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. 2021 Apr 2;86(7):5026-5046.
doi: 10.1021/acs.joc.0c02971. Epub 2021 Mar 16.

Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

Toolika Agrawal  1 , Robert T Martin  2 , Stephen Collins  1 , Zachary Wilhelm  2 , Mytia D Edwards  1 , Osvaldo Gutierrez  2 , Joshua D Sieber  1
Affiliations

Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

Toolika Agrawal et al. J Org Chem. .

Abstract

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N-alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected examples of chiral 1,2-diamine- and urea-derived biologically active molecules.
Scheme 1
Scheme 1. Synthetic Strategies toward the Synthesis of 1,2-Diamines
Scheme 2
Scheme 2. Proposed Allylation Strategy toward the Synthesis of 1,2-Diamines
Scheme 3
Scheme 3. Proposed Reaction Catalytic Cycle
Scheme 4
Scheme 4. Imine Generality in the Cu-Catalyzed Reductive Coupling To Access 1,2-Diamino Synthons 18
Conditions: 9 (0.400 mmol), 15a (96.6 mg, 0.48 mmol), Cu(OAc)2 (5 mol %), PCy3 (6.5 mol %), t-BuOH (76 μL, 0.80 mmol), Me(MeO)2SiH (99 μL, 0.80 mmol), and 1.0 mL of toluene, rt 24 h followed by treatment with NH4F/MeOH. See the Supporting Information for more details. A single diastereomer of product was obtained in all cases by analysis of the unpurified reaction mixture by 1H NMR spectroscopy. Yields represent isolated yield. Reaction performed at 65 °C. Isolated as an inseparable mixture of 18 and urea 19.
Scheme 5
Scheme 5. Stereochemistry Determination
Scheme 6
Scheme 6. Synthetic Applications
Figure 2
Figure 2
Structures and relative free energies (in kcal/mol, with respect to separate LCuH catalyst and reactants) of possible hydrocupration pathways, optimized using B3LYP-D3/def2SVP-CPCM(toluene), M06-L/def2SVP-gas//B3LYP-D3/def2SVP-CPCM(toluene) (in parentheses), and B3LYP-D3/def2TZVPP-gas//B3LYP-D3/def2SVP-CPCM(toluene) {in braces}.
Figure 3
Figure 3
Structures and relative free energies (in kcal/mol, with respect to separate LCuH catalyst and reactants) for proposed mechanistic pathway, optimized using B3LYP-D3/def2SVP-CPCM(toluene), M06-L/def2SVP-gas//B3LYP-D3/def2SVP-CPCM(toluene) (in parentheses), and B3LYP-D3/def2TZVPP-gas//B3LYP-D3/def2SVP-CPCM(toluene) {in braces}. Optimized structures of transition states visualized with CYLview are shown (with PCy3 ligand faded out for clarity).
Figure 4
Figure 4
(A) Distortion–Interaction analysis of key diastereomeric C–C bond formation transition states. Electronic energies reported at B3LYP-D3/def2SVP-CPCM(toluene) level of theory. (B) Noncovalent Interaction analysis of key diastereomeric C–C bond formation transition states. Color code for the atoms is shown.
Figure 5
Figure 5
Energetic comparison of s-trans and s-cis conformations of an (E)-enamide system with chiral oxazolidinone, with steric hindrance causing allylic strain highlighted. Structures optimized using B3LYP-D3/def2SVP-CPCM(toluene) (Hrel and Grel shown in kcal/mol).
Scheme 7
Scheme 7. Mechanistic Implications Relevant to Catalyst-Controlled Enantioinduction
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