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SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITION CHEMISTRY TOWARD HETEROCYCLES AND NATURAL PRODUCTS This is the fifty-ninth volume in the series THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products. Edited by Albert Padwa and William H. Pearson. Copyright # 2002 John Wiley & Sons, Inc. ISBN: 0-471-38726-6

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  • SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITIONCHEMISTRY TOWARD HETEROCYCLES

    AND NATURAL PRODUCTS

    This is the fifty-ninth volume in the series

    THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

    The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry

    Toward Heterocycles and Natural Products. Edited by Albert Padwa and William H. Pearson.

    Copyright # 2002 John Wiley & Sons, Inc.ISBN: 0-471-38726-6

  • THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

    A SERIES OF MONOGRAPHS

    EDWARD C. TAYLOR AND PETER WIPF, Editors

    ARNOLD WEISSBERGER, Founding Editor

  • SYNTHETIC APPLICATIONSOF 1,3-DIPOLAR

    CYCLOADDITIONCHEMISTRY TOWARDHETEROCYCLES ANDNATURAL PRODUCTS

    Edited by

    Albert PadwaDepartment of Chemistry

    Emory University

    William H. Pearson

    Department of Chemistry

    University of Michigan

    AN INTERSCIENCE1 PUBLICATION

    JOHN WILEY & SONS, INC.

  • Designations used by companies to distinguish their products are often claimed as trademarks.

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    Copyright # 2002 by John Wiley & Sons, Inc., New York. All rights reserved.

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    This publication is designed to provide accurate and authoritative information in regard to the

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    ISBN 0-471-22190-2

    This title is also available in print as ISBN 0-471-38726-6.

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  • The Chemistry of Heterocyclic CompoundsIntroduction to the Series

    The chemistry of heterocyclic compounds is one of the most complex and

    intriguing branches of organic chemistry, of equal interest for its theoretical

    implications, for the diversity of its synthetic procedures, and for the physiological

    and industrial significance of heterocycles.

    The Chemistry of Heterocyclic Compounds has been published since 1950 under

    the initial editorship of Arnold Weissberger, and later, until his death in 1984,

    under the joint editorship of Arnold Weissberger and Edward C. Taylor. In 1997,

    Peter Wipf joined Prof. Taylor as editor. This series attempts to make the

    extraordinarily complex and diverse field of heterocyclic chemistry as organized

    and readily accessible as possible. Each volume has traditionally dealt with

    syntheses, reactions, properties, structure, physical chemistry, and utility of com-

    pounds belonging to a specific ring system or class (e.g., pyridines, thiophenes,

    pyrimidines, three-membered ring systems). This series has become the basic

    reference collection for information on heterocyclic compounds.

    Many broader aspects of heterocyclic chemistry are recognized as disciplines of

    general significance that impinge on almost all aspects of modern organic

    chemistry, medicinal chemistry, and biochemistry, and for this reason we initiated

    several years ago a parallel series entitled General Heterocyclic Chemistry, which

    treated such topics as nuclear magnetic resonance, mass spectra, and photoche-

    mistry of heterocyclic compounds, the utility of heterocycles in organic synthesis,

    and the synthesis of heterocycles by means of 1,3-dipolar cycloaddition reactions.

    These volumes were intended to be of interest to all organic, medicinal, and

    biochemically oriented chemists, as well as to those whose particular concern is

    heterocyclic chemistry. It has, however, become increasingly clear that the above

    distinction between the two series was unnecessary and somewhat confusing, and

    we have therefore elected to discontinue General Heterocyclic Chemistry and to

    publish all forthcoming volumes in this general area in The Chemistry of Hetero-

    cyclic Compounds series.

    It is a major challenge to keep our coverage of this immense field up to date. One

    strategy is to publish Supplements or new Parts when merited by the amount of new

    material, as has been done, inter alia, with pyridines, purines, pyrimidines,

    quinazolines, isoxazoles, pyridazines and pyrazines. The chemistry and applica-

    tions to synthesis of 1,3-dipolar cycloaddition reactions in the broad context of

    organic chemistry were first covered in a widely cited two-volume treatise edited by

    Prof. Albert Padwa that appeared in 1984. Since so much has been published on this

    fascinating and broadly useful subject in the intervening years, we felt that a

    Supplement would be welcomed by the international chemistry community, and we

  • are immensely grateful to Prof. Padwa and Prof. Pearson for tackling this arduous

    task. The result is another outstanding contribution to the organic and heterocyclic

    chemistry literature that we are delighted to publish within The Chemistry of

    Heterocyclic Compounds series.

    EDWARD C. TAYLOR

    Department of Chemistry

    Princeton University

    Princeton, New Jersey

    PETER WIPF

    Department of Chemistry

    University of Pittsburgh

    Pittsburgh, Pennsylvania

    vi The Chemistry of Heterocyclic Compounds: Introduction to the Series

  • Preface

    Cycloaddition reactions figure prominently in both synthetic and mechanistic

    organic chemistry. The current understanding of the underlying principles in this

    area has grown from a fruitful interplay between theory and experiment. The monu-

    mental work of Rolf Huisgen and co-workers in the early 1960s led to the general

    concept of 1,3-dipolar cycloaddition. Few reactions rival this process in the number

    of bonds that undergo transformation during the reaction, producing products

    considerably more complex than the reactants. Over the years, this reaction has

    developed into a generally useful method for five-membered heterocyclic ring

    synthesis, since many 1,3-dipolar species are readily available and react with a wide

    variety of dipolarophiles.

    The last comprehensive survey of this area dates back to 1984, when the two-

    volume set edited by Padwa, ‘‘1,3-Dipolar Cycloaddition Chemistry,’’ appeared.

    Since then, substantial gains in the synthetic aspects of this chemistry have

    dominated the area, including both methodology development and a body of

    creative and conceptually new applications of these [3þ 2]-cycloadditions inorganic synthesis. The focus of this volume centers on the utility of this

    cycloaddition reaction in synthesis, and deals primarily with information that has

    appeared in the literature since 1984. Consequently, only a selected number of

    dipoles are reviewed, with a major emphasis on synthetic applications. Both

    carbonyl ylides and nitronates, important members of the 1,3-dipole family that

    were not reviewed previously, are now included. Discussion of the theoretical,

    mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have been

    kept to a minimum, but references to important new work in these areas are given

    throughout the 12 chapters.

    Beyond the ability of the 1,3-dipolar cycloaddition reaction to produce hetero-

    cycles, its importance extends to two other areas of organic synthesis, both of which

    are included in the current volume. First, the heteroatom-containing cycloadducts

    may be transformed into a variety of other functionalized organic molecules,

    whether cyclic or acyclic. Second, many 1,3-dipolar cycloadditions have the ability

    to generate rings (and functionality derived from transformations of such rings)

    containing several contiguous stereocenters in one synthetic operation. The con-

    figurations of these new stereocenters arise from the geometry of the dipole and

    dipolarophile as well as the topography (endo or exo) of the cycloaddition. An

    additional stereochemical feature arises when the reactive p faces of either of thecycloaddends are diastereotopic. Relative stereocontrol in 1,3-dipolar cycloaddi-

    tions is dealt with in some detail, and asymmetric versions of these dipolar

    cycloadditions represent an entirely new aspect of the current reference work.

    In recent years, numerous natural and unnatural products have been prepared by

    synthetic routes that have a 1,3-dipolar cycloaddition as a crucial step in their

  • synthesis. Consequently, this reaction has become recognized as an extremely

    important transformation in the repertoire of the synthetic organic chemist.

    ALBERT PADWA

    Department of Chemistry

    Emory University

    Atlanta, Georgia

    WILLIAM H. PEARSON

    Department of Chemistry

    University of Michigan

    Ann Arbor, Michigan

    viii Preface

  • Contents

    1 NITRONES 1

    Raymond C. F. Jones

    2 NITRONATES 83

    Scott E. Denmark and Jeromy J. Cottell

    3 AZOMETHINE YLIDES 169

    L. M. Harwood and R. J. Vickers

    4 CARBONYL YLIDES 253

    Mark C. McMills and Dennis Wright

    5 THIOCARBONYL YLIDES 315

    Grzegorz Mloston and Heinz Heimgartner

    6 NITRILE OXIDES 361

    Volker Jager and Pedro A. Colinas

    7 NITRILE YLIDES AND NITRILE IMINES 473

    John T. Sharp

    8 DIAZOALKANES 539

    Gerhard Maas

    9 AZIDES 623

    Chin-Kang Sha and A. K. Mohanakrishnan

    10 MESOIONIC RING SYSTEMS 681

    Gordon W. Gribble

    11 EFFECT OF EXTERNAL REAGENTS 755

    Shuji Kanemasa

    12 ASYMMETRIC REACTIONS 817

    Kurt Vesterager Gothelf and Karl Anker Jorgensen

    INDEX 901

  • SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITIONCHEMISTRY TOWARD HETEROCYCLES

    AND NATURAL PRODUCTS

    This is the fifty-ninth volume in the series

    THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

  • CHAPTER 1

    Nitrones

    Raymond C. F. Jones and Jason N. Martin

    Department of Chemistry, Loughborough University,

    Loughborough, United Kingdom

    1.1. Nitrones and the 1,3-Dipolar Cycloaddition Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . 2

    1.2. Toward Natural Products through Nitrone Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . 3

    1.3. Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

    1.4. Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

    1.5. Quinolizidines, Indolizidines, and Pyrrolizidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

    1.6. Peptides and Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

    1.7. Sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

    1.8. Sulfur- and Phosphorus-Containing Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

    1.9. Catalytic Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

    1.10. Pyrrolidines, Piperidines, and Other Amines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

    1.11. Isoxazolidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

    1.11.1. Nitrones by the 1,3-ATP Process. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

    1.11.2. Intramolecular Oxime–Alkene Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . 54

    1.11.3. Intramolecular Nitrone–Alkene Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . 55

    1.11.4. Isoxazolidines from Intermolecular Nitrone Cycloaddition Reactions. . . . . . . . . . 59

    1.12. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

    The synthetic utility of the 1,3-dipolar cycloaddition reaction is evident from the

    number and scope of targets that can be prepared by this chemistry. As one of the

    most thoroughly investigated 1,3-dipoles, nitrones are arguably the most useful

    through their ability to generate nitrogen- and oxygen-based functionality from the

    cycloadducts as well as the potential to introduce multiple chiral centers stereo-

    selectively. A comprehensive review of all nitrone cycloadditions would fill many

    volumes; instead, this chapter will focus upon the highlights of synthetic endeavor

    through 1,3-dipolar cycloaddition reactions of nitrones since 1984.

    The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry

    Toward Heterocycles and Natural Products. Edited by Albert Padwa and William H. Pearson.

    Copyright # 2002 John Wiley & Sons, Inc.ISBN: 0-471-38726-6

    1

  • 1.1. NITRONES AND THE 1,3-DIPOLARCYCLOADDITION REACTION

    Nitrones (or azomethine oxides) (1–7) were first prepared by Beckmann in 1890

    (8,9) and named from a shortening of ‘‘nitrogen–ketones’’ by Pfeiffer in 1916 to

    emphasize their similarity to ketones (10). While aromatic N-oxides also contain

    the nitrone moiety, they retain the name of the N-oxides whose reactivity they more

    closely resemble. The general terms aldo- and keto-nitrones are used on occasion to

    distinguish between those with and without a proton on the a-carbon, respectively,and nitrones exist in (E)- and (Z)-forms that may interconvert. Their chemistry is

    hugely varied and frequently reviewed, but it is ultimately dominated by their use as

    1,3-dipoles for cycloaddition reactions. In 1960, Huisgen proposed the now widely

    accepted concept of the 1,3-dipolar cycloaddition reaction (11–20) in which the

    formation of the two new bonds occurs as a concerted (but not simultaneous)

    process, rejecting Firestone’s proposed reaction via a diradical intermediate on the

    basis of stereospecificity (21–26). Ironically, Huisgen himself then went on to

    demonstrate the first example of a two-step cycloaddition, using a thiocarbonyl

    ylide 1,3-dipole (27).

    The most common nitrone 1,3-dipolar cycloaddition (DC) reaction (28–35) is the

    formation of an isoxazolidine using alkene dipolarophiles (Scheme 1.1), although

    other multiply bonded systems may also be used (alkynes, allenes, isocyanates,

    nitriles, thiocarbonyls, etc.). The isoxazolidine cycloadduct contains up to three new

    chiral centers and, as with other 1,3-dipoles, the highly ordered transition state

    often allows the regio- and stereochemical preference of a given nitrone to be

    predicted. This prediction is achieved through a consideration of steric and electronic

    factors, but most significantly through the frontier molecular orbital (FMO) theory

    proposed by Fukui (36,37), for which he shared the 1981 Nobel Prize.

    A number of cyclic nitrones have been developed that avoid the issue of nitrone

    (E/Z) isomerization by permitting only a single geometry about the C����N doublebond and so reduce the number of possible cycloaddition products. Cyclic nitrones

    have also become popular as facially differentiated reagents, allowing predictable

    NO

    R1

    R3R4

    ON

    R4R3

    R1

    NO

    R1

    R2

    R2R2

    ** *1,3-DC

    isoxazolidine

    nitrone

    (E)

    (Z)

    Scheme 1.1

    2 Nitrones

  • asymmetric induction through their ability to enforce the cycloaddition reaction at

    one or other face of the 1,3-dipole. In recent years, the effect of catalysis on the rate

    and selectivity of the nitrone cycloaddition reaction has been examined from which

    impressive results have begun to emerge. Thus, nitrones represent a powerful tool in

    modern synthetic chemistry, whose limits are still being explored more than a

    century after their discovery.

    1.2. TOWARD NATURAL PRODUCTS THROUGHNITRONE CYCLOADDITIONS

    With a wealth of nitrone-derived cycloadditions reported in the literature, we

    have sought to arrange this survey according to the synthetic target (e.g., nucleo-

    sides or amino acids) or, where more relevant, grouped by the nature of the

    cycloaddition partners (e.g., those derived from sugars). Where a total synthesis is

    concerned, this task is straightforward, but with more speculative and develop-

    mental papers it would be possible to classify the same work in a number of ways.

    Apologies, then, to authors who feel misplaced. Naturally, there is a degree of

    overlap between many of our groupings, and in each case we have attempted to

    direct the reader to relevant work. Section 1.11 on isoxazolidine synthesis covers a

    particularly broad range of reactions and it is here we have collected some of the

    most significant reports in which the major aim of the work was to characterize a

    novel nitrone cycloaddition reaction rather than achieve the total synthesis of a

    given target molecule.

    1.3. NUCLEOSIDES

    Nucleosides are potent antibiotic, antitumor, and antiviral agents, vital in

    chemotherapy for acquired immune deficiency syndrome/human immunodeficiency

    virus (AIDS/HIV). The polyoxins (e.g., 1a–b), and closely related nikkomycins arepyrimidine nucleoside antibiotics that are potent inhibitors of the biosynthesis of

    chitin, a major structural component of the cell wall of most fungi (Scheme 1.2).

    Merino and co-workers (38,39) reported the total synthesis of (þ)-polyoxin J 1band of the isoxazolidine analogue of thymine polyoxin C, by nucleophilic addition

    to chiral sugar nitrones. By a 1,3-dipolar cycloaddition route, they have prepared

    polyoxin analogues 2 in which the furanose ring of the parent nucleoside issubstituted by an isoxazolidine (40). Thus, nitrone 3, prepared in six steps fromserine (58% overall yield), afforded four isoxazolidine cycloadducts in excellent

    yield (93%) in its reaction with vinyl acetate. The product mixture contained

    predominantly the (3R,5S)-adduct 4a and its C(5) epimer the (3R,5R)-adduct 4b,separable by chromatography, along with an inseparable mixture of the two C(3)

    epimers. Isoxazolidines 4a and 4b were used as a mixture or separately to glycosy-late silylated thymine 5 or uracil 6. Acidic cleavage of the acetonide of the (3R,5S)-adducts 7a–b afforded the amino alcohols, which were oxidized to the acids with

    1.3. Nucleosides 3

  • 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) and bis(acetoxy)iodobenzene (BAIB)

    before esterification with diazomethane to give 2a or 2b. The C(5) epimer of eachN,O-nucleoside was accessed by similar treatment of the diastereomeric isoxazo-

    lidine adduct (3R,5R) 4b. In earlier work, this group also prepared a relatedoxazolidinyl thymine nucleoside (side-chain amino acid replaced by��CH2OH) viathe addition of the corresponding d-glyceraldehyde-derived nitrone with the sodiumenolate of methyl acetate (41). The amino acid side of nikkomycin Bz was

    synthesized by a nitrone cycloaddition route by Tamura et al. (42).

    Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by

    the use of various C-functionalized chiral nitrones in order to enforce enantioselec-

    tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as

    in the work of Merino et al. (40), that asymmetric induction is at best partial with

    dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot

    completely direct the addition to the nitrone. After poor results with menthol ester-

    and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-

    lidine 8a and its diastereomer 8b in near quantitative yield using the N-glycosyl

    OAc

    N

    N

    O

    Boc

    OAc

    BnOO

    OH OH

    N

    NH

    O

    R1

    O

    CO2H

    R2HN

    N

    H

    O

    NO

    Boc

    Bn

    N

    N

    OSiMe3R

    OSiMe3

    TMSOTf

    DCM

    H2N O

    O

    OH

    OH

    NH2

    O

    N

    O

    Boc

    O

    N

    Bn

    NH

    O

    O

    R

    N

    N O

    N

    NH

    O

    R

    O

    MeO2C

    H2N

    Bn

    (1b) polyoxin J

    R1 = Me,

    (2a)(2b)

    (3) (4a) (47%)

    93%4 isomers

    3

    (7a)(7b)

    ii TEMPO, BAIB

    iii CH2N2, Et2O

    i 70% aq AcOH

    (5) R = Me(6) R = H

    R1 = CH2OH, R2 = H

    (1a) polyoxin C

    5

    R = MeR = H

    R2 =

    R = MeR = H

    Boc = tert-butyloxycarbonyl

    Scheme 1.2

    4 Nitrones

  • nitrone 9 of Vasella, derived from d-ribofuranose. Adduct 8a was coupled withthymine before removal of the sugar auxiliary to afford N,O-nucleoside 10.

    Among a number of other homochiral furanosyl- and isoxazolidinylthymine

    targets, these workers also applied an achiral cycloaddition approach with vinyl

    acetate to successfully prepare the antiviral agent d4T (11) and its 2-methylanalogue (Fig. 1.1) (45). In more recent work, similar nitrones [9, R¼Me orbenzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-

    (46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues.

    NR O

    EtO2C H

    N OR

    EtO2C

    OAc

    OTBDMSO

    O O

    NH

    O

    EtO2C

    N

    NH

    O

    O

    (9) (8a) (5R) 47%

    (8b) (5S) 48%

    i ii-iii

    (10)R =

    5

    Reagents: i vinyl acetate, ethyl glyoxalate, 60 ˚C, 14h; ii bovine serum albumin (BSA),

    thymine, TMSOTf, MeCN, ∆, 1 h; iii 3.7% HCl in EtOH, room temperature (rt), 3 h.

    Scheme 1.3

    NH

    N

    N

    O

    NH2NHO

    OHO

    NHN

    O

    O

    N

    N

    N

    NMe2

    NHO

    OH

    OH

    OH

    (11) (12)

    2

    (13)

    Figure 1.1

    1.3. Nucleosides 5

  • Elsewhere, Langlois and co-worker (48) applied a 3-hydroxyaminoborneol-derived

    nitrone to the total synthesis of (þ)-carbovir (12), the enantiomer of a potentreverse transcriptase inhibitor for the treatment of AIDS.

    Mandal and co-workers (49,50) (Scheme 1.4) prepared five- and seven-membered

    carbocyclic nucleosides including the (þ)-dimethylaminopurine compound 13(3.3% from d-glucose) and its enantiomer. Aminocyclopentitol (�)-14 is anintermediate in the synthesis of the carbocyclic nucleosides (�)-noraristeromycin(15) and (�)-nepalocin A (16) and has been prepared in enantiopure form by Galloset al. (50a) from nitrone 17 by condensation of the corresponding d-ribose derivedaldehyde 18 with BnNHOH (Scheme 1.4). Thus, intramolecular cycloaddition ofnitrone 17 affords tricyclic adduct 19 as a single enantiomer, which is converted to(�)-14 after N��O bond reduction (Zn/AcOH) and debenzylation (ammoniumformate, 10% Pd��C).

    In contrast to the installation of the nucleobase via nucleophilic substitution of a

    suitable leaving group on the isoxazolidinyl cycloadduct, Colacino et al. (51) and

    Sindona and co-workers (52,53) prepared isoxazolidinyl nucleosides using vinyl

    nucleobases as the dipolarophile (Scheme 1.5). In Sindona’s work, while a three-

    component reaction of hydroxylamine, formaldehyde, and 20 afforded a complexmixture of cycloadducts and byproducts, the known dipole 21 reacted with N-9-vinyladenine (20) in benzene at reflux to afford a racemic mixture of adduct 22 andits enantiomer (45%). The ester function was then used to effect a resolution by pig

    N

    NN

    N

    NH2

    HO OH

    HO

    N

    NN

    N

    NH2

    HO OH

    HO2C

    O

    O

    X

    H

    H

    O

    O H

    H

    ON

    Bn

    O OH

    HO NH2

    H

    (18) X = O

    (17) X = N (Bn)Oi

    iii-iv

    (19) (−)-(14)

    (15) (16)

    ii

    Reagents: i BnNHOH, EtOH, 15 min, 95%; ii C6H5Cl, ∆, 30 min, 62%; iii Zn, AcOH, Et2O, rt, 48 h, 78%;

    iv NH4HCO2, 10% Pd-C, MeOH, ∆, 1 h 75%.

    Scheme 1.4

    6 Nitrones

  • liver esterase (PLE) enzyme-catalyzed hydrolysis to afford the enantiomerically

    pure acid 23.The discovery of spirocyclic nucleosides with anti-HIV-1 activity has prompted

    Chattopadhyaya and co-workers (54,55) to prepare spiroisoxazolidine nucleo-

    sides (Scheme 1.6). Thus, after proving the reactivity of related systems in an

    N

    NN

    N

    NH2

    ON

    Bn

    CO2R

    N

    NN

    N

    NH2

    BnN

    OBu

    O O

    C6H6, 104 ˚C96 h

    (21) (20)

    (22) R = Bu

    (23) R = HPLE

    Scheme 1.5

    O

    O

    N

    NH

    O

    O

    XN

    OMe

    MMTrOO

    N

    NH

    O

    OMMTrO

    ON

    OX

    H

    Me

    ON

    NH

    O

    OHO

    ON

    HO

    Me

    HO

    i-ii

    (24) X = CH2(26) X = SiMe2

    (25) X = CH2(27) X = SiMe2

    56%70%

    (28)

    3′ 2′

    Reagents: i H2O2, KF, KHCO3, MeOH, tetrahydrofuran (THF);

    MMTr = para-methoxyphenyldiphenylmethyl

    ii 80% AcOH, 40 ˚C, 1 h.

    Scheme 1.6

    1.3. Nucleosides 7

  • intermolecular sense, nucleoside nitrone 24 (or the isomeric 2 0-O-allyl-3 0-nitrones)were prepared from the corresponding ketones to afford the spirotricyclic

    cycloadduct 25. Similarly, a reagent with a vinyl silyl ether tether (26) gave therelated tricyclic adduct 27, which was desilylated by hydrogen peroxide mediatedTamao oxidation to afford the spiroisoxazolidine nucleoside 28. Related nitroneswere earlier prepared by Tronchet et al. (56–59) for studies of nucleophilic addition

    to the nitrone function.

    1.4. LACTAMS

    The continued importance of b-lactam ring systems in medicine has encourageda number of research groups to investigate their synthesis via a nitrone cycloaddi-

    tion protocol. Kametani et al. (60–62) reported the preparation of advanced

    intermediates of penems and carbapenems including (þ)-thienamycin (29) andits enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (�)-menthyl

    N

    MenO2C H

    Bn O

    CO2Bn

    NS

    R2

    O

    HOH H

    CO2H

    R1

    (34) NMe2

    NH

    NHO

    R1O

    R2H H

    N O

    MenO2C

    Bn

    CO2Bn

    (35)

    (36)

    OH

    N O

    MenO2C

    Bn

    CO2Bn

    NHO

    HO

    CO2MenH H

    CO2H

    (E )-(30) (31a) (30%) (31b) (30%)

    (32)

    (33)

    i

    steps ii-vi

    R1 = H, R2 = OAc

    R1 = TBDMS, R2 =

    R1 = TBDMS, R2 =

    (29) R1 = H, R2 = CH2NH2

    R1 = Me, R

    Men = menthyl; TBDMS = tert-butyldimethylsilyl

    2 =

    Reagents: i H2, PtO2, MeOH, 20 h, then DCC, MeCN, 60 ˚C, 3 h, 39%; ii TBDMSCl,

    Et3N, dimethyl formamide (DMF), 16 h, 80%; iii NaOH aq (1 M ), THF,

    MeOH then HCl aq (1 M ), 81%; iv TBDMSCl, Et3N, DMF, 18 h, 94%; v AcOH

    aq (2.5 M ), THF, 6 h then NaHCO3 aq (5%); vi Pb(OAc)4, KOAc, DMF, 40 ˚C, 1 h, 70%.

    Scheme 1.7

    8 Nitrones

  • glyoxal hydrate and benzylhydroxylamine but found it exerted incomplete stereo-

    control in its cycloaddition to benzyl crotonate. The major isolated products, a 1:1

    mixture of isoxazolidines 31a and 31b, are rationalized as the consequence of endoor exo addition to the more reactive (E) form of nitrone (30), respectively.Simultaneous O- and N-debenzylation and N��O bond hydrogenolysis of 31bgave an amino alcohol intermediate, which was used without purification for

    dicyclohexylcarbodiimide (DCC)-mediated cyclization to afford the b-lactam 32.Silylation of the hydroxyl and the amide nitrogen was followed by hydrolysis of the

    menthyl ester, which also brought about N-desilylation. Reinstallation of the silyl

    groups through two steps, before insertion of the C(4) acetyl group by oxidative

    acetoxylation with lead tetraacetate, afforded the lactam 33, a known intermediateen route to (þ)-thienamycin (29). An earlier, related total synthesis of 29 by thisgroup using a homochiral N-(2-phenylethyl) auxiliary afforded similar low yields of

    the desired isoxazolidine adducts (60).

    The unusually potent and broad spectrum antibacterial action of (þ)-thienamy-cin is tempered by its instability at high concentration and susceptibility to

    decomposition by renal dehydropeptidase I. In 1984, Shih and co-workers (62a) at

    Merck reported that the 1-b-methylcarbapenem 34 demonstrated increased chemi-cal and metabolic stability while retaining high antibiotic activity. Work published

    by Ito et al. (63) described the preparation of a 1-b-methylcarbapenem intermediate(35) via a nitrone cycloaddition that gave an equimolar amount of all four possibleadducts. Later, intermediate 35 was prepared by Ihara et al. (64,65) by intramo-lecular cycloaddition of a complex chiral alkenyl nitrone to afford a single

    stereoisomer (51%). Separately, Kang and Lee (66), then Jung and Vu (67),

    prepared 1-b-methylcarbapenem intermediate (36) and a synthetic precursorrespectively, via intramolecular nitrone–alkene 1,3-dipolar cycloaddition reactions

    with complete diastereocontrol.

    Alcaide et al. (68,69) recently published their studies of the intramolecular 1,3-

    dipolar cycloaddition reactions of alkynyl-b-lactams in which they found that thedesired cycloaddition was in competition with a reverse-Cope elimination. The

    reaction of alkynyl aldehydes 37a–c with N-methylhydroxylamine afforded amixture of products depending on the reaction conditions and the chain length

    separating the alkyne and the lactam (Scheme 1.8). Thus, up to three separate

    NO

    CHOPhO HHMeNHOH

    Et3N NO

    PhO HH NMe

    O

    PhMe, ∆

    NO

    PhO HH

    ON

    Me

    Hn

    15%

    (37a)

    (37b)

    (37c)

    n = 1

    n = 2

    n = 3

    (38) (39)

    Scheme 1.8

    1.4. Lactams 9

  • nitrones were identified from the reaction mixture including two from a complex

    proposed mechanism. Thus, alkynyl nitrone (38) was formed from the condensationof 37c with N-methylhydroxylamine in refluxing toluene, and underwent a 1,3-dipolar cycloaddition to afford the homochiral isoxazoline 39 via addition to theless sterically crowded upper face of 38. Significantly, the isolated yield of thecycloadduct is very low (15%), the product ratio favoring the nitrone (38:39¼ 3:1).

    Chmielewski and co-workers (70–73) prepared the b-lactam skeleton via anitrone cycloaddition to a sugar ene lactone dipolarophile providing latent polyol

    functionality at C(3) of the lactam (Scheme 1.30, Section 1.7). In other lactam

    cycloaddition chemistry, Rigolet et al. (74) prepared various spirocyclic adducts,

    including 40–42 from the corresponding methylene lactams (75) or the unstablemethylene isoindolones 43, the latter showing enhanced yields for the cycloadditionof N-benzyl-C-phenyl nitrone to the exocyclic double bond under microwave

    irradiation (Scheme 1.9) (76). Related spiroisoxazolidinyl lactams were reported

    by Fisera and co-workers (77). Funk and Daggett (78) prepared similar spirocyclic

    lactams (e.g., 44) via the cycloaddition reaction of exocyclic nitrone 45 (derivedfrom cyclohexanone) with unsaturated esters (Scheme 1.10). The N��O bondcleavage of isoxazolidine (46) makes available the nitrogen for spontaneouslactamization to the spirocyclic product 44.

    Cycloaddition to endocyclic unsaturation has been used by many researchers for

    the preparation of isoxazolidinyl adducts with g-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids

    (Scheme 1.20, Section 1.6) (79,80). A related a,b-unsaturated lactam has beenprepared by a nitrone cycloaddition route in the total synthesis of the fungal

    metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting

    materials is given in the work of Chiacchio et al. (82) who prepared isoxa-

    zolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11).

    NO4-Me-C6H4

    O N

    NOMe

    Ph

    COPh

    Ph

    CH2PhNPh

    O

    NO

    N

    N

    ON

    O

    O

    Me

    MePhOC

    COPh

    Ph

    Ph

    O N

    NO4-Me-C6H4

    CH2Ph

    Ph110 ˚C, 4 h (27%) or microwave (61%)

    (40) (41)

    (42)(43)

    Scheme 1.9

    10 Nitrones

  • The acyclic precursor is an a,b-unsaturated amido aldehyde that was condensedwith N-methylhydroxylamine to generate the nitrone (E)-48, which then underwenta spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the

    isoxazolidinyl lactam 47. The observed product arises via the (E)-nitrone transitionstate A [or the (Z)-nitrone equivalent] in which the position of the benzyl group a tothe nitrone effectively controls the two adjacent stereocenters while a third

    stereocenter is predicted from the alkene geometry. Both transition states maintain

    the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-

    diaxial interaction with the nitrone methyl or oxygen found in transition state B.Semiempirical PM3 calculations confirm the extra stability, predicting exclusive

    formation of the observed product 47. Related cycloadducts from the intramole-cular reaction of nitrones containing ester- rather than amide-tethered alkene

    functionality are also known (83-85).

    NBn O

    CO2Me

    PhMe, ∆

    O

    NBn

    CO2Me

    H2, 1 atm

    Pd(OH)2

    HN

    O OH

    (46) (44)(45)

    Scheme 1.10

    N

    Ph

    Me

    O

    Ph

    N

    Me

    O

    N MeH

    H

    N

    Me

    O

    Me O

    HBn

    H

    (B)

    N ON

    H

    H Ph

    Ph

    Me

    Me

    O

    N

    O

    NO

    Me

    HH

    H

    Ph

    H

    Me Bn

    (A)

    (E)-(48) (47)

    Scheme 1.11

    1.4. Lactams 11

  • 1.5. QUINOLIZIDINES, INDOLIZIDINES,AND PYRROLIZIDINES

    The title compounds, quinolizidines, indolizidines, and pyrrolizidines (86), are

    characterized by the presence of a bridgehead nitrogen atom in six,six-, six,five-, or

    five,five-membered bicyclic ring systems, respectively. The polyhydroxylated

    indolizidines and pyrrolizidines have a range of biological effects through their

    inhibition of glycosidase enzymes, including some examples of antiviral activity.

    The nitrogen and nearby oxygen functionality lend themselves to a nitrone

    cycloaddition strategy, as demonstrated by McCaig et al. (87,88) in their synthesis

    of each enantiomer of the indolizidine lentiginosine (49) and related pyrrolizidines(Scheme 1.12). Chiral cyclic nitrone 50 was prepared from doubly methoxymethyl(MOM) protected diethyl d-tartrate via oxidation of the corresponding pyrrolidinewith Davis’ reagent. The cycloaddition reaction of nitrone 50 with benzyl but-3-enoate in toluene at reflux gave a single cycloadduct 51 in 44% yield after 4 days.Reductive N��O bond cleavage and concomitant recyclization with the pendantester function gave a lactam (52), which was reduced to the amine with borane–dimethyl sulfide complex. Radical deoxygenation at C-7 of the imidazolylthio-

    N

    O

    MOMO MOMO

    MOMO

    MOMO

    MOMO

    OMOM

    N O

    H

    CO2Bn

    N

    HHO

    HON

    HOR

    O

    N

    S

    N

    i

    ii

    iii-iv

    v-vi

    (49)

    (50) (51)

    (52) R = H

    (53) R =

    7

    Reagents: iCH2=CHCH2CO2Bn, toluene, ∆, 4 days, 44%; ii Zn, AcOH, 60 ˚C, 2 h, 83%;iii BH3•Me2S, THF, rt, 4 h, then EtOH, ∆, 3 h, 95%; iv 1,1′-thiocarbonyldiimidazole,

    ClCH2CH2Cl, ∆, 2 h, then rt overnight, 83%; v Bu3SnH, AIBN, toluene, ∆, 3 h, 53%; vi HCl aq (6M), rt, overnight, 60%.

    Scheme 1.12

    12 Nitrones

  • carbonyl derivative 53 and removal of the MOM protecting groups in acid affordeda single isomer of lentiginosine (þ)-49. By an identical scheme, these workersprepared (�)-49 from the enantiomer of isoxazolidine cycloadduct 51.

    A similar approach has been applied by Brandi and co-workers (89–97) using

    chiral 3- and 3,4-substituted pyrrolidine nitrones. With such dipoles they

    have prepared a number of hydroxylated indolizidines (89–92,95) including (�)-hastanecine and (�)-croalbinecine (96). As before, N��O bond cleavage wasfollowed by recyclization, this time through nucleophilic substitution of the

    terminal hydroxyl moiety derived from the dipolarophile, as its tosylate. These

    workers have recently reported the synthesis of a related monohydroxylated nitrone

    by oxidation of the N-hydroxypyrrolidine to afford an 11:1 mixture of the two

    separable regioisomers (95). Indolizidine and pyrrolizidine skeletons were then

    prepared from this material. In another elegant synthesis, Holmes and co-workers

    (98) prepared the indolizidine core of the allopumiliotoxins (54) (Scheme 1.13).Retrosynthetic analysis suggested an isoxazolidinyl intermediate, ultimately

    derived by an intramolecular cycloaddition reaction of alkenyl nitrone 55. Thedesired cycloadduct 56 was the major product isolated from a mixture containingsmall amounts of three other diastereomers and afforded the target skeleton 54 or itsC(3) epimer after extensive synthetic manipulation (98). In other work on the

    intramolecular nitrone cycloaddition (99), this group has published intermediates in

    the total synthesis of the indolizidine alkaloid gephyrotoxin (100) as well as the

    total synthesis of spiropiperidine natural product histrionicotoxin (Scheme 1.49,

    Section 1.10) (101). Kibayashi and co-worker (102,103) reported two total

    syntheses of the indolizidine (þ)-monomorine I (57), both of which rely on thesame cycloaddition reaction of an achiral methyl glyoxalate-derived nitrone and a

    homochiral allyl ether. The resultant mixture of isoxazolidines was a 3:1 mixture in

    favor of the desired product in 76% combined yield.

    The rare reports of quinolizidine formation by a nitrone cycloaddition strategy

    include the racemic total synthesis of lasubine II (58), one of a series of relatedalkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme

    1.14) (104). While these alkaloids were previously accessed by intermolecular

    nitrone cycloaddition reactions, this more recent report uses an intramolecular

    approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59affords predominantly the desired bridged adduct 60 along with two related

    N

    O

    H

    OH

    N

    OTBDMS

    O

    OBz

    NO

    OBz

    OTBDMS N

    H

    (54) (56) (55)

    3

    (57)

    Scheme 1.13

    1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 13

  • diastereomers. Reductive N��O cleavage of 60 with Zn/AcOH provided a trisub-stituted piperidine (61) which, after formation of the silyl ether from the hydroxylgroup, was cyclized in a melt of 2-hydroxypyridine at 160 �C. The stereochemistryat this position [C(2) in lasubine II numbering] was inverted under Mitsunobu

    conditions to afford the desilylated lactam 62 and, after reduction of the carbonylwith LiAlH4, afforded the target compound (�)-58.

    A recent article describes the use of an unusual nitrone–alkene intramolecular

    cycloaddition–retrocycloaddition–intramolecular cycloaddition strategy (Scheme

    1.15). Here, Cordero et al. (83) used a pyrrolidine nitrone to afford the isoxazo-

    lidine skeleton before installation of the alkenyl ester side chain of 63 by Mitsunobumethodology employing a polymer supported triphenylphosphine. Thermally

    induced retrocycloaddition of 63 in o-dichlorobenzene at 150 �C afforded anunisolated nitrone (64) that underwent an intramolecular cycloaddition to afforda second isoxazolidine (65). Removal of the p-methoxybenzyl (PMB) protectinggroup and mesylation of the revealed hydroxyl was followed by hydrogenolytic

    N��O bond cleavage, to free the amine nitrogen for nucleophilic attack at the carboncarrying the mesylate to afford indolizidine (66).

    CO2MeN

    Ar

    O

    MeO

    OMe

    NH

    OH

    Ar

    CO2Me

    H

    N

    OH

    H

    MeO

    OMe

    N

    OH

    Ar

    H

    O

    N

    O

    Ar

    CO2Me

    (59)

    Ar =

    i

    iii-v

    vi

    (60) (61)

    (62)(±)-(58)

    22

    ii

    Reagents: i PhMe, ∆, 1 h, 60%; ii Zn, AcOH, 65 ˚C, 4 h, 95%; iii TMS-imidazole, DCM, 4 h; iv 160 ˚C, 2 h, then TBAF, THF, 2 h, 50% (from 61); v Ph3P, PhCO 2H, diethylazodicarboxylate (DEAD),

    DCM, rt, 2 days, then KOH, MeOH, rt, 6 h, 74%; vi LiAlH4, THF, ∆, 4 h, 76%.

    Scheme 1.14

    14 Nitrones

  • These authors also showed that the indolizidine skeleton can be prepared from

    cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkylidenecyclo-

    propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidineadducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105–108) predominantly but not exclusively (109–111). Thermally induced rearrange-

    ment of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71(107,108). These authors propose reaction via initial N��O bond homolysis of 70 todiradical 72 followed by ring expansion through relief of the cyclopropyl ring strainforming the carbonyl of a second diradical intermediate 73, which cyclizes to affordthe isolated piperidinone 71.

    In this way, spirocyclopropyl adduct 74 (from cycloaddition of 75 and 76) wasused to prepare gephyrotoxins (106) and lentiginosine (49) (Scheme 1.17)(105,112). In the latter case, pyrolysis of adduct 74 afforded indolizidinone 77(45%) along with the amino ketone 78 (55%), the predominance of the latter beingaccredited to the steric hindrance of the diradical coupling by the bulky TBDPS

    groups. Reduction of the carbonyl of 77 was achieved with sodium borohydrideafter conversion to the tosyl hydrazone before final desilylation of 79 with HFafforded 49, allowing the authors to challenge the published absolute stereochem-istry. The presence of a phenyl group (particularly when substituted by electron-

    donating groups) on the nitrogen atom of the isoxazolidine exerts a powerful

    activation of the rearrangement, allowing the thermolysis reaction to occur at much

    NOEtO2C

    HO

    O

    PMBO

    N

    HO

    OO

    H

    N

    O

    O

    PMBO

    O

    NO

    HPMBO

    OO

    (63) (64)

    (65)(66)

    i

    ii

    Reagents: i o-Cl2C6H4, 150 ˚C, 3 h, 74%; ii trifluoroacetic acid (TFA), DCM rt,

    then MsCl, EtMs = methanesulfonyl

    3N, DCM, 0 ˚C, then H2, Pd-C, MeOH.

    Scheme 1.15

    1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 15

  • R1

    R2 R3 NR4

    OO

    N

    R4

    R3

    R1 R2

    NO

    R4

    R1R2

    R3

    NO

    R4

    R1R2

    R3N

    O

    R4

    R1

    R3

    R2

    N

    O

    R4

    R1

    R3

    R2

    (67)

    (68)

    (69) (70)

    (72)(71) (73)

    4 5

    Scheme 1.16

    N

    O

    TBDPSO OTBDPS

    HN

    OTBDPS

    OTBDPSO

    N

    TBDPSO OTBDPS

    O

    H

    N

    ORH

    OR

    N

    OOTBDPSH

    OTBDPSi ii

    iii

    R = TBDPS

    R = H

    (75) (76) (74) (77)

    (79)

    (49)

    (78)iv

    Reagents: i PhH, rt, 7 days, 75%; ii xylenes, 140 ˚C, 1.5 h, 45%; iii TsNHNH2, MeOH,

    7 h, then NaBH

    TBDPS = tert-butyldiphenylsilyl

    4, 65 ˚C, 20 h, 45%; iv 40% aq HF, CH3CN, rt, 2 days, 70 %.

    Scheme 1.17

    16 Nitrones

  • lower temperatures (97). The authors were also able to prepare adducts from

    bicyclopropylidene (80) (113–117) and methylene spirocyclopropyl dipolarophiles(81–83) (118–120), which were transformed on heating into spirocyclopropylpiperidones (e.g., 84) from dipolarophile 81, as aza-analogues of the illudin familyof cytotoxic sesquiterpenes (85a–b) (Fig. 1.2). This rearrangement has beenapplied to the synthesis of racemic indolizidine elaeokanine A and precursors

    of (�)-lupinine and (�)-epilupinine (121) and related targets (122) as well as (2S)-4-oxopipecolic acid, a rare amino acid found in the virginiamycin cyclic peptides

    (123).

    This work has since been extended to cyclobutyl isoxazolidine adducts (e.g., 86)from the cycloaddition of 87 to methylenecyclopropane (88) (Scheme 1.18) (124–127). Thermolysis afforded a mixture of products, of which the bicyclic azepinone

    (89) predominated. Spirocyclic adducts were also prepared from an intramolecularreaction in the synthesis of cyclic amines (Scheme 1.72, Section 1.11.3).

    A further rearrangement route to bicyclic aminoketones has been investigated by

    Padwa et al. (128–134) (Scheme 1.19). Building on the allene–nitrone cycloaddi-

    tions reported by Tufariello, the alkenylisoxazolidine adducts 90 and 91 were

    N

    OtBuO

    H

    OtBu

    O

    OH

    HO R

    RMeO2C

    (83) n = 0, 1, R = H, Cl

    (80) (81)

    (82) (85a) Illudin S (R = OH)(85b) Illudin M (R = H)

    (84)

    n

    Figure 1.2

    N

    O

    NO

    FVT

    NO

    25%100 ˚C, 4 days90%

    (86)(87) (89)

    (88)

    FVT = flash vacuum thermolysis

    Scheme 1.18

    1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 17

  • prepared from the reaction of the corresponding cyclic nitrones 92 and 93,respectively, and an electron-deficient allene dipolarophile, with chemoselection

    for the more hindered, more electron-deficient alkene in almost every case. The

    pyrrolizidine and indolizidine skeletons were prepared by thermolysis of these

    adducts at 80–90 �C (sealed tube, 8 h) to afford the bicyclic aminoketones 94 and 95via a proposed diradical mechanism.

    1.6. PEPTIDES AND AMINO ACIDS

    3-Hydroxy-4-methylproline (96) is a common structural feature of theechinocandins and mulundocandins, which exhibit specific fungicidal activities,

    and as such this moiety has been retained in a number of synthetic antifungal

    agents. Langlois and Rakotondradany (80) have prepared the natural (2S,3S,4S)

    form of 96 by the 1,3-dipolar cycloaddition of (1-ethoxy)ethoxymethyl protecteda,b-unsaturated g-lactam (97) [prepared from (S)-pyroglutaminol] (79) with excessN-methylnitrone, which affords the desired adduct 98 (70%) along with theregioisomer 99 (9%) (Scheme 1.20). Quantitative reduction of the lactam carbonylwith diisobutylaluminum hydride (DIBAL) and sodium cyanoborohydride was

    followed by a protection exchange, N��O cleavage, Cope elimination, and enantioselec-tive hydrogenation to afford the target amino acid 96, isolated as the hydrochloride.

    Similarly, Kibayashi and co-workers (135) installed both chiral centers in the

    unusual peptide-like antibiotic (þ)-negamycin (100) by a cycloaddition strategy(Scheme 1.21). d-Gulose-derived nitrone d-101 was reacted with carbobenzoxy(Cbz)-protected allylamine to afford an inseparable mixture of two isoxazolidines,

    102 and its C(3) epimer. After N-protection exchange, reduction of the esterfunction allowed separation as the corresponding alcohols 103. Tosylation, homo-logation with NaCN and nitrile hydrolysis in methanol afforded the correct chain

    length at C(3) of the (3R,5R) isomer 104 before activated ester coupling of thehydrazide moiety and deprotection gave the natural product (þ)-100 (135).

    The use by Langlois of an amidoalcohol (79,80) is an unusual strategy for the

    construction of a-amino acids. More commonly, the required amine and carboxylicacid functionalities are carried into the cycloaddition in the dipolarophile, as a

    homochiral alkenyl a-amino acid derivative. Importantly, this introduces a second

    N

    O

    CO2Me•

    Me

    N O

    H CO2MeMe

    N

    H CO2MeMe

    On n

    (90) n = 1(91) n = 2

    (94) n = 1(95) n = 2

    (92) n = 1(93) n = 2

    n

    Scheme 1.19

    18 Nitrones

  • N and O function into the molecule and has been used to prepare hydroxyarginines

    (136,137), hydroxyornithines (136–138), b-lysine, b-leucine, and b-phenyl-b-alanine (139,140), the low-calorie sweetener aspartame (141) and the antitumor

    antibiotic acivicin (142–144).

    NO

    Boc

    OPN

    O

    Me

    NO

    Boc

    OP

    NO

    Me

    NH

    OH

    OHMe

    O

    NO

    Boc

    OP

    ON

    Me

    toluene, 110 ˚C

    (99) (9%)(97) (98) (70%)

    (96)

    P = CH(Me)OEt

    steps

    2

    34

    Scheme 1.20

    CbzHN R

    O NBn

    CbzHN

    OH NH2

    NH

    N

    O Me

    CO2H

    CbzHNNO

    Aux

    CO2Me

    Aux =(103) R1 = CH2OH

    (104) R1 = CH2CN

    3

    3

    D-(101)

    (100)

    (102) R1 = CO2Me

    i-iii

    iv

    v

    vi-x

    5

    Reagents: i PhMe, ∆; ii 10% HCl, MeOH, 40 ˚C; iii BnBr, K2CO3, DMF, 50 ˚C; iv LiAlH4, Et2O,0 ˚C to rt; v TsCl, EtN(iPr)2, DCM, 0 ˚C to rt then NaCN, dimethyl sulfoxide (DMSO), 80 ˚C;

    vi HCl,

    EtOH, rt; vii aq NaOH, MeOH, rt; viii EtOCOCl, Et3N, PhMe, 0 ˚C; ix H2NN(Me)CH2CO2Bn, PhMe,

    0 ˚C to rt; xH2, 10% Pd-C, MeOH, aq AcOH.

    O

    O O

    O

    O

    Scheme 1.21

    1.6. Peptides and Amino Acids 19

  • An unusual route was described by Tamura et al. (42,84,85,145–148) in which

    b-substituted a-amino acid precursors were formed by a tandem transesterificationand cycloaddition process (Scheme 1.22). The alkenyl nitrone 105 was formed bythe treatment of chiral nitrone 106 (with a carboxylic ester substituent on thenitrone carbon atom) with an unsaturated alcohol in the presence of catalytic TiCl4.

    Spontaneous intramolecular dipolar cycloaddition of this reagent afforded adduct

    107 and a diastereomer with moderate selectivity (3:1) using (R)-a-phenylethylchiral auxiliary on the nitrone nitrogen atom. Thus, after further synthetic

    manipulation including ruthenium-mediated oxidative cleavage of the aromatic

    ring, adduct 107 afforded the b-functionalized a-amino esters 108. Similarly,b-aminoalcohol functionality was introduced with a small measure of stereoselec-tivity into intermediates of potent oligoamide renin inhibitors through the use of a

    homochiral alkenylamine dipolarophile (149).

    Peptide functionality may be prepared in a homochiral dipolarophile for

    subsequent cycloaddition reaction, as demonstrated in the synthesis of peptidomi-

    metic isoxazolidine anatagonists of human neurokinin-A by Brandi and co-workers

    (150) (Scheme 1.23). The 1,3-dipolar cycloaddition of macrocyclic maleic acid

    diamide (109) to a tert-butoxypyrrolidine nitrone (110) afforded in 86% yield a25:1 mixture in favor of 111 (via transition state exo-A) over its regioisomer (fromexo-B) after a 27 h reaction in refluxing toluene. Comparable yields but lowerselectivities were observed in DMSO, indicating that, with the existence of an

    equilibrium excluded, a conformational change in the peptide enforces a change in

    regioselectivity. The observed products are rationalized in terms of double asym-

    metric induction. First, the alkene functionality of the macrocyclic dipolarophile

    109 can only reasonably be approached via an exo transition state, and so endo

    NOR*

    MeO2C OHAr

    R CO2Me

    CH2OAc

    NHBoc

    OON

    OR*

    Ar H

    H

    N

    OAr

    R*O

    O

    HH

    H

    1,3-DC

    TiCl4, 4A mol sieves, ClCH2CH2Cl

    R* = (R)-1-Ph-ethylAr = p-MeO-C6H4

    (106) (105)

    (107)(108) R = CO2H, CH2OH, N3

    steps

    Scheme 1.22

    20 Nitrones

  • approach (endo approach to the top face of 109 is arrowed) is excluded on stericgrounds. Additionally, the dipole 110 is also facially discriminating, only toleratingreaction at the face opposite the bulky C-tert-butoxy substituent. Furthermore, the

    dipolarophile 109 exerts a preference for reaction at its lower face as drawn (viatransition state exo-A), through steric crowding of the upper face by the indolemoiety of the tryptophan residue (exo-B).

    Alternatively, some of the desired amino acid functionality may be contained

    within the nitrone fragment, as in the synthesis of homochiral allyl glycines by

    Katagiri et al. (151), which reveals the carboxylate by hydrolysis of a lactone in the

    dipole (Scheme 1.24). Here, thermolysis of nitroso Meldrum’s acid (112) via anitrosoketene intermediate 113 and reaction with l-menthone gave the separablenitrones 114a (26%) and 114b (28%) by a [3 þ 2] cycloaddition, although a

    ONH

    NH

    O

    HN

    NHO

    O

    HN

    NOOt-Bu

    NO

    t-BuO

    O

    N

    HN

    O HN

    NH

    O

    O

    Ph

    HN

    Ph

    NO

    H H

    H

    t-BuO

    H

    (111)

    (109)

    (110)

    (110)

    exo-B

    exo-A

    endo

    Scheme 1.23

    1.6. Peptides and Amino Acids 21

  • possible [4 þ 2] addition and 1,2-migration pathway was also acknowledged.Cycloaddition of nitrone 114a with allyltrimethylsilane under high pressureproceeds to the isoxazolidine 115 as a single isomer in excellent yield (90%),which becomes quantitative with boron trifluoride–diethyl etherate catalysis. The

    high stereoselection is explained through steric hindrance of the lower face of the

    nitrone by the pendant isopropyl group of the menthyl auxiliary, allowing addition

    of the dipolarophile to the upper face only. The carboxylic acid functionality was

    revealed by hydrolysis of the oxazolidinone to give 116 and afforded the (S)-allylglycine 117 by N��O bond hydrogenolysis followed by a Peterson-type eliminationwith boron trifluoride. The isomeric nitrone (114b) afforded (R)-117 by identicaltreatment. Another significant use of this strategy is the preparation of pyroglutamic

    acids (118 ) by Merino et al. (152,153) using the cycloaddition of furfuryl nitroneswith acrylate esters or the acrylamide of Oppolzer’s bornane-10,2-sultam chiral

    auxiliary (Scheme 1.25). As a key step in the synthesis, the furfuryl side chain

    was used as latent carboxylate functionality, conversion being achieved using

    ruthenium-mediated oxidation (RuO2��NaIO4). Semiempirical and ab initio calcu-lations supported the experimental findings in which (3R,5R) isomer 119 wasconsistently found to be the major product.

    As part of their exploration of peptide secondary structure, Hermkens et al.

    (154) reported an innovative use of the nitrone dipolar cycloaddition

    O

    O

    O

    N

    O

    O

    OH

    O

    NH2

    −CO2

    NC

    O

    O

    ONH

    TMS

    OH

    O

    O

    ON

    O

    O

    ON

    O

    O

    TMS

    NO

    O O−acetone

    (114a) (26%)(112) (113) (114b) (28%)i

    iiiii-iv

    (S)-(117) (116) (115)

    Reagents: i Allyltrimethylsilane, 800 MPa, toluene, 40 ˚C, 90%; ii 0.15 M aq NaOH,

    4 h, 100%; iii H2, Pd-C, MeOH, 88%; iv BF3•Et2O, MeCN, 3 h, 100%.

    Scheme 1.24

    22 Nitrones

  • (Scheme 1.26).The reaction of homochiral amino acid derived nitrone 120 withthe complex allyl amide 121 afforded a mixture of three isoxazolidinediastereoismers. Catalytic hydrogenolysis of the benzyl ester and Cbz protecting

    groups was followed by amide coupling with O-(1H-benzotriazol-1-yl)-N,N,N 0,N 0-tetramethyluronium tetrafluoroborate (TBTU) and acidolysis of the Boc and tert-

    butyl ester. The resultant macrobicyclic isoxazolidinyllactam b-turn mimics (e.g.,122) were tested for activity in a human platelet aggregation assay, in which thenegative results suggest that a b-turn is not present in the bioactive form of thereceptor.

    O NR

    ON

    SO2

    O

    N

    Boc

    HO

    CO2Me

    (118)(119)

    steps

    Scheme 1.25

    BocHN

    NCbz

    NHCbzHN

    N

    O

    CO2Bn

    CbzHN

    NO

    Bnt-BuCO2

    CO2t-Bu

    NO

    N

    N

    H2N

    NH

    O

    CO2HO

    BnHO2C

    H

    NHH2N

    i-iv(120)

    (121)

    (122)

    Reagents: i PhMe, 15 kbar, 50 ˚C, 2 days; ii H2, Pd-C, MeOH, iii DMF, TBTU, pH 8.0, rt;

    iv TFA, PhOH, H2O, (i-Pr)3SiH (88:5:5:2).

    Scheme 1.26

    1.6. Peptides and Amino Acids 23

  • 1.7. SUGARS

    Carbohydrates are in common use in nitrone cycloaddition chemistry, whether in

    the synthesis of homochiral dipoles from a readily available chiral pool (155–162)

    or as off-the-shelf homochiral dipolarophiles (163–165), and also constitute

    important synthetic targets (166–168). The carbohydrate-derived nitrones of

    Vasella and co-workers (169) are among the earliest examples of homochiral cyclic

    nitrone 1,3-dipoles and applications include the addition of methyl methacrylate to

    the spirocyclic nitrone 123 (Scheme 1.27). The isoxazolidine 124 was the majorproduct isolated from a mixture containing the C(2) epimer 125 and two regioi-somers (83:2:7.5:7.5, respectively). The assignment of stereochemistry of adduct

    124 is supported by X-ray crystallography and, against expectation, the configura-tion at C(4) of the major product is consistent with the approach of the dipolar-

    ophile to the sterically crowded face of the nitrone 123 (anti to the C(4) to O bond).The diasteromeric excess (de) at C(2) of 81% (124:125¼ 83:2%) indicates a strongpreference for the ester in an endo position in the transition state. Reaction of 123with methyl acrylate afforded a more complex mixture, which showed that reaction

    proceeds with a similar regiochemical preference but with little facial or endo–exo

    selectivity.

    Elsewhere, the reaction of styrene with nitrones derived from cyclic acetals of

    d-erythrose (e.g., 126) or d-threose has afforded a mixture of diastereomericisoxazolidines (Scheme 1.28) (170,171). In all cases, nuclear magnetic resonance

    (NMR) analysis suggests that the major product contains the C(3)/C(4 0) erythro

    O

    N

    O

    O O

    O

    O CO2Me N

    O

    H

    CO2Me

    N

    O

    H

    CO2Me

    CHCl3, 70 ˚C 30 min

    (123) (124)

    2

    (125)

    4

    4

    Scheme 1.27

    O

    O

    NO

    OH

    Ph

    Ph

    (126)

    O

    O

    ON

    Ph

    Ph

    OH

    (127)

    toluene, ∆, 10 h77%

    3

    4

    5

    4′2

    Scheme 1.28

    24 Nitrones

  • C(3)/C(5) cis product (e.g., 127) and was confirmed by X-ray crystallography.The stereoselectivity of addition increases with the bulk of the N-substituent of the

    nitrone, and is rationalized through the less-hindered endo approach of the

    dipolarophile to the more reactive (Z)-nitrone. While the stereoselection was

    unpredictable, all of the nitrones exhibited total regioselectivity for the 5-phenyl

    isoxazolidines. This work bears some similarity to the approach of DeShong et al.

    (172,173) who prepared amino- and deoxy-sugars from the cycloaddition of non-

    carbohydrate derived nitrone acetals (Scheme 1.29). Reaction of 128 with vinyl-trimethylsilane afforded a diastereomeric mixture of isoxazolidine intermediates

    129, which underwent a complex bond cleavage cascade induced by treatment withdilute HF, ultimately to afford a single a,b-unsaturated aldehyde 130. Thisintermediate is a latent 5-hydroxyaldehyde and, once revealed by enal reduction

    and acetonide hydrolysis, underwent a ring closure to afford the trideoxyhexose

    sugar rhodinose 131 as a mixture of anomers. The ethyl vinyl ether-derived adduct132 afforded the 3-amino-5-hydroxyaldehyde 133 by a more familiar hydrogeno-lytic N��O bond cleavage and spontaneously formed the amino sugar daunosamine(134), isolated as the protected methyl glycoside (135).

    NOMe SiMe3

    OO

    MeH

    OO

    MeH

    NO

    R

    OMe

    R1O

    OR2

    NHR1O

    OH

    OH

    MeOO

    MeH

    CHO

    NOBn OEt

    OO

    Me

    HH

    OH

    CHO

    Me

    H2N

    OH

    R = Me R = Bn

    (128) (129)

    (133)

    (132)

    (130)

    (134) R1 = R2 = H

    (135) R1 = Ac, R2 = Me

    iv

    ii

    iii-iv

    vi

    (131)

    Reagents: i CH2=CHSiMe3, 80 ˚C, 24 h, 90%; ii 50% aq HF, MeCN, rt, 30 min; iii H2, 5% Pd-C, EtOH, 2 h; iv 2% aq HCl, acetone, rt, 40 % from 128; v CH2=CHOEt, ∆, 72 h, 93%; vi H2, 5% Pd(OH)2, 10% HCl / MeOH, 48 h, then Ac2O, py, 4-(dimethylamino)pyridine (DMAP), 24 h rt

    Scheme 1.29

    1.7. Sugars 25

  • The most commonly reported carbohydrate-derived dipolarophiles are the

    a,b-unsaturated lactones (70–73,174–177). Chmielewski and co-workers (73)prepared the polyol b-lactam 136 via a nitrone cycloaddition strategy based onthe Tufariello approach (178) and took advantage of the regioselectivity of the

    cycloaddition of nitrones to ene–lactones, in which the nitrone oxygen is added at

    C(3) of the sugar d-lactone (Scheme 1.30). Adduct 137 was the sole product of thecycloaddition of N-phenyl-C-(4-methoxyphenyl)nitrone with enelactone 138, butunexpectedly, conventional N��O bond hydrogenolysis resulted in deamination. Theisoxazolidine ring of 137 was successfully opened after conversion to 139 by esterhydrolysis and protection of the acid (as the benzyl ester) and hydroxy moieties

    (as silyl ethers). The acyclic aminoester intermediate 140 underwent ring-closure mediated by 2-chloro-1-methylpyridinium iodide to afford the b-lactamskeleton 136.

    In recent work, Chmielewski and co-workers (174) reported the highly stereo-

    selective reaction of ene–lactones with chiral pyrrolidine nitrone (141) to affordtricyclic adducts (Scheme 1.31). A 1:1 mixture of ene–lactone 142 and nitrone 141provided adduct 143 with an uncharacterized isomer (97:3) (91%) while homo-chiral d-glycero (138) gave the adduct 144 as a single diastereomer (88%). A 2:1mixture of racemic 138 and nitrone 141 afforded a 91:1 mixture of the two possibleadducts, representing an effective kinetic resolution of the racemic lactone.

    O

    OAc

    O

    N

    Ph

    O

    H

    Ar

    NO Ph

    ArHOTBDMSO

    TBDMSOH

    O

    OAc

    O

    ON Ar

    Ph

    H H

    TBDMSONHPh

    TBDMSO OH

    CO2H

    Ar

    ON Ar

    Ph

    CO2Bn

    OTBDMS

    OTBDMS

    PhMe, N2, ∆, 8 h,

    80%

    i-ii

    iii

    iv

    (138)

    (136) (140)

    (139)(137)

    Ar = 4-MeO-Ph

    3

    Reagents: i KOH, dioxane, H2O, rt, overnight, then BnBr, 18-crown-6, DMF, 60%; ii TBDMSCl,

    imidazole, DMF, 0 ˚C, then rt, overnight, 90%; iii H2, 2 atm, 10% Pd-C, EtOH, 2 h,

    85%; iv 2-chloro-1-methylpyridium iodide, Et3N, DCM, rt, 2 h, 80%.

    Scheme 1.30

    26 Nitrones

  • Observed adducts arise through exo addition of the lactone to the re–re face of the

    nitrone 141, which avoids an unfavorable C����O/O-tert-butyl steric clash.Langlois and co-workers (179) found the same exo stereochemical preference

    through double asymmetric induction of a related ene–lactone (R)-145 with theirwell-explored and efficient camphor-derived oxazoline nitrone (1S)-146 (Scheme1.32). They found the cycloaddition components form a matched pair and allowed

    kinetic resolution of the racemic lactone in up to 70% enantiomeric excess (ee).

    They suggest the selectivity for exo adduct 147 arises through destabilization of theendo transition state by a steric clash between dipolarophile ring hydrogens and the

    bornane moiety.

    Borrachero et al. (180) prepared a number of sugar isoxazolidines by the

    reaction of carbohydrate-functionalized nitrones with nitroalkenes (Scheme 1.33).

    They found a matched pair of chiral sugar cycloaddition reaction partners to be

    O

    ON Ot-Bu

    H HH

    Ot-Bu

    O

    OAc

    O

    OAc

    O

    N

    t-BuO Ot-Bu

    O

    OO

    O

    ON Ot-Bu

    H HH

    Ot-Bu

    O

    (138)

    (141)

    (142)

    (144)

    (143)

    88% 91%

    Scheme 1.31

    N

    O

    O

    O

    O

    C11H23N

    O

    OO

    OH

    H C11H23

    H

    (1S)-(146) (R)-(145) (147) exo

    80 ˚C, 12 h

    84%

    Scheme 1.32

    1.7. Sugars 27

  • much more effective than a single carbohydrate auxiliary, which also suffered some

    isomerization on silica gel. In all the isoxazolidine adducts, the nitro group is at

    C(4) and the trans geometry of the alkene is maintained, as expected. Thus, the

    reaction of nitrone 148 with alkene 149 (both derived from a-d-galactose) affordeda 7:1 mixture of the two possible exo adducts 150 and 151. The ratio is improved byusing a matched pair of a-d-xylose-derived components (152 and 153) to afford a9:1 mixture of adducts 154 and 155. Similarly, Wightman and co-workers (181)found excellent yields and stereoselectivies in the addition of a d-lyxose-derivednitrone to d-mannosyl- and d-galactosyl alkenes, although each cycloadditioncontributes only one new chiral centre to the target aza-C-disaccharides (e.g.,

    156). Brandi and co-workers (182,183) used their tartaric and malic acid derivednitrones in the preparation of a number of pseudo-aza-C-disaccharides (e.g., 157)and reported significant rate and yield enhancements under high pressure (184).

    The intramolecular cycloaddition of an alkenyl nitrone by Tronchet in 1972 was

    the first example using a sugar derivative (185). Since then, many researchers

    investigated the intramolecular reaction of nitrones generated from sugars, in

    particular those from O-allyl carbohydrates, which can give rise to tetrahydro-

    pyanyl- or oxepanyl-isoxazolidine cycloadducts (Scheme 1.34) (186–193). Shing’s

    work demonstrates that the stereochemical outcome depends only on the relative

    configuration at C(2) and C(3) of the sugar (192). Thus, threo d-hexose-derivedallenylnitrone 158 (from 3-O-allyl-d-glucose 159) afforded oxepane 160 only(isolated as the tetraacetate) while the regioisomeric tetrahydropyran (161) was

    NBn O

    R NO2

    R

    PhMe

    O

    O

    OO

    O

    O

    O

    O

    BnO

    O

    HN

    OH

    OH

    OH

    OH

    HO

    OH

    OH

    N OBn

    R

    R

    NO2

    (156)

    N OBn

    R

    R

    NO2

    O

    HO

    HO

    OH

    OH

    NHHO

    HO (157)

    Gal =

    Xyl =

    (148) R = Gal

    (152) R = Xyl

    (149) R = Gal

    (153) R = Xyl

    (150) R = Gal

    (154) R = Xyl

    (151) R = Gal

    (155) R = Xyl

    50−100 ˚C

    Scheme 1.33

    28 Nitrones

  • not observed. Conversely, a tetrahydropyranyl adduct was the sole product of an

    analogous erythro alkenyl nitrone derived from d-mannose. The authors proposetwo interconvertible chair-like transition state conformations for tetrahydropyran

    formation by intramolecular cycloaddition of threo-nitrone 158 (transition states Aand B). Both conformations incur unfavorable 1,3-diaxial interactions andthe tetrahydropyranyl product is not observed, while no such impediment exists

    in the erythro series. Exclusive formation of oxepane (160) from nitrone (158) canthus be rationalized via the relatively favored seven-membered transition state C.Yields for the unprotected carbohydrates are moderate and the presence of

    decomposition products has prompted further work on benzyl–ether protected

    derivatives.

    1.8. SULFUR- AND PHOSPHORUS-CONTAININGCOMPOUNDS

    While nitrones have demonstrated reactivity toward a number of sulfur-

    containing dipolarophiles including C����S multiply bonded molecules, by far the

    O

    O OH

    OH

    HO

    OH

    O

    ON

    HO

    HOHO

    OH

    Me

    O

    OH

    N

    Me

    O

    HOHO

    OH

    ON

    HO

    RO

    Me

    O

    O N

    HO

    R

    Me

    (B)

    (A)

    OOH

    R

    NO

    Me

    (C)

    O

    OH

    HOHO

    OH

    N O

    Me

    OH

    OH

    OH

    R =

    (159)(158)

    (161)

    (160)

    i

    Reagents: i MeNHOH•HCl, NaHCO3, 80% aq EtOH, ∆, 48 h.

    Scheme 1.34

    1.8. Sulfur- and Phosphorus-Containing Compounds 29

  • most common are the vinyl sulfur compounds (194,195). The known cycloaddition

    reaction of chiral vinyl sulfoxide dipolarophiles with acyclic nitrones has now been

    extended to cyclic dipoles by two independent groups. The reaction of tetra-

    hydropyridine N-oxide 93 with (S)-p-tolyl vinyl sulfoxides (162) in ether for 7–10days afforded exclusively the exo adducts, with 163a as the major product alongwith its diastereomer 163b in 89–98% de and 85–97% yield (Scheme 1.35) (196).The high regio- and stereoselectivity of the addition was first confirmed for selected

    adducts by reduction with TMSI/NaI to enantiomeric sulfides [e.g., 163b (R¼Me)to 164]. Reductive cleavage of the N��O bond of adduct 163a (R¼Me) andsimultaneous desulfurization with Ni/Al amalgam afforded the known piperidine

    natural product (þ)-sedridine (165) along with its C(7) epimer. To overcome thisepimerization, selective cleavage of the N��O bond was followed by protection ofthe amino functionality before desulfurization with Raney nickel. Deprotection

    with TMSI rapidly and efficiently reveals the enantiomerically pure natural product

    165 (97% yield).The reaction of tetrahydropyridine N-oxide (93) (n¼ 1) with a chiral sulfinyl

    maleimide dipolarophile (166) has been reported (Scheme 1.36), but afforded themajor product 167 with only modest stereoselectivity, despite the use of a

    N

    O

    S

    R

    O

    p-TolN

    O

    H

    R

    Sp-Tol

    HN

    O

    H

    R

    Sp-Tol

    H

    N

    O

    H

    S-p-TolN

    OH

    SH

    R′p-Tol

    NH

    OH

    (92) (162) (163a)

    (163b)

    (164)

    R′ = H

    R′ = CO2CH3

    i

    iiiii

    v-vi

    (165)

    iv

    .. .. ..

    ..

    Reagents: i Et2O, rt, 7−10 days, 85−97%; ii TMSI, NaI; iii Ni/Al, aq KOH, MeOH, rt, 2 h, 93%; iv ClCO2CH3, aq K2CO3, rt, 18 h, 98%;

    v W-6 Raney Ni, H2, MeOH, 18 h, 84%; vi TMSI, DCM, ∆, 1 h, then MeOH, rt, 10 min, 97%.

    O O

    O

    Scheme 1.35

    30 Nitrones

  • homochiral sulfoxide carrying a bornyl alcohol chiral auxiliary (R*) (197).

    Conversely, reaction with 1-pyrroline N-oxide (92) afforded an inseparable mixtureof products.

    Aggarwal et al. (198) reported nitrone cycloaddition reactions with the unusual

    disulfoxide dipolarophile trans-2-methylene-1,3-dithiolane (168) (Scheme 1.37).The question of exo/endo selectivity of the cycloaddition reaction is avoided by the

    use of this C2-symmetric dipolarophile for which only two transition states are

    N

    O

    N

    O

    O

    S

    BnDCM

    N

    O

    O

    BnNO

    H S

    R O

    H

    OHR =

    (92) n = 0(93) n = 1

    n

    (166) (167)

    −78 ˚C..

    n

    *

    *

    *R

    O

    Scheme 1.36

    S

    S

    O

    O

    NMe

    O

    Ph

    S

    S

    O

    N

    Me

    OH

    Ph

    O

    (A)

    O

    O

    SS O

    N

    PhMe

    O

    S

    S

    O

    (B)

    N

    Me

    OH

    Ph

    O

    O

    SS O

    N

    PhMe

    86%

    (170)

    (169) (170) 0%

    (169)

    (168)

    DCMrt, 13 h

    Scheme 1.37

    1.8. Sulfur- and Phosphorus-Containing Compounds 31

  • possible. Thus, the reaction of 168 with N-methyl-C-phenyl nitrone can lead to twodiastereomeric products 169 and 170, but only 169 is observed, via the favoredtransition state A. The disfavored transition state B is characterized by a repulsionbetween the nitrone phenyl moiety and the sulfinyl oxygen. The complete regio-

    selectivity for 4,4-disubstitution in the isoxazolidine cycloadducts is unusual for

    addition of a nitrone to 1,1-disubstituted alkenes. Similarly, high selectivities were

    also found in the reaction of 168 with simple cyclic nitrones.Elsewhere, the intramolecular cycloaddition of a nitrone carrying a vinyl

    sulfoxide or vinyl sulfone moiety has been examined (Scheme 1.38) (199). The

    nitrone reagents 171a–b were generated by condensation of an N-substitutedhydroxylamine with the corresponding aldehydes 172a and 172b followed bythermal cheletropic removal of SO2. The cis-fused cycloadducts 173 predominate inthe cycloaddition reactions of the 5-dienylnitrones (171a, n¼ 1) with either sulfideor sulfone substituents and is explained in terms of a more highly strained transition

    state for the trans isomer. In contrast, of the 6-dienyl analogues 171b (n¼ 2), onlythe sulfones retain stereoselectivity. The phenylsulfide adduct 173 (x¼ 0) has beentransformed into a bicyclic azetidine, a rare heterocyclic 4,5-ring system. A four-

    membered ring system has also been utilized in the more common intermolecular

    cycloaddition of vinyl sulfones in which electrochemically generated 1-phenylsul-

    fonylcyclobutene (174) was reacted with a range of nitrones to afford cyclobutenylisoxazolidines (175) (Scheme 1.39) (200).

    SO2

    CHO

    S(O)xPhS(O)xPh

    NO

    R(173)

    NO

    H

    H

    Ph(O)xS

    R

    i-ii

    (172a)(172b)

    n = 1n = 2

    (171a)(171b)

    n = 1n = 2

    n

    Reagents: i RNHOH•HCl, NaOMe, rt; ii PhMe, 95 ˚C

    nn

    Scheme 1.38

    SO2Ph

    NR1O

    R2

    NO

    H

    PhO2S R2

    R1

    (174) (175)

    Scheme 1.39

    32 Nitrones

  • The use of C-furfuryl nitrones by Merino and co-workers (201) as latent

    carboxylate functionality (see Section 1.7) has inspired the development of an

    analogous C-thiazolyl nitrone. Thus, after reaction of this dipole with acrylate

    esters, the authors take advantage of the thiazolyl-to-formyl synthetic equivalence

    to reveal aldehyde functionality after reduction with sodium cyanoborohydride.

    There have been simultaneous reports of the intramolecular cycloaddition of

    alkenyl nitrones bearing alkenylsulfide (202,203) or alkenylsulfone substitutents

    (Scheme 1.40) (203). In both cases, the isolated products were the corresponding

    fused bicyclic isoxazolidine adducts 178 and 179, respectively.Brandi and co-workers (204) utilized phosphorus chirality in a dipolarophile for

    a 1,3-dipolar cycloaddition reaction with 2,2-dimethyl-3,4-pyrroline-N-oxide (87)(Scheme 1.41). They found diastereoselectivity was possible through judicious

    choice of the substitution at phosphorus of vinylphosphine oxides and sulfides. The

    most successful additions were between the dipole 87 and P-diallyl-P-tert-butyl-phosphine oxide 180 or the corresponding phosphine sulfide 181. These adducts,isolated in good yields (84 and 80%, respectively) show almost total diasteroselec-

    tivities for the isoxazolidines 182 and 183 over the corresponding enantiomericadducts, with stereochemical assignments based on X-ray crystallographic analysis

    of sulfide 183. In later work, an enantiopure nitrone generated from l-tartaric acidwas reacted with a racemic dihydro-1-phenylphosphole, to give predominantly the

    (S)-P product over its (R)-P enantiomer (3:1, 91% total yield) along with the

    unreacted (R)-phosphole (27%) almost completely resolved (> 96% ee) (205).

    N

    S(O)x

    O

    Bu

    Ph

    S(O)xO

    N

    Bu

    Ph

    H

    H

    S ON

    H

    H R2

    R1

    N

    S

    R1

    R2O

    (179) x = 0, 2(176) (177)(178)

    Scheme 1.40

    N

    O

    P

    X

    t-Bu

    CHCl3

    (87)

    N

    OP

    t-Bu

    25 ˚C, 10−15 days

    (182) X = O

    (183) X = S

    (180) X = O

    (181) X = S

    X

    Scheme 1.41

    1.8. Sulfur- and Phosphorus-Containing Compounds 33

  • 1.9. CATALYTIC CYCLOADDITIONS

    The widespread use of chiral nitrones or dipolarophiles in enantioselective

    cycloaddition reactions relies on effective asymmetric induction in the synthesis of

    the homochiral cycloaddition component. Thus, chiral catalysts that could control a

    cycloaddition reaction at substoichiometric levels would be powerful additions to

    the synthetic literature. The search for such catalysts, the fastest growing field of

    cycloaddition chemistry, has made significant progress since the pioneering work of

    Kanemasa in 1992 and the first enantioselective nitrone cycloaddition reaction in

    1994. This field is now regularly reviewed (33,35,206). Much work has concen-

    trated on the use of salts of magnesium, zinc, copper and titanium (84,85,207–216)

    including the use of complexes of bis(oxazoline) (184) (217–220) and tetraaryl-dioxolanedimethanols (TADDOLs) (185) (Fig. 1.3) [221,222]. Elsewhere, nickelcatalysis in the presence of an unusual bis(oxazoline) was reported (223) as well as

    the cycloaddition of a platinum-coordinated nitrile dipolarophile (224). A number

    of workers have used metal complexes of 2,2 0-dihydroxy-1,1 0-binaphthyl (BINOL)(186) and its derivatives, including those with aluminium (225–227) and lantha-nides (228–230). Other use of lanthanides includes the reactions catalyzed by

    Eu(fod)3 [europium tris(6,6,7,7,8,8,8-heptafluoro-2-2-dimethyl-3,5-octanedionate)]

    (231) or lanthanide triflates, both in solution (232) and on polymer support (233).

    Trimethylsilyl triflates have also been employed (234,235) while alternatives to the

    BINOL ligands include binaphthylphosphine complexes with palladium (236,237).

    In earlier work, the cycloadditions of chiral chromium tricarbonyl (238–240) or

    iron tricarbonyl complexed (241) nitrones have been investigated.

    1.10. PYRROLIDINES, PIPERIDINES, AND OTHER AMINES

    The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made

    attractive targets for total synthesis, particularly since many contain a hydroxyl moiety

    adjacent to the amino group. This functionality is the case with the pseudodisto-

    mins–piperidines with antitumor activity isolated from the Okinawan tunicate

    Pseudodistoma kanako. The limited availability of the natural material has prompted

    N N

    O OR R

    RRPh PhM

    X X

    O

    O OTiX2

    O O

    OM Me

    (184) X = OTf, SbF6, etc.

    Ts = paratoluenesulfonyl

    (185) X = Cl, OTf, OTs, etc. (186) X = Cl, OTf, OTs, etc.

    Figure 1.3

    34 Nitrones

  • a number of total syntheses, including the preparation of tetrahydropseudodistomin

    (187) by Naito et al. (Scheme 1.42) (243). The cycloaddition of the knowntetradecanal-derived nitrone 188 with (þ)-Boc-vinylglycinol (189) afforded amixture of four diastereoisomers in 79% combined yield. Isomer 190 was convertedto the bicyclic structure 191 via ring closure through nitrogen onto the side chainafter mesylation of the pendant alcohol. This bicycle was subjected to simultaneous

    N-benzyl and N��O hydrogenolysis, followed by amine deprotection with TFA, toafford the natural product 187. These workers have also used the cycloaddition ofallyl alcohols to nitrones to prepare the related piperidinol alkaloids (þ)-azimicacid and (þ)-julifloridine (244). Elsewhere, the formation of a bicyclic systemsimilar to 191 was used to prepare polysubstituted 4-hydroxypiperidines (245,246)and a-amino ester 192, the A-ring of cylindrospermopsin (247).

    A number of other simple cyclic amine targets with oxygen substitution have

    been prepared using a nitrone cycloaddition strategy to provide both the N- and

    O-functionalities. These include the pyrrolidines darlinine 193 and analogues (248),(þ)-preussin (194) (249) and the piperidines (�)-allosedamine (195) (250), and therelated structure 196 (251) as well as analogous b-aminoketones (Fig. 1.4) (252).

    The oxygen atom has also been used to generate other functionalities, such as the

    aldehyde moiety in Kibayashi’s syntheses of (�)-coniine (197) and its enantiomer(Scheme 1.43) (253). Here, reaction of tetrahydropyridine N-oxide 93 with asilylated chiral allyl ether dipolarophile 198 delivered the adduct 199 with thedesired bridgehead stereochemistry via the ‘‘inside alkoxy effect’’. Desilylation and

    hydrogenolytic N��O bond rupture with palladium(II) chloride provided the diol 200

    NBn

    OC13H27

    OH

    NHBoc

    C13H27 NH

    OH

    NH2

    MeO2C NH

    OH

    OH

    (192)

    NO

    C13H27

    HOH

    NHBoc

    Bn

    NC13H27

    NHBoc

    O

    BnMsO

    (187)

    (188) (189)

    (191)

    (190)

    i

    ii

    iii-iv

    Reagents: i PhMe, ∆, 94 h, 14%; ii MsCl, py, 0 ˚C; iii 10% Pd(OH)2-C, H2, MeOH, rt;

    iv TFA, DCM, rt.py = Pyridine

    Scheme 1.42

    1.10. Pyrrolidines, Piperidines, and Other Amines 35

  • from which the aldehyde function of 201 was formed by periodic acid oxidativecleavage. The side chain was lengthened by one carbon atom using a Wittig

    reaction followed by hydrogenation to afford the desired product (�)-coniine (197).The same aldehyde intermediate was later used by these workers in the synthesis of

    N

    Bn

    OHN

    Bn

    Ph

    OH

    (195)

    N

    Me

    OH

    Ph N

    OH

    Ph

    Me

    C9H19

    (196)

    (194)(193)

    Figure 1.4

    NH

    OH

    OH

    N

    O

    H

    H

    TBDPSO

    NH

    OTBDPS

    N

    O

    NH

    CHON N

    O

    H

    NH2

    (197)(201)

    (200)

    (93)

    (198)

    (199)

    i ii-iii

    iv-v

    visteps

    (202)

    Reagents: i PhMe, δ, 14 h, 69%; ii 1 M aq Bu4NF, THF, 45 ˚C, 1.5 h, 86%; iii H2, PdCl2, MeOH, 6.5 atm, 37 h, 91%;

    iv CbzCl, aq Na2CO3, DCM, rt, 16 h, 85%; v HIO4, THF, H2O, 0 ˚C, 2 h, 84%;

    vi Ph3 PMeBr, BuLi, THF, then H2, Pd-C, MeOH.

    Scheme 1.43

    36 Nitrones

  • the macrocyclic polyamine lactam alkaloid (�)-oncinotine (202) (254). Elsewhere,a substituted form of nitrone (93) was prepared by intramolecular 1,3-azaprotio-cyclotransfer (1,3-APT; see Section 1.11.1) and reacted with a diene dipolarophile

    in the synthesis of the tricyclic coccinelline alkaloid epi-hippodamine 203 inracemic form (Fig. 1.5) (255).

    The utility of the intramolecular cycloaddition reaction lies in its ability to form

    a bicyclic system during the addition and so lead to products of greater complexity

    (19,256). Chiacchio et al. (82) used the intramolecular cycloaddition of a nitrone

    containing an a,b-unsaturated amide in the same molecule to generate pyrrolidi-nones or piperidinones after N��O bond hydrogenolysis (Scheme 1.11, Section 1.4).While this strategy has been shown to allow access to substituted piperidines (257),

    the preparation of the cyclic amine rather than amide in the intramolecular

    cycloaddition reaction is far more commonplace. LeBel and Whang (258), who

    published the first example of an intramolecular nitrone cycloaddition in 1959,

    more recently reported a racemic total synthesis of the Dendrobatidae alkaloid

    pumiliotoxin C 204 (Scheme 1.44) (259). The desired alkenylnitrone 205, preparedby the condensation of the corresponding N-alkylhydroxylamine and phenylsulfo-

    nyl aldehyde, underwent a thermally induced intramolecular cycloaddition to afford

    exclusively the bridged isoxazolidine adduct 206 (74%). After reductive isoxazo-lidine ring opening of the bridged adduct to give piperidine 207, the authors tookadvantage of the newly generated hydroxyl moiety as a potential leaving group.

    Thus, a carbanion generated a to the sulfone displaced the tosylate to close thecarbocyclic ring of the target molecule 204, which was revealed after desulfonationwith sodium amalgam and N-deprotection.

    In a related strategy, the dihydropiperidine skeleton of the macrocyclic alkaloid

    cannabisativine (208) (Fig. 1.6), isolated from the leaves and roots of the commoncannabis plant, was prepared with regio- and stereoselectivity using an intramole-

    cular allylsilane–nitrone cycloaddition reaction as a key step (260).

    It has long been recognized that nitrone cycloadditions may allow access to

    spirocyclic ring systems. Such systems are inherently difficult to synthesize by

    conventional methods, yet are a structural component of a number of biologically

    active natural materials. Two common strategies have emerged for spirocycle

    generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic

    version, the carbon atom (arrowed) of the nitrone C����N double bond of dipole 209carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will

    N

    HH

    HMe

    (203)

    Figure 1.5

    1.10. Pyrrolidines, Piperidines, and Other Amines 37

  • add a new C��C bond here to create the desired spiro stereocenter in the adduct 210(potentially as a mixture of regioisomers). Alternatively, the spirocycle may be

    formed from the endocyclic nitrone 211, which carries the alkene functionality inthe substituent on the corresponding carbon atom of the C����N bond in the dipole(arrowed). Thus, the conformational preference of the side-chain alkene with

    respect to the nitrone function is crucial to the eventual product, which may be a

    fused spiroisoxazolidine (212) or the bridged regioisomer (213).An example of the exocyclic strategy is the recent 22-step synthesis by Snider

    and Lin (261) of (�)-FR901483 214, a novel immunosuppressant isolated from the

    NO

    PhO2SH

    HMe

    N

    X

    MeH

    H

    R1

    (204)

    N

    X

    ROH

    PhO2S

    NOMe

    H

    PhO2SH

    H

    X = R = H

    X = Boc, R = Ts

    (205) (206)

    (207)

    PhMe, ∆, 7 h

    74%

    i

    ii-iii

    iv

    X = Boc, R1 = SO2Ph

    X = R1 = H

    v-vi

    Reag