Pyrrolidinones derived from (S)-pyroglutamic acid. Part 2. Conformationally constrained kainoid analogues

Article abstract of DOI:10.1039/b002001j

Derivation of pyrrolidinones from (S)-pyroglutamic acid was described. The procedure permitted the sequential modification of C-3 and C-4 substituents of the kainoids. This allowed access to a diverse range of compounds. The pyrrolidinone ring conformation appeared to be controllable by the nature of remote substituents on the heterocyclic ring.

Full text of DOI:10.1039/b002001j

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Pyrrolidinones derived from (S)-pyroglutamic acid. Part 2.1
Conformationally constrained kainoid analogues
James Dyer,a Amanda King,a Steve Keelingb and Mark G. Moloney*a
1
a The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, UK OX1 3QY. E-mail: mark.moloney@chem.ox.ac.uk
b GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
UK SG1 2NY
Received (in Cambridge, UK) 13th March 2000, Accepted 2nd June 2000
Published on the Web 24th July 2000
Novel conformationally constrained glutamate analogues are readily available from (S)-pyroglutamic acid
using a bicyclic lactam as a synthetic template; diastereocontrolled modification of the pyrrolidine ring using
a sequential conjugate addition–substitution strategy permits access to several kainoid analogues in a versatile
strategy. The pyrrolidinone ring conformation appears to be controllable by the nature of remote substituents
on the heterocyclic ring.
In the preceding paper,1 we detailed our methodology using a
bicyclic template derived from (S)-pyroglutamic acid for the
diastereocontrolled synthesis of C-3 substituted pyroglut-
aminols and pyroglutamates 1a–c. In this paper, we describe
the further elaboration of these templates, leading ultimately to
the 4-aryl-5-oxo and 4-arylmethyl-5-oxo analogues 1d of kainic
Scheme 1
acid† 2;2 this strategy allows for the sequential modification of
readily available by direct plumbation of an aromatic ring or by
lead/boron exchange of an arylboronic acid. Elaboration to the
desired C-4 aryl functionalised pyroglutamates would then
require only a short sequence of steps.
C-3 and C-4 substituents of the kainoids, thereby permitting
access to a diverse range of compounds. There has been
considerable recent interest in the development of novel meth-
odology to provide access to kainoids and their analogues,3,4
including organometallic5–7 and radical approaches.8,9 These
analogues may be considered to be conformationally restricted
forms of glutamate; such compounds are of importance as
excitatory amino acid analogues3 and as conformationally
controlling peptidomimetics.10–13
We expected to develop an efficient and versatile route to
analogues of the kainoid group of amino acids from enone 3
(Scheme 1) using the bicyclic system to control diasteroselec-
tivity. As described in the preceding paper,1 the C-7 ethoxy-
carbonyl activating group of 3 is of crucial importance for
efficient conjugate addition, but it also offered considerable
potential for further manipulation at C-7 after the conjugate
addition step since the β-dicarbonyl system thus generated can
be easily alkylated.14 Furthermore, we expected to be able to use
the β-dicarbonyl moiety of 4 for α-arylation reactions using
aryllead() triacetates, a strategy which has been developed in
detail in recent years.15,16 The required lead() reagents are
Ring functionalisation by arylation and alkylation
Although the tricarboxylate conjugate adduct 4b (Scheme 1)
was found not to react when subjected to phenyllead triacetate,
presumably due to the substantial steric hindrance from the
bulky C-6 substituent, the tert-butyloxycarbonylmethyl com-
pound 4a proved to be suitable for the introduction of a variety
of aryl groups to give moderate to excellent combined yields of
the diastereomeric products 5 and 6 (Scheme 2 and Table 1);
aryllead reagents with either electron withdrawing or electron
donating groups on the aromatic ring were applicable. However,
the diastereomeric products 5 and 6 could be separated only
with difficulty. In the case of phenyllead triacetate (generated in
situ from lead() tetraacetate and phenylboronic acid), the
reaction proved to be sluggish, and the product was obtained in
only 20% yield even after a 3 day reaction at room temperature.
Optimisation of this reaction, by using an increased number of
equivalents of aryllead reagent and heating the reaction at
reflux for 3 days gave a greatly improved yield of 86% of the
† IUPAC name for kainic acid is (2-carboxy-4-isopropenylpyrrolidin-3-
yl)acetic acid.
DOI: 10.1039/b002001j
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
This journal is © The Royal Society of Chemistry 2000
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Scheme 2
Table 1 Arylations and alkylations of lactam 4a giving products 5, 6
Yield (%)
Compound
R
5
6
a
b
c
d
e
f
Ph
61
45
67
42
50
52
26
34
25
27
17
18
22
22
12
41
o-MeOC6H4
m-MeOC6H4
p-MeC6H4
p-CF3C6H4
p-BrC6H4
p-MeOC6H4
PhCH2
g
h
diastereomeric products 5a and 6a in a ratio of 2.4:1, and the
stereochemistry of 5a was established by NOE studies (Fig. 1).
The exo orientation of the C-7 phenyl group was determined
from a set of enhancements observed between the ortho protons
of this group, H-4exo and the ortho protons of the C-2 phenyl
ring. The exo orientation of the C-6 substituent was also
confirmed by the observation of enhancements between the
spacially proximal hydrogens H-2, H-4endo, and H-6.
The reaction of 4a with o-methoxyphenyllead triacetate
(generated in situ from lead() tetraacetate and o-methoxy-
phenylboronic acid16) under the above conditions for 2 days
gave, after careful chromatography, a mixture of unreacted
starting material 4a (27%), the desired diastereomeric products
5b and 6b in 40% overall yield, and the acetate 7; α-acetoxyl-
ation is a well documented side-reaction for lead() carboxyl-
ates.17 This latter product may arise due to the greater steric
Fig. 1 NOE data for selected compounds.
bulk of the o-methoxyphenyl group, thus allowing the com-
peting acetoxylation process to occur. A cleaner and higher
yielding arylation reaction was achieved with o-methoxy-
phenyllead() triacetate (prepared according to the literature
method16), giving a 72% yield of 5b and 6b in a ratio of 1.7:1.
The m-methoxyphenyl derivatives 5c:6c were obtained in 84%
yield and a ratio of 4:1. The p-methylphenyl, p-trifluoromethyl-
phenyl and p-bromophenyl derivatives 5d–f and 6d–f were
obtained in combined yields of 60, 72 and 74% respectively as
2.3:1 ratio of diastereomers. The stereochemical assignment of
these stereoisomers was possible by the presence of NOE spec-
troscopic enhancements from either the methylene of the C-6
substituent or H-5 to the o-aromatic protons of the C-7 sub-
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Scheme 3
Table 2 Deprotections of lactams 5, 6 giving products 10, 11
Fig. 2
Yield
(%)
Compound
Ratio
Product
Rf
5a, 6a
5g, 6g
5h
2.1:1
2.3:1
—
10a, 11a
10b, 11b
10c
0.24, 0.32
0.22, 0.27
0.20
81
38
86
77
6h
—
11c
0.27
stituent for the diastereomers 5, or from H-6 to the same
aromatic protons for diastereomer 6 (Fig. 1). However, unlike
the cases outlined above, reaction with p-methoxyphenyl-
lead() triacetate proved to be very problematic; the best result
was obtained when lactam 4a was converted to the corre-
sponding enolate (NaH–THF) followed by treatment with
p-methoxyphenyllead() triacetate and pyridine at rt for 5 days.
Purification by column chromatography gave the products 5g
and 6g in a yield of 38% as a 2.3:1 ratio.
The alkylation at C-7 of bicyclic lactam 4a was also investi-
gated. Conversion of lactam 4a to the corresponding enolate
(NaH–THF) followed by addition of benzyl bromide gave
the products 5h and 6h in a yield of 75% as a 1:1.2 ratio.
Stereochemical assignment using a series of NOE experiments
as before was possible for both diastereomers of 5h and 6h (Fig.
1). Alternatively, alkylation of 4a with α-iodovalerolactam 8c
(readily obtained from N-benzylvalerolactam 8a in three steps
via the chloride 8b) gave the diastereomeric products 9a, b in
36% yield (ratio 1:1), and the stereochemistry of 9b was
assigned by NOE analysis (Fig. 1).
NMR spectrum which showed a similar distinctive splitting
pattern for each diastereomer as observed for the arylated
bicyclic compounds 5, 6. Thus, the signals from the methylene
protons α to the tert-butyl ester were coincident for the trans-C-
3/4 compound 13, and separated by 2.7 ppm for the cis-C-3/4
compound 12. The alcohols 12, 13 (1:1) were treated with
TFA to remove the tert-butyl group, and then oxidised using
ruthenium() oxide/sodium periodate and methylated with
diazomethane; the expected diastereomers 15a and 16a were
each obtained in 33% yield. The stereochemical assignment of
15a and 16a as shown was confirmed from NOE experiments
Conversion to pyroglutamate derivatives
Deprotection of lactams 5a, g, h and 6a, g, h, by exposure
to TFA in dichloromethane for 15 minutes gave the expected
alcohols 10a–c and 11a–c in moderate to excellent yield
(Scheme 3 and Table 2); unlike the arylated bicyclic starting
materials which were separable only with difficulty by chrom-
atography, each of the diastereomerically pure alcohols 10 and
11 could be easily obtained. As with the starting lactams 5 and
6, the endo aryl compounds 11 had greater Rf values than their
C-4 epimers 10.
performed on each diastereomer, the results of which are shown
in Fig. 2. The diastereomer 16a showed enhancements between
the H-2 and the C-6 methylene substituent, and between the
H-3 and the C-4 ortho-phenyl signals, which were indicative of
the all-trans disposition of H-2, -3 and -4. The diastereomer 15a
displayed enhancements between the C-4 ortho-phenyl signal
and that of H-2, and the cis disposition of H-2 and the C-3
substituent was indicated from the enhancement of the meth-
ylene signal on irradiation of H-2. In addition to the NOE
In order to realise our goal of developing a short synthesis of
the kainoid group of amino acids using this strategy, removal
of the C-7 ethoxycarbonyl substituent of intermediates 5, 6 was
required; the C-7 exo stereochemistry was desired for the most
commonly occurring and most biologically active kainoids.4
Hydrolysis and decarboxylation of 10a with sodium hydroxide
in ethanol at room temperature followed by heating under
vacuum gave the product diastereomers 12 and 13, along with
the acid 14. Further heating of this mixture effected complete
decarboxylation, giving an overall yield of the products 12, 13
of 82% in a ratio of 1:1.4; noteworthy is the high proportion of
the product 12 possessing the desired kainic acid configuration.
1
data, the H NMR spectra of these compounds displayed the
previously discussed features for these diastereomeric arylated
compounds; thus, the methylene signal was coincident for the
trans-C-3/4 compound 16a and split for the cis-C-3/4 com-
pound 15a, which could be attributed to the shielding environ-
ment imposed upon the methylene hydrogens when positioned
cis to the anisotropic phenyl ring.
1
The diastereomers were identified from examination of the H
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
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Table 3 Coupling constants and dihedral angles
Coupling constant/
C(2)H–C(3)H
Dihedral angle/Њ
Compound
Hza
15a (R = H)
15a
6.0 (6.5)
5.5 (5.5)
6.5 (6.5)
8.0 (8.0)
2.5 (2.5)
118
117
121
153
125
16a
15b
16b
a In CDCl3 (C6D6).
Table 4 Selected 1H NMR spectroscopic data for compounds 5, 6
δ
Compound
H-2
H-4endo
H-4exo
CH2COtBu
Rf
Although it was anticipated that better diastereocontrol
would be obtained if the decarboxylation step was performed
on the bicyclic lactams 5 and 6, in practice the initial ester
hydrolysis step proved to be unreliable. Thus, hydrolysis with
alcoholic sodium hydroxide of the phenyl adduct 5a, 6a (2:1)
gave slow ethyl ester hydrolysis and decarboxylation, along with
some tert-butyl ester hydrolysis. Complete tert-butyl ester
hydrolysis resulted upon repetition of this reaction at 50 ЊC for
5–8 h to give acid 17 as a mixture of diastereomers at C-7.
Hemiaminal ether deprotection was then easily achieved by
treatment with TFA in dichloromethane for 4.5 h at room tem-
perature to give 18, and alcohol oxidation was effected using
ruthenium() oxide–sodium periodate. The crude dicarboxylic
acid product was immediately converted to the dimethyl ester
(MeOH, H2SO4, reflux) to give the expected product as the two
diastereomers 15a and 16a. However, the two minor products
19a, 19b were also isolated in low yield from this sequence,
arising from incomplete hydrolysis in the initial step. Hydrolysis
of the dimethyl ester 16a by treatment with sodium hydroxide
in aqueous tetrahydrofuran gave the diacids 20a, b in high
yield (83%) in a ratio of 1:3.8, that is, favouring the trans-
C-3/4 arrangement. This was confirmed by re-esterification
with methanol–conc. H2SO4 which gave a 1:5 diastereomeric
mixture of the dimethyl ester product 15a and 16a.
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
5f
6.43
6.37
6.38
6.41
6.43
6.37
6.42
6.36
6.42
6.48
6.41
6.35
6.29
6.17
3.97
3.90
3.98
3.90
3.73
3.90
3.70
3.88
3.70
3.85
3.97
3.89
3.78
3.12
4.43
4.35
4.42
4.20–4.33
4.46
4.36
4.43
4.27
4.44
4.29
4.43
4.21–4.38
4.23
4.16
1.64, 2.42
2.70–2.78
1.71, 2.70
2.63, 2.93
1.66, 2.45
2.74–2.76
1.66, 2.43
2.72
1.64, 2.39
2.69–2.81
1.67, 2.38
2.63–2.73
2.58–2.70
2.26–2.42
0.19
0.21
0.11
0.30
0.36
0.36
0.38
0.38
0.39
0.49
0.29
0.40
0.19
0.29
6f
5h
6h
overall yields of 7 and 31% respectively from the alcohol 10c.
1
The H NMR spectrum of the trans-C-3/4 compound 16b was
amenable to NOE analysis for stereochemical determination,
and the significant enhancements are shown in Fig. 2.
Enhancements between H-4, the methylene protons of the C-3
substituent, and H-2 indicated their cis relationship; this stereo-
chemistry would be expected for the major diastereomer on
consideration of steric interactions.
The C-4 disubstituted derivative 21 was readily obtained
using the above oxidation–esterification sequence on pyrrol-
idinone 10a in good yield (41%), but under the same conditions
the alcohol 11a gave no product.
Conformational studies
This synthetic route represents a novel and simple, but poten-
tially generalisable approach to highly functionalised pyrrol-
idinones, and is complementary to existing literature protocols.
In particular, it provides access to novel pyroglutamate
analogues of the kainoid group of amino acids possessing
substituents with π-electron density at C-4; the synthesis of
conformationally constrained pyroglutamates has attracted
recent attention.18 It was apparent from examination of the 1H
NMR spectra of the final dimethyl ester pyroglutamates 15a, b
and 16a, b, as well as the unsubstituted derivative 15 (R = H),1
that the coupling constants between the H-2 and H-3 varied
between diastereomers and with the type of C-4 substituent
(Table 3); molecular modelling studies of each of these com-
pounds19 confirmed these experimental findings, since the H-2–
H-3 dihedral angle was found to vary depending on the nature
of the C-4 substituent, and appears to be greatest for the more
sterically congested C-4 (aryl) series of compounds 6a, b. Thus,
it would appear that analogues of well defined glutamate con-
formers could be available by variation in the C-4 substituent of
compounds of type 15 and 16.
Attempted hydrolysis and decarboxylation of the benzyl
compound 6h proved to be problematic. Because of the easier
hydrolysis which had been observed for lactams 10a and 11a,
attention was turned towards the hydrolysis of the readily
separable benzyl compounds 10c and 11c. Selective ethyl ester
hydrolysis of 11c with NaOH (1 M), treatment with TFA then
with RuO2–NaIO4 and finally with diazomethane, gave the
dimethyl monoethyl ester and trimethyl ester products 22a and
22b in yields of 23% and 25% respectively. This result shows
that some ethyl ester hydrolysis had occurred, but highlights the
sterically hindered nature of the C-4 esters in substrates of this
type.
A similar sequence was used for compound 10c; hydrolysis
with NaOH gave the carboxylic acid 23 in a yield of 99%.
NMR spectroscopy
In common with the simpler systems discussed in the preceding
paper, a consistent pattern was observed with regard to chem-
ical shifts and coupling constant values in the NMR spectra
(Table 4). Thus, for the aryl adducts 5a–e and 6a–e, H-4endo has
a lower chemical shift than H-4exo with ∆δ of about 0.4; how-
Decarboxylation (heating at 135 ЊC at 0.5 mbar), deprotection
(TFA), oxidation and esterification (diazomethane) gave the
completely separated product diastereomers 15b and 16b in
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ever, 6h is exceptional, and this difference is more than double, a
result which can be attributed to the anisotropy of the adjacent
benzyl substituent. Similar anisotropy is responsible for the well
separated resonances of the C-6 methylene substituent protons
of the exo aryl diastereomers 5, but coincident resonance in
endo aryl 6.
128.03, 128.46, 128.60 and 128.81 (ArCH), 134.10 (ArC),
138.37 (ArC), 169.90, 170.68 and 170.88 (3 × CO).
Data for 6a. Rf 0.21; νmax(film)/cmϪ1 2980 (s), 1368 (m), 1245
(s), 1154 (s), 1050 (m), 1028 (m), 701 (m), 665 (m); δH (500
MHz, CDCl3) 1.25 (3H, t, J 7.0, CH3CH2), 1.44 (9H, s,
t
C(CH3)3), 2.70–2.78 (2H, m, CH2CO2 Bu), 3.08–3.12 (1H, m,
H-6), 3.90 (1H, dd, J 9.0 and 7.5, H-4endo), 4.12 (1H, dd, J 14.0
and 7.5, H-5), 4.21–4.33 (2H, m, CH3CH2), 4.35 (1H, dd, J 9.0
and 6.0, H-4exo), 6.37 (1H, s, H-2), 7.33–7.44 (8H, m, ArH),
7.48–7.50 (2H, m, ArH); δC (125.8 MHz, CDCl3) 14.00
Experimental
For general experimental procedures, see our earlier reports.14,20
t
(CH3CH2), 28.03 (C(CH3)3), 34.48 (CH2CO2 Bu), 47.38 (C-6),
General arylation methods
62.00 and 62.16 (CH3CH2 and C-5), 68.41 (C-7) and 72.48
(C-4), 81.54 (C(CH3)3), 86.53 (C-2), 126.12, 128.00, 128.46 and
128.74 (ArCH), 135.41 (ArC), 137.98 (ArC), 169.42, 170.28
and 171.09 (3 × CO); m/z (CI(NH3)) 466 (M ϩ Hϩ, 100%);
HRMS 466.2230, C27H32NO6 requires 466.2231.
Method 1. To a mixture of lead() tetraacetate, arylboronic
acid and mercury() acetate in an inert atmosphere was added
ethanol-free chloroform and the mixture was then stirred at
40 ЊC for 2 h. A solution of the lactam 4a in chloroform was
then added and the mixture heated at reflux for 72 h. After
cooling to rt the mixture was filtered through Celite, washed
with chloroform, and the organic layer washed with sulfuric
acid (10% aq.). The aqueous phase was washed twice with
chloroform and the combined organic phases were dried
(MgSO4), filtered and evaporated in vacuo prior to purification.
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-6-tert-Butoxycarbonyl-
methyl-7-ethoxycarbonyl-7-o-methoxyphenyl-3-oxa-8-oxo-2-
phenyl-1-azabicyclo[3.3.0]octanes 5b and 6b
According to Method 1, lactam 4a (73 mg, 0.19 mmol) was
reacted with 2-methoxyphenylboronic acid (59 mg, 0.38 mmol),
lead() tetraacetate (0.18 g, 0.38 mmol), mercury() acetate
(12 mg, 0.04 mmol), and pyridine (89 mg, 1.1 mmol) in CHCl3
(10 ml) at reflux for 2 days. Work-up and purification by flash
column chromatography (EtOAc–DCM, 50:1) gave several
products, including lactam 4a (20 mg, 27%), the aryl product 5b
and the acetate product 7 (4 mg, 5%).
Method 2. To a solution of the lactam 4a in ethanol-free
chloroform was added pyridine and the aryllead() complex.
The mixture was then heated at reflux under an argon atmos-
phere for the specified period. After cooling, the mixture was
worked-up as above.
According to Method 2, o-methoxyphenyllead() triacetate
(0.22 g, 0.44 mmol) and the lactam 4a (86 mg, 0.22 mmol) were
reacted in pyridine (87 mg, 1.1 mmol) and CHCl3 (6 ml) at
reflux for 3 days. Work-up gave the crude mixture as a yellow
glass which was shown to be a mixture of product diastereo-
mers 5b, 6b (1.7:1), along with some starting lactam 4a, which
was purified by flash column chromatography (DCM–MeOH–
Et3N, 200:1:1) to give the product as incompletely separable
diastereoisomers (79 mg, 72%).
Method 3. To a stirred solution of the lactam 4a in THF at rt
was added sodium hydride (1.1 eq.). After 1 h this solution was
transferred to a solution of the aryllead() complex (1.5 eq.) in
pyridine (2 ml), using THF (1 ml) to rinse the flask out. The
mixture was then stirred at room temperature. After 3 days
another aliquot of pyridine (2 ml) and aryllead() complex
(1.2 eq.) was added. The mixture was then worked-up after a
further 2 days as above.
Method 4. A solution of lactam 4a and the required aryllead
compound15,21 (1.05 eq.) was heated under reflux in chloroform
(10 ml) with pyridine (3 eq.) for 72 h. The reaction mixture was
cooled to rt, diluted with chloroform (10 ml), washed with 2 M
HCl (10 ml) and water (15 ml), dried (MgSO4) and the solvent
removed in vacuo.
Data for 5b. Rf 0.11 (Et2O–Petrol (30–40), 1:2); νmax(film)/
cmϪ1 1718 (s), 1493 (m), 1459 (m), 1367 (m), 1308 (m), 1248 (s),
1154 (s), 1026 (m), 755 (m), 700 (m); δH (500 MHz, CDCl3) 1.24
(3H, t, J 7.0, CH3CH2), 1.40 (9H, s, C(CH3)3), 1.71 (1H, dd,
t
J 16.5 and 12.0, CHHCO2 Bu), 2.70 (1H, dd, J 16.5 and 3.5,
t
CHHCO2 Bu), 3.69–3.73 (1H, m, H-5), 3.76–3.82 (4H, m, H-6
and OCH3), 3.98 (1H, t, J 8.5, H-4endo), 4.23–4.30 (2H, m,
CH3CH2), 4.42 (1H, dd, J 8.5 and 6.0, H-4exo), 6.38 (1H, s, H-2),
6.89–6.94 (2H, m, ArH), 7.12–7.14 (1H, m, ArH), 7.29–7.32
(1H, m, ArH), 7.35–7.43 (3H, m, ArH), 7.56–7.58 (2H, m,
ArH); δC (125.8 MHz, CDCl3) 14.05 (CH3CH2), 28.00
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-6-tert-Butoxycarbonyl-
methyl-7-ethoxycarbonyl-3-oxa-8-oxo-2,7-diphenyl-1-aza-
bicyclo[3.3.0]octanes 5a and 6a
According to Method 1, lactam 4a (0.30 g, 0.77 mmol) was
reacted with phenylboronic acid (0.19 g, 1.5 mmol), lead()
tetraacetate (0.72 g, 1.5 mmol), mercury() acetate (49 mg, 0.15
mmol), and pyridine (0.37 g, 4.62 mmol) in CHCl3 (30 ml) at
reflux for 3 days to give after work-up and purification using
flash column chromatography (Et2O–cyclohexane, 1:3) the
product as a colourless glass of diastereomeric ratio 5a:6a of
2.4:1 (0.31 g, 86%).
t
(C(CH3)3), 34.76 (CH2CO2 Bu), 43.12 (C-6), 55.07 (OCH3),
61.76 (C-5), 61.92 (CH3CH2), 67.31 (C-7), 72.69 (C-4), 80.98
(C(CH3)3), 87.02 (C-2), 111.24 (ArCH), 121.53 (ArCH), 123.81
(ArCH), 126.07 (ArCH), 128.34 (ArCH), 128.50 (ArCH),
128.72 (ArCH), 129.50 (C-16), 138.54 (ArC), 156.90 (ArC),
t
170.02 (CO2CH2CH3), 171.47 (C(O)N)
ϩ
CO2 Bu); m/z
(APCIϩ) 496 (M ϩ Hϩ, 21%), 440 (100).
Data for 5a. Rf 0.19; νmax(film)/cmϪ1 2980 (s), 1368 (m), 1245
(s), 1154 (s), 1050 (m), 1028 (m), 701 (m), 665 (m); δH (500
MHz, CDCl3) 1.31 (3H, t, J 7.0, CH3CH2), 1.41 (9H, s,
Data for 6b. Rf 0.30 (DCM–EtOAc, 50:1); [α]D26 ϩ148.4
(c 0.31 in CHCl3); νmax(film)/cmϪ1 1720 (s), 1494 (m), 1461 (m),
1368 (m), 1309 (m), 1252 (s), 1224 (s), 1154 (s), 1026 (m), 755
(m), 699 (m); δH (500 MHz, CDCl3) 1.25 (3H, t, J 7.0,
CH3CH2), 1.41 (9H, s, C(CH3)3), 2.63 (1H, dd, J 17.0 and 3.0,
t
C(CH3)3), 1.64 (1H, dd, J 16.5 and 11.5, CHHCO2 Bu), 2.42
t
(1H, dd, J 16.5 and 4.0, CHHCO2 Bu), 3.58–3.62 (1H, m, H-6),
t
t
3.69–3.74 (1H, m, H-5), 3.97 (1H, dd, J 9.0 and 7.5, H-4endo),
4.35 (2H, q, J 7.0, CH3CH2), 4.43 (1H, dd, J 9.0 and 6.0,
H-4exo), 6.43 (1H, s, H-2), 7.11–7.13 (2H, m, ArH), 7.30–7.45
(6H, m, ArH), 7.57–7.59 (2H, m, ArH); δC (125.8 MHz,
CHHCO2 Bu), 2.93 (1H, dd, J 17.0 and 11.5, CHHCO2 Bu),
3.02–3.06 (1H, m, H-6), 3.84 (3H, s, OCH3), 3.90 (1H, dd, J 8.5
and 7.0, H-4endo), 4.11–4.15 (1H, m, H-5), 4.20–4.33 (3H, m,
CH3CH2 and H-4exo), 6.41 (1H, s, H-2), 6.97 (1H, d, J 8.0,
ArH), 7.00–7.03 (1H, m, ArH), 7.32–7.39 (5H, m, ArH), 7.46–
7.48 (2H, m, ArH); δC (125.8 MHz, CDCl3) 14.33 (CH3CH2),
t
CDCl3) 14.01 (CH3CH2), 28.00 (C(CH3)3), 35.99 (CH2CO2 Bu),
44.49 (C-6), 61.32 (C-5), 62.40 (CH3CH2), 69.72 (C-7) and
72.68 (C-4), 81.28 (C(CH3)3), 86.99 (C-2), 126.11, 127.95,
t
28.02 (C(CH3)3), 34.32 (CH2CO2 Bu), 47.54 (C-6), 55.71
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
2797

View Article Online
(OCH3), 61.62 (CH3CH2), 61.85 (C-5), 66.67 (C-7), 72.52 (C-4),
81.06 (C(CH3)3), 86.76 (C-2), 112.26 (ArCH), 121.09 (ArCH),
125.57 (ArCH), 126.16 (ArCH), 128.39 (ArCH), 128.58
(ArCH), 128.77 (ArCH), 129.35 (ArCH), 138.25 (ArC), 157.28
(ArC), 169.09 (C(O)N), 170.87 (CO2CH3CH2), 171.69
mmol) to yield the title compound as two separate diastereo-
mers 5d and 6d in a ratio of 2.3:1 as yellow oils (115 mg, 60%).
Data for 5d. 81 mg, 42%; Rf 0.38 (petrol–EtOAc, 3:1);
νmax(film)/cmϪ1 2980 (m), 2933 (m), 1724 (br, s), 1515 (w);
δH (400 MHz, CDCl3) 1.30 (3H, t, J 7.1, CH2CH3), 1.44 (9H, s,
t
(CO2 Bu); m/z (APCIϩ) 496 (M ϩ Hϩ, 33%), 440 (100), 262
t
(57); HRMS (CIϩ) 496.2335, C28H33NO7 (M ϩ Hϩ) requires
496.2335.
C(CH3)3), 1.66 (1H, dd, J 16.4 and 11.2, CHCO2 Bu), 2.33 (3H,
t
s, ArCH3), 2.43, (1H, dd, J 16.4 and 3.8, CHCO2 Bu), 3.53–3.62
(1H, m, H-6), 3.70 (1H, dd, J 13.7 and 7.5, H-4endo), 3.86–4.00
(1H, m, H-5), 4.33 (2H, q, J 7.0, CH2CH3), 4.42–4.45 (1H, m,
H-4exo), 6.42 (1H, s, H-2), 7.00 (2H, d, J 8.2, ArH), 7.14 (2H, d,
J 8.2, ArH), 7.34–7.60 (5H, m, ArH), δC (100.7 MHz, CDCl3)
14.05 (CH2CH3), 20.85 (ArCH3), 26.78 (C(CH3)3), 34.36
Data for acetate 7. Rf 0.30 (EtOAc–petrol (40–60), 1:2);
νmax(film)/cmϪ1 1728 (s), 1370 (m), 1231 (m), 1155 (m); δH (500
MHz, CDCl3) 1.31 (3H, t, J 7.0, CH3CH2), 1.45 (9H, s,
C(CH3)3), 2.23 (3H, s, COCH3), 2.51 (1H, dd, J 17.0 and 11.0,
t
t
t
CHHCO2 Bu), 2.86 (1H, dd, J 17.0 and 3.5, CHHCO2 Bu),
3.12–3.16 (1H, m, H-6), 3.88–3.93 (2H, m, H-4H and H-5),
4.27–4.37 (2H, m, CH3CH2), 4.37–4.42 (1H, m, H-4H), 6.33
(1H, s, H-2), 7.33–7.39 (3H, m, ArH), 7.44–7.46 (2H, m, ArH);
δC (125.8 MHz, CDCl3) 13.98 (CH3CH2), 21.07 (COCH3),
(CH2CO2 Bu), 47.23 (C-6), 61.95 (CH2CH3), 62.16 (C-5), 68.04
(C-7), 72.57 (C-4), 81.30 (C(CH3)3), 86.38 (C-2), 126.01, 127.74,
128.67, 129.03 and 132.34 (ArCH), 137.67 and 137.96 (ArC),
169.45, 170.34 and 170.71 (CO); m/z (CI, NH3) 480 (MHϩ,
30%), 424 (100); HRMS 480.2385. C28H33NO6 (M ϩ Hϩ)
requires 480.2386.
t
28.02 (C(CH3)3), 34.71 (CH2CO2 Bu), 44.68 (C-6), 61.27 (C-5),
62.63 (CH3CH2), 72.58 (C-4), 81.69 (C(CH3)3), 87.16 (C-2),
88.07 (C-7), 126.14, 128.49 and 128.86 (ArCH), 137.69 (ArC),
165.19, 166.63, 169.37 and 170.57 (4 × CO); m/z (CI(NH3)) 448
(M ϩ Hϩ, 92%), 392 (69); HRMS (CIϩ) 448.1971, C23H30NO8
(M ϩ Hϩ) requires 448.1971.
Data for 6d. 34 mg, 18%; Rf 0.38 (petrol–EtOAc, 3:1);
νmax(film)/cmϪ1 2980 (m), 2933 (m), 1724 (br, s), 1515 (w);
δH (400 MHz, CDCl3) 1.30 (3H, t, J 7.1, CH2CH3), 1.41 (9H,
s, C(CH3)3), 2.36 (3H, s, ArCH3), 2.72, (2H, d, J 7.6, CH2-
t
CO2 Bu), 3.08–3.12 (1H, m, H-6), 3.86–3.90 (1H, m, H-4endo),
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-6-tert-Butoxycarbonyl-
methyl-7-ethoxycarbonyl-7-m-methoxyphenyl-3-oxa-8-oxo-2-
phenyl-1-azabicyclo[3.3.0]octanes 5c and 6c
4.01–4.15 (1H, m, H-5), 4.24–4.29 (1H, m, H-4exo), 4.34 (2H, q,
J 7.1, CH2CH3), 6.36 (1H, s, H-2), 7.20–7.60 (9H, m, ArH);
δC (100.7 MHz, CDCl3) 13.66 (CH2CH3), 20.27 (ArCH3), 27.43
t
(C(CH3)3), 35.45 (CH2CO2 Bu), 44.17 (C-6), 61.00 (C-5), 61.62
According to Method 4, lactam 4a (118 mg, 0.30 mmol) and
m-methoxyphenyllead triacetate21 (161 mg, 0.42 mmol) were
reacted together to give a pale yellow oil (126 mg, 84%). The
two diastereomers 5c and 6c were present in the ratio 4:1 but
were not separable by flash column chromatography.
(CH2CH3), 69.02 (C-7), 72.10 (C-4), 80.45 (C(CH3)3), 86.59
(C-2), 125.79, 127.61, 127.96, 128.11, 128.32 and 128.97
(ArCH), 137.23 and 138.36 (ArC), 169.52, 170.53 and 170.23
(CO); m/z (CI, NH3) 480 (MHϩ, 30%), 424 (100); HRMS
480.2385. C28H33NO6 (MHϩ) requires 480.2386.
Data for 5c. 101 mg, 67%; Rf 0.36 (petrol–EtOAc, 3:1);
νmax(CHCl3)/cmϪ1 2982 (m), 1720 (br, s), 1515 (m); δH (400
MHz, CDCl3) 1.32 (3H, t, J 7.1, CH2CH3), 1.41 (9H, s,
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-6-tert-Butoxycarbonyl-
methyl-7-ethoxycarbonyl-3-oxa-8-oxo-2-phenyl-7-p-trifluoro-
methylphenyl-1-azabicyclo[3.3.0]octanes 5e and 6e
t
C(CH3)3), 1.66 (1H, dd, J 16.5 and 11.5, CHCO2 Bu), 2.45 (1H,
t
dd, J 16.5 and 3.7, CHCO2 Bu), 3.54–3.58 (1H, m, H-6), 3.60
According to Method 4, lactam 4a (106 mg, 0.27 mmol) was
reacted with p-trifluoromethylphenyllead triacetate21 (151 mg,
0.36 mmol) to yield two separate diastereomers 5e, 6e in a 2.3:1
ratio (104 mg, 72%).
(3H, s, OCH3), 3.73 (1H, dd, J 13.8 and 7.7, H-4endo), 3.85–3.95
(1H, m, H-5), 4.35 (2H, q, J 7.1, CH2CH3), 4.44–4.48 (1H, m,
H-4exo), 6.43 (1H, s, H-2), 6.64–7.61 (9H, m, ArH); δC (50.3
MHz, CDCl3) 13.91 (CH2CH3), 27.91 (C(CH3)3), 35.74
t
(CH2CO2 Bu), 44.29 (C-6), 54.96 (ArOCH3), 61.11 (C-5), 62.40
Data for 5e. Yellow oil; 72 mg, 50%; Rf 0.39 (petrol–EtOAc,
3:1); νmax(film)/cmϪ1 3019 (br, m), 2930 (m), 1721 (br, s), 1515
(w); δH (400 MHz, CDCl3) 1.31 (3H, t, J 7.1, CH2CH3), 1.41
(CH2CH3), 69.70 (C-7), 72.89 (C-4), 81.32 (C(CH3)3), 86.67
(C-2), 113.02, 114.15, 120.60, 126.23, 128.78 and 129.03
(ArCH), 135.6, 138.75 and 160.12 (ArC), 170.0, 170.2 and
171.29 (CO); m/z (CI, NH3) 440 (52%); HRMS 496.2335.
C28H33NO6 (M ϩ Hϩ) requires 496.5485.
t
(9H, s, C(CH3)3), 1.64 (1H, dd, J1 16.4, J2 10.7, CHCO2 Bu),
t
2.39 (1H, dd, J1 16.4, J2 4.0, CHCO2 Bu), 3.63–3.74 (2H, m,
H-4endo and H-6), 3.97–4.01 (1H, m, H-5), 4.35 (2H, q, J 7.1,
CH2CH3), 4.42–4.46 (1H, m, H-4exo), 6.42 (1H, s, H-2), 7.26
(2H, d, J 7.2, ArH), 7.38–7.47 (3H, m, ArH), 7.56 (2H, m,
ArH), 7.61 (2H, d, J 7.2, ArH); δC (100.7 MHz, CDCl3) 13.98
Data for 6c. 25 mg, 17%; Rf 0.36 (petrol–EtOAc, 3:1); νmax
/
cmϪ1 (CHCl3) 2982 (m), 1720 (s), 1515 (m); δH (400 MHz,
CDCl3) 1.25 (3H, t, J 7.1, CH2CH3), 1.44 (9H, s, C(CH3)3),
t
(CH2CH3), 27.96 (C(CH3)3), 35.80 (CH2CO2 Bu), 44.32 (C-6),
t
2.74–2.76 (2H, m, CH2CO2 Bu), 3.08–3.11 (1H, m, H-6), 3.82
61.35 (C-5), 62.72 (CH2CH3), 69.66 (C-7), 72.56 (C-4), 81.58
(C(CH3)3), 87.03 (C-2), 125.72, 125.75, 126.02, 128.51, 128.64,
128.67 and 128.99 (ArCH), 138.09 and 138.10 (ArC), 169.21,
170.12 and 170.43 (CO); m/z (CI, NH3) 534 (MHϩ, 12%), 478
(100); HRMS 534.2097. C28H33NO6 (M ϩ Hϩ) requires
534.2103.
(3H, s, OCH3), 3.90 (1H, dd, J 8.9 and 7.3, H-4endo), 4.12 (1H,
dt, J 7.2 and 7.2, H-5), 4.28 (2H, q, J 7.1, CH2CH3), 4.32–4.38
(1H, m, H-4exo), 6.37 (1H, s, H-2), 6.88–7.60 (9H, m, ArH);
δC (50.3 MHz, CDCl3) 13.91 (CH2CH3), 27.91 (C(CH3)3), 34.5
t
(CH2CO2 Bu), 47.9 (C-6), 55.2 (ArOCH3), 61.9 (C-5), 62.05
(CH2CH3), 68.2 (C-7), 72.2 (C-4), 81.5 (C(CH3)3), 86.6 (C-2),
113.1, 114.2, 120.2, 128.7, 129.0 and 129.8 (ArCH), 137.0,
138.1 and 159.9 (ArC), 169.7, 170.2 and 171.3 (CO); m/z (CI,
NH3) 440 (52%); HRMS 496.2335. C28H33NO6 (M ϩ Hϩ)
requires 496.5485.
Data for 6e. Colourless oil; 22%; Rf 0.49 (petrol–EtOAc,
3:1); νmax(film)/cmϪ1 3019 (br), 2930 (m), 1721 (br, s), 1515 (w);
δH (400 MHz, C6D6) 0.69 (3H, t, J 7.1, CH2CH2), 1.24 (9H, s,
t
C(CH3)3), 2.69–2.81, (2H, m, CH2CO2 Bu), 2.98–3.02 (1H, m,
H-6), 3.73 (2H, q, J 7.1, CH2CH3), 3.83–3.86 (1H, m, H-4endo),
3.89–3.93 (1H, m, H-5), 4.28–4.31 (1H, m, H-4exo), 6.48 (1H, s,
H-2), 7.14–7.18 (3H, m, ArH), 7.29 (2H, d, J 8.4, ArH), 7.40
(2H, d, J 7.2, ArH), 7.61 (2H, d, J 7.4, ArH); δC (101 MHz,
CDCl3) 14.0 (CH2CH3), 28.1 (C(CH3)3), 34.8 (CH2CO2 Bu),
47.2 (C-6), 62.0 (CH2CH3), 62.6 (C-5), 68.3 (C-7), 72.3 (C-4),
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-7-Ethoxycarbonyl-6-tert-
butoxycarbonylmethyl-7-p-methylphenyl-3-oxa-8-oxo-2-phenyl-
1-azabicyclo[3.3.0]octanes 5d and 6d
t
According to Method 4, lactam 4a (156 mg, 0.40 mmol) was
reacted with p-methylphenyllead triacetate21 (200 mg, 0.55
2798
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804

View Article Online
81.8 (C(CH3)3), 86.2 (C-2), 125.0, 125.9, 126.0, 128.3 and 128.9
(ArCH), 136.1, 137.8 and 139.1 (ArC), 168.6, 169.7 and 170.3
(CO); m/z (CI, NH3) 534 (MHϩ, 12%), 478 (100); HRMS
534.2097. C28H33NO6 (M ϩ Hϩ) requires 534.2103.
quenched by adding NH4Cl (sat. aq.) (2 ml) and then water
(5 ml) to dissolve the white precipitate. The mixture was
extracted with DCM (3 × 10 ml), dried (MgSO4) and evapor-
ated in vacuo to give a colourless oil which was purified using
flash column chromatography (EtOAc–cyclohexane, 5:1) to
give the products as single diastereomers as colourless oils in a
total yield of 75%.
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-7-p-Bromophenyl-6-tert-
butoxycarbonylmethyl-7-ethoxycarbonyl-3-oxa-8-oxo-2-phenyl-
1-azabicyclo[3.3.0]octanes 5f and 6f
Data for 5h. 0.21 g, 34%; Rf 0.19 (EtOAc–cyclohexane, 5:1);
[α]D23 ϩ66.6 (c 0.35 in CHCl3); νmax(film)/cmϪ1 2980 (w), 1727 (s),
1368 (m), 1221 (m), 1156 (m), 700 (m); δH (300 MHz, CDCl3)
1.34 (3H, t, J 7.0, CH3CH2), 1.47 (1H, s, C(CH3)3), 2.58–2.70
According to Method 2, lactam 4a (33 mg, 0.08 mmol) was
reacted with p-bromophenyllead() triacetate (92 mg, 0.17
mmol) in pyridine (34 mg, 0.42 mmol) and CHCl3 (2 ml) at
reflux for 41 h giving, after work-up, a yellow oil containing
solid material. The crude product ratio 5f:6f was 2.3:1. Purifi-
cation by column chromatography (Et2O–petrol (40–60), 1:2)
gave the inseparable products 5f:6f (34 mg, 74%).
t
(2H, m, CH2CO2 Bu), 2.98 (1H, d, J 14.0, CHHPh), 3.19–3.27
(1H, m, H-6), 3.32–3.39 (1H, m, H-5), 3.49 (1H, d, J 14.0,
CHHPh), 3.78 (1H, dd, J 9.0 and 7.5, H-4endo), 4.23 (1H, dd,
J 9.0 and 6.0, H-4exo), 4.25–4.34 (2H, m, CH3CH2), 6.29 (1H, s,
H-2), 7.05–7.36 (10H, m, ArH); δC
(50.3 MHz, CDCl3) 14.1
Data for 5f. Rf 0.29; νmax(film)/cmϪ1 2979 (w), 1721 (s), 1492
(w), 1368 (m), 1243 (m), 1153 (m), 1079 (w), 1028 (w), 1012 (w),
757 (w), 741 (w), 699 (w); δH (300 MHz, CDCl3) 1.31 (3H, t, J
7.0, CH3CH2), 1.41 (9H, s, C(CH3)3), 1.67 (1H, dd, J 16.5 and
t
(CH3CH2), 28.0 (C(CH3)3), 33.8 and 35.7 (CH2CO2 Bu and
CH2Ph), 45.4 (C-6), 61.8 (C-5), 62.1 (CH2CH3), 64.8 (C-7), 72.5
(C-4), 81.6 (C(CH3)3), 86.5 (C-2), 126.3, 127.0, 128.2, 128.3,
128.7 and 130.5 (ArCH), 135.5 (ArC), 137.8 (ArC), 170.6,
171.9 (3 × CO); m/z (APCIϩ) 480 (M ϩ Hϩ, 58%); HRMS
(CIϩ) 480.2386, C28H34NO6 (M ϩ Hϩ) requires 480.2386.
t
t
11.0, CHHCO2 Bu), 2.38 (1H, dd, 16.5 and 4.0, CHHCO2 Bu),
3.56–3.72 (2H, m, H-5 and H-6), 3.97 (1H, dd, J 9.0 and 7.5,
H-4endo), 4.34 (2H, q, J 7.0, CH3CH2), 4.43 (1H, dd, J 9.0 and
6.0, H-4exo), 6.41 (1H, s, H-2), 6.98–7.02 (2H, m, ArH), 7.36–
7.50 (5H, m, ArH), 7.54–7.57 (2H, m, ArH); δC (50.3 MHz,
Data for 6h. 0.25 g, 41%; Rf 0.29 (EtOAc–cyclohexane, 5:1);
[α]D26 ϩ146.3 (c 0.23 in CHCl3); νmax(film)/cmϪ1 2980 (w), 1728 (s),
1710 (s), 1368 (m), 1226 (m), 1155 (m), 701 (m); δH (300 MHz,
CDCl3) 1.30 (3H, t, J 7.0, CH3CH2), 1.41 (9H, s, C(CH3)3),
t
CDCl3) 14.0 (CH3CH2), 28.0 (C(CH3)3, 35.8 (CH2CO2 Bu),
44.3 (C-6), 61.3 (C-5), 62.5 (CH3CH2), 69.3 (C-7), 72.5 (C-4),
81.4 (C(CH3)3), 87.0 (C-2), 122.2 (ArC), 126.0, 128.6, 128.9,
129.8, 131.9 (ArCH), 133.1 (ArC), 138 (ArC), 169.4, 170.3
and 170.5 (3 × CO); m/z (APCIϩ) 546 (M(81Br) ϩ Hϩ, 12%),
544 (M(79Br) ϩ Hϩ, 8), 490 (100); HRMS (CIϩ) 544.1335,
C27H3179BrNO6 requires 544.1335.
t
2.26–2.42 (2H, m, CH2CO2 Bu), 2.55–2.62 (1H, m, H-6), 3.12
(1H, t, J 8.5, H-4endo), 3.20 (1H, d, J 14.0, CHHPh), 3.47 (1H, d,
J 14.0, CHHPh), 3.90–3.97 (1H, m, H-5), 4.16 (1H, dd, J 8.5
and 6.0, H-4exo), 4.21–4.31 (2H, m, CH3CH2), 6.17 (1H, s, H-2),
7.26–7.45 (10H, m, ArH); δC (50.3 MHz, CDCl3) 14.1
t
(CH3CH2), 28.0 (C(CH3)3), 35.13 and 36.47 (CH2CO2 Bu and
Data for 6f. Rf 0.40; δH (300 MHz, CDCl3) 1.25 (3H, t, J 7.0,
CH3CH2), 1.45 (9H, s, C(CH3)3), 2.63–2.73 (2H, m, CH2CO2-
tBu), 3.02–3.09 (1H, m, H-6), 3.89 (1H, dd, J 9.0 and 7.0
H-4endo), 4.08–4.15 (1H, m, H-5), 4.21–4.38 (3H, m, H-4exo and
CH3CH2), 6.35 (1H, s, H-2), 7.28–7.57 (9H, m, ArH); other
data as for 5f above.
CH2Ph), 41.2 (C-6), 62.0 (CH3CH2), 62.8 (C-5), 65.4 (C-7), 72.4
(C-4), 81.4 (C–CH3)3), 86.2 (C-2), 126.00, 127.2, 128.4, 128.6,
128.7 and 130.8 (ArCH), 136.0 (ArC), 138.1 (ArC), 169.7,
170.6 and 171.0 (3 × CO); m/z (APCIϩ) 480 (M ϩ Hϩ, 16%),
424 (100); HRMS (CIϩ) 480.2386, C28H34NO6 (M ϩ Hϩ)
requires 480.2386.
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-6-tert-Butoxycarbonyl-
methyl-7-ethoxycarbonyl-7-p-methoxyphenyl-3-oxa-8-oxo-2-
phenyl-1-azabicyclo[3.3.0]octanes 5g and 6g
N-Benzylvalerolactam 8a22,23
To a stirred solution of δ-valerolactam (1.95 g, 20 mmol) in dry
THF (27 ml) at 0 ЊC was added pre-washed sodium hydride
(0.57 g, 24 mmol). After stirring for 30 mins, benzyl bromide
(3.7 g, 22 mmol) was added and stirring was continued at rt for
2 h and then heated under reflux for 19 h. After cooling to rt,
the reaction was quenched with sat. NH4Cl (10 ml) and the
aqueous phase washed with EtOAc (3 × 15 ml). The organic
layers were combined, washed with water (15 ml), dried
(MgSO4) and the solvent removed in vacuo to yield a yellow oil.
The oil was purified by flash column chromatography (petrol–
EtOAc, 2:1) to give the title compound (1.6 g, 85%). Rf 0.11
(petrol–EtOAc, 2:1); νmax (film)/cmϪ1 3028 (w), 2945 (m), 2965
(m), 1650 (s); δH (200 MHz, CDCl3) 1.78–1.81 (4H, m, 2 × H-4
and 2 × H-5), 2.48 (2H, t, J 6.5, 2 × H-3), 3.20 (2H, t, J 6.0,
2 × H-6), 4.61 (2H, s, CH2Ph), 7.25–7.35 (5H, m, ArH); m/z
(CI, NH3) 190 (MHϩ, 100%).
According to Method 3, lactam 4a (57 mg, 0.15 mmol) was
reacted with p-methoxyphenyllead() triacetate (0.20 g, 0.40
mmol) to give a yellow/brown oil (73 mg) which was purified
using flash column chromatography (Et2O–cyclohexane, 1:2)
to give the inseparable products 5g:6g in the ratio 2.3:1 as a
colourless glass (45 mg, 38%); Rf 0.18 (Et2O–petrol (40–60).
Data for 5g. δH (300 MHz, CDCl3) 1.41 (9H, s, C(CH3)3),
t
1.68 (1H, dd, J 16.5 and 11.0, CHHCO2 Bu), 2.41 (1H, dd,
t
J 16.5 and 4.0, CHHCO2 Bu), 3.79 (3H, s, OCH3), 6.41 (1H, s,
H-2), 6.84–6.87 (2H, m, ArH), 7.02–7.05 (2H, m, ArH); m/z
(APClϩ) 496 (M ϩ Hϩ, 79%) 440 (100).
Data for 6g. δH (300 MHz, CDCl3) 1.41 (9H, s, C(CH3)3),
t
2.68–2.71 (2H, m, CH2CO2 Bu), 3.82 (3H, s, OCH3), 6.41 (1H,
s, H-2), 7.02–7.05 (2H, m, ArH), 6.93–6.96 (2H, m, ArH);
m/z data as above for 5g.
N-Benzyl-3-chlorovalerolactam 8b and N-benzyl-3,3-dichloro-
valerolactam
(2R,5S,6S,7S)- and (2R,5S,6S,7R)-7-Benzyl-6-tert-butoxycarb-
onylmethyl-7-ethoxycarbonyl-3-oxa-8-oxo-2-phenyl-1-azabi-
cyclo[3.3.0]octanes 5h and 6h
To a stirred solution of lactam 8b (1.3 g, 7.0 mmol) in dry THF
(10 ml) at Ϫ78 ЊC under an inert atmosphere, was added sec-
butyllithium (0.91 M in hexanes, 8.5 ml, 7.7 mmol) and the
reaction mixture was stirred for 30 mins. Toluene-p-sulfonyl
chloride (2.0 g, 11 mmol) in dry THF (5 ml) was added and the
reaction mixture slowly warmed to rt. After 16 h the resulting
suspension was quenched with sat. NH4Cl (20 ml) and the
aqueous layer was washed with EtOAc (3 × 10 ml). The organic
To a stirred suspension of pre-washed NaH (32 mg, 1.4 mmol)
in THF in a nitrogen atmosphere (3 ml) was added a solution of
the lactam 4a (0.50 g, 1.3 mmol) in THF (6 ml) at 0 ЊC. Benzyl
bromide (0.24 g, 1.4 mmol) was then added to the solution
which was then heated at reflux for 14 h; the reaction was
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
2799

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layers were combined, washed with water (15 ml), dried
(MgSO4), and the solvent removed in vacuo to yield a yellow oil.
Purification by flash column chromatography (petrol–EtOAc,
3:2) afforded both the mono-substituted product 8b as a yellow
solid (1.11 g, 71%) and the dichloro product as an orange solid
(0.075 g, 4%).
(C-7), 72.47 (C-4), 80.77 (C(CH3)3), 86.68 (C-2), 126.11, 127.30,
127.40, 127.85, 128.14, 128.40 and 128.50 (ArCH), 136.87,
137.01 and 138.06 (ArC), 168.99, 170.03, 171.72 and 172.17
(CO); m/z (CI, NH3) 577 (MHϩ, 100%), 521 (8); HRMS
577.2907. C33H41N2O7 (MHϩ) requires 577.2914.
Data for 9b. 48 mg, 17%; Rf 0.54 (petrol–EtOAc, 1:1);
νmax(CHCl3)/cmϪ1 3020 (m), 1718 (s), 1637 (s); δH (400 MHz,
CDCl3) 1.32 (3H, t, J 7.1, CH2CH3), 1.46 (9H, s, C(CH3)3),
1.50–1.56, (1H, m, ring proton), 1.82–1.96 (2H, m, CH2), 2.21–
2.29 (1H, m, ring proton), 2.53 (2H, d, J 5.4, CH2), 2.84–2.89
(1H, m, H-6), 3.16–3.22 (2H, m, CH2), 3.36 (1H, dd, J 12.8 and
5.1, ring proton), 3.89–3.91 (2H, m, H-4endo and H-5), 4.26–4.37
(3H, m, H-4exo and CH2CH3), 4.60 (1H, d, J 14.8, CHHPh),
4.63 (1H, d, J 14.8, CHHPh), 6.37 (1H, s, H-2), 7.25–7.50 (10H,
m, ArH); δC (100.7 MHz, CDCl3) 14.12 (CH2CH3), 22.63
(CH2), 23.41 (CH2), 28.02 (C(CH3)3), 36.44 (CH2), 41.77 (C-6),
44.83 (CH2), 46.06 (CH2), 50.52 (CH2Ph), 61.74 (CH2CH3),
63.14 (C-5), 65.56 (C-7), 71.78 (C-4), 81.44 (C(CH3)3), 87.08
(C-2), 126.02, 126.26, 127.18, 127.51, 128.00, 128.04, 128.31
and 128.65 (ArCH), 137.15 and 138.36 (ArC), 167.85, 169.78,
171.01 and 171.78 (CO); m/z (CI, NH3) 577 (MHϩ, 100%), 521
(8); HRMS 577.2907, C33H41N2O7 (MHϩ) requires 577.2914.
Data for 8b. Rf 0.28 (petrol–EtOAc, 2:1); mp 72–73 ЊC;
νmax(CHCl3)/cmϪ1 3012 (m), 2963 (m), 1649 (s), 1494 (m); δH
(500 MHz, CDCl3) 1.79 (1H, m, H-5), 2.22 (3H, m, 2 × H-4 and
H-5), 3.25 (2H, m, 2 × H-6), 4.46 (1H, d, J 14.6, CHHPh), 4.52
(1H, t, J 4.5, CHCl), 4.73 (1H, d, J 14.6, CHHPh), 7.25–7.36
(5H, m, ArH); δC (125.8 MHz, CDCl3) 18.41 (C-5), 30.95 (C-4),
46.89 (C-6), 50.46 (CH2Ph), 54.97 (C-3), 127.55, 127.97 and
128.62 (ArCH), 136.38, (ArC), 166.02 (C-2); m/z (CI, NH3) 226
(MHϩ, 37Cl, 12%), 224 (MHϩ, 35Cl, 39), 190 (100); HRMS
224.0842. C12H15NOCl (M ϩ Hϩ) requires 224.0842.
Dichlorovalerolactam. Rf 0.47 (petrol–EtOAc, 2:1); mp 70–
73 ЊC; νmax (CHCl3)/cmϪ1 2969 (m), 1678 (s); δH (500 MHz,
CDCl3) 2.01–2.07 (2H, m, 2 × H-5), 2.77–2.80 (2H, m, 2 × H-
4), 3.30 (2H, t, J 6.2, 2 × H-6), 4.60 (2H, s, CH2Ph), 7.25–7.36
(5H, m, ArH); δC (125.8 MHz, CDCl3) 19.93 (C-5), 43.56 (C-4),
47.13 (C-6), 51.30 (CH2Ph), 82.92 (C-3), 127.73, 127.93 and
128.71 (ArCH), 135.84 (ArC), 163.68 (C-2); m/z (CI, NH3) 262
(M ϩ Hϩ, 12%), 260 (69), 258 (100), 224 (35), 190 (100).
General method for deprotection
To a solution of the N,O-acetal in DCM at rt was added TFA.
After the specified time period, the acid was neutralised by
careful addition of saturated aqueous sodium hydrogen
carbonate solution or an aqueous solution of sodium hydroxide
with stirring in an ice bath. After separation of the two layers,
and extraction of the aqueous with DCM, the organics were
dried (MgSO4) and evaporated in vacuo to give the crude prod-
uct which was purified using flash column chromatography.
N-Benzyl-3-iodovalerolactam 8c
A solution of lactam 8b (388 mg, 1.2 mmol) and sodium iodide
(32 mg, 2.2 mmol) in acetone (10 ml) were heated under reflux
for 17 h. After cooling to rt, the resulting precipitate was
removed by filtration and the filtrate concentrated in vacuo. The
concentrate was dissolved in EtOAc (10 ml), washed with water
(10 ml), dried (MgSO4) and the solvent removed in vacuo. Puri-
fication by flash column chromatography (petrol–EtOAc, 1:1)
afforded the title compound 8c as a yellow oil (510 mg, 90%). Rf
0.40 (petrol–EtOAc, 1:1); νmax(CHCl3)/cmϪ1 3007 (m), 1636 (s);
δH (200 MHz, CDCl3) 1.78–1.85 (1H, m, H-5), 2.01–2.10 (1H,
m, H-5), 2.18–2.29 (2H, m, 2 × H-4), 3.35–3.42 (2H, m, 2 × H-
6), 4.42 (1H, d, J 14.5, CHHPh), 4.82, (1H, d, J 14.5, CHHPh),
4.92–4.95 (1H, m, CHCl), 7.26–7.37 (5H, m, ArH); δC (125.8
MHz, CDCl3) 20.53 (C-5), 23.17 (C(3)), 32.49 (C-4), 46.85
(C-6), 50.52 (CH2Ph), 127.52, 128.00 and 128.66 (ArCH),
136.65 (ArC), 167.84 (C-2); m/z (CI, NH3) 316 (MHϩ, 42%),
190 (100); HRMS 316.0198, C12H15NOI (M ϩ Hϩ) requires
316.1476.
(2S,3S,4R)- and (2S,3S,4S)-3-tert-Butoxycarbonylmethyl-4-
ethoxycarbonyl-2-hydroxymethyl-5-oxo-4-phenylpyrrolidines
10a and 11a
Following the general method, the lactam 5a, 6a (2.1:1) (0.17 g,
0.35 mmol), was reacted with TFA (1.5 ml) in DCM (10 ml)
for 45 min. Purification using flash column chromatography
(EtOAc–petrol (40–60), 1:1 and then EtOAc–petrol (40–60)–
MeOH, 200:200:15) gave the title compound as two diastereo-
mers in a combined yield of 81%.
Data for 10a. White crystalline solid (70 mg, 53%); Rf 0.24
(EtOAc–petrol (40–60)–MeOH, 20:15:2); [α]D22 Ϫ42.0 (c 0.35,
CHCl3); mp 138–142 ЊC; νmax(CHCl3)/cmϪ1 3424 (m), 3248 (m,
br), 1720 (s), 1369 (m), 1228 (s), 1154 (s), 1095 (m), 1055 (m),
1037 (m), 946 (w), 701 (m); δH (300 MHz, CDCl3, c 34.6 mg
mlϪ1) 1.30 (3H, t, J 7.0, CH3CH2), 1.40 (9H, s, C(CH3)3), 1.86
(2R,5S,6S,7R)- and (2R,5S,6S,7S)-7-(N-Benzyl-2-oxopiperidin-
3-yl)-6-tert-butoxycarbonylmethyl-7-ethoxycarbonyl-3-oxa-8-
oxo-2-phenyl-1-azabicyclo[3.3.0]octanes 9a and 9b
t
Lactam 4a (195 mg, 0.50 mmol) in dry THF (2 ml) was reacted
with sodium hydride (17 mg, 0.70 mmol) and subsequently with
a solution of iodolactam 8c (150 mg, 0.48 mmol) in dry THF
(2 ml). Purification by flash column chromatography (petrol–
EtOAc, 3:2), gave the two separable diastereomers 9a and 9b in
a 1.1:1 ratio and as pale yellow oils (102 mg, 36%).
(2H, d, J 7.5, CH2CO2 Bu), 3.24–3.29 (1H, m, H-3), 3.55 (1H,
br s, OH), 3.53–3.61 (3H, m, H-2 and CHHOH), 3.76 (1H, dd,
J 11.5 and 3.0, CHHOH), 4.24–4.41 (2H, m, CH3CH2), 7.19–
7.38 (5H, m, ArH), 7.56 (1H, br s, NH); δC (125.8 MHz,
t
CDCl3) 13.96 (CH3CH2), 27.95 (C(CH3)3), 36.01 (CH2CO2 Bu),
41.07 (C-3), 59.01 (C-2), 62.42 (CH3CH2), 63.63 (CH2OH),
64.85 (C-4), 81.22 (C(CH3)3), 127.83, 128.45 and 128.61
(ArCH), 134.13 (C-6), 170.47, 171.31 and 173.87 (3 × CO); m/z
(APCIϩ) 378 (M ϩ Hϩ, 14%), 322 (100), 250 (9); HRMS
378.1917, C20H28NO6 requires 378.1917.
Data for 9a. 54 mg, 19%; Rf 0.64 (petrol–EtOAc, 1:1);
νmax(CHCl3)/cmϪ1 3020 (m), 1718 (s), 1637 (s); δH (400 MHz,
CDCl3) 1.27 (3H, t, J 7.2, CH2CH2), 1.44 (9H, s, C(CH3)3),
1.69–1.96, (4H, m, 2 × CH2), 2.06–2.09 (1H, m, ring proton),
2.88–2.92 (1H, m, ring proton), 3.18–3.27 (3H, m, H-6 and
CH2), 3.44–3.48 (1H, m, ring proton), 3.86–3.92 (1H, m, H-
4endo), 4.06–4.15 (1H, m, H-5), 4.21–4.31 (3H, m, H-4exo and
CH2CH3), 4.53 (1H, d, J 14.8, CHHPh), 4.58 (1H, d, J 14.8,
CHHPh), 6.27 (1H, s, H-2), 7.16–7.47 (10H, m, ArH); δC (100.7
MHz, CDCl3) 13.96 (CH2CH3), 22.69 (CH2), 22.99 (CH2),
28.09 (C(CH3)3), 35.11 (CH2), 42.00 (C-6), 45.02 (CH2), 48.82
(CH2), 50.29 (CH2Ph), 61.47 (CH2CH3), 62.81 (C-5), 65.60
Data for 11a. Colourless oil (38 mg, 28%); Rf 0.32 (EtOAc–
petrol (40–60)–MeOH, 20:15:2); [α]D23 Ϫ14.1 (c 0.425 in CHCl3);
νmax(film)/cmϪ1 3336 (m, br), 2979 (m), 1724 (s), 1368 (m), 1300
(m), 1232 (m), 1153 (s), 1063 (m), 847 (w), 699 (m); δH (300
MHz, CDCl3, c 9 mg mlϪ1) 1.28 (3H, t, J 7.0, CH3CH2), 1.44
t
(9H, s, C(CH3)3), 2.53 (1H, dd, J 17.0 and 10.0, CHHCO2 Bu),
t
2.72 (2H, dd, J 17.0 and 2.5, CHHCO2 Bu and OH), 3.18–3.25
(1H, m, H-3), 3.52 (1H, dd, J 12.0 and 5.5, CHHOH), 3.67–
2800
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804

View Article Online
3.71 (1H, m, H-2), 3.80 (1H, dd, J 12.0 and 3.0, CHHOH),
4.22–4.32 (2H, m, CH3CH2), 6.41 (1H, br s, NH), 7.29–7.41
(3H, m, ArH), 7.44–7.48 (2H, m, ArH ortho- to C-6); δC
(50.3 MHz, CDCl3) 14.1 (CH3CH2), 27.9 (C(CH3)3), 34.6
3.06 (1H, d, J 14.5, CHHPh), 3.24 (1H, dd, J 16.0 and 7.5, H-
2), 3.40–3.47 (1H, m, CHHOH), 3.45 (1H, d, J 14.5, CHHPh),
3.60–3.69 (1H, m, CHHOH), 4.20–4.31 (2H, m, CH3CH2), 6.43
(1H, s, NH), 7.23–7.34 (5H, m, ArH); δC (50.3 MHz, CDCl3, c
64 mg mlϪ1) 13.9 (CH3CH2), 28.0 (C(CH3)3), 33.4 and 35.2
t
(CH2CO2 Bu), 42.4 (C-3), 59.9 (C-2), 62.0 (CH3CH2), 62.8
t
(CH2OH), 63.8 (C-4), 81.8 (C(CH3)3), 127.7, 128.0 and 128.3
(ArCH), 136.3 (C-6), 169.6, 171.8 and 173.1 (3 × CO); m/z
(APCIϩ) 378 (M ϩ Hϩ, 8%), 322 (100).
(CH2CO2 Bu and CH2Ph), 41.3 (C-3), 59.3 (C-2), 59.8 (C-4),
61.9 (CH3CH2), 63.1 (CH2OH), 81.5 (C(CH3)3), 127.0, 128.3
and 130.2 (ArCH), 135.9 (C-7), 170.9, 171.6 and 175.3
(3 × CO); m/z (APCIϩ) 392 (M ϩ Hϩ, 6%), 336 (100); HRMS
392.2073, C21H30NO6 requires 392.2073.
(2S,3S,4R)- and (2S,3S,4S)-3-tert-Butoxycarbonylmethyl-4-
ethoxycarbonyl-2-hydroxymethyl-4-p-methoxyphenyl-5-oxo-
pyrrolidines 10b and 11b
(2S,3S,4R)-4-Benzyl-3-tert-butoxycarbonylmethyl-4-ethoxy-
carbonyl-2-hydroxymethyl-5-oxopyrrolidine 11c
Following the general method, lactam 5g, 6g (31 mg), was
reacted with TFA (0.3 ml) in DCM (2 ml) for 45 min. Purifi-
cation by recrystallisation from EtOAc–petrol (40–60) gave the
major diastereomer 10b as a white solid (4 mg, 25%). Purifi-
cation of the mother liquor by chromatography (EtOAc–petrol
(40–60)–MeOH, 20:20:2) gave the minor diastereomer 11b as a
colourless oil (2 mg, 13%).
Following the general method, the lactam 6h (0.11 g, 0.23
mmol), was reacted with TFA (0.65 ml) in DCM (13 ml) for 1 h.
Purification using flash column chromatography (EtOAc–
petrol (40–60)–MeOH, 20:15:1) gave the title compound as a
colourless crystalline solid, as a single diastereomer (70 mg,
77%); Rf 0.27 (EtOAc–petrol (40–60)–MeOH, 20:15:1); mp
110–111 ЊC; [α]D24 ϩ58.3 (c 0.12 in CHCl3); νmax(CDCl3, c 10 mg
mlϪ1)/cmϪ1 3424 (m), 3333 (m, br), 1710 (s), 1369 (m), 1300 (m),
1198 (m), 1153 (s); δH (300 MHz, CDCl3, c 10 mg mlϪ1) 1.33
(3H, t, J 7.0, CH3CH2), 1.46 (9H, s, C(CH3)3), 2.11 (1H, t, J 6.0,
Data for 10b. White crystalline solid; Rf 0.22 (EtOAc–petrol
(40–60)–MeOH, 20:20:2); mp 156–159 ЊC; [α]D25 Ϫ153.3 (c 0.015
in CHCl3); νmax(CDCl3, c 7.5 mg mlϪ1)/cmϪ1 3425 (m), 3330 (m,
br), 2983 (w), 1718 (s), 1613 (w), 1514 (m), 1477 (m), 1370 (m),
1253 (s), 1154 (s); δH (300 MHz, CDCl3, c 7.3 mg mlϪ1) 1.30
(3H, t, J 7.0, CH3CH2), 1.41 (9H, s, C(CH3)3), 1.85 (2H, dd,
t
OH), 2.29 (1H, dd, J 16.5 and 8.5, CHHCO2 Bu), 2.38 (1H, dd,
t
J 16.5 and 5.0, CHHCO2 Bu), 2.60–2.67 (1H, m, H-3), 2.98–
3.06 (1H, m, H-2), 3.15 (1H, d, J 14.0, CHHPh), 3.40 (1H, d,
J 14.0, CHHPh), 3.47–3.54 (2H, m, CH2OH), 4.18–4.36 (2H,
m, CH3CH2), 6.20 (1H, br s, NH), 7.21–7.31 (5H, m, ArCH);
δC (50.3 MHz, CDCl3, c 98 mg mlϪ1) 14.2 (CH3CH2), 27.9
t
J 17.0 and 9.0, CHHCO2 Bu), 1.96 (2H, dd, J 17.0 and 6.0,
t
CHHCO2 Bu), 2.74 (1H, br t, J 6.0, OH), 3.27–3.33 (1H, m,
H-3), 3.51–3.65 (2H, m, H-2 and CHHOH), 3.78–3.88 (4H, m,
CHHOH and OCH3), 4.26–4.38 (2H, m, CH3CH2), 6.83 (1H,
br s, NH), 6.86–6.91 (2H, m, ArH), 7.12–7.17 (2H, m, ArH); δC
(125.8 MHz, CDCl3, c 7.5 mg mlϪ1) 13.98 (CH3CH2), 27.98
t
(C(CH3)3), 35.5 and 36.5 (CH2CO2 Bu and CH2Ph), 37.3 (C-3),
60.2 (C-2), 60.7 (C-4), 61.8 (CH3CH2), 63.9 (CH2OH), 81.5
(C(CH3)3), 126.9, 128.3 and 130.9 (ArCH), 135.9 (C-7), 170.1,
170.0 and 174.3 (3 × CO); m/z (APCIϩ) 392 (M ϩ Hϩ, 21%),
336 (100); HRMS 392.2073, C21H30NO6 (M ϩ Hϩ) requires
392.2073.
t
(C(CH3)3), 36.27 (CH2CO2 Bu), 41.11 (C-3), 55.29 (OCH3),
58.72 (C-2), 62.42 (CH3CH2), 63.89 (C-4), 64.00 (CH2OH),
81.35 (C(CH3)3), 114.04 (ArC), 126.22 (C-6), 129.57 (ArC),
158.99 (MeO-C), 170.63, 171.50 and 173.39 (3 × CO); m/z
(APCIϩ) 408 (M ϩ Hϩ, 25%), 352 (100), 280 (23).
(2S,3S,4R)- and (2S,3S,4S)-3-tert-Butoxycarbonylmethyl-2-
hydroxymethyl-5-oxo-4-phenylpyrrolidines 12 and 13
Data for 11b. Rf 0.27 (EtOAc–petrol (40–60)–MeOH,
20:20:2); [α]D26 Ϫ18.0 (c 0.05 in CHCl3); νmax(film)/cmϪ1 3351
(m), 1725 (s), 1712 (s), 1515 (m), 1298 (m), 1254 (s), 1183 (m),
To a solution of 10a (69 mg, 0.18 mmol) in EtOH (5 ml) at rt
was added NaOH (1M, aq., 1.1 ml, 1.1 mmol) with stirring.
After 5 h, water (15 ml) was added and the solution extracted
with EtOAc (5 × 15 ml). Drying (MgSO4) and evaporation in
vacuo gave the title compound as a white solid (17 mg, 30%).
Acidification of the aqueous layer with HCl (1 M, aq.) then
extraction with EtOAc, drying (MgSO4) and evaporation in
vacuo gave a colourless gum (42 mg), which was a mixture of
the title compounds and the acid 14. The combined material
was heated in vacuo (0.8 mbar) at 135 ЊC for 30 min to give the
title compounds as a white solid consisting of a 1:1 mixture
of 12 and 13 (46 mg, 82%). Rf 0.28 (EtOAc–petrol (40–60)–
MeOH, 20:15:2); νmax(CHCl3)/cmϪ1 3424 (m), 3312 (m, br),
1698 (s), 1369 (m), 1152 (s), 1090 (m);
1155 (s), 1068 (m), 1037 (m); δH (500 MHz, CDCl3, c 2 mg mlϪ1
)
1.29 (3H, t, J 7.0, CH3CH2), 1.45 (9H, s, C(CH3)3), 2.52 (1H,
t
dd, J 17.0 and 10.0, CHHCO2 Bu), 2.71 (1H, dd, J 17.0 and 2.5,
t
CHHCO2 Bu), 3.17–3.21 (1H, m, H-3), 3.55 (1H, dd, J 12.0 and
5.5, CHHOH), 3.66–3.70 (1H, m, H-2), 3.80–3.83 (4H, m,
CHHOH and OCH3), 4.23–4.29 (2H, m, CH3CH2), 6.06 (1H,
br s, NH), 6.90–6.93 (2H, m, ArH), 7.38–7.41 (2H, m, ArH);
δC (125.8 MHz, CDCl3, c 2 mg mlϪ1) 14.15 (CH3CH2), 27.98
t
(C(CH3)3), 34.47 (CH2CO2 Bu), 42.46 (C-3), 55.26 (OCH3),
59.57 (C-2), 62.03 (CH3CH2), 62.93 (C-4 and CH2OH), 81.98
(C(CH3)3), 113.80 (ArC meta- to C-6), 128.26 (C-6), 129.13
(ArC), 159.06 (MeOC), 169.86, 172.21 and 172.87 (3 × CO);
m/z (APCIϩ) 408 (M ϩ Hϩ, 23%), 352 (100).
Data for 12. δH (500 MHz, CDCl3, c 2 mg mlϪ1) 1.38 (9H, s,
C(CH3)3), 1.87 (1H, dd, J 17.0 and 7.5, CHHCO2 Bu), 1.96
(1H, br s, OH), 2.10 (1H, dd, J 17.0 and 8.0, CHHCO2 Bu),
t
(2S,3S,4S)-4-Benzyl-3-tert-butoxycarbonylmethyl-4-ethoxy-
carbonyl-2-hydroxymethyl-5-oxopyrrolidine 10c
t
2.84–2.90 (1H, m, H-3), 3.50–3.53 (1H, m, H-2), 3.55–3.61 (1H,
m, CHHOH), 3.79 (1H, dd, J 11.0 and 3.5, CHHOH), 3.98
(1H, d, J 9.5, H-4), 6.68 (1H, s, NH), 7.13–7.15 (2H, m, ArH),
Following the general method, the lactam 5h (85 mg, 0.22
mmol), was reacted with TFA (0.5 ml) in DCM (10 ml) for 1 h.
Purification using flash column chromatography (EtOAc–petrol
(40–60), 1:1 then EtOAc–petrol (40–60)–MeOH, 20:15:1)
gave the title compound as a colourless oil, as a single diastereo-
mer (60 mg, 86%); Rf 0.20 (EtOAc–petrol (40–60)–MeOH,
20:15:1); [α]D23 ϩ13.91 (c 0.115 in CHCl3); νmax(CDCl3, c 9 mg
mlϪ1)/cmϪ1 3424 (m), 3245 (m, br), 1719 (s), 1370 (m), 1251 (m),
7.24–7.38 (3H, m, ArH); δC (125.8 MHz, CDCl3, c 30 mg mlϪ1
)
t
27.85 (C(CH3)3), 35.27 (CH2CO2 Bu), 37.47 (C-3), 51.60 (C-4),
60.29 (C-2), 64.07 (CH2OH), 80.80 (C(CH3)3), 127.41, 128.71,
128.78 and 129.26 (ArCH), 135.22 (C-6), 171.16 and 178.74
(2 × CO); other data as below for 13.
1155 (s), 1098 (s), 1040 (m); δH (300 MHz, CDCl3, c 9 mg mlϪ1
)
Data for 13. δH (500 MHz, CDCl3, c 2 mg mlϪ1) 1.38 (9H, s,
C(CH3)3), 1.96 (1H, br s, OH), 2.44–2.53 (2H, m, CH2CO2 Bu),
2.58–2.65 (1H, m, H-3), 3.46 (1H, d, J 10.0, H-4), 3.55–3.61
(2H, m, CHHOH and H-2), 3.82–3.86 (1H, m, CHHOH), 6.48
t
1.29 (3H, t, J 7.0, CH3CH2), 1.48 (9H, s, C(CH3)3), 2.42 (1H,
t
dd, J 16.5 and 7.5, CHHCO2 Bu), 2.59 (1H, br t, OH), 2.70–
t
2.76 (1H, m, H-3), 2.76 (1H, dd, J 16.5 and 7.0, CHHCO2 Bu),
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
2801

View Article Online
(1H, s, NH), 7.24–7.38 (5H, m, ArH); δC (125.8 MHz, CDCl3,
7.14 (2H, m, ArH), 7.29–7.37 (3H, m, ArH); δC (125.8 MHz,
c 30 mg mlϪ1) 27.91 (C(CH3)3), 37.81 (CH2CO2 Bu), 42.01 (C-3),
CDCl3) 34.07 (CH2CO2Me), 40.18 (C-3), 50.45 (C-4), 51.75 and
52.87 (2 × CO2CH3), 58.59 (C-2), 127.82, 128.91 and 129.19
(ArCH), 134.19 (C-6), 171.31, 171.76 and 176.65 (3 × CO); m/z
292 (M ϩ Hϩ, 100%); HRMS 292.1193, C15H17NO5 requires
292.1185. HPLC purity: de = 94% (40% EtOH–n-heptane, 1 ml
minϪ1, λ = 215 nm, Chiralpak AD column).
t
54.47 (C-4), 59.90 (C-2), 63.72 (CH2OH), 81.27 (C(CH3)3),
127.41, 128.71, 128.78 and 129.26 (ArCH), 137.84 (C-6), 170.82
and 177.45 (2 × CO); m/z (APCIϩ) 250 (100%), 306 (M ϩ Hϩ,
10); HRMS 306.1705, C17H24NO4 requires 306.1705.
(2S,3S,4R)- and (2S,3S,4S)-2-Methoxycarbonyl-3-methoxy-
carbonylmethyl-5-oxo-4-phenylpyrrolidines 15a and 16a
Data for 16a. Rf 0.22 (EtOAc–petrol (40–60), 2:1); [α]D23 ϩ4.7
(c 0.3 in CHCl3); mp 97–98 ЊC; νmax(CHCl3)/cmϪ1 3430 (m),
3248 (m, br), 1719 (s), 1438 (m), 1148 (s), 700 (m); δH (500 MHz,
CDCl3) 2.67–2.76 (2H, m, CH2CO2Me), 2.87–2.93 (1H, m,
H-3), 3.55 (4H, s and d, J 10.0, CO2CH3 and H-4), 3.78 (3H, s,
CO2CH3), 4.21 (1H, d, J 8.0, H-2), 6.74 (1H, br s, NH), 7.21–
7.23 (2H, m, ArH ortho- to C-6), 7.29–7.30 (1H, m, ArH), 7.34–
7.37 (2H, m, ArH); δC (62.9 MHz, CDCl3) 35.7 (CH2CO2Me),
44.9 (C-3), 51.7 (C-4), 52.7 and 53.3 (CO2CH3), 58.0 (C-2),
127.7, 128.7 and 128.9 (ArCH), 136.7 (C-6), 171.2 and 175.9
(2 × CO); m/z 292 (M ϩ Hϩ, 100%); HRMS (electrospray)
292.1179, C15H17NO5 requires 292.1185. HPLC purity:
de = 100% (40% EtOH–n-heptane, 1 ml minϪ1, λ = 215 nm,
Chiralpak AD column).
Method 1. To a solution of the phenylated adduct 5a, 6a
(2:1) (0.874 g, 1.9 mmol) in THF–water–EtOH (3:2:1, 30 ml)
was added NaOH (0.45 g, 11 mmol). The biphasic mixture was
then stirred at rt for 37.5 h. The mixture was acidified with HCl
(2 M, aq.) and then evaporated directly in vacuo to give a yellow
gum and white solid. This residue was dissolved in TFA–water
(7 ml–2 ml) and stirred at 30 ЊC for 2 h. Solvent evaporation
in vacuo gave a cloudy pink oil which was dissolved in NaOH
(2 M, aq., 16 ml) and extracted with DCM (2 × 10 ml). The
aqueous layer was then acidifed with HCl (2 M, aq., 16 ml) and
extracted with EtOAc (3 × 20 ml). Drying (MgSO4) and evap-
oration in vacuo gave a yellow gum. Ths material (0.256 g) was
stirred vigorously with ruthenium() oxide hydrate (27 mg, ca.
20 mol%) and NaIO4 (0.880 g, 4.1 mmol, ca. 4 eq.) in a mixture
of CH3CN–CCl4–water, 2:2:3 (35 ml) for 14 h. Acidification
with HCl (1 M, aq.) and extraction with EtOAc (4 × 15 ml)
gave a pale yellow foam. Treatment of this foam with MeOH
(10 ml), and H2SO4 (conc., 6 drops) under reflux for 16 h gave,
after extraction with EtOAc, drying (MgSO4), and evaporation
in vacuo, a colourless oil which was purified using flash column
chromatography (EtOAc–cyclohexane, 2:1) to give the title
compounds 15a and 16a as two single diastereomers as colour-
less crystalline solids.
(2S,3S,4R)- and (2S,3S,4S)-4-Ethoxycarbonyl-3-methoxy-
carbonylmethyl-2-methoxycarbonyl-5-oxo-4-phenylpyrrolidines
19a, b
Data for 19a. νmax(film)/cmϪ1 3312 (m), 1732 (s), 1438 (m),
1381 (m), 1219 (s), 1109 (m); δH (500 MHz, CDCl3) 1.28 (3H, t,
J 7.0, CH3CH2), 2.48 (1H, dd, J 16.0 and 6.5, CHHCO2Me),
2.97 (1H, dd, J, 16.0 and 7.0, CHHCO2Me), 3.15–3.19 (1H, m,
H-3), 3.31 (3H, s, CO2CH3), 3.38 (3H, s, CO2CH3), 3.62 (1H, d,
J 11.0, H-2), 7.03 (1H, br s, NH), 7.20–7.22 (2H, m, ArH),
7.28–7.36 (3H, m, ArH); m/z 364 (M ϩ Hϩ, 100%); HRMS
(electrospray) 364.1405, C18H22NO7 requires 364.1396.
Method 2. To compounds 12 and 13 (1:1 ratio) (29 mg, 0.10
mmol) in DCM (3 ml) was added TFA (1.5 ml) with swirling.
The homogeneous solution was left to stand at rt for 1 h and
then the solvent was removed in vacuo at 40 ЊC to give a colour-
less glass. To this material (24 mg, 0.1 mmol) in CCl4 (2 ml) and
CH3CN (2 ml) was added a solution of NaIO4 (81 mg, 0.38
mmol) in water (3 ml) and then ruthenium() oxide hydrate
(2.5 mg). The mixture was stirred vigorously for 3 h, then HCl
(2 M, aq., 6 drops) and water (10 ml) were added. Extraction
with EtOAc (3 × 15 ml), drying (MgSO4) and evaporation in
vacuo gave a grey–green glass (42 mg), which was dissolved in
MeOH (2 ml) and then H2SO4 (conc., 2 drops) added. After
heating at reflux for 4.75 h the mixture was cooled to rt, water (5
ml) was added and then the solution was extracted with EtOAc
(2 × 15 ml). Drying (MgSO4) and evaporation in vacuo gave a
yellow oil which was purified using flash column chrom-
atography (EtOAc–petrol (40–60), 2:1) to give the two single
title diastereomers 15a and 16a as colourless crystalline solids
(2 × 9 mg, 65%).
Data for 19b. νmax(film)/cmϪ1 3312 (m, br), 1732 (s), 1438 (m),
1381 (m), 1219 (s), 1109 (m); δH (500 MHz, CDCl3) 1.28 (3H, t,
J 7.0, CH3CH2), 2.81–2.89 (2H, m, CH2CO2Me), 3.50–3.57
(1H, m, H-3), 3.65 (3H, s, CO2CH3), 3.72 (3H, s, CO2CH3),
4.25–4.29 (3H, d, J 10.0 and q, J 7.0, H-2 and CH3CH2), 6.26
(1H, br s, NH), 7.32–7.40 (3H, m, ArH), 7.44–7.46 (2H, m,
ArH); δC (50.3 MHz, CDCl3) 14.0 (CH3CH2), 33.3
(CH2CO2Me), 45.8 (C-3), 52.0 and 52.6 (2 × CO2CH3), 59.0 (C-
2), 62.3 (CH3CH2), 63.5 (C-4), 127.9, 128.1 and 128.3 (ArCH),
135.6 (C-6) 168.9, 170.7, 171.5 and 172.7 (4 × CO).
(2S,3S,4R)- and (2S,3S,4S)-2-Carboxy-3-carboxymethyl-5-oxo-
4-phenylpyrrolidines 20a, b
To a stirred solution of 16a (52 mg, 0.18 mmol) in THF–water–
MeOH, (3:2:1, 2 ml) was added NaOH (29 mg, 0.72 mmol) at
rt. After 16 h water was added and the solution extracted with
EtOAc (1 × 15 ml). The aqueous phase was acidified with HCl
(1 M, aq.) which gave a white precipitate. Extraction with
EtOAc (4 × 15 ml), drying (MgSO4) and evaporation in vacuo
gave the title compound as a colourless glass (39 mg, 83%)
consisting of two diastereomers 20a, b (1:4); νmax (KBr)/cmϪ1
3255 (m, br), 3035 (m, br), 2928 (m, br), 1713 (s), 1660 (s), 1407
(m), 1236 (s), 760 (m), 702 (s).
Method 3. To a solution of the diacid 20a, b (4:1 ratio) (32
mg) in MeOH (2 ml) was added H2SO4 (conc., 2 drops) and the
solution heated at reflux for 48 h. After cooling to rt, water
was added and the solution extracted with EtOAc. Drying
(MgSO4) and evaporation in vacuo gave a pale yellow oil which
was purified using flash column chromatography (EtOAc–
petrol (40–60), 2:1) to give the product as two diastereomers
15a (4 mg, 11%), 16a (25 mg, 70%).
Data for 20a. δH (500 MHz, CD3OD) 1.94 (1H, dd, J 17.5 and
9.5, CHHCO2H), 2.54 (1H, dd, J 17.5 and 5.5, CHHCO2H),
3.44–3.47 (1H, m, H-3), 3.96 (1H, d, J 9.0, H-4), 4.09 (1H, d,
J 7.5, H-2), 7.14–7.16 (2H, ArH ortho- to C-6), 7.23–7.36 (3H,
m, ArH); m/z (APCIϩ) 264 (M ϩ Hϩ, 94%); HRMS (FABϩ)
264.0875, C13H14NO5 requires 264.0872.
Data for 15a. Rf 0.27 (EtOAc–petrol (40–60), 2:1); [α]D23 ϩ72.6
(c 0.135 in CHCl3); mp 147–148 ЊC; νmax(CHCl3)/cmϪ1 3429
(m), 3235 (m, br), 1718 (s), 1438 (m), 1171 (s), 701 (m); δH (500
MHz, CDCl3) 2.07 (1H, dd, J 17.0 and 8.5, CHHCO2CH3),
2.53 (1H, dd, J 17.0 and 7.0, CHHCO2CH3), 3.28–3.34 (1H, m,
H-3), 3.60 (3H, s, CO2CH3), 3.84 (3H, s, CO2CH3), 4.03 (1H,
d, J 8.9, H-4), 4.10 (1H, d, J 6.5, H-2), 6.41 (1H, br s, NH),
Data for 20b. δH (500 MHz, CD3OD) 2.65–2.74 (2H, m,
CH2CO2H), 2.78–2.83 (1H, m, H-3), 3.62 (1H, d, J 9.0, H-4),
4.19 (1H, d, J 7.5, H-2), 7.23–7.36 (5H, m, ArH); δC (125.8
2802
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804

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MHz, CD3OD) 37.41 (CH2CO2H), 46.69 (C-3), 55.02 (C-4),
60.25 (C-2), 128.58, 129.79 and 130.01 (ArCH), 139.06 (C-6),
173.17, 173.33 and 178.78 (3 × CO).
7.34 (5H, m, ArH); δC (125.8 MHz, CDCl3) 14.15 (CH3CH2),
34.31 (CH2CO2Me), 36.40 (CH2Ph), 39.55 (C-3), 51.92 and
52.56 (2 × CO2CH3), 58.84 (C-2), 60.16 (C-4), 62.09 (CH3CH2),
127.02, 128.38 and 130.91 (ArCH), 135.28 (C-7), 169.55,
170.38, 171.13 and 173.34 (4 × CO); m/z (APCIϩ) 400
(M ϩ Naϩ, 52%), 378 (M ϩ Hϩ, 100); HRMS (CIϩ) 378.1553,
C19H24NO7 requires 378.1553.
(2S,3S,4R)-3-tert-Butoxycarbonylmethyl-4-ethoxycarbonyl-2-
methoxycarbonyl-5-oxo-4-phenylpyrrolidine 21
To a solution of compound 10a in CH3CN (0.5 ml) and CCl4
(0.5 ml) was added a solution of NaIO4 (20 mg, 0.10 mmol) in
water (0.75 ml) and then ruthenium() oxide hydrate (0.6 mg).
The mixture was stirred vigorously at rt for 2 h and then a
solution of diazomethane in diethyl ether was added with
stirring which was continued for 5 min. Water (5 ml) was then
added to the mixture which was then extracted with EtOAc
(3 × 10 ml). Drying (MgSO4) and evaporation in vacuo gave a
black oil which was purified using column chromatography
(EtOAc–petrol (40–60), 1:1) to give the title compound 21 as a
colourless oil (4 mg, 41%); Rf 0.27 (EtOAc–petrol (40/60), 1:1);
[α]D23 Ϫ26.3 (c 0.175 in CHCl3); νmax(film)/cmϪ1 3202 (m, br), 2979
(m), 2927 (m), 1725 (s), 1448 (m), 1368 (m), 1219 (s), 1154 (s),
1029 (m), 736 (m), 703 (m); δH (500 MHz, CDCl3) 1.26 (3H, t,
J 7.0, CH3CH2), 1.42 (9H, s, C(CH3)3), 1.81–1.85 (1H, m,
Data for 22b. Rf 0.21 (EtOAc–petrol (40–60), 6:5); νmax(film)/
cmϪ1 3316 (w, br), 3233 (w, br), 1739 (s), 1711 (s), 1437 (m),
1379 (m), 1222 (s), 1066 (m), 990 (m), 770 (m), 706 (m); δH (300
MHz, CDCl3) 2.46 (1H, dd, J 16.5 and 6.5, CHHCO2Me), 2.68
(1H, dd, J 16.5 and 7.0, CHHCO2Me), 3.00–3.08 (1H, m, H-3),
3.19 (1H, d, J 14.0, CHHPh), 3.44 (1H, d, J 14.0, CHHPh),
3.58 (3H, s, CO2CH3), 3.70 (3H, s, CO2CH3), 3.81 (3H, s,
CO2CH3), 4.02 (1H, d, J 8.5, H-2), 6.39 (1H, br s, NH), 7.23–
7.32 (5H, m, ArH); δC (128.5 MHz, CDCl3) 34.37
(CH2CO2Me), 36.52 (CH2Ph), 39.56 (C-3), 51.94, 52.57 and
52.76 (3 × CO2CH3), 58.68 (C-2), 60.18 (C-4), 127.06, 128.40
and 130.88 (ArCH), 135.17 (C-7), 170.06, 170.32, 171.10 and
173.21 (4 × CO); m/z (APCIϩ) 386 (M ϩ Naϩ, 40%), 364
(M ϩ Hϩ, 100); HRMS (CIϩ) 364.1396, C18H22NO7 (M ϩ Hϩ)
requires 364.1396.
t
t
CHHCO2 Bu), 2.05–2.14 (1H, m, CHHCO2 Bu), 3.82 (3H, s,
CO2CH3), 3.93–3.98 (2H, m, H-2 and H-3), 4.27 (2H, q, J 7.0,
CH3CH2), 6.31 (1H, s, NH), 7.27–7.38 (5H, m, ArH); δC (125.8
MHz, CDCl3) 13.84 (CH3CH2), 27.97 (C(CH3)3), 36.82
(2S,3S,4S)-4-Benzyl-3-tert-butoxycarbonylmethyl-4-carboxy-2-
hydroxymethyl-5-oxopyrrolidine 23
t
(CH2CO2 Bu), 44.04 (C-3), 52.77 (CO2CH3), 57.35 (C-2), 62.63
(CH3CH2), 63.64 (C-4), 81.26 (C(CH3)3), 127.98, 128.43 and
128.74 (ArCH), 133.77 (C-6), 169.31, 170.41, 171.07 and 172.35
(4 × CO); m/z (APCIϩ) 406 (M ϩ Hϩ, 5%), 350 (100); HRMS
406.1866, C21H28NO7 requires 406.1866.
To a solution of the alcohol 10c (60 mg, 0.15 mmol) in EtOH
(5 ml) was added NaOH (1 M, aq., 0.92 ml, 0.92 mmol). The
mixture was stirred at rt for 5 h and then water (20 ml) was
added and the mixture extracted with EtOAc (1 × 10 ml). Acid-
ification of the aqueous layer with HCl (2 M, 1.5 ml), extraction
with EtOAc (4 × 20 ml), drying (MgSO4) and evaporation in
vacuo gave the title compound as a colourless foam (55 mg,
99%); νmax (CDCl3)/cmϪ1 3417 (w), 3300 (br, s), 1724 (br, s), 1456
(m), 1394 (s), 1370 (s), 1155 (s), 843 (m); δH (300 MHz, CDCl3)
1.47 (9H, s, C(CH3)3), 2.48 (1H, dd, J 16.5 and 8.0, CHH-
(2S,3S,4R)-4-Benzyl-4-ethoxycarbonyl-2-methoxycarbonyl-3-
methoxycarbonylmethyl-5-oxopyrrolidine 22a and (2S,3S,4R)-4-
benzyl-2,4-bis(methoxycarbonyl)-3-methoxycarbonylmethyl-5-
oxopyrrolidine 22b
To a solution of alcohol 11c (47 mg, 0.12 mmol) in EtOH (3 ml)
was added NaOH (1 M, aq., 0.72 ml, 0.72 mmol) and the mix-
ture stirred at rt for 20.5 h. Water (15 ml) was then added and
the solution extracted with EtOAc (1 × 10 ml). Acidification
with HCl (2 M, aq., 2 ml), extraction with EtOAc (3 × 15 ml),
drying (MgSO4) and evaporation in vacuo gave a colourless
foam (33 mg). This foam was then dissolved in DCM (2 ml)
and TFA (0.25 ml) was added with swirling at rt. After 1 h
the solvent was removed in vacuo and then more rigorously
removed under high vacuum (2 mbar) to give an opaque pale
brown gum.
To a solution of this gum in CH3CN (1 ml) and CCl4 (1 ml)
was added a solution of NaIO4 (71 mg, 0.33 mmol) in water
(1.5 ml) and then ruthenium() oxide hydrate (2 mg). The mix-
ture was stirred vigorously at rt for 5 h and then a solution of
diazomethane in diethyl ether added at 0 ЊC with stirring until
the effervescence ceased and the upper ether layer remained
yellow. The excess diazomethane was allowed to evaporate at rt
for several hours and then the mixture was extracted with
EtOAc (3 × 10 ml), dried (MgSO4) and evaporated in vacuo to
give a colourless oil (29 mg). Purification using column chrom-
atography (EtOAc–petrol (40–60), 6:5) gave 22a (10 mg, 23%)
as a single diastereomer as a colourless oil and 22b as a colour-
less oil.
t
CO2 Bu), 2.93–3.10 (3H, m), 3.10–3.23 (1H, br s), 3.24–3.36
(1H, d, J 14.0), 3.36–3.52 (1H, br s) (CH2Ph, H-2, CHH-
t
CO2 Bu, H-3 and CHHOH), 3.56–3.79 (2H, br s, CHHOH and
OH), 7.16–7.29 (5H, m, ArH), 7.52 (2H, br s, NH and CO2H);
t
δC (50.3 MHz, CDCl3) 28.0 (C(CH3)3), 33.6 (CH2CO2 Bu), 36.5
(CH2Ph), 40.4 (C-3), 58.5 (C-4), 59.4 (C-2), 61.7 (CH2OH), 82.0
(C(CH3)3), 127.3, 128.4 and 130.2 (ArCH), 135 (C-7), 171.6,
173.3 and 176.9 (3 × CO); m/z (APCIϩ) 386 (M ϩ Naϩ, 2%),
320 (21), 264 (100); m/z (APCIϪ) 362 ((MϪ H)Ϫ, 7%), 318 (35),
262 (100); HRMS (FABϩ) 364.1780, C19H26NO6 requires
364.1760.
(2S,3S,4R)- and (2S,3S,4S)-4-Benzyl-2-methoxycarbonyl-3-
methoxycarbonylmethyl-5-oxopyrrolidines 15b and 16b
The acid 23 was heated at 135 ЊC/0.7 mbar for 2 h, and then at
150 ЊC for 1 h to give a colourless glass; to this material in DCM
(4 ml) was added TFA (0.75 ml) with swirling at rt. After stand-
ing for 1 h the solvent was removed in vacuo and more rigor-
ously removed by heating at 30 ЊC at 0.7 mbar for 12 h to give a
pale yellow glass. To a solution of this glass in CH3CN (2 ml)
and CCl4 (2 ml) was added a solution of NaIO4 (120 mg, 0.56
mmol) in water (3 ml) followed by ruthenium() oxide hydrate
(4 mg). After stirring the mixture vigorously for 3 h, a solution
of diazomethane in diethyl ether was added with stirring at 0 ЊC
until the upper ether layer remained yellow. After allowing the
excess diazomethane to evaporate at rt the mixture was
extracted with EtOAc (3 × 10 ml), and then dried (MgSO4) and
evaporated in vacuo to give a dark grey oil which was purified
using flash column chromatography (EtOAc–petrol (40–60),
2:1) to give 15b (3 mg, 7%) as a colourless oil which slowly
crystallised, and 16b (14 mg, 31%) as a colourless oil, both as
single diastereomers.
Data for 22a. Rf 0.27 (EtOAc–petrol (40–60), 6:5); [α]D23 ϩ69.0
(c 0.335 in CHCl3); νmax(film)/cmϪ1 3318 (w, br), 3234 (w, br),
1738 (s), 1709 (s), 1438 (m), 1378 (m), 1219 (s), 1065 (m), 1009
(m), 770 (m), 705 (m); δH (300 MHz, CDCl3) 1.33 (3H, t, J 7.0,
CH3CH2), 2.48 (1H, dd, J 16.5 and 6.5, CHHCO2Me), 2.69
(1H, dd, J 16.5 and 7.5, CHHCO2Me), 3.00–3.08 (1H, m, H-3),
3.18 (1H, d, J 14.0, CHHPh), 3.43 (1H, d, J 14.0, CHHPh),
3.58 (3H, s, CO2CH3), 3.70 (3H, s, CO2CH3), 4.02 (1H, d, J 8.5,
H-2), 4.19–4.36 (2H, m, CH3CH2), 6.34 (1H, br s, NH), 7.21–
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804
2803

View Article Online
Data for 15b. Rf 0.21 (EtOAc–petrol (40–60), 2:1); [α]D23 ϩ5.6
(c 0.13 in CHCl3); mp 108–111 ЊC; νmax(film)/cmϪ1 3233 (w,
br), 1735 (s), 1707 (s), 1437 (m), 1380 (m), 1260 (m), 1213 (s),
1178 (m), 1015 (m), 699 (m); δH (500 MHz, CDCl3) 2.50
(1H, dd, J 16.5 and 9.5, CHHCO2Me), 2.63 (1H, dd, J 16.5 and
5.0, CHHCO2Me), 3.04–3.13 (2H, m, H-4 and CHHPh), 3.26
(1H, dd, J 15.0 and 4.0, CHHPh), 3.65 (3H, s, CO2CH3), 3.78
(3H, s, CO2CH3), 4.01 (1H, d, J 2.5, H-2), 5.98 (1H, br s, NH),
7.22–7.24 (3H, m, ArH), 7.30–7.33 (2H, m, ArH); δC (125.8
MHz, CDCl3) 31.16 and 32.95 (CH2CO2Me and CH2Ph),
38.42 (C-3), 43.48 (C-4), 51.94 and 52.80 (2 × CO2CH3), 58.14
(C-2), 126.58, 128.39 and 128.72 (ArCH), 138.36 (C-7), 171.56,
171.88 and 177.43 (3 × CO); m/z (APCIϩ) 306 (M ϩ Hϩ,
100%), 246 (79); HRMS (CIϩ) 306.1341, C16H19NO5 requires
306.1341.
the EPSRC National Mass Spectrometry Service Centre at
Swansea.
References
1 For Part 1, see J. H. Bailey, D. T. Cherry, J. Dyer, M. G. Moloney,
M. J. Bamford, S. Keeling and R. B. Lamont, J. Chem. Soc., Perkin
Trans. 1, 2000, preceding paper (DOI: 10.1039/b001999m).
2 J. Dyer, S. Keeling and M. G. Moloney, Chem. Commun., 1998, 461.
3 M. G. Moloney, Nat. Prod. Rep., 1999, 16, 485.
4 M. G. Moloney, Nat. Prod. Rep., 1998, 15, 205.
5 M.-R. Schneider, P. Klotz, I. Ungureanu, A. Mann and C.-G.
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6 M. V. Chevliakov and J. Montgomery, Angew. Chem., Int. Ed.,
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7 P. Barraclough, P. Hudhomme, C. A. Spray and D. W. Young,
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8 J. S. Bryans, J. M. Large and A. F. Parsons, J. Chem. Soc., Perkin
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9 J. S. Bryans, J. M. Large and A. F. Parsons, J. Chem. Soc., Perkin
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10 M. D. Fletcher and M. M. Campbell, Chem. Rev., 1998, 98, 763.
11 A. Dutta, in Specialist Periodical Reports, Amino acids, Peptides and
Proteins, ed. J. S. Davies, Royal Society of Chemistry, Cambridge,
1998.
12 S. Hanessian, G. McNaughton-Smith, H.-G. Lombart and W. D.
Lubell, Tetrahedron, 1997, 53, 12789.
13 J. Gante, Angew. Chem., Int. Ed. Engl., 1994, 33, 1699.
14 M. J. Beard, J. H. Bailey, D. T. Cherry, M. G. Moloney, S. B. Shim,
K. Statham, M. Bamford and R. B. Lamont, Tetrahedron, 1996, 52,
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15 J. T. Pinhey, in Comprehensive Organometallic Chemistry II, ed. A.
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16 J. T. Pinhey, Aust. J. Chem., 1991, 44, 1353.
17 G. M. Rubottom, in Oxidation in Organic Chemistry, ed. W. H.
Trahanovsky, Academic, London, 1982, ch. 1.
Data for 16b. Rf 0.17 (EtOAc–petrol (40–60), 2:1); [α]D23 ϩ67.9
(c 0.66 in CHCl3); νmax(film)/cmϪ1 3231 (w), 1735 (s), 1703 (s),
1437 (m), 1377 (m), 1327 (m), 1213 (s), 1180 (m), 992 (m),
703 (m); δH (500 MHz, CDCl3) 2.35 (1H, dd, J 16.0 and 6.5,
CHHCO2Me), 2.45 (1H, dd, J 16.0 and 5.0, CHHCO2Me), 2.82
(1H, dd, J 14.0 and 8.5, CHHPh), 3.26 (1H, dd, 14.0 and 3.5,
CHHPh), 3.65 (3H, s, CO2CH3), 3.76 (3H, s, CO2CH3), 4.08
(1H, d, J 6.0, H-2), 6.53 (1H, br s, NH), 7.24–7.37 (5H,
m, ArH); δH (500 MHz, C6D6) 2.00 (1H, dd, J 16.0 and 7.0,
CHHCO2Me), 2.06 (1H, dd, J 16.0 and 5.5, CHHCO2Me),
2.40–2.44 (1H, m, H-4), 2.60–2.65 (1H, m, H-3), 2.80 (1H, dd,
J 14.0 and 8.5, CHHPh), 3.18 (3H, s, CO2CH3), 3.21 (4H, s
and dd, J 14.0 and 4.5, CO2CH3 and CHHPh), 3.62 (1H, d,
J 6.5, H-2), 6.98 (1H, t, J 7.5, ArH), 7.05–7.15 (5H, m, ArH
and NH); δC (125.8 MHz, CDCl3) 36.14 (CH2Ph), 36.93
(CH2CO2Me), 39.53 (C-3), 47.62 (C-4), 51.70 and 52.62
(2 × CO2CH3) 58.29 (C-2), 126.63, 128.59 and 129.15 (ArCH),
138.10 (C-7), 171.38, 171.58 and 177.16 (3 × CO); m/z (APCIϩ)
306 (M ϩ Hϩ, 100%), 246 (60); HRMS (CIϩ) 306.1341,
C16H19NO5 requires 306.1341.
18 V. Soloshonok, C. Cai, V. J. Hruby and L. V. Meervelt, Tetrahedron,
1999, 55, 12045.
19 Structures optimised with Spartan (3-21G or PM3 semi-empirical
basis set in the gas phase) or Chem 3D Pro 3.5 (PM3 basis set).
20 J. H. Bailey, D. T. Cherry, K. M. Crapnell, M. G. Moloney, S. B.
Shim, M. Bamford and R. B. Lamont, Tetrahedron, 1997, 53, 11731.
21 H. C. Bell, J. R. Kalman, J. T. Pinhey and S. Sternhell, Aust.
J. Chem., 1979, 32, 1521.
22 D. I. McGee and M. Ramaseshan, Synlett, 1994, 743.
23 A. F. Abdel-Magid, B. D. Harris and C. A. Maryanoff, Synlett,
1994, 81.
Acknowledgements
We thank EPSRC and GlaxoWellcome for funding of student-
ships to J. D., and we wish to gratefully acknowledge the use
of the EPSRC Chemical Database Service at Daresbury24 and
24 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746.
2804
J. Chem. Soc., Perkin Trans. 1, 2000, 2793–2804