Pyrrolidinones derived from (S)-pyroglutamic acid. Part 1. Conformationally constrained glutamate

Article abstract of DOI:10.1039/b001999m

Novel conformationally constrained pyroglutaminols and pyroglutamates are readily available using an α,β-unsaturated bicyclic lactam as a template for diastereocontrolled enolate additions in the key step; zinc enolates are particularly effective in this regard. The bicyclic ring system both controls and permits the determination of ring stereochemistry. The utility of this methodology is demonstrated by a formal total synthesis of the NMDA receptor agonist, CPAA 11. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b001999m

View Article Online / Journal Homepage / Table of Contents for this issue
Pyrrolidinones derived from (S)-pyroglutamic acid. Part 1.
Conformationally constrained glutamate
Jonathan H. Bailey,a David T. Cherry,a James Dyer,a Mark G. Moloney,*a Mark J. Bamford,b
Steve Keelingb and R. Brian Lamontb
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 pyroglutaminols and pyroglutamates are readily available using an
α,β-unsaturated bicyclic lactam as a template for diastereocontrolled enolate additions in the key step;
zinc enolates are particularly effective in this regard. The bicyclic ring system both controls and permits
the determination of ring stereochemistry. The utility of this methodology is demonstrated by a formal
total synthesis of the NMDA receptor agonist, CPAA 11.
Much recent attention has focused on the use of highly func-
tionalised pyrrolidinones as excitatory amino acid analogues1
and as conformationally controlling peptidomimetics.2–5 We
have recently been interested in the development of method-
ology for the convenient synthesis of such functionalised
pyrrolidinones, since this class of compounds has potent and
wide-ranging biological activity. Our initial investigations have
examined the hemiaminal ethers 1a,b† derived from pyro-
diastereoselection in alkylations of the lactam enolate were dis-
appointing, although recent work suggests that high levels of
exo-23 or endo-24–26 alkylation may be possible using carefully
controlled reaction conditions or modified substrates.
The application of the enones 2a,c to cycloaddition reactions
has also attracted considerable attention, because of the possi-
bility of simultaneous functionalisation and control of stereo-
chemistry at two ring positions,27–30 and 2a has recently found
application in the synthesis of peptidomimetics31,32 and stereo-
defined glutamates33,34 and pyroglutamates.35 Although conju-
gate additions to simple α,β-unsaturated lactams have been
reported to be difficult,36 activated pyrrolidinones14,37–49 and
bicyclic lactams9,19,20,50–54 have been successfully functionalised
in this manner. The activated systems 2b,c were of considerable
interest to us because of their expected higher reactivity to con-
jugate addition, and we report here in detail the synthesis of
functionalised pyrrolidinones which uses such a strategy in
the key step; this methodology has previously been reported
in preliminary form.55 Noteworthy is that, despite the acidity of
H-5 of 2c, as evidenced by its facile dimerisation to 3, the
chiral integrity of this position is maintained;27,56 that com-
plete chiral integrity can indeed be lost in a protected simple
∆3,4-pyroglutamate has been demonstrated in the course of a
Diels–Alder reaction.57 For the reasons postulated in Seebach’s
Principles of Self Regeneration of Stereocentres, the bicyclic
system ensures that deprotonation of H-5 of 2c always regen-
erates the original (most stable) ring stereochemistry upon
reprotonation.58 The high acidity of related compounds59,60 and
similar dimerisations are already known,12,31 and a natural
product of similar structure has been reported.61 A related
bicyclic system has been investigated exhaustively by Meyers
and co-workers, who have examined various types of
ring manipulations to access a diversity of functionalised
products.62–64
glutaminol6,7 for alkylations at C-7 via the lactam enolate,8,9
and similar work by other groups has been reported in recent
years.6,9–22 We were attracted to this template since it could be
readily prepared in enantiopure form, and the hydroxy and
amide functionalities were simultaneously protected by a single
benzylidene protecting group; this protecting group also pro-
vided a bicyclic template which might be expected to exert good
diastereocontrol and additionally provided a linking group
suitable for anchoring to an inert support. In the event,
Conjugate addition reactions
We initially investigated conjugate additions to the enone 2a,
prepared by our previously reported method.27 Although the
addition of the enolate of dimethyl malonate to enone 2a under
kinetic conditions (LDA at Ϫ78 ЊC) returned unreacted starting
material, the Stefanofsky conditions65,66 (1 equivalent NaNH2
† This nomenclature conforms to IUPAC Recommendations 1995
(Pure Appl. Chem., 1995, 67, 1309).
DOI: 10.1039/b001999m
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792
This journal is © The Royal Society of Chemistry 2000
2783

View Article Online
Table 1 Conjugate additions to 2c
Diastereomer
ratiod
Yield
(%)
Product
Conditionsa
4c
4c
5a
5b
5c
5d
5e
5f
A
B
C
A
D
E
F
G
H
1b
30
70
60
54
72
77
27
56
53
1b
1b
1:1
1:1:4.5:4.5
1:5.5:43.5
c
1:5:9:35
1:17:17:74
5g
a A = NaNH2 (1 eq.), DMPU, THF; B = NaNH2 (13 mol%), DMPU,
THF; C = K2CO3, Bu4NHSO4; D = Ba(OH)2 (10 mol%), EtOH;
E = Zn, ultrasound, THF, DMPU (9% v/v), 30–35 ЊC; F = Zn, ultra-
sound, dioxane, 35 ЊC; G = Zn, ultrasound, THF, Ϫ5 ЊC; H = Zn, ultra-
sound, THF, Ϫ10 ЊC. b Only (6S,7S) diastereomer obtained. c Not
determined. d After purification.
Fig. 1 NOE data for selected compounds.
in refluxing THF–HMPA) gave the desired product 4a in 57%
yield. Application of the same conditions but with substitution
of DMPU for HMPA gave a 55% yield of the same product.
However, an attempt to extend this reaction to other nucleo-
philes (Meldrum’s acid, methyl thiophenylacetate,54 methyl
phenylacetate and tert-butyl acetate) was unsuccessful. Sub-
sequent elaboration of 4a by generation of the dienolate
(3 equivalents of LDA) followed by quenching with benzyl
bromide at Ϫ78 ЊC, gave the all-trans product 4d in 37% yield,
whose stereochemistry at C-6 and C-7 was confirmed by single
crystal X-ray spectroscopic analysis.67
In an effort to gain improved generality for this conjugate
addition, we examined the vinyl selenide 2b and the acylated
lactam 2c, prepared as previously described,27 since both were
expected to be more reactive than 2a. Conjugate addition of
dimethyl malonate to 2b using the NaNH2 (1 equivalent)–
DMPU–THF conditions gave the product 4b in 45% yield as
a single diastereomer, whose stereochemistry was assumed on
the basis of the assignment discussed above. However, enone 2c
proved to be substantially more reactive, and application of
the same reaction conditions gave a 30% isolated yield of the
desired adduct 4c, the stereochemistry of which was assigned by
NOE difference spectroscopy (Fig. 1). Irradiation of H-5, the
known stereocentre, caused a 6.5% enhancement of H-4exo
and a 6.3% enhancement of the malonate side-chain proton,
indicating that the malonate group is on the exo-face of the
molecule and therefore that H-6 has the endo-configuration.
This assignment was confirmed by irradiation of H-6endo and of
the malonate side-chain proton which caused enhancements of
H-4endo (9.6%) and H-7 (7.2%) respectively, indicative of the
all-trans arrangement of ring substituents, which would be
expected to be thermodynamically preferred. Repetition of this
reaction with a catalytic quantity of NaNH2 (13 mol%) gave a
greatly improved isolated yield of 70% of 4c, again as the same
diastereomer.
Interestingly, addition reactions to 2c proved to be much
more general than those to 2a, and the enolates of several
dicarbonyl derivatives gave the expected adducts 5a–c in
moderate to very good yield (Table 1). Conjugate addition of
triethyl methanetricarboxylate under phase transfer condi-
tions68 (Bu4NHSO4, K2CO3, anhydrous toluene at 60 ЊC) gave
the expected adduct 5a as a single diastereomer in 60% yield,
whose relative stereochemistry was assigned by NOE analysis
(Fig. 1). The cis arrangement of H-5 and H-7 and of H-4endo
and H-6endo was confirmed by 2 and 4% enhancements respec-
tively; the C-6/7 substituents thus adopt the expected thermo-
dynamically more stable trans arrangement. Since trialkyl
methanetricarboxylates can be easily converted to malonic
esters,69 this route would readily provide access to compounds
of type 4c. The reactions of methyl cyanoacetate and ethyl
acetoacetate each gave an inseparable mixture of diastereomers
5b,c in 54 and 72% yields respectively; in the latter case, no
intramolecular trapping of the C-7 enolate by the acetyl
carbonyl group was observed, contrary to
a literature
observation for additions with (E)-chalcone.70 However,
again Meldrum’s acid, methyl thiophenylacetate and tert-butyl
acetate gave complex mixtures of unidentifiable products under
the above conditions.
Of interest was the possibility of trapping the intermediate
enolate of the Michael addition of malonate with an alkylating
agent, prior to quenching, in order to generate trans-6,7-
disubstituted products directly; thus, enone 2c was treated with
dimethyl malonate under the conditions described above, fol-
lowed by benzyl bromide, and the mixture stirred at room tem-
perature for 3 h. Careful purification by silica chromatography
(eluant 3:1 petrol–EtOAc) allowed isolation of three products;
the major product was the simple Michael adduct 4c (37%),
with no addition of benzyl bromide. The remaining two proved
to be a diastereomeric mixture of the alkylated lactams 6a,b
obtained in 41% combined yield respectively. The former
product 6a displayed allylic coupling (J 2 Hz) between H-4 and
H-6, and mass spectrometry indicated the required molecular
mass, but attempted determination of the stereochemistry at
C-7 by NOE difference spectroscopy was not successful. The
minor product 6b could not be isolated in pure form, but its 1H
NMR spectrum displayed similarities to the major product 6a.
In particular there was the same allylic coupling pattern
between H-4 and H-6, and the aromatic region indicated the
2784
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792

View Article Online
Scheme 1
presence of two phenyl rings. The proposed mechanism for
which in turn gave a 2.0% enhancement of one of the methylene
formation of compounds 4c and 6 is shown in Scheme 1.
Deprotonation of the starting enone 2c (path a), operating in
competition with the conjugate addition reaction (path b),
would generate an enolate capable of alkylating at either the
α- or γ-positions. Reaction, however, clearly proceeds via the
more stabilised β-dicarbonyl enolate to give the product 6 as a
diastereomeric mixture; the major diastereomer is likely to be
the exo-benzyl one 6a on the basis of our earlier work.8 A simi-
lar deconjugative dialkylation in a monocyclic pyrrolidinone
has recently been reported.71 Attempts to alkylate lactam 4c by
deprotonation with NaH or KHMDS followed by reaction with
benzyl bromide were not successful.
protons α to the tert-butyl ester, thus indicating the exo-
orientations of H-7 and the C-6 substituent. More significantly,
irradiation of H-4endo gave a 10.8% enhancement of H-6 con-
firming the assignment of stereochemistry at C-6, this being
consistent with the expected stereochemistry derived from exo
(less hindered) conjugate addition of the Reformatsky reagent.
The major diastereomer was therefore assigned the relative
stereochemistry arising from exo-attack by the organometallic
reagent at C-6 followed by exo-protonation, giving the trans-
C-6/7 relative stereochemistry as expected on steric grounds,
that is (6S,7S)-5d (Fig. 1). The assignment of the stereo-
chemistry of the other diastereomers came from equilibration
studies. Attempted equilibration of the mixture of isomers 5d
obtained from the reaction with tert-butyl bromoacetate did
not lead to a significant change in the diastereoisomer ratio,
consistent with the fact that the product formation is operating
under thermodynamic control: thus, a 15:1 ratio of diastereo-
mers of 5d (in favour of the 6S,7S adduct) was, after standing
for 3 days in CDCl3, found to have an almost unchanged ratio
(11:1). Conversely, a sample enriched in the original minor
diastereomer by careful HPLC purification (containing only
17% of the 6S,7S diastereomer 5d) was found to equilibrate
when dissolved in CDCl3 to a ratio of 1:1 after 8 days; thus, this
diastereomer was assigned to be epimeric at C-7, that is, was
the (6S,7R)-8a. Further treatment of this mixture with NaH
for 2 h at rt followed by an aqueous methanol quench gave a
product in which the 6S,7S diastereomer 5d had increased to
86:14; thus the diastereomeric ratio was completely reversed.
The least abundant diastereomer (0.2% of the total product)
was expected to have 6R,7R absolute stereochemistry 8b. The
diastereoselectivity of the other cases leading to 5e–g is
expected to be similar.
Attention was therefore turned to other enolates and their
equivalents for the conjugate addition reaction. Silyl ketene
acetals were of interest, since reports exist of the 1,4-conjugate
additions without any competing 1,2-additions using Lewis
acid catalysis.72 These additions have been reported in dry
acetonitrile,73 and we expected that the competing dimerisation
reaction to give 3 would be minimised under such anhydrous
conditions. Silyl ketene acetal 7 and enone 2c were therefore
stirred in dry acetonitrile, and the expected adduct 5d was
obtained in 47% yield as an 8:1 mixture in favour of the all-
trans diastereomer shown. Although this proved to be a simple
procedure, high yielding and convenient alternatives to effect
conjugate addition were still needed, and Reformatsky reagents
offered considerable promise in this regard, but surprisingly few
applications for conjugate additions, especially for diastereo-
selective additions,74,75 have been reported.76–78 We were pleased
to find that the Reformatsky reagents which were derived from
several bromoesters, generated in THF using ultrasonic irradi-
ation,79,80 when treated with enone 2c gave the products 5d–g
(Table 1); these were generally obtained as predominantly one
diastereomer, with minor amounts of the other diastereomers.
The yields of the reaction were found to be highly solvent
dependent, and for the reaction of the Reformatsky reagent
derived from tert-butyl bromoacetate, THF and diglyme gave
better yields of 5d than dioxane and toluene (50, 52, 18 and
39% respectively); the best yield, of 77%, was obtained in a
DMPU and THF solvent mixture. However, the competing
dimerisation reaction described above, leading to adduct 3,
was observed when formation of the Reformatsky reagent was
attempted in situ in the presence of the enone 2c; pre-formation
of the Reformatsky reagent was therefore essential. Further
investigations showed that no reaction occurred at 0 ЊC, and
warming to about 20 ЊC only gave a sluggish rate, with the
optimum temperature range for the addition reaction being
30–35 ЊC. Ethyl bromoacetate gave only a low yield (27%) of
the corresponding adduct using the unoptimised conditions.
In the case of methyl 2-bromopropionate and α-bromophenyl-
propionate, the Reformatsky reagents needed to be generated at
Ϫ6 ЊC, with the subsequent addition at not greater than 0 ЊC.
Under these conditions, the products 5f,g were obtained
in yields of 56 and 53% respectively as a mixture of several
diastereomers (Table 1).
Elaboration to pyroglutamates
The convenient entry to these lactams would be of value only
if selective deprotection was possible, thereby allowing access
to functionalised pyrrolidinones. Treatment of lactam 5a with
TFA gave a rapid reaction in which the deprotected pyro-
glutaminol 9a was obtained in excellent yield. However, the
1
In the one case amenable to H NOE analysis (the major
diastereomer of compound 5d, Fig. 1), for which the requisite
NOE results were obtained by using a mixed CDCl3–C6D6
(1:1.7) solvent in which H-4endo, H-5, H-6 and H-7 were
resolved, irradiation of H-5 gave a 1% enhancement of H-7
same conditions, when applied to the Reformatsky adduct
5d gave only a 45% yield of the required product 9b. Since
the O,N-hemiaminal ether cleavage was faster than that of the
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792
2785

View Article Online
tert-butyl ester, application of shorter reaction times (15 min)
for 5d was found to give a high yielding (79%) formation of
the desired pyrrolidinone 9b.
just resolved doublet of doublets typically in the range δ 3.7–
3.9, but the H-4exo signal often occurred as a well resolved doub-
let of doublets at lower field (δ 4.2–4.5). The chemical shift
value for H-6 was typically in the range of δ 3.0–3.6, except for
those compounds with a C-7 aromatic substituent, which gave
higher field resonances centred about δ 2.6. These trends appear
to be quite general and are valuable in the establishment of
structural assignments. Therefore, in addition to controlling
the stereochemistry of ring manipulations, the bicyclic system
also facilitates the determination of ring stereochemistry by
a consideration of chemical shift, coupling constant and NOE
data.
Selective hydrolysis of the ethyl ester over the tert-butyl ester
of 5d was readily achieved using an aqueous solution of sodium
hydroxide in ethanol; however, the yield of carboxylic acid 5h
was dependent on reaction time and temperature, and the best
conditions were either 3.75 h at room temperature, or 1 h at rt
followed by 1 h at 40 ЊC, giving high product yields in the range
88–98%; longer periods of time at room temperature gave lower
yields. The starting diastereomeric ratio of 1:6 favouring the
trans-C-6/7 isomer of adduct 5d changed to give a diastereo-
meric ratio of 1:16 in the carboxylic acid product 5h, presum-
ably also in favour of the trans-C-6/7 isomer, although this was
not determined. Decarboxylation was readily effected by heat-
ing at low pressure to give compound 5i in high crude yield
(~94%). However, this compound proved to be considerably
more acid sensitive than similarly hemiaminal ether protected
analogues; deprotection occurred even in deuterochloroform
over a 12 h period, reaching completion after several days. An
alternative route to access compound 5i directly was Krapcho
dealkoxycarbonylation.81 Compound 5d was heated for 4 h at
150 ЊC in wet DMSO with LiCl, and although complete ethyl
ester cleavage was achieved, partial N,O-acetal deprotection
also occurred. This could be taken to completion by treating the
crude material with TFA in dichloromethane, and chromato-
graphy then gave the expected alcohol product 10a in 81%
yield.
Evidence for association phenomena of 10a in solution came
1
from the observation that the H NMR spectra recorded in
CDCl3 were dependent on concentration; changes in the shift
of the NH and OH signals, and in the splitting of the OH and
of the adjacent methylene signals were evident. At greater con-
centration (30 mg mlϪ1) these methylene signals were displayed
as a doublet of doublets as a result of a large geminal coupling
and a smaller vicinal coupling to H-2. There was no coupling
to the exchanging OH, which was displayed as a broad singlet.
At low concentration (ca. 1 mg mlϪ1), the OH exhibited
coupling to the adjacent methylene protons and appeared as a
broad triplet, and the methylene signals were observed to be
multiplets.
Conclusion
Hemiaminal ether deprotection of compound 5i was easily
achieved by treatment with TFA in DCM for 40 min to give the
alcohol 10a in a yield of 55%. This compound has been
reported as an intermediate82 in the synthesis of (Ϫ)-(2S,3R)-2-
carboxypyrrolidine-3-acetic acid (CPAA) 11,54 an NMDA
receptor agonist,83 and the synthesis of 10a by the bicyclic
lactam route therefore constitutes a formal total synthesis of
11. Removal of the tert-butyl ester of 10a by further treatment
with TFA and subsequent oxidation of the resulting hydroxy
acid using ruthenium tetraoxide with direct methyl esterifi-
cation (diazomethane) of the diacid gave the dimethyl ester
10c in 53% yield over the three steps from alcohol 10a. This
compound is a conformationally restricted form of glutamic
acid.
Highly functionalised pyrrolidinones are available in a short
sequence from pyroglutamic acid, in which a bicyclic ring
system both controls and permits the determination of ring
stereochemistry; the method is novel and simple but potentially
generalisable. The utility of this methodology is demonstrated
by a formal total synthesis of the NMDA receptor agonist,
CPAA.
Experimental
For general experimental procedures and the preparation of
lactams 2a–2c, see our earlier reports.8,27
(؉)-(2R,5S,6R)-6-[Bis(methoxycarbonyl)methyl]-8-oxo-2-
phenyl-3-oxa-1-azabicyclo[3.3.0]octane 4a
1H NMR spectroscopy
A mixture of enone 2a (0.10 g, 0.50 mmol), dimethyl malonate
(0.10 g, 0.75 mmol), sodium amide (0.020 g, 0.52 mmol),
DMPU (1 cm3), and THF (10 cm3) was refluxed for 3 h under
nitrogen. The mixture was quenched with cold water, extracted
with ethyl acetate, and the organic phase washed with cold
water. The organic layer was dried over MgSO4, concentrated
in vacuo and the crude product purified by flash column
chromatography (EtOAc–petrol 1:1, Rf 0.2) (0.075 g, 45%)
(Found: C, 61.3; H, 5.9; N, 4.4. Cl7H19NO6 requires C, 61.3; H,
5.7; N, 4.2%); [α]D ϩ134.3 (c 1.05 in CHCl3); λmax(CHCl3)/nm
259 (log ε 1.5); νmax(CHCl3)/cmϪ1 1757 (s), 1736 (s), 1708 (s);
δH (200 MHz, CDCl3) 2.68–2.75 (2H, m, H-7endo and
CH(CO2Me)2), 2.85–3.05 (1H, m, H-6endo), 3.56 (1H, d, J 10.0,
H-7exo), 3.70–3.80 (7H, m, 2 × OCH3 and H-4endo), 4.00 (1H, m,
H-5), 4.34 (1H, dd, J 8.5, JЈ 6.5, H-4exo), 6.35 (1H, s, H-2), 7.30–
7.50 (5H, m, ArH); δC (50.3 MHz, CDCl3) 38.70 (C-6), 52.94
(C-7), 54.90 (OCH3), 62.86 (C-5), 72.43 (C-4), 86.88 (C-2),
126.14, 128.66, 128.86 and 138.61 (ArC), 168.28, 168.48,
175.10 (3 × CO); m/z (CI) 334 (M ϩ Hϩ, 100%), 228 (5), 201 (7),
172 (12), 144 (7), 105 (9).
Earlier studies8,17 on simple derivatives of bicyclic lactam 1a
have highlighted consistent correlations between certain signals
in the 1H NMR spectra.‡ Thus, it has been observed that the H-2
signal always occurs as a singlet in the chemical shift range of
6.3–6.5 ppm, and this is a useful peak for the indication of
diastereomeric purity. The signal corresponding to H-4endo
occurs at a significantly lower chemical shift than that of H-4exo
and since the observed coupling constants for H-4endo are con-
sistently almost identical at ~8 Hz, this resonance often appears
as a triplet or poorly resolved doublet of doublets. In contrast,
the H-4exo exhibits a large geminal coupling (~8 Hz) to H-4endo
and a smaller coupling (~6 Hz) to H-5, and therefore often
appears as a well resolved doublet of doublets. The signals aris-
ing from the two C-6 hydrogens were dependent on the struc-
ture, with a small difference between H-6exo and H-6endo being
observed for exo-products and a large difference for endo-
products 1a (RЈ ≠ H). This has been explained using a steric
argument.17 Similiar consistencies in the 1H NMR spectra of all
the compounds 4 and 5 prepared in the current study were
noted. For example, all these compounds exhibited a similar
splitting pattern and chemical shift separation (∆δ) for H-4exo
and H-4endo. The H-4endo signal was often observed as a triplet or
(2R,5S,6R,7S)-6-[Bis(methoxycarbonyl)methyl]-8-oxo-2-
phenyl-7-phenylselenyl-3-oxa-1-azabicyclo[3.3.0]octane 4b
A mixture of vinyl selenide 2b (0.050 g, 0.14 mmol), dimethyl
malonate (28 mg, 0.21 mmol), sodium amide (6 mg, 0.14 mmol)
and DMPU (1 cm3) in THF (10 cm3) was refluxed for 5 h under
‡ Similar correlations have been observed in pyroglutamate systems.84
2786
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792

View Article Online
nitrogen. The mixture was quenched with cold water (10 cm3),
extracted with EtOAc, and the organic phase washed with brine
(10 cm3). The organic fractions were dried (MgSO4) and con-
centrated in vacuo to afford the crude product as a pale yellow
oil; initial purification by bulb-to-bulb distillation (100 ЊC, 1
mmHg) gave a thick, dark oil. The product was isolated by flash
column chromatography (EtOAc–petrol 3:7, Rf 0.4) to give the
major product 4b as a colourless solid (0.025 g, 45%). Mp 140–
142 ЊC (Found: C, 56.7; H, 4.55. C23H22NO6Se requires C, 57.6;
H, 4.68%); νmax(CHCl3)/cmϪ1 1189, 1438, 1708, 1735, 1755;
δH (500 MHz, CDCl3) 2.68–2.73 (1H, m, H-6), 2.99 (1H, dd,
J 8.5, JЈ 8.5, H-4endo), 3.73 (3H, s, OCH3), 3.76 (1H, d, J 7.5,
CH(CO2Me)2), 3.80 (3H, s, OCH3), 3.96 (1H, m, H-5), 4.15
(1H, d, J 10.0, H-7), 4.23 (1H, dd, J 8.5, JЈ 8.5, H-4exo), 6.18
(1H, s, H-2), 7.30–7.43 (8H, m, ArH), 7.68 (2H, m, ArH); δC
(125.7 MHz, CDCl3) 43.97, 48.51 (C-6), 52.91, 52.98 (C-7),
60.29 (C-5), 72.63 (C-4), 87.20 (C-2), 125.94, 126.19, 128.43,
128.70, 129.27, 129.38, 136.56 and 138.20 (ArC), 167.96,
172.20 (2 × CO); m/z 490 (M ϩ Hϩ, 70%), 334 (90), 202
(100).
52.8 (2 × CH3), 60.2 (C-5), 72.4 (C-4), 86.9 (C-2), 126.1, 126.1,
128.6, 128.7, 128.9, 129.7, 138.1, 138.7 (ArC), 168.3, 168.7 and
176.7 (3 × CO); m/z (CI(NH3)) 424 (M ϩ Hϩ, 100%), 291
(10), 262 (12), 105 (12), 91(28).
Attempted tandem Michael-trapping reaction of enone 2c
Dimethyl malonate (522 mg, 3.94 mmol) was added to a sus-
pension of sodium amide (81 mg, 1.97 mmol) in dry THF (30
cm3) and DMPU (2 cm3) and the mixture was stirred at rt for
5 min. Enone 2c (539 mg, 1.97 mmol) in THF (5 cm3) was
added via syringe and the mixture heated at reflux for 3 h. The
mixture was cooled, benzyl bromide (338 mg, 1.97 mmol) was
added and stirring was continued at rt for 2.5 h. The reaction
was quenched by pouring the mixture into NH4Cl(aq)–MeOH
(100 cm3, 1:1) and the aqueous portion extracted with EtOAc
(2 × 20 cm3). Organic extracts were combined, washed with
water and brine, dried (MgSO4) and the solvent removed
in vacuo to give a yellow oil. Analysis by 1H NMR spectroscopy
indicated the presence of three products in a ratio of 8:5:1,
and these were isolated by silica chromatography (petrol–EtOAc
3:1) as malonate adduct 4c (0.29 g, 37%), and the benzyl
derivatives 6a,b.
(؉)-(2R,5S,6R,7S)-6-[Bis(methoxycarbonyl)methyl]-7-ethoxy-
carbonyl-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 4c
Data for 6a: 0.25 g, 34%; Rf 0.3 (petrol–EtOAc 2:1);
νmax(CHCl3)/cmϪ1 1719 (s), 1704 (s), 1222 (s); δH (500 MHz,
CDCl3) 1.27 (3H, t, J 7, CH3), 3.38–3.39 (2H, m, CH2Ph), 4.18–
4.26 (2H, m, CH2CH3), 4.33 (1H, dd, J 13.5 and 2, H-4), 4.54
(1H, dd, J 13.5 and 2, H-4), 5.03 (1H, t, J 2, H-6), 5.89 (1H, s,
H-2), 7.19–7.30 (6H, m, ArH), 7.37–7.44 (4H, m, ArH); m/z
(CI(NH3)) 364 (MHϩ, 100%).
Data for 6b: 0.051 g, 7%; Rf 0.2 (petrol–EtOAc 2:1); δH (200
MHz, CDCl3) 1.32 (3H, t, J 7, CH3), 3.34–3.38 (2H, m,
CH2Ph), 4.15–4.33 (2H, m, CH2CH3), 4.37–4.66 (2H, m, H-4),
5.11–5.15 (1H, m, H-6), 6.78–6.85 (2H, m, ArH), 7.09–7.43
(8H, m, ArH).
Dimethyl malonate (0.31 mg, 2.3 mmol) was added to a suspen-
sion of sodium amide (47 mg, 1.2 mmol) in dry THF (30 cm3)
and DMPU (2 cm3) and the mixture stirred at rt for 5 min.
Alkene 2c (0.32 g, 1.2 mmol) in THF (5 cm3) was added and the
mixture heated at reflux for 3 h. The reaction was quenched by
pouring the mixture into NH4Cl(aq)–MeOH (100 cm3, 1:1)
and the aqueous portion extracted with EtOAc (2 × 20 cm3).
Organic extracts were combined, washed with water and brine,
dried (MgSO4) and the solvent removed in vacuo to give an oil
which was purified by silica chromatography (petrol–EtOAc
3:1) to give the desired product 4c (0.14 g, 30%). Rf 0.1 (petrol–
EtOAc 2:1); [α]D ϩ79.6 (c 1.5 in CHCl3); νmax(CHCl3)/cmϪ1
1737 (s), 1714 (s), 1602 (m); δH (500 MHz, CDCl3) 1.35 (3H, t,
J 7, CH2CH3), 3.37–3.42 (1H, m, H-6endo), 3.61 (1H, d, J 8.5,
CH(CO2Me)2), 3.73 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.81–
3.89 (1H, m, H-4endo), 3.87 (1H, t, J 9.5, H-7), 3.96–4.00 (1H, m,
H-5), 4.20–4.35 (2H, m, CH2CH3), 4.42 (1H, dd, J 8.5 and 6,
H-4exo), 6.33 (1H, s, H-2), 7.31–7.38 (3H, m, ArH), 7.42–7.46
(2H, m, ArH); δC (50.3 MHz, CDCl3) 14.02 (CH2CH3), 41.24
(C-6), 52.93 and 55.98 (C-7 and C-9), 53.66 (CO2CH3), 61.04
(C-5), 62.10 (CH2CH3), 72.66 (C-4), 87.07 (C-2), 126.1, 128.7
and 129.0 (ArCH), 138.3 (ArC), 168.0, 168.2, 168.4 and 170.3
(4 × CO); m/z (CI(NH3)) 406 (MHϩ, 100%), 274 (31), 150
(43), 133 (14); HRMS 406.1502. C20H24NO8 (MHϩ) requires
406.1502.
(؉)-(2R,5S,6R,7S)-7-Ethoxycarbonyl-6-[tris(ethoxycarbonyl)-
methyl]-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5a
To enone 2c (0.19 g, 0.71 mmol) under N2(g) was added triethyl
methanetricarboxylate (0.20 g, 0.85 mmol), tetrabutyl-
ammonium hydrogen sulfate (12 mg, 0.035 mmol), toluene
(3 cm3) and anhydrous potassium carbonate (29 mg, 0.21
mmol). The mixture was stirred at rt for 40 min and then at
60 ЊC for 4 h. After cooling to rt, water (5 cm3) was added and
this mixture was extracted with diethyl ether (2 × 10 cm3). The
combined organic phases were washed with brine (10 cm3),
dried (MgSO4) and evaporated in vacuo to give an orange oil.
Purification using flash column chromatography (EtOAc–
light petroleum 1:3) yielded 5a as a colourless oil as a single
diastereomer (0.22 g, 61%). Rf 0.24; [α]D25 ϩ57.12 (c 0.55 in
CHCl3) (Found: C, 59.44; H, 6.46; N, 2.68. C25H31NO10 requires
C, 59.40; H, 6.18; N, 2.77%); νmax(film)/cmϪ1 1737 (s), 1714
(s); δH (200 MHz, CDCl3) 1.23 (9H, t, J 7.0, 3 × CH3), 1.34 (3H,
t, J 7.0, CH3CH2), 3.63 (1H, dd, J 7.5 and 4.5, H-6), 3.75 (1H, t,
J 8.5, H-4endo), 4.00–4.10 (2H, m, H-5 and H-7), 4.19–4.37 (8H,
m, 4 × OCH2), 4.43 (1H, dd, J 8.0 and 6.0, H-4exo), 6.32 (1H, s,
H-2), 7.30–7.45 (5H, m, ArH); δH (500 MHz, C6D6) 0.79 (9H, t,
J 7.0, 3 × CH3), 1.05 (3H, t, J 7.0, CH3CH2), 3.86 (6H, q, J 7.0,
3 × OCH2CH3), 3.89 (1H, t, J 8.0, H-4endo), 4.00 (1H, dd, J 7.5
and 4.0, H-6), 4.05–4.19 (2H, 2 × dq, J 11.0 and 7.0, CH3CH2),
4.26–4.29 (1H, m, H-5), 4.46 (1H, d, J 7.5, H-7), 4.52 (1H, dd,
J 8.0 and 6.0, H-4exo), 6.55 (1H, s, H-2), 6.99–7.08 (3H, m,
ArH), 7.51–7.53 (2H, dd, J 8.5 and 1.5, ArCH ortho- to C(9));
δC (50.3 MHz, CDCl3) 13.6 (3 × CH3), 14.0 (CH3CH2), 42.4
(C-6), 55.9 (C-7), 61.1 (C-5), 62.1 (CH3CH2), 63.0 (C(CO2-
CH2CH3)3), 67.8 (C(CO2Et)3), 72.5 (C-4), 87.4 (C-2), 126.0,
128.6 and 128.9 (ArCH), 138.6 (C-9), 166.1, 169.6 and 171.7
(3 × CO); m/z (CI(NH3)) 506 (M ϩ Hϩ, 100%), 274 (77), 250
(76), 233 (63).
(؉)-(2R,5S,6S,7S)-7-Benzyl-6-[bis(methoxycarbonyl)methyl]-8-
oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 4d
Lactam 4a (0.15 g, 0.5 mmol) in THF (5 cm3) was added drop-
wise to a pre-cooled LDA (0.9 cm3, 1.6 mmol mlϪ1, 1.4 mmol)
in THF (5 cm3) at Ϫ78 ЊC and stirred for 1 h. To this mixture
was added a solution of benzyl bromide (0.077 g, 0.5 mmol) in
THF (3 cm3) and the mixture was stirred for 2 h at Ϫ78 ЊC. The
mixture was quenched with cold water, diluted with EtOAc (30
cm3) and washed with water (2 × 25 cm3). The crude product
was purified by flash column chromatography (EtOAc–hexane
l : l) to give the title compound 4d (0.071 g, 37%). Mp 108–
109 ЊC; Rf 0.8 (Found: C, 67.8; H, 5.8; N, 3.3. C24H25NO6
requires C, 68; H, 6.0; N, 3.3%); [α]D (c 0.06 in CHCl3) ϩ126.7;
νmax(CHCl3)/cmϪ1 2980 (m), 1750 (m), 1734 (s), 1707 (s), 1225
(s); λmax(CHCl3)/nm 265 (log ε 1.9); δH (200 MHz, CDCl3) 2.6
(1H, m, H-6), 3.0 (1H, m, H-4endo), 3.05 (2H, m, CH2Ph), 3.2
(1H, m, H-7), 3.35 (1H, d, J 8.8, CH(CO2Me)2), 3.75 (6H, s,
2 × CH3), 4.0 (1H, m, H-4exo), 4.2 (1H, m, H-5), 6.3 (1H, s,
H-2), 7.2–7.5 (10H, m, ArH); δC (50 MHz, CDCl3) 35.4
(PhCH2), 41.3 (C-6), 49.5 (C-7), 53.2 (CH(CO2Me)2), 52.7 and
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792
2787

View Article Online
(2R,5S,6R,7S)-7-Ethoxycarbonyl-6-[cyano(methoxycarbonyl)-
methyl]-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5b
General method of Reformatsky reagent conjugate addition
Activated zinc powder and iodine (20 mol% of the enone) were
placed in a round-bottom flask under an inert atmosphere. The
specified solvent (usually THF) and then the bromoester were
added and the contents subjected to sonication (decolouration
of brown I2 occurred). A solution of enone 2c in the specified
solvent was then added via cannula, keeping the contents at
the specified temperature. Sonication may have then been con-
tinued at the specified temperature for a further 15 min. The
reaction was quenched by adding a mixture of water and ice
and stirring for 5 min or until the ice had melted. Ammonium
chloride solution (sat. aq.) was then added to dissolve the pre-
cipitate, if formed, and the mixture then extracted with ethyl
acetate or DCM. Drying (MgSO4) and evaporation in vacuo
gave the crude product as a liquid or oil which was purified by
flash column chromatography to yield the product as a mixture
of diastereomers.
To a stirred suspension of NaNH2 (80–90%, 34 mg, 0.74 mmol)
in THF (5 cm3) and DMPU (2 cm3) was added methyl cyano-
acetate (0.146 g, 1.47 mmol). After 5 min at rt, enone 2c (0.201
g, 0.735 mmol) in THF (17 cm3) was added. After 10 min the
mixture was heated at reflux for 20 min and then cooled to rt.
Water (30 cm3) was added and, following extraction of the solu-
tion with EtOAc (3 × 50 cm3), the organics were dried (MgSO4)
and evaporated in vacuo. Purification using flash column
chromatography (EtOAc–light petroleum, 1:2) gave the prod-
uct 5b as a pale yellow, viscous gum (0.15 g, 54%) consisting of
four diastereomers in a ratio of 48:41:9:2. Only NMR
spectroscopic data for the major diastereomer (A) and the
next major diastereomer (B) are quoted. Rf 0.24 (EtOAc–light
petroleum 1:2) (Found: C, 61.50; H, 5.65; N, 7.36. C19H20N2O6
requires C, 61.28; H, 5.41; N, 7.52%); νmax(CHCl3)/cmϪ1 2254
(w), 1753 (s), 1722 (s); δH (500 MHz, C6D6) 1.03–1.09 (6H, m,
CH3CH2, (A and B)), 2.68 (1H, d, J 8.5, H-7 (B) or H-10 (B)),
2.82 (1H, d, J 8.0, H-7 (A), or H-10 (A)), 3.06 (3H, s, CO2CH3
(B)), 3.10 (3H, s, CO2CH3 (A)), 3.20–3.29 (2H, m, H-6 (A
and B)), 3.31–3.38 (3H, m, H-4endo (A), H-4endo (B) and H-5
(B)), 3.51 (1H, dd, J 13.5 and 7.0, H-5 (A)), 3.58 (1H, d,
J 10.8, H-7 (A) or H-10 (A)), 3.65 (1H, d, J 10.0, H-7 (B) or
H-10 (B)), 3.96–4.17 (6H, m, H-4exo (A and B) and CH3CH2
(A and B)), 6.26 (1H, s, H-2 (A)), 6.34 (1H, s, H-2 (B)), 7.06–
7.14 (6H, m, ArH, (A and B)), 7.44–7.48 (4H, m, o-ArH, (A
and B)); δC (50.3 MHz, CDCl3) 13.9 and 14.0 (CH3CH2), 39.2
(C-6), 42.3 (C-7), 54.1 (CO2CH3), 55.2 and 55.5 (C-5), 59.83
and 60.8 (C-10), 62.5 (CH3CH2), 71.3 and 71.6 (C-4), 87.3
and 87.5 (C-2), 114.3 (CN), 126.2, 128.8 and 129.2 (ArCH),
137.5 (C-9), 164.9, 167.5, 167.8, 168.9 and 169.8 (CO); m/z
(CI(NH3)) 390 (M ϩ NH4ϩ, 12%), 373 (M ϩ Hϩ, 53), 291 (23),
274 (100).
(2R,5S,6S,7S)-7-Ethoxycarbonyl-6-tert-butoxycarbonylmethyl-
8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5d
Method 1. A solution of enone 2c (0.16 g, 0.59 mmol) and
ketene silyl acetal 7 (0.20 g, 0.88 mmol) in CH3CN (5 cm3) was
stirred at 55 ЊC for 1 h. Another aliquot of acetal (74 mg) was
then added, and after 30 min the solvent was evaporated in
vacuo. Purification by flash column chromatography (EtOAc–
petrol (40–60) 1:4) gave the title compound 5d as a colourless
oil (0.11 g, 47%) having a diastereomeric composition of 8a:8b,
8:1.
Method 2. Following the general procedure, tert-butyl bromo-
acetate (5.4 g, 28 mmol), zinc (3.0 g, 46 mmol) and iodine
(0.23 g, 1.8 mmol) were sonicated at 35–40 ЊC in THF (75 cm3)
for 15 min. After stirring for 30 min at rt, DMPU (12 cm3) was
added, followed by a solution of enone 2c (2.5 g, 9.2 mmol) in
THF (20 cm3) at 0 ЊC. The mixture was quickly brought to 35–
40 ЊC by careful heating and was then sonicated for 15 min at
this temperature. After stirring at rt for 30 min the reaction was
worked-up and extracted with EtOAc to give an orange liquid.
Dry flash chromatography (EtOAc–petrol (40–60) 1:3) par-
tially removed the DMPU to give an orange liquid. Further
purification using flash column chromatography (EtOAc–petrol
(40–60) 2:7) gave the title compound as a colourless oil consist-
ing of two diastereomers (5d:8a, 6:1) (2.8 g, 77%), with a
de у98% at position C-6. Rf 0.13 (EtOAc–light petroleum 1:5)
(Found: C, 65.55; H, 7.03; N, 3.39. C21H27NO6 requires C, 64.77;
H, 6.99; N, 3.60%); νmax(CHCl3)/cmϪ1 1718 (s), 1370 (s), 1154
(s); δH (500 MHz, C6D6) (major diastereomer, 5d) 1.03 (3H, t,
J 7.0, CH3CH2), 1.25 (9H, s, C(CH3)3), 1.81 (1H, dd, J 16.5 and
(2R,5S,6R,7S)-7-Ethoxycarbonyl-6-[ethoxycarbonyl(acetyl)-
methyl]-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5c
To a stirred solution of enone 2c (0.16 g, 0.59 mmol) and
ethyl acetoacetate (0.077 g, 0.59 mmol) in ethanol (5 cm3) at
rt was added activated barium hydroxide (ca. 10 mol%, 11
mg, activated by heating barium hydroxide octahydrate at
200 ЊC for 3.5 h). After 24 h, hydrochloric acid (1 M, aq.)
was added to bring the acidity of the mixture to pH 4. Water
(30 cm3) was added and the mixture was then extracted with
EtOAc (3 × 20 cm3) and the organics washed with brine,
dried (MgSO4), and evaporated in vacuo to give a yellow oil.
Purification using flash column chromatography (EtOAc–light
petroleum 1:3) gave the product 5c as a colourless oil (0.17 g,
72%), consisting of four diastereomers in an approximate
ratio of 1:1:4.5:4.5. Only the NMR spectroscopic data for
the two major diastereomers (A and B) are quoted. Rf 0.30
(EtOAc–light petroleum 1:3) (Found: C, 62.74; H, 6.38; N,
3.39. C21H25NO7 requires C, 62.52; H, 6.25; N, 3.47%);
νmax(CHCl3)/cmϪ1 1718 (s), 1740 (s), 700 (m); δH (500 MHz,
CDCl3) 1.29–1.32 (12H, m, 2 × CH3CH2 (A and B)), 2.27
(6H, s, CH3CO (A and B)), 3.33–3.41 (2H, m, H-6 (A and
B)), 3.69 (2H, d, J 9.0, H-7 or C(10)H (A and B)), 3.74–3.77
(2H, m, H-5 (A) and H-7 (A) or H-10 (A)), 3.79 (1H, d,
J 9.6, H-7 (A) or H-10 (A)), 3.84–3.89 (2H, m, H-4 (A and B)),
3.96–4.00 (1H, m, H-5 (B)), 4.16–4.34 (8H, m, 2 × CH3CH2
(A and B)), 4.44 (2H, dd, J 8.5 and 6.0, H-4 (A and B)), 6.31
(1H, s, H-2 (B)), 6.32 (1H, s, H-2 (A)), 7.31–7.45 (10H, m,
ArH (A and B)); δC (50.3 MHz, CDCl3) 13.8, 13.9 and 14.1
(CH3CH2), 29.5 and 29.6 (CH3CO), 10.3 and 10.5 (C-6), 56.1
and 56.2 (C-10), 60.9, 61.5, 61.9, 62.0, 62.1, 62.4 and 62.5
(C-5, C-7 and CH3CH2), 72.9 (C-4), 87.0 (C-2), 126.1, 128.7
and 129.0 (ArCH), 138.5 and 138.6 (C-9), 167.7, 168.1, 168.7,
170.4 and 170.8 (CO), 201.5 (CH3CO); m/z (CI(NH3)) 404
(M ϩ Hϩ, 100%), 274 (10).
t
t
9.5, CHHCO2 Bu), 2.12 (1H, dd, J 16.5 and 5.5, CHHCO2 Bu),
3.01–3.06 (1H, m, H-6), 3.27 (1H, d, J 10.5, H-7), 3.26–3.31
(1H, m, H-5), 3.56 (1H, t, J 8.5, H-4endo), 3.99–4.13 (2H, 2 × dq,
J 11.0 and 7.0, CH2CH3), 4.16 (1H, dd, J 8.5 and 6.0, H-4exo),
6.37 (1H, s, H-2), 7.05–7.16 (3H, m, ArH), 7.53–7.55 (2H, m,
ArH); δH (500 MHz, CDCl3) 1.34 (3H, t, J 7.0, CH3CH2), 1.44
t
(9H, s, C(CH3)3), 2.45 (1H, dd, J 16.5 and 10.0, CHHCO2 Bu),
t
2.61 (1H, dd, J 16.5 and 4.5, CHHCO2 Bu), 3.04–3.10 (1H,
m, H-6), 3.61 (1H, d, J 11.0, H-7), 3.84–3.88 (2H, m, H-4endo
and H-5), 4.22–4.35 (2H, 2 × dq, J 11.0 and 7.0, CH3CH2),
4.39–4.43 (1H, m, H-4exo), 6.32 (1H, s, H-2), 7.31–7.38 (3H,
m, ArH), 7.44–7.46 (2H, m, ArH); δC (50.3 MHz, CDCl3)
(major diastereomer, 5d) 14.0 (CH2CH3), 27.9 (CH3)3C),
t
38.3 (CH2CO2 Bu), 39.4 (C-6), 57.3 (C-7), 61.9 (CH2CH3), 62.7
(C-5), 72.4 (C-4), 81.6 (C(CH3)3), 86.9 (C-2), 126.2, 128.6 and
128.9 (ArCH), 138.4 (C-9), 168.6 and 170 (3 × CO); δH (250
MHz, CDCl3) (minor diastereomer, 8a) 1.31 (3H, t, J 7.0,
CH3CH2), 1.44 (9H, s, C(CH3)3), 2.48 (1H, dd, J 16.5 and 10.0,
t
t
CHHCO2 Bu), 2.62 (1H, dd, J 16.5 and 6.0, CHHCO2 Bu),
2.81–2.93 (1H, m, H-6), 3.72 (1H, d, J 8.5, H-7), 3.79 (1H, dd,
J 8.0 and 6.5, H-4), 4.14 (1H, q, J 7.0, H-5), 4.20–4.28 (3H, m,
2788
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792

View Article Online
CH3CH2 and H-4), 6.34 (1H, s, H-2), 7.32–7.47 (5H, m, ArH);
m/z (CI(NH3)) 390 (M ϩ Hϩ, 100%), 334 (46).
worked-up, and extracted with DCM to give a grey transparent
oil. Purification using flash column chromatography (EtOAc–
petrol (40–60) 1:3) gave incompletely separated diastereomers.
A minor amount (8 mg) of 8b was isolated. Rf 0.17 (EtOAc–
petrol (40–60) 1:4); νmax(film)/cmϪ1 1724 (s), 1368 (m), 1259
(m), 1224 (m), 1154 (s), 700 (w); δH (500 MHz, CDCl3) 1.33
(3H, t, J 7.0, CH3CH2), 1.46 (9H, s, C(CH3)3), 2.45 (1H, dd,
Diastereomer A. νmax(film)/cmϪ1 2982 (m), 1739 (s), 1712 (s),
1456 (m), 1369 (m), 1267 (s), 1181 (s), 702 (m); δH (500 MHz,
CDCl3) 1.22 (3H, d, J 7.0, CH3CH), 1.34 (3H, t, J 7.0,
CH3CH2), 2.63–2.68 (1H, m, H-10), 3.00–3.05 (1H, m, H-6),
3.66 (3H, s, CO2CH3), 3.76 (1H, t, J 8.0, H-4endo), 3.80 (1H,
d, J 10.5, H-7), 3.87–3.92 (1H, m, H-5), 4.21–4.35 (3H, m,
CH3CH2 and H-4exo), 6.32 (1H, s, H-2), 7.33–7.38 (3H, m,
ArH), 7.44–7.45 (2H, m, ArH); δC (50.3 MHz, CDCl3) 14.1 and
14.4 (CH3CH2 and CH3CH), 41.3 (C-6), 45.4 (C-10), 51.9
(CO2CH3), 56.2 (C-7), 60.3 (C-5), 61.9 (CH3CH2), 72.1 (C-4),
86.9 (C-2), 125.90, 128.4 and 128.7 (ArCH), 138.9 (C-9), 168.5,
170.8 and 174.1 (3 × CO); m/z (CI(NH3)) 362 (M ϩ Hϩ, 100%);
HRMS 362.1604, C19H21NO6 requires 362.1604.
t
J 16.5 and 9.0, CHHCO2 Bu), 2.52 (1H, dd, J 16.5 and 7.0,
t
CHHCO2 Bu), 3.32 (1H, d, J 6.5, H-7), 3.39–3.44 (1H, m, H-6),
3.56 (1H, t, J 8.5, H-4), 4.08 (1H, dd, J 8.5 and 6.5, H-4), 4.27
(2H, q, J 7.0, CH3CH2), 4.34–4.38 (1H, m, H-5), 6.34 (1H,
s, H-2), 7.33–7.39 (3H, m, ArH), 7.43–7.46 (2H, m, ArH);
δC (125.8 MHz, CDCl3) 14.09 (CH3CH2), 27.97 (C(CH3)3),
t
33.77 and 35.99 (C-4 and CH2CO2 Bu), 56.13, 59.94, 61.85 and
62.09 (C-4, C-5, C-7 and CH3CH2), 81.71 (C(CH3)3), 87.78
(C-2), 125.89, 128.44 and 128.69 (ArCH), 138.05 (C-9), 168.21,
170.04 and 172.54 (3 × CO); m/z (APCIϩ) 390 (M ϩ Hϩ,
19%), 334 (100); HRMS (CIϩ) 390.1917. C21H28NO6 requires
390.1917.
Diastereomer B. νmax(film)/cmϪ1 2982 (m), 1735 (s), 1713 (s),
1456 (m), 1372 (m), 1264 (s), 1205 (s), 1177 (s), 702 (m); δH (500
MHz, CDCl3) 1.20 (3H, d, J 7.0, CH3CH), 1.35 (3H, t, J 7.0,
CH3CH2), 2.63–2.69 (1H, m, H-10), 3.02–3.07 (1H, m, H-6),
3.69 (1H, d, J 10.5, H-7), 3.71 (3H, s, CO2CH3), 3.80 (1H,
t, J 8.0, H-4endo), 3.85–3.89 (1H, m, H-5), 4.24–4.36 (3H, m,
CH3CH2 and H-4exo), 6.32 (1H, s, H-2), 7.33–7.38 (3H, m,
ArH), 7.44–7.45 (2H, m, ArH); δC (125.8 MHz, CDCl3) 14.10
and 15.58 (CH3CH2 and CH3CH), 42.92 (C-6), 45.56 (C-10),
52.05 (CO2CH3), 56.69 (C-7), 61.68 (C-5), 61.97 (CH3CH2),
72.42 (C-4), 86.85 (C-2), 125.90, 128.42 and 128.71 (ArCH),
138.08 (C-9), 168.81, 170.50 and 174.50 (3 × CO); m/z
(CI(NH3)) 362 (M ϩ Hϩ, 100%); HRMS 362.1609, C19H21NO6
requires 362.1604.
Epimerisation experiments on the adduct 5d
Preparative HPLC {33 × 4.6 mm 5 Micron ABZϩPLUS,
mobile phase A [H2O ϩ 0.1% (v/v) formic acid], mobile phase B
[95:5 (v/v) MeCN–H2O ϩ 0.07% formic acid], gradient (0 to
100% B in 3.5 min holding for 1.0 min then returned to 0% B
over 0.2 min), 3.0 ml minϪ1} was used to partially separate the
two diastereomers 5d and 8a. A sample enriched in the minor
diastereomer (5d:8a, 1:5) was found after 8 days to have a ratio
of 5d:8a, 1:1, and on treatment with NaH (excess) in THF for
2 h at rt, quenching with water–MeOH, 1:1 at rt, and extrac-
tion with EtOAc, drying (MgSO4) and evaporation in vacuo,
a ratio of 5d:8a, 6:1 was obtained. A sample of 5d:8a, 15:1
was shown to have a ratio of 5d:8a, 11:1 after standing in
CDCl3 for 3 days.
(2R,5S,6R,7S)-7-Ethoxycarbonyl-6-[(methoxycarbonyl)(phen-
yl)]methyl-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5g
(2R,5S,6S,7S)-7-Ethoxycarbonyl-6-ethoxycarbonylmethyl-8-
oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5e
Following the general procedure, methyl ( )-α-bromophenyl-
acetate (0.37 g, 1.62 mmol), zinc (0.18 mg, 2.71 mmol) and
iodine (14 mg, 0.11 mmol) were sonicated at Ϫ6 ЊC (ice–brine
bath) in THF (6 cm3) for 4 min. A solution of the enone 2c in
THF (2 cm3) was then added over 10 min at Ϫ10 ЊC, washing
out the flask with THF (2 cm3). Stirring was continued at Ϫ10
to Ϫ6 ЊC for 30 min and then at rt for 2 min. The reaction was
worked-up, using DCM for extraction, to give a grey gelatin-
ous solid. Purification using flash column chromatography
(EtOAc–petrol (40–60) 1:3) gave incompletely separated
diastereomers (20 mg, 9%) and (100 mg, 44%).
Following the general Reformatsky addition procedure, ethyl
bromoacetate (0.14 g, 0.85 mmol), zinc (84 mg, 1.2 mmol) and
iodine (18 mg, 0.14 mmol) were sonicated at 35 ЊC in dioxane (5
cm3) for 5 min. A solution of enone 2c (0.19 g, 0.71 mmol) in
dioxane (5 cm3) was then added and sonication was continued
for 10 min. After standing for 18.5 h the mixture was worked-up
and extracted with DCM to give a dark yellow oil. Purification
using flash column chromatography (EtOAc–light petroleum
2:5) gave a colourless oil consisting of mostly one diastereo-
mer. Rf 0.33 (EtOAc–light petroleum 2:5) (Found: C, 62.89; H,
6.34; N, 3.73. C19H23NO6 requires C, 63.15; H, 6.42; N, 3.88%);
νmax(CHCl3)/cmϪ1 1729 (s), 700 (m); δH (500 MHz, CDCl3) 1.26
(3H, t, J 7.0, OCH2CH3), 1.33 (3H, t, J 7.0, OCH2CH3), 2.53
(1H, dd, J 17.0 and 10.0, CHHCO2Et), 2.68 (1H, dd, J 17.0 and
5.0, CHHCO2Et), 3.07–3.13 (1H, m, H-6), 3.64 (1H, d, J 11.0,
H-7), 3.84–3.89 (2H, m, H-4endo and H-5), 4.12–4.17 (2H, m,
OCH2CH3), 4.23–4.34 (2H, m, CO2CH2CH3), 4.38–4.43 (1H,
m, H-4exo), 6.32 (1H, s, H-2), 7.31–7.45 (5H, m, ArH); δC (50.3
MHz, CDCl3) 14.1 (2 × CH2CH3), 37.1 (CH2CO2Et), 39.5
(C-6), 47.3 (C-7), 61.1 and 62.0 (2 × OCH2CH3), 62.7 (C-5),
72.3 (C-4), 86.8 (C-2), 126.0, 128.5 and 128.8 (ArCH), 138.1
(C-9), 168.1, 170.1 and 171.0 (3 × CO); m/z (CI(NH3)) 379
(M ϩ NH4ϩ, 3%), 362 (100).
Diastereomer A. νmax(film)/cmϪ1 1734 (s), 1708 (s), 753 (m),
701 (m); δH (500 MHz, C6D6) 0.74 (3H, t, J 7.0, CH3CH2), 3.07
(3H, s, CO2CH3), 3.09 (1H, d, J 11.5, H-7), 3.25 (1H, d, J 10.5,
H-11), 3.46–3.50 (1H, m, H-5), 3.56–3.72 (3H, m, H-6, overlap
with 2 × dq, J 11.0 and 7.0, CH3CH2), 3.80 (1H, t, J 8.5,
H-4endo), 4.36 (1H, dd, J 8.5 and 6.0, H-4exo), 6.41 (1H, s, H-2),
6.92–7.18 (8H, m, ArH), 7.61–7.62 (2H, m, ArH); δC (125.8
MHz, CDCl3) 13.85 (CH3CH2), 45.85 (C-6), 52.50 (OCH3),
55.73 (C-7), 57.00 (C-11), 61.55 (CH3CH2), 62.33 (C-5), 72.68
(C-4), 86.87 (C-2), 125.94, 126.57, 128.30, 128.37, 128.45,
128.74 and 129.02 (ArCH), 135.24 (C-10), 138.27 (ArC),
168.15, 170.45 and 172.58 (3 × CO); m/z (CI(NH3)) 424 (M ϩ
Hϩ, 100%), 352 (3), 244 (13); HRMS 424.1759, C24H26NO6
requires 424.1760.
(2R,5S,6R,7S)-7-Ethoxycarbonyl-6-[1-(methoxycarbonyl)-
ethyl]-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5f
Diastereomer B. νmax(film)/cmϪ1 1738 (s), 1711 (s), 702 (m),
666 (m); δH (500 MHz, C6D6) 1.12 (3H, t, J 7.0, CH3CH2), 3.09
(1H, t, J 7.5, H-4), 3.14 (1H, d, J 11.0, H-7), 3.18 (3H, s,
CO2CH3), 3.21–3.25 (2H, m, H-4 and H-5), 3.50–3.55 (1H, m,
H-6), 3.58 (1H, d, J 10.0, H-11), 4.13–4.23 (2H, 2 × dq, J 11.0
and 7.0, CH3CH2), 6.35 (1H, s, H-2), 6.93–7.12 (8H, m, ArH),
7.50 (2H, dd, J 8.5 and 1.5, ArH); δC (50.3 MHz, CDCl3)
Following the general procedure, methyl ( )-2-bromopropion-
ate (0.26 g, 1.6 mmol), zinc (0.17 mg, 2.6 mmol) and iodine (13
mg, 0.10 mmol) were sonicated at 0–5 ЊC in THF (6 cm3) for 7
min. A solution of the enone 2c in THF (2 cm3) was then added
over 10 min, washing out the flask with THF (2 cm3). The
mixture was then sonicated for 15 min at 0–5 ЊC, and then
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792
2789

View Article Online
14.1 (CH3CH2), 46.5 (C-6), 52.3 (CH3CO2), 54.7 (C-7), 57.7
(C-11), 61.0 (C-5), 61.9 (CH3CH2), 71.9 (C-4), 86.9 (C-2), 126.1,
128.6, 129.0 and 129.5 (ArCH), 135.8 (C-10), 138.2 (C-9),
169.0, 170.7 and 172 (3 × CO); m/z (CI(NH3)) 424 (M ϩ Hϩ,
100%), 325 (3), 244 (8); HRMS 424.1760, C24H26NO6 requires
424.1760.
5d:8a (0.23 g, 0.60 mmol) in EtOH (15 cm3) was added NaOH
solution (1 M, 3 cm3) at rt. The mixture was stirred at rt for 1 h
and then at 40 ЊC for 1 h. Water (50 cm3) was then added and
the solution extracted with EtOAc (10 cm3). Acidification of the
aqueous with HCl (2 M) followed by extraction with EtOAc
(4 × 20 cm3) gave, after drying (MgSO4) and evaporation in
vacuo, 5h as a colourless foam (0.21 g, 95%) as a mixture of
two diastereomers (ca. 1:16); νmax(film)/cmϪ1 2940 (m), 1722 (s),
1368 (m), 1221 (m), 1154 (s), 700 (m); δH (300 MHz, CDCl3)
(major diastereomer) 1.45 (9H, s, C(CH3)3), 2.49 (1H, dd, J 17.5
General method of N,O-acetal 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 carb-
onate solution or an aqueous solution of sodium hydroxide
with stirring in an ice bath. After separating the two layers,
and extracting the aqueous phase with DCM, the combined
organic phases were dried (MgSO4) and evaporated in vacuo to
give the crude product which was purified using flash column
chromatography.
t
t
and 11.0, CHHCO2 Bu), 2.89–3.01 (2H, m, CHHCO2 Bu and
H-6), 3.61 (1H, d, J 11.0, H-7), 3.82–3.97 (2H, m, H-4endo
and H-5), 4.48 (1H, dd, J 8.5 and 6.0, H-4exo), 6.30 (1H, s,
H-2), 7.35–7.49 (5H, m, ArH), 8.64 (1H, br s, COOH);
δC (50.3 MHz, CDCl3) (major diastereomer) 28.0 (C(CH3)3),
t
38.4 (CH2CO2 Bu), 39.6 (C-6), 54.5 (C-7), 62.9 (C-5), 72.6
(C-4), 81.7 (C(CH3)3), 86.7 (C-2), 126.0, 128.6 and 129.1
(ArCH), 137.3 (C-9), 169.4, 170.5 and 171.6 (3 × CO); m/z
(APCIϪ) 360 ((M Ϫ H)Ϫ, 100%), 260 (94); HRMS 362.1600,
C19H24NO6 requires 362.1603.
(؊)-(2S,3R,4S)-4-Ethoxycarbonyl-2-hydroxymethyl-5-oxo-3-
[tris(ethoxycarbonyl)methyl]pyrrolidine 9a
Following the general method, the adduct 5a (0.19 g, 0.37
mmol) was reacted with TFA (0.5 cm3) in DCM (20 cm3) for
40 min. The solvent was removed in vacuo and the resultant
orange liquid was purified using flash column chromatography
(EtOAc–light petroleum 2:1, then EtOAc–light petroleum–
MeOH 20:10:1) to give the title compound 9a as a colourless
oil (0.14 g, 93%). Recrystallisation from hot EtOAc–light
petroleum gave 9c as fine white crystals (0.097 g, 68%) as a
single diastereomer. Rf 0.22 (EtOAc–light petroleum 4:1); [α]D22
Ϫ10.8 (c 1.0 in CH3OH) (Found: C, 51.82; H, 6.53; N, 3.41.
C18H27NO10 requires C, 51.80; H, 6.52; N, 3.36%); mp 101 ЊC;
νmax(CHCl3)/cmϪ1 3428 (w), 3440 (m), 1737 (s), 1303 (s), 1138
(s); δH (200 MHz, CD3OD) 1.28 (9H, t, J 7.0, 3 × CH3), 1.30
(3H, t, J 7.0, CH3CH2), 3.22 (1H, dd, J 4.0 and 3.0, H-3), 3.36
(1H, d, J 4.5, H-4), 3.57 (1H, dd, J 10.0 and 8.0, CHHOH),
3.67–3.73 (1H, m, H-2), 3.82–3.88 (1H, dd, J 10.0 and 3.0,
CHHOH), 4.21 (2H, q, J 7.0, OCH2), 4.26 (6H, q, J 7.0,
3 × OCH2CH3); δC (50.3 MHz, CD3OD) 12.6 (3 × OCH2CH3),
12.9 (CH3CH2), 41.6 (C-3), 53.2 (C-4), 58.4 (C-2), 61.7 (OCH2),
62.6 (3 × OCH2), 65.4 (CH2OH), 68.8 (C(CO2Et)3), 166.1
(4 × CO2Et), 172.3 (CONH); m/z (CI(NH3)) 418 (M ϩ Hϩ,
100%), 187 (15).
(2R,5S,6R)-6-tert-Butoxycarbonylmethyl-8-oxo-2-phenyl-3-oxa-
1-azabicyclo[3.3.0]octane 5i
The acid 5h (0.21 g, 0.57 mmol) was heated at 135 ЊC at 0.7
mbar for 35 min to give a pale yellow oil which was purified
using flash column chromatography (EtOAc–light petroleum
1:2) to give the title compound as a colourless oil (0.11 g,
63%). Rf 0.30 (EtOAc–petrol (40–60) 1:2); [α]D23 ϩ118.7 (c 1 in
CHCl3); νmax(film)/cmϪ1 2925 (m), 1722 (s), 1368 (m), 1251 (w),
1218 (w), 1151 (m), 700 (m); δH (300 MHz, CDCl3) 1.45 (9H, s,
t
C(CH3)3), 2.41–2.74 (5H, m, H-6, H-7 and CH2CO2 Bu), 3.70–
3.75 (1H, t J 8.5, H-4endo), 3.84–3.89 (1H, m, H-5), 4.34 (1H, dd,
J 8.5 and 6.5, H-4exo), 6.34 (1H, s, H-2), 7.33–7.46 (5H, m,
ArH); δC (50.3 MHz, CDCl3) 28.0 (C(CH3)3), 35.8 (C-6), 39.6
t
and 40.3 (C-7 and CH2CO2 Bu), 64.7 (C-5), 76.5 (C-4), 81.3
(C(CH3)3), 86.7 (C-2), 125.9, 128.4 and 128.6 (ArCH), 138.4
(C-9), 170.7 and 176.0 (2 × CO); m/z (APCIϩ) 318 (M ϩ Hϩ,
100%), 262 (37); HRMS (CIϩ) 318.1705, C18H24NO4 (M ϩ Hϩ)
requires 318.1705.
(2S,3R)-3-tert-Butoxycarbonylmethyl-2-hydroxymethyl-5-oxo-
pyrrolidine 10a
(2R,3S,4S)-3-tert-Butoxycarbonylmethyl-4-ethoxycarbonyl-2-
Lactam 5i (0.11 g, 0.42 mmol) was reacted with TFA (1.5 cm3)
in DCM (10 cm3) for 40 min. Work-up and extraction of the
aqueous phase with DCM gave a colourless crystalline solid (35
mg) which was purified using flash column chromatography
(EtOAc–petrol 1:1 and then EtOAc–petrol–MeOH 40:10:3)
to give the title compound 10a as a colourless crystalline solid
(45 mg, 55%). Rf 0.28 (EtOAc–petrol–MeOH 40:10:3); mp 99–
102 ЊC; [α]D23 ϩ20.0 (c 0.11 in CHCl3); νmax(CHCl3)/cmϪ1 3432
(m), 3366 (m, br), 1720 (s), 1697 (s), 1370 (m), 1151 (s), 1094 (s);
δH (500 MHz, CDCl3, c 30 mg mlϪ1) 1.45 (9H, s, C(CH3)3), 2.08
hydroxymethyl-5-oxopyrrolidine 9b
Following the general method, the Reformatsky adduct 5d (6:1
diastereomer ratio) (44 mg, 0.11 mmol) was reacted with TFA
(0.5 cm3) in DCM (7 cm3) for 15 min. Purification using flash
column chromatography (EtOAc–light petroleum 1:2, then
EtOAc–light petroleum–MeOH 20:15:2) gave the title com-
pound 9b as a colourless oil consisting of a 1:5 mixture of
diastereomers (27 mg, 79%). Rf 0.23; νmax(film)/cmϪ1 3266 (m),
2982 (m), 1728 (s), 1367 (m), 1258 (m), 1154 (s); δH (300 MHz,
CDCl3) (major diastereomer) 1.30 (3H, t, J 7.0, CH3CH2), 1.44
(9H, s, C(CH3)3), 2.47 (1H, dd, J 16.0 and 7.5, CHHCO2 Bu),
2.50 (1H, dd, J 16.0 and 6.5, CHHCO2 Bu), 2.81–2.90 (2H, m,
H-3 and OH), 3.26 (1H, d, J 7.0, H-4), 3.45–3.50 (1H, m, H-2),
3.63 (1H, dd, J 11.5 and 6.5, CHHOH), 3.77 (1H, dd, J 11.5
and 3.5, CHHOH), 4.24 (2H, q, J 7.0, CH3CH2), 7.16 (1H, br s,
NH); δC (50.3 MHz, CDCl3) (major diastereomer) 14.0 (CH3-
t
(1H, dd, J 5.5 and 17.0, CHHCO2 Bu), 2.36 (1H, dd, J 7.5 and
t
16.0, H-4), 2.47 (1H, dd, J 7.0 and 16.0, H-4), 2.50–2.57 (1H, m,
t
t
H-3), 2.65 (1H, dd, J 9.0 and 17.0 (CHHCO2 Bu), 3.44–3.47
(1H, m, H-2), 3.52 (1H, dd, J 6.5 and 11.5, CHHOH), 3.73 (1H,
dd, J 3.0 and 11.5, CHHOH), 3.92 (1H, br s, OH), 7.35 (1H,
br s, NH); δH (500 MHz, CDCl3, c 3 mg mlϪ1) 1.45 (9H, s,
t
C(CH3)3), 2.08 (1H, dd, J 5.5 and 17.0, CHHCO2 Bu), 2.36
t
CH2), 28.0 (C(CH3)3), 36.6 (C-3), 39.0 (CH2CO2 Bu), 54.1
(1H, dd, J 7.0 and 16.0, H-4), 2.47 (1H, dd, J 7.5 and 16.0, H-4),
2.50–2.57 (1H, m, H-3), 2.65 (1H, dd, J 9.0 and 17.0 (CHH-
(C-4), 60.1 (C-2), 61.9 (CH3CH2), 64.5 (CH2OH), 81.5
(C(CH3)3), 169.8, 170.4 and 172.2 (3 × CO); m/z (APCIϩ)
302 (M ϩ Hϩ, 47%), 246 (100); HRMS 302.1604, C14H25NO6
requires 302.1604.
t
CO2 Bu), 2.74 (1H, br t (unresolved), OH), 3.44–3.47 (1H,
m, H-2), 3.53–3.58 (1H, m, CHHOH), 3.74–3.76 (1H, m,
CHHOH), 6.66 (1H, br s, NH); δC (50.3 MHz, CDCl3) 28.0
t
(C(CH3)3), 32.5 (C-3), 36.6 and 40.0 (C-4 and CH2CO2 Bu)
(2R,5S,6S,7S)-6-tert-Butoxycarbonylmethyl-7-carboxy-8-oxo-
2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 5h
61.8 (C-2), 64.5 (CH2OH), 81.1 (C(CH3)3), 171.0 and 178.4
(2 × CO); m/z (APCIϩ) 459 (2M ϩ Hϩ, 23%), 230 (M ϩ Hϩ,
71), 174 (100).
To a solution of a 1:6 mixture of the Reformatsky adducts
2790
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792

View Article Online
10 C. Herdeis, A. Aschenbrenner, A. Kirfel and F. Schwabenlander,
Tetrahedron: Asymmetry, 1997, 8, 2421.
11 N. Langlois, O. Calvez and M.-O. Radom, Tetrahedron Lett., 1997,
38, 8037.
12 T. Nagasaka and T. Imai, Chem. Pharm. Bull., 1997, 45, 36.
13 T. Nagasaka and T. Imai, Heterocycles, 1995, 41, 1927.
14 C. Herdeis, H. P. Hubmann and H. Lotter, Tetrahedron: Asymmetry,
1994, 5, 119.
15 D. Griffart-Brunet and N. Langlois, Tetrahedron Lett., 1994, 35,
119.
(2S,3R)-3-Carboxymethyl-2-hydroxymethyl-5-oxopyrrolidine
10b
To a solution of compound 10a (16 mg, 0.07 mmol) in DCM
(1.5 cm3) was added TFA (0.6 cm3) dropwise at rt. The flask was
swirled and left to stand at rt for 1 h. The solvent was then
removed in vacuo, and then under high vacuum (2 mbar) for
several days to give the crude title compound 10b as a colourless
gum (33 mg). νmax (film)/cmϪ1 3316 (s, br), 2934 (m, br), 1674 (s),
1394 (m), 1318 (m), 1277 (m), 1225 (m), 1202 (m), 1087 (w),
1054 (w); δH (500 MHz, CD3OD) 2.11 (1H, dd, J 16.5 and 4.5,
CHHCO2H), 2.48 (1H, dd, J 18.0 and 9.5, H-4H), 2.58–2.69
(3H, m, H-4, H-3 and CHHCO2H), 3.45 (1H, dd, J 9.0 and 4.0,
H-2), 3.56 (1H, dd, J 11.5 and 5.5, CHHOH), 3.66 (1H, dd,
J 11.5 and 4.0, CHHOH); δC (125.8 MHz, CD3OD) 34.06
(C-3), 37.68 and 39.49 (C-4 and CH2CO2H), 63.01 (C-2), 65.05
(CH2OH), 175.42 and 179.81 (2 × CO); m/z (APCIϩ) 174
(M ϩ Hϩ, 100%).
16 D. Griffart-Brunet and N. Langlois, Tetrahedron Lett., 1994, 35,
2889.
17 R. W. Armstrong and J. A. DeMattei, Tetrahedron Lett., 1991, 32,
5749.
18 Y. Hamada, O. Hara, A. Kawai, Y. Ohno and T. Shiori, Tetrahedron,
1991, 47, 8635.
19 S. Hanessian and V. Ratovelomanana, Synlett, 1991, 222.
20 S. Hanessian and V. Ratovelomanana, Synlett, 1990, 501.
21 N. E. Allen, Tetrahedron, 1989, 30, 1905.
22 Y. Hamada, A. Kawai, Y. Kohno, O. Hara and T. Shioiri, J. Am.
Chem. Soc., 1989, 111, 1524.
23 R. Zhang, F. Brownewell and J. S. Madalengoitia, Tetrahedron Lett.,
1999, 40, 2707.
24 M. Fujita, O. Kitagawa, Y. Yamada, H. Izawa, H. Hasegawa and
T. Taguchi, J. Org. Chem., 2000, 65, 1108.
(2S,3R)-3-Methoxycarbonylmethyl-2-methoxycarbonyl-5-
oxopyrrolidine 10c
To a solution of crude 10b (18 mg) in CH3CN (1 cm3) and CCl4
(2 cm3) was added a solution of NaIO4 (60 mg, 0.28 mmol)
in water (1.5 cm3) and then ruthenium() oxide hydrate
(2 mg). The mixture was stirred vigorously for 4.5 h and then
diazomethane in diethyl ether was added with stirring at 0 ЊC.
The excess diazomethane was then quenched with acetic acid
(2 drops). After evaporating half the volume of diethyl ether,
the mixture was extracted with EtOAc (2 × 10 cm3). Drying
(MgSO4) and evaporation in vacuo gave a yellow oil which was
purified using flash column chromatography (EtOAc–petrol
(40–60) 4:1) to give the title compound 10c as a colourless oil
(8 mg, 53% from compound 10a). Rf 0.21 (EtOAc–petrol (40–
60) 4:1); [α]D23 ϩ32.9 (c 0.34 in CHCl3); νmax(film)/cmϪ1 3351 (w,
br), 3244 (w, br), 1736 (s), 1702 (s), 1438 (m), 1380 (m), 1214 (s),
1181 (m), 996 (m); δH (500 MHz, CDCl3) 2.15 (1H, dd, J 17.0
and 7.0, CHHCO2Me), 2.57 (1H, dd, J 16.0 and 8.0, H-4H),
2.68 (1H, dd, J 17.0 and 9.0, CHHCO2Me), 2.78 (1H, dd, J 16.0
and 6.0, H-4H), 2.91–1.98 (1H, m, H-3), 3.72 (3H, s, CO2CH3),
3.79 (3H, s, CO2CH3), 4.03 (1H, d, J 5.5, H-2), 6.27 (1H, br s,
NH); δC (125.8 MHz, CDCl3) 35.07 (C-3), 35.73 and 38.11
(CH2CO2Me and C-4), 51.93 and 52.75 (CO2CH3), 59.82 (C-2),
166.96, 171.49 and 176.08 (3 × CO); m/z (APCIϩ) 216 (M ϩ
Hϩ, 100%), 431 (33); HRMS (CIϩ) 216.0872, C9H13NO5
requires 216.0872.
25 O. Hara, J. Takizawa, T. Yamatake, K. Makino and Y. Hamada,
Tetrahedron Lett., 1999, 40, 7787.
26 J. H. Bailey, A. T. J. Byfield, P. J. Davis, A. C. Foster, M. Leech,
M. G. Moloney, M. Müller and C. K. Prout, J. Chem. Soc., Perkin
Trans. 1, 2000, 1977.
27 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.
28 M. Bamford, M. Beard, D. T. Cherry and M. G. Moloney,
Tetrahedron: Asymmetry, 1995, 6, 337.
29 N. Langlois, N. V. Bac, N. Dahuron, J.-M. Delcroix, A. Deyine,
D. Griffart-Brunet, A. Chiaroni and C. Riche, Tetrahedron, 1995,
51, 3571.
30 K. Shimamoto and Y. Ohfune, Tetrahedron Lett., 1989, 30, 3803.
31 R. Zhang, A. Mamai and J. S. Madalengoitia, J. Org. Chem., 1999,
64, 547.
32 R. Zhang and J. S. Madalengoitia, J. Org. Chem., 1999, 64, 330.
33 J. Ezquerra, C. Pedregal, I. Merino, J. Florez, J. Barluenga, S.
Garcia-Granda and M.-A. LLorca, J. Org. Chem., 1999, 64, 6554.
34 N. Langlois, Tetrahedron Lett., 1999, 40, 8801.
35 V. Soloshonok, C. Cai, V. J. Hruby, L. V. Meervelt and
N. Mischenko, Tetrahedron, 1999, 55, 12031.
36 L. E. Overman and A. J. Robichaud, J. Am. Chem. Soc., 1989, 111,
300.
37 A. G. M. Barratt, J. Head, M. L. Smith, N. S. Stock, A. J. P. White
and D. J. Williams, J. Org. Chem., 1999, 64, 6005.
38 G. Guillena, B. Mancheno, C. Najera, J. Ezquerra and C. Pedregal,
Tetrahedron, 1998, 54, 9447.
39 J. Cossy, M. Cases and D. G. Pardo, Synlett, 1998, 507.
40 H. Nakamura, Y. Oba and A. Murai, Tetrahedron Lett., 1993, 24,
2779.
41 M. P. Cook and C. M. Pollock, J. Org. Chem., 1993, 58, 7474.
42 C. Herdeis and H. P. Hubmann, Tetrahedron: Asymmetry, 1992, 3,
1213.
43 H. Nagashima, H. Wakamatsu, N. Ozaki, T. Ishii, M. Watanabe,
T. Tajima and K. Itoh, J. Org. Chem., 1992, 57, 1682.
44 W. J. Koot, H. Hiemstra and W. N. Speckamp, Tetrahedron Lett.,
1992, 33, 7969.
Acknowledgements
We thank EPSRC and GlaxoWellcome for funding of student-
ships to DTC and JD, and we wish to gratefully acknow-
ledge the use of the EPSRC Chemical Database Service at
Daresbury85 and the EPSRC National Mass Spectrometry
Service Centre at Swansea.
45 K. C. Woo and K. Jones, Tetrahedron Lett., 1991, 32, 6949.
46 P. Somfai, M. H. Hua and D. Tanner, Tetrahedron Lett., 1991, 32,
283.
References
1 M. G. Moloney, Nat. Prod. Rep., 1999, 16, 485.
2 M. D. Fletcher and M. M. Campbell, Chem. Rev., 1998, 98, 763.
3 A. Dutta, in Specialist Periodical Reports “Amino acids, Peptides and
Proteins”, ed. J. S. Davies, Royal Society of Chemistry, Cambridge,
1998.
4 S. Hanessian, G. McNaughton-Smith, H.-G. Lombart and W. D.
Lubell, Tetrahedron, 1997, 53, 12789.
5 J. Gante, Angew. Chem., Int. Ed. Engl., 1994, 33, 1699.
6 J. K. Thottathil, C. Przybyla, M. Malley and J. Z. Gougoutas,
Tetrahedron Lett., 1986, 27, 1533.
7 J. K. Thottathil, J. M. Moniot, R. H. Mueller, M. K. Y. Wong and
T. P. Kissick, J. Org. Chem., 1986, 51, 3140.
8 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,
3719.
9 J. E. Baldwin, M. G. Moloney and S. B. Shim, Tetrahedron Lett.,
1991, 32, 1379.
47 T. J. Hagen, Synlett, 1990, 63.
48 M. Yanagida, K. Hashimoto, M. Ishida, H. Shinozaki and H.
Shirahama, Tetrahedron Lett., 1989, 30, 3799.
49 H. Nagashima, N. Ozaki, M. Washiyama and K. Itoh, Tetrahedron
Lett., 1985, 26, 657.
50 S. Hanessian and S. Ninkovic, J. Org. Chem., 1996, 61, 5418.
51 S. Hanessian, S. Ninkovic and U. Reinhold, Tetrahedron Lett., 1996,
37, 8971.
52 H. Yoda, H. Kitayama, T. Katagiri and K. Takabe, Tetrahedron,
1992, 48, 3313.
53 A. I. Meyers and L. Snyder, J. Org. Chem., 1992, 57, 3814.
54 N. Langlois and R. Z. Andriamialisoa, Tetrahedron Lett., 1991, 32,
3057.
55 J. Dyer, S. Keeling and M. G. Moloney, Chem. Commun., 1998, 461.
56 J. Dyer, S. Keeling and M. G. Moloney, Tetrahedron Lett., 1996, 37,
4573.
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792
2791

View Article Online
69 H. P. Pagett, I. G. Csendes and H. Rapoport, J. Org. Chem., 1979,
57 J. Ezquerra, C. Pedregal, I. Collado, B. Yruretagoyena and A.
Rubio, Tetrahedron, 1995, 51, 10107.
44, 3492.
58 D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed.
Engl., 1996, 35, 2708.
59 F. Zanardi, L. Battistini, G. Rassu, M. Cornia and G. Casiraghi,
J. Chem. Soc., Perkin Trans. 1, 1995, 2471.
70 A. Garcia-Raso, J. Garcia-Roso, J. V. Sinisterra and R. Mestres,
J. Chem. Educ., 1986, 63, 443.
71 I. Baussanne, A. Chiaroni, H. P. Housson, C. Riche and J. Royer,
Tetrahedron Lett., 1994, 35, 3931.
60 F. Zanardi, L. Battistini, M. Nespi, G. Rassu, P. Spanu, M. Cornia
and G. Casiraghi, Tetrahedron: Asymmetry, 1996, 7, 1167.
61 R. Grote, A. Zeeck, J. Stumpfel and H. Zahner, Liebigs Ann. Chem.,
1990, 525.
62 A. H. Fray and A. I. Meyers, J. Org. Chem., 1996, 61, 3362.
63 A. H. Fray and A. I. Meyers, Tetrahedron Lett., 1992, 33, 3575.
64 C. A. Busacca and A. I. Meyers, J. Chem. Soc., Perkin Trans. 1,
1991, 2299.
72 P. Perlmutter, Conjugate Additions in Organic Synthesis, Pergamon,
Oxford, 1992.
73 Y. Kita, J. Segawa, J.-i. Haruta, H. Yasuda and Y. Tamura, J. Chem.
Soc., Perkin Trans. 1, 1982, 1099.
74 J. Leonard, E. Diez-Barra and S. Merino, Eur. J. Org. Chem., 1998,
2051.
75 J. Leonard, Contemp. Org. Synth., 1994, 1, 387.
76 M. W. Rathke and P. Weipert, in Comprehensive Organic Synthesis,
Pergamon, Oxford, 1991, vol. 2.
65 Y. N. Stefanovsky and L. Z. Viteva, Monatsh. Chem., 1981, 112, 125.
66 Y. N. Stefanovsky and L. Z. Viteva, Monatsh. Chem., 1980, 111,
1287.
77 J. Boersma, in Comprehensive Organometallic Chemistry, ed. G.
Wilkinson, Pergamon, Oxford, 1982, vol. 2.
67 Atomic coordinates have been deposited with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on
request, from Cambridge Crystallographic Data Centre, 12 Union
Rd, Cambridge, UK CB2 1EZ, CCDC reference number 207/446.
The structures were solved and refined with full matrix least squares
analysis using SHELXTL (G. M. Sheldrick, Nicolet Instrument
Corporation, SHELXTL PLUS V3.4, 1988). Crystal data and data
collection parameters for compound 4d: C24H25NO6; M = 423.47;
orthorhombic; space group P212121; µ(Cu-Kα) = 0.72 mmϪ1; R =
0.049; unit cell dimensions a = 8.143(6), b = 9.410(8), c = 28.78(2) Å;
V = 2205(5) Å3; temperature = 295 K; Z = 4; measured reflections
78 N. Goasdoue and M. Gaudemar, J. Organomet. Chem., 1972, 39, 17.
79 B.-H. Han and P. Boudjouk, J. Org. Chem., 1982, 47, 5030.
80 F. A. J. Kerdesky, R. J. Ardecky, M. V. Lakshmikantham and
M. P. Cava, J. Am. Chem. Soc., 1981, 103, 1992.
81 A. P. Krapcho, Synthesis, 1982, 805.
82 T. Sato, K. Matsubayashi, K. Yamamoto, H. Ishikawa, H. Ishibashi
and M. Ikeda, Heterocycles, 1995, 40, 261.
83 C. Tsai, J. A. Schnider and J. Lehmann, Neurosci. Lett., 1988, 92,
298.
84 J. Ezquerra, C. Pedregal, A. Rubio, B. Yruretagoyena, A. Escribano
and F. Sanchez-Ferrando, Tetrahedron, 1993, 49, 8665.
85 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746.
3218; Dc = 1.28 g cmϪ3
68 J. Skarzewski, Synthesis, 1990, 1125.
.
2792
J. Chem. Soc., Perkin Trans. 1, 2000, 2783–2792