Synthesis Polar Compound

Tetrahedron 63 (2007) 1224712275
Tetrahedron report number 817
Intramolecular 1,3-dipolar cycloaddition reactions in targeted syntheses

Vijay Naira,b,* and T. D. Sujaa
a
Organic Chemistry Section, Chemical Sciences Division, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695 019, Kerala, India b Jawaharlal Nehru Centre for Advanced Scientic 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12272 Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12275
1. Introduction Historically, the synthesis of diazoacetic acid ester by Curtius in 18831 and its reaction with unsaturated
Keywords: Intramolecular 1,3-dipolar cycloaddition; Huisgen reaction; 1,3Dipole; Azomethine ylide; Azomethine imine; Carbonyl ylide; Nitrile oxide; Azide; Nitrone; Mesionic compound; Betaine; Natural product synthesis; 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, diisobutylaluminum hydride; DMF, dimethyl formamide; DMSO, dimethyl sulfoxide; Et, ethyl; IAC, intramolecular azide cycloaddition; IDC, intramolecular dipolar cycloaddition; INC, intramolecular nitrone cycloaddition; INOC, intramolecular nitrile oxide cycloaddition; LDA, lithium diisopropylamide; LSD, lysergic acid diethylamide; m-CPBA, meta-chloroperoxybenzoic acid; MEM, methoxyethoxymethyl; MVK, methyl vinyl ketone; Ms, mesyl; nAChR, nicotinic acetylcholine receptor; NCS, N-chlorosuccinimide; pfb, peruorobutyrate; RCM, ring-closing metathesis; TBAF, tetrabutylammonium uoride; TBAT, tetrabutylammonium triphenyldiuorosilicate; TBS, tertiary-butyldimethylsilyl; tBu, tertiary butyl; TFA, triuoroacetic acid; 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
carboxylic esters reported by his younger colleague, Buchner, in 1888 may constitute the embryonic events in the discovery of 1,3-dipolar cycloadditions.2 Important contributions in subsequent years by Buchner,2 Beckmann,3 Werner, Buss,4 and others for the generation of 1,3-dipoles are also noteworthy. This eld, however, lay dormant until 1963, when Huisgen, recognizing the generality of these reactions, created the conceptual framework for the 1,3-dipolar cycloadditions (Huisgen reaction) and provided the much-needed mechanistic rationalization for the process.5 He invoked the intermediacy of dipoles in some well-known reactions. Later, Sustmann classied the dipolar cycloaddition reactions into three types based on the orbital interactions.6 With a better understanding of the mechanistic events and the large body of experimental results provided by Huisgen, the area of 1,3-dipolar cycloadditions witnessed enormous progress. The impact was felt mostly in the realm of heterocyclic synthesis. In due course, dipolar cycloaddition reactions became a trusted tool in targeted synthesis, especially in those involving the construction of heterocyclic systems.7
12248
V. Nair, T. D. Suja / Tetrahedron 63 (2007) 1224712275
1.1. Dipolar cycloaddition as a synthetic strategy The impact of dipolar cycloaddition reactions in the area of heterocyclic synthesis is in many ways comparable to that of DielsAlder reactions on carbocyclic synthesis. In fact, the availability of various classes of dipoles and dipolarophiles has allowed a greater degree of versatility. The discovery of new dipolar species was followed by applications of their reactions in targeted syntheses. Even though all dipolar cycloaddition reactions are, in principle, closely related processes, their applications are seldom discussed together in the chemical literature. The main reason for this anomaly is the vast variety of heterocyclic systems produced in such reactions. Discussions on heterocyclic synthesis generally follow a product-class-based approach. Although convenient, such an approach fails to address the underlying similarities of the various processes involved. There has been no concerted attempt to categorize various dipolar cycloadditions used in the synthesis of natural products, apart from an excellent book edited by Padwa.8 A discussion on dipolar cycloadditions by Wade published in 1991 is also worth mentioning, although its emphasis is on the general aspects of dipolar cycloadditions.9 This article will focus on the use of dipolar cycloaddition reactions in the total synthesis of natural products or analogues. The discussion is limited to the literature published after 1991 and instances in which the dipolar cycloaddition serves as a key step of the synthesis and is not intended to be comprehensive. For convenience, the examples are classied on the basis of the dipole involved. 2. Nitrones 1,3-Dipolar cycloaddition reactions of nitrones with alkenes leading to isooxazolidines are a long-known and a well-studied area.10 Nitrones are usually generated by the condensation of an aldehyde and an N-substituted hydroxylamine11 or the oxidation of a hydroxylamine.12 Reductive ring opening of isoxazolidines by hydrogenation with Pd or Raney nickel provides access to g-amino alcohols.13 Synthesis of bridged, medium-sized rings has been accomplished by the intramolecular nitrone cycloaddition (INC) reaction of alkenyl nitrones derived from amino acids. This protocol has been applied to the synthesis of 3-amino-5hydroxyazepines and other N-heterocycles (Scheme 1).14
R1 o-NBSN n 1 O a R1 o-NBSN n 2 N O R2 b-c R1 HN n 3 OH NHR2
derivatives. Nitrone 5 derived from 3-O-allyl-D-glucose 4 (and 3-O-allyl-D-altrose) underwent an INC reaction to afford the oxepane, which was isolated as tetraacetate 6. On the other hand, 3-O-allyl-D-allose 7 (and 3-O-allyl-D-mannose) afforded the tetrahydropyran derivatives 9 and 10 under similar reaction conditions (Scheme 2). The formation of oxepanes from glucose and altrose derivatives may be rationalized by invoking the unfavorable 1,3-diaxial interactions present in the transition states leading to the formation of the tetrahydropyran products.15 In a very recent paper, Shing and co-workers reported that the nitrones derived from hept-6-enoses possessing a trans acetonide group in the chain exclusively afforded the bridged isoxazolidines after INC reactions. These results are in accordance with the computational models, which suggest that the transition state leading to the endo product (i.e., the bridged bicyclo[4,2,1]isoxazolidine) is more stabilized than that leading to the exo product. The cycloadducts were further transformed into the calystegine analogues 14 and 15, tropane 16, and a hydroxylated aminocycloheptane derivative 17 in a few steps (Scheme 3).16 Chiral polyhydroxylated amino ve-, six-, or seven-membered carbocycles have been synthesized via an INC reaction of aldehyde 19 derived from 1,2,5,6-di-O-isopropylidine-a-D-ribo-hexafurano-3-ulose 18, which is readily prepared from D-glucose (Scheme 4). The cycloadducts 20 and 21 are useful intermediates in the synthesis of various bioactive compounds such as enzyme inhibitors, antibiotics, and bioactive nucleosides.17 INC reactions in which the nitrone or olen partners are part of cyclic systems can lead to tricyclic frameworks. For example, 3-oxa- or 3-aza-nitrones spontaneously afforded tricyclic derivatives, which could serve as intermediates in alkaloid synthesis (Scheme 5).18 The use of INC reactions of 5-alkenyl- or 5-homoalkenyl proline for the synthesis of azabicyclo[x.3.0]alkane amino acids with heteroatom-substituted side chains has been reported (Scheme 6). These compounds are particularly attractive constrained dipeptide mimics, due to their ability to serve as conformationally xed surrogates of peptide-turn secondary structures.19 INC reactions of silicon-tethered 4-hydroxy-2-isoxazolidine-2-oxides afforded a new class of silicon heterocycles 29, which possess a complex framework of hydroxylated amino acids with an ethoxycarbonyl group, a nitroacetal bicyclic system, and a cyclic silyl ether. The product on Tamao oxidation and subsequent reduction afforded the non-natural amino acid derivative 30 (Scheme 7).20 A synthesis of stereodened aminopolyols was achieved by the INC reaction of nitrones with a silicon tether derived from a- or b-hydroxy carbonyl compounds. The fused bicyclic transition state involved in the concerted cycloaddition renders the reaction highly stereoselective. Tamao oxidation of the silicon heterocycle and the usual hydrogenolysis of the cycloadduct isoxazolidine revealed the additional hydroxyl groups of the target molecule, which is usually isolated as the acetate 34 (Scheme 8).21
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, 60 C, 1.5 h.
Cyclic ether moieties are common motifs in many important marine natural products like brevetoxin B and ciguatoxin. Shing and Zhong employed the INC reaction effectively to construct oxepanes and tetrahydropyrans from sugar

HO HO O OH 4 HO HO O OH 7 O OH OH OH 8 a HO HO O OAc OAc 9, 8% O OH OH OH 5 O b AcO AcO + O OAc OAc 10, 33% a HO HO N N O b O 55% OAc 6 N O AcO N O AcO O AcO AcO OAc O O
12249
Scheme 2. (a) MeNHOH$HCl, NaHCO3, 80% EtOH, reux, 48 h; (b) Ac2O, DMAP, Py, CH2Cl2, rt.
OR1 OHC O O R2NHOH.HCl 12 11 HO HO HO HO 14 R1, R2 = Ac, Bn O NMe or HO HO HO 15 i
R2
O N
R2
R1O O O endo-TS OH or NH2 16 HO HO NH or OH OH
R 1O O O 13 OH H2N OH HO HO 17 OH
Scheme 3. (i) NaHCO3, MeCN, rt.

O O O 18 Ph Ph HH O N O OH H 20 H O + O O H OH O 21 Ph Si Ph O 31 O N O H 22 X = O, N-benzyl H 23 X H H Me Ph O Si Ph Bn N O 33

O O O O OHC
O O R2
R1 O N O + Cl Si 28 a
EtO2C R1 O N O R
2
O b, c R1 O NH2 OH R2 OAcOAc 30
OH 19 N H O O
HO 27 CO2Et R1, R2 = alkyl, aryl or H
O Si 29
Scheme 7. (a) ImH, CH3CN; (b) Tamao oxidation; (c) reduction.

Ph Ph O Si Bn N O 32 Boc OH OAc 34
Scheme 4. (a) BnNHOH, EtOH, rt, 20 h, 82%, 4:1.
CO2Me
a, b
Me
N X
c) Tamao oxidation d) reduction AcO
HN
Scheme 5.
Scheme 8. (a) DIBALH, 78 C, 30 min; (b) BnNHOH, 78 C to rt, 79%.
a N O O 24 CO2tBu O N
N O
CO2tBu + O N
N O
CO2tBu
A Lewis acid-mediated INC reaction of the tricyclic oxime 35 directly produced the isoxazolidine derivative of estrone 36 (Scheme 9).22 Kang and co-workers reported a route to cephalosporin derivatives with cyclic substituents at the 3-position. 3-Alkylidene-4-carboxylic acid derivative 37 was treated with methylhydroxylamine hydrochloride in the presence of a base.
Ph 25
Ph
26
Scheme 6. (a) BnNHOH$HCl, NaHCO3, EtOH, H2O, 71%, 9:1.
12250
N OH H H MeO 35 H MeO a

H N O H H 36 H
Scheme 9. (a) BF3$OEt2.
The nitrone produced was reuxed in benzene to effect the cycloaddition with the exocyclic olen to afford a single adduct 38. Similarly, a nitrile oxide cycloaddition was also carried out to furnish the derivative 40 (Scheme 10).23 Haouamine A is a cytotoxic polycyclic alkaloid of marine origin, with a unique 3-aza-[7]-paracyclophane moiety in the structural framework. It exhibits selective activity against a human colon carcinoma cell line HT-29. Haouamine A has been synthesized earlier from the pentacyclic intermediate 47 using a microwave-assisted intramolecular DielsAlder reaction. Weinreb utilized an INC reaction for the synthesis of the indene ring of the pentacyclic indenotetrahydropyridine derivative 47. Aldehyde 43 on treatment with N-benzylhydroxylamine produced the transient nitrone 44, which was heated without isolation to afford the cycloadduct 46. Formation of the kinetically favored cycloadduct 45 was also observed, but this could be converted into the more stable isomer 46 by prolonged heating in toluene. The conversion of 45 into 46 presumably involves a thermal cycloreversion and a subsequent cycloaddition. The cycloadduct was later converted into the desired pentacyclic compound 47 (Scheme 11).24
R1 a R1 N O 37 R1 2 CO2R2 S O b,c R
1
Sung and Hee reported an enantioselective synthesis of the azetedinone fragment of the antibiotic, 1b-methyl carbapenem. Lactone 49 was prepared from ethoxyethyl ether 48 in three steps. Reduction of 49 afforded the corresponding lactol, which was heated with p-methoxybenzylhydroxylamine and base to generate the nitrone 51. The desired cycloadduct 52 was formed in 80% overall yield from 49 as a single isomer. Further synthetic operations were carried out on 52 to arrive at b-lactam 53 (Scheme 12). It is noteworthy that the four contiguous stereocenters in 53 were xed during the cycloaddition reaction.25
a CN 48 O 49 H HO 51 PMB heat N 80% O O N PMB H 52 O 53 NH OH O O 50 OTBS H H OH b
EtO
CO2Et
Scheme 12. (a) DIBALH, CH2Cl2, 78 C to rt; (b) p-MeOC6H4CH2NHOH, Et3N, hydroquinone, benzene, reux.
Erythroidene 58 and spirojatamol 59 are two sesquiterpenes with an intriguing spirobicyclo[5.4]decane framework. Fukumoto reported a short synthesis of both sesquiterpenes in their racemic form by employing an INC reaction as the pivotal step. Ene-nitrone 55 was prepared from 4-isopropylcyclohexenone 54. Nitrone 55 on heating afforded two diastereomeric cycloadducts 56 and 57, of which the major
R1 S S N O O N 38 S N R1 N O N 40 O R2O2C 41 R2O2C 39 S NOH
NMe2
N O R2O2C
= PhCH2CONH R = Ph2CH
R2O2C
Scheme 10. (a) MeNHOH$HCl, Py, CHCl3, MeOH, then benzene, reux, 87%; (b) NH2OH$HCl, Py, 82%; (c) NCS, Py, Et3N, CHCl3, 71%.
OMe OMe O O O 42 OMe MeO MeO O N H 45 b 46 Ph + 43 Ph 44 OMe OMe a
OMe
135 C O
OMe
MeO O N H H 47 Ph MeO NH Br
MeO
Scheme 11. (a) BnNHOH, toluene, 135 C; (b) toluene, 135 C.

O O N a N 54 55 33% 56 Ph 22% 57
12251
Ph O +
Ph
56 and OH 58 59 59' + OH
Scheme 13. (a) Toluene, 180 C, sealed tube.
diastereomer 56 possessed the desired stereochemistry. Further reactions on 56 were carried out to synthesize both erythroidene 58 and spirojatamols 59 and 590 in racemic forms (Scheme 13).26 Romero and co-workers have developed a synthetic route to enantiomerically pure chromane derivatives like 65 using an intramolecular dipolar cycloaddition (IDC) of the nitrone and alkene as a key step. Chromane itself is known to exhibit modest antibacterial activity. The authors employed nitrones with a chiral substituent on the nitrogen, which also possessed an oxygen functional group. This allowed for a Lewis-acid chelation involving the nitrone oxygen and, as a result, provided very good diastereoselectivity for the cycloaddition. The cycloadducts were then subjected to routine synthetic operations to furnish various enantiopure chromane derivatives. A representative example is provided in Scheme 14.27 Halichlorine and pinnaic acid are two marine natural products known to exhibit interesting biological properties. Both compounds contain an azaspiro[4.5]decane core structure. A stereospecic synthesis of this structural unit has been achieved by employing the INC reaction. Oxime 67 prepared from dithiane 66 was heated in the presence of benzyl acrylate at 140 C. Nitrone 68 that was generated underwent smooth cycloaddition to provide a single cycloadduct
69 in 92% yield. The latter adduct was then subjected to various chemical transformations to afford azaspiro[4.5]decane 71 as a single isomer. The conversion of 70 into 71 proceeds through a hetero-Michael additionreversion sequence with elimination of benzyl acrylate (Scheme 15).28 The indolizidine ring system is widespread in many biologically active alkaloids. Polyhydroxylated indolizidines act as structural analogues of sugars and can competitively interact with glycosidases. In an enantioselective synthesis of hydroxylated indolizidines, Brandi employed the INC reaction of a pyrroline nitrone 72 derived from L-malic acid. Initial attempts to deprotect the THP ether and attach an olenic tether met with difculties associated with the racemization of the intermediate hydroxynitrone. Therefore, nitrone 72 was initially masked as the adduct 73 by a dipolar cycloaddition with ethyl acrylate (or styrene). Subsequent hydrolysis of the THP ether and attachment of the olenic tether via a Mitsunobu inversion proceeded without any racemization. The substrate on heating underwent cycloreversion to reveal the nitrone and subsequent INC cycloaddition to furnish the isoxazoline derivative. Deprotection, mesylation, and hydrogenolysis afforded the indolizidine derivative 77 (Scheme 16).29 ()-Histrionicotoxin 85 is a spiropiperidine alkaloid isolated from the brightly colored poison-arrow frog,
O N Ph H
HO Cl Ph N O O OH a HO Cl Zn O N O HO 61 H N HN CF3 OH H H H2N O O
H O
Ph
24% 63 O N Ph H H O
60
S H
OH H
71% 62
65
64
Scheme 14. (a) 2 equiv ZnCl2, 40 C, CH2Cl2.
12252

OTHP THPO HO a N 67 OTHP O BnO N O H 69

O BnO N O 68 CO2Me O BnO b HN HO H 70 CO2Bn HO H 71 MeO2C H
CO2Bn
66
Scheme 15. (a) Xylene, 140 C, 92%; (b) 1,2-dichlorobenzene, reux, 84%.
OTHP R N O 72 O PMBO O R = Ph, CO2Et R
PMBO H OTHP Mitsunobu O N 73 O PMBO H O N 76 O reaction R
O H O N 74 O HO H N 77 O O a R
N O 75
Scheme 16. (a) o-Dichlorobenzene, 150 C, 3 h, 74%.
OBn
4 steps X
X O
78
(CH2)3OTBDPS NHOH 79
(CH2)3OTBDPS
N O 80
(CH2)3OTBDPS
X = (+)-10,2-camphor sultam CN
Ph X b O
(CH2)3OTBDPS N O 81 Ph
5 steps
BnO
c N O 82 Ph
BzO
N O 83
CN
BzO
N O 84
CN
N H HO (-)-Histrionicotoxin 85
Scheme 17. (a) Toluene, 80 C, 6 h; (b) 75 C, 85%; (c) toluene, sealed tube, 190 C, 3.5 h, 80%.
Dendrobates histrionicus. It is known to act as non-competitive inhibitor of nicotinic acetylcholine receptors and is also employed as probe to study neuromuscular signal transmission. In an enantioselective synthesis of ()-histrionicotoxin by Holmes and co-workers, an imaginative use of the INC reaction is demonstrated. The cyclic nitrone 80 is generated by a hydroxylaminealkyne cyclization and is protected as the cycloadduct 81 by treating with styrene. The side chain on isoxazolidine 81 was modied to install the a,b-unsaturated nitrile group. Compound 82 was heated in a sealed
tube at 190 C in toluene to promote the cycloreversion dipolar cycloaddition sequence. The cycloadduct 84 was obtained as a single isomer in high yield and, in the process, all three chiral centers present in the natural product were xed. The (Z)-enediyne units were installed using Storks iodophosphorane methodology to complete the synthesis of 85 (Scheme 17).30 Holmes has reported another route employing the INC reaction for the synthesis of azaspirocycloundecane skeleton 90,
12253
which is the precursor of all of the known histrionicotoxin alkaloids (Scheme 18). Conjugate addition of the oxime derived from 86 to the a,b-unsaturated nitrile generates an equimolar mixture of the nitrone 87 and the kinetically favored cycloadduct 88. Further heating of this mixture generally afforded a mixture of isoxazolidine derivatives 8890. The authors have optimized the conditions for the conversion of 88 and the epimer 89 into the required cycloadduct 90.31
O i O N CN NC
benzene to afford the nitrone 98 as a 5:1 mixture of cis and trans isomers. The nitrone solution was then reuxed to furnish the diastereomeric cycloadducts in a 16:1 ratio. Interestingly, the stereoselectivity of this reaction is rather high when compared to that of similar nitroneolen cycloadditions (Scheme 20).33 Baldwin has recently employed the INC reaction to synthesize the amaryllidaceae alkaloids, ()-haemanthidine 105, (+)-pretazettine 106, and (+)-tazettine 107, from D-mannose in enantiopure form. Alkenylhydroxylamine 103 for the INC reaction was produced from the alkenyl acetal, which, in turn, was obtained from a-methyl-D-mannopyranoside. The dipolar cycloaddition was carried out by heating the crude nitrone 103 in benzene. The cycloadduct was further transformed into the alkaloid, ()-haemanthidine 105. (+)Pretazettine 106 and (+)-tazettine 107 were sequentially synthesized from 105 by taking advantage of the well-established chemical relationship between these alkaloids (Scheme 21).34 A synthesis of the 1-azaspiro[4.5]decane core found in cylindricine-type alkaloids has been accomplished by the INC reaction (Scheme 22). The stable cyclic nitrone 110 underwent cycloaddition when reuxed in benzene. Electronic effects caused by the presence of the silyl group at the alkene moiety controlled the regiochemistry.35 The azaspirocyclic core of pinnaic acid was also synthesized by White and co-workers by employing a transannular nitroneolen cycloaddition. Ring-closing metathesis (RCM) of 113 produced a diastereomeric mixture of the macrocyclic oxaziridine 115. Simultaneous hydrolysis of the oxaziridine and the ketal afforded the hydroxylamine-ketone, which underwent an immediate condensation to afford the nitrone 117. After chromatographic removal of the minor Z-isomer, a toluene solution of the nitrone was reuxed to furnish a single cycloadduct 118 (Scheme 23). Since the cyclic nitrone is not large enough to allow the nitrone oxygen to pass through the ring, the cycloaddition occurs preferentially at the rear face of the trans double bond. Hydrolysis of the lactone and reductive cleavage of the isoxazolidine afforded the dihydroxy amino ester representing the azaspirocyclic core structure of pinnaic acid 119.36 Kita has combined the kinetic resolution of a racemic hydroxynitrone with a subsequent dipolar cycloaddition to achieve a high enantioselectivity for the cycloadducts. He
N O CN 88
NC 86
CN CN 87
NC
N O 88
+ NC
+ N O 90 83% CN
NC
N O 89 CN
CN ii
ii
88%
Scheme 18. (i) NH2OH$HCl, NaOAc, MeOH, 25 C; (ii) chlorobenzene, sealed tube, 180 C.
Lepadiformine, a tricyclic indolizidine alkaloid, isolated from Clavelina lepadiformis, exhibits cytotoxic activity toward several tumor strains in vitro. In a convergent stereoselective synthesis by Weinreb, the indolizidine core of lepadiformine was prepared by the INC reaction of the cyclic nitrone 92. The latter nitrone was derived from the linear acyclic oxime acetal 91, which contains all of the carbon atoms necessary for the construction of the tricyclic core. The stable nitrone 92 was thermolyzed to obtain a single isoxazolidine cycloadduct 93. The linking chain of the nitrone assumes a boat-like conformation and the dipolarophile approaches the nitrone from the face opposite to the bulky phenoxymethyl group. Amino alcohol 94, derived by reduction of the isoxazolidines, was further elaborated into the target lepadiformine 95 (Scheme 19).32 Pretazettine is a member of the crinine class of amaryllidaceae alkaloids, exhibiting antiviral and antitumor activities. An advanced intermediate for the synthesis of pretazettine was constructed by employing an intramolecular nitrone olen cycloaddition. Aldehyde 97 was treated with the oxalate salt of N-(a-methylbenzyl)hydroxylamine and base in
N OH + OPh 91 OPh O O NHOH
C6H13 a
C6H13 N O H OPh b
92
N O H OPh 93
C6H13 c NH OH H OPh 94
C6H13 C6H13 N H 95 OH
Scheme 19. (a) 3 N HCl, THF, 4 h, rt, 92%; (b) DMSO, 190 C, 16 h, 63%; (c) Zn dust, AcOH, H2O, 45 C, 3 h, 91%.
12254

CO2Et S Li CH(OMe)2 S 96 R= O O CO2Et O S Ph 16:1 N H Me 100 Ph S S 97 R CHO Me a Ph NHOH S S R N 98 O 5:1 Ph Me CO2Et
S S
CO2Et O N +
H 99 Me
Scheme 20. (a) Benzene, K2CO3, rt.
CO2Et Br HO MeO OH O OMe O O 102 O O O H Ar CO2Et O N H H 104 Me Ph MeO N 105 O b OH OH O O O H Ar H 3 steps O O
CO2Et Ar N 103 H O Me Ph O O c O a
OMe OMe
101
MeO 106
MeO 107
Scheme 21. (a) Benzene, 80 C, 65%; (b) MeI, MeOH, then HCl and NaHCO3; (c) NaOH, MeOH.
NO O R O O a SiMe3 c Cl R O O NH HO 109 SiMe3 N O 111 R O N O 112 SiMe3 (CH2)4 O O
SiMe3 SiMe3 b R N O 110 R= (CH2)4
108
R O
NH S O O
Scheme 22. (a) NaN(SiMe3)2, THF, 78 C, then chloronitrosocyclohexane; (b) concd HCl; (c) Ni2B, H2, MeOH; (d) benzene, 80 C, 208 h.
O O O RCM N3 O O 113 O H O HO N H O O 116 117 OO N b O N O O H H 118 HO H HO pinnaic acid 119 HN MeO2C H 4:1 N3 O O 114 R N O O a
115
Scheme 23. (a) p-TsOH, MeOH/H2O, 70%; (b) toluene, reux, 64%.
12255
employed this strategy for the catalytic enantioselective synthesis of ()-rosmarinecine. The acyl donor 122 functionalized with the dipolarophile was used in the kinetic resolution of the nitrone 121 by Candida antarctica lipase fraction B (CAL-B). The enantio-enriched cycloadduct 123 was then used in the synthesis of ()-rosmarinecine 124 (Scheme 24).37
OH OR O + NH 120 O O H N O 123 CO2Et N N O 121 HO H 122 OH OH EtO O O CO2Et a-b 60% 91% ee
in turn, is made from L-glutamic acid and (+)-2-S-but-3-en2-ol. The dipolar cycloaddition was achieved in the presence of acid and the isoxazolidine 136 was obtained in 67% yield (96:4) selectively (only the major isomer shown in Scheme 26). The endo product was obtained as the major isomer from cis-nitrone 136 intermediate, which reacts faster than the trans intermediate. Reductive cleavage and amide formation with indoleacetic acid furnished the intermediate 137, which was further elaborated to complete the synthesis of the natural product 138.41
OMe BnO O O 133 OH HO N H 134 OMe a H OBn 135 N O
124 (-)-rosmarinecine
Scheme 24. (a) Ethoxyacetylene, RuCl2(p-cymene)2, acetone; (b) CAL-B, MeCN.

N O
O H N S H O2 137 NAcO H OBn
Cylindrospermopsins are potent hepatotoxins. They inhibit the translational step of protein synthesis and are non-competitive inhibitors of uridine monophosphate synthesis complex. The construction of an A-ring synthon for the cylindrospermopsin 131 has been reported by Williams (Scheme 25). The INC reaction was employed to create three contiguous stereocenters in the target. Nitrone 127, readily obtainable from the commercially available oxazinone 125, on heating underwent cycloaddition to afford the adduct with the required stereochemistry, along with traces of a regioisomeric product. Reduction of the isoxazolidine 129 and further transformations afforded the target compound 130.38,39 Employing the same methodology, Williams and co-workers later reported a concise asymmetric synthesis of 7-epicylindrospermopsin 132, a hepatotoxin, which is isolated from Aphanizomenon ovalisporum.40
Ph Ph t-BocN 125 H O O O O O N O 129 HO H O3SO N NH NH2HN O O NH O3SO N NH N H O NH 126 HO NH CO2Me 130 OH O NH a O O N 127 OH O O O 128 O N
H OBn 136
N HO HN H (-)-(19R)-ibogamin-19-ol 138 H
Scheme 26. (a) 1.5 M H2SO4, 8 h, 47 C, 67%, 96:4.
3. Nitrile oxides Nitrile oxides are generally prepared by Mukaiyama reaction of primary nitro compounds with isocyanates42 or by the oxidation of oximes with NaClO in the presence of a weak base.43 Most nitrile oxides are very reactive and are often generated in situ to avoid dimerization. The cycloadducts, isoxazoles or isoxazolidines, are well-known precursors of amino alcohols and a-hydroxy cyclopentanones (Fig. 1).44 Albicanol is a drimane sesquiterpene isolated from Diplophyllum albican in 1997. In Fukumotos approach to the synthesis of albicanol, a diastereoselective formation of the isoxazoline 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 transition state devoid of any unfavorable non-bonding interactions contributes toward the diastereoselectivity. Reductive hydrolysis followed by methylenation afforded the optically pure albicanol 143 (Scheme 27).45
Cylindrospermopsin 131
OH N H 7-Epicylindrospermopsin 132

Scheme 25. (a) Toluene, 200 C, sealed tube, 78%.
()-(19R)-Ibogamin-19-ol is a monoterpene indole alkaloid obtained from Tabernaemontana quadrangularis. In its rst enantioselective synthesis, the 2-azabicyclo[2.2.2]octane part was constructed by the stereoselective INC reaction of the nitrone 135 derived from hydroxylamine 134, which,
N + N O
Figure 1.
12256

O N NOH a
of the oxime. Thus, the oxime 152 on treatment with NaOCl in triethylamine afforded the cycloadduct 153, which is a key intermediate in the synthesis of trehazolin 154 (Scheme 29).47 The construction of the C-ring of taxol was accomplished by Mioskowski and co-workers by the intramolecular [3+2] cycloaddition reaction of a nitrile oxide generated in situ. Thus, the oxime 155 on treatment with NaOCl furnished the tricyclic isoxazoline 156 as a separable mixture of diastereomers (4:1) in 46% yield (Scheme 30).48
OSEM a H OH HO N 155 OH O N 156 OSEM
139
140 O N OH c H 142 H
141
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 possessing a broad spectrum of biological activities. Azadiradione is a member of the limonoid group of havanensin. An intramolecular dipolar cycloaddition approach has been successfully employed in the synthesis of the CDE fragment of the insect antifeedant, 12-hydroxyazadiradione 151. Apart from its potent biological activity, the target compound 151 could also serve as a precursor for C-secolimonoids. In the approach of Mateos and co-workers, a-cyclocitral 144 was subjected to routine synthetic manipulations to afford the oxime 145, which was then treated with sodium hypochlorite to generate the corresponding nitrile oxide. The latter underwent cycloaddition to afford the isoxazoline 147 in 50% yield. Parallel operations involving the nitrile oxide generated from the nitro compound 146 afforded the isoxazoline 147 in 73% yield. Subsequently, the isoxazoline ring was cleaved to the hydroxy ketone 148 and further transformations led to the target compound 151 (Scheme 28).46 A crucial step in the synthesis of trehazolin 154, an antibiotic pseudosaccharide, involved the nitrile oxide cycloaddition. The key step for the synthesis of the azide was the oxidation followed by the intramolecular [3+2] cycloaddition reaction
Scheme 30. (a) NaOCl, 46%.
Nicolaou has employed an intramolecular nitrile oxideolen cycloaddition to synthesize the urethane-cyclohexenone part of calicheamycinone, the enediyne antibiotic calicheamycin. Oxime 158 was accessed from tetronic acid in a few steps. Treatment of aldoxime 158 with aqueous sodium hypochlorite in dichloromethane afforded the diastereomeric cycloadducts 159 and 160 in a 4:1 ratio (65% combined yield) along with a small amount of the ester 161 (Scheme 31). Further transformations produced keto-isoxazole 162, which was then employed in the synthesis of the target compound (Scheme 31).49 The intramolecular nitrile oxide cycloaddition (INOC) reaction plays a crucial role in the synthesis of the trans-hydrindane derivative 165, a potential intermediate for the synthesis of the C2-symmetric pentacyclic alkaloid,
O a or b H N c OH H O
X CHO 144 OR X= NOH , 145 X = NO2, 146 H I d OR H
147 O OH H O
148
149

150
151
Scheme 28. (a) NaClO, CH2Cl2 for 145; (b) PhNCO, Et3N, benzene, 25 C for 146; (c) Pd/C, H2, AcOH, NaOAc; (d) LiCl, Pd(PPh3)4, Bu3(3-furyl)Sn, THF, reux, 60%.
OH N O BzO OMe O 152 BzO OMe a O N O OMe O 153 OMe HO HO O OH HN N O H OH trehazolin 154 OH H OH OH
HO
Scheme 29. (a) 5% NaOCl, Et3N.

O N O H OMEM 160 (14%) + BzO OMEM 161 (20%) O OH
12257
HO O O 157 BzO
O N OH a BzO MEMO
O N O +
OMEM 158
BzO H 159 (51%)
O AcO O
O N O
TMS
162
Scheme 31. (a) NaOCl, CH2Cl2, H2O, 0 C.
papuamine. Nitroalkene 164 was prepared from racemic anhydride 163 in a few steps. Nitrile oxide formed in situ by the reaction of 164 with PhNCO underwent cyclization to afford the racemic trans-hydrindane 165 (Scheme 32).50
H O O H O 163 H 164 H N NO2 a H H H O
and cycloaddition of the nitrile oxide from 173 were achieved by treating it with NaClO. The reaction yielded a diastereomeric mixture of isoxazolines in 86% yield (20:1). Catalytic hydrogenation followed by hydride reduction and subsequent dehydration afforded 176 and 177 (Scheme 34).52
trans-hydrindane 165 CO2Et
a NOH
H N O CO2Et 174
b O OH CO2Et 175
c-e H O or O 176 H O O 177
Scheme 32. (a) PhNCO, benzene, 72%.
Gabosines C and E are two unusual carbo-sugars that, respectively, exhibit antibiotic and inhibitory activities toward the biosynthesis of cholesterol. An alkenyl oxime 167 derived from D-ribose is employed for the construction of the carbocyclic framework. The INOC reaction of the oxime 167 was conducted by exposing it to sodium hypochlorite, thereby affording the required oxazolidine 168. The ketone functionality and the hydroxymethyl substituent at the C-2 position were then unmasked by the reductive cleavage of the oxazolidine. Elimination of benzoic acid with DABCO and deprotection of the hydroxyl groups completed the synthesis of gabosine C 172 and gabosine E 171 (Scheme 33).51 Butenolides, ()-mintlactone 176 and (+)-isomintlactone 177, were enantioselectively synthesized by employing the INOC reaction as the key step (Scheme 34). The generation
N THFO a CHO OH 166 O O 167 OBz OH
173
Scheme 34. (a) NaOCl, 84%, 20:1; (b) H2, Raney-Ni, B(OMe)3; (c) Me4NBH(OAc)2 for 176 and Zn(BH4)2 for 177; (d) p-TSOH; (e) POCl3, Py.
Shishido and Omodani reported the rst enantioselective synthesis of the fragrant sesquiterpene, nanaimoal 182, which is isolated from Acanthodoris nanaimoensis. Epoxide 178 was prepared by Sharpless asymmetric epoxidation of geraniol. Synthesis of the aldehyde 179 possessing a quaternary stereocenter was achieved by the rearrangement of the epoxide 178 with methylaluminum bis(4-bromo-2,6-ditert-butyl)phenoxide. Chain extension of the aldehyde to nitroolen 180 was followed by the generation of the nitrile oxide by treatment with isocyanate. A diastereomeric mixture of isoxazolidines was produced by the INOC reaction. Further reactions including the reductive cleavage of the
N O THFO b O O 168 d 100% OBz THFO O O 169 OBz
OH HO HO
OH c
O THPO
OH THPO + O
OH d 95% HO HO
OH HO HO
OH
O O 170
O 170'
OH (+)-gabosine E 171
OH (+)-gabosine C 172
Scheme 33. (a) NaOCl, Et3N, CH2Cl2, 60%; (b) H2, Raney-Ni, EtOH, AcOH, 89%; (c) DABCO, THF, 80%; (d) TFA, CH2Cl2.
12258

HO H
O a OTBS 178 b O Br 181 179 N OTBS nanaimoal 182 180 CHO OHC OTBS O2N OTBS
isoxazolidine and its transformation into the bicyclic system yielded the target compound 182 (Scheme 35).53
TESO 189 O b HO N
HO N O 191 a
Br
190 O N d O
OH 192
H c OH
catalyst Br
But But O O Al t Bu Me But
193
194
OH illudin C 195
Scheme 35. (a) Catalyst, CH2Cl2, 97%; (b) p-ClC6H4NCO, Et3N, benzene, 100%.
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%.
An unconventional approach to the antibiotic lactone, crassin acetate 188, also involves the INOC reaction as a key step. Macrocycle 184 was constructed by the intramolecular alkylation of lithioalkyne derived from 183, with allyl bromide. The secondary alcohol derived from the acetonide was converted into the nitro ether by usual synthetic protocols. Nitro derivative 185 was treated with phenyl isocyanate to generate the nitrile oxide, which underwent concomitant cycloaddition to form the tricyclic isoxazole 187 with newly formed stereocenters at C-1 and C-14 (Scheme 36).54 Illudins are a class of tricyclic sesquiterpenes isolated from several fungi. They differ in the number and position of hydroxyl substituents and the degree of unsaturation in the tricyclic framework. They exhibit varying degrees of antimicrobial and anticancer activities. In a concise synthesis of ()-illudin C 195, Funk has utilized an intramolecular nitrile oxideolen cycloaddition. The dianion generated from the oxime 190 was coupled to cyclopropyl ketone 191 to afford the oxime 192, which serves as the precursor for the INOC reaction. The treatment of 193 with chloramine T afforded the isoxazoline 194 as a single stereoisomer in nearly quantitative yield. Isoxazole on reductive hydrolysis and dehydration afforded illudin C 195 in 8.2% overall yield (Scheme 37).55 Ray and co-workers synthesized a pyrimidoazepinone derivative by employing an INOC reaction. The target compound is a potential intermediate for the synthesis of pyrimidoazepine-based folic acid derivatives. Oxime 196 was treated with N-chlorosuccinimide to generate the
corresponding oximoyl chloride. Subsequent addition of base effected the generation of the nitrile oxide and its cycloaddition with the terminal olen. Isoxazoline 197 was then reductively cleaved to afford the hydroxy ketone 198. Later, they utilized an INOC reaction of oxime with alkyne to construct the oxazole-fused pyrimidoazepine derivative (Scheme 38).56,57
O b HN HN O 196 N N Ph HN O N N O Ph 197 O NH CO2H O HN H2N N N H Z = CH2/NH 199 Ph 198 N N N OMe O OH
OMe NOH a N N
OMe N
HO2C
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 traditional Chinese medicines for the treatment of coronary heart,
O a Br
OH OH
OTBS O NO2 b
183 OTBS O N O
184 OTBS O
4 1 14
185 OH O O N O OAc crassin acetate 188
186
+
187
Scheme 36. (a) LiN(TMS)2, THF, 74%, then H3O , 92%; (b) PhNCO, Et3N, benzene, 80 C, 74%.

OAc O MOMO MOMO OMOM NOH 200 201 202 203 a H O N O OAc O O
12259
MOMO
Scheme 39. (a) 7% NaOCl, CH2Cl2, 100%, 5.3:1.
cerebrovascular diseases, and neurasthenic insomnia. The tricyclic framework of tanshinones was constructed by the INOC reaction of oxime acetate 201 as a key step, the latter compound being obtained from phthalide 200. Treatment of 201 with NaOCl quantitatively furnished the isoxazolines 202 as separable diastereomers in a ratio of 5.3:1. Reductive cleavage of the isoxazoline, acid-catalyzed cyclization to form the furan ring, and subsequent oxidation using Fremys salt afforded ortho-quinone 203 (Scheme 39). The tricyclic ring system 203 is the common structural unit (BCD rings) found in the tanshinones.58 Cassiol 208 is an aglycon of the antiulcerogenic natural product, cassioside. Shishido reported an enantioselective synthesis of (+)-cassiol using INOC strategy for the construction of the cyclohexenone core possessing an asymmetric quaternary carbon center (C-4). Starting from N-acyl oxazolidinone 204, the optically pure oxime 206 was made by a sequence involving an Evans asymmetric aldol condensation, reduction, oxidation, and condensation with NH2OH. Oxime 206 on treatment with aqueous NaOCl at room temperature underwent an INOC reaction to yield the isoxazole 207 as a single isomer in 88% yield. The introduction of the carbon chain at the C-3 position completed the synthesis of cassiol (Scheme 40).59
O N O O 204 a OH O N O O b-e
PivO
NOH a
O N
O O
OTBS OSEM 209 PivO
OTBS OSEM 210 PivO
O N + OTBS H OSEM 212
O O
OTBS H O OSEM 211 (11:1)
O O
Scheme 41. (a) NaClO, CH2Cl2, 0 C, Et3N, 95%.
reaction sequence employs either an intramolecular silyl nitronate olen cycloaddition (INSOC) or an INOC as the key transformation. The second oxazoline ring was constructed by another INOC reaction at a later stage (Scheme 42).61 4. Carbonyl ylides62 Carbonyl ylides can be generated in situ by thermolysis or photolysis of oxiranes63ac and 1,3,4-oxazolidines.63df Another well-documented method for the generation of carbonyl ylides involves the rhodium-catalyzed decomposition of a-diazoketones containing another carbonyl group.64 Oxazolin-4-one is a mesionic carbonyl ylide. Oxidopyrilium ylides available from pyrones also belong to this group (Fig. 2).65 Carbonyl ylides are generally very reactive and undergo facile dipolar cycloaddition with alkenes and alkynes.66 The oxo-bridged tricyclic ring system is the basic structural unit of phorbol. The latter compound is a member of the trigliane family of diterpenes and has been known to possess tumor-promoting activity. The basic tricyclic ring system of phorbol has been synthesized in one step from olen-tethered diazoketone 221 via an IDC reaction (Scheme 43). The signicance of this reaction lies in the formation of an isomer with the correct stereochemistry of the newly formed stereocenters present in the phorbol skeleton.67 Pseudolaric acids A and B are two cytotoxic diterpenes identied as the active principles of traditional Chinese medicine. These closely related compounds are characterized by the presence of a perhydroazulene skeleton bearing trans-fused acetoxy and lactone groups. The basic structural framework of pseudolaric acids was constructed by
Ph
205 Ph O
OTHP f NOH 206
OTHP
N O 207
HO 208
OH OH
Scheme 40. (a) n-Bn2BOTf, i-Pr2NEt, 4-methylpent-4-enal, CH2Cl2, 78 C; (b) 2,3-dihydropyran, PPTS, CH2Cl2; (c) LiAlH4, THF; (d) Swern oxidation; (e) NH2OH$HCl, AcONa, MeOH, rt; (f) 7% aq NaOCl, CH2Cl2, rt, 88%.
Takahashi and co-workers have reported the use of the cycloaddition of the nitrile oxide for the synthesis of the C-ring of paclitaxol. The advanced intermediate 209 containing the A-ring was treated with NaClO to generate the nitrile oxide 210, which underwent an INOC reaction to afford the adduct 210. A minor amount of an undesired seven-membered ring product 212 was also formed via a cationic cyclization (Scheme 41).60 An interesting synthetic approach to bisisoxazolidinesubstituted pyridinone tetracycles has been reported. The
12260
TMSO Ph N O O R Ph O R 213 Ph 214 NO2
Ph
OTMS N INSOC O H NO2 R Ph N O H 217 R H Ph N O INOC R O H Ph H 219 N O N O O R
215
N O O R 216
218
INOC
Scheme 42.
R HN
O R'
O O
intermediate and trapping with humulene in successive DielsAlder reactions (Scheme 45).69 Colchicine is an important alkaloid isolated from meadow saffron and is known to exhibit powerful antimitotic activity. Schmaltz and co-workers have applied a rhodium-catalyzed IDC reaction as the pivotal step in a total synthesis of ()colchicine. The key substrate for the domino sequence was prepared from the bifunctional building block 237. Enantioselective transformation of Weinreb amide unit to the propargyl alcohol derivative and aromatic acylation produced the diazoketone 238. The Rh2(OAc)4-triggered intramolecular dipolar cycloaddition of the a-diazoketone 238 with the unactivated alkyne was carried out in toluene at 110 C to afford the oxatetracyclic compound 239 with nearly complete diastereoselectivity. Having completed the carbon skeleton, the conversion of the C-ring into the a-oxygenated tropolone and the conversion of the oxygen functionality of the B-ring into the acetamide were realized by a series of conventional reactions. The overall yield of ()-colchicine 240 and ()-isocolchicine 241 was approximately 1% over 15 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. On treatment with Rh(II) at room temperature, 243 produced epoxyindanone 244, which, on thermolysis, gave 9,10benzo-12-oxatricyclo[6.3.1.00,0]dodecanedione 245. Reaction of 243 at elevated temperature directly afforded 245 as the sole product. Enhanced reactivity was observed, due to the gem-dialkyl effect with the substrate having two methyl substituents (RMe, in 245b) (Scheme 47).71 Ergot alkaloids isolable from the ergot fungus Claviceps purpurea are famous for their activity in the treatment of hypertension, migraine, and prolactin-dependent disorders. Lysergic acid diethylamide (LSD) is a powerful hallucinogen belonging to this family. Lysergic acid was rst isolated by Stoll, and enormous efforts by several groups on the synthesis of this molecule have been reported. Padwa and co-workers applied the IDC reaction of isom unchnone to the alkenyl group for the construction of the CD ring of lysergic acid. Isom unchnone precursor 246 was assembled
Figure 2.
CHO
H O H O N2 221 a 55%
H O H
220
O 222
Scheme 43. (a) Rh2(OAc)4, CH2Cl2.
employing a rhodium-catalyzed cycloaddition of chiral diazoketone 224. The required trans disposition at C-4 and C-10 was achieved during an IDC reaction (Scheme 44).68
OBn OBn CHN2 a O Cl OBn OMEM 224 O H OMEM 225 O O + H
10 4
OBn O O
OMEM 1.25:1 225'
223
Scheme 44. (a) 1% Rh2(OAc)4, benzene, rt, 66%.
Pycnidione 234, eupenifeldin 235, and epolone B 236 are members of a family of tropolone fungal metabolites known to possess important biological activities. These compounds are structurally similar, with an identical tropolone ring attached to sesquiterpene backbones. Baldwin employed an intramolecular dipolar cycloaddition of a carbonyl ylide to a pendant alkyne for the construction of the tropolone moiety in the synthesis of pycnidione and epolone B analogues. Phthalic acid was transformed into a-diazoketone 227 in two steps. The latter ketone on treatment with Rh2(OAc)4 in dichloromethane afforded the tetracyclic ring system via the IDC reaction of the carbonyl ylide with the terminal acetylene. Acid-catalyzed cleavage of the oxa-bridge afforded the benzotropolone derivative. The natural product analogues were then synthesized by generating reactive quinone-methides from the benzotropolone

O CO2H CO2H 226 O 227 O d O O O OR 230 231 RO H 232 H O H O HO H O O OH O pycnidione 234 H O O H H HO H OH O O OH O OH OH O MeO H 233 O OMe O O O N2 O a O O 228 e O O b,c 93% O 229 OR O
12261
-CH2O
epolone B 236
eupenifeldin 235
Scheme 45. (a) Rh2(OAc)4, CH2Cl2, rt, 74%; (b) 6 N HCl, dioxane, 93%; (c) NaH, MeI, DMF, 73%; (d) p-xylene, 150 C, 60%; (e) p-xylene, 150 C, 231 (4 equiv), 20%.
OTBS O MeO MeO OMe 237 MeO NHCOMe MeO OMe O OMe (-)-Colchicine 240 and MeO 238 O N2 MeO I N OMe MeO OMe O MeO a
MeO OTBS MeO OMe O O
239
NHCOMe OMe OMe O (-)-Isocolchicine 241
Scheme 46. (a) Rh2(OAc)4, toluene, 110 C, 7 h, 98% de.
CO2Me CHN2 O 242
CO2Me N2 O 243 HO HR O O b
OMe R R a O R R O
OMe 25 C R 80 C O 244 O R R O
O O 245a-b 245a R = H, 78% 245b R = Me, 92%
Scheme 47. (a) Rh(II), 25 C; (b) Rh(II), 80 C.
12262
from the tricyclic olen in eight steps. It underwent a cycloaddition and insertion reaction in the presence of Rh2(pfb)4. Notably, the reaction showed more chemoselectivity and a faster rate compared to that using Rh2(OAc)4. Cleavage of oxabicycle followed by BartonMcCombie reaction afforded lysergic acid (Scheme 48).72
O N O N2 N Bz 246 247 OMe a O MeO H O O O N MeO H 3 steps N Bz O O N H
and an imino group for the alkenyl moiety would provide the exact core structure of ribasine.74
O O O a O N2 CO2Et 252 H EtO 253

O O O O ribasine 254 N
Scheme 50. (a) Rh2(tfa)4, toluene, 110 C.

N 248 Bz
MeO2C
H N H
NH lysergic acid 249
Scheme 48. (a) Rh2(pfb)4, CH2Cl2.
Padwa and co-workers have investigated extensively the intramolecular dipolar cycloaddition of pushpull carbonyl ylides generated by the action of rhodium(II) on diazoimides. The strategy was employed for the construction of the pentacyclic skeleton of aspidosperma family of alkaloids. Diazoimide 250 derived from 3-carboxy-3-ethyl-2-piperidone and N-methyl indol-3-acetyl chloride was treated with Rh2(OAc)4. The resulting rhodium carbenoid underwent cyclization to generate the carbonyl ylide, which spontaneously reacted with the indole double bond to afford the pentacyclic derivative 251. The cycloaddition reaction created four new stereocenters with complete diastereoselectivity. The diastereoselectivity is the consequence of an endo addition with regard to the dipole and this is also in accord with the lowest-energy transition state. Further transformations of the highly oxygenated polycyclic system 251 afforded 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 Padwa and co-workers (Scheme 50). o-Allylphenyl-substituted a-diazoketone 252 underwent an IDC reaction by the formation of the cyclic carbonyl ylide along with dipolar cycloaddition of the diazo group in the presence of Rh2(tfa)4. Incorporation of an aldehyde group instead of ethoxycarbonyl
OMe N O N Et 250 O N2 O N O O a
()-Aspidophytine 262 is a member of the family of aspidosperma alkaloids. These alkaloids possess a common pentacyclic framework and show diverse biological activities. Synthesis of aspidophytine has been reported by Corey and later by Fukuyama. Recently, Padwa and Oneto employed the IDC reaction as a key step for the construction of the aspidosperma skeleton. Diazoimide 257 was prepared by the coupling of acid chloride 255 and diazolactam 256. In the crucial Rh2(OAc)4-catalyzed reaction, the diazoimide 257 underwent carbonyl ylide cycloaddition with the indole ring to afford the pentacyclic indane ABCDE framework. The IDC reaction furnished a single isomer 259 with the required stereochemistry at the newly formed four stereocenters. Acid treatment of 259 afforded the lactone 261, which was transformed into aspidophytine 262, by routine protocols (Scheme 51).75 Very recently, Padwa extended the IDC reaction of push pull carbonyl ylides to the synthesis of hexacyclic frameworks associated with kopsifoline alkaloids. These are structurally related to, and possibly derived from, aspidosperma alkaloids. Diazoketone 263 was subjected to rhodium-catalyzed decomposition to afford the cycloadduct 264 as a single isomer. Further synthetic transformations were carried out to construct the hexacyclic skeleton 265 of the kopsifoline alkaloid (Scheme 52).76 Boger reported the synthesis of both isomers of vindoline 272 by a tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction. The intramolecular DielsAlder reaction of the alkene-tethered 1,3,4-oxadiazole 269 followed by the loss of nitrogen furnished the carbonyl ylide 270, which underwent an endo stereoselective dipolar cycloaddition with the indole ring to form the pentacyclic core having six contiguous stereocenters. Substrate 269 for the tandem cycloaddition was prepared from N-methyl-6-methoxytryptamine 266. It is noteworthy that vindoline constitutes the most complex half of vinblastine and vincristine, the two bisindole alkaloids clinically used as antineoplastic drugs (Scheme 53).77
O N O N Et O N CO2Me Et O CO2Me 251 O
Scheme 49. (a) Rh2(OAc)4, benzene, 50 C, 95%.

COCl + MeO OMe 255 O N O O CO2Me 258 O N O O d-f MeO H OMe MeO2C 260 N O OH MeO OMe N O N O O MeO OMe N N O O CO2-t-Bu MeO N OMe 259 256 CO2Me MeO OMe O N O O H CO2Me CO2-t-Bu c N HN O CO2-t-Bu O a O N N2 257 O N CO2-t-Bu O CO2Me b
12263
MeO OMe
H 261
aspidophytine 262
, 92%; (b) Rh2(OAc)4, 97%; (c) BF3$OEt2, 70%; (d) MgI2, MeCN, 75%; (e) AcCl, Et3N; (f) SmI2, 90%. Scheme 51. (a) MS 4 A
O
O N N CH2CO2Me O O N H CO2Me SO2Tol 264 CO2Me H
O N N2 O SO2Tol CO2Me 263
O OH N H CO Me 2 SO2Tol 265
Scheme 52. (a) Rh2(OAc)4, benzene, 80 C, 98%.

NH O MeO N 267 O N Et O MeO N 269 O N MeO O N 271 MeO Et OBn CO2Me N . HO OAc CO2Me N N N BnO d -N2 MeO O N 270 N Et OBn CO2Me O N N
NH2 a-b MeO N 266
HO2C 268 BnO c
Et
desilylation protocols, and by the deprotonation of the imines derived from a-amino acids.79 Azomethine imines act as precursors to pyrazolidines and have been prepared by the reaction of 1,2-disubstituted hydrazines with carbonyl compounds (Fig. 3).80 An intramolecular azomethine iminealkene cycloaddition has been employed for the synthesis of a differentially protected trifunctional spiro-diamino acid scaffold, which nds use in combinatorial synthesis. The sequence of events involves an intramolecular Michael addition of hydrazone 273 to afford the azomethine imine 274, which then reacts with the terminal olen in an intramolecular dipolar cycloaddition to afford the tricyclic pyrazoline 275. Reductive cleavage of the NN bond and further routine synthetic manipulations afforded spiro-diamino acid 276 in 30% overall yield from 273. The ketone precursor of 273 can be directly transformed into 275 in one-pot by treating with tert-butyl carbazate, albeit in lower yield (Scheme 54).81
(-)-vindoline 272
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, dihydropyrroles, and pyrroles.78 They have been generated by thermolysis or photolysis of aziridines, uorine-mediated
N N
Figure 3.
12264

CO2Me NNHBoc CO2Me 273 274 CO2Me N NBoc CO2H N Alloc NHBoc N N 283 MOMO H 84% dr = 1.37:1 N H 286

N NBoc
in three steps. Treatment of 284 with sarcosine in DMF at 100110 C generated the azomethine ylide 285, which was intercepted by the pendant alkene. The intramolecular dipolar cycloaddition afforded a pair of diastereomers 286 (1.37:1) in 84% yield. Subsequent reductive dehydroxylation by zinc and formic acid produced the target compound 287 (Scheme 57).84
MOMO Br CHO MeHN a N 285 H N Me b-c 84% (2 steps) N 287 H N Me 284 CO2H MOMO N Me
275
276
Scheme 54. (a) EtOH, reux, 72 h, 75%.
1-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32) 279 is a reserpine antagonist and it also potentiates amphetamine-induced self-stimulation and L-dopa-induced increase in motor activity. The fused pyrazole core of FS32 has been prepared by the intramolecular dipolar cycloaddition (IDC) reaction of a 3-alkyl sydnone 277, which serves as a masked azomethine imine moiety with an alkene tether. Substrate 277 on boiling in xylene underwent the IDC reaction, followed by a rapid aromatization with the ejection of CO2, nally resulting in the formation of the fused pyrazole 278. The cyclohexane ring was oxidized under air using Pt/ C, HClO4, and acetic acid to complete the synthesis of the pyrazole-ring system (Scheme 55).82
Ph R N N O OMe Ph O 277 a N N OMe R 278 b Ph N N R 279 (FS-32) R = (CH2)3N(CH3)2
Scheme 57. (a) DMF, heat; (b) HCl, 60 C; (c) Zn, AcOH.
Epperson and Gin have accomplished the enantiospecic synthesis of the bridged aza-tricyclo[5.3.0.04,8]decane core of asparagamine A, a pyrrolizidine alkaloid isolated from Asparagus racemosus showing potent antioxytocin activity. They employed the optically pure N-trimethylsilylmethyl vinylogous amide 288, synthesized from an L-glutamic acid derivative, as the precursor for the azomethine ylide 289. The latter ylide was generated by treating 288 with Tf2O followed by tetrabutylammonium triphenyldiuorosilicate (TBAT). An intramolecular cycloaddition reaction initiated by Z-enol triate formed exclusively then generated the bridged pyrrazolidine core 290 with an angular C8-E-butenyl substituent in 51% yield with complete regio- and stereospecicity (Scheme 58).85
Et Et F Me3Si O N a H EtS O 288 EtS H O 289 OTf 290 Me3Si OTf N N EtS H O
Scheme 55. (a) Xylene, 130 C, 46%; (b) Pt/C, air, HClO4, AcOH.
Overman reported the synthesis of triazacyclopenta[cd]pentalenes 282 by the IDC reaction of azomethine imines. The dipole was generated by the condensation of dihydropyrrole a-ketoester 280 with thiosemicarbazide. The construction of the target ring system is a crucial step in the synthesis of complex guanidine alkaloids such as pala uamine and styloguanidine. It is noteworthy that the IDC reaction exhibits a good degree of functional-group tolerance (Scheme 56).83 A facile construction of the hexahydropyrrolo[3,2-f]pyridine tricyclic framework has been achieved in six steps. The target heterocyclic system 287 is a conformationally restricted nicotinoid and assumes importance as potential nicotinic acetylcholine receptor (nAChR)-targeting ligand. Starting from 3-bromopyridine, the aldehyde 284 was constructed
O RN EtO2C 280 CO2Me RN a EtO2C H2N
Scheme 58. (a) Tf2O, CHCl3, 23 C, TBAT, 65 C, 24 h, 51%.
Employing the IDC reaction of an azomethine ylide, Takano accomplished the total synthesis of ()-mesembrine 294, an alkaloid obtained from Sceletium namaquense. Thermolysis of aziridine ester 291 in xylene afforded pyrrolidine lactone 293 in 85% yield. The reaction is noteworthy for the
RN HN N S 281 O CO2Me HN N S NH CO2Me
282
R = Cbz, SES or SEM
Scheme 56. (a)NH2NHCSNH2, AcOH, 70 C.
12265
stereoselective formation of three new chiral centers, including a tertiary carbon. The bulky benzyloxymethyl group occupies the equatorial position in the transient azomethine ylide 292, thus leading to the formation of a single isomer 293. Lactone 293 is then converted into ()-mesembrine 294 and its N-methyl derivative through a synthetic sequence involving eight steps (Scheme 59).86
OMe H MeO O OBn 291 OMe MeO MeO H OBn O N Bn H O 293 O H N Bn OBn a O N Bn OMe O O 292 MeO
of Sarain A (Scheme 60). Very recently, Weinreb and coworkers have prepared an advanced intermediate for the total synthesis of sarain A employing a similar strategy.87b It is noteworthy that Heathcock had also employed a similar dipolar cycloaddition route to construct the core structure of sarain.87c,d Ogasawara and co-workers have developed a synthetic route to both enantiomers of necine base, dihydroxyheliotridane, starting from (R)-O-benzylglycidol. The diastereofacial selectivity of the dipolar cycloaddition reaction is controlled by the tether length between the dipole and dipolarophile. The homoallylic aziridinic ester 303a rapidly transformed into azomethine ylide at 260 C in diphenyl ether and underwent the IDC reaction to afford d-lactone 305 along with its 2,3 epimer 3050 . The stereochemical outcome is consistent with the involvement of a chair-like transition state 304. The allylic aziridine ester 303 underwent the IDC reaction under similar conditions, however, presumably through an envelope-like transition state 306, as it contains a shorter chain, and afforded g-lactones 307 and 308 with opposite diastereofacial selectivity. d-Lactone 305 was further elaborated to complete the synthesis of ()-dihydroxyheliotridane 309. The other enantiomer, (+)-dihydroxyheliotridane 3090 , was obtained from the g-lactone 307 (Scheme 61).88 Pandey and co-workers reported a formal total synthesis of ()-pancracine, which belongs to 5,11-methanomorphanthridine family of alkaloids, utilizing the azomethine IDC reaction (Scheme 62).89a The precursor for the IDC reaction was prepared by N-alkylation of a,a-bis(trimethylsilyl)alkylamine 311 with diiodide 310 and further Heck coupling with MVK. The non-stabilized azomethine ylide 314 was generated by the AgF-mediated double desilylation of 313. The sterically favored endo attack of the azomethine ylide on the alkene furnished the 5,11-methanomorphanthridine skeleton with suitable side chains at C-4 and C-11. Hydrolysis of the benzoyl group, mesylation, and subsequent ring closure via the kinetic enolate of the methyl ketone afforded a pentacyclic derivative. Olen 316 obtained by the reductive elimination of the ketone has been employed as a key intermediate in Overmans total synthesis of ()-pancracine.89b,c 6. Azides
MeO
OBn
N O Me H (-)-mesembrine 294
Scheme 59. (a) Xylene, sealed tube, 250 C, 20 min.
Sarain A is a polycyclic alkaloid of marine origin possessing a unique structural array unprecedented in natural products. The tightly fused central tricyclic core of sarain A was constructed by Weinreb and co-workers by employing an intramolecular azomethine ylidealkene cycloaddition.87a Thermolysis of the aziridine moiety in substrate 297 generated a transient azomethine ylide, which subsequently cyclized to afford the adduct 299 in 73% yield (Scheme 60). Interestingly, the efciency of the cycloaddition was heavily dependent on the nature of the protecting groups on the amide nitrogen and side-chain oxygen. The cycloadduct was then transformed into the allylsilane derivative 300. Ferric chloride-catalyzed cyclization of the allylsilane onto the N-acyliminium species afforded 302, the tricyclic core
Bn N O Bn CO2Bu-t 295 BnHN OMe MeO 296 O Bn N N Bn Bn N H MeO 298 OMe TMS OH Ts N Bn N H b Ts N TMS 300 H 301 H H N Bn Ts N H 302 H H N Bn 299 O N O Bn N a
297
MeO
OMe
Bn N
OMe OMe
Azides constitute a very important class of dipoles and the azide group can be easily incorporated into organic compounds by nucleophilic displacement reactions.90 The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (Fig. 4) whereas cycloaddition to an alkyne affords a triazolidine derivative.91 The latter reaction has received much attention recently, due to its ability to deliver macromolecules.92,93 Azidealkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. Both pathways have been made use of in total synthesis and a few selected examples are described. The enantioselective synthesis of ()-slaframine 323, a toxic indolizidine alkaloid isolated from the fungus Rhizoctonia
Scheme 60. (a) o-Dichlorobenzene, 320 C, 78%; (b) FeCl3, CH2Cl2, 78 C to rt, 61%.
12266

H n=1 a H OBn n = 0, 303a n = 1, 303b H OBn 70% 1:3 N Bn H O O H OBn + N Bn H O N Bn O O 304 OBn 70% H N Bn H H OBn O O 305 HO H + N Bn H H OH H O H H OBn O 8% 305'
O N Bn O
N (-)- dihydroxyheliotridane 309 H H OBn HO H
n=0 a
Bn N
H O H O 306
H OH H N
307
O 308
(+)- dihydroxyheliotridane 309'
Scheme 61. (a) Diphenyl ether, 260 C.

TMS + I 310 O d OBz TMS HN TMS 311 OH a-b I N 312 O TMS TMS OBz
O O
O O
O O 313 N
TMS
O O N 314 H OH OBz
O H O O 315 N H OBz O O 316
OH H N H
Scheme 62. (a) K2CO3, MeCN; (b) BzCl, Et3N, CH2Cl2; (c) Pd(OAc)2, PPh3, K2CO3, MVK; (d) AgF, MeCN, 56%.
leguminicola, has been accomplished via an intramolecular azide dipolar cycloaddition (IAC) as the key step. Starting from 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 tosylate with azide and subsequent thermolysis produced the imine. Neither the azide 319 nor the cycloadduct 320 was isolated. Further structural manipulations delivered 323 (Scheme 63).94 An enantioselective synthesis of the pyrrolizidine alkaloid, (+)-crotanecine 326, also utilizes the IAC reaction as a key step. Tosylate 324 derived from 2,3-O-isopropylidene-Derythrose was treated with sodium azide in DMF to afford the imine 325 directly. Further synthetic transformation of the imine afforded the alkaloid 326 (Scheme 64).95 Crinane 332 is a non-natural alkaloid possessing a 5,10bethanophenanthridine skeleton, which is typical of the
N
PMB O N OTIPS 317 OH Ts HO 319 PMB OTIPS a-c
Ts HO
PMB d-e OTIPS 318 OTs Ts PMB OTIPS N 320 N N
HO
N3 OTIPS f-g
OTIPS Ts N H2N 322
H OAc N
Ts
N N PMB OH
321
N PMB
(-)-slaframine 323
N N N
Figure 4.
Scheme 63. (a) TsCl, Et3N, DMAP, CH2Cl2; (b) DIBALH, THF, 0 C; (c) N-tosyl-N-methyl pyrrolidine perchlorate, CH2Cl2, 0 C; (d) NaN3, DMF, 60 C; (e) toluene, reux; (f) MsCl, Et3N, CH2Cl2; (g) NaBH4, EtOH, 0 C, then K2CO3, reux.

THPO O O TsO 324 a O THPO N 325 N O HO H OH OH
12267
(+)-crotanecine 326
Scheme 64.
Amaryllidaceae family. Pearson and Schkeryantz utilized the IAC to achieve a racemic synthesis of crinane. Conversion of acetate 327 into the carboxylic acid 328 by IrelandClaisen rearrangement was followed by reduction and azidation to furnish the precursor 329 for the IAC reaction. Thermolysis of the azido olen 329 generated the cycloadduct triazoline 330, which on rapid extrusion of nitrogen quantitatively furnished the imine 331. The latter imine on reduction and subsequent treatment with Eschenmosers salt afforded crinane 332 in 23% overall yield (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 cycloaddition for the racemic synthesis of 338. Azido alkene 334 was synthesized starting from homoveratric acid 333. Thermolysis of the azide 334 followed by sodium borohydride reduction directly afforded the alkaloid tylophorine in 82% yield. Presumably, the iminium salt 337 is formed via the intermediates 335 and 336 (Scheme 66).97
a, b O O 327 O O N N N 330 -N2 OAc O O 328 O
Pearson has also employed a similar strategy for the synthesis of the alkaloids, swainsonine and g-lycorane.98 Molander has employed the intramolecular azideenone dipolar cycloaddition reaction in the synthesis of an azaspirocyclic ketoaziridine, which could serve as the intermediate for the antitumor alkaloid, cephalotaxine 343. Azido-enone 341 was constructed by the Pd(0)-catalyzed coupling of vinyl iodide 339 and arylzinc chloride 340. The cycloadduct presumably 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 of the antitumor agents, mitomycin C and FR-900482. An azideallylsilane 1,3-dipolar cycloaddition has been employed for the construction of the benzazoc-3-ene derivative 347. A completely diastereoselective dipolar cycloaddition afforded the triazoline 345 and the latter compound on photolysis furnished the aziridine 346 (Scheme 68). Formation of the eight-membered ring was achieved by the action of
c, d CO2H
O N3 O 329
O f, g O H O N 331 N
crinane 332
Scheme 65. (a) LDA, THF, 78 C; (b) TBSCl, 78 C to reux; (c) LiAlH4, THF; (d) Ph3P, DEAD, (PhO)2P(O)N3, CH2Cl2; (e) toluene, reux, 100%; (f) NaBH3CN, AcOH; (g) CH2N(Me)2I, THF, 50 C.
OMe OMe MeO CO2H 333 MeO OMe 334 OMe MeO MeO OMe MeO b 82% MeO OMe 337 OMe tylophorine 338 Cl MeO OMe 335 OMe Cl MeO a N3 MeO
OMe N N N
-N2
N MeO OMe 336 Cl MeO
N Cl
Scheme 66. (a) Benzene, 130 C; (b) NaBH4, MeOH.
12268

TBSO O I + O 339 N3 ZnCl 340 OH MeO N OTBS 342 (-)-cephalotaxine 343 341 O O O N O O N3 O TBSO O a O O b
Scheme 67. (a) Pd(dba)3, TFP, DMF, THF, 25 C; (b) xylene, 131 C, 48 h, 76%.
An intramolecular azidealkene cycloaddition features as the key step in the enantioselective synthesis of the watersoluble B-vitamin, (+)-biotin 362. The macrothiolactonization of the carboxylic acid 354, available in a few steps from L-(+)-cysteine, affords the 10-membered thiolactone 355, albeit in low yield. The urethane moiety was then replaced with a carbamoyl azide 356 and the latter azide on thermolysis in water afforded a mixture of isomers 360 and 361 in a 3:2 ratio. Both isomers are carried through the synthesis to furnish (+)-biotin. The initially formed cycloadduct 357 presumably loses nitrogen assisted by the proximal nucleophilic sulfur atom to form a tricyclic sulfonium intermediate 359. The carboxylic acid side chain of biotin is released by the hydrolytic opening of the latter compound (Scheme 70).102
O O OBu-t BnN N N N b S
4
uoride ion on the silylaziridine. It was observed that when the hydroxyl group of 346 was protected, aziridine cleavage did not occur. The authors suggest that the function of the uoride from TBAF is to reversibly deprotonate the hydroxyl to promote a homo-Brook rearrangement. Various other bases in aprotic media were also found to be effective in promoting the transformation, thus providing support for this mechanistic proposal.100
OH TMS N3 344 OH TMS H c HN 347 a N N 345 TMS H N OH OH b
O t-BuO NH H HS 354 O BnN N N N S O 357 O BnN H NH H H + HN H O NBn H H O S BnN O a
HN
S O 356 O
COOH
O 355
N N N
BnN H S O
N H H H2O
358
359 O HN H NH H H S (CH2)4COOH 362
N 346
S (CH2)4COOH 360
S (CH2)4COOH 361
Scheme 68. (a) Toluene, reux, 90%; (b) benzene, rt, hn, 77%; (c) TBAF, DMF, 20 C.
Ciufolini has also utilized a similar strategy for the synthesis of benzazocenone, a potential intermediate for the synthesis of mitomycinoidic antitumor agents. Azido alkene 350 required for the cycloaddition was synthesized by an ene reaction between 2-methoxypropene and 2-(2-azidophenyl)acetaldehyde 348. Azide 350 underwent an IAC reaction to yield the triazoline 351 as a mixture of anti and syn (7:1) isomers. Photochemical extrusion of nitrogen and subsequent hydrolysis furnished 353 (Scheme 69).101
MeO O a N3 348 + OMe 349 OR c N OMe N 352 OMe HN 353 O N3 350 OR O b OMe OMe N N N 351 OMIP OR
Scheme 70. (a) PhOP(O)Cl2, DMF, CH2Cl2, 24%; (b) H2O, autoclave, 145 C, 42%.
The tricyclic ring system present in the aspidosperma alkaloid, vindoline, has been constructed by the IAC reaction. Azido olen 363 underwent cycloaddition, and immediate loss of nitrogen by the intermediate afforded the aziridine 364 as a single isomer. Reductive opening of the aziridine, N-acylation, and C-alkylation completed the construction of the CDE-ring system of vindoline (Scheme 71).103
Ph O 363 HN Ph H O O H CO2Me OMe 365 d-e Ph O 366 N H CO2Me OMe CO2Me N3 OMe a 80% O 364 Ph N H CO2Me OMe b-c
Scheme 71. (a) Benzene, reux; (b) Li, NH3, THF, 78 C; (c) AcOH; (d) BrCH2COCl, NaHCO3, THF; (e) t-BuOK, benzene, reux.
Scheme 69. (a) Lewis acid, CH2Cl2, rt; (b) toluene, reux, cat. K2CO3, 55%; (c) hn, moist THF.
Bisbenzocyclooctadiene lignan lactones like ()-steganacine and ()-steganone have been shown to possess

Ph O 367 B(OH)2 Br a 77% OTBDMS MeO 368 OMe MeO OMe 369 R1= R2 OTBDMS MeO 370a =O 370b R1 = OAc, R2 = H OMe b R1 R2 Ph N MeO OMe N N O
2 R1 R
12269
N3
371a, b
Scheme 72. (a) Pd(Ph3P)4, Cs2CO3, dioxane/EtOH, 130 C, microwave; (b) o-dichlorobenzene, 210 C, 15 min, microwave, 43% for 371a or DMF, 120 C, 15 min, microwave, 76% for 371b.
signicant anticancer activity. Their unnatural 7-aza analogues also exhibit potent biological activity and, at the same time, do not present any stereoselection problems in the synthesis. A microwave-assisted intramolecular azide alkyne cycloaddition has been employed in the synthesis of such compounds possessing a 1,2,3-triazole ring. Thus, biaryl-azidoalkyne 370, obtained by sequential Suzuki coupling, propargylation, and azidation, readily afforded dibenzotriazolo[1,5]azocine 371. Conventional heating was ineffective in promoting the cycloaddition reaction. In the acetate derivative 371b, the lesser rigidity would account for the lower activation energy and, hence, the high yield of the product (Scheme 72).104 The triazole analogue of a dehydropyrrolizidine alkaloid has been constructed through the IDC reaction of azidoalkyne 373 (Scheme 73). The product, 5,6-dihydro-4H-pyrrole[1,2-c][1,2,3]triazole 374, assumes importance, since analogues of dehydropyrrolizidine alkaloids are potent antitumor agents.105
HO OH N3 372 OTBS a N N N 373 N N N 374 OH OTBS
O N Ph 375 O
O S Et
O N Ph 376 O
S Et
SEt O O N Bn 377 SEt
Ac2O N 73% Bn 378 H
OAc + O N 13% Bn 379 H
N Bn 380
N H H pumilotoxin C 381
Scheme 74. (a)Ac2O, p-TsOH (trace), D.
Scheme 73. (a) Toluene, reux, 24 h, 59%.
7. Mesionic and miscellaneous dipoles65 Padwa and Kuethe reported a formal synthesis of decahydroquinoline alkaloid, ()-pumilotoxin C 381 by employing a tandem Pummerer-isom unchnone dipolar cycloaddition reaction. Pummerer reaction of imidosulfoxide 375 generated an isom unchnone dipole 376, which underwent a cycloaddition reaction with the tethered olen. The cycloaddition directly afforded a-pyridones 378 and 379. Both compounds were independently converted into the pyridine 380, which is a known precursor to pumilotoxin. a-Pyridones 378 and 379 arise from the oxo-bridge cleavage of 377 and subsequent acetylation by the excess acetic anhydride (Scheme 74).106 Padwa has also employed Pummerer reactiondeprotonationcycloaddition cascade for the synthesis of many other
naturally occurring alkaloids. The pivotal step of all these syntheses is the cycloaddition reaction of a mesionic isom unchnone dipole. The alkaloids synthesized by this methodology include onychnine, dielsiquinone, lupinine, anagyrine, and costaclavine. The syntheses of all of these alkaloids are summarized in a single publication. As a representative example, the synthesis of dielsiquinone is presented in Scheme 75. Pummerer-induced generation of the isom unchnone dipole 384, subsequent cycloaddition with the pendant alkene and oxabicyclic ring cleavage of the cycloadduct were achieved essentially in one step by treating the imidosulfoxide 382 with excess acetic anhydride in the presence of a catalytic amount of p-TsOH. Pyridone derivative 386 was further transformed into the alkaloid, dielsiquinone, in a few steps to complete its rst total synthesis. The power of this synthetic methodology is evident from the number and variety of the targets that it has achieved.107 A general synthesis of tetrahydroindoles via dipolar cycloaddition of m unchnones generated from N-acyl amino acid derivatives has been reported. An alkynone moiety attached on the acyl unit reacts with the m unchnone 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
12270
O O N R SEt O a O SEt N O R 383 SEt O N R 384 O SEt O N O R 385 N R 386 OAc O O N H 387 OMe O O
R = p-OMeC6H4 382
Scheme 75. (a) Ac2O, p-TsOH, 68%.
incorporating some features of camptothecin was synthesized using this methodology.108

CO2Me HN O O O + TMS O O N TMS O O N O TMS O -CO2 N O TMS 388 389 O O N TMS CO2Me a-b
unit. Oxidopyridinium betaine 399 was generated by the bromine-mediated oxidative rearrangement of the furfuryl amine derivative 398. The stable oxidopyridinium betaine underwent cycloaddition on heating in toluene with the endocyclic double bond to afford the adduct 400 in 70% yield. Reductive removal of the sulfonyl and carbonyl groups and double bond isomerization afforded the 3-methyl-1-aza-tricyclo[5.2.1.03,8]decane skeleton 402 (Scheme 78).110
O O N
N H SO2Ph 398
N SO2 399 Ph SO2Ph c, d 59%
SO2Ph O
SO2Ph b H N H 400 O
e H N H 401 82%
390
391
392
H N H 402
Scheme 76. (a) LiI, EtOAc, heat; (b) Ac2O, 70120 C.
()-Alloyohimbane 397 was synthesized by Padwa using the intramolecular dipolar cycloaddition of thioisom unchnone 395 produced by the reaction of thiocarboline 393 and bromo acid chloride 394. Reduction of polycyclic heterocycle 396 furnished alloyohimbane 397 (Scheme 77).109
O NH N H 393 S + 394 O N S N H 396 H b N H H 397 N Cl Br a N H 395 H N S O
Scheme 78. (a) Br2, AcOH, H2O, 0 C, 77%; (b) toluene, reux, 70%; (c) L-Selectride, PhNTf2, 78 C; (d) HCO2H, Et3N, PdCl2(PPh3)2, 60 C; (e) Na(Hg), Na2HPO2, THF, t-BuOH.
Scheme 77. (a) Et3N, heat; (b) Raney-Ni, then LAH.
The hetisine class of alkaloids is characterized by the presence of a 3-methyl-1-aza-tricyclo[5.2.1.03,8]decane substructure embedded in the carbon scaffold. Synthetic efforts toward the alkaloids of this class have been scarce, presumably due to the challenges in constructing the tricyclic framework. Gin and Peese recently reported a methodology based on the intramolecular cycloaddition of an oxidopyridinium dipole for the synthesis of the aza-tricyclic
Gin and Peese employed a modication of this strategy in the total synthesis of the hetisine alkaloid nominine. The dipolarophile component was accessed from 3-methylcyclohexenone and was coupled to the oxidopyridinium betaine precursor 404 via a Staudinger reactionreduction sequence. The diastereomeric mixture was converted into isoquinolinium betaine on treatment with TFA. The betaine on heating at 180 C afforded two easily separable isomeric cycloadducts. Although the required isomer was the minor product, thermal re-equilibration of the isolated undesired cycloadduct allowed the production of the desired isomer without loss of material. The nitrile functionality of the cycloadduct was converted into a methylene unit and the aromatic ring was subjected to Birch reduction to reveal a diene unit. An intramolecular DielsAlder reaction furnished the essential carbon framework of nominine. The synthesis of nominine was completed by a Wittig reaction of the ketone and an allylic hydroxylation (Scheme 79).111 Kozikowski has synthesized tricyclic cocaine analogues with an extra ring that binds N-8 and C-6, thereby xing the nitrogen lone pair spatially. The intramolecular dipolar cycloaddition of 3-hydroxypyridinium betaine 411 with the butenyl side chain at nitrogen produced the 6-bridged

OMe CHO + CN 403 N3 O MeO 404 O H N H 407 OH H N H H 409

12271
OMe a CN N H O MeO 405
OMe
OMe
N OMe CN O 406
CN OMe
H N HH 408 O H H nominine 410 N
H N
Scheme 79. (a) PBu3, NaBH(OAc)3, CH2Cl2; (b) TFA, CH2Cl2; (c) THF, 180 C, 97%, 1:3.6.
tropenone isomer. Further advancement via the reduction of enone and introduction of a butyl moiety at C-2 afforded 414 and 415 as an inseparable mixture of cocaine analogues (Scheme 80).112
Ph O N 412 411 N Ph 414 + 415 Ph a N
O Ph
O Ph
may well feature in the biosynthesis of these diterpenes. ()-Bipinnatin J 417 is initially synthesized enantioselectively using a NozakiHiyamaKishi macrocyclization reaction. The biomimetic conversion of ()-bipinnatin J into (+)-intricarene was best carried out by oxidation with m-CPBA, acetylation, and subsequent elimination of acetic acid. Betaine 420 thus formed underwent transannular cycloaddition to afford (+)-intricarene 421 directly (Scheme 81).113
413 N
8. Conclusions Undoubtedly the area of dipolar cycloaddition reactions has progressed enormously since Huisgens seminal contributions and rationalization of the process. The examples of dipolar cycloadditions in targeted syntheses described above span the entire spectrum of organic synthesis. The versatility of this class of reactions makes it a very powerful synthetic tool. Recent advances in computational methods are revealing the ne aspects of the electronic interactions in dipolar cycloadditions and this is likely to trigger more efforts to apply this uniquely powerful class of reactions in targeted syntheses.
Scheme 80. (a) Xylene, reux, 36%.
Trauner has employed a [5+2] intramolecular cycloaddition of a pyrilium betaine and a butenolide for the synthesis of (+)-intricarene 421, which belongs to a class of diterpenes characterized by the presence of a furanocembranoid skeleton and additional transannular carbon carbon bonds. The authors synthesized a few members of the series and postulated that the dipolar cycloaddition
HO O O a Br O O 416 H O O (-)-bipinnatin J 417 O d O H O O O 420 H O O H O O OH b H O O 418 O H
O c
AcO O H O 419 H
(+)-intricarene 421
Scheme 81. (a) CrCl2, 72%; (b) m-CPBA; (c) Ac2O, DMAP, Py, 81% from 417; (d) base, DMSO, 150 C, 26%.
12272
Acknowledgements The authors thank Council of Scientic and Industrial Research (CSIR), India for nancial assistance and research fellowships. References and notes
1. 2. 3. 4. 5. Curtius, T. Ber. Dtsch. Chem. Ges. 1883, 16, 2230. Buchner, E. Ber. Dtsch. Chem. Ges. 1888, 21, 2637. Beckmann, E. Ber. Dtsch. Chem. Ges. 1890, 23, 3331. Houk, K. N.; Gonzalez, Y. L. Acc. Chem. Res. 1995, 28, 81 and references cited therein. (a) Huisgen, R. Angew. Chem. 1963, 75, 604; (b) Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494; (c) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565; (d) Huisgen, R. J. Org. Chem. 1968, 31, 2291; (e) Huisgen, R. J. Org. Chem. 1976, 41, 403; (f) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; WileyIntersciences: New York, NY, 1984; (g) Huisgen, R. The Adventure Playground of Mechanisms and Novel Reactions: Proles, Pathways and Dreams; Seeman, J. I., Ed.; American Chemical Society: Washington, DC, 1994. (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301; (b) Houk, K. N.; Yamaguchi, K. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, NY, 1984; Vol. 2, p 407; (c) Sustmann, R. Tetrahedron Lett. 1971, 2717; (d) Sustmann, R. Pure Appl. Chem. 1974, 40, 569. (a) Padwa, A. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, rgensen, p 1069; For reviews see: (b) Gothelf, K. V.; J K. A. Chem. Rev. 1998, 98, 863; (c) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223. Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; John Wiley and Sons: New Jersey, NJ, 2003. Wade, P. A. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol 4, p 1111. (a) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Intersciences: New York, NY, 1984; p 83; (b) Tufariello, J. T. Acc. Chem. Res. 1979, 12, 396; (c) Banerji, A.; Bandhopadhyaya, D. J. Indian Chem. Soc. 2004, 10, 87. LeBel, N. A.; Whang, J. J. J. Am. Chem. Soc. 1959, 81, 6334. Katritzki, A. R.; Ciu, X.; Long, Q.; Yang, B.; Wilox, A. L.; Zhang, Y.-K. Org. Prep. Proced. Int. 2000, 32, 175. Torssell, K. B. G. Nitrile Oxides Nitrones and Nitronates in Organic Synthesis; VCH: Weinheim, 1988. Liu, Y.; Maden, A.; Murray, W. V. Tetrahedron 2002, 58, 3159. Shing, T. K. M.; Zhong, Y.-L. Tetrahedron 2001, 57, 1573. Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207. Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S. B. Tetrahedron 1996, 52, 11265. Aurich, H. G.; Geiger, M.; Gentes, C.; K oster, H. Tetrahedron Lett. 1996, 37, 841. Manzoni, L.; Arosio, D.; Belvisi, L.; Bracci, A.; Colombo, M.; Invernizzi, D.; Scolastico, C. J. Org. Chem. 2005, 70, 4124.
6.
7.
8.
9. 10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
20. Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J. Am. Chem. Soc. 1996, 118, 9446. 21. Ishikawa, T.; Kudo, T.; Shigemori, K.; Saito, S. J. Am. Chem. Soc. 2000, 122, 7633. 22. Frank, E.; W olng, J.; Aukszi, B.; K onig, V.; Schneider, T. R.; Schneider, G. Tetrahedron 2002, 58, 6843. 23. Kang, H.-Y.; Cho, Y. S.; Koh, H. Y.; Chang, M. H. Synlett 1995, 907. 24. Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8, 2309. 25. Sung, H. K.; Hee, S. L. Tetrahedron Lett. 1995, 36, 6713. 26. Tokunaga, Y.; Yagihashi, M.; Ihara, M.; Fukumoto, K. J. Chem. Soc., Chem. Commun. 1995, 955. 27. Zhao, Q.; Han, F.; Romero, D. L. J. Org. Chem. 2002, 67, 3317. 28. Lee, S.; Zhao, S. P. Org. Lett. 1999, 1, 681. 29. Cordero, F. M.; Gensini, M.; Goti, A.; Brandi, A. Org. Lett. 2000, 2, 2475. 30. Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.; Adams, J. P. J. Am. Chem. Soc. 1999, 121, 4900. 31. Horsley, H. T.; Holmes, A. B.; Davies, J. E.; Goodman, J. M.; Silva, M. A.; Pascu, S. I.; Collins, I. Org. Biomol. Chem. 2004, 2, 1258. 32. Werner, K. M.; de los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999, 64, 686. 33. Baldwin, S. W.; Aube, J.; McPhail, A. T. J. Org. Chem. 1991, 56, 6546. 34. Baldwin, S. W.; Debenham, J. S. Org. Lett. 2000, 2, 99. 35. Oppolzer, W.; Bochet, C. G. Tetrahedron: Asymmetry 2000, 11, 4761. 36. White, J. D.; Blakemore, P. R.; Korf, E. A.; Yokochi, A. F. T. Org. Lett. 2001, 3, 413. 37. Akai, S.; Tanimoto, K.; Kanao, Y.; Omura, S.; Kita, Y. Chem. Commun. 2005, 2369. 38. Looper, R. E.; Williams, R. M. Tetrahedron Lett. 2001, 42, 769. 39. Looper, R. E.; Williams, R. M. Angew. Chem., Int. Ed. 2004, 43, 2930. 40. Looper, R. E.; Runnegar, M. T. C.; Williams, R. M. Tetrahedron 2006, 62, 4549. 41. Hock, S.; Borschberg, H.-J. Helv. Chim. Acta 2006, 89, 512. 42. Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339. 43. (a) Larsen, K. E.; Torsell, K. B. G. Tetrahedron 1984, 40, 2985; (b) de la Cruz, P.; Espildora, E.; Garcia, J. J.; de la Hoz, A.; Langa, F.; Martin, N.; Sanchez, L. Tetrahedron Lett. 1999, 40, 4889. 44. (a) Caramella, P.; Grunanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Intersciences: New York, NY, 1984; p 291; (b) J ager, V.; Colinas, P. A. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003; p 361. 45. Shishido, K.; Tokunaga, Y.; Ohmachi, N.; Hiroya, K.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Chem. Commun. 1989, 1093. 46. (a) Mateos, A. F.; Coca, G. P.; Gonz alez, R. R.; Hern andez, C. T. J. Org. Chem. 1996, 61, 9097; (b) Mateos, A. F.; Coca, G. P.; Gonz alez, R. R. Tetrahedron 2005, 61, 8699. 47. Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J. Am. Chem. Soc. 1992, 114, 10065. 48. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Le Gall, T.; Shin, D.-S.; Falck, J. R. J. Org. Chem. 1995, 60, 7209.
12273
49. Smith, A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno, Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7612. 50. Saha, A.; Battacharjya, A. Chem. Commun. 1997, 495. 51. Lygo, B.; Swiatyj, M.; Trabsa, H.; Voyle, M. Tetrahedron Lett. 1994, 35, 4197. 52. Shishido, K.; Irie, O.; Shibuya, M. Tetrahedron Lett. 1992, 33, 4589. 53. Omodani, T.; Shishido, K. J. Chem. Soc., Chem. Commun. 1994, 2781. 54. Tius, M. A.; Reddy, N. K. Tetrahedron Lett. 1991, 32, 3605. 55. Aungst, R. A., Jr.; Chan, C.; Funk, R. L. Org. Lett. 2001, 3, 2611. 56. Miller, M. L.; Ray, P. S. Tetrahedron 1996, 52, 5739. 57. Miller, M. L.; Ray, P. S. Heterocycles 1997, 45, 501. 58. Shishido, K.; Takata, T.; Omodani, T.; Shibuya, M. Chem. Lett. 1993, 557. 59. Irie, O.; Fujiwar, Y.; Nemoto, H.; Shishido, K. Tetrahedron Lett. 1996, 37, 9229. 60. Nakai, K.; Doi, T.; Takahashi, T. Synlett 2005, 866. 61. Huang, K. S.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2000, 65, 499. 62. For the rst report of intramolecular dipolar cycloaddition reactions of carbonyl ylides by: Eberbach, W.; Brokatsky, J.; Fritz, H. Angew. Chem., Int. Ed. Engl. 1980, 19, 47. 63. (a) Grifn, G. W. Angew. Chem., Int. Ed. Engl. 1971, 10, 537; (b) Wong, J. P. K.; Fahmi, A. A.; Grifn, G. W.; Bhacca, N. S. Tetrahedron 1981, 37, 3345; (c) Bertoniere, N. R.; Grifn, G. W. Organic Photochemistry; Chapman, O. L., Ed.; Decker: New York, NY, 1973; Vol. 3, Chapter 2; (d) Bekhazi, M.; Smith, P. J.; Warkentin. Can. J. Chem. 1984, 62, 1646; (e) Keus, D.; Kaminski, M.; Warkentin, J. J. Org. Chem. 1984, 49, 343; (f) Warkentin, J. J. Chem. Soc., Perkin Trans. 1 2000, 2161. 64. Wee, A. G. G. Curr. Org. Synth. 2006, 3, 499. 65. Grast, M. E.; McBride, B. J.; Douglass, J. G., III. Tetrahedron Lett. 1983, 24, 1675. 66. (a) McMills, M. C.; Wright, D. Synthetic Applications of 1,3Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003; p 253; (b) 1,3Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; WileyIntersciences: New York, NY, 1984. 67. McMills, M. C.; Zhuang, L.; Wright, D. L.; Watt, W. Tetrahedron Lett. 1994, 35, 8311. 68. Chiu, P.; Chen, B.; Cheng, K. F. Org. Lett. 2001, 3, 1721. 69. Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard, G. J. Org. Lett. 1999, 1, 1933. 70. Graening, T.; Bette, V.; Neud or, J.; Lex, J.; Schmalz, H.-G. Org. Lett. 2005, 7, 4317. 71. Padwa, A.; Boonsombat, J.; Rashatasakhon, P.; Willis, J. Org. Lett. 2005, 7, 3725. 72. Mariano, J. P., Jr.; Osterhout, M. H.; Padwa, A. J. Org. Chem. 1995, 60, 2704. 73. Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. 74. Padwa, A.; Precedo, L.; Semones, M. A. J. Org. Chem. 1999, 64, 4079. 75. Oneto, J. M. M.; Padwa, A. Org. Lett. 2006, 8, 3275. 76. Hong, X.; France, S.; Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 512. 77. Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539. 78. (a) Harwood, L. M.; Vickers, R. J. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
79. 80. 81. 82. 83. 84. 85. 86. 87.
88. 89.
90. 91.
92. 93. 94. 95. 96. 97. 98.
99. 100. 101. 102. 103. 104. 105.
and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003; p 169; (b) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. Lown, J. W. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, NY, 1984; Vol. 1, p 653. (a) Oppolzer, W. Tetrahedron Lett. 1970, 11, 2199; (b) Oppolzer, W. Tetrahedron Lett. 1970, 11, 3091. Dolle, R. E.; Barden, M. C.; Brennan, P. E.; Ahmed, G.; Tran, V.; Ho, D. M. Tetrahedron Lett. 1999, 40, 2907. Yeu, J.-P.; Yeh, J.-T.; Chen, T.-Y.; Uang, B.-J. Synthesis 2001, 1775. Belanger, G.; Hong, F.-T.; Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67, 7880. Zhai, H.; Liu, P.; Luo, S.; Fang, F.; Zhao, M. Org. Lett. 2002, 4, 4385. Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778. Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239. (a) Sisco, J.; Weinreb, S. M. J. Org. Chem. 1991, 56, 3210; (b) Hong, S.; Yang, J.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2078; (c) Henke, B. R.; Kouklis, A. J.; Heathcock, C. H. J. Org. Chem. 1992, 57, 7056; (d) Heathcock, C. H.; Clasby, M.; Grifth, D. A.; Henke, B. R.; Sharp, M. J. Synlett 1995, 467. Hashimura, K.; Tomita, S.; Hiyora, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1995, 2291. (a) Pandey, G.; Banerjee, P.; Kumar, R.; Puranik, V. G. Org. Lett. 2005, 7, 3713; (b) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005; (c) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4602. Smith, P. A. S.; Rowe, C. D.; Bruner, L. B. J. Org. Chem. 1969, 34, 3430. (a) Sha, C.-K.; Mohanakrishnan, A. K. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons: New Jersey, NJ, 2003; p 623; (b) Uhle, F. C. J. Org. Chem. 1976, 32, 1596; (c) Branch, C. L.; Pearson, M. J. J. Chem. Soc., Chem. Commun. 1981, 946. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297. Binder, W. H.; Klinjer, C. Curr. Org. Chem. 2006, 10, 1791. Choi, J.-R.; Han, S.; Cha, J. K. Tetrahedron Lett. 1991, 32, 6469. Bennet, R. B., III; Cha, J. K. Tetrahedron Lett. 1990, 31, 5437. Schkeryantz, J. M.; Pearson, W. H. Tetrahedron 1996, 52, 3107. Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990, 31, 7571. (a) Pearson, W. H.; Schkeryantx, J. M. J. Org. Chem. 1992, 57, 6783; (b) Pearson, W. H.; Walavalkar, R. Tetrahedron 1994, 50, 12293. Molander, G. A.; Hiersemann, M. Tetrahedron Lett. 1997, 38, 4347. Ducray, R.; Cramer, N.; Ciufolini, M. A. Tetrahedron Lett. 2001, 42, 9175. Ciufolini, M. A.; Chen, M.; Lovett, D. P.; Deaton, M. V. Tetrahedron Lett. 1997, 38, 4355. Deroose, F. D.; De Clercq, P. J. J. Org. Chem. 1995, 60, 321. Guo, Z.; Schultz, A. G. Tetrahedron Lett. 2004, 45, 919. Beryozkina, T.; Appukkuttan, P.; Mont, N.; van der Eycken, E. Org. Lett. 2006, 8, 487. Pearson, W. H.; Bergmeier, S. C.; Stephen, C.; Chytra, J. A. Synthesis 1990, 156.
12274
106. Kuethe, J. T.; Padwa, A. Tetrahedron Lett. 1997, 38, 1505. 107. Padwa, A.; Heidlbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368. 108. Hutchison, D. R.; Nayyar, N. K.; Martinelli, M. J. Tetrahedron Lett. 1996, 37, 2887. 109. Heidelbaugh, T. M.; Liu, B.; Padwa, A. Tetrahedron Lett. 1998, 39, 4757.
110. Peese, K. M.; Gin, D. Y. Org. Lett. 2005, 7, 3323. 111. Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 8734. 112. Smith, M. P.; George, C.; Kozikowski, A. P. Tetrahedron Lett. 1998, 39, 197. 113. Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901.
V. Nair, T. D. Suja / Tetrahedron 63 (2007) 1224712275 Biographical sketch
12275
Vijay Nair received his Ph.D. degrees from the Banaras Hindu University (1967, with Professor R. H. Sahasrabudhey) and the University of British Columbia (1969, with Jim Kutney) and he was a post-doctoral fellow with Gilbert Stork at Columbia University. After a 16 year career (outstanding scientist award, 1981) with Lederle Laboratories (American Cyanamid Company) in Pearl River, New York, he returned to India and joined the Regional Research Laboratory (CSIR) in 1990. During 19972001 he was the Director of the Institute. Dr. Nairs research interests are in the areas of CAN mediated CC and Cheteroatom bond forming reactions, multicomponent reactions, and dipolar cycloadditions. Dr. Nair has been an invited speaker at a number of major international conferences including ICOS-15 in Nogoya in 2004. He is a Fellow of the Indian Academy of Sciences. Recently, he was awarded the silver medal of the Chemical Research Society of India.
T. D. Suja was born in Kerala, India. She received her Master degree in Chemistry from the University of Calicut in 2000. Subsequently, she joined doctoral research in the research group of Dr. Vijay Nair at NIIST (formerly RRL), Trivandrum. She was awarded Ph.D. degree from Kerala University in 2006. Currently, she is a post-doctoral fellow in the research group of Dr. Kak-Shan Shia at the NHRI, Zhunan, Taiwan. Her research interests include radical reactions and medicinal chemistry.

Synthesis Polar Compound

Uploaded by

Copyright:

Available Formats

Synthesis Polar Compound

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Synthesis Polar Compound

Uploaded by

Copyright:

Available Formats

Tetrahedron 63 (2007) 1224712275

Tetrahedron report number 817

Intramolecular 1,3-dipolar cycloaddition reactions in targeted syntheses

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

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

OR1 OHC O O R2NHOH.HCl 12 11 HO HO HO HO 14 R1, R2 = Ac, Bn O NMe or HO HO HO 15 i

R1O O O endo-TS OH or NH2 16 HO HO NH or OH OH

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

HO 27 CO2Et R1, R2 = alkyl, aryl or H

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

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

c) Tamao oxidation d) reduction AcO

Scheme 8. (a) DIBALH, 78 C, 30 min; (b) BnNHOH, 78  C to rt, 79%.

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

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

Scheme 9. (a) BF3$OEt2.

OMe OMe O O O 42 OMe MeO MeO O N H 45 b 46 Ph + 43 Ph 44 OMe OMe a

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

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

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

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

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

O BnO N O 68 CO2Me O BnO b HN HO H 70 CO2Bn HO H 71 MeO2C H

OTHP R N O 72 O PMBO O R = Ph, CO2Et R

PMBO H OTHP Mitsunobu O N 73 O PMBO H O N 76 O reaction R

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

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

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

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

CO2Et Br HO MeO OH O OMe O O 102 O O O H Ar CO2Et O N H H 104 Me Ph MeO N 105 O b OH OH O O O H Ar H 3 steps O O

SiMe3 SiMe3 b R N O 110 R= (CH2)4

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

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

O H N S H O2 137 NAcO H OBn

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

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

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

Scheme 30. (a) NaOCl, 46%.

X CHO 144 OR X= NOH , 145 X = NO2, 146 H I d OR H

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

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

BzO H 159 (51%)

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

trans-hydrindane 165 CO2Et

c-e H O or O 176 H O O 177

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

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

But But O O Al t Bu Me But

185 OH O O N O OAc crassin acetate 188

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

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

OTBS OSEM 209 PivO

OTBS OSEM 210 PivO

O N + OTBS H OSEM 212

OTBS H O OSEM 211 (11:1)

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

OTHP f NOH 206

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

TMSO Ph N O O R Ph O R 213 Ph 214 NO2

OTMS N INSOC O H NO2 R Ph N O H 217 R H Ph N O INOC R O H Ph H 219 N O N O O R

Scheme 8. (a) DIBALH, 78 C, 30 min; (b) BnNHOH, 78 C to rt, 79%.

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

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

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

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

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

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

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

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

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

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

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

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

Scheme 76. (a) LiI, EtOAc, heat; (b) Ac2O, 70120 C.