Synthesis, X-ray Crystallographic and Computational Analysis of 2,3

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Chapter 8

Synthesis, X-ray Crystallographic and Computational Analysis of 2,3-Dideoxy-αand β-D-erythro-Hexopyranosyl Cyanides: Anomeric Effect of the Cyano Group Madeline Rotella, Mark Bezpalko, Nicholas Piro, Nicholas Lazzara, Scott Kassel, Deanna Zubris, and Robert Giuliano* Department of Chemistry, Villanova University, Villanova, Pennsylvania 19085, United States *E-mail: [email protected]

The synthesis of two 2,3-dideoxy glycosyl cyanides was carried out by the Ferrier reaction of O-peracetylated D-glucal with trimethylsilyl cyanide and Lewis acid catalysts, chemoselective reduction of the double bond in the products, and deacylation. X-ray crystallographic analysis of the products revealed features consistent with the anomeric effect of the cyano group, similar to other glycosyl cyanides that are included for comparison. Computational studies were carried out to evaluate the energies and geometrical parameters of conformations in which the cyano group is axial and equatorial in both model and synthesized compounds.

Introduction The anomeric effect is generalized in the iconic text by Eliel, Wilen, and Mander as the preference for a gauche conformation in structural units of the type R-O-C-X where X is an electronegative group such as halogen (1). An unshared pair of electrons on the oxygen is antiperiplanar to X in the more stable conformation (Figure 1).

© 2017 American Chemical Society Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 1. Generalized anomeric effect.

For a simple structure such as chloromethyl methyl ether the gauche conformation is more stable by approximately 2 kcal/mol (2). The term “anomeric effect” has its origin in carbohydrate chemistry, where a 2:1 α/β equilibrium ratio (preference for the axial methoxy group) in methyl α- and β-D-glucopyranosides was first noted by Edward and later termed the “anomeric effect” by Lemieux (3, 4). Studies of equilibria of acetylated aldohexopyranoses by Lemieux and Chü revealed preferences for the α anomers (axial OAc) of -0.94 and -1.48 kcal/mol respectively for peracylated xylo and lyxo-pyranoses (4). While not limited to carbohydrates, it is in the structure and reactions of glycosides that the anomeric effect has been most widely studied, although to this day the exact nature of its origins is still not completely understood. Contributions from electrostatic interactions (dipole-dipole) or hyperconjugative effects (donor-acceptor electron delocalization) involving non-bonded heteroatom lone pairs are the most widely cited factors (5, 6). Accompanying the hyperconjugative effects would be a lengthening of the C-1-C-X bond in the anomer in which the electronegative group is axial and a shortening of the O-5-C-1 bond relative to the anomer in which the electronegative group is equatorial. Hyperconjugative effects were not shown to be responsible for the anomeric effect in a computational study that suggested that electrostatic interactions and Pauli repulsions dominate the conformational preference in substituted tetrahydropyrans (7). The anomeric effect in carbohydrates has been most widely studied where the anomeric substituent is a halogen or the oxygen of a free sugar or glycoside. The focus of the study presented here is on the anomeric effect of the cyano group in hexopyranosyl cyanides. Values for the anomeric effect of the cyano group in systems such as those in Figure 1, in cyclohexane, oxane, and in carbohydrates have been reported based on computational, equilibration and NMR studies. Ab-Initio studies at the 6-31G* level of theory of systems of the type R-O-C-X where R = methyl and X = CN indicated an energy difference between gauche and trans conformations of approximately 1.43 kcal/mol (8). The energy differences between gauche and trans conformations of 3-hydroxypropanenitrile are 0.65 and 1.77 kcal/mol depending on the H-O-C-C dihedral angle (9). In an equilibration study of tetra-O-acety-1-bromo-D-glucopyranosyl cyanides and their analogs in the D-galacto series, the anomeric effect of the cyano group was estimated to be 2.42 kcal/mol and 1.95 kcal/mol, respectively, in the gluco- and galacto- series (10). Variable temperature NMR studies of cyanocyclohexane and cyanotetrahydropyran gave ring inversion ΔH° (ax→eq) values of -0.18 and +0.36 156 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


kcal/mol (11). In a study of conformational preferences of 2-cyano derivatives of oxane, thiane, and selenane using natural bond order (NBO) analysis with the B3LYP/6-311+G(3df,2p) wave functions, stabilization of the 2-cyanooxane conformation with the axial cyano group was found (ΔG173(solv) = 0.57 kcal/mol; solv = CCl4) along with expected lengthening of the C-CN bond and shortening of the O-C(CN) bond in the conformation in which the cyano group is axial (12). In addition to the nO−σ*C-CN interaction (HCAE) these authors also propose an nO−π*CN through-space interaction as contributors to the greater stability of the axial CN conformation. In a study published in 2013, the values of ΔE (anomeric) for 2-cyanooxane was found to be in the range 0.96 – 1.22 kcal/mol depending on the basis set and computational method; the origin of the stabilization was found to correlate with exchange components and not electrostatic effects (13). The origin of the anomeric effect in these heterocycles was also probed in a different study reported in 2016 that ascribed the stabilization of conformations with axial cyano groups to “cooperative and uncooperative impacts” of the hyperconjugative effect, Pauli exchange-type repulsions, and dipole-dipole interactions, but not nO−π*CN stabilization. In this report, the LC-ωPBE/6-311+G** calculated ΔG value for equatorial vs axial conformations of 2-cyanooxane was 0.94 kcal/mol (14). While there is a lack of general agreement on the origins and magnitude of the anomeric effect, the observed preference for conformations in which an electronegative group occupies an axial position has dramatic effects on both carbohydrate structure and reactivity. We have encountered these effects in our laboratory in research on phytotoxin synthesis based on carbohydrates that contain a cyano group at the anomeric position. The synthesis, structural studies, and computational analysis of these glycosyl cyanides are the focus of this article.

Results and Discussion Glycosyl cyanides have been used in the synthesis of glycosyl amino acids (15–17), formyl (18) and carboxyglycosides (19), heterocyclic C-glycosides (20) and nucleosides (21), exo-glycals (22), and aminomethyl glycosides (23). Additional applications of glycosyl cyanides in the synthesis of heterocycles have been described in a recent review (24). During the course of our studies of the synthesis of the phytotoxin diplopyrone from carbohydrates, we utilized glycosyl cyanides that were readily prepared by the addition of trimethylsilyl cyanide to glycals in the presence of boron trifluoride diethyl ether (Scheme 1). The procedure of Grynkiewicz and BeMiller used for the preparation of 2 gave exclusively the α-anomer (25). Other procedures for the synthesis of glycosyl cyanides also favor the formation of the α-anomer, with moderate to excellent stereoselectivities for most glycal substrates (26, 27). The preference for α-anomers in Ferrier I reactions such as these has been ascribed to the anomeric effect and conformational effects in the glycal substrate (28). Selective reduction of the alkene in 2 gave diacetate 3, which was deacylated to give diol nitrile 4 as a solid that was recrystallized from chloroform. 157 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 1. Synthesis of 2,3-dideoxy-α-D-erythro-hexopyranosyl cyanide (4).

For the synthesis of β-cyano glycoside 7, we used the procedure of Ghosh and coworkers, which was reported to give a 5:2 ratio of α/β anomers 2 and 5 (Scheme 2) (26). In our hands the yield was 64% and the α/β anomeric ratio was 3:2. Optimal conditions for reduction of the alkene required prior sonication of the suspension of alkene in methanol, and the use of 1% by weight of catalyst (10% Pd/C). Heavier catalyst loadings resulted in faster reaction times but also the formation of products from reduction of the nitrile group. The β-glycosyl cyanide 6 was separated and deacylated with p-toluenesulfonic acid in refluxing methanol or with catalytic sodium methoxide in methanol (Zemplén method) at -20 °C to give 7, which was recrystallized from ethyl acetate. Caution had to be observed in deacylations with sodium methoxide in order to avoid epimerization and also the formation of imidate ester side products (20). These transformations allowed the selective manipulation of reducible functional groups in the glycosyl cyanides (29).

Scheme 2. Synthesis of 2,3-dideoxy-α-D-erythro-hexopyranosyl cyanide (7).

158 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


The x-ray crystallographic analyses of 2,3-dideoxy-α- and β-D-erythrohexopyranosyl cyanides 4 and 7 were carried out and tables of atomic coordinates, bond lengths, bond angles, and other data are available through the Cambridge Crystallographic Data Center (CCDC) (30). ORTEP diagrams of (Figure 2) reveal that both adopt a chair conformation with axial (4) and equatorial (7) cyano groups. Also noteworthy is the gg conformation adopted at the C5-C-6 bond. The C-4-C-5-C-6-O-6 torsion angles are 48. 3° (4) and 63.7° (7) and the O-1-C-5-C-6-O-6 torsion angles are 73.7° (4) and 58.38° (7).

Figure 2. ORTEP diagrams of 4 and 7. Bond distances for C-1-CN and O-5-C-1 obtained from our crystallographic and computational data for 4 and 7 are shown in Figure 3 along with references for crystallographic data reported in the literature (31–34). Calculated bond length values for compounds 4 and 7 are shown beneath those obtained from crystallographic data. The trends that emerge from comparisons of these bond distances are the expected lengthening of the C-1-CN bond in the α-anomers and shortening of O-5-C-1 bond, and vice versa in the β-anomers of the glycosyl cyanides. The trend seems to hold across various configurations in the pyranosides and also in the presence (or absence) of functionality at other ring carbons. Side-by-side comparisons of data for 12 and 13 and 14 and 15 are valuable in that the only changes in structure are the anomeric configurations. Compound 8, previously synthesized in our laboratory, also exhibits lengthening of the C-1-CN compared to what is observed for β-glycosides 7, 10, 11, and 13. Computational analyses were carried out to in an effort to determine the magnitude of the anomeric effect in glycosyl nitriles 4 and 7, and to compare calculated bond lengths with those obtained from crystallographic data. Structures that were analyzed computationally are shown in Figure 4. Calculated bond lengths and conformational energy differences were determined using B3LYP/6-31+G* in the gas phase and in solvent (water), and using B3LYP/6-311++G** in the gas phase. Results are shown in Tables 1 – 4. The methods used and model compounds chosen are similar to those used by Tvaroška and coworkers in their calculations of the anomeric effects of peroxy and hydroperoxy groups (35). For 2-cyanooxanes 18 and 19, the calculated standard free energy difference is 0.61 kcal/mol, favoring the axial CN group in 159 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


19 (gas phase, B3LYP/6-311++G**) as shown in Table 2. This value is close to that reported by Sorensen and coworkers (12) (0.57 kcal/mol, CCl4 as solvent, ε = 2.228, MP2/6-311+G(2df,2p) but less than that reported by Ghanbarpour and Nori-Shargh (14) (0.94 kcal/mol, gas phase, LC-ωPBE/6-311+G**) and da Silva and coworkers (13) (0.96 – 1.22 kcal/mol for HF/6-31G(d,p), MP2, and CCSD(T) methods. Our calculated value for ΔG° of -0.72 kcal/mol for cyanocyclohexanes 20 and 21 (gas phase, B3LYP/6-311++G**) is larger than that determined by NMR techniques (-0.2 kcal/mol) (36). The gas-phase ΔG° value is 0.05 kcal/mol at the B3LYP/6-311++G** level with only a slight preference for 4 over 7 (Table 2).

Figure 3. Selected bond distances in glycosyl cyanides from crystallographic data and computational analysis (gg conformer of 4 and 7; B3LYP/6-311++G**, gas phase).



Figure 4. Structures analyzed computationally in this work.

The enthalpies and Gibbs free energies calculated for 4 and 7 were found to be highly dependent on both the C-5-C-6 and C-6-O-6 conformations, which may result in a smaller than expected calculated anomeric effect for these cyano sugars. As shown in Table 4, the value for ΔG° in 4 (axial CN) increases from 0.20 to 0.57 to 0.59 kcal/mol in going from the tg, to gg, to gt conformations, while in 7 (equatorial CN) the progression is from 0.00 to 0.10 to 0.64 kcal/mol in going from gg to tg to gt. The crystallographic analyses of 4 and 7 indicate that gg conformations are adopted for both in the solid state. The calculated energy differences probed by systematically changing the O-1-C-5-C-6-O-6 and C-5-C6-O-6-H torsion angles reveal a large influence of these parameters on compound stability in both the glycosyl cyanides and their carbocyclic analogs. As a result, it is difficult to separate and quantify the relatively small stabilization due to the anomeric effect of the CN group in 4 and 7. In a study of C-C and C-O bond conformations of hydroxylmethyl groups in carbohydrates and their J-couplings, Serianni and coworkers (37) noted that the introduction of a hydroxyl group at C-4 in 22 affected the relative stabilities of rotamers in 23 and 24 with gg and gt being the most stable in 23 and tg being the most stable in 24 (Figure 5). Bond lengths were determined computationally for the C-1-CN and O-5-C1 bonds. The calculated bond lengths reported in Figure 3 for the C-1-CN and O-5-C-1 bonds in 4 and 7 are based on the gg conformation, (Table 3 and Figure 6, B3LYP/6-311++G**, gas phase). In α-anomer 4, the calculations show that the C-1-CN bond is lengthened over what it is in the β-anomer 7, as expected. A slight shortening of the O-5-C-1 bond in 4 is also observed.



Table 1. The B3LYP/6-31+G* calculated geometrical parameters (r and Δr in Å) and the relative enthalpy and Gibbs free energy (ΔH° and ΔG° in kcal mol−1) in the gas-phase and in solution (water as solvent) for 4 vs 7 and 17 vs 16. Each structure is represented as the gt conformer of the –CH2OH substituent.

a

Axial(4)

Equatorial(7)

Δ(Eq−Ax)

H°gas

−553.574478a

−553.573885a

0.34b

G°gas

−553.619849a

−553.619651a

0.12b

r(C1-CN)gas

1.487c

1.473c

−0.014c

r(C1-O5)gas

1.421c

1.425c

0.004c

H°solv

−553.592738a

−553.591777a

0.61b

G°solv

−553.638355a

−553.637770a

0.37b

r(C1-CN)solv

1.493c

1.476c

−0.017c

r(C1-O5)solv

1.426c

1.429c

0.003c

Axial(17)

Equatorial(16)

Δ(Eq−Ax)

H°gas

−517.656098a

−517.654200a

1.19b

G°gas

−517.702172a

−517.700546a

1.02b

r(C1-CN)gas

1.473c

1.470c

−0.003c

r(C1-O5)gas

1.548c

1.547c

−0.001c

H°solv

−517.672237a

−517.671142a

0.69b

G°solv

−517.718283a

−517.717533a

0.47b

r(C1-CN)solv

1.475c

1.471c

−0.004c

r(C1-O5)solv

1.549c

1.548c

−0.001c

H° and G° in Hartrees. Δr(Eq−Ax) in Å.

b

ΔH°(Eq−Ax) and ΔG°(Eq−Ax) in kcal mol−1.

c

r and



Table 2. The B3LYP/6-311++G** gas-phase calculated geometrical parameters (r and Δr in Å) and the relative enthalpy and Gibbs free energy (ΔH° and ΔG° in kcal mol−1) for 4 vs 7, 17 vs 16, 19 vs 18, and 21 vs 20, with a gt conformer of the –CH2OH substituent.

a

Axial(4)

Equatorial(7)

Δ(Eq−Ax)

H°gas

−553.727387a

−553.726822a

0.35b

G°gas

−553.772682a

−553.772609a

0.05b

r(C1-CN)

1.482c

1.468c

−0.014c

r(C1-O5)

1.420c

1.424c

0.004c

Axial(17)

Equatorial(16)

Δ(Eq−Ax)

H°gas

−517.798773a

−517.796915a

1.17b

G°gas

−517.844797a

−517.843458a

0.84b

r(C1-CN)

1.468c

1.465c

−0.003c

r(C1-O5)

1.546c

1.545c

−0.001c

Axial(19)

Equatorial(18)

Δ(Eq−Ax)

H°gas

−363.958084a

−363.95698a

0.69b

G°gas

−363.996597a

−363.995620a

0.61b

r(C1-CN)

1.484c

1.469c

−0.015c

r(C1-O5)

1.420c

1.421c

0.001c

Axial(21)

Equatorial(20)

Δ(Eq−Ax)

H°gas

−328.033622a

−328.072602a

−0.53b

G°gas

−328.034462a

−328.073746a

−0.72b

r(C1-CN)

1.468c

1.464c

−0.004c

r(C1-O5)

1.550c

1.548c

−0.002c

H° and G° in Hartrees. Δr(Eq−Ax) in Å.

b


c

r and


164


Table 3. The B3LYP/6-311++G** gas-phase calculated geometrical parameters (r and Δr in Å) for 4, 7, 17, and 16, with tg, gg, and gt conformers of the –CH2OH substituent defined by dihedral angles Φ O1(C)-C5-C6-O6 and φ C5-C6-O6-H. Axial(4)

Equatorial(7)

Δ(Eq−Ax)

Axial(17)

Equatorial(16)

Δ(Eq−Ax)

Φ(°) tg gg gt

168.01 −79.82 63.33

178.93 −66.93 56.90

10.92 12.82 −6.43

169.62 −60.29 60.12

176.69 −77.77 61.41

7.07 −17.48 1.29

φ(°) tg gg gt

280.56 60.46 303.43

178.45 58.55 304.53

−102.11 −1.91 1.1

287.38 −60.29 60.12

176.69 −77.77 61.41

−110.69 −17.48 1.29

r(C1-CN)(Å) tg gg gt

1.482 1.483 1.482

1.468 1.468 1.468

−0.014 −0.015 −0.014

1.468 1.468 1.468

1.465 1.469 1.465

−0.003 0.001 −0.003

r(C1-O-5)(Å) tg gg gt

1.422 1.420 1.420

1.424 1.424 1.424

0.002 0.004 0.004

1.545 1.547 1.546

1.545 1.549 1.545

0.000 0.002 −0.001

Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Table 4. The B3LYP/6-311++G** gas-phase calculated relative enthalpy and Gibbs free energy (bΔH° and ΔG° relative to lowest energy conformer (4 vs 7, 16 vs 17) in kcal mol-1) with tg, gg, and gt conformers of the –CH2OH substituent defined by dihedral angles Φ O1(C)-C5-C6-O6 and φ C5-C6-O6-H (see Table 3).


ΔH°

ΔH°

H°gas tg gg gt

Axial(4) −553.728276a −553.727435a −553.727387a

−0.08b 0.45b 0.48b

Axial(17) −517.801381a −517.799395a −517.798773a

0.53b 1.77b 2.16b

H°gas tg gg gt

Equatorial(7) −553.727988a −553.728151a −553.726822a

0.10b 0.00b 0.83b

Equatorial(16) −517.802220a −517.799162a −517.796915a

0.00b 1.92b 3.33b

ΔG°

a

ΔG°

G°gas tg gg gt

Axial(4) −553.773312a −553.772722a −553.772682a

0.20b 0.57b 0.59b

Axial(17) −517.846666a −517.844998a −517.844797a

0.69b 1.73b 1.86b

G°gas tg gg gt

Equatorial(7) −553.773477a −553.773629a −553.772609a

0.10b 0.00b 0.64b

Equatorial(16) −517.847762a −517.845373a −517.843458a

0.00b 1.50b 2.70b

H° and G° in Hartrees.

b


Figure 5. Model compounds studied by Serianni et al. (Reproduced from reference (38). Copyright 2004, ACS).

Figure 6. Illustration of tg, gg, and gt conformers of the –CH2OH substituent for 7.


In summary, these calculations and crystallographic analyses support the expected differences in bond lengths that are consistent with the classical anomeric effect in glycosyl cyanides. The anomeric effect of the cyano group in such compounds, while not new to this report, is confirmed by our studies that also revealed larger than expected effects of C-5-CH2OH and C-6-O-H conformations on the stability of carbohydrates in which the cyano group is axial or equatorial.

Experimental


General Procedures Melting points were recorded on a Thomas-Hoover apparatus and they are uncorrected. Thin-layer chromatography was carried out on aluminum foil-backed silica gel plates (EMD) coated with a fluorescent indicator. Plates were developed with cerium molybdate stain. Flash chromatography was carried out using 230-400 mesh silica gel. NMR spectra were recorded on a Varian (Agilent) Mercury 300 Plus spectrometer in CDCl3 or CD3OD for 1H NMR at 300.0 MHz, tetramethysilane reference, δ = 0.0 ppm, and, 13C NMR 70.0 MHz, CDCl3 reference, δ = 77.0 ppm. Spectral assignments were confirmed using DEPT, 13C detected HETCOR, and gHMBC experiments. Crystallography Experimental procedures for the crystallographic analysis of 4 and 7 are included in supplementary data along with tables of crystal data and structure refinement, thermal parameters, bond lengths, bond angles, and torsion angles. These data have been deposited with the Cambridge Crystallographic Data Centre (30). Computational Methods Crystallographic .cif data files for 7 were used as inputs and structurally modified as needed for HF/6–31G* geometry optimizations for all structures shown in Figure 4. Subsequent B3LYP/6-31+G* optimized geometries were obtained with analytic harmonic frequencies examined to determine the nature of the stationary points observed; calculations were conducted both in the gas-phase and in water as a continuum dielectric. Gas-phase geometries were then optimized for varied dihedral angles Φ O1(C)-C5-C6-O6 and φ C5-C6-O6-H at the B3LYP/6-311++G** level of theory using Spartan10. Relative energies (H° and G°) are reported for the B3LYP optimized structures and include zero-point energy corrections. 4,6-Di-O-acetyl-2,3-dideoxy-α-D-erythro-hexopyranosyl Cyanide 3 To a stirring solution of 2 (25) (1.664 g, 7 mmol) in methanol (30 mL) was added 10% Pd/C (1.7 mg, 1% by wt.). Dissolution of 2 in methanol required sonication for approximately 40 min (prior to adding catalyst). The mixture 166 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


was stirred under hydrogen at atmospheric pressure (balloon) and progress was monitored by 1H NMR. The reaction could also be carried out using a Burrell wrist-action shaker or a Parr apparatus (30 psi). Complete reduction typically occurred after 1-2 days. The reaction mixture was filtered through Celite using an additional portion of methanol (10 mL) and the filtrate was concentrated under reduced pressure to give 1.36 g (81%) of 3 as an oil: Rf 0.3 (40% ethyl acetate-hexanes), [α]D +56.2 (c, 1.0, dichloromethane, lit (25) [α]D +37, 1H NMR (300 MHz, CDCl3) δ 4.85 (d, 1H, J1,2 = 5.4, H-1), 4.70 (ddd, 1H, J = 4.8, 10.5, 10.6, H-4), 4.28 (dd, 1H, J5,6 or J5,6′ = 4.8, J6,6′ = 12.3 H-6 or H-6′), 4.15 (dd, 1H, J5,6 or J5,6′ = 2.4, J6,6′ = 12.3 H-6 or 6′), 3.94 (m, 1H, H-5), 2.3-1.8, (m, 4H, H-2,2′, H-3,3′), 2.10 (s, 3H, CH3), 2.08 (s, 3H, CH3); 13C NMR (75.4 MHz, CDCl3) δ 170.7, 169.8 (C=O), 116.6 (CN), 74.3, 66.3, 64.2, 62.3, 27.6, 25.4, 20.9, 20.7. The 1HNMR spectrum of 3 (300 MHz) matched that reported (200 MHz) (25). HRMS calcd for C1H16NO5[M + H]+: 242.1028. Found: 242.1026. 2,3-Dideoxy-α-D-erythro-hexopyranosyl Cyanide 4 To a stirring solution of diacetyl derivative 3 (205 mg, 0.85 mmol) in anhydrous methanol (20 mL) at -20 °C was added drops of commericially available 25% sodium methoxide/methanol until the solution remained basic (approximately 0.25 mL total). Starting material was consumed after 2.5 h as evidenced by TLC (9:1) chloroform methanol. A scoop of Dowex 50H+ resin was added and after stirring briefly the mixture was filtered and concentrated. Purification by flash chromatography (38) gave 4 (92, mg, 69%) as a solid: Rf 0.17 (9:1 CHCl3-CH3OH), mp 78-80 °C, [α]D + 66 (c, 1.2, methanol), 1H NMR (300 MHz, CD3OD) δ 4.95 (m, 1H, H-1), 4.86 (bs, 2H, OH), 3.85 (dd, 1H, J = 1.8, 12.3, H-4), 3.67 (dd, 1H, J = 4.5, 13.5, H-5), 3.45 (m, 2H, H-6,6′), 2.07 – 1.63 (m, 4H, H-2,2′, H-3,3′); 13C NMR (75.4 MHz, CD3OD) δ 117.2 (CN), 79.7 (C-1), 64.54, 63.8, 61.1, 28.4, 27.7. Recrystallization from chloroform gave a sample for x-ray analysis. HRMS calcd for C7H11NO3Na [M + Na]+: 180.0641. Found: 180.0637 Deacetylation of 3 was also carried out by acid-catalyzed methanolysis. A mixture of 3 (184 mg, 0.76 mmol) and p-TsOH (7.3 mg, 5 mol%, dried at 40 °C under 25 mm vacuum for 24 h) and anhydrous methanol (8 mL) was stirred under reflux for 10 h. TLC (9:1 chloroform/methanol) showed only traces of starting material and product. Barium carbonate was added and after stirring 5 min the mixture was filtered through a pad of Celite and concentrated under reduced pressure to a residue that was purified by flash chromatography to give 62 mg (52%) of 4. 4,6-Di-O-acetyl-2,3-dideoxy-β-D-erythro-hexopyranosyl Cyanide 6 To a stirring solution of a mixture of 2 and 5 (26) (0.72 g 2.88 mmol) in methanol (15 mL) sonicated for approximately 40 min was added 10% Pd/C (7.6 mg) and the mixture was. The mixture was shaken in a Burrell wrist-action shaker under hydrogen at atmospheric pressure (balloon) overnight, filtered through Celite using an additional portion of methanol (10 mL) and the filtrate 167 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

was concentrated under reduced pressure. Separation of product mixture was carried out by flash chromatography (30% ethyl acetate/hexanes) to give 184 mg (26%) of α-anomer 3 and 172 mg (25%) of β-anomer 6 as oils. Compound 6 had: Rf 0.24 (40% ethyl acetate-hexanes), [α]D +45 (c, 1.2, chlorororm), 1H NMR (300 MHz, CDCl3) δ 4.69 (ddd, 1H, J = 4.8, 10.5, 10.2, H-4), 4.26 (dd, 1H, J1,2a = 10.5, J1,2e = 3.3, H-1), 4.16 (m, 2H, H-6,6′), 3.56 (m, 1H, H-5), 2.4-1.5, (m, 4H, H-2,2′, H-3,3′), 2.06 (s, 3H, CH3), 2.01 (s, 3H, CH3); 13C NMR (75.4 MHz, CDCl3) δ 170.7, 169.78 (C=O), 116.9 (CN), 76.6, 66.2, 65.4, 62.6, 29.0, 28.2, 20.9, 20.8. HRMS calcd for C1H16NO5[M + H]+: 242.1028. Found: 242.1028.


2,3-Dideoxy-β-D-erythro-hexopyranosyl Cyanide 7 To a stirring solution of diacetyl derivative 6 (172 mg, 0.71 mmol) in anhydrous methanol (18 mL) at -20 °C was added a few drops of commericially available 25% sodium methoxide/methanol until the solution remained basic (approximately 0.2 mL total). Starting material was consumed after 2 h as evidenced by TLC (9:1) chloroform methanol. A scoop of Dowex 50H+ resin was added and after stirring briefly the mixture was filtered and concentrated. Purification by flash chromatography gave 7 (81, mg, 73%) as a solid: Rf 0. 13 (9:1 chloroform-methanol), mp 138-139.5 °C, [α]D + 78.9 (c, 1.0, methanol), 1H NMR (300 MHz, CD3OD) δ 4.90 (bs, 2H, OH), 4.40 (dd, 1H, J = 11.7, 2.4, H-4), 3.84 (dd, 1H, J1,2a = 12.3, J1,2e = 2.1, H-1), 3.65 (dd, 1H, J = 6.3, 12.3, H-6 or H-6′), 3.41 (ddd, 1H, H-6 or H-6′), 3.19 (m, 1H, H-5), 2.20 – 1.40 (m, 4H, H-2,2′, H-3,3′); 13C NMR (75.4 MHz, CD3OD) δ 117.9 (CN), 83.6 (C-1), 64.9, 64.4, 61.3, 31.1, 29.5. Recrystallization from ethyl acetate gave a sample for x-ray analysis. HRMS calcd for C6H11O3 [M - CN]+: 131.0708. Found: 131.0705

Acknowledgments and Dedication The authors thank the Chemistry Department of Villanova University for financial support. The honor of being included in this volume is particularly meaningful for us as two of our former faculty members knew Ernest Eliel very well. Jose R. de la Vega obtained his doctorate from the Universidad de la Habana in Cuba and was a faculty member at Villanova from 1961-1998. Walter W. Zajac, Jr. was a faculty member at Villanova from 1959-2000. Jose, a physical chemist, and Walter, an organic chemist, both spoke very fondly of Ernest Eliel as a scientist and educator.

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Synthesis, X-ray Crystallographic and Computational Analysis of 2,3

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