Asymmetric Total Synthesis of the Epothilone Sagopilone – From Research to Development

Abstract

We describe our successful efforts for the translation of our research strategy that was focused on a broad structural modification of the natural product epothilone B, to the production of the distinct drug candidate sagopilone in a kg scale. By a direct comparison of the research and development procedures we address some important aspects to be considered for an up-scaling process.

1 Introduction and Concept

2 Preparation of Building Block A

2.1 Research Sequence A1––A3–A4–A5–A6–A7–A8–A9– A10–(A12–)A13

2.2 Development Sequence A11–A12–A13

3 Preparation of Building Block B

3.1 Research Sequence B1–B2–B3–B4–(B6–B7)–B9–B10

3.2 Development Sequence B1–B2–B3–B4–B5–B8–B10

4 Preparation of Building Block C

4.1 Research Sequence C1–C2–C3–C4–C6–C7–C9–C10–C11–C12

4.2 Development Sequence C1–C2–C5–C8–C9–C10–C11–C12

5 Preparation of Building Block BC

5.1 Research

5.2 Development

6 Preparation of the Final Sequence ABC

6.1 Research

6.2 Development

7 Summary

Key words

sagopilone - epothilone - natural product - asymmetric synthesis - macrocycles

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