Synthesis and solid state conformation of phenylalanine mimetics constrained in a proline-like conformation.

Article abstract of DOI:10.1039/b406450j

We present the synthesis of five- and six-membered cyclic phenylalanine mimics (1, 9, 16 and 17) that are constrained in a proline-like conformation. The five-membered mimetic 16 was prepared by Ring Closing Metathesis (RCM) of diene 15, itself prepared b

Full text of DOI:10.1039/b406450j

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A R T I C L E
Synthesis and solid state conformation of phenylalanine mimetics
constrained in a proline-like conformation
James Gardiner and Andrew D. Abell*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand.
E-mail: andrew.abell@canterbury.ac.nz; Fax: +64-3-3642110; Tel: +64-3-3642818
Received 29th April 2004, Accepted 11th June 2004
First published as an Advance Article on the web 27th July 2004
We present the synthesis of five- and six-membered cyclic phenylalanine mimics (1, 9, 16, and 17) that are constrained in
a proline-like conformation. The five-membered mimetic 16 was prepared by Ring Closing Metathesis (RCM) of diene
15, itself prepared by -benzylation of the L-methionine derived oxazolidinone 10, followed by oxidative elimination,
ring hydrolysis and N-allylation. The six-membered mimetic 1 was prepared by allylating the L-phenylalanine-derived
oxazolidinone 5, followed by hydrolysis, N-allylation and RCM. Olefins 1 and 16 were catalytically hydrogenated to
give 9 and 17, respectively. The solid state structures of 9 and 16 were determined by X-ray crystallography and their
conformations compared with that of 1.
We envisage that a range of mimetics B could be prepared by
Introduction
Ring Closing Metathesis (RCM) of dienes of type A, as depicted
in Scheme 1. In this paper, we report full details for the synthesis
of the six-membered mimetic 1 (Scheme 2) and further examples
(Scheme 3) of this important class of amino acid mimetic, in
particular the five-membered -substituted dehydroproline-based
mimetic 16 and the saturated analogues 9 and 17. A benzyl sub-
stituent was incorporated at the -position of 16 to allow detailed
comparison of its X-ray structure (as reported here, Fig. 3) with that
of 1, although as with the synthesis of 1, the synthetic methodology
lends itself well to the incorporation of a variety of substituents at
this position. We also present an X-ray structure analysis of 9 and a
comparison of its solid-state conformation with that of 1 and 16.
The introduction of an unnatural amino acid(s) into a key position(s)
in the primary sequence of a peptide or protein allows modification
of its biological properties in a controllable way. The result of such
a modification is to alter the spatial arrangement of key groups on
the peptide backbone. This then defines, or modifies, a key binding
domain that can interact with a biological receptor, or enzyme, to
elicit a biological response. Conformationally constrained amino
acid mimics have found widespread use in this context.1
In a previous communication we reported the synthesis and
X-ray crystal structure of a configurationally and conformation-
ally well-defined 1,2,3,6-tetrahydropyridine-based phenylalanine
mimetic 1.2 This derivative was the first rational example of a new
and important class of mimetic of general structure B (Scheme 1)
in which the constituent amino acid (phenylalanine in the case of
1) is constrained in a proline-like conformation. A combination of
an amino acid with a proline N–C cyclisation provides a useful
medicinal and biochemical tool since proline, and its derivatives,
are known to play a key role in the stabilisation of secondary protein
structure.1 The extra substitution in B, relative to proline, expands
the possibilities of generating secondary structure in oligomers de-
rived from them, e.g. through – stacking and other noncovalent
interactions. We initially chose to incorporate a benzyl group at the
-position as in 1 to mimic the side-chain of phenylalanine for this
exact reason, and because it is commonly found at the P1 subsite of
many proteases that we have an interest in inhibiting.3 [Note the use
of Schechter–Berger nomenclature4 – the residues on the N-terminal
side of the peptide bond that is cleaved are denoted (in order) P1–Pn,
and those on the C-terminus are denoted P1′–Pn′. In turn, the corre-
sponding subsites on the enzyme are denoted Sn–Sn′].
Results and discussion
The synthesis of the dehydroproline mimic 16 (Scheme 3) is based
on our method reported in a preliminary communication for the
preparation of 1 (Scheme 2).2 Here, a diastereoselective allylation
of the phenylalanine-derived oxazolidinone 55 gave 6, which was
hydrolysed to give 7. Allylation on the amide nitrogen gave diene
8, and this was finally cyclised on treatment with catalyst 2 (Fig. 1)
to give 1. The ee of the N-protected -allyl phenylalanine 7, an
important intermediate here and in several other syntheses,6 was
shown to be >95%.7 The synthesis of the dehydroproline mimic
16 (Scheme 3) required a somewhat more difficult stereospecific
incorporation of a vinyl group, rather than the allyl group of the
six-membered series (refer step (i) Scheme 2), at the -position of
phenylalanine. To achieve this we chose to use the methylsulfanyl-
ethyl side-chain of L-methionine as a masked vinyl group and to
then benzylate at the -position in what is effectively the reverse of
the sequence used in the preparation of 1. A consequence of this ap-
proach is that the absolute configurations of 16 and 1 are opposite.
Of course both stereochemistries are potentially available in each
case by using either the D or L starting amino acid.
Hence, L-methionine was reacted with benzaldehyde and benzoyl
chloride to give the diastereomerically pure trans oxazolidinone 10
in 63% overall yield after chromatography.5 Literature8 suggested
Fig. 1 RCM catalysts.
Scheme 1 RCM approach to -substituted cyclic amino acid mimics.
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0
2 3 6 5

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Scheme 2 Reagents and conditions: (i) LiHMDS, THF, −78 °C then allyl
bromide, 93%; (ii) NaOH, MeOH, reflux then CH2N2, 0 °C, 91%; (iii) NaH,
allyl bromide, DMF, 0 °C, 31%; (iv) 2, benzene, reflux, 94%; (v) H2, pal-
ladium-on-carbon, MeOH, rt, 95%.
that the next step, i.e. deprotonation of the methionine-derived
oxazolidinone 10 at C4, should be achievable using a sterically
non-hindered base such as LDA or LDEA. However, these condi-
tions proved problematic in our case. Treatment of 10 with n-butyl
lithium and pyrrolidine at −50 °C,9 followed by benzylation of the
resultant enolate from the face opposite the C2 phenyl group did,
however, give 11 as a single diastereoisomer in 61% yield after
chromatography. To our knowledge this is the first example of
the use of a pyrrolidine-based base to generate lithium enolates
of amino acid-based oxazolidinones. A by-product (18) was also
isolated from this reaction in 23% yield.
With the key alkylated oxazolidinone 11 in hand we carried out
an oxidation of its methionine side chain with hydrogen peroxide in
acetic acid to give the sulfoxide, which was followed by a thermal
elimination at 200 °C in a sealed tube10 to give the vinyl oxazolidi-
none 12 in 86% yield over two steps.An X-ray crystal structure of 12
was determined (Fig. 2) to confirm the stereochemical outcome of
the alkylation reaction depicted in Scheme 3 step (ii). The absolute
configuration of 12 follows from the absolute configuration of 10,
which is defined by that of the starting amino acid, L-methionine.5
The vinyl oxazolidinone 12 was next hydrolysed with aqueous so-
dium hydroxide to give the acid 13, and this was esterified to give
methyl ester 14 in 99% yield over two steps. Deprotonation of 14
with sodium hydride in dimethylformamide at 0 °C, followed by the
addition of allyl bromide, gave diene 15 in 31% yield after purifica-
tion. A further 51% of 14 was also recovered and recycled to obtain
more diene. Finally, diene 15 was heated at reflux, in the presence
of catalyst 4, to give the dehydroproline mimic 16 as a white crys-
talline solid in 94% yield after chromatography.11 Recrystallisation
of 16 from ethyl acetate/petroleum ether gave crystals suitable for
X-ray analysis. Hydrogenation of 16 in the presence of palladium-
on-carbon under a hydrogen atmosphere, gave the saturated proline-
based mimic 17 in 95% yield after purification. Attempts to obtain
crystals of 17 suitable for X-ray analysis were unsuccessful.
Scheme 3 Reagents and conditions: (i) (a) NaOH, (b) PhCHO, CH2Cl2,
reflux, (c) PhCOCl, CH2Cl2, 0 °C to rt, 63% over 3 steps; (ii) pyrrolidine,
n-BuLi, benzyl bromide, THF, −50 °C, 61%; (iii) (a) H2O2, acetic acid,
94%, (b) xylene, 200 °C sealed tube, 93%; (iv) NaOH, MeOH, reflux, 99%;
(v) CH2N2, Et2O, 0 °C, 100%; (vi) NaH, allyl bromide, DMF, 0 °C, 31%,
51% recovered starting material; (vii) 4, benzene, reflux, 94%; (viii) H2,
palladium-on-carbon, MeOH, rt, 95%.
mational restriction with the N–C peptide backbone torsions 
(defined by C8–N–C3–C2, see Table 1) being +38.7(2)°/+40.2(2)°
and −47.7(3)°, respectively. In both cases the benzoyl and benzyl
groups are anti, despite differences in the conformation of the ring
in each mimic. It is interesting to note that the sign and magnitude of
X-ray structure analysis
With the solid-state structures of 1, 9 and 16 in hand a confor-
mational comparison could now be made (Fig. 3 and Table 1).
The six-membered rings of 12 and 9 impact significant confor-
Fig. 2 X-ray crystal structure of 4-vinyl-oxazolidinone 12.
2 3 6 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0

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Table 1 Key torsion angles for compounds 1, 9 and 16. See Fig. 3 for
crystallographic numbering scheme
0.0365Å. Slight pyramidalisation of nitrogen was observed, with
the bond angles at N summing to 358.55°, and the benzoyl group
deviating from the plane of the pyrrolidine ring. Minimal twisting of
the amide bond was observed, with a  torsion angle of −0.79(19)°,
compared with +0.3(4)° for 9 and −4.33/−5.99° for 1 (Table 1).
Acomparison of the solid state structures of 16 and 1 reveals that,
while the two mimics possess opposite stereochemistry at C3 (crys-
tallographic numbering) both have a positive  torsion angle about
the N–C bond, and hence have the same ‘conformational sense’
(Fig. 3). It would be interesting to see if the ‘conformational sense’
of 17 is opposite to 16 as was the case for 1 and 9, but unfortunately
we were unable to grow suitable crystals of 17 for X-ray analysis.
No.
C8–N–C3–C2
N–C3–C2–O2
O8–C8–N–C3



1
9
+38.7/+40.2
−47.7
−137.48
+145.3
−5.99/−4.43
+0.3
Conclusion
16
+52.86
−138.36
−0.79
In summary, we present for the first time a synthesis of the opti-
cally active five-membered cyclic phenylalanine mimic (16) that is
constrained in a proline-like conformation. The synthetic sequence
utilises a combination of Grubbs’RCM chemistry to form the cycle,
Seebach oxazolidinone chemistry to introduce an -benzyl group
with control of absolute configuration, and a methionine side chain
to provide a masked vinyl group. The methodology is amenable to
incorporation of a range of groups at the -position15 and control of
the absolute configuration by starting with either a D or L amino acid
and the nature of the N-protecting group used in the oxazolidinone
preparation.15 A comparison of the structures of the five-membered
mimetic 16, with the six-membered mimic 1, reveals that, while the
two mimics possess opposite configurations at C3, both have the
same ‘conformational sense’ (Fig. 3).
Hydrogenation of 1 and 16 gave the saturated piperidine and
proline analogues 9 and 17, respectively. The solid-state conforma-
tion of 9 showed that the N–C bond had undergone an inversion
or ‘conformational flip’ relative to its precursor 1, as revealed by
the opposite sign of the respective  torsion angles as defined in
Table 1. Thus, peptidomimetics incorporating either 1 or 9 could,
conceivably, adopt significantly different conformations. This
reinforces the idea that control of conformation is critical to the
design and synthesis of peptidomimetics. It also highlights an abil-
ity to induce a significant conformational change by means of a
small chemical manipulation that does not effect configuration i.e.
the configuration of a compound does not necessarily define its
conformation.
the peptide backbone torsion angles () of 1 [+38.7(2)°/+40.2(2)°]
and its saturated analogue 9 [−47.7(3)°], reflect a ‘conformational
flip’of almost 90° clockwise rotation about the N–C bond (Fig. 3).
This is despite the fact that both 1 and 9 have the same absolute con-
figuration. It is also worth noting that the ring atoms of 9, denoted
by N–C3–C4–C5–C6–C7, adopt a distinct boat conformation and
the  torsion angle for 9, as defined by N–C3–C2–O2 (Table 1),
is +145.3, with the adjacent torsion angles defined by N–C3–C2–
O1 and C8–N–C3–C15 being −40.0(3)° and +71.4(3)° respectively.
In addition, ‘twisting’ was not observed about the amide bond of
9 – the  torsion, defined by O8–C8–N–C3 (Table 1), is +0.3(4)°
compared with −4.33 / −5.99° for 1 – and no significant pyramida-
lisation of the amide nitrogen of 9 was evident with the angles at N
summing to 359.5°.
An analysis of the X-ray structure of the five-membered ring
mimic 16 reveals that it adopts a similar geometry to that of 1 and 9.
The  torsion angle for 16 (see Table 1) is +52.86(13)°, a value sig-
nificantly shorter than that for proline,13,14 but longer than that of the
six-membered mimics 1 and 9 (+38.7(2)/+40.2(2)° and −47.7(3)°
respectively). The  torsion angle for 16 is −138.36(13)° (see
Table 1), with the adjacent torsion angles defined by N–C3–C2–O1
and C8–N–C3–C15 having values of +44.99(14)° and −68.67(15)°
respectively. The dehydroproline ring of 16, defined by N–C3–C4–
C5–C6, adopts an essentially planar conformation, with N deviat-
ing from the least squares plane defined by the other 4 atoms by
Fig. 3 X-Ray crystal structures for 1, 9 and 16 with perspective drawings (below) looking along the N–C bond indicating the respective  torsion angles
defined by C8–N–C3–C2 (the benzoyl phenyl rings have been omitted for clarity).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0
2 3 6 7

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give (+)-9 as a white solid (21 mg, 92%).An analytical sample and a
crystal suitable for X-ray crystallography were obtained by the dif-
fusion of petroleum ether into a solution of (+)-9 dissolved in ethyl
acetate. Mp 100–102 °C; []20D = +163.0°, c = 1.0 CHCl3; max cm−1
Experimental
Proton NMR spectra were recorded on a Varian 500 MHz NMR
spectrometer. Carbon NMR spectra were recorded on a Varian
300 MHz NMR spectrometer operating at 75 MHz. Melting points
were measured on a Gallenkamp electrothermal melting point ap-
paratus. Infrared spectra were obtained using a Shimadzu 8201PC
series FTIR interfaced with an Intel 486 PC operating Shimadzu’s
HyperIR software. Mass spectrometry data were detected on Kratos
MS80 RFA and Micromass LCT TOF mass spectrometers. Optical
rotations were measured on a Perkin Elmer polarimeter Model 341.
All solvents were dried and freshly distilled prior to use. Dry de-
gassed solvents were obtained by means of multiple freeze-pump-
thaw cycles.
1
2949, 1736, 1630; H NMR (CDCl3)  1.35 (m, 1H, CH), 1.61
(m, 2H, CH2), 1.75 (m, 2H, CCHa and CH), 2.15 (m, 1H, CCHb),
2.34 (m, 1H, NCHa), 3.05 (d J = 13.7 Hz, 1H, PhCHa), 3.29 (m,
1H, NCHb), 3.81 (s, 3H, OMe), 4.05 (d J = 13.7 Hz, 1H, PhCHb),
7.24–7.40 (m, 10H, PhH); 13C NMR (CDCl3)  15.7, 21.3, 28.9,
39.0, 43.3, 52.2, 63.8, 126.6, 127.9, 128.3, 129.4, 131.1, 136.7,
136.8, 171.4, 173.5; HRMS calcd for C21H23NO3 (M) 337.1678,
found 337.1675.
(2R,4R)-3-Benzoyl-4-benzyl-4-(2-methylsulfanyl-ethyl)-2-
phenyl-oxazolidin-5-one, (+)-11 and (3S)-N-[3-methylsulfanyl-
1-(pyrrolidine-1-carbonyl)-propyl]-benzamide 18
(2R)-1-Benzoyl-2-benzyl-1,2,3,6-tetrahydro-pyridine-2-
carboxylic acid methyl ester (+)-12
n-Butyl lithium (4.045 mL of a 2 M solution in THF, 8.07 mmol,
1.1 eq.) was added to a −50 °C solution of pyrrolidine (0.614 mL,
7.33 mmol, 1 eq.) in dry THF (5 mL) under argon, and the solu-
tion was stirred at −20 °C for 30 min. The mixture was recooled
to −50 °C and a solution of oxazolidinone (+)-105 (2.5 g, 7.33 mmol,
1 eq.) in dry THF (15 mL) added slowly. The mixture was stirred
at −50 °C for 20 min whereupon benzyl bromide (1.311 mL,
11.02 mmol, 1.5 eq.) was added slowly and the reaction mixture
stirred at −50 °C for 1 h, then warmed to rt overnight. The dark yel-
low solution was quenched with saturated aqueous NH4Cl solution
(10 mL) and the aqueous layer extracted with ether (3 × 20 mL).
The ether extracts were combined and washed with water (20 mL),
dried (MgSO4), and the solvent removed under reduced pressure.
Purification by radial chromatography (ethyl acetate/petroleum
ether 1:9) gave a fraction containing (+)-11 (1.925 g, 61%) as a
white solid. Further elution (ethyl acetate/petroleum ether 1:1) gave
a fraction containing 18 as a white solid (511 mg, 29%). Data for
(+)-11: mp = 120–122 °C; []20D = +14.3°, c = 1.0 CHCl3; max cm−1
1788, 1654; 1H NMR (CDCl3)  2.22 (s, 3H, SMe), 2.69–2.75 (m,
1H, CHaCH2SMe), 2.84–2.98 (m, 3H, CHbCH2SMe), 3.37 and 3.88
(dd J = 13.4 Hz, 2H, CH2Ph), 5.36 (s, 1H, C2H), 6.66 (d J = 5.9 Hz,
2H, PhH), 6.74 (d J = 5.9 Hz, 2H, PhH), 7.03 (m, 4H, PhH), 7.13
(m, 2H, PhH), 7.39 (m, 2H, PhH), 7.44 (m, 3H, PhH); 13C NMR
(CDCl3)  15.4, 29.2, 36.9, 40.1, 68.7, 90.4, 125.6, 127.2, 127.9,
128.1, 128.2, 129.0, 130.1, 135.0, 136.1, 169.3, 173.5; HMRS calcd
for C26H26NO3S (M + H) 432.1633, found 432.1637; C26H25NO3S
requires C, 72.36; H, 5.84; N, 3.25; S, 7.43; found: C, 72.39; H,
6.04; N, 3.47; S, 7.24%. Data for 18: 1H NMR (CDCl3)  1.85 (m,
2H, 2 × NCH2CHa), 1.98 (m, 3H, 2 × NCH2CHb and CHaCH2SMe),
2.08 (m, 4H, SMe and CHbCH2SMe), 2.56 (m, 2H, CH2SMe), 3.41
(m, 1H, NCHa), 3.48 (m, 1H, NCHb), 3.53 (ddd J = 6.1, 10.1 and
16.9 Hz, 1H, NCHa), 3.73 (ddd J = 6.6, 10.0 and 16.8 Hz, 1H,
NCHb), 5.07 (m, 3H, NH and PhH), 7.45 (m, 1H, PhH), 7.80 (t
J = 7.3 Hz, 2H, PhH); 13C NMR (CDCl3)  15.6, 24.0, 25.9, 30.2,
32.3, 46.0, 46.5, 50.3, 127.1, 128.3, 131.5, 133.7, 166.8, 169.8;
HRMS calcd for C16H23N2O2S (M + H) 307.1480, found 307.1484.
Catalyst 2 (114 mg, 0.14 mmol, 5 mol%) in dry degassed CH2Cl2
(3 mL), was added to a solution of diene (+)-8 (1 g, 2.75 mmol,
1 eq.) in dry degassed CH2Cl2 (25 mL) under nitrogen, and the mix-
ture was stirred at rt for 2 h. The solvent was removed under reduced
pressure to give a dark brown residue that was purified by radial
chromatography (ethyl acetate/petroleum ether 1:3) to give (+)-1
as a white solid (867 mg, 94%). An analytical sample and crystals
suitable for X-ray crystallography were obtained by the diffusion
of petroleum ether into a solution of (+)-1 dissolved in ethyl ac-
etate. Mp = 122–123 °C; []20D = +38.2°, c = 1.0 CHCl3; max cm−1
1
2947, 1742, 1634; H NMR (CDCl3)  2.43 (m, 1H, CCHaCH),
2.78 (m, 1H, CCHbCH), 3.18 (d J = 13.2 Hz, 1H, PhCHa), 3.62
(d J = 13.2 Hz, 1H, PhCHb), 3.68 (s, 3H, OMe), 3.80 (m, 1H,
NCHaCH), 4.10 (m, 1H, NCHbCH), 5.67 (m, 1H, CCH2CH),
5.88 (m, 1H, NCH2CH), 7.15–7.52 (m, 10H, PhH); 13C NMR
(CDCl3)  28.5, 38.9, 46.8, 51.9, 62.7, 124.6, 125.3, 127.0, 127.9,
128.1, 128.4, 130.5, 130.5, 135.7, 135.8, 172.4, 172.6; HRMS calcd
for C21H21NO3 (M) 335.1521, found 335.1520; C21H21NO3 requires
C, 75.19; H, 6.31; N, 4.18; found: C, 74.94; H, 6.23; N, 4.19%.
(2R)-2-(Allyl-benzoyl-amino)-2-benzyl-pent-4-enoic acid
methyl ester (+)-82
Sodium hydride (1.486 g of 60% in mineral oil, 37.2 mmol, 3 eq.)
was slowly added to a 0 °C solution of methyl ester (−)-77 (4 g,
12.4 mmol, 1 eq.) and allyl bromide (3.215 mL, 37.2 mmol, 3 eq.)
in DMF (120 mL). The mixture was stirred at 0 °C for 1.5 h, then at
room temperature for 30 min, whereupon the solution was quenched
with saturated aqueous NH4Cl and extracted with ethyl acetate
(3 × 10 mL). The ethyl acetate extracts were combined and washed
with water (2 × 10 mL), brine (10 mL), dried (MgSO4) and the
solvent removed under reduced pressure. Purification by column
chromatography (ethyl acetate/petroleum ether 1:3) gave an initial
fraction of pure starting material (−)-7 (920 mg, 23%). Further elu-
tion gave pure diene (+)-8 as a white solid (1.343 g, 30%). Mp 92–
93 °C; []20D = +64.3° (c = 1.0 CHCl3); max cm−1 3323, 2924, 1732,
1
1
1628; H NMR (500 MHz, CDCl3)  H NMR (CDCl3) 2.73 (m,
2H, NCH2CH), 3.09 (m, 1H, CCHaCH), 3.22 (d J = 13.7 Hz,
1H, PhCHa), 3.63 (m, 1H, CCHbCH), 3.69 (d J = 13.7 Hz, 1H,
PhCHb), 3.75 (s, 3H, OMe), 5.08–5.34 (m, 4H, 2 × CHCH2), 5.54
(m, 1H, NCH2CHCH2), 5.87 (m, 1H, CCH2CHCH2), 7.21–7.43
(10H, PhH); 13C NMR (CDCl3) 36.1, 36.6, 49.4, 52.0, 67.9, 116.6,
119.9, 126.2, 126.9, 128.2, 128.3, 129.4, 130.7, 132.2, 136.4, 136.5,
136.8, 172.7, 172.7; HRMS calcd for C23H24NO3 (M − H) 362.1756,
found 362.1758.
(2R,4R)-3-Benzoyl-4-benzyl-2-phenyl-4-vinyl-oxazolidin-5-one
(+)-12
Hydrogen peroxide (0.289 mL of a 50% w/w solution, 4.25 mmol,
1.4 eq.) was added to a solution of oxazolidinone (+)-11 (1.312 g,
3.04 mmol, 1 eq.) in acetic acid (6 mL) and the mixture stirred at
rt for 4 h. Dichloromethane (20 mL) was added and the solution
was carefully neutralised with saturated aqueous Na2CO3. The or-
ganic phase was separated and washed with water (10 mL), dried
(MgSO4) and the solvent removed under reduced pressure to give
the intermediate sulfoxide as a tan solid (1.26 g, 94%) that was not
purified further. 1H NMR (CDCl3)  2.70 (s, 3H, SOMe), 2.84–3.32
(m, 4H, CH2CH2SMe), 3.41 (d J = 13.6 Hz, 1H, CHaPh), 3.91 (br d
J = 13.6 Hz, 1H CHbPh), 5.50 (m, 1H, H2), 6.63 (m, 2H, PhH), 6.73
(m, 2H, PhH), 7.05 (m, 4H, PhH), 7.16 (m, 2H, PhH), 7.36 (m, 2H,
PhH), 7.44 (m, 3H, PhH). The sulfoxide was dissolved in degassed
m-xylene (20 mL), sealed under vacuum in a glass tube, and heated
(2R)-1-Benzoyl-2-benzyl-piperidine-2-carboxylic acid methyl
ester (+)-9
10% Palladium-on-carbon (4.5 mg, 20% w/w) was added to a solu-
tion of olefin (+)-1 (23 mg, 0.07 mmol) in dry methanol (1.5 mL)
and the mixture stirred vigorously under hydrogen for 12 h. The
mixture was then filtered through a small bed of Celite™, washed
with methanol, and the solvent removed under reduced pressure to
2 3 6 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0

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at 200 °C for 16 h. Removal of the solvent under reduced pressure
and purification of the residue by radial chromatography (ethyl
acetate/petroleum ether 1:3) gave the vinyl oxazolidinone (+)-12 as
a white solid (998 mg, 93%).An analytical sample and crystals suit-
able for X-ray crystallography were obtained by the diffusion of pe-
troleum ether into a solution of (+)-12 dissolved in ethyl acetate. Mp
148–149 °C; []20D = +139.0°, c = 1.0 CHCl3; max cm−1 3034, 2939,
1801, 1649; 1H NMR (CDCl3)  3.51 (d J = 13.7 Hz, 1H, CHaPh),
4.06 (d J = 13.7 Hz, 1H, CHbPh), 5.58 (d J = 13.7 Hz, CHa), 5.64
(m, 2H, CHb and CHCH2), 6.61 (d J = 7.3 Hz, 2H, PhH), 6.73
(m, 3H, PhH), 7.06 (m, 4H, PhH), 7.16 (t J = 7.3 Hz, 1H, PhH),
7.21 (t J = 7.3 Hz, 1H, PhH), 7.41 (m, 4H, PhH); 13C NMR (CDCl3)
 40.6, 69.1, 90.4, 117.9, 125.8, 127.0, 127.8, 128.3, 128.9, 129.6,
129.8, 130.1, 135.1, 135.8, 135.9, 168.8, 171.5; HRMS calcd for
C25H21NO3 (M) 383.1521, found 383.1521; C25H21NO3 requires C,
78.2; H, 5.5; N, 3.7; found C, 77.8; H, 5.6; N, 3.7%.
NCH2CHCH2), 5.34 (m, 1H, NCH2CHCH2), 5.36 (d J = 3.4 Hz,
1H, CCHCHa), 5.39 (d J = 3.4 Hz, 1H, CCHCHb), 6.22 (m, 1H,
CCHCH2), 7.24–7.42 (m, 10H, PhH); 13C NMR (CDCl3)  39.6,
50.7, 52.3, 70.1, 116.6, 117.3, 126.4, 126.9, 128.1, 128.1, 129.7,
131.0, 134.9, 135.8, 136.2, 136.5, 171.8, 173.0; HRMS calcd for
C22H24NO3 (M + H) 350.1756, found 350.1763; C22H23NO3 requires
C, 75.6; H, 6.6; N, 4.0; found: C, 75.6; H, 6.5; N, 4.0%.
(2R)-1-Benzoyl-2-benzyl-2,5-dihydro-1H-pyrrole-2-carboxylic
acid methyl ester (−)-16
Catalyst 4 (18 mg, 0.02 mmol, 5 mol%) in dry degassed ben-
zene (0.5 mL) was added to a solution of diene (−)-15 (156 mg,
0.45 mmol) in dry degassed benzene (5 mL), under nitrogen, and
the mixture stirred at reflux for 16 h. The solvent was removed
under reduced pressure to give a dark brown residue that was puri-
fied by radial chromatography (ethyl acetate/petroleum ether 1:3)
to give (−)-16 as a white solid (133 mg, 94%). An analytical sample
and a crystal suitable for X-ray crystallography were obtained by
the diffusion of petroleum ether into a solution of (−)-16 dissolved
in ethyl acetate. []20D = −116.6°, c = 1.0 CHCl3; max cm−1 2951,
1738, 1645; 1H NMR (CDCl3)  3.29 (d J = 13.7 Hz, 1H, PhCHa),
3.47 (d J = 15.2 Hz, 1H, NCHa), 3.83 (s, 3H, OMe), 3.93 (d
J = 15.2 Hz, 1H, NCHb), 3.99 (d J = 13.7 Hz, 1H, PhCHb), 5.71 (s,
2H, CH2CHCH and CH2CHCH), 7.19–7.40 (m, 10H, PhH); 13C
NMR (CDCl3)  38.0, 52.7, 56.9, 76.6, 126.4, 126.5, 127.6, 128.3,
129.3, 129.8, 130.7, 136.4, 136.5, 169.1, 171.6; HRMS Calcd for
C20H20NO3 (M + H) 322.1443, found 322.1444.
(2R)-2-Benzoylamino-2-benzyl-but-3-enoic acid 13
Sodium hydroxide (209 mg, 5.22 mmol, 2 eq. in 2 mL of water) was
added to a solution of oxazolidinone (+)-12 (998 mg, 2.61 mmol,
1 eq.) in MeOH (20 mL) and the mixture refluxed for 1 h. The
solution was cooled and concentrated under reduced pressure. The
residue was taken up in water, acidified to pH 1 with 10% HCl, and
extracted with ether (3 × 10 mL). The combined ether extracts were
washed with brine (10 mL), dried (MgSO4) and the solvent removed
under reduced pressure to give acid 13 as a white solid (760 mg,
99%). 1H NMR (CDCl3)  3.54 (d J = 13.7 Hz, 1H, CHaPh), 3.74
(d J = 13.7 Hz, 1H, CHbPh), 5.38 (m, 2H, CHCH2), 6.18 (m,
1H, CHCH2), 6.87 (s, 1H, NH), 7.20–7.27 (m, 5H, PhH), 7.42
(t J = 7.3 Hz, 2H, PhH), 7.52 (t J = 7.3 Hz, 1H, PhH), 7.67 (m,
2H, PhH); HRMS calcd for C18H18NO3 (M + H) 296.1287, found
296.1286.
Preparation of (2R)-1-Benzoyl-2-benzyl-pyrrolidine-2-
carboxylic acid methyl ester (−)-17
10% palladium-on-carbon (3.6 mg, 20% w/w) was added to a solu-
tion of olefin (−)-16 (18 mg, 0.06 mmol) in dry methanol (1.5 mL),
and the mixture stirred vigorously under hydrogen for 12 h. The
mixture was then filtered through a small bed of Celite™, washed
with methanol, and the solvent removed under educed pressure
to give (−)-17 as a white solid (17 mg, 95%). []20D = −106.5°,
c = 1.0 CHCl3; max cm−1 2930, 1736, 1634, 1408; 1H NMR (CDCl3)
1.32 (m, 1H, CH2CHaCH2), 1.81 (m, 1H, CH2CHbCH2), 2.07 (m,
1H, CCHa), 2.22 (m, 1H, CCHb), 2.82 (m, 1H, NCHb), 3.13 (d
J = 13.7 Hz, 1H, PhCHa), 3.82 (s, 3H, OMe), 4.01 (d J = 13.7 Hz,
1H, PhCHb), 7.24–7.46 (m, 10H, PhH); 13C NMR (CDCl3) 23.6,
34.5, 37.4, 51.7, 52.5, 68.7, 126.7, 127.1, 128.1, 128.2, 130.1,
131.2, 136.7, 136.8, 169.3, 174.3; HRMS calcd for C20H21NO3 (M)
323.1521, found 323.1523.
(2R)-2-Benzoylamino-2-benzyl-but-3-enoic acid methyl ester
(+)-14
Ethereal diazomethane was added to a 0 °C solution of acid 13
(760 mg, 2.58 mmol) in ether (20 mL) until the bright yellow co-
lour persisted over an extended period. The mixture was stirred at rt
for 2 h, whereupon the reaction was quenched with the addition of
a few drops of acetic acid. The solvent was removed under reduced
pressure to give methyl ester (+)-14 as a colourless oil (797 mg,
100%). []20D = +54.1°, c = 1.0 CHCl3; max cm−1 3464, 1749, 1645,
1
1543; H NMR (CDCl3)  3.43 (d J = 13.7 Hz, 1H, CHaPh), 3.83
(s, 1H, OMe), 3.92 (d J = 13.7 Hz, 1H, CHbPh), 5.33 (m, 2H,
CHCH2), 6.20 (m, 1H, CHCH2), 7.00 (br s, 1H, NH), 7.09 (m,
2H, PhH), 7.21 (m, 3H, PhH), 7.42 (t J = 7.8 Hz, 2H, PhH), 7.51 (t
X-Ray crystallography
J = 7.3 Hz, 1H, PhH), 7.71 (dd J = 7.3 and 1.2 Hz, 2H, PhH); 13
C
Data were collected with a Siemens SMART CCD area detector,
using graphite monochromatised MoK radiation ( = 0.71073 Å).
The intensities were corrected for Lorentz and polarisation effects
and for absorption.16 The structure was solved by direct methods
using SHELXS17 and refined on F2, using all data, by full-matrix
least-squares procedures using SHELXTL.18 CCDC reference
numbers 234480–234482. See http://www.rsc.org/suppdata/ob/
b4/b406450j/ for crystallographic data in .cif or other electronic
format.
NMR (CDCl3)  40.0, 53.0, 65.8, 116.3, 126.9, 127.1, 128.3, 128.6,
129.9, 130.0, 131.6, 134.7, 135.6, 136.2, 166.4, 172.2; HRMS calcd
for C19H19NO3 (M) 309.1359, found 309.1365; C19H19NO3 requires
C, 73.7; H, 6.2; N, 4.5; found: C, 73.3; H, 6.2; N, 4.4%.
(2R)-2-(Allyl-benzoyl-amino)-2-benzyl-but-3-enoic acid methyl
ester (−)-15
Sodium hydride (238 mg of 60% in oil, 5.94 mmol, 3 eq.) was slowly
added to an ice-cooled solution of methyl ester (+)-14 (612 mg,
1.98 mmol, 1 eq.) and allyl bromide (0.514 mL, 5.94 mmol, 3 eq.)
in DMF (20 mL). The solution was stirred at 0 °C for 1.5 h and then
at rt for 30 min. The mixture was quenched with saturated aqueous
NH4Cl and extracted with ethyl acetate (3 × 10 mL). The ethyl ac-
etate extracts were combined and washed with water (2 × 10 mL),
brine (10 mL), dried (MgSO4) and the solvent removed under
reduced pressure. Purification by radial chromatography (ethyl
acetate/petroleum ether 15:85) gave a fraction containing 311 mg
(51%) of starting material (+)-14. Further elution gave the diene
(−)-15 as a clear yellow oil (214 mg, 31%). []20D = −62.8°, c = 1.0
Crystal data for 1. C21H21NO3, M = 335.39, orthorhombic,
a = 11.000(4), b = 13.360(4), c = 24.060(4) Å, U = 3535.9(18) Å3,
T = 293(2) K, space group P212121, Z = 8, (Mo–K) = 0.71073 Å,
13962 reflections measured, 6730 unique (Rint = 0.0398 which were
used in all calculation. The final wR(F2) was 0.0779 (all data).2
(CCDC RefCode FIJQOE)
Crystal data for 9. C21H23NO3, M = 337.40, orthorhombic,
a = 7.582(7), b = 13.621(16), c = 17.52(2) Å, U = 1809(3) Å3,
T = 168(2) K, space group P212121, Z = 4, (Mo–K) = 0.71073 Å,
7931 reflections measured, 3582 unique (Rint = 0.0432 which were
used in all calculation. The final wR(F2) was 0.0867 (all data).
(CCDC No 234480)
1
CHCl3; max cm−1 3395, 1736, 1624; H NMR (CDCl3)  3.33 (d
J = 13.4 Hz, 1H, CHaPh), 3.38 (m, 1H, NCHa), 3.64 (m, 1H, NCHb),
3.81 (s, 3H, OMe), 4.03 (d J = 13.4 Hz, 1H, CHbPh), 4.99 (m, 2H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0
2 3 6 9

View Article Online
6 (a) J. Duan and Z. Lu, PCT Int. Appl. (2003), 123 pp., WO 2003053940,
A1 20030703, CAN 139:85367, AN 2003:511306; K. Dolbeare,
G. F. Pontoriero, S. K. Gupta, R. K. Mishra and R. L. Johnson, J. Med.
Chem., 2003, 46, 727; (b) D. P. Boatman, C. O. Ogbu, M. Eguchi,
H.-O. Kim, H. Nakanishi, B. Cao, J. P. Shea and M. Kahn, J. Med.
Chem., 1999, 42, 1367; (c) E. M. Khalil, A. Pradhan, W. H. Ojala,
W. B. Gleason, R. K. Mishra and R. L. Johnson, J. Med. Chem., 1999,
42, 2977; (d) J. E. Baldwin, V. Lee and C. J. Schofield, Heterocycles,
1992, 34, 903; for related examples see; (e) B. M. Trost and K. Dogra,
J. Am. Chem. Soc., 2002, 124, 7256; (f) A. B. Smith III, M. C. Guzman,
P. A. Sprengeler, T. P. Keenan, R. C. Holcomb, J. L. Wood, P. J. Carroll
and R. Hirschmann, J. Am. Chem. Soc., 1994, 116, 9947.
7 J. Gardiner and A. D. Abell, Tetrahedron Lett., 2003, 44, 4227.
8 D. Seebach and A. Fadel, Helv. Chim. Acta, 1985, 68, 1243.
9 (a) J.-P. Begue, D. Bonnet-Delpon, D. Bouvet and M. H. Rock, J.
Chem. Soc., Perkin Trans. 1, 1998, 1797; (b) R. K. Thaper, Y. K. Kumar,
S. M. D. Kumar, S. Misra and J. M. Khanna, Org. Process Res. Dev.,
1999, 3, 476.
Crystal data for 12. C25H21NO3, M = 383.43, orthorhombic,
a = 8.612(4), b = 9.467(6), c = 24.782(15) Å, U = 2020(2) Å3,
T = 293(2) K, space group P212121, Z = 4, (Mo–K) = 0.71073 Å,
8002 reflections measured, 2030 unique (Rint = 0.0336 which were
used in all calculation. The final wR(F2) was 0.0868 (all data).
(CCDC No 234482)
Crystal data for 16. C20H19NO3, M = 321.86, monoclinic,
a = 19.516(4), b = 7.211(15), c = 24.682(15) Å, U = 3378(12) Å3,
T = 168(2) K, space group C2/c, Z = 8, (Mo–K) = 0.71073 Å,
20377 reflections measured, 3414 unique (Rint = 0.0436 which
were used in all calculation. The final wR(F2) was 0.1071 (all data).
(CCDC No 234481)
Acknowledgements
10 T. Weber, R. Aeschimann, T. Maetzke and D. Seebach, Helv. Chim.
Acta, 1986, 69, 1365.
We gratefully acknowledge financial support from a Royal Society
of New Zealand Marsden grant. We also thank Professors Peter Steel
and Ward Robinson (UC) for help with the X-ray crystallography.
11 It is interesting to note that the sterically demanding diene 15 was suc-
cessfully cyclised in excellent yield using catalyst 4, whilst catalysts 2
and 3 were unreactive in this regard. This is consistent with the fact that
catalysts with extended tethers, i.e. 4, are known to effect RCM of steri-
cally demanding substrates.12
Notes and references
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2 A. D. Abell, J. Gardiner, A. J. Phillips and W. T. Robinson, Tetrahedron
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3 D. C. Martyn, A. J. Vernall, B. M. Clark and A. D. Abell, Org. Biomol.
Chem., 2003, 1, 2103–2110; A. D. Abell, Lett. Pept. Sci., 2001, 8,
267–272; B. C. H. May and A. D. Abell, J. Chem. Soc., Perkin Trans. 1,
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12 (a) P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc, 1996,
118, 100; (b) S. T. Nguyen and R. H. Grubbs, J. Am. Chem. Soc, 1993,
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7202; (d) A. J. Phillips and A. D. Abell, Aldrichim. Acta, 1999, 32, 75.
13 C. Toniolo, Int. J. Peptide Protein Res., 1990, 35, 287.
14 Proline torsion angles vary in the literature depending on the structure
and environment of the molecule i.e. proline adopts a constrained but
fluid system.
15 D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed.,
1996, 35, 2748.
4 I. Schechter and A. Berger, Biochem. Biophys. Res. Commun., 1967, 27,
157.
5 A. Fadel and J. Salaun, Tetrahedron Lett., 1987, 28, 2243.
16 G. M. Sheldrick, SADABS, University of Göttingen, Germany, 1998.
17 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
18 G. M. Sheldrick, SHELXTL, Bruker Analytical X-ray Systems, 1997.
2 3 7 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 3 6 5 – 2 3 7 0