Methodology for Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones

Article abstract of DOI:10.1002/ejoc.201500620

A new synthetic route towards chiral 3,5-disubstituted pyrrol-2-ones by starting from amino acids has been developed. The sequence features the conversion of amino acids into their corresponding alkynoic acid derivative followed by a Pd-catalyzed hydrosta

Full text of DOI:10.1002/ejoc.201500620

FULL PAPER
DOI: 10.1002/ejoc.201500620
Methodology for Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
[a]
[a]
[a]
[a]
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Ondrej Krenk, Jirí Kratochvíl, Marcel Spulák, Vladimír Buchta, Jirí Kunes,
Lucie Nováková,[a] Mukund Ghavre,*[a] and Milan Pour*[a]
Dedicated to Professor Tomásˇ Hudlický on the occasion of his 66th birthday[‡]
Keywords: Nitrogen heterocycles / Amino acids / Alkynes / Chiral pool / Green chemistry
A new synthetic route towards chiral 3,5-disubstituted pyr- Pd-catalyzed hydrostannylation of the triple bond and Stille
rol-2-ones by starting from amino acids has been developed.
The sequence features the conversion of amino acids into
their corresponding alkynoic acid derivative followed by a
cross-coupling reaction. A series of lactam analogues of anti-
fungal 3-(aryl)-5-hydroxymethyl-2,5-dihydrofuran-2-ones
have thus been prepared.
under basic conditions to produce ketodiester 5, which then
underwent an intramolecular cyclization to afford polysub-
stituted pyrrol-2-one 6 (Scheme 1, case A). In another
method, β-keto ester 7 underwent an intramolecular cycli-
zation, and then the aryl group at C-3 was introduced by
an Ullmann-type reaction to afford compound 9 (Scheme 1,
case B).[4b] Anwar et al.[4c] tethered an l-threonine-based
oxazolidine to a substituted malonate (i.e., 11), which then
underwent cyclization to provide bicyclic compound 12.
Upon cleavage of the oxazolidine functionality, lactam 13
was obtained (Scheme 1, case C).
Introduction
Five-membered heterocycles are prevalent in the nature.
Furanones and pyrrolones especially are present as an inte-
gral part of a number of alkaloids and toxins.[1,2] Some time
ago, we reported the discovery of new antifungal agents
based on the furan-2-one scaffold.[3] As a sequel to this re-
search, the next logical step involves the preparation of the
lactam analogues (Figure 1).
All of these examples involve the use of amino acids and
include intramolecular cyclizations. The design of these syn-
theses is specific to tetramic acid derivatives that require an
enolic OH group at C-4. According to these protocols, it is
mandatory to start with specific precursors to obtain par-
ticular substitution patterns on the pyrrol-2-one moiety,
which impose limitations to the preparations of larger li-
braries. Hence, we envisaged a synthesis that would enable
the preparation of variously substituted pyrrol-2-ones by
employing a single protocol.
Figure 1. 3,5-Disubstituted furan-2-ones (1) and pyrrol-2-ones (2).
There are a few reported syntheses of chiral pyrrol-2-
ones, and most of them deal with the preparation of the
closely related tetramic acids and their analogues.[2] An
overview of the most important methods is summarized in
Scheme 1. Prousis et al.[4a] treated anhydride 3 with ester 4
Herein, we describe a facile synthetic route to give
enantiopure 3,5-disubstituted pyrrol-2-ones. This strategy
assures the preparation of a large number of compounds by
merely choosing different precursors at a late stage in the
[a] Department of Inorganic & Organic Chemistry, Department of synthesis. This approach utilizes the use of metal-catalyzed,
Biological & Medical Sciences, and Department of Analytical
high yielding reactions, and natural feedstocks, thus
Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
fulfilling two principles of green chemistry.[5] The antimi-
crobial activity for some of these pyrrol-2-ones is also pre-
sented.
University in Prague,
Akademika Heyrovského 1203, 50005 Hradec Králové, Czech
Republic
E-mail: mukundghavre01@gmail.com
pour@faf.cuni.cz
http://www.faf.cuni.cz/en/
Results and Discussion
Our retrosynthetic analysis of polysubstituted pyrrol-2-
ones A (Scheme 2) involves the introduction of an aryl moi-
[‡] In recognition of his contributions to the field of organic syn-
thesis
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500620.
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Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
Scheme 1. Reported strategies for the synthesis of chiral pyrrol-2-ones (LDA = lithium diisopropylamide, THF = tetrahydrofuran, Cbz
= carbobenzyloxy, DMSO = dimethyl sulfoxide, Boc = tert-butoxycarbonyl).[4]
ety at C-3 through a Pd-catalyzed Stille cross-coupling reac- was obtained by derivatization of D, and propargylic amine
tion. The tributyltin group at C-3 and the hydrogen atom D may be easily accessed from an amino acid by employing
at C-4 in structure B are positioned cis to each other by a a Corey–Fuchs reaction[6] or a Seyferth–Gilbert homologa-
hydrostannylation of the corresponding alkyne. Alkyne C tion.[7]
In accord with the retrosynthetic analysis, l-serine was
converted into alkyne 17 in five steps by a linear sequence
of reactions that were carried out in 42% overall yield.[8–12]
This sequence involved a Fischer–Speier esterification of
the l-serine,[8] protection of free alcohol as a tert-butyldi-
methylsilyl (TBS) ether,[9] protection of the amine by treat-
ment with Boc2O,[10] partial reduction of the ester to give
the corresponding aldehyde,[11] and in the final step, a
Seyferth–Gilbert homologation to give alkyne 17.[12] The
same transformation was also achieved by using a Corey–
Fuchs protocol,[6] but lower yields resulted. Mono-Boc-pro-
tected alkyne 17 was then treated with LDA and Boc an-
hydride in THF at –78 °C to obtain 18 (Scheme 3). The
purpose of masking the amine with two Boc groups was
to neutralize the acidic protons that may interfere in the
forthcoming steps.
Scheme 2. Retrosynthetic analysis of 3,5-disubstituted pyrrol-2-
ones (FGI = functional group interconversion).
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M. Ghavre, M. Pour et al.
FULL PAPER
Scheme 3. Preparation of organotin compound 20.
Scheme 4. Synthesis of the series of TBS ethers 22a–22f (dba =
dibenzylideneacetone, TFP = tri(2-furyl)phosphine, DMF = N,N-
dimethylformamide).
The derivatization of 18 by treatment with LDA and
methyl chloroformate furnished ester 19 in moderate yield
(62%).[13] Compound 19 was then subjected to a hydro-
stannylation by using Bu3SnH/Pd(PPh3)4 in dichlorometh-
ane (DCM) to afford organostannane 20 in good yield
(78%).[14] As expected, the addition of Bu3SnH was regio-
selective because of electronic factors and the steric bulk of
di-Boc group at one terminus of the alkyne.
Stille coupling reactions were subsequently carried out
between 20 and a number of aryl iodides (Scheme 4).[15]
Pd2(dba)3/tri(2-furyl)phosphine/CuI was selected as the
catalytic system for the coupling step.[16] Aryl iodides that
have either electron-donating or -withdrawing substituents
at the para position were chosen to examine their effect on
the reactivity. Six such derivatives (i.e., 21a–21f) were pre-
pared in yields of 71–95%.[17] To trigger the cyclization of
21, the removal of the two Boc groups was attempted by a
number of methods, including the use of HCl/dioxane,[18]
trifluoroacetic acid (TFA),[19] and tert-butyldimethylsilyl
trifluoromethanesulfonate (TBDMSOTf).[20] However,
none of these methods produced the desired γ-lactam. Un-
der mild acidic conditions, one of the Boc groups was re-
moved, whereas harsher or more forcing conditions cleaved
both the Boc and TBS groups, which resulted in the forma-
tion of a dihydropyran-2-one derivative. Finally, treatment
of 21a–21f with LiBr in acetonitrile at reflux temperature
for 24 h produced lactams 22a–22f yields of 45–84%.[10]
Scheme 5. Synthesis of 5-methylidenepyrrol-2-ones 24a–24f.
The removal of the TBS group was achieved by treating stability, thus promoting the elimination of the ester func-
22a–22f with a mixture of acetic acid, THF, and water in tionality. A series of 5-methylidene-substituted pyrrol-2-
3:1:1 ratio (Scheme 5),[21] which afforded alcohols 23a–23f ones were thus synthesized by using alcohols 23a–23f,
in 51–85% yield. Other methods were attempted to remove acetyl chloride, and triethylamine. The final compounds
the TBS group, including TBAF/THF (TBAF = tetra-n- 24a–24f were obtained in 37–95% yield.
butylammonium fluoride),[22] K2CO3/methanol,[23] and
Because esterification at the final stage was unsuccessful,
NaHCO3/methanol.[24] Unfortunately, all of these led to eli- we derivatized the alcohol as an aryloxy group. In line with
mination products 24a–24f. our previous results, we hoped that the lower leaving group
To extend the library of compounds for the purpose of ability of the aryloxy group would suppress the elimination
screening their bioactivities,[3] we prepared various esters process.[3a] According to a modified synthetic plan, the
(see also Figure 1). Different esterification approaches were amino group of methyl l-serinate 25 was protected as a
attempted, but the esters underwent rapid elimination to carbamate to furnish compound 26 (88% yield), which was
furnish the 5-methylidenepyrrol-2-ones. Because of the ex- then subjected to a Mitsunobu reaction by using phenol,
tended conjugation system, products 24a–24f have extra triphenylphosphine, and diethyl azodicarboxylate (DEAD,
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Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
Scheme 6. Attempted preparation of aryloxy derivative (Tr = tri-
phenylmethyl).
Scheme 6). Somewhat surprisingly, compound 27 was iso-
lated in 63% yield instead of the desired phenyl ether. We Scheme 7. Synthesis of l-alanine-based pyrrol-2-ones.
expect that elimination occurred through neighboring
group participation by the -NH of the carbamate.
Pyrrol-2-ones 35a, 35b, and 35e were isolated in moderate
Hence, methyl l-serinate hydrochloride salt 25 was pro-
tected by a bulky trityl group to obtain alcohol 28 in 50%
yield.[25] The Mitsunobu reactions of 28 yielded aryl ethers
29 (59–79% yield), which corroborates our prediction about
the formation of acrylate derivative 27. Because of the
yields (59–67%).
Antimicrobial Activity
The TBS-protected intermediates 22a–22f, the 5-
bulky nature of the trityl group, the nitrogen atom is not (hydroxymethyl)pyrrol-2-ones 23a–23f, the 5-methyl-
available for the neighboring group participation. Unfortu- idenepyrrol-2-ones 24a–24f, and the alanine-based pyrrol-
nately, when partial reduction of 29 was attempted by using 2-ones 35a, 35b, and 35e were evaluated for their in vitro
diisobutylaluminum hydride (DIBALH) in toluene, no de- antifungal activity against a set of human pathogenic fungi,
sired product was observed.
including representatives of both yeast and filamentous
To examine the scope of the method with respect to the strains (see Table 1). Silicon-containing molecules have
amino acid component, l-alanine-based pyrrol-2-ones were shown biological activity,[29] which was the reason to in-
prepared by this protocol. Alkyne 30 was synthesized from clude 22a–22f in the investigation. The results show that the
methyl l-alaninate in three steps according to published TBS-protected alcohols 22a and 22d, which are methoxy-
methods (Scheme 7).[26–28] The NH moiety in 30 was then and chloro-substituted compounds, respectively, exhibit
protected by another Boc group using LDA and (Boc)2O good to moderate activity (1.95–62.5 μm). Among the 5-(hy-
to furnish alkyne 31 in 79% yield. The alkyne was derivat- droxymethyl)pyrrol-2-ones, 23d and 23f exhibited moderate
ized with LDA/methyl chloroformate to afford methyl ester to low activity (31.25–1000 μm). Additionally, the 5-methyl-
32, and hydrostannylation of 32 yielded compound 33.[14] idenepyrrol-2-ones 24e and 24f showed only moderate ac-
Stille coupling reactions were then carried out with 33, aryl tivity (15.62–500 μm). Out of the alanine-based compounds,
iodides, Pd2(dba)3, tri(2-furyl)phosphine, and CuI in DMF only 4-bromopyrrol-2-one 35e showed moderate activity
to obtain 34a, 34b, and 34e.[15,16] Three aryl iodides were (31.25–250 μm) against all strains of the fungi. These com-
employed in the coupling reactions, each exerting different pounds were also tested for their antibacterial activity
electronic effects on the phenyl ring.
against eight strains of bacteria (four Gram-positive and
Finally, the cyclizations of 34a, 34b, and 34e were ac- four Gram-negative). However, none of them showed prom-
complished by employing LiBr in acetonitrile at reflux.[10] ising activity at the test concentration of 1000 μm.
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M. Ghavre, M. Pour et al.
FULL PAPER
Table 1. Antifungal activity of pyrrol-2-one derivatives.[a]
make the resultant compound analogous to the highly cyto-
static combretastatins.[31] Hence, further studies are focused
on the synthesis and assessment of the biological activities
of 3,4-diaryl-substituted pyrrol-2-ones.
Strain[b] Time [h] 22a
22d
35e
23d
23f
24e
24f
CA1
CA1
CA2
CA2
CP
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
7.81
7.81
62.5
250
1000
250
1000
599
Ͼ1000 125
62.5
125
62.5
250
250
250
250
250
125
62.5
125
31.25 125
125
62.5
125
62.5
62.5
125
500
31.25 31.25 62.5
7.81 15.62 62.5
31.25 62.5 62.5
15.62 31.25 250
125
1.95
7.81
3.9
500
31.25
250
31.25
62.5
Experimental Section
CP
125
7.81
15.62 62.5
7.81 62.5
15.62 62.5
250
62.5
General Methods: All substances were purchased from Sigma–
Aldrich and used as received. THF was freshly distilled from so-
dium benzophenone ketyl. DMF was dried with molecular sieves
(3 Å). All anhydrous reactions were performed in flame-dried
Schlenk tubes under Ar. Analytical thin-layer chromatography was
conducted on E. Merck TLC plates (silica gel 60 F254, aluminum
back). Silica gel 60 (230–400 mesh) for column chromatography
was purchased from E. Merck. Melting points were measured with
a Kofler block or Büchi B-545 melting point apparatus. The 1H
and 13C NMR spectroscopic data were recorded in CDCl3, [D6]-
DMSO, and CD3OD solutions at ambient temperature with a Var-
ian Mercury-Vx BB 300 instrument (300 MHz for 1H NMR and
75 MHz for 13C NMR) or a Varian NMR 500 spectrometer
(500 MHz for 1H NMR and 125 MHz for 13C NMR). Chemical
shifts were recorded as δ values in parts per million (ppm) and
were indirectly referenced to tetramethylsilane by the solvent signal.
Coupling constants (J) are reported in Hertz. Infrared spectra were
recorded on a Nicolet 6700 FTIR spectrophotometer. Low resolu-
tion mass spectra were measured on a Finnigan LTQ XL appara-
tus, whereas high resolution mass spectra were recorded on a Syn-
apt G2-Si spectrometer. Optical rotations were measured on a
Kruss polarimeter P3000. Characterization data for known com-
pounds were consistent with literature values.
CK1
CK1
CK2
CK2
CT
125
250
125
250
500
31.25 31.25
7.81
62.5
125
125
31.25 31.25
31.25 62.5
31.25 31.25
62.5
62.5
62.5
62.5
62.5
62.5
62.5
500
15.62 15.62 31.25 500
31.25 62.5
7.81 7.81
31.25 31.25 62.5
15.62 7.81 62.5
31.25 31.25 62.5
15.62 15.62 31.25 31.25 62.5
62.5
15.62 15.62 31.25 125
62.5
3.9
CT
31.25 Ͼ1000 1000
62.5
CG
CG
CL
CL
TA
TA
AF
AF
AC
125
1000
125
62.5
62.5
62.5
62.5
1000
62.5
31.25
125
31.25
62.5
62.5
31.25 125
62.5
62.5
125
62.5
3.9
7.81
31.25 250
15.62 31.25 31.25 31.25 31.25
15.62 31.25 31.25 31.25 62.5
62.5
62.5
AC
TM
TM
7.81
31.25 7.81
31.25 7.81
62.5
62.5
62.5
250
15.62 125
15.62 250
[a] The minimum inhibitory concentrations (MIC) values are pro-
vided in μmolL–1 and defined as 80% inhibition of the growth
of the control. [b] CA1 = Candida albicans ATCC44859, CA2 =
C. albicans ATCC90028, CP = Candida parapsilosis ATCC22019,
CK1 = Candida krusei ATCC 6258, CK2 = C. krusei E28, CT =
Candida tropicalis 156, CG = Candida glabrata 20/I, CL = Candida
lusitaniae 2446/I, TA = Trichosporon asahii 1188, AF = Aspergillus
fumigatus 231, AC = Absidia corymbifera 272, TM = Trichophyton
mentagrophytes 445 (the MIC values were determined after 72 and
120 h).
(R)-tert-Butyl
[1-(tert-Butyldimethylsilyloxy)but-3-yn-2-yl]carb-
amate (17) – Procedure A: K2CO3 (2.3 g, 16.65 mmol) was added
to an ice-cooled solution of the corresponding aldehyde (3.37 g,
11.11 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate
(3.2 g, 16.65 mmol) in MeOH (20 mL). The resulting solution was
stirred at 0 °C for 1 h and then at room temp. for 14 h. The reaction
mixture was filtered through Celite, and the filtrate was treated with
a saturated aqueous solution of NH4Cl (5 mL). The MeOH was
removed under reduced pressure, and H2O (25 mL) was added. The
resulting solution was then extracted with EtOAc (50 mL). The
combined organic extracts were dried with MgSO4, and the solvent
was removed under reduced pressure. The residue was purified by
column chromatography on silica gel [ethyl acetate (EA)/hexanes,
10:90] to give alkyne 17 (2.46 g, 8.21 mmol, 74% yield) as a color-
less oil. [α]2D5 = –8.88 (c = 0.02, ethanol). 1H NMR (300 MHz,
CDCl3): δ = 4.93 (s, 1 H), 4.42 (s, 1 H), 3.67 (d, J = 4.7 Hz, 2 H),
2.19 (d, J = 2.3 Hz, 1 H), 1.41 (s, 9 H), 0.86 (s, 9 H), 0.04 (s, 3 H),
0.03 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.78, 81.84,
79.82, 71.03, 65.28, 44.66, 28.27 (3 C), 25.77 (3 C), 18.27, –5.41,
Conclusions
In summary, we have developed a linear synthetic route
towards a new class of enantiopure 3,5-disubstituted pyrrol-
2-ones. This chiral pool driven method enables the synthesis
of variously substituted pyrrol-2-ones by using different
coupling agents at a late stage in the synthesis. Thus, this
approach offers a versatile protocol for the preparation of
libraries of this class of compounds. The synthesis utilizes
natural feedstocks (i.e., l-serine and l-alanine) and catalytic
reactions, thus complying with two principles of green
chemistry. Antimicrobial activity was evaluated for twelve
strains of fungi and eight strains of bacteria. Only two silyl-
oxy compounds (i.e., 22a and 22d) displayed notable ac-
tivity (comparable to ketoconazole). We speculate that the
main reason for the observed activity profile of 23a–23f was
a rapid elimination that took place at the C-5 side chain to
give 24. Under assay conditions, highly reactive 24 under-
went fast decomposition prior to penetration into the fun-
gal cell.[30] In the case of 22a and 22d, the elimination was
most likely sufficiently slow so that the compounds could
be delivered inside the cells and interact with the cell struc-
tures. A primary conclusion to be drawn from the available
data is that the electron-withdrawing substituents on the
phenyl ring slightly enhance the activity of compound. The
–5.46 ppm. IR [attenuated total reflectance (ATR)-Ge]: ν
=
˜
max
3312, 2931, 2858, 2118, 1698, 1507, 1367, 1252, 1170, 1121, 837,
778 cm–1. MS: m/z (%) = 244.1 (44), 200.3 (100). HRMS: calcd. for
C15H29NO3SiNa [M + Na]+ 322.1812; found 322.1814.
tert-Butyl N-[(tert-Butoxy)carbonyl]-N-{(2R)-1-[(tert-butyldimethyl-
silyl)oxy]but-3-yn-2-yl}carbamate (18) – Procedure B: A solution of
mono-Boc-substituted alkyne 17 (5.70 g, 19.0 mmol) in dry THF
(50 mL) was cooled to –78 °C under argon. LDA (1.5 m in THF,
13.3 mL, 19.90 mmol) was added dropwise by syringe over 20 min.
The reaction mixture was stirred at –78 °C for 1.5 h. A cooled solu-
tion of (Boc)2O (8.29 g, 38.0 mmol) in dry THF (50 mL) was slowly
added by cannula to the reaction mixture over 15 min at –78 °C,
introduction of an aryl group at the C-4 position would and the resulting mixture was stirred overnight at –78 °C. The reac-
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Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
tion was quenched by the addition of a saturated NaHCO3 solution
(2 mL), and the mixture was warmed to room temp. The volatiles
were removed by rotary evaporation, and the residue was purified
by column chromatography (SiO2; EA/hexanes, 10:90) to afford 18
(6.91 g, 17.29 mmol, 91% yield) as a colorless oil. [α]2D5 = –6.03 (c
compound 20 (0.8 g, 1.07 mmol) and 4-methoxyiodobenzene
(0.3 g, 1.28 mmol) in DMF (3 mL each) were simultaneously
poured into the reaction mixture. Subsequently, CuI (0.22 g,
1.18 mmol) was added, and the resulting mixture was stirred at
25 °C for 14 h under argon. The reaction was filtered through Ce-
lite, and the filter cake was rinsed with ethyl acetate (50 mL). The
filtrate was washed with water (20 mL), and the organic layer was
concentrated. The resulting residue was purified by column
1
= 0.26, ethanol). H NMR (500 MHz, CDCl3): δ = 5.18–5.15 (m,
1 H), 4.04 (t, J = 9.5 Hz, 1 H), 3.81 (dd, J = 9.8, 5.9 Hz, 1 H), 2.27
(d, J = 2.4 Hz, 1 H), 1.48 (s, 9 H), 0.85 (s, 9 H), 0.03 (s, 3 H), 0.02
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.1 (2 C), 82.7, chromatography (SiO2; EA/hexanes, 20:80) to give 21a (0.557 g,
79.6, 72.3, 64.2, 49.9, 28.0 (3 C), 25.8 (3 C), 18.21, –5.43 (2 C) ppm. 0.098 mmol, 93% yield) as a pale yellow oil. [α]2D5 = –13.48 (c =
1
IR (ATR-Ge): ν
= 3313, 2932, 2858, 2123, 1747, 1708, 1473, 0.04, ethanol). H NMR (500 MHz, CDCl3): δ = 7.26–7.23 (m, 2
˜
max
1368, 1153, 1118, 839, 778 cm–1. MS: m/z (%) = 260.3 (25), 244.1 H), 6.85–6.82 (m, 2 H), 6.30 (d, J = 8.3 Hz, 1 H), 5.40–5.35 (m, 1
(55), 200.3 (100). HRMS: calcd. for C20H37NO5SiNa [M + Na]+
422.2347; found 422.2339.
H), 3.99 (t, J = 10.0 Hz, 1 H), 3.83–3.81 (m, 1 H), 3.80 (s, 3 H),
3.79 (s, 3 H), 1.5 (s, 18 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.04, 159.51, 152.81
(2 C), 136.39, 132.51, 129.58, 128.44 (2 C), 113.74 (2 C), 82.08 (2
C), 62.89, 56.63, 55.25, 52.03, 28.05 (6 C), 25.83 (3 C), 18.19, –5.34,
Methyl (4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyldi-
methylsilyl)oxy]pent-2-ynoate (19) – Procedure C: A solution of di-
Boc-substituted alkyne 18 (2.61 g, 6.53 mmol) in dry THF (15 mL)
was cooled to –78 °C under argon. LDA (1.5 m in THF, 5.66 mL,
7.18 mmol] was added dropwise by syringe over 15 min, and the
reaction mixture was stirred at –78 °C for 2 h. Methyl choroformate
(0.56 mL, 7.18 mmol) was added dropwise by syringe at –78 °C,
and the mixture was stirred overnight at –78 °C. The reaction was
quenched by the addition of saturated NaHCO3 (1 mL), and the
mixture was warmed to room temp. The volatiles were removed by
rotary evaporation, and the residue was purified by column
chromatography (SiO2; EA/hexanes, 10:90) to afford 19 (1.85 g,
4.04 mmol, 62% yield) as a colorless oil. [α]2D5 = –5.55 (c = 0.16,
ethanol). 1H NMR (500 MHz, CDCl3): δ = 5.34 (dd, J = 8.6,
6.1 Hz, 1 H), 4.02 (dd, J = 9.8, 8.8 Hz, 1 H), 3.88 (dd, J = 9.8,
5.9 Hz, 1 H), 3.74 (s, 3 H), 1.50 (s, 18 H), 0.86 (s, 9 H), 0.04 (s, 3
H), 0.03 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 153.6,
151.6 (2 C), 84.1, 83.3 (2 C), 75.9, 63.6, 52.7, 49.6, 28.0 (6 C), 25.8
–5.39 ppm. IR (ATR-Ge): ν
= 2929, 1729, 1698, 1513, 1345,
˜
max
1249, 1173, 1120, 834, 776 cm–1. MS: m/z (%) = 565.2 (5)
[M + H]+, 448.4 (13), 366.3 (45), 350.1 (100), 317.4 (15), 218.3 (16).
Methyl (2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-phenylpent-2-enoate (21b): Light yellow oil
1
(71% yield). [α]2D5 = 0.87 (c = 0.02, ethanol). H NMR (500 MHz,
CDCl3): δ = 7.37–7.25 (m, 5 H), 6.41 (d, J = 8.2 Hz, 1 H), 5.45
(dt, J = 8.5, 6.7 Hz, 1 H), 4.03 (t, J = 9.3 Hz, 1 H), 3.86 (dd, J =
9.8, 6.8 Hz, 1 H), 3.82 (s, 3 H), 1.51 (s, 9 H), 0.90 (s, 3 H), 0.09 (d,
J = 6.6 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.63,
152.69, 137.05, 136.77, 134.40, 128.20, 127.94, 127.17, 82.01, 62.70,
56.49, 51.92, 27.96, 25.75, 18.10, –5.42, –5.46 ppm. IR (ATR-Ge):
ν
= 2979, 2953, 2931, 2888, 2857, 1735, 1701, 1495, 839,
˜
max
778 cm–1. MS: m/z (%) = 336.5 (100) [M + H – 2Boc]+, 319.8 (5).
HRMS: calcd. for C28H45NO7SiNa [M + Na]+ 558.2865; found
558.2863.
(3 C), 18.19, –5.44 (2 C) ppm. IR (ATR-Ge): ν
= 2955, 2858,
˜
max
2244, 1755, 1722, 1369, 1251, 1152, 1119, 837, 778 cm–1. MS: m/z
(%) = 302.1 (10), 257.3 (100). HRMS: calcd. for C22H39NO7SiNa
[M + Na]+ 480.2406; found 480.2393.
Methyl (2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-(4-methylphenyl)pent-2-enoate (21c): Light yel-
low oil (85% yield). [α]2D5 = –10.24 (c = 0.06, ethanol). 1H NMR
(500 MHz, CDCl3): δ = 7.25–7.18 (m, 2 H), 7.16–7.10 (m, 2 H),
6.35 (d, J = 8.3 Hz, 1 H), 5.41–5.39 (m, 1 H), 4.00–3.98 (m, 1 H),
3.87–3.79 (m, 1 H), 3.82 (s, 3 H), 2.34 (s, 3 H), 1.49 (s, 18 H), 0.88
(s, 9 H), 0.07 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
167.94, 152.78, 137.91, 136.75, 134.25, 133.47, 129.01, 127.12,
82.10, 62.86, 56.61, 52.01, 28.05, 25.83, 21.14, 18.20, –5.34,
Methyl (2E,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-(tributylstannyl)pent-2-enoate (20) – Procedure
D: A suspension of di-Boc-substituted alkyne ester 19 (4.45 g,
9.72 mmol) and Pd(PPh3)4 (0.56, 0.486 mmol) in dry DCM
(40 mL) was cooled to –20 °C under argon. Bu3SnH (2.75 mL,
10.21 mmol) was added dropwise by syringe over 10 min, and the
reaction mixture was stirred at –20 °C for 5 h. After the starting
material was completely consumed (as monitored by TLC), the vol-
atiles were removed by rotary evaporation, and the residue was
purified by column chromatography (SiO2; EA/hexanes, 5:95) to
afford 20 (5.67 g, 7.57 mmol, 78% yield) as a pale yellow liquid.
–5.38 ppm. IR (ATR-Ge): ν
= 2979, 2954, 2930, 2857, 1736,
˜
max
1701, 1348, 1176, 838 cm–1. MS: m/z (%) = 350.4 (100) [M + H –
2Boc]+, 333.8 (8). HRMS: calcd. for C29H47NO7SiNa [M + Na]+
572.3023; found 572.3019.
Methyl (2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-(4-chlorophenyl)pent-2-enoate (21d): Yellow oil
(89% yield). [α]2D5 = –11.58 (c = 0.10, ethanol). 1H NMR (500 MHz,
CDCl3): δ = 7.28–7.23 (m, 4 H), 6.39 (d, J = 8.3 Hz, 1 H), 5.42
(dd, J = 10.0 Hz, 1 H), 3.97 (t, J = 9.3 Hz, 1 H), 3.82 (dd, J = 9.8,
6.8 Hz, 1 H), 3.79 (s, 3 H), 1.47 (s, 18 H), 0.86 (s, 9 H), 0.06 (s, 3
H), 0.04 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.25,
152.75 (2 C), 136.00, 135.78, 135.47, 133.98, 128.74 (2 C), 128.44
(2 C), 82.23 (2 C), 62.70, 56.42, 52.12, 28.03 (6 C), 25.80 (3 C),
1
[α]2D5 = –3.01 (c = 0.17, ethanol). H NMR (500 MHz, CDCl3): δ
= 6.19 (d, J = 7.3 Hz, 1 H), 5.38–5.33 (m, 1 H), 3.89 (t, J = 9.3 Hz,
1 H), 3.75 (dd, J = 9.8, 6.8 Hz, 1 H), 3.66 (s, 3 H), 1.48–1.42 (m,
24 H), 1.30–1.23 (m, 6 H), 0.94–0.91 (m, 6 H), 0.86–0.83 (m, 18
H), 0.03 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.9, 152.6 (2 C), 146.4, 139.5, 81.9 (2 C), 62.7, 58.1, 51.29,
28.74 (3 C), 28.01 (6 C), 27.17 (3 C), 25.79 (3 C), 18.13, 13.58 (3
C), 10.33 (3 C), –5.38, –5.42 ppm. IR (ATR-Ge): ν
= 2956,
˜
max
2929, 1740, 1703, 1463, 1367, 1346, 1251, 1160, 1120, 838,
18.16, –5.36, –5.40 ppm. IR (ATR-Ge): ν
= 2928, 1732, 1698,
˜
max
777 cm–1. MS: m/z (%) = 738.2 (100), 569.2 (50), 460.3 (25).
1391, 1345, 1233, 1119, 835, 776 cm–1. MS: m/z (%) = 570.1 (1) [M
+ H]+, 370.5 (100), 353.4 (14).
Methyl (2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-(4-methoxyphenyl)pent-2-enoate (21a) – Pro-
Methyl
(2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-2-(4-bromo-
cedure E: A suspension of Pd2(dba)3·CHCl3 (0.055 g, 0.053 mmol) phenyl)-5-[(tert-butyldimethylsilyl)oxy]pent-2-enoate (21e): Light
1
and tri(2-furyl)phosphine (0.074 g, 0.32 mmol) in dry DMF (5 mL)
was stirred at 25 °C for 1 h under argon. Solutions of organotin
yellow oil (95% yield). [α]2D5 = 2.05 (c = 0.04, ethanol). H NMR
(500 MHz, CDCl3): δ = 7.47–7.41 (m, 2 H), 7.22–7.17 (m, 2 H),
Eur. J. Org. Chem. 2015, 5414–5423
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5419

M. Ghavre, M. Pour et al.
6.41 (d, J = 8.1 Hz, 1 H), 5.43–5.41 (m, 1 H), 4.00–3.96 (m, 1 H), 7.21–7.15 (m, 2 H), 4.25 (m, 1 H), 3.78 (d, J = 5.5 Hz, 2 H), 2.33
FULL PAPER
3.87–3.83 (m, 1 H), 3.81 (s, 3 H), 1.49 (s, 18 H), 0.88 (s, 9 H), 0.07
(s, 3 H), 1.49 (s, 18 H), 0.08 (s, 5 H) ppm. 13C NMR (125 MHz,
(s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.19, 152.76, [D4]methanol): δ = 174.97, 141.88, 139.57, 138.32, 130.16, 129.99,
136.28, 136.17, 135.51, 131.40, 129.08, 122.18, 82.27, 62.70, 56.42, 128.09, 128.08, 65.12, 60.44, 26.31, 21.33, 19.11, –5.33, –5.34 ppm.
52.15, 28.04, 25.81, 18.18, –5.35, –5.38 ppm. IR (ATR-Ge): ν
=
IR (ATR-Ge): ν
= 3195, 2927, 2891, 2855, 2733, 2361, 1677,
˜
˜
max
max
2979, 2932, 2858, 1733, 1698, 1508, 1489, 837, 778 cm–1. MS: m/z 1619, 1309, 1126, 875, 837 cm–1. MS: m/z (%) = 318.5 (100) [M +
(%) = 636.5 (100) [M + Na]+, 538.4 (22), 506.3 (12), 406.2 (15). H]+, 216.0 (1), 188.4 (1). HRMS: calcd. for C18H28NO2Si [M +
HRMS: calcd. for C28H44NO7BrSiNa [M + Na]+ 636.1964; found
636.1967.
H]+ 318.1890; found 318.1892.
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(4-chlorophenyl)-
2,5-dihydro-1H-pyrrol-2-one (22d): Yellow solid (45% yield); m.p.
113–115 °C. [α]2D5 = 9.12 (c = 0.03, DMF). 1H NMR (500 MHz,
[D4]methanol): δ = 7.84–7.81 (m, 2 H), 7.4 (d, J = 2.4 Hz, 1 H),
7.38–7.35 (m, 2 H), 4.28 (dt, J = 5.4, 2.0 Hz, 1 H), 3.79 (d, J =
5.4 Hz, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C
NMR (125 MHz, [D4]methanol): δ = 174.40, 143.37, 137.14,
135.41, 131.68, 129.69 (2 C), 129.52 (2 C), 64.90, 60.55, 26.29,
Methyl (2Z,4R)-4-{Bis[(tert-butoxy)carbonyl]amino}-5-[(tert-butyl-
dimethylsilyl)oxy]-2-(3,4-dichlorophenyl)pent-2-enoate (21f): Yellow
oil (90% yield). [α]2D5 = –9.39 (c = 0.09, ethanol). 1H NMR
(500 MHz, CDCl3): δ = 7.41 (d, J = 2.0 Hz, 1 H), 7.36 (d, J =
8.3 Hz, 1 H), 7.15 (dd, J = 8.3, 2.4 Hz, 1 H), 6.42 (d, J = 8.3 Hz,
1 H), 5.46–5.41 (m, 1 H), 3.98–3.94 (m, 1 H), 3.82 (dd, J = 9.8,
6.8 Hz, 1 H), 3.80 (s, 3 H), 1.48 (s, 18 H), 0.86 (s, 9 H), 0.06 (s, 3
H), 0.04 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.68,
152.74 (2 C), 137.80, 137.40, 134.28, 132.35, 132.10, 130.14, 129.48,
126.90, 82.34 (2 C), 62.56, 56.27, 52.23, 28.00 (6 C), 25.77 (3 C),
19.09, –5.34, –5.35 ppm. IR (ATR-Ge): ν
= 3183, 2954, 1698,
˜
max
1491, 1256, 1104, 830, 772 cm–1. MS: m/z (%) = 338.4 (100) [M +
H]+, 279.2 (2), 206.3 (3). HRMS: calcd. for C17H25ClNO2Si [M +
H]+ 338.1343; found 338.1352.
18.14, –5.39, –5.42 ppm. IR (ATR-Ge): ν
= 2927, 2856, 1697,
˜
max
1626, 1491, 1471, 1256, 1105, 1091, 831, 775 cm–1. MS: m/z
(%) = 603.7 (13) [M + H]+, 404.4 (95), 278.4 (59), 260.5 (88), 235.5
(100).
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(4-bromophenyl)-
2,5-dihydro-1H-pyrrol-2-one (22e): Light yellow solid (82% yield);
m.p. 112–114 °C. [α]2D5 = 9.87 (c = 0.01, methanol). 1H NMR
(500 MHz, [D4]methanol): δ = 7.79–7.74 (m, 2 H), 7.56–7.50 (m, 2
H), 7.42 (d, J = 2.0 Hz, 1 H), 4.29–4.27 (m, 1 H), 3.81–3.78 (m, 2
H), 0.88 (s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 174.37, 143.48, 137.22, 132.54, 132.10, 129.94,
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(4-methoxyphenyl)-
2,5-dihydro-1H-pyrrol-2-one (22a) – Procedure F: LiBr (1.67 g,
19.22 mmol) was added to the solution of TBS ester 21a (1.09 g,
1.92 mmol) in dry acetonitrile (25 mL). The suspension was heated
at reflux and stirred for 8 h. Additional LiBr (1.67 g, 19.22 mmol)
was added and the mixture heated at reflux for another 8 h. Be-
cause the reaction had not reached completion, a third portion of
LiBr (1.67 g, 19.22 mmol) was added and the mixture heated at
reflux for another 8 h. The reaction mixture was cooled to room
temp. and then filtered through paper. The filter cake was rinsed
with ethyl acetate (25 mL). The filtrate was concentrated, and the
residue was purified by column chromatography (SiO2; EA/hex-
anes, 50:50) to obtain 22a (0.40 g, 1.2 mmol, 63% yield) as a yellow
solid; m.p. 111–113 °C. [α]2D5 = 4.22 (c = 0.03, methanol). 1H NMR
(500 MHz, [D4]methanol): δ = 7.78–7.75 (m, 2 H), 7.21 (d, J =
2.0 Hz, 1 H), 6.93–6.90 (m, 2 H), 4.23 (dt, J = 5.6, 2.0 Hz, 1 H),
3.79 (s, 3 H), 3.76 (d, J = 5.6 Hz, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H),
0.07 (s, 3 H) ppm. 13C NMR (125 MHz, [D4]methanol): δ = 175.07,
161.41, 140.60, 137.83, 129.47 (2 C), 125.52, 114.76 (2 C), 65.22,
123.54, 64.86, 60.58, 26.28, 19.09, –5.37 ppm. IR (ATR-Ge): ν
˜
max
= 2928, 2857, 1698, 1508, 1488, 1105, 1078, 831, 820, 774 cm–1.
MS: m/z (%) = 384.1 (100) [M + 2]+, 382.9 (65) [M + H]+. HRMS:
calcd. for C17H25BrNO2Si [M + H]+ 382.0838; found 382.0836.
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(3,4-dichlorophen-
yl)-2,5-dihydro-1H-pyrrol-2-one (22f): White solid (45% yield); m.p.
118–120 °C. [α]2D5 = 4.30 (c = 0.03, ethanol). H NMR (500 MHz,
1
CDCl3): δ = 8.00 (d, J = 1.5 Hz, 1 H), 7.72 (dd, J = 8.3, 1.5 Hz, 1
H), 7.43 (d, J = 8.3 Hz, 1 H), 7.32 (br. s, 1 H), 7.20 (s, 1 H), 4.30
(t, J = 6.6 Hz, 1 H), 3.78 (dd, J = 9.8, 5.4 Hz, 1 H), 3.57–3.60 (m,
1 H), 0.89 (s, 9 H), 0.07 (s, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 171.76, 140.44, 135.44, 132.67, 132.61, 131.27, 130.36,
128.88, 126.33, 64.77, 59.03, 25.76 (3 C), 18.18, –5.44, –5.49 ppm.
IR (ATR-Ge): ν
= 3193, 2929, 2857, 1693, 1681, 1615, 1538,
˜
max
1472, 1360, 1256, 1122, 1099, 837, 776 cm–1. MS: m/z (%) = 372.7
(100) [M + H]+ , 277.6 (1), 242.4 (2). HRMS: calcd. for
C17H24Cl2NO2Si [M + H]+ 372.0953; found 372.0952.
60.35, 55.69, 26.32, 19.11, –5.31, –5.33 ppm. IR (ATR-Ge): ν
=
˜
max
3188, 2954, 1693, 1492, 1253, 1106, 832, 776 cm–1. MS: m/z (%) =
334.4 (100) [M + H]+. HRMS: calcd. for C18H28NO3Si [M + H]+
334.1838; found 334.1851.
(5R)-5-(Hydroxymethyl)-3-(4-methoxyphenyl)-2,5-dihydro-1H-
pyrrol-2-one (23a) – Procedure G: TBS-protected 22a (0.2934 g,
0.879 mmol) was stirred in a mixture of solvents AcOH/THF/H2O
(3:1:1, 10 mL) at 25 °C for 8 h. The volatiles were removed by ro-
tary evaporation at room temp., and the residue was purified by
column chromatography (SiO2; 100 % EA) to give 23a (0.162 g,
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-phenyl-2,5-dihydro-
1H-pyrrol-2-one (22b): Light yellow solid (84% yield); m.p. 116–
117 °C. [α]2D5 = 8.20 (c = 0.02, ethanol). 1H NMR (500 MHz,
CDCl3): δ = 7.85 (dt, J = 8.3, 1.3 Hz, 2 H), 7.43–7.29 (m, 3 H),
6.57 (s, 1 H), 4.32–4.27 (m, 1 H), 3.84 (ddt, J = 9.7, 5.2, 0.8 Hz, 1
H), 3.61–3.42 (m, 1 H), 0.91 (s, 9 H), 0.09 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 172.11, 138.82, 138.75, 137.76, 131.32,
128.68, 128.43, 128.42, 127.10, 65.13, 58.81, 25.79, 18.21, –5.41,
0.739 mmol, 84% yield) as a white solid; m.p. 174–176 °C. [α]2D5
=
21.58 (c = 0.02, DMF). 1H NMR (500 MHz, [D4]methanol): δ =
7.81–7.78 (m, 2 H), 7.27 (d, J = 2.0 Hz, 1 H), 6.94–6.91 (m, 2 H),
4.26 (dt, J = 5.9, 2.0 Hz, 1 H), 3.80 (s, 3 H), 3.71–3.60 (m, 2
H) ppm. 13C NMR (125 MHz, [D4]methanol): δ = 175.07, 161.47,
140.46, 137.83, 129.50 (2 C), 125.54, 114.76 (2 C), 64.20, 60.58,
–5.44 ppm. IR (ATR-Ge): ν
= 2927, 2856, 2361, 1898, 642,
˜
max
1513, 1377, 1124, 1106, 836, 778 cm–1. MS: m/z (%) = 304.4 (100)
[M + H]+, 174.4 (5), 89.1 (3). HRMS: calcd. for C17H26NO2Si [M
+ H]+ 304.1733; found 304.1732.
55.70 ppm. IR (ATR-Ge): ν
= 3229, 2937, 2841, 1654, 1643,
˜
max
(5R)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(p-tolyl)-2,5-di- 1615, 1569, 1510, 1459, 1445, 1253, 1177, 1102, 1026, 868, 833,
hydro-1H-pyrrol-2-one (22c): Light yellow solid (60% yield); m.p.
800 cm–1. MS: m/z (%) = 220.5 (100) [M + H]+, 202.1 (40), 174.3
(14), 112.1 (14). HRMS: calcd. for C12H14NO3 [M + H]+ 220.0974;
found 220.0972.
1
123–124 °C. [α]2D5 = 4.41 (c = 0.01, ethanol). H NMR (500 MHz,
[D4]methanol): δ = 7.72–7.66 (m, 2 H), 7.27 (d, J = 2.0 Hz, 1 H),
5420
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5414–5423

Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
(5R)-5-(Hydroxymethyl)-3-phenyl-2,5-dihydro-1H-pyrrol-2-one was purified by column chromatography (SiO2; EA/hexanes, 50:50)
(23b): White solid (80% yield); m.p. 158–160 °C. [α]2D5 = 10.36 (c =
0.02, methanol). 1H NMR (500 MHz, [D4]methanol): δ = 7.86–
to afford 24a (0.02 g, 0.0091 mmol, 95% yield) as a white solid;
m.p. 128–130 °C. 1H NMR (500 MHz, [D4]methanol): δ = 7.90–
7.76 (m, 2 H), 7.39–7.36 (m, 2 H), 7.35 (s, 1 H), 7.32 (d, J = 7.0 Hz, 7.87 (m, 2 H), 7.21 (s, 1 H), 6.95–6.93 (m, 2 H), 5.00 (s, 1 H), 4.92
1 H), 4.28 (dt, J = 5.9, 2.0 Hz, 1 H), 3.71 (dd, J = 11.0, 5.4 Hz, 1 (s, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (125 MHz, [D4]methanol): δ
H), 3.64 (dd, J = 11.0, 6.3 Hz, 1 H) ppm. 13C NMR (125 MHz, = 173.33, 161.77, 144.56, 136.20, 129.81 (2 C), 129.78, 125.15,
[D4]methanol): δ = 174.73, 142.67, 138.40, 132.98, 129.54, 129.35, 114.94 (2 C), 98.11, 55.73 ppm. IR (ATR-Ge): ν
= 3182, 2961,
˜
max
128.21, 64.02, 60.70 ppm. IR (ATR-Ge): ν
= 3234, 2958, 2926,
2926, 2853, 1686, 1643, 1608, 1507, 1458, 1260, 1177, 1099, 1035,
833, 818 cm–1. MS: m/z (%) = 202.6 (100) [M + H]+, 87.6 (80),
73.6 (40). HRMS: calcd. for C12H12NO2 [M + H]+ 202.0868; found
202.0868.
˜
max
2855, 1707, 1655, 1619, 1448, 1261, 1075, 863, 800, 723 cm–1. MS:
m/z (%) = 190.3 (100) [M + H]+, 172.6 (13). HRMS: calcd. for
C11H12NO2 [M + H]+ 190.0868; found 190.0871.
3-Phenyl-5-methylidene-2,5-dihydro-1H-pyrrol-2-one (24b): Yellow
solid (48% yield). H NMR (500 MHz, CDCl3): δ = 7.91 (d, J =
7.8 Hz, 2 H), 7.45–7.34 (m, 3 H), 7.14 (s, 1 H), 5.02 (s, 1 H), 4.92
(s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.96, 141.90,
135.63, 130.88, 130.43, 129.04, 128.66, 127.37, 97.82 ppm. IR
(5R)-5-(Hydroxymethyl)-3-(p-tolyl)-2,5-dihydro-1H-pyrrol-2-one
(23c): White solid (83% yield); m.p. 160–161 °C. [α]2D5 = –1.98 (c =
0.01, methanol). 1H NMR (500 MHz, [D4]methanol): δ = 7.75–
7.69 (m, 2 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.22–7.15 (m, 2 H), 4.27
(ddd, J = 6.2, 5.5, 2.0 Hz, 1 H), 3.70 (dd, J = 11.0, 5.5 Hz, 1 H),
3.63 (dd, J = 11.0, 6.3 Hz, 1 H), 2.34 (s, 3 H) ppm. 13C NMR
(125 MHz, [D4]methanol): δ = 174.92, 141.71, 139.62, 138.28,
130.15, 129.98, 128.10, 64.12, 60.65, 21.31 ppm. IR (ATR-Ge):
1
(ATR-Ge): ν
= 3184, 2927, 2854, 2247, 1710, 685, 1640, 449,
˜
max
1232, 1074, 867, 790, 742 cm–1. MS: m/z (%) = 172.6 (100) [M +
H]+, 129.7 (1), 89.4 (8), 73.4 (13). HRMS: calcd. for C11H10NO [M
+ H]+ 172.0763; found 172.0761.
ν
= 3232, 2931, 2871, 1666, 1655, 1617, 1512, 1382, 1078, 893,
˜
max
849 cm–1. MS: m/z (%) = 204.4 (100) [M + H]+, 186.6 (18), 73.3
(15). HRMS: calcd. for C12H14NO2 [M + H]+ 204.1025; found
204.1022.
5-Methylidene-3-(p-tolyl)-2,5-dihydro-1H-pyrrol-2-one (24c): White
solid (37% yield). 1H NMR (500 MHz, [D4]methanol): δ = 7.83–
7.77 (m, 2 H), 7.27 (s, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 5.02 (s, 1
H), 4.95 (s, 1 H), 2.34 (s, 3 H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 173.19, 144.53, 140.12, 136.58, 131.06, 130.15,
(5R)-3-(4-Chlorophenyl)-5-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-
2-one (23d): White solid (51% yield); m.p. 141–143 °C. [α]2D5 = 23.79
1
129.78, 128.32, 98.55, 21.36 ppm. IR (ATR-Ge): νmax = 3190, 2926,
˜
(c = 0.01, DMF). H NMR (500 MHz, [D4]methanol): δ = 7.87–
2855, 1684, 1639, 1615, 1509, 1461, 1352, 1185, 839, 822 cm–1. MS:
m/z (%) = 186.3 (100) [M + H]+, 148.7 (1), 75.3 (12). HRMS: calcd.
for C12H12NO [M + H]+ 186.0919; found 186.0917.
7.84 (m, 2 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.39–7.36 (m, 2 H), 4.29
(td, J = 5.9, 2.0 Hz, 1 H), 3.73–3.63 (m, 2 H) ppm. 13C NMR
(125 MHz, [D4]methanol): δ = 174.37, 143.24, 137.12, 135.44,
129.72 (2 C), 129.52 (2 C), 63.92, 60.76 ppm. IR (ATR-Ge): ν
˜
max
3-(4-Chlorophenyl)-5-methylidene-2,5-dihydro-1H-pyrrol-2-one
(24d): White solid (50 % yield); m.p. 120–122 °C. 1H NMR
(500 MHz, [D4]methanol): δ = 7.95–7.92 (m, 2 H), 7.41–7.38 (m, 3
H), 5.08 (s, 1 H), 5.00 (s, 1 H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 172.69, 152.76, 144.65, 144.38, 135.80, 135.29,
= 3231, 2924, 2853, 1647, 1611, 1490, 1379, 1095, 1079, 872,
827 cm–1. MS: m/z (%) = 224.5 (100) [M + H]+, 87.6 (75), 73.6 (40),
59.4 (10). HRMS: calcd. for C11H11ClNO2 [M + H]+ 224.0478;
found 224.0480.
132.41 (2 C), 131.34, 130.17, 99.51 ppm. IR (ATR-Ge): ν
=
˜
max
(5R)-3-(4-Bromophenyl)-5-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-
2-one (23e): White solid (85% yield); m.p. 159–160 °C. [α]2D5 = 19.36
(c = 0.01, ethanol). H NMR (500 MHz, [D4]methanol): δ = 7.82–
7.75 (m, 2 H), 7.56–7.49 (m, 2 H), 7.44 (d, J = 1.9 Hz, 1 H), 4.31–
4.25 (m, 1 H), 3.71–3.61 (m, 2 H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 174.30, 143.30, 137.15, 132.53, 132.07, 129.95,
3240, 2926, 1705, 1642, 1512, 1449, 1260, 1035, 793, 746, 694 cm–1.
MS: m/z (%) = 206.7 (76) [M + H]+, 89.5 (80), 75.6 (100), 73.7
(80). HRMS: calcd. for C11H9ClNO [M + H]+ 206.0373; found
206.0376.
1
3-(4-Bromophenyl)-5-methylidene-2,5-dihydro-1H-pyrrol-2-one
(24e): Yellow solid (52 % yield); m.p. Ͼ200 °C. 1H NMR
(500 MHz, [D4]methanol): δ = 7.87 (dd, J = 8.7, 0.7 Hz, 2 H), 7.58–
7.52 (m, 2 H), 7.40 (s, 1 H), 5.08 (d, J = 0.9 Hz, 1 H), 5.01 (s, 1
H) ppm. 13C NMR (125 MHz, [D4]methanol): δ = 172.61, 144.37,
135.32, 132.71, 132.65, 132.45, 131.72, 130.34, 130.13, 123.95,
123.56, 63.87, 60.76 ppm. IR (ATR-Ge): ν
= 3231, 2933, 1656,
˜
max
1612, 1587, 1382, 1077, 892, 825 cm–1. MS: m/z (%) = 270.1 (100),
268.7 (68) [M + H]+, 240.5 (15). HRMS: calcd. for C11H11BrNO2
[M + H]+ 267.9973; found 267.9973.
(5R)-3-(3,4-Dichlorophenyl)-5-(hydroxymethyl)-2,5-dihydro-1H-
pyrrol-2-one (23f): White solid (63 % yield); m.p. 160–162 °C.
[α]2D5 = 17.57 (c = 0.02, DMF). 1H NMR (500 MHz, [D4]methanol):
δ = 8.14 (d, J = 2.0 Hz, 1 H), 7.78 (dd, J = 8.3, 2.0 Hz, 1 H), 7.53
(d, J = 8.3 Hz, 1 H), 7.52 (d, J = 5.7 Hz, 1 H), 4.30 (dt, J = 5.7,
1.7 Hz, 1 H), 3.75–3.63 (m, 2 H) ppm. 13C NMR (125 MHz, [D4]-
methanol): δ = 173.93, 144.45, 135.84, 133.39, 133.36, 133.29,
99.55 ppm. IR (ATR-Ge): ν
= 3180, 2924, 2791, 2719, 2370,
˜
max
2344, 2141, 1694, 1662, 1643, 1522, 1353, 1198, 1073, 868,
849 cm–1. MS: m/z (%) = 250.6 (100) [M + H]+, 89.3 (7), 73.3 (10).
HRMS: calcd. for C11H9BrNO [M + H]+ 249.9868; found
249.9865.
3-(3,4-Dichlorophenyl)-5-methylidene-2,5-dihydro-1H-pyrrol-2-one
(24f): Yellow solid (44 % yield); m.p. 125–126 °C. 1H NMR
(500 MHz, [D4]methanol): δ = 8.21 (d, J = 2.4 Hz, 1 H), 7.86 (dd,
J = 8.3, 2.0 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.47 (s, 1 H), 5.11
(s, 1 H), 5.04 (s, 1 H) ppm. 13C NMR (125 MHz, [D4]methanol): δ
= 172.26, 144.23, 133.90, 133.57, 132.41, 131.75, 131.68, 131.02,
131.53, 129.98, 127.87, 63.75, 60.83 ppm. IR (ATR-Ge): ν
=
˜
max
3490, 2926, 2877, 1697, 1622, 1466, 1358, 1229, 1070, 1028, 870,
833, 721 cm–1. MS: m/z (%) = 260 (2 37Cl, 100) [M + H]+, 258 (80)
[M + H]+. HRMS: calcd. for C11H10Cl2NO2 [M + H]+ 258.0089;
found 258.0088.
128.01, 130.13, 100.28 ppm. IR (ATR-Ge): ν
= 3272, 2928,
˜
max
3-(4-Methoxyphenyl)-5-methylidene-2,5-dihydro-1H-pyrrol-2-one
(24a) – Procedure H: Acetyl chloride (0.0082 mL, 0.115 mmol) was
added to a solution of TBS-protected alcohol 23a (0.035 g,
0.105 mmol) and triethylamine (0.016 mL, 0.115 mmol) in dry
THF (2 mL) at 0 °C, and the reaction mixture was stirred for 1 h.
The volatiles were removed by rotary evaporation, and the residue
1708, 1684, 1641, 1541, 1492, 1260, 1099, 793, 694 cm–1. MS: m/z
(%) = 240.5 (100) [M + H]+, 272.6 (78) [M + Na]+. HRMS: calcd.
for C11H8Cl2NO [M + H]+ 239.9984; found 239.9983.
Methyl 3-Phenoxy-2-(tritylamino)propanoate (29a): DEAD (40 wt.-
% in toluene, 6.63 mL, 15.2 mmol) was added dropwise to a solu-
Eur. J. Org. Chem. 2015, 5414–5423
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5421

M. Ghavre, M. Pour et al.
FULL PAPER
tion of methyl 3-hydroxy-2-(tritylamino)propanoate (5.00 g,
13.8 mmol), phenol (1.43 g, 15.2 mmol), and triphenylphosphine
(3.99 g, 15.2 mmol) in toluene (60 mL) at 0 °C under argon. The
reaction mixture was warmed to room temperature, stirred for 3 h,
and then diluted with ethyl acetate (100 mL). The organic layer
was washed with 1 n HCl (50 mL), a saturated NaHCO3 solution
(50 mL), and then brine (50 mL). The organic extract was concen-
trated by rotary evaporation, and the residue was purified by col-
umn chromatography (SiO2; EtOAc/hexanes, 20:80) to afford 29a
(4.78 g, 79% yield) as a colorless oil. [α]2D5 = 5.03 (c = 0.53, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.66–7.33 (m, 15 H), 7.28–6.98
(m, 5 H), 7.3 (m, 2 H), 4.36 (dd, J = 9.3, 4.9 Hz, 1 H), 4.14 (dd, J
= 9.3, 6.4 Hz, 1 H), 3.86 (s, 1 H), 3.31 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 173.39, 158.36, 145.63 (3 C), 129.33,
129.21, 128.65 (6 C), 127.79 (6 C), 127.55, 126.41 (3 C), 120.99,
–3.55 (c = 0.11, methanol). 1H NMR (500 MHz, CDCl3): δ = 7.29–
7.23 (m, 2 H), 6.88–6.81 (m, 2 H), 6.42 (d, J = 8.4 Hz, 1 H), 5.38
(dd, J = 8.3, 6.9 Hz, 1 H), 3.80 (s, 6 H), 1.5 (s, 18 H), 1.48 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.12,
159.43, 152.66, 137.35, 134.13, 129.59, 128.48, 113.72, 82.22, 55.25,
51.93, 50.78, 28.03, 28.00, 27.78, 19.22 ppm. IR (ATR-Ge): ν
=
˜
max
2979, 1698, 1513, 1367, 1345, 1249, 1172, 1122, 834 cm–1. MS: m/z
(%) = 336 (10) [M + H – Boc]+, 219.3 (100), 160.5 (16). HRMS:
calcd. for C23H33NO7Na [M + Na]+ 458.2157; found 458.2155.
Methyl (2Z)-4-{Bis[(tert-butoxy)carbonyl]amino}-2-phenylpent-2-
enoate (34b): Colorless oil (70% yield). [α]2D5 = –3.61 (c = 0.05,
1
methanol). H NMR (500 MHz, CDCl3): δ = 7.35–7.31 (m, 5 H),
6.50 (d, J = 8.3 Hz, 1 H), 5.44–5.39 (m, 1 H), 3.79 (s, 3 H), 1.49–
1.48 (s, 21 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.81,
152.62 (2 C), 139.22, 137.15, 134.57, 128.25 (2 C), 127.89, 127.30
(2 C), 82.24 (2 C), 51.90, 50.71, 27.99 (6 C), 18.10 ppm. IR (ATR-
114.54, 70.85, 70.23, 56.10, 51.74 ppm. IR (ATR-Ge): νmax = 2949,
˜
1734, 1599, 1492, 1448, 1243, 908, 732, 706 cm–1. HRMS: calcd.
for C29H28NO3 [M + H]+ 438.2069; found 438.2071.
Ge): ν
= 2980, 1699, 1435, 1368, 1345, 1234, 1165, 1123 cm–1.
˜
max
MS: m/z (%) = 235 (100), 218 (40), 189 (58), 157 (46), 128 (23).
HRMS: calcd. for C22H31NO6Na [M + Na]+ 428.2049; found
428.2055.
tert-Butyl [(S)-But-3-yn-2-yl]carbamate (30): Employing procedure
A afforded compound 30 (81% yield) as a white solid; m.p. 83–
84 °C. [α]2D5 = –59.13 (c = 0.023, CHCl3); ref.[32] [α]2D0 = –59.4 (c =
1
Methyl (2Z)-4-{Bis[(tert-butoxy)carbonyl]amino}-2-(4-bromophen-
yl)pent-2-enoate (34e): Colorless oil (77% yield). [α]2D5 = 10.83 (c =
0.14, ethanol). 1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J =
8.31 Hz, 2 H), 7.19 (d, J = 8.31 Hz, 2 H), 6.50 (d, J = 8.31 Hz, 1
H), 5.44–5.42 (m, 1 H), 3.79 (s, 3 H), 1.51–1.48 (m, 21 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 167.30, 152.66, 140.67, 136.30,
133.38, 131.40 (2 C), 129.16 (2 C), 122.10, 82.42 (2 C), 52.08, 50.69,
0.014, CHCl3). H NMR (500 MHz, CDCl3): δ = 4.79–4.63 (br. s,
1 H), 4.54–4.40 (br. s, 1 H), 2.24 (d, J = 2.3 Hz, 1 H), 1.44 (s, 9
H), 1.39 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 154.59, 84.53, 70.09, 38.24, 28.33, 22.53 ppm. IR (ATR-Ge):
ν
˜
= 3327, 2980, 1681, 1527, 1366, 1338, 1252, 1163 cm–1. MS:
max
m/z (%) = 129 (15), 70 (100). HRMS: calcd. for C9H15NO2Na [M
+ Na]+ 192.1000; found 192.1000.
28.05 (6 C), 27.80, 19.03 ppm. IR (ATR-Ge): ν
= 2979, 2936,
˜
max
tert-Butyl N-[(tert-Butoxy)carbonyl]-N-[(2S)-but-3-yn-2-yl]carb-
amate (31): Employing procedure B afforded compound 31 (79%
yield) as a white solid; m.p. 41–42 °C. [α]2D5 = –12.44 (c = 0.90,
methanol). 1H NMR (500 MHz, CDCl3): δ = 5.15 (dd, J = 7.0,
2.5 Hz, 1 H), 2.26 (d, J = 2.5 Hz, 1 H), 1.52 (d, J = 7.0 Hz, 3 H),
1.49 (s, 18 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 151.82,
1723, 1704, 1626, 1434, 1344, 1168, 1125, 828, 757 cm–1. MS: m/z
(%) = 269 (100), 239.6 (5). HRMS: calcd. for C22H30BrNO6Na [M
+ Na]+ 506.1154; found 506.1158.
(S)-3-(4-Methoxyphenyl)-5-methyl-1,5-dihydro-2H-pyrrol-2-one
(35a): Employing procedure F afforded compound 35a (63% yield)
as a white solid; m.p. 133–134 °C. [α]2D5 = 16.59 (c = 0.02, meth-
anol). 1H NMR (500 MHz, [D4]methanol): δ = 7.77 (d, J = 8.8 Hz,
2 H), 7.22 (d, J = 2.0 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H), 4.25 (dd,
J = 6.9, 2.1 Hz, 1 H), 3.80 (s, 3 H), 1.31 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 174.61, 161.34, 144.97, 136.20,
129.45, 125.56, 114.74, 55.69, 53.88, 18.88 ppm. IR (ATR-Ge):
82.92, 82.77, 70.42, 43.34, 27.96, 20.51 ppm. IR (ATR-Ge): ν
=
˜
max
3274, 2980, 1738, 1696, 1370, 1345, 1240, 1172, 1153, 1128 cm–1.
MS: m/z (%) = 189 (24), 158 (100), 129 (60), 96 (90). HRMS: calcd.
for C14H23NO4Na [M + Na]+ 292.1525; found 292.1524.
Methyl (4S)-4-{Bis[(tert-butoxy)carbonyl]amino}pent-2-ynoate (32):
Employing procedure C afforded compound 32 (89% yield) as a
colorless oil. [α]2D5 = –2.26 (c = 0.08, ethanol). 1H NMR (500 MHz,
CDCl3): δ = 5.39–5.27 (m, 1 H), 3.73 (s, 3 H), 1.55 (d, J = 7.3 Hz,
3 H), 1.50 (s, 18 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 153.74,
151.29, 87.08, 83.34, 74.14, 52.55, 43.12, 27.92, 19.87 ppm. IR
ν
= 3192, 2955, 1690, 1644, 1511, 1258, 1237, 1178, 1025,
˜
max
830 cm–1. MS: m/z (%) = 204.1 (100) [M + H]+, 96 (35). HRMS:
calcd. for C12H14NO2 [M + H]+ 204.1025; found 204.1027.
(S)-5-Methyl-3-phenyl-1,5-dihydro-2H-pyrrol-2-one (35b): Pale yel-
low solid (59% yield); m.p. 112–114 °C. [α]2D5 = 6.67 (c = 0.56, eth-
(ATR-Ge): ν
= 2981, 2245, 1748, 1719, 1604, 1369, 1255, 1154,
˜
max
1123 cm–1. MS: m/z (%) = 355.2 (100), 299.2 (20), 172.2 (18), 140.3
(22). HRMS: calcd. for C16H25NO6Na [M + Na]+ 350.1581; found
350.1580.
1
anol). H NMR (500 MHz, CDCl3): δ = 7.85–7.83 (m, 2 H), 7.40–
7.31 (m, 3 H), 7.15 (d, J = 2.0 Hz, 1 H), 6.78 (s, 1 H), 4.30 (dq, J
= 6.9, 1.7 Hz, 1 H), 1.37 (d, J = 7.3 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 172.40, 144.32, 135.92, 131.38, 128.53,
Methyl (2E,4S)-4-{Bis[(tert-butoxy)carbonyl]amino}-2-(tributyl-
stannyl)pent-2-enoate (33): Employing procedure D afforded com-
pound 33 (55% yield) as a colorless oil. [α]2D5 = 0.82 (c = 0.01,
128.44 (2 C), 127.12 (2 C), 52.29, 18.95 ppm. IR (ATR-Ge): ν
˜
max
= 3193, 2924, 1678, 1508, 1449, 1363, 1213, 869, 796, 695 cm–1.
MS: m/z (%) = 174.1 (100) [M + H]+, 96 (5). HRMS: calcd. for
C11H12NO [M + H]+ 174.0919; found 174.0922.
1
ethanol). H NMR (500 MHz, CDCl3): δ = 6.33 (d, J = 7.6 Hz, 1
H), 5.32–5.43 (m, 1 H), 3.68 (s, 3 H), 1.48 (s, 18 H), 1.46–0.86 (m,
27 H), 1.41 (d, J = 6.9 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.85, 152.41, 151.16, 136.39, 81.95 (2 C), 52.06,
51.16, 28.69 (3 C), 27.92 (6 C), 27.09 (3 C), 18.96, 13.54 (3 C),
(S)-3-(4-Bromophenyl)-5-methyl-1,5-dihydro-2H-pyrrol-2-one (35e):
Light yellow solid (67% yield). [α]2D5 = 7.49 (c = 0.01, methanol).
1H NMR (500 MHz, [D4]methanol): δ = 7.77 (d, J = 8.0 Hz, 2 H),
7.52 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 2.0 Hz, 1 H), 4.29 (dq, J =
7.1, 2.0 Hz, 1 H), 1.33 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 173.86, 147.62, 135.58, 132.54 (2 C), 132.17
10.21 (3 C) ppm. IR (ATR-Ge): ν
= 2957, 2932, 2872, 2855,
˜
max
1740, 1712, 1604, 1368, 1344, 1169, 1124 cm–1. MS: m/z (%) = 619.4
(10) [M + H]+, 386.3 (63), 330.4 (100).
Methyl (2Z)-4-{Bis[(tert-butoxy)carbonyl]amino}-2-(4-meth-
oxyphenyl)pent-2-enoate (34a): Employing procedure E afforded
(2 C), 129.96, 123.44, 54.11, 18.67 ppm. IR (ATR-Ge): νmax = 3192,
˜
2926, 1681, 1618, 1483, 1363, 1216, 1069, 1009, 872, 845 cm–1. MS:
compound 34a (80% yield) as a white solid; m.p. 78–79 °C. [α]2D5
=
m/z (%) = 253.9 (75) [M + 2]+, 252.0 (100), 229 (33), 97 (22).
5422
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5414–5423

Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
HRMS: calcd. for C11H11BrNO [M + H]+ 252.0024; found
252.0026.
[10] J. N. Hernández, M. A. Ramírez, V. S. Martín, J. Org. Chem.
2003, 68, 743–746.
[11] P. Garner, J. M. Park, Org. Synth. 1992, 70, 18–28.
[12] D. Bélanger, X. Tong, S. Soumaré, Y. L. Dory, Y. Zhao, Chem.
Eur. J. 2009, 15, 4428–4436.
[13] I. N. Michaelides, B. Darses, D. J. Dixon, Org. Lett. 2011, 13,
664–667.
Supporting Information (see footnote on the first page of this arti-
cle): General methods and NMR spectroscopic data.
[14] G. Reginato, A. Mordini, A. Capperucci, A. Degl’Innocenti, S.
Manganiello, Tetrahedron 1998, 54, 10217–10226.
[15] J. Pavlík, I. Snajdr, J. Kunesˇ, M. Spulák, M. Pour, J. Org. Chem.
2009, 74, 703–709.
[16] S. P. Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123,
9468–9469.
[17] We developed an intermediate (i.e., 3-iodo-5-substituted-1,5-di-
hydro-2H-pyrrol-2-one) that could be used as the electrophilic
halide in the coupling reaction. However, this compound was
prepared in poor yield.
Acknowledgments
ˇ
ˇ
This work was supported by the Czech Science Foundation (project
number 15-07332S). M. G. thanks the European Social Funds and
the State Budget of the Czech Republic (project number CZ.1.07/
2.3.00/30.0061). Graduate students (O. K. and J. K.) thank the
Charles University, Prague for the scholarship support (project
numbers GAUK 25510 and SVV 260183).
[18] G. Han, M. Tamaki, V. J. Hruby, J. Pept. Res. 2001, 58, 338–
[1] a) S. Zapf, T. Anke, O. Sterner, Acta Chem. Scand. 1995, 49,
233–234; b) D. K. J. Black, Bull. Chem. Soc. Jpn. 1966, 23,
1123–1127; c) T. Hiyama, H. Oishi, K. Nishide, H. Saimoto,
341.
[19] A. S. Ripka, R. S. Bohacek, D. H. Rich, Bioorg. Med. Chem.
Lett. 1998, 8, 357–360.
Bull. Chem. Soc. Jpn. 1987, 60, 2139–2150; d) J. Coombs, E. [20] a) M. Sakaitani, Y. Ohfune, Tetrahedron Lett. 1985, 26, 5543–
Lattmann, H. M. R. Hoffmann, Bioorg. Med. Chem. 1998, 9,
1367–1371.
5546; b) M. Sakaitani, Y. Ohfune, J. Org. Chem. 1990, 55, 870–
876.
[2] B. J. L. Royles, Chem. Rev. 1995, 95, 1981–2001.
[21] A. Kawai, O. Hara, Y. Hamada, T. Shioiri, Tetrahedron Lett.
1988, 29, 6331–6334.
ˇ
ˇ
[3] a) P. Senel, L. Tichotová, I. Votruba, V. Buchta, M. Spulák, J.
Kunesˇ, M. Nobilis, O. Krenk, M. Pour, Bioorg. Med. Chem.
[22] E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,
ˇ
2010, 18, 1988–2000; b) M. Pour, M. Spulák, V. Buchta, P.
6190–6191.
Kubanová, M. Voprsˇalová, V. Wsól, H. Fáková, P. Koudelka,
H. Pourová, R. Schiller, J. Med. Chem. 2001, 44, 2701–2706.
[4] a) K. C. Prousis, J. Markopoulos, V. Mckee, O. Igglessi-Marko-
poulou, Tetrahedron 2010, 66, 3944–3950; b) M. I. García-Ar-
anda, M. T. García-López, M. J. Pérez de Vega, R. González-
Muñiz, Tetrahedron Lett. 2014, 55, 2142–2145; c) M. Anwar,
A. R. Cowley, M. G. Moloney, Tetrahedron: Asymmetry 2010,
21, 1758–1770; d) A. A. Peshkov, V. A. Peshkov, Z. Li, O. P.
Pereshivko, E. V. Van der Eycken, Eur. J. Org. Chem. 2014,
6390–6393; e) S. Ke, Y. Zhang, W. Shu, Z. Zhang, L. Shi, Y.
Liang, K. Wang, Z. Yang, C. R. Chim. 2011, 14, 1071–1079; f)
C. A. Holloway, C. J. Matthews, Y. Jeong, M. G. Moloney,
C. F. Roberts, M. Yaqoob, Chem. Biol. Drug Des. 2011, 78,
[23] D. T. Hurst, A. G. McInnes, Can. J. Chem. 1965, 43, 2004–
2011.
[24] D. A. Evans, V. J. Cee, T. E. Smith, D. M. Fitch, P. S. Cho, An-
gew. Chem. Int. Ed. 2000, 39, 2533–2536; Angew. Chem. 2000,
112, 2633.
[25] H. Wallberg, M. H. Xu, G. Q. Lin, X. S. Lei, P. Sun, K. Parkes,
T. Johnson, B. Samuelsson, PCT Int. Patent Appl., WO
2007068474 A1 20070621, 2007.
[26] M. Sinha, V. R. Dola, A. Soni, P. Agarwal, K. Srivastava, W.
Haq, S. K. Puri, S. B. Katti, Bioorg. Med. Chem. 2014, 22,
5950–5960.
[27] R. C. F. Jones, L. E. Seager, M. R. J. Elsegood, Synlett 2011, 2,
211–214.
229–235; g) M. D. Andrews, A. G. Brewster, K. M. Crapnell, [28] H. D. Dickson, S. C. Smith, K. W. Hinkle, Tetrahedron Lett.
A. J. Ibbett, T. Jones, M. G. Moloney, K. Prout, D. Watkin, J.
Chem. Soc. Perkin Trans. 1 1998, 223–236; h) A. Basso, L.
Banfi, A. Galatini, G. Guanti, F. Rastrelli, R. Riva, Org. Lett.
2009, 11, 4068–4071; i) S. Pinheiro, R. C. da Silva Júnior, A. S.
de Souza, J. W. de M. Carneiro, E. M. F. Muri, O. A. C. An-
tunes, Tetrahedron Lett. 2009, 50, 2402–2404; j) J. T. Binder, B.
Crone, S. F. Kirsch, C. Liébert, H. Menz, Eur. J. Org. Chem.
2007, 1636–1647.
2004, 45, 5597–5599.
[29] a) G. A. Showell, M. J. Barnes, J. O. Daiss, J. S. Mills, J. G.
Montana, R. Tacke, J. B. H. Warneck, Bioorg. Med. Chem.
Lett. 2006, 16, 2555–2558; b) R. Tacke, F. Popp, B. Möller, B.
Theis, C. Burschka, A. Hamacher, M. U. Kassack, D. Schep-
mann, B. Wünsch, U. Jurva, E. Wellner, ChemMedChem 2008,
3, 152–164; c) D. Troegel, F. Möller, C. Burschka, R. Tacke,
Organometallics 2009, 28, 3218–3224; d) D. Troegel, F. Möller,
R. Tacke, J. Organomet. Chem. 2010, 695, 310–313; e) G. A.
Bikzhanova, I. S. Toulokhonova, S. Gately, R. West, Silicon
Chem. 2005, 3, 209–217.
[5] P. Anastas, J. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, New York, 1998, p. 30.
[6] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
[7] J. C. Gilbert, U. Weerasooriya, J. Org. Chem. 1982, 47, 1837–
1845.
[30] On the contrary, analogous 5-methylidene species in the furan-
2-one series were highly active, see ref.[3]
.
[8] A. Campbell Pinheiro, C. Roland Kaiser, C. M. N. Thais, S. A.
Carvalho, E. Ferreira da Silva, L. Feitosa, M. Henriques,
A. L. P. Candea, M. C. S. Lourenco, M. V. Nora de Souza, Me-
dicinal Chemistry 2011, 7, 611–623.
[9] K. A. Novachek, A. I. Meyers, Tetrahedron Lett. 1996, 37,
1743–1746.
[31] G. R. Pettit, S. B. Singh, M. R. Boyd, E. Hamel, R. K. Pettit,
J. M. Schmidt, F. Hogan, J. Med. Chem. 1995, 38, 1666–1672.
[32] H. D. Dickson, S. C. Smith, K. W. Hinkle, Tetrahedron Lett.
2004, 45, 5597–5599.
Received: May 13, 2015
Published Online: July 17, 2015
Eur. J. Org. Chem. 2015, 5414–5423
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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