Enaminone-based synthesis of (S)-3-(pyrazolyl)alanines from L-aspartic acid

Article abstract of DOI:10.1055/s-2006-942435

Protected N(1′)-substituted (5)-3-(4-methoxycarbonyl-1H-pyrazol-5-yl) alanines 7a-h were prepared in 34-94% yields by acid-catalysed cyclocondensations of chiral enaminone 5, available from L-aspartic acid, with hydrazines 6a-h hydrochlorides. Deprotectio

Full text of DOI:10.1055/s-2006-942435

2376
PAPER
Enaminone-Based Synthesis of (S)-3-(Pyrazolyl)alanines from L-Aspartic Acid
E
naminone-Based
r
Synthes
o
is of
(
S
)
-3-(
P
š
yrazolyl)alanine
U
s
from
L
-Aspartic
rAcid šič, David Bevk, Samo Pirc, Lidija Pezdirc, Branko Stanovnik,* Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: branko.stanovnik@fkkt.uni-lj.si; E-mail: jurij.svete@fkkt.uni-lj.si
Received 7 December 2005; revised 10 March 2006
Dedicated to Professor Miha Tišler, Professor Emeritus of the University of Ljubljana, on the occasion of his 80th birthday
An important synthetic approach towards non-racemic 3-
Abstract: Protected N(1¢)-substituted (S)-3-(4-methoxycarbonyl-
heteroarylalanines is the chiron approach, where the het-
erocyclic ring is formed by heterocyclisation of alanine
derivative with a suitable functional moiety at b-position,
1H-pyrazol-5-yl)alanines 7a–h were prepared in 34–94% yields by
acid-catalysed cyclocondensations of chiral enaminone 5, available
from L-aspartic acid, with hydrazines 6a–h hydrochlorides. Depro-
tection of 7a,b,e by catalytic hydrogenation afforded the corre- such as formyl group and a-halo ketone, ynone, and dicar-
sponding free pyrazoylalanines 8a,b,e. On the other hand, 1-benzyl
6-methyl (S)-2-benzyloxycarbonylamino-4-oxohexanedioate (4),
precursor of the enaminone 5, reacted with hydrazines 6 in two dif-
ferent ways. In the reactions of 4 with (hetero)arylhydrazines 6b,e,i,
the five-membered ring was formed and the corresponding 3-pyra-
zolylalanine esters 10b,i and 10¢e were obtained, whilst treatment of
4 with hydrazine hydrate (6a) and methylhydrazine (6h) led to the
formation of the six-membered ring furnishing tetrahydropyridazi-
nones 11a,h.
bonyl moiety. For example, (S)-5-bromo-4-oxonorvaline
derivatives were transformed with ambident nucleophiles
into protected (thiazol-4-yl)-, 3-(indolizin-3-yl)-, and 3-
(imidazo[1,2-x]azin-2-yl)alanines,7,8 reactions of a-amino
acid vicinal tricarbonyls with ambident nucleophiles gave
3-(quinoxalinyl)-, 3-(pyrazinyl)-, and 3-(1,2,4-triazi-
nyl)alanines,9a while a-amino acid ynones were used in
the synthesis of pyridinyl-, pyrazolyl-, isoxazolyl-, and
(1,2,3-triazolyl)alanines.9b Similarly, (S)-3-formylala-
nines were used as the key intermediates in the synthesis
of 3-([1,2,4]triazolo[4,3-x]azin-3-yl)alanines8 and in
three-component Hantzsch and Biginelli cyclocondensa-
tions leading to 3-(pyridinyl)alanines and 3-(pyrimidi-
nyl)alanines.10
Key words: amino acids, enaminones, hydrazines, cyclizations,
pyrazoles
Non-proteinogenic a-amino acids represent an important
group of compounds, not only due to their occurrence in
nature and their pharmaceutical and biological applica-
tions, but also because of their utilisation in organic syn-
thesis and in asymmetric transformations.1 A group of
such a-amino acids are 3-heteroarylalanines,2,3 useful as
the non-proteinogenic analogues of histidine and tryp-
tophane. Several 3-heteroarylalanines, such as (S)-3-(1H-
pyrazol-1-yl)alanine,3 mimosine,4 (S)-3-(4-carboxy-3-fu-
ryl)alanine,5 and (S)-azatyrosine,6 have been isolated from
natural sources, mostly from plants (Figure 1).
Recently, a series of alkyl 2-substituted 3-(dimethylami-
no)propenoates and their analogues have been prepared as
versatile reagents for the preparation of various heterocy-
clic systems and in the synthesis of functionalised hetero-
cycles, including 3-heteroarylalanine derivatives.11 In this
context, Young and co-workers have previously reported
utilisation of a-(dimethylaminomethylidene)pyroglutam-
ic acid esters in the ‘ring switching’ synthesis of 3-pyra-
zolyl, isoxazolyl, and pyrimidinyl substituted alanines via
hydrolysis of the enamino group into the formyl group
followed by treatment with ambident nucleophiles.12 Lat-
er on, we reported an improved variation of Young’s
methodology,13 which has been extended also on the prep-
aration of 3-heteroaryl substituted alaninols,14 lactic ac-
ids,15 and propane-1,2-diols.16 The same enaminones were
also used as the key intermediates in a stereoselective a-
amination of 5-substituted g-lactams and g-lactones, via
nitrosation of the dimethylaminomethylidene group fol-
lowed by catalytic hydrogenation of the intermediate
oximes.17 Recently, (+)-camphor derived enaminone,
(1R,4E,5S)-4-[(dimethylamino)methylidene]-1,8,8-trimethyl-
2-oxabicyclo[3.2.1]octan-3-one, was transformed via
nitrosation into the corresponding 4-oximino analogue,
which, upon treatment with alkylmagnesium halides, fur-
nished (1R,4S,5S)-4-dialkylamino-1,8,8-trimethyl-2-oxa-
bicyclo[3.2.1]octan-3-ones as novel non-proteinogenic
amino acid derivatives containing a terpene moiety.18
O
OH
HO
N
N
COOH
NH2
N
N
COOH
NH2
COOH
NH2
(S)-3-(1H-pyrazol-1-yl)alanine
(Citrulus vulgaris)
mimosine
(S)-azatyrosine
(Mimosa pudica) (Streptomyces chibaensis)
O
COOH
HOOC
NH2
(S)-3-(4-carboxy-3-furyl)alanine
(Phyllotopsis nidulans)
Figure 1 Some examples of naturally occurring 3-heteroaryl-
alanines
SYNTHESIS 2006, No. 14, pp 2376–2384
x
x.
x
x
.
2
0
0
6
Advanced online publication: 26.06.2006
DOI: 10.1055/s-2006-942435; Art ID: T16605SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enaminone-Based Synthesis of (S)-3-(Pyrazolyl)alanines from L-Aspartic Acid
2377
O
In continuation of our work in this field, we now report
another enaminone-based methodology for the prepara-
tion of 3-pyrazolylalanines 8 via transformation of (S)-N-
(benzyloxycarbonyl)aspartic acid 1-benzyl ester (1) into
1-benzyl 6-methyl (5E,2S)-5-[(dimethylamino)meth-
ylidene]-2-benzyloxycarbonylamino-4-oxohexanedioate
(5), followed by treatment with hydrazine derivatives 6
and hydrogenolytic deprotection.
O
O
i
COOBn
HOOC
+
NHCOOBn
O
1
2
O
O
ii
O
COOBn
The key intermediate, 1-benzyl 6-methyl (5E,2S)-5-
[(dimethylamino)methylidene]-2-benzyloxycarbonyl-
amino-4-oxohexanedioate (5), was prepared in three steps
from 1-benzyl (S)-N-(benzyloxycarbonylamino)aspartate
(1), available in three steps from L-aspartic acid according
to the literature procedures.19 Following closely related
examples from the literature,20 the acid 1 was first coupled
with Meldrum’s acid (2) to give the intermediate 3, which
was then heated in anhydrous methanol to afford 1-benzyl
6-methyl (S)-2-benzyloxycarbonylamino-4-oxohexane-
dioate (4) in 66% yield over two steps. Further treatment
of 4 with N,N-dimethylformamide dimethyl acetal (DMF-
DMA) gave the desired enaminone 5 in almost quantita-
tive yield. Cyclocondensations of 5 with hydrazines 6a–
e,h hydrochlorides in methanol at room temperature or in
ethanol under reflux afforded the corresponding fully pro-
tected 3-pyrazolylalanines 7a–e,h in 57–94% yields. Fur-
ther deprotection of compounds 7a,b,e by catalytic
hydrogenation in the presence of Pd–C furnished the free
amino acids 8a,b,e in 75–82% yields. On the other hand,
acid-catalysed cyclocondensations of 5 with the less reac-
tive 3-hydrazino-6-phenylpyridazine (6f) and 2-hydrazi-
nopyrimidine (6g) in refluxing ethanol were accompanied
by partial transesterification. Consequently, mixtures of
the major benzyl esters 7f,g and the minor ethyl esters
7¢f,g were formed. Chromatographic separation afforded
pure compounds 7f, 7g, 7¢f, and 7g (Scheme 1).
O
O
OH NHCOOBn
3
4
iii
COOBn
MeOOC
NHCOOBn
NMe2
5'
1
6
iv, v
COOBn
4
2
3
5
MeOOC
O
NHCOOBn
5
2'
N
N
1'
N
R
R
3'
N
vi
5'
COOBn
COOH
4'
1
MeOOC
N
MeOOC
3
2
NHCOOBn
NH2
8a,b,e
7a–h
Compound
R
R
N
H
Ph
7a, 8a
7b, 8b
7c
COOEt
MeOOC
4-MeOC6H4
C6F5
pyridin-2-yl
6-phenylpyridazin-3-yl
pyrimidin-2-yl
Me
7d
NHCOOBn
7'f,g
minor products
7e, 8e
7f, 7'
7g, 7'g
7h
Scheme 1 Reagents and conditions: (i) DCC, DMAP, CH2Cl2, –5
°C; (ii) MeOH, reflux; (iii) DMFDMA, CH2Cl2, r.t.; (iv) RNHNH2
(6a–h)·HCl, MeOH or EtOH, r.t. or reflux; (v) chromatographic sepa-
ration (column chromatography followed by MPLC); (vi) H2 (1 bar);
10% Pd–C, MeOH, r.t.
Due to the b-keto ester moiety, which is included along
positions 4–6 in 1-benzyl 6-methyl (S)-2-benzyloxycar-
bonylamino-4-oxohexanedioate (4), this compound is
also a suitable precursor for the synthesis of 3-pyrazolyl-
alanines. Consequently, 4 was treated with hydrazines
6a,b,e,h,i. Surprisingly, two types of products were ob-
tained. Reactions of 4 with phenylhydrazine (6b), and 4-
nitrophenylhydrazine (6i) gave (S)-3-(1-aryl-5-oxo-4,5-
dihydro-1H-pyrazol-3-yl)-N-(benzyloxycarbonyl)ala-
nine benzyl esters 10b and 10i. Similarly, treatment of 4
with 2-hydrazinopyridine (6e) led to the protected (S)-3-
[3-oxo-1-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-5-
yl]alanine 10e. On the other hand, reactions of 4 with hy-
drazine hydrate (6a) and methylhydrazine (6h) led to the
formation of the six-membered ring to afford the corre-
sponding tetrahydropyridazinones 11a,h. The reaction
mechanism could be explained by initial formation of the
intermediate hydrazone 9. Further cyclisation of the hy-
drazone 9 can take place, either to the methoxycarbonyl
group leading to pyrazolylalanine 10 (Path A), or to the
benzyloxycarbonyl group leading to the pyridazinone 11
(Path B). Unfortunately, we do not have a firm explana-
tion for this selectivity, which, on the other hand, might be
attributed to steric and/or electronic factors. Apparently,
cyclisation of less nucleophilic and sterically more de-
manding N-arylhydrazones 9b,e,i takes place preferential-
ly to the position 6, while in the case of more nucleophilic
and sterically less demanding hydrazones 9a,h cyclisation
to the position 1 is favoured (Scheme 2).
Structures of compounds 4, 5, 7, 8, 10, and 11 were deter-
mined by spectroscopic (IR, H and 13C NMR, MS,
1
HRMS) methods and by elemental analyses for C, H, and
N. Compounds 4, 5, 7¢f,g, 8a,b,e, 10i, and 11a,h were not
isolated in analytically pure form. Their identities were
confirmed by 13C NMR and HRMS spectroscopy.
The configuration around the C(5)=C(5¢) bond in com-
pound 5 was determined by HMBC spectroscopy on the
basis of long-range coupling constants (3JC–H) between the
methylidene proton [HC(5¢)] and the carbonyl carbon at-
oms [O=C(4) and O=C(6)], measured from the antiphase
splitting of cross peaks in the HMBC spectrum. General-
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

2378
U. Uršič et al.
PAPER
COOBn
compound 10¢e, HC(4¢) appeared as a singlet at 5.31 ppm
and was in agreement with the proposed tautomeric form
10¢. Higher stability of the 3-oxo-1,2-dihydro-3H-pyra-
zole tautomeric form 10¢ in the case of compound 10¢e
could be due to intramolecular N·····H hydrogen bond be-
tween the HN(1¢) and the pyridine ring nitrogen atom
N(1¢¢) (Figure 3).
R
Compound
MeOOC
9a, 11a
9b, 10b
9e, 10'e
9h, 11h
9i, 10i
H
Ph
O
NHCOOBn
4
pyridin-2-yl
Me
4-NO2C6H4
i
R
5
3
NHCOOBn
N1'
2
6
Path A
– MeOH
4
MeOOC
O
N 2'
1 COOBn
5'
1688 cm–1
N
N
R
N
R
N
R'
3'
COOBn
4'
~1720 cm–1
1
3
O
O
2
H
R
N
NH
Ala
N
NHCOOBn
10b,e,i
9a,b,e,h,i
H
N 2'
3'
C
Ala
10
O
10'
N1'
N 1'
Path B – BnOH
O
R = pyridin-2-yl
5'C
H
N 2'
4'
5'
3'
H
Ala
4'
R
1N
Ala
10b,i
H ~ 3.3 and 3.5 ppm (2 × d)
R
N
H
10'e
6
O
2N
HO
N
N
δ
H = 5.31 ppm (s)
5
3
δ
N2'
3'
NHCOOBn
3'
4'
4
O
Ala
NH
MeOOC
COOBn
10''
1'
COOBn
Ala =
11a,h
5'
NHCOOBn
10'e
NHCOOBn
Figure 3
Scheme 2 Reagents and conditions: (i) RNHNH2 (6a,b,e,h,i),
MeOH, r.t.
Finally, we tried to establish possible (partial) racemisa-
tion, which might accompany cyclisations of 4 and 5 with
hydrazine derivatives 6. First, 1H NMR spectra of 10 mg
of compound 7a in the presence of 10 mg, 20 mg, and 30
mg of tris[3-(heptafluoropropylhydroxymethylene)-D-
camphorato]europium were taken. Unfortunately, these
spectra were not very informative, due to strong broaden-
ing of characteristic signals. On the other hand, 1H NMR
spectrum of the free amino acid 8b in the presence of
equimolar amount of (+)-camphor-10-sulfonic acid ex-
hibited a single set of signals. Similarly, the Mosher
amide, prepared by acylation of 8b with (R)-a-methoxy-
a-trifluoromethylphenylacetic acid [(R)-Mosher acid],
was found to be isomerically pure according to 1H NMR.
Finally, HPLC analysis of compounds 7a,e,h and 11a,h
on a chiral stationary phase resulted in elution of single
peaks, which supported enantiomeric purity of these com-
pounds. Despite the fact that the results of this study were
not completely unambigous, they indicated that cyclisa-
tions of 4 and 5 with hydrazine derivatives 6 probably pro-
ceed racemisation-free.
ly, the magnitude of the coupling constant 3JC–H for nuclei
with cis-configuration around the C=C bond is smaller
(2–6 Hz) than that for trans-oriented nuclei (8–12
Hz).11b,c,f,21–23 In compound 5, the magnitudes of coupling
constants, JC(4)–H(5¢) = 6.6 Hz (trans) and 3JC(6)–H(5¢) = 4.8
3
Hz (cis) showed the (E)-configuration around the
C(5)=C(5¢) bond (Figure 2).
H
NMe2
5'
1
3JH(5')–C(4) = 6.6 Hz (trans)m
3JH(5')–C(6) = 4.8 Hz (cis)
6
C
4
C
MeO
COOBn
2
5
3
O
O
NHCOOBn
5
Figure 2 Determination of configuration around the C(5)=C(5¢)
bond in enaminone 5 by HMBC spectroscopy
Like other pyrazolones,24 the 3-pyrazoylalanine deriva-
tives 10 can also exist in three tautomeric forms, 10 and/
or 10¢, and/or 10¢¢. Differentiation between these three
tautomeric forms is possible by IR and NMR. In our case, In conclusion, N(1¢)-substituted (S)-3-(4-methoxycarbon-
yl-1H-pyrazol-5-yl)alanines were prepared from chiral
enaminone 5, available in six steps from L-aspartic acid,
via acid-catalysed cyclocondensations with hydrazines 6
followed by deprotection. In addition to the previously
published ‘ring switching’ approach,12–16 this methodolo-
gy represents an alternative route towards 3-heteroaryl-
alanines via L-aspartic acid derived acyclic enaminone 5.
compounds 10b,i were isolated as the 5-oxo-4,5-dihydro-
1H-pyrazole tautomers, while compound 10¢e was isolat-
ed as the 3-oxo-1,2-dihydro-3H-pyrazole tautomer. All
compounds, 10b,i and 10¢e, exhibited C=O absorption
bands at 1719–1733 cm–1, corresponding to the COOBn
groups and the ring C=O group of the pyrazolone tau-
tometic form 10. Compound 10¢e also exhibited another
C=O absorption band at 1688 cm–1, which is in agreement
with typical literature vibrations for 3-oxo-1,2-dihydro-
3H-pyrazoles.24,25 On the other hand, the appearance of
the 4¢-CH2 group as two doublets at ca 3.3 and 3.5 ppm in
the 1H NMR spectra of 10b,i clearly supported the 5-oxo-
4,5-dihydro-1H-pyrazole tautomeric forms. In the case of
Melting points were determined on a Kofler micro hot stage. The 1H
NMR spectra were obtained on a Bruker Avance DPX 300 spec-
trometer at 300 MHz for 1H NMR and 75.5 MHz for 13C NMR, us-
ing DMSO-d6 and CDCl3 as solvents and tetramethylsilane as the
internal standard. Mass spectra were recorded on an AutoSpecQ
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

PAPER
Enaminone-Based Synthesis of (S)-3-(Pyrazolyl)alanines from L-Aspartic Acid
2379
spectrometer. IR spectra were obtained on a Perkin–Elmer Spec-
trum BX FTIR spectrophotometer. Microanalyses were performed
on a Perkin-Elmer CHN Analyser 2400 II. Column chromatography
was performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm).
Medium pressure liquid chromatography (MPLC) was performed
with Büchi isocratic system with detection on silica gel (Merck,
Lichrospher® 60, 0.012 mm); column dimensions: 15 × 450 mm
(wet filled); UV detection (254 nm); sample amount: 150 mg per
each run. HPLC analyses of compounds 7a,e,h and 11a,h were per-
formed on a Hewlett–Packard Liquid Chromatograph 1050; col-
umn: Supelcosil (S)-DNBPG (250 × 4.6 mm); mobile phase:
EtOAc–n-hexane (50:50 or 75:25); flow: 2 mL/min; UV detector
(254 nm).
was purified by column chromatography followed by MPLC. Frac-
tions containing the product were combined and evaporated in vac-
uo to give 7a. Experimental, analytical, and spectral data for
compound 7a are given in Tables 1– 4.
Method B: A mixture of 5 (0.468 g, 1 mmol), EtOH (10 mL), and
hydrazine hydrochloride 6b,c (1 mmol) or hydrazine 6d–g (1
mmol) and 37% aq HCl (3 drops, ca 1 mmol) was refluxed for 1–16
h. Volatile components were evaporated in vacuo and the residue
was purified by column chromatography followed by MPLC. Frac-
tions containing the product were combined and evaporated in vac-
uo to give compounds 7b–g and 7¢f,g. Compounds 7b,c were
obtained in pure form upon column chromatography purification.
Experimental, analytical, and spectral data for compound 7b–g and
7¢f,g are given in Tables 1– 4.
Meldrum’s acid (1), 4-dimethylaminopyridine (DMAP), N,N¢-dicy-
clohexylcarbodiimide (DCC), N,N-dimethylformamide dimethyl
acetal (DMFDMA), hydrazines 6a–e,h,i, tris[3-(heptafluoropropyl-
hydroxymethylene)-D-camphorato]europium, (R)-a-methoxy-a-
(trifluoromethyl)phenylacetic acid [(R)-Mosher acid], and (+)-cam-
phor-10-sulfonic acid are commercially available (Sigma–Aldrich).
(S)-N-(Benzyloxycarbonyl)aspartic acid 1-benzyl ester (1),19 3-hy-
drazino-6-phenylpyridazine (6f),26 and 2-hydrazinopyrimidine
(6g)27 were prepared according to the literature procedures.
Method C: A mixture of 5 (0.468 g, 1 mmol), MeOH (10 mL),
methylhydrazine (6h; 0.046 g, 1 mmol), and 37% aq HCl (3 drops,
ca 1 mmol) was stirred at r.t. for 18 h. The reaction mixture was
evaporated in vacuo to one-third of the initial volume (ca 3 mL).
Water was added dropwise until a slight turbidity appeared, and the
mixture was left in a refrigerator (+4 °C) for several hours. The pre-
cipitate was collected by filtration to give 7h. Experimental, analyt-
ical, and spectral data for compound 7h are given in Tables 1– 4.
1-Benzyl 6-Methyl (2S)-2-Benzyloxycarbonylamino-4-oxohex-
anedioate (4)
Preparation of Free (S)-3-(1H-Pyrazol-5-yl)alanines 8a,b,e;
General Procedure
This compound was prepared according to a slightly modified pro-
cedure described previously for closely related compounds.20 A so-
lution of DCC (5.674 g, 27.5 mmol) in anhyd CH2Cl2 (25 mL) was
slowly added to a solution of Meldrum’s acid 2 (3.603 g, 25 mmol),
compound 1 (8.934 g, 25 mmol), and DMAP (3.360 g, 27.5 mmol)
in anhyd CH2Cl2 (55 mL) at –5 °C. The reaction mixture was stirred
at –5 °C for 2.5 h and was then allowed to warm slowly to r.t. (ca 1
h), filtered, and the precipitate was washed with anhyd CH2Cl2 (25
mL). The filtrate was washed with 1 M aq NaHSO4 (2 × 170 mL)
and brine (2 × 170 mL), dried over anhyd Na2SO4, filtered, and the
filtrate was evaporated in vacuo. The residue was dissolved in an-
hyd MeOH (150 mL) and heated under reflux for 5 h. Volatile com-
ponents were evaporated in vacuo and the residue was cyrstallised
from cyclohexane to give 4. Experimental, analytical, and spectral
data for compound 4 are given in Tables 1– 4.
A mixture of 7 (1 mmol), MeOH (25 ml), and 10% Pd–C (0.1 g) was
hydrogenated (1 bar H2, r.t.) for 24 h. The catalyst was removed by
filtration through a short pad of Celite® and washed with MeOH (ca
50 mL). The filtrate was evaporated in vacuo to give 8a,b,e. Exper-
imental, analytical, and spectral data for compounds 8a,b,e are giv-
en in Tables 1– 4.
Cyclocondensations of 4 with Free Hydrazines 6a,b,e,h,i; Gen-
eral Procedures for the Preparation of Protected (S)-3-(1H-
pyrazol-3-yl)alanines 10b,e,i and Tetrahydropyridazinones
11a,h
Method A: A mixture of 4 (0.310 g, 0.75 mmol), MeOH (10 mL),
and hydrazine 6 (0.75 mmol) was stirred at r.t. for 5–96 h and then
evaporated in vacuo. The residue was purified by column chroma-
tography followed by MPLC. Fractions containing product were
combined and evaporated in vacuo to give compounds 10b,i and
11a,h. Compound 11a was obtained in pure form upon column
chromatography purification. Experimental, analytical, and spectral
data for compound 10b,i and 11a,h are given in Tables 1– 4.
6-Benzyl 1-Methyl (2E,5S)-2-[(Dimethylamino)methylidene]-5-
benzyloxycarbonylamino-3-oxohexanedioate (5)
DMFDMA (0.75 mL, 5.2 mmol) was added to a solution of 4 (2.065
g, 5 mmol) in anhyd CH2Cl2 and the mixture was stirred at r.t. for
3.5 h and then evaporated in vacuo. The residue was purified by col-
umn chromatography. Fractions containing the product were com-
bined and evaporated in vacuo to give 5. Experimental, analytical,
and spectral data for compound 5 are given in Tables 1– 4.
Method B: A mixture of 4 (0.310 g, 0.75 mmol), MeOH (10 mL),
and 2-hydrazinopyridine (6e; 0.082 g, 0.75 mmol) was stirred at r.t.
for 22 h. The reaction mixture was evaporated in vacuo to one-third
of the initial volume (ca 3 mL). Water was added dropwise until a
slight turbidity appeared, and the mixture was left in a refrigerator
(+4 °C) for several hours. The precipitate was collected by filtration
to give 10e. Experimental, analytical, and spectral data for com-
pound 10e are given in Tables 1– 4.
Acid-Catalysed Cyclocondensations of 5 with Hydrazine Hy-
drochlorides 6a–h; General Procedures for the Preparation of
Protected (S)-3-(1H-pyrazol-5-yl)alanines 7a–h and 7¢f,g
Method A: A mixture of 5 (0.468 g, 1 mmol), MeOH (10 mL), and
hydrazine hydrochloride 6a (0.068 g, 1 mmol) was stirred at r.t. for
16 h. Volatile components were evaporated in vacuo and the residue
Table 1 Experimental and Physical Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11
Method Time (h) Column chromatography, MPLCa
Compound R
Yield (%) Mp (°C), crystallisation solvent
4
–
–
–
–
66
98
57
88–94 (cyclohexane)
212–216 (CHCl3)
86–90 (toluene)
5
–
–
Column chromatography: A (2:1)
7a
H
A
16
Column chromatography: A (2:1)
MPLC: A (1:1)
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

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PAPER
Table 1 Experimental and Physical Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11 (continued)
Method Time (h) Column chromatography, MPLCa
Compound R
Yield (%) Mp (°C), crystallisation solvent
7b
Ph
B
1
Column chromatography: A (1:2)
Column chromatography: A (1:2)
94
Oil
7c
4-Methoxyphenyl
Pentafluorophenyl
B
B
4.5
5
82
73
Oil
Oil
7d
Column chromatography: A (1:2)
MPLC: A (1:5)
7e
7f
Pyridin-2-yl
B
B
2
Column chromatography: A (1:1)
85
53
89–93
49–52
6-Phenylpyridazin-3-yl
1.5
Column chromatography: A (1:2)
MPLC: A (2:3)
7¢f
7g
6-Phenylpyridazin-3-yl
Pyrimidin-2-yl
B
B
B
1.5
5
Column chromatography: A (1:2)
MPLC: A (2:3)
27
45–48
Oil
Column chromatography: B (20:1) 34
MPLC: A (100:0)
7¢g
Pyrimidin-2-yl
5
Column chromatography: B (20:1) 22
MPLC: A (100:0)
Oil
7h
8a
Me
C
–
18
–
–
–
–
62
82
75
82
44
102–104 (MeOH–H2O)
210–213
H
18
8b
Ph
–
22.5
21.5
20
173–176 (CH2Cl2)
183–186 (DMSO–Et2O)
Oil
8e
Pyridin-2-yl
Ph
–
10b
A
Column chromatography: A (2:1)
MPLC: A (1:1)
10e
10i
Pyridin-2-yl
B
A
22
96
–
96
69
110–112 (MeOH–H2O)
Oil
4-Nitrophenyl
Column chromatography: A (2:1)
MPLC: A (1:1)
11a
11h
H
A
A
5
Column chromatography: A (2:1)
37
39
101–105
Me
24
Column chromatography: A (2:1)
MPLC: A: (2:1)
96–98 (MeOH–H2O)
a A: EtOAc–hexanes, B: CHCl3–MeOH.
Table 2 Analytical, MS, and IR Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11
IR (cm–1)
[a]D
20
Compound Molecular formula analysis
EI–MS (m/z)
EI–HRMS (m/z)
4
Anal. Calcd for C22H23NO7 (413.42): C,
278 [M+ – COOBn]
63.91; H, 5.61; N, 3.39. Found: C, 64.71; H, FAB: 414 [MH+]
5.82; N, 3.76.
3308, 3034, 2941, 1748, 1740, 1714, +17.2 (c = 0.37,
1689, 1533, 1298, 1260, 1139, 1079, CHCl3)
1022, 735, 696
5
Anal. Calcd for C25H28N2O7 (468.50): C,
64.09; H, 6.02; N, 5.98. Found: C, 63.69; H, Calcd: 468.189652.
468 [M+]
3327, 2932, 1722, 1639, 1578, 1499, +26.3 (c = 0.31,
1423, 1381, 1283, 1210, 1111, 1057, CHCl3)
740, 698
6.34; N, 6.16.
Found: 468.190880.
7a
7b
7c
Anal. Calcd for C23H23N3O6 (437.45): C,
63.15; H, 5.30; N, 9.61. Found: C, 63.35; H,
5.41; N, 9.44.
3327, 2950, 1743, 1719, 1693, 1539, +0.52 (c = 0.11,
1500, 1336, 1275, 1214, 1093, 735,
697
CHCl3)
Anal. Calcd for C29H27N3O6 (513.54): C,
67.83; H, 5.30; N, 8.18. Found: C, 67.83; H,
5.40; N, 7.95.
3338, 2950, 1732, 1710, 1687, 1556, +3.2 (c = 0.31,
1526, 1502, 1290, 1255, 1224, 1098, CHCl3)
1055, 770, 753, 697
Anal. Calcd for C30H29N3O7 (543.57): C,
66.29; H, 5.38; N, 7.73. Found: C, 66.18; H,
5.63; N, 7.69.
3354, 2951, 1717, 1555, 1518, 1251, –7.5 (c = 0.27,
1215, 1096, 1052, 1027, 837, 738,
697
CHCl3)
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

PAPER
Enaminone-Based Synthesis of (S)-3-(Pyrazolyl)alanines from L-Aspartic Acid
2381
Table 2 Analytical, MS, and IR Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11 (continued)
IR (cm–1)
[a]D
20
Compound Molecular formula analysis
EI–MS (m/z)
EI–HRMS (m/z)
7d
Anal. Calcd for C29H22F5N3O6 (603.49): C,
604 [MH+]
3360, 2954, 1718, 1533, 1520, 1266, +1.7 (c = 0.30,
1213, 1096, 996, 850, 697 CHCl3)
57.72; H, 3.67; N, 6.96. Found: C, 57.99; H, 694 [M – CH2Ph+]
3.88; N, 6.79.
FAB: 604 [MH+]
Calcd: 604.150702.
Found: 604.151890.
7e
7f
Anal. Calcd for C28H26N4O6 (514.53): C,
65.36; H, 5.09; N, 10.89. Found: C, 65.58; H,
5.34; N, 10.62.
3355, 2952, 1720, 1560, 1522, 1475, –21.4 (c = 0.37,
1439, 1265, 1207, 1097, 1059, 785,
737, 698
CHCl3)
Anal. Calcd for C33H29N5O6 (591.61): C,
67.00; H, 4.94; N, 11.84. Found: C, 67.02; H,
5.05; N, 11.92.
3380, 2952, 1720, 1547, 1452, 1431, –3.0 (c = 0.29,
1262, 1207, 1094, 1060, 785, 746,
696
CHCl3)
7¢f
7g
Anal. Calcd for C28H27N5O6 (529.54): C,
63.51; H, 5.14; N, 13.23. Found: C, 64.15; H, Calcd: 529.196134.
5.65; N, 12.88.
529 [M+]
3330, 2929, 2851, 1721, 1627, 1547, –7.9 (c = 0.11,
1453, 1432, 1381, 1261, 1210, 1093, CHCl3)
1028, 783, 748, 695
Found: 529.198050.
Anal. Calcd for C27H25N5O6 (515.52): C,
515 [M+]
3337, 2952, 1717, 1580, 1563, 1524, –7.9 (c = 0.22,
1423, 1380, 1262, 1213, 1198, 1083, CHCl3)
737, 698
62.91; H, 4.89; N, 13.59. Found: C, 62.29; H, 606 [M – CH2Ph+]
5.12; N, 13.13.
Calcd: 515.180484.
Found: 515.181850.
7¢g
Anal. Calcd for C22H23N5O6 (453.45): C,
58.27; H, 5.11; N, 15.44. Found: C, 58.38; H,
5.32; N, 15.22.
3346, 2953, 1719, 1580, 1562, 1524, –17.0 (c = 0.23,
1424, 1380, 1262, 1211, 1199, 1026, CHCl3)
737, 699
7h
Anal. Calcd for C24H25N3O6 (451.47): C,
63.85; H, 5.58; N, 9.31. Found: C, 64.03; H,
5.72; N, 9.41.
3311, 3035, 2951, 1735, 1705, 1682, +0.82 (c = 0.38,
1557, 1530, 1500, 1452, 1374, 1299, CHCl3)
1282, 1263, 1241, 1198, 1059, 1040,
730, 694
8a
8b
8e
Anal. Calcd for C8H11N3O4 (213.19): C,
45.07; H, 5.20; N, 19.71. Found: C, 42.30; H, Calcd: 214.082781.
5.46; N, 17.94.
214 [MH+]
3423, 3047, 2959, 1732, 1715, 1662, –58.4 (c = 0.07,
1602, 1530, 1443, 1344, 1240, 1143, DMSO)
1102, 966, 932, 538
Found: 214.083520.
Anal. Calcd for C14H15N3O4 (289.29): C,
58.13; H, 5.23; N, 14.53. Found: C, 57.99; H, Calcd: 290.114081.
5.45; N, 13.72.
290 [MH+]
3421, 3062, 2951, 2849, 1712, 1623, +57.1 (c = 0.15,
1561, 1502, 1411, 1384, 1269, 1253, MeOH)
1200, 1099, 986, 772, 696, 538, 507
Found: 290.115050.
Anal. Calcd for C13H14N4O4 (290.28): C,
290 [M+]
3434, 3017, 2951, 1717, 1617, 1594, –24.8 (c = 0.07,
1580, 1564, 1475, 1439, 1406, 1310, DMSO)
1258, 1199, 1091, 1001, 932, 783,
721, 537
53.79; H, 4.86; N, 19.30. Found: C, 53.36; H, FAB: 291 [MH+]
5.04; N, 18.45.
Calcd: 290.101505.
Found: 290.102620.
10b
10e
10i
Anal. Calcd for C27H25N3O5 (471.51): C,
68.78; H, 5.34; N, 8.91. Found: C, 68.83; H,
5.68; N, 8.68.
3340, 3034, 2929, 1719, 1595, 1561, +7.1 (c = 0.31,
1526, 1499, 1454, 1411, 1347, 1265, CHCl3)
1215, 1194, 1058, 755, 695
Anal. Calcd for C26H24N4O5 (470.52): C,
66.09; H, 5.12; N, 11.86. Found: C, 66.35; H,
5.20; N, 11.90.
3318, 3034, 2957, 1733, 1688, 1595, –23.6 (c = 0.29,
1539, 1498, 1445, 1341, 1288, 1263, CHCl3)
1184, 1147, 1049, 781, 750, 698
Anal. Calcd for C27H24N4O7 (516.50): C,
516 [M+]
3407, 3341, 3034, 2955, 1727, 1596, +14.8 (c = 0.23,
1516, 1499, 1454, 1329, 1273, 1214, CHCl3)
1111, 1057, 854, 752, 698
62.79; H, 4.68; N, 10.85. Found: C, 62.32; H, 607 [M – CH2Ph+]
4.95; N, 10.15.
Calcd: 516.164499.
Found: 516.166100.
11a
11h
Anal. Calcd for C15H17N3O5 (319.31): C,
56.42; H, 5.37; N, 13.16. Found: C, 56.92; H, Calcd: 319.116821.
5.62; N, 12.77.
319 [M+]
3321, 2959, 1723, 1689, 1536, 1440, –95.8 (c = 0.20,
1404, 1385, 1359, 1335, 1258, 1234, CHCl3)
1167, 1111, 1053, 984, 750, 699
Found: 319.117950.
333 [M+]
Anal. Calcd for C16H19N3O5 (333.34): C,
57.65; H, 5.75; N, 12.61. Found: C, 58.50; H, Calcd: 333.132471.
6.18; N, 12.17. Found: 333.133150.
3296, 3060, 2951, 2929, 1720, 1656, –133.7 (c = 0.11,
1542, 1435, 1353, 1330, 1272, 1216, CHCl3)
1179, 1153, 1104, 1024, 947, 735,
696
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

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Table 3 1H NMR Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11
1H NMR [d (ppm)]a
Compound Solvent
4
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.13 [dd, J = 4.2, 18.5 Hz, 1 H, HaC(3)], 3.30 [dd, J = 4.5, 18.1 Hz, 1 H, HbC(3)], 3.41 (s, 2 H, 5-CH2), 3.69 (s, 3 H,
OMe), 4.63 [deg br dt, J = 4.3, 8.3 Hz, 1 H, HC(2)], 5.10, 5.16 [2 × s, 4 H, 2 × PhCH2], 5.73 (d, J = 7.9 Hz, 1 H, NH),
7.25–7.41 (m, 10 H, 2 × Ph)
5
2.78, 3.18 (2 × br s, 6 H, NMe2), 3.25 [dd, J = 3.8, 17.7 Hz, 1 H, HaC(3)], 3.51 [dd, J = 4.9, 17.7 Hz, 1 H, HbC(3)],
3.72 (s, 3 H, OMe), 4.65 [deg br dt, J = 4.5, 8.8 Hz, 1 H, HC(2)], 5.10 (s, 2 H, PhCH2), 5.12, 5.18 (2 × d, J = 12.8 Hz,
2 H, PhCH2), 5.95 (d, J = 9.0 Hz, 1 H, NH), 7.26–7.36 (m, 10 H, 2 × Ph), 7.71 [s, 1 H, HC(5¢)]
7a
7b
7c
3.48 [br d, J = 5.9 Hz, 2 H, H2C(3)], 3.78 (s, 3 H, OMe), 4.80 [deg br dt, J = 6.2, 7.9 Hz, 1 H, HC(2)], 5.06, 5.14 (2 × s,
4 H, 2 × PhCH2), 6.03 (d, J = 8.3 Hz, 1 H, NHCOOBn), 7.25–7.34 (m, 10 H, 2 × Ph), 7.91 [s, 1 H, HC(3¢)]; HN(1¢)
exchanged
3.37 [dd, J = 4.9, 14.3 Hz, 1 H, HaC(3)], 3.50 [dd, J = 10.6, 14.3 Hz, 1 H, HbC(3)], 3.81 (s, 3 H, OMe), 4.54 [br ddd,
J = 4.5, 8.7, 10.2 Hz, 1 H, HC(2)], 4.95, 5.03 (2 × d, J = 12.4 Hz, 2 H, PhCH2), 5.07 (s, 2 H, PhCH2), 5.72 (d, J = 8.7
Hz, 1 H, NH), 7.20–7.48 (m, 15 H, 3 × Ph), 7.98 [s, 1 H, HC(3¢)]
3.31 [dd, J = 4.5, 14.3 Hz, 1 H, HaC(3)], 3.46 [dd, J = 10.9, 13.9 Hz, 1 H, HbC(3)], 3.80, 3.83 (2 × s, 6 H, 2 × OMe),
4.55 [deg ddd, J = 4.5, 8.7, 10.9 Hz, 1 H, HC(2)], 4.95, 5.03 (2 × d, J = 12.4 Hz, 2 H, PhCH2), 5.07 (s, 2 H, PhCH2),
5.75 (d, J = 8.3 Hz, 1 H, NH), 6.94 (d, J = 8.7 Hz, 2 H, C6H4), 7.20–7.37 (m, 12 H, 2 × Ph, 2 H of C6H4), 7.95 [s, 1
H, HC(3¢)]
7d
7e
CDCl3
CDCl3
3.31 [dd, J = 8.7, 14.3 Hz, 1 H, HaC(3)], 3.46 [dd, J = 5.6, 14.7 Hz, 1 H, HbC(3)], 3.82 (s, 3 H, OMe), 4.47 [deg br
dt, J = 6.5, 7.9 Hz, 1 H, HC(2)], 4.97 (s, 2 H, PhCH2), 5.06, 5.11 (2 × d, J = 12.8 Hz, 2 H, PhCH2), 5.50 (d, J = 7.9
Hz, 1 H, NH), 7.22–7.35 (m, 10 H, 2 × Ph), 8.07 [s, 1 H, HC(3¢)]
3.73 [dd, J = 11.3, 13.6 Hz, 1 H, HaC(3)], 3.83 (s, 3 H, OMe), 3.98 [dd, J = 4.5, 13.6 Hz, 1 H, HbC(3)], 5.01 (s, 2 H,
PhCH2), 5.07 [br ddd, J = 4.6, 8.2, 11.5 Hz, 1 H, HC(2)], 5.19 (s, 2 H, PhCH2), 6.95 (d, J = 7.9 Hz, 1 H, NH), 7.23–
7.37 [m, 11 H, 2 × Ph, HC(5¢¢)], 7.84–7.88 [m, 2 H, HC(3¢¢), HC(4¢¢)], 8.02 [s, 1 H, HC(3¢)], 8.38 [dt, J = 1.4, 4.9 Hz,
1 H, HC(6¢¢)]
7f
CDCl3
CDCl3
3.85 (s, 3 H, OMe), 4.00 [dd, J = 11.3, 13.6 Hz, 1 H, HaC(3)], 4.21 [dd, J = 4.5, 13.6 Hz, 1 H, HbC(3)], 4.95, 5.00
(2 × d, J = 12.4 Hz, 2 H, PhCH2), 5.08 [br ddd, J = 4.4, 9.0, 11.3 Hz, 1 H, HC(2)], 5.20 (s, 2 H, PhCH2), 6.36 (d, J =
9.0 Hz, 1 H, NH), 7.20–7.39 (m, 10 H, 2 × Ph), 7.53–7.57 (m, 3 H, Ph), 7.99 [d, J = 9.4 Hz, 1 H, HC(5¢¢)], 8.05–8.10
(m, 2 H, Ph), 8.08 [s, 1 H, HC(3¢)], 8.11 [d, J = 8.3 Hz, 1 H, HC(4¢¢)]
7¢f
1.27 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.89 (s, 3 H, OMe), 4.02 [dd, J = 10.9, 13.6 Hz, 1 H, HaC(3)], 4.15–4.24 (m, 2 H,
CH3CH2), 4.19 [dd, J = 3.0, 7.5 Hz, 1 H, HbC(3)], 4.95, 5.00 (2 × d, J = 12.4 Hz, 2 H, PhCH2), 4.93–5.01 [m, 1 H,
HC(2)], 6.28 (d, J = 8.3 Hz, 1 H, NH), 7.20–7.39 (m, 5 H, Ph), 7.53–7.58 (m, 3 H, Ph), 8.00 [d, J = 9.0 Hz, 1 H,
HC(5¢¢)], 8.07–8.12 (m, 2 H, OPh), 8.09 [s, 1 H, H–C(3¢)], 8.13 [d, J = 9.8 Hz, 1 H, H–C(4¢¢)]
7g
CDCl3
CDCl3
3.83 [dd, J = 10.9, 13.2 Hz, 1 H, HaC(3)], 3.84 (s, 3 H, OMe), 4.00 [dd, J = 4.5, 13.2 Hz, 1 H, HbC(3)], 5.00, 5.18
(2 × s, 4 H, 2 × PhCH2), 5.12 [br ddd, J = 4.9, 9.0, 10.9 Hz, 1 H, HC(2)], 6.33 (d, J = 8.3 Hz, 1 H, NH), 7.23–7.38 [m,
11 H, 2 × Ph, HC(5¢¢)], 8.08 [s, 1 H, HC(3¢)], 8.74 [d, J = 4.9 Hz, 2 H, HC(4¢¢), HC(6¢¢)]
7¢g
1.25 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.84 [dd, J = 10.9, 13.2 Hz, 1 H, HaC(3)], 3.87 (s, 3 H, OMe), 3.99 [dd, J = 4.9,
13.2 Hz, 1 H, HbC(3)], 4.11–4.24 (m, 2 H, CH3CH2), 5.00 (s, 2 H, PhCH2), 5.07 [br ddd, J = 5.3, 9.1, 10.9 Hz, 1 H,
HC(2)], 6.26 (d, J = 8.7 Hz, 1 H, NH), 7.25–7.38 [m, 6 H, Ph, HC(5¢¢)], 8.11 [s, 1 H, HC(3¢)], 8.87 [d, J = 4.5 Hz, 2
H, HC(4¢¢), HC(6¢¢)]
7h
CDCl3
3.37 [dd, J = 5.7, 14.3 Hz, 1 H, HaC(3)], 3.51 [dd, J = 9.0, 14.7 Hz, 1 H, HbC(3)], 3.77, 3.81 (2 × s, 6 H, NMe, OMe),
4.54–4.63 [m, 1 H, HC(2)], 5.03 (s, 2 H, PhCH2), 5.12, 5.18 (2 × d, J = 12.4 Hz, 2 H, PhCH2), 5.91 (d, J = 7.9 Hz, 1
H, NH), 7.26–7.40 (m, 10 H, 2 × Ph), 7.78 [s, 1 H, HC(3¢)]
+
8a
DMSO-d6 3.20 [dd, J = 7.9, 14.7 Hz, 1 H, HaC(3)], 3.34 (br s, 3 H, NH3 ), 3.37 [dd, J = 5.3, 15.8 Hz, 1 H, HbC(3)], 3.67 [dd,
J = 5.6, 7.9 Hz, 1 H, HC(2)], 3.73 (s, 3 H, OMe), 8.04 [s, 1 H, HC(3¢)]
+
8b
8e
DMSO-d6 3.17 [d, J = 7.9 Hz, 2 H, H2C(3)], 3.32 (br s, 3 H, NH3 ), 3.52 [t, J = 7.9 Hz, 1 H, HC(2)], 3.79 (s, 3 H, OMe), 7.49–
7.57 (m, 5 H, Ph), 8.00 [s, 1 H, HC(3¢)]
+
DMSO-d6 3.32 (br s, 3 H, NH3 ), 3.45 [dd, J = 9.4, 13.6 Hz, 1 H, HaC(3)], 3.59 [dd, J = 5.7, 9.0 Hz, 1 H, HbC(3)], 3.80 (s, 3 H,
OMe), 3.91 [dd, J = 5.7, 13.6 Hz, 1 H, HC(2)], 7.51 [ddd, J = 1.1, 4.9, 7.5 Hz, 1 H, HC(5¢¢)], 7.79 [ddd, J = 1.1, 7.5,
8.3 Hz, 1 H, HC(4¢¢)], 8.08 [ddd, J = 0.8, 1.9, 8.3 Hz, 1 H, HC(3¢¢)], 8.09 [s, 1 H, HC(3¢)], 8.55 [ddd, J = 0.8, 1.9, 4.9
Hz, 1 H, HC(6¢¢)]
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

PAPER
Enaminone-Based Synthesis of (S)-3-(Pyrazolyl)alanines from L-Aspartic Acid
2383
Table 3 1H NMR Data for Compounds 4, 5, 7, 7¢, 8, 10, and 11 (continued)
1H NMR [d (ppm)]a
Compound Solvent
10b
CDCl3
3.02 [d, J = 5.5 Hz, 2 H, H2C(3)], 3.26 [d, J = 23.4 Hz, 1 H, HaC(4¢)], 3.41 [d, J = 23.6 Hz, 1 H, HbC(4¢)], 4.78 [deg
br dt, J = 5.5, 8.0 Hz, 1 H, HC(2)], 5.10 (s, 2 H, PhCH2), 5.13, 5.26 (2 × d, J = 12.1 Hz, 2 H, PhCH2), 5.71 (d, J = 8.2
Hz, 1 H, NH), 7.17 (tt, J = 1.9, 7.5 Hz, 1 H, Ph), 7.25–7.39 (m, 12 H, 2 × Ph, 2 H Ph), 7.75 (ddd, J = 2.3, 3.4, 8.7 Hz,
2 H, Ph)
10e
CDCl3
3.07 [dd, J = 4.9, 15.5 Hz, 1 H, HaC(3)], 3.22 [dd, J = 5.3, 15.5 Hz, 1 H, HbC(3)], 4.76 [deg br dt, J = 5.0, 8.6, Hz, 1
H, HC(2)], 5.12, 5.13 (2 × s, 2 H, PhCH2), 5.13, 5.20 (2 × d, J = 12.4 Hz, 2 H, PhCH2), 5.31 [s, 1 H, HC(4¢)], 5.87 [d,
J = 8.7 Hz, 1 H, NHCO], 7.13 [ddd, J = 1.1, 5.3, 7.2 Hz, 1 H, HC(5¢¢)], 7.23–7.38 (m, 10 H, 2 × Ph), 7.68 [d, J = 8.3
Hz, 1 H, HC(3¢¢)], 7.79 [ddd, J = 1.5, 7.2, 8.7 Hz, 1 H, HC(4¢¢)], 8.23 [ddd, J = 0.9, 1.7, 5.2 Hz, 1 H, HC(6¢¢)]; HN(1¢)
exchanged
10i
CDCl3
CDCl3
CDCl3
3.05 [d, J = 5.7 Hz, 2 H, H2C(3)], 3.32 [d, J = 23.4 Hz, 1 H, HaC(4¢)], 3.48 [d, J = 23.4 Hz, 1 H, HaC(4¢)], 4.71–4.83
[m, 1 H, HC(2)], 5.10 (s, 2 H, PhCH2), 5.13, 5.28 (2 × d, J = 12.1 Hz, 2 H, PhCH2), 5.66 (d, J = 6.8 Hz, 1 H, NH),
7.23–7.33 (m, 10 H, 2 × Ph), 7.95, 8.21 (2 × br d, J = 9.4 Hz, 4 H, C6H4)
11a
11h
2.55 [dd, J = 14.7, 16.6 Hz, 1 H, HaC(4)], 3.23 [dd, J = 6.4, 16.2 Hz, 1 H, HbC(4)], 3.36, 3.43 (2 × d, J = 16.8 Hz, 2
H, CH2COOMe), 3.75 (s, 3 H, OMe), 4.32 [ddd, J = 4.9, 6.8, 14.7 Hz, 1 H, HC(5)], 5.13 (s, 2 H, PhCH2), 5.71 (br s,
1 H, NHCOOBn), 7.31–7.38 (m, 5 H, Ph), 8.44 [br s, 1 H, HN(1)]
2.49 [dd, J = 15.1, 16.2 Hz, 1 H, HaC(4)], 3.23 [dd, J = 6.4, 16.2 Hz, 1 H, HbC(4)], 3.35 (s, 3 H, NMe), 3.36, 3.40 (d,
J = 16.6 Hz, 2 H, CH2COOMe), 3.74 (s, 3 H, OMe), 4.23 [ddd, J = 4.5, 6.8, 15.6 Hz, 1 H, HC(5)], 5.12 (s, 2 H, PhCH2),
5.79 (br s, 1 H, NH), 7.28–7.40 (m, 5 H, Ph)
a ‘deg’ = degenerate.
Table 4 13C NMR Data for Compounds 4, 5, 7f,g, 7¢f,g, 8a,b,e, and 11a,h
Compound Solvent
13C NMR [d (ppm)]
4
5
CDCl3
CDCl3
45.0, 49.2, 50.4, 52.8, 67.5, 68.0, 128.5, 128.60, 128.64, 128.8, 128.9, 129.0, 135.6, 136.5, 156.4, 167.3, 170.9, 201.0
25.4, 34.3, 43.5, 49.5, 51.4, 51.5, 67.2, 67.3, 128.37, 128.39, 128.5, 128.6, 128.8, 136.2, 136.9, 156.6, 159.1, 168.2,
172.3, 194.3
7f
CDCl3
CDCl3
CDCl3
CDCl3
D2O
28.7, 52.1, 54.3, 67.0, 67.6, 116.5, 122.7, 127.0, 127.6, 128.2, 128.3, 128.4, 128.5, 128.8, 128.9, 129.6, 130.9, 135.7,
135.9, 136.9, 143.8, 145.0, 155.7, 156.5, 159.2, 164.1, 171.6
7¢f
7g
7¢g
14.5, 28.6, 52.1, 54.1, 62.0, 66.9, 116.5, 122.9, 127.1, 127.6, 128.2, 128.3, 128.8, 129.6, 130.9, 135.7, 136.9, 143.8,
145.1, 155.7, 156.4, 159.3, 164.1, 171.7
28.9, 52.1, 54.4, 67.1, 67.6, 116.5, 120.2, 128.3, 128.4, 128.6, 128.8, 128.8, 129.0, 135.9, 136.8, 143.5, 145.4, 156.5,
157.0, 159.3, 164.4, 171.8
14.5, 29.0, 52.1, 54.2, 61.9, 67.0, 116.5, 120.2, 128.3, 128.4, 128.8, 136.9, 143.5, 145.6, 156.4, 157.1, 159.3, 164.4,
172.0
8a
8b
8e
29.3, 35.9, 53.3, 53.3, 55.4, 112.9, 167.1, 174.5
DMSO-d6 28.2, 52.0, 53.1, 112.8, 127.6, 129.8, 130.0, 139.5, 142.0, 145.1, 164.3, 169.9
DMSO-d6, 27.3, 48.9, 53.5, 115.1, 116.2, 122.8, 139.2, 139.8, 143.2, 148.4, 152.5, 162.7, 173.0
80 °C
11a
11h
CDCl3
CDCl3
32.2, 42.4, 46.8, 52.9, 67.6, 128.5, 128.7, 129.0, 136.4, 151.1, 156.4, 166.3, 169.6
32.3, 36.9, 42.6, 47.1, 52.8, 67.5, 128.5, 128.6, 129.0, 136.5, 150.6, 156.4, 164.6, 169.6
and Lek d.d., a new Sandoz company (Ljubljana, Slovenia). The au-
Acknowledgment
thors wish to express their gratitude to the Alexander von Humboldt
Foundation, Germany, for the donation of a Büchi medium pressure
liquid chromatograph.
The financial support from the Slovenian Research Agency through
grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully
acknowledged. We acknowledge with thanks the financial support
from pharmaceutical companies Krka d.d. (Novo mesto, Slovenia)
Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York

2384
U. Uršič et al.
PAPER
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Synthesis 2006, No. 14, 2376–2384 © Thieme Stuttgart · New York