Enantioselective Syntheses of (-)-Kinamycin F and (-)-Lomaiviticin Aglycon

Abstract

Synthetic studies of the diazofluorene antitumor antibiotics, the kinamycins and lomaiviticins, are described.The kinamycins 1-3 and lomaiviticins 5, 6 constitute a unique family of bacterial metabolites with unusual molecular architectures and powerful anticancer and antimicrobial activities (Figure 1). 1 The kinamycins were first isolated in the early 1970s by Omura and co-workers. 2 Contributions from several research groups, 3 over a period of nearly 25 years, established their molecular structures and revealed the presence of a diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group, which had not been previously identified among natural products. Many different kinamycins are now known, and these are distinguished primarily by the acylation pattern about the oxygenated D-ring. Kinamycins A (1), 2 C (2), 2 and F (3) 4 are representative.In 2001, the C 2 -symmetric metabolites lomaiviticins A and B (5 and 6, respectively) were isolated in a collaborative effort by researchers at Wyeth and the University of Utah. 5 The lomaiviticins share the signature diazofluorene of the kinamycins, but several structural differences exist between the two classes of metabolites. Most notably, the two halves of the lomaiviticins are united by a single carbon-carbon bond (red in 5 and 6). Within lomaiviticin B (6), the tertiary (C-3/C-3′) hydroxyl groups have undergone 1,2-addition to the adjacent ketone functions, to form a rigid bis(tetrahydrofuranol) structure. Additional significant differences include the presence of dihydroxynaphthoquinone residues in the lomaiviticins (as opposed to a juglone residue in the kinamycins) and 2-4 2,6-dideoxyglycosides, a-oleandrose, and b-N,N-dimethylpyrrolosamine, about the periphery of the lomaiviticins.In 2008 our research group embarked on a journey to synthesize the kinamycins and lomaiviticins. Our studies have yielded a general route to the diazofluorene substructure, as well as syntheses of kinamycin F (3), 6 lomaiviticin aglycon (4), 7 and the carbohydrate residues 8 of the lomaiviticins. Prior to, and contemporaneous with, our own studies, several other groups have also advanced this area of research. The Porco, 9 Nicolaou, 10 and Ishikawa 11 research groups developed syntheses of several kinamycins, which preceded our work in this area. These investigations provided the first insights into the stability and reactivity of the diazofluorene functional group in multistep synthetic settings.

Synthetic Studies Directed toward Dideoxy Lomaiviticinone Lead to Unexpected 1,2-Oxazepine and Isoxazole Formation

“…2,3 Lomaiviticinone, the aglycone common to lomaiviticin A and B, was recently prepared by an 11-step synthesis reported by Herzon and co-workers. 4 As expected lomaiviticinone prepared by this route was isolated as a rigid polycyclic ring system formed by closure of the C3/C3’ tertiary alcohols onto the neighboring C1/C1’ keto groups (Figure 1). In anticipation of DNA cleavage studies, and simplified synthetic obstacles, we considered it advantageous to access C3/C3’ dideoxy lomaiviticinone, an aglycone with free-rotation about the C2-C2’ carbon-carbon bond as found in lomaiviticin A, the more abundant and studied of the two dimeric diazofluorene natural products.…”

“…The diazofluorene antitumor antibiotics lomaiviticins A and B have attracted considerable attention from the synthetic community due to their molecular complexity, potent cell cytotoxicity, and scarcity in nature. , Lomaiviticinone, the aglycone common to lomaiviticin A and B, was recently prepared by an 11-step synthesis reported by Herzon and co-workers . As expected lomaiviticinone prepared by this route was isolated as a rigid polycyclic ring system formed by closure of the C3/C3′ tertiary alcohols onto the neighboring C1/C1′ keto groups (Figure ).…”

“…7 , Scheme ). In this case we anticipated base-catalyzed addition of 7 to naphthazarin 1 under oxidative conditions would afford adduct 19 appropriately functionalized for an intramolecular Heck reaction as demonstrated by Herzon’s group . In the event, our plan was once again thwarted leading to a 46% yield of isoxazole quinone 18 without 19 being observed (Scheme ).…”

“…In this case we anticipated base-catalyzed addition of 7 to naphthazarin 1 under oxidative conditions would afford adduct 19 appropriately functionalized for an intramolecular Heck reaction as demonstrated by Herzon’s group. 4 In the event, our plan was once again thwarted leading to a 46% yield of isoxazole quinone 18 without 19 being observed. In this case the desired carbon-carbon bond formation ( 19 + 1 Π 20 ) was followed by undesired reorganization of oxidation state ( 21 Π 24 ) followed by oxidative cyclization ( 24 Π 18 ).…”