Dissertation/Thesis Abstract

Development of a second-generation epoxide-based methodology for the construction of polypropionates: Application to the synthesis of the C1-C7, C8-C12, and C10-C15 polypropionate fragments of lankanolide. Stereoselective construction of all-anti polypropionate modules: Synthesis of the C5-C10 fragment of streptovaricins U and D
by Rodriguez Berrios, Raul R., Ph.D., University of Puerto Rico, Rio Piedras (Puerto Rico), 2010, 373; 3412088
Abstract (Summary)

Polypropionates are a common structural feature of many natural products, which present a broad range of biological activities and therapeutic potential. The polypropionate unit consists of a carbon skeleton with alternating methyl and hydroxy groups with a specific configuration. The construction of these chains has attracted great interest among synthetic chemists due to the challenge represented by the elaboration of their array of contiguous chiral centers. Although, different approaches have been developed for the synthesis of polypropionates, aldol related approaches have been the most widely used methodologies. An approach that has received less attention involves the cleavage of epoxides with a carbon nucleophiles. In this line, several groups have developed different approaches, which involve the stereoselective synthesis of epoxy alcohols and their regioselective cleavage with organocuprates or organoaluminum reagents. The applications of these epoxide-based methodologies to the construction of polypropionate units continues to gain interest because of recent advances in stereoselective epoxidation reactions and regioselective epoxide cleavage processes.

Our contribution to this area has been the development of an epoxide-based methodology for polypropionate construction using organoalanes. Indeed, a concise non aldol approach for the stereoselective construction of all- anti polypropionate fragments was developed. In our laboratory the iterative epoxide-based methodology consists of the anti-selective epoxidation of cis homoallylic alcohols using the VO(acac)2-catalyzed conditions followed by epoxide ring opening with a propynyl aluminum reagent as key steps.

We have incorporated the use of the Sharpless asymmetric epoxidation and an in situ derivatization methodology for the synthesis of optically active first-generation TIPS-protected epoxy alcohols (1c-f). We have also expanded our approach into a second-generation methodology that uses optically active monoprotected 2,3-epoxy diols as more effective precursors for polypropionate construction. For this, we prepared various monoprotected 2,3-epoxy alkanol derivatives (27a-e) with different protecting groups (i.e., TIPS, TBS, Bn and PMB) via the Sharpless asymmetric epoxidation of the corresponding allylic alcohols. We have shown that the new incorporated free primary hydroxy group of our second-generation TIPS-protected 2,3-epoxy alcohol substrates can be converted into a methyl group, offering an alternative access to the first-generation optically active TIPS-protected epoxides.

The incorporation of the primary alcohol in our substrates also increases the flexibility and efficiency in the allylic epoxidation and epoxide-cleavage reactions, allowing us to expand our first-generation method. In addition, we examined the effects of the hydroxy protecting groups (TIPS, TBS, PMB and Bn) in our new substrates and determined their role in the regioselectivity of the epoxide cleavage reactions. These studies were performed systematically exploring different reaction conditions and organoaluminum derivatives. These included trimethylaluminum, diethylpropynylaluminun, diethyltrimethylsilylethynylalane and different Oprotected propargylalanes. Additionally, other studies related to the cleavage of the second-generation TIPS-protected 2,3-epoxy alcohols using Cu-catalyzed alkenyl Grignard reagents were performed.

A substrate-controlled stereoselective epoxidation of free and monoprotected homoallylic diols was developed. This second-generation approach was based on the incorporation of a directing primary alcohol at the C2 methyl group, which changes the nature of the vanadium ester intermediate or the m-CPBA facial selectivity providing a new diastereoselectivity manifold for the preparation of 3,4-epoxy alcohols. This modification favored the formation of C2-syn epoxy alcohol, some of which were not previously available using the standard homoallylic alcohol substrates.

To further demonstrate the synthetic potential of our second-generation methodology we engaged in extensive studies aimed at the synthesis of the C1-C15 polypropionate chain of lankanolide. Lankanolide is the aglycone of lankamycin. Lankamycin is a 14-membered macrolide antibiotic that exhibits moderate antibacterial activity against a number of Gram-positive microorganisms. The molecule consists of a lactone ring that contains twelve stereogenic centers with a specific configuration.

Two complementary linear syntheses of the C1-C7/C8-C15 and C8-C15 polypropionate fragments of lankanolide were performed. For the C1-C7/C8-C15 pathway, two trans epoxides, 54a-syn and 54e-syn, were stereoselectively synthesized in 31% and 21% overall yields from epoxide 27a, respectively, using the vanadium catalyzed procedure. Furthermore, the application of the m-CPBA epoxidation for the synthesis of epoxide 54a-syn showed superior stereoselectivity than the vanadium-catalyzed procedure. The cleavage of epoxides 54e-syn and 54a-syn with a TMS-alkynyl alane produced exclusively the desired 1,3-diol regioisomers 140 and 154, respectively. The challenging anti,syn,syn stereotetrad 140 gave us the opportunity to synthesize the anti-acetonide 149, which was very useful for the elucidation of the relative stereochemistry of the acyclic fragment as well as the measurement of its J coupling constants. (Abstract shortened by UMI.)

Indexing (document details)
Advisor: Prieto, Jose A.
Commitee: Carballeira, Nestor, Colon, Jorge L., Rivera, Jose M., Rodriguez, Abimael
School: University of Puerto Rico, Rio Piedras (Puerto Rico)
Department: Chemistry
School Location: United States -- Puerto Rico
Source: DAI-B 71/07, Dissertation Abstracts International
Subjects: Organic chemistry
Keywords: Epoxides, Homoallylic epoxidations, Lankanolide, Organoaluminum, Polypropionates, Streptovaricin D and U
Publication Number: 3412088
ISBN: 9781124092836
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