Pyrrolidinones derived from (S)-pyroglutamic acid. Part 3. β-Aminopyrrolidinones

Article abstract of DOI:10.1039/b106782f

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to α, β-unsaturated bicyclic lactam 1a gave the corresponding β-amino products 9a-g in good yield and excellent diastereo- selectivity. These products can be manipulated to afford enantiopure β-aminopyrrolidinones of potential application as conformationally-constrained, substituted glutamate templates of well-defined stereochemistry.

Full text of DOI:10.1039/b106782f

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Pyrrolidinones derived from (S)-pyroglutamic acid. Part 3.
ꢀ-Aminopyrrolidinones
Philip W. H. Chan,a Ian F. Cottrellb and Mark G. Moloney*a
1
a The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, UK OX1 3QY. E-mail: mark.moloney@chem.ox.ac.uk
b Department of Process Research, Merck Sharp and Dohme Research Laboratories,
Hertford Rd, Hoddesdon, Herts., UK EN11 9BU
Received (in Cambridge, UK) 26th July 2001, Accepted 19th September 2001
First published as an Advance Article on the web 25th October 2001
The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to α,β-
unsaturated bicyclic lactam 1a gave the corresponding β-amino products 9a–g in good yield and excellent diastereo-
selectivity. These products can be manipulated to afford enantiopure β-aminopyrrolidinones of potential application
as conformationally-constrained, substituted glutamate templates of well-defined stereochemistry.
Much attention has focused on the use of asymmetric β-amino
Results and discussion
acids as α-amino acid surrogates,1 and more recently these
Conjugate addition reactions
compounds have found application in stereochemically well-
defined bicyclic templates as mechanism-based protease
inhibitors2 and artificial receptors.3 Such compounds can
now be accessed by a diversity of synthetic methodology.4–6
A particularly valuable approach to this class of compound is
by diastereocontrolled or enantiocontrolled conjugate addition
of nitrogen nucleophiles to an α,β-unsaturated system.7 We
have recently reported the application of the unsaturated
bicyclic lactam 1a derived from pyroglutamic acid for the syn-
thesis of highly functionalised pyrrolidinones8,9 as excitatory
amino acid analogues.10 A key step in this synthesis used a
conjugate addition of a zinc enolate, and the efficiency of
this process suggested that an obvious extension would be to
heteroatom nucleophiles. Although the conjugate addition of
amines,11–14 azides,15 amine equivalents,16–22 and more recently
chiral amines23,24 is relatively well known for acyclic systems25,26
and for unsaturated lactones,27 these reactions are less common
in pyrrolidinone substrates.28 However, Langlois and Calvez29
and we30,31 recently disclosed that conjugate addition of
nitrogen nucleophiles to unsaturated bicyclic lactams was
viable. A related bicyclic lactam, extensively investigated by
Meyers, has been shown to undergo conjugate addition with
a variety of carbon and heteroatom nucleophiles under
mild conditions,32,33 and the value of aminopyrrolidinones as
novel ligand systems is evident from some work of Rapoport
and Williams.34 We report here that the α,β-unsaturated lactam
1a is a useful template for conjugate additions of nitrogen
nucleophiles, giving the corresponding β-amino products
9a–g in good yield with high diastereocontrol, providing
a direct route to conformationally well-defined β-amino-γ-
lactams.
We found that the enone 1b was unreactive with benzylamine
and O-benzylhydroxylamine under the reported reaction con-
ditions for closely related substrates,35,36 although conditions
for the successful conduct of this transformation have been
recently reported.29,37,38 However, the activated lactam 1a was
found to be highly reactive with benzylamine in DCM con-
taining 2–10 equivalents of water as a proton source (Scheme 1),
Scheme 1
and the observed products were the dimer 239 (arising by the
direct condensation of 2 molecules of 1a) and adduct 3a
(arising by initial conjugate addition of benzylamine followed
by trapping of the resulting enolate with enone 1a), in yields of
60 and 30% respectively, both as single diastereomers but whose
relative stereochemistry could not be assigned due to over-
lapping signals in their 1H NMR spectra. For this reason also,
the structure of 3a could not be unequivocally confirmed,
and another possibility was adduct 4. That product 3a in fact
possessed the structure shown, and not the alternative 4, which
would have arisen by initial dimerisation of 1b to 2 followed by
conjugate addition of benzylamine and might have been
expected to possess a similar NMR spectrum to 3a, was shown
by treating dimer 2 with benzylamine; dimer 2 was recovered
DOI: 10.1039/b106782f
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006
This journal is © The Royal Society of Chemistry 2001
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almost quantitatively. Similar dimerisations have been reported
in the conjugate additions of thiols to unsaturated lactones40
and also in a related enone system.41 The acidity of the γ-
hydrogen of lactam 1a, crucial to this dimerisation process,
has been used to synthetic advantage in a related system.42
Alteration of the number of equivalents of water, the reaction
time, the solvent (DCM or THF), the proton source (by using
nitrophenol or dinitrophenol in place of water) or the amine (by
using aniline or sodium phthalimide in place of benzylamine)
did not prevent the formation of these dimeric products, nor
could simple conjugate addition be obtained. However, the fact
that the product 3a was obtained at all indicated that conjugate
addition was indeed possible, although clearly quenching of the
intermediate enolate formed in this process was problematic.
Fig. 1
surprisingly gave the enamine 7, albeit in low yield (18%); alter-
natively, treatment with TFA–CH2Cl2 gave the pyroglutaminol
8 directly in 40% yield. These reactions most likely proceed by
protonation of the tautomer 6b followed by elimination across
the C-6–C-7 bond with concomitant loss of nitrogen.
In keeping with the above results, the activated enone 1a
was found to give a very rapid reaction with a variety of other
α-nucleophiles,45 including substituted hydroxylamines and
hydrazines, to give the corresponding adducts 9a–g in almost
quantitative yield (Scheme 3 and Table 1); in all cases, one
Since the unfavourable basicity of benzylamine was clearly
the cause of the dimerisation process, examination of less
basic azide was made. However, sodium azide addition to 1a
in acetic acid–THF solvent in fact gave pyrazoline 5a as a single
diastereomer in excellent yield (80%) (Scheme 2); p-nitro-
Scheme 3
diastereomer was obtained predominantly, although up to four
diastereomers could be detected by 13C NMR spectroscopy for
9a, b, e and f. A significant improvement in the diastereo-
selectivity for 9g was obtained by using the more bulky nucleo-
phile, O-benzyl-N-benzylhydroxylamine, and in this case the
adduct was stable enough to permit chromatographic purifica-
tion. In the case of the phenylhydrazine adduct 9a, the regio-
selectivity of addition was established by careful 1H NMR
spectroscopic analysis in dry d6-DMSO, which did not indicate
the presence of an NH2 group, consistent with the addition of
the terminal amine function as expected.
Scheme 2
These reactions proved to be easily reproducible except in the
case of dimethylhydrazine, which gave variable amounts of the
expected product 9d along with some of the dimeric product 3b,
as indicated by spectroscopic analysis of the crude reaction
mixture. The stereochemistry of the major adducts 9a, c, f,
and g was shown to be (2R,5S,6S,7R) by a series of NOE
experiments (Table 1), corresponding to the expected exo- (less
hindered) approach of the amine nucleophile followed by exo-
protonation to give the C-6–C-7 trans-product; the major
adducts for 9b, d, and e are also expected to possess this stereo-
chemistry, but this could not be confirmed due to their in-
stability. Therefore, not only does the bicyclic ring system of 1
control the stereochemistry of the addition process, but it also
facilitates the assignment of stereochemistry by NOE analysis,
since the C(2)H C(4)Hendo C(6)Hendo and C(5)H C(7)Hexo
enhancement sequence is easily detected.
benzenesulfonyl azide and mesyl azide were unreactive under
these conditions. Although crystalline, no suitable X-ray
crystallographic data for compound 5a could be obtained and
regiochemical and stereochemical analysis was performed
indirectly. Thus, NOE difference spectroscopy indicated a cis-
arrangement of C(2)H, C(4)Hendo and C(6)H, confirming that
the cycloaddition occurred to the less hindered exo-face of
lactam 1a (Fig. 1). Further structural characterisation of com-
pound 5a (R = H) was achieved by conversion (Ac2O, Et3N,
Ϫ5 ЊC) to the N-acetyl derivative 5b in 67% yield, along with 6%
of its isomer 6a. The structure of 5b was confirmed by 1H
NMR long range coupling experiments [pulsed field gradient
HQMC (5 : 3 : 4)], which showed that the newly introduced
carbonyl function was only three bonds removed from the
C-7 ester carbonyl function. The conjugate addition of azides
to give similar adducts in related systems has been previously
reported.43,44 Treatment of pyrazoline 5a with acetic acid
The hydrazine derivatives 9a–d were found to be unstable to
silica and aqueous conditions, undergoing facile β-elimination,
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Table 1 Reaction of enone 1a with nitrogen nucleophiles, and NOE spectroscopic data for the major diastereomers of the products 9a, c, f and g
NOE Enhancement (%)
Nucleophile RH
Product
Yield (%)
Diastereomer ratioa
H-2–H-4endo
H-4endo–H-6
H-5–H-7
PhNHNH2
9a
9b
9c
9d
9e
9f
93
92
92
92d
93
96
99
12 : 1 : 1 : 1
12 : 2 : 2 : 1
10 : 1 : 1
3.2
—
2.2
—
—
1.8
1.9
8.8
—
3
—
—
26
Ίb
—
Ίb
—
—
2
NH2CONHNH2
PhCONHNH2
Me2NNH2
HONH2
PhCH2ONH2
PhCH2ONH2(CH2Ph)
c
—
16 : 7 : 4 : 1
20 : 2 : 2 : 1
9 : 1
9g
7.4
5
a Estimated from the 1H NMR spectrum. b NOE Enhancement not integrated although enhancement was detected. c Not determined. d Crude yield,
which contains some of the dimeric product 3b.
and the phenylhydrazine adduct 9a was also found to be prone
to aerial oxidation, and readily converted to the orange azo
derivative 9h (λmax = 273 nm) on standing over 18 hours. This
compound was sufficiently stable to allow chromatographic
purification, and stereochemical assignment was possible
using standard NOE techniques, confirming the earlier assign-
ment for the starting material (Scheme 3). Due to their evident
instability, deprotection of these compounds was not
attempted. Even though the hydroxylamine adducts 9e–g were
more robust, attempted N–O reductive cleavage nonetheless led
to decomposition.
Since the instability of some of these adducts was due to a
Fig. 2
facile β-elimination process under acidic conditions, alkylations
relationship of C(2)H, C(4)Hendo and C(6)H was evident from
at C-7 were examined in order to block the elimination reaction.
their respective mutual enhancements. Irradiation of the C(5)H
Good yields of the alkylated adducts 10 and 11 (Scheme 4)
signal was found to give a 1.5% enhancement of the newly
introduced benzylic methylene protons, indicating that alkyla-
tion proceeded from the exo-face of the bicyclic ring and the
absolute stereochemistry of the adduct was therefore (6S,7R).
The next major isomer (7S)-10Љ was also isolated in partially
purified form, and its stereochemistry at C-6 shown to be the
same as isomer 10Ј by NOE, implying that the C-7 stereo-
chemistry must be epimeric with 10Ј. The remaining minor
diastereomers of 10 must therefore be epimeric at C-6 relative
to 10Ј and 10Љ, i.e. of (6R) stereochemistry, but this mode of
conjugate addition is not favoured due to the sterically encum-
bered addition pathway. Separation of the methyl derivatives
10b was not possible, precluding stereochemical analysis.
The C(6)Hendo stereochemistry of 10 and 11 confirms the
preferred stereochemistry for the amine conjugate addition, but
there is clearly poor diastereoselectivity of the alkylation step at
C-7. Similar poor diastereoselectivity of alkylation reactions
has also been observed in related systems.8,9 This stereo-
chemical outcome appears to be due to competing steric
directing effects from both the C-6 amine substituent, which
favours endo-alkylation at C-7, and the inherent stereochemical
Scheme 4
bias of the bicyclic lactam system, which favours exo-alkylation
at C-7.46 However, it is possible that a further endo-directing
could be achieved by treating 9f (mixture of diastereomers)
with NaH and then benzyl bromide or methyl iodide (61 and
58% respectively) but with poorer diastereoselectivity than in
the simple conjugate additions (43 : 24 : 4 : 1 and 8 : 8 : 1 : 1
effect at C-7 is due to a favourable electronic interaction of
the enolate π-system with the nitrogen lone pair of the lactam
ring.47
respectively); in contrast to their precursor 9f, the products 10
and 11 were indeed stable to silica as expected. However, the
Deprotection reactions
adduct 9g was found to be unreactive to alkylation, probably
due to the steric bulk of the C-6 substituent. Using the same
alkylation conditions, the hydroxylamine adduct 9e gave
unsaturated bicyclic lactam 12 in low yield and as a single
diastereomer whose stereochemistry could not be assigned by
NOE analysis; we have previously observed similar products
which arise from an elimination–alkylation sequence under
the conditions of this reaction.8 Careful purification of the
diastereomeric mixture 10 allowed the isolation of the major
diastereomer (7R)-10Ј as a gum whose stereochemistry was
assigned by a series of NOE experiments (Fig. 2); the cis-
Having demonstrated that adducts 9 were readily available, in
some cases with high stereochemical control, it was of interest
to examine their suitability for further elaboration. O-Benzyl
deprotection of partially purified 10 (10Ј–10Љ = 93 : 7) was not
possible with Zn–HOAc or Zn–HCl, from which unreacted
starting material was recovered, but deprotection could be
readily achieved under catalytic hydrogenation conditions with
ethanol solvent to give the product 13 as an inseparable
diastereomeric mixture (Scheme 4) in good yield (53%) in a
ratio of 14 : 1; that N–O bond cleavage occurred was evident
from the molecular ion signal in the mass spectrum at 381 Da.
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006
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established that alcohol 16b was enantiopure, at least within
the detection limits of NMR spectroscopy, a significant result
since this demonstrated that substrate 1a is not epimerised at
C-5 under the basic reaction conditions required for the con-
jugate addition (Scheme 3). This confirms earlier results which
indicate that enone 1a is stereochemically robust: thus, Diels–
Alder39 and conjugate addition reactions using Reformatsky
reagents8 have previously been shown to proceed without loss
of stereochemistry at C-5. This is despite the acidity of this
position, as evidenced by the facile dimerisation described
above (Scheme 1). The design of the bicyclic lactam system,
which exploits the elegant work of Seebach as espoused in his
Principles of Self-Regeneration of Stereocentres,52 ensures that,
even if deprotonation at C-5 had occurred, the original stereo-
chemistry would be returned upon reprotonation; in this sense,
the bicyclic system acts as a stereochemical “protecting group”.
Fig. 3
Alternatively, ester hydrolysis was examined; although
standard alkaline hydrolysis conditions returned unreacted
starting material, the use of bis(tributyltin) oxide in refluxing
toluene48 gave concomitant hydrolysis and decarboxylation of
9f and g affording the lactams 14a and 15a (as an inseparable
6.5 : 1 mixture) and 14b (single diastereomer only) in yields of
62 and 70% respectively (Scheme 5). This method however did
not yield the corresponding product from the semicarbazide
adduct 9b, instead giving only decomposition. Confirmation of
the stereochemistry again came from an NOE analysis similar
to that discussed above (Fig. 3).
1H NMR spectroscopy
In earlier studies, it has been noted that consistent patterns
in the NMR spectra of variously substituted bicyclic lactams
are observed, and these patterns have been maintained in the
compounds prepared in the present work.8,9 Unsurprisingly,
the C(2)H resonance is similar but non-identical across all
diastereomers, and serves as a useful marker for diastereomeric
purity. The signal arising from C(4)Hendo was found to be con-
sistently more upfield typically by 0.2–0.5 ppm from its geminal
partner, C(4)Hexo (Table 2). Furthermore, C(4)Hendo usually
appeared as a triplet or poorly resolved doublet of doublets
with a coupling constant of about 8 Hz (this has also been
observed in alkyl substituted systems8,9) and C(4)Hexo appeared
as a multiplet or doublet of doublets. The signal due to C(7)H
appeared at 3.78–4.50 ppm and as a doublet (J = 9–10 Hz).
Hydrogenolysis of 14b using HOAc (4 bar, 2 days)49 as
solvent gave the N-benzyl lactam 16a in diastereomerically
pure form, in 44% yield after ion exchange (Dowex 50W-X8);
the use of ethanol as solvent gave no reaction. Similarly, the
benzyloxyamino mixture 14a–15a under the same conditions
gave the acetate salt of compound 16a in excellent yield (97%),
although as a mixture of diastereomers.
Initial acidic deprotection of 14b gave trans-alcohol 16b in
81% yield, and subsequent hydrogenolysis followed by ion-
exchange gave the trans-aminolactam 16c in 75% yield. Except
for intermediate 16b, for which dynamic effects in the NMR
spectrum precluded NOE analysis, stereochemistry was again
Conclusion
We have shown that although conjugate addition of simple
amines to an α,β-unsaturated pyrrolidinone is problematic, the
addition of activated nitrogen nucleophiles gives excellent
yields of the expected adducts with high diastereoselectivity.
These can be selectively deprotected under standard conditions
to give good yields of enantiopure β-aminopyrrolidinones,
further demonstrating the synthetic value of bicyclic lactam
systems derived from pyroglutamic acid.
1
confirmed by NOE (Fig. 3). Noteworthy was that in the H
NMR spectrum, the resonance of C(4)H (pro-R) was found to
appear at a higher field than its geminal C(4)H (pro-S) signal
for both compounds 16a and 16b; this was presumably due to
the adjacent amino substituent.
The enantiopurity of alcohol 16b was established by con-
version to the corresponding α-methoxy-α-(trifluoromethyl)-
phenylacetic acid (MTPA) derivatives with (Ϫ)- and ( )-MTPA
chloride and pyridine in DCM at room temperature (yields
91 and 85% respectively).50,51 The 19F NMR spectrum of the
former compound gave only one resonance as expected at
Ϫ71.87 ppm whilst two peaks were observed at Ϫ71.87 and
Ϫ71.89 ppm in the spectrum of the latter compound. This
Experimental
For general experimental procedures and the preparation of
lactams 1a and b, see our earlier reports.39,46
Scheme 5
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Table 2 1H NMR data for the products 5 and 9a–h
Compound
δH-2
δH-4endo
δH-4exo
δH-7
5
6.35
6.35
6.30
6.42
6.31
6.44
6.49
6.47
3.80 (t, J 9.2)
4.51 (dd, J 8.1, 6.4)
4.23 (dd, J 8.6, 6.5)
4.01 (dd, J 10.0, 6.3)
3.93–4.05 (m)
—
9a
9b
9c
9e
9f
9g
9h
3.86 (dd, J 8.6, 6.5)
3.80 (dd, J 8.7, 6.5)
3.61 (dd, J 8.5, 6.6)
3.75 (t, J 8.2)
3.46–3.49 (m)
3.39 (t, J 8.0)
3.93 (d, J 10.3)
3.87 (d, J 9.9)
3.93–4.05 (m)
4.03 (d, J 7.8)
3.78 (d, J 9.6)
4.29–4.39 (m)
4.48 (d, J 9.0)
4.05–4.25 (m)
3.87 (dd, J 12.1, 6.0)
3.84 (br t, J 7.2)
4.41–4.47 (m)
4.02–4.07 (m)
General method A: conjugate addition
solved in THF (7.5 ml) was then added slowly dropwise and the
reaction mixture was allowed to stir for 30 min. Water (15 ml)
was added and the solution was extracted with DCM (3 ×
15 ml). The combined organic layers were then washed with
saturated sodium bicarbonate (2 × 15 ml), dried over MgSO4,
filtered and concentrated in vacuo to give a bright yellow gum
which was then purified by recrystallisation (1 : 1 petrol–
EtOAc) to give the product 5a as a white solid (111 mg, 80%);
Rf 0.28 (1 : 1 petrol–EtOAc); [α]2D5 ϩ74.1 (c 1.3, CHCl3); mp
130.0–132.5 ЊC; found C 57.03; H 4.58; N 18.15; calculated C
56.96; H 5.10; N 17.71%; νmax(film)/cmϪ1 3304 (m), 2983 (w),
1718 (s), 1454 (w); δH (500 MHz, CDCl3) 1.34 (3H, t, J 7.1,
CH3), 3.80 (1H, t, J 9.2, C(4)Hendo), 4.12 (1H, ddd, J 8.8, 6.4 and
2.0, C(5)H), 4.33 (2H, q, J 7.1, CH3CH2), 4.51 (1H, dd, J 8.1
and 6.4, C(4)Hexo), 5.35 (1H, d, J 2.1, C(6)H), 6.35 (1H, s,
C(6)H), 7.33–7.44 (5H, m, ArCH), 9.02 (1H, s, NH); δC (125.8
MHz, CDCl3) 13.94 (CH3), 61.85 (C-5), 63.53 (CH3CH2), 69.28
(C-4), 72.73 (C-10), 83.47 (C-6), 87.89 (C-6), 125.79, 128.58
and 129.03 (ArCH), 137.35 (ArC), 166.94 and 171.34 (2 × CO)
(NMR assignments follow the numbering shown in Fig. 1);
m/z (electrospray) 317 (M ϩ Hϩ, 100%), 289 (35), 275 (15).
To a stirred solution of the nitrogen nucleophile in DCM,
MeOH or THF containing 1–10 equivalents of water, was
added slowly dropwise enone 1a or b dissolved in the same
solvent and the solution allowed to stir for 1–20 h at RT. Brine
(20 ml) was added to the reaction mixture and extracted with
EtOAc (3 × 20 ml). The combined organic layers were then
washed with water (2 × 20 ml), dried over MgSO4 and filtered.
Concentration in vacuo gave the title compound as a mixture of
diastereomers. The reactions using hydrazine nucleophiles were
not subjected to aqueous work-up.
Dimer 246
Reaction of enone 1a (0.8 mmol) with benzylamine (2 equiv.) in
DCM (2.5 ml) and water (2 equiv.) for 45 min according to
general method A gave dimer 2 as a bright yellow gum; Rf 0.26
(2 : 1 petrol–EtOAc); δH (500 MHz, CDCl3) 1.24 (3H, t, J 7.2,
CH3), 1.39 (3H, t, J 7.2, CH3), 3.24 (1H, dd, J 8.5 and 5.3,
C(6)H), 3.42 (3H, d, J 8.4, C(7)H), 3.62–3.69 (2H, m, C(4)H
and C(12)H), 3.73–3.77 (1H, m, C(5)H), 4.05–4.14 (3H, m,
CH2CH3 and C(4)H), 4.24 (1H, d, J 8.9, C(12)H), 4.33–4.39
(2H, m, CH2CH3), 6.17 and 6.26 (2H, 2 × s, C(2)H and
C(10)H), 7.30–7.41 (8H, m, ArCH), 7.51–7.53 (2H, m, ArCH),
7.80 (1H, s, C(14)H); m/z (APCIϩ) 547 (M ϩ Hϩ, 100%).
(1R,3aS,3bR,6aS)-6-Acetyl-7-oxo-1-phenyl-2,3,3a,3b,6,6a,7,7a-
octahydro-1H-2-oxa-4,5,6,7a-tetraazacyclopenta[a]pentalene-
6a-carboxylic acid ethyl ester 5b and (1R,3aS,3bR,6aS)-4-
acetyl-7-oxo-1-phenyl-2,3,3a,3b,4,6a,7,7a-octahydro-1H-2-oxa-
4,5,6,7a-tetraazacyclopenta[a]pentalene-6a-carboxylic acid
ethyl ester 6a
Adduct 3a
Reaction of enone 1a (0.8 mmol) with benzylamine (1 equiv.)
in DCM (2.5 ml) and water (1 mmol) for 45 min according to
general method A gave dimer 3a as a bright yellow gum and as
a mixture of diastereomers in a ratio of 7 : 2 : 1; Rf 0.11 (2 : 1
petrol–EtOAc); νmax(film)/cmϪ1 3310 (w), 2982 (m), 1740 (s),
1708 (s); δH (500 MHz, CDCl3) 1.17 and 1.34 (6H, m, 2 × CH3),
3.38–4.71 (15H, m, 2 × CH2CH3, NHCH2Ph, 2 × C(4)H, 2 ×
C(12)H, C(5)H, C(13)H, C(6)H, C(14)H, C(7)H), 6.24 and
6.37, 6.28 and 6.42, 6.30 and 6.35 (2H, 2 × s, C(2)H and C(10)H
for each diastereomer), 7.21–7.51 (15H, m, ArCH); δC (125.8
MHz, CDCl3) 13.75, 13.85 and 14.01 (2 × CH3), 40.64 and
44.66 (C-15), 52.27, 52.42 and 52.77 (NHCH2Ph), 54.58, 54.68,
55.02, 57.44, 59.41, 59.84, 60.99, 65.55, 65.68 (C-5, C-13, C-6,
and C-14), 62.02, 62.47 and 62.59 (2 × CH3CH2), 70.29, 72.40
and 73.43 (C-4 and C-12), 87.18, 87.29, 87.55 and 88.45 (C-2
and C-10), 125.63, 125.85, 126.10, 127.49, 127.82, 127.91,
128.05, 128.38, 128.53, 128.60, 128.78 and 128.96 (ArCH),
136.77, 138.31 and 138.39 (ArC), 168.33, 169.82, 170.98,
171.17, 171.42 and 174.28 (4 × CO); m/z (APCIϩ) 654 (M ϩ
Hϩ, 100%); HRMS 653.2736, C37H39N3O8 (Mϩ) requires
653.2737.
Triethylamine (106 mg, 1.05 mmol) was added to a solution of
the triazoline 5a (166 mg, 0.53 mmol) dissolved in CHCl3 (5 ml)
whilst stirring at Ϫ5 ЊC. Acetic anhydride (54 mg, 0.53 mmol)
was then added and the reaction mixture was allowed to stir for
4 h. Citric acid (10% in water, 25 ml) was added and the organic
layer was partitioned, dried over MgSO4, filtered and evacuated
in vacuo. Purification of the crude product was carried out
using flash column chromatography (2 : 1 petrol–EtOAc as
eluent). Evaporation in vacuo gave the product as a pale white
gum (138 mg, 73%) in a ratio of 5b–6a = 11 : 1; Rf 0.25 (2 : 1
petrol–EtOAc); νmax(film)/cmϪ1 2985 (w), 1762 (s), 1726 (s),
1707 (s); m/z (electrospray) 359 (M ϩ Hϩ, 55%), 331 (100).
Data for 5b: δH (200 MHz, CDCl3) 1.42 (3H, t, J 7.2,
CH3CH2), 2.58 (3H, s, COCH3), 3.69–3.81 (1H, m, C(4)Hendo),
3.97 (1H, dd, J 9.6 and 6.3, C(5)H), 4.31–4.58 (3H, m, C(4)Hexo
and CH3CH2), 4.90 (1H, s, C(6)H), 6.37 (1H, s, C(6)H), 7.30–
7.48 (5H, m, ArCH); δC (50.3 MHz, CDCl3) 13.88 (CH3), 22.11
(CH3), 54.43 (C-5), 63.25 (C-6), 63.93 (CH3CH2), 68.47 (C-4),
88.42 (C-6), 98.62 (C-10), 125.96, 126.20, 128.79 and 129.31
(ArCH), 137.19 (ArC), 164.39, 167.50 and 168.96 (3 × CO)
(NMR assignments follow the numbering for 5a shown in
Fig. 1); data for 6a: δH (200 MHz, CDCl3) 1.42 (3H, t, J 7.2,
CH3CH2), 2.63 (3H, s, COCH3), 3.29 (1H, t, J 8.9, C(4)H), 4.15
(1H, q, J 7.1, C(5)H), 4.31–4.58 (3H, m, C(4)H and CH3CH2),
4.86 (1H, s, C(6)H), 6.33 (1H, s, C(6)H), 7.30–7.48 (5H, m,
ArCH); δC (50.3 MHz, CDCl3) 13.88 (CH3), 22.11 (CH3), 53.03
(C-5), 60.64 (C-6), 64.17 (CH3CH2), 67.33 (C-4), 87.44 (C-6),
98.62 (C-10), 125.96, 126.20, 128.79 and 129.31 (ArCH), 137.59
(؉)-(1R,3aS,3bR,6aS)-7-Oxo-1-phenyl-2,3,3a,3b,6,6a,7,7a-
octahydro-1H-2-oxa-4,5,6,7a-tetraazacyclopenta[a]pentalene-
6a-carboxylic acid ethyl ester 5a
Glacial acetic acid (26 mg, 0.44 mmol) was added to a solution
of sodium azide (57 mg, 0.88 mmol) dissolved in water (2.5 ml)
whilst stirring at RT. The enone 1a (120 mg, 0.44 mmol) dis-
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006
3001

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(ArC), 164.39, 167.50 and 168.96 (3 × CO) (NMR assignments
follow the numbering for 5a shown in Fig. 1).
(m); δH (500 MHz, CDCl3) 1.30 (3H, t, J 7.1, CH3CH2), 3.80
(1H, dd, J 8.7 and 6.6, C(4)Hendo), 3.87 (1H, d, J 9.9, C(7)H),
3.95 (1H, dd, J 12.1 and 6.4, C(5)H), 4.01 (1H, dd, J 10.0 and
6.3, C(4)Hexo), 4.18–4.31 (3H, m, CH3CH2 and C(6)H), 4.62
(1H, br s, NHNHCO), 5.81 (2H, br s, NH2), 6.30 (1H, s,
C(2)H), 7.30–7.48 (5H, m, ArCH), 7.73 (1H, br s, NHNHCO);
δC (125.8 MHz, CDCl3) 14.09 (CH3), 55.64 (C-7), 60.89 (C-5),
62.23 (CH3CH2), 64.21 (C-6), 70.30 (C-4), 87.27 (C-2), 126.04,
126.88, 128.53 and 128.68 (ArCH), 137.11 and 137.56 (2 ×
ArC), 161.72, 167.96, 169.66 and 175.47 (4 × CO); m/z (electro-
spray) 349 (M ϩ Hϩ, 100%).
7-Ethoxycarbonyl-8-oxo-2-phenyl-6-amino-3-oxa-1-azabicyclo-
[3.3.0]oct-6-ene 7
Triazoline 5a (100 mg, 0.35 mmol) was treated with glacial
acetic acid (1 equiv.) in dichloromethane, the solvent removed
and the product isolated by chromatography (3 : 1 light
petroleum–ethyl acetate) to give the product 7 as a yellow oil
(16 mg, 18%); Rf 0.24; νmax(film)/cmϪ1 3583 (w), 3332 (m), 1730
(s), 1692 (s), 1647 (s); δH (500 MHz, CDCl3) 1.33 (3H, t, J 7.2,
CH3CH2), 3.36 (1H, t, J 8.9, C(4)Hendo), 4.26 (2H, q, J 7.1,
CH3CH2), 4.45 (1H, dd, J 6.0 and 8.1, C(5)H), 4.71 (1H, dd,
J 6.2 and 8.8, C(4)Hexo), 5.68 (2H, br s, NH2), 6.17 (1H, s,
C(2)H), 7.30–7.49 (3H, m, ArCH), 7.50–7.60 (2H, m, ArCH);
δC (125.8 MHz, CDCl3) 14.44 (CH3), 59.86 (C-5), 60.20
(CH3CH2), 70.82 (C-4), 86.95 (C-2), 103.5 (C-6), 126.19, 128.52
and 128.86 (ArCH), 138.16 (ArC), 146.68, 164.99 and 169.80
(2 × CO); m/z (electrospray) 289 (M ϩ Hϩ, 100%); HRMS
289.1188, C15H17N2O4 (M ϩ Hϩ) requires 289.1188.
6-[2-Benzoylhydrazino]-7-ethoxycarbonyl-8-oxo-2-phenyl-3-
oxa-1-azabicyclo[3.3.0]octane 9c
Using general method A, benzoylhydrazine (59 mg, 0.44 mmol)
was reacted with enone 1a (119 mg, 0.44 mmol) in MeOH
(5 ml) to give the product 9c as a yellow gum (165 mg, 92%) and
as an inseparable diastereomeric mixture in a ratio of 10 : 1 : 1.
Data for the major isomer (2R,5S,6S,7R): νmax(film)/cmϪ1
3280 (m), 3064 (w), 1736 (s), 1709 (s), 1654 (s); δH (500 MHz,
C6D6) 0.92 (3H, t, J 7.1, CH3CH2), 3.61 (1H, dd, J 8.5 and
6.6, C(4)Hendo), 3.85 (1H, q, J 6.5, C(5)H), 3.93–4.05 (4H, m,
C(4)Hexo, C(7)H and CH3CH2), 4.33 (1H, dd, J 10.2 and
6.6, C(6)H), 6.42 (1H, s, C(2)H), 7.01–7.15 (5H, m, ArCH),
7.44–7.46 (2H, m, ArCH), 7.71–7.76 (3H, m, ArCH), 8.45 (1H,
br s, NH); δC (125.8 MHz, C6D6) 14.01 (CH3), 57.46 (C-7),
61.54 (C-5), 61.90 (CH3CH2), 65.75 (C-6), 70.46 (C-4), 87.61
(C-2), 126.52, 127.40, 127.54, 127.81, 128.01, 128.20, 128.62,
131.65 and 132.01 (ArCH), 132.58, 133.07 and 138.68 (3 ×
ArC), 168.91 and 170.62 (2 × CO); m/z (electrospray) 448
(M ϩ Kϩ, 10%), 432 (M ϩ Naϩ, 20), 427 (M ϩ NH4ϩ, 45), 410
(M ϩ Hϩ, 100).
4-Amino-5-hydroxymethyl-2-oxo-2,5-dihydro-1H-pyrrole-3-
carboxylic acid ethyl ester 8
To a solution of triazoline 5a (160 mg, 0.051 mmol) in dichloro-
methane was added trifluoroacetic acid, and the mixture stirred
for 15 min. The solvent was removed, and the product 8 isolated
by chromatography (EtOAc then 10 : 1 EtOAc–MeOH) as a
yellow gum (40 mg, 40%); Rf 0.19 (EtOAc); νmax(film)/cmϪ1 3333
(s), 1702 (s), 1689 (s), 1657 (s), 1652(s); δH (500 MHz, CDCl3)
1.30 (3H, t, J 7.1, CH3CH2), 3.50 (1H, dd, J 10.5 and 6.8,
CHOH), 4.01 (1H, br s, OH), 4.08 (1H, br d, J 9.9, C(2)H),
4.16–4.29 (2H, m, CH3CH2), 4.31 (1H, br s, CHOH), 5.99
(2H, br s, NH2), 8.23 (1H, br s, NH); δC (125.8 MHz, CDCl3)
14.32 (CH3), 57.41 (C-2), 60.15 (CH3CH2), 63.56 (CH2OH),
100.9 (C-4), 147.13 (C-3), 165.28 and 168.23 (2 × CO);
m/z (electrospray) 201 (M ϩ Hϩ, 100%); HRMS 201.0875,
C8H12N2O4 (M ϩ Hϩ) requires 201.0879.
7-Ethoxycarbonyl-6-hydroxyamino-8-oxo-2-phenyl-3-oxa-1-
azabicyclo[3.3.0]octane 9e
Using general method A, hydroxylamine hydrochloride (27 mg,
0.39 mmol) was reacted with sodium acetate (32 mg, 0.39 mmol)
and the enone 1a (107 mg, 0.39 mmol) in MeOH (5 ml) for 1 h
to give the product 9e as a yellow gum (112 mg, 93%) in an
inseparable diastereomeric mixture in a ratio of 16 : 7 : 4 : 1.
Data for the major isomer (2R,5S,6S,7R): νmax(film)/cmϪ1 3374
(br s), 1737 (s), 1715 (s); δH (300 MHz, CDCl3) 1.34 (3H, t,
J 7.1, CH3CH2), 3.75 (1H, t, J 8.2, C(4)H), 3.80–3.91 (1H, m,
C(5)H), 4.03 (1H, d, J 7.8, C(7)H), 4.05–4.25 (1H, m, C(4)H),
4.26–4.42 (4H, m, CH2CH3 and C(6)H), 5.73 (1H, br s, NH),
6.31 (1H, s, C(2)H), 7.31–7.60 (5H, m, ArCH); δC (50.3 MHz,
CDCl3) 14.06 (CH3), 54.90 (C(7)H), 60.40 (C(5)H), 62.43
(CH3CH2), 66.81 (C-6), 70.46 (C-4), 87.34 (C-2), 125.93, 128.53
and 128.92 (ArCH), 137.72 (ArC), 168.31 and 170.42 (2 × CO);
m/z (electrospray) 307 (M ϩ Hϩ, 35%), 274 (100).
7-Ethoxycarbonyl-8-oxo-2-phenyl-6-(2-phenylhydrazino)-3-oxa-
1-azabicyclo[3.3.0]octane 9a
Using general method A, phenylhydrazine (36 mg, 0.33 mmol)
was reacted with the enone 1a (90 mg, 0.33 mmol) in MeOH
(10 ml) for 1 h to give the title compound 9a as a bright yellow
gum (116 mg, 93%) in a diastereomeric ratio of 12 : 1 : 1 : 1.
Data for the major isomer (2R,5S,6S,7R): Rf 0.45 (1 : 1
petrol–EtOAc); νmax(film)/cmϪ1 3312 (w), 2982 (w), 1740 (s),
1708 (s), 1603 (m), 1496 (m); δH (500 MHz, CDCl3) 1.34 (3H, t,
J 7.1, CH3CH2), 3.86 (1H, dd, J 8.6 and 6.5, C(4)Hendo), 3.93
(1H, d, J 10.3, C(7)H), 4.01 (1H, q, J 6.5, C(5)H), 4.16 (1H, dd,
J 10.3 and 6.5, C(6)H), 4.23 (1H, dd, J 8.6 and 6.5, C(4)Hexo),
4.25–4.36 (2H, m, CH3CH2), 5.31 (1H, br s, NH), 6.35 (1H, s,
C(2)H), 6.82–6.91 (3H, m, ArCH), 7.20–7.45 (7H, m, ArCH);
δC (125.8 MHz, CDCl3) 14.13 (CH3), 55.78 (C-7), 61.50 (C-5),
62.05 (CH3CH2), 64.73 (C-6), 70.58 (C-4), 87.10 (C-2), 112.16,
112.72, 112.93, 119.48, 120.17, 126.00, 128.46, 128.74 and
129.24 (ArCH), 137.67 and 148.69 (2 × ArC), 168.10 and
169.64 (2 × CO); m/z 382 (M ϩ Hϩ, 60%), 380 (100).
7-Ethoxycarbonyl-6-benzyloxyamino-8-oxo-2-phenyl-3-oxa-1-
azabicyclo[3.3.0]octane 9f
Using general method A, O-benzylhydroxylamine hydro-
chloride (86 mg, 0.54 mmol) was reacted with sodium acetate
(44 mg, 0.54 mmol) and enone 1a (134 mg, 0.49 mmol) in
MeOH (5 ml). Concentration in vacuo gave the product 9f as a
yellow gum (187 mg, 96%) as an inseparable diastereomeric
mixture in a ratio of 20 : 2 : 2 : 1.
Data for the major isomer (2R,5S,6S,7R): Rf 0.55 (1 : 1
petrol–EtOAc); found C 66.14; H 6.02; N 7.25; calculated C
66.65; H 6.10; N 7.07%; νmax(film)/cmϪ1 3240 (w), 1745 (s), 1712
(s); δH (500 MHz, C6D6) 1.06 (3H, t, J 7.1, CH3), 3.46–3.49 (1H,
m, C(4)Hendo), 3.51–3.55 (1H, m, C(5)H), 3.78 (1H, d, J 9.6,
C(7)H), 3.87 (1H, dd, J 12.1 and 6.0, C(4)Hexo), 4.02–4.08 (1H,
m, CH3CHH), 4.11–4.18 (2H, m, CH3CHH and C(6)H), 4.51
(2H, s, NHOCH2), 5.30 (1H, br s, NH), 6.44 (1H, s, C(2)H),
7.07–7.40 (7H, m, ArCH), 7.48–7.58 (2H, m, ArCH); δC (125.8
6-[2-(Aminocarbonyl)hydrazino]-7-ethoxycarbonyl-8-oxo-2-
methyl-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 9b
Using general method A, semicarbazide hydrochloride (33 mg,
0.30 mmol) was reacted with sodium acetate (24 mg, 0.30 mmol)
and the enone 1a (74 mg, 0.27 mmol) in MeOH (5 ml) for 1 h
to give the product 9b as a bright yellow gum (189 mg, 92%)
and as an inseparable diastereomeric mixture in a ratio of
12 : 2 : 1 : 1.
Data for the major isomer (2R,5S,6S,7R): νmax(film)/cmϪ1
3589 (m), 3464 (m), 2983 (w), 1735 (s), 1707 (s), 1690 (s), 1579
3002
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006

View Article Online
MHz, CDCl3) 13.97 (CH3), 54.52 (C-7), 60.55 (C-5), 61.80
(CH3CH2), 64.14 (C-6), 70.27 (C-4), 76.55 (OCH2), 86.96 (C-2),
125.40, 128.08, 128.31, 128.52 and 128.59 (ArCH), 136.77 and
137.61 (2 × ArC), 167.73 and 169.90 (2 × CO); m/z (electro-
spray) 397 (M ϩ Hϩ,75%), 122 (100).
7-Benzyl-6-benzyloxyamino-7-ethoxycarbonyl-8-oxo-2-phenyl-3-
oxa-1-azabicyclo[3.3.0]octane 10
Using general method B, the adduct 9f (289 mg, 0.7 mmol)
was reacted with pre-washed sodium hydride (58 mg, 60%,
14.6 mmol) and benzyl bromide (174 µl, 14.6 mmol) in THF
(10 ml) and refluxed for 18 h. Purification by flash column
chromatography (5 : 1, 4 : 1 and then 1 : 1 petrol–EtOAc as
eluent) gave three diastereomers of the title compound 10 (217
mg, 61% overall yield), from which only the (2R,5S,6S,7S)
isomer 10Ј could be obtained in pure form.
Data for (ϩ)-(2R,5S,6S,7R)-isomer 10Ј: concentration in
vacuo of one of the fractions gave the product as a bright yellow
gum (46 mg, 13%); Rf 0.46 (2 : 1 petrol–EtOAc); [α]2D5 ϩ120.3
(c 1.2, CHCl3); νmax(film)/cmϪ1 3205 (w), 1744 (s), 1442 (m),
1028 (m); δH (500 MHz, CDCl3) 1.29 (3H, t, J 7.1, CH3CH2),
3.09 (1H, t, J 7.8, C(4)Hendo), 3.22 (1H, d, J 14.1, CHHPh), 3.60
(1H, dd, J 9.2 and 6.6, C(6)H), 3.61 (1H, d, J 14.0, CHHPh),
3.98 (1H, dd, J 13.5 and 6.7, C(5)H), 4.08 (1H, dd, J 8.3 and
6.5, C(4)Hexo), 4.23–4.29 (2H, m, CH3CH2), 4.62 (1H, d, J 11.6,
OCHHPh), 4.65 (1H, d, J 11.6, OCHHPh), 6.08 (1H, d, J 9.3,
NH), 6.20 (1H, s, C(2)H), 7.27–7.43 (15H, m, ArCH); δC (128.5
MHz, CDCl3) 13.94 (CH3), 36.68 (CH2Ph), 61.81 (C-5), 62.10
(CH3CH2), 64.57 (C-6), 70.87 (C-4), 76.34 (OCH2Ph), 86.42
(C-2), 125.99, 127.14, 128.11, 128.42, 128.50, 128.55, 128.70
and 130.82 (ArCH), 136.06, 137.09 and 137.77 (3 × ArC),
168.90 and 170.74 (2 × CO); m/z (APCIϩ) 487 (M ϩ Hϩ, 100%);
HRMS 487.2238, C29H31N2O5 (M ϩ Hϩ) requires 487.2233.
6-O,N-Dibenzylhydroxyamino-7-ethoxycarbonyl-8-oxo-2-phenyl-
3-oxa-1-azabicyclo[3.3.0]octane 9g
Using general method A, N-benzyl-O-benzylhydroxylamine53
(154 mg, 0.72 mmol) dissolved in MeOH (10 ml) reacted with
the enone 1a (197 mg, 0.72 mmol) in MeOH (5 ml). Concen-
tration in vacuo of the mixture gave the product 9g as a yellow
gum (348 mg, 99%) in a diastereomeric ratio of 9 : 1.
Found C 71.42; H 6.08; N 6.06; calculated C 71.59; H 6.21;
N 5.76%; νmax(film)/cmϪ1 3064 (w), 3032 (w), 2981 (w), 2876 (w),
1742 (s), 1715 (s); m/z (APCIϩ) 487 (M ϩ Hϩ, 100%).
Data for the major isomer (2R,5S,6S,7R): δH (500 MHz,
C6D6) 1.05 (3H, t, J 7.1, CH3CH2), 3.39 (1H, t, J 8.0, C(4)Hendo),
3.64 (1H, d, J 12.9, NCHHPh), 3.70 (1H, d, J 12.9, NCHHPh),
3.84 (1H, br t, J 7.2, C(4)Hexo), 3.98 (1H, br s, C(5)H), 4.02–4.08
(1H, m, CH3CHH), 4.14–4.21 (2H, m, CH3CHH and C(6)H),
4.29–4.39 (3H, m, C(7)H and NOCH2Ph), 6.49 (1H, s, C(2)H),
7.04–7.58 (15H, m, ArCH); δC (50.3 MHz, CDCl3) 14.19 (CH3),
55.28 (C-7), 59.62 (C-5), 61.40 (CH3CH2), 61.86 (C-4), 69.95
(C-6), 70.99 (NCH2Ph), 76.95 (OCH2Ph), 87.61 (C-2), 126.59,
128.40, 128.83, 129.32, 130.13, and 130.71 (ArCH), 136.85 and
139.15 (3 × ArC), 169.02 and 170.65 (2 × CO).
Data for the minor isomer (2R,5S,6S,7S): δH (500 MHz,
C6D6) 1.05 (3H, t, J 7.1, CH3CH2), 3.09 (1H, t, J 8.0, C(4)H),
3.64 (1H, d, J 12.9, NCHHPh), 3.70 (1H, d, J 12.9, NCHHPh),
3.76 (1H, br t, J 7.2, C(4)H), 3.98 (1H, br s, C(5)H), 4.02–4.08
(1H, m, CH3CHH), 4.14–4.21 (2H, m, CH3CHH and C(6)H),
4.29–4.39 (1H, m, C(7)H), 4.50–4.55 (2H, m, NOCH2Ph), 6.61
(1H, s, C(2)H), 7.04–7.58 (15H, m, ArCH).
7-Ethoxycarbonyl-6-benzyloxyamino-7-methyl-8-oxo-2-phenyl-
3-oxa-1-azabicyclo[3.3.0]octane 11
Using general method B, the adduct 9f (120 mg, 0.30 mmol)
was reacted with pre-washed sodium hydride (24 mg, 60%,
0.61 mmol) and methyl iodide (38 µl, 0.61 mmol) in THF
(10 ml) at reflux for 1 h. Purification by flash column chroma-
tography (3 : 1 and then 1 : 1 petrol–EtOAc as eluent) gave
the product 11 (72 mg, 58%), as an inseparable mixture of
diastereomers in a ratio of 10 : 10 : 1 : 1; Rf 0.5 (1 : 1 petrol–
EtOAc); νmax(film)/cmϪ1 3068 (w), 2990 (w), 2952 (m), 2852 (w),
1790 (s), 1496 (m), 1451 (s); δH (500 MHz, CDCl3) 1.27, 1.28
and 1.30 (3H, t, J 7.1, CH3CH2), 1.50, 1.53, 1.55 and 1.62 (3H,
s, CH3), 3.41 (t, J 7.6), 3.71–3.77 (m), and 3.87 (1H, dd, J 8.6
and 6.6, C(4)Hendo and C(6)H), 4.03 (q, J 6.7) and 4.16–4.29
(4H, m, CH3CH2, C(4)Hexo and C(5)H), 4.67 and 4.68 (2H, s,
OCH2Ph), 5.68 (br s) and 6.14 (1H, d, J 8.5, NH), 6.27 and 6.35
(1H, s, C(2)H), 7.31–7.44 (10H, m, ArCH); δC (128.5 MHz,
CDCl3) 13.95, 14.02 and 14.38 (CH3CH2), 19.06 (CH3), 59.10
and 59.21 (C-7), 60.11 and 61.58 (C-5), 61.85 and 61.90
(CH3CH2), 67.13 and 71.87 (C-6), 70.73 (C-4), 76.38 and 76.56
(OCH2Ph), 86.31, 86.69 and 86.87 (C-2), 125.97, 126.04,
126.43, 128.20, 128.41, 128.45, 128.63, 128.72 and 128.78
(ArCH), 136.91, 137.01, 137.48 and 137.72 (2 × ArC), 169.24
and 170.45, 172.08 and 174.45 (2 × CO); m/z (APCIϩ) 411
(M ϩ Hϩ, 100%); HRMS 411.1919, C23H27N2O5 (M ϩ Hϩ)
requires 411.1912.
7-Ethoxycarbonyl-8-oxo-2-phenyl-6-(2-phenylazo)-3-oxa-1-
azabicyclo[3.3.0]octane 9h
Adduct 9a (90 mg, 0.33 mmol) was dissolved in DCM (5 ml)
and stirred at RT for 18 h, and the reaction mixture concen-
trated in vacuo to give a dark orange gum. Purification by flash
column chromatography (2 : 1 petrol–EtOAc as eluent) and
evaporation in vacuo gave the title compound 9h (20 mg,
35%) and as an inseparable diastereomeric mixture in a ratio
of 17 : 2 : 1.
Data for the major isomer (2R,5S,6S,7R): Rf 0.62 (1 : 1
petrol–EtOAc); νmax(film)/cmϪ1 1718 (s), 1624 (w), 1496 (w);
λmax 273 nm (log ε 4.04); δH (500 MHz, CDCl3) 1.35 (3H, t,
J 7.1, CH3CH2), 4.02–4.07 (1H, m, C(4)Hendo), 4.26–4.38 (2H,
m, CH3CH2), 4.41–4.47 (2H, m, C(4)Hexo and C(5)H), 4.48 (1H,
d, J 9.0, C(7)H), 5.02–5.05 (1H, m, C(6)H), 6.47 (1H, s, C(2)H),
7.31–7.67 (10H, m, ArCH); δC (125.8 MHz, CDCl3) 14.14
(CH3), 55.36 (C-7), 60.29 (C-5), 62.12 (CH3CH2), 70.18 (C-4),
77.66 (C-6), 87.52 (C-2), 113.41, 121.95, 122.70, 126.00, 126.20,
127.16, 128.51, 128.51, 128.82, 128.98, 129.11, 129.50, 129.72,
131.74 and 134.43 (ArCH), 137.75 and 151.15 (2 × ArC),
167.60 and 170.58 (2 × CO); m/z (electrospray) 380 (M ϩ Hϩ,
100%).
Attempted alkylation of the hydroxylamine adduct 9e: formation
of (؉)-(2R,7R)-7-ethoxycarbonyl-7-benzyl-8-oxo-2-phenyl-3-
oxa-1-azabicyclo[3.3.0]oct-5-ene 12
General method B: alkylation
Using general method B, the hydroxylamine adduct 9e (100 mg,
0.33 mmol) was reacted with pre-washed sodium hydride
(26 mg, 60%, 0.65 mmol) and benzyl bromide (112 mg,
0.65 mmol) in THF (10 ml) and refluxed for 18 h. Purification
by flash column chromatography (5 : 1 and then 4 : 1 petrol–
EtOAc as eluent) and concentration in vacuo gave compound 12
as a single diastereomer (30 mg, 25%). Rf 0.58 (1 : 1 petrol–
EtOAc); [α]2D5 ϩ201.5 (c 0.8, CHCl3); found C 72.64; H 5.93;
N 4.31; calculated C 72.71; H 5.82; N 3.85%; δH (500 MHz,
CDCl3) 1.29 (3H, t, J 7.1, CH3CH2), 3.39 (1H, d, J 13.5,
To a stirred solution of pre-washed sodium hydride in THF
under an N2 atmosphere at 0 ЊC was added adduct dissolved in
THF. On warming to RT, the solution was allowed to stir for
20 min. The alkyl halide was then added and the reaction
mixture was brought up to reflux for 1–18 h. On cooling to RT,
the reaction mixture was quenched with saturated NH4Cl(aq.)
(25 ml), extracted with EtOAc (3 × 20 ml), washed with water
(2 × 25 ml) and dried over MgSO4. Filtration and concentration
in vacuo gave the crude product.
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006
3003

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CHHPh), 3.42 (1H, d, J 13.5, CHHPh), 4.19–4.28 (2H, m,
CH3CH2), 4.35 (1H, dd, J 13.4 and 1.7, C(4)Hendo), 4.56 (1H, dd,
J 13.4 and 1.9, C(4)Hexo), 5.05 (1H, t, J 1.8, C(6)H), 5.91 (1H, s,
C(2)H), 7.21–7.30 (5H, m, ArCH), 7.38–7.48 (5H, m, ArCH);
δC (125.8 MHz, CDCl3) 13.94 (CH3), 39.06 (CH2Ph), 61.97
(CH3CH2), 62.90 (C-4), 70.03 (C-7), 86.23 (C-2), 96.89 (C-6),
126.48, 126.95, 127.92, 128.58, 129.52, 129.59 and 130.15
(ArCH), 135.26 and 136.06 (ArC), 145.45 (C-5), 168.85 and
169.63 (2 × CO); m/z (APCIϩ) 386 (M ϩ Naϩ, 5%), 364 (M ϩ
Hϩ, 100).
dd, J 8.7 and 5.0, C(6)H), 3.97 (1H, m, C(5)H), 4.22 (1H, dd,
J 8.3 and 6.7, C(4)Hexo), 4.71 (2H, s, NOCH2Ph), 5.61 (1H, br s,
NH), 6.28 (1H, s, C(2)H), 7.29–7.45 (10H, m, ArCH); δC (50.3
MHz, CDCl3) 37.71 (C-7), 59.35 (C-5), 63.97 (C-6), 66.71 (C-4),
78.79 (OCH2Ph), 87.72 (C-2), 125.80, 126.00, 128.23, 128.45,
128.52, 128.59, 129.03 and 129.18 (ArCH), 137.16 and 138.28
(2 × ArC), 175.27 (CO).
Data for 15a: δH (300 MHz, CDCl3) 2.67 (2H, dd, J 8.8
and 4.7, C(7)H), 3.64 (1H, m, C(4)Hendo), 3.72 (1H, td, J 8.7 and
5.0, C(6)H), 3.97 (1H, m, C(5)H), 4.22 (1H, dd, J 8.3 and 6.7,
C(4)Hexo), 4.71 (2H, s, NOCH2Ph), 5.61 (1H, br s, NH), 6.33
(1H, s, C(2)H), 7.29–7.45 (10H, m, ArCH); δC (50.3 MHz,
CDCl3) 37.71 (C-7), 60.39 (C-5), 63.97 (C-6), 70.42 (C-4), 76.42
(OCH2Ph), 87.07 (C-2), 125.80, 126.00, 128.23, 128.45, 128.52,
128.59, 129.03 and 129.18 (ArCH), 137.16 and 138.28 (ArC),
175.27 (CO).
General method C: hydrogenolysis
To a vigorously stirred solution of the starting material dis-
solved in absolute ethanol, EtOAc or glacial acetic acid in a
Fischer–Porter apparatus was added palladium supported on
carbon (Pd/C). The heterogeneous solution was then evacuated
and flushed with H2 six times at RT. The reaction mixture was
subjected to H2 at the given pressure and time. The mixture was
filtered through Celite and the resultant filtrate was concen-
trated in vacuo. Purification of the crude product was carried
out by either flash column chromatography or ion-exchange
chromatography.
(؉)-(2R,5S,6S)-6-O,N-Dibenzylhydroxyamino-8-oxo-2-phenyl-
3-oxa-1-azabicyclo[3.3.0]octane 14b
Bis(tributyltin) oxide (5.41 ml, 10.60 mmol) was added to the
bicyclic lactam 9g (2.58 g, 5.31 mmol) dissolved in toluene (75
ml) and then refluxed for 18 h. On cooling to RT, a mixture of
EtOAc (50 ml) and saturated sodium bicarbonate (50 ml) was
added and the organic layer was separated. The aqueous layer
was further extracted using EtOAc (2 × 50 ml) and the com-
bined organic layers were washed with water (100 ml), dried
over MgSO4, filtered and concentrated in vacuo. Purification of
the crude product was carried out using flash column chroma-
tography (3 : 1 and then 2 : 1 petrol–EtOAc as eluent) which
gave the product 14b as a white solid (1.54 g, 70%). Rf 0.17 (3 : 1
petrol–EtOAc); mp 72–74 ЊC; [α]2D5 ϩ92 (c 1.2, CHCl3); found C
75.25; H 6.40; N 7.28; calculated C 75.30; H 6.30; N 6.80%;
νmax(film)/cmϪ1 3031 (w), 2877 (w), 1711 (s), 1496 (w), 1454 (w),
1349 (m); δH (500 MHz, CDCl3) 2.63 (1H, dd, J 16.1 and 8.2,
C(7)H), 3.02 (1H, m, C(7)H), 3.51 (1H, ddd, J 10.0, 8.3 and 5.7,
C(6)H), 3.68 (1H, br t, J 6.9, C(4)Hendo), 3.82 (1H, d, J 13.0,
NCHHPh), 3.98 (1H, d, J 13.0, NCHHPh), 4.13–4.19 (2H, m,
C(4)Hexo and C(5)H), 4.35 (1H, br d, J 10.0, NOCHHPh), 4.45
(1H, d, J 10.4, NOCHHPh), 6.34 (1H, s, C(2)H), 7.11–7.14
(2H, m, ArCH), 7.30–7.45 (13H, m, ArCH); δC (125.8 MHz,
CDCl3) 38.05 (C-7), 61.42 (NCH2Ph), 62.35 (C-5), 67.20 (C-6),
70.91 (C-4), 76.46 (NOCH2Ph), 86.87 (C-2), 125.74, 125.99,
127.92, 128.26, 128.39, 128.42, 128.46, 128.60, 129.01 and
129.89 (ArCH), 136.05, 136.13 and 138.11 (ArC), 174.61 (CO);
m/z (APCIϩ) 415 (M ϩ Hϩ, 100%).
(2R,5S,6S,7S)-6-Amino-7-benzyl-7-ethoxycarbonyl-8-oxo-2-
phenyl-3-oxa-1-azabicyclo[3.3.0]octane 13
Using general method C, a diastereomeric mixture of the
adduct 10 (70 mg, 0.14 mmol) was reacted with palladium
(80 mg, 10% on carbon) in absolute ethanol (15 ml) and H2
(2 bar) for 18 h. Purification by flash column chromatography
(1 : 3 petrol–EtOAc and then EtOAc as eluent) gave the product
13 as a pale yellow gum (29 mg, 53%) as an inseparable
diastereomeric mixture in a ratio of 14 : 1.
Data for (2R,5S,6S,7S)-isomer: Rf 0.29 (1 : 5 petrol–EtOAc);
νmax(film)/cmϪ1 3409 (w), 3341 (w), 1732 (s), 1704 (s), 1454 (w),
1026 (m); δH (500 MHz, CDCl3) 1.33 (3H, t, J 7.1, CH3CH2),
3.14 (1H, dt, J 7.9 and 6.1, C(5)H), 3.24 (1H, d, J 14.2,
CHHPh), 3.50 (1H, d, J 14.2, CHHPh), 3.78 (1H, dd, J 8.6 and
5.8, C(4)Hendo), 4.03 (1H, d, J 8.0, C(6)H), 4.07 (1H, dd, J 8.6
and 6.5, C(4)Hexo), 4.26–4.33 (2H, m, CH3CH2), 6.35 (1H, s,
C(2)H), 7.14–7. 34 (10H, m, ArCH); δC (50.3 MHz, CDCl3)
14.16 (CH3), 34.55 (CH2Ph), 62.04 (CH3CH2), 62.10 (C-5),
63.15 (C-6), 65.94 (C-7), 70.36 (C-4), 87.10 (C-2), 126.23,
127.07, 128.31, 128.42, 128.67, 130.49, and 131.39 (ArCH),
135.76 and 137.36 (2 × ArC), 170.75 and 172.66 (2 × CO);
m/z (APCIϩ) 381 (M ϩ Hϩ, 100%); HRMS 381.1818, C22-
H25N2O4 (M ϩ Hϩ) requires 381.1811.
(؉)-(2S,3S)-3-Amino-1-benzyl-2-hydroxymethyl-5-oxopyr-
rolidine 16a
(2R,5S,6S)-6-Benzyloxyamino-8-oxo-2-phenyl-3-oxa-1-aza-
bicyclo[3.3.0]octane 14a and (2R,5S,6R)-6-benzyloxyamino-8-
oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane 15a
Using general method C, lactam 14a (112 mg, 0.27 mmol) was
reacted with Pd/C (336 mg, 10%) in glacial acetic acid (20 ml)
and H2 (4 bar) for 48 h. Purification by ion-exchange chroma-
tography (water and then 2 M ammonia in water as eluent) and
concentration in vacuo gave the product 16a as an orange gum
(22 mg, 44%); [α]2D5 ϩ157 (c 0.6, H2O); νmax(film)/cmϪ1 3289 (m),
2926 (w), 1666 (s), 1451 (m); δH (500 MHz, D2O) 2.08 (1H, dd,
J 17.7 and 3.3, C(4)H), 2.75 (1H, dd, J 17.7 and 7.8, C(4)H),
3.16 (1H, d, J 2.9, C(2)H), 3.32–3.41 (1H, m, C(3)H), 3.51 (1H,
dd, J 12.6 and 2.6, CHHOH), 3.65 (1H, dd, J 12.6 and 3.6,
CHHOH), 4.05 (1H, d, J 15.4, NCHHPh), 4.70 (1H, d, J 15.2,
NCHHPh), 7.17–7.29 (5H, m, ArCH); δC (125.8 MHz, D2O)
40.01 (C-4), 44.70 (NHCH2), 47.09 (C-2), 59.49 (CH2OH),
68.41 (C-3), 127.94, 128.23 and 129.23 (ArCH), 135.93 (ArC),
176.98 (CO); m/z (APCIϩ) 221 (M ϩ Hϩ, 100%), HRMS
221.1290, C12H17N2O2 (M ϩ Hϩ) requires 221.1290.
Bis(tributyltin) oxide (0.52 ml, 10.20 mmol) was added to
lactam 9f (202 mg, 5.10 mmol) dissolved in toluene (10 ml) with
stirring and was then brought to reflux for 18 h. On cooling to
RT, a mixture of EtOAc (20 ml) and saturated sodium bicar-
bonate (20 ml) was added and the organic layer was separated.
The aqueous layer was further extracted using EtOAc (2 ×
20 ml) and the combined organic layers were washed with water
(50 ml), dried over MgSO4, filtered and concentrated in vacuo.
Purification of the crude product was carried out using flash
column chromatography (2 : 1 followed by 1 : 1 and then 1 : 2
petrol–EtOAc as eluent) which gave the product 14a–15a as a
yellow gum (102 mg, 62%) and as an inseparable diastereomeric
mixture in a ratio of 6.5 : 1; Rf 0.27 (1 : 1 petrol–EtOAc);
νmax(film)/cmϪ1 3246 (w), 3031 (w), 2917 (w), 1708 (s), 1495 (w),
1454 (w), 1355 (m); m/z (APCIϩ) 325 (M ϩ Hϩ, 100%); HRMS
325.1552, C19H21N2O3 (M ϩ Hϩ) requires 325.1552.
General method D: deprotection
Data for 14a: δH (300 MHz, CDCl3) 2.67 (2H, dd, J 8.8 and
4.7, C(7)H), 3.52 (1H, dd, J 9.2 and 8.3, C(4)Hendo), 3.72 (1H,
Trifluoroacetic acid was added to a stirred solution of the
starting material dissolved in either DCM or CHCl3 at RT for
3004
J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006

View Article Online
the indicated time. Brine (20 ml) was then added to the reaction
mixture and extracted with EtOAc (3 × 20 ml). The combined
organic layers were then washed with water (2 × 20 ml),
dried over MgSO4 and filtered. Concentration in vacuo and
purification by flash column chromatography gave the title
compound.
MHz, CDCl3) Ϫ71.87 (CF3); m/z (APCIϩ) 543 (M ϩ Hϩ, 65%),
423 (100).
The corresponding derivative from ( )-MTPA-Cl was pre-
pared using a similar method: initial 1H and 19F NMR analysis
indicated the presence of two diastereomers 17b in a ratio of
1 : 1; Rf 0.39 (1 : 3 petrol–EtOAc); δF (235.2 MHz, CDCl3)
Ϫ71.87 and Ϫ71.89 (2 × CF3).
(؉)-(2S,3S)-3-O,N-Dibenzylhydroxyamino-2-hydroxymethyl-5-
oxopyrrolidine 16b
Acknowledgements
Using general method D, the starting material 14a (20 mg,
0.05 mmol) dissolved in CHCl3 (3 ml) was reacted with trifluoro-
acetic acid (0.5 ml) for 1 h. Purification by flash column
chromatography (10 : 1 EtOAc–MeOH as eluent) and evapor-
ation in vacuo gave the title compound 16b as a yellow gum
(13 mg, 81%); Rf 0.36 (8 : 1 EtOAc–MeOH); [α]2D5 ϩ54 (c 0.8,
CHCl3); νmax(film)/cmϪ1 3307 (m), 1685 (s), 1496 (w), 1207 (m);
δH (500 MHz, CDCl3) 2.45 (1H, br dd, J 16.6 and 8.6, C(4)H),
2.64 (1H, br s, C(4)H), 3.37–3.45 (2H, m, C(3)H and CHHOH),
3.67–3.70 (1H, m, CHHOH), 3.76 (1H, d, J 12.9, NCHHPh),
3.81 (1H, br s, C(2)H), 3.93 (1H, d, J 12.9, NCHHPh), 4.36–
4.42 (2H, m, NOCH2Ph), 6.93 (1H, br s, NH), 7.11–7.38 (10H,
m, ArCH); δC (125.8 MHz, CDCl3) 59.05 (C-2), 60.35 (C-3),
62.63 (NCH2Ph), 64.42 (CH2OH), 76.43 (NOCH2Ph), 127.72,
128.11, 128.31, 128.41, 129.01 and 129.75 (ArCH), 136.41 and
136.61 (2 × ArC), 177.08 (CO); m/z (APCIϩ) 327 (M ϩ Hϩ,
100%); HRMS 327.1709, C19H23N2O3 (M ϩ Hϩ) requires
327.1709.
We thank EPSRC and Merck Sharp and Dohme for funding
of a studentship to PWHC, and we wish to gratefully acknowl-
edge the use of the EPSRC Chemical Database Service
at Daresbury54 and the EPSRC National Mass Spectrometry
Service Centre at Swansea.
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1
Initial H and 19F NMR analysis indicated a diastereomeric
excess of at least 95%. Purification by flash column chroma-
tography (1 : 2 petrol–EtOAc as eluent) gave the product 17a as
a yellow gum (21 mg, 91%); Rf 0.39 (1 : 3 petrol–EtOAc);
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1453 (m), 1253 (s), 1170 (s); δH (500 MHz, CDCl3) 2.31 (1H,
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J. Chem. Soc., Perkin Trans. 1, 2001, 2997–3006