Graduate Thesis Or Dissertation
 

Synthetic Studies towards Highly Oxygenated Furanyl Diterpenoids

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  • The furanyl diterpenoid family of natural products has drawn the attention of both synthetic organic chemists and pharmacologists due to their complex structural architectures and diverse biological activity. Among them, wortmannin has been most extensively studied for biological activities. All these furanyl diterpenoids consist of a highly strained naptha[1,8-bc]furan core, which is key to their biological activities. Three prototypical members of this family are (+)-halenaquinone, wortmannin and wortmannolone. We set out to develop a unified approach to access all these furanyl diterpenoids. Halenaquinone was our first target to exploit our proposed unified approach towards total synthesis of furanyl diterpenoids. The enantioselective total synthesis of halenaquinone has been accomplished in 12/14-step longest linear sequence (LLS). The key steps in the synthetic sequence involved (a) an improved protocol for the proline sulfonamide-catalyzed Yamada-Otani reaction which lowered the catalyst loading and improved the reaction rate to provide the key cyclohexenone moiety in high levels of diastereo- and enantioselectivity; (b) a novel Pd- mediated Walker/ dehydrogenation/oxidation cascade protocol to introduce the furan ring; (c) a selective hydrogenation of the enone in the presence of the dibromoaryl ring to provide the key carboxylic acid intermediate; (d) regioselective Friedel-Crafts acylation to construct the tetracyclic ring system; and (e) a late-stage oxidative Bergman cyclization of the diacetylene intermediates to introduce the quinone moiety and complete the total synthesis of (–)-halenaquinone. Significant tetracyclic core structures of wortmannin and wortmannolone have been accomplished. An efficient and robust synthetic route towards the trans-fused D-E ring system of wortmannin and wortmannolone has been developed. The key steps involved in the synthesis of advanced aldehyde intermediate are (a) 1,4-reduction (b) Sagusa-type oxidation and (c) a palladium-catalyzed cross coupling reaction. This advanced intermediate containing the trans-fused D-E ring served as the substrate for subsequent crucial Yamada-Otani reaction. A significant advancement has been achieved in proline sulfonamide- catalyzed Yamada-Otani reaction substrate scope, which was earlier limited to only benzylic aldehydes. To our knowledge, this work is the first example of employing non-benzylic aldehyde in Yamada-Otani reaction. Besides diastereoselectivity, controlling regioselectivity of the in situ generated enamine (i.e. to maintain the C8-9 olefin geometry) was an additional challenge with the non-benzylic aldehydes during the course of the Yamada- Otani reaction. We have synthesized the desired cyclohexenone containing all-carbon quaternary center as a single in excellent regio- and stereoselectivity and good yield. This cyclohexenone intermediate is designed to serve as a key common intermediate for the total synthesis of wortmannin and wortmannolone. Selective Bayer-Villiger oxidation and solvolysis of the cyclohenone ring produced the corresponding aldehyde. Another key discovery is the construction of the B-lactone ring of wortmannin via a one-pot stereoselctive oxyamination / reduction/ N-O bond cleavage/ lactonization cascade protocol installing the C1 stereochemistry. We have extended the substrate scope for our novel Pd-catalyzed oxidative cascade to the non-aromatic wortmannin/wortmannolone system synthesizing the advanced furanyl aldehyde intermediates containing the crucial furan-ring of wortmannin and wortmannolone. Multiple strategies have been explored to build up the pentacyclic core of wortmannolone.
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  • Ongoing Research
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  • 2018-10-04 to 2019-11-04

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