[(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester: Synthesis and Application

Physicochemical property

[(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester has a boiling point of 320.8±31.0 °C. Its density is predicted to be 1.08±0.1 g/cm³. 

Synthetic routes

Fig. 1 The synthetic step 1 of [(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester.

Add ketone (100 mg) to a solution of tert-butyl (naphthalen-2-ylmethoxy)carbamate (568.7 mg) and cinchona-derived chiral bifunctional tetraalkylammonium bromide catalyst (92.1 mg, 0.104 mmol, 10 mol%) in toluene (2.97 mL, 0.35 M) at 0°C. Add 50% w/v aqueous KOH (0.14 mL, 1.248 mmol, 1.2 equivalents) and water (0.603 mL) to the reaction mixture. Stir the reaction mixture until the starting material is disappeared at 0°C. After the reaction is completed, dilute the reaction mixture with ethyl acetate (10 mL). Wash the reaction mixture with water (5 mL × 2). Dry the reaction mixture over anhydrous magnesium sulfate. Filter the reaction mixture. Concentrate the reaction mixture in vacuo. Purify the residue by column chromatography (silica gel, hexane:EtOAc = 5:1). ¹H NMR (400 MHz, CDCl₃) δ 7.82 (dd, J= 8.7, 5.9 Hz, 4H), 7.48 (td, J = 6.4, 3.4 Hz, 3H), 4.99 (dd, J = 24.2, 9.6 Hz, 2H), 4.67-4.74 (m, 1H), 2.35-2.46 (m, 3H), 2.09-2.29 (m, 3H), 1.55 (s, 9H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ 216.5, 157.3, 133.6, 133.4, 132.6, 129.0, 128.6, 128.3, 127.9, 127.2, 126.6, 126.5, 82.5, 79.1, 57.3, 41.7, 37.4, 28.6, 26.9 ppm [1].

Fig. 2 The synthetic step 2 of [(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester.

Add a solution of L-selectride (1M in THF, 0.46 mL, 1.2 equivalents) to a solution of tert-butyl (S)-(naphthalen-2-ylmethoxy)(3-oxocyclopentyl)carbamate (163.4 mg) in THF (2.4 mL) at -78°C. Stir the mixture for 2 hours. Stir the mixture at room temperature with sequential treatment of H₂O, methanol, 1N NaOH and H₂O₂ (30% solution in water). After 30 minutes of stirring, dilute the mixture with EtOAc. Wash the mixture with brine solution several times. Dry the combined organic layer over MgSO₄. Concentrate the combined organic layer in vacuo. Purify the residue by silica gel column chromatography (hexane:EtOAc = 3:1). ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.86 (m, 4H), 7.45-7.57 (m, 3H), 5.05 (q, J= 9.8 Hz, 2H), 4.44 (qd, J = 8.8, 5.2 Hz, 1H), 4.14-4.18 (m, 1H), 2.41 (s, 1H), 2.13-2.20 (m, 1H), 1.87-2.05 (m, 2H), 1.72-1.81 (m, 2H), 1.57-1.69 (m, 1H), 1.53-1.56 (m, 9H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ 157.3, 133.5, 133.3, 132.5, 128.9, 128.5, 128.2, 127.8, 127.1, 126.5, 126.3, 82.0, 78.9, 72.2, 60.1, 38.9, 34.8, 28.5, 26.4 ppm [1].

Fig. 3 The synthetic step 3 of [(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester.

Charge mixture of tert-butyl[(1R,3R)-3-hydroxycyclopentyl](naphthalen-2-ylmethoxy)carbamate (50 mg) with chloroacetic acid (14.5 mg, 1.1 equivalents) and triphenyl phosphine (40.4 mg, 1.1 equivalents) with argon. Add THF (1.4 mL) to the mixture. Cool the mixture to 0°C. Add diisopropyl azodicarboxylate (31.1mg, 1.1 equivalents) dropwise to the mixture. Stir the solution at room temperature for 4 hours until the starting material disappeared. Once the reaction is complete, concentrate the mixture in vacuo. Purify the resulting oil by silica gel column chromatography (hexane:EtOAc = 5:1). Concentrate the combined product in vacuo. Redissolve the combined product in methanol (1.4 mL). Add sodium carbonate (16.3mg, 1.1equivalents) to the solution. Stir the resulting mixture at room temperature for 2 hours. Concentrate the reaction mixture in vacuo. Dilute the reaction mixture with DCM. Wash the organic layer with saturated NaHCO3 solution. Dry the organic layer with MgSO4. Concentrate the organic layer under reduced pressure. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (dd, J= 5.5, 3.7 Hz, 4H), 7.46-7.53 (m, 3H), 5.01 (s, 2H), 4.66-4.73 (m, 1H), 4.37-4.41 (m, 1H), 1.98-2.08 (m, 3H), 1.73-1.87 (m, 2H), 1.55-1.58 (m, 1H), 1.53 (s, 9H) ppm. ¹³C NMR  (101 MHz, CDCl₃) δ 157.5, 133.4, 133.3, 133.1, 128.5, 128.3, 128.2, 127.8, 127.0, 126.4, 126.3, 81.7, 78.7, 72.7, 59.4, 38.2, 34.3, 28.5, 26.6 ppm [1].

Fig. 4 The synthetic step 4 of [(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester.

Add a catalytic amount of acetone-washed (5×1 mL) and Raney-Ni (4200; slurry in water; active catalyst) to a solution of tert-butyl[(1R,3S)-3-hydroxycyclopentyl](naphthalen-2-ylmethoxy)carbamate (156.6 mg) in EtOAc (2.5 mL). Stir the reaction mixture under hydrogen atmosphere at room temperature. Stir the mixture for 18 hours. Filter the reaction mixture through Celite pad. Wash the reaction mixture with EtOAc. Combine the filtrate and washings. Concentrate the filtrate. Purify the residue by silica gel column chromatography (hexane:EtOAc = 4:1) [1].

Application

As a synthetic intermediate for GCN2 inhibitors

[(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester is the intermediate of the synthesis of GCN2 inhibitors. General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors.  Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK.  In mice, compd. I engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID.  We also demonstrate the ability of compd. I to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice.  In the LL2 syngeneic mouse model, compd. I demonstrates significant tumor growth inhibition (TGI) as a single agent.  Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compd. I demonstrating the complementarity of these two mechanisms [2].

As a synthetic intermediate for a novel indole pharmacophore

Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been assocd. with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi).  However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. [(1R,3S)-3-Hydroxycyclopentyl]carbamic acid tert-butyl ester is the