A Flexible Asymmetric Approach to Methyl 5‐Alkyltetramates and Its Application in the Synthesis of Cytotoxic Marine Natural Product Belamide A

Abstract

By using a methyl tetramate derivative (R)- or (S)-9 as a novel chiral building block, a direct, flexible, and highly enantioselective approach to methyl (R)- or (S)-5-alkyltetramates (2) is disclosed. Among the synthesized methyl 5-alkyltetramates 2, methyl 5-methyltetramate (2 a) is found in cytotoxic mirabimide E (4) and dysideapyrrolidone (5), and methyl 5-benzyltetramate (2 g) is a substructure in the potent antineoplastic dolastatin 15 (3). On the basis of this method, the first asymmetric synthesis of the antimitotic tetrapeptide belamide A (7) has been achieved in seven steps from (S)-9, with an overall yield of 23.8 %. Not only have the structure and absolute configuration of (+)-belamide A (7) been confirmed, but also the solvent used for recording the (13) C NMR spectrum, the (13) C NMR spectrum data correlation, and optical rotation data of natural belamide A (7) have been revised.

Naturally occurring tetramic acid products: isolation, structure elucidation and biological activity

“…154 All amino acids of 150 were assigned as L-congurations following hydrolysate analysis with chiral HPLC and these stereochemical assignments were later validated by asymmetric total synthesis of 152. 154,155 Compound 152 was found to be cytotoxic to MCF7 and HCT-116 cell lines with IC 50 values of 1.6 mM and 0.74 mM, respectively. In addition, 152 showed classic microtubule depolymerizing effects toward A-10 cells at 20 mM.…”

Studies toward the Synthesis of Smenamide A, an Antiproliferative Metabolite from Smenospongia aurea: Total Synthesis of ent-Smenamide A and 16-epi-Smenamide A

“…The optical rotation measured for this material well matched the reported value ([α] D = −62.3; lit. −63), 22 indicating its high enantiopurity.…”

“…103–104 22 ]; [α] D 20 = −62.3 ( c = 1.0, CHCl 3 ) [lit. −63.0 ( c = 1.0, CHCl 3 ) 22 ]; IR (neat) ν max : 3238, 3030, 2939, 2848, 1683, 1623, 1497, 1455, 1365, 1344, 1232, 989, 806, 700 cm –1 ; 1 H NMR: (400 MHz, CDCl 3 ): δ 7.32–7.20 (3H, m, ArH), 7.14 (2H, d, J = 7.1, ArH), 5.6 (br s, NH), 5.04 (1H, s, H-10), 4.33 (1H, m, H-8), 3.83 (3H, s, OCH 3 ), 3.17 (1H, dd, J = 13.7, 3.4, H a -7), 2.78 (1H, dd, J = 13.7, 7.6, H b -7); 13 C NMR (100 MHz, CDCl 3 ) δ 177.2, 173.7, 136.3, 129.1, 128.4, 126.8, 94.0, 58.4, 58.1, 38.3. HRMS (ESI) m / z calcd for C 12 H 14 NO 2 [M + H] + 204.1019; found 204.1011.…”

Conformationally Assisted Lactamizations for the Synthesis of Symmetrical and Unsymmetrical Bis-2,5-diketopiperazines

“…Cyclization of 18a – e occurred under conditions similar to those used for the cyclization of 4a – c and gave the desired bis-2,5-DPKs 19a – e in yields of 72–88% (Scheme , Table ). Samples 19a – e (Table ) showed the advantage of our base-assisted lactamization of open chain N -Cbz-protected peptidoyl benzotriazolides for synthesis of DKPs derivatives since direct lactamization of N -protected dipetides to form DKPs using peptide coupling reagents often requires harsh conditions, ,, and the deprotection/cyclization strategy can lead to extended procedures and lower yields. , …”