Harmata Strategies and Tactics in Organic Synthesis

1. Auflage 2014
ISBN: 978-0-12-417191-6
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band Volume 10, 320 Seiten

Reihe: Strategies and Tactics in Organic Synthesis

A classic in the area of organic synthesis, Strategies and Tactics in Organic Synthesis provides a forum for investigators to discuss their approach to the science and art of organic synthesis. Rather than a simple presentation of data or a secondhand analysis, we are given stories that vividly demonstrate the power of the human endeavor known as organic synthesis and the creativity and tenacity of its practitioners. Firsthand accounts of each project tell of the excitement of conception, the frustration of failure and the joy experienced when either rational thought or good fortune gives rise to the successful completion of a project. This book series shows how synthesis is really done, and we are educated, challenged and inspired by these accounts, which portray the idea that triumphs do not come without challenges. We also learn that we can meet challenges to further advance the science and art of organic synthesis, driving it forward to meet the demands of society, in discovering new reactions, creating new designs and building molecules with atom and step economies that provide solutions through function to create a better world. - Presents state-of-the-art developments in organic synthesis - Provides insight and offers new perspective to problem-solving - Written by leading experts in the field

Autoren/Hrsg.

Harmata, Michael

Leseproben

Chapter 2 (-)-Berkelic Acid
Lessons Learned From Our Investigations on a Scalable Total Synthesis
Tamara Arto; Abraham Mendoza2; Francisco J. Fañanás1; Félix Rodríguez1    Instituto Universitario de Química Organometálica “Enrique Moles,” Universidad de Oviedo, Julián Clavería, Oviedo, Spain
1 Corresponding authors: email address: [e-mail], [e-mail]
2 Current address: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden. Abstract
This account describes the scalable and convergent synthesis of (-)-berkelic acid. The key reaction of this synthesis is a silver-catalyzed cascade reaction that allows the construction of the central core of the natural product in just one step. Introduction of the lateral chain was achieved by an umpolung alkylation reaction. Keywords Antitumor agents Cascade reactions Natural products Spiro compounds Total synthesis 1 Introduction: Isolation and Interest on Berkelic Acid
Bioactive secondary metabolites (natural products) have proven to be a rich source of drugs and they have also served as an inspiration for the development of analogues with enhanced bioactivities.1 These natural products are usually isolated from organisms living in conventional environments. However, in recent years, a high priority has been placed on obtaining natural products from organisms that survive extraordinary environments (extreme-tolerant microorganisms and extremophiles).2 Organisms capable of growing under extreme conditions have evolved developing unique metabolic pathways that provide singular compounds with structures different from those produced by conventional life forms. This has made extremophiles treasure troves for natural product chemists and biotechnology/pharmaceutical industries. Berkeley Pit Lake is a clear example of an extreme environment (Figure 1). This lake, near the town of Butte in the US state of Montana, was formed when an abandoned open-pit copper mine, shut down in the 1980s, was flooded with infiltrating ground water. This has resulted in the formation of a highly acidic (pH 2.5) and metal-contaminated pool. Nowadays, Berkeley Pit Lake is a dangerous place at risk of a serious ecological disaster and in evident need of remediation. However, this polluted lake has proven to be an appropriate ecosystem for the growth of different bacteria, algae, and protozoans. Several unknown natural products have been isolated from these extremophiles.3 One of them, (-)-berkelic acid, was isolated in 2006 by Stierle and coworkers from a Penicillium species collected from the surface of Berkeley Pit Lake.4 This novel chroman spiroacetal derivative was found to effectively inhibit the matrix metalloproteinase-3 in the micromolar range (GI50 = 1.87 µM) and caspase-1 in the millimolar range (GI50 = 0.098 mM). The isolation team also reported that (-)-berkelic acid exhibited selective activity toward the ovarian cancer cell line OVCAR-3 (GI50 = 91 nM). However, the cytotoxicity against these specific tumor cells has been subject of some controversy because a synthetic sample of material obtained by Snider and coworkers did not show significant activity.5 This fact reinforces the need for a deeper study on the bioactivity of this natural product and its analogues. Figure 1 Berkeley Pit Lake in Butte (Montana, US) and structure of (-)-berkelic acid. 2 Structural Assignation and Previous Total Syntheses of (-)-Berkelic Acid
In 2008, just 2 years after the isolation of the natural product, Fürstner and coworkers reported the synthesis of the enantiomer of the methyl ester of berkelic acid.6 The extensive NMR work and crystallographic experiments performed served to revise the originally proposed structure of the natural product by reassigning the relative stereochemistry at C18 and C19 (Figure 2). However, the relative configuration of the lateral quaternary stereocenter at C22 and the absolute stereochemistry of the natural product were unresolved at this time. Although the authors could not access the natural product because they reached a compound just one step away from the target, this pioneering work may be considered as the first far-reaching synthetic approach to berkelic acid. Figure 2 Stierle's original and Fürstner's revised structures of (-)-berkelic acid. Snider and coworkers published the first complete total synthesis of (-)-berkelic acid 1 in 2009, confirming the reassignments made by Fürstner and establishing the stereochemistry at C22 and the absolute configuration of the natural product.7 The key step of this synthesis was an oxa-Pictet–Spengler reaction between intermediates 4 and 5 that delivered the tetracyclic core 3 in basically one step (Scheme 1). Elongation of the lateral chain was achieved by creating the C21–C22 bond through an aldol reaction between trimethylsilyl ketene acetal 2 and the C21-aldehyde derived from 3 followed by oxidation of the resulting aldol product to the 1,3-ketoester derivative. The synthesis proceeded with a longest linear sequence of 13 steps (no less than 20 global steps considering available starting materials) in 2% global yield allowing the final isolation of 11.1 mg of synthetic (-)-berkelic acid 1 for the first time. Scheme 1 Snider's synthesis of (-)-berkelic acid. Soon after Snider's synthesis appeared, De Brabander and coworkers published a different approach to berkelic acid based on the coupling of the two natural product-inspired fragments 6 (related to spicifernin) and 7 (related to pulvilloric acid) (Scheme 2).8 The key step of the synthesis relied on the in situ formation of the exocyclic enol ether 6 by cycloisomerization of alkynol derivative 8 and further formal [4 + 2]-cycloaddition reaction with heterodiene 7 (formed in situ) from acetal 9. As a difference with respect to all other total syntheses of (-)-berkelic acid published to this point, in this strategy the C20–C24 lateral chain was incorporated into fragment 6 at an early stage and before the construction of the central polycyclic core. Although this approach is original in its biosynthetic basis, it is somewhat less convergent and modular than the others. The synthesis proceeded with a longest linear sequence of 10 steps (no less than 17 global steps considering available starting materials) in 10% global yield (improved by recycling some intermediates). However, the efficiency of the strategy was compromised by the need for using two equivalents of the advanced intermediate 8 in the key step of the synthesis. Nonetheless, 3.7 mg of (-)-berkelic acid could be finally obtained. Scheme 2 De Brabander's synthesis of (-)-berkelic acid. Following their initial studies on the real structure of (-)-berkelic acid previously mentioned, Fürstner and coworkers published in 2010 a total synthesis of this natural product.9 The successful route was based on an aldol reaction between methyl ketone 13 and benzaldehyde derivative 14 to give enone derivative 12 (Scheme 3). A subsequent deprotection/1,4-addition/spiroacetalization cascade reaction delivered the tetracyclic core 11. Installation of the lateral chain was achieved by oxidative rupture, reduction, and iodination of the alkene of 11 to obtain the corresponding C20-iodide. An iodine–lithium exchange followed by addition of the formed organolithium compound to aldehyde 10 and further oxidation of the alcohol obtained afforded (-)-berkelic acid 1 after a hydrogenolysis of the benzyl ester. The synthesis proceeded with a longest linear sequence of 19 steps (no less than 26 global steps considering available starting materials) in 5% global yield allowing the final isolation of 4.7 mg of (-)-berkelic acid. Scheme 3 Fürstner's synthesis of (-)-berkelic acid. While the three reported total syntheses of (-)-berkelic acid allowed access to synthetic samples of the natural product, achieving a scalable and modular synthesis of this target remained, for various reasons, an unmet challenge. It should also be noted that Pettus’10 and Brimble’s11 groups have also reported formal total syntheses of (-)-berkelic acid. 3 Our Approach to Berkelic Acid from Research on New Methodology: Model Studies
Our interest on the synthesis of (-)-berkelic acid stemmed from our work on multicomponent coupling reactions involving alkynol derivatives.12 We and others have demonstrated that the metal-catalyzed cycloisomerization reaction of alkynol derivatives is a powerful strategy to synthesize cyclic enol ethers.13 While working on this project we...