Could Diastereoselectivity in the Presence of O-2 Chiral Nonparticipating Groups Be an Indicator of Glycopyranosyl Oxacarbenium Ions in Glycosylation Reactions?

Abstract

Although long postulated, the existence of glycopyranosyl oxacarbenium ions as intermediates or transition states (TS) in chemical glycosylation reactions has not been convincingly demonstrated experimentally. It is anticipated that elucidation of such reactive species will greatly assist synthetic chemists to control the α/β stereoselectivity by rational means. Previous density functional theory (DFT) calculations from our group found that the torsion potential about C-2-O-2 in protected glycopyranosyl donors changed from a conventional 3-fold rotor to a 2-fold rotor with a strong syn (CH-2-C-2-O-2-CPg) preference once the donor was ionized to its oxacarbenium ion. This suggested to us that if CPg of the protecting group was a chiral carbon, then diastereoselectivity might be observed in glycosylation reactions that proceed through oxacarbenium ions. The hypothesis to test is as follows: if a nonparticipating O-2 racemic chiral protecting group exhibits diastereoselectivity in glycosylation reactions, then the reaction probably proceeds through an oxacarbenium ion intermediate or TS. We present data for O-2 ether-protected d-glucopyranosyl donors where the racemic protecting group 1-methyl 1'-methylcyclopropylmethyl (MCPM) provides the chirality. MCPM proves to be more activating than the O-2-benzyl ether, and in cases where the donor is otherwise deactivated, several examples of moderate diastereoselectivity are found. These results can be interpreted to indicate that a continuum of reactivity exists where some glycosyl donors form oxacarbenium ions in glycosylation reactions but more reactive donors do not. The strongly activating properties of the cyclopropylmethyl ether functionality and the ability to induce diastereoselectivity with chiral derivatives strongly suggest widespread applications.

Mechanism of Glycosylation of Anomeric Sulfonium Ions

“…= 0.01), methanol was strongly associated with the donor and favorably oriented for nucleophilic displacement due to hydrogen bond formation at O3–Ac ( d O3n-H = 1.96 Å) and O2 ( d O2–H = 2.35 Å). All attempts to locate an S N 2 transition state without hydrogen bonding 18 either failed or resulted in spontaneous hydrogen bond formation during optimization. The S N 2 precursor Cpx1 is a donor–acceptor complex that also exhibits dual hydrogen bonding ( d O3n-H = 1.99 Å, d O2–H = 2.19 Å) and orients methanol favorably for subsequent nucleophilic attack ( d O–C1 = 3.08 Å, ∠O–C1–S= 101°).…”

“…18 Thus, it is possible that the chirality of ( S )-(phenylthiomethyl)benzyl at C-2 of donors controls the anomeric outcome of glycosylations even if it proceeds through an S N 1-like mechanism.…”

The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface

“…340 Realizing that covalent intermediates and contact ion pairs (CIPs) are not necessarily subject to the same conformational restrictions, Whitfield and Kumar hypothesized that the dependence of glycosylation selectivity on the configuration of a chiral O2 protecting group would be indicative of an oxacarbenium ion intermediate. 341 In the event the change in selectivity observed between the R - and S -isomers on coupling of both armed and disarmed 2- O -[ R,S -1-(cyclopropyl)ethyl]-protected D-glucopyranosyl donors with various alcohols was not sufficient to allow meaningful conclusions to be drawn.…”

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2011–2012

“…Used to show that some glycosyl donors form oxacarbenium ions in glycosylation reactions but more reactive donors do not (Kumar & Whitfield, 2012) -Cyclosophorooctadecaoses -succinyl substituted TOF (DHB) As chiral additives in capillary electrophoresis of flavanones -Cyclosophorooctadecaoses -acetyl or succinyl substituted…”