university of groningen rhodium-catalyzed boronic acid ......complementary rhodium-catalyzed aca of...

University of Groningen

Rhodium-catalyzed boronic acid additionsJagt, Roelof Bauke Christiaan

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2006

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Jagt, R. B. C. (2006). Rhodium-catalyzed boronic acid additions: a combinatorial approach tohomogeneous asymmetric catalysis. s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 24-06-2021

https://research.rug.nl/en/publications/rhodiumcatalyzed-boronic-acid-additions(f6b6f774-c1f4-4035-a131-f1f4d52bf232).html

Rhodium-Catalyzed Boronic Acid Additions A Combinatorial Approach to

Homogeneous Asymmetric Catalysis

Richard B. C. Jagt

R. B. C. Jagt, “Rhodium-Catalyzed Boronic Acid Additions; A Combinatorial Approach to Homogeneous Asymmetric Catalysis”, Ph.D. Thesis, University of Groningen, The Netherlands, 2006.

ISBN: 90-367-2710-3

ISBN: 90-367-2711-1 (electronic version)

The work described in this thesis was carried out at the Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, The Netherlands.

Financial support was received from DSM Pharmaceutical Products, the Ministry of Economic Affairs, and the Chemical Sciences division of the Netherlands Organization for Scientific Research (NWO/CW), administered through the NWO/CW Combichem program.

RIJKSUNIVERSITEIT GRONINGEN

Rhodium-Catalyzed Boronic Acid Additions A Combinatorial Approach to

Homogeneous Asymmetric Catalysis

Proefschrift

ter verkrijging van het doctoraat in de

Wiskunde en Natuurwetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus, dr. F. Zwarts,

in het openbaar te verdedigen op

vrijdag 8 september 2006

om 14.45 uur

door

Roelof Bauke Christiaan Jagt

geboren op 19 oktober 1977

te Emmen

Promotores: Prof. Dr. B. L. Feringa

Prof. Dr. Ir. A. J. Minnaard

Beoordelingscommissie: Prof. Dr. J. B. F. N. Engberts

Prof. Dr. J. N. H. Reek

Prof. Dr. J. G. de Vries

ISBN: 90-367-2710-3

Voor mijn ouders.

04_Contents.doc

Contents

Chapter 1 Introduction

1.1 The Impact of Molecular Chirality

1.2 The Preparation of Enantiopure Molecules

1.3 Asymmetric Conjugate Addition Reactions

1.4 1,2-Arylations Using Organometallic Reagents

1.5 A Ligand Library Approach to Asymmetric Catalysis

1.6 Aims and Outline of this Thesis

1.7 References and Notes

1

1

2

3

6

12

16

17

Chapter 2 Enantioselective Synthesis of 2-Aryl-4-piperidones

2.1 Introduction

2.2 Results and Discussion

2.2.1 Preliminary Studies

2.2.2 Scope of the Reaction

2.3 Further Developments

2.4 Conclusions

2.5 Experimental Section


25

26

29

29

32

33

34

35

41

Chapter 3 Tandem Conjugate Addition/Protonation:

Enantioselective Synthesis of α-Amino Acids

3.1 Introduction


45

46

52

04_Contents.doc

Contents

3.3 Conclusions



56

57

58

Chapter 4 Enantioselective Synthesis of Diarylmethanols

4.1 Introduction


4.2.1 Preliminary Studies and Mechanistic Considerations

4.2.2 Ligand Library Approach



4.4 Conclusions



63

64

66

66

69

75

77

78

78

84

Chapter 5 Enantioselective Synthesis of N-protected Diarylmethylamines

5.1 Introduction



5.2.2 Screening of a Primary Ligand Library

5.2.3 Introduction of the N,N-Dimethylsulfamoyl Protecting Group

5.2.4 Screening of a Secondary Ligand Library


5.2.6 Removal of the N,N-Dimethylsulfamoyl Group

5.3 Conclusions



89

90

92

92

92

95

97

99

101

101

102

110

04_Contents.doc

Rhodium-Catalyzed Boronic Acid Additions

Chapter 6 An Entry to Diversity in 3-Aryl- and

3-Alkenyl-3-hydroxyoxindoles

6.1 Introduction


6.2.1 The Synthesis of Racemic 3-Substituted-3-hydroxyoxindoles

6.2.2 Enantioselective Synthesis of 3-Phenyl-3-hyroxyoxindoles


6.4 Conclusions



113

114

117

117

119

124

124

125

130

Chapter 7 Enantioselective Synthesis of Trifluoromethyl

Substituted Tertiary Alcohols

7.1 Introduction


7.3 Conclusions



135

136

137

139

140

143

Summary

147

Samenvatting

153

Acknowledgements 159

04b_Emptypage.doc

1

05_Chapter 1.doc

Chapter 1 Introduction

1.1 The Impact of Molecular Chirality

Chirality1 is an important aspect of the most fundamental processes of life.2 The sugars that

constitute DNA and RNA possess a uniform stereochemical configuration. The proteins

encoded by these oligonucleotides, crucial for the chemical transformations in cells, consist

of chiral α-amino acids that occur exclusively in the L-configuration. Without this chiral

homogeneity, the biomachinery that makes up all known living organisms would not be

able to function. Even in the most elementary forms of life, such as bacteria,3 a myriad of

different chiral molecules are involved in complex signaling pathways. Receptor proteins

on the cell membrane or within the cytoplasm or cell nucleus can specifically bind to one

enantiomer of a chiral “messenger” molecule and initiate a corresponding cellular response.

These diastereomeric interactions are the key to modern drug development.4

The interactions between biological systems and synthetic chiral molecules has a huge

impact on contemporary everyday life and applications range from flavors, fragrances, and

food additives to agrochemicals and life-saving drugs. Homochirality in drugs is as old as

the first therapeutic agents isolated from natural sources, such as quinine and morphine.

However, as products of synthetic chemistry, until recently chiral drugs were manufactured

as racemates. The assumption that only one enantiomer of a drug has biological activity and

the other serves as “isomeric ballast”4 has turned out to be a rather dangerous one. The two

enantiomers of a compound most frequently bind to different receptors, and therefore have

completely different physiological effects. The presence of the “wrong” enantiomer has, in

some cases, been known to cause serious side-effects. This has resulted in severe

restrictions5 to the production of bioactive molecules and at present time “single-

Chapter 1

2

05_Chapter 1.doc

enantiomer drugs have a commanding presence in the global pharmaceutical landscape”.6

The development of efficient methodologies for the synthesis of the individual enantiomers

of an asymmetric target compound is, therefore, of continuous interest to scientists in both

industry and academia.

1.2 The Preparation of Enantiopure Molecules

Routes to single enantiomers of small molecules can be classified into three groups:

1) chiral pool technology, 2) resolution of racemic mixtures, and 3) asymmetric synthesis.

The former is the most straightforward route to enantiopure compounds and starts from

homochiral biomolecules which are provided by natural processes such as agriculture or

fermentation. However, the lack of availability of both enantiomers for most naturally

occurring compounds severely limits the scope of this methodology and many chiral

building blocks can only be obtained by synthetic procedures.7

The “classical” resolution of racemic mixtures by diastereomeric crystallisation, to date,

often constitutes the industrial method of choice to obtain large quantities of enantiopure

compounds.8 However, unless it can be recycled, half of the racemic starting material (the

“unwanted” enantiomer) is a waste-product. This intrinsic property of classical resolutions

poses a major disadvantage from an atom-economy point of view.9 The same disadvantage

applies to chemical or enzymatic kinetic resolutions, involving a reaction in which one of

the two enantiomers reacts more rapidly than the other based on a difference in transition

state Gibbs energy. Although in certain cases, (dynamic) kinetic resolution can lead to

complete conversion of the starting material by in situ racemization, generally one

enantiomer reacts whereas the other remains intact.

The remaining option for the preparation of enantiopure molecules involves the

introduction of chirality to a prochiral substrate by asymmetric induction.10 This may

involve the use of stoichiometric amounts of chiral reagent or a chiral auxiliary followed by

the subsequent diastereoselective introduction of a stereogenic center. However, the use of

equimolar amounts of valuable chiral auxiliary materials makes these approaches rather

Introduction

3

05_Chapter 1.doc

unappealing. A far more attractive form of stereoselective synthesis involves the

application of asymmetric catalysts. A relatively small amount of enantiopure catalyst can,

in an ideal scenario, produce large quantities of enantiopure product. Although powerful

biocatalytic methods exist, employing enzymes or antibodies as catalysts,11 their

biomolecular homochirality often poses a problem when the “non-natural” enantiomer of

the product is desired. Recently, directed evolution methods have resulted in enzymes

which produce the unnatural enantiomers in excess.12 Alternatively, chemical catalysts can

be adapted to provide the desired enantiomer of the product by choosing the appropriate

enantiomer of the ligand. Although asymmetric organocatalysis – based on the use of small

organic molecules as catalysts − is an emerging field,13 in the last decades considerable

progress has been made in the development of highly active metal-catalyzed asymmetric

transformations based on enantiopure ligands complexed to a (transition) metal core.14 The

pioneering work of Knowles, Noyori, and Sharpless on chirally-catalyzed hydrogenation

and oxidation reactions, for which they received the 2001 Nobel prize in chemistry,15 has

opened the field of homogeneous asymmetric catalysis. Asymmetric reductions and

oxidations have been developed to an extent that they are in some cases used for industrial

production of enantiomerically enriched compounds. However, in catalytic asymmetric

carbon-carbon bond forming reactions high catalytic activity and enantioselectivity are less

well established.

1.3 Asymmetric Conjugate Addition Reactions

The asymmetric conjugate addition (ACA) of organometallic reagents to electron-deficient

alkenes constitutes an important approach for enantioselective carbon-carbon bond

formation.16 In recent years, numerous chiral catalysts have been introduced for this

asymmetric reaction.17 A breakthrough in the field was achieved by our group in 1996 with

the introduction of chiral monodentate phosphoramidite L1, which proved to be a highly

efficient ligand in the copper-catalyzed ACA of dialkylzinc reagents to enones (e.g.

Scheme 1.1, reaction a).18,19 Phosphoramidites comprise a class of cost-effective and easily

tunable ligands that have since proven useful in a host of different reactions (vide infra).

Chapter 1

4

05_Chapter 1.doc

Although the highly enantioselective copper-catalyzed conjugate addition of diphenylzinc,

using the same catalyst, has been reported for 2-cyclohexenone,20 the lack of readily

available diarylzinc reagents severely limits this method. A more convenient reaction for

the formation of sp2-sp3 carbon-carbon bonds, introducing a stereogenic centre, is the

complementary rhodium-catalyzed ACA of boronic acids pioneered by Miyaura and

Hayashi in 1998 (e.g. Scheme 1.1, reaction b).21 Excellent enantioselectivities have been

achieved in the addition of aryl and alkenyl groups to a broad range of both cyclic and

acyclic α,β-unsaturated enones employing BINAP as a chiral ligand.

O 0.5 mol% Cu(OTf)21 mol% L1

toluene, -30 oC

Et2Zn (1.2 equiv)

O

>98% ee

OO

P N

(S,R,R)-L1

a)

b)

O 3 mol% Rh(acac)(eth)23 mol% BINAP

dioxane/H2O : 10/1, 100 oC

PhB(OH)2 (3 equiv)

O

PPh2PPh2

(S)-BINAP97% ee

Scheme 1.1 Two complementary ACA reactions

Since its introduction, this reaction has received increasing attention.22,23 Rhodium-

catalyzed conjugate additions of arylstannane,24 arylsilicon,25 aryltitanium,26 and

alkenylzirconium27 reagents have also been reported. However, from a practical point of

view, boronic acids remain the most interesting arylating reagents because they are shelf

stable, readily available, and compatible with a large variety of functional groups.28 The

chiral ligands employed in the rhodium-catalyzed addition of arylboronic acids are mostly

bidentate and comprise biaryl bis-phosphines,21a,29 ferrocenyl-based bis-phosphines,29c

bis-β-naphthol (BINOL) based diphosphonites,30 amidomonophosphines,31 N-heterocyclic

carbenes,32 a P-chiral phosphine,33 and dienes.34 Some other bis-phosphine ligands,

although efficient in the rhodium-catalyzed hydrogenation, fail to induce high reactivity

Introduction

5

05_Chapter 1.doc

and/or selectivity in the rhodium-catalyzed conjugate addition to enones.22,29a,c Recently, it

was shown by our group that monodentate phosphoramidite L2 is an exceptionally efficient

ligand for the rhodium-catalyzed ACA of arylboronic acids to enones (Scheme 1.2).35

Enantioselectivities comparable to those obtained with BINAP have been achieved, while

the reaction rate is greatly enhanced. Employing L2 as a ligand, using 1 mol% of catalyst,

>99% conversion was reached within 5 min at 100 oC. Miyaura and co-workers confirmed

the successful use of phosphoramidites in this reaction.36

O 3 mol% Rh(acac)(eth)27.5 mol% (S)-L2

dioxane/H2O : 10/1, 100 oC

ArB(OH)2 (3 equiv)

O

OO

P

(S)-L2

N

Up to 98% ee

R

Scheme 1.2 Rhodium/phosphoramidite-catalyzed ACA of arylboronic acids

The mechanism for the rhodium-catalyzed addition of boronic acids (Scheme 1.3) has been

investigated by Hayashi et al.37 and all intermediates were identified by NMR. In order to

displace the acetylacetonate (acac), and to generate the catalytically active hydroxy species,

the presence of water and high temperatures are needed (step A). It was shown that, starting

from the hydroxy species, the reaction is faster than when the “precatalyst” prepared from

Rh(acac)(C2H4)2 and BINAP was used. A phenyl-rhodium complex and B(OH)3 are formed

after transmetallation of the phenyl group from boron to rhodium (step B). After

coordination of the substrate (step C), insertion of 1 into the phenyl-rhodium bond gives an

oxa-π-allyl species (step D). Hydrolysis of this species gives the desired phenylated product

2 and regenerates the catalytically active hydroxy species (step E). As water is involved in

forming the active hydroxy species and acts as a proton donor facilitating the

transmetallation, its presence is essential in order to complete the catalytic cycle. A major

drawback of the use of water, in combination with high temperature, is hydrolysis of

phenylboronic acid to benzene (step F). For this reason, the arylboronic acid is often added

in excess (3-5 equiv) compared to the enone.22

Chapter 1

6

05_Chapter 1.doc

Rh PhP*

P*

RhP*

P*

BPh B(OH)2

B(OH)3

FH2O C

R'

OB(OH)3

+

Ph-H

1

Rh OHP*

P*Rh(acac)(eth)2

+ 2P*A

H2O

R'

O

2Ph H2O

R'

O

Ph

Rh

P*

P*

Ph R'

O

DE

R

R

R

R

Scheme 1.3 Proposed catalytic cycle for the rhodium-catalyzed asymmetric conjugate addition reaction

Inspired by the catalytic cycle proposed by Hayashi et al.,37 it was recently found that the

use of a [Rh(OH)(cod)]2 (cod = 1,5-cyclooctadiene) or [RhCl(cod)]2/KOH catalyst

precursor allows the reaction to be carried out at room temperature with only 1.5 equiv of

boronic acid.38

1.4 1,2-Arylations Using Organometallic Reagents

Over the past 20 years, enantioselective formation of chiral diarylmethanols and

diarylmethylamines has attracted a great deal of interest.39 Enantiopure derivatives of these

compounds are important intermediates for the synthesis of biologically active molecules.40

In 1998, Miyaura and co-workers demonstrated the rhodium-catalyzed addition of

arylboronic acids to aromatic aldehydes under conditions similar to those used for their

conjugate addition to enones.41,42 In an asymmetric version of this reaction, employing

MeO-MOP as chiral ligand, 41% ee was achieved for the addition of phenylboronic acid to

Introduction

7

05_Chapter 1.doc

1-naphthaldehyde (Scheme 1.4, reaction a). An attempt by Frost et al. to improve the

enantioselectivity of this reaction by using sparteine or bis-oxazolines as ligands remained

unsuccessful (

Chapter 1

8

05_Chapter 1.doc

reaction. Hayashi et al. reported excellent enantioselectivities in the addition of

arylboroxines to a range of N-tosyl- and N-nosyl-benzaldimines (Scheme 1.5) employing

L5 and L6, respectively.50

O

NPPh2

L4

Ph

Ph

Ph

Ph

L5NHBoc

L6

NPPh2

PPh2

(R,R)-DeguPHOS

Bn

Figure 1.1 Ligands reported in the 1,2-addition of arylboronic acids to benzaldimines

NPG

HR1

ArB(OH)2 (2 equiv)

[RhCl(C2H4)2]2 (3 mol%)

L5 or L6 (3 mol%)

KOH/H2O

dioxane, 60 oC, 6 h

HNPG

R1

R2

PG = S (Tosyl)

S NO2 (Nosyl)

PG = Tosyl: L5, 95-99% eePG = Nosyl: L6, 95-99% ee

O

O

O

O

Scheme 1.5 Arylboronic acid addition to N-tosyl and N-nosyl protected benzaldimines

Next to the rhodium-catalyzed arylation of aldehydes and imines, a successful alternative

for such reactions can be found in the addition of diarylzinc reagents employing in situ

formed complexes of zinc with chiral aminoalcohols and diols as catalysts.51 In contrast to

the addition of dialkylzinc reagents, however, addition of diphenylzinc to aldehydes also

proceeds quite efficiently without the presence of a catalyst. This background reaction

makes it difficult to achieve high enantioselectivities. In 1997, Dosa and Fu reported the

first enantioselective catalytic addition of diphenylzinc to aldehydes employing axially

chiral ferrocene-based ligand L7 (Figure 1.2).52 The addition of diphenylzinc to

p-chlorobenzaldehyde provided the product alcohol with an enantioselectivity of 57% ee.

Introduction

9

05_Chapter 1.doc

In 1999, Pu et al. reported high ee values in the addition of diphenylzinc to aldehydes using

L8a as a ligand (Scheme 1.6).53 This chiral binaphthol was also previously employed as a

highly enantioselective catalyst in the addition of dialkylzinc.54 Interestingly, the authors

observed that when 20 mol% L8a was pretreated with 40 mol% of diethylzinc, the resulting

chiral PhZnEt complex facilitated the addition of diphenylzinc with a considerable increase

in enantioselectivity.55

FeN

MeMeMe

MeMe

L7

OHO

Ph

Ph

Figure 1.2 Ferrocene ligand employed by Dosa and Fu

Cl

CHO+ Ph2Zn

OHOH

Ar

Ar

OC6H13

C6H13O

F

C6H13O

F

L8a

L8b

Ar =

Cl

Ph

OH

20 mol% L840 mol% Et2Zn

Et2O, RT, 10 h:

CH2Cl2, RT, 5 h:

86% yield, 94% ee

92% yield, 95% ee

Ar =

Scheme 1.6 Addition of diphenylzinc to aldehydes using diethylzinc as an additive

The use of fluorinated binaphthol-type ligands, resulting in an enhanced reaction rate, was

reported by Pu in 2000.56 Various aromatic aldehydes were converted with diphenylzinc in

the presence of 20 mol% of (S)-L8b in dichloromethane. After 5 h at room temperature the

products were formed with good enantioselectivities in high yields. In 1999 Bolm and

Muñiz reported ferrocene-based ligands L9 and L10 (Figure 1.3) in the addition of

diphenylzinc to aldehydes.57 The addition of diphenylzinc to p-chlorobenzaldehyde and

Chapter 1

10

05_Chapter 1.doc

ferrocenecarboxaldehyde, employing ligand L9, proceeded with 90% and >96% ee,

respectively. However, the enantioselectivity for the reaction of other aromatic or aliphatic

aldehydes was considerably lower (3-75%) due to the background reaction. Also here, the

use of a mixture of diphenyl- and diethylzinc (in a 1 : 2 ratio) significantly increased the

enantioselectivity.58 For the addition of diphenylzinc to p-chlorobenzaldehyde an ee of 99%

was achieved. Using a similar procedure, L9 catalyzed the reaction of diphenylzinc with a

range of aldehydes with very high enantioselectivity. This methodology has been adapted

by Bolm and Bräse to the addition of diphenylzinc to imines (Scheme 1.7).59 The addition

of diphenylzinc to a range of in situ formed N-formylimines with different electronic and

steric modifications proceeded with high enantioselectivities.

FeN

O

CPh2OH FeN

O

PhCPh2OH

L9 L10

Figure 1.3 Ferrocene ligands employed by Bolm and Muñiz

SO2Tol

HN H

O

R

N H

O

R

ZnEt2/ZnPh2

ZnEt2/ZnPh2 H

(Rp,S)-L11 (10 mol%)

HN H

O

ROH

N

Ph

Ph

(Rp,S)-L11Up to 97% ee

Scheme 1.7 Catalytic asymmetric phenyl transfer reaction onto N-formylimines

Introduction

11

05_Chapter 1.doc

Several alternative systems for the addition of mixtures of diphenylzinc and diethylzinc to

aldehydes have been reported.60 Triphenylborane was recently found to be an interesting

alternative to diphenylzinc as a phenyl source.61 It is commercially available in bulk

quantities and rather inexpensive compared to diphenylzinc. All these methods are,

however, limited to the addition of phenyl groups. More general systems that facilitate the

addition of a range of aryl groups, as is the case for the addition of arylboronic acids, are

limited. Recently, however, Bolm et al.62 reported an excellent hybrid method in which the

aryl transfer reagent was generated by mixing arylboronic acids with an excess of

diethylzinc (Scheme 1.8).63 Subsequently, a multigram scale application was described.64

Employing ligand L9, the addition of different aryls to a range of benzaldehydes proceeded

with enantioselectivities from 31 to 95% ee. The presence of catalytic amounts of a

dimethylpolyethyleneglycol (DiMPEG, Mw = 2000 g mol-1) further improved the

enantioselectivities.65

CHOR

ArB(OH)2Et2Zn (7.2 equiv)

10 mol% L910 mol% DiMPEG

10 oC, 12 h

ROH

Ar

Scheme 1.8 Use of in situ generated zinc reagents from diethylzinc and arylboronic acids

High enantioselectivities in the arylation of benzaldehydes, using a mixture of arylboronic

acids and diethylzinc, have recently also been achieved using chiral binaphthol

dicarboxamides,66 hydroxy oxazolines,67 ferrocene based silanols,68 aminonaphtholes,69 a

camphor-derived γ-amino thiol,70 and β-amino alcohol-based catalysts.63b,71 In addition to

boronic acids, also their boroxine trimers have been used successfully in combination with

diethylzinc.72 All of these methods, however, are dependent on the use of an excess of

rather expensive and reactive diethylzinc. From a practical and industrial point of view, the

development of a direct catalytic addition of boronic acids to aldehydes with high

enantioselectivity is more desirable.

Chapter 1

12

05_Chapter 1.doc

1.5 A Ligand Library Approach to Asymmetric Catalysis

The identification of suitable asymmetric catalysts still poses one of the most challenging

endeavours of contemporary organic chemistry.14 Current mechanistic knowledge is not

sufficient to “design” catalysts which will induce high enantioselectivity. All

stereoselective syntheses are based on the principle that the products are formed via

diastereomeric transition states with a difference in Gibbs energy of activation (∆∆G‡).1b

Seemingly insignificant variations in the catalyst or substrate structure and reaction

conditions, corresponding to minute differences in transition state energy (∆∆G‡ ≅ 1-2

kcal/mol), can cause significant changes in ee. Moreover, the degree of structural

recognition that is a prerequisite for selective catalysts also renders them highly substrate

dependent. In many asymmetric reactions the ligand structure must be optimized for each

substrate class.

The relationship between ligand structure and the chemical and physical properties of

derived complexes is a central theme in many branches of chemistry. In essence, the

problems involved with developing asymmetric catalysts are similar to those encountered

by medicinal chemists when developing a new drug that is required to undergo selective

diastereomeric interactions with a specific receptor protein. Conventional drug

development, until recently, involved the laborious process of synthesizing and evaluating

hundreds to thousands of organic compounds in a one-at-a-time fashion in an attempt to

enhance biological activity and selectivity. In the 1990s pressure within the pharmaceutical

industry to speed up the drug discovery process, combined with the increasing political and

social pressure on drug prices, have resulted in a paradigm-shift in the field.

“Combinatorial chemistry”73 became the new standard in drug development, dramatically

cutting the time and costs associated with serial drug discovery. The basic principle of this

new philosophy is the parallel synthesis of a library of compounds, followed by high-

throughput screening in order to identify the most promising leads (Scheme 1.9). More

focussed libraries can subsequently be tested in order to optimize the results. In contrast to

the “classical” iterative serial approach, different compounds with a modular build-up are

generated simultaneously, in a systematic manner, under identical reaction conditions, so

Introduction

13

05_Chapter 1.doc

that the products of all possible combinations of a set of building blocks are obtained.

Although combinatorial chemistry was initially met with resistance from the chemical

community because of its “black-box” character, its practice is now widespread in chemical

biology and medicinal chemistry as a tool to systematically investigate structural

requirements that are beyond rational design. Mechanistic insight remains very important,

as it helps in the selection of suitable parameters.

Design

TraditionalSynthesis

ParallelSynthesis

ParallelScreening

SerialScreening

Scheme 1.9 Serial and parallel approaches to synthesis and screening

Also in the field of asymmetric homogeneous catalysis, scientists have recognized the

power of the combinatorial chemistry approach. Currently, the development of efficient

catalysts for asymmetric catalysis is still largely empirical and often a result of knowledge-

based intuition or serendipity. Divergent ligand synthesis strategies, in which several

analogues of a promising ligand-type are prepared, appears to be an especially fruitful

strategy in this area. However, the synthetic procedures for chiral ligands are often lengthy

and unsuitable for such an approach. Due to limited time and resources usually only a small

set of possibilities can be explored in a serial fashion. There is a clear need for a more

methodical approach in which the structure of the catalyst is systematically varied.

The parallel synthesis of chiral ligands with a modular build-up,74 coupled to high-

throughput screening,75 may effectively address the problems involved with the

optimization of asymmetric catalysts.76 Such a diversity-based approach will also allow for

the identification of an optimal catalyst for each particular substrate, or class of substrates,

thus overcoming the problem of generality that arises when only a small number of chiral

catalysts are available. Although in combinatorial approaches, focussed on biological

activity, it is quite common to use libraries of mixtures of compounds, such strategies are

problematic in studies related to the identification of homochiral catalysts.77 Due to the

Chapter 1

14

05_Chapter 1.doc

extreme sensitivity of reaction rate and selectivity to small structural variations, the

examination of mixtures of catalysts can give rise to misleading conclusions (i.e. two

effective catalysts that afford high ee values, but with opposite configurations, will give a

perception of low selectivity). Even though it was recently shown that catalysts derived

from mixtures of two different monodentate ligands can give superior results to their

respective homocombinations,78 it is still preferable to employ parallel reactions in which

one ligand is produced per vial. This strategy offers the advantage that each ligand structure

is available spatially addressable and pure. Impressive results have been obtained with

solid-phase bound libraries,79 however, in general the translation of this chemistry to

solution phase can be quite problematic. Parallel synthesis of asymmetric catalysts is,

therefore, mostly performed in solution phase.

Chiral ligands, employed in a parallel synthesis/screening approach, require a modular

build-up with easily connectable components. From an industrial perspective, where

successful catalytic procedures will be subject to scale-up, the ligands should also be cost-

effective when produced in larger quantities.76d After a seminal report of Gilbertson et al.

on the synthesis of modular ligand libraries of phosphane-containing polypeptides for

asymmetric hydrogenation,80 several reports have appeared concerning the parallel

synthesis of ligand libraries for asymmetric catalysis.76 Amino acid building blocks81 have

proven a popular choice in initial explorations at the interface of combinatorial chemistry

and asymmetric catalysis.82 Recently, Lefort et al. reported the automated parallel synthesis

and in situ screening of libraries of monodentate phosphoramidite ligands in rhodium-

catalyzed hydrogenation reactions.83 This ligand class has been proven to be highly

successful in a wide variety of metal-catalyzed enantioselective reactions, including:

1) rhodium-catalyzed hydrogenations84 and conjugate additions of trifluoroborates85 and

boronic acids,35 2) a palladium-catalyzed intramolecular Heck coupling,86 3) copper-

catalyzed ring-opening of oxabicyclic alkenes,87 desymmetrization of epoxides,88 conjugate

additions of diorganozinc reagents,19,20 and allylic alkylations,89 and 4) iridium-catalyzed

allylic substitutions.90 A different member of the ligand family is required for most of these

reaction-types and often for each individual substrate class.

Introduction

15

05_Chapter 1.doc

The protocol of Lefort et al.83 allows for the parallel preparation of a solution phase library

of phosphoramidites in a 96-well format in one day and their subsequent in situ parallel

screening (Scheme 1.10). Other monodentate ligands, such as phosphites and phosphinites,

should also be highly suitable for a similar approach. Their automated parallel synthesis

has, however, yet to be reported.

PO

OCl

HN(R1)R2

*

PO

ON(R1)R2*

Et3N

Orbital Shaker

Parallel

Filtration

Metal

Precursors

Prochiral

SubstratesSolution Phase Library

96-Well Microplate

Et3N HCl- ( )

Crude Phosphoramidite

96-well Oleophobic Filterplate

Parallel

Reactor

OO

P ClPO

OCl* =

R3

R3R4

R4

, OOP Cl

R3

R3

Scheme 1.10 Protocol for the synthesis of a phosphoramidite library

Phosphochloridites can be readily prepared from the corresponding diols and an excess of

PCl3. With the help of a liquid handling robot, stock solutions of the phosphorchloridites,

amines, and triethylamine were dispensed directly into a 96-well oleophobic filterplate. The

vials were vortexed for 2 h, after which parallel filtration into a 96-well titerplate − in order

to remove the precipitated Et3N·HCl salt − gave the liquid phase ligand library. The ligand

stock solutions can be transfered to a parallel reactor for in situ complexation to a

(transition) metal. The methodology offers the possibility to test multiple metals and

substrates concurrently. Duursma et al. recently used this technology in order to screen a

library of phosphoramidites in the rhodium-catalyzed conjugate addition of

Chapter 1

16

05_Chapter 1.doc

vinyltrifluoroborates to cyclic and acyclic enones, effectively testing 96 ligands on two

substrates in one run.85b It was shown that the method results in quick discovery of leads for

effective enantioselective catalysts. Considering the broad range of asymmetric reactions

that are catalyzed by monodentate phosphorus ligands,91 and the recently introduced

possibility of using combinations of monodentate ligands,78 the methodology at hand has an

enormous potential in the efficient development of highly enantioselective catalysts that

have currently remained elusive.

1.6 Aims and Outline of this Thesis

As described in §1.3, the rhodium-catalyzed conjugate addition of boronic acids is a highly

convenient method for the simultaneous construction of sp2-sp3 carbon-carbon bonds and

stereogenic centers. Monodentate phosphoramidite ligands lead to highly enantioselective

catalysts in this reaction. In part, the aim of this thesis is to expand the scope of this

reaction with more challenging substrates, leading to useful chiral products. In Chapter 2

the enantioselective synthesis of 2-aryl-4-piperidones by rhodium/phosphoramidite-

catalyzed conjugate addition of arylboronic acids is described. This class of piperidones are

important intermediates in the preparation of both naturally occurring alkaloids and a range

of synthetic drugs. Chapter 3 describes an investigation into the feasibility of a selective

rhodium/phosphoramidite-catalyzed addition of arylboronic acids to dehydroalanine

derivatives. In this “tandem-reaction” the introduction of an aryl-substituent at the

β-position by conjugate addition needs to proceed with concomitant control of the chirality

at the α-center. The products are unnatural α-amino acids, which are increasingly important

in the fields of drug discovery and protein engineering.

It becomes apparent in §1.4 that catalysts for the conjugate addition of arylboronic acids to

alkenes are often also suitable for their 1,2-addition to benzaldehydes and N-protected

benzaldimines. The products of such reactions are important building blocks for a range of

organic compounds with pharmaceutical properties. The powerful method of parallel

synthesis and in situ screening of phosphoramidite ligands, as described in §1.5, offers the

potential to find the most efficient catalyst for both of these substrate classes. The second

Introduction

17

05_Chapter 1.doc

aim of this thesis is the development of new rhodium/phosphoramidite-catalysts for the 1,2-

addition of arylboronic acids to aldehydes and imines. In Chapter 4 the enantioselective

synthesis of diarylmethanols through the rhodium/phosphoramidite-catalyzed addition of

arylboronic acids to aldehydes is described. Chapter 5 describes the asymmetric synthesis

of N-protected diarylmethylamines from their corresponding imines. In addition, the

possibility of using activated ketones as substrates for this reaction has been investigated. In

Chapter 6 the synthesis of 3-aryl-3-hydroxyoxindoles through 1,2-addition of arylboronic

acids to isatins will be described. Finally, in Chapter 7 the addition of arylboronic acids to

2,2,2-trifluoroacetophenones is discussed.


1. Chirality (Greek, handedness, derived from the word stem χειρ~, ch[e]ir~, hand~) is a “dissymmetry” property important in several branches of science. An object or a system is called chiral if it differs from its mirror image. The term chirality was coined by Lord Kelvin: (a) W. T. Kelvin, Baltimore Lectures on Molecular Dynamics and the Wave Theory of Light, C. J. Clay and Sons: London, 1904. For further stereochemical definitions, see (b) E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley: New York, 1994.

2. (a) F. Krick, Life Itself, McDonald & Co.: London, 1981. (b) M. Gardner, The Ambidextrous Universe, 2nd Ed., C. Scribner: New York, Harmondsworth: UK, 1982.

3. For a review on chemical signaling among bacteria, see: G. J. Lyon, T. W. Muir, Chem. Biol. 2003, 10, 1007.

4. E. J. Ariens, W. Soudijin, P. B. M. W. M. Timmermans (Eds.), Stereochemistry and Biological Activity of Drugs, Blackwell Scientific Publications: Oxford, 1983.

5. Food and Drug Administration, Fed. Reg. 1992, 22:249.

6. A. M. Rouhi, Chem. Eng. News 2003, 81, 45.

7. S. Hanessian, Total Synthesis of Natural Products: the “Chiron” approach, Pergamon Press: Oxford, 1983.

8. (a) J. Jacques, A. Collet, S. H. Wilen, Enantiomers, racemates, and resolutions, Wiley: New York, 1981. (b) A. N. Collins, G. N. Sheldrake, J. Crosby (Eds.), Chirality in Industry II, Wiley: Chichester, 1997. (c) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten Hoeve, R. M. Kellogg, Q. B. Boxterman, A. J. Minnaard,

Chapter 1

18

05_Chapter 1.doc

B. Kaptein, S. van der Sluis, L. Hulshof, J. Kooistra, Angew. Chem. Int. Ed. 1998, 37, 2349.

9. B. M. Trost, Angew. Chem. Int. Ed. Engl. 1995, 34, 259.

10. J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric Catalysis, Wiley: New York, 1995.

11. (a) J. Wagner, R. A. Lerner, C. F. Barbaras III, Science 1995, 270, 1797. (b) A. M. Klibanov, Nature 2001, 409, 241.

12. For reviews on the directed evolution of enantioselective enzymes, see: (a) M. T. Reetz, Tetrahedron 2002, 58, 6595; (b) M. T. Reetz, Proc. Natl. Acad. Sci. USA 2004, 101, 5716; (b) M. T. Reetz In Methods in Enzymology, Vol. 388, D. E. Robertson, J. P. Noel (Eds.), Elsevier: San Diego, 2004, 238. See also: (d) N. J. Turner, Trends Biotechnol. 2003, 21, 474.

13. A. Berkessel, H. Gröger (Eds.), D. MacMillan, Asymmetric Organocatalysis: From Biomimetic Synthesis to Applications in Asymmetric Synthesis, Wiley-VCH: Weinheim, 2005.

14. E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis, Vol. 1-3, Springer: Berlin, 1999.

15. (a) W. S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998. (b) R. Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008. (c) K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2024.

16. K. Tomioka, Y. Nagaoka In Comprehensive Asymmetric Catalysis, Vol. 3, E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Springer: Berlin, 1999, §31.1.

17. (a) N. Krause, A. Gerold, Angew. Chem. Int. Ed. 1997, 36, 186. (b) N. Krause, Angew. Chem. Int. Ed. 1998, 37, 283. (c) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346. (d) N. Krause, A. Hoffman-Röder, Synthesis 2001, 171. (e) B. L. Feringa, R. Naasz, R. Imbos, L. A. Arnold In Modern Organocopper Chemistry, N. Krause (Ed.), Wiley-VCH: Weinheim, 2002, Chapter 7, 224. (f) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. 2002, 3221. (f) A. Alexakis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660.

18. For the first example of chiral phosphine ligands in this reaction (30% ee), see: A. Alexakis, J. Frutos, P. Mangeney, Tetrahedron: Asymmetry 1993, 4, 2427.

19. (a) A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew. Chem. Int. Ed. 1996, 35, 2374. (b) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem. Int. Ed. 1997, 36, 2620. (c) R. Naasz, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed. 2001, 40, 927. (d) F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, B. L. Feringa, Angew. Chem. Int. Ed. 2001, 40, 930. (e) L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2003,

Introduction

19

05_Chapter 1.doc

125, 3700. (f) R. Šebesta, M. G. Pizzuti, A. J. Boersma, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2005, 1711.

20. D. Peña, F. Lopez, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2004, 1836.

21. (a) Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai, N. Miyaura, J. Am. Chem. Soc. 1998, 120, 5579. For the first (non-asymmetric) rhodium-catalyzed conjugate addition of aryl- and alkenylboronic acids, see: (b) M. Sakai, H. Hayashi, N. Miyaura, Organometallics 1997, 16, 4229.

22. For a recent review, see: (a) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829; (b) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169.

23. For some recent results of conjugate additions to other α,β-unsaturated systems, see: (a) R. Shintani, K. Ueyama, I. Yamada, T. Hayashi, Org. Lett. 2004, 6, 3425 for fumaric and maleic substrates; (b) J. F. Paquin, C. Defieber, C. R. J. Stephenson, E. M. Careira, J. Am. Chem. Soc. 2005, 127, 10850 and (c) T. Hayashi, N. Tokunaga, K. Okamoto, R. Shintani, Chem. Lett. 2005, 34, 1480 for enals; (d) J. F. Paquin, C. R. J. Stephenson, C. Defieber, E. M. Carreira, Org. Lett. 2005, 7, 3821 for acrylic esters; (e) R. Shintani, W. L. Duan, T. Nagano, A. Okada, T. Hayashi, Angew. Chem. Int. Ed. 2005, 44, 4611 for maleimides; (f) R. Shintani,, T. Kimura, T. Hayashi, Chem. Commun. 2005, 25, 3212 for Weinreb amides; (g) G. Chen, N. Tokunaga, T. Hayashi, Org. Lett. 2005, 7, 2285 and references therein for coumarins.

24. (a) S. Oi, M. Moro, S. Ono, Y. Inoue, Chem. Lett. 1998, 27, 83. (b) T. Hayashi, M. Ishigedani, J. Am. Chem. Soc. 2000, 122, 976. (c) S. Oi, M. Moro, H. Ito, Y. Honma, S. Miyano, Y. Inoue, Tetrahedron 2002, 58, 91. (d) M. Dziedzic, M. Malecka, B. Furman, Org. Lett. 2005, 7, 1725.

25. S. Oi, Y. Honma, Y. Inoue, Org. Lett. 2002, 4, 667.

26. (a) T. Hayashi, N. Tokunaga, K. Yoshida, J. W. Han, J. Am. Chem. Soc. 2002, 124, 12102. (b) N. Tokunaga, K. Yoshida, T. Hayashi, Proc. Natl. Acad. Sci. U. S . A. 2004, 101, 5445.

27. K. C. Nicolaou, W. Tang, P. Dagneau, R. Faraoni, Angew. Chem. Int. Ed. 2005, 44, 3874.

28. (a) N. Miyaura, Z. Suzuki, Chem. Rev. 1995, 95, 2457. (b) D. G. Hall (Ed.), Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, Wiley-VCH: Weinheim, 2005.

29. (a) R. Amengual, V. Michelet, J.-P. Genêt, Synlett 2002, 1791. (b) M. Pucheault, S. Darses, J.-P. Genêt, Eur. J. Org. Chem. 2002, 3552. (c) Q. Shi. L. Xu, X. Li, X. Jia, R. Wang, T. T.-L. Au-Yeung, A. S. C. Chan, T. Hayashi, R. Cao, M. Hong, Tetrahedron Lett. 2003, 44, 6505. (d) J. Madec, G. Michaud, J.-P. Genêt, A. Marinetti, Tetrahedron: Asymmetry 2004, 15, 2253. (e) W.-Y. Yuan, L.-F. Chun,

Chapter 1

20

05_Chapter 1.doc

L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Tetrahedron Lett. 2005, 46, 509. (f) M. Ogasawara, H. L. Ngo, T. Sakamoto, T. Takahashi, W. Lin, Org. Lett. 2005, 7, 2881. (g) K. Vandyck, B. Matthys, M. Willen, K. Robeyns, L. van Meervelt, J. van der Eycken, Org. Lett. 2006, 8, 363.

30. M. T. Reetz, D. Moulin, A. Gosberg, Org. Lett. 2001, 3, 4083.

31. M. Kuriyama, K. Nagai, K. Yamada, Y. Miwa, T. Taga, K. Tomioka, J. Am. Chem. Soc. 2002, 124, 8932.

32. Y. Ma, S. Song, C. Ma, Z. Sun, Q. Chai, M. B. Andrus, Angew. Chem. Int. Ed. 2003, 42, 5871.

33. T. Imamoto, K. Sugita, K. Yoshida, J. Am. Chem. Soc. 2005, 127, 11934.

34. (a) T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003, 125, 11508. (b) C. Defieber, J.-F. Paquin, S. Serna, E. M. Carreira, Org. Lett. 2004, 6, 3873. (c) Y. Otomaru, A. Kina, R. Shintani, T. Hayashi, Tetrahedron: Asymmetry 2005, 16, 1673. (d) Y. Otomaru, K. Okamoto, R. Shintani, T. Hayashi, J. Org. Chem. 2005, 70, 2503. (e) F. Läng, F. Breher, D. Stein, H. Grützmacher, Organometallics 2005, 24, 2997. (f) R. Shintani, K. Okamoto, Y. Otomaru, K. Ueyama, T. Hayashi, J. Am. Chem. Soc. 2005, 127, 54. (g) R. Shintani, K. Okamoto, T. Hayashi, Chem. Lett. 2005, 34, 1294. (h) F.-X. Chen, A. Kina, T. Hayashi, Org. Lett. 2006, 8, 341.

35. (a) J.-G. Boiteau, R. Imbos, A. J. Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 681; see also: Org. Lett. 2003, 5, 1385. (b) J.-G. Boiteau, A. J. Minnaard, B. L. Feringa, J. Org. Chem. 2003, 68, 9481. (c) A. Duursma, R. Hoen, J. Schuppan, R. Hulst, A. J. Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 3111.

36. Y. Iguchi, R. Itooka, N. Miyaura, Synlett. 2003, 1040.

37. T. Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, J. Am. Chem. Soc. 2002, 124, 5052.

38. (a) R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem. 2003, 68, 6000. (b) S. L. X. Martina, A. J. Minnaard, B. Hessen, B. L. Feringa, Tetrahedron Lett. 2005, 46, 7159.

39. For a recent review on catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines, see: F. Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem. Soc. Rev. 2006, 35, 454.

40. A. F. Harms, W. Hespe, W. T. Nauta, R. F. Rekker, Drug Design 1976, 6, 1.

41. M. Saikai, M. Ueda, N. Miyaura, Angew. Chem. Int. Ed. 1998, 37, 3279.

42. For the addition of arylboronic acids to aldehydes leading to racemic products, see: reference 41 and: (a) M. Ueda, N. Miyaura, J. Org. Chem. 2000, 65, 4450; (b) A. Fürstner, H. Krause, Adv. Synth. Catal. 2001, 343, 343.

Introduction

21

05_Chapter 1.doc

43. C. Moreau, C. Hague, A. S. Weller, C. G. Frost, Tetrahedron Lett. 2001, 42, 6957.

44. A. Fürstner, H. Krause, Adv. Synth. Catal. 2001, 42, 6957.

45. T. Focken, J. Rudolph, C. Bolm, Synthesis 2005, 429.

46. (a) T. Hayashi, M. Ishigedani, J. Am. Chem. Soc. 2000, 122, 976. (b) M. Ueda, N. Miyaura, J. Organomet. Chem. 2000, 595, 31.

47. T. Hayashi, M. Kawai, N. Tokunaga, Angew. Chem. Int. Ed. 2004, 43, 6125.

48. M. Kuriyama, T. Soeta, X. Hao, Q. Chen, K. Tomioka, J. Am. Chem. Soc. 2004, 126, 8128.

49. D. J. Weix, Y. Shi, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, 1092.

50. (a) N. Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126, 13584. (b) Y. Otomaru, N. Tokunaga, R. Shintani, T. Hayashi, Org. Lett. 2005, 7, 307.

51. For reviews on the addition of zinc reagents to aldehydes, see : (a) R. Noyori, M. Kitamura, Angew. Chem. Int. Ed. 1991, 30, 49; (b) K. Soai, S. Niwa, Chem. Rev. 1992, 92, 883; (c) L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757.

52. (a) P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62, 444. (b) P. I. Dosa, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 445.

53. W.-S. Huang, L. Pu, J. Org. Chem. 1999, 64, 4222.

54. (a) W.-S. Huang, Q.-S. Hu, L. Pu, J. Org. Chem. 1998, 63, 1364. (b) W.-S. Huang, Q.-S. Hu, L. Pu, J. Org. Chem. 1999, 64, 7940.

55. This phenomenon was also observed by Blacker, see: J. Blacker In Proceedings of the 3rd International Conference on the Scale Up of Chemical Processes, T. Laird (Ed.), Scientific Update Mayfield: East Sussex, 1998, 74.

56. W.-S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145.

57. C. Bolm, K. Muñiz, Chem. Commun. 1999, 1295.

58. (a) C. Bolm, N. Hermans, J. P. Hildebrand, K. Muñiz, Angew. Chem. Int. Ed. 2000, 39, 3465. (b) J. Rudolph, C. Bolm, P. O. Norrby, J. Am. Chem. Soc. 2005, 127, 1548.

59. N. Hermanns, S. Dahmen, C. Bolm, S. Bräse, Angew. Chem. Int. Ed. 2002, 41, 3692.

60. For a review, see reference 39. (a) C. Bolm, M. Kesselgruber, A. Grenz, N. Hermanns, A. J. P. Hildebrand, New. J. Chem. 2001, 25, 13. (b) C. Bolm, M. Kesselgruber, N. Hermanns, J. P. Hildebrand, G. Raabe, Angew. Chem. Int. Ed. 2001, 40, 1488. (c) G. Zhao, X.-G. Li, X.-R. Wang, Tetrahedron: Asymmetry 2001, 12, 399. (d) D.-H. Ko, K. H. Kim, D.-C. Ha, Org. Lett. 2002, 4, 3759. (e) M. G.

Chapter 1

22

05_Chapter 1.doc

Pizzuti, S. Superchi, Tetrahedron: Asymmetry 2005, 16, 2263. (f) M. Fontes, X. Verdaguer, L. Solà, M. A. Pericàs, A. Riera, J. Org. Chem. 2004, 69, 2532. (g) M. Hatano, T. Hiyamoto, K. Ishihara, Adv. Synth. Catal. 2005, 347, 1561. (h) Y.-C. Qin, L. Pu, Angew. Chem. Int. Ed. 2006, 45, 273. (i) I. Schiffers, T. Rantanen, F. Schmidt, W. Bergmans, L. Zani, C. Bolm, J. Org. Chem. 2006, 71, 2320.

61. (a) J. Rudolph, F. Schmidt, C. Bolm, Adv. Synth. Catal. 2004, 346, 867. (b) S. Dahmen, M. Lormann, Org. Lett. 2005, 7, 4597.

62. C. Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850.

63. For recent examples, see: (a) J.-X. Ji, J. Wu, T. T.-L. Au-Yeung, C.-W. Yip, R. K. Haynes, A. S. C. Chan, J. Org. Chem. 2005, 70, 1095; (b) A. L. Braga, D. S. Lüdtke, P. H. Schneider, F. Vargas, A. Schneider, L. A. Wessjohann, M. W. Paixão Tetrahedron Lett. 2005, 46, 7827 and references cited in these articles.

64. J. Rudolph, F. Schmidt, C. Bolm, Synthesis 2005, 840.

65. For further studies on the effect of additives in this reaction, see: (a) J. Rudolph, N. Hermanns, C. Bolm, J. Org. Chem. 2004, 69, 3997; (b) J. Rudolph, M. Lormann, C. Bolm, S. Dahmen, Adv. Synth. Catal. 2005, 347, 1361.

66. K. Ito, Y. Tomita, T. Katsuki, Tetrahedron Lett. 2005, 46, 6083.

67. C. Bolm, F. Schmidt, L. Zani, Tetrahedron: Asymmetry 2005, 16, 2299.

68. S. Özçubukçu, F. Schmidt, C. Bolm, Org. Lett. 2005, 7, 1407.

69. J.-X. Ji, J. Wu, T. T.-L. Au-Yeung, C.-W. Yip, R. K. Haynes, A. S. C. Chan, J. Org. Chem. 2005, 70, 1093.

70. P.-Y. Wu, H.-L. Wu, B.-J. Uang, J. Org. Chem. 2006, 71, 833.

71. A. L. Braga, D. S. Lüdtke, F. Vargas, M. W. Paixão, Chem. Commun. 2005, 2512.

72. X. Wu, X. Liu, G. Zhao, Tetrahedron: Asymmetry 2005, 16, 2299.

73. For a brief history of combinatorial chemistry, see: K. C. Nicolaou, R. Hanko, W. Hartwig, In Handbook of Combinatorial Chemistry, Vol. 1, K. C. Nicolaou, R. Hanko, W. Hartwig (Eds.), Wiley-VCH: Weinheim, 2002, 3.

74. (a) B. Jandeleit, D. Schaefer, T. S. Powers, H. W. Turner, W. H. Weinberg, Angew. Chem. Int. Ed. 1999, 38, 2494. (b) M. T. Reetz, Angew. Chem. Int. Ed. 2001, 40, 284.

75. (a) A. Duursma, A. J. Minnaard, B. L. Feringa, Tetrahedron 2002, 58, 5773. (b) M. T. Reetz, Angew. Chem. Int. Ed. 2002, 41, 1335.

76. For reviews on the field of catalyst development by combinatorial chemistry in general, see reference 74a and: (a) A. H. Hoveyda, Chem. Biol. 1998, 5, R187; (b) B. Archibald, O. Brümmer, M. Devenney, S. Gorer, B. Jandeleit, T. Uno, W. H.

Introduction

23

05_Chapter 1.doc

Weinberg, T. Weskamp, In Handbook of Combinatorial Chemistry, Vol. 2, K. C. Nicolaou, R. Hanko, W. Hartwig (Eds.), Wiley-VCH: Weinheim, 2002, 885. For reviews on the field of asymmetric catalyst development by combinatorial chemistry, see: (c) A. H. Hoveyda, In Handbook of Combinatorial Chemistry, Vol. 2, K. C. Nicolaou, R. Hanko, W. Hartwig (Eds.), Wiley-VCH: Weinheim, 2002, 991; (d) J. G. de Vries, A. H. M. de Vries, Eur. J. Org. Chem. 2003, 799; (e) C. Gennari, U. Piarulli, Chem. Rev. 2003, 103, 3071.

77. There are exceptions, see: (a) C. Hinderling, P. Chen, Angew. Chem. Int. Ed. 1999, 38, 2253; (b) P. Krattiger, C. McCarthy, A. Pfaltz, H. Wennemers, Angew. Chem. Int. Ed. 2003, 42, 1722.

78. For selected examples, see: (a) D. Peña, A. J. Minnaard, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Org. Biomol. Chem. 2003, 1, 1087; (b) M. T. Reetz, T. Sell, A. Meiswinkel, G. Mehler, Angew. Chem. Int. Ed. 2003, 42, 790; (c) C. Monti, C. Gennari, U. Piarulli, J. G. de Vries, A. H. M. de Vries, L. Lefort, Chem. Eur. J. 2005, 11, 6701; (d) R. Hoen, J. A. F. Boogers, H. Bernsmann, A. J. Minnaard, A. Meetsma, T. D. Tiemersma-Wegman, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 4209.

79. N. E. Leadbeater, M. Marco, Chem. Rev. 2002, 102, 3217.

80. S. R. Gilbertson, X. Wang, Tetrahedron Lett. 1996, 37, 6475.

81. G. Liu, J. A. Ellmann, J. Org. Chem. 1995, 60, 7712.

82. (a) B. M. Cole, K. D. Schimizu, C. A. Krueger, J. P. A. Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem. Int. Ed. 1996, 35, 1668. (b) K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, Angew. Chem. Int. Ed. 1997, 36, 1704. (c) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901. (d) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 5315. (e) C. Gennari, S. Ceccarelli, U. Piarulli, C. A. G. N. Montalbetti, R. F. W. Jackson, J. Org. Chem. 1998, 63, 5312. (f) A. J. Brouwer, H. J. van der Linden, R. M. J. Liskamp, J. Org. Chem. 2000, 65, 1750. (g) I. Chataigner, C. Gennari, U. Piarulli, S. Ceccarelli, Angew. Chem. Int. Ed. 2000, 39, 916.

83. (a) L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, Org. Lett. 2004, 6, 1733. (b) M. van den Berg, D. Peña, A. J. Minnaard, B. L. Feringa, L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, Chim. Oggi 2004, 22, detachable insert: Chiral Catalysis-Asymmetric Hydrogenation, 18. (c) J. G. de Vries, L. Lefort, Chem. Eur. J. 2006, 12, 4722.

84. (a) M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van Esch, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc. 2000, 122, 11539. (b) D. Peña, A. J. Minnaard, J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc. 2002, 124, 14552. (c) M. van den Berg, A. J. Minnaard, R. M. Haak, M. Leeman, E. P. Schudde, A. Meetsma, B. L. Feringa, A. H. M. de Vries, C. E. P. Maljaars, C. E. Willans, D. Hyett, J. A. F.

Chapter 1

24

05_Chapter 1.doc

Boogers, H. J. W. Henderickx, J. G. de Vries, Adv. Synth. Catal. 2003, 345, 308. (d) L. Panella, B. L. Feringa, J. G. de Vries, A. J. Minnaard, Org. Lett. 2005, 7, 4177. (e) L. Panella, A. Marco Aleixandre, G. J. Kruidhof, J. Robertus, B. L. Feringa, J. G. de Vries, A. J. Minnaard, J. Org. Chem. 2006, 71, 2026.

85. (a) A. Duursma, J.-G. Boiteau, L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, A. J. Minnaard, B. L. Feringa, J. Org. Chem. 2004, 69, 8045. (b) A. Duursma, L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2004, 2, 1682.

86. (a) R. Imbos, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2002, 124, 184. (b) R. Imbos, A. J. Minnaard, B. L. Feringa, J. Chem. Soc., Dalton Trans. 2003, 2017.

87. F. Bertozzi, M. Pineschi, F. Macchia, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Org. Lett. 2002, 4, 2703.

88. F. Del Moro, P. Crotti, V. Di Bussolo, F. Macchia, M. Pineschi, Org. Lett. 2003, 5, 1971.

89. (a) H. Malda, A. W. van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett. 2001, 3, 1169. (b) A. W. van Zijl, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Adv. Synth. Catal. 2004, 346, 413.

90. For iridium-catalyzed allylic alkylation reactions, see: (a) B. Bartels, C. Garcia-Yebra, G. Helmchen, Eur. J. Org. Chem. 2003, 1097. For iridium-catalyzed allylic amination reactions, see: (b) T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 15164; (c) G. Lipowsky, G. Helmchen, Chem. Commun. 2004, 116. For iridium-catalyzed allylic etherification reactions, see: (d) F. Lopez, T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125, 3426.

91. See references 17, 19, 35, 84-90, and: (a) R. Imbos, Catalytic Asymmetric Conjugate Additions and Heck Reactions, Ph.D. Thesis, University of Groningen, 2002, 1-24. (b) A. Duursma, Asymmetric Catalysis with Chiral Monodentate Phosphoramidite Ligands, Ph.D. Thesis, University of Groningen, 2002, 6-17.

06_Chapter_2.doc

Chapter 2 Enantioselective Synthesis of 2-Aryl-4-piperidones

NCO2Bn

O

NCO2Bn

ORh(acac)(C2H4)2 (3 mol%)phosphoramidite (7.5 mol%)

(ArBO)31,4-dioxane/H2O, 100 ºC

R

Up to 99% eeHigh yields

Piperidones are important intermediates in the preparation of natural occurring alkaloids

and synthetic pharmacophores. In this chapter the highly enantioselective synthesis of

2-aryl-4-piperidones by rhodium/phosphoramidite-catalyzed conjugate addition of

arylboroxines to 2,3-dihydro-4-pyridones is described.1 A variety of products with

sterically and electronically different R-substituents have been obtained in high isolated

yield and with excellent ee’s up to 99%.

Part of this chapter has been published: R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J.

Minnaard, “Enantioselective Synthesis of 2-Aryl-4-piperidones via Rhodium/

Phosphoramidite-Catalyzed Conjugate Addition of Arylboroxines”, Org. Lett. 2005, 7,

2433.

26

06_Chapter_2.doc

Chapter 2

2.1 Introduction

The piperidine ring system (1, Figure 2.1) is a frequently encountered heterocyclic unit in

natural compounds and drug candidates.2 Naturally occurring piperidine alkaloids (e.g.

2-11) and their synthetic analogues are of great interest to the pharmaceutical industry.

NH

NH

CO2H NH

piperidine 1 pipecolic acid 2 coniine 3

NH

HO

Me (CH2)7CO2H

carpamic acid 4

NH

HN O

OHN

NH

Cl

Cl

NH

OH

DKP593A 5 histrionicotoxin 6

NH

N

NH

N

N NCH3

HOO OH

O OH

H3C

anabasine 8 anabasamine 9 rohitukine 11

NC2H5

O

O

O

campedine 10

OHHO O

NCH3

morphine 7

Figure 2.1 Naturally occurring piperidine alkaloids

Considering the extensive range of biological activities these compounds exhibit, it is not

surprising that (according to an assertion of Watson et al.) between 1988 and 1998

thousands of piperidine-derived compounds were mentioned in clinical and preclinical

studies.3 Piperidones serve an important role en route to substituted piperidines4 and can

also be found as a part of more complex biologically active compounds.5 Therefore the

development of short, enantioselective routes to substituted piperidones is a major goal.6

27

06_Chapter_2.doc

Enantioselective Synthesis of 2-Aryl-4-piperidones

Although few naturally occurring piperidine alkaloids contain the arylpiperidine moiety

(8-11), the structural unit is an integral part of many polycyclic alkaloids (e.g. morphine, 7).

Simple synthetic arylpiperidines have received increasing attention due to their biological

activities, often resembling those of more complicated natural alkaloids. Many 3-aryl- and

4-arylpiperidines are potent opioid receptor antagonists and can be regarded as structurally

simplified forms of morphine.7 2-Arylpiperidines are of noteworthy interest as being

integrated in biologically active benzo[a]- and indolo[2,3-a]quinolizidine compounds.8

Recent biological studies of 2-arylpiperidines show a range of biological activities for this

class of structures, revealing their potential use in the treatment of mental and

cardiovascular diseases.9 An excellent example is found in a class of antidepressants, which

have a common structural pattern based on a 2-arylpiperidine moiety (Figure 2.2).10, 11

NH

Ph

HNAr

12

N

NR2

Me

F NR2O13

Figure 2.2 A class of antidepressants with a 2-arylpiperidine moiety

Compound 13, developed by Glaxo Group Ltd., UK, is particularly useful for the treatment

or prevention of depressive states and/or anxiety. It owes its unique pharmacological

properties to a strong affinity with the NK1 tachykinin receptor, one of three tachykinin

receptors identified (tachykinins are a family of peptide neurotransmitters).11 As a

consequence of the significance of 2-arylpiperidines, the development of efficient methods

for their enantioselective synthesis is an important objective. However, most of the existing

methods rely on the use of a stoichiometric amount of chiral reagents.12

Dihydropyridones of the type 14 (Figure 2.3) are versatile synthetic building blocks: they

are easy to prepare, air-stable, and their functionality allows a variety of chemical

transformations.13 Short, stereocontrolled synthesis of piperidine, indolizidine, quinolizine,

and cis- and trans-decahydroquinoline alkaloids have been reported using 2,3-dihydro-4-

pyridones as chiral building blocks.14 An attractive catalytic route toward enantiopure

28

06_Chapter_2.doc

Chapter 2

2-substituted piperidones is based on the enantioselective conjugate addition to readily

available N-protected 2,3-dihydro-4-pyridones (14).15 Until recently, however, no suitable

procedures have been developed.16,17,18

N

O

PG 1,4-addition or reduction

[2 + 2] photocycloaddition

1,2-addition

enolate alkylationor acetoxylation

14

Figure 2.3 Versatile 2,3-dihydro-4-pyridone building block (PG = Protecting Group)

Very few catalytic enantioselective routes for the synthesis of 2-substituted piperidines

have been reported.19 Recently, our group reported the synthesis of 2-alkyl-4-piperidones

with high enantiomeric excess applying the copper-catalyzed conjugate addition of

dialkylzinc reagents to 14 employing phosphoramidite ligand L1 (Scheme 2.1).17 It was

noted that this type of substrate is less reactive towards 1,4-addition than cyclic enones, e.g.

2-cyclohexenone.

N

O

PGN

O

PGR

Cu(OTf)2 (5 mol%)

L1 (10 mol%)

R2Zn

PG = CO2Bn

PG = CO2Ph

PG = CO2Me

PG = CO2Et

PG = CO2tBu

PG = p-Tosyl14

R = Me, R = Et,

R = iPr, R = Bu 15

Up to 97% ee

Up to 87% yield

OO

P N

Ph

PhL1

14a: 14e: 14c: 14d: 14e: 14f:

Scheme 2.1 Catalytic enantioselective addition of zinc reagents to N-substituted

2,3-dihydro-4-pyridones

Although highly enantioselective 1,4-addition of diphenylzinc, using the same catalyst, has

been reported for 2-cyclohexenone,20 the lack of readily available diarylzinc reagents

severely limits this method. A more convenient method for the introduction of aryl and

alkenyl moieties is the asymmetric rhodium-catalyzed conjugate addition of boronic acids

29

06_Chapter_2.doc


pioneered by Hayashi and Miyaura.21,22 Recently we have demonstrated that rhodium-

catalyzed conjugate additions of arylboronic acids to enones can be achieved with high

efficiency and excellent enantioselectivities employing monodentate phosphoramidite L2

(Figure 2.4).23

OO P N

L2

Figure 2.4 Chiral monodentate phosphoramidite ligand L2

During our studies, Hayashi et al. reported the enantioselective addition of arylzinc

chlorides to 2,3-dihydro-4-pyridones with excellent enantioselectivities.24 In that study, it

was confirmed that this type of substrate is less reactive toward 1,4-addition compared to

enones. The rhodium/BINAP-catalyzed conjugate addition of phenylboronic acid failed to

proceed to full conversion, although the enantioselectivity was excellent. We envisioned

that introduction of aryl groups in N-protected 2,3-dihydro-4-pyridones, using the

rhodium/phosphoramidite-catalyzed conjugate addition of arylboronic acids, could provide

a pathway to 2-substituted 4-piperidones that is complementary to our work with

dialkylzinc reagents.



Substrate 14a was prepared in three steps from 4-piperidone monohydrate hydrochloride

and benzyl chloroformate (Scheme 2.2, route a), following a literature procedure of Park

et al.15a for the synthesis of ethyl 3,4-dihydro-4-oxo-1-(2H)-pyridinecarboxylate. The

desired product was obtained as a white solid in an overall yield of 64%. The alternative

one-pot procedure of Comins et al. (Scheme 2.2, route b)15b starting from

4-methoxypyridine suffered from low reproducibility, providing 14a in 10% to 63% yield.

30

06_Chapter_2.doc

Chapter 2

N

OMe

NH

O 1) ClCO2Bn, NaOH

H2O, Et2O

2) Br2, (HOCH2)2

. HClNCO2Bn

OOBr 1) DBU, Me2SO, 85 oC

2) 3M HCl, MeOH NCO2Bn

O

a)

b)1) K(i-PrO)3BH, THF, i-PrOH

2) ClCO2Bn

3) 3M HClNCO2Bn

O

14a

14a

10-63% yield

64% overall yield

(3 steps)

Scheme 2.2 Preparation of 14a according to a) Park and b) Comins

Initial screening of the conjugate addition of phenylboronic acid to 14a was performed

under standard conditions in a mixture of 1,4-dioxane/water (10/1) at 100 oC with a catalyst

generated from 3 mol% Rh(acac)(C2H4)2 and 7.5 mol% L2. As in the report of Hayashi,

with 3 equiv of phenylboronic acid, the reaction did not go to completion according to 1H-NMR (Table 2.1, entry 1). The enantioselectivity was, however, excellent (96% ee).

Water acts as a proton donor and facilitates the transmetallation, therefore the use of water

is essential in order to complete the catalytic cycle (see Chapter 1, §1.3). A drawback of the

use of water, especially in combination with high temperature, is the hydrolysis of

phenylboronic acid to benzene. The arylboronic acid is therefore commonly added in

excess (3-5 equiv) compared to the enone. Milder conditions can be provided by generating

phenylboronic acid in situ from phenylboroxine ((PhBO)3) and one equiv of water with

respect to boron (entries 2-6). Phenylboronic acid exists in equilibrium with its trimeric

species and is released in the course of the reaction (Figure 2.5). Hayashi has demonstrated

that the use of arylboroxines has a beneficial effect on both conversion and

enantioselectivity in the conjugate addition to highly deactivated 1-alkenylphosphonates.25

Dehydration of arylboronic acids results in the corresponding boroxines in quantitative

yield by azeotropic removal of water from their xylene solution or heating neat in vacuo at

145 oC.26 The use of boroxines did not immediately improve the conversion, but did

improve the enantioselectivity to an excellent ee of 99%. Upon slow addition of water,

31

06_Chapter_2.doc


thereby preventing premature hydrolysis of the boroxine, the reaction could be driven to

84% conversion using 1 equiv of boroxine (entry 4) and to full conversion using 3 equiv of

the reagent (entry 6), retaining 99% ee.

Table 2.1 Optimization of the reaction conditions for the rhodium-catalyzed conjugate

addition to 14a

N

O

CO2Bn

Rh(acac)(C2H4)2 (3 mol%)

(R)-L2 (7.5 mol%)

"PhB"

1,4-dioxane/H2O, 100 oCN

O

CO2Bn

14a 15a

entry “PhB” (equiv) condition a conv. (%) b ee (%)c

1 PhB(OH)2 (3.0) A 80 96

2 (PhBO)3 (1.0) B 60 99

3 (PhBO)3 (3.0) B 75 99

4 (PhBO)3 (1.0) C 84 99

5 (PhBO)3 (2.0) C 92 99

6 (PhBO)3 (3.0) C >99 99

a All reactions were performed on 0.2 mmol scale with 3 mol% Rh(acac)(C2H4)2 and 7.5 mol% (R)-L at 100 ºC for

2 h. Condition A: 0.55 mL of 1,4-dioxane/H2O (10/1). Condition B: 0.5 mL of 1,4-dioxane, 1 equiv of H2O to

boron. Condition C: 0.5 mL of 1,4-dioxane, slow addition of water by syringe pump. b Determined by 1H NMR. c

Determined by chiral HPLC.

Ph BOH

OHB

O BO

BOPh

Ph

Ph

-3 H2O

+3 H2O

Figure 2.5 Equilibrium between phenylboronic acid and phenylboroxine

32

06_Chapter_2.doc

Chapter 2


With these optimized conditions in hand, the scope of the asymmetric conjugate addition of

arylboroxines to 14a was investigated. High ee values could be obtained with a variety of

sterically and electronically diverse arylboroxines (Table 2.2, entries 1-9). Meta- and para-

tolyl groups could be introduced with high yield and high enantioselectivity (entries 3

and 4).

Table 2.2 Scope of arylboroxines in the rhodium-catalyzed asymmetric 1,4-addition to 14a

NCO2Bn

O

NCO2Bn

ORh(acac)(C2H4)2 (3 mol%)

(R)-L2 (7.5 mol%)

(ArBO)3 (3 equiv)

1,4-dioxane, 100 oC

slow addition of H2O14a 15R

entrya Ar product yield (%)b ee (%)c,d

1 Ph 15a 86 e 99 (R)

2 o-(Me)C6H4 15b 82 e 24 (R)

3 m-(Me)C6H4 15c 92 e 98 (R)

4 p-(Me)C6H4 15d 86 e 95 (R)

5 p-(MeO)C6H4 15e 85 e 96 (R)

6 m,p-(MeO)2C6H3 15f 86 e 98 (R)

7 p-(F)C6H4 15g 71 94 (R)

8 p-(F),o-(Me)C6H3 15h 75 47 (R)

9 p-(Cl)C6H4 15i 55 96 (R)

a All reactions were performed in duplicate with both enantiomers of the ligand on 0.2 mmol scale with 3 mol% Rh(acac)(C2H4)2 and 7.5 mol% L2 at 100 ºC for 2 h. b Isolated yield. c Determined by chiral HPLC. d The absolute

configuration was established by comparison of the optical rotation with literature values or by analogy (see

experimental section). e Thin layer chromatography shows a spot-to-spot conversion in 2 h.

33

06_Chapter_2.doc


A dramatic drop in enantioselectivity was observed for the introduction of more sterically

demanding ortho-substituted aryl groups (entry 2 and 8), illustrating a possible limitation of

the catalytic method. Products with one or two electron-donating substituents on the aryl

were obtained in high yield with high enantioselectivity (entries 5 and 6). However,

electron-withdrawing chloro and fluoro groups resulted in slower reaction, leading to

incomplete conversions (entries 7, 8, 9). Despite this observation, the enantioselectivity is

largely independent of the electronic nature of the substituents. All para- and meta-

substituted products were obtained with excellent ee values between 94 and 98%.

NCO2Bn

O

NH

O

Rh(acac)(C2H4)2 (3 mol%)

(S)-L2 (7.5 mol%)1,4-dioxane, 100 oC

slow addition of H2O

14a (S)-16

1)

(PhBO)3

(3equiv)

+2) 10 mol% Pd/C

H2 (Ca. 1 atm)

MeOH, 20 oC, 4h79% yield, 99% ee

(2 steps)

0.5 g

Scheme 2.3 Conjugate addition on a 0.5 gram scale and subsequent deprotection

To show the applicability of this reaction for synthesis on a laboratory scale, it was

performed on a 0.5 gram (2.2 mmol) scale (Scheme 2.3). After flash chromatography, the

product was isolated in 86% yield with 99% ee. Subsequent removal of the

benzyloxycarbonyl group by hydrogenation using palladium on carbon, according to a

literature procedure,24 afforded piperidone (S)-16 in 92% isolated yield and 79% overall

yield over the two steps.


Cationic palladium(II) complexes show relative high rates for transmetallation of

organoboron compounds, a process which is generally slow for transition metals.27 This has

stimulated research toward their use in conjugate addition reactions where the

34

06_Chapter_2.doc

Chapter 2

transmetallation is a critical step. Miyaura et al. reported both palladium-based catalyst-

systems that are able to transfer arylboronic acids28 and the asymmetric palladium-

catalyzed conjugate addition of aryltrifluoroborates.29 The asymmetric conjugate addition

of arylboronic acids had, however, been elusive. Shortly after publication of our results

regarding this arylation,30 Gini et al. developed a Pd(O2CCF3)2/Me-DuPHOS (Figure 2.6)

catalyst for the efficient and highly enantioselective addition of arylboronic acids to a

variety of α,β-unsaturated enones in a THF/H2O (10/1) mixture.31

NCO2Bn

O

NCO2Bn

O

14a (R)-15a

60% yield, 99% ee

Pd(OCCF3)2 (5 mol%)

PP

(R,R)-Me-DuPHOS (5.5 mol%)

THF/H2O: 10/1, 70 oC, 22 h

PhB(OH)2 (3 equiv)

(R,R)-Me-DuPHOS

Figure 2.6 Palladium-catalyzed asymmetric conjugate addition of phenylboronic acid

Addition of phenylboronic acid to 14a with this system at 70 oC proceeds with essentially

complete enantioselectivity (>99% ee). Although full conversion of the starting material

was reached within 22 h, 15a was obtained in a relatively low yield of 60%.

2.4 Conclusions

In summary, we have shown that conjugate addition of arylboroxines with a rhodium/

phosphoramidite catalyst can be used to prepare 2-aryl-4-piperidones in high isolated yield

(82–92%) and with excellent enantioselectivity (up to 99% ee).

35

06_Chapter_2.doc



General remarks. All air- and moisture-sensitive manipulations were carried out under a

dry nitrogen atmosphere using standard Schlenk techniques. 1,4-Dioxane was distilled from

sodium before use. 1H-NMR and 13C-NMR spectra were recorded on a Varian 300

(300 and 75 MHz, respectively) in CDCl3 unless stated otherwise. Mass spectra (HRMS)

were recorded on an AEI MS-902. Optical rotations were measured on a Schmidt and

Haensch Polartronic MH8. Rh(acac)(C2H4)2 was purchased from Strem and used without

further purification. All other chemicals were purchased from Acros and used as received.

Flash chromatography was performed using silica gel 60 Å (Merck, 230-400 mesh).

Phosphoramidite ligands (S)-L2 and (R)-L2 were prepared from the corresponding

H8-bis-β-naphthol, PCl3, and diethylamine according to a previously reported procedure.23

All arylboroxines were prepared according to a modified literature procedure from the

corresponding arylboronic acids by heating in vacuo overnight at 145 °C in a drying

pistol.25

Benzyl 3,4-dihydro-4-oxo-1-(2H)-pyridinecarboxylate (14a). This compound was

synthesized from 4-piperidone monohydrate hydrochloride and benzyl

chloroformate following the literature procedure for ethyl 3,4-dihydro-4-oxo-1-

(2H)-pyridinecarboxylate.15a The product was obtained as a white solid in 64%

yield. 1H NMR δ = 7.85 (bs, 1H), 7.40-7.37 (m, 5H), 5.35 (bs, 1H), 5.27 (s, 2H), 4.05 (t, J = 7.3 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H); 13C NMR δ = 193.2, 152.5, 143.3,

134.8, 128.7, 128.4, 107.7, 69.0, 42.5, 35.6. Physical and spectral data were in full

agreement with the literature.24

General Procedure for the rhodium/phosphoramidite-catalyzed asymmetric conjugate

addition to 2,3-dihydro-4-pyridones (15). In a flame dried Schlenk tube flushed with

nitrogen, 1.55 mg (6.0 µmol, 3 mol%) of Rh(acac)(C2H4)2 and 5.93 mg (15.0 µmol, 7.5

mol%) of phosphoramidite L2 were dissolved in 0.5 mL of 1,4-dioxane. After stirring for

15 min at room temperature, 46.2 mg (0.2 mmol) of substrate 1 and 0.6 mmol of the

arylboroxine were added and the resulting mixture was stirred at reflux conditions with

N

O

CO2Bn

36

06_Chapter_2.doc

Chapter 2

N

O

CO2Bn

slow addition of a 20 vol% solution of water in 1,4-dioxane by syringe pump (0.1 mL/h)

during 2 h. The reaction mixture was subsequently cooled to RT, diluted with 2 mL of

ether, and passed through a pad of silica gel. The solvent was removed in vacuo. Reactions

were performed in duplicate, using both enantiomers of the ligand. Enantioselectivity did

not differ more than 1% between duplos.

(S)- and (R)-Benzyl-4-oxo-2-phenylpiperidine-1-carboxylate (15a). The crude product

was purified by flash column chromatography (n-pentane/Et2O: 1/2) to

give (R)-15a, in the case of the (R)-L2 ligand, as a white solid in 86%

isolated yield with 99% ee (Table 2.2, entry 1). The ee was determined on

a Chiralcel OD-H column with n-heptane/2-propanol: 90/10, flow = 0.5

mL/min. Retention times: 27.3 min [(S)-enantiomer], 29.8 min [(R)-enantiomer]. 1H NMR

δ = 7.36 (m, 7H), 7.29-7.24 (m, 3H), 5.84 (bs, 1H), 5.25 (d, J = 12.3 Hz, 1H), 5.2 (d, J =

12.3 Hz, 1H), 2.86 (dd, J = 15.5, 7.0 Hz, 1H), 2.57-2.50 (m, 1H), 2.37 (d, J = 15.8 Hz, 1H); 13C NMR δ = 207.0, 155.3, 139.6, 136.2, 128.7, 128.5, 128.1, 127.9, 127.6, 126.6, 67.7,

54.5, 44.1, 40.4, 38.8. Physical and spectral properties were in full agreement with the

literature.16

(S)- and (R)-Benzyl-4-oxo-2-o-tolylpiperidine-1-carboxylate (15b). The crude product

was purified by flash chromatography (n-pentane/Et2O: 1/2) to give (R)-

15b, in the case of the (R)-L2 ligand, as a clear oil in 82% isolated yield

with 24% ee (Table 2.2, entry 2). The ee was determined on a Chiralcel

OJ column with n-heptane/2-propanol: 90/10, flow = 1.0 mL/min.

Retention times: 14.7 min [(S)-enantiomer], 23.5 min [(R)-enantiomer]. 1H NMR δ = 7.35-

7.29 (m, 3H), 7.23-7.18 (m, 6H), 5.75 (bs, 1H), 5.18 (d, J = 12.0 Hz, 1H), 5.14 (d, J = 12.2

Hz, 1H), 4.28 (bs, 1H), 3.25 (bs, 1H), 2.86 (dd, J = 15.6, 5.5 Hz, 1H), 2.80 (dd, J = 15.4,

5.5 Hz, 1H), 2.58-2.46 (m, 1H), 2.46 (d, J = 17.1 Hz, 1H), 2.26 (s, 3H); 13C NMR δ =

207.8, 155.1, 138.6, 136.4, 136.1, 128.5, 128.1, 127.9, 127.8, 126.2, 126.1, 67.7, 52.8, 44.7,

40.8, 38.9, 19.2. Physical and spectral properties were in full agreement with the

literature.16

N

O

CO2Bn

37

06_Chapter_2.doc


N

O

CO2Bn

N

O

CO2Bn

N

O

CO2BnO

(S)- and (R)-Benzyl-4-oxo-2-m-tolylpiperidine-1-carboxylate. (15c). The crude product

was purified by flash chromatography (n-pentane/Et2O: 1/2) to give

(R)-15c, in the case of the (R)-L2 ligand, as a clear oil in 92% isolated

yield with 98% ee (Table 2.2, entry 3). The ee was determined on a

Chiralcel OD-H column with n-heptane/2-propanol: 90/10, flow = 0.5

mL/min. Retention times: 25.1 min [(S)-enantiomer], 29.0 min [(R)-enantiomer]. The

absolute configuration was assigned by analogy. [α]D = +90.9° (c = 0.52, CHCl3, 98% ee); 1H NMR δ = 7.02-7.39 (m, 5H), 7.14-7.21 (m, 1H), 6.95-7.03 (m, 3H), 5.75 (bs, 1H), 5.21

(d, J = 12.5 Hz, 1H), 5.14 (d, J = 12.5 Hz, 1H), 4.23 (m, 1H), 3.15 (m, 1H), 2.94 (d, J =

15.4 Hz, 1H), 2.79 (dd, J = 15.4, 7.0 Hz, 1H), 2.49 (m, 1H), 2.32 (m, 1H), 2.26 (s, 3H); 13C

NMR δ = 207.3, 155.4, 139.6, 138.5, 136.2, 128.6, 128.4, 128.2, 127.9, 127.3, 123.6, 67.7,

54.5, 44.1, 40.5, 38.9, 29.6, 21.4; HRMS calcd for C20H21NO3 323.1521 found 323.1517.

(S)- and (R)-Benzyl-4-oxo-2-p-tolylpiperidine-1-carboxylate (15d). The crude product

was purified by flash chromatography (n-pentane/Et2O: 1/2) to give

(R)-15d, in the case of the (R)-L2 ligand, as a clear oil in 86% isolated

yield with 95% ee (Table 2.2, entry 4). The ee was determined on a

Chiralcel OJ column with n-heptane/2-propanol: 90/10, flow = 1.0

mL/min. Retention times: 27.3 min [(S)-enantiomer], 30.8 min [(R)-enantiomer]. The

absolute configuration was assigned by analogy. [α]D = +81.3° (c = 0.64, CHCl3, 95% ee);

1H NMR δ = 7.28-7.42 (m, 5H), 7.07-7.20 (m, 4H), 5.82 (bs, 1H), 5.26 (d, J = 12.2 Hz,

1H), 5.19 (d, J = 12.2 Hz, 1H), 4.25 (m, 1H), 3.18 (m, 1H), 2.98 (td, J = 15.6, 3.2, 1.2

Hz,1H), 2.83 (dd, J = 15.4, 6.6 Hz , 1H), 2.51 (m, 2H), 2.33 (s, 3H); 13C NMR δ = 207.3,

155.4, 137.4, 136.5, 136.2, 129.4, 128.5, 128.2, 127.9, 126.6, 67.7, 54.3, 44.1, 40.5, 38.8,

20.9; HRMS calcd for C20H21NO3 323.1521 found 323.1515.

(S)- and (R)-Benzyl-2-(4-methoxyphenyl)-4-oxopiperidine-1-carboxylate (15e). The

crude product was purified by flash chromatography (n-pentane/Et2O:

1/2) to give (R)-15e, using the (R)-L2 ligand, as a clear oil in 85%

isolated yield with 96% ee (Table 2.2, entry 5). The ee was

determined on a Chiralcel OD-H column with n-heptane/2-propanol:

38

06_Chapter_2.doc

Chapter 2

N

O

CO2BnO

O

N

O

CO2BnF

90/10, flow = 0.5 mL/min. Retention times: 35.8 min [(S)-enantiomer], 39.9 min [(R)-

enanti

university of groningen rhodium-catalyzed boronic acid ......complementary rhodium-catalyzed aca of...

Documents