Enantioselective Synthesis of β‑Fluoro Amines via β‑Amino α‑Fluoro Nitroalkanes and a Traceless Activating Group Strategy

Preparation of a range of enantioenriched β-fluoro amines (α,β-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp³-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver β-amino-α-fluoro nitroalkanes with high enantio- and diastereoselection. A denitration step renders the nitro group “traceless” and delivers secondary, tertiary, or vinyl alkyl fluorides embedded within a <i>vicinal</i> fluoro amine functional group. A synthesis of each possible stereoisomer of a β-fluoro lanicemine illustrates the potential ease with which fluorinated small molecules relevant to neuroscience drug development can be prepared in a stereochemically comprehensive manner

Alkene Diamination Using Electron-Rich Amines: Hypervalent Iodine-Promoted Inter-/Intramolecular C–N Bond Formation

A combined inter-/intramolecular oxidative diamination of terminal alkenes is described that uses a hypervalent iodine oxidant and a nucleophilic amine to produce 3-aminoindolines at room temperature. This operationally straightforward and metal-free protocol is compatible with a broad range of functional groups. A mechanism involving the conversion of the amine to an electrophilic nitrogen source is advanced and used to identify a protocol effective with substoichiometric amounts of iodide and commercially available phenyl iodobenzene diacetate (PIDA) as the stoichiometric oxidant

Silyl Imine Electrophiles in Enantioselective Catalysis: A Rosetta Stone for Peptide Homologation, Enabling Diverse <i>N</i>‑Protected Aryl Glycines from Aldehydes in Three Steps

We report that <i>N</i>-(trimethylsilyl)­imines serve in the Bis­(AMidine)-catalyzed addition of bromonitromethane with a high degree of enantioselection. This allows for the production of a range of protected α-bromo nitroalkane donors (including Fmoc) for use in Umpolung Amide Synthesis (UmAS). Hence, peptide homologation with nonnatural aryl glycine amino acids is achieved in three steps from aromatic aldehydes, which are plentiful and inexpensive. Epimerization during the homologation step is circumvented by avoiding an α-amino acid intermediate

Achiral Counterion Control of Enantioselectivity in a Brønsted Acid-Catalyzed Iodolactonization

Highly enantioselective halolactonizations have been developed that employ a chiral proton catalyst–<i>N</i>-iodosuccinimide (NIS) reagent system in which the Brønsted acid is used at catalyst loadings as low as 1 mol %. An approach that modulates the <i>achiral</i> counterion (equimolar to the <i>neutral chiral ligand</i>–proton complex present at low catalyst loadings) to optimize the enantioselection is documented for the first time in this transformation. In this way, unsaturated carboxylic acids are converted to γ-lactones in high yields (up to 98% ee) using commercially available NIS

Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle–metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity (<i>K</i>_a), enthalpy of binding (Δ<i>H</i>), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides

Achiral Counterion Control of Enantioselectivity in a Brønsted Acid-Catalyzed Iodolactonization

Highly enantioselective halolactonizations have been developed that employ a chiral proton catalyst–<i>N</i>-iodosuccinimide (NIS) reagent system in which the Brønsted acid is used at catalyst loadings as low as 1 mol %. An approach that modulates the <i>achiral</i> counterion (equimolar to the <i>neutral chiral ligand</i>–proton complex present at low catalyst loadings) to optimize the enantioselection is documented for the first time in this transformation. In this way, unsaturated carboxylic acids are converted to γ-lactones in high yields (up to 98% ee) using commercially available NIS

Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle–metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity (<i>K</i>_a), enthalpy of binding (Δ<i>H</i>), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides

Enantioselective Addition of Bromonitromethane to Aliphatic <i>N</i>‑Boc Aldimines Using a Homogeneous Bifunctional Chiral Organocatalyst

This report details the enantioselective synthesis of β-amino-α-bromo nitroalkanes with β-alkyl substituents, using homogeneous catalysis to prepare either antipode. Use of a bifunctional Brønsted base/acid catalyst allows equal access to either enantiomer of the products, enabling the use of Umpolung Amide Synthesis (UmAS) to prepare the corresponding L- or D-α-amino amide bearing alkyl side chainsoverall, in only four steps from aldehyde. The approach also addresses an underlying incompatibility between bromonitromethane and solid hydroxide bases

Brønsted Acid Catalyzed Phosphoramidic Acid Additions to Alkenes: Diastereo- and Enantioselective Halogenative Cyclizations for the Synthesis of <i>C</i>- and <i>P</i>‑Chiral Phosphoramidates

The first highly diastereo- and enantioselective additions of a halogen and phosphoramidic acid to unactivated alkenes have been developed, catalyzed by a chiral Brønsted acid. A unique feature of these additions is the opportunity for stereocontrol at two noncontiguous chiral centers, carbon and phosphorus, leading to cyclic <i>P</i>-chiral phosphoramidates. In addition to their inherent value, the phosphoramidates are precursors to enantioenriched epoxy allylamines

Brønsted Acid Catalyzed Phosphoramidic Acid Additions to Alkenes: Diastereo- and Enantioselective Halogenative Cyclizations for the Synthesis of <i>C</i>- and <i>P</i>‑Chiral Phosphoramidates

The first highly diastereo- and enantioselective additions of a halogen and phosphoramidic acid to unactivated alkenes have been developed, catalyzed by a chiral Brønsted acid. A unique feature of these additions is the opportunity for stereocontrol at two noncontiguous chiral centers, carbon and phosphorus, leading to cyclic <i>P</i>-chiral phosphoramidates. In addition to their inherent value, the phosphoramidates are precursors to enantioenriched epoxy allylamines