Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of α‐Branched Esters Using 2‐Substituted Allyl Electrophiles

Abstract

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters with 2-substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal-centered reactivity and the source of enantiocontrol are independent. This feature is unique to simultaneous catalysis events and permits logical tuning of the supporting ligands without compromising enantioselectivity.

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

“…The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd‐cooperative catalysis [8,14–22] . Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)−O−C1‐ammonium enolate 21 ( Scheme 6).…”

“…In addition to resolving the remaining structural questions regarding the absolute stereochemistry of the quaternary stereogenic centers in the major enantiomers of 2, 10-12, this also enables us to propose a tentative model for stereoinduction via correlation with our previous investigations. [20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6).…”

“…[20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6). Here, the oxyanion and nitrile moieties are anti-co-planar, and the ensemble is rigidified by a n O !σ* CÀ S interaction resulting in shielding of the Si face by the benzyl (Bn) substituent of the catalyst which directs alkylation to the Re face giving 22.…”

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

“…The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd‐cooperative catalysis [8,14–22] . Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)−O−C1‐ammonium enolate 21 ( Scheme 6).…”

“…In addition to resolving the remaining structural questions regarding the absolute stereochemistry of the quaternary stereogenic centers in the major enantiomers of 2, 10-12, this also enables us to propose a tentative model for stereoinduction via correlation with our previous investigations. [20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6).…”

“…[20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6). Here, the oxyanion and nitrile moieties are anti-co-planar, and the ensemble is rigidified by a n O !σ* CÀ S interaction resulting in shielding of the Si face by the benzyl (Bn) substituent of the catalyst which directs alkylation to the Re face giving 22.…”

Direct electrochemical synthesis of pentafluorophenyl esters via oxyl-radical-promoted nucleophilic aromatic substitution

“…Lastly, using α-amino acid esters as the nucleophiles afforded dipeptides 58–60 in 70–92% yields and without epimerization (all ≥99 : 1 dr), which can be challenging in peptide synthesis. 99–101 Although these outcomes are consistent with the well-established performance of PFP esters in a range of applications, 16–55 these results showcase that these electrophiles are highly effective acyl surrogates ( i.e. , providing high yield and minimizing racemization) with a broad range of nucleophiles and without needing to re-optimize reaction conditions.…”

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

“…The efforts to mitigate these problems are summarized in Table 2. The side product was identified as 22 (Figure 2), presumably resulting from 70 (61) 60:40 2 phosphate as the leaving group, as has been reported by Snaddon and co-workers [19].…”

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

“…The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd‐cooperative catalysis [8,14–22] . Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)−O−C1‐ammonium enolate 21 ( Scheme 6).…”

“…In addition to resolving the remaining structural questions regarding the absolute stereochemistry of the quaternary stereogenic centers in the major enantiomers of 2, 10-12, this also enables us to propose a tentative model for stereoinduction via correlation with our previous investigations. [20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6).…”

“…[20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6). Here, the oxyanion and nitrile moieties are anti-co-planar, and the ensemble is rigidified by a n O !σ* CÀ S interaction resulting in shielding of the Si face by the benzyl (Bn) substituent of the catalyst which directs alkylation to the Re face giving 22.…”

Direct electrochemical synthesis of pentafluorophenyl esters via oxyl-radical-promoted nucleophilic aromatic substitution

“…Lastly, using α-amino acid esters as the nucleophiles afforded dipeptides 58–60 in 70–92% yields and without epimerization (all ≥99 : 1 dr), which can be challenging in peptide synthesis. 99–101 Although these outcomes are consistent with the well-established performance of PFP esters in a range of applications, 16–55 these results showcase that these electrophiles are highly effective acyl surrogates ( i.e. , providing high yield and minimizing racemization) with a broad range of nucleophiles and without needing to re-optimize reaction conditions.…”

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

“…The efforts to mitigate these problems are summarized in Table 2. The side product was identified as 22 (Figure 2), presumably resulting from 70 (61) 60:40 2 phosphate as the leaving group, as has been reported by Snaddon and co-workers [19].…”

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

“…The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd‐cooperative catalysis [8,14–22] . Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)−O−C1‐ammonium enolate 21 ( Scheme 6).…”

“…In addition to resolving the remaining structural questions regarding the absolute stereochemistry of the quaternary stereogenic centers in the major enantiomers of 2, 10-12, this also enables us to propose a tentative model for stereoinduction via correlation with our previous investigations. [20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6).…”

“…[20,22] The sense of enantioselectivity is consistent with our prior disclosures describing enantioselective allylation via Lewis base/Pd-cooperative catalysis. [8,[14][15][16][17][18][19][20][21][22] Accordingly, we propose a tentative stereoselectivity model whereby allylation occurs via the (E)À OÀ C1ammonium enolate 21 (Scheme 6). Here, the oxyanion and nitrile moieties are anti-co-planar, and the ensemble is rigidified by a n O !σ* CÀ S interaction resulting in shielding of the Si face by the benzyl (Bn) substituent of the catalyst which directs alkylation to the Re face giving 22.…”

Direct electrochemical synthesis of pentafluorophenyl esters via oxyl-radical-promoted nucleophilic aromatic substitution

“…Lastly, using α-amino acid esters as the nucleophiles afforded dipeptides 58–60 in 70–92% yields and without epimerization (all ≥99 : 1 dr), which can be challenging in peptide synthesis. 99–101 Although these outcomes are consistent with the well-established performance of PFP esters in a range of applications, 16–55 these results showcase that these electrophiles are highly effective acyl surrogates ( i.e. , providing high yield and minimizing racemization) with a broad range of nucleophiles and without needing to re-optimize reaction conditions.…”

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

“…The efforts to mitigate these problems are summarized in Table 2. The side product was identified as 22 (Figure 2), presumably resulting from 70 (61) 60:40 2 phosphate as the leaving group, as has been reported by Snaddon and co-workers [19].…”