Pyrrolidinones derived from (S)-pyroglutamic acid: penmacric acid and analogues.

Article abstract of DOI:10.1039/b303924b

Alkylation reactions using alpha-halolactams or lactam enolates derived from bicyclic lactam templates can proceed with high endo- or exo- diastereoselectivity respectively. In the latter case, stereochemical correction by means of enolate generation and hindered phenol quench is possible with moderate efficiency. This protocol has been applied to the synthesis of protected penmacric acid and its analogues.

Full text of DOI:10.1039/b303924b

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Pyrrolidinones derived from (S )-pyroglutamic acid:
penmacric acid and analogues†
Muhammed Anwar, Jonathan H. Bailey, Laura C. Dickinson, Hermia J. Edwards,
Rajesh Goswami and Mark G. Moloney*
The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, OX1 3QY
Received 10th April 2003, Accepted 13th May 2003
First published as an Advance Article on the web 5th June 2003
Alkylation reactions using α-halolactams or lactam enolates derived from bicyclic lactam templates can proceed with
high endo- or exo- diastereoselectivity respectively. In the latter case, stereochemical correction by means of enolate
generation and hindered phenol quench is possible with moderate efficiency. This protocol has been applied to the
synthesis of protected penmacric acid and its analogues.
Introduction
Functionalised pyrrolidinones have emerged as an important
class of architecturally well-defined and synthetically readily
available templates which are now finding extensive application
as conformationally controlling peptidomimetics1–6 or as
pharmacologically active agents,7,8 especially in the area of
neuroexcitatory chemistry.9,10 Natural products containing a
pyrrolidine core are well-known, and exhibit diverse biological
activity; recently identified unusual examples include kaito-
cephalin,11 lemonomycin12 and aeruginosin.13 Over the last
leguminous tree Pentaclethra macrophylla, commonly known as
“owala seeds” or “pauco nuts”, in less than 0.5% w/w of the dry
bean endosperm; these legumes are indigenous to the humid
lowlands of West Africa, the seeds of which are both a staple
food in the local diet, and also find application for their medi-
cinal value.58,59 These seeds also contain proline, pipecolic acid,
5-hydroxypipecolic acid and betaine. The absolute configur-
decade, significant advances in general synthetic methods,
providing access to this class of compounds with excellent
stereocontrol, have been made. Two general strategies have
been developed: the elaboration of chiral templates, exemplified
by the elegant work of Meyers and co-workers, which uses
chiral O,N-acetal bicyclic lactams,14,15 and the preparation of
functionalised pyrrolidinones using ring closure reactions,
exemplified by the recent work by Soloshonok et al.16 and of
Alvarez-Ibarra et al..17 Our own work in this area has made use
of the hemiaminal ethers‡ 1a and 1b derived from pyro-
glutamic acid as a chiral template.18,19 These compounds are of
value since they can be readily prepared in enantiopure form;
the hydroxyl and amide functionalities are simultaneously
protected by a single benzylidene protecting group, making for
economy in molecular mass; and the protecting group provides
a bicyclic template which might be expected to exert good dia-
stereocontrol. We20–26 and others,18,19,25,27–49 have demonstrated
that the introduction of functionality α-, β- and γ- to the lactam
carbonyl of 1 is readily possible in a stereocontrolled sense. The
robustness of this protocol has been demonstrated by its recent
application for the synthesis of multi-kilo quantities of 3,5-di-
substituted-2-pyrrolidinones for evaluation as collagen-induced
thrombocyte aggregation inhibitors by Yee et al. at Boehringer
Ingelheim.50 The stereocontrol in reactions of lactam templates
has been of some interest32,43,51–53 and we have shown that
unusual stereocontrol is possible for bicyclic lactam 1b by the
application of remote steric effects around the ring periphery.54
We have demonstrated that this approach provides access to
novel kainoid analogues22,24 and conformationally well-defined
amino acid analogues,55 and report here its application to the
synthesis of analogues of penmacric acid.
1
ation of penmacric acid was initially assigned from H NMR
studies in association with CD measurements and this was later
supported by a single crystal X-ray structure.60 Detailed 1H
NMR studies indicate the solution Cs envelope conformation
of the acid is very close to that observed in the solid state, in
which C(3)–C(2)–N(1)–C(5) are co-planar (torsion angle
Ϫ3.3Њ) with C-4 out of this plane (the angle between this plane
and that of C(3)–C(4)–C(5) is 32.3Њ).61,62 A number of chemical
studies were carried out on penmacric acid by the Belgian
workers who originally reported its isolation;63 thus, the lactam
of penmacric acid is hydrolysed under a variety of acidic condi-
tions to the substituted adipic acid 3 which recloses in dilute
acid solution to give either of two possible substituted pipecolic
acids 4 and 5 (Scheme 1). Despite detailed chemical studies
nothing is known about the biological origin or role of
penmacric acid.
The possibility of a synthetic strategy to access penmacric
acid from bicyclic lactam 1a by either of two key disconnec-
tions, via an α-halolactam and a suitable glycine enolate
equivalent (Fig. 1a) or a lactam enolate and a glycinyl cation
equivalent (Fig. 1b) is readily apparent, and our work in that
regard is discussed herein. The expected inversion of stereo-
chemistry in the alkylation step of route a would give the
desired 3(R) stereochemistry of penmacric acid, but introduc-
tion of the required stereochemistry at the 1Ј position was
less certain in the same step. That route b was likely to be a
realistic prospect had been demonstrated earlier by Young and
co-workers,64,65 who showed that related additions using pyro-
glutamic acid and N-tosyl imines proceeded in a highly stereo-
controlled fashion, and more recently that similar control in
analogous aldehyde additions was also possible.66
Penmacric acid 2 was first isolated in 1975 independently
in British56 and Belgian57 laboratories from the seeds of the
† Part V. For parts I–IV see refs. 20–22, 24
‡ This nomenclature conforms to IUPAC recommendations 1995, see
ref. 76.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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 3
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Fig. 1
Scheme 1
Scheme 2
could not be established directly by NOE analysis due to over-
lapping signals in the 1H NMR spectrum, but was made
indirectly by comparison of 1H NMR spectra, [α]D and Rf
values using a previously established protocol;26,38,43,54 thus, the
endo- diastereomer 8a possessed higher Rf and optical rotation
data, and a bigger difference in the chemical shift values for
C(6)Hexo and C(6)Hendo, than the exo- diastereomer 9a, for
which C(6)Hexo and C(6)Hendo were overlapping. Reaction of
endo- iodide 7a under these conditions gave an exo : endo prod-
uct 9a : 8a in a ratio of 1.7 : 1. Reaction of exo- iodide 7b with
the sodium enolate of methyl cyanoacetate gave endo- and exo-
lactams 8b and 9b in excellent 84% overall yield and a 5.4 : 1
ratio (each as a mixture of diastereomers at C-1Ј); the stereo-
chemistry of 8b was established by NOESY analysis (Fig. 2),
and that of 9b by observation of overlapping signals for
C(6)Hexo and C(6)Hendo, which is characteristic of the C-7exo
stereochemistry as demonstrated from the rules noted above.
We assume that the diastereochemical attrition in these
reactions is a result of the epimerisation of starting 7a and
7b catalysed by the release of iodide in the course of the
displacement reaction.
Results and discussion
Reactions with glycine enolates
Our initial investigation was based on the observation that
α-chlorolactams 6 could be readily prepared by treating the
lactam enolate derived from 1a with p-toluenesulfonyl chlor-
ide (Scheme 2); reaction of lactam 6 under Finkelstein condi-
tions (NaI–acetone) gave good yields (70%) of the endo- and
exo- iodides 7a,b, in a ratio of up to 6 : 1; the exo-iodide 7b
predominated regardless of the endo : exo ratio of the start-
ing material. Direct synthesis of these iodides by trapping of
the enolate of lactam 1a with either I2 or NIS, as reported by
Meyers and co-workers,67 proved to be unsatisfactory,
giving low yields and product mixtures which were difficult to
purify.
Iodides 7a,b proved to be useful alkylating agents; reaction of
exo-iodide 7b with the sodium enolate of dimethyl malonate
(generated using sodium hydride in THF) gave two products in
a combined yield of 80%, which were identified as the endo-8a
and exo-9a malonates in a ratio of 2.1 : 1. Their stereochemistry
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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tions69 proceeded in low yield (10%); this has proved to be a
recurring problem in this reaction (vide infra). Although
application of acidic conditions (TFA or p-TsOH) for depro-
tection of lactams 8c,d and 9c,d gave mixtures of inseparable,
unidentifiable products, it was found that the neutral conditions
of Fasth and co-workers (NH2OH, EtOH, H2O)70 gave com-
pletely selective deprotection of the endo- imines 8c and 8cЈ to
give amines 12a and 13a in yields of 87 and 46% respectively,
and each of these was reprotected to give the N-acetyl deriv-
ative 12b and 13b (Ac2O, Et3N, CHCl3,) in yields of 62 and 58%
(Scheme 3). A similar sequence for the exo- imine 9c gave the
corresponding N-acetyl derivative 14. Careful NOE analysis of
12b and 13b indicated a large enhancement of the C(7)H signal
occurs on irradiation of C(6)Hexo but not on irradiation of
C(6)Hendo, confirming the C(7)Hexo assignment made earlier for
the imines 8c and 8cЈ. Assignment of C(1Ј)H as (R) and (S)
respectively for these compounds is more tentative, and assumes
that intramolecular H-bonding stabilises the conformation
indicated; this is consistent with the observation that for the
amides 12b and 13b, in the IR spectrum, the NH frequency is
observed at 3310 and 3326 cmϪ1 and the lactam carbonyls at
1690 and 1680 cmϪ1 respectively (these are lower than those
displayed in compounds for which hydrogen bonding is not
possible71). In this arrangement, C(1Ј)H for lactam 12b exhibits
NOE enhancements with both C(6)Hexo and C(6)Hendo, as
expected, but C(1Ј)H for lactam 13b shows a NOE only with
C(6)Hendo (Scheme 3). Such a conformation is consistent with
the observed JH-7/H1Ј values of 3.5 and 3.0 Hz for 12a and 12b
respectively.
Fig. 2
The use of the glycinate anion derived from N-(diphenyl-
methylene)glycine ethyl ester (formed by treatment with LDA
in THF at 0 ЊC) in this reaction with exo-iodide 7b gave a
diastereomeric mixture of products 8c and 8cЈ (epimeric at
C-1Ј) and 9c (single diastereomer, but unassigned stereo-
chemistry at C-1Ј) in yields of 20, 6 and 63% respectively,
whose stereochemistry could not be unequivocally established
by NOE spectroscopy, but was made by comparison with
compounds 8d, 8dЈ and 9d (Scheme 2); the empirical rules
mentioned above failed in this case.26,38,43,54 Repetition of this
reaction with endo-iodide 7a gave the most polar isomer exo-9c
in good yield (63%) as the major product. This selectivity could
not be improved using the anion of N-(diphenylmethylene)-
glycine tert-butyl ester, which similarly gave three isomers of the
products 8d and 8dЈ (epimeric at C-1Ј) and 9d in yields of 17, 14
and 39% respectively. In this case, however, the stereochemistry
of C(7)H could be assigned on the basis of NOE data (Fig. 2)
and these assignments are further supported by consistency
with the rules of thumb cited above. However, no information
about the stereochemistry at C(1Ј) was forthcoming, and the
configuration of this stereocentre remains unassigned for all
three products; for compounds 8c,d and 9c,d, J1Ј-7 values of
between 2.5 and 4.0 Hz were consistent with a C(1Ј)H–C(7)H
gauche conformation. It was observed that whereas the
exo-isomer 9d was indefinitely stable when stored at 4 ЊC, the
endo- isomers 8d and 8dЈ decomposed within a few weeks. The
clear predominance of the exo- isomer product in all reac-
tions of these glycine imines contrasted with the workable
endo- selectivity in the formation of 8a, and this was undesir-
able for the synthesis of penmacric acid. Surprisingly, reaction
of exo- iodide 7b with the lithium anion of the Schöllkopf
bislactim ether68 gave not the expected product of substitu-
tion, but instead lactam 1a and dimer 10 in good yield (66%).
Reaction of iodides 7a,b with the anions of 2-phenyl-5-oxa-
zolone, diethylacetamidomalonate and methyl nitroacetate gave
no products of substitution, but instead returned starting
materials, often with epimerisation at C(7)H.
However, O,N-deprotection under acidic conditions (TFA,
CH2Cl2) for all of 8d, 8dЈ and 9d led to consumption of starting
material and very poor mass recovery of a product which pos-
sessed the correct molecular weight for the desired product;
suspecting that the problematic step was the strong acidic acetal
deprotection, application of an alternative three step depro-
tection sequence (hydrogenation, oxidation and esterification)
for lactam 14 was attempted, and this gave lactam 15 (23% over
the three steps), which is a diastereomer of penmacric acid in
protected form.
Although this route provided access to epimers of penmacric
acid, because of the poor diastereoselectivity in the alkylation
step leading to imines 8d, 8dЈ and 9d, and difficulties with
deprotection, an alternative route was investigated.
Reaction with imines
The alternative disconnection, indicated in Fig. 1b, based on
reaction of a lactam enolate with a glycine cation equivalent
was of interest. The addition of pyroglutamate enolates to
aldehydes and imines has been studied in some detail64–66 and
similar processes have been briefly examined in the case of
bicyclic lactam 1a.26 These reactions have been found to pro-
ceed with some diastereocontrol; for example, reaction of the
lactam enolate of 1a with benzaldehyde gave a product mixture
consisting of 16a and 17a in a ratio of exo- : endo- = 2 : 1
(Scheme 4). Reaction of this same lactam enolate with chloral
gave adducts 16b and 17b with high endo- selectivity (1 : 2.7)
and excellent overall yield (86%, Scheme 4); their stereo-
chemistry was assigned on the basis of C(6)H chemical shift
values as discussed above. Intending to apply the Corey–Link
procedure for amino acid synthesis,72 endo-17b was converted in
one pot to azido ester 18 in 41% yield, but this compound
appeared by NMR spectroscopic analysis to be a mixture of
diastereomers and all attempts to manipulate either the azide or
O,N-acetal function failed.
With this precedent, we anticipated that the required stereo-
chemistry for penmacric acid would be available from the
reaction of lactam 1a with an activated imine. However, these
additions proved not to be so stereoselective as the aldehyde
additions indicated above. Thus, the N-tosyl imine derived from
The endo-malonate 8a could be readily deprotected to give
the corresponding alcohol 11a in 67% yield, but oxidation of
this product to the carboxylic acid 11b under Sharpless condi-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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Scheme 3
benzaldehyde was reacted with the enolate of 1a, and this was
epimeric mixtures favouring the endo-isomer were more
found to give a high yield of exo-adduct 19a only, but as a
mixture of diastereomers at the C-1Ј position. Careful crystal-
lization of this mixture enabled isolation of the (2R,5S,7S,1ЈR)
diastereomer suitable for single-crystal X-ray analysis, and
this confirmed the earlier stereochemical assignment.73 This
structure also confirmed the shallow concave structure of the
bicyclic ring system, which probably accounts for the low
diastereoselectivity in reactions at C-7, and also indicated the
presence of intermolecular hydrogen bonding between NHTs
and lactam carbonyl components. Deprotection (TFA, DCM),
oxidation using the Sharpless conditions69 and immediate
treatment with diazomethane gave succinimide 20 in low yield,
with no phenyl group cleavage as intended; we have previously
observed such decarboxylations and further oxidations in these
systems. Application of the N-tosyl imine derived from
furfuraldehyde to this sequence similarly gave the exo- adduct
19b in excellent yield, as a 2 : 1 mixture of diastereomers at the
C-1Ј position, and whose stereochemistry was established by
NOESY analysis and by consideration of C(6)H chemical shift
data, but this time oxidative cleavage of the furyl ring and
immediate protection (diazomethane) successfully gave ester 21
as a single diastereomer, albeit in low yield (21%). The indicated
C(7)exo stereochemistry was established again by the similar
chemical shift values for C(6)H (δ 2.1 and 2.3). O,N-Acetal
ring cleavage, further oxidation and esterification gave the C-7
exo-epimer of penmacric acid 22, as a 5 : 1 mixture of
diastereomers at the C-1Ј position, whose stereochemistry
(apart from C-1Ј) was established by NOESY analysis (Scheme
4).
likely. However, a recent finding has been that switching from
O,N-acetal 1a to analogue 1b led to a marked increase in
endo-selectivity for alkylation reactions, and this we attributed
to increased planarity of the intermediate enolate structure
with consequent enhancement of stereoelectronic control for
the reaction.23 This phenomenon appears to be general in
pyrrolidinone systems, and has attracted some attention.74 Of
interest, therefore, was the outcome of reactions of lactam 1b
with an N-tosyl imine (Scheme 5). Once again, however,
exclusive exo-aminoalkylation at C-7 occurred with the N-tosyl
imine derived from furfuraldehyde, to give 23 in excellent yield
(76%), mostly as a single diastereomer, as established from the
similar C(6)H values (δ 1.9 and 2.2) and from NOESY analysis.
The (R)- stereochemistry at C-1Ј was tentatively assigned by
NOESY analysis, and assumes H-bonding between NH and the
lactam carbonyl (as indicated by the IR spectrum, in which the
NH frequency was at 3350 and 3250, and the lactam carbonyl
at 1689 cmϪ1).
In an attempt to correct this undesirable stereochemical out-
come, epimerisation of the C-7 position of exo- lactam adduct
19b to convert it to the endo- isomer 24a was performed using
NaH (2.2 eq.) in refluxing THF for 5 hours, followed by
quenching of the reaction mixture with di-tert-butylphenol
(Scheme 6). The endo- adduct 24a (indicated by the wide separ-
ation of the C(6)H signals at δ 1.3 and 2.3, and from NOESY
analysis (Fig. 3)) was formed in 27% yield, but 45% of the
starting material was also recovered, although these were read-
ily separable by chromatography. Epimerisation of lactam 23
under these conditions gave 26% of the desired product 24b,
but also 45% of recovered starting material and 22% of the
elimination product 25; facile eliminations of β-amino lactams
The high exo-stereoselectivity of these reactions had been
surprising, since all our earlier work had indicated that C-7
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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Scheme 4
Scheme 5
have been previously reported.64 The C(7) endo- stereo-
chemistry was initially postulated on the basis of the widely
separated chemical shift values for C(6)H (δ 1.3 and 2.22) and
confirmed by NOE analysis (Fig. 3), and the (S)-stereo-
chemistry at C-1Ј was again tentatively assigned by NOESY
analysis, assuming H-bonding between NH and the lactam
carbonyl (as indicated by the IR spectrum, in which the NH
resonated at 3350 and 3250, and the lactam carbonyl resonated
at 1687 cmϪ1). The conformation indicated in Fig. 3 is consist-
ent with the observed JH-7/H1Ј values of 5.2 and 5.0 Hz for com-
pounds 24a,b respectively. When 2.5 equivalents of LDA were
used followed by quenching with di-tert-butylphenol, 22% of
the endo-adduct 24a was obtained, but application of this reac-
tion to lactam 23 gave only 18% of the epimerised endo-adduct
24b still as a mixture of diastereomers at C-1Ј. Compound 24b
was converted to ester 26 in low yield (Scheme 6), whose
stereochemistry was again assigned by C(6)H chemical shift
values (δ 1.9 and 2.4) and confirmed by NOESY (Fig. 3) and a
JH-7/H1Ј value of 4.3 Hz. Deprotection (TFA, 45%) was followed
by the usual oxidation-protection sequence, and gave lactam
27b in 8% yield over the three steps, a compound with the
correct relative configuration for penmacric acid. This
compound also proved to be prone to elimination to give
compound 28.
In conclusion, we have demonstrated that alkylation reac-
tions using α-halolactams or lactam enolates derived from
bicyclic lactam templates can proceed with high endo- or
exo- diastereoselectivity respectively. In the latter case, stereo-
chemical correction by means of enolate generation and
hindered phenol quench is possible with moderate efficiency.
This protocol has been applied to the synthesis of protected
penmacric acid and its analogues.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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Scheme 6
ЊC. (Found: C, 43.92; H, 3.48; N4.28. C12H12NO2I requires C,
43.79; H, 3.67; N,4.26%); [α]D ϩ244 (c 1.0 CHCl3); νmax(CHCl3)/
cmϪ1 1718(s); δH(200 MHz, CDCl3) 2.38–2.52(1H, m,
C(6)Hendo), 3.05–3.20(1H, m, C(6)Hexo), 3.79(1H, dd, J 10.0,
9.5 Hz, C(4)Hendo), 4.12–4.35(2H, m, C(5)H and C(4)Hexo),
5.05(1H, dd, J 10.0, 7.5 Hz, C(7)H), 6.35(1H, s, C(2)H),
7.32–7.53(5H, m, ArH); δC(50.3 MHz, CDCl3) 18.3(C(6)),
37.0(C(7)), 58.1(C(5)), 71.2(C(4)), 87.98(C(2)), 126.2, 128.7,
129.0, 136.3, 173.4; m/e[Probe CIϩ, (NH3)] 330(100%, MHϩ),
202(70). The second product (Rf = 0.3) was the exo iodide
7b which was recrystallised from diethyl ether–petrol to give
colourless needles (3.4 g, 54%). Mp 85–87 ЊC. (Found: C, 43.84;
H, 3.37; N, 4.11. C12H12NO2I requires C, 43.79; H, 3.67; N,
4.26%); [α]D ϩ105.3 (c 1.0 CHCl3); νmax(CHCl3)/cmϪ1 1718(s);
δH(200 MHz, CDCl3) 2.36–2.64(2H, m, C(6)H), 3.66(1H, m,
C(4)H), 4.22–4.40(2H, m, C(5)H and C(4)H), 4.61(1H, dd,
J 6.5, 5.5 Hz, C(7)H), 6.31(1H, s, C(2)H), 7.30–7.50(5H, m,
ArH); δC(50.3 MHz, CDCl3) 19.05(C(6)), 38.52(C(7)),
57.90(C(5)), 70.73(C(4)), 86.96(C(2)), 126.2, 128.9, 129.1,
137.9, 175.4(C(8)); m/e [Probe CI, NH3] 330(MHϩ, 95%),
202(100).
Fig. 3
Experimental
(2R,5S,7R) and (2R,5S,7S )-1-Aza-3-oxa-8-oxo-2-phenyl-7-
(di(methoxycarbonyl)methyl) bicyclo[3.3.0]octane 8a and 9a
For detailed experimental procedures, see our earlier work.26
NMR signals for different C-1Ј diastereomers where rele-
vant are labeled as A and B whenever they could be resolved;
otherwise, both signals are superimposed.
Dimethyl malonate (187 mg, 1.41 mmol) was added to a
rapidly stirred suspension of sodium hydride (60% in mineral
oil (40 mg, 1.0 mmol)) in dry THF (20 ml) at 0 ЊC. When evolu-
tion of bubbles had ceased the reaction was stirred for a further
15 minutes. A solution of exo iodide 7b (310 mg, 0.95 mmol)
in THF (5 ml) was added and the reaction stirred at 0 ЊC for
30 minutes. Water (10 ml) was added and the aqueous layer
extracted with DCM (2 × 30 ml). The combined organic frac-
tions were dried (MgSO4) and the solvent removed under
reduced pressure to yield the product as a mixture of 2
diastereomers 8a : 9a (ratio approximately 2 : 1) which were
separated by flash column chromatography (ethyl acetate–
petrol = 1 : 9 gradient to ethyl acetate–petrol = 1 : 1). The first
isomer (Rf = 0.6, ethyl acetate–petrol = 1 : 1) was endo malonate
8a which was a colourless oil (170 mg, 53%). [α]D ϩ139 (c 3.0
CHCl3); νmax(CHCl3)/ cmϪ1 1736(s), 1704(s), 1438, 1357, 1270;
δH(200 MHz, CDCl3) 2.01–2.13(1H, m, C(6)Hendo), 2.51–
2.66(1H, m, C(6)Hexo), 3.52–3.73(2H, m, C(4)Hendo and C(7)H),
3.78(3H, s, OCH3), 3.80(3H, s, OCH3), 3.92(1H, d, J 6.5 Hz,
C(1Ј)H), 4.13–4.32(2H, m, C(4)Hexo and C(5)H), 6.29(1H, s,
(2R,5S,7S )- and (2R,5S,7R)-1-Aza-3-oxa-8-oxo-2-phenyl-7-
iodobicyclo[3.3.0]octane 7a and 7b
A crude mixture of chlorides 6 (4.50 g, 18.9 mmol)26 and
sodium iodide (5.68 g, 37.9 mmol) was refluxed in acetone
(200 ml) for 10 hours. The solvent was removed in vacuo to give
a solid residue that was partitioned between water (40 ml) and
DCM (50 ml). The aqueous layer was extracted with ethyl
acetate or DCM (2 × 50 ml) and the combined organic layers
were washed with brine (50 ml) and dried (MgSO4). The solvent
was removed under reduced pressure giving a dark oil that con-
tained two products which were separated by flash column
chromatography (ethyl acetate–petrol = 1 : 4 gradient to ethyl
acetate–petrol = 1 : 1). The first isolated product (Rf = 0.5, ethyl
acetate–petrol = 1 : 1) was the endo iodide 7a which was
recrystallised from diethyl ether–petrol or chloroform–petrol to
give the product as colourless needles (1.0 g, 16%). Mp 125–7
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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C(2)H), 7.29–7.45(5H, m, ArH); δC(50.3 MHz, CDCl3)
28.48(C(6)), 44.93(C(7)), 51.14, 52.74, 52.80, 56.84,
72.18(C(6)), 87.18(C(2)), 126.0, 128.4, 128.6, 138.4, 168.1,
168.6, 175.4; m/e[probe CIϩ, NH3] 334(MHϩ,100%). The sec-
ond isomer, a pale oil, (Rf = 0.5) was exo malonate 9a (85 mg,
27%). [α]D ϩ134 (c 1.05 CHCl3); νmax(CHCl3)/cmϪ1 1704, 1736;
δH(200 MHz, CDCl3) 2.05–2.38(2H, m, C(6)H), 3.27–3.47(2H,
m, C(4)Hendo and C(7)H), 3.70(3H, s, OCH3), 3.79(3H, s,
OCH3), 3.96(1H, d, J 5.5 Hz, C(1Ј)H), 4.04–4.28(2H, m,
C(4)Hexo and C(5)H), 6.31(1H, s, C(2)H), 7.34–7.43(5H, m,
ArH); δC(50.3 MHz, CDCl3) 24.39(C(6)), 43.73(C(7)), 51.88,
52.71, 52.83, 57.05, 70.60(C(4)), 87.46(C(2)), 125.8, 128.4,
128.5, 138.7, 167.9, 168.2, 177.2; m/e[probe CIϩ, NH3]
334(MHϩ,100%); HRMS 334.1291; MHϩ requires 334.1291.
LDA (0.30 mmol) under nitrogen in THF (10 ml) precooled to
Ϫ78 ЊC. After stirring for 15 minutes a solution of endo-iodide
7a (100 mg, 0.30 mmol) in THF (5 ml) was added. The reaction
was stirred at Ϫ78 ЊC for 1 hour, warmed to room temperature
and quenched with water (10 ml). The aqueous layer was
extracted with DCM (3 × 20 ml), the combined organic extracts
were dried (MgSO4) and the solvent removed in vacuo. The
product was obtained as a mixture of diastereomers which were
separated by flash column chromatography (ethyl acetate–
petrol = 1 : 20 gradient to 1 : 1). The endo- product 8c (Rf = 0.55
ethyl acetate–petrol = 1 : 1) was a pale yellow oil that
decomposed upon standing at room temperature (29 mg, 20%).
δH(500 MHz, CDCl3) 1.24(3H, t, J 7.0 Hz, CH3CH2), 2.53–
2.59(1H, m, C(6)Hendo), 2.63–2.69(1H, m, C(6)Hexo), 3.67–
3.71(1H, m, C(7)H), 3.77(1H, dd, J 8.0, 8.0 Hz, C(4)Hendo),
4.10–4.21(3H, m, H5 and OCH2), 4.33(1H, dd, J 6.0, 8.0 Hz,
C(4)Hexo), 4.71(1H, d, J 3.0 Hz, H-1Ј), 6.24(1H, s, C(2)H), 7.29–
7.65(15H, m, ArH); δC(125 MHz, CDCl3) 14.15(CH3),
24.79(C(6)), 48.81(C(7)), 56.82(C(5)), 61.22, 63.80, 72.21(C(4)),
86.77(C(2)), 125.9, 127.9, 128.1, 128.3, 128.4, 128.5, 128.6,
128.8, 130.5, 136.5, 138.9, 139.5, 170.6, 172.9, 176.2; m/e[probe
CIϩ, NH3] 469(MHϩ, 100%); HRMS 469.2127, MHϩ requires
469.21273.
The second isomer 8cЈ was a minor component which was
crystallised from ether as translucent needles (8 mg,
5.6%). Mp 166–7 ЊC; [α]D ϩ32(c 0.85 CHCl3); (Found: C,
74.18; H, 5.35; N, 5.52. C29H28N2O4 requires C, 74.34; H, 6.02;
N, 5.98%); νmax(CHCl3)/cmϪ1 1730(s), 1709(s); δH(500
MHz, CDCl3) 1.28(3H, t, J 7.0 Hz, CH3), 2.06–2.12(1H, m,
C(6)Hendo), 2.53–2.59(1H, m, C(6)Hexo), 3.39–3.45(1H, m,
C(7)H), 3.67(1H, dd, J 8.0, 8.0 Hz, C(4)Hendo), 4.10–4.28(4H,
m, C(5)H and OCH2, and C(4)Hexo), 4.50(1H, d, J 4.0 Hz, H-
1Ј), 6.39(1H, s, C(2)H), 7.21–7.68(15H, m, ArH); δC(125
MHz, CDCl3) 14.08(CH3), 26.56(C(6)), 48.25(C(7)),
56.72(C(5)), 61.33, 64.84, 72.37(C(4)), 87.10(C(2)), 126.0,
127.5, 128.1, 128.3, 128.4, 128.7, 128.9, 130.6, 135.9, 139.0,
170.2, 172.1, 176.2; m/e [probe CIϩ, NH3] 469(MHϩ, 100%),
182(90%).
(2R,5S,7R) and (2R,5S,7S )-1-Aza-3-oxa-8-oxo-2-phenyl-7-
(methyloxycarbonylcyanomethyl) bicyclo[3.3.0]octane 8b and 9b
To NaH (39.0 mg, 1.0 mmol) in THF (5 ml) at 0 ЊC was added
methyl cyanoacetate (123 mg, 1.2 mmol) and the solution
stirred for 30 minutes under nitrogen. A solution of exo-iodide
7b (273 mg, 0.83 mmol) in THF (15 ml) was added to the reac-
tion mixture at 0 ЊC. After 1 hour the reaction mixture was
quenched with aqueous saturated ammonium chloride. Ethyl
acetate (20 ml) and cold water (15 ml) were added to the reac-
tion mixture and the aqueous layer was extracted with EtOAc
(3 × 10 ml). The organic layers were washed with brine (20 ml),
then dried (MgSO4). Solvent removed in vacuo yielded a brown
oil which was purified by flash column chromatography on
silica [EtOAc–petrol(40/60), 1 : 2] to give endo-8b (176 mg, 71%)
as a pale yellow oil and a mixture of diastereomers. Rf = 0.37
[EtOAc–petrol(40/60), 2 : 3]; νmax/cmϪ1 (CHCl3) 3027, 2341,
2254, 1753, 1712, 1603, 1403, 1265, 1209; δH(400 MHz, CDCl3)
1.98–2.10(1H, m, C(6)Hendo(A
ϩ B)), 2.65–2.75(1H, m,
C(6)Hexo(A ϩ B)), 3.57–3.63(1H, m, C(7)H(A ϩ B)), 3.64–
3.74(1H, m, C(4)Hendo(A ϩ B)), 3.85(3H, s, CO2CH3(A)),
3.87(3H, s, CO2CH3(B)), 4.01–4.04(1H, m, C(1Ј)H(A), 4.19–
4.29(2H, m, C(5)H(A ϩ B) and C(1Ј)H(B)), 4.23–4.39(1H, m,
C(4)Hexo(A
ϩ B)), 6.29(1H, s, C(2)H(A)), 6.32(1H, s,
The third isomer to be recovered from the column (Rf = 0.25)
was product 9c (90 mg, 63%), a colourless solid which was
recrystallised from diethyl ether or chloroform–petrol. Mp 138–
40 ЊC. (Found: C, 74.17; H, 5.82; N, 5.98. C29H28N2O4 requires
C(2)H(B)), 7.41–7.49(5H, m, ArH(A ϩ B)); δC(400 MHz,
CDCl3) 27.80, 28.8(C(6)(A ϩ B)), 36.90, 38.10(C(1Ј)(A ϩ B)),
45.5, 45.7(C(7)(A ϩ B)), 53.6, 53.9(CO2CH3(A ϩ B)), 56.6,
57.8(C(5)(A ϩ B)), 70.6, 72.1(C(4)(A ϩ B)), 87.3(C(2)(A ϩ B)),
89.9, 114.4, 115.0(CN(A ϩ B)), 125.9, 126.0, 128.5, 128.6,
128.8, 128.9(PhCH(A ϩ B)), 135.5, 137.8, 138.1(PhC(A ϩ B)),
164.5, 165.2(CO2Me(A ϩ B)), 172.8, 173(C(8)(A ϩ B)); m/e
(CIϩ) 301 (MHϩ, 45%), 274 (10), 246 (30), 213 (20), 204 (40);
HRMS 301.1185, MHϩ requires 301.1188.
The second product was the exo-substituted product 9b (32
mg, 12.9%) as a yellow oil. Rf = 0.22 [EtOAc–petrol(40/60), 2 :
3]; νmax(CHCl3)/cmϪ1 3684, 3010, 2433, 2253, 1754, 1713, 1601,
1580, 1521, 1476, 1423, 1283, 1190; δH(400 MHz, CDCl3) 2.29–
2.43(2H, m, C(6)H(A ϩ B)), 3.30–3.40(1H, m, C(7)H(A ϩ B)),
3.40–3.50(1H, m, C(4)Hendo(A ϩ B)), 3.80(3H, s, COOCH3(A)),
C, 74.34; H,6.02; N, 5.98%); [α]D Ϫ106 (c 1.0 CHCl3); νmax
-
(CHCl3)/cmϪ1 1731, 1698; δH(500 MHz, CDCl3) 1.26(3H, t, J
7.0 Hz, CH3), 2.17–2.24(1H, m, C(6)Hendo), 2.86–2.91(1H, m,
C(6)Hexo), 3.43–3.50(2H, m, C(7)H and C(4)Hendo), 4.13–
4.28(3H, m, OCH2 and C(4)Hexo), 4.36–4.41(1H, m, C(5)H),
4.66(1H, d, J 2.5 Hz, H-1Ј), 6.26(1H, s, C(2)H), 7.00–7.62(15H,
m, ArH); δC(125 MHz, CDCl3) 14.14(CH3), 25.59(C(6)),
48.98(C(7)), 59.02(C(5)), 61.35, 65.29, 72.16(C(4)), 86.60(C(2)),
125.8, 127.8, 128.1, 128.2, 128.4, 128.7, 128.9, 130.6, 135.7,
138.2, 139.1, 170.3, 172.9, 176.1; m/e [probe CIϩ, NH3]
469(100%, MHϩ), 362(30).
3.90(3H, s, COOCH3(B)), 4.03–4.32(3H, m, C(5)H, C(4)Hexo
,
C(1Ј)H(A ϩ B)), 6.31(1H, s, C(2)H(A)), 6.34(1H, s, C(2)H(B)),
7.40(5H, m, ArH(A ϩ B)); δC(400 MHz, CDCl3) 24.3(C(6)(A ϩ
B)), 38.2, 39.2(C(1Ј)(A ϩ B)), 44.5, 44.6(C(7)(A ϩ B)), 53.4,
54.1(CO2CH3), 56.9, 57.2(C(5)(A ϩ B)), 70.6(C(4)(A ϩ B)),
87.6(C(2)(A ϩ B)), 114.1, 114.8(CN(A ϩ B)), 125.8, 126.0,
128.5, 128.7, 128.8(PhCH(A ϩ B)), 137.8, 138.1(PhC(A ϩ B)),
164.4, 165.0(CO2Me(A ϩ B)), 174.6, 175.1(C(8)(A ϩ B)); m/e
(CIϩ) 301.0 (MHϩ, 100%); HRMS 301.1193, MHϩ requires
301.1188.
(2R,5S,7R) and (2R,5S,7S )-1-Aza-3-oxa-8-oxo-2-phenyl-7-
[tert-butyloxycarbonyl(benzhydrylideneamino)methyl]bicyclo-
[3.3.0]octane 8d, 8dЈ and 9d
N-(Diphenylmethylene)glycine tert-butyl ester (0.480 g,
1.63 mmol) in THF (20 ml) was added to a solution of LDA
(1.52 mmol) in THF (15 ml) at Ϫ78 ЊC and under nitrogen. The
resulting bright yellow solution was stirred at Ϫ78 ЊC for
15 minutes, exo iodide 7b (0.500 g, 1.52 mmol) in THF (20 ml)
was added and the reaction mixture was stirred at Ϫ78 ЊC for
1 hour and then at room temperature for a further 16 hours,
during which time it decolourised. The solvent was removed
under reduced pressure and ethyl acetate (50 ml) added. The
resulting organic phase was washed with distilled water (4 ×
20 ml), dried over magnesium sulfate and evaporated to
dryness, yielding a yellow oil which was purified by flash
(2R,5S,7R) and (2R,5S,7S )-1-Aza-3-oxa-8-oxo-2-phenyl-7-
[ethyloxycarbonyl(benzhydrylideneamino)methyl]bicyclo[3.3.0]-
octane 8c, 8cЈ and 9c
A solution of N-(diphenylmethylene)glycine ethyl ester (85 mg,
0.32 mmol) in THF (5 ml) was added dropwise to a solution of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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column chromatography on silica (10 : 1 petroleum ether : ethyl
acetate). The endo- product 8d was a yellow solid (0.144 g,
17%): Mp 42–46 ЊC; Rf 0.40 (3 : 1 petroleum ether: ethyl acet-
ate); (Found: C, 75.20; H, 6.38; N, 5.47. C31H32N2O4 requires C,
74.98; H, 6.49; N, 5.64%); [α]2D3 ϩ218 (c 0.05, CHCl3);
νmax(CHCl3)/cmϪ1 1727 (CO); δH(500 MHz, CDCl3) 1.43(9H, s,
C(CH3)3), 2.52–2.58(1H, m, C(6)Hexo), 2.68–2.73(1H, m,
C(6)Hendo), 3.66(1H, ddd, J 9.5, 9.5, 3.0 Hz, C(7)H), 3.81(1H,
dd, J 8.0, 8.0 Hz, C(4)Hendo), 4.15–4.19(1H, m, C(5)H), 4.34(1H,
dd, J 8.0, 6.0 Hz, C(4)Hexo), 4.62(1H, d, J 3.0 Hz, C(1Ј)H), 6.
26(1H, s, C(2)H), 7.30–7.66(15H, m, ArH); δC(50.3 MHz,
CDCl3) 24.31(C(6)), 27.89(C(CH3)3), 48.93(C(7)), 56.89(C(5)),
64.43(C(1Ј)), 72.24(C(4)), 81.65(OC(CH3)3), 86.88(C(2)), 126.2,
127.8, 128.1, 128.3, 128.5, 128.6, 128.8, 129.0, 129.3, 130.3,
60.25, 60.58, 161.3, 164.8; m/e [probeCIϩ, NH3] 367(100%,
MHϩ).
(2S,4R)-4-[Di(methoxycarbonyl)methyl]-2-hydroxymethyl-5-
oxopyrrolidine 11a
endo-Malonate 8a (0.100 g, 0.3 mmol) and trifluoroacetic acid
(0.72 ml, 9.38 mmol) in dichloromethane (10 ml) were stirred at
room temperature for 3 hours, and the reaction mixture was left
to stand for 16 hours. The dichloromethane solvent was
removed under reduced pressure. The resulting oil was purified
by flash column chromatography on silica (15 : 1 ethyl acetate–
MeOH gradient to 9 : 1), to give the product 11a as a glassy
yellow oil (0.049 g, 67%): Rf 0.59 (3 : 1 ethyl acetate–MeOH);
(Found: C, 46.52; H, 5.84; N, 4.31. C10H15NO6 requires C,
48.98; H, 6.16; N, 5.71%); [α]2D1 ϩ24 (c 1.2, CHCl3); νmax(thin
film)/cmϪ1 3355(br), 1735, 1688; δH(200 MHz, CDCl3) 1.66–
1.82(1H, br m, C(3)H), 2.27–2.41(1H, br m, C(3)H), 3.13–
3.25(1H, br m, C(4)H), 3.39–3.48(1H, br m, CHHOH), 3.73–
3.88(9H, m, 2 × OCH3, C(2)H, CHHOH, C(1Ј)H), 4.47 and
7.57(2 × br s, 2H, NH and OH); δC(125.8 MHz, CDCl3)
26.43(C(3)), 41.47(C(4)), 51.27 and 54.51(C(2) and C(1Ј)),
52.69 and 52.73(2 × OCH3), 64.83(CH2OH), 168.4 and 168.9
(2 × CO2Me), 177.13(C(5)); MS(APCIϩ) m/e 246 (MHϩ, 20%),
214(45), 186(3), 182(100).
130.6(ArC), 137.0, 139.3, 139.9(4Њ ArC), 170.2, 172.8 and
t
176.9(Ph C᎐N, C(8) and CO Bu); m/e (probe CI; NH ) 497
᎐
2
2
3
(MHϩ, 20%), 397 (73), 182 (100).
The second isomer 8dЈ was a white solid, which was recrystal-
lised from petroleum ether–ethyl acetate (0.116 g, 14%): mp
125–127 ЊC; Rf 0.32 (3 : 1 petroleum ether: ethyl acetate); [α]2D3 ϩ
59 (c 0.14, CHCl3); νmax (CHCl3)/cmϪ1 1712 (CO); δH(500 MHz,
CDCl3) 1.54(9H, s, C(CH3)3), 2.02–2.08(1H, m, C(6)Hendo),
2.58–2.65(1H, m, C(6)Hexo), 3.51(1H, ddd, J 10.0, 10.0, 4.0 Hz,
C(7)Hexo), 3.71(1H, dd, J 8.0, 8.0 Hz, C(4)Hendo), 4.13–4.19(1H,
m, C(5)H), 4.29(1H, dd, J 8.0, 8.0 Hz, C(4)Hexo), 4.41(1H,
d, J 4.0 Hz, C(1Ј)H), 6.48(1H, s, C(2)H), 7.27–7.88(15H, m,
ArH); δH(50.3 MHz, CDCl3) 26.83(C(6)), 27.94(C(CH3)3),
48.23(C(7)), 56.64(C(5)), 65.66(C(1Ј)), 72.36(C(4)), 81.77(OC-
(CH3)3), 87.14(C(2)), 126.1, 126.3, 127.8, 128.3, 128.6, 128.8,
(2S,4R)-2-Carboxy-4-[di(methoxycarbonyl)methyl]-5-
oxopyrrolidine 11b
Sodium periodate (0.208 g, 0.97 mmol) and ruthenium()
chloride (0.010 g) were added to a solution of lactam 11a
(0.056 g, 0.23 mmol) in tetrachloromethane (7 ml), acetonitrile
(7 ml) and water (10 ml) and the mixture was stirred vigorously
at room temperature for 4 hours. Methanol (2 ml) was added to
the resulting orange/brown mixture to destroy excess oxidant
and the mixture was stirred for a further 20 minutes. Water
(15 ml) and ethyl acetate (15 ml) were added and the layers were
separated. Brine (10 ml) was added to the aqueous layer, which
was then extracted with ethyl acetate (3 × 15 ml). The combined
organic layers were washed with brine, dried (MgSO4) and
evaporated under reduced pressure to give a red/brown oil,
which was subjected to flash column chromatography on silica
(ethyl acetate). The product (5.6 mg, 10%) was obtained as a
brown oil after chromatography (3 : 1 ethyl acetate–MeOH):
νmax (thin film)/cmϪ1 3334(br) (NH and OH), 1735(s), 1704(sh),
1437; δH(500 MHz, CDCl3) 2.06–2.10(1H, br m, C(3)H),
2.68(1H, br m, C(3)H), 3.16–3.17(1H, br m, C(4)H), 3.71(3H, s,
OCH3), 3.76(3H, s, OCH3), 3.81–3.89(1H, br m, C(1Ј)H)),
4.23(1H, br m, C(2)H), 4.65 and 7.59(2H, 2 × br s, OH and
NH); m/e (APCIϪ) 258 (M – Hϩ, 38%), 226 (62), 200 (26), 182
(100).
129.1, 130.7(ArC), 136.4, 139.4(4ЊArC), 169.4, 172.0 and
t
176.7(Ph C᎐N, C(8) and CO Bu); m/e (probe CI, NH ) 497
᎐
2
2
3
(MHϩ, 100%), 397 (22), 395 (11); HRMS (CI) 497.2460, MHϩ
requires 497.2440.
The third diastereomer (0.297g, 39%) was a transparent glass
9d which solidified very slowly. Mp 94–96 ЊC; Rf 0.19 (3 : 1
petroleum ether: ethyl acetate); [α]2D3 Ϫ49.6 (c 1.8, CHCl3); νmax
-
(thin film)/cmϪ1 1730(sh) (ester CO), 1704 (lactam CO); δH(500
MHz, CDCl3) 1.44 (9H, s, C(CH3)3), 2.16–2.21(1H, m,
C(6)Hendo), 2.89–2.94(1H, m, C(6)Hexo), 3.40–3.43(1H, m,
C(7)H), 3.48(1H, dd, J 8.5, 8.0 Hz, C(4)Hendo), 4.25(1H, dd,
J 8.0, 6.0 Hz, C(4)Hexo), 4.39–4.42(1H, m, C(5)H), 4.56(1H, d,
J 2.5 Hz, C(1Ј)H), 6.27(1H, s, C(2)H), 7.01–7.83(15H, m,
ArH); δC(50.3 MHz, CDCl3) 25.49(C(6)), 27.89(C(CH3)3),
50.19(C(7)),
59.13(C(5)),
65.92(C(1Ј),
72.28(C(4)),
81.86(C(CH3)3), 86.65(C(2)), 126.1, 128.0, 128.3, 128.5, 128.6,
128.9, 129.1, 130.3, 130.7(ArC), 136.1, 138.5, 139.5(4Њ ArC),
t
169.8, 172.8 and 176.7(Ph2C = N, C(8) and CO2 Bu); m/e(probe
CI, NH3) 497(MHϩ, 100%), 395 (10), 390 (12), 289 (10); HRMS
(CI) 497.2463, MHϩ requires 497.2440.
Reaction of iodides 7b with Schöllkopf reagent
(2R,5S,7R,1ЈR)-1-Aza-3-oxa-8-oxo-2-phenyl-7-[amino(ethoxy-
carbonyl)methyl]bicyclo[3.3.0]octane 12a
n-Butyllithium (2.5 M solution in hexanes (0.238 ml, 0.60
mmol)) was added dropwise to a solution of (2R)-2,5-dihydro-
2-isopropyl-3,6-dimethoxypyrazine68 (0.55 mmol, 102 mg) in
THF (10 ml) at Ϫ78 ЊC. The reaction was stirred for 15 minutes
and a solution of exo-iodide 7b (250 mg, 0.750 mmol) in THF
(5 ml) added. The reaction was warmed to room temperature
and stirred for a further 15 minutes. Water (10 ml) was added
and then aqueous layer extracted with DCM (3 × 30 ml). The
combined organic fractions were dried (MgSO4) and the solvent
removed in vacuo to give a pale oil which was purified by flash
column chromatography (ethyl acetate–petrol = 3 : 7 gradient to
ethyl acetate–petrol = 3 : 2) to give dimer 10 which was a pale
yellow low melting solid (68 mg, 66%); νmax(CHCl3)/cmϪ1 1240,
1437, 1462, 1700; δH(CDCl3) 0.64 (6H, d, J 7.0 Hz, 2 × CH3),
1.02(6H, d, J 7.0 Hz, 2 × CH3), 2.25(2H, m, 2 × CH(Me)2),
3.52(6H, s, OMe), 3.65(2H, m, 2 × CHMe2), 3.75(6H, s, OMe),
3.88(1H, d, J 4.0 Hz, CHN), 4.52(1H, d, J 4.0 Hz, CHN).
δC(50.3 MHz, CDCl3) 16.39, 19.06, 31.47, 52.28, 52.49, 57.76,
A 0.5 M solution of hydroxylamine hydrochloride in 80% v/v
EtOH in water (2.0 ml) was added to a solution of imine 8c
(0.228 g, 0.49 mmol) in dichloromethane (25 ml) and the solu-
tion was heated under reflux for 16 hours. Dichloromethane (15
ml) was then added and the organic phase was washed with 5%
sodium hydrogen carbonate solution (2 × 10 ml) and dried over
magnesium sulfate and the solvent was removed in vacuo. The
resulting yellow oil was purified by flash column chromato-
graphy on silica (ethyl acetate eluent) to give the product as a
pale yellow oil (0.129 g, 87%): Rf 0.53 (3 : 1 ethyl acetate–
MeOH); [α]2D1 ϩ186 (c 1.04, CHCl3); νmax(thin film)/cmϪ1
3397(w), 1732, 1704; δH(200 MHz, CDCl3) 1.28(3H, t, J 7.0 Hz,
OCH2CH3), 1.95–2.10(1H, m, C(6)H), 2.21–2.36(1H, m,
C(6)H), 3.45(1H, ddd, J 10.0, 10.0, 3.0 Hz, C(7)H), 3.64(1H,
dd, J 8.0, 8.0 Hz, C(4)H), 4.03–4.27(5H, m, OCH2CH3, C(5),
C(4)H and C(1Ј)H), 6.30(1H, s, C(2)H), 7.31–7.47(m, 5H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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ArH); δC(50.3 MHz, CDCl3) 14.08(CH3), 24.02(C(6)), 49.2
and 52.64(C(1Ј) and C(7)), 56.54(C(5)), 61.36(OCH2CH3),
71.96(C(4)), 86.77(C(2)), 126.2, 128.6, 128.8(ArC), 139.0(4Њ
ArC), 173.9 and 176.8(C(8) and CO2Et); m/e (electrospray)
305(MHϩ, 100%), 288(86), 257(6); HRMS(CI) 304.1423, MHϩ
requires 304.1433.
C(2)H), 6.41(1H, br d, J 9.0 Hz, NH), 7.34–7.40(5H, m, ArH);
δC(50.3 MHz, CDCl3) 13.90(OCH2CH3), 23.08(CH3C(O)N),
28.88(C(6)), 48.38 and 50.81(C(7) and C(1Ј)), 56.74(C(5)),
62.02(OCH2CH3), 72.14(C(4)), 86.63(C(2)), 126.1, 128.6,
128.9(ArC), 138.1(ArC), 170.4, 171.5 and 175.6(CH3C(O)N,
C(8) and CO2Et); m/e (probe CI, NH3) 347(MHϩ, 100%),
288(4), 273(4), 231(10), 211(5), 202(28).
(2R,5S,7R,1ЈS)-1-Aza-3-oxa-8-oxo-2-phenyl-7-[amino(ethoxy-
carbonyl)methyl]bicyclo[3.3.0]octane 13a
(2R, 5S, 7S )-1-Aza-3-oxa-8-oxo-2-phenyl-7-[N-acetylamino-
(ethoxycarbonyl)methyl]bicyclo[3.3.0]octane 14
This compound was prepared from imine 8cЈ on a 0.110 g scale
by the above method, except that the number of equivalents
and the molarity of the hydroxylamine hydrochloride solu-
tion were doubled and the time of reflux was 2 hours. Flash
column chromatography on silica afforded the product as an
orange oil (0.033 g, 46%): Rf 0.41 (3 : 1 ethyl acetate–MeOH);
(Found: C, 62.92; H, 7.33; N, 8.16. C16H20N2O4 requires C,
63.14; H, 6.62; N, 9.20%); [α]2D1 ϩ141 (c 1.25, CHCl3); νmax(film)/
cmϪ1 3386(w), 1735, 1701; δH(200 MHz, CDCl3) 1.31(3H, t,
J 7.0 Hz, OCH2CH3), 2.02–2.17(1H, m, C(6)H), 2.45–2.59(1H,
m, C(6)H), 3.53–3.68(3H, m, C(7)H, C(4)H and C(5)H),
4.06–4.30(4H, m, C(4)H, C(1Ј)H and OCH2CH3), 6.31(1H,
s, C(2)H), 7.32–7.45(5H, m, ArH); δC(125 MHz, CDCl3)
14.11(OCH2CH3), 28.05(C(6)), 48.94 and 54.69(C(7) and
A 1 M solution of hydroxylamine hydrochloride in 80%
v/v EtOH in water (0.51 ml) was added to a solution of
exo imine 9c (60 mg, 0.13 mmol) in dichloromethane (25 ml)
and the mixture heated under reflux for 16 hours. Dichloro-
methane (15 ml) was added and the organic phase was washed
with 5% sodium hydrogen carbonate solution (2 × 10 ml). The
aqueous layers were combined and extracted with ethyl
acetate (2 × 15 ml). The combined organic layers were dried
(MgSO4) and the solvent removed in vacuo to yield the crude
amine as a brown oil. This was immediately treated with acetic
anhydride (39 mg, 0.38 mmol) and triethylamine (38 mg,
0.38 mmol) in chloroform (10 ml). The mixture was stirred at
Ϫ5 ЊC for 10 minutes then at 0 ЊC for a further 4 hours. It
was washed with citric acid solution (10% in H2O; 3 × 10 ml)
and dried(MgSO4). The solvent was removed in vacuo and the
crude oil was purified by flash column chromatography (ethyl
acetate) to give the product 14 as a colourless oil (40 mg, 61%
over 2 steps): Rf 0.12 (1 : 6 petrol–ethyl acetate); νmax (thin film)/
cmϪ1 2924(br m), 1737(s), 1700(s), 1667(s); δH(200 MHz,
CDCl3) 1.14(3H, t, J 7.0 Hz, OCH2CH3), 2.03(3H, s, CH3C-
(O)), 2.12–2.24(1H, m, C(6)Hendo), 2.38–2.51(1H, m, C(6)Hexo),
3.01–3.10(1H, m, C(7)H), 3.42(1H, dd, J 8.5, 8.5 Hz, C(4)Hendo),
4.00–4.28(4H, m, C(5)H, C(4)Hexo and OCH2CH3), 4.90(1H,
dd, J 5.0, 8.5 Hz, C(1Ј)H), 6.28(1H, s, C(2)H), 6.81(1H, br d,
J 8.5 Hz, NH), 7.37–7.39(5H, m, ArH); δC(50.3 MHz, CDCl3)
13.85(OCH2CH3), 23.04(H3CC(O)), 25.48(C(6)), 47.73 and
53.08(C(7) and C(1Ј)), 57.37(C(5)), 61.93(OCH2CH3),
71.49(C(4)), 86.90(C(2)), 125.7, 128.4 and 128.6(ArC), 138.4(4
ЊC), 169.9(2 × CO), 176.3(CO); m/e(APCIϩ) 347(MHϩ, 100%),
HRMS(CIϩ) 347.1607, MHϩ requires 347.1606.
C(1Ј)),
56.62(C(5)),
61.36(OCH2CH3),
72.10(C(4)),
86.72(C(2)), 126.0, 128.4, 128.6(ArC), 138.5(4Њ ArC), 173.5
and 175.9(C(8) and CO2Et); m/e (APCIϩ) 305(MHϩ, 97%),
288(100), 242(14), 231(19), 204(94).
(2R,5S,7R,1ЈR)-1-Aza-3-oxa-8-oxo-2-phenyl-7-[N-acetylamino-
(ethoxycarbonyl)methyl]bicyclo[3.3.0]octane 12b
At Ϫ5 ЊC, acetic anhydride (0.042 g, 0.41 mmol) was added to a
solution of amine 12a (0.10 g, 0.33 mmol) and triethylamine
(0.067 g, 0.66 mmol) in chloroform (9 ml). The mixture was
stirred at Ϫ5 ЊC for 10 minutes and then at 0 ЊC for a further 4
hours. Following washing with citric acid solution (10% in H2O;
3 × 8 ml) and drying over magnesium sulfate, the solvent was
evaporated. The resulting yellow oil was purified by flash
column chromatography on silica (1 : 1 petroleum ether–ethyl
acetate gradient to 1 : 3) to give the product, a pale yellow oil
(0.071 g, 62%): Rf 0.14 (1 : 3 petroleum ether–ethyl acetate);
(Found: C, 62.26; H, 6.84; N, 7.68. C18H22N2O5 requires C,
62.42; H, 6.40; N, 8.09%); [α]2D5 ϩ120 (c 0.20, CHCl3); νmax (film)/
cmϪ1 3313, 1739, 1703, 1690; δH(500 MHz, CDCl3) 1.28(3H, t,
J 7.0 Hz, OCH2CH3), 2.01(3H, s, CH3C(O)), 2.14–2.20(1H, m,
C(6)Hendo), 2.54–2.60(1H, m, C(6)Hexo), 3.27(1H, ddd, J 10.5,
10.5, 3.5 Hz, C(7)Hexo), 3.66(1H, dd, J 8.0, 8.0 Hz, C(4)Hendo),
4.07–4.16(1H, m, C(5)H), 4.17–4.27(3H, m, C(4)Hexo and
OCH2CH3), 4.84(1H, dd, J 8.5, 3.5 Hz, C(1Ј)H), 6.23(1H, s,
C(2)H), 7.11(1H, br d, J 8.5 Hz, NH), 7.29–7.42(5H, m, ArH);
δC(50.3 MHz, CDCl3) 13.98(OCH2CH3), 22.94(H3CC(O)),
28.22(C(6)), 48.19 and 51.51(C(7) and C(1Ј)), 57.07(C(5)),
61.82(OCH2CH3), 72.26(C(4)), 86.89(C(2)), 126.2, 128.7,
129.0(ArC), 138.6(4Њ ArC), 169.9, 170.7 and 176.9(CH3C(O)N,
C(8) and CO2Et); m/e (probe CI, NH3) 347(MHϩ, 100%),
303(4), 288(4), 273(7), 231(14), 211(8), 202(26).
(2S,4S )-N-Benzyl-2-methoxycarbonyl-4-[N-acetylamino-
(ethoxycarbonyl)methyl]-5-oxopyrrolidine 15
Lactam 14 (50 mg, 0.14 mmol) was hydrogenated to yield the
crude alcohol product (40 mg): νmax (film)/cmϪ1 3286(br m, OH,
NH), 1738(s, ester CO), 1672(s, lactam CO); m/e (APCIϩ) 349
(MHϩ, 100%). This was immediately oxidized according to the
Sharpless protocol69 to give a white solid (12 mg) LRMS
(APCIϩ) m/e 363 (MHϩ, 100%), which was in turn immediately
treated with diazomethane in ether. The solvent was removed
in vacuo to give a pale yellow oil which was purified by flash
column chromatography on silica (ethyl acetate). The product
was obtained as a mixture of C-1Ј diastereomers in a ratio of
1 : 2 (12 mg, 23% over 3 steps): Rf 0.31, 0.24 (EtOAc);
νmax (film)/cmϪ1 3320(br m), 1742(s), 1695(s); δH(500 MHz,
CDCl3) (major diastereomer) 1.21(3H, t, J 7.0 Hz, OCH2CH3),
2.06(3H, s, CH3C(O)), 2.27–2.33(1H, m, C(3)H), 2.46–2.51(1H,
m, C(3)H), 2.98–3.03(1H, m, C(4)H), 3.68(3H, s, OCH3), 3.98–
4.01(2H, m, NCHPh and C(2)H), 4.08–4.20(2H, m, OCH2-
CH3), 4.88(1H, dd, J 3.5, 9.0 Hz, C(1Ј)H), 4.99(d, J 15.0 Hz,
1H, NCHPh), 7.17–7.39(5H, m, ArH), 7.23(1H, d, J 8.5 Hz,
NH); δH(500 MHz, CDCl3)(minor diastereomer) 1.32(3H, t,
J 7.0 Hz, OCH2CH3), 2.02(s, 3H, CH3C(O)), 2.27–2.33(1H, m,
C(3)H), 2.67–2.71(1H, m, C(3)H), 3.47–3.52(1H, m, C(4)H),
3.69(3H, s, OCH3), 3.91(1H, dd, J 1.5, 9.5 Hz, C(2)H), 3.98–
4.01(1H, m, NCHPh), 4.21–4.32(m, 2H, OCH2CH3), 4.80(1H,
dd, J 3.5, 8.5 Hz, C(1Ј)H), 4.97(1H, d, J 14.5 Hz, NCHPh),
6.35(1H, d, J 8.0 Hz, NH), 7.17–7.39(5H, m, ArH); m/e (probe
CI, NH3) 377 (MHϩ, 100%).
(2R,5S,7R,1ЈS )-1-Aza-3-oxa-8-oxo-2-phenyl-7-[N-acetylamino-
(ethoxycarbonyl)methyl]bicyclo[3.3.0]octane 13b
This compound was prepared from amine 13a on a 0.067 g scale
by the same method as above and was obtained as a pale oil
(0.045 g, 58%). Rf 0.15 (1 : 3 petroleum ether–ethyl acetate);
(Found: C, 62.72; H, 6.58; N, 7.09. C18H22N2O5 requires C,
62.42; H, 6.40; N, 8.09%) [α]2D5 ϩ200 (c 0.46, CHCl3); νmax (thin
film)/cmϪ1 3326m(br), 1742(s), 1704(s), 1680(s); δH(200 MHz,
CDCl3) 1.30(3H, t, J 7.0 Hz, OCH2CH3), 1.75–1.91(1H, m
C(6)Hendo), 2.10(3H, s, CH3C(O)), 2.52–2.67(1H, m, C(6)Hexo),
3.49(1H, dd, J 7.5, 7.5 Hz, C(4)Hendo), 3.79–3.91(1H, m,
C(7)Hexo), 4.14(1H, m, C(5)H), 4.19–4.32(3H, m, C(4)Hexo and
OCH2CH3), 4.88(1H, dd, J 9.0, 3.0 Hz, C(1Ј)), 6.30(1H, s,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
2372

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(2R,5S,7S,1ЈRS )-7-(Phenyl-N-tosylaminomethyl)-8-oxo-2-
phenyl-1-aza-3-oxabicyclo[3.3.0]octane 19a
22% over two steps). Rf = 0.47 [EtOAc–Petrol (40/60), 1 : 1],
νmax(CHCl3)/cmϪ1 3053, 2983, 1700, 1600, 1422, 1265, 1220;
δH(400 MHz, CDCl3) 2.32 and 2.36(3H, s, CH3(A ϩ B)), 2.40–
2.50(1H, m, C(4)H(A ϩ B)), 2.51–2.60(1H, m, C(4)H(A)),
2.70–2.80(1H, m, C(4)H(B)), 2.82 and 2.86(3H, m, NCH3-
(A ϩ B)), 3.22–3.44(1H, m, C(3)H(A ϩ B)), 4.48–4.52(1H, m,
C(1Ј)H(A)), 4.70–4.79(1H, m, C(1Ј)H(B)), 6.20(1H, d, J 3.6 Hz,
NH), 6.53(1H, d, J 8.9 Hz, NH), 6.90–7.55(9H, m, ArH
and FurylH(A ϩ B)); δC(400 MHz, CDCl3) 21.41 and
21.47 (CH3(A)), 24.74–24.82(CH3(B)), 30.96 and 31.36(C(4)-
n
To BuLi (0.65 ml, 1.3 mmol) at 0 ЊC in THF (6 ml) under
nitrogen was added diisopropylamine (0.2 ml, 1.2 mmol) and
the mixture stirred for 15 minutes at Ϫ78 ЊC. A solution of the
lactam 1a (220 mg, 1.1 mmol) in THF (5 ml) was added, and
after 30 minutes, N-benzylidene-4-methyl-benzenesulfonamide
(365 mg, 1.4 mmol) in THF (4 ml) was added to the mixture
and stirring continued for 1 hour. The reaction mixture was
then quenched with aqueous saturated sodium bicarbonate
solution (5 ml), and the mixture extracted with ethyl acetate (30
ml). The combined organic extracts were washed with brine,
dried (MgSO4) and concentrated in vacuo to yield a yellow oil.
Purification using flash column chromatography [EtOAc–petrol
(40/60), 1 : 1] gave a white crystalline solid 19a as a mixture of
inseparable diastereomers at C-1Ј (397 mg, 79%). Rf = 0.34
[EtOAc–Petrol(40/60), 1 : 2]; νmax(CHCl3)/cmϪ1 1692, 1599,
(A
ϩ B)), 44.63 and 44.89(C(3)(A ϩ B)), 57.54 and
58.64(C(1Ј)(A ϩ B)), 126.9, 127.2, 127.2, 127.4, 128.5, 128.5,
126.7, 128.8, 129.3, 129.4(ArC and FurylC(A ϩ B)), 136.3,
136.5, 137.2, 143.5(ArC), 161.7 and 177.4(C(2) and C(5)-
(A ϩ B)); m/e(CIϩ) 373(MHϩ, 20%), 260, 250, 208, 202, 155;
HRMS 373.1222, MHϩ requires 373.1224; 390.1488,
MϩNH4ϩ requires 390.1487.
1495, 1356; δH(400 MHz, CDCl3) 1.78–1.85(1H, m, C(6)Hendo
(A)), 2.00–2.07(3H, m, C(6)Hexo(A), C(6)Hendo and C(6)Hexo(B)),
2.31 and 2.34(3H, s, CH3(A B)), 3.01–3.07(1H, m,
C(7)H(A)), 3.17–3.20(2H, m, C(7)H(B) and C(5)H(A or B)),
3.30–3.34(1H, t, J 9.0 Hz, C(4)Hendo(A ϩ B)), 3.76–3.83(1H, m,
-
(2R,5S,7S,1ЈRS )-7-(N-Tosylamino-furan-2-yl-methyl)-8-oxo-2-
phenyl-1-aza-3-oxa-bicyclo[3.3.0]octane 19b
ϩ
To nBuLi (0.7 ml, 1.7 mmol) at 0 ЊC in THF (10 ml) was added
diisopropylamine (0.26 ml, 1.9 mmol) and the mixture cooled
to Ϫ78 ЊC. A solution of lactam 1a (289 mg, 1.42 mmol) in
THF (5 ml) was then added to the reaction mixture at Ϫ78 ЊC.
After 30 minutes, N-furan-2-ylmethylene-4-methyl-benzene-
sulfonamide (461 mg, 1.85 mmol) in THF (5 ml) was added to
the mixture and then after stirring for 1 hour at the same tem-
perature, the reaction mixture was quenched with aqueous
saturated sodium bicarbonate solution (20 ml). Water (30 ml)
was added and the mixture extracted with ethyl acetate (30 ml).
The aqueous layer was extracted with ethyl acetate (3 × 20 ml)
and the combined organic extracts were washed with brine,
dried over MgSO4 and concentrated in vacuo to yield the crude
product as a mixture of diastereomers. Purification by chrom-
atography [EtOAc–Petrol (40/60), 1 : 1] gave a pale yellow
solid (530 mg, 82%). Rf = 0.54 [EtOAc–Petrol (40/60), 7 : 3];
νmax(CHCl3)/cmϪ1 3355, 3270, 1697, 1599, 1495, 1452; δH(400
MHz, CDCl3) 1.96–2.06(1H, m, C(6)Hendo(A)), 2.08–2.13(2H,
m, C(6)Hendo, C(6)Hexo(B)), 2.21–2.30(1H, C(6)Hexo(A)), 2.35
and 2.36(3H, s, CH3(A ϩ B)), 3.13–3.20(1H, m, C(7)H(B)),
3.22–3.30(1H, m, C(7)H(A)), 3.32–3.37(1H, m, C(4)Hendo(A ϩ
B)), 3.60–3.62(1H, m, C(5)H(B)), 3.79–3.88(1H, m, C(5)H(A)),
4.06–4.17(1H, m, C(4)Hexo(A ϩ B)), 4.73(1H, t, J 6.5 Hz,
C(1Ј)H(A)), 4.78–4.85(1H, m, C(1Ј)H(B)), 6.02–6.17(2H, m,
FurylH(A ϩ B) and 1H, m, SO2NH(A)), 6.22 and 6.23(1H, s,
C(2)H(A ϩ B)), 6.43–6.45(1H, d, J 8.45 Hz, SO2NH(B)), 7.12–
7.20(3H, m, ArH and FurylH), 7.25–7.36(5H, m, ArH), 7.57–
7.69(2H, m, ArH); δC(400 MHz, CDCl3) 21.43 and
21.47(CH3(A ϩ B)), 24.76 and 25.13(C(6)(A ϩ B)), 48.69
and 49.24(C(7)(A ϩ B)), 52.45 and 52.75(C(1Ј)(A ϩ B)), 57.02
and 57.16(C(5)(A ϩ B)), 71.23(C(4)(A ϩ B)), 86.84 and
87.05(C(2)), 108.73, 108.83, 110.17, 110.29, 125.8, 126.4, 126.8,
127.1, 128.3, 128.4, 128.6, 129.3, 129.4, 129.6, 136.8, 137.5,
138.2, 138.3, 142.4, 142.4, 143.0, 143.3(ArC and FurylC), 176.4
and 176.7; m/e (CIϩ) 453(MHϩ, 90%), 282(100), 204(15),
157(30); HRMS 453.1484, MHϩ requires 453.1485.
C(5)H(B or A)), 3.99–4.04 and 4.05–4.16(1H, m, C(4)Hexo
-
(A ϩ B)), 4.39–4.48 and 4.65–4.75(1H, m, C(1Ј)H(A ϩ B)),
6.17 and 6.25(1H, s, C(2)H(A ϩ B)), 6.41 and 6.61(1H, 2 × d, J
3.2 and 8.7 Hz, NH(A ϩ B)), 7.01–7.17 and 7.20–7.37 and
7.43–7.52(14H, m, ArH); δC(400 MHz, CDCl3) 21.4 and
21.5(CH3(A
ϩ B)), 25.1 and 25.6(C(6)(A ϩ B)), 50.0
and 50.2(C(7)(A ϩ B)), 56.8 and 57.2(C(5)(A ϩ B)), 58.6 and
59.6(C(1Ј)(A ϩ B)), 71.1 and 71.3(C(4)(A ϩ B)), 86.8 and
87.1(C(2)(A ϩ B)), 125.8, 125.9, 126.8, 127.2, 127.5, 127.6,
127.9, 128.1, 128.3, 128.4, 128.5, 128.6, 129.1, 129.3(PhC(A ϩ
B)), 136.3, 136.8, 137.7, 137.9, 138.0(PhC(A ϩ B)), 142.7 and
143.1(CSO2N, CCH3 (A ϩ B)), 176.5 and 177.2(C(8)(A ϩ B));
m/e (CIϩ) 463(MHϩ, 55%), 292, 203, 166; HRMS 463.1691,
MHϩ requires 463.1690.
(3S, 1ЈRS )-N-Methyl-3-(phenyl-N-tosylaminomethyl)-
succinimide 20
To a solution of lactam 19a (168 mg, 0.36 mmol) in DCM (5
ml) at room temperature was added TFA (0.3 ml, 3.6 mmol).
After 1 hour solvent was removed in vacuo and the product
purified by flash colum chromatography (6% MeOH in EtOAc)
to give a pale yellow oil (72 mg, 53%). Rf = 0.28 (100% EtOAc)
or 0.48 (EtOAc–MeOH, 1 : 16); νmax/cmϪ1 3684, 3436, 3037,
2401, 1682, 1521; δH(400 MHz, CD3OD) 1.83–1.88(1H, m,
C(3)H(A ϩ B)), 1.95–2.03(1H, m, C(3)H(A)), 2.10–2.14(1H, m,
C(3)H(B)), 2.32 and 2.36(3H, s, CH3(A ϩ B)), 2.86–2.94(1H,
m, C(4)H(A ϩ B)), 3.09–3.13(1H, m, C(2)H(A)), 3.30–3.36(1H,
m, C(2)H(B)), 3.38–3.48(2H, m, CH2OH(A ϩ B)), 4.63–
4.64(1H, d, J 6.7 Hz, C(6)H(A)), 4.84–4.88(1H, d, J 4.2 Hz,
C(6)H(B)), 7.08–7.57(9H, m, ArH and FurylH(A ϩ B)); δC(400
MHz, CD3OD) 21.76 and 21.80(CH3(A ϩ B)), 26.26 and
26.54(C(3)(A ϩ B)), 48.85 and 49.04(C(4)(A ϩ B)), 55.80 and
56.01(C(2)(A ϩ B)), 59.42 and 60.16(C(6)(A ϩ B)), 66.01 and
66.16(CH2OH(A ϩ B)), 128.5, 128.6, 128.6, 129.0, 129.2, 129.3,
129.5, 129.7, 130.6, 130.8,(ArC), 139.5, 139.9 and 144.9(PhC(A
ϩ B)), 179.4(C(5)(A ϩ B)); m/e 375(MHϩ, 100%); HRMS
375.1378, MHϩ requires 375.1383.
(2R, 5S, 7S, 1ЈRS )-7-(Methyloxycarbonyl-N-tosylamino-
methyl)-8-oxo-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octane 21
To a stirred solution of the above pyrrolidinone (133 mg,
0.35 mmol) in CH3CN (3 ml) and CCl4 (3 ml) was added a
solution of NaIO4 (760 mg, 3.5 mmol) in water (4.5 ml) and
then RuCl3.H2O (7.4 mg cat.). The mixture was stirred vigor-
ously overnight. The solvents were removed in vacuo and the
residue was dissolved in THF (4 ml) and then a solution of
diazomethane in ether was added with stirring. Water (20 ml)
was added and the mixture extracted with EtOAc (3 × 20 ml).
The organic phases were combined, dried over MgSO4 and con-
centrated in vacuo to give succinimide 20 as a yellow oil (32 mg,
To a stirred solution of lactam 19b (435 mg, 0.96 mmol) in
CH3CN (5 ml) and CCl4 (5 ml) was added a solution of NaIO4
(2.1 g, 9.62 mmol) in water (7.5 ml) and RuCl3ؒH2O (20 mg
cat.). The mixture was stirred vigorously for 4 hours. The sol-
vents were removed in vacuo and the residue was dissolved in
THF. A solution of diazomethane in ether was then added with
stirring which was continued for 30 minutes. Water (20 ml) was
added to the mixture and the aqueous layer extracted with ethyl
acetate (3 × 20 ml). The organic phases were combined, dried
over MgSO4 and concentrated in vacuo to give lactam 21 as a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
2373

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colourless oil and mixture of diastereomers which was purified
by flash column chromatography on silica [EtOAc–Petrol (40/
60), 3 : 2] (90 mg, 21% over two steps). Rf = 0.35 [EtOAc–Petrol
(40/60), 7 : 3]; [α]2D2 ϩ98 (c 1, CHCl3); νmax(CHCl3)/cmϪ1 3332,
3020, 1744, 1708, 1598, 1482, 1354, 1264, 1210, 1165; δH(400
MHz, CDCl3) 2.05–2.12(1H, m, C(6)Hendo), 2.26–2.33(1H, m,
C(6)Hexo), 2.38(3H, s, ArCH3), 3.02–3.09(1H, m, C(7)H), 3.35–
3.45(4H, m, C(4)Hendo and CO2CH3), 4.01–4.08(1H, m, C(5)H),
4.16–4.22(1H, m, C(4)Hexo), 4.26–4.30(1H, dd, J 5.6 and 9.9 Hz,
C(1Ј)H), 6.01–6.03(1H, d, J 9.9 Hz, SO2NH), 6.24(1H, s,
C(2)H), 7.20–7.45(7H, m, ArH), 7.69–7.81(2H, m, ArH); δC(400
MHz, CDCl3) 21.04(CH3), 24.48(C(6)), 48.08(C(7)), 52.94(CO2-
CH3), 56.44(C(1Ј)), 57.23(C(5)), 71.24(C(4)), 87.09(C(2)),
125.9, 125.9, 127.3, 128.4, 128.5, 128.6, 128.7, 129.1, 129.6,
129.7, 135.9 and 136.4, 138.3, 138.4 and 143.8(ArC),
170.2(CO2Me), 175.48(C(8)); m/e(CIϩ) 445(MHϩ, 100%), 289,
274, 242; HRMS 445.1433, MHϩ requires 445.1435.
the mixture stirred for 30 minutes. N-Furan-2-ylmethylene-4-
methyl-benzenesulfonamide (154 mg, 0.62 mmol) in THF
(2 ml) was added to the reaction mixture. The reaction mixture
was quenched after stirring for 1 hour, with aqueous saturated
ammonium chloride solution (1 ml). Water (20 ml) was added
and the mixture extracted with ethyl acetate (10 ml). The aque-
ous layer was then extracted with ethyl acetate (3 × 15 ml) and
the combined organic extracts were washed with brine, dried
(MgSO4) and concentrated in vacuo to yield a brown liquid.
Purification of this yellow liquid using flash column chromato-
graphy [EtOAc–Petrol (40/60), 3 : 2] gave a pale yellow solid
(168 mg, 76%). Rf = 0.29 [EtOAc–Petrol (40/60), 2 : 3]; [α]2D2 ϩ72
(c 1, CHCl3); νmax(CHCl3)/cmϪ1 3350, 3250, 3026, 1689, 1406,
1265, 1222, 1210, 1162; δH(400 MHz, CDCl3) 1.85–2.02(3H, s,
C(2)CH3(A ϩ B) and 1H, m, C(6)H(A) and 2H, m, C(6)H(B)),
2.11–2.22(1H, m, C(6)H(A)), 2.37 and 2.38(3H, s, CH3(A ϩ
B)), 3.17–3.28(1H, m, C(5)H(B) and 1H, m, C(7)H(B)), 3.31–
3.37(1H, m, C(7)H(A)), 3.45–3.52(1H, m, C(4)Hendo(A ϩ B)),
3.56–3.63(1H, m, C(5)H(A)), 3.89–4.00(1H, m, C(4)Hexo(A ϩ
B)), 4.71–4.79(1H, m, C(1Ј)H(A ϩ B)), 6.01–6.12(2H, m,
FurylH(A ϩ B)), 6.64–6.67(1H, d, J 9.1 Hz, SO2NH(A ϩ B)),
6.84–6.85 and 7.05–7.16(1H, m, FurylH(A ϩ B)), 7.15–
7.20(2H, m, ArH(A ϩ B)), 7.26–7.41(5H, m, ArH(A ϩ B)),
7.59–7.66(2H, m, ArH(A ϩ B)); δC(400 MHz, CDCl3) 21.45
and 21.51(CH3(A ϩ B)), 25.51 and 26.69(C(6)(A ϩ B)),
25.62(CH3(A ϩ B)), 50.56 and 52.22(C(7)(A ϩ B)), 52.33 and
(2S,4S,1ЈRS )-2-Methyloxycarbonyl-4-(methyloxycarbonyl-N-
tosylaminomethyl)-5-oxopyrrolidine 22
To a solution of lactam 21 (557 mg, 1.25 mmol) in DCM (10
ml) at room temperature was added TFA (0.96 ml, 12.53 mmol)
while stirring. After 1 hour, the solvent was removed in vacuo
and the product purified by flash column chromatography (15%
MeOH in EtOAc) to give a pale yellow oil (146 mg, 33%). Rf =
0.35 (MeOH–EtOAc, 1 : 9); νmax(CHCl3)/cmϪ1 3368, 1743, 1691,
1598, 1438, 1342, 1210, 1163; δH(400 MHz, CDCl3) 1.89–
1.96(1H, m, C(3)H), 2.04–2.11(1H, m, C(3)H), 2.36–2.44(3H, s,
CH3), 3.05–3.11(1H, m, C(4)H), 3.38(3H, s, CO2CH3), 3.44–
3.48(1H, m, CHHOH), 3.68–3.71(1H, m, CHHOH), 3.75–
3.83(1H, m, C(2)H), 4.11–4.23(1H, br, OH), 4.33–4.36(1H, dd,
J 4.0 and 9.9 Hz, C(1Ј)H), 6.70–6.72(1H, d, J 9.9 Hz, NHTs),
7.24–7.29(2H, m, ArH), 7.63(1H, br, NH), 7.67–7.78(2H, m,
ArH); δC(400 MHz, CDCl3) 21.50(CH3), 24.52(C(3)),
44.19(C(4)),52.55(CO2CH3),54.75(C(2)),56.01(C(1Ј)),65.15(CH2-
OH), 127.2, 127.4, 129.4, 129.6, 136.2, 143.4 and 143.8(ArC),
170.4(CO2Me), 177.0(CO); m/e(CIϩ) 357(MHϩ, 100%), 297,
186, 154; HRMS 357.1120, MHϩ requires 357.1117.
To a stirred solution of the above alcohol (100 mg, 0.28
mmol) in CH3CN (2 ml) and CCl4 (2 ml) was added a solution
of NaIO4 (600 mg, 2.81 mmol) in water (3 ml) and the mixture
stirred at room temperature for 10 minutes. Then RuCl3.H2O
(6.50 mg cat.) was added and the mixture stirred vigorously
overnight. The solvents were removed in vacuo and the residue
was dissolved in THF. A solution of diazomethane in ether was
then added with stirring which was continued for 30 minutes.
Water (10 ml) was added to the mixture and extracted with
ethyl acetate (3 × 10 ml). The organic phases were combined,
dried (MgSO4) and concentrated in vacuo to give ester 22 a
yellow oil (37 mg, 25% over two steps). Rf = 0.52 (100% EtOAc);
νmax(CHCl3)/cmϪ1 3025, 2326, 1743, 1410, 1320, 1224, 1163;
δH(400 MHz, CDCl3) 2.28–2.35(1H, m, C(3)H), 2.37–2.48(4H,
m, CH3 and C(3)H), 2.85–2.94(1H, m, C(4)H), 3.48(3H, s,
CO2CH3), 3.78(3H, s, CO2CH3), 4.20(1H, m, C(2)H), 4.25–
4.35(1H, dd, J 9.6 and 4.3 Hz, C(1Ј)H), 6.19(1H, d, J 8.8 Hz,
SO2NH), 6.48(1H, br, NH), 7.27–7.31(2H, m, ArH), 7.69–
7.76(2H, m, ArH); δC(400 MHz, CDCl3) 21.52(CH3),
26.36(C(3)), 42.36(C(4)), 52.71(CO2CH3) 55.25 and 55.37(C(1Ј)
and C(2)), 127.3, 127.3, 129.56, 136.7 and 143.7(ArC), 170.3,
172.1(CO2CH3), 175.4 and 175.7(CO); m/e(CIϩ) 385(MHϩ,
100%), 325, 182, 155; HRMS 385.1069, MHϩ requires
385.1068.
52.49(C(1Ј)(A
ϩ B)), 58.94 and 59.05(C(5)(A ϩ B)),
70.14(C(4)(A ϩ B)), 94.00 and 94.23(C(2)(A ϩ B)), 108.76,
110.1, 110.3, 124.9, 125.0, 126.8, 127.1, 127.9, 128.1, 128.2,
129.3, 129.5,136.8, 137.7, 142.38, 142.5, 142.6, 143.3,
150.0(ArC and FurylC(A ϩ B)), 171.5 and 171.9(C(8)(A ϩ B));
m/e(CIϩ) 467 (MHϩ, 100%); HRMS 467.1640, MHϩ requires
467.1639.
(2R, 5S, 7R, 1ЈS )-7-(N-Tosylaminofuran-2-ylmethyl)-8-oxo-2-
phenyl-1-aza-3-oxa-bicyclo[3.3.0]octane 24a
n
To BuLi (0.54 ml, 1.14 mmol, 2.12 M in hexane) at 0 ЊC in
THF (6 ml) was added diisopropylamine (0.17 ml, 1.23 mmol)
and the mixture stirred for 15 minutes. The mixture was cooled
down to Ϫ78 ЊC in an acetone–dry ice bath. A solution of
lactam 19b (207 mg, 0.45 mmol) in THF (5 ml) was added to
the mixture. After 30 minutes, 2,6-di-tert-butylphenol (264 mg,
1.28 mmol) in THF (5 ml) was added. Water (20 ml) was then
added and the mixture extracted with ethyl acetate (10 ml). The
aqueous layer was then extracted with ethyl acetate (3 × 15 ml)
and the combined organic extracts were washed with brine,
dried (MgSO4) and concentrated in vacuo to yield the product,
which was purified by flash column chromatography to give
lactam 24a as a pale yellow solid (37 mg, 19%). Rf = 0.37
[EtOAc–Petrol(40/60), 2 : 3]; [α]2D2 ϩ114 (c 1, CHCl3); νmax(film)/
cmϪ1 3040, 2400, 1695, 1601, 1522, 1476, 1428, 1238; δH(400
MHz, CDCl3) 1.45–1.53(1H, m, C(6)Hendo), 2.35(3H, s, CH3),
2.39–2.49(1H, m, C(6)Hexo), 2.68–2.72(1H, t,
J 8.1 Hz,
C(4)Hendo), 3.40–3.47(1H, m, C(7)H), 3.98–4.02(1H, m, C(5)H),
4.03–4.10(1H, m, C(4)Hexo), 4.73–4.77(1H, dd, J 5.2, 9.6 Hz,
C(1Ј)H), 4.90(1H, br s, OH), 5.98–6.17(2H, m, FurylH),
6.19(1H, s, C(2)H), 7.05–7.07(1H, d, J 9.6 Hz, NH), 7.13–
7.83(10H, m, ArH and FurylH); δC(400 MHz, CDCl3)
21.44(CH3), 25.84(C(6)), 47.85(C(7)), 52.18(C(1Ј)), 56.61(C(5)),
72.01(C(4)), 86.76(C(2)), 109.6, 110.5(FurylC), 125.9 126.4,
126.7, 128.5, 128.8, 129.3, 129.7, 137.7, 138.2, 142.1, 142.8 and
143.6(ArC), 176.6(C(8)); m/e(CIϩ) 453(MHϩ, 20%), 282(100%);
HRMS 453.1484, MHϩ requires 453.1493.
(2R, 5S, 7S, 1ЈR)-7-(N-Tosylaminofuran-2-yl-methyl)-8-oxo-2-
phenyl-2-methyl-1-aza-3-oxabicyclo[3.3.0]octane 23
(2R, 5S, 7R, 1ЈS )-7-(N-Tosylaminofuran-2-ylmethyl)-8-oxo-2-
phenyl-2-methyl-1-aza-3-oxabicyclo[3.3.0]octane 24b
n
To BuLi (0.26 ml, 0.57 mmol, 2.35 M in hexane) at 0 ЊC in
THF (3 ml) was added diisopropylamine (0.1 ml, 0.62 mmol)
and the mixture stirred for 15 minutes at Ϫ78 ЊC. A solution of
lactam 1b (103 mg, 0.47 mmol) in THF (2 ml) was added and
To lactam 23 (73 mg, 0.15 mmol) in dry THF (5 ml) under
nitrogen was added NaH (18.8 mg, 0.47 mmol, 60% dispersed
in mineral oil) at 0 ЊC and the mixture heated to reflux for
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
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5 hours. The mixture was then quenched with 2, 6-di-tert-
butylphenol (160 mg, 0.78 mmol) in THF (2 ml) at 0 ЊC. Water
(10 ml) was added and the mixture extracted with ethyl acetate
(10 ml). The aqueous layer was extracted with EtOAc (3 ×
15 ml) and the combined organic extracts were washed with
brine, dried (MgSO4) and concentrated in vacuo to yield a
brown liquid. Purification of this yellow liquid using flash
column chromatography gave lactam 24b as a pale yellow oil
(20 mg, 27%) and a side product 25 (13 mg, 20%). Rf =
0.32 [EtOAc–Petrol(40/60), 3 : 7]; [α]2D2 ϩ20 (c 1, CHCl3);
νmax(CHCl3)/cmϪ1 3350, 3250, 3026, 1686, 1349, 1289, 1163;
δH(400 MHz, CDCl3) 1.31–1.41(1H, m, C(6)Hendo), 1.80(3H, s,
C(2)CH3), 2.22–2.31(1H, m, C(6)Hexo), 2.30(3H, s, CH3), 3.10–
3.15(1H, t, J 7.6 Hz, C(4)Hendo), 3.31–3.36(1H, m, C(7)H),
3.84–3.94(2H, m, C(5)H and C(4)Hexo), 4.68–4.72(1H, dd J 9.7,
5.0 Hz, C(1Ј)H), 4.93(1H, br, SO2NH), 5.97–6.08(2H, m,
FurylH), 7.06–7.76(10H, m, ArH and FurylH); δC(400 MHz,
CDCl3) 20.02(CH3), 26.15(C(2)CH3), 27.73(C(6)), 50.14(C(7)),
52.63(C(1Ј)), 58.79(C(5)), 70.61(C(4)), 94.69(C(2)), 106.1,
110.0(FurylC), 125.5, 127.0, 127.3, 127.8, 128.7, 128.9, 129.8,
130.0, 130.3, 130.5, 130.7(ArC), 138.4 and 139.6(ArC),
142.5(FurylC), 143.2, 143.3, 144.1(CSO2N, CCHЈ3),
173.0(C(8)); m/e(CIϩ) 467(MHϩ, 30%); HRMS 467.1640, MHϩ
requires 467.1641.
(2S, 4R, 1ЈS )-2-Hydroxymethyl-4-(methyloxycarbonyl-N-
tosylaminomethyl)-5-oxopyrrolidine 27a
To a solution of ester 26 (60 mg, 0.13 mmol) in DCM (5 ml)
at room temperature was added trifluoroacetic acid (0.09 ml,
1.3 mmol) and the solution stirred for 1 h. The solvent was
removed in vacuo to give a pale orange gum which was purified
by flash column chromatography (10% MeOH in EtOAc) to
give alcohol 27a as a pale yellow oil (21 mg, 45%). Rf =
0.39 (EtOAc–MeOH), 5 : 1); [α]2D0 ϩ203 (c 1, CHCl3),
νmax(CHCl3)/cmϪ1 3344, 3020, 1741, 1698, 1494, 1290, 1164;
δH(400 MHz, CD3OD) 1.72–1.78(1H, m, C(3)H), 2.18–
2.26(1H, m, C(3)H), 2.43(3H, s, CH3Ph), 2.92–3.02(1H, m,
C(4)H), 3.32(3H, s, CO2CH3), 3.44–3.70(3H, m, CH2OH and
C(2)H)), 4.26(1H, d, J 5.6 Hz, C(1Ј)H), 7.37(2H, d, J 8.2 Hz,
ArH), 7.32(2H, d, J 8.4 Hz, ArH); δC(400 MHz, CDCl3),
21.89(CH3Ph), 26.26(C(3)), 46.03(C(4), 50.29(CO2CH3),
53.11(C(2)), 73.77(CHOH), 128.7, 130.9, 131.0, 131.3(ArCH),
139.5(CSO2), 145.3(PhCCH3), 172.7(CO2Me), 177.7(C(5));
m/e(TOF ESϩ) 357 (MHϩ, 100%); HRMS 357.1131, MHϩ
requires 357.1120.
(2S, 4R, 1ЈS )-2-Methyloxycarbonyl-4-(methyloxycarbonyl-N-
tosylaminomethyl)-5-oxopyrrolidine 27b
To a stirred solution of lactam 27a (45 mg, 0.13 mmol) in
CH3CN (2 ml) and CCl4 (2 ml) was added a solution of NaIO4
(0.248 g, 1.24 mmol) in water (3 ml) and the mixture stirred at
room temperature for 10 minutes. RuCl3ؒH2O (6.50 mg) was
added, and the mixture was stirred vigorously overnight. Di-
chloromethane (10 ml) was added and the aqueous layer was
extracted with dichloromethane (2 × 15 ml). The solvent was
evaporated and residue was dissolved in THF. A solution of
diazomethane in ether was then added with stirring which con-
tinued for 30 minutes. Water (20 ml) was added and the aqueous
layer extracted with ethyl acetate (3 × 15 ml). The organic
phases were combined, dried (MgSO4) and concentrated in
vacuo to give a colourless oil which was purified by flash column
chromatography on silica [EtOAc–Petrol (40/60), 2 : 3] giving
the product 27b as a yellow oil (8 mg, 17%). Rf = 0.41 (EtOAc–
Petrol, 2 : 3); νmax(CHCl3)/cmϪ1 3042, 1703, 1412, 1259, 1210,
1134; δH(400 MHz, CDCl3) 1.81–1.87(1H, m, C(3)H), 1.96–
2.24(1H, m, C(3)H), 2.43(3H, s, PhCH3), 2.96–3.04 (1H, m,
C(4)), 3.45(3H, s, CO2CH3), 3.52(3H, s, CO2CH3), 3.50(1H, br,
NH) 3.74–3.82(1H, m, C(2)H), 4.5(1H, m, C(1Ј)H), 7.01(1H,
br, NH), 7.28(2H, d, J 8.6 Hz, ArH), 7.74(2H, d, J 8.3 Hz,
ArH); δC(400 MHz, CDCl3), 21.4(CH3Ph), 23.0(C(3)),
43.6(C(4)), 52.3(CO2CH3), 53.7(CO2CH3), 55.4(C(1Ј)),
64.4(C(2)), 126.3, 127.1, 129.3, 129.6,(ArC), 136.9(CSO2N),
143.4(CCH3), 170.6(CO2CH3), 175.9(C(5); m/e(APCIϩ) 385
(MHϩ, 100%); HRMS 385.1072, MHϩ requires 385.1069.
6-Furan-2-ylmethylene-3-methyl-3-phenyltetrahydropyrrolo-
[1,2-c]oxazol-5-one 25
Oil, Rf = 0.64 (EtOAc–Petrol, 3 : 7); [α]2D2 ϩ39 (c 1, CHCl3),
νmax(CHCl3)/cmϪ1 1674, 1475, 1256, δH(400 MHz, CDCl3)
2.02(3H, s, C(2) CH3), 2.86(1H, m, C(6)H), 3.32(1H, m,
C(6)H), 3.63(1H, m, C(4)H), 4.12(1H, m, C(5)H), 4.24(1H,
m, C(4)H) 6.51(1H, m, FurylH), 6.58(1H, d, J 3.4 Hz,
C(1Ј)H), 7.19–7.56(6H, m, FurylH and C6H5), δC(400 MHz,
CDCl3), 25.52(C(2)CH3), 25.87(C(6)), 70.49(C(4)), 94.96(C(2)),
112.1(FurylC), 114.0(FurylC), 125.1, 127.9, 128.3(PhCH),
143.7(ArC), 144.2(CHc), 151.9(C(1Ј)), 167.93(C(8)); m/e(CIϩ)
296 (MHϩ, 100%); HRMS 296.1130, MHϩ requires 296.1287.
(2R, 5S, 7R, 1ЈS )-7-(Methoxycarbonyl-N-tosylmethyl)-8-oxo-2-
phenyl-2-methyl-1-aza-3-oxabicyclo[3.3.0]octane 26
To a stirred solution of lactam 24b (200 mg, 0.43 mmol) in
CH3CN (3 ml) and CCl4 (3 ml) was added a solution of NaIO4
(0.96g, 4.5 mmol) in water (5 ml) and RuCl3.H2O (10 mg cat.).
The mixture was stirred vigorously for 4 hours. Dichloro-
methane (10 ml) was added and the aqueous layer extracted
with dichloromethane (2 × 15 ml). The solvent was evaporated
and the residue was dissolved in THF. A solution of diazo-
methane in ether was then added with stirring which continued
for 30 minutes. Water (20 ml) was added and the aqueous layer
extracted with ethyl acetate (3 × 15 ml). The organic phases
were combined, dried (MgSO4) and concentrated in vacuo to
give a light orange oil which was purified by flash column
chromatography on silica [EtOAc–Petrol (40/60), 2 : 3] to give
ester 26, a colourless oil (43 mg, 22% over two steps). Rf = 0.26
(EtOAc–Petrol, 2 : 3); [α]2D2 ϩ129 (c 1, CHCl3), νmax(CHCl3)/
cmϪ1 3020(m), 1741(m), 1680(s), 1216(s); δH(400 MHz, CDCl3)
1.90–2.02(1H, m, C(6)Hendo), 1.94(3H, s, C(2)CH3), 2.32–
2.38(1H, m, C(6)Hexo), 2.48(3H, s, CH3), 3.30–3.36(1H, m,
C(7)H), 3.59(3H, s, CO2CH3), 3.68–3.72(1H, t, J 15.7 Hz,
C(4)Hendo), 4.02–4.07(1H, m, C(5)H), 4.12–4.16(1H, m,
C(4)Hexo), 4.34–4.40(1H, dd, J 4.3, 9.2 Hz, C(1Ј)H), 6.08(1H, d,
J 9.3 Hz, NH), 7.27–7.52(7H, m, ArH), 7.78(2H, d, J 8.8 Hz,
ArH); δC(400 MHz, CDCl3), 21.52(CH3Ph), 25.56(C(2)CH3),
26.75(C(6)), 49.30(C(7)), 52.61(CO2CH3), 54.48(C(1Ј)),
58.60(C(5)), 69.89(C(4)), 94.39(C(2)), 124.9, 126.4, 127.4.
127.7, 128.0, 128.5, 129.5, 129.9(ArC), 143.3 and 143.6(CSO2N
and CCH3), 170.1(C(8) and 171.1 and CO); m/e(CIϩ) 458
(MHϩ, 100%), 339(55); HRMS 459.1584, MHϩ requires
459.1590.
Acknowledgements
We wish to gratefully acknowledge the use of the EPSRC
Chemical Database Service at Daresbury75 and the EPSRC
National Mass Spectrometry Service Centre at Swansea. R.G.
gratefully acknowledges support from the Felix Foundation
and M. A. from the Pakistani Ministry of Science and
Technology.
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CCDC reference number 208237. See http://www.rsc.org/suppdata/
ob/b3/b303924b/ for crystallographic data in .cif or other electronic
format.Crystal data and data collection parameters for compound
19a. C26H26N2O4S, M = 462.56, orthorhombic, a = 14.089(3), b =
6.305(2), c = 25.875(5), V = 2298.5 Å3, space group P 212121, Z = 4,
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= 1.5418 Å, µ = 6.18 cmϪ1; ω/2θ scan (0 ≤ 2θ ≤ 144Њ; Ϫ1 ≤ h ≤ 9; Ϫ1 ≤
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 6 4 – 2 3 7 6
2376