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. 2012;16(1):26-34.
doi: 10.1021/op2002613.

Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres

Erin M Skoda  1 , Gary C Davis, Peter Wipf
Affiliations

Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres

Erin M Skoda et al. Org Process Res Dev. 2012.

Abstract

Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogs have been prepared on up to 160 g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II' β-turn secondary structures and display impressive biological properties, including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.

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Figures

Figure 1
Figure 1
Representative synthetic transformations of allylic amine building blocks.
Figure 2
Figure 2
Representative allylic amine building blocks obtained with alkyne hydro(carbo)metalation-imine addition methods.
Figure 3
Figure 3
Structure of (E)-alkene peptide isosteres as peptide bond replacements.
Figure 4
Figure 4
Mitochondrial targeting agents based on the antibiotic gramicidin S.
Figure 5
Figure 5
The crystal structure of JP4-039 reveals a type II′ β-turn.
Figure 6
Figure 6
Crystal structure of 49.
Figure 7
Figure 7
Crystal structure of 49 showing four solvent channels.
Scheme 1
Scheme 1
Ni-catalyzed intermolecular coupling to prepare enantiomerically enriched allylic amines.
Scheme 2
Scheme 2
Reductive coupling of alkynes with N-arylsulfonyl imines.
Scheme 3
Scheme 3
α-Acylvinyl anion addition to imines (major:Σminor refers to the ratio of the major product as drawn to the sum of all minor products).
Scheme 4
Scheme 4
Rh(I)-catalyzed addition of alkenyl trifluoroborates to N-tert-butylsulfinylimines.
Scheme 5
Scheme 5
Hydrozirconation/transmetalation/imine addition approach to trisubstituted allylic amines.,
Scheme 6
Scheme 6
Microwave-accelerated Stille crosscouplings of 25c.
Scheme 7
Scheme 7
Pd-catalyzed arylation of iodoalkene 26 and trifluoromethylation of iodoalkene 32.
Scheme 8
Scheme 8
Alkyne carboalumination/sulfinyl imine addition as a stereoselective entry to (E)-allylic amines.
Scheme 9
Scheme 9
Synthesis of (E)-iodoalkene 44 by hydrozirconation of internal alkyne 43.
Scheme 10
Scheme 10
Synthesis of allylic amine 50.
Scheme 11
Scheme 11
Completion of the synthesis of the protected alkene peptide isostere 57.
Scheme 12
Scheme 12
Synthesis of trisubstituted (E)-alkene peptide isostere 61 designed for mitochondrial targeting and scavenging of ROS.
Scheme 13
Scheme 13
Large-scale synthesis of allylic amine intermediate (S)-65.
Scheme 14
Scheme 14
Completion of the enantioselective synthesis of JP4-039 from carbamate (S)-65.
Scheme 15
Scheme 15
Stereoselective synthesis of the difluorinated analog 68 from (S)-65.
Scheme 16
Scheme 16
2nd Generation synthesis of XJB-5-131 from (S)-65.
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