Total synthesis of chloropeptin II (complestatin) and chloropeptin I.
The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.
Garfunkle
Joie
J
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Kimball
F Scott
FS
Trzupek
John D
JD
Takizawa
Shinobu
S
Shimamura
Hiroyuki
H
Tomishima
Masaki
M
Boger
Dale L
DL
D002733:Chlorophenols / Q000138:chemical synthesis*; D003500:Cyclization; D007211:Indoles / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
D002733:Chlorophenols; D007211:Indoles; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; C090485:chloropeptin I; C023490:complestatin; C030374:indole