Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

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1 Journal Club (3) Tomoya akamura Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic Justin T. Malinowski, Robert J. Sharpe, Jeffrey S. Johnson Science 03, 30, Introduction -. Pactamycin Ø Pactamycin (Figure ) was isolated from Streptomyces pactum var. pactum in 96 by Argoudelis et al.. Ø The bioactivity profile of pactamycin is notable; it displays antitumor property. Ø owever, pactamycin s therapeutic benefits have yet to be realized due to its high cytotoxicity. Reducing cytotoxicity is necessary for medicinal application. Ø Genetic engineering studies have reignited its possibility for medicinal application; 7-deoxy and 8 -hydroxy derivatives displayed diminished cytotoxicity. An efficient synthesis platform of pactamycin and its derivatives is needed. 7 () 3 () 8'' Figure. Pactamycin. Four functional groups are attached to cyclopentane core. -. Previous work Ø 3-step total synthesis of pactamycin was realized by anessian and co-workers (Scheme ). 3 Scheme. 3-step total synthesis of pactamycine by anessian and co-workers. C PMP 7 steps TBDPS 6 steps 3 TBDPS 3 PMP PMP = TBDPS = Si t Bu () PMBz 7 () steps 3 steps 3 7 () 3 () () Ø Stepwise construction of functional groups. It is difficult to apply this methodology to the synthesis of other derivatives. A more practical synthesis solution is needed.

2 Journal Club (3) Tomoya akamura -3. This work Ø -step total synthesis of pactamycin was achieved. Ø Modular construction (Figure ); after the formation of the cyclopentanone structure (a core skeleton of pactamycin), four functional groups were introduced. Easily applicable to the synthesis of other derivatives! 3 R R 3 () X R () Figure. Modular introduction of functionality. -. Author s strategy symmmetrical substituents (a) (b) reduction 3 achiral 3 Mannich reaction pactamycin Bn Figure 3. (a) Authors choice of starting material. (b) Mannich addition and reduction steps. Ø As a starting material for the asymmetric synthesis of pactamycin, authors chose a symmetrical α-ureido-,-pentanedione as a starting material (Figure 3). Ø In the C C bond construction (Mannich reaction), diastereoselectivity considerations are prevented due to the symmetrical methyl ketone substituents at C center. They could focus on the enantioselective C amino incorporation in Mannnich reaction. Ø Diastereoselective diketone monoreduction provides the cyclopentane skeleton of Pactamycin. Argoudelis, A. D., et al. Antimicrob. Agents Chemother. 96, 96, () Iwasaki, M., et al. Antibiot. 0, 6, anessian, S., et al. J. rg. Chem. 0, 77,

3 Journal Club (3) Tomoya akamura. Results and Discussion -. Formation of cyclopentanone core structure Scheme. Formation of cyclopentanone core structure. + 3 (. equiv.) Bn 7 (0 mol%) 78 C to 6 C, -36 h intermolecular Mannich reaction TBSTf (. equiv.),6-lutidine (3.0 equiv.) 78 C, 30 min TBS protection Bn 6 88% R TBS Bn 70% 98: er attack from back side LTBA = LiAl( t Bu) 3 LTBA (.0 equiv.) 3 C, h monoreduction LDA (3. equiv.) C (. equiv.) 78 C to C, h intermolecular aldol reaction S 7 R R Bn 7% Bn 8 70% TBS TBS = Si t Bu Tf = S,6-lutidine = LDA = CF 3 Li TBS TBS 3 78 C, - min S (0.0 equiv.) 78 C to rt, h ozonolysis to form aldehyde a (3.0 equiv.) Bn 0 C, 30 min Bn 9 0 0% ( steps) intramolecular aldol reaction TBS TBS (80 equiv.) a ( equiv.) / (7/) 0 C, h nucleophilic epoxidation Bn 8% TBDPSCl (3.0 equiv.) Et 3 (3.0 equiv.) DMAP (0 mol%) 0 C to rt, 8 h TBDPS protection TBDPS 76% Bn TBDPS = Si t Bu DMAP = Crucial branch point for the synthesis of derivertives! Ø (intermolecular Mannich reaction): Mannich product was obtained in (R) conformation at C- (98: enantiomeric ratio) because diketone and catalyst form complex (Figure ). Ø (monoreduction): The monoreduction of diketone proceeded with high diastereoselectivity. (R,R,7S)-product was selectively obtained, probably because of the between and atoms and steric hindrance. 3 Figure. A complex formed by diketone and catalyst 7.

4 Journal Club (3) Tomoya akamura Ø 9 0 (intramolecular aldol reaction): C stereocenter was inverted during the cylization to form the correct C isomer, probably because the formed isomer can be stabilized by the between and atoms. Ø 0 (nucleophilic epoxidation): ucleophilic epoxidation proceeded with high diastereoselectivity, probably because of the between and atoms. -. Modular introduction of functionality to complete the synthesis of pactamycin Scheme 3. Modular introduction of functionality to complete the synthesis of pactamycin. bulky attack from front side bulky TBS TBS attack to TBS this point TBDPS TBDPS TBDPS 7 (0.0 equiv.) MgBr (0.0 equiv.) Sc(Tf) 3 (3.0 equiv.) () () () Bn 0 C, h Bn 60 C, h Bn 76% nucleophilic addition 3 7% sterically hindered ring opening of epoxide () 66% TBAF (.0 equiv.) 0 C, 30 min primary alcohol deprotection of TBS and TBDPS 8 (. equiv.) K C 3 (.0 equiv.) () DMA () Bn 0 C, 3 h Bn () acylation () 90% C 6 80% TBAF = n Bu F Pd() /C (0.8 equiv.) ( atm) rt, 0 min () DMA = deprotection of CBn () 8% Ø 3 (nucleophilic addition): Because of the sterically demanding TBDPS group, Grinard reagent attacks from the front side. Ø 3 (ring opening of epoxide): Because of the sterically demanding TBDPS group, 3-acetylaniline 7 attacks the less hindered side of epoxide. Ø 6 (acylation): nly a highly reactive primary alcohol was acylated. 3. Conclusion Ø The authors achieved the total synthesis of pactamycin in steps and.9% overall yield. Ø The modular construction enables the synthesis and investigation of pactamycin derivatives.

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