Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

A new synthesis of the important amino acid 2-aminosuberic acid from aspartic acid is reported. The methodology involves the alternate preparation of (S)-2-aminohept-6-enoate ester as a building block and its diversification through a cross-metathesis reaction to prepare the title compounds. The utility of the protocol is demonstrated through the preparation of three suberic acid derivatives of relevance to the design and the synthesis of peptides of biological relevance.


(S)-tert-Butyl 4-(4-ethoxy-4-oxobutyl)-2,2-dimethyl-oxazolidine-3-carboxylate (6)
This was prepared in a manner similar as described in [27]. Palladium on charcoal (150 mg) was added portion wise to a stirring solution of the compound 5 (2.5 g, 7.94 mmol) in ethyl acetate (15 mL) at room temperature and the heterogeneous solution was stirred under hydrogen atmosphere for 6 h. It was then filtered through Celite and the filter cake was thoroughly washed with ethyl acetate (30 mL). The combined filtrate was concentrated in vacuo to furnish the product 6 as a colorless liquid.

(S)-tert-Butyl 4-(4-hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate (7)
To a stirred suspension of LiAlH 4 (0.673 g, 18.05 mmol) in dry THF (30 mL), a solution of the ester 6 (5.68 g, 18.05 mmol) in THF (20 mL) was added drop wise at 0 °C under nitrogen atmosphere. It was stirred for 2 h at room temperature and then quenched under ice-cold condition with saturated KOH solution. The reaction mixture was then filtered through celite and the filtrate was concentrated under reduced pressure to give colourless crude product which was purified by chromatography over silica using mixture of petroleum ether and ethyl acetate (4:1) as eluent to afford colourless oil 7.

(S)-tert-Butyl 2,2-dimethyl-4-(pent-4-enyl)oxazolidine-3-carboxylate (9)
To a cold (−78 °C) stirred solution of oxalyl chloride (0.25 mL, 2.90 mmol) in anhydrous CH 2 Cl 2 (10mL), anhydrous DMSO (0.41 mL, 5.19 mmol) was added over seven minutes under nitrogen atmosphere. The mixture was then allowed to warm to −60 °C over a period of 20 min. Then a solution of the alcohol 7 (500 mg, 1.92 mmol) in CH 2 Cl 2 (3 mL) was added drop wise over 13 minutes. The mixture was warmed to -45 °C over 30 minutes. A solution of N-methylmorpholine (1.1 mL, 11.41 mmol), in CH 2 Cl 2 (1 mL) was then added slowly. The mixture was allowed to warm to 0 °C and then transferred to a separating funnel charged with icecold 1 M HCl solution (25 mL) and CH 2 Cl 2 (30 mL). The two phases were separated. The organic phase was then successively washed with water (50 mL) and brine (40 mL). Resulting organic layer was dried over MgSO 4 and concentrate under reduced pressure to give the crude aldehyde 8, which was used for next step without purification.
The olefination of the aldehyde 8 was carried out as described in our earlier work [S1]. n-BuLi (2 M in hexane, 0.95 mL) was added dropwise over 10 min to a stirred suspension of the Wittig salt (MePh 3 P + Br − ) (696 mg, 1.94 mmol) in dry THF (2 mL) at 0 °C under argon atmosphere and the resulting solution was allowed to come to 10 °C over 30 min when the solution turned deep yellow. It was cooled to 0 °C and then a solution of the aldehyde 8 (350 mg, 1.29 mmol) in THF (5 mL) was added drop wise over 15 min while stirring. Stirring was continued at this condition for 30 min and then it was allowed to come to room temperature and further stirred for 3 h. The reaction mixture was then quenched with aqueous NH 4 Cl solution (5 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed successively with water (1×40 mL) and brine (1 × 40 mL), and then dried over MgSO 4 . It was then filtered and the filtrate was concentrated in vacuo to leave S6 the crude product which was purified by flash chromatography over silica gel using a mixture of ethyl acetatehexane (1:49) to give the product 9 as a colorless oil.

(S)-2-(tert-Butoxycarbonylamino)hept-6-enoic acid (10)
The oxidation was carried out in a similar manner as described by us [S1]. An aqueous solution of chromic acid (8 mL, 8 equiv) was added dropwise to a vigorously stirred solution of 9 (550 mg, 2.06 mmol) in acetone (10 mL) and stirring was continued for 2 h at rt. The reaction mixture was then quenched by isopropyl alcohol and the acetone was evaporated under reduced pressure. The resulting mixture was then poured into water (40 mL) and extracted with ether (3 × 25 mL).The organic layer was washed successively with water (3 × 20 mL), brine (30 mL) and then dried over MgSO 4 . It was filtered and the filtrate was concentrate to leave the crude product as a yellowish liquid, which on chromatographic purification over silica using petroleum ether/ethyl acetate (1:1) as eluent afforded the product 10 as a colorless liquid.
The organic extract was then dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to leave a crude product, which was purified by column chromatography on silica gel using ethyl acetate in petroleum ether (1:49) solvent provided the compound 11 as a colorless liquid.

General procedure of hydrogenation
This was carried out in a similar manner as described in [12]. Pd/C (30 mg) was added to a stirring solution of cross metathesis product 14a/14b/14c (0.50 mmol) in dry MeOH (5 mL). The resulting mixture was then stirred for 2 h at room temperature under hygrogen atmosphere. The reaction mixture was then filtered through celite, the filter cake was washed with methanol (5 mL) and the combined filtrate was concentrated in vacuo. The residue thus obtained was subjected to column chromatographic purification over silica gel using appropriate mixture of ethyl acetate in hexane to provide the hydrogenated product 15a-c respectively as colorless viscous liquids.