Synthesis of Organoboronic Acids and Applications in Asymmetric

Sybrand Jonker Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis Synthesis of OrganoboronicSynthesis Acids and Applications in Asymmetric Organocatalysis Sybrand Jonker

ISBN 978-91-7911-388-9

Department of Organic Chemistry

Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2021

Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis Sybrand Jonker Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Friday 12 February 2021 at 14.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B.

Abstract Allyl- and allenylboronic acids are valuable reagents in organic synthesis due to their configurational stability and high reactivity. Few allyl- and allenylboronates are commercially available. Therefore, both the preparation and synthetic application of these organoboronic acids are subjects of study. A copper-catalyzed method for the synthesis of tetrasubstituted allenylboronic acids is presented in this thesis. Several enantioselective applications of these allenylboronic acids are presented, including the synthesis of chiral α-amino acid derivatives. Applications of γ,γ-disubstituted allylboronic acids in asymmetric organocatalysis are also presented in this thesis. Varying the E-Z geometry of the allylboron reagents allowed for stereodivergent synthesis of products bearing up to three stereocenters. A common element in the asymmetric methodologies described in this thesis is the application of BINOL-type organocatalysts. The most notable example is the methodology developed for the preparation of α-chiral allylboronic acids via asymmetric homologation of olefinic boronic acids. The resulting chiral boronic acids are of high synthetic interest, which is demonstrated by the wide variety of synthetic applications including allylboration, oxidation, and a purification sequence leading to isolated α-chiral allylboronic acids.

Keywords: Boronic acid, BINOL, allylboration, propargylation, homologation, stereoselective synthesis, asymmetric synthesis, organocatalysis, allylboronic acid, allenylboronic acid.

Stockholm 2021 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-187390

ISBN 978-91-7911-388-9 ISBN 978-91-7911-389-6

Department of Organic Chemistry

Stockholm University, 106 91 Stockholm

SYNTHESIS OF ORGANOBORONIC ACIDS AND APPLICATIONS IN ASYMMETRIC ORGANOCATALYSIS

Sybrand Jonker

Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis

Sybrand Jonker ©Sybrand Jonker, Stockholm University 2021

ISBN print 978-91-7911-388-9 ISBN PDF 978-91-7911-389-6

Cover: Sørfjorden and its enantiomorph as seen from Odda (Norway) by Sybrand Jonker

Printed in Sweden by Universitetsservice US-AB, Stockholm 2021 “Pain is inevitable. Suffering is optional.”

Haruki Murakami What I Talk About When I Talk About Running

Abstract

Allyl- and allenylboronic acids are valuable reagents in organic synthesis due to their configurational stability and high reactivity. Few allyl- and allenylboronates are commercially available. Therefore, both the preparation and synthetic application of these organoboronic acids are subjects of study. A copper-catalyzed method for the synthesis of tetrasubstituted allenylboronic acids is presented in this thesis. Several enantioselective applications of these allenylboronic acids are presented, including the synthesis of chiral α-amino acid derivatives. Applications of γ,γ-disubstituted allylboronic acids in asymmetric organocatalysis are also presented in this thesis. Varying the E-Z geometry of the allylboron reagents allowed for stereodivergent synthesis of products bearing up to three stereocenters. A common element in the asymmetric methodologies described in this thesis is the application of BINOL-type organocatalysts. The most notable example is the methodology developed for the preparation of α-chiral allylboronic acids via asymmetric homologation of olefinic boronic acids. The resulting chiral boronic acids are of high synthetic interest, which is demonstrated by the wide variety of synthetic applications including allylboration, oxidation, and a purification sequence leading to isolated α-chiral allylboronic acids.

i Populärvetenskaplig sammanfattning

I världen omkring oss finns det många objekt som kan kallas ‘väns- terhänta’ eller ‘högerhänta’. Exempel inkluderar verktyg som en sax, en korkskruv, en golfklubba, men också naturligt förekommande ting som ett snäckskal och arrangemanget av en blommas kronblad. Alla dessa objekt har gemensamt att deras spegelbild inte kan passas över sig självt, likt en höger- och vänsterhand. Kemister kallar sådana objekt kirala. Många molekyler är kirala, så även molekyler som används i mediciner. Eftersom molekyler och enzymer som styr människokroppen är kirala har en molekyls spegelbildsform en stark inverkan på hur den interagerar med kroppen. Detta är precis som i den makroskopiska värl- den: en vänsterhand är inte lämplig för att klippa med en högerhänt sax. För att molekyler ska interagera förutsägbart med människokrop- pen är det nödvändigt för kemister att kunna styra valet av spegelbildsform när de syntetiserar dem. I denna avhandling presenteras en ny metod för syntes av allenyliska borsyror genom kopparkatalyserad borylering, samt utveckling av en ny syntes av kirala allylborsyror via homologering av olefiniska borsyror. De allenyliska och allyliska borsyrorna som framställts kan sedan användas till propargylborering och allylborering av aldehyder, ketoner, iminer, indoler, och hydrazonestrar med en hög grad av kontroll över den resulterande stereokemin. I de fall som produkten har mer än ett stereocenter kan man genom att förändra reaktionsbetingelserna kon- trollera varje stereocenter separat: man säger att reaktionen är stereodivergent. Som exempel kan icke-naturliga aminosyraderivat produce- ras med denna nya metodologi. Många av de asymmetriska metoderna som presenteras i denna avhandling involverar organiska katalysatorer av BINOL-typ vilka har visat sig vara mycket effektiva för asymmetriska transformationer av borsyror.

ii Abbreviations

B2nep2 Bis(neopentyl glycolato)diboron B2pin2 Bis(pinacolato)diboron BINOL 1,1′-Bi-2-naphthol Bdan 1,8-Diaminonaphtaleneboron Bpin Pinacolatoboron cod 1,5-Cyclooctadiene Cy Cyclohexyl danH2 1,8-Diaminonaphtalene d.r. Diastereomeric ratio dba Dibenzylideneacetone DCM Dichloromethane DFT Density Funtional Theory DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMSO Dimethyl sulfoxide ee Enantiomeric excess equiv. Equivalents HBcat Catecholborane HBpin Pinacolborane HFIP Hexafluoroisopropanol LDA Lithium diisopropylamide [M] Metal MTPA α-Methoxy-α-trifluoromethylphenylacetyl NMR Nuclear Magnetic Resonance r.t. Room temperature TESOTf Triethylsilyl trifluoromethanesulfonate TMS Trimethylsilyl Δ�SR Difference in chemical shift between MTPA epimers

iii List of publications

This document is based on the following publications, referred to in the text by their Roman numerals I-IV.

I. Copper-catalyzed Synthesis of Allenylboronic Acids. Ac- cess to Sterically Encumbered Homopropargylic Alcohols and Amines by Propargylboration Jian Zhao, Sybrand J. T. Jonker, Denise N. Meyer, Göran Schulz, C. Duc Tran, Lars Eriksson and Kálmán J. Szabó Chem. Sci., 2018, 9, 3305–3312.

II. Catalytic Asymmetric Propargyl- and Allylboration of Hy- drazonoesters: A Metal-Free Approach to Sterically En- cumbered Chiral α-Amino Acid Derivatives Sybrand J. T. Jonker, Colin Diner, Göran Schulz, Hiroaki Iwamoto, Lars Eriksson and Kálmán J. Szabó Chem. Commun., 2018, 54, 12852–12855.

III. Catalytic Asymmetric Allylboration of Indoles and Dihy- droisoquinolines with Allylboronic Acids: Stereodivergent Synthesis of up to Three Contiguous Stereocenters Rauful Alam, Colin Diner, Sybrand Jonker, Lars Eriksson and Kálmán J. Szabó Angew. Chem. Int. Ed. 2016, 55, 14417–14421.

IV. Organocatalytic Synthesis of α-Trifluoromethyl Al- lylboronic Acids by Enantioselective 1,2-Borotropic Migra- tion Sybrand J. T. Jonker, Ramasamy Jayarajan, Tautvydas Kireilis, Marie Deliaval, Lars Eriksson and Kálmán J. Szabó J. Am. Chem. Soc. 2020, 142, 21254–21259.

iv Reprint permissions

Permissions to reprint the following publications were obtained from their respective publishers:

I. J. Zhao, S. J. T. Jonker, D. N. Meyer, G. Schulz, C. D. Tran, L. Eriksson, K. J. Szabó, Chem. Sci., 2018, 9, 3305– 3312. Copyright © 2018 Royal Society of Chemistry. Open access article licensed under a Creative Commons Attribu- tion 3.0 Unported License.

II. S. J. T. Jonker, C. Diner, G. Schulz, H. Iwamoto, L. Eriks- son, K. J. Szabó, Chem. Commun., 2018, 54, 12852–12855. Copyright © 2018 Royal Society of Chemistry. Open access article licensed under a Creative Commons Attribu- tion 3.0 Unported License.

III. R. Alam, C. Diner, S. Jonker, L. Eriksson, K. J. Szabó, Angew. Chem. Int. Ed. 2016, 55, 14417–14421. Copyright © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. Open access article licensed under a Creative Commons Attribution-NonCommercial 4.0 International Licence.

IV. S. J. T. Jonker, R. Jayarajan, T. Kireilis, M. Deliaval, L. Eriksson, K. J. Szabó, J. Am. Chem. Soc. 2020, 142, 21254–21259. Copyright © 2020 American Chemical Society. Open access article licensed under an ACS AuthorChoice Creative Commons Attribution 4.0 International Licence.

v Previous document based on this work

This thesis builds partly on the author’s half-time report titled “Asymmetric synthesis using allenyl- and allylboronic acids” (defended on June 17th, 2020). The introduction (Chapter 1) has been updated with the current literature. Of the papers included in this thesis, papers I-III were part of the half-time report. By chapters, the contribution from the half-time report is as follows:

Chapter 1: This chapter was included in the half-time report; for this thesis it has been reviewed and updated. It has been shortened by approx. 30%, and approx. 25% of the text and references are new.

Chapter 2: This chapter was included in the half-time report; for this thesis it has been reviewed and updated. Approx. 20% of the text and references are new.

Chapter 3: Section 3.1 was included in the half-time report; approx. 10% of the text and references are new. Section 3.2 is entirely new.

vi Contents

Abstract ...... i

Populärvetenskaplig sammanfattning ...... ii

Abbreviations ...... iii

List of publications ...... iv

Reprint permissions ...... v

Previous document based on this work ...... vi

1. Introduction ...... 1 1.1 Synthesis of allylboronates ...... 1 1.2 Synthetic applications of allylboronates ...... 5 1.3 Synthesis of allenylboronates ...... 8 1.4 Synthetic applications of allenylboronates ...... 9 1.5 Qualitative comparison of various organoboronates ...... 10 1.6 Aim of this thesis ...... 12

2. Synthesis and applications of allenylboronic acids ...... 13 2.1 Synthesis of allenylboronic acids by borylation of propargylic carbonates (Paper I) 13 2.2 Application of allenylboronic acids to catalytic asymmetric propargylation of ketones (Paper I) ...... 19 2.3 Application of allenylboronic acids towards chiral a-amino acid derivatives (Paper II) 27

3. Synthesis and applications of allylboronic acids ...... 34 3.1 Applications of achiral allylboronic acids in stereoselective synthesis (Papers II and III) ...... 34 3.1.1 Stereodivergent preparation of chiral a-amino acid derivatives (Paper II) .. 34 3.1.2 Stereodivergent allylboration of indole and 3-methyl indole (Paper III) ...... 37 3.1.3 Stereoselective allylboration of 3,4-dihydroisoquinolines (Paper III) ...... 42 3.2 Synthesis and applications of chiral allylboronic acids (Paper IV) ...... 46 3.2.1 Preparation of chiral allylboronic acids by catalytic asymmetric homologation of olefinic boronic acids (Paper IV) ...... 48 3.2.2 In situ allylboration and oxidation of chiral allylboronic acids (Paper IV) .. 54

vii 3.2.3 Extended asymmetric allylboration enabled by purified chiral allylboronic acids (Paper IV) ...... 57

4. Conclusions and outlook ...... 63

5. Acknowledgement ...... 65

6. List of contributions ...... 67

7. References ...... 68

viii 1. Introduction

Allyl- and allenylboronates are valuable tools for synthetic chemistry. One of their biggest advantages is that these highly reactive species are configurationally stable and refrain from borotropic rearrangement. This is in contrast to reactive allylic organometallic reagents such as organolithium, organomagnesium, and organozinc species. Such reagents have a stable η3 state or undergo metallotropic rearrangements (Scheme 1) due to the fluxional nature of the metal-allyl fragment.1

OR R1 [M] [M] R2 [M] R1 R1 B or or OR 1 2 2 R2 R R R1 R [M] R2

[1,3] shift E/Z isomerization η3 coordination configurationally stable Scheme 1. Configurational instability of the metal-allyl fragment.

Few allyl- and allenylboronates are commercially available. There- fore, both the preparation and synthetic application of allyl- and allenylboronates are subjects of study.

1.1 Synthesis of allylboronates

One of the earliest examples of preparation of allylboronates comes from Miyaura and co-workers who were able to synthesize β- and γ- substituted allyl pinacolboronate (allyl-Bpin) compounds from allylic 2 esters and carbonates using palladium catalyst Pd(dba)2 and B2pin2. A disadvantage of this approach is the competing homocoupling of the allylic compound to form a diene. A later study by Morken and co- workers has demonstrated how Ni(cod)2 catalyst could be employed for borylation of allylic chlorides and acetates to afford allyl-Bpin compounds.3 Publications by Ito and co-workers have shown how a Cu- alkoxide catalyst with a phosphine ligand can be used for borylation of

1 allylic carbonates such as 1 to afford α-branched allyl-Bpin compounds 3 (Scheme 2).4–7 A similar approach has been shown by Szabó, Marder and co-workers for the copper-catalyzed borylation of allylic alcohols 8 activated by the Lewis acid Ti(Oi-Pr)4. As a general trend, copper- catalyzed borylation procedures showed a high degree of regioselectivity for an SN2’-type substitution over an SN2-type substitution product. By contrast, a study by Ito and co-workers found that applying a Pd(dba)2 catalyst gave almost equal parts SN2-type and SN2’-type borylation due to the η3 hapticity of the Pd-allyl intermediate.4 Hall and co-worker have reported how allylic halides can be used for the enantioselective synthesis of α-branched allyl boronates through a chiral Cu-catalyzed 9 SN2’ reaction with Grignard reagents. This approach has also been employed by Pietruszka and co-workers to obtain tetraol-based α-chiral allylboronates.10 Other successful strategies to synthesize allylboronates include hydroboration reactions,11–13 and direct transition-metal free borylation of alcohols using B2pin2 and Cs2CO3 as reported by Szabó, Fernández and co-workers.14

Ito and co-workers, 2007 Me t-Bu 5% Cu(Ot-Bu) N P OCO2Me 5% (R,R)-QuinoxP* Bpin + B2pin2 N P o Ph THF, 0 C, 48 h Ph t-Bu Me 1 2 3 77% yield (R,R)-QuinoxP* 95% ee

Scheme 2. Cu-catalyzed borylation as reported by Ito and co-workers.

Szabó and co-workers have shown that allylic alcohols can be borylated to afford linear γ-substituted allylboronates using a Pd pincer 15,16 17 complex catalyst or [Pd(MeCN)4][BF4]2. Szabó and co-workers also demonstrated that a Pd catalyst could be used for the direct synthesis and isolation of allylboronic acids, using B2(OH)4 4 as a boron source18 (Scheme 3). The resulting allylboronic acids were found to be much more reactive than their diol-protected analogs, as they can be dehydrated to form a boroxine, the corresponding anhydrous trimer of boronic acids. This increased reactivity allows allylboronic acids to directly react with a wide variety of compounds without the need for activation or catalysis. Applications of allylboronic acids include direct allylboration of electrophilic substrates such as ketones,19 α-ketoesters,20 imines,21 and hydrazones.22

Szabó and co-workers, 2012

0.5-5 mol% H2PdCl4 OH R HO OH allylboronic R OH or + B B R B acid OH DMSO/H2O or MeOH OH HO OH r.t. 4 up to 80% yield

Scheme 3. Pd-catalyzed borylation with B2(OH)4 to access isolated allylboronic acids as reported by Szabó and co-workers.

Ley and co-workers have reported the homologation of boronic acids by carbenoid TMS-diazomethane 6 (Scheme 4).23 Prior to homologation, the boronic acids were dehydrated to the corresponding boroxine, such as 5. A selection of racemic benzyl and allyl a-TMS Bpin compounds (such as 7) were obtained by in situ protection of the homologation product with pinacol. Interestingly, it was found that the reaction results in retention of the a-TMS group when the boroxine is used, but desilylation is observed in the reaction of the boronic acid. Ley and co-workers demonstrated how achiral a-desilylated allylboronic acids resulting from homologation of olefinic boronic acids can be used for in situ allylboration of aldehydes24 as well as indoles.25 Following the same concept, Wang and co-workers were able to obtain racemic benzyl a- TMS Bpin compounds by homologation of arylboronic acids with TMS- diazomethane.26 After isolation it was possible to use the Bpin compounds in a Suzuki-Miyaura cross-coupling with aryl iodides, preserving the TMS group in the coupling product.

Ley and co-workers, 2017

B 1. 3.6 equiv. DIPEA SiMe3 O O toluene, 85 oC B B + Me3Si N2 Bpin O 2. pinacol, r.t. 5 6 7 60% yield Scheme 4. Homologation of boroxines using TMS-diazomethane as reported by Ley and co-workers.

Molander and co-workers reported the homologation of boronates using in situ generated carbenoid trifluorodiazoethane (9), affording ra- 27 cemic benzyl, alkyl, allyl, and propargyl a-CF3 boronates (Scheme 5). The homologation product could be in situ chlorinated, brominated, and oxidized to a secondary alcohol. In a follow-up study, Molander and co-worker found that the double homologation of boronic acids can

3 be realized by dehydration to the boroxine prior to homologation.28 The a,b-bis(trifluoromethyl)boronates that were obtained through two suc- cessive insertions of trifluorodiazoethane exhibited selectivity towards the syn diastereomer. The diazotation of 2,2,2-trifluoroethylamine by nitrous acid affording trifluorodiazoethane (9) was first reported by Gil- man and co-worker.29 Carreira and co-workers have demonstrated that trifluorodiazoethane (9) can be generated and immediately used for cy- clopropanation30,31, cyclopropenation32, and homologation of carbon- yls.33

Molander and co-workers, 2013

1. p-tolyl-SiCl3 2. KHF2 CF3 BF3K + CF3 N2 DCM, r.t. BF3K

8 9 10 78% yield Scheme 5. Homologation of boronates using trifluorodiazoethane as reported by Molander and co-workers.

Aggarwal and co-workers utilized chiral lithiated carbamates for the asymmetric homologation of olefinic Bpin compounds to obtain a-chiral allylboronates, which could be reacted with aldehydes in an asymmetric 34 allylboration. Two examples of enantioenriched a-CF3 allylboronates have been reported by Aggarwal and co-workers by insertion of the chiral 2-trifluoromethyl oxirane (12) into a olefinic Bpin ester (Scheme 6).35 The borylation procedure starts by deprotonation of the oxirane, which then forms an ate complex with Bpin compound 11. Subsequent 1,2-borotropic migration facilitates the ring opening with inversion of stereochemistry to afford allylboronate 13.

Aggarwal and co-workers, 2020

o Bpin CF O 1. LDA, THF, -15 C 3 + OTES Bpin 2. TESOTf, toluene, r.t. CF3 62% yield 11 12 13 99% ee

Scheme 6. Enantioselective method towards a-CF3 allylboronates as reported by Aggarwal and co-workers.

4 1.2 Synthetic applications of allylboronates

The first example of an allylboration with allylboronates was reported by Hoffmann and co-workers36 who studied the diastereoselec- tive allylboration of aldehydes using allyl pinacolboronates (allyl-Bpin). The key finding of this study is that isomers 14a and 14b result in opposite diastereomers 16a and 16b when reacting with benzaldehyde 15a. This is a consequence of allylboration reactions proceeding via a six-membered Zimmerman-Traxler transition state9,37 (Scheme 7).

Hoffmann and co-workers, 1979

OH O Bpin Bpin + O Ph Ph Ph 16a 14a 15a Zimmerman-Traxler transition state

OH O Bpin Bpin + O Ph Ph Ph 14b 15a 16b

Scheme 7. Allylboration reactions proceed via a Zimmerman-Traxler transition state.

The first example of an enantioselective allylboration was reported by Brown and co-workers,38 using chiral B-allyldiisopinocam- pheylborane to obtain homoallylic alcohols in high optical purity. Sub- sequently, many advances have been made in the field of asymmetric allylboration of aldehydes. Hall and co-worker have demonstrated that the Lewis acid SnCl4 chelated by a chiral diol can catalyze allylboration of aldehydes in an enantioselective manner.39 A similar approach towards the same goal was reported by Kobayashi and co-workers by 40 using Lewis acid Zn(OH)2 alongside a chiral bidentate ligand. Morken and co-workers have reported catalytic asymmetric allylboration using 41 a Ni(cod)2 catalyst in conjunction with a chiral phosphonite ligand. A seminal study by Antilla and co-workers demonstrated that chiral phosphoric acids can be utilized to catalyze enantioselective allylboration of aldehydes by allyl-Bpin 14b (Scheme 8).42 The synthetic scope of this transformation was extended to stereodivergent alkoxyallylation by Chen and co-workers.43 Pellegrinet, Goodman and co-workers have provided mechanistic insight into the transition states leading to the

5 facial selectivity in this reaction.44 A study by Pericàs has demonstrated that the chiral phosphoric acid catalyst for asymmetric allylboration of aldehydes can be immobilized on a polystyrene resin.45 This innovation allows it to be re-used up to 18 times. Recently, Hoveyda and co-workers demonstrated the utility of an aminophenol ligand in catalytic asymmetric allylboration to afford homoallylic alcohols in a Z-selective manner.46 This methodology could be applied to the total synthesis of antitumor agent mycothiazole.

Antilla and co-workers, 2010 Ar O O 5 mol% (R)-TRIP-PA OH P OH Bpin + O O Ph toluene, 0 °C Ph i-Pr i-Pr

14b 15a 17 96% yield 99% ee i-Pr (R)-TRIP-PA 98:2 d.r. Scheme 8. Catalytic asymmetric allylboration as reported by Antilla and co-workers.

Ketones are known to be less reactive than aldehydes, and their allylboration is considered to be challenging. Schaus and co-workers have reported that the relatively more reactive allyldiisopropoxyborane could be used instead of allyl-Bpin 14b to afford the asymmetric al- 47 lylboration product of various ketones. Organocatalyst 3,3′-Br2- BINOL 20-(S) was used to induce enantioselectivity in this reaction. The addition of more than one equivalent of isopropanol was observed to drastically increase the enantioselectivity of the reaction. Following this observation, Schaus and co-workers switched to 1,3-propanediol- protected allylboronic ester 18 combined with a tert-butanol additive (Scheme 9).48 This allowed them to decrease the catalyst loading to only 2 mol%. Using the same organocatalyst, Szabó and co-workers were able to extend the scope of this allylboration to γ,γ-disubstituted allylboronates, affording homoallylic alcohols bearing two vicinal quaternary stereocenters (Scheme 9).19 In this study, allylboronic acids were mixed with a selection of aliphatic alcohols for in situ formation of the allylboronic ester. This increased flexibility allowed them to settle on tert-butanol as a suitable aliphatic alcohol.

6 Schaus and co-workers, 2009

O O 4 mol% 20-(S) HO B + O 2 equiv t-BuOH Ph Ph Br 18 19a toluene/PhCF3, r.t. 21 96% yield HO 97:3 d.r. Szabó and co-workers, 2015 98% ee HO Br 15 mol% 20-(S) HO OH O (S)-3,3’-Br2BINOL B + Ar 20-(S) OH Ar 3 equiv t-BuOH 3 Å molecular sieves 22a 19b 23 toluene, 0 °C 75% yield 94% ee 98:2 d.r. Scheme 9. A selection of methods for catalytic asymmetric allylborations of ketones.

Senanayake and co-workers have shown that 3,3′-F2-BINOL in com- bination with an allyl-Bnep compound (neopentyl ester) can be used for the asymmetric allylboration of ketones.49 In an extensive study by Shibasaki and co-workers a variety of Cu-catalyzed asymmetric allylborations and propargylations were demonstrated.50 Allyl-Bpin and allenyl-Bpin compounds were reacted with ketones in the presence of a novel chiral bisphosphine ligand. Studies by Pietruszka and co-workers report the stereodivergent allylboration of aldehydes10 and ketones51 using a tetraol-based a-chiral allylboronic dimer. The stereoconfiguration of the a-center of the boronate controls the E/Z selectivity of the homoallylic alcohol product, whereas the chiral tetraol controls the enantioselection. Hoveyda and co-workers have reported several studies on the catalytic asymmetric allylboration of fluoroketones52–54 and α- ketoesters55 using allyl-Bpin compounds directed by a chiral aminophenol ligand. Recently Meek and co-workers have shown how allylic 1,1- diboronate Bpin compounds can undergo asymmetric allylboration with ketones after an enantioselective transmetallation of one of the boron centers by a chiral copper catalyst.56 Efforts by Morken and co-workers have shown that allyl-Bpin compounds can be efficiently employed for the asymmetric allylboration of enones using a palladium57 or nickel58 catalyst. An early example of the allylboration of imines has been reported by Shibasaki and co-workers who have studied the asymmetric allylation of ketimines catalyzed by a chiral copper catalyst.59 The asymmetric allylboration of acyl aldimines using an allyl isopropylboronate and chi- 60 ral catalyst 3,3′-Ph2-BINOL was reported by Schaus and co-workers

7 A similar approach was taken to the allylboration of in situ generated sulfonylhydrazines. It was found that the allylboration products of these compounds undergo an allylic diazene rearrangement to afford a diene.61 Successful efforts have been made by Hoveyda and co-workers towards the allyboration of aldimines by reaction with allyl-Bpin compounds and a chiral aminophenol.62,63 The reaction of allylic 1,1-diboronate Bpin compounds reported by Meek and co-workers could also be extended to aldimines.64 Kobayashi and co-workers have demonstrated how a chiral Zn catalyst provided access to chiral α-amino acid derivatives through allylboration of a hydrazonoester with an α-branched allyl-Bpin compound.65

1.3 Synthesis of allenylboronates

One of the earliest reports of an allenylboronate came from Yama- moto and co-workers who have synthesized allenylboronic acid from propargyl magnesium bromide and trimethyl borate.66 Early research published by Hayashi and co-workers have shown that allenylboronates can be obtained via asymmetric hydroboration of 1,3-enynes with HBcat (catecholborane) catalyzed by a chiral palladium catalyst.67 The resulting axially chiral allenes could be obtained in up to 61% ee. More recently, the hydroboration approach to the synthesis of allenylboronates has been explored by Engle and co-workers68 and Hoveyda and co-workers.69 In these studies, chiral allenyl-Bpin compounds could be generated in excellent ee through enantioselective hydroboration of 1,3-enynes with HBpin or B2pin2 catalyzed by a chiral copper catalyst.

Ito and co-workers, 2008 10 mol% Cu(Ot-Bu) Me 10 mol% Xantphos H B pin Me + 2 2 • Bpin O OCO2Me THF, 50 oC PPh2 PPh2 24 2 25 Xantphos 60% yield Scheme 10. Cu-catalyzed borylation of propargylic carbonates as reported by Ito and co-workers.

A study by Ito and co-workers demonstrated a new Cu-catalyzed approach to the synthesis of allenylboronates such as 25.70 Propargylic carbonates were borylated with B2pin2 (2) using copper(I) tert-butoxide

8 and Xantphos to afford allenyl-Bpin compounds (Scheme 10). It was also demonstrated that the point chirality of an enantiopure propargylic carbonate could be transferred to axial chirality in the allene using this methodology. Szabó and co-workers have demonstrated a similar reactivity for the regiodivergent borylation71 and cross-coupling72 of propargylic carbonates using Pd/Cu dual catalysis. Recently, Ye and co-workers report the preparation of allenyl-Bdan compounds (1,8-diaminonaphtaleneboron) via a copper(I) catalyzed borylation of propargylic alcohols using diboron source Bpin-Bdan.73

1.4 Synthetic applications of allenylboronates

The first asymmetric propargylboration was reported by Yamamoto and co-workers. Allenylboronic acid was esterified with a dialkyl tar- trate and subsequently reacted with an aldehyde in an enantioselective manner.66 An early study by Hayashi and co-workers demonstrated that the axial chirality of asymmetric allenyl-Bcat (catechol ester) compounds could be translated into point chirality in an enantioselective propargylboration of aldehydes.67 Ito and co-workers have demonstrated similar reactivity of chiral allenyl-Bpin compounds towards al- 70 dehydes activated by Lewis acid BF3 · Et2O. The earliest example of a catalytic asymmetric propargylboration has been reported by Fandrick, Senanayake and co-workers who employed a propargylic Bpin compound together with a chiral copper catalyst to enantioselec- tively form an allenyl cuprate species which could undergo propargylation with aldehydes.74 A complementary reaction profile has been found by Jarvo and co-workers.75 They have reported that ketones and α- ketoesters react with an allenyl-Bpin compound in the presence of a chiral silver catalyst. The transient allenylsilver species that is generated under these conditions reacts to form densely functionalized quaternary stereocenters. The stereodivergent propargylboration reaction of aldehydes using allenyl-Bpin compounds catalyzed by a chiral phosphoric acid has been demonstrated by Roush76, Chen and co-workers.77 Schaus and co-workers have reported the use of organocatalyst 3,3′- Br2-BINOL 20-(S) in the asymmetric propargylboration of a broad variety of ketones using allenylboronic glycol esters such as 26 under mi- crowave irradiation (Scheme 11).78 It was even shown that a racemic

9 allenylboronate could undergo kinetic resolution in its reaction with a ketone.

Br Schaus and co-workers, 2011 HO 10 mol% 20-(S) HO O O + HO • B Ph O Ph µwaves Br 26 19a 27 (S)-3,3’-Br2BINOL 85% yield 20-(S) 94% ee Scheme 11. Catalytic asymmetric propargylboration using allenylboronates under microwaves reported by Schaus and co-workers.

A study by Petasis and co-workers has shown that allenylboronic acids can be utilized in a multicomponent reaction where an in situ formed imine is allenylated or propargylated.79 This so-called borono- Mannich reaction could be used to access racemic allenyl- and propar- gylamino acids. A subsequent study by Pyne and co-workers has demonstrated how an alcohol directing group can induce excellent re- giocontrol in the borono-Mannich reaction between allenylation (α-attack) and propargylation (γ-attack) by using secondary or primary amines respectively.80 Hoveyda and co-workers have shown that an allenyl-Bpin compound can react with an aldimine catalyzed by a chiral aminophenol ligand to afford homoallenyl amines in good enantioselectivity.81

1.5 Qualitative comparison of various organoboronates

Allyl- and allenylboronic acids have a more versatile reactivity profile compared to their boronate analogs. Reactivity in allylboration and propargylation reactions is mainly governed by the availability of the empty pp-orbital of boron to act as an electron acceptor. A qualitative comparison of reactivity for selected allylboronates is shown in Scheme 12. This comparison is also valid for the corresponding allenylboronates. The pinacol ester is the least reactive. The diol has restricted rotation along the B-O bond, positioning the oxygen’s lone pairs into place to donate electron density into the boron’s empty pp-orbital. This makes the boron a poorer Lewis acid. The acyclic alkyl ester has rotational freedom around the B-O bond, but its reactivity is still hampered. A

10 catechol ester is more reactive since the aromatic diol is withdrawing electron density from the oxygen’s lone pairs, hindering them from donating to the boron. The boronic acid is highly reactive due to its ability to self-condensate and form the anhydrous boroxine. The high reactivity of boroxines is attributed to the decreased conjugation of the geminal oxygen atoms. Inspection of its structure shows that it has only one oxygen atom per boron, where the others have two. The BINOL-ester is also expected to be a highly reactive species. The binaphthol moiety withdraws electron density from the geminal oxygens, and the seven- membered ring that makes up the BINOL ester is relatively strained.

B O O O OH O O O B B B B B B B O O O HO O O

R R R R R R

Increasing reactivity towards allylboration

Scheme 12. Qualitative comparison of the reactivity of selected allylboronates

The increased reactivity of boronic acids compared to their Bpin analogs has been taken advantage of in a number of recent publications (Scheme 13). In the total synthesis of diterpene (+)-pleuromutilin by Reisman and co-workers a catalytic asymmetric allylboration was carried out with allylboronic acid 28 using catalyst 20-(R).82 Zhang and co-workers have used allylboronic acids such as 22a for the asymmetric stereodivergent allylboration of iminoisatins such as 31.83

Reisman and co-workers, 2018 O HO 20 mol% 20-(R) (+)-pleuromutilin + OTrt OH tBuOH TrtO B 3 Å molecular sieves 28 OH 29 toluene, 0 °C 30 O O 44% yield

Zhang and co-workers, 2017 OH OH Ph Ph OH DCM B + N NH OH 3 Å molecular sieves O O 22a N N H 31 H 32 85% yield generated in-situ 95:5 d.r.

Scheme 13. Demonstrated utility of allylboronic acids in recent reports.

11 1.6 Aim of this thesis

The previous sections of this chapter have summed up the most important studies in the preparation and synthetic application of allyl- and allenylboronates. Significant innovations have been made, but there is still room for improvement when it comes to synthesis and application of allyl- and allenylboron reagents. Some aspects of the methodologies presented in this thesis solve the limitations of previously reported methodologies. These aspects can be summarized as follows:

1. The reactivity of allenylboronic acids is higher than that of its boronic ester analogs, such as allenyl-Bpin compounds. There- fore, access to allenylboronic acids is crucial for the further development of asymmetric propargylboration. This thesis aims to develop new procedures for the synthesis and purification of allenylboronic acids.

2. The strategy of using a BINOL-type catalyst for asymmetric allylboration and propargylboration has been reported previously. However, it has mainly been applied to aldehydes and ketones. With allyl- and allenylboronic acids in hand, we aimed to develop BINOL-catalyzed methodologies for asymmetric allylborations and propargylborations that go beyond the scope of previous studies.

3. Several homologation reactions of organoboronates by diazomethane derivatives have been studied previously, but a catalytic asymmetric method has been lacking. Therefore, this thesis aims to develop a methodology for the BINOL-catalyzed asymmetric homologation of olefinic organoboronates.

4. In addition, this thesis aims to provide a method for the purification of a-chiral allylboronic acids. These types of compounds have never before been reported. We have also aimed to explore the applications of these new a-chiral allylboronic acids in stereoselective synthesis.

12 2. Synthesis and applications of allenylboronic acids

2.1 Synthesis of allenylboronic acids by borylation of propargylic carbonates (Paper I)

The preparation of allenylboronates has long been a subject of synthetic studies (section 1.3). Reported methodologies have produced allenylboronic esters, but the highly reactive allenylboronic acids were mostly inaccessible. We envisioned a synthetic method in which a propargylic carbonate such as 33a is borylated using a copper(I) catalyst, reminiscent to the work published by Ito and co-workers.70 Key innovations introduced by our new procedure are (1) the use of tetrahy- droxydiboron 4 as a boron source, (2) addition of ethylene glycol (34) as an in situ protecting group of the allenylboronic acid product 35 and (3) the in situ generation of the copper catalyst. Tetrasubstituted boronic acid 35a was obtained in 76% 1H NMR yield via the new copper-catalyzed borylation (Table 1, entry 1). Al- lenylboronic acids 35 are sensitive to oxygen and silica gel. They can be obtained by quenching the basic reaction mixture with an aqueous 0.5 M HCl solution followed by extraction of the boronic acid 35 in degassed toluene. This work-up hydrolyzes the ethylene glycol and methyl esters on the boron and reveals the allenylboronic acid by 1H NMR. The identity of the active catalyst is probably CuOMe. This copper(I) species is generated in situ from mesitylcopper (I) and methanol. A number of alternative routes for in situ generation of the catalyst have been explored (Table 1, entries 2-5). It is possible to generate the catalyst from CuCl and a selection of alkali methoxides, resulting in a lowered 1H NMR yield (49-65%) for product 35a. Utilizing CuI combined with LiOMe proved inefficient, as the yield for product 35a was found to be 29%. Replacing phosphite ligand P(OMe)3 by phosphine PPh3 gave a decreased yield of 46% (entry 6). When PCy3 or P(O-iPr)3

13 was used, none of the desired allenylboronic acid was observed (entries 7 and 8). Instead, the analogous protodeborylated allene was found, indicating that boronic acid 35a is formed in the reaction mixture and undergoes subsequent decomposition. 1,3-Propanediol was found to be a poorly performing protecting group, resulting in 49% yield (entry 9). In fact, borylation in the absence of any diol gave 66% yield (entry 10) suggesting that 1,3-propanediol has a negative effect on the reaction. Omission of 3 Å molecular sieves revealed that these are not a critical factor in the reaction (entry 11). Increasing the reaction temperature from -20 °C to 0 °C (entry 12) gave more protodeborylated allene and a diminished yield of allenylboronic acid 35a, demonstrating its instability. A borylation reaction was attempted using THF as the solvent instead of MeOH (entry 13) and no reaction was observed.

Table 1. Various reaction conditions for the Cu-catalyzed borylation of propargylic carbonate 33a. 10 mol% mesitylcopper(I) OH allenylboronic HO OH 20 mol% P(OMe)3 OH • B acid OCO2Me + B B + HO OH HO OH MeOH 3 Å molecular sieves 33a 4 34 35a Ph -10 °C, 24 h Ph

Entry Conditions Crude yieldb (%)

1 No change 76

2 CuClc and KOMed are used instead of mesitylcopper 52

3 CuClc and NaOMed are used instead of mesitylcopper 49

4 CuClc and LiOMed are used instead of mesitylcopper 65

5 CuIc and LiOMed are used instead of mesitylcopper 29

6 PPh3 is used instead of P(OMe)3 46

7 PCy3 is used instead of P(OMe)3 0

8 P(O-iPr)3 is used instead of P(OMe)3 0

9 1,3-Propanediol is used instead of ethylene glycol 49

10 No ethylene glycol is added 66

11 No 3 Å molecular sieves are added 75

12 Reaction temperature is 0 °C 16e

13 THF is used instead of MeOH 0

a 33a (0.1 mmol), 4 (0.15 mmol), mesitylcopper(I) (0.01 mmol), P(OMe)3 (0.02 mmol), ethylene glycol (0.3 mmol) and 3 Å molecular sieves were stirred in MeOH (1 mL) at -10 °C for 24 h. bYield determined by 1H NMR using naphthalene as internal standard. c10 mol%. d20 mol%. eThe product decomposes via protodeborylation.

14 Using the optimized conditions (Table 1, entry 1), the borylation was extended to a number of propargylic carbonates. Boronic acid 35b was formed in excellent yield of 94% at 0.1 mmol scale, and a reduced yield of 62% at 3 mmol scale (Table 2, entry 1). Tetrasubstituted boronic acids 35c-e were obtained in 59-67% yield (entries 2-4). Car- bonates bearing a racemic quaternary stereocenter gave allenylboronic acids 35f-h in 63-85% yield (entries 5-7). The ability of a strained cyclopropane ring to be opened by a Cu-catalyzed borylation has previously been reported in the literature.84 For these conditions it was found that an activated cyclopropane ring could also be used as a leaving group, affording 35i in 59% yield (entry 8). The synthetic scope of this borylation is limited to tetrasubstituted allenylboronic acids. This is illustrated by the final entry in Table 2; trisubstituted allenylboronic acid 35j was obtained in a modest yield of 34%.

15 Table 2. Synthetic scope for the Cu-catalyzed synthesis of allenylboronic acids 35b-j.

10 mol% mesitylcopper(I) 3 2 3 R R R HO OH 20 mol% P(OMe)3 OH allenylboronic OH 2 acid OCO Me + B B + HO R • B 2 MeOH OH 1 HO OH R 1 33 4 34 3 Å molecular sieves R 35 -10 °C, 24 h

Entry Substrate Product Crude yieldb (%)

OH OCO2Me • B OH 1 33b 35b 94 62c

OH OCO Me • B 2 OH 2 33c 35c 67

OH OCO2Me • B OH 3 33d 35d 61

OH • B OCO Me OH 4 2 33e 35e 59

OH • B OCO2Me OH 5 33f 35f 80

OH • B OCO2Me OH 6 33g 35g 63

OCOPh OH • B OH OCO2Me PhOCO 7 33h 35h 83

MeO2C OH CO Me • B 2 MeO2C OH 8 CO2Me 33i 35i 59

OH • B OCO2Me OH 9 33j 35j 34

a 33 (0.1 mmol), 4 (0.15 mmol), mesitylcopper(I) (0.01 mmol), P(OMe)3 (0.02 mmol), ethylene glycol (0.3 mmol) and 3 Å molecular sieves were stirred in MeOH (1 mL) at -10 °C for 24 h. bYield determined by 1H NMR using naphthalene as internal standard. cYield at 3 mmol scale.

16 The proposed mechanism for the copper-catalyzed borylation reaction (Scheme 14) has been exemplified by the transformation of 33a → 35a. The catalytic cycle starts with a transmetallation between the in situ formed catalyst 36 and the diboron ester to generate the copper- boron species 37. Transmetallation between a similar copper(I) alkoxide and a diboron ester has previously been reported, and the resulting copper-boron species has been characterized.85 Addition of 37 into the triple bond of the propargylic carbonate gives species 38. This syn-addition is likely reversible. Decarboxylative elimination of the formed intermediate leads to the formation of allenyl boronate 35a and regen- eration of the catalyst 36. The insertion-elimination sequence leading to 33a → 35a can be regarded as a SN2’ substitution reaction.

OR 35a • B RO OR OR I LnCu OMe B B + CO RO OR 2 36 Ph MeO OR B OR

I OR Cu Ln OR B OCO2Me RO I LnCu B 37 Ph OR 38

OCO Me Ph 2

33a Scheme 14. Proposed catalytic cycle for the Cu-catalyzed borylation reaction.

The crude allenylboronic acid extract that is obtained from the work- up procedure can be used without further purification for propargylboration (see section 2.2). However, if it is necessary, the allenylboronic acids can be further purified. A methodology for the purification and deprotection of boronates86 developed by Santos and co-workers was applied to the newly synthesized allenylboronic acids. Stirring the extracted boronic acid 35a in the presence of diethanolamine (39) resulted in a solid precipitate of 40a (Scheme 15), which was isolated by filtra- tion. Column chromatography of 40a on silica gel resulted in decomposition.

17 crude pure OH allenylboronic H H OH allenylboronic N O N • B acid HO OH • B • B acid OH 39 HCl (aq.) OH O toluene toluene, r.t., 30 min 35a 40a 35a 73% yield Ph Ph extraction Ph solid precipitate

crude pure OH allenylboronic H H OH allenylboronic N O N • B acid HO OH • B • B acid OH 39 HCl (aq.) OH O toluene toluene, r.t., 24 h 59% yield 35b 40b extraction 35b solid precipitate Scheme 15. Purification of the allenylboronic acids by esterification with diethanolamine 39.

Diethanolamine ester 40a was deprotected by a biphasic mixture of aqueous 0.5 M HCl and toluene to reobtain the purified allenylboronic acid 35a in 73% overall yield. The same purification sequence could be performed for 35b, which was obtained in 59% yield.

H pinacol N O HO OH H ester O N • B 39 • B O X O 41a toluene, 40 °C, 48 h 40b no reaction Ph Ph Scheme 16. Attempted transesterification of pinacolester 41a with diethanolamine 39.

In the original report by Santos and co-workers an alkyl-Bpin ester was transesterified with diethanolamine.86 A similar transesterification has been attempted with pinacol ester 41a (Scheme 16). However, even at elevated temperature and elongated reaction time, transesterification to 40b was not observed for allenylboronic ester 41a. A selection of alternative diboron sources were explored for the borylation of propargylic carbonate 33a (Scheme 17). Using B2pin2 2, the pinacol ester 41a was obtained using the same borylation conditions as described above. The pinacol was subsequently removed via an oxi- dative hydrolysis procedure previously described by Petasis and co- workers,79 providing an alternative path towards boronic acid 35a in 63% 1H NMR yield.

18 pinacol allenylboronic ester acid 10 mol% mesitylcopper(I) 20 mol% P(OMe)3 O 3 equiv. NaIO4 OH • B OCO Me + B2pin2 • B 2 MeOH O OH HCl, THF:H2O (4:1) 3 Å molecular sieves 33a 2 41a r.t., 2h 35a -10 °C, 24 h Ph Ph 63% yield Ph

10 mol% mesitylcopper(I) 20 mol% P(OMe) O neopentyl 3 ester OCO Me + B2nep2 • B 2 MeOH O 3 Å molecular sieves 33a 42 43 -10 °C, 24 h Ph Ph 67% yield

H H 10 mol% mesitylcopper(I) 20 mol% P(OMe) O O 3 + • B OCO2Me B O O O MeOH B pinanediol 3 Å molecular sieves 33a O 44 45 ester Ph -5 °C, 5 h H 52% yield Ph

Scheme 17. Borylation of carbonate 33a using various alternative diboron sources.

A borylation with B2nep2 (42) afforded the neopentyl ester 43 in 67% 1H NMR yield. Attempted purification of 43 using silica gel chromatography was unsuccessful. A direct synthesis of the analogous pinanediol ester 45 was carried out using the corresponding diboron ester 44. Using conditions that were slightly modified in temperature and reaction time, allenylboronate 45 was obtained in 52% isolated yield after silica gel chromatography.

2.2 Application of allenylboronic acids to catalytic asymmetric propargylation of ketones (Paper I)

Allenylboronic acids 35a-e exhibited a broad scope in propargylboration reactions. Stirring boronic acid 35b and 4-bromobenzaldehyde (15b) for 10 minutes at room temperature in the presence of 3 Å molecular sieves resulted in homopropargylic alcohol 46a in 87% isolated yield (Table 3, entry 1). The analogous 4-bromoacetophenone (19b)

19 afforded alcohol 46b in 72% isolated yield after 24 h at room temperature (Table 3, entry 2). Formation of the sterically demanding C-C bond between two quaternary carbons required no activation, demonstrating the high reactivity of allenylboronic acid 35b. Aldimines 47a and 47b were also propargylated in yields ranging between 63-83% using the same conditions (entries 3-5). The homopropargylic amine resulting from 3,4-dihydroisoquinoline (48a) and boronic acid 35b was isolated in a satisfying yield of 96% (entry 6). Furthermore, the indoline 46g was obtained in 82% isolated yield from boronic acid 35a (entry 7). Even though indole (49a) is an enamine, it is propargylated at the 2- position because it has a reactive imine tautomer.

Table 3. Propargylboration of allenylboronic acids with various electro- philes. R2 toluene OH allenylboronic 1 acid X 3 Å molecular sieves X R2 R R2 • B + OH Y 2 Y 1 R 24 h, r.t. R 35 R2 R2 46

Entry Boronic acid Electrophile Product Yieldb (%)

O OH H 1 35bc 15b 46a 87 Br Br

O HO

Me Br 2 35b Br 19b 46b 72 NHMe NMe

H 3 35b 47a 46c 63

NH2 NSiMe3 H 4 35b 47b 46d 83

NH2 NSiMe3 H 5 35e 47b 46e 65

NH N

6 35b 48a 46f 96

NH NH 7 35a 49a Ph 46g 82

aElectrophile (0.15 mmol), 35 (0.1 mmol) and 3 Å molecular sieves are stirred in toluene at r.t. for 24 h. bIsolated yield. cReaction time is 10 min.

20 Allenyl-Bpin compounds are known to react with aldehydes when activated by a Lewis acid.70 Submitting pinacol ester 41b and 4-bromobenzaldehyde (15b) to identical reaction conditions as described above (Table 3, entry 1), did not result in homopropargylic alcohol 46a (Scheme 18). The same unreactive outcome was observed between pinacol ester 41a and ketone 19b or imine 47a. The inert behavior of the Bpin compounds highlights the versatile reaction profile of allenylboronic acids under similar reaction conditions.

toluene O pinacol 3 Å molecular sieves OH O ester + • B H O X Br 10 min, r.t. Br 41b 15b 46a no reaction

toluene O pinacol 3 Å molecular sieves HO O ester + • B Me Ph O X Br 24 h, r.t. Br Ph 41a 19b 46h no reaction

toluene NMe pinacol 3 Å molecular sieves NHMe O ester + • B H Ph O X 24 h, r.t. Ph 41a 47a 46i no reaction

Scheme 18. Attempted propargylboration reactions using pinacol esters 41a-b.

Pinane derivatives are commonly used as chiral auxiliary groups on boron.38 Therefore, pinanediol ester 45 could be envisioned to induce stereoselection in a possible propargylboration reaction. In an attempted reaction of 45 and 4-bromoacetophenone (19b) at identical conditions as described above (Table 3, entry 2) no reactivity was observed after 24 hours (Scheme 19).

H toluene O O 3 Å molecular sieves HO • B + O Me X Ph pinanediol 24 h, r.t. ester Br Br 45 19b 46j no reaction Ph

Scheme 19. Attempted asymmetric allylboration of ketone 19b with chiral allenylboronic ester 45.

21 Catalytic asymmetric propargylation of ketones has been studied in many published works (see section 1.4 above).50,74,75,78 Tetrasubstituted allenylboronic acid 35b can undergo a stereoselective propargylboration reaction with ketone 19b in the presence of BINOL catalyst 20-(S) and 2 equivalents of EtOH. The resulting alcohol 46b was obtained in 95% isolated yield and 94% ee (Table 4, entry 1). This method is valuable because it enables stereoselective access to densely functionalized propargylic alcohols bearing two vicinal quaternary carbons. The im- portance of EtOH to the stereoselection was revealed when the reaction was carried out without EtOH, resulting in 44% ee (entry 2). Even when a full equivalent of BINOL 20-(S) was used in the absence of EtOH, only 77% ee was observed (entry 3). Substituting EtOH for its bulkier analogue t-BuOH at otherwise optimized conditions resulted in a modest 55% ee (entry 4). When the enantiomer 20-(R) of the catalyst was employed, the expected product 46b-(S) was obtained in comparable yield and ee (entry 5).

Table 4. Varied reaction conditions for the catalytic asymmetric propargylboration of ketone 11b.

Br O 15 mol% 20-(S) HO HO OH 2 equiv. EtOH + Me • B HO OH toluene Br 3 Å molecular sieves Br Br 35b 19b 48 h, r.t. 46b (S)-Br2-BINOL 20-(S)

Entry Conditions Yieldb (%) ee (%)

1 No change 95 94

2 15 mol% 20-(S) and no EtOH is used 86 44

3 100 mol% 20-(S) and no EtOH is used 82 77

4 t-BuOH is used instead of EtOH 91 55

5 15 mol% 20-(R) was used instead of 20-(S) 93 -94

a35b (0.1 mmol), 20, and EtOH or t-BuOH (0.2 mmol) are stirred in toluene with 3 Å molecular sieves for 3 h. 19b (0.15 mmol) was added and the mixture is stirred at r.t. for 48 h. bIsolated yield.

The asymmetric propargylboration reaction was carried out as described above with acetophenones 19a-f (Table 5). Parent acetophenone (19a) gave the corresponding alcohol in 75% yield and 97% ee (entry 1). A number of substituents at the 4-position were examined, namely cyano 19c (67% yield, 91% ee, entry 2) and acetate 19d (90% yield,

22 96% ee, entry 3). A reaction between boronic acid 35c and 4-bromoacetophenone 19b gave 77% yield and 90% ee (entry 4). The homopropargylic alcohols 46k-q were all obtained as viscous oils that could not be crystallized for single crystal X-ray diffraction. A selection of 4-sulfone substituted alcohols 46o-q were prepared in uniform yields ranging 62- 64% and 94-99% ee (entries 5-7). Homopropargylic alcohol 46o was obtained in 70% yield and 96% ee on a 0.5 mmol scale, using a double catalyst loading of 30 mol% 20-(S) and 90 h reaction time. It was expected that these sulfones could be crystallized to allow single-crystal X-ray diffraction, but the crystallization attempts were unsuccessful.

Table 5. Synthetic scope for the catalytic asymmetric propargylboration of ketones. 15 mol% 20-(S) R2 O HO R1 OH allenylboronic 2 equiv. EtOH acid + R2 • B Me OH toluene 2 2 3 R R R1 R 3 Å molecular sieves R3 35 19 48 h, r.t. 46

Entry Boronic acid Acetophenone Product Yieldb (%) ee (%)

O HO

1 35b Me 19a 46k 75 97 H O HO

Me 2 35b 19c 46l 67 91 NC NC O HO

Me 3 35b 19d 46m 90 96 AcO AcO O HO 4c 35c Me 19b 46n 77 90 Br Br O HO Me d 5 35b O 19e O 46o 62 94 e e S S 70 96 O O O HO Me c O Ph 6 35a 19e O 46p 63 96 S S O O O HO Me O 7c 35e 19f O 46q 64 99 S S Ph Ph O O

a35 (0.1 mmol), 20-(S), and EtOH (0.2 mmol) are stirred in toluene with 3 Å molecular sieves for 3 h. 19 (0.15 mmol) is added and the mixture is stirred at r.t. for 48 h. bIsolated yield. cReaction time is 72 h. dReaction time is 90 h. 20 mol% 20-(S). e0.5 mmol scale, using 30 mol% 20-(S) and 90 h reaction time.

23 After several attempts of derivatization, the biphenyl ester 51 was adequately crystallizable for structural analysis. Compound 51 was obtained in 71% isolated yield by deprotonation of tertiary alcohol 46o using n-BuLi, followed by esterification with biphenyl acyl chloride 50 (Scheme 20). From the resulting crystal structure, the configuration of the stereogenic center was assigned as (R). Based on this finding, all of the analogues 46k-q were assigned accordingly.

HO 1. n-BuLi

O 2. O O S O Cl O 46o O S 71% yield Stereocenter assigned as (R) 50 O 51 by single crystal X-ray diffraction

Scheme 20. Derivatization of alcohol 46o to obtain crystalline ester 51.

It was not possible to efficiently react racemic allenylboronic acid 35g under the reaction conditions as described in Table 5 above. In- creasing the stoichiometry of BINOL 20-(S) to a full equivalent, omit- ting EtOH from the reaction, and heating the mixture to 45 °C resulted in the densely functionalized alcohol 52 in 31% isolated yield and 96% ee (Scheme 21). This tertiary alcohol bearing two adjacent quaternary stereocenters was obtained as a single diastereomer. It is noteworthy to point out that allenylboronic acid 35g did not react with ketone 19b when BINOL 20-(S) was excluded from the reaction mixture. This observation points to the activating effect that BINOL has on boronic acids87 as well as highlighting the steric demand of the C-C bond that needs to be formed in order to produce alcohol 52.

O HO OH 1 equiv. 20-(S) isolated yield 31% + (62% with respect to the • B Me OH toluene reactive enantiomer of 35g) Br 3 Å molecular sieves Br 22 h, 45 °C >99:1 d.r., 96% ee racemic 35g 19b 52

Scheme 21. Kinetic resolution of boronic acid 35g to afford alcohol 52 in high stereoselectivity.

It can be concluded from the perfect diastereomeric ratio and excellent ee, that only one of the two enantiomers of boronic acid 35g will

24 participate in a reaction under these conditions. Schaus and co-workers have reported previous examples of chiral racemic allenylboronates reacting in high selectivity.78 This example of kinetic resolution (Scheme 21) results in a theoretical maximum yield of 50%. When this is taken into consideration, it can be concluded that the isolated yield of 52 is 62% with respect to reaction of a single enantiomer of 35g. In previous studies by Roush, Chen, and Schaus the stereoselection in propargylboration reactions using allenylboron derivatives was based on a model assuming a six-membered transition state.76–78 The model for the above reaction catalyzed by BINOL-type catalyst 20-(S) is also based on this approximation. The proposed stereoselection model for the asymmetric propargylation is given in Scheme 22 for the reaction of allenylboronic acid 35b with ketone 19a. The reactive species 53 is a di-ester of allenylboronic acid 35b and catalyst 20-(S). This assumption is based on theoretical studies that conclude that di-esters of boronic acids and BINOL-type ligands are more reactive than mono-esters of BINOL.87,88

Br TS 1 O OH Re-face approach Me O B O Ph • Disfavored n-Bu Br 46k-(S) Me Me (S) minor enantiomer Br O O + Me • B O 19a Br 53 Br TS 2 O HO Me O B O Si-face approach Ph • Favored n-Bu Br Me Me (R) 46k-(R) major enantiomer Scheme 22. Proposed stereoinduction model for the facial selectivity of the propargylboration reaction.

The BINOL ester 53 has two diastereotopic faces. When ketone 19a approaches BINOL ester 53 from the Re-face (Re-face of the ketone, TS 1), it leads to the observed minor enantiomer 46k-(S) (Scheme 22). It is proposed that this transition state is disfavored due to a steric clash (marked in red) between the methyl group of the ketone, and the Br-atom at the 3 position of BINOL 20-(S). Si-face approach of ketone 19a (TS 2) leads to the observed major enantiomer 46k-(R). In this case

25 there is no significant steric congestion between the ketone 19a and the Br-atoms on the 3 and 3’ positions of BINOL ester 20-(S) in TS 2. It has been demonstrated that allenylboronic acids will react with ketones in a racemic propargylation reaction without the need for activation (Table 3). In the context of asymmetric catalysis, this racemic background reaction is in competition with the enantioselective reaction. The role of EtOH is to suppress the direct racemic propargylation. Experimental studies have demonstrated that aliphatic alcohols have the potential to inhibit the reactivity of organoboronic acids.87 The proposed catalytic cycle of the asymmetric propargylation (Scheme 23) starts with the esterification of the allenylboronic acid 35b to form ethyl ester 54. Indeed, an 1H NMR experiment in which 35b in toluene-d8 and 2 equiv. of EtOH were stirred at room temperature in the presence of 3 Å molecular sieves revealed that there is no free boronic acid present after 1 hour. Ester 54 is inhibited from the direct reaction with ketone 19a. It is transesterified with BINOL catalyst 20-(S) to form the reactive chiral ester 53, which undergoes asymmetric propargylation according to the transition state outlined in Scheme 22. The second role of EtOH in the reaction is to liberate the BINOL moiety from the initial product 55 through transesterification, thereby regenerating catalyst 20-(S).

B(OR)2 OEt OH Br 2 EtOH O • B • B OEt OH Ph HO 46k 54 35b HO 20-(S) Br

2 EtOH 2 EtOH

Br Br O O B • B O O O Br Ph Br 53 55

Me 19a

Scheme 23. Proposed catalytic cycle for the catalytic asymmetric propargylboration reaction.

26 2.3 Application of allenylboronic acids towards chiral a-amino acid derivatives (Paper II)

Amino acids are the “building blocks of life”. Consequently, there is high interest in development of new methodologies for the synthesis of chiral amino acids. Racemic79,89 and enantiopure90 chiral α-amino acid derivatives have been obtained by propargylboration in previous studies. Utilization of allenylboronic acids provides a novel catalytic asymmetric methodology to these valuable products. Reacting hydrazonoester 56 with allenylboronic acid 35b in the presence of 10 mol% 57-(S) afforded chiral α-amino acid derivative 58a-(R) in 79% isolated yield and 92% ee (Table 6, entry 1). Previous metal- catalyzed procedures89,90 for propargylation of hydrazones have shown competing allenylation (α-attack) and propargylation (γ-attack) due to an allenyl-metalloid intermediate. The reaction presented here proceeds via direct propargylboration and has excellent regioselectivity. Opti- mized isolated yield was observed after 48 h, however it was found that a shorter reaction time of 24 h already resulted in an isolated yield of 67% and comparable 90% ee (entry 2). Doubling the catalyst loading from 10 mol% to 20 mol% did not result in a significant improvement of the yield or ee (entry 3). It is common for reactions to become less selective at raised temperatures. Accordingly, elevating the reaction mixture to room temperature resulted in a drop of the observed enantioselectivity to 76% ee (entry 4). Substituting catalyst 57-(S) for its brominated analogue 20-(S) did not prove successful, leading to a low 25% isolated yield and 28% ee (entry 5). Interestingly, addition of 2 equiv. EtOH to the reaction mixture completely destroyed the enantioselectivity of the reaction (entry 6). This is in contrast with previous studies of asymmetric reactions of boronic acids catalyzed by BINOL- type catalysts. These studies have shown that addition of an aliphatic alcohol enhances the enantioselectivity due to the alcohol inhibiting the racemic background reaction that is in with competition the catalytic process.19,48 In this case, it has been found that the racemic background reaction does not happen under the optimized conditions. A reaction in the absence of BINOL 57-(S) under otherwise identical conditions did not afford any product (entry 7). This observation once again highlights the activating effect of BINOL on the reactivity of organoboronic esters. When the reaction temperature is increased to room temperature, it is

27 found that hydrazonoester 56 still reacted directly with boronic acid 35b in 68% isolated yield (entry 8).

Table 6. Varied reaction conditions for the catalytic asymmetric propargylboration of hydrazonoester 56.

H O Ph O Ph HO OH conditions + NH NH • B HO OH N toluene HN EtO 3 Å molecular sieves EtO H (S)-BINOL 35b O 56 O 58a-(R) 57-(S)

Entry Catalyst Additive t (h) T (°C) Yieldb (%) ee (%)

1 10 mol% 57-(S) None 48 0 79 92

2 10 mol% 57-(S) None 24 0 67 90

3 20 mol% 57-(S) None 48 0 78 94

4 10 mol% 57-(S) None 24 r.t. 83 76

5 10 mol% 20-(S) None 48 0 25 28

6 10 mol% 57-(S) 2 equiv. EtOH 48 0 52 0

7 No catalyst None 48 0 0 N/A

8 No catalyst None 24 r.t. 68 0

a35b (0.12 mmol), 56 (0.1 mmol) and 57-(S) (0.01 mmol) are stirred in toluene with 3 Å molecular sieves. bIsolated yield.

A 1 mmol scale-up of the synthesis of chiral α-amino acid derivative 58a-(R) could be carried out without a significant loss in yield or enantioselectivity (Table 7). It is fortunate that commercially available catalyst 57-(S) is an order of magnitude cheaper compared to its 3,3’- substituted analogues, making it especially suitable for a scalable synthesis. Substituting the catalyst for its enantiomer 57-(R) resulted in the expected product 58a-(S) in 81% isolated yield, which has the same absolute configuration as naturally occurring chiral α-amino acids. Us- ing the same catalytic system, allenylboronic acids 35a-e could be applied for the preparation of a selection of chiral homopropargylic α-amino acid derivatives 58b-e in 56-66% yield and 84-92% ee.

28 Table 7. Synthetic scope for the catalytic asymmetric propargylboration of hydrazonoester 67.

O Ph O Ph R2 10 mol% 57-(S) OH allenylboronic + NH NH 1 R2 • B acid N HN R OH toluene, 0 °C, 48 h EtO 3 Å molecular sieves EtO R1 35 O 56 O R2 R2 58

O Ph O Ph O Ph

NH NH NH HN HN HN EtO EtO EtO 58a-(R) 58a-(S)d 58be O 79% yieldb O 81% yieldb O 66% yieldb 75% yieldb, c 92% ee 84% ee 92% ee O Ph O Ph O Ph

NH NH NH HN Ph HN HN EtO EtO EtO 58c 58df 58eg O O 66% yieldb 56% yieldb O 63% yieldb 90% ee 92% ee 92% ee

a35 (0.12 mmol), 56 (0.1 mmol) and 57-(S) (0.01 mmol) are stirred in toluene with 3 Å molecular sieves. bIsolated yield. cReaction at 1 mmol scale. dUsing 57-(R) instead of 57-(S). eReaction temperature is -10 °C. fReaction time is 72 h gReaction time is 24 h.

Unfortunately, products 58a-e resisted crystallization and could not be analyzed via X-ray diffraction. Following a methodology reported by Burk and co-workers91 the N-N bond of the hydrazine in 58a-(R) was cleaved using SmI2, and the resulting amino ester 59 was obtained in a modest yield of 37% (Scheme 24). A side reaction of aminoester 59 to form the corresponding diketopiperazine is likely the source of the reduced yield. The absolute configuration of the chiral α-amino ester could be elucidated by synthesis of the Mosher’s amides 61. Mosher’s acid and the corresponding acyl chloride 60 have been well studied and are often used to elucidate stereocenters of secondary alcohols92 and amines.93 Scheme 24 reports the difference in chemical shift Δ�SR that was found using 1H NMR, allowing for unambiguous assignment of the stereochemistry for 58a-(R) as (R). Analogues 58b-e were assigned accordingly.

29 O Difference in chemical shift SR O Ph Δδ = δ61-(S) − δ61-(R) Cl 60 NH 2.2 equiv. SmI2 MeO CF3 MPTA +0.07 HN NH2 HN -0.04 +0.04 EtO EtO O THF / MeOH 2 equiv. DIPEA -0.04 +0.04 10 mol% DMAP +0.01 O 30 min, r.t. O O+0.05 +0.18 DCM, r.t., 1 h 58a-(R) 59 37% yield 61 56% yield

Scheme 24. Structural elucidation of amino acid derivative 68a by the Mosher 1H NMR method.

Mosher amides (such as 61) will adopt a conformation in which the α-hydrogen and the CF3 group are both in the same plane as the car- 94 bonyl group (See Scheme 25). The chemical shift values of the CO2Et moiety in 61-(S) are lower than values of the CO2Et moiety in 61-(R), hence the negative difference in chemical shift Δ�SR. The reason for this is the anisotropic shielding of the CO2Et moiety in 61-(S) by the phenyl group (Scheme 25). Conversely, Δ�SR is positive for the alkyne moiety, as it is shielded by the phenyl group in 61-(R). It is worthwhile to point out that the stereochemical label of acyl chloride 60-(R) is not carried through into the corresponding product amide 61-(S). This is strictly not an inversion of stereochemistry, but rather a consequence of reordered priority according to the Cahn-Ingold-Prelog naming con- vention.

n-Bu H F H NH O H F 2 (R) MeO HN H,O,CF O EtO O 3 F EtO coplanar + Cl n-Bu O N (S) CF3 H Ph O MeO CF3 O(S) OEt MeO 59 60-(R) 61-(S) 61-(S) anisotropic magnetic shielding of CO2Et moiety

anisotropic magnetic shielding of alkyne moiety

n-Bu H F H NH O H F 2 (S) HN H,O,CF O EtO O 3 F EtO coplanar + Cl n-Bu O N (R) CF3 H OMe O CF3 OMe MeOO(R) OEt Ph 59 60-(S) 61-(R) 61-(R)

Scheme 25. Conformation and magnetic shielding in Mosher amide 61.

30 n-Bu n-Bu H F F O OEt O O H F F ϕ1 F O F ϕ2 EtO F O N ϕ1 ϕ F O n-Bu 2 F H Ph N H ϕ2 OEt MeO H Ph ϕ N MeO 1 H MeO Ph 61-(S) 61-(S)’ 61-(S)’’ 0.0 kcal mol-1 +1.6 kcal mol-1 +3.2 kcal mol-1 = 1o = 29o = -62o = 25o = -151o = 27o ϕ1 ϕ2 ϕ1 ϕ2 ϕ1 ϕ2

Scheme 26. Conformation of 61-(S) confirmed by DFT calculations.

In order to confirm that Mosher amide 61-(S) adopts the H,O,CF3 coplanar conformation, the dihedral angle j1 has been examined by DFT calculations† (Scheme 26). Indeed, in the lowest energy conformation 61-(S), the dihedral angle j1 is found to be 1° and the dihedral angle j2 is found to be 29°. Comparison of 61-(S) with its rotamers 61-(S)’ and 61-(S)’’ results in an increase in relative energy of 1.6 kcal mol-1 and 3.2 kcal mol-1 respectively.

The facial selectivity that governs the enantioselection in the propargylation of hydrazonoester 56 (Scheme 27) probably follows a similar model to that of the ketones (Scheme 22). It is exemplified by the reaction of 56 with boronic acid 35b and catalyst 57-(S) in Scheme 27. Si-face approach of the hydrazonoester to BINOL ester 62 (Si-face of the hydrazonoester, TS 3) results in the observed minor enantiomer 58a-(S). It is likely that TS 3 is disfavored due to steric repulsion (marked) between the ethyl ester of 56 and the hydrogen atom on the 3’ position of the BINOL moiety. This steric repulsion is absent in the favored transition state TS 4 resulting from Re-face approach of the hydrazonoester, leading to the observed major enantiomer 58a-(R).

†The calculations were performed using the B3LYP-D3 functional95–98 as implemented in the Gaussian 09 program package.99 The 6-31G(d,p) basis set was used for the geometry optimizations. Implicit solvation using the SMD100 model with the parameters for chloroform was included in the geometry optimization. Single-point calculations were carried out on the basis of the optimized structures with the 6-311+G(2d,2p) basis set. The reported energies (kcal mol-1) are Gibbs free energies in solution.

31 EtO O H O Ph Si-face approach n-BuO NH Me HN • B N O Disfavored EtO Me H HN O O 58a-(S) H O Ph TS 3 (S) Ph O minor enantiomer + NH • B N O EtO H 62 56 O Ph O EtO O H n-BuO NH Me HN • B Re-face approach N O Favored EtO Me HN O H O 58a-(R) TS 4 (R) Ph major enantiomer Scheme 27. Proposed stereoinduction model for the facial selectivity of the propargylboration reaction.

The proposed catalytic cycle is exemplified by the reaction of 56 with boronic acid 35b and catalyst 57-(S) in Scheme 28. Since the reaction is carried out under anhydrous conditions, it is probable that allenylboronic acid 35b exists as its boroxine 63. This is possible due to the absence of aliphatic alcohol that would otherwise break up the trimeric anhydride 63. Esterification of the boroxine with BINOL 57-(S) results in the reactive chiral ester 62, and also releases one equivalent of H2O. Asymmetric propargylation occurs between 62 and 56 according to TS 4 in Scheme 27, forming the immediate product 64. One possible pathway for the BINOL catalyst 57-(S) to be released from 64 is through hydrolysis with two equivalents of H2O, which is one equivalent more than what is released during esterification of the boroxine. The notion that the catalytic system would require a full equivalent of H2O to be turned over implies that the reaction conditions might not be strictly anhydrous.

32 3 Å O Ph B O O molecular OH 58a sieves H • (RO)2B NH • B B B N HO O OH EtO 63 35b HO 57-(S) boroxine O H

H2O 2 H2O

H H O O BzHN B • B N O O H OEt H 62 O 64

NHBz N EtO 56 O

Scheme 28. Proposed catalytic cycle for the alcohol-free catalytic asymmetric propargylboration reaction.

An alternative mechanism could be considered for direct anhydrous transfer of the BINOL moiety from immediate product 64 to boroxine 63, without the intermediate stage of “free” BINOL 57-(S). This specu- lative pathway (Scheme 29) would be more agreeable with the anhydrous conditions of the reaction mixture.

H H B O O O O BzHN B(OR)2 • B B BzHN B N O N O • B + O + OEt H OEt H O 63 O 64 62 58a

Scheme 29. Alternative pathway for the anhydrous transfer of BINOL 57-(S).

33 3. Synthesis and applications of allylboronic acids

3.1 Applications of achiral allylboronic acids in stereoselective synthesis (Papers II and III)

3.1.1 Stereodivergent preparation of chiral a-amino acid derivatives (Paper II)

Geranylboronic acid 22a is a γ,γ-disubstituted allylboronic acid that is prepared from the commercially available monoterpenoid geraniol (Scheme 3).18 It has been utilized in catalytic asymmetric allylboration with ketones (Scheme 9).19 Submitting allylboronic acid 22a to identical conditions as reported for the propargylboration of hydrazonoester 56 resulted in chiral α-amino acid derivative 65a containing two vicinal stereocenters (Scheme 30). This catalytic asymmetric allylboration reaction could be carried out in a fully stereodivergent manner. Catalyst 57-(S) resulted in the formation of the (R,S) stereoisomer 65a in 71% isolated yield, 84% ee and 97:3 d.r. Employing 57-(R) afforded the (S,R) stereoisomer 65b in 78% isolated yield with identical enantio- and diastereoselectivity. Nerylboronic acid 22b, the Z-isomer of 22a, could be used under identical conditions to access the (R,R) isomer 65c from BINOL 57-(S) in 81% isolated yield (Scheme 31). The (S,S) isomer 65d could be obtained from BINOL 57-(R) in 75% isolated yield. The enantioselectivity for both of these products was 84% ee, while the observed diastereoselectivity was 98:2 d.r., which is slightly more selective than epimers 65a-b.

34 E 10 mol% NHBz OH NHBz 57-(S) HN B N (R,S) EtO OH geranylboronic + EtO 3 Å molecular sieves acid 71% yield toluene, 0 °C, 48 h O O 84% ee 22a 56 65a 97:3 d.r.

E 10 mol% NHBz OH NHBz 57-(R) HN B N (S,R) geranylboronic + EtO OH EtO acid 3 Å molecular sieves toluene, 0 °C, 48 h O 78% yield O 84% ee 22a 56 65b 97:3 d.r.

Scheme 30. Asymmetric allylboration of hydrazonoester 56 with geranylboronic acid 22a.

10 mol% NHBz Z NHBz 57-(S) HN N (R,R) nerylboronic + EtO OH EtO 3 Å molecular sieves B acid toluene, 0 °C, 48 h O 81% yield OH O 84% ee 56 65c 98:2 d.r. 22b

10 mol% NHBz Z NHBz 57-(R) HN N (S,S) nerylboronic + EtO OH EtO 3 Å molecular sieves B acid toluene, 0 °C, 48 h O 75% yield OH O 84% ee 56 65d 98:2 d.r. 22b

Scheme 31. Asymmetric allylboration of hydrazonoester 56 with nerylboronic acid 22b.

Similar to its propargylic analog, the homoallylic chiral α-amino acid derivative 65a could be reduced in modest yield to afford the corresponding amino ester 66. Using Mosher’s amide 67, the absolute configuration at the α-carbon could be assigned as (R). This is the same configuration as was found for the propargylic analog 58a. The differences in chemical shift Δ�SR that were found for the 1H NMR analysis of the Mosher’s amides 67 are reported in Scheme 32.

35 O Ph O Difference in chemical shift ΔδSR = δ67-(S) − δ67-(R) NH Cl HN 60 MPTA 2.2 equiv. SmI2 NH2 MeO CF3 HN EtO -0.03 +0.09 EtO O +0.12 -0.03 +0.28 O THF / MeOH O 2 equiv. DIPEA O +0.10 +0.22 30 min, r.t. 10 mol% DMAP +0.06 65a 66 67 +0.09 DCM, r.t., 1 h 29% yield 46% yield +0.01 +0.04

Scheme 32. Structural elucidation of amino acid derivative 65a by the Mosher 1H NMR method.

Several attempts at derivatization of amino ester 66 have been made towards the goal of a structural analysis by X-ray diffraction. Unfortu- nately, all these derivatives were found to be viscous oils and an ade- quate crystalline sample could not be obtained. Ultimately the 4-bromobenzoyl derivative 69 of hydrazine 65b was obtained through an amide bond formation with 4-bromobenzoyl chloride (68) (Scheme 33). Even though this was an enantioenriched sample of amide 69, the major and minor enantiomer crystallized together in a single unit cell, which only allowed for the elucidation of the relative stereochemistry.

Br O 69 X-ray crystal structure Cl NHBz HN Br 68 NHBz EtO O N EtO O 2 equiv. DIPEA 10 mol% DMAP 65b 69 O DCM, r.t., 24 h 47% yield

Scheme 33. Amide 69 allowed for the elucidation of the relative stereochemistry of products 65a-d.

Allylborations have been well-studied, and experimental work sug- gests that hydrazones (such as 56) undergo allylboration according to the Zimmerman-Traxler-type transition state.22 Similar to the models of asymmetric induction that have already been presented in Schemes 22 and 27, it is reasonable to assume that the active species is the chiral BINOL ester 70 of the allylboronic acid (Scheme 34). The stereoinduction for the allylboration follows the same facial selectivity as the propargylboration in Scheme 27. In the event of Si-face approach of the hydrazonoester 56 to 70, it is highly probable that TS 5 has a higher

36 activation barrier due to steric clash (marked) arising between the ethyl ester of 56 and the hydrogen atom on the 3’ position of the BINOL moiety. This is confirmed by the (S,R) enantiomer 65b being identified as the minor product. Re-face approach of hydrazonoester leads to TS 6 which forms the (R,S) enantiomer 65a as the major product. There- fore, it can be concluded that TS 6 has a lower activation barrier.

TS 5 NHBz H HN EtO O Si-face approach O EtO N B Disfavored O O 65b HN O (S,R) H minor enantiomer H Ph O NHBz + N B O EtO 70 H 56 O TS 6 H NHBz HN EtO O O EtO B Re-face approach N O Favored O H 65a HN O H (R,S) major enantiomer Ph

Scheme 34. Proposed stereoinduction model for the facial selectivity of the allylboration reaction.

3.1.2 Stereodivergent allylboration of indole and 3-methyl indole (Paper III)

Indole is a commonly occurring scaffold in biomolecules and phar- macologically active substances. It has a reactive imine tautomer that can undergo allylboration reactions at the 2-position. A study elucidat- ing the kinetics of indole allylboration using various tetraol-based α-chiral allylboronic dimers has been carried out by Pietruszka and co-workers.101 Since different allylboronates led to different rates of product formation, it can be concluded that the tautomerization of indole is not the rate-determining step. However, tautomerization must certainly precede the allylboration step, since the transformation was found to be a pseudo-zero-order process. Reaction of allylboronic acid 22a with indole (49a) in the presence of 15 mol% of catalyst 20-(S) afforded indoline 71 in 94% isolated yield and excellent 99% ee (Table 8, entry 1). This reaction could be carried

37 out under mild conditions (r.t., 24 h) in the presence of molecular sieves. MeOH was employed as aliphatic alcohol to suppress the racemic background reaction. A reaction in the absence of MeOH gave the expected product in 56% ee, demonstrating the essential role that it plays for the enantioselectivity (entry 2). When MeOH was substituted for HFIP a suboptimal 86% yield and 96% ee were observed for the reaction. A selection of BINOL-type catalysts 57-(S), 72-75-(S) were tested for this reaction. Bis(trifluoromethyl)phenyl analog 72-(S) gave 88% yield and 94% ee (entry 4), underperforming only slightly compared to 20-(S). Iodinated analog 73-(S) demonstrated aptitude for stereoselection (98% ee). However, the isolated yield of product 71 (12% yield) did not ex- ceed the catalyst loading (15 mol%). This can be an indication that BINOL 73-(S) could not be turned over in the reaction mixture. Neither parent BINOL 57-(S) nor derivatives 74-(S) and 75-(S) gave any product formation (entries 6-8). In a previous study of allylboration of hydrazones, DMSO was used as a solvent.22 Under these conditions it was found that addition of 1 equiv. DMSO had an inhibiting effect (entry 9). This can be attributed to its ability to coordinate to the boron center, reducing its Lewis acidity.

38 Table 8. Varied reaction conditions for the catalytic asymmetric allylboration of indole 49a.

OH B 15 mol% 20-(S) NH NH OH allylboronic + acid 3 equiv. MeOH 22a 49a 3 Å molecular sieves 71 toluene, r.t., 24 h

Entry Conditions Yieldb (%) ee (%)

1 No change 94 99

2 No MeOH is added 67 56

3 3 equiv. HFIP is used instead of MeOH 86 96

4 15 mol% 72-(S) is used instead of 20-(S) 88 94

5 15 mol% 73-(S) is used instead of 20-(S) 12 98

6 15 mol% 57-(S) is used instead of 20-(S) 0 N/A

7 15 mol% 74-(S) is used instead of 20-(S) 0 N/A

8 15 mol% 75-(S) is used instead of 20-(S) 0 N/A

9 1 equiv. DMSO is added to the reaction mixture 44 90

a22a (0.15 mmol), 58a (0.1 mmol), MeOH (0.3 mmol), and 20-(S) (0.015 mmol) are stirred in toluene with 3 Å molecular sieves at r.t. for 24 h. In all reactions a single diastereomer (>98:2 by 1H NMR) was obtained. bIsolated yield.

Br ArF I Br H HO HO HO HO HO O O P HO O HO HO HO HO HO Br I Br H 20-(S) 57-(S) 72-(S) 73-(S) 74-(S) 75-(S)

CF3 CF3

Using slightly modified conditions (40 °C, 48 h, 2 equiv. MeOH) and a double catalyst loading, the allylboration of indole and γ,γ-disubstituted E-allylboronic acid 22a could be extended to its higher-substituted analog 3-methylindole (skatole, 49b) (Scheme 35). The resulting indoline 76a contained three contiguous stereocenters and was obtained in 72% isolated yield, 98% ee and 98:2 d.r. Repeating the allylboration of skatole 49b at a 0.5 mmol scale afforded 76a in 87% isolated yield. No loss in enantio- or diastereoselectivity was observed in the scale-up. Employing catalyst 20-(R) for this reaction led to product 76b (the enantiomer of 76a) in 77% yield, 90% ee and 98:2 d.r.

39 E 30 mol% (S,S,R) OH 20-(S) B NH NH OH geranylboronic + acid 2 equiv. MeOH 22a 49b 3 Å molecular sieves 76a toluene, 40 °C, 48 h 72% yield 98% ee 98:2 d.r.

E 30 mol% (R,R,S) OH 20-(R) B NH NH OH geranylboronic + acid 2 equiv. MeOH 22a 49b 3 Å molecular sieves 76b toluene, 40 °C, 48 h 77% yield 90% ee 98:2 d.r.

Scheme 35. Asymmetric allylboration of 3-methylindole 49b with geranylboronic acid 22a.

Using Z-allylboronic acid 22b and catalyst 20-(S) resulted in indoline 76c in 77% yield, 94% ee and 98:2 d.r. (Scheme 36). Repeating the reaction with catalyst 20-(R) gave its enantiomer 76d in 82% yield, 90% ee and 98:2 d.r. Under these conditions for the catalytic asymmetric allylboration, boronic acid 22b was found be less reactive compared to 22a. As a result, reaction times were extended to 60 h to allow for increased yields.

30 mol% (S,S,S) Z 20-(S) NH nerylboronic + NH OH 2 equiv. MeOH B acid 49b 3 Å molecular sieves 76c OH 22b toluene, 40 °C, 60 h 77% yield 94% ee 98:2 d.r.

30 mol% (R,R,R) Z 20-(R) NH nerylboronic + NH OH 2 equiv. MeOH B acid 3 Å molecular sieves OH 49b 76d 22b toluene, 40 °C, 60 h 82% yield 90% ee 98:2 d.r.

Scheme 36. Asymmetric allylboration of 3-methylindole (49b) with nerylboronic acid 22b.

Substrate 5-bromo-3-methylindole (49c) could be used to obtain brominated indoline 77 in 62% isolated yield and 98% ee as a single diastereomer (Scheme 37). This brominated derivative does not only provide access to further functionalization, such as cross-couplings, it also allowed for the structural elucidation of the indoline products. Treating

40 77 with 4 M HCl in dioxane resulted in the salt 77 · HCl. The absolute and relative stereochemistry of all products 71, 76a-d was elucidated from the crystal structure that could be obtained from the HCl salt of 77. 22a E OH B OH 30 mol% 20-(S) NH Br NH Br 2 equiv. MeOH 49c 3 Å molecular sieves 77 toluene, 40 °C, 48 h 62% yield 98% ee >99:1 d.r. 77 · HCl X-ray crystal structure Scheme 37. Asymmetric allylboration of 5-bromo-3-methylindole 49c with geranylboronic acid 22a.

The equilibrium that exists between 3-methylindole (49b) and the tautomeric imine enantiomers 49b-(S) and 49b-(R) allows for the formation of three stereogenic centers in a single synthetic step. The stereocenter on the 3-position of the skatole will be preconfigured before allylboration occurs. Of the two possible enantiomers of 49b, only one imine will react. This is an example of dynamic kinetic resolution. Sim- ilar to the previously discussed catalytic asymmetric allylborations and propargylations, reaction 22a + 49b → 76a occurs through BINOL ester 78 that proceeds via a Zimmerman-Traxler-type transition state. The four possible transition states that can arise in this reaction with catalyst 20-(S) have been studied by DFT modelling.87 It was found that transition states TS 7 and TS 8, (Scheme 38) arising from skatole 49b- (R) have an increased activation barrier due to steric repulsion (marked in red). Re-face approach of 49b-(S) (Re-face of the skatole) results in TS 9 which is found to be the least favored transition state. TS 10 is the only transition state that leads to the observed major product 76a, and it is found to have the lowest activation barrier. There is no steric repulsion between the indole and the Br atom on the BINOL moiety, nor is there an incompatibility with the (S)-configured methyl group on the 3-position of skatole 49b-(S).

41 Br TS 7 Re-face approach O NH B N O Disfavored Br H Br +7.1 kcal mol-1 O + N B O Br 49b-(R) 78 Br TS 8 O B NH Si-face approach N O Disfavored Br +5.8 kcal mol-1

Br TS 9 Re-face approach O B NH N O Disfavored Br H Br O +12.6 kcal mol-1 + N B O 78 Br 49b-(S) Br TS 10 O NH B Si-face approach N O Favored Br (S,S,R) 76a major diastereomer -1 0.0 kcal mol major enantiomer

Scheme 38. Origin of the facial selectivity that was found for the allylboration reaction of 3-methylindole (49b).

3.1.3 Stereoselective allylboration- of 3,4 dihydroisoquinolines (Paper III)

Catalytic asymmetric allylboration of imines is still considered to be a synthetic challenge. A fundamental problem is posed by the possibil- ity of imine E→Z isomerisation catalysed —unfortunately— by the allylboronate.21 This apparent lack of stereofidelity in imines interferes with the outcome of the otherwise reliable Zimmerman-Traxler transition state. Cyclic imines, such as 3,4-dihydroisoquinoline (48a) do not have the ability to isomerize, as they are permanently locked in the Z

42 configuration. Their allylboration has been reported by Chong and co- workers using a 3,3’-bis(trifluoromethyl)phenyl analog of BINOL in stoichiometric amounts together with an allylboronate.102 Aggarwal and co-workers have reported that α-chiral allyl-Bpin compounds can react in asymmetric allylboration with ketones and imines after being activated by n-BuLi.103 This approach of chirality transfer affords homoallylic alcohols, amines, and even indolines bearing up to two adjacent quaternary stereocenters. Reaction of allylboronic acid 22a with 3,4-dihydroisoquinoline (48a) using 20 mol% of BINOL catalyst 72-(S) and 40 mol% of pyridylphenol 79 afforded isoquinoline 80a in 74% yield and 90% ee (Table 9, entry 1). Reaction conditions identical to those that were previously found ideal for the asymmetric allylboration of indole (entry 2) resulted in 67% yield and a disappointing 24% ee. A control reaction in the absence of BINOL 72-(S) and HFIP at milder conditions (24 h, r.t.) demonstrated that the racemic background reaction is feasible and indeed requires suppression (entry 3).

Table 9. Varied reaction conditions for the catalytic asymmetric allylboration of 3,4-dihydroisoquinoline 48a.

ArF 20 mol% 72-(S) NH HO OH 40 mol% 79 OH B + N OH HO toluene N allylboronic 3 Å molecular sieves acid MeOH quench CF3 22a 48a 80a 79 72-(S) CF3

Entry Catalyst Alcohol 79 (equiv.) t (h) T (°C) Yieldb (%) ee (%)

1c 72-(S) 3 equiv. HFIP 0.4 48 40 74 90

2c 20-(S) 3 equiv. MeOH 0 24 25 67 24

3c None None 0 24 25 67 N/A

a22a (0.12 mmol), 48a (0.1 mmol), 79, HFIP or MeOH, and 72-(S) (0.02 mmol) are stirred in toluene with 3 Å molecular sieves. In all reactions a single diastereomer (>98:2 by 1H NMR) was obtained. bIsolated yield. c0.15 mmol of 22a was used.

43 Table 10. Synthetic scope for the catalytic asymmetric allylboration of 3,4-dihydroisoquinolines 48a-d.

20 mol% 72-(S) 40 mol% 79 NH OH N R1 B + OH 3 equiv. HFIP R2 toluene, 40 °C, 48 h R1 allylboronic 22 48 3 Å molecular sieves 2 80 acid R MeOH quench 80b · HCl X-ray crystal structure

Entry Boronic acid Substrate Product Yieldb (%) ee (%) d.r.

NH OH B N 1 E OH 22a 48a 80a 74 90 98:2

NH N 2 22a 48b 80b 72 91 98:2

Br Br

NH Br Br N 3 22a 48c 80c 66 87 98:2

4 22a N 48d 80d 42 93 98:2 MeO MeO MeO OMe

NH Z N 5 OH 22b 48a 80e 77 97 98:2 B OH

NH Br Br N 6 22b 48c 80f 72 96 98:2

NH OH N B 7 22c 48a 80g 81 89 N/A OH

Br NH 8 22c N 48c Br 80h 97 82 N/A

a22 (0.12 mmol), 48 (0.1 mmol), 79 (0.04 mmol), HFIP (0.3 mmol), and 72-(S) (0.02 mmol) are stirred in toluene with 3 Å molecular sieves at 40 °C for 48 h. In all reactions a single diastereomer (>98:2 by 1H NMR) was obtained. bIsolated yield.

44 The reaction conditions that were optimized for the allylboration of 3,4-dihydroisoquinoline (48a) could be extended to the 7-bromo analog 48b to afford product 80b in 72% isolated yield and 91% ee. (Table 10, entry 2) Treatment of 80b with 4 M HCl in dioxane resulted in salt 80b · HCl from which a crystalline sample could be obtained for structure elucidation via X-ray diffraction. The 5-bromo analog 80c could be obtained in 66% isolated yield and 87% ee respectively (entry 3). Al- lylboration of 6,7-dimethoxy-3,4-dihydroisoquinoline (48d), which can be obtained via a Bischler-Napieralski reaction, resulted in a modest isolated yield of 42% and 93% ee (entry 4). This can be attributed to the electron donating character of the methoxy substituents, specifi- cally the one at the 6-position. The decreased electrophilic character of the imine C-N π* orbital is likely to hamper the reactivity of 48d. The reaction of Z-allylboronic acid 22b gave access to product 80e (the epimer of 80a) in 77% isolated yield and 97% ee (entry 5), as well as 80f (the epimer of 80b) in 72% isolated yield and 96% ee (entry 6) Reactions with γ,γ-dimethylboronic acid 22c allowed for the prenylation of 48a to obtain product 80g in 81% yield and 89% ee (entry 7). Prenylation of brominated 3,4-dihydroisoquinoline 48c gave product 80h in 97% isolated yield and 82% ee (entry 8). The facial selectivity that is observed for the allylboration can be rationalized by considering the possible transition states that can arise between the reactive BINOL ester 81 and the 3,4-dihydroisoquinoline. A model for the stereoinduction of BINOL-type ligands in asymmetric allylboration of 3,4-dihydroisoquinolines has seen precedence in previous experimental studies.102 The enantioselection mechanism for this reaction has been exemplified by the reaction of 48a + 22a → 80a catalyzed by 72-(S) (Scheme 39). The transition state TS 11 that results from the 3,4-dihydroisoquinoline (48a) approaching the BINOL ester 81 from the Si-face (Si-face of the imine) is shown to have steric incom- patibilities (marked) between the H atoms on the 3-position of the 3,4- dihydroisoquinoline and the (trifluoromethyl)phenyl group on the BINOL moiety. It follows that disfavored TS 11 leads to the observed minor enantiomer. Re-face approach of 48a towards BINOL ester 81 affords a more favorable steric arrangement in TS 12, resulting the in the lower energy barrier that leads to the observed major enantiomer 80a.

45 TS 11 ArF O NH Si-face approach B N O Disfavored H ArF 80a-(S,S) H (S,S) F Ar minor enantiomer O + N B O F 81 Ar 48a NH ArF TS 12 O N B 80a-(R,R) Re-face approach O Favored ArF (R,R) major enantiomer

Scheme 39. Proposed stereoinduction model for the facial selectivity of the allylboration reaction.

3.2 Synthesis and applications of chiral allylboronic acids (Paper IV)

The first example of an asymmetric homologation of boronates was reported by Matteson and co-workers.104 Dichloromethyllithium was used to transform a chiral ester of phenylboronic acid to an a-chloro benzylboronic ester. Subsequently the a-chloroboronic ester was con- verted into the desired product by methyl magnesium bromide.104 In a follow-up study, Matteson and co-worker found that addition of ZnCl2 improved the stereoselectivity of the transformation.105 This approach is commonly referred to as the Matteson homologation (Scheme 40). Both its synthetic applications105–111 and mechanism112,113 have been the subject of studies. Notably, Hoffmann and co-workers employed the findings by Matteson and co-workers towards the synthesis of an a- chiral allylboronate, which could undergo allylboration with benzaldehyde to afford an homoallylic alcohol in >98% ee.114

Li Cl R2 R2 R2 H R2 Cl Zn 3 1. Cl O R MgX O O Cl O 2 2 2 Cl 2 Cl B R R1 B R B R B R O O O 2. ZnCl O R1 2 H 1 R1 R3 Cl R

Scheme 40. General principle of the Matteson homologation as summarized by Aggarwal and coworkers115, and Matteson.116

The most attractive feature of the Matteson homologation is the capability for iterative asymmetric homologation, allowing for a grow- ing carbon chain with full stereocontrol. Armstrong and co-workers have demonstrated this strategy by employing four consecutive homologations in the formal total synthesis of tautomycin.117 Another, more recent example are the six sequential homologation steps in the total synthesis of lagunamide A reported by Kazmaier and co-workers.118 Aggarwal and co-workers have developed a methodology for the asymmetric homologation of organoboronates using chiral lithiated carbamates.34 This strategy of reagent control is orthogonal to the substrate control of the Matteson homologation. Under reagent control, different stereoisomers of the same molecule can easily be synthesized. The reagent control strategy allowed Aggarwal and co-workers to report the first total synthesis of baulamycins A and B, along with a number of its diastereomers.119 Synthetic methods for enantioselective introduction of a CF3 group are of high interest to the discovery and production of pharmaceuticals. a-Chiral boronates as reagents are known to react with high stereofidelity in a wide scope of applications such as cross coupling120,121, ole- fination122, oxidation to the corresponding alcohol122,123, alde- hyde122,124,125, acid124 and more.126 The study of the enantioselective preparation of a-chiral trifluoromethylated boronates is valuable but has only recently been ventured into. The first example of a chiral a- CF3 boronate with high optical purity was reported in 2017 by Yu and co-workers, who were able to employ the chiral diphosphine Josiphos to induce enantioselectivity in a Cu-catalyzed borylation of b-trifluoromethyl-a,b-unsaturated ketones.127 Arnold and co-workers reported an asymmetric B-H insertion of trifluoromethyldiazo compounds catalyzed by an enzyme developed through directed evolution.128 This method affords chiral a-CF3 alkyl boronates that can be hydrolyzed to the corresponding boronic acid under mildly acidic conditions. Recently, work by Aggarwal and co-workers provides access to a broad variety of chiral a-CF3 Bpin compounds containing a b-silyl ether by ring opening of chiral 2-trifluoromethyl oxirane35 (see scheme 6 section in section 1.1).

47 3.2.1 Preparation of chiral allylboronic acids by catalytic asymmetric homologation of olefinic boronic acids (Paper IV)

Olefinic boroxine 82a was reacted with trifluorodiazoethane (9) in the presence of iodo-BINOL catalyst 73-(R), ethanol, and molecular sieves. The reaction gave allylboronate 84a with full conversion at 40 °C for 48 h. Oxygen-sensitive allylboronate 84a was protected by 1,8- diaminonaphtalene (85, danH2) prior to silica-gel chromatography. Al- lyl-Bdan compound 86a was isolated in 69% yield and 98% ee (Table 11, entry 1). Allyl-Bdan compounds 86 are also slightly oxygen-sentiv- ite. Consequently, the isolated yields are systematically lower than the corresponding 19F NMR yields. The reactivity profile of a diazoalkane inserting into an olefinic boronate has previously been shown in racemic homologations (see section 1.1). The asymmetric homologation with diazocompound 9 and the Matteson homologation have a number of similar features. The key step in both methods is the stereoselective 1,2-borotropic migration. Both methods use substrate control to direct the stereochemical outcome of the homologation. The key innovation of the method reported in this chapter is that the chiral diol is a catalyst dynamically bonded to boron, instead of a static chiral ester. Thus, application of stoichiometric amounts of chiral auxiliaries can be avoided. In addition, the strongly basic lithium-alkyl reagents can be replaced by diazomethane derivatives.

48 Table 11. Varied reaction conditions for the asymmetric homologation of boroxine 82a

NH2

20 mol% 73-(R) NH2 CF3 CF3 B 2 equiv. EtOH 1.5 equiv. 85 H O O + OEt N CF3 N2 B B B B 3 Å molecular sieves DCM OEt o HN O DCM 1 h, 40 C 48 h, 40 °C 82a 9 84a 86a ⅓ equiv. 3 equiv.

Entry Conditions 19F NMR yieldb (%) Yieldc (%) ee (%)

1 No change >95 69 98

2 10 mol% of 73-(R) is used 22 12 96

3 20 mol% of 20-(R) is used 34 9 88

4 30 mol% of 20-(R) is used >95 73 94

5 20 mol% of 72-(R) is used 8 trace 43

6 20 mol% of 57-(R) is used 8 4 72

7 Boronic acid is used as received 54 18 97

8 i-PrOH is used instead of EtOH 81 44 96

9 No alcohol is used 14 4 47

10 No alcohol, no catalyst is used 18 trace 0

11 No molecular sieves are added 7 trace 84

12 Reaction at room temperature instead of 40 oC 9 3 96

13 Solvent is toluene instead of DCM 33 14 92

a82a (0.033 mmol), 73-(S) (0.02 mmol) and EtOH (0.2 mmol) and 9 (0.3 mmol) are stirred in DCM with 3 Å molecular sieves for 48 h at 40 oC. 85 (0.15 mmol) is added and the mixture is stirred for 1 h at 40 °C. bYield determined by 19F NMR using trifluorotoluene as an internal standard. cIsolated yield.

Reducing the catalyst loading from 20 mol% to 10 mol% resulted in a major drop in yield, but a practically unchanged enantioselectivity (Table 1, entry 2). Utilizing 20 mol% bromo-BINOL 20-(R) for the homologation proved detrimental (entry 3), but when the catalyst loading was increased to 30 mol% a good yield of 73% and acceptable 94% ee were observed (entry 4). Both 3,3’-bis(trifluoromethyl)phenyl BINOL analog 72-(R) (entry 5) and simple BINOL 57-(R) (entry 6) gave lower stereoselectivity than 73-(R). Olefinic boroxine 82a can be obtained from the commercially available olefinic boronic acid through reflux in a Dean-Stark apparatus, or by drying over molecular sieves. When the commercially available olefinic boronic acid substrate was used as received, it resulted in a reduced yield of 54% by 19F NMR and 18% isolated yield, whereas the enantioselectivity was unaffected (entry

49 7). Similar to the other BINOL-boronic acid catalytic systems presented in this thesis, the structure of the aliphatic alcohol additive plays an important role. Substituting EtOH by i-PrOH resulted in a lower isolated yield of 44% but did not affect the enantioselectivity of the reaction (entry 8). In the absence of aliphatic alcohol (entry 9), the reaction gave a mixture of products from which only 4% of product 86a could be obtained in a poor 47% ee. Direct reaction of olefinic boroxine 82a with trifluorodiazoethane (9) resulted in a similar reaction mixture in which only a trace of the product 86a was observed (entry 10). It is crucial to conduct the reaction under anhydrous conditions, which is ensured by the use of molecular sieves. Omission of the sieves (entry 11) revealed that trace water (likely from the diazoethane stock solution) interferes with the reaction. A mixture of products was observed, and a trace of product was obtained in 84% ee. When the reaction was conducted at room temperature, only a small amount of product was obtained with excellent 96% ee (entry 12). A significant decline in reactivity and a small drop in enantioselectivity was also observed for the reaction in toluene as the solvent (entry 13).

CF 1.5 equiv. 3 pinacol B O DCM O 1 h, 40 °C 87 20 mol% 73-(R) CF3 65% yield B 2 equiv. EtOH O O + OEt CF3 N2 B B B 3 Å molecular sieves OEt O DCM CF3 48 h, 40 °C 1.5 equiv. 84a H 82a 9 (1S,2S,3R,5S) B O ⅓ equiv. 3 equiv. (+)-pinanediol O DCM 1 h, 40 °C 88 75% yield >99:1 d.r. Scheme 41. Alternative protections of allylboronic ester 84a.

Allylboronic ester 84a, which is the immediate product of the asymmetric homologation, can be protected with pinacol or pinanediol under the same conditions as with 1,8-diaminonaphtalene (Scheme 41). Allyl- Bpin compound 87 was obtained in 65% isolated yield. Pinanediol ester 88 was isolated in 75% yield as a single diastereomer. The asymmetric homologation procedure that yields the a-chiral allyl-Bdan compound could be scaled up ten-fold to 1 mmol scale, affording 86a in a gratifying 78% isolated yield and 98% ee (Table 12). Fol- lowing the optimized conditions as reported in Table 11, a selection of

50 a-chiral allylboronic acids could be obtained and subsequently protected with 1,8-diaminonaphtalene (Table 12). Crotyl analog 86b was isolated in 48% yield and 99% ee. The boroxine of 3-phenyl-1-propen- 1-ylboronic acid gave product 86c in 59% yield and 96% ee. Cinnamyl- boronic acid analog 86d was obtained in 54% yield and 93% ee using 20 mol% of catalyst 73-(R). When the catalyst loading was increased to 30 mol%, a yield of 61% and 94% ee was observed. In fact, all allylboronic acids 86d-g that originate from styrylboroxines required 30 mol% catalyst loading to produce acceptable yield and enantioselectivity. This is further exemplified by the reaction affording 4-bromo substituted product 86e. A catalyst loading of 30 mol% afforded 86e in 50% yield and 94% ee, whereas 20 mol% of catalyst gave only 26% isolated yield and a slightly reduced 89% ee. A crystal structure of 86e was obtained by X-ray diffraction, and accordingly the absolute configuration at the stereogenic a-carbon was assigned as (S). Under the same conditions, 4-chloro substituted product 86f was obtained in 70% yield and 86% ee. It is likely that the reduced enantioselectivity for this product is caused by the enhanced reactivity of the substrate. 4-Trifluoro- methyl substituted product 86g was isolated in 51% yield and 90% ee. Extending the synthetic scope to asymmetric homologation using TMS-diazomethane could be achieved by a slight change in reaction conditions (Scheme 42). Boroxine 87 was reacted with TMS-diazomethane 6 in toluene at increased temperature of 60 °C for 3 h using 30 mol% of catalyst 73-(R). Protection of the a-TMS allylboronic acid with 1,8-diaminonaphtalene was unsuccessful, but pinanediol-protected allylboronic ester 90 was obtained in 51% yield as a single diastereomer after 1 h at 40 °C.

51 Table 12. Synthetic scope for the asymmetric homologation affording a-chiral allylboronates 86.

R 20 or 30 mol% 73-(R) CF3 CF3 2 equiv. EtOH 1.5 equiv. 85 H B + OEt N O O CF3 N2 R B R B 3 Å molecular sieves DCM B B OEt HN R O DCM 1 h, 40 °C 48 h, 40 °C 82 R 9 84 86 ⅓ equiv. 3 equiv.

CF3 CF3 CF3 CF3 Bdan Bdan Bdan Bdan

86a 86b 86c 86d 78% yieldb, c 48% yieldb 59% yieldb 61% yieldb, d 54% yieldb 98% ee 99% ee 96% ee 94% ee 93% ee

CF3 CF3 CF3 Bdan Bdan Bdan

Br 86e Cl 86f CF3 86g 50% yieldb, d 26% yieldb 70% yieldb, d 51% yieldb, d 94% ee 89% ee 86e X-ray crystal structure 86% ee 90% ee

a82 (0.033 mmol), 73-(S) (0.02 mmol) and EtOH (0.2 mmol) and 9 (0.3 mmol) are stirred in DCM with 3 Å molecular sieves for 48 h at 40 °C. 85 (0.15 mmol) is added and the mixture is stirred for 1 h at 40 °C. bIsolated yield. cReaction at 1 mmol scale. d0.03 mmol 73-(S) instead of 0.02 mmol.

ArF 1.5 equiv. 30 mol% 73-(R) (1S,2S,3R,5S) SiMe3 2 equiv. EtOH SiMe3 B (+)-pinanediol O H O O + OEt B Me3Si N2 ArF B B B 3 Å mol. sieves toluene O F Ar O toluene OEt 1 h, 40 °C F 3 h, 60 °C ArF 87 6 89 90 ⅓ equiv. 3 equiv. 51% yield >99:1 d.r. Scheme 42. Formation and protection of trimethyl silyl analog 89.

The proposed stereoinduction model for the asymmetric homologation exemplified by the reaction of 82a + 9 → 86a catalyzed by 73-(R) is shown in Scheme 43. The reactive species is assumed to be the BINOL-ester 91, formed from catalyst 73-(R) and boroxine 82a. Tri- fluorodiazoethane (9) can approach 91 with either of its enantiotopic faces to form an ate complex. Computational studies by Ley and co- workers indicate that the diazo moiety adopts an anti-periplanar position relative to the olefin moiety prior to the borotropic migration.23 Re-face approach of 9 (Re-face of the diazoethane) gives intermediate ate complex 92, which in turn produces allylboronic ester 93 after 1,2-

52 borotropic migration. This results in product 86a-(R) which is the observed minor enantiomer. Accordingly, route 91 → 92 → 93 is disfavored due to a steric hindrance arising between the CF3 group on the diazoethane and the iodo substituent on the 3-position of the BINOL (marked). This steric hindrance is not present in the event of Si-face approach of 9 (Si-face of the diazoethane). The resulting pathway of 91 → 94 → 95 leads to formation of the major enantiomer 86a-(S).

I I

Re-face approach O H n-Hex HO n-Hex N N 86a-(R) Disfavored O O (R) I CF3 1,2-borotropic CF migration 3 minor enantiomer I N I O n-Hex 92 93 N B + O 91 9 CF H 3 I I I CF3 O n-Hex CF3 O n-Hex N N 86a-(S) Si-face approach O H Favored O 1,2-borotropic H (S) migration major enantiomer I 94 I 95

Scheme 43. Proposed stereoinduction model for the 1,2-borotropic migration.

The proposed catalytic cycle for the homologation is shown in Scheme 44. In the initial step of the catalytic cycle, EtOH breaks up the boroxine to form ethyl boronate 96. This prevents the direct reaction between boroxine 82a and diazoethane 9. Transesterification between catalyst 73-(R) and ethyl ester 96 leads to the reactive species 91. Diazoethane 9 coordinates to 91 to form ate complex 94. Subsequent 1,2-borotropic migration cleaves leaving group N2 to form allylboronate 97. Transesterification of 97 with EtOH leads to turnover of catalyst 73-(R) and generates a-chiral allylboronic ester 84a, as the immediate product.

53 84a CF3 OEt OEt B 2 EtOH B B I OEt O O OEt B B OH O 96 OH I 73-(R) ⅓ 82a 2 EtOH 2 EtOH

I I O O B B O O I I 97 CF3 91

N 2 H CF I 3 O O I N N B N N 9 H CF 94 3

Scheme 44. Proposed catalytic cycle for the asymmetric homologation of olefinic boroxine 82a.

3.2.2 In situ allylboration and oxidation of chiral allylboronic acids (Paper IV)

The in situ formed a-chiral allylboronate 84a (generated under conditions as described in section 3.2.1) can be used for allylboration of aldehyde 15b. In order to avoid the side reaction of diazocompound 9 and aldehyde 15b, the excess diazocompound 9 was removed by evap- oration. Addition of 4-bromobenzaldehyde (15b) to transient allylboronate 84a resulted in homoallylic alcohol 98a in 60% yield and 98% ee. Alcohol 98a was obtained as a single diastereomer and with full selectivity towards the E-isomer (Table 13). Benzyl-substituted homoallylic alcohol 98b was obtained in 47% yield and 94% ee. As mentioned above (see Table 12), aromatic olefinic boroxines (leading to alcohols 98c-e) were reacted in the presence of 30 mol% BINOL catalyst. Reaction of the cinnamylboronic acid derivative resulted in homoallylic alcohol 98c in 41% yield and 90% ee. The reaction of 4-trifluoromethyl substituted boronate 84g and 15b afforded homoallylic alcohol 98d in 42% yield and 90% ee. Chlorinated analog 98e was obtained in 48% yield and 75% ee. The allylboration steps leading to 98d and 98e were carried out at a slightly reduced temperature (30 °C) to

54 increase the enantioselectivity. An attempt to extend the in situ allylboration to 4-bromoacetophenone proved unsuccessful, as only a trace amount of the desired product 98f was observed.

Table 13. Synthetic scope for the in situ allylboration of aldehyde 15b. R 20 or 30 mol% 73-(R) 1.5 equiv. CF3 OH 2 equiv. EtOH ArCHO 15b B + OEt CF3 O O CF3 N2 R B 3 Å molecular sieves DCM B B OEt R R O DCM 4 h, 40 °C Br 48 h, 40 °C 82 R 9 84 98 ⅓ equiv. 3 equiv.

OH OH OH

CF3 CF3 CF3

Br Br Br 98a 98b 98c 60% yieldb 47% yieldb 41% yieldb, c 98% ee 94% ee 90% ee

OH OH HO Me CF3 CF3 CF3

Br 98d Br 98e Br 98f 42% yieldb, c, d 48% yieldb, c, d trace 90% ee 75% ee CF3 Cl

a82 (0.033 mmol), 73-(S) (0.02 mmol) and EtOH (0.2 mmol) and 9 (0.3 mmol) are stirred in DCM with 3 Å molecular sieves for 48 h at 40 °C. The volume is reduced by Ar flow, 15b (0.15 mmol) is added and the mixture is stirred for 4 h at 40 °C. In all reactions a single diastereomer (>98:2 by 1H NMR) was obtained. bIsolated yield. c0.03 mmol 73-(S) instead d of 0.02 mmol. The allylboration was done at 30 °C instead of 40 °C.

The allylborations of 4-bromobenzaldehyde (15b) with a-chiral allylboronic acids are expected to proceed through Zimmerman-Traxler transition states (see Scheme 51 below in section 3.2.3). According to this model, the absolute stereoconfiguration at the a-carbon of product 98 is expected to be (R). The (R) configuration was confirmed by Mosher ester analysis of alcohol 98a. Scheme 45 shows the differences in chemical shift Δ�SR that were found for the 1H NMR analysis of the Mosher’s esters 99. A detailed explanation of the Mosher analysis is given in Scheme 25 in section 2.3 above.

55 Difference in chemical shift ΔδSR = δ99-(S) − δ99-(R)

OH 2 equiv. DIPEA OMPTA O 10 mol% DMAP +0.13 -0.12 -0.02 CF3 +0.06 CF3 + +0.02 -0.08 Cl DCM, r.t., 1 h +0.13 Br Br -0.02 MeO CF3 +0.06 -0.02 98c 60 99 52% yield

Scheme 45. Structural elucidation of homoallylic alcohol 98c by the Mosher 1H NMR method.

The in situ allylboration of 4-bromobenzaldehyde (15b) was extended to a-silyl allylboronic ester 89 to afford homoallylic alcohol 100 in 52% isolated yield and 91% ee (Scheme 46). Homoallylic alcohol 100 was obtained as a single diastereomer and with full E-selectivity.

ArF 30 mol% 73-(R) 1.5 equiv. OH 2 equiv. EtOH SiMe3 B ArCHO 15b O O + OEt SiMe3 Me3Si N2 ArF B B B 3 Å mol. sieves toluene ArF O OEt toluene 4 h, 40 °C Br 3 h, 60 °C ArF 87 6 89 100 ⅓ equiv. 3 equiv. 52% yield F 91% ee Scheme 46. In situ allylboration using a-silyl allylboronate 89.

As an alternative to allylboration, allylboronic esters 84 can be oxidized in situ to allylic alcohols 101 by a mixture of NaOH and H2O2 (Table 14). The homologation step to afford the allylboronic acid was carried out as reported in Table 1, after which the DCM and excess diazoethane was removed by argon flow and the solvent was changed to toluene. Subsequent oxidation occurred in high stereofidelity. Grat- ifyingly, oxidation of allylboronic ester 84a afforded allylic alcohol 101a129 in 78% yield and 99% ee. Cinnamyl alcohol derivative 101b130 was isolated in 64% yield and 90% ee, and allylic alcohol 101c was obtained in 50% isolated yield and 96% ee. The absolute configurations of allylic alcohols 101 could be confirmed as (S) based on their optical rotation values.

56 Table 14. Oxidation of allylboronic esters 84 to allylic alcohols 101.

R 20 or 30 mol% 73-(R) NaOH CF3 CF3 2 equiv. EtOH H2O2 B + OEt O O CF3 N2 R B R OH 3 Å molecular sieves toluene B B OEt R O DCM 18 h, r.t. 48 h, 40 °C 82 R 9 84 101 ⅓ equiv. 3 equiv.

CF3 CF3 CF3

OH OH OH 101a 101b 101c 78% yieldb 64% yieldb, c 50% yieldb 99% ee 90% ee 96% ee

a82 (0.033 mmol), 73-(S) (0.02 mmol) and EtOH (0.2 mmol) and 9 (0.3 mmol) are stirred in DCM with 3 Å molecular sieves for 48 h at 40 °C. The volume was reduced by Ar flow and solvent is changed to toluene. NaOH (0.3 mmol) and H O (0.3 mmol) are added at 0 °C and the mixture is stirred for 18 h. bIsolated yield. c0.03 mmol 73-(S). 2 2

3.2.3 Extended asymmetric allylboration enabled by purified chiral allylboronic acids (Paper IV)

Suginome and co-workers have demonstrated that an aryl-Bdan group can be hydrolyzed to the free arylboronic acid under acidic conditions.131 An adaptation of this method made it possible to hydrolyze allyl-Bdan compounds 86a and 86d to the corresponding allylboronic acids 102 (Scheme 47). The procedure required relatively acidic conditions (solvent DME/3N H2SO4 6:5). Nevertheless, the acidic hydrolysis afforded boronic acids 102 in high conversion in a clean reaction. The precipitated 1,8-diaminonaphtalene salt could be removed by centrifu- gation. Extraction with degassed toluene followed by an aqueous 0.5 M HCl wash resulted in purified a-CF3 allylboronic acid. Indeed, extraction of hydrolyzed allylboronic acids 102 in deuterated chloroform 1 13 19 (CDCl3) revealed the free boronic acid in the recorded H, C, F, and 11B NMR spectra (Scheme 48).

57 CF3 H 1. DME/H2SO4 (aq.) CF3 N 18 h, r.t. B OH B HN 2. Extraction in Et2O OH 3. HCl (aq.) wash allylboronic 4. Switch solvent to CDCl3 86a 102a acid 96% conversion

CF3 H 1. DME/H2SO4 (aq.) CF3

N 18 h, r.t. B OH B HN 2. Extraction in Et O 2 OH 3. HCl (aq.) wash allylboronic

4. Switch solvent to CDCl 3 acid 86d 102b 99% conversion

Scheme 47. Acidic hydrolysis of allyl-Bdan compounds 86a and 86d.

2H 2H 19

F NMR

CF3 1H OH B OH 102b

11B NMR 1H 1H 1H

Scheme 48. Recorded NMR spectra of the 1H, 19F, and 11B nuclides of a-CF3 allylboronic acid 102b in CDCl3.

Purified allylboronic acid 102a in toluene could be reacted with aldehyde 15b to form product 98a in 43% isolated yield (with respect to 86a) and 98% ee (Table 15, entry 1). The reaction time of 10 minutes is significantly shorter than the in situ procedure leading to the same product (4 hours). Homoallylic alcohol 98c was obtained from a-chiral cinnamylboronic acid 102b in 53% yield and 93% ee after 4 hours (entry 2). Allylboration of ketone 19b with boronic acid 102a led to tertiary homoallylic alcohol 98f in 67% isolated yield and 98% ee (entry 3). This is in contrast to the in situ allylboration procedure, for which only a trace of homoallylic alcohol 98f formed (Table 13). A reaction between 102b and cyclohexanone 103 gave product 98g in 72% yield and 91% ee (entry 4). Interestingly, racemic 2-methylcyclohexanone (103b) gave

58 alcohol 98h bearing three adjacent stereocenters as a single diastereomer in 50% yield and excellent 97% ee (entry 5). Ethyl bromopyruvate (103c) was reacted with boronic acid 102b to produce densely functionalized alcohol 98i in 72% yield and 82% ee (entry 6). The relative stereoconfiguration of alcohol 98i was tentatively assigned based on similar products reported in the literature.51 Allylboration of indole (49a) with boronic acid 102b afforded homoallylic indoline 98j in 62% yield and 93% ee (entry 7). In addition, the reaction 3-methylindole (49b) with 102b gave indoline 98k bearing three adjacent stereocenters as a single major diastereomer in 48% yield, 89% ee (entry 8). This is another example of kinetic dynamic resolution in the allylboration of skatole. Another example is mentioned above in section 3.1.2. Moreover, the allylboration of 3,4-dihydroisoquinoline (48a) with 102b gave product 98l in 54% isolated yield and 93% ee. Finally, fluorinated chiral α-amino acid derivative 98m could be obtained in 72% yield and 98% ee from the reaction between hydrazonoester 56 and allylboronic acid 102a (entry 10). The increased reaction rate (entries 1, 2) and broadened scope (entries 3-10) of the allylborations reported in Table 15 can be attributed to self-condensation of boronic acids 102 under the anhydrous reaction conditions, thereby forming the more reactive boroxine.

59 Table 15. Allylborations using free allylboronic acid 102. X

CF3 Y R2 H 1. DME/H2SO4 (aq.) CF3 N 1.5 equiv. 2 R1 B 18 h, r.t. OH X R R1 B CF HN Y 3 2. Extraction in toluene OH 3 Å molecular sieves 3. HCl (aq.) wash toluene R1 allylboronic 18 h, r.t. 86 acid 102 98

Entry Allylboronic acid Electrophile Product Yieldb (%) ee (%)

CF3 O OH OH B H CF3 1 102a OH 15b 98a 43c 98 Br Br OH CF3 CF3 OH B d 2 102b OH 15b Br 98c 53 93

O HO Me CF3 Me 3 102a 19b 98f 67 98 Br Br OH CF O 3

4 102b 103a 98g 72 91 OH O CF3

5 102b 103b 98h 50e 97

HO Br O EtO CF3 EtO Br O 6 102b O 103c 98i 72 82

NH CF3

7 102b 49a 98j 62 93

NH CF NH 3 8 102b 49b 98k 48 89

N CF3 9 102b 48a 98l 54 93

NHBz NHBz N HN EtO CF 10 102a EtO 56 3 98m 72f 98 O O a 86 (0.1 mmol) is dissolved in DME, 3 N H2SO4 (aq.) is added. After 18 h the boronic acid 102 is extracted into toluene, the electrophile (0.15 mmol) and molecular sieves are added, and stirred for 18 h. In all reactions a single diastereomer (>98:2 by 1H NMR) was obtained. bIsolated yield. cReaction time is 10 min. dReaction time is 4 h. e0.1 mmol of 103b is used. f0.09 mmol of 56 is used.

60 It has previously been discussed (section 1.5) and demonstrated (section 2.2) in this thesis that free organoboronic acids outperform their ester counterparts in terms of reactivity. The same applies to a-chiral allylboronic acids. Neither pinacol ester 87 nor pinanediol ester 88 (Scheme 49) underwent allylboration with ketone 19b under the same reaction conditions (or increased temperature to 40 °C) as the corresponding allylboronic acid 102a (Table 15, entry 3).

Me CF 3 CF3 Br H 1.5 equiv. 19b HO Me B O O B CF3 O or O X 3 Å molecular sieves Br 87 88 toluene 98f no reaction 18 h, 40 °C

Scheme 49. Boronic esters 87 and 88 are inert towards ketone 19b.

When the reaction between free allylboronic acid 102a and ketone 19b (Table 15, entry 3) was repeated with the addition of 2 equivalents of EtOH, the allylboration was completely inhibited (Scheme 50). These conditions emulate the in situ allylboration (Table 13). As mentioned above (Table 13) the reaction of 84 and ketone 19b gave only traces of 98f under in situ conditions.

CF3 Br H 1. DME/H SO (aq.) CF HO Me N 2 4 3 1.5 equiv. 19b B 18 h, r.t. OH CF3 B HN X 2. Extraction in toluene OH 2 equiv. EtOH Br 3. HCl (aq.) wash toluene 86a 102a 18 h, r.t. 98f no reaction

Scheme 50. Aliphatic alcohol EtOH inhibits the allylboration of 19b.

The allylborations reported in Tables 13 and 15 are expected to proceed via a Zimmerman-Traxler-type transition state. A model for the allylboration of aldehydes by a-chiral allylboronates has previously been described by Hall and co-worker.9 Two possible transition states for the allylboration of aldehyde 15b by free boronic acid 102b are compared in Scheme 51. Re-face approach of 15b (Re-face of the aldehyde) leads to TS 13 in which the a-CF3 group must adopt an axial position.

61 This disfavored transition state results in (R,S)-Z alcohol 104, which is not observed as a product. Indeed, Si-face approach of 15b (Si-face of the aldehyde) gives the more agreeable TS 14 in which the a-CF3 is equatorial. Both the predicted double bond geometry and the absolute configuration of 98c matches with what is observed experimentally from the reaction (Table 15, entry 2). TS 13 OH H OH Re-face approach B O OH CF Disfavored Br 3 CF Br 3 104 CF3 is axial (R,S)-Z CF3 O not observed OH H B + OH 102b Br 15b CF3 is equatorial TS 14 OH OH CF3 H CF3 B OH O Si-face approach Favored Br 98c Br (S,R)-E observed product

Scheme 51. Competing transition states for the allylboration of aldehyde 15b using a-chiral allylboronic acid 102b.

The stereochemical outcome that is observed for free a-chiral allylboronic acids is not trivial for all allylboronates. For allylborations with boronic esters and boranes with bulky groups on the boron (such as pinacol in Bpin esters), it has been reported that an equatorial position of the a-substituent in the Zimmerman-Traxler TS is actually less favored. This is due to the gauche strain between the a-substituent and the ester on boron (see TS 15 in Scheme 52).132–135 As the axial a-group induces 1,3-diaxial strain (TS 16), the E/Z selectivity can be low. Be- cause of the small size of allylboronic acid 102b (Scheme 51), TS 14 is strongly favored over TS 13. This results in exclusive formation of the E stereoisomer in the above allylboration reactions (Table 15).

O H Rα H O B Rα is equatorial: O Rα is axial: O B O strain between Rα and Bpin O 1,3-diaxial strain TS 15 Br H Rα TS 16 Br

Scheme 52. Strain arising from the transition states for allylboration of aldehyde 15b using an allyl-Bpin ester.

62 4. Conclusions and outlook

In this thesis the synthetic utility of allyl- and allenylboronic acid chemistry is demonstrated by several examples. A new copper-catalyzed procedure for the direct synthesis of allenylboronic acids is reported. The utility of these highly reactive and configurationally stable reagents has been demonstrated. Allenylboronic acids were used in catalytic asymmetric propargylations of electrophilic substrates such as ketones as well as hydrazonoesters. The latter electrophile afforded chiral α-amino acid derivatives. Enantioselective allylboration of cyclic imines such as 3-methylindole and 3,4-dihydroisoquinolines is also reported. The propargyl- and allylboration reactions presented in this thesis proceed via cyclic six-membered transition states. The source of the facial selection is that the various BINOL-type organocatalysts form highly reactive chiral esters with the boronic acids. Addition of an aliphatic alcohol is often found to be beneficial to the enantioselectivity of these transformations. The purpose of this alcohol additive is two- fold, as it (1) inhibits the racemic background reaction and (2) facilitates the turnover of the catalyst. A recurring aspect in the asymmetric methodologies presented in this thesis is the dynamic covalent bonding of boron that allows for the utilization of BINOL-type organocatalyst. Notably, this concept has been extended beyond allylboration and propargylboration reactions. An asymmetric homologation of olefinic boronic acids catalyzed by a BINOL-type ligand has been developed, affording access to chiral α- trifluoromethyl allylboronic acids that are of high synthetic interest. The utility of the newly reported chiral allylboronic acids is demonstrated through applications such as in situ allylboration and oxidation of chiral allylboron species. After purification, free α-chiral allylboronic acids have been employed in a diverse set of direct asymmetric allylboration reactions of ketones, indoles, and imines.

63 Organoboronic acids are versatile reagents. The above homologation concept can be applied to other organoboronic acids and diazoalkane reagents. Considering the high reactivity of organoboronic acids compared to the commonly used boronate analogs, new and valuable stereoselective transformations can be designed based on the products of the above asymmetric homologation reactions.

64 5. Acknowledgement

First and foremost, I would like to thank my supervisor Professor Kálmán J. Szabó for giving me the opportunity to start a career in research, and for patiently guiding this work. I would be lucky to ever have a supervisor like you again. Tack så mycket, Kálmán. I would like to express my thanks to Professor Pher Andersson and Dr. Nicklas Selander as well as Dr. Marvin Lübcke, Dr. Colin Diner, and Dr. Jonas Ståhle for taking the time to read this thesis and provide valuable suggestions. My sincerest gratitude goes out to all my collaborators: Dr. Colin Diner, Dr. Jayarajan Ramasamy, Dr. Rauful Alam, Dr. Jian Zhao, Denise Meyer, Marie Deliaval, Göran Schulz, Tautvydas Kireilis, Duc Tran, and Dr. Hiroaki Iwamoto. I would also like to thank Dr. Lars Eriksson for helping us out with the structural elucidations. Thank you, Dr. Maria Biosca Brull, for your calculations of the Mosher’s amide. I would like to thank my PhD brother and sister, long-time office mates Marvin and Denise. It’s been an honor to share this journey from start to finish as middle sibling with the both of you! I am grateful for past and present members of the Szabó research group for providing such a pleasant work environment: Dong, Miguel, Xingguo, Qiang, Martin Hedberg, Dominik, Kevin, Linus, Erik, Denis, Martin de Wit, Lujia, Soumitra, Nadia, Weiming and Antonio. My thanks go out all my past and present lunchmates at the Department of Organic Chemistry, as well as all the people who have joined me for Thursday night drinks and banter at Gröna Villan. I would like to thank Matic Hriberšek and Kilian Colas for being great friends and gracious hosts of so many parties and boardgames. Angela van der Werf and Peeter Kanter: thank you for many fun eve- nings playing boardgames together and thanks for running along Brunnsviken with me! Michael and Denise Meyer: thank you for your friendship all these years! Marvin Lübcke and Beichen Chen: let’s keep baking lussekatter together!

65 I’d like to thank my friends Tony Zhao, Jonas Ståhle, Thibault An- gles d’Ortoli, Marie Deliaval, Jayarajan Ramasamy, Colin Diner, Ga- briella Kervefors, and meme lord Catarina Santos. Alexander Ricke, thank you for being a good friend and for helping me drive the moving truck! A special thank-you goes out to Göran Schulz and Tim Seedorf for being enthusiastic hosts in Hannover. I am very grateful to Ting for being supportive when I wrote the bulk of this thesis in April 2020, and for the times we shared together. I will always remember our trip to Greece. I would like to thank my cousins Chiel, Vivianne, Duco, Anne-Renee, Quinten, my aunt Saskia and my opa Hans for visiting the city that has been my home these past five years. Finally, I am thankful to my parents Steven and Ciska, and my sister Merte for all their emotional support. Dankjewel!

Illustration 1. A view of Gamla stan from the old city hall tower.

66 6. List of contributions

Paper I Repeated the substrate scope for the borylation reactions with B2(OH)2. Optimized the borylation reactions with other diboron compounds. Did part of the substrate scope for the catalytic asymmetric propargylation reactions. Carried out derivatization reactions and obtained a crystal structure of the product. Wrote part of the Supplementary Information and minor parts of the manuscript.

Paper II Did some of the optimization reactions. Carried out all of the reactions that are presented in the final manuscript. Wrote all of the Supplemen- tary Information and the first draft of the manuscript.

Paper III Carried out parts of the optimization and substrate scope for the asymmetric allylboration of 3,4-dihydroisoquinolines. Repeated the asymmetric allylboration of 3-methylindole after the reaction had been optimized. Wrote parts of the Supplementary Information.

Paper IV Found the proof of principle of the asymmetric homologation reaction as well as significant parts of the optimization. Partly explored the synthetic scope of the asymmetric homologation and subsequent protections/allylborations. Performed significant work on the hydrolysis of the allyl-Bdan boronates and isolation the air sensitive boronic acids. Carried out significant parts of the applications of the purified α-chiral boronic acids. Wrote parts of the Supplementary Information.

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