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Studies toward the total synthesis of gnidimacrin :The macrolactonization strategy

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Studies toward the total synthesis of gnidimacrin :
其他題名:	The macrolactonization strategy
作者:	D'Angelo, Noel.
面頁冊數:	309 p.
附註:	Adviser: Paul A. Wender.
附註:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1864.
Contained By:	Dissertation Abstracts International65-04B.
標題:	Chemistry, Organic.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128639
ISBN:	0496759019

Studies toward the total synthesis of gnidimacrin :The macrolactonization strategy
D'Angelo, Noel.

Studies toward the total synthesis of gnidimacrin :The macrolactonization strategy [electronic resource] - 309 p.

Adviser: Paul A. Wender.

Thesis (Ph.D.)--Stanford University, 2004.

In designing a synthesis of gnidimacrin, an approach was developed based on the Wender group's successful total syntheses of phorbol and resiniferatoxin. Towards this end, the BC bicyclic core was assembled in nine steps, and the sidechain portion of gnidimacrin was also synthesized. Attaching the sidechain to the bicyclic core and installing the five-membered A-ring were formidable challenges. Installing the tricyclic core with the full sidechain proved unsuccessful, so a shorter sidechain, the olefin sidechain, was used instead. This sidechain was added to the BC cycloadduct using a high-yielding Barbier reaction. The A-ring was subsequently installed with a catalytic, palladium-mediated enyne cyclization, culminating a high-yielding, eight-step sequence from the cycloadduct.

ISBN: 0496759019Subjects--Topical Terms:

193634
Chemistry, Organic.

Studies toward the total synthesis of gnidimacrin :The macrolactonization strategy
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520 # $a In designing a synthesis of gnidimacrin, an approach was developed based on the Wender group's successful total syntheses of phorbol and resiniferatoxin. Towards this end, the BC bicyclic core was assembled in nine steps, and the sidechain portion of gnidimacrin was also synthesized. Attaching the sidechain to the bicyclic core and installing the five-membered A-ring were formidable challenges. Installing the tricyclic core with the full sidechain proved unsuccessful, so a shorter sidechain, the olefin sidechain, was used instead. This sidechain was added to the BC cycloadduct using a high-yielding Barbier reaction. The A-ring was subsequently installed with a catalytic, palladium-mediated enyne cyclization, culminating a high-yielding, eight-step sequence from the cycloadduct.
520 # $a The daphnane diterpenoids are a remarkable family of compounds that are noteworthy for their structural complexity and exciting biological activities. This is especially true for gnidimacrin, a 1-alkyldaphnane diterpenoid whose structure and biological profile distinguish it even among other daphnanes. Since its isolation in 1976, gnidimacrin has proven to be a potent antitumor compound in vitro and in vivo. In addition, studies on its mode of action have suggested that its antitumor activity is related to its ability to bind and activate protein kinase C. Gnidimacrin, therefore, represents a promising lead in the field of cancer therapy. However, its low natural abundance represents a major obstacle towards further development as a clinical candidate. This study sought to address this scarcity by developing a total synthesis of gnidimacrin, thereby providing access to analogs that would allow for a better understanding of the structural basis for gnidimacrin's activity.
520 # $a The next objective, the formation of the macrocyclic lactone, also required extensive experimentation. After attaching the remaining portion of the sidechain, the preparation of a suitable macrolactonization precursor was pursued using both a beta and alpha C-ring epoxide. Success was ultimately obtained with the alpha epoxide, thereby providing a suitable macrolactonization precursor currently in 41 total steps and 0.12% yield from commercially available materials. This study provides an entryway for exploring the final stages of the gnidimacrin synthesis. More importantly, it provides a method for preparing biologically active gnidimacrin analogs.
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