Control of Asymmetry in the Radical Addition Approach to Chiral Amine Synthesis

Abstract

The state-of-the-science in asymmetric free radical additions to imino compounds is presented, beginning with an overview of methods involving stereocontrol by various chiral auxiliary approaches. Chiral N-acylhydrazones are discussed with respect to their use as radical acceptors for Mn-mediated intermolecular additions, from design to scope surveys to applications to biologically active targets. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and a variety of alkyl iodides may be employed as radical precursors, as discussed in a critical review of the functional group compatibility of the reaction. Applications to amino acid and alkaloid synthesis are presented to illustrate the synthetic potential of these versatile stereocontrolled carbon–carbon bond construction reactions. Asymmetric catalysis is discussed, from seminal work on the stereocontrol of radical addition to imino compounds by non-covalent interactions with stoichiometric amounts of catalysts, to more recent examples demonstrating catalyst turnover.

Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog

“…Taking guidance from the tubulysins, we required that the ideal method would be applicable to strategic construction of either the Cβ-Cγ or Cγ–Cδ bonds of γ-amino acids (as shown for Tup and Tuv, Scheme 1 ) and independent of substituents at the α-position. Stereoselective intermolecular additions of alkyl radicals to the C=N bonds are well-suited to this need; these reactions have been reviewed, 18 – 26 and new ones continue to develop. 27 , 28 , 29 We introduced a photolysis method 30 , 31 for this reaction type which employs Mn 2 (CO) 10 to generate alkyl radicals, leading to efficient additions of primary and secondary alkyl iodides to chiral N -acylhydrazones.…”

“… 32 – 35 The availability of efficient primary radical addition has opened many new synthetic applications; with earlier methods, primary alkyl radicals were prone to premature reduction or other side reactions (e.g., addition of ethyl radical under triethylborane or diethylzinc initiation). 20 – 26 The functional group tolerance and non-basic conditions of this method show excellent potential for synthesis of multifunctional amines; 36 – 41 the tubulysin γ-amino acids would test this potential. Indeed, our initial studies on tubulysins achieved preparation of Tuv precursor A and Tup itself ( B ) via these Mn-mediated radical addition reactions.…”

Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O-Benzyltubulysin V Benzyl Ester

“…Radical additions to imino compounds offer a useful carbon–carbon bond construction approach to chiral amine synthesis. 1 Seminal efforts to generalize this reaction for intermolecular coupling led to stereocontrolled alkylborane-, zinc-, and tin-mediated additions by Naito, 2 Bertrand, 3 and our group. 4 A significant early limitation on this chemistry restricted the scope of radicals to simple 2° and 3° alkyls, usually from reagents in large excess, due to unfavorable halogen atom transfer or competitive reduction of the radicals.…”

“…Radical additions to imino compounds offer a useful carbon–carbon bond construction approach to chiral amine synthesis . Seminal efforts to generalize this reaction for intermolecular coupling led to stereocontrolled alkylborane-, zinc-, and tin-mediated additions by Naito, Bertrand, and our group .…”

Alkyl Radical Addition to Aliphatic and Aromatic N-Acylhydrazones Using an Organic Photoredox Catalyst

“…Often, such reactions have limited applicability to imines from aliphatic aldehydes, as these substrates are subject to competing aza-enolization by deprotonation of the α-carbon . We have addressed this issue through the use of radical additions to CN bonds of hydrazones. − In support of that objective, our group developed a versatile Mn-mediated radical addition to chiral N -acylhydrazones, which enabled the asymmetric synthesis of chiral amines using both primary and secondary radicals (Scheme a) . These reactions are compatible with additional functionality in both radicals and acceptors, facilitating applications in complex molecule synthesis. , While very effective for aliphatic imino acceptors, the Mn-mediated additions were unsuccessful with hydrazones derived from aromatic aldehydes.…”