Spiruchostatins A (1) and B (2), isolated from a culture broth Pseudomonas sp. by Shinya and co-workers in 2001, exhibit potent histone deacetylase (HDAC) inhibitor. A closely related depsipeptide FK228 (3), a powerful HDAC inhibitor, was previously isolated from Chromobacterium violaceum by Fujisawa Pharmaceutical Co. Ltd.. Therefore, these natural products are expected to be promising candidates for novel molecular-targeted anti cancer agents. The attractive biological activities and unique structural features prompted us to undertake the total syntheses of 1, 2 and 3. We envisioned that spiruchostatin A (1) would be elaborated through the disulfide bond formation of 4. Macrocyclic compound 4 can be synthesized through macrolactonization of seco-acid 5. The synthesis began with the preparation of intermediate 20, the substrate for the key macrolactonization. Coupling product 20 was efficiently prepared from 6 with 7 using a combination of HATU and HOAt at low temperature. After deprotection of the PMB and allyl groups, seco-acid 5 was obtained. The critical macrolactonization of 5 was best achieved by employing the Shiina protocol (MNBA and DMAP in CH_2Cl_2 at rt). Finally, disulfide bond formation by exposure to iodine followed by deprotection of TBS group completed the total synthesis of 1. Total synthesis of spiruchostatin B (2) has not yet been mentioned in the literature, and the stereochemistry at C5" of 2 has not clearly assigned. Therefore, we attempted determination of C5" configuration in 2; segment (5S)-22 would be produced through condensation of D-allo-isoleucine 21a with D-cysteine derivative. Finally, synthetic product 2 was prepared in a similar manner as 1 (22+7→→23→→2), and C5" stereochemistry of 2 was determined to be (S)-configuration. We envisioned that FK228 (3) would be constructed efficiently from the coupling reaction of two segments 24 with 25 followed by macrolactonization and disulfide bond formation. Initial attempts to achieve the pivotal macrolactonization of seco acid 15-epi-26 under usual Shiina conditions failed. After screening several reaction conditions, we solved this problem using Mitsunobu conditions, producing the desired 16-membered depsipeptide 27(26→27). Finally disulfide bond formation produced the target 3, whose spectroscopic properties were identical with those of natural product 3. In conclusion, we have accomplished total synthesis of spiruchostatin A (1), B (2), and FK228 (3) in a convergent manner. The C5" stereochemistry of 2 was determined to be (S)-configuration by the present synthesis.
