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

SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITION
CHEMISTRY TOWARD HETEROCYCLES
AND NATURAL PRODUCTS
This is the fifty-ninth volume in the series
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products. Edited by Albert Padwa and William H. Pearson.
Copyright # 2002 John Wiley & Sons, Inc.
ISBN: 0-471-38726-6
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
A SERIES OF MONOGRAPHS
EDWARD C. TAYLOR AND PETER WIPF, Editors
ARNOLD WEISSBERGER, Founding Editor
SYNTHETIC APPLICATIONS
OF 1,3-DIPOLAR
CYCLOADDITION
CHEMISTRY TOWARD
HETEROCYCLES AND
NATURAL PRODUCTS
Edited by
Albert Padwa
Department of Chemistry
Emory University
William H. Pearson
Department of Chemistry
University of Michigan
AN INTERSCIENCE
1
PUBLICATION
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The Chemistry of Heterocyclic Compounds
Introduction to the Series
The chemistry of heterocyclic compounds is one of the most complex and
intriguing branches of organic chemistry, of equal interest for its theoretical
implications, for the diversity of its synthetic procedures, and for the physiological
and industrial significance of heterocycles.
The Chemistry of Heterocyclic Compounds has been published since 1950 under
the initial editorship of Arnold Weissberger, and later, until his death in 1984,
under the joint editorship of Arnold Weissberger and Edward C. Taylor. In 1997,
Peter Wipf joined Prof. Taylor as editor. This series attempts to make the
extraordinarily complex and diverse field of heterocyclic chemistry as organized
and readily accessible as possible. Each volume has traditionally dealt with

syntheses, reactions, properties, structure, physical chemistry, and utility of com-
pounds belonging to a specific ring system or class (e.g., pyridines, thiophenes,
pyrimidines, three-membered ring systems). This series has become the basic
reference collection for information on heterocyclic compounds.
Many broader aspects of heterocyclic chemistry are recognized as disciplines of
general significance that impinge on almost all aspects of modern organic
chemistry, medicinal chemistry, and biochemistry, and for this reason we initiated
several years ago a parallel series entitled General Heterocyclic Chemistry, which
treated such topics as nuclear magnetic resonance, mass spectra, and photoche-
mistry of heterocyclic compounds, the utility of heterocycles in organic synthesis,
and the synthesis of heterocycles by means of 1,3-dipolar cycloaddition reactions.
These volumes were intended to be of interest to all organic, medicinal, and
biochemically oriented chemists, as well as to those whose particular concern is
heterocyclic chemistry. It has, however, become increasingly clear that the above
distinction between the two series was unnecessary and somewhat confusing, and
we have therefore elected to discontinue General Heterocyclic Chemistry and to
publish all forthcoming volumes in this general area in The Chemistry of Hetero-
cyclic Compounds series.
It is a major challenge to keep our coverage of this immense field up to date. One
strategy is to publish Supplements or new Parts when merited by the amount of new
material, as has been done, inter alia, with pyridines, purines, pyrimidines,
quinazolines, isoxazoles, pyridazines and pyrazines. The chemistry and applica-
tions to synthesis of 1,3-dipolar cycloaddition reactions in the broad context of
organic chemistry were first covered in a widely cited two-volume treatise edited by
Prof. Albert Padwa that appeared in 1984. Since so much has been published on this
fascinating and broadly useful subject in the intervening years, we felt that a
Supplement would be welcomed by the international chemistry community, and we
are immensely grateful to Prof. Padwa and Prof. Pearson for tackling this arduous
task. The result is another outstanding contribution to the organic and heterocyclic
chemistry literature that we are delighted to publish within The Chemistry of

Heterocyclic Compounds series.
E
DWARD C. TAYLOR
Department of Chemistry
Princeton University
Princeton, New Jersey
PETER WIPF
Department of Chemistry
University of Pittsburgh
Pittsburgh, Pennsylvania
vi The Chemistry of Heterocyclic Compounds: Introduction to the Series
Preface
Cycloaddition reactions figure prominently in both synthetic and mechanistic
organic chemistry. The current understanding of the underlying principles in this
area has grown from a fruitful interplay between theory and experiment. The monu-
mental work of Rolf Huisgen and co-workers in the early 1960s led to the general
concept of 1,3-dipolar cycloaddition. Few reactions rival this process in the number
of bonds that undergo transformation during the reaction, producing products
considerably more complex than the reactants. Over the years, this reaction has
developed into a generally useful method for five-membered heterocyclic ring
synthesis, since many 1,3-dipolar species are readily available and react with a wide
variety of dipolarophiles.
The last comprehensive survey of this area dates back to 1984, when the two-
volume set edited by Padwa, ‘‘1,3-Dipolar Cycloaddition Chemistry,’’ appeared.
Since then, substantial gains in the synthetic aspects of this chemistry have
dominated the area, including both methodology development and a body of
creative and conceptually new applications of these [3 þ 2]-cycloadditions in
organic synthesis. The focus of this volume centers on the utility of this
cycloaddition reaction in synthesis, and deals primarily with information that has
appeared in the literature since 1984. Consequently, only a selected number of

dipoles are reviewed, with a major emphasis on synthetic applications. Both
carbonyl ylides and nitronates, important members of the 1,3-dipole family that
were not reviewed previously, are now included. Discussion of the theoretical,
mechanistic, and kinetic aspects of the dipolar-cycloaddition reaction have been
kept to a minimum, but references to important new work in these areas are given
throughout the 12 chapters.
Beyond the ability of the 1,3-dipolar cycloaddition reaction to produce hetero-
cycles, its importance extends to two other areas of organic synthesis, both of which
are included in the current volume. First, the heteroatom-containing cycloadducts
may be transformed into a variety of other functionalized organic molecules,
whether cyclic or acyclic. Second, many 1,3-dipolar cycloadditions have the ability
to generate rings (and functionality derived from transformations of such rings)
containing several contiguous stereocenters in one synthetic operation. The con-
figurations of these new stereocenters arise from the geometry of the dipole and
dipolarophile as well as the topography (endo or exo) of the cycloaddition. An
additional stereochemical feature arises when the reactive p faces of either of the
cycloaddends are diastereotopic. Relative stereocontrol in 1,3-dipolar cycloaddi-
tions is dealt with in some detail, and asymmetric versions of these dipolar
cycloadditions represent an entirely new aspect of the current reference work.
In recent years, numerous natural and unnatural products have been prepared by
synthetic routes that have a 1,3-dipolar cycloaddition as a crucial step in their
synthesis. Consequently, this reaction has become recognized as an extremely
important transformation in the repertoire of the synthetic organic chemist.
A
LBERT PADWA
Department of Chemistry
Emory University
Atlanta, Georgia
WILLIAM H. PEARSON
Department of Chemistry

University of Michigan
Ann Arbor, Michigan
viii Preface
Contents
1 NITRONES 1
Raymond C. F. Jones
2 NITRONATES 83
Scott E. Denmark and Jeromy J. Cottell
3 AZOMETHINE YLIDES 169
L. M. Harwood and R. J. Vickers
4 CARBONYL YLIDES 253
Mark C. McMills and Dennis Wright
5 THIOCARBONYL YLIDES 315
Grzegorz Mloston and Heinz Heimgartner
6 NITRILE OXIDES 361
Volker Jager and Pedro A. Colinas
7 NITRILE YLIDES AND NITRILE IMINES 473
John T. Sharp
8 DIAZOALKANES 539
Gerhard Maas
9 AZIDES 623
Chin-Kang Sha and A. K. Mohanakrishnan
10 MESOIONIC RING SYSTEMS 681
Gordon W. Gribble
11 EFFECT OF EXTERNAL REAGENTS 755
Shuji Kanemasa
12 ASYMMETRIC REACTIONS 817
Kurt Vesterager Gothelf and Karl Anker Jorgensen
INDEX 901
SYNTHETIC APPLICATIONS OF 1,3-DIPOLAR CYCLOADDITION

CHEMISTRY TOWARD HETEROCYCLES
AND NATURAL PRODUCTS
This is the fifty-ninth volume in the series
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
CHAPTER 1
Nitrones
Raymond C. F. Jones and Jason N. Martin
Department of Chemistry, Loughborough University,
Loughborough, United Kingdom
1.1. Nitrones and the 1,3-Dipolar Cycloaddition Reaction . . 2
1.2. Toward Natural Products through Nitrone Cycloadditions 3
1.3. Nucleosides . 4
1.4. Lactams 8
1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 12
1.6. Peptides and Amino Acids . 18
1.7. Sugars 24
1.8. Sulfur- and Phosphorus-Containing Compounds 29
1.9. Catalytic Cycloadditions . . 34
1.10. Pyrrolidines, Piperidines, and Other Amines 34
1.11. Isoxazolidines 47
1.11.1. Nitrones by the 1,3-ATP Process. 48
1.11.2. Intramolecular Oxime–Alkene Cycloaddition . . 54
1.11.3. Intramolecular Nitrone–Alkene Cycloadditions . 55
1.11.4. Isoxazolidines from Intermolecular Nitrone Cycloaddition Reactions. 59
1.12. Conclusion. . 68
The synthetic utility of the 1,3-dipolar cycloaddition reaction is evident from the
number and scope of targets that can be prepared by this chemistry. As one of the
most thoroughly investigated 1,3-dipoles, nitrones are arguably the most useful
through their ability to generate nitrogen- and oxygen-based functionality from the
cycloadducts as well as the potential to introduce multiple chiral centers stereo-

selectively. A comprehensive review of all nitrone cycloadditions would fill many
volumes; instead, this chapter will focus upon the highlights of synthetic endeavor
through 1,3-dipolar cycloaddition reactions of nitrones since 1984.
The Chemistry of Heterocyclic Compounds, Volume 59: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products. Edited by Albert Padwa and William H. Pearson.
Copyright # 2002 John Wiley & Sons, Inc.
ISBN: 0-471-38726-6
1
1.1. NITRONES AND THE 1,3-DIPOLAR
CYCLOADDITION REACTION
Nitrones (or azomethine oxides) (1–7) were first prepared by Beckmann in 1890
(8,9) and named from a shortening of ‘‘nitrogen–ketones’’ by Pfeiffer in 1916 to
emphasize their similarity to ketones (10). While aromatic N-oxides also contain
the nitrone moiety, they retain the name of the N-oxides whose reactivity they more
closely resemble. The general terms aldo- and keto-nitrones are used on occasion to
distinguish between those with and without a proton on the a-carbon, respectively,
and nitrones exist in (E)- and (Z)-forms that may interconvert. Their chemistry is
hugely varied and frequently reviewed, but it is ultimately dominated by their use as
1,3-dipoles for cycloaddition reactions. In 1960, Huisgen proposed the now widely
accepted concept of the 1,3-dipolar cycloaddition reaction (11–20) in which the
formation of the two new bonds occurs as a concerted (but not simultaneous)
process, rejecting Firestone’s proposed reaction via a diradical intermediate on the
basis of stereospecificity (21–26). Ironically, Huisgen himself then went on to
demonstrate the first example of a two-step cycloaddition, using a thiocarbonyl
ylide 1,3-dipole (27).
The most common nitrone 1,3-dipolar cycloaddition (DC) reaction (28–35) is the
formation of an isoxazolidine using alkene dipolarophiles (Scheme 1.1), although
other multiply bonded systems may also be used (alkynes, allenes, isocyanates,
nitriles, thiocarbonyls, etc.). The isoxazolidine cycloadduct contains up to three new
chiral centers and, as with other 1,3-dipoles, the highly ordered transition state

often allows the regio- and stereochemical preference of a given nitrone to be
predicted. This prediction is achieved through a consideration of steric and electronic
factors, but most significantly through the frontier molecular orbital (FMO) theory
proposed by Fukui (36,37), for which he shared the 1981 Nobel Prize.
A number of cyclic nitrones have been developed that avoid the issue of nitrone
(E/Z) isomerization by permitting only a single geometry about the C
ÀÀ
ÀÀ
N double
bond and so reduce the number of possible cycloaddition products. Cyclic nitrones
have also become popular as facially differentiated reagents, allowing predictable
N
O
R
1
R
3
R
4
O
N
R
4
R
3
R
1
N
O
R

1
R
2
R
2
R
2
*
*
*
1,3-DC
isoxazolidine
nitrone
(E)
(Z)
Scheme 1.1
2 Nitrones
asymmetric induction through their ability to enforce the cycloaddition reaction at
one or other face of the 1,3-dipole. In recent years, the effect of catalysis on the rate
and selectivity of the nitrone cycloaddition reaction has been examined from which
impressive results have begun to emerge. Thus, nitrones represent a powerful tool in
modern synthetic chemistry, whose limits are still being explored more than a
century after their discovery.
1.2. TOWARD NATURAL PRODUCTS THROUGH
NITRONE CYCLOADDITIONS
With a wealth of nitrone-derived cycloadditions reported in the literature, we
have sought to arrange this survey according to the synthetic target (e.g., nucleo-
sides or amino acids) or, where more relevant, grouped by the nature of the
cycloaddition partners (e.g., those derived from sugars). Where a total synthesis is
concerned, this task is straightforward, but with more speculative and develop-

mental papers it would be possible to classify the same work in a number of ways.
Apologies, then, to authors who feel misplaced. Naturally, there is a degree of
overlap between many of our groupings, and in each case we have attempted to
direct the reader to relevant work. Section 1.11 on isoxazolidine synthesis covers a
particularly broad range of reactions and it is here we have collected some of the
most significant reports in which the major aim of the work was to characterize a
novel nitrone cycloaddition reaction rather than achieve the total synthesis of a
given target molecule.
1.3. NUCLEOSIDES
Nucleosides are potent antibiotic, antitumor, and antiviral agents, vital in
chemotherapy for acquired immune deficiency syndrome/human immunodeficiency
virus (AIDS/HIV). The polyoxins (e.g., 1a–b), and closely related nikkomycins are
pyrimidine nucleoside antibiotics that are potent inhibitors of the biosynthesis of
chitin, a major structural component of the cell wall of most fungi (Scheme 1.2).
Merino and co-workers (38,39) reported the total synthesis of (þ)-polyoxin J 1b
and of the isoxazolidine analogue of thymine polyoxin C, by nucleophilic addition
to chiral sugar nitrones. By a 1,3-dipolar cycloaddition route, they have prepared
polyoxin analogues 2 in which the furanose ring of the parent nucleoside is
substituted by an isoxazolidine (40). Thus, nitrone 3, prepared in six steps from
serine (58% overall yield), afforded four isoxazolidine cycloadducts in excellent
yield (93%) in its reaction with vinyl acetate. The product mixture contained
predominantly the (3R,5S)-adduct 4a and its C(5) epimer the (3R,5R)-adduct 4b,
separable by chromatography, along with an inseparable mixture of the two C(3)
epimers. Isoxazolidines 4a and 4b were used as a mixture or separately to glycosy-
late silylated thymine 5 or uracil 6. Acidic cleavage of the acetonide of the (3R,5S)-
adducts 7a–b afforded the amino alcohols, which were oxidized to the acids with
1.3. Nucleosides 3
2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) and bis(acetoxy)iodobenzene (BAIB)
before esterification with diazomethane to give 2a or 2b. The C(5) epimer of each
N,O-nucleoside was accessed by similar treatment of the diastereomeric isoxazo-

lidine adduct (3R,5R) 4b. In earlier work, this group also prepared a related
oxazolidinyl thymine nucleoside (side-chain amino acid replaced by ÀÀCH
2
OH) via
the addition of the corresponding d-glyceraldehyde-derived nitrone with the sodium
enolate of methyl acetate (41). The amino acid side of nikkomycin Bz was
synthesized by a nitrone cycloaddition route by Tamura et al. (42).
Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by
the use of various C-functionalized chiral nitrones in order to enforce enantioselec-
tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as
in the work of Merino et al. (40), that asymmetric induction is at best partial with
dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot
completely direct the addition to the nitrone. After poor results with menthol ester-
and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-
lidine 8a and its diastereomer 8b in near quantitative yield using the N-glycosyl
OAc
N
N
O
Boc
OAc
Bn
O
O
OH OH
N
NH
O
R
1

O
CO
2
H
R
2
HN
N
H
O
N
O
Boc
Bn
N
N
OSiMe
3
R
OSiMe
3
TMSOTf
DCM
H
2
NO
O
OH
OH
NH

2
O
N
O
Boc
O
N
Bn
NH
O
O
R
N
NO
N
NH
O
R
O
MeO
2
C
H
2
N
Bn
(1b) polyoxin J
R
1
= Me,

(2a)
(2b)
(3)
(4a)
(47%)
93%
4 isomers
3
(7a)
(7b)
ii TEMPO, BAIB
iii CH
2
N
2
, Et
2
O
i 70% aq AcOH
(5) R = Me
(6) R = H
R
1
= CH
2
OH, R
2
= H
(1a) polyoxin C
5

R = Me
R = H
R
2
=
R = Me
R = H
Boc = tert-butyloxycarbonyl
Scheme 1.2
4 Nitrones
nitrone 9 of Vasella, derived from d-ribofuranose. Adduct 8a was coupled with
thymine before removal of the sugar auxiliary to afford N,O-nucleoside 10.
Among a number of other homochiral furanosyl- and isoxazolidinylthymine
targets, these workers also applied an achiral cycloaddition approach with vinyl
acetate to successfully prepare the antiviral agent d4T (11) and its 2-methyl
analogue (Fig. 1.1) (45). In more recent work, similar nitrones [9,R¼ Me or
benzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-
(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues.
N
RO
EtO
2
CH
N
O
R
EtO
2
C
OAc

O
TBDMSO
OO
N
H
O
EtO
2
C
N
NH
O
O
(9)
(8a) (5R) 47%
(8b) (5S) 48%
i
ii-iii
(10)
R =
5
Reagents:
i
vinyl acetate, ethyl glyoxalate, 60 ˚C, 14h;
ii
bovine serum albumin (BSA),
thymine, TMSOTf, MeCN, ∆, 1 h;
iii
3.7% HCl in EtOH, room temperature (rt), 3 h.
Scheme 1.3

NH
N
N
O
NH
2
N
HO
O
HO
NHN
O
O
N
N
N
NMe
2
N
HO
OH
OH
OH
(11) (12)
2
(13)
Figure 1.1
1.3. Nucleosides 5
Elsewhere, Langlois and co-worker (48) applied a 3-hydroxyaminoborneol-derived
nitrone to the total synthesis of (þ)-carbovir (12), the enantiomer of a potent

reverse transcriptase inhibitor for the treatment of AIDS.
Mandal and co-workers (49,50) (Scheme 1.4) prepared five- and seven-membered
carbocyclic nucleosides including the (þ)-dimethylaminopurine compound 13
(3.3% from d-glucose) and its enantiomer. Aminocyclopentitol (À)-14 is an
intermediate in the synthesis of the carbocyclic nucleosides (À)-noraristeromycin
(15) and (À)-nepalocin A (16) and has been prepared in enantiopure form by Gallos
et al. (50a) from nitrone 17 by condensation of the corresponding d-ribose derived
aldehyde 18 with BnNHOH (Scheme 1.4). Thus, intramolecular cycloaddition of
nitrone 17 affords tricyclic adduct 19 as a single enantiomer, which is converted to
(À)-14 after NÀÀO bond reduction (Zn/AcOH) and debenzylation (ammonium
formate, 10% PdÀÀC).
In contrast to the installation of the nucleobase via nucleophilic substitution of a
suitable leaving group on the isoxazolidinyl cycloadduct, Colacino et al. (51) and
Sindona and co-workers (52,53) prepared isoxazolidinyl nucleosides using vinyl
nucleobases as the dipolarophile (Scheme 1.5). In Sindona’s work, while a three-
component reaction of hydroxylamine, formaldehyde, and 20 afforded a complex
mixture of cycloadducts and byproducts, the known dipole 21 reacted with N-9-
vinyladenine (20) in benzene at reflux to afford a racemic mixture of adduct 22 and
its enantiomer (45%). The ester function was then used to effect a resolution by pig
N
N
N
N
NH
2
HO OH
HO
N
N
N

N
NH
2
HO OH
HO
2
C
O
O
X
H
H
O
O
H
H
O
N
Bn
OO
H
HO NH
2
H
(18) X = O
(17) X = N (Bn)O
i
iii-iv
(19)
(−)-(14)

(15)
(16)
ii
Reagents:
i
BnNHOH, EtOH, 15 min, 95%;
ii
C
6
H
5
Cl, ∆, 30 min, 62%;
iii
Zn, AcOH, Et
2
O, rt, 48 h, 78%;
iv
NH
4
HCO
2
, 10% Pd-C, MeOH, ∆, 1 h 75%.
Scheme 1.4
6 Nitrones
liver esterase (PLE) enzyme-catalyzed hydrolysis to afford the enantiomerically
pure acid 23.
The discovery of spirocyclic nucleosides with anti-HIV-1 activity has prompted
Chattopadhyaya and co-workers (54,55) to prepare spiroisoxazolidine nucleo-
sides (Scheme 1.6). Thus, after proving the reactivity of related systems in an
N

N
N
N
NH
2
O
N
Bn
CO
2
R
N
N
N
N
NH
2
Bn
N
OBu
OO
C
6
H
6
, 104 ˚C
96 h
(21)
(20)
(22) R = Bu

(23) R = H
PLE
Scheme 1.5
O
O
N
NH
O
O
X
N
O
Me
MMTrO
O
N
NH
O
O
MMTrO
O
N
O
X
H
Me
O
N
NH
O

O
HO
O
N
HO
Me
HO
i-ii
(24) X = CH
2
(26) X = SiMe
2
(25) X = CH
2
(27) X = SiMe
2
56%
70%
(28)
3′
2′
Reagents:
i
H
2
O
2
, KF, KHCO
3
, MeOH, tetrahydrofuran (THF);

MMTr = para-methoxyphenyldiphenylmethyl
ii
80% AcOH, 40 ˚C, 1 h.
Scheme 1.6
1.3. Nucleosides 7
intermolecular sense, nucleoside nitrone 24 (or the isomeric 2
0
-O-allyl-3
0
-nitrones)
were prepared from the corresponding ketones to afford the spirotricyclic
cycloadduct 25. Similarly, a reagent with a vinyl silyl ether tether (26) gave the
related tricyclic adduct 27, which was desilylated by hydrogen peroxide mediated
Tamao oxidation to afford the spiroisoxazolidine nucleoside 28. Related nitrones
were earlier prepared by Tronchet et al. (56–59) for studies of nucleophilic addition
to the nitrone function.
1.4. LACTAMS
The continued importance of b-lactam ring systems in medicine has encouraged
a number of research groups to investigate their synthesis via a nitrone cycloaddi-
tion protocol. Kametani et al. (60–62) reported the preparation of advanced
intermediates of penems and carbapenems including (þ)-thienamycin (29) and
its enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (À)-menthyl
N
MenO
2
CH
Bn O
CO
2
Bn

N
S
R
2
O
HO
HH
CO
2
H
R
1
(34)
NMe
2
NH
NH
O
R
1
O
R
2
HH
N
O
MenO
2
C
Bn

CO
2
Bn
(35)
(36)
OH
N
O
MenO
2
C
Bn
CO
2
Bn
NH
O
HO
CO
2
Men
HH
CO
2
H
(E
)-(30)
(31a) (30%)
(31b) (30%)
(32)

(33)
i
steps
ii-vi
R
1
= H, R
2
= OAc
R
1
= TBDMS, R
2
=
R
1
= TBDMS, R
2
=
(29)
R
1
= H, R
2
= CH
2
NH
2
R
1

= Me, R
Men = menthyl; TBDMS = tert-butyldimethylsilyl
2
=
Reagents:
i
H
2
, PtO
2
, MeOH, 20 h, then DCC, MeCN, 60 ˚C, 3 h, 39%;
ii
TBDMSCl,
Et
3
N, dimethyl formamide (DMF), 16 h, 80%;
iii
NaOH aq (1 M ), THF,
MeOH then HCl aq (1 M
), 81%;
iv
TBDMSCl, Et
3
N, DMF, 18 h, 94%;
v
AcOH
aq (2.5 M ), THF, 6 h then NaHCO
3
aq (5%);
vi

Pb(OAc)
4
, KOAc, DMF, 40 ˚C, 1 h, 70%.
Scheme 1.7
8 Nitrones
glyoxal hydrate and benzylhydroxylamine but found it exerted incomplete stereo-
control in its cycloaddition to benzyl crotonate. The major isolated products, a 1:1
mixture of isoxazolidines 31a and 31b, are rationalized as the consequence of endo
or exo addition to the more reactive (E) form of nitrone (30), respectively.
Simultaneous O- and N-debenzylation and NÀÀO bond hydrogenolysis of 31b
gave an amino alcohol intermediate, which was used without purification for
dicyclohexylcarbodiimide (DCC)-mediated cyclization to afford the b-lactam 32.
Silylation of the hydroxyl and the amide nitrogen was followed by hydrolysis of the
menthyl ester, which also brought about N-desilylation. Reinstallation of the silyl
groups through two steps, before insertion of the C(4) acetyl group by oxidative
acetoxylation with lead tetraacetate, afforded the lactam 33, a known intermediate
en route to (þ)-thienamycin (29). An earlier, related total synthesis of 29 by this
group using a homochiral N-(2-phenylethyl) auxiliary afforded similar low yields of
the desired isoxazolidine adducts (60).
The unusually potent and broad spectrum antibacterial action of (þ)-thienamy-
cin is tempered by its instability at high concentration and susceptibility to
decomposition by renal dehydropeptidase I. In 1984, Shih and co-workers (62a) at
Merck reported that the 1-b-methylcarbapenem 34 demonstrated increased chemi-
cal and metabolic stability while retaining high antibiotic activity. Work published
by Ito et al. (63) described the preparation of a 1-b-methylcarbapenem intermediate
(35) via a nitrone cycloaddition that gave an equimolar amount of all four possible
adducts. Later, intermediate 35 was prepared by Ihara et al. (64,65) by intramo-
lecular cycloaddition of a complex chiral alkenyl nitrone to afford a single
stereoisomer (51%). Separately, Kang and Lee (66), then Jung and Vu (67),
prepared 1-b-methylcarbapenem intermediate (36) and a synthetic precursor

respectively, via intramolecular nitrone–alkene 1,3-dipolar cycloaddition reactions
with complete diastereocontrol.
Alcaide et al. (68,69) recently published their studies of the intramolecular 1,3-
dipolar cycloaddition reactions of alkynyl-b-lactams in which they found that the
desired cycloaddition was in competition with a reverse-Cope elimination. The
reaction of alkynyl aldehydes 37a–c with N-methylhydroxylamine afforded a
mixture of products depending on the reaction conditions and the chain length
separating the alkyne and the lactam (Scheme 1.8). Thus, up to three separate
N
O
CHOPhO
HH
MeNHOH
Et
3
N
N
O
PhO
HH
N
Me
O
PhMe, ∆
N
O
PhO
HH
O
N

Me
H
n
15%
(37a)
(37b)
(37c)
n = 1
n = 2
n = 3
(38) (39)
Scheme 1.8
1.4. Lactams 9
nitrones were identified from the reaction mixture including two from a complex
proposed mechanism. Thus, alkynyl nitrone (38) was formed from the condensation
of 37c with N-methylhydroxylamine in refluxing toluene, and underwent a 1,3-
dipolar cycloaddition to afford the homochiral isoxazoline 39 via addition to the
less sterically crowded upper face of 38. Significantly, the isolated yield of the
cycloadduct is very low (15%), the product ratio favoring the nitrone (38:39 ¼ 3:1).
Chmielewski and co-workers (70–73) prepared the b-lactam skeleton via a
nitrone cycloaddition to a sugar ene lactone dipolarophile providing latent polyol
functionality at C(3) of the lactam (Scheme 1.30, Section 1.7). In other lactam
cycloaddition chemistry, Rigolet et al. (74) prepared various spirocyclic adducts,
including 40–42 from the corresponding methylene lactams (75) or the unstable
methylene isoindolones 43, the latter showing enhanced yields for the cycloaddition
of N-benzyl-C-phenyl nitrone to the exocyclic double bond under microwave
irradiation (Scheme 1.9) (76). Related spiroisoxazolidinyl lactams were reported
by Fisera and co-workers (77). Funk and Daggett (78) prepared similar spirocyclic
lactams (e.g., 44) via the cycloaddition reaction of exocyclic nitrone 45 (derived
from cyclohexanone) with unsaturated esters (Scheme 1.10). The NÀÀO bond

cleavage of isoxazolidine (46) makes available the nitrogen for spontaneous
lactamization to the spirocyclic product 44.
Cycloaddition to endocyclic unsaturation has been used by many researchers for
the preparation of isoxazolidinyl adducts with g-lactams derived from pyrogluta-
minol and is discussed later in this chapter as a synthesis of unusual amino acids
(Scheme 1.20, Section 1.6) (79,80). A related a,b-unsaturated lactam has been
prepared by a nitrone cycloaddition route in the total synthesis of the fungal
metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting
materials is given in the work of Chiacchio et al. (82) who prepared isoxa-
zolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11).
N
O
4-Me-C
6
H
4
O
N
N
O
Me
Ph
COPh
Ph
CH
2
Ph
NPh
O
NO

N
N
ON
O
O
Me
Me
PhOC
COPh
Ph
Ph
O
N
N
O
4-Me-C
6
H
4
CH
2
Ph
Ph
110 ˚C, 4 h (27%)
or microwave (61%)
(40)
(41)
(42)
(43)
Scheme 1.9

10 Nitrones
The acyclic precursor is an a,b-unsaturated amido aldehyde that was condensed
with N-methylhydroxylamine to generate the nitrone (E)-48, which then underwent
a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the
isoxazolidinyl lactam 47. The observed product arises via the (E)-nitrone transition
state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group a to
the nitrone effectively controls the two adjacent stereocenters while a third
stereocenter is predicted from the alkene geometry. Both transition states maintain
the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-
diaxial interaction with the nitrone methyl or oxygen found in transition state B.
Semiempirical PM3 calculations confirm the extra stability, predicting exclusive
formation of the observed product 47. Related cycloadducts from the intramole-
cular reaction of nitrones containing ester- rather than amide-tethered alkene
functionality are also known (83-85).
N
Bn O
CO
2
Me
PhMe, ∆
O
N
Bn
CO
2
Me
H
2
, 1 atm
Pd(OH)

2
HN
OOH
(46)
(44)
(45)
Scheme 1.10
N
Ph
Me
O
Ph
N
Me
O
N
Me
H
H
N
Me
O
Me
O
H
Bn
H
(B)
NO
N

H
H
Ph
Ph
Me
Me
O
N
O
N
O
Me
H
H
H
Ph
H
Me Bn
(A)
(E)-(48)
(47)
Scheme 1.11
1.4. Lactams 11
1.5. QUINOLIZIDINES, INDOLIZIDINES,
AND PYRROLIZIDINES
The title compounds, quinolizidines, indolizidines, and pyrrolizidines (86), are
characterized by the presence of a bridgehead nitrogen atom in six,six-, six,five-, or
five,five-membered bicyclic ring systems, respectively. The polyhydroxylated
indolizidines and pyrrolizidines have a range of biological effects through their
inhibition of glycosidase enzymes, including some examples of antiviral activity.

The nitrogen and nearby oxygen functionality lend themselves to a nitrone
cycloaddition strategy, as demonstrated by McCaig et al. (87,88) in their synthesis
of each enantiomer of the indolizidine lentiginosine (49) and related pyrrolizidines
(Scheme 1.12). Chiral cyclic nitrone 50 was prepared from doubly methoxymethyl
(MOM) protected diethyl d-tartrate via oxidation of the corresponding pyrrolidine
with Davis’ reagent. The cycloaddition reaction of nitrone 50 with benzyl but-3-
enoate in toluene at reflux gave a single cycloadduct 51 in 44% yield after 4 days.
Reductive NÀÀO bond cleavage and concomitant recyclization with the pendant
ester function gave a lactam (52), which was reduced to the amine with borane–
dimethyl sulfide complex. Radical deoxygenation at C-7 of the imidazolylthio-
N
O
MOMO
MOMO
MOMO
MOMO
MOMO
OMOM
N
O
H
CO
2
Bn
N
H
HO
HO
N
H

OR
O
N
S
N
i
ii
iii-iv
v-vi
(49)
(50)
(51)
(52) R = H
(53) R =
7
Reagents:
i
CH
2
=CHCH
2
CO
2
Bn, toluene, ∆, 4 days, 44%;
ii
Zn, AcOH, 60 ˚C, 2 h, 83%;
iii
BH
3
•Me

2
S, THF, rt, 4 h, then EtOH, ∆, 3 h, 95%;
iv
1,1′-thiocarbonyldiimidazole,
ClCH
2
CH
2
Cl, ∆, 2 h, then rt overnight, 83%;
v
Bu
3
SnH, AIBN, toluene, ∆, 3 h, 53%;

vi
HCl aq (6M), rt, overnight, 60%.
Scheme 1.12
12 Nitrones
carbonyl derivative 53 and removal of the MOM protecting groups in acid afforded
a single isomer of lentiginosine (þ)-49. By an identical scheme, these workers
prepared (À)-49 from the enantiomer of isoxazolidine cycloadduct 51.
A similar approach has been applied by Brandi and co-workers (89–97) using
chiral 3- and 3,4-substituted pyrrolidine nitrones. With such dipoles they
have prepared a number of hydroxylated indolizidines (89–92,95) including (À)-
hastanecine and (À)-croalbinecine (96). As before, NÀÀO bond cleavage was
followed by recyclization, this time through nucleophilic substitution of the
terminal hydroxyl moiety derived from the dipolarophile, as its tosylate. These
workers have recently reported the synthesis of a related monohydroxylated nitrone
by oxidation of the N-hydroxypyrrolidine to afford an 11:1 mixture of the two
separable regioisomers (95). Indolizidine and pyrrolizidine skeletons were then

prepared from this material. In another elegant synthesis, Holmes and co-workers
(98) prepared the indolizidine core of the allopumiliotoxins (54) (Scheme 1.13).
Retrosynthetic analysis suggested an isoxazolidinyl intermediate, ultimately
derived by an intramolecular cycloaddition reaction of alkenyl nitrone 55.The
desired cycloadduct 56 was the major product isolated from a mixture containing
small amounts of three other diastereomers and afforded the target skeleton 54 or its
C(3) epimer after extensive synthetic manipulation (98). In other work on the
intramolecular nitrone cycloaddition (99), this group has published intermediates in
the total synthesis of the indolizidine alkaloid gephyrotoxin (100) as well as the
total synthesis of spiropiperidine natural product histrionicotoxin (Scheme 1.49,
Section 1.10) (101). Kibayashi and co-worker (102,103) reported two total
syntheses of the indolizidine (þ)-monomorine I (57), both of which rely on the
same cycloaddition reaction of an achiral methyl glyoxalate-derived nitrone and a
homochiral allyl ether. The resultant mixture of isoxazolidines was a 3:1 mixture in
favor of the desired product in 76% combined yield.
The rare reports of quinolizidine formation by a nitrone cycloaddition strategy
include the racemic total synthesis of lasubine II (58), one of a series of related
alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme
1.14) (104). While these alkaloids were previously accessed by intermolecular
nitrone cycloaddition reactions, this more recent report uses an intramolecular
approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59
affords predominantly the desired bridged adduct 60 along with two related
N
O
H
OH
N
OTBDMS
O
OBz

N
O
OBz
OTBDMS
N
H
(54) (56) (55)
3
(57)
Scheme 1.13
1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 13
diastereomers. Reductive NÀÀO cleavage of 60 with Zn/AcOH provided a trisub-
stituted piperidine (61) which, after formation of the silyl ether from the hydroxyl
group, was cyclized in a melt of 2-hydroxypyridine at 160

C. The stereochemistry
at this position [C(2) in lasubine II numbering] was inverted under Mitsunobu
conditions to afford the desilylated lactam 62 and, after reduction of the carbonyl
with LiAlH
4
, afforded the target compound (Æ)-58.
A recent article describes the use of an unusual nitrone–alkene intramolecular
cycloaddition–retrocycloaddition–intramolecular cycloaddition strategy (Scheme
1.15). Here, Cordero et al. (83) used a pyrrolidine nitrone to afford the isoxazo-
lidine skeleton before installation of the alkenyl ester side chain of 63 by Mitsunobu
methodology employing a polymer supported triphenylphosphine. Thermally
induced retrocycloaddition of 63 in o-dichlorobenzene at 150

C afforded an
unisolated nitrone (64) that underwent an intramolecular cycloaddition to afford

a second isoxazolidine (65). Removal of the p-methoxybenzyl (PMB) protecting
group and mesylation of the revealed hydroxyl was followed by hydrogenolytic
NÀÀO bond cleavage, to free the amine nitrogen for nucleophilic attack at the carbon
carrying the mesylate to afford indolizidine (66).
CO
2
Me
N
Ar
O
MeO
OMe
N
H
OH
Ar
CO
2
Me
H
N
OH
H
MeO
OMe
N
OH
Ar
H
O

N
O
Ar
CO
2
Me
(59)
Ar =
i
iii-v
vi
(60)
(61)
(62)
(±)-(58)
2
2
ii
Reagents:
i
PhMe, ∆, 1 h, 60%;
ii
Zn, AcOH, 65 ˚C, 4 h, 95%;
iii
TMS-imidazole, DCM, 4 h;

iv
160 ˚C, 2 h, then TBAF, THF, 2 h, 50% (from 61);
v
Ph

3
P, PhCO
2
H, diethylazodicarboxylate (DEAD),
DCM, rt, 2 days, then KOH, MeOH, rt, 6 h, 74%;
vi
LiAlH
4
, THF, ∆, 4 h, 76%.
Scheme 1.14
14 Nitrones
These authors also showed that the indolizidine skeleton can be prepared from
cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkylidenecyclo-
propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidine
adducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105–
108) predominantly but not exclusively (109–111). Thermally induced rearrange-
ment of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71
(107,108). These authors propose reaction via initial NÀÀO bond homolysis of 70 to
diradical 72 followed by ring expansion through relief of the cyclopropyl ring strain
forming the carbonyl of a second diradical intermediate 73, which cyclizes to afford
the isolated piperidinone 71.
In this way, spirocyclopropyl adduct 74 (from cycloaddition of 75 and 76) was
used to prepare gephyrotoxins (106) and lentiginosine (49) (Scheme 1.17)
(105,112). In the latter case, pyrolysis of adduct 74 afforded indolizidinone 77
(45%) along with the amino ketone 78 (55%), the predominance of the latter being
accredited to the steric hindrance of the diradical coupling by the bulky TBDPS
groups. Reduction of the carbonyl of 77 was achieved with sodium borohydride
after conversion to the tosyl hydrazone before final desilylation of 79 with HF
afforded 49, allowing the authors to challenge the published absolute stereochem-
istry. The presence of a phenyl group (particularly when substituted by electron-

donating groups) on the nitrogen atom of the isoxazolidine exerts a powerful
activation of the rearrangement, allowing the thermolysis reaction to occur at much
N
O
EtO
2
C
H
O
O
PMBO
N
HO
O
O
H
N
O
O
PMBO
O
N
O
H
PMBO
O
O
∆
(63)
(64)

(65)
(66)
i
ii
Reagents:
i
o-Cl
2
C
6
H
4
, 150 ˚C, 3 h, 74%;
ii
trifluoroacetic acid (TFA), DCM rt,
then MsCl, Et
Ms = methanesulfonyl
3
N, DCM, 0 ˚C, then H
2
, Pd-C, MeOH.
Scheme 1.15
1.5. Quinolizidines, Indolizidines, and Pyrrolizidines 15