synthetic applications of 1,3 dipolar cycloaddition chemistry toward heterocycles and natural products

The most common nitrone 1,3-dipolar cycloaddition DC reaction 28–35 is theformation of an isoxazolidine using alkene dipolarophiles Scheme 1.1, althoughother multiply bonded systems may

SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITION

CHEMISTRY TOWARD HETEROCYCLESAND NATURAL PRODUCTS

This is the fifty-ninth volume in the series THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

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

Copyright # 2002 John Wiley & Sons, Inc.

ISBN: 0-471-38726-6

A SERIES OF MONOGRAPHS

EDWARD C TAYLOR AND PETER WIPF, EditorsARNOLD WEISSBERGER, Founding Editor

SYNTHETIC APPLICATIONS

OF 1,3-DIPOLAR CYCLOADDITION

CHEMISTRY TOWARD HETEROCYCLES AND

NATURAL PRODUCTS

Edited byAlbert Padwa

Department of Chemistry Emory University

William H Pearson

Department of Chemistry University of Michigan

AN INTERSCIENCE 1

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Introduction to the Series

The chemistry of heterocyclic compounds is one of the most complex andintriguing branches of organic chemistry, of equal interest for its theoreticalimplications, for the diversity of its synthetic procedures, and for the physiologicaland industrial significance of heterocycles

The Chemistry of Heterocyclic Compounds has been published since 1950 underthe 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 theextraordinarily complex and diverse field of heterocyclic chemistry as organizedand readily accessible as possible Each volume has traditionally dealt withsyntheses, 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 basicreference collection for information on heterocyclic compounds

Many broader aspects of heterocyclic chemistry are recognized as disciplines ofgeneral significance that impinge on almost all aspects of modern organicchemistry, medicinal chemistry, and biochemistry, and for this reason we initiatedseveral years ago a parallel series entitled General Heterocyclic Chemistry, whichtreated 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, andbiochemically oriented chemists, as well as to those whose particular concern isheterocyclic chemistry It has, however, become increasingly clear that the abovedistinction between the two series was unnecessary and somewhat confusing, and

we have therefore elected to discontinue General Heterocyclic Chemistry and topublish 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 Onestrategy is to publish Supplements or new Parts when merited by the amount of newmaterial, 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 oforganic chemistry were first covered in a widely cited two-volume treatise edited byProf Albert Padwa that appeared in 1984 Since so much has been published on thisfascinating and broadly useful subject in the intervening years, we felt that aSupplement would be welcomed by the international chemistry community, and we

are immensely grateful to Prof Padwa and Prof Pearson for tackling this arduoustask The result is another outstanding contribution to the organic and heterocyclicchemistry literature that we are delighted to publish within The Chemistry ofHeterocyclic Compounds series.

Cycloaddition reactions figure prominently in both synthetic and mechanisticorganic chemistry The current understanding of the underlying principles in thisarea 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 generalconcept of 1,3-dipolar cycloaddition Few reactions rival this process in the number

of bonds that undergo transformation during the reaction, producing productsconsiderably more complex than the reactants Over the years, this reaction hasdeveloped into a generally useful method for five-membered heterocyclic ringsynthesis, since many 1,3-dipolar species are readily available and react with a widevariety of dipolarophiles

The last comprehensive survey of this area dates back to 1984, when the volume set edited by Padwa, ‘‘1,3-Dipolar Cycloaddition Chemistry,’’ appeared.Since then, substantial gains in the synthetic aspects of this chemistry havedominated the area, including both methodology development and a body ofcreative and conceptually new applications of these [3þ 2]-cycloadditions inorganic synthesis The focus of this volume centers on the utility of thiscycloaddition reaction in synthesis, and deals primarily with information that hasappeared in the literature since 1984 Consequently, only a selected number ofdipoles are reviewed, with a major emphasis on synthetic applications Bothcarbonyl ylides and nitronates, important members of the 1,3-dipole family thatwere not reviewed previously, are now included Discussion of the theoretical,mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have beenkept to a minimum, but references to important new work in these areas are giventhroughout the 12 chapters

two-Beyond the ability of the 1,3-dipolar cycloaddition reaction to produce cycles, its importance extends to two other areas of organic synthesis, both of whichare included in the current volume First, the heteroatom-containing cycloadductsmay be transformed into a variety of other functionalized organic molecules,whether cyclic or acyclic Second, many 1,3-dipolar cycloadditions have the ability

hetero-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 anddipolarophile as well as the topography (endo or exo) of the cycloaddition Anadditional 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 dipolarcycloadditions represent an entirely new aspect of the current reference work

In recent years, numerous natural and unnatural products have been prepared bysynthetic routes that have a 1,3-dipolar cycloaddition as a crucial step in their

synthesis Consequently, this reaction has become recognized as an extremelyimportant transformation in the repertoire of the synthetic organic chemist.

1 NITRONES 1Raymond C F Jones

Volker Jager and Pedro A Colinas

John T Sharp

Gerhard Maas

Chin-Kang Sha and A K Mohanakrishnan

CHEMISTRY 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

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-DIPOLAR

CYCLOADDITION 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 toemphasize their similarity to ketones (10) While aromatic N-oxides also containthe nitrone moiety, they retain the name of the N-oxides whose reactivity they moreclosely resemble The general terms aldo- and keto-nitrones are used on occasion todistinguish 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 ishugely varied and frequently reviewed, but it is ultimately dominated by their use as1,3-dipoles for cycloaddition reactions In 1960, Huisgen proposed the now widelyaccepted concept of the 1,3-dipolar cycloaddition reaction (11–20) in which theformation of the two new bonds occurs as a concerted (but not simultaneous)process, rejecting Firestone’s proposed reaction via a diradical intermediate on thebasis of stereospecificity (21–26) Ironically, Huisgen himself then went on todemonstrate the first example of a two-step cycloaddition, using a thiocarbonylylide 1,3-dipole (27)

The most common nitrone 1,3-dipolar cycloaddition (DC) reaction (28–35) is theformation of an isoxazolidine using alkene dipolarophiles (Scheme 1.1), althoughother multiply bonded systems may also be used (alkynes, allenes, isocyanates,nitriles, thiocarbonyls, etc.) The isoxazolidine cycloadduct contains up to three newchiral centers and, as with other 1,3-dipoles, the highly ordered transition stateoften allows the regio- and stereochemical preference of a given nitrone to bepredicted This prediction is achieved through a consideration of steric and electronicfactors, but most significantly through the frontier molecular orbital (FMO) theoryproposed 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 nitroneshave also become popular as facially differentiated reagents, allowing predictable

NO

R1

ON

R4

R3

R1

NO

asymmetric induction through their ability to enforce the cycloaddition reaction atone or other face of the 1,3-dipole In recent years, the effect of catalysis on the rateand selectivity of the nitrone cycloaddition reaction has been examined from whichimpressive results have begun to emerge Thus, nitrones represent a powerful tool inmodern synthetic chemistry, whose limits are still being explored more than acentury after their discovery.

NITRONE CYCLOADDITIONS

With a wealth of nitrone-derived cycloadditions reported in the literature, wehave 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 thecycloaddition partners (e.g., those derived from sugars) Where a total synthesis isconcerned, 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 ofoverlap between many of our groupings, and in each case we have attempted todirect the reader to relevant work Section 1.11 on isoxazolidine synthesis covers aparticularly broad range of reactions and it is here we have collected some of themost significant reports in which the major aim of the work was to characterize anovel nitrone cycloaddition reaction rather than achieve the total synthesis of agiven target molecule

Nucleosides are potent antibiotic, antitumor, and antiviral agents, vital inchemotherapy for acquired immune deficiency syndrome/human immunodeficiencyvirus (AIDS/HIV) The polyoxins (e.g., 1a–b), and closely related nikkomycins arepyrimidine nucleoside antibiotics that are potent inhibitors of the biosynthesis ofchitin, 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 preparedpolyoxin 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 excellentyield (93%) in its reaction with vinyl acetate The product mixture containedpredominantly 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

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

Chiacchio et al (43,44) investigated the synthesis of isoxazolidinylthymines bythe 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 withdipoles whose chiral auxiliary does not maintain a fixed geometry and so cannotcompletely 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

NO

Boc

OAc

Bn

OO

OH OH

NNH

O

NOBoc

Bn

N N

OSiMe 3 R

OSiMe 3

TMSOTf DCM

NOBoc

ON

Bn

NHO

OR

ii TEMPO, BAIB iii CH2 N 2 , Et 2 O

i 70% aq AcOH

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

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 isoxazolidinylthyminetargets, these workers also applied an achiral cycloaddition approach with vinylacetate to successfully prepare the antiviral agent d4T (11) and its 2-methylanalogue (Fig 1.1) (45) In more recent work, similar nitrones [9, R¼ Me orbenzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues.

N

EtO2C H

NOR

EtO2C

NNHO

NH2N

HOO

HO

NHN

O

O

NNNNMe2

NHO

OHOHOH

2

(13)

Figure 1.1

Elsewhere, Langlois and co-worker (48) applied a 3-hydroxyaminoborneol-derivednitrone 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-memberedcarbocyclic 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 Gallos

et 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 asuitable leaving group on the isoxazolidinyl cycloadduct, Colacino et al (51) andSindona and co-workers (52,53) prepared isoxazolidinyl nucleosides using vinylnucleobases 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

NNNN

NH2

HO OH

HO

NNNN

Reagents: i BnNHOH, EtOH, 15 min, 95%; ii C 6 H 5 Cl, ∆, 30 min, 62%;

iii Zn, AcOH, Et 2 O, rt, 48 h, 78%; iv NH 4 HCO 2 , 10% Pd-C, MeOH, ∆, 1 h 75%.

Scheme 1.4

liver esterase (PLE) enzyme-catalyzed hydrolysis to afford the enantiomericallypure acid 23.

The discovery of spirocyclic nucleosides with anti-HIV-1 activity has promptedChattopadhyaya and co-workers (54,55) to prepare spiroisoxazolidine nucleo-sides (Scheme 1.6) Thus, after proving the reactivity of related systems in an

NNNN

NH2

ONBn

CO2R

NNNN

NH2Bn

O

X

NOMe

MMTrO

NHO

OMMTrO

O

NO

XHMe

NHO

OHO

O

NHO

intermolecular sense, nucleoside nitrone 24 (or the isomeric 20-O-allyl-30-nitrones)were prepared from the corresponding ketones to afford the spirotricycliccycloadduct 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

The continued importance of b-lactam ring systems in medicine has encouraged

a number of research groups to investigate their synthesis via a nitrone tion protocol Kametani et al (60–62) reported the preparation of advancedintermediates of penems and carbapenems including (þ)-thienamycin (29) andits enantiomer (Scheme 1.7) They prepared the chiral nitrone 30 from (
)-menthyl

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

glyoxal hydrate and benzylhydroxylamine but found it exerted incomplete control in its cycloaddition to benzyl crotonate The major isolated products, a 1:1mixture of isoxazolidines 31a and 31b, are rationalized as the consequence of endo

stereo-or exo addition to the mstereo-ore reactive (E) fstereo-orm 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 fordicyclohexylcarbodiimide (DCC)-mediated cyclization to afford the b-lactam 32.Silylation of the hydroxyl and the amide nitrogen was followed by hydrolysis of thementhyl ester, which also brought about N-desilylation Reinstallation of the silylgroups through two steps, before insertion of the C(4) acetyl group by oxidativeacetoxylation with lead tetraacetate, afforded the lactam 33, a known intermediate

en 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 ofthe desired isoxazolidine adducts (60)

The unusually potent and broad spectrum antibacterial action of cin is tempered by its instability at high concentration and susceptibility todecomposition by renal dehydropeptidase I In 1984, Shih and co-workers (62a) atMerck reported that the 1-b-methylcarbapenem 34 demonstrated increased chemi-cal and metabolic stability while retaining high antibiotic activity Work published

(þ)-thienamy-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 singlestereoisomer (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 reactionswith complete diastereocontrol

Alcaide et al (68,69) recently published their studies of the intramolecular dipolar cycloaddition reactions of alkynyl-b-lactams in which they found that thedesired cycloaddition was in competition with a reverse-Cope elimination Thereaction of alkynyl aldehydes 37a–c with N-methylhydroxylamine afforded amixture of products depending on the reaction conditions and the chain lengthseparating the alkyne and the lactam (Scheme 1.8) Thus, up to three separate

PhOH H

ONMe

nitrones were identified from the reaction mixture including two from a complexproposed mechanism Thus, alkynyl nitrone (38) was formed from the condensation

of 37c with N-methylhydroxylamine in refluxing toluene, and underwent a 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 polyolfunctionality at C(3) of the lactam (Scheme 1.30, Section 1.7) In other lactamcycloaddition 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 cycloaddition

1,3-of N-benzyl-C-phenyl nitrone to the exocyclic double bond under microwaveirradiation (Scheme 1.9) (76) Related spiroisoxazolidinyl lactams were reported

by Fisera and co-workers (77) Funk and Daggett (78) prepared similar spirocycliclactams (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 forthe 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 fungalmetabolite leptosphaerin (81) A report of lactam synthesis from acyclic startingmaterials is given in the work of Chiacchio et al (82) who prepared isoxa-zolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11)

N

O4-Me-C6H4

N

OMe

PhCOPhPh

CH 2 Ph N Ph O

NO

NN

ONO

O

Me

MePhOC

COPh

PhPh

NO4-Me-C6H4

CH2PhPh

110 ˚C, 4 h (27%)

or microwave (61%)

(42) (43)

Scheme 1.9

The acyclic precursor is an a,b-unsaturated amido aldehyde that was condensedwith N-methylhydroxylamine to generate the nitrone (E)-48, which then underwent

a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of theisoxazolidinyl 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 thirdstereocenter is predicted from the alkene geometry Both transition states maintainthe 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 exclusiveformation of the observed product 47 Related cycloadducts from the intramole-cular reaction of nitrones containing ester- rather than amide-tethered alkenefunctionality are also known (83-85)

N

CO 2 Me PhMe, ∆

ONBn

CO2Me

H 2 , 1 atm Pd(OH)2

Me

O

PhNMeO

HH

NMe

O

HBn

H

(B)

NH

Me

HH

H

PhH

(A)

Scheme 1.11

1.5 QUINOLIZIDINES, INDOLIZIDINES,

AND PYRROLIZIDINES

The title compounds, quinolizidines, indolizidines, and pyrrolizidines (86), arecharacterized by the presence of a bridgehead nitrogen atom in six,six-, six,five-, orfive,five-membered bicyclic ring systems, respectively The polyhydroxylatedindolizidines and pyrrolizidines have a range of biological effects through theirinhibition of glycosidase enzymes, including some examples of antiviral activity.The nitrogen and nearby oxygen functionality lend themselves to a nitronecycloaddition 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-

OMOM

NO

H

CO2Bn

N

HHO

7

Reagents: i CH2=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

carbonyl derivative 53 and removal of the MOM protecting groups in acid afforded

a 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) usingchiral 3- and 3,4-substituted pyrrolidine nitrones With such dipoles theyhave 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 theterminal hydroxyl moiety derived from the dipolarophile, as its tosylate Theseworkers have recently reported the synthesis of a related monohydroxylated nitrone

by oxidation of the N-hydroxypyrrolidine to afford an 11:1 mixture of the twoseparable regioisomers (95) Indolizidine and pyrrolizidine skeletons were thenprepared 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, ultimatelyderived 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 theintramolecular nitrone cycloaddition (99), this group has published intermediates inthe total synthesis of the indolizidine alkaloid gephyrotoxin (100) as well as thetotal synthesis of spiropiperidine natural product histrionicotoxin (Scheme 1.49,Section 1.10) (101) Kibayashi and co-worker (102,103) reported two totalsyntheses of the indolizidine (þ)-monomorine I (57), both of which rely on thesame cycloaddition reaction of an achiral methyl glyoxalate-derived nitrone and ahomochiral allyl ether The resultant mixture of isoxazolidines was a 3:1 mixture infavor of the desired product in 76% combined yield

The rare reports of quinolizidine formation by a nitrone cycloaddition strategyinclude the racemic total synthesis of lasubine II (58), one of a series of relatedalkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme1.14) (104) While these alkaloids were previously accessed by intermolecularnitrone cycloaddition reactions, this more recent report uses an intramolecularapproach to form the desired piperidine ring Thus, cycloaddition of nitrone 59affords predominantly the desired bridged adduct 60 along with two related

NO

diastereomers Reductive N

O cleavage of 60 with Zn/AcOH provided a stituted piperidine (61) which, after formation of the silyl ether from the hydroxylgroup, was cyclized in a melt of 2-hydroxypyridine at 160C The stereochemistry

trisub-at this position [C(2) in lasubine II numbering] was inverted under Mitsunobuconditions 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 intramolecularcycloaddition–retrocycloaddition–intramolecular cycloaddition strategy (Scheme1.15) 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 Thermallyinduced retrocycloaddition of 63 in o-dichlorobenzene at 150C afforded anunisolated nitrone (64) that underwent an intramolecular cycloaddition to afford

a 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

OH

Ar

CO2MeH

(62)

(±)-(58)

2 2

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 Ph 3 P, PhCO 2 H, diethylazodicarboxylate (DEAD),

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

Scheme 1.14

These authors also showed that the indolizidine skeleton can be prepared fromcyclopropyl 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 TBDPSgroups 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 powerfulactivation of the rearrangement, allowing the thermolysis reaction to occur at much

NOEtO2C

OPMBO

NHO

OOH

NO

OPMBO

O

NO

HPMBO

OO

∆

(65) (66)

R3

NO

R4

R1

R2

R3N

N

OH

N

ORH

OR

NO

OTBDPSH

lower temperatures (97) The authors were also able to prepare adducts frombicyclopropylidene (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 family

of 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 4-oxopipecolic acid, a rare amino acid found in the virginiamycin cyclic peptides(123)

(2S)-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 byPadwa et al (128–134) (Scheme 1.19) Building on the allene–nitrone cycloaddi-tions reported by Tufariello, the alkenylisoxazolidine adducts 90 and 91 were

prepared from the reaction of the corresponding cyclic nitrones 92 and 93,respectively, and an electron-deficient allene dipolarophile, with chemoselectionfor the more hindered, more electron-deficient alkene in almost every case Thepyrrolizidine and indolizidine skeletons were prepared by thermolysis of theseadducts at 80–90C (sealed tube, 8 h) to afford the bicyclic aminoketones 94 and 95via a proposed diradical mechanism.

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 antifungalagents 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 wasfollowed 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 theunusual 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 chainlength 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 theconstruction of a-amino acids More commonly, the required amine and carboxylicacid functionalities are carried into the cycloaddition in the dipolarophile, as ahomochiral alkenyl a-amino acid derivative Importantly, this introduces a second

N

O

CO 2 Me

• Me

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

(92) n = 1

(93) n = 2

n

Scheme 1.19

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 antitumorantibiotic acivicin (142–144).

NOBoc

OP

NOMe

NH

OH

OHMe

O

NOBoc

OP

ONMe

CO2H

CbzHNN

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,

An unusual route was described by Tamura et al (42,84,85,145–148) in whichb-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 syntheticmanipulation including ruthenium-mediated oxidative cleavage of the aromaticring, 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 ahomochiral alkenylamine dipolarophile (149)

Peptide functionality may be prepared in a homochiral dipolarophile forsubsequent 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 aciddiamide (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 anequilibrium excluded, a conformational change in the peptide enforces a change inregioselectivity 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*

NOR*

H

N

OAr

R*

OO

HHH

steps

Scheme 1.22

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, thedipolarophile 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 containedwithin the nitrone fragment, as in the synthesis of homochiral allyl glycines byKatagiri et al (151), which reveals the carboxylate by hydrolysis of a lactone in thedipole (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 [3þ 2] cycloaddition, although a

ONH

NHOHNNHOO

HN

NO

O

Ph

HN

possible [4þ 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 Thehigh stereoselection is explained through steric hindrance of the lower face of thenitrone by the pendant isopropyl group of the menthyl auxiliary, allowing addition

of the dipolarophile to the upper face only The carboxylic acid functionality wasrevealed 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 pyroglutamicacids (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 chiralauxiliary (Scheme 1.25) As a key step in the synthesis, the furfuryl side chainwas used as latent carboxylate functionality, conversion being achieved usingruthenium-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 NHTMS

OHO

O

OO

O

OTMS

−acetone

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

i

ii iii-iv

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

4 h, 100%; iii H 2 , Pd-C, MeOH, 88%; iv BF 3 •Et 2 O, MeCN, 3 h, 100%.

Scheme 1.24

(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 protectinggroups was followed by amide coupling with O-(1H-benzotriazol-1-yl)-N,N,N0,N0-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

NBoc

HO

CO2Me

(118) (119)

CO2t-Bu

NONN

H2N

NH

O

CO2HO

(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

124is supported by X-ray crystallography and, against expectation, the 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 reactionproceeds with a similar regiochemical preference but with little facial or endo–exoselectivity.

configura-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(40) erythro

O

NO

O

OH

CO2Me

NOH

ONPh

PhOH

(127)

toluene, ∆, 10 h

4 5

4 ′ 2

Scheme 1.28

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 thenitrone, and is rationalized through the less-hindered endo approach of thedipolarophile to the more reactive (Z)-nitrone While the stereoselection wasunpredictable, all of the nitrones exhibited total regioselectivity for the 5-phenylisoxazolidines 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 reductionand acetonide hydrolysis, underwent a ring closure to afford the trideoxyhexosesugar rhodinose 131 as a mixture of anomers The ethyl vinyl ether-derived adduct

132afforded the 3-amino-5-hydroxyaldehyde 133 by a more familiar lytic N

O bond cleavage and spontaneously formed the amino sugar daunosamine(134), isolated as the protected methyl glycoside (135)

hydrogeno-NO

OOMe

H

OOMe

H

NOR

OMe

ii

iii-iv vi

(131)

Reagents: i CH 2=CHSiMe 3 , 80 ˚C, 24 h, 90%; ii 50% aq HF, MeCN, rt, 30 min; iii H 2 , 5% Pd-C, EtOH, 2 h; iv 2% aq HCl, acetone, rt, 40 % from 128; v CH 2=CHOEt, ∆, 72 h, 93%; vi H 2 , 5% Pd(OH) 2 , 10% HCl / MeOH, 48 h, then Ac 2 O, py, 4-(dimethylamino)pyridine (DMAP), 24 h rt

Scheme 1.29

The most commonly reported carbohydrate-derived dipolarophiles are thea,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 thecycloaddition of nitrones to ene–lactones, in which the nitrone oxygen is added atC(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 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

stereo-O

OAc

O

N Ph

O

H Ar

N

ArHO

TBDMSO

OOAc

O

Ph

CO2BnOTBDMSOTBDMS

PhMe, N2,

∆, 8 h, 80%

i-ii

iii

iv (138)

(139) (137)

Ar = 4-MeO-Ph 3

Reagents: i KOH, dioxane, H 2 O, rt, overnight, then BnBr, 18-crown-6, DMF, 60%; ii TBDMSCl, imidazole, DMF, 0 ˚C, then rt, overnight, 90%; iii H 2 , 2 atm, 10% Pd-C, EtOH, 2 h, 85%; iv 2-chloro-1-methylpyridium iodide, Et 3 N, DCM, rt, 2 h, 80%.

Scheme 1.30

Observed adducts arise through exo addition of the lactone to the re–re face of thenitrone 141, which avoids an unfavorable C


O/O-tert-butyl steric clash.

Langlois and co-workers (179) found the same exo stereochemical preferencethrough 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 allowedkinetic 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 thebornane moiety

Borrachero et al (180) prepared a number of sugar isoxazolidines by thereaction of carbohydrate-functionalized nitrones with nitroalkenes (Scheme 1.33).They found a matched pair of chiral sugar cycloaddition reaction partners to be

OO

O

OH

H C11H23H

80 ˚C, 12 h 84%

Scheme 1.32

much more effective than a single carbohydrate auxiliary, which also suffered someisomerization on silica gel In all the isoxazolidine adducts, the nitro group is atC(4) and the trans geometry of the alkene is maintained, as expected Thus, thereaction of nitrone 148 with alkene 149 (both derived from a-d-galactose) afforded

a 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 wasthe first example using a sugar derivative (185) Since then, many researchersinvestigated the intramolecular reaction of nitrones generated from sugars, inparticular those from O-allyl carbohydrates, which can give rise to tetrahydro-pyanyl- or oxepanyl-isoxazolidine cycloadducts (Scheme 1.34) (186–193) Shing’swork demonstrates that the stereochemical outcome depends only on the relativeconfiguration 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

O

O

O

OBnO

O

HN

OHOH

OHOH

HO

OH

OH

N OBn

HO

OH

OHNHHO

(150) R = Gal (154) R = Xyl

(151) R = Gal (155) R = Xyl

50 −100 ˚C

Scheme 1.33

not observed Conversely, a tetrahydropyranyl adduct was the sole product of ananalogous erythro alkenyl nitrone derived from d-mannose The authors proposetwo interconvertible chair-like transition state conformations for tetrahydropyranformation 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 ofdecomposition products has prompted further work on benzyl–ether protectedderivatives

N

MeOHO

HO

OH

ON

HO

RO

(B)

(A)

OOH

RN

O

Me

(C)

OOH

HOHO

OH

N OMe

OHOH

Reagents: i MeNHOH•HCl, NaHCO 3 , 80% aq EtOH, ∆, 48 h.

Scheme 1.34

most common are the vinyl sulfur compounds (194,195) The known cycloadditionreaction of chiral vinyl sulfoxide dipolarophiles with acyclic nitrones has now beenextended 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 selectedadducts by reduction with TMSI/NaI to enantiomeric sulfides [e.g., 163b (R¼ Me)

to 164] Reductive cleavage of the N

O bond of adduct 163a (R ¼ Me) andsimultaneous desulfurization with Ni/Al amalgam afforded the known piperidinenatural 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 Deprotectionwith 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 sulfinylmaleimide dipolarophile (166) has been reported (Scheme 1.36), but afforded themajor product 167 with only modest stereoselectivity, despite the use of a

Reagents: i Et 2 O, rt, 7 −10 days, 85−97%; ii TMSI, NaI; iii Ni/Al, aq KOH, MeOH, rt, 2 h, 93%;

iv ClCO 2 CH 3 , aq K 2 CO 3 , rt, 18 h, 98%; v W-6 Raney Ni, H 2 , MeOH, 18 h, 84%;

vi TMSI, DCM, ∆, 1 h, then MeOH, rt, 10 min, 97%.

O

Scheme 1.35