Catalytic protodeboronation of pinacol boronic esters: formal anti-Markovnikov hydromethylation of alkenes

Abstract

Pinacol boronic esters are highly valuable building blocks in organic synthesis. In contrast to the many protocols available on the functionalizing deboronation of alkyl boronic esters, protodeboronation is not well developed. Herein we report catalytic protodeboronation of 1°, 2° and 3° alkyl boronic esters utilizing a radical approach. Paired with a Matteson-CH₂-homologation, our protocol allows for formal anti-Markovnikov alkene hydromethylation, a valuable but unknown transformation. The hydromethylation sequence was applied to methoxy protected (-)-Δ8-THC and cholesterol. The protodeboronation was further used in the formal total synthesis of δ-(R)-coniceine and indolizidine 209B.

Scheme 1. Protodeboronation and its application in synthesis.

Scheme 2. Substrate scope of the photoredox catalyzed protodeboronation. Conditions: 1a–n (0.2 mmol), PhLi (0.22 mmol), Et₂O (2 mL), thiophenol (0.22 mmol), Ir-catalyst PC1 (2.5 mol%) in MeOH/acetone (1 : 1, 2 mL). Isolated yields, unless otherwise noted. ^aYield determined by GC. [Ir] = Ir(dFCF₃ppy)₂(dtbbpy)PF₆ (PC1).

Scheme 3. Radical probe experiment and proposed mechanism.

Scheme 4. Formal total synthesis of δ-(R)-coniceine (9) and indolizidine 209B (13). Reagents and conditions: (a) s-BuLi (1.2 equiv.), (+)-sparteine (1.2 equiv.) Et₂O, –78 °C, 3 h then isopropyl pinacol borate (1.3 equiv.), –78 °C, 2 h; (b) vinyllithium (1.3 equiv.), Et₂O, –78 °C to rt, 30 min then tert-butyl 2-iodoacetate (2.0 equiv.), MeCN, hν, 50 °C, 24 h; (c) PhLi (1.1 equiv.), Et₂O, 0 °C to rt, 30 min then PhSH (1.1 equiv.), PC1 (2.5%), blue LED, MeOH/acetone, 16 h; (d) HCl in dioxane, rt, 8 h then EDC·HCl (2.0 equiv.), DMAP (20 mol%), Hünig's base (2.0 equiv.), CH₂Cl₂, rt, over night; (e) see ref. 57; (f) isopropenyllithium (1.3 equiv.), Et₂O, –78 °C to rt, 30 min then ethyl 2-iodoacetate (5.0 equiv.), MeCN, hν, 50 °C, 24 h; (g) TFA (10 eq.), CH₂Cl₂, 0 °C to rt, 2 h then NEt₃ (20 equiv.), CH₂Cl₂, rt, 12 h; (h) (3,5-bis(trifluoromethyl)phenyl)lithium (1.3 equiv.), Et₂O, –78 °C, 1 h then PhSH (1.3 equiv.), PC1 (2.5%), blue LED, MeOH/acetone, 16 h; (i) see ref. 58.

Scheme 5. Formal alkene hydromethylation. Homologation: 14a–k (0.05–0.2 mmol, 1.0 equiv.), CH₂Br₂ (2.0–3.0 equiv.), n-butyllithium (1.5–2.0 equiv.) in THF or Et₂O: protodeboronation: 15a–k (0.05–0.2 mmol, 1.0 equiv., used as crude from homologation step), PhLi (1.1 equiv.), Et₂O (0.5–2.0 mL), thiophenol (1.1 equiv.), PC1 (2.5 mol%) in MeOH/acetone (1 : 1, 0.5–2.0 mL). Yield corresponds to the two-step homologation-protodeboronation sequence. For the hydroboration step, we refer to the ESI. ^aDerived from O-Ts-protected phenol, O–S cleavage during reaction.