1987年由Rithner團隊在Streptomyces achromogenes中所分離出三種化合物，兩種具有抗菌活性的已知化合物Tomaymycin和Oxotomaymycin為具有吡咯 [1,4] 苯二氮平 (pyrrolo[1,4]benzodiazepines, PBDs) 骨架的生物鹼，第三種為本篇主要化合物PD 125375。PD 125375具有5-6-5三環結構且含有兩個連續的手性中心，在吡咯烷上具有一個E組態的2-亞乙基吡咯烷取代，而結構與Tomaymycin類似。雖然PD 125375與Tomaymycin皆有2-亞乙基吡咯烷的結構，但PD 125375的生物合成途徑及全合成尚未被研究。
本篇論文對PD 125375的三環核心結構的合成特別感興趣。在此已經開發了一種簡明的策略，咪唑羰基脯氨醇衍生物和吡咯在DBU的催化下進行偶合反應得到脯氨酸–吡咯偶聯產物。在經由保護基團的操作後，用IBX將伯醇氧化成醛。出乎意料的是，醛化合物直接進行分子內的佛瑞德–克來福特反應，得到了三環化合物。5-6-5三環核心結構可以在5個合成步驟中得到單一立體異構體。

PD 125375 and the well-known antibiotic Tomaymycin, a pyrrolobenzodiazepine (PBD) alkaloid, were isolated from the Streptomyces achromogenes and characterized by C. Rithner. It has a 5-6-5 tricyclic core with two contiguous chiral carbons, as well as the E-form of 2-ethylidene on the pyrrolidine ring, which was structurally related to Tomaymycin. Although the novel structure of PD 125375 includes the 2-ethylidenepyrrolidine moiety also present in Tomaymycin, the biosynthetic pathway leading to PD 125375 has not been studied.
We were particularly interested in the synthesis of the tricyclic core structure of PD 125375. We have developed a concise strategy to synthesize the proline-pyrrole coupled product from N-(1-imidazolylcarbonyl)prolinol derivative and pyrrole under the catalysis of DBU. After protecting group manipulations, the oxidation of primary alcohol to aldehyde was accomplished with IBX. Unexpectedly, the oxidized adduct underwent concomitant intramolecular Friedel-Crafts reaction to afford the ring-closure product. The 5-6-5 tricyclic core could be obtained as a single stereoisomer in 5 synthetic steps.

1.Procópio, R. E.; Silva, I. R.; Martins, M. K.; Azevedo, J. L.; Araújo, J. M. Brazilian. J. Infect. Dis. 2012, 5, 466–471.
2.Rithner, C. D.; Bunge, R. H.; Bloem, R. J.; French, J. C. J. Org. Chem. 1987, 52, 300–302.
3.Sakai, H.; Arima, K.; Kohsaka, M.; Tamura G.; Imanaka, H. J. Antibiot. 1972, 25, 437–444.
4.Kariyone, K.; Yazawa, H.; Kohsaka, M. Chem. Pharm. Bull. 1971, 19, 2289–2293.
5.Hurley, L. H. Acc. Chem. Res. 1980, 13, 263–269.
6.Braekman, J. C.; Daloze, D. S.; Stoller, C.; Van Soest, R.W. M. Biochem. Syst. Ecol. 1992, 20, 417–431.
7.Mostad, A.; Romming, C.; Storm, B. Acta. Chem. Scand. 1978, 9, 639–645.
8.Brazhnikova, M. G.; Konstantinova, N. V.; Mesentsev, A. S. J. Antibiot. 1972, 25, 668–673.
9.Hurley, L. H.; Thurston, D. E. Pharm. Res. 1984, 2, 52–59.
10.Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G. Bioorg. Med. Chem. Lett. 2003, 13, 3955–3958.
11.Hecht, S. M.; Leber, J. D.; Hoover, J. R. E.; Holden, K. G.; Johnson, R. K. J. Am. Chem. Soc. 1988, 110, 2992–2993.
12.Mesentsev, A. S.; Kuliaeva, V. V.; Rubashev, L. M. J. Antibiot. 1974, 27, 866–873.
13.Kuramoto, M.; Miyake, N.; Ishimaru, Y.; Ono, N.; Uno, H. Org. Lett. 2008, 10, 5465–5468.
14.Nanteuil, G. D.; Ahond, A.; Gulhem, J.; Poupat, C. Tetrahedron 1985, 41, 6019–6033.
15.Pettit, G. R.; McNulty, J.; Herald, D. L.; Doubek, D. L.; Chapuis, J.-C.; Schmidt, J. M.; Tackett, L. P.; Boyd, M. R. J. Nat. Prod. 1997, 60, 180–183.
16.Maximov, O. B.; Fedoreyev, S. A.; Utkina, N. K.; Ilyin, S. G.; Reshetnyak, M. V. Tetrahedron Lett. 1986, 27, 3177–3180.
17.Crews, P.; Gautschi, J. T.; Whitman, S; Holman, T. R. J. Nat. Prod. 2004, 67, 1256–1261.
18.Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001, 2001, 237–243.
19.Mourabit, A. A.; Travert, N. J. Am. Chem. Soc. 2004, 126, 10252–10253.
20.Takay, T.; Tozuka, Z. J. Antibiot. 1983, 36, 142–146.
21.Lippmaa, E.; Pehk, T. Org. Magn. Reson. 1970, 2, 581–604.
22.Takay, T.; Tozuka, Z.; Takasugi, H. J. Antibiot. 1983, 36, 276–282.
23.Rubiralta, M.; Lopez, I.; Diez, A. Tetrahedron 1996, 52, 8581–8600.
24.Sarpong, R.; Heller, S. T.; Schultz, E. E. Angew. Chem. Int. Ed. 2012, 51, 8304–8308.
25.Black, D. StC.; Mielczarek, M.; Bhadbhade, M.; Chen, R.; Kumar, N. Tetrahedron 2015, 71, 8925–8942.
26.Piggott, M. J.; Baell, J. B.; Rahmani, R., etc. J. Med. Chem. 2016, 59, 9686–9720.
27.Sumathi, S.; Balasubramanian, K. K.; Velavan, A. Org. Biomol. Chem. 2012, 10, 6420–6431.
28.Studer, A.; Chou, C. M.; Chatterjee, I. Angew. Chem. Int. Ed. 2011, 50, 8614–8617.
29.Choi, Y.; Chung, S. J.; Kim, M.; Gajulapati, K.; Kim, C.; Jung, H. Y.; Goo, J.; Lee, K.; Kaur, N.; Kang, H. J. Chem. Commun. 2012, 48, 11443–11445.
30.Bai, X.; Dang, Q.; Xiang, J.; Zhu, T. J. Org. Chem. 2010, 75, 8147–8154.
31.Nagasawa, K.; Iwata, M.; Kanoh, K.; Imaoka, T. Chem. Commun. 2014, 50, 6991–6994.
32.Alvarez, M.; Albericio, F.; Lorente, A.; Pla, D.; Canedo, L. M. J. Org. Chem. 2010, 75, 8508–8515.
33.蔣佳穎，國立臺灣師範大學碩士論文，106年
34.Nagasawa, K.; Iwata, M.; Kamijoh,Y.; Yamamoto, E.; Yamanaka, M. Org. Lett. 2017, 19, 420–423.
35.Jamieson, C.; Simpson, I.; Caldwell, N.; Campbell, P. S.; Potjewyd, F.; Watson, A. J. B. J. Org. Chem. 2014, 79, 9347–9354.
36.Boas, U.; Munch, H.; Hansen, J. S.; Pittelkow, M.; Christensen, J. B. Tetrahedron Letters 2008, 49, 3117–3119.
37.Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2329–2925.