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Review
. 2014:343:1-32.
doi: 10.1007/128_2013_481.

Control of asymmetry in the radical addition approach to chiral amine synthesis

Gregory K Friestad  1
Affiliations
Review

Control of asymmetry in the radical addition approach to chiral amine synthesis

Gregory K Friestad. Top Curr Chem. 2014.

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.

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Figures

Fig. 1
Fig. 1
Disconnecting a C–C bond of a chiral amine suggests an imino compound (e.g., imine, oxime, hydrazone, etc.) and an organic halide as precursors.
Fig. 2
Fig. 2
Radical Addition to Imino Compounds.
Fig. 3
Fig. 3
Naito stereocontrol model proposed for additions to camphorsultam-functionalized glyoxylic oxime ethers. (a) Lewis acid chelation induces rigidity and electron-deficiency into the N-acylhydrazone radical acceptor (LA = Lewis acid). (b) Benzyl substituent of 4-benzyl-2-oxazolidinone provides facial diferentiation of the C=N bond.
Fig. 3
Fig. 3
Naito stereocontrol model proposed for additions to camphorsultam-functionalized glyoxylic oxime ethers. (a) Lewis acid chelation induces rigidity and electron-deficiency into the N-acylhydrazone radical acceptor (LA = Lewis acid). (b) Benzyl substituent of 4-benzyl-2-oxazolidinone provides facial diferentiation of the C=N bond.
Figure 4
Figure 4
Representative γ-amino acids with strategic bond disconnections at the γ–δ and β–γ carbons.
Fig. 5
Fig. 5
Some hypothetical multipoint binding of a Lewis acid by N-acylhydrazones bearing additional ester functionality
Fig. 6
Fig. 6
Two-point binding of a Lewis acid by a generalized N-acylhydrazone structure.
Scheme 1
Scheme 1
Radical addition to glyoxylate imines.
Scheme 2
Scheme 2
Radical addition to N-sulfinylimines
Scheme 3
Scheme 3
Representative preparations of chiral N-acylhydrazones
Scheme 4
Scheme 4
Role of oxazolidinone substituents on diastereoselectivity in isopropyl radical addition
Scheme 5
Scheme 5
A one-pot condensation–radical addition of N-acylhydrazones
Scheme 6
Scheme 6
Control of stepwise annulation
Scheme 7
Scheme 7
Retrosynthetic disconnection of coniine
Scheme 8
Scheme 8
Radical addition to 5-tosyloxypentanal hydrazone 18
Scheme 9
Scheme 9
Synthesis of (R)-coniine
Scheme 10
Scheme 10
Retrosynthetic analysis of quinine
Scheme 11
Scheme 11
Mn-mediated radical addition en route to quinine
Scheme 12
Scheme 12
Conversion of quinolizidine 28 to quincorine
Scheme 13
Scheme 13
Addition to a β-alkoxyhydrazone without β-elimination
Scheme 14
Scheme 14
Addition of a 3-silyloxyalkyl iodide to an N-acylhydrazone
Scheme 15
Scheme 15
Conversion of radical adduct to N-trifluoroacetamide
Scheme 16
Scheme 16
Radical addition to ketimine 47
Scheme 17
Scheme 17
Control experiments with electron-rich aromatics
Scheme 18
Scheme 18
Functionality variations in Mn-mediated coupling attempts for quinine synthesis
Scheme 19
Scheme 19
Stereoconvergent routes to chiral amines
Scheme 20
Scheme 20
Asymmetric addition of isopropyl iodide to glyoxylate oxime ether
Scheme 21
Scheme 21
Radical addition in the presence of cinchona alkaloid salts of hypophosphorous acid.
Scheme 22
Scheme 22
Catalytic asymmetric radical addition to N-benzoylhydrazones in the presence of a cinchona alkaloid salt
Scheme 23
Scheme 23
Binaphthol-derived Bronsted acid catalyst for asymmetric radical addition to N-arylimines
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References

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    1. For examples of aza-enolization of imino compounds by organometallic reagents see: Stork G, Dowd SR. J Am Chem Soc. 1963;85:2178–2180.Wittig G, Frommeld HD, Suchanek P. Angew Chem Int Ed Engl. 1963;2:683.Guerrier L, Royer J, Grierson DS, Husson H-P. J Am Chem Soc. 1983;105:7754–7755.Enders D, Diez E, Fernandez R, Martin-Zamora E, Munoz JM, Pappalardo RR, Lassaletta JM. J Org Chem. 1999;64:6329–6336.

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    1. Reviews of radical additions to imines and related acceptors: Friestad GK. In: Topics In Current Chemistry: Radicals in Synthesis III. Gansauer A, Heinrich M, editors. Vol. 320. Springer-Verlag; Berlin: 2012. pp. 61–92.Friestad GK. Chiral Amine Synthesis. In: Nugent T, editor. Methods, Developments and Applications. Wiley-VCH; Weinheim, Germany: 2010. pp. 51–74.Miyabe H, Yoshioka E, Kohtani S. Curr Org Chem. 2010;14:1254–1264.Yamada K, Tomioka K. Chem Rev. 2008;108:2874–2886.Friestad GK. Tetrahedron. 2001;57:5461–5496.

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