tert-Butoxycarbonyl-D-leucine → tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate

HRID 2363539Notes

Reaction equation

HRID 2363539 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][NH:32][CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C2N=NNC=2C=CC=1.CC[N+](CCCN(C)C)=C=N>ClCCl>[CH:35]1([CH:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][N:32]([C:14](=[O:16])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1

Participants

6

Reactant 4

HCID 637604tert-Butoxycarbonyl-D-leucineHCID 218833923-(Dimethylamino)propyl-ethyl-(iminomethylidene)azaniumHCID 546741702,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamideHCID 178418300HCID 178418300, compound

Product 1

HCID 131729483tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

N-(tert-Butoxycarbonyl)-D-leucine (72.7 mg, 0.314 mmol), 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (95 mg, 0.286 mmol) from Example 74, and hydroxybenzotriazole (48.1 mg, 0.314 mmol) were combined in dichloromethane (10 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.056 mL, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water. The separated organic layer was reduced in volume, and the crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) and eluted first with 10% to 100% ethyl acetate/hexanes and then with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26 (dd, J=7.2, 24.0, 1H), 7.91 (d, J=8.6, 1H), 4.48-4.36 (m, 1H), 4.12-3.96 (m, 1H), 3.87 (dd, J=7.4, 10.3, 1H), 3.70 (ddd, J=8.0, 14.4, 23.7, 1H), 3.40 (dd, J=5.7, 12.3, 1H), 2.77 (s, 1H), 2.58 (d, J=6.1, 1H), 2.08 (s, 1H), 2.01 (dd, J=5.6, 10.4, 2H), 1.96-1.55 (m, 17H), 1.54-1.50 (m, 9H), 1.49-1.37 (m, 2H), 1.19 (qdd, J=12.3, 22.3, 24.7, 11H), 1.00 (t, J=6.6, 3H), 0.88 (d, J=6.6, 1H).

Workup

  1. customThe reaction was quenched with water
  2. washeluted first with 10% to 100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-39311ebe21464ef79acca969e5276c49
Source dataset
uspto-grants-2014_04
Patent number
US08691865B2

Reaction notes

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