Key words Gilmann reaction - Mitsunobu reaction - Yamaguchi esterification - amide coupling - total synthesis - jomthonic acid A
Actinomycetes are a major source of structurally diverse secondary metabolites that exhibit antagonism to Gram-positive bacteria. Igarashi and co-workers recently reported the isolation and characterization of the modified amino acid derivative jomthonic acid A (1 ; Figure [1 ]) from the culture broth of a soil-derived actinomycete of the genus Streptomyces sp. BB47.[2 ] Compound 1 contains four stereocenters and several unusual structural features, such as the 4-methyl-(2E ,4E )-hexa-2,4-dienoate and β-methylphenylalanine fragments. Jomthonic acid A exhibits antidiabetic and antiatherogenic activities against mouse ST-13 preadiopocytes and it also inhibits the differentiation of preadipocytes into mature adipocytes at 2–50 μM.
Figure 1
In continuation of our interest in the total synthesis of bioactive natural products,[3 ] we have developed a convergent synthesis of jomthonic acid A (1 ). Our retrosynthetic analysis of 1 (Scheme [1 ]) suggested that it might be derived from the amido ester 2 through deprotection followed by oxidation. Compound 2 might be prepared from 4-methylhexa-2,4-dienoic acid (3 ) and amino ester 4 through amide coupling.[4 ] Compound 4 might be assembled from azide 5 and alcohol 6 under Yamaguchi conditions.[5 ] Compound 5 might, in turn, be obtained from trans -cinnamyl alcohol (7 ) by epoxidation, regioselective ring opening of the epoxide with the Gilmann reagent, and Mitsunobu reaction followed by oxidation. Likewise, alcohol 6 might be obtained by Frater–Seebach alkylation of ethyl (3R )-3-hydroxybutanoate.[6 ]
Scheme 1 Retrosynthetic analysis of jomthonic acid A (1 )
Our synthetic approach began with commercially available trans -cinnamyl alcohol (7 ; Scheme [2 ]). This was converted into the chiral epoxy alcohol 9 in 87% yield by Sharpless asymmetric epoxidation. Regioselective ring opening of epoxide 9 with the Gilmann reagent gave diol 10 in 68% yield.[7 ] Next, selective protection of the primary hydroxy group of 1,2-diol 10 by TBDMSCl/imidazole/Bu2 SnO in CH2 Cl2 at 0 °C for two hours gave silyl ether 11 in 93% yield. Subsequently, 11 was converted into the corresponding azide 12 in 85% yield under Mitsunobu conditions by using diphenyl phosphorazidate (DPPA) and DIAD in anhydrous THF at 0 °C to room temperature.[8 ]
[9 ] Subsequent deprotection of silyl ether 12 with TBAF in THF afforded alcohol 13 (95% yield).[10 ] The purity of compound 13 was determined by LC/MS analysis, and the diastereomeric excess was found to be 98% (see Supporting Information). Compound 13 , on further oxidation with TEMPO and PhI(OAc)2 in CH2 Cl2 –H2 O (4:1) gave acid 5 in 93% yield.[11 ]
Scheme 2 Synthesis of fragment 5
In parallel, compound 6 , required for the Yamaguchi esterification, was prepared from commercially available ethyl (3R )-3-hydroxybutanoate (8 ; Scheme [3 ]). Frater–Seebach alkylation of 8 gave 1,3-diol 14 .[6 ]
[12 ] Selective protection of the primary hydroxy group of this 1,3-diol with TBDPSCl/imidazole/Bu2 SnO in CH2 Cl2 at 0 °C to room temperature gave silyl ether 6 in 93% yield.
Scheme 3 Synthesis of fragment 6
Having both coupling partners in hand, we performed a Yamaguchi esterification of acid 5 with silyl ether 6 to give the azide derivative 15 in 68% yield (Scheme [4 ]).[5 ]
[13 ] Reduction of azide 15 with H2 (1 atm) over Pd/C gave amine 4 in 90% yield. Compound 2 was obtained in 68% yield by O -(benzotriazol-1-yl)-N ,N ,N ′,N ′-tetramethyluronium tetrafluoroborate (TBTU)-mediated coupling of amine 4 with acid 3 , prepared from tiglic aldehyde by a reported procedure.[4 ]
[14 ] Subsequently, the silyl group was removed by treatment with HF·Py in CH3 CN at 0 °C to room temperature to afford the alcohol 16 in 85% yield.[15 ] Finally oxidation of 16 with TEMPO and PhI(OAc)2 in CH2 Cl2 –H2 O (4:1) gave the target compound 1 . Spectroscopic data for this product were consistent with the reported values.[2 ]
Scheme 4 Synthesis of jomthonic acid A (1 )
In conclusion, the first stereoselective total synthesis of jomthonic acid A was achieved by a convergent approach with an 8.0% overall yield by employing a Sharpless asymmetric epoxidation, a Gilmann reaction, a Mitsunobu azidation, hydrogenation, a Yamaguchi esterification, and amide coupling as the key steps.