An organocatalytic biomimetic approach to α-aminophosphonatesby Dorota Kowalczyk, Łukasz Albrecht

Chem. Commun.


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This journal is © The Royal Society of Chemistry 2012 Chem. Commun., 2014, 00, 1-3 | 1

Cite this: DOI: 10.1039/x0xx00000x

Received 00th January 2012,

Accepted 00th January 2012

DOI: 10.1039/x0xx00000x

Organocatalytic Biomimetic Approach to α-Aminophosphonates

Dorota Kowalczyk,a and Łukasz Albrechta,*

A novel biomimetic approach to optically active αaminophosphonates utilizing readily available acylphosphonates and 2-chlorobenzylamine as starting materials has been described. The enantioselective protonation constitutes the main enantiodifferentiating step in the developed strategy. This nature-inspired approach proceeds efficiently and in a highly stereoselective manner. α-Aminophosphonates and α-aminophosphonic acids constitute an important group of naturally occurring compounds that can be considered as isoelectronic analogues of the natural α-amino acids (Scheme 1). As such they have received a considerable interest over the years.1 Their biological activity including antiviral,2 antibacterial,3 antifungal4 and anticancer5 activity is well recognized. Furthermore, they inhibit activity of various proteolytic enzymes including HIV protease,6 renin,7 synthase,8 or PTPases.9 Importantly, the absolute configuration of αaminophosphonic acids and their derivatives determines the biological activity of this group of compounds.10 This can be exemplified by the Alafosfalin, a dipeptide consisting of an alanine and a phosphaalanine residues.11 Due to the presence of two stereogenic centers in the molecule, it can exists as four different stereoisomers. However, only one exhibits strong antibacterial activity. Consequently, the development of methods for the enantioselective preparation of α-aminophosphonic acid derivatives is of significant interest to the chemical community.

Scheme 1. α-Aminophosphonic acids as isosters of α-amino acids.

Most enantioselective methods for the synthesis of optically active α-aminophosphonates rely on the construction of the C-P bond via a Pudovik reaction of H-phosphonates with imines (Scheme 2, top).12,13 Various organocatalytic activation strategies including H-bonding13a or bifunctional13b,c catalysis and Brønsted acid13d,e or base13f,g activation, have been successfully employed to accomplish this reaction. To our surprise, alternative, enantioselective methods for the synthesis of α-aminophosphonates are scarcer and usually provide more elaborated derivatives.14 Furthermore, no method based on an enantioselective protonation exists in the literature.

Scheme 2. Enantioselective, biomimetic synthesis of αaminophosphonates via a Brønsted base catalysis.

Herein, we report a novel and biomimetic approach to biologically relevant α-aminophosphonates 3 (Scheme 2, bottom). It utilizes a base-catalyzed isomerization of a double bond in the corresponding N-benzylimines 5 followed by a hydrolytic deprotection of the amine moiety. Such a synthetic strategy is nature-inspired as it mimics an enzyme promoted transamination process that converts α-keto acids into α-amino acids in the biological systems.15 Notably, a biomimetic

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DOI: 10.1039/C4CC09477H

COMMUNICATION Journal Name 2 | Chem. Commun., 2014, 00, 1-3 This journal is © The Royal Society of Chemistry 2012

Brønsted base catalyzed synthesis of α-amino acids from α-keto esters has been recently described in the literature.16

In the designed biomimetic synthetic strategy, a chiral Brønsted base catalyst serves a dual purpose. Firstly, it deprotonates the corresponding N-benzylimines 5 in the benzylic position to afford an allylic-type carbanion that can be described by two mesomeric structures 6a and 6b. Secondly, it protonates the anion 6b in the α-position to the phosphoryl group to give after hydrolysis the desired α-aminophosphonate 3. At this stage the stereochemistry of the product is established. For this reason the chiral catalyst has to provide an efficient discrimination of the two enantiotopic faces of an anion 6b in order to achieve stereodifferentiating transformation. Due to the size of a proton this task is particularly difficult and enantioselective strategies based on the protonation reaction are receiving increasing attention of the chemical community in recent years.17

However, at the outset of our studies the synthesis of the Nbenzylimines 5 derived from acylphosphonates 1 seemed particularly challenging (Scheme 3). The literature search showed that the availability of such a system is quite limited presumably due to the liability of the C-P bond in acylphosphonates 1 that manifests during the formation of the imine 5. Initial addition of the amine 2 to phosphonate 1 yields tetrahedral intermediate that can further react according to two different reaction pathways. Elimination of the water molecule yields desired imine 5 (Scheme 3, route a). However, at this stage the cleavage of the C-P bond can also occur to give the corresponding amide 8 and H-phosphonate 9 as products (Scheme 3, route b). Therefore, in order to develop an efficient and biomimetic approach to α-aminophosphonates 3 studies on the condensation reaction between 1 and 2 were undertaken.