Heterocycles in Natural Product Synthesis E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch
• Veröffentlichungsjahr: 2011

Seitenzahl: 851

Beschreibung

Filling a gap on the market, this handbook and ready reference is unique in its discussion of the usefulness of various heterocyclic systems in the synthesis of natural products. Clearly structured for easy access to the information, each chapter is devoted to a certain class of heterocycle, providing a tabular presentation of the natural products to be covered containing the particular heterocyclic ring system along with their biological profile, occurrence and most important physical properties, backed by the appropriate references. In addition, the application of the heterocyclic system to the synthesis of natural products ic covered in detail. Of great interest to organic, natural products, medicinal and biochemists, as well as those working in the pharmaceutical and agrochemical industry.

Leseprobe

Table of Contents

Cover

Related Titles

Title page

Copyright page

Preface

List of Contributors

Part One: Strained Heterocycles in the Synthesis of Natural Products

1 Aziridines in Natural Product Synthesis

1.1 Introduction

1.2 Synthesis of Natural Products Containing Aziridine Units

1.3 Synthesis of Natural Products Involving the Transformation of an Aziridine Moiety

1.4 Conclusion

2 Azetidine and Its Derivatives

2.1 Introduction

2.2 Structural Description of Azetidines

2.3 Synthetic Methodologies for the Formation of Azetidine Rings

2.4 Synthesis of Mugineic Acids

2.5 Synthesis of Penaresidins

2.6 Structural Description of Azetidin-2-ones

2.7 Synthetic Methodologies for the Formation of Azetidin-2-ones

2.8 Synthesis of Penicillin

2.9 Synthesis of Cephalosporin

2.10 Conclusion

Acknowledgment

3 Epoxides and Oxetanes

3.1 Introduction

3.2 Epoxides in Natural Product Synthesis

3.3 Oxetane in Natural Product Synthesis

3.4 Conclusion

Acknowledgment

Part Two: Common Ring Heterocycles in Natural Product Synthesis

4 Furan and Its Derivatives

4.1 Introduction

4.2 Natural Products Containing the Furan Ring

4.3 Furan Derivatives as Reagents in the Synthesis of Natural Products

4.4 Summary

5 Pyran and Its Derivatives

5.1 Introduction

5.2 Application of Pyran Moieties in the Synthesis of Natural Products

5.3 Conclusion

6 Pyrrole and Its Derivatives

6.1 Introduction

6.2 Synthesis of Pyrrole Natural Products

6.3 Synthesis of Non-pyrrole Natural Products from Pyrrole Derivatives

6.4 Conclusion

Notes added in proofs

Acknowledgments

7 Indoles and Indolizidines

7.1 Introduction

7.2 Applications of Indoles and Indolizidines in the Synthesis of Natural Products

7.3 Conclusion

Acknowledgment

8 Pyridine and Its Derivatives

8.1 Introduction

8.2 Application of the Pyridine Moiety in the Synthesis of Natural Products

8.3 Conclusion

Acknowledgment

9 Quinolines and Isoquinolines

9.1 Introduction

9.2 Application of Quinolines and Isoquinolines in the Synthesis of Natural Products

9.3 Conclusion

10 Carbazoles and Acridines

10.1 Introduction to Carbazoles

10.2 Total Synthesis of Carbazole Alkaloids

10.3 Introduction to Acridines

10.4 Synthesis of Acridines and Acridones

11 Thiophene and Other Sulfur Heterocycles

11.1 Introduction

11.2 Synthesis of Natural Products Containing Thiophene

11.3 Synthesis of Natural Products Containing Other Sulfur Heterocycles

11.4 Conclusion

Acknowledgments

12 Oxazole and Its Derivatives

12.1 Introduction

12.2 Mono-Oxazoles

12.3 Unconnected Bis- and Tris-Oxazoles

12.4 Cyclic Polyheterocyclic Metabolites Containing Single Oxazole Residues

12.5 Conjugated Bis-Oxazoles

12.6 Tris- and Poly-Oxazoles

13 Thiazoline and Thiazole and Their Derivatives

13.1 Introduction

13.2 General Methods for the Synthesis of Thiazoline and Thiazole Derivatives

13.3 Thiazole and Thiazoline-Containing Natural Products

13.4 Conclusions

14 Pyrimidine and Imidazole

14.1 General Introduction

14.2 Pyrimidine-Based Natural Products

14.3 Imidazole-Based Natural Products

14.4 Conclusion

Acknowledgment

Part Three: Natural Products Containing Medium and Large Ring-Sized Heterocyclic Systems

15 Oxepines and Azepines

15.1 Introduction

15.2 Synthesis of the Heterocyclic Core of Selected Natural Products Containing Oxepines

15.3 Synthesis of the Heterocyclic Core of Selected Natural Products Containing Azepines

15.4 Synthesis of the Heterocyclic Core of Selected Natural Products Containing Oxazapines

15.5 Conclusion

Acknowledgments

16 Bioactive Macrocyclic Natural Products

16.1 General

16.2 Natural Products Containing Azoles

16.3 Pyridine- and Piperidine-Containing Natural Products

16.4 Indole- and Imidazole-Containing Natural Products

16.5 Pyran- and Furan-Containing Natural Products

16.6 Piperazic Acid-Containing Natural Products

16.7 Mixed Heterocyclic Systems

16.8 Conclusions

Index

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The Editors

Prof. Krishna C. Majumdar

University of Kalyani

Department of Chemistry

Kalyani, W.B. 741235

Indien

Prof. Shital K. Chattopadhyay

University of Kalyani

Department of Chemistry

Kalyani, W.B. 741235

Indien

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Preface

Heterocycles are significant because of their biological activity and their applications in diverse fields, reflected by the fact that heterocycles constitute more than half of known organic compounds. Heterocyclic moieties are ubiquitous in important classes of naturally occuring compounds, for example, alkaloids, vitamins, hormones, and antibiotics. They are also widely prevalent in pharmaceuticals, herbicides, dyes and many other application-oriented materials.

Many natural products possess heterocyclic moieties, and many of them are important in terms of their biological activities and application in different fields; for example, “taxol” isolated from the yew tree is an anticancer drug.

To the best of our knowledge, there is currently no comprehensive publication which deals with systematic survey of literature on the heterocycles for the synthesis of natural products in the form of a ready reference. The present book is an attempt to bridge this gap. Emphasis has been given to the current literature while including the earlier literature as references. Different heterocycles are classified according to their ring size under different sections and subsections. Sources, synthetic aspects, relevant biological activities and important physical properties and applications of the natural products are described. Unfortunately not all the important heterocycles, such as coumarins and flavones, could be included due to the restricted size of the book. However, available literature in these areas has already been adequately reviewed. This may be the subject of a future edition on the basis of the feedback of this edition received from the users.

We are grateful to our contributors for their valuable contributions which have made this project successful. We are also grateful to the members of our research groups for their untiring assistance during the course of this project. Finally we do hope that this will be a valuable secondary source book for the concerned readers.

K.C. Majumdar

S.K. Chattopadhyay

List of Contributors

Laura Alvarez

Universidad Autónoma del Estado de Morelos

Centro de Investigaciones Químicas

Avenida Universidad 1001

Col. Chamilpa 62209

Cuernavaca, Morelos

Mexico

Alicia Boto

Instituto de Productos Naturales y Agrobiología CSIC

Avda. Astrofisico Fco. Sánchez, 3

38206 La Laguna, Tenerife

Spain

Candice Botuha

IPCM – UPMC Univ Paris 6

Case Courrier 183

4 place Jussieu

75252 Paris Cedex 05

France

Sarah M. Bronner

University of California

Department of Chemistry and Biochemistry

607 Charles Young Drive East, Box 951569

Los Angeles, CA 90095-1569

USA

Fabrice Chemla

IPCM – UPMC Univ Paris 6

Case Courrier 183

4 place Jussieu

75252 Paris Cedex 05

France

Kongara Damodar

Indian Institute of Chemical Technology

Organic Chemistry Division-I

Uppal Road

Hyderabad 500007

India

Biswanath Das

Indian Institute of Chemical Technology

Organic Chemistry Division-I

Uppal Road

Hyderabad 500007

India

Bidyut Kumar Dinda

Indian Institute of Technology

Department of Chemistry

Kharagpur W.B. 721302

India

Franck Ferreira

IPCM – UPMC Univ Paris 6

Case Courrier 183

4 place Jussieu

75252 Paris Cedex 05

France

Neil K. Garg

University of California

Department of Chemistry and Biochemistry

607 Charles Young Drive East, Box 951569

Los Angeles, CA 90095-1569

USA

Antonio Garrido Montalban

Arena Pharmaceuticals, Inc.

6166 Nancy Ridge Drive

San Diego, CA 92121

USA

Konstanze K. Gruner

Technische Universität Dresden

Department Chemie

Bergstr. 66

01069 Dresden

Germany

G.-Yoon J. Im

University of California

Department of Chemistry and Biochemistry

607 Charles Young Drive East, Box 951569

Los Angeles, CA 90095-1569

USA

Paula Kiuru

University of Helsinki

Faculty of Pharmacy, Division of Pharmaceutical Chemistry

PO Box 56 (Viikinkaari 5 E)

FI-00014 Helsinki

Finland

David W. Knight

Cardiff University

School of Chemistry, Main College

Park Place

Cardiff CF10 3AT

UK

Hans-Joachim Knölker

Technische Universität Dresden

Department Chemie

Bergstr. 66

01069 Dresden

Germany

Vipan Kumar

Guru Nanak Dev University

Department of Applied Chemistry

Amritsar 143005

India

Mohinder P. Mahajan

Guru Nanak Dev University

Department of Applied Chemistry

Amritsar 143005

India

Krishna C. Majumdar

University of Kalyani

Department of Chemistry

Kalyani, W.B. 741235

India

Dipakranjan Mal

Indian Institute of Technology

Department of Chemistry

Kharagpur W.B. 721302

India

Hideto Miyabe

Hyogo University of Health Sciences

School of Pharmacy

Minatojima

Kobe 650-8530

Japan

Okiko Miyata

Kobe Pharmaceutical University

4-19-1 Motoyamakita, Higashinada

Kobe 658-8558

Japan

Siti Mariam Mohd Nor

Universiti Putra Malaysia

Department of Chemistry

Faculty of Science

43400 UPM Serdang

Selangor

Malaysia

Shovan Mondal

University of Kalyani

Department of Chemistry

Kalyani, W.B. 741235

India

Takeaki Naito

Kobe Pharmaceutical University

4-19-1 Motoyamakita, Higashinada

Kobe 658-8558

Japan

Willem A.L. van Otterlo

University of the Witwatersrand

Molecular Sciences Institute School of Chemistry

PO Wits

2050 Johannesburg

South Africa

Alejandro Pérez-Luna

IPCM – UPMC Univ Paris 6

Case Courrier 183

4 place Jussieu

75252 Paris Cedex 05

France

Darren L. Riley

University of the Witwatersrand

Molecular Sciences Institute School of Chemistry

PO Wits

2050 Johannesburg

South Africa

Tetsuya Sengoku

Shizuoka University

Department of Materials Science, Faculty of Engineering

3-5-1 Johoku

Naka-ku

Hamamatsu

Shizuoka 432-8561

Japan

Brateen Shome

Indian Institute of Technology

Department of Chemistry

Kharagpur W.B. 721302

India

Masaki Takahashi

Shizuoka University

Department of Materials Science, Faculty of Engineering

3-5-1 Johoku

Naka-ku

Hamamatsu

Shizuoka 432-8561

Japan

Zhengshuang Xu

Peking University Shenzhen Graduate School

School of Chemical Biology and Biotechnology

University Town of Shenzhen

Xili, Nanshan District

Shenzhen 518055

China

and

The Hong Kong Polytechnic University

Department of Applied Biology and Chemical Technology

Hung Hom, Kowloon, Hong Kong

China

Tao Ye

Peking University Shenzhen Graduate School

School of Chemical Biology and Biotechnology

University Town of Shenzhen

Xili, Nanshan District

Shenzhen 518055

China

and

The Hong Kong Polytechnic University

Department of Applied Biology and Chemical Technology

Hung Hom, Kowloon, Hong Kong

China

Jari Yli-Kauhaluoma

University of Helsinki

Faculty of Pharmacy, Division of Pharmaceutical Chemistry

PO Box 56 (Viikinkaari 5 E)

FI-00014 Helsinki

Finland

Hidemi Yoda

Shizuoka University

Department of Materials Science, Faculty of Engineering

3-5-1 Johoku

Naka-ku

Hamamatsu

Shizuoka 432-8561

Japan

Part One: Strained Heterocycles in the Synthesis of Natural Products

1

Aziridines in Natural Product Synthesis

Candice Botuha, Fabrice Chemla, Franck Ferreira and Alejandro Pérez-Luna

1.1 Introduction

The aziridinyl ring has attracted considerable attention over the last 20 years. A number of reviews dedicated to the synthesis of aziridines has appeared, dealing mainly with the preparation of this small heterocycle [1] and its reactions [2]. Very few have focused on natural product synthesis using aziridines.

This review is devoted to the occurrence of the aziridine moiety in the total synthesis of natural products (Table 1.1). Aziridines can be present in the natural product itself, or can serve as intermediates in the course of the natural product synthesis. Only the synthesis of truly natural products will be discussed here, and the synthesis of analogs or non-natural products will not be developed [3]. This review covers the literature from 1986, and follows the previous review [4] focused on aziridines in natural product synthesis.

Table 1.1 Aziridine-based natural products.

1.2 Synthesis of Natural Products Containing Aziridine Units

The ability of aziridines to undergo highly stereo- and regioselective ring-opening reactions has been exploited in nature. A number of natural products possessing an aziridine ring have been shown to possess potent biological activity, which is closely associated with the reactivity of the strained heterocycle.

1.2.1 Synthesis of Aziridine-2,3-Dicarboxylic Acid

Among natural products containing aziridines, C2-symmetric aziridine-2,3-dicarboxylic acid 4, a metabolite of Streptomyces MD 398-A1 [5a] was prepared in enantiopure form in few steps from L-(+)-diethyl tartrate [5b]. An optimized synthetic pathway to aziridine-2,3-dicarboxylate precursor 3 of naturally- occurring aziridine 4 was published later, removing the epimerization tendency of synthetic intermediates by using anti-3-azido-2-hydroxy-succinate 2 (Scheme 1.1) [6].

Scheme 1.1 Aziridine-2,3-carboxylic acid.

1.2.2 Synthesis of (Z)-Dysidazirine

While the first enantioselective synthesis of antifungal active (Z)-dysidazirine 7 isolated from the marine sponge Dysidea fragilis [7a] was achieved by a Darzens-type synthesis of cis-N-sulfinylaziridine carboxylic acid [7b], a very recent synthesis includes the transformation of tosylated imine 5 into azirine carboxylate 6 as a key step (Scheme 1.2) [8].

Scheme 1.2 (Z)-Dysidazirine.

1.2.3 Syntheses of Mitomycins

In the field of total synthesis of natural products containing an aziridine ring, most efforts of synthetic organic chemists have been dedicated to mitomycins, a class of very potent antibacterial and anticancer compounds isolated [17] from extracts of genus Streptomyces, a filamentous gram-positive soil bacterium. The most abundant mitomycins in nature are represented in Scheme 1.3. Mitomycin C [17a], besides mitomycin A [17b] and K [17c], has become the most effective drug of the series against non-small-cell lung carcinoma and other soft and solid tumors [23]. Despite significant medicinal features, syntheses of this class of compounds (furthermore in racemic form) have been reported only four times over the past 30 years [24].

Scheme 1.3 General mitomycins.

Since the first synthesis of a mitomycin by Kishi [18], only few organic chemists have succeeded to achieve a total synthesis of a mitomycin since serious difficulties occurred during the construction of both reactive quinone and aziridine rings with the elimination of methanol from the 9a position (Scheme 1.3). Mitomycins A and C were successfully synthesized by Fukuyama and co-workers in 18 steps from a readily available chalcone [19]. An intramolecular azide-olefin cycloaddition on 8 gave exclusively tetracyclic aziridine 9. Isomitomycin intermediate 10 was then obtained in few steps providing mitomycin A by a subsequent reaction with Al(i-OPr)3. A final ammonolysis step gave mitomycin C (Scheme 1.4).

Scheme 1.4 Mitomycin A and C.

Subsequent improvement for the total synthesis of mitomycin C was reported later by the same authors using highly reactive bridgehead iminium species in the key steps [20]. The required C-9a methoxy group was introduced under mild acidic conditions to give 13 in 60% yield via highly strained iminium ion 12 which was obtained from compound 11 through acidic treatment. Transformation of the aromatic ring of 13 using hydrogenolysis followed by oxidation with DDQ afforded the desired quinone ring of isomitomycin A in 77% yield. Isomitomycin A was then converted to (±)-mitomycin C via isomitomycin C 15 in 85% yield by treatment with NH3 in methanol (Scheme 1.5).

Scheme 1.5 Mitomycin C.

Danishefsky and colleagues have designed a short total synthesis of the densely functionalized mitomycin K from parent mitomycins A and C by elimination of the carbamate at position 10 [21]. Introduction of N-methyl aziridine from an olefin was achieved in only 3 steps by 1,3-dipolar cycloaddition. Reaction of methylthiophenyl azide with imide 16 provided triazoline 17 which was then transformed to 18 in two steps. N-methylaziridine 19, an advanced intermediate to mitomycin K, was obtained by irradiation at 254 nm (Scheme 1.6).

Scheme 1.6 Mitomycin K.

A facile method was set up for the transformation of azidomitosenes 20 into mitomycins (introduction of the C9a methoxy group) by using an oxidation reaction of the C9-9a double bond with MoO5·hexamethylphosphoramide (HMPA). Specifically, oxidation of 20 afforded in 46% 21 from which the fused N-methylaziridine ring could be constructed. 22 led to the mitomycin K in two steps. (Scheme 1.7) [22].

Scheme 1.7 Mitomycin K.

1.2.4 Syntheses of FR-900482 and FR-66979

Antitumor antibiotic natural products FR-900482 and FR-66979 (Scheme 1.8) isolated from Streptomyces sandaensis [9] are structurally related to mitomycin C and possess similar biological activities. They have proven to be less toxic than mitomycins in clinical cancer chemotherapeutics. In addition of the biomedical potential, the uncommon structure and the synthetic problem related to the construction of both aziridine ring and the hemiacetal functionality of FR-900482 and FR-66979 have attracted the attention of a number of synthetic chemists. Although several approaches have been explored to construct these highly functionalized structures, only six total syntheses have been accomplished and two formal syntheses [10, 25] have been reported to date.

Scheme 1.8 FR-66979 and FR-900482.

The first total synthesis of (±)-FR-900482 was realized in 41 steps from readily available N-benzylamine [11]. In this strategy, the authors introduced the aziridine ring at the end of the synthesis to prevent any lability of the three-membered ring under acidic condition. Azide 24 was prepared by ring opening of epoxide 23 with NaN3 followed by the transformation of the resulting alcohol to a mesylate. Upon oxidative treatment of 24 to exchange the PMB-protecting group on the aromatic ring for a dimethyl acetal, reduction of azide 25 by PPh3 in the presence of a base furnished aziridine 26 which was then advanced to the target compound (Scheme 1.9). An enantioselective total synthesis of (+)-FR-900482 was reported later on by the same group with a slight modification of the initial route [12].

Scheme 1.9 (±)-FR-900482.

Danishefsky reported a total synthesis of racemic FR-900482 [13] in which the installation of the 9,10-aziridine ring was carried out following the precepts founded by Kishi and colleagues in their synthesis of mitomycins [26]. Compound 27 was treated in sequence with Tf2O and pyridine, PPh3, NH4OH and finally methylchloroformate to furnish aziridine 28 in 72% overall yield (Scheme 1.10).

Scheme 1.10 (±)-FR-900482.

Naturally occurring FR-66979 has been synthesized in racemic form with a method comprising an original homo-Brook-mediated aziridine fragmentation of compound 30 providing the eight-membered ring benzazocenol 31. The aziridine ring and the end of the total synthesis [16] were achieved subsequently from epoxide 32 following a described procedure (Scheme 1.11) [11].

Scheme 1.11 (±)-FR-66979.

The first enantioselective synthesis of the enantiomer of FR-900482 was developed by Terashima [27] starting from FK-973 [10], the more stable semisynthetic triacetyl derivatives of FR-900482. In the same time, a second total synthesis of both enantiomers was accomplished in a convergent manner in a 57 steps sequence using classical methods for the introduction of the aziridine ring [14].

Shorter enantioselective total syntheses of (+)-FR-900482 and (+)-FR-66979 were reported by Williams and co-workers and described the installation of the labile aziridine ring in the very beginning of the synthesis. In this purpose, aziridine 35 was prepared in 7 steps from compounds 33 and 34 (Scheme 1.12) [15].

Scheme 1.12 (+)-FR-900482.

1.3 Synthesis of Natural Products Involving the Transformation of an Aziridine Moiety

1.3.1 Nucleophilic Ring-Opening of Aziridines for Natural Product Synthesis

The usefulness of aziridines in organic synthesis is greatly related to their facility to undergo nucleophilic ring opening to relieve ring strain. In the case of “unactivated” alkyl-substituted or unsubstituted aziridines, acid catalysis is usually required. Conversely, it is well known that aziridines bearing nitrogen electron-withdrawing substituents such as carbonyl, sulfonyl, sulfinyl, phosphoryl, and phosphinyl are activated towards nucleophilic ring opening as the developing negative charge on nitrogen is stabilized. A wide array of nucleophiles can be used and in most cases, the regio- and stereoselectivity of the ring opening is predictable, a matter of paramount relevance when it comes to design a synthetic plan. While selectivity issues are highly dependent on the substrate and the reaction conditions, steric congestion is often at the origin of regioselectivity (nucleophilic attack occurring at the less congested terminus) and stereoselectivity is frequently related to a ring opening resulting from an anti attack (stereospecific SN2). A tremendous body of work has been disclosed in the field and the subject has been comprehensively reviewed. The use of nucleophilic ring opening of aziridines in the context of natural product synthesis, illustrated hereafter through representative examples, provides a good indication of the reaction’s synthetic potential.

1.3.1.1 Carbon-Centered Nucleophiles

Nucleophilic ring opening of aziridines with carbon nucleophiles is mainly achieved using organometallic reagents. In spite of an early report in the 1970s [28], this type of reaction only started to become customary in natural product synthesis following seminal reports in the late 1980s concerning the use of organocuprate or Grignard reagents to open N-alkyl aziridines in the presence of BF3 Et2O [29] or to open N-tosyl aziridines (with no need of Lewis acidic activation) [30].

Ring opening of aziridines with organocopper reagents has proved useful for a number of syntheses. In a first example, as part of their studies on the synthesis of carbapenem antibiotics using aziridine ring openings [2a], Tanner and co-workers developed an enantioselective entry to naturally occurring (+)-PS-5 (Scheme 1.13) [31]. Reaction of LiEt2Cu with chiral trans-2,3-aziridino alcohol 36 afforded in 70% yield sulfonamido alcohol 37 which proved suitable for β-lactam ring construction and was advanced to a known intermediate of (+)-PS-5. As a result of the complexation of the reagent to the free C-1 hydroxyl group, nucleophilic attack occurred highly regioselectively at the C-2 carbon, in a behavior analogous to that of related epoxy alcohols. Ring opening took place with inversion of configuration and thus provided the requisite stereochemistry for the stereogenic centers of the final product. Interestingly, the related ring opening of the analogous 3-benzyloxyethyl substituted aziridino alcohol using excess Me3Al took place at the C-3 carbon [32], a transformation that proved useful for the preparation of non-natural 1β-methylcarbapenem antibiotics [33].

Scheme 1.13 (+)-PS-5.

In addition to cuprates, addition of Grignards has also been often used, most of the time under copper catalysis. For instance, Harrity and co-workers disclosed a formal synthesis of (−)-dihydropinidine wherein the tetrahydropyridine ring was constructed through a two-step [3 + 3] annelation sequence involving the reaction between alkylmagnesium reagents such as 38 bearing a pendant 1,3-dioxolane moiety and terminal N-sulfonyl aziridines (Scheme 1.14) [34]. Specifically, 38 was reacted with aziridine 39 in the presence of 20 mol % CuBr to afford intermediate 40, which, upon acidic hydrolysis without intermediate purification, led to piperidine 41 in 78% overall yield.

Scheme 1.14 (–)-Dihydropinidine.

In a related [3 + 3] annelation strategy, the allylmagnesium reagent obtained following deprotonation/transmetallation of methallyl alcohol was found to react with terminal N-sulfonyl aziridines, but this time with no need of copper salt addition (Scheme 1.15). The resulting 1,5-aminoalcohol could undergo ring closure to piperidines using palladium catalysis or Mitsunobu conditions, thus affording 2-alkylpiperidines with an exo methylene moiety at C-5, in what represents an improved approach to the related [3 + 3] cycloaddition reaction between aziridines and palladium-trimethylenemethane (Pd-TMM) species (see Section 1.3.2.4). In its application to synthesis, nucleophilic ring opening of enantiopure aziridine 42 and subsequent cyclization led to piperidine 43 that could be advanced to nuphar alkaloids (−)-deoxynupharidine, (−)-castoramine and (−)-nupharolutine [35, 36]. The same approach has also been used for the construction of the spiropiperidine motif in the formal synthesis of (±)-perhydrohistrionicotoxin [37].

Scheme 1.15 Nuphar alkaloids.

Copper-bromide promoted coupling of arylmagnesium derivatives with terminal enantiopure N-butoxycarbonyl (N-Boc) aziridines is pivotal in the design of a very recent approach to renieramycin alkaloids based on the use of aziridines derived from (S)-serine as linchpins to bring together both tetrahydroisoquinoline parts of the target molecules (Scheme 1.16) [38]. First, homologation of densely substituted arylmagnesium 44 was effected by nucleophilic ring opening of enantiopure terminal N-Boc aziridine 45. Intermediate 46 was then further elaborated through a Pictet–Spengler reaction involving aziridine 47. The right and left part of the molecules were connected through a second copper -promoted coupling between 48 and arylgrignard 49 which afforded 50, reaction of which with benzyloxyacetaldehyde led to a bistetrahydroisoquinoline common intermediate to (−)-renieramycins M and G and (−)-jorumycin, three alkaloids with potent antitumor antibiotic activities.

Scheme 1.16 Renieramycins.

Interestingly, copper-catalyzed nucleophilic ring opening of N-alkyl 2-methyleneaziridines by Grignard reagents does not require Lewis-acidic activation of the heterocycle if carried out at room temperature (Scheme 1.17). It results in the highly regioselectivity formation of a metalloenamine that can then be alkylated in the presence of electrophiles. Building on this chemistry, a concise synthesis of the hemlock alkaloid (S)-coniine was achieved from enantiopure methyleneaziridine 51 using a multicomponent strategy involving: ring opening, alkylation of the resulting metalloenamine 52 with a 1,3-difunctionalized electrophile, and diastereoselective reduction followed by in situ cyclization [39].

Scheme 1.17 (S)-Coniine.

In addition to organocopper and organomagnesium reagents, ring opening of aziridines by lithium carbanions has also been used for synthetic purposes. The reaction between α-(phenylsulfonyl) lithio anions and N-phosphinyl or N-sulfonyl aziridines plays a key role in the strategy developed by Craig and co-workers for the synthesis of pyrrolidine-containing alkaloids (+)-monomorine I [40], (+)-preussin [41] and (±)-lepadiformine [42], built around the base-mediated 5-endo-trig intramolecular addition of amides onto vinylic sulfones. The case of (±)-lepadiformine is illustrative (Scheme 1.18). Ring opening at the least-substituted carbon of N-SES aziridine 53 by PhSO2CH2Li led to 3-amino sulfone 54. In situ generation of the requisite vinylic sulfone from this precursor enabled pyrrolidine formation following 5-endo-trig cyclization and afforded 55 that was advanced to the target compound.

Scheme 1.18 (±)-Lepadiformine.

Smith III and Kim have designed a very elegant strategy for the construction of indolizidine alkaloids using a three-component linchpin coupling involving a lithiated silyl dithiane, an epoxide and a N-tosyl aziridine (Scheme 1.19) [43, 44]. Nucleophilic ring opening of 5-alkoxy epoxides 56 by the lithio anion 57 of 1,3-dithiane resulted in the formation of a lithium alcoholate intermediate that underwent a solvent-controlled Brook rearrangement upon addition of HMPA. The lithiated dithiane derivative thus produced, could then be used to effect the nucleophilic ring opening of N-tosyl aziridines 58, to afford, in fine, stereodefined 1,5-amino alcohols 59 that are suitable for indolizidine construction. This convergent approach has already proved successful for the preparation of (−)-indolizidine 223AB from enantiopure epoxide 60 and aziridine 61, and for the preparation of alkaloid (−)-205B from enantiopure epoxide 62 and aziridine 63.

Scheme 1.19 (–)-Indolizidine 223AB and alkaloid (–)-205B.

Ring opening of aziridines with carbon nucleophiles other than carbanions, though less common, has also proved useful for the synthesis of natural products. In an early example, Baldwin and co-workers disclosed an access to γ-alkylidene glutamates based on the reaction of carbonyl stabilized Wittig reagent 64 with enantiopure N-acyl and N-sulfonyl aziridine-2-carboxylates derived from serine (Scheme 1.20) [45]. For instance, the enantiopure ylide resulting from ring opening of aziridine 65 at the less-substituted carbon was further modified to provide 4-methylene (2S)-glutamic acid and Z-4-ethylene (2S)-glutamic acid.

Scheme 1.20 Alkylideneglutamic acids.

Nakagawa and co-workers disclosed a concise approach to Calabar alkaloids based on the nucleophilic ring opening of N-benzyloxy-aziridine by 1,3-dimethylindole and subsequent intramolecular interception by nitrogen of the resulting indolenium (Scheme 1.21) [46]. In the optimized conditions involving activation of the aziridine by Sc(OTf)3 in the presence of trimethylsilyl chloride (TMSCl), adduct 66 was obtained in 90% yield. This intermediate could be advanced to (±)-desoxyeseroline, a known intermediate of naturally occurring physostigmine.

Scheme 1.21 (±)-Physostigmine.

Potassium cyanide was recently used efficiently for the ring opening of monosubstituted allylglycine derived N-sulfonyl aziridine 67 (used as mixture of diastereoisomers) (Scheme 1.22) [47]. The resulting β-aminonitrile moiety of adduct 68 could then be used for the construction of the 2-amino-tetrahydropyrimidine ring required to complete the synthesis of tetrahydrolathyrine.

Scheme 1.22 Tetrahydrolathyrine.

1.3.1.2 Nitrogen-Centered Nucleophiles

Ring opening of aziridines with nitrogen nucleophiles, mainly amines and azides, has attracted considerable attention from organic chemists as a result of the increasing interest in diamine compounds for synthetic and pharmaceutical purposes. Quite surprisingly however, its use for the synthesis of natural products has so far been limited. As probable reasons, one might put forward both a limited number of targets bearing the diamino moiety and the fact that amines are generally not inert to mainstream Lewis or Brønsted acidic aziridine ring opening promoters. Nonetheless, specially in the field of amino acid synthesis using aziridine-2-carboxylates as substrates, some elegant applications have been disclosed.

Amines are sufficiently nucleophilic to attack aziridines without the presence of a promoter. Shiba and co-workers took advantage of it to perform the ring opening of enantiopure trans-N-tosyl aziridine-2-carboxylate 69 with ammonia (Scheme 1.23) [48]. The attack took place regioselectively at C-3 in an SN2 manner and thus afforded diamine 70 in 52% yield which was then converted into the hydrobromide salt of naturally occurring L-epicapreomycidin.

Scheme 1.23 L-epi-Capreomycidin.

The reaction between amino acid carboxylates and N-tosyl aziridine-2- carboxylates has been used for the preparation of peptidyl derivatives (Scheme 1.24). In spite of moderate levels of regioselectivity, ring opening in methanol of aziridines 71 and 72 by nucleophilic attack of L-histidine at C-3 in the presence of 1M sodium hydroxide, was used for the preparation of FR900490 [49], feldamycin [50] (from 71) and melanostatin [50] (from 72).

Scheme 1.24 FR-900490, feldamycin and melanostatin.

In another related example, sodium pipecolinate was found to react highly efficiently with monosubstituted enantiopure N-tosyl aziridine 73 (Scheme 1.25). The corresponding piperidine adduct was obtained in 88% yield and was used to prepare verruculotoxin [51].

Scheme 1.25 Verruculotoxin.

Other nucleophiles that have been used for the opening of aziridines without promoter are imidazole and 1,2,4-oxadiazolidine-3,5-dione (Scheme 1.26). Their reaction with (S)-serine derived enantiopure aziridine 74, which has also proved useful in the context of ring opening with carbon nucleophiles (see Section 1.3.1.1), was carried out by Baldwin and co-workers to synthesize (S)-β-pyrazolylalanine and (S)-quiscalic acid [52].

Scheme 1.26 (S)-β-Pyrazolylalanine.

From another perspective, as part of their studies on palladium-catalyzed dynamic kinetic asymmetric transformations, Trost and co-workers have developed a strategy towards pyrrolopiperazinones based on an annulation reaction between 5-bromopyrrole-2-carboxylate esters and vinyl aziridines (for a related cycloaddition reaction between vinyl aziridines and isocyanates see Section 1.3.2.4) (Scheme 1.27) [53]. In this transformation, following an asymmetric allylic alkylation step wherein the nitrogen of the pyrrole behaves as a good nucleophile for the regioselective ring opening of the aziridine, the pendant ester group serves as electrophile for lactam formation. Specifically, enantioselective palladium-catalyzed annulation of racemic 75 and 76 provided pyrrolopiperazinone 77 in 72% yield and 95% enantiomeric excess. 77 was then found to be a suitable intermediate for the synthesis of pyrrole alkaloids longamide B (and thus longamide B methyl ester, hanishin and cyclooroidin) and agesamides A and B.

Scheme 1.27 Longamides and agesamides.

Finally, as illustrated in the synthesis of (−)-agelastatin A disclosed by Yoshimitsu, Ino and Tanaka, azides are also efficient nucleophiles to perform the ring opening of aziridines (Scheme 1.28) [54]. In the present example, unlike basic nitrogen nucleophiles such as ammonia and benzylamine that led to exclusive addition to the oxazolidinone core of 78, sodium azide attacked the aziridine ring selectively to produce the azidated product 79 following cleavage of the weak outer bond of the tricyclic system.

Scheme 1.28 (–)-Agelastatin A.

1.3.1.3 Oxygen-Centered Nucleophiles

Nucleophilic ring opening of aziridines with oxygen nucleophiles provides direct access to amino alcohol units that are ubiquitous in nature. In general, aziridines, that show a lower reactivity towards this type of nucleophiles than structurally related epoxides, require activation of the nitrogen atom to undergo ring opening either by attachment of an electron-withdrawing group or by Brønsted or Lewis acids.

Ring opening using water as nucleophile leads directly to hydroxy amine derivatives and was promoted by strong organic Brønsted acids such as p-toluenesulfonic acid (TsOH) and trifluoroacetic acid (TFA). Tanner and co-workers used this strategy in their synthesis of (−)-balanol (Scheme 1.29) [55–57], wherein treatment of enantiomerically pure N-acyl aziridine 80 with water in the presence of TsOH resulted in the near-exclusive ring opening at C-4 and led in 71% yield to amino alcohol 81 that was advanced to the natural product. The remarkable regioselectivity of the opening seemed to be related to both conformational and electronic effects of the fused bicyclic aziridine as it proved general for other nucleophiles and for ring opening of the analogous epoxide.

Scheme 1.29 (–)-Balanol.

Olofsson and Somfai used a TFA-mediated ring opening of a vinyl aziridine by water to synthesize D-erythro-sphingosine in enantiomerically pure form (Scheme 1.30) [58]. Specifically, crude unprotected aziridine 82 prepared from the parent vinylic 1,2-amino alcohol by Mitsunobu ring closure afforded regio- and stereoselectively anti amino alcohol 83 in 62% yield.

Scheme 1.30 D-erythro-Sphingosine.

In the same vein, Trost and Dong performed the regio- and stereoselective hydrolytic ring opening of enantiopure fused bicyclic tosyl aziridine 84 on route to the non-natural (+) enantiomer of agelastatin A (Scheme 1.31) [59, 60]1). Of the several conditions examined (CAN or BF3 Et2O in aqueous acetonitrile, variable amounts of TFA in aqueous acetone or dioxane at different temperatures), only treatment with TFA in dioxane/water under microwave heating (150 °C) gave high (84%) reproducible results. Interestingly, as the synthetic plan required oxidation of the hydroxy amine to the corresponding α-amino ketone, direct oxidative ring opening was also developed. Reaction of 84 in DMSO in the presence of 0.7 equiv In(OTf)3 led directly to 85 in 91% yield through a mechanism believed to involve attack of DMSO to the In(III) activated aziridine.

Scheme 1.31 (+)-Agelastatin A.

Nucleophilic ring opening of aziridines using carboxylate anions is rather common in the context of total synthesis. Very popular is the opening of aziridines containing 2-carboxylate or 2-carboxamide functionalities as it generally occurs regioselectively at C-3 and affords α-amino acid derivatives. Carboxylic acids themselves can operate this reaction in neutral conditions. For instance, Okawa and co-workers disclosed a total synthesis of cyclic peptide actinomycin D wherein ester bond formation between two dipeptide fragments was achieved in 45–55% yield through nucleophilic ring opening of 2-carboxamide-N-acyl aziridine 86 by the acid moiety of dipeptide 87 (Scheme 1.32) [61].

Scheme 1.32 Actinomycin D.

Alternatively, Cardillo and co-workers operated the ring opening of a similar aziridine in milder conditions using acetic anhydride in the presence of pyridine (Scheme 1.33) [62].

Scheme 1.33 L-allo-Threonine.

A nice illustration of the synthetic complementarity between opening by carboxylate and hydrolytic ring opening of N-benzyl aziridine-2-carboxylates can be found in the work of Ishikawa and co-workers (Scheme 1.34) [63]. Treatment of enantiopure cis-aziridine 88 with TsOH in the presence of water led in excellent regio- and stereoselectivity to hydroxy amine 89 that was then used to prepare a known intermediate of (+)-lactacystin. However, when a similar approach was projected to access D-erythro-sphingosine, ring opening under analogous conditions of cis- or trans-aziridines 90 and 91 occurred with lower regioselectivity, a result that also contrasts with the opening of 82 in Somfai’s approach (see above Scheme 1.30). Conversely, reaction with acetic acid was completely regio- and stereoselective and afforded acetoxy amines 92 and 93 that were used to reach the desired target.

Scheme 1.34 (+)-Lactacystin and D-erythro-sphingosine.

Interestingly, Loncaric and Wulff evidenced that in the case of N-benzhydryl aziridine-2-carboxylate 94, treatment with excess carboxylic acid resulted not only in ring opening at the benzylic position, but also in the subsequent in situ deprotection and acetyl transfer (Scheme 1.35). This sequence was elegantly exploited to prepare (−)-chloramphenicol enantioselectively [64].

Scheme 1.35 (–)-Chloramphenicol.

A similar mechanism might be operating in the ring opening of unprotected aziridine 95 to afford erythro-sphingosine N-acetate 96 following treatment in refluxing benzene first with HCl and then with amberlyst A 26 in the acetate form (Scheme 1.36) [65].

Scheme 1.36 D-erythro-Sphingosine triacetate.

Worthy of note, in addition to the above mentioned examples starting form aziridine-2-carboxylates, some examples of nucleophilic ring opening by acetates of fused bicyclic vinyl aziridines have been disclosed. In an approach to potent trehalase inhibitor (±)-trehazoline, Mariano and co-workers used acetic acid to achieve the ring opening of bicyclic N-MEM aziridine 97 obtained by photocyclization of 1-MEM-3-pivaloylmethylpyridinium perchlorate (Scheme 1.37) [66]. The use of a chiral inductor for the aziridination instead of the MEM group provided an enantiodivergent formal synthesis of the natural (+) and unnatural (−) enantiomers.

Scheme 1.37 (±)-Trehazolamine.

Similarly, in order to determine the optical rotation of a well established intermediate to (−)-balanol with absolute optical purity, Hudlicky and Sullivan carried out the ring opening of bicyclic N-acetyl vinyl aziridine 98 with acetic acid in the presence of trimethylsilyl triflate (TMSOTf) (Scheme 1.38) [67]. While nucleophilic attack of the acetate occurred unsurprisingly at the allylic position, only moderate levels of diastereoselectivity were achieved.

Scheme 1.38 (–)-Balanol.

The use of nucleophilic ring opening of aziridines with alcohols for the synthesis of natural products has been rather limited so far. As previously, activation by Brønsted or Lewis acids is generally required. In an example of the first type, opening of N-acyl aziridine 99 by methanol promoted by sulfuric acid was found to be highly regio- and stereoselective, presumably as a result of conformational constraints of the bicyclic structure (Scheme 1.39) [68]. The resulting amino ether was used for the synthesis of E ring monosaccharide unit of calicheamicin γ1I. In an example of the second type, Lewis-acidic activation with BF3.Et2O was used to promote the addition of allyl alcohol to a 2,3-aziridino-γ-lactone in the synthesis of the non-natural enantiomer of polyoxamic acid [69].

Scheme 1.39 Calicheamicin.

From a different angle, Jouillé and co-workers have developed a highly convergent route to ustiloxins through the copper-catalyzed ethynyl aziridine ring opening by phenol derivatives (Scheme 1.40) [70, 71]. In a representative application to the synthesis of cyclopeptide ustiloxins D and F, 2-carboxamide-aziridine 100 was coupled regio- and stereoselectively with β-hydroxy tyrosine derivative 101 in 90% yield.

Scheme 1.40 Ustiloxins.

Remarkably, clean regio- and stereoselective nucleophilic ring opening of enantiopure 2-carboxylate-N-nosyl aziridine 102 by methanol, useful to synthesize β-methoxytyrosine, could be carried out with no activation, probably due to the fact that the electron-rich phenol moiety weakens the C–N benzylic bond (Scheme 1.41) [72]. As a matter of fact, in the presence of TFA or copper salts, the diastereoselectivity of the reaction was moderate, as ring opening seemed to be occurring both via SN1 and SN2 mechanisms.

Scheme 1.41 β-Methoxytyrosine.

In a last example involving this time nucleophilic ring opening in basic conditions, aziridino alcohol 103 led to the regio- and stereoselective formation of the known intermediate of bestatin 104, upon treatment with formaldehyde in the presence of cesium carbonate via internal attack of the hydroxide anion of the hemiacetal formed in situ (Scheme 1.42) [73].

Scheme 1.42 Bestatin.

1.3.1.4 Halogen Nucleophiles

Ring opening of aziridines by halogen nucleophiles has been used only very recently for the purpose of natural product synthesis. Hydrogen bromide has been extensively used in the ring opening of aziridines to generate vicinal bromo amines. In the context of the synthesis of (+)-bromoxone, Maycock and co-workers described the use of 0.1 M HBr in MeOH to open selectively without any activation on the aziridine nitrogen N-PMB-aziridine 105 in the presence of an epoxide. The strategy was successfully applied to install the vinyl bromide moiety of the naturally occurring (+)-bromoxone (Scheme 1.43) [74].

Scheme 1.43 (+)-Bromoxone.

Ring opening of aziridine 106 with tetraethylammonium chloride and TFA afforded with inversion and a total regio- and stereoselectivity the desired tetrahydroquinoline core of the virantmycin (Scheme 1.44) [75].

Scheme 1.44 Virantmycin.

In the total synthesis of chlorodysinosin A, Hanessian and co-workers used cerium (III) chloride, an inexpensive and non-toxic inorganic salt to promote selective ring opening of N-Bus aziridine 107 to form the corresponding 3-chloro sulfonamide 108 with an excellent regioselectivity (Scheme 1.45) [76].

Scheme 1.45 Chlorodysinosin A.

1.3.1.5 Reductions

Reductive ring opening of aziridines can be highly regioselective by using catalytic hydrogenation. A very selective C–N bond cleavage was achieved on aziridine 109 using palladium on charcoal to produce carbamate protected L-ristosamine derivative 110, a useful synthon which after carbamate deprotection afforded L-ristosamine methyl glycoside, a 2,3,6-trideoxy-3-amino-hexopyranose member of 2,6-dideoxy sugars. A similar series of transformation successfully afforded L-daunosamine methyl glycoside (Scheme 1.46) [77].

Scheme 1.46 L-Ristosamine.

1.3.2 Cycloaddition Reactions and Rearrangements

Aziridines have been used as partners in various cycloaddition reactions in order to obtain cyclic adducts. Intramolecular [3 + 2] cycloadditions of aziridines with olefinic moieties have been reported, as well as the [2,3]-Wittig rearrangement of vinylaziridines.

1.3.2.1 Aziridines in [3 + 2] Cycloadditions

Aziridinyl esters are known to be precursors of azomethine ylides [78] and to react with olefinic moieties in a [3 + 2] cycloaddition reaction. This key step was used by Takano and co-workers in the total synthesis of acromelic acid A (Scheme 1.47) [79]. Aziridine 111 reacted under thermal conditions to form the corresponding pyrrolidinyl cycloadduct stereoselectively, an advance intermediate to acromelic acid A.

Scheme 1.47 Acromelic acid A.

The same key step has also been used [80] by the same authors in a total synthesis of (−)-kainic acid, as depicted in Scheme 1.48. This key step has also been used in a synthesis of the unnatural N-demethyl mesembrine [81].

Scheme 1.48 (–)-Kainic acid.

Related to these [3 + 2] cycloaddition reactions, the thermal rearrangement of vinylaziridines such as 112 bearing an electron-withdrawing group (prepared through triazene pyrolysis) into pyrrolines was used by Hudlicky and co-workers in a formal synthesis of various pyrrolizidinyl heterocycles such as (±)-supinidine, (±)-isoretronecanol and (±)-trachelantamidine (Scheme 1.49) [82].

Scheme 1.49 (±)-Supinidine, (±)-isoretronecanol and (±)-trachelantamidine.

The same key step was applied by the same authors to the preparation of bicyclic compound 113, which is an advanced intermediate in the synthesis of (±)-retronecine and (±)-heliotridine, as well as (±)-platynecine, (±)-hastanecine, (±)-turneforcidine and (±)-dihydroxyheliotridane (Scheme 1.50) [83].

Scheme 1.50 Retronecine.

1.3.2.2 Aziridines in [2,3]-Wittig Rearrangements

The utility of the [2,3]-Wittig rearrangement of vinyl aziridines [84] in natural product synthesis was largely demonstrated by Somfai and co-workers. For example, an enantioselective total synthesis of indolizidine 209D was achieved using the [2,3]-Wittig rearrangement of the enolate derived from aziridine 114 (Scheme 1.51) as a key step [85, 86].

Scheme 1.51 Indolizidine 209D.

The same key step was applied to the total synthesis of the indolizidine 209B. In this case, the [2,3]-Wittig rearrangement of the enolate derived from the substituted vinylaziridine 115 was used (Scheme 1.52) [86].

Scheme 1.52 Indolizidine 209B.

The total synthesis of racemic monomorine and indolizidine 195B have also been achieved using the [2,3]-Wittig rearrangement of vinyl aziridine 116 by the same authors (Scheme 1.53) [87].

Scheme 1.53 (±)-Monomorine and (±)-indolizidine 195B.

1.3.2.3 Aziridines in Iodide-Mediated Rearrangements

Another way to realize the rearrangement of vinyl aziridines into pyrrolines is the SN2’ ring opening of vinyl aziridines with iodide ion followed by ring closure. This methodology was early recognized by Hudlicky and co-workers as an efficient way to achieve the synthesis of pyrrolizidinyl alkaloids (Scheme 1.54) [82, 88]. The SN2’ ring opening of aziridine 117 afforded the iodo compound 118 which gave the bicyclic compound 119 upon ring closure.

Scheme 1.54 (±)-Supinidine.

A similar reaction was later applied by Somfai in a formal synthesis of (−)-anisomycin (Scheme 1.55) [89].

Scheme 1.55 (–)-Anisomycin.

1.3.2.4 Aziridines in Miscellaneous Rearrangements

The Lewis acid-mediated rearrangement of N-acyl aziridines into oxazolidin-2-ones was used in a straightforward synthesis of threo phenylserine (Scheme 1.56) [90]. Interestingly this rearrangement was shown to occur with retention of the configuration. By contrast, the same rearrangement, when applied to N-acyl aziridines, leads to the oxazoline formation (and not the oxazolidinone). This was applied to the total synthesis of (non-natural) Bn-protected (L)-threo sphingosine [58].

Scheme 1.56threo-Phenylserine.

The stereoselective Lewis acid-catalyzed rearrangement of aziridinyl alcohols 120 and 121 into β-amino aldehydes was applied in a total synthesis of (±)-crinane and (±)-mesembrine (Scheme 1.57) [91].

Scheme 1.57 (±)-Crinane and (±)-mesembrine.

Vinylaziridines have been reported to undergo carbon monoxide insertion under palladium (0) catalysis. This method allowed the formation of β-lactams and was applied by Tanner and Somfai for the total synthesis of the carbapenem (+)-PS-5 (Scheme 1.58) [92].

Scheme 1.58 (+)-PS-5.

The insertion of isocyanates can also been achieved under palladium (0) catalysis, leading to imidazolidin-2-ones. This strategy was used by Trost and co-workers in the total synthesis of (+)-pseudodistomin D (Scheme 1.59) [93]. The insertion occurred enantioselectively in the presence of chiral ligand 122 to afford enantioenriched imidazolidin-2-one 123.

Scheme 1.59 (+)-Pseudodistomin D.

(−)-Pseudoconhydrin was prepared by Harrity and co-workers through a [3 + 3] cycloaddition strategy involving the aziridine 124 and a palladium-trimethylenemethane complex (Scheme 1.60) [94].

Scheme 1.60 (–)-Pseudoconhydrin.

A formal synthesis of (±)-perhydrohistrionicotoxin has been reported through an interesting carbenoid rearrangement of a lithiated aziridine prepared by deprotonation of 125, insertion of the resulting carbenoid into BuLi and subsequent β-elimination (Scheme 1.61) [95].

Scheme 1.61 (±)-Perhydrohistrionicotoxin.

An elegant synthesis of α-cedrene was reported using the ability of aziridinyl hydrazones to behave as alkyl radical acceptors/precursors. Hydrazone 126 underwent a radical cascade upon reduction of the xanthate moiety to afford after hydrolysis tricyclic compound 127 (Scheme 1.62) [96].

Scheme 1.62 α-Cedrene.

1.3.3 Synthesis of Natural Products Involving the Transformation of an Aziridinium Moiety

The chemistry of aziridiniums has been reviewed recently [97]. In this section only the examples where a true aziridinium ion is involved will be reviewed, since the activation of aziridines under Brønsted conditions has been developed in Section 1.3.1. Aziridiniums are prepared mainly through intramolecular substitution of a leaving group by nitrogen atom engaged in an aziridinyl moiety. Their reactivity is mainly related to ring enlargement reactions.

Biomimetic syntheses of (−)-vincadifformine and (−)-tabersonine have been reported by Kuehne and co-workers through the ring opening reactions of the aziridinium derived from the pentacyclic chloro compound 128 (Scheme 1.63) [98].

Scheme 1.63 (–)-Vincadifformine and (–)-tabersonine.

The in situ mesylation of amino alcohol 129 followed by the reaction with dibutylcuprate was reported by Tanner and Somfai to occur with retention of the configuration. This was explained by a mechanism involving the intramolecular displacement of mesylate by nitrogen. Ring opening of the resulting aziridinium ion 130 with dibutylcuprate afforded an advanced intermediate in the total synthesis of depentylperhydrohistrionicotoxin derivatives (Scheme 1.64) [99].

Scheme 1.64 Depentylperhydrohistrionicotoxin.

Aziridinium ion 132 formed through iodoamination of 131 followed by nucleophilic anchimeric assistance by the vicinal tertiary amine was intramolecularly opened by a proximal ester moiety to afford (+)-croomine in an elegant single step (Scheme 1.65) [100].

Scheme 1.65 (+)-Croomine.

The formation of an aminoalcohol unit through the Pummerer-like rearrangement of N-sulfinylaziridine 133 was used in a total synthesis of D-(−)-erythro-sphingosine by Davis and co-workers (Scheme 1.66) [101].

Scheme 1.66 D-(–)-erythro-Sphingosine.

The stereoselective rearrangement of pyrrolidine-2-methanols into 3- hydroxypiperidines has been extensively studied by Cossy and co-workers [97], and has found several efficient applications in total synthesis. The substituted prolinol 134 has served in the total synthesis of (−)-pseudoconhydrin (Scheme 1.67) [102].

Scheme 1.67 (S)-Pseudoconhydrin.

The synthesis of the piperidinyl core of (−)-velbanamine [103], as well as the synthesis or formal synthesis of various drugs such as (−)-zamifenacin [104], (–)-paroxetine [105] and reboxetine [106] have also been reported using the same type of methodology.

1.4 Conclusion

The aziridines have been named “the epoxides’ ugly cousins” [2], and in fact the reactions of aziridines have received little interest compared with those of epoxides. However, the use of aziridines in the total synthesis of natural products has attracted increasing interest over the past 15 years. Besides the considerable amount of work devoted to aziridine-containing natural products (mitomycins and azinomycins) as well as to related synthetic targets, the aziridine ring has been used as an efficient precursor for the synthesis of 1,2-amino alcohols and other polyfunctionalized structures. Undoubtedly this synthetic potential is directly related to the ability to prepare stereo- and enantioselectively the aziridinyl core and will increase in the future.

Note

1) Intermediate 84 is prepared from achiral starting materials using enatioselective catalytic reactions with chiral ligands available in both enantiomeric forms. Synthesis of the natural (−) enantiomer of agelastatin should thus mirror the sequence used for the (+) enantiomer.

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