.g., hemiacetals (aldoses), hemiketals (ketoses) or acetals and https://doi.org/10.3390/M1382 ketals (O-glycosides)] [2]. Academic Editor: Kristof Van Hecke As potential drug candidates, carbohydrate mimics have accordingly gained increased interest, because of their ability to modulate the activity of carbohydrate-processing en- Received: 21 April 2022 zymes, while circumventing the enzymatic and chemical instability of sugars in mam- Accepted: 1 June 2022 mals [3–5]. Efforts have thus been devoted to using carbohydrates as synthetic intermedi- Published: 7 June 2022 ates to generate glycomimetics via chiron approaches. Publisher’s Note: MDPI stays neutral One class of saccharide analogues that is currently attracting a surge of interest is that with regard to jurisdictional claims in of iminosugars. These small molecules, also known as azasugars, are a class of compounds published maps and institutional affil- capable of acting as inhibitors or enhancers of many enzymes that act on glycosides, iations. prominently on glycosidases [6–8], and glycosyltransferases [9]. They have become the most popular class of glycomimetics reported to date, being able, for instance, to regulate the folding and transport of glycoproteins (e.g., chaperone effect), to alter the glycosylation profile of eukaryotic cells, to interfere in the carbohydrate and glycoconjugate metabolism, Copyright: © 2022 by the authors. and to stop virus attachment and the infection of host cells [6–8,10,11]. Licensee MDPI, Basel, Switzerland. In our ongoing research directed towards iminosugars, we exploited the alpha and This article is an open access article beta forms of 2,3,5-tri-O-benzyl-D-xylofuranose 1 to prepare imino-L-arabinitol-C-glycosyl distributed under the terms and compounds as simplified UDP-Galf -transferase inhibitors [12–17]. Compound 1 was conditions of the Creative Commons further used by Martin and others, as a surrogate to build analogues of ( )-steviamine [18], Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ (+)-1-azafagomine [19], and radicamines A, and B [20,21], etc. The spectral characterization 1 13 4.0/). data of compound 1 (IR, H- and C-NMR, HRMS) and its ent- derivative was described Molbank 2022, 2022, M1382. https://doi.org/10.3390/M1382 https://www.mdpi.com/journal/molbank Molbank 2022, 2022, M1382 2 of 11 Molbank 2022, 2022, x FOR PEER REVIEW 2 of 11 in [22–24]; however, to our knowledge, the X-ray crystal structures of the enantiomers enantiomers have not so far been determined. Herein, we report the synthesis of 2,3,5-tri- have not so far been determined. Herein, we report the synthesis of 2,3,5-tri-O-benzyl-, - O-benzyl-α,β-D-xylofuranose (with a different method, see Section 2.1 below, and experi- D-xylofuranose (with a different method, see Section 2.1 below, and experimental part), mental part), and the crystallographic description (Ortep structure, 3-D Hirshfeld surface and the crystallographic description (Ortep structure, 3-D Hirshfeld surface and crystal and crystal packing) of 2,3,5-tri-O-benzyl-D-xylofuranose mixing both anomers. packing) of 2,3,5-tri-O-benzyl-D-xylofuranose mixing both anomers. 2. Results and Discussion 2. Results and Discussion 2.1. Synthesis 2.1. Synthesis Our investigation commenced from D-xylose, which was converted into 2,3,5-tri-O- Our investigation commenced from D-xylose, which was converted into 2,3,5-tri-O- benzyl-α,β-D-xylofuranose 1 in 29% overall yield over three steps with only one purifica- benzyl-, -D-xylofuranose 1 in 29% overall yield over three steps with only one purification tion (Scheme 1). Following typical conditions, D-xylose was inserted in a mixture of dry (Scheme 1). Following typical conditions, D-xylose was inserted in a mixture of dry methanol and acetyl chloride, and the reaction mixture was heated at 30 °C for 3.5 h. The methanol and acetyl chloride, and the reaction mixture was heated at 30 C for 3.5 h. crude mixThe ture was ne crude mixtur utralized b e was y add neutralized ition of a b by asic r addition esin. C of om a p basic ound resin. 2 was th Compound en reacted 2 was then with an exce reacted ss of bwith enzylan brom excess ide and N of benzyl aH in DMF bromide at 20 and °C NaH for 20 in hDMF to afford m at 20 eC thyl for 2,20 3,5- h to afford methyl 2,3,5-tri-O-benzyl-, -D-xylofuranoside 3. Compound 1 (/ ca. 2:3, CDCl tri-O-benzyl-α,β-D-xylofuranoside 3. Compound 1 (α/β ca. 2:3, CDCl3 solution, 25 °C) was obtained thro solution, ugh su 25 bseC) que was nt hydro obtained lysis thr by ough treatm subsequent ent with a m hydr ixtolysis ure of g by lac tria eatment l acetic with acid a mixture of glacial acetic acid and 1 M aq. HCl solution at 80 C for 17 h, followed by 4 h at 100 C. and 1 M aq. HCl solution at 80 °C for 17 h, followed by 4 h at 100 °C. Scheme 1. Synthesis of 2,3,5-tri-O-benzyl-α,β-D-xylofuranose. Scheme 1. Synthesis of 2,3,5-tri-O-benzyl-, -D-xylofuranose. 2.2. Structural Commentary 2.2. Structural Commentary The structure of D-xylofuranose 1 was confirmed beyond doubt by single crystal X-ray The structure of D-xylofuranose 1 was confirmed beyond doubt by single crystal X- diffraction studies performed upon crystals belonging to non-centrosymmetric Sohncke ray diffraction studies performed upon crystals belonging to non-centrosymmetric space group, P2 2 2 , at the Mo K radiation and at low temperature (100 K) with refined 1 1 1 Sohncke space group, P2 2 2 , at the Mo Kα radiation and at low temperature (100 K) 1 1 1 Flack parameter close to 0. Additional redundant measurements on a copper source but with refined Flack parameter close to 0. Additional redundant measurements on a copper at room temperature and limited to a resolution of (sin/) = 0.6 Å confirmed the ‒1 source but at room temperature and limited to a resolution of (sinθ/λ) = 0.6 Å confirmed significance of the Flack parameter in line with the starting D-xylose derivative. the significance of the Flack parameter in line with the starting D-xylose derivative. The molecule found to occupy the asymmetric unit consists of a furanose ring sub- The molecule found to occupy the asymmetric unit consists of a furanose ring sub- stituted by two O-benzyl groups at C2 and C3, one Met-OBn group in position 4 and stituted by two O-benzyl groups at C2 and C3, one Met-OBn group in position 4 and one one hydroxyl group in position 1. Completion of the independent atom model (IAM) hydroxyl group in position 1. Completion of the independent atom model (IAM) refine- refinement with all hydrogen atoms constrained to geometric positions suggested slight ment with all hydrogen atoms constrained to geometric positions suggested slight disor- disorder of the central O-benzyl group at C3 treated as static over two close sites and der of the central O-benzyl group at C3 treated as static over two close sites and the hy- the hydroxy group at C1 in an equatorial position. Nevertheless, at that stage, the first droxy group at C1 in an equatorial position. Nevertheless, at that stage, the first 3residual residual peak in the Fourier difference synthesis—albeit low (<0.3e.Å ) but almost twice peak in the Fourier difference synthesis—albeit low (<0.3e.Å ) but almost twice the value the value of the second peak—was located in the axial position of C1 in the vicinity of of the second peak—was located in the axial position of C1 in the vicinity of the disordered the disordered O-benzyl group. The possibility that the two anomeric forms could be O-benzyl group. The possibility that the two anomeric forms could be present inside the present inside the crystal was therefore checked. We ended up with the confirmation that crystal was therefore checked. We ended up with the confirmation that crystallization of crystallization of the neat mixture of alpha and beta anomers (unknown ratio) trapped the the neat mixture of alpha and beta anomers (unknown ratio) trapped the α-form in large -form in large majority over the form (ca. 0.89(1):0.11(1)). Carbohydrate hemiacetals majority over the β form (ca 0.89(1):0.11(1)). Carbohydrate hemiacetals can obviously exist can obviously exist in two anomeric isoforms, either in the solid or liquid state. In the case in two anomeric isoforms, either in the solid or liquid state. In the case of compound 1, of compound 1, the anomer is heavily favored in the crystal state, whereas in CDCl at the α anomer is heavily favored in the crystal state, whereas in CDCl3 at 25 °C, the equi- 25 C, the equilibrium is shifted towards the form. One may therefore advocate for the librium is shifted towards the β form. One may therefore advocate for the selective crys- selective crystallization of the - over the -anomer (e.g., optical resolution). However, tallization of the α- over the β-anomer (e.g., optical resolution). However, there is no evi- there is no evidence that the neat amorphous solid did not already contain the two forms dence that th in an e neat amorp / ratiohof ous so 89:11, lid did and not already contain th its dissolution in CDCl e two forms slowly shifted in an αthe /β ra mutar tio otation of 89:11, and its dissolution in CDCl3 slowly shifted the mutarotation equilibrium towards Molbank 2022, 2022, x FOR PEER REVIEW 3 of 11 Molbank 2022, 2022, M1382 3 of 11 a ca. 2:3 ratio in favor of the β form. Further diffraction measurement at low temperature equilibrium towards a ca. 2:3 ratio in favor of the form. Further diffraction measurement and at extended resolution allowed us to perform a Hirshfeld atom refinement (HAR) to at low temperature and at extended resolution allowed us to perform a Hirshfeld atom document in greater detail the structural parameters of 1 including those of the H atoms refinement (HAR) to document in greater detail the structural parameters of 1 including Molbank 2022, 2022, x FOR PEER REVIEW 3 of 11 (Figures 1, 2, and 5, plus Tables 1‒3, and Figure S1 and Table S1 in the supporting infor- those of the H atoms (Figures 1, 2, and 5, plus Tables 1–3, and Figure S1 and Table S1 in the mation (SI)). supporting information (SI)). The furanose group flexibility was found uncorrelated to the disorder of the central The furanose group flexibility was found uncorrelated to the disorder of the central O-Bn group, a disorder that could be considered as essentially dynamic. While the major a ca. 2:3 ratio in favor of the β form. Further diffraction measurement at low temperature O-Bn group, a disorder that could be considered as essentially dynamic. While the major α form can be seen to be stabilized by an intramolecular hydrogen bond with O2, graph- and at extended resolution allowed us to perform a Hirshfeld atom refinement (HAR) to form can be seen to be stabilized by an intramolecular hydrogen bond with O2, graph-set set symbol S(5), (see Table 2) and benefit from developing a weak intermolecular H-bond document in greater detail the structural parameters of 1 including those of the H atoms symbol S(5), (see Table 2) and benefit from developing a weak intermolecular H-bond (see (see below Figure 1, and crystal packing analysis in Figure 4), the minor β-form can find (Figures 1, 2, and 5, plus Tables 1‒3, and Figure S1 and Table S1 in the supporting infor- below Figure 1, and crystal packing analysis in Figure 4), the minor -form can find in O3 in O3 a ‘lifeline’ in a hydrophobic environment to make an intramolecular h-bond (graph- mation (SI)). a ‘lifeline’ in a hydrophobic environment to make an intramolecular h-bond (graph-set, set, symbol S(6)). The furanose group flexibility was found uncorrelated to the disorder of the central symbol S(6)). O-Bn group, a disorder that could be considered as essentially dynamic. While the major α form can be seen to be stabilized by an intramolecular hydrogen bond with O2, graph- set symbol S(5), (see Table 2) and benefit from developing a weak intermolecular H-bond (see below Figure 1, and crystal packing analysis in Figure 4), the minor β-form can find in O3 a ‘lifeline’ in a hydrophobic environment to make an intramolecular h-bond (graph- set, symbol S(6)). (a) (b) Figure 1. (a) Molecular structure of (α)-1 with numbering scheme and anisotropic displacement el- Figure 1. (a) Molecular structure of ()-1 with numbering scheme and anisotropic displacement lipsoids drawn at the 50% probability level, hydrogen atoms being represented by spheres of arbi- ellipsoids drawn at the 50% probability level, hydrogen atoms being represented by spheres of trary radius; (b) Ortep view of the minor (β)-1 compound. Dotted line in cyan highlights the intra- arbitrary radius; (b) Ortep view of the minor ( )-1 compound. Dotted line in cyan highlights the molecular h-bond. intramolecular h-bond. (a) (b) The conformational analysis of the furanose ring (Figure 2) based on its internal dihe- dral angles and its deviation from planarity showed that the pseudorotational phase angle Figure 1. (a) Molecular structure of (α)-1 with numbering scheme and anisotropic displacement el- P 11 and the maximum puckering amplitude n 35 (see Table 1) [25,26]. Thus, this lipsoi = ds drawn at the 50% probability level, hydrogen atom=s being represented by spheres of arbi- max ring trary radius adopts ; ( a b conformation ) Ortep view of close the minor ( to T ,βwher )-1 compou e C2 and nd. Dotted line in cy C3 deviate by 0.116 an highlights the and 0.443 intra- Å, (by molecu 0.467 lar h-bo and nd. 0.058), respectively, from the plane through atoms C1(B)/C4/O4(B). (a) (b) (c) Figure 2. Close-up of the sugar ring puckering C3-endo, C2-exo (N-type) conformations for the (a) α form, and (b) β form. (c) Conformation of the 2,3,5-tri-O-benzyl-β-D-arabinofuranose analogue, depicted in the CCDC Refcode: LUHROX. The conformational analysis of the furanose ring (Figure 2) based on its internal di- (a) ( hedral angles and its deviation bfrom p) ( lanarity showed that the pseudoro c) tational phase angle P ≅ 11° and the maximum puckering amplitude νmax ≅ 35 (see Table 1) [25,26]. Thus, Figure 2. Close-up of the sugar ring puckering C3-endo, C2-exo (N-type) conformations for the (a) Figure 2. Close-up of the sugar ring puckering 3 C3-endo, C2-exo (N-type) conformations for the this ring adopts a conformation close to T2, where C2 and C3 deviate by 0.116 and ‒0.443 α form, and (b) β form. (c) Conformation of the 2,3,5-tri-O-benzyl-β-D-arabinofuranose analogue, (a) form, and (b) form. (c) Conformation of the 2,3,5-tri-O-benzyl- -D-arabinofuranose analogue, Å, (by 0.467 and ‒0.058), respectively, from the plane through atoms C1(B)/C4/O4(B). depicted in the CCDC Refcode: LUHROX. depicted in the CCDC Refcode: LUHROX. Table 1. Hydrogen bonds [Å and °.]. The conformational analysis of the furanose ring (Figure 2) based on its internal di- A search in the Cambridge Structural Database (CSD, [27]) revealed the structure of a hedral angles and its deviation from planarity showed that the pseudorotational phase D—H...A d(D—H) d(H...A) d(D...A) <(DHA) homologous compound (CCDC Refcode: LUHROX, [28]) which is the 2,3,5-tri-O-benzyl- angle P ≅ 11° and the maximum puckering amplitude νmax ≅ 35 (see Table 1) [25,26]. Thus, -D-arabinofuranose O1—H1...O2 0 (see Figur.964( e 210 c)) whose geometric1.938(11) parameters2.5739 are(7 listed) in1 T2 able1.3(8) 2 for this ring adopts a conformation close to T2, where C2 and C3 deviate by 0.116 and ‒0.443 #1 comparison. The torsion angles of (, )-1, C2—O2—C21—C22 = 69.10 (6) and C5—O5— O1—H1...O5 0.964(10) 2.548(10) 3.3601(7) 142.0(8) Å, (by 0.467 and ‒0.058), respectively, from the plane through atoms C1(B)/C4/O4(B). Table 1. Hydrogen bonds [Å and °.]. D—H...A d(D—H) d(H...A) d(D...A) <(DHA) O1—H1...O2 0.964(10) 1.938(11) 2.5739(7) 121.3(8) #1 O1—H1...O5 0.964(10) 2.548(10) 3.3601(7) 142.0(8) Molbank 2022, 2022, M1382 4 of 11 C41—C42 = 83.03(6) are gauche, meaning that the two opposite substituents are not fully extended, bringing the respective centroids of the phenyl rings to a distance of 11.1 Å (2Å shorter than in the conformers of the homologous structure, LUHROX). Altogether with the O-benzyl group axially positioned at C3 with the ring overhanging orthogonally the furanose, the overall conformation adopted inside the crystal features a folding or closing trend for a ‘three petal flower ’, conversely to the ‘open’ homologous structure. Table 1. Hydrogen bonds [Å and ] . D—H...A d(D—H) d(H...A) d(D...A) <(DHA) O1—H1...O2 0.964(10) 1.938(11) 2.5739(7) 121.3(8) #1 0.964(10) 2.548(10) 3.3601(7) 142.0(8) O1—H1...O5 O1B—H1B...O3 0.964(10) 2.299(11) 2.9095(7) 120.4(8) #2 C23—H23...O1 1.010(7) 2.299(11) 3.1929(7) 158.84(8) #1 1 1 C27—H27...O5 1.084(8) 2.3889(11) 3.4537(7) 166.88(8) 1 #1 #2 Symmetry transformations used to generate equivalent atoms: 1 x, 1/2+y, 3/2 z; x 1, y, z. Table 2. Geometrical parameters of the torsion angles ( ) and pseudorotation parameters ( ) of the furanose ring for the two coexisting anomers (I) and molecules A and B of D-arabinofuranose hemiacetal analogue [25]. (4) (4) Torsion Angle ()-I (b)-I Molecule A Molecule B C4—O4—C1—C2 4.55 (11) 17.4 (10) 32.47 (3) 33.58 (3) O4—C1—C2—C3 24.39 (13) 29.29 (12) 41.02 (3) 41.29 (3) C1—C2—C3—C4 33.41 (7) 32.07 (11) 34.19 (3) 33.51 (3) C1—O4—C4—C3 17.55 (9) 2.2 (6) 15.85 (3) 13.88 (3) C2—C3—C4—O4 32.07 (10) 21.6 (8) 10.74 (3) 13.07 (3) H1—O1—C1—O4 99.8 (6) 67.17 (8) 54.2 (3) 66.8 (1) X syn syn syn syn C3—C4—C5—O5 167.42 (5) 167.42 (5) 172.2 (3) 173.8 t t t t t + (2) /
/ Phase angle (P) 11.1 (2) 13.5(17) 327.3 324.4 Puckering amplitude ( ) 35.0 (1) 32.6 (7) 41.3 41.6 max (3) S or N N N N N (1) (2) t + (3) For anti, = 180 90 , and for syn, = 0 90 .
= 180 ,
= 60 and
= 60 . For south S-type, (4) P = 180 90 , and for north N-type, P = 0 90 . Data for molecules A and B of compound 1 homologous molecules were retrieved from the CSD (Refcode: LUHROX). Inside the crystal (, )-1, the molecules spiral around the 2-fold screw axis at 0,y, 1 1 3 and ,y, in antidromic infinite chains, C (7), via distant H-bond interactions between 4 2 4 the hydroxy O1 donor and O5 of the Met-OBn chain of the vicinal molecule at the po- #1 #1 sition #1 1 x, y+1/2, 3/2 z (d O1(–H1)O5 = 3.360Å, \ (O1–H1O5 ) = 142.0 ), interactions reinforced by shorter non-conventional H-bonds between C27 and O5 (d #1 #1 C27(–H27)O5 = 3.454 Å, \ (C27–H27O5 ) = 166.9 ), and also C23 and O1 at #2 x 1, #2 #2 y, z (d C23(–H23)O1 = 3.193 Å, \ (C23–H23O1 ) = 158.8 ). These are the specific points of contact in the crystal which appear as red spots on the largely blue Hirshfeld surface of (, )-1 (Figure 3) [29]. The molecular packing of (/ )-1 features along the ab plane ‘hydrophilic’ and ‘hy- drophobic’ layers containing the benzyl groups with some disorder and whose most notice- #3 able interaction is C45–H45 (Cg4) (Cg4 referring to the centroid of the C42/C47 phenyl 1 1 #3 #3 ring at position #3: x+ , y, 1 z, d H45Cg4 = 2.563(1)Å,\ (C45–H45Cg4) ) = 151.4 ) 2 2 (Figure 4a). Analysis of the Hirshfeld surface indicated that this type of interaction (CH/HC) accounted for a fourth of the contact contribution of the overall surface, which is more than twice the (OH/HO) contribution, but exceeds the van der Waals in- teractions by 61.9 %. The same ratios can be observed for LUHROX although its molecular assembly differs with molecules A and B, of the asu, making h-bonded interactions via the O1–H1O4 h-bonds between their central furanose rings, the chained dimers piling up in columns along the a direction of its monoclinic, P 2 , unit cell (Figure 4b). 1 Molbank 2022, 2022, M1382 5 of 11 Molbank 2022, 2022, x FOR PEER REVIEW 5 of 11 Figure 3. (Top) views of the 3-D Hirshfeld surface plotted over dnorm in the range from ‒0.3365 to Figure 3. (Top) views of the 3-D Hirshfeld surface plotted over d in the range from 0.3365 to norm 1.1653 a.u, (Middle) over the shape-index property highlighting C‒H… π interactions and (Below) 1.1653 a.u, (Middle) over the shape-index property highlighting C–H . . . interactions and (Below) the 2-D fingerprint plots of the mixture of D- showing close contacts of all contributions in the crystal the 2-D fingerprint plots of the mixture of D- showing close contacts of all contributions in the crystal and those delineated into the three main types of interactions. di and de denote the closest internal and those delineated into the three main types of interactions. d and d denote the closest internal Molbank 2022, 2022, x FOR PEER REVIEW i e 6 of 11 and external distances in Å from a point on the surface. and external distances in Å from a point on the surface. The molecular packing of (α/β)-1 features along the ab plane ‘hydrophilic’ and ‘hy- drophobic’ layers containing the benzyl groups with some disorder and whose most no- #3 ticeable interaction is C45–H45 ⋯π(Cg4) (Cg4 referring to the centroid of the C42/C47 : + #3 #3 phenyl ring at position #3 x ½, ½‒y, 1‒z, d H45···Cg4 = 2.563(1)Å, ∠ (C45–H45···Cg4) ) = 151.4°) (Figure 4a). Analysis of the Hirshfeld surface indicated that this type of interaction (C···H/H···C) accounted for a fourth of the contact contribution of the overall surface, which is more than twice the (O···H/H···O) contribution, but exceeds the van der Waals interactions by 61.9 %. The same ratios can be observed for LUHROX although its molec- ular assembly differs with molecules A and B, of the asu, making h-bonded interactions via the O1–H1···O4 h-bonds between their central furanose rings, the chained dimers pil- ing up in columns along the a direction of its monoclinic, P 21, unit cell (Figure 4b). (a) (b) Figure 4. (a) Partial view of the crystal packing of (α,β)-1 (ca. 89:11) along the a axis. O-H···O hydro- Figure 4. (a) Partial view of the crystal packing of (, )-1 (ca. 89:11) along the a axis. O-HO gen bonds are shown as cyan dotted lines; (b) for comparison, a view of the LUHROX packing along hydrogen bonds are shown as cyan dotted lines; (b) for comparison, a view of the LUHROX packing the a axis, also highlighting the extended conformation of the homologous molecule is reported. along the a axis, also highlighting the extended conformation of the homologous molecule is reported. 3. Materials and Methods 3.1. General Remarks Unless otherwise stated, all reagents and starting materials were purchased from commercial sources and used as received. Methanol (anhydrous, 99.8%) was purchased from Sigma-Aldrich Chimie S.a.r.l— 38297 Saint-Quentin-Fallavier CEDEX, France. N,N- Dimethylformamide (ACS reagent, ≥ 99.8%) was purified by passage through a column containing activated alumina under nitrogen pressure (Dry Solvent Station GT S100, Glass Technology, Geneva, CH). Amberlite® IRA-400 was prepared in its OH‾ form by passing 1 M KOH until the effluent was free of chloride ions, it was then washed with distilled H2O until neutral and then with MeOH. NMR spectra were recorded at 298 K with a Bruker Avance III HD nanobay 400 MHz spectrometer equipped with a BBO probe— Brucker France S.A.S., 67166 Wissembourg CEDEX. The structure of compound 1 (α/β ca 1 13 2:3, CDCl3 solution) was assigned with the aid of 1 D [ H NMR, C NMR, Distortionless Enhancement by Polarization Transfer (DEPT)] and 2 D Correlation Spectroscopy 1 13 [(1H−1H COSY, and H− C Heteronuclear Single Quantum Coherence (HSQC)] experi- ments. H NMR (400 MHz) chemical shift values are listed in parts per million (ppm), relative to the corresponding nondeuterated solvent. Data are reported as follows: chem- ical shift (ppm on the δ scale), multiplicity (s = singlet, d = doublet, and po = partially overlapped), coupling constant 21 (Hz), and integration. Acquisition of the C NMR (101 MHz) spectrum of compound 1 (α/β ca 2:3, CDCl3 solution) was performed on a broad- band decoupled mode. Chemical shift values are given in ppm, and are related to the corresponding nondeuterated solvent. High-resolution mass spectra were recorded with a Bruker maXis ESI qTOF ultrahigh-resolution mass spectrometer coupled to a Dionex Ultimate 3000 RSLC system. MS data were acquired in positive mode and were processed using Data Analysis 4.4 software (Bruker). The infrared spectrum of compound (α,β)-1 was recorded neat with a Thermo Scientific Nicolet IS10 FTIR spectrometer using dia- mond ATR golden gate sampling (Thermo Fisher Scientific, 28199 Bremen, Germany), and –1 is reported in wave numbers (cm ). Analytical thin-layer chromatography (TLC) was per- formed with Merck Silica Gel 60 F254 precoated plates ‒ VWR Avantor, F-93114 Rosny- sous-Bois CEDEX, France. Visualization of the developed chromatogram was performed under ultraviolet light (254 nm) and on staining by immersion in aqueous, acidic ceric ammonium molybdate followed by charring at ca. 150 °C. Column chromatography was performed in air on Silica Gel 60 (230–400 mesh) with petroleum ether (bp 40–65 °C) and ethyl acetate (EtOAc) as eluents. Organic solutions were concentrated under reduced pressure with a Büchi rotary evaporator ‒ BÜCHI SARL, 91140 Villebon-sur-Yvette, France. Conformation, crystal packing and geometrical parameters for the LUHROX D- Molbank 2022, 2022, M1382 6 of 11 3. Materials and Methods 3.1. General Remarks Unless otherwise stated, all reagents and starting materials were purchased from commercial sources and used as received. Methanol (anhydrous, 99.8%) was purchased from Sigma-Aldrich Chimie S.a.r.l—38297 Saint-Quentin-Fallavier CEDEX, France. N,N- Dimethylformamide (ACS reagent, 99.8%) was purified by passage through a column containing activated alumina under nitrogen pressure (Dry Solvent Station GT S100, Glass Technology, Geneva, CH). Amberlite®IRA-400 was prepared in its OH form by passing 1 M KOH until the effluent was free of chloride ions, it was then washed with distilled H O until neutral and then with MeOH. NMR spectra were recorded at 298 K with a Bruker Avance III HD nanobay 400 MHz spectrometer equipped with a BBO probe—Brucker France S.A.S., 67166 Wissembourg CEDEX. The structure of compound 1 (/ ca. 2:3, 1 13 CDCl solution) was assigned with the aid of 1 D [ H NMR, C NMR, Distortionless Enhancement by Polarization Transfer (DEPT)] and 2 D Correlation Spectroscopy [(1H 1H 1 13 1 COSY, and H C Heteronuclear Single Quantum Coherence (HSQC)] experiments. H NMR (400 MHz) chemical shift values are listed in parts per million (ppm), relative to the corresponding nondeuterated solvent. Data are reported as follows: chemical shift (ppm on the scale), multiplicity (s = singlet, d = doublet, and po = partially overlapped), coupling constant J (Hz), and integration. Acquisition of the C NMR (101 MHz) spectrum of compound 1 (/ ca. 2:3, CDCl solution) was performed on a broad-band decoupled mode. Chemical shift values are given in ppm, and are related to the corresponding non- deuterated solvent. High-resolution mass spectra were recorded with a Bruker maXis ESI qTOF ultrahigh-resolution mass spectrometer coupled to a Dionex Ultimate 3000 RSLC system. MS data were acquired in positive mode and were processed using Data Analysis 4.4 software (Bruker). The infrared spectrum of compound (, )-1 was recorded neat with a Thermo Scientific Nicolet IS10 FTIR spectrometer using diamond ATR golden gate sampling (Thermo Fisher Scientific, 28199 Bremen, Germany), and is reported in wave numbers (cm ). Analytical thin-layer chromatography (TLC) was performed with Merck Silica Gel 60 F254 precoated plates—VWR Avantor, F-93114 Rosny-sous-Bois CEDEX, France. Visualization of the developed chromatogram was performed under ultraviolet light (254 nm) and on staining by immersion in aqueous, acidic ceric ammonium molybdate followed by charring at ca. 150 C. Column chromatography was performed in air on Silica Gel 60 (230–400 mesh) with petroleum ether (bp 40–65 C) and ethyl acetate (EtOAc) as eluents. Organic solutions were concentrated under reduced pressure with a Büchi rotary evaporator—BÜCHI SARL, 91140 Villebon-sur-Yvette, France. Conformation, crystal pack- ing and geometrical parameters for the LUHROX D-arabinofuranose hemiacetal analogue were obtained from the Cambridge Structural Database (CSD, Version 5.42; Nov 2021, Cam- bridge, UK [27]). Hirshfeld surface of (, )-1 was drawn using CrystalExplorer 17.5-f4e298a, University of Western, Australia [29]. X-ray structure determination at rt and 100K was per- formed on a Rigaku rotating anode—ELEXIENCE SA, 91371 Verrières-le-Buisson CEDEX, France. X-ray data were then processed using CrystalClear 2.0, Tokyo, Japan [30] or CrysAl- isPro 1.171.41.121a, Yarnton, UK [31]. In both cases, the structure was solved by intrinsic phasing methods (SHELXT Version 2018/2, University of Göttingen, Germany [32]). Re- finement was done subsequently by full-matrix least-squares against F (SHELXL Version 2018/3, University of Göttingen, Germany) [33]). Ultimately, it was pursued with the Hirsh- feld atom refinement (HAR; [34]) with the NoSpherA2 [35] implementation in OLEX2-1.5, Durham University, UK [36]. Bijvoet analyses were performed with Platon (version170914, Utrecht University, The Netherlands). 3.2. Procedures and Characterization Data 3.2.1. Synthesis of 2,3,5-Tri-O-benzyl-, -D-xylofuranose (, )-1 A single-necked round-bottomed flask under argon atmosphere was charged with AcCl (2.5 mL, ca. 35.0 mmol) and dry MeOH (300 mL), and the solution was stirred at 20 C for 30 min. D-xylose (5.0 g, 33.3 mmol) was then added and the reaction mixture Molbank 2022, 2022, M1382 7 of 11 was stirred for 3.5 h at 30 C. Resin Amberlite IRA-400 (OH form) was added until pH 8, and the solution was filtered through a cotton plug and concentrated under vacuum. The crude product (Rf 0.6; SiO , CH Cl /MeOH 8:2, v/v) was obtained as a light-yellow oil, 2 2 2 and used in the next step without further purification. To the just-generated methyl , -D-xylofuranoside (2) under argon atmosphere, cooled to 0 C with an ice water bath, were successively added anhydrous DMF (100 mL) and NaH (60% dispersion in mineral oil, 8.0 g, 200.0 mmol) portionwise; the resulting suspension was stirred continuously at the same temperature for 30 min. Benzyl bromide (17.0 mL, 143.0 mmol) was then added dropwise, and the reaction mixture was allowed to reach room temperature. Stirring was pursued for 20 h and the temperature was adjusted to 0 C (ice water bath). Water (50 mL) was added, dropwise, and the aqueous phase was extracted twice, with Et O (2 150 mL). Next, combined organic layers were washed with H O (100 mL), sat. aq. NaHCO (100 mL) and brine (100 mL). The organic phase was dried 2 3 (MgSO ), filtered over a cotton plug and the solvent was removed by rotary evaporation. A single-necked round-bottomed flask under air atmosphere was charged with the mixture of and -anomers of 2,3,5-Tri-O-benzyl-, -D-xylofuranoside (3) [Rf 0.4 ( anomer), Rf 0.2 ( anomer); SiO , petroleum ether/EtOAc 9:1, v/v], glacial acetic acid (63 mL, ca. 1.1 mol) and aq. HCl (1 M, 16 mL, ca. 0.58 mol) and the solution mixture was heated for 17 h at 80 C and 4 h at 100 C. The mixture was allowed to reach room temperature and the solution was neutralized by addition of a 5 M aq. solution of KOH (5 M). The aqueous phase was extracted with EtOAc (2 150 mL) and the combined organic layers were washed with H O (100 mL), aq. sat. NaHCO (100 mL) and aq. sat. 2 3 NaCl (100 mL). The organic phase was dried (MgSO ), filtered over a cotton plug and the solvent was removed through rotary evaporation. The crude product was purified by column chromatography (SiO , petroleum ether/EtOAc 8:2, v/v) to give 1 as a colorless syrup (4.1 g, 29.3% over three steps). Mixture of anomers (/ ca. 2:3, CDCl solution, 25 C). Rf 0.2 (SiO , petroleum 3 2 ether/EtOAc 8:2, v/v). H NMR (400 MHz, CDCl ): 7.58–7.33 (po, 15H, H ), 5.65 (br 3 Ar d, J , 4.2 Hz, 0.4H, H-1), 5.46 (br s, 0.6H, H-1 ), 4.84–4.50 (po, 7H, 3 OCH Ph, 1 2 2 3 3 3 OCH Ph , H-4, H-4 ), 4.49–4.26 (po, 1H, OH, OH ), 4.26 (dd, J , 5.5 Hz, J , 2 3 4 2 3 3 3 3 3.1 Hz, 0.6H, H-3 ), 4.23 (dd, J , 4.7 Hz, J , 2.7 Hz, 0.4H, H-3), 4.18 (br dd, J , 3.1 Hz, 3 4 2 3 2 3 3 3 3 J , 0.8 Hz, 0.6H, H-2 ), 4.10 (dd, J , 4.2 Hz, J , 2.7 Hz, 0.4H, H2), 3.98–3.78 (po, 2H, 1 2 1 2 2 3 0 13 H-5, H-5 ) ppm. C NMR (101 MHz, CDCl ): 138.1 (C, C ), 137.7 (C, C ), 137.5 (C, 3 Ar Ar C ), 137.4 (C, C ), 137.3 (C, C ), 136.9 (C, C ), 128.4–127.7 (CH, CH , CH ), Ar Ar Ar Ar Ar Ar 101.6 (CH, C-1 ), 95.9 (CH, C-1), 86.5 (CH, C-2 ), 81.4 (CH, C-2), 81.2 (CH, C-3 ), 81.0 (CH, C-3), 79.6 (CH, C-4 ), 77.0 (CH, C-4), 73.4 (CH , OCH Ph ), 73.3 (CH , OCH Ph), 2 2 2 2 72.7 (CH , OCH Ph), 72.4 (CH , OCH Ph ), 72.1 (CH , OCH Ph), 71.6 (CH , OCH Ph ), 2 2 2 2 2 2 2 2 68.7 (CH , C-5 ), 68.3 (CH , C5) ppm. IR (neat): v˜ = 3419 (O–H), 3030 (C–H ), 2886 (C– 2 2 Ar H), 1454 (C=C), 1056 (C–O), 735 (C–H ), 696 (C–H ) cm . HRMS (ESI): m/z calcd. for Ar Ar C H NaO [M + Na] 443.1826, found 443.1826. 26 28 5 3.2.2. Crystallization of 2,3,5-Tri-O-benzyl-, -D-xylofuranose (, )-1 (ca. 89:11) Single crystals of (, )-1 (ca. 89:11) were grown by standing the crude mixture of 2,3,5-tri-O-benzyl-D-xylofuranose at 4 C for 3 days. Massive colorless blocks showed up covering part of the inner walls of the balloon. X-ray structure determination was carried out by collecting diffraction data first at room temperature (rt) on a Rigaku rotating anode using microfocused Cu K radiation l = 1.54187 Å (Table S1, see SI), then after cooling the crystal down to 100K using microfocused Mo K radiation l = 0.71073 Å. Crystal data, data collection and structure refinement details are summarized in Table 3 (see below). X-ray data were processed using CrystalClear 2.0 [30] or CrysAlisPro 1.171.41.121a [31], respectively. In both cases, the structure was solved by intrinsic phasing methods (SHELXT Version 2018/2 [32]). Its refinement was done subsequently by full-matrix least-squares against F (SHELXL Version 2018/3 [33]), with hydrogen atoms constrained to idealized geometries and riding isotropic displacement parameters for the rt (sin/ = 0.6 Å ) Molbank 2022, 2022, M1382 8 of 11 dataset, or freely refined with some distance restraints for the 100K (sin/ = 0.7 Å ) dataset. Ultimately, it was tentatively pursued further with the Hirshfeld atom refinement (HAR; [34]) with the NoSpherA2 [35] implementation in OLEX2-1.5 [36], using B3YLP DFT functional [37] and basis set def2-SVP [38] accounting for the non-spherical nature of the electron distribution, which helped us to remove density residuals lying along the covalent bonding (Figure 5). Most H atoms were refined anisotropically and independently except certain H atoms in disordered parts, and refractory to ISOR (SHELXL) restraint benefits. The disordered O3-bonded benzyl group with restraints upon 1,2 (sd 0.01) and 1,3 (sd 0.04) distances similar to those in the benzyl group bonded to O5 was refined over two static sites with an occupancy ratio of 0.54(1):0.46(1). The small electronic density residual around the C1 position could be interpreted as potential coexistence of alpha/beta anomers inside the crystal with a ratio refined to 88.7(2):11.3(2). This almost anecdotical mixture did not harm the significance of the ‘double-checked’ Flack absolute structure parameter [39] in favor of ( 2S: 2R,3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (0.89) (0.11) and consistent with the known configuration of the D-xylose starting material. The HAR Crystal structure was deposited at the Cambridge Crystallographic Data Centre as CCDC 2150903 [40]. The data can be obtained free of charge from the CCDC via http://www.ccdc. cam.ac.uk/getstructures (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk). Table 3. Crystal data, data collection and structure refinement details of compound 1. Identification code 2,3,5-Tri-O-benzyl--D-xylofuranose (, )-1 (89:11) Empirical formula, (weight) C H O , (420.48) 26 28 5 Temperature (K) 100(2) Diffractometer Rigaku® XtaLabPro mm003+Pilatus200k 0.71073 Wavelength (Å) Crystal system, space group P2 2 2 , Orthorhombic 1 1 1 a = 6.9002(1) Unit cell dimensions b = 13.1783(2) (Å, = =
= 90 ) c = 23.9751(5) Volume (Å ) 2180.13(6) Z, Calculated density (Mg/m ) 4, 1.281 0.088 Absorption coefficient (mm ) F(000) 896 Theta range for data collection ( ) 2.98 to 30.25 9 h 9, Limiting indices 17 k 18, 33 l 33 Reflections collected/unique 55,919/6102 R(int) 0.0370 Completeness to q (%) 99.8 max (iUCR) Gaussian and Multi-scan Absorption correction method 1.000 and 0.302 IAM HAR Refinement method Shelxl NoSpherA2 Data/restraints/parameters 6102/416/419 6102/484/693 1.028 1.1284 Goodness-of-fit on F R1, 0.0338, 0.0171, Final R indices [I > 2s(I)] wR2 0.0896 0.0305 R1, 0.0352, 0.0185, R indices (all data) wR2 0.0903 0.0307 Absolute structure parameter [39] 0.02(15) 0.07(14) Largest diff. peak and hole (e.Å ) 0.273 and 0.192 0.145 and 0.124 Molbank 2022, 2022, x FOR PEER REVIEW 9 of 11 Theta range for data collection (°) 2.98 to 30.25 ‒9 ≤ h ≤ 9, Limiting indices ‒17 ≤ k ≤ 18, ‒33 ≤ l ≤ 33 Reflections collected / unique 55919 / 6102 R(int) 0.0370 Completeness to θ max (iUCR) (%) 99.8 Gaussian and Multi-scan Absorption correction method 1.000 and 0.302 IAM HAR Refinement method Shelxl NoSpherA2 Data / restraints / parameters 6102 / 416 / 419 6102 / 484 / 693 Goodness-of-fit on F 1.028 1.1284 R1, 0.0338, 0.0171, Final R indices [I>2σ(I)] wR2 0.0896 0.0305 R1, 0.0352, 0.0185, R indices (all data) wR2 0.0903 0.0307 [39] Absolute structure parameter ‒0.02(15) 0.07(14) ‒3 Molbank Larg 2022 es,t d 2022 iff,. M1382 peak and hole (e.Å) 0.273 and ‒0.192 0.145 and ‒0.124 9 of 11 (a) (b) Figure 5. Wire visualizations of the residual electron density maps over the molecular structure of Figure 5. Wire visualizations of the residual electron density maps over the molecular structure compound 1 after (a) IAM and (b) HAR refinement. The residual density was calculated with Olex2 of compound 1 after (a) IAM and (b) HAR refinement. The residual density was calculated with −3 −3 Ofrom fcf files and plotted on a grid of 0.05 Å with an iso-value of 0.121 eÅ (0.10 eÅ , respectively) 3 3 Olex2 Ofrom fcf files and plotted on a grid of 0.05 Å with an iso-value of 0.121 eÅ (0.10 eÅ , (green = positive, red = negative). respectively) (green = positive, red = negative). Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, Table S1: Experimental details for XRD performed at room temperature using copper radiation, Figure S1: Supplementary Materials: The following are available online, Table S1: Experimental details for Bijvoet pair analyses to assess the absolute configuration of compound 1 (α/β ca. 89:11), Figure S2: XRD performed at room temperature using copper radiation, Figure S1: Bijvoet pair analyses to 1 13 H NMR (400 MHz, CDCl3) spectrum of compound 1 (α/β ca. 2:3), Figure S3: C NMR (101 MHz, assess the absolute configuration of compound 1 (/ ca. 89:11), Figure S2: H NMR (400 MHz, CDCl3) spectrum of compound 1 (α/β ca. 2:3). CDCl ) spectrum of compound 1 (/ ca. 2:3), Figure S3: C NMR (101 MHz, CDCl ) spectrum of 3 3 compound 1 (/ ca. 2:3). Author Contributions: Conceptualization, C.N.; funding acquisition, I.G.; synthetic methodology, B.T.; NMR analysis, C.N.; X-ray collection and structure solving, P.R.; writing—original draft, re- Author Contributions: Conceptualization, C.N.; funding acquisition, I.G.; synthetic methodology, view and editing, P.R. and C.N. All authors have read and agreed to the published version of the B.T.; NMR analysis, C.N.; X-ray collection and structure solving, P.R.; writing—original draft, re- manuscript. view and editing, P.R. and C.N. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the CNRS (Centre National de la Recherche Scientifique). Funding: This research was funded by the CNRS (Centre National de la Recherche Scientifique). Data Availability Statement: The X-ray data are available at CCDC under ref. code CCDC Data Availability Statement: The X-ray data are available at CCDC under ref. code CCDC 2150903. 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