Carbohydrates - Tools for Stereoselective Synthesis E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 434

Veröffentlichungsjahr: 2012

Beschreibung

Closing a gap in the literature, this comprehensive book presents the utility of carbohydrate derivatives as chiral auxiliaries, reagents, complex ligands and organocatalysts, together with details of their preparation, as well as their successful application in stereoselective synthesis. Divided into four parts: * Carbohydrate Auxiliaries * Carbohydrate Reagents * Carbohydrate Ligands * Carbohydrate Organocatalysts It is an indispensable source for every organic chemist.

Leseprobe

Table of Contents

Cover

Related Titles

Title page

Copyright page

Foreword

Preface

List of Contributors

Part I Carbohydrate Auxiliaries

1 Reactions of Nucleophiles with Electrophiles Bound to Carbohydrate Auxiliaries

1.1 Introduction

1.2 Strecker Reactions

1.3 Ugi Reactions

1.4 Allylations

1.5 Mannich-Type Reactions

1.6 Addition of Phosphites

1.7 Dynamic Kinetic Resolution of α-Chloro Carboxylic Esters

2 1,4-Addition of Nucleophiles to α,β-Unsaturated Carbonyl Compounds

2.1 Introduction

2.2 1,4-Additions to Acrylic Amides and Acrylic Esters

2.3 1,4-Addition to 4- and 2-Pyridones

3 Reaction of Enolates

3.1 Introduction

3.2 Aldol Alkylation

3.3 Aldol Addition

3.4 Concluding Remarks

4 Cycloadditions

4.1 Diels–Alder Reactions

4.2 1,3-Diploar Cycloadditions

4.3 [2 + 2] Cycloadditions

5 Cyclopropanation

5.1 Introduction

5.2 Epoxidation

5.3 Construction of Chiral Sulfur and Phosphorus Centers

5.4 Chiral Phosphorus Compounds

5.5 Concluding Remarks

Part II Carbohydrate Reagents

6 Hydride Reductions and 1,2-Additions of Nucleophiles to Carbonyl Compounds Using Carbohydrate-Based Reagents and Additives

6.1 Introduction

6.2 Hydride Reductions

6.3 1,2-Additions of Nucleophiles to Carbonyl Compounds

7 Aldol-Type Reactions

7.1 Introduction

7.2 Titanium Lewis Acids for Enolate Formation

7.3 1,2-Additions of Nucleophiles to Carbonyl Compounds Using Stoichiometric Reagents

Part III Carbohydrate Ligands

8 Hydrogenation Reactions

8.1 Introduction

8.2 Hydrogenation of C=C and C=N Bonds

8.3 P-Donor Ligands

8.4 P–N Donors

8.5 P–S Donors

Acknowledgments

9 Hydroformylations, Hydrovinylations, and Hydrocyanations

9.1 Hydroformylation Reactions

9.2 Hydrovinylation Reactions

9.3 Hydrocyanation Reactions

9.4 Hydrosilylation Reactions

9.5 Conclusion

10 Carbohydrate-Derived Ligands in Asymmetric Tsuji–Trost Reactions

10.1 Introduction

10.2 Ligands

10.3 Conclusions

Acknowledgments

11 Carbohydrate-Derived Ligands in Asymmetric Heck Reactions

11.1 Introduction

11.2 Ligands

11.3 Conclusions

Acknowledgments

12 1,4-Addition of Nucleophiles to α,β-Unsaturated Carbonyl Compounds

12.1 Copper-Catalyzed Reactions–Introduction

12.2 Copper-Catalyzed Reactions–Ligands

12.3 Enantioselective Copper-Catalyzed 1,4-Addition of Organometallics to α,β-Unsaturated Carbonyl Compounds

12.4 Rhodium-Catalyzed Reactions

12.5 Conclusions

13 1,2-Addition of Nucleophiles to Carbonyl Compounds

13.1 Introduction

13.2 Addition of Organometallic Reagents to Aldehydes

13.3 Addition of Trimethylsilyl Cyanide to Ketones. P=O,O Ligands

13.4 Conclusion

14 Cyclopropanation

Part IV Carbohydrate Organocatalysts

15 Oxidations

15.1 Oxidations

15.2 Conclusion

16 Enantioselective Addition Reactions Catalyzed by Carbohydrate-Derived Organocatalysts

16.1 Introduction

16.2 Strecker, Mannich, and Nitro-Mannich Reactions

16.3 Michael Additions

16.4 Miscellaneous Reactions

16.5 Outlook

Acknowledgment

Index

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The Editor

Dr. Mike Martin Kwabena Boysen

University of Hannover

Institute of Organic Chemistry

Schneiderberg 1

30167 Hannover

Germany

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Foreword

Among the organic compounds provided by nature, carbohydrates are those which contain the highest density of stereochemical information. In addition, carbohydrates are cheap and readily available in large quantities. Logically, carbohydrates, in particular monosaccharides, emerged as valuable enantiomerically pure starting materials for numerous total syntheses of interesting natural products and drugs. In spite of these attractive properties, carbohydrates have almost been ignored as tools for stereodifferentiation in stereoselective syntheses for a long time. This may be traced back to some frustrating experiences of leading researchers in the field as well as to the widespread impression among chemists that carbohydrates, although they can be sweet, sometimes tasting and even convertible to stimulating liquids, are difficult to handle and to purify if they do not crystallize.

It is a great benefit of the book Carbohydrates–Tools for Stereoselective Synthesis and a particular merit of the editor Mike Boysen and the authors he invited that they convincingly show how useful and efficient carbohydrates actually are as stereodifferentiating tools in a broad range of stereoselective reactions. In a number of cases, these stereoselective conversions finally paved an elegant way to access interesting enantiomerically pure products of quite different structures.

In the chapters of the book, the authors describe briefly, but comprehensively, carbohydrates in their function as chiral auxiliaries in diastereoselective reactions (Part I), as stereoselective reagents (Part II), as the decisive chiral ligands of enantioselective catalysts (Part III), and as organo-catalysts in enantioselective syntheses (Part IV). The subdivision according to the type of reaction provides a profound survey over the accomplishments achieved so far. Clear schemes displaying the reactions and all required information concerning conditions, yield, stereoselectivity, and original literature enlarge the profit the reader can gain from this book. In many cases, the interpretation of the stereodifferentiating effects induced by carbohydrate is also outlined, thus stimulating interested chemists to let their own ideas climb up the dense chirality of the carbohydrates. The book is a competent and inspiring source for preparative chemists aiming at demanding chiral target compounds on innovative paths.

Horst Kunz

Mainz, November 2012

Preface

Carbohydrates are arguably one of the most important classes of natural products. They serve as important energy sources and energy storage compounds in both animals and plants, and are essential as integral parts of structural fibers for plants, fungi, insects, spiders, and crustaceans. Apart from this, glycoconjugates – carbohydrate structures covalently bound to proteins and lipids – have been recognized to play a fundamental role in biological recognition and signaling processes on a cellular level.

From the point of view of synthetic organic chemistry, carbohydrates are primarily of interest to scientists working in the fields of glycoconjugates and glycomimics. As far as total synthesis of complex natural products and medicinal chemistry are concerned, simple carbohydrates – mainly monosaccharides – are occasionally used as inexpensive enantiopure chiral starting materials. In these ex-chiral-pool syntheses, some or all of the stereocenters of the carbohydrates are incorporated in the target structure. Application of carbohydrates as starting materials for the design of chiral auxiliaries, reagents, complex ligands, or organocatylsts, that is, as synthetic tools for de novo setup of stereocenters, on the other hand, has long been avoided by chemists. This may be due in part to some deeply rooted prejudices against carbohydrate chemistry, which I have encountered myself ever since I started working with carbohydrate compounds during my PhD time: carbohydrates are frequently believed to be “difficult” substrates because of their manifold functional groups, and I have even been asked whether it is at all possible to purify these “sticky” and “over-functionalized” compounds. Thus, carbohydrates have often been regarded as unsuitable or impractical for the design of stereodifferentiating agents for asymmetric synthesis. The foundation of these prejudices is, however, quickly dispelled by proper research of the literature, revealing highly successful examples of all kinds of carbohydrate-based tools for the setup of new stereocenters.

In this context, we set out to collect successful and instructive examples for carbohydrate tools in stereoselective synthesis for this book. It is the first publication to give the reader a comprehensive overview of today’s scope and limitations of these tools, which in some areas have already become indispensable supplements to the arsenal for modern stereoselective synthesis. This book covers all four types of carbohydrate tools comprising a furanose- or a pyranose-type scaffold; open chain structures and derivatives of tartaric acid are only included in some exceptional cases. Our aim is not only to bring carbohydrate tools to the awareness of the readers, but also to encourage them to apply these to their advantage in their own synthetic efforts as they often complement the scope of more traditionally used stereodifferentiating agents. Further, we would like to motivate especially young researchers to use their creativity and skills to add their own contributions to the toolbox of carbohydrate-derived stereodifferentiating agents: carbohydrate scaffolds offer unique opportunities for both the design and optimisation of novel synthetically useful tools.

I would like to thank Ms. Elke Maase, who helped me to initiate this book project, and Ms. Lesley Belfit, whose help during the editing and production process was invaluable. Finally, I would like thank all authors who contributed to this venture!

Mike Boysen

Hannover, October 2012

List of Contributors

Ana Alcudia

CSIC – Universidad de Sevilla

Investigaciones Químicas

C/Américo Vespucio, s/n, Isla de la Cartuja

41092 Seville

Spain

David Benito

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Analítica i Química Orgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Omar Boutureira

University of Oxford

Department of Chemistry

Chemistry Research Laboratory

12 Mansfield Road

Oxford OX1 3TA

UK

Mike M.K. Boysen

Leibniz University of Hannover

Institute of Organic Chemistry

Schneiderberg 1B

30167 Hannover

Germany

Sergio Castillón

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Analitica i Química Orgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Carmen Claver

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Física i Inorgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Benjamin G. Davis

University of Oxford

Department of Chemistry

Chemistry Research Laboratory

12 Mansfield Road

Oxford OX1 3TA

UK

Yolanda Díaz

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Analítica i Química Orgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Montserrat Diéguez

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Física i Inorgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Inmaculada Fernández

Universidad de Sevilla

Facultad de Farmacia

Departamento de Química y Farmacéutica

c/Prof. Garcia Gonzalez 2

41012 Seville

Spain

Maria Victoria García

CSIC – Universidad de Sevilla

Investigaciones Químicas

C/Américo Vespucio, s/n, Isla de la Cartuja

41092 Seville

Spain

Noureddine Khiar

CSIC – Universidad de Sevilla

Investigaciones Químicas

C/Américo Vespucio, s/n, Isla de la Cartuja

41092 Seville

Spain

Jun-An Ma

Tianjin University

Department of Chemistry

Nankai Wu, Weijin Road 92

Tianjin 300072

China

Patricia Marcé

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Analítica i Química Orgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

M. Isabel Matheu

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Analítica i Química Orgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Zhiwei Miao

Nankai University

Research Institute of Elemento-Organic Chemistry

Tianjin 300071

China

Brian Nettles

Colorado State University

Department of Chemistry

220 W Lake Street

Fort Collins, CO 80523

USA

Oscar Pàmies

Universitat Rovira i Virgili

Facultat de Química

Departament de Química Física i Inorgànica

C/Marcel·lí Domingo s/n

43007 Tarragona

Spain

Rocío Recio

CSIC – Universidad de Sevilla

Investigaciones Químicas

C/Américo Vespucio, s/n, Isla de la Cartuja

41092 Seville

Spain

Yian Shi

Colorado State University

Department of Chemistry

220 W Lake Street

Fort Collins, CO 80523

USA

Kin-ichi Tadano

Keio University

Department of Applied Chemistry

3-14-1 Hiyoshi

Kohoku-ku

Yokohama 223-8522

Japan

Kiichiro Totani

Seikei University

Department of Materials and Life Science

3-3-1 Kichijoji-kitamachi

Musashino-shi

Tokyo 180-8633

Japan

O. Andrea Wong

Colorado State University

Department of Chemistry

220 W Lake Street

Fort Collins, CO 80523

USA

Guang-Wu Zhang

Tianjin University

Department of Chemistry

Nankai Wu, Weijin Road 92

Tianjin 300072

China

Part I

Carbohydrate Auxiliaries

General Remarks on the Use of Pseudo-Enantiomers of Carbohydrate Tools

The application of pseudo-enantiomers is of great importance when carbohydratederived chiral tools are used: While d-monosaccharides are easily available from the chiral pool, the corresponding l-enantiomers are mostly expensive and in some cases even unavailable. For the preparation of a pseudo-enantiomer of a given carbohydrate tool, a carbohydrate scaffold with opposite configuration at relevant stereocenters is chosen. These relevant stereocenters are usually those directly involved in the events determining the direction of the asymmetric induction, that is, the one(s) carrying the substrate (in the case of carbohydrate auxiliaries), coordinating metal centers (in the case of carbohydrate ligands), or shielding one face of a substrate. The remaining stereocenters, which are further from the reacting sites, are neglected and may have any configuration. Thus the synthesis of a pseudo-enantiomeric tool can start from other l-monosaccharides, which are more readily available, that is, l-rhamnose and l-fucose and even d-carbohydrates may be employed. By this approach the preparation of a real enantiomer from an expensive l-enantiomer of a d-carbohydrate can be avoided altogether. Attractive and powerful as this approach may be it is important to note that choosing suitable a pseudo-enantiomeric auxiliary offering high levels of stereoinduction is by no means trivial. Usually, several tentative pseudo-enantiomers can be envisioned for a given carbohydrate tool but which of them – if any – gives high levels of stereoinduction cannot, unfortunately, be predicted. Therefore, finding suitable pseudo-enantiomers remains a process of trial and error. With this in view, unsurprisingly, some highly efficient carbohydrate tools have remained without any suitable pseudo-enantiomer (e.g., the Duthaler–Hafner reagent, Chapter 7).

1

Reactions of Nucleophiles with Electrophiles Bound to Carbohydrate Auxiliaries

Zhiwei Miao

1.1 Introduction

Carbohydrates are widespread chiral natural products found worldwide and they have been transformed into diverse, interesting chiral products in ex-chiral pool syntheses. However, carbohydrates were not used as chiral auxiliaries in stereoselective syntheses for a long time. About 30 years ago Vasella reported the earliest example of carbohydrate auxiliaries tools in organic synthesis [1]. During the following decades, carbohydrates slowly became recognized as versatile starting materials for chiral auxiliaries in stereoselective reactions, and today a multitude of structures has been developed and applied to various reactions [2].

1.2 Strecker Reactions

The three-component Strecker reaction as well as the hydrocyanation of imines (modified Strecker reaction) are fundamental carbon–carbon bond-forming processes [3], which are efficient methods for preparing α-amino acids (Scheme 1.1).

Scheme 1.1 Strecker-type reactions for the synthesis of α-amino acids.

In 1987 Kunz and coworkers first reported pivaloyl protected d-galactosyl amine 3 as a very useful tool for asymmetric aminonitrile syntheses [4]. Galactosyl amine 3 can be obtained from penta-O-pivaloyl-β-d-galactopyranose 1 by reaction with trimethylsilyl azide/tin tetrachloride to give the galactosyl azide 2 followed by hydrogenation (Scheme 1.2) [4].

Scheme 1.2 Synthesis of d-galactosyl amine 3.

Condensation of 3 with aldehydes 4 yields galactosyl aldimines 5, which undergo highly diastereoselective Strecker reactions with trimethylsilyl cyanide (TMSCN) in the presence of Lewis acids (Scheme 1.3). The observed diastereoselectivity is a result of the attack of the cyanide anion on the face of the (E)-imine opposite to the sterically demanding 2-O-pivaloyl group. Separation of the minor diastereoisomer and subsequent hydrolysis with hydrochloric acid affords the corresponding enantiomerically pure α-amino acid 7 (R = p-ClC6H4).

Scheme 1.3 Kunz’s asymmetric Strecker reactions with a galactose-derived chiral auxiliary.

The solvent has a strong impact on the direction of the stereoinduction. Stannic chloride in tetrahydrofuran or zinc chloride in isopropanol give α-aminonitriles with the (R) configuration with high diastereoselectivity [4a, b], while zinc chloride in chloroform reverses the direction of the asymmetric induction in favor of the (S) enantiomer [4c]. Therefore, this method is highly attractive for the preparation of α-amino acid derivatives as by simply changing the reaction conditions the aminonitrile product can be obtained in both configurations from the d-configured galactose auxiliary in a stereodivergent manner (Scheme 1.3).

Kunz ascribed the high selectivity of the Strecker reactions to steric and stereoelectronic effects arising from the carbohydrate auxiliary in combination with the Lewis acid. In the transition state (Figure 1.1) the activating Lewis acid catalyst ZnCl2 is apparently coordinated by the imine nitrogen and the carbonyl oxygen of the 2-O-pivaloyl group. This complex is preferably attacked by the cyanide, which is liberated in the polar medium from TMSCN, from the sterically less hindered rear face, that is, the Si face of the imine [4a].

Figure 1.1 Proposed transition-state of Strecker reactions with the galactose auxiliary.

After the successful syntheses of d-amino acids via Lewis-acid-catalyzed Strecker reactions with galactosylamine 3 as the stereodifferentiating auxiliary, Kunz has developed the pivaloylated-arabinosylamine 10 as a new chiral auxiliary [5]. Apart from the missing hydroxy methyl group at C5, d-arabinose is a mirror image of d-galactose and therefore arabinosylamine can be regarded as a pseudo-enantiomer of d-galactosylamine 3. To prepare pivaloylated-arabinosylamine 10, the peracetylated arabinopyranose is transformed into arabinopyranosyl azide 8, as has been described by Paulsen and coworkers [6]. After deacetylation and subsequent pivaloylation, 8 gives arabinopyranosyl azide 9, which is subsequently reduced by hydrogenation with Raney nickel to furnish the auxiliary 10 (Scheme 1.4).

Scheme 1.4 Synthetic pathway to arabinosylamine 10.

By using the arabinosylamine 10 in the Strecker reaction l-amino nitriles have been successfully obtained. To this end, 10 was condensed with aldehydes to give the N-arabinosylimines 11, which with TMSCN/tin tetrachloride furnish the α-amino nitriles 12. The diastereoselectivity was determined as 7–10:1 in favor of the l-diastereomer after hydrolysis and cleavage of the aminonitrile from the auxiliary Hydrolysis of pure 12 with hydrogen chloride/formic acid forms exclusively l-phenylglycine (Scheme 1.5) [5].

Scheme 1.5 Synthesis of α-l-amino nitriles 12 by Strecker reaction on a d-arabinose template.

The asymmetric Strecker synthesis using carbohydrate auxiliaries has also been studied in some detail by Zhang using a d-glucose-based chiral template [7]. In continuation of Kunz’s studies a general protocol for the asymmetric synthesis of α,β-diamino acids involving enantiomerically pure α-amino aldehydes, O-pivaloylated glucopyranosylamine, and TMSCN was developed. The α-aminoaldehydes 14 reacted with glucopyranosylamine 13 in CH2Cl2 to give the corresponding imines 15a and 15b in high yields. The nucleophilic addition of TMSCN to aldimines 15a and 15b employed CuBr·Me2S as promoter to activate the C=N group and afforded α,β-diaminonitriles 16a and 16b, respectively. The absolute configuration of the new stereocenter formed in the Strecker reaction is predominantly controlled by the carbohydrate auxiliary, which overrules the stereoinduction by the stereocenter stemming from the amino aldehyde part. The diastereoselectivities were 96% and 82% de, respectively, indicating only a small matched/mismatched effect between carbohydrate auxiliary and the stereocenters from the amino-aldehyde substrates. The bis-hydrochlorides 17a and 17b were obtained by hydrolysis of the α,β-diaminonitriles in acidic medium (Scheme 1.6).

Scheme 1.6 Asymmetric synthesis of α,β-diamino acids via Strecker reaction of aldimines 15.

Zhang and coworkers also studied the copper(I)-promoted Strecker reaction of sugar-modified α,β-unsaturated imines [8]. Under acidic conditions, the imines 19 were prepared from glucosyl-amine 13 and a series of substituted cinnamic aldehydes 18. The nucleophilic addition of TMSCN to aldimines 19 afforded the products 20 with the aid of CuBr·Me2S (1 equiv.) as the Lewis acid. In all reactions, only 1,2- rather than 1,4-addition products were observed [9]. This indicates that the carbohydrate auxiliary plays a significant role in controlling the regio- and diastereoselective 1,2-addition of cyanide to the α,β-unsaturated aldimines. The (R)-configured 2-amino-4-phenylbut-3-enoic acids 21 can be obtained by hydrolysis of compounds 20 in acidic medium (Scheme 1.7).

Scheme 1.7 Copper(I)-induced regio- and diastereoselective Strecker reaction.

Figure 1.2 shows the proposed transition state 23 leading to products 20. It is very similar to the one invoked by Kunz for Strecker reactions of galactose-modified imines. The Lewis acid CuBr is coordinated to both the N-atom of the imine and one of the O-atoms of the 2-O-pivaloyl group. This would decrease the electron density at the C-atom of the C=N moiety and direct the attachment of cyanide.

Figure 1.2 Proposed transition-state for Strecker reactions of α,β-unsaturated imines bound to a d-glucose-derived template.

1.3 Ugi Reactions

The terms Ugi four-component reaction (Ugi-4CR) or Ugi four-component condensation (U-4CC) usually refer to the reaction of an amine (usually a primary amine; less frequently ammonia or a secondary amine), a carbonyl compound (an aldehyde), an isocyanide, and a carboxylic acid [10]. In the course of the reaction two peptide bonds and one carbon–carbon bond are formed and a new chiral center is created (Scheme 1.8) [11].

Scheme 1.8 General outline of a four-component Ugi reaction.

A major difficulty in conducting Ugi reactions stereoselectively is that reaction conditions for the transformations vary considerably (e.g., solvent, temperature, and highly diverse starting materials) and consequently the reactions follow different mechanisms. In one successful example Kunz employed his galactosylamine auxiliary as chiral template in the Ugi reaction (Scheme 1.9) [12].

Scheme 1.9 Asymmetric Ugi reaction using a galactose-derived chiral auxiliary.

When galactosylamine 3 was allowed to react with an aldehyde, an isocyanide, and a carboxylic acid (preferably formic acid) in the presence of zinc chloride in THF, N-galactosyl amino acid amide derivatives 24 were obtained in almost quantitative yield and high dr. The N-galactosyl amino acid amide derivatives 24 can be transformed into a series of valuable chiral products, for example, 1,2-diamines and β-amino alcohols. At −25 °C (for aliphatic imines −78 °C) d-configured amino acid derivatives 24 were formed with a diastereoselectivity of about 95:5 (Scheme 1.9). After acidolytic cleavage of the N-glycosidic bond the tetra-O-pivaloyl-galactose 25 is reisolated in quantitative yield. Hydrolysis of the amino acid amides 26 and subsequent deprotonation gives the free α-d-amino acids 27 [12].

The arabinosylamine 10 also was applied in Ugi reaction by Kunz and shows a slightly enhanced reactivity in comparison to the galactosylamine [5, 13]. At −25 °C, 10 reacts with aldehydes, tert-butyl isocyanide, and formic acid in the presence of zinc chloride in THF to form the N-formyl-N-arabinosyl amino acid amides 28 in almost quantitative yield. The diastereomeric ratio for the l-amino acid derivatives 28 ranges from 22:1 to 30:1. The free enantiomerically pure l-amino acids 31 can easily be released from the carbohydrate templates by a two-step acidic hydrolysis and the carbohydrate template can be recovered in quantitative yield (Scheme 1.10).

Scheme 1.10 Stereoselective synthesis of l-amino acid derivatives 31 using a d-arabinose-derived auxiliary.

Kunz and coworkers introduced their chiral carbohydrate based auxiliaries successfully onto a solid phase [14]. They synthesized 2,3,4-tri-O-pivaloylated-β-d-galactopyranosyl azide bearing a hydroxyl-functionalized spacer unit at the C6 position of the galactose and immobilized this on a solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated α-amino acid amides 32 (Scheme 1.11).

Scheme 1.11 Kunz’s auxiliary made available on solid phase and its use in an Ugi reaction.

Pellicciari et al. have reported the stereoselective synthesis and preliminary biological evaluation of (+)- and (−)-3-methyl-5-carboxythien-2-ylglycine (3-MATIDA), 36 and 37. They used chiral sugar based auxiliaries 3 and 10 to prepare the enantiomerically pure unnatural amino acids using a U-4CR [15]. The reaction of thiophene carbaldehyde 33 with tert-butyl isocyanide, formic acid, and d-galactosylamine 3 or d-arabinosylamine 10, respectively, in the presence of zinc chloride in THF at −25 °C and subsequent cleavage afforded the N-formyl-N-galactosyl amino acid amide 34 in a 17:1 diastereomeric ratio and the N-formyl-N-arabinosyl amino acid amides 35 in a 32:1 diastereomeric ratio, respectively (Scheme 1.12).

Scheme 1.12 Enantioselective preparation of carboxythiophene α-amino acids by Ugi reactions.

Ugi and coworkers have presented a highly improved sugar derived auxiliary, which was tested as amine compounds for peptide synthesis [16]. Glucopyranosides 39 were prepared from methyl α-d-glucopyranoside (38) by methylation. Subsequent acetolysis to give 40 followed by ammonolysis yielded 41, which was transformed into the auxiliary tetra-O-methyl glucopyranosylamine 42 [17] by mesylation and subsequent treatment with gaseous ammonia in a one-pot reaction developed by Vasella (Scheme 1.13) [18].

Scheme 1.13 Synthetic pathway to tetra-O-methyl-glucopyranosylamine auxiliary 42.

Glycosylamine 42 has been tested as chiral template in various types of Ugi reaction, and the results show that the major diastereomers of the products 43 have the d-configuration at the newly installed stereocenter [19]. Trifluoroacetic acid (TFA) in combination with a soft base can cleave the Ugi product 43 into peptide 44 and the carbohydrate auxiliary (Scheme 1.14).

Scheme 1.14 Formation of α-acylamino acid derivatives 44 by diastereoselective Ugi reaction on carbohydrate template 42.

In 1995, Ugi examined the stereoselective syntheses of peptide derivatives with acetylated 1-amino-glucopyranose 45 as the chiral template [20]. The acetylated amino-glucopyranose 45 as auxiliary is prepared from readily available N-acetylglucosamine in three steps [21]. Condensation of an aldehyde with the amine 41 yielded glucosyl aldimines 46, which reacted with isocyanide and acid in the presence of zinc chloride to form the N-glucosyl peptide derivatives 47 in good yields (Scheme 1.15).

Scheme 1.15 Selection of Ugi reaction products obtained with amino-glucopyranose as auxiliary.

Ugi also reported a thiasugar as a chiral auxiliary for the stereoselective reaction four-component synthesis of amino acids [22]. According to Ingles and Whistler’s method [23] 5-desoxy-5-thio-d-xylose 49 can be prepared in six steps from d-xylose 48. This product can be peracylated to 50 by an excess of isobutanoyl chloride in pyridine. In the presence of tin tetrachloride, 50 can be converted into azide 51 by treatment with trimethylsilyl azide. The anomerically pure β-amine hydrochloride 52 is obtained from the α/β-azide mixture 51 by reduction with 1,3-propanedithiol. During workup, β-amine 53 can be precipitated from an etheric solution as the hydrochloride salt 52 (Scheme 1.16) [24].

Scheme 1.16 Synthesis of thiasugar auxiliary 52 from d-xylose.

The free amine 53 and isovaleraldehyde are subsequently converted into the imine 54, which is reacted under Ugi reaction conditions with zinc chloride diethyl etherate, tert-butyl isocyanide, and benzoic acid. The product 55 is formed in 92% de (diastereomeric ratio 24:1) and a yield of 92%. The readily crystallizing product 56 is obtained from 55 by removing its O-acyl groups by aminolysis with methyl amine. The O-deacylated chiral auxiliary 49 can be cleaved off under mild acidic conditions to afford the N-benzoyl-d-leucine-tert-butylamide 57 (R = tBu) (Scheme 1.17) [25].

Scheme 1.17 Stereoselective U-4CR with thiasugar auxiliary 53.

1.4 Allylations

Homoallyl amines are useful precursors of a various compounds, especially β-amino acids and β-lactam antibiotics, which can be obtained by subsequent functionalization of the double bond. An attractive method for the synthesis of homoallyl amines is the organometallic allylation of chiral imines carrying a chiral template on the nitrogen, which can be successively removed [26].

Kunz reported that (S)-configured homoallylamines can be synthesized diastereoselectively by the Lewis acid induced addition of allylsilanes to Schiff bases of tetra-O-pivaloyl-galactosylamine 3 (Scheme 1.18) [27a, c] giving moderate to good diastereoselectivity for imines 5 with non-aliphatic residues. The nucleophilicity of the allylic organometallic compound can be improved by changing the metal from silicon to tin [27c]. Thus imine 5 with R = 4-Cl-C6H4 was converted into the corresponding homoallyl amines 58 by using allyltributylstannane instead of allyltrimethylsilane under identical conditions, resulting in an increased yield, but reduced asymmetric induction.

Scheme 1.18 Asymmetric synthesis of (S)-configured homoallyl amines using galactosyl amine 3.

When the reaction is conducted with the O-pivaloyl-protected l-fucosylamine 59 instead of N-galactosylamine 3, the (R)-configured homoallyl amines 61 can be isolated in high diastereoselectivities [27b, c]. The advantage of this reaction is that most N-fucosyl-homoallyl-amines 61 are crystalline and can be obtained as the pure (R) diastereomer or as a strongly enriched mixture simply by recrystallization (Scheme 1.19) [27b, c]. It should be noted that allyltributylstannane is used instead of allyl trimethylsilane in the allylic addition of the corresponding β-L-fucosyl imines 60 (R = nPr).

Scheme 1.19 Asymmetric synthesis of (R)-configured homoallyl amines using fucosyl amine 58.

Schiff bases derived from glucosyl amines and aliphatic aldehydes do not react with allyltrimethylsilane under the same conditions. Even at low temperature (−78 °C), only anomerization and decomposition occurred. However, these imines could be converted into the corresponding homoallylamines using allyltributylstannane instead of the silane at −78 °C, and SnCl4 (1.2 equiv) was used to activate the imine.

The homoallylamines 62 can be released from the carbohydrate template using aqueous HCl in methanol. Homoallylamine hydrochlorides 62 could easily be N-protected and were subsequently oxidized to yield the N-protected β-amino acid 64, which was finally deprotected to the corresponding β-amino acid 65 (Scheme 1.20).

Scheme 1.20 Conversion of N-galactosyl-N-homoallylamines into β-amino acids.

A tentative reaction mechanism was proposed by the authors. In the transition state the tin atom of the Lewis acid SnCl4 has octahedral coordination, with sites occupied by chlorine atoms, the imine nitrogen and the carbonyl oxygen of the (C2) pivaloyloxy group; one of the four chlorines is removed when allyltrimethylsilane is added. The SN2′-type attack of the allylic compound occurs preferentially from the rear face of the imine, as the 2-O pivaloyl group effectively shields the front face. The mechanism indicates that the pivaloyl group in the aldimines 5 and 60 plays a significant role in controlling the diastereoselective addition of allyltrimethylsilane (Figure 1.3).

Figure 1.3 Transition state proposed by Kunz for the allylation reaction of glycosyl imines.

1.5 Mannich-Type Reactions

Mannich-type reactions are among the most important transformations in organic chemistry because they afford synthetically and biologically important β-amino carbonyl compounds [28]. Asymmetric Mannich-type reactions provide useful routes for the synthesis of optically active β-amino ketones or esters that are versatile chiral building blocks in the preparation of many nitrogen-containing biologically important compounds [29].

The first asymmetric Mannich reactions were diastereoselective and involved the addition of preformed enolates and enamines to performed imines using stoichiometric amount of chiral auxiliaries [30]. More recently, direct catalytic asymmetric Mannich-type reactions have been reported [31]. The transformations are catalyzed by both organometallic complexes and metal-free organic catalysis. The different catalysts are highly stereoselective and complementary in their applicability and selectivity.

During investigations on Mannich-type reaction, N-galactosyl aldimines 5 were employed as the chiral template [32]. Like α-amino acids generated by the Strecker reaction, β-amino acid derivatives accessible via Mannich reactions are important building blocks for the construction of natural products [33]. The N-galactosyl-β-amino acid esters 67 were obtained by the treatment of silyl ketene acetals 62 with the Schiff bases 5 in the presence of zinc chloride at −78 to −30 °C within 24 h. The β-phenyl-β-alanine ester derivatives 68 can be removed from the carbohydrate template almost quantitatively with HCl in methanol (Scheme 1.21).

Scheme 1.21 Diastereoselective Mannich-type reaction of ketene acetals with imine 5 for the synthesis of β-alanine derivatives.

The diastereoselective Mannich reaction of O-pivaloylated N-galactosyl aldimines 5 containing two new stereocenters bis-silyl ketene acetals 70, which was reported by Kunz, proved an efficient stereoselective access to chiral β-amino acid derivatives 71 [34]. The yields and diastereoselectivities of these Mannich reactions are high and only two of the four possible diastereomers are formed. In most cases one of them is obtained in large excess. The N-glycosidic bond of compound 71 was readily cleaved under mildly acidic conditions to give enantiomerically pure β-amino acids or their hydrochlorides 72 (Scheme 1.22). To assign the configuration of the β-amino acids 73, 2,3-diphenyl-β-alanine 72 was released from 71 with 0.01M HCl in methanol. Subsequent reduction with lithium aluminum hydride yields 3-amino-2,3-diphenylpropanol 73.

Scheme 1.22 Diastereoselective synthesis of β-amino acids 73.

To extend the scope of asymmetric reactions using N-glycosyl imines to N-alkyl or N-aryl amino acid derivatives, O-pivaloylated galactosyl bromide 74 was employed in Mannich reactions of N-alkyl and N-aryl aldimines 75 with O-trimethylsilyl ketene acetals 76. The reactions were carried out in a one-pot procedure to give the β-amino acid esters 77 in high yield and with moderate diastereoselectivity (Scheme 1.23) [35].

Scheme 1.23 Diastereoselective synthesis of β-amino acid esters via an in situ glycosylation method.

3,4-dihydroisoquinoline (78) reacted with silyl ketene acetal 79 after activation by N-galactosylation to give the β-amino acid ester 80 with high diastereoselectivity (Scheme 1.24) [35].

Scheme 1.24 Diastereoselective synthesis of β-amino acid ester 80 from dihydroquinoline 78.

In 1989, Kunz reported the stereoselective tandem Mannich–Michael reactions for the synthesis of piperidine alkaloids again using galactosylamine 3 as an effective chiral auxiliary [36]. A subsequent publication described how the N-galactosyl aldimines 5 react with silyl dienol ether 81 in the presence of zinc chloride in tetrahydrofuran at −20 °C to give the Mannich bases 82/83 with high diastereoselectivities. The Michael addition then occurs to give the dehydropiperidones 84/85 in high yields upon hydrolysis with 1M HCl (Scheme 1.25) [37].

Scheme 1.25 Diastereoselective synthesis of N-galactosyldehydropiperidones 84 and 85.

In 2004, Kunz reported the application of arabinosylamine 10 as a suitable pseudo enantiomeric auxiliary to the galactosylamine 3 [38a]. N-Arabinosylimines 11 react with silyl dienol ether 81 in a domino Mannich–Michael reaction sequence to give 2-substituted 5,6-dehydropiperidinones 86. The 2-substituted dehydropiperidinones are formed with opposite stereochemistry compared to those from the tandem Mannich–Michael reaction with d-galactosylamine as auxiliary (Scheme 1.26).

Scheme 1.26 Diastereoselective synthesis of 2-substituted N-arabinosyl dehydropiperidinones 86.

1.6 Addition of Phosphites

Vasella and coworkers first reported the stereoselective synthesis of α-aminophosphonic acids by means of carbohydrate auxiliaries [39, 40]. In the first experiments N-mannofuranosylnitrones 87 (R = iPr, CH2OBn, Me) were reacted with lithium dialkyl phosphites, affording the corresponding α-aminophosphonic acids with up to 90% de [39]. In a second approach, which was amenable to a wider range of N-mannosylnitrones 87, tris(trimethylsilyl)phosphite (88) was employed under acid catalysis with HClO4, giving (R)-N-hydroxyphenylphosphaglycines 90 in high yield and with an optical purity of 88% after acidic work-up. Hydrogenolysis of 90 gives (R)-phenylphosphaglycines 91, with optical purities of up to 88% (Scheme 1.27) [40].

Scheme 1.27 Synthesis of (R)-phenylphosphaglycine 91 using a mannose-derived carbohydrate auxiliary.

In 1992 Kunz and coworkers reported the stereoselective synthesis of α-aminophosphonic acid derivatives from O-pivaloylated galactosylamine as chiral auxiliary [41]. The galactosyl amine 3 was reacted with various aldehydes to give N-galactosyl aldimines 5, which were reacted with diethyl phosphite to furnish the four diastereomeric N-galactosylphenyl phosphonoglycine esters 92 in high yield by catalysis with tin(IV) chloride in THF (Scheme 1.28). The new stereocenter in esters 92 was preferentially obtained in (S)-configuration, and the anomeric configuration was predominantly β, except for the cases with R = 2-MeOC6H4 and R = Pr, where substantial amounts of the α-anomers were found.

Scheme 1.28 Synthesis arylphosphonoglycine esters using carbohydrate auxiliary 3.

The (R)-configured aminophosphonic acids can be obtained by employing the l-fucose-derived Schiff base 93 as a pseudo enantiomeric auxiliary [41]. The diastereomeric mixture of the addition products 94 was treated with 1M hydrogen chloride in methanol at room temperature, giving the carbohydrate template and the α-aminobenzylphosphonate hydrochloride 96 in quantitative yield (Scheme 1.29).

Scheme 1.29 Diastereoselective synthesis of (R)-aminophosphonates using l-fucose auxiliary.

Miao has also reported the diastereospecific formation of α-aminophosphonic acids derivatives in high yield via a Mannich-type reaction [42]. The reaction was performed by using O-pivaloylated galactosylamine 3 as a chiral template and boron trifluoride diethyl etherate as a catalyst in THF. Imines 5 [4b] of aromatic aldehydes and diethyl phosphite were converted into N-galactosyl α-aminoalkylphosphonates 97 with diastereomeric ratios higher than 19:1 (Scheme 1.30).

Scheme 1.30 Synthesis of N-galactosyl α-aminoalkylphosphonates 97.

The diastereomerically pure compounds 97 were obtained by simple recrystallization from n-hexane and diethyl ether. To determine the absolute configuration of the main isomer of the diethyl phosphite addition to N-galactosyl aldimines 5, a single-crystal X-ray diffraction study of 97 (R = p-Cl) was performed. The molecular structure of 97 (R = p-Cl), shown in Figure 1.4, proves that the absolute configuration of the main product is (S) [42].

Figure 1.4 ORTEP presentation of the crystal structure of 97 (R = p-Cl).

Figure 1.5 shows a possible mechanism for the reaction. The preferred formation of the (S)-configured diastereomers of 97 can be rationalized by an attack of diethyl phosphite from the Si side of N-galactosylaldimines 5. Initially, the Lewis acid boron trifluoride is coordinated to the imine nitrogen of 5. The Re-face of the imine is shielded by the 2-O-pivaloyl group, leaving the Si-face exposed. Upon attack of the diethyl phosphite in the transition state, one fluoride may be removed from the Lewis acid and the vacant coordination site may then be filled by the carbonyl oxygen of the 2-O-pivaloyl group.

Figure 1.5 Plausible reaction mechanism of the addition of phosphites to galactosyl imines 5.

In 2009, Miao reported the stereoselective synthesis of α-amino(phenyl)methyl (phenyl)phosphinic acids with d-galactosylamine as chiral auxiliary [43]. Aldimines 5 of aromatic aldehydes and ethyl phenylphosphinate 98 were converted into N-galactosylarylphosphonoglycine esters 99 with diastereomeric ratios higher than 20:1. α-Amino(phenyl)methyl-(phenyl)phosphinic acids 100 can be obtained by treatment with 1M hydrogen chloride in methanol (Scheme 1.31).

Scheme 1.31 Synthesis of N-galactosyl arylphosphonoglycine esters 99.

1.7 Dynamic Kinetic Resolution of α-Chloro Carboxylic Esters

Another interesting application of carbohydrate-derived auxiliaries is the dynamic kinetic resolution of racemic α-halogenated carboxylic esters [44]. Park reported a d-glucose-derived auxiliary in the dynamic resolution of α-halo esters in an asymmetric nucleophilic substitution [45, 46]. α-Chloro-α-phenyl ester (αRS)-101 was obtained as a diastereomeric mixture by the reaction of diacetone-d-glucose and racemic α-chloro-α-phenylacetyl chloride in the presence of Et3N. Treatment of (αRS)-101 with various amines, and diisopropylethylamine (DIPEA) in the presence of tetrabutylammonium iodide (TBAI), gave the amino acid derivatives 102 in high yields and high diastereomeric ratios. After treatment of esters 102 in methanol with Et3N at room temperature, the chiral auxiliary was successfully removed (Scheme 1.32).

Scheme 1.32 Dynamic kinetic resolution of α-chloro ester 101 in nucleophilic substitution.

Park also employed d-allofuranose as auxiliary for the dynamic kinetic resolution of α-chloro esters in nucleophilic substitutions [46]. Using the same reaction conditions previously for d-glucose derivative 101 and benzylamine as the nucleophile, dynamic resolution of α-chloro acetate 104 took place with high stereoselectivity, affording 105 in moderate isolated yield with 90:10 dr (αS:αR) (Scheme 1.33).

Scheme 1.33 Dynamic kinetic resolution of α-chloro ester 104 in nucleophilic substitution.

Based on the results, a plausible mechanism for the nucleophilic substitutions of d-glucose derivatives and d-allose derivatives has been suggested (Figure 1.6) [46]. The authors proposed two transition states in which the α-R group and the C=O bond in the ester substituent adopt an s-cis conformation, while the ester carbonyl group is in an eclipsed position relative to the hydrogen atom at C3 of the furanose. The nucleophilic attack of an amine nucleophile may then be aided by hydrogen bond formation with one oxygen atom from the 5,6-O and 1,2-O dioxolanes of the chiral auxiliaries in (αR)-101 and (αS)-101, respectively. These tentative transition states explain the (S)-configurations of the products observed for both the d-glucose and d-allose derived auxiliary.

Figure 1.6 Proposed transition state structures for dynamic kinetic resolution of α-halo esters of glucose- and allose-derived carbohydrate auxiliaries.

References

1 Vasella, A. (1977) Helv. Chim. Acta, 60, 1273.

2 (a) Cintas, P. (1991) Tetrahedron, 47, 6079; (b) Reissig, H.U. (1992) Angew. Chem. Int. Ed. Engl., 31, 288; (c) Kunz, H. and Rück, K. (1993) Angew. Chem. Int. Ed. Engl., 32, 336; (d) Hale, K.J. (1993) Second Supplement to the Second Edition of Rodd’s Chemistry of Carbon Compounds, vol. 1E/F/G (ed. M. Sainsbury), Elsevier, Amsterdam, Chapter 23b, p. 273; (e) Kunz, H. (1995) Pure Appl. Chem., 67, 1627; (f) Hultin, P.G., Earle, M.A., and Sudharshan, M. (1997) Tetrahedron, 53, 14823; (g) Knauer, S., Kranke, B., Krause, L., and Kunz, H. (2004) Curr. Org. Chem., 8, 1739; (h) Boysen, M.M.K. (2007) Chem. Eur. J., 13, 8648; (i) Lehnert, T., Özüduru, G., Grugel, H., Albrecht, F., Telligmann, S.M., and Boysen, M.M.K. (2011) Synthesis, 2685.

3 (a) Enders, D. and Shilvock, J.P. (2000) Chem. Soc. Rev., 29, 359; (b) Merino, P., Marqués-López, E., Tejero, T., and Herrera, R.P. (2009) Tetrahedron, 65, 1219.

4 (a) Kunz, H. and Sager, W. (1987) Angew. Chem. Int. Ed. Engl., 26, 557; (b) Kunz, H., Sager, W., Schanzenbach, D., and Decker, M. (1991) Liebigs Ann. Chem., 649; (c) Kunz, H., Sager, W., Pfrengle, W., and Schanzenbach, D. (1988) Tetrahedron Lett., 29, 4397.

5 Kunz, H., Pfrengle, W., Rück, K., and Sager, W. (1991) Synthesis, 1039.

6 Paulsen, H., Györgydeak, Z., and Friedmann, M. (1974) Chem. Ber., 107, 1568.

7 Wang, D., Zhang, P.F., and Yu, B. (2007) Helv. Chim. Acta, 90, 938.

8 Zhou, G.B., Zheng, W.X., Wang, D., Zhang, P.F., and Pan, Y.J. (2006) Helv. Chim. Acta, 89, 520.

9 Porter, J.R., Wirschun, W.G., Kuntz, K.W., Snapper, M.L., and Hoveyda, A.H. (2000) J. Am. Chem. Soc., 122, 2657.

10 Ugi, I., Offermann, K., Herlinger, H., and Marquarding, D. (1967) Justus Liebigs Ann. Chem., 7091.

11 (a) Dömling, A. (2006) Chem. Rev., 106, 17; (b) Dömling, A. and Ugi, I. (2000) Angew. Chem. Int. Ed., 39, 3168.

12 (a) Kunz, H. and Pfrengle, W. (1988) J. Am. Chem. Soc., 110, 651; (b) Kunz, H. and Pfrengle, W. (1988) Tetrahedron, 44, 5487.

13 Kunz, H., Pfrengle, W., and Sager, W. (1989) Tetrahedron Lett., 30, 4109.

14 Zech, G. and Kunz, H. (2004) Chem. Eur. J., 10, 4136.

15 Costantino, G., Marinozzi, M., Camaioni, E., Natalini, B., Sarichelou, I., Micheli, F., Cavanni, P., Faedo, S., Noe, C., Moroni, F., and Pellicciari, R. (2004) Farmaco, 59, 93.

16 Ugi, I., Marquarding, D., and Urban, R. (1982) Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, vol. 6 (ed. B. Eeinstein), Marcel Dekker, New York, p. 245.

17 Preobrazhenskaya, M.N. and Suvorov, N.N. (1965) Zh. Obshch. Khim., 85, 888.

18 Aebischer, B.M., Hanssen, H.W., Vasella, A.T., and Schweizer, W.B. (1982) J. Chem. Soc. Perkin Trans. 1, 2139.

19 Goebel, M. and Ugi, I. (1991) Synthesis, 1095.

20 Lehnhoff, S., Goebel, M., Karl, R.M., Klösel, R., and Ugi, I. (1995) Angew. Chem. Int. Ed. Engl., 34, 1104.

21 (a) Micheel, F. and Klemer, A. (1961) Adv. Carbohydr. Chem., 16, 95; (b) Pfleiderer, W. and Bühler, E. (1966) Chem. Ber., 99, 3022.

22 Ross, G.F., Herdtweck, E., and Ugi, I. (2002) Tetrahedron, 58, 6127.

23 Ingles, D.L. and Whistler, R.L. (1962) J. Org. Chem., 27, 3896.

24 (a) Birkofer, L. and Ritter, A. (1965) Angew. Chem. Int. Ed. Engl., 4, 417; (b) Paulsen, H., Gyorgydeak, Z., and Friedmann, M. (1974) Chem. Ber., 107, 1568; (c) Strumpel, M.K., Buschmann, J., Szilagyi, L., and Gyorgydeak, Z. (1999) Carbohydr. Res., 318, 91.

25 Ross, G.F. and Ugi, I. (2001) Can. J. Chem., 79, 1934.

26 (a) Yamamoto, Y., Nishii, S., Maruyama, K., Komatsu, T., and Ito, W. (1986) J. Am. Chem. Soc., 108, 7778; (b) Yamamoto, Y., Komatsu, T., and Maruyama, K. (1984) J. Am. Chem. Soc., 106, 5031; (c) Yamamoto, Y., Komatsu, T., and Maruyama, K. (1985) J. Chem. Soc., Chem. Commun., 814.

27 (a) Laschat, S. and Kunz, H. (1990) Synlett, 51; (b) Laschat, S. and Kunz, H. (1990) Synlett, 629; (c) Laschat, S. and Kunz, H. (1991) J. Org. Chem., 56, 5883.

28 (a) Risch, N., Arend, M., and Westermann, B. (1998) Angew. Chem., Int. Ed. Engl., 37, 1044 and references therein; (b) Tramontini, M. and Angiolini, L. (1994) Mannich Bases, Chemistry and Uses, CRC Press, Boca Raton, FL, and references therein; (c) Volkmann, R.A. (1991) Comprehensive Organic Synthesis, vol. 1 (eds B.M. Trost and I. Fleming), Pergamon, Oxford, UK, p. 355 and references therein.

29 Vilaivan, T., Bhanthumnavin, W., and Sritana-Anant, Y. (2005) Curr. Org. Chem., 9, 1315.

30 (a) Seebach, D. and Hoffmann, M. (1998) Eur. J. Org. Chem., 1337; (b) Aoyagi, Y., Jain, R.P., and Williams, R.M. (2001) J. Am. Chem. Soc., 123, 3472 and references therein; (c) Evans, D.A., Urpi, F., Somers, T.C., Clark, J.S., and Bilodeau, M.T. (1990) J. Am. Chem. Soc., 112, 8215; (d) Kober, R., Papadopoulos, K., Miltz, W., Enders, D., Steglich, W., Reuter, H., and Puff, H. (1985) Tetrahedron, 42, 1693; (e) Palomo, C., Oiarbide, M., Landa, A., Gonzales-Rego, M.C., Garcia, J.M., Gonzales, A., Odriozola, J.M., Martin-Pastor, M., and Linden, A. (2002) J. Am. Chem. Soc., 124, 8637 and references therein.

31 (a) Córdova, A. (2004) Acc. Chem. Res., 37, 102; (b) Loh, T.P. and Chen, S.L. (2002) Org. Lett., 4, 3647.

32 Kunz, H. and Schanzenbach, D. (1989) Angew. Chem. Int. Ed. Engl., 28, 1068.

33 (a) Braun, M., Sacha, H., Galle, D., and El-Alali, A. (1995) Tetrahedron Lett., 36, 4213; (b) Ojima, I., Habus, I., Zhao, M., Georg, G.I., and Jayasinghe, L.R. (1991) J. Org. Chem., 56, 1681.

34 Kunz, H., Burgard, A., and Schanzenbach, D. (1997) Angew. Chem. Int. Ed. Engl., 36, 386.

35 Allef, P. and Kunz, H. (2000) Tetrahedron: Asymmetry, 11, 375.

36 Kunz, H. and Pfrengle, W. (1989) Angew. Chem. Int. Ed. Engl., 28, 1067.

37 Weymann, M., Pfrengle, W., Schanzenbach, D., and Kunz, H. (1997) Synthesis, 1151.

38 (a) Kranke, B., Hebranlt, D., Schulz-Kukula, M., and Kunz, H. (2004) Synlett, 671; (b) Kranke, B., and Kunz, H. (2006) Can. J. Chem., 84, 625.

39 Huber, R., Knierzinger, A., Obrecht, J.-P., and Vasella, A. (1985) Helv. Chim. Acta, 68, 1730.

40 Huber, R. and Vasella, A. (1987) Helv. Chim. Acta, 70, 1461.

41 Laschat, S. and Kunz, H. (1992) Synthesis, 90.

42 Wang, Y.D., Wang, F., Wang, Y.Y., Miao, Z.W., and Chen, R.Y. (2008) Adv. Synth. Catal., 350, 2339.

43 Wang, Y.D., Wang, Y.Y., Yu, J., Miao, Z.W., and Chen, R.Y. (2009) Chem. Eur. J., 15, 9290.

44 For examples using other auxiliaries see: (a) Valenrod, Y., Myung, J., Ben, R.N. (2004) Tetrahedron Lett., 45, 2545; (b) Nam, J., Lee, S.-K., and Park, Y.S. (2003) Tetrahedron, 59, 2397; (c) Nam, J., Lee, S.-K., Kim, K.Y., and Park, Y.S. (2002) Tetrahedron Lett., 43, 8253; (d) Lee, S.-K., Nam, J., and Park, Y.S. (2002) Synlett, 790; (e) Ben, R.N. and Durst, T. (1999) J. Org. Chem., 64, 7700.

45 Kim, H.J., Shin, E.K., Chang, J.Y., Kim, Y., and Park, Y.S. (2005) Tetrahedron Lett., 46, 4115.

46 Kim, H.J., Kim, Y., Choi, E.T., Lee, M.H., No, E.S., and Park, Y.S. (2006) Tetrahedron, 62, 6303.

2

1,4-Addition of Nucleophiles to α,β-Unsaturated Carbonyl Compounds

Kiichiro Totani and Kin-ichi Tadano

2.1 Introduction

In this chapter we describe the 1,4-additions of various nucleophiles to α,β-unsaturated carbonyl groups on carbohydrate templates. Many examples have revealed that carbohydrates serve as effective chiral auxiliaries for realizing useful levels of diastereoselectivity [1–8]. As acyclic 1,4-addition acceptors, acrylic amides or acrylic esters on a carbohydrate template are described. Then, as cyclic acceptors, 2- and 4-pyridones are also exemplified.

2.2 1,4-Additions to Acrylic Amides and Acrylic Esters

As an early example concerning the utility of carbohydrate-based auxiliaries for stereoselective carbon–carbon bond formation, Kunz and Pees reported in 1989 the stereoselective 1,4-addition of the carbon nucleophile generated from diethylaluminum chloride to a d-xylose-derived N-cinnamoyl 2-oxazinone 2 [9, 10]. The substrate 2 was synthesized by N-cinnamoylation of 3,5-O,N-oxazin-2-one derivative 1, which in turn was synthesized from d-xylose (Scheme 2.1) [9]. The 1,4-addition of diethylaluminum chloride to 2 at –80 °C proceeded with remarkable π-facial selectivity to provide (S)-3-phenylpentanoyl derivative 3 in high yield with 74% diastereomeric excess (de). Hydrolysis of 3 with HCl provided enantioenriched (3S)-phenylpentanoic acid 4, the absolute stereochemistry of which was confirmed by comparison of its optical rotation to the reported [α]d (the yield and ee of 4 were not reported).

Scheme 2.1 1,4-Addition of an ethyl nucleophile to d-xylose-derived N-cinnamoyl-2-oxazinone 2.

Later, the Kunz group demonstrated other stereoselective syntheses of chiral β-branched carboxylic acids using the 1,4-addition of organometallic species to carbohydrate-derived N-acyloxazolidinones [10–12]. Thus, oxazolidinone 5 as the auxiliary for the 1,4-addition was synthesized from d-galactose via azidonitration of 3,4,6-tri-O-pivaloyl-d-galactal, followed by hydrolysis and oxazoline formation via a Staudinger–aza-Wittig reaction cascade (Scheme 2.2).

Scheme 2.2 Synthesis of d-galactosamine-derived N-acylated oxazolidinones 6 and subsequent 1,4-additions with various organoaluminum species.

Conversion of 5 into the N-acyl derivatives 6 by deprotonation with methylmagnesium bromide was followed by treatment with the two α,β-unsaturated acyl chlorides. The resulting N-acyloxazolidin-2-ones 6, fused with per-O-pivaloylated d-galactopyranose at C1 and C2, were subjected to 1,4-additions with various organoaluminum chlorides at low temperature. As a result, β-substituted N-acyl derivatives were obtained in high to excellent diastereoselectivity and in moderate to high yield. In all cases, attack of the carbon nucleophiles occurred from the front side, opposite the pivaloyloxy group installed at C3. The configurations of the newly introduced stereocenters at the β-carbon of 7 were determined after removal of the d-galactose moiety by alkaline hydrolysis in the presence of hydrogen peroxide, producing 8. The oxazolidinone-type template 5 was recovered efficiently. On 1,4-addition of the (diisobutyl)aluminum reagent to 6 with R1 = Ph, the (S)-adduct 7 was obtained in diastereomerically pure form (>98% de). Using the α,β-unsaturated carbonyl derivative 6, the Kunz group also explored the formation of β-branched α-halo carboxylic acid derivatives via 1,4-addition of dialkylaluminum chlorides followed by treatment with N-chlorosuccinimide [13].

To obtain the opposite enantiomers of 8, the Kunz group designed another carbohydrate-based template as a chiral auxiliary. For this purpose, they chose d-arabinose-based bicyclic oxazolidin-2-one 10 as the auxiliary, which in turn was synthesized from readily available 3,4-di-O-acetyl-d-arabinal via de-O-acetylation, per-O-pivaloylation, and then azidonitration, providing the 2-azido derivative 9. By using the analogous route employed for the synthesis of 5, the 2-azido sugar 9 was efficiently converted into 10 (Scheme 2.3) [12]. Obviously, the two bicyclic oxazolidin-2-one derivatives 5 and 10 have a pseudo-enantiomeric relationship in constituting a chiral environment [14]. A cinnamoyl or crotonyl group was introduced into the oxazolidin-2-one moiety in 10 by the same procedure used for the preparation of 6. As shown in Scheme 2.3, the 1,4-additions of several carbon nucleophiles to the resulting unsaturated amides 11 proceeded with moderate to high diastereoselectivity to provide the β-branched N-acyl oxazolidin-2-ones 12 with the opposite configuration at the β-carbon, compared to those in the adducts 7. The auxiliary moiety in the 1,4-addcut 12 (R1 = Ph, R2 = Et) was efficiently removed with H2O2 in an aqueous solution in the presence of LiOH to provide (S)-3-phenylpentanoic acid 13