Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides

Abstract

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.

FIGURE 1

Four diastereomeric glycals, and their 4-deoxypentenoside isosteres.

FIGURE 2

PPFMO analysis of the dimethyl ether of 4-deoxyallal (analog of 3). Pairs of 1s functions are superimposed onto the 2py orbitals at C1 and C2 to produce asymmetric wavefunctions (χ), whose coefficients c_α and c_β are used to derive p, the net electronic polarization per orbital (in purple). 2p orbitals and added s-functions are spatially separated for clarity, and +/− values refer to the sign of the coefficients for each lobe (open/filled).

FIGURE 3

Electron density maps of the 4-deoxyglucal derivative (analog of 11) with the C3 methyl ether in the tg conformation (left) or the gt conformation (right). In the case of gt, the electron density map reveals an incidental (but superfluous) hyperconjugation between the hybrid orbital at C2 and a lone pair on O3 (extended green lobe), creating an artificial polarization in the β direction.

FIGURE 4

PPFMO analysis of dimethyl ether analogs of 3-deoxyglucal (9) and 3-deoxy-β-glc (26), starting from alternate half-chair conformations. For each 2p orbital, p(n), the net electronic polarization is presented as a filled lobe (purple).

SCHEME 1

Synthesis of D-allal derivatives.^{a a}Reagents and conditions: (a) PhSH, BF₃. Et₂O, CH2Cl2, −78 ºC (69%); (b) NaOMe, MeOH, rt; (c) PhCH(OMe)₂, p-TsOH, rt; (d) DMDO, CH₂Cl₂, −78 ºC; (e) Et₂NH, THF, rt; (f) BnBr, Bu₄NI, NaH, DMF, rt (36% over 5 steps); (g,h) same as steps (d,e) (59% over 2 steps); (i,j) same as steps (b,f) (92% over 2 steps); (k) NaH, CS₂, MeI, THF, rt; (l) Bu₃SnH, AIBN, DMF, 120 ºC; (m) NaOMe, MeOH, rt; (n) BnBr, Bu₄NI, NaH, THF, rt (22% over 4 steps).

SCHEME 2

Synthesis of D-gulal derivatives.^{a a}Reagents and conditions: (a) PhSH, SnCl4, CH₂Cl₂, −20 ºC (98%); (b) DMDO, CH₂Cl₂, −78 ºC; (c) Et2NH, THF, rt; (d) NaOMe, MeOH, rt; (e) BnBr, Bu₄NI, NaH, THF, rt (76% yield over 4 steps); (f) PhCH(OMe)₂, p-TsOH, rt (70% over 2 steps); (g) same as steps (b), (c), and (e) (45% over 3 steps).

SCHEME 3

Synthesis of 3- and 4-deoxyglucal derivatives.^{a a} Reagents and conditions: (a) NaH, CS, MeI, THF, rt; (b) Bu SnH, AIBN, PhCH, reflux (54% isolated yield for 8, 82% for 11); (c) BH₃-THF, Bu₂BOTf, THF, −78 ºC; (d) BnBr, Bu₄NI, NaH, THF, rt (73% over 2 steps); (e) BnBr, Bu₄NI, NaH, DMF, rt; (f) iBu₂AlH, CH₂Cl₂, 0 ºC; (g) same as step (e); (h) DDQ, tBuOH, pH 7 phosphate buffer, CH₂Cl₂, rt (61% over 4 steps). PMB = p-methoxybenzyl; PMP = p-methoxyphenyl.

SCHEME 4

Synthesis of 3-deoxygalactal derivatives.^{a a} Reagents and conditions: (a) NaH, CS₂, MeI, THF, rt; (b) Bu₃SnH, AIBN, PhCH₃, reflux (75% over 2 steps); (c) Li-naphthalenide (2.5 equiv), THF, −40 ºC (78%); (d) AcOH/THF/H₂O, 45 ºC; (e) BnBr, Bu₄NI, NaH, DMF, rt (66% over 2 steps); (f) same as step (c) (60%).

SCHEME 5

Synthesis of 2,4- and 3,4-dideoxypentenosides.^{a a} Reagents and conditions: (a) NaH, CS₂, MeI, THF, rt; (b) Bu₃SnH, AIBN, PhCH₃, reflux; (c) AcOH/THF/H₂O, 45 ºC (81% over 3 steps for 18, 56% for 19, 50% for 24, 87% for 25); (d) TEMPO, BAIB, H₂O/CH₂Cl₂, rt; (e) DMFDNPA, DMF, 200 ºC (58% isolated yield over 2 steps for 20, 60% for 21 and 26, 28% for 27).

SCHEME 6

Synthesis of D-xylal and L-arabinal.^{a a} Reagents and conditions: (a) Li/naphthalenide, THF, −40 ºC (quantitative).