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. 2024 Apr 23;15(20):7725-7731.
doi: 10.1039/d4sc00822g. eCollection 2024 May 22.

Enantioselective synthesis of α-aryl α-hydrazino phosphonates

Saúl Alberca  1 , Javier Romero-Parra  2 , Israel Fernández  3 , Rosario Fernández  1 , José M Lassaletta  4 , David Monge  1
Affiliations

Enantioselective synthesis of α-aryl α-hydrazino phosphonates

Saúl Alberca et al. Chem Sci. .

Abstract

Catalysts generated in situ by the combination of pyridine-hydrazone N,N-ligands and Pd(TFA)2 have been applied to the addition of arylboronic acids to formylphosphonate-derived hydrazones, yielding α-aryl α-hydrazino phosphonates in excellent enantioselectivities (96 → 99% ee). Subsequent removal of the benzyloxycarbonyl (Cbz) N-protecting group afforded key building blocks en route to appealing artificial peptides, herbicides and antitumoral derivatives. Experimental and computational data support a stereochemical model based on aryl-palladium intermediates in which the phosphono hydrazone coordinates in its Z-configuration, maximizing the interactions between the substrate and the pyridine-hydrazone ligand.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Biologically active molecules derived from α-aryl α-hydrazino phosphonates.
Scheme 1
Scheme 1. Enantioselective transformations of phosphono hydrazones towards α-aryl α-amino phosphonates (A) and α-aryl α-hydrazino phosphonates (B, this work).
Scheme 2
Scheme 2. Scope of the reaction. Yields of isolated products after column chromatography. Enantiomeric excesses were determined by HPLC on chiral stationary phases aReactions performed at 0.2 mmol scale. bReaction time: 20 h. c(S)-3Ao was synthesized employing ent-L5.
Fig. 2
Fig. 2. Progression of ratios (%) of (E)-1A (in blue), (Z)-1A (in black) and (R)-3Aa (in red) under catalytic conditions (0.2 mmol). Estimated by 31P-NMR. (Top) starting from (E)-1A. (Bottom) starting from (Z)-1A.
Fig. 3
Fig. 3. Computed reaction profile for the key enantiodetermining step from intermediates INT1. Relative free energies (ΔG, at 333 K) and bond distances are given in kcal mol−1 and angstroms, respectively.
Fig. 4
Fig. 4. (Left): Contour plots of the reduced density gradient isosurfaces (density cutoff of 0.04 a.u.) for TSR(Z). The greenish surfaces indicate attractive non-covalent interactions (computed at the PCM(dichloroethane)-M06L/def2-SVP level). (Right): (a) comparative activation strain analyses (PCM(dichloroethane)-M06L/def2-SVP level) and (b) energy decomposition analyses (ZORA-M06L/DZP//PCM(dichloroethane)-M06L/def2-SVP level) of the key enantiodetermining step projected onto the C⋯C bond-forming distance and involving the R (solid lines) and S (dotted lines) pathways.
Scheme 3
Scheme 3. Transformations of adducts 3 into appealing targets. aFrom (S)-3Ao.
See this image and copyright information in PMC

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