Stereocontrolled one-step synthesis of difunctionalised cispentacin derivatives through ring-opening metathesis of norbornene β-amino acids

Article abstract of DOI:10.1002/ejoc.201403493

Through the ring-opening metathesis of norbornene or oxanorbornene β-amino acids with ethylene in the presence of certain Ru catalysts, a facile and convenient stereocontrolled one-step method was devised for the preparation of divinylated cispentacins an

Full text of DOI:10.1002/ejoc.201403493

FULL PAPER
DOI: 10.1002/ejoc.201403493
Stereocontrolled One-Step Synthesis of Difunctionalised Cispentacin
Derivatives through Ring-Opening Metathesis of Norbornene β-Amino Acids
[a]
[a]
[a]
[a,b]
˝
Loránd Kiss, Márton Kardos, Eniko Forró, and Ferenc Fülöp*
Keywords: Medicinal chemistry / Drug design / Amino acids / Peptidomimetics / Enantioselective synthesis / Metathesis /
Fused-ring systems
Through the ring-opening metathesis of norbornene or
oxanorbornene β-amino acids with ethylene in the presence
of certain Ru catalysts, a facile and convenient stereocon-
trolled one-step method was devised for the preparation of
scaffolds for peptide chemistry and for the synthesis of novel
functionalised materials through olefinic bond transforma-
tions. The ring-opening metathesis proceeds without affect-
ing the chiral centres of the starting molecules, so that their
divinylated cispentacins and oxacyclic cispentacin stereoiso- stereochemistry was conserved and determines the configu-
mers with four chiral centres. The products are interesting
ration of the chiral centres in the products.
functionalised derivatives, in pharmaceutical research (Fig-
ure 1). These compounds are of great significance as precur-
sors of β-lactams, as key elements of various bioactive
products, and as antitumoral, antibacterial, antiviral and
cardioprotective agents.[3a,3b] As conformationally rigid
building blocks, these small molecules are of appreciable
interest for the synthesis of peptides, and they therefore
have a considerable impact in the fields of biomolecules and
drug discovery.[3c–3f] Starting from acyclic alkenylated β-
amino acid stereoisomers, ring-closing metathesis (RCM)
has been used efficiently for the synthesis of cyclic β-amino
acids with a ring C–C double bond in their structure that
are otherwise difficult to access.[4] Moreover, π-π or CH-π
interactions play significant roles in the structural stabilisa-
tion of peptides, influencing their secondary structures,
strands and helices, and they have therefore found applica-
tions in medicinal chemistry.[5]
Introduction
Metathesis is one of the most useful transition-metal-cat-
alysed reactions for the creation of one or more C–C double
bonds in a molecule. Its variations have been utilised ef-
ficiently for the synthesis of various classes of compounds,
natural products, polymers and small biomolecules.[1]
A
number of amino acids and peptides have been synthesised
or modified and a series of other structural manipulations
have been achieved by applying cross-metathesis (CM) reac-
tions.[2] Conformationally restricted unusual, nonproteinog-
enic amino acids or oligopeptides containing an alkene
moieties play a crucial role in the construction of novel
“new-generation” peptides that exhibit improved stabilities
against enzymes or metabolic degradation. The carbon–car-
bon double-bond-linked cyclic oligopeptides may have sig-
nificant effects on helical structures, and may therefore play
an important role in influencing biological properties, and
consequently may have a considerable impact in drug re-
search.[2]
Cyclic β-amino acids have been a focus of interest of syn-
thetic and medicinal chemists over the past two decades due
to the increasing importance of such small molecules, for
example, (1R,2S)-2-aminocyclopentanecarboxylic acid (cis-
pentacin; 1), (1R,2S)-2-amino-4-methylenecyclopentane-
carboxylic acid (icofungipen; 2), BAY Y9379 (3), (2R,3S)-3-
aminooxetane-2-carboxylic acid (oxetin; 4) and some highly
Figure 1. Several bioactive β-amino acids.
The goal of the present work was to develop a stereocon-
trolled route to novel divinylated cispentacin stereoisomers,
which, because of the newly created olefinic bonds, are use-
ful precursors for further functionalisation. The Ru-cata-
lysed ring-opening metathesis (ROM) of di-exo- or di-endo-
norbornene β-amino acids allowed the stereocontrolled
preparation of a series of divinyl-substituted cispentacins,
which, with the exception of one isomer, were not accessible
by previously described methods (Schemes 1 and 2).[6]
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
6720 Szeged, Eötvös u. 6, Hungary
E-mail: fulop@pharm.u-szeged.hu
http://www.pharm.u-szeged.hu/gyki
[b] Stereochemistry Research Group of the Hungarian Academy of
Sciences, University of Szeged,
6720 Szeged, Eötvös u. 6, Hungary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403493.
Eur. J. Org. Chem. 2015, 1283–1289
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L. Kiss, M. Kardos, E. Forró, F. Fülöp
FULL PAPER
Scheme 1. Stereocontrolled synthesis of divinylated cispentacin derivative from norbornene β-amino esters through oxidative ring opening
and Wittig reaction.[6]
Scheme 2. Stereocontrolled synthesis of divinylated cispentacin de-
rivatives from norbornene β-amino esters through ROM.
Figure 2. Commercially available catalysts used in this work.
Results and Discussion
ROM is a convenient method for the synthesis of func- Notably, with G1 and HG1 catalyst, an amount of starting
tionalised olefins from cyclic or bicyclic unsaturated precur- material was also recovered. The configuration of the
sors.[1] The ROM of unsaturated bicyclic systems such as stereogenic centres in the product (Ϯ)-6 was predetermined
norbornene[7] or oxanorbornene derivatives[8] is a widely by the structure of the starting norbornene β-amino ester
and efficiently used method for the synthesis of novel fused, (Ϯ)-5. Compound (Ϯ)-6 was synthesised earlier in 30%
spiro or bridged systems or polycyclic (carbocyclic or overall yield from (Ϯ)-5 by OsO4-catalysed C–C double
heterocyclic) derivatives.
bond dihydroxylation, followed by NaIO4 oxidation by ring
We started our investigations into the synthesis of 3,5- cleavage and a Wittig reaction with triphenylmethyl-
difunctionalised cispentacins by reacting racemic di-exo- phosphonium bromide/tBuOK.[6a] Not only was the yield
norbornene N-benzoylated ethyl ester (Ϯ)-5[6a] with ethyl- of the ROM of (Ϯ)-5 to (Ϯ)-6 significantly higher in com-
ene in the presence of a number of commercially available parison with the oxidative ring-opening method,[6a] but the
common catalysts (Figure 2). The reactions were performed transformation could also be accomplished in one step in-
systematically in anhydrous CH2Cl2 under an Ar and ethyl- stead of three steps, without the use of large amounts of
ene atmosphere in the presence of Grubbs 1st generation solvents, silica gel, or toxic OsO4 and phosphorane.
(G1), Grubbs 2nd generation (G2), Hoveyda–Grubbs 1st
generation (HG1), and Hoveyda–Grubbs 2nd generation could not be prepared by a previously published method),[6]
(HG2) catalysts. a stereoisomer of (Ϯ)-6, was accessed from norbornene
A novel divinylated cispentacin derivative (Ϯ)-8 (which
During stirring of the mixture of (Ϯ)-5 and catalyst in amino ester (Ϯ)-7, which was obtained by epimerisation at
anhydrous CH2Cl2 at 20 °C for 2 h (reaction monitored by C-2 of di-exo-derivative (Ϯ)-5 in the presence of NaOEt in
TLC), the desired divinylated product (Ϯ)-6, in which the EtOH. The ROM was performed at room temperature with
two novel vinyl groups are trans with respect to the ester each catalyst, and afforded the corresponding disubstituted
and amide moieties, was isolated in moderate yields (33– cyclopentane β-amino ester (Ϯ)-8, with the ester and amide
41%) after separation from the accompanying polymeric groups in a trans relationship, in 20–80% isolated yields,
materials by column chromatography, with the best yield the highest yield being achieved with the HG1 catalyst
being attained with HG2 catalyst (Scheme 3 and Table 1). (Table 1).
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Synthesis of Difunctionalised Cispentacin Derivatives
Table 2. Isolated yields for compounds (Ϯ)-10 and (Ϯ)-12 in ROM
reactions with various catalysts.
Scheme 3. Stereocontrolled synthesis of divinylated cispentacin
stereoisomers (Ϯ)-6 and (Ϯ)-8.
Table 1. Isolated yields for compounds (Ϯ)-6 and (Ϯ)-8 in ROM
reactions with various catalysts.
rification from the polymeric materials formed; interest-
ingly, the best yield in this case was achieved with the G1
catalyst, however a quantity of starting material was also
recovered (Scheme 4, Table 2).
In view of the relevance of heteroatom-containing cyclic
β-amino acids and, in particular, O-containing derivatives
such as oxetin (4), we extended the synthesis to the prepara-
tion of O-heterocyclic counterparts. Thus, oxanorbornene
amino ester (Ϯ)-14[7e,9] derived from amino acid (Ϯ)-13 was
transformed under standard conditions into the N-benzoyl-
ated derivative (Ϯ)-15. O-Heterocyclic amino ester (Ϯ)-15
and its stereoisomer (Ϯ)-17 [prepared from (Ϯ)-15 by epi-
merisation with NaOEt] were then submitted to ROM reac-
tions in the presence of ethylene with different catalysts
(Figure 2). However, in contrast to their carbocyclic ana-
logues (Schemes 3 and 4), only the HG1 catalyst proved
suitable in these transformations, giving the corresponding
tetrahydrofuran β-amino ester stereoisomers (Ϯ)-16 and
(Ϯ)-18 in good yields after purification by column
chromatography (Scheme 5).
Racemic di-endo-norbornene β-amino ester (Ϯ)-9 was
then subjected to ROM with ethylene, with all four cata-
lysts, and gave the novel all-cis 3,5-divinyl-substituted cis-
pentacin derivative (Ϯ)-10, albeit in rather modest yields
(6–31%); the highest yield was obtained with the HG2 cata-
lyst (Scheme 4, Table 2).
We then set out to develop a functionalisation procedure
for the divinylated cispentacin derivative through a cross
metathesis (CM) reaction. Accordingly, we selected an α,β-
unsaturated ester, methyl acrylate, which was used as a CM
reaction partner in transformations with two stereoisomers
of divinylated cispentacin derivatives, (Ϯ)-8 and (Ϯ)-10.
The reactions were carried out with all four catalysts in
anhydrous CH2Cl2 heated to reflux under an Ar atmo-
sphere for 6 h; the best yields of the corresponding CM ad-
ducts (Ϯ)-19 and (Ϯ)-20 were attained in both cases with
the HG2 catalyst; only trace amounts of the target sub-
stances were formed with the other three catalysts (Fig-
ure 2). Given that (Ϯ)-20 was identical to the material pre-
pared earlier by an alternative route,[6b] it may be concluded
that the CM reaction proceeded with E selectivity; the con-
figuration of the newly created C–C double bonds in (Ϯ)-
Scheme 4. Stereocontrolled synthesis of divinylated cispentacin
stereoisomers (Ϯ)-10 and (Ϯ)-12.
The all-cis divinylated amino ester (Ϯ)-10 could not be 19 and (Ϯ)-20 involves E geometry (Scheme 6).
synthesised by oxidative ring opening and Wittig reaction
The above synthetic approach was adapted for access to
methodology.[6b] Epimerisation of di-endo-amino ester (Ϯ)- enantiomerically pure target substances. We present here a
9 led, through a change in the configuration, to amino ester synthetic route for the preparation of two optically pure
(Ϯ)-11, ring opening of which resulted in the new divinyl- products. Enantiomerically enriched forms of 6 and 8, for
ated cispentacin stereoisomer (Ϯ)-12 in 68% yield after pu- example, were synthesised from β-lactam enantiomer (+)-
Eur. J. Org. Chem. 2015, 1283–1289
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Kiss, M. Kardos, E. Forró, F. Fülöp
FULL PAPER
Scheme 5. Stereocontrolled synthesis of divinylated oxacispentacin stereoisomers (Ϯ)-16 and (Ϯ)-18.
Scheme 6. Synthesis of functionalised cispentacin derivatives (Ϯ)-19 and (Ϯ)-20 by CM.
21 with an enantiomeric excess (ee) value of Ͼ98%
(enantiomeric ratio, er 99:1), by enantioselective enzymatic
ring opening of racemic azetidinone (Ϯ)-21.[10] Lactam (+)-
21 was converted by ethanolysis through (+)-23, followed
by benzoylation into optically active ester (+)-5 (Scheme 7).
The er of this compound, determined by chiral HPLC
analysis (see the Experimental Section) was found to be
95:5.
Scheme 8. Synthesis of optically pure divinylated amino esters (+)-
6 and (–)-8.
Conclusions
A stereocontrolled, one-step method for the preparation
of stereoisomers of novel divinylated cispentacin derivatives
and oxacyclic cispentacins with multiple chiral centres from
di-exo- and di-endo-norbornene or oxanorbornene β-amino
acids has been developed by ROM. Since the stereocentres
are unaffected during the transformation, the configuration
Scheme 7. Synthesis of optically pure amino ester (+)-5.
Amino ester (+)-5, in the presence of ethylene and the of the stereogenic centres of the target molecules is pre-
HG1 catalyst, underwent ring opening to furnish divinyl- determined by the configuration of the chiral centres of the
ated cispentacin derivative (+)-6 (er = 95:5). Similar to the starting materials. Functionalisation of divinylated cispen-
racemates, epimerisation of (+)-5 provided (–)-7, ROM tacin derivatives with an unsaturated ester has been per-
transformation of which led to divinylated transpentacin formed by CM, giving highly functionalised derivatives
derivative (–)-8 (er = 95:5; Scheme 8).
with multiple stereocentres. Due to the olefinic bond in
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Synthesis of Difunctionalised Cispentacin Derivatives
DMSO): δ = 15.0, 36.4, 45.1, 46.2, 52.8, 54.1, 60.6, 116.3, 117.5,
127.9, 129.2, 132.1, 125.5, 139.2, 139.3, 166.9, 172.1 ppm. MS (ESI,
pos): m/z = 314 [M + 1]. C19H23NO3 (313.40): calcd. C 72.82, H
7.40, N 4.47; found C 72.51, H 7.72, N 4.12.
their structure, the divinylated cispentacin stereoisomers
may be regarded as valuable small molecule precursors for
further functionalisations, as demonstrated by a CM
example and for the construction of novel peptides contain-
ing π-bond systems.
Ethyl (1R*,2R*,3R*,4S*)-3-Benzamidobicyclo[2.2.1]hept-5-ene-2-
carboxylate (11): Yield 69% (560 mg); white solid; m.p. 107–
109 °C; Rf = 0.28 (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
[D6]DMSO): δ = 1.16 (t, J = 7.10 Hz, 3 H, CH3), 1.38–1.43 (m, 1
H, CH2), 1.67–1.72 (m, 1 H, CH2), 2.31–2.34 (m, 1 H, 1-H), 2.96–
2.99 (m, 1 H, 4-H), 3.17–3.20 (m, 1 H, 2-H), 4.06–4.14 (m, 2 H,
Experimental Section
General Procedure for the Ring-opening Metathesis Reaction: To a
solution of norbornene amino ester 5, 7, 9, 11, 15 or 17 (142 mg)
in anhydrous CH2Cl2 (15 mL), catalyst (5 mol-%) was added and
the mixture was stirred at 20 °C under an ethylene atmosphere for
2 h (reaction monitored by TLC). H2O (2 drops) was then added
and the mixture was concentrated under reduced pressure and puri-
fied by column chromatography on silica gel.
OCH2), 4.50–4.54 (m, 1 H, 3-H), 6.17–6.21 (dd, J1 = 2.5, J2
=
6.12 Hz, 1 H, 6-H), 5.42–5.47 (m, 1 H, 5-H), 7.40–7.52 (m, 3 H,
Ar-H), 7.73–7.77 (m, 2 H, Ar-H), 7.99 (br. s, 1 H, NH) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 15.0, 46.2, 46.3, 47.9, 50.7, 55.6,
61.0, 128.2, 129.0, 132.0, 135.1, 135.4, 138.9, 167.5, 174.8 ppm. MS
(ESI, pos): m/z = 286 [M + 1]. C17H19NO3 (285.34): calcd. C 71.56,
H 6.71, N 4.91; found C 71.90, H 6.40, N 4.58.
Ethyl
(1R*,2S*,3S*,5R*)-2-Benzamido-3,5-divinylcyclopentane-
carboxylate (6): Yield 33–41% (52–65 mg);[6a] white solid; m.p. 99–
101 °C; Rf = 0.52 (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 1.17 (t, J = 7.10 Hz, 3 H, CH3), 1.52–1.58 (m, 1 H,
CH2), 2.04–2.12 (m, 1 H, CH2), 2.77–2.82 (m, 1 H, 1-H), 2.96–3.11
(m, 2 H, 3-H and 5-H), 4.08–4.17 (m, 2 H, OCH2), 4.60–4.66 (m,
1 H, 2-H), 5.03–5.12 (m, 4 H, =CH), 5.80–5.89 (m, 2 H, =CH),
6.80 (br. s, 1 H, NH), 7.42–7.58 (m, 3 H, Ar-H), 7.78–7.83 (m, 2
H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.8, 40.0,
45.7, 48.6, 53.8, 56.8, 60.7, 115.5, 116.0, 128.2, 129.0, 131.9, 135.3,
140.5, 141.2, 167.0, 172.7 ppm. MS (ESI, pos): m/z = 314 [M + 1].
C19H23NO3 (313.40): calcd. C 72.82, H 7.40, N 4.47; found C
72.58, H 7.20, N 4.10.
Ethyl
(1R*,2R*,3S*,5R*)-2-Benzamido-3,5-divinylcyclopentane-
carboxylate (12): Yield 16–68% (25–107 mg); white solid; m.p. 69–
71 °C; Rf = 0.4 (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 1.24 (t, J = 7.15 Hz, 3 H, CH3), 1.62–1.67 (m, 1 H,
CH2), 2.31–2.36 (m, 1 H, CH2), 2.58–2.63 (m, 1 H, 1-H), 2.97–3.03
(m, 1 H, 3-H), 3.11–3.15 (m, 1 H, 5-H), 4.16–4.22 (m, 2 H, OCH2),
4.74–4.78 (m, 1 H, 2-H), 5.06–5.25 (m, 4 H, =CH), 5.82–5.87 (m,
2 H, =CH), 6.19 (br. s, 1 H, NH), 7.42–7.55 (m, 3 H, Ar-H), 7.72–
7.77 (m, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
15.0, 37.7, 46.4, 46.9, 55.6, 56.3, 60.9, 115.9, 116.5, 128.1, 129.1,
131.9, 135.5, 138.9, 140.7, 166.7, 174.2 ppm. MS (ESI, pos): m/z =
314 [M + 1]. C19H23NO3 (313.40): calcd. C 72.82, H 7.40, N 4.47;
found C 73.12, H 7.09, N 4.73.
Ethyl
(1R*,2S*,3S*,4S*)-3-Benzamidobicyclo[2.2.1]hept-5-ene-2-
carboxylate (7): Yield 78% (620 mg); white solid; m.p. 129–131 °C;
Rf = 0.25 (n-hexane/EtOAc, 3:1). H NMR (400 MHz, DMSO): δ
Ethyl (1R*,2S*,3R*,4S*)-3-Benzamido-7-oxabicyclo[2.2.1]hept-5-
ene-2-carboxylate (15): Yield 68% (330 mg); white solid; m.p. 117–
119 °C; Rf = 0.42 (n-hexane/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 1.21 (t, J = 7.10 Hz, 3 H, CH3), 2.86–2.90 (m, 1 H, 2-
H), 4.12–4.24 (m, 2 H, OCH2), 4.73–4.78 (m, 1 H, 3-H), 4.88–4.91
(dd, J1 = 8.15, J2 = 3.08 Hz, 1 H, 1-H), 5.19–5.22 (m, 1 H, 4-H),
6.57–6.61 (m, 2 H, 5-H and 6-H), 7.39 (br. s, 1 H, NH), 7.42–7.57
(m, 3 H, Ar-H), 7.77–7.82 (m, 2 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 14.7, 48.1, 52.4, 60.9, 80.4, 82.8, 128.1,
129.0, 132.1, 135.1, 136.4, 139.0, 167.2, 172.1 ppm. MS (ESI, pos):
m/z = 286 [M + 1]. C16H17NO4 (287.31): calcd. C 66.89, H 5.96,
N 4.88; found C 66.50, H 5.61, N 5.14.
1
= 1.19 (t, J = 7.10 Hz, 3 H, CH3), 1.48–1.52 (m, 1 H, CH2), 1.77–
1.81 (m, 1 H, CH2), 2.74–2.77 (m, 1 H, 1-H), 3.07–3.11 (m, 2 H,
2-H and 4-H), 3.95–4.08 (m, 3 H, OCH2, 3-H), 6.04–6.10 (m, 1 H,
6-H), 6.27–6.31 (m, 1 H, 5-H), 7.46–7.54 (m, 3 H, Ar-H), 7.82–
7.86 (m, 2 H, Ar-H), 8.46 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 15.0, 45.3, 47.4, 49.5, 50.4, 54.7, 60.8,
128.2, 129.0, 132.0, 135.4, 136.3, 137.2, 137.2, 173.4 ppm. MS (ESI,
pos): m/z = 286 [M + 1]. C17H19NO3 (285.34): calcd. C 71.56, H
6.71, N 4.91; found C 71.20, H 6.99, N 4.56.
Ethyl (1S*,2S*,3S*,5R*)-2-Benzamido-3,5-divinylcyclopentanecarb-
oxylate (8): Yield 20–80% (32–127 mg); white solid; m.p. 114–
116 °C Rf = 0.36 (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 1.25 (t, J = 7.15 Hz, 3 H, CH3), 1.69–1.77 (m, 1 H,
CH2), 2.03–2.08 (m, 1 H, CH2), 2.74–2.79 (m, 1 H, 5-H), 3.04–3.09
(m, 1 H, 3-H), 3.10–3.15 (m, 1 H, 1-H), 4.06–4.13 (m, 2 H, OCH2),
4.42–4.49 (m, 1 H, 2-H), 4.98–5.20 (m, 4 H, =CH), 5.67–5.76 (m,
2 H, =CH), 6.18 (br. s, 1 H, NH), 7.47–7.55 (m, 3 H, Ar-H), 7.74–
7.77 (m, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
15.1, 37.0, 44.4, 49.4, 54.4, 58.5, 60.6, 116.0, 116.7, 128.1, 129.1,
132.0, 135.3, 139.0, 140.4, 166.7, 173.5 ppm. MS (ESI, pos): m/z =
314 [M + 1]. C19H23NO3 (313.40): calcd. C 72.82, H 7.40, N 4.47;
found C 72.50, H 7.11, N 4.11.
Ethyl (2R*,3S*,4R*,5S*)-4-Benzamido-2,5-divinyltetrahydrofuran-
3-carboxylate (16): Yield 79% (123 mg); white solid; m.p. 98–
100 °C; Rf = 0.5 (n-hexane/EtOAc, 2:1). 1H NMR (400 MHz,
CDCl3): δ = 1.25 (t, J = 7.15 Hz, 3 H, CH3), 3.14–3.18 (m, 1 H, 3-
H), 4.16–4.23 (m, 2 H, OCH2), 4.44–4.48 (m, 1 H, 2-H), 4.72–4.77
(m, 2 H, 5-H, 4-H), 5.27–5.32 (m, 2 H, =CH), 5.41–5.49 (m, 2 H,
=CH), 5.96–6.04 (m, 2 H, =CH), 7.12 (br. s, 1 H), 7.45–7.56 (m, 3
H, Ar-H), 7.79–7.83 (m, 2 H, Ar-H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 14.7, 53.7, 57.2, 61.1, 81.3, 83.1, 117.8, 117.9,
128.2, 129.0, 132.2, 135.0, 137.6, 138.0, 168.0, 172.2 ppm. MS (ESI,
pos): m/z = 314 [M + 1]. C18H21NO4 (315.37): calcd. C 68.55, H
6.71, N 4.44; found C 68.20, H 6.39, N 4.10.
Ethyl
(1S*,2R*,3S*,5R*)-2-Benzamido-3,5-divinylcyclopentane- Ethyl (1R*,2R*,3R*,4S*)-3-Benzamido-7-oxabicyclo[2.2.1]hept-5-
carboxylate (10): Yield 6–31% (10–50 mg); colourless oil; Rf = 0.53
ene-2-carboxylate (17): Yield 48% (310 mg); white solid;; m.p. 118–
(n-hexane/EtOAc, 3:1). 1H NMR (400 MHz, [D6]DMSO): δ = 1.17
120 °C Rf = 0.44 (n-hexane/EtOAc, 1:1). 1H NMR (400 MHz,
(t, J = 7.10 Hz, 3 H, CH3), 1.82–1.97 (m, 2 H, CH2), 2.91–3.00 (2 CDCl3): δ = 1.27 (t, J = 7.15 Hz, 3 H, CH3), 2.89–2.93 (m, 1 H, 2-
H, 3-H and 5-H), 3.27–3.32 (m, 1 H, 1-H), 3.97–4.08 (m, 2 H, H), 4.14–4.20 (m, 2 H, OCH2), 4.58–4.63 (m, 1 H, 3-H), 4.93–4.96
OCH2), 4.81–4.88 (m, 1 H, 2-H), 5.01–5.19 (m, 4 H, =CH), 5.79– (dd, J1 = 8.15, J2 = 3.18 Hz, 1 H, 1-H), 5.22–5.25 (m, 1 H, 4-H),
6.02 (m, 2 H, =CH), 7.29 (br. s, 1 H, NH), 7.48–7.59 (m, 3 H, Ar- 6.39 (br. s, 1 H, NH), 6.47–6.50 (m, 1 H, 5-H), 5.56–5.59 (m, 1 H,
H), 7.68–7.74 (m, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]-
6-H), 7.49–7.56 (m, 3 H, Ar-H), 7.80–7.84 (m, 2 H, Ar-H) ppm.
Eur. J. Org. Chem. 2015, 1283–1289
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Kiss, M. Kardos, E. Forró, F. Fülöp
FULL PAPER
13C NMR (100 MHz, [D6]DMSO): δ = 14.9, 49.9, 64.8, 61.2, 78.8,
85.1, 128.5, 128.8, 132.2, 134.8, 136.3, 136.7, 167.5, 171.2 ppm. MS
(ESI, pos): m/z = 288 [M + 1]. C16H17NO4 (287.31): calcd. C 66.89,
H 5.96, N 4.88; found C 66.51, H 6.30, N 4.53.
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Ethyl (2R*,3R*,4R*,5S*)-4-Benzamido-2,5-divinyltetrahydrofuran-
3-carboxylate (18): Yield 68% (106 mg); white solid; m.p. 128–
130 °C; Rf = 0.3 (n-hexane/EtOAc, 2:1). 1H NMR (400 MHz, [D6]-
DMSO): δ = 1.18 (t, J = 7.15 Hz, 3 H, CH3), 3.42–3.46 (m, 1 H,
3-H), 3.99–4.11 (m, 2 H, OCH2), 4.21–4.28 (m, 1 H, 4-H), 4.52–
4.57 (m, 1 H, 2-H), 4.63–4.67 (m, 1 H, 5-H), 5.14–5.19 (m, 2 H,
=CH), 5.30–5.36 (m, 2 H, =CH), 5.74–5.79 (m, 1 H, =CH), 5.91–
5.98 (m, 1 H, =CH), 7.44–7.53 (m, 3 H, Ar-H), 7.84–7.91 (m, 2 H,
Ar-H), 8.62 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 15.0, 54.9, 58.1, 61.1, 80.1, 83.6, 118.2, 118.6, 128.1,
129.1, 129.3, 132.3, 135.6, 137.2, 169.5, 171.4 ppm. MS (ESI, pos):
m/z = 314 [M + 1]. C18H21NO4 (315.37): calcd. C 68.55, H 6.71,
N 4.44; found C 68.19, H 6.37, N 4.79.
(2E,2ЈE)-Dimethyl
3,3Ј-[(1R*,3S*,4S*,5S*)-4-Benzamido-5-(eth-
oxycarbonyl)cyclopentane-1,3-diyl]diacrylate (19): Yield 51%
(42 mg); white solid; m.p. 78–80 °C; Rf = 0.47 (n-hexane/EtOAc,
1
1:1). H NMR (400 MHz, [D6]DMSO): δ = 1.16 (t, J = 7.15 Hz, 3
H, CH3), 1.58–1.64 (m, 1 H, CH2), 2.03–2.10 (m, 1 H, CH2), 2.97–
3.03 (m, 1 H, 5-H), 3.21–3.35 (m, 1 H, 1-H), 3.38–3.44 (m, 1 H, 3-
H), 3.61 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 3.93–4.09 (m, 2 H,
OCH2), 4.50–4.57 (m, 1 H, 4-H), 5.86–5.94 (m, 2 H, =CH), 6.85–
6.90 (m, 1 H, =CH), 6.94–7.00 (m, 1 H, =CH), 7.45–7.58 (m, 3 H,
Ar-H), 7.80–7.86 (m, 2 H, Ar-H), 8.61 (br. s, 1 H, NH) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 14.9, 35.8, 42.5, 47.8, 52.1, 52.2,
54.1, 58.1, 61.0, 121.8, 122.3, 128.1, 129.1, 132.2, 134.9, 148.7,
150.1, 166.6, 166.7, 166.9, 172.9 ppm. MS (ESI, pos): m/z = 430
[M + 1]. C23H27NO7 (429.47): calcd. C 64.32, H 6.34, N 3.26; found
C 64.01, H 6.02, N 2.88.
Characterisation of the Enantiomers: All the NMR spectra recorded
for the enantiomeric substances were the same as for the corre-
sponding racemic materials.
The er values were determined by HPLC [Chiralpack IA column;
n-hexane/IPA (90:10); flow rate: 0.5 mL/min; detection at 260 nm].
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Ethyl (1S,2S,3R,4R)-3-Benzamidobicyclo[2.2.1]hept-5-ene-2-carb-
oxylate [(+)-5]:[6a] Yield 83%; white solid; [α]2D5 = +50.4 (c = 0.5,
EtOH); Rt = 18.30 min (antipode: 19.64).
Ethyl (1S,2R,3R,5S)-2-Benzamido-3,5-divinylcyclopentanecarboxyl-
ate [(+)-6]:[6a] Yield 39%; white solid; [α]2D5 = +48.5 (c = 0.5, EtOH);
Rt = 12.24 min (antipode: 10.57).
Ethyl (1S,2R,3R,4R)-3-Benzamidobicyclo[2.2.1]hept-5-ene-2-carb-
oxylate [(–)-7]: Yield 65%;white solid; [α]2D5 = –102.7 (c = 0.5,
EtOH); Rt = 12.37 min (antipode: 17.98).
Ethyl (1R,2R,3R,5S)-2-Benzamido-3,5-divinylcyclopentanecarboxyl-
ate [(–)-8]: Yield 64%; white solid; [α]2D5 = –22.5 (c = 0.5, EtOH);
Rt = 25.17 min (antipode: 22.69).
Acknowledgments
The authors are grateful to the Hungarian Research Foundation
(OTKA) (grant numbers K100530, K108943, NK81371 and
TÁMOP-4.2.2.A-11/1/KONV-2012-0035) for financial support.
This work was further supported by the Hungarian Academy of
Sciences (János Bolyai Research Scholarship to L. K.).
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Received: November 19, 2014
Published Online: January 9, 2015
Eur. J. Org. Chem. 2015, 1283–1289
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