Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates

Abstract

Imidazoline I₂ receptors (I₂-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I₂-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I₂-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I₂-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer's disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives.

Keywords: (pyrrolidine-2-yl)phosphonate; imidazoline I2 receptor ligand; phosphonic ester; phosphoproline; pyrroline; α-aminophosphonate.

Figure 1

I₂-IR ligands CR4056 and BU99008, with the imidazole/imidazoline nucleus in color.

Scheme 1

Outline of the previously reported work on representative B06, with the key reactions that led to access to B06red, BIN05, and PIP01 and significant in vivo results. General structures I and II of diversely substituted pyrrolidine-2-phosphonates reported in this work and key reactions.

Scheme 2

(a) General reaction to synthesize starting materials 1a–1g. (b) Reduction of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates 1a and 1b. (c) Reduction of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates 1c–1g. (d) X-ray structure of 2d. Reagents and conditions: i. AgOAc cat., CH₃CN, rt, overnight (Ref. [1]). ii. NaOH 0.05 M, THF/H₂O, rt, 2.5 h (Ref. [11]). iii. Pd/C 20%, isopropanol, 300 psi, rt, 8 h. iv. NaBH₃CN, CH₃CN/H₂O/AcOH, rt, 1 h.

Figure 2

Representative coupling constants (Hz): ¹H-P (blue), ¹H-¹H (pink) and ¹³C-P (green).

Scheme 3

Putative intermediates from the reaction of bicyclic iminophosphonates with Dowex Marathon-A resin in grey. (a) Resulting products from the hydrolysis and reduction of bicyclic iminophosphonates 3a–3e. (b) Synthesis of 5 containing a heavy atom (Br). (c) X-ray of compound 5. Reagents and conditions: i. Dowex Marathon-A resin, MeOH. ii. Dowex Marathon-A resin, MeOH and H₂, PtO₂ (cat), AcOH, rt 24 h or 48 h. iii. NaBH₃CN, MeOH, AcOH, 4-bromobenzaldehyde, rt, 2 h.

Figure 3

Representative coupling constants (Hz) ¹³C-P (green).

Figure 4

Structure of the four previously reported compounds B06, B06red, BIN05 and PIP01 (1e) and the two selected compounds, 2e and 4e, evaluated in this paper as I₂-IR ligands. Highlighted in blue is the α-phenyliminophosphonate moiety, and highlighted in orange is the α-phenylaminophosphonate moiety and in grey the monocycles.