Synthesis of bicyclic 2,6-diketopiperazines via a three-step sequence involving an Ugi five-center, four-component reaction

Article abstract of DOI:10.1016/j.tet.2012.07.064

A three-step sequence involving an Ugi five-center, four-component reaction (U-5C-4CR), amide N-detertbutylation and cyclocondensation has been developed for easy access to diverse bicyclic 2,6-diketopiperazine (2,6-DKP) derivatives. In the key step, aromatic aldehydes were successfully coupled with cyclic α-amino acids and isocyanides in the course of U-5C-4CR. Boron trifluoride-acetic acid complex was developed as a new N-detertbutylating agent effective at rt.

Full text of DOI:10.1016/j.tet.2012.07.064

Tetrahedron 68 (2012) 8222e8230
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of bicyclic 2,6-diketopiperazines via a three-step sequence involving an
Ugi five-center, four-component reaction
,
a
b
a
a
Maciej Dawidowski a , Franciszek Herold , Marcin Wilczek , Jadwiga Tur1o , Andrzej Chodkowski ,
*
a
a
ꢀ
Anna Gomo1ka , Jerzy Kleps
a Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
b Laboratory of NMR Spectroscopy, Faculty of Chemistry, University of Warsaw, Pasteura 1 Str., 02-093 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2012
Received in revised form 21 June 2012
Accepted 17 July 2012
Available online 21 July 2012
A three-step sequence involving an Ugi five-center, four-component reaction (U-5C-4CR), amide N-de-
tertbutylation and cyclocondensation has been developed for easy access to diverse bicyclic 2,6-
diketopiperazine (2,6-DKP) derivatives. In the key step, aromatic aldehydes were successfully coupled
with cyclic
a-amino acids and isocyanides in the course of U-5C-4CR. Boron trifluoride-acetic acid
complex was developed as a new N-detertbutylating agent effective at rt.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reaction
Multicomponent reaction
Amide N-detertbutylation
Isocyanide
2,6-Diketopiperazine
1. Introduction
In our recent reports we developed a straightforward synthetic
route toward bicyclic 2,6-diketopiperazines (2,6-DKP) of high and
stereoselective anticonvulsant activity (Scheme 1).1 As a key in-
termediate, this strategy utilized a (R)-mandelate-derived acyclic
precursor 1, which upon treatment with base underwent a facile
intramolecular cyclocondensation (Scheme 1), to furnish bioactive
(S,S) isomer of 2 (ADD408003). An ongoing medicinal chemistry
project required rapid access to derivatives of ADD408003 with
different aryl substituents and aliphatic chains, as a first step of lead
optimization. For this purpose, the present methodology proved
inapplicable, due to the low availability of enantiopure (R)-man-
delic acid derivatives.
Scheme 1. Synthesis of ADD408003. aMaximal electroshock seizure test.2 bPsycho-
motor test.3
We turned our attention to the Ugi five-center four-component
reaction (U-5C-4CR), as it has proven ability to deliver quick access
to structurally diverse DKP precursors.4 The first applications of U-
5C-4CR condensation in the synthesis of 2,6-DKP derivatives were
reported by Ugi et al. (Scheme 2).5 However, reaction conditions
employed for the direct cyclocondensation of Ugi products would
most likely cause racemization of the stereochemically labile phe-
nylglycine fragment of 2.1b Moreover, Ugi’s reports did not describe
synthesis of 2,6-DKPs lacking substituents on the imide nitrogen.
Finally, to the best of our knowledge, there have been few attempts
to couple aromatic aldehydes with cyclic a-amino acids (i.e., proline
and pipecolic acid) in the course of U-5C-4CR.6
The U-5C-4CR/amide N-detertbutylation/intramolecular
cyclocondensationsequencewasexamined(Scheme3). Thisstrategy
was based on the following assumptions: (a) the U-5C-4CR con-
densationofa cyclic a-aminoacid, aromatic aldehyde, andisocyanide
would proceed with high yield and diastereoinduction toward the
desired (S,S) configuration of 3; (b) the resulting diastereomeric
mixtures would be separable on a few-gram scale, at one or more
* Corresponding author. Tel.: þ48 22 57 20 646; fax: þ48 22 57 20 631; e-mail
address: maciej.dawidowski@wum.edu.pl (M. Dawidowski).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.064

M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
8223
Scheme 2. U-5C-4CR reaction in synthesis of 2,6-DKPs.
Scheme 3. Possible route to desired ADD408003 derivatives.
stages; (c) the use of tert-butyl isocyanide as a convertible iso-
cyanide7 would introduce a tert-butyl group that would be readily
cleavable from N-tert-butylamido moiety of 3 in a mild and selective
process; (d) conditions of the post-condensation reactions would not
cause substantial inversion of stereocenters of 4 and 5.
to Godet’s findings no significant differences in chemical yields
were observed upon switching between various Lewis acids (Table
1, entries 4e7). The diastereoselectivity was only slightly sensitive
toward the presence and type of the catalyst. FeCl3 was selected for
further reactions because of the ease and safety of use compared to
the more hazardous TiCl4.
2. Results and discussion
Other investigated aromatic aldehydes underwent U-5C-4CR
condensation with
L-proline and tert-butyl isocyanide, with
For the U-5C-4CR condensation, cyclic
a-amino acid (S)-proline,
chemical yields ranging from 68% to 77% (Table 2, entries 1e4). As
4-chlorobenzaldehyde, tert-butyl isocyanide, and methanol were
investigated as the model substrates (Table 1). We were delighted
to find that these coupling partners reacted smoothly, even in
catalyst-free conditions, with the diastereoinduction in favor of the
U-5C-4CR condensation of aromatic aldehydes with secondary and
cyclic
plored this reaction further. Changing to other secondary
acids, we found that -pipecolinic acid and N-phenylglycine gave
a
-amino acids has to date received little attention, we ex-
a
-amino
L
desired (2S,
a
S)-configuration of the product 3a. Optimization of the
lower yields (Table 2, entries 5 and 6, respectively). However, the
stereoselectivity was two-fold improved in the former case.
Switching from tert-butyl to benzyl or tert-octyl isocyanide (Wal-
borsky’s reagent) improved neither yield nor diastereoselectivity of
the U-5C-4CR condensation (Table 2, entries 7 and 8, respectively).
Importantly, with the exception of 3e, all diastereomeric mixtures
were efficiently resolved by means of column chromatography on
silica gel.
reaction conditions led to the conclusion that slightly higher yields
were obtained when a Lewis acid was used as a promoter. In gen-
eral, this was in agreement with the data presented recently by
Godet et al. for U-5C-4CR condensations employing primary
amino acids and aromatic aldehydes.8 However, in the case of
secondary -amino acids the differences in yields between cata-
a-
a
lyzed and uncatalyzed processes were less pronounced. In contrast
Table 1
Optimization of U-5C-4CR conditions
Entrya
Additiveb
Time (h)
drc
Yieldd
1
2
3
4
5
6
7f
d
24
48
24
24
24
24
24
4.5:1
4.5:1
5:1
3:1
4:1
77%
73%
67%
80%
d
TEA
BF3$Et2O
FeCl3
TiCl4
TiCl4
82% (72%)e
88%
4:1
4.5:1
80%
a
Unless otherwise stated, the reactions were carried out on 0.2 mmol scale in 0.1 M solutions, at rt.
5 mol %.
dr (2S,aS)-3a/(2S,aR)-3a estimated by HPLC method.
Crude yields estimated by HPLC.
Isolated yield on a 16.8 mmol scale.
Reaction was performed at ꢀ15 ꢁC.
b
c
d
e
f

8224
M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
Table 2
Synthesis of U-5C-4CR adducts
Entrya
Amino acid
Aldehyde
Isocyanide
Major diastereomer
Yieldb
drc
1
72% (50%)
4:1
2
68% (50%)
4.5:1
3
4
5
71% (52%)
77% (44%)
46%
3.5:1
4:1
9:1
6
24%
d
7
54% (38%)
4.5:1
8
52% (36%)
4:1
a
The reactions were carried out on a 16.8 mmol scale in 0.17 M solutions, at rt, in the presence of 5 mol % of FeCl3. With the exception of 3e and 3f, all stereoisomeric
mixtures were efficiently resolved by column chromatography.
b
Isolated yield, sum of diastereomers. In parentheses: isolated yield of the major isomer.
c
Estimated by 1H NMR of crude products.

M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
8225
In the next step, a mild and selective N-detertbutylation of Ugi
adducts 3 was required to furnish acyclic DKP precursors 4. The
In the last step, the cyclocondensation of the respective stereo-
chemically pure 2,6-DKP precursors 4 gave the final 2,6-DKPs 5 with
yields ranging from 87% to 96% (Table 5). The reactions were accom-
panied by a slight degree of epimerization. However, the diastereomers
were efficiently separated by column chromatography on silica gel.
optimization was initiated with (2S,aS)-3a as a model compound
and TFA as a dealkylating acid (Table 3).9 Unfortunately, under
these conditions, no anticipated product was formed and starting
Table 3
Optimization of amide N-detertbutylation conditions
Entrya
Conditions
Time (h)
Yieldb
drc
1
2
3
4
5
6
7
8
9
TFA, rt
TFA, reflux
2.5 equiv TsOH, reflux
BF3$OEt2, rt,
BF3$2CH3COOH, rt
BF3$2CH3COOH, rt
BF3$2CH3COOH, 40 ꢁC
BF3$2CH3COOH, 90 ꢁC
BF3$2CH3COOH, 90 ꢁ
BF3$OEt2, 90 ꢁ
24
8
24
24
4
24
4
4
Noned
Noned
Nonee
None
d
d
d
d
23%
99:1
99:1
99:1
1:3
d
79% (74%)f
70%g
19%g,h
Noneg,i
30%g,j
C
17
24
10
C
1:2
a
All reactions were carried out on 0.1 mmol scale.
b
c
d
e
f
Crude yields estimated by HPLC method after quenching with ammoniaeice followed by a standard work-up.
dr of (2S, S)-4a/(2S, R)-4a.
No conversion.
a
a
Compound 5a (14%) (dr¼1:2) was formed.
Isolated yield on a 6.9 mmol scale.
g
h
i
Conversion (100%).
Compound 5a (32%) (dr¼1:1) was formed.
Compound 5a (50%) (dr¼1:2.5) was formed.
Compound 5a (22%) (dr¼1:2.5) was formed.
j
material was detected by HPLC. Increasing the temperature did not
facilitate the process. Upon changing the acid to 2.5 equiv of TsOH,
only some epimerized cyclic product 5a was formed. BF3$Et2O
proved ineffective at rt. Interestingly, upon changing the type of
the BF3 complex to BF3$2CH3COOH a remarkable enhancement of
N-detertbutylation was obtained.10 The reaction was completed
after 24 h at rt (Table 3, entry 6). When the temperature was el-
evated to 40 ꢁC, full conversion was achieved after 4 h. Upon fur-
ther increasing the temperature, the potentially useful
3. Conclusions
We have developed a three-step sequence leading to various
bicyclic 2,6-DKPs with aromatic substituents at carbon C-4. In the
key step, the U-5C-4CR condensation of secondary a-amino acids,
aromatic aldehydes and tert-butyl isocyanide was utilized to gen-
erate the convertible N-tert-butylamido-esters. The novel
BF3$2CH3COOH-promoted N-detertbutylation at rt was developed
to provide access to 2,6-DKP precursors. Application of this meth-
odology to the synthesis of novel potential anticonvulsant agents is
in progress and will be reported in due course.
dealkylation/cyclocondensation of (2S,aS)-3a to 5a was observed.
However, the reaction proceeded with significant level of epime-
rization of products 4a and 5a. Unfortunately, both stereocenters of
product 5a were affected and the complete cyclocondensation at
90 ꢁC for 17 h furnished enantiomeric mixtures.11 Thus, the prac-
tical application of this one-pot process was diminished by the
formation of the inseparable enantiomeric mixtures. Analogous
results were observed for BF3$OEt2 complex at 90 ꢁC (Table 3, entry
10), however, the reaction proceeded more slowly. A considerable
amount of epimerized acyclic product 4a was still detected after
24 h.
4. Experimental section
4.1. General
The NMR spectra were obtained on a 500 MHz spectrometer at
rt. Chemical shifts (d) were expressed in parts per million (ppm)
relative to tetramethylsilane (TMS) or residual solvent peaks used as
the internal references. The following abbreviations were used to
describe the peak patterns: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), p (pseudo-), and b (broad-). Coupling
constants (J) were in hertz (Hz). The FT-IR spectra were recorded
from thin film on KBr pellets. High resolution mass spectra (HRMS)
were obtained using time-of-flight (TOF) spectrometer with elec-
trospray ionization (ESI). Optical rotations were measured using
a sodium lamp (589 nm). Melting points were determined in open
capillary tubes. HPLC analyses were carried out on a RP-18 column.
Other derivatives of (2S,
butylated at rt, with yields ranging from 57% to 81% (Table 4). The
reaction was also applied to (2S, R)-3 stereoisomers. Of note, the
dealkylation reaction of (2S, R)-3a isomers, even under these mild
aS)-3 were also successfully N-detert-
a
a
conditions, was accompanied by a slight degree of subsequent
cyclocondensation. No epimerization was detected in this case. The
tert-octyl group of (2S,
aS)-3g was also cleaved by BF3$2CH3COOH
complex, at rt (Table 4, entry 6).

8226
M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
Table 4
Table 5
N-Dealkylation of U-5C-4CR products
Synthesis of 2,6-DKP derivatives 5 by intramolecular cyclocondensation of the
corresponding diastereomers of 4
Entrya
Substrate
Product
Yieldb
74%
Entrya
Substrate
Major product
Yieldb
drc
1
(2S,
a
a
S)-3a
R)-3a
1
(2S,
(2S,
(2S,
a
a
a
S)-4a
R)-4a
S)-4b
92% (72%)
9:1
2
3
(2S,
76%c
2
3
88% (68%)
90% (73%)
8.5:1
(2S,a
S)-3b
75%
9:1
4
5
(2S,
a
a
S)-3c
S)-3d
57%
65%
4
5
(2S,
a
S)-4c
87% (66%)
8.5:1
(2S,
(2S,
(2S,
a
a
S)-4d
S)-4e
92% (79%)
96% (77%)
9:1
6
(2S,a
S)-3g
81%
6
9.5:1
a
The reactions were carried out on 0.3e8.5 mmol scale with excess of
BF3$2CH3COOH (3 mL per 1 mmol of substrate).
b
Isolated yield of dealkylated product.
(4R,8aS)-5a was isolated in 9% yield.
c
a
The reactions were performed on a 0.2e4.5 mmol scale.
b
Isolated yield, sum of diastereoisomers. In parentheses: isolated yield of the
major isomer.
c
Estimated by 1H NMR of crude products.
The sample concentration was approximately 0.5 mg/mL, injection:
20
Thin-layer chromatography (TLC) was run on silica gel (60-F254
m
L, flow rate 1.0 mL/min, temperature: 30 ꢁC, detection 224 nm.
)
was added, followed by isocyanide (1.0 equiv). The mixture was
stirred at rt for 24 h and the volatiles were removed under reduced
pressure. The resulting crude diastereomeric mixtures were puri-
fied and resolved by FC.
plates. The spots were visualized by ultraviolet light (254 nm) or
iodine vapors. Flash column chromatography (FC) was carried out
on silica gel 60 (particle size: 0.040e0.063 mm). Reagents were
purchased from commercial sources and used as received. Solvents
employed for FC were purified by passing through a short column of
silica gel (Petroleum ether, PE) or by distillation (ethyl acetate).
Methanol and absolute ethanol employed as reaction solvents were
purchased from commercial sources and used as received. Reagent-
grade DCM was used for extractions.
4.2.1. (2S,
chlorophenyl)methyl)-pyrrolidine-2-carboxylic acid methyl ester
(2S, S)-3a and (2S, R)-3a. From -proline (2.32 g, 20.16 mmol),
aS)- and (2S,aR)-1-(1-tert-Butyl-carbamoyl-1-(4-
a
a
L
4-chlorobenzaldehyde (16.80 mmol, 2.36 g) and tert-butyl iso-
cyanide (2.00 mL, 16.80 mmol); FC (gradient: petroleum ether/
AcOEt 10:1 to 5:2): yield 4.26 g (72%): 2.94 g (50%) of (2S,
aS)-3a,
4.2. General procedure for the U-5C-4CR condensation
0.40 g (7%) of (2S, R)-3a and 0.92 (15%) of diastereomeric mixture.
a
(2S,
a
S)-3a: pale-yellow oil; TLC: Rf¼0.18 (petroleum ether/AcOEt
To a stirred solution of
aldehyde (1.0 equiv) in MeOH (100 mL) iron (III) chloride (5 mol %)
a-amino acid (1.2 equiv) and aromatic
a 20
3:1); ½ ꢂD ꢀ5.2 (c 1, CHCl3); IR (KBr): 837, 1204, 1454, 1535, 1678,

M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
8227
1732, 2966, 3302; 1H NMR (CDCl3, 500 MHz):
d
1.39 (s, 9H, C(CH3)3),
pale-yellow solid; mp 49e50 ꢁC; TLC: Rf¼0.17 (PE/AcOEt 3:1); ½a D20
ꢂ
1.84 (m, 2H, H-4, H0-4),1.89 (m,1H, H-3), 2.03 (m,1H, H0-3), 2.68 (m,
ꢀ4.6 (c 1, CHCl3); IR (KBr) 758, 1171, 1215, 1363, 1452, 1514, 1678,
1H, H-5), 3.20 (m,1H, H0-5), 3.30 (dd, 3J1¼9.0, 3J2¼4.0, 1H, H-2), 3.52
1738, 2872, 2966, 3296; 1H NMR (CDCl3, 500 MHz):
d 1.41 (s, 9H,
4
(s, 3H, OCH3), 4.07 (s, 1H, H-
a
), 7.21 (dt, 3J¼8.0, J¼2.0, 2H, H-30,
C(CH3)3), 1.80e1.94 (m, 3H, H-3, H-4, H0-4), 2.04 (m, 1H, H0-3), 2.71
(m, 1H, H-5), 3.20 (m, 1H, H0-5), 3.47 (dd, 3J1¼9.5, 3J2¼3.5, 1H, H-2),
H-50), 7.27 (dt, 3J¼8.0, 4J¼2.0, 2H, H-20, H-60), 7.56 (br s, 1H, CONH);
13C NMR (CDCl3, 125 MHz):
d
24.4 (C-4), 29.0 (C(CH3)3), 31.0 (C-3),
3.57 (s, 3H, OCH3), 4.37 (s, 1H, H-
a
), 6.93 (dd, 3J1¼5.0, 3J2¼3.5, H-40),
3
3
51.0 (C(CH3)3), 52.0 (OCH3), 54.4 (C-5), 61.8 (C-2), 73.4 (C-
a), 128.9
6.97 (d, J¼3.0, 1H, H-30), 7.23 (d, J¼5.0, H-50), 7.64 (br s, 1H,
(C-30, C-50), 130.7 (C-20, C-60), 134.4 (C-40), 136.1 (C-10), 170.7
(CONH), 176.0 (COOCH3); HPLC: retention time 7.5 min (MeCN/H2O
60:40); HRMS (ESIþ) calcd for C18H2515ClN2O3Na: 375.1451
CONH); 13C NMR (CDCl3, 125 MHz):
d 24.5 (C-4), 28.8 (C(CH3)3), 31.0
(C-3), 50.9 (C(CH3)3), 51.9 (OCH3), 54.0 (C-5), 61.4 (C-2), 68.4 (C-a),
126.1 (C-30), 126.7 (C-50), 128.3 (C-40), 139.5 (C-20), 170.2 (CONH),
176.0 (COOCH3); HRMS (ESIþ) calcd for C16H24N2O3SNa 347.1405
(MþNa)þ found 375.1460. (2S,
a
R)-3a: white wax; mp 96e98 ꢁC;
TLC: Rf¼0.24 (petroleum ether/AcOEt 3:1); ½a D20
ꢂ
ꢀ82.3 (c 1, CHCl3);
(MþNa)þ found: 347.1408. (2S,
R)-3c: pale-yellow oil; TLC: Rf¼0.24
a
IR (KBr): 837, 1204, 1454, 1516, 1682, 1744, 2962, 3333; 1H NMR
(PE/AcOEt 3:1); ½a D20
ꢀ63.4 (c 1, CHCl3); IR (KBr) 701, 758, 1172,
ꢂ
(CDCl3, 500 MHz):
d
1.32 (s, 9H, C(CH3)3), 1.70e1.86 (m, 2H, H-4, H0-
1203, 1364, 1391, 1436, 1456, 1510, 1685, 1736, 2855, 2923, 2964,
4), 1.90 (m, 1H, H-3), 2.08 (m, 1H, H0-3), 2.47 (m, 1H, H-5), 2.90 (ddd,
3337; 1H NMR (CDCl3, 500 MHz):
d 1.36 (s, 9H, C(CH3)3), 1.76 (m, 1H,
2J¼9.5, 3J1¼7.5, 3J2¼4.0, 1H, H0-5), 3.50 (dd, 3J1¼9.0, 3J2¼3.0, 1H, H-
H-4), 1.84 (m, 1H, H0-4), 1.90 (m, 1H, H-3), 2.09 (m, 1H, H0-3), 2.65
2), 3.68 (s, 3H, OCH3), 4.18 (s, 1H, H-
a), 7.22 (br s, 1H, CONH), 7.26
(m, 1H, H-5), 2.91 (m, 1H, H0-5), 3.56 (dd, 3J1¼9.5, 3J2¼3.5, 1H, H-2),
(dt, 3J¼8.5, 4J¼2.5, 2H, H-30, H-50), 7.30 (dt, 3J¼8.5, 4J¼2.5, 2H, H-20,
3.70 (s, 3H, OCH3), 4.57 (s, 1H, H-
a
), 6.94 (dd, 3J1¼5.0, 3J2¼3.5, 1H,
H-60); 13C NMR (CDCl3, 125 MHz):
d
23.8 (C-4), 28.6 (C(CH3)3), 29.8
H-40), 6.97 (d, 3J¼3.0, 1H, H-30), 7.26 (m, 2H, H-50, CONH); 13C NMR
(C-3), 50.7 (C(CH3)3, C-5), 51.9 (OCH3), 63.6 (C-2), 72.3 (C-
a
), 128.5
(CDCl3, 125 MHz): d 24.0 (C-4), 28.7 (C(CH3)3), 30.0 (C-3), 49.9 (C-5),
(C-30, C-50), 130.3 (C-20, C-60), 133.8 (C-40), 135.3 (C-10), 170.1
(CONH), 175.0 (COOCH3); HPLC: retention time 9.8 min (MeCN/H2O
60:40); HRMS (ESIþ) calcd for C18H2515ClN2O3Na: 375.1451
(MþNa)þ found 375.1426.
50.9 (C(CH3)3), 52.0 (OCH3), 63.3 (C-a
), 67.1 (C-2), 125.9 (C-30), 126.3
(C-50), 128.2 (C-40), 138.7 (C-20), 169.7 (CONH), 175.2 (COOCH3);
HRMS (ESIþ) calcd for C16H24N2O3SNa 347.1405 (MþNa)þ found:
347.1399.
4.2.2. (2S,
naphthyl)methyl)-pyrrolidine-2-carboxylic
(2S, S)-3b and (2S, R)-3b. From -proline (2.32 g, 20.16 mmol), 2-
a
S)- and (2S,
a
R)-1-(
a
-tert-Butyl-carbamoyl-
a
-(2-
4.2.4. (2S,
pyrrolidine-2-carboxylic acid methyl ester (2S,
3d. From -proline (2.32 g, 20.16 mmol), 3-furancarboxaldehyde
a
S)- and (2S,
a
R)-(
a
-tert-Butyl-carbamoyl-
a
-(3-furyl)methyl)-
acid methyl
ester
aS)-3d and (2S,
aR)-
a
a
L
L
naphthaldehyde (16.80 mmol, 2.63 g) and tert-butyl isocyanide
(16.80 mmol, 1.46 mL) and tert-butyl isocyanide (2.00 mL,
(2.00 mL, 16.80 mmol); FC (gradient: PE/AcOEt 10:1 to 3:1): yield
16.80 mmol); FC (gradient: PE/AcOEt 8:1 to 1:1): yield 3.97 g (77%):
4.23 g (68%): 3.12 g (50%) of (2S,
a
S)-3b, 0.23 g (4%) of (2S,
S)-3b: yellow oil;
þ16.9 (c 1, CHCl3); IR (KBr): 752,
a
R)-3b
2.29 g (44%) of (2S,
a
S)-3d, 0.42 g (7%) of (2S,
a
R)-3d and 1.26 (24%) of
S)-3d: white solid; mp 57e58 ꢁC; TLC:
ꢀ2.6 (c 1, CHCl3); IR (KBr) 603, 758, 874,
and 0.88 (14%) of diastereomeric mixture. (2S,
a
diastereomeric mixture. (2S,a
TLC: Rf¼0.15 (PE/AcOEt 3:1); ½a D20
ꢂ
Rf¼0.11 (PE/AcOEt 3:1); ½a D20
ꢂ
1204, 1367, 1454, 1508, 1678, 1736, 2870, 2966, 3298; 1H NMR
1023, 1170, 1203, 1364, 1456, 1518, 1676, 1735, 2843, 2873, 2965,
(CDCl3, 500 MHz):
d
1.42 (s, 9H, C(CH3)3), 1.78e1.94 (m, 3H, H-3, H-
3300; 1H NMR (CDCl3, 500 MHz):
d 1.40 (s, 9H, C(CH3)3), 1.80e1.94
4, H0-4), 2.02 (m,1H, H0-3), 2.76 (m,1H, H-5), 3.26 (m,1H, H0-5), 3.37
(m, 3H, H-3, H-4, H0-4), 2.05 (m, 1H, H0-3), 2.64 (m, 1H, H-5), 3.20 (m,
(dd, 3J1¼9.0, 3J2¼3.5, 1H, H-2), 3.39 (s, 3H, OCH3), 4.26 (s, 1H, H-
a
),
1H, H0-5), 3.44 (dd, 3J1¼10.0, 3J2¼4.0, 1H, H-2), 3.58 (s, 3H, OCH3),
7.38 (dd, 3J¼8.5, 4J¼1.5, 1H, H-30), 7.46 (m, 2H, H-60, H-70), 7.69 (br s,
4.02 (s, 1H, H-
a
), 6.25 (ps, 1H, H-40), 7.33 (pt, J¼4.0, 1H, H-20), 7.39
4
1H, CONH), 7.73e7.82 (m, 4H, H-10, H-40, H-50, H-80); 13C NMR
(ps, 1H, H-50), 7.70 (br s, 1H, CONH); 13C NMR (CDCl3, 125 MHz):
(CDCl3, 125 MHz):
d
24.2 (C-4), 28.8 (C(CH3)3), 30.8 (C-3), 50.8
), 126.2 (C-30),
d
24.6 (C-4), 28.9 (C(CH3)3), 30.9 (C-3), 50.8 (C(CH3)3), 51.9 (OCH3),
(C(CH3)3), 51.5 (C-5), 54.3 (OCH3), 61.7 (C-2), 74.1 (C-
a
54.2 (C-5), 61.5 (C-2), 64.9 (C-
a
), 110.4 (C-40), 121.5 (C-30), 142.2 (C-20),
126.2 (C-70),126.2 (C-60),127.6 (C-10),128.1 (C-80),128.2 (C-40),128.9
(C-50), 133.2 (C-4a0), 133.3 (C-8a0), 134.9 (C-20), 170.9 (CONH), 175.9
(COOCH3); HRMS (ESIþ) calcd for C22H28N2O3Na: 391.1998
143.2 (C-20), 170.8 (CONH), 176.2 (COOCH3); HRMS (ESIþ) calcd for
C16H24N2O4Na 331.1634 (MþNa)þ found: 331.1623. (2S,
aR)-3d: white
solid; mp 56e57 ꢁC; TLC: Rf¼0.17 (PE/AcOEt 3:1); ½a 2D0
ꢂ ꢀ62.5 (c 1,
(MþNa)þ found: 391.1976. (2S,
a
R)-3b: yellow oil; TLC: Rf¼0.24 (PE/
CHCl3); IR (KBr) 602, 874, 1023, 1161, 1203, 1364, 1456, 1516, 1685,
AcOEt 3:1); ½a 2D0
ꢂ
ꢀ98.0 (c 1, CHCl3); IR (KBr): 752, 1204, 1362, 1454,
1736, 2855, 2926, 2963, 3337; 1H NMR (CDCl3, 500 MHz):
d 1.36 (s,
1508, 1678, 1740, 2870, 2966, 3337; 1H NMR (CDCl3, 500 MHz):
9H, C(CH3)3), 1.75 (m, 1H, H-4), 1.82 (m, 1H, H0-4), 1.90 (m, 1H, H-3),
d
1.34 (s, 9H, C(CH3)3), 1.75 (m, 1H, H-4), 1.83 (m, 1H, H0-4), 1.91 (m,
2.08 (m, 1H, H0-3), 2.60 (m, 1H, H-5), 2.89 (m, 1H, H0-5), 3.48 (dd,
1H, H-3), 2.10 (m, 1H, H0-3), 2.55 (m, 1H, H-5), 2.96 (m, 1H, H0-5),
3J1¼9.5, 3J2¼3.5, 1H, H-2), 3.70 (s, 3H, OCH3), 4.23 (s, 1H, H-
a), 6.35
3.58 (dd, 3J1¼9.5, 3J2¼3.0, 1H, H-2), 3.66 (s, 3H, OCH3), 4.36 (s, 1H,
(ps, 1H, H-40), 7.32 (br s, 1H, CONH), 7.38 (pt, 1H, H-20), 7.40 (ps, 1H,
H-
a
), 7.31 (br s, 1H, CONH), 7.44e7.50 (m, 3H, H-30, H-60, H-70),
H-50); 13C NMR (CDCl3, 125 MHz):
d
24.0 (C-4), 28.8 (C(CH3)3), 29.9
7.76e7.83 (m, 4H, H-10, H-40, H-50, H-80); 13C NMR (CDCl3,125 MHz):
23.9 (C-4), 28.6 (C(CH3)3), 29.9 (C-3), 50.8 (C-5), 51.1 (C(CH3)3),
), 126.0 (C-30), 126.0 (C-70), 126.1
(C-3), 49.7 (OCH3), 50.8 (C(CH3)3), 52.0 (C-5), 62.8 (C-a), 63.4 (C-2),
d
110.5 (C-40), 120.3 (C-30), 141.8 (C-50), 143.1 (C-20), 170.2 (CONH), 175.3
(COOCH3); HRMS (ESIþ) calcd for C16H24N2O4Na 331.1634 (MþNa)þ
found: 331.1641.
51.8 (OCH3), 63.8 (C-2), 73.5 (C-
a
(C-60), 127.6 (C-10), 128.0 (C-80), 128.0 (C-40), 128.7 (C-50), 133.1 (C-
4a0), 133.1 (C-8a0), 134.5 (C-20), 170.5 (COOCH3), 175.4 (CONH2);
HRMS (ESIþ) calcd for C22H28N2O3Na: 391.1998 (MþNa)þ found:
391.2010.
4.2.5. (2R,
methyl)-piperidine-2-carboxylic acid methyl ester (2R,
(2R, S)-3e. From -pipecolic acid (2.60 g, 20.16 mmol), benzalde-
aR)- and (2R,aS)-1-(
a-tert-Butyl-carbamoyl-
a-phenyl-
aR)-3e and
a
D
4.2.3. (2S,
thiophene)methyl)-pyrrolidine-2-carboxylic acid methyl ester
(2S, S)-3c and (2S, R)-3c. From -proline (2.32 g, 20.16 mmol),
2-thiophenecarboxaldehyde (16.80 mmol, 1.60 mL) and tert-butyl
isocyanide (2.00 mL, 16.80 mmol); FC (gradient: PE/AcOEt 8:1 to
a
S)- and (2S,
a
R)-1-(
a
-tert-Butyl-carbamoyl-
a
-(2-
hyde (16.80 mmol, 1.70 mL) and tert-butyl isocyanide (2.00 mL,
16.80 mmol); FC (gradient: PE/AcOEt 9:1 to 3:1): yield 2.59 g (46%)
of inseparable diastereomeric mixture. White wax; mp 43e46 ꢁC;
a
a
L
TLC: Rf¼0.39 (PE/AcOEt 3:1); 1H NMR (CDCl3, 500 MHz): (2R,
aR)-
3e (major): d
1.38 (s, 9H, C(CH3)3), 1.45e1.53 (m, 2H, H-4, H0-4),
1:1): yield 3.85 g (71%): 2.84 g (52%) of (2S,
aS)-3c, 0.44 g (8%) of
1.59 (m, 1H, H-3), 1.64e1.72 (m, 2H, H-5, H0-5), 2.02 (m, 1H, H0-3),
2.40 (dt, 2J¼12.5, 3J1¼3J2¼3.5, 1H, H-6), 2.81 (td, 2J¼3J1¼12.5,
(2S, R)-3c and 0.57 (11%) of diastereomeric mixture. (2S,
a
a
S)-3c:

8228
M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
3J2¼4.5, 1H, H0-6), 3.60 (pt, 3J¼4.0, 1H, H-2), 3.68 (s, 3H, OCH3),
HRMS (ESIþ) calcd for C22H34N2O3Na: 397.2467 (MþNa)þ found
4.37 (s, 1H, H-
NH); (2R,
a
), 7.24e7.29 (m, 6H, H-20, H-30, H-40, H-50, H-60,
397.2454.
a
S)-3e (minor):
d
1.86e1.93 (m, 1H, H0-3), 2.44e2.50 (m,
3
1H, H-6), 3.00 (m, 2J¼12.5, 3J1¼10.0, J2¼2.5, 1H, H0-6), 3.27 (pt,
4.2.8. (2S,
chlorophenyl)methyl)-pyrrolidine-2-carboxylic acid methyl ester
(2S, S)-3h and (2S, R)-3h. From -proline (2.32 g, 20.16 mmol),
aS)- and (2S,aR)-1-(a-Benzyl-carbamoyl-a-(4-
3J¼4.5, 1H, H-2), 3.62 (s, 3H, OCH3), 4.33 (s, 1H, H-
a
), the
R)-3e di-
R)-3e (major): 21.1
(C-5), 25.3 (C-4), 28.5 (C-3), 28.7 (C(CH3)3), 45.7 (C-6), 50.8
(C(CH3)3), 51.4 (OCH3), 59.6 (C-2), 73.0 (C-
), 128.0 (C-40), 128.4 (C-
20, C-60), 129.2 (C-30, C-50), 137.0 (C-10), 171.0 (CONH), 173.6
(COOCH3); (2R, S)-3e (minor): 21.6 (C-5), 25.7 (C-4), 47.5 (C-6),
50.5 (C(CH3)3), 58.8 (C-2), 71.4 (C-
), 128.1 (C-40), 128.3 (C-20, C-60),
129.5 (C-30, C-50), 135.2 (C-10), 170.9 (CONH), 173.5 (COOCH3); the
remaining 1H signals overlap with the signals of (2R,
a
a
a
L
astereomer; 13C NMR (CDCl3, 125 MHz): (2R,
a
d
benzaldehyde (16.80 mmol, 1.70 mL) and benzyl isocyanide
(2.10 mL, 16.80 mmol); FC (gradient: PE/AcOEt 4:1 to 1:1): yield
a
3.22 g (52%): 2.20 g (36%) of (2S,
a
S)-3h, 0.69 g (11%) of (2S,
a
S)-3h
S)-3h: white solid;
ꢂ ꢀ113.1 (c 0.713,
and 0.33 g (6%) of diastereomeric mixture. (2S,
a
a
d
mp 109e111 ꢁC; TLC: Rf¼0.07 (PE/AcOEt 3:1); ½a 2D0
a
CHCl3); IR (KBr): 699, 756, 1015, 1090, 1170, 1202, 1490, 1517, 1660,
1730, 2847, 2932, 2950, 3030, 3064, 3293; 1H NMR (CDCl3,
remaining 13C signals overlap with the signals of (2R,
a
R)-3e di-
500 MHz): d
1.78e1.87 (m, 3H, H-3, H-4, H0-4), 2.01 (m, 1H, H0-3),
astereomer; HRMS (ESIþ) calcd for C19H28N2O3Na: 355.1998
2.69 (m, 1H, H-5), 3.19 (m, 1H, H0-5), 3.33 (dd, 3J1¼9.5, 3J2¼4.0, 1H,
(MþNa)þ found 355.1987.
H-2), 3.45 (s, 3H, OCH3), 4.27 (s, 1H, H-
a
), 4.51 (d, 3J¼6.0, 2H, H-
b,
H0- ), 7.19e7.36 (m, 9H, H-20, H-30, H-50, H-60, H-200, H-300, H-400, H-
b
4.2.6. rac-N-Phenyl-N-(
a
-tert-butyl-carbamoyl-
a
-phenylmethyl)-
500, H-600), 7.95 (pt, 3J¼5.5, 1H, CONH); 13C NMR (CDCl3, 125 MHz):
aminoacetic acid methyl ester 3f. From N-phenylglycine (3.05 g,
20.16 mmol), benzaldehyde (16.80 mmol, 1.70 mL) and tert-butyl
isocyanide (2.00 mL, 16.80 mmol); FC (gradient: PE/AcOEt 6:1 to
3:1): yield 1.42 g (24%). Yellow powder; mp 119e121 ꢁC; TLC:
Rf¼0.44 (PE/AcOEt 3:1); IR (KBr): 696, 750, 1174, 1220, 1453, 1503,
1538, 1599, 1674, 1739, 2966, 3062, 3314; 1H NMR (CDCl3,
d 24.1 (C-4), 30.6 (C-3), 43.3 (C-b), 51.7 (OCH3), 54.3 (C-5), 61.9 (C-2),
72.7 (C-a
), 127.4 (C-400), 127.8 (C-20, C-60), 128.6 (C-200, C-600), 128.7
(C-300, C-500), 130.5 (C-30, C-50), 134.3 (C-40),135.5 (C-10), 138.4 (C-100),
171.4 (CONH), 175.6 (COOCH3); HRMS (ESIþ) calcd for
C21H2315ClN2O3Na: 409.1295 (MþNa)þ found 409.1287. (2S,
aR)-
ꢂ
3h: white solid; mp 126e127 ꢁC; TLC: Rf¼0.11 (PE/AcOEt 3:1); ½a D20
500 MHz):
d
1.34 (s, 9H, C(CH3)3), 3.68 (s, 1H, H-2), 3.73 (s, 3H,
þ35.0 (c 1.427, CHCl3); IR (KBr): 699, 756, 1014, 1090, 1159, 1204,
OCH3), 3.80 (m, 2J¼18.5, 1H, H0-2), 5.23 (s, 1H, H-
a
), 6.70 (d, 3J¼8.0,
1491, 1515, 1661, 1730, 2844, 2950, 3029, 3317; 1H NMR (CDCl3,
2H, H-200, H-600), 6.87 (t, 3J¼8.0,1H, H-400), 7.24e7.30 (m, 4H, H-20, H-
500 MHz): d
1.73 (m, 1H, H-4), 1.80 (m, 1H, H0-4), 1.88 (m, 1H, H-3),
60, H-300, H-500), 7.30e7.39 (m, 3H, H-30, H-40, H-50); 13C NMR (CDCl3,
2.05 (m, 1H, H0-3), 2.49 (m, 2J¼9.5, 3J1¼3J2¼8.0, 1H, H-5), 2.90 (ddd,
3
125 MHz):
70.1 (C-
d
28.7 (C(CH3)3), 49.5 (C-2), 51.5 (C(CH3)3), 52.7 (OCH3)
2J¼9.5, 3J1¼7.5, 3J2¼3.0, 1H, H0-5), 3.49 (dd, J1¼9.5, 3J2¼3.5, 1H, H-
a
), 113.2 (C-200, C-600), 119.2 (C-400), 128.9 (C-40), 129.3 (C-20,
2), 3.54 (s, 3H, OCH3), 4.41 (dd, 2J¼15.0, 3J¼6.0, 1H, H-
b), 4.42 (s, 1H,
C-60), 129.6 (C-30, C-50), 129.9 (C-300,C-500), 136.1 (C-10), 147.5 (C-100),
170.5 (CONH), 173.9 (COOCH3); HRMS (ESIþ) calcd for
C21H26N2O3Na: 377.1841 (MþNa)þ found 377.1829.
H-
a
), 4.50 (dd, 2J¼15.0, 3J¼6.0, 1H, H-
b
0), 7.23e7.34 (m, 9H, H-20, H-
30, H-50, H-60, H-200, H-300, H-400, H-500, H-600), 7.74 (pt, 3J¼5.5, 1H,
CONH); 13C NMR (CDCl3, 125 MHz):
d 23.6 (C-4), 29.5 (C-3), 43.3 (C-
b
), 50.3 (C-5), 51.8 (OCH3), 63.3 (C-2), 70.8 (C-a
), 127.4 (C-400), 127.7
4.2.7. (2S,
moyl- -phenylmethyl)-pyrrolidine-2-carboxylic acid methyl ester
(2S, S)-3g and (2S, R)-3g. From -proline (2.32 g, 20.16 mmol),
benzaldehyde (16.80 mmol, 1.70 mL) and 1,1,3,3-tetramethylbutyl
isocyanide (3.10 mL, 16.80 mmol); FC (gradient: PE/AcOEt 9:1 to
a
S)- and (2S,
a
R)-
a
-(1-(1,1,3,3-Tetramethylbutyl)-carba-
(C-20, C-60), 128.6 (C-200, C-600), 128.7 (C-300, C-500), 130.6 (C-30, C-50),
134.0 (C-40), 134.5 (C-10), 138.4 (C-100), 171.0 (CONH), 174.8
(COOCH3); HRMS (ESIþ) calcd for C21H2315ClN2O3Na: 409.1295
(MþNa)þ found 409.1301.
a
a
a
L
3:1): yield 3.27 g (54%): 2.28 g (38%) of (2S,
a
S)-3g, 0.44 g (7%) of
S)-3g:
ꢀ3.1 (c 0.667,
4.3. General procedure for BF3$2CH3COOH-mediated N-
detertbutylation
(2S,aS)-3g and 0.55 (9%) of diastereomeric mixture. (2S,a
colorless oil; TLC: Rf¼0.26 (PE/AcOEt 3:1); ½a D20
ꢂ
CHCl3); IR (KBr): 701, 759, 1170, 1212, 1454, 1519, 1672, 1736, 2872,
The appropriate Ugi product 3 was dissolved in BF3$2CH3COOH
(w36% BF3 basis, 3 mL per 1 mmol of substrate), at 40 ꢁC. After
15 min, the mixture was allowed to reach rt and stirred until total
consumption of the starting material (TLC), typically for 24 h. The
resulting solution was poured onto excess of crushed ice and made
alkaline with 25% aqueous solution of ammonia. The mixture was
extracted with DCM (3ꢃ40 mL). The combined organic phase was
washed with water (30 mL), dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by FC.
2906, 2952, 3312; 1H NMR (CDCl3, 500 MHz):
d
1.04 (s, 9H, C(CH3)3),
2
0
0
1.44 (s, 3H, CCH3), 1.50 (s, 3H, CCH3 ), 1.73 (d, J¼15.0, 1H, CH2 ), 1.79
2
(d, J¼15.0, 1H, CH2 ), 1.78e1.90 (m, 3H, H-3, H-4, H0-4), 2.02 (m, 1H,
0
H0-3), 2.70 (m, 1H, H-5), 3.22 (m, 1H, H0-5), 3.31 (dd, 3J1¼10.0,
3J2¼4.0, 1H, H-2), 3.51 (s, 3H, OCH3), 4.09 (s, 1H, H-
a), 7.22e7.32 (m,
5H, H-20, H-30, H-40, H-50, H-60), 7.70 (br s, 1H, CONH); 13C NMR
0
(CDCl3, 125 MHz):
d
24.4 (C-4), 28.3 (C(CH3)2), 29.1 (C(CH3 )2), 30.9
(C(CH3)3), 31.8 (C(CH3)3), 31.7 (C-3), 51.8 (OCH3), 53.5 (CH2), 54.8
(C-5), 55.1 (C(CH3)2) 61.9 (C-2), 74.4 (C-a
), 128.4 (C-40), 128.7 (C-30,
C-50), 129.4 (C-20, C-60), 137.6 (C-10), 171.0 (CONH), 176.0 (COOCH3);
HRMS (ESIþ) calcd for C22H34N2O3Na: 397.2467 (MþNa)þ found
4.3.1. (2S,
dine-2-carboxylic acid methyl ester (2S,
(2.44 g, 6.90 mmol) and BF3$2CH3COOH (21 mL); FC (gradient:
a
S)-1-(
a
-Carbamoyl-
a
-(4-chlorophenyl)methyl)-pyrroli-
397.2493. (2S,
a 2D0
1513, 1679, 1739, 2871, 2906, 2952, 3338; 1H NMR (CDCl3,
a
R)-3g: colorless oil; TLC: Rf¼0.30 (PE/AcOEt 3:1);
aS)-4a. From (2S, S)-3a
a
½
ꢂ
ꢀ62.5 (c 0.680, CHCl3); IR (KBr): 699, 757, 1163, 1206, 1453,
petroleum ether/AcOEt 2:1 to 0:1): yield 1.51 g (74%) of (2S,
a
S)-4a.
500 MHz):
d
0.98 (s, 9H, C(CH3)3), 1.40 (s, 3H, CCH3), 1.41 (s, 3H,
White solid; mp 114e116 ꢁC; TLC: Rf¼0.28 (AcOEt); ½a D20
ꢂ
ꢀ2.9 (c
0
CCH3 ), 1.72 (m, 3H, H-4, CH2), 1.83 (m, 1H, H0-4), 1.89 (m, 1H, H-3),
0.92, CHCl3); IR (KBr): 818, 1204, 1489, 1678, 1732, 2851, 2955, 3190,
2.04 (m, 1H, H0-3), 2.51 (m, 1H, H-5), 2.94 (m, 1H, H0-5), 3.54 (dd,
3306, 3431; 1H NMR (CDCl3, 500 MHz): 1.88 (m, 3H, H-3, H-4, H0-
d
3J1¼9.5, 3J2¼3.5, 1H, H-2), 3.66 (s, 3H, OCH3), 4.25 (s, 1H, H-
a
),
4), 2.04 (m, 1H, H0-3), 2.72 (m, 1H, H-5), 3.27 (m 1H, H0-5), 3.35 (dd,
7.24e7.38 (m, 6H, H-20, H-30, H-40, H-50, H-60, CONH); 13C NMR
3J1¼9.5, 3J2¼5.0, 1H, H-2), 3.53 (s, 3H, OCH3), 4.22 (s, 1H, H-
a), 5.62
(CDCl3, 125 MHz):
d
23.9 (C-4), 28.7 (C(CH3)2), 29.1 (C(CH3 )2), 29.7
(br s, 1H, CONH) 7.27 (dt, 2H, H-30, H-50), 7.30 (dt, 3J¼9.0, 4J¼2.5, 2H,
0
(C-3), 31.7 (C(CH3)3), 31.8 (C(CH3)3), 50.4 (OCH3), 52.0 (CH2), 52.9
(C-5), 55.0 (C(CH3)2) 63.4 (C-2), 72.4 (C-
), 128.1 (C-40), 128.4 (C-20,
C-60), 129.7 (C-30, C-50), 136.2 (C-10), 170.4 (CONH), 175.2 (COOCH3);
H-20, H-60), 7.59 (br s,1H, CONH0); 13C NMR (CDCl3,125 MHz):
d
23.8
), 128.5
(C-30, C-50), 130.3 (C-20, C-60), 134.1 (C-40), 135.2 (C-10), 174.5
a
(C-4), 30.4 (C-3), 51.0 (OCH3), 53.6 (C-5), 61.8 (C-2), 72.0 (C-a

M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
8229
(CONH), 175.4 (COOCH3); HPLC: retention time 24.9 min (MeCN/
H2O 25:75); HRMS (ESIþ) calcd for C14H1715ClN2O3Na: 319.0826
(MþNa)þ found 319.0854.
CONH), 6.32 (ps, 1H, H-40), 7.36 (pt, 1H, H-20), 7.44 (ps, 1H, H-50),
7.70 (br s, 1H, CONH0); 13C NMR (CDCl3, 125 MHz):
24.5 (C-4), 30.8
), 110.5 (C-40),
d
(C-3), 52.0 (C-5), 54.3 (OCH3), 61.6 (C-2), 64.0 (C-
a
120.8 (C-30), 142.3 (C-20), 143.4 (C-20), 174.7 (CONH2), 176.2
(COOCH3); HRMS (ESIþ) calcd for C12H16N2O4Na 275.1008 (MþNa)þ
found: 275.1016.
4.3.2. (2S,
dine-2-carboxylic acid methyl ester (2S,
(0.30 g, 0.85 mmol) and BF3$2CH3COOH (3 mL); FC (gradient: pe-
troleum ether/AcOEt 4:1 to 0:1): yield 0.19 g (76%) of (2S, R)-4a
and 20 mg (9%) of (4R,8aS)-5a. Yellow oil; TLC: Rf¼0.36 (AcOEt);
a 2D0
ꢀ110.3 (c 1.125, CHCl3); IR (KBr): 821, 1204, 1489, 1682, 1732,
a
R)-1-(
a
-Carbamoyl-
a
-(4-chlorophenyl)methyl)-pyrroli-
a
R)-4a. From (2S, R)-3a
a
a
4.3.6. (2S,
carboxylic acid methyl ester (2S,
5.46 mmol) and BF3$2CH3COOH (20 mL); FC (gradient: PE/AcOEt 2:1
a
S)-1-(
a
-Carbamoyl-
a
-phenylmethyl)-pyrrolidine-2-
a
S)-4e. From (2S, S)-3g (1.97 g,
a
½
ꢂ
2847, 2951, 3202, 3333, 3437; 1H NMR (CDCl3, 500 MHz):
d
1.76 (m,
to 0:1): yield 1.16 g (81%) of (2S,
a
S)-4e. White solid; mp 147e148 ꢁC;
þ5.30 (c 1, CHCl3); IR (KBr): 759, 1171,
1H, H-4), 1.85 (m, 1H, H0-4), 1.93 (m, 2J2¼17.5, 3J1¼8.0, 3J2¼3.5,
TLC: Rf¼0.30 (AcOEt); ½a D20
ꢂ
3J3¼3.5, 1H, H-3), 2.06 (m, 2J2¼18.0, J1¼9.0, 1H, H0-3), 2.52 (ddd,
1205,1454,1673,1732, 2849, 2949, 3188; 1H NMR (CDCl3, 500 MHz):
3
2J2¼9.0, 3J1¼8.0, 3J2¼7.5, 1H, H-5), 2.96 (ddd, 2J2¼9.0, 3J1¼7.5,
3J2¼4.0, 1H, H0-5), 3.50 (dd, 3J1¼9.5, 3J2¼3.5, 1H, H-2), 3.68 (s, 3H,
d
1.80e1.95 (m, 3H, H-3, H-4, H0-4), 2.03 (m, 1H, H0-3), 2.74 (m, 1H,
H-5), 3.29 (m, 1H, H0-5), 3.36 (dd, 3J1¼9.5, 3J2¼4.0, 1H, H-2), 3.50 (s,
OCH3), 4.41 (s, 1H, H-
a
), 5.47 (br s, 1H, CONH) 7.26 (m, 2H, H-30, H-
3H, OCH3), 4.24 (s, 1H, H-a), 5.65 (br s, 1H, CONH), 7.28e7.36 (m, 5H,
50), 7.32 (dt, 3J¼8.5, J¼2.0, 2H, H-20, H-60), 7.56 (br s, 1H, CONH0);
H-20, H-30, H-40, H-50, H-60), 7.64 (br s, 1H, CONH0); 13C NMR (CDCl3,
125 MHz): 24.5 (C-4), 30.9 (C-3), 51.9 (OCH3), 54.6 (C-5), 62.0 (C-2),
73.4 (C-
4
13C NMR (CDCl3, 125 MHz):
d
23.4 (C-4), 29.3 (C-3), 49.8 (C-5), 51.7
d
(OCH3), 62.7 (C-2), 69.8 (C-
a
), 128.5 (C-30, C-50), 130.6 (C-20, C-60),
a
), 128.7 (C-40), 128.8 (C-30, C-50), 129.4 (C-20, C-60), 136.8 (C-
133.9 (C-40), 134.0 (C-10), 174.3 (CONH2), 174.7 (COOCH3); HPLC:
retention time 40.2 min (MeCN/H2O 25:75); HRMS (ESIþ) calcd for
C14H1715ClN2O3Na: 319.0826 (MþNa)þ found 319.0816.
10), 175.0 (CONH2), 176.2 (COOCH3); HRMS (ESIþ) calcd for
C14H18N2O3Na: 285.1210 (MþNa)þ found 285.1224.
4.4. General procedure for intramolecular cyclocondensation
4.3.3. (2S,
2-carboxylic acid methyl ester (2S,
2.77 mmol), and BF3$2CH3COOH (8 mL); FC (gradient: PE/AcOEt 2:1
a
S)-1-(
a
-Carbamoyl-
a
-(2-naphthyl)methyl)-pyrrolidine-
a
S)-4b. From (2S, S)-3b (1.02 g,
a
To a stirred solution of appropriate 2,6-DKP precursor 4 in ab-
solute EtOH (5 mL per 1 mmol of substrate), NaOH (1 equiv) was
added at rt. After dissolution of the hydroxide, the mixture was
quenched with saturated aqueous solution of ammonium chloride
(100 mL). The resulting cloudy solution was extracted with DCM
(3ꢃ30 mL). The combined organic phase was washed with water
(20 mL), dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by FC.
to 0:1): yield 0.66 g (75%) of (2S,
a
S)-4b. White solid; mp 52e54 ꢁC;
þ25.8 (c 0.936, CHCl3); IR (KBr): 748,
TLC: Rf¼0.28 (AcOEt); ½a D20
ꢂ
818, 1204, 1369, 1435, 1508, 1674, 1732, 2851, 2924, 3198, 3333,
3429; 1H NMR (CDCl3, 500 MHz):
d
1.86 (m, 3H, H-3, H-4, H0-4),
2.04 (m, 1H, H0-3), 2.79 (m, 1H, H-5), 3.32 (m, 1H, H0-5), 3.41 (dd,
3J1¼9.5, 3J2¼4.0, 1H, H-2), 3.38 (s, 3H, OCH3), 4.42 (s, 1H, H-
a), 5.91
(br s, 1H, CONH), 7.38 (dd, 3J¼8.5, 4J¼2.0, 1H, H-30), 7.47 (m, 2H, H-
60, H-70), 7.67 (br s, 1H, CONH0), 7.76e7.83 (m, 4H, H-10, H-40, H-50,
4.4.1. (4S,8aS)-4-(4-Chlorophenyl)-perhydropyrrolo[1,2-a]pyrazine-
1,3-dione (4S,8aS)-5a. From (2S,aS)-4a (1.23 g, 4.14 mmol) and
H-80); 13C NMR (CDCl3, 125 MHz):
d
24.2 (C-4), 30.8 (C-3), 51.6 (C-5),
54.3 (OCH3), 61.9 (C-2), 73.3 (C-
a
), 126.3 (C-30), 126.3 (C-70), 126.4
NaOH (166 mg, 1 equiv); FC (gradient: petroleum ether/AcOEt 5:1
to 2:1): yield 1.01 (92%): 0.79 g (72%) of (4S,8aS)-5a and 0.22 (20%)
of diastereomeric mixture. White solid; mp 146e147 ꢁC; TLC:
(C-60), 127.6 (C-10), 128.1 (C-80), 128.3 (C-40), 128.7 (C-50), 133.2 (C-
4a0), 133.2 (C-8a0), 134.1 (C-20), 174.8 (COOCH3), 175.9 (CONH2);
HRMS (ESIþ) calcd for C18H20N2O3Na: 335.1372 (MþNa)þ found
335.1360.
Rf¼0.25 (petroleum ether/AcOEt 3:1); ½a D20
ꢀ114.7 (c 0.935, CHCl3);
ꢂ
IR (KBr): 802, 1014, 1092, 1261, 1319, 1489, 1697, 2851, 2920, 2962,
3229; 1H NMR (500 MHz, CDCl3): 1.92 (m, 2H, H-7, H-70), 2.26 (m,
d
4.3.4. (2S,
2-carboxylic acid methyl ester (2S,
8.54 mmol), and BF3$2CH3COOH (26 mL); FC (gradient: PE/AcOEt
a
S)-1-(
a
-Carbamoyl-
a
-(2-thiophene)methyl)-pyrrolidine-
1H, H-8), 2.32 (m, 1H, H0-8), 2.80 (pq, 2J¼3J1¼7.5¼3J2¼8.5, 1H, H-6),
3.20 (m, 2J¼8.5, 3J1¼8.0, 3J2¼3.5,1H, H0-6), 3.64 (dd, 3J1¼8.5, 3J2¼3.0,
1H, H-8a), 4.81 (s, 1H, H-4), 7.35 (dt, 3J¼8.5, 4J¼2.0, 2H, H-30, H-50),
7.40 (dt, 3J¼8.5, 4J¼2.0, 2H, H-20, H-60), 8.02 (br s, 1H, NH); 13C NMR
a
S)-4c. From (2S, S)-3c (2.77 g,
a
2:1 to 0:1): yield 1.32 g (57%) of (2S,
a
ꢂ
S)-4c. Pale-yellow solid; mp
ꢀ4.0 (c 1, CHCl3); IR (KBr)
172e173 ꢁC; TLC: Rf¼0.44 (AcOEt); ½a 2D0
(CDCl3, 125 MHz): d 22.4 (C-7), 27.4 (C-8), 51.8 (C-6), 57.0 (C-8a),
628, 699, 757, 1204, 1379, 1435, 1634, 1672, 1729, 2806, 2948, 3174,
63.3 (C-4), 128.4 (C-30, C-50), 129.1 (C-20, C-60), 132.7 (C-40), 134.4 (C-
10), 171.4 (C-3), 173.8 (C-1); HPLC: retention time 49.1 min (MeCN/
H2O 25:75); HRMS (ESIþ) calcd for C13H1215ClN2O2Na2: 309.0377
(MꢀHþ2Na)þ found 309.0393.
3390; 1H NMR (CDCl3, 500 MHz):
d
1.82e1.92 (m, 3H, H-3, H-4, H0-
4), 2.03 (m, 1H, H0-3), 2.76 (m, 1H, H-5), 3.28 (m, 1H, H0-5), 3.51 (dd,
3J1¼9.5, 3J2¼3.5, 1H, H-2), 3.58 (s, 3H, OCH3), 4.54 (s, 1H, H-
a), 5.73
(br s, 1H, CONH), 6.96 (dd, 3J1¼5.0, 3J2¼3.5, H-40), 7.03 (d, 3J¼3.0, 1H,
H-30), 7.26 (d, 3J¼4.5, H-50), 7.66 (br s, 1H, CONH0); 13C NMR (CDCl3,
4.4.2. (4R,8aS)-4-(4-Chlorophenyl)-perhydropyrrolo[1,2-a]pyrazine-
1,3-dione (4R,8aS)-5a. From (2S,aR)-4a (0.21 g, 0.71 mmol) and
125 MHz):
2), 67.3 (C-
d
24.4 (C-4), 31.0 (C-3), 52.0 (OCH3), 54.1 (C-5), 61.5 (C-
a
), 126.3 (C-30), 126.9 (C-50), 128.3 (C-40), 138.5 (C-20),
NaOH (28 mg, 1 equiv); FC (gradient: petroleum ether/AcOEt 5:1 to
2:1): yield 165 mg (88%): 128 mg (68%) of (4R,8aS)-5a and 37 mg
(20%) of diastereomeric mixture. White solid; mp 173e175 ꢁC;
174.0 (CONH2), 176.1 (COOCH3); HRMS (ESIþ) calcd for
C12H16N2O3SNa 291.0779 (MþNa)þ found: 291.0771.
TLC: Rf¼0.14 (petroleum ether/AcOEt 3:1); ½a D20
ꢀ112.8 (c 0.968,
ꢂ
4.3.5. (2S,
carboxylic acid methyl ester (2S,
7.26 mmol) and BF3$2CH3COOH (22 mL); FC (gradient: PE/AcOEt
a
S)-1-(
a
-Carbamoyl-
a
-(3-furyl)methyl)-pyrrolidine-2-
CHCl3); IR (KBr): 822, 1014, 1088, 1219, 1319, 1493, 1705, 2804,
a
S)-4d. From (2S, S)-3d (2.24 g,
a
2924, 2962, 3221; 1H NMR (500 MHz, CDCl3):
d 1.83 (m, 2H, H-7,
H-70), 2.14 (m, 2H, H-6, H-8), 2.23 (m, 1H, H0-8), 2.82 (td, 2J¼9.0,
3
2:1 to 0:1): yield 1.19 g (65%) of (2S,
a
S)-4d. White solid; mp
3J1¼9.0, J2¼2.0, 1H, H0-6), 3.18 (pt, 3J1¼8.0, 1H, H-8a), 4.03 (s, 1H,
159e161 ꢁC; TLC: Rf¼0.30 (AcOEt); ½a 2D0
ꢂ
þ1.3 (c 1, CHCl3); IR (KBr)
H-4), 7.31 (dt, 3J¼8.5, J¼2.0, 2H, H-30, H-50), 7.37 (dt, 3J¼8.5,
4
874, 1022, 1159, 1205, 1677, 1729, 2802, 2924, 2952, 3152; 1H NMR
4J¼2.0, 2H, H-20, H-60), 7.98 (br s, 1H, NH); 13C NMR (125 MHz,
(CDCl3, 500 MHz):
d
1.80e1.95 (m, 3H, H-3, H-4, H0-4), 2.05 (m, 1H,
CDCl3): d 21.0 (C-7), 24.7 (C-8), 52.1 (C-6), 65.9 (C-8a), 71.0 (C-4),
H0-3), 2.68 (m, 1H, H-5), 3.28 (m, 1H, H0-5), 3.46 (dd, 3J1¼9.5,
129.0 (C-30, C-50), 130.3 (C-20, C-60), 134.4 (C-40), 134.7 (C-10), 171.0
(C-3), 171.8 (C-1); HPLC: retention time 56.3 min (MeCN/H2O
3J2¼4.0, 1H, H-2), 3.58 (s, 3H, OCH3), 4.18 (s, 1H, H-
a), 5.71 (br s, 1H,

8230
M. Dawidowski et al. / Tetrahedron 68 (2012) 8222e8230
25:75); HRMS (ESIþ) calcd for C13H1315ClN2O2Na: 287.0563
of 2 and 0.19 g (19%) of diastereomeric mixture. White solid; mp
(MþNa)þ found 287.0578.
122e124 ꢁC; Rf¼0.24 (PE/AcOEt 3:1); ½a 2D0
ꢀ132.8 (c 0.621, CHCl3);
ꢂ
HRMS (ESIꢀ) calcd for C13H13N2O2: 229.0971 (MꢀH)ꢀ found
229.0961. Physical constants and NMR spectral data match those
previously reported.1a
4.4.3. (4S,8aS)-4-(2-Naphthyl)-perhydropyrrolo[1,2-a]pyrazine-1,3-
dione (4S,8aS)-5b. From (2S,aS)-4b (0.50 g, 1.60 mmol) and NaOH
(64 mg, 1 equiv); FC (gradient: PE/AcOEt 5:1 to 2:1): yield 0.40 g
(90%): 0.33 g (73%) of (4S,8aS)-5b and 76 mg (19%) of di-
astereomeric mixture. White solid; mp 123e124 ꢁC (dec); TLC:
Acknowledgements
Rf¼0.22 (PE/AcOEt 3:1); ½a D20
ꢀ79.4 (c 1.097, CHCl3); IR (KBr): 752,
ꢂ
Financial support was provided by the Committee for Scientific
Research, Poland (Grant No. N N405 623138) and Medical Univer-
sity of Warsaw (Young Researcher Grant to M.D.).
815, 1239, 1317, 1354, 1705, 1695, 2817, 2965, 3215; 1H NMR
(500 MHz, CDCl3): d
1.93 (m, 2H, H-7, H-70), 2.28 (m, 2H, H-8, H0-8),
2.85 (pq, 2J¼3J1¼7.5¼3J2¼8.5, 1H, H-6), 3.25 (td, 2J¼3J1¼8.5, 3J2¼3.5,
1H, H0-6), 3.70 (dd, 3J1¼8.5, 3J2¼3.0, 1H, H-8a), 5.01 (s, 1H, H-4), 7.49
(m, 2H, H-60, H-70), 7.60 (dd, 3J¼8.5, 4J¼2.0, 1H, H-30), 7.78e7.87 (m,
4H, H-10, H-40, H-50, H-80), 8.55 (br s, 1H, NH); 13C NMR (CDCl3,
Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds. Sup-
plementary data related to this article can be found online at http://
dx.doi.org/10.1016/j.tet.2012.07.064.
125 MHz): d 22.5 (C-7), 27.4 (C-8), 51.8 (C-6), 57.2 (C-8a), 64.1 (C-4),
125.0 (C-30),125.8 (C-10),126.5 (C-70),126.5 (C-60),127.6 (C-80),128.1
(C-40), 128.8 (C-50), 131.7 (C-20), 133.1 (C-4a0), 133.1 (C-8a0), 171.9
(C-3), 174.1 (C-1); HRMS (ESIþ) calcd for C17H16N2O2Na: 303.1110
(MþNa)þ found 303.1138.
References and notes
4.4.4. (4S,8aS)-4-(2-Thiophene)-perhydropyrrolo[1,2-a]pyrazine-1,3-
dione (4S,8aS)-5c. From (2S,aS)-4c (1.26 g, 4.70 mmol) and NaOH
1. (a) Herold, F.; Dawidowski, M.; Wolska, I.; Chodkowski, A.; Kleps, J.; Tur1o, J.;
Zimniak, A. Tetrahedron: Asymmetry 2007, 18, 2091; (b) Dawidowski, M.; Herold,
F.; Wilczek, M.; Kleps, J.; Wolska, I.; Tur1o, J.; Widomski, P.; Bielejewska, A.
Tetrahedron: Asymmetry 2009, 20, 1759; (c) Dawidowski, M.; Herold, F.;
Chodkowski, A.; Kleps, J.; Szulczyk, P.; Wilczek, M. Eur. J. Med. Chem. 2011, 46,
4859; (d) Dawidowski, M.; Herold, F.; Chodkowski, A.; Kleps, J. Eur. J. Med. Chem.
2012, 48, 347.
2. Castel-Branco, M. ,M.; Alves, G. ,L.; Figueiredo, I. ,V.; Falcao, A. ,C.; Caramona, M.
,M. Methods Find. Exp. Clin. Pharmacol. 2009, 31, 101.
3. Barton, M. E.; Klein, B. ,D.; Wolf, H. H.; White, H. S. Epilepsy Res. 2001, 47, 217.
(188 mg, 1 equiv); FC (gradient: PE/AcOEt 5:1 to 2:1): yield 0.97 g
(87%): 0.73 g (66%) of (4S,8aS)-5c and 0.23 g (19%) of di-
astereomeric mixture. Pale-yellow solid; mp 131e132 ꢁC; TLC:
Rf¼0.23 (PE/AcOEt 3:1); ½a D20
ꢀ184.6 (c 1, CHCl3); IR (KBr) 706, 759,
ꢂ
1243, 1317, 1349, 1681, 1693, 1709, 1726, 2821, 2923, 3101, 3206; 1H
~
NMR (500 MHz, CDCl3): d
1.84e2.00 (m, 2H, H-7, H-70), 2.30 (m, 2H,
H-8, H0-8), 2.78 (pq, 2J¼3J1¼3J2¼8.5, 1H, H-6), 3.23 (td, 2J¼3J1¼8.5,
3J2¼3.5,1H, H0-6), 3.89 (dd, 3J¼8.5, 3J2¼3.0, 1H, H-8a), 5.01 (s, 1H, H-
4), 6.96e7.02 (m, 2H, H-30, H-40), 7.31 (d,1H, 3J¼5.0, H-50), 8.20 (br s,
€
€
4. (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Demharter, A.; Horl, W.; Eberhardt,
€
H.; Ugi, I. Angew. Chem., Int. Ed. 1996, 35, 173; (c) Ugi, I.; Demharter, A.; Horl, W.;
Schmid, T. Tetrahedron 1996, 52, 11657; (d) Ecker, H. Molecules 2012, 17, 1074.
€
5. (a) Ugi, I.; Horl, W.; Hanusch-Kompa, C.; Schmid, T.; Herdtweck, E. Heterocycles
1H, NH); 13C NMR (CDCl3, 125 MHz):
d 22.6 (C-7), 27.3 (C-8), 51.7
€
1998, 47, 965; (b) Ugi, I.; Ebert, B.; Horl, W. Chemosphere 2001, 43, 75; (c)
(C-6), 57.6 (C-8a), 60.8 (C-4), 125.4 (C-30), 126.4 (C-50)þ, 127.3 (C-40),
138.4 (C-20), 170.6 (C-3), 171.7 (C-1); HRMS (ESI ) calcd for
C11H12N2O2SNa 259.0517 (MþNa)þ found: 259.0510.
€
Constabel, F.; Ugi, I. Tetrahedron 2001, 57, 5785; (d) Domling, A.; Huang, Y.
Synthesis 2010, 17, 2859.
6. To the best of our knowledge there has been only one, simultaneous report:
Mandai, H.; Irie, S.; Mitsudo, K.; Suga, S. Molecules 2011, 16, 8815.
7. For examples of the application of ‘convertible isocyanides’, see: (a) Zhou, H.;
Zhang, W.; Yan, B. J. Comb. Chem. 2010, 12, 206; (b) Guchhait, S. ,K.; Madaan, C.
Org. Biomol. Chem. 2010, 8, 3631; (c) Gilley, C. ,B.; Buller, M. ,J.; Kobayashi, Y. Org.
Lett. 2007, 9, 3631; (d) Gilley, C.; Kobayashi, Y. J. Org. Chem. 2008, 73, 4198; (e)
Nikulnikov, M.; Tsirulnikov, S.; Kysil, V.; Ivachtchenko, A.; Krasavin, M. Synlett
2009, 260; (f) Strocker, A. ,M.; Keating, T. ,A.; Tempest, P. ,A.; Armstrong, R. ,W.
Tetrahedron Lett. 1996, 37, 1149; (g) Pirrung, M. ,C.; Ghorai, S.; Ibarra-Rivera, T. ,R.
J. Org. Chem. 2009, 74, 4110; (h) Hulme, C.; Ma, L.; Cherrier, M.-P.; Romano, J. ,J.;
Morton, G.; Duquenne, C.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000, 41,
1883; (i) Dai, Q.; Xie, X.; Xu, S.; Ma, D.; Tang, S.; She, X. Org. Lett. 2011, 13, 2302.
8. Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M. ,A. Org. Lett.
2004, 19, 3281.
4.4.5. (4S,8aS)-4-(3-Furyl)-perhydropyrrolo[1,2-a]pyrazine-1,3-
dione (4S,8aS)-5d. From (2S,aS)-4d (0.87 g, 3.45 mmol) and NaOH
(178 mg, 1 equiv); FC (gradient: PE/AcOEt 5:1 to 2:1): yield 0.72 g
(92%): 0.62 (79%) of (4S,8aS)-5d and 0.10 g (13%) of diastereomeric
mixture. White solid; mp 125e126 ꢁC; TLC: Rf¼0.14 (PE/AcOEt 3:1);
½
a 2D0
ꢂ
ꢀ99.1 (c 1, CHCl3); IR (KBr) 602, 766, 799, 875, 901, 1023, 1159,
1243, 1259, 1319, 1353, 1698, 2806, 2969, 3113; 1H NMR (500 MHz,
CDCl3):
d
1.80e1.98 (m, 2H, H-7, H-70), 2.25 (m, 1H, H-8), 2.31 (m,
1H, H0-8), 2.74 (pq, 2J¼3J1¼3J2¼8.5, 1H, H-6), 3.15 (td, 2J¼3J1¼8.5,
3J2¼3.5, 1H, H0-6), 3.77 (dd, 3J¼8.5, 3J2¼3.0, 1H, H-8a), 4.74 (s, 1H,
H-4), 6.44 (ps, 1H, H-40), 7.44 (m, 2H, H-20, H-50), 8.12 (br s, 1H, NH);
9. TFA is most widely utilized for this type of reaction, also for similar substrates,
see: Ref. 8. For more examples and other amide de-tertbutylating agents, see:
(a) Schleicher, K. ,D.; Jamison, T. ,F. Org. Lett. 2007, 9, 875; (b) Zhou, F.; Ding, K.;
ꢁ
€
Cai, Q. Chem.dEur. J. 2011, 17, 12268; (c) Takacs, E.; Varga, C.; Skoda-Foldes, R.;
13C NMR (CDCl3, 125 MHz):
d 22.5 (C-7), 27.2 (C-8), 51.5 (C-6), 57.6
ꢁ
Kollar, L. Tetrahedron Lett. 2007, 48, 2453; (d) Mahalingam, A. ,K.; Wu, X.;
(C-8a), 57.7 (C-4), 109.9 (C-40), 120.1 (C-30), 140.6 (C-20), 143.9 (C-50),
171.5 (C-3), 173.8 (C-1); HRMS (ESIꢀ) calcd for C11H11N2O3 219.0770
(MꢀH)ꢀ found: 219.0780.
Alterman, M. Tetrahedron Lett. 2006, 47, 3051; (e) Lacey, R. ,N. J. Chem. Soc. 1960,
1633; (f) Conover, L. ,H.; Butler, K.; Johnston, J. ,D.; Korst, J. ,J.; Woodward, R. ,B.
J. Am. Chem. Soc. 1962, 84, 3222.
10. Formation of the desired product was probably enhanced due to the improved
solubility of the substrate.
11. The [a] values of the purified and separated diastereomers equaled 0, which
D
4.4.6. (4S,8aS)-4-Phenylperhydropyrrolo[1,2-a]pyrazine-1,3-dione
indicated the formation racemates. This was further confirmed by conducting
the reaction for compound 3e, followed by analysis of the cyclocondensation
products by chiral HPLC method described in Ref. 1b.
2. From (2S,
aS)-4e (1.09 g, 4.16 mmol) and NaOH (166 mg,1 equiv);
FC (gradient: PE/AcOEt 5:1 to 2:1): yield 0.92 g (96%): 0.77 g (77%)