synthesis polar compound

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Tetrahedron report number 817

Intramolecular 1,3-dipolar cycloaddition reactions intargeted syntheses

Vijay Naira,b,*and T. D. Sujaa

aOrganic Chemistry Section, Chemical Sciences Division, National Institute for Interdisciplinary Science and Technology (CSIR),

Trivandrum 695 019, Kerala, IndiabJawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, Karnataka, India

Received 20 September 2007

Available online 29 September 2007

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12247

1.1. Dipolar cycloaddition as a synthetic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12248

2. Nitrones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12248

3. Nitrile oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12255

4. Carbonyl ylides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12259

5. Azomethine imines and azomethine ylides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12263

6. Azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12265

7. Mesionic and miscellaneous dipoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12269

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12271

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12272

References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12272Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12275

1. Introduction

Historically, the synthesis of diazoacetic acid ester byCurtius in 18831 and its reaction with unsaturated

carboxylic esters reported by his younger colleague,Buchner, in 1888 may constitute the embryonic eventsin the discovery of 1,3-dipolar cycloadditions.2 Importantcontributions in subsequent years by Buchner,2 Beck-mann,3 Werner, Buss,4 and others for the generation of1,3-dipoles are also noteworthy. This field, however, laydormant until 1963, when Huisgen, recognizing the gen-erality of these reactions, created the conceptual frame-work for the 1,3-dipolar cycloadditions (Huisgen

reaction) and provided the much-needed mechanisticrationalization for the process.5 He invoked the interme-diacy of dipoles in some well-known reactions. Later,Sustmann classified the dipolar cycloaddition reactionsinto three types based on the orbital interactions.6 Witha better understanding of the mechanistic events and thelarge body of experimental results provided by Huisgen,the area of 1,3-dipolar cycloadditions witnessed enormousprogress. The impact was felt mostly in the realm of het-erocyclic synthesis. In due course, dipolar cycloadditionreactions became a trusted tool in targeted synthesis,especially in those involving the construction of hetero-cyclic systems.7

Keywords: Intramolecular 1,3-dipolar cycloaddition; Huisgen reaction; 1,3-Dipole; Azomethine ylide; Azomethine imine; Carbonyl ylide; Nitrileoxide; Azide; Nitrone; Mesionic compound; Betaine; Natural product syn-thesis; Alkaloid.

Abbreviations: Ac, acetyl; aq, aqueous; Boc, tertiary butoxy carbonyl;CAL-B, Candida antarctica lipase fraction B; DABCO, 1,4-diazabicyclo-[2.2.2]octane; DMAP, 4-dimethylaminopyridine; DIBALH, diisobutyl-aluminum hydride; DMF, dimethyl formamide; DMSO, dimethyl sulfoxide;Et, ethyl; IAC, intramolecular azide cycloaddition; IDC, intramoleculardipolar cycloaddition; INC, intramolecular nitrone cycloaddition; INOC,intramolecular nitrile oxide cycloaddition; LDA, lithium diisopropylamide;LSD, lysergic acid diethylamide; m-CPBA, meta-chloroperoxybenzoicacid; MEM,methoxyethoxymethyl;MVK, methyl vinyl ketone; Ms, mesyl;nAChR, nicotinic acetylcholine receptor; NCS, N-chlorosuccinimide; pfb,perfluorobutyrate; RCM, ring-closing metathesis; TBAF, tetrabutylam-monium fluoride; TBAT, tetrabutylammonium triphenyldifluorosilicate;TBS, tertiary-butyldimethylsilyl;

t

Bu, tertiary butyl; TFA, trifluoroaceticacid; THF, tetrahydrofuran; Ts, tosyl.* Corresponding author. Tel.: +91 471 2490406; fax: +91 471 2471712;

e-mail: [email protected]

00404020/$ - see front matter 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2007.09.065

Tetrahedron 63 (2007) 1224712275
mailto:[email protected]:[email protected]


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1.1. Dipolar cycloaddition as a synthetic strategy

The impact of dipolar cycloaddition reactions in the area ofheterocyclic synthesis is in many ways comparable to that ofDielsAlder reactions on carbocyclic synthesis. In fact, theavailability of various classes of dipoles and dipolarophileshas allowed a greater degree of versatility. The discovery

of new dipolar species was followed by applications of theirreactions in targeted syntheses. Even though all dipolarcycloaddition reactions are, in principle, closely relatedprocesses, their applications are seldom discussed togetherin the chemical literature. The main reason for this anomalyis the vast variety of heterocyclic systems produced in suchreactions. Discussions on heterocyclic synthesis generallyfollow a product-class-based approach. Although conve-nient, such an approach fails to address the underlying sim-ilarities of the various processes involved. There has been noconcerted attempt to categorize various dipolar cycloaddi-tions used in the synthesis of natural products, apart froman excellent book edited by Padwa.8 A discussion on dipolarcycloadditions by Wade published in 1991 is also worthmentioning, although its emphasis is on the general aspectsof dipolar cycloadditions.9 This article will focus on the useof dipolar cycloaddition reactions in the total synthesis ofnatural products or analogues. The discussion is limited tothe literature published after 1991 and instances in whichthe dipolar cycloaddition serves as a key step of the synthesisand is not intended to be comprehensive. For convenience,the examples are classified on the basis of the dipoleinvolved.

2. Nitrones

1,3-Dipolar cycloaddition reactions of nitrones with alkenesleading to isooxazolidines are a long-known and a well-stud-ied area.10 Nitrones are usually generated by the condensa-tion of an aldehyde and an N-substituted hydroxylamine11

or the oxidation of a hydroxylamine.12 Reductive ring open-ing of isoxazolidines by hydrogenation with Pd or Raneynickel provides access to g-amino alcohols.13

Synthesis of bridged, medium-sized rings has been accom-plished by the intramolecular nitrone cycloaddition (INC)reaction of alkenyl nitrones derived from amino acids. Thisprotocol has been applied to the synthesis of 3-amino-5-hydroxyazepines and otherN-heterocycles (Scheme 1).14

o-NBSNO

R1

o-NBSN N

O

R1

R2

HN

OH

NHR2R1

n

a

n n

b-c

1 2 3

R1= alkyl

R2= Me, Bn

n = 1, 2

Scheme 1. (a) R2NHOH$HCl, NaHCO3, CaCl2, rt, 14 h, 1576%; (b)

PhSH, K2CO3, DMF, rt; (c) Zn, AcOH, 60C, 1.5 h.

Cyclic ether moieties are common motifs in many importantmarine natural products like brevetoxin B and ciguatoxin.

Shing and Zhong employed the INC reaction effectively toconstruct oxepanes and tetrahydropyrans from sugar

derivatives. Nitrone 5 derived from 3-O-allyl-D-glucose 4(and 3-O-allyl-D-altrose) underwent an INC reaction toafford the oxepane, which was isolated as tetraacetate 6. Onthe other hand, 3-O-allyl-D-allose 7 (and 3-O-allyl-D-man-nose) afforded the tetrahydropyran derivatives 9 and 10 undersimilar reaction conditions (Scheme 2). The formation ofoxepanes from glucose and altrose derivatives may be ratio-

nalized by invoking the unfavorable 1,3-diaxial interactionspresent in the transition states leading to the formation ofthe tetrahydropyran products.15

In a very recent paper, Shing and co-workers reported thatthe nitrones derived from hept-6-enoses possessing a transacetonide group in the chain exclusively afforded thebridged isoxazolidines after INC reactions. These resultsare in accordance with the computational models, whichsuggest that the transition state leading to the endoproduct(i.e., the bridged bicyclo[4,2,1]isoxazolidine) is more stabi-lized than that leading to theexoproduct. The cycloadductswere further transformed into the calystegine analogues 14and15, tropane16, and a hydroxylated aminocycloheptanederivative 17 in a few steps (Scheme 3).16

Chiral polyhydroxylated amino five-, six-, or seven-mem-bered carbocycles have been synthesized via an INCreaction of aldehyde19derived from 1,2,5,6-di-O-isopropyl-idine-a-D-ribo-hexafurano-3-ulose18, which is readily pre-pared from D-glucose (Scheme 4). The cycloadducts20 and21are useful intermediates in the synthesis of various bioac-tive compounds such as enzyme inhibitors, antibiotics, andbioactive nucleosides.17

INC reactions in which the nitrone or olefin partners are partof cyclic systems can lead to tricyclic frameworks. For

example, 3-oxa- or 3-aza-nitrones spontaneously affordedtricyclic derivatives, which could serve as intermediates inalkaloid synthesis (Scheme 5).18

The use of INC reactions of 5-alkenyl- or 5-homoalkenylproline for the synthesis of azabicyclo[x.3.0]alkane aminoacids with heteroatom-substituted side chains has been re-ported (Scheme 6). These compounds are particularly attrac-tive constrained dipeptide mimics, due to their ability toserve as conformationally fixed surrogates of peptide-turnsecondary structures.19

INC reactions of silicon-tethered 4-hydroxy-2-isoxazo-lidine-2-oxides afforded a new class of silicon heterocycles29, which possess a complex framework of hydroxylatedamino acids with an ethoxycarbonyl group, a nitroacetal bi-cyclic system, and a cyclic silyl ether. The product on Tamaooxidation and subsequent reduction afforded the non-naturalamino acid derivative30 (Scheme 7).20

A synthesis of stereodefined aminopolyols was achieved bythe INC reaction of nitrones with a silicon tether derivedfroma- or b-hydroxy carbonyl compounds. The fused bicy-clic transition state involved in the concerted cycloadditionrenders the reaction highly stereoselective. Tamao oxidationof the silicon heterocycle and the usual hydrogenolysis of thecycloadduct isoxazolidine revealed the additional hydroxyl

groups of the target molecule, which is usually isolated asthe acetate34 (Scheme 8).21

12248 V. Nair, T. D. Suja / Tetrahedron 63 (2007) 1224712275


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A Lewis acid-mediated INC reaction of the tricyclic oxime35directly produced the isoxazolidine derivative of estrone36(Scheme 9).22

Kang and co-workers reported a route to cephalosporinderivatives with cyclic substituents at the 3-position. 3-Alkyl-

idene-4-carboxylic acid derivative 37 was treated with meth-ylhydroxylamine hydrochloride in the presence of a base.

O

O

HO

OH

OH

HO

O

N

O

AcO

AcOOAc

OAc

O

O

HO

OH

OH

HO

O

NO

HO

OH

HO

OH

O

N O

AcO

OAc

AcO

OAc

O

N O

AcO

OAc

Ac

+

O

OAc

O

N OHO

OH

HO

OH

4 5

7

a b

a b

6

8 9, 8% 10, 33%

55%

Scheme 2. (a) MeNHOH$HCl, NaHCO3, 80% EtOH, reflux, 48 h; (b) Ac2O, DMAP, Py, CH2Cl2, rt.

NMe

HOHO

HO

HO

OHC

OR1

O O R2NHOH.HCl

N OR

2

O O

R1O

N

OR2

O O

R1O

NH

OH

OHHO

HO

O

HOOH

NH2HO

HO

H2NOH

OHHO

HO

OH

i

endo-TS

or or or

11

12

R1, R2 = Ac, Bn 13

14 15 16 17

Scheme 3. (i) NaHCO3, MeCN, rt.

O

O

OO

O

O

O

O

O

OHC

OH

O

O

ON

O

Ph

OH

HH

H

O

O

O

N

O

Ph

OH

HH

H

+a

1918

20 21

Scheme 4. (a) BnNHOH, EtOH, rt, 20 h, 82%, 4:1.

XN

O

XN

O

H

HHH

22 23X = O, N-benzyl

Scheme 5.

N

O

O

N

ON

CO2tBu

CO2tBu

CO2tBu

O

Ph

N

ON

O

Ph

a

+

24 25 26

Scheme 6. (a) BnNHOH$HCl, NaHCO3, EtOH, H2O, 71%, 9:1.

N

O

O

R1

R2

CO2EtHO

SiCl N OO

EtO2C

O Si

R1

R2O

O

OH

NH2

OAcR1

R2 OAc

+

R1, R2= alkyl, aryl or H

27 28

29 30

a b, c

Scheme 7. (a) ImH, CH3CN; (b) Tamao oxidation; (c) reduction.

O CO2Me

SiPh

Ph

SiOMe

ON

Bn

PhPh

SiOMe

O

NBn

Ph

Ph HN

OAc

Boc

AcO OH

a, b

c) Tamao oxidation

d) reduction

31 32

33 34

Scheme8. (a) DIBALH, 78 C, 30 min; (b) BnNHOH,78 C to rt, 79%.

12249V. Nair, T. D. Suja / Tetrahedron 63 (2007) 1224712275


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The nitrone produced was refluxed in benzene to effect thecycloaddition with the exocyclic olefin to afford a singleadduct38. Similarly, a nitrile oxide cycloaddition was alsocarried out to furnish the derivative 40 (Scheme 10).23

Haouamine A is a cytotoxic polycyclic alkaloid of marineorigin, with a unique 3-aza-[7]-paracyclophane moiety inthe structural framework. It exhibits selective activityagainst a human colon carcinoma cell line HT-29. Haou-amine A has been synthesized earlier from the pentacyclicintermediate 47 using a microwave-assisted intramolecular

DielsAlder reaction. Weinreb utilized an INC reaction forthe synthesis of the indene ring of the pentacyclic indenote-trahydropyridine derivative 47. Aldehyde 43 on treatmentwithN-benzylhydroxylamine produced the transient nitrone44, which was heated without isolation to afford the cyclo-adduct46. Formation of the kinetically favored cycloadduct45 was also observed, but this could be converted into themore stable isomer 46 by prolonged heating in toluene.The conversion of45into46presumably involves a thermalcycloreversion and a subsequent cycloaddition. The cyclo-adduct was later converted into the desired pentacyclic com-pound47 (Scheme 11).24

Sung and Hee reported an enantioselective synthesis of theazetedinone fragment of the antibiotic, 1b-methyl carbape-nem. Lactone 49 was prepared from ethoxyethyl ether 48in three steps. Reduction of49 afforded the correspondinglactol, which was heated with p-methoxybenzylhydroxyl-amine and base to generate the nitrone 51. The desired cy-cloadduct 52 was formed in 80% overall yield from 49 as

a single isomer. Further synthetic operations were carriedout on 52 to arrive atb-lactam53 (Scheme 12). It is notewor-thy that the four contiguous stereocenters in 53 were fixedduring the cycloaddition reaction.25

CN

OEtO

O O

ON

H

H

OH

PMBNH

OTBS

O

CO2EtH H

O OH

HO N

O

PMB heat

a b

48 49 50

51 52 53

80%

Scheme 12. (a) DIBALH, CH2Cl2, 78C to rt; (b) p-MeOC6H4CH2-

NHOH, Et3N, hydroquinone, benzene, reflux.

Erythroidene58and spirojatamol59are two sesquiterpeneswith an intriguing spirobicyclo[5.4]decane framework. Fu-kumoto reported a short synthesis of both sesquiterpenesin their racemic form by employing an INC reaction as thepivotal step. Ene-nitrone55was prepared from 4-isopropyl-cyclohexenone54. Nitrone55 on heating afforded two dia-stereomeric cycloadducts 56 and 57, of which the major

MeO

H

H H

OHN

MeO

H

H H

O

HN

35 36

a

Scheme 9. (a) BF3$

OEt2.

N

S

O

R1

OCO2R

2

N

S

O N

R1

OR2O2C

N

S

O N

R1

OR2O2C

N

SR1

OR2O2C

NMe2

N

SR1

O

R2O2C

NOH

a

b,c

R1= PhCH2CONHR2= Ph2CH

37

38 39

40 41

Scheme 10. (a) MeNHOH$HCl, Py, CHCl3, MeOH, then benzene, reflux, 87%; (b) NH2OH$HCl, Py, 82%; (c) NCS, Py, Et3N, CHCl3, 71%.

O

OMe

OMe

N

OMeO

H

MeO

PhO

N

Ph

H

MeO

OMe

NH

H

MeO

MeO

Br

OMe

N

OMe

OMe

O

Ph

O

OMe O

+

135 C

42 4344

45 46 47

a

b

Scheme 11. (a) BnNHOH, toluene, 135 C; (b) toluene, 135 C.



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diastereomer56possessed the desired stereochemistry. Fur-ther reactions on56were carried out to synthesize both ery-throidene58 and spirojatamols59and 590 in racemic forms(Scheme 13).26

Romero and co-workers have developed a synthetic route toenantiomerically pure chromane derivatives like65using anintramolecular dipolar cycloaddition (IDC) of the nitroneand alkene as a key step. Chromane itself is known to exhibitmodest antibacterial activity. The authors employed nitroneswith a chiral substituent on the nitrogen, which also pos-sessed an oxygen functional group. This allowed fora Lewis-acid chelation involving the nitrone oxygen and,as a result, provided very good diastereoselectivity for thecycloaddition. The cycloadducts were then subjected to rou-tine synthetic operations to furnish various enantiopurechromane derivatives. A representative example is providedinScheme 14.27

Halichlorine and pinnaic acid are two marine natural prod-ucts known to exhibit interesting biological properties.Both compounds contain an azaspiro[4.5]decane core struc-ture. A stereospecific synthesis of this structural unit hasbeen achieved by employing the INC reaction. Oxime 67prepared from dithiane 66 was heated in the presence of benz-yl acrylate at 140 C. Nitrone68 that was generated under-went smooth cycloaddition to provide a single cycloadduct

69in 92% yield. The latter adduct was then subjected to var-ious chemical transformations to afford azaspiro[4.5]decane71as a single isomer. The conversion of70into71proceedsthrough a hetero-Michael additionreversion sequence withelimination of benzyl acrylate (Scheme 15).28

The indolizidine ring system is widespread in many biologi-cally active alkaloids. Polyhydroxylated indolizidines act asstructural analogues of sugars and can competitively interactwith glycosidases. In an enantioselective synthesis of hy-droxylated indolizidines, Brandi employed the INC reactionof a pyrroline nitrone 72 derived from L-malic acid. Initialattempts to deprotect the THP ether and attach an olefinictether met with difficulties associated with the racemizationof the intermediate hydroxynitrone. Therefore, nitrone 72was initially masked as the adduct 73 by a dipolar cyclo-addition with ethyl acrylate (or styrene). Subsequent hydro-lysis of the THP ether and attachment of the olefinic tether

via a Mitsunobu inversion proceeded without any racemiza-tion. The substrate on heating underwent cycloreversion toreveal the nitrone and subsequent INC cycloaddition to fur-nish the isoxazoline derivative. Deprotection, mesylation,and hydrogenolysis afforded the indolizidine derivative 77(Scheme 16).29

()-Histrionicotoxin 85 is a spiropiperidine alkaloid iso-lated from the brightly colored poison-arrow frog,

O

N

O

Ph

OH

N

O

Ph

OH

ONPh

+

+

a

33% 22%

and

54 5556 57

56

58 59 59'

Scheme 13. (a) Toluene, 180 C, sealed tube.

O

NO

OHPh

O

OH

HN

HN

CF3

S

HH

O

ON

HO

Ph

ZnClCl

O

H2N

OH

HH

O

O

NHO

Ph

H

H

O

O

NHO

Ph

H

H

24%

71%

60

61

62

63

65 64

a

Scheme 14. (a) 2 equiv ZnCl2, 40C, CH2Cl2.



6/29

Dendrobates histrionicus. It is known to act as non-competi-tive inhibitor of nicotinic acetylcholine receptors and is alsoemployed as probe to study neuromuscular signal transmis-sion. In an enantioselective synthesis of ()-histrionicotoxinby Holmes and co-workers, an imaginative use of the INCreaction is demonstrated. The cyclic nitrone 80is generatedby a hydroxylaminealkyne cyclization and is protected asthe cycloadduct81 by treating with styrene. The side chain

on isoxazolidine81 was modified to install thea,b-unsatu-rated nitrile group. Compound 82 was heated in a sealed

tube at 190 C in toluene to promote the cycloreversiondipolar cycloaddition sequence. The cycloadduct 84 wasobtained as a single isomer in high yield and, in the process,all three chiral centers present in the natural product werefixed. The (Z)-enediyne units were installed using Storksiodophosphorane methodology to complete the synthesisof85 (Scheme 17).30

Holmes has reported another route employing the INC reac-tion for the synthesis of azaspirocycloundecane skeleton90,

S S

NO

OTHP

BnO

O

H

MeO2C

HO

H

H

NO

OTHP

BnO

O

NHO

THPO

CO2Bn

HN

HO

BnO

O

H

CO2Me

CO2Bn

a

b

66 67 68

69 70 71

Scheme 15. (a) Xylene, 140 C, 92%; (b) 1,2-dichlorobenzene, reflux, 84%.

N

HO

OO

H

N

OTHP

O

R

NOR

H OTHP

NOR

O

OPMBO

H

N

O

O

PMBO

O

R

O N

PMBO

OO

H

R = Ph, CO2Et

Mitsunobu

reaction

a

72 7374

75

76 77

Scheme 16. (a)o-Dichlorobenzene, 150 C, 3 h, 74%.

X

(CH2)3OTBDPS

O

NHOH

NX

O O

(CH2)3OTBDPS

Ph

NBnO

O

Ph

CN

NH

HO

NX

O O

(CH2)3OTBDPS

NBzO

O

CN

Ph

NBzO

CN

(CH2)3OTBDPS

OBn4 steps

a

5 steps c

(-)-Histrionicotoxin 85

X = (+)-10,2-camphor sultam

b

7879

80

81 82

83 84

O

Scheme 17. (a) Toluene, 80 C, 6 h; (b) 75 C, 85%; (c) toluene, sealed tube, 190 C, 3.5 h, 80%.



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which is the precursor of all of the known histrionicotoxinalkaloids (Scheme 18). Conjugate addition of the oxime de-rived from 86 to the a,b-unsaturated nitrile generates anequimolar mixture of the nitrone 87 and the kinetically fa-vored cycloadduct88. Further heating of this mixture gener-ally afforded a mixture of isoxazolidine derivatives 8890.The authors have optimized the conditions for the

conversion of 88 and the epimer 89 into the requiredcycloadduct90.31

O

NC CN

N

O

NC

CN

N

OCN

NC

NO

CN

CN

N

O

NC

CN

N

O

NC

CN

+

+ +

i

ii ii

86 87 88

88 8990

88%83%

Scheme 18. (i) NH2OH$HCl, NaOAc, MeOH, 25C; (ii) chlorobenzene,

sealed tube, 180 C.

Lepadiformine, a tricyclic indolizidine alkaloid, isolatedfromClavelina lepadiformis, exhibits cytotoxic activity to-ward several tumor strains in vitro. In a convergent stereo-selective synthesis by Weinreb, the indolizidine core oflepadiformine was prepared by the INC reaction of the cyclicnitrone 92. The latter nitrone was derived from the linearacyclic oxime acetal 91, which contains all of the carbonatoms necessary for the construction of the tricyclic core.

The stable nitrone92was thermolyzed to obtain a single iso-xazolidine cycloadduct93. The linking chain of the nitroneassumes a boat-like conformation and the dipolarophile ap-proaches the nitrone from the face opposite to the bulky phe-noxymethyl group. Amino alcohol94, derived by reductionof the isoxazolidines, was further elaborated into the targetlepadiformine95 (Scheme 19).32

Pretazettine is a member of the crinine class of amaryllida-ceae alkaloids, exhibiting antiviral and antitumor activities.An advanced intermediate for the synthesis of pretazettinewas constructed by employing an intramolecular nitroneolefin cycloaddition. Aldehyde97was treated with the oxa-late salt of N-(a-methylbenzyl)hydroxylamine and base in

benzene to afford the nitrone98 as a 5:1 mixture of cis andtrans isomers. The nitrone solution was then refluxed tofurnish the diastereomeric cycloadducts in a 16:1 ratio. Inter-estingly, the stereoselectivity of this reaction is rather highwhen compared to that of similar nitroneolefin cycloaddi-tions (Scheme 20).33

Baldwin has recently employed the INC reaction to synthe-size the amaryllidaceae alkaloids, ()-haemanthidine 105,(+)-pretazettine106, and (+)-tazettine107, from D-mannosein enantiopure form. Alkenylhydroxylamine 103 for the INCreaction was produced from the alkenyl acetal, which, inturn, was obtained from a-methyl-D-mannopyranoside.The dipolar cycloaddition was carried out by heating thecrude nitrone 103 in benzene. The cycloadduct was furthertransformed into the alkaloid, ()-haemanthidine105. (+)-Pretazettine 106 and (+)-tazettine 107 were sequentiallysynthesized from105by taking advantage of the well-estab-lished chemical relationship between these alkaloids(Scheme 21).34

A synthesis of the 1-azaspiro[4.5]decane core found in cylin-dricine-type alkaloids has been accomplished by the INC re-action (Scheme 22). The stable cyclic nitrone 110 underwentcycloaddition when refluxed in benzene. Electronic effectscaused by the presence of the silyl group at the alkene moietycontrolled the regiochemistry.35

The azaspirocyclic core of pinnaic acid was also synthesizedby White and co-workers by employing a transannularnitroneolefin cycloaddition. Ring-closing metathesis(RCM) of 113 produced a diastereomeric mixture of themacrocyclic oxaziridine 115. Simultaneous hydrolysis ofthe oxaziridine and the ketal afforded the hydroxylamine-ke-

tone, which underwent an immediate condensation to affordthe nitrone 117. After chromatographic removal of the minor

Z-isomer, a toluene solution of the nitrone was refluxed tofurnish a single cycloadduct118(Scheme 23). Since the cy-clic nitrone is not large enough to allow the nitrone oxygento pass through the ring, the cycloaddition occurs preferen-tially at the rear face of the trans double bond. Hydrolysisof the lactone and reductive cleavage of the isoxazolidine af-forded the dihydroxy amino ester representing the azaspiro-cyclic core structure of pinnaic acid119.36

Kita has combined the kinetic resolution of a racemic hy-droxynitrone with a subsequent dipolar cycloaddition toachieve a high enantioselectivity for the cycloadducts. He

C6H13

NHOH

OPh

O

O

N

HOPh

C6H13

O

N

C6H13

H

OH

N O C6H13

H

OPh

N OH

O

OPh

+

NH OH C6H13

H

OPh

b

91 92

93 94

c

95

a

Scheme 19. (a) 3 N HCl, THF, 4 h, rt, 92%; (b) DMSO, 190 C, 16 h, 63%; (c) Zn dust, AcOH, H2O, 45C, 3 h, 91%.



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S

S Li

CH(OMe)2

S

S

CO2Et

R

N

Ph

Me

O

O

O

Me

Ph

NHOH

S

S

CHO

CO2Et

R

NO

S

S

R

H

CO2Et

Me

Ph

+N

O

S

S

R

H

CO2Et

Me

Ph

R =

a

5:1

16:1

96 97 98

99 100

Scheme 20. (a) Benzene, K2CO3, rt.

N

OO

O

Me

H

PhH

CO2Et

H

Ar

O

Br

MeOOH

HO

OMe

N

OO

OH

MeO OH

ArO

O

CO2Et

H

OMe

OMe

N

O

O

O

MeO

ArO

O

CO2Et

H

NO

MePhH

N

O

MeO

O

O

3 steps

b c

101 102 103

104 105 106 107

a

Scheme 21. (a) Benzene, 80 C, 65%; (b) MeI, MeOH, then HCl and NaHCO3; (c) NaOH, MeOH.

O

R

SiMe3

OO

NH

S

O

O

NO

Cl

N

R

OO

(CH2)4

SiMe3

N

R

OO

SiMe3N

O

R

O

SiMe3

NH

HO

(CH2)4R

OO

O

SiMe3

R =

a108

110

111

112

109

b

cd

Scheme 22. (a) NaN(SiMe3)2, THF, 78C, then chloronitrosocyclohexane; (b) concd HCl; (c) Ni2B, H2, MeOH; (d) benzene, 80

C, 208 h.

O

O

N3

O

RCM

O

NH

O

O

HO NOO

O

O

O

N3

O

NO

H

H

O

O

H

O

N

O

OO

OR

HN

HO

H

H

MeO2C

HO

4:1

a

b

113 114 115

116 117 118 pinnaic acid 119

Scheme 23. (a)p-TsOH, MeOH/H2O, 70%; (b) toluene, reflux, 64%.



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employed this strategy for the catalytic enantioselective syn-thesis of ()-rosmarinecine. The acyl donor122functional-ized with the dipolarophile was used in the kinetic resolutionof the nitrone 121 by Candida antarctica lipase fraction B(CAL-B). The enantio-enriched cycloadduct 123 was thenused in the synthesis of ()-rosmarinecine 124 (Scheme 24).37

NH

OH

NO

OR

O

OEtO

O CO2Et

N O

O

CO2Et

H

O

N

HO H

OH

OH

+a-b

120 121 122

123 124

60%91% ee

(-)-rosmarinecine

Scheme 24. (a) Ethoxyacetylene, RuCl2(p-cymene)2, acetone; (b) CAL-B,MeCN.

Cylindrospermopsins are potent hepatotoxins. They inhibitthe translational step of protein synthesis and are non-com-petitive inhibitors of uridine monophosphate synthesiscomplex. The construction of an A-ring synthon for the cy-lindrospermopsin 131 has been reported by Williams(Scheme 25). The INC reaction was employed to create threecontiguous stereocenters in the target. Nitrone 127, readilyobtainable from the commercially available oxazinone125, on heating underwent cycloaddition to afford the adductwith the required stereochemistry, along with traces of aregioisomeric product. Reduction of the isoxazolidine 129and further transformations afforded the target compound130.38,39 Employing the same methodology, Williams and

co-workers later reported a concise asymmetric synthesisof 7-epicylindrospermopsin 132, a hepatotoxin, which is iso-lated fromAphanizomenon ovalisporum.40

t-BocN

OPh

Ph

O

O

NHO

O

NO O

N

O

OO

HH

NH

HO

CO2Me

OH

NH

N

O

N N NH

OH

H

O3SO

OH

N NH2HN

NH

NH

O

O

O3SO

HHO

N

O

OO

Cylindrospermopsin

131

a

125 126 127

128

129 130

7-Epicylindrospermopsin

132

Scheme 25. (a) Toluene, 200 C, sealed tube, 78%.

()-(19R)-Ibogamin-19-ol is a monoterpene indole alkaloidobtained fromTabernaemontana quadrangularis. In its firstenantioselective synthesis, the 2-azabicyclo[2.2.2]octane

part was constructed by the stereoselective INC reactionof the nitrone135 derived from hydroxylamine134, which,

in turn, is made from L-glutamic acid and (+)-2-S-but-3-en-2-ol. The dipolar cycloaddition was achieved in the presenceof acid and the isoxazolidine136was obtained in 67% yield(96:4) selectively (only the major isomer shown in Scheme26). The endo product was obtained as the major isomerfrom cis-nitrone 136 intermediate, which reacts faster thanthe trans intermediate. Reductive cleavage and amide forma-

tion with indoleacetic acid furnished the intermediate 137,which was further elaborated to complete the synthesis ofthe natural product138.41

OO OH OMe

OMe

NH

HO

BnO

N O

H H

OBn

N

H H

OBn

AcO

O

NSO2

N

H

H

HN

HO

N O

H

OBn

(-)-(19R)-ibogamin-19-ol138

a

133134

135

136137

Scheme 26. (a) 1.5 M H2SO4, 8 h, 47C, 67%, 96:4.

3. Nitrile oxides

Nitrile oxides are generally prepared by Mukaiyama reac-tion of primary nitro compounds with isocyanates42 or bythe oxidation of oximes with NaClO in the presence ofa weak base.43 Most nitrile oxides are very reactive andare often generated in situ to avoid dimerization. The cyclo-adducts, isoxazoles or isoxazolidines, are well-known pre-cursors of amino alcohols and a-hydroxy cyclopentanones(Fig. 1).44

Albicanol is a drimane sesquiterpene isolated from Diplo-

phyllum albican in 1997. In Fukumotos approach to the syn-thesis of albicanol, a diastereoselective formation of theisoxazoline 142 from the alkenyl nitrile oxide 141, which,in turn, is derived from (+)-WielandMiescher ketone 139,has been employed. A chair-like conformation of the transi-tion state devoid of any unfavorable non-bonding interac-tions contributes toward the diastereoselectivity. Reductivehydrolysis followed by methylenation afforded the opticallypure albicanol143 (Scheme 27).45

N O+ ON

Figure 1.



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O

N

O

H

O

NOH

OH

H

N

O

b c

a

139 140 141

142 143

albicanol

Scheme 27. (a) 7% aq NaOCl, 90%; (b) H2, Raney-Ni, B(OMe)3, 100%; (c)Zn, CH2Br2, TiCl4, 60%.

Limonoids are degraded diterpenes, generally possessinga broad spectrum of biological activities. Azadiradione isa member of the limonoid group of havanensin. An intramo-lecular dipolar cycloaddition approach has been successfullyemployed in the synthesis of the CDE fragment of the insect

antifeedant, 12-hydroxyazadiradione151. Apart from its po-tent biological activity, the target compound 151 could alsoserve as a precursor forC-secolimonoids. In the approach ofMateos and co-workers, a-cyclocitral144 was subjected toroutine synthetic manipulations to afford the oxime 145,which was then treated with sodium hypochlorite to generatethe corresponding nitrile oxide. The latter underwent cyclo-addition to afford the isoxazoline147in 50% yield. Paralleloperations involving the nitrile oxide generated from thenitro compound 146 afforded the isoxazoline 147 in 73%yield. Subsequently, the isoxazoline ring was cleaved tothe hydroxy ketone 148 and further transformations led tothe target compound 151 (Scheme 28).46

A crucial step in the synthesis of trehazolin 154, an antibioticpseudosaccharide, involved the nitrile oxide cycloaddition.The key step for the synthesis of the azide was the oxidationfollowed by the intramolecular [3+2] cycloaddition reaction

of the oxime. Thus, the oxime152on treatment with NaOClin triethylamine afforded the cycloadduct 153, which isa key intermediate in the synthesis of trehazolin 154(Scheme 29).47

The construction of the C-ring of taxol was accomplished byMioskowski and co-workers by the intramolecular [3+2] cy-

cloaddition reaction of a nitrile oxide generated in situ. Thus,the oxime155on treatment with NaOCl furnished the tricy-clic isoxazoline156as a separable mixture of diastereomers(4:1) in 46% yield (Scheme 30).48

OSEM

OHNHO

O N

OSEM

OH

H

155 156

a

Scheme 30. (a) NaOCl, 46%.

Nicolaou has employed an intramolecular nitrile oxideole-fin cycloaddition to synthesize the urethane-cyclohexenonepart of calicheamycinone, the enediyne antibiotic caliche-amycin. Oxime 158 was accessed from tetronic acid ina few steps. Treatment of aldoxime 158 with aqueous sodiumhypochloritein dichloromethane afforded the diastereomericcycloadducts 159 and 160 in a 4:1 ratio (65% combinedyield) along with a small amount of the ester 161 (Scheme31). Further transformations produced keto-isoxazole 162,which was then employed in the synthesis of the target com-pound (Scheme 31).49

The intramolecular nitrile oxide cycloaddition (INOC) reac-tion plays a crucial role in the synthesis of the trans-hydrin-dane derivative 165, a potential intermediate for thesynthesis of the C2-symmetric pentacyclic alkaloid,

CHO

HOR I

X

HOR

O

HO N

HOH

O

O

HO

OH

X= NOH , 145X = NO2, 146

a or b c

d

144 147 148

149 150 151

Scheme 28. (a) NaClO, CH2Cl2for 145; (b) PhNCO, Et3N, benzene, 25C for146; (c) Pd/C, H2, AcOH, NaOAc; (d) LiCl, Pd(PPh3)4, Bu3(3-furyl)Sn, THF,

reflux, 60%.

NHO

BzO

O

OOMe

OMe NO

BzO

O

O

OMe

OMe

trehazolin

a

152 153154

O

OH

HOHO

HNO

N

OH

OH

OH

H

H OH

OH

Scheme 29. (a) 5% NaOCl, Et3N.



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papuamine. Nitroalkene164was prepared from racemic an-hydride 163 in a few steps. Nitrile oxide formed in situ by thereaction of164with PhNCO underwent cyclization to affordthe racemictrans-hydrindane165 (Scheme 32).50

O

O

O

H

H

NO2H

H

ON

H

HH

a

163 164 trans-hydrindane 165

Scheme 32. (a) PhNCO, benzene, 72%.

Gabosines C and E are twounusual carbo-sugars that, respec-tively, exhibit antibiotic and inhibitory activities toward thebiosynthesis of cholesterol. An alkenyl oxime 167 derivedfrom D-ribose is employed for the construction of the carbo-

cyclic framework. The INOC reaction of the oxime167wasconducted by exposing it to sodium hypochlorite, thereby af-fording the required oxazolidine 168. The ketone functional-ity and the hydroxymethyl substituent at the C-2 positionwere then unmasked by the reductive cleavage of the oxazo-lidine. Elimination of benzoic acid with DABCO and depro-tection of the hydroxyl groups completed the synthesis ofgabosine C172and gabosine E 171(Scheme 33).51

Butenolides, ()-mintlactone 176 and (+)-isomintlactone177, were enantioselectively synthesized by employing theINOC reaction as the key step (Scheme 34). The generation

and cycloaddition of the nitrile oxide from 173 wereachieved by treating it with NaClO. The reaction yieldeda diastereomeric mixture of isoxazolines in 86% yield(20:1). Catalytic hydrogenation followed by hydride reduc-tion and subsequent dehydration afforded 176 and 177(Scheme 34).52

NOH

CO2EtO

N

H

CO2Et

O

OH

CO2Et

O

O

H

O

O

H

173 174 175 176 177

a b

or

c-e

Scheme 34. (a) NaOCl, 84%, 20:1; (b) H2, Raney-Ni, B(OMe)3; (c)Me4NBH(OAc)2for176and Zn(BH4)2for177; (d)p-TSOH; (e) POCl3, Py.

Shishido and Omodani reported the first enantioselective syn-thesis of the fragrant sesquiterpene, nanaimoal 182, whichis isolated from Acanthodoris nanaimoensis. Epoxide178 was prepared by Sharpless asymmetric epoxidationof geraniol. Synthesis of the aldehyde179possessing a qua-ternary stereocenter was achieved by the rearrangement ofthe epoxide178 with methylaluminum bis(4-bromo-2,6-di-tert-butyl)phenoxide. Chain extension of the aldehyde tonitroolefin180was followed by the generation of the nitrileoxide by treatment with isocyanate. A diastereomeric mix-ture of isoxazolidines was produced by the INOC reaction.Further reactions including the reductive cleavage of the

O

HO

O

OON

OH

OMEM

BzO

ON

MEMO

BzOH

OO

ON

OO

OTMS

AcO

a

157 158

162

159(51%)

ON

BzOH

OO

OMEM

+

160(14%)

O

OMEM

BzO

O OH

+

161(20%)

Scheme 31. (a) NaOCl, CH2Cl2, H2O, 0C.

OH

HO CHO

OH

HO

N

O

O

THFO

OH

OBz

N O

THFO

OBzOO

OO

O OH

THFO

OBz

OO

H

THPO

OO

H

THPO

HO

OH

H

HO

HO

OH

O O O O O O O OH

HO

+

a

(+)-gabosine C(+)-gabosine E

166 167 168 169

170 170' 172171

b

d

d

95%

100%

c

Scheme 33. (a) NaOCl, Et3N, CH2Cl2, 60%; (b) H2, Raney-Ni, EtOH, AcOH, 89%; (c) DABCO, THF, 80%; (d) TFA, CH 2Cl2.



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isoxazolidine and its transformation into the bicyclic systemyielded the target compound182(Scheme 35).53

O

OTBS

OHCOTBS

O

But

Br

ButAl

O

But

But

Br

Me

O2N

OTBS

NO

OTBS

CHO

a

178 179 180

181 nanaimoal 182

catalystb

Scheme 35. (a) Catalyst, CH2Cl2, 97%; (b)p-ClC6H4NCO, Et3N, benzene,100%.

An unconventional approach to the antibiotic lactone, cras-sin acetate 188, also involves the INOC reaction as a keystep. Macrocycle184was constructed by the intramolecularalkylation of lithioalkyne derived from 183, with allyl bro-mide. The secondary alcohol derived from the acetonide

was converted into the nitro ether by usual synthetic proto-cols. Nitro derivative 185 was treated with phenyl isocyanateto generate the nitrile oxide, which underwent concomitantcycloaddition to form the tricyclic isoxazole187with newlyformed stereocenters at C-1 and C-14 (Scheme 36).54

Illudins are a class of tricyclic sesquiterpenes isolated fromseveral fungi. They differ in the number and position ofhydroxyl substituents and the degree of unsaturation in thetricyclic framework. They exhibit varying degrees of antimi-crobial and anticancer activities. In a concise synthesis of()-illudin C 195, Funk has utilized an intramolecular nitrileoxideolefin cycloaddition. The dianion generated from theoxime190was coupled to cyclopropyl ketone191to afford

the oxime192, which serves as the precursor for the INOCreaction. The treatment of193 with chloramine T affordedthe isoxazoline194as a single stereoisomer in nearly quan-titative yield. Isoxazole on reductive hydrolysis and dehy-dration afforded illudin C 195 in 8.2% overall yield(Scheme 37).55

Ray and co-workers synthesized a pyrimidoazepinone de-rivative by employing an INOC reaction. The target com-pound is a potential intermediate for the synthesis ofpyrimidoazepine-based folic acid derivatives. Oxime 196was treated with N-chlorosuccinimide to generate the

corresponding oximoyl chloride. Subsequent addition ofbase effected the generation of the nitrile oxide and its cyclo-addition with the terminal olefin. Isoxazoline197 was thenreductively cleaved to afford the hydroxy ketone198. Later,they utilized an INOC reaction of oxime with alkyne to

construct the oxazole-fused pyrimidoazepine derivative(Scheme 38).56,57

N

NHN

O

OMeNOH

N

Ph

N

NHN

O

OMe

N

ON

Ph

N

NHN

O

OMe

N

OHO

Ph

HN

NH2N NH

Z

O

NH

CO2H

HO2CO

Z = CH2/NH

ba

196 197 198

199

Scheme 38. (a) NCS, CH2Cl2, rt, then Et3N; (b) Raney-Ni, MeOH, AcOH,H2, 44%.

Tanshinones are quinoidal abietane-derived diterpenes,which constitute the active principle of certain traditionalChinese medicines for the treatment of coronary heart,

Br

O OOHOH OTBS

O

NO2

OTBSO

N O

OTBSO

O

N

OHO

OAc

O

ab

183 184 185

186 187

14

1

4

crassin acetate 188

Scheme 36. (a) LiN(TMS)2, THF, 74%, then H3O+

, 92%; (b) PhNCO, Et3N, benzene, 80C, 74%.

TESO

Br

H

NHO

O

OH

N

OH

ON

O

HO

H

NHO

OH

a

b c d

189 190

O

191

192

193 194 illudin C 195

Scheme 37. (a) 3 equiv t-BuLi, THF, 78 C, 68%; (b) chloramine T,EtOH, 40 C, 99%; (c) Raney-Ni, H2, B(OH)3, MeOH, H2O; (d) MsCl,Et3N, CH2Cl2, DBU, rt, 73%.



13/29

cerebrovascular diseases, and neurasthenic insomnia. Thetricyclic framework of tanshinones was constructed by theINOC reaction of oxime acetate201as a key step, the lattercompound being obtained from phthalide200. Treatment of201 with NaOCl quantitatively furnished the isoxazolines202as separable diastereomers in a ratio of 5.3:1. Reductivecleavage of the isoxazoline, acid-catalyzed cyclization toform the furan ring, and subsequent oxidation using Fremyssalt affordedortho-quinone203 (Scheme 39). The tricyclicring system 203 is the common structural unit (BCD rings)found in the tanshinones.58

Cassiol 208 is an aglycon of the antiulcerogenic naturalproduct, cassioside. Shishido reported an enantioselectivesynthesis of (+)-cassiol using INOC strategy for the con-struction of the cyclohexenone core possessing an asymme-tric quaternary carbon center (C-4). Starting from N-acyloxazolidinone204, the optically pure oxime 206 was madeby a sequence involving an Evans asymmetric aldol conden-sation, reduction, oxidation, and condensation with NH2OH.Oxime206 on treatment with aqueous NaOCl at room tem-perature underwent an INOC reaction to yield the isoxazole207as a single isomer in 88% yield. The introduction of thecarbon chain at the C-3 position completed the synthesis ofcassiol (Scheme 40).59

N O

O O

Ph

N O

O

Ph

OH O

NOH

OTHP

O

N

OTHP

O

OH

OH

HO

a b-e

f

204 205

206 207 208

Scheme 40. (a) n-Bn2BOTf, i-Pr2NEt, 4-methylpent-4-enal, CH2Cl2,78 C; (b) 2,3-dihydropyran, PPTS, CH2Cl2; (c) LiAlH4, THF; (d) Swernoxidation; (e) NH2OH$HCl, AcONa, MeOH, rt; (f) 7% aq NaOCl, CH2Cl2,rt, 88%.

Takahashi and co-workers have reported the use of the cyclo-addition of the nitrile oxide for the synthesis of the C-ringof paclitaxol. The advanced intermediate 209 containingthe A-ring was treated with NaClO to generate the nitrile ox-ide210, which underwent an INOC reaction to afford the ad-duct210. A minor amount of an undesired seven-memberedring product212 was also formed via a cationic cyclization(Scheme 41).60

An interesting synthetic approach to bisisoxazolidine-substituted pyridinone tetracycles has been reported. The

reaction sequence employs either an intramolecular silylnitronate olefin cycloaddition (INSOC) or an INOC asthe key transformation. The second oxazoline ring wasconstructed by another INOC reaction at a later stage(Scheme 42).61

4. Carbonyl ylides62

Carbonyl ylides can be generated in situ by thermolysis orphotolysis of oxiranes63ac and 1,3,4-oxazolidines.63df An-other well-documented method for the generation of carbo-nyl ylides involves the rhodium-catalyzed decomposition ofa-diazoketones containing another carbonyl group.64 Oxa-zolin-4-one is a mesionic carbonyl ylide. Oxidopyriliumylides available from pyrones also belong to this group(Fig. 2).65 Carbonyl ylides are generally very reactive andundergo facile dipolar cycloaddition with alkenes andalkynes.66

The oxo-bridged tricyclic ring system is the basic structuralunit of phorbol. The latter compound is a member of the tri-gliane family of diterpenes and has been known to possesstumor-promoting activity. The basic tricyclic ring systemof phorbol has been synthesized in one step from olefin-teth-ered diazoketone221via an IDC reaction (Scheme 43). Thesignificance of this reaction lies in the formation of an iso-mer with the correct stereochemistry of the newly formedstereocenters present in the phorbol skeleton.67

Pseudolaric acids A and B are two cytotoxic diterpenes iden-tified as the active principles of traditional Chinese medi-cine. These closely related compounds are characterizedby the presence of a perhydroazulene skeleton bearing

trans-fused acetoxy and lactone groups. The basic structuralframework of pseudolaric acids was constructed by

OO

NOH

MOMOOMOM

OAc

NO

MOMO H

MOMO OAc

O

O

O

a

200 201 202 203

Scheme 39. (a) 7% NaOCl, CH2Cl2, 100%, 5.3:1.

O O

PivO

O

OSEM

OTBS

NOH

OSEM

OTBS

N

O

O O

PivO

O

NO

HOSEM

OTBSO O

PivO

O

H OSEM

OTBS+

a

209 210

211 212(11:1)

Scheme 41. (a) NaClO, CH2Cl2, 0C, Et3N, 95%.



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employing a rhodium-catalyzed cycloaddition of chiral diaz-oketone224. The required trans disposition at C-4 and C-10was achieved during an IDC reaction (Scheme 44).68

OBnCl

OBn

O CHN2

O

OMEM

O

OBn

OMEM

HO

+O

OBn

OMEM

HOa

1.25:1223 224 225 225'

10

4

Scheme 44. (a) 1% Rh2(OAc)4, benzene, rt, 66%.

Pycnidione 234, eupenifeldin 235, and epolone B 236 aremembers of a family of tropolone fungal metabolites knownto possess important biological activities. These compoundsare structurally similar, with an identical tropolone ringattached to sesquiterpene backbones. Baldwin employedan intramolecular dipolar cycloaddition of a carbonyl ylideto a pendant alkyne for the construction of the tropolonemoiety in the synthesis of pycnidione and epolone B ana-logues. Phthalic acid was transformed into a-diazoketone227 in two steps. The latter ketone on treatment withRh2(OAc)4 in dichloromethane afforded the tetracyclicring system via the IDC reaction of the carbonyl ylide withthe terminal acetylene. Acid-catalyzed cleavage of theoxa-bridge afforded the benzotropolone derivative. The nat-

ural product analogues were then synthesized by generatingreactive quinone-methides from the benzotropolone

intermediate and trapping with humulene in successiveDielsAlder reactions (Scheme 45).69

Colchicine is an important alkaloid isolated from meadowsaffron and is known to exhibit powerful antimitotic activity.Schmaltz and co-workers have applied a rhodium-catalyzedIDC reaction as the pivotal step in a total synthesis of ()-colchicine. The key substrate for the domino sequence wasprepared from the bifunctional building block237. Enantio-selective transformation of Weinreb amide unit to the prop-argyl alcohol derivative and aromatic acylation produced thediazoketone 238. The Rh2(OAc)4-triggered intramoleculardipolar cycloaddition of thea-diazoketone238with the un-activated alkyne was carried out in toluene at 110 C to af-ford the oxatetracyclic compound 239 with nearly

complete diastereoselectivity. Having completed the carbonskeleton, the conversion of the C-ring into the a-oxygenatedtropolone and the conversion of the oxygen functionality ofthe B-ring into the acetamide were realized by a series ofconventional reactions. The overall yield of ()-colchicine240and ()-isocolchicine241 was approximately 1% over15 steps (Scheme 46).70

Recently, Padwa and co-workers synthesized [6.3.1.00,0]-dodecanedione substructure of the icetexane diterpene,komaroviquinone, known for its trypanocidal activity. Ontreatment with Rh(II) at room temperature, 243 producedepoxyindanone 244, which, on thermolysis, gave 9,10-benzo-12-oxatricyclo[6.3.1.00,0]dodecanedione 245. Reac-tion of 243 at elevated temperature directly afforded 245as the sole product. Enhanced reactivity was observed, dueto the gem-dialkyl effect with the substrate having twomethyl substituents (RMe, in245b) (Scheme 47).71

Ergot alkaloids isolable from the ergot fungus Clavicepspurpurea are famous for their activity in the treatment ofhypertension, migraine, and prolactin-dependent disorders.Lysergic acid diethylamide (LSD) is a powerful hallucino-gen belonging to this family. Lysergic acid was first isolatedby Stoll, and enormous efforts by several groups on the syn-thesis of this molecule have been reported. Padwa andco-workers applied the IDC reaction of isomunchnone to

the alkenyl group for the construction of the CD ring oflysergic acid. Isomunchnone precursor 246 was assembled

O

N

R

PhO

TMSO

INSOCO

N

Ph

H R

OTMS

O

N

Ph

H R

NO2

O

NO

N

O

O

H

Ph

H R

O

N

Ph

H R

O

NO2

R

Ph

INOC

INOCO

N

R

Ph

O

213

214 215

217

216

218 219

Scheme 42.

HN

O OR

R'O

O

Figure 2.

ON2

O

H

H

O

O

H

H

HCHO

220221 222

55%

a

Scheme 43. (a) Rh2(OAc)4, CH2Cl2.



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O

RO

O

H

O

MeO

O

H O

H

O

OMe

O

O

HH

OHO

O

H O

H

O

HO OH

OH

O

O

H O

H

O

HO OH

OH

O

O OR

-CH2O

OO

O OR

OO

O

ON2

O

O O

O

CO2H

CO2H

ab,c

de

229

230 231

232

233

93%

226

227 228

epolone B 236 eupenifeldin 235

pycnidione 234

Scheme 45. (a) Rh2(OAc)4, CH2Cl2, rt, 74%; (b) 6 N HCl, dioxane, 93%; (c) NaH, MeI, DMF, 73%; (d) p-xylene, 150C, 60%; (e) p-xylene, 150 C,231

(4 equiv), 20%.

MeO

MeO

OMe

I

N

O

OMe

MeO

MeO

OMe

NHCOMe

O

OMe

MeO

MeOOMe

OTBS

O

ON2

MeO

MeO

OMe

NHCOMe

OMe

O

MeO

MeO

OMe

O

OTBS

Oa

237

and

238 239

(-)-Colchicine 240 (-)-Isocolchicine 241

Scheme 46. (a) Rh2(OAc)4, toluene, 110C, 7 h, 98% de.

O

O O

OMe

R R

O

O O

OMe

R R

O

N2

O

R R

CO2Me

HO

OO

O

RR

H

CO2Me

O

CHN2

245aR = H, 78%

245bR = Me, 92%

a

25 C

80 C

b242 243

244245a-b

Scheme 47. (a) Rh(II), 25 C; (b) Rh(II), 80 C.



16/29

from the tricyclic olefin in eight steps. It underwent a cyclo-addition and insertion reaction in the presence of Rh2(pfb)4.Notably, the reaction showed more chemoselectivity anda faster rate compared to that using Rh2(OAc)4. Cleavageof oxabicycle followed by BartonMcCombie reactionafforded lysergic acid (Scheme 48).72

N

Bz

N

O

O

N2OMe

O

N

N

MeO

O O

Bz

H H

O N

N

MeO

O O

Bz

H

NH

NMeO2C

H

H

lysergic acid 249

a 3 steps

246 247 248

Scheme 48. (a) Rh2(pfb)4, CH2Cl2.

Padwa and co-workers have investigated extensively the in-tramolecular dipolar cycloaddition of pushpull carbonylylides generated by the action of rhodium(II) on diazo-imides. The strategy was employed for the construction ofthe pentacyclic skeleton of aspidosperma family of alka-loids. Diazoimide250derived from 3-carboxy-3-ethyl-2-pi-peridone and N-methyl indol-3-acetyl chloride was treatedwith Rh2(OAc)4. The resulting rhodium carbenoid under-went cyclization to generate the carbonyl ylide, which spon-taneously reacted with the indole double bond to afford thepentacyclic derivative251. The cycloaddition reaction cre-ated four new stereocenters with complete diastereoselectiv-ity. The diastereoselectivity is the consequence of an endoaddition with regard to the dipole and this is also in accordwith the lowest-energy transition state. Further transfor-mations of the highly oxygenated polycyclic system 251afforded a key intermediate of vindoline (Scheme 49).73

A successful attempt toward the synthesis of oxabicyclo-

[3.2.1]octane ring of ()-ribasine 254 was made by Padwaand co-workers (Scheme 50). o-Allylphenyl-substituteda-diazoketone252underwent an IDC reaction by the forma-tion of the cyclic carbonyl ylide along with dipolar cycloaddi-tion of the diazo group in the presence of Rh2(tfa)4.Incorporation of an aldehyde group instead of ethoxycarbonyl

and an imino group for the alkenyl moiety would provide theexact core structure of ribasine.74

O

N2CO2Et

O

EtO

OH O

O

N

OO

Oa

ribasine252 253

254

Scheme 50. (a) Rh2(tfa)4, toluene, 110C.

()-Aspidophytine262is a member of the family of aspido-sperma alkaloids. These alkaloids possess a common penta-cyclic framework and show diverse biological activities.Synthesis of aspidophytine has been reported by Coreyand later by Fukuyama. Recently, Padwa and Oneto em-ployed the IDC reaction as a key step for the construction

of the aspidosperma skeleton. Diazoimide 257was preparedby the coupling of acid chloride255and diazolactam256. Inthe crucial Rh2(OAc)4-catalyzed reaction, the diazoimide257underwent carbonyl ylide cycloaddition with the indolering to afford the pentacyclic indane ABCDE framework.The IDC reaction furnished a single isomer 259 with therequired stereochemistry at the newly formed four stereo-centers. Acid treatment of 259 afforded the lactone 261,which was transformed into aspidophytine 262, by routineprotocols (Scheme 51).75

Very recently, Padwa extended the IDC reaction of pushpull carbonyl ylides to the synthesis of hexacyclic frame-works associated with kopsifoline alkaloids. These arestructurally related to, and possibly derived from, aspido-sperma alkaloids. Diazoketone 263 was subjected torhodium-catalyzed decomposition to afford the cycloadduct264 as a single isomer. Further synthetic transformationswere carried out to construct the hexacyclic skeleton 265of the kopsifoline alkaloid (Scheme 52).76

Boger reported the synthesis of both isomers of vindoline 272by a tandem intramolecular [4+2]/[3+2] cycloaddition cas-cade reaction. The intramolecular DielsAlder reaction ofthe alkene-tethered 1,3,4-oxadiazole 269 followed by theloss of nitrogen furnished the carbonyl ylide 270, which un-derwent an endo stereoselective dipolar cycloaddition with

the indole ring to form the pentacyclic core having six contig-uous stereocenters. Substrate269 for the tandem cycloaddi-tion was prepared from N-methyl-6-methoxytryptamine266. It is noteworthy that vindoline constitutes the most com-plex half of vinblastine and vincristine, the two bisindolealkaloidsclinically used as antineoplastic drugs (Scheme 53).77

N

N

O O

EtO

N2O

OMe

N

ON

O

CO2Me

O

Et

N

N

O

O

O Et

CO2Me

a

250 251

Scheme 49. (a) Rh2(OAc)4, benzene, 50C, 95%.



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NMeO

NH2

NMeO

NH

O

N

NBnO

EtHO2C

N

N

O

MeOO

OBn

Et

CO2Me

N

N

O

MeOO

OBn

Et

CO2Me

NMeO

N

O

N

N

O

Et

BnO

.

N

N

MeO

HO CO2MeOAc

-N2

a-b

c

d

(-)-vindoline

266 267

268

269

271 272

270

Scheme 53.(a)CDI,H2NNHCOCO2Me; (b) TsCl, Et3N; (c) EDCI,DMAP;(d) 1,3,5-triisopropylbenzene, 230 C.

5. Azomethine imines and azomethine ylides

Azomethine ylides are precursors to pyrrolidines, dihydro-

pyrroles, and pyrroles.78

They have been generated by ther-molysis or photolysis of aziridines, fluorine-mediated

desilylation protocols, and by the deprotonation of the im-ines derived from a-amino acids.79 Azomethine imines actas precursors to pyrazolidines and have been prepared bythe reaction of 1,2-disubstituted hydrazines with carbonylcompounds (Fig. 3).80

An intramolecular azomethine iminealkene cycloadditionhas been employed for the synthesis of a differentially pro-tected trifunctional spiro-diamino acid scaffold, which findsuse in combinatorial synthesis. The sequence of events in-volves an intramolecular Michael addition of hydrazone273to afford the azomethine imine 274, which then reactswith the terminal olefin in an intramolecular dipolar cyclo-addition to afford the tricyclic pyrazoline 275. Reductive

cleavage of the NN bond and further routine synthetic ma-nipulations afforded spiro-diamino acid276 in 30% overallyield from273. The ketone precursor of273can be directlytransformed into 275 in one-pot by treating with tert-butylcarbazate, albeit in lower yield (Scheme 54).81

N

OMe

MeO

COCl

NMeO

N

OMe

O

CO2-t-Bu

O

CO2Me

O

HN

O O

CO2Me

CO2-t-Bu

N

N

O

MeO

OMe

OH

OO

N

N

O

MeO

OMe CO2Me

O

CO2-t-Bu

H

NMeO

N

OMe

O

O CO2-t-Bu

ON2

CO2Me

N

N

MeO

OMe H

OO

N

N

O

MeOOMe

OH OH

MeO2C

OO

+ a b

c

aspidophytine 262

d-f

255 256

257

258 259

260 261

O

Scheme 51. (a) MS 4 A, 92%; (b) Rh2(OAc)4, 97%; (c) BF3$OEt2, 70%; (d) MgI2, MeCN, 75%; (e) AcCl, Et3N; (f) SmI2, 90%.

N

SO2Tol

O

O

O

CO2Me

N2

CO2MeN

SO2Tol

N

O

OO

H CO2Me

CH2CO2Mea

N

SO2Tol

N

H CO2Me

H

OOH

263 264 265

Scheme 52. (a) Rh2(OAc)4, benzene, 80C, 98%.

+

NN

NN

NN

Figure 3.



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CO2Me

NNHBoc

N

CO2Me

NBoc

N NBoc

CO2Me

N Alloc

CO2H

NHBoc

a

273

274

275 276

Scheme 54. (a) EtOH, reflux, 72 h, 75%.

1-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole(FS-32)279 is a reserpine antagonist and it also potentiatesamphetamine-induced self-stimulation and L-dopa-inducedincrease in motor activity. The fused pyrazole core of FS-32 has been prepared by the intramolecular dipolar cycload-

dition (IDC) reaction of a 3-alkyl sydnone277, which servesas a masked azomethine imine moiety with an alkene tether.Substrate277on boiling in xylene underwent the IDC reac-tion, followed by a rapid aromatization with the ejection ofCO2, finally resulting in the formation of the fused pyrazole278. The cyclohexane ring was oxidized under air using Pt/C, HClO4, and acetic acid to complete the synthesis of thepyrazole-ring system (Scheme 55).82

PhNN

O

OMeR

O

NN

OMe

Ph

R

NN

Ph

R

(FS-32)R = (CH2)3N(CH3)2

a b

277 278 279

Scheme 55. (a) Xylene, 130 C, 46%; (b) Pt/C, air, HClO4, AcOH.

Overman reported the synthesis of triazacyclopenta[cd]pen-talenes282 by the IDC reaction of azomethine imines. Thedipole was generated by the condensation of dihydropyrrolea-ketoester280with thiosemicarbazide. The construction ofthe target ring system is a crucial step in the synthesis ofcomplex guanidine alkaloids such as palauamine and stylo-guanidine. It is noteworthy that the IDC reaction exhibitsa good degree of functional-group tolerance (Scheme 56).83

A facile construction of the hexahydropyrrolo[3,2-f]pyridinetricyclic framework has been achieved in six steps. The tar-get heterocyclic system287 is a conformationally restrictednicotinoid and assumes importance as potential nicotinicacetylcholine receptor (nAChR)-targeting ligand. Startingfrom 3-bromopyridine, the aldehyde 284 was constructed

in three steps. Treatment of284with sarcosine in DMF at100110 C generated the azomethine ylide 285, whichwas intercepted by the pendant alkene. The intramoleculardipolar cycloaddition afforded a pair of diastereomers 286(1.37:1) in 84% yield. Subsequent reductive dehydroxyl-ation by zinc and formic acid produced the target compound287(Scheme 57).84

N

Br

N

CHO

MOMO

MeHN

CO2H

N

MOMO

N

Me

N

N

H

H

MOMO

Me

N

N

H

H Me84% (2 steps)

283 284 285

286 287

84%

dr = 1.37:1

a

b-c

Scheme 57. (a) DMF, heat; (b) HCl, 60 C; (c) Zn, AcOH.

Epperson and Gin have accomplished the enantiospecificsynthesis of the bridged aza-tricyclo[5.3.0.04,8]decane coreof asparagamine A, a pyrrolizidine alkaloid isolated from

Asparagus racemosus showing potent antioxytocin activity.They employed the optically pure N-trimethylsilylmethylvinylogous amide 288, synthesized from an L-glutamicacid derivative, as the precursor for the azomethine ylide289. The latter ylide was generated by treating 288 withTf2O followed by tetrabutylammonium triphenyldifluorosi-licate (TBAT). An intramolecular cycloaddition reaction ini-tiated by Z-enol triflate formed exclusively then generatedthe bridged pyrrazolidine core290with an angularC8-E-bu-

tenyl substituent in 51% yield with complete regio- and ste-reospecificity (Scheme 58).85

N

EtS O

Me3Si

Et

O

H

F

N

EtS O

Me3Si

Et

OTf

HN

OTf

O

EtS H

a

288 289 290

Scheme 58. (a) Tf2O, CHCl3, 23C, TBAT, 65 C, 24 h, 51%.

Employing the IDC reaction of an azomethine ylide, Takanoaccomplished the total synthesis of ()-mesembrine294, analkaloid obtained fromSceletium namaquense. Thermolysisof aziridine ester291in xylene afforded pyrrolidine lactone293 in 85% yield. The reaction is noteworthy for the

RN

EtO2C

CO2Me

ORN

CO2MeN NH

O

HN

S

RN

EtO2C CO2MeHN

N

S

H2N

a

R = Cbz, SES or SEM

280 281 282

Scheme 56. (a)NH2NHCSNH2, AcOH, 70C.



19/29

stereoselective formation of three new chiral centers, includ-ing a tertiary carbon. The bulky benzyloxymethyl group oc-cupies the equatorial position in the transient azomethineylide 292, thus leading to the formation of a single isomer293. Lactone 293 is then converted into ()-mesembrine294 and itsN-methyl derivativethrough a synthetic sequenceinvolving eight steps (Scheme 59).86

ON

OBn

OBn

H

H

MeO

OMe

ON

OMe

MeO

OBn

O

Bn

N

MeO

OMe

MeO

H

MeO

MeO

O

OBnO

N

H

Bn

H

O OBn

(-)-mesembrine

a

291

292

293

294

Scheme 59. (a) Xylene, sealed tube, 250 C, 20 min.

Sarain A is a polycyclic alkaloid of marine origin possessinga unique structural array unprecedented in natural products.The tightly fused central tricyclic core of sarain A wasconstructed by Weinreb and co-workers by employing anintramolecular azomethine ylidealkene cycloaddition.87a

Thermolysis of the aziridine moiety in substrate 297 gener-ated a transient azomethine ylide, which subsequentlycyclized to afford the adduct 299 in 73% yield (Scheme

60). Interestingly, the efficiency of the cycloaddition washeavily dependent on the nature of the protecting groupson the amide nitrogen and side-chain oxygen. The cycload-duct was then transformed into the allylsilane derivative 300.Ferric chloride-catalyzed cyclization of the allylsilane ontothe N-acyliminium species afforded 302, the tricyclic core

of Sarain A (Scheme 60). Very recently, Weinreb and co-workers have prepared an advanced intermediate for the to-tal synthesis of sarain A employing a similar strategy.87b It isnoteworthy that Heathcock had also employed a similar di-polar cycloaddition route to construct the core structure ofsarain.87c,d

Ogasawara and co-workers have developed a synthetic routeto both enantiomers of necine base, dihydroxyheliotridane,starting from (R)-O-benzylglycidol.The diastereofacial selec-tivity of the dipolar cycloaddition reaction is controlled by thetether length between the dipole and dipolarophile. The ho-moallylic aziridinic ester303arapidly transformed into azo-methine ylide at 260 C in diphenyl ether and underwentthe IDC reaction to afford d-lactone 305 along with its 2,3 epi-mer3050. The stereochemical outcome is consistent with theinvolvement of a chair-like transition state 304. The allylicaziridine ester303underwent the IDC reaction under similarconditions, however, presumably through an envelope-liketransition state 306, as it contains a shorter chain, and affordedg-lactones 307 and 308 with opposite diastereofacial selectiv-ity. d-Lactone 305 was further elaborated to complete thesynthesis of ()-dihydroxyheliotridane 309. The other enan-tiomer, (+)-dihydroxyheliotridane 3090, was obtained fromtheg-lactone 307(Scheme 61).88

Pandey and co-workers reported a formal total synthesis of()-pancracine, which belongs to 5,11-methanomorphanthri-dine family of alkaloids, utilizing the azomethine IDC reac-tion (Scheme 62).89a The precursor for the IDC reactionwas prepared by N-alkylation ofa,a-bis(trimethylsilyl)alkyl-amine311with diiodide310and further Heck coupling withMVK. The non-stabilized azomethine ylide 314 was gener-ated by the AgF-mediated double desilylation of 313. The

sterically favored endo attack of the azomethine ylide onthe alkene furnished the 5,11-methanomorphanthridine skel-eton with suitable side chains at C-4 and C-11. Hydrolysis ofthe benzoyl group, mesylation, and subsequent ring closurevia the kinetic enolate of the methyl ketone afforded a penta-cyclic derivative. Olefin 316 obtained by the reductiveelimination of the ketone has been employed as a key inter-mediate in Overmans total synthesis of ()-pancracine.89b,c

6. Azides

Azides constitute a very important class of dipoles and theazide group can be easily incorporated into organic com-pounds by nucleophilic displacement reactions.90 The dipo-lar cycloaddition of an azide to an alkene furnishesa triazoline derivative (Fig. 4) whereas cycloaddition to analkyne affords a triazolidine derivative.91 The latter reactionhas received much attention recently, due to its ability todeliver macromolecules.92,93

Azidealkene cycloadducts can extrude nitrogen at elevatedtemperatures to form aziridines or imines, depending uponthe substrate and reaction conditions. Both pathways havebeen made use of in total synthesis and a few selected exam-ples are described.

The enantioselectivesynthesis of ()-slaframine 323, a toxicindolizidine alkaloid isolated from the fungus Rhizoctonia

N

Bn

CO2Bu-t

O

MeO OMeBnHN

N N

OH

TsBn

TMS

NBn

N

MeO

O

Bn

OMe

N N BnTs

H

H

H

TMS

NBnN

MeO

O

Bn

OMe

N N BnTs

H

H

H

H

N NO

BnBnH

H

OMe

OMe

a

b

295

296

297

298 299

300 301 302

Scheme 60. (a) o-Dichlorobenzene, 320 C, 78%; (b) FeCl3, CH2Cl2,78 C to rt, 61%.



20/29

leguminicola, has been accomplished via an intramolecularazide dipolar cycloaddition (IAC) as the key step. Startingfrom 317, the amino functionality at the C-6 position of()-slaframine was introduced by reduction with DIBALH.The IAC precursor was produced by the displacement of to-sylate with azide and subsequent thermolysis produced theimine. Neither the azide 319 nor the cycloadduct 320 wasisolated. Further structural manipulations delivered 323(Scheme 63).94

An enantioselective synthesis of the pyrrolizidine alkaloid,(+)-crotanecine326, also utilizes the IAC reaction as a keystep. Tosylate 324 derived from 2,3-O-isopropylidene-D-erythrose was treated with sodium azide in DMF to affordthe imine 325 directly. Further synthetic transformation ofthe imine afforded the alkaloid 326 (Scheme 64).95

Crinane 332 is a non-natural alkaloid possessing a 5,10b-ethanophenanthridine skeleton, which is typical of the

NBn

O

OBn

O

H

OO

N

OBnH

H

Bn

NBn

OO

OBnH

ONBn

OBn

O

H

H

H

ONBn

OBn

O

H

H

H

ONBn

OBn

O

H

H

H

N

HOOH

H HH

ONBn

OBn

O

H

H

H

N

HOOH

H HH

n

+n = 1

n = 0

+

a

a

70%

8%

70%

(-)- dihydroxyheliotridane 309

(+)- dihydroxyheliotridane 309'

1:3

304

n = 0, 303an = 1, 303b

305 305'

306

307 308

Scheme 61. (a) Diphenyl ether, 260 C.

O

O N OBz

O

O

O N

TMS

TMS

OBz

O

O

O

I

N

TMS

TMS

OBz

O

O N

O

OBz

H

H

HN

TMS

TMS

OH

O

O N

OH

H

H

OH

H

O

O

I

I+

a-b c

310 311 312

313 314

315 316

d

Scheme 62. (a) K2CO3, MeCN; (b) BzCl, Et3N, CH2Cl2; (c) Pd(OAc)2, PPh3, K2CO3, MVK; (d) AgF, MeCN, 56%.

O N

PMB

OH

OTIPS

a-cHO

OTs

OTIPS

NTs PMB

N

OH

N

OTIPS

Ts

PMB

HOOTIPS

NTs PMB

N

N N

NN

OTIPS

Ts

PMB

HOOTIPS

NTs PMB

N3

N

OAc

H2N

H

d-e

317 318

319 320

321

f-g

322 (-)-slaframine 323

Scheme 63. (a) TsCl, Et3N, DMAP, CH2Cl2; (b) DIBALH, THF, 0C; (c)

N-tosyl-N-methyl pyrrolidineperchlorate,CH2Cl2, 0C;(d) NaN3, DMF, 60

C;

(e) toluene, reflux; (f) MsCl, Et3N, CH2Cl2; (g) NaBH4, EtOH, 0 C, thenK2CO3, reflux.

+ N N NN N

N

Figure 4.



21/29

Amaryllidaceae family. Pearson and Schkeryantz utilizedthe IAC to achieve a racemic synthesis of crinane. Conver-sion of acetate 327 into the carboxylic acid 328 byIrelandClaisen rearrangement was followed by reductionand azidation to furnish the precursor 329for the IAC reac-tion. Thermolysis of the azido olefin 329 generated thecycloadduct triazoline 330, which on rapid extrusion ofnitrogen quantitatively furnished the imine331. The latterimine on reduction and subsequent treatment withEschenmosers salt afforded crinane 332 in 23% overallyield (starting from cyclohexenone) (Scheme 65).96

Tylophorine 338, belonging to the phenanthroindolizidine

family of alkaloids, is known to possess antitumor activity.Pearson employed the azidealkene dipolar cycloadditionfor the racemic synthesis of338. Azido alkene334was syn-thesized starting from homoveratric acid 333. Thermolysisof the azide334 followed by sodium borohydride reductiondirectly afforded the alkaloid tylophorine in 82% yield. Pre-sumably, the iminium salt 337 is formed via the intermedi-ates335 and 336 (Scheme 66).97

Pearson has also employed a similar strategy for the synthe-sis of the alkaloids, swainsonine and g-lycorane.98

Molander has employed the intramolecular azideenonedipolar cycloaddition reaction in the synthesis of an azaspir-ocyclic ketoaziridine, which could serve as the intermediatefor the antitumor alkaloid, cephalotaxine 343. Azido-enone341was constructed by the Pd(0)-catalyzed coupling of vi-nyl iodide 339 and arylzinc chloride 340. The cycloadductpresumably loses nitrogen to afford the aziridine 342(Scheme 67).99

Benzazoc-3-ene unit (e.g.,347) is a structural moiety, which

has been recognized as a useful precursor for the synthesis ofthe antitumor agents, mitomycin C and FR-900482. Anazideallylsilane 1,3-dipolar cycloaddition has been em-ployed for the construction of the benzazoc-3-ene derivative347. A completely diastereoselective dipolar cycloadditionafforded the triazoline345and the latter compound on pho-tolysis furnished the aziridine346 (Scheme 68). Formationof the eight-membered ring was achieved by the action of

THPO

TsO

O

O

N

HOOH

OH

H

NTHPO

O

Oa

324 325 (+)-crotanecine 326

Scheme 64.

O

O

OAc

N

OO

O

O CO2H

O

O NH

O

ON3

O

O

N

N

N

-N2

a, b c, d e

f, g

327 328 329

330 331 crinane 332

Scheme 65. (a) LDA, THF, 78 C; (b) TBSCl, 78 C to reflux; (c) LiAlH4, THF; (d) Ph3P, DEAD, (PhO)2P(O)N3, CH2Cl2; (e) toluene, reflux, 100%;(f) NaBH3CN, AcOH; (g) CH2N(Me)2I, THF, 50

C.

MeO

OMe

CO2H

MeO

OMe

OMe

MeO

N3

Cl

MeO

OMe

OMe

MeO Cl

N

MeO

OMe

OMe

MeO Cl

NN

N

-N2

MeO

OMe

OMe

MeO

N

Cl

MeO

OMe

OMe

MeO

N

333

334

336

335

337 tylophorine 338

82%

a

b

Scheme 66. (a) Benzene, 130 C; (b) NaBH4, MeOH.



22/29

fluoride ion on the silylaziridine. It was observed that whenthe hydroxyl group of346was protected, aziridine cleavagedid not occur. The authors suggest that the function of thefluoride from TBAF is to reversibly deprotonate the hydrox-yl to promote a homo-Brook rearrangement. Various otherbases in aprotic media were also found to be effective in pro-moting the transformation, thus providing support for thismechanistic proposal.100

N3

OH

TMS

N

NN

OH

TMS

H

N

OH

TMS

H HN

OH

a b

c

344 345

346 347

Scheme 68. (a) Toluene, reflux, 90%; (b) benzene, rt, hn, 77%; (c) TBAF,DMF, 20 C.

Ciufolini has also utilized a similar strategy for the synthesisof benzazocenone, a potential intermediate for the synthesisof mitomycinoidic antitumor agents. Azido alkene 350required for the cycloaddition was synthesized by an enereaction between 2-methoxypropene and 2-(2-azidophenyl)-acetaldehyde348. Azide350 underwent an IAC reaction toyield the triazoline351as a mixture ofantiandsyn(7:1) iso-mers. Photochemical extrusion of nitrogen and subsequenthydrolysis furnished353 (Scheme 69).101

N3

O

+

N3 OMe

O

MeO

N

NN

OMe

OR

HN

OMIP

O

OMe

N OMe

OR

N OMe

OR

348 350 351

353

a

352

b

c

349

Scheme 69. (a) Lewis acid, CH2Cl2, rt;(b) toluene, reflux,cat. K2CO3, 55%;(c)hn, moist THF.

An intramolecular azidealkene cycloaddition features asthe key step in the enantioselective synthesis of the water-soluble B-vitamin, (+)-biotin362. The macrothiolactoniza-tion of the carboxylic acid 354, available in a few stepsfrom L-(+)-cysteine, affords the 10-membered thiolactone355, albeit in low yield. The urethane moiety was thenreplaced with a carbamoyl azide 356 and the latter azide

on thermolysis in water afforded a mixture of isomers 360and 361 in a 3:2 ratio. Both isomers are carried throughthe synthesis to furnish (+)-biotin. The initially formed cy-cloadduct 357 presumably loses nitrogen assisted by theproximal nucleophilic sulfur atom to form a tricyclic sulfo-nium intermediate 359. The carboxylic acid side chain ofbiotin is released by the hydrolytic opening of the lattercompound (Scheme 70).102

HSCOOH

NHt-BuO

O

H

4

S

O

HN

O

OBu-t

S

O

BnN

O

N N

N

S

O

BnN

O

N N

N

S

O

BnN

O

N

NN

BnN N

S

O

O

HH H H2O

BnN NH

S (CH2)4COOH

O

HH H

+ HN NBn

S (CH2)4COOH

O

HH H

HN NH

S (CH2)4COOH

O

HH H

a

354 355 356

357 358 359

360 361 362

b

Scheme 70. (a) PhOP(O)Cl2, DMF, CH2Cl2, 24%; (b) H2O, autoclave,145 C, 42%.

The tricyclic ring system present in the aspidosperma alka-loid, vindoline, has been constructed by the IAC reaction.Azido olefin 363 underwent cycloaddition, and immediateloss of nitrogen by the intermediate afforded the aziridine364as a single isomer. Reductive opening of the aziridine,N-acylation, and C-alkylation completed the constructionof the CDE-ring system of vindoline (Scheme 71).103

O OMe

CO2MeN3

PhPh

N

O OMe

H

CO2Me

Ph

HN

O OMe

H

CO2MeH

N

O OMe

H

CO2Me

O

Ph

a b-c

d-e

80%

363 364

365 366

Scheme 71. (a) Benzene, reflux; (b) Li, NH3, THF, 78C; (c) AcOH; (d)

BrCH2COCl, NaHCO3, THF; (e) t-BuOK, benzene, reflux.

Bisbenzocyclooctadiene lignan lactones like ()-stegana-cine and ()-steganone have been shown to possess

O

I

N3

O

O ZnCl

TBSOO

N3

TBSO

O

O

N

O

OO

OTBS

N

OO

MeO

OH

+ a

b

(-)-cephalotaxine 343

339 340 341

342

Scheme 67. (a) Pd(dba)3, TFP, DMF, THF, 25C; (b) xylene, 131 C, 48 h,

76%.



23/29

significant anticancer activity. Their unnatural 7-aza ana-logues also exhibit potent biological activity and, at thesame time, do not present any stereoselection problems in

the synthesis. A microwave-assisted intramolecular azidealkyne cycloaddition has been employed in the synthesisof such compounds possessing a 1,2,3-triazole ring. Thus,biaryl-azidoalkyne370, obtained by sequential Suzuki cou-pling, propargylation, and azidation, readily afforded diben-zotriazolo[1,5]azocine 371. Conventional heating wasineffective in promoting the cycloaddition reaction. In theacetate derivative 371b, the lesser rigidity would accountfor the lower activation energy and, hence, the high yieldof the product (Scheme 72).104

The triazole analogue of a dehydropyrrolizidine alkaloid hasbeen constructed through the IDC reaction of azidoalkyne373 (Scheme 73). The product, 5,6-dihydro-4H-pyrrole-[1,2-c][1,2,3]triazole 374, assumes importance, since ana-logues of dehydropyrrolizidine alkaloids are potent antitumoragents.105

OTBSHO

N N N N

NN

OHOTBS

N3

OHa

373 374372

Scheme 73. (a) Toluene, reflux, 24 h, 59%.

7. Mesionic and miscellaneous dipoles65

Padwa and Kuethe reported a formal synthesis of decahydro-quinoline alkaloid, ()-pumilotoxin C 381 by employinga tandem Pummerer-isomunchnone dipolar cycloadditionreaction. Pummerer reaction of imidosulfoxide 375 gener-ated an isomunchnone dipole376, which underwent a cyclo-addition reaction with the tethered olefin. The cycloadditiondirectly afforded a-pyridones378and379. Both compoundswere independently converted into the pyridine 380, whichis a known precursor to pumilotoxin. a-Pyridones 378and 379 arise from the oxo-bridge cleavage of 377 andsubsequent acetylation by the excess acetic anhydride(Scheme 74).106

Padwa has also employed Pummerer reactiondeprotona-tioncycloaddition cascade for the synthesis of many other

naturally occurring alkaloids. The pivotal step of all thesesyntheses is the cycloaddition reaction of a mesionicisomunchnone dipole. The alkaloids synthesized by thismethodology include onychnine, dielsiquinone, lupinine,anagyrine, and costaclavine. The syntheses of all of thesealkaloids are summarized in a single publication. As arepresentative example, the synthesis of dielsiquinone is pre-sented inScheme 75. Pummerer-induced generation of theisomunchnone dipole 384, subsequent cycloaddition withthe pendant alkene and oxabicyclic ring cleavage of thecycloadduct were achieved essentially in one step by treatingthe imidosulfoxide 382 with excess acetic anhydride in thepresence of a catalytic amount ofp-TsOH. Pyridone deriva-tive386was further transformed into the alkaloid, dielsiqui-none, in a few steps to complete its first total synthesis. Thepower of this synthetic methodology is evident from thenumber and variety of the targets that it has achieved.107

A general synthesis of tetrahydroindoles via dipolar cyclo-addition of munchnones generated from N-acyl amino acidderivatives has been reported. An alkynone moiety attachedon the acyl unit reacts with the munchnone intermediate(e.g., 390) to afford a primary cycloadduct, which readily

loses CO2 to furnish the tetrahydroindole derivative(Scheme 76). A topoisomerase-I inhibitor skeleton

B(OH)2

O

Br

MeO

OMe

OTBDMS MeO

OMe

OTBDMS

O

MeO

OMe

N3

R2R1

Ph

NN

N

R1R2Ph

MeO

OMe

b370aR1= R2= O

370bR1= OAc, R2= H

a

77%

367

368

369

371a, b

Scheme 72. (a) Pd(Ph3P)4, Cs2CO3, dioxane/EtOH, 130C, microwave; (b) o-dichlorobenzene, 210 C, 15 min, microwave, 43% for 371aor DMF, 120 C,

15 min, microwave, 76% for 371b.

O

N

PhO

S

O

Et

N O

Bn

OAc

N O

Bn

SEt

N

Bn

O

H

HNH

H

H

O

N

PhO

SEt

N

O

SEt

OBn

Ac2O

a

+

synthesis polar compound

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