Synthesis of the Tetrahydroisoquinoline Alkaloid (±)-Renieramycin G and a (±)-Lemonomycinone Analogue from a Common Intermediate

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1 Synthesis of the Tetrahydroisoquinoline Alkaloid (±)-Renieramycin G and a (±)-Lemonomycinone Analogue from a Common Intermediate Philip Magnus* and Kenneth S. Matthews Department of Chemistry and Biochemistry, University of Texas at Austin J. Am Chem. Soc. 2005, ASAP. (±)-Renieramycin G (±)-Lemonomycinone amide Shinya Wipf Group 1 9/4/2005

2 Tetrahydroisoquinoline Antitumor Antibiotics The tetrahydroquinoline family of antitumor antibiotics has been studied since naphthriydinomycin was isolated in 1974 by Kluepfel et al. The two core structures of this family are the quinone A and the aromatic core B. To date, nearly 60 natural products in this family have been isolated, and hundreds of synthetic analogues have been reported. A B Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, Shinya Wipf Group 2 9/4/2005

3 Tetrahydroisoquinoline Antitumor Antibiotics Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, Shinya Wipf Group 3 9/4/2005

4 Tetrahydroisoquinoline Antitumor Antibiotics Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, Shinya Wipf Group 4 9/4/2005

5 Renieramycins: Isolation and Biological Activity Renieramycines are isolated from various marine sponges belonging to genera Reniera, Xestospongia, aliclona, Cribrochalina, and eopetrosia. The ring systems and their relative stereochemistry are identical with those of saframycins which exhibit strong cytotoxicity against cultured cells and antitumor activity against several experimental tumors. Renieramycins A D, and have moderate antimicrobial activities. Renieramycin G has cytotoxicity against human cancer cells with MIC values of 0.5 and 1.0 µg/ml against KB and LoVo cell lines, respectively. Shinya Wipf Group 5 9/4/2005

6 Total Synthesis of Renieramycins Fukuyama: First Total Synthesis of (±)-Renieramycin A C Bn Ac Ac C MM R Bn Cbz MM R Bn R R Pictet Spengler 29 steps from 0.5% overall yield C Fukuyama, T. et al. Tetrahedron Lett. 1990, 31, Shinya Wipf Group 6 9/4/2005

7 Total Synthesis of Renieramycins Danishefsky: First Asymmetric Total Synthesis of Cribrostatin IV (Renieramycin ) C Pomeranz Fritsch C yclization R C R PG R R PG R R Lynchpin Mannich Cyclization C 2 R PG R R R 32 steps from 1.7% overall yield C Danishefsky, S. J. et al. J. Am. Chem. Soc. 2005, 127, Shinya Wipf Group 7 9/4/2005

8 Total Synthesis of Renieramycins Williams: First Asymmetric Total Synthesis of ( )-Renieramycin G C 2 I Bn Ph Ph Boc Ph Ph Boc Bn Pictet Spengler R R R R R R C R R R Intramolecular Pictet Spengler R R 23 steps from 7.9% overall yield C 2 Bn Williams, R. M. et al. J. Am. Chem. Soc. 2005, ASAP. Shinya Wipf Group 8 9/4/2005

9 Lemonomycin: Isolation and Biological Activity Lemonomycin was isolated in 1964 from Streptomyces candidus. owever, the structure was not elucidated until Lemonomycin contains the unusual aldehyde hydrate and the sugar moiety, and is the only member in this family of tetrahydroisoquinoline antibiotics. Lemonomycin has interesting antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, as well as cytotoxicity against a human colon tumor cell line. Shinya Wipf Group 9 9/4/2005

10 Total Synthesis of Lemonomycin Stoltz: First Asymmetric Total Synthesis of ( )-Lemonomycin Bn Xc PG B I R TIPS R TIPS C Pictet Spengler 2 15 steps from 3.1% overall yield 2 Stoltz, B. M. et al. J. Am. Chem. Soc. 2003, 125, Shinya Wipf Group 10 9/4/2005 Bn Br

11 ew Strategy for the 1,3-cis-Substituted Tetrahydroisoquinolines Pictet Spengler Approach C1 ucleophilic Addition Approach β α Magnus, P. et al. rg. Lett. 2003, 5, Shinya Wipf Group 11 9/4/2005

12 Synthesis of Common Intermediate Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP. Shinya Wipf Group 12 9/4/2005

13 (±)-Renieramycin G Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP. Shinya Wipf Group 13 9/4/2005

14 (±)-Lemonomycinone Amide Magnus, P. et al. J. Am. Chem. Soc. 2005, ASAP. Shinya Wipf Group 14 9/4/2005

15 Summary A general approach to both mono- and bistetrahydroisoquinoline alkaloids from a common advanced intermediate has been developed. Bn I t Bu 32% yield (10 steps) Bn SPh Boc Bn 18% yield (8 steps) (±)-Renieramycin G Bn TIPS Bn Bn 16% yield (9 steps) (±)-Lemonomycinone amide Shinya Wipf Group 15 9/4/2005