2,5-Disubstituted pyrrolidines: Synthesis by enamine reduction and subsequent regioselective and diastereoselective alkylations

Article abstract of DOI:10.1039/b604183c

Methodology for the diastereoselective synthesis of 2,5-disubstituted pyrrolidines by reduction of enamines derived from pyroglutamic acid is reported; the nature of nitrogen protection was found to be critical for the stereochemical control of the reaction outcome. Regioselective manipulation of the C-2 and C-5 substituents is possible, providing access to differently substituted pyrrolidines for a limited number of cases. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604183c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
2,5-Disubstituted pyrrolidines: synthesis by enamine reduction and subsequent
regioselective and diastereoselective alkylations†
Syed Raziullah Hussaini and Mark G. Moloney*
Received 21st March 2006, Accepted 9th May 2006
First published as an Advance Article on the web 31st May 2006
DOI: 10.1039/b604183c
Methodology for the diastereoselective synthesis of 2,5-disubstituted pyrrolidines by reduction of
enamines derived from pyroglutamic acid is reported; the nature of nitrogen protection was found to be
critical for the stereochemical control of the reaction outcome. Regioselective manipulation of the C-2
and C-5 substituents is possible, providing access to differently substituted pyrrolidines for a limited
number of cases.
The pyrrolidine ring nucleus forms the core of many natural
products, and exhibits wide-ranging biological activity.1–6 In order
Results and discussion
to provide rapid access to these systems, we7,8 have been interested
in the development of reliable chemistry for the stereocontrolled
manipulation of any or all ring positions of pyroglutamic acid.9,10
In particular, 2,5-disubstituted pyrrolidines 1 are compounds of
considerable importance,11 and reliable diastereoselective access
to these systems continues to generate interest.12,13 Our focus has
more recently turned to manipulation of the lactam carbonyl of py-
roglutamate 2a as a route to these systems, and of particular value
is the Eschenmoser ring contraction,14,15 involving condensation
of thiolactam 2b with an a-bromoester. This reaction can occur
under particularly mild conditions, especially when the bromo
component is substituted with two electron withdrawing groups,
and is tolerant of a range of other functional groups, and as a
result has been extensively applied by Rapoport16 and others.17–19
However, it is known that reduction of the enaminone products
from the Eschenmoser contraction is highly substrate and reagent
dependent, being particularly easy for b-enamino (mono)esters,
and that cis-stereocontrol with catalytic hydrogenation and trans-
stereocontrol with metal hydrides is possible;20 an exhaustive
review of the chemistry of enaminone systems has recently
appeared,21 and a detailed analysis of the push–pull effect which
operates in these systems reported.22 Our plan was to further
examine the scope of this process, with the specific aim of defining
enabling methodology for the preparation of 2,5-disubstituted
pyrrolidines 1 by chain extension at either or both of the 2 and 5
positions of pyroglutamate 2a (Scheme 1); some of this work has
appeared in preliminary form.23,24
The key step of the sequence is activation of the lactam carbonyl
of pyroglutamic acid ethyl ester 2a25 as the thiocarbonyl derivative
2b, achieved using either P2S5 or Lawesson’s reagent; we found
that this was most reliably achieved with crude ester 2a using
commercially available HPLC-grade dichloromethane at room
temperature for only 1.5 h using our published method.24 Excellent
yields (82%) of the corresponding product 2b were obtained which
could be readily purified by a single chromatographic step on
up to a 12 g scale. Thiolactam 2b could be readily converted
to enamine 2c in quantitative yield under standard Eschenmoser
coupling conditions, thus securing the necessary starting material
for further studies.
Reductions selectively leading to trans-pyrrolidines
Lactams 2c and 3 (as a 1 : 2 mixture of E/Z geometric isomers,
prepared by Eschenmoser contraction of 2b with ethyl 2-bromo-3-
oxo-3-phenylpropionate26) were subjected to reduction conditions
which had been successfully applied to related enamine substrates
substituted with a single ester function (Scheme 2).20 However, the
enamine function proved to be particularly resistant to reduction
and reaction of 3 and 2c could only be achieved with sodium
borohydride to give alcohols 4a,b (yields 71 and 80% respectively),
resulting from C-2 ester reduction and not enamine reduction.
An attempt to activate this system by protection of the nitrogen
functionof 2cand3asthecorrespondingBOCderivativesrequired
forcing conditions, but gave 5a and 5b in 73 and 23% yield
respectively. However, this enamine function still proved to be
unreactive, since for example reaction of 5a with NaBH4 gave only
enamine 6 from C-2 ester reduction and debenzoylation (11%).
Interestingly, application of conditions (nBuLi, CuI, Et2O) to 3
and 5a recently reported to be successful for conjugate additions to
lactam-derived enamine systems19 was not successful, illustrating
the lack of reactivity of this enamine system.
Scheme 1
Because of the complications of chemoselectivity in the differ-
ently substituted enamine substrate 3, reductions of diester 2c were
examined in more detail (Scheme 2). Sodium cyanoborohydride in
ethanol at pH 3–527 gave product 7a, although this product could
not be separated from an unidentified impurity. Catalytic hydro-
genation (H2, Pt/C or Pd/C, 4.5 atm) also returned unreacted
The Department of Chemistry, Chemistry Research Laboratory, The Univer-
sity of Oxford, Mansfield Road, Oxford, UK OX1 3TA
† Electronic supplementary information (ESI) available: Copies of selected
1H NMR spectra. See DOI: 10.1039/b604183c
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Scheme 2
starting material, indicating a substantial lowering of reactivity
of b-enamino diesters relative to their b-enamino monoester
counterparts, but application of more forcing conditions (H2,
PtO2.H2O,‡ TFA–HOAc (1 : 3), 4.5 atm, 48 h)26 gave a quantitative
yield of a 1 : 2 ratio of an inseparable cis- : trans-product mixture
7a (this stereochemical assignment was established subsequently
on the benzoyl derivative 7b, vide infra). This approach provides
a convenient solution to the problem of the difficult reduction
of b-enamino esters which has been noted in the literature.17,26–28
Benzoylation of the amine nitrogen of 7a (PhCOCl, py, 30–
40 ◦C) proceeded without difficulty to give a separable mixture
of cis- and trans-7b in excellent yield but variable cis- : trans-ratio,
suggesting the possibility of equilibration during the acylation
reaction. Acetylation (Ac2O, py) proceeded in good yield and gave
a mixture of cis- and trans-7c.
different diastereomers of 7b could be readily distinguished (in the
1H NMR spectrum of compounds cis- and trans-7b (in CDCl3), all
3 ester methylene, H-2 and H-6 signals were co-incident at about
d 4.1–4.4 for the cis-product, but in the trans-compound, one of
the ester methylenes was upfield from the others by 0.3 ppm, and
H-2 and H-6 (which were almost co-incident (Dd 0.05 ppm)) were
downfield by Dd 0.2 ppm of the remaining two ester methylenes),
direct assignment of relative stereochemistry was not possible.
Furthermore, the 1H NMR spectrum exhibited overlapped signals
and extensive broadening for cis-7b, presumably as a result of
rotameric equilibration, but those of trans-7b did not.§ A better
spread of chemical shift values was possible in C6D6, but not
enough to enable stereochemical assignment, and rotameric effects
were still evident. However, variable temperature (VT) analysis
(373 K in d6-DMSO) resulted in significant sharpening of all
signals, and enabled acquisition of NOE data (Fig. 1). For cis-
7b, irradiation of both C(2)H and C(5)H, in addition to a weak
mutual enhancement, gave clear enhancements at C(3)H and
C(4)H, and the stereochemistry of trans-7b was indicated by C(2)H
enhancements at C(3)H and C(3)Hꢀ and by C(5)H enhancements
at C(3)Hꢀ and C(4)Hꢀ, with no C(2)H–C(5)H enhancements. Inde-
pendent stereochemical assignment was possible by single crystal
X-ray analysis of pyrrolidine cis-7b,23 which confirmed these NOE
The assignment of relative stereochemistry in these systems
proved to be of particular difficulty but was of considerable
1
importance. Since useful correlations of stereostructure and H
NMR spectroscopic data had previously been established in our
pyroglutamate systems29,30 it seemed feasible that a similar analysis
might prove fruitful in this case; however, rotameric equilibria, not
present for the pyroglutamates, proved to be a serious complication
for these pyrrolidines, as might be expected. Although the two
‡ PtO2 obtained from BDH proved to give shortest reaction times and to
be the most reliable.
§ Copies of selected 1H NMR spectra are available in electronic form (see
accompanying ESI data).†
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Fig. 1 NOESY data for selected compounds.
Fig. 2 Preferred conformations in 2,5-disubstituted pyrrolidines.
results; the crystal structure indicated a conformation in which the
C-2 substituent was pseudoaxial, the C-5 group pseudoequatorial,
the C-3 was out of plane of the remaining ring atoms, and the
nitrogen was slightly pyramidalised (Fig. 2). Presumably this
arrangement minimises eclipsing interactions in the ring which
would arise in a di(pseudoequatorial) conformer. Unfortunately,
a similar crystallographic analysis was not possible for trans-
7b, since it was an oil. Further investigation of pyrrolidines 7b
indicated that the pure cis-isomer could be converted (NaH–
DMF–0 ◦C → RT) to a cis- : trans-product mixture (1.7 : 1), and
that treatment of the pure trans-7b with LDA at low temperature
also gave recovered starting material in which the trans-isomer
predominated (5.7 : 1). This clearly indicates that equilibration of
the two isomers is possible; we presume that initial b-elimination,
favoured by a highly acidic C(6)H and good N-benzoyl leaving
group followed by ring re-closure, is responsible for this outcome
under these conditions (Scheme 3, a and b). Unexpected retro-
Michael additions of cyclic b-aminoesters have been observed
previously.31
Reductions selectively leading to cis-pyrrolidines
We subsequently found that reversal of the order of steps leading
to the intermediate benzamide 7b permitted reduction under
milder conditions and consequent isolation of the cis-isomer.
Thus, protection of the enamine function21 of 2c under forcing
conditions (PhC(O)Cl, Et3N, DCM, DMAP, 2 days at reflux) gave
N-benzoyl derivative 8 in 41% yield (Scheme 2), whose structure
Scheme 3
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Scheme 4
was confirmed by single crystal X-ray analysis,¶ and this was
susceptible to reduction under significantly milder conditions than
enamine 2c (10% Pd–C, H2, 5 atm, 24 h, EtOH : DCM = 10 : 1)
to give pyrrolidine 7b, this time as a 9 : 1 mixture of cis : trans-
isomers in 80% yield. However, since we later found (vide supra)
that alkylation of the enolate derived from cis-7b gave only the
corresponding trans-products, due to the same facile ring opening–
ring closing equilibration illustrated in Scheme 3, this compound
was of limited synthetic utility for our purpose.
analysis at room temperature (Fig. 1); thus, irradiation of C(5)H
gave significant enhancements at C(2)H, NCHH, C(3)H, C(4)H,
while irradiation of H-2 gave significant enhancements at C(5)H,
NCHH, C(3)H, C(4)H, consistent with the cis-stereochemistry.
Simple molecular modelling calculations (Chem3D with MM2
parameters) suggested that the cis-2,5-isomer was more stable
than the corresponding 2,5-trans-isomer by 4.8 kJ mol−1, and
that the preferred conformation was one in which the C-2 and
C-5 substituents were pseudodiaxial and trans- to the bulky tert-
butoxycarbonylmethyl substituent on a slightly pyramidalised
nitrogen atom (Fig. 2).
Since the crucial equilibration process of Scheme 3a,b leading
to trans-products 7b seemed likely to depend on the good leaving
ability of the N-benzoyl groups of 7b, it was of interest to apply an
amine protecting group which did not withdraw electron density
from the nitrogen. However, protection of the amine group of com-
pounds like 2c and 7a is difficult due either to the delocalised nature
of the amine lone pair or the hindered nature of the amine function,
respectively, and a further complication for derivatives of 7a is their
highly basic and polar characteristics which makes for difficult
isolation. Although it was possible to alkylate enamine 2c giving
compounds 9a and 9b (Scheme 4), these compounds could not be
subsequently reduced by catalytic hydrogenation; in the case of 9c,
ring cleavage resulted very efficiently, giving heptanedioate 10. On
the other hand, attempts at introducing N-Me or N-Bn groups into
7a by standard alkylation-type approaches gave recovered starting
material and/or low yield of product, and attempted reductive
amination with benzaldehyde gave no identifiable material. De-
protonation of amine 7a (cis : trans = 1 : 2) with LiHMDS at 0 ◦C
followed by reaction with tert-butyl bromoacetate was successful,
however, and gave the desired adduct 7d in 50% yield (Scheme 2), as
the cis-isomer exclusively; this isomer is likely to be favoured since
an all anti-conformational arrangement of contiguous substituted
ring positions is possible (similar conformational preference for
the anti-substitution pattern in related acylated oxazolidines has
been demonstrated).32–35 Significantly, this tertiary amine could
be readily purified by chromatography on silica, unlike related
compounds which required distillation.36 Noteworthy also was
that the 1H NMR spectrum of this compound at room temperature
gave well resolved signals, unlike the N-benzoyl protected 7b
which required VT analysis at 373 K to give useful spectra,23
and its stereochemical assignment was based on careful NOE
Alkylation reactions at C-2 and C-5
We anticipated that compound 7b would prove to be a useful
synthetic template enabling direct modification of either the C-
2 ethoxycarbonyl or C-5 bis(ethoxycarbonyl)methyl substituents,
but observed some unexpected complications in its reactivity
(Scheme 5). Attempted reduction of the C-2 ethoxycarbonyl of 7b
(whichhadbeen straightforwardfor enamines 2c,3, giving alcohols
4a,b as noted above in Scheme 1) proved to be problematic, and
formation of amide 11a (40%), along with the inseparable by-
products 11b (6%) and 11c (7%), was observed. These results are
also consistent with a facile b-elimination of starting 7b, which
in this case is followed by a,b-double bond and ester reduction
(either once or twice) to give the observed products (Scheme 3).
In an effort to extend the C-6 (bisethoxycarbonyl)methyl
substituent using a standard alkylation strategy, deprotonation
at the more acidic malonate-type centre followed by electrophilic
quench was examined. Treatment of pure trans-7b with NaH
then benzyl bromide in DMF gave a 51% yield of trans-12a. The
stereochemistry of 12a was unequivocally assigned by VT/NOE
analysis in d6-DMSO at 373 K (Fig. 1). Significantly, irradiation
of the benzylic system gave enhancements at C(2)H, C(3)H and
C(4)H, suggesting a preferred conformation in which this group
is folded under the heterocyclic ring (Fig. 2). By contrast, the cis-
starting material 7b gave none of the expected cis-product 13a,
but instead a 59% yield of trans-12a (which was of identical [a]D to
the material prepared from trans-7b). In each of these reactions,
starting material (about 10%) was recovered as a mixture of cis-
and trans-isomers but without loss of [a]D, indicating that racemi-
sation was not occurring in the reaction. Since the same trans-12a
was obtained from either cis or trans-7b, optimisation was carried
out on a cis–trans-mixture of 7b and conditions were established
which increased the alkylation yield up to 73%. These results
are also consistent with the facile cis–trans-equilibration of 7b as
described above (Scheme 3, a and b), followed by selective alkyla-
tion of the trans-isomer in the equilibrium mixture (Scheme 3,
c). Moreover, isolation of identical trans-12a from either cis
or trans-7b ruled out the possible formation of ent-trans-12a
¶ CCDC reference numbers 602416 and 602417. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b604183c. Crystal data
and data collection parameters for compound 8: C21H25NO7, T = 150 K,
M = 403.43, monoclinic, a = 8.8317(5), b = 10.1281(5), c = 12.0240(7)
3
A, V = 1047.9 A . Space group P21, Z = 2, Dx = 1.279 mg m−3, l =
0.096 mm−1. The compound was crystallised from EtOAc–petrol. Crystal
data and data collection parameters for compound 22b: C33H37NO6, T =
150 K, M = 543.66, monoclinic, a = 8.3002(2), b = 33.6715(4), c =
˚
˚
3
−3
˚
˚
10.5310(2) A, V = 2943.0 A . Space group P21, Z = 4, Dx = 1.227 mg m
,
l = 0.084 mm−1. The compound was crystallised from EtOAc–petrol.
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Scheme 5
by initial epimerisation at C-2 of cis-7b followed by alkylation at
C-6 (Scheme 3, d and e). Alternatively, methylation of pure trans-
7b with KH–methyl triflate gave a 88% yield of trans-12b. The
stereochemistry of 12b was again assigned by VT/NOE analysis in
d6-DMSO at 373 K (Fig. 2§), and confirmed by single crystal X-ray
analysis;23 this indicated a conformation in which both the C-2 and
C-5 substituents were pseudoaxial, that C-3 was out of plane of
the remaining ring atoms, the benzoyl carbonyl group was directed
towards the C-5 substituent, and C(6)Me was located under the
heterocyclic ring. The cis-starting material 7b also gave none of the
expected cis-product 13b under these conditions, but instead a 25%
yield of trans-12b. Again, in these reactions, recovered starting
material 7b which was isolated had been equilibrated to a cis-,
trans-mixture. The equilibration sequence shown in Scheme 3
therefore appears to be operating in this case too.
Having compounds 12a,b in hand gave the opportunity to
confirm our earlier hypothesis concerning equilibration by elimi-
nations in derivatives 7b, since the acidic malonyl H-6 proton was
now blocked; when 12b was treated with base followed by benzyl
bromide, alkylation at C-2 occurred to give a 2 : 3 mixture of cis-
and trans-adducts 14, but only in low yield (27%); presumably this
is a result of steric hindrance at the C-2 position due to the proxim-
ity of the distal C-6 methyl group, by analogy with the structure of
pyrrolidine 12b as determined from its NOE analysis (Fig. 2). An
attempt to alkylate benzyl derivative 12a gave none of the expected
product, and this is consistent with a highly hindered conforma-
tion in which the benzyl group is folded over the C-2 position.
Alternatively, regioselective C-2 modification was also possible:
double deprotonation of trans-7b with excess LDA (5 equivalents)
and alkylation (excess MeI) gave monomethyl adduct 15 in good
overall yield (54%). In this compound, the room temperature 1H
NMR spectrum exhibited very broad signals, but at 373 K (d6-
DMSO) a highly resolved spectrum was observed; NOE analysis
(Fig. 1) indicated the expected enhancements around the ring,
but no C-2(Me)/C(5)H enhancements, consistent with the trans-
relative stereochemistry. This tentative assignment is corroborated
by the observation that in the 1H NMR spectrum, the OCH2CH3
signals were not coincident, and that C(6)H did not lie under these
signals; this arrangement has also been observed for other trans-
isomers as described above. We believe that this outcome arises
because the intermediate dienolate which is formed alkylates at
the more reactive enolate position and in an anti-sense to the
benzoyl group (which is itself trans- to the C-5 malonate residue)
with a kinetic pseudoaxial preference (Scheme 6).
Scheme 6
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Scheme 7
When this procedure was applied to cis-7b, a low yield (25%)
of ent-15 was obtained, since the material from this reaction
exhibited opposite optical rotation to product 15 from the reaction
with trans-7b; this could be improved to a yield of 40% by
using lithium tetramethylpiperidide (3 equivalents) as the base.
This result is consistent with the fact that the trans-C(2)Me–
C(5)H stereochemistry is the thermodynamically more stable
arrangement in these systems. In this case, in the presence of
5 equivalents of base (LDA), cis-7b can be expected to form
the corresponding cis-dienolate A (Scheme 7); however, now the
retro-Michael addition which would otherwise equilibrate the less
favourable cis-isomer to the more favourable trans- one (as shown
in Scheme 3) is not favoured due to the intermediacy of the
adjacent dianion B, so epimerisation to the trans-dienolate C can
only occur by direct anion inversion at C-2. By a ring flip, this
gives the enolate derived from ent-trans-7b, which of course then
alkylates with the same diastereoselectivity as trans-7b, to give
ent-15.
The use of LiHMDS as base also enabled direct formation of the
dienolate derived from 7b, but treatment of this with excess methyl
iodide gave a poor yield of pyrrolidine 16 (5%) and as a mixture of
diastereomers. This alkylation sequence was not successful using
benzyl bromide, or 1,2-dibromoethane.
In the N-alkyl cis-pyrrolidine series (Scheme 8), compound 7d
proved to be amenable to further manipulation, so that reaction
with NaH and ethyl triflate in CH2Cl2, or benzyl bromide in DMF
at room temperature, gave products 17a,b in 32% (along with 29%
of recovered starting material) and 36% respectively. The regiose-
lectivity of these alkylations was confirmed by the disappearance
of C(6)H–C(5)H COSY correlations, and HMBC and HMQC
correlations. Furthermore, coupling constants of >18.5 Hz in-
dicated the presence of geminal protons of NCH2CO2t-Bu thus
confirming that alkylations occurred at C-6 and not a- to the tert-
butyl ester. For the ethyl derivative 17a, irradiation of CH2CO2t-
Bu gave enhancement to C(5)H, while irradiation of C(2)H
resulted in significant enhancement to C(5)H, suggesting cis-
stereochemistry. For the benzyl derivative 17b, irradiation of
C(5)H gave significant enhancements at C(2)H, C(3)H, C(4)HHꢀ,
CH2Ph, and CH2CO2t-Bu, suggesting the cis-stereochemistry. For
these compounds, molecular modelling calculations (Chem3D
with MM2 parameters) suggested that the cis-2,5-isomers are
more stable than the corresponding trans-2,5-isomers by between
2.0–4.5 kJ mol−1. The importance of heterocyclic N-alkylcarbonyl
derivatives as conformational controlling elements in biologically
relevant ligands has recently been reported.37
Reductions
A key difficulty in the reduction of these highly functionalised
systems is therefore the ease with which equilibration can occur
across the 2,5-disubstituted pyrrolidine system (Scheme 3 and
Scheme 7); it was of interest to compare the reductive behaviour in
systems for which the C-2 ester substituent was not present. Thus,
alcohol 4b, prepared as shown in Scheme 2, was subjected to a
range of reductive conditions (including PtO2, H2; NaCNBH3;
NaBH4–HOAc), but none gave the desired reduction products.
Protection of the alcohol as the TBDPS, methyl ether and
acetate derivatives 18, 19 and 20 could be achieved in good yield
(92, 52 and 100% respectively) and for the latter two at least,
catalytic reduction was successful, giving pyrrolidine 21 (after N-
benzylation) and 22a in good yield (77 and 100% respectively) but
as a mixture of inseparable diastereomers. The 1H NMR spectrum
Scheme 8
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Scheme 9
of pyrrolidine 21 (in CDCl3) showed broadening of signals, and
variable temperature analysis (373 K in d6-DMSO) also failed
to give a resolved spectrum; however, in C6D6 better resolution
was achieved. In the case of 22a, immediate trityl protection
gave product 22b, in which acetyl migration had occurred, whose
structure and relative stereochemistry was confirmed by single
crystal X-ray analysis,¶ or protection with benzoyl chloride and
pyridine gave benzamide 22c (Scheme 9).
visualised using UV light (254 nm) or a solution of 5% w/v
dodeca-molybdophosphoric acid in EtOH followed by heat. Flash
column chromatography was carried out using Sorbisil(tm) C60
H(40–60 mm) silica gel.
(S)-2-Ethyloxycarbonyl-5-thioxo-pyrrolidine 2b38,39
To a suspension of Lawesson’s reagent (16.00 g, 38.71 mmol) in
CH2Cl2 (150 ml) was added ester 2a (12.15 g, 77.41 mmol) as a
solution in CH2Cl2 (150 ml) and the reaction mixture stirred for
1.5 hours. The solvent was removed under reduced pressure and
the residue was divided into 2 portions which were purified by
flash column chromatography [EtOAc : petrol (40–60) 2 : 3] to
give 2b (11 g, 82%) as viscous oil. Rf = 0.22 (3 : 1 petrol (40–60) :
EtOAc); mmax/cm−1 (neat) 3181, 1741, 1503; dH (400 MHz, CDCl3)
1.27 (3H, t, J 7.0, OCH2CH3), 2.27–2.36 (1H, m, C(3)HH), 2.49–
2.58 (1H, m, C(3)HH), 2.86–3.02 (2H, m, C(4)H2), 4.23 (2H, q,
J 7.0, OCH2CH3), 4.51 (1H, dd, J 8.7, 6.2, C(2)H), 8.54 (1H, br,
NH); m/z (APCI+) 174 (M + H+, 100%).
Conclusion
We have identified conditions suitable for the reduction of
enamines substituted with ester functions, derived from pyrog-
lutamic acid enabling generation of synthetic intermediates which
permit regioselective C-2 or C-6 manipulation, providing access
to trans- or cis-2,5-disubstituted pyrrolidines. Furthermore, an
effective spectroscopic protocol involving 1H NOE analysis at
high temperature (373 K) has been identified which minimises
conformational effects and permits detailed stereochemical as-
signments to be made in these highly conformationally mobile
systems; where possible, these have been confirmed independently
by crystallographic analysis.
(S)-5-(Di(ethoxycarbonyl)methylidene)-pyrrolidine-2-carboxylic
acid ethyl ester 2c26
Experimental
Diethyl 2-bromomalonate (18.6 g, 78.0 mmol), NaHCO3 (13.1 g,
156 mmol) and CH2Cl2 (150 ml) were added to thiolactam 2b
(6.75 g, 39.0 mmol). The suspension was heated under reflux
for 48 hours, cooled, washed with water, dried with MgSO4, and
evaporated. Silica gel chromatography [petrol (40–60) : EtOAc 3 :
2] afforded the enamine 2c (11.6 g, 100%) as viscous oil. Rf = 0.58
(3 : 2 petrol (40–60) : EtOAc); [a]2D6 = −28.9 (c = 1.26, CHCl3);
mmax/cm−1 (neat) 1743, 1691, 1649, 1573; dH (400 MHz, CDCl3)
1.15–1.24 (9H, m, 3 × OCH2CH3), 2.03–2.11 (1H, m, C(3)HH),
2.23–2.33 (1H, m, C(3)HH), 2.99–3.14 (2H, m, C(4)H2), 4.06–4.17
(6H, m, 3 × OCH2CH3), 4.37 (1H, dd, J 8.8, 5.6, C(2)H), 9.57
(1H, br, NH); dC (50 MHz, CDCl3) 14.1 (OCH2CH3), 14.3 (2 ×
OCH2CH3), 25.9 (C(3)), 33.2 (C(4)), 59.7, 59.8 (2 × OCH2CH3),
60.8 (C(2)), 61.7 (OCH2CH3), 88.8 (NCC), 167.5, 169.4, 171.1,
172.1 (C(5), 3 × CO2C2H5); m/z (APCI+) 300 (M + H+, 2%), 254
(100%).
1H NMR spectra were recorded on Varian Gemini 200 (200
MHz) and Bruker AM-500 (500 MHz) spectrometers. 13C NMR
spectra were recorded on the same spectrometers at 50.3 MHz
and at 125.8 MHz respectively. Low resolution mass spectra were
recorded on a VG Masslab 20–250 spectrometer using the CI
or on a Hewlet Packard series 1050 spectrometer using APCI
in the (APCI+) mode or ES in the (ES+) mode. Sealed mass-
to-charge (m/z) peaks are quoted in Daltons as percentage of
the base peak. Accurate mass spectra were recorded on a VG
Autospec spectrometer operating in positive ion electrospray
mode by Dr N. J. Oldham and Mr R. Proctor at the Dyson
Perrins Laboratory, Oxford. Gas chromatography mass spectra
(GCMS) were recorded on a VG Trio-1 spectrometer. Thin layer
chromatography (TLC) was performed using Merck aluminium
foil backed sheets precoated with Kieselgel 60 F254. Plates were
2606 | Org. Biomol. Chem., 2006, 4, 2600–2615
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(S)-Methyl 5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-
ylidene)pyrrolidine-2-carboxylate 3
for 6 hours. Glacial acetic acid was then carefully added to the
mixture with stirring and cooling in an ice bath until pH 5.0 was
reached. The mixture was partitioned between CH2Cl2 and water.
The organic layer was washed with saturated solution of NaHCO3,
water and brine, dried with MgSO4, and the solvent evaporated.
Silica gel chromatography [EtOAc : MeOH 95 : 5] gave alcohol 4b
(2.1 g, 80%) as viscous oil. Rf = 0.26 (3 : 7 petrol (40–60) : EtOAc);
[a]D22 = +19.3 (c = 0.14, CHCl3); mmax/cm−1 (neat) 3416, 1644, 1567;
dH (400 MHz, CDCl3) 1.27 (3H, t, J 7.1, OCH2CH3), 1.28 (3H,
t, J 7.1, OCH2CH3), 1.73–1.80 (1H, m, C(3)HH), 2.05–2.15 (1H,
m, C(3)HH), 2.78 (1H, s, OH), 3.02–3.20 (2H, m, C(4)H2), 3.52
(1H, dd, J 11, 6.7, CHHOH), 3.71 (1H, dd, J 11, 4.0, CHHOH),
3.98–4.01 (1H, m, C(2)H), 4.14–4.28 (4H, m, 2 × OCH2CH3),
9.59 (1H, br, NH); dC (50 MHz, CDCl3) 14.3 (2 × OCH2CH3),
23.8 (C(3)), 33.8 (C(4)), 59.6 (2 × OCH2CH3), 60.4 (C(2)), 66.1
(CH2OH), 87.3 (NCC), 167.8, 169.7, 172.7 (C(5), 2 × CO2C2H5);
m/z (APCI+) 258 (M + H+, 8%), 212 (100%); HRMS (M + H+)
258.1340, C12H20NO5 requires 258.1341.
To ethyl 2-bromo-3-oxo-3-phenylpropionate40 (3.30 g, 12.2 mmol)
and NaHCO3 (2.04 g, 24.4 mmol) was added a solution
of (S)-methyl 5-thioxopyrrolidine-2-carboxylate.27,41,42 (0.970 g,
6.10 mmol) in CH2Cl2 (86 ml). The suspension was heated
under reflux for 36 hours, cooled, filtered through celite, and the
solvent evaporated. Silica gel chromatography [Toluene : EtOAc
4 : 1] afforded the enamine 3 (0.960 g, 50%), as a mixture of
diastereomers in a ratio of 1 : 2, as brown oil. Rf = 0.31 (3 : 1
petrol (40–60) : EtOAc); mmax/cm−1 (neat) 3038, 1746, 1685, 1600,
1528, 1477; dH (200 MHz, CDCl3) 0.63–0.72 (3H, m, OCH2CH3),
2.07–2.41 (2H, m, C(3)H2), 3.05–3.24 (2H, m, C(4)H2), 3.66–3.89
(5H, m, OCH2CH3, OCH3), 4.44–4.56 (1H, m, C(2)H), 7.23–7.59
(5H, m, C6H5), 9.47 (1H, br, NH (minor diastereomer)), 10.94
(1H, br, NH (major diastereomer)); dC (50 MHz, CDCl3) (major,
minor) 13.3,13.4 (OCH2CH3), 25.3, 26.0 (C(3)), 33.0, 32.4 (C(4)),
52.6 (CO2CH3), 59.4, 59.1 (OCH2CH3), 61.3, 60.7 (C(2)), 98.7,
96.5 (NCC), 125.2, 126.7, 127.6, 127.9, 128.1, 128.9, 129.6, 130.7
(C6H5),142.5, 143.2 (quaternary ArC), 168.8, 169.5, 171.2, 171.5,
173.2,172.0 (C(5), CO2CH3, CO2C2H5), 195.0, 194.8 (C6H5CO);
m/z (APCI+) 318 (M + H+, 8%), 272 (100%); HRMS (M + H+)
318.1340, C17H20NO5 requires 318.1341.
(S)-N-tert-Butoxycarbonyl-5-(1-ethoxycarbonyl-2-oxo-2-phenyl-
ethylidene)-pyrrolidine-2-carboxylic acid methyl ester 5a
To a solution of enamine 3 (1.00 g, 3.15 mmol) in CH2Cl2 (10 ml)
at 0 ◦C was added triethylamine (0.65 ml, 4.7 mmol), di-tert-butyl
dicarbonate (0.97 g, 4.7 mmol) as a solution in CH2Cl2 (15 ml),
and (dimethylamino)pyridine (0.39 g, 3.2 mmol) as a solution in
CH2Cl2 (15 ml). The mixture was refluxed for 48 hours, cooled,
washed with water and brine, dried with MgSO4, and evaporated.
Silica gel chromatography [toluene : EtOAc 4 : 1] afforded the
carbamate 5a (0.96 g, 73%) as a mixture of diastereomers in a ratio
of 1 : 2.25, as viscous yellow oil. Rf = 0.55 (3 : 2 petrol (40–60) :
EtOAc); mmax/cm−1 (neat) 3040, 1744, 1707, 1664, 1602, 1522, 1477;
dH (400 MHz, CDCl3) (major) 0.86 (3H, t, J 7.1, OCH2CH3), 1.21
(9H, s, C(CH3)3), 2.06–2.10 (1H, m, C(3)HH), 2.30–2.38 (1H, m,
C(3)HH), 3.09–3.15 (2H, m, C(4)H2), 3.74 (3H, s, OCH3), 3.91–
4.03 (2H, m, OCH2CH3), 4.58 (1H, dd, J 9.4, 3.3, C(2)H), 7.35–
7.39 (3H, m, ArH), 7.85–7.88 (2H, m, ArH); dC (100 MHz, CDCl3)
13.6 (OCH2CH3), 26.0 (C(3)), 27.7 (C(CH3)3), 31.6 (C(4)), 52.3
(CO2CH3), 60.4 (OCH2CH3), 62.6 (C(2)), 83.2 (C(CH3)3), 112.2
(NCC), 127.8, 128.6, 131.6 (ArC), 138.9 (quaternary ArC), 150.0,
155.2, 167.1, 172.0 (C(5), CO2CH3, CO2C2H5, COC(CH3)3), 192.2
(C6H5CO); m/z (CI+) 418 (M + H+, 12%), 318 (100%), 272 (45%);
HRMS (M + H+) 418.1858, C22H28NO7 requires 418.1866. dH
(400 MHz, CDCl3) (minor) 0.96 (3H, t, J 7.1, OCH2CH3), 1.43
(9H, s, C(CH3)3), 2.06–2.10 (1H, m, C(3)HH), 2.30–2.38 (1H,
m, C(3)HH), 2.67–2.70 (1H, m, C(4)HH), 2.79–2.85 (1H, m,
C(4)HH), 3.76 (3H, s, OCH3), 3.91–4.03 (2H, m, OCH2CH3),
4.65 (1H, dd, J 9.3, 3.3, C(2)H), 7.43–7.47 (3H, m, ArH), 7.73–
7.75 (2H, m, ArH); dC (100 MHz, CDCl3) 14.1 (OCH2CH3),
26.1 (C(3)), 27.8 (C(CH3)3), 31.7 (C(4)), 52.4 (CO2CH3), 60.6
(OCH2CH3), 62.6 (C(2)), 83.3 (C(CH3)3), 115.6 (NCC), 128.2,
128.6, 132.1 (ArC), 139.6 (quaternary ArC), 150.5, 155.5, 166.6,
171.8 (C(5), CO2CH3, CO2C2H5, COC(CH3)3), 193.6 (C6H5CO).
(S)-Ethyl 2-(5-(hydroxymethyl)pyrrolidin-2-ylidene)-3-oxo-3-
phenylpropanoate 4a
To a solution of enamine 3 (0.10 g, 0.32 mmol) in absolute ethanol
(3 ml) was added sodium borohydride (0.050 g, 1.3 mmol) at
0
◦C and stirred for 10 minutes, and then at room temperature
for 5 hours. Glacial acetic acid was then carefully added to the
mixture with stirring and cooling in an ice bath, until pH 5.0
was reached. The solvent was evaporated in vacuo and silica gel
chromatography [EtOAc] afforded the alcohol 4a (0.070 g, 71%),
as a mixture of diastereomers in a ratio of 1 : 5, as a viscous oil. Rf =
0.36 (EtOAc); mmax/cm−1 (neat) 3340, 3044, 1659, 1589, 1476; dH
(400 MHz, CDCl3) (major) 0.71 (3H, t, J 7.0, OCH2CH3), 1.67–
1.75 (1H, m, C(3)HH), 2.03–2.13 (1H, m, C(3)HH), 3.08–3.18
(2H, m, C(4)H2), 3.31 (1H, dd, J 11.4, 6.9, CHHOH), 3.64–3.86
(3H, m, CHHOH, OCH2CH3), 4.04–4.51 (1H, m, C(2)H), 7.25–
7.60 (5H, m, C6H5), 11.01 (1H, br, NH); dC (100 MHz, CDCl3)
13.5 (OCH2CH3), 22.8 (C(3)), 33.0 (C(4)), 59.5 (OCH2CH3), 62.5
(C(2)), 64.6 (CH2OH), 98.1 (NCC), 125.6, 127.6, 129.4 (ArC),
143.5 (quaternary ArC), 169.13, 173.0 (C(5), COOC2H5), 195.2
(C6H5CO); m/z (APCI+) 290 (M + H+, 4%), 244 (100%). dH
(400 MHz, CDCl3) (minor) 1.24 (3H, t, J 7.1, OCH2CH3), 1.67–
1.75 (1H, m, C(3)HH), 2.03–2.13 (1H, m, C(3)HH), 2.59–2.61
(2H, m, C(4)H2), 3.42–3.58 (2H, m, CH2OH), 3.64–3.86 (1H, m,
C(2)H), 4.04–4.51 (2H, m, OCH2CH3), 7.25–7.6 (5H, m, C6H5),
9.47 (1H, br, NH); dC (100 MHz, CDCl3) 14.6 (OCH2CH3), 23.8
(C(3)), 31.7 (C(4)), 59.1 (OCH2CH3), 61.6 (C(2)), 65.1 (CH2OH),
95.6 (NCC), 125.6, 128.4, 131.7 (ArC), 142.9 (quaternary ArC),
170.1, 170.8 (C(5), CO2C2H5), 195.4 (C6H5CO).
(S)-Diethyl 2-(2-(hydroxymethyl)pyrrolidin-5-ylidene)malonate 4b
(S)-N-tert-Butoxycarbonyl-5-(ethoxycarbonylethylidene)-2-
hydroxymethylpyrrolidine 6
To a solution of enamine 2c (3.0 g, 10 mmol) in absolute ethanol
(150 ml) was added sodium borohydride (1.5 g, 40 mmol) at 0 ◦C
and stirring continued for 30 minutes, then at room temperature
To a solution of carbamate 5a (0.20 g, 0.48 mmol) in abso-
lute ethanol (10 ml) was added sodium borohydride (0.040 g,
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0.96 mmol) at 0 ◦C and the reaction was refluxed for 23 hours.
Glacial acetic acid was then carefully added to the mixture with
stirring and cooling in an ice bath, until pH 5.0 was reached.
The mixture was partitioned between CH2Cl2 and water. The
organic layer was washed with saturated solution of NaHCO3,
water and brine, dried with MgSO4, and the solvent evaporated.
Silica gel chromatography [petrol (40–60) : EtOAc 3 : 2] afforded
alcohol 6 (0.014 g, 11%). Rf = 0.60 (3 : 2 petrol (40–60) :
EtOAc); dH (400 MHz, CDCl3) 1.41–1.44 (3H, m, OCH2CH3),
1.48 (9H, s, C(CH3)3), 1.93–2.31 (2H, m, C(3)H2), 2.94–3.07 (1H,
m, C(4)HH), 3.38–3.45 (1H, m, C(4)HH), 4.09–4.24 (4H, m,
CH2OH, 2 × OCH2CH3), 4.57–4.6 (1H, m, C(2)H), 6.55 (1H, m,
CHCO2Et); dC (125 MHz, CDCl3) 14.1 (OCH2CH3), 25.4 (C(3)),
HCH2CH2), 28.3 (C(CH3)3), 29.5 (C(4)), 59.2, 61.3 (CH2OH,
OCH2CH3), 62.1 (C(2)), 95.6 (C(CH3)3), 96.8 (CHCO2Et), 156.5,
168.6, 171.5 (C(5), COC(CH3)3, CO2C2H5); m/z (CI+) 366 (M +
H+, 100%), 112 (65%); m/z (EI+) 286 (1%), 224 (100%).
reference number 20927323). The trans-diastereomer, on the other
hand, was found to be a transparent oil.
(ii) Preparation by reduction of amide 8. The amide 8 (0.12 g,
0.30 mmol) was dissolved in CH2Cl2 (1 ml) to which was added
10% Pd/C (0.07 g) in EtOH (10 ml). The hydrogenation apparatus
was flushed 3 times with hydrogen, and finally set to a pressure
of 5 atm and the mixture stirred for 23.5 hours. Careful filtration
R
through Celiteꢀ using EtOAc, followed by solvent removal gave
amine (0.10 g, 80%) as a separable mixture of cis- and trans-
diastereomers 7b, in a ratio of 9 : 1 using silica gel chromatography
[petrol (40–60) : EtOAc 3 : 2].
trans-7b. Rf = 0.50 (3 : 2 petrol (40–60) : EtOAc); [a]2D5 = −137
(c = 0.1, CHCl3); mmax/cm−1 (neat) 3061, 1736, 1648, 1603; dH
(400 MHz, CDCl3) 1.01 (3H, t, J 7.1, OCH2CH3), 1.26 (3H,
t, J 7.1, OCH2CH3), 1.29 (3H, t, J 7.1, OCH2CH3), 1.94–1.98
(1H, m, C(3)Hꢀ), 2.21–2.32 (3H, m, C(3)H, C(4)HꢀH), 3.80–3.91
(2H, m, OCH2CH3), 4.10–4.26 (4H, m, 2 × OCH2CH3), 4.39
(1H, d, J 5.2, NCHCH), 4.44–4.46 (1H, m, C(2)H), 4.99 (1H,
dd, J 5.2, 10.8, C(5)H), 7.32–7.39 (5H, m, C6H5); dC (100 MHz,
CDCl3) 13.8, 13.9, 14.0 (3 × OCH2CH3), 26.1 (C(4)), 29.5 (C(3)),
52.0 (NCHCH), 56.9 (C(5)), 61.3, 61.4, 61.6 (3 × OCH2CH3),
62.5 (C(2)), 126.8, 128.2, 129.9 (ArC), 136.6 (quaternary ArC),
167.8, 168.2, 171.4, 171.8 (3 × CO2C2H5, C6H5CO); m/z (APCI+)
406 (M + H+, 100%), 246 (40%), 105 (5%); HRMS (M + H+)
406.1862, C21H28NO7 requires 406.1866. dH (VT) (500 MHz, 373 K
in d6-DMSO) 1.02 (3H, t, J 6.5, OCH2CH3), 1.21 (3H, t, J
7, OCH2CH3), 1.26 (3H, t, J 7, OCH2CH3), 1.93–1.94 (1H,
m, C(3)Hꢀ), 2.12–2.15 (2H, m, C(4)HꢀH), 2.31–2.39 (1H, m,
C(3)H), 3.91 (2H, br, OCH2CH3), 4.13–4.15 (3H, m, OCH2CH3,
NCHCH), 4.20–4.24 (2H, m, OCH2CH3), 4.49 (1H, dd, J 2.5, 9.0,
C(2)H), 4.80–4.83 (1H, m, C(5)H), 7.37–7.51 (5H, m, C6H5).
(2S,5S and 2S,5R)-5-(Di(ethoxycarbonyl)methyl)-pyrrolidine-
2-carboxylic acid ethyl ester 7a
The enamine 2c (1.00 g, 3.30 mmol) was dissolved in HOAc
(7.50 ml) to which was added Adams’ catalyst (0.16 g) in TFA
(2.5 ml). The hydrogenation apparatus was flushed 3 times with
hydrogen, and finally set to a pressure of 4.5 atm and the mixture
R
stirred for 48 hours. Careful filtration through Celiteꢀ using
EtOAc, followed by solvent removal, gave a residue which was
dissolved in CH2Cl2 (50 ml) and washed with dilute aqueous
ammonia (3.2%) (50 ml), water and brine. The solution was dried
over MgSO4 and the solvent removed to give quantitative yield
(1.01 g) of amine 7a as in inseparable mixture of diastereomers
in a ratio of 1 : 2. Rf = 0.37 (3 : 2 petrol (40–60) : EtOAc);
mmax/cm−1 (neat) 3349, 1735; dH (400 MHz, CDCl3) (major) 1.26–
1.32 (9H, m, 3 × OCH2CH3), 1.61–1.65 (1H, m, C(4)HH), 1.85–
1.90 (1H, m, C(3)HH), 1.95–2.01 (1H, m, C(4)HH), 2.16–2.23
(1H, m, C(3)HH), 3.30 (1H, d, J 9.3, NCHCH), 3.79–3.82 (1H,
m, C(2)H), 3.91 (1H, dd, J 9.3, 7.3, C(5)H), 4.13–4.25 (6H, m,
3 × OCH2CH3); dC (100 MHz, CDCl3) 13.8 (3 × OCH2CH3), 29.1
(C(4)), 29.2 (C(3)), 56.9 (C(5)), 58.6 (NCHCH), 59.3 (C(2)), 61.0,
61.4, 61.5 (3 × OCH2CH3), 168.0, 168.4, 175.2 (3 × CO2C2H5);
m/z (APCI+) 302 (M + H+, 18%), 142 (100%).
cis-7b. Mp 80–82 ◦C Rf = 0.48 (3 : 2 petrol (40–60) : EtOAc);
[a]2D5 = +10 (c = 0.1, CHCl3); mmax/cm−1 (neat) 1732, 1650; dH
(400 MHz, CDCl3) 1.21 (3H, t, J 6.5, OCH2CH3), 1.26 (3H,
t, J 7.0, OCH2CH3), 1.30 (3H, t, J 7.0, OCH2CH3), 2.06 (3H,
br, C(3)H2, C(4)Hꢀ), 2.46 (1H, br, C(4)H), 4.11–4.32 (8H, m,
C(2)H, NCHCH, 3 × OCH2CH3), 4.88–4.94 (1H, m, C(5)H),
7.35–7.45 (5H, m, C6H5); dC (100 MHz, CDCl3) 13.9, 14.0, 14.1
(3 × OCH2CH3), 27.9 (C(4)), 29.7 (C(3)), 54.9 (NCHCH), 57.4
(C(5)), 61.3 (3 × OCH2CH3), 61.5 (C(2)), 125.8, 128.4, 130.3
(ArC), 136.6 (quaternary ArC), 167.8, 172.1 (3 × CO2C2H5,
C6H5CO); m/z (ES+) 428 (M + Na, 100%), 406 (M + H+, 90%),
360 (22%), 246 (35%); HRMS (M + H+) 406.1857, C21H28NO7
requires 406.1866. dH (VT) (500 MHz, 373 K in d6-DMSO) 1.18
(3H, t, J 7, OCH2CH3), 1.21 (3H, t, J 7.5, OCH2CH3), 1.25 (3H,
t, J 7.5, OCH2CH3), 1.97–2.00 (2H, m, C(3)Hꢀ, C(4)Hꢀ), 2.20
(1H, br, C(3)H), 2.30–2.31 (1H, m, C(4)H), 4.01 (1H, d, J 7.5,
NCHCH), 4.07–4.12 (4H, m, 2 × OCH2CH3), 4.18–4.21 (2H, m,
OCH2CH3), 4.30–4.31 (1H, m, C(2)H), 4.81 (1H, dd, J 6.0, 7.5
C(5)H), 7.36–7.51 (5H, m, C6H5). dH (400 MHz, C6D6) 0.84 (3H,
t, J 7.1, OCH2CH3), 0.92 (3H, t, J 7.1, OCH2CH3), 1.02 (3H,
t, J 7, OCH2CH3), 1.32 (1H, br, C(3)H), 1.61 (1H, br, C(3)Hꢀ),
2.08–2.18 (1H, m, C(4)Hꢀ), 2.32 (1H, br, C(4)H), 3.74–3.95 (2H,
m, OCH2CH3), 4.00–4.04 (3H, m, C(2)H, OCH2CH3), 4.14–4.23
(2H, m, OCH2CH3), 4.76 (1H, br, NCHCH), 5.19 (1H, br, C(5)H),
7.00–7.07 (3H, m, ArH), 7.57–7.60 (2H, m, ArH).
(2S,5S and 2S,5R)-N-Benzoyl-5-(di(ethoxycarbonyl)methyl)-
pyrrolidine-2-carboxylic acid ethyl ester 7b
(i) Preparation by protection of amine 2c. Dry benzoyl chlo-
ride (3.20 ml, 27.4 mmol) was added to a solution of amine
2c (0.83 g, 2.7 mmol) in dry pyridine (2.50 ml, 30.7 mmol)
and the reaction was allowed to stir for 4 hours between 30–
◦
◦
40 C. The reaction was quenched and neutralised at 0 C with
2 M HCl and stirred for 1 hour. CH2Cl2 (50 ml) was added
and the organic layer was washed with water and brine. It was
dried with MgSO4 and evaporated to give a mixture (1.0 g, 93%)
of cis- and trans-diastereomers, in variable ratios separable by
silica gel chromatography [petrol (40–60) : EtOAc 3 : 2]. A small
sample of cis- was recrystallised from EtOAc, petrol (40–60), to
give transparent crystals, for single crystal X-ray analysis (CCDC
2608 | Org. Biomol. Chem., 2006, 4, 2600–2615
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(2S,5S and 2S,5R)-N-Acetyl-5-(di(ethoxycarbonyl)methyl)-
pyrrolidine-2-carboxylic acid ethyl ester 7c
(NCH2CO, 3 × CO2C2H5); m/z (ES+) 438 (M + Na, 100%), 416
(M + H+, 40%); HRMS (M + H+) 416.2283, C20H34NO8 requires
416.2284.
Acetic anhydride (0.31 ml, 3.3 mmol) was added to a solution of
amine 7a (0.10 g, 0.33 mmol) in pyridine (0.30 ml, 3.7 mmol) and
the reaction was allowed to stir for 24 hours at room temperature.
The reaction was quenched with water. Dichloromethane was
added and the organic layer was washed with 10% HCl, water,
saturated solution of NaHCO3, water and brine, dried with MgSO4
and the solvent evaporated. Silica gel chromatography ([petrol
(40–60) : EtOAc 1 : 1] afforded the amide 7c (0.110 g, 100%) as a
separable mixture of diastereomers in a 1 : 3.8 ratio.
Minor diastereomer: Rf = 0.46 (2 : 3 petrol (40–60) : EtOAc);
mmax/cm−1 (neat) 1740, 1651; dH (400 MHz, CDCl3) 1.23–1.28 (9H,
m 3 × OCH2CH3), 1.95 (3H, s, NCOCH3), 1.98–2.02 (1H, m,
C(3)Hꢀ), 2.16–2.42 (3H, m, C(3)H, C(4)HꢀH), 4.11–4.25 (6H,
m, 3 × OCH2CH3), 4.33–4.36 (1H, m, C(2)H), 4.40 (1H, d, J
4.7, NCHCH), 4.72–4.76 (1H, m, C(5)H); dC (100 MHz, CDCl3)
13.9, 14.0, 14.1 (3 × OCH2CH3), 22.1 (NCOCH3), 26.1 (C(4)),
29.4 (C(3)), 51.6 (NCHCH), 57.2 (C(5)), 61.2, 61.9 (C(2), 3 ×
OCH2CH3), 168.0, 168.4, 170.4, 172.2 (NCOCH3, 3 × CO2C2H5);
m/z (APCI+) 344 (M + H+, 20%), 298 (23%), 184 (54%), 142
(100%); HRMS (M + H+) 344.1712, C16H26NO7 requires 344.1709.
Major diastereomer: Rf = 0.30 (2 : 3 petrol (40–60) : EtOAc);
mmax/cm−1 (neat) 1732, 1651; dH (400 MHz, CDCl3) 1.20–1.28
(9H, m 3 × OCH2CH3), 2.01 (3H, s, NCOCH3), 2.11–2.25
(4H, m, C(3)HH, C(4)HH), 4.05–4.24 (6H, m, 3 × OCH2CH3),
4.32–4.35 (1H, m, C(2)H), 4.60–4.68 (2H, m, C(5)H, NCHCH);
dC (100 MHz, CDCl3) 13.9, 14.0, 14.1 (3 × OCH2CH3), 22.6
(NCOCH3), 26.1 (C(4)), 28.7 (C(3)), 53.3 (NCHCH), 57.7 (C(5)),
61.1, 61.2, 61.4 (C(2), 3 × OCH2CH3), 167.8, 170.9, 171.3, 172.1
(NCOCH3, 3 × CO2C2H5); m/z (APCI+) 344 (M + H+, 100%),
298 (18%), 184 (23%), 142 (35%); HRMS (M + H+) 344.1699,
C16H26NO7 requires 344.1709.
(S)-N-Benzoyl-5-(di(ethoxycarbonyl)methylidene)-pyrrolidine-2-
carboxylic acid ethyl ester 8
To a solution of enamine 2c (1.88 g, 6.30 mmol) in dry CH2Cl2
(25 ml) were added dry triethylamine (2.60 ml, 18.89 mmol),
dry benzoyl chloride (1.50 ml, 12.6 mmol) and (dimethy-
lamino)pyridine (0.77 g, 6.3 mmol) as a solution in CH2Cl2 (5 ml).
The mixture was refluxed for 48 hours, cooled, quenched and
washed with saturated solution of NH4Cl, water and brine, dried
with MgSO4, and the solvent evaporated. Silica gel chromatogra-
phy [petrol (40–60) : EtOAc 7 : 3] afforded the enamide 8 (1.0 g,
41%) as bright yellow crystals. Mp 85–87 ◦C, Rf = 0.37 (3 : 2
petrol (40–60) : EtOAc); [a]2D6 = −60 (c = 0.08, CHCl3); mmax/cm−1
(neat) 1740; dH (400 MHz, CDCl3) 1.08 (3H, t, J 7.1, OCH2CH3),
1.29–1.38 (6H, m, 2 × OCH2CH3), 2.12–2.31 (1H, m, C(3)HH),
2.34–2.42 (1H, m, C(3)HH), 3.02–3.11 (1H, m, C(4)HH), 3.16–
3.23 (1H, m, C(4)HH), 3.76–3.81 (1H, m, OCHHCH3), 3.89–3.92
(1H, m, OCHHCH3), 4.11–4.21 (4H, m, 2 × OCH2CH3), 4.84 (1H,
dd, J 9.8, 2.0, C(2)H), 7.34–7.47 (3H, m, ArH), 7.50–7.60 (2H, m,
ArH); dC (100 MHz, CDCl3) 14.0, 14.1, 14.4 (3 × OCH2CH3), 25.4
(C(3)), 31.6 (C(4)), 59.8 (2 × OCH2CH3), 61.7 (OCH2CH3), 63.4
(C(2)), 109.6 (NCC), 128.3, 128.7, 131.9 (ArC), 133.8 (quaternary
ArC), 157.0 (C(5)), 165.3, 166.0, 171.1, 171.3 (C(5), 3 × CO2C2H5,
C6H5CO); m/z (ES+) 404 (M + H+, 60%), 358 (55%), 254 (100%);
HRMS (M + H+) 404.1697, C21H26NO7 requires 404.1709.
(S)-N-Methyl-5-(di(ethoxycarbonyl)methylidene)-pyrrolidine-2-
carboxylic acid ethyl ester 9a
To NaH (0.030 g, 0.75 mmol) in dry CH2Cl2 (2 ml) at room tem-
perature under argon was added enamine 2c (0.11 g, 0.38 mmol)
as a solution in dry CH2Cl2 (2 ml) and the solution stirred for
2.75 hours. Methyl triflate (0.11 ml, 0.94 mmol) was added at
−30 ◦C and the reaction allowed to come to room temperature
over 3 hours. The reaction was quenched with 2 M HCl at 0 ◦C,
neutralised with saturated solution of NaHCO3 and extracted with
CH2Cl2. The organic layer was washed with brine, dried over
MgSO4 and the solvent evaporated. Silica gel chromatography
[petrol (40–60) : EtOAc 1 : 1] afforded the N-methyl enamine 9a as
yellow oil (0.022 g, 19%). Rf = 0.56 (1 : 1 petrol (40–60) : EtOAc);
mmax/cm−1 (neat) 1741, 1688, 1578; dH (500 MHz, CDCl3) 1.27–1.34
(9H, m, 3 × OCH2CH3), 2.05–2.10 (1H, m, C(3)Hꢀ), 2.25–2.33
(1H, m, C(3)H), 2.87 (NCH3), 3.07–3.14 (1H, m, C(4)Hꢀ), 3.26–
3.32 (1H, m, C(4)H), 4.16–4.27 (7H, m, C(2)H, 3 × OCH2CH3);
dC (125 MHz, CDCl3) 14.1, 14.2 (3 × OCH2CH3), 25.6 (C(3)), 33.1
(C(4)), 35.7 (NCH3), 60.0, 61.5 (3 × OCH2CH3), 68.9 (C(2)), 91.5
(NCC), 165.0, 167.5, 171.1 (C(5), 3 × CO2C2H5); m/z (ES+) 336
(M + Na, 84%), 314 (M + H+, 50%), 268 (100%); HRMS (M +
H+) 314.1609, C15H24NO6 requires 314.1604.
(2S,5R)-N-tert-Butoxycarbonylmethyl-5-(di(ethoxycarbonyl)-
methyl)-pyrrolidine-2-carboxylic acid ethyl ester 7d
A 1 M solution of LiHMDS (0.52 ml) in THF was added to
a solution of amine 7a (0.10 g, 0.34 mmol) in THF (3 ml) at
0 ◦C and stirred for 15 minutes. tert-Butyl bromoacetate (0.12 ml,
0.69 mmol) was added dropwise as a solution in THF (2 ml) and
the reaction was allowed to come to room temperature and stir for
7 hours. The reaction was quenched at 0 ◦C by adding a saturated
solution of NH4Cl, followed by addition of water and EtOAc. The
organic layer was separated, washed with brine, dried with MgSO4
and the solvent evaporated. Silica gel chromatography ([petrol
(40–60) : EtOAc 4 : 1] afforded the amine 7d (0.072 g, 50%) as a
transparent oil. Rf = 0.36 (4 : 1 petrol (40–60) : EtOAc); [a]D22
=
−24.6 (c = 0.13, CHCl3); mmax/cm−1 (neat) 1735; dH (400 MHz,
CDCl3) 1.21–1.27 (9H, m, 3 × OCH2CH3), 1.43 (9H, s, C(CH3)3),
1.81–1.87 (1H, m, C(4)Hꢀ), 1.94–2.02 (1H, m, C(3)Hꢀ), 2.14–
2.27 (2H, m, C(3)H, C(4)H), 3.45 (1H, d, J 18.3, NCHHCO),
3.48 (1H, d, J 8.1, NCHCH), 3.61 (1H, d, J 18.3, NCHHCO),
3.73 (1H, t, J 7.6, C(2)H), 3.89–3.84 (1H, m, C(5)H), 4.08–4.21
(6H, m, 3 × OCHHCH3); dC (100 MHz, CDCl3) 14.0, 14.1,
14.2 (3 × OCH2CH3), 28.2 (C(CH3)3), 28.6 (C(3)), 29.5 (C(4)),
53.0 (NCH2CO), 57.5 (NCHCH), 60.4, 61.1 (3 × OCH2CH3),
62.5 (C(5), 64.9 (C(2)), 81.0 (C(CH3)3), 168.0, 168.3, 170.9, 174.0
(S)-N-Ethyl-5-(di(ethoxycarbonyl)methyl)-pyrrolidine-2-
carboxylic acid ethyl ester 9b
To a suspension of NaH (0.18 g, 7.4 mmol) in dry CH2Cl2 (5 ml)
was added a solution of enamine 2c (1.11 g, 3.71 mmol) in CH2Cl2
(5 ml) at 0 ◦C. The mixture was stirred at this temperature for 15
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minutes followed by stirring at room temperature for 2.5 hours.
Ethyl triflate (1.21 ml, 9.27 mmol) was added to the mixture
between −40 and −30 ◦C and the reaction allowed to come
to room temperature and stir for 24 hours. The reaction was
quenched with water at 0 ◦C. Dichloromethane was added and the
organic layer was washed with water and brine. It was dried with
MgSO4 and evaporated under vacuum, using room temperature
water bath. Silica gel chromatography ([petrol (40–60) : EtOAc 3 :
2] afforded the N-ethyl enamine 9b (0.70 g, 58%) as transparent
oil. Rf = 0.39 (3 : 2 petrol (40–60) : EtOAc); [a]2D4 = +3.5 (c = 0.1,
CHCl3); mmax/cm−1 (neat) 1741, 1689, 1571; dH (500 MHz, CDCl3)
1.13 (3H, t, J 7.2, NCH2CH3), 1.25–1.33 (9H, m 3 × OCH2CH3),
2.02–2.08 (1H, m, C(3)HH), 2.20–2.28 (1H, m, C(3)HH), 3.08–
3.16 (1H, m, C(4)HH), 3.19–3.26 (1H, m, NCHHCH3), 3.31–3.40
(2H, m, C(4)HH, NCHHCH3), 4.16–4.28 (7H, m, C(2)H, 3 ×
OCH2CH3); dC (125 MHz, CDCl3) 11.8 (NCH2CH3), 14.0, 14.1,
14.2 (3 × OCH2CH3), 25.6 (C(3)), 33.4 (C(4)), 43.2 (NCH2CH3),
59.6, 61.0, (3 × OCH2CH3), 65.6 (C(2)), 91.5 (NCC), 163.3 (C(5)),
167.9, 171.5 (3 × CO2C2H5); m/z (ES+) 350 (M + Na, 82%),
328 (M + H+, 30%), 282 (100%); HRMS (M + H+) 328.1763,
C16H26NO6 requires 328.1760.
water and brine. The solution was dried over MgSO4 and the
solvent removed to give amine 10 (0.074 g, 73%) as transparent
oil. Rf = 0.51 (3 : 2 petrol (40–60) : EtOAc); mmax/cm−1 (CHCl3)
3350, 1732, 1682; dH (400 MHz, CDCl3) 1.17–1.35 (9H, m, 3 ×
OCH2CH3), 1.37–1.42 (2H, m, C(3)H2), 1.43 (9H, s, C(CH3)3),
1.57–1.71 (2H, m, C(4)H2), 1.84–1.90 (2H, m, C(2)H2), 2.15
(1H, br, NH), 3.17–3.33 (4H, m, C(5)H, C(1)H, NHCH2), 4.10–
4.20 (6H, m, 3 × OCH2CH3); dC (100 MHz, CDCl3) 14.0, 14.2
(3 × OCH2CH3), 23.5 ((C(4)), 28.0 (C(CH3)3), 28.5 (C(2)), 32.8
(C(3)), 49.8 (NHCH2), 51.8 (C(1)), 60.7 (C(5)), 61.1, 61.4 (3 ×
OCH2CH3), 81.2 (C(CH3)3), 169.3, 170.9, 174.3 (3 × CO2C2H5,
NHCH2CO); m/z (ES+) 418 (M + Na, 100%), 418 (M + H+, 89%);
HRMS (M + H+) 418.2440, C20H36NO8 requires 418.2441.
(S)-Diethyl 2-(4-benzamido-5-hydroxypentyl)malonate 11a
To a solution of amide 7b (1.27 g, 3.12 mmol) in absolute ethanol
(50 ml) was added sodium borohydride (0.470 g, 12.5 mmol) at 0 ◦C
and stirring continued for 30 minutes, then at room temperature
for 15 hours. Glacial acetic acid was then carefully added to the
mixture with stirring and cooling in an ice bath, until pH 5.0
was reached. The mixture was partitioned between CH2Cl2 and
water. The organic layer was washed with saturated solution of
NaHCO3, water and brine, dried with MgSO4, and evaporated.
Silica gel chromatography [CH2Cl2 : MeOH 9 : 1] afforded the
alcohol 11a (0.46 g, 40%). Rf = 0.79 (9 : 1 CH2Cl2 : MeOH);
dH (400 MHz, CDCl3) 1.18–1.27 (6H, m, 2 × OCH2CH3), 1.39–
1.48 (2H, m, CHCH2CH2), 1.59–1.71 (2H, m, CH2CHCH2), 1.87–
1.97 (2H, m, CH2CH(CO2Et)2), 3.33 (1H, t, J 7.4, CH(CO2Et)2),
3.65–3.69 (2H, m, CH2OH), 4.09–4.24 (5H, m, HNCH, 2 ×
OCH2CH3), 6.60 (1H, br, NH), 7.35–7.58 (3H, m, ArH), 7.76–7.81
(2H, m, ArH); dC (100 MHz, CDCl3) 14.0, 14.2 (2 × OCH2CH3),
23.8 (CHCH2CH2), 28.4 (CH2CH(CO2Et)2), 30.7 (CH2CHCH2),
51.7, 51.8 (CH(CO2Et)2, HNCH), 61.4 (2 × OCH2CH3), 65.0
(CH2OH), 128.3, 128.6, 131.6 (ArC), 134.2 (quaternary ArC),
168.2, 169.4 (2 × CO2C2H5); m/z (CI+) 366 (M + H+, 100%),
112 (65%); m/z (EI+) 334 (27%), 320 (6%), 122 (18%), 105 (100%)
along with minor amounts of triethyl (S)-5-(benzoylamino)-1,1,5-
pentanetricarboxylate 11b (0.08 g, 6%) Rf = 0.96 (9 : 1 CH2Cl2 :
MeOH); [a]D25 = +19.2 (c = 0.19, CHCl3); mmax/cm−1 (neat)
3329, 1732, 1645; dH (400 MHz, CDCl3) 1.21–1.25 (6H, m, 2 ×
OCH2CH3), 1.28 (3H, t, J 7.1, OCH2CH3), 1.78–1.84 (2H, m,
CHCH2CH2), 1.90–2.05 (4H, m, HNCHCH2, CH2CH(CO2Et)2),
3.31 (1H, t, J 7.5, CH(CO2Et)2), 4.11–4.26 (6H, m, 3 ×
OCH2CH3), 4.80 (1H, dt, J 5.3, 7.3, HNCH), 6.74 (1H, d, J
7.7, NH), 7.42–7.54 (3H, m, ArH), 7.79–7.82 (2H, m, ArH); dC
(100 MHz, CDCl3) 14.1 (3 × OCH2CH3), 23.0 (CHCH2CH2),
28.2 (CH2CH(CO2Et)2), 32.2 (HNCHCH2), 51.7 (CHCO2Et),
52.3 (HNCH), 61.4, 61.6 (3 × OCH2CH3), 127.0, 128.6, 131.7
(ArC), 133.9 (quaternary ArC), 167.0, 169.2, 172.4 (COPh, 3 ×
CO2C2H5); m/z (CI+) 408 (M + H+, 100%), 334 (25%), 122
(15%), 105 (20%); HRMS (M + H+) 408.2023, C21H30NO7 requires
408.2022 and minor amounts of ethyl (S)-6-(benzoylamino)-7-
hydroxy-2-(hydroxymethyl)heptanoate 11c (0.07 g, 7% (1 : 1)) Rf =
0.52 (9 : 1 CH2Cl2 : MeOH); (Diastereomer 1) dH (400 MHz,
CDCl3) 1.21 (3H, t, J 7.1, OCH2CH3), 1.36–1.46 (2H, m,
CHCH2CH2), 1.60–1.69 (2H, m, NHCHCH2), 1.73–1.79 (2H, m,
HOCH2CHCH2), 2.51–2.55 (1H, m, CHCO2Et), 3.67–3.75 (2H,
m, OHCH2CHNH), 4.08–4.14 (2H, m, HOCH2CHCO2Et), 4.22
(S)-N-tert-Butoxycarbonylmethyl-5-(di(ethoxycarbonyl)-
methylidene)-pyrrolidine-2-carboxylic acid ethyl ester 9c
A 1 M solution of LiHMDS (0.6 ml) in THF was added to a
solution of enamine 2c (0.12 g, 0.40 mmol) in THF (4 ml) at
0 ◦C and stirred for 15 minutes. tert-Butyl bromoacetate (0.13 ml,
0.78 mmol) was added drop wise as a solution in THF (3 ml) and
the reaction was allowed to come to room temperature and stir for
6 hours. The reaction was quenched at 0 ◦C by adding a saturated
solution of NH4Cl, followed by addition of water and EtOAc.
EtOAc layer was separated, dried with MgSO4 and evaporated.
Silica gel chromatography ([petrol (40–60) : EtOAc 4 : 1] afforded
the N-alkylated enamine 9c (0.044 g, 27%) as yellow oil. Rf =
0.68 (4 : 1 petrol (40–60) : EtOAc); [a]2D3 = +105.6 (c = 0.04,
CHCl3); mmax/cm−1 (neat) 1750, 1716, 1682, 1578; dH (400 MHz,
CDCl3) 1.15–1.28 (9H, m, 3 × OCH2CH3), 1.42 (9H, s, C(CH3)3),
2.01–2.09 (1H, m, C(3)HH), 2.25–2.35 (1H, m, C(3)HH), 3.00–
3.10 (1H, m, C(4)HH), 3.16–3.24 (1H, m, C(4)HH), 3.71 (1H,
d, J 18.8, NCHHCO), 3.99 (1H, d, J 18.8, NCHHCO), 4.03–
4.22 (6H, m, 3 × OCH2CH3), 4.34 (1H, dd, J 8.9, 4.0, C(2)H);
dC (100 MHz, CDCl3) 14.1, 14.3 (3 × OCH2CH3), 25.9 (C(3)),
27.9 (C(CH3)3), 33.0 (C(4)), 49.5 (NCH2CO), 60.7, 61.2, 61.6 (3 ×
OCH2CH3), 67.0 (C(2)), 82.3 (C(CH3)3), 93.0 (NCC), 163.8, 167.0,
171.1 (C(5), NCH2CO, 3 × CO2C2H5); m/z (ES+) 436 (M + Na,
58%), 414 (M + H+, 82%), 368 (100%); HRMS (M + H+) 414.2130,
C20H32NO8 requires 414.2128.
(S)-Triethyl 5-(2-tert-butoxy-2-oxoethylamino)pentane-1,1,5-
tricarboxylate 10
The enamine9c (0.10 g, 0.24mmol)was dissolved inHOAc(7.5 ml)
to which was added Adams’ catalyst (0.05 g) in TFA (2.5 ml).
The hydrogenation apparatus was flushed 3 times with hydrogen,
and finally set to a pressure of 4.5 atm and the mixture stirred for
R
48 hours. Careful filtration through Celiteꢀ using EtOAc, followed
by solvent removal, gave a residue which was dissolved in CH2Cl2
(50 ml) and washed with dilute aq. ammonia (3.2%) (50 ml),
2610 | Org. Biomol. Chem., 2006, 4, 2600–2615
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(2H, q, J 7.1, OCH2CH3), 4.78 (1H, m, HNCH), 7.00 (1H, d,
J 7.9, NH), 7.36–7.53 (3H, m, ArH), 7.75–7.80 (2H, m, ArH);
dC (100 MHz, CDCl3) 14.1 (OCH2CH3), 22.8 (CHCH2CH2),
26.8 (HNCHCH2), 33.0 (HOCH2CHCH2), 50.6 (CHCO2Et),
52.2 (HNCH), 60.6 (HOCH2CHCO2Et), 61.7 (OCH2CH3), 64.7
(OHCH2CHNH), 127.0, 128.6, 131.9 (ArC), 133.7 (quater-
nary ArC), 167.6, 172.8 (COPh, CO2C2H5); m/z (CI+) 324
(M + H+, 100%), 122 (65%). (Diastereomer 2) dH (400 MHz,
CDCl3) 1.29 (3H, t, J 7.1, OCH2CH3), 1.36–1.46 (2H, m,
CHCH2CH2), 1.60–1.69 (2H, m, NHCHCH2), 1.73–1.79 (1H, m,
HOCH2CHCHH), 1.89–1.93 (1H, m, HOCH2CHCHH), 2.51–
2.55 (1H, m, CHCO2Et), 3.63–3.66 (2H, m, OHCH2CHNH),
4.08–4.14 (3H, m, HOCH2CHCO2Et, HNCH), 4.22 (2H, q, J
7.1, OCH2CH3), 6.82 (1H, d, J 8.2, NH), 7.36–7.53 (3H, m, ArH),
7.75–7.80 (2H, m, ArH); dC (100 MHz, CDCl3) 14.1 (OCH2CH3),
23.4 (CHCH2CH2), 27.9 (HNCHCH2), 31.0 (HOCH2CHCH2),
50.6 (CHCO2Et), 51.6 (HNCH), 60.6 (OHCH2CHCO2Et), 62.8
(OCH2CH3), 65.4 (OHCH2CHNH), 127.0, 128.6, 131.6 (ArC),
134.2 (quaternary ArC), 168.2, 175.1 (COPh, CO2C2H5).
9.0, 2.0, C(5)H), 7.19–7.25 (5H, m, CH2C6H5), 7.43–7.47 (3H, m,
COArH), 7.50–7.52 (2H, m, COArH).
(2S,5S)-N-Benzoyl-5-(1,1-di(ethoxycarbonyl)ethyl)pyrrolidine-2-
carboxylic acid ethyl ester 12b
From MeI. To a suspension of NaH (0.04 g, 1 mmol) in THF
(1 ml) was added drop wise a solution of cis-7b (0.20 g, 0.4◦9 mmol)
◦
in THF (2 ml) at 0 C. After 30 minutes of stirring at 0 C, MeI
(0.11 g, 0.77 mmol) was added as a solution in THF (1 ml) and
the mixture was allowed to come to room temperature and stirred
for 27 hours. Water was added at 0 ◦C followed by extraction with
Et2O. The Et2O layer was dried with MgSO4 and evaporated. Silica
gel chromatography ([petrol (40–60) : EtOAc 3 : 2] afforded the title
compound 12b (0.050 g, 25%) as white crystals. A small sample
was recrystallised from EtOAc, petrol (40–60), to give transparent
crystals, for single crystal X-ray analysis (CCDC reference number
20927423). trans-7b gave the same yield under similar conditions.
From MeOTf. To a suspension of KH (0.0280 g, 0.676 mmol)
in dry Et2O (4.5 ml) was added a solution of trans-7b (0.23 g,
0.56 mmol) in dry Et2O (2 ml) at 0 ◦C under argon. The mixture
was stirred at this temperature for 15 minutes followed by stirring
at room temperature for 2.5 hours. Methyl triflate (0.10 ml,
0.84 mmol) was added to the mixture between −40 and −30 ◦C and
the reaction allowed to come to room temperature over 2.5 hours.
The reaction was quenched with 2 M HCl at 0 ◦C, and neutralised
with saturated solution of NaHCO3. EtOAc was added and the
organic layer was washed with brine. It was dried with MgSO4 and
the solvent evaporated. Silica gel chromatography [petrol (40–60) :
EtOAc 3 : 2] afforded the title compound 12b (0.21 g, 88%). Mp 74–
76 ◦C; Rf = 0.49 (3 : 2 petrol (40–60) : EtOAc); [a]2D5 = −94.4 (c =
0.3, CHCl3); mmax/cm−1 (neat) 1726, 1657; dH (400 MHz, CDCl3)
0.99 (3H, t, J 7.0, OCH2CH3), 1.18–1.30 (6H, m, 2 × OCH2CH3),
1.51 (3H, s, NCHCCH3), 1.92–1.93 (1H, m, C(3)Hꢀ), 1.98–2.03
(1H, m, C(4)H), 2.27–2.41 (2H, m, C(3)H, C(4)Hꢀ), 3.76–3.99
(2H, m, OCH2CH3), 4.03–4.33 (4H, m, 2 × OCH2CH3), 4.54 (1H,
d, J 7.9, C(2)H), 5.42 (1H, d, J 7.4, C(5)H), 7.30–7.43 (3H, m,
ArH), 7.46–7.53 (2H, m, ArH); dC (100 MHz, CDCl3) 13.8, 13.9
(3 × OCH2CH3), 17.0 (NCHCCH3), 27.2 (C(4)), 30.4 (C(3)), 52.1
((NCHCCH3), 60.1 (C(5)), 61.2, 61.3, 61.4 (3 × OCH2CH3), 63.6
(C(2)), 127.7, 128.2, 130.2 (ArC), 136.8 (quaternary ArC), 170.6,
171.1, 172.3, 173.1 (NCO, 3 × CO2C2H5); m/z (ES+) 442 (M +
Na, 100%), 420 (M + H+, 12%); HRMS (M + H+) 420.2019,
C22H30NO7 requires 420.2022. dH (VT) (500 MHz, 373 K in d6-
DMSO) 0.96 (3H, t, J 7, OCH2CH3), 1.17 (3H, t, J 7, OCH2CH3),
1.24 (3H, t, J 7, OCH2CH3), 1.44 (3H, s, NCHCCH3), 1.88–
1.90 (1H, m, C(3)Hꢀ), 1.90–1.97 (1H, m, C(4)H), 2.15–2.23 (1H,
m, C(4)Hꢀ), 2.30–2.41 (1H, m, C(3)H), 3.83 (2H, dq, J 7, 5,
OCH2CH3), 4.04 (2H, dq, J 7, 5, OCH2CH3), 4.19 (2H, q, J 7,
OCH2CH3), 4.58 (1H, dd, J 8.0, 1.5, C(2)H), 5.21 (1H, dd, J 9.0,
1.5, C(5)H), 7.39–7.44 (5H, m, C6H5).
(2S,5S)-N-Benzoyl-5-(di(ethoxycarbonyl)(benzyl)methyl)-
pyrrolidine-2-carboxylic acid ethyl ester 12a
To NaH (0.05 g, 2 mmol) in dry DMF (3 ml) at 0 ◦C was added
amide 7b (0.800 g, 1.97 mmol) (mixture of both diastereomers)
as a solution in dry DMF (9 ml) and the solution stirred for
15 minutes. Dry benzyl bromide (0.24 ml, 2.0 mmol) was added
◦
at 0 C and stirred for 5 minutes followed by room temperature
stirring for 17.5 hours. The reaction was quenched with saturated
solution of NH4Cl at 0 ◦C and extracted with CH2Cl2. The organic
layer was washed with water, dried over MgSO4 and evaporated.
Silica gel chromatography (2 columns [petrol (40–60) : EtOAc
3 : 2] and [CH2Cl2 : EtOAc 4 : 1]) afforded the title compound
12a as colourless oil (0.71 g, 73%). Rf = 0.48 (3 : 2 petrol (40–
60) : EtOAc); [a]D25 = −66 (c = 0.1, CHCl3); mmax/cm−1 (neat)
1736, 1656; dH (400 MHz, CDCl3) 0.96 (3H, br, OCH2CH3), 1.03
(3H, t, J 7.1, OCH2CH3), 1.23–1.30 (3H, br, m, OCH2CH3), 1.87
(1H, br, C(3)Hꢀ), 2.15 (1H, br, C(4)H), 2.21–2.33 (2H, m, C(3)H,
C(4)Hꢀ), 3.46 (2H, br, CH2C6H5), 3.77–3.82 (2H, br, OCH2CH3),
3.87–3.95 (1H, m, OCHHCH3), 3.99–4.05 (1H, m, OCHHCH3),
4.10–4.18 (1H, m, OCHHCH3), 4.19–4.24 (1H, m, OCHHCH3),
4.51 (1H, dd, J 9.0, 1.7, C(2)H), 5.58 (1H, br, C(5)H), 7.13–
7.23 (5H, m, CH2C6H5), 7.34–7.4 (3H, m, COArH), 7.56–7.57
(2H, m, COArH); dC (100 MHz, CDCl3) 13.5, 13.6, 13.9 (3 ×
OCH2CH3), 27.3 (C(4)), 30.0 (C(3)), 40.1 (CH2C6H5), 61.1, 61.2,
61.5 (3 × OCH2CH3), 62.1 (C(5)), 63.8 (C(2)), 65.1 (NCHCBn),
126.5, 128.0, 130.2 (CH2ArC), 136.7 (quaternary CH2ArC),128.3,
128.4, 130.5 (COArC), 137.3 (quaternary COArC), 169.5, 170.1
(2 × CO2C2H5), 172.4 C(2)CO2C2H5), 173.6 (NCO); m/z (ES+)
518 (M + Na, 100%), 496 (M + H+, 22%); HRMS (M + H+)
496.2346, C28H34NO7 requires 496.2335.
dH (VT) (500 MHz, 373 K in d6-DMSO) 0.96 (3H, t, J 7,
OCH2CH3), 1.04–1.07 (3H, m, OCH2CH3), 1.20 (3H, t, J 7,
OCH2CH3), 1.88–1.90 (1H, m, C(3)Hꢀ), 2.14–2.16 (1H, m, C(4)H),
2.19–2.26 (1H, m, C(4)Hꢀ), 2.29–2.38 (1H, m, C(3)H), 3.35 (2H, s,
OCH2C6H5), 3.83 (2H, q, J 7, OCH2CH3), 3.91–3.95 (1H, m,
OCHHCH3), 3.99–4.03 (1H, m, OCHHCH3), 4.15 (2H, q, J 7,
OCH2CH3), 4.54 (1H, dd, J 9.5, 2.5, C(2)H), 5.63 (1H, dd, J
N-Benzoyl-5-(1,1-di(ethoxycarbonyl)ethyl)-2-benzyl-pyrrolidine-2-
carboxylic acid ethyl ester 14
n
To a 1.6 M solution of BuLi in hexanes (0.30 ml, 0.45 mmol)
in THF (3 ml) was added diisopropylamine (40 ll, 0.49 mmol),
at 0 ◦C and stirred for 15 minutes. The temperature was lowered
to −78 ◦C and trans-amide 12b (0.16 g, 0.25 mmol) was added
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as a solution in THF (2 ml) and stirred for 30 minutes. Benzyl
bromide (75 ll, 0.49 mmol) was added and the reaction mixture
allowed to come to room temperature and stir for 4 hours. The
reaction was quenched at 0 ◦C by adding saturated solution of
NH4Cl (1.5 ml) followed by addition of water and EtOAc. The
EtOAc layer was separated, dried with MgSO4 and evaporated.
Silica gel chromatography ([petrol (40–60) : EtOAc 7 : 3] afforded
the title compound 14 (0.050 g, 27%) as an inseparable mixture
of trans- and cis-diastereomers in a ratio of 3 : 2 along with 41%
recovery of starting material. Rf = 0.42 (3 : 2 petrol (40–60) :
EtOAc); mmax/cm−1 (neat) 1736, 1669, 1602, 1479; m/z (ES+) 532
(M + Na, 22%), 510 (M + H+, 80%), 420 (100%); HRMS (M +
H+) 510.2499, C29H35NO7 requires 510.2499.
dH (400 MHz, CDCl3) (trans-diastereomer) 1.13–1.37 (9H, m,
3 × OCH2CH3), 1.77–1.79 (4H, m, C(4)H, NCHCCH3), 2.09–2.15
(1H, m, C(4)Hꢀ), 2.42–2.44 (1H, m, C(3)H), 2.63–2.73 (C(3)Hꢀ),
3.13 (1H, br, CHHC6H5), 3.20 (1H, d, J 7.5, CHHC6H5), 4.08–
4.17 (2H, m, OCH2CH3), 4.24–4.32 (4H, m, 2 × OCH2CH3),
6.66–6.7 (1H, m, C(5)H), 7.19–7.59 (8H, m, ArH), 7.79–7.86
(2H, m, NCOArH); dC (100 MHz, CDCl3) 12.3 (NCHCCH3),
13.7, 13.9, 14.6 (3 × OCH2CH3), 23.2 (C(4)), 31.0 (C(3)), 36.4
(CH2C6H5), 60.7, 62.6, 62.7 (3 × OCH2CH3), 62.9 (C(5)), 66.4
(C(2)), 71.9 (NCHCCH3), 127.1, 128.8, 131.9, 140.9, 139.1, 139.9
(ArC), 132.7, 137.1 (quaternary ArC), 166.1, 168.0, 171.1, 172.1
(NCO, 3 × COOC2H5).
of nBuLi in hexanes (1.65 ml, 1.65 mmol, 1 M) to a solution
of 2,2,6,6-tetramethylpiperidine (0.29 ml, 1.7 mmol) in THF at
−78 ◦C. After 15 minutes, the reaction flask was transferred to
an ice bath for 5 minutes, then was cooled to −78 ◦C. A solution
◦
of cis-7b (0.22 g, 0.55 mmol) in THF (3 ml) at −78 C was then
added to the cold solution of LTMP. After 30 minutes, the mixture
was warmed to 0◦ for 5 minutes, then was cooled to −78 ◦C and
MeI (0.14 ml, 2.2 mmols) was added. After 1 hour, the reaction
mixture was warmed to 0 ◦C for 5 minutes and saturated solution
NaHCO3 (2 ml) and brine (2 ml) were added sequentially. The
resulting mixture was extracted with EtOAc thoroughly, dried over
MgSO4, and evaporated. Silica gel chromatography ([petrol (40–
60) : EtOAc 3 : 2] afforded the methylated amide ent-15 (0.10 g,
40%). Rf = 0.43 (3 : 2 petrol (40–60) : EtOAc); product from trans-
[a]2D3 = −23 (c = 0.013, CHCl3); product from cis-[a]2D4 = +13 (c =
0.04, CHCl3); mmax/cm−1 (neat) 1726, 1657; dH (400 MHz, CDCl3)
1.14 (3H, br, OCH2CH3), 1.24–1.41 (6H, m, 2 × OCH2CH3),
1.77 (3H, br, C(2)CH3), 1.94–2.04 (1H, m, C(3)H), 2.14–2.28
(2H, m, C(3)Hꢀ, C(4)Hꢀ), 2.37 (1H, br, C(4)H), 3.32 (1H, br,
NCHCH), 3.91–4.27 (6H, m, 3 × OCH2CH3), 4.79 (1H, br,
C(5)H), 7.27–7.49 (5H, m, C6H5); dC (100 MHz, CDCl3) 13.8, 13.9,
14.1 (3 × OCH2CH3), 23.1 (C(2)CH3), 26.2 (C(4)), 36.7 (C(3)),
54.1 (NCHCH), 59.7 (C(5)), 61.4, 61.5, 61.6 (3 × OCH2CH3),
67.42 (C(2)), 125.3, 127.2, 129.9 (ArC), 136.9 (quaternary ArC),
166.7, 167.6, 170.2, 173.6 (NCO, 3 × COOC2H5); m/z (ES+) 442
(M + Na, 100%), 420 (M + H+, 45%); HRMS (M + H+) 420.2023,
C22H30NO7 requires 420.2022. dH (VT) (500 MHz, 373 K in d8-
toluene) 0.91–0.94 (3H, m, OCH2CH3), 1.03–1.07 (6H, m 2 ×
OCH2CH3), 1.75 (3H, s, C(2)CH3), 1.92–1.95 (1H, m, C(3)H),
2.03–2.05 (1H, m, C(3)Hꢀ), 2.24–2.26 (1H, m, C(4)H), 2.32–2.34
(1H, m, C(4)Hꢀ), 3.76 (1H, br, NCHCH), 3.77–3.87 (2H, m,
OCH2CH3), 3.97–4.03 (4H, m, 2 × OCH2CH3), 4.96–5.0 (1H,
m, C(5)H), 7.06–7.10 (3H, m, ArH), 7.43–7.45 (2H, m, ArH).
dH (400 MHz, CDCl3) (cis-diastereomer) 1.13–1.37 (9H, m,
3 × OCH2CH3), 1.77–1.79 (4H, m, C(4)H, NCHCCH3), 2.42–
2.44 (1H, m, C(4)Hꢀ), 2.57–2.61 (1H, m, C(3)Hꢀ), 2.63–2.73 (2H,
m, C(3)H, CHHC6H5), 3.02 (1H, d, J 7.4, CHHC6H5), 4.08–
4.17 (2H, m, OCH2CH3), 4.24–4.32 (4H, m, 2 × OCH2CH3),
5.83–5.85 (1H, m, C(5)H), 7.19–7.59 (8H, m, ArH), 7.79–7.86
(2H, m, NCOArH); dC (100 MHz, CDCl3) 12.3 (NCHCCH3),
13.8, 14.1, 14.6 (3 × OCH2CH3), 24.0 (C(4)), 31.6 (C(3)), 45.5
(CH2C6H5), 60.4, 62.6, 62.7 (3 × OCH2CH3), 62.9 (C(5)), 66.4
(C(2)), 71.9 (NCHCCH3), 127.1, 128.8, 131.9, 140.9, 139.1, 139.9
(ArC), 132.7, 137.1 (quaternary ArC), 166.0, 168.0, 170.7, 172.3
(NCO, 3 × CO2C2H5).
N-Benzoyl-5-(1,1-di(ethoxycarbonyl)ethyl)-2-methyl-pyrrolidine-
2-carboxylic acid ethyl ester 16
A 1 M solution of LiHMDS (1.94 ml) in THF was added to a
solution of trans-amide 7b (0.26 g, 0.65 mmol) in THF (5 ml) at
0 ◦C and stirred for 15 minutes. Methyl iodide (0.16 ml, 2.6 mmol)
was added and the reaction was allowed to come to room
temperature and stir for 20 hours. The reaction was quenched
at 0 ◦C by adding saturated solution of NH4Cl, followed by
addition of water and EtOAc. The organic layer was separated,
washed with water and brine, dried with MgSO4 and evaporated.
Silica gel chromatography [petrol (40–60) : EtOAc 7 : 3] afforded
the doubly methylated amide 16 (0.014 g, 5%) as a mixture of
inseparable diastereomers in a ratio of 1 : 3, along with amide
12b (0.012 g, 4.0%) and recovered starting material 7b (0.091 g,
35%). The stereochemistry of the two diastereomers of product 16
could not be established. Rf = 0.55 (3 : 2 petrol (40–60) : EtOAc);
mmax/cm−1 (neat) 1725, 1642; dH (400 MHz, CDCl3) 0.99–1.14
(9H, m, 3 × OCH2CH3 (minor diastereomer)), 1.23 (3H, t, J 7.2,
OCH2CH3), 1.29 (3H, t, J 7.0, OCH2CH3), 1.34 (3H, t, J 7.2,
OCH2CH3), 1.51 (3H, s, NCHCCH3 or C(2)CH3), 1.63 (3H, s,
NCHCCH3 or C(2)CH3), 1.92–2.00 (2H, m, C(3)HH), 2.27–2.42
(2H, m, C(4)HH), 3.79–3.91 (6H, m, 3 × OCH2CH3 (minor
diastereomer)), 4.09–4.23 (6H, m, 3 × OCH2CH3), 5.00 (1H, br,
C(5)H (minor diastereomer)), 5.41 (1H, br, C(5)H), 7.35–7.46
(2S,5S)-N-Benzoyl-5-(di(ethoxycarbonyl)methyl)-2-methyl-
pyrrolidine-2-carboxylic acid ethyl ester 15
Using LDA as a base. Diisopropylamine (0.19 ml, 1.4 mmol)
was added as solution in THF (3 ml) to a 1.5 M solution of
nBuLi in hexanes (0.84 ml, 1.3 mmol), at 0 ◦C and stirred for
15 minutes. Temperature was lowered to −78 ◦C and trans-7b
(0.10 g, 0.25 mmol) was added as a solution in THF (4 ml) and the
reaction was allowed to come to room temperature (2.5 hours).
The temperature was again lowered to −78 ◦C and MeI (0.16 ml,
2.5 mmol) was added as a solution in THF (3 ml) and the reaction
was allowed to come to room temperature and stir for 24 hours. At
◦
0 C, a saturated solution of NH4Cl was added and the mixture
was extracted with EtOAc. The organic layer was washed with
water and brine, dried with MgSO4 and evaporated. Silica gel
chromatography [petrol (40–60) : EtOAc 3 : 2] afforded amide
15 (0.060 g, 54%) as a yellow oil. cis-Amide 7b using the same
procedure gave a lower yield (25%) of the ent-15. This yield was
improved using the following procedure.
Using LTMP as a base. A solution of lithium tetram-
ethylpiperidide (LTMP) was prepared by the addition of a solution
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(5H, m, C6H5); dC (100 MHz, CDCl3 (major diastereomer) 13.8,
13.9, 14.1 (3 × OCH2CH3), 17.1 (NCHCCH3), 25.1, 26.7 (C(4),
C(3)), 29.7 (C(2)CH3), 52.1 (NCHCCH3), 57.5 (C(5)), 61.2, 61.3,
61.4 (3 × OCH2CH3), 68.4 (C(2)), 126.9, 127.7, 129.4 (ArC),
137.5 (quaternary ArC), 170.9, 171.1, 172.4, 174.3 (NCO, 3 ×
CO2C2H5); m/z (ES+) 456 (M + Na, 100%), 434 (M + H+, 20%);
HRMS (M + H+) 434.2184, C23H32NO7 requires 434.2179.
(C(CH3)3), 126.8, 128.5, 130.7 (ArC), 138.4 (quaternary ArC),
168.9, 170.6, 171.1, 173.4 (NCH2CO, 3 × CO2C2H5); m/z (ES+)
528 (M + Na, 100%), 506 (M + H+, 13%); HRMS (M + H+)
528.2562, C27H39NO8Na requires 528.2573.
(S)-Diethyl 2-(2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidin-5-
ylidene)malonate 18
(2S,5R)-N-tert-Butoxycarbonylmethyl-5-(di(ethoxycarbonyl)-
(ethyl)methyl)-pyrrolidine-2-carboxylic acid ethyl ester 17a
To a solution of alcohol 4b (0.87 g, 3.4 mmol) in dry CH2Cl2
(6 ml) was added dry triethylamine (0.56 ml, 4.0 mmol), tert-
butyldiphenylsilyl chloride (2.03 g, 7.41 mmol) as a solution
in dry CH2Cl2 (2 ml), and (dimethylamino)pyridine (0.020 g,
0.15 mmol) as a solution in dry CH2Cl2 (2 ml) and the mixture
was stirred for 48 hours. Water and CH2Cl2 were added and
CH2Cl2 layer was washed with saturated solution of NH4Cl, water
and brine, dried with MgSO4, and the solvent evaporated. Silica
gel chromatography [petrol (40–60) : EtOAc 4 : 1] afforded the
protected alcohol 18 (1.5 g, 92%) as transparent oil. Rf = 0.76 (3 : 2
petrol (40–60) : EtOAc); [a]2D1 = −27.5 (c = 1.24, CHCl3); mmax/cm−1
(neat) 3357, 3020, 1681, 1643, 1565; dH (500 MHz, CDCl3) 1.06
(9H, s, C(CH3)3), 1.28–1.34 (6H, m 2 × OCH2CH3), 1.74–1.79
(1H, m, C(3)HH), 2.05–2.10 (1H, m, C(3)HH), 3.09–3.17 (2H, m,
C(4)H2), 3.55 (1H, dd, J 10.4, 6.4, CHHOTBDPS), 3.64 (1H, dd, J
10.4, 4.4, CHHOTBDPS), 4.00–4.04 (1H, m, C(2)H), 4.20 (2H, q,
J 7.1, OCH2CH3), 4.23–4.25 (2H, m, OCH2CH3), 7.38–7.45 (6H,
m, 2(rings) × 3ArCH), 7.64–7.65 (4H, m, 2(rings) × 2ArCH), 9.73
(1H, s, NH); dC (125 MHz, CDCl3) 14.3 (2 × OCH2CH3), 19.0
(C(CH3)3), 23.7 (C(3)), 26.6 (C(CH3)3), 33.8 (C(4)), 59.4, 59.5 (2 ×
OCH2CH3), 61.2 (C(2)), 66.5 (CHHOTBDPS), 87.2 (NCC), 127.7
(2(rings) × 2ArC), 129.7 (2 (rings) × 1ArC), 132.8 (2 (rings) ×
1quaternary ArC), 135.4 (2(rings) × 2ArC), 167.7, 169.6, 172.3
(C(5), 2 × CO2C2H5); m/z (ES+) 518 (M + Na, 35%), 496 (M +
H+, 100%), 450 (32%); HRMS (M + H+) 496.2511, C28H38NO5Si
requires 496.2519.
To NaH (0.016 g, 0.40 mmol) in dry CH2Cl2 (1 ml) at 0 ◦C
was added amine 7d (0.097 g, 0.23 mmol) as a solution in dry
CH2Cl2 (2 ml) and the solution stirred for 15 minutes, followed
by 2.5 hours of stirring at room temperature. Ethyl triflate (37 ll,
0.28 mmol) was added at 0 ◦C and the reaction allowed to come
to room temperature and stir for 20 hours. The reaction was
quenched with water at 0 ◦C and extracted with CH2Cl2. The
organic layer was washed with brine, dried over MgSO4 and
evaporated. Silica gel chromatography [petrol (40–60) : EtOAc
4 : 1] afforded the ethylated amine 17a as yellow oil (0.033 g,
32%) along with recovered starting material 7a (0.028 g, 29%).
Rf = 0.42 (4 : 1 petrol (40–60) : EtOAc); mmax/cm−1 (neat) 1733;
dH (500 MHz, CDCl3) 0.86 (3H, t, J 7.5, CCH2CH3), 1.18–1.27
(9H, m, 3 × OCH2CH3), 1.46 (9H, s, C(CH3)3), 1.92–2.17 (6H,
m, C(3)H2, C(4)H2, CH2CH3), 3.50 (1H, d, J 18.6, NCHHCO),
3.62 (1H, d, J 18.6, NCHHCO), 3.74–3.77 (1H, m, C(2)H),
4.06–4.22 (7H, m, C(5)H, 3 × OCH2CH3);dC (100 MHz, CDCl3)
9.5 (CCH2CH3), 14.0, 14.2 (3 × OCH2CH3), 26.3 (CCH2CH3),
27.8 ((C(3)), 28.3 (C(CH3)3), 28.6 (C(4)), 53.0 (NCH2CO), 60.3,
60.7, 60.9 (3 × OCH2CH3), 62.4 (NCHCEt), 64.1 (C(2)), 65.6
(C(5), 80.9 (C(CH3)3), 170.8, 171.1, 171.3, 174.0 (NCH2CO, 3 ×
CO2C2H5); m/z (ES+) 466 (M + Na, 100%), 444 (M + H+, 27%);
HRMS (M + H+) 444.2586, C22H38NO8 requires 444.2597.
(2S,5R)-N-tert-Butoxycarbonylmethyl-5-(di(ethoxycarbonyl)-
(benzyl)methyl)-pyrrolidine-2-carboxylic acid ethyl ester 17b
(S)-Diethyl 2-(2-(methoxymethyl)pyrrolidin-5-ylidene)malonate 19
To NaH (0.02 g, 0.48 mmol) in dry DMF (2 ml) at 0 ◦C was added
amine 7d (0.10 g, 0.25 mmol) as a solution in dry DMF (2 ml)
and the solution stirred for 15 minutes. Dry benzyl bromide (58 ll,
0.48 mmol) was added at 0 ◦C and stirred for 5 minutes followed by
room temperature stirring for 24 hours. The reaction was quenched
with saturated solution of NH4Cl at 0 ◦C and extracted with
CH2Cl2. The organic layer was washed with water and brine, dried
over MgSO4 and evaporated. Silica gel chromatography [petrol
(40–60) : EtOAc 4 : 1] afforded the benzylated amine 17b as
transparent oil (0.044 g, 36%). Rf = 0.77 (7 : 3 petrol (40–60) :
EtOAc); mmax/cm−1 (neat) 1732, 1604; dH (500 MHz, C6D6) 0.78–
0.84 (6H, m, 2 × OCH2CH3), 0.93 (3H, t, J 7.0, OCH2CH3),
1.32 (3H, s, C(CH3)3), 1.38 (6H, s, C(CH3)3), 2.18–2.31 (3H, m,
C(3)H2, C(4)H), 2.34–2.39 (1H, m, C(4)Hꢀ), 3.21 (1H, d, J 13.7,
CHHC6H5), 3.65 (1H, d, J 13.7, CHHC6H5), 3.83 (1H, d, J 18.7,
NCHHCO), 3.84–3.93 (4H, m, 2 × OCH2CH3), 4.0–4.03 (3H,
m, C(2)H, OCH2CH3), 4.10 (1H, d, J 18.7, NCHHCO), 4.63
(1H, t, J 6.6, C(5)H), 7.0–7.35 (5H, m, C6H5); dC (100 MHz,
C6D6) 13.9, 14.0, 14.1 (3 × OCH2CH3), 28.2 (C(CH3)3), 28.4, 29.3
(C(3), C(4)), 39.7 (CH2C6H5), 53.5 (NCH2CO), 60.4, 61.1, 61.2
(3 × OCH2CH3), 64.5 (NCHCBn), 66.4 (C(2)), 66.6 (C(5), 80.6
Alcohol 4b (0.31 g, 1.2 mmol) was dissolved in dry CH2Cl2 (2 ml)
and added to a solution of 2,6-di-tert-butyl-4-methylpyridine
(0.75 g, 3.7 mmol) in dry CH2Cl2 (3 ml) at room temperature.
The solution was cooled to 0 ◦C and methyl triflate (0.41 ml,
3.7 mmol) was added. After being stirred at room temperature
for 20 hours, the mixture was poured into saturated solution
of NaHCO3 and extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4, and evaporated. Silica gel
chromatography [petrol (40–60) : EtOAc 3 : 2] gave methyl ether
19 (0.17 g, 52%) as yellow liquid. Rf = 0.51 (2 : 3 petrol (40–60) :
EtOAc); mmax/cm−1 (neat) 3309, 1643, 1247; dH (400 MHz, CDCl3)
1.24 (3H, t, J 7.1, OCH2CH3), 1.25 (3H, t, J 7.1, OCH2CH3),
1.61–1.68 (1H, m, C(3)HH), 2.03–2.11 (1H, m, C(3)HH), 2.97–
3.06 (1H, m, C(4)HH), 3.10–3.18 (1H, m, C(4)HH), 3.23 (1H, dd,
J 9.4, 7.7, CHHOMe), 3.32 (3H, s, OCH3), 3.40 (1H, dd, J 9.4,
4.1, CHHOMe), 3.98–4.01 (1H, m, C(2)H), 4.12 (2H, q, J 7.1,
OCH2CH3), 4.16 (2H, q, J 7.1, OCH2CH3), 9.56 (1H, br, NH);
dC (100 MHz, CDCl3) 14.3 (2 × OCH2CH3), 24.0 (C(3)), 33.6
(C(4)), 59.1 (C(2)), 59.5 (CH2OCH3), 59.5, 59.7 (2 × OCH2CH3),
75.4 (CH2OMe), 87.3 (NCC), 167.7, 169.6, 172.4 (C(5), 2 ×
COOC2H5); m/z (ES+) 294 (M + Na, 100%), 272 (M + H+, 2%),
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226 (96%); HRMS (M + Na) 294.1317, C13H21NO5Na requires
74.5 (CH2OMe), 127.1, 128.6, 129.6 (ArC), 138.6 (quaternary
ArC), 167.9, 168.4, 170.4 (NCOPh, 2 × CO2C2H5). dH (400 MHz,
C6D6) trans-diastereomer, 0.83–0.97 (6H, m 2 × OCH2CH3), 1.68–
1.72 (1H, m, C(3)HHꢀ), 1.94–2.06 (1H, m, C(3)HHꢀ), 2.16–2.24
(1H, m, C(4)HHꢀ), 2.25–2.39 (1H, m, C(4)HHꢀ), 2.70 (5H, br,
OCH3, CH2OMe), 3.89–4.09 (5H, m, C(2)H, 2 × OCH2CH3),
4.87 (1H, br, NCHCH), 5.22 (1H, br, C(5)H), 7.01–7.09 (3H, m,
ArH), 7.61–7.62 (2H, br, ArH); dC (100 MHz, C6D6) 14.1 (2 ×
OCH2CH3), 26.2 (C(4)), 27.8 (C(3)), 52.5 (NCHCH), 57.5 (C(5)),
59.7 (C(2), CH2OCH3), 61.4 (2 × OCH2CH3), 73.9 (CH2OMe),
127.8, 128.6, 130.0 (ArC), 138.9 (quaternary ArC), 167.5, 168.6,
170.9 (NCOPh, 2 × CO2C2H5); HRMS (M + H+) 378.1922,
C20H28NO6 requires 378.1917.
294.1317.
(S)-Diethyl 2-(2-(acetoxymethyl)pyrrolidin-5-ylidene)malonate 20
Acetic anhydride (4.60 ml, 48.5 mmol) was added to a solution of
alcohol 4b (1.25 g, 4.85 mmol) in dry pyridine (4.50 ml, 54.3 mmol)
and the reaction was allowed to stir for 1.5 h at room temperature.
Glacial acetic acid was then added to the mixture with cooling
in an ice bath until pH 5.0 was reached and stirred for 1 h. The
mixture was partitioned between CH2Cl2 and water. The organic
layer was washed with saturated solution of NaHCO3, water and
brine, dried with MgSO4 and evaporated to give the acetate 20
(1.45 g, 100%). Rf = 0.44 (1 : 1 petrol (40–60) : EtOAc); mmax/cm−1
(neat) 3306, 1745, 1688, 1646, 1570; dH (400 MHz, CDCl3) 1.21
(3H, t, J 7.1, OCH2CH3), 1.27 (3H, t, J 7.1, OCH2CH3), 1.66–
1.75 (1H, m, C(3)HH), 2.06 (3H, s, OCOCH3), 2.10–2.19 (1H,
m, C(3)HH), 3.01–3.20 (2H, m, C(4)H2), 3.87 (1H, dd, J 11.2,
7.5, CHHOAc), 4.05–4.09 (1H, m, C(2)H), 4.11–4.22 (5H, m,
CHHOAc, 2 × OCH2CH3), 9.58 (1H, br, NH); dC (100 MHz,
CDCl3) 14.3 (2 × OCH2CH3), 20.7 (OCOCH3), 24.2 (C(3)), 33.3
(C(4)), 58.4 (C(2)), 59.7 (2 × OCH2CH3), 66.4 (CH2OAc), 87.9
(NCC), 167.6, 169.6, 170.7, 172.3 (C(5), OCOCH3, 2 × CO2C2H5);
m/z (ES+) 300 (M + H+, 25%), 254 (100%); HRMS (M + H+)
300.1439, C14H22NO6 requires 300.1447.
(2S,5S)-N-Diethyl-2-(N-acetyl-2-(trityloxymethyl)pyrrolidine-5-
yl)malonate 22b
The enamine 20 (1.16 g, 3.88 mmol) was dissolved in HOAc
(7.5 ml) to which was added Adams’ catalyst (0.164 g) in TFA
(2.5 ml). The hydrogenation apparatus was flushed 3 times with
hydrogen, and finally set to a pressure of 4.5 atm and the mixture
R
stirred for 72 hours. Careful filtration through Celiteꢀ using
EtOAc, followed by solvent removal, gave a residue which was
dissolved in CH2Cl2 (50 ml) and washed with dilute aqueous am-
monia (3.2%) (50 ml), water and brine. The solution was dried over
MgSO4 and the solvent removed to give crude amine 22a (1.05 g)
as an inseparable cis- : trans-mixture. This mixture of amine 22a
(0.090 g, 0.33 mmol) was dissolved in dry CH2Cl2 (2 ml) and added
to a solution of triphenylmethyl chloride (0.10 g, 0.36 mmol) in dry
CH2Cl2 (1 ml), followed by addition of (dimethylamino)pyridine
(0.01 g, 0.09 mmol) as a solution in dry CH2Cl2 (1 ml) and dry
triethyl amine (0.06 ml, 0.6 mmol), and the mixture was stirred for
24 hours. The mixture was poured into ice–water and extracted
with CH2Cl2. The organic layer was washed with saturated
solution of NH4Cl, water and brine, dried with MgSO4, and evap-
orated. Silica gel chromatography ([petrol (40–60) : EtOAc 4 : 1
then petrol (40–60) : EtOAc 3 : 2]) afforded the amide 22b (0.050 g,
59%, over 2 steps) as white crystals. Mp 148–150 ◦C; Rf = 0.38 (3 : 2
petrol (40–60) : EtOAc); [a]2D5 = −12.9 (c = 0.03, CHCl3); mmax/cm−1
(neat) 1728, 1642; dH (400 MHz, CDCl3) 1.22–1.29 (6H, m 2 ×
OCH2CH3), 1.88 (3H, s, NCOCH3), 1.92–2.05 (2H, m, C(3)H2),
2.06–2.18 (2H, m, C(4)H2), 3.05 (1H, dd, J 9.4, 8.2, CHHO(Ph)3),
3.13 (1H, dd, J 9.4, 4.0, CHH(Ph)3), 3.90–3.96 (1H, m, C(2)H),
4.11–4.23 (4H, m, 2 × OCH2CH3), 4.49–4.53 (1H, m, C(5)H), 4.56
(1H, d, J 4.2, NCHCH), 7.23–7.33 (9H, m, 3(rings) × 3ArCH),
7.36–7.43 (6H, m, 3(rings) × 2ArCH); dC (100 MHz, CDCl3) 14.0,
14.1 (2 × OCH2CH3), 22.7 (NCOCH3), 25.7 (C(4)), 27.2 (C(3)),
50.4 (NCHCH), 56.76 (C(5)), 59.2 (C(2)), 61.2 (2 × OCH2CH3),
64.4 (CH2OC(Ph)3), 87.1 (OC(Ph)3), 127.2 (3(rings) × 1ArC),
127.9 (3(rings) × 2ArC), 128.5 (3(rings) × 2ArC), 143.6 (3(rings) ×
1 quaternary ArC), 168.2, 168.6, 170.0 (NCOCH3, 2 × CO2C2H5);
m/z (ES+) 566 (M + Na, 72%), 544 (M + H+, 100%); HRMS (M +
H+) 544.2700, C33H38NO6 requires 544.2699.
(S)-Diethyl 2-(N-benzoyl-2-(methoxymethyl)pyrrolidin-5-
yl)malonate 21
The enamine 19 (0.11 g, 0.39 mmol) was dissolved in HOAc
(7.5 ml) to which was added Adams’ catalyst (0.050 g) in TFA
(2.5 ml). The hydrogenation apparatus was flushed 3 times with
hydrogen, and finally set to a pressure of 4.5 atm and the mixture
R
stirred for 48 hours. Careful filtration through Celiteꢀ using
EtOAc, followed by solvent removal, gave a residue which was
dissolved in CH2Cl2 (50 ml) and washed with dilute aqueous
ammonia (3.2%) (50 ml), water and brine. The solution was
dried over MgSO4 and the solvent removed to give crude amine
(0.096 g) as an inseparable cis- : trans-mixture. Dry benzoyl
chloride (3.20 ml, 27.4 mmol) was added to a solution of this amine
(0.096 g, 0.35 mmol) in dry pyridine (0.32 ml, 3.9 mmol) and the
reaction was allowed to stir for 3 hours at room temperature. The
reaction was quenched and neutralised at 0 ◦C with 2 M HCl and
stirred for 1 hour. Dichloromethane (50 ml) was added and the
organic layer was washed with water and brine. It was dried with
MgSO4 and evaporated. Silica gel chromatography [petrol (40–
60) : EtOAc 3 : 2] afforded the amide 21 (0.11 g, 77%, over 2 steps)
as an inseparable mixture of cis- and trans-diastereomers, in a ratio
of 2 : 1. Rf = 0.5 (3 : 2 petrol (40–60) : EtOAc); mmax/cm−1 (neat)
1728, 1632, 1260; m/z (ES+) 400 (M + Na, 100%), 378 (M + H+,
37%), 218 (15%); dH (400 MHz, C6D6) cis-diastereomer, 0.83–0.97
(6H, m 2 × OCH2CH3), 1.30–1.47 (1H, m, C(3)HHꢀ), 1.68–1.72
(1H, m, C(3)HHꢀ), 2.08–2.14 (1H, m, C(4)HHꢀ), 2.16–2.24 (1H, m,
C(4)HHꢀ), 2.91 (3H, s, OCH3), 3.23–3.25 (1H, br. m, CH2OMe),
3.85 (1H, br, C(2)H), 3.89–4.09 (4H, m, 2 × OCH2CH3), 4.45
(1H, br, NCHCH), 5.12 (1H, q, J 7.5, C(5)H), 7.01–7.09 (3H,
m, ArH), 7.41–7.46 (2H, br. m, ArH); dC (100 MHz, C6D6) 14.1,
14.2 (2 × OCH2CH3), 26.2 (C(4)), 27.7 (C(3)), 55.5 (NCHCH),
57.8 (C(5)), 58.7 (C(2), CH2OCH3), 61.3, 61.7 (2 × OCH2CH3),
N-Benzoyl-2-(acetoxymethyl)-5-(di(ethoxycarbonyl)methyl)-
pyrrolidine-2-methyl acetate 22c
The enamine 20 (1.17 g, 3.89 mmol) was dissolved in HOAc
(7.5 ml) to which was added Adams’ catalyst (0.164 g) in TFA
2614 | Org. Biomol. Chem., 2006, 4, 2600–2615
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(2.5 ml). The hydrogenation apparatus was flushed 3 times with
hydrogen, and finally set to a pressure of 3 atm and the mixture
4 S. Hanessian, M. Bayrakdarian and X. Luo, J. Am. Chem. Soc., 2002,
124, 4716–4721.
5 G. T. Wang, Y. W. Chen, S. Wang, R. Gentles, T. Sowin, W. Kati, S.
Muchmore, V. Giranda, K. Stewart, H. Sham, D. Kempf and W. G.
Laver, J. Med. Chem., 2001, 44, 1192–1201.
R
stirred for 72 hours. Careful filtration through Celiteꢀ using
EtOAc, followed by solvent removal, gave a residue which was
dissolved in CH2Cl2 (50 ml) and washed with dilute aq. ammonia
(3.2%) (50 ml), water and brine. The solution was dried over
MgSO4 and the solvent removed to give the amine as white
liquid. Dry benzoyl chloride (0.50 ml, 4.2 mmol) was added to
a solution of amine (0.123 g, 0.42 mmol) in dry pyridine (0.40 ml,
4.7 mmol) and the reaction was allowed to stir for 24 hours at
room temperature. Glacial acetic acid was then added to the
mixture with cooling in an ice bath until pH 5.0 was reached
and stirred for 1 hour. The mixture was partitioned between
CH2Cl2 and water. CH2Cl2 layer was washed with saturated
solution of NaHCO3, water and brine, dried with MgSO4, and
the solvent evaporated. Silica gel chromatography [petrol (40–
60) : EtOAc 1 : 1] resulted in an inseparable mixture of amide
diastereomers 22c (0.12 g, 82% over 2 steps) in a ratio of 5 :
2. Rf = 0.41 (1 : 1 petrol (40–60) : EtOAc); mmax/cm−1 (neat)
1745, 1636, 1578; m/z (ES+) 428 (M + Na, 69%), 406 (M +
H+, 100%); dH (400 MHz, CDCl3) Major-diastereomer, 1.25–
1.33 (6H, m 2 × OCH2CH3), 1.78–1.90 (1H, m, C(3)HHꢀ), 1.99
(3H, s, CO2CH3), 2.04–2.20 (1H, m, C(4)HH), 2.26–2.30 (1H,
m, C(3)HHꢀ), 2.33–2.40 (1H, m, C(4)HH), 3.90–3.95 (1H, m,
CHHOAc), 3.99–4.02 (2H, m, CHHOAc, C(2)H), 4.11–4.31 (5H,
m, NCHCH, 2 × OCH2CH3), 4.78–4.85 (1H, m, C(5)H), 7.37–
7.62 (5H, m, C6H5); dC (100 MHz, CDCl3) 13.9 (2 × OCH2CH3),
20.7 (CO2CH3), 26.7 (C(3)), 27.1 (C(4)), 54.1 (NCHCH), 57.5
(C(5)), 58.4 (C(2)), 61.4, 61.5 (2 × OCH2CH3), 64.4 (CH2OAc),
126.2, 128.6, 129.7 (ArC), 138.8 (quaternary ArC), 167.9, 167.8,
170.4, 171.9 (NCOPh, 2 × CO2C2H5, CO2CH3). dH (400 MHz,
CDCl3) Minor-diastereomer, 1.25–1.33 (6H, m 2 × OCH2CH3),
1.78–1.90 (1H, m, C(3)HHꢀ), 1.99 (3H, s, CO2CH3), 2.04–2.20
(2H, m, C(3)HHꢀ, C(4)HH), 2.26–2.30 (1H, m, C(4)HH), 3.65–
3.72 (1H, m, CH2OAc), 4.11–4.31 (5H, m, C(2)H, 2 × OCH2CH3),
4.51 (1H, br, NCHCH), 4.78–4.85 (1H, m, C(5)H), 7.37–7.62
(5H, m, C6H5); dC (100 MHz, CDCl3) 14.0 (2 × OCH2CH3), 20.7
(CO2CH3), 25.7 (C(4)), 27.5 (C(3)), 51.3 (NCHCH), 56.8 (C(5)),
58.4 (C(2)), 61.4, 61.5 (2 × OCH2CH3), 64.9 (CH2OAc), 126.8,
128.5, 130.0 (ArC), 137.0 (quaternary ArC), 167.9, 167.8, 170.4,
171.9 (NCOPh, 2 × CO2C2H5, CO2CH3).
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SRH gratefully acknowledges support from The University of
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for a Graduate Studentship Award, and Lancaster Synthesis for
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The Royal Society of Chemistry 2006
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