4
A. MAESTRO ET AL.
Table 4. Screening of the phosphorus substituent for the aza-Henry reaction of a-iminophosphonates 3.
Entry
Comp
R
Solvent
t (h)
%Conv.
%ee
1
2
3
4
5
6
5a
5c
5d
5d
5d
5d
Me
Et
No
No
No
CH2Cl2
CHCl3
Toluene
24
6
24
24
36
36
95
100
95
90
95
27
30
45
68
67
80
iPr
iPr
iPr
iPr
100
b) Macchiarulo, A. R.; Pellicciari. Exploring the Other Side of
Biologically Relevant Chemical Space: Insights into Carboxylic,
Sulfonic and Phosphonic Acid Bioisosteric Relationships. J.
formed under solvation conditions. An inverse dependence
of the enantioselectivity into the polarity of the solvent is
observed if non coordinating solvents are used (Table 4,
Entries 4-5). This dependence probably arises from a dimin-
ishing in the difference of the energy of activation for the
formation of the two enantiomers due to a stabilization of
both possible diastereomeric transition states in a polar solv-
ent, rational for reactions with ionic transition states. An
optimal enantiomeric excess of 80% was obtained when the
reaction was performed at room temperature in toluene. As
in the case of the cyanation reaction this process can be
extended to other aromatic a-iminophosphonates bearing
electron donating or electron withdrawing groups with
almost equal enantioselectivities.[13b]
ꢀ
Mol. Graphics Modell. 2007, 26, 728. c) Sienczyk, M.; Winiarski,
L.; Kasperkiewicz, P.; Psurski, M.; Wietrzyk, J.; Oleksyszyn, J.
Synthesis and Activity Study of Phosphonamidate Dipeptides as
Potential Inhibitors of VanX. Bioorg. Med. Chem. Lett. 2011,
21, 7224. d) Atherton, F. R.; Hassall, C. H.; Lambert, R. W.
Synthesis and Structure-activity Relationships of Antibacterial
Phosphonopeptides Incorporating (1-Aminoethyl)Phosphonic
Acid and (Aminomethyl)Phosphonic Acid. J. Med. Chem. 1986,
29, 29. e) Yao, G.; Ye, M.; Huang, R.; Li, Y.; Pan, Y.; Xu, Q.;
Liao, Z.; Wang, H. Synthesis and Antitumor Activities of Novel
Rhein a-Aminophosphonates Conjugates. Bioorg. Med. Chem.
ꢀ
Lett. 2014, 24, 501. f) Bonarska, D.; Kleszczynska, H. Sarapuk.
Antioxidative Activity of Some Phenoxy and
Organophosphorous Compounds. J. Cell Mol. Biol. Lett. 2002,
7, 929.
[3] a) Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral Drugs: An
Overview. Int. J. Biomedical Sci. 2002, 6, 85. b) Kasprzyk-
Hordern, B. Pharmacologically Active Compounds in the
Environment and Their Chirality. Chem. Soc. Rev. 2010, 39,
4466.
Conclusions
The enantioselective functionalization of a-aminophospho-
nates with nucleophiles has been achieved through an
umpolung process consisting in the oxidation of tetrasubsti-
tuted a-aminophosphonates to a-iminophosphonates fol-
lowed by the organocatalyzed addition of nucleophile
reagents such as cyanide and nitromethane.
[4] a) Stamper, C.; Bennett, B.; Edwards, T.; Holz, R. C.; Ringe, D.;
Petsko, G. Inhibition of the Aminopeptidase from Aeromonas
proteolytica by l-Leucinephosphonic Acid. Spectroscopic and
Crystallographic Characterization of the Transition State of
Peptide Hydrolysis. Biochemistry 2001, 40, 7035. b) Kafarski, P.;
Lejczak, B.; Szewczyk, J. Optically Active 1 Amino Alkane
Phosphonic Acids Di Benzoyl l Tartaric Anhydride as an
Effective Agent for the Resolution of Racemic Di Phenyl 1
Amino Alkane Phosphonates. Can. J. Chem. 1983, 61, 2425. c)
Solodenko, V. A.; Kukhar, V. P. Stereoselective Papain-catalyzed
Synthesis of Alafosfalin. Tetrahedron Lett. 1989, 32, 66. d)
Polyak, M. S. Antibiotics of the Phosphonic Acid Group.
Antibiot. Med. Biotekhnol. 1987, 32, 66.
Acknowledgments
ꢀ
Financial support by Ministerio de Economıa, Industria
Competitividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco
(GV, IT 992-16) is gratefully acknowledged.
y
[5] Chen, L. Recent Advances in the Catalytic Asymmetric
Construction of Phosphorus-Substituted Quaternary Carbon
Stereocenters. Synthesis 2018, 50, 440.
[6] Riant, O.; Hannedouche, J. Asymmetric Catalysis for the
Construction of Quaternary Carbon Centres: nucleophilic
Addition on Ketones and Ketimines. Org. Biomol. Chem. 2007,
5, 873
[7] a) Velez del Burgo, A.; Ochoa de Retana, A. M.; de los Santos,
J. M.; Palacios, F. Reaction of 2H-Azirine-Phosphine Oxides
and -Phosphonates with Enolates Derived from b-Keto Esters.
J. Org. Chem. 2016, 81, 100. b) Palacios, F.; Velez del Burgo,
A.; Ochoa de Retana, A. M. Selective Synthesis of Substituted
Pyrrole-2-Phosphine Oxides and -Phosphonates from 2H-
Azirines and Enolates from Acetyl Acetates and Malonates. J.
Org. Chem. 2011, 81, 9472. c) de los Santos, J. M.; Ochoa de
Retana, A. M.; Palacios, F. Michael Addition of Amine
References
[1] a) Van der Jeught, K.; Stevens, C. V. Direct Phosphonylation of
Aromatic Azaheterocycles. Chem. Rev. 2009, 109, 2672. b)
Berlicki, L.; Kafarski, P. Computer-Aided Analysis and Design
of Phosphonic and Phosphinic Enzyme Inhibitors as Potential
Drugs and Agrochemicals. Curr. Org. Chem. 2005, 9, 1829. c)
Kafarski, P.; Lejczak, B. Aminophosphonic Acids of Potential
Medical Importance. Cur. Med. Chem: Anti-Cancer Ag. 2001, 1,
301.
[2] a) Hirschmann, R.; Smith, III, A. B.; Taylor, C. M.; Benkovic,
P. A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Venkovic,
S. J. Peptide Synthesis Catalyzed by an Antibody Containing a
Binding Site for Variable Amino Acids. Science 1994, 265, 234.