SYNTHETIC APPLICATIONSOF 1,3-DIPOLARCYCLOADDITION

CHEMISTRY 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.

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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

A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR AND PETER WIPF, Editors

ARNOLD WEISSBERGER, Founding Editor

SYNTHETIC APPLICATIONSOF 1,3-DIPOLARCYCLOADDITION

CHEMISTRY 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.

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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.

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