REGIO- AND STEREOSELECTIVE SYNTHESES AND · PDF fileThe aim was the preparation of...
-
Upload
nguyenhuong -
Category
Documents
-
view
220 -
download
3
Transcript of REGIO- AND STEREOSELECTIVE SYNTHESES AND · PDF fileThe aim was the preparation of...
Institute of Pharmaceutical Chemistry
University of Szeged
REGIO- AND STEREOSELECTIVE SYNTHESES AND SOME
TRANSFORMATIONS OF 1,3-N,N- AND
1,3-O,N-HETEROCYCLES
PhD thesis
by Iván Kanizsai
Szeged
2007
2
Contents
page
List of publications and lectures related to the thesis 1
Abbreviations 4
1. Introduction and Aims 5
2. Literature Survey 6
2.1. γ- and δ-oxocarboxylic acids 6
2.2. Aminocarbohydrazides as tridentate reagents 7
2.3. Preparation from diamines with oxocarboxylic acids 11
2.4. Isocyanide-based multicomponent reactions; Ugi reactions 12
2.4.1. Ugi reactions in methanol 12
2.4.2. Water as solvent for Ugi and other multicomponent reactions 14
2.5. Syntheses and some tranformations of natural alkaloids 15
2.5.1. Syntheses of Sedum alkaloids and their analogues 15
2.5.2. Ephedra alkaloids; transformations of norephedrine 17
3. Results and Discussion 18
3.1. Syntheses of pyrazolo[3,4-d]pyrimidine derivatives 18
3.2. Syntheses and transformations of 5,6-dehydronorcantharidin derivatives 21
3.3. Multicomponent reactions with oxabicycloheptene-based β-amino acids 23
3.3.1. Use of methanol as solvent 24
3.3.2. Use of water as solvent 25
3.3.3. Transformations of the resulting β-lactam 17 26
3.4. Reactions of oxanorbornenediamine with γ- and δ-oxocarboxylic acids 27
3.4.1. Preparation of pyrrolo- and isoindoloquinazolines 27
3.4.2. Establishment of the structures 29
3.5. Syntheses of Sedum alkaloid analogues and transformations of norephedrines 30
3.5.1. Syntheses of Sedum alkaloid analogues 31
3.5.2. Transformations of chiral norephedrines 35
4. Summary 39
5. References 40
Acknowledgements
Appendix
3
List of publications and lectures related to the thesis
Full papers
I. Ferenc Miklós, Iván Kanizsai, Pál Sohár, Géza Stájer:
Preparation and structure of pyrazolo[3,4-d]pirimidinones
J. Mol. Struct. 610, 41-46 (2002) if: 1.44
II. Iván Kanizsai, Zsolt Szakonyi, Reijo Sillanpää, Ferenc Fülöp:
A comparative study of the multicomponent Ugi reactions of an oxabicycloheptene-based
β-amino acid in water and in methanol
Tetrahedron Lett. 47, 9113-9116 (2006) if: 2.484
III. Iván Kanizsai, Ferenc Miklós, Pál Sohár, Antal Csámpai, Reijo Sillanpää, Géza Stájer:
Preparation and structure of pyrrolo[2,1-b] and isoindolo[1,2-b]epoxyquinazolines
J. Mol. Struct. (2007) accepted for publication,
doi.: 10.1016/j.molstruc.2006.07.019 if: 1.44
IV. Zsolt Szakonyi, Matthias D’hooghe, Iván Kanizsai, Ferenc Fülöp, Norbert DeKimpe:
Synthesis of bicyclic carbamates as precursors of Sedum alkaloid derivatives
Tetrahedron 61, 1595-1602 (2005) if: 2.61
V. Iván Kanizsai, Zsolt Szakonyi, Reijo Silanpää, Matthias D’hooghe, Norbert DeKimpe
and Ferenc Fülöp:
Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclisation
of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine
Tetrahedron: Asymmetry 17, 2857-2863 (2006) if: 2.429
Other publications
1. Ferenc Miklós, Iván Kanizsai, Steven Thomas, Erich Kleinpeter, Reijo Sillanpää,
Géza Stájer:
Preparation and structure of diexo-oxanorbornane-fused 1,3-heterocycles
Heterocycles 63, 63-74 (2004)
2. Géza Stájer, Ferenc Miklós, Iván Kanizsai, Ferenc Csende, Reijo Sillanpää, Pál Sohár:
Application of furan as a diene: Preparation of condensed 1,3-oxazines by retro Diels-
Alder reactions
Eur. J. Org. Chem. 3701-3706 (2004)
4
3. Iván Kanizsai, Szilvia Gyónfalvi, Zsolt Szakonyi, Ferenc Fülöp, Reijo Sillanpää:
Synthesis of bi- and tricyclic β-lactam libraries in aqueous medium
Green Chem. (2007) accepted for publication
Scientific lectures
1. Iván Kanizsai, Matthias D’hooghe, Zsolt Szakonyi, Ferenc Fülöp, Norbert deKimpe:
Synthesis of bicyclic carbamates as precursors to Sedum alkaloid derivatives;
Bilateral Scientific and Technological Cooperation Workshop (BWTS)
19 September 2003, Ghent, Belgium, p. 22.
2. Szakonyi Zsolt, D’hooghe Matthias, Kanizsai Iván, Ferenc Fülöp, DeKimpe Norbert:
Pirrolidin- és piperidinvázas heterociklusok szintézise alkenil-imidátok és karbamátok
elektrofil ciklizációjával.
MTA Heterociklusos Kémiai Munkabizottság elıadóülése
Balatonszemes, 2004. május 20-21.
3. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:
Izoindol-kondenzált heterociklusok elıállítása retro Diels-Alder reakcióval
Clauder Ottó Emlékverseny
Visegrád, 2004. október 14-15. p 27.
4. Kanizsai Iván, Miklós Ferenc:
Izoindol-kondenzált O,N-heterociklusok elıállítása retro Diels-Alder reakcióval
XXVII. Kémiai Elıadói Napok
Szeged, 2004. október 25-27. pp 51-53.
5. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:
Izoindol-kondenzált O, N- és N, N-heterociklusok elıállítása retro Diels-Alder reakcióval
Szegedi Ifjú Kémikusok elıadóülés
Szeged, 2005. január 12.
6. Iván Kanizsai, Ferenc Miklós, Pál Sohár, Géza Stájer:
Preparation of isoindole-condensed heterocycles via retro Diels-Alder reactions
Joint Meeting on Medicinal Chemistry
20-23 June 2005, Vienna, Austria, PO-38, S-96.
5
7. Kanizsai Iván, Miklós Ferenc, Sohár Pál, Stájer Géza:
Heterociklusok elıállítása oxokarbonsavakból diaminokkal és hidrazidokkal
Vegyészkonferencia
2005. június 28-30, Hajdúszoboszló, P-40.
8. Kanizsai Iván, Szakonyi Zsolt, Fülöp Ferenc:
Ugi-reakció alkalmazása β-laktámok szintézisére vizes és metanolos közegben
Congressus Pharmaceuticus Hungaricus
2006. május 25-27, Budapest, P-12.
9. Gyónfalvi Szilvia, Kanizsai Iván, Szakonyi Zsolt, Fülöp Ferenc:
Vizes közegő Ugi-reakció alkalmazása β-laktámok elıállítására
Congressus Pharmaceuticus Hungaricus
2006. május 25-27, Budapest, P-11.
10. Kanizsai Iván, Gyónfalvi Szilvia, Szakonyi Zsolt, Fülöp Ferenc:
Bi- és triciklusos β-laktámok elıállítása metanolos és vizes közegben
Heterociklusos Munkabizottsági Ülés
Balatonszemes, 2006. június 7-9.
11. Iván Kanizsai, Szilvia Gyónfalvi, Zsolt Szakonyi, Ferenc Fülöp:
Synthesis of bi- and tricyclic β-lactams via Ugi-4C-3C reactions in water and organic
media
Bilateral Scientific and Technological Cooperation Workshop (BWTS)
10 July 2006, Ghent, Belgium; pp. 13-15.
6
Abbreviations
DIBAL: diisobutylaluminium hydride
DMAP: 4-methylaminopyridine
LDA: lithium diisopropylamide
MCC: multicomponent condensation
MCR: multicomponent reaction
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NIS: N-iodosuccinimide
PP1: protein phosphatase 1
PP2A: protein phosphatase 2A
PP2B: protein phosphatase 2B
PTSA: p-tolylsulfonic acid
RCM: ring-closing metathesis
rDA: retro Diels-Alder
TBAF: tetra-n-butylammonium flouride
TEA: triethylamine
TFA: trifluoroacetic acid
TMSCl: trimethylsilyl chloride
TMSI: trimethylsilyl iodide
U-4CC: Ugi-4-component condensation
U-4C-3CR: Ugi-4-centre-3-component reaction
U-5C-4CR: Ugi-5-centre-4-component reaction
7
1. Introduction and Aims
One of the research topics at the Institute of Pharmaceutical Chemistry, University of
Szeged, has been the study of cyclocondensation with a view to obtaining saturated and par-
tially saturated condensed heterocycles. The reactions of bi- or trifunctional β-aminoacids and
derivatives, e.g. aminoalcohols, diamines, carboxamides or aminohydrazides, with γ- or δ-
oxoacids have afforded a great number of cis-, trans- and diexo- or diendo-fused 1,3-O,N- and
N,N-heterocycles, e.g. isoindolones, oxazines and quinazolines. The bi-, tri-, tetra- and penta-
cyclic compounds prepared are stereochemically interesting and pharmacologically active.1-3
In our laboratory, Stájer et al. developed a new method for the preparation of O,N-
heterocycles based on the retro Diels-Alder (rDA) reaction.4 Starting from diendo- or diexo-3-
aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acids or their derivatives, such as amides, hy-
drazides, etc., partially saturated parent heterocycles are built up on cyclopentadiene, which is
finally removed by heating to melting on a preparative scale. Earlier, similar heteromono- and
bicyclic structures were accessible only under more forceful reaction conditions, e.g. flash
vacuum pyrolysis. It is important to note that the closing step takes place under mild condi-
tions only when the target compound acquires a (hetero)aromatic or quasi(hetero)aromatic
character, e.g. oxazinone, thioxooxazinone, oxazinethione or pyrimidinones. Nevertheless,
only a few literature data describe similar rDA reactions, when the rDA products exhibit a
quasi-aromatic, e.g. a 1,3-oxazine character.5-8
The aim of this thesis was to extend the above cyclocondensations to new oxabi-
cyclonorbornene heterocycles, starting from β-amino acid and its derivatives, e.g. the dia-
mine. For furan, which was found to be a “good-leaving” moiety in our compounds, further
transformations via the rDA method were also attempted. As the pharmacological importance
of pyrazole-containing heterocycles was known, we prepared heterocycles, e.g. pyrazo-
lo[3,4-d]pyrimidines, via cyclocondensation, starting from oxocarboxylic acid derivatives, for
pharmacological tests.
Our cooperation with the Department of Organic Chemistry at the University of Ghent
allows research in the field of electrophile-induced cyclizations and the syntheses of recently
reported alkaloids. The aim was the preparation of Pomgranaceae alkaloid analogues, in spite
of their instability even under mild conditions, which meant a good synthetic challenge. Fur-
ther, regio- and diastereoselective cyclizations, starting from (+)- and (-)-norephedrines, were
also attempted.
In accordance, the present work deals with extension of the cyclocondensation of oxa-
bicyclo[2.2.1]heptene-β-amino acid, its derivative diamine and a pyrazolaminocarbohydrazide
8
to the preparation of heterocycles. The second part of my work relates to a new method for
the synthesis of Sedum alkaloid analogues, the transformation of γ-lactams derived from (+)-
and (-)-norephedrine and their preparation via electrophile-induced cyclization.
2. Literature Survey
2.1. γ- and δ-oxocarboxylic acids
The preparation and applications of the γ- and δ-oxocarboxylic acids are wellknown in
the literature.9-11 Although use of the Grignard reagent or organolithium compounds results in
oxocarboxylic acids, the most commonly applied method is the Friedel-Crafts reaction12,13
because of its simplicity and good to excellent yields. In our laboratory, a broad range of oxo-
carboxylic acids, e.g. aliphatic, alicyclic and bicyclic analogues, have been prepared by means
of the Friedel-Crafts reaction. The general preparation of these compounds is carried out by
the reaction of an alicyclic and bicyclic anhydride and an aryl component, e.g. toluene, ben-
zene or chlorobenzene, in the presence of 1 or 2 equivalents of AlCl3. A variation starts from
dicarboxylic acids or aroyl-substituted analogues which are transformed to anhydrides by the
use of acetic anhydride. The Friedel-Crafts reaction has led to diaryl-substituted alicyclic and
bicyclic oxocarboxylic acids.14,15 The stereochemistry of the mono- and disubstituted oxocar-
boxylic acids has been established by NMR measurements.16 To apply methanobenzocyclo-
octene oxoacids, morphine analogue pharmacophores were synthetized.17
The reactions of bi- or trifunctional compounds of β-aminoacids and their derivatives,
e.g. aminoalcohols, diamines or aminocarbohydrazides, with aldehydes or oxocarboxylic ac-
ids furnish O,N- or N,N-heterocycles. The configurations of the starting oxocarboxylic acids
can change during the reactions. Earlier studies have dealt with the epimerization of cis-2-
acylcyclohexane-1-carboxylic acid and diendo- or diexo-3-acyloxanorbornane and norbor-
nane-2-carboxylic acid derivatives.18 The cis→trans epimerization of cyclohexane analogues
occurs when they are reacted with diamines as basic reagents or boiled in EtOH and water on
the use of NaOH.19,20 Trans compounds can also be epimerized to cis compounds under simi-
lar conditions.21 The norbornane analogues, as bicyclic compounds, are rigid and hence the
configuration of the starting material usually remains during cyclization.21,22 On the other
hand, refluxing of diendo-3-toluylbicyclonorbornane-2-carboxylic acid or its 6-exo-phenyl
analogue in the presence of HCl or triethylamine (TEA), results in the exo-aroyl-endo-
carboxylic acid isomer. A similar endo→exo epimerization occurs during the esterification of
diendo-3-toluylbicyclonorbornane-2-carboxylic acid.23 Endo→exo aroyl isomerization on the
9
norbornene ring was already known21 when diexo starting materials were transformed into
diendo compounds in the presence of basic reagents.
Numerous publications have reported diastereoselective one-pot reactions of chiral
aminoalcohols and racemic oxocarboxylic acids. Meyers et al. applied the reactions of (R)-
phenylglycinol with oxoacids, e.g. levulinic acid, and from the bicyclic lactams generated
natural compounds.24 Amat et al. also studied the stereoselective cyclocondensations of chiral
aminoalcohols, e.g. (R)-phenylglycinol, when oxazolopiperidones were prepared from race-
mic or prochiral δ-oxoesters. These procedures involved the dynamic kinetic resolution of
racemic substrates and/or desymmetrization of a diastereotopic or enantiotopic ester chain and
provided a route to the synthesis of substituted chiral bicyclic lactams in high yields.25 A large
number of natural piperidine-based alkaloids and bioactive compounds have been prepared
from aminoalcohols.26
In our Institute, Stájer et al. made a systematic study of the syntheses and stereochem-
istry of saturated or partially saturated isoindolone-fused heterocycles. For the preparations,
aliphatic, alicyclic and bicyclic γ-oxocarboxylic acids were reacted with β-amino acids, ami-
noalcohols, carboxamides, diamines or aminocarbohydrazides.27
2.2. Aminocarbohydrazides as tridentate reagents
A systematic economical synthetic pathway to aminocarbohydrazides has been devel-
oped, starting from (bi)cyclic anhydrides: ammonolysis and then Hoffman degradation results
in a β-amino acid. Esterification of this with SOCl2 and EtOH or MeOH, followed by reflux-
ing with N2H4 affords the aminocarbohydrazide in good yields (~70%) (Scheme 1).
O
O
O
O
OH
NH2
O
NH2
O
OH
NH2
O
OEt
NH2
O
NHNH2
cc. NH4OH NaOCl
SOCl2/EtOH
H2N NH2
Scheme 1
Several publications have described the cyclocondensations of aliphatic, alicyclic or
aromatic aminocarbohydrazides with 2-aroyl and 2-alkyloxocarboxylic acids.9 Generally, two
processes occurred, the first step either involving the formation of a Schiff base from the pri-
10
mary amino group with the aroyl group (pathway A), resulting in pyridazino[6,1-b]quinazoli-
nes, or the formation of an imine by reaction of the hydrazide primary amino group with the
aroyl moiety (pathway B), furnishing phthalazino[1,2-b]quinazolines (Scheme 2).
-H2O
NH
N
O
NH2
Ar
OHO NH
N
O
NH2
Ar OHO
NH
N
O
Ar
HN O
NH
NH2
O
N
Ar
O
OH
N
O N
ONH2
Ar
N
NN
O
Ar
-H2O
NH
NH2
+OH
O
Ar
O
Ar = p-tolyl
O
NH2
pathway A
pathway B
pyridazino[6,1-b]quinazoline
: cis- or trans-cyclohexane or diendo-norbornane
phenylcis- or trans-cyclo-hexane, diendo- or diexo-norbornene
phthalazino[1,2-b]quinazoline
-H2O
:
-H2O -H2O
Scheme 2
In the past decade, many efforts have been made to synthetize different heterocyclic
rings. Recently, anthranilic hydrazides were reacted with 2-formylbenzoic acid, 2-acetylben-
zoic acid, 2-benzoylbenzoic acid28 or phthalic anhydride29 to obtain phthalazino[1,2-b]quina-
zolines. From succinic anhydride,30 pyridazino[6,1-b]quinazolines were obtained. The reac-
tions of anthranilic hydrazide, its saturated derivative or diexo bicyclic analogues with 4-
oxocarboxylic acids resulted in saturated or partially saturated pyridazino[6,1-b]- and phtha-
lazino[1,2-b]quinazolines.31 Tetra- and pentacyclic analogues were also prepared by applying
cyclohexane or diendo-norbornane oxocarboxylic derivatives. The saturated cis- and trans-2-
amino-1-cyclohexanecarbohydrazides reacted with 2-aroyl-1-cyclohexanecarboxylic acids or
3-(p-chlorobenzoyl)propionic acid to furnish pyridazino[6,1-b]quinazolines.31 From cis ami-
nocarbohydrazides, mixtures of cis and trans tetracyclic diastereoisomers were obtained and
this focused attention onto the stereochemical outcome of this cyclocondensation. The cis
starting configuration changed to trans during the ring closure. The resulting N,N-heterorings
are pharmacological potentially active compounds, e.g. the pyridazino[6,1-b]quinazolines
11
exhibit antiallergic32 and herbicidal activity33,34 and the phthalazino[1,2-b]quinazolines act as
anti-inflammatory35 and analgesic36 pharmacophores.
When diendo-3-aminobicyclo[2.2.1]hept-5-ene-2-carbohydrazide and its diexo ana-
logue were treated with a cis-cyclohexane oxoacid, phthalazino[1,2-b]quinazoline, penta-
cyclic heterocompounds were obtained. These compounds underwent transformation in rDA
reactions: the cyclopentadiene split off from the heterocycle on gentle heating and the reaction
yielded pyrimidino[2,1-a]phthalazines (Scheme 3).37
N
NN
O
Ar
phthalazino[1,2-b]quinazoline
N
NN
O
Ar
pyrimidino[2,1-a]phthalazine
∆
Scheme 3
In an extension of this cycloreversion to a double rDA process, when two molecules of
cyclopentadiene were removed, pyrimido[1,2-b]pyridazines were obtained in the reaction of
diexo or diendo carbohydrazides with the adduct from trans-p-toluoylacrylic acid and cyclo-
pentadiene (Scheme 4).38
N
NN
O
Ar
NH2
NHNH2
O
COOH
Ar
O
2 N
NN
O
Ar
Ar = p-tolyl
pyrimido[1,2-b]pyridazine
∆
Scheme 4
Pyrazole-fused pyrimido[2,1-a]phthalazines were also prepared from phthalic anhydride with
5-aminopyrazole-4-hydrazide.39
For a further extension of the method, oxoesters were applied. From the reactions of 2-
(2-oxocyclopentyl or -cyclohexyl)acetate with diexo or diendo aminocarbohydrazides, mix-
tures of pyridazino[6,1-b]-, isoindolo[2,1-a]quinazolines and cyclopenta- or hexane-fused
pyridazines were obtained. The products could be separated by column chromatography. As
mechanism A shows, the primary amino group on the bicyclic skeleton attacks the carbonyl
carbon and forms a Schiff base, which stabilizes in a spirocompound and converts into isoin-
dolo[2,1-a]- or pyridazino[6,1-b]quinazolines. When the nucleophilic attack occurs from the
12
secondary amine in the ring, isoindolo[2,1-a]quinazolines are obtained (pathway A, protocol
1). In the second variation, the primary amino group of the hydrazide takes part in the in-
tramolecular cyclization, affording pyridazino[6,1-b]quinazolines (pathway A, protocol 2). In
process B, the carbonyl and the primary amino group of the hydrazide react and afford pyri-
dazinones (Scheme 5).
NH2
NHNH2
O
+O
( )n
n = 1,2diexo, diendo
-H2O
N
NHNH2
O
NH
N
O
NH2
N
N
ONH2
O
1
2
NH
N
OHN O
NH2
NHN
O
NHN
O
21
isoindolo[2,1-a]quinazoline pyridazino[6,1-b]quinazoline
pyridazinone
( )
( )
n
n
( )n
( )n
( )n
( )n
-H2O(diexo)
+ +
O
EtO
OEtO
O
EtO
O
EtO
-norbornene-based
amino acid
-EtOH
-EtOH -EtOH
BA
n = 1 n =1, 2
n = 1, 2
Scheme 5
The isoindolo[2,1-a]quinazolines, as quasi-aromatic systems, can be transformed into pyrro-
lo[1,2-a]pyrimidine (n = 1) via a rDA process. However, thermolysis does not take place in
the case of bisacylhydrazide compounds because there conjugation can not arise in the elec-
tron system by splitting-off of the cyclopentadiene moiety (Scheme 6). 40,41
13
N
N
ONH2
O
NH
N
OHN O
N
N
ONH2
O
NH
N
OHN O
pyridazino[6,1-b]quinazolineisoindolo[2,1-a]quinazoline
pyrrolo[1,2-a]pyrimidine
Scheme 6
2.3. Preparation from diamines with oxocarboxylic acids
By variation of the diamines and oxocarboxylic acids, a broad range of heterocycles
can be synthetized. In a systematic study, Stájer et al. employed diamines with β-amino acids
or carboxamides and 4-aroyl-and 3-alkyloxocarboxylic acids in the reactions.9 Two primary
amino groups can attack the carbonyl carbon: the amino on the ring forms a Schiff base, and
the other amino group cyclizes with the iminocarbon when two intramolecular cyclizations
are possible stereochemically (Scheme 7).
NH2
NH2+
OH
O
R
O
NH2
N
R
HO O
N
NH R
O
N
NH R
ONH
N
NH
N
O O
RR
NH
NHR
OHONH
NH
R
O
HO
-H2O
++
: n = 0: o-phenylenediamine, n = 1: 1,3-diaminoalkanes or cis- or trans-cyclohexane diexo-norbornane and norbornenediamines
n
X
X XXX
X
X
X
propionic acid derivatives,
cis-cyclohexane
diendo-norbornane; X = CH2
diexo-norbornane; X = O, CH2
R = Me, p-tolyl or p-chlorophenyl
-H2O -H2O
Scheme 7
14
In an exceptional case, the extra acylation of the secondary amine takes place in the
reaction after the ring closure and a new heterocyclic system is formed. For instance, the reac-
tions between diexo-norbornane/enediamines and levulinic acid furnished methylene-bridged
pyrrole-condensed 1,4-benzodiazepinones besides the pyrrolo[2,1-b]quinazolinones.42 Gener-
ally, the diamines react with equimolar γ-oxocarboxylic acids during refluxing in the presence
of p-tolylsulfonic acid (PTSA), and N-heterorings with new chiral centres are formed. In these
reactions, the configurations of the starting oxocarboxylic acids, i.e. the cis, trans, diexo or
diendo structures, are retained during the cyclization.43-47 Via other synthetic routes, pyrrolidi-
none derivatives have been obtained by means of the action of microwaves or in the presence
of Al2O3, using ethyl levulinate and aliphatic diamines.48
In the reactions of cyclohexane γ-oxocarboxylic acid and alicyclic diamines, the satu-
rated isoindole-condensed pyrrolidine and piperidine derivatives are formed.49 On application
of the aroylcyclohexane- or aroylnorbornanecarboxylic acids and stereoisomeric cycloalkane-
1,3-diamines, polycyclic heterocycles with five or more new chiral centres are formed; stereo-
isomers have been isolated by means of column chromatography.50-52 The aryl-substituted
aroyloxocarboxylic acids condense with aliphatic diamines: 1,2- or 1,3-diaminoalkanes yield
isoindolone analogues.53-55 In other preparations, compounds with morphine-like structures
have been synthetized. The methanobenzocyclooctene oxoacid reacted with 1,2-, 1,3- and 1,4-
diamines to afford pentacyclic benzo[g]pyrimido[2,1-i]indolones and benzo[g][1,3]diazepi-
no[2,1-i]indolones. The products proved to be analgesic pharmacophores.56 Diexo-norbor-
nane- and oxabicyclonorbornane-fused 1,3-N,N-heterocyclic isoindol(on)es were also pre-
pared. From diexo-bicyclo[2.2.1]heptane oxoacids with diaminoalkanes, imidazo-, pyrimido-
and diazepino[2,1-a]isoindolones were synthetized.57 Starting from the diexo-3-aroyloxabi-
cyclonorbornane oxoacid, the imidazo- and diazepino[2,1-a]isoindolone analogues were pre-
pared.58 The reactions of o-phenylenediamine and aromatic 1,2-diamines yielded isoindo-
lo[2,1-a]benzimidazolones.57,58
2.4. Isocyanide-based multicomponent reactions; Ugi reactions
2.4.1. Ugi reactions in methanol
Combinatorial syntheses provide possibilities via which to generate diverse chemical
libraries which are available to multiply the range of potential pharmacologically active com-
pounds. Multicomponent condensation (MCC), in which several components are reacted in a
one-pot reaction, is one of the important strategies in combinatorial chemistry.59 The most
commonly used and cited MCC is the Ugi reaction.60 This reaction type can be divided into
15
three subtypes: the Ugi-4-component condensation (U-4CC), the Ugi-4-centre-3-component
reaction (U-4C-3CR) and the Ugi-5-centre-4-component reaction (U-5C-4CR). The reactions
are generally carried out in organic solvents, e.g. in MeOH, and can be aligned as isocyanide-
based multicomponent reactions (MCRs).
A traditional U-4CC incorporates a carboxylic acid, an amine, a carbonyl compound
and an isocyanide in a one-pot condensation. For example, α-acetocarboxamides are synthe-
tized in this way in good yields and with good diastereoselectivity (Scheme 8). This method
has been utilized for the preparation of peptidomimetics.61,62
O
OHR1R2 NH2+ +
R3 H
O
+ R4 NCO
R1
O
N
NH
R2
R3
R4
R1 N
OHNR4
R2
R3
O
Scheme 8
For the other types of Ugi reactions (U-4C-3CR and U-5C-4CR), α- or β-amino acids
can be used as starting materials, containing two functional groups on the same compound,
and afford α- or β-amino acid derivatives and β-lactams. Starting from α-amino acids, trans-
alicyclic or exo-endo bicyclic β-amino acids, Ugi adducts, e.g. α- and β-amino acid ester
derivatives, can be obtained via the U-5C-4CR. Through the generation of a Schiff base, an
oxazinone is formed. In the next step, this intermediate reacts with molecules of the solvent.
As the carbonyl and amino groups are situated relatively distant from each other, intramolecu-
lar cyclization (similarly to the U-4C-3CR) can not occur, and the reaction furnishes linear
products (Scheme 9).
COOH
NH2R1+
R2 H
O
-H2O
COO
NHR1
HR2
R3 NC
HN
O
O
NR3
R1
R2
R4 OH
NH
OHN
O
O
R4
R1R2
R3(MeOH)
Scheme 9
16
The N-methyl-substituted exo-endo-oxabicyclo[2.2.1]hept-5-ene-based β-amino acid has been
used as starting material for the U-5C-4CR protocol. The Ugi adducts generated have been
applied for the synthesis of chiral α-amino acid derivatives.63,64
The most commonly used and cited reaction type is the U-4C-3CR, in which N-
substituted β-lactams are generated from cis-cycloalkane/ene- and bicyclic, diexo- or diendo-
β-amino acids. The reaction mechanism proposed for the U-4C-3CR has been explained. In
the first step, the β-amino acid reacts with the appropriate aldehyde, resulting in a protonated
Schiff base. The next step is the addition of the isocyanide, affording the β-lactam via intra-
molecular cyclization and rearrangement (Scheme 10).
NH2
COOH
R1 H
O
+
-H2O
NH
R1
O
O C N R2
NH2
R1
O
O
NR2
NH
O
O
R1
N
R2N
O
R1
O
NH
R2
MeOH
: cis cyclopentane, cyclohexane, cyclohexene diexo norbornane or norbornene
R1 = Et, nPr, Ph, p-OMePh, etc.
R2 = tert-butyl, cyclohexyl, benzyl
Scheme 10
β-Lactams have proved to be enzyme inhibitors (serine and cysteine protease) and an-
tibiotics.65 Through the Ugi reaction, a large number of N-substituted β-lactams with very
diverse structures can be prepared. In our Institute, cis alicyclic (e.g. cyclopentane or cyclo-
hexane) and diexo-bicyclo[2.2.1]heptane and -5-ene β-amino acids have been utilized for the
U-4C-3CR in MeOH. The β-lactams obtained could be successfully applied for the synthesis
of β-amino acid derivatives, e.g. the corresponding free amino acids and their esters.66-68
2.4.2. Water as solvent for Ugi and other multicomponent reactions
Water has become a versatile solvent in recent years. It is inexpensive and environ-
mentally benign, and allows new reactivity. Water can accelerate reactions and even control
the diastereoselectivity of reactions. Moreover, most Ugi products are less soluble in water,
which facilitates precipitation of the target compound from the reaction mixture.69-71 The clas-
17
sical MCRs, such as the Mannich and Biginelli reactions, were carried out in water. β-
Aminocarbonyl compounds were synthetized in good to excellent yields, but with modest
diastereoselectivity via three-component Mannich reaction.72 Water could be also utilized as
solvent for the exothermic Biginelli reaction to obtain dihydropyrimidines.73 The most impor-
tant MCRs, such as the Passareni and Ugi reactions, have been accomplished in water. Pir-
rung and Mironov investigated the accelerating effect of water in the Passerini and Ugi reac-
tions.74,75 It was found that the significant acceleration effect was due to the hydrophobic ef-
fect and the large cohesive energy of water.76
Pirrung et al. focused on the U-4C-3CR of aliphatic β-amino acids in water, using 1 M
glucose solution to accelerate the reaction. β-Lactams were obtained in good purity in good to
excellent yields.75,77 Other strained β-lactams were also synthetized by means of β-keto ac-
ids.78 The reactions failed in organic media; this condensation was carried out in water with
only moderate yields in 3 days. Nevetheless, 1 M glucose solution was necessary or 5 v/v% of
CHCl3 or toluene as phase-transfer catalyst for the successful reactions. In contrast, a number
of literature data have revealed a considerable decrease in reaction rate, and in some cases the
Ugi reaction was not accelerated by water.79
2.5. Syntheses and some transformations of natural alkaloids
2.5.1. Syntheses of Sedum alkaloids and their analogues
The Sedum species, e.g. S. acre, S. bulbiferum and S. anglicum, contain 2- and 2,6-
disubstituted piperidines (Figure 1). These natural alkaloids possess a 1,3-aminoalcohol struc-
ture, e.g. sedamine, sedridine, allosedridine and halosine.80,81 The pharmacological reports in
recent years revealed that the aminoalcohol moiety and the subsituent at position 2 determine
memory-enhancing properties and lead to potential pharmacological application against Alz-
heimer disease.82
N
Me
OH
sedamine
N
Me
Me
OH
sedridine
NH
OH
Me
halosaline
Figure 1
A high number of synthetic pathways towards Sedum alkaloids are available in the lit-
erature.83 Most of the synthetic strategies can be divided into one or other of two groups. In
the first group, the preformed starting compounds possess a nitrogen heterocycle, e.g. a pyri-
18
dine or a piperidine moiety, and a side-chain is appended to the skeleton. These protocols
should be aligned as the reduction of ketopiperidine with Raney-Ni or LiAlH4,84 a Grignard
reaction85 or 1,3-dipolar cycloaddition, e.g. the reactions of (piperidine-based) nitrones with
alkenes (Scheme 112).86 Most of these reactions have been found not to be enantioselective: a
racemic mixture of aminoalcohols is obtained in almost all cases. However, the stereochemi-
cal outcome of 1,3-cycloadditions can be controlled.86 The regioisomer isoxazolidine formed
can be opened by reduction with Raney-Ni/H2 or LiAlH4, resulting in Sedum alkaloids. In the
other synthetic pathway, the piperidine ring is built up by a variety of techniques, such as Mi-
chael addition87 and ring-closing metathesis (RCM) reactions (Scheme 11).88
N
R1
R2
OH
N
O
N
1. LDA,
R2CHO
2. DIBAL
N
R1
R2
O
N
R1
CHO
1. R2MgBr
2. TFA
AcO OAc
(RCM)
NH R2
O
R1
(Michael addition)
N
OO R2
H2/Pt/C or
LiAlH4
DIBAL, etc. R1 = Me, H, COOEt, etc.
R2 = Me, Ph.
R1 = Boc
R2 = Me, Et
1. KOtBu
2. R2MgBr
3. LiAlH4R1 = COOEt, Me
R2 = Ph
1. Me2Si(Cl)CHCH=CH
2. DIBAL
3. Mitsunobu reaction
4. Grubbs' catalyst
5. TBAF then H2, Pd/C
6. Na/Hg, K2HPO4
R1 = H
R2 = nPr
R1 = H
R2 = Ph.
1. H2, Pd/C
2. KOH, HCl, NaOH
R21.2. (MeI then) LiAlH4
R1 = H, (Me)
R2 = Me, Ph, iPr
R1 = H,
R2 = Me, Ph
Scheme 11
The synthetic pathway includes the generation of bicyclic carbamates as precursors to the
synthesis of Sedum alkaloids. In this strategy, the final step is ring opening with either KOH
in EtOH or LiAlH4 to obtain the target alkaloid analogues.89-93 Bicyclic carbamates can be
reached by starting from N-Boc-subtituted piperidines, because of the features of the N-Boc
group. This protecting group is able to react intramolecularly as an electrophile or as a nucleo-
phile. The intramolecular reactivity generally stems from the presence of an electrophilic car-
bon atom, due to a good leaving group, a halonium ion or a carbenium ion attached to the
electrophilic centre. This centre is then attacked by the appreciable negative charge on the
19
carbonyl oxygen of the Boc group.94 The intramolecular cyclization of N-Boc compounds
occurs when adequately strong electrophilic reactants are used, e.g. N-iodosuccinimide (NIS),
N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS).95 In a special example, with an
N-Boc-2-piperidine alcohol derivative, CBr4/PPh3 must be used for successful cyclization.96
2.5.2. Ephedra alkaloids; transformations of norephedrine
Ephedra plants, including E. sinica, E. intermedia and E. equisetina, contain alkaloids
with a 1,2-aminoalcohol structure in quantities of from 0.5% up to 2.5%: mainly (-)-ephedrine
and pseudoephedrine. Some ephedrine derivatives can be identified as minor compounds, e.g.
D-methylephedrine, N-methyl-pseudoephedrine and norephedrine.97,98 The Ephedra alkaloids
exhibit general sympathomimetic behaviour activation of the α1-adrenergic receptor, similarly
to the catecholamines.99-102
(1R,2S)- and (1S,2R)-norephedrine and their derivatives are used extensively as start-
ing materials for asymmetric syntheses, components of chiral ligands, or catalysts and
resolution agents103 (Scheme 12).
Ph OH
NH2Me
(1R,2S)- or (1S,2R)-norephedrine
ON
O
PhMe
O
R
chiral auxiliary for exo double bond
transformation
N
N
NH
NH
Ph
OHMe
OHMe
Ph
PhP
O
chiral ligand with Cu(II)in asymmetric syntheses
NH
O
Me Ph
OH
PhMe
NH OH
Ru(III)-catalysed asymmetric hydrogenation
O NH
NHO
Me
Ph
OH
Me
Ph
OH
addition to Et2Zn
to aldehydes
O
N
NR
Ph
Me
O
aldol synthesis
N
N
OO
NPh
Me
Ph
Me
PYBOX catalyst
NH
Ph
O
Me
Li Li
epoxide openingto alcohol
N
Me
Ph
F3C
N
Li
Li
N
N
MeOBN R
H
Me Ph
enantioselective reduction of prochiral ketones
Scheme 12
20
(+)-Norephedrine has been used as intermediate for the synthesis of naturally occur-
ring alkaloids, e.g. (+)-Geldanamicin,104 (+)-Discodermolide105 and Rhizoxin.106 In this proc-
ess, syn or anti aldol intermediates are generated for further enantioselective transformations.
In other cases, the chiral alcohol is a moiety of the target compound, e.g. (+)-norephedrine-
based cyanoacetamide, which exhibits a scytalone dehydratase inhibitory effect.107
As ligands, norephedrine derivatives have been used for the enantioselective hydro-
genation of acetophenone.108 (1R,2S)-Norephedrine-based heterocyclic derivatives have
proved to be excellent catalysts in stereoselective aldol syntheses109 or the asymmetric addi-
tion of Et2Zn to a high number of aldehydes.110-112 The norephedrine derivatives can be
utilized for the stereoselective rearrangement of alicyclic or aliphatic epoxides to allylic alco-
hols. For this, the (di)lithiated norephedrine-based diamine catalysts furnish the best enan-
tioselectivity.113
1,3,2-Oxazaborolidines derived from chiral norephedrines are available for the enanti-
oselective reduction of oximethers and prochiral ketones.114 Other ring-closed compounds,
e.g. 1,2,3-oxathiazolidinones, may be applied to generate optically active sulfinamides and
sulfoxides.115 Other heterocycles, e.g. oxazolidines, are valuable in asymmetric syntheses, e.g.
as chiral auxiliaries in enantioselective domino reactions.116 1,3-N,O-Heterocycles e.g. oxa-
zoli(di)nes, can readily be formed by ring closure, using dehydrating agents under thermal
conditions,117 or condensation reactions with acetals118 or ketoacids.119 Other N-containing
heterocycles have also been synthetized. The N-alkylation of norephedrines allows the syn-
thesis of substituted piperidine derivatives.120 Moreover, polyhydroxylated piperidines pre-
pared from both norephedrine enantiomers have proved to be inhibitors of α-glucosidases.121
Starting from chiral norephedrines, tricyclic γ-lactams122 can be prepared, similarly to the
condensation of 1,2-aminoalcohols with γ-oxoacids.25,123 Further, thiolactams have been pre-
pared by thio-Claisen rearrangement.124
3. Results and Discussion
3.1. Syntheses of pyrazolo[3,4-d]pyrimidine derivativesI
The reactions of 5-amino-1-phenyl-4-pyrazolecarbohydrazide (1) with γ- or δ-oxo-
carboxylic acids were carried out. The starting 1, prepared from ethyl 2-cyano-3-ethoxy-
acrylate by treatment with phenylhydrazine and N2H4,125 was refluxed in chlorobenzene with
oxocarboxylic acids A, C-E and G, in the presence of PTSA and the products were purified
on an Al2O3 column. On application of levulinic acid (A), 1-phenyl-7-methyl-8,9-dihydro-
pyrazolo[3´,4´:4,5]pyrimido[5,6-b]pyridazin-4-one (2) was obtained (Scheme 13). When 3-p-
21
chlorobenzoylpropionic acid (C) and 4-p-tolylbutyric acid (D) were applied, the reactions
afforded 1-phenyl-7-p-chlorophenyl-8,9-dihydropyrazolo[3´,4´:4,5]pyrimido[5,6-b] pyri-
dazin-4-one (3) and 1-phenyl-7-p-tolyl-8,9-dihydro-10H-pyrazolo[3´,4´:4,5]pyrimi-
do[5,6-b][1,2]diazepin-4-one (4). The reaction of cis-2-toluoylcyclohexanecarboxylic acid (E)
resulted in the tetracyclic compound 1-phenyl-7-p-tolyl-7ar,8,9,10,11,11ac-hexahydropyrazo-
lo[3´,4´:4,5]pyrimido[5,6-b]phthalazin-4-one (5). With diendo-3-p-toluoylbicyclo[2.2.1]hept-
ane-3-carboxylic acid (F), the diendo-8,11-methano-1-phenyl-7-p-tolyl-7a,8,9,10,11,11a-
hexahydropyrazolo[3´,4´:4,5]pyrimido[5,6-b]phthalazin-4-one (6) was prepared.
N
N
Ph
NH2
O
NHNH2
NN
PhN
NN
O
Me
NN
PhN
NN
O
ArNN
PhN
N
O
5 6
1
GE
A B C
D
NN
PhN
NN
O
Ar
2
3
NN
PhN
N
O
NAr
COOH
Me
O
A
COOH
Ar
O
C
Ar = C6H4Cl(p)
4
COOH
O
ArD
COOH
Ar
O
Ar = C6H4Me(p) Ar = C6H4Me(p)
Ar = C6H4Me(p)
COOH
O
Ar
N Ar
Scheme 13
Via these reactions, pyrazole-based pyrimido[5,6-b]pyridazinones 2 and 3, pyrimi-
do[5,6-b][1,2]diazepinone 4 and pyrimido[5,6-b]phthalazinones 5 and 6 were synthetized.
The bisacyl hydrazide derivatives depicted in Scheme 2 (pathway A) were not generated
through this protocol. This can probably be explained in terms of the less basic character of
the aromatic primary amino group of 1, which does not furnish the Schiff base, the cyclocon-
densation passing through a hydrazone intermediate (Scheme 2, pathway B).
22
The structures of 2-4 were established by 2D NMR techniques. Ring D in 5 is cis, the
C(Ar)=N carbon is equatorial, and the C(N)=N carbon is axial to the ring D. The deshielding
is due to the anisotropy of the sp2 N atom. For product 6, the unaltered diendo annelation of
the starting norbornane was proved by DNOE measurements.
In the second part, the pyrazole-condensed pyrrolotriazepinone was prepared. Hy-
drazide 1 was acetylated with Ac2O, and then cyclized with levulinic acid. Instead of the ex-
pected triazepinone compound, the ring-closed derivatives 3-phenyl-8-methylpyrazo
lo[3,4-b]azepin-5(4H)-one 7 and 5-acetylamino-1-phenyl-5a-methyl-6,7-dihydropyrro
lo[1,2-g]pyrazolo[3,4-d]pyrimidin-4-one 8 were isolated on SiO2 by means of column chro-
matography. The possible ring closure can take place in two ways. The primary amino group
of 1a is acylated by levulinic acid, and the intermediate forms the pyrazoloazepine 7 by in-
tramolecular cyclization on the pyrazole carbon and elimination of the hydrazide. When the
Schiff base is formed from levulinic acid and the primary amino group and the NH next to the
CO in the carbohydrazide then cyclizes, the pyrrolopyrimidine 8 is obtained (Scheme 14).
NN
Ph
NH2
NHNHAc
O
NN
Ph
N
N
O NHAc
O
Me
8
NN
Ph
NH
Me
O
7
1a
NN
Ph
N
NHNHAc
O
Me
OHO
NN
Ph
NH
N
ONHAc
Me
O
HO
-H2O
NN
Ph
NH
NHNHAc
O
O
OMe
-H2O
NN
Ph
NH
Me OH H
O-H2O -H2O
COOH
Me
O
A
COOH
Me
O
A
AB
CA
B
Scheme 14
The non-planar structure of ring B in 7 and 8 hinders the electron delocalization,
which leads to a more pronounced polarization of the C=O bond. Consequently, the 13C NMR
line of the carbonyl carbon is downfield-shifted. For 7 and 8, an upfield shift of the C-9b line
was found as compared with compounds 2-6. Similarly, the olefinic carbon bound to C-3a in
7 significantly influences the chemical shift of this carbon, which has a higher value, relative
to the data measured for compounds 2-6 and 8, where the substituent on C-3a is a carbonyl
group.
23
The similar pyrazolo[3,4-d]pyrimidine compounds are found to be selective kinase in-
hibitors, inhibiting glycogen synthase kinase-3,126 tyrosine kinases127,128 and cyclin-dependent
kinase.129 When attached to nucleosides, they depress virus replication (HIV-1 and DNA
viruses).130 The derivatives with this structure are adenosine 1A receptor antagonists and
substitution on C-4 and C-6 increases the effect.131 The tricyclic pyrazolo[3,4-d]pyrimidi-
no[1,2-b][1,2,4]triazines show moderate pharmacological effects in vitro, as antiviral agents
against herpes simplex-1, and cytotoxicity.132
3.2. Syntheses and transformations of 5,6-dehydronorcantharidin derivatives
Cantharidin (Figure 1) was originally identified as a biologically active constituent of
the dried body of Chinese blister beetle (Mylabris phalerata or M. cichorii) and Spanish fly.
Cantharidin inhibits Ser/Thr protein phosphatases 1 (PP1) and 2A (PP2A), which control
many cellular processes, such as the regulation of cell proliferation and differentiation. Nu-
merous studies of cantharidin analogues have had the aim of the discovery of potent and se-
lective inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). The
syntetic pathway of cantharidin and its analogues involved the preparation of the Diels-Alder
adduct with furan and dimethylmaleic anhydride, followed by hydrogenation and transforma-
tion into different carboxylic acid derivatives, e.g. diesters or amides. Although several can-
tharidin derivatives have been synthetized, their inhibitory effects were in all cases re-
duced.133-136 The unsaturated analogue 5,6-dehydronorcantharidin (Figure 2) has also been
prepared and its pharmacological effect studied. These experiments proved that demethylation
of the cantharidin resulted in the same biological effect, but the products are less nephro-
toxic.137,138
O
O
O
O
1
5
2
34
6
O
O
O
O
cantharidin norcantharidin
Figure 2
The structure-activity relationship showed that the bridging ethereal oxygen is crucial
for activity. Moreover, a hydrophobic character, e.g. the saturated double bond at position
C5/C6 is beneficial for the inhibition of protein phosphatase 2B (PP2B). Although the anhy-
dride or dicarboxylate moiety and methyl groups at positions C2 and C3 are also beneficial
for depression of the activities of PP1 and PP2A, methyl substituents cause very toxic side-
effects, such as nephrosis and severe gastritis. Recent investigations have focused attention on
24
norcantharidin and its unsaturated analogue, which exhibit similar pharmacological effects,
with significant anticancer properties, but they are less toxic.139,140
As a continuation of the earlier research into the pharmacological features of 5,6-de-
hydronorcantharidin derivatives, and especially the antitumour activity found for N-acyl-3-
carbamoyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (10), some saturated and partially
saturated analogues, β-lactams and 1,3-N,N-heterocycles, were synthetized. The aim was the
ring closure of the β-amino acid 11 and diamine 14. An antibacterial, serine protease-inhibi-
tory effect and antitumour activity were supposed. Chemically, the rDA reactions of these
derivatives were of interest because it was known that, on thermolysis, furan is a “good-
leaving” group in the molecule.
Maleic anhydride was reacted with furan to give the Diels-Alder adduct 5,6-dehydro-
norcantharidin 9. Ammonolysis resulted in compound 10, and Hofmann degradation then fur-
nished diexo-3-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid 11. Esterification of
11 with SOCl2 in EtOH, followed by the ammonolysis of 12 and LiAlH4 reduction of the car-
boxamide 13, afforded the diamine 14 (Scheme 15). It should be emphasized that the final
step of LiAlH4-mediated reduction was carried out under very mild conditions because the
oxabicyclic compounds are sensitive to temperature. The reaction mixture must be cooled to
-15 ºC for successful transformation. Higher temperatures, even 0 ºC or room temperature,
resulted in a complex reaction mixture.
SOCl2/EtOH
LiAlH4
O
OOO
O
NH2
OEt
O
NH2OH
O
O
NH2
NH2
O
O
O
O
O
NH2NH2
O ONH3/MeOH
O
OH
ONaOCl
NH2
O NH4OH
9 10 11
121314
Scheme 15
The oxabicyclo β-amino acid 11 and diamine 14 prepared reacted in two ways. diexo-
3-Amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (11) was cyclized by means of
aldehydes and isonitriles in U-4C-3CRs, to give N-substituted β-lactams. Moreover, diexo-3-
amino-7-oxabicyclo[2.2.1]hept-5-ene-2-methanamine (14) with γ- and δ-oxocarboxylic acids
was cyclized to furnish isoindolone derivatives.
25
3.3. Multicomponent reactions with oxabicycloheptene-based β-amino acids II
The cis alicyclic, diexo and diendo bicyclic β-amino acids have been used for the U-
4C-3CR in organic solvent. The main conception was the extension of the U-4C-3CR for ox-
abicyclo[2.2.1]hept-5-ene-based β-amino acids, using MeOH and water as solvents, in order
to compare the obtained yields, reaction times and diastereoselectivities. On the other hand,
the possible further transformations of the β-lactams were also attempted.
The building blocks utilized in the Ugi reactions to construct the β-lactam library are depicted
in Figure 3.
O
NH2
O
OH
Cl
O
H
H3C
O
H
H3CO
O
H
O
H
O
H
NC
NC
11 A B C
D a bE
Figure 3
Generally, β-amino acid 11 was used in a small excess (1.1 equiv.) and was reacted with ali-
phatic (A or B) or aromatic aldehydes (C, D or E) and tert-butyl or cyclohexyl isocyanide (a
or b) in MeOH or in water. The proposed reaction mechanism is displayed in Scheme 16.
O
NH2
O
OH
O
HN
O
O
R2 N
O
HN
O
N
O
R2
R1
O
N
O
R1 HN
O
R2
-H2O
C
O
HN
O
O
R1
CNR2
15-24
11
MeOH or water
R1 CHO;
A-E a or b
A-E: a or b:
R1
Scheme 16
26
3.3.1. Use of methanol as solvent
At first, MeOH was used as solvent to carry out the U-4C-3CR. To a suspension of 1.1
equivalents of β-amino acid 11 in MeOH, the required aldehyde (1 equiv.) was added at room
temperature. After stirring for 45 min at room temperature, 1 equivalent of tert-butyl or
cyclohexyl isocyanide was added dropwise to the solution, which was next stirred for 3 days
at ambient temperature. The crude products 15-24 were obtained in yields of 43-76% and the
diastereomeric ratio ranged from 56:44 (16) up to 87:13 (17) (Table 1).
Table 1
Compound R1 R2 dr Yield (%)
15 Et tBu 62:38 61 16 Et cyclohexyl 56:44 76 17 tBu tBu 87:13 71 18 tBu cyclohexyl 82:18 65 19 C6H4Cl(p) tBu 62:38 52 20 C6H4Cl(p) cyclohexyl 79:21 76 21 C6H4Me(p) tBu 78:22 55 22 C6H4Me(p) cyclohexyl 86:14 43 22 C6H4OMe(p) tBu 64:36 48 24 C6H4OMe(p) cyclohexyl 69:31 45
Compounds 15-20 had an average purity of over 90% without purification (based on 1H NMR
measurements). For compounds 21-24, further purification was necessary by means of flash
chromatography in order to remove the remaining aldehyde. On use of the aliphatic alde-
hydes, the intramolecular Ugi cyclization afforded higher yields, and for compound 17 the
highest diastereomeric ratio (87:13) was found. A high average diastereoselectivity, but de-
creased yields were obtained when the aromatic aldehydes were used.
Compounds 17 and 19 were prepared for X-ray crystallography so as to determine the
relative configurations of the major diastereoisomers (Figure 4). For the major isomers, the
configuration of the substituent at position C-2 remains the same position relative to the
annelation H-atoms.
27
17 19
Figure 4
3.3.2. Use of water as solvent
The Ugi reactions were carried out in water, starting from the same materials to allow
comparison with the results in MeOH (Table 2). To 1.1 equivalent of β-amino acid 11 in a
minimal amount of water (200 µL), aldehyde (1 equiv.) was added dropwise. Next, ap-
proximately 1 mL of water was added dropwise until the components had completely dis-
solved. After vigorous stirring for 30 min at room temperature, the corresponding isocyanide
(1 equiv.) was added to the mixture. Precipitation of products 16-22 and 24 started immedi-
ately. In the cases of compounds 15 and 23, some precipitation was detected, but extraction
was necessary for complete isolation. It was found that the cyclizations proceeded success-
fully in distilled water in from 3 h up to 1 day, and the precipitation depended greatly on the
concentrations besides the type of the starting materials. Precipitation occured when less wa-
ter-soluble amino acids (the bicyclic oxabicyclo- and bicyclo[2.2.1]heptane-based amino ac-
ids were found appropriate) were used.141
Table 2
Compound R1 R2 dr Yield (%)
15a Et tBu 67:33 71%
16b Et cyclohexyl 60:40 61%
17b tBu tBu 100:0 59%
18b tBu cyclohexyl 80:20 64%
19b C6H4Cl(p) tBu 52:48 69%
20b C6H4Cl(p) cyclohexyl 55:45 55%
21b C6H4Me(p) tBu 58:42 54%
22b C6H4Me(p) cyclohexyl 75:25 54%
23a C6H4OMe(p) tBu 57:43 51%
24b C6H4OMe(p) cyclohexyl 63:37 47%
a isolated by extraction b precipitated compound, isolated by filtration
28
The ideal concentrations were achieved when starting components had just dissolved.
After the addition of the isocyanide, the solution became slightly opalescent because of pre-
cipitation of the target molecules. We tested both concentrated and diluted mixtures in order
to investigate the precipitation process. When the components had only partially dissolved,
the yields were lower. In dilute solutions, the products were not precipitated, or only partially.
Organic solvent extraction was therefore necessary to isolate them. When the reaction time
was prolonged to 3 days, the yields were similar to those when the reaction mixture was satu-
rated with the starting materials. In accordance with these experiments, we assume that a
“personalized” amount of water is necessary to optimize acceleration of the reaction with pre-
cipitation in water.
The best result was observed for compound 17 containing the bulky tert-butyl sub-
stituents. The reaction time was only 3 h and the diastereomeric ratio was 100:0. Derivatives
15-12 and 24 were isolated in average purities of over 90% and further purification was not
necessary for NMR measurements. For product 23, chromatographic purification was neces-
sary because of the residual anisaldehyde. Table 3 presents NMR data on the H atom at posi-
tion 2, the melting point intervals for the mixtures of diastereoisomers and the reaction times.
Table 3
Com-pound
R1 R2 2-H (ppm) major/minor
M.p. (○C)
Time (h)
15a Et tBu 3.65 (t)/3.72 (m) 97-106 24
16b Et cyclohexyl 3.68-3.74 (m) 159-166 15
17b tBu tBu 3.75 (s) 176-178 3
18b tBu cyclohexyl 3.84 (br s) 160-164 6
19b C6H4Cl(p) tBu 3.96/3.95 (s) 165-169 15
20b C6H4Cl(p) cyclohexyl 3.93/3.92 (s) 155-176 15
21b C6H4Me(p) tBu 3.97/3.96 (s) 135-141 15
22b C6H4Me(p) cyclohexyl 3.94/3.93 (s) 122-138 15
23a C6H4OMe(p) tBu 3.96/3.95 (s) 120-134 24
24b C6H4OMe(p) cyclohexyl 3.93/3.92 (s) 129-141 24
3.3.3. Transformations of the resulting β-lactam 17
To demonstrate the possibility of further transformations of the resulting azetidinone
derivatives, compound 17 was converted into the corresponding carboxylic acid 25 or ethyl
ester 26 by means of acid-catalysed solvolysis in the presence of water or EtOH. A saturation
process with H2 at atmospheric pressure was carried out, catalysed by Pd on charcoal, to yield
derivative 27 (Scheme 17). Another conversion was performed with LiAlH4 or LDA in an
attempt to synthetize hydroxy-substituted amino acid derivatives 28a or 28b, but the target
29
compounds could not be isolated from the complex reaction mixture. To utilize the oxano-
rbornene moiety of compound 17, the rDA protocol was attempted by classical methods
(heating to the melting point, and refluxing in a high-boiling point solvent) and microwave-
assisted thermolysis (150-250 °C, 100-200 W, for from 10 min up to 1 h, in o-dichloro-
benzene or solvent-free, on SiO2 or AlCl3/toluene), but only the starting material could be
detected; the rDA product 29 was not formed.
O
N
O
NH
O
2526
27
HCl/H2OHCl/EtOH
H2/Pd
17
HH
O
NH
COOH
NH
O.HCl
HH
O
N
O
NH
O
HH
63%56%
90%
O
NH
COOEt
NH
O.HCl
HH
N
O
NH
O
NH
O
LDA or
LiAlH4
NH
OH
or
COOH
NH
OH
28a 28b
29
COOH
O
O
HN
Scheme 17
3.4. Reactions of oxanorbornenediamine with γ- and δ-oxocarboxylic acidsIII
The oxanorbornene diamine skeleton was cyclized with several oxoacids. This
protocol, which resulted in 1,3-N,N-heterocycles, followed the reaction route described earlier
(Scheme 7).
3.4.1. Preparation of pyrrolo- and isoindoloquinazolines
Diamine 14 was reacted with aliphatic (B and C), alicyclic (E), bicyclic (G, H and K)
and aromatic (I and J) γ-oxocarboxylic acids (Scheme 18). The cyclocondensation is illus-
trated here by the example of the reaction of diamine 14 and 3-p-tolylpropionic acid (B).
When diamine 14 was boiled with equimolar 3-p-tolylpropionic acid (B) in chlorobenzene,
30
the Schiff base was formed. This intermediate can cyclize into quinazolines by forming a C-N
bond between the primary amine of the metheneamine and the imine carbon. Next, the final
cyclization step resulted in a pyrrolo[2,1-b]quinazoline, compound 30. Potentially four iso-
mers (pyrrolo[2,1-b] and [1,2-b]quinazolines) could be formed in this protocol, but only one
isomer could be isolated from the reaction mixture (Scheme 7). A similar result was obtained
when 3-p-chlorobenzoylpropionic acid (D) was used; aryl diexo-5,8-epoxypyrrolo[2,1-
b]quinazolin-1-one derivative 31 was isolated. When cis-2-p-tolylcyclohexanecarboxylic acid
(E) was used, the reaction afforded the cis- and trans-condensed decahydro-5a-p-tolyl-1,4-
epoxy-diexo-5H,12H-isoindolo[1,2-b]quinazolin-10-one pentacyclic derivatives 32a and 32b
(Figure 4); in the latter case, the oxocyclohexane acid isomerized. The results showed that the
configuration of the starting aroylcarboxylic acid often changed in the reactions. With diendo-
3-benzoylbicyclo[2.2.1]heptane-2-carboxylic acid (G) or the diendo-6-phenyl-3-
benzoyl[2.2.1]heptane-2-carboxylic acid (H), 1,4-epoxy-diendo-6,9-methano-diexo-5H,12H-
isoindolo[1,2-b]quinazolin-10-ones 33 and 34 were obtained.
NH2
O
NH2
NO
NH
O
Ar
N
NH
O
Ar
O
N
O
Ar
NH
O
14
30 Ar = C6H4Me(p)
31 Ar = C6H4Cl(p)
32a: cis, 32b: trans
Ar = C6H4Me(p)
37a
37b
E G or H
K
J
N
O
Ar
NH
O
I
N
O
Ph
NH
OR
33 R = H34 R = Ph
H
H
H
H
H
H
H
HH
H
N
NH
O
Ar
O
37c
H
H
H
H
H
H
H
HH
H
H
H
NH
N OO
36
H
H
H
H H
N
O
N
O O
O
35
HH
H
H
COOH
Ar
O
B, C
COOH
Ar
OCOOH
OAr
COOH
H
O
COOH
O
H H
H
COOH
O
Ar
R
Ar = C6H4Me(p)
Scheme 18
31
When 2-formylbenzoic acid (I) was reacted, 6-(3-oxoisobenzofuran-1-yl)-1,4-epoxyhexa-
hydro-diexo-isoindolo[1,2-b]quinazolin-11-one (35) was obtained because I cyclized with the
diamine, but underwent partial lactonization and the NH group was substituted. The hepta-
cyclic octahydro-1,4-epoxy-8,10-ethanobenz[6,7]indolo[7a,1-b]quinazolin-7-one (36) was
formed in the reaction with methanobenzocyclooctenoxocarboxylic acid (J).17 The adduct K
of trans-3-p-tolylacrylic acid and cyclopentadiene, containing a mixture of the exo-aroylnor-
bornene-endo-carboxylic acid and endo-aroylnorbornene-exo-carboxylic acid, epimerizes to
diendo- and diexo-aroylnorbornenecarboxylic acids in the reaction. Hence, four isoindo-
lo[1,2-b]quinazolinone isomers were expected, and the isolation of three of these succeeded
on column chromatography: the two diexo diastereoisomers, 37a and 37b, and one diendo
isomer, 37c.
In an attempt to gain a rDA product, compounds 30–37 were heated under different
conditions, such as refluxing in chlorobenzene or o-dichlorobenzene, or by heating to the
melting point, but no transformations were detected. These large, high-melting molecules
appear to be thermostable and give no rDA products under such conditions.
3.4.2. Establishment of the structures
The constitutions of the compounds were proved via the IR and NMR spectra. For 30
and 31, similarly to 32a,b, 35, 36 and 37a,b,c the diexo annelation of the oxanorbornene to
perhydropyrimidine follows from the doublet structure of the H-1 signal. This also holds for
the norbornene ring in 37a,b. For 30 and 31, the endo position of the tolyl group was con-
firmed by DIFFNOE measurements. In the cases of 32a and 32b, the orientation of H-5’
changes from equatorial in 32a to axial in 32b. The stereostructures of 32a and 32b are de-
picted in Figure 5.
O
NH
N
O O
NH
N H
H
H
O
32a 32b
H
H
H
H
H
H
1
6
1'
6'
4'
7'
4'5'
5'
H
H
Figure 5
DIFFNOE experiments provided a direct evidence for the endo position of the phenyl group
and H-1 in 33 and 34. The H-1 and H-6 signals confirmed that the norbornane moiety in 33
32
and 34 (and also in norbornene 37c) is diendo. For 35, the constitution was proved by the IR
and NMR data. In the IR spectrum, the γ-lactone and γ-lactam carbonyl bands (at 1761 and
1694 cm–1) are observed in the expected intervals. NOE was not observed between H-1 (and
also H-6) and the diazaketoacetal-H (NCHN). These H atoms lie on opposite side of the mo-
lecular skeleton and the exo orientation of the former may be supposed; consequently, the two
chirality centres have opposite configurations. For 36, the NOE proves sterically close-lying
positions for H-5’ and H-1, together with diexo annelation of the norbornene moiety.
The structures of 37a-c were established by NOE experiments and X-ray crystallography.
37a 37b
37c
Figure 6
3.5. Syntheses of Sedum alkaloid analogues and transformations of norephedrine
The preparation and transformation of 1,3-O,N-heterocycles such as bicyclic oxazi-
nones and oxazolidines are among the main research topics at the Institute of Pharmaceutical
Chemistry. These compounds or their derivatives are frequently encountered in nature. Since
the syntheses of these materials are very often based on the transformation of five- or six-
membered heterocycles with an imine function, this research has led to collaboration with the
research group of Prof. Norbert De Kimpe at the Faculty of Bioscience Engineering, Univer-
33
sity of Ghent. Within that cooperation, I have participated in a project aimed at devising syn-
thetic pathways to produce or transform natural compound analogues.
3.5.1. Syntheses of Sedum alkaloid analoguesIV
The main research initially focused on the synthesis of Pomgranaceae alkaloids. The
original assumption was that the target compound was accessible following a known synthetic
procedure starting from piperidine. The retrosynthetic route is depicted in Scheme 19.
NH
N
N
N
NH
P
O
PhPh
N P
O
PhPh
Boc
N
Boc
N
Scheme 19
The phosphorylated carbamate 40 was prepared in three steps according to literature
methods.142-144 The piperidine was reacted with either tBuOCl or NCS and the resulting N-
chlorinated intermediate was treated with a strong base to furnish compound 38 in moderate
yields (Scheme 20). The 2,3,4,5-tetrahydropyridine (piperideine) trimer obtained was phos-
phorylated with Ph2PH(O), and the amine 39 was then protected by means of (Boc)2O
(Scheme 20).
A. tBuOCl NaOMe
B. NCS KOH/MeOH
45%
33%
75%Ph2PH(O)
Boc2O, TEA
DMAP
80%
N
H
N
N
N
N3
NH Ph
PhP
ON
Ph
PhP
O
38
3940
Boc
Scheme 20
The modified Horner reaction between the phosphorylated carbamate 40 and various
α,β-unsaturated aldehydes or benzaldehyde resulted in enamides 41a-f and 42 in good to ex-
cellent yields (Scheme 21 and Table 4).145 Deprotection of enamide 42 with trifluoroacetic
acid (TFA) in CH2Cl2 afforded 2-benzylpiperideine 43 in excellent yield.
34
N PPh
Ph
O
NPh
NR1
R2
nBuLi,
(R1)(R2)CH=CHCHO
-78°C rt
nBuLi, PhCHO
-78°C rt
40
NPh
43
TFA
81%
BocBoc Boc
41a-f 42 E/Z: 77/23
90%33-68%
Scheme 21
The deprotection method therefore seemed suitable for the preparation of piperideine alka-
loids bearing alkenyl substituents at position 2 [e.g. 2-(2’-propenyl)-1-piperideine (R1 = R2 =
H), an alkaloid in Punica granatum (see I) and related alkaloids (II-IV) (Figure 6)].146
N
I
N
II
NHIII
NH
IV
N Ph
OH
V
2-(2-Propenyl)-piperidine
Nigrifactin α-Conicein β-Conicein 1-Phenyl-2-(3,4,5,6-tetrahydropyridine-2-
yl)ethanol
Figure 7
The results of modified Horner reactions are presented in Table 4. In every case, predomi-
nantly the E isomers were formed. In the cases of 41c (R1 = methyl) and 41f (R1 = p-
methoxyphenyl), only the E isomer was obtained. The yields were established after flash
chromatography on silica.
Table 4
Compound R1 R2 Yield (%) E/Z
41a H H 47 67/33 41b Me H 54 86/14 41c Me Me 60 100/0 41d iPr H 53 92/8 41e Ph H 68 76/24 41f C6H4OMe(p) H 33 100/0
To obtain Pomgranaceae alkaloid analogues 44a-c, removal of the protecting group of
compounds 38a-c was first attempted with inorganic acids such as HCl or H2SO4. In all cases,
decomposition of the starting materials was detected. Deprotection was also unsuccessful ei-
ther when TFA was used in the presence of thioanisol or thiophenol, or microwave-assisted
solvent-free thermolysis on SiO2 was applied. In each case, only a complex reaction mixture
was observed. When mild condition and reagents were used, e.g. trimethylsilyl chloride
(TMSCl) or trimethylsilyl iodide (TMSI) itself or with phenol, conversion was detected
35
(Scheme 22). TMSCl and phenol (1:3) were first used as deprotecting agent, in accordance
with the literature reports.147 This method seemed effective and conversion was observed, but
the reaction time was 1 day, and instead of dienes 44a-c, unsaturated bicyclic carbamates 45a-
f were formed. To improve the efficiency of this protocol, enamides 41a-f were reacted with
TMSI and phenol in a ratio of 1:1 and the reaction time was reduced to 30 min; under these
conditions, acceptable yields (41-70%) were achieved (Scheme 22).
N
Boc
R1
R2N O
O
R1
R2
41a-f (E,E) and (Z,E)
NR1
R2
45a-f44a-c
deprotectiontechniques
1. TMSI/phenol2. NaOH
41-70%
Scheme 22
The possible reaction mechanism is shown in Scheme 23. The combination of TMSI
and phenol leads to the formation of trimethylsilyl phenoxide147 with the liberation of HI. In
this medium, the Boc group was cleaved with the expulsion of isobutene, and the resulting
oxygen anion underwent intramolecular trapping by an iminium species formed in situ due to
the presence of HI. It should be noted that the double bond shifts from its initial position in
the carbamate ring to the piperidine ring.
H+
H+N
R1
R2O
Me
O
OSi
NR1
R2O OMe
MeMe
SiMe
MeMe
NR1
R2O O
SiMe
Me
Me
NR1
R2O O
SiMe Me
Me
OH-
45a-f
N
OO
SiMeMe
R1
R2
Me
N
OOR1
R2
N
OOR1
R2
H
N
OOR1
R2
H
N
OOR1
R2
H+
Me
Me
Me
MeMe
Scheme 23
The obtained yields of derivatives 45a-f are listed in Table 5.
36
Table 5
Compounds R1 R2 Yield (%)
45a H H 41 45b Me H 52 45c Me Me 60 45d iPr H 48 45e Ph H 70 45f C6H4OMe(p) H 46
The first efforts to open unsaturated bicyclic carbamates 45a-e into 1,3-aminoalcohols
(analogues of V; Figure 7) were not successful. Neither N-methyl-substituted derivatives 46a-
e nor aminoalcohols 47A (a-e), 47B (a-e) could be synthetized (Scheme 24).
45a-e46
N
OOR1
R2
A. KOH/MeOH,EtOH or H2O
B. TFA
NH
OH
R1
R2N
OH
R1
R2Me
LiAlH4
47A (a-e)
N
OH
R1
R2
47B (a-e)
Scheme 24
When unsaturated bicyclic carbamates 45a and 45b were reduced either with NaCNBH3 or
with NaBH4, a mixture of diastereomers [48a (cis/trans = 86/14) and 48b (cis/trans = 88/12)]
was obtained. NOESY experiments demonstrated that the major component was the cis iso-
mer in each case. Reduction of 45c with NaBH4 in glacial AcOH resulted in only the cis com-
pound 48c. Afterwards, 48a and 48b were reduced by means of LiAlH4, resulting in racemic
Sedum alkaloids such as (2R*,2’S*)-N-methylallosedridine 49a and (2R
*,2’S*)-1-(1-methyl-
piperidin-2-yl)butan-2-ol 49b after purification by column chromatography (Scheme 25).148
N
OOR
N
Me
OH
RN
OOR
H
N
OOR
H
+
45a-c cis-48a-c trans-48a-c 49a,b
Na(CN)BH3/AcOH
LiAlH4
NaBH4/AcOH
80% (R = H)95% (R = Et)50% (R = Ph)
80% (R = Et)76% (R = Ph)
60-65%H H
Scheme 25
37
3.5.2. Transformations of chiral norephedrinesV
In this field of my research work, the electrophile-induced cyclization149 of alkenyl
1,3-oxazolidines derived from chiral norephedrines (natural 1,2-aminoalcohols) and transfor-
mation of the resulting γ-lactams were performed.
The syntheses of the chiral 3-(3-butenyl)-1,3-oxazolidines 54 and 55 were
accomplished by two methods. The starting materials (1R,2S)- (50) and (1S,2R)-norephedrine
(51) were acylated with 4-pentenoyl chloride150 in CH2Cl2 in the presence of TEA, resulting
in amides 52 and 53. The ring closure of the hydroxyamides 52 and 53 was performed by
reflux in toluene in the presence of a catalytic amount of PTSA, which afforded oxazoline
derivatives 54 and 55 in good yields. In an alternative method, chiral oxazolines 54 and 55
were obtained directly in one-step syntheses by the reaction of norephedrine and 3-butenoic
acid in toluene under reflux in the presence of a catalytic amount of PTSA. However, the
yields of the 2-oxazolines 54 and 55 were then much lower as compared with the two-step
procedure. Treatment of 2-oxazolines 54 and 55 with Br2 or with I2 resulted in pyrrolidinones
56-63 as a 50:50 (X = Br) or 57:43 (X = I) mixture of diastereomers (Schemes 26 and 27).
OHPh
NH2Me
OHPh
NH
Me
O
N
OPh
Me
OHPh
NMe
O
X OHPh
NMe
O
X
(R)
(S)
(R)
(S)
(S)
(R)
(R)+
52
545660
5761
X = BrX = I
50
N
OPh
Me
(R)
(S)N
OPh
Me
(R)
(S)
X
H2O
1.1. equiv. 4-pentenoyl chloride1.1.equiv. TEA
90%
1 equiv. 3-butenoic acid PTSA
43% ∆∆
86%
1.1 equiv. Br2, 56%
or 3 equiv. I2, 77%
X
Scheme 26
The 1S,2R-norephedrine 51 was also transformed into lactams 58, 59, 62 and 63 via a three-
step protocol (Scheme 27).
38
OHPh
NH2Me
(S) OHPh
(R) NH
Me
O
(S)
(R) N
OPh
Me
(S) OHPh
(R) NMe
O
X OHPh
NMe(S)
O
X
+
53
555862
5963
X = BrX = I
51
1.1. equiv. 4-pentenoyl chloride1.1.equiv. TEA
57%
1 equiv. 3-butenoic acid PTSA
45% ∆∆
83%
1.1 equiv. Br2, 53%
or 3 equiv. I2, 74%
Scheme 27
The electrophile-induced cyclization of 2-(3-butenyl)oxazolines 54 and 55 was highly regio-
selective, but less diastereoselective, and only the formation of five-membered ring products
was observed. The diastereoisomeric γ-lactams 56 and 57 were easily separated by column
chromatography, resulting in one isomer in a crystalline form which was suitable for X-ray
diffraction analysis. Accordingly, this X-ray diffraction analysis revealed the structure of γ-
lactam 56 as (R)-5-bromomethyl-1-[(1R,2S)-1-hydroxy-1-phenylpropan-2-yl]pyrrolidin-2-one
(Figure 8). The diastereomeric ratio was determined by 1H NMR, and the relative stereo-
chemistry of the oily product 57 was established by NOESY.
Figure 8
The cyclization of (4S,5R)-2-oxazoline 54 was also attempted with PhSeBr in CH2Cl2.
However, only an unseparable mixture of compounds was obtained. Under similar conditions,
the intermediate amide 52 underwent an electrophile-induced lactonization instead of the
expected lactamization.149 The iminolactone 64 obtained decomposed upon chromatographic
purification on silica gel. When 64 was stirred with SiO2 in CH2Cl2, the known151 racemic
lactone 65 was obtained in 95% yield (Scheme 28).
39
N
OPh
Me
(R)
(S)
54
OHPh
NMe (S)
(R)
O SePh OO
SePhPhSeBr
90%
64 65
SiO2
95%
Scheme 28
The synthesis of pyrrolo[2,1-c][1,4]oxazines 66 from γ-lactams 56 and 60 by cycliza-
tion with bases such as NaOMe or NaH failed. The latter bicyclic morpholines 66 could be
suitable precursors of stereodefined 2,3,5-trisubstituted morpholines. Such compounds have
received considerable interest in recent years.152 However, γ-lactams 56 and 60 underwent
ring closure to yield pyrrolo[2,1-b]oxazol-5-one 67 in a diastereoselective fashion instead of
the expected pyrrolo[2,1-c][1,4]oxazine 66 (Scheme 29).
OHPh
NMe
O
X
N
O
O
MePh
Me
HOHPh
NMe
O
OHPh
NMe
O
X
NaH
-HH
-X
N
O
O
Ph
Me
H
67
Scheme 29
Bicyclic compound 67 was also prepared in 80% yield by an alternative synthesis via
tandem cyclization of (1R,2S)-norephedrine 50 with levulinic acid (Scheme 30).
OHPh
NH2Me
OHPh
(S) NMe
O
X
56,60
50
N
OPh
Me
O
(R)
(S) N
O
O
MePh
Me
6766
COOH
O
Me
NH
O
Me
COOHPh
Me
OHPh
NMe
Me
COOH68a 68b
NH
OPh
Me
Me
COOH
68c
(R)
(R)
(S)(R)
(S)
(R)
(R)
(S)
Scheme 30
40
This reaction is highly stereoselective as only a single diastereomer was detected in
the crude reaction mixture. The stereochemical outcome of this cyclization was also corre-
lated with Meyer’s work.153 The first step of the cyclocondensation process is the reaction of
norephedrine with the γ-ketoacid, resulting in a three-component tautomeric mixture.154,155
From the tautomeric mixture, only intermediate 68c is a suitable participant for the second
cyclization step to result in (2R,3S,7aS)-3,7a-dimethyl-2-phenylpyrrolo[2,1-b]oxazol-5(6H)-
one (67) (Scheme 30).
41
4. Summary
The preparation of 62 new compounds has been discussed.
From the reactions of pyrazole aminocarboxylic hydrazides 1 and diexo-oxanorbornene-
diamine 14 with γ- and δ-oxocarboxylic acids, N,N-heterocycles such as pyrazolo[3,4-d]pyri-
midino[5,6-b]phthalazines, pyrazolo[3,4-d]pyrimido[5,6-b]pyridazinones 2-6, pyrrolo[2,1-b]-
and isoindolo[1,2-b]quinazolines 30-37 were synthetized. When the starting pyrazole amino-
carbohydrazide was modified by acylation, it underwent a special ring closure involving hy-
drazide elimination and resulted in a pyrazoloazepine 7. Starting from maleic anhydride and
furan, 5,6-dehydronorcantharidin was prepared. Ammonolysis and Hoffman degradation af-
forded diexo-oxabicyclo[2.2.1]hept-5-ene amino acid 11, from which the corresponding dia-
mine 14 was prepared. With oxoacids, isoindolone derivatives 30-37 were obtained by cyclo-
condensation. For 37a-c, diastereoisomers were separated: for 37a and 37b, X-ray examina-
tions revealed that the oxanorbornene and norbornene moieties are in the diexo position and
the diastereoisomers differ in the positions of the epoxy group and methylene bridge. In 37a,
the situation is the opposite and there is a “head-foot” structure, while in 37b, the epoxy and
methylene groups are in the same position and exhibit a “head-head” structure. In 37c, the
norbornene is diendo and the oxanorbornene is diexo, and there is a “head-foot” position. β-
Amino acid 11 was applied for the U-4C-3CR in pure water and MeOH, to study the solution
effect. In this, β-lactam derivatives 15-24 were obtained and the yields, diastereoselectivities
and reaction times were compared. With water as solvent, the yields were found to those in
MeOH. The diastereoselectivity was also similar or better in some cases, and excellent di-
astereoselectivity could be observed for 17. The advantage of water was that compounds 16-
22 and 24 were precipitated in good yields and good purities, and thus the use of organic sol-
vent was not necessary.
A new synthetic route was devised for the synthesis of bicyclic carbamates such as 1,3-O,N-
heterocycles 45a-f. In the final step, the intramolecular cyclization was carried out under mild
conditions instead of with strong electrophilic reactants such as NBS or NIS. The subsequent
hydrogenation of the unsaturated bicyclic carbamates and ring opening resulted in the racemic
Sedum alkaloids 49a and 49b, in good yields. The electrophile-induced cyclization was also
carried out from enantiopure (+)- or (-)-norephedrines. From the chiral oxazolines 54 and 55,
new chiral 1,5-disubstituted pyrrolidinones 56-63 were obtained. The cyclocondensation of 5-
halomethyl-γ-lactams resulted in good yields of bicyclic lactam 67, containing a tetrahydro-
pyrrolo[2,1-b]oxazole skeleton. This molecule was alternatively prepared in high yields via
the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.
42
5. References
1. G. Bernáth, G. Stájer, F. Fülöp, P. Sohár, J. Heterocycl. Chem. 37, 439 (2000)
2. G. Bernáth, Bull. Soc. Chim. Belg. 130, 509 (1994)
3. I. Dell’Aica, L. Sartor; P. Galletti, D. Giacomini, A. Quintavalla, F. Calabrese; C.
Giacometti, E. Brunetta, F. Piazza, C. Agostini, S. Garbisa, J. Pharm. Exp. Therap.
316, 539 (2006)
4. G. Stájer, F. Csende, F. Fülöp, Curr. Org. Chem. 7, 1423 (2003)
5. L. A. Paquette (Ed.), Organic Reactions, Vol. 52, p. 27 Wiley, New York, (1998)
6. M. Bortolussi, R. Bloch, A. Loupy, J. Chem. Res. (S) 34 (1998)
7. M. Bortolussi, Ch. Cinquin, R. Bloch, Tetrahedron Lett. 37, 8729 (1996)
8. G. Stájer, F. Miklós, I. Kanizsai, F. Csende, R. Sillanpää, P. Sohár Eur. J. Org.
Chem. 3701 (2004)
9. F. Csende, G. Stájer, Heterocycles 53, 6 (2000)
10. F. Csende, Acta Chim. Sloven. 49, 663 (2002)
11. F. Csende, G. Stájer, Heterocycles 57, 1353 (2002)
12. L. F. Fieser, F. C. Novello, J. Am. Chem. Soc. 64, 802 (1942)
13. W. V. Curran, A. Ross, J. Med. Chem. 27, 273 (1974)
14. P. Sohár, G. Stájer, A. E. Szabó, F. Fülöp, J. Szúnyog, G. Bernáth, J. Chem. Soc.,
Perkin Trans. 2 599 (1987)
15. G. Stájer, A. E. Szabó, G. Bernáth, P. Sohár, Heterocycles 38, 1061 (1994)
16. P. Sohár, G. Stájer, G. Bernáth, Magn. Reson. Chem. 25, 856 (1987)
17. F. Miklós, F. Csende, G. Stájer, P. Sohár, R. Sillanpää, G. Bernáth, J. Szúnyog, Acta
Chem. Scand. 52, 322 (1998)
18. D. Bortwick, D. J. Curry, A. Poynton, W. B. Whalley, J. W. Hooper, J. Chem. Soc.,
Perkin Trans. 1 2435 (1980)
19. P. Sohár, G. Stájer, A. E. Szabó, G. Bernáth, J. Mol. Struct. 382, 187 (1996)
20. K. D. Klika, P. Tähtinen, M. Dalhquist, J. A. Szabó, G. Stájer, J. Sinkkonen, K.
Pihlaja, J. Chem. Soc., Perkin Trans. 2 687 (2000)
21. G. Stájer, A. E. Szabó, F. Csende, G. Argay, P. Sohár, J. Chem. Soc., Perkin Trans. 2
657 (2002)
22. S. Frimpong-Manso, K. Nagy, G. Stájer, G. Bernáth, P. Sohár, J. Heterocycl. Chem.
29, 221 (1992)
43
23. F. Miklós, P. Sohár, A. Csámpai, R. Sillanpää, M. Péter, G. Stájer, Heterocycles 57,
2309 (2002)
24. M. D. Groaning, A. I. Meyers, Tetrahedron 56, 9843 (2000)
25. M. Amat, M. Canto, N. Llor, V. Ponzo, M. Perez, J. Bosch, Angew. Chem. Int. Ed.
41, 335 (2002)
26. M. Amat, M. Perez, N. Llor, M. Martinelli, E. Molins, J. Bosch, Chem. Commun.
1602 (2004); M. Amat, N. Llor, J. Hidalgo, C. Escolano, J. Bosch, J. Org. Chem. 68,
1919 (2003)
27. F. Csende, G. Stájer, Curr. Org. Chem. 9, 1261 (2005)
28. V. Pestellini, M. Gherlardoni, C. Bianchini, A. Liquori, Boll. Chim. Pharm. 117, 54
(1978)
29. L. A. Schemchuk, V. P. Chernykh, I. L. Ivanova, E. L. Snitkovskii, M. V. Zhirov, A.
V. Turov, Zh. Org. Khim. 35, 286 (1999)
30. V. Balasubramaniyan, N. P. Argade, Ind. J. Chem. 27B, 906 (1988)
31. G. Bernáth, F. Miklós, G. Stájer, P. Sohár, Z. Bölcskei, D. Menyhárd, J. Heterocycl.
Chem. 35, 201 (1998)
32. F. Schwender, B. R. Sunday, J. J. Kerbleski, D. J. Herzig, J. Med. Chem. 23, 964
(1980)
33. T. Kappe, J. Heterocycl. Chem. 36, 1111 (1998)
34. D. Csányi, G. Hajós, G. Timár, Z. Riedl, A. Kotschy, T. Kappe, L. Párkányi, O.
Egyed, M. Kajtár-Peredy, S. Holly, Eur. J. Org. Chem. 133 (2002)
35. M. Razvi, T. Ramalingam, P. B. Sattur, Indian J. Chem. 29B, 399 (1990)
36. V. Pestellini, M. Gherlardoni, G. Volterra, P. Soldato, Eur. J. Med. Chem. 13, 296
(1978)
37. P. Sohár, F. Miklós, A. Csámpai, G. Stájer, J. Chem. Soc., Perkin Trans. 1 558
(2001)
38. F. Miklós, G. Stájer, P. Sohár, Z. Bölcskei, Synlett 67 (2000)
39. A. Santagati, M. Santagati, M. Modica, F. Russo, Heterocycles 34, 923 (1992); A.
Santagati, M. Santagati, F. Russo, J. Heterocycl. Chem. 28, 545 (1991)
40. G. Stájer, A. E. Szabó, G. Túrós, P. Sohár, R. Sillanpää, Eur. J. Org. Chem. 4154
(2005)
41. G. Stájer, F. Miklós, P. Sohár, R. Sillanpää, Eur. J. Org. Chem. 4153 (2001)
42. G. Stájer, A. E. Szabó, A. Csámpai, P. Sohár, Eur. J. Org. Chem. 1318 (2004)
43. P. Aeberli, W. J. Houlihan, J. Org. Chem. 33, 2402 (1968)
44
44. P. Aeberli, W. J. Houlihan, J. Org. Chem. 34, 165 (1969)
45. P. Lonvet, F. Thomasson, C. Luu-Duc, J. Heterocycl. Chem. 31, 39 (1994)
46. A. Chimirri, S. Grasso, P. Monforte, G. Romeo, M. Zappalá, Heterocycles 36, 865
(1993)
47. F. Csende, G. Bernáth, Zs. Böcskei, P. Sohár, G. Stájer, Heterocycles 45, 323 (1997)
48. J. F. Pilard, B. Klein, F. T. Boullet, J. Hamelin, Synlett 219 (1992)
49. G. Stájer, F. Csende, G. Bernáth, P. Sohár, Heterocycles 37, 883 (1994)
50. A. E. Szabó, G. Stájer, P. Sohár, R. Sillanpää, G. Bernáth, Acta Chem. Scand. 49,
751 (1995)
51. P. Sohár, G. Stájer, A. E. Szabó, A. E. Szabó, J. Szúnyog, G. Bernáth, Heterocycles
48, 175 (1998)
52. G. Stájer, R. Sillanpää, K. Pihlaja, Acta Chem. Scand. 48, 603 (1994)
53. P. Sohár, G. Stájer, A. E. Szabó, G. Bernáth, J. Mol. Struct. 382, 187 (1996)
54. G. Stájer, A. E. Szabó, F. Csende, G. Argay, P. Sohár, J. Chem. Soc., Perkin Trans. 2
657 (2002)
55. P. Sohár , A. Csámpai, G. Magyarfalvi, A. E. Szabó, G. Stájer, Monatsh. Chem. 135,
1519 (2004)
56. F. Miklós, G. Stájer, P. Sohár, G. Bernáth, R. Sillanpää, Heterocycles 48, 1407
(1998)
57. F. Miklós, A. Hetényi, P. Sohár, G. Stájer, Monatsh. Chem. 135, 839 (2004)
58. F. Miklós, I. Kanizsai, S. Thomas, E. Kleinpeter, R. Sillanpää, G. Stájer,
Heterocycles 63, 63 (2004)
59. D. J. Ramón M., Yus, Angew. Chem. Int. Ed. 44, 1602 (2005)
60. A. Dömling, Chem. Rev. 106, 17 (2006)
61. H. Bock, I. Ugi, J. Pract. Chem. 339, 385 (1997)
62. V. G. Nenajdenko, A. V. Gulevich, E. S. Balenkova, Tetrahedron 62, 5922 (2006)
63. A. Basso, L. Banfi, R. Riva, G. Guanti, Tetrahedron Lett. 45, 587 (2004)
64. A. Basso, L. Banfi, R. Riva, G. Guanti, J. Org. Chem. 70, 575 (2005)
65. A. Clemente, A. Domingos, A. P. Grancho, J. Iley, R. Moreira, J. Neres, N. Palma,
A. B. Santana, Bioorg. Med. Chem. Lett. 11, 1065 (2001); I. Dell'Aica, L. Sartor, P.
Galletti, D Giacomini., A. Quintavalla, F. Calabrese, C. Giacometti, E. Brunetta, F.
Piazza; C Agostini. S. Garbisa, J. Pharm. Exp. Therapeutics 316, 539 (2006); R.
Moreira, A. B. Santana; J. Iley, J. Neres, K. T. Douglas; P. N. Norton.; M. B. Hurst-
house, J. Med. Chem. 48, 4861 (2005)
45
66. S. Gedey, J. Van der Eycken, F. Fülöp, Org. Lett. 4, 1967 (2002)
67. S. Gedey, P. Vainiotalo, I. Zupkó, P. A. A. De Witte, F. Fülöp, J. Heterocycl. Chem.
40, 951 (2003)
68. S. Gedey, J. Van der Eycken, F. Fülöp, Lett. Org. Chem. 1, 215 (2004)
69. C.-J. Li, L. Chen, Chem. Soc. Rev. 35, 68 (2006)
70. C.-J. Li, Chem. Rev. 105, 3095 (2005)
71. C.-J. Li, Chem. Rev. 93, 2023 (1993)
72. Y. Masaki, K. Yamazaki, H. Kawai, T. Yamada, A. Itoh, Y. Arai, H. Furukawa,
Chem. Pharm. Bull. 54, 591 (2006); T. P. Loh, S. B. K. W. Liung, K.-L. Tan, L.-L.
Wei, Tetrahedron 56, 3227 (2000); N. Azizi, L. Torkiyan, M. R. Saidi, Org. Lett. 8,
2079 (2006)
73. A. K. Bose, M. S. Manhas, S. Pednekar, S. N. Ganguly, H. Dang, W. He, A. Man-
dadi, Tetrahedron Lett. 46, 1901 (2005)
74. M. A. Mironov, M. N. Ivantsova, M. I. Tokarewa, V. S. Mokrushin, Tetrahedron
Lett. 46, 3957 (2005)
75. M. C. Pirrung, K. D. Sarma, J. Am. Chem. Soc. 126, 444 (2004)
76. M. C. Pirrung, Eur. J. Chem. 12, 1312 (2006)
77. M. C. Pirrung, K. D. Sarma, Tetrahedron 61, 11456 (2005)
78. M. C. Pirrung, K. D. Sarma, Synlett 1425 (2004)
79. M. A. Mironov, M. N. Ivantsova, V. S. Mokushin, Mol. Divers. 6, 193 (2003)
80. J. F. Stevens, H. T. Hart, H. Hendriles, T. M. Malique, Phytochemistry 31, 3917
(1992)
81. J. H. Kim, H. T. Hart, J. F. Stevens, Phytochemistry 41, 1319 (1996)
82. O. Meth-Conh, C.-Y. Yu, P. Lestage, M.-C. Lebrum, D.-H. Cagniard, P. Renard,
Eur. Pat. 1050531 (2000)
83. R. W. Bates, K. Sa-Ei, Tetrahedron 58, 5957 (2002); B. Kang, S. Chang, Tetrahe-
dron 60, 7353 (2004)
84. T. Shono, Y. Matsumura, K. Tsubata, K. Uchida, J. Org. Chem. 51, 2590 (1986); H.
Suzuki, S. Aoyagi, C. Kibayashi, J. Org. Chem. 60, 9115 (1995)
85. D. Passarella, A. Barilli, F. Belinghieri, P. Fassi, S. Riva, A. Sacchetti, A. Silvani, B.
Danieli, Tetrahedron: Asymmetry 16, 2225 (2005)
86. J. J. Tufariello, S. A. Ali, Tetrahedron Lett. 47, 4647 (1978); S.-I. Murahashi, Y.
Imada, M. Kohno, T. Kawakami, Synlett 395 (1993); R. W. Bates, J. Boonsonbat,
Org. Biomol. Chem. 3, 520 (2005)
46
87. T. Wakabayashi, K. Watanabe, Y. Kato, M. Saito, Chem. Lett. 223 (1977); S. G.
Pyne, P. Bloem, S. L. Chapman, C. E. Dixon, R. Griffith, J. Org. Chem. 55, 1086
(1990)
88. S. Raghavan, A. Rajender, Tetrahedron 60, 5059 (2004)
89. D. L. Comins, H. J. Hong, J. Org. Chem. 58, 5035 (1993)
90. S. Mill, C. Hootelé, Can. J. Chem. 74, 2434 (1996)
91. T. Uyehara, N. Chiba, I. Suzuki, Y. Yamamoto, Tetrahedron Lett. 32, 4371 (1991)
92. E. Akiyama, M. Hirama, Synlett 100 (1996)
93. S. Brocherieux-Lanoy, H. Dhimane, J.-C. Poupon, C. Vanucci, G. Lhommet, J.
Chem. Soc., Perkin Trans.1 2163 (1997)
94. C. Agami, F. Couty, Tetrahedron 58, 2701 (2002)
95. K. A. Parker, R. O’Fee, J. Am. Chem. Soc. 105, 654 (1982); J. M. Jorda-Gregory, M.
E. Gonzales-Rosende, P. Cava-Montesinos, J. Sapulveda-Arques, R. Galeazzi, M.
Orena, Tetrahedron: Asymmetry 11, 3769 (2000)
96. R. J. DeVita, M. T. Goulet, M. W. Wyvratt, M. H. Fishner, J. L. Lo, Y. T. Yang, K.
Cheng, R. G. Smith, Bioorg. Med. Chem. Lett. 9, 2621 (1999)
97. B. T. Schaneberg, S. Crockett, E. Bedin, I. A. Khan, Phytochemistry 62, 911 (2003)
98. M. S. Som, I. G. Carabin, J. C. Griffiths, G. A. Burdock, Toxicology Lett. 150, 97
(2004)
99. E. A. Carlini, Pharm. Biochem. Behav. 75, 501 (2003)
100. M. A. H. Ismail, M. N. Y. Aboul-Enein, K. A. M. Abonzid, R.-A. T. Serya, Bioorg.
Med. Chem. 14, 898 (2006)
101. H. Yu, R. B. Rothman, C. M. Dersch, J. S. Partille, K. C. Rice, Bioorg. Med. Chem.
8, 2689 (2000)
102. M. Osorio-Oliveres, M. C. Rezende, S. Sapulveda-Boza, B. K. Cassels, A. Fierro,
Bioorg. Med. Chem. 12, 4055 (2004)
103. M. D. Goodyear, M. L. Hill, J. P. West, A. J. Whitehead, Tetrahedron Lett. 46, 8535
(2005); K. W. Kells, N. H. Nielsan, R. J. Armstrong-Chong, J. M. Chong, Tetrahe-
dron 58, 10287 (2002)
104. M. B. Ambrus, E. L. Meredith, B. L. Simmons, B. B. V. Soma Sekhar, E. J. Hicken,
Org. Lett. 4, 3549 (2002); M. B. Andrus, E. L. Meredith, E. J. Hicken, B. L. Sim-
mons, R. R. Glancey, W. Ma, J. Org. Chem. 68, 8162 (2003)
105. B. W. Day, C. O. Kangari, K. S. Avor, Tetrahedron: Asymmetry 13, 1161 (2002)
106. J. Hong, J. D. White, Tetrahedron 60, 5653 (2004)
47
107. G. S. Basarab, D. B. Jordan, T. C. Gehret, R. S. Schwarts, Z. Wawrzak, Bioorg. Med.
Chem. Lett. 9, 1613 (1999); G. S. Basarab, D. B. Jordan, T. C. Gehret, R. S.
Schwarts, Bioorg. Med. Chem. 10, 4143 (2002)
108. C. G. Frost, P. Mendoca, Tetrahedron: Asymmetry 11, 1845 (2000); A. J. Sandee, D.
G. I. Petra, J. N. H. Reek, P. C. J. Kamer, P. W. N. M. van Leenwen, Chem. Eur. J.
7, 1202 (2001); X. Cheng, P. N. Horton, M. B. Hursthouse, K. V. Hii, Tetrahedron:
Asymmetry 15, 2241 (2004); S. Bastin, R. J. Eaves, C. W. Edwards, O. Ichihara, M.
Whittaker, M. Wills, J. Org. Chem. 69, 5405 (2004); A. S. Y. Yim, M. Wills, Tetra-
hedron 61, 7994 (2005)
109. J. F. Vaughn, S. R. Hitchcock, Tetrahedron: Asymmetry 15, 3449 (2004); S. R.
Hitchcock, D. M. Casper, J. F. Vaughn, J. M. Finefield, G. M. Ferrence, J. M. Esken,
J. Org. Chem. 69, 714 (2004)
110. G. Blay, I. Fernandez, A. Marco-Alexandre, J. R. Pedeo, Tetrahedron: Asymmetry
16, 1207 (2005)
111. Y. Wu, H. Ynu, Y. Wu, K. Ding, Y. Zhou, Tetrahedron: Asymmetry 11, 3543 (2000)
112. T. Hayase, T. Sugiyama, M. Suzuki, T. Shibata, K. Soai, J. Fluor. Chem. 84, 1
(1997)
113. P. C. Brookes, D. J. Milne, P. J. Murphy, B. Spolaore, Tetrahedron 58, 4675 (2002);
M. Abedjkonh, D. Pettersen, S. O. Nilcson Lill, Ö. Davidsson, P. Ahlberg, Chem.
Eur. J. 7, 4368 (2001); S. E. de Sousa, P O’Brien, H. C. Steffens, Tetrahedron Lett.
40, 8423 (1999); S. J. Oxenburg, P. O’Brien, M. R. Shipton, Tetrahedron Lett. 45,
9053 (2004)
114. A. S. Demir, Ö. Sesenoglu, H. Aksoy-Cam, H. Kaye, K. Aydongan, Tetrahedron:
Asymmetry 14, 1335 (2004); M. Ortiz-Marciales, E. Gonzales, M. De Jesus, S.
Espinosa, W. Correa, J. Martinez, R. Figueroa, Org. Lett. 5, 3447 (2003); V. Ste-
panko, M. Ortiz-Marcialez, W. Correa, M. De Jesus, S. Espinosa, L. Ortu, Tetrahe-
dron: Asymmetry 17, 112 (2006); M. P. Krzeminski, M. Zaidlewitz, Tetrahedron:
Asymmetry 14, 1463 (2003)
115. Z. Han, D. Krishnamurty, P. Grover, Q. K. Fang, X. Su, H. S. Wilkinson, Z.-H. Lu,
D. Magiera, C. H. Senanayake, Tetrahedron 61, 6386 (2005)
116. H. Pellisier, Tetrahedron 62, 1619 (2006)
117. R. Somanathan, H. R. Aguilar, I. A. Rivero, G. Aguirre, L. H. Hellberg, Z. Yu, J. A.
Thomas J. Chem. Res. (M) 348 (2001)
118. M. García-Valverde, R. Pedrosa, M. Vicente, Tetrahedron 52, 10761 (1996)
48
119. J. A. Ragan, M. C. Claffey, Heterocycles 41, 57 (1995)
120. C. Agami, F. Couty, G. Evano, Tetrahedron: Asymmetry 11, 4639 (2000)
121. T. Tite, M.-C. Lallemand, E. Poupon, N. Kunesch, F. Tillequin, C. Gravier-Pelletier,
Y. Le Merrer, H.-P. Husson, Bioorg. Med. Chem. 12, 5091 (2004)
122. A. B. Bahajaj, M. H. Moore, J. M. Vernon, Tetrahedron 60, 1235 (2004)
123. A. I. Meyers, S. V. Downing, M. J. Weiser, J. Org. Chem. 66, 1413 (2001)
124. K. C. Majumdar, S. Ghosh, M. Ghosh, Tetrahedron 59, 7251 (2003)
125. P. Schmidt, I. Druey, Helv. Chim. Acta. 39, 986 (1956); A. Dorrow, E. Hinz Chem.
Ber. 91, 1839 (1958)
126. A. J. Peat, D. Garrido, J. A. Boucheron, S. L. Schweicker, S. H. Dickerson, J. R.
Wilson, T. Y. Wang, S. A. Thomson, Bioorg. Med. Chem. Lett. 14, 2127 (2004)
127. M. Backlund, M. Ingelman-Sundberg, Cell Signal. 17, 39 (2005)
128. F. Carlomagno, D. Vitagliano, T. Guida, F. Basolo, M. D. Castellone, R. M. Melillo,
A. Fusco, M. Santoro, J. Clin. Endocrinol. Metab. 88, 1897 (2003)
129. J. A. Markwalder, M. R. Arnone, P. A. Benfield, M. Boisclair, C. R. Burton, C. H.
Chang, S. S. Cox, P. M. Czerniak, C. L. Dean, D. Doleniak, R. Graftsrom, B. A.
Harrison, R. F. Kaltenbach, D. A. Nugiel, K. A: Rossi, S. R. Sherk, L. M. Sisk, P.
Stouten, G. L. Trainor, P. Worland, S. P. Seitz, J. Med. Chem. 47, 5894 (2004)
130. O. Moukha-Chafiq, M. L. Taha, H. B. Lazrek, J. J. Vassuer, E De Clercq,
Nucleosides Nucleotides Nucleic Acids 21, 165 (2002)
131. S. Guccione, M. Modica, J. Longmore, D. Shaw, G. U. Barretta, A. Santagati, M.
Santagati, F. Russo, Bioorg. Med. Chem. Lett. 6, 59 (1996); M. Chebib, R. J. Quinn,
Bioorg. Med. Chem. 5, 311 (1997); N. P. Peet, N. L. Lentz, S. Sunder, M. W.
Dudley, A. M. L. Ogden, J. Med. Chem. 35, 3263 (1992)
132. E. R. El-Bendary, F. A. Badria, Arch. Pharm. Pharm. Med. Chem. 333, 99 (2000)
133. A. McCluskey, C. Taylor, R. J. Quinn, M. Suganuma H. Fujiki, Bioorg. Med. Chem.
Lett. 6, 1025 (1996)
134. M. Sodeoka, Y. Baba, S. Kobayashi, N. Hirukawa. Bioorg. Med. Chem. Lett. 7, 1833
(1997)
135. A. McCluskey, C. Walkom, M. C. Bowyer, S. P. Ackland, E. Gardiner, J. A. Sakoff,
Bioorg. Med. Chem. Lett. 11, 2941 (2001)
136. Y. Baba, N. Hirukawa, M. Sodeoka, Bioorg. Med. Chem. 13, 5164 (2005)
137. F. L. Liu, T. Jiang, D. S. Zuo, X. Qi , X. L. Zhan, Chin. J. Org. Chem. 22, 761
(2002)
49
138. L. P. Deng, F. M. Liu, H. Y. Wang, J. Heterocycl. Chem. 42, 13 (2005)
139. S. H. Kok, S. J. Cheng, C. Y. Hong, J. J. Lee, S. K. Lin, Y. S. Kuo, C. P. Chiang, M.
Y. P. Kuo, Cancer Lett. 217, 43 (2005)
140. M. E. Hart, R. E. Chamberlain, C. Walkom, J. A. Sakoff , A. McCluskey, Bioorg.
Med. Chem. Lett. 14, 1969 (2004)
141. I. Kanizsai, S. Gyónfalvi, Z. Szakonyi, F. Fülöp, R. Sillanpää, Green Chem. (2007)
accepted for publication
142. N. De Kimpe, C. Stevens, J. Org. Chem. 58, 2904 (1993)
143. R. C. Miller, J. Chem. Soc., Perkin Trans. 1 2013 (1959)
144. A. Couture, E. Deniau, P. Grandclaudon, S. Lebrun, S. Léonce, P. Renard, B. Pfeif-
fer, Bioorg. Med. Chem. 8, 2113 (2000)
145. S. Lebrun, A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron 55, 2659 (1999)
146. M. F. Roberts, B. T. Cromwell, D. E. Webster, Phytochemistry 6, 711 (1967)
147. E. Kaiser, J. P. Tam, T. M. Kubiak, R. B. Merrifield, Tetrahedron Lett. 29, 303
(1988)
148. H. Takahata, M. Kubota, N. Ikota, J. Org. Chem. 64, 8594 (1999)
149. S. Robin, G. Rousseau, Tetrahedron 54, 13681 (1998)
150. S. B. Rosenblum, T. Huynh, A. Afonso, H. R. Davis Jr., Tetrahedron 31, 5735
(2000)
151. M. Tiecco, L. Testaferri, M.Tingoli, D. Bartoli, R. Balducci, J. Org. Chem. 55, 429
(1990)
152. M. D’hooghe, T. Vanlangendonck, K. W. Törnroos, N. De Kimpe, J. Org. Chem. 71,
4678 (2006)
153. A. I. Meyers, L. E. Burgess, J. Org. Chem. 56, 2292 (1991); A. I. Meyers, L. E.
Burgess, J. Org. Chem. 57, 1656 (1992)
154. F. Fülöp, G. Bernáth, J. Mattinen, K. Pihlaja, Tetrahedron 45, 4317 (1989)
155. L. Lázár, F. Fülöp, Eur. J. Org. Chem. 3025 (2003)
Acknowledgements
I am greatful to for Prof. Ferenc Fülöp, Head of the Institute of Pharmaceutical Chem-
istry, University of Szeged, for the possibility to work for my thesis in the Institute.
I would like to express my deepest thanks to Prof. Géza Stájer for his encouragement
and guidance of my work. As supervisor, his advice has greatly helped me during all stages of
my PhD work.
My thanks are due to Prof. Pál Sohár for the IR and NMR spectroscopic measurements
and valuable interpretations, and to Prof. Reijo Sillanpää for his help in the X-ray work.
I would also like to thank Prof. Norbert De Kimpe for providing me with working fa-
cilities in the University of Ghent.
I am likewise grateful to Dr. Zsolt Szakonyi and Dr. Ferenc Miklós for facilitating my
laboratory work with practical advice.