Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

Abstract

The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β-mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α-glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide-based carbohydrate synthesis.

Keywords: carbohydrates; glycosylation; mechanism; organic synthesis; sulfoxides.

Scheme 1

The challenging glycosylation of a deoxycholic ester is feasible using sulfoxide‐based glycosyl donors. DTBMP=2,6‐di‐tert‐butyl‐4‐methylpyridine.

Scheme 2

At sufficiently low temperatures, glycosyl sulfenate 5 can be isolated from glycosylations involving glycosyl sulfoxides. MOM=methoxymethyl ether.

Scheme 3

Proposed mechanism for triflic anhydride activated glycosylation of sulfoxide donors, accounting for the glycosyl sulfenate byproduct.

Scheme 4

Dependence of stereoselectivity upon order of addition of glycosyl acceptor versus activating agents. TBDMS=tert‐butyldimethylsilyl.

Scheme 5

Proposed mechanisms for the formation of β‐mannopyranoside 13 and α‐mannopyranoside 14.

Scheme 6

NMR studies of intermediate glycosyl triflate 17.

Scheme 7

Differing selectivities in the glycosylation of mannosyl sulfoxides and glucosyl sulfoxide 19.

Scheme 8

Stereoselective formation of α‐glucopyranoside 21α by virtue of a Curtin–Hammett kinetic scenario.

Scheme 9

Crich's cation‐clock. a) Intramolecular Sakurai reaction of mannosyl sulfoxide 23 and b) competing O‐glycosylation with isopropanol, or C‐glycosylation CH₂=C(CH₃)CH₂TMS. TTBP=2,4,6‐tri‐tert‐butylpyrimidine.

Scheme 10

Natural abundance ¹³C NMR KIE study, on formation of a) mannopyranosides 29 α and 29 β and b) glucopyranosides 30 α and 30 β.

Scheme 11

Activation of oxathiane ketal‐(S)‐oxide 33 and oxathiane ether‐(S)‐oxide 34 by umpolung S‐arylation. Reproduced from ref. 28b.

Scheme 12

The equilibrium between the ³ H ₄ and ⁴ H ₃ oxacarbenium conformers 37 and 38 can govern the overall stereoselectivity of glycosylation

Scheme 13

Dehydrative glycosylation using Ph₂SO and triflic anhydride.

Scheme 14

Mechanisms for dehydrative glycosylation involving a) an oxosulfonium species 42 or b) a glycosyl triflate 43.

Scheme 15

Catalytic cycle for sulfoxide covalent catalysis.

Scheme 16

Sulfoxide covalent catalysis with dibutyl sulfoxide and diphenyl sulfonic anhydride

Scheme 17

Activation of glycal 50 using Ph₂SO and triflic anhydride.

Scheme 18

Labelling study using ¹⁸O‐labelled Ph₂SO (96 % ¹⁸O‐incorporation).

Scheme 19

a) Proposed mechanism for glycal activation, incorporating disulfonium species 57. b) Proposed mechanism for glycal activation, incorporating C‐2‐oxosulfonium dication 60.

Scheme 20

¹³C NMR tracking of the ¹⁸O‐label position relative to the ¹³C‐label in the activation of glucal 63.

Scheme 21

Synthetic routes to a glycosyl triflate 67 species.

Scheme 22

Triflic anhydride activation of MPBT 68 and BSP 69.

Scheme 23

Ph₂SO/triflic anhydride activation of thioglycosides 66.

Scheme 24

Formation of byproduct 71 and 72. BSP=1‐benzenesulfinyl piperidine.

Scheme 25

Stereoselective oxidation of glycosyl oxathianes using isotopically labelled Ph₂S¹⁸O/Tf₂O. Reproduced from ref. 47.

Scheme 26

a–d) Possible reaction pathways for the oxidation of generic oxathiane 77. Mechanisms are depicted as S_N2 processes for simplicity, although it is likely that some mechanisms may proceed via sulfurane intermediates. Reproduced from ref. 52.

Scheme 27

An allyl sulfoxide–sulfenate rearrangement is utilised to probe the kinetic and thermodynamic preferences of sulfoxide formation and equilibration from a) β‐thioxyloside 83 β and b) α‐thioxyloside 83 α. mCPBA= meta‐chloroperoxybenzoic acid.