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An oxocarbenium ion at the anomeric carbon of a cyclic glycosyl fragment. Positive charge is delocalized between that carbon and the ring oxygen. A counterion can remain nearby and influence which face a nucleophile approaches.

An oxocarbenium ion is a cationic species stabilized by adjacent oxygen donation, commonly represented by carbon-cation and oxonium resonance contributors. Reversible acetal opening can expose a locally planar carbon for attack from either face.

Treat the reacting carbon skeletons as an activated glycosyl donor and a 3-substituted indole. The new linkage is an anomeric-carbon–indole-C2 carbon–carbon bond, not a bond to indole nitrogen. A plausible purely chemical pathway is a dissociative electrophilic aromatic substitution:

The drawn donor and product have opposite anomeric faces: the anomeric leaving group is on the same face as the hydroxymethyl substituent, while the new carbon substituent is on the opposite face. Thus the target has net inversion at the anomeric carbon. A tight ion pair with the departing group shielding its original face can rationalize opposite-face capture in this proposed pathway. A freely solvated planar oxocarbenium ion would not by itself guarantee exclusive inversion; competing faces, hydrolysis and other products remain possible without an experimentally specified chemical promoter. This is a plausible non-enzymatic mechanism, not a claim that the uncatalysed reaction is rapid or clean in neutral water.

E, with the axial anomeric acetate, hydrolyses faster. The tert-butyl substituent strongly favours the chair in which it is equatorial, so the two substrates cannot freely interchange axial and equatorial acetate simply by an inexpensive ring inversion. protonation activates the anomeric acetoxy leaving group. As its C–O bond cleaves to release acetic acid, a lone pair on the endocyclic oxygen donates into the developing anomeric orbital, producing an oxocarbenium ion. water attacks that carbon, and deprotonation gives the cyclic hemiacetal. Attack from either face accounts for the unspecified anomeric configuration of OH in the product.

The axial C–OAc bond in E can adopt antiperiplanar geometry relative to an endocyclic oxygen lone pair. This favourable $n_O\to {\sigma }_{C-O}^{\ast }$ interaction assists departure in the ionization transition state. The corresponding bond in F is poorly aligned in its preferred chair; achieving comparable overlap requires an unfavourable chair change, placing tert-butyl axial, or substantial ring distortion. The distinction is stereoelectronic control of acetal hydrolysis, rather than merely counting steric crowding in the products.

An axial acetal can itself receive ground-state stabilization from the anomeric effect, so “axial means unstable” is not an adequate rate argument. What matters is the relative Gibbs energy of activation for the departing bond and the geometry of lone-pair assistance. Conformationally locked model acetals experimentally demonstrate faster acid-catalysed cleavage of the axially oriented isomer, although their numerical rate ratios should not be transferred to these different substrates.^[ref]

With triethylamine present, proton transfer from thiophenol produces a more nucleophilic thiolate population. sulfur attacks the anomeric epoxide carbon C1 from the face opposite its epoxide C–O bond. Displacement by backside attack opens the epoxide, breaks C1–O, and leaves the former epoxide oxygen attached to C2. protonation of that alkoxide by thiophenol or triethylammonium gives G: SPh at C1 on the front face and OH at C2 on the back face, a trans relationship. This is inversion at C1 with retention of the C2 C–O bond; there is no need to invert every stereocentre. Rapid protonation also suppresses competing silyl transfer by the alkoxide.

Without added base, neutral thiophenol is less nucleophilic. acid-assisted cleavage at the anomeric epoxide bond can instead be accompanied by donation from the ring oxygen, giving an oxocarbenium ion with charge shared with the ring oxygen. thiophenol capture from the face that puts SPh back on the original epoxide face, followed by deprotonation, gives H with SPh and C2–OH both on the back face, the net-retention pathway. An ion-pair or highly asynchronous opening can provide this outcome; the drawing does not establish a long-lived free carbocation.

The distinction is configuration, not a mandatory fixed chair. For the closely matching trisilylated substrate, the primary study obtained both anomers with thiophenol alone, and established an unusual inverted chair for the alpha thioglycoside by NMR and crystallography. Thus H should be explained as an accessible product, not asserted to be the sole product or necessarily to have axial SPh in its preferred conformation.^[ref]

Protonation of a spiroacetal oxygen makes the adjacent C–O bond easier to cleave. Reversible opening gives an oxocarbenium ion, in which the spiro carbon is locally planar. The tethered alcohol can attack either face; deprotonation closes the acetal and regenerates acid. Repetition interconverts the spiro epimers while retaining the other stereogenic centres. Methanol can participate in reversible proton transfer or trapping, but there is no need to invert the remote carbon centres.

First hydrolyze the benzylidene acetal. Protonate one acetal oxygen and break its bond to the Ph-CH centre, giving one free alcohol and a benzylic oxocarbenium ion. Water attacks that centre; proton transfers give a hemiacetal. Protonate the remaining acetal-derived OR group and cleave it to release the second alcohol and benzaldehyde.

The resulting unsaturated hydroxy ester isThe OH on the allyl-substituted methine is gamma to the ester carbonyl. Protonation of that carbonyl enables intramolecular OH attack to give a five-membered tetrahedral intermediate. Proton transfer to methoxy and collapse expel methanol, followed by deprotonation to give the alpha,beta-unsaturated gamma-lactone.

The other liberated OH remains CH${}_2$OH. Both C=C units survive: one is the allyl substituent and the other becomes the lactone's conjugated double bond. Hydrolysis to a hydroxy acid followed by lactonization is an alternative sequence under the aqueous acid; direct acid-catalysed intramolecular ester exchange gives the same atom mapping.

D is $(\mathrm{MeO}{)}_2\mathrm{CHC}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{O}}_2\mathrm{Me}$, and E is $\mathrm{OHCC}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{O}}_2\mathrm{Et}$. D results from transesterification; E results from acid-catalysed acetal hydrolysis.

For D, methoxide attacks the ester carbonyl carbon and moves the carbonyl $\pi$ pair to oxygen. Collapse of the tetrahedral reaction intermediate reforms C=O and expels ethoxide. Proton transfer with the methanol solvent regenerates methoxide. Excess methanol favours replacement of the ethyl ester by a methyl ester; the dimethyl acetal survives these basic conditions.

For E, protonate one acetal oxygen, then break its C–O bond with the pair going to oxygen, releasing methanol and forming an oxocarbenium ion. Water attacks that carbon. Deprotonation gives a hemiacetal; protonation of its remaining methoxy oxygen permits loss of a second methanol. The hydroxyl oxygen's lone pair forms C=O during this loss, and deprotonation gives the aldehyde, regenerating the acid catalyst.

The spectroscopy is consistent with these products. D has one ester carbonyl near $1745\mathrm{c}{\mathrm{m}}^{-1}$ and six carbon-13 NMR environments: acetal CH, two distinct chain $\mathrm{C}{\mathrm{H}}_2$ sites, carbonyl, ester $\mathrm{OC}{\mathrm{H}}_3$, and the two equivalent acetal $\mathrm{OC}{\mathrm{H}}_3$ groups. Thus seven carbon atoms give six resonances. E has separate ester and aldehyde carbonyl bands, approximately $1745$ and $1730\mathrm{c}{\mathrm{m}}^{-1}$, and six distinct carbon atoms: two carbonyls, two chain methylenes and the two ethyl carbons.

The secondary alcohol of H condenses with the aldehyde under acid catalysis to form a hemiacetal, then loses water to an oxocarbenium ion. Its tethered E alkene attacks the aldehyde-derived carbon through a chair-like six-membered arrangement: the alkene carbon farther from the alcohol forms the new C–C bond, placing a carbocation at the nearer alkene carbon. Trifluoroacetate captures that cation; the basic methanolic work-up cleaves the trifluoroacetate ester to reveal the ring hydroxyl group. This is a Prins cyclization.

Number the product ring from oxygen through the aldehyde-derived carbon as C2, then the alkene-derived methyl-bearing carbon C3, the hydroxyl-bearing carbon C4, the intervening methylene C5 and the original alcohol carbon C6. A chair keeping the bulky C2 side chain and C6 hydroxymethyl group equatorial predicts 2,6-cis substitution. Suprafacial alkene capture preserves the E-alkene-derived relationship, giving 2,3-trans between the C2 side chain and C3 methyl. Preferred equatorial trapping of the C4 cation gives 3,4-trans, hence the 2,4,6-cis arrangement of the substituent-bearing bonds in the favoured chair. In the printed flat-ring orientation, draw the C2 side chain, C4 hydroxyl and C6 hydroxymethyl behind the plane, and C3 methyl in front. Existing stereocentres in the aldehyde side chain and at C6 are retained; they anchor the absolute face of this assignment.

The first two operations invert the allylic hydroxyl group. Triphenylphosphine adds to the azodicarboxylate, generating the reagent pair that converts the alcohol into an alkoxyphosphonium leaving group. Benzoate displaces it with inversion at carbon, giving the inverted benzoate ester. Methoxide then cleaves that ester by nucleophilic acyl substitution, retaining the newly inverted carbon–oxygen stereochemistry because cleavage occurs at the acyl group, not by substitution at the stereogenic carbon.

The inverted allylic alcohol exchanges with the orthoacetate under acid catalysis. Ethanol loss produces an allyl ketene acetal, schematically $\mathrm{C}{\mathrm{H}}_2=\mathrm{C}(\mathrm{OEt})-\mathrm{O}-(\mathrm{allyl})$. A six-membered suprafacial Johnson-Claisen rearrangement breaks the allylic C–O bond, shifts the ring alkene by one position and forms the new bond from the original alkene terminus to the ketene-acetal CH${}_2$. The result is the $-\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{O}}_2\mathrm{Et}$ substituent at the carbon that was the remote end of the original double bond. A chair-like transition state placing the larger substituents away from axial crowding explains the stereochemical transfer; the inverted alcohol configuration selects the corresponding face.

Finally, TiCl${}_4$ activates the anomeric methoxy group and methoxide departure creates an oxocarbenium ion. Hydride transfer from triethylsilane replaces that methoxy substituent by hydrogen. The ring oxygen and pendant OTBS group remain intact. The sequence is inversion, stereospecific allylic rearrangement, then reductive removal of the anomeric methoxy group, rather than direct reduction or hydrolysis of the ester introduced by the Claisen step.

Acid-promoted union of a carbonyl-derived oxocarbenium ion with a tethered alkene to form a ring. Cation trapping and the preferred cyclization conformation determine the final substitution and stereochemistry.