SECTION 4. Stereoelectronic Effects (S.E.) and Reactivity of Acetals and Related Functions

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1 SECTIN 4 Stereoelectronic Effects (S.E.) and Reactivity of Acetals and Related Functions (2018) 1

2 2

3 Conformation of acetals 3

4 STEREELECTRNIC EFFECTS and xygen Basicity, Bond Length and Preferential Cleavage in Acetal ydrolysis (theory) 4

5 Bürgi-Dunitz Angle of Attack on Carbonyl Group. Evidence from X-Rays Diffraction Analysis In molecular containing an amino group and a ketone (119), X-rays shows the N:---C= bond too long for a bond but too short for no bonding. In 120, the RRC= unit (120 to 121) deviates from coplanarity. In 1,8-disubstituted naphtalene, both substituents are splayed outward. In 122, the C- bond is splayed outward, but the C-N bond leans inward. J.D. Dunitz et al. elv. Chim. Acta 1978, 61,

6 No Evidence in Favor of Stereoelectronic Control in Acetal ydrolysis in Early Studies In 10 anomeric pairs of alkyl glucopyranosides, the b-anomers were hydrolyzed times faster than the a-anomers. R R R R R faster than R R R R R Feather arris Also, ydrolysis of p-nitrophenoxy 127 is p-independent in the p range Spontaneous hydrolysis of 127 is 3.3 times slower than 128. It was first concluded that there was no evidence that acetal cleavage is subject to stereoelectronic control. It was later disclaimed as 128 could hydrolyzed via boat conformer 129. Kirby 6

7 Evidence of Stereoelectronic Control in ydrolysis Came with Conformationally Rigid Acetal Compounds ydrolysis 131 (0.1 N Cl) is > 3000 faster than 130 Kirby Spontaneous hydrolysis Relative rate: 1 ~10,000 Ar C Relative rate: 1 ~1.2 x Ar 7

8 ydration of Enol Ether vs lefin Relative rate: Kresge-Wiseman Relative rate:

9 Evidence of Stereoelectronic Control in Acetal Formation Antiperiplanar Lone Pair ypothesis 9

10 Strength of the Anomeric Effect as a Function of Leaving Group Y E (X = ) N F -2.0 N F E (X = N 2 ) Energy parameters e, e N for electronic component of anomeric effect due to, N (kcal/mol) F. GREIN and P. DESLNGCAMPS. Can. J. Chem. 70, 604 (1992). F. GREIN. In "The Anomeric Effect and Associated Stereoelectronic Effects". Chap. 11 : Anomeric and Reverse Anomeric Effect in Acetals and Related Functions. Edited by G.R.J. Thatcher. ACS Symposium Series 539, Washington, D.C.,

11 INFRARED 11

12 Relative Energy of TS in the Formation of a and b Glycosides Experimental Results P. DESLNGCAMPS, S. LI, Y.L. DRY. rg. Lett. 6, 505 (2004). 12

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14 Relative Rate of Formation of a and b Glycosides from Enol Ether T (h) A alpha beta P. Deslongchamps, S. Li, Y.L. Dory. rg. Lett. 2004, 6,

15 RESUME F EXPERIMENTAL RESULTS Intermediates 6b is 0.63 kcal/mol lower than 6a 11E 11Z 19 TFA/benzene TFA/benzene 1b (100%) (kinetic) TFA/Me 1a 1b (80:20) (kinetic) P. Deslongchamps, S. Li, Y.L. Dory. rg. Lett. 2004, 6, a 1b (68:32) (thermodynamic) 15

16 Formation of Spiroketals 16

17 Various Cyclization Pathways in Acetal Formation 17

18 Cyclization Versus ydrolysis as a Function as a Ring Size 18

19 Cyclization Versus Addition of Methanol as a Function of Ring Size 19

20 Molecular Modeling (AM1) of Ketal Formation as a Function of Ring Size 20

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22 DEFINITINS 3 Factors: (1) Proton Affinity: E (enthalpy) (bond length 1.6 Å) between ketal + + and ketal - + (2) Decompression energy: E (enthalpy) between ketal - + and oxocarbenium ion (3) Entropy: (bond cleavage and ring closure) 22

23 Angle = definition at TS Bond Model = n- * TS is not found in ketal (a constraint C- bond length at 1.6 Å is selected) 23

24 Relative Rates of ydrolysis of a Series of Ketals S. Li, Y.L. DRY, P. DESLNGCAMPS. Israel J. of Chem. 2000, 40,

25 Relative Rate of ydrolysis of 5-, 6- and 7-Membered Aryl Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 25

26 Relative Rate of ydrolysis of 5- and 6-Membered Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 26

27 Relative Rate of ydrolysis of 5- to 7-Membered and Acyclic Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 27

28 Relative Rate of ydrolysis of 7-Membered Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 28

29 Relative Rate of ydrolysis of Dimethoxy and Diethoxy Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 29

30 CNCLUSIN N ALKYL AND ARYL KETALS YDRLYSIS 30

31 S. Li, P. Deslongchamps. Tetrahedron Lett. 35, 5641 (1994). P. Deslongchamps, Y.L. Dory, S. Li. Tetrahedron 56, 3533 (2000). C.A. Bunton, R.. De Wolfe. J. rg. Chem. 30, 1371 (1954). 31

32 RELATIVE STABILITY: xenium Energies (RF 6-31G*) C 3 + C 3 C C 3 0 kcal/mol C 3 C 2 C + 3 C 2 C 2 + C C C kcal/mol 19.1 kcal/mol 32

33 Relative Rates of Acetals of Formaldehyde, Aldehyde, and Ketone ACETALS x x 10 3 reverse of bimolecular processes (entropy) intramol. proc. methoxy less basic than ethoxy 1 x x x 10 7 reverse of intramol. proc. bimolecular processes methoxy ethoxy (2 cleavages) entropy 3.7 x x x x x reverse of intramol. proc. methoxy (2 cleavages) entropy bimolecular processes ethoxy methoxy (2 cleavages) (1 cleavage) ethoxy (2 cleavages) 33

34 a- vs t Bonds in Carbonyl Group and Antibonding rbitals 34

35 Nucleophilic Addition on Ketone and yperconjugation S. Cieplak, B. D. Tait, C. R. Johnson, J. Am. Chem. Soc., 1989, 111, G. Deslongchamps, P. Deslongchamps. rg. Biomol. Chem. 2011, 9,

36 Nucleophilic Addition on Adamantanone - Cieplak Effect M. Kaselj, W. S. Chung, W. J. le Noble, Chem. Rev., 1999, 99, G. Deslongchamps, P. Deslongchamps. rg. Biomol. Chem. 2011, 9,

37 Synperiplanar Stereoelectronic Effect and ydrolysis in Acetal 37

38 Acetals with Synperiplanar Lone Pairs: Crystal-Structure-Reactivity 1 n x Ar n = 1.32 x = : a marked lengthening of x and shortening of n By comparison with 3: no significant change CNCLUSIN: The anomeric effect due to the synperiplanar n -c* C- overlap in acetal 3 is less efficient than the antiperiplanar one in simple TP acetals 1 in their respective ground state. P. Deslongchamps, P.G. Jones, S. Li, A.J. Kirby, S Kuusela, Y. Ma. J. Chem. Soc., Perkin Trans. 2, 1997,

39 ow About ydrolysis? 1 n x Ar 3 n x Ar In spontaneous hydrolysis, 3 is slightly faster than The ground state of 3 is in a boat, thus containing more energy than 1 which is in a chair form. 3 is thus energetically closer to TS. 2. TS is late resembling the corresponding cyclic oxenium ion in both reactions. 39

40 ydrolysis of b-glycosides via Anti- and Synperiplanar Pathways ( - ) R chair R R R half-chair R R R TS + R R + + R twist-boat N.B. The syn pathway goes through a half-chair which is higher in energy than the twist-boat. In cyclohexane, half-chair = 10 kcal/mol and twist-boat = 5 kcal/mol. 40

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42 Reactivity of Cyclic xocarbenium Ion Ac + BF 3 :Et 2 R R Nu R Nu a R Nu + b R Nu R Nu a Nu R Nu + b R Nu N.B. (1) True with weak nucleophiles. (2) With strong nucleophile, no selectivity due to early transition state (approach the diffusion limit). K.. WERPEL et al. J. rg. Chem. 2009, 74, (Review). 42

43 Substitution at Anomeric Center with t bond S N 1 pathway: S N 2 pathway:. B. Bürgi, J. D. Dunitz, E. Shefter, J. Am. Chem. Soc., 1973, 95, G. Deslongchamps, P. Deslongchamps, rg. Biomol. Chem. 2011, 9,

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45 SN2 reaction of α-d-glucopyranosides EXPLDED or LSE TS Chan, J.F.*; Sannikova, N.; Tang, A.; Bennett, A.J.* JACS 2014, 136,

46 Relative Rate of Acetolysis of Glycopyranosides (Electrostatic Stabilization by Electron Lone Pairs on xocarbenium Ion) Stabilization of oxocarbenium by axial C 4 -X group Results of relative rates: 3 (0.5), 4 (1.6), 5 (0.6), 6 (0.5) (similar) 2 is slightly faster (2.4) 1 is much faster (24) M. Miljkovic, D. Yeagley, P. Deslongchamps, Y.L. Dory. J. rg. Chem. 1997, 62,

47 Electrostatic Interaction on 4-Substituted Tetrahydropyran xocarbenium Ion explanation K.A. WERPEL et al. J.Am.Chem.Soc. 2003, 125,

48 Electrostatic Interaction on Tetrahydropyran xocarbenium Ion Influence on Chemical Reactivity N.B. 3 is stabilized by hyperconjugation from C2- axial? ther explanation next slide K.A. WERPEL, M.T. YANG. J.rg.Chem. 2009, 74,

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50 Stabilized by hyperconjugation? 50

51 BBA ypothesis and yperconjugation 51

52 RÉSUMÉ: Relative Stability and Reactivity of xocarbenium Ion in the Presence of R Group Nu R trans Nu highly favored + + R Nu R disfavored R Nu cis R Nu R Nu cis favored R + + R disfavored R Nu trans R Nu disfavored? Nu R Nu + R + favored R Nu trans Nu cis Reverse results when R is replaced by alkyl group in first two examples (K.. Woerpel). 52

53 Strong vs weak nucleophiles in glycoside formation Beaver, M.G.; Woerpel, K.A. J. rg. Chem. 2010, 75, Yang, M.T.; Woerpel, K.A. J. rg. Chem. 2009, 74,

54 Increasing polarity of solvent stabilizes the oxocarbenium ion Woerpel and co-workers have discovered that stereoselectivity is greater in C 3 CN than in C 2 Cl 2. Increasing the polarity of the solvent results in stabilization of the cationic intermediate and subsequently reduces the rate of nucleophilic addition. As the rate of nucleophilic addition is decreased from the diffusion limit regime, greater facial selectivity for the stereoelectronically preferred product would be observed. Beaver, M.G.; Woerpel, K.A. J. rg. Chem. 2010, 75, Shenoy, S.R.; Smith, D.M., Woerpel, K.A. J. Am. Chem. Soc. 2006, 128,

55 J.-F. Parent, P. Deslongchamps. rg. Biomol. Chem. 2016, 14,

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57 a b Glycosylation of unsubstituted bicyclic pyranoside. 57

58 a b Glycosylation of equatorial Bn bicyclic pyranoside. 58

59 a b Glycosylation of axial Bn bicyclic pyranoside. 59

60 Glucoside/mannoside glycosidation (1,2-cis) D. Crich, S. Sun, J. rg.chem. 1996, 61, 4506; Tetrahedron 1998, 54, D. Crich et al. Nat. Chem. 2012, 4, 663. M. Bols, M. Pedersen et al. rg. Lett. 2014, 16, M. Bols et al. Chem. Commun. 2015, 51,

61 D. Crich, S. Sun, J. rg.chem. 1996, 61, 4506; Tetrahedron 1998, 54, D. Crich et al. Nat. Chem. 2012, 4, 663. M. Bols, M. Pedersen et al. rg. Lett. 2014, 16, M. Bols et al. Chem. Commun. 2015, 51,

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63 FACTRS INFLUENCING TE GLYCSYLATIN STEPS (1) Conformation of donor ( 4 C 1, 1 C 4, 1 S 3, 0 S 2 ) and the corresponding oxocarbenium ion (halfchair 4 1 or 1 4 ) at the transition states (possibility of conformational change). (2) Inductive effect of exocyclic R groups at C 3, C 4, C 6 and hyperconjugation stabilizing or destabilizing. (3) Electrostatic stabilization of oxocarbenium ion by exocyclic R groups. (4) S N 1-like (or S N 2-like) process and Bürgi & Dunitz angle of attack. (5) Polarity of solvent favoring S N 1 or S N 2 process and early or late transition state. (6) Transient glycosyl donor intermediate (e.g. glycosyl triflate) or contact ion pair (CIP) and solvent-separated ion pair (SSIP). (7) Steric effects and stereoelectronic effects (antiperiplanar versus synperiplanar hypothesis) and reaction trajectory. (8) 13 C and 2 primary kinetic isotope effects (KIE). (9) FM based ab initio calculation. (10) - orbital model. (11) Bent bond model and the antiperiplanar (BBA) hypothesis. 63

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72 xygen at C 3 and lost of selectivity Lavinga,.; Tran, V.T.; Woerpel, K.A. rg. Biomol. Chem. 2014, 12,

73 Key parameters in glycosidation reaction: Summary 73

74 Ring conformation: Summary 74

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80 D. E. Evans, V. J. Cee, S. J. Siska. J. Am. Chem. Soc. 2006, 128,

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83 Gauche Effect (yperconjugation) S. Wolfe, Acc. Chem. Res. 1972, 5, 102. N. C. Craig et al. J. Am. Chem. Soc. 1997, 119,