Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B)

Academic Article
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related to degree

  • Breazzano, Steven Philip, Ph.D. in Organic Chemistry, Scripps Research 2009 - 2013

publication date

  • 2011

abstract

  • Recently, we reported the first total synthesis of chloropeptin II (1, complestatin), the more strained and challenging of the two naturally occurring chloropeptins. Central to the design of the approach and by virtue of a single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II to chloropeptin I, the route also provided a total synthesis of chloropeptin I. Herein, we report a complementary and divergent oxidation of chloropeptin II (1, complestatin) to either complestatin A (2, neuroprotectin A) or complestatin B (3, neuroprotectin B), providing the first synthesis of the natural products and establishing their remaining stereochemical assignments. Key to the approach to complestatin A (2, neuroprotectin A) was the development of two different single-step indole oxidations (HCl-DMSO and NBS, THF-H(2)O) that avoid the rearrangement of chloropeptin II (1) to chloropeptin I (4), providing the 2-oxindole 2 in superb yields (93% and 82%). With a mechanistic understanding of features that impact the latter oxidation and an appreciation of the intrinsic reactivity of the chloropeptin II indole, its modification (NCS, THF-H(2)O; Cs(2)CO(3), DMF-H(2)O) provided a two-step, single-pot oxidation of chloropeptin II (1) to afford directly the 3-hydroxy-2-oxindole complestatin B (3, neuroprotectin B). Extensive studies conducted on the fully functionalized synthetic DEF ring system of chloropeptin II were key to the unambiguous assignment of the stereochemistry as well as the exploration and subsequent development of the mild oxidation conditions used in the synthesis of complestatin A and B.