University of Groningen Copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition in natural product synthesis Huang, Yange IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2013 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Huang, Y. (2013). Copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition in natural product synthesis. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 03-10-2021 Copper-catalyzed Asymmetric Allylic Alkylation and Asymmetric Conjugate Addition in Natural Product Synthesis Yange Huang This Ph.D. thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, The Netherlands. The authors of this thesis wish to thank the NRSC-Catalysis for scientific research funding. Printed by: Ipskamp Drukkers B.V., Enschede, The Netherlands RIJKSUNIVERSITEIT GRONINGEN Copper-catalyzed Asymmetric Allylic Alkylation and Asymmetric Conjugate Addition in Natural Product Synthesis Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op vrijdag 20 september 2013 om 12.45 uur door Yange Huang Geboren op 1 september 1984 te Taicang, China Promotores: Prof. dr. B. L. Feringa Prof. dr. ir. A. J. Minnaard Copromotor: Dr. M. Fañanás-Mastral Beoordelingscommissie: Prof. dr. F. J. Dekker Prof. dr. G. Roelfes Prof. dr. J. G. de Vries ISBN: 978-90-367-6343-1 (book) 978-90-367-6342-4 (electronic) Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. -Sir Winston Churchill To Yang (my wife) & Xiyuan (my son) Table of Contents 1. Copper-catalyzed Asymmetric Allylic Alkylation and Asymmetric Conjugate Addition in Natural Product Synthesis 1 1.1 Introduction 2 1.2 Copper-catalyzed ACA 2 1.2.1 ACA with organozincs 3 1.2.2 ACA with organoaluminum 9 1.2.3 ACA with Grignard reagents 13 1.2.4 ACA with organosilicon reagent 18 1.3 Copper-catalyzed AAA 18 1.3.1 AAA with organozinc reagents 18 1.3.2 AAA with organoaluminum reagents 19 1.3.3 AAA with Grignard reagents 20 1.3.4 AAA with organoboranes 22 1.3.5 AAA with organolithiums 23 1.4 Conclusion 24 1.5 Outline of this thesis 24 1.6 References 25 2. Formal synthesis of (R)-(+)-Lasiodiplodin 29 2.1 Introduction 30 2.2 Biosynthesis of Lasiodiplodin 30 2.3 Previous catalytic asymmetric syntheses 31 2.4 Formal synthesis of (R)-(+)-Lasiodiplodin 33 2.4.1 First retrosynthetic analysis 33 2.4.2 Results and discussion 34 2.4.3 Second retrosynthetic analysis 34 2.4.4 Results and discussion 35 2.5 Conclusion 36 2.6 Experimental Section 36 2.7 References and notes 40 3. A Concise Asymmetric Synthesis of (-)-Rasfonin 43 3.1 Introduction 44 3.2 Previous total syntheses of Rasfonin 44 3.3 Total synthesis of Rasfonin 46 3.3.1 Retrosynthetic analysis 46 3.3.2 Synthesis of upper half of Rasfonin 47 3.3.3 Synthesis of lower half of Rasfonin 48 3.4 Conclusion 53 3.5 Experimental Section 53 3.6 References 63 4. A Novel Catalytic Asymmetric Route towards Skipped Dienes with a Methyl-Substituted Central Stereogenic Carbon 65 4.1 Introduction 66 4.2 Previous methodologies 66 4.3 Synthesis of starting materials 68 4.4 Results of the Cu-catalyzed AAA and discussion 74 4.5 Conclusion 78 4.6 Experimental Section 78 4.7 References and notes 95 5. Towards a Total Synthesis and Structure Elucidation of Phorbasin B 99 5.1 Introduction 100 5.2 Previous synthesis of Phorbasins 100 5.3 First retrosynthetic analysis of Phorbasin B 101 5.4 Results and discussion 102 5.5 Second retrosynthesis of Phorbasin B 104 5.6 Results and discussion 105 5.7 Conclusion 108 5.8 Experimental Section 109 5.9 References 118 6. Total Synthesis of (S)-(–)-zearalenone 121 6.1 Introduction 122 6.2 Biosynthesis of zearalenone 122 6.3 Previous synthesis of zearalenone 123 6.4 Retrosynthetic analysis 125 6.5 Results and discussion 125 6.6 Biological studies 128 6.7 Conclusion 129 6.8 Experimental Section 129 6.9 References and notes 137 Summary Summary (English) 139 Samenvatting (Nederlands) 143 Acknowledgements 147 Chapter 1 Chapter 1 Copper‐Catalyzed Asymmetric Allylic Alkylation and Asymmetric Conjugate Addition in Natural Product Synthesis This chapter gives an introduction on copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition in natural product synthesis. Alternative catalytic asymmetric syntheses of the natural products prepared by Cu-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition will also be presented. 1 Chapter 1 1.1 Introduction Catalytic asymmetric C-C bond forming reactions using organometallic reagents are among the most important organic transformations.1 The asymmetric conjugate addition (ACA, Scheme 1, a) and asymmetric allylic alkylation (AAA, Scheme 1, b) are particular versatile in enantioselective C-C bond forming reactions.2 Especially applying ACA, the intermediate enolate formed could be further functionalized (Scheme 1, c) by reaction with other electrophiles (one-pot transformations) introducing to two vicinal stereocenters. These transformations are frequently applied in the synthesis of complex biologically active molecules.1 The major part of this chapter is concerned with the application in the total synthesis of natural products using copper-complex catalyzed AAA and ACA as the key step. Scheme 1. General scheme of AAA, ACA and enolate functionalization. 1.2 Copper-catalyzed ACA Copper-catalyzed ACA of organometallics (Grignard reagents, organozinc reagents, organoaluminum compounds and organosilicon reagents) to Michael acceptors (cyclic enones, acyclic enones, nitro-olefins, unsaturated lactones, unsaturated lactams, dehydropiperidinones, α,β-unsaturated esters, thioesters, amides and imides) has been a highly active research field in recent decades.3 Since the first discovery of ferrocenyl ligands such as TaniaPhos and JosiPhos as efficient ligands in the copper-catalyzed ACA of Grignard reagents, several other chiral ligands were discovered for the copper-catalyzed ACA including phosphines, phosphoramidites, phosphonites, peptides, NHC ligands, phosphine-phosphites and aminophosphine ligands. 2 Chapter 1 1.2.1 ACA with organozincs The copper-catalyzed ACA of organozinc reagents has been a longstanding objective in the field of ACA. A major breakthrough was achieved by the group of Feringa in 1996 based on the development of a BINOL-derived monodentate phosphoramide L1.4 Employing this ligand in the copper-catalyzed ACA of cyclic enones using dialkylzinc reagents for C-C bond formation was achieved in high yield, chemoselectivity, efficiency and enantioselectivity. An important feature is that phosphoramide ligands are readily accessible and due to their modular structure can be readily tuned for a specific 5 application. This methodology was applied in the synthesis of PGE1 methyl ester 6 (Scheme 2) using copper-catalyzed ACA of dialkylzinc 3 to cyclopentenone 1 followed by trapping with aldehyde 2 as the key step.6 The diastereoselectivity of the aldehyde trapping was only moderate (threo/erythro=83/17), however, reduction using Zn(BH4)2 followed by separation of the diastereomers gave advanced intermediate 5 as a single diastereomer with 94% ee. After another 5 steps PGE1 methyl ester 6 was obtained in high yield. In this way PGE1 methyl ester 6 was obtained in 7% overall yield with 94% optical purity in 7 steps from 1. Scheme 2. Total synthesis of PGE1methyl ester 6. Recently the group of Aggarwal reported a stereocontrolled organocatalytic synthesis of 7 PGF2α 13 in only 7 steps (Scheme 3). Intermolecular aldol reaction catalyzed by 2 mol% of proline 8 gave product 9 which underwent hemiacetal formation to 10 and an intramolecular aldol condensation to form α,β-unsaturated aldehyde 11. After acetal formation product 12 was obtained in 14% overall yield with 98% ee. PGF2α 13 was prepared in 5 steps from aldehyde 12. In this way PGE2α 13 was obtained in 4% overall yield with 98% optical purity in 7 steps from 7. 3 Chapter 1 OH OH OH COOH 8 O O N 2mol% O Intramolecular O H aldol condensation O then O O [Bn2NH2][OCOCF3] O O O 7 9 10 11 HO O O MeOH HO 13 O HO COOH 12, 14% based on 7 98% ee Scheme 3. Total synthesis of PGF2α 13. In 2001 Hoveyda et al. reported a tandem reaction using the copper-catalyzed ACA of organozinc to cyclic enones with peptide-based phosphine ligand L2 which is easily accessible from commercially available components (Scheme 4).8 This methodology was applied to the synthesis of the natural product, Clavularin B (17).