Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of (R)- and (S)-N-Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected (R)- and (S)-2,3-diaminopropylphosphonates were synthesized from (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of (R)- and (S)-2-(N-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of (R)- and (S)-2-(N-Bn-amino)-3-acetoxypropylphosphonates.


Introduction
The usefulness of aziridines for both organic and medicinal chemistry has been intensively explored over the decades [1][2][3][4][5][6][7][8][9][10][11]. The aziridine ring has been found in the structure of biologically relevant compounds, such as naturally occurring mitomycins A, B, C 1-3 [12,13], porfiromycin 4 [14], azinomycins A and B 5-6 [15] showing antiproliferative activity or ficellomycin 7 [16] exhibiting antibacterial activity ( Figure 1). On the other hand, C-substituted aziridines can serve as useful building blocks for the synthesis of a wide range of various compounds containing amino functions, e.g., amino acids, amino alcohols, and diamines. Due to the high strain of the three-membered ring, aziridines readily undergo highly regio-and stereospecific ring-opening reactions with a broad spectrum of nucleophiles that makes them powerful tools in synthetic chemistry. However, the regioselectivity of the ring-opening of functionalized aziridines depends on the nature of the substituent attached to the nitrogen atom [17]. In general, activated aziridines, i.e., aziridines bearing an electro-withdrawing group at nitrogen e.g., acyl, sulfonyl, or phosphoryl, undergo ring cleavage reactions on the less-hindered carbon atom under relatively mild conditions. The second class of aziridines constitutes non-activated aziridines that possess an electron-donating substituent e.g., alkyl group and they must be activated by the formation of aziridinium ion or its equivalent prior to ring opening while regioselectivity of these reactions depends on the nature of nucleophile, electrophile, and substituent present at the C2 position [8]. Among the large variety of structurally diverse compounds containing an aziridine framework, aziridinephosphonates are of special interest. Due to the presence of both an aziridine ring and a phosphonic function which mimics the carboxylate group from amino acids, they can exhibit interesting biological properties. For example, compounds 8, 9a, and 10 have been reported to possess high antibacterial activity, comparable with Ampicillin and Streptomycin [18], whereas aziridines 9b and 11-12 were found active against  colon cancer cells ( Figure 2) [19]. On the other hand, aziridinephosphonates can be successfully employed as convenient substrates for the synthesis of aminophosphonates, which have attracted tremendous importance in medicinal chemistry as they are structurally related to amino acids and thereby can act as false substrates or inhibitors for enzymes or receptors [20][21][22]. Among the various functionalized phosphonates, α-amino and β-aminophosphonates belong to the well-studied group of compounds. Over decades, numerous phosphonate analogs of amino acids have been synthesized and found application in both organic and medicinal chemistry, including the preparation of more complex compounds ( Figure 3). For example, 3-aminopropylphosphonic acid 13  is an agonist of GABAB receptor [23], while L-2-amino- 4-phosphonobutyric acid 14 (L-AP4) was found to be a selective group III metabotropic glutamate receptor agonist that acts at mGlu4, mGlu8, mGlu6, and Among the large variety of structurally diverse compounds containing an aziridine framework, aziridinephosphonates are of special interest. Due to the presence of both an aziridine ring and a phosphonic function which mimics the carboxylate group from amino acids, they can exhibit interesting biological properties. For example, compounds 8, 9a, and 10 have been reported to possess high antibacterial activity, comparable with Ampicillin and Streptomycin [18], whereas aziridines 9b and 11-12 were found active against  colon cancer cells ( Figure 2) [19]. Among the large variety of structurally diverse compounds containing an aziridine framework, aziridinephosphonates are of special interest. Due to the presence of both an aziridine ring and a phosphonic function which mimics the carboxylate group from amino acids, they can exhibit interesting biological properties. For example, compounds 8, 9a, and 10 have been reported to possess high antibacterial activity, comparable with Ampicillin and Streptomycin [18], whereas aziridines 9b and 11-12 were found active against  colon cancer cells ( Figure 2) [19]. On the other hand, aziridinephosphonates can be successfully employed as convenient substrates for the synthesis of aminophosphonates, which have attracted tremendous importance in medicinal chemistry as they are structurally related to amino acids and thereby can act as false substrates or inhibitors for enzymes or receptors [20][21][22]. Among the various functionalized phosphonates, α-amino and β-aminophosphonates belong to the well-studied group of compounds. Over decades, numerous phosphonate analogs of amino acids have been synthesized and found application in both organic and medicinal chemistry, including the preparation of more complex compounds ( Figure 3). For example, 3-aminopropylphosphonic acid 13  is an agonist of GABAB receptor [23], while L-2-amino- 4-phosphonobutyric acid 14 (L-AP4) was found to be a selective group III metabotropic glutamate receptor agonist that acts at mGlu4, mGlu8, mGlu6, and On the other hand, aziridinephosphonates can be successfully employed as convenient substrates for the synthesis of aminophosphonates, which have attracted tremendous importance in medicinal chemistry as they are structurally related to amino acids and thereby can act as false substrates or inhibitors for enzymes or receptors [20][21][22]. Among the various functionalized phosphonates, α-amino and β-aminophosphonates belong to the well-studied group of compounds. Over decades, numerous phosphonate analogs of amino acids have been synthesized and found application in both organic and medicinal chemistry, including the preparation of more complex compounds ( Figure 3). For example, 3-aminopropylphosphonic acid 13 (3-APPA) is an agonist of GABA B receptor [23], while L-2-amino-4-phosphonobutyric acid 14 (L-AP4) was found to be a selective group III metabotropic glutamate receptor agonist that acts at mGlu4, mGlu8, mGlu6, and mGlu7 receptors [24]. Compounds 15 have been designed as phosphonate analogs of homoserine, an important amino acid involved in physiologically relevant transformation [25]. Phosphonate proline analogs 16 were found to serve as chiral catalysts for aldol reaction [26], and some of them have exhibited promising biological activity when incorporated in phosphonodipeptide structures [27].

General Information
The 1 H, 13 C, and 31 P NMR spectra were taken in CDCl 3 on the Bruker Avance III spectrometers (600 MHz) with TMS as the internal standard at 600, 151, and 243 MHz, respectively. Coupling constants J are given in Hz. The IR spectra were measured on an Infinity MI-60 FT-IR spectrometer. Melting points were determined on a Boetius apparatus and were uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of this faculty on Perkin-Elmer PE 2400 CHNS analyzer, and their results were found to be in good agreement (±0.3%) with the calculated values. Polarimetric measurements were conducted with an Optical Activity PolAAr 3001 apparatus. The HPLC separations were performed using a Waters HPLC system consisting of binary HPLC pump (Waters 2545), a diode array detector (Waters 2998) and an Chiralpack column AD, 0.46 × 25 cm with a particle size of 10 µm. The following adsorbents were used: column chromatography, Merck silica gel 60 (70-230 mesh), analytical TLC, and Merck TLC plastic sheets silica gel 60 F254. The TLC plates were developed in chloroform-methanol, dichloromethanemethanol and hexane-isopropanol solvent systems. Visualization of spots was achieved with iodine vapors. All solvents were purified by methods described in the literature. 2,3-Epoxypropylphosphonates 30 [59,62], 3-azido-2-hydroxypropylphosphonates 31 [53] and (aziridin-2-yl)methylphosphonates 33 [54] were obtained according to procedures described in the literature.
The 1 H-, 13 C-and 31 P-NMR spectra of all newly synthesized compounds are provided in Supplementary Materials.

Conclusions
Racemic and enantiomerically enriched (aziridin-2-yl)methylphosphonates 33 were transformed into N-protected derivatives 24 (N-Boc) and 25 (N-Bn), which were then used as convenient substrates for the synthesis of propylphosphonates respectively functionalized with amino and hydroxyl groups at C2 and C3.
While catalytic hydrogenation of N-Boc-aziridine 24 gave diethyl 2-(tert-butoxycarbonylamino)propylphosphonate 26 as a single product, nucleophilic ring-opening reactions in 24 with both trimethylsilyl azide and acetic acid occurred at C2 and C3 atoms of the aziridine ring leading to the formation of two regioismers, i.e., 2-amino- 3