Application of the Nazarov Cyclization Reaction to the Synthesis of Guanacastepenes and Taiwaniaquinoids

This dissertation, "Application of the Nazarov Cyclization Reaction to the Synthesis of Guanacastepenes and Taiwaniaquinoids" by Shuoliang, Li, 李碩梁, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled APPLICATION OF THE NAZAROV CYCLIZATION REACTION TO THE SYNTHESIS OF GUANACASTEPENES AND TAIWANIAQUINOIDS Submitted by LI Shuoliang for the degree of Doctor of Philosophy at The University of Hong Kong in December 2006 The guanacastepenes are a novel family of natural products isolated and identified by Clardy in 2000-2001. Guanacastepene A is a potent antibiotic, demonstrating activity against methycillin and vancomycin-resistant strains of Staphylococcus aureus and Enterococcus faecalis. The guanacastepenes are characterized by a [5,7,6] tricyclic ring system with a highly oxidized hemisphere and a hydrophobic southern domain. Synthesis of the guanacastepene framework has been carried out by the application of carbene cyclization cycloaddition cascade (CCCC) reaction to construct the B, C-rings and a Nazarov cyclization to append the A-ring. A model study revealed that the hydroazulene core 1.38a bearing the correct stereochemistry at C11 and C12 of guanacastepene A could be synthesized with 98% yield via the Nazarov reaction of 1.37a using Lewis or Bronsted acids of moderate strength. In addition, a novel carbocationic rearrangement after the Nazarov cyclization of 1.37a which yields spirocyclic [4,5] decenones such as 1.43a with a 93:7 ratio in 96% yield via a secondary pathway, was found to be favored when strong Lewis or Bronsted acids were used instead. The CCCC reaction was used to construct the B, C-rings. Starting from L-glutamic acid, the key diazoketone 2.44c was synthesized in 29 steps. The CCCC reaction of 2.44c occurred under rhodium catalysis to give the desired 2.43c with 53% yield as the major product, which was readily isolated and purified by crystallization. α-Hydroxylation of the C-ring and silyl protection was found to result in an unexpected rearrangement and oxa-bridge opening to give 2.70. Subsequently, decarboxylation, olefination, ring opening and reduction of 2.43c, followed by the addition of the enone moiety generated 2.94. Treatment of 2.94 with boron trifluoride-etherate induced a Nazarov cyclization to furnish a single diastereomeric product 2.93 with 85% yield. Although the structure of this product has not been proven due to the inability to obtain its crystal structure, several characteristics suggest that it bears the tricyclic framework of the guanacastepenes: an NOE profile that shows the syn stereochemistry of the methyl and isopropyl groups on the A-ring, and the existence of dynamic conformers which related diastereomers bearing the wrong relative stereochemistry such as 2.23 do not have. The Nazarov reaction was also applied to the synthesis of members of another family of tricyclic diterpenoids, the taiwaniaquinoids, some of which show antitumor activity. Using commercially available β-cyclocitral, the total synthesis of taiwaniaquinol B was completed in five steps via an aromatic Nazarov reaction of 3.2 to give 3.1 in high yield. Besides the Nazarov reaction strategy, another route was used to generate 3.1 from 3.10 via enone 3.12 using sequential cationic cyclizations. Compound 3.12 was derivatized to 3.13, which completes formal total syntheses of taiwaniaquinol B, and taiwaniaquinone D, H. OTBDPSOO OEt O N 1.37a 1.43a 1.38a 2.44c CO Et O HO CO Et OTBDPS OTBS 2.43c 2.70