α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

Article abstract of DOI:10.1016/j.tet.2013.11.008

A new and simple synthesis of novel N-protected methyl 5-substituted-4- hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates ar

Full text of DOI:10.1016/j.tet.2013.11.008

Tetrahedron 69 (2013) 11092e11108
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a-Amino acid derived enaminones and their application in the
synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-
carboxylates and other heterocycles
a
,
a
,
,b
Uros Groselj , Mojca Zorz , Amalija Golobic , Branko Stanovnik b, Jurij Svete a
ꢀ a
ꢀ a
ꢀ
*
ꢀ
ꢀ
a
ꢀ
ꢀ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva cesta 5, PO Box 537, 1000 Ljubljana, Slovenia
b EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-
carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps
starting from N-protected -amino acids. The key intermediates are enaminones, which can also be
Received 17 September 2013
Received in revised form 18 October 2013
Accepted 4 November 2013
Available online 8 November 2013
a
isolated, characterized, and used for the construction of other functionalized heterocycles, before they
spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation
but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
b-Keto esters
Enaminones
Pyrroles
Reduction
Heterocycles
1. Introduction
aminomethylenemalonate derivatives gives 3-hydroxypyrrole-2,4-
dicarboxylates.22e25 Enaminonitriles have been cyclized to 2-cyano
Pyrroles represent one of the most important groups of het-
erocyclic compounds. For the synthesis, reactivity, physical prop-
erties, and natural occurrence of pyrroles and their numerous
applications see some of the selected literature.1e11
3-hydroxypyrrole-4-carboxylates.26,27 Synthesis of oxopyrrolidine
derivatives followed by oxidation furnished the corresponding
pyrroles.28,29 Enamines, derived from
a-amino acids and dimethyl
acetylenedicarboxylate, cyclize in the presence of sodium meth-
oxide to 4-hyxroxypyrrole-2,3-dicarboxylates.30 Similarly, 4-
hyxroxypyrrole-2,3-dicarboxylates were prepared in one-step
Not taking into consideration the tetramic acids,12 there are
numerous ways for the synthesis of 3- (i.e., 4-)-hydroxypyrroles.13
The parent 3-hydroxypyrrole is highly unstable and was prepared
by mild methanolysis of its trimethylsilyl derivative.14,15
from acetylenic esters and
bodiimide under neutral conditions,31 or in the presence of
transition-metal oxides.32 Cyclization of
-alkoxycarbonyl- -ami-
a-amino acids with isocyanide or car-
Differently substituted 4-hydroxypyrrole-3-carboxylic esters
have been prepared in several ways. They can be synthesized via
base-catalyzed Dieckmann cyclization of Schiff bases derived from
a
a
nohydrazones with dialkyl acetylenedicarboxylates gave 4-
hydroxy-1H-pyrrole-2,3-dicarboxylates.33
b
-keto esters and
chloroacetyl- -aminocrotonic esters cyclize into 4-hydroxypyrrole-
3-carboxylic esters.17,18 Enamines derived from
-amino acids react
rapidly with trifluoroacetic anhydride to give the corresponding
pyrrole derivatives.19 Reaction of enamines, prepared from
-keto
esters or -keto nitriles, with -keto aldehydes furnish 4-
hydroxypyrrole-3-carboxylic esters.20 In the same way, a three-
component reaction of -dicarbonyl compounds with arylglyoxals
a
-amino acid esters.16 Under basic conditions,
a
-
While investigating the possibility of constructing various het-
erocycles from protected ornithine ((S)-Boc-Orn(Z)-OH (1k)) via
the corresponding b-keto ester 2k, the reaction of 2k with N,N-
b
a
dimethylformamide dimethyl acetal (DMFDMA) yielded, upon
chromatographic isolation, supposedly the expected enaminone
3k. By chance, the product was left to stand overnight in a closed
flask, which after opening smelled strongly of dimethylamine.
Subsequent 1H NMR investigation revealed that the desired
enaminone 3k spontaneously cyclized into 4-hydroxy-pyrrole 4k,
which is in equilibrium with the corresponding 4-oxo tautomer 4k0
with traces of enaminone 3k as detected by mass spectrometry. A
subsequent SciFinder literature search revealed that there are no
b
b
a
b
in the presence of ammonium acetate gives 2-alkyl-5-aryl-4-
hydroxypyrrole-3-carboxylates.21 The Dieckmann condensation of
* Corresponding author. Tel.: þ386 1 2419 100; fax: þ386 1 2419 220; e-mail
enaminones of type A derived from N-protected a-amino acid b-
ꢀ
address: uros.groselj@fkkt.uni-lj.si (U. Groselj).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.008

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11093
Table 1
Synthesized
keto esters reported in the literature. Even more, the literature
search for N-carbamate protected 5-substituted-4-hydroxypyrrole-
3-carboxylates of type B or its 4-oxo-4,5-dihydro tautomers of type
C gave no hits (Fig. 1). This prompted us to investigate the subject
further. Thus, herein we report the results of this research: (i)
a novel and simple methodology for the construction of N-pro-
tected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates of
type B/C in a two-step synthesis starting from commercially
available N-protected amino acid esters via enaminone in-
termediates, (ii) further transformations of pyrrole derivatives, and
(iii) potential application of enaminone intermediates of type A in
the construction of various heterocycles with orthogonally pro-
tected amino and carboxy groups.
b-keto esters 2aeq
Entry
R
PG
(R) or
(S)
b-Keto Yield Ref.
ester
(%)
1
2
3
H
Me
Me
Boc
Boc
Cbz
d
2a
2b
2c
76
91
92
34
35
36,37
(S)
(S)
4
5
Boc
Cbz
(S)
(S)
2d
2e
73
62
38
39
6
7
8
9
Boc
Boc
Cbz
Phth
(R)
(S)
(S)
(S)
2f
65
87
73
88
d
2g
2h
2i
35,40
35
41
10
Ph
Boc
(R)
2j
78
d
Fig. 1. SciFinder literature search for compounds of type AeC as of September 2013.
11
12
Boc
Boc
(S)
(S)
2k
2l
95
89
d
d
2. Results and discussion
13
14
15
16
Cbz
Cbz
Boc
(S)
(S)
(R)
d
2m
2n
2o
2p
85
83
87
84
d
d
d
d
The starting
-amino acids 1aeo, dipeptide 1p,
1q, and N-Boc- -alanine (1r), respectively, using Masamunee-
b
-keto esters 2aer were prepared from N-protected
a
a
,b
-unsaturated -amino acid
a
b
Claisen condensation (Scheme 1, Table 1). The stereochemical in-
tegrity of the chiral products, derived from nonracemic starting
compounds, has not been checked at any level of further
transformations.
17
d
2q
17
42
the enaminone intermediate 3, a quick isolation (flash column
chromatography) has to be done when most of the starting -keto
b
ester 2 transforms into enaminone intermediate 3 before the
buildup of the final pyrrole product 4/40, as judging by TLC-analysis.
The isolated enaminone 3 has to be characterized immediately due
to the spontaneous cyclization into the respective pyrrole product
4/40. Thus, in the case of
b
-keto ester 2f, beside the final pyrrole
derivatives 4f/4f0 also the enaminone intermediate 3f was isolated.
When -keto ester 2a was treated with excess DMFDMA at elevated
b
temperature, the 4-oxopyrrole-3-carboxylate 5a was isolated in
40% yield, formed via enaminone 3a and pyrroles 4a/4a0 (R¼H).
Reaction of 5a with phenylhydrazine hydrochloride (6) gave the
substitution product 7a in 16%, the structure of which was de-
termined by single crystal X-ray analysis (Fig. 3). Attempts to pre-
pare the C5 unsubstituted pyrrole derivatives 4a/4a0 in one-step
failed due to the formation of 5a and other by-products. Therefore,
2a was treated with excess DMFDMA at room temperature fol-
lowed by isolation of enaminone 3a in 76% yield. The enaminone 3a
was left to stand in an open flask overnight at room temperature to
cyclize into the desired C5 unsubstituted pyrrole derivatives 4a/4a0.
Scheme 1. Synthesis of b-keto esters 2aer.
Next,
b-keto esters 2aeq were treated with N,N-dime-
thylformamide dimethyl acetal (DMFDMA) (1e3 equiv) in anhy-
drous toluene at room temperature or at elevated temperature. The
acidic methylene group of the b-keto esters 2 reacts with DMFDMA
to give the corresponding enaminone intermediates44 3 followed
by in situ cyclization into the final 4-hydroxy-pyrrole-3-
carboxylates 4, which are in equilibrium with 4-oxo-pyrrole-3-
carboxylate tautomers 40 (Scheme 2, Table 2). In principle, N-Cbz-
or N-Boc-protected enaminone intermediates 3 can be isolated and
characterized before they cyclize into the corresponding pyrrole
derivatives 4/40. The progress of the transformation of the starting
The reaction of N-phthaloyl protected b-keto ester 2i, as expected,
stopped at the enaminone product 3i in 73% yield due to the fully
protected amino group. Transformations of 2p and 2q into re-
spective pyrrole derivatives failed, complex mixture of products
b
-keto esters 2 into pyrrole derivatives 4/40 via enaminone in-
termediates 3 can be followed by simple thin layer chromatography
(TLC). As generally observed, the initially formed enaminone in-
termediate 3 has a much smaller retention factor (Rf) compared to
were formed. Finally, the reaction of N-Boc-b-alanine derived b-
keto ester 2r also stopped at the enaminone 3r45 stage. Even after
prolonged heating of 3r, the cyclization into the corresponding
dihydropyridine 8r did not take place. Upon treatment of 3r with t-
BuOK in anhydrous THF the desired six-membered heterocycle 8r
was obtained in 52% yield. The structure of 8r was confirmed by
the starting
tained upon cyclization of enaminone intermediates 3, have
a similar retention factor as the starting -keto ester 2, only the spot
on the TLC-plate is more ‘stretched’ (see Fig. 2). In order to obtain
b
-keto ester 2. The final pyrrole derivatives 4/40, ob-
b

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11094
single crystal X-ray analysis (Scheme 2, Table 2, Fig. 4). In the re-
actions of N-protected -keto esters 2 with excess DMFDMA, no N-
methylated side products were observed.46
least, this must be due to the massive 1,5-repulsion47 between the
OH and i-Pr groups in the 4-hydroxy tautomeric form 4d (this strain
is partially relieved in the 4-oxo tautomer 4d0) (see Table 2).
b
Scheme 2. Synthesis of pyrrole derivatives 4/40, 5a, 7a, and dihydropyridine 8r.
Table 2
Synthesized enaminones 3 and pyrrole derivatives 4/40
Entry
R
PG
T (ꢀC) 3, yield 4/40 (solvent)
Yield
(%)
(%)
1
2
3
H
Me
Me
Boc rt
Boc 75
Cbz 75
3a, 76
d
4a/4a0¼1:0.38a
4b/4b0¼1:0.54a
4c/4c0¼1:0.62b
100c
33
58
d
4
5
Boc 75
Cbz 75
d
d
4d/4d0¼0.08:1a
4e/4e0¼1:0.12a
54
67
6
7
8
9
Boc 75
Boc 75
Cbz 75
Phth rt
3f, 47
d
4f/4f0¼1:0.74a
4g/4g0¼1:0.70a
4h/4h0¼1:0.66a
d
41
84
48
d
d
Fig. 2. TLC-follow up of the transformation of the starting b-keto esters 2 into final
3i, 73
pyrrole products 4/40 via enaminone intermediates 3. As a mobile phase mixtures of
EtOAc and petroleum ether were used.
10
Ph
Boc 75
d
4j/4j0¼1:0.35a
72
C15
11
12
Boc 75
Boc 75
d
d
4k/4k0¼1:1a
96
55
C16
4l/4l0¼1:0.61a
C13
O2
C11
C6
13
14
Cbz rt
Cbz rt
d
d
4m/4m0¼1:0.85a 45
C12
C10
N3
C14
C4
4n/4n0¼0.24:1a
66
O3
C3
C5
N1
N2
C9
C7
15
Boc 75
d
4o/4o’¼1:0.28a
71
C8
C1
C2
a
1H NMR in DMSO-d6.
1H NMR in CDCl3.
Prepared from 3a.
O1
C17
b
c
O5
O4
Equilibrium between the 4-hydroxy 4 and the 4-oxo 40 tauto-
C18
meric forms in DMSO is shifted toward the 4-hydroxy form with the
exception of 5-i-Pr (4d/4d0¼0.08:1) and 5-tert-butoxymethyl (4n/
4n0¼0.24:1) substituted pyrrole derivatives. In the former case at
Fig. 3. Single crystal X-ray analysis of pyrrole 7a.

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11095
namely alkylations and reductions. Alkylation of 4g/4g0 in DMF in
the presence of K2CO3 with benzyl bromide gave the C5-benzylated
product 9g in 73% yield, exclusively, whereas reaction with 4k/4k0
furnished the major C-alkylated product 9k and the minor O-
alkylated product 10k in 48% and 12% yields, respectively. Similarly,
reaction of 4g/4g0 with methyl iodide furnished the major C-alky-
lated product 11g and the minor O-alkylated product 12g in
54% and 18% yields, respectively, while the same reaction with 4k/
4k0 produced only the O-methylated product 12k in 41% yield
(Scheme 5, Table 3). The structure of 9g was confirmed by single
crystal X-ray analysis (Fig. 6). Alkylations of similar systems are
described in the literature.17,28,55e57
C2
C1
O2
C3
O1
N1
C6
i
C9
O5
C10
C5
C4
O3
C9
C11
O4
C8
Fig. 4. Single crystal X-ray analysis of dihydropyridine derivative 8r.
Literature reported NaCNBH3 reduction of a pyrrole structur-
ally similar to pyrroles 4/40 gave 4-hydroxypyrrolidine product as
a mixture of stereoisomers.58 Similarly, reduction of 4g/4g0 with
2 equiv of NaBH4 in MeOH at room temperature gave four prod-
ucts in a ratio of 13g/14g/15g/16g¼1:0.67:0.67:0.73, which were
chromatographically separated. Products 13g and 14g are di-
astereoisomers formed after the reduction of the endocyclic
double bond and the keto group, while products 15g and 16g are
diastereoisomers formed after the additional reduction of the
ester group to the hydroxymethyl group. In the 1H and 13C NMR
spectra of the isolated products, two rotamers/conformers of
different ratios can be observed. HPLC analysis of each of the
Cyclization of enaminone intermediates 3 into pyrrole products
4/40 can formally take place either as a 1,4-addition followed by
elimination of dimethylamine or, alternatively, via 1,2-addition of
the protected amine to the imine functionality of the resonance
structure 30 (enabled by the pushepull system) followed by elim-
ination. Considering Baldwin’s rules,48,49 the former is classified as
5-endo-trig cyclization and is therefore unfavorable, whereas the
latter is a favorable 5-exo-trig cyclization (Scheme 3).
products on
a chiral column shows they are racemic di-
astereoisomers. For HPLC analysis and for the NMR-observed
rotamers/conformers see Supplementary data. When the same
reaction was performed at ꢁ5 ꢀC, only 13g and 14g were formed
in a ratio of 13g/14g¼47:53, which makes this reduction diaster-
eoselective (two out of four possible diastereoisomers). Single
crystal X-ray analysis of 13g and 14g revealed their relative ste-
reochemistry (see Figs. 7 and 8). The relative configuration of 15g
and 16g has been confirmed by reduction of 13g and 14g, re-
spectively, with large excess NaBH4. In the same way, reduction
of 4k/4k0 at ꢁ5 ꢀC gave only two diastereoisomers 13k and 14k
in a 1:1 ratio, which could, unfortunately, not be separated
(Scheme 6, Table 4). The relative configuration of 13k and 14k has
been assigned on the basis of 1H NMR spectra of 13g and 14g,
respectively.
As there are no N-protected-a-amino-b-keto ester derived
Scheme 3. The proposed mechanism for the cyclization considering the Baldwin’s
rules.
enaminone intermediates of type A (see Fig. 1) reported in the lit-
erature, we wanted to show they could be useful synthons in the
synthesis of various heterocyclic systems. In the case of stable fully
N-protected enaminone 3i, the reaction with phenylhydrazine hy-
drochloride (6) gave pyrazole 17i in 81% yield, while reaction with
3-amino-1H-pyrazole-4-carboxylate (18) furnished compound 19i
in 32% yield. On the other hand, the partially N-protected (Boc, Cbz,
dipeptide) enaminone intermediates 3 first had to be prepared in
Although pyrrole derivatives 4/40 with various substituents in
position 5 could easily be prepared in low to very good yields
(33e96%), most of them are subjected to partial aerial oxidation at
position 5, which could not be prevented given the way the prod-
ucts were isolated (column chromatography) (Scheme 4). The same
observation has been made previously with other N-substituted
and N-unsubstituted 4-hydroxypyrroles.20,50e54 Thus, in the worst
case of pyrrole derivatives 4b/4b0, after isolation, ca. 15% of the
corresponding oxidation decomposition product is present (see
Fig. 5). Other pyrrole derivatives are less susceptible to oxidation, in
particular ornithine- 4k/4k0 and lysine-derived pyrroles 4l/4l0,
which are not oxidized even after prolonged storage (ca. 2 months).
situ from the corresponding
b-keto esters 2 and DMFDMA in
CH2Cl2, and then cyclized in MeOH with various dinucleophiles
before they cyclized into pyrroles 4/40 (see Fig. 2 and the accom-
panying explanation). In that way, the in situ generated enaminone
intermediates 3h, 3k, 3l, and 3p, prepared from the corresponding
b-keto esters, gave with hydrazine 6 pyrazole products 17h, 17k,
17l, and 17p, respectively. Furthermore, reaction of enaminone in-
termediate 3l with benzamidine hydrochloride (20), 3-amino-1H-
pyrazole-4-carboxylate (18), and 5-(methylthio)-1H-1,2,4-triazol-
3-amine (21) yielded pyrimidine 22l, pyrazolo-pyrimidine 19l, and
triazolo-pyrimidine 23l, respectively (Scheme 7, Table 5). All these
reactions proceed via initial acid catalyzed substitution of the
dimethylamino group by the more nucleophilic part of the dinu-
cleophile followed by cyclization to the ketone.44 The structure of
17i was confirmed by single crystal X-ray analysis (Fig. 9). The
structures of bicyclic heterocycles 19i, 19l, and 23l were postulated
on the basis of structures of related products obtained via closely
related transformations.59e61
Scheme 4. Aerial oxidation of 5-substituted-4-hydroxy/4-oxo-pyrroles 4/40.
Phenylalanine 4g/4g0 and ornithine 4k/4k0 derived 4-
hydroxypyrroles have been selected for further transformations,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11096
1
Fig. 5. Section of the H NMR spectra of pyrrole derivatives 4b and 4b0 (a) in DMSO-d6 immediately after isolation; (b) after prolonged standing in DMSO-d6.
C15
C16
C17
C14
C13
O2
O1
C19
C3
C20
C2
C18
C4
C12
O3
C1
N
C7
C21
C6
O4
C5
C8
C9
O5
C22
C25
C24
C11
C10
Scheme 5. Alkylation of 4g/4g0 and 4k/4k0 with BnBr and MeI.
C23
Fig. 6. Single crystal X-ray analysis of pyrrole 9g.
C8
C9
Table 3
Products of alkylation of 4g/4g0 and 4k/4k0 with BnBr and MeI
C10
C7
Entry
1
Reactants
Product
R
R1
Yield (%)
73
4g/4g0þBnBr
9g
Bn
C11
O1
2
3
4
4k/4k0þBnBr
4g/4g0þMeI
4k/4k0þMeI
9k
Bn
Bn
Me
48
12
54
C6
C5
O5
C18
C1
10k
11g
C2
N1
C12
5
6
12g
12k
Me
Me
18
41
C17
O3
C4
C14
O4
C3
C15
C13
O2
C16
Fig. 7. Single crystal X-ray analysis of pyrrolidine 13g.
3. Conclusions
A new methodology for the synthesis of N-protected methyl
5-substituted-4-hydroxypyrrole-3-carboxylates in two steps
pyrroles 4/40 are subjected to aerial oxidation, but can nevertheless
be used in further transformations, for example, alkylations and
reductions. Reduction of 4/40 with NaBH4 yielded two out of four
racemic pyrrolidine diastereoisomers, their relative configuration
was determined by single crystal X-ray analysis. Pyrroles 4/40 are
challenging substrates for stereoselective reductions/additions to
produce differently functionalized pyrrolidines. Finally, it has been
shown that the until now unreported enaminone intermediates 3
has been introduced. Starting N-protected
a-amino acids 1 are
transformed into the corresponding -keto esters 2 using Masa-
b
muneeClaisen homologation followed by reaction with DMFDMA
thus giving enaminone intermediates 3, which spontaneously or
upon heating cyclize to 4-hydroxy-pyrrole products 4, which are in
equilibrium with their 4-oxo tautomers 40. Unfortunately, some

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11097
C15a
O5a
technical grade Na2SO4. Melting points were determined on
a Kofler micro hot stage and on SRS OptiMelt MPA100dAutomated
Melting Point System. The NMR spectra were obtained on a Bruker
UltraShield 500 plus at 500 MHz for 1H and 126 MHz for 13C nu-
cleus, using DMSO-d6 and CDCl3 with TMS as the internal standard,
as solvents. Mass spectra were recorded on an Agilent 6224 Accu-
rate Mass TOF LC/MS, IR spectra on a Bruker ALPHA FT-IR spec-
trophotometer. Microanalyses were performed on a PerkineElmer
CHN Analyzer 2400 II. Thin layer chromatography was performed
on a pre-coated Merck silica gel 60 F254 plates (0.25 mm). Column
chromatography (CC) was performed on silica gel (Silica gel 60,
particle size: 0.035e0.070 mm). Medium-pressure liquid chroma-
O3a
C18a
C3a
O6a
C13a
C4a
N1a
C17a
C12a
C14a
O4a
C2a
C16a
C1a
C11a
O1a
C10a
C5a
C9a
C6a
C7a
€
tography (MPLC) was performed with Buchi Flash Chromatography
C8a
€
€
System (Buchi Fraction Collector C-660, Buchi Pump Module C-605,
Buchi Control Unit C-620) on silica gel (LiChrosphereÒ Si 60 (12
mm)
Fig. 8. Single crystal X-ray analysis of pyrrolidine 14g.
€
and/or LiChroprepÒ Si 60 (15e25
mm)); column dimensions (wet
Scheme 6. NaBH4 reduction of 4g/4g0 and 4k/4k0.
Table 4
Products of reduction of 4g/4g0 and 4k/4k0 with NaBH4
Entry
Reactants
R
Product ratio
Product
Yield (%)
19
1
4g/4g0, rt
13g/14g/15g/16g¼1:0.67:0.67:0.73
13g
14g
15g
16g
7
18
6
2
3
4
5
6
4g/4g0, ꢁ5 ꢀC
4k/4k0, ꢁ5 ꢀC
13g/14g¼47:53
13k/14k¼50:50
13g
14g
33
36
7
8
a
13kþ14ka
80
Could not be separated by column chromatography.
can be isolated and characterized as well as used in the construc-
filled): 22ꢂ460 mm, 36ꢂ460 mm and 40ꢂ460 mm; backpressure:
10e20 bar; detection: UV 254 nm. HPLC analyses were performed
on an Agilent 1260 Infinity LC using CHIRALPAK AD-H (0.46 cm
øꢂ25 cm) and CHIRALCEL OD-H (0.46 cm øꢂ25 cm) as chiral col-
umns. Optical rotations were recorded on a PerkineElmer 241MC
polarimeter.
tion of other
a-amino acid derived heterocycles with various
dinucleophiles. So formed orthogonally protected heterocycles can
be, if needed, introduced into various peptide sequences. Fully N-
protected enaminones are stable compounds.
4. Experimental section
4.1. General
All chemicals were of reagent grade and used as supplied, unless
stated otherwise. They were purchased from SigmaeAldrich.
Starting compounds 1i,62 1p,63 1q,64 and 1865 were prepared fol-
lowing the literature procedures.
All reactions were performed under Argon in dried glassware
using anhydrous solvents except when using aqueous reagents.
Solvents for extractions and chromatography were of technical
grade and were distilled prior to use. Extracts were dried over
The structures of novel compounds 2f, 2j, 2kep, 3a, 3f, 3i, 4a/
4a0e4h/4h0, 4j/4j0e4o/4o0, 5a, 7a, 8r, 9g, 9k, 10k, 11g, 12g, 12k,
13ge16g, 13k/14k, 17h, 17i, 17k, 17l, 17p, 19i, 19l, 22l, and 23l were
determined by spectroscopic methods (1H NMR, 13C NMR, 2D-NMR,

ꢀ
11098
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
22l
17k,h,l,p
19l
23l
Scheme 7. Synthesis of heterocyclic systems from enaminones 3.
Table 5
C14
C18
O2
Heterocycles prepared from enaminones 3
C15
C13
Entry Product
R
PG
X, Y
Yield (%)
C12
N3
C11
C5
C6
C10
C9
C16
1
2
3
4
17h
17i
Cbz
Phth
Boc
Boc
d
d
d
d
11
81
45
51
C4
C17
O3
C19
O1
17k
17l
C7
C3
C8
C27
C20
C21
N1
C22
C26
C2
O4
5
6
17p
19i
d
49
32
C1
C23
C25
C24
N2
Phth
Boc
X¼CH
Y¼CO2Me
Fig. 9. Single crystal X-ray analysis of pyrazole 17i.
7
19l
X¼CH
10
Y¼CO2Me
4.2. Synthesis of b-keto esters from N-protected amino acid-
sdgeneral procedure 1 (GP1)
8
9
22l
23l
Boc
Boc
d
17
9
X¼N
To a solution/suspension of N-protected amino acid (10 mmol)
in anhydrous THF (50 mL) under argon was added CDI (2.01 g,
12.00 mmol) and the resulting reaction mixture was stirred at room
temperature for 2 h, followed by the addition of a solid mixture of
MgCl2 (0.95 g, 9.80 mmol) and methyl potassium malonate (2.37 g,
15.00 mmol). The reaction mixture was stirred at room tempera-
ture for additional 24 h. Volatile components were evaporated in
vacuo, the residue was dissolved in EtOAc (150 mL) and washed
with NaHSO4 (1 M in H2O, 50 mL), NaCl (aq satd, 50 mL), NaHCO3
(aq satd, 20 mL), and NaCl (aq satd, 50 mL). The organic phase was
dried over anhydrous Na2SO4, filtered, and volatile components
evaporated in vacuo. The residue was purified by column
Y¼SMe
IR, HRMS) and by elemental analyses for C, H, and N. Compounds
4a/4a0e4h/4h0, 4j/4j0e4o/4o0, and 13k/14k were characterized as
mixtures of tautomers/stereoisomers, respectively. Compounds 2k,
2o, 3i, 4d/4d0, 8r, 9g, 13ge16g, 17i, 17l, and 22l were obtained in
analytically pure form. Identities of novel compounds, not obtained
in analytically pure form, were confirmed by 13C NMR and HRMS.

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11099
rt
chromatography (CC). Fractions containing the product were
combined and volatile components evaporated in vacuo.
(87%) of white solid; mp 84.5e87.0 ꢀC (lit.:35 mp 85e87 ꢀC). [
a
]
D
rt
ꢁ53.1 (c 0.4, MeOH) (lit.:40
[
a]
ꢁ64.8 (c 0.68, MeOH)). 1H NMR
D
(500 MHz, DMSO-d6):
d
1.31 (s, 9H, Boc); 2.69 (dd, J¼10.4; 13.9 Hz,
4.2.1. Methyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate
(2a).34 General procedure 1 (GP1): Prepared from 1a (1.75 g); CC
(EtOAc/petroleum ether¼1:2). Yield: 1.76 g (76%) of yellow oil. 1H
1H, Ha of H2C(5)); 3.05 (dd, J¼4.6; 13.9 Hz, 1H, Hb of H2C(5)); 3.62
(s, 3H, CO2Me); 3.66 (d, J¼3.0 Hz, 2H, H2C(2)); 4.20e4.26 (m, 1H,
HeC(4)); 7.17e7.30 (m, 5H, Ph); 7.35 (d, J¼8.1 Hz, 1H, NH).
NMR (500 MHz, DMSO-d6): d 1.38 (s, 9H, Boc); 3.60 (s, 2H, CH2); 3.63
(s, 3H, CO2Me); 3.85 (d, J¼5.9 Hz, 2H, CH2); 7.13 (t, J¼5.9 Hz,1H, NH).
4.2.8. (S)-Methyl 4-(((benzyloxy)carbonyl)amino)-3-oxo-5-
phenylpentanoate (2h).35 General procedure
1
(GP1): Prepared
4.2.2. (S)-Methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate
(2b).35 General procedure 1 (GP1): Prepared from 1b (1.89 g); CC
(EtOAc/petroleum ether¼1:2). Yield: 2.23 g (91%) of white solid; mp
from 1h (3.02 g); CC (EtOAc/petroleum ether¼1:2). Yield: 2.60 g
rt
(73%) of pink solid; mp 75.4e76.7 ꢀC (lit.:35 mp 78e80 ꢀC). [
a]
D
ꢁ48.0 (c 0.27, MeOH). 1H NMR (500 MHz, DMSO-d6):
d 2.70 (dd,
48.2e50.6ꢀC (lit.:35 mp 50e52ꢀC). [
a
]rDt ꢁ47.1 (c 0.25, MeOH).1H NMR
J¼10.6; 13.9 Hz,1H, Ha of H2C(5)); 3.11 (dd, J¼4.3; 13.9 Hz,1H, Hb of
H2C(5)); 3.62 (s, 3H, CO2Me); 3.71 (s, 2H, H2C(2)); 4.33e4.39 (m,1H,
HeC(4)); 4.98 (s, 2H, CH2 of Cbz); 7.19e7.37 (m, 10H, 2ꢂPh); 7.82 (d,
J¼8.2 Hz, 1H, NH).
(500 MHz, CDCl3) for the major isomer:
d
1.36 (d, J¼7.2 Hz, 3H, CH3);
1.45 (s, 9H, Boc); 3.55 (d, J¼15.8 Hz,1H, Ha of CH2); 3.60 (d, J¼15.9 Hz,
1H, Hb of CH2); 3.75 (s, 3H, CO2Me); 4.34e4.42 (m, 1H, CH); 5.11 (d,
J¼7.0 Hz, 1H, NH). 1H NMR (500 MHz, CDCl3) for the minor isomer:
d
3.45(s, 2H, CH2); 3.81 (s, 3H, CO2Me). Isomer ratio is 5:1.
4.2.9. (S)-Methyl 4-(1,3-dioxoisoindolin-2-yl)-3-oxo-5-
phenylpentanoate (2i).41 General procedure 1 (GP1): Prepared from
4.2.3. (S)-Methyl 4-(((benzyloxy)carbonyl)amino)-3-oxopentanoate
(2c).36 General procedure 1 (GP1): Prepared from 1c (2.25 g); CC
(EtOAc/petroleum ether¼2:3). Yield: 2.57 g (92%) of brownish-
1i (2.95 g); CC (EtOAc/petroleum ether¼1:1). Yield: 3.10 g (88%) of
rt
white solid; mp 123e128 ꢀC. [
a]
ꢁ2.4 (c 0.26, CH2Cl2). nmax 2945,
D
1748, 1711, 1604, 1495, 1466, 1456, 1442, 1383, 1338, 1306, 1287, 1257,
1208, 1187, 1149, 1096, 1067, 1029, 997, 976, 948, 878, 826, 779, 757,
ꢁ29.9 (c 0.44, MeOH) (lit.:37
[a
]
ꢁ36.3 (c 0.69,
rt
rt
orange oil. [
a
]
D
D
MeOH)). 1H NMR (500 MHz, DMSO-d6):
d
1.20 (d, J¼7.3 Hz, 3H,
720, 706, 655, 639, 620 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 3.25
CH3); 3.61 (s, 3H, CO2Me); 3.65 (d, J¼4.7 Hz, 2H, H2C(2)); 4.13e4.20
(dd, J¼11.4; 13.9 Hz, 1H, Ha of H2eC(5)); 3.51 (dd, J¼4.8; 13.9 Hz, 1H,
Hb of H2eC(5)); 3.60 (s, 3H, CO2Me); 3.83 (d, J¼16.7 Hz, 1H, Ha of
H2eC(2)); 3.89 (d, J¼16.7 Hz, 1H, Hb of H2eC(2)); 5.32 (dd, J¼4.8;
11.4 Hz, 1H, HeC(4)); 7.07e7.22 (m, 5H, Ph); 7.80e7.84 (m, 4H,
(m, 1H, CH); 5.04 (s, 2H, CH2 of Cbz); 7.30e7.40 (m, 5H, Ph); 7.77 (d,
J¼7.3 Hz, 1H, NH). 13C NMR (126 MHz, DMSO-d6):
d 15.6, 45.2, 51.9,
55.5, 65.7, 127.8, 127.9, 128.4, 136.9, 155.9, 167.5, 203.4.
indoline).13C NMR (126 MHz, DMSO-d6):
d 32.7, 45.9, 52.0, 59.7,123.4,
4.2.4. (S)-Methyl 4-((tert-butoxycarbonyl)amino)-5-methyl-3-
oxohexanoate (2d)..38 General procedure 1 (GP1): Prepared from
1d (2.17 g); CC (EtOAc/petroleum ether¼1:2). Yield: 1.99 g (73%) of
126.6, 128.3, 128.8, 130.8, 134.9, 136.9, 167.1, 167.2, 198.2; EI-HRMS: m/
z¼352.1179 (MHþ); C20H18NO5 requires: m/z¼352.1179 (MHþ).
rt
20
orange oil. [
a]
þ11.3 (c 0.29, CH2Cl2) (lit.:38
[a
]
þ28.2 (c 0.62,
4.2.10. (R)-Methyl 4-((tert-butoxycarbonyl)amino)-3-oxo-4-
phenylbutanoate (2j). General procedure 1 (GP1): Prepared from 1j
D
D
CHCl3)). 1H NMR (500 MHz, DMSO-d6):
d
0.80 (d, J¼6.8 Hz, 3H, Me);
0.85 (d, J¼6.9 Hz, 3H, Me); 1.40 (s, 9H, Boc); 2.05e2.13 (m, 1H, CH);
3.60 (s, 2H, CH2); 3.61 (s, 3H, CO2Me); 3.88 (dd, J¼6.4; 8.3 Hz, 1H,
CH); 7.29 (d, J¼8.3 Hz, 1H, NH).
(2.51 g); CC (EtOAc/petroleum ether¼1:2). Yield: 2.42 g (78%) of
rt
yellow-orange solid; mp 93e96 ꢀC. [
a]
D
þ1.1 (c 0.38, CH2Cl2). nmax
3380, 2980, 2907,1734,1720,1686,1518,1456,1439,1392,1366,1352,
1321, 1301, 1280, 1253, 1209, 1159, 1072, 1044, 1025, 1011, 954, 923,
883, 864, 829, 805, 779, 753, 719, 701, 666 cmꢁ1. 1H NMR (500 MHz,
4.2.5. (S)-Methyl 4-(((benzyloxy)carbonyl)amino)-6-methyl-3-
oxoheptanoate (2e).39 General procedure 1 (GP1): Prepared from
1e (2.65 g); CC (EtOAc/petroleum ether¼1:2). Yield: 1.99 g (62%) of
DMSO-d6):
d
1.39 (s, 9H, Boc); 3.49 (d, J¼16.5 Hz,1H, Ha-C(2)); 3.55 (s,
3H, CO2Me); 3.67 (d, J¼16.5 Hz, 1H, Hb-C(2)); 5.39 (d, J¼8.2 Hz, 1H,
orange oil. [
a
]
rDt ꢁ8.8 (c 0.30, CHCl3) (lit.:39
[
a
]
rDt ꢁ6.8ꢀ (c 1.0, CHCl3)).
HeC(3)); 7.29e7.42 (m, 5H, Ph); 7.79 (d, J¼8.1 Hz, 1H, NH). 13C NMR
1H NMR (500 MHz, DMSO-d6):
d
0.85 (d, J¼6.6 Hz, 3H, H3C(7)); 0.88
(126 MHz, DMSO-d6): d 28.1, 45.8, 51.8, 63.8, 78.7, 128.1, 128.4, 128.6,
(d, J¼6.6 Hz, 3H, H3C(70)); 1.39e1.50 (m, 2H, H2C(5)); 1.57e1.66 (m,
1H, HeC(6)); 3.61 (s, 3H, CO2Me); 3.63 (s, 2H, H2C(2)); 4.08e4.14
(m, 1H, HeC(4)); 5.05 (s, 2H, CH2 of Cbz); 7.28e7.41 (m, 5H, Ph);
7.76 (d, J¼7.9 Hz, 1H, NH).
136.0, 155.2, 167.1, 200.1; EI-HRMS: m/z¼208.0962 (MHþꢁBoc);
C11H14NO3 requires: m/z¼208.0968 (MHþꢁBoc).
4.2.11. (S)-Methyl 7-(((benzyloxy)carbonyl)amino)-4-((tert-butox-
ycarbonyl)amino)-3-oxoheptanoate (2k). General procedure 1 (GP1):
Prepared from 1k (3.66 g); CC (EtOAc/petroleum ether¼1:1). Yield:
4.2.6. (R)-Methyl 4-((tert-butoxycarbonyl)amino)-3-oxooctanoate
(2f). General procedure 1 (GP1): Prepared from 1f (2.31 g); CC
4.01 g (95%) of yellowish solid; mp 79.6e83.9 ꢀC. [
a
]
D
rt ꢁ4.3 (c 0.26,
(EtOAc/petroleum ether¼1:3). Yield: 1.87 g (65%) of white solid;
CH2Cl2). C21H30N2O7 requires: C, 59.70; H, 7.16; N, 6.63. Found C,
59.46; H, 7.39; N, 6.66. nmax 3353, 2987, 2938, 2856, 1748, 1718,
1695, 1683, 1516, 1449, 1439, 1403, 1393, 1369, 1319, 1299, 1248,
1158, 1128, 1071, 1053, 1019, 955, 940, 919, 858, 791, 773, 751, 731,
rt
mp 46e49 ꢀC. [
a]
ꢁ1.7 (c 0.18, CH2Cl2). nmax 3365, 2982, 2953,
D
2931, 2860, 1749, 1719, 1686, 1518, 1466, 1439, 1394, 1367, 1321,
1288, 1268, 1247, 1161, 1140, 1107, 1077, 1048, 1034, 1007, 944, 929,
856, 826, 779, 758, 730, 628 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
694, 641 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.34e1.52 (m, 3H,
d
0.85 (t, J¼6.5 Hz, 3H, CH3); 1.19e1.31 (m, 4H, 2ꢂCH2); 1.39 (s, 9H,
3H of CH2); 1.40 (s, 9H, Boc); 1.63e1.74 (m, 1H, 1H of CH2);
2.95e3.05 (m, 2H, 2H of CH2); 3.60 (d, J¼2.2 Hz, 2H, H2C(2)); 3.62 (s,
3H, CO2Me); 3.95e4.01 (m, 1H, CH); 5.02 (s, 2H, CH2 of Cbz); 7.27 (t,
J¼5.7 Hz, 1H, NH); 7.29e7.40 (m, 6H, Ph, NH). 13C NMR (126 MHz,
Boc); 1.42e1.49 (m, 1H, 1H of CH2); 1.58e1.68 (m, 1H, 1H of CH2);
3.59 (s, 2H, CH2); 3.61 (s, 3H, CO2Me); 3.90e3.97 (m, 1H, CH); 7.32
(d, J¼7.6 Hz, 1H, NH). 13C NMR (126 MHz, DMSO-d6):
d 13.8, 21.7,
27.5, 28.1, 28.8, 45.3, 51.8, 59.7, 78.4, 155.6, 167.5, 203.7; EI-HRMS:
m/z¼188.1282 (MHþꢁBoc); C9H18NO3 requires: m/z¼188.1281
(MHþꢁBoc).
DMSO-d6): d 25.9, 26.4, 28.1, 39.8, 45.3, 51.8, 59.4, 65.2, 78.4, 127.73,
127.75, 128.3, 137.3, 155.6, 156.1, 167.5, 203.4; EI-HRMS: m/
z¼323.1598 (MHþꢁBoc); C16H23N2O5 requires: m/z¼323.1601
(MHþꢁBoc).
4.2.7. (S)-Methyl 4-((tert-butoxycarbonyl)amino)-3-oxo-5-
phenylpentanoate (2g).35 General procedure
1
(GP1): Prepared
4.2.12. (S)-Methyl 8-(((benzyloxy)carbonyl)amino)-4-((tert-butox-
from 1g (2.65 g); CC (EtOAc/petroleum ether¼1:2). Yield: 3.09 g
ycarbonyl)amino)-3-oxooctanoate (2l). General procedure 1 (GP1):

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11100
Prepared from 1l (3.80 g); CC (EtOAc/petroleum ether¼1:1). Yield:
1437, 1401, 1321, 1233, 1149, 1047, 1028, 1001, 932, 738, 698 cmꢁ1. 1H
NMR (500 MHz, DMSO-d6):
rt
3.88 g (89%) of white solid; mp 76.7e78.2 ꢀC. [
a
]
ꢁ24.9 (c 0.27,
d
2.82 (dd, J¼9.6; 14.0 Hz, 1H, Ha of
D
MeOH). nmax 3351, 3065, 3033, 2985, 2953, 2931, 2867, 1748, 1718,
1685, 1522, 1478, 1454, 1438, 1402, 1368, 1329, 1268, 1244, 1226,
1161, 1140, 1092, 1078, 1062, 1025, 1008, 940, 921, 905, 886, 856,
779, 757, 739, 727, 695, 626 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
CH2); 3.13 (dd, J¼4.8; 14.0 Hz, 1H, Hb of CH2); 3.55e3.75 (m, 4H,
2ꢂCH2); 3.64 (s, 3H, CO2Me); 4.52e4.59 (m, 1H, CH); 5.05 (s, 2H,
CH2 of Cbz); 7.12e7.41 (m, 10H, 2ꢂPh); 7.51 (t, J¼6.1 Hz, 1H, NH);
8.43 (d, J¼7.7 Hz, 1H, NH). 13C NMR (126 MHz, DMSO-d6):
d 34.7,
d
1.20e1.49 (m, 5H, 5H of CH2); 1.39 (s, 9H, Boc); 1.58e1.68 (m, 1H,
43.3, 45.8, 51.9, 59.6, 65.6, 126.4, 127.8, 127.8, 128.2, 128.4, 129.2,
137.0, 137.6, 156.5, 167.6, 169.6, 202.1; EI-HRMS: m/z¼413.1706
(MHþ); C22H25N2O6 requires: m/z¼413.1707 (MHþ).
1H of CH2); 2.94e3.01 (m, 2H, 2H of CH2); 3.58e3.65 (m, 2H,
H2C(2)); 3.61 (s, 3H, CO2Me); 3.90e3.95 (m, 1H, HeC(4)); 5.00 (s,
2H, CH2 of Cbz); 7.24 (t, J¼5.5 Hz, 1H, NH); 7.28e7.39 (m, 6H, Ph,
NH). 13C NMR (126 MHz, DMSO-d6):
d
22.7, 28.2, 28.7, 29.0, 40.0,
4.2.17. (Z)-Methyl 4-acetamido-3-oxo-5-phenylpent-4-enoate
(2q).42 General procedure 1 (GP1): Prepared from 1q (2.05 g); CC
(EtOAc/petroleum ether¼1:1). Yield: 445 mg (17%) of yellow oil.
nmax 3212, 3002, 2957, 1746, 1697, 1646, 1625, 1521,1487, 1436, 1363,
1328, 1289, 1272, 1219, 1185, 1142, 1054, 1008, 995, 978, 944, 925,
41.4, 45.3, 51.9, 59.8, 65.1, 78.5,127.7, 128.4, 137.3, 155.6,156.0, 167.5,
203.6; EI-HRMS: m/z¼337.1753 (MHþꢁBoc); C17H25N2O5 requires:
m/z¼337.1758 (MHþꢁBoc).
4.2.13. (S)-7-tert-Butyl 1-methyl 4-(((benzyloxy)carbonyl)amino)-3-
oxoheptanedioate (2m). General procedure 1 (GP1): Prepared from
880, 846, 808, 756, 687, 659, 630, 615 cmꢁ1
.
1H NMR (500 MHz,
d 2.03 (s, 3H, COMe); 3.64 (s, 3H, CO2Me); 3.76 (s, 2H,
DMSO-d6):
1m (3.37 g); CC (EtOAc/petroleum ether¼1:4). Yield: 3.35 g (85%) of
CH2); 7.19 (s, 1H, CH); 7.37e7.49 (m, 3H, 3H of Ph); 7.63e7.67 (m,
rt
orange oil. [
a]
þ5.5 (c 0.87, CH2Cl2). nmax 3342, 3066, 3033, 2977,
2H, 2H of Ph); 9.76 (s, 1H, NH). 13C NMR (126 MHz, DMSO-d6):
D
2955, 1714, 1587, 1519, 1453, 1438, 1393, 1367, 1320, 1237, 1149,
1043, 1028, 1003, 946, 914, 845, 810, 776, 736, 697, 655 cmꢁ1 1H
NMR (500 MHz, DMSO-d6): 1.39 (s, 9H, t-Bu); 1.61e1.70 (m,1H, Ha
d 22.4, 45.0, 51.9, 128.7, 129.7, 130.2, 131.4, 132.9, 133.4, 167.9, 170.0,
.
192.1; EI-HRMS: m/z¼262.1071 (MHþ); C14H16NO4 requires: m/
d
z¼262.1074 (MHþ).
of H2C(5)); 1.92e2.02 (m, 1H, Hb of H2C(5)); 2.24 (t, J¼7.5 Hz, 2H,
H2C(6)); 3.61 (d, 1H, J¼16.4 Hz, Ha of H2C(2)); 3.61 (s, 3H, CO2Me);
3.67 (d, 1H, J¼16.4 Hz, Hb of H2C(2)); 4.09e4.16 (m, 1H, CH); 5.05 (s,
2H, CH2 of Cbz); 7.27e7.42 (m, 5H, Ph); 7.78 (d, J¼7.9 Hz, 1H, NH).
4.2.18. Methyl 5-((tert-butoxycarbonyl)amino)-3-oxopentanoate
(2r).43 General procedure 1 (GP1): Prepared from 1r (1.89 g); CC
(EtOAc/petroleum ether¼1:2). Yield: 1.94 g (79%) of yellow oil. 1H
13C NMR (126 MHz, DMSO-d6):
d
24.5, 27.7, 31.0, 45.4, 51.9, 59.2,
NMR (500 MHz, DMSO-d6):
CH2); 3.11 (q, J¼6.7 Hz, 2H, CH2); 3.62 (s, 2H, CH2); 3.62 (s, 3H,
CO2Me); 6.79 (t, J¼4.9 Hz, 1H, NH).
d
1.37 (s, 9H, Boc); 2.66 (t, J¼6.8 Hz, 2H,
65.8, 79.8, 127.8, 127.9, 128.4, 136.8, 156.2, 167.4, 171.5, 202.7; EI-
HRMS: m/z¼394.1865 (MHþ); C20H28NO7 requires: m/z¼394.1860
(MHþ).
4.3. Synthesis of 4-hydroxypyrrole derivatives and/or enami-
4.2.14. (S)-Methyl 4-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-
3-oxopentanoate (2n). General procedure 1 (GP1): Prepared from 1n
none intermediates from
(GP2)
b-keto estersdgeneral procedure 2
(2.95 g); CC (EtOAc/petroleum ether¼1:2). Yield: 2.92 g (83%) of
rt
light orange oil. [
a
]
þ20.2 (c 0.26, CHCl3). nmax 3339, 2973, 2877,
To a solution of b-keto ester (1 equiv) in anhydrous toluene (V1)
D
1714, 1499, 1455, 1437, 1393, 1364, 1322, 1218, 1192, 1086, 1057,
under argon was added DMFDMA (1.0e3.0 equiv) and the resulting
reaction mixture was stirred at room temperature or at elevated
temperature (T1) for t1 h till completion of the reaction judging by
TLC-analysis (see Fig. 2 and the accompanying discussion). Volatile
components were evaporated in vacuo and the residue was as
quickly as possible purified/separated by column chromatography
(CC). Fractions containing the isolated/separated product(s) were
combined, respectively, and volatile components evaporated in
vacuo. The products were characterized as soon as isolated and
stored under argon.
1025, 1002, 912, 879, 845, 775, 738, 697 cmꢁ1. 1H NMR (500 MHz,
DMSO-d6):
d
1.11 (s, 9H, t-Bu); 3.53 (dd, J¼5.2; 9.4 Hz, 1H, Ha of
H2C(5)); 3.58e3. 64 (m, 1H, Hb of H2C(5)); 3.62 (s, 3H, CO2Me); 3.64
(d, 1H, J¼16.6 Hz, Ha of H2C(2)); 3.70 (d, 1H, J¼16.6 Hz, Hb of
H2C(2)); 4.27e4.32 (m, 1H, HeC(4)); 5.07 (s, 2H, CH2 of Cbz);
7.31e7.40 (m, 5H, Ph); 7.63 (d, J¼7.7 Hz,1H, NH). 13C NMR (126 MHz,
DMSO-d6): d 27.0, 46.7, 51.8, 60.3, 60.9, 65.7, 73.0, 127.8, 127.9, 128.3,
136.9, 156.1, 167.3, 201.9; EI-HRMS: m/z¼352.1758 (MHþ);
C18H26NO6 requires: m/z¼352.1755 (MHþ).
4.2.15. (R)-Methyl 4-((tert-butoxycarbonyl)amino)-6-(methylthio)-
4.3.1. Methyl
4-((tert-butoxycarbonyl)amino)-2-((dimethylamino)
3-oxohexanoate (2o). General procedure 1 (GP1): Prepared from 1o
methylene)-3-oxobutanoate (3a). General procedure 2 (GP2): Pre-
pared from 2a (432 mg, 1.868 mmol), PhMe (V1¼10 mL), DMFDMA
(2.49 g); CC (EtOAc/petroleum ether¼1:2). Yield: 2.67 g (87%) of
rt
yellow solid; mp 55.1e57.6 ꢀC. [
C
a]
þ17.4 (c 0.30, CH2Cl2).
(827
m
L, 5.60 mmol), room temperature, t1¼3 h, CC (EtOAc). The
D
13H23NO5S requires: C, 51.13; H, 7.59; N, 4.59. Found C, 51.10; H,
isolation and characterization must be done as quick as possible
because of the decomposition of 3a into 4a! Yield: 407 mg (76%) of
orange oil. nmax 3412, 2977, 2933, 1694,1644,1581,1489,1425,1386,
1365, 1275, 1248, 1209, 1164, 1113, 1098, 1039, 1006, 977, 946, 869,
7.79; N, 4.60. nmax 3361, 2981, 2913, 1748, 1718, 1685, 1516, 1460,
1438, 1393, 1369, 1324, 1285, 1267, 1245, 1221, 1159, 1138, 1089,
1054, 1028, 1008, 942, 923, 891, 854, 806, 779, 762, 735, 691, 650,
617 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6):
d
1.39 (s, 9H, Boc);
767 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.37 (s, 9H, Boc); 2.74 (s,
1.68e1.78 (m, 1H, 1H of CH2); 1.88e1.97 (m, 1H, 1H of CH2); 2.03 (s,
3H, SMe); 2.38e2.50 (m, 2H, 2H of CH2); 3.61 (s, 3H, CO2Me);
3.57e3.69 (m, 2H, H2C(2)); 4.07e4.14 (m, 1H, CH); 7.41 (d, J¼7.6 Hz,
3H, NMe); 3.25 (s, 3H, NMe); 3.64 (s, 3H, CO2Me); 3.96 (d, J¼5.9 Hz,
2H, CH2); 6.66 (t, J¼5.8 Hz, 1H, NH); 7.75 (s, 1H, CH). 13C NMR
(126 MHz, DMSO-d6):
d 28.2, 41.7, 46.9, 48.5, 50.7, 77.7, 98.3, 155.8,
1H, NH). 13C NMR (126 MHz, DMSO-d6):
d
14.5, 28.1, 28.8, 29.7, 45.4,
157.5, 167.4, 191.7; EI-HRMS: m/z¼287.1600 (MHþ); C13H23N2O5
51.9, 58.7, 78.6, 155.6, 167.5, 203.3; EI-HRMS: m/z¼206.0848
requires: m/z¼287.1601 (MHþ).
(MHþꢁBoc); C8H16NO3S requires: m/z¼206.0845 (MHþꢁBoc).
4.3.2. 1-tert-Butyl 3-methyl 4-hydroxy-1H-pyrrole-1,3-dicarboxylate
(4a) and 1-tert-butyl 3-methyl 4-oxo-4,5-dihydro-1H-pyrrole-1,3-
dicarboxylate (4a0). Enaminone 3a (300 mg, 1.05 mmol) was left
to stand in an open flask for 20 h to cyclize into 4a/4a0. Afterward,
the residue was dissolved in anhydrous PhMe (50 mL) and rotated
4.2.16. Methyl 4-(2-(((benzyloxy)carbonyl)amino)acetamido)-3-oxo-
5-phenylpentanoate (2p). General procedure 1 (GP1): Prepared from
1p (3.56 g); CC (EtOAc/petroleum ether¼2:1). Yield: 3.49 g (84%) of
yellow oil. nmax 3308, 3063, 3031, 2952, 1714, 1662, 1515,1498, 1454,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11101
on rotary evaporator (P¼80 mbar) for 30 min at 40 ꢀC followed by
removal of volatile components. The residue was re-dissolved in
anhydrous PhMe (50 mL) and the procedure on the rotary evap-
orator was repeated. This was done twice more followed by drying
on high vacuum. The residue was characterized without any ad-
ditional purification and stored under argon. Yield: 223 mg (93%;
100% conversion) of orange oil; 4a/4a0¼1:0.38 (in DMSO-d6). nmax
3400, 2980, 1732, 1695, 1579, 1524, 1476, 1444, 1392, 1369, 1341,
1299, 1239, 1145, 1122, 1088, 1034, 979, 953, 912, 845, 762, 733,
EI-HRMS: m/z¼290.1018 (MHþ); C15H16NO5 requires: m/
z¼290.1023 (MHþ).
4.3.6. 1-tert-Butyl 3-methyl 4-hydroxy-5-isopropyl-1H-pyrrole-1,3-
dicarboxylate (4d) and 1-tert-butyl 3-methyl 5-isopropyl-4-oxo-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4d0). General procedure
2
(GP2): Prepared from 2d (273 mg, 1 mmol), PhMe (V1¼5 mL),
DMFDMA (0.295 mL, 2.0 mmol), T1¼75 ꢀC, t1¼3 h, CC (EtOAc/pe-
troleum ether¼1:3). Yield: 154 mg (54%) of white solid; mp
94e97.0 ꢀC; 4d/4d0¼0.08:1 (in DMSO-d6). C14H21NO5 requires: C,
59.35; H, 7.47; N, 4.94. Found C, 59.34; H, 7.45; N, 4.95. nmax 2972,
2878,1747,1721,1697,1575,1465,1439,1371, 1323, 1306,1230,1215,
1191, 1139, 110.4, 1073, 1032, 965, 930, 904, 840, 825, 798, 767, 736,
716, 631 cmꢁ1. 1H NMR (500 MHz, DMSO-d6) for 4a:
d 1.55 (s, 9H,
Boc); 3.73 (s, 3H, CO2Me); 6.63 (d, J¼2.6 Hz, 1H, HeC(5)); 7.51 (d,
J¼2.6 Hz, 1H, HeC(2)); 8.98 (s, 1H, OH). 1H NMR (500 MHz, DMSO-
d6) for 4a0:
d 1.51 (s, 9H, Boc); 3.69 (s, 3H, CO2Me); 4.24 (s, 2H,
H2C(5)); 8.91 (s, 1H, OH). 13C NMR (126 MHz, DMSO-d6) for 4a and
4a0:
27.4, 27.5, 51.0, 51.1, 55.9, 83.9, 84.6, 102.3, 110.1, 111.5, 122.3,
702, 620 cmꢁ1 1H NMR (500 MHz, DMSO-d6) for 4d:
. d 1.25 (d,
d
J¼7.0 Hz, 6H, 2ꢂMe); 1.55 (s, 9H, Boc); 2.46e2.53 (m, 1H, CH); 3.75
144.8, 147.5, 161.5, 163.1, 163.5, 191.9; EI-HRMS: m/z¼242.1021
(s, 3H, CO2Me); 7.45 (s, 1H, HeC(2)), 7.72 (s, 1H, OH). 1H NMR
(MHþ); C11H16NO5 requires: m/z¼242.1023 (MHþ).
(500 MHz, DMSO-d6) for 4d0:
d
0.76 (d, J¼6.9 Hz, 3H, Me); 1.07 (d,
J¼7.0 Hz, 3H, Me); 1.51 (s, 9H, Boc); 2.46e2.53 (m, 1H, CH); 3.68 (s,
4.3.3. 1-tert-Butyl 3-methyl 5-((dimethylamino)methylene)-4-oxo-
4,5-dihydro-1H-pyrrole-1,3-dicarboxylate (5a). General procedure 2
(GP2): Prepared from 2a (448 mg, 1.937 mmol), PhMe (V1¼10 mL),
3H, CO2Me); 4.16 (d, J¼3.4 Hz, 1H, HeC(5)); 8.98 (s, 1H, HeC(2)). 13
C
NMR (126 MHz, DMSO-d6) for 4d0:
d 16.0, 17.0, 27.5, 29.5, 51.1, 69.8,
84.2, 111.1, 147.7, 161.4, 164.1, 194.6; EI-HRMS: m/z¼284.1494
DMFDMA (858
m
L, 5.81 mmol), T1¼90 ꢀC, t1¼3 h, CC (EtOAc/
(MHþ); C14H22NO5 requires: m/z¼284.1492 (MHþ).
MeOH¼10:1). Yield: 230 mg (40%) of brown semisolid. nmax 2930,
1724, 1650, 1568, 1482, 1432, 1389, 1348, 1299, 1248, 1219, 1185,
1148, 1102, 1011, 987, 934, 897, 848, 785, 757, 733, 708, 650 cmꢁ1. 1H
4.3.7. 1-Benzyl 3-methyl 4-hydroxy-5-isobutyl-1H-pyrrole-1,3-
dicarboxylate (4e) and 1-benzyl 3-methyl 5-isobutyl-4-oxo-4,5-
NMR (500 MHz, DMSO-d6):
d
1.54 (s, 9H, Boc); 3.29 (s, 6H, NMe2);
dihydro-1H-pyrrole-1,3-dicarboxylate (4e0). General procedure
2
3.66 (s, 3H, CO2Me); 8.03 (s, 1H, CH); 8.23 (s, 1H, CH). 13C NMR
(GP2): Prepared from 2e (225 mg, 0.7 mmol), PhMe (V1¼2.5 mL),
DMFDMA (0.207 mL, 1.4 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/pe-
troleum ether¼1:2). Yield: 157 mg (67%) of yellow oil; 4e/
4e0¼1:0.12 (in DMSO-d6). nmax 3446, 3168, 3067, 3042, 2955, 2866,
1753, 1688, 1621, 1584, 1536, 1499, 1456, 1438, 1396, 1369, 1332,
1287, 1256, 1204, 1185, 1175, 1120, 1098, 1052, 1030, 1004, 971, 919,
826, 744, 718, 695, 677, 647 cmꢁ1. 1H NMR (500 MHz, DMSO-d6) for
(126 MHz, DMSO-d6): d 27.5, 43.9, 46.6, 50.7, 84.5, 111.1, 112.2, 142.4,
146.9, 147.9, 162.6, 171.5; EI-HRMS: m/z¼297.1445 (MHþ);
C
14H21N2O5 requires: m/z¼297.1445 (MHþ).
4.3.4. 1-tert-Butyl 3-methyl 4-hydroxy-5-methyl-1H-pyrrole-1,3-
dicarboxylate (4b) and 1-tert-butyl 3-methyl 5-methyl-4-oxo-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4b0). General procedure
2
4e:
d
0.76 (d, J¼6.7 Hz, 6H, 2ꢂCH3); 1.69e1.78 (m, 1H,
(GP2): Prepared from 2b (1.23 g, 5.00 mmol), PhMe (V1¼15 mL),
DMFDMA (1.48 mL, 10 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/petro-
leum ether¼1:2). Yield: 431 mg (33%) of orange oil; 4b/4b0¼1:0.54
(in DMSO-d6). nmax 3398, 3003, 2984, 2956, 2936, 1727, 1692, 1579,
1541, 1477, 1455, 1370, 1303, 1283, 1248, 1188, 1144, 1080, 1044, 939,
869, 846, 795, 766, 743, 703, 633 cmꢁ1. 1H NMR (500 MHz, DMSO-
(CH3)2CHCH2); 2.57 (d, J¼7.1 Hz, 2H, (CH3)2CHCH2); 3.74 (s, 3H,
CO2Me); 5.36 (s, 2H, CH2 of Cbz); 7.34e7.46 (m, 3H, 3H of Ph);
7.48e7.53 (m, 2H, 2H of Ph); 7.56 (s,1H, HeC(2)), 7.96 (s,1H, OH). 1H
NMR (500 MHz, DMSO-d6) for 4e0:
d 1.45e1.53 (m, 1H,
(CH3)2CHCH2); 3.68 (s, 3H, CO2Me); 4.35 (dd, J¼3.9, 7.2 Hz, 1H,
HeC(5)); 9.03 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6) for 4e:
d6) for 4b:
d
1.55 (s, 9H, Boc); 2.22 (s, 3H, Me); 3.73 (s, 3H, CO2Me);
d 21.9, 28.2, 32.3, 51.1, 69.1, 109.2, 117.5, 121.7, 128.6, 128.7, 128.8,
7.48 (s, 1H, HeC(2)); 7.97 (s, 1H, OH). 1H NMR (500 MHz, DMSO-d6)
134.7, 141.8, 149.6, 163.6; EI-HRMS: m/z¼332.1491 (MHþ);
for 4b0:
d
1.38 (d, J¼7.1 Hz, 3H, Me); 1.52 (s, 9H, Boc); 3.69 (s, 3H,
C
18H22NO5 requires: m/z¼332.1492 (MHþ).
CO2Me); 4.25 (q, J¼7.1 Hz, 1H, HeC(5)); 8.93 (s, 1H, HeC(2)). 13C
NMR (126 MHz, CDCl3) for 4b and 4b0:
d
10.5,16.5, 28.06, 28.10, 51.6,
4.3.8. (R)-Methyl 4-((tert-butoxycarbonyl)amino)-2-((dimethylamino)
methylene)-3-oxooctanoate (3f) and 1-tert-butyl 3-methyl 5-butyl-4-
hydroxy-1H-pyrrole-1,3-dicarboxylate (4f), and 1-tert-butyl 3-methyl
5-butyl-4-oxo-4,5-dihydro-1H-pyrrole-1,3-dicarboxylate (4f0). General
procedure 2 (GP2): Prepared from 2f (330 mg, 1.15 mmol), PhMe
(V1¼10 mL), DMFDMA (0.678 mL, 4.59 mmol), T1¼75 ꢀC, t1¼3 h, CC
((1) EtOAc/petroleum ether¼1:2 to elute 4f/4f0; (2) EtOAc to elute 3f).
51.9, 63.0, 84.7, 85.1, 106.5, 111.0, 112.0, 120.5, 142.4, 149.2, 162.6,
163.2, 166.7, 195.9; EI-HRMS: m/z¼256.1179 (MHþ); C12H18NO5
requires: m/z¼256.1179 (MHþ).
4.3.5. 1-Benzyl 3-methyl 4-hydroxy-5-methyl-1H-pyrrole-1,3-
dicarboxylate (4c) and 1-benzyl 3-methyl 5-methyl-4-oxo-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4c0). General procedure
2
(GP2): Prepared from 2c (140 mg, 0.5 mmol), PhMe (V1¼2 mL),
DMFDMA (0.148 mL, 1.0 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/pe-
troleum ether¼1:2). Yield: 85 mg (58%) of orange oil; 4c/
4c0¼1:0.62 (in DMSO-d6). nmax 3412, 2953, 2925, 1731, 1698, 1580,
1538, 1498, 1448, 1401, 1367, 1298, 1215, 1183, 1099, 1037, 976, 941,
912, 806, 753, 729, 696, 652, 632 cmꢁ1. 1H NMR (500 MHz, CDCl3)
4.3.8.1. Compounds 4f/f40. Elutes first from the column. Yield:
142 mg (41%) of yellowish oil; 4f/4f0¼1:0.74 (in DMSO-d6). nmax
3401, 2956, 2932, 2872, 2862, 1734, 1695, 1627, 1582, 1535, 1459,
1438, 1393, 1370, 1315, 1277, 1251, 1145, 1095, 1069, 1049, 968, 932,
848, 751, 711, 619 cmꢁ1. 1H NMR (500 MHz, DMSO-d6) for 4f:
d 0.88
(t, J¼7.3 Hz, 3H, Me); 1.22e1.31 (m, 2H, 2H of CH2); 1.41e1.44 (m,
2H of CH2); 1.56 (s, 9H, Boc); 2.71 (t, J¼7.4 Hz, 2H, 2H of CH2); 3.74
(s, 3H, CO2Me); 7.48 (s, 1H, HeC(2)); 7.91 (s, 1H, OH). 1H NMR
for 4c:
Cbz); 7.05 (s, 1H, HeC(2)); 7.34e7.46 (m, 5H, Ph); 7.58 (s, 1H, OH).
1H NMR (500 MHz, CDCl3) for 4c0:
d 2.33 (s, 3H, Me); 3.85 (s, 3H, CO2Me); 5.36 (s, 2H, CH2 of
d
1.54 (d, J¼7.0 Hz, 3H, Me); 3.82
(500 MHz, DMSO-d6) for 4f0:
d
0.82 (t, J¼7.3 Hz, 3H, Me); 0.97e1.06
(s, 3H, CO2Me); 4.22 (q, J¼7.0 Hz, 1H, HeC(5)); 5.31 (d, J¼12.4 Hz,
(m, 1H, 1H of CH2); 1.07e1.14 (m, 1H, 1H of CH2); 1.52 (s, 9H, Boc);
1.85e1.93 (m, 1H, 1H of CH2); 2.01e2.07 (m, 1H, 1H of CH2); 3.69 (s,
3H, CO2Me); 4.31 (dd, J¼3.0; 6.5 Hz, 1H, HeC(5)); 9.00 (s, 1H,
2H, CH2 of Cbz); 7.34e7.46 (m, 5H, Ph); 9.03 (s, 1H, HeC(2)). 13C
NMR (126 MHz, CDCl3) for 4c and 4c0:
d 10.3, 16.4, 51.6, 51.9, 62.9,
69.4, 69.6, 107.4, 111.9, 112.3, 120.5, 128.7, 128.82, 128.86, 128.95,
128.99, 129.2, 134.2, 134.5, 142.5, 150.5, 162.2, 162.7, 166.5, 195.4;
HeC(2)). 13C NMR (126 MHz, DMSO-d6) for 4f and 4f0:
d 13.7, 13.8,
21.8, 21.9, 23.2, 24.3, 27.4, 27.5, 28.8, 31.5, 51.0, 51.1, 66.0, 84.1, 84.6,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11102
108.6, 110.7, 118.1, 121.5, 141.0, 147.6, 148.3, 161.5, 163.7, 163.9, 194.9;
EI-HRMS: m/z¼298.1649 (MHþ); C15H24NO5 requires: m/
z¼298.1649 (MHþ).
(V1¼10 mL), DMFDMA (0.354 mL, 2.4 mmol), T1¼rt, t1¼12 h, the
product precipitated from the reaction mixture and was collected
by filtration under reduced pressure and washed with petroleum
rt
ether. Yield: 350 mg (73%) of white solid; mp 187.0e190.0 ꢀC. [
a
]
D
4.3.8.2. Compound 3f. Elutes second from the column. Yield:
188 mg (47%) of yellowish oil. nmax 3349, 2955, 2932, 2872, 1696,
1639, 1576, 1488, 1455, 1423, 1363, 1281, 1244, 1206, 1165, 1094,
1042, 1003, 969, 915, 870, 915, 870, 836, 777, 731, 638, 608 cmꢁ1. 1H
þ5.8 (c 0.27, CH2Cl2). C23H22N2O5 requires: C, 67.97; H, 5.46; N, 6.89.
Found C, 68.19; H, 5.44; N, 6.96. nmax 2947, 2936, 1769, 1706, 1676,
1639,1611,1580,1496, 1466,1434,1417, 1376,1322,1278, 1212,1188,
1165, 1113, 1097, 1077, 1059, 1044, 969, 918, 889, 868, 808, 795, 771,
NMR (500 MHz, DMSO-d6):
d
0.81e0.87 (m, 3H, Me); 1.18e1.32 (m,
749, 729, 701, 653 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d 2.92 (s, 3H, 3H
5H, 5H of CH2); 1.36 (s, 9H, Boc); 1.56e1.65 (m, 1H, 1H of CH2); 2.73
(br s, 3H, NMe2); 3.25 (br s, 3H, NMe2); 3.63 (s, 3H, CO2Me); 4.72 (td,
J¼3.6; 9.1 Hz, 1H, HeC(3)); 6.52 (d, J¼8.6 Hz, 1H, NH); 7.74 (s, 1H,
of NMe2); 3.27 (s, 3H, 3H of NMe2); 3.43 (dd, J¼11.7; 14.1 Hz, 1H, Ha
of H2C(5)); 3.55 (dd, J¼4.4; 14.0 Hz, 1H, Hb of H2C(5)); 3.70 (s, 3H,
CO2Me); 5.95 (dd, J¼4.3; 11.7 Hz, 1H, HeC(4)); 7.07e7.12 (m, 1H, 1H
of Ph); 7.13e7.22 (m, 4H, 4H of Ph); 7.63 (dd, J¼3.0; 5.5 Hz, 2H,
CH). 13C NMR (126 MHz, DMSO-d6):
d 13.9, 21.9, 28.0, 28.2, 31.7,
41.4, 46.9, 50.7, 56.2, 77.5, 98.6, 155.3, 157.6, 167.5, 195.2; EI-HRMS:
indoline); 7.72 (dd, J¼3.1; 5.4 Hz, 2H, indoline); 7.76 (s, 1H, CH). 13
C
m/z¼343.2226 (MHþ); C17H31N2O5 requires: m/z¼343.2227 (MHþ).
NMR (126 MHz, CDCl3): d 35.2, 42.8, 48.2, 51.5, 60.7, 123.2, 126.5,
128.5, 129.0, 131.9, 133.8, 138.2, 159.1, 167.9, 168.2, 192.9; EI-HRMS:
4.3.9. 1-tert-Butyl 3-methyl 5-benzyl-4-hydroxy-1H-pyrrole-1,3-
m/z¼407.1590 (MHþ); C23H23N2O5 requires: m/z¼407.1601 (MHþ).
dicarboxylate (4g) and 1-tert-butyl 3-methyl 5-benzyl-4-oxo-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4g0). General procedure
2
4.3.12. 1-tert-Butyl 3-methyl 4-hydroxy-5-phenyl-1H-pyrrole-1,3-
(GP2): Prepared from 2g (186 mg, 0.58 mmol), PhMe (V1¼3 mL),
DMFDMA (0.177 mL, 1.2 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/pe-
troleum ether¼1:2). Yield: 161 mg (84%) of yellow oil; 4g/
4g0¼1:0.70 (in DMSO-d6). nmax 3401, 2979, 2952, 2934, 1732, 1695,
1627, 1579, 1534, 1495, 1456, 1439, 1392, 1370, 1278, 1254, 1192,
1143, 1047, 981, 846, 753, 729, 703, 630 cmꢁ1. 1H NMR (500 MHz,
dicarboxylate (4j) and 1-tert-butyl 3-methyl 4-oxo-5-phenyl-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4j0). General procedure
2
(GP2): Prepared from 2j (361 mg, 1.17 mmol), PhMe (V1¼5 mL),
DMFDMA (0.518 mL, 3.51 mmol), T1¼75 ꢀC, t1¼2 h, CC (EtOAc/pe-
troleum ether¼1:2). Yield: 270 mg (72%) of orange oil; 4j/
4j0¼1:0.35 (in DMSO-d6). nmax 3400, 2980, 2952, 1736, 1691, 1619,
1578, 1531, 1497, 1476, 1455, 1436, 1392, 1369, 1322, 1282, 1244,
1207, 1142, 1101, 1075, 1032, 995, 962, 939, 844, 812, 773, 756, 739,
DMSO-d6) for 4g: d 1.34 (s, 9H, Boc); 3.76 (s, 3H, CO2Me); 4.14 (s, 2H,
CH2); 7.00e7.03 (m, 2H, 2H of Ph); 7.12e7.28 (m, 3H, 3H of Ph); 7.58
(s, 1H, HeC(2)), 8.27 (s, 1H, OH). 1H NMR (500 MHz, DMSO-d6) for
705, 695, 636 cmꢁ1. 1H NMR (500 MHz, DMSO-d6) for 4j:
d 1.29 (s,
4g0:
d
1.55 (s, 9H, Boc); 3.23 (dd, J¼2.6; 13.8 Hz, 1H, Ha of CH2); 3.39
9H, Boc); 3.78 (s, 3H, CO2Me); 7.27e7.31 (m, 2H, 2H of Ph);
(dd, J¼6.4; 13.9 Hz, 1H, Hb of CH2); 3.62 (s, 3H, CO2Me); 4.59 (dd,
J¼2.6; 6.3 Hz, 1H, HeC(5)); 6.93e6.97 (m, 2H, 2H of Ph); 7.12e7.28
(m, 3H, 3H of Ph); 8.71 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-
7.35e7.41 (m, 3H, 3H of Ph); 7.66 (s,1H, HeC(2)); 8.19 (s,1H, OH). 1H
NMR (500 MHz, DMSO-d6) for 4j0:
d 1.28 (br s, 9H, Boc); 3.70 (s, 3H,
CO2Me); 5.33 (s, 1H, HeC(5)), 7.19e7.22 (m, 2H, 2H of Ph);
7.27e7.31 (m, 2H, 2H of Ph); 7.35e7.41 (m, 1H,1H of Ph); 9.20 (s, 1H,
d6) for 4g and 4g0:
d 27.1, 27.5, 28.9, 34.9, 51.09, 51.12, 66.4, 84.4,
84.7, 108.8, 111.0, 115.5, 122.3, 125.7, 127.08, 127.45, 128.21, 128.26,
129.1, 134.3, 140.3, 142.2, 147.6, 148.2, 161.2, 163.5, 163.8, 194.4; EI-
HRMS: m/z¼332.1490 (MHþ); C18H22NO5 requires: m/z¼332.1492
(MHþ).
HeC(2)). 13C NMR (126 MHz, DMSO-d6) for 4j and 4j0:
d 27.0, 27.2,
51.19, 51.25, 69.4, 84.0, 84.6, 108.7, 109.2, 123.4, 126.5, 126.7, 127.5,
128.1, 128.7, 129.7, 130.9, 142.2, 147.3, 148.2, 161.6, 163.7, 164.8,
192.5; EI-HRMS: m/z¼318.1332 (MHþ); C17H20NO5 requires: m/
z¼318.1336 (MHþ).
4.3.10. 1-Benzyl 3-methyl 5-benzyl-4-hydroxy-1H-pyrrole-1,3-
dicarboxylate (4h) and 1-benzyl 3-methyl 5-benzyl-4-oxo-4,5-
4.3.13. 1-tert-Butyl 3-methyl 5-(3-(((benzyloxy)carbonyl)amino)
propyl)-4-hydroxy-1H-pyrrole-1,3-dicarboxylate (4k) and 1-tert-bu-
tyl 3-methyl 5-(3-(((benzyloxy)carbonyl)amino)propyl)-4-oxo-4,5-
dihydro-1H-pyrrole-1,3-dicarboxylate (4h0). General procedure
2
(GP2): Prepared from 2h (249 mg, 0.7 mmol), PhMe (V1¼2 mL),
DMFDMA (0.207 mL, 1.4 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/pe-
troleum ether¼1:2). Yield: 123 mg (48%) of orange oil; 4h/
4h0¼1:0.66 (in DMSO-d6). nmax 3402, 3151, 3086, 3063, 3030, 2952,
2859, 1732, 1694, 1629, 1581, 1535, 1495, 1454, 1440, 1399, 1367,
1312, 1253, 1218, 1189, 1162, 1107, 1044, 979, 913, 878, 847, 823, 779,
dihydro-1H-pyrrole-1,3-dicarboxylate (4k0). General procedure
2
(GP2): Prepared from 2k (6.77 g, 16.03 mmol), PhMe (V1¼70 mL),
DMFDMA (3.56 mL, 24.1 mmol), T1¼75 ꢀC, t1¼2 h, CC (EtOAc/pe-
troleum ether¼1:1). Yield: 6.65 g (96%) of yellow oil; 4k/4k0¼1:1
(in DMSO-d6). nmax 3367, 2950, 2872, 1698, 1578, 1529, 1440, 1395,
1370, 1280, 1240, 1196, 1143, 1070, 1043, 1027, 967, 915, 845, 752,
.
750, 735, 698, 645 cmꢁ1 1H NMR (500 MHz, DMSO-d6) for 4h:
d
3.76 (s, 3H, CO2Me); 4.14 (s, 2H, CH2); 5.26 (s, 2H, CH2 of Cbz);
697, 609 cmꢁ1. 1H NMR (500 MHz, DMSO-d6) for 4k:
d 1.46e1.64 (m,
7.01e7.05 (m, 2H, 2H of Ph); 7.11e7.17 (m, 1H, 1H of Ph); 7.19e7.24
(m, 2H, 2H of Ph); 7.31e7.38 (m, 3H, 3H of Ph); 7.41e7.48 (m, 2H, 2H
of Ph); 7.60 (s, 1H, HeC(2)); 8.40 (s, 1H, OH). 1H NMR (500 MHz,
2H, 2H of CH2); 1.56 (s, 9H, Boc); 2.72 (t, J¼7.4 Hz, 2H of CH2);
2.90e3.03 (m, 2H, 2H of CH2); 3.74 (s, 3H, CO2Me); 5.01 (s, 2H, CH2
of Cbz); 7.23 (t, J¼5.7 Hz, 1H, NH); 7.27e7.39 (m, 5H, Ph); 7.51 (s, 1H,
1
DMSO-d6) for 4h0:
d
3.22 (dd, J¼2.7; 13.9 Hz, 1H, 1H of CH2); 3.34
HeC(2)); 8.03 (s, 1H, OH). H NMR (500 MHz, DMSO-d6) for 4k0:
(dd, J¼6.3; 14.1 Hz, 1H, 1H of CH2); 3.62 (s, 3H, CO2Me); 4.65 (dd,
J¼2.7; 6.2 Hz, 1H, HeC(5)); 5.40 (s, 2H, CH2 of Cbz); 6.80e6.83 (m,
2H, 2H of Ph); 7.11e7.17 (m, 2H, 2H of Ph); 7.31e7.38 (m, 4H, 4H of
Ph); 7.51e7.54 (m, 2H, 2H of Ph); 8.81 (s, 1H, HeC(2)). 13C NMR
d 1.10e1.20 (m, 1H, Ha of CH2); 1.23e1.34 (m, 1H, Hb of CH2); 1.51 (s,
9H, Boc); 1.84e1.92 (m, 1H, Ha of CH2); 2.01e2.07 (m, 1H, Hb of
CH2); 2.90e3.03 (m, 2H, 2H of CH2); 3.70 (s, 3H, CO2Me); 4.33 (dd,
J¼3.1; 6.5 Hz, 1H, HeC(5)); 4.99 (s, 2H, CH2 of Cbz); 7.27e7.39 (m,
6H, 5H of Ph, NH); 9.00 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-
(126 MHz, DMSO-d6) for 4h and 4h0:
d 28.9, 34.8, 51.16, 51.17, 66.4,
68.8, 68.9, 109.6, 111.8, 116.5, 122.2, 125.7, 127.0, 127.7, 128.1, 128.2,
128.49, 128.53, 128.58, 128.63, 128.67, 128.70, 129.1, 134.1, 134.7,
135.0, 140.0, 142.3, 149.0, 149.3, 161.0, 163.3, 163.6, 194.2; EI-HRMS:
m/z¼366.1337 (MHþ); C21H20NO5 requires: m/z¼366.1336 (MHþ).
d6) for 4k and 4k0:
d 21.1, 23.1, 26.8, 27.4, 27.5, 29.7, 40.0, 51.08, 51.14,
65.1, 65.2, 65.8, 84.2, 84.8, 108.7, 110.7, 117.3, 121.8, 127.7, 127.8,
128.3, 137.2, 137.3, 141.1, 147.6, 148.3, 156.0, 156.1, 161.5, 163.6, 164.0,
194.8; EI-HRMS: m/z¼433.1967 (MHþ); C22H29N2O7 requires: m/
z¼433.1969 (MHþ).
4.3.11. (S)-Methyl 2-((dimethylamino)methylene)-4-(1,3-
dioxoisoindolin-2-yl)-3-oxo-5-phenylpentanoate (3i). General pro-
cedure 2 (GP2): Prepared from 2i (416 mg, 1.18 mmol), PhMe
4.3.14. 1-tert-Butyl 3-methyl 5-(4-(((benzyloxy)carbonyl)amino)bu-
tyl)-4-hydroxy-1H-pyrrole-1,3-dicarboxylate (4l) and 1-tert-butyl 3-

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11103
methyl 5-(4-(((benzyloxy)carbonyl)amino)butyl)-4-oxo-4,5-dihydro-
1H-pyrrole-1,3-dicarboxylate (4l0). General procedure 2 (GP2): Pre-
pared from 2l (218 mg, 0.5 mmol), PhMe (V1¼2 mL), DMFDMA
(0.148 mL, 1.0 mmol), T1¼75 ꢀC, t1¼1 h, CC (EtOAc/petroleum
ether¼1:2). Yield: 123 g (55%) of orange oil; 4l/4l0¼1:0.61 (in
DMSO-d6). nmax 3368, 3160, 3089, 3065, 3032, 2976, 2936, 2865,
1694, 1626, 1579, 1530, 1455, 1439, 1394, 1370, 1278, 1242, 1191,
1143, 1046, 1027, 9670, 847, 751, 697, 609 cmꢁ1. 1H NMR (500 MHz,
1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6) for 4n and 4n0:
d
26.9,
27.4, 51.2, 51.9, 59.3, 66.6, 68.3, 68.5, 69.0, 72.4, 72.7, 109.0, 111.6,
115.6, 123.3, 128.28, 128.32, 128.41, 128.52, 128.54, 128.55, 134.9,
135.1, 143.4, 149.0, 149.2, 161.3, 163.3, 164.2, 193.4; EI-HRMS: m/
z¼362.1590 (MHþ); C19H24NO6 requires: m/z¼362.1598 (MHþ).
4.3.17. 1-tert-Butyl 3-methyl 4-hydroxy-5-(2-(methylthio)ethyl)-1H-
pyrrole-1,3-dicarboxylate (4o) and 1-tert-butyl 3-methyl 5-(2-
(methylthio)ethyl)-4-oxo-4,5-dihydro-1H-pyrrole-1,3-dicarboxylate
(4o0). General procedure 2 (GP2): Prepared from 2o (410 mg,
1.34 mmol), PhMe (V1¼10 mL), DMFDMA (0.594 mL, 4.02 mmol),
T1¼75 ꢀC, t1¼2 h, CC (EtOAc/petroleum ether¼1:3). The product has
an unpleasant smell! Yield: 300 g (71%) of yellow oil; 4o/
4o0¼1:0.28 (in DMSO-d6). nmax 3410, 2978, 2951, 2918, 1738, 1693,
1626, 1580, 1533, 1459, 1437, 1390, 1370, 1276, 1246, 1188, 1142,
DMSO-d6) for 4l:
d 1.28e1.46 (m, 4H, 4H of CH2); 1.54 (s, 9H, Boc);
2.67e2.74 (m, 2H, CH2); 2.96e3.02 (m, 2H, CH2); 3.74 (s, 3H,
CO2Me); 4.99 (s, 2H, CH2 of Cbz); 7.23 (t, J¼5.8 Hz, 1H, NH);
7.28e7.39 (m, 5H, Ph); 7.49 (s,1H, HeC(2)); 7.95 (s,1H, OH). 1H NMR
(500 MHz, DMSO-d6) for 4l0:
d 0.97e1.08 (m, 1H, Ha of CH2);
1.09e1.20 (m, 1H, Hb of CH2); 1.28e1.46 (m, 2H, 2H of CH2); 1.51 (s,
9H, Boc); 1.84e1.93 (m, 1H, Ha of CH2); 1.98e2.08 (m, 1H, Hb of
CH2); 2.90e2.96 (m, 2H, CH2); 3.69 (s, 3H, CO2Me); 4.31 (dd, J¼3.1;
6.5 Hz, 1H, HeC(5)); 4.99 (s, 2H, CH2 of Cbz); 7.28e7.39 (m, 6H, 5H
of Ph, NH); 8.99 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6) for
.
1109, 1066, 961, 847, 750 cmꢁ1 1H NMR (500 MHz, DMSO-d6) for
4o: 1.56 (s, 9H, Boc); 2.08 (s, 3H, SMe); 2.54e2.62 (m, 2H, 2H of
d
CH2); 2.97e3.04 (m, 2H, 2H of CH2); 3.74 (s, 3H, CO2Me); 7.50 (s, 1H,
1
4l and 4l0:
d
19.7, 23.2, 26.7, 27.4, 27.5, 29.0, 29.2, 29.3, 40.2, 51.07,
HeC(2)); 8.12 (s, 1H, OH). H NMR (500 MHz, DMSO-d6) for 4o0:
51.12, 65.1, 66.0, 84.2, 84.7, 108.7, 110.6, 117.8, 121.6, 127.72, 127.74,
128.3, 137.2, 137.3, 141.1, 147.6, 148.3, 156.0, 156.1, 161.5, 163.6, 164.0,
194.8; EI-HRMS: m/z¼447.2119 (MHþ); C23H31N2O7 requires: m/
z¼447.2126 (MHþ).
d
1.52 (s, 9H, Boc); 2.01 (s, 3H, SMe); 2.17e2.46 (m, 4H, 2ꢂCH2); 3.69
(s, 3H, CO2Me); 4.40 (dd, J¼3.5; 6.6 Hz, 1H, HeC(5)); 8.96 (s, 1H,
HeC(2)). 13C NMR (126 MHz, DMSO-d6) for 4o and 4o0:
14.6, 14.63,
d
23.7, 27.3, 27.4, 27.5, 28.7, 32.9, 51.07, 51.12, 65.1, 84.3, 84.9, 108.7,
110.6, 116.3, 122.0, 141.7, 147.6, 148.2, 161.5, 163.5, 163.9, 194.3; EI-
HRMS: m/z¼316.1212 (MHþ); C14H22NO5S requires: m/z¼316.1213
(MHþ).
4.3.15. 1-Benzyl 3-methyl 5-(3-(tert-butoxy)-3-oxopropyl)-4-
hydroxy-1H-pyrrole-1,3-dicarboxylate (4m) and 1-benzyl 3-methyl
5-(3-(tert-butoxy)-3-oxopropyl)-4-oxo-4,5-dihydro-1H-pyrrole-1,3-
dicarboxylate (4m0). General procedure 2 (GP2): Prepared from 2m
(433 mg, 1.1 mmol), PhMe (V1¼3 mL), DMFDMA (0.325 mL,
2.2 mmol), T1¼rt, t1¼15 h, CC (EtOAc/petroleum ether¼1:2). Yield:
200 g (45%) of orange-yellow oil; 4m/4m0¼1:0.85 (in DMSO-d6).
nmax 3423, 3411, 3034, 2977, 2953, 2934, 1722, 1697, 1629, 1582,
1537, 1498, 1456, 1440, 1400, 1366, 1317, 1218, 1187, 1148, 1111, 1067,
4.3.18. Methyl 5-((tert-butoxycarbonyl)amino)-2-((dimethylamino)
methylene)-3-oxopentanoate (3r).45 General procedure
2 (GP2):
Prepared from 2r (310 mg, 1.26 mmol), PhMe (V1¼7 mL), DMFDMA
(0.524 mL, 3.55 mmol), T1¼75 ꢀC, t1¼4 h, volatile components were
evaporated in vacuo and the residue dried in high vacuum. Yield:
100% conversion; yellow oil. 1H NMR (500 MHz, DMSO-d6):
d 1.36
1027, 981, 952, 913, 846, 751, 698, 645 cmꢁ1
.
1H NMR (500 MHz,
(s, 9H, Boc); 2.66 (t, J¼7.2 Hz, 2H, 2H of CH2); 2.73 (br s, 3H, NMe2);
3.11 (q, J¼7.0 Hz, 2H, 2H of CH2); 3.19 (br s, 3H, NMe2); 3.63 (s, 3H,
CO2Me); 6.63 (s, 1H, NH); 7.64 (s, 1H, CH).
DMSO-d6) for 4m: 1.37 (s, 9H, t-Bu); 2.34e2.40 (m, 2H, 2H of CH2);
d
2.93e2.99 (m, 2H, 2H of CH2); 3.73 (s, 3H, CO2Me); 5.38 (s, 2H, CH2
of Cbz); 7.36e7.45 (m, 3H, 3H of Ph); 7.46e7.52 (m, 2H, 2H of Ph);
7.55 (s, 1H, HeC(2)), 8.18 (s, 1H, OH). 1H NMR (500 MHz, DMSO-d6)
4.4. (E)-1-tert-Butyl 3-methyl 4-hydroxy-5-((2-
phenylhydrazono)methyl)-1H-pyrrole-1,3-dicarboxylate (7a)
for 4m0:
d
1.36 (s, 9H, t-Bu); 2.05e2.29 (m, 4H, 4H of CH2); 3.70 (s,
3H, CO2Me); 4.45 (dd, J¼3.3, 6.3 Hz,1H, HeC(5)); 5.30 (d, J¼12.3 Hz,
1H, Ha of Cbz); 5.35 (d, J¼12.4 Hz, 1H, Hb of Cbz); 7.36e7.45 (m, 3H,
3H of Ph); 7.46e7.52 (m, 2H, 2H of Ph); 9.01 (s, 1H, HeC(2)). 13C
To a solution of 5a (403 mg, 1.36 mmol) in MeOH (10 mL) was
added PhNHNH2$HCl (6) (197 mg, 1.36 mmol) and the resulting
reaction mixture was stirred at room temperature for 2 h and under
reflux for 2 h. The reaction mixture was cooled to 0 ꢀC and the
resulting precipitate collected by filtration and washed with cold
MeOH (1 mL, 0 ꢀC). Yield: 80 mg (16%) of yellow-orange solid; mp
128e142 ꢀC. nmax 3283, 3166, 2977, 1754, 1682, 1593, 1541, 1496,
1450, 1434, 1371, 1330, 1302, 1259, 1245, 1199, 1152, 1076, 1061, 994,
NMR (126 MHz, DMSO-d6) for 4m and 4m0:
d 19.4, 24.7, 27.6, 27.7,
28.6, 34.5, 51.1, 51.2, 65.0, 68.7, 69.1, 79.6, 80.0, 109.4, 111.2, 116.4,
121.9, 128.2, 128.50, 128.53, 128.54, 128.6, 128.7, 134.8, 135.0, 141.5,
149.0, 149.4, 161.3, 163.3, 164.1, 171.1, 171.4, 194.4; EI-HRMS: m/
z¼348.1076 (MHꢁt-Buþ); C17H18NO7 requires: m/z¼348.1078
(MHꢁt-Buþ).
979, 935, 912, 869, 852, 814, 745, 703, 689, 617 cmꢁ1
.
1H NMR
4.3.16. 1-Benzyl 3-methyl 5-(tert-butoxymethyl)-4-hydroxy-1H-pyr-
role-1,3-dicarboxylate (4n) and 1-benzyl 3-methyl 5-(tert-butox-
ymethyl)-4-oxo-4,5-dihydro-1H-pyrrole-1,3-dicarboxylate
(4n0). General procedure 2 (GP2): Prepared from 2n (282 mg,
0.8 mmol), PhMe (V1¼5 mL), DMFDMA (0.148 mL, 1.0 mmol), T1¼rt,
t1¼12 h, CC (EtOAc/petroleum ether¼1:2). Yield: 193 g (66%) of
orange oil; 4n/4n0¼0.24:1 (in DMSO-d6). nmax 2973, 2875, 1722,
1582,1535,1440,1404,1364,1307,1270,1225,1187,1158,1118,1094,
1035, 975, 915, 890, 832, 755, 698, 643 cmꢁ1. 1H NMR (500 MHz,
(500 MHz, DMSO-d6): 1.60 (s, 9H, Boc); 3.77 (s, 3H, CO2Me); 6.77
d
(t, J¼7.4 Hz, 1H of Ph); 6.88 (d, J¼7.8 Hz, 2H, 2H of Ph); 7.24 (t,
J¼7.9 Hz, 2H, 2H of Ph); 7.60 (s, 1H, CH); 8.60 (s, 1H, HeC(2)); 9.95
(br s, 1H); 10.39 (s, 1H). 13C NMR (126 MHz, DMSO-d6):
d 27.4, 51.3,
85.8, 108.1, 111.4, 112.6, 118.9, 124.0, 129.4, 133.7, 144.5, 146.3, 147.8,
162.3; EI-HRMS: m/z¼360.1549 (MHþ); C18H22N3O5 requires: m/
z¼360.1554 (MHþ).
4.5. Synthesis of 1-tert-butyl 3-methyl 4-oxo-5,6-
dihydropyridine-1,3(4H)-dicarboxylate (8r)
DMSO-d6) for 4n:
d 1.12 (s, 9H, t-Bu); 3.74 (s, 3H, CO2Me); 4.48 (s,
2H, 2H of t-BuOCH2); 5.38 (s, 2H, CH2 of Cbz); 7.35e7.44 (m, 3H, 3H
of Ph); 7.49e7.52 (m, 2H, 2H of Ph); 7.62 (s, 1H, HeC(2)); 8.41 (s, 1H,
To a solution of 3r (317 mg, 1.055 mmol) in anhydrous THF
(5 mL) under argon was added t-BuOK (118 mg, 1.055 mmol) and
the resulting reaction mixture was stirred under argon at room
temperature for 30 min. Then HCl (1 mL,1 M in H2O) was added and
the mixture was stirred for additional 5 min at room temperature.
The reaction mixture was poured into EtOAc (150 mL) and washed
OH). 1H NMR (500 MHz, DMSO-d6) for 4n0:
d 0.94 (s, 9H, t-Bu); 3.69
(s, 3H, CO2Me); 3.71e3.76 (m, 1H, Ha of t-BuOCH2); 3.97 (dd, J¼3.2;
10.0 Hz, 1H, Hb of t-BuOCH2); 4.45 (dd, J¼1.7; 3.3 Hz, 1H, HeC(5));
5.32 (d, J¼12.2 Hz, 1H, Ha of Cbz); 5.35 (d, J¼12.4 Hz,1H, Hb of Cbz);
7.35e7.44 (m, 3H, 3H of Ph); 7.45e7.48 (m, 2H, 2H of Ph); 9.08 (s,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11104
with NaCl (aq sat, 2ꢂ30 mL). The organic phase was dried over
anhydrous Na2SO4, filtered, and volatile components evaporated in
vacuo. The residue was purified by column chromatography [(1)
EtOAc/petroleum ether¼1:2 to elute the nonpolar impurities; (2)
EtOAc/petroleum ether¼2:1 to elute the product]. Fractions con-
taining the product 6r were combined and volatile components
evaporated in vacuo. Yield: 140 mg (52%) of yellowish solid; mp
88.9e91.3 ꢀC. C12H17NO5 requires: C, 56.46; H, 6.71; N, 5.49. Found
C, 56.26; H, 6.82; N, 5.53. nmax 2977, 2949, 1736, 1683, 1587, 1454,
1438, 1396, 1369, 1345, 1316, 1269, 1247, 1210, 1193, 1141, 1047, 1037,
(126 MHz, DMSO-d6): d 21.4, 27.3, 29.8, 40.2, 51.3, 65.1, 76.1, 85.4,
110.6, 123.5, 125.0, 127.71, 127.74, 128.0, 128.29, 128.32, 128.5, 137.1,
137.2, 142.4, 147.9, 156.0, 162.6; EI-HRMS: m/z¼523.2432 (MHþ);
C
29H35N2O7 requires: m/z¼523.2439 (MHþ).
4.6.2.2. Compound 9k. Elutes second from the column. Yield:
280 mg (48%) of yellowish oil. nmax 3366, 3031, 2976, 2950, 2933,
2872, 1711, 1578, 1523, 1496, 1440, 1391, 1370, 1282, 1224, 1199,
1138, 1072, 1040, 992, 852, 841, 760, 731, 696, 627 cmꢁ1. 1H NMR
(500 MHz, DMSO-d6):
d 0.95e1.05 (m, 1H, Ha of CH2); 1.06e1.16
1004, 970, 887, 837, 793, 761, 690, 653 cmꢁ1
CDCl3):
1.58 (s, 9H, Boc); 2.60e2.65 (t, J¼7.4 Hz, 2H, 2H of CH2);
3.81 (s, 3H, CO2Me); 3.98e4.03 (t, J¼7.4 Hz, 2H, 2H of CH2); 8.81 (s,
.
1H NMR (500 MHz,
(m, 1H, Hb of CH2); 1.58 (s, 9H, Boc); 1.87 (dt, J¼4.6; 12.8 Hz, 1H, Ha
of CH2); 2.17 (dt, J¼4.3; 13.3 Hz, 1H, Hb of CH2); 2.86e2.99 (m, 2H,
2H of CH2); 3.05 (d, J¼13.3 Hz, 1H, Ha of CH2); 3.24 (d, J¼13.4 Hz,
1H, Hb of CH2); 3.60 (s, 3H, CO2Me); 4.97 (d, J¼12.5 Hz, 1H, Ha of
CH2); 5.01 (d, J¼12.5 Hz, 1H, Hb of CH2); 6.87e6.91 (m, 2H, 2H of
Ph); 7.12e7.23 (m, 3H, 3H of Ph); 7.28e7.39 (m, 6H, 5H of Ph, NH);
d
1H). 13C NMR (126 MHz, DMSO-d6):
d 27.4, 35.6, 42.2, 51.3, 84.4,
106.8, 150.3, 150.9, 163.9, 188.1; EI-HRMS: m/z¼256.1190 (MHþ);
C
12H18NO5 requires: m/z¼256.1185 (MHþ).
8.76 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6):
d 23.4, 27.5,
4.6. Alkylation of 4-hydroxypyrrole derivativesdgeneral
procedure 3 (GP3)
33.3, 41.7, 51.1, 65.2, 75.8, 85.0, 111.0, 127.2, 127.7, 127.8, 128.2,
128.3, 129.0, 133.9, 137.2, 147.4, 156.1, 160.9, 164.0, 196.7; EI-HRMS:
m/z¼523.2434 (MHþ); C29H35N2O7 requires: m/z¼523.2439
(MHþ).
To a solution of 4-hydroxypyrrole derivative (1 equiv) in anhy-
drous DMF (V1) under argon were added RX (X¼Br, I) and K2CO3
(2 equiv). The resulting reaction mixture was stirred at room
temperature for t1. Volatile components were evaporated in vacuo,
the residue was dissolved/suspended in EtOAc (150 mL), and
washed with NaCl (aq satd, 2ꢂ30 mL). The organic phase was dried
over anhydrous Na2SO4, filtered, and volatile components evapo-
rated in vacuo. The residue was purified/separated by column
chromatography (CC). Fractions containing the isolated/separated
product(s) were combined, respectively, and volatile components
evaporated in vacuo.
4.6.3. 1-tert-Butyl 3-methyl 5-benzyl-4-methoxy-1H-pyrrole-1,3-
dicarboxylate (12g) and 1-tert-butyl 3-methyl 5-benzyl-5-methyl-4-
oxo-4,5-dihydro-1H-pyrrole-1,3-dicarboxylate (11g). General pro-
cedure 3 (GP3): Prepared from 4g (441 mg, 1.33 mmol), DMF
(V1¼10 mL), MeI (0.335 mL, 5.32 mmol), K2CO3 (368 mg,
2.66 mmol), 24 h, CC (EtOAc/petroleum ether¼1:5).
4.6.3.1. Compound 12g. Elutes first from the column. Yield:
83 mg (18%) of yellowish oil. nmax 3159, 3085, 3063, 3029, 2981,
2937, 2837, 1744, 1720, 1599, 1530, 1495, 1455, 1436, 1366, 1332,
1275, 1256, 1191, 1144, 1112, 1071, 1012, 971, 926, 896, 846, 806, 754,
4.6.1. 1-tert-Butyl 3-methyl 5,5-dibenzyl-4-oxo-4,5-dihydro-1H-pyr-
role-1,3-dicarboxylate (9g). General procedure 3 (GP3): Prepared
from 4g (463 mg, 1.40 mmol), DMF (V1¼10 mL), BnBr (0.221 mL,
1.82 mmol), K2CO3 (390 mg, 2.80 mmol), 48 h, CC (EtOAc/petroleum
ether¼1:5). Yield: 434 mg (73%) of white solid; mp 124.5e128.0 ꢀC.
726, 698 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.34 (s, 9H, Boc);
3.70 (s, 3H, OMe); 3.77 (s, 3H, CO2Me); 4.15 (s, 2H, CH2); 7.01 (d,
J¼7.8 Hz, 2H, 2H of Ph); 7.14e7.19 (m,1H,1H of Ph); 7.26 (t, J¼7.6 Hz,
2H, 2H of Ph); 7.68 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6):
C
25H27NO5 requires: C, 71.24; H, 6.46; N, 3.32. Found C, 71.41; H,
d 27.0, 29.0, 51.23, 62.2, 85.3, 110.5, 122.2, 123.9, 125.9, 127.4, 128.3,
6.18; N, 3.31. nmax 3104, 3083, 3064, 3029, 3006, 2984, 2968, 2947,
2932, 2860, 1742, 1720, 1689, 1573, 1494, 1476, 1455, 1442, 1387,
1368, 1340, 1332, 1311, 1297, 1257, 1224, 1185, 1171, 1139, 1086, 1069,
1037, 1014, 982, 957, 917, 880, 854, 837, 808, 791, 767, 756, 726, 700,
139.7, 145.3, 147.8, 162.4; EI-HRMS: m/z¼346.1645 (MHþ);
C
19H24NO5 requires: m/z¼346.1649 (MHþ).
4.6.3.2. Compound 11g. Elutes second from the column. Yield:
638, 622 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d
1.59 (br s, 9H, Boc);
250 mg (54%) of yellowish oil. nmax 3088, 3064, 3031, 2979, 2950,
2935,1712,1577, 1496, 1477, 1452,1438,1385,1369,1298,1283,1225,
1195,1143,1097,1074, 996, 945, 917, 898, 876, 854, 838, 794, 761, 729,
3.26 (d, J¼13.4 Hz, 2H, 2H of CH2); 3.47 (m, 2H, 2H of CH2); 3.52 (s,
3H, CO2Me); 6.95 (d, J¼5.6 Hz, 4H, 4H of Ph); 7.16e7.28 (m, 6H, 6H
of Ph); 8.39 (s, 1H, HeC(2)). 13C NMR (126 MHz, DMSO-d6):
d
27.6,
702, 690, 637, 609 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.50 (s, 3H,
41.2, 51.1, 76.7, 84.8, 111.3, 127.3, 128.3, 129.1, 134.0, 147.4, 160.5,
163.6, 196.6; EI-HRMS: m/z¼422.1958 (MHþ); C25H28NO5 requires:
m/z¼422.1962 (MHþ).
Me); 1.58 (s, 9H, Boc); 3.08 (d, J¼13.5 Hz, 1H, Ha of CH2); 3.29 (d,
J¼13.5 Hz, 1H, Hb of CH2); 3.62 (s, 3H, CO2Me); 6.88e6.92 (m, 2H, 2H
of Ph); 7.16e7.24 (m, 3H, 3H of Ph); 8.68 (s, 1H, HeC(2)). 13C NMR
(126 MHz, DMSO-d6):
d 21.9, 27.6, 41.2, 51.1, 72.5, 84.7, 109.4, 127.2,
4.6.2. 1-tert-Butyl 3-methyl 4-(benzyloxy)-5-(3-(((benzyloxy)car-
bonyl)amino)propyl)-1H-pyrrole-1,3-dicarboxylate (10k) and 1-tert-
butyl 3-methyl 5-benzyl-5-(3-(((benzyloxy)carbonyl)amino)propyl)-
4-oxo-4,5-dihydro-1H-pyrrole-1,3-dicarboxylate (9k). General pro-
cedure 3 (GP3): Prepared from 4k (480 mg, 1.11 mmol), DMF
(V1¼12 mL), BnBr (0.175 mL, 1.44 mmol), K2CO3 (307 mg,
2.22 mmol), 48 h, CC (EtOAc/petroleum ether¼1:2).
128.2, 128.9, 134.5, 147.3, 161.2, 163.1, 197.0; EI-HRMS: m/z¼346.1645
(MHþ); C19H24NO5 requires: m/z¼346.1649 (MHþ).
4.6.4. 1-tert-Butyl 3-methyl 5-(3-(((benzyloxy)carbonyl)amino)pro-
pyl)-4-methoxy-1H-pyrrole-1,3-dicarboxylate (12k). General pro-
cedure 3 (GP3): Prepared from 4k (444 mg, 1.027 mmol), DMF
(V1¼12 mL), MeI (0.194 mL, 3.081 mmol), K2CO3 (284 mg,
2.054 mmol), 48 h, CC (EtOAc/petroleum ether¼1:3). Yield: 190 mg
(41%) of yellowish oil. nmax 3368, 2976, 2936, 2874, 1708,1597, 1529,
1454, 1409, 1367, 1274, 1254, 1194, 1146, 1122, 1091, 1071, 1009, 847,
4.6.2.1. Compound 10k. Elutes first from the column. Yield:
72 mg (12%) of yellowish oil. nmax 3363, 2948, 2872, 1749, 1713,
1596, 1528, 1454, 1440, 1421, 1367, 1273, 1255, 1146, 1092, 987, 914,
753, 697 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.56 (s, 9H, Boc);
847, 752, 733, 696 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d
1.46e1.58
1.58e1.64 (m, 2H, 2H of CH2); 2.67e2.73 (m, 2H, 2H of CH2);
2.97e3.03 (m, 2H, 2H of CH2); 3.68 (s, 3H, OMe); 3.74 (s, 3H,
CO2Me); 5.01 (s, 2H, CH2 of Cbz); 7.27e7.40 (m, 6H, 5H of Ph, NH);
(m, 2H, 2H of CH2); 1.56 (s, 9H, Boc); 2.60e2.68 (m, 2H, 2H of CH2);
2.95 (q, J¼6.7 Hz, 2H of CH2); 3.76 (s, 3H, CO2Me); 4.89 (s, 2H, CH2);
4.99 (s, 2H, CH2); 7.25 (d, J¼5.6 Hz, 1H, NH); 7.27e7.40 (m, 8H, 8H of
Ph); 7.41e7.47 (m, 2H, 2H of Ph); 7.63 (s, 1H, HeC(2)). 13C NMR
7.59 (s, 1H, HeC(2)). 13C NMR (126 MHz, CDCl3):
d
21.0, 28.0, 29.1,
39.9, 51.4, 62.7, 66.4, 85.2, 110.9, 124.29, 124.33, 128.0, 128.5, 136.9,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11105
144.9, 148.4, 156.5, 163.5; EI-HRMS: m/z¼447.2128 (MHþ);
enantiomer)¼12.2 min; EI-HRMS: m/z¼336.1795 (MHþ);
C
23H31N2O7 requires: m/z¼447.2126 (MHþ).
C
18H26NO5 requires: m/z¼336.1805 (MHþ).
4.7. Reduction of 4-hydroxypyrrole derivativesdgeneral pro-
cedure 4 (GP4)
4.7.1.3. Compound 15g. Elutes third from the column. Yield:
90 mg (18%) of white solid; mp 128e129 ꢀC. C17H25NO4 requires: C,
66.43; H, 8.20; N, 4.56. Found C, 66.71; H, 8.50; N, 4.55. nmax 3419,
3324, 2971, 2897, 1657, 1476, 1453, 1413, 1364, 1249, 1223, 1168,
1120, 1083, 1051, 1028, 997, 941, 917, 868, 826, 780, 769, 734, 699,
To a solution of 4-hydroxypyrrole derivative (1 equiv) in MeOH
(V1) under argon at T1 was added NaBH4 (2 equiv, added portion
wise) and the resulting mixture was vigorously stirred for t1. The
reaction was quenched with the addition of NaHCO3 (aq satd,
15 mL). After stirring of the reaction mixture for an additional
10 min at room temperature, volatile components were evaporated
in vacuo (mainly MeOH), the residue was dissolved/suspended in
EtOAc (150 mL), and washed with NaCl (aq satd, 2ꢂ20 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and vol-
atile components evaporated in vacuo. The residue was purified/
separated by column chromatography (CC). Fractions containing
the isolated/separated product(s) were combined, respectively, and
volatile components evaporated in vacuo.
614 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
. d 1.43 (s, 9H, Boc);
1.94e2.06 (m,1H, HeC(3)); 2.77e3.19 (m, 2.5H,1.5H of CH2Ph, Ha of
H2C(2)); 3.31e3.45 (m, 1.5H, 0.5H of CH2Ph, Ha of CH2OH);
3.51e3.66 (m, 2H, Hb of H2C(2), Hb of CH2OH); 3.71 (dt, J¼3.7;
10.3 Hz, 1H, HeC(5)); 3.79e3.91 (m, 1H, HeC(4)); 4.41 (t, J¼5.2 Hz,
1H, CH2OH); 4.79e4.94 (m, 1H, CHOH); 7.13e7.21 (m, 1H, 1H of Ph);
7.23e7.35 (m, 4H, 4H of Ph) (two conformers). 13C NMR (126 MHz,
DMSO-d6):
d 28.2, 32.4, 33.8, 45.5, 48.3, 48.8, 58.9, 64.9, 69.3, 70.0,
78.3, 78.7, 125.8, 128.1, 129.2, 139.8, 154.5 (two conformers); EI-
HRMS: m/z¼208.1333 (MHꢁBocþ); C12H18NO2 requires: m/
z¼208.1332 (MHꢁBocþ). HPLC analysis: CHIRALCEL OD-H, n-hex-
ane/i-PrOH¼90:10, flow rate: 1.0 mL/min, 25 ꢀC, UV:
¼210 nm, t1
l
4.7.1. rel-(3S,4S,5S)-1-tert-Butyl 3-methyl 5-benzyl-4-
hydroxypyrrolidine-1,3-dicarboxylate (13g), rel-(3R,4S,5S)-1-tert-bu-
tyl 3-methyl 5-benzyl-4-hydroxypyrrolidine-1,3-dicarboxylate (14g),
rel-(2S,3S,4R)-tert-butyl 2-benzyl-3-hydroxy-4-(hydroxymethyl)pyr-
rolidine-1-carboxylate (15g), and rel-(2S,3S,4S)-tert-butyl 2-benzyl-3-
hydroxy-4-(hydroxymethyl)pyrrolidine-1-carboxylate (16g). General
procedure 4 (GP4): Prepared from 4g (516 mg, 1.56 mmol), MeOH
(V1¼8 mL), NaBH4 (118 mg, 3.12 mmol), T1¼rt, 1 h, ratio of products:
13g/14g/15g/16g¼1:0.67:0.67:0.73, CC [(1) EtOAc/petroleum
ether¼1:3 to elute/separate products 13g and 14g; (2) EtOAc/pe-
troleum ether¼3:1 to elute/separate products 15g and 16g].
(first enantiomer)¼15.0 min, t2 (second enantiomer)¼30.0 min.
4.7.1.4. Compound 16g. Elutes fourth from the column. Yield:
30 mg (6%) of white solid; mp 133e134 ꢀC. C17H25NO4 requires: C,
66.43; H, 8.20; N, 4.56. Found C, 66.58; H, 8.40; N, 4.56. nmax 3351,
3320, 2932,1644,1604,1495,1474,1416,1367,1335,1308,1244,1166,
1139, 1104, 1080, 1050, 1008, 956, 879, 853, 821, 777, 741, 724,
694 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.17 and 1.39 (s, 9H, Boc);
1.84e1.96 and 1.97e2.10 (m, 1H, HeC(3)); 2.54e2.64 and 2.76e2.86
and 3.01e3.09 (m, 1H); 2.92e2.99 (m, 1H); 3.16 (deg t, J¼8.9; 9.7 Hz,
1H); 3.25 (deg t, J¼9.3; 10.0 Hz, 1H); 3.31e3.41 (m, 1H); 3.41e3.57
(m, 1H); 3.86e3.95 (m, 2H, HeC(4), HeC(5)); 4.54e4.64 (m, 1H,
CH2OH); 5.13e5.21 (m, 1H, CHOH); 7.12e7.31 (m, 5H, 5H of Ph) (two
4.7.1.1. Compound 13g. Elutes first from the column. Yield:
100 mg (19%) of white solid; mp 85e90 ꢀC. C18H25NO5 requires: C,
64.46; H, 7.51; N, 4.18. Found C, 64.25; H, 7.84; N, 4.18. nmax 3434,
2975, 1737, 1671, 1603, 1495, 1477, 1454,1438,1394, 1366, 1308,1253,
1212, 1159, 1114, 1091, 1049, 1028, 982, 949, 924, 865, 834, 751, 699,
conformers). 13C NMR (126 MHz, DMSO-d6):
d 27.8, 28.2, 33.7,
34.6, 44.5, 45.6, 45.9, 46.8, 60.4, 60.9, 61.4, 70.4, 70.9, 77.9,
78.1, 125.6, 127.8, 127.9, 129.8, 129.9, 139.9, 153.7 (two conformers);
EI-HRMS: m/z¼208.1333 (MHꢁBocþ); C12H18NO2 requires: m/
z¼208.1332 (MHꢁBocþ). HPLC analysis: CHIRALCEL OD-H, n-hex-
666, 607 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
. d 1.44 (s, 9H, Boc);
2.78e3.02 (m,1H, Ha of CH2Ph); 3.05e3.20 (m,1.5H, 0.5 Hb of CH2Ph,
HeC(3)); 3.31e3.41 (m, 0.5H, 0.5 Hb of CH2Ph); 3.44e3.57 (m,1H, Ha
of H2C(2)); 3.60 (s, 3H, CO2Me); 3.60e3.76 (m, 1H, Hb of H2eC(2));
3.80 (dt, J¼3.8; 10.6 Hz, 1H, HeC(5)); 4.09 (d, J¼8.5 Hz, 1H, HeC(4));
5.50 (d, J¼20.5 Hz, 1H, OH); 7.16e7.23 (m, 1H, 1H of Ph); 7.24e7.34
(m, 4H, 4H of Ph) (two conformers). 13C NMR (126 MHz, DMSO-d6):
ane/i-PrOH¼93:7, flow rate: 1.0 mL/min, 25 ꢀC, UV:
¼210 nm, t1
l
(first enantiomer)¼7.7 min, t2 (second enantiomer)¼9.0 min.
4.7.2. rel-(3S,4S,5S)-1-tert-Butyl 3-methyl 5-benzyl-4-
hydroxypyrrolidine-1,3-dicarboxylate (13g) and rel-(3R,4S,5S)-1-
tert-butyl 3-methyl 5-benzyl-4-hydroxypyrrolidine-1,3-dicarboxylate
(14g). General procedure 4 (GP4): Prepared from 4g (216 mg,
0.65 mmol), MeOH (V1¼2 mL), NaBH4 (49 mg, 1.30 mmol),
T1¼ꢁ5 ꢀC, 1 h, ratio of products: 13g/14g¼47:53, CC (EtOAc/petro-
leum ether¼1:3 to separate products 13g and 14g).
d
28.2, 32.23, 33.6, 45.9, 46.2, 47.8, 47.9, 51.4, 64.2, 64.4, 70.4, 71.1,
78.6, 79.0, 125.9, 128.2, 129.2, 139.4, 154.3, 170.3 (two conformers);
EI-HRMS: m/z¼236.1280 (MHꢁBocþ); C13H18NO3 requires: m/
z¼236.1281 (MHꢁBocþ). HPLC analysis: CHIRALPAK AD-H, n-hex-
ane/i-PrOH¼93:7, flow rate: 1.0 mL/min, 25 ꢀC, UV:
¼210 nm, t1
l
(first enantiomer)¼8.8 min, t2 (second enantiomer)¼9.9 min.
4.7.2.1. Compound 13g. Elutes first from the column. Yield:
73 mg (33%) of white solid.
4.7.1.2. Compound 14g. Elutes second from the column. Yield:
40 mg (7%) of white solid; mp 87e89 ꢀC. C18H25NO5 requires: C,
64.46; H, 7.51; N, 4.18. Found C, 64.26; H, 7.90; N, 4.18. nmax 3416,
2975, 1735, 1664, 1495, 1477, 1454, 1394, 1366, 1337, 1251, 1201,
4.7.2.2. Compound 14g. Elutes second from the column. Yield:
80 mg (36%) of white solid.
1164, 1127, 1081, 1028, 948, 858, 750, 700, 666 cmꢁ1
.
1H NMR
4.7.3. rel-(3S,4S,5S)-1-tert-Butyl 3-methyl 5-(3-(((benzyloxy)car-
bonyl)amino)propyl)-4-hydroxypyrrolidine-1,3-dicarboxylate (13k)
and rel-(3R,4S,5S)-1-tert-butyl 3-methyl 5-(3-(((benzyloxy)carbonyl)
amino)propyl)-4-hydroxypyrrolidine-1,3-dicarboxylate
(14k). General procedure 4 (GP4): Prepared from 4k (925 mg,
2.14 mmol), MeOH (V1¼10 mL), NaBH4 (162 mg, 4.28 mmol),
T1¼ꢁ5 ꢀC, 1 h, CC (EtOAc/petroleum ether¼1:2).
(500 MHz, DMSO-d6):
d 1.17 and 1.39 (s, 9H, Boc); 2.58e2.75 (m, 1H,
0.5H of HeC(3), 0.5H of CH2Ph); 2.80e2.99 (m, 2H, 1.5H of CH2Ph,
0.5H of HeC(3)); 3.23e3.46 (m, 2H, H2C(2)); 3.55e3.68 (br s, 3H,
CO2Me); 3.90e4.02 (m, 1H, HeC(5)); 4.23e4.31 (m, 1H, HeC(4)),
5.67 (br s, 1H, OH), 7.13e7.31 (m, 5H, 5H of Ph) (two conformers).
13C NMR (126 MHz, DMSO-d6):
d 27.7, 28.1, 33.3, 34.1, 45.5, 46.3,
47.6, 48.7, 51.9, 60.9, 61.3, 72.6, 73.5, 78.4, 78.6, 125.8, 127.9, 128.0,
129.8, 139.3, 153.5, 172.6, 173.2 (two conformers). HPLC analysis:
CHIRALPAK AD-H, n-hexane/i-PrOH¼93:7, flow rate: 1.0 mL/min,
4.7.3.1. Diastereoisomers 13k and 14k. Elute together, could not
be separated by CC. Yield: 753 mg (80%) of colorless oil; 13k/
14k¼1:1. nmax 3352, 2972, 2952, 1689, 1672, 1528, 1476, 1454, 1398,
25 ꢀC, UV:
l¼210 nm, t1 (first enantiomer)¼9.5 min, t2 (second

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11106
1366, 1309, 1245, 1212, 1164, 1130, 1025, 941, 912, 867, 773, 737,
697 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
1.29e1.64 (m, 4H); 1.38
(6) (131 mg, 0.9 mmol), t1¼3 h, CC (EtOAc/petroleum ether¼1:3).
rt
d
Yield: 53 mg (11%) of orange oil. [
a
]
D
þ25.8 (c 0.59, CH2Cl2). nmax
(s, 9H, Boc); 2.86e3.13 (m, 3H); 3.35e3.54 (m, 2H); 3.57e3.70 (m,
1H); 3.61 (s,1.5H, CO2Me); 3.64 (s,1.5H, CO2Me); 4.23e4.28 (m, 0.5H,
CH); 4.32 (br s, 0.5H, CH); 5.00 (s, 2H, CH2 of Cbz); 5.32 (br s, 0.5H,
OH); 5.50 (br s, 0.5H, OH); 7.20e7.39 (m, 6H, 5H of Ph, NH) (two
3380, 3063, 3030, 2951, 1697, 1597, 1548, 1499, 1453, 1437, 1415,
1375, 1336, 1265, 1242, 1226, 1183, 1154, 1101, 1076, 1039, 1020, 971,
942, 911, 878, 846, 808, 765, 733, 695 cmꢁ1 1H NMR (500 MHz,
.
CDCl3):
d
3.07 (dd, J¼6.1; 13.1 Hz, 1H, Ha of CH2); 3.16 (dd, J¼10.1;
conformers). 13C NMR (126 MHz, DMSO-d6):
d
24.3, 25.4, 26.1, 26.2,
13.0 Hz, 1H, Hb of CH2); 3.93 (s, 3H, CO2Me); 5.02 (d, J¼12.3 Hz, 1H,
Ha of Cbz); 5.15 (dd, J¼12.3 Hz, 1H, Hb of Cbz); 5.23e5.31 (m, 1H,
NHCH); 6.71 (d, J¼7.2 Hz, 2H, 2H of Ph); 6.92 (d, J¼7.4 Hz, 2H, 2H of
Ph); 7.03e7.10 (m, 2H, 2H of Ph); 7.11e7.16 (m,1H,1H of Ph); 7.20 (d,
J¼10.2 Hz, 1H, NH); 7.27e7.40 (m, 8H, Ph 8H of Ph); 8.02 (s, 1H,
26.7, 28.1, 39.8, 40.7, 45.6, 46.0, 47.8, 48.0, 48.7, 51.4, 51.9, 54.9, 59.1,
59.4, 62.2, 62.4, 65.07, 65.10, 70.9, 71.6, 72.9, 73.5, 78.4, 78.6, 78.7,
127.69, 127.73, 128.3, 137.31, 137.35, 153.8, 154.1, 156.07, 156.09, 170.3,
172.8, 173.1 (two conformers); EI-HRMS: m/z¼437.2278 (MHþ);
C
22H33N2O7 requires: m/z¼437.2282 (MHþ). HPLC analysis: CHIR-
HeC(3)). 13C NMR (126 MHz, CDCl3):
d 41.2, 49.2, 52.0, 66.8, 111.7,
ALCEL OD-H, n-hexane/i-PrOH¼90:10, flow rate: 1.0 mL/min, 25 ꢀC,
126.5, 126.8, 128.0, 128.1, 128.5, 128.6, 129.0, 129.2, 129.3, 136.3,
136.5, 138.0, 142.5, 147.4, 155.9, 165.0; EI-HRMS: m/z¼456.1912
(MHþ); C27H26N3O4 requires: m/z¼456.1918 (MHþ).
UV:
l¼210 nm, t1 (first isomer)¼18.8 min, t2 (second isomer)¼
22.6 min, t3 (third isomer)¼27.2 min, t4 (fourth isomer)¼29.4 min.
4.8. Synthesis of rel-(2S,3S,4R)-tert-butyl 2-benzyl-3-hydroxy-
4-(hydroxymethyl)pyrrolidine-1-carboxylate (15g) and rel-
(2S,3S,4S)-tert-butyl 2-benzyl-3-hydroxy-4-(hydroxymethyl)
pyrrolidine-1-carboxylate (16g)
4.9.2. (S)-Methyl 5-(1-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)-1-
phenyl-1H-pyrazole-4-carboxylate (17i). General procedure
5
(GP5): Prepared from 3i (128 mg, 0.315 mmol), MeOH (V2¼2 mL),
PhNHNH2$HCl (6) (46 mg, 0.315 mmol), t1¼3 h, CC (EtOAc/petro-
leum ether¼1:3). Yield: 116 mg (81%) of white solid; mp
rt
To a solution of 13g or 14g (30 mg, 0.09 mmol) in MeOH (2 mL)
at 30 ꢀC was added NaBH4 (76 mg, 2 mmol) and the resulting re-
action mixture was stirred at 30 ꢀC for 1 h, followed by addition of
NaHCO3 (aq satd, 5 mL). The resulting mixture was stirred at rt for
0.5 h, followed by extraction with EtOAc (3ꢂ20 mL). The combined
organic phase was dried over anhydrous Na2SO4, filtered, and vol-
atile components evaporated in vacuo. The residue was purified by
column chromatography (EtOAc/petroleum ether¼3:1). Fractions
containing the product 15g (from 13g) or 16g (from 14g) were
combined and volatile components evaporated in vacuo.
108e111 ꢀC. [
a
]
þ5.6 (c 0.09, CH2Cl2). C27H21N3O4 requires: C,
D
71.83; H, 4.69; N, 9.31. Found C, 71.91; H, 4.63; N, 9.11. nmax 3062,
3030, 2950, 1776, 1710, 1597, 1546, 1500, 1467, 1454, 1436, 1416,
1380, 1330, 1261, 1227, 1192, 1174, 1125, 1085, 1071, 1031, 1004, 983,
967, 947, 921, 874, 846, 772, 714, 695, 639 cmꢁ1. 1H NMR (500 MHz,
CDCl3):
d
3.71 (dd, J¼7.3; 13.8 Hz, 1H, Ha of CH2); 3.86 (s, 3H,
CO2Me); 3.99 (dd, J¼9.0; 13.9 Hz, 1H, Hb of CH2); 6.05 (dd, J¼7.2;
9.0 Hz, 1H, CH); 7.05e7.19 (m, 7H, 7H of Arl); 7.18e7.33 (m, 3H, 3H
of Arl); 7.59e7.69 (m, 4H, 4H of Arl); 8.06 (s, 1H, HeC(3)). 13C NMR
(126 MHz, CDCl3): d 36.9, 51.2, 51.8, 112.9, 123.2, 126.9, 127.4, 128.6,
129.0, 129.3, 129.4, 131.5, 134.0, 137.1, 139.1, 142.4, 144.5, 163.6,
167.8; EI-HRMS: m/z¼452.1588 (MHþ); C27H22N3O4 requires: m/
z¼452.1605 (MHþ).
4.8.1. Compound 15g. Prepared from 13g. Yield: 13 mg (47%) of
white solid.
4.8.2. Compound 16g. Prepared from 14g. Yield: 11 mg (40%) of
white solid.
4.9.3. (S)-Methyl 5-(12,12-dimethyl-3,10-dioxo-1-phenyl-2,11-dioxa-
4,9-diazatridecan-8-yl)-1-phenyl-1H-pyrazole-4-carboxylate
(17k). General procedure 5 (GP5): Prepared from 2k (425 mg,
1.006 mmol), CH2Cl2 (V1¼5 mL), DMFDMA (0.164 mL, 1.107 mmol),
MeOH (V2¼5 mL), PhNHNH2$HCl (6) (132 mg, 0.905 mmol), t1¼4 h,
CC (EtOAc/petroleum ether¼1:4). Yield: 250 mg (45%) of yellow oil.
4.9. Cyclization of enaminone intermediates with dinucleo-
philesdgeneral procedure 5 (GP5)
To a solution of
b-keto ester (1 equiv) in anhydrous CH2Cl2 or
[a
]
rDt þ19.0 (c 0.32, CH2Cl2). nmax 3366, 2976, 2950, 2872, 1697, 1597,
toluene (V1) under Argon was added DMFDMA (1.1 equiv) and the
resulting reaction mixture was stirred at room temperature till most
1549, 1499, 1454, 1414, 1366, 1341, 1263, 1163, 1101, 1044, 1016, 971,
.
917, 868, 807, 766, 694 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
of the starting
b-keto ester A reacted into enaminone intermediate B
d
1.10e1.38 (m, 2H, 2H of CH2); 1.33 (s, 9H, Boc); 1.65e1.74 (m, 1H,
judging by TLC-analysis (see Fig. 2 and the accompanying discus-
sion). If the reaction is left for too long, the enaminone intermediate
B cyclizes into pyrrole product C. Volatile components were evapo-
rated in vacuo and the residue was dissolved in MeOH (V2) followed
by addition of dinucleophile hydrochloride (0.9 equiv) or dinucleo-
phile (0.9 equiv) and HCl (0.9 equiv). Reactions with stable isolated
enaminone 3i were carried out in the same manner with the addi-
tion of 1 equiv of dinucleophile and HCl. The resulting reaction
mixture was stirred for 30 min at room temperature, t1 under reflux,
and additional 12 h at room temperature. Volatile components were
evaporated in vacuo and the residue was purified/separated by col-
umn chromatography (CC) and/or MPLC. Fractions containing the
isolated/separated product(s) were combined, respectively, and
volatile components evaporated in vacuo. Products that precipitated
from the reaction mixture were collected by filtration and washed
with cold MeOH (2 mL, 0 ꢀC).
Ha of CH2); 1.75e1.88 (m, 1H, Hb of CH2); 2.79e2.97 (m, 2H, 2H of
CH2); 3.83 (s, 3H, CO2Me); 4.75e4.86 (m,1H, CH); 4.98 (s, 2H, CH2 of
Cbz); 6.78 (d, J¼8.7 Hz, 1H, NH); 7.18 (br s, 1H, NH); 7.27e7.39 (m,
5H, 5H of Ph); 7.39e7.51 (m, 2H, 2H of Ph); 7.53e7.63 (m, 3H, 3H of
Ph); 8.07 (s, 1H, HeC(3)). 13C NMR (126 MHz, DMSO-d6):
d 26.2,
28.0, 31.4, 46.7, 51.8, 65.1, 78.7, 110.8, 126.4, 127.70, 127.75, 128.3,
129.4, 129.5, 137.3, 138.4, 142.0, 148.3, 154.7, 156.0, 163.8; EI-HRMS:
m/z¼523.2546 (MHþ); C28H35N4O6 requires: m/z¼523.2551 (MHþ).
4.9.4. (S)-Methyl 5-(13,13-dimethyl-3,11-dioxo-1-phenyl-2,12-dioxa-
4,10-diazatetradecan-9-yl)-1-phenyl-1H-pyrazole-4-carboxylate
(17l). General procedure 5 (GP5): Prepared from 2l (436 mg,
1.0 mmol), CH2Cl2 (V1¼2 mL), DMFDMA (0.162 mL, 1.1 mmol),
MeOH (V2¼2 mL), PhNHNH2$HCl (6) (131 mg, 0.9 mmol), t1¼4 h, CC
(EtOAc/petroleum ether¼1:2). Yield: 274 mg (51%) of white solid;
mp 143e145 ꢀC. [
a
]
rDt ꢁ23.0 (c 0.27, CH2Cl2). C29H36N4O6 requires: C,
64.91; H, 6.76; N, 10.44. Found C, 64.73; H, 6.64; N, 10.33. nmax 3385,
3299, 3108, 3070, 3036, 3001, 2981, 2930, 2904, 2866, 2847, 1711,
1593, 1546, 1494, 1470, 1453, 1434, 1413, 1388, 1367, 1339, 1315,
1286, 1262, 1238, 1227, 1167, 1142, 1124,1101, 1089, 1069, 1056, 1041,
1020, 989, 974, 946, 925, 912, 891, 872, 863, 812, 800, 785, 766, 756,
4.9.1. (S)-Methyl 5-(1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-
1-phenyl-1H-pyrazole-4-carboxylate (17h). General procedure
5
(GP5): Prepared from 2h (355 mg, 1.0 mmol), CH2Cl2 (V1¼2 mL),
DMFDMA (0.162 mL, 1.1 mmol), MeOH (V2¼2 mL), PhNHNH2$HCl

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11107
741, 706, 695, 657, 626 cmꢁ1
.
1H NMR (500 MHz, DMSO-d6):
Ha of CH2); 2.19e2.31 (m, 1H, Hb of CH2); 3.14e3.26 (m, 2H, 2H of
CH2); 3.98 (s, 3H, CO2Me); 4.02 (s, 3H, CO2Me); 4.89e4.96 (m, 1H,
CH); 5.08 (s, 2H, CH2 of Cbz); 6.40e6.64 (m, 2H, 2ꢂNH); 7.29e7.38
(m, 5H, 5H of Ph); 8.67 (s, 1H, CH); 9.19 (s, 1H, CH). 13C NMR
d
0.96e1.08 (m, 1H, Ha of CH2); 1.09e1.39 (m, 3H, 3H of CH2); 1.33
(s, 9H, Boc); 1.64e1.75 (m, 1H, Ha of CH2); 1.75e1.85 (m, 1H, Hb of
CH2); 2.82e2.96 (m, 2H, 2H of CH2); 3.84 (s, 3H, CO2Me); 4.82 (dt,
J¼5.4; 8.6 Hz,1H, CH); 5.00 (s, 2H, CH2 of Cbz); 6.76 (d, J¼8.8 Hz,1H,
NH); 7.18 (t, J¼5.6 Hz, 1H, NH); 7.29e7.40 (m, 5H, 5H of Ph);
7.41e7.53 (m, 2H, 2H of Ph); 7.54e7.63 (m, 3H, 3H of Ph); 8.07 (s,1H,
(126 MHz, CDCl3): d 23.0, 28.3, 29.1, 31.9, 40.8, 48.8, 52.0, 53.4, 66.6,
80.2, 103.7, 111.7, 128.1, 128.2, 128.5, 136.7, 148.4, 148.9, 153.7, 155.4,
156.5, 162.5, 164.1; EI-HRMS: m/z¼570.2552 (MHþ); C28H36N5O8
requires: m/z¼570.2558 (MHþ).
HeC(3)). 13C NMR (126 MHz, DMSO-d6):
d 22.9, 28.0, 28.7, 33.5,
39.8, 46.6, 51.8, 65.1, 78.7, 110.8, 126.4, 127.7, 127.8, 128.3, 129.39,
129.45, 137.3, 138.4, 142.0, 148.5, 154.7, 156.1, 163.9; EI-HRMS: m/
z¼537.2707 (MHþ); C29H37N4O6 requires: m/z¼537.2708 (MHþ).
4.9.8. (S)-Methyl 4-(13,13-dimethyl-3,11-dioxo-1-phenyl-2,12-dioxa-
4,10-diazatetradecan-9-yl)-2-phenylpyrimidine-5-carboxylate
(22l). General procedure 5 (GP5): Prepared from 2l (524 mg,
1.2 mmol), CH2Cl2 (V1¼2 mL), DMFDMA (0.192 mL, 1.3 mmol),
MeOH (V2¼3 mL), benzamidine hydrochloride (20) (173 mg,
1.10 mmol), t1¼4 h, precipitates from the reaction mixture. Yield:
4.9.5. Methyl 5-(1-(2-(((benzyloxy)carbonyl)amino)acetamido)-2-
phenylethyl)-1-phenyl-1H-pyrazole-4-carboxylate
(17p). General
procedure 5 (GP5): Prepared from 2p (1.63 g, 3.95 mmol), CH2Cl2
(V1¼20 mL), DMFDMA (0.641 mL, 4.345 mmol), MeOH (V2¼30 mL),
PhNHNH2$HCl (6) (514 mg, 3.555 mmol), t1¼1 h, CC [(1) EtOAc/
petroleum ether¼1:2 to elute the nonpolar impurities; (2) EtOAc/
petroleum ether¼1:1 to elute the product]. Yield: 1.0 g (49%) of
orange semisolid. nmax 3338, 3030, 2951, 1699, 1676, 1598, 1547,
1498,1454,1437,1415,1375,1347,1264, 1230,1153,1112,1093,1046,
95 mg (17%) of white solid; mp 153.5e155.1 ꢀC. [
a]
rt ꢁ50.0 (c 0.33,
D
CH2Cl2). C30H36N4O6 requires: C, 65.68; H, 6.61; N, 10.21. Found C,
65.92; H, 6.52; N, 10.22. nmax 3357, 3091, 3068, 3036, 2988, 2970,
2950, 2920, 2861, 1729, 1683, 1571, 1525, 1456, 1425, 1383, 1364,
1343, 1325, 1308, 1268, 1247, 1213,1167, 1149,1107, 1090, 1073,1050,
1032, 1005, 988, 958, 918, 880, 857, 843, 827, 814, 778, 766, 754,
1029, 1002, 971, 940, 918, 882, 808, 785, 738, 693, 659 cmꢁ1
.
1H
705, 692, 678, 647, 623 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d 1.32
NMR (500 MHz, DMSO-d6):
d
3.03 (dd, J¼6.8; 13.2 Hz, 1H, Ha of
(s, 9H, Boc); 1.34e1.54 (m, 4H, 4H of CH2); 1.62e1.75 (m, 2H, 2H of
CH2); 2.94e3.06 (m, 2H, 2H of CH2); 3.92 (s, 3H, CO2Me); 5.00 (s,
2H, CH2 of Cbz); 5.35 (dt, J¼5.6; 8.1 Hz, 1H, CH); 7.23e7.42 (m, 7H,
7H of Ph); 7.54e7.63 (m, 3H, 3H of Ph); 8.52e8.59 (m, 2H, 2ꢂNH);
CH2); 3.21 (dd, J¼8.9; 13.2 Hz, 1H, Hb of CH2); 3.54 (dd, J¼6.0;
17.1 Hz,1H, Ha of CH2); 3.63 (dd, J¼6.3; 16.8 Hz,1H, Hb of CH2); 3.86
(s, 3H, CO2Me); 5.04 (d, J¼12.5 Hz, 1H, Ha of CH2); 5.09 (d,
J¼12.6 Hz, 1H, Hb of CH2); 5.23 (q, J¼8.4 Hz, 1H, CH); 6.76e6.82 (m,
2H, 2H of Ph); 6.97e7.01 (m, 2H, 2H of Ph); 7.10e7.27 (m, 4H, 4H of
Ph); 7.29e7.44 (m, 6H, 6H of Ph); 7.45e7.51 (m, 1H, 1H of Ph); 7.65
(t, J¼6.1 Hz,1H, NH); 8.07 (s,1H, HeC(3)); 8.39 (d, J¼8.5 Hz,1H, NH).
9.19 (s, 1H, HeC(5)). 13C NMR (126 MHz, DMSO-d6):
d 23.4, 27.7,
28.2, 29.1, 33.7, 40.1, 52.7, 52.8, 65.1, 78.0, 119.8, 127.7, 128.3,
128.6,128.8,131.9,136.2,137.3,155.7,156.1,159.3,164.6,164.7,171.9;
EI-HRMS: m/z¼549.2703 (MHþ); C30H37N4O6 requires: m/
z¼549.2708 (MHþ).
13C NMR (126 MHz, DMSO-d6):
d 39.3, 43.7, 46.8, 51.8, 65.7, 111.3,
126.3, 126.6, 127.7, 127.8, 128.3, 128.4, 128.9, 129.0, 129.2, 136.5,
136.9, 137.9, 142.0, 146.7, 156.5, 163.7, 168.6; EI-HRMS: m/
z¼513.2127 (MHþ); C29H29N4O5 requires: m/z¼513.2132 (MHþ).
4.9.9. (S)-Methyl 7-(13,13-dimethyl-3,11-dioxo-1-phenyl-2,12-dioxa-
4,10-diazatetradecan-9-yl)-2-(methylthio)-[1,2,4]triazolo[1,5-a]py-
rimidine-6-carboxylate (23l). General procedure 5 (GP5): Prepared
from 2l (524 mg, 1.2 mmol), CH2Cl2 (V1¼2 mL), DMFDMA (0.192 mL,
1.3 mmol), MeOH (V2¼3 mL), 5-(methylthio)-1H-1,2,4-triazol-3-
amine (21) (140 mg, 1.08 mmol), HCl (0.540 mL, 1.08 mmol, 2 M
4.9.6. (S)-Dimethyl
7-(1-(1,3-dioxoisoindolin-2-yl)-2-phenylethyl)
pyrazolo[1,5-a]pyrimidine-2,6-dicarboxylate (19i). General pro-
cedure 5 (GP5): Prepared from 3i (338 mg, 0.83 mmol), MeOH
(V2¼10 mL), methyl 3-amino-1H-pyrazole-4-carboxylate (18)
(118 mg, 0.83 mmol), HCl (37% in H2O, three drops, ca. 0.07 mL),
in EtOAc), t1¼4 h, CC (EtOAc) then MPLC (EtOAc/petroleum
rt
ether¼1:2). Yield: 66 mg (9%) of orange oil. [
a]
þ1.7 (c 0.37,
D
t1¼18 h, CC (EtOAc/petroleum ether¼1:2). Yield: 130 mg (32%) of
CH2Cl2). nmax 3341, 3090, 3065, 3033, 2977, 2933, 2868, 1709, 1634,
1597, 1497, 1455, 1435, 1366, 1315, 1277, 1237, 1202, 1158, 1093,
1044, 1003, 916, 860, 811, 794, 737, 698, 677, 631, 606 cmꢁ1. 1H NMR
rt
white solid; mp 68e78 ꢀC. [
a
]
þ11.1 (c 0.09, CH2Cl2). nmax 2951,
D
1777, 1709, 1607, 1560, 1517, 1467, 1454, 1433, 1369, 1328, 1278, 1199,
1173, 1155, 1121, 1090, 1011, 987, 962, 926, 910, 872, 790, 718, 698,
(500 MHz, DMSO-d6): d 0.99e1.13 (m, 1H, 1H of CH2); 1.25e1.52 (m,
672, 639 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
3.95 (s, 3H, CO2Me);
2H, 2H of CH2); 1.29 (s, 9H, Boc); 1.50e1.64 (m, 1H, 1H of CH2);
1.82e1.93 (m, 1H, 1H of CH2); 2.05e2.18 (m, 1H, 1H of CH2); 2.72 (s,
3H, SMe); 3.01 (dd, J¼6.5; 12.7 Hz, 2H, 2H of CH2); 3.94 (s, 3H,
CO2Me); 5.01 (s, 2H, CH2 of Cbz); 5.67 (s, 1H, CH); 7.27 (t, J¼5.8 Hz,
1H, NH); 7.29e7.39 (m, 5H, 5H of Ph); 7.4 (br d, J¼5.7 Hz, 1H, NH);
3.96 (s, 3H, CO2Me); 3.98 (dd, J¼7.7; 14.1 Hz, 1H, Ha of CH2); 4.50
(dd, J¼8.6; 13.9 Hz, 1H, Hb of CH2); 7.14e7.24 (m, 6H, 5H of Ph, CH);
7.64e7.69 (m, 2H, 2H of Arl); 7.73e7.77 (m, 2H, 2H of Arl); 8.63 (s,
1H, CH); 9.08 (s, 1H, CH). 13C NMR (126 MHz, CDCl3):
d 33.3, 52.0,
53.0, 53.3, 103.6, 113.7, 123.3, 127.1, 128.4, 129.3, 131.5, 134.2, 136.4,
148.4, 149.1, 149.8, 152.9, 162.5, 164.1, 168.2; EI-HRMS: m/
z¼485.1454 (MHþ); C26H21N4O6 requires: m/z¼485.1456 (MHþ).
9.01 (s, 1H, CH). 13C NMR (126 MHz, DMSO-d6):
d 13.4, 23.1, 27.7,
28.0, 28.9, 29.9, 39.8, 53.2, 65.1, 78.8, 112.7, 127.8, 128.3, 137.3, 152.2,
154.8, 155.1, 155.9, 156.1, 164.4, 169.1; EI-HRMS: m/z¼559.2313
(MHþ); C26H35N6O6S requires: m/z¼559.2333 (MHþ).
4.9.7. (S)-Dimethyl 7-(13,13-dimethyl-3,11-dioxo-1-phenyl-2,12-
dioxa-4,10-diazatetradecan-9-yl)pyrazolo[1,5-a]pyrimidine-2,6-
dicarboxylate (19l). General procedure 5 (GP5): Prepared from 2l
(524 mg, 1.2 mmol), CH2Cl2 (V1¼2 mL), DMFDMA (0.192 mL,
1.3 mmol), MeOH (V2¼3 mL), 3-amino-1H-pyrazole-4-carboxylate
(18) (152 mg, 1.08 mmol), HCl (0.540 mL, 1.08 mmol, 2 M in
4.10. Single crystal X-ray structure analysis for compounds 7a,
8r, 9g, 13g, 14g, and 17i
Single crystal diffraction data for compounds 8r, 13g, 14g, and
17i have been collected on an Agilent SuperNova dual source dif-
EtOAc), t1¼4 h, CC (EtOAc) then MPLC (EtOAc/petroleum
fractometer with an Atlas detector at room temperature with Mo
rt
ꢁ
ether¼1:2). Yield: 73 mg (10%) of orange oil. [
a
]
þ16.4 (c 0.42,
K
a
radiation (0.71073 A) for 8r and 17i and Cu K
a
radiation
D
ꢁ
CH2Cl2). nmax 3369, 3065, 3032, 2976, 2951, 2866, 1704, 1608, 1519,
1495, 1455, 1435, 1391, 1367, 1283, 1241, 1215, 1203, 1158, 1099,
1044, 1013, 985, 934, 910, 861, 824, 794, 775, 747, 697, 678,
(1.54184 A) for 13g and 14g, respectively. These data were pro-
cessed using CrysAlis PRO software.66 Single crystal diffraction data
for compounds 7a and 9g, have been collected on a Nonius Kappa
637 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
1.38 (s, 9H, Boc); 1.38e1.53
CCD diffractometer at room temperature with Mo K
(0.71073 A) and graphite monochromator using the Nonius Collect
a
radiation
ꢁ
(m, 1H, 1H of CH2); 1.53e1.71 (m, 3H, 3H of CH2); 1.87e1.99 (m, 1H,

ꢀ
U. Groselj et al. / Tetrahedron 69 (2013) 11092e11108
11108
Software.67 These reflection data were processed using DENZO
software.68 All structures were solved by direct methods, using
SIR97.69 A full-matrix least-squares refinement on F2 was employed
with anisotropic displacement parameters for all non-hydrogen
atoms. H atoms were placed at calculated positions and treated
as riding. SHELXL97 software70 was used for structure refinement
and interpretation. Drawings of the structures were produced using
ORTEP-3.71 Structural and other crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 954147eCCDC 954152,
for 7a, 8r, 9g, 13g, 14g, and 17i, respectively. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
ving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
20. San Feliciano, A.; Caballero, E.; Pereira, J. A. P.; Puebla, P. Tetrahedron 1989, 45,
6553e6562.
21. Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J. Org. Chem. 2008, 73,
2090e2095.
22. Rapoport, H.; Holden, K. G. J. Am. Chem. Soc. 1962, 84, 635e642.
23. Momose, T.; Tanaka, T.; Yokota, T. Heterocycles 1977, 6, 1821e1826.
24. Momose, T.; Tanaka, T.; Yokota, T.; Nagamoto, N.; Yamada, K. Chem. Pharm. Bull.
1978, 26, 2224e2232.
25. Kazembe, T. C.-G.; Taylor, D. A. Tetrahedron 1980, 36, 2125e2132.
26. Murata, T.; Sugawara, T.; Ukawa, K. Chem. Pharm. Bull. 1973, 21, 2571e2575.
27. Murata, T.; Sugawara, T.; Ukawa, K. Chem. Pharm. Bull. 1978, 26, 3080e3100.
28. Campaigne, E.; Shutske, G. M. J. Heterocycl. Chem. 1974, 11, 929e936.
29. Campaigne, E.; Shutske, G. M.; Payne, J. C. J. Heterocycl. Chem. 1977, 14, 329e331.
ꢀ
30. Kolar, P.; Tisler, M. Synth. Commun. 1994, 24, 1887e1893.
31. Alizadeh, A.; Hosseinpour, R.; Rostamnia, S. Synthesis 2008, 2462e2466.
32. Paul, V. L.; Yakaiah, T.; Reddy, A. R.; Shekhar, A. C.; Rao, P. S.; Narsaiah, B. Synth.
Commun. 2010, 40, 3152e3158.
33. Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.; Giorgi, G.; Mantellini, F.;
Nicolini, S. Adv. Synth. Catal. 2011, 353, 595e605.
34. Theberge, C. R.; Zercher, C. K. Tetrahedron 2003, 59, 1521e1527.
35. Mansour, T. S.; Evans, C. A. Synth. Commun. 1990, 20, 773e781.
36. Wirtz, L.; Kazmaier, U. Eur. J. Org. Chem. 2011, 7062e7065.
37. Hashiguchi, S.; Kawada, A.; Natsugari, H. Synthesis 1992, 403e408.
38. Liu, J.; Ma, X.; Liu, Y.; Wang, Z.; Kwong, S.; Ren, Q.; Tang, S.; Meng, Y.; Xu, Z.; Ye,
T. Synlett 2012, 783e787.
39. Milewska, M. J.; Polonski, T. Synthesis 1988, 475e477.
40. Raddatz, P.; Radunz, H.-E.; Schneider, G.; Schwartz, H. Angew. Chem., Int. Ed.
Engl. 1988, 27, 426e427.
Acknowledgements
Financial support from the Slovenian Research Agency through
grants P1-0179 and J1-0972 is gratefully acknowledged. We thank
the pharmaceutical companies Boehringer-Ingelheim (Biberach,
Germany), Krka d. d. (Novo mesto, Slovenia), and Lek d. d., a Sandoz
company (Ljubljana, Slovenia), for financial support.
41. Essersi, A.; Touati, R.; Ben Hassine, B. Lett. Org. Chem. 2010, 7, 69e72.
42. Doi, T.; Kokubo, M.; Yamamoto, K.; Takahashi, T. J. Org. Chem. 1998, 63,
428e429.
Supplementary data
43. Moreau, R. J.; Sorensen, E. J. Tetrahedron 2007, 63, 6446e6453.
44. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433e2480.
Copies of the 1H NMR and 13C NMR spectra of the products and
HPLC data are available. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2013.11.008. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
ꢀ
45. Kralj, D.; Friedrich, M.; Groselj, U.; Kiraly-Potpara, S.; Meden, A.; Wagger, J.;
Dahmann, G.; Stanovnik, B.; Svete, J. Tetrahedron 2009, 65, 7151e7162.
46. Fairley, G.; Hall, C.; Greenwood, R. Synlett 2013, 570e574.
47. Quinkert, G.; Egert, E.; Griesinger, C. Aspects of Organic Chemistry: Structure;
Helvetica Chimica Acta: Basel, Switzerland, 1996; p 430.
48. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736.
49. Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42,
3846e3852.
References and notes
50. Davoll, J. J. Chem. Soc. 1953, 3802e3811.
51. Chantegrel, B.; Gelin, S. J. Heterocycl. Chem. 1978, 15, 1215e1219.
52. Takahashi, M.; Funaki, T.; Honda, H.; Yokoyama, Y.; Takimoto, H. Heterocycles
1982, 19, 1921e1924.
1. Pyrroles, Part One: The Synthesis and the Physical and Chemical Aspects of the
Pyrrole Ring; Jones, R. A., Ed.; Chemistry of Heterocyclic Compounds; John Wiley
& Sons: New York, NY, 1992; Vol. 48.
2. Pyrroles, Part 2: The Synthesis, Reactivity, and Physical Properties of Substituted
Pyrroles; Jones, R. A., Ed.; Chemistry of Heterocyclic Compounds; John Wiley &
Sons: New York, NY, 1992; Vol. 48.
3. Five-membered Rings with One Heteroatom and Fused Carbocyclic Derivatives;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Comprehensive Heterocyclic
Chemistry II; Pergamon: Oxford, UK, 1996; Vol. 2, pp 1e1102.
4. Five-membered Rings with one Heteroatom together with their Benzo- and other
Carbocyclic-Fused Derivatives; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Comprehensive Heterocyclic Chemistry III; Pergamon: Oxford, UK, 2008; Vol. 3,
pp 1e1304.
5. Black, D. S. Product Class 13: 1H-pyrroles In Maas, G., Ed.. Science of Synthesis;
Georg Thieme: Stuttgart, Germany, 2002; Vol. 9, pp 441e552.
6. Russel, J. S.; Pelkey, E. T.; Yoon-Miller, S. J. P. Prog. Heterocycl. Chem. 2009, 21,
145e178.
53. McNab, H.; Monahan, L. C.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1988,
759e764.
54. Gelin, S. J. Org. Chem. 1979, 44, 3053e3057.
55. Campaigne, E.; Shutske, G. M. J. Heterocycl. Chem. 1975, 12, 67e74.
56. Treibs, A.; Ohorodnik, A. Liebigs Ann. Chem. 1958, 611, 149e161.
57. Berner, H.; Schulz, G.; Reinshagen, H. Monatsh. Chem. 1977, 108, 915e927.
58. Verdie, P.; Subra, G.; Chevallet, P.; Amblard, M.; Martinez, J. Int. J. Pept. Res. Ther.
2007, 13, 337e343.
59. Shipps, G. W., Jr.; Rosner, K. E.; Popovici-Muller, J.; Deng, Y.; Wang, T.; Curran, P.
J. (Neogenesis Pharmaceuticals, Inc., USA). Application: WO, 2003, 249 pp.
60. Shikhaliev, K. S.; Krylski, D. V.; Potapov, A. Y.; Nefedov, S. E.; Sidorenko, O. E.
Russ. Chem. Bull. 2008, 57, 1268e1272.
ꢀ
ꢀ
ꢀ
ꢀ
61. Ahmetaj, S.; Velikanje, N.; Groselj, U.; Sterbal, I.; Prek, B.; Golobic, A.; Kocar, D.;
Dahmann, G.; Stanovnik, B.; Svete, J. Mol. Divers. 2013, 17, 731e743.
62. Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721e2724.
63. Miyazawa, T.; Yamada, T.; Kuwata, S. Bull. Chem. Soc. Jpn. 1988, 61, 606e608.
64. Liu, S.-j.; Yang, L.; Jin, Z.; Huang, E.-f.; Wan, D. C. C.; Lin, H.-q.; Hu, C. ARKIVOC
2009, 333e348.
7. Russel, J. S.; Pelkey, E. T. Prog. Heterocycl. Chem. 2009, 20, 122e151.
8. Russel, J. S.; Pelkey, E. T.; Yoon-Miller, S. J. P. Prog. Heterocycl. Chem. 2011, 22,
143e180.
65. Dressen, D.; Garofalo, A. W.; Hawkinson, J.; Hom, D.; Jagodzinski, J.; Marugg, J.
L.; Neitzel, M. L.; Pleiss, M. A.; Szoke, B.; Tung, J. S.; Wone, D. W. G.; Wu, J.;
Zhang, H. J. Med. Chem. 2007, 50, 5161e5167.
9. Russel, J. S.; Pelkey, E. T.; Greger, J. G. Prog. Heterocycl. Chem. 2011, 23, 155e194.
10. Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39,
ꢂ
ꢂ
4402e4421.
66. Agilent Technologies. CrysAlis PRO. Version 1.171.35.11; Agilent Technologies:
Yarnton, Oxfordshire, England, 2011.
11. Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264e287.
12. Royles, B. J. L. Chem. Rev. 1995, 95, 1981e2001.
67. Collect Software; Nonius, BV: Delft, The Netherlands, 1998.
68. Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data Collected in
Oscillation Mode In Carter, C. W., Jr., Sweet, R. M., Eds.; Methods in Enzymology.
Macromolecular Crystallography, Part A; Academic: New York, NY, 1997; Vol.
276, pp 307e326.
69. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Gua-
gliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999,
32, 115e119.
13. McNab, H.; Monahan, L. C. 3-Hydroxypyrroles In Pyrroles, Part 2: The Synthesis,
Reactivity, and Physical Properties of Substituted Pyrroles; Jones, R. A., Ed.;
Chemistry of Heterocyclic Compounds; John Wiley & Sons: New York, NY, 1992;
Vol. 48, pp 525e616.
14. Capon, B.; Kwok, F. C. Tetrahedron Lett. 1986, 27, 3275e3278.
15. Capon, B.; Kwok, F. C. J. Am. Chem. Soc. 1989, 111, 5346e5356.
16. Treibs, A.; Ohorodnik, A. Liebigs Ann. Chem. 1958, 611, 139e149.
17. Benary, E.; Konrad, R. Ber. Dtsch. Chem. Ges. 1923, 56, 44e52.
18. Wolfbeis, O. S.; Junek, H. Monatsh. Chem. 1979, 110, 1387e1405.
19. Gupta, S. K. Synthesis 1975, 726e727.
70. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, A64, 112e122.
71. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 567.