Synthesis of Organoboronic Acidsand Applications in AsymmetricOrganocatalysis Sybrand Jonker

Sybrand Jonker    Synth

esis of Organ

oboronic A

cids and A

pplications in

Asym

metric O

rganocatalysis

Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2021

Department of Organic Chemistry

ISBN 978-91-7911-388-9

Synthesis of Organoboronic Acids andApplications in Asymmetric OrganocatalysisSybrand Jonker

Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry atStockholm University to be publicly defended on Friday 12 February 2021 at 14.00 inMagnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B.

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

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

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

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

Department of Organic Chemistry

Stockholm University, 106 91 Stockholm

SYNTHESIS OF ORGANOBORONIC ACIDS AND APPLICATIONSIN ASYMMETRIC ORGANOCATALYSIS 

Sybrand Jonker

Synthesis of OrganoboronicAcids and Applications inAsymmetric Organocatalysis 

Sybrand Jonker

©Sybrand Jonker, Stockholm University 2021 ISBN print 978-91-7911-388-9ISBN 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 MurakamiWhat I Talk About When ITalk About Running

i

Abstract

Allyl- and allenylboronic acids are valuable reagents in organic syn-thesis 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 al-lylboron 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 devel-oped for the preparation of α-chiral allylboronic acids via asymmetric homologation of olefinic boronic acids. The resulting chiral boronic ac-ids 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.

ii

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 spegel-bildsform 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 borsy-ror. 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 stereo-divergent. Som exempel kan icke-naturliga aminosyraderivat produce-ras med denna nya metodologi.

Många av de asymmetriska metoderna som presenteras i denna av-handling involverar organiska katalysatorer av BINOL-typ vilka har visat sig vara mycket effektiva för asymmetriska transformationer av borsyror.

iii

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 Δ𝛿SR Difference in chemical shift between MTPA epimers

iv

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.

v

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 ac-cess 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 ac-cess 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 ac-cess article licensed under an ACS AuthorChoice Creative Commons Attribution 4.0 International Licence.

vi

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 ap-prox. 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.

vii

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

viii

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

1

1. Introduction

Allyl- and allenylboronates are valuable tools for synthetic chemis-try. 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 rea-gents have a stable η3 state or undergo metallotropic rearrangements (Scheme 1) due to the fluxional nature of the metal-allyl fragment.1

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 al-lenylboronates 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 esters and carbonates using palladium catalyst Pd(dba)2 and B2pin2.2 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 com-pounds.3 Publications by Ito and co-workers have shown how a Cu-alkoxide catalyst with a phosphine ligand can be used for borylation of

[M]R1

R2

[M]

R1 R2

R1

R2 [M]

[M]R2

R1or or

η3 coordinationE/Z isomerization[1,3] shift

BR1

R2OR

OR

configurationallystable

2

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 activated by the Lewis acid Ti(Oi-Pr)4.8 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 SN2’ reaction with Grignard reagents.9 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

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 complex catalyst15,16 or [Pd(MeCN)4][BF4]2.17 Szabó and co-workers also demonstrated that a Pd catalyst could be used for the direct syn-thesis 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 di-rectly 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

PhPhN

N P

P

Me

t-Bu

t-Bu

MeB2pin2+

Ito and co-workers, 2007

OCO2Me Bpin5% Cu(Ot-Bu)

5% (R,R)-QuinoxP*

THF, 0 oC, 48 h

(R,R)-QuinoxP*2 3

77% yield95% ee

1

3

Scheme 3. Pd-catalyzed borylation with B2(OH)4 to access isolated al-lylboronic 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 homologa-tion, the boronic acids were dehydrated to the corresponding boroxine, such as 5. A selection of racemic benzyl and allyl a-TMS Bpin com-pounds (such as 7) were obtained by in situ protection of the homolo-gation product with pinacol. Interestingly, it was found that the reac-tion 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 com-pounds in a Suzuki-Miyaura cross-coupling with aryl iodides, preserving the TMS group in the coupling product.

Scheme 4. Homologation of boroxines using TMS-diazomethane as re-ported by Ley and co-workers.

Molander and co-workers reported the homologation of boronates

using in situ generated carbenoid trifluorodiazoethane (9), affording ra-cemic benzyl, alkyl, allyl, and propargyl a-CF3 boronates (Scheme 5).27 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

up to 80% yield

OHR +

Szabó and co-workers, 2012

or0.5-5 mol% H2PdCl4

DMSO/H2O or MeOHr.t.

allylboronic acidB OH

OHRB B

OH

OHHO

HOR

OH4

BO

BO

BO

Me3Si N2 Bpin

SiMe3

+

1. 3.6 equiv. DIPEA toluene, 85 oC

2. pinacol, r.t.760% yield

5 6

Ley and co-workers, 2017

4

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

Scheme 5. Homologation of boronates using trifluorodiazoethane as re-ported 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 allylboration.34 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.

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

CF3 N2+

1. p-tolyl-SiCl32. KHF2

1078% yield

8 9

Molander and co-workers, 2013

BF3K BF3K

CF3

DCM, r.t.

O

CF3Bpin +

1. LDA, THF, -15 oC

2. TESOTf, toluene, r.t.

Aggarwal and co-workers, 2020

OTESBpin CF3

62% yield99% ee11 1312

5

1.2 Synthetic applications of allylboronates

The first example of an allylboration with allylboronates was re-ported 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).

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 to-wards the same goal was reported by Kobayashi and co-workers by using Lewis acid Zn(OH)2 alongside a chiral bidentate ligand.40 Morken and co-workers have reported catalytic asymmetric allylboration using a Ni(cod)2 catalyst in conjunction with a chiral phosphonite ligand.41 A seminal study by Antilla and co-workers demonstrated that chiral phosphoric acids can be utilized to catalyze enantioselective allylbora-tion 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

OBpin

Ph

OBpin

Ph

Ph

OH

Ph

O

BpinPh

O+

Ph

OHBpin +

Hoffmann and co-workers, 1979

Zimmerman-Traxler transition state14a

14b

15a

15a

16a

16b

6

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-work-ers 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.

Scheme 8. Catalytic asymmetric allylboration as reported by Antilla and co-workers.

Ketones are known to be less reactive than aldehydes, and their al-

lylboration 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-lylboration product of various ketones.47 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 qua-ternary 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.

BpinPh

O

Ph

OH O

OP OH

O+5 mol% (R)-TRIP-PA

toluene, 0 °C

Ar

i-Pri-Pr

i-Pr (R)-TRIP-PA

Antilla and co-workers, 2010

14b 15a 1796% yield99% ee98:2 d.r.

7

Scheme 9. A selection of methods for catalytic asymmetric allylbora-tions 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 al-lylborations 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 stereoconfigura-tion of the a-center of the boronate controls the E/Z selectivity of the homoallylic alcohol product, whereas the chiral tetraol controls the en-antioselection. 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 aminophe-nol 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-ral catalyst 3,3′-Ph2-BINOL was reported by Schaus and co-workers60

HO

HO

Br

Br

(S)-3,3’-Br2BINOL 20-(S)

BPh

O+

4 mol% 20-(S)

2 equiv t-BuOHtoluene/PhCF3, r.t.

Ph

Schaus and co-workers, 2009

HOO

O

BOH

OH Ar

O+

15 mol% 20-(S)

3 equiv t-BuOH3 Å molecular sieves

toluene, 0 °C

Szabó and co-workers, 2015

Ar

HO

18 19a 2196% yield97:3 d.r.98% ee

22a 19b 2375% yield94% ee98:2 d.r.

8

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 com-pounds and a chiral aminophenol.62,63 The reaction of allylic 1,1-diboro-nate 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 deriva-tives through allylboration of a hydrazonoester with an α-branched al-lyl-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 allenyl-boronates 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.

Scheme 10. Cu-catalyzed borylation of propargylic carbonates as re-ported 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

B2pin2+ OPPh2 PPh2

Xantphos

OCO2Me • Bpin

10 mol% Cu(Ot-Bu)10 mol% Xantphos

THF, 50 oC

Ito and co-workers, 2008

MeMe

H

24 2 2560% yield

9

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 reac-tivity for the regiodivergent borylation71 and cross-coupling72 of propar-gylic carbonates using Pd/Cu dual catalysis. Recently, Ye and co-work-ers report the preparation of allenyl-Bdan compounds (1,8-dia-minonaphtaleneboron) via a copper(I) catalyzed borylation of propar-gylic 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) com-pounds could be translated into point chirality in an enantioselective propargylboration of aldehydes.67 Ito and co-workers have demon-strated similar reactivity of chiral allenyl-Bpin compounds towards al-dehydes activated by Lewis acid BF3 · Et2O.70 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 propargyla-tion 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 gener-ated under these conditions reacts to form densely functionalized qua-ternary stereocenters. The stereodivergent propargylboration reaction of aldehydes using allenyl-Bpin compounds catalyzed by a chiral phos-phoric 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 va-riety of ketones using allenylboronic glycol esters such as 26 under mi-crowave irradiation (Scheme 11).78 It was even shown that a racemic

10

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

Scheme 11. Catalytic asymmetric propargylboration using allenyl-boronates 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-at-tack) and propargylation (γ-attack) by using secondary or primary amines respectively.80 Hoveyda and co-workers have shown that an al-lenyl-Bpin compound can react with an aldimine catalyzed by a chiral aminophenol ligand to afford homoallenyl amines in good enantioselec-tivity.81

1.5 Qualitative comparison of variousorganoboronates

Allyl- and allenylboronic acids have a more versatile reactivity pro-

file 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

HO

HO

Br

Br

(S)-3,3’-Br2BINOL 20-(S)

Ph

O+

10 mol% 20-(S)

µwaves

Schaus and co-workers, 2011

• B O

OPh

HO

26 19a 2785% yield94% ee

11

catechol ester is more reactive since the aromatic diol is withdrawing electron density from the oxygen’s lone pairs, hindering them from do-nating to the boron. The boronic acid is highly reactive due to its ability to self-condensate and form the anhydrous boroxine. The high reactiv-ity of boroxines is attributed to the decreased conjugation of the gemi-nal 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.

Scheme 12. Qualitative comparison of the reactivity of selected al-lylboronates

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 car-ried 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

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

BO

OBO

OBO

OBOH

HOB

OBOBO

O

OB

Increasing reactivity towards allylboration

R R R R R R

20 mol% 20-(R)

DCM

O

O

BOH

OHTrtO

O

OTrt

HO

BOH

OH

tBuOH3 Å molecular sieves

toluene, 0 °C

(+)-pleuromutilin+

NH

O

N

OHPh

3 Å molecular sieves+

generated in-situ

NH

O

NH

OHPh

Reisman and co-workers, 2018

Zhang and co-workers, 2017

28 29 3044% yield

22a31 32

85% yield95:5 d.r.

12

1.6 Aim of this thesis

The previous sections of this chapter have summed up the most im-portant 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 de-velopment of asymmetric propargylboration. This thesis aims to develop new procedures for the synthesis and purification of al-lenylboronic acids.

2. The strategy of using a BINOL-type catalyst for asymmetric al-lylboration 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 diazome-thane 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 purifi-cation 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 stere-oselective synthesis.

13

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 syn-

thetic studies (section 1.3). Reported methodologies have produced al-lenylboronic esters, but the highly reactive allenylboronic acids were mostly inaccessible. We envisioned a synthetic method in which a pro-pargylic carbonate such as 33a is borylated using a copper(I) catalyst, reminiscent to the work published by Ito and co-workers.70 Key inno-vations 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 me-thyl 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 cat-alyst from CuCl and a selection of alkali methoxides, resulting in a lowered 1H NMR yield (49-65%) for product 35a. Utilizing CuI com-bined 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

14

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 insta-bility. 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.

+OCO2Me• B

10 mol% mesitylcopper(I)20 mol% P(OMe)3

MeOH 3 Å molecular sieves

-10 °C, 24 h

B BHO

HO OH

OHOH

OH

HOOH+

allenylboronic acid

No change

CuClc and KOMed are used instead of mesitylcopper

CuClc and NaOMed are used instead of mesitylcopper

CuClc and LiOMed are used instead of mesitylcopper

CuIc and LiOMed are used instead of mesitylcopper

PPh3 is used instead of P(OMe)3

PCy3 is used instead of P(OMe)3

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

1,3-Propanediol is used instead of ethylene glycol

No ethylene glycol is added

No 3 Å molecular sieves are added

Reaction temperature is 0 °C

THF is used instead of MeOH

Entry Conditions Crude yieldb (%)

1

2

3

4

5

6

7

8

9

10

11

12

13

76

52

49

65

29

46

0

0

49

66

75

16e

0

a33a (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 Åmolecular sieves were stirred in MeOH (1 mL) at -10 °C for 24 h. bYield determined by 1H NMR using naphthalene asinternal standard. c10 mol%. d20 mol%. eThe product decomposes via protodeborylation.

Ph Ph33a 4 34 35a

15

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 bo-ronic 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 cy-clopropane ring to be opened by a Cu-catalyzed borylation has previ-ously 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%.

16

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

•

MeO2C

MeO2C

Entry Substrate Crude yieldb (%)

1

2

3

4

5

6

7

8

9

a33 (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 Åmolecular sieves were stirred in MeOH (1 mL) at -10 °C for 24 h. bYield determined by 1H NMR using naphthalene asinternal standard. cYield at 3 mmol scale.

OCO2Me

OCO2Me

OCO2Me

OCO2Me

OCO2Me

OCO2Me

OCO2Me

OCO2Me

OCOPh

CO2MeCO2Me

• BOH

OH

• BOH

OH

• BOH

OH

• BOH

OH

• BOH

OH

BOH

OH

• BOH

OH

• B OH

OH

• BOH

OH

PhOCO

33b

33c

33d

33e

33f

33g

33h

33i

33j

35b

35c

35d

35e

35f

35g

35h

35i

35j

9462c

67

61

59

80

63

83

59

34

Product

+

R1OCO2Me

R2 R3

•R2

R3

B

R1

10 mol% mesitylcopper(I)20 mol% P(OMe)3

MeOH 3 Å molecular sieves

-10 °C, 24 h

B BHO

HO OH

OH OH

OH

HOOH+

allenylboronic acid

33 4 34 35

17

The proposed mechanism for the copper-catalyzed borylation reac-tion (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-ad-dition 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.

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 propargyl-boration (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 ex-tracted 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 decompo-sition.

LnCuI OMe B BOR

ORRO

RO

BOR

MeO OR

BCuILn

OCO2Me

PhRO

OR

LnCuI BOR

OR

OCO2MePh

• BOR

OR

Ph+ CO2 36

37

38

33a

35a

18

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.

Scheme 16. Attempted transesterification of pinacolester 41a with di-ethanolamine 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.

OH

OH

Ph

crudeallenylboronic

acid •O H

• BOH

OH

Ph

pureallenylboronic

acid

• BOH

OHcrude

allenylboronic acid • B

N

• B HOHN

OH

toluene, r.t., 30 min

B

Ph

N

OHCl (aq.)

tolueneextraction

solid precipitate

HOHN

OH

toluene, r.t., 24 h

O

O H• B

OH

OHpure

allenylboronic acidHCl (aq.)

tolueneextraction

solid precipitate

73% yield

59% yield

35a 40a 35a

39

35b 40b 35b

39

pinacolester HO

HN

OH

toluene, 40 °C, 48 h

• B

Ph

N

O

O H• B

Ph

O

O

no reactionX

41a

39

40b

19

Scheme 17. Borylation of carbonate 33a using various alternative di-boron sources.

A borylation with B2nep2 (42) afforded the neopentyl ester 43 in 67% 1H NMR yield. Attempted purification of 43 using silica gel chromatog-raphy 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 propargylbora-

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

+OCO2Me• B

10 mol% mesitylcopper(I)20 mol% P(OMe)3

MeOH 3 Å molecular sieves

-10 °C, 24 h

OH

OH

allenylboronic acid

Ph Ph

B2pin2

pinacolester

• B

Ph

O

O 3 equiv. NaIO4

HCl, THF:H2O (4:1)r.t., 2h

+OCO2Me

10 mol% mesitylcopper(I)20 mol% P(OMe)3

MeOH 3 Å molecular sieves

-10 °C, 24 hPh

B2nep2

neopentylester• B

Ph

O

O

+OCO2Me

10 mol% mesitylcopper(I)20 mol% P(OMe)3

MeOH 3 Å molecular sieves

-5 °C, 5 hPh

pinanediolester

• B

Ph

BB O

OO

O

H

H

O

OH

35a63% yield

4367% yield

33a 2 41a

33a 42

33a 44 4552% yield

20

afforded alcohol 46b in 72% isolated yield after 24 h at room tempera-ture (Table 3, entry 2). Formation of the sterically demanding C-C bond between two quaternary carbons required no activation, demon-strating the high reactivity of allenylboronic acid 35b. Aldimines 47a and 47b were also propargylated in yields ranging between 63-83% us-ing the same conditions (entries 3-5). The homopropargylic amine re-sulting 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.

35 46

Entry Boronic acid Yieldb (%)

1

2

3

4

6

7

5

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.

15b

19b

47a

47b

48a

49a

47b

46a

46b

46c

46d

46f

46g

46e

87

72

63

83

96

82

65

Product

•R2

R2

B

R1OH

OHX

R2Y YR2 R2

X R2 R1toluene

3 Å molecular sieves

24 h, r.t.+

allenylboronic acid

Electrophile

35bc

35b

35b

35b

35b

35a

35e

H

O

Br

Me

O

Br

H

NMe

H

NSiMe3

N

NH

H

NSiMe3

OH

Br

Br

HO

NHMe

NH2

NH

NH

NH2

Ph

21

Allenyl-Bpin compounds are known to react with aldehydes when activated by a Lewis acid.70 Submitting pinacol ester 41b and 4-bromo-benzaldehyde (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 pi-nacol ester 41a and ketone 19b or imine 47a. The inert behavior of the Bpin compounds highlights the versatile reaction profile of allenyl-boronic acids under similar reaction conditions.

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 at-tempted reaction of 45 and 4-bromoacetophenone (19b) at identical conditions as described above (Table 3, entry 2) no reactivity was ob-served after 24 hours (Scheme 19).

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

toluene3 Å molecular sieves

24 h, r.t.

+pinacolester

• B O

OH

NMe NHMe

PhXPh

toluene3 Å molecular sieves

24 h, r.t.

+pinacolester

• B O

OMe

O

Br

Ph

Br

XPh

toluene3 Å molecular sieves

10 min, r.t.

+pinacolester

• B O

OH

O

Br

OH

Br

X

HO

41a

41a

41b 15b 46a no reaction

19b 46h no reaction

47a 46i no reaction

toluene3 Å molecular sieves

24 h, r.t.

+ Me

O

Br

Ph

Br

XHO

pinanediolester

• B

Ph

O

OH

45 19b 46j no reaction

22

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 pro-pargylic 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 compara-ble yield and ee (entry 5).

Table 4. Varied reaction conditions for the catalytic asymmetric pro-

pargylboration of ketone 11b.

The asymmetric propargylboration reaction was carried out as de-

scribed 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,

15 mol% 20-(S)2 equiv. EtOH

toluene 3 Å molecular sieves

48 h, r.t.

+ Me

O

Br

• BOH

OH

Br

HO

(S)-Br2-BINOL20-(S)

No change

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

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

t-BuOH is used instead of EtOH

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

Entry Conditions Yieldb (%)

1

3

2

4

5

95

82

86

91

93

ee (%)

94

77

44

55

-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.

HO

HO

Br

Br35b 19b 46b

23

96% ee, entry 3). A reaction between boronic acid 35c and 4-bromoace-tophenone 19b gave 77% yield and 90% ee (entry 4). The homopropar-gylic 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 ob-tained 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 ex-pected 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 propargylbora-tion of ketones.

Entry Boronic acid Yieldb (%)

1

2

3

4c

5d

6c

7c

19a

19c

19d

19b

19e

19e

19f

46k

46l

46m

46n

46o

46p

46q

75

67

90

77

6270e

63

64

Product

•R2

R2

B

R1OH

OH+

allenylboronic acid

Acetophenone

35b

35b

35b

35c

35b

35a

35e

Me

O

H

Me

O

NC

Me

O

R3R2 R2

R1

R3

HO15 mol% 20-(S)2 equiv. EtOH

toluene 3 Å molecular sieves

48 h, r.t.

Me

O

AcO

Me

O

Br

Me

O

SO

O

Me

O

SO

O

Me

O

SPh

O

O

HO

HO

HO

HO

HO

Ph

HO

HO

NC

AcO

Br

SO

O

SO

O

SPh

O

O

ee (%)

97

91

96

90

9496e

96

99

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.

35 19 46

24

After several attempts of derivatization, the biphenyl ester 51 was adequately crystallizable for structural analysis. Compound 51 was ob-tained 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.

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 ob-servation 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.

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 excel-lent ee, that only one of the two enantiomers of boronic acid 35g will

HO

SO

O

O

SO

O

O

Ph

Cl

O

Stereocenter assigned as (R)by single crystal X-ray diffraction

2.

1. n-BuLi

71% yield

46o

50 51

• BOH

OH+ Me

O

Br Br

HO1 equiv. 20-(S)

toluene 3 Å molecular sieves

22 h, 45 °C racemic 35g

isolated yield 31%(62% with respect to thereactive enantiomer of 35g)

>99:1 d.r., 96% ee19b 52

25

participate in a reaction under these conditions. Schaus and co-workers have reported previous examples of chiral racemic allenylboronates re-acting 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

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

PhO

Me•

Me

Me n-Bu

BO

O

Br

Br

O

Me•

Me

Me n-Bu

BO

O

Br

BrPh

B•

Re-face approach

Si-face approach

OH

HO

(S)minor enantiomer

(R)major enantiomer

Favored

Disfavored

+ Me

O

O

O

Br

Br

TS 1

TS 253

19a

46k-(R)

46k-(S)

26

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 acti-vation (Table 3). In the context of asymmetric catalysis, this racemic background reaction is in competition with the enantioselective reac-tion. 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 pro-posed 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 pre-sent 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).

Scheme 23. Proposed catalytic cycle for the catalytic asymmetric pro-pargylboration reaction.

•

•

BOH

OH

Ph

O

20-(S)

53

46k

O

O

Br

Br

HO

HO

Br

Br

BO

O

Br

BrO

Ph

• BOEt

OEt

B

2 EtOH

2 EtOH2 EtOH

Me

O

B(OR)2

19a

35b54

55

27

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 stud-ies. Utilization of allenylboronic acids provides a novel catalytic asym-metric methodology to these valuable products.

Reacting hydrazonoester 56 with allenylboronic acid 35b in the pres-ence 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 enan-tioselectivity 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 enanti-oselectivity 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

28

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 pro-pargylboration of hydrazonoester 56.

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 enan-tioselectivity (Table 7). It is fortunate that commercially available cat-alyst 57-(S) is an order of magnitude cheaper compared to its 3,3’-substituted analogues, making it especially suitable for a scalable syn-thesis. 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 ap-plied for the preparation of a selection of chiral homopropargylic α-amino acid derivatives 58b-e in 56-66% yield and 84-92% ee.

conditions

toluene 3 Å molecular sieves

+B

OH

OH

O

EtOHN

(S)-BINOL57-(S)

Entry Yieldb (%)

1

2

3

4

6

79

67

78

83

52

ee (%)

92

90

94

76

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.

HO

HO

H

H

5

7

8

25

0

68

28

N/A

0

T (°C)

0

0

0

r.t.

0

0

0

r.t.

t (h)

48

24

48

24

48

48

48

24

Additive

None

None

None

None

2 equiv. EtOH

None

None

None

Catalyst

10 mol% 57-(S)

10 mol% 57-(S)

20 mol% 57-(S)

10 mol% 57-(S)

10 mol% 57-(S)

10 mol% 20-(S)

No catalyst

No catalyst

NNH

O

EtO

PhO

NH

PhO

•

35b 56 58a-(R)

29

Table 7. Synthetic scope for the catalytic asymmetric propargylbora-tion of hydrazonoester 67.

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 re-duced 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 Δ𝛿SR that was found using 1H NMR, allowing for unambiguous assignment of the stereochemistry for 58a-(R) as (R). Analogues 58b-e were assigned ac-cordingly.

PhO

HNNH

10 mol% 57-(S)

toluene, 0 °C, 48 h3 Å molecular sieves

+

O

EtO

R2 R2

HNNNH

O

EtO

PhO

NH

PhO

•R2

R2

B

R1OH

OH allenylboronic acid R1

O

EtO

PhO

O

EtOHN

NH

PhO

O

EtOHN

NH

O

EtOHN

NH

PhO

O

EtOHN

NH

PhO

O

EtOHN

NH

PhO

Ph

58a-(R)79% yieldb75% yieldb, c92% ee

58a-(S)d81% yieldb92% ee

58be66% yieldb84% ee

58c66% yieldb90% ee

58df56% yieldb92% ee

58eg63% yieldb92% 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.

35 56 58

30

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-bonyl group94 (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 Δ𝛿SR. The reason for this is the anisotropic shielding of the CO2Et moiety in 61-(S) by the phenyl group (Scheme 25). Conversely, Δ𝛿SR 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.

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

PhO

O

EtOHN

NH

O-0.04

-0.04

+0.05 +0.18

+0.07+0.04

+0.04+0.01

2.2 equiv. SmI2

THF / MeOH30 min, r.t.

2 equiv. DIPEA10 mol% DMAP

DCM, r.t., 1 h

Cl

O

MeO CF3

Difference in chemical shiftΔδSR = δ61-(S) − δ61-(R)

37% yield 56% yield58a-(R) 59

60

61

EtONH2

O

OHN

MPTA

O

OHN

H

CF3

MeO OH

NH MeO Ph

60-(R)

(R)

(S)(S)

61-(S)59

EtO

n-Bu

FFF

n-BuOEt

O

61-(S)

+

anisotropic magneticshielding of CO2Et moiety

OHN

H

CF3

OH

NH Ph OMe

O

ClCF3 OMe

60-(S)

(S)

(R)(R)

61-(R)59

EtO

n-Bu

FFF

n-BuOEt

O

61-(R)

+

anisotropic magneticshielding of alkyne moiety

OMeO

H,O,CF3coplanar

H,O,CF3coplanar

O

EtONH2H

O

EtONH2H

O

ClMeO CF3

31

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 confor-mation 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 pro-pargylation of hydrazonoester 56 (Scheme 27) probably follows a simi-lar 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.

OH

NH MeO Ph

FFF

n-BuOEt

O

61-(S)0.0 kcal mol-1ϕ1 = 1o ϕ2 = 29o

ϕ1 ϕ2 O

NH MeO Ph

FFF

61-(S)’+1.6 kcal mol-1ϕ1 = -62o ϕ2 = 25o

ϕ1 ϕ2

61-(S)’’+3.2 kcal mol-1ϕ1 = -151o ϕ2 = 27o

H OEtO

n-Bu

O

NH MeO Ph

FFF

H

n-Bu

O

EtOϕ2

ϕ1

32

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 allenyl-boronic 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 path-way 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.

NNH

O

EtO

PhO

NMe

Me

n-Bu

O

O

H

H

B•

Si-face approach

Re-face approach

(S)minor enantiomer

(R)major enantiomer

Favored

Disfavored

+O

O

H

H

BO

O

H

HHN

Ph

O

•

EtO O

•Me

Me

n-Bu

B

HN

Ph

O

N

EtO O

EtOHN

NH

HNNH

PhO

62 56

TS 3

TS 458a-(R)

58a-(S)O

EtO

O

PhO

33

Scheme 28. Proposed catalytic cycle for the alcohol-free catalytic asym-metric 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 anhy-drous conditions of the reaction mixture.

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

O

OBO

BO

57-(S)

62

58a

O

O

H

H

HO

HO

H

H

BO

O

H

HN

• B • BOH

OH

• B

2 H2O H2O

boroxine

3 Å molecular

sieves

NNHBz

EtO

BzHN

OEt

O

O

EtON

NH

PhO

(RO)2B

56

35b63

64

B•OBO

BO

O

O

H

H

• BB O

O

H

HN

BzHN

OEt

O

+ +

B(OR)2NBzHN

OEt

O63 64 62 58a

34

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 re-action 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 dia-stereoselectivity.

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 ob-tained from BINOL 57-(R) in 75% isolated yield. The enantioselectivity for both of these products was 84% ee, while the observed diastereose-lectivity was 98:2 d.r., which is slightly more selective than epimers 65a-b.

35

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

Scheme 31. Asymmetric allylboration of hydrazonoester 56 with neryl-boronic acid 22b.

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

10 mol% 57-(S)

BOH

OH

HNE

3 Å molecular sievestoluene, 0 °C, 48 h

geranylboronic acid

+

BOH

OH

10 mol% 57-(R)

E

3 Å molecular sievestoluene, 0 °C, 48 h

geranylboronic acid

+

71% yield84% ee97:3 d.r.

NNHBz

O

EtO

NNHBz

O

EtO

NHBz

EtO

O

HNNHBz

EtO

O 78% yield84% ee97:3 d.r.

(R,S)

(S,R)

22a 56 65a

22a 56 65b

BOH

OH

Z10 mol% 57-(S)

3 Å molecular sievestoluene, 0 °C, 48 h

nerylboronic acid

+

10 mol% 57-(R)

3 Å molecular sievestoluene, 0 °C, 48 hB

OH

OH

Z

nerylboronic acid

+

NNHBz

O

EtO

NNHBz

O

EtO

HNNHBz

EtO

O

HNNHBz

EtO

O

81% yield84% ee98:2 d.r.

75% yield84% ee98:2 d.r.

(R,R)

(S,S)

22b56 65c

22b56 65d

36

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-bro-mobenzoyl 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.

Scheme 33. Amide 69 allowed for the elucidation of the relative stereo-chemistry 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 stereoinduc-tion for the allylboration follows the same facial selectivity as the pro-pargylboration 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

-0.03

-0.03

+0.22

2.2 equiv. SmI2

THF / MeOH30 min, r.t.

2 equiv. DIPEA10 mol% DMAP

DCM, r.t., 1 h

Cl

O

MeO CF3

Difference in chemical shiftΔδSR = δ67-(S) − δ67-(R)

29% yield

HNNH

EtO

O

PhO

NH2EtO

O

HNO

O

MPTA

46% yield

+0.10

+0.09 +0.06

+0.01

+0.04

+0.09+0.12

+0.28

65a 66 67

60

HNNHBz

EtO

O 2 equiv. DIPEA10 mol% DMAPDCM, r.t., 24 h

Cl

O

Br NNHBz

EtO

O

O

Br

47% yield

69 X-raycrystal structure

65b 69

68

37

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.

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-chi-ral allylboronic dimers has been carried out by Pietruszka and co-work-ers.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

NHN

B

Si-face approach

Re-face approach Favored

Disfavored

+O

O

H

H

BO

OH

H

(R,S)major enantiomer

O

OH

HNB

HHN

Ph

O

EtO O

Ph

O

EtO O

HNNHBz

EtO

O

(S,R)minor enantiomer

HNNHBz

EtO

O

70

NNHBz

O

EtO56

TS 5

TS 6

65b

65a

38

out under mild conditions (r.t., 24 h) in the presence of molecular sieves. MeOH was employed as aliphatic alcohol to suppress the racemic back-ground 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 prod-uct formation (entries 6-8). In a previous study of allylboration of hy-drazones, 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.

39

Tab